The optimal temperature for cerebral protection during hypothermic circulatory arrest is not known. This study was undertaken to test the hypothesis that deeper levels of cerebral hypothermia (< 10 degrees C) confer better protection against neurologic injury during prolonged hypothermic circulatory arrest ("colder is better"). Twelve male dogs (20 to 25 kg) were placed on closed-chest cardiopulmonary bypass via femoral artery and femoral/external jugular vein. Using surface and core cooling, tympanic membrane temperature was lowered to 18 degrees to 20 degrees C (deep hypothermia, n = 6) or 5 degrees to 7 degrees C (profound hypothermia, n = 6). After 2 hours of hypothermic circulatory arrest, animals were rewarmed to 35 degrees to 37 degrees C on cardiopulmonary bypass. All were mechanically ventilated and monitored in an intensive care unit setting for 20 hours. Neurologic assessment was performed every 12 hours using a species-specific behavior scale that yielded a neurodeficit score ranging from 0% to 100%, where 0 = normal and 100% = brain dead. After 72 hours, animals were sacrificed and examined histologically for neurologic injury. Histologic injury scores were assigned to each animal (range, 0 [normal] to 100 [severe injury]). At the end of the observation period, profoundly hypothermic animals had better neurologic function (neurodeficit score, 5.7% +/- 4.0%) compared with deeply hypothermic animals (neurodeficit score, 41% +/- 9.3%; p < 0.006). Every animal had histologic evidence of neurologic injury, but profoundly hypothermic animals had significantly less injury (histologic injury score, 19.2 +/- 1.2 versus 48.3 +/- 1.5; p < 0.0001).
"However, there is a controversy as to the possible detrimental effects with the use of profound hypothermia on cortical functions following these surgeries (Deleon et al., 1998). Although many studies validate neuroprotection by profound hypothermia during surgical situations (Gillinov et al., 1993; Haka-Ikse, Blackwood, & Steward, 1978; Sailhamer et al., 2007), other studies show significant neurological complications such as impaired mental and memory development in patients undergoing surgeries using such low temperatures (Deleon et al., 1998; Khaladj et al., 2006). Several studies link these neurological complications to swelling, cytoplasmic voculation and cytoskeletal disruption of the neurons caused by hypothermia (Emery & Lucas, 1995). "
[Show abstract][Hide abstract] ABSTRACT: Surgical procedures using hypothermic temperatures have been linked to complications such as seizures, impaired mental development and impaired memory. Although there is some evidence that the profound hypothermia (<12 ( composite function)C) used in these procedures may be contributing to these neurological impairments, skepticism remains because of lack of evidence from experimental studies isolating the effects of hypothermia on neuronal networks. In order to attain a better understanding of profound hypothermia effects on neurons during surgical procedures, we applied cold to a cultured in-vitro neuronal network. The typical pattern of activity of such cultures is in the form of synchronized bursts, in which most of the recorded neurons fire action potentials in a short time period. In most cases, the bursting activity shows one or more repeating precise spatio-temporal patterns (motifs) that are sustained over long periods of time. In this experimental study, neuronal networks grown on microelectrode arrays (MEA) are subjected to profound hypothermia for an hour and the collective dynamics of the network as a whole are assessed. We show, by using a similarity analysis that compares changes in the time delays between neuronal activation at different burst motifs, that neuronal networks survive total inhibition by profound hypothermia and retain their intrinsic synchronized burst motifs even with substantial generalized neuronal degeneration. By applying multiple sessions of cold, we also show a marked monotonic reduction in the rate of burst firing and in the number of spikes of each neuron after each session.
"From the onset, reports have confirmed that hypothermia reduces cerebral oxy gen metabolism in animals and in humans (Bigelow et aI., 1950; Lougheed and Kahn, 1955; Ausman et aI., 1993), a feature thought to impart the brain with in creased resilience to ischemic insults. To date, many re ports have convincingly validated neuroprotection by cooling tissues to 10° to 20°C (Lougheed and Kahn, 1955; Rosomoff, 1957; Michenfelder and Milde, 1992; Gillinov et aI., 1993; Shaver et aI., 1995; Rokkas et aI., 1995), but no cellular studies of deep hypothermia exist to describe the underlying protective mechanisms. We therefore studied hypothermic protection in cul tured cortical neurons. "
[Show abstract][Hide abstract] ABSTRACT: Although profound hypothermia has been used for decades to protect the human brain from hypoxic or ischemic insults, little is known about the underlying mechanism. We therefore report the first characterization of the effects of moderate (30 degrees C) and profound hypothermia (12 degrees to 20 degrees C) on excitotoxicity in cultured cortical neurons exposed to excitatory amino acids (EAA; glutamate, N-methyl-D-aspartate [NMDA], AMPA, or kainate) at different temperatures (12 degrees to 37 degrees C). Cooling neurons to 30 degrees C and 20 degrees C was neuroprotective, but cooling to 12 degrees C was toxic. The extent of protection depended on the temperature, the EAA receptor agonist employed, and the duration of the EAA challenge. Neurons challenged briefly (5 minutes) with all EAA were protected, as were neurons challenged for 60 minutes with NMDA, AMPA, or kainate. The protective effects of hypothermia (20 degrees and 30 degrees C) persisted after rewarming to 37 degrees C, but rewarming from 12 degrees C was deleterious. Surprisingly, however, prolonged (60 minutes) exposures to glutamate unmasked a temperature-insensitive component of glutamate neurotoxicity that was not seen with the other, synthetic EAA; this component was still mediated via NMDA receptors, not by ionotropic or metabotropic non-NMDA receptors. The temperature-insensitivity of glutamate toxicity was not explained by effects of hypothermia on EAA-evoked [Ca2+]i increases measured using high- and low-affinity Ca2+ indicators, nor by effects on mitochondrial production of reactive oxygen species. This first characterization of excitotoxicity at profoundly hypothermic temperatures reveals a previously unnoticed feature of glutamate neurotoxicity unseen with the other EAA, and also suggests that hypothermia protects the brain at the level of neurons by blocking, rather than slowing, excitotoxicity.
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