Anesthetic Protection of Neurons Injured by Hypothermia and Rewarming

Abstract

Background Mild hypothermia is neuroprotective following cerebral ischemia but surgery involving profound hypothermia (PH, temperature <18 °C) is associated with neurological complications. Rewarming (RW) from PH injures hippocampal neurons by glutamate excitotoxicity, N-methyl-D-aspartate receptors and intracellular calcium. Because neurons are protected from hypoxia-ischemia by anesthetics that inhibit N-methyl-D-aspartic acid receptors, we tested whether anesthetics protect neurons from damage caused by PH/RW. Methods Organotypic cultures of rat hippocampus were used to model PH/RW injury, with hypothermia at 4°C followed by RW to 37°C and assessment of cell death 1 or 24 h later. Cell death and intracellular Ca2+ were assessed with fluorescent dye imaging and histology. Anesthetics were present in the culture media during PH and RW or only RW. Results Injury to hippocampal CA1, CA3, and dentate neurons following PH and RW involved cell swelling, cell rupture, and adenosine triphosphate loss; this injury was similar for 4 through 10 h of PH. Isoflurane (1 and 2%), sevoflurane (3%) and xenon (60%) reduced cell loss but propofol (3 μM) and pentobarbital (100 μM) did not. Isoflurane protection involved reduction in N-methyl-D-aspartate receptor-mediated Ca2+ influx during RW but did not involve γ-amino butyric acid receptors or KATP channels. However, cell death increased over the next day. Conclusions Anesthetic protection of neurons rewarmed from 4°C involves suppression of N-methyl-D-aspartate receptor-mediated Ca2+ overload in neurons undergoing adenosine triphosphate loss and excitotoxicity. Unlike during hypoxia/ischemia, anesthetics acting predominately on γ-amino butyric acid receptors do not protect against PH/RW. The durability of anesthetic protection against cold injury may be limited.

Neuroprotective effects of deep hypothermia in refractory status epilepticus

“…Deep hypothermia has not been used for RSE, but is routinely used to protect the brain or spinal cord when circulatory arrest is needed in cardiac surgery and neurosurgery . Many of the complications reported after deep hypothermia are the result of induced circulatory arrest, not of hypothermia itself …”

Deep hypothermia for the treatment of refractory status epilepticus

“…Deep hypothermia is routinely used to protect the brain or spinal cord when circulatory arrest is needed in cardiac surgery [52], vascular surgery [53] and neurosurgery [54]. Most of the complications reported after deep hypothermia are the result of induced circulatory arrest, not the result of hypothermia itself [55, 56], although the potential for adverse effects, especially for very deep hypothermia, is significant [57]. …”

Xenon Improves Neurologic Outcome and Reduces Secondary Injury Following Trauma in an In Vivo Model of Traumatic Brain Injury*

“…Since the discovery that xenon was an NMDA receptor antagonist [24] and the subsequent demonstration that xenon has neuroprotective properties in models of ischemic injury [25][26][27][28][29][30][31][32][33][34] there has been a resurgence of interest in the use of xenon as a neuroprotectant. Clinical trials are currently evaluating xenon in different types of ischemic injury (e.g.…”

“…Following the discovery that xenon is an NMDA receptor antagonist [21][22][23][24], xenon was shown to be neuroprotective in a number of in vitro and in vivo models of ischemic injury [25][26][27][28][29][30][31][32][33][34] and xenon is currently undergoing clinical trials as a treatment for ischemic brain injury [35,36] and post-operative delirum [37].…”