OPTIMIST-ically moving towards targeted non-invasive surfactant therapy?

January 14, 2022

MANUSCRIPT CITATION

Dargaville PA, Kamlin COF, Orsini F, Wang X, De Paoli AG, Kanmaz Kutman HG, Cetinkaya M, Kornhauser-Cerar L, Derrick M, Özkan H, Hulzebos CV, Schmölzer GM, Aiyappan A, Lemyre B, Kuo S, Rajadurai VS, O’Shea J, Biniwale M, Ramanathan R, Kushnir A, Bader D, Thomas MR, Chakraborty M, Buksh MJ, Bhatia R, Sullivan CL, Shinwell ES, Dyson A, Barker DP, Kugelman A, Donovan TJ, Tauscher MK, Murthy V, Ali SKM, Yossuck P, Clark HW, Soll RF, Carlin JB, Davis PG; OPTIMIST-A Trial Investigators. Effect of Minimally Invasive Surfactant Therapy vs Sham Treatment on Death or Bronchopulmonary Dysplasia in Preterm Infants With Respiratory Distress Syndrome: The OPTIMIST-A Randomized Clinical Trial. JAMA 2021 Dec 13. Online ahead of print. PMID 34902013

REVIEWED BY

Clyde J. Wright, MD
Associate Professor
Section of Neonatology
Department of Pediatrics
Children’s Hospital Colorado and
University of Colorado School of Medicine

Kirsten Glaser, MD
Division of Neonatology, Department of Women’s and Children’s Health
University of Leipzig Medical Center, Leipzig, Germany

Nicolas A. Bamat, MD MSCE
Assistant Professor
Division of Neonatology, Children’s Hospital of Philadelphia
Department of Pediatrics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania

TYPE OF INVESTIGATION

Treatment

QUESTION

In preterm infants with a gestational age of 25-28 weeks supported by continuous positive airway pressure (CPAP) and requiring 30% FiO2 within 6 hours of birth (P), does minimally invasive surfactant therapy (I) compared to continued CPAP (C) decrease death or bronchopulmonary dysplasia (O) at 36 weeks’ postmenstrual age (T)?

METHODS

  • Design: Randomized controlled trial
  • Allocation: Infants were randomized 1:1 via a computer-generated code in permuted block sizes of 2, 4, or 6 and stratified by study center and gestational age. Multiple births were randomized independently.
  • Blinding: Clinicians and parents were blinded to the study intervention. The infant’s bedspace was screened to prevent external view and central monitors disconnected during the procedure
  • Follow-up period: To hospital discharge
  • Setting: 33 tertiary-level neonatal intensive care units in Australia, Canada, Israel, New Zealand, Qatar, Singapore, Slovenia, the Netherlands, Turkey, the UK, and the US.
  • Patients:
    • Inclusion criteria included inborn birth and NICU admission at a gestational age range of 25 weeks 0 days and 28 weeks 6 days. Patients had to be supported by CPAP or noninvasive positive pressure ventilation for respiratory insufficiency at a level of 5 – 8 cm H2O and requiring FIO2 of 0.30 or greater within the first 6 hours of life. Caffeine therapy was not protocolized.
    • Exclusion criteria included prior intubation, clinical judgment of imminent need for intubation, respiratory insufficiency not caused by RDS, or presence of a serious congenital anomaly.
  • Intervention:
    • MIST Intervention
      • Surfactant was instilled using a 16-gauge vascular catheter or a proprietary catheter inserted into the trachea via direct laryngoscopy (Hobart method). Surfactant was administered in 3-4 aliquots, with a 10 second pause between each. CPAP was applied throughout.
      • Due to this study design, this group received early rescue surfactant (ie, first treatment when reaching an FiO2 threshold of 0.30 and this was administered
    • Control
      • The sham intervention consisted of transient repositioning only.
    • Intubation criteria (criteria applied to both MIST and Control arms)
      • FIO2 of >45 or greater (or by clinician discretion when requiring FIO2 >0.40), severe/recurrent apnea, persistent respiratory acidosis.
      • It is important to note, this was the first treatment with surfactant for subjects in the control arm and the second treatment with surfactant for subjects randomized to the MIST arm
  • Outcomes:
    • Primary outcome: composite of death prior to 36 wks’ postmenstrual age (PMA) or BPD assessed at 36 wks’ PMA.
      • Criteria for BPD diagnosis at 36 wks’ PMA:
        • Infants were supported with mechanical ventilation, CPAP, or high-flow nasal cannula therapy at a rate of ≥2 L/min, or
        • Infants were receiving supplemental oxygen with actual or effective FIO2 of 0.30 or greater,

or

        • Infants were receiving oxygen with FIO2 less than 0.30 and did not pass a room air trial or no room air trial was done per physician request
    • Secondary outcomes:
      • Individual components of the primary outcome of the primary composite
      • pneumothorax requiring drainage, need for intubation within 72 hours of birth, grade III or IV intraventricular hemorrhage, the composite of death during hospitalization or major morbidity,
      • Major morbidity was defined as any of the following: intra-ventricular hemorrhage grade III or IV; cystic periventricular leukomalacia; retinopathy of prematurity stage 3 or greater; or physiological bronchopulmonary dysplasia.
    • Other protocolized secondary outcomes not reported: length of stay in the intensive care unit (variably defined worldwide), hospital billings and calculated cost of hospitalization, and outcomes beyond the first hospitalization, including death or major disability at 2 years’ postmenstrual age and respiratory morbidity during the first 2 years
  • Analysis and Sample Size:
    • to detect an absolute risk reduction of 13% (RR reduction of 33%) in the incidence of death or bronchopulmonary dysplasia (estimated at 38% in the control group) with 90% power the study aimed to recruit 606 infants.
    • Statistical details are as follows: Treatment effects were estimated with generalized linear models (GLM), adjusting for gestational age strata and incorporating a cluster-robust SE calculation to account for clustering by study site. No adjustments for multiple comparisons were made so the findings for the analyses of the secondary outcomes should be interpreted as exploratory. Preplanned exploratory subgroup analyses included gestational age strata. Two-tailed P values <.05 were labeled as significant. “
  • Patient follow-up: % included in primary outcome assessment
    • MIST: 241/242
    • Control: 244/244

MAIN RESULTS

A total of 488 infants were randomized, 242 to MIST and 244 to control. Due to the interference of COVID-19 with clinical research activities, the trail steering committee ceased enrollment early. One infant randomized to MIST was not included in the primary outcome analysis as consent was withdrawn. Enrolled subjects had a mean gestational age at birth of 27.3 weeks’ and a birth weight of approximately 930 grams.

Primary outcome

No statistically significant difference in the primary outcome was found between groups. Death or bronchopulmonary dysplasia assessed at 36 weeks’ PMA occurred in 105 infants (43.6%) in the MIST group and in 121 infants (49.6%) in the control group (RD, −6.3% [95% CI, −14.2% to 1.6%]; RR, 0.87 [95% CI, 0.74 to 1.03]; P = .10).

For the components of the primary outcome, death prior to 36 weeks was not statistically different between groups. Death occurred prior to 36 weeks’ PMA in 24 infants (10.0%) in the MIST group and in 19 infants (7.8%) in the control group (RD, 2.1% [95% CI, −3.6% to 7.8%]; RR, 1.27 [95% CI, 0.63 to 2.57]; P = .51). The incidence of bronchopulmonary dysplasia in survivors to 36 weeks’ PMA was reduced in the MIST group (81/217 [37.3%] vs 102/225 [45.3%] in the control group; RD, −7.8% [95% CI, −14.9% to −0.7%]; RR, 0.83 [95% CI, 0.70 to 0.98]; P = .03).

Secondary outcomes

Among the secondary outcomes, the following had statistically significant reduction in the MIST group

  • the need for intubation within 72 hours of birth (36.5% vs 72.1% in the control group; RD, −35.8% [95% CI, −47.2% to −24.4%]; RR, 0.50 [95% CI, 0.40 to 0.64]; P < .001),
  • pneumothorax requiring drainage (4.6% vs 10.2%; RD, −5.8% [95% CI, −10.2% to −1.4%]; RR, 0.44 [95% CI, 0.25 to 0.78]; P = .005),
  • intubation at any time (54.8% vs 81.1% in the control group; RD, −26.7% [95% CI, −39.8% to −13.5%]; RR, 0.67 [95% CI, 0.54 to 0.84]),
  • incidence of patent ductus arteriosus requiring medical therapy (35.3% vs 45.5%; RD, −10.5% [95% CI, −20.2% to −0.9%]; RR, 0.77 [95% CI, 0.60 to 0.99]),
  • need for oxygen therapy at home in survivors to hospital discharge (14.7% vs 21.9%; RD, −7.1% [95% CI, −11.6% to −2.5%]; RR, 0.68 [95% CI, 0.52 to 0.88]),
  • requirement for surfactant therapy via endotracheal tube (32.8% vs 68.4%; RD, -35.7% [95% CI, -47.7 to -23.7]; RR, 0.48 [95% CI, 0.37 to 0.62])
  • duration of the following therapies:
    • mechanical ventilation (1 day vs 4 days in the control group; median difference, −1.96 [95% CI, −3.19 to −0.73] days)
    • CPAP (17 days vs 22 days; median difference, −4.62 [95% CI, −8.41 to −0.84] days)
    • mechanical ventilation plus CPAP (25 days vs 32 days; median difference, −8.13 [95% CI, −13.98 to −2.27] days)
    • all forms of mechanical respiratory support (40 days vs 45 days; median difference, −6.42 [95% CI, −11.95 to −0.89 days])

Subgroup analyses

The authors performed preplanned exploratory analysis by gestational age subgroups. For the outcome of death prior to 36 weeks’ PMA, there was a statistically significant interaction between treatment and gestational age strata (control group favored at lower gestational age and MIST group favored at higher gestational age; P = .01 for interaction). Furthermore, evidence of interaction was found for the need for intubation within 72 hours of birth which was 49% for the MIST group vs 72% for the control group within the gestational age stratum of 25 to 26 weeks and was 29% vs 72% within the gestational age stratum of 27 to 28 weeks (P = .02 for interaction).

CONCLUSION

The authors conclude that minimally invasive surfactant therapy does not reduce death/BPD in preterm infants with respiratory distress syndrome supported with CPAP. However, they state that “given the statistical uncertainty reflected in the 95% CI, a clinically important effect cannot be excluded.”

COMMENTARY

The burden of BPD remains unacceptably high among infants born <28wks’ GA (1). Avoiding mechanical ventilation (MV) with preferential non-invasive (NI) support modestly reduces BPD (NNT 17-35) (2). This limited treatment effect may be explained by high rates of NI support failure. There is an urgent need to investigate whether minimally invasive surfactant therapy (MIST) can reduce NI support failure, MV exposure and BPD.

Multiple studies have interrogated thin catheter administration of surfactant. A Cochrane review concluded that the thin catheter method was superior to endotracheal tube surfactant administration (3). However, the majority of included studies enrolled subjects of GA >28 wks’ at low risk of developing BPD. Thus, whether early rescue surfactant treatment via thin catheter prevents BPD in high-risk subjects is unknown.

The OPTIMIST-A trial addresses this knowledge gap. This large, international trial randomized subjects <28 wks’ GA on CPAP and >30% FiO2 to continued NI support or early rescue surfactant via MIST. Despite a significant decrease in MV exposure, there was no statistically significant difference in the primary outcome (death or BPD). Importantly, a subgroup analysis revealed an interaction between GA and death (favoring control at lower GA) and exposure to mechanical ventilation (favoring MIST to a greater extent at higher GA).

How do these findings fit into what we already know? These data are indispensable as they inform the effect of early rescue MIST in the most relevant target population (<28 wks) and compared to the current standard of care (CPAP). These data encourage stratification of infants <28 wks GA. In this study, MIST had a greater reduction in MV at <72 hours in the 27-28 wk stratum. The finding that the benefit of early rescue surfactant administration via a thin catheter increased in infants at higher GA is consistent with the findings of Gopel (4) and Kribs (5).

Alternatively stated, the potential benefit of MIST wanes with decreasing GA, and therefore we must be cognizant of potential harms. These data demonstrate that GA modifies the relationship of MIST with mortality, with a trend towards increased death at lower GA. It is not known whether complications of MIST administration contributed to this finding. Other studies have demonstrated a potential signal for harm with the exposure at decreasing GA. Rates of focal intestinal perforation increase with thin catheter surfactant, primarily in these most immature babies (6). Together, these data support implementing this approach by first targeting those who clearly stand to more likely benefit (27-28 wks’ GA). Furthermore, the optimal treatment criteria, timing and delivery mode that provides the greatest benefit while minimizing potential harm remains to be defined in the less mature, highest-risk neonates (22-26 wks’ GA). There is an urgent need for well-elaborated trials like this in the tiniest babies – including, in particular, infants born at completed 23-26 weeks’ GA. Given the low numbers of these extremely high-risk patients at any one center, such as study would only be possible through a wide scale collaborative effort.

REFERENCES

  1. Siffel C, Kistler KD, Lewis JFM, Sarda SP. Global incidence of bronchopulmonary dysplasia among extremely preterm infants: a systematic literature review. J Matern Fetal Neonatal Med 2021; 34 11:1721-31.
  2. Wright CJ, Polin RA. Noninvasive Support: Does It Really Decrease Bronchopulmonary Dysplasia? Clin Perinatol 2016; 43 4:783-98.
  3. Abdel-Latif ME, Davis PG, Wheeler KI, De Paoli AG, Dargaville PA. Surfactant therapy via thin catheter in preterm infants with or at risk of respiratory distress syndrome. Cochrane Database Syst Rev 2021; 5:CD011672.
  4. Gopel W, Kribs A, Ziegler A, Laux R, Hoehn T, Wieg C, et al. Avoidance of mechanical ventilation by surfactant treatment of spontaneously breathing preterm infants (AMV): an open-label, randomised, controlled trial. Lancet 2011; 378 9803:1627-34.
  5. Kribs A, Roll C, Gopel W, Wieg C, Groneck P, Laux R, et al. Nonintubated Surfactant Application vs Conventional Therapy in Extremely Preterm Infants: A Randomized Clinical Trial. JAMA Pediatr 2015; 169 8:723-30.
  6. Hartel C, Paul P, Hanke K, Humberg A, Kribs A, Mehler K, et al. Less invasive surfactant administration and complications of preterm birth. Scientific reports 2018; 8 1:8333.

 

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