Design and rationale of the CHILL phase II trial of hypothermia and neuromuscular blockade for acute respiratory distress syndrome

doi:10.1016/j.conctc.2023.101155

. 2023 Jun:33:101155.

doi: 10.1016/j.conctc.2023.101155. Epub 2023 May 18.

Design and rationale of the CHILL phase II trial of hypothermia and neuromuscular blockade for acute respiratory distress syndrome

Carl B Shanholtz¹, Michael L Terrin², Thelma Harrington¹, Caleb Chan¹, Whittney Warren³, Robert Walter³, Faith Armstrong⁴, Jeffrey Marshall⁴, Rachel Scheraga⁵, Abjihit Duggal⁵, Perry Formanek⁶, Michael Baram⁷, Majid Afshar⁸, Nathaniel Marchetti⁹, Sunit Singla¹⁰, John Reilly¹¹, Dan Knox¹², Nitin Puri¹³, Kevin Chung¹⁴, Clayton H Brown², Jeffrey D Hasday¹

Affiliations

¹ Department of Medicine, University of Maryland School of Medicine, Baltimore, MD, USA.
² Department of Epidemiology & Public Health, University of Maryland School of Medicine, Baltimore, MD, USA.
³ Department of Pulmonary and Critical Care Medicine, Brooke Army Medical Center, San Antonio, TX, USA.
⁴ Baltimore Washington Medical Center, Glen Burnie, MD, USA.
⁵ Respiratory Institute, Cleveland Clinic, Cleveland, OH, USA.
⁶ Department of Medicine, Loyola University Medical Center, Maywood, IL, USA.
⁷ Department of Medicine, Sidney Kimmel College of Medicine USA, Philadelphia, PA, USA.
⁸ Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA.
⁹ Department of Thoracic Medicine and Surgery, Lewis Katz School of Medicine at Temple University, Philadelphia, PA, USA.
¹⁰ Division of Pulmonary, Critical Care, Sleep, and Allergy Medicine, University of Illinois at Chicago, Chicago, IL, USA.
¹¹ Department of Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.
¹² Division of Pulmonary and Critical Care Medicine, Intermountain Medical Center, Murray, UT, USA.
¹³ Division of Critical Care, Cooper University Health Care, USA.
¹⁴ Department of Medicine, F. Edward Hebert School of Medicine, Uniformed Services University of the Health Sciences, Bethesda, MD, USA.

PMID: 37228902
PMCID: PMC10191700
DOI: 10.1016/j.conctc.2023.101155

Design and rationale of the CHILL phase II trial of hypothermia and neuromuscular blockade for acute respiratory distress syndrome

Carl B Shanholtz et al. Contemp Clin Trials Commun. 2023 Jun.

. 2023 Jun:33:101155.

doi: 10.1016/j.conctc.2023.101155. Epub 2023 May 18.

Authors

Affiliations

¹ Department of Medicine, University of Maryland School of Medicine, Baltimore, MD, USA.
² Department of Epidemiology & Public Health, University of Maryland School of Medicine, Baltimore, MD, USA.
³ Department of Pulmonary and Critical Care Medicine, Brooke Army Medical Center, San Antonio, TX, USA.
⁴ Baltimore Washington Medical Center, Glen Burnie, MD, USA.
⁵ Respiratory Institute, Cleveland Clinic, Cleveland, OH, USA.
⁶ Department of Medicine, Loyola University Medical Center, Maywood, IL, USA.
⁷ Department of Medicine, Sidney Kimmel College of Medicine USA, Philadelphia, PA, USA.
⁸ Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA.
⁹ Department of Thoracic Medicine and Surgery, Lewis Katz School of Medicine at Temple University, Philadelphia, PA, USA.
¹⁰ Division of Pulmonary, Critical Care, Sleep, and Allergy Medicine, University of Illinois at Chicago, Chicago, IL, USA.
¹¹ Department of Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.
¹² Division of Pulmonary and Critical Care Medicine, Intermountain Medical Center, Murray, UT, USA.
¹³ Division of Critical Care, Cooper University Health Care, USA.
¹⁴ Department of Medicine, F. Edward Hebert School of Medicine, Uniformed Services University of the Health Sciences, Bethesda, MD, USA.

PMID: 37228902
PMCID: PMC10191700
DOI: 10.1016/j.conctc.2023.101155

Abstract

The Cooling to Help Injured Lungs (CHILL) trial is an open label, two group, parallel design multicenter, randomized phase IIB clinical trial assessing the efficacy and safety of targeted temperature management with combined external cooling and neuromuscular blockade to block shivering in patients with early moderate-severe acute respiratory distress syndrome (ARDS). This report provides the background and rationale for the clinical trial and outlines the methods using the Consolidated Standards of Reporting Trials guidelines. Key design challenges include: [1] protocolizing important co-interventions; [2] incorporation of patients with COVID-19 as the cause of ARDS; [3] inability to blind the investigators; and [4] ability to obtain timely informed consent from patients or legally authorized representatives early in the disease process. Results of the Reevaluation of Systemic Early Neuromuscular Blockade (ROSE) trial informed the decision to mandate sedation and neuromuscular blockade only in the group assigned to therapeutic hypothermia and proceed without this mandate in the control group assigned to a usual temperature management protocol. Previous trials conducted in National Heart, Lung, and Blood Institute ARDS Clinical Trials (ARDSNet) and Prevention and Early Treatment of Acute Lung Injury (PETAL) Networks informed ventilator management, ventilation liberation and fluid management protocols. Since ARDS due to COVID-19 is a common cause of ARDS during pandemic surges and shares many features with ARDS from other causes, patients with ARDS due to COVID-19 are included. Finally, a stepwise approach to obtaining informed consent prior to documenting critical hypoxemia was adopted to facilitate enrollment and reduce the number of candidates excluded because eligibility time window expiration.

Keywords: Acute respiratory distress syndrome; Neuromuscular blockade; Randomized controlled trial; Therapeutic hypothermia.

PubMed Disclaimer

Conflict of interest statement

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Cited by

Hypothermia protects against ventilator-induced lung injury by limiting IL-1β release and NETs formation.
Nosaka N, Borges V, Martinon D, Crother TR, Arditi M, Shimada K. Nosaka N, et al. Elife. 2025 Jun 24;14:RP101990. doi: 10.7554/eLife.101990. Elife. 2025. PMID: 40553503 Free PMC article.

References

1. Ranieri V.M., Rubenfeld G.D., Thompson B.T., Ferguson N.D., Caldwell E., Fan E., Camporota L., Slutsky A.S. Acute respiratory distress syndrome: the Berlin Definition. JAMA, J. Am. Med. Assoc. 2012;307:2526–2533. - PubMed
1. Tschumperlin D.J., Oswari J., Margulies A.S. Deformation-induced injury of alveolar epithelial cells. Effect of frequency, duration, and amplitude. Am. J. Respir. Crit. Care Med. 2000;162:357–362. - PubMed
1. Webb H.H., Tierney D.F. Experimental pulmonary edema due to intermittent positive pressure ventilation with high inflation pressures. Protection by positive end-expiratory pressure. Am. Rev. Respir. Dis. 1974;110:556–565. - PubMed
1. Dreyfuss D., Soler P., Basset G., Saumon G. High inflation pressure pulmonary edema. Respective effects of high airway pressure, high tidal volume, and positive end-expiratory pressure. Am. Rev. Respir. Dis. 1988;137:1159–1164. - PubMed
1. The Acute Respiratory Distress Syndrome Network Ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury and the acute respiratory distress syndrome. The Acute Respiratory Distress Syndrome Network. N. Engl. J. Med. 2000;342:1301–1308. - PubMed

Grants and funding

LinkOut - more resources

Full Text Sources

[1] Ranieri V.M., Rubenfeld G.D., Thompson B.T., Ferguson N.D., Caldwell E., Fan E., Camporota L., Slutsky A.S. Acute respiratory distress syndrome: the Berlin Definition. JAMA, J. Am. Med. Assoc. 2012;307:2526–2533. - PubMed

[2] Ranieri V.M., Rubenfeld G.D., Thompson B.T., Ferguson N.D., Caldwell E., Fan E., Camporota L., Slutsky A.S. Acute respiratory distress syndrome: the Berlin Definition. JAMA, J. Am. Med. Assoc. 2012;307:2526–2533. - PubMed

[3] Tschumperlin D.J., Oswari J., Margulies A.S. Deformation-induced injury of alveolar epithelial cells. Effect of frequency, duration, and amplitude. Am. J. Respir. Crit. Care Med. 2000;162:357–362. - PubMed

[4] Tschumperlin D.J., Oswari J., Margulies A.S. Deformation-induced injury of alveolar epithelial cells. Effect of frequency, duration, and amplitude. Am. J. Respir. Crit. Care Med. 2000;162:357–362. - PubMed

[5] Webb H.H., Tierney D.F. Experimental pulmonary edema due to intermittent positive pressure ventilation with high inflation pressures. Protection by positive end-expiratory pressure. Am. Rev. Respir. Dis. 1974;110:556–565. - PubMed

[6] Webb H.H., Tierney D.F. Experimental pulmonary edema due to intermittent positive pressure ventilation with high inflation pressures. Protection by positive end-expiratory pressure. Am. Rev. Respir. Dis. 1974;110:556–565. - PubMed

[7] Dreyfuss D., Soler P., Basset G., Saumon G. High inflation pressure pulmonary edema. Respective effects of high airway pressure, high tidal volume, and positive end-expiratory pressure. Am. Rev. Respir. Dis. 1988;137:1159–1164. - PubMed

[8] Dreyfuss D., Soler P., Basset G., Saumon G. High inflation pressure pulmonary edema. Respective effects of high airway pressure, high tidal volume, and positive end-expiratory pressure. Am. Rev. Respir. Dis. 1988;137:1159–1164. - PubMed

[9] The Acute Respiratory Distress Syndrome Network Ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury and the acute respiratory distress syndrome. The Acute Respiratory Distress Syndrome Network. N. Engl. J. Med. 2000;342:1301–1308. - PubMed

[10] The Acute Respiratory Distress Syndrome Network Ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury and the acute respiratory distress syndrome. The Acute Respiratory Distress Syndrome Network. N. Engl. J. Med. 2000;342:1301–1308. - PubMed

Save citation to file

Email citation

Add to Collections

Add to My Bibliography

Your saved search

Create a file for external citation management software

Your RSS Feed

Design and rationale of the CHILL phase II trial of hypothermia and neuromuscular blockade for acute respiratory distress syndrome

Affiliations

Design and rationale of the CHILL phase II trial of hypothermia and neuromuscular blockade for acute respiratory distress syndrome

Authors

Affiliations

Abstract

Conflict of interest statement

Similar articles

Cited by

References

Grants and funding

LinkOut - more resources

Full Text Sources

Abstract

Conflict of interest statement

Similar articles

Cited by

References

Related information

Grants and funding

LinkOut - more resources

Full Text Sources