MANUSCRIPT CITATION

Marlow N, Barrington KJ, ODonnell CPF, Miletin J, Naulaers G, Cheung PY, Corcoran JD, Khuffash E, Boylan GB, Livingstone V, Pons G, Straňák Z, Van Laere D, Macko J, Wiedermannova H, Dempsey EM; HIP consortium. Outcomes of extremely preterm infants who participated in a randomised trial of dopamine for treatment of hypotension (the HIP trial) at 2 years corrected age. Arch Dis Child Fetal Neonatal Ed. 2025 Jan 19:fetalneonatal-2024-327894. PMID: 39832819.

REVIEWED BY

Name, Title: N Rao1, H Gowda2
Institution: 1.Birminghan Women’s and Children’s NHS Foundation Trust. 2. University Hospitals of Birmingham NHS Trust.
Email: Narasimha.rao@nhs.net

TYPE OF INVESTIGATION

Treatment

QUESTION

In extremely preterm infants born before 28 weeks of gestation with hypotension, does early treatment with dopamine infusion, compared to a restrictive approach (placebo), improve survival without neurodevelopmental impairment at 24 months corrected age?

METHODS

• Design: Prospective follow-up study of infants who participated in a randomised controlled trial (RCT) (HIP trial) comparing dopamine versus placebo to treat hypotension in extremely preterm infants.
• Allocation: Randomized
• Blinding: Double-blind design
• Follow-up period: Until 24 months corrected age.
• Setting: 10 tertiary neonatal centres across Europe and Canada.
• Patients:
  • Inclusion Criteria:
    • Infants born before 28 weeks of gestation with low mean arterial blood pressure (MAP).
    • Enrolled in the original HIP trial between February 2015 and September 2017.
    • Survived initial NICU care and were available for follow-up at 24 months CA.
  • Exclusion Criteria:
    • Major congenital anomalies or chromosomal abnormalities.
    • Infants who did not survive beyond NICU discharge.
    • Lost to follow-up after discharge.
  • Intervention:
    • Dopamine Infusion Group:
      • Received dopamine infusion for treating hypotension.
      • Goal: Increase MAP above predefined thresholds.
    • Placebo Group:
      • Managed with a restrictive approach (no dopamine infusion unless required).
      • Additional inotropes (e.g., epinephrine) were used as rescue therapy if needed.

• Outcomes:
  • Primary Outcome:
    • Survival without neurodevelopmental impairment (NIDD) at 24 months corrected age. Defined as the absence of cerebral palsy (GMFCS ≥2), Bayley-3 composite scores ≥85, and no moderate/severe hearing or vision impairment.
  • Secondary Outcomes:
    • Neurodevelopmental outcomes at 24 months CA, including:
      • Bayley-3 composite scores (Cognitive, Language, Motor).
      • Cerebral palsy diagnosis (GMFCS classification).
      • Hearing and vision impairment.
    • Respiratory and gastrointestinal complications.
    • Growth parameters (height, weight, and head circumference at 24 months CA).
    • Hospital readmission rates post-NICU discharge.

• Analysis and Sample Size:
  • Statistical analysis
    • Logistic regression for binary outcomes.
    • Linear regression for continuous variables.
    • Random-effects models used to adjust for centre variability.
    • Odds ratios (ORs) with 95% confidence intervals (CIs) were reported.
  • Sample size
    • Original HIP trial sample: 58 infants (27 in the dopamine group, 28 in the placebo group).
    • Follow-up sample: 55 infants (21 survivors in the dopamine group, 20 in the placebo group).
• Patient follow-up: % included in analysis
  • 95% follow-up rate (55 out of 58 infants).
  • Three infants were lost to follow-up.
  • No additional deaths after NICU discharge.
  • All survivors were evaluated for neurodevelopmental outcomes.

MAIN RESULTS

CONCLUSION

The HIP trial follow-up provides preliminary evidence that dopamine may improve survival without neurodevelopmental impairment, but the study was too small to confirm this definitively. Additionally, concerns about dopamine’s impact on growth and endocrine function warrant further investigation. Until more extensive trials provide more precise guidance, clinicians should individualise treatment decisions, balancing the benefits of dopamine in improving circulation against its potential long-term effects.

COMMENTARY

Hypotension is common in extremely preterm infants, affecting nearly half of those weighing under 1000 g in the early postnatal period (1). However, there is no consensus on a definition, and thresholds for intervention vary widely. Many NICUs initiate treatment when mean arterial pressure (MAP) falls below gestational age in weeks (2). Dopamine is often used as first-line therapy and is effective in increasing MAP, though its long-term benefits remain uncertain (3,4).

 

The Hypotension in Preterm Infants (HIP) trial was the first multicentre RCT to compare dopamine versus placebo in treating hypotension in infants under 28 weeks (5). The initial trial was stopped early due to recruitment challenges and found no significant difference in survival to 36 weeks without severe brain injury. The follow-up assessed 55 infants at 2 years of corrected age (6).

 

Outcomes
• Primary Outcome:
Survival without neurodevelopmental impairment (NIDD) was 48% in the dopamine group compared to 25% in the placebo group (OR ~2.8, p=0.078). Although this difference was not statistically significant, the trend indicates potential benefits.
• Secondary Outcomes:
Rates of cerebral palsy, hearing or vision impairment, and Bayley-III cognitive and motor scores were similar across groups. However, dopamine-treated infants were significantly shorter and lighter at 2 years, raising concerns about growth suppression, potentially linked to dopamine’s known endocrine effects (7).

 

These findings suggest that avoiding dopamine did not worsen neurodevelopmental outcomes in this small sample; however, a significant difference cannot be ruled out. The study raises two key clinical concerns: whether a restrictive approach may reduce survival without impairment, and whether dopamine may influence postnatal growth.

 

Clinical Implications

This study supports a nuanced approach to managing hypotension. In stable infants showing signs of adequate perfusion, the immediate use of dopamine can be safely deferred. The results emphasise the importance of evaluating systemic status (e.g., capillary refill, lactate, urine output) rather than focusing on an isolated BP value (8). However, the lower survival rate without impairment in the placebo group suggests that some infants might benefit from early inotropic support, indicating that a purely restrictive approach could be inadequate in specific cases.

 

The observed growth impairment also requires clinical attention. Practitioners should consider monitoring both growth and endocrine function in infants exposed to dopamine. If future research confirms this effect, it could influence vasopressor choice and treatment thresholds.

 

Conclusion

The HIP trial follow-up underscores the complexity of managing hypotension in extremely preterm infants. While it does not provide definitive answers, it raises significant questions about long-term outcomes and emphasises the necessity for individualised care. Until larger trials offer clearer guidance, clinicians must carefully evaluate the potential benefits and risks of dopamine in the early neonatal period.

REFERENCES

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2. Stranak Z, Semberova J, Barrington K, O’Donnell C, Marlow N, Naulaers G, et al. International survey on diagnosis and management of hypotension in extremely preterm babies. Eur J Pediatr [Internet]. 2014 Jun 1 [cited 2025 Feb 27];173(6):793–8. Available from: https://pubmed.ncbi.nlm.nih.gov/24390060/
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6. Marlow N, Barrington KJ, Odonnell CPF, Miletin J, Naulaers G, Cheung PY, et al. Outcomes of extremely preterm infants who participated in a randomised trial of dopamine for treatment of hypotension (the HIP trial) at 2 years corrected age. Arch Dis Child Fetal Neonatal Ed [Internet]. 2025 [cited 2025 Feb 1]; Available from: https://pubmed.ncbi.nlm.nih.gov/39832819/
7. Filippi L, Pezzati M, Poggi C, Rossi S, Cecchi A, Santoro C. Dopamine versus dobutamine in very low birthweight infants: endocrine effects. Arch Dis Child Fetal Neonatal Ed [Internet]. 2007 Sep [cited 2025 Feb 27];92(5):F367. Available from: https://pmc.ncbi.nlm.nih.gov/articles/PMC2675359/
8. Mullaly R, El-Khuffash AF. Haemodynamic assessment and management of hypotension in the preterm. Arch Dis Child Fetal Neonatal Ed [Internet]. 2024 Mar 1 [cited 2025 Feb 27];109(2):120–7. Available from: https://fn.bmj.com/content/109/2/120