Timing of hydrocortisone therapy in neonates with shock: A systematic review, metaanalysis and clinical practice guideline

Viraraghavan Vadakkencherry Ramaswamy ¹ Gunjana Kumar ² Abdul Kareem Pullattayil S ³ Abhishek S Aradhya ⁴ Pradeep Suryawanshi ⁵ Mohit Sahni ⁶ SUPREET KHURANA ⁷ Shiv Sajan Saini ⁸ Ravishankar Kanithi ⁹ Shashi Kant Dhir ¹⁰ Deepak Chawla ⁷ Praveen Kumar ⁸ KIRAN MORE ^11*

• ¹ Ankura Hospital For Women and Children, Hyderabad, India
• ² National Institute of Medical Sciences and Research, Jaipur, Rajasthan, India
• ³ Queen's University, Kingston, Ontario, Canada
• ⁴ Ovum Woman and Child Speciality Hospital, Bangalore, Karnataka, India
• ⁵ Bharati Vidyapeeth's Medical College, Pune, Maharashtra, India
• ⁶ Nirmal Hospital, Surat, India
• ⁷ Government Medical College and Hospital, Chandigarh, Chandigarh, India
• ⁸ Post Graduate Institute of Medical Education and Research (PGIMER), Chandigarh, Haryana, India
• ⁹ Soumya Children's Hospital, Hyderabad, India
• ¹⁰ Guru Gobind Singh Medical College and Hospital, Farīdkot, Punjab, India
• ¹¹ MRR Children’s Hospital, Thane, India

Background: The effect of timing of initiation of hydrocortisone in neonatal shock has not been evaluated. The objective of this systematic review was to compare the effect of earlier vs. later initiation of hydrocortisone in neonatal shock. Methods: Medline, Embase and CENTRAL were searched from inception until 15th May 2024. Randomized controlled trials (RCTs) and non-RCTs were eligible for inclusion. A random effects meta-analysis was used to synthesize data. The evidence certainty was evaluated according to GRADE. A clinical practice guideline was formulated by as recommended by the GRADE group.Results: Of the 3,757 title and abstracts screened, 20 studies were included: 7 RCTs and 13 non-RCTs. While clinical benefit or harm could not be ruled out for the outcome of mortality from the meta-analysis of RCTs (early - Risk ratio (RR): 0.46, 95% confidence interval (CI): 0.03 - 7.92; late - RR: 0.43, 95% CI: 0.12 - 1.47), non-RCTs included in the narrative review suggested that late hydrocortisone initiation might be associated with increased risk of mortality. Meta-analysis indicated that early and late hydrocortisone administration may be associated with an increased response to treatment therapy (early- RR: 1.85, 95% CI: 1.26 - 2.71; late - RR: 2.50, 95% CI: 1.16 - 5.39). Late hydrocortisone initiation might increase the risk of necrotizing enterocolitis (NEC) ≥ stage 2 (RR: 2.46, 95% CI: 1.19 - 5.08). The evidence certainty was very low for most of the outcomes evaluated. Conclusion: Early use of hydrocortisone in neonates with shock requiring vasopressors is associated with better outcomes and no major adverse effects. Later institution of hydrocortisone therapy in neonatal shock may improve the response to therapy but might possibly be associated with adverse outcomes including mortality and NEC. The results are to be interpreted with caution as the evidence certainty was predominantly very low.