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

Summary

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

Conditions

• Late-Onset Neonatal Sepsis
• Extreme Prematurity
• Neonatal Hypotension

Interventions

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.

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

Sponsors & Collaborators

• Sunnybrook Health Sciences Centre

  collaborator OTHER

• The Hospital for Sick Children

  collaborator OTHER

• London Health Sciences Centre

  collaborator OTHER

• Windsor Regional Hospital

  collaborator OTHER

• Foothills Medical Centre

  collaborator OTHER

• Health Sciences Centre, Winnipeg, Manitoba

  collaborator OTHER

• St. Boniface Hospital

  collaborator OTHER

• Jewish General Hospital

  collaborator OTHER

• St. Justine's Hospital

  collaborator OTHER

• IWK Health Centre

  collaborator OTHER

• University College Cork

  collaborator OTHER

• Coombe Women and Infants University Hospital

  collaborator OTHER

• Island Health, Victoria, BC

  collaborator OTHER

• Assaf-Harofeh Medical Center

  collaborator OTHER_GOV

• Dayton Children's Hospital

  collaborator OTHER

• Banner University Medical Center

  collaborator OTHER

• Methodist Healthcare

  collaborator OTHER

• Hospital Universitario La Paz

  collaborator OTHER

• McMaster Children's Hospital

  collaborator OTHER

• Children's Hospital of Eastern Ontario

  collaborator OTHER

• BC Women's Hospital & Health Centre

  collaborator OTHER

• Stony Brook University

  collaborator OTHER

• The Children's Hospital at Montefiore

  collaborator OTHER

• Golisano Children's Hospital

  collaborator UNKNOWN

• Mount Sinai Hospital, Canada

  lead OTHER

Principal Investigators

• Amish Jain, MBBS, MRCPCH, PhD · Mount Sinai Hospital, Canada

Eligibility

Min Age

21 Weeks

Max Age

32 Weeks

Sex

ALL

Healthy Volunteers

No

Timeline & Regulatory

Start

2023-02-06

Primary Completion

2026-06-30

Completion

2027-03-31

Countries

• United States
• Canada
• Ireland
• Israel
• Spain

Study Locations