Anesth Analg 2003;96:1460-1466
© 2003 International Anesthesia Research Society
NEUROSURGICAL ANESTHESIA
Anesthetic Technique Influences Brain Temperature, Independently of Core Temperature, During Craniotomy in Cats
Kirstin M. Erickson, MD, and
William L. Lanier, MD
Department of Anesthesiology, Mayo Clinic and Mayo Medical School, Rochester, Minnesota
Address correspondence and reprint requests to William L. Lanier, MD, Department of Anesthesiology, Mayo Clinic, 200 First St., S.W., Rochester, MN 55901. Address e-mail to lanier.william{at}mayo.edu
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Abstract
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Because anesthetic technique has the potential to dramatically affect cerebral blood flow and metabolism (two determinants of brain thermoregulation), we tested the hypothesis that, after craniotomy, anesthetic technique would influence brain temperature independent of core temperature. Twenty-one cats (2.7 ± 0.4 kg; mean ± SD) undergoing a uniform right parasagittal craniotomy received 1) halothane 1.5% end-expired and normocapnia (HN), 2) halothane 1.5% and hypocapnia (HH), or 3) large-dose pentobarbital and normocapnia (PN) (n = 7 per group). Heating devices initially maintained core and right subdural normothermia (38.0°C). Thereafter, cranial heating was discontinued. Brain-to-core temperature gradients during the 3 h study were greatest in the right subdural area, averaging -2.5°C ± 0.9°C in HN, -2.5°C ± 0.8°C in HH, and -4.1°C ± 1.1°C in PN. Gradients within the unexposed left subdural area and in the right cortex 0.5 and 1.0 cm below the brain surface were -0.8°C ± 0.5°C to -1.1°C ± 0.6°C for both HN and HH but were twice this amount in PN (-1.9°C ± 0.5°C to -2.1°C ± 0.7°C) (P < 0.05 for PN versus HN and HH). Deep barbiturate anesthesia can reduce brain temperature independently of core temperature, presumably by reducing the metabolic rate and associated brain heat production. The magnitude is sufficient to augment any direct cerebroprotective properties of the barbiturates.
IMPLICATIONS: Deep barbiturate anesthesia reduced brain temperature independently of body temperature in cats and significantly more than the reduction seen with halothane anesthesia. The magnitude of temperature reduction was sufficient to account for cerebral protection by barbiturates independently of any other properties of the drug.
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Introduction
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Initial investigations into cerebral protection by hypothermia demonstrated increased tolerance to ischemia with profound levels of hypothermia (1,2). Additional research has determined that small alterations in brain temperature influence postischemic outcome in animal models (1,3–5). In the most dramatic examples, a 1.2°C change in pericranial temperature was reported to produce a threefold difference in cortical infarct volume in a halothane-anesthetized rat model of focal cerebral ischemia (5). In a halothane-anesthetized canine model of global cerebral ischemia, a 1°C change in core and pericranial temperature was associated with a significant alteration in postischemic neurologic function and brain histology (4). These results are consistent with retrospective data in humans in which temperature variations as small as 1.0°C were associated with altered outcome after acute stroke (6).
On the basis of these and a host of related studies, investigators have begun examining the possibility of reducing core temperature during surgery to, in turn, reduce brain temperature and protect the brain from injury associated with craniotomy and neurologic surgery (7,8). Inasmuch as a broad variety of anesthetics are used clinically for neurologic surgery and these same anesthetics are used in animal models of cerebral protection, this research examined the relationship between anesthetic technique and brain thermoregulation. Specifically, the purpose of this study was to test the hypothesis that, by virtue of known effects of anesthetics on cerebral blood flow (CBF) and metabolic rate (CMR) (2), the choice of anesthetic technique will potentially affect brain temperature independently of core temperature. If true, such a finding might influence the choice of anesthetic when brain temperature reduction is desired for cerebroprotection during craniotomy in humans. Additionally, a positive finding in our research might lead to a reinterpretation of older cerebral protection literature in which protective effects of anesthetics were often reported without reference to temperature or in which the studies were conducted with measurement of core, rather than brain or pericranial, temperature. Our research used a model of craniotomy in cats to test the hypothesis that, when compared with a control anesthetic of normocapnia during halothane inhalation, brain-to-core temperature gradients are augmented by either 1) hypocapnia during halothane anesthesia due to reduced CBF (2,9) or 2) deep barbiturate anesthesia as a result of both reduced CBF and CMR (2,10).
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Methods
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After approval by the Institutional Animal Care and Use Committee, 21 purpose-bred cats (Harlan-Sprague-Dawley, Indianapolis, IN) of a consistent age (7.6 ± 1.6 mo; mean ± SD) and weight (2.7 ± 0.4 kg) were fasted for 12 h while having free access to water. Anesthesia was induced in a PlexiglasTM box containing 2.5%–3.5% halothane in oxygen. The trachea was intubated with a 3.5-mm-internal-diameter cuffed tube (Rüsch, Kernen, Germany), and the lungs were mechanically ventilated (Model 613; Harvard Apparatus, Holliston, MA). The ventilator was initially set at a tidal volume of 20–25 mL/kg, and the respiratory rate was adjusted to maintain arterial carbon dioxide tension (PaCO2) near 25 mm Hg. Anesthesia was maintained with halothane 1.5% end-expired in oxygen during the surgical preparation (Rascal II; Ohmeda, Louisville, CO). Forelimb veins were cannulated bilaterally for the administration of fluids and drugs. After a bolus of pancuronium 1.0 mg IM, a continuous infusion of 0.2 mg · kg-1 · h-1 was begun. The Lead II electrocardiogram was monitored continuously for heart rate (Model 90603A; SpaceLabs, Redmond, WA). Retrocardiac esophageal temperature was measured with a thermistor (Model 401; Yellow Springs Instrument Co., Yellow Springs, OH), and core temperature was maintained near 38.0°C by using a heating pad and infrared lights. A femoral artery was cannulated and used for blood sampling (Model 1306; Instrumentation Laboratory, Lexington, MA) and continuous arterial pressure monitoring (Model 78; Grass Instrument Co., Quincy, MA). Whole-blood glucose was measured (Model 1500, Sidekick; Yellow Springs Instrument Co.).
Thereafter, the animal was placed in the prone position with the head secured in a head holder. After a midline scalp incision, the scalp and temporalis muscles were reflected bilaterally. Gold electrodes were attached to the calvarium bilaterally for measurement of the biparietal electroencephalogram (EEG) by using a polygraph and strip recorder (Model 7; Grass Instrument Co.). Over the left cerebral hemisphere, a 3- to 4-mm-diameter burr hole was placed. A small slit was made in the dura, and a 0.7-mm-diameter flexible thermistor (Model 555; Yellow Springs Instrument Co.) was advanced under the dura, 6–8 mm into the subdural space. The left temporalis muscle and pericranial skin were then returned to an approximation of their original presurgical positions, and the skin margins were glued in place with cyanoacrylate glue (Super Glue; Duro, Avon, OH). Thereafter, a 2.4 x 1.2 cm parasagittal craniectomy was performed over the right hemisphere. After hemostasis, the dura in the middle of the craniotomy site was incised, making a 2- to 4-mm coronal slit. As with the left hemisphere, a small flexible thermistor was advanced 6–8 mm into the subdural space, so that the tip remained within the area of the open craniotomy. The remaining dura within the craniotomy was left intact to hold the subdural thermistor in place and to prevent inadvertent measurement of ambient temperature. Additionally, a flexible thermistor was placed vertically into the cortex via an 18-gauge, blunt-tipped introducer needle to measure temperature 0.5 cm beneath the brain surface. Temperature 1.0 cm beneath the brain surface was quantified by using a 22-gauge (0.7-mm-diameter) needle thermistor (Model 552; Yellow Springs Instrument Co.) also placed perpendicular to the brain surface. A separate thermistor (Model 401; Yellow Springs Instrument Co.) was used to record ambient temperature.
Heating pads and infrared heating lamps were used to maintain core temperature near 38°C. Additional heating lamps were used before and during baseline conditions to increase subdural brain temperature to near 38°C. A tinfoil-wrapped Elizabethan collar was placed around the cat’s neck to prevent any infrared light directed at the trunk from heating the head. Similarly, a tinfoil reflecting plate was used to differentially alter right and left brain warming before baseline measurements were obtained.
The cats were divided into three study groups. In the halothane/normocapnia group (HN; n = 4 males and 3 females), cats remained anesthetized with halothane 1.5% end-expired, and inspired CO2 was added to increase PaCO2 to 40 mm Hg. In the halothane/hypocapnia group (HH; n = 5 males and 2 females), halothane anesthesia was maintained without supplemental inspired CO2; hence, PaCO2 remained near 25 mm Hg. In the pentobarbital/normocapnia group (PN; n = 5 males and 2 females), cats were maintained at normocapnia with added CO2, as above. The inspired halothane was discontinued, and anesthesia was maintained instead with pentobarbital: an initial loading dose of 24.0–39.3 mg/kg in divided doses followed by an infusion of 10–20 mg · kg-1 · h-1 to produce profound burst suppression or electrocortical inactivity on the EEG. Further study of this group was not begun until end-expired halothane had declined to 
0.1%. In all cats, sodium bicarbonate was given as needed to maintain base excess near zero.
During the baseline period, core and right subdural temperatures were maintained at 38°C, whereas temperatures at the other sites were allowed to passively stabilize. After baseline measurements, brain warming was discontinued while core temperature was maintained at 38°C. Temperatures and physiologic variables were recorded at 15-min intervals, and blood gasses and acid-base status were assessed every 30 min for 3 h. At the completion of the study, the brains were dissected to confirm placement of the thermistors.
Brain-to-core temperature gradients were calculated from each brain site, at each measurement interval, by using the formula: gradient = brain temperature - core temperature. When post hoc analysis revealed that temperature gradients achieved near-plateau values shortly after brain heating was discontinued, a simple average of the 15-min to 3-h gradients was performed in each cat and tabulated for the various study groups. Physiologic data within a given study group were compared between the baseline and formal study periods by using paired Student’s t-tests.
Data among groups were compared by using an analysis of variance and post hoc Bonferroni’s correction of unpaired Student’s t-tests. A probability of <0.05 was considered statistically significant.
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Results
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Weight and systemic physiologic variables are reported in Table 1. As expected, HH cats had lesser PaCO2 and greater pH values. Further, blood pressure tended to be less in PN cats, though even in this group blood pressure remained within the normal range for cats without the use of pressor drugs. Mean hematocrit was less in PN cats, despite the fact that overall fluid administration during the entirety of the study did not significantly differ among groups (25.7 ± 14.4 mL of 0.9% saline solution in HN, 33.1 ± 11.7 mL in HH, and 34.2 ± 9.0 mL in PN) (P = 0.37 by analysis of variance).
In HN and HH, the EEG during baseline conditions typically consisted of mixed 3- to 12-Hz activity with an amplitude ranging from 5–50 µV. Brain cooling during the study period did not meaningfully affect frequency, but it reduced amplitude, typically to 5–30 µV. In the PN group, five cats had electrocortical inactivity during baseline and throughout the formal study. The remaining two cats had burst suppression (burst for 8% and 18% of the time, respectively) during baseline measurement; however, the EEG activity progressively diminished during the remainder of the study as a result of adjusting the pentobarbital dose. Both had attained electrocortical inactivity by the 60- and 75-min measurement periods, respectively. The total pentobarbital dose in PN cats was 114.5 ± 13.6 mg/kg.
During baseline conditions, with right epidural temperature maintained the same as core temperature in all groups, the temperatures within the right brain parenchyma and left subdural space were slightly warmer, by an average of 0.4°C more, than core temperature (Table 2, Fig. 1A–C). Once the cranial warming was ceased, the brain-to-core temperature gradient in all brain sites significantly declined to less than core values (P < 0.05) in all groups, with the most dramatic alterations occurring in the first 15 min (Fig. 1A–C). Specifically, in all brain areas in all groups, 57%–91% of the maximum (i.e., 180-min) brain-to-core temperature gradients were achieved by 15 min. Gradients during the remainder of the 3-h study (i.e., beginning with the 15-min measurement) were greatest in the right subdural area, averaging -2.5°C ± 0.9°C in HN, -2.5°C ± 0.8°C in HH, and -4.1°C ± 1.1°C in PN (P < 0.05 for PN versus HN and HH). Average gradients within the unexposed left subdural area, as well as gradients within the right cortex at 0.5 and 1.0 cm below the brain surface, ranged from -0.9°C ± 0.5°C to -1.1°C ± 0.6°C in the collective HN and HH groups but were twice this amount in the PN group (P < 0.05 for PN versus HN and HH) (Table 2, Fig. 1A–C).
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Figure 1. Brain-to-core temperature gradients in cats anesthetized with (A) halothane and normocapnia, (B) halothane and hypocapnia, or (C) pentobarbital and normocapnia. Each data point represents the mean value for seven cats. Estimates of variability are presented in Table 2.
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On postmortem examination, gross dissection of the brains revealed no evidence of perithermistor or intracranial hemorrhage. The 0.5-cm temperature probe tips were located in either cortical gray matter (44%) or cortical white matter (56%). The 1.0-cm temperature probe tips were located at the interface of the cortical white matter and the lateral ventricle, protruding slightly into the ventricle in 38% or remaining exclusively in the cortical white matter in 62%. When extrapolated to the human brain, the probe locations were comparable to placement in the superior parietal lobule of the cortex for the 0.5-cm thermistor and at the interface of the cortical white matter and the lateral ventricle, superior to the hippocampus (Susan L. Stoddard, PhD, Mayo Clinic, Rochester, MN, personal communication, 2002).
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Discussion
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A previous report from our laboratory introduced a mechanistic model of brain thermoregulation, in which brain temperature is determined by three factors: 1) CBF, which facilitates heat exchange between the brain and the core; 2) CMR, which generates heat; and 3) heat exchange with the environment via conduction, convection, and radiation (3). In our research, we tested the implications of this model in response to three anesthetic techniques that were selected for their differing effects on CBF and CMR. The HN control group received 1.5% (1.3 minimum alveolar anesthetic concentration) (11) of the vasodilating anesthetic halothane during normocapnia, a technique that should have produced the greatest combination of CBF and CMR of the three study groups. To this we compared an equal concentration of halothane during conditions of hypocapnia (HH group), a technique that should not have meaningfully differed from the control group in CMR but should have produced a significant reduction in CBF (2). It is estimated that during halothane anesthesia CBF declines by 2%–4% for each 1.0 mm Hg reduction in PaCO2 (9,12). Given the 15 mm Hg difference in PaCO2 in the HH group compared with the control HN group, we estimate a 30%–60% reduction in CBF. In the third study group (PN), the large-dose pentobarbital anesthetic, which produced EEG depression, should have reduced both CBF and CMR by 50%–60% (2,10). Hence, the anesthetic techniques were chosen to represent the extreme effects (HN and PN) of CBF and CMR, as well as to afford an opportunity to tease out the independent effects of CBF versus CMR (HH versus HN and PN). Furthermore, these three anesthetic techniques were evaluated under conditions of unilateral craniotomy, which should have enhanced the potential for heat exchange with the environment, even though the associated dura remained intact. Observations on the contralateral side of the brain were made with the dura and surface of the cortex not exposed. Thus, our experimental design permitted a point-by-point evaluation of the three-compartment mechanistic model of thermoregulation as mentioned above.
During baseline conditions, core and right subdural temperatures were maintained at normothermia. With this study design, the temperatures of the remaining brain areas tended to be greater than the core. This slight increase of temperature in unexposed brain is consistent with research in both awake and anesthetized animal models and humans (3,13) and likely reflects the effect of endogenous heat production by cerebral metabolism. Additionally, during baseline conditions in our experiments, the 0.5- and 1.0-cm sites were warmer than the more superficial subdural surface, again reflecting the likely relationship between heat production by metabolism and heat loss from the brain or cranial surface that is documented in the literature (13–15).
After cranial warming was discontinued, brain temperatures decreased most dramatically in the initial 15 minutes and thereafter reached near-plateau values for the remainder of the study. The rapid establishment of this new near-equilibrium state likely reflects the small mass of the cat’s brain; hence, the time to reequilibration would likely be larger in humans and other species with larger brains. Of note, the temperature reductions in the exposed right subdural area were much greater than in either of the intracortical measurement sites or in the unexposed left subcortical measurement site (Fig. 1A–C). Hence, our model confirmed the importance of environmental exposure as a source of brain heat loss during craniotomy, as previously observed clinically (13). During our study, brain-to-core temperature gradients were least in the HN group, the group that should have had the greatest combination of heat production by CMR and replenishment of any heat losses as a result of a luxury CBF. Specifically, in HN cats, the mean right subdural gradient was -2.5°C ± 0.9°C, and the mean left subdural and right parenchymal brain tissue gradients ranged from -0.8°C ± 0.5°C to -1.1°C ± 0.6°C (Table 2). When hypocapnia was added to this same background anesthetic (HH group) to diminish CBF without affecting CMR, the temperature gradients did not meaningfully differ from those in the HN control group. From this, we conclude that, even with CBF in HH reduced by one-third to one-half of the values anticipated in the HN control group, the remaining CBF was more than adequate to maintain the equilibrium among stable core and ambient temperatures versus brain temperatures.
In our experiments, the brain’s equilibrium temperature differed from that in the control HN group only in the PN group, a group in which the anesthetic should have dramatically reduced both CBF and CMR. In this setting, the gradients were almost twice as great in the PN group as compared with the same times and brain areas in the HN and HH groups. In PN, the mean right subdural gradient was -4.1°C ± 1.0°C, and the mean left subdural and right parenchymal brain ranged from -1.9°C ± 0.5°C to -2.1°C ± 0.7°C. When the observed temperature changes in the three study groups are compared with the estimated changes in CBF and CMR, we conclude that the unique temperature changes in PN were primarily the result of metabolic depression. Specifically, the diminished heat production resulting from metabolic depression was sufficient to establish a new equilibrium in the relationship between heat loss to the environment and CBF-facilitated heat exchange between the brain and body core. In contrast, in HH, when CBF was reduced independently of changes in CMR, the equilibrium temperature did not differ from that in the HN control group.
Of note, our study design used halothane and pentobarbital, two commonly used anesthetics in the field of cerebral ischemia and outcome research. These drugs also represent the extreme effects of anesthetics on CBF and CMR. Certainly, clinical application of these findings could be strengthened by repeating the experiment with more modern anesthetics (e.g., isoflurane, sevoflurane, and propofol) that are often used in the care of patients having craniotomy and who are at high risk for ischemic brain injury. Anesthetic-related reductions in brain temperature of the magnitude we report, independent of reductions in core temperature, have implications for cerebral protection by anesthetics.
As reviewed by Lanier (1) and Wass and Lanier (3), there is now an extensive body of literature demonstrating that temperature reductions of 1°C–6°C can protect the brain from ischemic injury. These temperature alterations are well within the range of brain-to-core temperature gradients identified in our study. Specifically, all three study groups (HN, HH, and PN) developed brain-to-core temperature gradients of this magnitude when compared with baseline conditions (i.e., conditions in which gradients should have mimicked the awake state). However, among the three anesthetics studied, the barbiturate-anesthetized PN group had temperature gradients far greater than needed to contribute to cerebral protection. Specifically, depending on the brain area under investigation, the gradients found in PN cats were 1.3°C to 4.0°C more than baseline and 0.9°C to 1.5°C more than in the HN control group (Table 2, Fig. 1, A and C). The potential significance of this observation is as follows.
In the 1997 near-comprehensive review of Polis and Lanier (16), the authors evaluated the cerebroprotective properties of anesthetics with respect to their effect on CMR. The most consistent evidence of cerebral protection occurred when the barbiturates were given in the setting of focal ischemia (see their table 3). In the 20 cited barbiturate articles available at that time, all published between 1974 and 1996, cerebral protection was reported in 19 of the 24 separate study protocols (results were equivocal in one study) (17–36). Brain or pericranial temperature was measured in only 5 of these 24 protocols (20,34–36). Rectal, esophageal, and pulmonary artery temperatures or some other extracranial "body temperature" was reported in 13 (17,18,20–22,25,27,29,31–33), whereas the remaining 6 had no mention at all of temperature quantification (19,23,24,26,28,30). Temperature was nearly universally not quantified during awakening (17–32,34,35), even in studies in which there was permanent clipping of the cerebral vessel. Aside from the facts that the barbiturate-treated groups would have had longer anesthetics in many of these studies and that barbiturates produce core hypothermia in laboratory animals (38), our study suggests that the barbiturates may also have produced isolated cerebral hypothermia in areas of brain at risk for ischemic injury in many of the above mentioned outcome studies. Because temperatures both during and after the onset of ischemia are operant in modulating neurologic outcome (3), it is quite possible that previous reports of barbiturate-related cerebroprotection actually observed, to some extent, hypothermia-related cerebroprotection. More modern studies have controlled both core and pericranial temperature and still reported cerebral protection by the barbiturates (34–36), hence demonstrating an anesthetic protective effect that is not dependent on the potentially confounding influence of brain temperature reduction. However, the bulk of studies often cited as offering evidence of protection by barbiturates cannot exclude the effects of isolated cerebral hypothermia as a confounding factor.
If this speculation on our part is correct, the existing literature may give an overly optimistic impression of direct cerebral protection by the barbiturates. However, in select neurosurgery patients, barbiturates may have an added indirect protective effect by enhancing the inevitable cerebral hypothermia that occurs during craniotomy (13). In contrast, when the brain is not exposed, the barbiturates may offer less impressive clinical protection, perhaps explaining the difficulty in demonstrating cerebral protection by barbiturates in the setting of cardiopulmonary bypass-associated cerebral injury (37,39).
In summary, our research determined that deep barbiturate anesthesia, which dramatically reduces CBF and CMR, reduces brain temperature independently of core temperature, particularly in brain regions underlying a craniotomy. This barbiturate effect is much more profound than the changes observed with anesthetics producing lesser effects on CBF and CMR. The magnitude of the barbiturate effect is in excess of the 1.0°C to 1.2°C change in temperature previously reported to modulate ischemic neurologic injury (4,5). This observation is of mechanistic importance in interpreting previous reports of cerebral protection by barbiturates. Barbiturate-related reductions in brain temperature, independent of core temperature, can possibly augment any other cerebral protective effects that barbiturates may have. It is quite possible that previous reports of direct, barbiturate-related cerebral protection actually observed, to some extent, hypothermia-related cerebral protection. Hence, barbiturate-associated changes in brain temperature may have some relevance to cerebral protection by anesthetics in the setting of craniotomy and surgery on the brain.
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Acknowledgments
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We are grateful to Rebecca M. Wilson for her expert technical support, Frank W. Sharbrough, MD, for assistance quantifying the EEG data, and Susan L. Stoddard, PhD, for help with comparative neuroanatomy.
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Footnotes
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This research was awarded the New Investigator Research Award by the Society of Neuroanesthesia and Critical Care, 2002.
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Accepted for publication January 23, 2003.
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H. D. Bauser-Heaton and H. G. Bohlen
Cerebral microvascular dilation during hypotension and decreased oxygen tension: a role for nNOS
Am J Physiol Heart Circ Physiol,
October 1, 2007;
293(4):
H2193 - H2201.
[Abstract]
[Full Text]
[PDF]
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Abstract
Introduction
