Clinical trial NCT02700828: Hydrocortisone Treatment In Systemic Low Blood Pressure During Hypothermia in Asphyxiated Newborns
Official title: Prospective, Randomized, Double-blind, Cohort Study of Hydrocortisone vs Placebo in Systemic Low Blood Pressure During Hypothermia Treatment in Asphyxiated Newborns
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
PHASE3
Conditions: Hypoxic-Ischemic Encephalopathy
Asphyxia
Keywords: Hypothermia treatment
Circulatory failure
Neonatal hypotension
Relative adrenal insufficiency
Hydrocortisone supplementation
Lead sponsor: Semmelweis University
Sponsor class: OTHER
First posted: 2016-03-07
Enrollment: 32
Sex: ALL
Maximum age (years): 72
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

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:

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.

Eligibility criteria: 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.

Primary outcomes:
measure: Compare mean arterial blood pressure (MAP) change in the patients receiving hydrocortisone vs placebo
timeFrame: 2 hours
Secondary outcomes:
measure: Frequency of initially low serum cortisol in hypotensive asphyxiated newborns undergoing therapeutic hypothermia
timeFrame: before hydrocortisone administration within max. 72 hours
measure: Length of dopamine treatment in the patients receiving hydrocortisone vs placebo
timeFrame: 72 hours
measure: Cumulative dopamine dose in the patients receiving hydrocortisone vs placebo
timeFrame: 72 hours
measure: Change in hourly diuresis in the patients receiving hydrocortisone vs placebo
timeFrame: 72 hours
measure: Change in the echocardiography parameters (fractional shortening and cardiac output) in the patients receiving hydrocortisone vs placebo
timeFrame: 72 hours
measure: Long term neurodevelopmental outcome in the patients receiving hydrocortisone vs placebo
timeFrame: 18-22 month
Other outcomes:
Locations:
city: Budapest
country: Hungary
facility: Semmelweis University, 1st Department of Paediatrics
state: Pest
Study officials:
affiliation: Semmelweis University, 1st Department of Paediatrics
name: Miklós Szabó, MD, PhD
role: STUDY_DIRECTOR
References:
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citation: 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.
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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.