search
Back to results

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

Primary Purpose

Hypoxic-Ischemic Encephalopathy, Asphyxia

Status
Completed
Phase
Phase 2
Locations
Hungary
Study Type
Interventional
Intervention
Hydrocortisone
Placebo
Sponsored by
Semmelweis University
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Hypoxic-Ischemic Encephalopathy focused on measuring Hypothermia treatment, Circulatory failure, Neonatal hypotension, Relative adrenal insufficiency, Hydrocortisone supplementation

Eligibility Criteria

undefined - 72 Hours (Child)All SexesDoes not accept healthy volunteers

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.

Sites / Locations

  • Semmelweis University, 1st Department of Paediatrics

Arms of the Study

Arm 1

Arm 2

Arm Type

Active Comparator

Placebo Comparator

Arm Label

Hydrocortisone

Placebo

Arm Description

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

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

Outcomes

Primary Outcome Measures

Compare mean arterial blood pressure (MAP) change in the patients receiving hydrocortisone vs placebo
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
Initially low serum cortisol - proven relative adrenal insufficiency
Length of dopamine treatment in the patients receiving hydrocortisone vs placebo
Compare dopamine treatment's length (in hours) in the patients receiving hydrocortisone vs placebo
Cumulative dopamine dose in the patients receiving hydrocortisone vs placebo
Compare cumulative dopamine dose (mcg/kg) in the patients receiving hydrocortisone vs placebo
Change in hourly diuresis in the patients receiving hydrocortisone vs placebo
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
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
Performance on motor and mental scales of Bayley II/III scales of infant development

Full Information

First Posted
February 24, 2016
Last Updated
April 19, 2023
Sponsor
Semmelweis University
search

1. Study Identification

Unique Protocol Identification Number
NCT02700828
Brief Title
Hydrocortisone Treatment In Systemic Low Blood Pressure During Hypothermia in Asphyxiated Newborns
Acronym
CORTISoL
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

2. Study Status

Record Verification Date
April 2023
Overall Recruitment Status
Completed
Study Start Date
February 2016 (Actual)
Primary Completion Date
November 2017 (Actual)
Study Completion Date
December 15, 2022 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
Semmelweis University

4. Oversight

Data Monitoring Committee
No

5. 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.
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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Hypoxic-Ischemic Encephalopathy, Asphyxia
Keywords
Hypothermia treatment, Circulatory failure, Neonatal hypotension, Relative adrenal insufficiency, Hydrocortisone supplementation

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2, Phase 3
Interventional Study Model
Parallel Assignment
Masking
ParticipantCare ProviderInvestigatorOutcomes Assessor
Allocation
Randomized
Enrollment
32 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Hydrocortisone
Arm Type
Active Comparator
Arm Description
Hydrocortisone is the pharmaceutical term for cortisol, the principal glucocorticoid secreted by the adrenal gland
Arm Title
Placebo
Arm Type
Placebo Comparator
Arm Description
Isotonic sodium chloride is an aqueous solution of 0.9 percent sodium chloride which is isotonic with the blood and tissue fluid
Intervention Type
Drug
Intervention Name(s)
Hydrocortisone
Other Intervention Name(s)
Solu-Cortef
Intervention Description
4 * 0,5 mg/kg /24 hours (in every 6 hours) iv., during hypothermia treatment (max. 72 hours)
Intervention Type
Drug
Intervention Name(s)
Placebo
Other Intervention Name(s)
Isotonic saline
Intervention Description
4 * 2 ml isotonic sodium chloride solution /24 hours (in every 6 hours) iv., during hypothermia treatment (max. 72 hours)
Primary Outcome Measure Information:
Title
Compare mean arterial blood pressure (MAP) change in the patients receiving hydrocortisone vs placebo
Description
Circulatory stability as measured by an increased MAP (5 mmHg) within two hours after drug administration
Time Frame
2 hours
Secondary Outcome Measure Information:
Title
Frequency of initially low serum cortisol in hypotensive asphyxiated newborns undergoing therapeutic hypothermia
Description
Initially low serum cortisol - proven relative adrenal insufficiency
Time Frame
before hydrocortisone administration within max. 72 hours
Title
Length of dopamine treatment in the patients receiving hydrocortisone vs placebo
Description
Compare dopamine treatment's length (in hours) in the patients receiving hydrocortisone vs placebo
Time Frame
72 hours
Title
Cumulative dopamine dose in the patients receiving hydrocortisone vs placebo
Description
Compare cumulative dopamine dose (mcg/kg) in the patients receiving hydrocortisone vs placebo
Time Frame
72 hours
Title
Change in hourly diuresis in the patients receiving hydrocortisone vs placebo
Description
Measure and compare the hourly diuresis (ml/kg/hour) in the patients receiving hydrocortisone vs placebo
Time Frame
72 hours
Title
Change in the echocardiography parameters (fractional shortening and cardiac output) in the patients receiving hydrocortisone vs placebo
Description
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)
Time Frame
72 hours
Title
Long term neurodevelopmental outcome in the patients receiving hydrocortisone vs placebo
Description
Performance on motor and mental scales of Bayley II/III scales of infant development
Time Frame
18-22 month

10. Eligibility

Sex
All
Maximum Age & Unit of Time
72 Hours
Accepts Healthy Volunteers
No
Eligibility Criteria
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. 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 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.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Miklós Szabó, MD, PhD
Organizational Affiliation
Semmelweis University, 1st Department of Paediatrics
Official's Role
Study Director
Facility Information:
Facility Name
Semmelweis University, 1st Department of Paediatrics
City
Budapest
State/Province
Pest
ZIP/Postal Code
1083
Country
Hungary

12. IPD Sharing Statement

Plan to Share IPD
No
Citations:
PubMed Identifier
19797281
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. Erratum In: N Engl J Med. 2010 Mar 18;362(11):1056.
Results Reference
background
PubMed Identifier
17015536
Citation
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.
Results Reference
background
PubMed Identifier
22161379
Citation
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.
Results Reference
background
PubMed Identifier
25039051
Citation
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.
Results Reference
background
PubMed Identifier
21336126
Citation
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.
Results Reference
background
PubMed Identifier
11207229
Citation
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.
Results Reference
background
PubMed Identifier
16452355
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.
Results Reference
background
PubMed Identifier
11331688
Citation
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.
Results Reference
background
PubMed Identifier
31155392
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.
Results Reference
result

Learn more about this trial

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

We'll reach out to this number within 24 hrs