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

Sponsor

Semmelweis University (Other)

Overall Status

Active, not recruiting

CT.gov ID

NCT02700828

Collaborator

(none)

Enrollment

Location

Arms

Duration (Months)

0.4

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

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.

Condition or Disease	Intervention/Treatment	Phase
Hypoxic-Ischemic Encephalopathy Asphyxia	Drug: Hydrocortisone Drug: Placebo	Phase 2/Phase 3

Detailed Description

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:

To study initial serum cortisol levels in asphyxiated newborns undergoing therapeutic hypothermia with late onset hypotension.
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:

Fluid replacement (volume bolus: 10-20 ml/kg isotonic saline, over 15 minutes, according to the clinician's decision)
In case of persisting hypotension: serum sample is collected for cortisol measurement.
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)

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.

Study Design

Study Type:

Interventional

Actual Enrollment :

32 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)

Primary Purpose:

Treatment

Official Title:

Prospective, Randomized, Double-blind, Cohort Study of Hydrocortisone vs Placebo in Systemic Low Blood Pressure During Hypothermia Treatment in Asphyxiated Newborns

Study Start Date :

Feb 1, 2016

Actual Primary Completion Date :

Nov 1, 2017

Anticipated Study Completion Date :

Feb 1, 2022

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Hydrocortisone Hydrocortisone is the pharmaceutical term for cortisol, the principal glucocorticoid secreted by the adrenal gland	Drug: Hydrocortisone 4 * 0,5 mg/kg /24 hours (in every 6 hours) iv., during hypothermia treatment (max. 72 hours) Other Names: Solu-Cortef
Placebo Comparator: Placebo Isotonic sodium chloride is an aqueous solution of 0.9 percent sodium chloride which is isotonic with the blood and tissue fluid	Drug: Placebo 4 * 2 ml isotonic sodium chloride solution /24 hours (in every 6 hours) iv., during hypothermia treatment (max. 72 hours) Other Names: Isotonic saline

Arm

Intervention/Treatment

Active Comparator: Hydrocortisone

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

Drug: Hydrocortisone

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

Other Names:

Solu-Cortef

Placebo Comparator: Placebo

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

Drug: Placebo

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

Other Names:

Isotonic saline

Outcome Measures

Primary Outcome Measures

Compare mean arterial blood pressure (MAP) change in the patients receiving hydrocortisone vs placebo [2 hours]
Circulatory stability as measured by an increased MAP (5 mmHg) within two hours after drug administration

Secondary Outcome Measures

Frequency of initially low serum cortisol in hypotensive asphyxiated newborns undergoing therapeutic hypothermia [before hydrocortisone administration within max. 72 hours]
Initially low serum cortisol - proven relative adrenal insufficiency
Length of dopamine treatment in the patients receiving hydrocortisone vs placebo [72 hours]
Compare dopamine treatment's length (in hours) in the patients receiving hydrocortisone vs placebo
Cumulative dopamine dose in the patients receiving hydrocortisone vs placebo [72 hours]
Compare cumulative dopamine dose (mcg/kg) in the patients receiving hydrocortisone vs placebo
Change in hourly diuresis in the patients receiving hydrocortisone vs placebo [72 hours]
Measure and compare the hourly diuresis (ml/kg/hour) in the patients receiving hydrocortisone vs placebo
Change in the echocardiography parameters (fractional shortening and cardiac output) in the patients receiving hydrocortisone vs placebo [72 hours]
Fractional shortening (FS%) and cardiac output (CO in ml/kg/min) measurements before and after hydrocortisone or placebo, during the first 72 hours (during hypothermia treatment)
Long term neurodevelopmental outcome in the patients receiving hydrocortisone vs placebo [18-22 month]
Performance on motor and mental scales of Bayley II/III scales of infant development

Eligibility Criteria

Criteria

Ages Eligible for Study:

N/A to 72 Hours

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

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.

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

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

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

Invasive arterial blood pressure measurement: umbilical arterial catheter or peripheral arterial catheter to measure invasively the arterial blood pressure.
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

A written informed consent has been obtained from a parent of each infant after explanation of the study.

Exclusion Criteria:

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