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Lung lavage for meconium aspiration syndrome in newborn

infants (Review)
Hahn S, Choi HJ, Soll R, Dargaville PA

This is a reprint of a Cochrane review, prepared and maintained by The Cochrane Collaboration and published in The Cochrane Library
2013, Issue 4
http://www.thecochranelibrary.com

Lung lavage for meconium aspiration syndrome in newborn infants (Review)


Copyright 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

TABLE OF CONTENTS
HEADER . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
ABSTRACT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
PLAIN LANGUAGE SUMMARY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
BACKGROUND . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
OBJECTIVES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
METHODS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
RESULTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
DISCUSSION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
AUTHORS CONCLUSIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
CHARACTERISTICS OF STUDIES . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
DATA AND ANALYSES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Analysis 1.1. Comparison 1 Lung lavage versus standard care, Outcome 1 Death. . . . . . . . . . . . . .
Analysis 1.2. Comparison 1 Lung lavage versus standard care, Outcome 2 Use of ECMO. . . . . . . . . . .
Analysis 1.3. Comparison 1 Lung lavage versus standard care, Outcome 3 Death or use of ECMO. . . . . . .
Analysis 1.4. Comparison 1 Lung lavage versus standard care, Outcome 4 Pneumothorax. . . . . . . . . . .
Analysis 1.5. Comparison 1 Lung lavage versus standard care, Outcome 5 Oxygenation index. . . . . . . . .
Analysis 1.6. Comparison 1 Lung lavage versus standard care, Outcome 6 Alveolar-arterial oxygen difference. . . .
Analysis 1.7. Comparison 1 Lung lavage versus standard care, Outcome 7 PaO2/FiO2. . . . . . . . . . . .
Analysis 2.1. Comparison 2 Lung lavage followed by surfactant bolus versus surfactant bolus, Outcome 1 Death. . .
Analysis 2.2. Comparison 2 Lung lavage followed by surfactant bolus versus surfactant bolus, Outcome 2 Pneumothorax.
ADDITIONAL TABLES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
HISTORY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
CONTRIBUTIONS OF AUTHORS . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
DECLARATIONS OF INTEREST . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
SOURCES OF SUPPORT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
DIFFERENCES BETWEEN PROTOCOL AND REVIEW . . . . . . . . . . . . . . . . . . . . .
INDEX TERMS
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Lung lavage for meconium aspiration syndrome in newborn infants (Review)


Copyright 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

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[Intervention Review]

Lung lavage for meconium aspiration syndrome in newborn


infants
Seokyung Hahn1 , Hyun Jin Choi2 , Roger Soll3 , Peter A. Dargaville4
1 Department of

Medicine, Seoul National University College of Medicine, Seoul, Korea, South. 2 Department of Preventive Medicine,
Seoul National University College of Medicine, Seoul, Korea, South. 3 Division of Neonatal-Perinatal Medicine, University of Vermont,
Burlington, Vermont, USA. 4 Department of Paediatrics, Royal Hobart Hospital, Hobart, Australia
Contact address: Seokyung Hahn, Department of Medicine, Seoul National University College of Medicine, 28 Yongon-dong Chongnogu, Seoul, 110-744, Korea, South. hahns@snu.ac.kr.

Editorial group: Cochrane Neonatal Group.


Publication status and date: New, published in Issue 4, 2013.
Review content assessed as up-to-date: 15 February 2013.
Citation: Hahn S, Choi HJ, Soll R, Dargaville PA. Lung lavage for meconium aspiration syndrome in newborn infants. Cochrane
Database of Systematic Reviews 2013, Issue 4. Art. No.: CD003486. DOI: 10.1002/14651858.CD003486.pub2.
Copyright 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

ABSTRACT
Background
Meconium aspiration syndrome (MAS) can occur when a newborn infant inhales a mixture of meconium and amniotic fluid into the
lungs around the time of delivery. Other than supportive measures, little effective therapy is available. Lung lavage may be a potentially
effective treatment for MAS by virtue of removing meconium from the airspaces and altering the natural course of the disease.
Objectives
To evaluate the effects of lung lavage on morbidity and mortality in newborn infants with MAS.
Search methods
We searched the Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library), MEDLINE, and EMBASE up
to December 2012; previous reviews including cross-references, abstracts, and conference proceedings; and expert informants. We
contacted authors directly to obtain additional data. We used the following subject headings and text words: meconium aspiration,
pulmonary surfactants, fluorocarbons, bronchoalveolar lavage, lung lavage, pulmonary lavage.
Selection criteria
Randomised controlled trials that evaluated the effects of lung lavage in infants with MAS, including those intubated for the purpose
of lavage. Lung lavage was defined as any intervention in which fluid is instilled into the lung that is followed by an attempt to remove
it by suctioning and/or postural drainage.
Data collection and analysis
The review authors extracted from the reports of the clinical trial, data regarding clinical outcomes, including mortality, requirement
for extracorporeal membrane oxygenation (ECMO), pneumothorax, duration of mechanical ventilation and oxygen therapy, length of
hospital stay, indices of pulmonary function, and adverse effects of lavage. Data analysis was done in accordance with the standards of
the Cochrane Neonatal Review Group.
Lung lavage for meconium aspiration syndrome in newborn infants (Review)
Copyright 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

Main results
Only four small randomised controlled trials fulfilled the selection criteria. For one of these trials, no data are available for the control
group. Two studies compared lavage using diluted surfactant with standard care. Meta-analysis of these two studies did not show a
significant effect on mortality (typical relative risk 0.42, 95% confidence interval [CI] 0.12 to 1.46; typical risk difference -0.10, 95%
CI -0.24 to 0.04) or the use of ECMO (typical relative risk 0.27, 95% CI 0.04 to 1.86; typical risk difference -0.15, 95% CI -0.35 to
0.04). For the composite outcome of death or use of ECMO, a significant effect favoured the lavage group (typical relative risk 0.33,
95% CI 0.11 to 0.96; typical risk difference -0.19, 95% CI -0.34 to -0.03; number needed to benefit [NNTB] 5). No other benefits
were reported. The other published study compared surfactant lavage followed by a surfactant bolus with surfactant bolus therapy alone
in MAS complicated by pulmonary hypertension. No significant improvements in mortality, pneumothorax, duration of mechanical
ventilation. or duration of hospitalisation were observed.
Authors conclusions
In infants with meconium aspiration syndrome, lung lavage with diluted surfactant may be beneficial, but additional controlled clinical
trials of lavage therapy should be conducted to confirm the treatment effect, to refine the method of lavage treatment, and to compare
lavage treatment with other approaches, including surfactant bolus therapy. Long-term outcomes should be evaluated in further clinical
trials.

PLAIN LANGUAGE SUMMARY


Lung lavage for meconium aspiration syndrome in newborn infants
Meconium aspiration syndrome (MAS) is a disease of the newborn lung in which meconium, the fetal stool, is passed before birth and
then is inhaled into the lung. Little effective treatment is available, other than supportive measures including artifical respiration and,
occasionally, the use of heart-lung bypass. This review examined whether cleansing the lung using a natural chemical called surfactant,
or another similar fluid, is helpful in MAS. This cleansing procedure is known as lung lavage. Lung lavage with diluted surfactant may
help improve the clinical course of infants with MAS, in particular, the likelihood of survival without the need for heart-lung bypass.
More trials will be needed to properly evaluate lavage treatment in MAS.

BACKGROUND

Description of the condition


Meconium aspiration syndrome (MAS) occurs when a newborn
infant inhales a mixture of meconium and amniotic fluid into the
lungs around the time of delivery. Intrapartum passage of meconium, the viscid secretion of the fetal intestine, occurs in up to
15% of deliveries at term (Wiswell 1993). Aspiration of meconium or meconium-stained amniotic fluid into the airways may
occur prenatally (during hypoxic fetal gasping), or immediately
after delivery as the first breaths are taken. Once inhaled, meconium migrates down the tracheobronchial tree, causing a variable
degree of airway obstruction as it disperses into the distal airspaces
(Tran 1980). Thereafter a toxic pneumonitis ensues, with hemorrhagic edema and exudation of plasma proteins into the alve-

olar space (Tyler 1978; Dargaville 2001). The function of pulmonary surfactant may be secondarily impaired, both by meconium (Moses 1991), and by plasma protein (Fuchimukai 1987).
In many infants with MAS, particularly those with coexisting asphyxia, there is an added component of pulmonary hypertension,
which may cause profound hypoxaemia. The reported incidence
of MAS varies widely, but is of the order of 1 to 2 per 1000 live
births (Wiswell 1993).
Approximately one-third of infants with MAS need mechanical
ventilatory support (Wiswell 1993), and many are treated with
high-frequency ventilation or nitric oxide, or both. Infants ventilated for MAS are often treated with exogenous surfactant, which
appears to reduce the use of extracorporeal membrane oxygenation (ECMO), but has no clear effect on mortality (Findlay 1996;
Lotze 1998; El Shahed 2007). Data regarding the effect of bolus surfactant therapy on pulmonary complications of MAS are
conflicting; one small trial demonstrated a benefit in terms of air

Lung lavage for meconium aspiration syndrome in newborn infants (Review)


Copyright 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

leak and duration of ventilation (Findlay 1996), but further studies have revealed no evidence of an effect on pulmonary complications (Lotze 1998, Chinese Collaborative Study Group 2005;
Maturana 2005). Meta-analysis of the data from these trials supports reduction in the use of ECMO, but not a reduced incidence
of pulmonary complications of MAS (El Shahed 2007).

Description of the intervention


In human infants, the history of lavage as a therapy for MAS extends back to the early 1970s, when saline lavage was used in the
delivery room to improve clearance of meconium from the airways
of meconium-stained babies (Burke-Strickland 1973). This technique was largely abandoned as a result of the increase in numbers
of infants with transient tachypnoea after saline lavage, ascribed
to lavage fluid retention in the lung (Carson 1976). Isolated reports of lung lavage in infants with established MAS subsequently
appeared (Ibara 1995; Mosca 1996), in which lavage with a total
volume of 20 to 40 mL/kg saline was performed, followed by bolus
administration of natural surfactant. Improvement in oxygenation
and carbon dioxide (CO2 ) clearance was noted in each case. Several research groups have reported their experience of lavage with
dilute surfactant in ventilated infants with MAS, on the whole
suggesting improvements in oxygenation and/or duration of ventilation in comparison with historical or concurrent controls (Su
1998; Lam 1999; Kowalska 2002; Schlsser 2002; Chang 2003;
Salvia-Roigs 2004; Dargaville 2007).

Why it is important to do this review


At present, the therapeutic emphasis in MAS is on providing supportive care, with little or no effort directed towards removal of
meconium from the lung as a means of halting disease progression. Recent data suggest that meconium can be safely removed
from the airspaces in MAS by lung lavage. The objective of this
review is to critically appraise the data from controlled trials of
lavage therapy in human infants with MAS, and thereby evaluate
the efficacy and safety of lung lavage as a treatment for this disease.
The following systematic review evaluates randomised controlled
trials that have studied the efficacy of lung lavage therapy in infants with MAS.

OBJECTIVES
To evaluate the effects of lung lavage on morbidity and mortality
in newborn infants with MAS.
Subgroup analyses: to evaluate the effects of the type of lavage
fluid, the volume of lavage fluid, and the timing of administration
of lavage fluid on morbidity and mortality in newborn infants
with MAS.

METHODS

Criteria for considering studies for this review


How the intervention might work
Recent experimental studies have suggested that lung lavage can
remove meconium from the lungs in MAS, and as a result can
improve lung function. In animal models of MAS, lung lavage
using total fluid volumes of 10 to 60 mL/kg has resulted in considerable improvement in oxygenation and/or pulmonary mechanics, associated with removal of one-third to one-half of the
meconium lodged in the airspaces (Paranka 1992; Ohama 1994;
Cochrane 1998; Ohama 1999; Dargaville 2003). Saline, surfactant, and perfluorocarbon have been studied as potential lavage fluids. Comparative data suggest that exogenous surfactant, whether
at full strength (Paranka 1992) or diluted in saline (Ohama 1994;
Cochrane 1998; Ohama 1999), is a more effective lavage fluid
than saline alone, in terms of both pulmonary function post lavage
and removal of meconium from the lung. Lavage with perfluorocarbon appears to be superior to saline lavage (Marraro 1998) but
less effective than dilute surfactant lavage (Dargaville 2003). The
volume of each lavage aliquot is another determinant of lavage
efficacy, with aliquot volumes of 15 mL/kg being more effective
than multiple 2- to 3-mL aliquots (Dargaville 2003), or aliquots
of 8 mL/kg (Dargaville 2008).

Types of studies
All randomised or quasi-randomised studies comparing therapeutic lung lavage with standard care in the management of infants
with MAS.

Types of participants
Newborn infants with MAS (infants delivered through meconium-stained amniotic fluid with early onset of respiratory distress, no other obvious cause for the distress, and either a characteristic chest X-ray or meconium found beyond the vocal cords at
or after delivery). This review includes infants already intubated at
the time of lavage, and infants intubated for the purpose of lavage.

Types of interventions
Lung lavage is defined as any intervention wherein fluid is instilled
into the lung, followed by an attempt to remove it by suctioning,
postural drainage, or both. Fluids that have been used for this

Lung lavage for meconium aspiration syndrome in newborn infants (Review)


Copyright 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

purpose include saline, full-strength and dilute surfactant, and


perfluorocarbon.
Standard care is defined as no lavage therapy, but it does include
routine suction of the endotracheal tube to maintain its patency.
For some studies, bolus surfactant therapy may be mandated as
part of standard care.
Types of outcome measures

Cochrane Neonatal Review Group trials register.


CENTRAL (The Cochrane Library, Issue 11, 2012).
MEDLINE and EMBASE electronic searches.
We constructed search strategies using the following MeSH terms
or keywords: meconium, meconium aspiration syndrome, pulmonary surfactants, lung surfactant, fluorocarbons, bronchoalveolar lavage, lung lavage, and pulmonary lavage.

Primary outcomes

Searching other resources

Death.
Use of ECMO.
Death or use of ECMO.
Pneumothorax.
All air leak (pneumothorax, pneumomediastinum,
pneumopericardium, pneumoperitoneum, pulmonary interstitial
emphysema).
Days of mechanical ventilation via an endotracheal tube.
Days of supplemental oxygen.
Length of stay in hospital.
Total cost of hospitalisation.

We screened for trials in conference proceedings of annual meetings of the American Thoracic Society, the Society for Pediatric
Research, the European Respiratory Society, and the European Society for Pediatric Research (December 2012); and in the reference
lists from the retrieved articles and from review articles. We had
personal communications with primary authors of the identified
studies to identify unpublished data.
We searched for any ongoing or recently completed and unpublished trials using clinicaltrials.gov, controlled-trials.com, and
who.int/ictrp.

The composite outcome of death or use of ECMO has been included in recognition that mortality is influenced by the availability of ECMO.

Data collection and analysis

Secondary outcomes

We used the methods of the Cochrane Neonatal Review Group


for data collection and analysis.

Indices of pulmonary function (including Oxygenation


Index, Alveolar-arterial oxygen difference, PF ratio) measured at
24, 48, and 72 hours.

Selection of studies

[definitions: Oxygenation index (OI) = (Mean airway pressure


FiO2 ) / PaO2 ; Alveolar-arterial oxygen difference (AaDO2 ) = FiO2
713 PaCO2 /0.8 PaO2 ; PF Ratio = PaO2 /FiO2 ]
Lung mechanics (compliance and resistance of the lung or the
respiratory system):
Adverse effects of lavage (acute hypoxaemia, bradycardia,
hypotension).

We included all randomised and quasi-randomised controlled trials that fulfilled the selection criteria described in the previous section. Two review authors independently reviewed the results of
the updated search and selected studies for inclusion. We resolved
any disagreement by discussion.

Data extraction and management

Search methods for identification of studies


We used the standard search methods of the Cochrane Neonatal
Review Group.
Electronic searches
We used the standardized search strategy of the Neonatal Review
Group as outlined in The Cochrane Library. The following sources
were searched between 1966 and December 2012 for eligible studies in any language:

We used a standard form for data extraction, which included a


collection of descriptive data on the study design, the study population (baseline characteristics and inclusion and exclusion criteria), and the method of intervention (type of lavage fluid, total
lavage volume, aliquot volume, and lavage fluid concentration),
and quantitative data regarding the outcome measures. Pneumothorax was counted only if it occurred after randomisation.
Two review authors independently extracted the data from included studies, and results were compared. The investigators of
included studies were asked to provide unpublished outcome data
where necessary.

Lung lavage for meconium aspiration syndrome in newborn infants (Review)


Copyright 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

Assessment of risk of bias in included studies


The quality of eligible studies was assessed using The Cochrane
Collaborations tool for assessing the risk of bias for randomised
controlled trials (RCTs) (Higgins 2011). Two review authors performed the assessment, and they resolved any difference of opinion by involving coauthors in the discussion.
The methodological quality of the studies was assessed using the
following criteria:
Sequence generation (checking for possible selection bias):
For each included study, we categorized the method used to
generate the allocation sequence as follows:
Low risk (any truly random process, e.g. random
number table; computer random number generator).
High risk (any nonrandom process, e.g. odd or even
date of birth; hospital or clinic record number).
Unclear risk.
Allocation concealment (checking for possible selection
bias): For each included study, we categorized the method used
to conceal the allocation sequence as follows:
Low risk (e.g. telephone or central randomisation;
consecutively numbered sealed opaque envelopes).
High risk (open random allocation; unsealed or nonopaque envelopes, alternation; date of birth).
Unclear risk.
Blinding (checking for possible performance bias): For each
included study, we categorized the methods used to blind study
participants and personnel from knowledge of which
intervention a participant received. Blinding was assessed
separately for different outcomes or classes of outcomes. We
categorized the methods as follows:
Low risk, high risk, or unclear risk for participants.
Low risk, high risk, or unclear risk for personnel.
Low risk, high risk, or unclear risk for outcome
assessors.
Incomplete outcome data (checking for possible attrition
bias through withdrawals, dropouts, and protocol deviations):
For each included study and for each outcome, we described the
completeness of data, including attrition and exclusions from the
analysis. We noted whether attrition and exclusions were
reported, the numbers included in the analysis at each stage
(compared with the total randomly assigned participants),
reasons for attrition or exclusion where reported, and whether
missing data were balanced across groups or were related to
outcomes. Where sufficient information was reported or
supplied by the trial authors, we included missing data in the
analyses again. We categorized the methods as follows:
Low risk (< 20% missing data).
High risk ( 20% missing data).
Unclear risk.
Selective reporting bias: For each included study, we
described how we investigated the possibility of selective
outcome reporting bias and what we found. We assessed the

methods as follows:
Low risk (where it is clear that all of the studys prespecified outcomes and all expected outcomes of interest to the
review have been reported).
High risk (where not all of the studys pre-specified
outcomes have been reported; one or more reported primary
outcomes were not pre-specified; outcomes of interest are
reported incompletely and so cannot be used; or study fails to
include results of a key outcome that would have been expected
to have been reported).
Unclear risk.
Other sources of bias: For each included study, we
described any important concerns that we had about other
possible sources of bias (e.g. whether a potential source of bias
was related to the specific study design, or whether the trial was
stopped early as the result of some data-dependent process). We
assessed whether each study was free of other problems that
could put it at risk of bias as follows:
Low risk; high risk; unclear risk.
Overall risk of bias [described in Table 8.5c in the
Handbook].
We made explicit judgements regarding whether studies were at
high risk of bias, according to the criteria given in The Cochrane
Handbook (Higgins 2011). With reference to (1) to (6) above,
we assessed the likely magnitude and direction of the bias, and
whether we considered it likely to influence the findings. If needed,
we planned to explore the impact of the level of bias by undertaking
sensitivity analyses (see Sensitivity analysis, later).

Measures of treatment effect


We performed statistical analyses using Review Manager software
(RevMan 2011). Dicotomous data were analysed using relative
risk (RR), risk difference (RD), and the number needed to benefit
(NNTB) or the number needed to harm (NNTH). The 95%
confidence intervals (CIs) were reported on all estimates.
Some continuous outcomes are only descriptively presented in
a table without statistical pooling because of the skewed nature
of the data; the weighted mean difference (WMD) was used for
pooling otherwise.

Dealing with missing data


For included studies, levels of attrition were noted. The impact
of including studies with high levels of missing data in the overall
assessment of treatment effect was explored through sensitivity
analysis.
All outcome analyses were performed on an intention-to-treat
basis(i.e. we included all participants randomly assigned to each
group in the analyses). The denominator for each outcome in each
trial was the number randomly assigned minus any participants
whose outcomes were known to be missing.

Lung lavage for meconium aspiration syndrome in newborn infants (Review)


Copyright 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

Assessment of heterogeneity

RESULTS

We examined heterogeneity between trials by inspecting the forest


plots and quantifying the impact of heterogeneity using the I2
statistic. If noted, we planned to explore the possible causes of
statistical heterogeneity using pre-specified subgroup analyses (e.g.
differences in study quality, participants, intervention regimens,
or outcome assessments).

Description of studies

Assessment of reporting biases


We planned to assess possible publication bias and other biases
using symmetry/asymmetry of funnel plots, but this was not applicable because an insufficient number of studies was included in
the meta-analysis for such an exploration.
For included trials that were recently performed (and therefore were prospectively registered), we explored possible selective reporting of study outcomes by comparing primary and secondary outcomes given in the reports versus primary and secondary outcomes proposed at trial registration, using the Websites
www.clinicaltrials.gov and www.controlled-trials.com. If such discrepancies were found, we planned to contact the primary investigators to obtain missing outcome data on outcomes pre-specified
at trial registration.

Data synthesis
Where meta-analysis was judged to be appropriate, the analysis
was done using Review Manager software (RevMan 2011), as supplied by The Cochrane Collaboration. We used the Mantel-Haenszel method to obtain estimates of typical relative risk and risk
difference. A fixed-effect model was primarily used for the metaanalysis after the statistical heterogeneity was investigated. Data
were analysed on an intention-to-treat basis.

Subgroup analysis and investigation of heterogeneity


Three subgroup analyses were planned a priori:
Type of lavage fluid (saline, surfactant, perfluorocarbon,
other).
Lavage aliquot volume (< 5 mL/kg, 5 mL/kg).
Timing of lavage: early (< 6 hours of life) or late ( 6 hours
of life).

Sensitivity analysis
We planned sensitivity analyses for use in situations where this
might affect the interpretation of significant results (e.g. where
risk of bias is associated with the quality of some of the included
trials or missing outcome data). None were thought necessary in
this review.

See: Characteristics of included studies; Characteristics of excluded


studies; Characteristics of ongoing studies.

Results of the search


Four randomised controlled trials were identified, one of which
(Ogawa 1997) was excluded as data on the nonlavaged control
group were not reported and are not now obtainable. In that study,
which has been published only in conference proceedings format,
six infants underwent lavage with five aliquots each of 2 mL/kg of
Surfacten-TA (6 mg/mL), and a further four infants received an
identical lavage using saline. Oxygenation and CO2 clearance were
better in the group lavaged with dilute surfactant than with saline,
but no formal comparisons with the control group are reported.

Included studies
Three studies are included in this review (Wiswell 2002;
Gadzinowski 2008; Dargaville 2011).
Wiswell 2002 performed a phase I/II randomised controlled trial
of surfactant lavage in conventionally ventilated infants with MAS
who were at least 35 weeks gestation and less than 72 hours of age,
and had an oxygenation index (OI) between 8 and 25 inclusive
on two separate blood gas analyses within a three-hour period.
Surfactant lavage was performed at a mean age of 14 hours using
6 aliquots of 8 mL/kg of KL4 (Surfaxin, Discovery Laboratories
Inc, Doylestown, PA). The concentration of surfactant phospholipid was 2.5 mg/mL for the first four aliquots, and 10 mg/mL
for the last two. Each lavage aliquot was instilled via the endotracheal tube while positive end-expiratory pressure continued, followed by closed endotracheal suctioning for 10 seconds, during
which positive-pressure ventilation was re-instituted. The infants
physiological state was allowed to recover after each lavage aliquot
before the next was administered. After the final aliquot, positive
end-expiratory pressure was maintained at 6 to 8 cm H2 O for at
least two hours. Control infants received conventional mechanical
ventilation and standard supportive measures at the discretion of
the site study investigator. In both groups, a treatment failure criterion (OI > 25 or OI 50% above baseline) had to be reached before rescue therapies such as high-frequency oscillatory ventilation
(HFOV), bolus surfactant therapy, inhaled nitric oxide (iNO),
and ECMO could be used.
Dargaville 2011 performed a multicenter randomised controlled
trial of diluted surfactant lavage in infants who had a diagnosis of
MAS. The infants were at least 36 weeks gestation and 2 kg birth
weight, less than 24 hours of age, and mechanically ventilated with
a mean airway pressure of at least 12 cm H2 O and an alveolar-

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arterial O2 difference (AaDO2 ) of at least 450 mmHg on two sequential blood gases. Surfactant lavage was performed at a mean
age of 13 hours using two aliquots of 15 mL/kg of bovine surfactant (Survanta, Abbott Laboratories, Columbus, OH) diluted
with saline to a phospholipid concentration of 5 mg/mL. Lavage
fluid was instilled over 20 seconds through a dispensing catheter
with the ventilator circuit disconnected. Three positive-pressure
inflations were then administered, followed by disconnection of
the ventilator circuit and suctioning of the instilled fluid. Control
infants received mechanical ventilation and standard supportive
measures. In both groups, ventilator management and the use of
HFOV, iNO, and bolus surfactant therapy were at the discretion
of the site study investigator, as was the decision to refer to ECMO.
Gadzinowski 2008 performed a randomised controlled trial of surfactant lavage followed by bolus surfactant treatment compared
with bolus surfactant treatment alone for MAS with pulmonary
hypertension. The infants were at least 35 weeks gestation and
less than 24 hours of age, and the diagnosis of pulmonary hypertension was based on standardised echocardiographic parameters.
Surfactant lavage was performed with a total lavage volume of 15
mL/kg and an aliquot volume of 3.75 mL/kg at the mean age of
9.7 hours, using diluted bovine surfactant (Survanta) at a phospholipid concentration of 5 mg/mL. Lavage and suctioning were
conducted via a closed system in four body positions: on the right
and left sides, and in the Trendelenburg and anti-Trendelenburg
positions. After the lavage treatment, one dose of bolus surfactant
(Survanta, 100 mg/kg) was given. The control group received one
dose of bolus surfactant (Survanta, 100 mg/kg) and conventional
treatment. After an echocardiographic assessment was conducted,
iNO was administered to both groups.

Excluded studies
Twelve studies were excluded from the analysis (Burke-Strickland
1973; Carson 1976; Rosegger 1987; Ogawa 1997; Su 1998; Lam
1999; Schlsser 2002; Kowalska 2002; Chang 2003; Salvia-Roigs
2004; Dargaville 2007; Armenta 2011). The rationale for exclusion is given in the table Characteristics of excluded studies.

Ongoing studies
Ongoing or unpublished trials are noted in the table
Characteristics of ongoing studies (McNamara 2006; Segal 2012;
Sur-Lu-Lav 2011).

Risk of bias in included studies


In the study by Wiswell et al (Wiswell 2002), randomisation was
performed by drawing a randomisation slip from a closed envelope,
with an allocation ratio of 2:1 (lavage:standard care). Treatment
was not blinded to the clinical team, although the one-year follow-

up was performed by an investigator who was blinded to the allocation. No exclusions were noted after randomisation, although
three of the 15 infants randomly assigned to surfactant lavage did
not receive the complete lavage series, two infants received only
four of the scheduled six lavage aliquots, and another received only
two aliquots. For the purposes of analysis, all infants were included
in their respective allocation groups. Other bias may have existed
in that the number of infants receiving rescue therapy exceeded
the number reaching treatment failure criteria, even though rescue
therapies were not permitted unless infants met treatment failure.
The study was conducted without a formal sample size calculation
and based on an estimate for assessing safety and potential efficacy
in a rather exploratory fashion.
The study by Dargaville et al (Dargaville 2011) described an
adequate process of randomisation and allocation concealment.
Among 66 enrolled infants, one infant randomly assigned to the
surfactant lavage group was too unstable to receive lavage and was
deemed to have been ineligible for enrolment. The intervention
was not blinded.
In the study by Gadzinowski et al (Gadzinowski 2008), no information is provided about random sequence generation, allocation
concealment, and blinding of the intervention.

Effects of interventions
LUNG LAVAGE VERSUS STANDARD CARE (Comparison
1)
Two studies compared lung lavage with standard care (Dargaville
2011; Wiswell 2002).
Death (Outcome 1.1)
Both studies reported on mortality, and one RCT reported no
events. No treatment effect on death was noted (typical RR 0.42,
95% CI 0.12 to 1.46; typical RD -0.10, 95% CI -0.24 to 0.04)
(Analysis 1.1).
Use of ECMO (Outcome 1.2)
Both RCTs reported on the number of infants who needed
ECMO. In one study (Dargaville 2011), only 25 of the 66 enrolled
infants were treated at centres at which ECMO was available. No
difference in the relative risk of ECMO was noted, although a
trend toward an interventional benefit was observed (typical RR
0.27, 95% CI 0.04 to 1.86; typical RD -0.15, 95% CI -0.35 to
0.04) (Analysis 1.2).
Death or use of ECMO (Outcome 1.3)
For both studies, the numbers of infants who received ECMO or
died could be calculated. Surfactant lavage significantly decreased
the combined outcome of death or requirement for ECMO (typical RR 0.33, 95% CI 0.11 to 0.96: typical RD -0.19, 95% CI
-0.34 to -0.03; NNTB 5) (Analysis 1.3). Each study showed a
result favouring the intervention.
Pneumothorax (Outcome 1.4)
Both studies reported on pneumothorax, but not on other air
leaks. No significant difference was observed between treatment

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Copyright 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

groups (typical RR 0.38, 95% CI 0.08 to 1.90, typical RD -0.07,


95% CI -0.19 to 0.05) (Analysis 1.4).
Days of mechanical ventilation
Duration of ventilation showed wide variation in both studies.
Median duration for mechanical ventilation was shorter in the
intervention group for both studies (Dargaville 2011); median 5.0
versus 6.3 days (Wiswell 2002); median 4.6 versus 7.6 days) (Table
1).
Days of supplemental oxygen
Dargaville 2011 reported days of oxygen therapy only for
survivors.The values were a little different between groups:
(Dargaville 2011): median 14 versus 14 days (Wiswell 2002):
mean 13.5 versus 12.1 days (Table 1).
Length of hospital stay
One study (Wiswell 2002) reported length of stay in the Neonatal
Intensive Care Unit, which differed little between groups (mean
12.7 vs 13.1 days). In the other study, the length of hospital stay
was similar in the two groups (Dargaville 2011): median 17 versus
19 days (Table 1).
Total cost of hospitalisation
None of the studies reported hospitalisation cost.
Indices of pulmonary function (Outcomes 1.5 and 1.6)
Both RCTs reported OI measured at 24, 48, and 72 hours. A
significant difference between groups was observed at 48 hours
after lavage treatment (WMD -6.20, 95% CI -12.11 to -0.29)
(Analysis 1.5). AaDO2 and pulmonary function (PF) ratio were
measured in one study (Dargaville 2011), which did not show
any significant differences between groups, although better results
appeared to be obtained in the treatment group over time after
use of lavage therapy (Analysis 1.6). Lung mechanics were not
reported in either study.
Adverse effects
In one study (Wiswell 2002), the instillation and recovery of the
six lavage aliquots took 50 to 60 minutes. In two infants the hypoxaemia that occurred during lavage was sufficiently pronounced
to halt the lavage procedure. Overall 5 of 15 infants required hand
ventilation to recover oxygen saturation after lavage. In one other
infant, the lavage procedure was stopped because of hypotension,
although this infant had coincident gram-negative sepsis. The occurrence and severity of episodes of hypoxaemia or hypotension
are not reported in the control group, and thus it is not possible
to make direct comparisons between groups. In the other study
(Dargaville 2011), two infants experienced transient bradycardia
at less than 100 beats per minute during lavage, with recovery by
five minutes after lavage. Five infants had an oxygen saturation
below 80% for longer than 10 minutes, with recovery to above
90% within 40 minutes in all cases. Six infants needed treatment
for hypotension during or immediately after lavage. Overall, cardiopulmonary indices were affected transiently, and the lavaged
infants and the control infants showed similar blood gas indices at
four hours post lavage. One infant died of intractable pulmonary
hypertension three hours after lavage.

LUNG LAVAGE FOLLOWED BY SURFACTANT BOLUS


VERSUS SURFACTANT BOLUS THERAPY FOR MAS
WITH PULMONARY HYPERTENSION (Comparison 2)
One study compared lung lavage followed by surfactant bolus versus surfactant bolus therapy for MAS with pulmonary hypertension (Gadzinowski 2008).
Death (Outcome 2.1)
No difference in the relative risk of mortality was noted; two deaths
were reported in the control group versus none in the lavage group
(RR 0.17, 95% CI 0.01 to 3.06) (Analysis 2.1).
Pneumothorax (Outcome 2.2)
No difference in the relative risk of pneumothorax was noted; two
episodes of pneumothorax were reported in the control group but
none in the lavage group (RR 0.17, 95% CI 0.01 to 3.06) (Analysis
2.2).
Days of mechanical ventilation
The difference between mean values in days of mechanical ventilation was less than one day (mean standard deviation [SD] 6.6
2.6 vs 7.3 1.7 days) (Table 2).
Length of the hospital stay
The length of hospital stay appeared to be shorter in the intervention group (mean SD: 16.4 5.4 vs 19.8 2.9 days) (Table 2).
Indices of pulmonary function
As a result of the small size of the study (7 vs 6 for treatment
vs control) and the skewed nature of the data (large difference
between reported mean and median values), we did not assess
the significance based on the test of means but just descriptively
presented the results (Table 3). The median value of OI measured
at 24 hours in the surfactant lavage group was lower than that
in the control group (2.8 vs 9.0). The OI measured at 48 hours
was, however, similar between groups (median 1.7 vs 1.8). AaDO2
measured at 24 and 48 hours in the lavage group appeared to be
lower than in the control group. Compliance and resistance are
not reported.
Adverse effects
Except for pneumothorax and death, adverse effects were not reported.
SUBGROUP ANALYSES
None of the planned subgroup analyses were possible.
Type of lavage fluid
All included studies used diluted surfactant for lavage.
Lavage aliquot volume
The aliquot volume was at least 5 mL/kg in all studies comparing
surfactant lavage with standard care, and less than 5 mL/kg in the
study comparing surfactant lavage followed by bolus surfactant
with surfactant bolus therapy.
Timing of lavage
The mean age when lavage was performed was greater than six
hours in all included studies.

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Copyright 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

DISCUSSION
Therapeutic lung lavage is an emerging treatment for MAS, which,
by virtue of removal of meconium from the lung, would appear
to have a potential advantage over the supportive measures currently employed for this condition. This review has identified three
small randomised controlled trials of lung lavage using surfactant
(Wiswell 2002; Gadzinowski 2008; Dargaville 2011).
In the meta-analysis of the trials comparing surfactant lavage and
standard care (Wiswell 2002; Dargaville 2011), a significant difference was noted in the composite outcome of death or use of
ECMO. Analysis of this outcome was necessary given that the
availability of ECMO clearly affects mortality. Any other primary
outcomes including mortality, pneumothorax, or use of ECMO
did not demonstrate a significant benefit. Among the secondary
outcomes examining pulmonary function, only OI at 48 hours
was improved significantly in the surfactant lavage group. In one
study in which a large total volume of lavage fluid was used, the
lavage procedure was relatively protracted and in some cases was
halted because of concern regarding hypoxaemia or hypotension
(Wiswell 2002). In the other study, the lavage procedure was completed in all infants, but some experienced transient bradycardia
and hypotension.
The two studies comparing surfactant lavage with standard care
varied considerably in the severity of disease of enrolled infants
at the time of recruitment (Wiswell 2002; Dargaville 2011). In
the study of Wiswell et al, infants with MAS of lesser severity
were targeted (mean OI 12 at enrolment), and no deaths and
relatively rapid weaning from ventilation were noted, in particular
in the lung lavage group. By contrast, the other study focused on
infants with severe disease (mean OI 25 at enrolment) (Dargaville
2011). In this case, no difference was discernible in duration of
mechanical ventilation, which was relatively prolonged in both
groups, but fewer infants who underwent lavage died or required
ECMO. This suggests that lung lavage has the greatest potential
for benefit in infants with severe disease, although the possibility
of an impact in milder cases on duration of ventilation or other
pulmonary outcomes needs further exploration.
The study comparing surfactant lavage followed by bolus surfactant with surfactant bolus therapy (Gadzinowski 2008) did not
show an effect on mortality, pneumothorax, days on mechanical
ventilation, or length of hospital stay. The intervention seemed to
improve oxygenation, with a lower OI at 24 hours.

Because of the small number of RCTs and the lack of sufficient


numbers of infants randomly assigned, the evidence regarding lung
lavage in MAS is thought to be insufficient to allow firm conclusions, although a beneficial effect is noted in some important outcomes. A recent systematic review focusing on surfactant lavage
therapy reviewed existing RCTs together with non-randomised
controlled studies for supporting evidence; the results of metaanalysis also suggested that surfactant lavage had significant effects
on mortality and morbidity for MAS (Choi 2012).
Subgroup analyses according to type of lavage fluid, lavage aliquot
volume, and timing of lavage were planned. However, none of the
planned subgroup analyses were possible. Additional studies will
be needed to fully assess the impact of these factors on the success
of lung lavage in MAS.
Of the few RCTs identified, only one was judged to have a low risk
of bias. The protocols of the other two studies were unavailable
for full assessment.
Further randomised controlled trials of lung lavage are needed to
properly evaluate the safety and efficacy of this treatment. A phase
III RCT (Segal 2012) evaluating the effect of surfactant lavage
compared with standard care had been registered, and is recorded
to have been terminated without completion. One trial comparing lavage with diluted surfactant versus standard care is currently
under way (McNamara 2006) and is aiming to recruit 60 infants.
Another trial (Sur-Lu-Lav 2011) undertaken to investigate the effect of surfactant lavage compared with standard care is registered.

AUTHORS CONCLUSIONS
Implications for practice
In infants with MAS, lung lavage with diluted surfactant may be
of benefit, but more evidence is required to allow firm conclusions
to be drawn.

Implications for research


Further controlled clinical trials of lung lavage in MAS are required
to confirm the treatment effect, refine the method of lavage, and
compare lung lavage versus other approaches, including surfactant
bolus therapy. Outcomes to be evaluated in further clinical trials
should include short- and long-term clinical outcomes, and any
adverse effects of lavage.

Lung lavage for meconium aspiration syndrome in newborn infants (Review)


Copyright 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

REFERENCES

References to studies included in this review


Dargaville 2011 {published data only}
Dargaville PA, Copnell B, Mills JF, Haron I, Lee JK,
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with dilute surfactant for meconium aspiration syndrome.
Journal of Pediatrics 2011;158(3):3839.
Gadzinowski 2008 {published data only}
Gadzinowski J, Kowalska K, Vidyasagar D. Treatment of
MAS with PPHN using combined therapy: SLL, bolus
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Wiswell 2002 {published data only}
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Walsh WF, et al.A multicenter, randomized, controlled trial
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References to studies excluded from this review


Armenta 2011 {published data only}
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lavage in meconium aspiration syndrome: A comparative
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Ogawa 1997 {published data only}


Ogawa Y. Bronchial lavage with surfactant solution for
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Rosegger H, Engele H, Haas J. Tracheobronchial
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References to ongoing studies

Chang 2003 {published data only}


Chang HY, Hsu CH, Kao HA, Hung HY, Chang JH,
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Formosan Medical Association 2003;102(5):32630.

McNamara 2006 {unpublished data only}


McNamara P. Surfactant lavage vs. Bolus surfactant in
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Dargaville 2007 {published and unpublished data}


Dargaville PA, Mills JF, Copnell B, Loughnan PM,
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aspiration syndrome: a preliminary report. Journal of
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Segal 2012 {unpublished data only}


Wiswell TE. Phase III randomized study of lucinactant
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NCT00004500) (accessed 19.02.2013).

Kowalska 2002 {published data only}


Kowalska K, Szymankiewicz M, Gadzinowski J. An
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drzewa tchawiczooskrzelowego roztworem naturalnego
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Sur-Lu-Lav 2011 {unpublished data only}


Nangia S. Comparison of surfactant lung lavage with
standard care in the treatment of meconium aspiration
syndrome (Sur-Lu-Lav). ClinicalTrials.gov(http://
clinicaltrials.gov/ct2/show/NCT01310621?term=Sur-LuLav&rank=1) (accessed 19.02.2013).

Lam 1999 {published data only}


Lam BCC, Yeung CY. Surfactant lavage for meconium
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Pt 1):101418.

Chinese Collaborative Study Group 2005


Chinese Collaborative Study Group for Neonatal
respiratory Diseases. Treatment of severe meconium
aspiration syndrome with porcine surfactant: a multicentre,

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10

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Choi HJ, Hahn S, Lee J, Park BJ, Lee SM, Kim HS,
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Dargaville 2001
Dargaville PA, South M, McDougall PN. Surfactant and
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Dargaville 2003
Dargaville PA, Mills JF, Headley BM, Chan Y, Coleman L,
Loughnan PM, et al.Therapeutic lung lavage in the piglet
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Dargaville PA, Copnell B, Tingay DG, Gordon MJ, Mills
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Marraro 1998
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Mosca F, Colnaghi M, Castoldi F. Lung lavage with a saline
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Moses D, Holm BA, Spitale P, Liu MY, Enhorning G.
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Ohama 1994
Ohama Y, Itakura Y, Koyama N, Eguchi H, Ogawa Y.
Effect of surfactant lavage in a rabbit model of meconium
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Ohama 1999
Ohama Y, Ogawa Y. Treatment of meconium aspiration
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Paranka MS, Walsh WF, Stancombe BB. Surfactant lavage
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Pediatric Research 1992;31(6):6258.
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Tran N, Lowe C, Sivieri EM, Shaffer TH. Sequential effects
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Tyler DC, Murphy J, Cheney FW. Mechanical and chemical
damage to lung tissue caused by meconium aspiration.
Pediatrics 1978;62(4):4549.
Wiswell 1993
Wiswell TE, Bent RC. Meconium staining and the
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Wiswell TE, Gannon CM, Jacob J, Goldsmith L, Szyld
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apparently vigorous meconium-stained neonate: results of

Lung lavage for meconium aspiration syndrome in newborn infants (Review)


Copyright 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

11

the multicenter, international collaborative trial. Pediatrics


2000;105(1 Pt 1):17.
Indicates the major publication for the study

Lung lavage for meconium aspiration syndrome in newborn infants (Review)


Copyright 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

12

CHARACTERISTICS OF STUDIES

Characteristics of included studies [ordered by study ID]


Dargaville 2011
Methods

International multicenter randomised controlled trial. 13 participating centres. Randomisation blinded, with a 1:1 allocation ratio
Intervention not blinded to either clinical team or assessors of in-hospital outcomes.
Complete follow-up with blinded assessment of outcome at two years of age (not yet
reported)

Participants

66 infants from 13 participating centres, who were of at least 36 weeks gestation and 2
kg birth weight, less than 24 hours of age, with a diagnosis of MAS. The infants were
eligible for enrolment if they were mechanically ventilated with mean airway pressure
of at least 12 cm H2 O and an alveolar-arterial oxygen difference of at least 450 mmHg
on two sequential blood gases. Subsequent improvement in oxygenation was allowable
as long as FiO2 remained > 0.5 before randomisation. One infant randomly assigned
to the lavage group who did not receive lavage was found to be ineligible because of
cardiopulmonary instability. 30 infants received surfactant lavage and 35 received no
lavage

Interventions

Surfactant lavage with total volume of 30 mL/kg, divided into two aliquots of 15 mL/
kg of bovine surfactant (Survanta, Abbott Laboratories, Columbus OH) with a phospholipid concentration of 5 mg/mL. Lavage fluid was instilled over 20 seconds through
a dispensing catheter with the ventilator circuit disconnected. Three positive-pressure
inflations were then administered, followed by disconnection of the ventilator circuit
and suction of the instilled fluid with a standard suction catheter for up to 30 seconds

Outcomes

Primary outcome: duration of respiratory support, defined as the cumulative duration


of all periods of intubation and nasal continuous positive airway pressure (CPAP)
Secondary outcomes: death, pneumothorax, duration of intubation, oxygen therapy,
HFOV, iNO, hospitalisation
Evaluation of the physiologic effects and safety of lavage: heart rate, mean blood pressure,
SpO2, blood gas analyses

Notes
Risk of bias
Bias

Authors judgement

Support for judgement

Random sequence generation (selection Low risk


bias)

Randomly permuted blocks of two or four,


stratified by study centre

Allocation concealment (selection bias)

Pre-prepared sequentially numbered sealed


opaque envelopes

Low risk

Lung lavage for meconium aspiration syndrome in newborn infants (Review)


Copyright 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

13

Dargaville 2011

(Continued)

Blinding of participants and personnel High risk


(performance bias)
All outcomes

Blinding of the intervention was not possible

Blinding of outcome assessment (detection Low risk


bias)
All outcomes

All outcomes were measured by objective


means

Incomplete outcome data (attrition bias)


All outcomes

Low risk

One infant was ineligible. Complete data


were available for 65 eligible infants

Selective reporting (reporting bias)

Low risk

The study protocol is available and all of


the studys pre-specified outcomes that are
of interest in the review have been reported
in the pre-specified way

Other bias

Low risk

The study appears to be free of other


sources of bias

Gadzinowski 2008
Methods

Single-centre randomised controlled trial. Randomisation blinded, with a 1:1 allocation


ratio
Intervention not blinded to clinical team or assessors of longer-term outcomes. Complete
follow-up with assessment up to two years of age

Participants

13 neonates of gestational age > 34 weeks, postnatal age less than 24 hours, with MAS
complicated by pulmonary hypertension diagnosed on the basis of echocardiographic
parameters. Seven infants received surfactant lavage followed by bolus surfactant treatment, and 6 received bolus surfactant treatment only

Interventions

Surfactant lavage with a total lavage volume of 15 mL/kg (aliquot volume 3.75 mL/kg)
of bovine surfactant (Survanta) at a phospholipid concentration of 5 mg/mL. Lavage
was conducted via a closed lavage and suctioning system, in four body positions: on the
right and left sides, and in the Trendelenburg and anti-Trendelenburg positions
After 2 mL of the solution was instilled, mechanical ventilation was continued
After 3 to 5 respiratory cycles, the secretions were suctioned
After lavage treatment, one dose of bolus Survanta (100 mg/kg) was given. Heart rate
and oxygen saturation were monitored

Outcomes

Primary outcome: (1) PaO2 ; (2) fraction of inspired oxygen; (3) oxygenation index; and
(4) alveolar-arterial oxygen difference
Secondary outcomes: length of time on mechanical ventilation; duration of iNO treatment; length of hospital stay; complications; and mortality

Notes
Risk of bias
Lung lavage for meconium aspiration syndrome in newborn infants (Review)
Copyright 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

14

Gadzinowski 2008

(Continued)

Bias

Authors judgement

Support for judgement

Random sequence generation (selection Unclear risk


bias)

The study is described as randomised, but


no information is provided about the sequence generation method

Allocation concealment (selection bias)

Not reported

Unclear risk

Blinding of participants and personnel Unclear risk


(performance bias)
All outcomes

Not reported (each group of infants was


managed by a different group of neonatologists)

Blinding of outcome assessment (detection Low risk


bias)
All outcomes

All outcomes were measured by objective


means

Incomplete outcome data (attrition bias)


All outcomes

Low risk

Complete data were available for all enrolled infants

Selective reporting (reporting bias)

Low risk

The study protocol is not available, and information is sufficient to permit judgement

Wiswell 2002
Methods

Multicenter randomised controlled trial


15 participating centres
Randomisation blinded, with a 2:1 allocation ratio (lavage vs control). Intervention not
blinded to clinical team or assessors of longer-term outcomes
Complete follow-up with assessment up to one year of age

Participants

22 infants (enrolled in nine participating centres) of gestational age > 34 weeks, postnatal
age up to 72 hours, with a diagnosis of MAS requiring mechanical ventilation
The infants were eligible for enrolment if oxygenation index (OI) was between 8 and
25, inclusive, on at least two of three consecutive blood gas analyses within a three-hour
period
15 infants received surfactant lavage and 7 received standard care

Interventions

Lung lavage with a total lavage volume of 48 mL/kg, divided into 6 aliquots each of 8
mL/kg
Lavage fluid was lucinactant (Surfaxin), at a phospholipid concentration of 2.5 mg/mL
for the first four lavage aliquots, and 10 mg/mL for the last two aliquots
Each aliquot was instilled down the endotracheal tube with the chest alternately left and
right side down, with suctioning after each instillation using a closed suctioning system
Recovery of blood pressure, heart rate, and oxygen saturation was mandated before
proceeding with further lavage aliquots

Lung lavage for meconium aspiration syndrome in newborn infants (Review)


Copyright 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

15

Wiswell 2002

(Continued)

Outcomes

Primary outcome: incidence of treatment failure, defined as an OI > 25 or an increase


in OI of 50% above baseline
Secondary outcomes: MAS-related mortality, oxygenation changes, need for rescue therapies (HFOV, bolus surfactant, iNO, ECMO), duration of ventilation
Longer-term outcomes: survival at 12 months, numbers of hospitalizations and respiratory illnesses in the first year of life, growth and development at 12 months

Notes
Risk of bias
Bias

Authors judgement

Support for judgement

Random sequence generation (selection Unclear risk


bias)

The study is described as randomised, but


no information about the sequence generation method is provided

Allocation concealment (selection bias)

Randomisation was performed by drawing


a randomisation slip from a closed envelope

Low risk

Blinding of participants and personnel Unclear risk


(performance bias)
All outcomes

Not reported

Blinding of outcome assessment (detection Low risk


bias)
All outcomes

All outcomes were measured by objective


means

Incomplete outcome data (attrition bias)


All outcomes

Low risk

ITT analysis was carried out

Selective reporting (reporting bias)

Unclear risk

The study protocol is not available, and information is sufficient to permit judgement

Other bias

High risk

(1) The study was conducted without a formal sample size calculation but based on an
estimate for assessing safety and potential
efficacy in a rather exploratory fashion
(2) The number of infants receiving rescue
therapy was greater than the number of infants with treatment failures, although rescue therapies were not allowed unless infants met treatment failure

Lung lavage for meconium aspiration syndrome in newborn infants (Review)


Copyright 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

16

Characteristics of excluded studies [ordered by study ID]

Study

Reason for exclusion

Armenta 2011

Surfactant lavage was compared with saline lavage

Burke-Strickland 1973

Nonrandomised case series

Carson 1976

Randomisation of infants to receive saline lavage or no lavage mentioned in methods, but no results presented

Chang 2003

Nonrandomised study over two time epochs

Dargaville 2007

Nonrandomised study with concurrent controls

Kowalska 2002

Nonrandomised study over two time epochs

Lam 1999

Nonrandomised study over two time epochs

Ogawa 1997

Randomised controlled trial; no data reported or obtainable for nonlavaged control group
Six infants received 5 2 mL/kg lavage with Surfacten-TA (6 mg/mL phospholipid), and 4 infants received
identical lavage, but with saline
A significant difference was noted between the two groups in both oxygenation and CO2 clearance after
lavage, favouring the group lavaged with dilute surfactant

Rosegger 1987

Nonrandomised study with concurrent controls

Salvia-Roigs 2004

Nonrandomised study of two different treatment schedules involving lavage, compared with historical
controls

Schlsser 2002

Nonrandomised study with concurrent controls

Su 1998

Nonrandomised study, no control group

Characteristics of ongoing studies [ordered by study ID]


McNamara 2006
Trial name or title

Surfactant Lavage versus Bolus Surfactant in Neonates With Meconium Aspiration

Methods

RCT

Participants

Meconium aspiration syndrome (n = 20)

Interventions

Surfactant lavage or surfactant bolus treatment

Outcomes

Primary outcome measures:


Change in oxygenation from baseline to one and six hours after treatment.

Lung lavage for meconium aspiration syndrome in newborn infants (Review)


Copyright 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

17

McNamara 2006

(Continued)

Change in dynamic pulmonary compliance from baseline to one and six hour after treatment.
Change in pulmonary artery pressure from baseline to one and six hour after treatment.
Measures of efficacy of ventilation and oxygenation at one hour and six hours after treatment.
Cardiac function by echocardiography at six hours after treatment
Secondary outcome measures:
Change in oxygenation, dynamic pulmonary compliance, and pulmonary vascular resistance from baseline
to 12, 24, and 48 hours after treatment
Measures of efficiency of ventilation and oxygenation at 12, 24, and 48 hours after treatment
Duration of mechanical ventilation, defined as the cumulative time of mechanical ventilation
Length of time on CPAP
Length of time with oxygen supplementation
Length of time on inotropes and maximum inotropic score
Need for and length of use of NO
Need for and length of use of ECMO
Time to full enteral feeds
Attainment of exit criteria
Development of significant pulmonary haemorrhage
Development of significant intracranial haemorrhage
Development of tension pneumothorax requiring drainage
Need for repeat surfactant
Length of stay in a level III NICU
Mortality
Starting date

2006

Contact information

Patrick McNamara, MD, patrick.mcnamara@sickkids.ca.


The Hospital for Sick Children, Toronto, Ontario, Canada

Notes

clinical trials.gov. identifier NCT00312507

Segal 2012
Trial name or title

Phase III Randomized Study of Lucinactant in Full Term Newborn Infants with Meconium Aspiration
Syndrome

Methods

Randomised controlled trial

Participants

69 infants (lucinactant n = 38; standard care n = 31)

Interventions

Lucinactant via bronchoalveolar lavage

Outcomes

Numbers of days receiving mechanical ventilation (lucinactant 10.2 9.96; standard care 8.1 8.52)
Air leak (lucinactant 2/38; standard care 0/31)
Intraventricular haemorrhage (lucinactant 0/38; standard care 1/31)
Death (lucinactant 0/38; standard care 0/31)

Starting date

Recruitment occurred between March 2000 and October 2002

Lung lavage for meconium aspiration syndrome in newborn infants (Review)


Copyright 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

18

Segal 2012

(Continued)

Contact information

Robert Segal; Discovery Laboratory

Notes

Clinical trials.gov. identifier NCT00004500.


Sponsored by Discovery Laboratories

Sur-Lu-Lav 2011
Trial name or title

Comparison of Surfactant Lung Lavage with Standard Care in the Treatment of Meconium Aspiration
Syndrome (Sur-Lu-Lav)

Methods

Randomised controlled trial

Participants

Inclusion criteria:
Gestation age 37 weeks
Cephalic presentation
Singleton pregnancy
Presence of meconium-stained amniotic fluid or staining of meconium in skin,umbilical cord, or nails
Nonvigorous babies
Presence of respiratory distress (Downes score 4)
Presence of meconium below vocal cords or chest x-ray; suggestive of meconium aspiration
Age < 2 hours
Exclusion criteria:
Major congenital malformations
Congenital heart disease
Hydrops fetalis
Air leaks
Pulmonary haemorrhage

Interventions

Lavage with 2 10 mL/kg aliquots of bovine surfactant or standard care


The diluted surfactant is instilled into the endotracheal tube over a period of 15 to 20 seconds
Once the instillation is complete, 5 manual breaths will be provided and the infant will be repositioned supine
The suction catheter will be inserted and advanced to a position approximately 5 mm past the end of the
endotracheal tube

Outcomes

Primary outcome: duration of oxygen therapy, severity of respiratory distress, need for mechanical ventilation
Secondary outcome: duration of mechanical ventilation, complications, incidence of sepsis, mortality, duration of hospital stay

Starting date

2011

Contact information

Sushma Nangia, MBBS, MD, DM drsnangia@gmail.com.


Kalawati Saran Childrens Hospital, Lady Hardinge Medical College

Notes

clinical trials.gov. identifier NCT01310621

Lung lavage for meconium aspiration syndrome in newborn infants (Review)


Copyright 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

19

DATA AND ANALYSES

Comparison 1. Lung lavage versus standard care

No. of
studies

No. of
participants

1 Death
2 Use of ECMO
3 Death or use of ECMO
4 Pneumothorax
5 Oxygenation index
5.1 measured at 24 hours
5.2 measured at 48 hours
5.3 measured at 72 hours
6 Alveolar-arterial oxygen
difference
6.1 measured at 24 hours

2
2
2
2
2
2
2
2
1

88
47
88
88

6.2 measured at 48 hours

Outcome or subgroup title

Statistical method

Effect size

Risk Ratio (M-H, Fixed, 95% CI)


Risk Ratio (M-H, Fixed, 95% CI)
Risk Ratio (M-H, Fixed, 95% CI)
Risk Ratio (M-H, Fixed, 95% CI)
Mean Difference (IV, Fixed, 95% CI)
Mean Difference (IV, Fixed, 95% CI)
Mean Difference (IV, Fixed, 95% CI)
Mean Difference (IV, Fixed, 95% CI)
Mean Difference (IV, Fixed, 95% CI)

0.42 [0.12, 1.46]


0.27 [0.04, 1.86]
0.33 [0.11, 0.96]
0.38 [0.08, 1.90]
Subtotals only
-1.90 [-7.56, 3.77]
-6.20 [-12.11, -0.29]
-3.56 [-8.72, 1.60]
Subtotals only

66

Mean Difference (IV, Fixed, 95% CI)

66

Mean Difference (IV, Fixed, 95% CI)

6.3 measured at 72 hours

66

Mean Difference (IV, Fixed, 95% CI)

7 PaO2 /FiO2
7.1 measured at 24 hours
7.2 measured at 48 hours
7.3 measured at 72 hours

1
1
1
1

66
66
66

Mean Difference (IV, Fixed, 95% CI)


Mean Difference (IV, Fixed, 95% CI)
Mean Difference (IV, Fixed, 95% CI)
Mean Difference (IV, Fixed, 95% CI)

-12.0 [-109.19, 85.


19]
-57.0 [-162.96, 48.
96]
-41.0 [-132.59, 50.
59]
Subtotals only
-1.0 [-54.61, 52.61]
27.0 [-26.63, 80.63]
26.0 [-24.96, 76.96]

88
88
88

Comparison 2. Lung lavage followed by surfactant bolus versus surfactant bolus

Outcome or subgroup title


1 Death
2 Pneumothorax

No. of
studies

No. of
participants

1
1

13
13

Statistical method
Risk Ratio (M-H, Fixed, 95% CI)
Risk Ratio (M-H, Fixed, 95% CI)

Lung lavage for meconium aspiration syndrome in newborn infants (Review)


Copyright 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

Effect size
0.18 [0.01, 3.06]
0.18 [0.01, 3.06]

20

Analysis 1.1. Comparison 1 Lung lavage versus standard care, Outcome 1 Death.
Review:

Lung lavage for meconium aspiration syndrome in newborn infants

Comparison: 1 Lung lavage versus standard care


Outcome: 1 Death

Study or subgroup

Intervention

Control

n/N

n/N

Risk Ratio

Weight

Wiswell 2002

0/15

0/7

Dargaville 2011

3/31

8/35

100.0 %

0.42 [ 0.12, 1.46 ]

Total (95% CI)

46

42

100.0 %

0.42 [ 0.12, 1.46 ]

M-H,Fixed,95% CI

Risk Ratio
M-H,Fixed,95% CI
Not estimable

Total events: 3 (Intervention), 8 (Control)


Heterogeneity: not applicable
Test for overall effect: Z = 1.36 (P = 0.17)
Test for subgroup differences: Not applicable

0.1 0.2

0.5

Favours lung lavage

10

Favours control

Analysis 1.2. Comparison 1 Lung lavage versus standard care, Outcome 2 Use of ECMO.
Review:

Lung lavage for meconium aspiration syndrome in newborn infants

Comparison: 1 Lung lavage versus standard care


Outcome: 2 Use of ECMO

Study or subgroup

Intervention

Control

n/N

n/N

Risk Ratio

Weight

Wiswell 2002

1/15

1/7

30.5 %

0.47 [ 0.03, 6.43 ]

Dargaville 2011

0/11

3/14

69.5 %

0.18 [ 0.01, 3.13 ]

Total (95% CI)

26

21

100.0 %

0.27 [ 0.04, 1.86 ]

M-H,Fixed,95% CI

Risk Ratio
M-H,Fixed,95% CI

Total events: 1 (Intervention), 4 (Control)


Heterogeneity: Chi2 = 0.25, df = 1 (P = 0.62); I2 =0.0%
Test for overall effect: Z = 1.33 (P = 0.18)
Test for subgroup differences: Not applicable

0.01

0.1

Favours lung lavage

10

100

Favours control

Lung lavage for meconium aspiration syndrome in newborn infants (Review)


Copyright 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

21

Analysis 1.3. Comparison 1 Lung lavage versus standard care, Outcome 3 Death or use of ECMO.
Review:

Lung lavage for meconium aspiration syndrome in newborn infants

Comparison: 1 Lung lavage versus standard care


Outcome: 3 Death or use of ECMO

Study or subgroup

Intervention

Control

n/N

n/N

Risk Ratio

Weight

Wiswell 2002

1/15

1/7

11.7 %

0.47 [ 0.03, 6.43 ]

Dargaville 2011

3/31

11/35

88.3 %

0.31 [ 0.09, 1.00 ]

Total (95% CI)

46

42

100.0 %

0.33 [ 0.11, 0.96 ]

M-H,Fixed,95% CI

Risk Ratio
M-H,Fixed,95% CI

Total events: 4 (Intervention), 12 (Control)


Heterogeneity: Chi2 = 0.08, df = 1 (P = 0.78); I2 =0.0%
Test for overall effect: Z = 2.04 (P = 0.042)
Test for subgroup differences: Not applicable

0.01

0.1

Favours lung lavage

10

100

Favours control

Analysis 1.4. Comparison 1 Lung lavage versus standard care, Outcome 4 Pneumothorax.
Review:

Lung lavage for meconium aspiration syndrome in newborn infants

Comparison: 1 Lung lavage versus standard care


Outcome: 4 Pneumothorax

Study or subgroup

Intervention

Control

n/N

n/N

Risk Ratio

Weight

Wiswell 2002

1/15

0/7

12.4 %

1.50 [ 0.07, 32.84 ]

Dargaville 2011

1/31

5/35

87.6 %

0.23 [ 0.03, 1.83 ]

Total (95% CI)

46

42

100.0 %

0.38 [ 0.08, 1.90 ]

M-H,Fixed,95% CI

Risk Ratio
M-H,Fixed,95% CI

Total events: 2 (Intervention), 5 (Control)


Heterogeneity: Chi2 = 1.00, df = 1 (P = 0.32); I2 =0.0%
Test for overall effect: Z = 1.17 (P = 0.24)
Test for subgroup differences: Not applicable

0.01

0.1

Favours lung lavage

10

100

Favours control

Lung lavage for meconium aspiration syndrome in newborn infants (Review)


Copyright 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

22

Analysis 1.5. Comparison 1 Lung lavage versus standard care, Outcome 5 Oxygenation index.
Review:

Lung lavage for meconium aspiration syndrome in newborn infants

Comparison: 1 Lung lavage versus standard care


Outcome: 5 Oxygenation index

Study or subgroup

Intervention

Mean
Difference

Control

Weight

IV,Fixed,95% CI

Mean
Difference

Mean(SD)

Mean(SD)

IV,Fixed,95% CI

Wiswell 2002

15

6.2 (15.5)

9.6 (11.1)

24.8 %

-3.40 [ -14.76, 7.96 ]

Dargaville 2011

31

16.3 (13.7)

35

17.7 (13.3)

75.2 %

-1.40 [ -7.93, 5.13 ]

100.0 %

-1.90 [ -7.56, 3.77 ]

1 measured at 24 hours

Subtotal (95% CI)

46

42

Heterogeneity: Chi2 = 0.09, df = 1 (P = 0.76); I2 =0.0%


Test for overall effect: Z = 0.66 (P = 0.51)
2 measured at 48 hours
Wiswell 2002

15

4.4 (4.3)

10.6 (13.8)

32.0 %

-6.20 [ -16.65, 4.25 ]

Dargaville 2011

31

10.3 (11.6)

35

16.5 (17.8)

68.0 %

-6.20 [ -13.37, 0.97 ]

100.0 %

-6.20 [ -12.11, -0.29 ]

Subtotal (95% CI)

46

42

Heterogeneity: Chi2 = 0.0, df = 1 (P = 1.00); I2 =0.0%


Test for overall effect: Z = 2.05 (P = 0.040)
3 measured at 72 hours
Wiswell 2002

15

3.3 (3.1)

8.4 (14.3)

23.2 %

-5.10 [ -15.81, 5.61 ]

Dargaville 2011

31

9.9 (11.7)

35

13 (12.7)

76.8 %

-3.10 [ -8.99, 2.79 ]

100.0 %

-3.56 [ -8.72, 1.60 ]

Subtotal (95% CI)

46

42

Heterogeneity: Chi2 = 0.10, df = 1 (P = 0.75); I2 =0.0%


Test for overall effect: Z = 1.35 (P = 0.18)

-20

-10

Favours lung lavage

Lung lavage for meconium aspiration syndrome in newborn infants (Review)


Copyright 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

10

20

Favours control

23

Analysis 1.6. Comparison 1 Lung lavage versus standard care, Outcome 6 Alveolar-arterial oxygen
difference.
Review:

Lung lavage for meconium aspiration syndrome in newborn infants

Comparison: 1 Lung lavage versus standard care


Outcome: 6 Alveolar-arterial oxygen difference

Study or subgroup

Intervention

Mean
Difference

Control

Mean(SD)

Mean(SD)

31

358 (202)

35

370 (200)

Weight

IV,Fixed,95% CI

Mean
Difference
IV,Fixed,95% CI

1 measured at 24 hours
Dargaville 2011

Subtotal (95% CI)

31

100.0 %

-12.00 [ -109.19, 85.19 ]

100.0 % -12.00 [ -109.19, 85.19 ]

35

Heterogeneity: not applicable


Test for overall effect: Z = 0.24 (P = 0.81)
2 measured at 48 hours
Dargaville 2011

Subtotal (95% CI)

31

258 (222)

31

35

315 (216)

100.0 %

-57.00 [ -162.96, 48.96 ]

100.0 % -57.00 [ -162.96, 48.96 ]

35

Heterogeneity: not applicable


Test for overall effect: Z = 1.05 (P = 0.29)
3 measured at 72 hours
Dargaville 2011

Subtotal (95% CI)

31

31

236 (189)

35

100.0 %

277 (190)

35

-41.00 [ -132.59, 50.59 ]

100.0 % -41.00 [ -132.59, 50.59 ]

Heterogeneity: not applicable


Test for overall effect: Z = 0.88 (P = 0.38)

-200

-100

Favours lung lavage

Lung lavage for meconium aspiration syndrome in newborn infants (Review)


Copyright 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

100

200

Favours control

24

Analysis 1.7. Comparison 1 Lung lavage versus standard care, Outcome 7 PaO2/FiO2.
Review:

Lung lavage for meconium aspiration syndrome in newborn infants

Comparison: 1 Lung lavage versus standard care


Outcome: 7 PaO2 /FiO2

Study or subgroup

Intervention

Mean
Difference

Control

Mean(SD)

Mean(SD)

31

148 (109)

35

149 (113)

Weight

IV,Fixed,95% CI

Mean
Difference
IV,Fixed,95% CI

1 measured at 24 hours
Dargaville 2011

Subtotal (95% CI)

31

35

100.0 %

-1.00 [ -54.61, 52.61 ]

100.0 %

-1.00 [ -54.61, 52.61 ]

100.0 %

27.00 [ -26.63, 80.63 ]

Heterogeneity: not applicable


Test for overall effect: Z = 0.04 (P = 0.97)
2 measured at 48 hours
Dargaville 2011

Subtotal (95% CI)

31

188 (110)

31

35

161 (112)

100.0 % 27.00 [ -26.63, 80.63 ]

35

Heterogeneity: not applicable


Test for overall effect: Z = 0.99 (P = 0.32)
3 measured at 72 hours
Dargaville 2011

Subtotal (95% CI)

31

31

187 (110)

35

161 (100)

100.0 %

26.00 [ -24.96, 76.96 ]

100.0 % 26.00 [ -24.96, 76.96 ]

35

Heterogeneity: not applicable


Test for overall effect: Z = 1.00 (P = 0.32)

-100

-50

Favours control

Lung lavage for meconium aspiration syndrome in newborn infants (Review)


Copyright 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

50

100

Favours lung lavage

25

Analysis 2.1. Comparison 2 Lung lavage followed by surfactant bolus versus surfactant bolus, Outcome 1
Death.
Review:

Lung lavage for meconium aspiration syndrome in newborn infants

Comparison: 2 Lung lavage followed by surfactant bolus versus surfactant bolus


Outcome: 1 Death

Study or subgroup

Intervention

Control

n/N

n/N

0/7

2/6

100.0 %

0.18 [ 0.01, 3.06 ]

100.0 %

0.18 [ 0.01, 3.06 ]

Gadzinowski 2008

Total (95% CI)

Risk Ratio

Weight

M-H,Fixed,95% CI

Risk Ratio
M-H,Fixed,95% CI

Total events: 0 (Intervention), 2 (Control)


Heterogeneity: not applicable
Test for overall effect: Z = 1.19 (P = 0.23)
Test for subgroup differences: Not applicable

0.01

0.1

Favours lung lavage

10

100

Favours control

Analysis 2.2. Comparison 2 Lung lavage followed by surfactant bolus versus surfactant bolus, Outcome 2
Pneumothorax.
Review:

Lung lavage for meconium aspiration syndrome in newborn infants

Comparison: 2 Lung lavage followed by surfactant bolus versus surfactant bolus


Outcome: 2 Pneumothorax

Study or subgroup

Intervention

Control

n/N

n/N

0/7

2/6

100.0 %

0.18 [ 0.01, 3.06 ]

100.0 %

0.18 [ 0.01, 3.06 ]

Gadzinowski 2008

Total (95% CI)

Risk Ratio

Weight

M-H,Fixed,95% CI

Risk Ratio
M-H,Fixed,95% CI

Total events: 0 (Intervention), 2 (Control)


Heterogeneity: not applicable
Test for overall effect: Z = 1.19 (P = 0.23)
Test for subgroup differences: Not applicable

0.01

0.1

Favours lung lavage

10

100

Favours control

Lung lavage for meconium aspiration syndrome in newborn infants (Review)


Copyright 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

26

ADDITIONAL TABLES
Table 1. Results of continuous variables (lung lavage versus standard care)

Study

Number of in- Days of mechanical ventilation Days of supplemental oxygen Length of hospital stay (days)
fants
(i/c)
Intervention

Control

Intervention

Control

Intervention

Control

Dargaville
2011

31/35

5.0 (3.3-8.7)

6.3 (3.9-8.1)

14 (6.7-21)

14 (11-18)

17 (11-25)

19 (15-25)

Wiswell 2002

7/15

4.6 (1.1-22.3)

7.6 (1.1-28)

13.5 9.3

12.1 10.7

12.7 8.7

13.1 10.3

i = intervention group; c = control group.


All variables expressed by mean standard deviation or median (interquartile range). Data from the survivors were used.

Table 2. Results of continuous variables (lung lavage followed by surfactant bolus versus surfactant bolus)

Study

Gadzinowski 2008

Number of infants
(i/c)

7/6

Days of mechanical ventilation

Length of hospital stay (days)

Intervention

Control

Intervention

Control

6.6 2.6

7.3 1.7

16.4 5.4

19.8 2.9

i = intervention group; c = control group.


All variables expressed by mean standard deviation.

Table 3. Results of indices of pulmonary function (lung lavage followed by surfactant bolus versus surfactant bolus)

Gadzinowski 2008
Intervention (n = 7)

Control (n = 6)

Oxygenation index (0 hours)

29.8 12.5 (median 25)

32.4 25 (median 24.3)

Oxygenation index (24 hours)

2.7 2.2 (median 2.8)

10.4 8.1 (median 9.0)

Oxygenation index (48 hours)

5.0 9.1 (median 1.7)

5.7 9.1 (median 1.8)

AaDO2 (0 hours)

575.6 91.0

589.5 95.8

AaDO2 (24 hours)

261.0 160.9

352.3 177.5

AaDO2 (48 hours)

178.3 144.0

226.0 239.8

i = intervention group; c = control group; AaDO2 = alveolar-arterial oxygen difference (mmHg),


All variables expressed by mean standard deviation or median.
Lung lavage for meconium aspiration syndrome in newborn infants (Review)
Copyright 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

27

HISTORY
Protocol first published: Issue 1, 2002
Review first published: Issue 4, 2013

Date

Event

Description

30 August 2011

New citation required and conclusions have changed

Search updated, studies added, analyses and texts


amended

20 July 2011

Amended

Authorship amended

2 May 2011

Amended

Converted to new review format.

30 August 2005

New citation required and conclusions have changed

Substantive amendment

CONTRIBUTIONS OF AUTHORS
Dr. Seokyung Hahn is the primary author of the review. She carried out study selection, assessment of study methodology, and data
extraction and wrote the review.
Dr. Hyun Jin Choi performed the initial search for the articles, assessed study methodology, extracted data, and collaborated with Dr.
Hahn in writing the review.
Dr. Peter Dargaville specified the objectives and the types of studies, participants, interventions, and outcomes to be included.
Dr. Roger Soll participated in assessing the study methodology, extracted data, and collaborated with Dr. Dargaville at an earlier stage
of the review.

DECLARATIONS OF INTEREST
Dr. Hahn and Dr. Choi declared no conflict of interest.
Dr. P. Dargaville has received support for animal laboratory studies of therapeutic pulmonary lavage from Abbott Australasia, and has
also been supported as an invited speaker by Abbott, and by Chiesi Farmaceutici.
Dr. Dargaville was Chief Investigator of the lessMAS trial, which is funded independent of industry, but for which Abbott Laboratories
has provided surfactant free of charge.
Dr. R. Soll has acted as a consultant and an invited speaker for several of the pharmaceutical companies that manufacture or distribute
surfactant preparations (Abbott Laboratories, Ross Laboratories, Chiesi Pharmaceuticals, Dey Laboratories, Burroughs Wellcome).

Lung lavage for meconium aspiration syndrome in newborn infants (Review)


Copyright 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

28

SOURCES OF SUPPORT
Internal sources
Menzies Research Institute Tasmania, Hobart, Australia.

External sources
National Evidence-based Healthcare Collaborating Agency, Korea, South.
National Research Foundation of Korea (NRF), Korea, South.
NRF grant funded by the Korea government (MEST); No. 2012-0000994.
Eunice Kennedy Shriver National Institute of Child Health and Human Development National Institutes of Health,
Department of Health and Human Services, USA.
Editorial support of the Cochrane Neonatal Review Group has been funded with Federal funds from the Eunice Kennedy Shriver
National Institute of Child Health and Human Development National Institutes of Health, Department of Health and Human
Services, USA, under Contract No. HHSN275201100016C.

DIFFERENCES BETWEEN PROTOCOL AND REVIEW


The composite outcome of death or use of ECMO was included as an outcome in view of the effects of ECMO, when available, on
mortality risk.

INDEX TERMS
Medical Subject Headings (MeSH)
Bronchoalveolar Lavage [ methods]; Infant, Newborn; Meconium Aspiration Syndrome [mortality; therapy]; Pulmonary Surfactants
[ therapeutic use]; Randomized Controlled Trials as Topic

MeSH check words


Humans

Lung lavage for meconium aspiration syndrome in newborn infants (Review)


Copyright 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

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