Clinical review

Management of severe malaria in children: proposed

guidelines for the United Kingdom
Kathryn Maitland, Simon Nadel, Andrew J Pollard, Thomas N Williams, Charles R J C Newton,
Michael Levin

Malaria is the most important vector borne disease

worldwide. Globally it results in an estimated 400 million infections and more than 1 million deaths each
year.1 Although malaria is a rare cause of hospital
admission in the United Kingdom, it constitutes a substantial health threat for people travelling in endemic
areas. The incidence of imported malaria is rising
throughout much of the developed world, largely
because of a global increase in long distance travel,
immigration, and the resurgence of malaria in many
tropical countries.24 Moreover, although Plasmodium
vivax was once the most common form of imported
malaria, it has since been superseded by P falciparum5
the only form of malaria that can be lethalwhich now
accounts for some 80% of reported cases. Around 15%
of episodes of malaria occur in children aged 15 years
or younger. Most of those affected are UK residents of
African ethnicity who have recently visited family in
endemic areas but have not taken preventive
measures.5 Nevertheless, even strict compliance with
preventive measures is never 100% effective, as
resistance to available chemoprophylactic agents is
increasing in many parts of the world.
Although most cases of P falciparum malaria in
patients presenting to health services in the UK are
uncomplicated, up to 10% become severe and life
threatening malaria, principally because of delays in
diagnosis and inadequate treatment.5 6 In uncomplicated disease, the clinical features of malaria are similar
in children and adults, but in severe disease, the clinical
spectrum, complications, and management differ and
merit the development of separate guidelines for children. We therefore propose the following guidelines
for the assessment and emergency management of
children with imported malaria.

Methods
Few data are available on the clinical spectrum of
severe malaria in children living in non-endemic areas.
As a result, the working definitions for severe malaria
that we use in this review draw heavily on studies conducted in critically sick children in Africa and on information obtained from personal archives of references,
the current guidelines from the World Health Organization,7 and the Advanced Paediatric Life Support
(APLS) guidelines.8 We have used the revised grading
system for evidence based guidelines (GRADE).9 We
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Summary points
Malaria is the most important imported mosquito
borne infection in the United Kingdom
As preventive measures are never 100% effective,
malaria should be suspected in any patient with
flu-like symptoms who has travelled to
malarious areas within a year
Most cases of severe malaria result from a failure
to expedite prompt same day diagnosis and
initiate appropriate treatment in patients with
suspected malaria
Oral quinine and chloroquine or pyrimethamine
with sulfadoxine should never be prescribed to
treat falciparum malaria in children
In children, the development of one or more
features of severe or complicated malaria
constitutes a medical emergency
The emergency assessment of a child with severe
malaria should follow the structured approach
advocated by the Advanced Paediatric Life
Support guidelines
If in doubt: admit, monitor closely, and seek
specialist advice

graded sources available for this review as follows: randomised controlled trials are grade 1+ (low risk of
bias); case-control studies, cohort studies, and observational studies are grade 2; case series are grade 3; and
expert opinion is grade 4. Most sources of evidence
come from grades 2 and 3. Where key recommendations are made, the strength of evidence is indicated as
grade 1-4 evidence.

Kenya Medical
Research Institute/
Wellcome Trust
Programme, Centre
for Geographic
Medicine
Research-Coast, PO
Box 230, Kilifi,
Kenya
Kathryn Maitland
lecturer in tropical
paediatrics
Thomas N Williams
Wellcome Trust senior
research fellow
Charles R J C
Newton
Wellcome Trust senior
research fellow
Department of
Paediatrics, St
Marys Hospital,
London W2 1NY
Simon Nadel
consultant in
paediatric intensive
care
Department of
Paediatrics,
University of
Oxford, John
Radcliffe Hospital,
Oxford OX3 9DU
Andrew J Pollard
consultant in
paediatric infectious
diseases
Brighton and
Sussex Medical
School, Medical
Research Building,
University of
Sussex, Falmer,
Brighton BN1 9PS
Michael Levin
professor in
experimental medicine
Correspondence to:
K Maitland
kmaitland@kilifi.
mimcom.net
BMJ 2005;331:33743

Scope of these guidelines

The guidelines we propose should not be seen as a
consensus statement but as recommendations to help
with the initial assessment and identification of
children at risk of complications, who require close
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Clinical review
monitoring or parenteral medication (box 1).
Although some principles of treatment may be
applicable to adults,7 some relate specifically to
children (in particular those concerning volume
resuscitation).

Clinical malaria
Malaria should be considered in any patient presenting
with a fever who has ever travelled to an area where
malaria is endemic. Although the first symptoms begin
10 days to four weeks after transmission by an infected
mosquito in most children, in exceptional cases
presentation can be as early as eight days or as late as
one year, particularly in malaria caused by P vivax,
P ovale, or P malariae or in children who have taken
prophylaxis. The illness generally begins with nonspecific flu-like symptoms that may include fever,
cough, headache, malaise, vomiting, and diarrhoea.
Supportive findings may include splenomegaly, thrombocytopenia, anaemia, and mild jaundice7; these
features are, however, often absent in the early stages of
disease. The presumptive diagnosis of malaria should
prompt urgent referral for immediate diagnosis and
management. Failure to expedite appropriate referral
may lead to the development of life threatening
disease. Thick and thin blood films, processed from an

Box 1: Recognising severe malaria

High risk: immediate risk of dying and urgent need
for supportive treatment
Depressed conscious level (any degree)
Active seizure activity
Irregular respirations or obstructed airway (pooling
saliva or vomit in mouth)
Hypoxia (oxygen saturations < 95%)
Evidence of shock (systolic blood pressure
< 80 mm Hg or < 70 mm Hg if patient aged < 1 year)
or two or more of the following: tachycardia, increased
work of breathing, cool peripheries, capillary refill
time 3 seconds, temperature gradient)
Clinical evidence of dehydration
Hypoglycaemia < 3 mmol/l
Metabolic acidosis (base deficit > 8 mmol/l)
Severe hyperkalaemia (potassium > 5.5 mmol/l)
Intermediate risk: need for high dependency care
Haemoglobin < 100 g/l
History of convulsions during this illness
Hyperparasitaemia > 5%
Visible jaundice
Plasmodium falciparum in a child with sickle cell
disease
Low risk: need admission for parenteral medication
Vomiting
Unable to take or comply with oral medication (see
note)
Low risk: need for observation
None of the above
Admit and observe on oral treatment (see note)
Note: Oral quinine (tablets or syrup) is unpalatable for
most children, hence it should never be prescribed for
young children.

338

ethylenediaminetetra-acetic acid (EDTA) sample by the

local haematology laboratory, are the mainstay of diagnosis. Direct liaison with the laboratory will ensure
urgent processing. Malaria can generally be excluded
by three negative thick blood films, taken 12 hours
apart; however, further films are warranted if clinical
suspicion remains high. Rapid diagnostic tests, such as
the OptiMAL assay, are being increasingly employed.
In general, these are quick and simple to use,
distinguish between the major forms of human
malaria, and may have some advantages over
microscopy, particularly in children with low density
parasitaemia, a characteristic that often applies to
those who have taken prophylaxis.10 11

Recognition of severe malaria

Emergency assessment and management
Over the past decade, there has been increasing recognition that severe falciparum malaria is a complex syndrome affecting many organ systems and has features
in common with the sepsis syndrome.12 In areas where
malaria is endemic, most deaths occur within hours of
admission, principally because the clinician fails to recognise impending circulatory collapse or respiratory
compromise. The latter is particularly true in children
with prolonged seizures. Raised intracranial pressure
may complicate cases in patients presenting in a
coma,13 prompting a cautious approach to volume
resuscitation in such children (grade 4 evidence; fig 1).
As for any other sick child presenting to hospital,
the initial management of a child with suspected
malaria should be guided by a rapid, structured, triage
assessment, aimed at identifying emergency and priority signs (fig 1).8 14 The sequence of clinical assessment
should include the early recognition of impending respiratory failure initially, followed by the detection of
shock, and neurological assessment. This approach will
guide early management towards the complications
that are the most commonly life threatening (fig 1).
Emergency management should not be delayed while
the diagnosis of malaria is confirmed. Unless an undue
delay is likely, the administration of specific antimalarial drugs can usually be deferred until resuscitation
treatments have been given and the diagnosis
confirmed. Nevertheless, if the clinical suspicion of
malaria is high, an intravenous infusion of quinine
should be started empirically after initial resuscitation,
even if the results are awaited. Experimental treatments, such as exchange transfusion, have no role in
the initial management of children with suspected
malaria and may distract attention from providing
urgent and simple life saving interventions (grade 4
evidence).

Initial assessment and emergency

treatments
Checking the childs airway and breathing is important
as severe malaria has characteristic respiratory
patterns.
Respiratory patterns of severe malaria
Irregular breathing or droolingThe presence of respiratory depression or irregular breathing should
alert the clinician to the presence of complex
seizures,15 iatrogenic respiratory depression (because
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Clinical review

RECOGNITION OF SEVERE MALARIA

High risk patients in need of urgent supportive management
Depressed conscious state (of any degree)
Status epilepticus
Tachypnoea or increased work of breathing
Irregular respirations or obstructed airway
Hypoxia (oxygen saturations <95%)
Evidence of hypovolaemic shock
Severe dehydration
Metabolic acidosis (base deficit >8)
Severe hyperkalaemia (potassium >5.5 mmol/l)

RAPID TRIAGE

- Initiate supportive treatments

- Loading dose of quinine (dihydrochloride) 20 mg/kg diluted in 20-40 ml and run over 4 hours

A&B: RESPIRATORY DISTRESS?

Check: Airway, breathing character, and
oxygen saturations
Airway patency:
- Drooling? Complex seizures
- Occluded? Tonic-clonic seizures
- Secretions/vomit
Breathing:
- Increased work of breathing (deep breathing)
- Tachypnoea >60 brpm if <1 year
>40 brpm if >1 year
- Hypoxia (pulse oximeter: O2 sats <95%)
Irregular respirations:
- Tonic-clonic or complex seizures?
- Raised intracranial pressure?

C: SHOCK?
Check: Pulse rate and volume, capillary
refill time, temperature gradient, blood
pressure, and conscious level
- Tachycardia >160 bpm if <1 year
>140 bpm if 2-5 years
>120 bpm if >5 years
- Increase rate and work of breathing
- Hypoxia (O2 sats <95%)
- Cold peripheries
- Increased capillary refill time (>2 seconds)
- Decreased urine output <1 ml/kg/hour
- Confusion and decreasing conscious level
- Hypotension (late feature) (systolic BP
<80 mm Hg or <70 mm Hg if <1 year

Yes
Yes
- Guedel airway
- Clear airway/wide bore suction catheter
- Rebreathing bag and oxygen (10 l/min)
- Consider: Shock
Hypoglycaemia
Seizure management (fig 2)
Urgent blood investigations
Blood glucose
Hypoglycaemia <3 mmol/l
Correct and consider: seizures/shock
Blood gas
Acidosis: Base deficit >5 mmol/l
Consider: Shock, severe anaemia
if pCO2 >5 kPa
Consider: Hypoventilation: seizures,
iatrogenic or raised intracranial pressure
FBC (+/- Group and Cross-match)
Anaemia: Hb <100 g/l Consider: transfusion
Urea and electrolytes (Na, K, Ca PO4, Mg)
Malaria blood film (from EDTA sample)
Thick film - to diagnose malaria
Thin film - to speciate malaria

Consider intracranial
pressure

A&B and oxygen (10 l/min) first then

Volume resuscitation
Insert 2 large intravenous cannulae
Take blood investigations
- Bolus of 20 ml/kg of colloid or 0.9% saline
or
- 20 ml/kg of 4.5% albumin if child in coma
Observe closely for response/deterioration
No response/worsening shock:
Repeat 20 ml/kg bolus
After 40 ml/kg: if signs of shock persist:
- Rapid sequence intubation
- Use central venous pressure monitoring
catheter to guide fluid management
Neurological deterioration:
Exclude: Seizures, hypoglycaemia, shock
Consider: Raised intracranial pressure

D: CONSCIOUS LEVEL/SEIZURES
Check: Conscious level (AVPU)
Pupillary response
Posture and tonic-clonic seizures
Complex seizures:
- Eye deviation
- Irregular breathing/drooling
Seizure management (fig 2)

Coma (unresponsive to pain)

Coma management - Check glucose
- ABC, nasogastric tube
- Elective intubation and ventilation
Consider: Hypoxia, hypoglycaemia, shock,
post-ictal state, raised intracranial pressure
Raised intracranial pressure?
- Decreasing level of consciousness
- Unequal, dilated, or poorly responsive pupils
- Focal neurological signs
- Abnormal posturing?
Late signs: Papilloedema, hypertension, and
relative bradycardia
Yes
Raised intracranial pressure management
- 30 degree "head-up" midline position
- No neck lines
- Elective ventilation
- Let pCO2 rise gradually into normal range
- Bolus of mannitol (0.5 g/kg over 5-10 min)
and repeat if raised intracranial pressure
persists
Cautious fluid resuscitation
- Use aliquots of 10 ml/kg 4.5% HAS to
correct coexisting shock
- Reassess after each aliquot

Fig 1 Triage and management algorithm for severe malaria in children. (The proposed algorithm has been developed by the authors, based on
APLS (UK) guidelines for the management of critically sick children and includes some principles of management practised at the Kenya
Medical Research Institute unit, Kilifi, Kenya. To date, this algorithm has not been prospectively evaluated)

of multiple anticonvulsant medications), or the

presence of raised intracranial pressure. High flow
oxygen and appropriate airway management are as
important as the administration of anticonvulsants.
Hypoglycaemia (blood sugar < 3 mmol/l) may
precipitate seizures or posturing and should be
considered in such cases.16
Respiratory distressTachypnoea and increased
work of breathing are common complications of
severe malaria in children. Studies conducted in Kenya
have shown that these signs are usually associated
with underlying metabolic acidosis (base deficit
> 8 mmol/l) (grade 3 evidence).17 Moreover, more
recent studies show that this metabolic acidosis is often
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associated with hypovolaemia (grade 2) and can safely

be treated with volume resuscitation by using colloid or
crystalloid (grade 2-3).18
Circulation
Hypovolaemic shock needs to be identified and
managed if present. Acidosis (base deficit > 8 mmol/l)
is a common feature of severe malaria and in children
is often accompanied by features of compensated
shock (grade 3 evidence).19 These include hypoxia,
increased work of breathing, tachycardia, altered
peripheral pulse volume, cool peripheries, prolonged
capillary refill time ( 2 seconds), and altered
consciousness (grade 3).19 Hypotension (systolic blood
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Clinical review
pressure < 80 mm Hg) complicates about 25% of
cases presenting with severe acidosis (base deficit
> 15 mmol/l).18 Delayed capillary refill time ( 2
seconds) is a reasonable prognostic indicator, especially
in children with a decreased conscious level (grade 3).20
Treatment
In the absence of coma (childrens Glasgow coma score
< 8), we have shown that volume resuscitation with
20-40 ml/kg of either 0.9% saline or 4.5% human
albumin solution safely corrects the haemodynamic
features of shock and improves renal function in Kenyan children with severe malaria (grade 2 evidence),18 21
and that pulmonary oedema is a rare complication
( < 0.5%; grade 2).21
Hypovolaemic shock and coma
In children presenting in coma (inability to localise
pain; childrens Glasgow coma score 8) we advise a
more cautious approach to volume expansion. A
recent phase II trial has shown that volume expansion
with human albumin solution may result in a lower
mortality (5%) than with saline (46%) in children with
shock and coma (grade 2).21 Until further data become
available from larger trials, we recommend that
human albumin solution should be considered the
resuscitation fluid of choice in the subgroup of
children who present with coma and features of shock
(grade 2-4).
Further management
Volume resuscitation should proceed cautiously in
children with shock and should be stopped once the
signs of circulatory failure have been reversed. Urine
output of < 1 ml/kg/hour, in the absence of urinary
retention or established renal failure, indicates
impaired renal perfusion secondary to hypovolaemia
and is a good non-invasive guide to fluid management
(grade 3 evidence). For any child with persisting
features of shock despite 40 ml/kg of fluid, we recommend elective intubation and ventilation, and placement of a central venous catheter to guide further fluid
management (grade 2).8 Patients with severe acidosis
may self ventilate their partial pressure of carbon dioxide (Pco2) to very low levels, as compensation for the
metabolic acidosis (grade 3). When initiating ventilation, great care should therefore be taken to avoid a
rapid rise of Pco2, even to normal levels, before acidosis has been partly corrected (grade 4). If the patient is
still shocked or if the shocked state returns then
treatment of shock should take priority, since cerebral
perfusion depends on an adequate blood pressure
(grade 4).
Disability: coma
Impaired consciousnessRapid assessment of neurological function should include an assessment of the
conscious level using either the AVPU scale (Alert,
responds to Voice, responds to Pain, or Unresponsive)8 or childrens Glasgow coma scale8 are adequate;
pupillary size, and reaction to light, in addition to
observing the childs posture and convulsive movements, if present. Other infections of the central nervous system or intracranial haemorrhage, rather than
malaria, should be considered as alternative diagnoses
in a child with neck stiffness or a full fontanel.22 23
Hypoglycaemia (blood sugar < 3 mmol/l) may
precipitate coma and should be excluded. The
340

cardinal features of cerebral malaria are impaired

consciousness, convulsions, abnormal neurological
signs, and opisthotonic posturing.7 Only in a small
proportion of children do these features suggest
raised intracranial pressure (grade 3 evidence).2426
Recent studies in children in Malawi have shown a
retinopathy that is peculiar to severe malaria and consists of patchy whitening of the retina in the macular
and extramacular areas, pale opacification of retinal
vessels, and white centred haemorrhages. In children
who die, a correlation between the density of haemorrhages in the retina with their density in the brain has
been found.24
Treatment
Initial management should include maintenance of the
airway, support of breathing, and immediate correction
of hypoglycaemia and volume deficits. Children who
remain unconscious (childrens Glasgow coma score
8) or have features suggestive of raised intracranial
pressure warrant elective intubation and ventilation.
For children with seizures, the decision to ventilate
should be delayed if they are in a postictal state, as long
as the airway is patent and respiration is not
compromised.
Further management
No adjunctive therapies have shown any benefit in
treatment of children in coma. Repeated seizures and
motor posturing movements are common in children
in coma. Their relation to raised intracranial pressure
has not been established (grade 3 evidence); nevertheless, because of the potential risk of raised intracranial
pressure, ventilation should aim to optimise the Pco2
in the normal range, as there is no evidence that
hyperventilation is beneficial in raised intracranial

AIRWAY
High flow oxygen
Check: glucose
Vascular or intraosseous access?

Lorazepam
0.1 mg/kg intravenous/intraosseous

Diazepam
0.5 mg/kg rectally

>10 minutes
Lorazepam
0.1 mg/kg intravenous/intraosseous

Vascular (intravenous) or
intraosseous access?

>10 minutes
Paraldehyde
0.4 mg/kg rectally, that is 0.8 ml/kg of prepared solution
Phenytoin
Loading dose: 18 mg/kg intravenous/intraosseous over 20 min
or
Phenobarbital
15-20 mg/kg intravenous/intraosseous over 10 min
If not controlled:
CALL ANAESTHETIST
Rapid sequence intubation with
Thiopental
4 mg/kg intravenous/intraosseous (induction dose)

Fig 2 Seizure management algorithm (recommended in the APLS

(UK) guidelines)

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Table 1 Antimalarial treatments

Drug
Proguanil with atovaquone (Malarone)

Mefloquine (Lariam)
Artemether with lumefantrine (Riamet or Coartem)

Uncomplicated malaria (oral medication)

Complicated malaria (parenteral medication)

Daily dose for 3 days: 5-8 kg: 2 paediatric 25 mg

tablets; 9-10 kg: 3 paediatric 25 mg tablets; 11-20
kg: 1 adult 100 mg tablet; 21-30 kg: 2 adult 100 mg
tablets; 31-40 kg: 3 adult 100 mg tablets; >40 kg
adult 100 mg tablets once daily

Quinine hydrochloride:
Loading dose 20 mg salt/kg intravenously (over
4 hours) then 10 mg/kg intravenously (over 4 hours)
8 hourly. Should be given for 7 days but if oral
medications are tolerated before this switch to
complete treatment with a full course of oral
medication as for uncomplicated malaria (proguanil
with atovaquone, mefloquine, or artemether with
lumefantrine)*

15 mg base/kg followed by a second dose of

10 mg/kg 8-24 hours later

The quinine loading dose should be omitted if the

patient has taken mefloquine prophylaxis in the
previous 24 hours or received a treatment dose
within the previous three days

Given at 0, 8, 24, 36, 48, and 60 hours 5-<15 kg

1 tab; 15-<25 kg 2 tabs; 25-<35 kg 3 tabs; 35 kg
4 tabs (adult dose)

*Avoid prescribing oral quinine in children as the bitter taste may affect compliance.

pressure (grade 4). Most patients will regain full

conscious level over the following 48 hours.
Management of seizures
Seizures are common in severe childhood malaria.
Most present as tonic-clonic convulsions, but 25% are
subtle or subclinical (grade 2-3 evidence), commonly
manifesting as eye deviation, an irregular respiratory
pattern, or drooling.14 Initiating high flow oxygen and
appropriate airway management are as important as
the administration of anticonvulsant drugs. Hypoglycaemia may precipitate seizures or posturing and
should be considered in such cases (grade 3). After
establishing an adequate airway and respiratory
support, specific management should follow the
evidence based consensus guideline advocated by the
Advanced Paediatric Life Support Group (fig 2).8
Seizure prophylaxis is not recommended. A recent trial
of prophylactic phenobarbital, at a loading dose of
20 mg/kg given intramuscularly, increased mortality in
Kenyan children with cerebral malaria. Mortality was
greatest in those receiving two or more doses of
diazepam, which may have caused respiratory depression in these unventilated children (grade 2).24
Nevertheless, the safe use of anticonvulsants in the setting of a modern paediatric intensive care setting is
likely to differ greatly from that in African centres
where ventilatory support is unavailable and should
follow the standard algorithm (fig 2).
Raised intracranial pressure
Monitoring of intracranial pressure and postmortem
studies in two separate series of malaria patients with
a prolonged and complicated course have shown
that brain swelling is a major feature in fatal cases
(grade 3 evidence).24 25 Nevertheless, in most cases,
signs suggestive of raised intracranial pressure
developed in the later stages of the illness (grade 3).
Signs include a declining conscious level, focal neurology including unequal, dilated, or poorly responsive
pupils, and abnormal posturing.8 28 29 Papilloedema
and the combination of hypertension and relative
bradycardia are late findings in acute raised intracranial pressure.25 Unilateral sluggish or absent pupillary responses are the only reliable signs (grade 3).29
We advocate caution in the diagnosis of raised intracranial pressure in children in the peri-ictal state, where
pupillary signs and conscious level may be misleading
(grade 4).
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Treatment
The development of features suggestive of raised
intracranial pressure should be considered a medical
emergency and should be treated by the rapid
induction of anaesthesia, tracheal intubation, mechanical ventilation, and close, and frequent monitoring of
blood gases (grade 4 evidence).8 To stabilise cerebral
blood flow, Pco2 should be kept within the normal
range. However, in patients with hyperventilation and
low initial Pco2, ventilation should allow the Pco2 to rise
to a normal range more gradually. Mannitol (0.5 mg/
kg) infused rapidly over five to 10 minutes may be
effective in lowering the intracranial pressure, but its
short term effect means that repeated doses are often
necessary (grade 3).28 Other forms of osmotherapy for
the management of raised intracranial pressure, such
as hypertonic saline, have not been evaluated in
children with severe malaria. Steroids are not
recommended as their effect on raised intracranial
pressure remains unclear and their use may adversely
affect outcome (grade 3).7

General management
Antimalarial medication
Parenteral quinine remains the antimalarial treatment
of choice for patients with severe falciparum malaria
(table 1). An initial loading dose (20 mg salt/kg)
should be given over four hours, followed by
10 mg/kg every eight hours (infused over four hours).
Clinicians should be aware that, because of the mode
of action of quinine, peripheral parasitaemia may not
decrease and might even continue to increase during
the first 24 hours of treatment. This rarely indicates
quinine resistance in children presenting from Africa;
however, resistance has been reported in Southeast
Asia, and advice on appropriate alternative treatments
should therefore be sought from one of the regional
centres if children presenting from that region fail to
respond appropriately within the first few days of
treatment.
Table 2 Glucose and electrolytes: corrective measures
Glucose/electrolyte
Glucose
Potassium
Total calcium

Treat if less than

Correct with

3 mmol/l

5 ml/kg of 10% dextrose

3.5 mmol/l

0.25 mmol/kg over 30 min

2 mmol/l

0.3 ml/kg 10% Ca gluconate over 30 min

Magnesium

0.75 mmol/l

0.2 ml/kg 50% MgSO4 over 30 min

Phosphate

0.7 mmol/l

0.2 mmol/kg of NaPO4 over 30 min

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Box 2: Anticipated complications

Very common
Hypoglycaemia (blood glucose < 3 mmol/l): often
correlates with disease severity. Maintenance fluids
containing 5-10% glucose should prevent this
complication
Hyperpyrexia: increases the risk of convulsions in
children and should be treated with antipyretics or
tepid sponging. Ibuprofen is superior to paracetamol
for reducing fever (grade 3 evidence); the dose should
be reduced in cases complicated by impaired renal
function.
Seizures and posturingsee under seizure
management

Glucose and electrolytes

Hypoglycaemia is a common complication of severe
malaria.7 16 Moreover, as quinine stimulates insulin
secretion, hypoglycaemia may also result from quinine
therapy. Blood glucose concentrations should therefore
be monitored serially. Derangements of electrolytes,
particularly hypokalaemia,30 hypophosphataemia, and
hypomagnesaemia are common31; serial monitoring
and correction are advised (grade 3 evidence; table 2).
Anticipated complications and management are
covered in box 2.

Common
Electrolyte derangement:
Hyperkalaemia may complicate cases with severe
metabolic acidosis at admission. Treatment should
follow standard Advanced Paediatric Life Support
guidelines

Role of exchange transfusion

Exchange transfusion has been advocated for hyperparasitaemia ( > 10%) in adult intensive care settings,
despite little evidence to indicate an improved
outcome (grade 2 evidence).32 Even when parasitaemia
exceeds 25%, most children respond rapidly to the
management outlined above. In children with persistent acidosis and multiorgan impairment who are not
responsive to these resuscitation treatments, exchange
transfusion may be considered as a means of rapidly
reducing the level of abnormally rigid red cells, or
parasite toxins (grade 2). This treatment, however,
remains experimental.

Hypokalaemia, hypophosphataemia, and

hypomagnesaemia are often apparent only after
admission after metabolic derangements have been
corrected (grade 3). Serial monitoring of plasma
electrolytes is suggested, correction should follow the
recommendations given by the Advanced Paediatric
Life Support guidelines (table 2)
Metabolic acidosis:
Resolves with the correction of hypovolaemia and
treatment of anaemia by adequate blood transfusion
No evidence to support the use of sodium bicarbonate
(grade 3)
Dichloroacetate reduces lactic acidosis in African
children, but effect on mortality unknown (grade 2)
Severe malaria anaemia:
Most patients will experience some reduction of
haemoglobin and do not require transfusion. The
decision to transfuse should be influenced by the
parasitaemia level and clinical condition of the patient
(grade 3)
Transfuse if the haemoglobin concentration falls
below an absolute value of 100 g/l (grade 4)
Uncommon
Secondary bacterial infection may occur (grade 3)
and empiric broad spectrum antibiotics are
warrantedsuch as ceftriaxone 100 mg/kg/day
Coagulation activation: Bleeding is rare despite the
customary thrombocytopenia of severe malaria
(platelet counts often < 50109/l; grade 3)

At the time of writing these guidelines, injectable

artesunate, an artemesinin based malaria drug, is being
evaluated in large multicentre trials in Southeast Asia
and Africa. Until the results of these trials are available,
intravenous quinine remains the drug of choice for
patients with severe malaria and should be prescribed
for seven days. However, in children who have fully
recovered clinically, the course of intravenous quinine
may be shortened by switching to a full oral course of
an appropriate non-quinine medication (grade 4
evidence). Because of its bitter taste, oral quinine is
often associated with poor compliance in children, and
we therefore strongly advocate alternative oral
preparations such as mefloquine (Lariam), proguanil
with atovaquone (Malarone), or artemether with lumi342

fantrine (Riamet and Coartem) to achieve full

parasitological cure.

Additional educational resources for health

professionals and patients
All sources provide information on health risks for
international travel, including information on malaria
risks for specific countries or regions, on antimalarial
prophylaxis, and on up to date health surveillance
UK based
Fit For Travel (www.fitfortravel.scot.nhs.uk)public
access website provided by the NHS (Scotland), which
gives travel health information for people travelling
abroad from the UK
Health Protection Agency (www.hpa.org.uk)An
independent body that protects the health and
wellbeing of everyone in England and Wales. The
agency has a critical role in protecting people from
infectious diseases
National Travel Health Network and Centre
(www.nathnac.org)Funded by the Department of
Health to promote clinical standards in travel
medicine (see, in particular, the Yellow Book,
www.nathnac.org/yellow_book/01.htm)
Non-UK based
World Health Organization International Travel and
Health (www.who.int/ith/en/) offers guidance on the
full range of health risks likely to be encountered at
specific destinations and associated with different types
of travel
Centers for Disease Control and Prevention,
Travelers Health (www.cdc.gov/travel/)US based
resource
Treatment advice
Telephone numbers of the main UK tropical centres
that may be consulted by health professionals are
available in the British National Formulary under
Antimalarial treatments

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Clinical review
Further management and prognosis
Frequent reassessment and close monitoring of
critically ill children will identify most complications.
Even in the absence of raised intracranial pressure,
coma may persist for several days. Unlike sepsis, severe
malaria is rarely complicated by refractory shock, perhaps because of the lack of gross capillary leak
syndrome (grade 3 evidence). Nevertheless, complications of fluid overload, including pulmonary oedema
or raised intracranial pressure, should be monitored
closely. Raised intracranial pressure may develop late
in a proportion of children, especially those presenting
in a coma. Some 10% of African children with cerebral
malaria develop persisting neurological sequelae
(grade 3)1 33 and an even greater proportion are left
with learning and language disorders34; nevertheless,
most experience has been drawn from a population for
whom use of and access to modern intensive care
facilities are not possible.
We thank the numerous scientific colleagues we have worked
with over the years for clinical guidance and illuminating discussions. We specifically thank several colleagues including
Suzanne Anderson, David Pace, Robert Tasker, and Shunmay
Yeung for their helpful feedback on earlier drafts of these guidelines, and Chris Whitty for constructive comments during the
review of this manuscript.
Contributors: All authors participated in editing the final
version of the guidelines. KM conceived the need for paediatric
guidelines, developed the consortium, and wrote the initial and
final drafts of the guidelines. TNW helped with the literature
search and provided specialist input on the management of
malaria. CRJCN provided specialist input pertaining neurological manifestations and treatment of severe malaria. SN provided
specialist advice on the management of critically ill children and
edited the guidelines such that they are appropriate to general
practice in most paediatric intensive care units in the United
Kingdom. AJP conceived the need for paediatric guidelines,
helped with the initial draft, and ensured that the guidelines
provided clear advice for frontline medical personnel. ML provided specialist infectious disease and intensive care advice and
edited several versions of the guidelines and is the guarantor.
Competing interests: None declared.
1

3
4
5

6
7
8

9
10

11

12
13
14

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Jelinek T, Schulte C, Behrens R, Grobusch MP, Coulaud JP, Bisoffi Z, et al.
Imported Falciparum malaria in Europe: sentinel surveillance data from
the European network on surveillance of imported infectious diseases.
Clin Infect Dis 2002;34:572-6.
Muentener P, Schlagenhauf P, Steffen R. Imported malaria (1985-95):
trends and perspectives. Bull WHO 1999;77:560-6.
Stoppacher R, Adams SP. Malaria deaths in the United States: case report
and review of deaths, 1979-1998. J Forensic Sci 2003;48:404-8.
Bradley D. Illness in England, Wales, and Northern Ireland associated with foreign travel: A baseline report to 2002. London: Travel Health Surveillance
Section, 2003:48-55.
Ladhani S, El Bashir H, Patel VS, Shingadia D. Childhood malaria in East
London. Pediatr Infect Dis J 2003;22:814-9.
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diseases cluster. Trans R Soc Trop Med Hyg 2000;94(suppl 1):S1-90.
Posner E, Advanced Paediatric Life Support Group. Advanced paediatric
life support: The practical approach. 3rd ed. London: BMJ Publishing Group,
2001.
Harbour R, Miller J. A new system for grading recommendations in evidence based guidelines. BMJ 2001;323:334-6.
Moody AH, Chiodini PL. Non-microscopic method for malaria diagnosis
using OptiMAL IT, a second-generation dipstick for malaria pLDH antigen detection. Br J Biomed Sci 2002;59:228-31.
Palmer CJ, Bonilla JA, Bruckner DA, Barnett ED, Miller NS, Haseeb MA,
et al. Multicenter study to evaluate the OptiMAL test for rapid diagnosis
of malaria in US hospitals. J Clin Microbiol 2003;41:5178-82.
Maitland K, Newton CRJC. Acidosis of severe falciparum malaria: heading for a shock? Trends Parasitol 2005;21:11-6.
Newton CR, Taylor TE, Whitten RO. Pathophysiology of fatal falciparum
malaria in African children. Am J Trop Med Hyg 1998;58:673-83.
American Heart Association. Pediatric advanced life support 1997-1999.
Emergency cardiovascular care programs. Dallas, TX: American Heart Association, 1997.

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15 Crawley J, Smith S, Kirkham F, Muthinji P, Waruiru C, Marsh K. Seizures

and status epilepticus in childhood cerebral malaria. Q J Med
1996;89:591-7.
16 White NJ, Miller KD, Marsh K, Berry CD, Turner RC, Williamson DH, et
al. Hypoglycaemia in African children with severe malaria. Lancet
1987;1:708-11.
17 English M, Waruiru C, Amukoye E, Murphy S, Crawley J, Mwangi I, et al.
Deep breathing in children with severe malaria: indicator of metabolic
acidosis and poor outcome. Am J Trop Med Hyg 1996;55:521-4.
18 Maitland K, Pamba A, Newton CR, Levin M. Response to volume resuscitation in children with severe malaria. Pediatr Crit Care Med 2003;4:42631.
19 Maitland K, Levin M, English M, Mithwani S, Peshu N, Marsh K, et al.
Severe P falciparum malaria in Kenyan children: evidence for hypovolaemia. Q J Med 2003;96:427-34.
20 Pamba A, Maitland K. Capillary refill: prognostic value in Kenyan
children. Arch Dis Child 2004;89:950-5.
21 Maitland K, Pamba A, English M, Peshu N, Marsh K, Newton CRJC, et al.
Randomized trial of volume expansion with albumin or saline in children
with severe malaria: preliminary evidence of albumin benefit. Clin Infect
Dis 2005;40:538-45.
22 Taylor TE, Fu WJ, Carr RA, Whitten RO, Mueller JG, Fosiko NG, et al. Differentiating the pathologies of cerebral malaria by postmortem parasite
counts. Nat Med 2004;10:143-5.
23 White VA, Lewallen S, Beare N, Kayira K, Carr RA, Taylor TE. Correlation
of retinal haemorrhages with brain haemorrhages in children dying of
cerebral malaria in Malawi. Trans R Soc Trop Med Hyg 2001;95:618-21.
24 Waller D, Crawley J, Nosten F, Chapman D, Krishna S, Craddock C, et al.
Intracranial pressure in childhood cerebral malaria. Trans R Soc Trop Med
Hyg 1991;85:362-4.
25 Newton CR, Kirkham FJ, Winstanley PA, Pasvol G, Peshu N, Warrell DA,
et al. Intracranial pressure in African children with cerebral malaria. Lancet 1991;337:573-6.
26 Walker O, Salako LA, Sowunmi A, Thomas JO, Sodeine O, Bondi FS.
Prognostic risk factors and post mortem findings in cerebral malaria in
children. Trans R Soc Trop Med Hyg 1992;86:491-3.
27 Crawley J, Waruiru C, Mithwani S, Mwangi I, Watkins W, Ouma D, et al.
Effect of phenobarbital on seizure frequency and mortality in childhood
cerebral malaria: a randomised, controlled intervention study. Lancet
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28 Newton CR, Chokwe T, Schellenberg JA, Winstanley PA, Forster D, Peshu
N, et al. Coma scales for children with severe falciparum malaria. Trans R
Soc Trop Med Hyg 1997;91:161-5.
29 Newton CR, Crawley J, Sowumni A, Waruiru C, Mwangi I, English M, et
al. Intracranial hypertension in Africans with cerebral malaria. Arch Dis
Child 1997;76:219-26.
30 Maitland K, Pamba A, Newton CR, Lowe B, Levin M. Hypokalemia in
children with severe falciparum malaria. Pediatr Crit Care Med
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31 Maitland K, Pamba A, Fegan G, Njuguna P, Nadel S, Newton CR, et al.
Electrolyte perturbations in Kenyan children with severe malaria complicated by acidosis. Clin Infect Dis 2005;40:9-16.
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33 Bondi FS. The incidence and outcome of neurological abnormalities in
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Corrections and clarifications

Italians fail to overturn restrictive reproduction law
This News article by Fabio Turone contained two
errors (BMJ 2005;330:1405, 18 Jun). The equal
opportunities minister, Stefania Prestigiacomo, was
elected into parliament through the Forza Italia
party (not the Alleanza Nazionale), and Francesco
Rutelli was not prime minister (as we stated) but
was a candidate for prime minister.
A farewell to alms
A confusion over an abbreviation in this letter by
Jeremiah Norris, resulted in an error in the name
of an organisation (BMJ 2005;331:48, 2 Jul). The
article should have referred to the International
Policy Network (not the International Policy
Institute).
PFI deals need more scrutiny after shareholders receive
big windfalls
In our haste to get the News section to press, we
mixed up our currency conversions in this article
by Matthew Limb: 81m is about $141m and
117m (BMJ 2005;330:1407, 18 Jun).

343