Temperature

Apart from occlusion efficacy and duration, temperature is the most important variable in studies of global ischemia. The early literature that dealt with temperature effects, particularly hypothermic protection, has been comprehensively reviewed (136). Specific consideration will be given below to the avoidance of confounding factors in rodent models due to temperature changes intrinsic to the experimental procedures. These factors arise via the opposing effects of brain heat loss during ischemia and postischemic hyperthermia that is recognized to occur in specific models, the latter potentially sensitizing the model to protective effects of drug-induced cooling. Persistent lack of attention to these parameters remains the most serious problem in experimental ischemia research (137).

Hypothermia during global ischemia is clearly protective (138-140). A critical observation is that, even with adequate control of body temperature, brain cooling that occurs during global ischemic insults in rodents can itself be sufficient to blunt the resulting injury (74,92,141). The unrecognized contributions of such effects to outcomes of earlier studies undoubtedly varied considerably, depending on the extent to which heat loss from the head had been limited by the type and geometry of any heat sources used to maintain rectal temperature. Although heating may preclude the study of prolonged occlusions (142), avoidance of heat loss is essential if rodent models are to be consistently applied among investigators and compared with studies involving larger animals. Temporalis muscle temperature measurement and control are often used for this purpose (74), but epidural probes provide a better index of brain temperature (143). An added concern is that even when superficial head temperature is maintained, deeper brain structures can lose temperature via respiratory cooling mechanisms, which can only be fully avoided by maintaining a warm, humid environment (144). Under conditions of surface warming alone, the magnitude of temperature drop in striatum was only 1°C during a 15-min interval of 2-VO ischemia (144), but a comparable decline was noted in cortex during only 5-min ischemia in the gerbil (145). Apart from the obvious impact of species mass, variations in ambient temperature could easily contribute to such differences (146). The consistent insult thresholds for rat and gerbil models obtained with epidural temperature control (Fig. 2) and the short occlusion durations required to produce hippocampal pathology argue against the practical need for more aggressive measures if large variations in ambient temperature and humidity are avoided. However, brain regions differ in their sensitivity to temperature change during ischemia (92), and it clearly becomes important to monitor and maintain deep brain temperature if consequences of long insults are to be reliably studied. Although thermocouple wires can be suitable for short-term measurements (147), telemetric methods are best suited to this purpose (145). However, both methods require chronic placement of either a guide cannula or the probe itself, and the interval required for subsequent recovery of brain blood flow and metabolism should be verified in the course of establishing this invasive procedure.

Temperature remains a critical variable following reperfusion and recovery from anesthesia. In the absence of maintained temperature control, rats cool sufficiently during this early postischemic period to influence the threshold for CA1 damage (Fig. 4). However, hippocampal pathology continues to evolve throughout a significant interval after global ischemia, during which outcome remains sensitive to temperature modulation. For example, intraischemic cooling alone was not protective when gerbils were aggressively rewarmed during early recirculation (148). Brief cooling of 20- to 30-min duration initiated at the time of recirculation was not protective in the gerbil when characteristic hyperthermia was subsequently allowed to occur (149). More prolonged postischemic hypothermia confers unequivocal long-term protection (150,151), and cooling is established as a major confound in pharmacologic protection studies that involved global ischemia models (152-154). Conversely, even delayed temperature elevation can worsen injury (155). These issues become particularly significant in view of the intrinsic hyperthermic intervals that characterize gerbil and some rat models (see above). Long-term temperature recording is therefore mandatory in any global ischemia experiment in which outcomes are to be compared between treatment groups. Deep brain temperature remains the gold standard, but the relative merits of brain versus body measurements must be weighed in a given study. Occasional discrepancies between brain and core temperatures have been reported in anesthetized gerbils (57). However, if appropriate measures are taken to minimize brain cooling and avoid substantive dissociation of these parameters during ischemia, core body temperature is probably an adequate endpoint during the postischemic phase of most studies. Repeated measurement of rectal temperature is tedious, provides limited information, and introduces

Figure 4 Postischemic temperature maintenance and insult severity. Rats were subjected to 4-vessel occlusion ischemia, producing ischemic depolarizations of varied durations, and CA1 neuronal survival was evaluated at 1 week. All rats experienced rigorous intraischemic control of brain and rectal temperature. In one group, rectal temperature control was maintained through approximately 90-min recirculation (closedcircles), whereas another group of animals recovered from anesthesia without further temperature control, permitting spontaneous cooling (open circles). In the absence of sustained postischemic temperature control, some hippocampi exhibited 30% to 40% neuronal preservation after insults that produced essentially complete CA1 loss in normothermic animals. Source: Unpublished observations, Howard EM, Nowak TS Jr. (University of Tennessee at Memphis, Memphis, Tennessee, USA).

Figure 4 Postischemic temperature maintenance and insult severity. Rats were subjected to 4-vessel occlusion ischemia, producing ischemic depolarizations of varied durations, and CA1 neuronal survival was evaluated at 1 week. All rats experienced rigorous intraischemic control of brain and rectal temperature. In one group, rectal temperature control was maintained through approximately 90-min recirculation (closedcircles), whereas another group of animals recovered from anesthesia without further temperature control, permitting spontaneous cooling (open circles). In the absence of sustained postischemic temperature control, some hippocampi exhibited 30% to 40% neuronal preservation after insults that produced essentially complete CA1 loss in normothermic animals. Source: Unpublished observations, Howard EM, Nowak TS Jr. (University of Tennessee at Memphis, Memphis, Tennessee, USA).

additional variables (156,157). Although rectal temperature monitoring may suffice to rule out gross artifact in preliminary work, continuous brain or body telemetry must be the expected standard for a definitive intervention study. Elaborate temperature control measures may become necessary should altered thermoregulation be observed in any treatment context (158).

Heat loss is a particularly critical problem in mouse models. As global ischemia studies in this species evolved comparatively recently, the need for temperature control during ischemia has been well recognized, and independent head temperature control has even been used in attempts to modulate injury (102). However, the 3-VO study in mice that identified an injury threshold comparable to rats and gerbils included brain temperature control (115) and cited the use of elevated ambient air temperature. Studies that demonstrated higher, strain-dependent injury thresholds indicated only maintained head surface temperature (114,116). Whether selective brain cooling can fully account for such differences in vulnerability remains to be established. Neither brain nor body temperature has been monitored for an extended period after global ischemia in mice, but telemetry has demonstrated profound spontaneous cooling after transient focal ischemia (159) and should prove essential in refining the use of this species in global ischemia models as well.

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