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Partial liquid ventilation for preventing death and morbidity in adults with acute lung injury and acute respiratory distress syndrome

  1. Imelda M Galvin1,*,
  2. Andrew Steel2,
  3. Ruxandra Pinto3,
  4. Niall D Ferguson4,
  5. Mark W Davies5

Editorial Group: Cochrane Anaesthesia, Critical and Emergency Care Group

Published Online: 22 JUL 2013

Assessed as up-to-date: 12 NOV 2012

DOI: 10.1002/14651858.CD003707.pub3


How to Cite

Galvin IM, Steel A, Pinto R, Ferguson ND, Davies MW. Partial liquid ventilation for preventing death and morbidity in adults with acute lung injury and acute respiratory distress syndrome. Cochrane Database of Systematic Reviews 2013, Issue 7. Art. No.: CD003707. DOI: 10.1002/14651858.CD003707.pub3.

Author Information

  1. 1

    Queen's University, Kingston, Ontario, Canada

  2. 2

    University of Toronto, Department of Anesthesiology and Interdepartmental Division of Critical Care Medicine, Toronto, Ontario, Canada

  3. 3

    Sunnybrook, Critical Care Medicine, Toronto, Ontario, Canada

  4. 4

    University Health Network and Mount Sinai Hospital, University of Toronto, Interdepartmental Division of Critical Care Medicine, Toronto, Ontario, Canada

  5. 5

    Department of Paediatrics & Child Health, The University of Queensland, Grantley Stable Neonatal Unit, Royal Brisbane and Women's Hospital, Brisbane, Queensland, Australia

*Imelda M Galvin, Queen's University, Kingston, Ontario, Canada. galvini@KGH.KARI.NET.

Publication History

  1. Publication Status: New search for studies and content updated (conclusions changed)
  2. Published Online: 22 JUL 2013

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Characteristics of included studies [ordered by study ID]
Hirschl 2002

MethodsMulti-centre, randomized controlled trial
Done between July 1995 and August 1996


Participants90 participants with ALI/ARDS from 18 centres in the USA

Inclusion criteria:

  • Bilateral infiltrates on CXR for ≤ 5 d;
  • Mechanically ventilated for ≤ 5 d;
  • FiO2 ≥ 0.5;
  • PaO2/FiO2 ratio > 60 and < 300, irrespective of the level of positive end-expiratory pressure; and
  • Aged 15 to 75 y.


The first 45 participants were stratified according to Murray lung Injury score ≤ 2.5 or > 2.5. They had their PaO2/FiO2 ratios determined at an FiO2 of 1

The second 45 participants also had to have an APACHE 2 score of < 30. They had their PaO2/FiO2 ratios determined at an FiO2 of ≥ 0.5

Exclusion criteria:

  • On ventilator support for diagnosed ALI/ARDS or with FiO2 > 0.4 for longer than 24 h;
  • On ventilator support for reasons other than diagnosed ALI/ARDS for longer than three days in the previous 21 d;
  • Tidal volume < 4 mL/kg;
  • Neuromuscular respiratory failure or cardiac disease causing the compromise in gas exchange;
  • Lung parenchymal or airway surgery within 30 d of screening;
  • Status asthmaticus or severe asthma currently under treatment with acute doses of systemic corticosteroids, or severe chronic obstructive pulmonary disease requiring long-term oxygen therapy;
  • Systolic blood pressure < 90 mm Hg, which cannot be adequately maintained with intravenous fluids and high-dose pressors;
  • Intubation primarily for chronic interstitial lung disease (e.g., sarcoidosis, idiopathic pulmonary fibrosis);
  • Any active air leak from the lung into the pleural space;
  • Seizures refractory to anticonvulsant therapy;
  • High risk of mortality within three months of screening for reasons other than ALI or ARDS or associated complications (e.g. terminal cancer with a high short-term risk of mortality);
  • Hypersensitivity to perfluorocarbons;
  • Pregnant females;
  • Receipt of any other experimental drug within 30 d of screening;
  • Significant renal dysfunction defined by (1) serum creatinine > 3.0 mg/dL or (2) an increase in serum creatinine of 0.8 mg/dL in 24 h;
  • Significant hepatic dysfunction defined by serum total bilirubin > 2.0 mg/dL and albumin < 2.5 g/dL; or a prothrombin time 3 s greater than control or > 1.5 times the upper limit of normal and an activated partial thromboplastin time > 1.5 times the upper limit of normal;
  • Significant haematologic dysfunction defined by platelet count < 75,000/mm3; a total white blood cell count < 1000/µL; or evidence of disseminated intravascular coagulation; and
  • In participants 46 to 90 y of age, high risk of mortality as defined by an APACHE II score ≥ 30.


InterventionsRandomly assigned to receive PLV or CMV for a maximum of four days for the first 45 participants and a maximum of five days for subsequent participants. Groups were allocated at a PLV-to-CMV ratio of 2:1. Perflurocarbon was administered at a dosage of 5 mL/kg increments based on ideal body weight to a maximum of 30 mL/kg. Each participant was assessed every four hours for the presence of a meniscus visible within the endotracheal tube during transient ventilator disconnect. If none was present, an additional 1 to 5 mL/kg aliquot of perflubron was administered. PLV was discontinued at the discretion of the investigator; no guidelines or rules regarding discontinuation of PLV were provided
The mean duration of perflubron administration was 80 ± 3 h, with a range of 17 to 120 h


OutcomesPrimary outcome:

  • VFDs to day 28. The initial primary outcome was oxygenation, but this was changed during the study to mean number of ventilator-free days to day 28. Ventilator-free days to day 28 were defined as follows: "On Day 28, each survivor received 1 point for every day following discontinuation of mechanical ventilation, including the day of extubation, if the patient remained successfully weaned for the remainder of the day. Participants who died during the first 28 d of the study received a VFD score of zero. Participants who were re-intubated had days counted toward a VFD only if they remained off the ventilator for the remainder of the 28-day period. For instance, if a participant was extubated for two days and then re-intubated for the remainder of the 28 d, the VFD was zero. Only those days for which the participant was extubated and remained extubated for the remainder of the 28-day experimental period counted toward VFD"


Secondary outcomes included:

  • 28 day mortality;
  • PaO2/FiO2 ratio, A-a gradient; and
  • lung mechanics.


Results: This study showed no difference in:

  • number of ventilator-free days (CMV = 6.7 ± 1.8 d, PLV = 6.3 ± 1.0 d, P = 0.85);
  • mortality at day 28 (CMV = 36%, PLV = 42%, P = 0.63); and
  • any pulmonary-related parameter.


Adverse events: The authors do not provide P values or confidence intervals for all adverse event outcomes but report higher incidence of adverse events in those receiving PLV (99%) than in those receiving CMV (96%). Hypoxia, hypotension, pneumothoraces, bradycardia, respiratory acidosis and cardiac arrest were all more common in the partial liquid ventilation group

Other relevant outcomes that were not reported:

The following outcomes, which we consider clinically relevant, were not reported:

  • Mortality (at discharge from ICU, at discharge from hospital and at one, two and five years);
  • Duration of mechanical ventilation;
  • Duration of respiratory support;
  • Duration of oxygen therapy;
  • Length of stay in the ICU;
  • Length of stay in hospital;
  • Infection (septicaemia, pneumonia);
  • Long-term cognitive impairment;
  • Long-term health-related quality of life;
  • Long-term lung function; and
  • Cost.


NotesThere are some concerns with this study regarding the following:

Methodological rigour and external validity:

Concerns regarding methodological rigour and generalizability of results due to changes in selection criteria and primary endpoints during the course of the study and exclusion of patients with refractory shock and renal, hepatic and haematological dysfunction

Adverse event reporting:

The authors conclude that “PLV may be performed reasonably safely in adult patients with respiratory failure with few adverse events, which appear to be transient, self limited and with appropriate vigilance, manageable”. This statement does not accurately represent the findings of the study, which showed a higher incidence of hypoxia, hypotension, pneumothoraces, bradycardia and cardiac arrest in the partial liquid ventilation group, most of which occurred at times of perfluorocarbon dosing, and at least four episodes of cardiac arrest were attributable to treatment in this group

Miscellaneous:

A large number of post hoc analyses are reported. Post hoc analyses showed more rapid discontinuation of ventilation in the PLV arm (P = 0.045), although participants who were randomly assigned to PLV had a longer length of CMV before randomization (P = 0.12). The time lag involved may explain the difference in rapidity of discontinuation, as those randomly assigned later may already be in the recovery phase of their illness

18 centres were involved, although only 4 centres enrolled more than 5 participants of the total 90 participants


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskQuote: “Randomization was performed according to a 2 or 6 block design ...“  

Comment: Probably done, as although the authors do not tell us the exact method of randomization used, they do tell us that randomization was performed

Allocation concealment (selection bias)Low riskQuote: “After granting of informed consent, a central office at Alliance Pharmaceutical was contacted for group assignment”

Comment: Probably done, as a centralized randomization process is described

Blinding (performance bias and detection bias)
All outcomes
Unclear riskQuotes:"This was a prospective, non blinded, randomized study…”

"After entry of 45 patients evaluation of the data suggested a trend ...."

"No monitoring committee was used"

"There was no follow up to ensure that investigators adhered to these (ventilation) guidelines"

 

Comment: Not done, as the authors clearly state from the outset that no blinding was employed. The outcome measures addressed-'ventilator free days', '28 day mortality' and 'physiological indices'-were objective and therefore were unlikely to be influenced by the lack of blinding. However, the fact that at least some of the investigators had access to unblinded interim data, together with the lack of any method of ensuring or measuring adherence to ventilation guidelines, raise concerns over possible performance bias

Blinding of outcome assessment (detection bias)
All outcomes
Low riskThere was no blinding of outcome measures, but the outcomes addressed were unambiguous and therefore were unlikely to be influenced significantly by the lack of blinding

Incomplete outcome data (attrition bias)
All outcomes
Low riskThe authors enrolled 90 participants but do not provide a statement of completeness of follow-up or any details of losses to follow-up. Results for primary and secondary outcomes are not presented in a way that allows the reader to determine whether all participants were followed up for the duration of the study.

However, adverse event data are presented in terms of absolute numbers, and for each event, these numbers add up to 90, so it is likely that all included participants were followed up for outcome

Selective reporting (reporting bias)Unclear riskQuotes: “No significant difference in the number of days free from ventilation at 28 days, the incidence of mortality or any pulmonary related parameter was noted”

“PLV may be performed safely in adult patients with respiratory failure with few adverse events, which appear to be transient, self limited and, with appropriate vigilance, manageable“

Comments: The authors provide unbiased reports for the primary and secondary outcome measures of ventilator-free days and 28 day mortality. Both of these are clearly defined in the methods section of the report, and both are reported in an unbiased way

However, the severity, seriousness and significance of adverse events are under-appreciated and under-reported

Other biasLow riskParticipants randomly assigned to the PLV group were randomly assigned an average of 25 h later than those who were randomly assigned to the CMV group

However, this baseline imbalance in pre-randomization of duration of ventilation is unlikely to have resulted in significant bias

Kacmarek 2006

MethodsProspective, multi-centre, randomized controlled trial
Done between December 1998 and December 2000


Participants311 participants with ARDS from 56 centres in North America and Europe

Inclusion criteria:

  • Risk factor for ALI/ARDS;
  • Prior mechanical ventilation for 120 h or less;
  • Acute, bilateral infiltrates on chest radiograph; and
  • PaO2/FiO2 of 200 mm Hg or less with an FiO2 of 0.5 or greater and PEEP of 5 cm H2O or greater.


Exclusion criteria:

  • Age younger than 16 or older than 65 y;
  • Acute Physiology and Chronic Health Evaluation (APACHE) II score ≥ 30;
  • Longer than 48 h since meeting inclusion criteria;
  • Inability to obtain informed consent;
  • Significant nonpulmonary organ dysfunction as defined by the following:
    • Chronic renal failure requiring dialysis;
    • Acute liver disease with significant hepatocellular or cholestatic liver injury (acute hepatitis or acute cholestasis);
    • Severe chronic liver disease (bilirubin > 3 mg/dL and serum albumin > 3 g/dL); or
    • Haematological dysfunction, defined by a total polymorphonuclear leukocyte (PMN) count < 0 .5 × 103/mL.
  • Systolic blood pressure < 90 mm Hg, unresponsive to treatment with fluids and vasopressors;
  • Congestive heart failure, defined by a pulmonary arterial occlusion pressure >18 mm Hg or by clinical examination;
  • Clinical history of decompensated left ventricular dysfunction as indicated by New York Heart Association Class III or IV or left ventricular ejection fraction < 30%;
  • Documented myocardial infarction within the previous three months; or life-threatening arrhythmia during the present hospital admission;
  • Glasgow Coma Score < 10 determined before administration of confounding medications, such as narcotics, sedatives or neuromuscular blockers;
  • Active air leak from the lung into the pleural space in the 24 h before randomization (chest tube to pleura vac with water seal without leak and not requiring suction for a minimum of 24 h was allowed);
  • Evidence of increased intracranial pressure or history of an intracerebral haemorrhage within the previous three months;
  • Status asthmaticus or severe asthma currently under treatment with pharmacological doses of intravenous corticosteroids;
  • Chronic lung disease requiring long-term oxygen therapy or presenting with a baseline FEV1 < 700 mL;
  • Spinal cord injury above T-1;
  • Myasthenia gravis or Guillain-Barre´ syndrome or other neurological disorder that impairs the patient’s ability to breath spontaneously;
  • Organ transplantation (i.e. bone marrow, heart, lung, liver, kidney, pancreas);
  • Seizures refractory to anticonvulsant therapy;
  • Acute parenchymal lung injury secondary to suspected overdose of narcotics;
  • Burn injury (2nd or 3rd degree) with greater than 30% of total body surface area or with a restrictive chest injury;
  • Life expectancy of < 3 months for other than ALI/ARDS-associated complications;
  • Positive blood test for HIV with CD-4 count < 200;
  • Received chemotherapy within 30 d before enrolment;
  • Morbid obesity (more than twice ideal body weight);
  • Tracheostomy;
  • Vascular lung disease with alveolar haemorrhage or pulmonary hypertension;
  • Hypersensivity to perfluorocarbons;
  • Positive serum β-human chorionic gonadotropin (HCG) indicating pregnancy; and
  • Received any other experimental treatment within 30 d before screening (except nitric oxide, provided nitric oxide had been discontinued at least 4 h before initiation of standardized mechanical ventilation).


InterventionsRandomly assigned to receive:

  • Conventional mechanical ventilation;
  • Low-dose partial liquid ventilation-instillation of PFC into the lungs to the level of the carina at zero-PEEP; or
  • High-dose partial liquid ventilation-instillation of PFC into the lungs to an ETT level 5 cm below the incisors at zero-PEEP.


Five participants did not receive the intended intervention (two randomly assigned to low-dose PLV and three randomly assigned to high-dose PLV never received PLV). However, analysis was performed on the basis of 'intention to treat'.


OutcomesPrimary outcome:

  • Ventilator-free days during the 28 dafter randomization, with a ventilator-free day defined as any day between randomization and 28 d post-randomization when the participant was not ventilated and sustained unassisted breathing for three or more consecutive days. Participants who died or required extracorporeal oxygenation during this period received no ventilator-free days. Participants who were re-intubated after extubation failure received ventilator-free days only from the time following final extubation.


Secondary outcomes:

  • All-cause 28 day mortality;
  • Time to unassisted ventilation;
  • Percentage of participants alive and off ventilation at Day 28;
  • Time to ARDS resolution defined as the time to a PaO2/FiO2 of 200 mm Hg or greater with a PEEP of 5 cm H2O or less and an FiO2 of 0.5 or less; and
  • Arterial blood gases, ventilator, physiological, laboratory and radiographic data obtained after stabilization on standardized ventilator settings at 12, 24, 48, 72, 96 and 120 h, and at 7, 14 and 28 d after randomization.


Results: This study reported:

  • More ventilator-free days in the CMV group (13.0 ± 9.3) than in both the low-dose PLV group (7.4 ± 8.5 d, P < 0.001) and the high-dose PLV group (9.9 ± 9.1 d; P = 0.043);
  • 28-Day mortality in the CMV group was only 15.0% versus 26.3% in the low-dose PLV group (P = 0.06) and 19.1% in the high-dose PLV group (P = 0.39);
  • Time to unassisted ventilation was shorter (12.5 vs 18.9 d, P < 0.001) in the CMV group than in the low-dose PLV group and in the high-dose PLV group (12.5 vs 13.9 d, P = 0.017);
  • Percentage of participants alive and off ventilation at 28 d was greater in the CMV group than in the low-dose PLV group (76 vs 53, P < 0.001) and in the high-dose PLV group (76 vs 61, P = 0.027); and
  • Time to resolution of ARDS/ALI was significantly faster in the CMV group than in the low-dose PLV group (12.5 vs 18.9 d, P < 0.001) and was faster in the CMV group than in the high-dose PLV group (10 vs 10.6 d, P = 0.12).


Adverse events:

Statistically significantly (P < 0.05) more episodes of pneumothoraces, hypoxia and hypotension in PLV groups than in the CMV group. The authors state that most of the hypoxic and hypotensive events in the PLV group occurred during the first 5 d of drug delivery and were associated with initial and subsequent filling of the lungs with perfluorocarbon. They attributed this to the need to interrupt ventilator support to administer the perfluorocarbon.

Other relevant outcomes that were not reported:

The following outcomes, which we considered clinically relevant, were not reported:

  • Mortality (at discharge from ICU, at discharge from hospital and at one, two and five years);
  • Duration of oxygen therapy;
  • Length of stay in the ICU;
  • Length of stay in the hospital;
  • Infection (septicaemia, pneumonia);
  • Long-term cognitive impairment;
  • Long-term health-related quality of life;
  • Long-term lung function; and
  • Cost.


NotesAlthough the study was generally well conducted and well reported, there are some concerns regarding the following:

Internal validity:

Investigators changed the target sample size on two occasions in response to protocol amendments and interim analyses, and the rationale for these changes is not well explained or justified.

Initially a total sample size of 480 was estimated for a power of ≥ 90% for a two-sided t test, to detect a 3 VFD difference between groups with an overall type 1 error of 5%. After protocol amendments, this was decreased to 260, and the number of VFD considered to represent a significant difference was increased from three to four. After interim analysis, the sample size was subsequently increased to 309 with a power of 80% for a two-sided t test to detect a 4 VFD difference between groups with an overall type 1 error of 5%.

External validity:

This study excluded patients with shock and severe nonpulmonary organ dysfunction, and the strict oxygenation criteria for inclusion meant that only those with severe lung injury were included. This limits its generalizability to a subset of critically ill patients with severe lung injury without multiple organ dysfunction.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskQuote: “Patients were randomly assigned to one of 4 groups...Group assignment was performed using a computerized randomization system”

 

Comment: Probably done, as the investigators describe a random method.

Allocation concealment (selection bias)Low riskQuote:"Group assignment was performed using a computerized randomization system."

Comment: Probably done, as the investigators describe a random method.

Blinding (performance bias and detection bias)
All outcomes
Low riskNo blinding of participants or personnel is described, but evidence for equal treatment of the two groups with respect to ancillary treatment comes from the fact that both groups received standardized ventilatory support, target gas exchange criteria for weaning were defined a priori and the number of weaning attempts per day was equal between the groups when these criteria were met and were not met.

Blinding of outcome assessment (detection bias)
All outcomes
Low riskNo blinding of outcome assessment is described, but the objective nature of the outcome measures used (i.e. ‘ventilator free days’, ‘time to unassisted ventilation’, ‘time to resolution of ARDS’, ‘percentage of patients alive and off ventilation at 28 days’ and ‘28 day mortality’) means that this is unlikely to result in significant bias.

Incomplete outcome data (attrition bias)
All outcomes
Low riskQuote: “311 patients who were enrolled were followed up for the 28 day study period“

 

Comment: Probably done, as all enrolled participants were followed up for the study period, and outcome data were reported for all enrolled participants.

Selective reporting (reporting bias)Low riskQuote “The primary outcome was ventilator free days during the 28 days following randomization. The secondary outcomes were mortality, time to unassisted ventilation …."

Comment: Study protocol is not available, but the primary and secondary outcomes as reported are clearly stated in the methods section of the report.

Other biasLow risk

 
Characteristics of excluded studies [ordered by study ID]

StudyReason for exclusion

Hirschl 1995Case series
Not randomized
No control group

Hirschl 1996Not randomized
No control group

Hirschl 1998Not randomized
No control group

Kazerooni 1996Not randomized
No control group

Meaney 1997Case series
Not randomized
No control group

Reickert 2001Not randomized
No control group

Schuster 2001This study compared chest radiograph filling patterns in participants with acute lung injury who had received low-dose (10 mL/kg) or high-dose perflubron (20ml/kg). There was no control group that did not receive perflubon.

 
Characteristics of ongoing studies [ordered by study ID]
Chen 2011

Trial name or titlePerfluorocarbon (PFC) Inhalation Treatment of Acute Lung Injury/Acute Respiratory Distress Syndrome

MethodsRandomized controlled single-blind trial with cross-over assignment

ParticipantsMechanically ventilated adults with acute lung injury

InterventionsExperimental: Perfluorocarbon Placebo Comparator: Sterile Water for Injection

OutcomesPrimary outcome measures: oxygenation index, respiratory mechanics

Secondary outcome measures: 3-y survival, ventilator-free days, 28-d mortality

Starting dateAugust 2011

Contact informationContact: Zhixin Liang, MD

Notes

 
Comparison 1. 28 day mortality - PLV versus CMV

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 28 Day Mortality2302Risk Ratio (M-H, Random, 95% CI)1.21 [0.79, 1.85]

 
Comparison 2. Ventilator Free Days - PLV versus CMV

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Days Free of Mechanical Ventilation at Day 282302Mean Difference (IV, Random, 95% CI)-2.24 [-4.71, 0.23]

 
Comparison 3. Adverse Events

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Hypoxia2302Risk Ratio (M-H, Random, 95% CI)1.77 [0.97, 3.24]

 2 Pneumothorax2302Risk Ratio (M-H, Random, 95% CI)2.06 [0.71, 5.95]

 3 Hypotension2302Risk Ratio (M-H, Random, 95% CI)1.38 [0.87, 2.19]

 4 Bradycardia2302Risk Ratio (M-H, Random, 95% CI)2.51 [1.31, 4.81]

 5 Cardiac Arrest2302Risk Ratio (M-H, Random, 95% CI)1.31 [0.56, 3.04]

 
Summary of findings for the main comparison.

Partial liquid ventilation compared with conventional mechanical ventilation for acute lung injury and acute respiratory distress syndrome

Patient or population: mechanically ventilated participants with acute lung injury and acute respiratory distress syndrome

Settings: Intensive care in Europe and North America

Intervention: Partial liquid ventilation

Comparison: Conventilation mechanical ventilation

OutcomesIllustrative comparative risks* (95% CI)Risk ratio
(95% CI)
No. of participants
(studies)
Quality of the evidence
(GRADE)
Comments

Assumed riskCorresponding risk

Conventional mechanical ventilationPartial liquid ventilation

28 d mortality1.8 per 10002.18 per 10001.21

(0.79 to 1.85)
302

(2)
⊕⊕⊝⊝
low1

Number of days free of mechanical ventilation in a 28 d periodThe number of days free of mechanical ventilation in the control groups during a 28 d period ranged from 3.7 to 22.3 dThe mean number of days free of mechanical ventilation in a 28 d period was 2.24 (4.71 to 0.23) d less in the PLV group than in the CMV group302

(2)
⊕⊕⊝⊝
low1

Adverse events

Hypoxia2.4 per 10004.2 per 10001.77

(0.97 to 3.24)
302

(2)
⊕⊕⊝⊝
low1

Pneumothorax1.0 per 10002.0 per 10002.06

(0.71 to 5.95)
302

(2)
⊕⊕⊝⊝
low1

Hypotension2.2 per 10003.0 per 10001.38

(0.87 to 2.19)
302

(2)
⊕⊕⊝⊝
low1

Bradycardia0.8 per 10002.0 per 10002.51

(1.31 to 4.81)
302

(2)
⊕⊕⊝⊝
low1

Cardiac arrest0.5 per 10000.7 per 10001.31

(0.56 to 3.04)
302

(2)
⊕⊕⊝⊝
low1

*The basis for the assumed risk (e.g. the mean control group risk across included studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: Confidence interval; RR: Risk ratio.

GRADE Working Group grades of evidence.
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.

 1.The 'low' quality grade was assigned on the basis that only two studies were eligible for inclusion in this meta-analysis, limiting the quantity of data available for analysis, and based on the fact that both studies excluded those with severe nonpulmonary organ dysfunction, limiting the generalizability of these results.