Physiologic Effects of Steroids in Cardiac Arrest (CORTICA)

Physiologic Effects of Stress Dose Corticosteroids in the Management of Inhospital Cardiac Arrest - CORTICA

Early stress-dose steroids are of uncertain efficacy in cardiac arrest. The current authors plan to conduct a prospective, randomized, placebo controlled evaluation of stress-dose steroids efficacy with repect to early postresuscitation hemodynamics, heart function, brain perfusion, and inflammatory response in vasopressor-requiring cardiac arrest. Patients will also be followed for organ dysfunction, potential, steroid-associated complications, and functional outcome at hospital discharge.

BACKGROUND AND RATIONALE Despite recent improvements in the quality of care, in-hospital cardiac arrest is still associated with a high probability of poor outcome. Patients resuscitated from vasopressor-requiring cardiac arrest frequently exhibit early postresuscitation hemodynamic instability that is poorly responsive to hemodynamic support with high vasopressor doses and intravenous fluids titrated to cardiac filling pressures of at least 12 mmHg. Furthermore, preceding studies indicate that postresuscitation disease is a "sepsis-like" syndrome characterized by plasma cytokine elevation, endotoxemia, coagulopathy and adrenal insufficiency contributing to postresuscitation shock. Steroids are currently being used for improving hemodynamics in septic patients, however, their effect on postresuscitation hemodynamics has not been thoroughly elucidated yet. OBJECTIVES To determine whether stress-dose steroid supplementation during and after cardiopulmonary resuscitation (CPR) improves the hemodynamic parameters (arterial blood pressure, cardiac output, cerebral blood flow) in patients with in-hospital cardiac arrest. Furthermore to study the effects of steroid administration on the inflammatory response and organ failures, and to determine potential, corticosteroid-associated complications such as hyperglycemia, infections, bleeding peptic ulcers and paresis. In summary, we aim to directly assess the physiological effects and safety of steroids during and after CPR. The possible clinical usefulness of steroids during and after CPR - in the context of early postresuscitation hemodynamic support - currently corresponds to an important knowledge gap, as recently acknowledged by Guidelines Evidence Reviewers. METHODS SETTING Intensive/coronary care units, (ICUs/CCUs) of the Evaggelismos Hospital, Athens, Greece (1,200 beds) and of the Larissa University Hospital, Larissa, Greece (700 beds). PATIENTS Inclusion criteria: Patients who have experienced an in-hospital, vasopressor-requiring cardiac arrest, according to guidelines for resuscitation from 2015. Exclusion criteria are reported in the dedicated subsection. ETHICS AND INFORMED CONSENT The study will be conducted in concordance with European Union Clinical Trials Regulation No 536/2014 and the Helsinki Declaration. Due to the emergency situation, consent will not be requested for steroid supplementation during CPR. The patients' families and patients who regain consciousness and communication ability during follow-up will be informed about the study as soon as possible, and any objection will result in exclusion of the patient data from any subsequent analyses. Informed, written next-of-kin consent and non-written patient consent (whenever feasible) will be requested as soon as possible for stress-dose hydrocortisone in postresuscitation shock and continued participation in the study. If consent cannot obtained before patient death, the patient's next of kin will be informed of the study and their permission for inclusion of the patient data in the subsequent analyses will be requested. All consent procedures will additionally be documented on the patient's medical record. The original protocol version has been approved by the Institutional Review Board (IRB) of Evaggelismos General Hospital on July 14 2016 (Approval No. 126/16-6-2016), and by the IRB of Larissa University Hospital on October 10, 2016 (Approval No. 46113/11-10-2016 - IRB Discussion No. 13/10-10-2016 Θ.6). Subsequent protocol amendments have been approved by the Evaggelismos IRB on January 24, 2017 (Approval No. 8/26-1-2017), and this has been communicated to the IRB of Larissa University Hospital. STUDY DESIGN We propose a prospective, randomized, double-blind, placebo-controlled, parallel- group clinical trial. RANDOMIZATION Research Randomizer version 4 (https://www.randomizer.org/) will be used by the study statistician for group allocation. For each study center, random numbers (range, 1-100) will be generated in sets of 4. Each random number of each set will be unique and correspond to 1 of the consecutively enrolled patients. In each set, an odd or even first number will result in assignment of the corresponding patient to the control or steroids group, respectively. In each study center, the group allocation rule will be known solely by the pharmacists who will prepare the study drugs. CPR AND POSTRESUSCITATION INTERVENTIONS We will enrol adult in-patients with cardiac arrest due to ventricular fibrillation/pulseless tachycardia not responsive to three direct current countershocks, or asystole, or pulseless electrical activity. Study treatments will be administered during the first CPR cycle postenrollment. Patients will be randomized to receive either methylprednisolone 40 mg (Steroids group) or normal saline placebo (Control group) on the first, postenrollment CPR cycle. Otherwise, advanced life support will be conducted according to the 2015 guidelines for resuscitation. After resuscitation, patients will be treated with either stress-dose hydrocortisone of 240 mg daily for 7 days maximum (Steroids group), or saline placebo (Control group). More specifically, at 4 hours after ROSC, patients will receive 100 mL/day (average pump infusion rate ~ 4.2 mL/h) of normal saline that will either contain the stress-dose of hydrocortisone (Steroids group) or solely saline placebo (Control group) for a maximum of 9 days. On days 8 and 9 the hydrocortisone dose of the Steroids group will be tapered to 120 mg and 60 mg, respectively, and finally discontinued on day 10 postrandomization. On ICU/CCU admission, patients will receive a central venous line, and an arterial line, either standard or as part of pulsatility index continuous cardiac output monitoring. Patients with a standard arterial line will also receive a pulmonary artery catheter, provided that attending physicians also agree to this. DOCUMENTATION AND PATIENT FOLLOW-UP CPR attempts will be documented according to the Utstein style. Hemodynamics and gas-exchange, electrolytes, glucose, central body temperature, lactate and administered fluids and vasopressor/inotropic support will be determined/recorded during CPR, and at ~20 min and ~4 hours as well as at 24, 48 and 72 hours after the return of spontaneous circulation (ROSC); ROSC will be defined as sustained presence of a palpable arterial pulse for at least 20 min. Postresuscitation cardiac output will be monitored for at least 72 hours post-ROSC, and postresuscitation cardiac function will be assessed by ultrasonography within the first hour after ICU admission and at 72 hours post-ROSC. Central-venous blood gas analysis will also be performed at the aforementioned time points and blood samples will be taken for the determination of cytokines at approximately 20 min and 4, 24, 48, and 72 hours post-ROSC. Follow-up during the first 10 days postrandomization will include 1) Determination/recording of hemodynamics and hemodynamic support, gas-exchange, fluid balance of the preceding 24 hours, and arterial blood lactate and central venous oxygen saturation at 9 a.m.; 2) Daily determinations of serum pro-inflammatory cytokines, and 3) Daily recording (within 8-9 a.m.) of laboratory data, and prescribed medication. The results of 4 daily determinations (1 every 6 hours) of blood glucose will also be recorded to subsequently analyze the incidence of hyperglycemia (blood glucose exceeding 200 mg/dL -11.1 mmol/L). Follow-up to day 60 post-ROSC will include organ failures, and ventilator-free days. Morbidity/complications throughout ICU/CCU and hospital stay, and times to ICU/CCU and hospital discharge will also be recorded. Study outcomes are reported in the dedicated subsection. PROTOCOL AMENDMENTS [Approved, January 24, 2017] Amendment: 1. Part A: Postresuscitation Cardiac Output (CO) has been moved from the primary to the secondary study outcomes (see also Outcome Measures' subsection). Reason for amendment: We ultimately anticipate to be able to collect such data in <50% of the patients. Part B: Furthermore, the measurement time point of "8 hours postresuscitation" will no longer be part of the protocol and this will apply for the total of the physiological measurements. This aims to limit attending investigator workload. Amendment 2: Further clarification regarding the "acceptable" time frame for ICU / CCU admission of successfully resuscitated patients. This is a very important logistical issue and will include measures (e.g. monitoring and medical service support and oversight) to optimize the quality of care until ICU admission and the specification of the "maximum acceptable time to ICU admission". In the VSE 1 and 2 studies, this time has been 12 hours. During 2016, the Evaggelismos Department of Intensive Care Medicine has experienced a reduction of 5 ICU beds (i.e. from 30 to 25) and 8 HDU (high-dependency unit) beds from 20 to 12. Therefore, regarding cardiac arrest patients, we have decided to extend the target time limit for admission to 24 hours. Regarding CORTICA, any further delay is to be reported as an "unpreventable" protocol breach, and in the case of a possible extreme circumstance (e.g. a severe flu outbreak), any patients with a projected ICU admission time of more than 48 hours will be excluded. Hence, "a projected ICU admission time of more than 48 hours" will constitute an additional exclusion criterion. Amendment 3: Further clarification of the "terminal illness" exclusion criterion - life expectancy of no more than 6 weeks): (i) Patients with metastatic cancer [with confirmed bone and/or brain metastases], and/or primary / metastatic disease causing respiratory failure with/without additional organ-system failures [as defined by a corresponding Sequential Organ Dysfunction Assessment (SOFA) subscore of 3 or 4]; (ii) Patients with a pre-arrest worst SOFA score of >=15 (this corresponds to a probability of death of at least 90%); and (ii) Patients with immunosuppression and a new, hospital-acquired septic complication). Amendment 4: Addition of the following Exclusion Criterion: "Any deviation from the hospital's standard resuscitative procedure" (e.g. poor adherence to the standard Advanced Life Support algorithm such as an epinephrine dosing error or use of atropine, or "unjustified" interruption of chest compressions compromising CPR quality). Amendment 5: Addition of the following Exclusion Criterion: Pre-arrest diagnosis of an "active" peptic ulcer; that is, either preceding gastroscopic confirmation of a peptic ulcer, or clinical evidence of acute, pre-arrest gastrointestinal bleeding, attributable to peptic ulcer disease. Amendment 6: Follow-up during the first 10 days: The time of determination of cytokines will be 20 min, 4, 24, 48, and 72 hours post ROSC [as specified in the corresponding outcome measure], and 7 days post-ROSC (that is, the determinations of day 4, 5, 6, 8, 9, and 10 will be cancelled); Reason for change: Study cost reduction. Amendment 7: An amendment of the statistical analysis plan enabling the inclusion of patients without return of spontaneous circulation (ROSC) was approved by the Evaggelismos Hospital IRB (Approval No. 527/11-11-2021), and by the Larissa University Hospital IRB (Approval No. 44243/10-11-2021. The rationale for this amendment pertained to the prevention of bias due to post-randomization exclusion. The amendment was actually prompted by a relevant peer review comments. STATISTICS Data will be reported as mean±standard deviation, or median (interquartile range), or number (percentage), unless otherwise specified. Distribution normality will be tested by Kolmogorov-Smirnov test. Dichotomous and categorical variables will be compared by two-sided chi-square or Fisher's exact test. Continuous variables will be compared by two-tailed, independent samples t test or Mann-Whitney exact U test. P- values of multiple t-test comparisons will be subjected to the Bonferroni correction. We will use mixed model analysis to compare repeatedly measured variables between the two groups. Survival data will be analyzed by a previously employed methodology of multivariable Cox regression. Based on previously published data on the mean arterial pressure at 24 hours postresuscitation, to detect an effect size d of 0.761 with an α error probability of 0.015 and power 0.80, we need to enroll a total of 78 patients (39 in each group). A target enrollment of 100 patients with ROSC for at least 20 min will likely adequately compensate for possible dropouts or missing data. Expected results pertain to a steroid-associated benefit with respect to the primary outcomes, consistent with results on secondary outcomes.

Intervention: Stress-dose Steroids. Patients will receive methylprednisolone 40 mg (on the first, postenrollment cardiopulmonary resuscitation cycle. Otherwise, advanced life support will be conducted according to the 2015 guidelines for resuscitation). After resuscitation, patients will be treated with stress-dose hydrocortisone 240 mg daily for 7 days maximum, followed by gradual taper over the next 2 days.

Intervention: Saline placebo. Patients will receive saline placebo on the first, postenrollment cardiopulmonary resuscitation cycle. Otherwise, advanced life support will be conducted according to the 2015 guidelines for resuscitation. After resuscitation, patients will be treated with saline placebo for a maximum of 9 days (i.e. 7 days corresponding to the stress-dose hydrocortisone treatment of the experimental arm plus 2 days corresponding to the gradual taper of the stress-dose hydrocortisone treatment of the experimental arm).

Methylprednisolone 40 mg during resuscitation and stress-dose hydrocortisone for postresuscitation shock

Early Postresuscitation Arterial Blood Pressure (mmHg) Measured Through Institution of Invasive Intra-arterial Pressure Monitoring (as Feasible).

Results on early postresuscitation, mean arterial blood pressure (mmHg) are provided for the first, pre-specified time point of measurement, i.e. at 20 min after the return of spontaneous circulation (ROSC).

Early Postresuscitation Central Venous Oxygen Saturation (%) Measured in Blood Samples Obtained Through a Central Venous Catheter Port (as Feasible).

Results on early postresuscitation central venous oxygen saturation (%) are provided for the first, pre-specified time point of measurement, I.e., 20 min after the return of spontaneous circulation (ROSC). Actually, and exclusively for this particular measurement, reasons for the failure of consistent data collection are given below.

Early Postresuscitation Arterial Blood Pressure (mmHg) Measured Through Institution of Invasive Intra-arterial Pressure Monitoring (as Feasible).

Results on early postresuscitation, mean arterial blood pressure (mmHg) are provided for the second, pre-specified time point of measurement, i.e. at 4 hours after ROSC.

Early Postresuscitation Central Venous Oxygen Saturation (%) Measured in Blood Samples Obtained Through a Central Venous Catheter Port (as Feasible).

Results on postresuscitation central venous oxygen saturation (%) are provided for the second, pre-specified time point of measurement, i.e., at 4 hours after ROSC.

Early Postresuscitation Arterial Blood Pressure (mmHg) Measured Through Institution of Invasive Intra-arterial Pressure Monitoring.

Results on postresuscitation, mean arterial blood pressure (mmHg) are provided for the third, pre-specified time point of measurement, i.e. at 24 hours after ROSC.

Early Postresuscitation Central Venous Oxygen Saturation (%) Measured in Blood Samples Obtained Through a Central Venous Catheter Port.

Results on postresuscitation central venous oxygen saturation (%) are provided for the third, pre-specified time point of measurement, i.e., at 24 hours after ROSC.

Early Postresuscitation Arterial Blood Pressure (mmHg) Measured Through Institution of Invasive Intra-arterial Pressure Monitoring.

Results on postresuscitation, mean arterial blood pressure (mmHg) are provided for the fourth, pre-specified time point of measurement, i.e. at 48 hours after ROSC.

Early Postresuscitation Central Venous Oxygen Saturation (%) Measured in Blood Samples Obtained Through a Central Venous Catheter Port.

Results on postresuscitation central venous oxygen saturation (%) are provided for the fourth, pre-specified time point of measurement, i.e., at 48 hours after ROSC.

Early Postresuscitation Arterial Blood Pressure (mmHg) Measured Through Institution of Invasive Intra-arterial Pressure Monitoring.

Results on postresuscitation, mean arterial blood pressure (mmHg) are provided for the fifth, pre-specified time point of measurement, i.e. at 72 hours after ROSC.

Early Postresuscitation Central Venous Oxygen Saturation (%) Measured in Blood Samples Obtained Through a Central Venous Catheter Port.

Results on postresuscitation central venous oxygen saturation (%) are provided for the fifth, pre-specified time point of measurement, i.e., at 72 hours after ROSC.

Results are provided on left ventricular end-diastolic area (LVEDA) and right ventricular diastolic area (RVEDA) by echocardiography within 12 hours and 72 hours after ROSC.

Results are provided on left ventricular ejection fraction (LVEF) and right ventricular ejection fraction (RVEF) within 12 hours and 72 hours after ROSC.

Eccentricity index (ECCI) is defined as the ratio of the left ventricular (LV) "longitudinal" (or anteroposterior) diameter to the LV "transverse" (or septo-lateral) diameter, measured at end diastole and end systole in a short-axis view. Pertinent results are provided for a first determination within 12 hours after ROSC and a second determination at 72 hours after ROSC.

Early Postresuscitation Cardiac Output (L/Min) Measured by Either Pulse Index Continuous Cardiac Output (PiCCO) or a Continuous Cardiac Output (CCO) Thermodilution Pulmonary Artery Catheter.

Early Postresuscitation Cardiac Output (L/Min) Measured by Either Pulse Index Continuous Cardiac Output (PiCCO) or a Continuous Cardiac Output (CCO) Thermodilution Pulmonary Artery Catheter.

Early Postresuscitation Cardiac Output (L/Min) Measured by Either Pulse Index Continuous Cardiac Output (PiCCO) or a Continuous Cardiac Output (CCO) Thermodilution Pulmonary Artery Catheter.

Early Postresuscitation Cardiac Output (L/Min) Measured by Either Pulse Index Continuous Cardiac Output (PiCCO) or a Continuous Cardiac Output (CCO) Thermodilution Pulmonary Artery Catheter.

Results are provided for core body temperature averaged over the following time intervals after ROSC: 1) 0-6 hours; 2) 6-12 hours; 3) 12-18 hours; 4) 18-24 hours; 5) 24-30 hours; 6) 30-36 hours; 7) 36-42 hours; and 42-48 hours.

Results are reported for 2 pairs of cerebral blood flow index (CBFI) measurements performed each time at a lower and a higher level of mean arterial pressure (MAP) at the following time points: 1) at 4 hours after ROSC and 2) at 72 hours after ROSC

Number of organ failure-free days during days 1 through 60 postrandomization. Organ failure free=corresponding Sequential Organ Failure Assessment Subscore <3; each subscore can have the following values: 0, 1, 2, 3, and 4; increasing values indicate worsening organ failure.

Logarithm (base 10)-transformed serum levels of tumor necrosis factor alpha (TNFa), interleukin (IL)-1 beta, IL-6, IL-8, and IL-10; blood samples were obtained by venipuncture.

Survival to hospital discharge with a Cerebral Performance Category (CPC) Score of 1 or 2. The CPC Score ranges can have the following values: 1, 2, 3, 4, and 5; lower Scores correspond to better outcomes, whereas higher Scores reflect worsening outcomes, e.g. a Score of 4 means Coma or Vegetative state, and a Score of 5 means Brain Death.

Episodes of 1) Hyperglycemia (defined as Blood Glucose >200 mg/dL), 2) Hypernatremia (defined as blood gas analysis-derived sodium ion concentration >150 mEq/L), and 3) Infections (defined as any microbiologically documented, intensive care unit-acquired, or hospital-acquired infection).

Inclusion Criteria: Adult in-patients with ROSC [for at least 20 min] after cardiac arrest due to Ventricular fibrillation/pulseless tachycardia not responsive to three direct current countershocks, or Asystole, or Pulseless electrical activity. Exclusion Criteria: Age <18 years Terminal illness (i.e. life expectancy <6 weeks e.g. due to metastatic cancer, or Sequential Organ Dysfunction Assessment score of 15 or more, or new septic complication in the presence of immunosuppression) or do-not- resuscitate status Cardiac arrest due to exsanguination (e.g. ruptured aortic aneurysm) Cardiac arrest before hospital admission Pre-arrest treatment with intravenous corticosteroids Any history of an allergic reaction Transmural myocardial infarction Previous enrollment in or exclusion from the current study. Confirmation of return of spontaneous circulation before study-drug administration, corresponding to "premature randomization" [reference 18] will also result in patient exclusion due to absence of vasopressor-requiring cardiac arrest. Additional Exclusion Criteria According to the Protocol Amendment approved on January 24, 2017: Any deviation from the hospital's standard resuscitative procedure. Pre-arrest diagnosis of an "active" peptic ulcer. Projected ICU admission time of more than 48 hours in case of a concurrent, special public health circumstance (e.g. severe flu outbreak) that may abruptly increase the demand for intensive care.

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