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.

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.

Respiratory Distress Syndrome, Adult

Sars-CoV2

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

Hypothermia

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.

Neuromuscular Blocking Agents

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.

Standard of Care

University of Maryland Medical Center

Pilot RCT of Therapeutic Hypothermia Plus Neuromuscular Blockade in COVID-19 Patients With ARDS

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

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.

Adverse events expected during cooling, including hemorrhage, bradycardia, and hypotension.

Total number of days alive and not admitted to the ICU in the first 28 days after

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

Direct ventilator measurement on machine initiated breath

Plateau pressure - PEEP (machine initiated breath)

Measured continuously from iv catheter, urinary catheter, or esophageal probe.

Total number of days alive and not on a ventilator in the first 28 days after enrollment

At the completion of the study, Dr. Hasday and colleagues will present the results of the long-term outcomes at national meetings and publish them in peer-reviewed journals and in ClinicalTrials.gov. Within one year of the publication of the main trial data (whichever occurs first, Dr. Hasday will make de-identified study data available to any individual who presents an appropriate question and analysis plan. The available information will include 1) descriptive documents (e.g. study protocol, code book/variable dictionary, data collection instruments, and de-identification methodology), and 2) de-identified data file.

Jeffrey Hasday

Professor of Medicine

University of Maryland, Baltimore

Randomized (1:1) control (non-blinded) trial

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.

Oral ambrisentan 2.5 - 5 mg, single dose, once daily

Oral placebo 2.5 - 5 mg, single dose, once daily

Oral ambrisentan 2.5 - 5 mg, single dose, once daily
Ambrisentan: Once daily oral dosing

Ambrisentan

Oral placebo 2.5 - 5 mg, single dose, once daily
Placebo

Placebo

Total

Sex: Female, Male

Ethnicity (NIH/OMB)

Race (NIH/OMB)

Region of Enrollment

Plasma samples collected at 0-1,1-6,18-30 and 40-60 hours after administration of the first ambrisentan dose.

Area Under the Curve for Ambrisentan Plasma Concentration

Hemodynamic data, including Fontan pressures, common atrial pressures and saturations, will be collected at the specified timepoints. Pressures and saturations will be measured from existing monitoring lines. Standard Fick calculations will be used to calculate pulmonary vascular resistance (calculated as trans-pulmonary gradient [Fontan pressure - atrial pressure] / pulmonary blood flow [Qp]) and reported in Wood Units x m^2.

Change in Pulmonary Vascular Resistance Index

Total chest tube drainage in mL in first 96hrs after Fontan

Amount of Chest Tube Drainage Post Fontan Operation

Chest tube duration will be calculated as the number of days from placement to removal.

pleural effusion/kalium

Pilot RCT of Therapeutic Hypothermia Plus Neuromuscular Blockade in COVID-19 Patients With ARDS

Ambrisentan in Single Ventricle

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