Steroid Treatment After Resuscitated Out-of-Hospital Cardiac Arrest
NCT ID: NCT04624776
Last Updated: 2023-03-29
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
Total Enrollment
158 participants
Study Classification
INTERVENTIONAL
Study Start Date
2020-10-10
Study Completion Date
2023-02-28
Brief Summary
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Comatose patients resuscitated from Out-of-Hospital Cardiac Arrest (OHCA) often develop a complicated systemic inflammatory response and have a poor prognosis with neurological damage being the most common cause of death. This study will investigate the anti-inflammatory and neuroprotective effect of early treatment with the glucocorticoid methylprednisolone measured by interleukin-6 and neuron-specific enolase levels in resuscitated comatose OHCA-patients.
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Detailed Description
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BACKGROUND:
Each year approximately 5400 individuals suffer from Out-of-Hospital Cardiac Arrest (OHCA) in Denmark and despite an improved prognosis 30-day mortality is around 90%. For OHCA patients resuscitated successfully and admitted to an Intensive Care Unit (ICU) the 30-day mortality remains higher than 50% due to a complicated systemic response, referred to as the Post Cardiac Arrest Syndrome (PCAS). PCAS consists of four interacting components: 1) ischemic/reperfusion brain injury, 2) myocardial dysfunction, 3) a systemic inflammatory response and 4) persistent stress from the triggering cause of the cardiac arrest, e.g. acute myocardial infarction. PCAS progresses during the first 1-2 days following resuscitated cardiac arrest, and the treatment aims to reduce neurologic injury by cooling the patient to 33-36° C, circulatory support with vasopressors, inotropics or mechanical devices as well as identification and treatment of reversible causes to the cardiac arrest, e.g. acute revascularization of an AMI.
Several studies have shown that the systemic inflammatory response is associated with a high risk of poor outcome following OHCA. Inflammatory markers associated with poor outcome include interleukin (IL) 6, high sensitivity C-reactive protein (hsCRP), leucocytes, IL-1b, IL-10, IL-13, tumor necrosis factor alpha (TNF-alpha) and procalcitonin. Despite of this, there is no specific treatment that addresses this complicated and life-threatening systemic response, and guidelines remain inconclusive in this field.
Anoxic irreversible brain injury remains the leading cause of death following resuscitated OHCA. The complex mechanism is one of the components in the PCAS and is thought to develop due to neuron apoptosis and reperfusion/ischemic injury. Further, the biomarker neuron-specific enolase (NSE) is correlated to neuron damage in the blood stream and has a strong predictive value for poor outcome following OHCA. Inhibiting the causes of the systemic inflammatory response and thereby potentially the brain injury in the very early stages following resuscitation from OHCA may therefore be key to optimizing post-cardiac arrest care.
Following resuscitated OHCA, the function of the adrenal gland is compromised due to global ischemia and reduced levels of the hormone steroid, glucocorticoid, are produced. Glucocorticoid has an important role in several physiologic processes including an anti-inflammatory systemic response. As a result, resuscitated cardiac arrest patients are affected by a severe inflammatory response, while the natural defense mechanism of the body to modulate inflammation is suppressed. Systemic treatment with steroids serves as an anti-inflammatory mediator and counteracts acute microcirculation injury and free radical formation, resulting in diminished vasodilation and reduction of edema, e.g. brain edema. Two small studies have shown signs of improved survival and neurologic outcome among patients who was given injections with glucocorticoids after in-hospital cardiac arrest. The incidence of adverse events was not higher in patients receiving glucocorticoids. Long-term treatment with glucocorticoids is associated with a series of side effects, whereas short-term treatment only has a few side effects. Systemic treatment with glucocorticoids could therefore be an important and safe factor in the treatment of resuscitated cardiac arrest patients that could potentially improve survival and neurological outcome.
Methylprednisolone and other glucocorticoids are used in pulse doses (\>250 mg prednisolone equivalent a day) in various acute immunologically mediated conditions/diseases such as organ transplantation to prevent organ rejection and certain rheumatic diseases with acute deterioration. All these conditions are associated with a severe inflammatory response, as seen in PCAS, and therefore methylprednisolone doses as high as 30 mg/kg (equivalent of 2.1 g for a person weighing 70 kg) are used in pulse therapy to obtain an adequate response and effect. Further, the advantage of pulse dose glucocorticoid treatment is better efficacy, but also a decrease in side effects due to a reduced need for longer lasting therapy exceeding days or weeks. The literature reports of possible cardiovascular side effects as bradycardia and arrhythmias associated to infusion of pulse doses of methylprednisolone/glucocorticoids if given within a short period of time, but the evidence is limited and not well supported. The Danish summary of product characteristics recommends an initial infusion of Solu-Medrol to be administered over a period of at least five minutes.
Based on the above knowledge the intervention in this study is 250 mg of methylprednisolone administered intravenously as a bolus infusion over five minutes.
In summary, following resuscitated OHCA, PCAS, a severe and life-threatening condition, is often developed. PCAS is associated with increased mortality and poor neurological outcome. Inhibition of this inflammatory response may have an important, yet relatively unknown, role in post-cardiac arrest care.
HYPOTHESIS:
Bolus infusion of 250 mg methylprednisolone in the pre-hospital setting will inhibit the systemic inflammatory response and minimize the degree of neurological injury in comatose, resuscitated Out-of-Hospital Cardiac Arrest (OHCA) patients.
SAMPLE SIZE:
The trial is powered at the co-primary endpoint. The investigators chose a priori to power the trial at the 'weakest' of the two endpoints, ensuring a sufficient power for both endpoints. As the investigators were not able to find data regarding the effect of methylprednisolone on IL-6 levels or NSE levels from OHCA admission, the trial was powered towards a single measurement drawn 48 hours after admission. In 171 patients from the investigators institution the mean (logarithmically transformed to approximate normal distribution) IL-6 level after 48 hours from admission was 4.19±1.27 (unpublished data). The investigators assumed that methylprednisolone would reduce the IL-6 level by 20%. With an α-level of 0.025, the trial would achieve a power of 0.90 if 112 patients were included. The mean (logarithmically transformed to approximate normal distribution) NSE level after 48 hours was 3.21±0.96 after 48 hours from admission (unpublished data). The investigators assumed that methylprednisolone would reduce the NSE level by 20%. With an α-level of 0.025, the trial would achieve a power of 0.90 if 114 patients were included. The investigators aimed to include 120 patients, to adjust for missingness due to withdrawn consent. Further, since a proportion of the patients were expected to die before complete assessment of the co-primary endpoint (i.e. blood sampling at 72 hours), randomization of patients will continue until a total of 120 patients have survived to blood sampling at 72 hours.
Each year approximately 5400 individuals suffer from Out-of-Hospital Cardiac Arrest (OHCA) in Denmark and despite an improved prognosis 30-day mortality is around 90%. For OHCA patients resuscitated successfully and admitted to an Intensive Care Unit (ICU) the 30-day mortality remains higher than 50% due to a complicated systemic response, referred to as the Post Cardiac Arrest Syndrome (PCAS). PCAS consists of four interacting components: 1) ischemic/reperfusion brain injury, 2) myocardial dysfunction, 3) a systemic inflammatory response and 4) persistent stress from the triggering cause of the cardiac arrest, e.g. acute myocardial infarction. PCAS progresses during the first 1-2 days following resuscitated cardiac arrest, and the treatment aims to reduce neurologic injury by cooling the patient to 33-36° C, circulatory support with vasopressors, inotropics or mechanical devices as well as identification and treatment of reversible causes to the cardiac arrest, e.g. acute revascularization of an AMI.
Several studies have shown that the systemic inflammatory response is associated with a high risk of poor outcome following OHCA. Inflammatory markers associated with poor outcome include interleukin (IL) 6, high sensitivity C-reactive protein (hsCRP), leucocytes, IL-1b, IL-10, IL-13, tumor necrosis factor alpha (TNF-alpha) and procalcitonin. Despite of this, there is no specific treatment that addresses this complicated and life-threatening systemic response, and guidelines remain inconclusive in this field.
Anoxic irreversible brain injury remains the leading cause of death following resuscitated OHCA. The complex mechanism is one of the components in the PCAS and is thought to develop due to neuron apoptosis and reperfusion/ischemic injury. Further, the biomarker neuron-specific enolase (NSE) is correlated to neuron damage in the blood stream and has a strong predictive value for poor outcome following OHCA. Inhibiting the causes of the systemic inflammatory response and thereby potentially the brain injury in the very early stages following resuscitation from OHCA may therefore be key to optimizing post-cardiac arrest care.
Following resuscitated OHCA, the function of the adrenal gland is compromised due to global ischemia and reduced levels of the hormone steroid, glucocorticoid, are produced. Glucocorticoid has an important role in several physiologic processes including an anti-inflammatory systemic response. As a result, resuscitated cardiac arrest patients are affected by a severe inflammatory response, while the natural defense mechanism of the body to modulate inflammation is suppressed. Systemic treatment with steroids serves as an anti-inflammatory mediator and counteracts acute microcirculation injury and free radical formation, resulting in diminished vasodilation and reduction of edema, e.g. brain edema. Two small studies have shown signs of improved survival and neurologic outcome among patients who was given injections with glucocorticoids after in-hospital cardiac arrest. The incidence of adverse events was not higher in patients receiving glucocorticoids. Long-term treatment with glucocorticoids is associated with a series of side effects, whereas short-term treatment only has a few side effects. Systemic treatment with glucocorticoids could therefore be an important and safe factor in the treatment of resuscitated cardiac arrest patients that could potentially improve survival and neurological outcome.
Methylprednisolone and other glucocorticoids are used in pulse doses (\>250 mg prednisolone equivalent a day) in various acute immunologically mediated conditions/diseases such as organ transplantation to prevent organ rejection and certain rheumatic diseases with acute deterioration. All these conditions are associated with a severe inflammatory response, as seen in PCAS, and therefore methylprednisolone doses as high as 30 mg/kg (equivalent of 2.1 g for a person weighing 70 kg) are used in pulse therapy to obtain an adequate response and effect. Further, the advantage of pulse dose glucocorticoid treatment is better efficacy, but also a decrease in side effects due to a reduced need for longer lasting therapy exceeding days or weeks. The literature reports of possible cardiovascular side effects as bradycardia and arrhythmias associated to infusion of pulse doses of methylprednisolone/glucocorticoids if given within a short period of time, but the evidence is limited and not well supported. The Danish summary of product characteristics recommends an initial infusion of Solu-Medrol to be administered over a period of at least five minutes.
Based on the above knowledge the intervention in this study is 250 mg of methylprednisolone administered intravenously as a bolus infusion over five minutes.
In summary, following resuscitated OHCA, PCAS, a severe and life-threatening condition, is often developed. PCAS is associated with increased mortality and poor neurological outcome. Inhibition of this inflammatory response may have an important, yet relatively unknown, role in post-cardiac arrest care.
HYPOTHESIS:
Bolus infusion of 250 mg methylprednisolone in the pre-hospital setting will inhibit the systemic inflammatory response and minimize the degree of neurological injury in comatose, resuscitated Out-of-Hospital Cardiac Arrest (OHCA) patients.
SAMPLE SIZE:
The trial is powered at the co-primary endpoint. The investigators chose a priori to power the trial at the 'weakest' of the two endpoints, ensuring a sufficient power for both endpoints. As the investigators were not able to find data regarding the effect of methylprednisolone on IL-6 levels or NSE levels from OHCA admission, the trial was powered towards a single measurement drawn 48 hours after admission. In 171 patients from the investigators institution the mean (logarithmically transformed to approximate normal distribution) IL-6 level after 48 hours from admission was 4.19±1.27 (unpublished data). The investigators assumed that methylprednisolone would reduce the IL-6 level by 20%. With an α-level of 0.025, the trial would achieve a power of 0.90 if 112 patients were included. The mean (logarithmically transformed to approximate normal distribution) NSE level after 48 hours was 3.21±0.96 after 48 hours from admission (unpublished data). The investigators assumed that methylprednisolone would reduce the NSE level by 20%. With an α-level of 0.025, the trial would achieve a power of 0.90 if 114 patients were included. The investigators aimed to include 120 patients, to adjust for missingness due to withdrawn consent. Further, since a proportion of the patients were expected to die before complete assessment of the co-primary endpoint (i.e. blood sampling at 72 hours), randomization of patients will continue until a total of 120 patients have survived to blood sampling at 72 hours.
Conditions
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Out-Of-Hospital Cardiac Arrest
Cardiac Arrest
Cardiac Arrest With Successful Resuscitation
Post Cardiac Arrest Syndrome
Systemic Inflammatory Response Syndrome
Neurological Injury
Study Design
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Allocation Method
RANDOMIZED
Intervention Model
PARALLEL
Investigator-initiated, 1:1 randomized, multicenter, double-blind, placebo-controlled clinical trial. A minimum of 120 unconscious OHCA patients will be randomized 1:1 after 5 minutes of sustained ROSC to an infusion of 250 mg (4 mL) methylprednisolone in the pre-hospital setting. The methylprednisolone will be given as a bolus infusion of 1 x 250 mg (1 x 4 mL) over a period of 5 minutes. Patients allocated to placebo will receive 4 mL of isotonic saline (NaCl 0.9%).
Primary Study Purpose
TREATMENT
Blinding Strategy
QUADRUPLE
Participants
Caregivers
Investigators
Outcome Assessors
Study Groups
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Methylprednisolone
A five minutes bolus infusion of 250 mg (4 mL) methylprednisolone to inhibit inflammatory and neurological damage following resuscitated out-of-hospital cardiac arrest. The infusion of methylprednisolone will be given following five minutes of sustainable ROSC in the prehospital setting.
Group Type
ACTIVE_COMPARATOR
Methylprednisolone
Intervention Type
DRUG
A dosis of 250 mg methylprednisolone is suspended in isotonic saline to a total volume of 4 mL prior to infusion.
Isotonic saline
A bolus infusion of 4 mL isotonic saline (NaCl 0.9%).
Group Type
PLACEBO_COMPARATOR
Isotonic saline
Intervention Type
DRUG
A bolus infusion of 4 mL isotonic saline (NaCl 0.9%).
Interventions
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Methylprednisolone
A dosis of 250 mg methylprednisolone is suspended in isotonic saline to a total volume of 4 mL prior to infusion.
Intervention Type
DRUG
Isotonic saline
A bolus infusion of 4 mL isotonic saline (NaCl 0.9%).
Intervention Type
DRUG
Other Intervention Names
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Solu-Medrol
Placebo
Eligibility Criteria
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Inclusion Criteria
1. Age ≥18 years
2. OHCA of presumed cardiac cause
3. Unconsciousness (GCS ≤8) upon pre-hospital randomization
4. Sustained ROSC for at least 5 minutes
5. Randomization and start of study medicine infusion within 30 minutes of sustained ROSC.
2. OHCA of presumed cardiac cause
3. Unconsciousness (GCS ≤8) upon pre-hospital randomization
4. Sustained ROSC for at least 5 minutes
5. Randomization and start of study medicine infusion within 30 minutes of sustained ROSC.
Exclusion Criteria
2. Asystole as primary ECG rhythm
3. Women of childbearing capacity
4. Known therapy limitation
5. Known allergy to methylprednisolone
6. Known pre-arrest modified Rankin Scale (mRS) score of 4-5
7. Temperature upon randomization \<30° C
8. \>30 minutes to sustained ROSC.
3. Women of childbearing capacity
4. Known therapy limitation
5. Known allergy to methylprednisolone
6. Known pre-arrest modified Rankin Scale (mRS) score of 4-5
7. Temperature upon randomization \<30° C
8. \>30 minutes to sustained ROSC.
Minimum Eligible Age
18 Years
Eligible Sex
ALL
Accepts Healthy Volunteers
No
Sponsors
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Christian Hassager
OTHER
Sponsor Role
lead
Responsible Party
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Christian Hassager
Professor, MD, DMSc, FESC
Responsibility Role
SPONSOR_INVESTIGATOR
Principal Investigators
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Christian Hassager, MD, DMSc
Role: PRINCIPAL_INVESTIGATOR
Department of Cardiology, The Heart Center, Rigshospitalet, Copenhagen, Denmark
Locations
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Rigshospitalet
Copenhagen, , Denmark
Site Status
Gentofte Hospital
Gentofte Municipality, , Denmark
Site Status
Countries
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Denmark
References
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Reference Type
BACKGROUND
Obling LER, Beske RP, Meyer MAS, Grand J, Wiberg S, Damm-Hejmdal A, Bjerre M, Frikke-Schmidt R, Folke F, Moller JE, Kjaergaard J, Hassager C. Inflammatory response after prehospital high-dose glucocorticoid to patients resuscitated from out-of-hospital cardiac arrest: A sub-study of the STEROHCA trial. Resuscitation. 2024 Sep;202:110340. doi: 10.1016/j.resuscitation.2024.110340. Epub 2024 Jul 31.
Reference Type
DERIVED
Obling LER, Beske RP, Meyer MAS, Grand J, Wiberg S, Mohr T, Damm-Hejmdal A, Forman JL, Frikke-Schmidt R, Folke F, Moller JE, Kjaergaard J, Hassager C. Effect of prehospital high-dose glucocorticoid on hemodynamics in patients resuscitated from out-of-hospital cardiac arrest: a sub-study of the STEROHCA trial. Crit Care. 2024 Jan 22;28(1):28. doi: 10.1186/s13054-024-04808-3.
Reference Type
DERIVED
Obling LER, Beske RP, Meyer MAS, Grand J, Wiberg S, Nyholm B, Josiassen J, Sondergaard FT, Mohr T, Damm-Hejmdal A, Bjerre M, Frikke-Schmidt R, Folke F, Moller JE, Kjaergaard J, Hassager C. Prehospital high-dose methylprednisolone in resuscitated out-of-hospital cardiac arrest patients (STEROHCA): a randomized clinical trial. Intensive Care Med. 2023 Dec;49(12):1467-1478. doi: 10.1007/s00134-023-07247-w. Epub 2023 Nov 9.
Reference Type
DERIVED
Obling LER, Beske RP, Wiberg S, Folke F, Moeller JE, Kjaergaard J, Hassager C. Steroid treatment as anti-inflammatory and neuroprotective agent following out-of-hospital cardiac arrest: a randomized clinical trial. Trials. 2022 Nov 22;23(1):952. doi: 10.1186/s13063-022-06838-0.
Reference Type
DERIVED
Other Identifiers
Review additional registry numbers or institutional identifiers associated with this trial.
EudraCT: 2020-000855-11
Identifier Type: -
Identifier Source: org_study_id
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