Cooling to Help Injured Lungs (CHILL) Phase IIB Randomized Control Trial of Therapeutic Hypothermia in Patients With ARDS
试验速览
- 阶段
- 2 期
- 状态
- 进行中（未招募）
- 入组人数
- 340
- 试验地点
- 38
- 主要终点
- 28-day ventilator-free days (VFDs)
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 CHILL trial is designed to evaluate whether TH combined with NMBA is beneficial in patients with ARDS. This Phase IIb randomized clinical trial is funded by the Department of Defense to compare TH (core temperature 34-35°C) + NMBA for 48h vs. usual temperature management in patients in 14 clinical centers with the Clinical Coordination Center and Data Coordinating Center at University of Maryland Baltimore. Planned enrollment is 340 over ~3.5 years of the 4-year contract. COVID-19 is considered an ARDS risk-factor and patients with ARDS secondary to COVID-19 pneumonia will be eligible for enrollment. Primary outcome is 28-day ventilator-free days. Secondary outcomes include safety, physiologic measures, mortality, hospital and ICU length of stay, and serum biomarkers collected at baseline and on days 1, 2, 3, 4, and 7.
详细描述
Brief summary:
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 CHILL trial is designed to evaluate whether TH combined with NMBA is beneficial in patients with ARDS. This Phase IIb randomized clinical trial is funded by the Department of Defense to compare TH (core temperature 34-35°C) + NMBA for 48h vs. usual temperature management in patients in 14 clinical centers with the Clinical Coordination Center and Data Coordinating Center at University of Maryland Baltimore. Planned enrollment is 340 over ~3.5 years of the 4-year contract. COVID-19 is considered an ARDS risk-factor and patients with ARDS secondary to COVID-19 pneumonia will be eligible for enrollment. Primary outcome is 28-day ventilator-free days. Secondary outcomes include safety, physiologic measures, mortality, hospital and ICU length of stay, and serum biomarkers collected at baseline and on days 1, 2, 3, 4, and 7.
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. Since COVID-19 is currently the most common cause of ARDS and will likely remain so for much of the CHILL enrollment period, patients with ARDS secondary to COVID-19 pneumonia are eligible for enrollment in CHILL. Our overall hypothesis is that TH is lung protective in ARDS. The hypothesis to be tested is that induced hypothermia (core temperature 34°-35°C) with NMB to prevent shivering is safe and beneficial in patients with moderate to severe ARDS (PaO2/FIO2 (P/F) ratio≤200) who are receiving NMB.
Focus of Study: We will conduct a multicenter RCT pilot of TH+NMB for 48h vs. usual temperature management in 340 patients with ARDS in 14 clinical sites.
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 85 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •endotracheal tube or tracheostomy in place and mechanically ventilated for ≤7 days;
- •admitted to a participating ICU
- •radiologic evidence of bilateral pulmonary infiltrates not fully explained by pleural effusions, atelectasis, or hydrostatic pulmonary edema
- •P/F ratio ≤200 with PEEP ≥8 cm H2O; If ABG values are not available, the P/F ratio may be inferred from SpO2 values based on Table 3 from Brown et al as long as following conditions are met:
- •SpO2 values are 80-96%
- •SpO2 is measured ≥10 min after any change in FIO2
- •PEEP is ≥ 8 cm H2O
- •the pulse oximeter waveform tracing is adequate
- •the qualifying inferred P/F ratio is confirmed 1-6h after initial determination.
- •access to an LAR to provide consent.
- •Criteria 3 AND 4 must be met within 72h of enrollment and randomization, not be fully explained by hydrostatic pulmonary edema, and must have occurred within 7 days of exposure to an ARDS-risk factor (including continuous exposure to persistent processes (e.g. sepsis, pneumonia, COVID-19).
- •Patients may be enrolled and decision about randomization delayed if all criteria other than P/F ratio ≤ 200 are met and then randomized if and when the P/F ratio ≤200 (as long as this occurs within 72h of randomization). Patients on high flow nasal oxygen or non-invasive pressure ventilation may be consented if they meet criteria for starting the 72h ARDS window but may not be enrolled and randomized until they are intubated.
排除标准
- •Missed moderate-severe ARDS window (>72hrs) - Window starts when patient is intubated with a qualifying P/F ratio of ≤ 200 with PEEP ≥ 8 cm H2O or on high flow nasal oxygen with well-fitting nasal cannula with flow ≥ 40 LPM and FiO2 ≥ 0.65 or on non-invasive pressure ventilation with PEEP ≥ 8 cm H2O and FiO2 ≥ 0.
- •Missed NMB window: (>48 hrs)
- •Missed mechanical ventilation window (>7 days)
- •Refractory hypotension (continuous infusion of >0.3 mcg/kg/min of norepinephrine or equivalent dose of other vasopressors within 2 hours prior to randomization)
- •Core temperature <35°C for ≥6 hours while not receiving CRRT on day of randomization
- •Significant, active bleeding (>3u blood products and/or surgical/IR intervention) on day of randomization
- •Platelets <10K/mm3 (uncorrected) on day of randomization
- •Active hematologic malignancy and not expected to survive 6 months
- •Skin process that 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 at time of randomization (excluding patients receiving full support EXCEPT CPR for cardiac arrest)
- •Not likely to remain intubated for ≥48h
- •Physician of record unwilling to participate
- •Severe underlying lung disease
- •Needs > 2 LPM or >28% continuous home O2 (adjusted for altitude)
- •On BIPAP (except for OSA)
- •Prior lung transplantation
- •Pregnant at time of randomization
- •BMI consistently >50 kg/m2
- •Known NYHA class IV heart disease
- •Acute Coronary Syndrome (MI, unstable angina) within 30 days of randomization
- •Cardiac arrest within 30 days of randomization with sequelae likely to increase mortality and/or time to ventilator liberation.
- •Burns over >20% of the body surface
- •Severe chronic liver disease (Child-Pugh score 12-15)
- •Previously randomized in CHILL study
- •Simultaneous enrollment in another inpatient interventional trial started during the current hospitalization.
- •On ECMO during the current hospitalization.
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)
Usual Temperature Management
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
28-day ventilator-free days (VFDs)
时间窗: Calculated at study day 28 or death (whichever occurs first)
Total number of days alive and not on a ventilator in the first 28 days after enrollment
次要结局
- 28-day ICU-free days(Calculated at study day 28 or death (whichever occurs first))
- non neurologic Sequential Organ Failure (SOFA) scores(At enrollment and study days 1, 2, 3, 4, 7, and 28)
- Mean airway pressure(Measured at randomization and daily as close to 0800 as possible on study days 1 2, 3, 4, and 7 or until extubation whichever occurs first)
- Plateau airway pressure(Measured at randomization and daily as close to 0800 as possible on study days 1 2, 3, 4, and 7 or until extubation whichever occurs first)
- Core temperature(Measured continuously and recorded at randomization and then every 2 hours through study day 4)
- Survival(calculated at 28, 60, and 90 days)
- Oxygen saturation (SpO2)(Measured at enrollment, every 2 hours on enrollment day, then once on day 2, 3, 4, 7 and 28)
- Airway driving pressure(Measured at randomization and daily as close to 0800 as possible on study days 1 2, 3, 4, and 7 or until extubation whichever occurs first)
- Oxygen saturation index(Measured at randomization and daily as close to 0800 as possible on study days 1 2, 3, 4, and 7 or until extubation whichever occurs first)
- Urine output(Daily on study day 1, 2, 3, 4, and 7)
- Serum electrolytes(Performed each evening on study days 1, 2, and 3)
- comprehensive metabolic panel blood test (includes sodium, potassium, chloride, bicarb, BUN, creatinine, glucose, albumin, total protein, AST, SLT, alkaline phosphatase, and bilirubin)(At randomization and each morning on study days 1, 2, 3, 4, and 7)
- Complete blood count with differential count and platelet count(At randomization and each morning on study days 1, 2, 3, 4, and 7)
- Plasma biomarkers measured by immunoassay and including IL-1ß, IL-6, IL-8, IL-18, surfactant protein D, soluble ICAM-1, MMP8, and soluble TNF receptor-I)(Collected at randomization and as close to 0800 as possible on study days 1 2, 3, 4, and 7 or until extubation whichever occurs first)
- Fingerstick blood glucose level(every 6 hour from randomization through study day 3)
研究者
Jeffrey Hasday
Professor of Medicine
University of Maryland, Baltimore