Pilot Randomized Clinical Trial of Therapeutic Hypothermia Plus Neuromuscular Blockade vs. Standard of Care in COVID-19 Patients With Moderate to Severe ARDS - the Cooling to Help Injured Lungs (CHILL) Pilot Study
试验速览
- 阶段
- 2 期
- 状态
- 撤回
- 试验地点
- 1
- 主要终点
- Targeted temperature compliance
研究概览
简要总结
Acute Respiratory Distress Syndrome (ARDS) is a serious condition that occurs as a complication of medical and surgical diseases, has a mortality of ~40%, and has no known treatment other than optimization of support. Data from basic research, animal models, and retrospective studies, case series, and small prospective studies suggest that therapeutic hypothermia (TH) similar to that used for cardiac arrest may be lung protective in patients with ARDS; however, shivering is a major complication of TH, often requiring paralysis with neuromuscular blocking agents (NMBA) to control. Since the recently completed NHLBI PETAL ROSE trial showed that NMBA had no effect (good or bad) in patients with moderate to severe ARDS, the investigators sought to evaluate whether TH combined with NMBA is beneficial in patients with ARDS. The investigators are scheduled to begin enrolling in a Department of Defense-funded Phase IIb multicenter RCT of TH (core temperature 34-35°C) + NMBA for 48h vs. usual temperature management in patients with ARDS with time on ventilator as the primary outcome. Since COVID-19 is now the most common cause of ARDS, we are conducting a pilot study to examine the safety and feasibility of including patients with COVID-19-associated ARDS in our upcoming trial. In this pilot, we will randomize 20 patients with COVID-19 and ARDS to either TH+NMBA for 48h or usual temperature management. The primary outcome is achieving and maintaining the target temperature. Secondary outcomes include safety, physiologic measures, mortality, hospital and ICU length of stay, and serum biomarkers collected on days 0, 1, 2, 3, 4, and 7.
详细描述
Background:
Despite recent advances in supportive care for patients with acute respiratory distress syndrome (ARDS), mortality remains >40%. Fever worsens and hypothermia mitigates animal models of ALI and in small non-randomized in patients with ARDS. Since hypothermia reduces oxygen utilization as long as shivering is blocked, TH may reduce injury in part by allowing lower levels of assisted ventilation. TH likely exerts additional lung protective effects by directly modifying temperature-dependent cellular processes in endothelium, epithelium, and leukocytes. Neuromuscular blockade (NMB) is the ultimate treatment to block shivering and is frequently used in patients with ARDS to facilitate ventilator management. Since the recently completed NHLBI PETAL ROSE trial showed that NMB caused conferred neither benefit nor harm in patients with moderate to severe ARDS, the investigators have bundled TH with NMB to reduce shivering. An open-label study of 8 ARDS patients showed that studying TH + NMB in patients with moderate to severe ARDS was feasible. Moreover, the patients treated with TH +NMB had more 28-day ventilator-free days (VFDs), ICU-free days (ICU-FDs) and greater hospital survival (75% vs. 25%; p = 0.027) than historical controls with ARDS and NMB but without TH. Within the limits of historical comparisons, these results support further study of TH in ARDS. A Department of Defense-funded Phase IIb multicenter trial of TH+NMB in patients with moderate to severe ARDS will begin enrolling in Fall, 2020. Since COVID-19 has become the most common cause of ARDS, it is important to understand whether patients with COVID-19-associated ARDS can be included in the multicenter trial.
Focus of Study: We will conduct a single-site feasibility and safety RCT pilot of TH+NMB for 48h vs. usual temperature management in 20 patients with COVID-19-associated ARDS. We will also analyze efficacy markers to help decide whether the treatment duration (48h) to be used in the multicenter trial is appropriate for patients with COVID-19-associated ARDS. The results of this pilot help us decide whether to include patients with COVID-19-associated ARDS in our planned multicenter trial of TH+NMB in ARDS from all causes or to pursue a separate trial focused on patients with COVID-19-associated ARDS.
Primary and secondary objectives: The primary objective is to assess the safety and feasibility of the 48h TH+NMB treatment protocol. The secondary objective is to compare the TH+NMB and control arms for efficacy markers to be used in the multicenter trial.
Study design: The CHILL trial is a single center RCT.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- None
盲法说明
Since it will be obvious to observers of the subjects whether they are in the treatment (TH+NMB) or control groups, the study is not masked but all treatments that determine outcome are protocolized.
入排标准
- 年龄范围
- 18 Years 至 65 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- 未提供
排除标准
- •Missed ARDS window (>48hrs)
- •Missed mechanical ventilation window (>7 days)
- •Refractory hypotension (> 0.2 mcg/kg/min of norepinephrine or equivalent dose for minimum of 6 h)
- •Core temperature <35.5°C while not receiving CRRT
- •Patient is unable to give consent and no legally authorized representative is available;
- •Significant, active bleeding (>3u blood products and/or surgical/IR intervention)
- •Platelets <10K/mm3 (uncorrected)
- •Active hematologic malignancy
- •Skin process precludes cooling device
- •Moribund, not likely to survive 72h
- •Pre-morbid condition makes it unlikely that patient will survive 28 days
- •Do Not Resuscitate status
- •Not likely to remain intubated for ≥48h
- •Physician unwilling to participate
- •Severe underlying lung disease
- •On BIPAP (except for OSA)
- •Prior lung transplantation
- •BMI >45 kg/m2
- •Known NYHA class IV heart disease
- •Acute Coronary Syndrome past 30 days (MI, unstable angina)
- •Cardiac arrest within 30 days of enrollment
- •burns over >20% of the body surface
- •severe chronic liver disease (Child-Pugh of 12-15)
- •Previously randomized in CHILL study
研究组 & 干预措施
Hypothermia + Neuromuscular blockade
Deep sedation and Neuromuscular blockade (NMB) and surface temperature management to maintain core temperature between 34 and 35°C for 48h, then rewarm to 36°C at 0.33°C per h and NMB discontinued when core temp reaches 35.5°C.
干预措施: Hypothermia (Device)
Hypothermia + Neuromuscular blockade
Deep sedation and Neuromuscular blockade (NMB) and surface temperature management to maintain core temperature between 34 and 35°C for 48h, then rewarm to 36°C at 0.33°C per h and NMB discontinued when core temp reaches 35.5°C.
干预措施: Neuromuscular Blocking Agents (Drug)
Standard of care
Acetaminophen and surface temperature management to maintain core temperature between 37°C and 38°C. Rewarming to 37°C for hypothermia ≤36°C with continuous renal replacement therapy.
干预措施: Standard of Care (Device)
结局指标
主要结局
Targeted temperature compliance
时间窗: Randomization through day 3
The total time in hours from beginning of cooling to beginning of rewarming during which the patient's core temperature was within the target range of 34-35°C.
次要结局
- Adverse event(Randomization through study day 3)
- 28-day ICU-free days(Calculated at study day 28 or death (whichever occurs first))
- Survival(calculated at 28, 60, and 90 days)
- non neurologic Sequential Organ Failure (SOFA) scores(At enrollment and study days 1, 2, 3, 4, 7, and 28)
- Plateau airway pressure(Measured at enrollment, every 4 hours on enrollment day, then once on day 2, 3, 4, and 7 or until extubation whichever occurs first)
- Mean airway pressure(Measured at enrollment, every 4 hours on enrollment day, then once on day 2, 3, 4, and 7 or until extubation whichever occurs first)
- Blood glucose(Every 4 hours until study hour 60)
- Oxygen saturation (SpO2)(Measured at enrollment, every 4 hours on enrollment day, then once on day 2, 3, 4, 7 and 28)
- Airway driving pressure(Measured at enrollment, every 4 hours on enrollment day, then once on day 2, 3, 4, and 7 or until extubation whichever occurs first)
- Oxygen saturation index(Measured at enrollment, every 4 hours on enrollment day, then once on day 2, 3, 4, and 7 or until extubation whichever occurs first)
- Serum electrolytes(Every 8 hours until study hour 60)
- Core temperature(Measured continuously and recorded at enrollment, every 2 hours on the day of enrollment, and mornings on study day 2, 3, 4, and 7)
- Urine output(Daily on study day 1, 2, 3, 4, and 7)
- comprehensive metabolic panel(Daily on study day 1, 2, 3, 4, and 7)
- Complete blood count with differential count and platelet count(Daily on study day 1, 2, 3, 4, and 7)
- Biomarkers(Daily on study day 1, 2, 3, 4, and 7)
- 28-day ventilator-free days(Calculated at study day 28 or death (whichever occurs first))
研究者
Jeffrey Hasday
Professor of Medicine
University of Maryland, Baltimore