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

Dopamine vs. Norepinephrine for Hypotension in Very Preterm Infants With Late-onset Sepsis: An International Comparative Effectiveness Research Project

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 an international 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. 16 centers in Canada, 2 centers in Ireland, 1 center in each of Israel, Spain and the UK, and 6 centers in the United States 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

Study Overview

• Status: Recruiting
• Conditions: Late-Onset Neonatal Sepsis; Neonatal Hypotension; Extreme Prematurity
• Intervention / Treatment: Drug: Dopamine; Drug: Norepinephrine

Detailed Description

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.

• Study Type: Observational
• Enrollment (Estimated): 550

Contacts and Locations

• Study Contact: Name: Laura Thomas, MSc; Phone Number: 172060 416-586-4800; Email: laura.thomas@sinaihealth.ca
• Study Contact Backup: Name: Amish Jain, MBBS, MRCPCH, PhD; Phone Number: 5459 416-586-4800; Email: amish.jain@sinaihealth.ca

Study Locations

• Canada
  • Alberta
    • Calgary, Alberta, Canada
      • Recruiting
      • Foothill's Medical Centre
      • Contact: Amuchou Soraisham
      • Principal Investigator: Amuchou Soraisham
      • Sub-Investigator: Essa El Awad
      • Sub-Investigator: Majeeda Kamaluddeen
  • British Columbia
    • Vancouver, British Columbia, Canada
      • Recruiting
      • BC Women's Hospital
      • Contact: Michael Castaldo
      • Principal Investigator: Michael Castaldo
    • Victoria, British Columbia, Canada, V8Z 6R5
      • Recruiting
      • Victoria General Hospital
      • Contact: Thevanisha Pillay; Email: Thevanisha.Pillay@islandhealth.ca
  • Manitoba
    • Winnipeg, Manitoba, Canada
      • Not yet recruiting
      • St.Boniface Hospital
      • Contact: Yasser ElSayed
      • Principal Investigator: Yasser ElSayed
    • Winnipeg, Manitoba, Canada
      • Recruiting
      • Winnipeg Health Sciences Centre
      • Contact: Deepak Louis
      • Principal Investigator: Deepak Louis
  • Nova Scotia
    • Halifax, Nova Scotia, Canada
      • Recruiting
      • IWK Health Centre
      • Contact: Walid El Naggar
      • Principal Investigator: Walid El Naggar
  • Ontario
    • Hamilton, Ontario, Canada
      • Recruiting
      • McMaster Children's Hospital
      • Contact: Amneet Sidhu
      • Principal Investigator: Amneet Sidhu
      • Principal Investigator: Muzafar Gani Abdul Wahab
    • London, Ontario, Canada
      • Recruiting
      • London Health Sciences Centre
      • Contact: Soume Bhattacharya
      • Principal Investigator: Soume Bhattacharya
      • Sub-Investigator: Renjini Lalitha
    • Ottawa, Ontario, Canada
      • Recruiting
      • Children's Hospital of Eastern Ontario
      • Contact: Laurent Renesme
      • Principal Investigator: Laurent Renesme
    • Toronto, Ontario, Canada
      • Recruiting
      • Mount Sinai Hospital
      • Contact: Laura Thomas, MSc; Email: laura.thomas@sinaihealth.ca
      • Principal Investigator: Amish Jain
      • Sub-Investigator: Prakesh Shah
      • Sub-Investigator: Ashraf Kharrat
      • Sub-Investigator: Poorva Deshpande
    • Toronto, Ontario, Canada
      • Recruiting
      • Sunnybrook Health Sciences Centre
      • Contact: Stephanie Fevrier, MSc; Email: stephanie.fevrier@sunnybrook.ca
      • Principal Investigator: Dany Weisz
    • Toronto, Ontario, Canada
      • Recruiting
      • Hospital for Sick Children
      • Contact: Bonny Jasani
      • Principal Investigator: Bonny Jasani
    • Windsor, Ontario, Canada
      • Recruiting
      • Windsor Regional Hospital
      • Contact: Sajit Augustine
      • Principal Investigator: Sajit Augustine
  • Quebec
    • Montréal, Quebec, Canada
      • Recruiting
      • Montreal Children's Hospital
      • Contact: Gabriel Altit
      • Principal Investigator: Gabriel Altit
      • Sub-Investigator: Marc Beltempo
    • Montréal, Quebec, Canada
      • Recruiting
      • Jewish General Hospital
      • Contact: Nina Nouraeyan
      • Principal Investigator: Nina Nouraeyan
    • Montréal, Quebec, Canada
      • Recruiting
      • CHU Sainte- Justine
      • Contact: Anie Lapointe
      • Principal Investigator: Anie Lapointe
      • Principal Investigator: Andreanne Villeneuve
• Ireland
  • Cork, Ireland
    • Recruiting
    • University Cork College
    • Contact: Eugene Dempsey
  • Dublin, Ireland
    • Not yet recruiting
    • Coombe Women & Infants University Hospital
    • Contact: Jan Miletin
• Israel
  • Be'er Ya'aqov, Israel
    • Recruiting
    • Shamir Medical Center
    • Contact: Sagee Nissimov
    • Principal Investigator: Sagee Nissimov, MD
• Spain
  • Madrid, Spain, 28046
    • Recruiting
    • La Paz University Hospital
    • Contact: María Carmen Bravo, MD; Email: mcarmen.bravo@salud.madrid.org
• United States
  • Arizona
    • Phoenix, Arizona, United States, 85006
      • Not yet recruiting
      • Banner-University Medical Center Phoenix
      • Contact: Suma Rao
  • Ohio
    • Dayton, Ohio, United States, 45404
      • Recruiting
      • Dayton Children's Hospital
      • Contact: Shreyas Arya
  • Texas
    • San Antonio, Texas, United States, 78229
      • Recruiting
      • Methodist Healthcare
      • Contact: Melissa Althouse, MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 4 months to 7 months (Child)
• Accepts Healthy Volunteers: No

• Sampling Method: Probability Sample

Study Population

All preterm infants born ≤32 weeks gestational age and > 48 hours of life with suspected sepsis with systemic hypotension admitted to the participating sites and meeting the above eligibility criteria will be included in the study.

Description

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

Study Plan

How is the study designed?

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
Dopamine Units; Units who have standardized their practice with the use of Dopamine as a first line agent.	Drug: Dopamine; 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; Units who have standardized their practice with the use of Norepinephrine as a first line agent.	Drug: Norepinephrine; 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

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Mount Sinai Hospital, Canada
• Collaborators: The Hospital for Sick Children; Sunnybrook Health Sciences Centre; Health Sciences Centre, Winnipeg, Manitoba; Stony Brook University; Assaf-Harofeh Medical Center; London Health Sciences Centre; Children's Hospital of Eastern Ontario; Jewish General Hospital; IWK Health Centre; McMaster Children's Hospital; St. Justine's Hospital; University College Cork; Hospital Universitario La Paz; St. Boniface Hospital; Banner University Medical Center; Foothills Medical Centre; Coombe Women and Infants University Hospital; BC Women's Hospital & Health Centre; Dayton Children's Hospital; Windsor Regional Hospital; Golisano Children's Hospital; Methodist Healthcare; The Children's Hospital at Montefiore; Island Health, Victoria, BC
• Investigators: Principal Investigator: Amish Jain, MBBS, MRCPCH, PhD, Mount Sinai Hospital, Canada

Study record dates

Study Major Dates

• Study Start (Actual): February 6, 2023
• Primary Completion (Estimated): June 30, 2026
• Study Completion (Estimated): March 31, 2027

Study Registration Dates

• First Submitted: April 12, 2022
• First Submitted That Met QC Criteria: April 20, 2022
• First Posted (Actual): April 26, 2022

Study Record Updates

• Last Update Posted (Estimated): July 8, 2025
• Last Update Submitted That Met QC Criteria: July 3, 2025
• Last Verified: July 1, 2025

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Vascular Diseases; Cardiovascular Diseases; Pathologic Processes; Infections; Systemic Inflammatory Response Syndrome; Inflammation; Infant, Newborn, Diseases; Neonatal Sepsis; Sepsis; Hypotension; Toxemia; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Autonomic Agents; Peripheral Nervous System Agents; Neurotransmitter Agents; Protective Agents; Adrenergic alpha-Agonists; Adrenergic Agonists; Adrenergic Agents; Cardiotonic Agents; Dopamine Agents; Sympathomimetics; Vasoconstrictor Agents; Norepinephrine; Dopamine
• Other Study ID Numbers: CTO 4009

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No