Is there literature surrounding the use of surfactant for RDS in pediatric patients besides neonates?

Is there literature surrounding the use of surfactant for RDS in pediatric patients besides neonates?

Comment by InpharmD Researcher

Surfactant therapy has been investigated in pediatric patients with respiratory distress syndrome (RDS) beyond the neonatal period, with available studies suggesting potential improvements in oxygenation and respiratory outcomes. However, evidence remains limited by small sample sizes, heterogeneous patient populations (ages ranging up to 21 years), and variability in surfactant formulations, dosing regimens, and administration strategies.

Background

A 2008 review of surfactant therapy for pediatric acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) described encouraging findings from controlled studies in children up to 21 years of age. Early studies evaluating intratracheal surfactant administration demonstrated improvements in oxygenation, with some reports of reduced ventilator days and intensive care unit length of stay (see Tables 1-2). A subsequent multicenter randomized controlled trial (see Table 3) evaluated calfactant (Infasurf®) in 153 pediatric patients with ALI/ARDS (age range, 1 week to 21 years) and found that surfactant therapy resulted in improved oxygenation, reduced oxygenation index, decreased mortality, and improved response to conventional mechanical ventilation compared with placebo. However, benefits appeared greatest among patients with direct lung injury forms of ALI/ARDS, and differences in study design, patient populations, and disease severity limited the generalizability of findings. [1]

A 2025 systematic review and meta-analysis evaluated the safety and efficacy of pulmonary surfactant therapy in children with ALI or ARDS. The analysis included 7 multicenter randomized controlled trials involving children aged 1 month to 18 years who received surfactant therapy compared with placebo. Surfactant use was associated with a reduction in mortality, increased ventilator-free days, and fewer adverse events; however, no significant differences were observed in duration of mechanical ventilation or oxygenation index. The authors concluded that while surfactant therapy may provide clinical benefit in critically ill children with ARDS, further research is needed due to variability among studies and uncertainty regarding its overall clinical impact. [2]

Literature Review

A search of the published medical literature revealed 4 studies investigating the researchable question:

Is there literature surrounding the use of surfactant for RDS in pediatric patients besides neonates?

Level of evidence

B - One high-quality study or multiple studies with limitations Read more→

Please see Tables 1-4 for your response.

Calf's lung surfactant extract in acute hypoxemic respiratory failure in children
Design	Multi-institutional, uncontrolled, observational trial N= 29
Objective	To assess the safety and short-term efficacy of calf's lung surfactant in pediatric respiratory failure
Study Groups	All patients (n= 29)
Inclusion Criteria	Bilateral, diffuse lung disease observed clinically and radiographically; mechanical ventilation; oxygenation index of >7
Exclusion Criteria	Status asthmaticus, postobstructive pulmonary edema, clinically important cardiac failure or uncorrected congenital heart disease
Methods	Endotracheal installation of 80 mL/m2 of Infasurf in four equal aliquots in rotating positions. Hand ventilation with FIO2 of 1.0, using peak pressures and rates approximating previous ventilator settings. Retreatment criteria included initial improvement of >25% in oxygenation index within 4 hrs and deterioration within 8 to 24 hrs.
Duration	2-year period
Outcome Measures	Improvement in oxygenation index, moderation of ventilator support, complications, mortality rate
Baseline Characteristics		All patients (n= 29)
	Age, years	4.7
	Median age, years	1.7
	Female	18
Results		All patients (n= 29)
	Improvement in oxygenation index	24 of 29 patients
	Mortality rate	14%
	Duration of ventilation, days	17.3 ± 3
	Pediatric ICU stay, days	20.5 ± 3
	Hospital stay, days	31 ± 5
Adverse Events	Three instances of airleaks (two pneumothoraces, one pneumopericardium); hypoxia with dose administration resolved with continued hand ventilation; one case of bronchospasm resolved with albuterol.
Study Author Conclusions	Administration of calf's lung surfactant appears to be safe and is associated with rapid improvement in oxygenation and moderation of ventilator support in children with acute hypoxemic respiratory failure. These results set the stage for a randomized, controlled study.
Critique	The study demonstrated significant improvement in oxygenation and ventilator parameters, but the lack of a control group and small sample size limit the ability to draw definitive conclusions about the efficacy of surfactant therapy. The study's open-label design and protocol violations may also impact the reliability of the results. Further randomized controlled trials are needed to confirm these findings.

Table 1 References:
[3] Willson DF, Jiao JH, Bauman LA, et al. Calf's lung surfactant extract in acute hypoxemic respiratory failure in children. Crit Care Med. 1996;24(8):1316-1322. doi:10.1097/00003246-199608000-00008

Instillation of calf lung surfactant extract (calfactant) is beneficial in pediatric acute hypoxemic respiratory failure
Design	Multi-institutional, prospective, randomized, controlled, unblinded trial N= 42
Objective	To assess the efficacy of calf lung surfactant extract in improving oxygenation and reducing the duration of mechanical ventilation and intensive care in pediatric patients with acute hypoxemic respiratory failure
Study Groups	Surfactant group (n= 21) Control group (n= 21)
Inclusion Criteria	Children with acute hypoxemic respiratory failure characterized by diffuse, bilateral pulmonary infiltrates, need for ventilatory support, and an oxygenation index of ≥7; term infants >1 day to 18 years of age
Exclusion Criteria	Preexisting chronic lung disease, status asthmaticus, cardiogenic pulmonary edema, lethal brain injury, or congestive heart failure and/or uncorrected congenital heart disease
Methods	Endotracheal instillation of 80 mL/m2 of Infasurf delivered in four equal aliquot portions in rotating positions. Hand ventilation during administration with an FIO2 of 1.0. Control patients were hand ventilated without surfactant instillation.
Duration	3-year study period
Outcome Measures	Primary: Mortality Secondary: Duration of mechanical ventilation, length of pediatric ICU stay, oxygenation improvement, extubation by 72 hours
Baseline Characteristics		Surfactant group (n= 21)	Control group (n= 21)
	Pediatric Risk of Mortality score	12 +/- 6	9 +/- 4
	Oxygenation index	25.9 +/- 20	20.5 +/- 11
	Ventilation index	45 +/- 31	38 +/- 22
	PaO2/FIO2 ratio	102 +/- 53	105 +/- 42
Results		Surfactant group (n= 21)	Control group (n= 21)	p-value
	Days on mechanical ventilation	4.2 fewer days	-	-
	Days in pediatric ICU	5 fewer days	-	-
	Extubated by 72 hours	8:17	1:18	<0.01
Adverse Events	Few complications reported. One patient had bronchospasm associated with instillation, resolved with albuterol. Two children in the surfactant group developed airleaks 3 to 5 days after administration, unlikely related to surfactant.
Study Author Conclusions	Administration of calf lung surfactant extract, calfactant, is safe and associated with rapid improvement in oxygenation, earlier extubation, and decreased requirement for intensive care in children with acute hypoxemic respiratory failure. Further study is needed before widespread use can be recommended.
Critique	The study demonstrated significant improvements in oxygenation and reduced time on mechanical ventilation and ICU stay. However, the study was originally designed to examine mortality, not these secondary outcomes. Lack of blinding and inclusion of patients from an earlier study may have influenced results. A larger, blinded, controlled trial is necessary for firm recommendations.

Table 2 References:
[4] Willson DF, Bauman LA, Zaritsky A, Dockery K, James RL, Stat M, et al. Instillation of calf lung surfactant extract (calfactant) is beneficial in pediatric acute hypoxemic respiratory failure. Crit Care Med. 1999;27:188-195. doi:10.1097/00003246-199901000-00050.

Effect of Exogenous Surfactant (Calfactant) in Pediatric Acute Lung Injury: A Randomized Controlled Trial
Design	Multicenter, randomized, blinded trial N= 153
Objective	To determine if endotracheal instillation of calfactant in infants, children, and adolescents with ALI would shorten the course of respiratory failure
Study Groups	Calfactant group (n= 77) Placebo group (n= 75)
Inclusion Criteria	Age 1 week to 21 years; enrollment within 48 hours of endotracheal intubation; radiological evidence of bilateral lung disease; oxygenation index higher than 7
Exclusion Criteria	Premature infants; children with preexisting lung, cardiac, or central nervous system disease
Methods	Intratracheal instillation of 2 doses of 80 mL/m2 calfactant or an equal volume of air placebo administered 12 hours apart. Patients were randomized and treatment was blinded. Ventilator guidelines were followed, and data were collected prospectively
Duration	July 2000 to July 2003
Outcome Measures	Primary: Ventilator-free days and mortality Secondary: Hospital course, adverse events, failure of conventional mechanical ventilation
Baseline Characteristics		Calfactant (n= 77)	Placebo (n= 75)
	Age, years	7.2 (6.4)	6.7 (6.4)
	Male	50 (65%)	41 (55%)
	Pediatric Risk of Mortality Score	15 (9.4)	14.1 (7.9)
Results		Calfactant (n= 77)	Placebo (n= 75)	p-value
	Mortality	15 (19%)	27 (36%)	0.03
	Ventilator-free days	13.2 ± 10	11.5 ± 10.5	0.21
	Conventional mechanical ventilation failure	13 (21%)	26 (42%)	0.02
Adverse Events	Immediate complications such as hypotension (9% vs. 1%) and transient hypoxia (12% vs. 3%) were more frequent in the calfactant group but resolved with intervention. No systemic complications were attributed to the intervention.
Study Author Conclusions	Calfactant acutely improved oxygenation and significantly decreased mortality in infants, children, and adolescents with ALI although no significant decrease in the course of respiratory failure measured by duration of ventilator therapy, intensive care unit, or hospital stay was observed.
Critique	The study was well-designed as a multicenter, randomized, and blinded trial, providing robust data on the efficacy of calfactant. However, it was underpowered to detect differences in ventilator-free days, and the inclusion of a higher number of immunocompromised patients in the placebo group may have influenced mortality outcomes. Future studies should stratify for immune status and mechanism of lung injury to better understand subgroup effects.

Table 3 References:
[5] Willson DF, Thomas NJ, Markovitz BP, et al. Effect of exogenous surfactant (calfactant) in pediatric acute lung injury: a randomized controlled trial. JAMA. 2005;293(4):470-476. doi:10.1001/jama.293.4.470

Treatment with bovine surfactant in severe acute respiratory distress syndrome in children: a randomized multicenter study
Design	Single-center pilot study followed by an open, randomized, parallel-group, multicenter comparison in Germany N= 35
Objective	To determine whether bovine surfactant given in cases of severe pediatric acute respiratory distress syndrome (ARDS) improves oxygenation
Study Groups	Surfactant group (n= 20) Nonsurfactant group (n= 15)
Inclusion Criteria	Children with ARDS after the 44th postconceptional week and under 14 years old, with PaO₂/FIO₂ <100 for at least 2 h, admitted for at least 4 h, ventilated for 12–120 h, and without heart failure or chronic lung disease
Exclusion Criteria	Patients under other investigational or experimental therapies, chronic lung disease, participation in other clinical studies, severe hypoxemia (PaO₂ <50 after 4 h of treatment)
Methods	A bovine surfactant was administered in 50 mg/kg increments (intratracheal bolus under continuous ventilation and positive end-expiratory pressure [PEEP] over maximally 5 min) as long as the PaO₂/FIO₂ ratio did not increase by 20% or decrease by 10%. Administration of 100 mg/kg bovine surfactant intratracheally was completed under continuous ventilation and PEEP, as soon as the PaO₂/FIO₂ dropped to <100 for 2 h (in the pilot study increments of 50 mg/kg so long as PaO₂/FIO₂ did not increase by 20%). A second equivalent dose within 48 h was permitted.
Duration	May 1997 to November 1999
Outcome Measures	Primary: Change in PaO₂/FIO₂ at 48 h Secondary: Survival, survival without rescue
Baseline Characteristics		Surfactant (n= 20)	Controls (n= 15)
	Median age (range; years)	3.5 (0–13)	4.5 (0–12)
	Female, n (%)	7 (35%)	7 (46.7%)
	Mean body weight (kg)	15.7±10.4	22.4±20.7
	Causative diagnosis pneumonia, n (%)	15 (68.2%)	11 (68.7%)
	Causative diagnosis sepsis, n (%)	7 (31.8%)	5 (31.3%)
	Lung injury score at randomization	3.0	3.3
Results		Surfactant (n= 20)	Controls (n= 15)	p-value
	Change in PaO₂/FIO₂at 48 h	+38 (0/122)	+22 (0/78)	*See below
	Mortality, n (%)	8 (44%)	9 (60%)	p=0.29
	Death and/or rescue, n (%)	11 (56%)	12 (80%)	p=0.13
	*PaO2/FIO2 was significantly higher in the surfactant group 2 h after the first surfactant dose (p<0.003). Even after 48 h the surfactant group patients still showed a trend toward a greater, but not significantly different, increase in PaO2/FIO2 ratio (presented as graph).
Adverse Events	No treatment associated adverse events were observed in the surfactant group; however, the expected risk of intermittent obstruction of the endotracheal tube with a short time deterioration in oxygenation was observed in three patients
Study Author Conclusions	Surfactant therapy in severe ARDS improves oxygenation immediately after administration. This improvement is sustained only in the subgroup of patients without pneumonia and that with an initial PaO₂/FIO₂ ratio higher than 65.
Critique	The study faced challenges in recruitment due to the decreasing incidence of ARDS in children, which led to an early termination. The small sample size and the high mortality rate in the study population may limit the generalizability of the findings. Despite these limitations, the study provides valuable insights into the potential benefits of surfactant therapy in pediatric ARDS, particularly in specific subgroups of patients.

Table 4 References:
[6] Möller JC, Schaible T, Roll C, et al. Treatment with bovine surfactant in severe acute respiratory distress syndrome in children: a randomized multicenter study. Intensive Care Med. 2003;29(3):437-446.