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Lung lavage for meconium aspiration syndrome in newborn infants

  1. Seokyung Hahn1,*,
  2. Hyun Jin Choi2,
  3. Roger Soll3,
  4. Peter A. Dargaville4

Editorial Group: Cochrane Neonatal Group

Published Online: 30 APR 2013

Assessed as up-to-date: 15 FEB 2013

DOI: 10.1002/14651858.CD003486.pub2


How to Cite

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.

Author Information

  1. 1

    Seoul National University College of Medicine, Department of Medicine, Seoul, Korea, South

  2. 2

    Seoul National University College of Medicine, Department of Preventive Medicine, Seoul, Korea, South

  3. 3

    University of Vermont, Division of Neonatal-Perinatal Medicine, Burlington, Vermont, USA

  4. 4

    Royal Hobart Hospital, Department of Paediatrics, Hobart, Tasmania, Australia

*Seokyung Hahn, Department of Medicine, Seoul National University College of Medicine, 28 Yongon-dong Chongno-gu, Seoul, 110-744, Korea, South. hahns@snu.ac.kr.

Publication History

  1. Publication Status: New
  2. Published Online: 30 APR 2013

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Characteristics of included studies [ordered by study ID]
Dargaville 2011

MethodsInternational 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)


Participants66 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


InterventionsSurfactant 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


OutcomesPrimary 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

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskRandomly permuted blocks of two or four, stratified by study centre

Allocation concealment (selection bias)Low riskPre-prepared sequentially numbered sealed opaque envelopes

Blinding of participants and personnel (performance bias)
All outcomes
High riskBlinding of the intervention was not possible

Blinding of outcome assessment (detection bias)
All outcomes
Low riskAll outcomes were measured by objective means

Incomplete outcome data (attrition bias)
All outcomes
Low riskOne infant was ineligible. Complete data were available for 65 eligible infants

Selective reporting (reporting bias)Low riskThe 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 biasLow riskThe study appears to be free of other sources of bias

Gadzinowski 2008

MethodsSingle-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


Participants13 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


InterventionsSurfactant 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


OutcomesPrimary 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

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskThe study is described as randomised, but no information is provided about the sequence generation method

Allocation concealment (selection bias)Unclear riskNot reported

Blinding of participants and personnel (performance bias)
All outcomes
Unclear riskNot reported (each group of infants was managed by a different group of neonatologists)

Blinding of outcome assessment (detection bias)
All outcomes
Low riskAll outcomes were measured by objective means

Incomplete outcome data (attrition bias)
All outcomes
Low riskComplete data were available for all enrolled infants

Selective reporting (reporting bias)Low riskThe study protocol is not available, and information is sufficient to permit judgement

Wiswell 2002

MethodsMulticenter 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


Participants22 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


InterventionsLung 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


OutcomesPrimary 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

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskThe study is described as randomised, but no information about the sequence generation method is provided

Allocation concealment (selection bias)Low riskRandomisation was performed by drawing a randomisation slip from a closed envelope

Blinding of participants and personnel (performance bias)
All outcomes
Unclear riskNot reported

Blinding of outcome assessment (detection bias)
All outcomes
Low riskAll outcomes were measured by objective means

Incomplete outcome data (attrition bias)
All outcomes
Low riskITT analysis was carried out

Selective reporting (reporting bias)Unclear riskThe study protocol is not available, and information is sufficient to permit judgement

Other biasHigh 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 [ordered by study ID]

StudyReason for exclusion

Armenta 2011Surfactant lavage was compared with saline lavage

Burke-Strickland 1973Nonrandomised case series

Carson 1976Randomisation of infants to receive saline lavage or no lavage mentioned in methods, but no results presented

Chang 2003Nonrandomised study over two time epochs

Dargaville 2007Nonrandomised study with concurrent controls

Kowalska 2002Nonrandomised study over two time epochs

Lam 1999Nonrandomised study over two time epochs

Ogawa 1997Randomised 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 1987Nonrandomised study with concurrent controls

Salvia-Roigés 2004Nonrandomised study of two different treatment schedules involving lavage, compared with historical controls

Schlösser 2002Nonrandomised study with concurrent controls

Su 1998Nonrandomised study, no control group

 
Characteristics of ongoing studies [ordered by study ID]
McNamara 2006

Trial name or titleSurfactant Lavage versus Bolus Surfactant in Neonates With Meconium Aspiration

MethodsRCT

ParticipantsMeconium aspiration syndrome (n = 20)

InterventionsSurfactant lavage or surfactant bolus treatment

OutcomesPrimary 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 date2006

Contact informationPatrick McNamara, MD,  patrick.mcnamara@sickkids.ca.

The Hospital for Sick Children, Toronto, Ontario, Canada

Notesclinical trials.gov. identifier NCT00312507

Segal 2012

Trial name or titlePhase III Randomized Study of Lucinactant in Full Term Newborn Infants with Meconium Aspiration Syndrome

MethodsRandomised controlled trial

Participants69 infants (lucinactant n = 38; standard care n = 31)

InterventionsLucinactant via bronchoalveolar lavage

OutcomesNumbers 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 dateRecruitment occurred between March 2000 and October 2002

Contact informationRobert Segal; Discovery Laboratory

NotesClinical trials.gov. identifier NCT00004500.

Sponsored by Discovery Laboratories

Sur-Lu-Lav 2011

Trial name or titleComparison of Surfactant Lung Lavage with Standard Care in the Treatment of Meconium Aspiration Syndrome (Sur-Lu-Lav)

MethodsRandomised controlled trial

ParticipantsInclusion 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

InterventionsLavage 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

OutcomesPrimary 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 date2011

Contact informationSushma Nangia, MBBS, MD, DM drsnangia@gmail.com.

Kalawati Saran Children's Hospital, Lady Hardinge Medical College

Notesclinical trials.gov. identifier NCT01310621

 
Comparison 1. Lung lavage versus standard care

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Death288Risk Ratio (M-H, Fixed, 95% CI)0.42 [0.12, 1.46]

 2 Use of ECMO247Risk Ratio (M-H, Fixed, 95% CI)0.27 [0.04, 1.86]

 3 Death or use of ECMO288Risk Ratio (M-H, Fixed, 95% CI)0.33 [0.11, 0.96]

 4 Pneumothorax288Risk Ratio (M-H, Fixed, 95% CI)0.38 [0.08, 1.90]

 5 Oxygenation index2Mean Difference (IV, Fixed, 95% CI)Subtotals only

    5.1 measured at 24 hours
288Mean Difference (IV, Fixed, 95% CI)-1.90 [-7.56, 3.77]

    5.2 measured at 48 hours
288Mean Difference (IV, Fixed, 95% CI)-6.20 [-12.11, -0.29]

    5.3 measured at 72 hours
288Mean Difference (IV, Fixed, 95% CI)-3.56 [-8.72, 1.60]

 6 Alveolar-arterial oxygen difference1Mean Difference (IV, Fixed, 95% CI)Subtotals only

    6.1 measured at 24 hours
166Mean Difference (IV, Fixed, 95% CI)-12.0 [-109.19, 85.19]

    6.2 measured at 48 hours
166Mean Difference (IV, Fixed, 95% CI)-57.0 [-162.96, 48.96]

    6.3 measured at 72 hours
166Mean Difference (IV, Fixed, 95% CI)-41.0 [-132.59, 50.59]

 7 PaO2/FiO21Mean Difference (IV, Fixed, 95% CI)Subtotals only

    7.1 measured at 24 hours
166Mean Difference (IV, Fixed, 95% CI)-1.0 [-54.61, 52.61]

    7.2 measured at 48 hours
166Mean Difference (IV, Fixed, 95% CI)27.0 [-26.63, 80.63]

    7.3 measured at 72 hours
166Mean 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 studiesNo. of participantsStatistical methodEffect size

 1 Death113Risk Ratio (M-H, Fixed, 95% CI)0.18 [0.01, 3.06]

 2 Pneumothorax113Risk Ratio (M-H, Fixed, 95% CI)0.18 [0.01, 3.06]

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

StudyNumber of infants

(i/c)
Days of mechanical ventilationDays of supplemental oxygenLength of hospital stay (days)



InterventionControlInterventionControlInterventionControl

Dargaville 201131/355.0 (3.3-8.7)6.3 (3.9-8.1)14 (6.7-21)14 (11-18)17 (11-25)19 (15-25)

Wiswell 20027/154.6 (1.1-22.3)7.6 (1.1-28)13.5 ± 9.312.1 ± 10.712.7 ± 8.713.1 ± 10.3

 i = intervention group; c = control group.
All variables expressed by mean ± standard deviation or median (interquartile range). Data from the survivors were used.
 
Table 2. Results of continuous variables (lung lavage followed by surfactant bolus versus surfactant bolus)

StudyNumber of infants

(i/c)
Days of mechanical ventilationLength of hospital stay (days)


InterventionControlInterventionControl

Gadzinowski 20087/66.6 ± 2.67.3 ± 1.716.4 ± 5.419.8 ± 2.9

 i = intervention group; c = control group.
All variables expressed by mean ± standard deviation.
 
Table 3. Results of indices of pulmonary function (lung lavage followed by surfactant bolus versus surfactant bolus)

Gadzinowski 2008

 Intervention (n = 7)Control (n = 6)

Oxygenation index (0 hours)29.8 ± 12.5 (median 25)32.4 ± 25 (median 24.3)

Oxygenation index (24 hours)2.7 ± 2.2 (median 2.8)10.4 ± 8.1 (median 9.0)

Oxygenation index (48 hours)5.0 ± 9.1 (median 1.7)5.7 ± 9.1 (median 1.8)

AaDO2 (0 hours)575.6 ± 91.0589.5 ± 95.8

AaDO2 (24 hours)261.0 ± 160.9352.3 ± 177.5

AaDO2 (48 hours)178.3 ± 144.0226.0 ± 239.8

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