Clinical trial NCT04624776: Steroid Treatment After Resuscitated Out-of-Hospital Cardiac Arrest
Official title: Steroid Treatment as Anti-inflammatory and Neuroprotective Agent Following Out-of-Hospital Cardiac Arrest. A Randomized Trial
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Out-Of-Hospital Cardiac Arrest
Cardiac Arrest
Cardiac Arrest With Successful Resuscitation
Post Cardiac Arrest Syndrome
Systemic Inflammatory Response Syndrome
Neurological Injury
Keywords: OHCA
PCAS
Inflammation
Neuroprotection
Methylprednisolone
Solu-Medrol
Lead sponsor: Rigshospitalet, Denmark
Sponsor class: OTHER
First posted: 2020-11-12
Enrollment: 158
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: 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 purpose: TREATMENT

Brief summary: 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.

Detailed description: 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.

Eligibility criteria: 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.

Exclusion Criteria:

1. Advanced life support termination-of-resuscitation 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.

Primary outcomes:
measure: Concentration of IL-6
timeFrame: Daily measurements from admission to 72 hours after admission
measure: Concentration of NSE
timeFrame: Daily measurements from admission to 72 hours after admission
Secondary outcomes:
measure: Markers of inflammation, biomarkers
timeFrame: Daily measurements the first three days following admission
measure: Markers of inflammation, cell count
timeFrame: Daily measurements the first three days following admission
measure: Markers of kidney and hepatic injury
timeFrame: Daily measurements the first three days following admission
measure: Marker of the coagulation system, biomarker
timeFrame: Plasma fibrinogen the first three days from admission
measure: Marker of the coagulation system, functional analysis
timeFrame: Thromboelastography at admission and at 48 hours
measure: Hemodynamics, Swan-Ganz catheter
timeFrame: Daily Swan-Ganz catheter measurements the first five days from admission
measure: Hemodynamics, arterial blood gasses (Lactate)
timeFrame: Arterial blood gasses bihourly the first 36 hours
measure: Hemodynamics, arterial blood gasses
timeFrame: Arterial blood gasses bihourly the first 36 hours
measure: Neuroprotection, biomarkers
timeFrame: Biomarkers the first three days from admission
measure: Cardiac protection, biomarkers
timeFrame: Biomarkers the first three days from admission
measure: Clinical endpoint, survival
timeFrame: 180 days following discharge
measure: Clinical endpoint, neurological outcome by mRS score
timeFrame: After five days of admission and at 30- and 180- days following discharge
measure: Safety, adverse events
timeFrame: From admission till 7 days following admission
Other outcomes:
Locations:
city: Copenhagen
country: Denmark
facility: Rigshospitalet
city: Gentofte
country: Denmark
facility: Gentofte Hospital
Study officials:
affiliation: Department of Cardiology, The Heart Center, Rigshospitalet, Copenhagen, Denmark
name: Christian Hassager, MD, DMSc
role: PRINCIPAL_INVESTIGATOR
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