Multicenter, Randomized, Controlled Study of Porcine Surfactant in Severe Respiratory Syncytial Virus-Induced Respiratory Failure

Marco Luchetti, MD; Federica Ferrero, MD; Carla Gallini, MD; Alfonso Natale, MD; Antonia Pigna, MD; Luca Tortorolo, MD; Giuseppe Marraro, MD

Disclosures

Pediatr Crit Care Med. 2002;3(3) 

In This Article

Abstract and Introduction

Objective: Recently, natural exogenous surfactant replacement has been used in experimental models and clinical trials for the treatment of severe respiratory syncytial virus (RSV) disease. The present study was aimed at verifying this hypothesis and confirming the results of our previous pilot study by assessing the effect of surfactant treatment in mechanically ventilated infants with severe RSV-induced respiratory failure.
Design: Multicenter, randomized, controlled study.
Setting: Six pediatric intensive care units staffed by full-time intensive care physicians.
Patients: A total of 40 infants (20 treated and 20 controls) with RSV-induced respiratory failure requiring conventional mechanical ventilation (CMV) were randomly assigned to either exogenous surfactant (treated group) or conventional treatment (control group) over a 1-yr period.
Interventions: Fifty milligrams per kilogram of body weight of porcine-derived natural surfactant (Curosurf) was administered. The drug was instilled by means of a syringe attached to a small suction catheter inserted into the endotracheal tube down to its tip, momentarily disconnecting the patient from CMV.
Main Outcome Measures: The assessment consisted of the following outcome variables: duration of CMV, length of intensive care unit stay, gas exchange, respiratory mechanics, re-treatment need, complications, and mortality.
Results: The two groups were similar with regard to demographics, Pediatric Risk of Mortality scores, and baseline PaO2/FiO2, PaCO2, and ventilator settings. A marked increase in PaO2/FiO2 and decrease in PaCO2 were observed in the treated group after surfactant administration. Hemodynamic parameters remained unchanged throughout the study period. Peak inspiratory pressure and static compliance were similar at baseline in the two groups. A decrease in peak inspiratory pressure and increase in static compliance were observed in the treated group after surfactant administration. Among surfactant-treated patients, 15 received the treatment within 24 hrs of admission, whereas the remainder (five patients) were treated later. Among children who were treated later, three needed an additional dose of surfactant. None of the children treated within 24 hrs needed an additional dose. Duration of CMV and length of stay in the intensive care unit were significantly shorter in the treated group (4.6 ± 0.8 and 6.4 ± 0.9 days, respectively) compared with the control group (5.8 ± 0.7 and 8.2 ± 1.1 days, respectively) (p < .0001). No relevant complications were observed, and all the infants survived.
Conclusions: Consistent with our previous study and others, this study shows that surfactant therapy improves gas exchange and respiratory mechanics and shortens CMV and intensive care unit stay in infants with severe RSV-induced respiratory failure.

Bronchiolitis is caused by respiratory syncytial virus (RSV)-induced damage of the terminal bronchioles and alveoli that mostly affects infants up to 2 yrs of age. The occurrence rate of RSV-associated hospitalization is reportedly increasing.[1]

To date, there is no specific therapy for bronchiolitis. The therapeutic use of bronchodilators, corticosteroids, epinephrine, ribavirin, heliox, and antibiotics has been controversial.[2,3]

The percentage of infants requiring conventional mechanical ventilation (CMV) is variable. CMV is reported to be necessary only in 9% of all infants hospitalized for RSV low respiratory tract infection.[4] This percentage is higher for infants in high-risk categories such as congenital heart disease (19.3%-24%), chronic lung disease (17%-25.3%), and immunodeficiencies (14%).[4,5]

There is no consensus on the optimal ventilation strategy for infants with RSV-induced respiratory failure. Ventilatory support used includes assisted and controlled ventilation with pressure or volume mode, but no study has shown the superiority of one mode over another.[3] The use of positive end-expiratory pressure (PEEP) in bronchiolitis is controversial, but, when a parenchymal restrictive disease is associated to the obstructive component, an adequate PEEP level is indicated, as it has been described by Hammer et al.[6] in the acute respiratory distress syndrome caused by RSV.

Endogenous surfactant activity can be impaired in the course of RSV disease for several reasons: a) the virus-induced damage of type II pneumocytes results in a reduction of surfactant synthesis[7]; b) the protein-rich edema causes an inactivation of surfactant by specific inhibitors and plasma components[8]; c) a damage of the alveolo-capillary membrane may cause a loss of surfactant into interstitium and blood[9]; d) artificial ventilation with large tidal volumes and high fractions of inspired oxygen can further deplete or damage alveolar and bronchial surfactant[10,11]; and e) lack or inactivity of surfactant further favors bronchiolar and alveolar collapse and lung permeability to macromolecules.[12]

As early as 1970, Macklem et al.[13] highlighted the role of bronchial surfactant in stabilizing peripheral airways and suggested that its absence may cause airway obstruction or collapse of the small bronchi with air trapping. The reacquisition of the stability and patency of the peripheral airways allows the reventilation of nonventilated alveoli and the resolution of atelectasis. The concomitant reduction in permeability of the blood-gas barrier to macromolecules allows for a reduced loss of surfactant into interstitium and blood.[14]

Recently, natural exogenous surfactant replacement has been used in experimental models and clinical trials for the treatment of diseases other than premature respiratory distress syndrome, such as the acute respiratory distress syndrome,[15,16,17,18] meconium aspiration syndrome,[19,20] and bronchiolitis,[21,22] with encouraging results.

A previous pilot study by our group[23] demonstrated the efficacy of surfactant treatment of severe bronchiolitis. The association of surfactant with artificial ventilation was found to be superior to artificial ventilation only in improving gas exchange, decreasing airway pressures, and shortening mechanical ventilation time and intensive care unit (ICU) stay.

The rationale for using surfactant treatment in RSV-induced respiratory failure is to restore the surfactant pool, so that while artificial ventilation with PEEP recruits alveoli, surfactant may stabilize them, maintain their patency, and thus restore ventilation of nonventilated areas.

The present study aimed at verifying the hypothesis that porcine surfactant (Curosurf) administration in mechanically ventilated infants with acute respiratory failure due to RSV infection improved gas exchange and respiratory mechanics and shortened the duration of mechanical ventilation and the length of ICU stay by 1 day compared with control. Secondary outcome variables were the improvement of gas exchange and respiratory mechanics, hemodynamic stability, need for re-treatment, incidence of complications, and mortality.

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