Dopamine vs. Norepinephrine for Hypotension in Very Preterm Infants With Late-onset Sepsis

Study Overview
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Brief Summary
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Fluid-unresponsive hypotension needing cardiotropic drug treatment is a serious complication in very preterm neonates with suspected late-onset sepsis (LOS; defined as culture positive or negative bloodstream infection or necrotizing enterocolitis occurring >48 hours of age). In Canada,  250 very preterm neonates receive cardiotropic drugs for LOS related fluid-unresponsive hypotension every year; of these  35-40% die. Unlike for adult patients, there is little evidence to inform practice. While several medications are used by clinicians, the most frequently used medications are Dopamine (DA) and Norepinephrine (NE). However, their relative impact on patient outcomes and safety is not known resulting in significant uncertainty and inter- and intra-unit variability in practice. Conducting large randomized trials in this subpopulation can be operationally challenging and expensive. Comparative effectiveness research (CER), is a feasible alternative which can generate high-quality real-world evidence using real-world data, by comparing the impact of different clinical practices. Aim: To conduct a national CER study, using a pragmatic clinical trial design, in conjunction with the existing infrastructure of the Canadian Neonatal Network to identify the optimal management of hypotension in very preterm neonates with suspected LOS. Objective: To compare the relative effectiveness and safety of pharmacologically equivalent dosages of DA versus NE for primary pharmacotherapy for fluid-unresponsive hypotension in preterm infants born ≤ 32 weeks gestational age with suspected LOS. Hypothesis: Primary treatment with NE will be associated with a lower mortality Methods: This CER project will compare management approach at the unit-level allowing inclusion of all eligible patients admitted during the study period. 15 centers in Canada have agreed to standardize their practice. All eligible patients deemed circulatory insufficient will receive fluid therapy (minimum 10-20 cc/kg). If hypotension remains unresolved: Dopamine Units: start at 5mics/kg/min, increase every 16-30 minutes by 5 mics/kg/min to a maximum dose of 15 mics/kg/min or adequate response Norepinephrine Units: start at 0.05 mics/kg/min, increase every 16-30 minutes by 0.05 mics/kg/min to maximum dose of 0.15/mics/kg/min or adequate response

Detailed Description
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In this study, we will use real world data (RWD; defined as data generated during routine clinical practice) collected by our national Canadian Neonatal Network (CNN), which will be further expanded for this project. The CNN is a well-established patient registry that includes members from 31 hospitals and 17 universities across Canada. The Network maintains a standardized NICU database and provides a unique opportunity for researchers to participate in collaborative projects. We will use the framework of Hypotheses Evaluating Treatment Effectiveness (HETE) research a form of comparative effectiveness research (CER). Patient registries are emerging as a new method for assessment of treatments under the framework of CER. We will evaluate treatment effectiveness of two routinely used primary therapies for hypotension management in very preterm neonates with suspected LOS after standardizing treatment strategies and with a priori hypothesis.

Official Title
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Dopamine vs. Norepinephrine for Hypotension in Very Preterm Infants With Late-onset Sepsis: A National Comparative Effectiveness Research Project

Conditions
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Late-Onset Neonatal Sepsis, Extreme Prematurity, Neonatal Hypotension

Intervention / Treatment
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* Drug: Dopamine
* Drug: Norepinephrine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: ≤32 weeks gestational age and > 48 hours of life Receiving primary vasopressor therapy with Dopamine or Norepinephrine in the context of suspected late-onset sepsis or necrotizing enterocolitis with systemic hypotension (defined as: culture positive or negative bloodstream infection) Exclusion Criteria: Known chromosomal or genetic anomalies Receiving primary therapy with agents other than Dopamine or Norepinephrine

Ages Eligible for Study
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Minimum Age: 21 Weeks
Maximum Age: 32 Weeks

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Dopamine Units<br>Units who have standardized their practice with the use of Dopamine as a first line agent. | Drug: Dopamine<br>* Start at 5mics/kg/min, increase every 16-30 minutes by 5 mics/kg/min to a maximum dose of 15 mics/kg/min or adequate response.<br>|
| Norepinephrine Units<br>Units who have standardized their practice with the use of Norepinephrine as a first line agent. | Drug: Norepinephrine<br>* Start at 0.05 mics/kg/min, increase every 16-30 minutes by 0.05 mics/kg/min to maximum dose of 0.15/mics/kg/min or adequate response<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| All cause in-hospital mortality | Death before discharge | From illness onset to discharge (home or to another hospital) - assessed up to a maximum of 36 weeks after date of birth | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Episode-related death | Episode-related death (yes or no- binary variable) | <14 days from illness onset | 
| Treatment failure rate | Need for further dose escalation or use of additional agents (treatment failure = hypotension unresolved after reaching max dose (15mics/kg/min in Dopamine units and 0.15 mics/kg/min in Norepinephrine units) | 90 minutes after initial vasopressor initiation (or sooner if secondary dose added or primary agent replaced as per clinical discretion) | 
| New diagnosis of severe neurological injury | Grade III or Grade IV intraventricular hemorrhage or periventricular leukomalacia (yes or no- binary variable) | From illness onset to discharge (home or to another hospital) - assessed up to a maximum of 36 weeks after date of birth | 
| Bronchopulmonary dysplasia | Need for oxygen or positive pressure respiratory support at 36 weeks postmenstrual age (PMA) (yes or no- binary variable) | Assessed at 36 weeks PMA | 
| Retinopathy of prematurity | Diagnosis of retinopathy of prematurity - assessed by clinical staff (yes or no - binary variable) | From illness onset to discharge (home or to another hospital) - assessed up to a maximum of 36 weeks after date of birth | 
| Length of hospital stay | Length of entire neonatal intensive care unit stay from admission to discharge | From admission date to discharge date - assessed up to a maximum of 36 weeks after date of birth |