Minocchieri S, Berry CA, Pillow JJ on behalf of the CureNeb Study Team Nebulised surfactant to reduce severity of respiratory distress: a blinded, parallel, randomised controlled trial Archives of Disease in Childhood – Fetal and Neonatal Edition Published Online First: 26 July 2018. doi: 10.1136/archdischild-2018-315051. PMID: 30049729
Dr. Deepak Chawla MD, DM
Government Medical College Hospital
TYPE OF INVESTIGATION
(P) In preterm neonates born at 29-33 weeks of gestation and needing 22-30% supplemental oxygen within 4 hours of age, (I) does the use of nebulized surfactant with nCPAP (C) compared with only nCPAP for respiratory support (O) decrease the need of intubation and duration of mechanical ventilation (T) at 72 hours of age?
- Design: Prospective, randomized, single center. Approved by local review board andprospectively registered with the Australian and New Zealand Clinical Trials Registry.
- Allocation: Allocation concealment by placing treatment allocation in sealed opaque, sequentially numbered envelopes.
- Setting: Single neonatal intensive care unit in Perth, Australia.
- Patients: Among neonates born at at 29-33 weeks of gestation, those with following inclusion criteria were eligible for enrolment.
- Inclusion Criteria: Age less than 4 hours, clinical signs suggestive of evolving mild to moderate RDS and on respiratory support with nCPAP of 5–8 cmH2O and FiO2 of 0.22–0.30 to maintain oxygen saturation of 86%–94%.
- Exclusion Criteria: Prior intubation or surfactant treatment, known pneumothorax, cardiorespiratory instability, cardiothoracic malformation and obvious chromosomal aberrations.
- Intervention: Enrolled neonates were randomized to intervention or control groups. Neonates randomized to the intervention group were administered 200 mg/kg of aerosolized surfactant (poractant) in addition to nCPAP. Surfactant was administered using a customized vibrating membrane nebulizer. A repeat dose of 100 mg/kg of aerosolized surfactant was given if oxygen requirement and/or respiratory distress (persistent tachypnoea >60 breaths/min, sternal or intercostal muscle recession, or grunting) persisted at 12 hours after the first dose. Neonates randomized to control group sham nebulization in addition to nCPAP.
- Blinding: Clinical team and outcome assessors were blinded. The treatment team used an opaque screen to administer either nebulized surfactant or sham nebulization. Further, the bubble CPAP water chambers were emptied and refilled after completion of nebulization so that any deposits of surfactant in the chamber are not detectable.
- Follow-up period: Enrolled neonates were followed up till disposition from the hospital.
- Primary outcome: The primary outcomes were need of intubation within 72 h of birth and duration of mechanical ventilation by 72 h of birth. Need of intubation was decided based on presence of one or more of the following criteria which indicated nCPAP failure: 1) FiO2 >0.35 over more than 30 min or >0.45 at any time; 2) >4 apneic episodes/hour or 2 apneic episodes requiring bag and mask ventilation; 3) 2 pH <7.2 with pCO2 >65 mm Hg in capillary or >60 mm Hg in arterial blood gas sample; and 4) intubation deemed necessary by the attending physician.
- Secondary outcomes: Secondary outcomes included the number of neonates who were intubated at 24 hours, 72 hours and 7 days after birth; time to intubation; total surfactant dose per kilogram; associated neonatal morbidities; and physiological stability following randomization.
- Analysis and Sample Size: Assuming a reduction in the need of intubation within 72 h of birth from 30% in the control group (based on historical data from the unit) to 5% in the treatment group, investigators needed to enroll 35 neonates in each group to detect a significant difference with power of 80% and a two-sided significance level of α=0.05. Analysis was done by intention-to-treat principle. Two gestation-specific strata were used – 29-31 weeks and 32-33 weeks of gestation.
- Patient Follow-Up: All the enrolled neonates were followed and analyzed for the primary outcome.
Of 360 neonates found eligible for enrolment during the study, only 64 (17.7%) were enrolled. The study was stopped prematurely due to insufficient funding/personnel.
Important baseline variables were comparable in the two groups. Neonates in the intervention group received first dose of nebulized surfactant at a mean age of about 3 hours (178±52 minutes).
- Primary outcome: The primary outcome of need of intubation within 72 h of birth was reduced in the nebulization group by 47% (relative risk: 0.53; 95% CI: 0.29 to 0.95). On subgroup analysis, this reduction in need of intubation was restricted to neonates born at 32-33 weeks of gestation.
- Secondary outcome: Proportions of neonates intubated at 24 h, 72 h and at 7 days were similar in the two groups. Neonates in the nebulized surfactant group took longer to reach the CPAP failure status and once intubated the duration of ventilation was longer. Mean dose of surfactant received, incidence of air leaks and reasons of CPAP failure were similar in the two groups.
Authors concluded that among neonates with mild RDS, administration of nebulized surfactant may promote the success of non-invasive respiratory support.
Nasal CPAP is the primary mode of respiratory support in the preterm neonates with RDS. In comparison to intubation, use of nCPAP is associated with reduced need of surfactant administration, intubation, and bronchopulmonary dysplasia in extremely preterm neonates.(1,2) Furthermore, prophylactic surfactant administration has not been found to be superior to early selective surfactant administration if nCPAP fails.(3) If surfactant administration is needed, administration by minimally invasive technique (MIST) using a thin catheter while baby is supported with nCPAP may be associated with better respiratory outcomes when compared to administration via an endotracheal tube, as in the INSURE approach.(4) With this background, the study reviewed here evaluates the role of a non-invasive approach of surfactant administration – by aerosolization.
This randomized controlled trial recruited moderately and very preterm neonates with mild RDS who needed FiO2 of less than 30% to maintain normoxia when supported by nCPAP.(5) Neonates in the intervention group received aerosolized surfactant while neonates in the control group received sham nebulization. The primary outcome of need of intubation was significantly reduced in the intervention group. Duration of ventilation and incidence of air leaks were similar in the two groups. This study presents an attractive non-invasive method of surfactant administration which can also potentially improve the ease of administration.
The study had higher than expected rates of intubation and surfactant use in both 29-31 weeks and 32-33 weeks of gestation study subgroups. This may be due to lower threshold of surfactant administration not only as defined in the study protocol but also on discretion of the clinical team. As a result, the reduced need of intubation in the intervention group observed in this study, may not be applicable to other healthcare settings which follow a selective surfactant administration strategy. An important limitation of study is low rate of recruitment due to non-availability of study personnel (17.7% of eligible neonates recruited) which also led to early stopping of the study. Although the effect size of the study intervention reaches significance, the confidence interval is wide with upper margin of relative risk nearing the point of no effect. Furthermore, the numbers presented for the primary outcome vary when presented at different places throughout the manuscript (Table 1). It is clear that even a small change in numbers can alter the effect size and its confidence interval for such a small study.
Table 1: Relative risk of primary outcome (need of intubation by 72h)
Source of numbers Intervention group
Calculated relative risk (95% CI) Primary outcome statement in text 11 (34.4%) 22 (68.8%) 0.50 (0.30 to 0.82) Calculated from subgroup analysis presented in text 13 (40.6%) 22 (68.8%) 0.60 (0.37-0.94) Calculated from study flow chart figure 14 (43.8%) 22 (68.8%) 0.64 (0.41-0.99)
MIST without need of endotracheal intubation is an attractive proposition. Of many methods of minimally invasive surfactant administration (including thin catheter, laryngeal mask airway and pharyngeal deposition), the aerosolized administration in least invasive. However, many questions including dose, timing and frequency of administration, method of aerosolization and target patient group most likely to be benefitted remain unanswered. Further research is warranted in investigating the use of different methods of minimally invasive or non-invasive methods of surfactant therapy. Such a research should be conducted in neonates in whom surfactant therapy is warranted as a standard practice.
- Subramaniam P, Ho JJ, Davis PG. Prophylactic nasal continuous positive airway pressure for preventing morbidity and mortality in very preterm infants. Cochrane Database Syst Rev 2016; 14;: CD001243.
- SUPPORT Study Group of the Eunice Kennedy Shriver NICHD Neonatal Research Network, Carlo WA, Finer NN, Walsh MC, Rich W, Gantz MG, et al. Target ranges of oxygen saturation in extremely preterm infants. N Engl J Med 2010; 362: 1959–69.
- Sandri F, Plavka R, Ancora G, Simeoni U, Stranak Z, Martinelli S, et al. Prophylactic or early selective surfactant combined with nCPAP in very preterm infants. Pediatrics 2010; 125: e1402–9.
- Dargaville PA, Aiyappan A, Cornelius A, Williams C, Paoli AGD. Preliminary evaluation of a new technique of minimally invasive surfactant therapy. Arch Dis Child – Fetal Neonatal Ed 2011; 96: F243–8.
- 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 2018; doi: 10.1136/archdischild-2018-315051