CPAP vs NIPPV: A COMPARATIVE EFFECTIVENESS RESEARCH
Condition: Respiratory Insufficiency Syndrome of Newborn
MeSH terms: Respiratory Insufficiency
Study type: Observational [Patient Registry]

Summary: 
      Aim: Investigators aim is to conduct two complementary and concurrent CER projects using a
      pragmatic clinical trial design and registry-based RWD to identify the optimal respiratory
      management practices for extremely preterm neonates and reduce the risk of BPD and SNI.

      Objectives: Two complementary objectives are proposed. Objective 1: To determine the efficacy
      and safety of "mandatory non-extubation" until 72 hours of postnatal age for preterm neonates
      born at 23 -25 weeks' GA who receive mechanical ventilation.

      Objective 2: To determine whether optimal nasal continuous positive airway pressure
      post-extubation is as efficacious as nasal intermittent positive pressure ventilation in
      preterm neonates born at 23 -28 weeks' GA who have received mechanical ventilation.
    

Detailed description: 
      Background and Importance: Preterm neonates <29 weeks' gestational age (GA) have a 10% risk
      of mortality, 15% risk of severe neurological injury (SNI) and 45% risk of bronchopulmonary
      dysplasia (BPD). Both SNI and BPD are associated with significant long-term impairment.
      Various management approaches to prevent these complications are adopted without rigorous
      evaluation because conducting large-scale randomized trials can be challenging. One area
      consistently associated with SNI and BPD is respiratory management of these neonates which is
      also the area lacking evidence-informed approach. Comparative effectiveness research (CER) of
      different management strategies using Real World Data (RWD) is suggested as an alternative to
      generate Real World Evidence (RWE). Hypotheses Evaluating Treatment Effectiveness (HETE)
      studies are a form of CER where two or more practices are compared to evaluate presence or
      absence of anticipated effect using specific hypothesis. In this proposal, investigators will
      study two specific respiratory management practices for preterm neonates <29 weeks' GA using
      this design under the auspices of our practice based research network of the Canadian Preterm
      Birth Network (CPTBN) which has extensive routine data collection for this population.

      Aim: Investigators aim to conduct two complementary and concurrent CER projects using a
      pragmatic clinical trial design and registry-based RWD to identify the optimal respiratory
      management practices for extremely preterm neonates and reduce the risk of BPD and SNI.

      Objectives: Two complementary objectives are proposed. Objective 1: To determine the efficacy
      and safety of "mandatory non-extubation" until 72 hours of postnatal age for preterm neonates
      born at 23 -25 weeks' GA who receive mechanical ventilation.

      Objective 2: To determine whether optimal nasal continuous positive airway pressure
      post-extubation is as efficacious as nasal intermittent positive pressure ventilation in
      preterm neonates born at 23 -28 weeks' GA who have received mechanical ventilation.

      Methods:

      Approach: These two CER projects will compare respiratory management approaches at the
      unit-level allowing investigators to study all eligible preterm neonates admitted to
      participating units. Twenty units in Canada have agreed to participate in each project, and
      The units have participated in the conception of the study, standardizing two-arms of the
      protocol and agreed on the project-specific data requirements.

      Duration: The study will run over 4 years. Sample size: Considering superiority approach
      investigators will study 800 neonates for project 1 (α=0.05, β=0.2, baseline rate 35-40% and
      30% relative risk reduction).

      If there was a true difference in risk of failure of 1% in CPAP group (30% vs 29%), then 1816
      patients were required to be 80% sure that the upper limit of a one-sided 97.5% confidence
      interval (or equivalently a 95% two-sided confidence interval) would exclude a difference in
      favour of the NIPPV group of more than 5% for neonates of 23 -28 weeks' GA for project 2.
      (modification in Nov 2021, uploaded later)

      Analyses: In order to generate information necessary for causal inference in a pragmatic
      experimental design, investigators will conduct three-pronged sensitivity analyses: logistic
      regression, propensity-score based analyses and instrumental variable analyses to confirm or
      refute our hypotheses and improve generalizability of results. Expertise: The research team
      includes the expertise of clinicians, researchers, epidemiologists, knowledge users, parents
      and statisticians.

      Expected outcomes: Through use of RWD collected by the CPTBN and HETE design, the proposal
      will result in identifying a superior respiratory management strategy and reduced risk of
      mortality, SNI, and BPD for extremely preterm neonates.
    

Intervention name(s): CPAP
Intervention type(s): Other
Intervention description(s): The two NRS strategies being compared will be initiated at the time of first extubation (NRS support practices prior to initial intubation will be as per local unit guidelines and practices) and all subsequent extubations (if applicable) until 32 weeks PMA. For instance, a unit adopting post-extubation NCPAP strategy will initiate this mode following the initial and all subsequent extubations until 32 weeks PMA whereas centres adopting post-extubation NIPPV will initiate NIPPV following initial and all subsequent extubations until 32 weeks PMA.
Other intervention name(s): NIPPV
Observational model: Cohort
Time perspective: Prospective
Sampling method: Non-Probability Sample
Study population: 
        Preterm neonates <29 weeks gestational age (including outborns) who have required
        mechanical ventilation at any time during their clinical course.
      
Keywords: CPAP; NIPPV; INFANT, PREMATURE; RESPIRATORY MANAGEMENT; POST-ESTUBATION