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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.

http://www.thecochranelibrary.com/

http://www.thecochranelibrary.com/



T A B L E O F C O N T E N T S

1HEADER . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1 ABSTRACT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

2PLAIN LANGUAGE SUMMARY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

2BACKGROUND . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

3OBJECTIVES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .3METHODS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

6RESULTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

9DISCUSSION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

9 AUTHORS’ CONCLUSIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

10REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

12CHARACTERISTICS OF STUDIES . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

20DATA AND ANALYSES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Analysis 1.1. Comparison 1 Lung lavage versus standard care, Outcome 1 Death. . . . . . . . . . . . . . 21

Analysis 1.2. Comparison 1 Lung lavage versus standard care, Outcome 2 Use of ECMO. . . . . . . . . . . 21

Analysis 1.3. Comparison 1 Lung lavage versus standard care, Outcome 3 Death or use of ECMO. . . . . . . 22

Analysis 1.4. Comparison 1 Lung lavage versus standard care, Outcome 4 Pneumothorax. . . . . . . . . . . 22

Analysis 1.5. Comparison 1 Lung lavage versus standard care, Outcome 5 Oxygenation index. . . . . . . . . 23

Analysis 1.6. Comparison 1 Lung lavage versus standard care, Outcome 6 Alveolar-arterial oxygen difference. . . . 24 Analysis 1.7. Comparison 1 Lung lavage versus standard care, Outcome 7 PaO2/FiO2. . . . . . . . . . . . 25

Analysis 2.1. Comparison 2 Lung lavage followed by surfactant bolus versus surfactant bolus, Outcome 1 Death. . . 26

Analysis 2.2. Comparison 2 Lung lavage followed by surfactant bolus versus surfactant bolus, Outcome 2 Pneumothorax. 26

26 ADDITIONAL TABLES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

28HISTORY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

28CONTRIBUTIONS OF AUTHORS . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

28DECLARATIONS OF INTEREST . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

28SOURCES OF SUPPORT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

29DIFFERENCES BETWEEN PROTOCOL AND REVIEW . . . . . . . . . . . . . . . . . . . . .

29INDEX TERMS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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




[Intervention Review]

Lung lavage for meconium aspiration syndrome in newborninfants

Seokyung Hahn1, Hyun Jin Choi2 , Roger Soll3, Peter A. Dargaville4

1Department 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. 3Division of Neonatal-Perinatal Medicine, University of Vermont,

Burlington, Vermont, USA. 4 Department of Paediatrics, Royal Hobart Hospital, Hobart, Australia

Contact address: SeokyungHahn, Departmentof Medicine, Seoul NationalUniversityCollege of Medicine, 28 Yongon-dongChongno-

gu, Seoul, 110-744, Korea, South. [email protected].

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.


A B S T R A C T

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 purposeof 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.

1Lung lavage for meconium aspiration syndrome in newborn infants (Review)


mailto:[email protected]

mailto:[email protected]



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.

P L A I N L A N G U A G E S U M M A R Y

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.

B A C K G R O U N D

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 meco-

nium, the viscid secretion of the fetal intestine, occurs in up to15% of deliveries at term ( Wiswell 1993). Aspiration of meco-

nium 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, meco-

nium 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 hem-

orrhagic edema and exudation of plasma proteins into the alve-

olar space (Tyler 1978; Dargaville 2001). The function of pul-

monary surfactant may be secondarily impaired, both by meco-

nium (Moses 1991), and by plasma protein (Fuchimukai 1987).

In many infants with MAS, particularly those with coexisting as-

phyxia, 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 venti-

lated for MAS are often treated with exogenous surfactant, which

appears to reduce the use of extracorporeal membrane oxygena-

tion (ECMO), but has no clear effect on mortality (Findlay 1996;

Lotze 1998; El Shahed 2007). Data regarding the effect of bo-

lus 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 stud-

ies have revealed no evidence of an effect on pulmonary compli-

cations (Lotze 1998, Chinese Collaborative Study Group 2005;

Maturana 2005). Meta-analysis of the data from these trials sup-

ports 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 ex-

tends back to the early 1970s, when saline lavage was used in the

delivery room to improve clearanceof meconium from the airways

of meconium-stained babies (Burke-Strickland 1973). This tech-

nique 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 re-

ports of lung lavage in infants with established MAS subsequently

appeared (Ibara 1995; Mosca 1996), in which lavage with a totalvolumeof 20 to 40 mL/kg salinewas performed,followedby bolus

administration of natural surfactant. Improvement in oxygenation

and carbon dioxide (CO2) clearance was noted in each case. Sev-

eral 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 ven-

tilation in comparison with historical or concurrent controls (Su

1998; Lam 1999; Kowalska 2002; Schlösser 2002; Chang 2003;

Salvia-Roigés 2004; Dargaville 2007).

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 con-

siderable improvement in oxygenation and/or pulmonary me-

chanics, 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, surfac-

tant, andperfluorocarbon havebeen studied as potentiallavage flu-

ids. 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 salinealone, in terms of both pulmonary function post lavage

and removal of meconium from the lung. Lavage with perfluoro-

carbon 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).

Why it is important to do this review

At present, the therapeutic emphasis in MAS is on providing sup-

portive care, with little or no effort directed towards removal of

meconium from the lung as a means of halting disease progres-

sion. Recent data suggest that meconium can be safely removed

from the airspaces in MAS by lung lavage. The objective of thisreview 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 in-

fants with MAS.

O B J E C T I V E S

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.

M E T H O D S

Criteria for considering studies for this review

Types of studies

All randomised or quasi-randomised studies comparing therapeu-

tic lung lavage with standard care in the management of infants

with MAS.

Types of participants

Newborn infants with MAS (infants delivered through meco-

nium-stained amniotic fluid with early onset of respiratory dis-

tress, no other obvious cause for the distress, and either a charac-

teristic chest X-ray or meconium found beyond the vocal cords at

or after delivery). This review includes infants already intubated atthe 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





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

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.

The composite outcome of death or use of ECMO has been in-

cluded in recognition that mortality is influenced by the availabil-

ity of ECMO.

Secondary outcomes

• Indices of pulmonary function (including Oxygenation

Index, Alveolar-arterial oxygen difference, PF ratio) measured at

24, 48, and 72 hours.[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).

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 followingsources

were searched between 1966 and December 2012 for eligible stud-

ies in any language:

• 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, pul-monary surfactants, lung surfactant, fluorocarbons, bronchoalve-

olar lavage, lung lavage, and pulmonary lavage.

Searching other resources

We screened for trials in conference proceedings of annual meet-

ings of the American Thoracic Society, the Society for Pediatric

Research, the European Respiratory Society, and the European So-

ciety 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 un-

published trials using clinicaltrials.gov, controlled-trials.com, and

who.int/ictrp.

Data collection and analysis

We used the methods of the Cochrane Neonatal Review Group

for data collection and analysis.

Selection of studies

We included all randomised and quasi-randomised controlled tri-

als that fulfilled the selection criteria described in the previous sec-

tion. 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

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

collection of descriptive data on the study design, the study pop-

ulation (baseline characteristics and inclusion and exclusion cri-

teria), and the method of intervention (type of lavage fluid, total

lavage volume, aliquot volume, and lavage fluid concentration),

and quantitativedata regarding the outcome measures.Pneumoth-

orax was counted only if it occurred after randomisation.

Two review authors independently extracted the data from in-

cluded studies, and results were compared. The investigators of

included studies were asked to provide unpublished outcome data

where necessary.





Assessment of risk of bias in included studies

The quality of eligible studies was assessed using The Cochrane

Collaboration’s tool for assessing the risk of bias for randomised

controlled trials (RCTs) (Higgins 2011). Two review authors per-

formed the assessment, and they resolved any difference of opin-

ion 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 non-

opaque 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 study’s pre-

specified outcomes and all expected outcomes of interest to the

review have been reported).

◦ High risk (where not all of the study’s 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.





Assessment of heterogeneity

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).

Assessment of reporting biases

We planned to assess possible publication bias and other biases

using symmetry/asymmetry of funnel plots, but this was not ap-

plicable because an insufficient number of studies was included in

the meta-analysis for such an exploration.

For included trials that were recently performed (and there-

fore were prospectively registered), we explored possible selec-

tive reporting of study outcomes by comparing primary and sec-

ondary outcomes given in the reports versus primary and sec-ondary outcomes proposed at trial registration, using the Websites

www.clinicaltrials.gov and www.controlled-trials.com. If such dis-

crepancies were found, we planned to contact the primary investi-

gators 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 sup-

plied by The Cochrane Collaboration. We used the Mantel-Haen-

szel method to obtain estimates of typical relative risk and risk

difference. A fixed-effect model was primarily used for the meta-analysis 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.

R E S U L T S

Description of studies

See: Characteristicsof included studies; Characteristicsof 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 andare 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

identicallavage 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 phospho-lipid 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 endotra-

cheal tube while positive end-expiratory pressure continued, fol-

lowed by closed endotracheal suctioning for 10 seconds, during

which positive-pressure ventilation was re-instituted. The infant’s

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 H2O 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 cri-

terion (OI > 25 or OI 50% above baseline) had to be reached be-

fore 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 H2O and an alveolar-





arterial O2 difference (AaDO2) of at least 450 mmHg on two se-

quential blood gases. Surfactant lavage was performed at a mean

age of 13 hours using two aliquots of 15 mL/kg of bovine sur-

factant (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 wasthe decision to refer to ECMO.

Gadzinowski 2008 performed a randomised controlledtrial of sur-

factant 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 hyper-

tension 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 phos-

pholipid 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; Schlösser 2002; Kowalska 2002; Chang 2003; Salvia-Roigés

2004; Dargaville 2007; Armenta 2011). The rationale for exclu-

sion 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 drawinga randomisationslip froma closedenvelope,

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 al-

location. 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 scheduledsix lavage aliquots, andanother received only

two aliquots. For the purposes of analysis, allinfants were includedin 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 infor-

mation 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.Inonestudy(Dargaville 2011),only25 ofthe 66enrolled

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 (typ-

ical 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





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); median5.0versus6.3 days ( Wiswell 2002); median4.6 versus7.6 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 effectsIn one study ( Wiswell 2002), the instillation and recovery of the

six lavage aliquots took 50 to 60 minutes. In two infants the hy-

poxaemia 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 oc-

currence 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 saturationbelow 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, car-

diopulmonary 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 ver-

sus surfactant bolus therapy for MAS with pulmonary hyperten-

sion (Gadzinowski 2008).Death (Outcome 2.1)

Nodifference in therelative risk of mortalitywas 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

nonein the lavagegroup(RR0.17, 95% CI0.01 to3.06) ( Analysis

2.2).

Days of mechanical ventilation

The difference between mean values in days of mechanical venti-

lation 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 interven-

tion 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 belower than in the control group. Compliance and resistance are

not reported.

Adverse effectsExcept for pneumothorax and death, adverse effects were not re-

ported.

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 lavageThe mean age when lavage was performed was greater than six

hours in all included studies.





D I S C U S S I O N

Therapeutic lunglavage is an emergingtreatmentfor MAS,which,

by virtue of removal of meconium from the lung, would appear

to have a potential advantage over the supportive measures cur-

rently employed for thiscondition. Thisreview 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 dif-

ference 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 washalted because of concern regarding hypoxaemia or hypotension

( Wiswell 2002). In the other study, the lavage procedure was com-

pleted 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) (Dargaville2011). 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 surfac-

tant 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 infantsrandomly assigned,the evidenceregarding lung

lavage in MAS is thought to be insufficient to allow firm conclu-

sions, although a beneficial effect is noted in some important out-

comes. A recent systematic review focusing on surfactant lavage

therapy reviewed existing RCTs together with non-randomisedcontrolled studies for supporting evidence; the results of meta-

analysis 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 toproperly 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 compar-

ing 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 ef-

fect of surfactant lavage compared with standard care is registered.

A U T H O R S ’ C O N C L U S I O N S

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 controlledclinical trialsof lung lavagein 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.





R E F E R E N C E S

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C H A R A C T E R I S T I C S O F S T U D I E S

Characteristics of included studies [ordered by study ID]

Dargaville 2011

Methods International multicenter randomised controlled trial. 13 participating centres. Ran-

domisation 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 H2O and an alveolar-arterial oxygen difference of at least 450 mmHg

on two sequential blood gases. Subsequent improvement in oxygenation was allowableas 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 phos-

pholipid 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 durationof 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

bias)

Low risk Randomly permuted blocks of two or four,

stratified by study centre

Allocation concealment (selection bias) Low risk Pre-prepared sequentially numbered sealed

opaque envelopes





Dargaville 2011 (Continued)

Blinding of participants and personnel

(performance bias)

All outcomes

High risk Blinding of the intervention was not possi-

ble

Blinding of outcome assessment (detection

bias)

All outcomes

Low risk 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 study’s 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 clinicalteam or assessors of longer-termoutcomes. 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 echocardiographicparameters. Seven infants received surfactant lavage followed by bolus surfactant treat-

ment, 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 treat-

ment; length of hospital stay; complications; and mortality

Notes

Risk of bias





Gadzinowski 2008 (Continued)


Random sequence generation (selectionbias)

Unclear risk The study is described as randomised, butno information is provided about the se-

quence generation method

Allocation concealment (selection bias) Unclear risk Not reported


(performance bias)

All outcomes

Unclear risk Not reported (each group of infants was

managed by a different group of neonatol-

ogists)


bias)

All outcomes


means


All outcomes

Low risk Complete data were available for all en-

rolled infants

Selective reporting (reporting bias) Low risk The study protocol is not available, and in-

formationis 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 outcomesComplete follow-up with assessment up to one year of age

Participants 22 infants (enrolledinnine 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





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 ther-apies (HFOV, bolus surfactant, iNO, ECMO), duration of ventilation

Longer-term outcomes: survival at 12 months, numbers of hospitalizations and respira-

tory illnesses in the first year of life, growth and development at 12 months

Notes

Risk of bias


Random sequence generation (selection

bias)

Unclear risk The study is described as randomised, but

no information about the sequence gener-

ation method is provided

Allocation concealment (selection bias) Low risk Randomisation was performed by drawing

a randomisation slip from a closedenvelope


(performance bias)

All outcomes

Unclear risk Not reported


bias)

All outcomes


means


All outcomes

Low risk ITT analysis was carried out

Selective reporting (reporting bias) Unclear risk The study protocol is not available, and in-

formationis sufficient to permit judgement

Other bias High risk (1) The study was conducted without a for-

malsample 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 in-

fants with treatment failures, although res-cue therapies were not allowed unless in-

fants met treatment failure





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 ofinfantsto receive salinelavage orno lavagementionedinmethods,butno 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-Roigés 2004 Nonrandomised study of two different treatment schedules involving lavage, compared with historical

controls

Schlösser 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.





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, [email protected] .

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





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, dura-

tion of hospital stay

Starting date 2011

Contact information Sushma Nangia, MBBS, MD, DM [email protected] Saran Children’s Hospital, Lady Hardinge Medical College

Notes clinical trials.gov. identifier NCT01310621





D A T A A N D A N A L Y S E S

Comparison 1. Lung lavage versus standard care

Outcome or subgroup titleNo. of

studies

No. of

participants Statistical method Effect size

1 Death 2 88 Risk Ratio (M-H, Fixed, 95% CI) 0.42 [0.12, 1.46]

2 Use of ECMO 2 47 Risk Ratio (M-H, Fixed, 95% CI) 0.27 [0.04, 1.86]

3 Death or use of ECMO 2 88 Risk Ratio (M-H, Fixed, 95% CI) 0.33 [0.11, 0.96]

4 Pneumothorax 2 88 Risk Ratio (M-H, Fixed, 95% CI) 0.38 [0.08, 1.90]

5 Oxygenation index 2 Mean Difference (IV, Fixed, 95% CI) Subtotals only

5.1 measured at 24 hours 2 88 Mean Difference (IV, Fixed, 95% CI) -1.90 [-7.56, 3.77]

5.2 measured at 48 hours 2 88 Mean Difference (IV, Fixed, 95% CI) -6.20 [-12.11, -0.29]


6 Alveolar-arterial oxygen

difference

1 Mean Difference (IV, Fixed, 95% CI) Subtotals only

6.1 measured at 24 hours 1 66 Mean Difference (IV, Fixed, 95% CI) -12.0 [-109.19, 85.

19]


96]


59]

7 PaO2/FiO2 1 Mean Difference (IV, Fixed, 95% CI) Subtotals only


7.2 measured at 48 hours 1 66 Mean Difference (IV, Fixed, 95% CI) 27.0 [-26.63, 80.63]

7.3 measured at 72 hours 1 66 Mean Difference (IV, Fixed, 95% CI) 26.0 [-24.96, 76.96]

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

Outcome or subgroup titleNo. of

studies

No. of

participants Statistical method Effect size

1 Death 1 13 Risk Ratio (M-H, Fixed, 95% CI) 0.18 [0.01, 3.06]

2 Pneumothorax 1 13 Risk Ratio (M-H, Fixed, 95% CI) 0.18 [0.01, 3.06]





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 Risk Ratio Weight Risk Ratio

n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI

Wiswell 2002 0/15 0/7 Not estimable

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 ]

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 1 2 5 10

Favours lung lavage Favours control

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



Outcome: 2 Use of ECMO



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 ]


Heterogeneity: Chi2 = 0.25, df = 1 (P = 0.62); I2 =0.0%



0.01 0.1 1 10 100






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



Outcome: 3 Death or use of ECMO



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 ]





0.01 0.1 1 10 100


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



Outcome: 4 Pneumothorax



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 ]





0.01 0.1 1 10 100






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



Outcome: 5 Oxygenation index

Study or subgroup Inter vention ControlMean

Difference WeightMean

Difference

N Mean(SD) N Mean(SD) IV,Fixed,95% CI IV,Fixed,95% CI

1 measured at 24 hours

Wiswell 2002 15 6.2 (15.5) 7 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 ]

Subtotal (95% CI) 46 42 100.0 % -1.90 [ -7.56, 3.77 ]




Wiswell 2002 15 4.4 (4.3) 7 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 ]

Subtotal (95% CI) 46 42 100.0 % -6.20 [ -12.11, -0.29 ]




Wiswell 2002 15 3.3 (3.1) 7 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 ]

Subtotal (95% CI) 46 42 100.0 % -3.56 [ -8.72, 1.60 ]



-20 -10 0 10 20






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

difference.



Outcome: 6 Alveolar-arterial oxygen difference



Difference



Dargaville 2011 31 358 (202) 35 370 (200) 100.0 % -12.00 [ -109.19, 85.19 ]

Subtotal (95% CI) 31 35 100.0 % -12.00 [ -109.19, 85.19 ]




Dargaville 2011 31 258 (222) 35 315 (216) 100.0 % -57.00 [ -162.96, 48.96 ]

Subtotal (95% CI) 31 35 100.0 % -57.00 [ -162.96, 48.96 ]




Dargaville 2011 31 236 (189) 35 277 (190) 100.0 % -41.00 [ -132.59, 50.59 ]

Subtotal (95% CI) 31 35 100.0 % -41.00 [ -132.59, 50.59 ]



-200 -100 0 100 200






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



Outcome: 7 PaO2/FiO2



Difference



Dargaville 2011 31 148 (109) 35 149 (113) 100.0 % -1.00 [ -54.61, 52.61 ]

Subtotal (95% CI) 31 35 100.0 % -1.00 [ -54.61, 52.61 ]




Dargaville 2011 31 188 (110) 35 161 (112) 100.0 % 27.00 [ -26.63, 80.63 ]

Subtotal (95% CI) 31 35 100.0 % 27.00 [ -26.63, 80.63 ]




Dargaville 2011 31 187 (110) 35 161 (100) 100.0 % 26.00 [ -24.96, 76.96 ]

Subtotal (95% CI) 31 35 100.0 % 26.00 [ -24.96, 76.96 ]



-100 -50 0 50 100

Favours control Favours lung lavage





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

Death.


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

Outcome: 1 Death



Gadzinowski 2008 0/7 2/6 100.0 % 0.18 [ 0.01, 3.06 ]

Total (95% CI) 7 6 100.0 % 0.18 [ 0.01, 3.06 ]





0.01 0.1 1 10 100


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

Pneumothorax.


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

Outcome: 2 Pneumothorax



Gadzinowski 2008 0/7 2/6 100.0 % 0.18 [ 0.01, 3.06 ]

Total (95% CI) 7 6 100.0 % 0.18 [ 0.01, 3.06 ]





0.01 0.1 1 10 100








H I S T O R Y

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

C O N T R I B U T I O N S O F A U T H O R S

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.

D E C L A R A T I O N S O F I N T E R E S T

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).





S O U R C E S O F S U P P O R T

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.

D I F F E R E N C E S B E T W E E N P R O T O C O L A N D R E V I E W

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.

I N D E X T E R M S

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



Documents

Lung Lavage 2013 MAS