Hydrocortisone Therapy Optimization During Hypothermia Treatment in Asphyxiated Neonates

Study Overview
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Brief Summary
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This is a prospective, single center, pharmacokinetic study of intravenous hydrocortisone therapy for systemic low blood pressure during hypothermia treatment in asphyxiated newborns. Patients will be allocated to hydrocortisone supplementation while receiving conventional inotropic therapy as needed. The hypothesis is that a detailed study of hydrocortisone pharmacokinetics during therapeutic hypothermia would help to personalize steroid supplementation in asphyxiated neonates. As the overall metabolic rate decreases with lower body temperature, drug metabolism is likely to be reduced as well, and lower doses, or less frequent dosing will be sufficient to achieve the targeted steroid range and biological effects in asphyxiated neonates with relative adrenal insufficiency. Thus, the investigators are planning to measure initial, baseline serum cortisol levels and serial serum cortisol levels after hydrocortisone supplementation in cooled asphyxiated neonates.

Detailed Description
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The ultimate goal of the present study, is to describe a new approach of more personalized and safe care to infants with birth asphyxia and hemodynamic instability. Asphyxiated infants often present with multiorgan failure and low blood pressure. Therapeutic hypothermia, the standard of care, could worsen hemodynamic instability; therefore, treatment of cardiovascular impairment represents a major challenge in this clinical setting. An association was previously described between hypotension and low serum cortisol values in this patient population, and it was suggested that relative adrenal insufficiency (RAI) is an important factor in the circulatory compromise of these patients. In the CORTISoL clinical trial, it was also demonstrated that low-dose hydrocortisone therapy was effective in the treatment of cardiovascular impairment in asphyxiated neonates; however, some gaps remain in the knowledge on optimal dosing. Importantly, steroid therapy should be administered at the lowest effective dose and for the shortest possible duration in this vulnerable population. In the current pharmacokinetic study, the investigators propose a stepwise approach to more detailed understanding of RAI and hydrocortisone pharmacokinetics in asphyxiated neonates. The findings would certainly aid clinical decision-making and allow for more personalized therapeutic interventions for the treatment of hemodynamic instability.

Official Title
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Hydrocortisone Therapy Optimization During Hypothermia Treatment in Asphyxiated Neonates - a Pharmacokinetic Study

Conditions
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Hypoxic-Ischemic Encephalopathy, Asphyxia, Hypotension, Circulatory Failure Neonatal

Intervention / Treatment
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* Drug: Hydrocortisone


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: gestational age ≥ 36 weeks provision of whole-body hypothermia treatment (as described by Azzopardi et al.) presence of systemic hypotension (defined as a mean arterial pressure less than the gestational age in weeks) indication for hydrocortisone treatment during hypothermia by the attending physician indwelling arterial catheter to take blood samples without additional painful punctures: umbilical arterial catheter or peripheral arterial catheter written informed parental consent Exclusion Criteria: infants who are expected to be > 6 hours of age (not suitable for cooling) critical congenital abnormalities genetic disease signed informed consent is unavailable

Ages Eligible for Study
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Maximum Age: 72 Hours

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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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Interventional Model Description: Pharmacokinetic analysis of the standard dose hydrocortisone therapy (0.5 mg/kg/6 hours) during hypothermia treatment, then compare the effects of the modified dose hydrocortisone therapy which will be determined based on the pharmacokinetic results.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Standard dose hydrocortisone<br>The standard dose of hydrocortisone therapy in neonates for hypotension is 0.5 mg/kg every 6 hours. | Drug: Hydrocortisone<br>* intravenous bolus hydrocortisone therapy during hypothermia treatment<br>* Other names: Solu-Cortef;|
| Active Comparator: Modified dose hydrocortisone<br>The modified dose of hydrocortisone therapy will be determined based on the pharmacokinetic results. | Drug: Hydrocortisone<br>* intravenous bolus hydrocortisone therapy during hypothermia treatment<br>* Other names: Solu-Cortef;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mean blood pressure increase | 5 mmHg increase in mean arterial blood pressure after drug administration | 2 hours | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cardiovascular management | Length, cumulative and peak dose of inotrope treatment | 72 hours | 
| Presence of relative adrenal insufficiency at baseline | Low serum cortisol level at baseline | Before hydrocortisone administration within max. 72 hours | 
| MRI outcome | Brain injury on MRI examinations | 4-10 days | 
| Long term neurodevelopmental outcome | Performance on motor and mental scales of Bayley III scales of infant development | 18-42 month | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Asphyxia, Hypothermia treatment, Relative adrenal insufficiency, Hydrocortisone supplementation, Hydrocortisone pharmacokinetics, Hypoxic-Ischemic Encephalopathy