Introduction

Meconium aspiration syndrome (MAS) is a common cause of severe respiratory distress in neonates, particularly term and post-term infants. Meconium-stained amniotic fluid occurs in 5–10% of all deliveries, with up to approximately 30% of neonates born after 42 weeks’ gestation being affected.[1] In ball-valve fashion, aspirated meconium can provoke partial airway obstruction (leading to air trapping and a high risk of air leak) or complete obstruction of small airways (leading to regional atelectasis). About 30% of babies with MAS will require mechanical ventilation; some will also require nitric oxide (NO) therapy or extracorporeal membrane oxygenation because of persistent pulmonary hypertension of the newborn in association with severe acute respiratory distress syndrome (ARDS).[2]

Progression of meconium into distal airspaces frequently results in development of chemical pneumonia. Moreover, meconium in the alveoli inactivates the surfactant system, contributing to a deterioration in lung mechanics and decreased lung compliance.[3,4] Thus, an optimal approach to treatment of MAS would be to remove residual meconium from the lung, thereby preserving surfactant activity. Studies have shown that administration of diluted surfactant solution by bronchoalveolar lavage (BAL) enables residual meconium to be washed out from the bronchial tree, resulting in enhanced surfactant activity and lung function both in animal models and in human newborns with MAS.[5–12]

The positive effects of modified porcine surfactant on lung function in animal models with MAS have been described in the literature.[13,14] Based on these findings, we evaluated the efficacy and safety of BAL with diluted surfactant saline suspension (porcine lipid extract surfactant [Curosurf®, Chiesi Farmaceutici SpA, Parma, Italy])Footnote 1 in mechanically ventilated term infants with severe ARDS due to MAS.

Materials and Methods

Patients

The study was conducted at the Neonatal Intensive Care Unit of the Vittore Buzzi Children’s Hospital, Milan, Italy. Participants in the study consisted of eight consecutive term infants requiring mechanical ventilation during the first 6 hours of life because of severe ARDS (arterial-alveolar oxygen tension ratio [a/ApO2] <0.2) due to MAS: ventilation criteria were fraction of inspired oxygen (FiO2) requirement >0.4; arterial partial pressure of carbon dioxide (PaCO2) >60mm Hg, and arterial partial pressure of oxygen (PaO2) <50mm Hg. Subjects were recruited over a 2-year period (from August 2001 to August 2003). The diagnosis of ARDS due to MAS was made according to radiological and clinical criteria (coarse infiltrates and areas of hyperaeration on chest x-ray, and tachydyspnoea with hypercapnia and hypoxia in the newborn with meconium-stained fluid in the airways). Infants with lethal congenital anomalies were excluded from the study. Mechanical ventilation consisted of synchronised intermittent positive-pressure ventilation with the option of volume guarantee (volume-targeted ventilation) [Dräger Babylog 8000 Plus, software version 5.0, Dräger Medical, Vienna, Austria].

The study was conducted with the approval of the Vittore Buzzi Children’s Hospital Ethics Committee. Subjects were included in the study only after written informed parental consent had been obtained.

Study Design

All study participants underwent BAL, consisting of 15 mL/kg of surfactant saline suspension (porcine lipid extract surfactant 80mg phospholipid/mL, diluted to a concentration of 5.3mg phospholipid/mL). As a result of this dilution, study participants received 80mg surfactant phospholipid/kg. BAL was administered in 2.5mL aliquots delivered to the end of the endotracheal tube. In cases of severe oxygen desaturation (arterial oxygen saturation [SaO2] <80%), BAL was halted and subjects underwent manual bagging until SaO2 returned to normal (>90%). After delivery of each aliquot of BAL, suctioning of meconium debris was conducted via a catheter (French size 8), using a negative pressure of 80–90mm Hg, until the tracheal fluids were clear of meconium.

Heart rate, systemic blood pressure and SaO2 were monitored continuously. Samples for arterial blood gas tension measurement (Radiometer Copenhagen, ABL700) were collected from an indwelling catheter immediately before BAL, and again at 3 and 6 hours after treatment. Ventilator settings (tidal volume, mean airway pressure and FiO2) were recorded at the time of arterial blood gas sampling. Chest x-rays were conducted before BAL, and at 6 and 24 hours after treatment. Echocardiography was performed daily to detect and monitor persistent pulmonary hypertension of the newborn.

For all subjects, tidal volume was set at 5 mL/kg, positive end-expiratory pressure at 4–5cm H2O, and inspiratory time at 0.3–0.4 seconds. Within the ranges stated, these parameters were adjusted to maintain SaO2 (as measured by pulse oximetry) at 91–96%, PaO2 at 40–75mm Hg, PaCO2 at 45–65mm Hg, and pH >7.25.

Statistical Methods

ANOVA with the Bonferroni post hoc test was used for statistical analysis. The significance level was taken as p < 0.05. Data are reported as means ± SD.

Results

The clinical characteristics of the study population are listed in table I. The mean age of study participants at administration of BAL was 3.5 (range 1–8) hours. The mean duration of the procedure was 35 ± 10 minutes.

Table I
figure Tab1

Baseline characteristics of the study population (n = 8)

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Efficacy

Radiological improvement was observed in all subjects 6 hours after BAL (air leak resolved in 2/8 patients; good reductions in coarse infiltrates and areas of hyperaeration on chest x-ray were observed in 6/8 patients).

Improvements in mean PaO2, PaCO2, pH, a/APO2 and oxygenation index (OI) were also observed 3 and 6 hours after BAL compared with pre-BAL values (p < 0.05 for pH and PaCO2 at 3 hours, p < 0.05 for all parameters at 6 hours [table II]). The mean length of mechanical ventilation was 2.88 ± 1.25 (range 1–5) days. The mean duration of oxygen supplementation was 4.25 ± 2.05 (range 3–8) days. Only one patient required NO therapy (5 ppm for 12 hours) for transient pulmonary hypertension. In two patients with pneumothorax prior to BAL, the lesions were no longer evident on the 6-hour post-treatment chest x-ray. In all babies, recovery of tracheal fluid during suctioning was incomplete (30–65% of the total lavage fluid volume instilled into the lung). However, all recovered tracheal fluids were clear of meconium at the end of BAL.

Table II
figure Tab2

Respiratory and ventilatory parameters before and 3 and 6 hours after bronchoalveolar lavage (BAL) [values are given as mean ± SD]

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Safety and Tolerability

BAL was well tolerated by all subjects. No changes in blood pressure or episodes of bradycardia were observed during the procedure. No episodes of pulmonary haemorrhage occurred. No patients died during the study or had adverse sequelae of any kind.

Discussion

The aim of this preliminary study was to evaluate the efficacy and safety of BAL with diluted porcine surfactant in mechanically ventilated term infants with ARDS due to MAS. Our results showed that slow administration of diluted surfactant in small amounts by BAL improved oxygen status and chest x-ray findings, and reduced the length of both mechanical ventilation and oxygen supplementation, without any major adverse effects, in this patient population.

Several factors account for the pathophysiology of MAS. First, high-molecular weight mucous glycoproteins in meconium give the substance adhesive properties, making it more likely to cause airway obstruction when inhaled. Secondly, meconium can cause chemical injury to the respiratory epithelium. Thirdly, many components of meconium, such as lipids, proteins and bilirubin, potently inhibit surfactant activity, contributing to severe respiratory failure in MAS.[15,16]

These findings have prompted research into the possible benefits of exogenous surfactant therapy in the treatment of ARDS due to MAS. One important finding from this research is that the mode of administration of such therapy contributes to its efficacy. In one study performed in an acute lung injury animal model, for example, bolus administration of surfactant was not as effective as the same surfactant administered by lung lavage.[17] The reason for this appears to be that exogenously administered surfactant is not distributed uniformly throughout the lung following bolus or aerosol administration.[18,19]

Numerous animal and clinical studies have shown that early lavage with surfactant solution significantly improves respiratory function in animals and neonates with acute lung injury and with MAS.[5,8,20,21] The procedure generally involves the initial administration of a relatively large volume of surfactant solution, but the excess fluid is drained immediately, leaving only a small residual volume of lavage fluid in the lungs (about 15%).[5,8] Repeated lavage followed by suctioning removes meconium and lung debris responsible for both airway obstruction and surfactant inactivation. Even if only about 15% of the administered surfactant is retained,[5,8] the improvement in lung compliance and better gas exchange indicate that surfactant administration was effective and distribution of the surfactant particles was homogenous.[5,8,17,21]

It is now known that the endogenous surfactant pool in humans is smaller than first estimated: the alveolar wash contains about 2 mmol/kg of saturated phosphatidylcholine/kg, which is equivalent to about 4 mg/kg surfactant, a relatively small pool size compared with other species.[22] Recognition of this fact has prompted evaluation of much lower doses of exogenous surfactant than had previously been used in surfactant deficiency/dysfunction. Both animal and human studies have now confirmed that BAL with a diluted surfactant solution first reduces the airway obstruction by removing meconium and airway proteinaceous debris, thereby reducing the risk of airway obstruction and subsequent surfactant inactivation, then, with the subsequent doses of the lavage fluid, achieves a homogeneous alveolar distribution of the surfactant particles.[5,7,8,20,23,24]

In neonatal piglets with acute lung injury, lavage administration of a variety of artificial and natural diluted surfactant preparations (4–4.5mg phospholipid/mL) improved oxygenation and other parameters of pulmonary function as effectively as undiluted surfactant (13.5mg phospholipid/mL).[19] It is likely that acute lung injury with surfactant deficiency could be effectively treated even with a simple surfactant administration, while the efficacy of treatment of MAS with diluted surfactant is probably more linked to removal of meconium and debris. In confirmation of that, tracheobronchial lavage with 15 mL/kg of diluted surfactant solution (5mg phospholipid/mL) administered in 2mL aliquots significantly improved oxygen status and reduced duration of ventilation and oxygen therapy, without adverse effects, in six neonates with severe MAS.[7] In another pilot study of 22 neonates with severe MAS, diluted surfactant BAL (15 mL/kg; 5mg phospholipid/mL) was associated with a lower OI and higher PaO2 at 1 hour, reduced duration of mechanical ventilation and less time in hospital, compared with historical controls.[20] Finally, a previous retrospective clinical study of 54 infants with MAS showed generally modest therapeutic effects with porcine surfactant.[25]

Our results also provide evidence that smaller doses of surfactant (i.e. 80 mg/kg of diluted porcine lipid extract surfactant, compared with the usual dosages of 200 or 100 mg/kg) are effective when administered as BAL in neonates with ARDS due to MAS.

Our study also showed that administration of surfactant solution in small (2.5mL) aliquots was well tolerated. Importantly, this approach would also be appropriate in patients with MAS-related haemodynamic instability, in whom BAL with large fluid volumes can overload the cardiorespiratory system.[26] Furthermore, patients in our study did not experience pulmonary haemorrhage, an event that has been reported in an earlier study.[27] It is well known that pulmonary haemorrhage is an event strictly linked to perinatal hypoxia, but our ‘gentler’ small-volume procedure probably does not increase the risk of injury to the pulmonary epithelium. There was also no increase in the incidence of pulmonary hypertension (only one patient needed a short course of inhaled NO for transient pulmonary hypertension revealed by an increased velocity of the tricuspid regurgitation jet at the ecochardiographic control without clinical significance), a condition frequently associated with MAS.[26]

Because of its low potential to cause fluid overload and severe hypoxaemia, the BAL regimen used in our study could be administered even to infants with very high baseline OI scores. Indeed, BAL with diluted surfactant (using small-volume aliquots) could be used in all newborns (including preterm infants receiving prolonged mechanical ventilation, who might benefit from BAL fractionated in very small amounts because this minimises the risks of interrupting mechanical ventilation during the lavage procedure) in whom accumulation of lung debris inhibits surfactant activity. Our results confirm that such treatment would be expected to facilitate weaning from ventilator and oxygen therapy.

The small number of subjects and the lack of controls are limitations of this study. Recent changes in the approach to mechanical ventilation of the neonate with MAS mean that supportive management in historic controls differs from current practice, making comparisons difficult.

Conclusion

Our preliminary study suggests that BAL with diluted porcine surfactant (phospholipid concentration 5.3 mg/mL), administered slowly and in small amounts, improved oxygen status, resolved chest x-ray abnormalities, and facilitated weaning from mechanical ventilation in infants with ARDS due to MAS. These benefits were achieved without adverse effects. Our findings suggest that BAL with diluted surfactant would be a reasonable adjunct to ventilation, antibacterials, chest physiotherapy, haemody- namic support and treatment of pulmonary hypertension (if indicated) in the management of MAS. However, larger randomised studies are required to validate the use of this procedure in the neonatal setting.