REVIEW

CURRENT
OPINION Severe pneumonia in intensive care: cause,
diagnosis, treatment and management:
a review of the literature
Gennaro De Pascale a, Giuseppe Bello a, Mario Tumbarello b, and
Massimo Antonelli a

Purpose of review
Severe pneumonia is a common disease that intensive care physicians have to face. The review highlights
recent findings about microbiology, diagnosis and treatment, including the management of critically ill
patients with severe respiratory failure.
Recent findings
Epidemiological and clinical risk factors strongly influence microbiological cause in patients with severe
pneumonia. In addition to typical respiratory pathogens, less common microrganisms and multidrug-
resistant (MDR) germs may cause severe lung infections. New molecular diagnostic techniques appear
promising for early detection of microbes involved in severe pneumonia. Antimicrobials remain the
mainstay of causative severe pneumonia treatment and the optimization of antibiotic therapy may be
obtained by applying their pharmacodynamic/pharmacokinetic properties. Several new strategies have
been implemented for the management of acute respiratory failure (ARF) due to severe pneumonia;
however, their extensive clinical application is limited by the need for well trained physicians and adequate
hospital centers.
Summary
Despite advancements in antibiotic and life-supportive treatments, severe pneumonia remains a leading
cause of intensive care unit (ICU) admission and death. Prompt and appropriate antimicrobial therapy is
essential. The use of new nonconventional strategies for ARF management might be effective in more
severe patients.
Keywords
acute respiratory failure, antimicrobial treatment, life-supportive strategies, molecular diagnostic techniques

INTRODUCTION (SCAP) and their application to the other severe

Severe pneumonia in intensive care unit (ICU) pneumonia categories may be only extrapolated.
patients represents a major concern for physicians Furthermore it might be difficult to discriminate
because of the high mortality and morbidity rate whether a pneumonia is really community-acquired
attributable to these episodes [1–3]. During past (CAP) or has been developing in a patient who was
decades many strategies have been implemented
with the aim to optimize the outcome of patients
a
with severe lung infections, and part of these efforts Istituto di Anestesiologia e Rianimazione and bIstituto di Malattie Infet-
is focused upon the need to best define and predict tive, Policlinico Universitario A. Gemelli, Università Cattolica del Sacro
& Cuore, Rome, Italy
illness severity [4 ]. Additionally to some other
available clinical scores, the last Infectious Diseases Correspondence to Massimo Antonelli, MD, Professor of Intensive Care
and Anesthesiology, Director, General Intensive Care Unit and Institute of
Society of America/American Thoracic Society Intensive Care and Anesthesiology, Policlinico Universitario A. Gemelli
(IDSA/ATS) guidelines have assessed major and Università Cattolica del Sacro Cuore, Largo A. Gemelli, 8, 00168 Rome,
minor criteria that seem to best define the severity Italy. Tel: +39 06 30 15 4889/39 06 30 15 4386/39 06 30 15 3226;
of community-acquired pneumonia (CAP) and fax: +39 06 30 13 450; e-mail: m.antonelli@rm.unicatt.it
&
decide the need for ICU admission [5,6 ]. It is note- Curr Opin Pulm Med 2012, 18:213–221
worthy that these scores were created for severe CAP DOI:10.1097/MCP.0b013e328351f9bd

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Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
 Infectious diseases

pneumonia, with regards to microbiological, diag-

KEY POINTS nostic, therapeutic and management aspects.

There are many factors that influence severe pneumonia
cause. Microbiological infective type strictly depends
upon the environment in which pneumonia is CAUSE AND EPIDEMIOLOGY
contracted and the immune condition of the patients. Causative agents of severe pneumonia may widely
differ, mainly depending upon epidemiological and

In ICU invasive diagnostic procedures are widely
available. However, new molecular techniques are clinical factors (Table 1). Up to 10% of hospitalized
being implemented to make microbiological diagnosis patients with CAP need intensive therapies because
not only faster but more accurate. of respiratory failure requiring mechanical venti-
lation and/or septic shock [5,14]. The frequency of

Antimicrobial therapy is still the primary causative
microbiologically documented CAP is around 25%
treatment of severe pneumonia, whereas the benefits of
other pharmacological measures remain in dispute. among in-patients, but the percentage of isolated
Pharmacodynamic/pharmacokinetic principle pathogens in SCAP may be higher, due to the avail-
application may optimize the clinical efficacy of drugs ability and extensive use of more reliable diagnostic
used to fight severe pneumonia. tools in ICU [15,16]. In a recent cohort analysis,
Restrepo et al. [1] observed Streptococcus pneumoniae,

Patients affected by severe pneumonia need life-
supportive interventions, especially for respiratory Staphylococcus aureus and Pseudomanas aeruginosa as
function. Beyond traditional ventilatory support, the main pathogens isolated in patients admitted to
unconventional strategies are becoming more ICU for severe pneumonia. S. pneumoniae , histori-
available. However, particular expertise is required in cally known as ‘Captain of Men of Death’ [17],
order for their survival benefits to surpass the harbors virulence factors that may induce an unbal-
potential complications. anced systemic inflammatory response syndrome
(SIRS) responsible for the disease severity, and this
condition has been demonstrated to be associated
&
with specific host genotypes [18 ]. Legionella pneu-
mophila is an agent well known to be responsible for
exposed to the healthcare environment [healthcare- SCAP and immune-mediated extrapulmonary
associated pneumonia (HCAP)] or has been acquired involvement is often reported [19]. Mortality rate
in the hospital setting [hospital-acquired pneumo- in Pseudomanas SCAP may be extremely high due to
&
nia (HAP)] [7,8 ]. Critically ill patients, already its capability to produce many virulence factors and
admitted to ICU, may subsequently develop severe protective biofilms [20]. S. aureus as causative agent
pneumonia [9] [ventilator-associated pneumonia of SCAP may be isolated from patients affected
(VAP); nonventilator ICU-acquired pneumonia by influenza. Furthermore the rate of methicillin
(NV-ICUAP)]. Both community-acquired or noso- resistance among severe community-acquired lung
comial pneumonia can progress to acute respiratory infections is growing continuously [21]. Among 128
distress syndrome (ARDS) and acute lung injury patients with S. aureus CAP studied by Taneja et al.
(ALI), which are associated with a mortality rate [22], 79% were admitted to ICU and 24 died. Forty-
of more than 50% [10]. three patients had initial cultures positive for methi-
The aim of this study is to review the current cillin-resistant strains [22]. Among viruses, adeno-
knowledge about ICU patients affected by severe virus, respiratory syncytial virus, seasonal influenza

Table 1. Most common causes of severe pneumonia

SCAP [5] (mainly drug-susceptible strains) Severe HCAP/HAP/‘late onset’ VAP [11–13] (mainly multidrug-resistant strains)

Streptococcus pneumoniae
Pseudomonas aeruginosa

Haemophilus influenzae
Acinetobacter spp.

Staphylococcus aureus
Enterobacteriaceae (Klebsiella pneumoniae; Escherichia coli; Enterobacter spp.)

Legionella spp.
Staphylococcus aureus

Gram-negative bacilli

Virus and fungi (mainly in immmunosuppressed population)

HAP, hospital-acquired pneumonia; HCAP, healthcare-associated pneumonia; SCAP, severe community-acquired pneumonia; SP, severe pneumonia; VAP,
ventilator-associated pneumonia.

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 Severe pneumonia in intensive care De Pascale et al.

and parainfluenza are mainly detected in respiratory detect S. pneumoniae and L. pneumophila infections
samples, often as mixed bacterial infections. Swine [5]. Main advantages of their use rely on high diag-
origin influenza A (H1N1 2009) developed in 214 nostic accuracy, immediate availability of the results
different countries causing 18 000 deaths and and good performance under antibiotic therapy. A
involved middle-age (20–40 years) patients, meta-analysis showed that Legionella urinary anti-
whereas obesity and pregnancy appeared to be gen test has excellent specificity (0.99) but lower
important risk factors for severe respiratory compli- sensitivity (0.74); however, the authors observed
&
cation occurrence (ALI/ARDS) [23 ]. Other pulmon- poor quality and publication bias in the available
ary pathogens among bacteria (Mycobacterium spp.), studies [34]. A recent prospective study upon a
viruses (herpesviruses), fungi (Aspergillus spp., Pneu- cohort of 171 adult patients hospitalized with
mocystis jiroveci, especially in patients with human CAP (ICU admission, 8%) observed a sensitivity of
immunodeficiency virus, Cryptococcus neoformans 71% and a specificity of 96% for pneumococcal
&
and endemic mycoses) and parasites may cause urinary antigen test [35 ]. In patients affected by
respiratory insufficiency in immunosuppressed severe pneumonia who did not still receive endo-
patients [24]. tracheal intubation (ETI), the diagnostic reliability
The real bacterial epidemiology of HCAP is still a of deep cough-produced sputum and nasopharyng-
challenge: about half of these pneumonia cases are eal aspirates is uncertain [36]. The application of
&
culture-negative [25 ]. However, those episodes noninvasive ventilation (NIV) enables the perform-
severe enough to need intensive therapies are better ance of fiberoptic broncoscopy (FOB) with bron-
documented microbiologically and they are usually choalveolar lavage (BAL) in hypoxemic patients
caused by multidrug-resistant (MDR) pathogens with pneumonia, without increasing the work of
&
[26]. A quarter of patients with HCAP die, due to breathing during FOB [37,38 ]. In patients under-
the severity of the disease [27,28]. Among 190 severe going ETI, many authors discourage routine use of
pneumonia cases (ARDS rate 37%) retrospectively endoatracheal aspirate for microbiological sampling
&&
analyzed by Schreiber et al. [29 ], the most com- [12]. Protected specimen brushing (PSB) and FOB
monly isolated pathogens in episodes classified as with BAL or miniBAL (performed without fiberoptic
HCAP were methicillin-resistant S. aureus (MRSA) guide) are invasive procedures used for microbio-
and P. aeruginosa. S. pneumoniae and methicillin- logical diagnosis of severe pneumonia in ICU
susceptible S. aureus were the most frequently iso- patients. Data from the literature do not favor the
lated pathogens in those classified as SCAP. Six use of bronchoscopic techniques over ‘blind’ ones,
leading MDR bacterial species have been identified so the choice strictly depends upon institutional
as causative agents of HAP/VAP: S. aureus, P. aerugi- resources and expertise [11]. Gram stain of respirat-
nosa, Klebsiella spp., Escherichia coli, Acinetobacter ory samples, available within a few hours, may help
baumannii, Enterobacter spp. The high frequency of clinicians in narrowing or broadening the antimi-
drug resistance and the co-existence of several crobial spectrum [13]. Current literature encourages
comorbidities are responsible for high mortality the use of quantitative cultures for the bacterial
rates, despite ICU admission [11,30]. Recently Esper- diagnosis of pneumonia in intubated patients
&&
atti et al. [31 ] observed in a large prospective cohort [11,39]. Early molecular detection methods, mainly
of ICU-acquired pneumonia that the causative using real-time polymerase chain reactions (PCRs),
&
agents (mainly P. aeruginosa and S. aureus) in are under development [40 ]. With regards to bac-
patients not mechanically ventilated were similar terial cause, multiplex amplification assays might
to those causing VAP, with similar mortality rate include frequently involved microorganisms, and in
(42 vs. 36%; P ¼ 0.4). cases of hospital-acquired infections, possible resist-
ance gene targets may be detected too [41]. A recent
Swedish study from the Karolinska University Hos-
DIAGNOSIS pital has compared traditional diagnostic methods
Pretreatment blood and lower respiratory tract with PCR-based methods in a cohort of 124 patients
samples for culture should be collected in all with CAP (6% were treated in ICU) [42]. The authors
&&
patients with severe pneumonia [32 ]. In a recent observed that by the implementation of this mol-
retrospective study involving 3116 consecutive ecular technology a higher microbiological yield
patients with CAP, Falguera et al. [33] developed a was achieved, with frequent mixed infection involv-
prediction score, including six variables, for estimat- ing S. pneumoniae and respiratory viruses. Despite
ing the risk of bacteremia. The authors observed that potentially enormous advantages of PCR-based
patients with a score value of at least 2 showed a diagnostic methods (rapidity, sensitivity, conven-
bloodstream infection rate ranging between 16 and ience), several limitations, such as the need of a
63%. Urinary antigen assays are available in order to quantitative cut-off in order to differentiate

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 Infectious diseases

colonizing bacteria from infectious ones or to detect including a b-lactam and either azithroomycin or a
living viruses from prolonged harmless shedding, respiratory fluoroquinolone; however, in the case of
still limit their wide distribution in clinical practice. suspicion of Psudomonas or MRSA involvement, the
In addition increased costs should be considered antibacterial scheme should cover also these patho-
[43]. Fungal antigen detection in BAL specimens gens. In addition to the activity against atypical
might be useful in the management of immuno- pathogens, macrolides have been advocated by
compromised patients with severe pneumonia, some authors as an adjunctive tool in severe pneu-
in which case aspergillosis, endemic mycosis and monia because of their presumed immunomodula-
&
Pneumocystis jiroveci are suspected [44,45 ]. How- tory properties. A recent multicenter prospective
&
ever, also in this field, the use of real-time PCR assays cohort study [51 ], conducted in 27 ICUs of 9
are showing promising results, as recently reported countries, showed that patients with SCAP showed
by Torelli et al. in a cohort of high-risk patients (60% a lower ICU mortality rate when treated with macro-
&
admitted to ICU) [46 ]. Inflammatory biomarkers, lides compared to fluoroquinolones (hazard ratio
such as procalcitonin (PCT), are frequently used as a 0.48; P ¼ 0.03). The empirical antimicrobial regimen
guide to define the length of antimicrobial therapy for HCAP, HAP and VAP proposed by current guide-
[47]. Nevertheless, in adjunction to novel molecu- lines [11–13] is a triple drug scheme including MRSA
lar-based diagnostic methods, they may be helpful and nonfermentative Gram-negative rods coverage.
to identify highest-risk severe pneumonia patients In a recent study conducted in four academic ICUs
&&
and to decide on the most appropriate site of care [52 ], better compliance to international recom-
&
[48,49 ]. mendations with regards to HCAP/HAP/VAP empir-
ical treatment was associated with increased
mortality. Nonadherence to guidelines mainly
TREATMENT included nonuse of combination therapy for
Patients affected by severe pneumonia need to be Gram-negative infections. However, the lack of
treated urgently and appropriately, given the randomization, the differences of baseline clinical
importance of rapid pathogens’ clearance in reduc- conditions and the higher frequency of Pseudomonas
ing infection-driven systemic inflammatory acti- pneumonia in the compliant group raise many con-
vation and preventing multiorgan dysfunction cerns about the clinical reliability of these results
[3,11,50]. Current guidelines for the treatment of [53]. The optimal treatment of severe pneumonia in
severe pneumonia in ICU may help physicians in critically ill patients includes the evaluation of
daily clinical practice (Table 2). IDSA/ATS recom- numerous variables that may influence final micro-
mendations [5] for the management of SCAP in ICU biological and clinical outcome. Antimicrobials
highlight the importance of a combination therapy with good pulmonary distribution (such as

Table 2. Empirical antibiotic approach for the treatment of severe pneumonia

CAP [5,32 ] HCAP/HAP/VAP [11–13]

&&

Absence of risk factors for P. aeruginosa and MRSA Antipseudomonal b-lactam (piperacillin–tazobactam, cefepime,
Non-antipseudomonal cephalosporin III imipenem, or meropenem)
(cefotaxime, ceftriaxone) plus
plus Antipseudomonal fluoroquinolone (ciprofloxacin or levofloxacin)
Macrolide (azithromycin) or respiratory fluoroquinolone or aminoglycoside (amikacin, gentamicin, tobramicyn)
(moxifloxacin, levofloxacin) plus
Linezolid or vancomycin
Presence of risk factors for P. aeruginosa and MRSA Early-onset VAP/HAP without risk factors for MDR pathogens
Antipseudomonal b-lactam (piperacillin–tazobactam, Aminopenicillin plus b-lactamase-inhibitor (amoxicillin–clavulanic
cefepime, imipenem, or meropenem) acid; ampicillin–sulbactam)
plus or
Ciprofloxacin or (macrolide plus aminoglycoside) Non-antipseudomonal cephalosporin II/III (cefuroxime,
plus cefotaxime, ceftriaxone)
Linezolid or vancomycin or
Respiratory fluoroquinolone (moxifloxacin, levofloxacin)
or
Ertapenem

CAP, community-acquired pneumonia; HAP, hospital-acquired pneumonia; HCAP, healthcare-associated pneumonia; MDR, multidrug-resistant; MRSA, methicillin-
resistant Staphylococcus aureus; SP, severe pneumonia; VAP, ventilator-associated pneumonia. In settings where the prevalence of multidrug-resistant Gram-
negative pathogens is particularly high, empirical colistin may be preferred to aminoglycosides or antipseudomonal fluoroquinolones in the management of
nosocomial pneumonia.

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 Severe pneumonia in intensive care De Pascale et al.

linezolid) should be preferred, or alternative therapies but also of the effective application of
additional administration strategies might be added well known beneficial interventions, grouped in
(aerosolized antibiotics); isolated microorganisms’ clinical ‘bundles’. Five key elements have been
minimal inhibitory concentrations (MICs) have to proposed by Rello [65] with the aim to obtain
be carefully considered and antibiotics’ bactericidal the best early treatment of patients with severe
properties may be optimized by applying their phar- pneumonia: ‘risk assessment’ (including pulse
macodynamic/pharmacokinetic properties (time- oxymetry and point-of-care lactates), ‘early fluid
dependent/concentration-dependent molecules) resuscitation’, ‘prompt oxygenation’, ‘immediate
[54]. In addition, pathophysiological changes occur- combined antibiotic therapy’ and ‘evaluation for
ring during severe infections (increased cardiac ICU admission’. When severe pneumonia is com-
output; leaky capillaries/altered protein binding; plicated by severe sepsis and septic shock, adherence
end-organ dysfunctions) modify drug clearance to a resuscitation interventions bundle within
(Cl) and volume of distribution (Vd) according to the first 6 h (measure of serum lactates, control of
their hydrophilic or lipophilic nature [55]. Given hypotension, early antibiotic administration after
their low pulmonary penetration, high aminoglyco- performing cultures) and 24 h (low-dose steroids
side doses (i.e. amikacin 25 mg/kg) are needed in administration, glucose control, maintenance of
order to reach effective peak concentrations in crit- inspiratory plateau pressure <30 cmH2O for mechani-
ically ill patients, especially those ones with severe cally ventilated patients) is associated with improved
&& & &
pneumonia [56]. A recent systematic review [57 ] outcome [66 ,67 ].
has confirmed the pharmacodynamic/pharmacoki- A major challenge that physicians attending to
netic advantages of prolonged/continuous infusion patients with severe pneumonia have to face is the
of b-lactams; however, antibiotics’ therapuetical management of acute respiratory failure (ARF)
drug monitoring (TDM) still represents the best tool requiring mechanical ventilation. Sequential sup-
to ensure optimal drugs exposure in critically ill portive interventions aimed to manage severe ARF
patients. Despite the optimal duration of severe in patients with pneumonia are summarized in
pneumonia being unclear, surrogate biomarkers, Fig. 1. NIV, delivered through a facial mask or a
like procalcitonin, may be useful to guide antibiotic helmet, represents a possible first-line intensive
therapy duration [58]. Some preclinical and clinical treatment for ARF, both in hypoxemic and hyper-
studies [59,60] suggest the use of steroids as an capnic patients [68]. Although the main reason for
adjunctive tool in critically ill patients with pneu- choosing NIV in patients with severe pneumonia
monia; however, evidence from current literature and ARF is to avoid the complications associated
does not recommend their extensive use in severe with invasive mechanical ventilation, clinicians
pneumonia [61]. Subgroups of patients (i.e. those have to carefully consider those elements that
with pulmonary immune reconstitution inflamma- may predict NIV failure, thus preventing dangerous
&
tory syndrome and with severe pneumonia evolving delays in performing ETI [69 ,70].
into ALI/ARDS despite adequate treatment) may Patients with severe pneumonia and severe ARF
benefit from their anti-inflammatory properties evolving into ALI/ARDS [acute onset, bilateral infil-
trates on chest X-ray, pO2/FiO2 ratio 200 mmHg
&
[62 ]. In light of its immunomodulatory properties,
the use of drotrecogin alfa activated (DAA) in (300 mmHg for ALI) and absence of clinical evi-
patients with severe pneumonia developing septic dence of left atrium hypertension] commonly need
shock has been proposed in the past [63]. However, invasive ventilation [71]. In these patients, a lung
given the negative results of a multinational protective ventilation strategy with a tidal volume
placebo-controlled trial of DAA in septic shock of 4–8 ml/kg of ideal body weight (IBW) and a
(PROWESS SHOCK), requested by the European plateau pressure (Pplat) of 30 cmH2O or less is
Medicines Agency and not yet published, the required in order not to perpetuate lung injury
molecule has been recently withdrawn from [10,72]. Currently, the optimal positive end-expir-
the market [http://www.emea.europa.eu]. Other atory pressure (PEEP) value has not been clearly
adjunctive therapies are under investigation, but established. However, a recent meta-analysis of
results are still unconvincing (prostaglandin inhibi- studies comparing different PEEP values for the
tors, anticoagulant agents, surfactant, immuno- management of ALI/ARDS (50% of patients were
globulin, statins, g-interferon) [64]. affected by severe pneumonia) observed that higher
PEEP (around 15 cmH2O) values were associated with
improved survival rate (P ¼ 0.03) [73]. Additionally,
MANAGEMENT conservative fluid strategies and early use of short-
Optimizing severe pneumonia management may term neuromuscular blocking agents are being
&
consist not only of the discovery of new associated with improved outcome [74,75 ].

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 Infectious diseases

Severe ARF due to SP

NIV contraindicationsa?

Yes No

NIV trial

Failure of NIV trialb

Protective invasive mechanical ventilation

Conservative fluids management strategy
Early, short term use of neuromuscular
blockers

PaO2:FiO2 < 100 and/or

Pplat > 30 cmH2O on low tidal volume ventilation
(4 ml/kg PBW) and/or
decompensated hypercapnia

HFOV ± iNOc
Prone positioning ± iNO
ECMO

FIGURE 1. Supportive strategies for the management of acute respiratory failure due to severe pneumonia. aSevere central
neurological disturbances, unstable hemodynamic conditions, organ dysfunction other than neurological, inability to protect
the airway or clear respiratory secretions, severe gastrointestinal bleeding, inability to fit the interface, undrained
pneumothorax. bFailure to maintain PaO2 : FiO2 ratio above 100, neurological impairment, persistence of dyspnea and
tachypnea, hemodynamic instability and intolerance of the interface. cConsidered in patients with high recruitment potential.
ARF, acute respiratory failure; ECMO, extracorporeal membrane oxygenation; HFOV, high-frequency oscillatory ventilation;
iNO, inhaled nitric oxide; NIV, noninvasive ventilation; PBW, predicted body weight; SP, severe pneumonia.

Patients whose gas exchanges are not adequately in adults) and high mean airway pressure (mPaw)
maintained are candidates for nonconventional may result in improved alveolar recruitment with
ventilatory supportive strategies. less risk of overdistension. Primary determinants of
One of these interventions is represented by oxygenation are the fixed mPaw and the fraction of
the prone position in patients with ARDS. The prin- inspired oxygen, whereas the pressure amplitude
cipal pathophysiological mechanisms that would of oscillation and the respiratory frequency are
&
improve oxygenation during prone positioning the main determinants of CO2 elimination [78 ].
include redistribution of ventilation and perfusion With the aim of reducing ventilation/perfusion
matching, alveolar recruitment and avoidance of mismatch, refractory hypoxemic ARDS patients
&
heart compression upon the lungs [76 ]. In a recent may benefit from the use of inhaled vasodilators.
meta-analysis of randomized controlled trials Inhaled nitric oxide (iNO) has been shown to
(RCTs) upon prone positioning in ALI and ARDS improve oxygenation in ARDS patients and, despite
&
patients, Sud et al. [77 ] observed that, in patients a lack of evidence to support its benefits with regards
with a PaO2/FiO2 below 100, the use of this to mortality rate and duration of mechanical venti-
ventilator-supportive strategy was associated with lation, its use may be a rescue intervention for the
reduced mortality. management of ARDS patients [79,80].
High-frequency oscillatory ventilation (HFOV) For those patients with severe hypoxemia unre-
is a ventilator mode which provides a small tidal sponsive to the above mentioned unconventional
volume by oscillating a bias gas flow in the airway. ventilatory strategies, extracorporeal membrane
&
The delivery of a small tidal volume at a high oxygenation (ECMO) may be considered [81 ].
respiratory frequency (generally 3–15 Hz; 3–6 Hz ECMO consists of extracting a large amount of

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 Severe pneumonia in intensive care De Pascale et al.

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