Hypothermic Centralization: New Use for Old Knowledge?

Potential neuroprotective effects with mild to moderate cerebral cooling have been clearly demonstrated after experimental hypoxic–ischemic injury.1 However, the difficulties of establishing an effective regime in clinical practice are formidable. In the absence of definitive evidence of clinical efficacy, it is essential that hypothermia be used safely. Pilot studies have suggested that, under tightly defined conditions, hypothermia is generally safe even in the severely asphyxiated infant,2–4 and multicenter, randomized, controlled trials are currently underway to further investigate different hypothermic strategies. Many of the clinical issues raised by Thoresen and Whitelaw5 can be readily understood in relation to the physiology of adaptation to hypothermia, including both the conservation and production of heat.Hypothermia leads to rapid peripheral vasoconstriction, ie, centralization of blood flow. This vasoconstriction occurs in a spatially and temporally controlled manner, dependent on tightly integrated input from central and skin thermoreceptors.6Although both core and skin temperatures are physiologically relevant, in man, the latter contributes only 20% to the onset threshold for vasoconstriction during cooling.7 Thus, external local warming with central hypothermia does not produce local vasodilatation, but rather leads to a small reduction in the core temperature threshold for vasoconstriction.8,9 Even very high skin temperatures cannot abolish the central initiation of vasoconstriction.8The effect of hypothermic centralization of blood flow is clearly demonstrated in Fig 1 of the article by Thoresen and Whitelaw.5 In both protocols, an increase in blood pressure occurs when cooling is initiated, followed by a resolution during rewarming, similar to previous reports, for example, in fetal sheep.10 In our experience, rewarming, performed slowly, does not result in clinically significant hypotension.4 A component of the changes observed in Fig 6B is potentially related to a handling effect, with a rise in blood pressure before rewarming.5The case described in Fig 3 of the article by Thoresen and Whitelaw5 was highly unstable, with swings in blood pressure not clearly attributable to heater activity before the selected event (A. Whitelaw, personal communication, 1999). The infant seems to have reached an equilibrium at a relatively low core temperature with little or only modest heater activity, and then was challenged with a rapid rise in both core and skin temperature. It is possible that hypothermic centralization temporarily supported this infant's blood pressure that, otherwise, for reasons such as impaired cardiac output, would have been marginal. Under these conditions, if rapidly warmed or otherwise challenged, cardiovascular instability would become manifest. In the combined Auckland and University College London experience,4 there were no cases of rapid rewarming, but the considerations discussed above suggest that it is improbable that changes in overhead warming without core temperature change can significantly impact on centralization.The other major response to hypothermia is increased heat production. This response is typically seen at a similar but not identical temperature threshold to vasoconstriction. During active cooling, temperature must be determined by the balance of endogenous heat production, external heat input from the overhead heater, and heat removal. Unlike adults, infants preferentially use brown fat (nonshivering thermogenesis) rather than shivering to produce heat.11 Postasphyxial seizures may also be an important source of both cerebral and peripheral thermogenesis.12Thus, factors that inhibit nonshivering thermogenesis or muscle activity, such as hypoxia and many anesthetic or sedative agents, result in altered heat production. Furthermore, spontaneous changes in the metabolic rates of infants during the evolution of hypoxic–ischemic encephalopathy may occur more frequently than previously recognized and also need to be met by appropriate adjustments in heat removal.In contrast to the present report,5 rapid falls in either rectal temperature or blood pressure were not observed during the maintenance phase of cooling in a larger, controlled pilot study of infants cooled to 34.5°C ± .5°C.4 Although, for example, anticonvulsants consistently reduced infant temperatures, this was a relatively slow change that could be readily anticipated. The major difference seems to be in the cooling strategies used. Thoresen and Whitelaw5 used fixed, usually low-output external heating, with limited cooling and relatively high cap temperatures, whereas the original protocol used lower cap temperatures, balanced by servo-controlled, maximal or near-maximal radiant heater activity.2,4 The use of maximal external heating must greatly reduce the relative contribution of endogenous thermal production to the infant's thermal balance and attenuate the impact of any reduction in thermogenesis.The use of therapeutic hypothermia unmasks dynamic changes in infant circulation and metabolism that we can usually ignore, because of the routine use of servo-controlled warming. This does not indicate that cooling is unsafe or difficult to manage, but rather that, as with any therapy, it must be applied with caution and knowledge of underlying physiologic principles.