Trial of Therapeutic Hypothermia in Patients With ARDS

Respiratory Distress Syndrome, Adult Clinical Trial

— CHILL  

Official title:

Cooling to Help Injured Lungs (CHILL) Phase IIB Randomized Control Trial of Therapeutic Hypothermia in Patients With ARDS

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT04545424
• Other study ID #: W81XWH2010432
• Status: Recruiting
• Phase: Phase 2
• Start date: June 29, 2021
• Est. completion date: September 30, 2025

Study information

• Verified date: May 2024
• Source: University of Maryland, Baltimore
• Contact: Carl B Shanholtz, MD
• Phone: 410-328-8141
• Email: cshanhol[@]som.umaryland.edu
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Description:

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.

Primary and secondary objectives: The primary objective is to assess the efficacy and safety of 48h TH+NMB in patients with ARDS compared with a control arm receiving usual temperature management. Secondary objectives include: (1) generating data to inform a decision about whether to proceed with a subsequent civilian population Phase III clinical trial of TH to reduce mortality in ARDS and to direct its study design; (2) analyzing biomarker and physiologic data to determine the mechanism(s) through which TH+NMB might exert benefit in ARDS

Study design: The CHILL trial is a multi-center RCT.

Intervention: The study intervention is TH to core temperature 34°-35°C + NMB for 48h. Patients in the TH+NMB arm will receive deep sedation, treatment with a neuromuscular blocking agent, and mechanical ventilation for at least 48h. Decisions about transition to unassisted breathing and extubation will be based on criteria in the CHILL study protocol.

TH+NMB: Once sedation and NMB are confirmed, TH to 34°-35°C will be initiated using surface cooling. 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 and will be performed at the discretion of the primary ICU team. TH+NMB will be aborted for persistent severe bradycardia with hypotension, uncontrolled bleeding, and intractable arrhythmias.

Usual temperature management: Patients will receive light sedation (RASS 0 to -1). During the 54h post-randomization 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. If core temperature ≤36°C, patients in this arm will receive surface warming to core temperature 37°C. Following the 54h treatment period, temperature will be managed at the discretion of the primary ICU team.

Concomitant Treatment: Proning and corticosteroid therapy is allowed.

Primary and Secondary Endpoints:

Primary endpoint: 28-day Ventilator-free days (VFDs). Decisions about ventilator weaning and extubation 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 for each of the first four study days. The time required to reach the target temperature and the percent of readings within the target range in the TH+NMB arm will be determined.

Secondary endpoints:

Clinical: (a) 28-day ICU-FDs: The 28-day ICU-FDs will be calculated at day 28; (b) baseline and day 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.

Physiologic: (a) day-3 and -7 driving pressure; (b) day-3 and day-7 oxygen saturation index (OSI).

Plasma Biomarker: Day 0, 1, 2, 3, 4, and 7 plasma will be collected and analyzed in the University of Maryland Cytokine Core Lab using in-house ELISAs (IL-1ß, IL-6, IL-8, IL-18, and sTNFR1) or ELISA kits purchased from R&D Systems (sRAGE, SP-D, sICAM-1, MMP8) and Helena Laboratories (Protein C).

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 ≥3u packed red blood cells or surgical or interventional radiologic intervention)

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

Schedule of Clinical and Laboratory Evaluations:

1. Definitions:

a. Baseline period: 24h prior to randomization b. Comprehensive metabolic panel (CMP):

includes basic electrolytes, BUN, creatinine, ALT, AST, alkaline phosphatase, bilirubin, calcium, magnesium, phosphate, C-reactive protein (CRP) c. CBC: complete blood count d. Driving Pressure = Plateau Pressure - PEEP with patient NOT making inspiratory effort (on NMB or post-NMB and observed RR at set ventilator rate) e. OSI = Mean airway pressure x 100 x FIO2/SpO2

2. Clinical and Research laboratory testing: Two purple/pink top tubes (EDTA; 12 ml blood total) will be collected for biomarker analysis just prior to randomization and as close to 0800 as possible on study days 1, 2, 3, 4, and 7 . Clinical laboratory testing required for secondary clinical outcomes at baseline and on study days 1, 2, 3, 4, and will be performed as part of usual clinical care whenever possible).

3. Day -7 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 between 18 and 75 years old receiving mechanical ventilation for ≤7 days will be screened and those who have bilateral pulmonary opacities not fully explained by pleural effusions, atelectasis, or hydrostatic pulmonary edema and a qualifying P/F ratio (P/F ≤200 with PEEP ≥8) for <72h will be enrolled and randomized. Patients who meet the criteria for pulmonary opacities but have not yet had a qualifying P/F ratio may be enrolled and monitored for potential randomization.

1. Pregnancy testing in women of child-bearing years

2. Obtain informed consent from patient or Legally Authorized Representative (LAR) depending on capacity

3. Complete the screening and enrollment portion of the Screening, Enrollment and Randomization CRF.

4. Enter data into the Medidata CHILL database, which will assign a unique subject ID.

5. The subject ID and patient identifiers are entered into a secure screening log.

3. Randomization:

1. If the patient has had a qualifying P/F ratio at the time of enrollment, proceed with randomization, otherwise follow until the patient has a qualifying P/F ratio, exits the 48h NMBA window or the 7 day mechanical ventilation window, or develops an exclusion.

2. Once patient meets criterion for randomization:

i. Obtain baseline plasma for research testing. If >24h since last CBC and CMP, send new samples to lab.

ii. Obtain treatment assignment from the automated, web-based randomization service provided by Cooperative Studies Program Coordinating Center (CSPCC).

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

iv. For TH+NMB arm, confirm adequate sedation (RASS -4 to -5) and NMBA(Train of four ≤2 twitch) and initiate TH protocol using surface cooling as soon as possible.

v. Complete the randomization section of the Screening, Enrollment, and Randomization CRF vi. Complete Baseline CRF

4.Day 1-4:

1. Fill out Daily CRFs and enter into Medidata database

2. Collect plasma for research testing.

3. Measure Driving Pressure and OSI

4. Make sure CBC and CMP sent every morning and a subsequent BMP, magnesium, and phosphate sent ~12h later.

5. Rewarming starts 48h after initially reaching target temperature (34°-35°C) on day 3

6. Complete Unassisted Breathing Checklist form if applicable

7. Assess for adverse events

5. Days 5-6:

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

6. Day 7:

1. Fill out Day 7 CRF and enter into Medidata database

2. Collect plasma for research testing.

3. Measure Driving Pressure and OSI

4. Make sure CBC are CMP sent

5. Complete Unassisted Breathing Checklist form if applicable

6. Assess for adverse events

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.

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 (P/F ≤ 200 while on PEEP ≥8 cm H2O) <72h in duration.

Data Analysis (see protocol for full description): Primary and secondary analyses will be performed according to the principle of intention-to-treat. The randomization is stratified only by site, which will be accounted for in the primary efficacy analysis. Three interim analyses will be performed after ~25%, ~50%, and ~75% of planned enrollment and a decision to halt the study for efficacy or harm will be made.

Primary and Secondary efficacy endpoints will be analyzed using Wilcoxon-Mann-Whitney rank sum test extended to account for stratification by site. Sub-group analysis will test for significant interaction between treatment effect and a priori established baseline characteristics (proning status, shock, COVID, P/F ratio, age, time between meeting ARDS criteria and randomization, and baseline biomarkers (IL-6, bicarb, and protein C)).

Data Management (see protocol for full description): Data for this RCT will be recorded on paper CRFs and entered into the Medidata database containing multiple automatic crosschecks.

Randomization Plan: Patients will be randomized by the web-based automated system operated by CSPCC using a 1:1 assignment ratio in small blocks of randomly varying size prepared for each site.

Subject Participation Duration: The duration of intervention is ~54h including time for cool down and rewarming. Physiologic and clinical parameters will be collected through study day 7. In hospital follow-up will include determination of 28-day VFDs and ICU-FDs, and day of hospital discharge and 60- and 90-day phone follow-up. When the patient regains competence, consent for continued participation will be obtained.

Study Duration: Completion of enrollment is anticipated by March 31, 2025 and study completion by July 1, 2025.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 340
• Est. completion date: September 30, 2025
• Est. primary completion date: June 3, 2025
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 75 Years

Eligibility

Inclusion Criteria:

1. endotracheal tube or tracheostomy in place and mechanically ventilated for =7 days;

2. admitted to a participating ICU

3. radiologic evidence of bilateral pulmonary infiltrates not fully explained by pleural effusions, atelectasis, or hydrostatic pulmonary edema

4. 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:

1. SpO2 values are 80-96%

2. SpO2 is measured =10 min after any change in FIO2

3. PEEP is = 8 cm H2O

4. the pulse oximeter waveform tracing is adequate

5. the qualifying inferred P/F ratio is confirmed 1-6h after initial determination.

5. access to an LAR to provide consent.

6. 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.

Exclusion Criteria:

1. 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 = 0.6.

2. Missed NMB window: (>48 hrs)

3. Missed mechanical ventilation window (>7 days)

4. Refractory hypotension (continuous infusion of >0.3 mcg/kg/min of norepinephrine or equivalent dose of other vasopressors within 2 hours prior to randomization)

5. Core temperature <35.5°C for =6 hours while not receiving CRRT on day of randomization

6. Significant, active bleeding (>3u blood products and/or surgical/IR intervention) on day of randomization

7. Platelets <10K/mm3 (uncorrected) on day of randomization

8. Active hematologic malignancy

9. Skin process that precludes cooling device

10. Moribund, not likely to survive 72h

11. Pre-morbid condition makes it unlikely that patient will survive 28 days

12. Do Not Resuscitate status at time of randomization (excluding patients receiving full support EXCEPT CPR for cardiac arrest)

13. Not likely to remain intubated for =48h

14. Physician of record unwilling to participate

15. Severe underlying lung disease

1. Needs > 2 LPM or >28% continuous home O2 (adjusted for altitude)

2. On BIPAP (except for OSA)

3. Prior lung transplantation

16. Pregnant at time of randomization

17. BMI consistently >50 kg/m2

18. Known NYHA class IV heart disease

19. Acute Coronary Syndrome (MI, unstable angina) within 30 days of randomization

20. Cardiac arrest within 30 days of randomization

21. Burns over >20% of the body surface

22. Severe chronic liver disease (Child-Pugh score 12-15)

23. Previously randomized in CHILL study

24. Simultaneous enrollment in another inpatient interventional trial started during the current hospitalization.

25. On ECMO during the current hospitalization.

Related Conditions & MeSH terms

• Acute Lung Injury
• Hypothermia
• Respiratory Distress Syndrome
• Respiratory Distress Syndrome, Adult
• Respiratory Distress Syndrome, Newborn

Intervention

Device:
• Hypothermia
Subjects will be cooled using either cooling blankets or gel-pad systems to maintain core temperature 34-35°C.

Drug:
• Neuromuscular Blocking Agents
Subjects in the TH + NMB arm will be deeply sedated using agents at the discretion of the primary ICU team, then start continuous iv infusion of either cisatracurium, atracurium, or vecuronium titrated to 2 twitches on train of four monitoring and further titrated to ablate visible shivering.

Device:
• Standard of care
Subjects who are hypothermic (=36°C) during CRRT will 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.

Locations

Country	Name	City	State
United States	Emory University	Atlanta	Georgia
United States	Johns Hopkins Hospital	Baltimore	Maryland
United States	University of Maryland Medical Center	Baltimore	Maryland
United States	Cooper Health System	Camden	New Jersey
United States	Loyola University Chicago	Chicago	Illinois
United States	Rush University Medical Center	Chicago	Illinois
United States	Cleveland Clinc	Cleveland	Ohio
United States	Brooke Army Medical Center	Fort Sam Houston	Texas
United States	University of Wisconsin	Madison	Wisconsin
United States	Yale University	New Haven	Connecticut
United States	Temple University	Philadelphia	Pennsylvania
United States	Thomas Jefferson University	Philadelphia	Pennsylvania
United States	University of Pennsylavia	Philadelphia	Pennsylvania
United States	Oregon Health & Science University	Portland	Oregon
United States	Intermountain Healthcare (Utah)	Salt Lake City	Utah

Sponsors (4)

Lead Sponsor	Collaborator
University of Maryland, Baltimore	KAI Research, United States Department of Defense, US Department of Veterans Affairs Cooperative Studies Program

Country where clinical trial is conducted

United States, 

References & Publications (40)

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Manthous CA, Hall JB, Olson D, Singh M, Chatila W, Pohlman A, Kushner R, Schmidt GA, Wood LD. Effect of cooling on oxygen consumption in febrile critically ill patients. Am J Respir Crit Care Med. 1995 Jan;151(1):10-4. doi: 10.1164/ajrccm.151.1.7812538. — View Citation

Nagarsekar A, Tulapurkar ME, Singh IS, Atamas SP, Shah NG, Hasday JD. Hyperthermia promotes and prevents respiratory epithelial apoptosis through distinct mechanisms. Am J Respir Cell Mol Biol. 2012 Dec;47(6):824-33. doi: 10.1165/rcmb.2012-0105OC. Epub 2012 Sep 6. — View Citation

National Heart, Lung, and Blood Institute PETAL Clinical Trials Network; Moss M, Huang DT, Brower RG, Ferguson ND, Ginde AA, Gong MN, Grissom CK, Gundel S, Hayden D, Hite RD, Hou PC, Hough CL, Iwashyna TJ, Khan A, Liu KD, Talmor D, Thompson BT, Ulysse CA, Yealy DM, Angus DC. Early Neuromuscular Blockade in the Acute Respiratory Distress Syndrome. N Engl J Med. 2019 May 23;380(21):1997-2008. doi: 10.1056/NEJMoa1901686. Epub 2019 May 19. — View Citation

Papazian L, Forel JM, Gacouin A, Penot-Ragon C, Perrin G, Loundou A, Jaber S, Arnal JM, Perez D, Seghboyan JM, Constantin JM, Courant P, Lefrant JY, Guerin C, Prat G, Morange S, Roch A; ACURASYS Study Investigators. Neuromuscular blockers in early acute respiratory distress syndrome. N Engl J Med. 2010 Sep 16;363(12):1107-16. doi: 10.1056/NEJMoa1005372. — View Citation

Peng CK, Huang KL, Wu CP, Li MH, Lin HI, Hsu CW, Tsai SH, Chu SJ. The role of mild hypothermia in air embolism-induced acute lung injury. Anesth Analg. 2010 May 1;110(5):1336-42. doi: 10.1213/ANE.0b013e3181d27e90. — View Citation

Potla R, Singh IS, Atamas SP, Hasday JD. Shifts in temperature within the physiologic range modify strand-specific expression of select human microRNAs. RNA. 2015 Jul;21(7):1261-73. doi: 10.1261/rna.049122.114. Epub 2015 May 27. — View Citation

Rice P, Martin E, He JR, Frank M, DeTolla L, Hester L, O'Neill T, Manka C, Benjamin I, Nagarsekar A, Singh I, Hasday JD. Febrile-range hyperthermia augments neutrophil accumulation and enhances lung injury in experimental gram-negative bacterial pneumonia. J Immunol. 2005 Mar 15;174(6):3676-85. doi: 10.4049/jimmunol.174.6.3676. — View Citation

Shah NG, Cowan MJ, Pickering E, Sareh H, Afshar M, Fox D, Marron J, Davis J, Herold K, Shanholtz CB, Hasday JD. Nonpharmacologic approach to minimizing shivering during surface cooling: a proof of principle study. J Crit Care. 2012 Dec;27(6):746.e1-8. doi: 10.1016/j.jcrc.2012.04.016. Epub 2012 Jul 2. — View Citation

Shah NG, Tulapurkar ME, Damarla M, Singh IS, Goldblum SE, Shapiro P, Hasday JD. Febrile-range hyperthermia augments reversible TNF-alpha-induced hyperpermeability in human microvascular lung endothelial cells. Int J Hyperthermia. 2012;28(7):627-35. doi: 10.3109/02656736.2012.690547. Epub 2012 Jul 26. — View Citation

Slack DF, Corwin DS, Shah NG, Shanholtz CB, Verceles AC, Netzer G, Jones KM, Brown CH, Terrin ML, Hasday JD. Pilot Feasibility Study of Therapeutic Hypothermia for Moderate to Severe Acute Respiratory Distress Syndrome. Crit Care Med. 2017 Jul;45(7):1152-1159. doi: 10.1097/CCM.0000000000002338. — View Citation

Tang ZH, Hu JT, Lu ZC, Ji XF, Chen XF, Jiang LY, Zhang C, Jiang JS, Pang YP, Li CQ. Effect of mild hypothermia on the expression of toll-like receptor 2 in lung tissues with experimental acute lung injury. Heart Lung Circ. 2014 Dec;23(12):1202-7. doi: 10.1016/j.hlc.2014.05.016. Epub 2014 Jun 24. — View Citation

Tulapurkar ME, Almutairy EA, Shah NG, He JR, Puche AC, Shapiro P, Singh IS, Hasday JD. Febrile-range hyperthermia modifies endothelial and neutrophilic functions to promote extravasation. Am J Respir Cell Mol Biol. 2012 Jun;46(6):807-14. doi: 10.1165/rcmb.2011-0378OC. Epub 2012 Jan 26. — View Citation

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* Note: There are 40 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	28-day ventilator-free days (VFDs)	Total number of days alive and not on a ventilator in the first 28 days after enrollment	Calculated at study day 28 or death (whichever occurs first)
Secondary	28-day ICU-free days	Total number of days alive and not admitted to the ICU in the first 28 days after	Calculated at study day 28 or death (whichever occurs first)
Secondary	Survival	28-day, 60-day, and 90-day mortality	calculated at 28, 60, and 90 days
Secondary	non neurologic Sequential Organ Failure (SOFA) scores	SOFA score excluding neurologic component - based on PaO2/FiO2 (0-4), BP and pressor requirement (0-4), bilirubin level (0-4), platelet count (0-4), and creatinine (0-14) with total composite score 0-20	At enrollment and study days 1, 2, 3, 4, 7, and 28
Secondary	Oxygen saturation (SpO2)	Pulse ox reading	Measured at enrollment, every 2 hours on enrollment day, then once on day 2, 3, 4, 7 and 28
Secondary	Plateau airway pressure	On ventilator-imitated breath; measured at enrollment, every 4 hours on enrollment day, then Measured at randomization and daily on study days 1, 2, 3, 4, and 7 or until extubation whichever occurs firstinitiated breath	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
Secondary	Mean airway pressure	Measured from ventilator during machine initiated breath	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
Secondary	Airway driving pressure	Plateau pressure - PEEP (machine initiated breath)	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
Secondary	Oxygen saturation index	Mean airway pressure x 100 x FiO2/SpO2	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
Secondary	Core temperature	Measured continuously from iv catheter, urinary catheter, or esophageal probe.	Measured continuously and recorded at randomization and then every 2 hours through study day 4
Secondary	Urine output	24 hour urine volume	Daily on study day 1, 2, 3, 4, and 7
Secondary	comprehensive metabolic panel blood test (includes sodium, potassium, chloride, bicarb, BUN, creatinine, glucose, albumin, total protein, AST, SLT, alkaline phosphatase, and bilirubin)	7 ml of blood collected in serum separator tubes; assay preformed in clinical lab	At randomization and each morning on study days 1, 2, 3, 4, and 7
Secondary	Complete blood count with differential count and platelet count	7 ml of blood collected in purple top tube; assay preformed in clinical lab	At randomization and each morning on study days 1, 2, 3, 4, and 7
Secondary	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)	12 ml blood draw in two green top tubes	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
Secondary	Serum electrolytes	performed in clinical lab	Performed each evening on study days 1, 2, and 3
Secondary	Fingerstick blood glucose level	POC blood glucose testing performed at bedside	every 6 hour from randomization through study day 3