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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
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
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1
1
2
2
3
3
6
9
9
10
12
20
21
21
22
22
23
24
25
26
26
26
28
28
28
28
29
29
[Intervention Review]
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.
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.
BACKGROUND
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
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).
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
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
Primary outcomes
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.
Secondary outcomes
Selection of studies
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.
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).
Assessment of heterogeneity
RESULTS
Description of studies
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.
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.
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-
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).
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
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.
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.
REFERENCES
Additional references
10
Marraro 1998
Marraro G, Bonati M, Ferrari A, Barzaghi MM, Pagani
C, Bortolotti A, et al.Perfluorocarbon broncho-alveolar
lavage and liquid ventilation versus saline broncho-alveolar
lavage in adult guinea pig experimental model of meconium
inhalation. Intensive Care Med 1998;24(5):5018.
Maturana 2005
Maturana A, Torres-Pereyra J, Salinas R, Astudillo P, Moya
FR, The Chile Surf Group. A randomized trial of natural
surfactant for moderate to severe meconium aspiration
syndrome. PAS. 2005; Vol. 57:1545.
Mosca 1996
Mosca F, Colnaghi M, Castoldi F. Lung lavage with a saline
volume similar to functional residual capacity followed
by surfactant administration in newborns with severe
meconium aspiration syndrome. Intensive Care Med 1996;
22(12):14123.
Moses 1991
Moses D, Holm BA, Spitale P, Liu MY, Enhorning G.
Inhibition of pulmonary surfactant function by meconium.
American Journal of Obstetrics and Gynecology 1991;164(2):
47781.
Ohama 1994
Ohama Y, Itakura Y, Koyama N, Eguchi H, Ogawa Y.
Effect of surfactant lavage in a rabbit model of meconium
aspiration syndrome. Acta Paediatrica Japonica 1994;36(3):
2368.
Ohama 1999
Ohama Y, Ogawa Y. Treatment of meconium aspiration
syndrome with surfactant lavage in an experimental rabbit
model. Pediatric Pulmonology 1999;28(1):1823.
Paranka 1992
Paranka MS, Walsh WF, Stancombe BB. Surfactant lavage
in a piglet model of meconium aspiration syndrome.
Pediatric Research 1992;31(6):6258.
RevMan 2011
The Nordic Cochrane Centre. The Cochrane Collaboration.
Review Manager (RevMan). 5.2. Copenhagan: The Nordic
Cochrane Centre. The Cochrane Collaboration, 2011.
Tran 1980
Tran N, Lowe C, Sivieri EM, Shaffer TH. Sequential effects
of acute meconium obstruction on pulmonary function.
Pediatric Research 1980;14(1):348.
Tyler 1978
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
meconium aspiration syndrome. Unresolved issues.
Pediatric Clinics of North America 1993;40(5):95581.
Wiswell 2000
Wiswell TE, Gannon CM, Jacob J, Goldsmith L, Szyld
E, Weiss K, et al.Delivery room management of the
apparently vigorous meconium-stained neonate: results of
11
12
CHARACTERISTICS OF STUDIES
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
Notes
Risk of bias
Bias
Authors judgement
Low risk
13
Dargaville 2011
(Continued)
Low risk
Low risk
Other bias
Low risk
Gadzinowski 2008
Methods
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
Not reported
Unclear risk
Low risk
Low risk
The study protocol is not available, and information is sufficient to permit judgement
Wiswell 2002
Methods
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
15
Wiswell 2002
(Continued)
Outcomes
Notes
Risk of bias
Bias
Authors judgement
Low risk
Not reported
Low risk
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
16
Study
Armenta 2011
Burke-Strickland 1973
Carson 1976
Randomisation of infants to receive saline lavage or no lavage mentioned in methods, but no results presented
Chang 2003
Dargaville 2007
Kowalska 2002
Lam 1999
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
Salvia-Roigs 2004
Nonrandomised study of two different treatment schedules involving lavage, compared with historical
controls
Schlsser 2002
Su 1998
Methods
RCT
Participants
Interventions
Outcomes
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
Notes
Segal 2012
Trial name or title
Phase III Randomized Study of Lucinactant in Full Term Newborn Infants with Meconium Aspiration
Syndrome
Methods
Participants
Interventions
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
18
Segal 2012
(Continued)
Contact information
Notes
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
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
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
Notes
19
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
Statistical method
Effect size
66
66
66
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
88
88
88
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)
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:
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 %
46
42
100.0 %
M-H,Fixed,95% CI
Risk Ratio
M-H,Fixed,95% CI
Not estimable
0.1 0.2
0.5
10
Favours control
Analysis 1.2. Comparison 1 Lung lavage versus standard care, Outcome 2 Use of ECMO.
Review:
Study or subgroup
Intervention
Control
n/N
n/N
Risk Ratio
Weight
Wiswell 2002
1/15
1/7
30.5 %
Dargaville 2011
0/11
3/14
69.5 %
26
21
100.0 %
M-H,Fixed,95% CI
Risk Ratio
M-H,Fixed,95% CI
0.01
0.1
10
100
Favours control
21
Analysis 1.3. Comparison 1 Lung lavage versus standard care, Outcome 3 Death or use of ECMO.
Review:
Study or subgroup
Intervention
Control
n/N
n/N
Risk Ratio
Weight
Wiswell 2002
1/15
1/7
11.7 %
Dargaville 2011
3/31
11/35
88.3 %
46
42
100.0 %
M-H,Fixed,95% CI
Risk Ratio
M-H,Fixed,95% CI
0.01
0.1
10
100
Favours control
Analysis 1.4. Comparison 1 Lung lavage versus standard care, Outcome 4 Pneumothorax.
Review:
Study or subgroup
Intervention
Control
n/N
n/N
Risk Ratio
Weight
Wiswell 2002
1/15
0/7
12.4 %
Dargaville 2011
1/31
5/35
87.6 %
46
42
100.0 %
M-H,Fixed,95% CI
Risk Ratio
M-H,Fixed,95% CI
0.01
0.1
10
100
Favours control
22
Analysis 1.5. Comparison 1 Lung lavage versus standard care, Outcome 5 Oxygenation index.
Review:
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 %
Dargaville 2011
31
16.3 (13.7)
35
17.7 (13.3)
75.2 %
100.0 %
1 measured at 24 hours
46
42
15
4.4 (4.3)
10.6 (13.8)
32.0 %
Dargaville 2011
31
10.3 (11.6)
35
16.5 (17.8)
68.0 %
100.0 %
46
42
15
3.3 (3.1)
8.4 (14.3)
23.2 %
Dargaville 2011
31
9.9 (11.7)
35
13 (12.7)
76.8 %
100.0 %
46
42
-20
-10
10
20
Favours control
23
Analysis 1.6. Comparison 1 Lung lavage versus standard care, Outcome 6 Alveolar-arterial oxygen
difference.
Review:
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
31
100.0 %
35
31
258 (222)
31
35
315 (216)
100.0 %
35
31
31
236 (189)
35
100.0 %
277 (190)
35
-200
-100
100
200
Favours control
24
Analysis 1.7. Comparison 1 Lung lavage versus standard care, Outcome 7 PaO2/FiO2.
Review:
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
31
35
100.0 %
100.0 %
100.0 %
31
188 (110)
31
35
161 (112)
35
31
31
187 (110)
35
161 (100)
100.0 %
35
-100
-50
Favours control
50
100
25
Analysis 2.1. Comparison 2 Lung lavage followed by surfactant bolus versus surfactant bolus, Outcome 1
Death.
Review:
Study or subgroup
Intervention
Control
n/N
n/N
0/7
2/6
100.0 %
100.0 %
Gadzinowski 2008
Risk Ratio
Weight
M-H,Fixed,95% CI
Risk Ratio
M-H,Fixed,95% CI
0.01
0.1
10
100
Favours control
Analysis 2.2. Comparison 2 Lung lavage followed by surfactant bolus versus surfactant bolus, Outcome 2
Pneumothorax.
Review:
Study or subgroup
Intervention
Control
n/N
n/N
0/7
2/6
100.0 %
100.0 %
Gadzinowski 2008
Risk Ratio
Weight
M-H,Fixed,95% CI
Risk Ratio
M-H,Fixed,95% CI
0.01
0.1
10
100
Favours control
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
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
Intervention
Control
Intervention
Control
6.6 2.6
7.3 1.7
16.4 5.4
19.8 2.9
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)
AaDO2 (0 hours)
575.6 91.0
589.5 95.8
261.0 160.9
352.3 177.5
178.3 144.0
226.0 239.8
27
HISTORY
Protocol first published: Issue 1, 2002
Review first published: Issue 4, 2013
Date
Event
Description
30 August 2011
20 July 2011
Amended
Authorship amended
2 May 2011
Amended
30 August 2005
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).
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.
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
29