Clinical trial NCT05836610: Hydrocortisone Therapy Optimization During Hypothermia Treatment in Asphyxiated Neonates
Official title: Hydrocortisone Therapy Optimization During Hypothermia Treatment in Asphyxiated Neonates - a Pharmacokinetic Study
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE4
Conditions: Hypoxic-Ischemic Encephalopathy
Asphyxia
Hypotension
Circulatory Failure Neonatal
Keywords: Hypothermia treatment
Relative adrenal insufficiency
Hydrocortisone supplementation
Hydrocortisone pharmacokinetics
Hypoxic-Ischemic Encephalopathy
Asphyxia
Lead sponsor: Semmelweis University
Sponsor class: OTHER
First posted: 2023-05-01
Enrollment: 50
Sex: ALL
Maximum age (years): 72
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SEQUENTIAL
Intervention 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.
Primary purpose: TREATMENT

Brief summary: 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: 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.

Eligibility criteria: 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

Primary outcomes:
measure: Mean blood pressure increase
timeFrame: 2 hours
Secondary outcomes:
measure: Cardiovascular management
timeFrame: 72 hours
measure: Presence of relative adrenal insufficiency at baseline
timeFrame: Before hydrocortisone administration within max. 72 hours
measure: MRI outcome
timeFrame: 4-10 days
measure: Long term neurodevelopmental outcome
timeFrame: 18-42 month
Other outcomes:
measure: Multiorgan failure
timeFrame: 72 hours
Locations:
city: Budapest
country: Hungary
facility: Semmelweis University Department of Pediatrics (Bókay street Unit)
state: Pest Megye
Study officials:
affiliation: Semmelweis University
name: Kata Kovacs, MD, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Semmelweis University
name: Miklós Szabó, MD, PhD
role: STUDY_DIRECTOR
References:
citation: Azzopardi DV, Strohm B, Edwards AD, Dyet L, Halliday HL, Juszczak E, Kapellou O, Levene M, Marlow N, Porter E, Thoresen M, Whitelaw A, Brocklehurst P; TOBY Study Group. Moderate hypothermia to treat perinatal asphyxial encephalopathy. N Engl J Med. 2009 Oct 1;361(14):1349-58. doi: 10.1056/NEJMoa0900854.
citation: Kovacs K, Szakmar E, Meder U, Szakacs L, Cseko A, Vatai B, Szabo AJ, McNamara PJ, Szabo M, Jermendy A. A Randomized Controlled Study of Low-Dose Hydrocortisone Versus Placebo in Dopamine-Treated Hypotensive Neonates Undergoing Hypothermia Treatment for Hypoxic-Ischemic Encephalopathy. J Pediatr. 2019 Aug;211:13-19.e3. doi: 10.1016/j.jpeds.2019.04.008. Epub 2019 May 30.
citation: Kovacs K, Szakmar E, Meder U, Cseko A, Szabo AJ, Szabo M, Jermendy A. Serum cortisol levels in asphyxiated infants with hypotension. Early Hum Dev. 2018 May;120:40-45. doi: 10.1016/j.earlhumdev.2018.03.003. Epub 2018 Apr 4. No abstract available.
citation: Watterberg KL. Hydrocortisone Dosing for Hypotension in Newborn Infants: Less Is More. J Pediatr. 2016 Jul;174:23-26.e1. doi: 10.1016/j.jpeds.2016.04.005. Epub 2016 May 4. No abstract available.
citation: Concepcion KR, Zhang L. Corticosteroids and perinatal hypoxic-ischemic brain injury. Drug Discov Today. 2018 Oct;23(10):1718-1732. doi: 10.1016/j.drudis.2018.05.019. Epub 2018 May 17.
citation: Sarkar S, Barks JD. Systemic complications and hypothermia. Semin Fetal Neonatal Med. 2010 Oct;15(5):270-5. doi: 10.1016/j.siny.2010.02.001. Epub 2010 Mar 12.