Hydrocortisone Treatment In Systemic Low Blood Pressure During Hypothermia in Asphyxiated Newborns

NCT ID: NCT02700828

Last Updated: 2023-04-21

Study Results

Results pending

The study team has not published outcome measurements, participant flow, or safety data for this trial yet. Check back later for updates.

Basic Information

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Recruitment Status

COMPLETED

Clinical Phase

PHASE2/PHASE3

Total Enrollment

32 participants

Study Classification

INTERVENTIONAL

Study Start Date

2016-02-29

Study Completion Date

2022-12-15

Brief Summary

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This is a prospective, randomized, double-blind, placebo controlled, single center study to compare low dose hydrocortisone vs placebo in systemic low blood pressure during hypothermia treatment in asphyxiated newborns. Patients will be allocated to one of the treatment arms (hydrocortisone or placebo) while receiving conventional inotropic therapy as needed.

The hypothesis is that cooled asphyxiated neonates develop relative adrenal insufficiency that may contribute to hypotension and lower efficacy of inotropic therapy in this patient population. Thus, the investigators are planning to measure initial serum cortisol levels and investigate the cardiovascular effects of low dose hydrocortisone supplementation besides conventional inotropic therapy in a placebo-controlled fashion.

Detailed Description

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Hypothesis:

The researchers hypothesized that asphyxiated neonates undergoing therapeutic hypothermia develop relative adrenal insufficiency that contributes to "late onset" (\>24 hours after birth) hypotension resistant to optimized pharmacological support.

Thus, the investigators are planning to measure initial serum cortisol levels and investigate the cardiovascular effects of low dose hydrocortisone supplementation.

Specific aims:

1. To study initial serum cortisol levels in asphyxiated newborns undergoing therapeutic hypothermia with late onset hypotension.
2. To demonstrate that in asphyxiated newborns undergoing therapeutic hypothermia and presenting with systemic hypotension resistant to optimized pharmacological support, low dose hydrocortisone supplementation restores normal blood pressure when compared to placebo.

Methodology:

* Prospective, randomized, double-blind, single center, cohort study
* 1st Department of Paediatrics, NICU, Semmelweis University, Hungary
* Starting date: 02/14/2016
* Patient number: 16 vs 16 (hydrocortisone vs placebo - based on previous observational study results)
* Intervention (hydrocortisone vs placebo) applied only during therapeutic hypothermia (max. 72 hours)
* Neurodevelopmental follow-up visit: Bayley II/III scale to evaluate the effect of hydrocortisone treatment on the neurological development at the age between 18 and 22 months.

Drugs for hypotension, the hydrocortisone protocol:

1. Fluid replacement (volume bolus: 10-20 ml/kg isotonic saline, over 15 minutes, according to the clinician's decision)
2. In case of persisting hypotension: serum sample is collected for cortisol measurement.
3. Randomization, irrespective of actual cortisol level. As the study is blinded, enrollment in the clinical trial will/shall not influence the clinical decision making about further interventions. A dedicated study assistant will be available to prepare the drug / placebo for the newborns.

* Inotropic therapy (dopamine, following the standard titration protocol)
* AND (at start of dopamine) hydrocortisone: 4 \* 0,5 mg/kg /24 hours (in every 6 hours) or placebo administration (the corresponding amount of isotonic saline)
4. After randomization, intervention is continued until the end of hypothermia treatment (max. 72 hours), with the same dose. Inotropic therapy will be titrated as needed.

Conditions

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Hypoxic-Ischemic Encephalopathy Asphyxia

Study Design

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Allocation Method

RANDOMIZED

Intervention Model

PARALLEL

Primary Study Purpose

TREATMENT

Blinding Strategy

QUADRUPLE

Participants Caregivers Investigators Outcome Assessors

Study Groups

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Hydrocortisone

Hydrocortisone is the pharmaceutical term for cortisol, the principal glucocorticoid secreted by the adrenal gland

Group Type ACTIVE_COMPARATOR

Hydrocortisone

Intervention Type DRUG

4 \* 0,5 mg/kg /24 hours (in every 6 hours) iv., during hypothermia treatment (max. 72 hours)

Placebo

Isotonic sodium chloride is an aqueous solution of 0.9 percent sodium chloride which is isotonic with the blood and tissue fluid

Group Type PLACEBO_COMPARATOR

Placebo

Intervention Type DRUG

4 \* 2 ml isotonic sodium chloride solution /24 hours (in every 6 hours) iv., during hypothermia treatment (max. 72 hours)

Interventions

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Hydrocortisone

4 \* 0,5 mg/kg /24 hours (in every 6 hours) iv., during hypothermia treatment (max. 72 hours)

Intervention Type DRUG

Placebo

4 \* 2 ml isotonic sodium chloride solution /24 hours (in every 6 hours) iv., during hypothermia treatment (max. 72 hours)

Intervention Type DRUG

Other Intervention Names

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Solu-Cortef Isotonic saline

Eligibility Criteria

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Inclusion Criteria

1. The infant will be assessed sequentially by criteria A, B and C, as described by the TOBY trial and listed below, to be eligible for hypothermia treatment.

A. Infants ≥ 36 completed weeks of gestation admitted to the NICU with at least one of the following:
* Apgar score of ≤ 5 at 10 minutes after birth
* Continued need for resuscitation, including endotracheal or mask ventilation, at 10 minutes after birth
* Acidosis within 60 minutes of birth (defined as any occurrence of umbilical cord, arterial or capillary pH \< 7.00)
* Base Deficit ≥ 16 mmol/L in umbilical cord or any blood sample (arterial, venous or capillary) within 60 minutes of birth

B. Moderate to severe encephalopathy, consisting of altered state of consciousness (lethargy, stupor or coma) AND at least one of the following:
* hypotonia
* abnormal reflexes including oculomotor or pupillary abnormalities
* absent or weak suck
* clinical seizures

C. At least 30 minutes duration of aEEG recording that shows abnormal background aEEG activity or seizures. There must be one of the following:
* normal background with some seizure activity
* moderately abnormal activity
* suppressed activity
* continuous seizure activity
2. Invasive arterial blood pressure measurement: umbilical arterial catheter or peripheral arterial catheter to measure invasively the arterial blood pressure.
3. During hypothermia treatment low blood pressure was detected and treated with the following:

* fluid therapy: 10-20 ml/kg isotonic NaCl if hypotension is still present
* inotropic therapy: dopamine in parallel with study intervention
4. A written informed consent has been obtained from a parent of each infant after explanation of the study.

Exclusion Criteria

1. Signed informed consent is unavailable.
2. Infants who are expected to be \> 6 hours of age (not suitable for cooling).
3. Congenital abnormalities, cardiac anomalies, meconium aspiration syndrome.
4. Low blood pressure coincides with high heart rate (\>120/min) in cooled infants, suggesting hypovolaemia.
5. Haematocrit level \< 35%.
6. Need for combined, ≥2 types of inotropic therapy.
Maximum Eligible Age

72 Hours

Eligible Sex

ALL

Accepts Healthy Volunteers

No

Sponsors

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Semmelweis University

OTHER

Sponsor Role lead

Responsible Party

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Agnes Jermendy MD PhD MPH

assistant lecturer

Responsibility Role PRINCIPAL_INVESTIGATOR

Principal Investigators

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Miklós Szabó, MD, PhD

Role: STUDY_DIRECTOR

Semmelweis University, 1st Department of Paediatrics

Locations

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Semmelweis University, 1st Department of Paediatrics

Budapest, Pest County, Hungary

Site Status

Countries

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Hungary

References

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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.

Reference Type BACKGROUND
PMID: 19797281 (View on PubMed)

Noori S, Friedlich P, Wong P, Ebrahimi M, Siassi B, Seri I. Hemodynamic changes after low-dosage hydrocortisone administration in vasopressor-treated preterm and term neonates. Pediatrics. 2006 Oct;118(4):1456-66. doi: 10.1542/peds.2006-0661.

Reference Type BACKGROUND
PMID: 17015536 (View on PubMed)

Ibrahim H, Sinha IP, Subhedar NV. Corticosteroids for treating hypotension in preterm infants. Cochrane Database Syst Rev. 2011 Dec 7;2011(12):CD003662. doi: 10.1002/14651858.CD003662.pub4.

Reference Type BACKGROUND
PMID: 22161379 (View on PubMed)

Rios DR, Moffett BS, Kaiser JR. Trends in pharmacotherapy for neonatal hypotension. J Pediatr. 2014 Oct;165(4):697-701.e1. doi: 10.1016/j.jpeds.2014.06.009. Epub 2014 Jul 16.

Reference Type BACKGROUND
PMID: 25039051 (View on PubMed)

Hebbar KB, Stockwell JA, Leong T, Fortenberry JD. Incidence of adrenal insufficiency and impact of corticosteroid supplementation in critically ill children with systemic inflammatory syndrome and vasopressor-dependent shock. Crit Care Med. 2011 May;39(5):1145-50. doi: 10.1097/CCM.0b013e31820eb4e4.

Reference Type BACKGROUND
PMID: 21336126 (View on PubMed)

Ng PC, Lam CW, Fok TF, Lee CH, Ma KC, Chan IH, Wong E. Refractory hypotension in preterm infants with adrenocortical insufficiency. Arch Dis Child Fetal Neonatal Ed. 2001 Mar;84(2):F122-4. doi: 10.1136/fn.84.2.f122.

Reference Type BACKGROUND
PMID: 11207229 (View on PubMed)

Ng PC, Lee CH, Bnur FL, Chan IH, Lee AW, Wong E, Chan HB, Lam CW, Lee BS, Fok TF. A double-blind, randomized, controlled study of a "stress dose" of hydrocortisone for rescue treatment of refractory hypotension in preterm infants. Pediatrics. 2006 Feb;117(2):367-75. doi: 10.1542/peds.2005-0869.

Reference Type BACKGROUND
PMID: 16452355 (View on PubMed)

Seri I, Tan R, Evans J. Cardiovascular effects of hydrocortisone in preterm infants with pressor-resistant hypotension. Pediatrics. 2001 May;107(5):1070-4. doi: 10.1542/peds.107.5.1070.

Reference Type BACKGROUND
PMID: 11331688 (View on PubMed)

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.

Reference Type RESULT
PMID: 31155392 (View on PubMed)

Kovacs K, Szakmar E, Dobi M, Varga Z, Meder U, Szabo AJ, McNamara PJ, Szabo M, Jermendy A. Neurodevelopmental outcome in infants with neonatal encephalopathy receiving hydrocortisone during therapeutic hypothermia: follow-up of the extended-CORTISoL trial. J Perinatol. 2025 Sep 22. doi: 10.1038/s41372-025-02428-5. Online ahead of print.

Reference Type DERIVED
PMID: 40983658 (View on PubMed)

Other Identifiers

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1Ped-AsphCort 001

Identifier Type: -

Identifier Source: org_study_id

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