CALIPSO: A Randomized Controlled Trial of Calfactant for Acute Lung Injury in Pediatric Stem Cell and Oncology Patients

Abstract

To assess if calfactant reduces mortality among children with leukemia/lymphoma or after hematopoietic cell transplantation (HCT) with pediatric acute respiratory distress syndrome (PARDS), we conducted a multicenter, randomized, placebo-controlled, double-blinded trial in 17 pediatric intensive care units (PICUs) of tertiary care children's hospitals. Patients ages 18 months to 25 years with leukemia/lymphoma or having undergone HCT who required invasive mechanical ventilation for bilateral lung disease with an oxygenation index (OI) > 10 and <37 were studied. Interventions used were intratracheal instillation of either calfactant or air placebo (1 or 2 doses). Forty-three subjects were enrolled between November 2010 and June 2015: 26 assigned to calfactant and 17 to placebo. There were no significant differences in the primary outcome, which was survival to PICU discharge (adjusted hazard ratio of mortality for calfactant versus placebo, 1.78; 95% confidence interval, .53 to 6.05; P = .35), OI, functional outcomes, or ventilator-free days, adjusting for risk strata and Pediatric Risk of Mortality (PRISM) score. Despite the risk-stratified randomization, more allogeneic HCT patients received calfactant (76% and 39%, respectively) due to low recruitment at various sites. This imbalance is important because independent of treatment arm and while adjusting for PRISM score, those with allogeneic HCT had a nonsignificant higher likelihood of death at PICU discharge (adjusted odds ratio, 3.02; 95% confidence interval, .76 to 12.06; P = .12). Overall, 86% of the patients who survived to PICU discharge also were successfully discharged from the hospital. These data do not support the use of calfactant among this high mortality group of pediatric leukemia/lymphoma and/or HCT patients with PARDS to increase survival. In spite of poor enrollment, allogeneic HCT patients with PARDS appeared to be characterized by higher mortality than even other high-risk immunosuppressed groups. Conducting research among these children is challenging but necessary, because survival to PICU discharge usually results in successful discharge to home.

The Current State of Pediatric Acute Respiratory Distress Syndrome

“…Tamburro and Kneyber, 53 Willson et al, 72 Willson et al, 73 Thomas et al, 74 Thomas et al 75 Tamburro and Kneyber, 53 Peter et al, 76 Tang et al, 77 Meduri et al, 78 Drago et al, 79 Yehya et al 80 87 Combes et al, 88 Dalton and Macrae 89 ARDS, acute respiratory distress syndrome; ECMO, extracorporeal membrane oxygenation; HFOV, high-frequency oscillatory ventilation; ICU, intensive care unit; iNO, inhaled nitric oxide; LOS, length of stay; MV, mechanical ventilation; NMB, neuromuscular blockade; PEEP, positive-end-expiratory pressure; PROSpect, PRone and OScillation Pediatric Clinical Trial; RCT, randomized controlled trial.…”

“…Subsequent trials of calfactant in direct-injury PARDS and PARDS following stem cell transplant and lucinactant for PARDS demonstrated no benefit for outcomes such as mortality, ventilation time, or LOS. [73][74][75] Given these data, the PALICC guidelines do not recommend routine use of surfactant in PARDS, 53 but recommend further studies to determine if other specific populations may benefit.…”

A shared protocol for porcine surfactant use in pediatric acute respiratory distress syndrome: a feasibility study

“…Unfortunately none of these data has been replicated in the second study in 2013 [8]. A more recent RCT published by Thomas on the use of calfactant in patients with leukemia/lymphoma or after hematopoietic stem cell transplantation and pARDS reported data that did not support the use of calfactant among this high mortality cohort to increase survival [9].…”

“…On the other hand, the lack of large, randomized controlled trial (RCT) in pARDS and surfactant use limited the evidence supporting clear benefit. Most of the studies are on small series except three RCT on the effect of calfactant [7–9]. The populations enrolled are poorly homogenous for surfactant dosing, age or underlying diseases.…”

“…Not all showed the same results when used in vivo. Poractant alfa seems to be the one with the best efficacy in terms of oxygenation improvement while calfactant has shown conflicting results [7–9].…”