Recovery from Coma Post-Cardiac Arrest Is Dependent on the Orexin Pathway

Abstract

Cardiac arrest (CA) affects >550,000 people annually in the United States whereas 80-90% of survivors suffer from a comatose state. Arousal from coma is critical for recovery, but mechanisms of arousal are undefined. Orexin-A, a hypothalamic excitatory neuropeptide, has been linked to arousal deficits in various brain injuries. We investigated the orexinergic system's role in recovery from CA-related neurological impairments, including arousal deficits. Using an asphyxial CA and resuscitation model in rats, we examine neurological recovery post-resuscitation in conjunction with changes in orexin-A levels in cerebrospinal fluid (CSF) and orexin-expressing neurons. We also conduct pharmacological inhibition of orexin post-resuscitation. We show that recovery from neurological deficits begins between 4 and 24 h postresuscitation, with additional recovery by 72 h post-resuscitation. Orexin-A levels in the CSF are lowest during periods of poorest arousal post-resuscitation (4 h) and recover to control levels by 24 h. Immunostaining revealed that the number of orexin-A immunoreactive neurons declined at 4 h post-resuscitation, but increased to near normal levels by 24 h. There were no significant changes in the number of neurons expressing melanin-concentrating hormone, another neuropeptide localized in similar hypothalamus regions. Last, administration of the dual orexin receptor antagonist, suvorexant, during the initial 24 h post-resuscitation, led to sustained neurological deficits. The orexin pathway is critical during early phases of neurological recovery post-CA. Blocking this early action leads to persistent neurological deficits. This is of considerable clinical interest given that suvorexant recently received U.S. Food and Drug Administration approval for insomnia treatment.

Spreading depolarization and repolarization during cardiac arrest as an ultra-early marker of neurological recovery in a preclinical model

“…The animal model of ACA and resuscitation employed in this study has been described previously [41][42][43][44]48 and is summarized in Fig. 1.…”

“…[33][34][35][36][37][38][39] Additionally, via measurement of tissue scattering, optical techniques can also interrogate neuronal damage caused by cytotoxic edema and dendritic beading. 24,40 In this study, we used a preclinical model of asphyxial CA (ACA) and cardiopulmonary resuscitation (CPR), 41,42 along with an ECoG and optical imaging platform 43,44 , to characterize SD during ACA and repolarization (RP) post-CPR. We show that earlier SD and earlier RP are both associated with better neurological outcome.…”

Overnight caloric restriction prior to cardiac arrest and resuscitation leads to improved survival and neurological outcome in a rodent model

“…While under mechanical ventilation, positive end expiratory pressure was maintained at 3 cmH2O and body temperature was monitored with a rectal probe and maintained at 37°C. Cardiac arrest was induced via an 8-minute duration of controlled asphyxia followed by cardiopulmonary resuscitation (CPR) until return of spontaneous circulation (ROSC) as previously described 22 . No isoflurane anesthesia was administered during or after CPR for the remainder of the experiment.…”

“…Neurological recovery was quantified using the Neurological Deficit Scale (NDS; Table 1). The NDS consists of components that measure arousal, brainstem function, motor and sensory activities, as described previously 22 . Neurological recovery was evaluated at 4, 24, 48 and 72h post-ROSC by well-trained personnel who were blind to dietary groupings.…”

High-speed quantitative optical imaging of absolute metabolism in the rat cortex

“…Ten male Wistar rats (weight ~300-400 g) were imaged for this study, and the animal preparation procedures are described in our previous publications [7,8,13,14]. Before the experiment, all rats were endotracheally intubated under isoflurane anesthesia.…”