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Lung lavage for meconium aspiration syndrome in newborn infants

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Authors

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

Background - Methods - Results - Characteristics of Included Studies - References - Data Tables & Graphs


1Department of Medicine, Seoul National University College of Medicine, Seoul, Korea, South [top]
2Department of Preventive Medicine, Seoul National University College of Medicine, Seoul, Korea, South [top]
3Division of Neonatal-Perinatal Medicine, University of Vermont, Burlington, Vermont, USA [top]
4Department of Paediatrics, Royal Hobart Hospital, Hobart, Australia [top]

Citation example: 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.

Contact person

Seokyung Hahn

Department of Medicine
Seoul National University College of Medicine
28 Yongon-dong Chongno-gu
110-744 Seoul
Korea, South

E-mail: hahns@snu.ac.kr

Dates

Assessed as Up-to-date: 15 February 2013
Date of Search: 01 December 2012
Next Stage Expected: 15 February 2015
Protocol First Published: Issue 1, 2002
Review First Published: Issue 4, 2013
Last Citation Issue: Issue 4, 2013

What's new

Date / Event Description

History

Date / Event Description
30 August 2011
New citation: conclusions changed

Search updated, studies added, analyses and texts amended

20 July 2011
Amended

Authorship amended

02 May 2011
Amended

Converted to new review format.

30 August 2005
New citation: conclusions changed

Substantive amendment

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.

Results

Only four small randomised controlled trials fulfilled the selection criteria. For one of these trials, no data are available for the control group. Two studies compared lavage using diluted surfactant with standard care. Meta-analysis of these two studies did not show a significant effect on mortality (typical relative risk 0.42, 95% confidence interval [CI] 0.12 to 1.46; typical risk difference -0.10, 95% CI -0.24 to 0.04) or the use of ECMO (typical relative risk 0.27, 95% CI 0.04 to 1.86; typical risk difference -0.15, 95% CI -0.35 to 0.04). For the composite outcome of death or use of ECMO, a significant effect favoured the lavage group (typical relative risk 0.33, 95% CI 0.11 to 0.96; typical risk difference -0.19, 95% CI -0.34 to -0.03; number needed to benefit [NNTB] 5). No other benefits were reported. The other published study compared surfactant lavage followed by a surfactant bolus with surfactant bolus therapy alone in MAS complicated by pulmonary hypertension. No significant improvements in mortality, pneumothorax, duration of mechanical ventilation. or duration of hospitalisation were observed.

Authors' conclusions

In infants with meconium aspiration syndrome, lung lavage with diluted surfactant may be beneficial, but additional controlled clinical trials of lavage therapy should be conducted to confirm the treatment effect, to refine the method of lavage treatment, and to compare lavage treatment with other approaches, including surfactant bolus therapy. Long-term outcomes should be evaluated in further clinical trials.

Plain language summary

Lung lavage for meconium aspiration syndrome in newborn infants

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

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Background

Description of the condition

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

Description of the intervention

In human infants, the history of lavage as a therapy for MAS extends back to the early 1970s, when saline lavage was used in the delivery room to improve clearance of meconium from the airways of meconium-stained babies (Burke-Strickland 1973). This technique was largely abandoned as a result of the increase in numbers of infants with transient tachypnoea after saline lavage, ascribed to lavage fluid retention in the lung (Carson 1976). Isolated reports of lung lavage in infants with established MAS subsequently appeared (Ibara 1995; Mosca 1996), in which lavage with a total volume of 20 to 40 mL/kg saline was performed, followed by bolus administration of natural surfactant. Improvement in oxygenation and carbon dioxide (CO2) clearance was noted in each case. Several research groups have reported their experience of lavage with dilute surfactant in ventilated infants with MAS, on the whole suggesting improvements in oxygenation and/or duration of ventilation in comparison with historical or concurrent controls (Su 1998; Lam 1999; Kowalska 2002; 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 considerable improvement in oxygenation and/or pulmonary mechanics, associated with removal of one-third to one-half of the meconium lodged in the airspaces (Paranka 1992; Ohama 1994; Cochrane 1998; Ohama 1999; Dargaville 2003). Saline, surfactant, and perfluorocarbon have been studied as potential lavage fluids. Comparative data suggest that exogenous surfactant, whether at full strength (Paranka 1992) or diluted in saline (Ohama 1994; Cochrane 1998; Ohama 1999), is a more effective lavage fluid than saline alone, in terms of both pulmonary function post lavage and removal of meconium from the lung. Lavage with perfluorocarbon appears to be superior to saline lavage (Marraro 1998) but less effective than dilute surfactant lavage (Dargaville 2003). The volume of each lavage aliquot is another determinant of lavage efficacy, with aliquot volumes of 15 mL/kg being more effective than multiple 2- to 3-mL aliquots (Dargaville 2003), or aliquots of 8 mL/kg (Dargaville 2008).

Why it is important to do this review

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

Objectives

To evaluate the effects of lung lavage on morbidity and mortality in newborn infants with MAS.

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

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Methods

Criteria for considering studies for this review

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 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 included in recognition that mortality is influenced by the availability 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 following sources were searched between 1966 and December 2012 for eligible studies 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, pulmonary surfactants, lung surfactant, fluorocarbons, bronchoalveolar lavage, lung lavage, and pulmonary lavage.

Searching other resources

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 External Web Site Policy, and WHO International Clinical Trials Registry Platform (ICTRP) External Web Site Policy.

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

Data extraction and management

We used a standard form for data extraction, which included a collection of descriptive data on the study design, the study population (baseline characteristics and inclusion and exclusion criteria), and the method of intervention (type of lavage fluid, total lavage volume, aliquot volume, and lavage fluid concentration), and quantitative data regarding the outcome measures. Pneumothorax was counted only if it occurred after randomisation.

Two review authors independently extracted the data from included studies, and results were compared. The investigators of included studies were asked to provide unpublished outcome data where necessary.

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 performed the assessment, and they resolved any difference of opinion by involving coauthors in the discussion.

The methodological quality of the studies was assessed using the following criteria:

  • Sequence generation (checking for possible selection bias): For each included study, we categorized the method used to generate the allocation sequence as follows:
    • Low risk (any truly random process, e.g. random number table; computer random number generator).
    • High risk (any nonrandom process, e.g. odd or even date of birth; hospital or clinic record number).
    • Unclear risk.
  • Allocation concealment (checking for possible selection bias): For each included study, we categorized the method used to conceal the allocation sequence as follows:
    • Low risk (e.g. telephone or central randomisation; consecutively numbered sealed opaque envelopes).
    • High risk (open random allocation; unsealed or 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 (greater than/or equal to 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 applicable because an insufficient number of studies was included in the meta-analysis for such an exploration.

For included trials that were recently performed (and therefore were prospectively registered), we explored possible selective reporting of study outcomes by comparing primary and secondary outcomes given in the reports versus primary and secondary outcomes proposed at trial registration, using the Websites ClinicalTrials.gov and Controlled-Trials.com External Web Site Policy. If such discrepancies were found, we planned to contact the primary investigators to obtain missing outcome data on outcomes pre-specified at trial registration.

Data synthesis

Where meta-analysis was judged to be appropriate, the analysis was done using Review Manager software (RevMan 2011), as supplied by The Cochrane Collaboration. We used the Mantel-Haenszel method to obtain estimates of typical relative risk and risk difference. A fixed-effect model was primarily used for the 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, greater than/or equal to 5 mL/kg).
  • Timing of lavage: early (< 6 hours of life) or late (greater than/or equal to 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.

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Results

Description of studies

Results of the search

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

Included studies

Three studies are included in this review (Wiswell 2002; Gadzinowski 2008; Dargaville 2011).

Wiswell 2002 performed a phase I/II randomised controlled trial of surfactant lavage in conventionally ventilated infants with MAS who were at least 35 weeks' gestation and less than 72 hours of age, and had an oxygenation index (OI) between 8 and 25 inclusive on two separate blood gas analyses within a three-hour period. Surfactant lavage was performed at a mean age of 14 hours using 6 aliquots of 8 mL/kg of KL4 (Surfaxin, Discovery Laboratories Inc, Doylestown, PA). The concentration of surfactant phospholipid was 2.5 mg/mL for the first four aliquots, and 10 mg/mL for the last two. Each lavage aliquot was instilled via the endotracheal tube while positive end-expiratory pressure continued, followed by closed endotracheal suctioning for 10 seconds, during which positive-pressure ventilation was re-instituted. The 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 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 H2O 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; Schlösser 2002; Kowalska 2002; Chang 2003; Salvia-Roigés 2004; Dargaville 2007; Armenta 2011). The rationale for exclusion is given in the table Characteristics of excluded studies.

Ongoing studies

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

Risk of bias in included studies

In the study by Wiswell et al (Wiswell 2002), randomisation was performed by drawing a randomisation slip from a closed envelope, with an allocation ratio of 2:1 (lavage:standard care). Treatment was not blinded to the clinical team, although the one-year follow-up was performed by an investigator who was blinded to the allocation. No exclusions were noted after randomisation, although three of the 15 infants randomly assigned to surfactant lavage did not receive the complete lavage series, two infants received only four of the scheduled six lavage aliquots, and another received only two aliquots. For the purposes of analysis, all infants were included in their respective allocation groups. Other bias may have existed in that the number of infants receiving rescue therapy exceeded the number reaching treatment failure criteria, even though rescue therapies were not permitted unless infants met treatment failure. The study was conducted without a formal sample size calculation and based on an estimate for assessing safety and potential efficacy in a rather exploratory fashion.

The study by Dargaville et al (Dargaville 2011) described an adequate process of randomisation and allocation concealment. Among 66 enrolled infants, one infant randomly assigned to the surfactant lavage group was too unstable to receive lavage and was deemed to have been ineligible for enrolment. The intervention was not blinded.

In the study by Gadzinowski et al (Gadzinowski 2008), no information is provided about random sequence generation, allocation concealment, and blinding of the intervention.

Effects of interventions

LUNG LAVAGE VERSUS STANDARD CARE (Comparison 1)

Two studies compared lung lavage with standard care (Dargaville 2011; Wiswell 2002).

Death (Outcome 1.1)

Both studies reported on mortality, and one RCT reported no events. No treatment effect on death was noted (typical RR 0.42, 95% CI 0.12 to 1.46; typical RD -0.10, 95% CI -0.24 to 0.04) (Analysis 1.1).

Use of ECMO (Outcome 1.2)

Both RCTs reported on the number of infants who needed ECMO. In one study (Dargaville 2011), only 25 of the 66 enrolled infants were treated at centres at which ECMO was available. No difference in the relative risk of ECMO was noted, although a trend toward an interventional benefit was observed (typical RR 0.27, 95% CI 0.04 to 1.86; typical RD -0.15, 95% CI -0.35 to 0.04) (Analysis 1.2).

Death or use of ECMO (Outcome 1.3)

For both studies, the numbers of infants who received ECMO or died could be calculated. Surfactant lavage significantly decreased the combined outcome of death or requirement for ECMO (typical RR 0.33, 95% CI 0.11 to 0.96: typical RD -0.19, 95% CI -0.34 to -0.03; NNTB 5) (Analysis 1.3). Each study showed a result favouring the intervention.

Pneumothorax (Outcome 1.4)

Both studies reported on pneumothorax, but not on other air leaks. No significant difference was observed between treatment groups (typical RR 0.38, 95% CI 0.08 to 1.90, typical RD -0.07, 95% CI -0.19 to 0.05) (Analysis 1.4).

Days of mechanical ventilation

Duration of ventilation showed wide variation in both studies. Median duration for mechanical ventilation was shorter in the intervention group for both studies (Dargaville 2011); median 5.0 versus 6.3 days (Wiswell 2002); median 4.6 versus 7.6 days) (Table 1).

Days of supplemental oxygen

Dargaville 2011 reported days of oxygen therapy only for survivors.The values were a little different between groups: (Dargaville 2011): median 14 versus 14 days (Wiswell 2002): mean 13.5 versus 12.1 days (Table 1).

Length of hospital stay

One study (Wiswell 2002) reported length of stay in the Neonatal Intensive Care Unit, which differed little between groups (mean 12.7 vs 13.1 days). In the other study, the length of hospital stay was similar in the two groups (Dargaville 2011): median 17 versus 19 days (Table 1).

Total cost of hospitalisation

None of the studies reported hospitalisation cost.

Indices of pulmonary function (Outcomes 1.5 and 1.6)

Both RCTs reported OI measured at 24, 48, and 72 hours. A significant difference between groups was observed at 48 hours after lavage treatment (WMD -6.20, 95% CI -12.11 to -0.29) (Analysis 1.5). AaDO2 and pulmonary function (PF) ratio were measured in one study (Dargaville 2011), which did not show any significant differences between groups, although better results appeared to be obtained in the treatment group over time after use of lavage therapy (Analysis 1.6). Lung mechanics were not reported in either study.

Adverse effects

In one study (Wiswell 2002), the instillation and recovery of the six lavage aliquots took 50 to 60 minutes. In two infants the hypoxaemia that occurred during lavage was sufficiently pronounced to halt the lavage procedure. Overall 5 of 15 infants required hand ventilation to recover oxygen saturation after lavage. In one other infant, the lavage procedure was stopped because of hypotension, although this infant had coincident gram-negative sepsis. The occurrence and severity of episodes of hypoxaemia or hypotension are not reported in the control group, and thus it is not possible to make direct comparisons between groups. In the other study (Dargaville 2011), two infants experienced transient bradycardia at less than 100 beats per minute during lavage, with recovery by five minutes after lavage. Five infants had an oxygen saturation below 80% for longer than 10 minutes, with recovery to above 90% within 40 minutes in all cases. Six infants needed treatment for hypotension during or immediately after lavage. Overall, cardiopulmonary indices were affected transiently, and the lavaged infants and the control infants showed similar blood gas indices at four hours post lavage. One infant died of intractable pulmonary hypertension three hours after lavage.

LUNG LAVAGE FOLLOWED BY SURFACTANT BOLUS VERSUS SURFACTANT BOLUS THERAPY FOR MAS WITH PULMONARY HYPERTENSION (Comparison 2)

One study compared lung lavage followed by surfactant bolus versus surfactant bolus therapy for MAS with pulmonary hypertension (Gadzinowski 2008).

Death (Outcome 2.1)

No difference in the relative risk of mortality was noted; two deaths were reported in the control group versus none in the lavage group (RR 0.17, 95% CI 0.01 to 3.06) (Analysis 2.1).

Pneumothorax (Outcome 2.2)

No difference in the relative risk of pneumothorax was noted; two episodes of pneumothorax were reported in the control group but none in the lavage group (RR 0.17, 95% CI 0.01 to 3.06) (Analysis 2.2).

Days of mechanical ventilation

The difference between mean values in days of mechanical ventilation was less than one day (mean ± standard deviation [SD] 6.6 ± 2.6 vs 7.3 ± 1.7 days) (Table 2).

Length of the hospital stay

The length of hospital stay appeared to be shorter in the intervention group (mean ± SD: 16.4 ± 5.4 vs 19.8 ± 2.9 days) (Table 2).

Indices of pulmonary function

As a result of the small size of the study (7 vs 6 for treatment vs control) and the skewed nature of the data (large difference between reported mean and median values), we did not assess the significance based on the test of means but just descriptively presented the results (Table 3). The median value of OI measured at 24 hours in the surfactant lavage group was lower than that in the control group (2.8 vs 9.0). The OI measured at 48 hours was, however, similar between groups (median 1.7 vs 1.8). AaDO2 measured at 24 and 48 hours in the lavage group appeared to be lower than in the control group. Compliance and resistance are not reported.

Adverse effects

Except for pneumothorax and death, adverse effects were not reported.

SUBGROUP ANALYSES

None of the planned subgroup analyses were possible.

Type of lavage fluid

All included studies used diluted surfactant for lavage.

Lavage aliquot volume

The aliquot volume was at least 5 mL/kg in all studies comparing surfactant lavage with standard care, and less than 5 mL/kg in the study comparing surfactant lavage followed by bolus surfactant with surfactant bolus therapy.

Timing of lavage

The mean age when lavage was performed was greater than six hours in all included studies.

Discussion

Therapeutic lung lavage is an emerging treatment for MAS, which, by virtue of removal of meconium from the lung, would appear to have a potential advantage over the supportive measures currently employed for this condition. This review has identified three small randomised controlled trials of lung lavage using surfactant (Wiswell 2002; Gadzinowski 2008; Dargaville 2011).

In the meta-analysis of the trials comparing surfactant lavage and standard care (Wiswell 2002; Dargaville 2011), a significant difference was noted in the composite outcome of death or use of ECMO. Analysis of this outcome was necessary given that the availability of ECMO clearly affects mortality. Any other primary outcomes including mortality, pneumothorax, or use of ECMO did not demonstrate a significant benefit. Among the secondary outcomes examining pulmonary function, only OI at 48 hours was improved significantly in the surfactant lavage group. In one study in which a large total volume of lavage fluid was used, the lavage procedure was relatively protracted and in some cases was halted because of concern regarding hypoxaemia or hypotension (Wiswell 2002). In the other study, the lavage procedure was completed in all infants, but some experienced transient bradycardia and hypotension.

The two studies comparing surfactant lavage with standard care varied considerably in the severity of disease of enrolled infants at the time of recruitment (Wiswell 2002; Dargaville 2011). In the study of Wiswell et al, infants with MAS of lesser severity were targeted (mean OI 12 at enrolment), and no deaths and relatively rapid weaning from ventilation were noted, in particular in the lung lavage group. By contrast, the other study focused on infants with severe disease (mean OI 25 at enrolment) (Dargaville 2011). In this case, no difference was discernible in duration of mechanical ventilation, which was relatively prolonged in both groups, but fewer infants who underwent lavage died or required ECMO. This suggests that lung lavage has the greatest potential for benefit in infants with severe disease, although the possibility of an impact in milder cases on duration of ventilation or other pulmonary outcomes needs further exploration.

The study comparing surfactant lavage followed by bolus surfactant with surfactant bolus therapy (Gadzinowski 2008) did not show an effect on mortality, pneumothorax, days on mechanical ventilation, or length of hospital stay. The intervention seemed to improve oxygenation, with a lower OI at 24 hours.

Because of the small number of RCTs and the lack of sufficient numbers of infants randomly assigned, the evidence regarding lung lavage in MAS is thought to be insufficient to allow firm conclusions, although a beneficial effect is noted in some important outcomes. A recent systematic review focusing on surfactant lavage therapy reviewed existing RCTs together with non-randomised controlled studies for supporting evidence; the results of 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 to properly evaluate the safety and efficacy of this treatment. A phase III RCT (Segal 2012) evaluating the effect of surfactant lavage compared with standard care had been registered, and is recorded to have been terminated without completion. One trial comparing lavage with diluted surfactant versus standard care is currently under way (McNamara 2006) and is aiming to recruit 60 infants. Another trial (Sur-Lu-Lav 2011) undertaken to investigate the effect of surfactant lavage compared with standard care is registered.

Authors' conclusions

Implications for practice

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

Implications for research

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

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).

Differences between protocol and review

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

Potential conflict of interest

  • None noted.

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Characteristics of studies

Characteristics of Included Studies

Dargaville 2011

Methods

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

Participants

66 infants from 13 participating centres, who were of at least 36 weeks' gestation and 2 kg birth weight, less than 24 hours of age, with a diagnosis of MAS. The infants were eligible for enrolment if they were mechanically ventilated with mean airway pressure of at least 12 cm H2O and an alveolar-arterial oxygen difference of at least 450 mmHg on two sequential blood gases. Subsequent improvement in oxygenation was allowable as long as FiO2 remained > 0.5 before randomisation. One infant randomly assigned to the lavage group who did not receive lavage was found to be ineligible because of cardiopulmonary instability. 30 infants received surfactant lavage and 35 received no lavage

Interventions

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

Outcomes

Primary outcome: duration of respiratory support, defined as the cumulative duration of all periods of intubation and nasal continuous positive airway pressure (CPAP)
Secondary outcomes: death, pneumothorax, duration of intubation, oxygen therapy, HFOV, iNO, hospitalisation

Evaluation of the physiologic effects and safety of lavage: heart rate, mean blood pressure, SpO2, blood gas analyses

Notes
Risk of bias table
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

Blinding of participants and personnel (performance bias) High risk

Blinding of the intervention was not possible

Blinding of outcome assessment (detection bias) Low risk

All outcomes were measured by objective means

Incomplete outcome data (attrition bias) 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 clinical team or assessors of longer-term outcomes. Complete follow-up with assessment up to two years of age

Participants

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

Interventions

Surfactant lavage with a total lavage volume of 15 mL/kg (aliquot volume 3.75 mL/kg) of bovine surfactant (Survanta) at a phospholipid concentration of 5 mg/mL. Lavage was conducted via a closed lavage and suctioning system, in four body positions: on the right and left sides, and in the Trendelenburg and anti-Trendelenburg positions

After 2 mL of the solution was instilled, mechanical ventilation was continued
After 3 to 5 respiratory cycles, the secretions were suctioned
After lavage treatment, one dose of bolus Survanta (100 mg/kg) was given. Heart rate and oxygen saturation were monitored

Outcomes

Primary outcome: (1) PaO2; (2) fraction of inspired oxygen; (3) oxygenation index; and (4) alveolar–arterial oxygen difference

Secondary outcomes: length of time on mechanical ventilation; duration of iNO treatment; length of hospital stay; complications; and mortality

Notes
Risk of bias table
Bias Authors' judgement Support for judgement
Random sequence generation (selection bias) Unclear risk

The study is described as randomised, but no information is provided about the sequence generation method

Allocation concealment (selection bias) Unclear risk

Not reported

Blinding of participants and personnel (performance bias) Unclear risk

Not reported (each group of infants was managed by a different group of neonatologists)

Blinding of outcome assessment (detection bias) Low risk

All outcomes were measured by objective means

Incomplete outcome data (attrition bias) Low risk

Complete data were available for all enrolled infants

Selective reporting (reporting bias) Low risk

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

Other bias Unclear risk

Wiswell 2002

Methods

Multicenter randomised controlled trial

15 participating centres

Randomisation blinded, with a 2:1 allocation ratio (lavage vs control). Intervention not blinded to clinical team or assessors of longer-term outcomes

Complete follow-up with assessment up to one year of age

Participants

22 infants (enrolled in nine participating centres) of gestational age > 34 weeks, postnatal age up to 72 hours, with a diagnosis of MAS requiring mechanical ventilation

The infants were eligible for enrolment if oxygenation index (OI) was between 8 and 25, inclusive, on at least two of three consecutive blood gas analyses within a three-hour period

15 infants received surfactant lavage and 7 received standard care

Interventions

Lung lavage with a total lavage volume of 48 mL/kg, divided into 6 aliquots each of 8 mL/kg

Lavage fluid was lucinactant (Surfaxin), at a phospholipid concentration of 2.5 mg/mL for the first four lavage aliquots, and 10 mg/mL for the last two aliquots

Each aliquot was instilled down the endotracheal tube with the chest alternately left and right side down, with suctioning after each instillation using a closed suctioning system

Recovery of blood pressure, heart rate, and oxygen saturation was mandated before proceeding with further lavage aliquots

Outcomes

Primary outcome: incidence of treatment failure, defined as an OI > 25 or an increase in OI of 50% above baseline
Secondary outcomes: MAS-related mortality, oxygenation changes, need for rescue therapies (HFOV, bolus surfactant, iNO, ECMO), duration of ventilation

Longer-term outcomes: survival at 12 months, numbers of hospitalizations and respiratory illnesses in the first year of life, growth and development at 12 months

Notes
Risk of bias table
Bias Authors' judgement Support for judgement
Random sequence generation (selection bias) Unclear risk

The study is described as randomised, but no information about the sequence generation method is provided

Allocation concealment (selection bias) Low risk

Randomisation was performed by drawing a randomisation slip from a closed envelope

Blinding of participants and personnel (performance bias) Unclear risk

Not reported

Blinding of outcome assessment (detection bias) Low risk

All outcomes were measured by objective means

Incomplete outcome data (attrition bias) Low risk

ITT analysis was carried out

Selective reporting (reporting bias) Unclear risk

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

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

Characteristics of excluded studies

Armenta 2011

Reason for exclusion

Surfactant lavage was compared with saline lavage

Burke-Strickland 1973

Reason for exclusion

Nonrandomised case series

Carson 1976

Reason for exclusion

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

Chang 2003

Reason for exclusion

Nonrandomised study over two time epochs

Dargaville 2007

Reason for exclusion

Nonrandomised study with concurrent controls

Kowalska 2002

Reason for exclusion

Nonrandomised study over two time epochs

Lam 1999

Reason for exclusion

Nonrandomised study over two time epochs

Ogawa 1997

Reason for exclusion

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

Reason for exclusion

Nonrandomised study with concurrent controls

Salvia-Roigés 2004

Reason for exclusion

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

Schlösser 2002

Reason for exclusion

Nonrandomised study with concurrent controls

Su 1998

Reason for exclusion

Nonrandomised study, no control group

Characteristics of ongoing studies

McNamara 2006

Study name

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.
Change in dynamic pulmonary compliance from baseline to one and six hour after treatment.
Change in pulmonary artery pressure from baseline to one and six hour after treatment.
Measures of efficacy of ventilation and oxygenation at one hour and six hours after treatment.
Cardiac function by echocardiography at six hours after treatment.

Secondary outcome measures:

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

Starting date

2006

Contact information

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

The Hospital for Sick Children, Toronto, Ontario, Canada

Notes

clinical trials.gov. identifier NCT00312507

Segal 2012

Study name

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

Contact information

Robert Segal; Discovery Laboratory

Notes

Clinical trials.gov. identifier NCT00004500.

Sponsored by Discovery Laboratories

Sur-Lu-Lav 2011

Study name

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 greater than/or equal to 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 greater than/or equal to 4)
  • Presence of meconium below vocal cords or chest x-ray; suggestive of meconium aspiration
  • Age < 2 hours

Exclusion criteria:

  • Major congenital malformations
  • Congenital heart disease
  • Hydrops fetalis
  • Air leaks
  • Pulmonary haemorrhage
Interventions

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

The diluted surfactant is instilled into the endotracheal tube over a period of 15 to 20 seconds

Once the instillation is complete, 5 manual breaths will be provided and the infant will be repositioned supine

The suction catheter will be inserted and advanced to a position approximately 5 mm past the end of the endotracheal tube

Outcomes

Primary outcome: duration of oxygen therapy, severity of respiratory distress, need for mechanical ventilation

Secondary outcome: duration of mechanical ventilation, complications, incidence of sepsis, mortality, duration of hospital stay

Starting date

2011

Contact information

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

Kalawati Saran Children's Hospital, Lady Hardinge Medical College

Notes

clinical trials.gov. identifier NCT01310621

Additional tables

1 Results of continuous variables (lung lavage versus standard care)

Study

Number of infants

(i/c)

Days of mechanical ventilation

Days of supplemental oxygen

Length of hospital stay (days)

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

Footnotes

i = intervention group; c = control group.
All variables expressed by mean ± standard deviation or median (interquartile range). Data from the survivors were used.

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

Study

Number of infants

(i/c)

Days of mechanical ventilation

Length of hospital stay (days)

Intervention

Control

Intervention

Control

Gadzinowski 2008

7/6

6.6 ± 2.6

7.3 ± 1.7

16.4 ± 5.4

19.8 ± 2.9

Footnotes

i = intervention group; c = control group.
All variables expressed by mean ± standard deviation.

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

Gadzinowski 2008

Intervention (n = 7)

Control (n = 6)

Oxygenation index (0 hours)

29.8 ± 12.5 (median 25)

32.4 ± 25 (median 24.3)

Oxygenation index (24 hours)

2.7 ± 2.2 (median 2.8)

10.4 ± 8.1 (median 9.0)

Oxygenation index (48 hours)

5.0 ± 9.1 (median 1.7)

5.7 ± 9.1 (median 1.8)

AaDO 2 (0 hours)

575.6 ± 91.0

589.5 ± 95.8

AaDO 2 (24 hours)

261.0 ± 160.9

352.3 ± 177.5

AaDO 2 (48 hours)

178.3 ± 144.0

226.0 ± 239.8

Footnotes

i = intervention group; c = control group; AaDO2 = alveolar-arterial oxygen difference (mmHg),
All variables expressed by mean ± standard deviation or median.

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References to studies

Included studies

Dargaville 2011

Dargaville PA, Copnell B, Mills JF, Haron I, Lee JK, Tingay DG, et al. Randomized controlled trial of lung lavage with dilute surfactant for meconium aspiration syndrome. Journal of Pediatrics 2011;158(3):383-9.

Gadzinowski 2008

Gadzinowski J, Kowalska K, Vidyasagar D. Treatment of MAS with PPHN using combined therapy: SLL, bolus surfactant and iNO. Journal of Perinatology 2008;28(Suppl 3):S56-66.

Wiswell 2002

Wiswell TE, Knight GR, Finer NN, Donn SM, Desai H, Walsh WF, et al. A multicenter, randomized, controlled trial comparing Surfaxin (Lucinactant) lavage with standard care for treatment of meconium aspiration syndrome. Pediatrics 2002;109(6):1081-7.

Excluded studies

Armenta 2011

Armenta JMV, Urbina EC, Herrera JC. Surfactant bronchial lavage in meconium aspiration syndrome: A comparative study. Intensive Care Medicine 2011;37:S317.

Burke-Strickland 1973

Burke-Strickland M, Edwards NB. Meconium aspiration in the newborn. Minnesota Medicine 1973;56:1031-5.

Carson 1976

Carson BS, Losey RW, Bowes WAJ, Simmons MA. Combined obstetric and pediatric approach to prevent meconium aspiration syndrome. American Journal of Obstetrics and Gynecology 1976;126(6):712-5.

Chang 2003

Chang HY, Hsu CH, Kao HA, Hung HY, Chang JH, Peng CC, et al. Treatment of severe meconium aspiration syndrome with dilute surfactant lavage. Journal of the Formosan Medical Association 2003;102(5):326-30.

Dargaville 2007

Published and unpublished data

Dargaville PA, Mills JF, Copnell B, Loughnan PM, McDougall PN. Therapeutic lung lavage in meconium aspiration syndrome: a preliminary report. Journal of Paediatric and Child Health 2007;43(7):539-45.

Kowalska 2002

Kowalska K, Szymankiewicz M, Gadzinowski J. An effectiveness of surfactant lung lavage (SLL) in meconium aspiration syndrome (MAS) [Skutecznosc plukania drzewa tchawiczo-oskrzelowego roztworem naturalnego surfaktantu (SLL) w leczeniu zespolu aspiracji smolki (MAS) - doniesienie wstepne]. In: Przeglad Lekarski. Vol. 59 Suppl 1. 2002:21-4.

Lam 1999

Lam BCC, Yeung CY. Surfactant lavage for meconium aspiration syndrome: a pilot study. Pediatrics 1999;103(5 Pt 1):1014-18.

Ogawa 1997

Ogawa Y. Bronchial lavage with surfactant solution for the treatment of meconium aspiration syndrome. In: Hot Topics in Neonatology Conference Book. Chicago: Ross Laboratories, 1997:259-64.

Rosegger 1987

Rosegger H, Engele H, Haas J. Tracheobronchial lavage-a supplementary measure in the initial management of meconium aspiration syndrome [Tracheobronchiallavage-eine ergänzende Maßnahme zur erstversorgung beim mekoniumaspirationssyndrom]. Wiener Klinische Wochenschrift 1987;99(24):843-7.

Salvia-Roigés 2004

Salvia-Roigés MD, Carbonell-Estrany X, Figueras-Aloy J, Rodriguez-Miguélez JM. Efficacy of three treatment schedules in severe meconium aspiration syndrome. Acta Paediatrica 2004;93(1):60-5.

Schlösser 2002

Schlössser RL, Veldman A, Fischer D, Allendorf A, von Loewenich V. Lavage with exogenous surfactant in neonatal meconium aspiration syndrome [Lavage mit exogenem surfactant bei neonataler mekoniumaspiration]. Zeitschrift für Geburtshilfe und Neonatologie. 2002;206(1):15-8.

Su 1998

Su BH, Hu PS, Peng CT, Tsai CH. The effect of bronchial lavage and surfactant supplement on severe meconium aspiration syndrome. Mid-Taiwan Journal of Medicine 1998;3:191-7.

Studies awaiting classification

  • None noted.

Ongoing studies

McNamara 2006

Unpublished data only

McNamara P. Surfactant lavage vs. Bolus surfactant in neonates with meconium aspiration. Clinical Trials (http://www.clinicaltrials.gov/ct2/show/NCT00312507?term=McNamara&rank=1) (accessed 19.02.2013).

Segal 2012

Unpublished data only

Wiswell TE. Phase III randomized study of lucinactant in full term newborn infants with meconium aspiration syndrome. Clinical Trials (http://www.clinicaltrials.gov/show/NCT00004500) (accessed 19.02.2013).

Sur-Lu-Lav 2011

Unpublished data only

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

Other references

Additional references

Chinese Collaborative Study Group 2005

Chinese Collaborative Study Group for Neonatal respiratory Diseases. Treatment of severe meconium aspiration syndrome with porcine surfactant: a multicentre, randomized, controlled trial. Acta Paediatrica 2005;94(7):896-902.

Choi 2012

Choi HJ, Hahn S, Lee J, Park BJ, Lee SM, Kim HS, et al. Surfactant lavage therapy for meconium aspiration syndrome: a systematic review and meta-analysis. Neonatology 2012;101(3):183-91.

Cochrane 1998

Cochrane CG, Revak SD, Merritt TA, Schraufstatter IU, Hoch RC, Henderson C, et al. Bronchoalveolar lavage with KL4-surfactant in models of meconium aspiration syndrome. Pediatric Research 1998;44(5):705-15.

Dargaville 2001

Dargaville PA, South M, McDougall PN. Surfactant and surfactant inhibitors in meconium aspiration syndrome. Journal of Pediatrics 2001;138(1):113-5.

Dargaville 2003

Dargaville PA, Mills JF, Headley BM, Chan Y, Coleman L, Loughnan PM, et al. Therapeutic lung lavage in the piglet model of meconium aspiration syndrome. American Journal of Respiratory and Critical Care Medicine 2003;168(4):456-63.

Dargaville 2008

Dargaville PA, Copnell B, Tingay DG, Gordon MJ, Mills JF, Morley CJ. Refining the method of therapeutic lung lavage in meconium aspiration syndrome. Neonatology 2008;94(3):160-3.

El Shahed 2007

El Shahed AI, Dargaville P, Ohlsson A, Soll RF. Surfactant for meconium aspiration syndrome in full term/near term infants. Cochrane Database of Systematic Reviews 2007, Issue 3. Art. No.: CD002054. DOI: 10.1002/14651858.CD002054.pub2.

Findlay 1996

Findlay RD, Taeusch HW, Walther FJ. Surfactant replacement therapy for meconium aspiration syndrome. Pediatrics 1996;97(1):48-52.

Fuchimukai 1987

Fuchimukai T, Fujiwara T, Takahashi A, Enhorning G. Artificial pulmonary surfactant inhibited by proteins. Journal of Applied Physiology 1987;62(2):429-37.

Higgins 2011

Higgins JPT, Green S (editors). Cochrane Handbook for Systematic Reviews of Interventions. Version 5.1.0 [updated March 2011]. The Cochrane Collaboration, 2011. Available from www.cochrane-handbook.org.

Ibara 1995

Ibara S, Ikenoue T, Murata Y, Sakamoto H, Saito T, Nakamura Y, et al. Management of meconium aspiration syndrome by tracheobronchial lavage and replacement of Surfactant-TA. Acta Paediatrica Japonica 1995;37(1):64-7.

Lotze 1998

Lotze A, Mitchell BR, Bulas DI, Zola EM, Shalwitz RA, Gunkel JH, et al. Multicenter study of surfactant (beractant) use in the treatment of term infants with severe respiratory failure. Journal of Pediatrics 1998;132(1):40-7.

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):501-8.

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. In: PAS. Vol. 57. 2005:1545.

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):1412-3.

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):477-81.

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):236-8.

Ohama 1999

Ohama Y, Ogawa Y. Treatment of meconium aspiration syndrome with surfactant lavage in an experimental rabbit model. Pediatric Pulmonology 1999;28(1):18-23.

Paranka 1992

Paranka MS, Walsh WF, Stancombe BB. Surfactant lavage in a piglet model of meconium aspiration syndrome. Pediatric Research 1992;31(6):625-8.

RevMan 2011

Review Manager (RevMan) [Computer program]. Version 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):34-8.

Tyler 1978

Tyler DC, Murphy J, Cheney FW. Mechanical and chemical damage to lung tissue caused by meconium aspiration. Pediatrics 1978;62(4):454-9.

Wiswell 1993

Wiswell TE, Bent RC. Meconium staining and the meconium aspiration syndrome. Unresolved issues. Pediatric Clinics of North America 1993;40(5):955-81.

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 the multicenter, international collaborative trial. Pediatrics 2000;105(1 Pt 1):1-7.

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Data and analyses

1 Lung lavage versus standard care

For graphical representations of the data/results in this table, please use the link under "Outcome or Subgroup."

Outcome or Subgroup Studies Participants Statistical Method Effect Estimate
1.1 Death 2 88 Risk Ratio (M-H, Fixed, 95% CI) 0.42 [0.12, 1.46]
1.2 Use of ECMO 2 47 Risk Ratio (M-H, Fixed, 95% CI) 0.27 [0.04, 1.86]
1.3 Death or use of ECMO 2 88 Risk Ratio (M-H, Fixed, 95% CI) 0.33 [0.11, 0.96]
1.4 Pneumothorax 2 88 Risk Ratio (M-H, Fixed, 95% CI) 0.38 [0.08, 1.90]
1.5 Oxygenation index 2 Mean Difference (IV, Fixed, 95% CI) Subtotals only
1.5.1 measured at 24 hours 2 88 Mean Difference (IV, Fixed, 95% CI) -1.90 [-7.56, 3.77]
1.5.2 measured at 48 hours 2 88 Mean Difference (IV, Fixed, 95% CI) -6.20 [-12.11, -0.29]
1.5.3 measured at 72 hours 2 88 Mean Difference (IV, Fixed, 95% CI) -3.56 [-8.72, 1.60]
1.6 Alveolar-arterial oxygen difference 1 Mean Difference (IV, Fixed, 95% CI) Subtotals only
1.6.1 measured at 24 hours 1 66 Mean Difference (IV, Fixed, 95% CI) -12.00 [-109.19, 85.19]
1.6.2 measured at 48 hours 1 66 Mean Difference (IV, Fixed, 95% CI) -57.00 [-162.96, 48.96]
1.6.3 measured at 72 hours 1 66 Mean Difference (IV, Fixed, 95% CI) -41.00 [-132.59, 50.59]
1.7 PaO2/FiO2 1 Mean Difference (IV, Fixed, 95% CI) Subtotals only
1.7.1 measured at 24 hours 1 66 Mean Difference (IV, Fixed, 95% CI) -1.00 [-54.61, 52.61]
1.7.2 measured at 48 hours 1 66 Mean Difference (IV, Fixed, 95% CI) 27.00 [-26.63, 80.63]
1.7.3 measured at 72 hours 1 66 Mean Difference (IV, Fixed, 95% CI) 26.00 [-24.96, 76.96]

2 Lung lavage followed by surfactant bolus versus surfactant bolus

For graphical representations of the data/results in this table, please use the link under "Outcome or Subgroup."

Outcome or Subgroup Studies Participants Statistical Method Effect Estimate
2.1 Death 1 13 Risk Ratio (M-H, Fixed, 95% CI) 0.17 [0.01, 3.06]
2.2 Pneumothorax 1 13 Risk Ratio (M-H, Fixed, 95% CI) 0.17 [0.01, 3.06]

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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.

This review is published as a Cochrane review in The Cochrane Library, Issue 4, 2013 (see http://www.thecochranelibrary.com External Web Site Policy for information).  Cochrane reviews are regularly updated as new evidence emerges and in response to feedback.  The Cochrane Library should be consulted for the most recent version of the review.