Systematic Review of Head Cooling in Adults

Health Technology Assessment 2012; Vol. 16: No.
45
ISSN 1366-5278
Systematic review of head cooling in

adults after traumatic brain injury
and stroke
B Harris, PJD Andrews, GD Murray, J Forbes

and O Moseley
November 2012
10.3310/hta16450
Health Technology Assessment

NIHR HTA programme
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Systematic review of head cooling in adults
after traumatic brain injury and stroke
B Harris,1,2* PJD Andrews,2 GD Murray,1 J Forbes1

and O Moseley3
1
School of Clinical Sciences and Community Health, University of Edinburgh,
Edinburgh, UK
2
NHS Lothian, Edinburgh, UK
3
NHS Ayrshire and Arran, Ayr, UK
*Corresponding author
Declared competing interests of authors: This project was funded by the NIHR Health Technology
Assessment programme (project number 07/37/32) and the authors’ institutions received money
through this. Only BH received salary from the grant (through employer, University of Edinburgh).
PA holds a grant from the European Society of Intensive Care Medicine for a trial of therapeutic
hypothermia in traumatic brain injury (Eurotherm3235 trial). Otherwise none declared.
Published November 2012

DOI: 10.3310/hta16450
This report should be referenced as follows:
Harris B, Andrews PJD, Murray GD, Forbes J, Moseley O. Systematic review of head cooling in adults
after traumatic brain injury and stroke. Health Technol Assess 2012;16(45).
Health Technology Assessment is indexed and abstracted in Index Medicus/MEDLINE, Excerpta

Medica/EMBASE, Science Citation Index Expanded (SciSearch®) and Current Contents®/
Clinical Medicine.
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DOI: 10.3310/hta16450 Health Technology Assessment 2012; Vol. 16: No. 45 iii
Abstract
Systematic review of head cooling in adults after traumatic

brain injury and stroke
B Harris,1,2* PJD Andrews,2 GD Murray,1 J Forbes1 and O Moseley3
1
School of Clinical Sciences and Community Health, University of Edinburgh, Edinburgh, UK
2
NHS Lothian, Edinburgh, UK
3
NHS Ayrshire and Arran, Ayr, UK
*Corresponding author
Background: Brain injuries resulting from trauma and stroke are common and costly.
Cooling therapy may reduce damage and potentially improve outcome. Head cooling
targets the site of injury and may have fewer side effects than systemic cooling, but there
has been no systematic review and the evidence base is unclear.
Objective: To assess the effect of non-invasive head cooling after traumatic brain injury
(TBI) and stroke on intracranial and/or core body temperature, functional outcome and
mortality, determine adverse effects and evaluate cost-effectiveness.
Review methods: Search strategy Major international databases [including MEDLINE,
EMBASE, Cumulative Index to Nursing and Allied Health Literature, Web of Science, the
British Library’s Electronic Table of Contents (Zetoc)], The Cochrane Library, trial registers,
country-specific databases (including China, Japan), Google Scholar, hypothermia
conference reports and reference lists of papers were searched with no publication or
language restrictions. The searches were conducted from March 2010 to April 2011, with
no back date restriction. Selection criteria For formal analysis of effect of head cooling on
functional outcome and mortality: randomised controlled trials (RCTs) of non-invasive head
cooling in TBI or stroke in adults (aged ≥ 18 years). RCT prespecified in protocol to include
adequate randomisation and blinded outcome assessment. For assessment of effect on
temperature and adverse effects of cooling methods/devices: studies of any type in TBI,
stroke, cardiac arrest and neonatal hypoxic–ischaemic encephalopathy (adverse effects
only). Data collection and analysis A study assessment and data collection form was
developed and piloted. Data on functional outcome, mortality, temperature change and
adverse effects of devices were sought and extracted. Two authors independently
assessed RCTs for quality using the Cochrane Renal Group checklist.
Results: Out of 46 head-cooling studies in TBI and stroke, there were no RCTs of suitable
quality for formal outcome analysis. Twelve studies had useable data on intracranial and
core body temperature. These included 99 patients who were cooled after TBI or stroke
and 198 patients cooled after cardiac arrest. The data were too heterogeneous for a single
summary measure of effect (many studies had no measure of spread) and are therefore
presented descriptively. The most effective techniques for which there were adequate data
(nasal coolant and liquid cooling helmets) could reduce intracranial temperature by ≥ 1 °C in
1 hour. The main device-related adverse effects were localised skin problems, which were
generally mild and self-limiting. There were no suitable data for economic modelling, but an
exploratory model of possible treatment effects and cost-effectiveness of head cooling in
TBI was created using local patient data.
© Queen’s Printer and Controller of HMSO 2012. This work was produced by Harris et al. under the terms of a commissioning contract issued by the Secretary of State for Health. This
issue may be freely reproduced for the purposes of private research and study and extracts (or indeed, the full report) may be included in professional journals provided that suitable
acknowledgement is made and the reproduction is not associated with any form of advertising. Applications for commercial reproduction should be addressed to NETSCC.
iv Abstract
Limitations: We conducted extensive and sensitive searches but found no good-quality

RCTs of the effect of head cooling on functional outcome that met the review inclusion
criteria. Most trials were small and/or of low methodological quality. However, if the trial
reports did not reflect the true quality of the research, there may be some excluded trials
that should have been included. Temperature data were often poorly reported which made
it difficult to assess the effect of head cooling on temperature.
Conclusions: Whether head cooling improves functional outcome or has benefits and
fewer side effects compared with systemic cooling or no cooling could not be established.
Some methods of head cooling can reduce intracranial temperature, which is an important
first step in determining effectiveness, but there is insufficient evidence to recommend its
use outside of research trials. The principal recommendations for research are that active
cooling devices show the most promise for further investigation and more robust proof of
concept of intracranial and core body temperature reduction with head cooling is required,
clearly showing whether temperature has changed and by how much.
Funding: The National Institute for Health Research Health Technology
Assessment programme.

DOI: 10.3310/hta16450 Health Technology Assessment 2012; Vol. 16: No. 45 v
Contents
List of abbreviations vii
Executive summary ix
1.
Background 1
The conditions and incidence: traumatic brain injury and stroke 1
The intervention: non-invasive head cooling 2
How the intervention might work 2
Measurement of temperature reduction 3
Cardiac arrest and neonatal hypoxic–ischaemic encephalopathy 3
The reason for undertaking this review 4
2. Aim and objectives 5
3.
Review methods 7
Differences between protocol and review 7
Criteria for considering studies for this review 7
Search methods for identification of studies 8
Data collection and analysis 9
Papers in languages other than English 10
Data extraction 10
Assessment of risk of bias 11
Data synthesis 11
4.
Results 13
Description of studies 13
Results of the search 13
Effects of interventions 14
Other applications of therapeutic head cooling 23
Historical reports of head cooling 24
5. Modelling of cost-effectiveness of head cooling 27

Literature review, Glasgow Coma Scale and Glasgow Outcome Scale 27
Sources of data and eligibility 27
Limitations of the data 28
Model 28
Methodology 29
Descriptive statistics 29
Results 30
Discussion 31
Conclusion: modelling of cost-effectiveness 32
6.
Public involvement 33
vi Contents
7.
Discussion 35
Impact of head cooling on functional outcome 35
Temperature reduction with head cooling 35
Head cooling compared with systemic cooling 36
Head-cooling terminology and search terms 37
Poor reporting of methods and temperature data 38
Chinese studies of head cooling 38
Potential biases in the review process 40
Agreements or disagreements with other reviews 40
8.
Conclusions 43
Acknowledgements 45
References 47
Appendix 1 Temperature measurement with head cooling 61
Appendix 2 Review protocol (final agreed version December 2008) 63
Appendix 3 Search strategies 81
Appendix 4 Study assessment and data collection form: systematic review of head
cooling (version 3) 97
Appendix 5 References to head-cooling studies 107
Appendix 6 Characteristics of studies 117
Appendix 7 Non-invasive head-cooling methods and devices 141
Appendix 8 Identifying patients with traumatic brain injury in the

WardWatcher database 167
Appendix 9 Information for members of the public 169
Health Technology Assessment programme 171

DOI: 10.3310/hta16450 Health Technology Assessment 2012; Vol. 16: No. 45 vii
List of abbreviations
ADL activities of daily living
APACHE Acute Physiology and Chronic Health Evaluation
BI Barthel Index
CCH craniocerebral hypothermia
CHIL Cerebral Hypothermia in Ischaemic Lesion trial
CI confidence interval
CONSORT Consolidated Standards of Reporting Trials
CPC cerebral performance category
CSF cerebrospinal fluid
CT computerised tomography
DGH district general hospital
ESS European Stroke Scale
FIM Functional Independence Measure
GCS Glasgow Coma Scale
GOS Glasgow Outcome Scale
HIE hypoxic–ischaemic encephalopathy
ICH intracranial haemorrhage
ICP intracranial pressure
ICU intensive care unit
MeSH medical subject heading
mRS modified Rankin Scale
N/A not applicable
NASA National Aeronautics and Space Administration
NDS neurological deficiency score
NIHSS National Institutes of Health Stroke Scale
ppm parts per million
RCT randomised controlled trial
ROSC return of spontaneous circulation
SAH subarachnoid haemorrhage
SD standard deviation
SDH subdural haemorrhage
SICS Scottish Intensive Care Society
SOD superoxide dismutase
TBI traumatic brain injury
All abbreviations that have been used in this report are listed here unless the abbreviation is well
known (e.g. NHS), or it has been used only once, or it is a non-standard abbreviation used only
in figures/tables/appendices, in which case the abbreviation is defined in the figure legend or in
the notes at the end of the table.

DOI: 10.3310/hta16450 Health Technology Assessment 2012; Vol. 16: No. 45 ix
Executive summary
Background
Brain injuries caused by stroke and trauma are common and costly in human and resource terms.
The result of traumatic brain injury (TBI) and stroke is a cascade of molecular and physiological
derangement, cell death, damage and inflammation in the brain. This, together with infection,
if present, commonly results in patients having an increased temperature, which is associated
with worse outcome. The usual clinical goal in TBI and stroke is therefore to reduce temperature
to normal, although achieving this can be difficult. Temperature may sometimes be reduced
to below normal (hypothermia) to reduce swelling if brain pressure is increased. However,
research evidence does not yet conclusively show whether or not cooling patients after TBI and
stroke improves their longer-term outcome (reduces death and disability). It is possible that
complications of cooling outweigh the benefits.
Cooling methods can be classified into those that cool the whole body (systemic cooling) and
those targeted at the head to cool the brain directly. They include invasive and non-invasive
techniques. Non-invasive head cooling is the subject of this review and these methods are
categorised into:
■■ heat loss from the upper airways by convection with gas or fluid flow or by conduction with
nasal or pharyngeal balloons
■■ heat loss through the skull by convection (fanning, hoods delivering cold air or water) or by
conduction (passive, e.g. ice, gel caps or active, e.g. liquid cooling).
In current clinical practice, cooling methods are most commonly delivered systemically. But
the logic behind head cooling is that it targets cooling where it is needed because it is brain
temperature, rather than body temperature, which is important for brain protection. It is also
thought that brain cooling may reduce the complications of hypothermia because relatively less
body temperature reduction is required, although the evidence for this is not robust.
Existing systematic reviews of cooling interventions after TBI and stroke have not differentiated
between cooling methods. We conducted this review to see if head cooling is effective in brain
injury and stroke.
Aim and objectives
The aim was to assess the effectiveness and cost-effectiveness of non-invasive head cooling in
adults after TBI and stroke, and provide a comprehensive assessment of head cooling research in
these patients.
The objectives were to:
1. assess the effect of non-invasive head cooling on intracranial temperature (measured inside
the skull and within the dura) and/or core body temperature (measured in an artery, the
oesophagus, bladder or rectum)
2. assess the impact of non-invasive head cooling on disability, assessed with a validated
outcome score, and mortality
x Executive summary
3. determine adverse effects or complications associated with head cooling or the specific
devices and methods used
4. assess the cost-effectiveness of head cooling in TBI and stroke
5. present the review results to members of the general public, in order to hear their views on
the concept and possible use and effectiveness of head cooling.
Review methods
Criteria for inclusion of studies

Studies or case reports of any kind, in adults with TBI or stroke of any severity, using any form of
non-invasive head cooling, were relevant. Studies of head cooling in cardiac arrest and neonatal
hypoxic–ischaemic encephalopathy (HIE), conditions in which head cooling has been more
commonly used, were also included if they had information on temperature reduction (cardiac
arrest) or adverse effects of cooling methods and devices (cardiac arrest and neonatal HIE).
Studies in which head cooling was used solely during surgery or combined with another cooling
intervention, excepting antipyretic drugs (e.g. paracetamol), were not relevant.
Search methods
The searches were not restricted by publication status, date or language. The following databases
and resources were searched using a wide variety of terms related to head/brain and cooling/
hypothermia plus condition-specific terms. Dates are for the most recent search.
Major international medical bibliographical databases

MEDLINE 1950 to 12 March 2011.
OLDMEDLINE 1948–65.
EMBASE 1980 to 2011 Week 10.
EMBASE Classic 1947–79.
Cumulative Index of Nursing and Allied Health Literature (CINAHL) 1937 to April 6 2010.
British Nursing Index and Archive 1985 to May 2010.
Web of Science Conference Proceedings Citation Index-Science 1990 to 19 July 2010.
Zetoc Conference Proceedings (8 August 2010).
ProQuest Dissertations & Theses (PQDT) database (25 March 2011).
The Cochrane Library

Cochrane Central Register of Controlled Trials (2011 Issue 1).
Cochrane Database of Systematic Reviews (2011 Issue 3).
Database of Abstracts of Reviews of Effects (2011 Issue 1).
Health Technology Assessment Database (2011 Issue 1).
NHS Economic Evaluation Database (2011 Issue 1).
Cochrane specialised trials registers

Cochrane Injuries Group (14 June 2010).
Cochrane Stroke Group (5 May 2010).
Other trial registers (last update all registers 6 March 2011)

World Health Organization International Clinical Trials Registry Platform.
Current Controlled Trials: the meta-register of controlled trials and International Standard
Randomised Controlled Trial Number (ISRCTN) register.
ClinicalTrials.gov.
National Research Register archive.
Stroke Trials Registry.

DOI: 10.3310/hta16450 Health Technology Assessment 2012; Vol. 16: No. 45 xi
Country-specific databases
Informit Health Collection (includes Australasian Medical Index) (6 February 2011).
China National Knowledge Database: China Academic Journals Medicine and Public Health
(hygiene) database (14 January 2011).
Japan Science and Technology Agency: J-EAST (16 August 2010), J-STAGE (5 February 2011),
journal@rchive (4 February 2011).
Latin American Caribbean Health Sciences Literature (5 February 2011).
Russian Academy of Sciences Bibliographies (25 March 2011).
Web search engines

Scirus (7 March 2011).
Google Scholar (26 March 2011).
Reference lists of relevant studies and reviews and of books on therapeutic hypothermia and
the proceedings of hypothermia conferences were checked. Investigators and manufacturers of
head-cooling equipment were contacted in writing.
Data collection and analysis

BH conducted the searches, with advice and help from the Cochrane Stroke Group Trials Search
Co-ordinator. All retrieved results were imported into Reference Manager (version 11, Thomson
Reuters, CA, USA), de-duplicated, and titles and abstracts screened to remove anything that did
not meet the review criteria. Where full review or further information to determine relevance
was required the complete paper was obtained and screened. This resulted in a final data set
of studies that met the review criteria, with full text where this existed, for detailed assessment
regarding inclusion and exclusion for analysis. From the final data set any studies that purported
to be randomised controlled trials (RCTs) were independently assessed for quality by BH and PA.
An intensive care doctor who spoke Chinese helped with papers in Chinese.
Only good-quality RCTs were prespecified for inclusion for formal analysis of patient outcome.
All studies (including proof-of-concept and case studies) that contained information on head-
cooling devices and methods, their efficacy in reducing temperature, ease of use and adverse
effects were included for descriptive reporting. Temperature, being a physical measure of a
physiological variable, was considered less susceptible to interpretation, even if, as was likely, full
blinding was not possible given the nature of the intervention.
We were unable to carry out the analysis plan specified in the protocol because we found no
good-quality RCTs that were suitable for inclusion in formal outcome analysis. Therefore, the
results are presented descriptively.
Results
There were 46 studies (with 52 associated reports) in TBI, stroke and brain injury (mixed TBI
and stroke population). There were 12 studies (15 reports) in cardiac arrest and 23 studies in
neonatal HIE.
Effect of head cooling on temperature

Twelve studies had useable data on the effect of head cooling on intracranial and/or core body
temperature data. Five were RCTs: one in TBI, two crossover trials in brain injury and two in
cardiac arrest. The other seven were descriptive reports: two in stroke, three in brain injury and
two in cardiac arrest.
xii Executive summary
The temperature data were simply tabulated because there was no straightforward method of
presentation that addressed all of the sources of heterogeneity (e.g. different patient populations,
reasons for cooling, method – upper airways or skull heat loss – and duration of cooling). Two of
the studies showed no effect of head cooling on temperature. Replication of normal nasal airflow
in intubated, brain-injured patients for 6 hours and ice packs to the head for 5–30 minutes in
patients after cardiac arrest who were already cool (mean oesophageal temperature ≤ 35.5 °C).
But otherwise the data showed that liquid head-cooling devices and an intranasal cooling device
could reduce temperature by around 1 °C or more, within 1 hour. This is promising and, in
particular, suggests that there may be a role for liquid head-cooling devices for induction and
maintenance of modest temperature reduction in TBI and stroke (the intranasal cooling device
was not designed for prolonged use). It was noteworthy that even in the presence of active body
warming (applied to prevent head cooling having a ‘knock-on’ effect on body temperature),
intracranial temperature was reduced with a liquid head-cooling device and could be reduced
below core body temperature.
Effect of head cooling on outcome

We prespecified that only good-quality RCTs with blinded outcome assessment would be used
to assess functional outcome and mortality. We were unable to establish that any of the trials
with control groups met these criteria. Two RCTs were ineligible because they had a crossover
design to assess proof of concept of intracranial temperature reduction with cooling consequently
applied for short periods only. Otherwise, reasons included insufficient information on methods,
outcome assessments that did not meet the review criteria and had either unblinded outcome
assessment or insufficient information to determine if outcome assessment was blinded.
Adverse effects of head-cooling methods

All information on cooling method or device-related adverse effects that could be found in
included or excluded studies, in studies in neonatal HIE, reviews of head cooling or in other
applications of head cooling was included. Provided that the devices were used correctly and
contraindications were observed, side effects from the cooling methods were generally minor and
were resolved without treatment after cooling stopped. They included whitening of the nose from
cold (with the intranasal device) and small areas of skin damage.
Complications and possible benefits: head cooling compared with

systemic cooling
We found no high-quality RCT evidence on the relative complications and benefits of head
cooling compared with systemic cooling in TBI and stroke, or cardiac arrest.
Modelling of cost-effectiveness of head cooling
The review searches produced no suitable data for economic modelling and therefore this was
unable to be undertaken. However, we did create an exploratory model of possible treatment
effects and the cost-effectiveness of head cooling using local data for patients with TBI. The
insight gained from the modelling was inevitably limited because of the lack of outcome data
with head cooling. The model took the Glasgow Coma Scale score as a rough proxy for how
severely injured a patient was and suggests that, if head cooling could reduce length of stay, there
may be a substantial reduction in costs as the location in which the treatment is given (critical
care) is very expensive.
However, the main benefit of head cooling for TBI is proposed to be improving the quality of life
and reducing disability over the patient’s lifetime. We found, somewhat surprisingly, that data on
the lifetime costs of TBI are not available in the UK, and therefore it was not possible to directly

DOI: 10.3310/hta16450 Health Technology Assessment 2012; Vol. 16: No. 45 xiii
assess the long-term cost. As a result, steps are now being taken in Scotland to address this and
we are working with a group of people under the auspices of the Acquired Brain Injury Managed
Clinical Network to improve data collection on patients with TBI. Nevertheless, extrapolating
from UK data on lifetime health- and social-care costs for people aged > 65 years, which are high,
does suggest that if head cooling can positively impact on the quality of life for TBI patients then
the intervention may be cost-effective.
Public involvement
In the UK, to date, head cooling in adults has been a research intervention and not part of normal
clinical care. As a result, there have been very few service users of head cooling. Those patients
who have had head cooling were critically ill, sedated and unconscious, with, consequently,
very limited or no awareness of the intervention. On the other hand, almost any member of the
public might be a potential service user in the future, and be thrust into that situation without
prior warning because head cooling is an acute intervention for sudden and unexpected health
emergencies. Therefore, during preparation of the report, the results of the review were presented
to members of the general public in order to give them an opportunity to comment on and
discuss the concept, possible use and effectiveness of head cooling, and also issues of consent for
research when people were too ill to consent for themselves. Those involved appreciated that this
kind of research might be something that people could be confronted with ‘out of the blue’ and
thought it was important that this was more widely known.
Conclusions
We found a larger number of studies than expected but few RCTs of confirmable quality and
none that allowed us to determine if head cooling improves functional outcome. The review
has shown that some methods of head cooling can reduce intracranial temperature, which is an
important first step in determining effectiveness, but the evidence is not robust.
Recommendations for research in traumatic brain injury and stroke

1. We suggest that active head-cooling devices are the most promising for further research.
2. More robust proof of concept of temperature reduction with head cooling is required.
The effectiveness of head cooling in achieving and maintaining both normothermia and
hypothermia should be assessed. Intracranial temperature should be measured (whenever
feasible), as well as core trunk temperature in the oesophagus (or pulmonary artery),
otherwise bladder, with rectal temperature a last resort. It should be absolutely clear in
study reports whether temperature has changed with cooling and by how much. Baseline
temperatures, duration of cooling, temperatures achieved with cooling, and temperature
change with cooling should be reported, with measures of central tendency and spread.
3. Head cooling, with and without body warming, should be compared with systemic cooling
to determine if complications, including shivering, infection and coagulation abnormalities,
are fewer.
4. In volunteers the effect on brain temperature gradients of different methods of head cooling
with and without body warming might be assessed with magnetic resonance spectroscopy
temperature measurement.
5. Head cooling as a method of treating raised intracranial pressure should be investigated.
6. The efficacy of head-cooling methods in maintaining cooling after induction of therapeutic
hypothermia with cold intravenous fluids should be assessed.
7. The tolerability and effectiveness (infection, shivering, temperature reduction, functional
outcome) of head cooling in achieving normothermia and hypothermia in awake patients
should be assessed.
xiv Executive summary
8. In stroke patients the effect of head cooling prior to, and during, thrombolysis should
be evaluated.
9. In stroke, the efficacy and tolerability of intranasal cooling combined with external head
cooling should be investigated (intranasal cooling may not be suitable for trauma patients).
Implications for practice in traumatic brain injury and stroke

1. Head cooling has potential as a means of reducing raised intracranial temperature when
this is clinically indicated, but there is insufficient evidence to recommend its use outside of
research trials.
2. Improved methods of recording and tracking patients after TBI are required throughout the
UK in order that the impact and costs can be measured.
Funding
Funding for this study was provided by the Health Technology Assessment programme of the
National Institute for Health Research.

DOI: 10.3310/hta16450 Health Technology Assessment 2012; Vol. 16: No. 45 1
Chapter 1
Background
The conditions and incidence: traumatic brain injury and stroke
Brain injuries resulting from stroke and trauma are common and costly in human and resource
terms. In England, approximately 130,000 people have a stroke each year, of whom about
one-quarter die and half of the survivors are left dependent on others.1 The incidence of head
injury is similar to that for stroke,2 although the incidence of death is lower, at 6–10 per 100,000
population per year.3 However, head injury is more common in younger people, and it has been
estimated that 4700 of those admitted to hospital each year would be unable to return to work at
6 weeks.2 A Scottish study found that 78% of patients with a severe injury had moderate or severe
disability 1 year later.4
Aside from the often devastating consequences for patients and their families, these brain insults
are expensive. Morbidity from head injury ‘far exceeds the capacity of UK neurorehabilitation
services’3 and the costs of stroke to the NHS are estimated at £2.8B per year, with the cost to the
wider economy about £1.8B more in disability and lost productivity.1
Although the primary mechanisms of brain injury are different in trauma, haemorrhage and
ischaemia [whether focal, as in ischaemic stroke, or global, as in cardiac arrest and neonatal
hypoxic–ischaemic encephalopathy (HIE)], the result is a cascade of excitotoxity, apoptosis
and inflammation.5,6 Inflammation, cell death and infection, if present, mean that increased
temperature is common after both stroke and brain injury.7,8 There is no universally agreed
definition of the threshold for pyrexia or where and how temperature should be measured in
these patients but, in one study, nearly 68% of patients had a rectal temperature ≥ 37 °C within
48 hours after severe traumatic brain injury (TBI)9 and 54% had an axillary temperature of
> 37.5 °C within 48 hours after stroke.10
Increased temperature is associated with worse outcome after both stroke and TBI.9,11 The
exact nature of the relationship in humans is hard to determine, as the time of onset of raised
temperature has an influence and temperature elevation can be a marker of more severe injury
and of infection, both of which are also associated with worse outcome,12 although one systematic
review11 suggests that infection may not play a significant part in the relationship in stroke. There
is considerable evidence from animal research that reducing temperature, and, more especially,
inducing hypothermia, reduces the extent of injury and that the sooner cooling is instigated the
more effective it is.6 However, there is insufficient high-quality prospective evidence to show
that normothermic or hypothermic temperature interventions improve functional outcome in
humans after TBI and stroke.13–15 This may be because it is difficult to cool patients early and
quickly enough and/or because the side effects of hypothermia, such as increased infection, may
outweigh the benefits in some circumstances.
Nevertheless, the usual clinical goal in TBI and stroke is to reduce raised temperature
to normothermia, although consistently achieving this can be difficult.16,17 In stroke it is
recommended that temperature is treated if > 37.5 °C.18 In brain injury, body temperature control
is recommended in the context of treating raised intracranial pressure (ICP).19 There are no
standard recommendations on the site of temperature measurement or methods of temperature
2 Background
reduction. In practice, choice of site of measurement is variable20,21 and cooling interventions are
usually systemic. Pharmacological intervention, generally with paracetamol, is the most common
first-line treatment, followed by a variety of physical systemic cooling interventions, which
include cooling blankets, ice packs and fanning.21,22
The intervention: non-invasive head cooling
Physical cooling methods can be classified into those targeted systemically and those targeted at
the head to cool the brain directly, and include invasive and non-invasive methods. Non-invasive
head cooling is the subject of this review and therefore invasive methods, such as antegrade and
retrograde cerebral perfusion and devices applied to brain tissue, which are mainly used during
surgery,23 are not included.
Methods of non-invasive head cooling are categorised into:
■■ Heat loss from the upper airways This takes place by convection with gas or fluid flow or
by conduction with nasal or pharyngeal balloons – whether or not these devices are truly
non-invasive is a moot point, but they have been included in this review.
■■ Heat loss through the skull This takes place by convection (fanning, hoods delivering cold air
or water) or by conduction (passive, e.g. ice, gel caps or active, e.g. liquid cooling); some of
the devices also have a neck band that theoretically may help cool the brain by reducing the
temperature of the carotid blood supply.24,25
Heat loss occurs as flow down temperature gradients from warm to cool. Convective cooling
methods use air/gas flow to remove heat; molecules are removed in bulk and transfer heat in
the process. Convective methods also allow heat loss by evaporation, a form of convection in
which bulk movement of molecules is achieved by water loss (changing water into water vapour
requires large amounts of heat). With conductive methods energy (heat) moves but the molecules
do not. Heat from the head is conducted through the wall of the device and either actively
removed by the circulating liquid coolant or passively absorbed by the frozen material (ice/gel).
Devices containing frozen material will warm up in this process and must be replaced regularly
to maintain cooling efficiency.
Non-invasive head-cooling methods are generally quick and easy to apply and may be suitable
for pre-hospital use, which are important considerations in reducing time to cooling if
neuroprotection is the aim. They also have potentially wide application because they can be used
in patients with a range of severity of illness, not just the most severely ill.
How the intervention might work
Although cooling interventions are more commonly delivered systemically, the logic behind
head cooling is that it targets cooling where it is needed because it is brain rather than trunk
temperature that is important in cerebral protection. It is also thought that head cooling may
reduce the complications of hypothermia because less body temperature reduction is required,
although the evidence for this is not robust.23
The great advantage of cooling, by comparison with most other neuroprotective interventions,
is that it has many potentially beneficial effects with regard to secondary injury mechanisms
and therefore cerebral protection. Hypothermia has even been described as ‘the ultimate
neuroprotective cocktail’.7 The effects of cooling are not fully understood but include reduction in

metabolic rate, modulation of cerebral blood flow, and the inflammatory response and reduction
of excitotoxic damage and cerebral oedema.6,26 Because cooling can be very effective in reducing
refractory ICP this is the most usual reason for instigating therapeutic hypothermia in severe
traumatic and haemorrhagic brain injury.27,28 In ischaemic stroke it is considered possible that
therapeutic hypothermia could extend the time window within which restoration of blood
supply, for example with thrombolysis, might be effective.29
Measurement of temperature reduction
If cooling, however delivered, is to have a neuroprotective effect, brain temperature must be

reduced. The primary measure of the effectiveness of head cooling with regard to temperature
reduction is a decrease in intracranial temperature. For the purposes of this review, intracranial
temperature is defined as temperature inside the skull and within the dura. In the absence of
intracranial temperature data, the secondary measure for this review is reduction in core trunk
temperature with head cooling, measured in an artery (usually pulmonary), the oesophagus,
bladder or rectum, on the assumption that for core trunk temperature to be reduced there must
have been some reduction in intracranial temperature. (For further explanation see Appendix 1.)
Cardiac arrest and neonatal hypoxic–ischaemic encephalopathy
The principal focus of this review is head cooling in TBI and stroke, in which the primary
problem is in the brain. However, in global (whole body) ischaemia, following cardiac arrest,
therapeutic hypothermia is considered to improve outcome, specifically with return of circulation
after ventricular fibrillation,30–32 although doubts have been raised over the quality of the
evidence.33 Therefore, during the protocol review process, we were asked to include the cardiac
arrest literature on head cooling in our searches because this could contribute information
about how effective these interventions are in reducing temperature, and on their ease of use
and side effects. Studies in cardiac arrest were not relevant for assessment of functional outcome
in this review. However, in our opinion, it is not yet clear to what extent whole-body cooling,
which includes myocardial cooling, contributes to improved outcome with hypothermia after
cardiac arrest, and whether or not head cooling alone is as effective as systemic cooling in this
systemic ischaemic injury. There is no comparative randomised controlled trial (RCT) but there
is some evidence, for example, that myocardial reperfusion injury, which can be ameliorated by
hypothermia, may contribute to post-arrest morbidity and mortality.34,35
Neonatal HIE is the other global ischaemic condition in which therapeutic hypothermia has
been shown to be of benefit.36,37 Head cooling has been commonly used as the means of achieving
hypothermia in neonatal HIE but whether or not it has advantages over systemic cooling has
not yet been assessed in a comparative RCT.36,38 However, a recent systematic review and meta-
analysis in neonatal HIE includes a subgroup analysis of systemic hypothermia (seven studies)
and head cooling (six studies) compared with normothermia, which shows that more adverse
functional outcomes were reduced with systemic cooling than with head cooling.38 It is relatively
easy to cool infants with head cooling as they have a smaller body–head ratio than adults and
therefore have less counterwarming from the trunk; also their skulls are not closed because
their fontanelles have not fused. Intracranial temperature is not measured clinically in infants
with neonatal HIE, but head cooling has a considerable ‘knock-on’ effect on body temperature
and body warming is required to control systemic hypothermia.39 The effect of head cooling on
temperature in neonates does not extrapolate to adults, but neonatal head-cooling research could
contribute information on adverse effects of methods and devices therefore it was included in the
review for this purpose.
4 Background
The reason for undertaking this review
Systematic reviews of cooling interventions after brain injury and stroke have not differentiated
between cooling methods. The only Cochrane review of a specific cooling intervention, for
example, is that of paracetamol for fever in children.40 In the reviews of cooling for acute stroke14
and of hypothermia for head injury15 the effect of temperature reduction on outcome has been
the focus rather than the method(s) of achieving this, although a distinction was made between
pharmacological and physical methods in stroke. Yet physical cooling methods differ in their
effectiveness and complications. The reason for using head cooling is that, theoretically, it may
have advantages over systemic cooling. Cooling is targeted to the site of injury where it is most
needed, therefore requiring less body temperature reduction relative to brain temperature, which
means that it may have fewer side effects than systemic physical methods. In order to determine
whether or not head cooling has an effect and whether or not there are advantages it was
necessary to review head cooling as an intervention.

Chapter 2
Aim and objectives
T he aim of this review was to assess the effectiveness and cost-effectiveness of non-invasive
head cooling in adults after TBI and stroke and provide a comprehensive assessment of head-
cooling research in these patients.
The objectives were:
1. Assessment of temperature change To assess what effect non-invasive head cooling has on
intracranial temperature and/or core trunk temperature in patients after TBI and stroke. This
objective was informed by studies in cardiac arrest as well as those in TBI and stroke.
2. Assessment of head cooling on outcome To assess what impact non-invasive head cooling
has on disability, assessed with a validated outcome score, and mortality in adults after TBI
and stroke.
3. Complications associated with head cooling To determine any adverse effects or
complications associated with head cooling or the specific devices and methods used. Studies
in TBI, stroke, cardiac arrest and neonatal HIE all provided information for this objective.
4. Health economic assessment To assess the cost-effectiveness of head cooling in TBI
and stroke.
5. Public involvement To present the results of the review to members of the general public, in
order to hear their views on the concept and possible use and effectiveness of head cooling,
and provide information on their views for clinicians and researchers planning to use or trial
head cooling.

Chapter 3
Review methods
Differences between protocol and review
The review protocol can be found in Appendix 2. We had consultancy support from Brenda
Thomas, Cochrane Stroke Group Trials Search Co-ordinator, and on her advice the outline
search strategy in the protocol was considerably extended to include, for example, EMBASE
classic, the British Library’s Electronic Table of Contents (Zetoc), British Nursing Index (BNI)
and BNI Archive, and Web of Science conference proceedings. Had time allowed we would also
have included additional country-specific databases in addition to those in the protocol (e.g.
WanFang, Panteleimon, IndMED, KoreaMed), Web of Science cited reference search (forward
search) and more hand-searching. The formal patent search was omitted owing to lack of time.
Of the head-cooling reports in the review (see Figure 1, which corresponds to the results of stage
2, trial identification and selection in the protocol) only studies that could potentially have been
RCTs were screened, assessed and had data extracted by two reviewers.
Criteria for considering studies for this review
Types of studies
Studies or case reports of any kind in adult humans after TBI and stroke, using any form of non-
invasive head cooling were searched for. Studies of head cooling in cardiac arrest and neonatal
HIE were also searched for to obtain information on temperature reduction (cardiac arrest) and
adverse effects of cooling methods and devices (cardiac arrest and neonatal HIE).
Types of participants
All adults (aged ≥ 18 years) admitted to hospital with TBI, or ischaemic or haemorrhagic stroke,
of any severity, and after resuscitation from cardiac arrest for the purposes of assessing efficacy of
head cooling in reducing temperature. Studies of cooling in neonatal HIE were included only for
information on adverse effects.
Types of intervention
Studies of any method of non-invasive head cooling of any duration given for the purposes of
fever reduction, inducing normothermia or hypothermia, or reducing disability and mortality
or reducing ICP were included. Studies in which head cooling was used solely during surgery or
combined with another cooling intervention, excepting antipyretic drugs, such as paracetamol,
were excluded.
Cooling intervention comparisons could include:
1. no cooling intervention or standard care

2. physical cooling interventions applied systemically or to parts of the body other than the
head, for example tepid sponging, ice packs, cooling blankets, intravascular cooling catheters
3. pharmacological cooling interventions, for example paracetamol, non-steroidal anti-
inflammatory drugs, cyclo-oxygenase inhibitors, ethymisole.
8 Review methods
Outcome measures
Primary outcomes
1. Intracranial temperature (inside the skull and within the dura) or core trunk temperature
(measured in an artery, the oesophagus, bladder or rectum). Comparisons could include
temperature with and without head cooling, temperature at baseline compared with
temperature at the end of cooling or the lowest temperature achieved.
2. All-cause mortality by end of follow-up.
3. Outcome assessed with a validated outcome score, i.e. Glasgow Outcome Scale (GOS),41 and
acute, functional or outcome assessments listed on the Internet Stroke Center.42
Other outcomes
1. Reduction in ICP.
2. Improvement in biochemical markers of injury, for example lactate–pyruvate ratio,
glutamate, cytokines.
3. Improvement in cross-sectional imaging.
4. Time from brain injury or onset of stroke to start of cooling, cooling rate (hourly
temperature reduction), and time from injury to target temperature and from device
application to achieving target temperature. These are indicators of the effectiveness of head-
cooling methods and devices and their ease of use, for example how quickly and easily they
can be applied.
Adverse effects
Complications actually or possibly attributable to the head-cooling intervention or the
specific device, for example infections, prolonged clotting time and bleeding complications,
scalp damage.
Search methods for identification of studies
Appendix 3 (search strategies) contains details of the searches and search terms. The searches
were not restricted by publication status, date or language.
Electronic searches
Dates given are for the most recent search.
Major international medical bibliographical databases

MEDLINE 1950 to 12 March 2011.
OLDMEDLINE 1948–65.
EMBASE 1980 to 2011 Week 10.
EMBASE Classic 1947–79.
Cumulative Index of Nursing and Allied Health Literature (CINAHL) 1937 to April 6 2010.
British Nursing Index (BNI) and BNI Archive 1985 to May 2010.
Web of Science Conference Proceedings Citation Index-Science (CPCI-S) 1990 to 19 July 2010.
Zetoc Conference Proceedings (8 August 2010).
ProQuest Dissertations & Theses (PQDT) database (25 March 2011).

Cochrane Central Register of Controlled Trials (CENTRAL) (2011 Issue 1).
Cochrane Database of Systematic Reviews (CDSR) (2011 Issue 3).
Database of Abstracts of Reviews of Effects (DARE) (2011 Issue 1).
Health Technology Assessment (HTA) database (2011 Issue 1).
NHS Economic Evaluation Database (NHS EED) (2011 Issue 1).


Cochrane Injuries Group (14 June 2010).
Cochrane Stroke Group (5 May 2010).
Other trial registers (last update all registers 6 March 2011)

World Health Organization International Clinical Trials Registry Platform (WHO ICTR).
Current Controlled Trials: the meta-register of controlled trials and International Standard
Randomised Controlled Trial Number (ISRCTN) register.
ClinicalTrials.gov.
National Research Register archive.
Stroke Trials Registry.
Informit Health Collection (includes Australasian Medical Index) (6 February 2011).
China National Knowledge Database (CNKI): China Academic Journals (CAJ) Medicine and
Public Health (hygiene) database (14 January 2011).
Japan Science and Technology Agency (JST): J-EAST (16 August 2010), J-STAGE (5 February
2011), journal@rchive (4 February 2011).
Latin American Caribbean Health Sciences Literature (LILACS) (5 February 2011).
Russian Academy of Sciences Bibliographies (25 March 2011).
Web search engines

Scirus (7 March 2011).
Google Scholar (26 March 2011).
Searching other resources

Reference lists of relevant studies and reviews and of books on therapeutic hypothermia and
the proceedings of hypothermia conferences were checked. Investigators and manufacturers of
head-cooling equipment were contacted in writing.
Data collection and analysis
Selection of studies
Bridget Harris conducted the searches with advice and help from Brenda Thomas, Cochrane
Stroke Group Trials Search Co-ordinator. All retrieved results were imported into Reference
Manager (version 11, Thomson Reuters, CA, USA), de-duplicated, and titles and abstracts
were screened by BH to remove anything that did not meet the review criteria with regard to
study type, participants, intervention and outcome (details above). Where full review or further
information to determine relevance was required the complete paper was obtained and screened
by BH. This resulted in a final data set of studies that met the review criteria, with full text, where
this existed, for detailed assessment regarding inclusion and exclusion for analysis. If there was
more than one report of a study all were included in order to facilitate complete data extraction.
The method for screening and assessing papers in languages other than English is detailed below.
The study assessment and data collection form was piloted by BH and PA (Appendix 4 contains
the final version used for the review). It includes the quality checklist we used to assess RCTs,
which was developed by the Cochrane Renal Group.43 Trials were not included or excluded on
the basis of an overall score on this checklist but according to whether they met the prespecified
inclusion criteria for the review.
From the final data set any studies that purported to be RCTs were independently assessed for
quality by BH and PA. Trials that had an adequate method of randomisation (see Appendix 4)
10 Review methods
were eligible for inclusion for formal analysis of the effect of head cooling on patient outcome.
Trials in which the assessor of disability outcome was not blinded were excluded from the formal
analysis as prespecified in the protocol. One of the reasons for this was because the intervention
could not be blinded.
In addition to RCTs any studies, including proof of concept and case studies, that contained
information on head-cooling devices and methods (presented in full in Appendix 7), their
efficacy in reducing temperature, ease of use and adverse effects were included for descriptive
reporting (as prespecified in the protocol). These studies were not formally assessed for
quality and bias; they are described and the temperature data and adverse effects tabulated. It
was considered that temperature, being a physical measure of a physiological variable, is less
susceptible to interpretation and bias than, for example, functional outcome, and it was therefore
reasonable to include information on the effect of head cooling on temperature, even if the
studies were not randomised or controlled, because this provides some evidence of proof of
concept (or otherwise).
Papers in languages other than English
A number of papers in foreign languages required full-text review: French (13), Italian (1),
Slovakian (1), German (11), Japanese (3), Russian (8) and Chinese (26). Some of these had no, or
an inadequate, English abstract so that it was not clear, for example, if the research was in humans
or animals or whether head cooling or systemic cooling had been used without reading at least
part of the paper. We had assistance from colleagues and friends with the requisite languages and
used Google Translate (http://translate.google.com) to eliminate papers that were not relevant.
A Chinese-speaking intensive care doctor helped with the Chinese papers. She read them all,
translated parts and went through them in detail with BH to assess quality and extract data. This
did not highlight any that, on grounds of quality, warranted formal professional translation but
we did have the study comparing head cooling with systemic cooling translated, as this was a
particular comparison of interest with very few studies.44 Because the other Chinese studies were
not formally translated in full it has been possible only to report the main points and reasons for
exclusion Appendix 6 (see Characteristics of Excluded Studies) compared with some of the studies
in English where we have reported in more detail, although this is sometimes simply because
there was more detail to report (the Chinese papers were mostly short).
Papers on head cooling in neonatal HIE in languages other than English were not assessed
because this was not the primary condition of interest and there are recent systematic reviews
(see Appendix 5, References to studies in neonatal hypoxic–ischaemic encephalopathy), which were
also consulted for information on adverse effects of head-cooling methods and devices, i.e. the
reason why papers on neonatal HIE were of interest.
Data extraction
BH and PA independently extracted data from RCTs using a standard form (see Appendix 4).
They were not blinded to authors, journal or results. Disagreements were resolved by discussion.
BH extracted data from all other studies. Where multiple reports of a trial were available,
discrepancies between the reports were noted. Where there was missing information attempts
were made to contact investigators.

Assessment of risk of bias
Randomised controlled trials were assessed for adequacy of the randomisation and allocation
concealment process, potential for selection bias after allocation and level of masking (blinding
of treatment provider, patient, outcome assessor, investigators and analysers of the data) (see
Appendix 4).
Data synthesis
We were unable to carry out the full analysis plan specified in the protocol (see Appendix 2)
because there were insufficient good-quality RCTs to undertake formal outcome analysis.
Briefly, had there been suitable RCT data, the following analysis was planned. For temperature
data the difference in means would have been calculated with 95% confidence intervals (CIs). If
sufficient good-quality trials for a meta-analysis had been found then a weighted mean difference
would have been calculated. Pooled relative risk and 95% CIs for all-cause mortality and good
neurological outcome would have been calculated using a random-effects model. Statistical
heterogeneity would have been assessed using the chi-squared test.
However, it was recognised in the protocol that, depending on what was found, description
of results might be all that was possible and the available temperature data are tabulated as a
descriptive record of the effect of head cooling. No attempt has been made to draw any statistical
inference. Data on adverse effects are reported descriptively.

Chapter 4
Results
T he main results are presented first – the description of studies and effects of the
interventions. The searches also provided examples of other conditions in which head
cooling has been used as a therapy and some descriptions of head cooling that are of historical
interest, and these are presented after the main results.
Description of studies
Refer to Appendix 6 for detailed information on studies included, excluded, awaiting assessment
and ongoing. Studies that included mixed populations of TBI and stroke are classified as studies
in brain injury.
Results of the search
Figure 1 shows the results of the search and selection process. In the box ‘Head-cooling reports
in the review’ the number of studies is given of each type found, with the number of reports in
parentheses, i.e. some studies had more than one report associated with them. There were 46
studies (with 52 associated reports) in TBI, stroke and brain injury and 12 studies (15 reports) in
cardiac arrest.
From the information available we were unable to reliably determine that there were any high-
quality RCTs in TBI or stroke with blinded outcome assessment (see Appendix 6, Characteristics
of included studies and Apendix 6, Characteristics of excluded studies).
Included studies
Most studies did not provide sufficient detail on temperatures for inclusion, for example
the target temperature was reported rather than the actual temperature reduction or they
used temperature measurement sites that did not meet the review criteria (see Appendix 6,
Characteristics of excluded studies). Temperature measurement sites that were valid for inclusion
were intracranial (inside the skull and within the dura) and/or core trunk (arterial, oesophageal,
bladder or rectal).
Twelve studies did have useable data on the effect of head cooling on intracranial and/or core
trunk temperature (see Table 2). Five were RCTs: one in TBI,45 two crossover trials in brain
injury46,47 and two in cardiac arrest.48,49 The other seven included studies were descriptive reports:
two in stroke,50,51 three in brain injury52–54 and two in cardiac arrest.55,56
All information on cooling method or device-related adverse effects that could be found in
included or excluded studies, studies in neonatal HIE, reviews of head cooling or in other
applications of head cooling was included. Studies in neonatal HIE are not described in
Appendix 6 because they were only relevant for information on adverse effects and advantages of
head-cooling devices and methods. References to studies in neonatal HIE lists all of the studies
that were found on searches and read to extract these data.
14 Results
Papers on head-cooling methods and devices were retained for information even if they
contained limited or no clinical data and are included in Appendix 7, which describes the
methods and devices that were found in this review.
Risk of bias in included studies

The four included RCTs had good allocation concealment, but none of the three in TBI and
brain injury45–47 had blinded outcome assessment. The last two46,47 were also crossover trials with
a primary physiological outcome. They were designed to assess proof of concept of intracranial
temperature reduction in response to particular cooling methods, with short intermittent cooling
periods rather than cooling as a sustained therapy that might influence outcome. Therefore, there
were no outcome data on TBI or stroke suitable for inclusion in the review. However, these RCTs
and the RCT in cardiac arrest49 did have data on temperature reduction with head cooling and
are included for that reason. Detailed assessment of all studies can be found in Appendix 6.
Types of interventions
In brief, the interventions used in included studies (listed in Appendix 5, References to studies
included in this review) were:
■■ heat loss from the upper airways:

–– nasal gas flow
–– nebulised intranasal perfluorocarbon with oxygen (Rhinochill)
■■ heat loss through the skull:
–– convective head fanning
–– conductive – passive ice and frozen gel caps
–– conductive – active liquid head- and neck-cooling devices.
None of the devices had automatic (closed-loop) temperature feedback. In a comparative study
of systemic cooling devices, those with automatic temperature control were shown to be more
effective and less labour intensive than manually controlled devices.17
Details of the applications of cooling are given in Table 1 and Appendix 6 (see Characteristics of
included studies). Details of the cooling methods and devices can be found in Appendix 7.
Effects of interventions
Effect of non-invasive head cooling on temperature

Table 1 (12 studies) shows the effect of head cooling on intracranial and/or core trunk
temperature and includes 99 patients who were cooled after TBI/stroke and 198 patients
(data available for 175) who were cooled after cardiac arrest. In addition to different patient
populations (TBI, stroke and cardiac arrest), there was considerable heterogeneity of cooling
intervention (methods and duration), indications for cooling and reporting of temperature
data (including some with no summary measure – for example, mean/median – and spread of
temperature change with cooling), therefore the results have simply been tabulated. There is no
straightforward way of presenting the data that addresses all of the sources of heterogeneity but
because the purpose is to assess the effect of head cooling on temperature the data are presented
by method of cooling. All of the TBI and stroke patients and none of the cardiac arrest patients
had intracranial temperature monitoring. Cardiac arrest data are not presented separately from
TBI and stroke but the aim of cooling after cardiac arrest was always hypothermia (target 33 °C
or 34 °C). Baseline temperatures in the out-of-hospital cardiac arrest patients were low (around
35.5 °C), which makes a hypothermic target easier to achieve than in TBI and stroke patients

Other searches 30 Electronic searches 22,507

References of review 19 MEDLINE 4903
Correspondence 13 OLDMEDLINE 221
Hand search 1 EMBASE 4593
EMBASE Classic 1446
CINAHL 1823
Excluded Full paper review/further BNI and Archive 711
Surgery 2 information 1173 WoS CPCI-S 550
Zetoc Conference Proceedings 445
PQDT 13
Cochrane CENTRAL 1863
Head-cooling reports in the review 148 CDSR 667
Included studies: DARE 142
RCTs TBI 1 (2)a HTA Database 10
Stroke 0 NHS EED 148
Brain injury 2 (3) Cochrane Injuries Group trials register 117
Cardiac arrest 1 (2) Cochrane Stroke Group trials register 108
Other TBI 0 WHO ICTRP 61
Stroke 2 (4) Current controlled trials:
Brain injury 3 meta register of controlled trials 236
Cardiac arrest 3 (4) ISRCTN register 45
ClinicalTrials.gov 145
Excluded studies: National Research Register archive 88
TBI 8 (9) Stroke Trials Registry 43
Stroke 24 (25) Informit Health Collection 28
Brain injury 6 CAJ 84
Cardiac arrest 8 (9) J-EAST 579
Volunteers 7 (8) J-STAGE 69
journal@rchive 324
Neonatal HIE studies 23 LILACS 8
Russian Academy of Sciences 14
Awaiting assessment 5 (see Appendix 5, Scirus 1413
References to studies awaiting Google Scholar 1610
assessment)
Ongoing studies:
TBI 0
Excluded 1053 Excluded 21,334
Stroke 5
All papers which did not include head Search overlap (duplicates) 3901
Brain injury 3
cooling in TBI, stroke, brain injury, Irrelevant 8395
cardiac arrest or neonatal HIE and/or Overlap and/or irrelevant 9038b
Reviews of head cooling 4
head-cooling devices or methods,
or which had no relevant outcomes,
Historical reports 10 (see Chapter 4,
or which were used during surgery
Historical reports of head cooling)
only, or were animal studies
Other applications (examples) 9 (see
Chapter 4, Other applications of
therapeutic head cooling)
Head-cooling devices and methods

(in addition to above) 14
(see Appendix 7)
FIGURE 1 Search results. a, Some studies had more than one report and the number in parentheses refers to the total
number of reports. b, Where it was possible to de-duplicate search results on import to Reference Manager duplicates
were counted. Otherwise, a record was not kept of whether the citation was excluded because it was a duplicate (less
common) or irrelevant.
who were not hypothermic at baseline. Hypothermia was the aim in only two of the eight TBI
and stroke studies in Table 1. Two of the studies in Table 1 showed no effect of head cooling.
Replication of normal, ambient temperature nasal airflow in intubated, brain-injured patients
for 6 hours46 and ice packs to the head for 5–30 minutes in patients after cardiac arrest who were
already cool (mean oesophageal temperature ≤ 35.5 °C).48
16 Results
TABLE 1a Effect of head cooling on intracranial and/or core trunk temperature: heat loss from the upper airways – nasal
airflow and intranasal evaporative coolant (Rhinochill, Benechill Inc., San Diego, CA, USA)
Effect of cooling
Type and purpose on intracranial Effect of cooling on
Authors of study Subjects Head-cooling intervention temperature core trunk temperature
Andrews Randomised, TBI and SAH 30-minute baseline, randomised Parenchymal Oesophageal
2005,46 controlled crossover (n = 15) to 6-hour airflow or 6 hours of Within-patient change Not reported
Harris trial of effect of no airflow then crossed over
in mean temperature
201057 restoration of nasal for further 6 hours. Airflow:
airflow on brain continuous through both nostrils with 6-hour airflow
temperature in orally at total rate of 115 ml/kg/minute compared with
intubated patients (commensurate with normal 6 hours of no
minute volume), range 6–13 l airflow –0.13 °C,
SD 0.55 °C, 95% CI
–0.43 °C to 0.17 °C.
Range of temperature
change: +0.55 °C to
–0.9 °C
Sung Non-randomised Stroke and TBI Intranasal cooling (Rhinochill) for Parenchymal Arterial, oesophageal,
2009,54 single group safety with clinical 1 hour for fever control (n = 9) n = 11: mean bladder or rectal
Abou-Chebl and feasibility study indication for or neuroprotection/ICP reduction reduction after n = 15: mean reduction
201158 and of intranasal cooling cooling (n = 15) (n = 6) (followed by local 1 hour of cooling after 1 hour of cooling
unpublished induction with the standard cooling methods) 1.4 ± 0.4 °C 1.1 ± 0.6 °C
Rhinochill device
Andreas Prospective Cardiac arrest Intranasal cooling (Rhinochill) N/A Oesophageal
200855 observational study after ROSC for 1 hour (followed by cooling Median (first to third
of feasibility and (n = 7) to 33 °C up to 24 hours with quartile) baseline
safety of Rhinochill another device) temperature : 35.4 °C
device (34.7 °C to 36 °C)
After 1 hour: 34.1 °C
(33.4 °C to 34.9 °C)
Difference: 1.3 °C
Cooling rate: 1.6 °C (1 °C
to 1.7 °C)/hour
Busch Descriptive study Cardiac arrest Intranasal cooling (Rhinochill) N/A Arterial, oesophageal,
2008;56 of effectiveness, after ROSC device for 1 hour (range bladder or rectal
201059 feasibility and safety (n = 84) 25–195 minutes) (followed Cooling rate median (first
of Rhinochill device by cooling to 33 °C up to to third quartile): 1.1 °C
12–24 hours with a systemic (0.7 °C to 1.5 °C)/hour
device)
PRINCE trial RCT of safety, Witnessed out-of- Intranasal cooling (Rhinochill) N/A Rectal, bladder or
Castrén feasibility, cooling hospital cardiac started during arrest and intravascular
2009;60 efficacy of Rhinochill arrest pre-ROSC continued until after hospital Mean difference between
201049 device (n = 194); 93 arrival (median duration cooled (n = 75) and
cooled (75 32 minutes), target temperature control patients (n = 42)
survived to 34 °C after hospital admission:
hospital), 101 –0.7 °C (p = 0.01)
uncooled control
patients (42
survived to
hospital)
PRINCE, Pre-ROSC IntraNasal Cooling Effectiveness.

TABLE 1b Effect of head cooling on intracranial and/or core trunk temperature: heat loss from the upper airways –
nasal airflow and intranasal evaporative coolant (Rhinochill): heat loss through the upper airways and through the skull
– nasal airflow and/or head fanning
Type and purpose Head-cooling Effect of cooling on Effect of cooling on core

Authors of study Subjects intervention intracranial temperature trunk temperature
Harris Randomised TBI and SAH Thirty-minute baseline, Parenchymal Oesophageal
2007;47 controlled (n = 12) each of four interventions Difference in mean Difference in mean
201057 crossover factorial in random order for temperature over last temperature over the last
trial of effect on 30 minutes with washout 5 minutes of preceding 5 minutes of preceding
temperature of between (1) enhanced washout minus mean washout minus mean
enhanced nasal nasal airflow, (2) head over last 5 minutes of over the last 5 minutes of
airflow and bilateral fanning (no head intervention = 0.15 °C with intervention = 0.13 °C with
head fanning bandages), (3) (1) + (2), nasal airflow (p = 0.001, nasal airflow (p = 0.005,
and (4) no intervention 95% CI 0.06 °C to 0.23 °C) 95% CI 0.04 °C to
1 = continuous and 0.26 °C with head 0.21 °C) and 0.19 °C with
unhumidified airflow fanning (p < 0.001, 95% CI head fanning (p < 0.001,
through both nostrils 0.17 °C to 0.34 °C) 95% CI 0.11 °C to
at twice the patient’s Estimate of combined effect 0.28 °C)
ventilated minute of airflow and fanning on Estimate of combined
volume + 20 ppm nitric temperature = 0.41 °C effect of airflow
oxide and fanning on
2 = bilateral head fanning temperature = 0.32 °C
with ambient air, total
air speed approximately
8 m s-1
TABLE 1c Effect of head cooling on intracranial and/or core trunk temperature: heat loss through the skull – passive
conductive methods – ice packs
Type and purpose Head-cooling Effect of cooling on Effect of cooling on core

Callaway RCT with Out-of-hospital Head cooling with N/A Oesophageal
200248 convenience cardiac arrest three 500-ml bags of ice Cooled group mean
sample of pre- (n = 27); 14 applied to head + one baseline: 35.5 ± 1.0 °C;
hospital head cooled (5 across neck (duration control patients
cooling during excluded from 5–10 minutes) 35.3 ± 1.7 °C;
cardiac arrest analysis because temperatures at end of
of incomplete cooling not reported
temperature
data); 13 Mean rate of temperature
uncooled control change in cooled group:
patients 0.07 ± 0.06 °C/minute
(95% CI –0.11 to –0.03)
Mean change in control
patients: 0.02 ± 0.06 °C/
minute (95% CI –0.05 to
0.02)
Difference: –0.05 °C/
minute (95% CI –0.106
to 0.007)
Forte 200952 Retrospective study TBI, SAH, Ice packs over Intracranial: Mean Oesophageal
of the effect of ice stroke, brain decompressive at baseline 37.1 °C Not reported
packs on ICP and tumour, after craniectomy site, duration (range 35.3–38.9 °C),
brain temperature decompressive 61.7 hours (range mean over 48 hours of
– not reported craniectomy 20–96 hours) depending cooling 35.2 °C (range
if prospective or for refractory on ICP and CT 33.6–37.6 °C); range of
retrospective intracranial temperature change with
hypertension cooling +0.3 °C to –4.5 °C
(n = 23)
18 Results
TABLE 1d Effect of head cooling on intracranial and/or core trunk temperature: heat loss through the skull – active
conductive methods – head and neck liquid cooling devices
Type and purpose Head- and neck-cooling Effect of cooling on Effect of cooling on core
COOL BRAIN Prospective, Stroke + ≥ 1 Pressurised liquid cooling Parenchymal Note: Active body
Stroke non-randomised TBI (n = 14); 8 helmet, temperature of Mean brain temperature warming
Trial Wang pilot trial of the cooled, 6 ‘control coolant not reported, reduction 1.84 °C (range Bladder: Not reported
2003;61 effectiveness of patients’ (not heads shaved 0.9–2.4 °C) within 1 hour
2004;50 head cooling in reported here) Mean brain minus bladder
Cooling duration unclear temperature difference
200462 reducing brain – up to 72 hours. Active
temperature during cooling = –1.6 °C
body warming to maintain
bladder temperature
> 33 °C, 35 °C if aged
> 45 years
Harris 200945 RCT to evaluate TBI (n = 25); Pressurised liquid Parenchymal or ventricular Note: Active body
a head-cooling 11 cooled, 10 cooling helmet, coolant Cooled group: warming
device in the uncooled control temperature not reported, Bladder
management of TBI patients (missing heads not shaved, Mean baseline = 37.9 °C;
temperature data duration 24 hours, target at 12 hours, 36.8 °C; at Not reported
n = 4) intracranial temperature 24 hours, 36.9°C Mean intracranial minus
33 °C, active body Control patients: bladder temperature
warming to maintain Mean baseline and over the 24-hour cooling
bladder temperature 12 hours, 37.9°C; period: –0.67 °C in the
36 °C at 24 hours 38.1°C; cooled group; +0.05 °C
difference from baseline in the control patients
in cooled group at (neither statistically
12 hours = 1.1°C, at significant)
24 hours = 1°C
12-hour mean difference
between cooled
patients and control
patients = –1.1 °C, at
24 hours –1.2 °C
Gaida 200851 Observational SAH (n = 6) Liquid cooling helmet Ventricular Arterial
study of head (CSZ Blanketrol) for brain Mean Mean
cooling for temperature > 37.8 °C baseline = 38.5 ± 0.6 °C baseline = 38.2 ± 0.6 °C
refractory fever after 2 hours of standard
management fever management, Mean at Mean at
duration 6 hours 6 hours = 37.5 ± 0.4 °C 6 hours = 37.4 ± 0.5 °C
Difference = 1 °C Difference 0.8 °C
TraumaTec Descriptive single Brain injury Liquid cooling helmet Intracranial Body temperature
Neuro-Wrap group study to Interim data on (TraumaTec Neuro-Wrap) Mean baseline temperature remained between
Neuro ICU determine rate n = 9, study aim for 8 hours 37.5 ± 1 °C 36.7 °C and 37.8 °C
Study and degree of n = 20 Target temperature N/A
brain cooling with Lowest temperature
Miller 35.5 ± 1.4 °C
200953 and TraumaTec Neuro-
unpublished Wrap Difference 2.0 °C
Table 2 (nine studies) summarises the temperature reduction data in Table 1 and includes all
those studies45,47,50–55,59 that had data on mean (or median) temperature reduction with head
cooling. The studies that are omitted are the Pre-ROSC IntraNasal Cooling Effectiveness
(PRINCE) trial,49 which did not report the temperature reduction in cooled patients,
and the two studies which showed no effect46,48 (only one of these46 had data on average
temperature reduction).

TABLE 2 Summary of average temperature reduction with head cooling
Cooling Intracranial temperature reduction Core trunk temperature reduction

Head-cooling method duration (total no. of cooled patients) (total no. of cooled patients)
Rhinochill 1 hour 1.4 °C (n = 11) 1.1–1.3 °Ca (n = 106)
Sung 2009,54 Andreas 2008,55 Busch 201059
Nasal airflow + head fanning 30 minutes 0.41 °C (n = 12) 0.32 °C (n = 12)

Harris 200747
Ice packs to craniectomy site 48 hours 1.9 °C (n = 23) Not reported

Forte 2009 52
Liquid cooling of head and neck 1–24 hours 1–2 °C (n = 34) 0.8 °C (n = 6)
Wang 2004,50 Harris 2009,45 Gaida 2008,51
TraumaTec Neuro-Wrap ICU Study Miller 200953
a Includes mean and median data, all other temperatures are mean reductions.
Functional outcome and mortality

We prespecified that only good-quality RCTs with blinded outcome assessment would be used
to assess functional outcome and mortality, and we were unable to establish that any of the trials
with control groups met these criteria. The RCTs in TBI and brain injury in Table 1 could not
be included in this analysis because of crossover design46,47 (these were designed to assess proof
of concept of intracranial temperature reduction with cooling applied for short periods only
rather than as a sustained therapy) and because we were unable to verify if outcome assessment
was blinded (no response from investigator).45 The primary outcome of this latter study45 was
determination of the effect of the head-cooling device on temperature in patients with TBI and
specifically maintenance of a core body–brain temperature gradient using active body warming.
Comparative assessment of outcome (mortality, GOS and functional independence measure)
at hospital discharge or 28 days after injury (whichever was sooner) was a secondary objective.
Six out of 12 patients in the cooled group and 4 out of 13 control patients died, but there was no
statistically significant difference between the groups on any of the outcome measures. However,
this study was too small (n = 25) to be powered to detect a difference in functional outcome (no
sample size calculation was provided to show how study size was determined).
For other trials that had information on outcome (details in Appendix 6, Characteristics of
excluded studies) the reasons for exclusion included insufficient information on methods,
for example to assess whether they were RCTs or to complete the quality checklist, outcome
assessments that did not meet the review criteria and either unblinded outcome assessment or
insufficient information to determine if outcome assessment was blinded.
Adverse effects and complications associated with head-cooling devices

and methods
All adverse effects that were reported in included or excluded studies, studies in neonatal HIE,
reviews of head cooling or in other applications of head cooling are included here, although
many studies reported no specific device or cooling method-related adverse effects. Adverse
effects are reported and described under the broad headings of heat loss from the upper airways
and heat loss through the skull, and were generally self-limiting and not serious (Table 3 provides
a summary). Descriptions of the methods and devices can be found in Appendix 7. Unless stated
to the contrary, all of the patients were unconscious and sedated.
20 Results
TABLE 3 Summary of device-related adverse effects and precautions
Adverse effects
Unconscious/sedated Conscious/unsedated Contraindications/precautions

Heat loss from upper airways
Nasal gas flow Nasal erosion Base of skull fracture
?Facial fractures
?Sinusitis
Requires sedation
Keep mouth open for exit flow
Rhinochill intranasal Cold-related nasal whitening (one Base of skull fracture

coolant severe) ?Facial fractures
Nose/mouth bleeds (one severe) Requires protected airway
Periorbital oedema Requires sedation
Nasal erythema/discharge Keep face uncovered and mouth open for exit
flow/reduce cold-related side effects
QuickCool nasal Headache, rhinorrhoea, redness, Base of skull fracture

balloons ulcers ?Facial fractures
?Sinusitis
Heat loss through skull

Face/head fanning Face fanning uncomfortable
Ice/frozen gel caps Headache

Cold can be hard to tolerate
Liquid head and neck Skin erosion? Pressure on scalp/skull with pressurised devices
cooling Scalp oedema (neonates)
Heat loss from the upper airways: convection

Nasal gas flow
The method used by Dohi and colleagues63 (nasal airflow through a Foley catheter with an
inflated balloon and the other nostril occluded with an epistaxis balloon) caused nasal erosion in
‘several’ patients, even although the intervention was used for a only ‘short period’. There was no
sinusitis, tympanic membrane injury or olfactory dysfunction. Dohi and colleagues63 commented
that ‘the procedure may cause an oppressive feeling due to the high volume of circulating air’ and
was suitable only in sedated patients (p. 410). They stressed the importance of the air being able
to exit through the mouth, as did Harris and colleagues.47 The methods used by Andrews and
colleagues46 and Harris and colleagues47 did not occlude the nostrils and no erosion was seen,
although care and lubrication was required when inserting the nasal catheters to avoid causing
a nosebleed. In personal testing, Harris57 found that it was difficult to swallow, as unless the air
delivery tubing was able to blow back out of the nostrils the air had nowhere to go and could
cause discomfort in the ears. With high flows of dry air stinging of the nasal mucosa could also
occur initially.57 Nasal gas flow is contraindicated with base of skull fracture, possibly with certain
facial fractures, and with sinusitis if an occlusive balloon is used.

Rhinochill (Benechill Inc., San Diego, CA, USA)

The Rhinochill device delivers inert perfluorocarbon coolant mixed with oxygen through
bilateral nasal prongs to the nasal cavity where the coolant is nebulised and evaporates removing
heat in the process. There is an overpressure relief valve. A protected airway is required and it is
contraindicated with base of skull fracture and some facial fractures. It is designed for induction
of cooling rather than prolonged use. The Rhinochill device has had considerable safety and
feasibility testing in animals and humans. Device-related adverse events have been generally
mild and self-resolving provided the device is managed correctly. The trial49 (n = 93) and study59
(n = 84) in cardiac arrest reported a total of 23 cases of nasal whitening (cold induced), five of
epistaxis (one in a patient with underlying coagulopathy), two of periorbital oedema, one of
perioral bleed and one of coolant in sinus. These all resolved. Patients who were able to undergo
olfactory function assessment were within normal limits.59 Busch and colleagues59 reported
that one patient with cardiogenic shock who was given high-flow oxygen (60–80 l/minute)
sustained cold-induced tissue damage, which persisted until death owing to cardiac failure. They
commented that ‘Essential safety measures that prevent tissue damage include uncovering the
face and keeping the mouth open during cooling, so that coolant vapor can escape from mouth
and nostrils’ (p. 947).
In the Rhinochill study in brain-injured patients (n = 15), transient minor nasal erythema
and discharge was seen on rhinoscopy (Dr Barbut, Benechill Inc., San Diego, CA, 14 April
2011, personal communication) and there was one device-related serious adverse event
– hypertension attributed to patient discomfort – which resolved by stopping the device
and giving sedation [www.benechill.com/wp/clinical-program/clinical/neuro-icu-cooling-
study/ (accessed 1 November 2010)]. There were no cold-related injuries in this study, but it
seems logical that cardiac arrest patients with reduced cardiac output and subnormal body
temperatures pre-hospital64 would be more at risk of cold-related tissue damage to the nose
than brain-injured patients in hospital who are likely to have a more normal cardiac output and
above-normal temperature.
One possible advantage of head cooling noted in the study in brain-injured patients, on the basis
of cooling results in two morbidly obese patients, was that brain temperature reduction may
be less affected by body mass than core trunk temperature reduction [www.benechill.com/wp/
clinical-program/clinical/neuro-icu-cooling-study/ (accessed 1 November 2010)] and Dr Barbut,
personal communication).
Heat loss from the upper airways: conduction

QuickCool (Lund, Sweden)
These bilateral nasal balloon catheters, perfused with cold saline, have been tested in unsedated
healthy volunteers (n = 10).65 Adverse effects were minor and resolved spontaneously. Ear nose
and throat examination showed increased nasal secretions (n = 9), redness (n = 3) and small ulcers
(n = 3). Subjects reported headache (n = 4), dizziness (n = 1) and rhinorrhoea (n = 7), and rated the
balloons as pleasant (n = 1), neutral (n = 3) and unpleasant (n = 6).
Heat loss through the skull: convection

Fanning of face or head
Mariak66 used face fanning for fever reduction in six conscious neurosurgical patients and
noted that ‘Generally all patients reported an unpleasant sensation when fanned’ (p. 281). Head
fanning, avoiding blowing air into the eyes, on the other hand is not generally perceived as
uncomfortable. It is sometimes assumed that the use of fans in the intensive care unit (ICU) is
associated with infection risk,67 but a review found no published data that electric fans spread
infection in clinical areas.68
22 Results
Heat loss through the skull: conduction

Passive: ice and gel caps
Callaway and colleagues48 used bags of ice round the head for cooling after cardiac arrest; there
were no adverse effects (if ineffectiveness in this instance is discounted) but it was difficult
to secure them for transport.48 In two studies69,70 with gel caps, both also in cardiac arrest, no
adverse effects were found but the investigators commented on the ease and speed (< 30 seconds)
with which the caps could be applied.
The scalp cooling studies, found with other applications of therapeutic head cooling (see below),
have provided some information on the effect of intense head cooling in conscious, unsedated
patients. Headache was quite common and some patients could not tolerate the cold. With the
lower-temperature gel devices in particular the dropout rate could be high – 9 out of 15 patients
in one study using a gel cap at –26 °C.71 Scalp cooling therapy seemed to be more tolerable with
liquid cooling caps at less cold temperatures, although warm clothing, blankets and even hot
water bottles and electric blankets are sometimes recommended to improve comfort (e.g. with
the Penguin Cold Cap).
Active: liquid head and neck cooling devices

Two (of 17) stroke patients72 and two (of 12) patients with TBI45 undergoing liquid head and
neck cooling had skin erosion/decubitus ulcers, but it is not clear if these were device related.
Yamada and colleagues72 give no details of the device but in the Harris and colleagues trial45
the helmet was pressurised at 15 mmHg (coolant temperature is not reported). Despite it being
pressurised, Harris and colleagues45 comment that the cap was not fully effective and give one
reason as ‘insufficient cap contact with the scalp’ (p. 1263).45 Wang and colleagues50 used a similar
device (coolant temperature and pressure not reported) and mention no device-related problems.
However, the necessity for close scalp contact may be problematic following brain injury, in the
presence of wounds and skull fractures for example, and if the constriction causes an increase
in ICP.
With an unpressurised liquid cooling helmet (TraumaTec Neuro-Wrap, TraumaTec Inc., San
Antonio, TX, USA) there were no device-related systemic or local complications including ‘skin
irritation of the scalp or neck, restriction of jugular venous drainage by the neck section resulting
in ICP elevations, or compression of neck structures resulting in barostimulation and changes in
blood pressure’ (Professor Robertson, Baylor College of Medicine, Houston, TX, 3 January 2011,
The studies in neonatal HIE that were assessed to find information on complications and benefits
related to head cooling are listed in Appendix 5 (see References to studies in neonatal hypoxic–
ischaemic encephalopathy). These were not limited to RCTs because any studies that were specific
to head cooling or head-cooling methods were of interest for this purpose. The only device-
related complications noted were in studies using liquid cooling caps (unpressurised, coolant
8–12 °C, 72-hour cooling) and these were scalp oedema39,73,74 and two cases of sclerodema,44
which can be caused by cold stress in neonates. All resolved spontaneously.
Complications and possible benefits: head cooling compared with

systemic cooling
We found no high-quality RCT evidence on the relative complications and benefits of head
cooling compared with systemic cooling in TBI and stroke, or cardiac arrest. What has been
found is presented descriptively here.
Three studies in TBI or brain injury directly compared head cooling and systemic cooling; all
also had normothermic control groups.44,75,76 One study was not randomised and had a somewhat

unusual head-cooling protocol, which meant that some patients may not have received head
cooling as it was applied intermittently ‘on each of three successive days for 0–6 hours (average
4.5 hours) according to the patient’s condition’ (p. 59).75 Possibly this may account for why there
seems to have been little difference in the temperatures in the head-cooled and systemically
cooled groups, although the actual temperatures are not reported. Another may have been
randomised but had insufficient detail to assess trial quality (e.g. method of randomisation,
blinded follow-up) and no actual temperatures reported, plus 40 out of 96 patients were not
followed up (GOS at 1 year).76 The third, in brain injury, also may have been randomised but
provided insufficient detail for assessment of study quality and no actual temperature data.44
Therefore, none were able to be included in the review for formal analysis, but the main
findings of the two studies that may have been randomised trials are briefly described here
for information.
Qiu and colleagues76 (n = 96) assessed thrombocytopenia (platelet count < 100 × 109/l) and found
similar rates in head-cooled (77%) and systemically cooled (75%) patients and lower rates in
control patients (36%). The patients who had thrombocytopenia were followed up (GOS at 1 year,
none lost to follow-up) and those in the control group had better outcomes (GOS score 4–5):
control patients 80%, head cooled 39%, systemically cooled 35%.76 This seems to imply that the
effect of cooling impacted adversely on outcome independently of thrombocytopenia as long as
1 year later.
In the study by Zhao and colleagues44 (n = 69), complication rates (pneumonia, gastrointestinal
bleed, arrhythmias, renal failure) were similar in systemically cooled patients (90.91%) and
control patients (91.67%) and head-cooled patients (39.13%). But good outcome (GOS score 5)
and mortality at hospital discharge were similar in head-cooled (56.5% and 21.7%, respectively)
and systemically cooled (54.5% and 22.7%, respectively) patients and worse in control patients
(25% and 45.8%, respectively).44
In neonatal HIE there were no noteworthy differences in systemic complications with head
cooling compared with standard care (for studies consulted, see Appendix 5, References to
studies in neonatal hypoxic–ischaemic encephalopathy). No RCTs in neonatal HIE have directly
compared systemic cooling with head cooling. However, Sarkar and colleagues77,78 carried out an
observational study and assessed the difference in multiorgan and pulmonary function between
head cooling and whole-body cooling and found no difference. They speculate that the reasons
for this may be that the target temperatures are not low enough to produce significant adverse
effects from hypothermia, and the differences in core temperatures between head-cooled and
whole body-cooled infants are not large enough (around 1 °C) to produce differences in benefit
or adverse effects.
A possible benefit of head cooling was observed in a small case series in neonatal HIE that
compared head cooling (n = 14) with whole-body cooling (n = 20) and found that it reduced the
incidence of severe cortical lesions.79 Whether or not this would translate to adults with TBI and
stroke is unknown, although logic suggests that cooling the more metabolically active cortices, as
non-invasive head cooling may do, could be of benefit.
Other applications of therapeutic head cooling
There were a number of databases in which limiting the search terms beyond cooling and brain/
head terms was not feasible (see Appendix 3). These searches provided examples of a range of
other conditions in which head cooling has been used as a therapy. The papers were not retained
as part of the formal search results but the conditions are listed here for information, with
24 Results
selected citations. Head cooling has been used for headache,80 epilepsy,81 multiple sclerosis,82
sudden deafness from ischaemia of the inner ear,83 and to alleviate environmental, occupational
and exertional heat strain.84,85 A more common use of head cooling is to cool the scalp to reduce
hair loss with certain types of chemotherapy.71,86,87 There are several commercially available scalp-
cooling devices. The Paxman Cooler and the DigniCap circulate coolant at around –5 °C and
+5 °C, respectively, and the Penguin Cold Cap and ChemoCap contain frozen gel at –25 °C. Sizing
the caps to fit closely improves contact and therefore cooling; sometimes hair is wetted prior to
application to increase cooling effectiveness (e.g. with the DigniCap).
Historical reports of head cooling
The use of cooling for injuries has a very long history with documentary evidence as far back
as Ancient Egypt (see Swan88 for a review), but references to head cooling are less common.
However, the searches did produce some descriptions of therapeutic head cooling that are of
historical interest, although with insufficient detail to be of use for the review.
In 1897, Charles Phelps, a New York surgeon, wrote a book on TBI – pistol wounds in particular.
He advocates shaving the head to aid diagnosis but also to facilitate heat loss and to ‘permit
the effective application of the ice-cap, which next to trephination, under indicated conditions,
is most nearly a directly curative resource’ (p. 223).89 The perceived benefit was reduction of
temperature and swelling, and a case study is reported of a patient who repeatedly became lucid
when the ice cap was in situ and feverish and delirious without it.
Oliver Waugh, a Canadian surgeon, described treatment of skull fractures in 1926. In cases of
‘mild’ skull fracture, i.e. patients who had experienced only brief disturbance of consciousness,
‘treatment should be an initial saline purgation (one ounce of Epsom salts), an ice cap applied
to the head and absolute rest for from ten days to two weeks’ (p. 1476).90 Patients with more
severe injury had a lumbar puncture with removal of cerebrospinal fluid if the pressure was
raised, an ice cap and regular Epsom salts orally or rectally ‘for its dehydrating effect on the
brain’ (p. 1478).90 Rest and quiet, with morphine if necessary, are emphasised. The rationale for
using ice caps is not explicitly stated, but the implication is that it was primarily for reduction of
swelling rather than reduction of temperature.
A 1962 German paper recommends ‘selective cranial hypothermia’ as an effective method of

reducing hypoxic damage and cerebral oedema after inadvertent perioperative cardiac arrest.91
The brain was cooled to 32–33 °C, about 1–1.5 °C lower than body temperature, and cooling
maintained for 4–6 days depending on the patient’s condition, followed by slow rewarming.
Details of the brain cooling method were to be the subject of a separate paper, but this seems not
to have been published.
There are a number of papers in Russian on head cooling from the 1960s and 1970s. These
contain descriptions of devices (see Appendix 7) and examples of conditions treated, which
included TBI,92,93 epilepsy and even psychiatric patients in whom head cooling apparently
provided temporary healing but did not prevent death.94 There were no RCTs and insufficient
detail on temperatures for formal inclusion in the review, but as they are relatively early reports
of head cooling it seemed logical to include them in this historical section. Brain temperatures
in the range of 22–30 °C with body temperatures of 33–36 °C are described.92,94 Ear canal
temperature (external auditory meatus/auditory canal wall near the tympanic membrane)
was used as a proxy for intracranial temperature,93,95,96 but Ioffe and Sumskii92 also measured

intracranial temperature directly in some of their patients using specially made temperature
sensors. These were sited in the silicone drains which were placed in the parenchyma or subdural
space during surgery, thus simultaneously achieving drainage and temperature measurement.92
This is an early report of the use of intracranial temperature measurement in humans outside the
operating theatre. Brain temperature was also sometimes inferred from a nomogram, developed
from experimental work and clinical experience, to predict intracranial temperatures at various
depths from observed body temperature, taking into account the patient’s weight and the start
time of cooling.97,98

Chapter 5
Modelling of cost-effectiveness of
head cooling
T he review searches produced no suitable data for economic modelling and therefore this was
unable to be undertaken. The purpose of the economic analysis presented here is to create
an exploratory model of possible treatment effects and the cost-effectiveness of head cooling
using local data for patients with TBI. Although the model will not formally assess the cost-
effectiveness of head cooling, it will enable a discussion regarding whether or not the treatment is
potentially cost-effective.
Literature review, Glasgow Coma Scale and Glasgow

Outcome Scale
There are currently no economic evaluation studies published on the cost-effectiveness of head
cooling in adult patients with TBI. This is because there has been insufficient research and the
clinical effectiveness of the treatment is not established.
The Glasgow Coma Scale (GCS) is a standardised neurological scale for recording and
communicating the conscious state following a brain injury. The GCS can be transformed to a
coma score and is used to evaluate patients from ‘3’ (deep coma or death) to ‘15’ (fully awake).
It is commonplace to use the scores to classify patients’ injury as severe (GCS ≤ 8), moderate
(GCS 9–12) or minor (GCS 13–15),99 and this approach will be taken in the economic evaluation.
It should be noted, however, that this is not a linear scale.
The GOS and the extended GOS assess the longer-term effects through measuring the health
and functional status of a patient after a treatment or an intervention. The GOS classifies
patient outcome into five categories (eight in the extended scale), which range from death to
good recovery.100
Sources of data and eligibility
Data used to inform the economic modelling process were taken from the Scottish Intensive
Care Society (SICS) WardWatcher database, which contains a record of patients who received
treatment in the critical care unit of the Western General Hospital, Edinburgh. There is no single
diagnostic category for TBI and Appendix 8 explains how patients were identified from that
database. From September 1994 to July 2010, 1039 patients with TBI were admitted, but pre-
sedation GCS was available only for 695 of these patients and outcome data (five-point GOS at
12 months) for 168, those admitted in 2007–9.
The data set is relevant as it was planned that head cooling would take place in critical care and be
available to all TBI patients in such a unit. Therefore, any patient in the data set would be eligible
for head cooling. Usually, a patient will be admitted to a critical care ward if he or she has a GCS
score of ≤ 12, which includes both moderately and severely injured patients.
28 Modelling of cost-effectiveness of head cooling
Limitations of the data
A severe limitation with the available information is lack of head-cooling outcome data. There
are outcome data, i.e. the GOS data described above, which are available for 168 patients
who received treatment for TBI in the critical care unit. But what is missing is a measure of
effectiveness of head cooling for a patient with TBI.
Ideally, outcome data that are specific to head cooling would be available, and would include the
health impact of the intervention and patients’ characteristics (e.g. age, gender, time and severity
of injury, etc.). The outcome information might then be generalisable to the local data set used
in this model. For example, if, according to a published study, head cooling is most effective
when administered quickly to younger patients, and a male aged 25 years old with a short time to
arrival to hospital is present in the data set, it would then be possible to predict the effect of head
cooling on that patient. These data could then be combined with the cost information to provide
some indication of the cost-effectiveness of the intervention.
However, the effect of head cooling is not yet established. It is not possible to say that if a patient
with a certain set of characteristics receives head cooling then there is evidence to suggest there
will be an improvement in health outcome. A method of counteracting the gaps in the literature
is to use expert opinion, for example a clinician could suggest what may happen to a patient after
head cooling. However, this method was discarded, as it was considered to be stretching the
definition of ‘expert opinion to support the data’ too far by asking a clinician to suggest a whole
set of outcomes for the data set.
It should be stressed that every effort was made to create a robust economic model. This included
multiple meetings with hospital consultants at a variety of hospital locations across Scotland,
meetings and discussions with academics associated with the University of Edinburgh, and
thorough literature reviews. However, despite the search for available evidence, it was concluded
there are very few data.
Similar head-cooling studies that include economic modelling, such as that of Gray and
colleagues,101 are not relevant, as these papers are focused on neonates, whereas our interest is
in adults. In fact, the paper by Gray and colleagues101 highlights the main issue surrounding
the economic modelling of head cooling in adults, i.e. the lack of head cooling outcome data
for adults. The outcome of head cooling in infants is modelled by taking data from a RCT.39
Therefore, in their economic model Gray and colleagues101 can base their outcome data on
published evidence, and it is exactly this sort of information which is missing for adults. It is
not appropriate to alter a variable, for example head cooling reduces the number of deaths by an
arbitrary amount that is not based on reliable evidence.
A large RCT with outcome data would provide a solution to the above problems and enable a
more informative economic model to be developed.
Model
A simple diagrammatic model of the TBI pathway is provided in Figure 2. The pathway starts
with assessment which includes GCS. From this point the patient would usually go to a
specialised unit (critical care), a district general hospital (DGH) or home. The severe and some
moderate patients tend to be admitted to critical care, which is where head-cooling treatment will
be delivered. These are the patients for whom data are available, as explained above.

Severe Specialist unit
Significant
A&E Assessed Moderate DGH Rehabilitation
head injury: yes
Significant Mild
head injury: no
FIGURE 2 The TBI pathway. A&E, accident and emergency department; DGH, district general hospital.
Methodology
Using the available data, the possible financial impact of head cooling on length of stay was
modelled, i.e. if head cooling changes the length of stay of patients within the critical care unit
would this have an economic impact? If the model assumes that the GCS can act as a rough proxy
for how severely injured the patient is, then it is possible to model the financial impact of head
cooling if it alters the length of stay associated with that level of injury.
Three scenarios are modelled:
■■ First, the cost associated with the status quo, which takes into account the proportional
split of patients between moderate and severe levels of injury and the cost of treating these
patients, is modelled.
■■ The second scenario investigates the financial cost if head-cooling increases by 1.5 days
the length of stay of moderately and severely injured patients. This scenario was modelled
in case applying head cooling lengthens patients’ stay in critical care as they undergo an
additional treatment.
■■ The third scenario examines the financial cost of head cooling decreasing a patient’s length
of stay by 1 day, with respect to moderately and severely injured patients. This scenario was
modelled in case the health benefits of head cooling enabled the patient to be moved on from
critical care earlier than in current practice.
Descriptive statistics
Presented below are background information contained in the data.
Variable No.
Individuals in model 695
Mean age (years) 42.31
Median age (years) 42.00
Males 532
Females 163
The mean lengths of stay of a moderately or severely injured patient, with the associated GCS
scores, are tabulated below. The mean lengths of stay associated with scenarios 2 and 3 are also
tabulated below.
Scenario 1: status quo
Severity of injury GCS score Length of stay (bed-days)

Severe ≤8 6.38
Moderate 9–12 6.75
Scenario 2: increase in length of stay

Severe ≤8 7.88
Scenario 3: decrease in length of stay

Severe ≤8 5.38
In addition, the cost per bed-day and equipment costs are outlined below. It is assumed that
no additional staff time would be needed to provide the head-cooling intervention, as these
patients have 1 : 1 nursing care, which would usually be sufficient to accommodate delivery of
cooling interventions. The cost per hospital bed-day is calculated from 2008–9 data published
by Information Services Division (ISD) Scotland for the ICU at the Western General Hospital,
Edinburgh. Equipment costs are based on the Olympic CoolCap System, which includes
reuseable cooling caps [costs were provided by the UK supplier Genesys Medical Solutions (UK)
Ltd in December 2010].
Variable Cost (£)

Cost per hospital bed-day 1472.13
Cost of equipment 13,500
Costs of staff 0
Results
It is expected that 69 patients per year would receive head cooling (because this was the average
number of patients admitted to critical care each year in this data set). The proportional split
between moderate and severe patients is 15% and 85%, respectively. The results of the three
scenario models are presented below.
Status quo
Severity of injury Cost (£)

Severe 550,664.44
Moderate 102,915.78
Total 653,580.22

Scenario 1

Severe 680,174.87
Moderate 125,770.56
Total 805,945.43a
a Includes equipment cost of £13,500.
Scenario 2

Severe 464,324.15
Moderate 87,679.25
Total 552,003.40a
a Includes equipment cost of £13,500.
Discussion
The insight gained from the modelling above is limited. Essentially, the model is taking the GCS
as a rough proxy for how severely injured the patient is and suggests that if head cooling could
impact on length of stay then there may be a substantial change in costs owing to the expensive
location of the treatment.102 Head cooling is delivered in critical care, which generates a relatively
expensive cost per bed-day. If the treatment alters the length of stay, and therefore the number of
bed-days, then the change in cost between the current treatment and treatment with head cooling
may be significant. However, it has been suggested by expert clinical opinion that head cooling
may not impact on the length of stay of any section of the pathway outlined in Figure 2 (length of
stay in critical care, DGH or rehabilitation).
The main benefit of head cooling for TBI is proposed to be improving the quality of life and
reducing disability over the patient’s lifetime, i.e. what happens to patients after they go home
and leave the mainly hospital-based pathway outlined in Figure 2. In addition, if there is an
improvement in the long-term health of the patient then this will not only impact on the lifestyle
of the patient, but will also require fewer health- and social-care support resources from the NHS
and local authorities. This information will therefore significantly impact on whether or not the
intervention is cost-effective, depending on the degree of health improvement and the size of the
health and social costs.
Unfortunately, there are no UK lifetime TBI costs and no head-cooling cost data available in the
literature, and therefore it is not possible to directly assess the long-term cost of TBI. We found
the lack of lifetime costs for TBI surprising but requests for information to the Department
of Health, the Scottish Office, the NHS Information Centre, the Trauma Audit and Research
Network, and the Scottish Acquired Brain Injury Managed Clinical Network confirmed the
lack of data. It stems, in part, from difficulty identifying patients who have had a TBI. The
International Classification of Diseases, Tenth Edition, codes S00–S09, covers injuries to the head
(S06 is specifically ‘intracranial injury’), but on initial admission to hospital it may not always be
obvious whether or not brain injury is due to trauma, and patients may have other injuries and
complex disease classification. In the USA there has been a concerted effort to collect data and
consequently much more information is available,103,104 but, unfortunately, the health-care system
is too different for this to translate to the UK. However, because this review has highlighted the
lack of lifetime data on TBI, steps are now being taken in Scotland to address the situation and
we are working with a group of people under the auspices of the Acquired Brain Injury Managed
Clinical Network to improve data collection on TBI. We hope that, in the longer term, access to
better data on the course of TBI will lead to benefits for these patients.
Although not related to TBI, Comas-Herrera and Wittenberg105 estimate that the lifetime health-
and social-care costs of those aged ≥ 65 years in England are £31,500 per person at 2006–7
prices, averaged across males and females. The lifetime costs for a male reported in this study are
£18,650 and £41,350 for a woman. These results compare favourably with those of Forder and
Fernández,106 who estimate that the average lifetime expected cost of care for a male is £22,300,
whereas for a female it is £40,400. The average for both genders is £31,700 per person in old age.
As seen in the descriptive statistics provided above, the average age of a patient with TBI is
around 42 years, which is much lower than the 65 years used as the cut-off point for the estimates
presented by Comas-Herrera and Wittenberg.105 In addition, the individuals in their study are
not reported to be disabled (although their health may deteriorate with age). The data in Comas-
Herrera and Wittenberg105 highlight just how expensive health- and social-care costs can be and
they may be much more if based on patients with TBI who have an average age of 42 years. It is
reasonable to suggest that the long-term cost implications of TBI are substantial, which implies
that if head cooling can improve the health of the patient and reduce the long-term costs of
health and social care then it has a realistic chance of being cost-effective.
In addition to a lack of lifetime TBI cost data, there are also no available outcome data, i.e. health
outcome data that evidence what happens to a patient after head cooling. There is no way to test
the argument set out above – that head cooling may be cost-effective if it achieves positive health
outcome and reduces the associated lifetime costs of health and social care. Thus, the model does
not capture the main benefit of head cooling, which is the impact on quality of life and disability
over the lifetime, and stops short of being a full economic evaluation, as there is no synthesis of
outcome data with costs.
Conclusion: modelling of cost-effectiveness
The limited model presented here does display the sensitivity of the costs to changes in length of
stay due to the expensive location of where head-cooling treatment is most likely to be delivered.
Critical care has a relatively high cost per bed-day; thus, if length of stay changes, the impact on
costs may be significant.
Unfortunately, good-quality data on outcome after head cooling are lacking and it is difficult
to surmise from the model presented here whether or not the intervention is currently cost-
effective. However, what the process has highlighted (and is the main conclusion of this model)
is that if head cooling can positively impact on the quality of life for patients with TBI then the
intervention may be cost-effective, owing to the high health- and social-care costs of severe brain
injury and resulting disability.

Chapter 6
Public involvement
I n the UK to date, head cooling in adults has been a research intervention and is not part
of normal clinical care. As a result, there have been very few service users of head cooling.
Those patients who have had head cooling were critically ill, sedated and unconscious, with
consequently very limited or no awareness of the intervention. Even if we could have contacted
them, it was difficult to know how they might contribute to this review from personal experience
of head cooling. However, almost any member of the public might be a potential service user in
the future, and thrust into that situation without prior warning because head cooling is an acute
intervention for sudden and unexpected health emergencies – TBI, stroke and cardiac arrest.
Therefore, during preparation of this report, the results of the review were presented to members
of the general public in order to give them an opportunity to comment on and discuss the
concept, possible use and effectiveness of head cooling, and also issues of consent to research in
sudden and acute illness.
People at a city centre church in Edinburgh were asked if they would like to take part in a
discussion, and 10 agreed. They ranged in age from 40 years to > 80 years: eight were women
and two men. The discussions took place in two groups (n = 4 and n = 6), with one of the men
in each group. Each person was given a one-page summary of the findings of the review, with
a brief overview of consent for this type of research, i.e. research in critically ill patients who
lack capacity to consent (see Appendix 9), together with photos of an intranasal cooling device
and a liquid head-cooling device. After they had read the information, they were invited to
comment, ask questions or discuss any aspect of the information. The researcher (BH) had no
pre-set agenda and what was said and discussed was led entirely by the group members, with the
researcher responding to questions and providing additional information as necessary. These
were not focus groups: the group members were not research participants but partners in an
opportunity for exchange of information, mutual learning and promotion of understanding.
What follows is an overview of the aspects discussed to indicate what was of interest and of note
to these members of the public.
With regard to head cooling, discussion ranged over the history of cooling, whether or not
testing had been carried out in animals or human volunteers and to what extent this was relevant
to people with brain injuries, hibernation in animals, whether or not cooling therapy was more
natural than drugs, group members’ experiences of cooling therapy, and the nature of head
cooling as an intervention compared with whole-body cooling.
Two people knew of babies with neonatal HIE: one had been cooled and was doing well. Another
knew of a child who had fallen into icy water and been submerged for some time but recovered.
Generally, it was felt to be important that cooling therapy was better known about by the public
and health-care professionals in some instances, because one group member said she was
surprised that a midwife friend did not know that cooling could be a therapy for babies with
birth asphyxia.
With regard to research, matters discussed included being asked to consider research when in
a state of shock after a relative’s sudden illness and how they might feel, how to decide what is
best, what happens if something goes wrong, what randomisation means, and differences in the
law between England and Scotland (something of which group members were not aware). One
34 Public involvement
retired general practitioner reported being better disposed to agree to take part in a cooling trial
than a drug trial because of concerns about pharmaceutical company-driven research. Most
group members had not considered that the reason for a trial is because there is uncertainty
over a treatment or that taking part in a trial does not necessarily mean getting an additional
treatment over and above normal care, but may mean getting no additional treatment.
Although the group members were initially not sure what they would be able to contribute, they
appreciated that this kind of research might be something that people could be confronted with
‘out of the blue’. They were interested to learn more about head cooling, and research in situations
of critical illness. It was certainly helpful from the research and clinical point of view to get an
idea of the range of questions and issues that may be relevant to people presented with this for
the first time, as would be the case with patients, and their families, who might be eligible for
head-cooling research in the future.

Chapter 7
Discussion
T his was a complex review that included TBI and stroke, and also cardiac arrest for
temperature reduction data, and cardiac arrest and neonatal HIE for adverse effects of
methods and devices.
Impact of head cooling on functional outcome
The searches found 46 studies of non-invasive head cooling in TBI, stroke and brain injury,
of which three were assessed as RCTs with good allocation concealment (see Figure 1). Good-
quality RCTs with blinded outcome assessment were prespecified for inclusion in analysis of
functional outcome, but none of the three met this criterion and was suitable for this purpose.
Temperature reduction with head cooling
For assessing the effect of head cooling on temperature, studies and trials in cardiac arrest were
eligible in addition to those in TBI and stroke. Twelve studies had useable data, including four
RCTs and four in cardiac arrest (see Table 1). There was considerable heterogeneity (of patients,
reasons for cooling and interventions) in these studies, making it difficult to summarise the data.
Two studies showed no effect,46,48 but in both cases this seems likely to be because of the methods
used. In one of these, ambient temperature nasal airflow delivered to intubated, ventilated
patients to replicate normal nose breathing showed no effect on intracranial temperature at a
distance from the nasopharynx.46 With this method the temperature gradient between the patient
and the airflow was relatively small. In the other, ice bags on the head and neck for 5–30 minutes
did not further reduce temperature in patients who were already on average hypothermic.48 This
method does not actively remove heat by coolant flow.
However, in broad terms the data indicate that liquid head- and neck-cooling devices and the
Rhinochill intranasal cooling device can reduce intracranial and/or core trunk temperature
by around 1 °C or more, within 1 hour in some studies (see Table 1). (These methods create
a relatively steep temperature gradient between the patient and the coolant, and actively
remove heat by coolant flow.) This is promising and, in particular, suggests that there may be
a role for liquid head-cooling devices for induction and maintenance of modest temperature
reduction in TBI and stroke (the Rhinochill device is not designed for prolonged use). A
small observational study51 showed that it was possible to successfully treat fever refractory to
standard management (paracetamol, metamizole, alcohol washing and ice packs) in this way
(see Table 1). It is noteworthy that, even in the presence of active body warming, intracranial
temperature was reduced with a liquid head-cooling device and could be reduced below core
trunk temperature.45,50
This is in contrast with mathematical modelling studies of head cooling, which are sometimes
cited to support the view that external head cooling with various devices, including liquid cooling
helmets, has a very limited effect on intracranial temperature. The modelling data, even when
incoming carotid temperature is varied (which is more realistic than models that treat it as fixed
36 Discussion
at 37 °C) suggest that these devices reduce brain temperature only superficially, up to about
18 mm below the parenchymal surface.107,108 Even if the usual site of parenchymal temperature
measurement – at 1 cm below the brain surface – is considered too superficial to provide valid
information on whether or not deeper brain is cooled, the data in this review include examples of
ventricular temperature and core body temperature reduction with head cooling (see Table 1). It
is hard to conceive that core trunk temperature would be reduced with head cooling, for example
with the Rhinochill intranasal cooling device, in the absence of some deeper brain temperature
reduction (see Appendix 1).
Head cooling compared with systemic cooling
The reason commonly given for using head cooling is that there may be fewer side effects
than with systemic hypothermia.109 Some investigators simply assume that cooling the head
and keeping the body warm will minimise systemic complications of hypothermia.45,50 Some
head-cooling device providers have also made that assumption. The TraumaTec website states:
‘Selective brain cooling with the Neuro-Wrap™ avoids the complications seen with full body
cooling … Complications of systemic hypothermia do not occur as systemic normothermia is
maintained’ (www.traumatec.com/traumatec-brain-injury.htm; accessed 28 April 2011). Also,
on the Benechill website, regarding the Rhinochill device: ‘it is core temperature reduction
that causes problems in cooling – not brain temperature reduction’ (www.benechill.com/wp/
resource/; accessed 28 April 2011).
Harris and colleagues45 were unable to achieve an intracranial temperature of 33 °C with head
cooling while maintaining bladder temperature at 36 °C with active warming (see Table 1),
although whether or not such a large temperature gradient is necessary or desirable remains
to be determined. Because a statistically significant intracranial body temperature was not
achieved, they concluded that their head-cooling device was not useful in management of TBI.
Nevertheless, mean intracranial temperature was reduced below body temperature by 0.67 °C,
and Wang and colleagues,50 also in the presence of active body warming, achieved a mean 1.6 °C
reduction of intracranial temperature below body temperature. This is a reversal of the norm,
in which intracranial temperature is usually higher than body temperature,110 and could well be
considered clinically relevant for that reason, although whether there is therapeutic benefit or
otherwise is not known. It is difficult to measure intracranial temperature gradients in humans
but, in animals, head cooling in the presence of body warming to normothermia has been
shown to significantly increase intracranial temperature gradients compared with systemic
normothermia and hypothermia, although, again, it is not known if this is harmful.111,112
This review found no high-quality RCT evidence on the relative complications and benefits of
head compared with systemic cooling in adults and there are no RCTs making that comparison in
neonatal HIE. However, there is some circumstantial evidence from other sources that is relevant
to the question of whether or not a hypothermic brain and relatively warmer body may produce
fewer complications than systemic hypothermia.
The side effects of systemic hypothermia at temperatures of 33–35 °C include pulmonary oedema,
rebound increases in ICP on rewarming, higher temperatures post hypothermia, coagulation
abnormalities, metabolic effects and immune suppression.113 However, the reporting and
definition of complications in clinical trials of systemic hypothermia is variable, which makes
assessing their impact difficult. Nevertheless, systematic reviews of trials of systemic hypothermia
after brain injury have shown a non-significant increase in occurrence of infections with cooling
therapies (i.e. not only with hypothermic therapy) in stroke14 and of pneumonia in hypothermia
for TBI.15 But whether or not head cooling results in fewer complications than systemic

hypothermia is likely to depend on the mechanisms by which the complications are caused,
how the cooling and warming of the blood as it circulates through a cooler brain and relatively
warmer body affects these, and how extreme the temperature gradients are.
With regard to infection, because immune response is modulated by the brain114,115 it seems
unwise to assume that brain cooling, with the body relatively warmer, will cause less immune
depression and infection than systemic cooling. The primary hormonal pathway for brain–
immune system interactions is the hypothalamic–pituitary–adrenal axis115 and, consequently, it
is thought that brain cooling does suppress immune function because the pituitary is cooled.116
Furthermore, if immune defence is accelerated and more efficient at increased temperatures,117
reducing brain temperature even to the normothermic range might increase morbidity and
mortality from infection.
Another undesirable effect of cooling is shivering, with the requirement for sedation to prevent
it. Shivering and stress response to cold may occur even if brain temperature alone is reduced
below the ‘set-point’, as cooling of the preoptic area of the hypothalamus is sufficient to cause
heat production and retention responses.118,119 Lim120 controlled brain temperature and core
trunk temperature independently in anaesthetised dogs using bilateral carotid antegrade cerebral
perfusion with independent control of body temperature. Cool brain–warm body and warm
brain–cool body conditions both produced shivering. Therefore, brain cooling, even if the body is
warm, may not prevent shivering.
If the question of whether or not head cooling does produce fewer complications than systemic
cooling is to be answered then a good-quality RCT is needed. There is a small safety and efficacy
study ongoing in stroke. The Cerebral Hypothermia in Ischaemic Lesion (CHIL) trial has a
head-cooling arm in China, a systemic hypothermia arm in Australia and a normothermic
control group, with blinded outcome assessment of the National Institutes of Health Stroke
Scale (NIHSS), modified Rankin Scale (mRS) and Barthel Index (BI) at 90 days (see Appendix 6,
Characteristics of ongoing studies).
Head-cooling terminology and search terms
There is no agreed terminology to describe cooling that is directed specifically at the head and
brain. In the absence of this we have previously suggested the term direct brain cooling and
developed the classification of head-cooling methods used in this review.23 This was in part an
attempt to provide an alternative to the term selective brain cooling, which has been commonly
and erroneously used in clinical papers to describe head-cooling interventions. Selective brain
cooling is a natural thermoregulatory mechanism in which brain temperature is reduced below
carotid blood, defined in the Glossary of terms for thermal physiology.121 Although applying
cooling to the head can reduce brain temperature below body temperature (see Table 1), this is
not physiological selective brain cooling.
Because the purpose of therapeutic cooling is to reduce brain temperature, investigators may
use head- and brain-related terms to describe cooling, even when they have used systemic
methods. Hayashi’s group in Japan for example refer to ‘brain hypothermia therapy’ and ‘cerebral
hypothermia’ but they use whole-body cooling.116,122
The lack of standard terminology makes literature searching more difficult. Key words are
variable, if used at all, in relation to cooling method. Medical subject headings (MeSH) do not
specifically help in searches for cooling interventions or cooling targeted at particular organs.
Gastric hypothermia is the only named method in the MeSH tree structure for therapeutic
38 Discussion
cooling and brain cooling crosses a number of subject areas. We used MeSH terms within
our searches but it would refine indexing and aid searching if cooling interventions were
incorporated, at least on the basic level of whether they are invasive or non-invasive, brain
directed or systemic.
A helpful consensus has recently been reached on a number of factors related to targeted
temperature management in critical care123 and this could usefully be extended to agreeing
terminology for cooling methods.
Poor reporting of methods and temperature data
Poor reporting of study methodology and/or temperature data were the main reasons why studies
were excluded (see Appendix 6, Characteristics of excluded studies). Poor reporting has ethical
implications as well as being frustrating for readers and reviewers. It is a recognised problem that
is being actively addressed by the CONSORT (Consolidated Standards of Reporting Trials) group
(www.consort-statement.org) with some success.124
If the studies found for this review, even if not randomised, had reported temperatures
satisfactorily there would have been more information on proof of concept of head cooling with
regard to temperature reduction. But many did not adequately report the cooling interventions,
the temperature outcomes, where temperature was measured or temperature management in
control groups (see Appendix 6).
A consensus report from a meeting of five international critical care societies has recently been
published, which includes criteria for reporting studies of targeted temperature management in
critical care. The therapeutic effect, safety and reproducibility of temperature management should
be reported just as with a drug, including:
Accurate reporting of the indication for temperature management, the interval between
disease onset and cooling, the management profile, including the rates of decrement and
increment as well as the temperatures achieved, and a comprehensive description of the
effects on each body system. (p. 1114).123
Therefore, in addition to rigour in reporting study design,125 information reported in head-

cooling studies should include sufficient detail on the cooling method(s) to allow replication,
the temperature measurement sites, actual temperatures in intervention and control groups
at baseline and with cooling and during rewarming, temperature management strategy (e.g.
normothermia or no intervention) and temperature in control groups, and complications/adverse
effects from cooling. Providing this information is particularly important because head-cooling
research is still largely at the explanatory stage of whether and to what extent different methods
reduce temperature.
Chinese studies of head cooling
Twenty-six of the studies on head cooling found for this review were Chinese. The reports were
generally relatively short and, unfortunately, none gave sufficient detail on methods to allow trial
quality to be adequately assessed or sufficient information on temperature. Poor reporting was
also found in a review of leading Chinese medical journals by the Chinese Cochrane Centre.126

It may be partly explained by lack of formal training in research methods and failure of journals
to adopt reporting criteria such as CONSORT,126,127 but is not limited to Chinese trials124 (and
see Appendix 6).
Information on the method of randomisation was missing or scanty (e.g. ‘computerised’, ‘number
method’) and sample size calculation and whether or not the analysis was on an intention-
to-treat basis were not reported. It was unclear if analysis was prespecified and sometimes
the time scales of result reporting were ambiguous (days on which blood tests were carried
out, for example), which suggested that positive results may have been selected for reporting
(e.g. see Xu and colleagues128). None of the Chinese studies reported on blinding of treatment
allocation, analysis or outcome assessment. In cooling studies it is not necessarily feasible to blind
investigators to treatment allocation but we considered that blinded outcome assessment was
important and therefore prespecified in the review protocol that studies in which this was not
undertaken would be excluded from the formal analysis.
Recently the Chinese Cochrane Centre conducted a study to assess the adequacy of
randomisation of peer-reviewed trials published in Chinese that purported to be RCTs.129 Trial
investigators were interviewed on the telephone and of 2235 studies only 207 (6.8%; 95% CI
5.9% to 7.7%) were found to be authentic RCTs. Most of those interviewed (85.6%) did not fully
understand randomisation when they claimed that their trials were randomised. However, 5.1%
did understand randomisation and still claimed that their trials were properly randomised when
they were not. Although we had limited success in contacting Chinese authors for this review,
the corresponding author of one study who did respond said that the trial was not randomised,
although in the paper it was reported to be randomised using a randomisation table.75
Selection bias owing to inadequate randomisation may be one reason for the relatively high
proportion of positive results that has been noted in Chinese trials.129 Those found in the searches
for this review were all positive and, although the inadequate reporting of methods has made
it impossible to assess their quality, it is plausible that selection bias and bias from unblinded
outcome assessment and analysis were contributing factors.
Typically, if hypothermia was the aim, only the target temperature for head cooling was reported
or, for reduction of fever, for example, the temperature at which the cooling device was set. The
actual temperatures prior to cooling and during induction, maintenance and reversion in the
intervention groups were not reported nor was the site of temperature measurement always
specified [when it was, this is noted under characteristics of included/excluded studies (see
Appendix 6)]. General information on the time to reach target temperature was sometimes
provided, for example Yang and colleagues130 noted that it took 30–60 minutes to achieve a brain
temperature of 35 °C and 3–4 hours to reach 32–35 °C. The implication is that large reductions
in brain temperature can be achieved rapidly with non-invasive head cooling, which could be
important and clinically relevant if more detailed information was available. There was also little
information on temperature management in control groups, for example normothermia. Most
papers simply stated that groups were treated the same with the exception of cooling.
A number of the Chinese stroke studies assessed outcome with the neurological deficiency score
(NDS) (see Appendix 6). This is not an assessment of functional outcome and is not considered
well validated by the Cochrane Stroke Group. It was not one of our prespecified assessment tools
(www.strokecenter.org/trials/scales/scales-overview.htm; accessed 24 April 2011).
Cerebral oedema volume was used as an outcome measure in several Chinese stroke studies and
a Japanese stroke study (see Appendix 6), but the methods used were not adequately explained.
This was not one of our prespecified outcomes because the validity of cerebral oedema volume
40 Discussion
as a measure of improvement in brain injury is not established and there is no agreed method of
measuring it (e.g. see Degos and colleagues131 and Lescot and colleagues132).
Ethical review and informed consent was not always reported in the Chinese studies. Medical
ethics in China has been described as ‘anaemic’, a state of affairs attributed to there having been
no equivalent to the Nuremberg Code because Second World War atrocities were not addressed,
as they were in Europe by the Nuremberg Trials.133 However, there have been considerable
developments in medical research ethics in China since the 1990s, which include the requirement
for ethical review.134 But there are philosophical differences between the principle of individual
autonomy on which ethics in Europe and North America are based, and the traditional Chinese
focus on ‘social harmony over individual interests’ (p. 1867).134 No single approach necessarily
has the monopoly on ethical ‘correctness’ and sensitivity to cultural differences is important.135
Medical treatment is not free in China.136 Hospitals receive little government subsidy and
therefore have to sell services. Drugs and medical consumables in particular are relatively
expensive and may be subject to corrupt pricing,137 and corrupt purchasing and prescribing
in hospitals.138 The issue of cost was touched on in some of the Chinese study reports and has
implications for trial validity. In one study, patients who were allocated to head cooling but
could not afford the head-cooling device were cooled with ice packs.139 Ou and colleagues140
investigated different durations of head cooling and noted that longer cooling increased the
cost for patients. This also meant that the timing of patients’ discharge from hospital was not
necessarily dictated by their condition but by their ability to pay for continued care, which is a
potentially confounding factor in studies where functional or neurological outcome after head
cooling was followed up on hospital discharge (e.g. see Dong and colleagues141).
This is not intended to single out Chinese studies for special criticism: it just happens that
they formed a large proportion of the studies found by searches for this review. In summary,
what we found with regard to reporting quality in the Chinese studies is consistent with a
recent systematic review of the quality of Chinese RCTs142 and a review of reporting quality in
leading Chinese medical journals,126 both undertaken by the Chinese Cochrane Centre. There
are initiatives to improve trial conduct and reporting in China, and such initiatives are already
having an effect elsewhere, although reporting is still not all that it should be.143
Potential biases in the review process
This systematic review addresses clear research questions and used predefined inclusion criteria
to select and appraise studies. We conducted extensive and sensitive searches but the possibility
of publication bias remains. There may be, for example, more trials published in Chinese journals
than we found. The majority of the trials found were small and/or, on the basis of the reports, of
low methodological quality. If the trial reports did not reflect the true quality of the trials then it
is possible that there are excluded trials that should have been included.
Agreements or disagreements with other reviews
Four previous reviews of head cooling were found: two, published in Chinese, in patients with
cerebral haemorrhage,144,145 one that included human and animal studies in TBI146 and one that
included human and animal studies in TBI, stroke, cardiac arrest and neonatal HIE.23 None
were systematic.

No head-cooling studies were included in the most recent Cochrane systematic reviews on
hypothermia for traumatic head injury,15 modest cooling therapies (35 °C to 37.5 °C) for
TBI,13 and cooling therapy for acute stroke (ischaemic or haemorrhagic).14 Sydenham and
colleagues15 excluded two head-cooling studies, one75 because the cooling intervention was
of < 12 consecutive hours’ duration, the other147 was not a RCT, another study76 was awaiting
assessment. Saxena and colleagues13 excluded five head-cooling studies46,47,50,76,147 for physiological
end points46,47, methodological reasons76 and target temperature outside the review scope,50,147
respectively. den Hertog and colleagues14 excluded three head-cooling studies50,148,149 because
the outcome measures were not relevant to the review (relevant outcome measures were
functional outcome, mortality, mean temperature 24 hours after start of cooling, cerebral
haemorrhage, complications).

Chapter 8
Conclusions
H ead cooling after cerebral insults potentially encompasses a wide spectrum from simple
fanning of the head after a mild stroke through to neuropreservation of the head by
cryonics after legal death but before biological death (Alcor Foundation, www.alcor.org/;
accessed 6 August 2010). In this review we have concentrated on non-invasive therapeutic head
cooling after TBI and stroke, although studies in cardiac arrest were also included for data on
temperature reduction, and studies in both cardiac arrest and neonatal HIE for adverse effects
of methods and devices. We found a larger number of studies than expected, but few RCTs of
confirmable quality and none that allowed us to determine if head cooling improves functional
outcome in TBI or stroke. The review has shown that some methods of head cooling can reduce
intracranial temperature, which is an important first step in determining effectiveness, but the
evidence is not robust.
However, a fundamental issue in TBI and stroke, regardless of the method of cooling, is that
the magnitude of temperature reduction (if any) necessary to improve functional outcome is
still unknown.13–15 Large RCTs are in progress to assess the effect of therapeutic hypothermia
compared with normothermia. Two in TBI – one of systemic hypothermia as a neuroprotectant
[the Prophylactic Hypothermia Trial to Lessen Traumatic Brain Injury (POLAR-RCT), http://
clinicaltrials.gov/ct2/show/NCT00987688] and the other of raised ICP (Eurotherm3235Trial,
www.controlled-trials.com/ISRCTN34555414/). In stroke, the EuroHYP trials (www.eurohyp.
org), for example, are collectively planned to assess therapeutic hypothermia using various
systemic cooling devices and also head cooling (see ‘i-Cool’ in Appendix 5, References to
ongoing studies, Stroke). The CHIL trial (see Appendix 5, References to ongoing studies, Stroke) is
comparing systemic hypothermia with head cooling and normothermia in stroke. There is still a
need for RCTs of the effect of normothermia (or near normothermia) compared with no cooling
in TBI and stroke.13,150,151
Recommendations for research in TBI and stroke:
1. We suggest that active head-cooling devices are the most promising for further research, i.e.
those that flow/circulate gas or liquid coolant.
2. More robust proof of concept of temperature reduction with head cooling is required.
The effectiveness of head cooling in achieving and maintaining both normothermia and
hypothermia should be assessed. Intracranial temperature should be measured (whenever
feasible), as well as core trunk temperature in the oesophagus (or pulmonary artery),
otherwise bladder, with rectal temperature being a last resort. It should be absolutely clear
in study reports whether or not temperature has changed with cooling and by how much.
Baseline temperatures, duration of cooling, temperatures achieved with cooling, and
temperature change with cooling should be reported, with measures of central tendency
and spread.
3. Head cooling, both with and without body warming, should be compared with systemic
cooling to determine if complications – including shivering, infection and coagulation
abnormalities – are fewer.
4. In volunteers, the effect on brain temperature gradients of different methods of head cooling
with and without body warming might be assessed with magnetic resonance spectroscopy
temperature measurement.
44 Conclusions
5. Head cooling as a method of treating raised ICP should be investigated.

6. The efficacy of head-cooling methods in maintaining cooling after induction of therapeutic
hypothermia with cold intravenous fluids should be assessed.
7. The tolerability and effectiveness (infection, shivering, temperature reduction, functional
outcome) of head cooling in achieving normothermia and hypothermia in awake patients
should be assessed.
8. In stroke patients, the effect of head cooling prior to, and during, thrombolysis should
be evaluated.
9. In stroke, the efficacy and tolerability of intranasal cooling combined with external head
cooling should be investigated. (Intranasal cooling may not be suitable for trauma patients.)
Implications for practice in TBI and stroke:
1. Head cooling has potential as a method of reducing raised intracranial temperature when
this is clinically indicated but there is insufficient evidence to recommend its use outside of
research trials.
2. Improved methods of recording and tracking patients after TBI are required throughout the
UK so that the impact and costs can be measured.
The overall aim of this review was to provide a comprehensive picture of head-cooling research
in adults after TBI and stroke. We believe that we have done this and that the review shows
that head cooling has promise as an intervention after TBI and stroke and therefore deserves
further investigation.

Acknowledgements
Contribution of authors
Bridget Harris (Research Fellow, University of Edinburgh, and Clinical Research Specialist,
Critical Care, NHS Lothian) managed the project, carried out the searches, wrote to investigators
and manufacturers, organised obtaining individual patient data for the economic model and
cleaned the data set, screened studies that were obtained on the searches for inclusion, extracted
data, compiled the presentation of the data, undertook the presentation of the results to the
public, and wrote the report.
Peter Andrews (Consultant, Critical Care Services and Honorary Professor, University of
Edinburgh) assisted with project management, and provided expert opinion for the economic
model, screening of studies for inclusion, extraction of data, and writing of the report.
Gordon Murray (Professor of Medical Statistics, University of Edinburgh) gave statistical and
methodological advice and support, and assisted with writing the report.
John Forbes (Reader in Health Economics, University of Edinburgh) supervised the economic
modelling and contributed to the report.
Owen Moseley (Health Economist, NHS Ayrshire and Arran) researched and wrote the
exploratory model on cost-effectiveness of head cooling in patients with TBI.
Thanks to those who helped
We are most grateful to:
Brenda Thomas, Cochrane Stroke Group Trials Search Co-ordinator, for essential expert
guidance and help with the searches and for searching the Cochrane Stroke Group trial register.
Karen Blackhall, Cochrane Injuries Group Trials Search Co-ordinator, for searching the
Cochrane Injuries Group trial register.
Dr Cathie Sudlow, Mike McDowell, Dr Alasdair FitzGerald, Angela Kellacher and Lillian Ford for
help sourcing individual patient outcome data in stroke and TBI.
Dr Wai Kwong for invaluable assistance with papers written in Chinese.
Dr Carlotta Bagna, Alison Bruce, Cristina Guarrera and Junko MacKenzie for assistance with
papers written in Italian, German, Russian and Japanese, and Dora Wirth (Languages) Ltd for
Russian and Chinese translations.
The members of the public who commented on, and discussed the findings of, the review.
We are also grateful to the following investigators and companies who did respond to our
requests for information: Dr Jasmin Arrich; Dr Denise Barbut (Benechill Inc.); Dr Lucian
Covaciu; Professor Wang Desheng; Dr Kenji Dohi; Dr Hinnerk Doll; Dr Inan Guler; Dr Rainer
46 Acknowledgements
Kollmar; Dr Sven Poli; Dr Wusi Qiu; Professor Claudia Robertson; Dr Muzaffar Siddiqui;
Professor Martin Smrcka; Professor Fritz Sterz; Dr Yoshimasa Takeda; Dr Frank Tortella; Dr
William Walsh; Dr Huan (John) Wang; Ioannis Anastasakis, TechNiche International; Heidi
Hughes, Cincinnati Sub-Zero Products Inc.; Becky Inderbitzen, Benechill Inc.; Richard Paxman,
Paxman Coolers Ltd; Polar Products, Inc.; Susanne Richard, TraumaTec Inc.; Lindsay Shearer,
Genesys Medical Solutions (UK) Ltd (Olympic Cool-Cap); Martin Waleij, Dignitana; and Todd
Yelavich, Penguin Cold Caps NZ Ltd.

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Appendix 1
Temperature measurement with
head cooling
I f cooling, however delivered, is to have a neuroprotective effect, brain temperature must be

reduced. Intracranial temperature is recognised as the gold standard for measuring brain
temperature, but invasive measurement is usually possible only in critically ill patients and at
a single site. The intracranial sites most commonly used clinically are subdural, parenchymal
(typically a centimetre or two into a frontal lobe) and ventricular. Invasive brain monitoring is
uncommon in stroke patients. A drawback is that a single site of measurement may not reflect
temperature across the brain, especially after injury and in the presence of head cooling when
hotter and cooler areas and gradients may be more marked.152,153
Intracranial temperature cannot be reliably predicted from body temperature. In neurosurgical

patients, temperature differences have, for example, been shown to range within patients from
–0.3 °C to 2.1 °C between frontal lobe and rectal temperatures,154 and between patients from
–0.7 °C to 2.3 °C between ventricular and pulmonary artery temperatures.155 Proxy measures of
intracranial temperature used in clinical practice include jugular bulb temperature (the jugular
bulbs are not within the cranium) and infrared thermometry in the ear canal. However, a number
of studies have questioned the accuracy and precision of the latter (e.g. Moran and colleagues156)
and both are potentially susceptible to contamination by scalp blood temperature,157 which is
of relevance with external head-cooling interventions and significant changes in environmental
temperature. True tympanic membrane temperature is rarely measured clinically, especially in
unconscious patients, because of the risk of perforating the ear drum.
However, head cooling does not reduce brain temperature in isolation, and venous return from
the cooled brain is likely to affect core trunk temperature.158 Indeed, in neonates body warming
is applied to prevent too great a core body temperature drop with head cooling.159 Therefore, in
the absence of intracranial temperature measurement, if core body temperature is reduced, this
is an indication that there has been heat loss from the head. Furthermore, the temperature of the
carotid supply to the brain will be reduced, which will, in turn, have a cooling effect on the brain.
If core body temperature is not reduced at all it is probably not unreasonable to assume that
intracranial temperature has not been significantly reduced. Thus, if core trunk temperature (in
an artery, e.g. pulmonary artery, oesophagus, bladder or rectum) reduces with head cooling it can
be inferred that the brain has been cooled.24,160
Therefore, for the purposes of assessing the effect of head cooling on brain temperature for this
review, intracranial temperature is defined as any temperature within the skull inside the dura.
A primary measure of the effectiveness of head cooling is reduction in intracranial temperature.
Core trunk temperature is used as proxy for brain temperature in the absence of intracranial
temperature measurement and defined as temperature measured in an artery (usually
pulmonary), the oesophagus, bladder or rectum. A secondary measure of the effectiveness of
head cooling is reduction in core trunk temperature on the assumption that for this to be reduced
there must have been some reduction in intracranial temperature.

Appendix 2
Review protocol (final agreed version
December 2008)
Detailed project description
Systematic Review of Head Cooling in Adults after Traumatic Brain Injury and Stroke (Project
Reference: 07/37/32)
Authors
Bridget Harris RGN, DipN, MSc, PhD
Peter JD Andrews MD, MBChB, FRCA
Gordon D Murray PhD, C Stat, FRCPE, FFPH, FRSE
John Forbes BA, MSc, PhD
NB the headings we have used are based on those for Cochrane Reviews.1
Although we are using Cochrane review methodology, this review does not qualify as a Cochrane
review because it straddles two Cochrane groups, stroke and injuries, and also because Cochrane
reviews of cooling in stroke and head injury do not as yet differentiate between methods of
achieving cooling. Nevertheless we have established links with the Cochrane Stroke Group, which
is based locally, and have discussed the review with the co-ordinating editor of the Cochrane
Stroke Group, the trials search co-ordinator and the statistical editor. They have agreed to give
consultancy support and this is costed for in the budget. Although we cannot have formal access
to the Cochrane Stroke Group, other than by paying for consultancy, informally it is possible to
seek to discuss any aspect of the review as members of the Cochrane Stroke Group are colleagues.
Ownership of the findings will remain with the review authors.
Background
The condition and incidence – traumatic brain injury and stroke
Brain injury due to stroke and trauma are common and costly in human and resource terms.
Stroke affects 130,000 people a year with about 450,000 living with severe disability;2 it ‘is
the third biggest cause of death in the United Kingdom and the largest single cause of severe
disability’.3 The incidence for head injury is similar to that for stroke,4 although the incidence of
death is lower at 6–10 per 100,000 population per year.5 However, head injury is more common
in younger people and it has been estimated that 4,700 of those admitted to hospital each year
would be unable to return to work at 6 weeks.4 In Scotland, 78% of patients with a severe injury
had moderate or severe disability one year later.6
Although the primary mechanisms of brain injury are different in trauma, haemorrhage and
ischaemia (whether focal as in ischaemic stroke or global as in cardiac arrest and neonatal
hypoxic ischaemic encephalopathy), the result is a cascade of excitotoxity, apoptosis and
inflammation.7,8 Inflammation, cell death, and infection if present, means that increased
temperature is common after both stroke and brain injury.9,10 There is no universal definition of
the threshold for pyrexia or where and how temperature should be measured but, for example,
64 Appendix 2
within 48 hours nearly 68% of patients had a rectal temperature ≥37 °C after severe traumatic
brain injury11 and 54% had an axilla temperature > 37.5 °C after stroke.12
Increased temperature is associated with worse outcome after both stroke and traumatic brain
injury.11,13 The exact nature of the relationship is hard to determine since the time of onset of
raised temperature has an influence and temperature elevation can be a marker of more severe
injury and of infection, both of which are also associated with worse outcome,14 although one
systematic review suggests infection may not play a significant part in the relationship in stroke.13
Nevertheless there is considerable evidence from animal research that reducing temperature,
and more especially inducing hypothermia, reduces the extent of the injury and that the sooner
cooling is instigated the more effective it is.8 However, with the exception of cardiac arrest and
neonatal hypoxic ischaemic encephalopathy, induction of hypothermia in humans has not yet
translated to improved outcome. This may be because it is difficult to cool patients early and
quickly enough and because the side effects of hypothermia, such as increased infection, may
outweigh the benefits in some circumstances.15–19
Although the focus of this review is head cooling in traumatic brain injury and stroke, in which
the primary problem is neurological, it is in cardiac arrest that hypothermia is clinically advised20
and most commonly used. Therefore we will include the cardiac arrest literature on head cooling
in our searches because this could contribute information about how effective these interventions
are in reducing temperature, and on their ease of use and side effects. A head cooling study in
cardiac arrest is included in systematic reviews of hypothermia for cardiac arrest21,22 but in this
study systemic hypothermia (bladder temperature 34 °C) was achieved.23 In our opinion it is not
yet clear to what extent myocardial cooling contributes to improved outcome with hypothermia
after cardiac arrest, and whether head cooling alone is as effective as systemic cooling in the
absence of myocardial cooling. There is some evidence that myocardial reperfusion injury, which
can be ameliorated by hypothermia, may contribute to post-arrest morbidity and mortality.24,25
The intervention – non-invasive head cooling

Cooling methods can be classified into those targeted systemically and those targeted at the head
to cool the brain. The brain is where cooling is needed after stroke and brain injury. Within these
two classifications there are invasive and non-invasive methods. Systemic cooling is the most
common intervention in standard practice.
Methods of non-invasive head cooling either induce heat loss from the upper airways by nasal
gas flow and nasal lavage, or heat loss through the skull by convection (fanning, cooling hoods)
and conduction (ice, cooling caps and helmets).26 Some cooling caps and helmets also have a
neck band which theoretically may cool the brain by decreasing the temperature of the carotid
blood supply.27 These non-invasive methods are generally quick and easy to apply and may be
suitable for pre-hospital use, which are important considerations in reducing time to cooling.
They also have potentially wide application because they can be used in patients with a range of
severity of illness, not just the most severely ill. Head cooling, however, is not in common use in
adults, the main application has been neonatal hypoxic-ischaemic injury,28 but around the world
there is developing interest in its use in adults.
Invasive methods of head cooling, such as antegrade and retrograde cerebral perfusion and open
irrigation of the brain surface, are used during surgery26 and will not be included in this review.
Standard temperature management in stroke and brain injury is generally aimed at reducing
hyperthermia, since there is insufficient evidence that inducing hypothermia improves outcome.
In stroke it is recommended that temperature is treated if above 37.5 °C.29 In brain injury
maintaining normothermia is recommended in the context of treating raised intracranial

pressure.30 Some neurological units have specific protocols,31 for example treating temperature
if above 38 °C and inducing hypothermia to 35 °C as part of the treatment for treating raised
intracranial pressure.32 There are no standard recommendations on the site of temperature
measurement or methods of temperature reduction. In practice choice of site of measurement
is variable31,33 and cooling interventions are systemic. Pharmacological intervention with
paracetamol is the most common first line treatment, followed by a variety of physical systemic
cooling interventions which include cooling blankets, ice packs and fanning.31,34
How the intervention might work – mechanisms and

temperature reduction
Mechanisms
Although cooling interventions are more commonly delivered systemically, the logic behind
brain cooling is that it targets cooling where it is needed because it is brain rather than trunk
temperature which is important in cerebral protection. It is also thought that brain cooling may
reduce the complications of hypothermia because less body temperature reduction is required,
although the evidence for this is not robust.26
The great advantage of cooling, by comparison with most other neuroprotective interventions, is
that it has multifactorial effects with regard to cerebral protection and prevention and reduction
of secondary insults. Hypothermia has even been described as ‘the ultimate neuroprotective
cocktail’.9 The effects of cooling are not fully understood but include reduction of metabolic rate,
modulation of cerebral blood flow and the inflammatory response and reduction of excitotoxic
damage and cerebral oedema.8,35 Because cooling can be very effective in reducing refractory
intracranial pressure this is the most usual reason for instigating physical cooling interventions in
severe traumatic and haemorrhagic brain injury.32,36 One of the attractions of cooling therapies is
that it is possible cooling could extend the time window within which restoration of blood supply,
e.g. with thrombolysis or resuscitation, might be effective.
Even if head cooling has a relatively modest effect on reduction of disability after brain injury
and stroke it may be cost effective since morbidity from head injury ‘far exceeds the capacity of
UK neurorehabilitation services’5 and the costs of stroke to the NHS are estimated at £2.8 billion
per year.3
Measurement of temperature reduction

If cooling, however delivered, is to have a neuroprotective effect brain temperature must be
reduced. Intracranial temperature is generally recognised as the gold standard for measuring
brain temperature, but it is usually only possible to measure it in critically ill patients and at a
single site, which may not reflect temperature across the brain especially after injury. Invasive
brain monitoring is uncommon in stroke patients. Proxy measures of brain temperature include
jugular bulb temperature (the jugular bulb is not within the cranium and is therefore not a
true intracranial temperature ) and infrared thermometry in the ear canal. But a number of
studies have questioned the accuracy and precision of the latter (e.g.37) and both are susceptible
to contamination by head skin temperature, which is a relevant factor with most head
cooling interventions.
However, head cooling does not reduce brain temperature in isolation and the venous return
from the cooled brain is likely to affect core trunk temperature.26 In the absence of intracranial
temperature measurement therefore, if core body temperature is reduced this indicates there has
been heat loss from the head and, furthermore, the temperature of the carotid supply to the brain
will be reduced which will in turn have a cooling effect on the brain. If core body temperature
is not reduced at all it is not unreasonable to assume that intracranial temperature has not
been significantly reduced either. Thus if core trunk temperature (e.g. in the pulmonary artery,
66 Appendix 2
oesophagus, bladder or rectum) reduces with head cooling it can be inferred that the brain has
been cooled.27,38 Indeed in neonates body warming is applied to prevent too great a core body
temperature drop with head cooling.28
Therefore, for the purposes of this head cooling review, brain temperature constitutes any
intracranial temperature and body temperature is core trunk temperature measured in the
pulmonary artery, oesophagus, bladder or rectum. Core trunk temperature will be used as proxy
for brain temperature in the absence of intracranial temperature measurement. However, we
will look at all temperature measurement data in studies of head cooling for the purposes of
descriptive reporting.
Why it is important to do this review

Reviews of cooling interventions after brain injury and stroke have not differentiated between
cooling methods. Among Cochrane reviews, for example, the only review of the effectiveness
of a specific cooling intervention is that of paracetamol for fever in children.39 In the reviews of
cooling for acute stroke and of hypothermia for head injury the effect of temperature reduction
on outcome is the focus and not the method(s) of achieving this.15,40 Yet cooling methods differ
in their effectiveness and complications and as further research is undertaken it may become
more obvious that not all cooling methods are equal, and that discrimination between methods is
necessary in reviews of the effect of cooling on outcome. By confining this review to head cooling
we are correcting for inconsistencies in methodology, equipment and temperature measurement
to a greater extent than existing systematic reviews of cooling after stroke, brain injury and
cardiac arrest. Theoretically head cooling has advantages over systemic cooling because it targets
cooling where it is needed, requires less body temperature reduction relative to brain temperature
reduction and therefore may have fewer side effects. We believe a review of non-invasive head
cooling as an intervention is now warranted. If we find sufficient good quality head cooling
research on either stroke or brain injury we will review the effects separately.
Service user involvement

To date, in the UK at least, head cooling has been a research intervention and not part of normal
clinical care. As a result there have been very few adult service users of head cooling. Those
patients who have had head cooling were severely ill and heavily sedated or unconscious and
consequently unaware of the intervention. Even if we could contact them, it is therefore difficult
to know how they might contribute to this review from personal experience of head cooling.
This is why the service users engaged with so far have been those who have had a stroke or brain
injury who are known to or have been cared for by the Lead Applicant.
However, during preparation of the report, the results of the review will be presented to members
of the general public, which might include people who have had a stroke or brain injury. It will
be of value and interest to hear their views on the concept and possible use and effectiveness of
head cooling and could provide useful information for planning future trials of head cooling.
Presenting research to the community is a strategy which has been used in the US to address
emergency research without consent, so called ‘waiver of consent’, for example in the National
Acute Brain Injury Study Hypothermia II (NABIS-H II). Since head cooling is an acute
intervention for unexpected and sudden health emergencies – stroke, brain injury and cardiac
arrest – we consider this would be an appropriate way to engage with people who might be
candidates for head cooling (service users) in the future.
Aims and objectives

Our overall aim is to assess the effectiveness of non-invasive head cooling in adults after
traumatic brain injury and stroke.

In order to achieve this we intend:
Firstly, to address the explanatory, mechanistic question of what the cooling interventions
achieve in terms of reducing brain temperature. If there is a clear effect, then we will explore
what characteristics of the intervention and/or patients are associated with the extent of brain
cooling. This objective will be informed by studies in cardiac arrest as well as those in stroke and
traumatic brain injury.
Secondly, to address the pragmatic, clinical question of what impact brain cooling has on patient
outcomes. Only the studies in stroke and traumatic brain injury will be relevant here, although
studies in cardiac arrest may highlight some potential adverse effects of cooling.
Thirdly, we aim to assess the cost effectiveness of head cooling in traumatic brain injury
and stroke.
Fourthly, we intend to present the results of the review to members of the general public in order
to hear their views on the concept and possible use and effectiveness of head cooling.
Ideally this will establish whether and to what extent head cooling is effective, in both brain
injury and stroke, and which methods are most suitable in which circumstances. However, the
degree to which we can establish this does depend on the nature and quality of the research
available. Nevertheless, we intend to provide a comprehensive picture of head cooling research
which will inform clinicians and guide researchers and which we can update as further studies
become available.
Specific objectives:
1. To assess the effects of non-invasive head cooling on:

i. intracranial temperature and/or core trunk temperature (pulmonary artery, oesophageal,
bladder, rectal)
ii. disability assessed with a validated outcome score
iii. mortality
iv. in adults after traumatic brain injury and stroke.
2. To determine any adverse effects or complications associated with head cooling or the
specific devices used.
3. To model the economic implications of managing traumatic brain injury and stroke using
head cooling.
4. To present the results of the review to members of the general public, in order to hear
their views on the concept and possible use and effectiveness of head cooling and
provide information on their views for clinicians and researchers planning to use or trial
head cooling.
5. To provide a comprehensive picture of head cooling research which will inform clinicians
and guide researchers.
Criteria for considering studies for this review

Types of studies
A record will be made of all studies or case reports in adult humans using any form of non-
invasive head cooling.
Of these only randomised controlled trials will be included in the formal analysis, but proof
of concept studies which give information on temperature reduction will be tabulated and
the temperature reduction assessed. Full blinding may not be feasible given the nature of the
68 Appendix 2
intervention but any trials in which the assessor of disability outcome was not blinded will be
excluded from the analysis. Temperature, being a concrete measure of a physiological variable, is
less susceptible to interpretation.
Types of participants
All adults (≥ 18 years) admitted to hospital with traumatic brain injury, or ischaemic or
haemorrhagic stroke, of any severity (and cardiac arrest for the purposes of assessing efficacy
of devices).
Types of intervention
Any method of non-invasive head cooling of any duration given for the purposes of fever
reduction, inducing normothermia or hypothermia, or reducing disability and mortality or
reducing intracranial pressure will be included. Studies in which direct brain cooling is combined
with another cooling intervention, excepting antipyretic drugs such as paracetamol, will
be excluded.
Types of outcome
Primary outcomes
■■ Intracranial temperature or core trunk temperature (measured in pulmonary artery,
oesophagus, bladder or rectum).
■■ All-cause mortality by end of follow-up.
■■ Outcome assessed with a validated outcome score e.g. Glasgow Outcome Scale (GOS),41
stroke scales and clinical assessment tools.42
Proxy outcomes
■■ Reduction in intracranial pressure.
■■ Improvement in biochemical markers of injury e.g. lactate/pyruvate ratio, glutamate,
cytokines.
■■ Improvement in cross-sectional imaging.
Secondary outcomes
Complications actually or possibly attributable to the head cooling intervention or the specific
device, e.g. infections, prolonged clotting time and bleeding complications, scalp damage; time
from brain injury or onset of stroke to start of cooling, cooling rate (hourly temperature reduction),
and time from injury to target temperature and from device application to achieving target
temperature. These are indicators of the effectiveness of the devices and their ease of use, e.g. how
quickly and easily they can be applied.
Note on outcome scales Typically, outcome scales are dichotomised to reflect people’s level of
dependence, although independence does not necessarily mean that a person has no residual
deficit. With the five point GOS, for example, 1 is death, scores of 2 or 3 indicate dependence
and scores of 4 or 5 independence of others in daily life. The American Heart Association Stroke
Outcome Classification is similar with levels I and II indicating independence, and III-V partial
or complete dependence. The Barthel Index on the other hand scores patients from 0 (total
dependence) to 100 (total independence) with a score of > 70 being classed as good outcome.
On the Scandinavian Stroke Scale a score of <30 points (range 0–58) has been defined as
poor outcome.43
Comparisons
Possible cooling intervention comparisons include:
■■ no cooling intervention or standard care

■■ physical cooling interventions applied systemically or to parts of the body other than the
head e.g. tepid sponging, ice packs, cooling blankets, intravascular cooling catheters
■■ pharmacological cooling interventions e.g. paracetamol, non-steroidal anti-inflammatory
drugs, cyclo-oxygenase inhibitors, ethymisole.
For evidence of temperature reduction, possible comparisons include temperature with and
without the device, temperature at baseline compared with target temperature or the lowest
temperature achieved.
Search methods for identification of studies

Support with searches has been budgeted for from the Cochrane Stroke Group Trials Search
Co-ordinator.
The planned search strategy is extensive because we suspect there is publication bias with
head cooling research. Dealing with publication bias is acknowledged to be problematic in
the Cochrane Handbook. The primary strategy is comprehensive searching, which is why our
search strategy goes beyond databases of published material. Furthermore head cooling is a
less mainstream intervention than other forms of cooling and trials may be found outside the
more usual databases. It is known, for example, that brain cooling has been used in China and
Japan and possibly South America and Russia, therefore the complete search strategy specifically
includes databases relevant to these countries. No language, publication date or publication state
restrictions will be imposed in search terms.
Databases to be searched:
■■ The Cochrane Library including: Cochrane Database of Systematic Reviews; Database

of Abstracts of Reviews of Effects; Cochrane Central Register of Controlled Trials (The
Cochrane Library 2005, Issue 1); Health Technology Assessment Database; NHS Economic
Evaluation Database.
■■ The Cochrane Injuries Group and the Cochrane Stroke Group will be asked for access
to their subject specific trials register and existing hand searches of journals and
conference proceedings.
■■ Other trials databases:
■■ Clinical Trials
■■ Current Controlled Trials
■■ Find a Clinical Trial
■■ National Research Register archive
■■ MEDLINE (January 1966 to most recent)
■■ Old MEDLINE (1950 to 1965)
■■ Ovid MEDLINE in process and other non-indexed citations
■■ EMBASE (1980 to most recent)
■■ Australasian Medical Index
■■ Chinese Biomedical Literature Database
■■ Japan Information Centre of Science and Technology
■■ Latin American Caribbean Health Sciences Literature
■■ Cumulative Index of Nursing and Allied Healthcare
■■ Scirus.
The search terms require refining but the principle employed will be to search in the first
instance for everything on the subject of head or brain cooling, aiming for sensitivity rather
than specificity. The initial search may be run without age limits in order to identify the full
range of brain cooling studies (including those in neonates), which will allow investigators
70 Appendix 2
and manufacturers involved with this technology to be identified and contacted. The titles and
abstracts of the studies found will then be searched to retrieve those which include adults with
traumatic brain injury or stroke or cardiac arrest.
Possible MEDLINE search terms:
1. ((brain or head or crani$or skull or cerebral or cortex or cortical or scalp or face or nasal or
nose or nasopharyngeal or airways) adj2 (cool$or cold or hypothermia)).mp.
2. limit 1 to humans
3. limit 2 to (“adult (19 to 44 years)” or “middle age (45 to 64 years)” or “middle aged (45 plus
years)” or “all aged (65 and over)” or “aged (80 and over)”)
Because the devices used for head cooling are varied and described in a number of different ways
it is likely to be unhelpful to search more specifically e.g. for helmets, caps, fans, etc.
‘Grey’ literature:
■■ Google Scholar: search with the exact phrases i) ‘head cooling’ and ii) ‘brain cooling’. Include
subject areas: biology, life sciences, and environmental science; engineering, computer
science and mathematics; medicine, pharmacology and veterinary science.
■■ Russian Academy of Science.
■■ Patent offices: UK Intellectual Property Office, European Patent Office, US Patent and
Trademark Office.
Reference lists:
■■ Reference lists of textbooks on hypothermia, traumatic brain injury and stroke, of reviews
and of relevant studies will be searched.
Correspondence:
■■ Investigators involved in previous studies, manufacturers of cooling equipment and persons

who have lodged patents for head cooling devices will be contacted.
Methods of the review

Some consultancy support has been budgeted for from the Cochrane Stroke Group.
Trial identification and selection

1. BH will conduct the searches and screen out from the results anything unrelated to non-
invasive head cooling, resolving uncertainty by discussion with PJDA. Any studies which
include head cooling as an intervention, regardless of reason for use, will be kept. This
will identify manufacturers of equipment, and possible complications and difficulties
with head cooling as a technology. The references of these studies will be searched. From
the information obtained in this initial screen BH will undertake the correspondence as
outlined above.
2. BH will screen the results from stage 1 for any reports on head cooling in traumatic brain
injury or stroke, resolving uncertainty by discussion with PJDA. Studies in other disease
states, e.g. cardiac arrest, will be kept if they can add to information about the efficacy of
devices in reducing temperature, their ease of use and side effects and contribute to the
exploratory analysis.
3. BH and PJDA will independently screen titles and abstracts of the reports resulting from
stage 2. Final identification for inclusion for formal analysis will be randomised controlled

trials of non-invasive head cooling in traumatic brain injury or stroke. Disagreements at any
stage will be resolved by discussion and consulting with GDM if necessary. Non-English
studies selected for inclusion will be translated. If more than one report of a trial is found all
will be included in order to facilitate complete data extraction.
4. Studies not suitable for inclusion for the formal primary and secondary analysis will be
reviewed for information suitable for exploratory analysis.
Data extraction
BH and PJDA will independently extract data using a standard form with disagreements resolved
by consultation with GDM. They will not be blinded to authors, journal or results. Where
multiple reports of a trial are included any discrepancies between the reports will be noted. If
there is missing information investigators of included trials will be written to.
The data to be collected will include: study name/ID; methods; participants – mechanism
of injury, age, gender, total number randomised, total randomised to each group, baseline
temperature ; interventions being tested – cooling methods and devices, target temperature,
duration of cooling; outcomes – intracranial and/or core trunk temperature attained, mortality,
dependency. Also information on the proxy and secondary outcomes listed above.
Quality assessment (assessment of validity of included studies)

The quality of the included studies will be assessed as part of the data collection procedure
(above) with regard to:
■■ adequacy of the randomization process

■■ adequacy of the allocation concealment process
■■ potential for selection bias after allocation
■■ level of masking (treatment provider, patient, outcome assessor, investigators and analysers
of the data).
The following quality checklist, developed by the Cochrane Renal Group,44 will be used (the
Cochrane Stroke Group does not have such a checklist):
■■ Allocation concealment:
–– A. Adequate – randomisation method described that would not allow investigator or
participant to know or influence intervention group before eligible participant entered in
the study.
–– B. Unclear – Randomisation stated but no information on method used is available.
–– C. Inadequate – Method of randomisation used such as alternate medical record
numbers or unsealed envelopes; any information in the study that indicated that
investigators or participants could influence the intervention group.
■■ Blinding:
–– Blinding of investigators: Yes/No/not stated
–– Blinding of participants: Yes/No/not stated
–– Blinding of outcome assessor: Yes/No/not stated
–– Blinding of data analysis: Yes/No/not stated
–– The above are not considered blinded if the treatment group can be identified in > 20%
of participants because of the side effects of treatment.
■■ Intention to treat:
–– Yes – specifically reported by the authors that intention-to-treat analysis was undertaken
and this was confirmed on study assessment.
–– Yes – not stated, but confirmed on study assessment.
72 Appendix 2
–– No – not reported and lack of intention-to-treat analysis confirmed on study assessment.

(Patients who were randomised were not included in the analysis because they did not
receive the study intervention, they withdrew from the study, or were not included
because of protocol violation).
–– No – stated but not confirmed upon study assessment.
–– Not stated.
■■ Completeness of follow-up:
–– Per cent of patients excluded or lost to follow-up.
Only randomised controlled trials which meet the study quality criteria, having obtained
missing data from the investigators if necessary, will be included in the formal analysis, taking
into account that blinding of investigators and participants to head cooling may not be feasible.
But any trials in which the assessor of disability outcome was not blinded will be excluded from
the analysis.
We plan to pace our work in order to spend sufficient time on the review in the early stages
so that the searches can be conducted and researchers written to as soon as possible to allow
maximum time for follow up. If there is ultimately still reasonable doubt over the quality of
studies we will not include them in the formal analysis, although we will log them in the interests
of a better description of this field of research. We intend that this should be an ongoing review
and will continue to pursue delayed information for inclusion in updates.
Data analysis
Primary analysis
For temperature data the difference in means will be calculated with 95% confidence intervals.
If there are sufficient good quality trials for a meta-analysis a weighted mean difference will be
calculated. Pooled relative risk and 95% confidence intervals for all-cause mortality and good
neurological outcome will be calculated using a random-effects model. Statistical heterogeneity
will be assessed using the chi-squared test.
It is likely to be appropriate to conduct sensitivity analyses of some aspects of head cooling, in

relation to all-cause mortality for example, but it is difficult to prespecify these precisely. Factors
which may be relevant include target temperature, cooling rate/time to target temperature,
duration of cooling and rate of rewarming.
All analyses and forest plots will be stratified for stroke versus traumatic brain injury, and versus
cardiac arrest for studies looking at temperature as the outcome. Observational data will be
tabulated as a descriptive record of available information but no attempt will be made to draw
any statistical inference.
Secondary analysis
The secondary analysis will assess the effect of cooling on proxy outcomes (intracranial pressure,
biochemical markers of injury, cross-sectional imaging).
Subgroup analyses
It is desirable to prespecify a limited number of relevant subgroup analyses but we are totally
dependent upon the data the trial authors have collected and reported. Based on the existing
literature all our specified sub-group analyses are of potential interest but in practice we are only
likely to have data to investigate one or two in any detail. Which ones we are ultimately able to
investigate will depend on the trials which are suitable for inclusion, as will the precise definitions
of the subgroup criteria which will of necessity be determined by the available data.

Almost all of the analyses will be descriptive, with forest plots stratified where possible by
relevant subgroups. If sufficient high quality studies can be identified then it will be possible to
explore subgroup effects more formally using meta-regression techniques, i.e. modelling how
study characteristics (relating to the patients or the interventions) impact upon the results.
Pre-specified subgroup analyses:
■■ Target temperature :
–– normothermia versus hypothermia,
–– mild versus moderate hypothermia.
(But definitions of these temperature ranges are not always consistent and therefore studies may
have non-equivalent target temperature ranges.45)
■■ Cooling duration, e.g. 24 hrs or less, 24 to 48 hrs, > 48 hrs. Time from injury to achieving
target temperature, e.g. within 6 hours, 12 hours, more than 12 hours.
■■ Rewarming strategy:
–– passive versus active,
–– rate of rewarming – if this data is available this would be the preferable analysis.
■■ Pharmacological adjuncts to physical cooling:

–– paracetamol versus no paracetamol,
–– any pharmacological cooling versus no pharmacological cooling.
■■ Head cooling method:

–– head versus head and neck,
–– temperature controlled devices versus methods without temperature control,
–– heat loss from the upper airways versus heat loss through the skull.
■■ ICP management strategy:

–– barbiturates versus no barbiturates.
In addition to the above there are other factors which would be relevant for subgroup analysis if
there is data, for example complications and adverse events, cooling rate (°C per hour), age > 60
versus 60 or younger in traumatic brain injury (there is a significant increase in poor outcome
above 60 years30).
Exploratory analysis
Studies not suitable for inclusion for formal analysis will be reviewed for information relating to
the primary, proxy and secondary outcomes, temperature reduction in particular, and this will be
tabulated and assessed.
Publication bias
We will attempt to assess publication bias using funnel plots as suggested in the
Cochrane Handbook.
Costs and economic analysis

The aim of the economic analysis is to assess the cost effectiveness of head cooling. The
perspective is the NHS and the relevant comparisons will include no use of head cooling
versus head cooling protocols for selected patient groups. The economic implications of
managing traumatic brain injury and stroke using direct brain cooling will be modelled using
a discrete event simulation model, rather than a simple cohort simulation model based on a
74 Appendix 2
Markov process. The primary justification for the discrete event simulation model is the very
different patient sub-groups who undergo direct brain cooling and the variability in baseline
characteristics, history, prognosis and expected health outcomes and resource costs. This will
allow more realistic modelling of virtual patient histories which are summarised to permit
estimates of resource costs and other treatment effects measured in terms of survival and
health related quality of life. Discrete event simulation has been used in a wide range of studies
examining new health technologies,46 including an investigation of the impact of selective health
cooling in a perinatal population.47
The model will be developed to compare different policies and guidelines for patient selection,
choice of technique and clinical setting for head cooling. Comparisons will include: no use
of head cooling and scenarios that add a cooling protocol to patient management. Particular
attention will be placed on how a cooling protocol could be introduced and scaled up to
accommodate a wider range of patients treated in critical care and other clinical units where head
cooling is feasible (e.g. acute stroke units).
The short run input parameters into the simulation will be obtained from the systematic overview
of the literature on treatment effects following head cooling. These will be combined with generic
estimates of key parameters for medium and longer run events for patients following traumatic
brain injury and stroke. Trauma and stroke care are both areas of medicine where existing
predictive models and the factors influencing survival and health related quality of life are
relatively well understood. Our plan is to calibrate the discrete event simulation with information
drawn from population based studies of functional outcomes following traumatic brain injury,48
comparisons of outcomes observed for brain injury and stroke patients49 and longitudinal studies
of patients with hypoxia of cardiac aetiology.
The introduction of head cooling will have direct and indirect effects on the organisation and
use of resources in critical care and other acute hospital settings. The human resources and the
equipment needed to monitor, induce and maintain hypothermic patients will be quantified
and valued using estimates based on a synthesis of reports derived from published literature and
unpublished material related to the costs of equipment acquisition and maintenance. Building
on our experience gained in an earlier HTA project where we modelled the costs and effects of
thrombolysis with recombinant tissue plasminogen activator for acute ischemic stroke,50,51 this
information will be complemented by expert opinion on the expected resource consequences
arising from the effects of head cooling on acute hospital pathways measured in terms of the
intensity and duration of care. We will populate the model initially with parameter values based
on our knowledge of resource requirements and then validate the base case and distributions
using expert concurrence from specialists with a particular interest in and experience of head
cooling who we will survey using our network of research contacts. Sensitivity analysis will be
conducted using both scenario analysis, allowing sub-sets of model parameters to vary according
to key clinical and economic decisions involving the numbers and case-mix of patients who are
head cooled, and probabilistic sensitivity analysis for patient level simulation models using the
approach of O’Hagen, Stevenson and Madan.52
With the same caveats as those outlined under subgroup analysis above, our prespecified
economic subgroup analyses are:
■■ Time from injury to achieving target temperature, e.g. within 6 hours, 12 hours, more
than 12 hours.
■■ Treatment in specialist unit versus not. Specialist units would include those specialising in
neuro or critical care; there is some evidence that they have better outcomes and are more
cost effective.53,54

Research governance
The sponsor for this systematic review is the University of Edinburgh.
Time-chart for major activities (in months)

1–14 Searches for published and unpublished studies
2–4 Pilot test of inclusion criteria
4–14 Inclusion assessments
3–4 Pilot test of validity criteria
4–14 Validity assessments
3–4 Pilot test of data collection
4–14 Data collection
4–14 Data entry
5–16 Missing information
14–17 Analysis
1–18 Preparation of report
Expertise
Bridget Harris will manage the project, carry out the searches, write to investigators and
manufacturers, screen studies for inclusion, extract data, carry out the analyses and write the
report. She will be supervised and assisted by Professor Andrews and Professor Murray with
whom she has worked and published before in a similar balance of roles.
Professor Andrews will give support with project management, screening of studies for inclusion,
extraction of data and assist with writing the report.
Professor Murray will give statistical and methodological advice and support, assist in the event
of uncertainty and disagreements over screening of studies and data extraction and with writing
the report.
Dr Forbes will supervise the economics analysis by an economics/operations research graduate

with experience of decision modelling, and contribute to the report.
We have links with the Cochrane Stroke Group who are based locally and have negotiated
access to support from them. We also have links with the Cochrane Injuries Group as Professor
Andrews is a reviewer.
Justification of support required

We are asking for salary for Bridget Harris (6 months WTE MH50, 70) and a contribution to
time for Professor Andrews (6 weeks WTE), Professor Murray and Dr Forbes (4 weeks WTE
each) over the 18 months we expect it will take us to complete the review. We believe this
represents good value because we are deploying our time and expertise cost-effectively, with the
least expensive member of the team (the lead applicant) having the largest workload but well
supervised by the more experienced members with their excellent specialist skills.
The only NHS costs are Professor Andrews’ time which is costed at current Consultant
National Rates.
Seven days consultancy costs for members of the Cochrane Stroke Group at £300/day are
required for support with searches and conduct of the review (total £2100).
76 Appendix 2
Dr Forbes will supervise the economic analysis with ten days assistance from an economics/
operations research graduate with experience of decision modelling at £300/day (total £3000).
For this analysis a software license (TreeAge Pro Suite) is required at a cost of £350.
We have estimated £3000 for translation costs. This is based on possibly requiring 6 papers of
3–3500 words each to be translated at a cost of £150/1000 words. It is hard to obtain translation
costs without having the papers, but the cost/1000 words is based on discussion with the
Cochrane Stroke Group, the School of Literature, Languages and Culture at the University of
Edinburgh and commercial translating services.
We have estimated £300 for interlibrary loans and photocopying, although we aim to work
electronically whenever possible in order to reduce paper use and avoid adding to greenhouse
gas emissions.
Any study on brain or head cooling

in humans identified and screened
for retrieval
Non-RCTs, studies in conditions other than

traumatic brain injury and stroke and in babies
and children will be retrieved to include in the
exploratory analysis on the efficacy of devices
in reducing temperature and their side effects –
simple tabulation may be all that is possible
RCTs in traumatic brain injury and

stroke in adults retrieved for more
detailed evaluation
RCTs excluded which give no information

on the effect of head cooling on primary and
proxy outcomes. Those which include
information on secondary outcomes, i.e.
complications due to head cooling and cooling
times, will be kept for inclusion in exploratory
analysis – simple tabulation may be all that is
possible
Potentially appropriate RCTs to be

included in the meta-analysis are
those which include information on
primary or proxy outcomes, i.e. brain
or body temperature, disability and
death, intracranial pressure,
biochemical markers,
cross-sectional imaging
FIGURE 1 Flow diagram. Based on the QUORUM statement.55

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Appendix 3
Search strategies
Major international medical bibliographic databases
MEDLINE 1950 to 12 March 2011 (last update)

Summary of search terms
1-8 = cooling/cooling therapies
10-15 = head/brain
18 = cooling/cooling therapies AND head/brain limited to human
19-23 = stroke
24-29 = traumatic brain injury
30-32 = cardiac arrest
33-42 = neonatal hypoxic ischaemic encephalopathy
45-47 = citations indexed as neither human nor animal
Running the search to line 18, i.e. cooling/cooling therapies AND head/brain limited to human
in MEDLINE 1950 to March Week 3 2010 produced 17,088 results. This was judged too many
to manage, so the search was made more specific by including selection terms for stroke, TBI,
cardiac arrest and neonatal hypoxic ischaemic encephalopathy.
During the process of developing and refining the MEDLINE search terms, it became apparent
that there were some studies that were not indexed as either human or animal, although some
were in fact human. Therefore, the final version of the search terms included a strategy to capture
these ‘not human not animal’ studies in order that human studies that were not indexed as
‘human’ did not get missed.
Search terms
1. hypothermia/ or hypothermia, induced/ or cryotherapy/
2. cold temperature / or ice/ or refrigeration/ or extreme cold/ or fever/th
3. (hypotherm$ or normotherm$).tw.
4. ((low or lower or reduc$) adj5 temperature $).tw.
5. (cool$ or cold or chill$ or RapidCool or QuickCool or Rhinochill or Benechill or
CoolSystems).tw.
6. (fan or fans or fanned or fanning).tw.
7. (cryother$ or cryogen$ or cryotreat$).tw.
8. (ice or icy or iced or ice-pack or icepack or refrigerat$ or froz$ or freez$).tw.
9. or/1-8
10. exp brain/ or exp head/ or exp skull/
11. (head or crani$ or skull or scalp or face).tw.
12. (brain or intracranial or cerebral or cerebrocranial or cortex or cortical or forebrain or
hemispher$).tw.
13. (neck or pharyn$ or nasopharyn$ or naso-pharyn$ or airway$).tw.
14. (intra-nasal or intranasal or nasal or transnasal or trans-nasal or nose or nostril$ or naso-
oral or nasooral or oro-nasal or oronasal).tw.
15. (hat or helmet or cap or hood or collar).tw.
16. or/10-15
82 Appendix 3
17. 9 and 16
18. limit 17 to humans
19. cerebrovascular disorders/ or exp basal ganglia cerebrovascular disease/ or exp brain
ischemia/ or exp carotid artery diseases/ or exp cerebrovascular trauma/ or exp intracranial
arterial diseases/ or exp “intracranial embolism and thrombosis”/ or exp intracranial
hemorrhages/ or stroke/ or exp brain infarction/ or vasospasm, intracranial/ or vertebral
artery dissection/
20. (stroke or poststroke or post-stroke or cerebrovasc$ or brain vasc$ or cerebral vasc$ or cva$
or apoplex$ or SAH).tw.
21. ((brain$ or cerebr$ or cerebell$ or cortical or vertebrobasilar or hemispher$ or intracran$ or
intracerebral or infratentorial or supratentorial or MCA or anterior circulation or posterior
circulation or basal ganglia) adj5 (isch?emi$ or infarct$ or thrombo$ or emboli$ or occlus$
or hypox$ or vasospasm)).tw.
22. ((brain$ or cerebr$ or cerebell$ or intracerebral or intracran$ or parenchymal or
intraventricular or infratentorial or supratentorial or basal gangli$ or subarachnoid) adj5
(haemorrhage$ or hemorrhage$ or haematoma$ or hematoma$ or bleed$)).tw.
23. or/19-22
24. craniocerebral trauma/ or brain injuries/ or exp brain concussion/ or exp brain hemorrhage,
traumatic/ or diffuse axonal injury/ or epilepsy, post-traumatic/
25. coma, post-head injury/ or exp head injuries, closed/ or head injuries, penetrating/ or exp
intracranial hemorrhage, traumatic/ or exp skull fractures/ or brain edema/
26. ((head or crani$ or cerebr$ or capitis or brain$ or forebrain$ or skull$ or hemispher$ or
intra-cran$ or inter-cran$) adj5 (injur$ or trauma$ or damag$ or wound$ or fracture$ or
contusion$)).tw.
27. ((brain or cerebral or intracranial) adj5 (edema or oedema or swell$)).tw.
28. (TBI or diffuse axonal injur$).tw.
29. or/24-28
30. heart arrest/ or exp heart failure/ or exp cardiopulmonary resuscitation/ or resuscitation/ or
heart massage/
31. ((cardiac or heart or cardiopulmonary or cardio pulmonary or cardio-pulmonary or
circulat$) adj5 (arrest or resuscita$ or massage or life support or reanimat$)).tw.
32. 30 or 31
33. Hypoxia-Ischemia, Brain/
34. ((brain or cerebral or global) adj (hypox$ or anox$) adj (ischaemi$ or ischemi$)).tw.
35. ((hypox$ or anox$) adj (ischaemi$ or ischemi$) adj encephalopath$).tw.
36. hypoxia, brain/ or asphyxia neonatorum/
37. ((birth or newborn or encephalopath$) adj5 (asphyxia$ or respiratory failure)).tw.
38. or/33-37
39. Exp infant, newborn/
40. (birth or infant$ or neonat$ or newborn$ or new born$ or perinatal or peri-natal or baby or
babies).tw.
41. 39 or 40
42. 38 and 41
43. 23 or 29 or 32 or 42
44. 18 and 43
45. 17 and (23 or 29 or 32 or 42) [ = everything including human]
46. 45 NOT 44
47. 46 NOT (humans/ or animals/)

OLDMEDLINE 1948–65
Search date: 4 April 2010.
Search terms
1. hypothermia/ or hypothermia, induced/ or cryotherapy/
2. cold temperature / or ice/ or refrigeration/ or extreme cold/ or fever/th
CoolSystems).tw.
9. or/1-8
10. exp brain/ or exp head/ or exp skull/
11. (head or crani$ or skull or scalp or face).tw.
hemispher$).tw.
16. or/10-15
17. 9 and 16
EMBASE 1980 to 2011 week 10

Last update: 12 March 2011.
The same issue with studies not indexed as either human or animal occurred in EMBASE as in
MEDLINE and lines 48–53 in the search were added to capture these.
Search terms
1. hypothermia/ or induced hypothermia/ or profound induced hypothermia/ or chill/ or
shivering/ or cryotherapy/ or low temperature / or low temperature procedures/
2. cold/ or cold air/ or cold exposure/ or cold treatment/ or cooling/ or cooling water/ or ice/ or
freezing/ or fever/th
CoolSystems).tw.
9. or/1-8
10. exp brain/ or exp head/ or exp skull/ or exp neck/ or exp pharynx/
11. (head or cranium or crani$ or skull or scalp or face).tw.
hemispher$).tw.
84 Appendix 3
15. helmet/ or (hat or helmet or cap or hood or collar).tw.

16. or/10-15
17. 9 and 16
18. limit 17 to human
19. cerebrovascular disease/ or basal ganglion hemorrhage/ or brain hematoma/ or brain
hemorrhage/ or brain infarction/ or brain ischemia/ or carotid artery disease/ or cerebral
artery disease/ or cerebrovascular accident/ or intracranial aneurysm/ or occlusive
cerebrovascular disease/ or stroke/ or stroke patient/ or stroke unit/
23. or/19-22
24. head injury/ or brain injury/ or traumatic brain injury/ or skull injury/ or brain concussion/
or brain contusion/ or brain damage/ or brain stem injury/ or cerebellum injury/ or diffuse
axonal injury/
25. exp skull fracture/ or postconcussion syndrome/ or traumatic epilepsy/ or coma/ or exp skull
fracture/ or brain edema/
contusion$)).tw.
29. or/24-28
30. exp heart failure/ or heart arrest/ or resuscitation/ or heart massage/
32. 30 or 31
33. brain ischemia/ or brain hypoxia/
36. (encephalopath$ adj5 (asphyxia$ or respiratory failure)).tw.
37. 33 or 34 or 35 or 36
38. exp newborn/
babies).tw.
40. 38 or 39
41. 37 and 40
42. newborn hypoxia/
43. ((birth or newborn or new born or neonat$) adj5 (asphyxia$ or hypoxia or respiratory
failure)).tw.
44. 42 or 43
45. 41 or 44
46. 23 or 29 or 32 or 45
47. 18 and 46
48. 17 and 46 [main search not restricted to human]

50. limit 48 to animals

51. limit 48 to animal studies
52. 49 or 50 or 51
53. 48 not 52
EMBASE Classic 1947–79

Search date: 13 May 2010.
During development of these search terms it was found necessary to add a strategy to increase
removal of animal studies (line 49).
Search terms
1. hypothermia/ or induced hypothermia/ or profound induced hypothermia/ or chill/ or
shivering/ or cryotherapy/ or low temperature / or low temperature procedure/
2. cold/ or cold air/ or cold exposure/ or cold treatment/ or cooling/ or cooling water/ or ice/ or
freezing/ or fever/th
CoolSystems).tw.
9. or/1-8
10. exp brain/ or exp head/ or exp skull/ or exp neck/ or exp pharynx/
11. (head or cranium or cranial or skull or scalp or face).tw.
12. (brain or intracranial or cerebral or cortex or cortical or forebrain or hemispher$).tw.
15. helmet/ or (hat or helmet or cap or hood or collar).tw.
16. or/10-15
17. 9 and 16
19. cerebrovascular disease/ or basal ganglion hemorrhage/ or brain hematoma/ or brain
hemorrhage/ or brain infarction/ or brain ischemia/ or carotid artery disease/ or cerebral
artery disease/ or cerebrovascular accident/ or intracranial aneurysm/ or occlusive
cerebrovascular disease/ or stroke/ or stroke patient/ or stroke unit/
23. or/19-22
24. head injury/ or brain injury/ or traumatic brain injury/ or skull injury/ or brain concussion/
or brain contusion/ or brain damage/ or brain stem injury/ or cerebellum injury/ or diffuse
axonal injury/
86 Appendix 3
25. exp skull fracture/ or postconcussion syndrome/ or traumatic epilepsy/ or coma/ or exp skull
fracture/ or brain edema/
contusion$)).tw.
29. or/24-28
30. exp heart failure/ or heart arrest/ or resuscitation/ or heart massage/
32. 30 or 31
33. brain ischemia/ or brain hypoxia/
36. (encephalopath$ adj5 (asphyxia$ or respiratory failure)).tw.
37. 33 or 34 or 35 or 36
38. exp newborn/
babies).tw.
40. 38 or 39
41. 37 and 40
42. newborn hypoxia/
43. ((birth or newborn or new born or neonat$) adj5 (asphyxia$ or hypoxia or respiratory
failure)).tw.
44. 42 or 43
45. 41 or 44
46. 23 or 29 or 32 or 45
47. 18 and 46
48. 17 and 46
49. (rat or rats or cat or cats or dog or dogs or gerbil or gerbils or rabbit or rabbits or baboon or
baboons).ti.
50. 48 not 49
Cumulative Index of Nursing and Allied Healthcare (CINAHL) 1937 to

6 April 2010
This search was conducted through EBSCO therefore no disease terms were included because
these make the search too complex for EBSCO.
Search terms
S18 S10 and S17
S17 S11 or S12 or S13 or S14 or S15 or S16
S16 TI ((hat or helmet or cap or hood or collar)) or AB ((hat or helmet or cap or hood or collar))
S15 TI ((intra-nasal or intranasal or nasal or transnasal or trans-nasal or nose or nostril* or
naso-oral or nasooral or oro-nasal or oronasal) ) or AB ( (intra-nasal or intranasal or
nasal or transnasal or trans-nasal or nose or nostril* or naso-oral or nasooral or oro-nasal
or oronasal))
S14 TI ((neck or pharyn* or nasopharyn* or naso-pharyn* or airway*)) or AB ((neck or pharyn*
or nasopharyn* or naso-pharyn* or airway*))
S13 TI ((brain or intracranial or cerebral or cortex or cortical or forebrain or hemispher*)) or AB
((brain or intracranial or cerebral or cortex or cortical or forebrain or hemispher*))
S12 TI ((head or cranium or cranial or skull or scalp or face)) or AB ((head or cranium or cranial
or skull or scalp or face))

S11 (MH “Brain+”) or (MH “Head+”) or (MH “Skull+”)

S10 (S1 or S2 or S3 or S4 or S5 or S6 or S7 or S8 or S9)
S9 TI ((hypotherm* or normotherm*)) or AB ( (hypotherm* or normotherm*))
S8 TI ((ice or icy or iced or ice-pack or icepack or refrigerat* or froz* or freez*)) or AB ((ice or
icy or iced or ice-pack or icepack or refrigerat* or froz* or freez*))
S7 TI ((cryother* or cryogen* or cryotreat*)) or AB ((cryother* or cryogen* or cryotreat*))
S6 TI ((fan or fans or fanned or fanning)) or AB ((fan or fans or fanned or fanning))
S5 TI ((cool* or cold or chill* or RapidCool or QuickCool or Rhinochill or Benechill or
CoolSystems)) or AB ((cool* or cold or chill* or RapidCool or QuickCool or Rhinochill or
Benechill or CoolSystems))
S4 TI ((low* N5 temperature *) or (reduc* N5 temperature *)) or AB ((low* N5 temperature *)
or (reduc* N5 temperature *))
S3 (MH “Shivering”)
S2 (MH “Cryotherapy”) or (MH “Cold+”) or (MH “Ice”) or (MH “Refrigeration”) or (MH
“Fever/TH”)
S1 (MH “Hypothermia”) or (MH “Hypothermia (NANDA)”) or (MH “Hypothermia (Saba
CCC)”) or (MH “Hypothermia, Induced”)
British Nursing Index (BNI) and BNI Archive 1985 to May 2010
(last update)
Search terms
1. hypothermia/
CoolSystems).tw.
8. or/1-7
During the development process this search was run with the addition of head terms but in the
end the search with hypothermia/cooling terms alone (as above) was used for the review because
there was some concern that relevant papers were being missed when head terms were added.
However, when the two sets of results were compared it turned out that no trials were missed
by including head terms, i.e. the search was sufficiently sensitive, therefore in future both sets of
terms could be used, as follows, which will increase specificity:
1. hypothermia/
CoolSystems).tw.
8. or/1-7
9. (head or cranium or cranial or skull or scalp or face).tw.
10. (brain or intracranial or cerebral or cortex or cortical or forebrain or hemispher$).tw.
88 Appendix 3

14. or/9-13
15. 8 and 14 (set downloaded)
16. 8 not 15 (set downloaded)
Web of Science Conference Proceedings Citation Index-Science

(CPCI-S) 1990 to 19 July 2010
After some initial investigation the search was confined to conference proceedings and did not
include science citations, as these were likely to be found on other databases.
Search terms
Topic (i.e. title, abstract, keywords, authors’ keywords), selected for each search line
Timespan all years
brain same hypotherm* or brain same cool*
Or
head same hypotherm* or head same cool*
Refine by subject area – the following subject areas were included (the number of results in each
area are shown, which facilitates the decision on what to include):
Clinical neurology
Surgery
Critical care medicine
Neurosciences
Cardiac & cardiovascular systems
Respiratory system
Thermodynamics
Engineering, electrical & electronic
Emergency Medicine
Multidisciplinary sciences
Anesthesiology
Engineering, biomedical
Physiology
Medicine, research & experimental
Medicine, general & internal
Neuroimaging
Engineering, multidisciplinary
Zetoc Conference Proceedings

Last update: 8 August 2010.
Search limited to conference proceedings because Journals are covered by MEDLINE and other
databases searched.
Searched separately for the following terms in ‘all fields’: brain hypotherm*, head hypotherm*,
brain cool*, head cool*
ProQuest Dissertations & Theses (PQDT)

Search terms: brain OR head AND cooling OR hypothermia in title

Last update: CENTRAL, DARE, HTA, NHS EED 2011 Issue 1.

Last update: CDSR 2011 Issue 3.
Cochrane Central Register of Controlled Trials (CENTRAL)

Cochrane Database of Systematic Reviews (CDSR)
Database of Abstracts of Reviews of Effects (DARE)
Health Technology Assessment (HTA) database
NHS Economic Evaluation Database (EED)
Search terms for CENTRAL (search terms for CDSR, DARE, HTA, EED based on CENTRAL
search terms):
#1 MeSH descriptor hypothermia this term only

#2 MeSH descriptor hypothermia, induced this term only
#3 MeSH descriptor cryotherapy this term only
#4 MeSH descriptor Cold Temperature this term only
#5 MeSH descriptor Ice this term only
#6 MeSH descriptor Refrigeration this term only
#7 MeSH descriptor Extreme Cold this term only
#8 MeSH descriptor Fever this term only with qualifiers: TH
#9 MeSH descriptor Shivering this term only
#10 (low* in Title, Abstract or Keywords near/6 temperature * in Title, Abstract or Keywords)
#11 (reduc* in Title, Abstract or Keywords near/6 temperature * in Title, Abstract or Keywords)
#12 (hypotherm* in Title, Abstract or Keywords or normotherm* in Title, Abstract
or Keywords)
#13 (cool* in Title, Abstract or Keywords or cold in Title, Abstract or Keywords or chill* in
Title, Abstract or Keywords or RapidCool in Title, Abstract or Keywords or QuickCool in
Title, Abstract or Keywords or Rhinochill in Title, Abstract or Keywords or Benechill in
Title, Abstract or Keywords or CoolSystems in Title, Abstract or Keywords)
#14 (fan in Title, Abstract or Keywords or fans in Title, Abstract or Keywords or fanned in Title,
Abstract or Keywords or fanning in Title, Abstract or Keywords)
#15 (cryother* in Title, Abstract or Keywords or cryogen* in Title, Abstract or Keywords or
cryotreat* in Title, Abstract or Keywords)
#16 (ice in Title, Abstract or Keywords or icy in Title, Abstract or Keywords or iced in Title,
Abstract or Keywords or ice-pack in Title, Abstract or Keywords or icepack in Title,
Abstract or Keywords or refrigerat* in Title, Abstract or Keywords or froz* in Title,
Abstract or Keywords or freez* in Title, Abstract or Keywords)
#17 (#1 or #2 or #3 or #4 or #5 or #6 or #7 or #8 or #9 or #10 or #11 or #12 or #13 or #14 or #15
or #16)
#18 MeSH descriptor Brain explode all trees
#19 MeSH descriptor Head explode all trees
#20 MeSH descriptor Skull explode all trees
#21 (head in Title, Abstract or Keywords or cranium in Title, Abstract or Keywords or cranial
in Title, Abstract or Keywords or skull in Title, Abstract or Keywords or scalp in Title,
Abstract or Keywords or face in Title, Abstract or Keywords)
#22 (brain in Title, Abstract or Keywords or intracranial in Title, Abstract or Keywords or
cerebral in Title, Abstract or Keywords or cortex in Title, Abstract or Keywords or cortical
in Title, Abstract or Keywords or forebrain in Title, Abstract or Keywords or hemispher* in
Title, Abstract or Keywords)
90 Appendix 3
#23 (neck in Title, Abstract or Keywords or pharyn* in Title, Abstract or Keywords or

nasopharyn* in Title, Abstract or Keywords or naso-pharyn* in Title, Abstract or Keywords
or airway* in Title, Abstract or Keywords)
#24 (intra-nasal in Title, Abstract or Keywords or intranasal in Title, Abstract or Keywords
or nasal in Title, Abstract or Keywords or transnasal in Title, Abstract or Keywords or
trans-nasal in Title, Abstract or Keywords or nose in Title, Abstract or Keywords or nostril*
in Title, Abstract or Keywords or naso-oral in Title, Abstract or Keywords or nasooral in
Title, Abstract or Keywords or oro-nasal in Title, Abstract or Keywords or oronasal in Title,
Abstract or Keywords)
#25 (hat in Title, Abstract or Keywords or helmet in Title, Abstract or Keywords or cap in Title,
Abstract or Keywords or hood in Title, Abstract or Keywords or collar in Title, Abstract
or Keywords)
#26 (#18 or #19 or #20 or #21 or #22 or #23 or #24 or #25)
#27 (#17 and #26)
#28 MeSH descriptor cerebrovascular disorders explode all trees
#29 (stroke in Title, Abstract or Keywords or poststroke in Title, Abstract or Keywords or
post-stroke in Title, Abstract or Keywords or cerebrovasc* in Title, Abstract or Keywords
or “brain vasc*” in Title, Abstract or Keywords or “cerebral vasc*” in Title, Abstract or
Keywords or cva* in Title, Abstract or Keywords or apoplex* in Title, Abstract or Keywords
or SAH in Title, Abstract or Keywords)
#30 (brain* in Title, Abstract or Keywords or cerebr* in Title, Abstract or Keywords or
cerebell* in Title, Abstract or Keywords or cortical in Title, Abstract or Keywords or
vertebrobasilar in Title, Abstract or Keywords or hemispher* in Title, Abstract or Keywords
or intracran* in Title, Abstract or Keywords or intracerebral in Title, Abstract or Keywords
or infratentorial in Title, Abstract or Keywords or supratentorial in Title, Abstract or
Keywords or MCA in Title, Abstract or Keywords or “anterior circulation” in Title, Abstract
or Keywords or “posterior circulation” in Title, Abstract or Keywords or “basal ganglia” in
#31 (isch* in Title, Abstract or Keywords or infarct* in Title, Abstract or Keywords or thrombo*
in Title, Abstract or Keywords or emboli* in Title, Abstract or Keywords or occlus* in Title,
Abstract or Keywords or hypox* in Title, Abstract or Keywords or vasospasm in Title,
#32 (#31 and #31)
#33 (brain* in Title, Abstract or Keywords or cerebr* in Title, Abstract or Keywords or
cerebell* in Title, Abstract or Keywords or intracerebral in Title, Abstract or Keywords or
intracran* in Title, Abstract or Keywords or parenchymal in Title, Abstract or Keywords
or intraventricular in Title, Abstract or Keywords or infratentorial in Title, Abstract or
Keywords or supratentorial in Title, Abstract or Keywords or “basal gangli*” in Title,
Abstract or Keywords or subarachnoid in Title, Abstract or Keywords)
#34 (haemorrhage* in Title, Abstract or Keywords or hemorrhage* in Title, Abstract or
Keywords or haematoma* in Title, Abstract or Keywords or hematoma* in Title, Abstract
or Keywords or bleed* in Title, Abstract or Keywords)
#35 (#33 and #34)
#36 (#28 or #29 or #32 or #35)
#37 MeSH descriptor Craniocerebral Trauma this term only
#38 MeSH descriptor Brain Injuries this term only
#39 MeSH descriptor brain concussion explode all trees
#40 MeSH descriptor Brain Hemorrhage, Traumatic explode all trees
#41 MeSH descriptor Diffuse Axonal Injury this term only
#42 MeSH descriptor Epilepsy, Post-Traumatic this term only
#43 MeSH descriptor Coma, Post-Head Injury this term only
#44 MeSH descriptor Head Injuries, Closed explode all trees

#45 MeSH descriptor Head Injuries, Penetrating this term only

#46 MeSH descriptor Intracranial Hemorrhage, Traumatic explode all trees
#47 MeSH descriptor skull fractures explode all trees
#48 MeSH descriptor brain edema this term only
#49 (head in Title, Abstract or Keywords or crani* in Title, Abstract or Keywords or cerebr*
in Title, Abstract or Keywords or capitis in Title, Abstract or Keywords or brain* in Title,
Abstract or Keywords or forebrain* in Title, Abstract or Keywords or skull* in Title,
Abstract or Keywords or hemispher* in Title, Abstract or Keywords or intra-cran* in Title,
Abstract or Keywords or inter-cran* in Title, Abstract or Keywords)
#50 (injur* in Title, Abstract or Keywords or trauma* in Title, Abstract or Keywords or damag*
in Title, Abstract or Keywords or wound* in Title, Abstract or Keywords or fracture* in
Title, Abstract or Keywords or contusion* in Title, Abstract or Keywords)
#51 (#49 and #50)
#52 (brain in Title, Abstract or Keywords or cerebral in Title, Abstract or Keywords or
intracranial in Title, Abstract or Keywords)
#53 (edema in Title, Abstract or Keywords or oedema in Title, Abstract or Keywords or swell*
in Title, Abstract or Keywords)
#54 (#52 and #53)
#55 (TBI in Title, Abstract or Keywords or “diffuse axonal injur*” in Title, Abstract
or Keywords)
#56 (#37 or #38 or #39 or #40 or #41 or #42 or #43 or #44 or #45 or #46 or #47 or #48 or #51 or
#54 or #55)
#57 MeSH descriptor Heart Arrest this term only
#58 MeSH descriptor Heart Failure explode all trees
#59 MeSH descriptor Cardiopulmonary Resuscitation explode all trees
#60 MeSH descriptor Resuscitation this term only
#61 MeSH descriptor Heart Massage this term only
#62 (cardiac in Title, Abstract or Keywords or heart in Title, Abstract or Keywords or
cardiopulmonary in Title, Abstract or Keywords or “cardio pulmonary” in Title, Abstract or
Keywords or cardio-pulmonary in Title, Abstract or Keywords or circulat* in Title, Abstract
or Keywords)
#63 (arrest in Title, Abstract or Keywords or resuscita* in Title, Abstract or Keywords or
massage in Title, Abstract or Keywords or “life support” in Title, Abstract or Keywords or
reanimat* in Title, Abstract or Keywords)
#64 (#62 and #63)
#65 (#57 or #58 or #59 or #60 or #61 or #64)
#66 MeSH descriptor Hypoxia-Ischemia, Brain this term only
#67 MeSH descriptor Hypoxia, Brain this term only
#68 MeSH descriptor Asphyxia Neonatorum this term only
#69 (brain in Title, Abstract or Keywords or cerebral in Title, Abstract or Keywords or global in
#70 (hypox* in Title, Abstract or Keywords or anox* in Title, Abstract or Keywords)
#71 (ischaemi* in Title, Abstract or Keywords or ischemi* in Title, Abstract or Keywords)
#72 (#69 and #70 and #71)
#73 (hypox* in Title, Abstract or Keywords or anox* in Title, Abstract or Keywords)
#74 (ischaemi* in Title, Abstract or Keywords or ischemi* in Title, Abstract or Keywords)
#75 encephalopath* in Title, Abstract or Keywords
#76 (#73 and #74 and #75)
#77 (birth in Title, Abstract or Keywords or newborn in Title, Abstract or Keywords or
encephalopath* in Title, Abstract or Keywords)
#78 (asphyxia* in Title, Abstract or Keywords or “respiratory failure” in Title, Abstract
or Keywords)
92 Appendix 3
#79 (#77 and #78)

#80 (#66 or #67 or #68 or #72 or #76 or #79)
#81 MeSH descriptor Infant, Newborn explode all trees
#82 (birth in Title, Abstract or Keywords or infant* in Title, Abstract or Keywords or neonat*
in Title, Abstract or Keywords or newborn* in Title, Abstract or Keywords or “new born*”
in Title, Abstract or Keywords or perinatal in Title, Abstract or Keywords or peri-natal
in Title, Abstract or Keywords or baby in Title, Abstract or Keywords or babies in Title,
#83 (#81 or #82)
#84 (#80 and #83)
#85 (#36 or #56 or #65 or #84)
#86 (#27 and #85)
Cochrane Injuries Group

Search date: 14 June 2010.
Search terms: (head or brain or intracranial or cerebral or cerebrocranial or cortex or cortical

or forebrain or hemisphere*) and ((Hypotherm* or normotherm* or cryother* or cryogen* or
cryotreat*) or ((low or lower* or reduc*) and temperature *))
Cochrane Stroke Group

Search date: 5 May 2010.
Search codes: Search method:1; Stage: Not specified; Condition: Not specified; Intervention type:
OTHER; Intervention code: hypothermia
Other trial registers
Last update: 6 March 2011 all registers.
Search terms: hypothermia and cooling (cool* where truncation was allowed); both terms were
searched for separately if OR was not an option.
Ongoing trials were only included as relevant if in stroke or TBI. Trials in cardiac arrest and
neonatal HIE which had not completed were excluded.
■■ World Health Organization International Clinical Trials Registry Platform (WHO ICTR) –
this includes:
–– Australian New Zealand Clinical Trials Registry
–– Chinese Clinical Trial Registry
–– Clinical Trials Registry – India
–– Clinical Research Information Service - Republic of Korea
–– German Clinical Trials Register
–– Iranian Registry of Clinical Trials
–– Japan Primary Registries Network
–– Pan African Clinical Trial Registry
–– Sri Lanka Clinical Trials Registry

–– The Netherlands National Trial Register.

–– [Note: Each of the databases in WHO ICTR was searched individually because Brenda
Thomas (Trials Search Co-ordinator Cochrane Stroke Group) had found that when the
whole WHO ICTR was searched there were fewer results than when each element was
searched individually.]
■■ Current Controlled Trials: the meta-register of controlled trials and International Standard
Randomised Controlled Trial Number (ISRCTN) register
■■ ClinicalTrials.gov
■■ National Research Register archive
■■ Stroke Trials Registry.
Informit Health Collection

As of 1 January 2010 this replaced and includes the Australasian Medical Index
Last update: 6 February 2011.
Search terms: hypothermia OR cool* in title with no limits.
China Academic Journals (CAJ) Medicine and public health

(hygiene) database in China Academic Journals
This forms part of the China National Knowledge Database (CNKI). CNKI is considered the
Chinese equivalent of PubMed and China Academic Journals (CAJ) is the most comprehensive,
full-text database of Chinese journals in the world, starting from 1915.
Last update: 14 January 2011.
Search terms – these were devised to work with head-cooling terms which are compatible with
translation from Chinese (including Google Translate):
In title (matching = precise) for:
brain cooling or head cooling

brain hypothermia or head hypothermia
local hypothermia or local cooling
focal hypothermia or focal cooling
selective hypothermia or selective cooling
focal moderate hypothermia or focal moderate hypothermia
cerebral hypothermia or cerebral cooling
cerebral cryotherapy or brain cryotherapy or head cryotherapy
local cryotherapy or focal cryotherapy or selective cryotherapy.
Japan Science and Technology Agency

J-EAST (updating of this database ceased in 2007) through Science
Links Japan
Last update: 16 August 2010.
Search terms – four separate searches using respectively: brain cooling, head cooling, brain
hypothermia, head hypothermia in title or keywords, no language or date limits.
94 Appendix 3
J-STAGE (Japan Science and Technology Information Aggregator, Electronic)

Search included journals, proceedings, reports and JST reports. Subject areas: ‘clinical medicine’
and ‘general medicine, social medicine and nursing sciences’. Search terms: head OR brain AND
cooling OR hypothermia, no language or date limits.
journal@rchive
Search terms: brain or head AND cooling or hypothermia in title, no language or date limits.
Latin-American and Caribbean System on Health Sciences

Information (LILACS)
Search terms: hypothermia OR cooling AND brain OR head in title.
Russian Academy of Sciences Bibliographies (coverage 1992 to present)

Accessed through University of Edinburgh portal.
Search terms: hypothermia or cooling in keywords.
Web search engines
Scirus
www.scirus.com/
Search terms: hypothermia or cooling in title; subject area: medicine; limited to humans; limited
to therapeutic hypothermia (the most relevant of the available options). (Note: human filter let
through a number of animal studies.)
Google Scholar
http://scholar.google.co.uk/
Search terms: at least one of the words ‘Head cooling’ ‘brain cooling’ anywhere in the article.
Date limit: 2006–11.
Subject areas: biology, life sciences, and environmental science; medicine, pharmacology and
veterinary science.
The date limit was set to 2006 onwards because a previous Google Scholar search had been
carried out in February 2006. The four papers found on this previous search were already in the
search results database, as they had been identified by other searches for this review.

Reference lists
Reference lists of books on hypothermia and of reviews and relevant studies were searched.
Books searched
1. Hayashi N. (editor) Brain hypothermia: pathology, pharmacology and treatment of severe brain
injury. Tokyo: Springer-Verlag; 2000.
2. Hayashi N, Bullock R, Dietrich DW, Maekawa T, Tamura A. Hypothermia for acute brain
damage: pathomechanism and practical aspects. Conference proceedings of 1st International
Brain Hypothermia Symposium. Tokyo: Springer-Verlag; 2004.
3. Hayashi N, Dietrich DW (editors). Brain hypothermia treatment. Tokyo: Springer-Verlag;
2004.
4. Maier CM, Steinberg GK (editors). Hypothermia and cerebral ischemia. New York, NY:
Humana Press; 2004.
5. Mayer SA, Sessler DI (editors). Therapeutic hypothermia. New York, NY: Marcel Dekker;
2005.
6. Tisherman SA, Stertz F (editors). Therapeutic hypothermia. New York, NY: Springer; 2005.
Conference proceedings
We searched the proceedings of all three International Hypothermia Symposia (Tokyo 2004,
Miami 2007, Lund 2009) and of the Therapeutic Temperature Management Conference
(Barcelona 2008).
Writing to investigators and device manufacturers
Investigators and manufacturers of head-cooling devices were written to with varying success. A
read receipt was asked for on e-mails but, unfortunately, even when investigators indicated that
they had read the e-mail a reply was not necessarily forthcoming. Manufacturers of devices are
perhaps understandably reluctant to release details of ongoing human research, although there
were notable exceptions, including Benechill, TraumaTec and Paxman.
The language barrier was a considerable problem in communicating with Chinese investigators,
mostly rendering it impossible to make contact. Given the amount of research being undertaken
in China and the ongoing work on quality improvement with regard to conduct and reporting,
it would seem sensible to include someone who can read and write Chinese and understands the
subject area as a member of the review team if at all possible. We have plans to do this for the
next iteration of the review.
Patent search
A formal patent search was included in the search strategy in the protocol but was not
undertaken owing to lack of time. Nevertheless, we had a number of patents on file as a result of
ongoing alerts for head cooling information through Google, and this helped with identifying
manufacturers of devices to contact.

Appendix 4
Study assessment and data collection form:
systematic review of head cooling (version 3)
98 Appendix 4
Name of reviewer:
Notes:

Study ID: (First author and initials, title of (primary) report, year)

Report ID: (study ID; First author and initials, title of secondary report, year)

Study population (tick all that apply)
TBI

Stroke

Cardiac arrest
neonatal HIE
Other - specify
Study in adults (≥18 years):

Yes

No
Mixed
Unclear

Study outcomes:

Randomized:
Yes

No

Unclear

Methods (quality checklist from Cochrane Renal Group)

Study design
(RCT – parallel group, crossover; observation – cohort, case-control; descriptive e.g. safety,
feasibility, case report)

Total study duration

Selection bias
Sequence generation (randomised trial)
Random: Yes/No/Unclear

Method:

Allocation sequence concealment
A. Adequate - randomisation method described that would not allow investigator or
participant to know or influence intervention group before eligible participant entered
in the study.
B. Unclear - Randomisation stated but no information on method used is available.
C. Inadequate - Method of randomisation used such as alternate medical record
numbers or unsealed envelopes; any information in the study that indicated that
investigators or participants could influence the intervention group.

Control for confounders (cohort study)
Yes/No/Unclear

Matching (case-control study)
Yes/No/Unclear

Performance and detection bias
Blinding (randomised trials and cohort studies)
Blinding of investigators: Yes/No/not stated
Blinding of participants: Yes/No/not stated
Blinding of outcome assessor: Yes/No/not stated
Blinding of data analysis: Yes/No/not stated
The above are not considered blinded if the treatment group can be identified in >
20% of participants because of the side effects of treatment.

Measurement of exposure (cohort and case-control studies) – differences between groups that
could affect outcome of interest e.g. in measurement of outcome of interest (was
measurement unbiased)

Case definition (case-control studies)

Attrition bias
Intention to treat
Yes - specifically reported by the authors that intention-to-treat analysis was
undertaken and this was confirmed on study assessment.
Yes - not stated, but confirmed on study assessment.
No - not reported and lack of intention-to-treat analysis confirmed on study
assessment. (Patients who were randomised were not included in the analysis because
they did not receive the study intervention, they withdrew from the study, or were not
included because of protocol violation).
No - stated but not confirmed upon study assessment.
Not stated.
100 Appendix 4
Completeness of follow-up (cohort, case-control studies)

Yes
No
Unclear

Other concerns about bias
e.g. if not blinded, systematic differences in care other than intervention

Participants
Total number
Setting
Mechanism of injury/diagnostic criteria

Age

Gender

Cooling interventions
Under intervention details give cooling methods, devices, pharmacological cooling. Possible
cooling interventions include:
non-invasive head cooling – cooling applied externally to head (+/-neck), nasal
and/or pharyngeal cooling;
no cooling intervention or standard care;
physical cooling interventions applied systemically or to parts of the body other than
the head e.g. tepid sponging, ice packs, cooling blankets and mattresses, intravascular
cooling catheters;
pharmacological cooling interventions e.g. paracetamol, non-steroidal anti-
inflammatory drugs, cyclo-oxygenase inhibitors, ethymisole.

Total number of intervention groups e.g. cooled groups, control groups:
For each intervention group
1. Intervention

Intervention details (sufficient for replication, if feasible)
Target temperature
Duration of intervention

Number allocated to group

Rewarming strategy
Controlled

Passive

Rate of rewarming (state °C/°F)

2. Intervention

Target temperature


Rewarming strategy
Controlled

Passive


3. Intervention

Target temperature


Rewarming strategy
Controlled

Passive


Barbiturates used:
No
Yes - give details:

Outcomes and Results

1. Intracranial temperature (state °C/°F)
Collected:
No
Yes
Time point(s) collected at:
Reported:
No
Yes
102 Appendix 4
Sample size

Missing participants (% of pts excluded or lost to follow-up)

Summary data for each intervention group (e.g. mean(SD) or 2x2 table)
Estimate of effect with confidence interval & p value

2. Core trunk temperature (state °C/°F) – PA, oesophagus, bladder or rectum
Collected:
No
Yes
Reported:
No
Yes

Sample size



3. Mortality
Collected:
No
Yes
Reported:
No
Yes

Sample size



4. Disability/dependency (include method of assessment e.g. GOS)
Collected:
No
Yes


Reported:
No
Yes

Sample size


Summary data for each intervention group (e.g. mean (SD) or 2x2 table)

5. Reduction in intracranial pressure
Collected:
No
Yes
Reported:
No
Yes

Sample size



6. Improvement in biochemical markers of injury e.g. lactate/pyruvate ratio, glutamate,
cytokines
Collected:
No
Yes
Reported:
No
Yes

Sample size


104 Appendix 4
7. Improvement in cross-sectional imaging

Collected:
No
Yes
Reported:
No
Yes

Sample size



8. Complications and adverse effects actually or possibly attributable to the head cooling
intervention or the specific device, e.g. infections, prolonged clotting time and bleeding
complications, scalp damage
Collected:
No
Yes

Reported:
No
Yes

Sample size



9. Time from brain injury or onset of stroke to start of cooling (not HIE)
Collected:
No
Yes

Reported:
No
Yes

Sample size




10. Cooling rate (e.g. hourly temperature reduction) (not HIE)
Collected:
No
Yes
Reported:
No
Yes

Sample size


11. Time from injury to target temperature (not HIE)

Collected:
No
Yes

Reported:
No
Yes

Sample size



12. Time from device application to achieving target temperature (not HIE)

Collected:
No
Yes

Reported:
No
Yes

Sample size

106 Appendix 4

Miscellaneous

Funding source

Declared conflicts of interest

Key conclusions of study authors
Miscellaneous comments from study authors
References to other relevant studies
Correspondence required
Miscellaneous comments by reviewers

Appendix 5
References to head-cooling studies
References to studies included in this review
Included traumatic brain injury studies

Harris B. Hypothermia (letter and authors’ response). J Neurosurg 2009;111:1296–7.
Harris OA, Muh CR, Surles MC, Pan Y, Rozycki G, Macleod J, et al. Discrete cerebral
hypothermia in the management of traumatic brain injury: a randomized controlled trial.
[Erratum appears in J Neurosurg 2009 Jun;110:1322.] J Neurosurg 2009;110:1256–64.
Included stroke studies (ischaemic and haemorrhagic)
Gaida BJ, Yaldizli OO, Mnk S, Muroi C, Mudra R, Fröhlich J. Treatment of resistant fever with
local cerebral cooling: P 029. Eur J Anaesthesiol 2008;25:11.
Wang DZ, Wang H, Lanzino G, Rose JA, Honings DS, Rodde MI, et al. Cooling helmet for
patients with brain ischemic and hemorrhagic infarctions: the COOL BRAIN-STROKE Trial. The
American Stroke Association 28th International Stroke Conference, 13 February 2003, Phoenix,
AZ.
Wang H, Olivero W, Lanzino G, Elkins W, Rose J, Honings D, et al. Rapid and selective cerebral
hypothermia achieved using a cooling helmet. J Neurosurg 2004;100:272–7.
Wang H, Wang D, Olivero W, Lanzino G, Honings D, Rodde M. Selective brain hypothermia
can be achieved with a cooling helmet: preliminary findings of the COOL BRAIN-stroke trial
(conference abstract). Stroke 2004;35:293.
Included brain injury studies (with traumatic brain injury and stroke)
Andrews PJ, Harris B, Murray GD. Randomized controlled trial of effects of the airflow through
the upper respiratory tract of intubated brain-injured patients on brain temperature and selective
brain cooling. Br J Anaesth 2005;94:330–5.
Forte LV, Peluso CM, Prandini MN, Godoy R, Rojas SSO. Regional cooling for reducing brain
temperature and intracranial pressure. Arq Neuropsiquiatr 2009;67:480–7.
Harris BA. Heat loss from the upper airways and through the skull: studies of direct brain cooling in
humans. PhD Thesis. Edinburgh: University of Edinburgh; 2010.
Harris BA, Andrews PJ, Murray GD. Enhanced upper respiratory tract airflow and head fanning
reduce brain temperature in brain-injured, mechanically ventilated patients: a randomized,
crossover, factorial trial. Br J Anaesth 2007;98:93–9.
Miller E. Determination of the rate and degree of selective brain cooling in adults with the
TraumaTec Neuro-Wrap (abstract P94). J Neurotrauma 2009;26:A25.
Sung G, Torbey M, Abou-Chebl A. Rhinochill: a novel brain hypothermia delivery device.
Neurology 2009;72:A75.
Abou-Chebl A, Sung G, Barbut D, Torbey M. Local brain temperature reduction via intranasal
cooling with the Rhinochill device: preliminary safety data in brain-injured patients. Stroke
2011;42:2164–69.
108 Appendix 5
Included cardiac arrest studies

Andreas J, Losert H, Bayegan K, Haugk M, Arrich J, Krizanac D, et al. Nasal cooling with a
new cooling device in patients after cardiac arrest and successful resuscitation. Resuscitation
2008;77:S29.
Busch H-J, Eichwede F, Fodisch M, Taccone FS, Wobker G, Schwab T, et al. Safety and feasibility
of nasopharyngeal evaporative cooling in the emergency department setting in survivors of
cardiac arrest. Resuscitation 2010;81:943–9.
Busch HJ, Janata A, Eichwede F, Fodisch M, Wobker G, Stephan T, et al. Safety and feasibility of a
new innovative cooling approach for immediate induction of therapeutic hypothermia in patients
after successful resuscitation. trans-nasal cooling after cardiac arrest (abstract P63). Circulation
2008;118:S1459.
Callaway CW, Tadler SC, Katz LM, Lipinski CL, Brader E. Feasibility of external cranial cooling
during out-of-hospital cardiac arrest. Resuscitation 2002;52:159–65.
Castrén M, Nordberg P, Svensson L, Taccone F, Vincent JL, Desruelles D, et al. Intra-arrest
transnasal evaporative cooling: a randomized, prehospital, multicenter study (PRINCE: Pre-
ROSC IntraNasal Cooling Effectiveness). Circulation 2010;122:729–36.
Castrén M and PRINCE collaborators. Intra-arrest trans-nasal evaporative cooling:a randomized
pre-hospital multicenter study: PRINCE (Pre-ROSC Intra Nasal Cooling Effectiveness).
American Heart Association Resuscitation Science Symposium, 15 November, 2009, Orlando, FL.
References to studies excluded from this review
Excluded traumatic brain injury studies

Fang A. The clinical effects of selective hypothermia and decompressive craniectomy on severe
traumatic brain injury. Zhejiang J Trauma Surg 2009;14:97–9.
Ioffe I, Sumskii LI. Cranio-cerebral hypothermia in the treatment of patients with cranio-cerebral
injuries.] [Russian.] Zh Vopr Neirokhir Im NN Burdenko 1977;1:9–14.
Kang, Yang J, Lisheng L, Wei Y. Selective mild hypothermia therapy on immune function in
patients with traumatic brain injury and prognosis. Shandong Med J 2004;44:35–6.
Liu WG, Qiu WS, Zhang Y, Wang WM, Lu F, Yang XF. Effects of selective brain cooling in
patients with severe traumatic brain injury: a preliminary study. J Int Med Res 2006;34:58–64.
Qiu W. A preliminary study on clinical effects of combinating noninvasive selective brain cooling
and decompressive craniectomy in severe traumatic brain injury. Proceedings of the International
Conference on Recent Advances in Neurotraumatology, Tianjin, China, 19–22 September
2007;45–47.
Qiu W, Shen H, Zhang Y, Wang W, Liu W, Jiang Q, et al. Noninvasive selective brain cooling
by head and neck cooling is protective in severe traumatic brain injury. J Clin Neurosci
2006;13:995–1000.
Qiu WS, Wang WM, Du HY, Liu WG, Shen H, Shen LF, et al. Thrombocytopenia after
therapeutic hypothermia in severe traumatic brain injury. Chin J Traumatol 2006;9:238–41.
Qiu W, Wang Y, Zhou Y, Ru J, Wang W. The clinical effects of selective hypothermia and
decompressive craniectomy on severe traumatic brain injury. J Hangzhou Normal Univ
2007;27:10–12.
Zhmurko SF. Cranio-cerebral hypothermia in patients with acute cranio-cerebral injury.

Excluded stroke studies (ischaemic and haemorrhagic)

Chen Q, Ou X, Yang Y, Li X, Liu Q. The effect of head hypothermia on the large-acreage cerebral
infarction (LCI) and hyperthermia patients serum CORT, SOD and LPO level. Chin J Prim Med
2006;13:20–1.
Dohi K, Jimbo H, Ikeda Y, Matsumoto K. Pharmacological brain cooling (PBC) by indomethacin;
a non-selective cyclooxygenase (COX) inhibitor in acute hemorrhagic stroke. Nosotchu
2000;22:429–34.
Dohi K, Jimbo H, Ikeda Y, Fujita S, Ohtaki H, Shioda S, et al. Pharmacological brain cooling with
indomethacin in acute hemorrhagic stroke: antiinflammatory cytokines and antioxidative effects.
Acta Neurochir 2006;96(Suppl.):57–60.
Dong G, Ou X, Yang Y, Chen Q. The effect of head hypothermia on the hypertensive intracerebral
hemorrhage associated with hyperthermia patients serum CORT, SOD and LPO levels. Pract J
Med Pharm 2005;22:1057–9.
Feng H, Shi D, Wang D, Xin X, Feng L, Zhang Y, et al. [Effect of local mild hypothermia on
treatment of acute intracerebral hemorrhage, a clinical study.] [Chinese.] Chung-Hua i Hsueh Tsa
Chih [Chin Med J] 2002;82:1622–4.
Hao Q, Zhang Z-B, Yang Y-F, Liu C-H. Assessment of batroxobin combined with local mild
hypothermia in the treatment of cerebral infarction. Chin J Cerebrovasc Dis 2008;5:121–4.
Inoue T, Kimura K, Iguchi Y, Shibazaki K, Matsumoto N, Iwanaga T. Local brain hypothermia
with use of cooling hat may improve patients’ outcome in acute severe ischemic stroke. Stroke
2007;38:499.
Li XL, Xia Q, Cheng ZX, Zhang YW, Liu QC [Influence of beginning time of hypothermia
treatment on prognosis of extensive cerebral infarction.] [Chinese.] Zhongguo Wei Zhong Bing Ji
Jiu Yi Xue/Chinese Critical Care Medicine 2005;17:180–2.
Liu RP, Li DX, Liang JZ, Liu CJ, Chen YF, Wang DX, et al. Nursing of hypothermia in treatment
of patients with acute cerebrovascular diseases. Chin J Nurs 1999;34:724–5.
Ou X, Hou S, Yang Y, Chen Q. Research of the treatment time of head hypothermia on
hyperthermia after hypertensive intracerebal hemorrhage. Heilongjiang Nurs J 2005;11:342–3.
Shuaib A, Kanthan R, Goplen G, Griebel R, el-Azzouni H, Miyashita H, et al. In-vivo
microdialysis study of extracellular glutamate response to temperature variance in subarachnoid
hemorrhage. Acta Neurochirurgica Suppl 1996;67:53–8.
Su Z-Q, Wang Y, Zhao Q-J, Sun X-Y, Yang H-Y, Wang D-S. Recent effect of local mild
hypothermia for improving neurological deficits in patients with cerebral hemorrhage. Chin Clin
Rehabil 2004;8:1816–17.
Takenobu Y, Oe H, Imakita S, Naito H, Naritomi H. Neuroprotective effect of local surface
cooling in acute ischemic stroke: P295. [Abstract 30th International Stroke Conference.] Stroke
2005;36:495A.
Tang Y, Zhang Y, Liu W, Wang D. Selective and mild hypothermia in the management of brain
injury. J Neurochem 2008;106:65–6.
Wang H, Wang D, Lanzino G, Elkins W, Olivero W. Differential interhemispheric cooling and
ICP compartmentalization in a patient with left ICA occlusion. Acta Neurochir 2006;148:681–3.
Wu L, Wang D, Zhou Y, Liu N, Xu S, Hui K, et al. Effect of adhesive dressing local and mild
hypothermia treatment for acute stroke. Chin J Immunol Neurol 2010;17:117–19.
110 Appendix 5
Xia Q, Qin S, Li X, et al. Efficacy of minimal injury aspiration in combination with head
hypothermia in the treatment of hypertensive intracerebral hemorrhagic cerebral hernia. Chin J
Geriatr Cardiovasc Cerebrovasc Dis 2003;5:184–5.
Xia Q, Yan C. Investigation into therapeutic effect of cerebral cryotherapy on large-acreage
cerebral infarction. Clin J Med Officer 2004;32:14–15.
Xu LX, Li XL, Zhang XD, Wu XF, Zhang XM. Clinical efficacy of head mild hypothermia in
treatment of hypertensive intracerebral hemorrhage. Chin J Geriatr Cardiovasc Cerebrovasc Dis
2002;4:327–9.
Xu E, Qi F, Wang J, Yan J, Pan L, Lu X. The clinical study of selective brain cooling in the
treatment of acute cerebral infarction. J Apoplexy Nerv Dis 2003;20:434–6.
Xu L, Han X, Li X, Yan C, Tang S. Effects of head hypothermia on levels of NO, SOD, Glut in
serum of patients with hypertensive intracerebral hemorrhage encephalocele. Pract J Med Pharm
2004;21:868–9, 872.
Yamada K, Moriwaki H, Oe H, Yamawaki T, Nagatsuka K, Oomura M, et al. The feasibility and
safety of mild brain hypothermia with local surface cooling in acute stroke. Stroke 2004;35:298.
Yang Y, Ou X, Chen Q. A study on time of head hypothermy for large acreage cerebral infarction
patients with central high fever. Chin Nurs Res 2006;20:45–6.
Zhang X, Liu X, Li W, Chen R. Effects of local mild hypothermia treatment on plasma
neuropeptide Y (NPY), neurotensin (NT), calcitonin gene-related peptide (CGRP) and
endotheline (ET) in patients with cerebral hemorrhage. Chin J Emerg Med 2006;15:47–9.
Zhang XM, Li XL, Tang SH, Liu QC. [Effect of head hypothermia on serum inflammatory
cytokines levels in patients with hypertensive intracerebral hemorrhage.] [Chinese.] Zhongguo
Wei Zhong Bing Ji Jiu Yi Xue/Chin Crit Care Med 2006;18:294–6.
Excluded brain injury studies (with traumatic brain injury and stroke)
Dohi K, Jimbo H, Abe T, Aruga T. Positive selective brain cooling method:a novel, simple, and
selective nasopharyngeal brain cooling method. Acta Neurochir Suppl 2006;96:409–12.
Mariak Z. Intracranial temperature recordings in human subjects. The contribution of the
neurosurgeon to thermal physiology. J Therm Biol 2002;27:219–28.
Mellergard P. Changes in human intracerebral temperature in response to different methods of
brain cooling. Neurosurgery 1992;31:671–7.
Wang W, Jiang Q, Chen J, Lu F, Zhao Z, Wu J. The study on cases of severe brain injury treated
with selective brain cooling. J Hangzhou Med Coll 2001;22:198–200.
Yang C, Liu H, Bo W, Wu H, Lang M, Xin X, et al. The effects of selective brain cooling
on prevention and treatment of common complications of severe brain injury. Chin J
Otorhinolaryngol Skull Base Surg 2006;12:410–13, 417.
Zhao B, Huang H, Zhang G. Treatment of severe brain injury with selective mild hypothermia of
brain. J Traum Surg 2003;5:420–2.
Excluded cardiac arrest studies

Busch H-J, Brunner M, Schwab H, Inderbitzen B, Barbut D, Schwab T. Pre-treatment with trans-
nasal cooling for the induction of therapeutic hypothermia in patients with cardiac arrest leads
to a significant faster achievement of target temperature during systemic cooling (poster). Albert
Ludwigs University Freiburg, Department of Cardiology and Angiology, Freiburg, Germany,
2008.

Hachimi-Idrissi S, Huyghens L, Van der Auwera M, Lauwaert I, Van Geffen G, Corne L. Doc,
Keep the Head Cool! (abstract no. 301). Annual Meeting of the Society for Academic Emergency
Medicine (SAEM). Acad Emerg Med 1999;6:472.
Hachimi-Idrissi S, Corne L, Ebinger G, Michotte Y, Huyghens L. Mild hypothermia induced by a
helmet device: a clinical feasibility study. Resuscitation 2001;51:275–81.
Hachimi-Idrissi S, Zizi M, Nguyen DN, Schiettecate J, Ebinger G, Michotte Y, et al. The evolution
of serum astroglial S-100 [beta] protein in patients with cardiac arrest treated with mild
hypothermia. Resuscitation 2005;64:187–92.
Holzer M, Bernard SA, Hachimi-Idrissi S, Roine RO, Sterz F, Mullner M. Hypothermia for
neuroprotection after cardiac arrest:systematic review and individual patient data meta-analysis.
Crit Care Med 2005;33:414–18.
Ikeda K, Kuroki Y, Yosikawa K, Yokoyama T, Utino H. Changes in urinary 8-hydroxy-2-
deoxyguanosine in patients with global brain ischemia undergoing brain hypothermia therapy:
comparison of whole body and selective head cooling (P330). Crit Care 2007;11:P330.
Nordberg P, Castrén M, Svensson L, Barbut D. New method of intra-arrest trans-nasal cooling
in Stockholm: The PRINCE II study. Third International Hypothermia Symposium, 2 September
2009, Lund, Sweden.
Storm C, Schefold JC, Kerner T, Schmidbauer W, Gloza J, Krueger A, et al. Prehospital cooling
with hypothermia caps (PreCoCa): a feasibility study. Clin Res Cardiol 2008;97:768–72.
Takeda Y, Fumoto K, Naito H, Morimoto N. Development of a pharyngeal cooling system that
enables brain temperature to be immediately reduced. Crit Care Med 2009;37:S250–7.
Wandaller C, Holzer M, Sterz F, Wandaller A, Arrich J, Uray T, et al. Head and neck cooling
after cardiac arrest results in lower jugular bulb than esophageal temperature. Am J Emerg Med
2009;27:460–5.
Excluded studies in volunteers

Corbett RJT, Laptook AR. Failure of localized head cooling to reduce brain temperature in adult
humans. Neuroreport 1998;9:2721–5.
Covaciu L. Intranasal cooling for cerebral hypothermia treatment. PhD thesis. Sweden: Uppsala
University; 2010.
Harris BA, Andrews PJ, Marshall I, Robinson TM, Murray GD. Forced convective head cooling
device reduces human cross-sectional brain temperature measured by magnetic resonance: a
non-randomized healthy volunteer pilot study. Br J Anaesth 2008;100:365–72.
Kuhnen G, Einer-Jensen N, Tisherman SA. Cooling methods. In Tisherman SA, Sterz F, editors.
Therapeutic hypothermia. Springer-Verlag: New York, NY; 2005. pp. 211–33.
Mariak Z, White MD, Lewko J, Lyson T, Piekarski P. Direct cooling of the human brain by heat
loss from the upper respiratory tract. J Appl Physiol 1999;87:1609–13.
Mariak Z, White MD, Lyson T, Lewko J. Tympanic temperature reflects intracranial temperature
changes in humans. Pflugers Arch 2003;446:279–84.
Shiraki K, Sagawa S, Tajima F, Yokota A, Hashimoto M, Brengelmann GL. Independence of brain
and tympanic temperatures in an unanesthetized human. J Appl Physiol 1988;65:482–6.
112 Appendix 5
References to studies in neonatal hypoxic–

ischaemic encephalopathy
Akisu M, Huseyinov A, Yalaz M, Cetin H, Kultursay N. Selective head cooling with hypothermia
suppresses the generation of platelet-activating factor in cerebrospinal fluid of newborn infants
with perinatal asphyxia. Prostag Leukotr Ess 2003;69:45–50.
Alkharfy TM. A simplified method for head cooling: feasibility and safety. J Neonatal Perinat Med
2010;3:127–34.
Battin MR, Dezoete JA, Gunn TR, Gluckman PD, Gunn AJ. Neurodevelopmental outcome of
infants treated with head cooling and mild hypothermia after perinatal asphyxia. Pediatrics
2001;107:480–4.
Battin MR, Penrice J, Gunn TR, Gunn AJ. Treatment of term infants with head cooling and mild
systemic hypothermia (35.0 degrees C and 34.5 degrees C) after perinatal asphyxia. Pediatrics
2003;111:244–51.
Battin MR, Thoresen M, Robinson E, Polin RA, Edwards AD, Gunn AJ; Cool Cap Trial Group.
Does head cooling with mild systemic hypothermia affect requirement for blood pressure
support? Pediatrics 2009;123:1031–6.
Gluckman PD, Wyatt JS, Azzopardi D, Ballard R, Edwards AD, Ferriero DM, et al. Selective head
cooling with mild systemic hypothermia after neonatal encephalopathy: multicentre randomised
trial. Lancet 2005;365:663–70.
Gunn AJ, Gluckman PD, Gunn TR. Selective head cooling in newborn infants after perinatal
asphyxia: a safety study. Pediatrics 1998;102:885–92.
Gunn AJ, Wyatt JS, Whitelaw A, Barks J, Azzopardi D, Ballard R, et al.; CoolCap Study Group.
Therapeutic hypothermia changes the prognostic value of clinical evaluation of neonatal
encephalopathy. J Pediatr 2008;152:55–8.
Horn AR, Woods DL, Thompson C, Eis I, Kroon M. Selective cerebral hypothermia for post-
hypoxic neuroprotection in neonates using a solid ice cap. S Afr Med J 2006;96:976–81.
Kilani RA. The safety and practicality of selective head cooling in asphyxiated human newborn
infants, a retrospective study. J Med Liban 2002;50:17–22.
Kumazawa K, Ibara S, Kobayashi K, Tokuhisa T, Maruyama H, Maede Y, et al. Changes of blood
glutamate levels in hypoxic ischemic encephalopathy patients undergoing brain hypothermia. In
Hayashi N, Bullock R, Dietrich DW, Maekawa T, Tamura A, editors. Hypothermia for Acute Brain
Damage: Pathomechanism and Practical Aspects. Tokyo: Springer Verlag; 2004. pp. 320–4.
Lin ZL, Yu HM, Lin J, Chen SQ, Liang ZQ, Zhang ZY. Mild hypothermia via selective head
cooling as neuroprotective therapy in term neonates with perinatal asphyxia:an experience from
a single neonatal intensive care unit. J Perinatol 2006;26:180–4.
Liu C-Q, Xia Y-F, Yuan Y-X, Li L, Qiu X-L. Effects of selective head cooling with mild
hypothermia on serum levels of caspase-3 and IL-18 in neonates with hypoxic-ischemic
encephalopathy. Chin J Contemp Pediatr 2010;12:690–2.
Rutherford MA, Azzopardi D, Whitelaw A, Cowan F, Renowden S, Edwards AD, et al. Mild
hypothermia and the distribution of cerebral lesions in neonates with hypoxic-ischemic
encephalopathy. Pediatrics 2005;116:1001–6.
Sarkar S, Barks JD, Bhagat I, Dechert R, Donn SM. Pulmonary dysfunction and therapeutic
hypothermia in asphyxiated newborns:whole body versus selective head cooling. Am J Perinatol
2009;26:265–70.

Sarkar S, Barks JD, Bhagat I, Donn SM. Effects of therapeutic hypothermia on multiorgan
dysfunction in asphyxiated newborns: whole-body cooling versus selective head
cooling. J Perinatol 2009;29:558–63.
Shao XM, Zhou WH. Efficacy and safety of selective head cooling with mild systemic
hypothermia after neonatal hypoxic ischemic encephalopathy. Hot Topics in Neonatology, 3
December 2005, Washington, DC.
Simbruner G, Haberl C, Harrison V, Linley L, Willeitner AE. Induced brain hypothermia in
asphyxiated human newborn infants:a retrospective chart analysis of physiological and adverse
effects. Intensive Care Med 1999;25:1111–17.
Thoresen M, Whitelaw A. Cardiovascular changes during mild therapeutic hypothermia and
rewarming in infants with hypoxic-ischemic encephalopathy. Pediatrics 2000;106:92–9.
Whitelaw A, Thoresen M. Clinical experience with therapeutic hypothermia in asphyxiated
infants. Dev Med Child Neurol Suppl 2001;86:30–1.
Wyatt JS, Gluckman PD, Liu PY, Azzopardi D, Ballard R, Edwards AD, et al.; CoolCap Study
Group. Determinants of outcomes after head cooling for neonatal encephalopathy. Pediatrics
2007;119:912–21.
Zhou W-H. Safety study of hypothermia for treatment of hypoxic-ischemic brain damage in term
neonates. Acta Pharmacol Sin 2002;23:64–8.
Zhou W-H, Cheng G, Shao X, Liu X, Shan R, Zhuang D, et al.; China Study Group. Selective
head cooling with mild systemic hypothermia after neonatal hypoxic-ischemic encephalopathy: a
multicenter randomized controlled trial in China. J Pediatr 2010;157:367–72.
Reviews in neonatal hypoxic–ischaemic encephalopathy

Edwards AD, Brocklehurst P, Gunn AJ, Halliday H, Juszczak E, Levene M, et al. Neurological
outcomes at 18 months of age after moderate hypothermia for perinatal hypoxic ischaemic
encephalopathy: synthesis and meta-analysis of trial data. BMJ 2010;340:c363.
Jacobs SE, Hunt R, Tarnow-Mordi WO, Inder TE, Davis PG. Cooling for newborns with hypoxic
ischaemic encephalopathy. Cochrane Database Syst Rev 2007;4:CD003311.
Schulzke SM, Rao S, Patole SK. A systematic review of cooling for neuroprotection in neonates
with hypoxic ischemic encephalopathy: are we there yet? BMC Pediatr 2007;7:30.
Shah PS. Hypothermia:a systematic review and meta-analysis of clinical trials. Semin Fetal
Neonatal Med 2010;15:238–46.
References to studies awaiting assessment
We have been unable to obtain the papers for the first three of these and have had no response to
requests for further information for the other two (see Appendix 6 for further details).
Bunatyan AA, Zolnikov SM, Smirnov OA. [Present day problems of anesthesiology and recovery
of consciousness.] [Russian.] L’vov: 1969. p.294.
Bunatyan AA, Zolnikov SM, Smirnov OA. Fourth International Symposium on Anesthesiology,
1969, Varna, Bulgaria, p. 503.
Ioffe YS, Smirnov OA. In Comatose states following cranio-cerebral trauma. Moscow; 1969. p. 126.
Skulec R, Truhlar A, Knor J, Seblova J, Cerny V. The practice of therapeutic mild hypothermia in
cardiac arrest survivors in the Czech republic. Minerva Anestesiol 2010;76:617–23.
114 Appendix 5
Skulec R, Truhlar A, Ostadal P, Telekes P, Knor J, Tichacek M, et al. [Current cooling methods for
induction of mild hypothermia in cardiac arrest survivors.] Vnitrni Lekarstvi 2009;55:1060–9.
References to ongoing studies
Stroke
i-Cool (Induction of Cooling) Pilot: a randomised trial comparing three methods for rapid
induction of therapeutic hypothermia in stroke patients:
■■ www.strokecenter.org/trials/TrialDetail.aspx?tid = 1098
■■ start date: 2010
■■ Dr Sven Poli.
The Cerebral Hypothermia in Ischaemic Lesion (CHIL) Trial: a randomised trial evaluating
systemic and local mild hypothermia on infarct expansion and salvage of the ischaemic
penumbra in acute ischaemic stroke (ACTRN12609000690257):

■■ Professor Christopher Levi.
Multiple Interventions for Neuroprotection Utilizing Thermal Regulation in the Emergent

Treatment of Stroke (MINUTES) study:

■■ Dr Muzaffar Siddiqui
■■ Siddiqui MM, Ludwig Y, Hussain MS, Manawadu D, Mateer A, Beaulieu C, Saqqur M,
Shuaib A. Multiple interventions for neuroprotection utilizing thermal regulation in
the emergent treatment of stroke:the MINUTES study. Int J Stroke 2008;3:140. (abstract
PO01–195).
Emergency room trial of brain cooling in stroke with the Rhinochill device:
■■ Dr Denise Barbut
■■ not started yet.
Study of brain cooling in stroke with the DigniCap:
■■ Martin Waleij, CEO Dignitana www.dignitana.com/

■■ start date: ?
■■ awaiting further details.
Brain injury
Determination of the rate and degree of selective brain cooling in adults with the TraumaTec
Neuro-Wrap®:
■■ started: 2009–10
■■ Miller E. Determination of the rate and degree of selective brain cooling in adults with the
TraumaTec Neuro-Wrap (abstract P94). J Neurotrauma 2009;26:A25.
Brain Cooling Study, Carle Foundation Hospital, Urbana, IL:

■■ Dr Huan Wang
■■ start date: June 2011
■■ awaiting further details
Trials of QuickCool nasal cooling balloons:
■■ ‘QuickCool is currently enrolling patients in clinical trials in Sweden and Denmark.

These studies investigate the safety and efficacy of the novel QuickCool Intranasal Brain
Cooling System in the following clinical areas: cardiac arrest, traumatic brain injury and
subarachnoid hemorrhage.’ www.quickcool.se//Contents.asp?id = 358 (accessed 8 May 2011).
References to other applications of head cooling
Bagic A, Theodore WH, Bonwetsch R, Greenfield J, Sato S. Treating epilepsy with head-neck
cooling without sedation. Epilepsia 2005;46:233.
Dougherty L. Comparing methods to prevent chemotherapy-induced alopecia. Cancer Nurs Pract
2006;5:31.
Hato N, Hyodo J, Takeda S, Takagi D, Okada M, Hakuba N, et al. Local hypothermia in the
treatment of idiopathic sudden sensorineural hearing loss. Auris Nasus Larynx 2010;37:626–30.
Kramer BA, Kadar AG, Clark K. Use of the Neuro-Wrap system for severe post-electroconvulsive
therapy headaches. J ECT 2008;24:152–5.
Macduff C, Mackenzie T, Hutcheon A, Melville L, Archibald H. The effectiveness of scalp
cooling in preventing alopecia for patients receiving epirubicin and docetaxel. Eur J Cancer Care
2003;12:154–61.
Massey CS. A multicentre study to determine the efficacy and patient acceptability of the
Paxman Scalp Cooler to prevent hair loss in patients receiving chemotherapy. Eur J Oncol Nurs
2004;8:121–30.
Reynolds, L. The effects of head and neck cooling on symptoms of multiple sclerosis. Thesis. Halifax,
NS: Dalhousie University; 2007.
Simmons SE, Saxby BK, McGlone FP, Jones DA. The effect of passive heating and head cooling
on perception, cardiovascular function and cognitive performance in the heat. Eur J Appl Physiol
2008;104:271–80.
Wickwire PJ, Bishop PA, Green JM, Richardson MT, Lomax RG, Casaru C, et al. Physiological
and comfort effects of a commercial ‘cooling cap’ worn under protective helmets. J Occup Environ
Hyg 2009;6:455–9.
References to historical reports of head cooling
Bukov VA, Bobkov IG, Smirnov OA, Zol’nikov SM. [The relationship between the temperature
of various regions of the brain and the body in craniocerebral hypothermia in clinical practice.]
Khirurgiia (Mosk) 1967;43:14–21.
Ioffe I, Sumskii LI. [Cranio-cerebral hypothermia in the treatment of patients with cranio-
cerebral injuries.] [Russian.] Zh Vopr Neirokhir Im NN Burdenko 1977;1:9–14.
Ivanov VV, Kolenko EA. [Local and cerebral hypothermia using thermoelectric apparatus in
severe craniocerebral trauma.] [Russian.] Vestn Khir Im II Grek 1969;102:105–7.
116 Appendix 5
Lojka J, Kravcova V, Kovacikova E, Gajdosova D, Nadvornik P. [1st experiences with

craniocerebral hypothermia.] [Slovak.] Rozhl Chir 1973;52:812–16.
Phelps C. Traumatic injuries of the brain and its membranes. In The classics of neurology and
neurosurgery library. New York, NY: Appleton and Company; 1897. pp. 223–4.
Schlag G. Cardiac arrest and resuscitation. Zbl Chir 1962;87:1273–90.
Smirnov O, Meshcherinov I. Analytical method for determination of temperature distribution in
the human head during craniocerebral hypothermia induced by ‘Kholod-2F’ apparatus. Biomed
Eng 1970;4:192–7.
Ugriumov VM, Zotov I, Bezukh MS. [Cranio-cerebral hypothermia and neuro-vegetative
blockade in the systematic treatment of injuries to the skull and brain.] [Russian.] ZhVopr
Neirokhir 1975;6:11–17.
Waugh OS. Acute cranial-cerebral injuries. Can Med Assoc J 1926;16:1475–9.
Zhmurko SF. [Cranio-cerebral hypothermia in patients with acute cranio-cerebral injury.]

Appendix 6
Characteristics of studies
Contents
■■ Characteristics of included studies:

–– traumatic brain injury
–– stroke – ischaemic, haemorrhagic, mixed
–– brain injury – heterogeneous cerebral problems including TBI and stroke
–– cardiac arrest
■■ Characteristics of excluded studies:
–– traumatic brain injury
–– stroke – ischaemic, haemorrhagic, mixed
–– brain injury – heterogeneous
–– cardiac arrest
–– studies in volunteers
■■ Studies awaiting assessment:
–– randomised controlled trials
–– other studies
■■ Characteristics of ongoing studies:
–– stroke
–– brain injury.
Within these headings, papers are listed in date (oldest first) and then alphabetical order. The full
reference details for all the papers in this appendix can be found in Appendix 5.
Studies in neonatal HIE were included in the report only if they provided information on
complications/adverse effects/advantages of head cooling and are not included in Characteristics
of studies. The studies are listed in Appendix 5 (see References to studies in neonatal hypoxic–
ischaemic encephalopathy).
118 Appendix 6
Characteristics of included studies
Randomised controlled trials: traumatic brain injury

Harris and colleagues 2009,45 Harris 2009161
Methods RCT to evaluate the Discrete Cerebral Hypothermia head-cooling system in the management of TBI
Participants Total n = 25, age mean ± SD cooled 38.1 (± 15) (one missing data), control patients 33.2 (± 20), age range 18–90 years, 22 male
TBI GCS ≤ 8
Participating sites: Level 1 trauma centre
Multicentre: No – single US site
Language: English
Allocation concealment: ‘Blindly randomized’ – computer-generated random numbers determined by Department of Biostatistics
‘assigned to each patient based on their order in the study and GCS score on initial assessment [severe (5–8) (n = 18) vs critical
(3–4) (n = 7)], to allow for block randomization and to provide an initial balance in severity between the 2 groups’ p. 1258
Outcome assessor blind: Not reported
Data analysis blinded: Not reported
Intention to treat: Yes, for as long as they contributed data (see Follow-up, below)
Groups comparable: The cooled group spent less time in the Emergency Department before enrolment. Four cooled had
craniotomy vs one control patient
Follow-up complete: No – complete data available for 21/25 patients, 11 cooled, 10 control patients. Two patients withdrawn by
families, one ICP monitor dislodged, one incomplete data acquisition owing to unreliable systemic temperature measurement
Temperature measurement sites: Intracranial: cooled group – two parenchymal, 10 ventricular; control patients – one
parenchymal, 12 ventricular; bladder
Interventions Head and neck cooling, head not shaved, water circulating device (Discrete Cerebral Hypothermia System) set to maximum cooling
(?temp), pressurised to 15 mmHg, with active body warming to bladder temperature 36 °C (‘to avoid systemic hypothermia’)
(n = 12) vs no head cooling – temperature management if any in this group (e.g. aim of normothermia) is not reported (n = 13).
Treatment of both groups ‘in accordance with the Brain Trauma Foundation’s (BTFs) Guidelines for the Management of Severe
Traumatic Brain Injury’ p. 1258 (BTF guidelines. J Neurotrauma 2007;24:S37–44). (Note these contain nothing on temperature
management apart from induced hypothermia so do not explain control group temperature management)
Time from injury to start of cooling: Within 48 hours of hospital admission
Time from start of cooling to target: Within 24 hours of cooling period
Target temperature: 33 °C intracranial, 2 of 11 patients with complete temperature data achieved target
Duration of cooling: 24 hours
Rewarming: Controlled rewarming 0.5 °C every 3 hours over 24 hours, monitoring continued to 72 hours from start of cooling
Outcomes 1. Effectiveness of the cooling cap in reducing intracranial temperature and establishing a core body/brain temperature gradient
(36 °C body/33 °C brain)
2. Mortality, GOS and FIM at days 1, 2, 3, 7, 14, 21 and 28, and at hospital discharge if this was prior to 1 month
Result 1
Baseline (estimated) intracranial temperature in the treatment group: 37.9 °C (95% CI 37.4 °C to 38.5 °C). After 12 hours cooling
mean intracranial temperature 36.8 °C (95% CI 36.1 °C to 37.5 °C). At 24 hours, 36.9 °C
Baseline mean intracranial temperature in the control group: 37.9 °C (95% CI 37.6 °C to 38.2 °C), after 12 hours 37.9 °C (95% CI
37.5 °C to 38.3 °C), at 24 hours 38.1 °C
Mean difference between intracranial and bladder temperature for 12-hour intervention period was −0.67 °C (p = 0.07) for the
treatment group and 0.05 °C (p = 0.67) for the control patients. ‘This showed a trend toward a greater temperature gradient in
the treatment group than in the control patients However, the cooling cap neither established nor maintained a significant cranial-
bladder temperature gradient’
Result 2
‘Six (50.0%) of 12 patients in the treatment group and 4 (30.8%) of 13 in the control group died (p = 0.43). The medians of the
maximum change in GOS and FIM scores during the study period (28 days) for both groups were 0. There was no significant
difference in complications between the groups (p-value range 0.20–1.0)’
Complications respiratory failure, shock, septicaemia, decubitus ulcer, cardiac arrest but no significant difference between groups.
Patients were checked every 12 hours for cold damage to skin while cooling cap was in situ
Two patients had decubitus ulcers, both in cooled group – ulcer location not reported

Notes Unclear whether or not the analysis plan was prespecified and no power calculation. There was no significant difference in any
of the outcome measures but lack of information regarding blinded follow-up excluded the outcome data from formal analysis.
However, the primary purpose of this study was feasibility not assessment of outcome and the temperature data are suitable for
inclusion in the review, with the caveat regarding why baseline intracranial temperature in cooled group was ‘estimated’ and how?
Awaiting response from investigator regarding blinded outcome analysis, estimated baseline brain temperature, baseline and 12-
hour bladder temperatures for both groups and whether or not decubitus ulcers were device related
Randomised controlled trials: stroke (ischaemic, haemorrhagic, mixed)

None.
Randomised controlled trials: brain Injury

Andrews and colleagues 2005,46 Harris 201057
Methods Crossover RCT of the effect of nasal airflow on intracranial and oesophageal temperature
Participants Total n = 15, mean age 43 (range 17–70) years, 9 female
TBI n = 9; SAH n = 6
Participating sites: Neurological ICU
Multicentre: No – single UK site
Language: English
Allocation concealment: Sealed, opaque envelopes provided by the trial statistician, opened during baseline period
Outcome assessor blind: No
Data analysis blinded: No, primary outcome analysis was prespecified
Intention to treat: Yes
Groups comparable: Within patient comparison, i.e. crossover trial
Follow-up complete: Yes
Temperature measurement sites: Intracranial (parenchyma), oesophageal
Interventions Thirty-minute baseline, randomised to 6 hours of airflow or 6 hours of no airflow then crossed over for further 6 hours. Airflow
continuous through both nostrils, at total rate of 115 ml/kg/minute (commensurate with normal minute volume), range 6–13 l
Time from injury to start of cooling: 0–5 days but proof of concept of temperature reduction, not for neuroprotection
Time from start of cooling to target: N/A, proof of concept
Target temperature : N/A, proof of concept
Rewarming: Passive (airflow stopped)
Outcomes Primary (prespecified): Within-patient change in mean intracranial temperature over 6-hour nasal airflow compared with 6 hours
with no airflow
Result: Mean –0.13 °C, SD 0.55 °C, 95% CI –0.43 °C to 0.17 °C. Range of temperature change: +0.55 °C to –0.9 °C
Secondary (exploratory): Difference between mean brain temperatures over last 5 minutes before airflow started and last
5 minutes of the first half hour with airflow
Result: Mean –0.04 °C, SD 0.16 °C, 95% CI –0.13 to 0.04 °C. Range of temperature change: +0.18 °C to –0.52 °C
Notes The published paper (Andrews and colleagues 2005) contains an error in the temperature data (minus signs were omitted) and
therefore the results reported in Harris 2010 are used in the review. Harris 2010 also supplied detailed information on methods.
The patients were orally intubated and ventilated and the purpose of the study was to see if flowing air through their noses would
reduce intracranial temperature (proof of concept)
120 Appendix 6
Harris and colleagues 2007,47 Harris 201057
Methods Randomised controlled crossover factorial trial of the effect of enhanced nasal airflow and bilateral head fanning on intracranial
and oesophageal temperature
Participants Total n = 12, mean age 43 (range 20–67) years, 6 female
TBI n = 8, SAH n = 4
Participating sites: Neurological ICU
Multicentre: No – single UK site
Language: English
Allocation concealment: Sealed, opaque envelopes provided by the trial statistician, opened during baseline period
Data analysis blinded: No, primary outcome analysis was prespecified
Groups comparable: Within-patient comparison, i.e. crossover trial
Follow-up complete: 1 of 12 lost to follow-up at 6 months
Temperature measurement sites: Intracranial (parenchyma); oesophageal
Interventions 30-minute baseline, each of four interventions in random order: (1) enhanced nasal airflow; (2) head fanning (no head bandages);
(3) 1 + 2; (4) no intervention. [(1) = continuous unhumidified airflow through both nostrils at twice the patient’s ventilated minute
volume + 20 ppm. nitric oxide; (2) = bilateral head fanning with ambient air, total air speed approximately 8 m/second-1]
Time from injury to start of cooling: 0–4 days but proof of concept of temperature reduction, not for neuroprotection
Time from start of cooling to target: N/A, proof of concept
Target temperature: N/A, proof of concept
Duration of cooling: Thirty minutes per intervention
Rewarming: Passive (airflow stopped)
Outcomes Primary (prespecified): Within-patient comparison of each patient’s mean brain temperature for the last 5 minutes of each
intervention with the last 5 minutes of the preceding washout
Result:
Difference in mean brain temperature over the last 5 minutes of preceding washout minus mean over the last 5 minutes of
intervention = 0.15 °C with nasal airflow (p = 0.001, 95% CI 0.06 °C to 0.23 °C) and 0.26 °C with head fanning (p < 0.001, 95% CI
0.17 °C to 0.34 °C). Estimate of combined effect of airflow and fanning on brain temperature was 0.41 °C
Difference in mean oesophageal temperature over last 5 minutes of preceding washout minus the mean over the last 5 minutes of
intervention = 0.13 °C with nasal airflow (p = 0.005, 95% CI 0.04 °C to 0.21 °C) and 0.19 °C with head fanning (p < 0.001, 95% CI
0.11 °C to 0.28 °C). Estimate of combined effect of airflow and fanning on temperature was 0.32 °C
Notes The patients were orally intubated and ventilated, and the purpose of the study was to see if the cooling interventions would reduce
intracranial temperature (proof of concept)

Randomised controlled trials: cardiac arrest

Pre-ROSC Intra-Nasal Cooling Effectiveness (PRINCE) trial
Castrén and colleagues 201049 (main study report); Castrén and
colleagues 200960 (conference abstract); http://clinicaltrials.gov/ct2/
show/NCT00808236 (trials registration entry)
Methods RCT of pre-hospital intra-arrest cooling with the Rhinochill device

Participants Total n = 194; mean age 66.1 years, 67 male cooled group; mean age 64.2 years, 79 male control patients
Out-of-hospital witnessed cardiac arrest, with CPR initiated by Emergency Medical Service within 20 minutes of collapse, no
organised rhythm or palpable pulse (i.e. no ROSC) by the time the airway was secured
Participating sites: Emergency Medical Service in 15 sites in five European countries, all sites had a pre-hospital physician service
Multicentre: Yes
Language: English
Allocation concealment: Numbered, sealed envelopes
Outcome assessor blind: Intended but not necessarily achieved
Data analysis blinded: Not reported
Groups comparable: Yes
Follow-up complete: No, three in each group had no outcome data
Temperature measurement sites: Infrared tympanic temperature pre-hospital and on admission then core temperature rectal
(60%), bladder (35%), intravascular (5%)
Interventions Intra-arrest intranasal cooling with Rhinochill device until transition to systemic cooling in hospital, median cooling duration
32 minutes (IQR 21–60 minutes) (n = 93) vs no cooling (n = 101). Target temperature 34 °C
Outcomes Primary: ROSC rate
Secondary: Survival to hospital discharge (but not powered to detect outcome differences), 24-hour SAE rate
Temperature results: Median time to target temperature (core) of 34 °C in the treatment group was 155 minutes (IQR
124–315 minutes) vs 284 minutes (IQR 172–471 minutes) in control patients. The mean core temperature was significantly lower
in treated patients when measured after hospital arrival: 35.1 °C (SD ± 1.3 °C) vs 35.8 °C (SD ± 0.9 °C), p = 0.01
Rates of survival: 31% control patients, 43.8% cooled group (p = 0.04, RR = 1.9)
Adverse events: Nasal whitening 13 (14%) of 93 patients during nasal cooling, resolved spontaneously in all five resuscitated
patients. No relationship between longer duration of treatment and nasal discoloration. Epistaxis: three patients (3.2%), serious
in one patient with an underlying coagulopathy secondary to hepatic failure. This was the only device-related SAE. Periorbital
emphysema occurred 75 minutes into treatment in one patient and resolved spontaneously within 24 hours. The total number of
SAEs that occurred within 7 days was seven in the treatment group and 14 in the control group
CPR, cardiopulmonary resuscitation; IQR, interquartile range; RR, relative risk; SAE, serious adverse event.
122 Appendix 6
Callaway and colleagues 200248
Methods RCT of pre-hospital intra-arrest head cooling

Participants Total n = 27, but five cooled patients were excluded because temperature measurements could not be completed, mean
68 ± 15 years hypothermia group; mean 80 ± 10 years control group; 18 male
Out-of-hospital cardiac arrest, convenience sample
Participating sites: City of Pittsburgh Emergency Medical Services
Multicentre: No
Language: English
Allocation concealment: Not reported
Intention to treat: No, five subjects with incomplete temperature measurements were excluded from analysis
Groups comparable: Unclear
Follow-up complete: Yes (all patients died in hospital)
Temperature measurement sites: Nasopharyngeal, tympanic, oesophageal
Interventions Pre-hospital head cooling with three 500-ml bags of ice round the head plus one bag over the neck during CPR after cardiac
arrest (n = 9) vs normothermia subjects receiving usual care but without cooling (n = 13). Temperature measurements every
5 minutes for 15 minutes until ROSC or discontinuation of resuscitation. Cooling was discontinued if core temperature reduced
below 34 °C or if spontaneous circulation was restored for at least 5 minutes
Outcomes Reduction in temperature, in-hospital mortality, adverse events/complications
Temperature results: Baseline oesophageal temperatures: 35.5 ± 1.0 °C cooled group, 35.3 ± 1.7 °C normothermia [sic] group, i.e.
patients were already cool. Temperatures were actually measured for 5–30 minutes in each group
The mean rate of change (± SD) of oesophageal temperature did not differ between hypothermia (−0.07 ± 0.06 °C/minute; 95% CI
−0.11 to −0.03) and normothermia (−0.02 ± 0.06 °C/minute; 95% CI −0.05 to 0.02) groups
Outcome at hospital discharge: No patient survived to hospital discharge
Adverse events/complications: No problems from use of ice bags for cooling except difficulty of securing them round the head for
transport
Notes Convenience sample who were randomised to cooling and control group, method of randomisation not reported, not blinded,
five subjects were excluded from analysis because serial temperature measurements could not be completed. Control group is
described as ‘normothermia’ group, although mean baseline temperature in both groups was below normal and did not change
Probably not reasonable to expect ice bags to reduce temperature within 5–30 minutes
CPR, cardiopulmonary resuscitation.
Other studies (not randomised controlled trials): traumatic brain injury

None.

Other studies (not randomised controlled trials): stroke (ischaemic,

haemorrhagic, mixed)
COOL BRAIN-stroke trial
Wang and colleagues 200361 (conference abstract), Wang and
colleagues 200462 (conference abstract); Wang and colleagues
200450 (main study report); www.strokecenter.org/trials/TrialDetail.
aspx?tid = 473 (Stroke Trials Registry entry)
Methods Prospective, non-randomised pilot study (according to Stroke Trials Registry entry) of the effectiveness of a head-cooling device in
reducing brain temperature
Participants Total n = 14 of whom eight were cooled; age and gender not reported
Acute ischaemic or haemorrhagic stroke (+ ≥ 1 TBI in main report)
Participating sites: single Neuro ICU, USA
Language: English
Follow-up complete: Follow-up not reported
Temperature measurement sites: Intracranial (parenchymal), bladder
Interventions Head and neck cooling with water-circulating cooling helmet, head shaved, body warming to maintain bladder temperature
> 33 °C, > 35 °C if age > 45 years + ‘standard’ stroke care (n = 8); ‘control patients’ had ‘standard’ stroke care, no information
about temperature management (n = 6)
Time from injury to start of cooling: Within 24 hours of admission
Time from start of cooling to target: ‘Mean of 3.4 hours (range 2–6 hours) to achieve a brain temperature < 34 °C’
Target temperature: Brain not stated but probably ≤ 34 °C; bladder 33–35 °C
Duration of cooling: Unclear but helmet in situ for up to 72 hours
Rewarming: ‘Mean 0.63°C/hour (range 0.15–1.45°C/hour) passive rewarming rate was observed’
Outcomes Change in intracranial temperature (0.8 cm below cortical surface) minus bladder temperature, cooling rate, complications
(The trials registry entry included NIHSS, mRS, BI and mortality as outcomes but these were not reported)
Temperature results in cooled patients: Mean overall brain–bladder temperature change –1.6 °C
Mean brain temperature reduction of 1.84 °C (range 0.9–2.4 °C) within 1 hour. Brain temperature < 34 °C in mean 3.4 hours,
bladder temperature < 36 °C in mean 6.67 hours
Notes There are discrepancies and omissions in the reports of this trial
According to the Stroke Trials Registry entry, the paper in the Journal of Neurosurgery is the main published report on the COOL
BRAIN-stroke trial, although the trial is not referred to by name in the paper (Wang and colleagues 2004). That report of the trial
includes at least one patient with TBI in addition to stroke patients, says the trial was randomised and includes a ‘control’ group
but no information on the comparability of the groups at baseline (Wang and colleagues 2004). However, a published abstract
(Wang and colleagues 2003), the preliminary report (Wang and colleagues 2004) and the completed entry in the Stroke Trials
Registry (which cites the published abstract and the Journal of Neurosurgery paper as the publications) state that the study
included only stroke patients and was not randomised. The results in the completed entry in the Stroke Trials Registry are the
same as those given in the Journal of Neurosurgery paper (Wang and colleagues 2004), with the addition of the following: ‘There
were no serious complications or adverse events. Efficacy data (NIHSS, Rankin) was not published’. The source of the results is
given as the two cited publications and ‘correspondence with the trial co-ordinator’
It is not reported how long patients were cooled for. According to the Stroke Trials Registry the helmet was to remain in situ for
72 hours. Brain temperature was monitored for ‘a mean of 48–72 hours’ (Wang and colleagues 2004a). Data are shown for an
‘illustrative case’ with TBI and this patient appears to have been cooled for 24 hours and the helmet removed at 48 hours
Apart from the illustrative case there is no information on age, gender, number with stroke vs TBI in cooled group or ‘control
patients’, i.e. the comparability of the groups is unknown
The preliminary report (Wang and colleagues 2004) includes six cooled stroke patients and the temperature results are based
on 300 data hours. The main report (Wang and colleagues 2004) includes eight cooled patients and the temperature results are
based on 277 data hours. There are no data on baseline temperature and no explanation of how the brain–bladder temperature
was calculated. There is no information on how many patients actually had body warming, but as it took up to 12 hours to reach a
bladder temperature of < 36 °C some patients may not have received it
With caveats, the temperature data in the cooled patients contribute to proof of concept of temperature reduction with head
cooling and is included in the review
124 Appendix 6
Gaida and colleagues 200851 (abstract only)
Methods Observational study of head and neck cooling for fever management
Participants n = 6, age and gender not reported
Aneurysmal SAH
Participating sites: Single Swiss Neuro ICU
Language: English
Temperature measurement sites: Intracranial (ventricular), arterial blood
Interventions Standard management (paracetamol, metamizole, alcohol washing, ice packs) plus head and neck cooling (CSZ Blanketrol head
and neck wrap) if brain temperature was still > 37.8 °C after 2 hours
Time from injury to start of cooling: N/A – fever management
Time from start of cooling to target: Achieved by 6 hours
Target temperature: Not reported but probably 37.5 °C
Rewarming: N/A
Outcomes Intracranial (ventricular) and arterial blood temperature after 6 hours of standard care plus head and neck cooling
Results: ‘Tbrain and Tblood after 6h of wrap cooling decreased significantly from Tbrain 38.5 ± 0.6 °C and Tblood 38.2 ± 0.6 °C to
37.5 ± 0.4 °C and 37.4 ± 0.5 °C (p < 0.0001 for both)’
Notes The temperature setting used is not stated but the circulating water temperature could be set between 4 °C and 42 °C
Other studies (not randomised controlled trials): brain injury

Forte and colleagues 200952
Methods Retrospective study of the effect of ice over decompressive craniectomy site on ICP and temperature reduction
Participants n = 23, mean age 48.9 (range 16–83) years, 13 female
Severe TBI n = 6: SAH 10; ischaemic stroke, four; brain tumour, two; ICH, one; plus refractory intracranial hypertension and
decompressive craniectomy
Participating sites: Neurosurgical ICUs in two Portuguese hospitals
Language: English
Temperature measurement sites: Intracranial (site not specified); oesophageal
Interventions Cooling by ice packs over decompressive craniectomy site
Time from injury to start of cooling: Not reported but cooling was for ICP reduction not neuroprotection
Time from start of cooling to target: Target was ICP reduction and cooling was continued to achieve this
Target temperature: Target variable was ICP ≤ 20 mmHg
Duration of cooling: Mean 61.7 (range 20–96) hours; time depended on stable ICP during rewarming and improvement on CT
Rewarming: ‘Gradual and passive rewarming of the brain, with the intermittent application of ice packs to the area of the
craniectomy’ keeping ICP stable and avoiding ‘abrupt’ rise in brain temperature
Outcomes ICP, temperature, mortality in ICU and GOS on discharge from ICU
Temperature results: Mean intracranial temperature reduced from 37.1 ºC (range 35.3–38.9 ºC), prior to cooling, to mean 35.2 ºC
(range 33.6–37.6 ºC) over 48 hours following start of cooling (p < 0.0001)
Range of temperature change with cooling +0.3 °C to –4.5 °C
ICP results: Mean ICP reduced from 28 mmHg (18–64 mmHg), in the pre-cooling period, to 13 mmHg (2–51 mmHg) in the post-
cooling period (p = 0.0001). ‘During the pre-cooling period, 19 of the 23 (82.60%) patients presented ICP higher than or equal to
20 mmHg and only two patients (8.69%) maintained an ICP over 20 mmHg after cooling’

TraumaTec Neuro-Wrap Neuro ICU Study

Miller 200953 (abstract of the protocol); interim data on nine patients
provided by principal investigator, Professor Claudia Robertson
(3 January 2011)
Methods Descriptive, non-randomised single group study to determine rate and degree of brain cooling with TraumaTec Neuro-Wrap
Participants Total n = 20, with the data provided are for the first nine; age and gender not reported
Brain injury
Participating sites: Single neuro ICU in USA
Language: English
Follow-up complete: No – interim data
Temperature measurement sites: Intracranial and core body (sites not specified)
Interventions Head and neck cooling for 8 hours with circulating water device (TraumaTec Neuro-Wrap)
Outcomes Rate and degree of intracranial cooling, complications
Temperature results: Mean start brain temperature 37.5 ± 1 °C; lowest brain temperature 35.5 ± 1.4 °C, difference 2.0 °C,
body temperature remained constant between 37.8 °C and 36.7 °C. Lowest brain temperature achieved was 33.1 °C, with
corresponding core temperature of 37.1 °C. Lowest core body temperature seen in any subject was 36.2 °C
Complications: No systemic complications or local complications attributable to the device, e.g. skin irritation of the scalp or neck,
restriction of jugular venous drainage by the neck section resulting in ICP elevations, or compression of neck structures resulting
in barostimulation and changes in blood pressure
Notes Graph supplied with unpublished data shows cooling for 6.5 hours
Rhinochill Neuro ICU Study

Sung and colleagues 200954 (abstract of protocol and interim
data); abstract of completed study www.benechill.com/wp/
clinical-program/clinical/neuro-icu-cooling-study/ (accessed 1
November 2010); full report (submitted for publication) provided
by Dr Denise Barbut (14 April 2011), now published as Abou-Chebl
and colleagues 201158
Methods Non-randomised single group safety and feasibility study of intranasal cooling induction with the Rhinochill device
Participants Total n = 15, mean age 50.3 (range 21–88) years, 9 female
Five ICH, 5 ischaemic stroke, 5 TBI with a clinical indication for cooling (e.g. raised ICP or fever), baseline NIHSS 26.7 ± 6.7
Participating sites: Three neuro ICUs in USA
Language: English
Follow-up complete: Yes, to planned 24 hours but one patient only received 30-minute cooling
Temperature measurement sites: Intracranial (parenchyma) n = 11; tympanic n = 10; core trunk rectal n = 10, bladder n = 2,
pulmonary artery n = 2, oesophageal n = 1
Interventions Intranasal cooling (Rhinochill) for 1 hour for fever control (n = 9) or neuroprotection/ICP reduction (n = 6), followed by local standard
cooling methods
Outcomes Temperature reduction and ICP reduction at 1 hour, adverse events, 24-hour follow-up (temperatures, vital signs, neurological
examination, rhinoscopy, chest radiograph, brief smell identification test if conscious), repeat rhinoscopy and smell test at 2 weeks
after cooling or discharge if sooner
Temperature results after 1 hour of cooling: Intracranial temperature reduction mean 1.4 ± 0.4 °C (n = 11 of 15), core trunk
temperature reduction 1.1 ± 0.6 °C (n = 15)
ICP results: Mean initial ICP = 16 mmHg, mean reduction after 1 hour of cooling = 5.2 mmHg (32.5%)
Complications: Transient minor nasal erythema and discharge was seen on rhinoscopy
One device-related serious adverse event: Mean arterial pressure rise (75–94 mmHg) within 15 minutes of start of cooling,
resolved by stopping the device and administering sedation
Notes Mean ICP was not raised, presumably because ≤ 6 of 15 patients were being cooled for raised ICP
Smell tests were possible in no patients at 2 weeks because dead (n = 6) or not conscious
Funded by Benechill Inc.
126 Appendix 6
Other studies (not randomised controlled trials): cardiac arrest

Andreas and colleagues 200855 (conference abstract)
Methods Prospective observational case series to assess preliminary safety and effectiveness of Rhinochill device
Participants Total n = 7, median (first to third quartile) age 68 (range 66–74) years, 6 male
Successfully resuscitated after cardiac arrest
Participating sites: The emergency department of a tertiary care university hospital in Austria
Language: English
Follow-up complete: Unclear – neurological outcome was assessed but when and whether in all patients is not reported
Temperature measurement sites: Oesophageal
Interventions Intranasal cooling with Rhinochill device for 60 minutes (followed by cooling to 33 °C up to 24 hours with another device)
Outcomes Temperature reduction at 60 minutes, safety
Temperature results: Median (first to third quartile) oesophageal temperature at baseline 35.4 °C (range 34.7–36 °C). After
60 minutes, 34.1 °C (range 33.4–34.9 °C). Cooling rate 1.6 °C (range 1–1.7 °C)/hour
Safety results: No adverse events related to cooling device
Two patients favourable neurological outcome (CPC 1 or 2), assessment point not reported but possibly hospital discharge
Notes
Busch and colleagues 200856 (conference abstract interim report);

Busch and colleagues 201059
Methods Multicentre single arm descriptive study of effectiveness, safety and feasibility of Rhinochill device
Participants Total n = 84, median (first to third quartile) age 71 (range 63 to 79) years, 64 male
Successfully resuscitated after cardiac arrest
Participating sites: 11 European emergency departments and ICUs (Austria, Belgium, Germany)
Language: English
Temperature measurement sites: Tympanic (n = 82); core: arterial (n = 17), oesophageal (n = 19), rectal (n = 22), bladder
(n = 26) = 84 (the four sites of core temperature measurement were analysed together as a composite core temperature)
Interventions Intranasal cooling with Rhinochill device for 60 minutes (followed by cooling to 33 °C up to 12–24 hours with a systemic device)
Outcomes Primary end points: cooling rate, time needed to achieve mild hypothermia (34 °C) and target temperature (33 °C), evaluation of
possible side effects of evaporative cooling in the nasopharynx and elsewhere
Secondary end points: survival rate and neurologic outcome (CPC) at hospital discharge
Adverse events: from time of enrolment to hospital discharge and olfactory function
Temperature results: actual cooling duration with Rhinochill median 60 (range 25–195) minutes. Composite core cooling rate
(n = 84) median (first to third quartile) 1.1 (0.7; 1.5) °C/hour (n = 84)
Cooling rate with arterial and oesophageal temperature – faster reacting sites – (n = 36) 1.4 (0.9; 2.0) °C/hour
Cooling rate with bladder and rectal temperature – slower reacting sites – (n = 48) 0.9 (0.5; 1.2) °C/hour
No patient reached 33 °C core temperature within 1 hour
Outcome results: 34 of 84 patients survived, 26 of 34 with favourable neurological outcome (CPC 1–2).
Device-related adverse events: In one patient with cardiogenic shock given high oxygen flow rate 60–80 l/minute, cold-induced
tissue damage (persisted until death due to cardiac failure), reversible cold-related nasal discolouration n = 10 (these patients had
lower oxygen flow rate 40–50 l/minute), epistaxis n = 2 (resolved), coolant in sinus (n = 1) (resolved), periorbital gas emphysema
n = 1 (resolved). Nine patients showed aspiration on chest radiograph but this did not have characteristic appearance of liquid
coolant aspiration
Eleven patients had olfactory function assessed and all were within normal limits
The authors’ note: ‘Essential safety measures that prevent tissue damage include uncovering the face and keeping the mouth
open during cooling, so that coolant vapor can escape from mouth and nostrils’ (p. 947)
Notes Benechill Inc. provided per patient payment in support of this study
If these patients are cool at baseline [mean core temperature was approximately 36 °C at baseline (figure 2)] and also have low
flow/cardiogenic shock nasal tissue discolouration/freezing is presumably more likely than in, for example, brain-injured patients,
who are warmer and possibly better perfused peripherally

Characteristics of excluded studies
Traumatic brain injury
Zhmurko 197193 (USSR study, language Russian) Not a randomised trial although there was a control group (n = 128)
TBI, n = 149 cooled but no information is given about their care. ICP values not reported
Interventions: Head cooling with passive (ice and salt) cooling helmet, target Insufficient information on temperature to assess temperature
temperature not reported. Cooling duration: mild TBI 8 hours (if ICP normal), reduction. Temperature measurement sites: axilla and ?ear canal
12 hours (raised ICP); moderate TBI (usually raised ICP) 2 × 8-hour cooling, (i.e. method described by Bukov VA, Vinogradov VI. Khirurgiya,
16-hour interval; severe TBI 2 × 12 hours’ cooling, 12-hour interval; skull 1968;10:50). It seems likely this was ear canal temperature
fracture 12 hours or 24 hours cooling × 2 or more because a slightly later paper by Bukov and Vinogradov reports that
‘temperature of the auditory canal wall near the tympanic membrane
Outcomes: ‘Disappearance of pathological symptoms’, hospital length of reflects temperature of the basal brain portion with a precision up
stay to ± 0.4 °C’ (Bukov et al. Determination of brain temperature during
cooling of the head. Vestn Khir Im II Grek 1970;104:113–14)
Ioffe and Sumskii 197792 [USSR study (Moscow), language Russian] Not a randomised trial
TBI, n = 56 (33 comatose, 9 sedated, 18 with tracheostomy for assisted Insufficient information on temperature to assess temperature
breathing) reduction. In hyperthermic patients the target brain temperature
Interventions: Convective head cooling with ‘fluidocraniotherm’ device, of 28–30 °C was not always achieved but normothermia was
lowest air temperature –5 °C, target temperature of cerebral cortex 28– achievable (decrease from 39.5–40 °C to 36.5–37 °C). Temperature
30 °C, maintaining rectal temperature at 33–34 °C. Duration: 6–29 hours measurement sites: intracranial (n = 15), external auditory meatus,
with repeat cooling if patients’ condition worsened (e.g. ICP rise). Two oesophagus, rectum. Note: This is an early report of the clinical use
patients required body warming (45 °C air) because of excessive rectal of intracranial temperature measurement in humans
temperature reduction
Outcomes: Mortality (? in hospital)
Kang and colleagues 2004162 (Language Chinese) Insufficient information on methods to assess quality. Patients
Total n = 81, of whom severe TBI (GCS 3–8) n = 40 ‘divided’ into groups
Interventions: In severe TBI group: head and neck cooling with cooling pads Insufficient information on temperature to assess temperature
and ‘drugs that reduce temperature ’ (n = 22) vs ‘normal care’ (n = 18) reduction
Outcomes: Immune function, mortality and disability
Liu and colleagues 200675 (Chinese study, published in English) Not a randomised trial. Although the paper reports that ‘each patient
TBI (GCS ≤ 8), total n = 66 was assigned to one of three groups according to a randomization
table’ [p. 59, according to the corresponding author it was not a
Interventions: Cooling started on admission or after craniotomy. Head randomised trial (personal communication, 12 January 2007)].
cooling with water circulating hood and neck cooling with frozen gel Described as ‘double-blind’ but unclear how investigators were
pads – brain surface temperature reduced to 33–35 °C ‘within 2 hours blinded to the intervention, no information on blinding of analysis
in most patients’, rectal temperature 36.5–37.5 °C (n = 22) vs systemic or outcome assessment or intention to treat (but intention to treat
hypothermia – aim rectal temperature 33–35 °C but ‘about 37 °C’ in presumed for GOS because follow-up numbers reported and no
results (n = 21) vs normothermia – brain and rectal temperatures ‘about mention of crossover)
37 °C throughout’ (n = 23)
Some patients in the head-cooled group may not have received head
Outcomes: ICP, SOD, complications of hypothermia, GOS at 2 years cooling. as it was applied intermittently ‘on each of three successive
days for 0–6 hours (average 4.5 hours) according to the patient’s
condition’ (p. 59)
Insufficient information on temperature to assess temperature
reduction. In the results rectal temperature in the systemic
hypothermia group is reported as ‘about 37 °C’ but the aim was
33–35 °C, communication with the corresponding author failed
to clarify this. Temperature measurement sites: ‘brain surface
temperature’, rectal
Mean (SD) ICP data are reported at 24, 48 and 72 hours after
injury and was not significantly different between head-cooled and
systemically cooled patients, and was significantly lower in these
groups than in the uncooled patients. But mean ICP was high in
all groups at all time points. The lowest reported values were in
systemically cooled patients at 72 hours: mean 26.48 ± 3.75 mmHg
128 Appendix 6
Qiu and colleagues 2006a147 (Chinese study published in English) Not a randomised trial
TBI (GCS ≤ 8), total n = 90 Temperature measurement sites: intracranial (10 mm below cortex or
Interventions: Mean 4.1 hours after admission or after craniotomy. Head where ICH was evacuated), rectal
cooling with water circulating hood and neck cooling with frozen gel Figure 1 shows brain temperature every 12 hours for 96 hours and
pads – brain temperature 33–35 °C ‘within 2 hr’, rectal temperature figure 2 the rectal temperature. But the scale was judged too small
37.5 °C (n = 45) vs normothermia – brain temperature ‘about’ 37 °C, rectal to reliably extract the data and it is not clear how the data were
temperature ‘about’ 38 °C (n = 45) calculated (e.g. at a single time point or over each 12-hour period).
Outcomes: ICP at 24, 48 and 72 hours after injury; complications of Cooling duration was 72 hours, followed by ‘natural rewarming’.
hypothermia; GOS 6 months By 90 hours, mean brain temperature still appears to be in the
cooled range below 35°C, i.e. 20 hours after start of cooling (figure
1). The text reports that: ‘After cessation of hypothermia, the brain
temperature returned to baseline in 8.4–20.6 h’ (p. 997). Baseline
was approximately 37 °C (figure 1)
Brain temperature appears to be consistently approximately 1 °C
lower than rectal temperature in the non-cooled patients (figures 1
and 2), which seems unusual
Qiu and colleagues 2006b76 (Chinese study published in English) Insufficient information on methods to assess quality. Patients
TBI (GCS ≤ 8), total n = 96 ‘randomised’/’categorised’ but no details. No intention-to-treat
analysis. Loss to follow-up: 40 of 96 patients enrolled did not have
Interventions: Head cooling with water circulating hood and neck cooling GOS at 1 year reported because it seems that only the patients who
with frozen gel pads to nasopharyngeal temperature 33–35 °C (n = 24) developed thrombocytopenia were followed up
vs systemic cooling – rectal temperature 34.5–36 °C ‘or at the similar
nasopharyngeal temperature’ to the head cooled group (n = 30) vs Insufficient information on temperature to assess temperature
‘normothermia’ (n = 42) reduction. Temperature measurement sites: nasopharyngeal,
intracranial (10 mm below cortex or where ICH was evacuated), rectal
Outcomes: Thrombocytopenia days 1, 3, 5 and 7; GOS at 1 year
Qiu and colleagues 2007163 (language Chinese) and Qiu and colleagues Not a randomised trial
2007164 (conference abstract in English) Insufficient information on temperature to assess temperature
TBI (GCS 4–8), total n = 37 reduction
Interventions: Head and neck cooling + decompressive craniectomy (n = 16)
vs normothermic control patients (n = 21)
Outcomes: ICP, complications, GOS 6 months
Fang 2009165 (language Chinese) Retrospective study – not a randomised trial

TBI (GCS 3–8), total n = 91 Insufficient information on temperature to assess temperature
Interventions: Hemicraniectomy + head and neck cooling (n = 49) vs reduction
hemicraniectomy (n = 42)
Outcomes: ICP and prognosis

Stroke: ischaemic
Xu and colleagues 2003166 (language Chinese) Insufficient information on methods to assess quality, although
Ischaemic stroke, total n = 44 ‘computerised’ randomisation is reported
Interventions: Head cooling (cooling hat) + routine care (n = 24) vs Insufficient information on temperature to assess temperature reduction.
routine care (n = 20) Site of temperature measurement: axilla
Outcomes: ESS days 7, 21, 90; BI days 21, 90
Xia and Yan 2004167 (language Chinese) Insufficient information on methods to assess quality, although
Ischaemic stroke, total n = 61 ‘computerised’ randomisation is reported
Interventions: Head cooling + routine care (n = 31) vs routine care Insufficient information on temperature to assess temperature reduction
(n = 30)
Outcomes: Infarct size at day 7, in-hospital mortality, NDS and ADL at
hospital discharge
Yamada and colleagues 200472 (Japanese study, conference abstract Not a randomised trial – feasibility and safety study
in English) No intracranial temperature measurements. Bladder temperature
Ischaemic stroke NIHSS > 1, n = 17 reported as unchanged with cooling but no actual bladder temperatures
Interventions: Head and neck cooling for 3–7 days, unsedated patients given
(‘no anaesthesia’) Sites of temperature measurement: jugular bulb, tympanic membrane,
Outcomes: adverse events, mortality, BI 3–10 months after stroke bladder, axilla
Two patients had skin erosion but whether that was due to the head-
cooling device is not reported
Contact with the author has not produced more information
Li and colleagues 2005168 (language Chinese) Not a randomised trial

Ischaemic stroke, total n = 92 Insufficient information on temperature to assess temperature reduction
Interventions: Head cooling within 6 hours of stroke (n = 31) vs within
7–10 hours (n = 31) vs within 11–14 hours (n = 30)
Outcomes: Infarct volume (CT) 2–3 days after cooling; in-hospital
mortality, NDS at hospital discharge
Takenobu and colleagues 2005169 (Japanese study, conference Not a randomised trial, control patients matched for age and ischaemic
abstract in English) area on CT
Ischaemic stroke, total n = 38 No temperature data
Interventions: Head and neck cooling with circulating coolant at 5 °C
(MC-3000, Mac-Eight, Japan) (n = 24) vs no cooling (n = 14)
Outcomes: Oedema volume day 6 (median), ischaemic volume day 33
(median) on CT
Chen and colleagues 2006170 (language Chinese) Insufficient information on methods to assess quality, though mentions
Ischaemic stroke with body temperature 39–40 °C, total n = 122 ‘computerised’ randomisation. No relevant functional outcome measures
Interventions: Head cooling (n = 49) vs tepid sponging and ice cold Insufficient information on temperature to assess temperature reduction.
saline bowel irrigation (n = 43) vs healthy control patients (n = 30) Site of temperature measurement: body (?where)
Outcomes: serum cortisol, lipid peroxide, SOD at days 2, 3, 4 after
raised temperature; NDS and ADL at hospital discharge
130 Appendix 6
Wang and colleagues 2006171 (US study, language English) Case study of head cooling in a patient with terminal ischaemic stroke in
Severe ischaemic stroke, 1.7-cm midline shift, n = 1 the COOL BRAIN-stroke trial
Intervention: Head and neck cooling, with body warming to maintain Sites of temperature measurement: bilateral parenchymal (0.8 cm below
body temperature at 35 °C cortical surface), body (?where)
Outcomes: Intracranial temperature and ICP in each hemisphere Although there was temperature data with head cooling this case study
was judged not relevant for inclusion in the review
The patient was hypothermic at baseline with body temperature
of 35 °C, the non-infarcted hemisphere temperature 35.1 °C and
the infracted hemisphere approximately 33.3 °C. When treatment
was withdrawn at the family’s request after 10 hours of cooling the
intracranial temperatures were approximately 27.5 °C and 19 °C. The
increase in temperature difference between the hemispheres was
interpreted as poorly perfused brain tissue being more susceptible
to head cooling, but in a moribund patient this is perhaps of more
academic interest than clinical relevance. The body warming and head
cooling may simply have accentuated the reduction in brain temperature
below body temperature which has been shown to occur with brain
death (Lyson, et al. Neurol Neurochir Pol 2006;40:269–75)
Yang and colleagues 2006130 (language Chinese) Not a randomised trial. No relevant functional outcome measures
Ischaemic stroke with temperature of ≥ 39 °C, total n = 136 Insufficient information on temperature to assess temperature reduction
Interventions: Head cooling until body temperature ≤ 37.5 °C (n = 30) vs
head cooling for 1–2 days (n = 34) vs head cooling for 3–4 days (n = 41)
vs head cooling for 5–6 days (n = 31)
Outcomes: recurrence of pyrexia; NDS and ADL at hospital discharge
Inoue and colleagues 2007172 (Japanese study, conference abstract Not a randomised trial
in English) Insufficient information on temperature to assess temperature
Ischaemic stroke, total n = 53 reduction. ‘Ear drum’ temperature 35.2 ± 0.3 °C during cooling. Sites of
Interventions: Active head and neck cooling at 5 °C for 3 days (n = 37); temperature measurement: ear drum, core body temperature (?where)
control patients with no head cooling (n = 16)
Outcomes: Mortality, complications, frequency of haemorrhagic infarct
and brain herniation within 7 days of stroke
Hao and colleagues 2008173 (language Chinese) Insufficient information on methods to assess quality (‘number method’
Ischaemic stroke, total n = 45 randomisation). No relevant functional outcome measures
Interventions: Head cooling + batroxobin (n = 22) vs normal Site of temperature measurement: tympanic
temperature + batroxobin (n = 23)
Outcomes: modified Edinburgh-Scandavian Stroke Scale at days 7, 14
and 21

Stroke: haemorrhagic
Shuaib and colleagues 1996174 (US study, language English) Not a randomised trial
SAH – three awake and alert, one GCS ≤ 8, total n = 4 No temperature data: ‘Uncertain about the exact degree of
Intervention: ‘Mild’ head cooling for 1 hour/day for 3–4 days (‘cooling cooling produced by the cooling hats.’ (p. 57). Site of temperature
hat’, Manson and Manson Engineering, Longview, WA) (n = 4) measurement: body (?where)
Outcomes: Extracellular glutamate (microdialysis) 1 hour before, during
and 1 hour after head cooling
Dohi and colleagues 2000175 (Japanese study, language Japanese); Not a randomised trial
Dohi and colleagues 2006176 (Japanese study, language English) Insufficient information on temperature to assess temperature reduction
Haemorrhagic stroke (ICH/SAH), total n = 89 with nasal airflow. In the Japanese paper the mean temperatures for
Intervention: Cooling induction immediately post operative (SAH n = 11) cases (37.8 ± 0.29 °C) and control patients (38.0 ± 0.18 °C) over the
or post admission (ICH n = 35) with rectal indomethacin 100 mg plus 4-day cooling period are reported, which is an indication of the effect of
8–12 l/minute chilled air (24 °C) via a ‘balloon catheter’ in one nostril indomethacin, but not for the period of induction of cooling with nasal
with airflow exiting through the mouth; cooling maintenance – brain airflow. How long nasal airflow was administered for induction is not
temperature 36.5–37.5 °C – with rectal indomethacin 6 mg/kg/day plus reported in these two papers but Dohi and colleagues (200663) says
room temperature regulation plus additional indomethacin to maximum ‘in general … for a short period’. Site of temperature measurement:
of 600 mg/day if needed (n = 46). Convenience control group (ICH 13, cerebral ventricle
SAH 30, n = 43).
Outcomes: CSF interleukin-1β and serum bilirubin at 1, 2, 4 and 7 days;
vasospasm (in patients with SAH); GOS 3 months
Feng colleagues 2002148 (language Chinese) Insufficient information on methods to assess quality. 1 : 1 matched
ICH, total n = 40 groups – not strictly randomised. No relevant outcome measures
Intervention: Active head cooling ‘controllable semiconductor brain- Insufficient information on temperature to assess temperature reduction
protecting freezer’ set at 6 °C + routine care (n = 20) vs routine care
(n = 20)
Outcomes: Cerebral oedema volume on CT (Tada formula) and ESS at 1
and 2 weeks
Haemorrhagic stroke, total n = 58 ‘computerised’ randomisation reported, not intention to treat. No
relevant outcome measures
Interventions: Head cooling with ‘head temperature control instrument’
(n = 28) vs control (n = 30) Insufficient information on temperature to assess temperature reduction
Outcomes: Cerebral oedema volume on CT, flow velocity in middle
cerebral artery, pulsatility index, NDS at 21 days
Su and colleagues 2004149 (language Chinese) Insufficient information on methods to assess quality. Patients ‘divided’
ICH, total n = 42 1 : 1 but no details on how. No relevant outcome measures
Interventions: Active head cooling with cooling pads (Harbin Institute of Insufficient information on temperature to assess temperature reduction.
Technology) on area of haemorrhage shown on CT (n = 21) + routine Site of temperature measurement: tympanic
care vs routine care (n = 21)
Outcomes: Cerebral oedema volume on CT (Duotian formula) and ESS at
1 and 2 weeks
Zhang and colleagues 2006178 (language Chinese) Insufficient information on methods to assess quality, although
ICH, total n = 70 ‘computerised’ randomisation is reported. No relevant outcome
measures
Interventions: Head and neck cooling + routine care (n = 35) vs routine
care (n = 35) Insufficient information on temperature to assess temperature reduction
Outcomes: Neuropeptide Y, neurotensin, calcitonin gene-related peptide,
endotheline at day 1, 7 and 14 post stroke
Xia and colleagues 2003179 (language Chinese) Probably case control. Insufficient information on methods to assess
Haemorrhagic stroke, total n = 263 quality
Interventions: Direct microscopic haematoma evacuation + head cooling Insufficient information on temperature to assess temperature reduction
(n = 132) vs direct microscopic haematoma evacuation alone (n = 131)
Outcomes: Re-bleeding rate, mortality, NDS and ADL on hospital
discharge
132 Appendix 6
Haemorrhagic stroke, total n = 91 ‘computerised’ randomisation is reported. No relevant functional
outcome measures
Interventions: Head cooling (n = 31) vs observation group (n = 30) vs
healthy control patients (n = 30) Insufficient information on temperature to assess temperature reduction.
Site of temperature measurement: scalp skin
Outcomes: Serum nitric oxide, SOD, glutamate, NDS and ADL at day 2
and day 7 or 10 (unclear)
Dong and colleagues 2005141 (language Chinese) Insufficient information on methods to assess quality. Patients ‘divided’
Haemorrhagic stroke with body temperature 38–40°C (high into groups, no details of what that means. No relevant functional
temperature), total n = 91 outcome measures
Interventions: Head cooling (n = 54) vs tepid sponging and ice cold Insufficient information on temperature to assess temperature reduction.
saline bowel irrigation (n = 37) Site of temperature measurement: body (?where)
Outcomes: Serum cortisol, lipid peroxide, SOD at days 2, 3, 4 after
high temperature; NDS and ADL at high temperature and on hospital
discharge
Ou and colleagues 2005140 (language Chinese) Insufficient information on methods to assess quality. Mentions
Haemorrhagic stroke, total n = 170 ‘computer’ randomisation but no details. No relevant functional outcome
measures
Interventions: Head cooling until body temperature ≤ 37.5 °C (n = 43) vs
head cooling for 1–2 days (n = 51) vs head cooling for 3–4 days (n = 38) Insufficient information on temperature to assess temperature reduction.
vs head cooling for 5–6 days (n = 38) Site of temperature measurement: body (?where)
Outcomes: Rate of pyrexia recurrence, NDS and ADL at hospital
discharge
Zhang and colleagues 2006180 (language Chinese) Insufficient information on methods to assess quality. Mentions
Haemorrhagic stroke, total n = 124 ‘computer’ randomisation but no details. No relevant functional outcome
measures
Interventions: Head cooling (n = 63) vs control (n = 61)
Insufficient information on temperature to assess temperature reduction
Outcomes: Interleukin-6, tumour necrosis factor alpha prior to treatment
and day 8; NDS and ADL ?at hospital discharge
Stroke: mixed
Liu and colleagues 1999139 (language Chinese) Insufficient information on methods to assess quality. ‘Computerised’
Mixed stroke, total n = 62 randomisation is reported but those who could not afford the head-
cooling device were cooled with ice packs
Interventions: Cooling (n = 31): either cooling mattress + ‘skull
temperature reducing instruments’ (in young patients) or head Insufficient information on temperature to assess temperature reduction
cooling + ice packs to abdomen and axillae (old and frail patients) or
head cooling alone with hat or ice packs (patients sensitive to cooling) vs
control patients (n = 31)
Outcomes: In-hospital mortality and length of hospital stay
Tang and colleagues 2008181 (Chinese study, English abstract) Conference abstract relating to development of a head-cooling device,
Mixed stroke, n = not reported which says ‘Data will also be presented from human positron emission
tomography studies showing a decrease in glucose metabolism in the
selectively cooled brain areas, and from clinical trials in haemorrhagic
and ischemic stroke patients’. One of the authors provided a full paper
on the PET study (Zhang and colleagues 2005182 in volunteers – see
Appendix 7) but had no copy of the full paper with the clinical data
Wu and colleagues 2010183 (language Chinese) Insufficient information on methods to assess quality. Abstract says
Mixed stroke, total n = 32 ‘randomised’ but paper suggests this was probably a case control study
– matched 1 : 1 – but unclear. No relevant functional outcome measures
Interventions: Head cooling over area of infarct or haemorrhage
(controllable semiconductor refrigeration apparatus, Harbin Institute of Insufficient information on temperature to assess temperature reduction.
Technology) within 6 hours of stroke for 48 hours or within > 6 hours for Sites of temperature measurement: nasal and tympanic
96 hours + conventional care (n = 16) vs conventional care (n = 16)
Outcomes: infarct and oedema volume 14 days; ESS at 14 and 30 days

Brain injury
Mellergard 1992184 (Swedish study, language English) Case studies of head cooling and nasopharyngeal cooling – judged
TBI and SAH (n = 5), all with shaved and bandaged heads to have insufficient detail for inclusion
1. Head cooling with frozen gel cap, no close or direct contact with exposed Some patients had more than one head-cooling method but not at
skin because of concerns about skin damage, for 2 hours (n = 3) the same time. The cooling was of an exploratory ad hoc nature,
meaning that coincidental temperature change or lack of it for other
2. Head and neck cooling with a liquid cooling helmet set to 15 °C for reasons cannot be ruled out. There is a graph for each cooling
4–5 hours (n = 2) method; each graph shows a single patient’s response. Otherwise
3. Nasopharyngeal cooling with chilled humidified oxygen at 5–10 l/minute the actual temperatures are not reported
through a Foley catheter in one nostril for ≥ 2 hours (n = 3) Sites of temperature measurement: intracranial (ventricular), epidural,
Outcomes: Temperature change rectal
Ventricular temperature reduction with:
1. No change
2. 0.5–0.6 °C reduction in one patient, no change in the other
3. Maximum 0.2 °C
Mariak and colleagues 200266 (Polish study, language English) Case studies of face fanning for fever reduction – judged to have
Brain injury with fever (n = 6) insufficient detail for inclusion
Face fanning, airflow 3.5 m/second, duration not reported, patients had This refers to earlier research presented in a conference abstract
dressings on their heads (Mariak and colleagues 1993185), which does not report actual
temperatures. The temperature reduction is reported in Mariak and
colleagues 200266
Sites of temperature measurement: intracranial (subdural), tympanic
In three of six patients subdural temperature decreased. Mean
reduction = 0.15 ± 0.18 °C. The authors comment that the low air
speed and head dressings may help to explain why there was not a
greater temperature reduction
Dohi and colleagues 200663 (Japanese study, language English) Technical note on nasopharyngeal cooling including two case studies
Severe TBI, (n = 2) – judged to have insufficient detail for inclusion
8–12 l/minute chilled air (24 °C) via a 16 g Foley ‘balloon’ catheter in one Sites of temperature measurement: intracranial (ventricular)
nostril, the other nostril occluded with an epistaxis balloon, the air exited In patients with SAH, ventricular temperature reduced from 37.8 °C
through the mouth plus head fanning. Duration of cooling: ‘in general … for to 34 °C (3.8 °C) in 45 minutes, in patients with TBI from 39 °C to
a short period’ 37 °C (2 °C) in 120 minutes
Wang and colleagues 2001186 (language Chinese) Insufficient information on methods to assess quality, although
Severe brain injury (GCS < 8), total n = 45 ‘computerised’ randomisation is reported
Interventions: Passive head and neck cooling (blue ice strips) (n = 22) vs Insufficient information on temperature to assess temperature
routine care (n = 23) reduction. Sites of temperature measurement: parenchymal or brain
surface and rectal
Outcomes: Mortality and GOS at hospital discharge
Zhao and colleagues 200344 (language Chinese) Insufficient information on methods to assess quality; ?’computer’
Severe brain injury (GCS ≤ 8) admitted within 12 hours of injury and having randomisation
had either evacuation of haematoma or decompressive craniectomy, total Insufficient information on temperature to assess temperature
n = 69 reduction
Interventions: Head cooling (n = 23) vs systemic hypothermia (n = 22) vs
normothermia (n = 24). When cooling was started is not reported
Outcomes: In-hospital complications (pneumonia, gastrointestinal bleed,
arrhythmias, renal failure), mortality and GOS at hospital discharge
Yang and colleagues 2006130 (language Chinese) Insufficient information on methods to assess quality, although
Severe brain injury (GCS ≤ 8), total n = 87 ‘computerised’ randomisation is reported
Interventions: Head and neck cooling (hat closely bandaged on) (n = 44) vs Insufficient information on temperature to assess temperature
control patients (n = 43) reduction. Site of temperature measurement: brain (?where)
Outcomes: ICP; ‘early complications’ – hyperglycaemia, epilepsy,
vasospasm, stress ulcer at 1 week after cooling; GOS 3 months
134 Appendix 6
Cardiac arrest
Hachimi-Idrissi and colleagues 1999187 (conference abstract, Belgian Non-randomised precursor to Hachimi-Idrissi and colleagues 2001, little
study, language English) information on cooling device (‘new helmet device’), probably Frigicap
Prehospital cardiac arrest, total n = 21, the first 11 were cooled, the Insufficient information on temperature to assess temperature reduction
subsequent 10 were control patients Site of temperature measurement: tympanic and bladder
Interventions: Head cooling with a helmet device (?passive) during
resuscitation for up to 4 hour (11) vs no cooling (n = 10)
Outcomes: Speed and effectiveness of helmet device to cool to target
temperature of 34 °C
‘No complication’ from the cooling helmet
Hachimi-Idrissi and colleagues 200169; Hachimi-Idrissi and RCT. Hachimi-Idriss and colleagues 2001 has inadequate information on
colleagues 2005188 (study of S100β with cooling which includes the randomisation method (‘prospectively blindly randomised’) or blinding
patients in Hachimi-Idrissi and colleagues 2001); additional information but Holzer and colleagues 2005 reports the method (random number
in Holzer and colleagues 2005189 (Belgian study, language English) tables, opaque envelopes) and that outcome assessors were blinded
Cardiac arrest – asystole or pulseless electrical activity, total n = 30 and includes data on an additional three patients
(plus three reported in Hachimi-Idrissi and colleagues 2005 and Holzer Insufficient information on temperature to assess temperature reduction.
and colleagues 2005) Hachimi-Idrissi and colleagues 2001 reports baseline tympanic
Interventions: Passive head cooling after ROSC and stabilisation in temperature but not baseline bladder, and time to target but not actual
emergency room with an aqueous glycerol helmet (Frigicap) –4ºC, end temperatures
applied over paper cap and changed every hour, duration of cooling Hachimi-Idrissi and colleagues 2005 (reports target was 33 °C) and
4 hours or until bladder temperature 34 °C (n = 16) vs no cooling – Holzer and colleagues 2005 include no temperature data
passive rewarming to 37 °C if hypothermic, paracetamol if temperature Site of temperature measurement: tympanic (infrared thermometer) and
>38 °C (n = 14) bladder
Outcomes: Feasibility and speed of helmet device to cool to target
temperature of 34 °C.
CPC at hospital discharge
‘No complication’ from the cooling helmet
Ikeda and colleagues 2007190 (conference abstract, Japanese study, Not a RCT
language English) No information on cooling methods except ‘selective head’ and ‘whole
Cardiac arrest, total n = 12 body’
Interventions: Selective head cooling (n = 7) vs whole body cooling Insufficient information on temperature to assess temperature reduction.
(n = 5), duration not reported, target temperature 34±1°C No information on temperature measurement sites
Outcomes: Urinary 8-hydroxy-2-deoxyguanosine, outcome at 28 days No response from authors to request for further information
after admission
Busch and colleagues 2008191 (conference abstract, German study, Non-randomised feasibility study of induction of hypothermia by
language English) transnasal cooling with historic control patients who had had standard
Cardiac arrest after ROSC, total n = 70 care
Interventions: transnasal head-cooling cooling (Rhinochill) followed by Insufficient information on temperature to assess body temperature
intravascular cooling (n = 19) vs intravenous 4 °C saline followed by reduction with head cooling. Temperature measurement sites: tympanic
intravascular cooling (n = 41) vs intravascular cooling alone (n = 10) and bladder or rectal
Outcomes: Time from hospital admission to target temperature; CPC These patients may also have been included in the paper by Busch and
and mortality at 7 days and hospital discharge colleagues 2010 (under included studies above)
Storm and colleagues 200870 (German study, language English) Non-randomised feasibility study: prehospital cooling with hypothermia
Cardiac arrest, total n = 49 caps (PreCoCa)
Interventions: Pre-hospital passive head cooling with gel cap after return Temperature measurement site (tympanic) did not meet inclusion criteria
of ROSC (n = 24) vs standard care control patients (n = 25) for this review
Outcomes: Change in tympanic temperature from pre-cooling to hospital
admission, adverse events until hospital admission (none related to the
device, e.g. freezing, tissue necrosis), outcome at hospital discharge

Nordberg and colleagues 2009192 (conference abstract, Swedish RCT – early report of Pre-ROSC Intra-Nasal Cooling Effectiveness II
study, language English) (PRINCE II)
Cardiac arrest, total planned n = 100, at time of report n = 15 No details on methods
Interventions: Prehospital, intra-arrest transnasal cooling with Rhinochill No temperature data reported
device (n = 7) vs standard care (n = 8), cooling duration not reported
Outcomes: Outcome at hospital discharge, adverse effects
Takeda and colleagues 2009193 (preliminary data); www.controlled- RCT. This trial has completed, report is in preparation, and a follow-on
trials.com/ISRCTN98089900 (Japanese study, conference abstract in trial is planned to look at outcome (with Dr Yoshimasa Takeda, 18 April
English) 2011, personal communication)
Cardiac arrest, n = 300, n = 3, reported in abstract Temperature measurement site (tympanic) did not meet inclusion criteria
Interventions: Active pharyngeal cooling during or immediately after for this review
resuscitation
Outcomes: Tympanic temperature, neurological recovery, mortality
Wandaller and colleagues 2009194 (Austrian study, language English) Non-randomised feasibility study of head cooling and head and neck
Cardiac arrest, total n = 11: n = 5 series 1, n = 6 series 2 cooling
Interventions: Series 1 active head cooling for 1 hour after ROSC Data not available for temperature change with head/head and neck
with MedCool Rapid Cooling System (n = 5); series 2, active head cooling alone:
cooling + neck cooling (n = 6). Rescue therapy: endovascular cooling if ‘We regret that we were not able to distinguish between the effects of
temperature not reduced by 1 °C after 1 hour, required by 4/5 in series head or head and neck cooling vs endovascular cooling on the different
1 and 2/6 in series 2, total cooling time 12 hours temperature sites’ (p. 464)
Outcome: Difference between jugular bulb temperature and Site of temperature measurement: tympanic, jugular bulb, oesophageal
oesophageal temperature
Device-related adverse events: None
Studies in volunteers
The following studies were excluded because they were proof-of-concept assessments of the
effect of a head-cooling method or device on intracranial temperature in volunteers, i.e. studies
that were not for therapeutic purposes in TBI, stroke or cardiac arrest. In four of the studies
(listed first), participants had brain injuries but most were conscious and eligible for these studies
because they had intracranial temperature monitoring as part of their normal care rather than
because of their injuries. The healthy volunteers (three studies) had non-invasive magnetic
resonance spectroscopy brain temperature measurement. Some of these studies provided
information on adverse effects.
Shiraki and colleagues 1988195 (Japanese study, language English) Observational study
n = 1, 12 years, male Site of temperature measurement: intracranial (lateral ventricle and
Conscious, 8 days after pineal tumour removal, undergoing radiotherapy, parenchyma 1 cm above ventricle) and oesophageal
ventricular drain/temperature monitoring in situ
Intervention: Face fanning with 25 ºC (ambient) air, body covered. One
convective session and one convective plus evaporative (body heating
with electric blanket to produce facial sweating); 20 minutes with
cooling followed by 20 minutes without
Outcome: No convincing effect on intracranial or oesophageal
temperature
Mariak and colleagues 1999196 (Polish study, language English) Observational study of the effect of extubation and restoration of airflow
n = 4, age 38–55 years, 2 female through the upper respiratory tract on temperature
Conscious, post surgery for minor SAH occurring 7–10 days earlier, Site of temperature measurement: intracranial (subdural and on midline
mildly hyperthermic (active warming inducing sweating) between frontal lobes and cribriform plate), oesophageal
Intervention/outcome: On extubation intracranial temperature above
the cribriform plate reduced by 0.4–0.85 °C (mean 0.55 ± 0.21 °C).
Intensive breathing induced a further reduction 0.20–0.30 °C (mean
0.26 ± 0.04 °C)
136 Appendix 6
Mariak and colleagues 2003197 (Polish study, language English) Non-randomised observational study to identify extracranial temperature
n = 14, age 28–70 years, 9 male sites that reliably and repeatably reflect intracranial temperature
Unanaesthetised patients after surgery for subdural haematoma (n = 8), Sites of temperature measurement: intracranial (subdural), tympanic
ICH (n = 2), brain tumour (n = 4); eight conscious with no neurological membrane, oesophageal and rectal
deficit, four GCS 9–14, 2 GCS 8; all had head dressings of various
kinds; mildly hyperthermic as a result of active post-op warming (n = 6),
feverish > 38 °C (n = 4), normothermic (n = 4)
Intervention: Face fanning 32.5 m/second for 20–30 minutes depending
on individual tolerance
Outcome: Mean decrease in subdural temperature 0.15 ± 0.18 °C,
mean decrease in oesophageal temperature 0.05 ± 0.09 °C, mean
decrease in rectal temperature 0.03 ± 0.07 °C
Adverse event: ‘Generally all patients reported an unpleasant sensation
when fanned’ (p. 281)
Kuhnen and colleagues 2005198 (language English) Observation of nasal airflow in an intubated patient with intracranial
n=1 temperature measurement at four points (35-, 28-, 21- and 14-mm
depth)
Intubated patient before removal of a deep brain tumour
Intervention/outcome: Nasal airflow increasing from 5–10–15 l over
20 minutes appeared to attenuate rise in brain temperature but the
patient was hypothermic throughout (all brain temperature points
< 36 °C)
Corbett and Laptook 1998199 (language English) Non-randomised crossover study – cap sequence and magnetic
Ten healthy volunteers, aged 22–47 years resonance spectroscopy measurement sequence alternated between
subjects
Intervention: Passive head-cooling session – two Elasto-gel head caps,
inner cap precooled to 4 ºC and outer to –20 ºC. Control session – same Site of temperature measurement: intracranial measured by magnetic
caps but prewarmed to 34 ºC (n = 9) or room temperature (n = 1). resonance spectroscopy, oral, axilla
Duration 50 minutes with each set of caps
Outcome: Mean superficial cortex temperature with cooling 36.8 ºC,
without 37 ºC. Mean thalamic temperature with cooling 36.6 ºC, without
36.6 ºC. Oral and axillary temperatures unchanged between sessions
Harris and colleagues 200824; Harris 201057 (PhD thesis) (language Non-randomised observational study
English) Site of temperature measurement: intracranial measured by magnetic
Five unsedated healthy volunteers, aged 31–48 years, 3 male resonance spectroscopy, oesophageal
Interventions: 30-minute head cooling followed by 30-minute head and
neck cooling with prototype convective cooling helmet delivering air
42.5 l/second at 14.5 °C
Outcome: Net brain temperature reduction with head cooling 0.45 °C
(SD 0.23 °C, p = 0.01, 95% CI 0.17–0.74°C); with head and neck
cooling 0.378 °C (SD 0.30 °C, p = 0.049, 95% CI 0.00 °C to 0.74 °C).
Equivalent net reductions in oesophageal temperature 0.16 °C (SD
0.04 °C) and 0.36 °C (SD 0.12 °C)
Adverse events: None
Covaciu 201065 (PhD thesis, Swedish study, language English) Non-randomised observational study
Ten unsedated healthy volunteers; mean age 22 years, range Site of temperature measurement: intracranial measured by magnetic
21–62 years, 9 male resonance spectroscopy, axilla (n = 4), rectal (n = 5)
Intervention: Active cooling with bilateral intranasal balloons (QuickCool)
at 20 °C, unilateral in one subject, for 60 minutes
Outcome: Brain temperature reduction measured by magnetic
resonance spectroscopy –1.7 ± 0.8°C (n = 9), brain temperature
reduction measured by phase mapping method –1.8 ± 0.8°C (n = 9),
rectal temperature reduction –0.5 ± 0.3°C (n = 5)
Adverse events: Ear, nose and throat examination showed increased
nasal secretions (n = 9), redness (n = 3), small ulcers (n = 3). Headache
(n = 4), dizziness (n = 1). Subsequent rhinorrhoea (n = 7). Balloons rated
as pleasant (n = 1), neutral (n = 3), unpleasant (n = 6). All fully recovered
by day 7 follow-up

Studies awaiting assessment
Randomised controlled trials
No RCTs awaiting assessment
Other studies
Smirnov and Mescherinov98 referenced human studies with the Kholod 2-F device in the USSR:
‘Similarly we treated results obtained by use of apparatus, Kholod 2-F, in clinical practice on
patients during operations on the heart, during neurosurgical operations, and during recovery of
consciousness.’ The references were:
■■ Bunatyan AA, Zolnikov SM, Smirnov OA. In Present Day Problems of Anesthesiology and
Recovery of Consciousness. [Russian.] L’vov; 1969. p. 294.
■■ Bunatyan AA, Zolnikov SM, Smirnov OA. Fourth International Symposium on
Anesthesiology. [Russian.] Varna; 1969. p. 503.
■■ Ioffe YS, Smirnov OA. In Comatose States following Cranio-Cerebral Trauma. [Russian.]
Moscow; 1969. p. 126.
The data on head cooling ‘during recovery of consciousness’ could be relevant but we have
been unable to obtain the papers, even through the National Library of Russia with whom our
Russian-speaking librarian has established good links and which supplied some of the other
papers in Russian.
Two papers200,201 suggested that head cooling was being used in cardiac arrest in Czechoslovakia.
The second of these was a survey of ICUs about therapeutic hypothermia in cardiac arrest, in
which 10% of the 90 units who responded reported using a helmet for cooling (Skulec and
colleagues 2010201). A request for further information has produced no response.
Characteristics of ongoing studies
Ongoing studies of head cooling in cardiac arrest are not included.
Stroke
Trial name or title Induction of Cooling (i-Cool) Pilot: A randomised trial comparing three methods for rapid induction of therapeutic
hypothermia in stroke patients
Methods Prospective, open, randomised, single-centre study
Participants Intubated, ventilated stroke patients with combined ICP-temperature probe (n = 30)
Interventions Hypothermia to a target core temperature 34 °C is induced with one of the following:
1. Cold infusions
2. Rhinochill device (BeneChill, USA)
3. Sovika cooling helmet [HVM Medical (now Sovika GmbH), Germany]
Outcomes Primary outcome: Speed of brain cooling during the first hour
Secondary outcomes: Safety aspects – intracranial bleeding or pulmonary complications, co-medication; examination
of effects on ICP and cerebral autoregulation
Starting date 2010
Contact information Dr Sven Poli
Center of Clinical Neurosciences, Heidelberg University, INF 400, 69120 Heidelberg, Germany
www.strokecenter.org/trials/TrialDetail.aspx?tid = 1098 (accessed 22 February 2011)
Notes
138 Appendix 6
Trial name or title The Cerebral Hypothermia in Ischaemic Lesion (CHIL) Trial: A randomised trial evaluating systemic and local
mild hypothermia on infarct expansion and salvage of the ischaemic penumbra in acute ischaemic stroke
(ACTRN12609000690257)
Methods RCT (block randomisation)
Participants Patients aged ≥ 18 years with acute hemispheric ischaemic stroke, NIHSS ≥ 8, presenting within 6 hours of onset of
symptoms or within 6 hours of when last seen unaffected, with evidence of hypoperfused but viable hemispheric brain
tissue on perfusion CT. n = 80
Interventions Systemic hypothermia (Australian centre): Target temperature 33 °C – induction with 30 ml/kg ice-cold Hartmann’s
solution, maintenance with intravascular cooling device
Local head cooling (Chinese centre – Harbin, China): No information
Control patients: Normothermia (< 38°C) as per standard care
Outcomes 1. Infarct expansion and penumbral salvage: Mean per cent penumbral salvage from baseline CT scan to 30-day scan,
hypothermia vs normothermia groups
2. Safety and clinical: Mortality, neurological deterioration as measured by a decline in the NIHSS of four points or more
(compared with baseline at 24 hours, 7 days and any time a neurological deterioration is suspected). Device-related,
infective and thromboembolic complications and adverse events. Blinded outcome assessment at 90 days: NIHSS, mRS
and BI
Starting date 2009
Contact information Professor Christopher Levi (christopher.levi@hnehealth.nsw.gov.au)
Hunter Stroke Research Group, John Hunter Hospital, Locked Bag 1, Hunter Region mail Centre NSW 2310, Australia
www.anzctr.org.au/trial_view.aspx?ID = 308341 (accessed 16 April 2011)
Notes Safety/efficacy study
No response to request for details of local head-cooling intervention
Trial name or title Multiple Interventions for Neuroprotection Utilizing Thermal Regulation in the Emergent Treatment of Stroke (MINUTES)
study
Methods Open label randomised study
Participants Patients with cortical stroke within 12 hours of onset or 6 hours from awakening from sleep (n = 70)
Interventions Combination therapy:
1. Two 2-g intravenous boluses of magnesium sulphate
2. Albumin 1.75 g/kg intravenous as a single dose
3. Minocycline 200 mg twice daily for 7 days
4. Atorvastatin 80 mg daily for 7 days
5. 12 hours of local cerebral hypothermia with circulating cooling cap (Cincinnati Sub-Zero head wrap)
Outcomes NIHSS at 48 hours, 1 week and 90 days (blinded assessor)
Starting date 2006
Contact information Dr Muzaffar Siddiqui
Division of Neurology University of Alberta/Grey Nuns Community Hospital, Edmonton, Canada
Notes Interim report: Siddiqui MM, Ludwig Y, Hussain MS, Manawadu D, Mateer A, Beaulieu C, et al. Multiple interventions
for neuroprotection utilizing thermal regulation in the emergent treatment of stroke: the MINUTES study. Int J Stroke
2008;3(Suppl. 1):140
Contains no data on the effect of head cooling
A methods paper is currently being prepared for publication (Dr Siddiqui,18 April 2011, personal communication)
Alberta Health Services information: www.capitalhealth.ca/NewsAndEvents/Features/2006/MINUTESstudy.htm
(accessed 16 April 2011)

Trial name or title Emergency room trial of brain cooling in stroke with the Rhinochill device
Methods
Participants
Interventions
Outcomes
Starting date
Contact information Dr Denise Barbutt
Becky Inderbitzen
c/o www.benechill.com/
Notes This trial is in the planning stage
Trial name or title Study of brain cooling in stroke with the DigniCap
Methods
Participants
Interventions
Outcomes
Starting date
Contact information Martin Waleij, CEO Dignitana
www.dignitana.com/
Notes Further information not available yet
Brain injury
Trial name or title Determination of the rate and degree of selective brain cooling in adults with the TraumaTec Neuro-Wrap
Methods Descriptive, non-randomised single group study to determine the rate and degree of brain cooling that can be achieved
using a new device, the Neuro-Wrap (TraumaTec Inc.)
Published protocol abstract: Miller (2009) Determination of the rate and degree of selective brain cooling in adults with
the TraumaTec Neuro-Wrap. J Neurotrauma 26:A25
Participants Adult neurointensive care patients with intracranial temperature monitoring as part of standard care (n = 20)
Interventions Application of Neuro-Wrap for 8 hours
Outcomes Rate and degree of change in brain and core body temperatures
Occurrence of hypotension and ICP change
Starting date 2010
Contact information Professor Claudia Robertson
Baylor College of Medicine, Houston, TX, USA
Susanne Richard
www.traumatec.com/
Notes Interim data has kindly been provided for nine subjects and is included in this review
140 Appendix 6
Trial name or title Delivery of selective hypothermia in brain injury patients using a cooling helmet, the COOL BRAIN Trial II: a feasibility and
safety study
Methods Prospective feasibility and safety study
Participants Patients with TBI, stroke or pre-hospital cardiac arrest, aged 18–80 years (n = 80–100)
Interventions Application of head- and neck-cooling device (WElkins, LLC, Roseville, CA, USA) pre-hospital, patients determined
to have severe brain injuries on arrival in the emergency department will continue to wear the device for 72 hours.
Temperature measurement sites intracranial and body core (rectal or bladder)
Outcomes Feasibility and safety
Primary hypothesis: Initiation of selective cerebral hypothermia prior to hospital arrival, inpatient setting or ambulatory
care units using a new head-and-neck cooling head cover is feasible and safe in patients with brain injury
Secondary hypothesis: Effective selective cerebral hypothermia using a new head-and-neck cooling head cover can be
achieved in patients with brain injury with their heads unshaved
Starting date June 2012
Contact information Huan (John) Wang, MD
Assistant Professor of Neurosurgery
Carle Foundation Hospital
University of Illinois College of Medicine at Urbana-Champaign
Director, Thermal Neuroscience Laboratory (TNL)
The Beckman Institute of Advanced Technology and Sciences
University of Illinois at Urbana-Champaign
Notes www.carle.org/notices/braincoolingstudy/brain-cooling-study.aspx (accessed 25 April 2011)
Funder: Joint Improvised Explosive Devices Defense Office (JIEDDO), Department of Defense, USA, Contract No:
HQ00342–10-C-0031 $700,000
Trial name or title Trials of QuickCool nasal cooling balloons

Methods
Participants TBI, cardiac arrest and SAH
Interventions
Outcomes
Starting date
Contact information QuickCool AB
Ideon Science Park Visiting address: Beta 6, Scheelevägen 17
SE-223 70 Lund
www.quickcool.se
Notes ‘QuickCool is currently enrolling patients in clinical trials in Sweden and Denmark. These studies investigate the safety
and efficacy of the novel QuickCool Intranasal Brain Cooling System in the following clinical areas: cardiac arrest, TBI
and subarachnoid hemorrhage’ www.quickcool.se//Contents.asp?id = 358 (accessed 8 May 2011)
We are awaiting further information from the company
Grande and colleagues give a very brief report of two patients who seem to have been cooled with QuickCool in their
review of hypothermia after TBI: ‘Our preliminary results from two patients exposed to selective brain cooling via the
nasal–oral cavity showed a relatively effective reduction of whole body temperature, but the difference between body
temperature and brain temperature was only 0.1 °C’ (Grande, et al. Acta Anaesthesiol 2009;53:1233–8: 1237)

Appendix 7
Non-invasive head-cooling methods
and devices
Contents
■■ Introduction.
■■ Heat loss from the upper airways.
–– Convective head-cooling methods and devices: nasal gas/nebulised coolant.
–– Active conductive (liquid) head-cooling methods and devices: nasal and
pharyngeal balloons.
■■ Heat loss through the skull.
–– Convective head-cooling methods and devices (air or water directed on the head).
–– Active conductive (liquid) head-cooling devices (circulating cold fluid).
–– Passive (non-circulating)conductive head-cooling methods and devices.
■■ Scalp-cooling devices.
–– Liquid (active) scalp-cooling caps.
–– Frozen gel (passive) scalp-cooling caps.
■■ Non-invasive neck-cooling devices.
■■ Personal cooling garments.
Introduction
Devices included in this appendix are those that have been developed for brain injury or cardiac
arrest or have been used in patients with these conditions. Where there is a current web address
for companies this has been included to provide some indication of which devices are ‘active’.
Methods of non-invasive head cooling are categorised into:
■■ Heat loss from the upper airways By convection with gas or fluid flow or by conduction with
nasal or pharyngeal balloons. Whether or not the devices used are truly non-invasive is a
moot point.
■■ Heat loss through the skull By convection (fanning, hoods/caps delivering cold air or water)
or by conduction (active, e.g. liquid cooling, or passive, e.g. ice, gel caps). Some of the
devices also have a neck band, which, theoretically, may help cool the brain by reducing the
temperature of the carotid blood supply.24,25
Liquid (active) cooling helmets contain circulating water with and without antifreeze. Heat
from the head is transferred by conduction through the helmet wall and then removed by
the circulating coolant.202 They have the benefit of being able to be maintained at a constant
temperature and some have the facility for temperature adjustment. This is potentially important
because there is a possibility of tissue freezing and necrosis if scalp temperature is reduced too
much. Passive (non-circulating) cooling caps, containing frozen gel, for example, will thaw and
have to be refrozen periodically but are simple and relatively inexpensive. The cheapest method is
142 Appendix 7
ice packs round the head. However, whether active or passive, the helmet/cap needs to be in close
contact with the scalp for optimum heat removal and may be pressurised to achieve this.
With the possible exception of the liquid cooling device developed at Harbin Medical
University in China, no head-cooling devices described here have automatic (closed-loop)
temperature feedback. In a comparative study of systemic cooling devices, those with automatic
temperature control were shown to be more effective and less labour intensive than manually
controlled devices.17
At the end of this appendix there are brief sections on scalp-cooling devices, which have
sometimes been used in brain injury, non-invasive neck-cooling devices and personal
cooling garments.
Neonatal head-cooling devices are not included here because they are unsuitable for adults,
for example the Olympic Cool-Cap (Natus Medical Inc., San Carlos, CA, USA) is specifically
designed and sized for neonates. For reviews that include examples of head-cooling techniques
used in neonatal HIE see Thoreson,203 which includes an early method used in the USSR
comprising induction by cold water spray over the head and maintenance with a liquid cooling
cap, and also Robertson and colleagues,204 which includes the Olympic Cool-Cap and some low-
technology methods including fans and water bottles.
Heat loss from the upper airways
Convective head-cooling methods and devices: nasal gas/nebulised coolant

Nasopharyngeal cooling through a Foley catheter (Figure 3)
Mellergard184 cut off the tip of a Foley catheter at an angle and passed the catheter through the
patient’s nostril with the opening facing upwards. The balloon was inflated with sodium chloride
0.9% and the catheter pulled back until the balloon stopped behind the choane nasi. Oxygen at
5–10 l/minute was flowed through the catheter via a copper coil in a bucket of iced water.
Placing the catheter this for back completely bypassed the nose and therefore did not utilise its
capacity for heat loss which may partly explain the lack of cooling effect. However, in patients
with a base of skull fracture this might mean less risk of pneumocephalus but the method would
still be contraindicated because passing the catheter through the nose could risk worsening the
fracture or the catheter entering the brain.
Thermo-radiating brain cooling (Figure 4)

A cooling induction method used by Dohi and colleagues;63,175,176 8–12 l/minute chilled air (24 °C)
via a 16 fg Foley ‘balloon’ catheter in one nostril, the other nostril was occluded with an epistaxis
balloon and the air exited through the mouth. It is not completely clear but it seems that the
Foley catheter balloon was inflated to prevent air leaking back out of the nostril, which may
have reduced the heat loss from the nose and contributed to nasal erosion.63 The importance of
enabling the air to exhaust from the mouth is emphasised.175 This method is contraindicated with
base of skull fracture and sinusitis.63
Bilateral nasal airflow

Continuous bilateral nasal airflow was used in two crossover trials in brain-injured patients.46,47
In the first trial the air was delivered through a sponge-tipped oxygen catheter in each nostril, at
room temperature and humidity and a rate of 115 ml/kg/minute (approximating normal, resting
minute volume).46 In the second, unhumidified air from the compressed air supply at twice the
patients’ minute ventilation volumes, plus 20 parts per million (ppm) nitric oxide gas (mucosal

39
Temperature (°C)
38
37
1 2 3 4 5 6 7
Time (hours)
FIGURE 3 ‘A schematic figure of how nasopharyngeal cooling was attempted through a Foley catheter positioned
behind the choane nasi. As seen in the inserted rectal and intraventricular temperature curves, nasopharyngeal cooling
had very limited effect on brain temperature’184 (figure 2). Reproduced with permission from Mellergard P. Changes in
human intracerebral temperature in response to different methods of brain cooling. Neurosurgery 1992;31:671–7.
FIGURE 4 (a) Thermo-radiating Brain Cooling (TRBC) was performed by nasopharyngeal cooling. (b) Scheme of
TRBC: artificial nasopharyngeal circulation with chilled air (24 °C, 9–12 l/minute)175 (figure 2, p. 431). Reproduced with
permission from Dohi K, Jimbo H, Ikeda Y, Matsumoto K. Pharmacological brain cooling (PBC) by indomethacin; a non-
selective cyclooxygenase (COX) inhibitor in acute hemorrhagic stroke. Nosotchu 2000;22:429–34.
vasodilatation to facilitate heat loss), and an 85-g lead weight over the facial vein on each side of
the nose, to facilitate intracranial venous drainage, considered important in heat loss from the
upper airway. Two methods of delivery were used. First, a Whispaflow valve with a paediatric
(uncuffed) tracheal tube in each nostril and, second (and more successfully from the ease of
delivery point of view), a double-airflow meter with oxygen tubing in each nostril.47 Nasal airflow
is contraindicated with base of skull fracture and possibly with facial fractures.
144 Appendix 7
Rhinochill Intranasal Cooling System (Benechill Inc., San Diego, CA,

USA): www.benechill.com/ (Figures 5 and 6)
This is a portable, battery-powered nasal cooling device that is primarily intended for induction
of cooling, particularly pre-hospital in patients experiencing cardiac arrest. Bilateral nasal prongs
(with rounded tips and spray ports on the dorsal surface) are inserted and inert perfluorocarbon
coolant mixed with oxygen is nebulised in the nasal cavity where it evaporates, removing heat
in the process. Gas exits through the nostrils or mouth along with any perfluorocarbon, which
does not evaporate. There is an overpressure relief valve. There is no closed-loop temperature
feedback. It is not designed for prolonged use (about 1 hour) and perfluorocarbon is expensive.
Rhinochill has been trialled in humans after cardiac arrest49,59 and used in brain-injured
patients.54 Contraindications to use include base of skull, and possibly nasal and orbital, fractures
and an unprotected airway.
Rapid hypothermia induction device (Figure 7)

This device has been developed for use pre-hospital by biomedical engineering students and
Professor Harikrishna Tandri at Johns Hopkins University. It consists of an air tank, a pressure
regulator and control mechanism, and two nasal prongs that are inserted into the nostrils.
Cold, dry air is flushed through the nostrils to increase evaporative heat loss from the nose and
cool the brain. Animal tests have been carried out but we have had no response to a request for
information on whether human testing has been conducted.
FIGURE 5 The Rhinochill device. Photo reproduced with permission from Benechill Inc., www.benechill.com.

FIGURE 6 Rhinochill device. (a) Tubing set. (b) Control unit59 (figure 1, p. 944). Reprinted from Resuscitation 81.
Busch H-J, Eichwede F, Fodisch M, Taccone FS, Wobker G, Schwab T, et al. Safety and feasibility of nasopharyngeal
evaporative cooling in the emergency department setting in survivors of cardiac arrest, 943–9, 2010, with permission
from Elsevier.
146 Appendix 7
FIGURE 7 The Rapid Hypothermia Induction Device, in development at Johns Hopkins University, is used by
emergency or ambulance personnel to rapidly administer therapeutic hypothermia treatment to victims of cardiac arrest.
Reproduced with permission from http://nciia.org/bmeidea2010 (accessed 4 March 2011).
Active conductive (liquid) head-cooling methods and devices: nasal and

pharyngeal balloons
QuickCool Intranasal System (QuickCool AB, Lund, Sweden): www.
quickcool.se/ (Figures 8 and 9)
This device comprises a portable pump and single patient use thin-walled balloon catheters. The
catheters are inserted bilaterally into the nostrils and perfused with cold saline to cool the brain
and to a lesser extent the body. There is no closed-loop temperature feedback. The device has
been tested in healthy volunteers,65 used in patients206 and is currently being trialled in cardiac
arrest, TBI and subarachnoid haemorrhage (SAH) (see Appendix 5, References to ongoing studies).
The healthy volunteer testing (n = 9) used magnetic resonance spectroscopy to measure brain
temperature: ‘After 60 minute of intranasal cooling brain temperature reduction was −1.7 ± 0.8 °C
as measured by MRSI and –1.8 ± 0.9 °C as measured by phase mapping method’ (p. 36).65
FIGURE 8 Photo: QuickCool AB, Lund.

Priming bag
(saline)
Balloon catheter
Heat exchanger
Heater–cooler unit
Roller pump
FIGURE 9 ‘Schematic representation of the cooling circuit used. Cold saline fills the nasal balloons by gravity and is
actively aspirated by pumps in order to be directed through the heat-exchanger machine. The height of the bag related
to nasopharynx is proportional to the pressure inside the balloons’205 (figure 1, p. 85). Reproduced from Resuscitation
76. Covaciu L, Allers M, Enblad P, Lunderquist A, Wieloch T, Rubertsson S. Intranasal selective brain cooling in pigs,
83–8, 2008, with permission from Elsevier.
Pharyngeal cooling cuff (Daiken Medical Company Ltd, Japan):

www.daiken-iki.co.jp/ (Figures 10 and 11)
This is designed for use in cardiac arrest.207 The pharyngeal cooling cuff is inserted into the
pharynx after tracheal intubation and saline at 5 °C is circulated through it at 500 ml/minute at a
pressure of 50 cmH2O. There is no closed-loop temperature feedback. The close proximity of the
carotids to the pharynx is said to facilitate cooling of carotid blood and thence the brain.
This cooling device was used during resuscitation after cardiac arrest in the Japanese i-Cool
trial, which has completed but not reported yet [www.controlled-trials.com/ISRCTN98089900
(accessed 4 March 2011)]. A significant decrease in tympanic temperature was shown
and another trial is planned to look at neurological outcome (Dr Yoshimasa Takeda,
Principal Investigator, Okayama University Medical School, Okayama, Japan, 18 April 2011,
Pharyngeal cooling device, Germany

A German pharyngeal device that circulates cool water has been tested in rats.208,209 There is no
human research as yet (Dr Doll, University of Witten-Herdecke, Cologne, Germany, 18 April
2011, personal communication).
148 Appendix 7
FIGURE 10 Pharyngeal cooling. Reproduced with permission from www.cc.okayama-u.ac.jp/~cool/e-intou.html

(accessed 17 April 2011).
FIGURE 11 Pharyngeal cooling cuff: equipped with pressure and temperature sensors that transmit perfusion data to
the circulator. Reproduced with permission from www.cc.okayama-u.ac.jp/~cool/e-cuff.html (accessed 17 April 2011).
Heat loss through the skull
Convective head-cooling methods and devices (air or water directed on

the head)
Head fanning
Fanning the head or face with ambient air using electric fans is a simple and relatively cheap
method of cooling the head. It does not produce large brain temperature reductions47 and
will not on its own induce hypothermia but may help to reduce fever.66 Face fanning can be
uncomfortable.197 Bilateral head fanning doubles the airflow and increases turbulence around
the head, which will increase heat loss. It is sometimes assumed that the use of fans in ICU is
associated with infection risk,67 but a review found no published data showing that electric fans
spread infection in clinical areas.68
RapidCool Hypothermia System (MedCool Inc., Wellesley, MA, USA)

(Figure 12)
This device (United States Patent 7507250) was tested in patients after cardiac arrest but is not
commercially available. It ‘… directs jets of cold water (1 °C to 4 °C) through the hair directly
to the scalp. Water is removed from the cooling cap by an aspiration system located about the
inner rim of the cap, fixed just above the ears of the patient’ (p. 461).194

FIGURE 12 MedCool rapid head-cooling device194 (figure 1, p. 461). Reproduced from Am J Emerg Med 27. Wandaller
C, Holzer M, Sterz F, Wandaller A, Arrich J, Uray T, et al. Head and neck cooling after cardiac arrest results in lower
jugular bulb than esophageal temperature, 460–5, 2009, with permission from Elsevier.
Kholod 2, Kholod 2-F and Thermokholod FV devices, USSR

(Figures 13–17)
These are variations of a convective head-cooling device using water or water and alcohol
[Kholod 2 (Figure 13) and 2-F (Figures 14 and 15)] and air [Thermokholod FV (Figure 16)],
respectively. They were developed in the USSR in the mid-1960s and used in TBI, cerebral
hypoxia (e.g. after cardiac arrest), epilepsy and surgery and do not seem to have had closed-loop
temperature feedback.96,97,210,211 Very limited patient data are reported, although ‘many clinical
trials’ are mentioned.210 Smirnov says of the Thermokholod FV that ‘As clinical tests have
shown, the brain can be cooled at various controlled rates (up to 0.3 °C/minute) and the reduced
temperature continuously maintained with an accuracy of ± 0.5 °C’ (p. 259).211 The Kholod 2
and 2-F could also be used for warming. Because body temperature reduced as a result of head
cooling, Smirnov and colleagues210 developed two body-warming devices – one electric and one
using air delivered through a transparent ‘tent’ weighted at the sides (Figure 17) – to maintain
body temperature (31–36 °C) during head cooling or for warming during surgery.210 The electric
body-warming device had closed-loop temperature control to the patient’s rectal temperature.
The complete ‘craniocerebral hypothermy’ system therefore consisted of three separate units: the
head cooling (or warming) unit (Kholod 2, Kholod 2-F or Thermokholod FV), the body warming
(or cooling) unit and a temperature measurement unit which could measure four temperatures
(tympanic membrane, nasopharynx, oesophagus and rectum). It seems that intracranial
temperature was inferred from tympanic temperature on the basis of experimental data in dogs.
The Kholod 2 and 2-F units are described by Smirnov.210 They used water, or a 10–20% mixture
of water and alcohol, as a coolant and had a helmet with a collecting chamber, an electric pump,
a heat exchanger and a temperature controller, housed in a wheeled cabinet. The helmet was
specially moulded to the head (anthropologists were consulted over the shape so that it would
fit a range of head sizes) and had evenly distributed tubes, with openings on the head side and
the coolant collecting chamber, which also acted as a head rest, under the head. The helmet was
adjusted to the patient’s head by a hinge and with the collecting chamber was height adjustable;
150 Appendix 7
c Section AB
1
5
4
3
A B
FIGURE 13 Diagram of Kholod 2 helmet. Apparatus for cooling (heating) of the brain (helmet). 1, Main pipe; 2, openings
for escape of heat carrier; 3, hollow elements (tubes); 4, collector; 5, stops restricting length of flow210 (figure 2, p. 344).
Smirnov O. New method for cooling (or heating) of the body and an apparatus for craniocerebral hypothermia. Biomed
Eng 1968;2:343–7. With kind permission from Springer Science and Business Media.
FIGURE 14 The ‘Kholod 2-F’ cold unit. 1, Control panel; 2, access door; 3, casing; 4, front wheel locking lever; 5,
carrying handles; 6, collecting chamber for heat carrier; 7, helmet210 (figure 3, p. 345). Smirnov O. New method for
cooling (or heating) of the body and an apparatus for craniocerebral hypothermia. Biomed Eng 1968;2:343–7. With kind
permission from Springer Science and Business Media.

FIGURE 15 Kholod 2-F device Photo: RIA Novosti 01.11.1970. Reproduced with permission from http://visualrian.com/
images/item/31265 (accessed 8 March 2011).
152 Appendix 7
6
Vaporizer of
heat exchanger
4
5 TRV-2M sensitive cylinder
1
Steam
valve
Compressor
Liquid valve
Condenser Receiver
FIGURE 16 The air and Freon system of the ‘Thermokholod FV’ apparatus. 1, VS-0.7–3 refrigerating plant; 2, heat
exchanger; 3, TRV-2M heat-regulating valve; 4, centrifugal ventilator; 5, lower air pressure conduit; 6, upper air pressure
conduit; 7, intake air conduit; 8, apparatus for jet cooling; 9, air collector211 (figure 3, p. 258). Smirnov O. A method of
increasing the efficiency of air hypotherms and an apparatus for craniocerebral cooling. Biomed Eng 1969;3:257–60.
With kind permission from Springer Science and Business Media.
4 5
1
2 3 6
ØØ
FIGURE 17 Apparatus for air heating (cooling) of the body. 1, Hot-air machine; 2, flexible hose; 3, funnel; 4, weights;
5, pneumatic casing; 6, ties210 (figure 5, p. 345). Smirnov O. New method for cooling (or heating) of the body and an
apparatus for craniocerebral hypothermia. Biomed Eng 1968;2:343–7. With kind permission from Springer Science and
Business Media.
in the Kholod 2-F these were detachable. Coolant was pumped through the heat exchanger into
the top of the helmet, through the tubes and sprayed out perpendicularly onto the head. ‘Stops’
restricted the reach of the coolant jets – quite how is not clear but presumably this was to avoid
liquid spraying beyond the helmet. The coolant drained into the collecting chamber, which had
openings for this purpose, and was recirculated. Coolant temperature could be automatically
controlled between –3°C and +14°C during cooling and between 33°C and 43°C during warming.
This method of head cooling was said to be more effective than other methods, such as rubber
helmets, because it was convective rather than conductive and overcame ‘adverse conditions
produced by the hair’.

The Thermokholod FV (Figure 16) blew cold air over the head and could be used over head
dressings.211 It seems to have been developed to avoid the problems associated with spraying
water on the head in the presence of wounds. Air was delivered to the surface of the head
in a way that broke up the current: ‘… into separate streams and distributed them evenly
over the treated surface in such a way as to ensure run-off of “exhausted” air. In this way
breakdown of the boundary layer of air at the surface of the head was achieved and a
compulsory convective heat exchange assured between the surface of the head and the air
current’ (p. 259).211
‘Fluidocraniotherm’
This device is similar to the Thermokholod FV but was developed and used in-house at the NV
Sklifosovskiy Scientific Research Institute of Emergency Medicine, Moscow, for craniocerebral
hypothermia, i.e. ‘predominant cooling of the brain through the external layers of the head’.92 It
cooled by forced convection of air. The reason given for using air was that it was suitable directly
after surgery; wounds were covered with ‘cerigelum’ or a collodion dressing. Fifty-six patients
were cooled with the ‘Fluidocraniotherm’. Some received repeat cooling if their intracranial
pressure and cerebral blood flow measurements showed their condition was worsening (how
these were measured is not described). The device had an inbuilt fan which blew air into a helmet
covering the whole head down to the eyebrows. The air temperature was controllable between
–5°C and 40°C and the patient’s temperature was measured either in the ear canal, oesophagus,
rectum or (n = 15) brain (see Chapter 4, Historical reports of head cooling for method). Target
brain temperature (cortex) was 28–30°C with rectal temperature of 33–43°C. In patients without
brain temperature monitoring (n = 41), brain temperature was inferred from nomograms (see
Chapter 4, Historical reports of head cooling). Temperature control seems to have been manual
rather than closed-loop. Cooling was delivered for 6–29 hours, during which time patients were
anaesthetised. Once temperature was lowered (after 2–18 hours), cooling was maintained by
ice packs on the head and over major blood vessels, and 1% aminopyrine given two or three
times daily.
Prototype convective cooling hood (KCI, Ferndown, Dorset, UK)

This device was tested in volunteers (n = 5) with magnetic resonance spectroscopy brain
temperature measurement; it is not commercially available.24 A hood and collar made of a double
layer of nylon, with holes for air flow in the inner layer, delivered air at approximately 14.5 °C
and 15 m s−1 through neoprene insulated tubing from the cooling machine in the scanner control
room. The hood and collar could be independently clamped off to allow head and/or neck
cooling to be delivered.
Active conductive (liquid) head-cooling devices (circulating cold fluid)

Swedish Air Force head-cooling helmet
Mellergard borrowed an Air Force cooling helmet for clinical use. It was:
… made of fabric enclosing the whole head and part of the neck [with] a system of thin
plastic channels on the inside, through which water circulated. The water was supplied
from a thermostat bath, with an optional temperature range between 5 and 40 °C, and
was continuously circulated through an electromechanical pump.184
Cincinnati Sub-Zero (CSZ) head wrap (Cincinnati Sub-Zero Products

Ltd, Cincinnati, OH, USA): www.cszmedical.com/ (Figures 18 and 19)
This is part of the whole-body hypothermia single-patient use Kool-Kit system, which is an
example of a combined head and body device, though either part can be used on their own.
Cold water is circulated through the head wrap by the Blanketrol III unit. The head wrap is
not pressurised. The company thought that the head wrap had been used on its own for head
154 Appendix 7
FIGURE 18 Cincinnati Sub-Zero (CSZ) head wrap. Photo reproduced with permission from CSZ Products Ltd, http://
www.cszmedical.com/Products/Hyper-Hypothermia/wholebodyhypothermia.htm (accessed 25 April 2011).
FIGURE 19 Blanketrol III. Photo reproduced with permission from CSZ Products Ltd, http://www.cszmedical.com/
Products/Hyper-Hypothermia/Blanketrol-III.aspx (accessed 25 April 2011).
cooling but had no details of any studies. Our searches showed it had been used by Gaida
and colleagues.51
TraumaTec Neuro-Wrap (TraumaTec Inc., San Antonio, TX, USA)

www.traumatec.com/ (Figure 20)
This is very similar to the CSZ head wrap but portable and is currently being trialled in
Neurosciences ICU patients53 (see Appendix 5, References to ongoing studies). The following
information was kindly provided by Professor Claudia Robertson the principal investigator:
The TraumaTec Neuro-Wrap is a helmet-shaped water blanket of soft plastic, with flaps
that fit snugly over the head and circumferentially around the neck. The cranial flaps are
designed to accommodate ICP monitors, head dressings, or other clinical paraphernalia,
and can be adjusted to ensure maximal surface contact. The Wrap has high-flow
fluid channels to create conductive heat transfer from the scalp and carotid arteries,
thus achieving cooling of the brain. Fluid circulation is provided by a small portable
refrigeration/pumping unit, designed specifically for this device.
(Professor Robertson, 3 January 2011, personal communication)

FIGURE 20 TraumaTec Neuro-Wrap. Photo courtesy of Susanne Richard, TraumaTec, Inc., San Antonio, TX.
Cool Brain Cooling Helmet (Figure 21)

This device originated as a spin-off from the National Aeronautics and Space Administration
(NASA) space suit technology and was used in the COOL BRAIN stroke study50. It consists of
two components, the head/neck liner (Figure 21) and the conditioning unit. The inner liner is
made of thin, urethane laminated nylon fabric with a circulating liquid cooling heat exchanger.
Over that is a pneumatic liner which is pressurised to improve contact with the head and neck.
The whole is adjustable to improve the fit and has access openings on each side over the Kocher
points and anteriorly at the midline of the neck. The conditioning unit is portable (mains or
battery power). It contains an insulated ice reservoir with heat exchanger and the control system
for temperature and coolant circulation. This device is now commercially available as the
WElkins EMT system (WElkins, LLC, Roseville, CA, USA; URL: welkinsmed.com).
156 Appendix 7
FIGURE 21 ‘Helmet worn by William Elkins, a NASA scientist, who invented this technology. The cooling helmet has
an outer pneumatic liner pressurized to allow close contact with the cranium and neck. The device also is adjustable to
fit a significant range of head sizes’50 (figure 1, p. 273). Reproduced with permission from Wang H, Olivero W, Lanzino
G, Elkins W, Rose J, Honings D, et al. Rapid and selective cerebral hypothermia achieved using a cooling helmet.
J Neurosurg 2004;100:272–7.
Discrete Cerebral Hypothermia System, CoolSystems Inc. (Alameda,

CA, USA) (Figure 22)
Harris and colleagues45 described their experience with this device. Pros were ease and speed of
application, facilitated by the portability of the device, and ease of use. Cons were problems with
regulation of water temperature, inadequate contact of the cap with the head (this was despite
the cap being pressurised) and the desired intracranial temperature and intracranial/bladder
temperature gradient not being achieved. The researchers suggested that a coolant other than
water might be better.
However, Harris and colleagues45 were aiming to achieve an intracranial temperature of 33 °C,
while bladder temperature was maintained at 36 °C with body warming. This is a challenging
target. The lack of success is attributed to deficiencies in the head-cooling device but it is
questionable whether such a large brain/body temperature difference is achievable in humans
without isolating the cerebral and corporal circulation from each other (e.g. Schwartz and
colleagues212), although even steeper gradients have been achieved in animals (e.g. Natale and
D’Alecy213 and Barone and colleagues214).

FIGURE 22 ‘The Discrete Cerebral Hypothermia System cooling cap. (a) Photograph of the cooling cap. (b) Photograph
of a patient from our study wearing the cooling cap. The ICP and temperature monitor can also be seen’45 (figure 1,
p. 1257). Reproduced with permission from Harris OA, Muh CR, Surles MC, Pan Y, Rozycki G, Macleod J, et al.
Discrete cerebral hypothermia in the management of traumatic brain injury: a randomized controlled trial. J Neurosurg
2009;110:1256–64 [Erratum appears in J Neurosurg 2009;110:1322.]
Device used at The Affiliated Hospital of Hangzhou Teachers

College, Hangzhou, Zhejiang, China (Figures 23 and 24).
This was a cooling cap with circulating water (4 °C) (Figure 23) and an adjustable neck band
containing frozen ‘blue ice’ packs (Figure 24).75,147 The water was circulated by a ‘hypothermia
machine’ (KN 01, EBM, Beijing, China) and the neck packs were replaced every 3–4 hours as
they thawed.
FIGURE 23 The cooling cap through which cold water circulated (Qiu and colleagues76,147 Liu and colleagues75). Photo
courtesy of Dr Wusi Qiu.
158 Appendix 7
FIGURE 24 The ‘blue ice’ packs for neck cooling (Qiu and colleagues.,76,147 Liu and colleagues75). Photo courtesy of Dr
Wusi Qiu.
Device developed at The First Clinical Hospital, Harbin Medical

University, Harbin, Heilongjiang Province, China
Zhang and colleagues182 and Tang and colleagues181 contain information on the development
of a head-cooling device. Zhang and colleagues182 is a study in two healthy volunteers with the
head-cooling device showing reduction of cerebral glucose metabolism with positron emission
tomography. Tang and colleagues181 refers to using the device in stroke patients but provides no
details and we have been unable to find more information. The other Chinese studies conducted
in Harbin found for the review appear to use the same device.148,149,183 It is a circulating water
device and described as ‘experimental apparatus for medical brain hypothermia controllable
semiconductor protection type refrigeration apparatus TER-40A from the Harbin Institute of
Technology Education thermal Research Development Office’.183 The Chinese centre for the CHIL
trial (see Appendix 5, References to ongoing studies) is Harbin, and we have contacted the Chief
Investigator for CHIL (in Australia) for more information. Our request has been received but we
have had no response yet.
Device developed by the Equipment Department, Jilin Provincial

Brain Hospital, Siping, Jilin, China
Description of a computerised cooling device that circulates water through a hat and pads at
temperatures of between 3 °C and 25 °C.215
Human brain hypothermia system developed by the Electronics and

Computer Education Department, Faculty of Technical Education
Gazi University, Ankara, Turkey
The system comprises ‘a microcontroller-based control card, four different temperature
measurement circuits, a electronic control card module, a water circulation system, a switching
mode power supply, and a helmet’ (p. 502).216 The temperature range is –5 °C to 46.15 °C because
it is intended that the device could also be used for hyperthermic tumour therapy. This device is
undergoing animal testing and has not yet been used in humans (Dr Guler, 28 February 2011,
Helmet for emergency cooling in head injury, Japan

A device is described which was developed by a team from Niigata Sangyo University, Tokyo
Denki University and Sapporo Medical University, School of Medicine. It uses a Peltier chip to
cool water, which circulates through the helmet.217,218 We have had no response to a request for
information on whether or not this has been used in humans.

Device developed at the Institute of Semiconductors, Academy of

Sciences of the USSR, A.P. Polenov Leningrad Scientific-Research
Neurosurgical Institute, USSR (Figures 25 and 26)
This device (Figure 25) had been used clinically for 2 years, although details were not reported,
and was said to have fewer complications than other methods of head cooling such as ‘spray
helmets’ (possibly the Kholod 2) and to be easier to use, provide better temperature control and
more reliable than devices that required the coolant to be replaced or Freon refrigerator devices.
It had two separate parts: a helmet containing a thermopile and a control unit. The helmet had
three layers (Figure 26). The outer part was reinforced glass fibre with 17 serially connected
thermocouples [‘intermetallic compounds on a base of bismuth telluride with branches having
p- and n-type conductivity’ (p. 240)]219 which generated cold. The middle layer, in which the
thermocouple cold-junction collectors sat, contained a heat-transfer liquid with a low freezing
point. This middle layer was filled and drained through a tube on the outside of the helmet. The
inner layer was stretchy rubber which was conformed to the head by adjusting the quantity of
heat-transfer liquid. A rubber hood covered with insulating material was placed over the whole
helmet to hold it tight to the head. The control unit had a temperature measurement circuit,
supplied the current (high current rectifier) and circulated the water which removed the heat
from the thermopile.
FIGURE 25 General view of electronic device for hypothermia of the brain219 (figure 1, p. 241). Kolenko E, Bezukh M.
Electronic device for hypothermia of the brain. Biomed Eng 1971;5:239–41. With kind permission from Springer Science
and Business Media.
2
3
FIGURE 26 Schematic cross-section of helmet. 1, Thermocouples; 2, collectors; 3, rubber membrane219 (figure 2,

p. 241). Kolenko E, Bezukh M. Electronic device for hypothermia of the brain. Biomed Eng 1971;5:239–41. With kind
permission from Springer Science and Business Media.
160 Appendix 7
Rubber, water circulating head-cooling device, USSR (Figure 27)

This is described as an easy-to-use helmet device, made of readily obtainable parts, which
circulates water at 8–10 °C.220 Use of the device in nine patients with TBI is mentioned but few
details are given.
5
1
4
2 6
FIGURE 27 1, Rubber helmet; 2, rubber tubing; 3, tap to run water into serpentine coil (4) in a case (5) with insulation
(6). The waste runs out into a washbasin220 (p. 47, translated from Russian). Reproduced with permission from Reut NI.
[Technic of continuous therapeutic craniocerebral hypothermia in acute craniocerebral injury.] [Russian.] Ortop Travmatol
Protez 1970;31:47–8.
Helmet for focal or global head cooling, USSR (Figure 28)

This device is described as being suitable for severe TBI with haemorrhage. No patient data are
reported.221 It seems to have been designed for either focal cooling, if one pocket has coolant flow,
or more global head cooling if all pockets are used.
a b c
FIGURE 28 Helmet, which reduces temperature for focal and global hypothermia: a, front; b, side; c, back221 (p. 68,
translated from Russian). Reproduced with permission from Okhrimenko NN, Zaikin VS. [Use of regional hypothermia of
the head for treating acute disorders of the cerebral circulation.] [Russian.] Voen Med Zh 1974;1:68–9.

Passive (non-circulating) conductive head-cooling methods and devices

Ice packs
Ice packs to the head have been used for cooling in brain injury52 and cardiac arrest.48 In patients
during out-of-hospital resuscitation, Callaway and colleagues48 put three bags each containing
500 ml of shaved ice around the head and draped a fourth bag across the neck. Forte and
colleagues’ patients52 had had decompressive craniectomy and the ice packs were applied to the
site of bone removal; unsurprisingly, this may be more effective in reducing temperature than in
patients with an intact cranium.
Rubber cooling helmet filled with ice and salt, Chita Medical
Institute, Chita, USSR (Figures 29 and 30)
Zhmurko93 reports on the cooling helmet designed and used at the Chita Medical Institute (now
the Chita State Academy of Medicine). This was adapted from a locally made rubber anti-gas
helmet and was made in different sizes so that it could be fitted tightly to the head to help ensure
uniform cooling. It had two layers, between which was a mixture of ground up ice or snow with
33% salt. This mixture produced a temperature of −21°C and could maintain hypothermia for up
to 3 hours; if longer cooling was required the helmet was refilled.
FIGURE 29 Rubber cooling helmet filled with ice and salt (figure 1 from Zhmurko93). Reproduced with permission
from Zhmurko SF. [Cranio-cerebral hypothermia in patients with acute cranio-cerebral injury.] [Russian.] Khirurgiia
1971;47:40–3.
FIGURE 30 Rubber cooling helmet shown on head (figure 2 from Zhmurko93). Reproduced with permission from
Zhmurko SF. [Cranio-cerebral hypothermia in patients with acute cranio-cerebral injury.] [Russian.] Khirurgiia
1971;47:40–3.
162 Appendix 7
Sovika head and neck cooling device (Sovika GmbH, Jesewitz,

Germany) www.sovika.de/ (Figures 31 and 32)
This is a portable reusable device with gel-filled pads. It is stored flat at 4 °C and wrapped round
the head and neck conforming to shape. This device is currently being trialled in the i-Cool pilot
study in stroke patients (see Appendix 5, References to ongoing studies).
FIGURE 31 Sovika head and neck cooling device. Photo courtesy of Sovika GmbH, Jesewitz, Germany.
FIGURE 32 Sovika head and neck cooling device in situ. Photo courtesy of Sovika GmbH, Jesewitz, Germany.

Other makes of gel cap

Other gel caps that have been used for head cooling are the Hypotherm Gel Kap (Flexoversal,
Hilden, Germany),184 the Frigicap (a scalp-cooling cap for chemotherapy) (Figure 33) refrigerated
to –4 °C, applied over a paper cap and replaced hourly to keep the cap temperature low,69 and an
elastogel cap (Figure 34) by Southwest Technologies (Kansas, MO) (www.elastogel.com/product-
catalog/hot-a-cold-therapy/head-facial-therapy), which was carried in a mobile fridge at –5 °C to
use in out-of-hospital cardiac arrest.70
FIGURE 33 Frigicap containing aqueous glycerol69 (figure 1, p. 277). Reproduced from Resuscitation 51. Hachimi-Idrissi
S, Corne L, Ebinger G, Michotte Y, Huyghens L. Mild hypothermia induced by a helmet device: a clinical feasibility study,
275–81, 2001, with permission from Elsevier.
FIGURE 34 Elastogel cap on a patient after cardiac arrest70 (figure 1, p. 98). Reproduced with permission from Storm C,
Schefold JC, Kerner T, Schmidbauer W, Gloza J, Krueger A, et al. Prehospital cooling with hypothermia caps (PreCoCa):
a feasibility study. Clin Res Cardiol 2008;97:768–72.
164 Appendix 7
Scalp-cooling devices
Scalp-cooling devices are listed separately here because they are not marketed for use in brain
injury. However, some of them may be suitable for brain cooling.
Liquid (active) scalp-cooling caps

■■ Paxman Scalp Cooler (Paxman Coolers Ltd, Huddersfield, UK; www.paxman-coolers.
co.uk). The company believes the device has been used in accident and emergency but has no
information on this and does not support uses other than scalp cooling.
■■ Dignicap (Dignitana, Lund, Sweden; www.dignitana.com/) is being used in a study in stroke
patients but details are not yet available.
■■ Scalp cooling system II (Amit Technology Science & Medicine Ltd, Doar Na Shimshon,
Israel; www.scsii.co.il/). We do not know if this has been used in brain injury or whether it
definitely uses liquid cooling; it is possibly a convective (air) cooling device. Requests for
information from the company have met with no response.
Frozen gel (passive) scalp-cooling caps

■■ Penguin Cold Cap (Penguin Cold Caps NZ Ltd, Greenhithe, New Zealand;
http://penguincoldcaps.co.nz). This has not been used in brain injury.
■■ ChemoCap (ChemoCap Products, Windsor, ON, Canada; www.chemocap.com/).
■■ There has been no response to our query about whether this has been used in brain injury.
Non-invasive neck-cooling devices
There are some devices designed to be used only on the neck with the intention that cooling the
carotids will cool the brain but there are limited patient data available.
Water-circulating Arctic Sun pads (Medivance Inc., Louisville, KY, USA; www.medivance.com/)
that are specially shaped for placement over the carotid triangles were used in nine patients with
SAH and intractable fever.222 Mean brain temperature reduced by about 0.5 °C within a few hours
but the reduction was not sustained. Emcools have developed their cooling pads for neck cooling
(Stroke.Pad, Emcools, Vienna, Austria) but there are few data as yet.223
There is a patent for a non-invasive neck cooling device that holds removable cold inserts over
the carotids (US Patent 6682552 – Brain cooling device and monitoring system) intended for
pre-hospital use in stroke patients. This was developed by Ramsden and colleagues224 at the
University of Saskatchewan, Saskatoon, SK, Canada, but requests for information about whether
it has actually been used in patients have met with no response.
The Sandhu Cerebral Cooling Collar (LifeCore Technologies Inc., Cleveland, OH, www.
lifecoretech.com) is somewhat similar, with a removable cool pack that fits round the front of
the neck. Ethical approval has been obtained to compare this device with a systemic surface
cooling device (Gaymar Industries Inc., Orchard Park, NY) for fever control in stroke patients
in neuro ICUs (investigator Dr Michael DeGeorgia, University Hospitals of Cleveland, Case
Medical Center, Cleveland, OH). (Scott Raybuck, Life Core Technologies LLC, Cleveland, OH,
Whether these latter two devices are much different from commercially available personal
cooling neck collars, for example Black Ice (Lakeland, TS, USA), is not yet clear.

Personal cooling garments
There is a somewhat grey area between medical devices for therapeutic clinical head cooling
and the myriad personal cooling systems for preventing heat strain, for example in multiple
sclerosis and for military and firefighting personnel. Some of these personal cooling systems
include head- and neck-cooling components, which are either soaked in water to activate and
cool by evaporation or contain phase-change packs (e.g. Polar Products Inc., Arkon, OH, USA;
http://store.polarsoftice.com). There are some liquid cooling garments but these are usually vests
and not for head cooling. Polar Products active ice head cap is an exception and is designed for
migraine sufferers. It has not been used in brain injury, although the company think it could be
suitable for that purpose.
Kim and Labat225 describe the design process for a liquid cooling hood which formed part
of the Minnesota Advanced Cooling Suit (MACS)-Delphi developed for use by astronauts
(https://taskbook.nasaprs.com/Publication/index.cfm?action = public_query_taskbook_
content&TASKID = 7267; accessed 2 May 2011). The new design was made of mesh with tubing
threaded through it (Figure 35).
FIGURE 35 Minnesota Advanced Cooling Suit (MACS)-Delphi hood new design225 (figure 5, p. 825). Kim DE, Labat K.
Design process for developing a liquid cooling garment hood. Ergonomics 2010;53:818–28, reprinted by permission of
Taylor & Francis Ltd, http://www.tandf.co.uk/journals.

Appendix 8
Identifying patients with traumatic brain
injury in the WardWatcher database
W e are very grateful to Angela Kellacher, Clinical Co-ordinator for WardWatcher, for her
help in setting up and running the initial search of WardWatcher.
The initial search used the Acute Physiology and Chronic Health Evaluation (APACHE)
diagnosis and the SICS diagnoses. In WardWatcher, the APACHE classification categorises
patients according to the primary diagnosis which has warranted their admission to intensive
care. The SICS diagnoses group patients into categories and allow reason for hospital admission
and multiple reasons for admission to intensive care to be captured. Neither would capture all
patients with TBI, hence both were used.
The APACHE codes were:
Medical
21. head trauma
23. intracranial haemorrhage (ICH)/subdural haemorrhage (SDH)/SAH
Surgical
43. head trauma
44. craniotomy for ICH/SDH/SAH
SICS diagnoses were:
109. Diffuse brain injury

110. Intracerebral contusions/haematoma
111. Extradural haematoma
112. Subdural haematoma
113. Other TBI
137. Intracerebral haemorrhage
301. Diffuse head injury
302. Intracerebral contusions/haematoma
303. Extradural haematoma
304. Subdural haematoma
305. Skull fracture
306. Other head trauma
311. Multiple trauma (including diffuse brain injury)
312. Multiple trauma (including intracerebral contusions/haematoma)
313. Multiple trauma (including extradural haematoma)
314. Multiple trauma (including subdural haematoma)
168 Appendix 8
Plus the following system failing code was included:
3. Neurological
The initial search produced a data set of patients with TBI but this also included patients who had
not had TBI, therefore the data set had to be cleaned by hand. This was undertaken as follows.
Patients were removed if:
■■ APACHE, primary diagnosis (hospital), primary diagnosis (unit) were all SAH/SAH (other)
and/or coiling was mentioned
■■ brain tumour as primary diagnosis/surgery for brain tumour when no mention of trauma
■■ seizures/cerebral abscess/cerebral infarction as primary diagnoses with no mention of
trauma/contusions
■■ ICH with thoraco/abdominal aortic aneurysm as primary diagnosis
■■ haemorrhage with hypertension as primary diagnoses and no mention of trauma/contusions
■■ ICH with pregnancy as primary diagnosis
■■ ICH associated with thrombotic disorders or leukaemia
■■ other vascular/neurological disorder as primary diagnosis.
Patients were kept if:
■■ trauma related to head was in any diagnosis (including relevant fractures, e.g. skull in ‘other’
diagnoses)
■■ extradural, epidural, SDH (note: although SDH can on rare occasions be aneurysmal, expert
consensus was that it was better to include these patients)
■■ diffuse brain injury
■■ intracerebral contusions.

Appendix 9
Information for members of the public
Head-cooling therapy after brain injury
You are being invited to read and comment on the following information because our research
team is interested in the views of members of the public.
Brain injury and cooling

Patients who have suffered a brain injury, for example from an accident or a stroke, often have a
raised temperature. This may increase damage from the injury and contribute to swelling in the
brain, which can increase damage further still. It is usual to give these patients cooling therapy
to try and restore their temperature to normal. If brain swelling is a particular problem, patients
may be cooled to below normal temperature (hypothermia therapy).
The usual cooling therapies include drugs, such as paracetamol, washing with cool water and
machines that circulate cold water through pads or blankets applied to the body. These therapies
reduce the temperature of the whole body. But for some time it has been thought that it could be
helpful to apply cooling to the head alone. This targets the site of the injury and may reduce the
side effects of cooling the entire body, particularly when temperature is reduced to below normal.
Head cooling is already being successfully used in babies who suffer brain damage from lack of
oxygen at birth. The problem with applying cooling to the head in adults is that it may not have
enough effect on brain temperature to be helpful. Head cooling is therefore not yet part of normal
care in adults and is still being researched.
Head-cooling research to date

We have recently reviewed the research evidence on head cooling in brain injury to assess the
current state of knowledge. The patients who received head cooling in these research studies were
very ill – unconscious and sedated – and had their brain temperature measured as part of their
normal care. Two main methods of head cooling were used:
■■ delivery of cooling gas through the nose

■■ helmets with cold water circulating through the lining.
On the next page there are photos of these methods.
Side effects from the cooling methods were generally minor and got better after cooling stopped.
They included whitening of the nose from cold and small areas of skin damage.
Head cooling reduced brain temperature by at least 1 °C within about 1 hour, which may be
potentially helpful. However, the research so far does not provide information on whether
patients recover better from their injuries as a result of head cooling. That is the real measure of
effectiveness of any treatment.
170 Appendix 9
Further research
In summary, we know that head cooling can reduce brain temperature but we do not yet know
enough about its effects on recovery to use it as part of normal care. Further research is needed
to assess this. Because this kind of research is done when people are very sick, they are not able
to give their own consent to take part in the research. Some people have a welfare guardian who
can give permission on their behalf, but otherwise a close family member is asked. The delay in
finding someone to give permission can mean that the person cannot take part in the research
at all. In England a doctor who is involved in the patient’s care, but who is not involved in the
research, can give permission. It is possible that the law will be changed in Scotland to allow this.
Any comments you may have about head-cooling therapy and research, including the issue of
permission, will be very much appreciated.

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Practice, University of East Anglia Sciences, University of Liverpool
Dr Sabyasachi Bhaumik, Medicine, University of East
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Systematic Review of Head Cooling in Adults

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Health Technology Assessment 2012; Vol. 16: No.

Systematic review of head cooling in

B Harris, PJD Andrews, GD Murray, J Forbes

Health Technology Assessment

Contact details are as follows:

How do I get a copy of HTA on DVD?

B Harris,1,2* PJD Andrews,2 GD Murray,1 J Forbes1

Published November 2012

This report should be referenced as follows:

Health Technology Assessment is indexed and abstracted in Index Medicus/MEDLINE, Excerpta

Criteria for inclusion in the HTA journal series

Systematic review of head cooling in adults after traumatic

Limitations: We conducted extensive and sensitive searches but found no good-quality

List of abbreviations vii

Executive summary ix

2. Aim and objectives 5

5. Modelling of cost-effectiveness of head cooling 27

Appendix 1 Temperature measurement with head cooling 61

Appendix 2 Review protocol (final agreed version December 2008) 63

Appendix 3 Search strategies 81

Appendix 5 References to head-cooling studies 107

Appendix 6 Characteristics of studies 117

Appendix 7 Non-invasive head-cooling methods and devices 141

Appendix 8 Identifying patients with traumatic brain injury in the

Appendix 9 Information for members of the public 169

Health Technology Assessment programme 171

Aim and objectives

The objectives were to:

Criteria for inclusion of studies

Major international medical bibliographical databases

The Cochrane Library

Cochrane specialised trials registers

Other trial registers (last update all registers 6 March 2011)

Web search engines

Data collection and analysis

Effect of head cooling on temperature

Effect of head cooling on outcome

Adverse effects of head-cooling methods

Complications and possible benefits: head cooling compared with

Modelling of cost-effectiveness of head cooling

Recommendations for research in traumatic brain injury and stroke

Implications for practice in traumatic brain injury and stroke

The conditions and incidence: traumatic brain injury and stroke

The intervention: non-invasive head cooling

Methods of non-invasive head cooling are categorised into:

How the intervention might work

Measurement of temperature reduction

If cooling, however delivered, is to have a neuroprotective effect, brain temperature must be

Cardiac arrest and neonatal hypoxic–ischaemic encephalopathy

The reason for undertaking this review

The objectives were:

Differences between protocol and review

Criteria for considering studies for this review

Cooling intervention comparisons could include:

1. no cooling intervention or standard care

Search methods for identification of studies

Major international medical bibliographical databases

The Cochrane Library

Cochrane specialised trials registers

Other trial registers (last update all registers 6 March 2011)