Mean Arterial Pressure After Out-of-hospital Cardiac Arrest

Official title

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

Overview

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.

Interventions

• Procedure Maintain MAP ≥ 90 mmHg
  Maintain MAP ≥ 90 mmHg for the 24 hours following inclusion by perfusion of norepinephrine
• Procedure Maintain MAP ≥ 65 mmHg
  Maintain MAP ≥ 65 mmHg for 24 hours after randomization through the perfusion of norepinephrine

Primary outcome measures

• Proportion of patients with a good neurofunctional outcome 180 days after inclusion [Time frame: 180 days after inclusion]

Secondary outcome measures (7)

• Proportion of patients alive at Intensive Care Unit discharge, at hospital discharge, at day 28 (D28) and six months (D180) after inclusion [Time frame: 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 [Time frame: From Intensive Care Unit admission to Intensive Care Unit discharge (up to 3 weeks)]
• Quality of life six months after inclusion [Time frame: 6 months after inclusion]
• Evaluation of Clinical Frailty at six months after inclusion [Time frame: Six months after inclusion]
• Number of ICU-free days at Day 28 [Time frame: Day 28]
• Number of ventilator-free days, number of catecholamine-free days and number of renal replacement therapy-free days at day 28 [Time frame: 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 [Time frame: From Intensive Care Unit admission to Intensive Care Unit discharge (up to 3 weeks)]

Eligibility criteria

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.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Single blind

Primary purpose

Treatment

Study locations

France · 27 centers

• CHU Brest - Hôpital de La Cavale Blanche — Brest
• CH Brive — Brive-la-Gaillarde
• CHU Caen — Caen
• CH Cholet — Cholet
• CH Dieppe — Dieppe
• CHU Dijon - Hôpital F. Mitterrand — Dijon
• CHD Vendée — La Roche-sur-Yon
• CH Versailles — Le Chesnay
• … and 19 more centers

Publications

• Chudeau N, Saulnier P, Parot-Schinkel E, Lascarrou JB, Colin G, Barbar SD, Painvin B, Pichon N, Du Cheyron D, Marchalot A, Jarousseau F, Delbove A, Morichau-Beauchant T, Girardie P, Salmon Gandonniere C, Thille AW, Quenot JP, Bailly P, Goudelin M, Martino F, Nigeon O, Merdji H, Brechot N, Bourenne J, Bougouin W, Muller G, Jozwiak M, Doyen D, Rouanet E, Cariou A, Guitton C; AfterROSC Network; CRICS PMID 40280607

Identifiers

NCT: NCT05486884 · CHM-2022/S03/07

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗