Purpose

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 and its metabolic impact is a major complication of TH, often requiring neuromuscular blockade (NMB) to control. NMB has now become part of standard of care for patients with moderate to severe ARDS. Since many of these patients are already receiving the ultimate anti-shivering therapy, the investigators reasoned that such patients would provide an ideal population for an RCT of TH in ARDS. The investigators have completed a retrospective study of patients with ARDS on NMB and an open label pilot study of TH in 8 such patients that demonstrated feasibility and safety of performing such an RCT. Furthermore, a comparison of the subjects in the open-label study with the historical controls from the retrospective study suggested that TH will be beneficial in patients with ARDS. To generate further support for grant applications to support a Phase IIb multicenter RCT, the investigators plan on performing a small pilot single center RCT of TH (core temperature 34-35°C) for 48h vs. standard of care in patients with ARDS who are receiving NMB. Primary outcome will be 28 day ventilator-free days and secondary outcomes will include physiologic measures, mortality, hospital and ICU length of stay, and serum biomarkers collected on days 0, 1, 2, 3, 4, and 7.

Condition

Eligibility

Eligible Ages
Between 18 Years and 80 Years
Eligible Genders
All
Accepts Healthy Volunteers
No

Inclusion Criteria

for Enrollment

1. Men and women

2. Any race and ethnicity

3. 18-80 years old

4. Endotracheally intubated or have a tracheostomy in place, and mechanically ventilated

5. Admitted to a participating ICU

6. have a P/F ratio <200 with PEEP ≥5 cm H2O

7. have radiologic evidence of bilateral pulmonary infiltrates

8. Respiratory process has occurred within one week of a condition known to be associated with ARDS

9. Respiratory process cannot be fully explained by hydrostatic pulmonary edema.

10. ARDS criteria must have been initially met within 48h of enrollment

11. have a Legally authorized representative (LAR) to provide consent

Additional inclusion criteria required for randomization:

1. receiving deep sedation and NMB for ≤12h by time of randomization and who will remain on NMB for an additional ≥48h

2. have a P/F ratio <200 with PEEP ≥5 cm H2O

Exclusion Criteria

  1. Missed ARDS window (>48hrs)
  2. Missed NMB window: (>12 hrs)
  3. Missed mechanical ventilation window (>7 days)
  4. Refractory hypotension ( > 0.2 mcg/kg/min of norepinephrine or equivalent dose for a minimum of 6 h)
  5. Core temperature <35.5°C while not receiving CRRT
  6. No Legally authorized representative
  7. Significant, active bleeding (>3u blood products and/or surgical or IR intervention)
  8. Platelets <10K (uncorrected)
  9. Active hematologic malignancy
  10. Skin process precludes cooling device
  11. Moribund, not likely to survive 72h
  12. Pre-morbid condition makes it unlikely that patient will survive 28 days
  13. Do Not Resuscitate status
  14. Not likely to remain intubated for ≥48h
  15. Physician unwilling to participate
  16. Severe underlying lung disease
  17. On home O2
  18. On BIPAP (except for OSA)
  19. prior lung transplantation
  20. BMI >45
  21. Known NYHA class IV heart disease
  22. Acute Coronary Syndrome (MI, unstable angina)
  23. Cardiac arrest within 30 days of enrollment 21 Previously randomized in CHILL study

Study Design

Phase
N/A
Study Type
Interventional
Allocation
Randomized
Intervention Model
Parallel Assignment
Intervention Model Description
Randomized (1:1) control (non-blinded) trial
Primary Purpose
Treatment
Masking
None (Open Label)
Masking Description
Since it will be obvious to observers of the subjects whether they are in the treatment (cooling) or control groups, the study is not masked but all treatments that determine outcome are protocolized.

Arm Groups

ArmDescriptionAssigned Intervention
Experimental
Hypothermia
Surface temperature management to maintain core temperature between 34 and 35°C for 48, then rewarm to 36°C at 0.33°C per h.
  • Device: Hypothermia
    Subjects will be cooled using either cooling blankets or gel-pad systems to maintain core temperature 34-35°C.
Active Comparator
Standard of care
Acetaminophen and surface temperature management to maintain core temperature between 37°C and 38°C.
  • Device: Standard of Care
    Subjects who are hypothermic (<37°C) will be receive surface warming to restore core temperature to 37°C. Patients with core temperature >38°C will receive 650 mg acetaminophen and, if temperature remains >38°C, surface cooling will be initiated to return core temperature to 37-38°C.

Recruiting Locations

University of Maryland Medical Center
Baltimore, Maryland 21201
Contact:
Jeffrey D Hasday, MD
410-328-8141
jhasday@som.umaryland.edu

More Details

NCT ID
NCT03376854
Status
Recruiting
Sponsor
University of Maryland

Study Contact

Jeffrey D Hasday, MD
410-328-8141
jhasday@som.umaryland.edu

Detailed Description

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. A small non-randomized controlled trial of therapeutic hypothermia (TH) in moribund patients with septic shock and ARDS showed improved survival (3 of 9 vs. 0 of 10) in the TH group. However, the study preceded modern ARDS definition and management and mortality in both groups was much higher than current experience. Since oxygen utilization decreases ~10% per 1°C reduction in core temperature, 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. However, cooling in critically ill patients is complicated by shivering and its adverse metabolic consequences. Neuromuscular blockade (NMB) is increasingly used in patients with ARDS to facilitate low tidal volume ventilation and prone positioning and based on results of the ACURASYS trial. Since NMB is the ultimate anti-shivering treatment, such patients offer a convenient population for an initial study of TH in ARDS. A retrospective study of 58 ARDS patients treated with NMB showed that NMB alone does not cause hypothermia. An open-label study of 8 ARDS patients showed that studying TH in NMB-treated ARDS patients was feasible. In this study, the TH-treated patients had greater 28-day ventilator-free days (VFDs), ICU-free days (ICU-FDs) and hospital survival (75% vs. 25%; p = 0.027) than historical controls. Within the limits of historical comparisons, these results support further study of TH in ARDS.

Focus of Study: The focus of the Cooling to Help Injured Lungs (CHILL) program is to test the central hypothesis that TH reduces mortality and morbidity in patients with ARDS in a Phase III randomized control trial (RCT). CHILL-RCT-pilot, a single-site Phase IIb RCT of TH vs usual temperature management in NMB-treated ARDS patients is the next step toward achieving this objective. CHILL-RCT-pilot has been started as a self-funded pilot with plans to transition to an NHLBI R33/61-funded phase contingent on grant funding. The data from the single-center study will provide additional data to support and plan a larger, more definitive multicenter Phase IIb or III trial.

Primary and secondary objectives: The primary objective is to assess in an RCT whether mild TH is beneficial in patients with ARDS. The single-center pilot will provide information for planning a multicenter Phase IIb RCT TH vs. usual temperature management in patients with moderate to severe ARDS (PaO2:FIO2 (P/F) ratio<150) who are receiving NMB as part of their clinical management.

Study design: The CHILL trial is a single center RCT.

Intervention: The study intervention is TH to core temperature 34°-35°C for 48h using surface cooling devices. As a prerequisite for randomization, all patients will receive deep sedation, continuous infusion of cisatracurium and mechanical ventilation for at least 48h. Decisions about transition to unassisted breathing, extubation, and transfer from ICU will be based on criteria in the CHILL study protocol.

TH arm: Once sedation and NMB are confirmed, TH to 34°-35°C will be initiated using either cooling blankets or Arctic Sun Device based on availability. Temperature will be measured from a central probe. Once target temperature is reached, TH will be maintained for 48h. Patients will then be rewarmed to 35.5°C by 0.3°C/h and the cooling devices removed. Post-TH fever suppression is not part of the CHILL protocol. Following ~54h treatment period, patients will receive antipyretics and surface cooling or warming at the discretion of the primary ICU team. Early stopping rules for TH include: persistent severe bradycardia, uncontrolled bleeding, and intractable arrhythmias.

Usual temperature management arm: Patients will receive sedation and NMB as described for the TH arm. During the 54h post-randomization/NMB treatment period, acetaminophen will be given for core temperature >38°C and surface cooling will be initiated if core temperature remains >38°C within ≥45 minutes of receiving acetaminophen and adjusted to maintain core temperature ≤38°C. Patients in the usual temperature management arm with core temperature <36.5°C will receive surface warming to restore core temperature to 37°C. Following the 54h treatment period, patients will receive antipyretics and surface cooling or warming at the discretion of the primary ICU team.

Concomitant Treatment: Since prone positioning independently improves survival in ARDS, starting and stopping rules for prone positioning have been protocolized.

Primary and Secondary Endpoints:

Primary endpoint: 28-day VFDs. Decisions about transition to unassisted breathing will be made based on criteria in the CHILL protocol. The 28-day VFDs will be calculated at day 28.

Intermediate endpoint: The low and high core temperatures in each 2-hour period will be recorded and the mean core temperature for each of the first four study days will be calculated.

Secondary endpoints:

Clinical: (a) 28-day ICU-FDs: Decisions about transfer out of the ICU will be made based on criteria in the CHILL protocol. The 28-day ICU-FDs will be calculated at day 28 and recorded on the Day 28 case report form (CRF); (b) day 0, 1, 2, 3, 4, and 7 non-neurologic SOFA score; (c) Glasgow coma score at hospital discharge; (d) 60- and 90-day survival; (e) 60- and 90-day functional status. The Montreal Cognitive Assessment Tool (MOCA) will be administered at ICU and hospital discharge.

Physiologic: (a) day-3 and day-7 driving pressure and change vs baseline; (b) day-3 and day-7 oxygen saturation index (OSI) and change vs. baseline OSI. These measurements will be performed at the same time of day as the baseline values.

Plasma Biomarker: Day 0, 1, 2, 3, 4, and 7 plasma IL-1ß, IL-6, IL-8, IL-18, soluble-RAGE, surfactant protein-D, soluble ICAM-1, MMP8, and soluble TNFRI.

Safety:

1. For the first 54h: (a) continuous cardiac monitoring for bradycardia with associated hypotension requiring i.v. fluid or vasopressors; (b) every 6h blood glucose measurement; (c) every 12 h potassium, magnesium and phosphate; (d) significant bleeding event (requiring 2u packed red blood cells or surgical or interventional radiologic intervention)

2. First 7 days: (a) Ventilator-associated pneumonia (VAP); (b) other secondary infections; (c) monitor for SAEs

Schedule of Clinical and Laboratory Evaluations:

1. Definitions:

1. Day 0: day of enrollment

2. Comprehensive metabolic panel (CMP): includes basic electrolytes, BUN, creatinine, ALT, AST, alkaline phosphatase, bilirubin, calcium, magnesium, and phosphate

3. CBC: complete blood count

4. Driving Pressure = Plateau Pressure - PEEP with patient NOT making inspiratory effort (on NMB or post-NMB and observed RR at set ventilator rate)

5. OSI = Mean airway pressure x 100 x FIO2/SpO2

2. Clinical and Research laboratory testing: One purple top (EDTA; 7 ml blood) tube will be collected for biomarker analysis at enrollment and on study days 1, 2, 3, 4, and 7 within 4h of randomization and at 8:00-10:00 on study days 1, 2, 3, 4, and 7. Clinical laboratory testing required for secondary clinical outcomes at enrollment and on study days 1, 2, 3, 4, and will be performed as part of usual clinical care whenever possible) at 6:00-10:00 AM and 6:00-10:00 PM

3. Day -2 to 0 (Screening and enrollment): To facilitate randomization within the inclusion window, we will consent and enroll based on partial fulfillment of randomization criteria and randomize once all criteria are met. Patients with ARDS and P/F<200 for <48h will be offered enrollment but will not be randomized until P/F ratio is <150 and they begin NMB

1. Pregnancy testing in women of child-bearing years

2. Obtain informed consent from Legally Authorized Representative (LAR)

3. Complete Screening Worksheet and Screening and Enrollment CRFs

4. If patient meets randomization criteria, proceed to randomization, otherwise follow until randomization criteria are met or patient exits the inclusion window (for ARDS, mechanical ventilation, or NMB).

3. Day 0 (Randomization day): Pt. identified in screen:

1. Randomize.

2. If patient does not have a central temperature probe, place esophageal probe.

3. Confirm adequate NMB (Train of four ≤1 twitch).

4. If patient is randomized to the TH arm, initiate TH protocol.

5. Obtain baseline plasma for research testing. If >8h since last CBC and CMP, send.

h. Complete Randomization Worksheet and Randomization and Baseline Data CRFs i. Note time cooling initiated and time patient first reached target temperature on Baseline Data CRF

4.Day 1-4:

1. Fill out Daily Data CRFs

2. Collect plasma for research testing (aliquot and store at -80°C).

3. Measure Driving Pressure and OSI

4. Make sure CBC and CMP sent every 12h

5. Rewarming starts after 48h cooling on day 3

6. Complete Unassisted Breathing Checklist form if applicable

5. Days 5-6:

a. Follow for ventilator status, ICU status, survival, SAEs b. Complete Unassisted Breathing Checklist form if applicable

6. Day 7:

a. Fill out Daily Data - Day 7 CRF b. Collect plasma for research testing. c. Measure Driving Pressure and OSI d. Make sure CBC and CMP sent e. Complete Unassisted Breathing Checklist form if applicable

7. Day 8-27:

a. Follow for ventilator status, ICU status, survival, SAEs b. Complete Unassisted Breathing Checklist form if applicable

8. Day 28:

1. Complete Day 28 CRF

2. Calculate 28 day VFDs and ICU-FDs

9. When patient is discharged from the ICU, complete ICU discharge CRF

10. When patient is discharged from the hospital, complete Hospital discharge CRF (make sure to obtain contact information for follow up)

11. Day 60 and 90: Follow up about patient status. Complete phone follow-up CRF.

Study population: Adult patients with moderate to severe ARDS based on Berlin criteria <48h in duration and who are receiving NMB for ≤12h at time of randomization.

Data Analysis: The group difference on the primary outcome variable, 28-day, will be tested with a permutation test for the difference in group means with alpha = 0.05 (two-tailed). For secondary clinical outcomes, t-tests, Wilcoxon, or chi-square tests for the comparison of two proportions will be used as appropriate. Mean differences will be estimated using 95% confidence intervals for all outcomes to further inform the decision whether to recommend proceeding to as well as to plan for a multicenter Phase IIb or Phase III trial.

Data Management: Data for this pilot RCT will be recorded on paper CRFs by Drs. Hasday, Shanholtz, or their designees. Completion of all fields will be checked in real-time by Drs. Hasday and Shanholtz. The forms have been designed to allow smooth transition to electronic data management to be provided by Axio Research, LLC once funding is approved.

Randomization Plan: The investigators will use a randomization protocol stratified for proning status using pre-generated random assignment lists. Assignments will be made using an in-house Excel-based assignment tool, which blinds the observer to the assignment list.

Subject Participation Duration: The duration of intervention, TH vs. usual temperature management, is 48h, followed by rewarming for 3-6h in the TH group. NMB can be stopped 52h after enrollment in the usual temperature management control group and when subjects are rewarmed to core temperature ≥35.5°C in the TH group. Physiologic and clinical parameters will be collected through study day 7. In hospital follow-up up to 90 days will include determination of 28-day VFDs and ICU-FDs, and day of hospital discharge. When the patient regains competence, consent for continued participation will be obtained

Study Duration: Completion of enrollment is anticipated within 2 years.

Notice

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