GLP-1 Analogs for Neuroprotection After Cardiac Arrest

In comatose patients resuscitated from out of hospital cardiac arrest, neurological injuries remain the leading cause of death. The in-hospital mortality is reported at 30-50%, and the total mortality, although improved substantially over the last decade, remain to be significant, in most countries up to 90%. The brain of a patient resuscitated after cardiac arrest (CA) may have suffered ischemia and when the spontaneous circulation is re-established, the subsequent reperfusion may cause further damage. Brain ischemia and the reperfusion injury lead to tissue degeneration and loss of neurological function, the extent dependent on duration and density of the insult. Temperature control and mild induced hypothermia (MIH) (33-36°C) mitigate this damage in the experimental setting and clinical trials have shown promising results in improving neurological function and survival. Recent large scale clinical trials however have investigated milder degree of hypothermia in this setting, which suggest a role for active neuroprotection outside of temperature management. Also recently, increased attention to the possible role of Glucagon-Like Peptide-1 (GLP-1) in neuroprotection has been raised, both in the context of ameliorating degenerative disease and in reducing inflammation on ischemic cerebral stroke.

Several experimental studies have shown that GLP-1 analogs has a beneficial effect in the treatment of various degenerative neurological diseases such as Alzheimer's disease and Parkinson's disease. GLP-1 analogs have been shown to reduce brain infarct size in mice after focal brain ischemia as well as to reduce heart infarct size in swine in a model of myocardial infarction.

Recent clinical testing in humans have demonstrated a benefit of GLP-1 infusion on myocardial infarct size and a larger salvage index in patients with myocardial infarction. The GLP-1 analogs were infused in acutely ill patients in many ways similar to cardiac arrest patients with no increased risk of adverse events.

This study is a double blinded randomized study seeking to evaluate the potential neuroprotective effects of GLP-1 analogs infused in comatose patients after out of hospital cardiac arrest.

Inclusion criteria

• Out of hospital cardiac arrest (OHCA) of presumed cardiac cause
• Sustained return of spontaneous circulation (ROSC)
• Unconsciousness (GCS <8 (Glasgow coma scale)) (patients not able to obey verbal commands)
• Sustained ROSC (Sustained ROSC: Sustained ROSC is when chest compressions have been not required for 20 consecutive minutes and signs of circulation persist)

Exclusion criteria

• Conscious patients (obeying verbal commands)
• Females of childbearing potential (unless a negative pregnancy test can rule out pregnancy within the inclusion window)
• In-hospital cardiac arrest (IHCA)
• OHCA of presumed non-cardiac cause, e.g. after trauma or dissection/rupture of major artery OR Cardiac arrest caused by initial hypoxia (i.e. drowning, suffocation, hanging).
• Known bleeding diathesis (medically induced coagulopathy (e.g. warfarin, clopidogrel) does not exclude the patient).
• Suspected or confirmed acute intracranial bleeding
• Suspected or confirmed acute stroke
• Unwitnessed asystole
• Known limitations in therapy and Do Not Resuscitate-order
• Known disease making 180 days survival unlikely
• Known pre-arrest cerebral performance category 3 or 4
• >4 hours (240 minutes) from ROSC to screening
• Systolic blood pressure <80 mm Hg in spite of fluid loading/vasopressor and/or inotropic medication/intra aortic balloon pump/axial flow device*
• Temperature on admission <30°C.
• Known allergy to GLP-1 analogs, including Exenatide
• Known pancreatitis
• Diabetic ketoacidosis,
• Uncorrected blood glucose at admission < 2.5 mmol/l.

• If the systolic blood pressure (SBP) is recovering during the inclusion window (220 minutes) the patient can be included.