Video Abstract
Exogenous surfactants to treat respiratory distress syndrome (RDS) are approved for tracheal instillation only; this requires intubation, often followed by positive pressure ventilation to promote distribution. Aerosol delivery offers a safer alternative, but clinical studies have had mixed results. We hypothesized that efficient aerosolization of a surfactant with low viscosity, early in the course of RDS, could reduce the need for intubation and instillation of liquid surfactant.
A prospective, multicenter, randomized, unblinded comparison trial of aerosolized calfactant (Infasurf) in newborns with signs of RDS that required noninvasive respiratory support. Calfactant was aerosolized by using a Solarys nebulizer modified with a pacifier adapter; 6 mL/kg (210 mg phospholipid/kg body weight) were delivered directly into the mouth. Infants in the aerosol group received up to 3 treatments, at least 4 hours apart. Infants in the control group received usual care, determined by providers. Infants were intubated and given instilled surfactant for persistent or worsening respiratory distress, at their providers’ discretion.
Among 22 NICUs, 457 infants were enrolled; gestation 23 to 41 (median 33) weeks and birth weight 595 to 4802 (median 1960) grams. In total, 230 infants were randomly assigned to aerosol; 225 received 334 treatments, starting at a median of 5 hours. The rates of intubation for surfactant instillation were 26% in the aerosol group and 50% in the usual care group (P < .0001). Respiratory outcomes up to 28 days of age were no different.
In newborns with early, mild to moderate respiratory distress, aerosolized calfactant at a dose of 210 mg phospholipid/kg body weight reduced intubation and surfactant instillation by nearly one-half.
Surfactant therapy is only approved for administration by intubation. However, neonatal intubation can be harmful. Aerosolized surfactant can avoid intubation and may be efficacious. However, clinical trials to date have been small and mostly uncontrolled and have had mixed results.
Our large, multicenter randomized controlled trial reveals that aerosolized surfactant, by using a novel delivery device, can be readily administered, independent of the nasal respiratory support circuit, and significantly reduces the need for neonatal intubation and instillation of liquid surfactant.
Animal-derived surfactants decrease morbidity and mortality among newborns with respiratory distress syndrome (RDS).1–5 Early surfactant administration decreases the risk of pulmonary injury and neonatal death compared to delayed treatment.6 Experts have suggested that treatment should begin as soon as signs of RDS appear.7
However, neonatal endotracheal intubation, necessary for intratracheal surfactant administration, can be difficult and harmful.8,9 First-attempt failure rates are high8,10 and multiple attempts are associated with complications.11,12 Lung injury occurs more frequently in newborns requiring intubation because even brief use of positive pressure breaths starts an inflammatory cascade, leading to alveolar damage.13–15
Less invasive methods of surfactant administration are being studied in an effort to avoid the complications of intubation; these include using an intratracheal catheter or supraglottic airway device. Both of these methods, however, still subject the neonate to airway manipulation and/or positive pressure breaths.16–19 Aerosol delivery of surfactant avoids manipulation of the airway and requires no technical skill.
In animal models of RDS, aerosolized surfactant improves gas exchange and lung mechanics similar to bolus instillation, with less physiologic disturbance.20–22 Animal studies suggest more homogeneous surfactant distribution with aerosol delivery.20,23 There have been only two small randomized controlled clinical trials (RCTs) of aerosolized surfactant; results were mixed, and the efficacy of this approach remains unclear.24,25
We conducted a large, multicenter RCT, comparing aerosolized surfactant to usual care in spontaneously breathing newborns with respiratory distress. We hypothesized that in newborns requiring noninvasive respiratory support for suspected or confirmed RDS, those who receive aerosolized surfactant between 1 and 12 hours of age would be less likely to require intubation for liquid surfactant administration than those who receive usual care during the first 4 postnatal days.
Methods
In this pragmatic clinical trial, we compared aerosolized calfactant (Infasurf; ONY Biotech, Amherst, NY) to usual care in newborns with early mild to moderate respiratory distress in 22 level III or IV NICUs in the United States. Before randomization, we obtained written informed consent from each infant’s parent(s) or guardian, either prenatally or shortly after birth. The protocol was approved by a national institutional review board (Western Institutional Review Board, Olympia, WA) as well as local institutional review boards, if required. The trial was monitored by an independent data and safety committee. Data analysis was conducted by an independent statistician. The completeness and accuracy of the data and analysis was assured by the sponsor’s clinical trial monitors, a contract research firm (Applied Healthcare Research Management, Buffalo, NY) retained by the sponsor, and by the study statistician. All data were available to the authors, who developed the article. The authors vouch for the accuracy and completeness of the data and adherence of the trial to the protocol. The trial was registered on www.clinicaltrials.gov on February 23, 2017, before the first patient was enrolled (identifier NCT03058666).
Participants
Two cohorts were recruited with separate randomization sequences at each site. Cohort 1 were newborns who were nonintubated, had not previously received surfactant, were >1 hour but <12 hours of age, and were with suspected or confirmed RDS requiring therapeutic administration of nasal respiratory support by nasal continuous positive airway pressure (nCPAP), high-flow nasal cannula, or noninvasive ventilation. Initially, there was an entry requirement for a fraction of inspired oxygen (Fio2) concentration of 0.25 to 0.40. Four months into the trial, it was discovered that several sites were using higher positive airway pressures to minimize Fio2. Because of this practice change, the minimum Fio2 requirement was removed in the fifth month of the trial. Cohort 2 were patients <24 hours of age who had received liquid surfactant by 1 hour of age and were then extubated to nasal respiratory support.
Exclusion criteria were a congenital anomaly limiting care or requiring surgery; hypotension with metabolic acidosis (a base deficit >10 mEq/L); hypoxemia (O2 saturation <88%) or hypercapnia (arterial partial pressure of carbon dioxide [Paco2] ≥60 mm Hg) unresponsiveness to intervention; grade 3 or 4 intraventricular brain hemorrhage; or acute hypoxic encephalopathy, defined as disturbed neurologic function, including abnormal tone and/or reflexes for gestational age, after a suspected perinatal hypoxic-ischemic event, as evidenced by a 5-minute Apgar score <5 and/or umbilical cord acidosis (pH <7.0 and/or based deficit ≥16 mmol/L).
Design
Each site was given separate sequential randomization codes in opaque envelopes. The study sponsor generated the code for each site using the Moses-Oakford algorithm. Group assignment was indicated by the next sequential envelope. Alternating blocks of size 2 and 4 were used but not revealed to investigators. The study was unblinded.
The aerosol group received 6 mL/kg body weight of 35 mg/mL calfactant suspension, 210 mg phospholipids/kg body weight, through a modified Solarys nebulizer. The Solarys device is approved by the Food and Drug Administration for delivering drugs to intubated patients. The distal end was modified to resemble a pacifier; the tip was an inverted dome, through which the calfactant aerosol was generated. (See Supplemental Fig 8 for photographs of the modified Solarys device.) The device is seated in the mouth with the patient in the “sniffing” position and secured by using a Tortle bonnet. As per the manufacturer, the rate of delivery is 0.20 ± 0.02 mL/minute. Aerosol delivery was continuous, not synchronized with inspiration. In preclinical and pilot studies, normal fluctuations in airway pressure while receiving noninvasive support did not significantly change during aerosol delivery. Infants in the aerosol group could receive up to 3 doses during the first 72 hours of age. Repeat dosing required a positive response to the previous dose (a reduction in Fio2 and/or airway pressure within 1 hour) and ≥4 hours from the start of the previous dose.
All data were extracted from the medical records during the first 28 days of age or until death or hospital discharge, whichever occurred first.
Study Outcomes
The primary outcome was endotracheal intubation and liquid surfactant instillation within the first 4 days of age. Gestational age, postnatal age, concurrent medical problems, and risk of respiratory failure are each important modifiers of whether an individual patient requires liquid surfactant therapy. The decision to intubate a newborn with RDS is both highly complex and individualized. During pretrial discussions, site investigators were unanimous that this critical decision be left up to the clinical provider; not only would it add pragmatic strength, but it would be ethically compliant with the infant’s best interest. We, therefore, did not set criteria for the primary end point nor require documentation of the clinician’s reasoning for making this decision. Secondary outcomes included respiratory support at 3, 7, and 28 days of age or hospital discharge, whichever was earlier. Safety outcomes included any adverse event during aerosol delivery; pneumothorax or other lung air leak; pulmonary hemorrhage; pneumonia (as determined by the clinical team); other severe complications of prematurity (grade 3 or 4 intraventricular hemorrhage, patent ductus arteriosus requiring treatment, hypotension requiring treatment, necrotizing enterocolitis stage ≥2, neutropenia, or sepsis).
Statistical Analysis
Measured outcomes were summarized by using standard descriptive statistics; except where noted differently, values are mean ± SD. Efficacy analyses were planned for each cohort separately. Primary outcome analyses, both intent to treat and as treated, were conducted by using a 1-sided Cochran-Mantel-Haenszel test, stratified by site. Robustness was assessed by using logistic regression, with the additional covariates (gestational age, birth weight, age when randomly assigned, sex, delivery mode, and antenatal steroids). The relative risk (RR) and corresponding 90% confidence interval (CI) were computed for the primary outcome. Group comparisons of secondary variables were performed by using the Cochran-Mantel-Haenszel test or Fisher’s exact test, depending on observed frequencies. A nominal significance level of 5% was used.
Study sample size was based on a proposed RR for the primary outcome. We estimated a 60% rate of intubation within the usual care group based on a study of supraglottic surfactant administration in a similar clinical population.26 A clinically meaningful effect was defined as a 20% relative decrease in the intubation rate. Calculations revealed a sample size of 229 per group (458 total) in cohort 1 would result in >80% power.
Results
Parents of 772 infants were approached for consent. Of these infants, 477 were randomly assigned into the 2 cohorts between April 2017 and June 2018 (Fig 1). Nearly all (96%) were enrolled in cohort 1. Having reached our sample size target for cohort 1, further enrollment in cohort 2 was discontinued. The remainder of this article refers to cohort 1 only.
CONSORT (Consolidated Standards of Reporting Trials) flow diagram for AERO-02 study. a It is presumed that most never met entry criteria; however, some consented patients may have not been randomly assigned for other reasons.
CONSORT (Consolidated Standards of Reporting Trials) flow diagram for AERO-02 study. a It is presumed that most never met entry criteria; however, some consented patients may have not been randomly assigned for other reasons.
The demographic characteristics and baseline respiratory supports were similar between the 2 study groups (Table 1). Although not required by study protocol, 322 of 457 infants had a chest radiograph on day 1; in all cases, the radiograph confirmed a diagnosis of RDS (Supplemental Fig 9). There were 230 infants randomly assigned to the aerosol group; 225 received 334 treatments at a median age of 5 hours (interquartile range [IQR]: 3–7); 149 (66%) received only one aerosol treatment, 43 (19%) received 2 treatments, and 33 (15%) received 3 treatments. There was no difference in the number of treatments when stratified by gestational age (2-week blocks) or birth weight (250 g blocks). The mean dose volume was 12.9 ± 4.7 mL, and administration took an average of 68 ± 34 minutes.
Characteristics of Patients at Random Assignment
| Characteristic | Aerosolized Calfactant (n = 230) | Usual Care (n = 227) |
|---|---|---|
| Male sex, No. (%) | 133 (58) | 136 (60) |
| Gestational age, wk, mean ± SD | 33.2 ± 3.2 | 33.1 ± 3.1 |
| Birth wt, g, mean ± SD | 2126 ± 828 | 2081 ± 769 |
| Singleton births, No. (%) | 162 (70) | 169 (74) |
| Vaginal delivery, No. (%) | 60 (26) | 77 (34) |
| Antenatal steroids for fetal lung maturation, No. (%) | ||
| None | 62 (27) | 58 (26) |
| <12 h before delivery | 39 (17) | 44 (19) |
| >12 h before delivery | 113 (49) | 109 (48) |
| Unknown | 16 (7) | 16 (7) |
| Apgar score, median (IQR) | ||
| 1 min | 7 (2) | 7 (2) |
| 5 min | 8 (1) | 8 (1) |
| Respiratory status at random assignment | ||
| Fio2, mean ± SD | 0.30 ± 0.10 | 0.32 ± 0.14 |
| nCPAP, No. (%) | 163 (71) | 158 (70) |
| NIPPV, No. (%) | 24 (10) | 26 (11) |
| High-flow nasal cannula, No. (%) | 6 (3) | 11 (5) |
| Supplemental oxygen only, No. (%) | 20 (9) | 15 (7) |
| Not recorded, No. (%) | 16 (7) | 17 (7) |
| Age at random assignmenta, No. (%) | ||
| <4 h | 96 (42) | 107 (51) |
| 4–8 h | 94 (41) | 68 (33) |
| >8 h | 40 (17) | 33 (16) |
| Characteristic | Aerosolized Calfactant (n = 230) | Usual Care (n = 227) |
|---|---|---|
| Male sex, No. (%) | 133 (58) | 136 (60) |
| Gestational age, wk, mean ± SD | 33.2 ± 3.2 | 33.1 ± 3.1 |
| Birth wt, g, mean ± SD | 2126 ± 828 | 2081 ± 769 |
| Singleton births, No. (%) | 162 (70) | 169 (74) |
| Vaginal delivery, No. (%) | 60 (26) | 77 (34) |
| Antenatal steroids for fetal lung maturation, No. (%) | ||
| None | 62 (27) | 58 (26) |
| <12 h before delivery | 39 (17) | 44 (19) |
| >12 h before delivery | 113 (49) | 109 (48) |
| Unknown | 16 (7) | 16 (7) |
| Apgar score, median (IQR) | ||
| 1 min | 7 (2) | 7 (2) |
| 5 min | 8 (1) | 8 (1) |
| Respiratory status at random assignment | ||
| Fio2, mean ± SD | 0.30 ± 0.10 | 0.32 ± 0.14 |
| nCPAP, No. (%) | 163 (71) | 158 (70) |
| NIPPV, No. (%) | 24 (10) | 26 (11) |
| High-flow nasal cannula, No. (%) | 6 (3) | 11 (5) |
| Supplemental oxygen only, No. (%) | 20 (9) | 15 (7) |
| Not recorded, No. (%) | 16 (7) | 17 (7) |
| Age at random assignmenta, No. (%) | ||
| <4 h | 96 (42) | 107 (51) |
| 4–8 h | 94 (41) | 68 (33) |
| >8 h | 40 (17) | 33 (16) |
NIPPV, noninvasive positive pressure ventilation.
Data are missing for 19 infants in the usual care group; the percentage shown is based on N = 208.
Primary Outcome
Intubation for liquid surfactant instillation occurred in 113 infants (50%) in the usual care group and 59 infants (26%) in the aerosol group, in an intent-to-treat analysis (P < .0001); RR: 0.51 (90% CI: 0.41–0.63). The number needed to treat to prevent 1 intubation is 5. Adjustment for gestational age, birth weight, age when randomly assigned, sex, delivery mode, and antenatal steroids did not impact significance (P < .0001). Rates of intubation were consistently lower for infants in the aerosolized calfactant group in all 2-week gestational age brackets except the lowest (23–24 weeks), in which all infants required intubation. (Fig 2). Age at first instillation was significantly later in the aerosol group (Table 2). Primary outcome efficacy varied by center but favored aerosolized calfactant in all but 2 centers (Fig 3).
Primary outcome (intubation for liquid surfactant) by gestational age. The percentage of infants intubated and treated with liquid surfactant instillation is shown for each study group (right hand) and broken down by 2-week gestational age blocks (left hand). The aerosolized calfactant group is shown in blue, and the usual care group is shown in red. * P <.005; ** P <.0001 by Fisher’s exact test.
Primary outcome (intubation for liquid surfactant) by gestational age. The percentage of infants intubated and treated with liquid surfactant instillation is shown for each study group (right hand) and broken down by 2-week gestational age blocks (left hand). The aerosolized calfactant group is shown in blue, and the usual care group is shown in red. * P <.005; ** P <.0001 by Fisher’s exact test.
Primary Efficacy Outcome: Intubation and Liquid Surfactant Instillation
| Intent to Treat | As Treated | As Treated and Eligiblea | ||||
|---|---|---|---|---|---|---|
| Aerosolized Calfactant | Usual Care | Aerosolized Calfactant | Usual Care | Aerosolized Calfactant | Usual Care | |
| Number included | 230 | 227 | 226 | 231 | 219 | 230 |
| Intubated, No. (%) | 59 (26)b | 113 (50) | 56 (25)b | 116 (50) | 52 (24)b | 115 (50) |
| Age at first intubation, h, mean ± SD | 24 ± 16c | 10 ± 13 | 25 ± 16c | 10 ± 13 | 26 ± 16c | 10 ± 13 |
| Intent to Treat | As Treated | As Treated and Eligiblea | ||||
|---|---|---|---|---|---|---|
| Aerosolized Calfactant | Usual Care | Aerosolized Calfactant | Usual Care | Aerosolized Calfactant | Usual Care | |
| Number included | 230 | 227 | 226 | 231 | 219 | 230 |
| Intubated, No. (%) | 59 (26)b | 113 (50) | 56 (25)b | 116 (50) | 52 (24)b | 115 (50) |
| Age at first intubation, h, mean ± SD | 24 ± 16c | 10 ± 13 | 25 ± 16c | 10 ± 13 | 26 ± 16c | 10 ± 13 |
Excludes 7 patients entered who did not meet the entry criteria and 1 patient in the aerosol group who did not receive the correct aerosol dose.
P < .001
P < .05, compared to usual care.
Forest plot of primary efficacy outcome by study sites. The primary outcome was intubation and instillation of liquid surfactant. n of N is the number who experienced this outcome divided by the number randomly assigned. Data are shown for cohort 1 only. The combined sites were the 6 that each enrolled <10 total patients. The RR of the primary outcome, with 95% CIs, is shown in right-hand column.
Forest plot of primary efficacy outcome by study sites. The primary outcome was intubation and instillation of liquid surfactant. n of N is the number who experienced this outcome divided by the number randomly assigned. Data are shown for cohort 1 only. The combined sites were the 6 that each enrolled <10 total patients. The RR of the primary outcome, with 95% CIs, is shown in right-hand column.
Protocol Violations
There were 14 infants with protocol violations. Six did not receive the assigned treatment; 1 infant randomly assigned to usual care received aerosol, and 5 infants randomly assigned to aerosol received usual care. Six infants exceeded eligibility requirements at randomization; each required Fio2 >0.40 and/or had hypercarbia. One infant did not meet the eligibility criteria; this infant was in room air at randomization. One infant received an incorrect aerosol dose. When infants were reassigned to the group that represented their actual treatment (as treated) and ineligible infants were removed (as treated and eligible), analysis of the primary outcome did not significantly change compared to the intent-to-treat analysis (Table 2).
Secondary Outcomes
There were no differences in respiratory support on days 3, 7, and 28 (discharge) between groups (Supplemental Table 5). The incidence of pulmonary air leaks was similar between groups (Table 3).
Pulmonary Air Leaks During First 72 Hours of Age
| Characteristic | Aerosolized Calfactant (n = 230) | Usual Care (n = 227) | P |
|---|---|---|---|
| Any air leak, No. (%) | 14 (6.1) | 11 (4.8) | .56 |
| Type of air leak, No. (%)a | .78b | ||
| Pneumothorax only | 8 (57) | 7 (64) | — |
| Pneumomediastinum only | 1 (7) | 2 (18) | — |
| Pulmonary interstitial emphysema only | 1 (7) | 1 (9) | — |
| Multiple air leaks | 4 (29) | 1 (9) | — |
| Relation to liquid surfactant, No. (%)a | .17b | ||
| Never received liquid surfactant | 3 (21) | 1 (9) | — |
| Before receiving liquid surfactant | 5 (36) | 1 (9) | — |
| After receiving liquid surfactant | 6 (43) | 9 (82) | — |
| Characteristic | Aerosolized Calfactant (n = 230) | Usual Care (n = 227) | P |
|---|---|---|---|
| Any air leak, No. (%) | 14 (6.1) | 11 (4.8) | .56 |
| Type of air leak, No. (%)a | .78b | ||
| Pneumothorax only | 8 (57) | 7 (64) | — |
| Pneumomediastinum only | 1 (7) | 2 (18) | — |
| Pulmonary interstitial emphysema only | 1 (7) | 1 (9) | — |
| Multiple air leaks | 4 (29) | 1 (9) | — |
| Relation to liquid surfactant, No. (%)a | .17b | ||
| Never received liquid surfactant | 3 (21) | 1 (9) | — |
| Before receiving liquid surfactant | 5 (36) | 1 (9) | — |
| After receiving liquid surfactant | 6 (43) | 9 (82) | — |
—, not applicable.
Percentage of all air leaks (not patients).
P value across all subgroups via Fisher’s exact test.
Of 334 aerosol treatments, 22 were briefly interrupted, primarily because of surfactant foaming around the pacifier. There were no monitor events (desaturation or bradycardia) during treatment that required intervention. One treatment was discontinued when pink-colored surfactant dribbled from the infant’s mouth. This infant had remained stable during treatment, and no lesions were noted in the mouth. In a laboratory investigation by the sponsor, it was determined that 0.1 mL of blood added to 1 mL of calfactant is sufficient to turn the material pink or red; we concluded that a trace amount of residual blood (either maternal or neonatal) in the infant’s mouth after birth was the likely cause.
One or more severe complications of prematurity occurred in 17 infants (7%) in the aerosol group and 14 infants (6%) in the usual care group. Chronic lung disease, defined as any respiratory support at 28 days of age, was diagnosed in 46 (20%) infants in the aerosol group and 38 infants (17%) in the usual care group (P = .38). There was 1 death in the usual care group due to nonrespiratory causes.
Post Hoc Analyses for Bias
Because the study was unblinded and the primary outcome was dependent on clinical decision-making, we explored for the possibility of treatment bias. Because the rate of intubation for liquid surfactant in our usual care group (50%) was lower than expected, there is no suggestion of overtreatment bias regarding the primary outcome in that group. We, therefore, focused on undertreatment bias within the aerosol group. There were 171 infants in that group who were never intubated; 154 of these had received <3 doses. If their condition worsened, we would expect that they would have received all 3 doses of aerosolized calfactant and/or be intubated for liquid surfactant, but neither happened. That leaves 17 infants who received all 3 aerosol doses allowed by protocol but were never intubated; if their condition worsened but they were not intubated, bias is created favoring the aerosol group. However, even if we consider all 17 to have been intubated, the difference in primary outcome rates between the 2 groups would still be significant, 33% vs 50% (RR: 0.66; 95% CI: 0.53–0.83; P = .0003). Additional post hoc analyses are presented in Supplemental Figs 4–7.
Discussion
This large, multicenter, RCT in neonates requiring noninvasive respiratory support for suspected or confirmed RDS revealed that aerosolized calfactant reduces the need for intubation and liquid surfactant instillation by nearly 50%. As a result, far fewer infants in the aerosol group were subjected to the potential harms of laryngoscopy and intubation.
To date, clinical trials of aerosolized surfactant administration in newborns with RDS have been small, mostly uncontrolled, and with mixed results. The first was by Robillard et al27 in 1964, who administered L-α-lecithin by microaerosol to 11 infants ranging from 680 to 3120 g birth weight; 8 infants showed improvement and survived to discharge. In the ensuing 55 years, there have been 6 published studies of aerosolized surfactant.24,25,28–31 Three of these were prospective, including 1 sequentially assigned pilot study30 and 2 RCTs24,25 ; in 1 RCT, researchers found a reduction in nCPAP failure rates,25 whereas, in the other, researchers found no differences.24
The efficacy of an aerosolized surfactant is likely dependent on a complex interaction among multiple factors, including the type of surfactant, nebulization method, lung recruitment strategy, age at administration, and RDS severity. Given the progressively worsening nature of lung injury with RDS, we would anticipate that aerosolized surfactant would be more effective earlier in the course of disease. We, therefore, selected infants with mild to moderate respiratory distress and treated them early, at a median age of 5 hours.
Surfactant delivery by aerosol is inefficient, but current clinical dosing may be far greater than needed to treat RDS. In lung-lavaged, spontaneously breathing rabbits, aerosolized surfactant improved lung function at a significantly lower dose than bolus.32 By using the lung deposition rate from that study (14%), the surfactant dose used in our study would equate to ∼29 mg/kg reaching the distal functional lung space, or approximately one-half the amount present in a healthy term infant.
Our study is the first to reveal the efficacy of an aerosolized surfactant delivery system that does not require a respiratory circuit interface. In all previous studies, researchers delivered aerosolized surfactant in-line with nCPAP, with the potential to interfere with respiratory support. By using a separate, pacifier interface, both the aerosol delivery and nCPAP flow can be managed independently, which should allow for safer patient care.
Recognizing that neonatal intubation is difficult and potentially harmful, less invasive methods have been sought; these include the use of an intratracheal catheter (minimally invasive surfactant therapy or less invasive surfactant administration) or a supraglottic device (surfactant administration through laryngeal or supraglottic airways). These methods appear to be safe and effective and may reduce the need for mechanical ventilation,16–19,33–35 but more studies are needed.36–38
Aerosolized surfactant delivery is different from other minimally invasive administration methods. Minimally invasive surfactant therapy and less invasive surfactant administration require laryngoscopy and catheter placement below the vocal cords,39 whereas surfactant administration through laryngeal or supraglottic airways requires placement of a specialized device into the supraglottic airway; both techniques require a skilled operator. Aerosolized surfactant delivery is unique in that no instrumentation of the airway is needed and no mechanical apparatus is introduced into the airway. Thus, aerosolization may be the gentlest, easiest, and least invasive approach.23
Our randomized, controlled study has several strengths, including a large sample size, wide range of gestational ages, and multicenter nature. We also believe that our pragmatic approach adds an important practical aspect. In this study, we enrolled relatively few infants <28 weeks’ gestation; many were ineligible because of intubation in the delivery room or having more severe respiratory distress. Sicker, more premature infants will more likely fail noninvasive respiratory support and require early surfactant treatment.40 Because a dose of aerosolized calfactant takes 1 to 2 hours to administer, we did not want to delay definitive treatment; this is consistent with the pragmatic nature of our study and best clinical practice. Our results suggest that aerosolized calfactant may have delayed intubation and liquid surfactant instillation in some infants who ultimately needed this intervention, but this did not adversely affect their respiratory outcomes.
The study was not blinded. A nontherapeutic sham procedure such as aerosolization of saline for the usual care group was deemed ethically unacceptable because it could complicate respiratory therapy with no benefit. Masking, by using a second team of care providers, was considered impractical; a recent pilot study of aerosolized surfactant had to be halted because of the financial burden imposed in part by such a design.25 More importantly, during a pretrial pilot study, an immediate positive clinical effect was noted in virtually all treated infants; masking would, therefore, be ineffective. Proper masking would also require separating parents from their newborn for 2 to 3 hours each time an aerosol treatment was given; we deemed that unacceptable from a family-centered perspective.
Chest radiographs were not required by study protocol, consistent with our pragmatic design and to minimize radiation exposure. Without radiographic confirmation, it is possible that some infants may have had etiologies other than RDS for their respiratory distress, such as transient tachypnea. However, >70% of infants had an early chest radiograph, and, in every case, their radiograph was consistent with RDS.
The unblinded intervention and lack of prespecified criteria for the primary outcome introduce the potential for treatment bias; however, post hoc analysis suggests that our primary outcome findings would remain significant in the event that treatment bias was present.
Conclusions
Aerosolized calfactant can be readily administered to newborn infants with mild to moderate respiratory distress and reduces the need for intubation and liquid surfactant instillation during the first 4 days of age. The use of aerosolized calfactant avoids the risks associated with endotracheal intubation and expands opportunities for surfactant therapy in the hospitalized patient.
Dr Cummings helped design the study, conducted initial data analyses, and created, reviewed, and revised all manuscript drafts including the final version; Drs Wilding and Egan conceptualized and designed the study (including data collection instruments), conducted data analyses, coordinated and supervised data collection, and worked on the drafts of the manuscript (including writing, table, and figure preparation and critical review of each draft version); Drs Gerday, Minton, Katheria, Albert, Flores-Torres, Famuyide, Lampland, Guthrie, Kuehn, Weitkamp, Fort, Abu Jawdeh, Ryan, Martin, Swanson, Mulrooney, Eyal, Gerstmann, and Kumar contributed to the acquisition of data and worked on the drafts of the manuscript (including writing, table, and figure preparation and critical review of each draft version); and all authors approved the final manuscript as submitted and agree to be accountable for all aspects of the work.
Deidentified individual participant data that underlie the results reported in this article will be made available, in addition to study protocols, informed consent, and statistical analysis plan. The data will be available beginning 3 months and ending 5 years after article publication to investigators whose proposed use of the data has been approved by an independent review committee identified for this purpose. Proposals should be directed to [email protected]. To gain access, data requestors will need to sign a data access agreement.
A complete list of Aero-02 investigators, along with affiliations, can be found in the Supplemental Information.
This trial has been registered at www.clinicaltrials.gov (identifier NCT03058666).
FUNDING: Aero-02 was funded by ONY Biotech, manufacturer of Infasurf, the surfactant used in this trial. Dr Egan, chief medical officer of ONY Biotech, collaborated with Drs Cummings and Wilding in the design of the trial. ONY Biotech provided the Solarys nebulizer and the Infasurf for the trial. ONY Biotech retained an independent data management organization (Applied Healthcare Research Management, Inc, Raleigh, NC) who provided the complete data set to Dr Cummings, the study chair and lead author, and Dr Wilding, the study biostatistician.
COMPANION PAPER: A companion to this article can be found online at www.pediatrics.org/cgi/doi/10.1542/peds.2020-021576.
Comments
RE: Bianco and Pillow
Bianco and Pillow noted that our clinical trial of an aerosolized surfactant to treat newborns with respiratory distress is the largest reported to date. In that randomized trial we found infants treated with aerosolized calfactant were significantly less likely to need intubation and liquid surfactant instillation.
Although Bianco and Pillow characterize our study’s clinician-driven outcomes as “shortcomings”, these study features were thoroughly vetted at a pre-trial investigators’ meeting. Determining when a newborn needs invasive surfactant therapy is a highly complex decision and standard practice among our study centers was individualized patient care decision-making. The investigators unanimously concluded that protocol-driven criteria would make the study infants’ care different, and inferior, to non-study patients. Our paper acknowledged the potential for outcome bias created by our pragmatic and ethical study design and provided additional analyses that suggest our findings would remain significant even if such bias were present.1
Bianco and Pillow noted the limited inclusion of infants < 28 weeks’ gestation. Again, this was a direct consequence of our pragmatic and ethical study design. Investigators did not want to interfere with optimal management of the smallest, most fragile infants who typically are intubated early and treated with liquid surfactant; we could not enroll a large number of infants below 28 weeks since most of them were presumably treated in this fashion and therefore ineligible.
Bianco and Pillow opined that the variability of non-invasive ventilatory (NIV) techniques created a potential source of bias. Concern would be that the two study groups were managed differently. However, as noted by Bianco and Pillow, the baseline distribution of NIV techniques was similar. In addition, although not reported in the paper, the distribution of NIV techniques was also similar between groups at each 6-hour time point through the first 72 hours, attesting to comparable NIV management between groups.
Bianco and Pillow commented on the “restricted” description of the technical features of the nebulizer set-up and aerosol particle size distribution. The multi-lumen inhalation catheter we used is similar to others reported in the literature.2 The gas outflow from the modified Solarys aerosol generator is 0.9 liters per minute which in bench studies does not significantly alter delivered airway pressures during NIV.3 We did not report the particle size distribution because particles in the respirable range are not necessary for aerosolized calfactant to achieve deep lung deposition. Virtually all inhaled calfactant would impact on the upper airways and rapidly spread distally;4 this is precisely what occurs after instilling liquid surfactant. Aerosolized calfactant does not rely on the inhaled airstream to be carried to its point of action. Drug loss from around the pacifier was recorded in our study and found to be minimal.
Bianco and Pillow noted that we estimated a lung deposition based on the average of 14% reported using a methodology that differed in some ways from our own. That was actually a conservative lower estimate. In an unpublished study in newborn lambs, using the methods employed on our trial, we measured deposition rates of > 20%.
References
1. Cummings JJ, Gerday E, Minton S, et al. Aerosolized Calfactant for Newborns With Respiratory Distress: A Randomized Trial. Pediatrics 2020;146(5):e20193967
2. Murgia X, Gastiasoro E, Mielgo V, et al. Surfactant and Perfluorocarbon Aerosolization During Different Mechanical Ventilation Strategies by Means of Inhalation Catheters. J Aerosol Med Pulm Drug Deliv 2012;25(2):23-31
3. Commarato CJ, Swartz D. Bench Testing of Effects of Solarys Infasurf Pacifier Aerosol System Device (Infasurf PAS Device). Report. Unpublished data on file, ONY Biotech, Amherst, NY
4. Kim K, Choib SQ, Zella ZA et al. Effect of Cholesterol Nanodomains on Monolayer Morphology and Dynamics. Proc Natl Acad Sci USA 2013;110(33):E3054-60
5. Swartz D, Ferguson W. Nebulization of Infasurf in Surfactant Deficient and Term Lambs. Report. Unpublished data on file, ONY Biotech, Amherst, NY
James J. Cummings, MD MS
Chief Medical Officer
ONY Biotech
Amherst, NY
RE: Comments by Bianco and Pillow
As noted by Bianco and Pillow, our clinical trial of an aerosolized surfactant to treat newborns with respiratory distress is the largest reported to date and showed that aerosolized calfactant significantly reduced the need for intubation and liquid surfactant instillation.
We take issue with their characterizing our study’s clinician-driven determination of treatment failure and lack of blinding as “shortcomings”. These study design features were thoroughly vetted at the pre-trial investigators’ meeting. Determining when a newborn needs invasive surfactant therapy is a highly complex decision and standard practice among our study centers was individualized patient care decision-making. The investigators unanimously concluded that to have protocol-driven criteria would have made the study infants’ care different, and potentially inferior, compared to non-study patients. Blinding was deemed not only impractical, but futile.
Bianco and Pillow fail to note that our paper specifically acknowledged the potential for outcome bias created by our pragmatic and ethical study design, and that we provided additional analyses that argued against such bias.1 We also designed our study so as not to interfere with optimal management of the smallest, most fragile infants who typically are intubated early and treated with liquid surfactant; we could not enroll a large number of infants below 28 weeks since most of them were presumably treated in this fashion.
Bianco and Pillow speculate that allowing a variety of non-invasive ventilatory (NIV) strategies could differentially affect the incidence of respiratory failure between study groups. That would require systematic management bias, not only among clinical providers at a given center but among all 22 centers in the trial. Such bias seems highly implausible. Nevertheless, we examined our study data and found that the distribution of NIV techniques was similar between groups, not only at study entry, but at each 6-hour time point through the first 72 hours of age, attesting to comparable NIV management between groups.
The multi-lumen inhalation catheter we used is similar to others reported in the literature.2 The gas outflow from the modified Solarys aerosol generator is 0.9 liters per minute which in bench studies does not significantly alter delivered airway pressures during NIV.3 We also believe that particle size is not relevant, since virtually all the inhaled calfactant impacts on the upper airways and rapidly spreads distally;4 this is precisely what occurs after instilling liquid surfactant. Particle size is only relevant if an aerosol must rely solely on the inhaled airstream to be carried to its point of action. Aerosolized calfactant does not. Drug loss from around the pacifier was recorded in our study and found to be minimal.
When estimating lung deposition we cited a methodology that differed in some ways from our own. Based on our novel approach and the unique characteristics of calfactant, we actually anticipated a somewhat higher rate of deposition; this was supported by unpublished preclinical studies in newborn lambs where we achieved lung deposition rates of > 20%.5 However, in our paper we decided to reference the published literature, knowing it would represent a conservative lower estimate.
References
1. Cummings JJ, Gerday E, Minton S, et al. Aerosolized Calfactant for Newborns With Respiratory Distress: A Randomized Trial. Pediatrics 2020;146(5):e20193967
2. Murgia X, Gastiasoro E, Mielgo V, et al. Surfactant and Perfluorocarbon Aerosolization During Different Mechanical Ventilation Strategies by Means of Inhalation Catheters. J Aerosol Med Pulm Drug Deliv 2012;25(2):23-31
3. Commarato CJ, Swartz D. Bench Testing of Effects of Solarys Infasurf Pacifier Aerosol System Device (Infasurf PAS Device). Report. Unpublished data on file, ONY Biotech, Amherst, NY
4. Kim K, Choib SQ, Zella ZA et al. Effect of Cholesterol Nanodomains on Monolayer Morphology and Dynamics. Proc Natl Acad Sci USA 2013;110(33):E3054-60
5. Swartz D, Ferguson W. Nebulization of Infasurf in Surfactant Deficient and Term Lambs. Report. Unpublished data on file, ONY Biotech, Amherst, NY
James J. Cummings, MD MS
Chief Medical Officer
ONY Biotech
Amherst, NY
RE: Surfactant aerosolization: technical details that matter
Cummings et al.1 reported the results from the trial comparing the oral aerosolization of Calfactant with the standard care in infants with Respiratory Distress Syndrome (RDS). This study enrolled 457 infants (gestational age 23-41 weeks), representing the largest trial on surfactant aerosolization conducted so far. The authors reported a significant decrease in the proportion of newborns intubated for liquid surfactant instillation in the intervention group.
Although the results appear to be encouraging, the trial has a few shortcomings that give rise to diverse interpretations. Glaser and Wright2 identified some important potential sources of bias in the study design, including the lack of a clear criteria for liquid surfactant therapy and the absence of a strict definition of failure of the intervention with aerosolized surfactant. They also raised a concern on the limited inclusion of infants <28 weeks’ gestation.
Another potential bias source is represented by the variability of the non-invasive ventilation (NIV) techniques allowed. The authors report an equal distribution of the techniques applied in the study arms at randomization. However, our understanding is that there was no protocol limitation on switching to another NIV technique during the observation period. Moreover, no data are available on the proportion of infants that may have been switched to another NIV strategy, which could have impacted on the incidence of respiratory failure.3
Additionally, we would like to comment on the restricted description of the technical features of the nebulizer set-up; we believe that the inclusion of relevant data such as the aerosol particle size distribution would facilitate the interpretation of the results. The authors speculate that their inhalation catheter system would allow a lung deposition of 29 mg/kg of surfactant on the basis of the average of 14 % deposition reported in a preclinical study by Bianco et al.4 Nevertheless, the surfactant preparation, nebulizer type, and its configuration within the NIV circuit were considerably different in these studies. Notably, vibrating-membrane nebulizers produce slow, small diameter particles that are transported by the bias flow, whereas inhalation catheters produce fast particles with a high momentum that may readily impact against the upper airways.5 Additionally, the prongs were fitted tightly to the animals in the by Bianco et al. study, whereas the pacifier used to keep in place the aerosolizing catheter described by Cummings et al. allows an undetermined amount of leaks which may have contributed to a significant drug loss.
Lastly, the inhalation catheter delivers a continuous air-flow to the mouth of the infants, which may have an impact on the NIV support level administered. Goikoetxea et al.5 reported a driving pressure-dependent increase of the distal airway pressure ranging between 0.5-1.5 cmH2O in vitro using a similar multi-lumen inhalation catheter. Therefore, the air-flow produced by the catheters in the mouth of the infants may have provided inadvertent additional respiratory support.
In summary, the aforementioned limitations may raise questions on the claim that the clinical benefit observed in a subset of the population studied can be attributable to aerosolized surfactant without any doubt.
References
1. Cummings, J. J., Gerday, E., Minton, S., Katheria, A. & Albert, G. Aerosolized Calfactant for Newborns With Respiratory Distress : A Randomized Trial. 146, (2020).
2. Glaser, K. & Wright, C. J. Aerosolized Calfactant in Infants With. 146, 0–3 (2020).
3. Lemyre, B., Davis, P. G., De Paoli, A. G. & Kirpalani, H. Nasal intermittent positive pressure ventilation (NIPPV) versus nasal continuous positive airway pressure (NCPAP) for preterm neonates after extubation. Cochrane Database Syst. Rev. (2017) doi:10.1002/14651858.CD003212.pub3.
4. Bianco, F. et al. From bench to bedside: In vitro and in vivo evaluation of a neonate-focused nebulized surfactant delivery strategy. Respir. Res. 20, (2019).
5. Goikoetxea, E. et al. In vitro surfactant and perfluorocarbon aerosol deposition in a neonatal physical model of the upper conducting airways. PLoS One 9, e106835 (2014).
RE: Choubey et al
We appreciate the comments offered by Choubey et al. We offer the following in reply.
Choubey et al stated that the requirement for surfactant in our study patients was much higher than described in the literature. That is incorrect. The reported incidence of 12.8% they cited refers to all neonatal intensive care unit (NICU) admissions, not only those with RDS.1 In our study population, which was limited to newborns with RDS requiring non-invasive respiratory support, the incidence of intubation for instilled surfactant in the usual care (control) group was actually lower than one might anticipate, based on a clinical trial reported just prior to starting our study.2 The 50% incidence of intubation for instilled surfactant in our control group, at a mean gestational age of 33 weeks, is consistent with results reported in the CureNeb study, which found a 68% incidence of intubation for instilled surfactant in the control group of newborns with RDS, at a slightly earlier mean gestational age of 31 weeks.3
As noted by Choubey et al, the primary outcome of our study was the need for intubation and instilled surfactant, as determined by the neonatologist. They concluded that this pragmatic approach would decrease generalizability. We disagree. By allowing NICUs to follow their own best practices, our study design increases, not decreases, the generalizability of our results. Indeed, the intended benefit of pragmatic trials is that they improve external validity, i.e., applicability to the real-world.4
Choubey at al suggest that our study approach using aerosolized calfactant introduces a significantly higher cost without any reduction in relevant clinical outcomes. We disagree on both counts. The additional cost related to aerosolized calfactant would represent an extremely small portion of overall hospitalization costs for a preterm infant with RDS and would be partly offset by the reduced need for intubation and instilled surfactant. We also found that among study infants with so-called “mild” RDS, those who received aerosolized calfactant weaned from respiratory support significantly faster than infants receiving usual care, suggesting additional cost-savings.5 In regard to reducing relevant clinical outcomes, we strongly believe that a nearly 50% reduction in intubation, as shown in our study, is highly relevant to the clinical care of the fragile newborn infant.
Lastly, Choubey et al suggest that future trials of aerosolized surfactant could focus on smaller preterm infants in an effort to reduce chronic lung disease among infants at highest risk. Despite a relatively small sample size, the lack of benefit we found in infants born at 23-26 weeks of gestation suggests otherwise. For a variety of reasons, drug delivery by aerosolization in non-intubated newborns is likely to be increasingly less effective with decreasing gestational age. Other alternatives to intubation that are both less invasive than intubation and still highly effective at delivering surfactant, such as supraglottic airway devices, carry significantly more promise for those infants at highest risk for adverse pulmonary outcomes, namely those born before 27 weeks of gestation.
RE: Surfactant aerosolization: technical details that matter
Cummings et al.1 recently reported the results from a clinical trial comparing the oral aerosolization of Calfactant delivered directly to the mouth using a nebulizing catheter modified with a pacifier, with the standard care in preterm and near term infants with Respiratory Distress Syndrome (RDS) that required non-invasive ventilation (NIV).
This study was a prospective, multicenter, randomized, unblinded trial that enrolled 457 infants (gestational age 23-41 weeks), representing the largest trial on surfactant aerosolization conducted so far. The authors reported a significant decrease in the proportion of newborns intubated for liquid surfactant instillation in the intervention group, although there were no differences in the ventilation support at 3, 7, and 28 days of age, nor in chronic lung disease rates.
The results appear to be encouraging and may boost the clinical development of a truly non-invasive surfactant therapy. However, the trial has a few shortcomings that give rise to diverse interpretations of the results. In a letter to the editor, Glaser and Wright2 identified some important potential sources of bias in the study design, including the lack of a clear criteria for liquid surfactant therapy, which is important given the intervention was not blinded and hence knowledge of prior surfactant exposure may influence decision to intubate. The absence of a strict definition of failure of the intervention with aerosolized surfactant was identified as a second important source of clinical bias. They also commented on the lack of data regarding the fraction of inspired oxygen, PaCO2, positive end-expiratory pressure, and mean airway pressure and raised a concern on the limited inclusion of infants <28 weeks’ gestation. Another potential bias source is represented by the variability of the NIV techniques allowed. The authors report an equal distribution of the techniques applied in the study arms at randomization. However, our understanding is that there was no protocol limitation on switching to another NIV technique during the observation period. Moreover, no data are available on the proportion of infants that may have been switched to another NIV strategy, which could have impacted on the incidence of respiratory failure.3
In addition to the concerns on the study design, we would like to comment on the restricted description of the technical features of the nebulizer set-up applied in the trial; we believe that the inclusion of relevant data such as the aerosol particle size distribution would facilitate the interpretation of the results of this study. In particular, the authors speculate that their set up would allow a lung deposition of 29 mg/kg of surfactant on the basis of the average of 14 % deposition reported in a preclinical study by Bianco et al.4. Nevertheless, the surfactant preparation, nebulizer type and principle of aerosol generation (vibrating-membrane nebulizer), and its configuration within the NIV circuit (between the Y-piece and nasal prongs) used by Bianco et al. differs considerably compared with the set-up of the Cummings et al. study: their trial delivered , surfactant directly to the mouth by a multi-lumen inhalation catheter system that uses pressurized gas to break-up the surfactant in small droplets. Notably, vibrating-membrane nebulizers produce slow, small diameter particles that are transported by the bias flow of the NIV, whereas inhalation catheters produce fast particles with a high momentum that may readily impact against the upper airways.5 Additionally, the prongs used as interface between the nebulizer and the animal nostrils by Bianco et al. were fitted tightly with almost no leaks, whereas the pacifier used to keep in place the aerosolizing catheter described by Cummings et al. allows an undetermined amount of leaks at the level of the mouth which may have contributed to a significant drug loss.6 Moreover, the 14 % lung deposition reported by Bianco et al. must be read in the context of a well characterized aerosol particle size distribution.4,7 For these reasons, we do not consider appropriate the lung deposition estimation of 29 mg/kg speculated in the trial.
As a last remark, there seems to be no standardization on the levels of pressure delivered. In addition to the surfactant aerosol, the inhalation catheter delivers a continuous air-flow to the mouth of the infants, which may have an impact on the NIV support level administered. Goikoetxea et al.5 reported a driving pressure-dependent increase of the distal airway pressure ranging between 0.5-1.5 cmH2O in vitro study using a similar multi-lumen inhalation catheter. At the recommended driving pressure, the inhalation catheter emitted an air-flow of approximately 1.1 L/min. Considering this, it is not unreasonable to speculate that the air-flow produced by the catheters in the mouth on the infants may have provided inadvertent additional respiratory support. Hence the intervention group may have received a higher than expected NIV support level, contributing to delayed or reduced intubation requirement for some infants. Unfortunately, even if the authors declare that in preclinical and pilot studies, normal fluctuations in airway pressure while receiving NIV support did not significantly change during aerosol delivery, this hypothesis cannot be entirely excluded given the paucity of relevant technical information on the nebulizer system..
In summary, the potential bias sources in terms of experimental design, together with the scarce information on relevant aerosol characteristics and nebulizer device may raise questions on the claim that the clinical benefit observed in a subset of the population studied can be attributable to aerosolized surfactant without any doubt.
References
1. Cummings, J. J., Gerday, E., Minton, S., Katheria, A. & Albert, G. Aerosolized Calfactant for Newborns With Respiratory Distress : A Randomized Trial. Pediatrics. 146, (2020).
2. Glaser, K. & Wright, C. J. Aerosolized Calfactant in Infants With. Pediatrics. 146, 0–3 (2020).
3. Lemyre, B., Davis, P. G., De Paoli, A. G. & Kirpalani, H. Nasal intermittent positive pressure ventilation (NIPPV) versus nasal continuous positive airway pressure (NCPAP) for preterm neonates after extubation. Cochrane Database Syst. Rev. (2017) doi:10.1002/14651858.CD003212.pub3.
4. Bianco, F. et al. From bench to bedside: In vitro and in vivo evaluation of a neonate-focused nebulized surfactant delivery strategy. Respir. Res. 20, (2019).
5. Goikoetxea, E. et al. In vitro surfactant and perfluorocarbon aerosol deposition in a neonatal physical model of the upper conducting airways. PLoS One 9, e106835 (2014).
6. Tarantini, F., Milesi, I., Murgia, X., Bianco, F. & Dellac, L. A Compartment-Based Mathematical Model for Studying Convective Aerosol Transport in Newborns Receiving Nebulized Drugs during Noninvasive Respiratory Support. Pharmaceutics. (2020).
7. Bianco, F. et al. Extended pharmacopeial characterization of surfactant aerosols generated by a customized eflow neos nebulizer delivered through neonatal nasal prongs. Pharmaceutics. (2020) doi:10.3390/pharmaceutics12040319.
RE: Aerosolized surfactant: What is the cost of avoiding intubation?
We read with great interest the pragmatic multi-center trial on aerosolized surfactant presented by the Aero-O2 study investigators.1 This is the largest clinical trial evaluating the efficacy of aerosolized surfactant for preterm infants with respiratory distress syndrome and adds to the recent data reported by CureNeb study team.2 We would like to congratulate the investigators for introducing a novel technique of delivering aerosolized surfactant using an interface resembling a pacifier. This ensures continuous aerosol delivery without loss of positive end-expiratory pressure. However, we would like to highlight a few issues and request clarifications regarding the trial.
The infants enrolled in the study had a mean gestation age of 33 weeks and mean birth weight of around 2.1kg. The number of infants born at ≤ 26 weeks were small (n=11). The proportion of infants requiring intubation for surfactant instillation was 26% in aerosolized surfactant group and 50% in usual care group. However, the requirement for surfactant reported in the current study is much higher than what is described in literature. A large prospective cohort data including 18 tertiary neonatal intensive care units (NICUs) reported that only 12.8% of infants born at 33 weeks require surfactant.3 Also, in the present trial, infants in the intervention group received higher surfactant doses (6ml/kg) and sometimes multiple treatments (up to 3 doses).
The primary outcome of the study was need for intubation and instillation of liquid surfactant. However, the oxygen requirement or respiratory distress score was not documented. Decision to ventilate a preterm infant is highly subjective and can vary from center to center. Although this approach contributes to the pragmatic design of the trial, it decreases its generalizability.
The authors have demonstrated the safety and feasibility of using this novel aerosol technique in multiple NICUs. However, the cost implications of using higher/multiple surfactant dosage has not been reported. We would like the investigators to explore and report the cost-effectiveness of this potentially beneficial non-invasive therapy. Providing a treatment modality with a significantly higher cost for an intervention not showing any reduction in relevant outcomes like chronic lung disease (CLD) or mortality limits its applicability outside of the research settings. In this trial, aerosolized surfactant did not seem to reduce the need for intubation and surfactant administration in extremely preterm infants. Future trials could test this treatment approach in smaller infants (≤28 weeks) and report if aerosolized surfactant has the potential to reduce CLD in this challenging population.
References
1. Cummings JJ, Gerday E, Minton S, et al. Aerosolized Calfactant for Newborns With Respiratory Distress: A Randomized Trial. Pediatrics. Published online October 1, 2020. doi:10.1542/peds.2019-3967
2. Minocchieri S, Berry CA, Pillow JJ, CureNeb Study Team. Nebulised surfactant to reduce severity of respiratory distress: a blinded, parallel, randomised controlled trial. Arch Dis Child Fetal Neonatal Ed. 2019;104(3):F313-F319. doi:10.1136/archdischild-2018-315051
3. Walsh MC, Bell EF, Kandefer S, et al. Neonatal outcomes of moderately preterm infants compared to extremely preterm infants. Pediatr Res. 2017;82(2):297-304. doi:10.1038/pr.2017.46