Mean Arterial Pressure After Out-of-hospital Cardiac Arrest (METAPHORE)

Mean Arterial Pressure After Out-of-hospital Cardiac Arrest: the METAPHORE Randomized Trial

Out-of-hospital cardiac arrest is a public health problem for which overall survival is below 10%. Post-cardiac arrest syndrome is the principal cause of death in intensive care units (ICU), due to refractory shock or brain injuries secondary to anoxia. Brain anoxia is responsible for severe neurological sequelae that may be aggravated by cerebral hypoperfusion during the first few hours after the return of spontaneous circulation. Current recommendations are to ensure that arterial blood pressure is sufficient for the perfusion of organs, but no minimum threshold mean arterial pressure (MAP) has been defined. In practice, most teams target a MAP of at least 65 mmHg. Several observational studies have shown a correlation between MAP and neurological prognosis, patients with a higher initial MAP having a better outcome. Recent pilot studies have demonstrated the feasibility of increasing the target MAP after cardiac arrest, but conflicting results have been obtained concerning patient prognosis. These findings may be explained by changes to the autoregulation of the brain after cardiac arrest, with a shift of the curve towards the right, or its abolition. Cerebral blood flow is dependent on MAP, and a target MAP of 65 mmHg for these patients may result in insufficient brain perfusion. Conversely, a too high MAP might cause brain lesions due to vasogenic edema, hemorrhagic complications or excess perfusion in conditions of diminished brain metabolism. An interventional study is required to evaluate the effect of increasing MAP on neurofunctional outcome after cardiac arrest. Given the data available for brain autoregulation, the correlation between MAP and prognosis, and the risks theoretically associated with a higher MAP, investigator plans to compare a standard threshold of MAP (≥ 65 mmHg) with a high threshold of MAP (≥ 90 mmHg). Investigator hypothesizes that a high MAP within the first 24 hours after cardiac arrest will improve neurofunctional outcome.

Study Overview

• Status: Recruiting
• Conditions: Cardiac Arrest; Out-of-hospital Cardiac Arrest (OHCA)
• Intervention / Treatment: Procedure: Maintain MAP ≥ 90 mmHg; Procedure: Maintain MAP ≥ 65 mmHg

• Study Type: Interventional
• Enrollment (Estimated): 1380
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Nicolas CHUDEAU; Phone Number: +33243432458; Email: nchudeau@ch-lemans.fr
• Study Contact Backup: Name: Christelle JADEAU; Phone Number: +33244710781; Email: cjadeau@ch-lemans.fr

Study Locations

• France
  • Brest, France, 29609
    • Recruiting
    • CHU Brest - Hôpital de la Cavale Blanche
    • Contact: pierre bailly, MD
    • Contact: Pierre BAILLY, MD; Phone Number: +332 98 34 71 84; Email: pierre.bailly@chu-brest.fr
  • Brive La Gaillarde, France, 19100
    • Recruiting
    • CH Brive
    • Contact: Nicolas PICHON, MD
    • Contact: Nicolas PICHON, MD; Phone Number: +335 55 92 64 79; Email: nicolas.pichon@ch-brive.fr
  • Caen, France, 14000
    • Recruiting
    • CHU caen
    • Contact: Damien DU CHEYRON, PhD; Phone Number: +332 31 06 47 16; Email: ducheyron-d@chu-caen.fr
    • Contact: Damien DU CHEYRON, PhD
  • Cholet, France, 49300
    • Recruiting
    • CH Cholet
    • Contact: Fabien JAROUSSEAU, MD
    • Contact: Fabien JAROUSSEAU, MD; Phone Number: +332 41 49 60 87; Email: fabien.jarousseau@ch-lemans.fr
  • Dieppe, France, 76200
    • Recruiting
    • Ch Dieppe
    • Contact: Antoine MARCHALOT, MD; Phone Number: +332 32 14 72 53; Email: amarchalot@ch-dieppe.fr
    • Contact: Antoine MARCHALOT, MD
  • Dijon, France, 21079
    • Recruiting
    • CHU Dijon - Hôpital F. Mitterrand
    • Contact: Jean-Pierre QUENOT, PhD; Phone Number: +333 80 29 36 85; Email: jean-pierre.quenot@chu-dijon.fr
    • Contact: Jean-Pierre QUENOT, PhD
  • La Roche-sur-Yon, France, 85925
    • Recruiting
    • CHD Vendee
    • Contact: gwenhael colin, MD
    • Contact: Gwenhael COLIN, MD; Phone Number: +332 51 44 60 35; Email: gwenhael.colin@ght85.fr
  • Le Chesnay, France, 78150
    • Not yet recruiting
    • CH Versailles
    • Contact: Marine PAUL, MD; Phone Number: +331 39 63 83 59; Email: mpaul@ch-versailles.fr
    • Contact: Marine PAUL, MD
  • Le Mans, France, 72000
    • Recruiting
    • Centre Hospitalier du Mans
    • Contact: Christelle JADEAU; Phone Number: +33244710781; Email: cjadeau@ch-lemans.fr
    • Contact: Nicolas CHUDEAU, MD
  • Lens, France, 62300
    • Recruiting
    • CH Dr Schaffner
    • Contact: Olivier NIGEON, MD; Phone Number: +332 21 69 10 88; Email: onigeon@ch-lens.fr
    • Contact: Olivier NIGEON, MD
  • Lille, France, 59037
    • Recruiting
    • Chu Lille
    • Contact: Patrick GIRARDIE, MD; Phone Number: +333 20 44 64 44; Email: patrick.girardie@chu-lille.fr
    • Contact: Patrick GIRARDIE, MD
  • Limoges, France, 87042
    • Recruiting
    • CHU Limoges
    • Contact: Marine GOUDELIN, MD; Phone Number: +335 55 05 62 74; Email: Marine.goudelin@chu-limoges.fr
    • Contact: Marine GOUDELIN, MD
  • Marseille, France, 13005
    • Recruiting
    • APHM - Hopital De La Timone
    • Contact: Jeremy BOURENNE, MD
    • Contact: Jérémy BOURENNE, MD; Phone Number: +334 13 42 95 66; Email: Jeremy.BOURENNE@ap-hm.fr
  • Massy, France, 91300
    • Not yet recruiting
    • Hopital Jacques Cartier
    • Contact: Wulfran BOUGOUIN, PhD; Phone Number: +336 48 03 74 39; Email: wulfran.bougouin@gmail.com
    • Contact: Wulfran BOUGOUIN, PhD
  • Nantes, France, 44093
    • Not yet recruiting
    • CHU Nantes
    • Contact: Jean-Baptiste Lascarrou, MD
    • Contact: Jean-Baptiste LASCARROU, MD; Phone Number: +332 40 08 73 76; Email: jeanbaptiste.lascarrou@chu-nantes.fr
  • Nice, France, 06001
    • Recruiting
    • CHU Nice - Hôpital Pasteur
    • Contact: Denis DOYEN, PhD; Phone Number: +334 92 03 55 10; Email: doyen.d@chu-nice.fr
    • Contact: Denis DOYEN, PhD
  • Nice, France, 06202
    • Recruiting
    • CHU Nice - Hôpital Archet
    • Contact: Mathieu JOSWIAK, MD; Phone Number: +334 92 03 55 10; Email: joswiak.m@chu-nice.fr
    • Contact: Mathieu JOSWIAK, MD
  • Nîmes, France, 30029
    • Recruiting
    • CHU Nimes
    • Contact: Saber Davide BARBAR, MD; Phone Number: +334 66 68 33 20; Email: saber.barbar@chu-nimes.fr
    • Contact: Saber Davide BARBAR, MD
  • Orléans, France, 45067
    • Not yet recruiting
    • CHR Orléans
    • Contact: grégoire muller, MD
    • Contact: Grégoire MULLER, MD; Phone Number: +332 38 51 44 46; Email: gregoire.muller@chr-orleans.fr
  • Paris, France, 75014
    • Not yet recruiting
    • Hopital Cochin
    • Contact: Alain CARIOU, PhD; Phone Number: +331 58 41 25 17; Email: alain.cariou@aphp.fr
    • Contact: Alain CARIOU, PhD
  • Paris, France, 75015
    • Recruiting
    • APHP - Hôpital Européen Georges Pompidou (HEGP)
    • Contact: Nicolas BRECHOT, PhD; Phone Number: +331 56 09 23 42; Email: nicolas.brechot@aphp.fr
    • Contact: Nicolas BRECHOT, PhD
  • Poitiers, France, 86021
    • Recruiting
    • CHU Poitiers
    • Contact: Arnaud THILLE, PhD; Phone Number: +335 49 44 43 67; Email: arnaud.THILLE@chu-poitiers.fr
    • Contact: Arnaud THILLE, PhD
  • Rennes, France, 35000
    • Recruiting
    • Chu Rennes
    • Contact: Benoit PAINVIN, MD; Phone Number: +332 99 28 43 21; Email: benoit.painvin@chu-rennes.fr
    • Contact: Benoit PAINVIN, MD
  • Saint-Denis, France, 93207
    • Recruiting
    • Centre Cardiologique du Nord
    • Contact: Tristan MORICHAU-BEAUCHANT, MD
    • Contact: Tristan MORICHAU-BEAUCHANT, MD; Phone Number: +331 49 33 48 91; Email: t.morichau-beauchant@ccn.fr
  • Strasbourg, France, 67091
    • Recruiting
    • CHRU Strasbourg - Nouvel Hôpital Civil
    • Contact: Hamid MERDJI, MD; Phone Number: +333 69 55 11 23; Email: hamid.merdji@chru-strasbourg.fr
    • Contact: Hamid MERDJI, MD
  • Tours, France, 37044
    • Recruiting
    • CHRU Tours - Hôpital Bretonneau
    • Contact: Charlotte SALMON GANDONNIERE, MD; Phone Number: +332 47 47 38 55; Email: charlotte.salmon@univ-tours.fr
    • Contact: Charlotte SALMON GANDONNIERE, MD
  • Vannes, France, 56000
    • Recruiting
    • CH Bretagne Atlantique
    • Contact: Agathe Delbove, MD
    • Contact: Agathe DELBOVE, MD; Phone Number: +332 97 01 43 06; Email: agathe.delbove@ch-bretagne-atlantique.fr

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Admission to ICU following an out-of-hospital cardiac arrest with an initially shockable or non-shockable rhythm ;
• Sustained ROSC defined as 20 minutes with signs of circulation without the need for chest compressions;
• Under invasive mechanical ventilation for coma, defined as a Glasgow score ≤ 8/15;
• Consent from a relative or of a procedure for emergency inclusion.

Exclusion Criteria:

• Age < 18 years ;
• In-hospital cardiac arrest (first cardiac arrest);
• Unwitnessed CA with initial rhythm of asystole
• Delay between ROSC and attempting randomisation > 6 hours ;
• Cardiac arrest in a context of multiple trauma ;
• Cardiac arrest in a context of hemorrhagic shock or severe hemorrhage necessitating hemostasis (surgery or radiological or endoscopic hemostasis) ;
• Cardiac arrest secondary to an acute brain disease (ischemic or hemorrhagic stroke, subarachnoid hemorrhage, severe traumatic brain injury) ;
• Refractory shock :

Defined as a MAP < 65 mmHg for more than one hour on norepinephrine or epinephrine at a dose > 1 µg/kg/min despite adequate fluid resuscitation ;

• Extracorporeal circulatory support prior to inclusion;
• Known allergy to norepinephrine or to any of its excipients;
• Decision to limit care before inclusion ;
• Modified Rankin score of 4 or 5 before cardiac arrest ;
• Inclusion in another interventional study in which the principal endpoint is neurological prognosis ;
• Pregnancy or breast feeding ;
• Adult patient deprived of freedom or under legal protection (patients under guardianship or curatorship) (article L1121-6 of the French Health Code) ;
• Non-French speaking;
• Patient already included in this trial ;
• Absence of social security cover.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: high MAP threshold; Norepinephrine will be titrated to maintain MAP ≥ 90 mmHg. This threshold will be maintained for the 24 hours following inclusion by the perfusion of norepinephrine at an appropriate dose. From 24 hours after inclusion until ICU discharge, a MAP ≥ 65 mmHg will be targeted	Procedure: Maintain MAP ≥ 90 mmHg; Maintain MAP ≥ 90 mmHg for the 24 hours following inclusion by perfusion of norepinephrine
Active Comparator: standard MAP threshold; Norepinephrine will be titrated to maintain MAP ≥ 65 mmHg. This target MAP will be maintained for 24 hours after randomization through the perfusion of norepinephrine at an appropriate flow rate. From 24 hours after inclusion until ICU discharge, a MAP ≥ 65 mmHg will be targeted	Procedure: Maintain MAP ≥ 65 mmHg; Maintain MAP ≥ 65 mmHg for 24 hours after randomization through the perfusion of norepinephrine

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Proportion of patients with a good neurofunctional outcome 180 days after inclusion	Good neurofunctional outcome will be defined by a modified Rankin scale (mRS) of 0 to 3.This score is a global evaluation scale for disability, with seven levels (0 = no symptoms; 6 = patient dead).This score will be measured by psychologist who will be blinded to the randomization arm.	180 days after inclusion

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Proportion of patients alive at Intensive Care Unit discharge, at hospital discharge, at day 28 (D28) and six months (D180) after inclusion	Proportion of patients alive at Intensive Care Unit discharge, at hospital discharge, at day 28 (D28) and six months (D180) after inclusion	From Intensive Care Unit admission to Intensive Care Unit discharge (up to 3 weeks), from hospital admission to hospital discharge (up to 12 weeks), 28 days and 180 days after inclusion
Proportion of patients alive at Intensive Care Unit discharge with good neurofunctionnal outcome	Good neurofunctional outcome will be defined by a modified Rankin scale (mRS) of 0 to 3.This score is a global evaluation scale for disability, with seven levels (0 = no symptoms; 6 = patient dead	From Intensive Care Unit admission to Intensive Care Unit discharge (up to 3 weeks)
Quality of life six months after inclusion	Quality of life is measured by EuroQol-5D-5L. It's a measure of health-related quality of life and comprises 5 dimensions (mobility, self-care, usual activities, pain/discomfort and anxiety/depression). EuroQol-5D-5L could be administered by telephone	6 months after inclusion
Evaluation of Clinical Frailty at six months after inclusion	Clinical Frailty is measured by the Clinical Frailty Scale (CFS). It summarizes the overall level of fitness or frailty of a patient with a score from 1 (very fit) to 9 (terminally ill)	Six months after inclusion
Number of ICU-free days at Day 28	Number of ICU-free days is calculated from the number of days alive outside the ICU by Day 28	Day 28
Number of ventilator-free days, number of catecholamine-free days and number of renal replacement therapy-free days at day 28	Number of ventilator-free days, number of catecholamine-free days and number of renal replacement therapy-free days is calculated from the number of days alive without invasive mechanical ventilation, catecholamine infusion or renal replacement therapy by Day 28	28 days after inclusion
Proportion of patients with acute kidney injury stage 3 and need for renal replacement therapy (RRT) within Intensive Care Unit stay and persistant need for RRT at Intensive Care Unit discharge	Acute kidney injury stage 3 is defined by at least one of the following criteria: serum creatinine concentration of more than 4 mg/dl (354 µmol/liter) or greater than 3 times the baseline creatinine level, anuria (urine output of 100 ml/day or less) for more than 12 hours, oliguria (urine output below 0.3 ml/kg/h or below 500 ml/day) for more than 24 hours;	From Intensive Care Unit admission to Intensive Care Unit discharge (up to 3 weeks)

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Cardiovascular complications	Cardiovascular complications are assessed by determining the number of patients presenting a severe cardiovascular complication within 7 days of inclusion	within 7 days after inclusion
Neurological complications	Neurological complications are asssessed by determining the number of patients presenting stroke (ischemic stroke, subarachnoid hemorrhage or cerebral hematoma), confirmed by imaging (CT-scan or MRI) within 7 days of inclusion (systematic cerebral imaging is not required by the protocol but only in case of clinical suspicion of stroke or for neuroprognostication)	within 7 days of inclusion
Cutaneous complications within 7 days of inclusion	Cutaneous complications are assessed by determining the number of patients presenting necrosis of the extremities within 7 days of inclusion	within 7 days of inclusion
Digestive complications within 7 days after inclusion	Digestive complications are assessed by determining the number of patients presenting a clinical suspicion of digestive ischemia, confirmed by imaging (CT-scan), endoscopy or exploratory laparotomy, within 7 days of inclusion	within 7 days of inclusion
Major bleeding within 7 days of inclusion	Major bleeding is assessed by determining the number of patients presenting one of the International Society on Thrombosis and Haemostasis (ISTH) criteria within 7 days of inclusion (fatal bleeding and/or symptomatic bleeding in a critical area or in an organ such as intracranial, intraspinal, intraocular, retroperitoneal, intra-articular, pericardial or intramuscular with compartment syndrome and/or bleeding causing a fall in hemoglobin level of 20 g.L-1 or more or leading to transfusion of two or more units of red cells)	within 7 days of inclusion
Global complications within 7 days of inclusion	Global complications are defined by the proportion of patients with at least one complication (cardiovascular, neurological, cutaneous, digestive or hemorrhagic) within 7 days of inclusion	within 7 days of inclusion
Proportion of patients with a good neurofunctional prognosis at six months in the subgroup of patients with an initial shockable cardiac arrest rhythm and in the subgroup of patients with an initial non-shockable cardiac arrest rhythm	Proportion of patients with a good neurofunctional prognosis at six months in the subgroup of patients with an initial shockable cardiac arrest rhythm and in the subgroup of patients with an initial non-shockable cardiac arrest rhythm	6 months after inclusion
Proportion of patients with a good neurofunctional prognosis at six months in the subgroup of patients with confirmed chronic arterial hypertension and in the subgroup of patients without chronic arterial hypertension	Proportion of patients with a good neurofunctional prognosis at six months in the subgroup of patients with confirmed chronic arterial hypertension and in the subgroup of patients without chronic arterial hypertension. Chronic high blood pressure is defined as need for chronic treatment prior to cardiac arrest;	6 months after inclusion
Proportion of patients with good neurofunctional prognosis at six months in the three risks subgroups of patients identified by CAHP score (< 150, 150-200 and > 200).	Proportion of patients with good neurofunctional prognosis at six months in the three risks subgroups of patients identified by CAHP score (< 150, 150-200 and > 200). The CAHP score represents a simple tool for early stratification of patients admitted in ICU after OHCA, using seven variables (age, rhythm, time from collapse to basic life support, time from basic life support to ROSC, location of cardiac arrest, epinephrine dose and arterial pH)	6 months after inclusion

Collaborators and Investigators

• Sponsor: Centre Hospitalier le Mans

Study record dates

Study Major Dates

• Study Start (Actual): September 28, 2024
• Primary Completion (Estimated): March 28, 2028
• Study Completion (Estimated): March 28, 2028

Study Registration Dates

• First Submitted: August 2, 2022
• First Submitted That Met QC Criteria: August 2, 2022
• First Posted (Actual): August 4, 2022

Study Record Updates

• Last Update Posted (Actual): March 26, 2025
• Last Update Submitted That Met QC Criteria: March 21, 2025
• Last Verified: March 1, 2025

More Information

Terms related to this study

• Keywords: outcome; cardiac arrest; cerebral blood flow; mean arterial pressure
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Heart Diseases; Heart Arrest; Out-of-Hospital Cardiac Arrest; Physiological Effects of Drugs; Peripheral Nervous System Agents; Anesthetics, Local; Anesthetics; Central Nervous System Depressants; Sensory System Agents; Benzocaine
• Other Study ID Numbers: CHM-2022/S03/07

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: After publication of the main results, the anonymized data necessary for carrying out additional analyses may be made available upon request addressed to the coordinating investigator and the scientific committee

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