Description of the condition
Acute lung injury (ALI), known in its most severe form as acute respiratory distress syndrome (ARDS), is a syndrome of severe respiratory failure characterized by acute onset severe hypoxaemia and bilateral chest infiltrates on chest x-ray, without evidence of left heart failure. ARDS was first described by Ashbaugh in 1967 (Ashbaugh 1967) in a case series that included one 11 year old child. The causes of ALI or ARDS are many. They may result from lung disease (pneumonia, aspiration or inhalation injury, lung trauma, fat emboli, near-drowning) or extrapulmonary causes (septicaemia, trauma and shock, cardio-pulmonary bypass, drug overdose, acute pancreatitis, transfusion) (Ware 2000). Malignancy and infection (septicaemia or pneumonia) are common underlying antecedents in children (Davis 1993; DeBruin 1992; Timmons 1991).
ALI or ARDS results in poor matching of ventilation and perfusion within the lung, and subsequent severe hypoxaemia. This situation is known as ventilation-perfusion (V/Q) mismatch. The syndrome is also characterized by severe heterogeneous atelectasis and decreased lung compliance. Hence, patients with ALI or ARDS universally require respiratory support and the mainstay of treatment is endotracheal intubation and mechanical ventilation (Tobin 2001). The syndrome is also characterized by a prominent pulmonary and systemic inflammatory response. There is loss of integrity of the alveolar-capillary barrier in the lung with increased inflammatory cell and oxygen free radical mediated injury and increased pulmonary and systemic pro-inflammatory cytokines (Ware 2000). ALI or ARDS is further complicated by ventilator-induced lung injury (VILI) and associated secondary inflammatory effects. VILI arises through either overdistention of the lung (volutrauma) or the use of high pressure within the lung (barotrauma), or a combination of these factors. Decreasing baro- and volutrauma may lower mortality and morbidity (Tobin 2001; van der Werf 2001).
Generally accepted mortality figures for ALI or ARDS in adults have ranged from 40% to 60% (Ware 2000) although studies have shown decreasing mortality over time (Abel 1998; Milberg 1995). Mortality in children seems to be somewhat greater, with typical rates higher than 60% (Costil 1995; Davis 1993; DeBruin 1992; Paret 1998; Timmons 1991). Mortality is often due to the primary disease process, especially septicaemia or associated multiple organ system failure (MOSF), rather than respiratory failure per se (Monchi 1998; Pfenninger 1996; Ware 2000; Zilberberg 1998) and therefore may not be amenable to alterations in ventilatory techniques.
Recent studies show a lower mortality with 'protective' ventilatory strategies or an 'open-lung' approach in adults with ARDS. This suggests that VILI does have a role in increasing mortality and that decreasing baro- and volutrauma may lead to improved survival (Abel 1998; Amato 1998; ARDS Network 2000; Baudouin 2001; Tobin 2001; van der Werf 2001). A recent Cochrane systematic review (Petrucci 2007) on ventilation with lower tidal volumes versus traditional tidal volumes in adults with ALI or ARDS concluded that whilst short-term mortality was reduced by using ventilation with lower tidal volume there was insufficient evidence to draw any conclusions about morbidity and long-term outcomes. Mortality and other outcomes have been shown to vary with the sex and age of the patient, the initial severity of the ALI or ARDS, the patient's condition, and the underlying cause of the ALI or ARDS (Davis 1993; DeBruin 1992; Monchi 1998; Paret 1998; Suntharalingam 2001; Ware 2000).
There is also substantial short- and long-term morbidity associated with these syndromes. Short-term morbidity leads to prolonged ventilator dependence and longer stays in the intensive care unit (ICU) and hospital. Long-term morbidity includes decreased lung function, decreased health-related quality of life, neurodevelopmental delay, cognitive impairments, and high rates of disability (Fanconi 1985; Rothenhausler 2001; Schelling 2000).
Description of the intervention
The mainstay of treatment of ALI or ARDS is mechanical ventilation. Many forms of additional therapies have been considered and some of these were subjected to randomized controlled trials. Adjuncts to mechanical ventilation have included extracorporeal life support (ECLS), inhaled nitric oxide, endogenous surfactant, prone positioning, high frequency ventilation, and a variety of pharmaceutical therapies (anti-inflammatory medication, antioxidants, anticytokine agents, prostaglandins) (Conner 2000; Sarnaik 1994). The ventilatory techniques that seem to improve outcomes in ALI or ARDS are the 'lung-protective' strategies that aim to decrease VILI (Brower 2000; van der Werf 2001).
Partial liquid ventilation (PLV) has been proposed as a less injurious form of respiratory support for patients with severe respiratory failure, ALI and ARDS. In 1991, Fuhrman et al (Fuhrman 1991) introduced the technique of using functional residual capacity (FRC) volumes of perfluorocarbon liquid (PFC) with conventional gas ventilation; they called it perfluorocarbon associated gas exchange (PAGE).
How the intervention might work
This technique has become known as PLV and consists of partially filling the lungs with PFC whilst continuing mechanical ventilation with a gas ventilator. Of the available techniques of liquid assisted ventilation, it is PLV which has the most promise for practical clinical application in intensive care. Various models of acute lung injury have shown the benefits of using PLV compared with conventional mechanical ventilation alone. Many animal studies have shown that PLV improves oxygenation, carbon dioxide (CO
Why it is important to do this review
Uncontrolled human studies using PLV in adults with ALI or ARDS have shown improvements in oxygenation and lung compliance in patients also on ECLS (Hirschl 1996), and improved gas exchange with haemodynamic stability and minimal adverse side effects in patients ventilated with PLV alone (Hirschl 1998). The efficacy of PLV in adults has been assessed in a separate Cochrane systematic review (Davies 2004a) and there is no evidence from randomized controlled trials to support or refute the use of PLV in adults with ALI or ARDS. A single uncontrolled study in six children with ARDS showed some improvement in gas exchange with three hours of PLV (Fedora 1999a). The optimal dose of PFC to use during PLV is unknown and its beneficial effects may be apparent at lower doses of PFC than the usual method where the initial dose of PFC is equivalent to the functional residual capacity (approximately 30 ml/kg). Variations in the technique of PLV may also include giving an initial dose of PFC with or without further top-up doses to maintain partial filling of the lungs (Davies 1999).
The primary objective was to assess whether PLV reduces mortality or duration of mechanical ventilation, or both, in children with ALI or ARDS.
Criteria for considering studies for this review
Types of studies
We included randomized controlled trials (RCTs). We excluded cross-over studies due to their inability to determine differences for clinically relevant medium- to long-term outcomes.
Types of participants
We included children from the age of 28 days to 18 years with ALI or ARDS from any cause who were intubated and being supported by a mechanical ventilator.
Definition of ALI (Bernard 1994):
- acute onset respiratory failure;
- bilateral opacities on chest x-ray consistent with pulmonary oedema;
- pulmonary artery wedge pressure less than 18 mm Hg or no clinical evidence of raised left atrial pressure;
- partial pressure of oxygen (PaO
2) to fraction of inspired oxygen (FiO 2) ratio less than or equal to 300 mm Hg.
Definition of ARDS (Bernard 1994):
- acute onset respiratory failure;
- bilateral opacities on chest x-ray consistent with pulmonary oedema;
- pulmonary artery wedge pressure less than or equal to 18 mm Hg or no clinical evidence of raised left atrial pressure;
2/FiO 2ratio less than or equal to 200 mm Hg.
Types of interventions
Partial liquid ventilation (PLV), partially filling the lungs with perfluorocarbon (PFC) whilst continuing mechanical ventilation with a gas ventilator, compared with other forms of ventilatory management without the use of PFC liquids or vapour.
Types of outcome measures
One or more of the following outcomes must have been reported.
- Mortality (28-day, or at discharge from ICU, at discharge from hospital, at 1, 2, and 5 years)
- Duration of mechanical ventilation
- Duration of respiratory support
- Duration of oxygen therapy
- Duration of stay in the intensive care unit (ICU)
- Duration of stay in hospital
- Infection (septicaemia, pneumonia)
- Long-term cognitive impairment
- Long-term neurodevelopment (cerebral palsy, sensorineural hearing loss, visual impairment, developmental delay)
- Long-term disability
- Long-term health-related quality of life
- Long-term lung function
Search methods for identification of studies
The original review (Davies 2004b) searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2003, Issue 2); MEDLINE (1966 to April 2003), CINAHL (1982 to April 2003), intensive care journals and conference proceedings; reference lists and 'grey literature' for RCTs of PLV in ALI or ARDS. Without language restrictions, we updated the search using the following databases.
- CENTRAL (The Cochrane Library 2011, Issue 11) (see Appendix 1)
- Ovid MEDLINE (1950 to November 2011) (with Daily Update) (see Appendix 2)
- Ovid EMBASE (1982 to November 2011) (see Appendix 3)
- SilverPlatter CINAHL (1982 to November 2011) (see Appendix 4)
Searching other resources
- Google Scholar.
- Clinical trial registries:
- World Health Organization (WHO) International Clinical Trials Registry Platform;
- Current controlled trials: MetaRegisters of controlled trials; International Standard Randomised Controlled Trial Number (ISRCTN) Register;
- International Federation of Pharmaceutical Manufacturers & Associations (IFPMA) Clinical Trials Portal.
Data collection and analysis
Selection of studies
The two authors worked independently to search for and assess trials for inclusion and their methodological quality. We resolved differences by discussion and consensus of the authors.
Data extraction and management
Data were extracted independently by the authors. We resolved differences by discussion and consensus. If necessary, we contacted investigators for additional information or data.
Assessment of risk of bias in included studies
We assessed studies using the Cochrane risk of bias instrument (Higgins 2011): 1) randomization, 2) allocation concealment, 3) blinding, and 4) missing participant data. Each were rated as being either adequate, unclear, or inadequate. At least two criteria must have been rated as adequate for the study to be included in the review.
Measures of treatment effect
Dichotomous data were presented as relative risks, and continuous data as weighted mean differences, along with their corresponding 95% confidence intervals.
Unit of analysis issues
To avoid unit of analysis errors, if included studies had more than two study arms we planned to either combine relevant groups to create a single pair-wise comparison or, if not possible, select one pair of interventions and exclude the others.
Assessment of heterogeneity
We planned to assess heterogeneity using the I
Assessment of reporting biases
For included studies, if the study protocol was available we assessed if the study’s pre-specified (primary and secondary) outcomes of interest had been reported in the pre-specified way. Patient reported outcomes were considered to be more subjective and more prone to bias. If a protocol was not available, we considered the potential for reporting bias to be unclear.
Results were combined unless diversity (clinical or statistical heterogeneity) suggested combination was unreasonable. Dichotomous data were presented as relative risks, and continuous data as weighted mean differences, along with their corresponding 95% confidence intervals.
Subgroup analysis and investigation of heterogeneity
Subgroup analyses were planned to determine whether the results differed in the following.
- severity of: a) overall illness (e.g. APACHE or SAPS score), or b) ALI or ARDS;
- aetiology of ALI or ARDS (e.g. septicaemia, pneumonia, trauma, burns).
Mortality and other outcomes have been shown to vary with the age of the patient, the initial severity of the ALI or ARDS, or patient condition (for example by APACHE score), and by the underlying cause of the ALI or ARDS (Monchi 1998; Suntharalingam 2001; Ware 2000).
- initial amount or dose of PFC;
- whether PLV was continuous or in intermittent doses;
- type of PFC (e.g. perflubron, Rimar).
The correct dose of PFC to use when initiating PLV is unknown. Variations in the technique of PLV may also include giving an initial dose of PFC with or without further top-up doses to maintain partial filling of the lungs. Various types of PFC with different physical and chemical properties may be used (Davies 1999).
- use of inhaled nitric oxide;
- use of surfactant;
- use of the prone position;
- high frequency ventilation.
Whilst the mainstay of treatment of ALI or ARDS is mechanical ventilation, additional therapies have been considered and some of these have been subjected to randomized controlled trials. Adjuncts to mechanical ventilation have included inhaled nitric oxide, endogenous surfactant, prone positioning, and high frequency ventilation (Conner 2000); all can be used in conjunction with PLV.
If two or more trials were included, we planned to pool the results using both a random-effects and fixed-effect model.
Description of studies
Eleven reports of nine studies were initially located by the original search strategy. Eight of the studies were excluded (see Characteristics of excluded studies). There were no disagreements between authors.
Only one study (Fuhrman 1998) was identified and found eligible for inclusion in this review. It has only been reported as an abstract in conference proceedings. We have contacted the first author of this study and the company that sponsored it but no further information and data were forthcoming from either source.
The study ran from January 1996 to April 1997 and enrolled 182 patients in 65 centres. At enrolment, patients were allocated to receive either PLV (N = 91) or conventional mechanical ventilation (control group, N = 91). The study was complicated by the fact that entry criteria, the use of other rescue therapies, and the primary outcome were modified at least twice during the study. These modifications included liberalization of the entry criteria and allowed use of adjunct therapies in the control group, such as high frequency ventilation or inhaled nitric oxide, or both. The study was stopped well short of the expected recruitment (less than 20%) because of an "abrupt decline" in mortality in the control group. Mortality at 28 days was 22% in the PLV group and 14% in the control group, but this difference did not reach statistical significance. It is not clear why the study did not continue thereafter. Other outcomes reported for PLV versus control were: overall mortality (not defined) 26% versus 20%; 28-day respiratory mortality 10% versus 10%; ventilator free days (not defined) 10.1 versus 12.4; and air leak 33% versus 30%. None of these outcomes showed statistically significant differences.
Results of the search
The updated search was conducted in November 2011. Out of 58 studies identified from the primary electronic databases (MEDLINE 15, EMBASE 42, CENTRAL 0, CINAHL 1) 12 were duplicates, leaving 46 abstracts or titles identified as original publications. Of these, 16 proved potentially relevant for full text review but after independent review no article met our eligibility criteria (Figure 1). The grey literature search identified one potentially relevant title and abstract but it was found to be ineligible after full text review.
|Figure 1. Flow diagram.|
The original review had one study which fulfilled the inclusion criteria (Fuhrman 1998).
The following studies were excluded from the original review:
The update search excluded 16 studies, none of which were RCTs.
Risk of bias in included studies
The study by Fuhrman et al was reported in abstract form only (Fuhrman 1998).
- Treatment allocation was randomized (exact method not stated)
- Whether allocation was adequately concealed is unknown
- Treatment was not blinded
- Whether the published outcomes were assessed by blinded evaluators is unknown (blinding of the assessment of death was not applicable)
Incomplete outcome data
- Follow-up rate was not reported
- Unclear, as the included study was an abstract and we were unable to locate a protocol
Other potential sources of bias
The fact that entry criteria, use of other rescue therapies, and the primary outcome were modified at least twice during the study, and that these were not adequately described in the abstract, made it difficult to assess the impact of the modifications on the quality of the available data.
Also, each study centre enrolled an average of only 2.8 patients into the study (182 patients in 65 centres); many of these centres would have enrolled only one or two patients into the study and many would have only treated one child with PLV. This may have led to wide variation in the application of PLV, the success of which may well be determined, in part, by how the PLV was applied.
Effects of interventions
Limited results were available from only one study (Fuhrman 1998) which was stopped prematurely. The only outcome of clinical significance that was available from the only published report of this trial was 28-day mortality. Although it was not reported, we assumed 100% follow up for analysis of this short-term outcome. There was no statistically significant difference between groups for this outcome, with a relative risk for 28-day mortality in the PLV group of 1.54 (95% confidence interval 0.82 to 2.9).
While it has been suggested that PLV is a promising alternative mode of mechanical ventilation for children with ALI or ARDS, there are no available data from adequately powered RCTs to determine whether PLV is effective, or not, in decreasing morbidity or mortality.
Summary of main results
The study by Fuhrman et al (Fuhrman 1998) was stopped prematurely and was, therefore, under-powered to detect any significant differences. The wide 95% confidence interval for 28-day mortality meant that a clinically significant difference cannot be excluded.
Overall completeness and applicability of evidence
It is unfortunate that the only RCT done so far to investigate PLV in children with ALI or ARDS (Fuhrman 1998) has not been published in full or that data on more clinically relevant outcomes (especially mortality at discharge and later, duration of both respiratory support and hospital stay, and long-term neurodevelopmental outcomes) are not forthcoming from the study investigators or the company that sponsored the trial.
Quality of the evidence
The limited information available from the published abstract of this study makes it difficult to do a complete assessment of study quality.
Potential biases in the review process
The under-reporting of RCTs due to publication bias has been well described (Dickersin 1987; Dickersin 1990; Dickersin 1993). In a systematic review of pharmaceutical industry sponsorship and research outcomes, Lexchin et al (Lexchin 2003) found that research funded by drug companies was less likely to be published. Some people consider the selection of reports for publication on the basis of 'positive results' or the failure of investigators to publish results with sufficient detail to allow judgments to be made about their validity as scientific misconduct (Chalmers 1990). It is unknown whether any of these factors are operating here.
Implications for practice
There is extremely limited evidence to support or refute the use of PLV in children with ALI or ARDS.
Implications for research
If children with ALI or ARDS are to be treated with PLV then adequately powered, high quality RCTs are still needed to assess its efficacy. Clinically relevant outcome measures should be assessed (especially mortality at discharge and later, duration of both respiratory support and hospital stay, and long-term neurodevelopmental outcomes) and the studies should be published in full.
We would like to thank and acknowledge Dr Bradley Johnston for providing methodological support and Dr Iris Henzi for screening the titles and abstracts. The authors of the original review (Davies 2004b) wish to thank Janet Wale for helping to write the plain language summary. The following reviewed and commented on the first version of this review (Davies 2004b) prior to its initial publication and their input is acknowledged: Dr Mike Bennett, Prof Nathan Pace, Dr John Carlisle, Dr Maureen Meade, Janet Wale, and Nete Villebro.
We would like to thank Philip H Sargent for his contribution to the original published review (Davies 2004b).
Data and analyses
- Top of page
- Authors' conclusions
- Data and analyses
- What's new
- Contributions of authors
- Declarations of interest
- Sources of support
- Differences between protocol and review
- Index terms
Appendix 1. Search strategy for CENTRAL,The Cochrane Library
#1 MeSH descriptor Respiratory Distress Syndrome, Newborn explode all trees
#2 MeSH descriptor Respiratory Distress Syndrome, Adult explode all trees
#3 ARDS or ALI
#4 acute lung injur*
#5 (#1 OR #2 OR #3 OR #4)
#6 MeSH descriptor Liquid Ventilation explode all trees
#7 MeSH descriptor Fluorocarbons explode all trees
#8 FLUOROCARBON* or partial liquid ventilation
#9 (#6 OR #7 OR #8)
#10 (#5 AND #9)
Appendix 2. Search strategy for Ovid MEDLINE
#1 (explode "Respiratory-Distress-Syndrome-Newborn" / all SUBHEADINGS in MIME,MJME,PT) or (explode "Respiratory-Distress-Syndrome-Adult" / all SUBHEADINGS in MIME,MJME,PT)
#2 ARDS or ALI or (acute near(lung injur*))
#3 FLUOROCARBON* or partial liquid ventilation
#4 (explode "Liquid-Ventilation" / all SUBHEADINGS in MIME,MJME,PT) or (explode "Fluorocarbons-" / all SUBHEADINGS in MIME,MJME,PT)
#5 (#1 or #2) and (#3 or #4)
#6 (randomized controlled trial.pt. or controlled clinical trial.pt. or randomized.ab. or placebo.ab. or drug therapy.fs. or randomly.ab. or trial.ab. or groups.ab.) and humans.sh.
#7 #5 and #6
Appendix 3. Search strategy for Ovid EMBASE
#1 (explode "respiratory-distress-syndrome" / all SUBHEADINGS in DEM,DER,DRM,DRR) or (explode "respiratory-distress" / all SUBHEADINGS in DEM,DER,DRM,DRR)
#2 explode "acute-lung-injury" / all SUBHEADINGS in DEM,DER,DRM,DRR
#3 RESPIRATORY DISTRESS SYNDROME or ARDS or ALI or (acute near (lung injur*))
#4 #1 or #2 or #3
#5 explode "fluorocarbon-" / all subheadings
#6 explode "liquid-ventilation"/ all subheadings
#7 fluorocarbon* or (liquid near ventilation)
#8 #5 or #6 or #7
#9 #4 and #8
#10 "RANDOMIZED-CONTROLLED-TRIAL"/ all subheadings
#11 "RANDOMIZATION"/ all subheadings
#12 "CONTROLLED-STUDY"/ all subheadings
#13 "MULTICENTER-STUDY"/ all subheadings
#14 "PHASE-3-CLINICAL-TRIAL"/ all subheadings
#15 "PHASE-4-CLINICAL-TRIAL"/ all subheadings
#16 "DOUBLE-BLIND-PROCEDURE"/ all subheadings
#17 "SINGLE-BLIND-PROCEDURE"/ all subheadings
#18 #10 or #11 or #12 or #13 or #14 or #15 or #16 or #17
#19 (RANDOM* or CROSS?OVER* or FACTORIAL* or PLACEBO* or VOLUNTEER*) in TI,AB
#20 (SINGL* or DOUBL* or TREBL* or TRIPL*) near ((BLIND* or MASK*) in TI,AB)
#21 #18 or #19 or #20
#22 HUMAN in DER
#23 (ANIMAL or NONHUMAN) in DER
#24 #22 and #23
#25 #23 not #24
#26 #21 not #25
#27 #9 and #26
Appendix 4. Search strategy for CINAHL
#1 (explode "Respiratory-Distress-Syndrome" / all TOPICAL SUBHEADINGS / all AGE SUBHEADINGS in DE) or (explode "Respiratory-Distress-Syndrome-Acute" / all TOPICAL SUBHEADINGS / all AGE SUBHEADINGS in DE)
#2 RESPIRATORY DISTRESS SYNDROME
#3 ARDS or ALI or (acute near (lung injur*))
#4 FLUOROCARBON* or liquid ventilation
#5 explode "Ventilation-Liquid" / all TOPICAL SUBHEADINGS / all AGE SUBHEADINGS in DE
#6 (#1 or #2 or #3) and (#4 or #5)
#7 PLACEBO* or random* or trial* or control* or compar* or blind*
#8 #6 and #7
Last assessed as up-to-date: 28 November 2011.
Protocol first published: Issue 4, 2002
Review first published: Issue 2, 2004
Contributions of authors
Conceiving and writing the original review: Mark Davies, Philip Sargent
Co-ordinating the review: Bradley Johnston and Alka Kaushal
Undertaking electronic searches: Alka Kaushal
Screening search result: Conor McDonnell, Alka Kaushal, Iris Henzi
Screening retrieved papers against inclusion criteria: Alka Kaushal
Obtaining and screening data on unpublished studies: Alka Kaushal
Entering data into Review Manager (RevMan 5.1): Alka Kaushal
Writing the review update: Alka Kaushal
Person responsible for reading and checking review before submission: Bradley Johnston, Conor McDonnell, Alka Kaushal
Further contributions for the original review can be found at Davies 2004b
Declarations of interest
Alka Kaushal: none known
Mark W Davies: none known
Conor G McDonnell: I am a non-paid consultant for Institute for Safe Medication Practices, Canada with regards to Pediatric Opioid Safety and national pediatric opioid recommendations.
Sources of support
- Grantley Stable Neonatal Unit, Royal Women's Hospital, Brisbane, Australia.
- Dept of Paediatrics and Child Health, University of Queensland, Brisbane, Australia.
- Mater Children's Hospital, Brisbane, Australia.
- No sources of support supplied
Differences between protocol and review
Medical Subject Headings (MeSH)
Acute Lung Injury [complications; mortality; *therapy]; Infant, Newborn; Liquid Ventilation [*methods; mortality]; Randomized Controlled Trials as Topic; Respiratory Distress Syndrome, Adult [complications; mortality; *therapy]; Respiratory Distress Syndrome, Newborn [complications; mortality; *therapy]
MeSH check words
Adolescent; Child; Child, Preschool; Humans; Infant
* Indicates the major publication for the study