Out-Of-Hospital Cardiac ArrestPhase 2STEROHCANCT04624776
Steroid Treatment After Resuscitated Out-of-Hospital Cardiac Arrest
A Phase 2 study testing Methylprednisolone and Isotonic saline in people with Out-Of-Hospital Cardiac Arrest and Cardiac Arrest, run by Christian Hassager at 2 sites in Denmark.
Trial 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. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Out-Of-Hospital Cardiac Arrest, Cardiac Arrest, Cardiac Arrest With Successful Resuscitation
- What is being tested?
- Methylprednisolone and Isotonic saline
- Type of treatment
- Injection or infusion
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 158 participants
- Where
- 2 sitesDenmark
- Study dates
- 10 Oct 2020to 28 Feb 2023
- Phase
- Phase 2
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Age ≥18 years
- OHCA of presumed cardiac cause
- Unconsciousness (GCS ≤8) upon pre-hospital randomization
- Sustained ROSC for at least 5 minutes
- Randomization and start of study medicine infusion within 30 minutes of sustained ROSC.
Who cannot join
- Advanced life support termination-of-resuscitation exclusion criteria
- Asystole as primary ECG rhythm
- Women of childbearing capacity
- Known therapy limitation
- Known allergy to methylprednisolone
- Known pre-arrest modified Rankin Scale (mRS) score of 4-5
- Temperature upon randomization <30° C
- >30 minutes to sustained ROSC.
Trial locations and contacts
2 sites in 1 country.
Denmark2 sites
Rigshospitalet
Copenhagen, 2100
Gentofte Hospital
Gentofte Municipality, 2820
About this study
Official title: Steroid Treatment as Anti-inflammatory and Neuroprotective Agent Following Out-of-Hospital Cardiac Arrest. A Randomized Trial
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.
Read the 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.
- Conditions
- Out-Of-Hospital Cardiac Arrest, Cardiac Arrest, Cardiac Arrest With Successful Resuscitation, Post Cardiac Arrest Syndrome, Systemic Inflammatory Response Syndrome, Neurological Injury
- Being tested
- Methylprednisolone, Isotonic saline
- Keywords
- OHCA, PCAS, Inflammation, Neuroprotection, Methylprednisolone, Solu-Medrol
- Medical subject headings
- Out-of-Hospital Cardiac Arrest, Heart Arrest, Post-Cardiac Arrest Syndrome, Systemic Inflammatory Response Syndrome, Trauma, Nervous System, Inflammation
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Also called Solu-Medrol
A dosis of 250 mg methylprednisolone is suspended in isotonic saline to a total volume of 4 mL prior to infusion.
Isotonic salineDrug
Also called Placebo
A bolus infusion of 4 mL isotonic saline (NaCl 0.9%).
| Study group | Role | What they receive |
|---|---|---|
| Methylprednisolone | Active comparator | 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. Receives: Drug: Methylprednisolone |
| Isotonic saline | Placebo comparator | A bolus infusion of 4 mL isotonic saline (NaCl 0.9%). Receives: Drug: Isotonic saline |
What is being measured
The primary outcome is the main question the study is designed to answer.
Concentration of IL-6
Interleukin 6 (ng/L)
Measured: Daily measurements from admission to 72 hours after admission
Concentration of NSE
Neuron-specific-enolase (ng/L)
Measured: Daily measurements from admission to 72 hours after admission
Secondary outcomes (13)
Markers of inflammation, biomarkers
High sensitivity C-reactive protein (hsCRP, mg/L) and plasma cytokine levels exemplified by IL-6 (ng/L)
Measured: Daily measurements the first three days following admission
Markers of inflammation, cell count
Leucocyte- and differential count (thousand cells/µL)
Measured: Daily measurements the first three days following admission
Markers of kidney and hepatic injury
Creatinine, ALAT, ASAT, BF and bilirubin (all in mg/L)
Measured: Daily measurements the first three days following admission
Marker of the coagulation system, biomarker
Plasma fibrinogen (mg/L)
Measured: Plasma fibrinogen the first three days from admission
Marker of the coagulation system, functional analysis
Thromboelastography (TEG, measured in minutes)
Measured: Thromboelastography at admission and at 48 hours
Hemodynamics, Swan-Ganz catheter
Measurements on Swan-Ganz catheter (CVP, PAP, PCWP - all in mmHg)
Measured: Daily Swan-Ganz catheter measurements the first five days from admission
Hemodynamics, arterial blood gasses (Lactate)
Arterial blood gasses (Lactate in mmol/L)
Measured: Arterial blood gasses bihourly the first 36 hours
Hemodynamics, arterial blood gasses
Arterial blood gasses (PaO2 and PaCO2 in kPa)
Measured: Arterial blood gasses bihourly the first 36 hours
Neuroprotection, biomarkers
Biomarkers TAU, NFL, NFM, NFH and GFAP (all in mmol/L)
Measured: Biomarkers the first three days from admission
Cardiac protection, biomarkers
TnT, TnI and CKMB (all in mmol/L).
Measured: Biomarkers the first three days from admission
Clinical endpoint, survival
Survival (yes/no, register based data from "The Medical Register of Births and Deaths" in Denmark)
Measured: 180 days following discharge
Clinical endpoint, neurological outcome by mRS score
Neurological outcome (modified Rankin Scale score, 0-6 symptom scale with higher scores indicating more severe symptoms)
Measured: After five days of admission and at 30- and 180- days following discharge
Safety, adverse events
Cumulated incidence of adverse events
Measured: From admission till 7 days following admission
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted12 Nov 2020
- Study start10 Oct 2020
- Primary completion15 Jul 2022
- Study completion28 Feb 2023
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (36)Papers the sponsor has linked to this study.
- Other trials for Out-Of-Hospital Cardiac ArrestStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- 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%).
- Masking
- Quadruple blind
- Who is masked
- Participant, Care provider, Investigator, Outcomes assessor
- Enrolment
- 158 participants (actual)
Sponsor and investigators
- Lead sponsor
- Christian Hassager
- Sponsor type
- University, hospital or other
- Responsible party
- Sponsor-investigator, Christian Hassager, Copenhagen University Hospital, Rigshospitalet
- Investigators
- Christian Hassager, MD, DMSc, Principal investigator, Department of Cardiology, The Heart Center, Rigshospitalet, Copenhagen, Denmark
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT04624776
- Sponsor's protocol ID
- EudraCT: 2020-000855-11
- Acronym
- STEROHCA
- Status last verified
- Mar 2023
- First submitted
- 12 Oct 2020
- Last updated
- 29 Mar 2023
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- Undecided
Publications
Sasson C, Rogers MA, Dahl J, Kellermann AL. Predictors of survival from out-of-hospital cardiac arrest: a systematic review and meta-analysis. Circ Cardiovasc Qual Outcomes. 2010 Jan;3(1):63-81. doi: 10.1161/CIRCOUTCOMES.109.889576. Epub 2009 Nov 10.
PubMed 20123673Soholm H, Wachtell K, Nielsen SL, Bro-Jeppesen J, Pedersen F, Wanscher M, Boesgaard S, Moller JE, Hassager C, Kjaergaard J. Tertiary centres have improved survival compared to other hospitals in the Copenhagen area after out-of-hospital cardiac arrest. Resuscitation. 2013 Feb;84(2):162-7. doi: 10.1016/j.resuscitation.2012.06.029. Epub 2012 Jul 13.
PubMed 22796541Neumar RW, Nolan JP, Adrie C, Aibiki M, Berg RA, Bottiger BW, Callaway C, Clark RS, Geocadin RG, Jauch EC, Kern KB, Laurent I, Longstreth WT Jr, Merchant RM, Morley P, Morrison LJ, Nadkarni V, Peberdy MA, Rivers EP, Rodriguez-Nunez A, Sellke FW, Spaulding C, Sunde K, Vanden Hoek T. Post-cardiac arrest syndrome: epidemiology, pathophysiology, treatment, and prognostication. A consensus statement from the International Liaison Committee on Resuscitation (American Heart Association, Australian and New Zealand Council on Resuscitation, European Resuscitation Council, Heart and Stroke Foundation of Canada, InterAmerican Heart Foundation, Resuscitation Council of Asia, and the Resuscitation Council of Southern Africa); the American Heart Association Emergency Cardiovascular Care Committee; the Council on Cardiovascular Surgery and Anesthesia; the Council on Cardiopulmonary, Perioperative, and Critical Care; the Council on Clinical Cardiology; and the Stroke Council. Circulation. 2008 Dec 2;118(23):2452-83. doi: 10.1161/CIRCULATIONAHA.108.190652. Epub 2008 Oct 23. No abstract available.
PubMed 18948368Stub D, Bernard S, Duffy SJ, Kaye DM. Post cardiac arrest syndrome: a review of therapeutic strategies. Circulation. 2011 Apr 5;123(13):1428-35. doi: 10.1161/CIRCULATIONAHA.110.988725. No abstract available.
PubMed 21464058Callaway CW, Donnino MW, Fink EL, Geocadin RG, Golan E, Kern KB, Leary M, Meurer WJ, Peberdy MA, Thompson TM, Zimmerman JL. Part 8: Post-Cardiac Arrest Care: 2015 American Heart Association Guidelines Update for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. Circulation. 2015 Nov 3;132(18 Suppl 2):S465-82. doi: 10.1161/CIR.0000000000000262. No abstract available.
PubMed 26472996Peberdy MA, Andersen LW, Abbate A, Thacker LR, Gaieski D, Abella BS, Grossestreuer AV, Rittenberger JC, Clore J, Ornato J, Cocchi MN, Callaway C, Donnino M; National Post Arrest Research Consortium (NPARC) Investigators. Inflammatory markers following resuscitation from out-of-hospital cardiac arrest-A prospective multicenter observational study. Resuscitation. 2016 Jun;103:117-124. doi: 10.1016/j.resuscitation.2016.01.006. Epub 2016 Jan 27.
PubMed 26826561Vaahersalo J, Skrifvars MB, Pulkki K, Stridsberg M, Rosjo H, Hovilehto S, Tiainen M, Varpula T, Pettila V, Ruokonen E; FINNRESUSCI Laboratory Study Group. Admission interleukin-6 is associated with post resuscitation organ dysfunction and predicts long-term neurological outcome after out-of-hospital ventricular fibrillation. Resuscitation. 2014 Nov;85(11):1573-9. doi: 10.1016/j.resuscitation.2014.08.036. Epub 2014 Sep 17.
PubMed 25238742Bro-Jeppesen J, Kjaergaard J, Stammet P, Wise MP, Hovdenes J, Aneman A, Horn J, Devaux Y, Erlinge D, Gasche Y, Wanscher M, Cronberg T, Friberg H, Wetterslev J, Pellis T, Kuiper M, Nielsen N, Hassager C; TTM-Trial Investigators. Predictive value of interleukin-6 in post-cardiac arrest patients treated with targeted temperature management at 33 degrees C or 36 degrees C. Resuscitation. 2016 Jan;98:1-8. doi: 10.1016/j.resuscitation.2015.10.009. Epub 2015 Oct 23.
PubMed 26525271Bro-Jeppesen J, Kjaergaard J, Wanscher M, Nielsen N, Friberg H, Bjerre M, Hassager C. Systemic Inflammatory Response and Potential Prognostic Implications After Out-of-Hospital Cardiac Arrest: A Substudy of the Target Temperature Management Trial. Crit Care Med. 2015 Jun;43(6):1223-32. doi: 10.1097/CCM.0000000000000937.
PubMed 25756419Fries M, Kunz D, Gressner AM, Rossaint R, Kuhlen R. Procalcitonin serum levels after out-of-hospital cardiac arrest. Resuscitation. 2003 Oct;59(1):105-9. doi: 10.1016/s0300-9572(03)00164-3.
PubMed 14580740Laver S, Farrow C, Turner D, Nolan J. Mode of death after admission to an intensive care unit following cardiac arrest. Intensive Care Med. 2004 Nov;30(11):2126-8. doi: 10.1007/s00134-004-2425-z. Epub 2004 Sep 9.
PubMed 15365608Dragancea I, Rundgren M, Englund E, Friberg H, Cronberg T. The influence of induced hypothermia and delayed prognostication on the mode of death after cardiac arrest. Resuscitation. 2013 Mar;84(3):337-42. doi: 10.1016/j.resuscitation.2012.09.015. Epub 2012 Sep 20.
PubMed 23000363Schneider A, Bottiger BW, Popp E. Cerebral resuscitation after cardiocirculatory arrest. Anesth Analg. 2009 Mar;108(3):971-9. doi: 10.1213/ane.0b013e318193ca99.
PubMed 19224811Stammet P, Collignon O, Hassager C, Wise MP, Hovdenes J, Aneman A, Horn J, Devaux Y, Erlinge D, Kjaergaard J, Gasche Y, Wanscher M, Cronberg T, Friberg H, Wetterslev J, Pellis T, Kuiper M, Gilson G, Nielsen N; TTM-Trial Investigators. Neuron-Specific Enolase as a Predictor of Death or Poor Neurological Outcome After Out-of-Hospital Cardiac Arrest and Targeted Temperature Management at 33 degrees C and 36 degrees C. J Am Coll Cardiol. 2015 May 19;65(19):2104-14. doi: 10.1016/j.jacc.2015.03.538.
PubMed 25975474Wiberg S, Hassager C, Schmidt H, Thomsen JH, Frydland M, Lindholm MG, Hofsten DE, Engstrom T, Kober L, Moller JE, Kjaergaard J. Neuroprotective Effects of the Glucagon-Like Peptide-1 Analog Exenatide After Out-of-Hospital Cardiac Arrest: A Randomized Controlled Trial. Circulation. 2016 Dec 20;134(25):2115-2124. doi: 10.1161/CIRCULATIONAHA.116.024088. Epub 2016 Nov 12.
PubMed 27838646
Study at a glance
From the registry record, last updated by the sponsor on 29 Mar 2023. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Steroid Treatment as Anti-inflammatory and Neuroprotective Agent Following Out-of-Hospital Cardiac Arrest. A Randomized Trial
- ClinicalTrials.gov ID
- NCT04624776
- Acronym / sponsor ID
- STEROHCA / EudraCT: 2020-000855-11
- 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
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 158 participants (actual)
- Lead sponsor
- Christian HassagerUniversity, hospital or other
- Study start
- 10 Oct 2020 (actual)
- Primary completion
- 15 Jul 2022 (actual)
- Study completion
- 28 Feb 2023 (actual)
- First posted
- 12 Nov 2020 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Quadruple blind (participant, care provider, investigator, outcomes assessor)
- Number of arms
- 2
- 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%).
| Arm | Type | Receives |
|---|---|---|
| Methylprednisolone | Active comparator | Drug: MethylprednisoloneA 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. |
| Isotonic saline | Placebo comparator | Drug: Isotonic salineA bolus infusion of 4 mL isotonic saline (NaCl 0.9%). |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (5 listed)
- Age ≥18 years
- OHCA of presumed cardiac cause
- Unconsciousness (GCS ≤8) upon pre-hospital randomization
- Sustained ROSC for at least 5 minutes
- Randomization and start of study medicine infusion within 30 minutes of sustained ROSC.
Key exclusion criteria (8 listed)
- Advanced life support termination-of-resuscitation exclusion criteria
- Asystole as primary ECG rhythm
- Women of childbearing capacity
- Known therapy limitation
- Known allergy to methylprednisolone
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| MethylprednisoloneAlso: Solu-MedrolA dosis of 250 mg methylprednisolone is suspended in isotonic saline to a total volume of 4 mL prior to infusion. | Drug | Methylprednisolone |
| Isotonic salineAlso: PlaceboA bolus infusion of 4 mL isotonic saline (NaCl 0.9%). | Drug | Isotonic saline |
Primary outcome
Concentration of IL-6
Time frame: Daily measurements from admission to 72 hours after admission
Interleukin 6 (ng/L)
Concentration of NSE
Time frame: Daily measurements from admission to 72 hours after admission
Neuron-specific-enolase (ng/L)
13 secondary outcomes
Markers of inflammation, biomarkers
Time frame: Daily measurements the first three days following admission
Markers of inflammation, cell count
Time frame: Daily measurements the first three days following admission
Markers of kidney and hepatic injury
Time frame: Daily measurements the first three days following admission
Marker of the coagulation system, biomarker
Time frame: Plasma fibrinogen the first three days from admission
Marker of the coagulation system, functional analysis
Time frame: Thromboelastography at admission and at 48 hours
Hemodynamics, Swan-Ganz catheter
Time frame: Daily Swan-Ganz catheter measurements the first five days from admission
Hemodynamics, arterial blood gasses (Lactate)
Time frame: Arterial blood gasses bihourly the first 36 hours
Hemodynamics, arterial blood gasses
Time frame: Arterial blood gasses bihourly the first 36 hours
Neuroprotection, biomarkers
Time frame: Biomarkers the first three days from admission
Cardiac protection, biomarkers
Time frame: Biomarkers the first three days from admission
Clinical endpoint, survival
Time frame: 180 days following discharge
Clinical endpoint, neurological outcome by mRS score
Time frame: After five days of admission and at 30- and 180- days following discharge
Safety, adverse events
Time frame: From admission till 7 days following admission
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 29 Mar 2023.
- Background: PubMed 20123673Sasson C, Rogers MA, Dahl J, Kellermann AL. Predictors of survival from out-of-hospital cardiac arrest: a systematic review and meta-analysis. Circ Cardiovasc Qual Outcomes. 2010 Jan;3(1):63-81. doi: 10.1161/CIRCOUTCOMES.109.889576. Epub 2009 Nov 10.
- Background: PubMed 22796541Soholm H, Wachtell K, Nielsen SL, Bro-Jeppesen J, Pedersen F, Wanscher M, Boesgaard S, Moller JE, Hassager C, Kjaergaard J. Tertiary centres have improved survival compared to other hospitals in the Copenhagen area after out-of-hospital cardiac arrest. Resuscitation. 2013 Feb;84(2):162-7. doi: 10.1016/j.resuscitation.2012.06.029. Epub 2012 Jul 13.
- Background: PubMed 18948368Neumar RW, Nolan JP, Adrie C, Aibiki M, Berg RA, Bottiger BW, Callaway C, Clark RS, Geocadin RG, Jauch EC, Kern KB, Laurent I, Longstreth WT Jr, Merchant RM, Morley P, Morrison LJ, Nadkarni V, Peberdy MA, Rivers EP, Rodriguez-Nunez A, Sellke FW, Spaulding C, Sunde K, Vanden Hoek T. Post-cardiac arrest syndrome: epidemiology, pathophysiology, treatment, and prognostication. A consensus statement from the International Liaison Committee on Resuscitation (American Heart Association, Australian and New Zealand Council on Resuscitation, European Resuscitation Council, Heart and Stroke Foundation of Canada, InterAmerican Heart Foundation, Resuscitation Council of Asia, and the Resuscitation Council of Southern Africa); the American Heart Association Emergency Cardiovascular Care Committee; the Council on Cardiovascular Surgery and Anesthesia; the Council on Cardiopulmonary, Perioperative, and Critical Care; the Council on Clinical Cardiology; and the Stroke Council. Circulation. 2008 Dec 2;118(23):2452-83. doi: 10.1161/CIRCULATIONAHA.108.190652. Epub 2008 Oct 23. No abstract available.
- Background: PubMed 21464058Stub D, Bernard S, Duffy SJ, Kaye DM. Post cardiac arrest syndrome: a review of therapeutic strategies. Circulation. 2011 Apr 5;123(13):1428-35. doi: 10.1161/CIRCULATIONAHA.110.988725. No abstract available.
- Background: PubMed 26472996Callaway CW, Donnino MW, Fink EL, Geocadin RG, Golan E, Kern KB, Leary M, Meurer WJ, Peberdy MA, Thompson TM, Zimmerman JL. Part 8: Post-Cardiac Arrest Care: 2015 American Heart Association Guidelines Update for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. Circulation. 2015 Nov 3;132(18 Suppl 2):S465-82. doi: 10.1161/CIR.0000000000000262. No abstract available.
- Background: PubMed 26826561Peberdy MA, Andersen LW, Abbate A, Thacker LR, Gaieski D, Abella BS, Grossestreuer AV, Rittenberger JC, Clore J, Ornato J, Cocchi MN, Callaway C, Donnino M; National Post Arrest Research Consortium (NPARC) Investigators. Inflammatory markers following resuscitation from out-of-hospital cardiac arrest-A prospective multicenter observational study. Resuscitation. 2016 Jun;103:117-124. doi: 10.1016/j.resuscitation.2016.01.006. Epub 2016 Jan 27.
- Background: PubMed 25238742Vaahersalo J, Skrifvars MB, Pulkki K, Stridsberg M, Rosjo H, Hovilehto S, Tiainen M, Varpula T, Pettila V, Ruokonen E; FINNRESUSCI Laboratory Study Group. Admission interleukin-6 is associated with post resuscitation organ dysfunction and predicts long-term neurological outcome after out-of-hospital ventricular fibrillation. Resuscitation. 2014 Nov;85(11):1573-9. doi: 10.1016/j.resuscitation.2014.08.036. Epub 2014 Sep 17.
- Background: PubMed 26525271Bro-Jeppesen J, Kjaergaard J, Stammet P, Wise MP, Hovdenes J, Aneman A, Horn J, Devaux Y, Erlinge D, Gasche Y, Wanscher M, Cronberg T, Friberg H, Wetterslev J, Pellis T, Kuiper M, Nielsen N, Hassager C; TTM-Trial Investigators. Predictive value of interleukin-6 in post-cardiac arrest patients treated with targeted temperature management at 33 degrees C or 36 degrees C. Resuscitation. 2016 Jan;98:1-8. doi: 10.1016/j.resuscitation.2015.10.009. Epub 2015 Oct 23.
- Background: PubMed 25756419Bro-Jeppesen J, Kjaergaard J, Wanscher M, Nielsen N, Friberg H, Bjerre M, Hassager C. Systemic Inflammatory Response and Potential Prognostic Implications After Out-of-Hospital Cardiac Arrest: A Substudy of the Target Temperature Management Trial. Crit Care Med. 2015 Jun;43(6):1223-32. doi: 10.1097/CCM.0000000000000937.
- Background: PubMed 14580740Fries M, Kunz D, Gressner AM, Rossaint R, Kuhlen R. Procalcitonin serum levels after out-of-hospital cardiac arrest. Resuscitation. 2003 Oct;59(1):105-9. doi: 10.1016/s0300-9572(03)00164-3.
- Background: PubMed 15365608Laver S, Farrow C, Turner D, Nolan J. Mode of death after admission to an intensive care unit following cardiac arrest. Intensive Care Med. 2004 Nov;30(11):2126-8. doi: 10.1007/s00134-004-2425-z. Epub 2004 Sep 9.
- Background: PubMed 23000363Dragancea I, Rundgren M, Englund E, Friberg H, Cronberg T. The influence of induced hypothermia and delayed prognostication on the mode of death after cardiac arrest. Resuscitation. 2013 Mar;84(3):337-42. doi: 10.1016/j.resuscitation.2012.09.015. Epub 2012 Sep 20.
- Individual participant dataSharing planned: Undecided
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Christian Hassager, MD, DMSc principal investigator
Department of Cardiology, The Heart Center, Rigshospitalet, Copenhagen, Denmark
2 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing Methylprednisolone and Isotonic saline in people with Out-Of-Hospital Cardiac Arrest and Cardiac Arrest, run by Christian Hassager at 2 sites in Denmark.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 5 inclusion and 8 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 29 Mar 2023. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 2 sites in Denmark. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Concentration of IL-6 (time frame: Daily measurements from admission to 72 hours after admission). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT04624776, which also lists 36 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 29 Mar 2023.