Lung-cOnservative Liquid VEntilation for the Induction of Ultra-Rapid COOLing After Cardiac Arrest (OverCool)

Out-of-hospital cardiac arrest (OHCA) affects over 356,000 individuals annually in the United States, with fewer than 10% surviving to hospital discharge, mirroring statistics from Europe. Post-cardiac arrest syndrome (PCAS), a condition causing multi-organ dysfunction, is a leading cause of mortality despite successful resuscitation efforts. Targeted temperature management (TTM) is recommended for comatose patients post-resuscitation to mitigate PCAS, but optimal temperature targets and cooling methods remain unclear. Experimental studies suggest that therapeutic hypothermia (32-34°C), induced rapidly after resuscitation, may provide significant clinical benefits.

Total liquid ventilation (TLV) with breathable liquids has been proposed to achieve ultra-rapid therapeutic hypothermia (URTH). This approach uses the lungs as a heat exchanger to achieve ultra-rapid cooling while maintaining normal gas exchange. It enables a reduction in core body temperature to the hypothermic range (33.0 ± 0.5°C) within 45 minutes in relevant experimental models.

The OverCool study is an open-label, single-arm, multi-centric pilot trial designed to evaluate the performance and safety of Vent2Cool, a medical device intended to induce ultra-rapid therapeutic hypothermia by TLV in resuscitated cardiac arrest patients. The primary objective is to demonstrate Vent2Cool's ability to achieve a target core temperature of 33.0 ± 0.5°C within 60 minutes from start of procedure in resuscitated patients admitted to the Intensive Care Unit following intra- or extra-hospital cardiac arrest. Secondary objectives include assessing procedural safety, cooling performance, feasibility in emergency settings, clinical outcomes, and the impact on biological markers.

Study Overview

• Status: Not yet recruiting
• Conditions: Cardiac Arrest; Post Cardiac Arrest Syndrome
• Intervention / Treatment: Device: Ultra-rapid therapeutic hypothermia induction by total liquid ventilation

Detailed Description

The "American Heart Association's 2022 Update" estimates that over 356,000 out-of-hospital cardiac arrests (OHCA) occur annually in the United States. These figures are consistant with data from European countries, where fewer than 10% of OHCA patients survive, despite 30% being successfully resuscitated before admission to intensive care units (ICU). The majority of these patients succumb to post-cardiac arrest syndrome (PCAS), a condition characterized by multi-organ failure.

To mitigate the severity of PCAS, current guidelines recommend continuous core temperature monitoring and active fever prevention through targeted temperature management (TTM) in patients who remain comatose following resuscitation from cardiac arrest. While TTM with a target temperature range of 32-36°C has been previously evaluated and applied in specific subpopulations, there is insufficient evidence to universally recommend one target temperature over another within this range. Conversely, experimental studies have demonstrated that the protective effects of therapeutic hypothermia (32-34°C) are strongly influenced by the rate of cooling initiated after resuscitation. These findings suggest that very early application of hypothermia may provide greater benefits compared to simply avoiding fever, emphasizing the importance of timely intervention.

In this context, Total Liquid Ventilation (TLV) with breathable liquids has been investigated in animal studies as a method to achieve ultra-rapid therapeutic hypothermia (URTH) following cardiac arrest. This innovative approach uses the lungs as a potent heat exchanger to achieve ultra-rapid cooling while preserving normal gas exchanges. TLV has demonstrated the capability to lower body core temperature from normothermia to the hypothermic range within 45 minutes, irrespective of body weight, in relevant experimental models. Furthermore, unlike earlier techniques of partial liquid ventilation, this method employs a lung-conservative liquid ventilation approach, which has been shown to be safe. The objective of the present OverCool study is to evaluate the performance and safety of the Vent2Cool device, designed to induce URTH by TLV safely following cardiac arrest.

Accordingly, OverCool is an open-label, single arm, non-comparative, multi-centric pilot study. The study primary objective is to demonstrate the ability of Vent2Cool to achieve a core body temperature of 33.0±0.5°C in less than 60 min after the start of the procedure in resuscitated patients admitted in the ICU after an intra- or extra-hospital cardiac arrest. The main secondary objectives are to demonstrate the safety of the procedure, the cooling performance, the ability to implement the procedure in the emergency setting of post-cardiac arrest management, the clinical outcomes and impact on biological markers.

• Study Type: Interventional
• Enrollment (Estimated): 24
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Sandrine Perrotto, PhD; Phone Number: +33187666102; Email: clinical.affairs@orixha.com
• Study Contact Backup: Name: Fabrice Paublant; Phone Number: +33660767729; Email: paublant@orixha.com

Study Locations

• France
  • Paris, France, 75014
    • Hopital Cochin - Service de Medecine intensive et reanimation au 27 rue du Faubourg Saint-Jacques
    • Contact: Alain Cariou, M.D.

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Patient resuscitated after extra- or intra-hospital cardiac arrest, from presumed cardiac or asphyxial origin, regardless of the heart rate initially recorded.
• Age between 18 and 84 years old
• Time between collapse and return of spontaneous circulation (ROSC) < 60 min
• Presumption, at the time of inclusion, of a possibility of starting Vent2Cool within a period of less than 120 min after ROSC.
• Unconscious (GCS <8, not able to obey verbal commands after sustained ROSC)
• Patient affiliated with a social security system (If applicable)
• Consent of the member of patients' family or that of the trusted person if present and able to understand; otherwise certificate of emergency inclusion in compliance with applicable regulations.
• Vent2Cool must be connected to a standard cuffed ETT of 7.0 mm to 9.0 mm internal diameter for the procedure.

Exclusion Criteria:

• Conscious patient
• Patient Ideal Body Weight less than 40 kgs or more than 93 kgs
• Traumatic cardiac arrest, drowning, exsanguination, or sepsis
• Temperature at admission < 34.0°C
• Need for veno-arterial extracorporeal circulation (Extracorporeal membrane of oxygenation, ECMO) before return of spontaneous circulation (refractory cardiac arrest)

• One of the following signs at echocardiography at hospital admission:

  • Acute cor pulmonale, defined by right ventricular enlargement with interventricular septal deviation, associated with a Tricuspid Annular Plane Systolic Excursion (TAPSE) < 12 mm and need for vasopressor agents
  • Time-velocity integral of subaortic flow < 10 m/s
• Wrong positioning or damage of the endotracheal tube.
• Women under 50 years old (childbearing age) or for women of >50 years old, a positive pregnancy test (urinary) in case of pregnancy suspicion by the investigator. Possible breastfeeding during the study.
• Suspicion of intracranial bleeding
• History of severe Chronic Obstructive Pulmonary Disease (COPD) with long-term home oxygen therapy
• Acute respiratory pathology (pneumothorax, pleurisy, pneumonia, suspicion of contusion or intra-pulmonary hemorrhage following resuscitation)
• COVID-19 positive test in case of clinical suspicion and/or epidemic context
• Excessive mucus in the upper airways

• Patient presenting at least one of the following criteria in the mechanical ventilation parameters at inclusion:

  • PEEP > 8 cm H2O
  • Plateau pressure> 25 cmH2O
  • Driving pressure> 15cmH2O

• Patient with at least one of the following criteria at inclusion:

  • PaO2< 80 mmHg
  • PaO2 / FiO2< 150 mmHg
  • PaCO2> 48 mmHg

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Treatment with Vent2Cool device; Vent2Cool is to be used to perform induction of Ultra-Rapid Therapeutic Hypothermia for the patients. The hypothermia maintenance and rewarming phases will be performed with an external TTM device as currently used in the investigation centres.	Device: Ultra-rapid therapeutic hypothermia induction by total liquid ventilation; Vent2Cool System is a targeted temperature management device used to induce ultra-rapid therapeutic hypothermia by total liquid ventilation.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Success rate of the Vent2Cool procedure (safe induction of ultra-rapid therapeutic hypothermia)	The primary end point is the success of the procedure. The success of the procedure is defined as the ability to reach a body core temperature (bladder temperature recommended) of 33.0±0.5°C and a safe return to conventional mechanical ventilation within less than one hour after Vent2Cool start. Start of the Vent2Cool procedure is defined as the opening of the Vent2Cool patient connector valve.	From start of Vent2Cool procedure to 60min after

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
modified Rankin Scale (mRS)	mRS will be evaluated at Day 28. The modified Rankin Scale is a scoring system on neurologic function ranging from 0-6, where 0 means no symptoms at all, higher numbers indicating increasing neurologic disabilities and 6 equals death.	At Day 28
Body Core Temperature	Core temperature (bladder recommended) at start of Vent2Cool procedure and for 36 h after the end of Vent2Cool procedure to include the maintenance and rewarming phases of TTM	From start of Vent2Cool procedure to 37 hours after
Delay between the start of the Vent2Cool procedure and body core temperature of 33,5°C	Duration in minutes from start of the Vent2Cool procedure (i.e. opening of the Vent2Cool patient connector valve) to Body Core Temperature inferior or equal to 33,5 °C	During the Vent2Cool procedure
Delay between return of spontaneous circulation (ROSC) and body core temperature of 33.5°C.	Duration in minutes from ROSC to body core temperature inferior or equal to 33,5 °C	From ROSC to end of Vent2Cool procedure
PaO2 and PaCO2	PaO2 and PaCO2 values from arterial blood gases sampled at inclusion and 10 and 25 minutes into the Vent2Cool procedure	Inclusion, 10 min and 25 min after start of Vent2Cool procedure
Patient Vital status	Patient Vital status collected at ICU discharge and/or Hospital discharge (if before Day 28) and systematically at Day 28. In case of death : cause of death	Until Day 28
Glasgow Outcome Score (GOS)	The Glasgow Outcome Scale (GOS) is an ordinal scale used to assess functional outcomes of patients following brain injury. GOS includes five grades: 5, good recovery; 4, moderate disability; 3, severe disability; 2, persistent vegetative; and 1, death.	At Day 28

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Cooling Rate in body core temperature	Cooling rate is expressed in °C/h and calculated as follows: temperature at start of Vent2Cool procedure - 33.5°C / duration to achieve a core temperature of 33.5°C	During the Vent2Cool procedure
Occurence of cooling overshoot	Number and percentage of patients for whom the core temperature value is lower than 32°C and / or 30°C within 60 minutes after the start of the Vent2Cool procedure	From start of Vent2Cool procedure to 60min after.
Early termination of the Vent2Cool procedure by the clinician before reaching a core target temperature below 33±0.5°C (failure of cooling induction)		During the Vent2Cool procedure
modified Cardiac Arrest Hospital Prognosis (mCAHP) Score	Value of the modified Cardiac Arrest Hospital Prognosis (mCAHP) Score. Scores of either <80; [80; 105[ or >105 predict of risk of poor outcomes of respectively at least 40%, at least 80% or at least 95%.	At inclusion
Prognostication according to the modified Cardiac Arrest Hospital Prognosis (mCAHP) score	Number of patients for which the mCAHP score predicted a poor outcome with a risk of at least 40 % (mCAHP <80), at least 80% (mCAHP [80; 105[) or at least 95 % (mCAHP ≥ 105) vs. the total number of patients within each mRS category at Day 28.	At inclusion
Neurofilament light chain (NFL)		At inclusion, Day1 and Day3
Neuron Specific Enolase (NSE)		At inclusion, Day 1 and Day 3
Heart rate measured from the EKG or invasive blood pressure signal		At inclusion, 10 min and 25 min after start of Vent2Cool procedure
Systemic systolic and diastolic invasive blood pressure		At inclusion, 10 min and 25 min after start of Vent2Cool procedure
Presence of arrhythmia or unexpected electrocardiographic abnormality on EKG examination during Vent2Cool procedure		During the Vent2Cool procedure
Occurrence of an episode of major systemic hypotension (invasive or non-invasive measurement) with systolic blood pressure < 60 mmHg during Vent2Cool procedure		During the Vent2Cool procedure
Presence or absence of pleural collection of perfluorocarbon in the lungs on thoracic computed tomography examination in patients surviving on Day 28 after cardiac arrest.	The images of the CT scans will also be kept for possible later centralized analyses, if necessary.	Day 28
Glasgow Coma Scale score		At inclusion, at Day 3 and at Day 28.
SOFA score		At Day 1 and Day 3
Percentage of patient with pulmonary infection		At Day 3
Oxygen desaturation based on SpO2	Occurence of desaturation episodes defined as SpO2<75% on pulsed oxymeter lasting at least 5 minutes during Vent2Cool procedure.	During Vent2Cool procedure.
Number and percentage of patients with severe hypercapnia	Severe hypercapnia defined as PaCO2>75 mmHg, in blood gases sampled at 10 and 25 minutes after start of Vent2Cool	At inclusion, 10 min and 25 min after start of Vent2Cool procedure
Number and Percentage of patients with severe hyperoxemia	Severe hyperoxemia defined as PaO2>400 mmHg, in blood gases sampled at 10 and 25 minutes after start of Vent2Cool	At inclusion, 10 min and 25 min after start of Vent2Cool procedure
Number and Percentage of patients with hypoxemia	Hypoxemia defined as PaO2 < 75 mmHg, in blood gases sampled at 10 and 25 minutes after start of Vent2Cool	At inclusion, 10 min and 25 min after start of Vent2Cool procedure
Pupillometry examination	Presence of pupillary light reflex and Neurological pupil index (NPi) at Day 1, 2 and 3	Day 1 to Day 3
Time of start of Vent2Cool procedure from the time of return of spontaneous circulation (ROSC)	Duration in minutes from ROSC to start of the Vent2Cool TLV procedure	From return of spontaneous circulation to start of Vent2Cool procedure
Time of start of Vent2Cool procedure from the patient's admission to ICU		From patient admission to ICU to start of Vent2Cool procedure
Duration of the Vent2Cool procedure	Time during which the patient is ventilated by Vent2Cool form start of Vent2Cool to end of TLV by lung draining procedure.	From the start of the Vent2Cool procedure to the end of the procedure
Vent2Cool performance parameters	based on device data recorded during the Vent2Cool procedure	During Vent2Cool procedure.
Ventilatory parameters after Vent2Cool procedure	Including measured values of: positive end-expiratory pressure (PEEP),; end-inspiratory pause pressure (Plateau pressure),; driving pressure and static pulmonary compliance.	At 1h, 2h, 12h, 24h, 48h and 72h after the start of the Vent2Cool procedure
Hospital Care data	For patients discharged alive from hospital and / or alive at Day 28.; Number of days under mechanical ventilation; Number of days in intensive care unit; Number of days before hospital discharge, if applicable	Until Day 28

Collaborators and Investigators

• Sponsor: ORIXHA

Study record dates

Study Major Dates

• Study Start (Estimated): March 1, 2025
• Primary Completion (Estimated): March 1, 2026
• Study Completion (Estimated): March 1, 2026

Study Registration Dates

• First Submitted: January 22, 2025
• First Submitted That Met QC Criteria: January 28, 2025
• First Posted (Actual): March 25, 2025

Study Record Updates

• Last Update Posted (Actual): March 25, 2025
• Last Update Submitted That Met QC Criteria: January 28, 2025
• Last Verified: January 1, 2025

More Information

Terms related to this study

• Keywords: Cooling; Therapeutic Hypothermia; Targeted Temperature Management; ROSC; Resuscitated Cardiac Arrest; Out of Hospital cardiac arrest; liquid ventilation
• Additional Relevant MeSH Terms: Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Vascular Diseases; Cardiovascular Diseases; Postoperative Complications; Pathologic Processes; Heart Diseases; Brain Injuries; Reperfusion Injury; Post-Cardiac Arrest Syndrome; Heart Arrest
• Other Study ID Numbers: AR23_0007; CIV-24-02-046114 (Other Identifier: EUDAMED)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No