The Danish Out-of-Hospital Cardiac Arrest Study - a Randomized, Placebo-controlled, Double-blind, Multi Center Trial
试验速览
- 阶段
- 3 期
- 状态
- 招募中
- 发起方
- 入组人数
- 1,000
- 试验地点
- 5
- 主要终点
- Early wakeup and extubation intervention primary endpoint: Days alive outside hospital
研究概览
简要总结
After resuscitation from Out-of-Hospital Cardiac Arrest (OHCA) patients experience Post Cardiac Arrest Syndrome due to ischemia and reperfusion injury. It consists of systemic inflammation, cerebral and myocardial dysfunction, and the condition that led to the arrest. Most OHCA patients will receive critical care intubated in an Intensive Care Unit (ICU). Despite this ~50% die; mainly due to brain injury. Several targets can be considered for improving outcomes. To dampen systemic inflammation and optimize cerebral perfusion seem important. Deep sedation has been required for targeted temperature management (TTM) but may also be brain protective. After end of sedation, many patients have some cerebral dysfunction that may facilitate delirium.
The aim of this trial is therefore to improve treatment of comatose OHCA patients by evaluating 4 interventions in a factorial design addressing each of these targets in a randomized clinical trial:
- Systemic inflammation: Anti-inflammatory treatment with high dose steroids (dexamethasone) or placebo.
- Cerebral perfusion: Backrest elevation during sedation at 5 or 35 degrees.
- Duration of sedation: Early wakeup call and potential extubation at ≤6 hours after admission or later as current standard practice at 28-36 hours.
- Delirium: Prophylactic treatment with anti-psychotic medication (olanzapine) or placebo.
The trial is designed as a phase III trial, randomizing 1000 patients at Danish cardiac arrest centers.
The primary endpoint is 90 days all-cause mortality for the interventions targeting systemic inflammation and cerebral perfusion, while it is days alive outside of hospital within 30 days for the interventions concerning duration of sedation and delirium.
The trial has potential to improve outcomes for comatose OHCA patients - a group with a grave prognosis with currently only limited evidence-based treatments.
详细描述
BACKGROUND
Initially resuscitated Out-of-Hospital Cardiac Arrest (OHCA) patients admitted to a hospital are often in an unstable condition necessitating both circulatory and respiratory support. Most of these patients experiences the Post Cardiac Arrest Syndrome (PCAS) immediately after resuscitation due to a whole-body ischemia and reperfusion injury. It consists of four elements: 1) a universal systemic inflammatory response, 2) cerebral dysfunction, 3) myocardial dysfunction, and 4) the precipitation condition that led to the cardiac arrest - often a coronary occlusion.
The majority of OHCA patients have a presumed cardiac cause for their cardiac arrest. These patients are all evaluated for immediate coronary revascularization, stabilized with vasopressors, inotropes or mechanical circulatory support, and if comatose further sedated, connected to a ventilator and given targeted temperature management (TTM) for at least 24 hours. Half of the admitted resuscitated OHCA patients still die during the hospitalization despite all these interventions. The main cause of death is withdrawal of life sustaining therapy due to irreversible brain injury.
Several targets can be approached in order to potentially improve the outcome of OHCA patients. During the initial phase early after hospital admittance, interventions to dampen the systemic inflammatory response and efforts to secure optimum cerebral perfusion pressure seem intuitive important. Deep sedation has been required for TTM but may also have brain protective effects. After discontinuation of the sedation when the TTM is over, most patients have some degree of cerebral dysfunction. This may make them more prone to develop delirium in the days after awakening which is an independent risk factor in critical ill patients.
The DANOHCA trial will therefore evaluate new potential interventions to each of these different targets: systemic inflammation, cerebral perfusion, duration of sedation, and delirium.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Factorial
- 主要目的
- Treatment
- 盲法
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
盲法说明
The pharmacological interventions will be placebo controlled, and participants, care providers, investigators, and outcome assessors are blinded.
The physiological interventions of early wakeup and extubation as well as the back-rest position are open label.
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Age ≥18 years
- •OHCA of presumed cardiac cause
- •Sustained ROSC, defined as persistent signs of circulation and no need for chest compressions or mechanical circulatory support for 20 minutes
- •Unconsciousness (GCS <9) (patients not able to obey verbal commands) after sustained ROSC at the time of randomization
排除标准
- •Females of childbearing potential if pregnancy is suspected (unless a negative HCG test can rule out pregnancy within the inclusion window)
- •Known bleeding diathesis (medically induced coagulopathy (e.g. warfarin, NOAC, clopidogrel) does not exclude the patient)
- •Suspected or confirmed acute intracranial bleeding
- •Suspected or confirmed acute stroke
- •Unwitnessed asystole
- •Known limitations in therapy and Do Not Resuscitate-order
- •Known disease making 180 days survival unlikely
- •Known pre-arrest CPC 3 or 4 functional status
- •>3 hours (180 minutes) from ROSC to screening
- •Systolic blood pressure <80 mm Hg despite fluid loading/vasopressor and/or inotropic medication (If the systolic blood pressure is recovering during the inclusion window of 180 minutes the patient may be included)
- •Use of intra-aortic balloon pump/axial flow device/ECMO (If the patient is weaned and the device is removed during the inclusion window of 180 minutes the patient may be included)
- •Temperature on admission <30°C
- •Known allergy for dexamethasone or olanzapine
- •Ongoing (within 48 h) treatment with olanzapine or dexamethasone
- •Known back or hip condition that precluded the patients from being positioned with backrest from 0 to 45-degree angle
- •Known or suspected Long QT Syndrome (LQTS)
- •Known active fungal disease. Localized skin lesions do not exclude patients from inclusion
- •Estimated body weight <45kg
研究组 & 干预措施
Dexamethasone intervention, active
As soon as possible after hospital admittance 20 mg of dexamethasonephosphate (Dexavit, Vital Pharma Nordic ApS, Denmark) will be given intravenously (i.v.) over 15 minutes - followed by 20 mg dexamethasonephosphate (or placebo) i.v. administered daily at 0600 (or at least 8 hours after initial dose) for two days, for a total of 3 doses.
For this arm the dexamethasonephosphate solution is provided in the "DANOHCA trial kit" in the form of Dexavit at a concentration of 4mg/mL stored in glass vials of 5mL; three vials are provided in total.
干预措施: Dexamethasone (Drug)
Dexamethasone intervention, placebo
As soon as possible after hospital admittance placebo (isotonic saline) will be given intravenously (i.v.) over 15 minutes - followed by placebo solution administered i.v. daily at 0600 (or at least 8 hours after initial dose) for two days, for a total of 3 doses.
For this arm the placebo solution is provided in the "DANOHCA trial kit" in the form of isotonic sodium chloride stored in glass vials of 5mL; three vials are provided in total.
干预措施: Dexamethasone (Drug)
Backrest elevation intervention, elevation to 35 degrees
As soon as possible after hospital admittance the patients will have their headrest positioned at 35 degrees straight elevation of backrest in Semi-Fowler's position (elevated lower limp position). This position will be maintained during the initial 72 hours or until extubated. Adherence to assigned stratum will be checked every 8 hours and cuff pressure will be assessed and corrected if needed at the same time during the intervention period. The backrest position intervention may be temporarily canceled by the treating physician if needed for procedures or mobilization but will return to the assigned position if invasive ventilator treatment with orotracheal intubation is continued. The intervention will be terminated if the patient is extubated, or a tracheostomy is performed, during the intervention period of 72 hours.
干预措施: Backrest elevation (Procedure)
Backrest elevation intervention, elevation to 5 degrees
As soon as possible after hospital admittance the patients will have their headrest positioned at 5 degrees straight elevation of backrest in Semi-Fowler's position. This position will be maintained during the initial 72 hours or until extubated. Adherence to assigned stratum will be checked every 8 hours and cuff pressure will be assessed and corrected if needed at the same time during the intervention period. The backrest position intervention may be temporarily canceled by the treating physician if needed for procedures or mobilization but will return to the assigned position if invasive ventilator treatment with orotracheal intubation is continued. The intervention will be terminated if the patient is extubated, or a tracheostomy is performed, during the intervention period of 72 hours.
干预措施: Backrest elevation (Procedure)
Early wake-up intervention, wake-up ≤6 hours after ICU admission
Patients will be subjected to a wakeup call and potential extubation after ≤6 hours after admission to the ICU. Definition for "ready for extubation" will be: GCS≥12, RASS 0- -1, able to raise arm or voluntary hand shake on command, spontaneous breathing trial and low ventilator settings (pressure support≤14, PEEP≤8 (10 if obese), and FiO2≤40%). A wakeup call may be aborted for the following reasons: seizures, respiratory distress, shock, or "other cause" with specification. Sedation prior to the scheduled wakeup calls is permitted in this early wakeup call group as needed for clinical care, while it is mandatory for the late wakeup call group. For both groups sedation as needed for clinical care will be permitted after the scheduled wakeup calls.
For this arm, information on the assigned time for wakeup call is provided in the "DANOHCA trial kit". The assigned time for wakeup will be noted in the electronic patient file.
干预措施: Early wakeup call (Procedure)
Early wake-up intervention, wake-up 28-36 hours after ICU admission
Patients will be subjected to a wakeup call and potential extubation after 28-36 hours after admission to the ICU. Definition for "ready for extubation" will be: GCS≥12, RASS 0- -1, able to raise arm or voluntary hand shake on command, spontaneous breathing trial and low ventilator settings (pressure support≤14, PEEP≤8 (10 if obese), and FiO2≤40%). A wakeup call may be aborted for the following reasons: seizures, respiratory distress, shock, or "other cause" with specification. Sedation prior to the scheduled wakeup calls is mandatory for this late wakeup call group. For both groups sedation as needed for clinical care will be permitted after the scheduled wakeup calls.
For this arm, information on the assigned time for wakeup call is provided in the "DANOHCA trial kit". The assigned time for wakeup will be noted in the electronic patient file.
干预措施: Early wakeup call (Procedure)
Olanzapine intervention, active
As soon as possible after arriving at the ICU olanzapine 10mg (dissolved tablet) is administered by feeding tube. Thereafter 10 mg olanzapine is administered by feeding tube (or orally in awake patients) the following two evenings at 1800 (with a minimum of 12 hours between the initial doses) for a total of 3 doses. Due to the potential QT-prolonging effect, and concern for arrythmia, patients will be excluded prior to randomization if Long QT Syndrome (LQTS) is suspected, and telemetry of heart rhythm is mandatory for 96 hours or until life sustaining therapies are withdrawn. In case of delirium patients are treated according to standard care most often including dexmedetomidine, haloperidol or midazolam.
For this arm the olanzapine tablets are provided in the "DANOHCA trial kit" in the form of olanzapin 10mg tablets (Accord Healthcare B.V., The Netherlands); three tablets are provided in total. Prior to administration by feeding tube the tablets are dissolved in water.
干预措施: Olanzapine (Drug)
Olanzapine intervention, placebo
As soon as possible after arriving at the ICU a placebo tablet (dissolved) is administered by feeding tube. Thereafter placebo will be administered by feeding tube (or orally in awake patients) the following two evenings at 1800 (with a minimum of 12 hours between the initial doses) for a total of 3 doses. Due to the potential QT-prolonging effect of olanzapine, and accompanying concern for arrythmia, patients will be excluded prior to randomization if LQTS is suspected, and telemetry of heart rhythm is mandatory for 96 hours or until life sustaining therapies are withdrawn. In case of delirium patients are treated according to standard care most often including dexmedetomidine, haloperidol or midazolam.
For this arm the placebo tablets are provided in the "DANOHCA trial kit" in the form of placebo tablets manufactured by the Pharmacy of the Capital Region; three tablets are provided in total. Prior to administration by feeding tube the tablets are dissolved in water.
干预措施: Olanzapine (Drug)
结局指标
主要结局
Early wakeup and extubation intervention primary endpoint: Days alive outside hospital
时间窗: 30 days
Counted as days alive outside of hospital after discharge
Back rest position intervention primary endpoint: All-cause mortality
时间窗: 90 days
Number of patients dying from all causes
Olanzapine intervention primary endpoint: Days alive outside hospital
时间窗: 30 days
Counted as days alive outside of hospital after discharge
Steroid intervention primary endpoint: All-cause mortality
时间窗: 90 days
Number of patients dying from all causes
次要结局
- Length of hospital stay(From randomization till discharge from hospital or in-patient rehabilitation, up to 90 days)
- Troponin I, Troponin T, and Creatine Kinase Myocardial Band(0-72 hours)
- CAM-ICU positive status(24 hours after extubation)
- modified Rankin Scale (mRS)(Up to 6 months)
- Number of patients dying from all causes(90 days)
- Neuron Specific Enolase and Neurofilament Light Chain levels(48 hours)
- Duration of intubation(Up to 90 days)
- Pharmacological treatment for delirium(From randomization till discharge from initial ICU stay, up to 90 days)
- Plasma Creatinine and use of dialysis(Creatinine: initial 72 hours; Dialysis: initial 30 days)
- Vasopressors and inotropic drugs(Initial ICU stay, during the first 36 hours)
- Mixed blood venous saturation(Assessed at 12, 24 and 36 hours and after this, once daily during initial ICU stay, up to 90 days)
- Unconsciousness(96 hours)
- CAM-ICU negative days(Up to 90 days)
- Cerebral Performance Category (CPC)(Up to 6 months)
研究者
Christian Hassager
Professor, MD, DMSc, FESC
Rigshospitalet, Denmark