Surfactant for meconium aspiration syndrome in full term/near term infants
Surfactant replacement therapy has been proven beneficial in the prevention and treatment of neonatal respiratory distress syndrome (RDS). The deficiency of surfactant or surfactant dysfunction may contribute to respiratory failure in a broader group of disorders, including meconium aspiration syndrome (MAS).
Objectives
To evaluate the effect of surfactant administration in the treatment of term/near-term infants with MAS.
Search strategy
Searches were made using The Cochrane Library (Issue 4, 2006), MEDLINE and EMBASE (1985 to December 2006), previous reviews including cross-references, abstracts, conference and symposia proceedings, expert informants, and journal hand searching. No language restrictions were applied. Authors were directly contacted to provide additional data.
Selection criteria
Randomised controlled trials which evaluated the effect of surfactant administration in term infants with meconium aspiration syndrome are included in the analyses.
Data collection and analysis
Data regarding clinical outcomes including mortality, treatment with extracorporeal membrane oxygenation (ECMO), pneumothorax, duration of assisted ventilation, duration of supplemental oxygen, intraventricular haemorrhage (any grade and severe IVH), and chronic lung disease, and were excerpted from the reports of the clinical trails by the review authors. Data analyses were done in accordance with the standards of the Cochrane Neonatal Review Group.
Main results
Four randomised controlled trials met inclusion criteria. The meta-analysis of 4 trials enrolling 326 infants showed no statistically significant effect on mortality (typical relative risk 0.98 (95% CI 0.41, 2.39), typical risk difference 0.00 (95% CI -0.05, 0.05). The risk of requiring extracorporeal membrane oxygenation was significantly reduced in a meta-analysis of two trials (n = 208); (typical relative risk 0.64, 95% CI 0.46, 0.91; typical risk difference -0.17, 95% CI -0.30, -0.04); number needed to treat to benefit 6 (95% CI 3, 25). One trial (n = 40) reported a statistically significant reduction in the length of hospital stay [mean difference - 8 days (95% CI -14, -3 days)]. There were no statistically significant reductions in any other outcomes studied (duration of assisted ventilation, duration of supplemental oxygen, pneumothorax, pulmonary interstitial emphysema, air leaks, chronic lung disease, need for oxygen at discharge or intraventricular haemorrhage).
Authors' conclusions
In infants with MAS, surfactant administration may reduce the severity of respiratory illness and decrease the number of infants with progressive respiratory failure requiring support with ECMO. The relative efficacy of surfactant therapy compared to, or in conjunction with, other approaches to treatment including inhaled nitric oxide, liquid ventilation, surfactant lavage and high frequency ventilation remains to be tested.
Plain language summaryThe lungs of newborn babies' can be damaged by meconium aspiration syndrome. Meconium aspiration syndrome is caused when a stressed baby passes a bowel movement while still in the womb and then breathes some of this material into the lungs. Pulmonary surfactant, the complex combination of chemicals that line the surface of the lung, may be altered or inactivated in babies who have meconium aspiration. It is thought that treatment with additional surfactant might be able to help overcome this damage. This review of trials found that surfactant can reduce breathing difficulties and breathing failure in babies suffering from meconium aspiration syndrome.
BackgroundThe deficiency of surfactant or surfactant dysfunction may contribute to respiratory failure in a broad group of disorders, including meconium aspiration syndrome (MAS). Meconium inhibits the surface tension lowering properties of surfactant (Chen 1985; Moses 1991). Instillation of meconium into the airways of term animals leads to acute mechanical obstruction and worsening pulmonary mechanics and gas exchange (Chen 1985; Tran 1980; Tyler 1978). A significant reduction in lung compliance, an increase in expiratory lung resistance and increased functional residual capacity can be demonstrated (Tran 1980). Investigators have postulated that the changes in compliance associated with meconium aspiration result from displacement of surfactant by free fatty acids (Clark 1987). In animals with experimentally induced meconium aspiration, treatment with large doses of natural surfactant extract improves compliance and ventilation (Sun 1993).Surfactant replacement therapy has been proven beneficial in the prevention and treatment of neonatal respiratory distress syndrome (RDS) (Soll 1992). Respiratory distress syndrome is due to a primary deficiency in the production and release of pulmonary surfactant. Surfactant therapy has been shown to improve oxygenation, decrease the need for ventilatory support, and improve clinical outcome in infants with RDS. Surfactant treated infants have a reduced mortality and a decreased incidence of pneumothorax.Uncontrolled studies of surfactant treatment in infants with MAS suggest that surfactant may be of benefit in MAS. In a pilot study of 7 infants with MAS treated with surfactant, all 7 infants demonstrated an improvement in respiratory failure (Auten 1991). Khammash and coworkers (Khammash 1993) treated 20 infants with severe MAS. Infants received an intratracheal dose of bovine surfactant extract (100 mg phospholipid/kg). Improvement in oxygenation index (OI) and arterial/alveolar ratio (a/A pO2) was noted in 75% of the treated infants in the six hours following surfactant instillation. None of the treated infants required further experimental therapy including extracorporeal membrane oxygenation (ECMO).Other approaches to prevent or treat MAS include amnioinfusion (infusion of saline into the amniotic cavity), oro/nasopharyngeal suctioning of meconium stained neonates before delivery and the use of surfactant lavage in infants with the diagnosis of MAS.In a systematic review, Hofmeyr and coworkers (Hofmeyr 2002) found that amnioinfusion in women with meconium stained liquor was associated with improvements in perinatal outcomes including the occurrence of MAS, particularly in settings where facilities for perinatal surveillance were limited. However, in a recent large multicenter, international, randomised controlled trial of amnioinfusion to prevent MAS (not included in the Hofmeyr review), a benefit from amnioinfusion could not be confirmed (Fraser 2005). Unlike the previous systematic overview, the authors concluded that for women in labor who have thick meconium staining of the amniotic fluid, amnioinfusion did not reduce the risk of moderate or severe MAS, perinatal death, or other major maternal or neonatal disorders (Fraser 2005).Vain and co-workers (Vain 2004) assessed the effectiveness of intrapartum suctioning for the prevention of MAS in a large multicenter randomised controlled trial. The primary outcome was the incidence of MAS. No significant difference between treatment groups was seen in the incidence of MAS, mortality, or in the duration of ventilation, oxygen treatment, and hospital care. The authors concluded that routine intrapartum oropharyngeal and nasopharyngeal suctioning of term-gestation infants born through meconium stained amniotic fluid does not prevent MAS. These findings led to change in clinical practice and routine suctioning of the oropharynx and the nasopharynx are currently not recommended (AAP 2006).The following systematic review evaluates randomised controlled trials that studied the effect of surfactant administration for the treatment of term/near term infants with MAS. Studies which utilized dilute surfactant solutions to lavage meconium from the airways are not included in this review.ObjectivesTo evaluate the effect of surfactant administration in the treatment of term or near term infants with meconium aspiration syndrome.Criteria for considering studies for this review
Randomised controlled trials comparing surfactant treatment to routine management of term/near-term infants with MAS.
Term or near-term infants with MAS (modified from the previous review, which planned to include only term infants).
Intratracheal administration of surfactant vs. placebo or no therapy. Studies that utilized dilute surfactant solutions to lavage meconium from the airways are not included in this review.
For the update of this review, the following primary and secondary outcomes were selected:PRIMARY OUTCOME:MortalitySECONDARY OUTCOMES:1. Treatment with extracorporeal membrane oxygenation (ECMO)2. Pneumothorax3. Pulmonary interstitial emphysema4. Air leaks (pneumothorax, pneumomediastinum, pulmonary interstitial emphysema)5. Duration of assisted mechanical ventilation (days)6. Duration of supplemental oxygen (days)7. Need for supplemental oxygen at discharge8. Chronic lung disease defined as need for oxygen therapy at 28 days or 36 weeks postmenstrual age9. Intraventricular haemorrhage (any grade)10. Severe IVH (grade III-IV)]11. Duration of hospital stay (days).Search methods for identification of studiesSee: Cochrane Neonatal Group methods used in reviews.The Cochrane Library (Issue 4, 2006) was searched in December 2006. A search was run in OVID MEDLINE (1966 to December 2006) using the following strategy: (exp Pulmonary Surfactants/ or surfactan:.mp. or Surface-Active Agents/ or (surfactan: adj2 lavage:).mp.) and (Meconium Aspiration Syndrome/ or Meconium/). A search was run in OVID EMBASE <1980>using the following strategy: (Lung Surfactant/ or exp Surfactant/ or (surfactan: adj2 lavage:).mp. or surfactan:.mp.) and (Meconium or Aspiration/ or meconium/).Previous reviews including cross references were searched. Abstracts published in Pediatric Research or electronically from Pediatric Academic Societies meetings were searched from 2000 to December 2006. No language restrictions were applied.Methods of the reviewFor each included study, information was collected regarding the method of randomisation, blinding, drug intervention, stratification, and whether the trial was single or multicenter. Information regarding trial participants including gestational age criteria, birth weight criteria, cause of respiratory failure, severity of respiratory failure, and postnatal age at the time of treatment was noted. Information on clinical outcome was extracted including mortality, treatment with ECMO, pneumothorax, pulmonary interstitial emphysema, chronic lung disease, duration of assisted ventilation, duration of supplemental oxygen, need for supplemental oxygen at discharge, duration of hospital stay, intraventricular haemorrhage (any grade and grades III and IV). Investigators or study sponsors were contacted for clarification or provision of data not specifically noted in the original report. For this update two review authors (AS, AO) independently evaluated all studies, abstracted the data on abstraction forms and compared the abstracted data and achieved agreement. One review author (AS) entered the data into RevMan 4.2.9 and the other review author (AO) checked the data for accuracy. Unpublished information on the subgroup of infants with MAS obtained from Lotze at al (Lotze 1998) included in the original review were entered unchanged. Unpublished information regarding the multicenter trial conducted in Chile and previously published in abstract form was obtained from the authors (Maturana 2005).The quality of included trials was evaluated independently by the review authors using the following criteria:Blinding of randomisationBlinding of interventionBlinding of outcome measure assessmentCompleteness of follow upThere are three potential answers to these questions: yes, no, cannot tell.The statistical methods included (typical) relative risk (RR), risk difference (RD), number needed to treat to benefit (NNTB) or number needed to treat to harm (NNTH) for dichotomous outcomes and weighed mean difference (WMD) reported with 95% confidence intervals (CI). A fixed effects model was used for meta-analysis. Heterogeneity was assessed using the I squared (I2) statistic.Description of studiesFor details see the Table 'Characteristics of included studies'.Studies included in this review:The study by Findlay and coworkers was a single centre study performed in the USA (Findlay 1996):
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Objective: To determine whether high-dose surfactant therapy improves the pulmonary morbidity of term infants ventilated for MAS.
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Population: Term newborn infants with MAS diagnosed by the presence of meconium below the vocal cords at birth and /or characteristic chest radiographic findings who needed ventilator support before six hours of age with a fractional inspired oxygen (Fi02 ) level of 0.5 or more, mean airway pressure of 7 cm of H2O or more and a/A pO2 ratio of 0.22 or less.
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Intervention: Infants in the study group received up to four doses of 150 mg (6ml)/kg beractant (Survanta), installed every 6 hours by continuous infusion for 20 minutes via a side hole endotracheal tube adapter. Infants in the control group received 6 ml/kg air placebo.
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Outcomes: Primary outcomes included decrease in Oxygen Index (OI), increase in a/A pO2 ratio and decrease in the need for respiratory support [mean airway pressure (MAP), ventilation days]. Secondary outcomes included the need for ECMO, incidence of air leaks, duration of oxygen therapy, discharge with supplemental oxygen, and mortality at less than 28 days of life.
The study by Lotze and coworkers was a multicenter study performed in the USA (Lotze 1998):
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Objective: To determine whether surfactant (beractant) administration to term newborns in respiratory failure and at risk for requiring ECMO treatment would significantly reduce the incidence of severe complications through 28 days of age and the need for ECMO.
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Population: Infants weighing 2000 g or more with gestational ages of 36 weeks or greater with respiratory failure secondary to MAS, sepsis or idiopathic persistent pulmonary hypertension of newborn (requiring FiO2 1.00 with OI of 15 - 39).
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Intervention: Infants were randomly assigned to receive either four doses of beractant 100 mg/kg or air placebo before ECMO treatment and four additional doses during ECMO, if ECMO was required (only infants with MAS are included in this analysis and the data were provided by the authors).
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Outcomes: Need for ECMO and incidence of severe complications (haemorraghic, neurologic, pulmonary, renal, cardiovascular, infectious, metabolic and technical) during the first 28 days of age or at discharge.
The Chinese Collaborative Study was a multicenter study performed in China (Chinese Collab. 2005):
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Objective: To evaluate the safety and efficacy of exogenous surfactant replacement therapy for MAS in term and near-term neonates.
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Population: Term and near term neonates with MAS (diagnosis based on the presence of meconium in the airways and/or meconium-stained amniotic fluid at delivery, typical chest X-ray findings, onset of respiratory distress, and abnormal blood gas findings indicating respiratory failure and acidosis), birth weight > 2500 g, postnatal age <>15 and need for mechanical ventilation for 1 - 2 h without improvement.
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Intervention: The infants in the surfactant group received an initial dose of porcine lung derived surfactant (Curosurf) at 200 mg/kg, and repeated doses of 200, 100 and 100 mg/kg were given at 6 - 12 h intervals to a maximum of four doses if OI increased by > 2 from baseline. The control group received the standard of care without a placebo.
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Outcomes: The primary outcomes were a reduction of OI to less than 10 and an increase of the pre-treatment a/A pO2 ratio of 100% over baseline 24 h after surfactant treatment. The secondary outcomes were duration of mechanical ventilation, incidence of complications and survival to discharge from hospital.
The study by Maturana and coworkers was a multicenter study performed in Chile (Maturana 2005):
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Objective: To evaluate if the use of up to 3 doses of surfactant administered as a bolus (150 mg/kg) versus placebo, reduces the number of days on mechanical ventilation in term infants with moderate to severe meconium aspiration syndrome.
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Population: Term newborns > 37 weeks of gestation with moderate to severe MAS (defined as the presence of meconium stained amniotic fluid and/or evidence of meconium in the lower airway, abnormal x-ray consistent with MAS and respiratory insufficiency defined as an oxygen requirement of > 50% in oxyhood to achieve saturation of > 90% or PaO2 > 50 mmHg if the patient was not ventilated, or an OI > 8 if the patient was on mechanical ventilation.
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Intervention: Infants were randomly assigned to receive either 150 mg /kg/dose (6ml) of Survanta or an equivalent amount of air as placebo every six hours for total of three doses if they remained intubated.
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Outcomes: The primary outcome was days on mechanical ventilation. Secondary outcomes included days requiring oxygen therapy with a target arterial oxygen saturation > 90%, air leaks (pneumothorax, pneumomediastinum, interstitial emphysema), persistent pulmonary hypertension (PPHN), OI after two hours following the first treatment dose and mortality before discharge.
Methodological qualityRandomised controlled trials that evaluated the effect of bolus surfactant administration in term or near term infants with MAS are included in the analysis. Specific methodologic issues are discussed below:Randomisation: The four included studies allocated treatments by randomisation. The Collaborative Chinese Study (Chinese Collab. 2005) and Maturana (Maturana 2005) used sealed randomisation envelopes. Findlay (Findlay 1996) did not report on the method of randomisation, but stated that physicians and nurses caring for the infants were unaware of the infants' assignment groups. Lotze (Lotze 1998) used a central randomizations service and stratified infants by primary diagnosis and disease severity.Blinding of treatment: In the study of Findlay and co-workers (Findlay 1996) the attending staff were unaware of treatment assignment. In the study by Lotze (Lotze 1998), the dosing investigator was prohibited from participating in any other aspects of infants' care and from revealing the treatment assignment. In the Chinese Collaborative Study (Chinese Collab. 2005), staff were not blinded to treatment groups. In the study by Maturana (Maturana 2005), the assigned treatment was administered by a person not involved in the direct patient care and was given behind a screen. The number of infants enrolled in the trial differed in the published abstract (Maturana 2005) and in the information obtained from the first author (three additional infants in the surfactant group and one additional infant in the control group). Differences noted between abstracts and full reports may indicate elements of bias/poor data quality control possibly including any of the following methodological issues: multiple looks at the data; changes in the definitions of outcomes; no preset sample size; closure of patient recruitment when statistical significance has been reached for the outcome under study and other sources of bias (Walia 1999).Blinding of outcome assessment: Outcomes were assessed by staff members unaware of treatment assignment in three of the four studies (Findlay 1996; Lotze 1998; Maturana 2005).Exclusion after randomisation: There were no exclusions after randomisation reported in any of the studies.ResultsSURFACTANT THERAPY VS. PLACEBO OR NO TREATMENT (COMPARISON 01): PRIMARY OUTCOME:Mortality (Outcome 01.01): All four studies enrolling 326 infants reported on mortality (Outcome Table 01.01). Surfactant had no statistically significant effect on mortality [typical RR 0.98 (95% CI 0.41, 2.39); typical RD 0.00 (95% CI -0.05, 0.05)]. Heterogeneity of treatment effect for this outcome was low (I2 = 0 %).SECONDARY OUTCOMES:Treatment with ECMO (Outcome 01.02): Two studies enrolling 208 patients reported on treatment with ECMO (Outcome Table 01.02). Surfactant statistically significantly reduced treatment with ECMO [typical RR 0.64 (95% CI 0.46, 0.91); typical RD -0.17 (95% CI -0.30, -0.04); NNT 6 (95% CI 3, 25). Heterogeneity of treatment effect for this outcome was moderate for RR (I2 = 50.4%) and low for RD (I2 = 0%)]Pneumothorax (Outcome 01.03): Three studies enrolling 269 infants reported on the occurrence of pneumothorax (Outcome Table 01.03). Surfactant did not statistically significantly reduce the occurrence of pneumothorax [typical RR 0.82 (95% CI 0.39, 1.73); typical RD -0.02 (95% CI -0.08, 0.05)]. Heterogeneity of treatment effect for this outcome was moderate for RR (I2 = 50.3%) and large for RD (I2 = 75.2%).Pulmonary interstitial emphysema (Outcome 01.04): One study enrolling 61 infants reported on the occurrence of interstitial emphysema (Outcome Table 01.04). Surfactant had no statistically significant effect on pulmonary interstitial emphysema [RR 0.55 (95% CI 0.18, 1.70); RD -0.10 (95% CI -0.30, 0.09)]. Tests for heterogeneity were not applicable.Air leaks (pneumothorax, pneumomediastinum, interstitial emphysema) (Outcome 01.05): One study enrolling 57 infants reported on a combination of air leaks (Outcome Table 01.05). Surfactant did not have a statistically significant effect on air leaks [RR 1.04 (95% CI 0.23, 4.71); RD 0.00 (95% CI -0.16, 0.16). Tests for heterogeneity were not applicable.Duration of assisted mechanical ventilation (days) (Outcome 01.06): Three studies enrolling 158 infants reported on duration of assisted mechanical ventilation (Outcome Table 01.06). Mechanical ventilated was stated as the outcome in all three studies, but if this included continuous positive airway pressure was not indicted. Surfactant had no statistically significant effect on the duration of assisted ventilation [WMD 0.60 days ( -0.41, 1.62)]. Heterogeneity of treatment effect for this outcome was moderate (I2 = 72.6%).Duration of supplemental oxygen (days) (Outcome 01.07): Two studies reported on duration of supplemental oxygen (Outcome Table 01.07). Surfactant did not statistically significantly reduce the duration of supplemental oxygen [WMD 0.40 (95% CI -2.83, 3.64). Heterogeneity of treatment effect for this outcome was large (I2 = 87.8%).Need for supplemental oxygen at discharge (Outcome 01.08): One study enrolling 40 infants reported on the need for oxygen at discharge (Outcome Table 01.08). Surfactant had no statistically significant effect on need for supplemental oxygen at discharge [RR 0.75 (95% CI 0.32, 1.77) RD -0.10 (95% CI -0.39, 0.19). Tests for heterogeneity were not applicable.Chronic lung disease (age at diagnosis not stated) (Outcome 01.09): One study enrolling 168 infants reported on chronic lung disease (Outcome Table 01.05). Surfactant had no statistically significant effect on chronic lung disease [RR 0.47 (95% CI 0.12, 1.80); RD -0.04 (95% CI -0.11, 0.03)]. Tests for heterogeneity not applicable.Intraventricular haemorrhage (any grade) (Outcome 01.10): Two studies enrolling 229 infants reported on the incidence of intraventricular haemorrhage (any grade) (Outcome Table 01.10). Surfactant had no statistically significant effect on intraventricular haemorrhage (any grade) [typical RR 0.67 (95% CI 0.31, 1.46); typical RD -0.04 (95% CI -0.12, 0.04)]. Heterogeneity of treatment effect for this outcome was moderate (RR, I2 = 47.5%; RD, I2 = 50.8%)].Severe intraventricular haemorrhage (grades III and IV) (Outcome 01.11): One study enrolling 168 infants reported on the incidence of severe intraventricular haemorrhage (grades III and IV) (Outcome table 01.11). Surfactant had no statistically significant effect on severe intraventricular haemorrhage (grades III and IV) [RR 2.79 (95% CI 0.30, 26.31); RD 0.02 (95% CI -0.02, 0.07).Tests for heterogeneity were not applicable.Duration of hospital stay (days) (Outcome 01.12): One study enrolling 40 infants reported on the duration of hospital stay. Surfactant statistically significantly reduced the duration of hospital stay [MD -8 days (95% CI -14, -3)]. Tests for heterogeneity were not applicable.DiscussionDeficiency and/or dysfunction of pulmonary surfactant may contribute to respiratory failure in a broad group of disorders including pneumonia, MAS, and adult respiratory distress syndrome. Four randomised controlled trials were identified that studied the effect of surfactant therapy in term/near-term infants with MAS. Three of the studies were placebo controlled using air as the placebo and in these three studies the outcomes were assessed blinded to group of allocation (Findlay 1996; Lotze 1998,Maturana 2005). In the fourth study, the clinical staff were not blinded to group allocation (Chinese Collab. 2005). The sample sizes of the studies were small with 40, 57, 61, and 168 infants enrolled (Findlay 1996; Maturana 2005; Chinese Collab. 2005; Lotze 1998). The number of infants enrolled in the study by Maturana and coworkers differed in the published abstract (Maturana 2005) and in the information obtained from the author. There were four more infants included in the report that we obtained from the authors.Surfactant treatment did not have a statistically significant effect on the primary outcome of mortality. In the meta-analysis of the results from two studies (Findlay 1996; Lotze 1998), surfactant treatment resulted in a statistically and clinically important reduction in the need for ECMO treatment with a NNTB of 6 (95% CI 3, 25). ECMO treatment was not available for the units in the Chinese Collaborative study (Chinese Collab. 2005) nor in the study from Chile (Maturana 2005). The one study (Findlay 1996) that reported on duration of hospital stay reported a reduction in hospital days. There were no other statistically significant reductions in any of the other important clinical outcomes (duration of assisted ventilation, duration of supplemental oxygen, air leaks, chronic lung disease, duration of assisted ventilation, need for supplemental oxygen at discharge and intraventricular haemorrhage). The trends for all respiratory tract associated outcomes favoured the use of surfactant.A number of investigators have attempted to treat meconium aspiration syndrome with diluted surfactant solutions used as a lavage to wash residual meconium from the airway (Ibara 1995; Ogawa 1996; Lam 1999). Wiswell and coworkers (Wiswell 2002) enrolled twenty-two infants [15 surfactant (Surfaxin) and 7 control]. There were non-significant trends for surfactant-lavaged infants to be weaned from mechanical ventilation earlier (mean of 6.3 vs 9.9 days, respectively), as well as to have a more rapid decline in their OI compared with control infants. The authors concluded that dilute Surfaxin lavage seemed a safe and potentially effective therapy in the treatment of MAS. The data support future prospective, controlled clinical trials of bronchoalveolar lavage with surfactant in neonates with MAS.Current evidence indicates that amnioinfusion prior to birth or suctioning of the oropharynx/nasopharynx prior to the delivery of the shoulders do not prevent MAS from occurring. At the present time, the two most promising interventions appear to be treatment with surfactant or surfactant lavage. As few infants have been studied to date further research is warranted possibly using a three armed trial with 1) surfactant administration, 2) surfactant lavage and 3) a control group receiving air.Clinical experience indicates that persistent pulmonary hypertension of the newborn (PPHN) is one of the major causes of death in infants with MAS (Hsieh 2004). There is evidence that meconium injury may directly trigger postnatal release of vasoconstrictors such as ET-1, TXA2, and prostaglandin E2 (PGE2), which play a role in development of pulmonary hypertension (Soukka 1998).Infants with MAS and PPHN are usually treated with oxygen, conventional and/or high frequency mechanical ventilation, inotropic support, induction of alkalosis, and sedation. When these measures fail, ECMO has been shown to improve the outcome (UK Collab 1996). Inhaled NO is frequently used for the treatment of newborns with severe pulmonary hypertension and respiratory failure. Consequently, increasing clinical and experimental evidence suggest that exogenous NO, given by inhalation, selectively reduces pulmonary vasoconstriction and improves oxygenation in a variety of pathological conditions of the newborn lungs, including meconium aspiration (Neonatal iNO 1997; Van Meurs 2003). In recent experimental data, Aaltonen (Aaltonen 2007) demonstrated that iNO in MAS is associated with diminished pulmonary hypertensive response as well as decreased DNA oxidation and neuronal damage in hippocampal tissue that may potentially have significant adverse long-term effects on the developmental status of the affected newborns.ECMO procedures are complex because they require systemic anticoagulation and major vessel cannulation. Studies on inhaled nitric oxide (iNO) therapy for PPHN have shown rapid improvement in oxygenation, reducing the need for ECMO therapy without affecting the mortality (Christou 2000; Clark 2000). Finer and Barrington (Finer 2000) showed that iNO treatment improves oxygenation in approximately 50% of term or near-term neonates with hypoxemic respiratory failure and reduces the combined end point of death or the need for ECMO therapy (relative risk, 0.73) as compared with control subjects. However, lack of an early response to iNO treatment within a few hours in patients who are referred for ECMO therapy and younger age at the time of presentation may indicate the need for ECMO therapy in at least 50% of patients with hypoxic respiratory failure (Fakioglu 2005).Authors' conclusions
Implications for practice
The results of this systematic review provides some support for the use of surfactant treatment in MAS. In infants with MAS leading to moderate to severe respiratory failure, surfactant administration will decrease the number of infants treated with extracorporeal membrane oxygenation. This may have implications especially in resource poor settings where ECMO is not available. In the only study reporting on the duration of hospital stay, this outcomes was significantly reduced.
Implications for research
Although surfactant therapy may be of use in severe meconium aspiration syndrome, the efficacy of surfactant therapy compared to other approaches including inhaled nitric oxide, liquid ventilation, and high frequency ventilation remains to be tested. Other approaches to surfactant therapy, including the use of surfactant lavage, may prove to be effective in the treatment of MAS. Trials that compare surfactant treatment to surfactant lavage and air (control) would be appropriate. The findings of this review need to be confirmed in randomised controlled trials of appropriate size.
Potential conflict of interestDr. R. Soll has acted as a consultant and invited speaker for several of the pharmaceutical companies which manufacture or distribute surfactant preparations (Abbott Laboratories, Ross Laboratories, Chiesi Pharmaceuticals, Dey Laboratories, Burroughs Wellcome). Dr. P. Dargaville has received support for basic science research in surfactant lavage studies from Abbott Australasia. Neither Dr. El Shahed nor Dr. Ohlsson have conflicts of interest to disclose.AcknowledgementsFor the original review we would like to thank Ms. Elizabeth Zola, PharmD for providing diagnosis specific data from the Survanta in Term Infants Study Group. For the updated review, we thank Dr. Andres Maturana for providing us with unpublished data from his study previously published in abstract form only. For the update of this review we thank Ms. Elizabeth Uleryk, Chief Librarian, the Hospital for Sick Children, Toronto, Ontario, Canada, for developing the search strategy for the literature retrieval.Characteristics of included studies
Study
Chinese Collab. 2005
Methods
MulticenterBlinding of randomizations: YesBlinding of treatment: NoComplete follow-up: YesBlinding of outcome measure: No
Participants
Term and near term neonates with MAS, BW > 2500 g, postnatal age <36>15 and needed mechanical ventilation for 1-2 h without improvement.No lethal congenital anomalies, IVH grade II-IV, Apgar score <3 n =" 87)" n =" 81)">50%, MAP >7cm H20, a/A pO2 ratio <0.22, n =" 20)" n =" 20)">2000 g, gestational age >36 wks, age <120> Grade I
Interventions
The treatment group (n = 87) received modified bovine surfactant extract (Survanta, 100 mg/kg) or air placebo (up to 4 doses prior to ECMO and 4 additional doses if ECMO was required)The control group (n = 81) received air placebo
Outcomes
PRIMARY: Need for ECMO, severe complications, mortality
Notes
Only infants with MAS are included in this reviewData for this group were obtained by the authors of the first version of this review
Allocation concealment
A – Adequate
Study
Maturana 2005
Methods
Multicenter (13 centers)Blinding of randomizations: YesBlinding of treatment: YesComplete follow-up: YesBlinding of outcome measure: Yes
Participants
Term infants > 37 weeks of gestation with moderate to severe MAS and respiratory insufficiency within the first 12 hours after birth
Interventions
The treatment group (n = 28) received 150 mg /kg/dose (6ml) of Survanta every 6 hours for a total of three doses if they remained intubatedThe control group (n = 29) received an equivalant amount of air as placebo
Outcomes
PRIMARY: Days of mechanical ventilationSECONDARY: Days requiring oxygen therapy with a target arterial oxygen saturation > 90%, air leaks, PPHN, OI 2 hours after the first treatment dose and mortality before discharge
Notes
Allocation concealment
A – Adequate
a a/A pO2 ratio = arterial-to alveolar oxygen tension ratioBW = birth weightIVH = Intraventricular hemorrhageMAS = meconium aspiration syndromeOI = oxyggen indexPPHN = persistent pulmonary hypertension of the neonate
Study
Reason for exclusion
Auten 1991
Sequential case study; no control group
Blanke 1993
Not randomized, no control group
Diniz 1995
Not randomized
Halliday 1996
Retrospective, not randomized
Ibara 1995
Saline lavage and surfactant replacement, not randomized
Khammash 1993
Sequential case study; no control group
Lam 1999
Not randomized, historical controls, surfactant used as lavage
Nakamura 2000
A randomized trial conducted in piglets
Ogawa 1996
Surfactant lavage
Wiswell 2002
Surfactant lavage
Comparison 01. Surfactant therapy vs.placebo or no therapy in term/near-term infants
Outcome title
No. of studies
No. of participants
Statistical method
Effect size
4
326
Relative Risk (Fixed) 95% CI
0.98 [0.41, 2.39]
2
208
Relative Risk (Fixed) 95% CI
0.64 [0.46, 0.91]
3
269
Relative Risk (Fixed) 95% CI
0.82 [0.39, 1.73]
1
61
Relative Risk (Fixed) 95% CI
0.55 [0.18, 1.70]
1
57
Relative Risk (Fixed) 95% CI
1.04 [0.23, 4.71]
3
158
Weighted Mean Difference (Fixed) 95% CI
0.60 [-0.41, 1.62]
2
97
Weighted Mean Difference (Fixed) 95% CI
0.40 [-2.83, 3.64]
1
40
Relative Risk (Fixed) 95% CI
0.75 [0.32, 1.77]
1
168
Relative Risk (Fixed) 95% CI
0.47 [0.12, 1.80]
2
229
Relative Risk (Fixed) 95% CI
0.67 [0.31, 1.46]
1
168
Relative Risk (Fixed) 95% CI
2.79 [0.30, 26.31]
1
40
Weighted Mean Difference (Fixed) 95% CI
-8.40 [-13.65, -3.15]
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No sources of support supplied
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Department of Paediatrics, Mount Sinai Hospital, Toronto CANADA
Medical Subject Headings (MeSH)
Infant, Newborn; Meconium Aspiration Syndrome [*drug therapy]; Pulmonary Surfactants [*therapeutic use]
MeSH check words
Humans
Title
Surfactant for meconium aspiration syndrome in full term/near term infants
Author(s)
El Shahed AIDargaville POhlsson ASoll RF
Contribution of author(s)
Amr I El Shahed:Updated the search for articlesExcerpted dataReviewed resultsWrote text of reviewPeter Dargaville:Performed the original search for articlesExcerpted dataReviewed resultsEdited text of reviewArne Ohlsson:Updated the search for articlesExcerpted dataReviewed resultsWrote text of reviewRoger F. Soll:Performed the original search for articlesExcerpted dataReviewed resultsEdited the text of updated review
Issue protocol first published
2000 Issue 2
Issue review first published
2000 Issue 2
Date of most recent amendment
May 16, 2007
Date of most recent SUBSTANTIVE amendment
May 16, 2007
What's New
This is an update of the review "Surfactant for meconium aspiration syndrome in full term infants" published in The Cochrane Library, Issue 2, 2002 (Soll 2002).The authorship of this review has been changed to: El Shahed AI, Dargaville P, Ohlsson A, Soll RF.Since this review was first published, two additional trials were identified.The increase in sample size has allowed for greater precision for some of the treatment effects. Surfactant treatment does not appear to have an effect on mortality, but does reduce the need for treatment with extracorporeal membrane oxygenation (ECMO). Surfactant treatment may reduce respiratory related outcomes and hospital stay in term/near-term infants with meconium aspiration syndrome.
Contact address
Dr Amr El Shahed Mount Sinai HospitalPaediatricsTorontoOntarioCANADAM5G 1X5E-mail: amrshahed@yahoo.com
DOI
10.1002/14651858.CD002054.pub2
Cochrane Library number
CD002054
Editorial group
Editorial group code
HM-NEONATAL
References to studies included in this review
Chinese Collaborative Study Group for Neonatal Respiratory Diseases. Treatment of severe meconium aspiration with porcine surfactant: a multicentre, randomized, controlled trial. Acta Paediatrica 2005;94:896-902.
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Findlay RD, Taeusch HW, Walther FJ. Surfactant replacement therapy for meconium aspiration syndrome. Pediatrics 1996;97:48-52.
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Lotze A, Mitchell BR, Bulas DI, Zola EM, Shalwitz RA, Gunkel HJ, et al. Multicenter study of surfactant (beractant) use in the treatment of term infants with severe respiratory failure. Journal of Pediatrics 1998;132:40-7.
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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. PAS2005:57:1545.
References to studies excluded from this review
Auten RL, Notter RH, Kendig, JW, Davis JM, Shapiro DL. Surfactant treatment of full-term newborns with respiratory failure. Pediatrics 1991;87:101-7.
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Blanke JG, Jorch G. Surfactant therapy in severe neonatal respiratory failure - multicenter study - II. Surfactant therapy in 10 newborn infants with meconium aspiration syndrom [Surfactanttherapie bei 10 Neugeborenem mit Mekoniumaspirationssyndrom]. Klinische Padiatrie 1993;205:75-8.
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Chen CT, Toung TJK, Rogers MC. Effect of intra-alveolar meconium on pulmonary surface tension properties. Critical Care Medicine 1985;13:233-6.
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References to other published versions of this review
Soll RF, Dargaville P. Surfactant for meconium aspiration syndrome in full term infants. Cochrane Database of Systematic Reviews 2000, Issue 2.
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