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Ann Thorac Surg 1998;65:454-460
© 1998 The Society of Thoracic Surgeons
Department of Anesthesiology, Neuroanesthesia Research Laboratory, Mayo Clinic and Mayo Medical School, Rochester, Minnesota, USA
Department of Surgery, Cardiac Surgery Laboratory, Mayo Clinic and Mayo Medical School, Rochester, Minnesota, USA
Accepted for publication August 13, 1997.
Dr Lanier, Department of Anesthesiology, Mayo Clinic, 200 First St SW, Rochester, MN 55905 (e-mail: lanier.william@mayo.edu)
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Abstract |
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Methods. Sixteen dogs were anesthetized either with inhaled halothane, 1.0 minimum alveolar concentration (ie, an anesthetic that should increase cerebral blood flow and minimally affect cerebral metabolism; n = 8), or with intravenous high-dose pentobarbital (ie, an anesthetic that should reduce cerebral blood flow and cerebral metabolism by approximately one half; n = 8). Normocapnia (alpha-stat technique) and a blood pressure near 90 mm Hg were maintained. Thermistors were placed in the esophagus (ie, the body core), in the parietal epidural space, and in the parietal brain parenchyma at depths of 1 and 2 cm. Initially, all temperatures were controlled at 38.0° ± 0.2°C (mean ± standard deviation). Thereafter, atrial-femoral artery CPB was initiated, and after 15 minutes at 38°C, the core temperature was decreased to 28°C over approximately 21 minutes. After 30 minutes at 28°C, the core temperature was returned to 38°C over approximately 21 minutes and was maintained at 38°C for the next 30 minutes.
Results. In halothane-anesthetized dogs, the mean brain-to-core temperature gradient always was 1.0°C or less for all brain sites during all phases of CPB. In contrast, in pentobarbital-anesthetized dogs, the mean brain temperature during active cooling typically exceeded the core temperature by 1.7° to 2.2°C. This brain-to-core temperature gradient persisted into the period of stable hypothermia. During the rewarming phase of CPB, the mean brain temperature was 2.9° to 3.4°C cooler than the core temperature. This trend of relative cerebral hypothermia persisted well into the period in which the core temperature was 38°C.
Conclusions. Deep barbiturate anesthesia resulted in a brain-to-core temperature gradient during CPB that was of a magnitude greater than the 1°C previously reported to modulate ischemic neurologic injury. We speculate that the timely administration of barbiturates (eg, during the latter stages of CPB) may be useful as part of a cerebroprotective regimen in humans undergoing CPB, in part because the barbiturates influence brain temperature.
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Introduction |
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This research [6] [7] and related investigations [8] [9] [10] [11] have generated controversy regarding the mechanism(s) by which anesthetics may protect the brain from ischemic injury. Traditionally, cerebral protection by anesthetics has been attributed to a simple metabolic depression [8] [12]. According to this line of reasoning, because the brain consumes less oxygen during metabolic depression, it is able to tolerate longer periods of incomplete ischemia (eg, as occur with hemodynamic shock or stroke) [12].
There are several limitations of the traditional theory to explain cerebral protection by anesthetics, even when it is restricted to the setting of incomplete ischemia. First, when different anesthetics or various doses of a given anesthetic are compared, there is no apparent relation between the cerebral metabolic rate of oxygen consumption (CMRO2) and the extent of cerebral protection [8] [9] [12]. Second, of the anesthetics that are cerebroprotective, protection appears to correlate best with the family of drugs that produce vasoconstriction (eg, the barbiturates) and, thus, diminish global cerebral blood flow [8] [12]. This paradox has been theorized to result from a reverse vascular steal phenomenon (ie, blood is shunted from normal brain to areas of brain at risk for ischemic injury), although experimental support for a reverse steal is limited [13]. Thus, currently, we do not know the mechanism(s) that underlies protection by anesthetics, including that associated with the single example of protection in humans (ie, barbiturate protection associated with CPB) [6].
Drummond [11] has suggested that the controversy surrounding anesthetic-related cerebroprotection may have been influenced, in part, by studies in which there were inadvertent changes in brain temperature. For example, much of the evidence of cerebroprotection by barbiturates resulted from studies in large animal models or in humans in which either temperature was not measured [14] or core—but not brain—temperature was measured [15] [16]. This is of importance because we now know that small reductions in cerebral temperature (ie, 1° to 6°C) have a profound, beneficial effect on outcome after cerebral ischemia [17] [18].
The present study expanded on these concepts. We speculated that, during barbiturate anesthesia, unexpected changes in brain temperature may have resulted from a direct effect of the drug on cerebral temperature. If present, such a barbiturate-related effect could be exploited to manage brain temperature better during CPB, in an attempt to improve outcome. Theoretically, for a barbiturate-induced temperature change to be relevant for cerebral protection, the drug simply would need to influence brain temperature by a quantity in excess of the minimum value reported to affect outcome (ie, 1.0° to 1.2°C) [17] [18] [19].
It previously has been theorized that brain temperature is influenced by a variety of factors, including cerebral blood flow (CBF) and CMRO2 [18] [20]. On the basis of this concept, the present study tested the hypothesis that high-dose barbiturates, which profoundly affect CBF and CMRO2 [12] [21], also have the potential to alter brain temperature, independent of core temperature. In contrast, halothane anesthesia, which affects CBF and CMRO2 to a much lesser extent [12] [21], should not produce independent changes in brain temperature. This hypothesis was tested in a canine model of hypothermic CPB and rewarming. Systemic temperature was manipulated from 38°C to 28°C, and back again, using the CPB circuit, while brain temperature followed passively.
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Material and Methods |
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Using a sagittal incision, the scalp was reflected laterally from the sagittal ridge. Bilateral parietal bur holes, measuring 1 cm in diameter, were created 1.5 cm lateral to the midline and 3 cm rostral to the lambdoidal ridge. Through these bur holes, epidural temperatures were measured by inserting catheter-style thermistors (model 555; YSI, Yellow Springs, OH) 1.5 cm rostral to the anterior margin of each hole. In addition, using the same bur holes, intraparenchymal brain temperatures were measured using needle thermistors (model 552; YSI) inserted perpendicular to the parietal cortex surface, to depths of 1 and 2 cm beneath the dura, bilaterally. (In pilot studies, we determined that the distal tips of the 1- and 2-cm intraparenchymal thermistors were located in the subcortical white matter and basal ganglia, respectively.) Thereafter, the bur holes were sealed with bone wax, and the portion of the needle thermistor that protruded beyond the dura was insulated thermally with foam tape (Microfoam; 3M, Minneapolis, MN).
A bifrontal and biparietal electroencephalogram was recorded using a polygraph and strip recorder (model 8-10; Grass, Quincy, MA) and gold cup electrodes were glued to the calvarium. To minimize insensible heat loss from the calvarium, the scalp was reapproximated toward the midline, without disrupting the intraparenchymal needle thermistor trajectory. Any gaps in the suture line were insulated with folded gauze sponges. Last, bilateral subtemporalis temperatures were measured using needle thermistors (model 552; YSI) inserted beneath the temporalis muscles bilaterally. Before each study, all the thermistors were calibrated manually using a mercury thermometer as a standard.
Core temperature was measured using a flexible vinyl thermistor (model 401; YSI) placed in the esophagus to the level of the right atrium. The position of the thermistor was confirmed by palpation at the time of thoracotomy.
Preparation for CPB was achieved by modifying previously described techniques [22]. Briefly, the dogs were placed in the right lateral decubitus position and a left anteriolateral thoracotomy was performed in the fourth intercostal space. Heparin (300 U/kg; Elkins-Sinn, Cherry Hill, NJ) was administered intravenously before cannulation. A single-stage 34F venous cannula (Bard, Tewksburg, MA) was inserted into the right atrial appendage. Then, to minimize insensible heat loss from the thoracic cavity, the skin margins of the thoracotomy were reapproximated using multiple perforating towel clips. Arterial cannulation was achieved by inserting a 16F catheter (Argyle, St. Louis, MO) into the right common femoral artery. Femoral cannulation was used to prevent cerebral hyperperfusion that is associated with inadvertent cannula tip malalignment.
A membrane oxygenator-heat exchanger (Maxima; Medtronic, Minneapolis, MN), open venous reservoir, serial arterial filter (Pall, Fajardo, Puerto Rico), and standard roller pump were used to provide nonpulsatile perfusion. The pump prime consisted of Plasmalyte solution (1,000 mL; Baxter, Deerfield, IL).
Once the preparatory period was complete, the anesthetic dose was adjusted to achieve a steady state. Specifically, dogs that received halothane were maintained at a 0.87% end-expired concentration (1.0 minimum alveolar concentration) and dogs that received barbiturates were given incremental intravenous pentobarbital in doses of 1 to 5 mg/kg to achieve and maintain electroencephalographic burst suppression.
Before CPB, core and cranial temperatures were maintained near 38.0° using convection-based surface warming techniques (Bair Hugger; Augustine Medical, Eden Prairie, MN). Fine regional temperature control was attained with supplemental heating lamps and pads. After a 20-minute stabilization period, CPB was initiated with flows of 100 mL · kg-1 · min-1. Before and during CPB, the FIO2 and total gas flows were adjusted to maintain the arterial oxygen tension at greater than 100 mm Hg and the arterial carbon dioxide tension near 35 mm Hg, sodium bicarbonate was given intravenously as needed to maintain the base deficit at 2 mEq/L or less, and an intravenous infusion of phenylephrine, 80 µg/mL, was administered as needed to maintain the mean arterial blood pressure near 90 mm Hg. During CPB, halothane anesthesia was maintained by adding 1% inspired halothane to the oxygenator using an agent-specific vaporizer, and the halothane concentration was confirmed using the Rascal II.
During the study, ambient temperature was maintained at 22°C. After the initiation of CPB, the core temperature was maintained at 38.0°C for 15 minutes (ie, the "baseline" phase). Thereafter, moderate hypothermia (ie, 28°C) was achieved over a period of approximately 21 minutes (ie, the "cooling" phase) and was maintained there for 30 minutes (ie, the "stable hypothermia" phase). The core temperature then was returned to 38°C over 21 minutes (ie, the "rewarming" phase) and maintained there for 30 minutes (ie, the "stable normothermia" phase). The core-to-heat exchanger temperature gradient was maintained at 10°C or less at all times to minimize the formation of gaseous emboli. Cerebral and systemic variables were recorded throughout the study.
At the completion of the study, the dogs were euthanized with high-dose pentobarbital (Sleep Away; Fort Dodge Laboratories, Fort Dodge, IA) and discontinuation of CPB.
Temperature gradients were calculated at each measurement interval using the following formula:
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Results |
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Comment |
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The differences between the effects of the two study anesthetics on brain temperature exceeded the 1.0° to 1.2°C previously reported to modulate ischemic neurologic injury [17] [19]. Because these differences may be exploited to manage brain temperature optimally during CPB, it is useful to review the origins of brain-to-core and regional brain temperature gradients. Brain temperature results from three major factors: CBF, cerebral metabolism, and the extracerebral environment [18] [20].
Cerebral Blood Flow
The amount of blood flowing to the brain (ie, CBF) and the brain-to-core temperature gradient determine the quantity and direction of heat exchange between these two compartments [20] [23]. For example, when the brain is warmer than the core, CBF tends to cool the brain. When the brain is cooler than the core, CBF tends to warm the brain. This relation explains why brain temperature and core temperature typically are in good agreement in the normal, intact brain [20] [23] [24] [25].
Alterations in PaCO2 that alter CBF, but have no meaningful effect on CMRO2, affect the brain-to-core temperature gradient [20]. In addition, as reviewed by Wass and Lanier [18], when the blood supply to the brain is reduced profoundly (eg, cerebral ischemia), heat delivery from the core to the brain is inadequate to compensate for environmental loss and cerebral hypothermia develops, beginning in the superficial brain areas.
Brain Heat Production
The brain has one of the highest metabolic rates in the entire body and, as a result of this metabolism, heat is produced [25]. This probably explains why the temperature of the resting brain often is reported to be 0.1° to 0.9°C warmer than the core temperature [20] [23] [24] [26].
Heat Exchange With the Environment
The third determinant of brain temperature is heat exchange with the environment [20]. We define this thermal environment in terms of the surrounding muscle and bone, as well as the extracorporeal environment. The phenomenon of heat exchange between the brain and the environment was documented clearly in two previous reports [24] [26] in which brain temperature was measured during craniotomy. Both groups of investigators reported that superficial brain structures were cooler than deeper structures, reflecting heat loss to the environment (ie, room temperature). For example, in the study by Stone and colleagues [26], the temperature 4 cm beneath the cortical surface was 36.9° ± 0.2°C (mean ± standard deviation); however, as the needle thermistor was withdrawn, the temperature decreased steadily to 33.3° ± 0.3°C (ie, a reduction of 3.6°C) at 1 cm beneath the cortical surface. A similar gradient between deep and superficial brain structures also has been reported in intact subjects with either nonischemic [20] [23] or ischemic [27] brains.
The results of the present study are in good agreement with this three-compartment model of brain temperature determinants. When dogs were given halothane, 1.0 minimum alveolar concentration (ie, an anesthetic that should have changed CBF, and hence heat flux from the core to the brain, and CMRO2, and hence endogenous heat production, minimally from the awake state) [12] [21], there was excellent agreement between the brain and core temperatures throughout the study. In contrast, when dogs were anesthetized with high-dose pentobarbital (ie, an anesthetic that should have diminished CBF and CMRO2 by 50% or more, compared with the awake state) [12] [21], the brain temperature typically lagged behind dynamic alterations in the core temperature.
The influence of environmental factors on brain temperature also was observed in pentobarbital-anesthetized dogs. In this group, temperatures at the more superficial measurement sites (ie, at the dura and 1 cm beneath the dura) were almost identical to the temperature at the subtemporalis measurement site (Fig 1). Further, the temperatures at these superficial sites differed more from the core temperature than did those at the deeper measurement site (ie, 2 cm beneath the dura). Such a pattern suggests that a barbiturate-induced brain-to-core thermal barrier resulted in superficial brain temperatures that were relatively less dependent on CBF, yet more dependent on heat exchange with the environment. In contrast, halothane-anesthetized dogs were more likely to exchange heat with the body core (mediated by a larger CBF) and to demonstrate proportionately less influence of environmental temperature on brain temperature.
Our research may help us better understand the broad-based mechanisms by which anesthetics protect the brain from ischemic injury in experimental laboratory preparations and humans. This issue recently has been reexamined, largely as a result of studies demonstrating that anesthetic cerebroprotection does not correlate with simple metabolic depression [8] [9] [10] [12]. Instead of metabolic depression, per se, as the origin of anesthetic-related protection, a more recent interpretation suggests that cerebroprotection by anesthetics may involve many mechanisms (eg, alterations in ion fluxes and excitatory amino acid metabolism) [10] [18]. The present research may have added one more item to the list of potential operant mechanisms: anesthetic modulation of temperature. It long has been known that, in the absence of rigid temperature control, the barbiturates (ie, the most protective of all anesthetics) [12] can reduce core temperature precipitously in animal models [28]. In addition, our research revealed that, under certain, clinically relevant conditions, the barbiturates also alter brain temperature independent of core temperature (Table 2; Fig 1), in a manner that potentially could influence outcome. This effect presumably is related largely to barbiturate-related cerebral vasoconstriction.
When extrapolated to the setting of anesthetic management during CPB in humans, it should be noted that barbiturate anesthesia shares many properties with recently introduced carbon dioxide tension management techniques [5] aimed at protecting the brain from injury. Induced vasoconstriction, regardless of whether it originates from CO2 manipulation [5] [20] or from barbiturates (Table 2; Fig 1), should limit heat exchange between the core and the brain. Thus, a potentially beneficial brain-to-core temperature gradient should be induced during rewarming (Table 2; Fig 1) and perhaps during static conditions as well. In addition to promoting hypothermia during rewarming (Table 2; Fig 1), vasoconstriction should attenuate tendencies toward cerebral hyperthermia [29] that possibly result from the jetting of hot blood from the thoracic aortic cannulation site into the brain during rewarming. (Our study did not evaluate the latter issue and instead was designed specifically to avoid such jetting of blood, by using a femoral arterial cannula for return from the CPB circuit.) Further, cerebral vasoconstriction, regardless of its origin, may lessen the fraction of cardiac output (or CPB output) that is directed to the brain. Thus, the fraction of CPB-associated emboli that are directed to the brain also may be reduced during CO2- or barbiturate-mediated vasoconstriction. However, unlike CO2 manipulation, barbiturate use may have the added benefit of dramatically reducing CMRO2 [21].
If our speculation is correct, we can envision possibly modifying management techniques to produce cerebral vasodilation during the cooling phases of hypothermic CPB (eg, by using pH-stat CO2 management [5] and a vasodilating anesthetic such as halothane [Table 2; Fig 1]) to promote brain cooling. In contrast, vasoconstrictive management techniques may be initiated later in a run of CPB-assisted circulation (eg, alpha-stat CO2 management [5] and barbiturate therapy [Table 2; Fig 1]) to capitalize on the potentially cerebroprotective aspects of the barbiturates, including selective brain cooling.
In summary, deep barbiturate anesthesia resulted in a gradient between the brain and core temperatures that was not present during halothane anesthesia. The observed gradient (ie, a phenomenon that presumably is related to the effects of pentobarbital on CBF and CMRO2) may be of relevance to the mechanism(s) by which anesthetics protect the brain from ischemic injury. When extrapolated to humans who are undergoing hypothermic CPB, hypothermia-mediated cerebroprotective therapy may be facilitated using an anesthetic with cerebral vasodilator or vasoconstrictor properties during systemic cooling or rewarming, respectively.
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Acknowledgments |
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TopAbstractIntroductionMaterial and MethodsResultsCommentAcknowledgmentsReferences |
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References |
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TopAbstractIntroductionMaterial and MethodsResultsCommentAcknowledgmentsReferences |
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1°C alter functional neurologic outcome and histopathology in a canine model of complete cerebral ischemia. Anesthesiology 1995;83:325-335.[Medline]
rd P, Smith M-L, et al. Preservation of brain temperature during ischemia in rats. Stroke 1990;21:758-764.This article has been cited by other articles:
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  K. M. Erickson and W. L. Lanier Anesthetic Technique Influences Brain Temperature, Independently of Core Temperature, During Craniotomy in Cats Anesth. Analg., May 1, 2003; 96(5): 1460 - 1466. [Abstract] [Full Text] [PDF]
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 C. T. Wass, J. R. Waggoner III, D. G. Cable, H. V. Schaff, D. R. Schroeder, and W. L. Lanier Selective convective brain cooling during hypothermic cardiopulmonary bypass in dogs Ann. Thorac. Surg., December 1, 1998; 66(6): 2008 - 2014. [Abstract] [Full Text] [PDF]
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 C. T. Wass, J. W. III, D. G. Cable, H. V. Schaff, D. R. Schroeder, and W. L. Lanier Selective convective brain cooling during normothermic cardiopulmonary bypass in dogs J. Thorac. Cardiovasc. Surg., June 1, 1998; 115(6): 1350 - 1357. [Abstract] [Full Text] [PDF]
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