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Anesth Analg 2000;91:140-144
© 2000 International Anesthesia Research Society

NEUROSURGICAL ANESTHESIA

Hypothermia Attenuates the Vasodilatory Response of Pial Arterioles to Hemorrhagic Hypotension in the Cat

Katsuyoshi Kishi, MD, Masahiko Kawaguchi, MD, Koukichi Kurehara, MD, Satoki Inoue, MD, Takanori Sakamoto, MD, Toshi Einaga, MD, Katsuyasu Kitaguchi, MD, and Hitoshi Furuya, MD

Department of Anesthesiology, Nara Medical University, Nara, Japan

Address correspondence and reprint requests to Katsuyoshi Kishi, MD, Department of Anesthesiology, Nara Medical University, 840 Shijo-cho, Kashihara, Nara 634-8522, Japan. Address e-mail to kishi{at}sikasenbey.or.jp


   Abstract
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 Abstract
Introduction
 Methods
 Results
 Discussion
 References
 
We investigated the effect of hypothermia on the vasodilatory response of pial arterioles to hemorrhagic hypotension. The cranial window technique was combined with microscopic video recording in an experiment involving 20 cats anesthetized with pentobarbital. The animals were randomly assigned to either a normothermic or a hypothermic group (32°C). Mean arterial pressure (MAP) was reduced in stepwise increments of 10 mm Hg (from 100 to 50 mm Hg) by blood withdrawal. The diameter of small (50–100 µm) and large (100–200 µm) pial arterioles was measured. In the normothermic group (n = 9), small and large arterioles dilated at a MAP of 60 and 50 mm Hg, and at a MAP of 70, 60, and 50 mm Hg, respectively, compared with baseline values obtained at a MAP of 100 mm Hg. In contrast, in the hypothermic group (n = 11), vasodilation of either small or large arterioles was absent. The percentage diameter of small and large arterioles (percentage of control) was significantly lower at a MAP of 70, 60, and 50 mm Hg in the hypothermic group than the normothermic group. Our in vivo study demonstrates that hypothermia impairs autoregulatory vasodilation of pial arterioles in response to hemorrhagic hypotension.

Implications: Deliberate mild hypothermia has been proposed as a means of providing cerebral protection during neurosurgical procedures. Our results suggest that cerebral blood flow autoregulation in response to hemorrhagic hypotension may be impaired during hypothermic conditions, indicating the importance of maintaining perfusion pressure during hypothermic therapy to prevent cerebral ischemia.


   Introduction
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 Abstract
 Introduction
Methods
 Results
 Discussion
 References
 
Autoregulation of cerebral blood flow (CBF) is an intrinsic ability of cerebral vessels that maintains CBF at a constant level over a wide range of perfusion pressures (1). Pial arterioles are the primary sites of autoregulatory function, changing their caliber in response to changes in blood pressure (2,3). Thus, variations in the diameter of pial arterioles have been used as an index of autoregulatory function. Although the mechanism of CBF autoregulation is not clearly understood, myogenic, metabolic, and neurogenic theories have been proposed to explain this phenomenon (4,5). In addition, it has been suggested that nitric oxide (NO) is involved in autoregulatory vasodilation during hypotension (6,7). Kajita et al. (6) demonstrated that NO release from isolated rat intracerebral arterioles increased in response to a decrease in transmural pressure. Jones et al. (7) reported that cortical suffusion of N{omega}nitro-D-arginine, a nitric oxide synthase inhibitor, raised the lower limit of autoregulation.

Investigations in laboratory animals have demonstrated that mild hypothermia is associated with a substantial decrease in histologic damage in models of both global and focal cerebral ischemia (8–10). Deliberate, mild hypothermia has been clinically applied to provide cerebral protection during neurosurgical procedures complicated by cerebral ischemia, such as cerebral aneurysm clipping or arteriovenous malformation resection, although the effects of mild hypothermia on neurologic outcome in such situations remains to be determined (11–13). To use this therapy safely, a clear understanding of the alterations in cerebral vascular reactivity induced by hypothermia is crucial.

Several studies have shown that hypothermia can alter both contractility and relaxation of blood vessels in the brain and in other vascular beds (14–16). Kawaguchi et al. (15) reported that mild hypothermia attenuated pial arteriolar vasodilation induced by nitroglycerin, a NO donor, in the cat. Booth et al. (16) suggested that hypothermia reduces the amount of NO release during nitroglycerin-induced vasodilation, as well as the vasodilatory response of vessels to NO. Because it appears likely that NO release and response of the vessels to NO may be modified during hypothermia, it is conceivable that autoregulation of CBF is also altered during hypothermia. However, most of the previous studies investigating the effects of hypothermia on CBF autoregulation were performed during cardiopulmonary bypass (17–19). There have been only a few reports to evaluate the influence of hypothermia on autoregulation during anesthesia without cardiopulmonary bypass (20,21). We, therefore, investigated the effect of hypothermia (32°C) on the vasodilatory response of pial arterioles to hemorrhagic hypotension in anesthetized cats.


   Methods
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 Abstract
 Introduction
 Methods
Results
 Discussion
 References
 
This study was approved by our Animal Experiment Committee. Twenty cats weighing 2.0 to 4.0 kg were used. Anesthesia was induced via inhalation of ethyl ether and was maintained with 1% to 2% isoflurane and 50% oxygen in nitrogen. After tracheal intubation and IM injection of 0.5 mg/kg pancuronium bromide, the lungs were mechanically ventilated to maintain end-tidal carbon dioxide partial pressure at 30 to 35 mm Hg. PETCO2 was measured continuously with a carbon dioxide analyzer. A double-lumen catheter was placed in the right femoral vein (one lumen was used for drug administration and the other for blood withdrawal). Isoflurane was discontinued. Then, 30 mg/kg IV pentobarbital was administered, followed by a continuous infusion of 6–10 mg · kg-1 · h-1 IV pentobarbital (22). Continuous infusion of 0.4 mg · kg-1 · h-1 pancuronium in lactated Ringer’s solution was initiated at a rate of 5 mL · kg-1 · h-1. The right femoral artery was cannulated for arterial pressure monitoring and blood gas analysis. Blood gases, pH, and hematocrit were measured periodically with a blood gas analyzer. During hypothermia, {alpha}-stat management (i.e., uncorrected for temperature) was used to monitor arterial carbon dioxide partial pressure and pH.

The head of each animal was secured in a stereotaxic frame. After midsagittal incision of the head, the right parietal bone was exposed, and a hole approximately 10 mm in diameter was made. The dura was carefully removed. The hole was filled with cerebrospinal fluid by lowering the animal’s head and covering the hole with glass, the edges of which were sealed with {alpha}-cyanoacrylate monomer (Alon-{alpha}; Touagousei Co., Tokyo, Japan).

Erythrocytes from 2 mL of blood were separated and rinsed with saline by centrifugation at 3000 rpm for 5 min, three times. To label erythrocytes with fluorescein isothiocyanate, the cells were incubated for 1 h in 10 mL phosphate-buffered saline (pH 7.8) containing fluorescein isothiocyanate (Sigma Chemical, St. Louis, MO) at 1 mg/mL. After infusion of IV fluorescein isothiocyanate-labeled erythrocytes, pial arterioles were visualized through a cranial window by using an intravital epifluorescence microscope and images of the vessels were recorded with a silicon-intensified target-tube video camera system (SIT; Hamamatsu Photonics, Hamamatsu, Japan) linked to a video recorder. The tape was later analyzed by using an image-analysis system (ARGUS-10; Hamamatsu Photonics). In observing the flow pattern of fluorescein isothiocyanate-erythrocyte vessels, branches in the direction of the flow stream were identified as arteries and arterioles. The opposite flow direction and branching pattern were used to identify veins. Pial arteriolar diameter was also measured with the image-analysis system. To measure the diameter of appropriately sized pial arterioles, the microscope was moved, if necessary. To measure vessel diameter in the same arterioles under different conditions and times, distribution of branches, divisions, curves, and crossings of arteries and veins were carefully checked and recorded manually on paper to create a chart. By using this chart, measurements of vessel diameters were obtained under different conditions at the same sites. The responses of small (50–100 µm) and large (100–200 µm) arterioles were analyzed separately to identify any size-dependent differences in responses.

A burr hole approximately 3 mm in diameter was made in the left parietal bone. Through this hole, a needle thermocouple sensor of 0.6 mm in diameter was inserted by pushing the tip approximately 1.5 cm into the brain, and brain temperature was continuously monitored with a digital thermometer (PTW-100A; Unique Medical, Tokyo, Japan). In a preliminary study, we observed brain temperature was constant at depths of 1.5 cm below the cortical surface. Desired temperatures were maintained by using a water blanket (Dual-Temp; Seabrook, Cincinnati, OH).

Animals were randomly allocated to one of two groups. In the normothermic control group (n = 9), brain temperature was maintained at 37°C. In the hypothermic group (n = 11), brain temperature was maintained at 32°C.

After 60 min of stabilization, blood was slowly withdrawn from the femoral venous catheter into a heparinized syringe until a mean arterial pressure (MAP) of 100 mm Hg was reached. Mean arterial pressure was kept at this level for 10 min, and the baseline diameters of small and large arterioles were measured. Then, MAP was reduced in stepwise increments of 10 mm Hg by slow withdrawal of blood and was kept at each level (90, 80, 70, 60, and 50 mm Hg) for 3 min before measuring vessel diameters. The diameter changes were expressed as percentage change from the baseline vessel diameter.

All values are expressed as mean ± SE. Statistical comparisons were made by using two-way analysis of variance with repeated measures, followed by Fisher’s protected least significant difference test. Differences were considered significant at P < 0.05.


   Results
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 Abstract
 Introduction
 Methods
 Results
Discussion
 References
 
At baseline, there were no significant differences in MAP, arterial blood pH, PaCO2, PaO2, and hematocrit between the normothermic and hypothermic groups (Table 1). Values for these variables at each level of MAP were not statistically different between the two groups. Arterial blood pH, PaCO2, PaO2, and temperature did not change significantly during hemorrhagic hypotension in both groups. In contrast, hematocrit was significantly lower at a MAP of 60 mm Hg (P < 0.05) and 50 mm Hg (P < 0.01) in the normothermic group and at a MAP of 70 mm Hg (P < 0.05) and 60 and 50 mm Hg (P < 0.01) in the hypothermic group, compared with the values at a MAP of 100 mm Hg.


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  		Table 1. Physiologic Values During Hemorrhagic Hypotension
 
The baseline diameters of small arterioles were 63 ± 4 µm and 68 ± 4 µm in the normothermic and hypothermic groups, respectively. There were no statistical differences in baseline diameter of small arterioles between the two groups. Figure 1 shows the changes in diameter of small arterioles during hemorrhagic hypotension in the normothermic and hypothermic groups. In the normothermic group, small arterioles significantly dilated at a MAP of 60 and 50 mm Hg compared with baseline (P < 0.01). In the hypothermic group, the diameters did not change during hemorrhagic hypotension. Diameters of small arterioles (percentage of control) were significantly smaller at a MAP of 70 mm Hg (P < 0.05) and 60 and 50 mm Hg (P < 0.01) in the hypothermic group than those in the normothermic group.



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  		Figure 1. Changes in diameter of small arterioles during hemorrhagic hypotension in the normothermic and hypothermic groups. In the normothermic group, small arterioles dilated at mean arterial pressures (MAPs) of 60 and 50 mm Hg compared with baseline (P < 0.01). In the hypothermic group, the diameters did not change during hemorrhagic hypotension. Diameters of small arterioles (percentage of control) were lower at MAPs of 70 mm Hg (P < 0.05) and 60 and 50 mm Hg (P < 0.01) in the hypothermic group than those in the normothermic group. Data are expressed as mean ± SE. *P < 0.01 versus control (at a MAP of 100 mm Hg),

 
The baseline diameters of large arterioles were 136 ± 7 µm and 144 ± 6 µm in the normothermic and hypothermic groups, respectively. There were no statistical differences between the two groups. Figure 2 shows the changes in diameter of large arterioles during hemorrhagic hypotension in the normothermic and hypothermic groups. In the normothermic group, large arterioles significantly dilated at a MAP of 70 mm Hg (P < 0.05) and 60 and 50 mm Hg (P < 0.01) compared with the baseline. In the hypothermic group, large arterioles significantly constricted at a MAP of 60 mm Hg P < 0.05) and 50 mm Hg (P < 0.01) compared with the baseline. Diameters of large arterioles (percentage of control) were significantly smaller at a MAP of 70, 60, and 50 mm Hg (P < 0.01) in the hypothermic group than those in the normothermic group.



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  		Figure 2. Changes in diameter of large arterioles during hemorrhagic hypotension in the normothermic and hypothermic groups. In the normothermic group, large arterioles significantly dilated at mean arterial pressures (MAPs) of 70 mm Hg (P < 0.05) and 60 and 50 mm Hg (P < 0.01) compared with the baseline. In the hypothermic group, large arterioles constricted at MAPs of 60 mm Hg (P < 0.05) and 50 mm Hg (P < 0.01) compared with the baseline. Diameters of large arterioles (percentage of control) were lower at MAPs of 70, 60, and 50 mm Hg (P < 0.01) in the hypothermic group than those in the normothermic group. Data are expressed as mean ± SE. *P < 0.01 versus control (at a MAP of 100 mm Hg), **P < 0.05 versus control.

 

   Discussion
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
References
 
Our results show that both small and large arterioles significantly dilated in response to hemorrhagic hypotension during normothermia in pentobarbital-anesthetized cats. However, this dilatory response was impaired when brain temperature was reduced to 32°C. Although CBF was not measured, the results suggest that CBF autoregulation in response to hemorrhagic hypotension may be impaired during hypothermia, indicating the importance of maintaining perfusion pressure during hypothermic therapy to avoid cerebral ischemia.

Kontos et al. (2) examined the effects of arterial blood pressure on cerebral arteries and arterioles by using a cranial window technique in normothermic pentobarbital-anesthetized cats. Between MAP of 110 and 160 mm Hg, autoregulatory adjustments in caliber, e.g., constriction when the pressure rose and dilation when the pressure decreased, occurred only in vessels larger than 200 µm in diameter. In contrast, when MAP decreased <=90 mm Hg, vessels <227 µm in diameter dilated. Below 70 mm Hg, dilation was maximum in the small arterioles (<100 µm in diameter). These findings are compatible with normothermic results, in which both small (50–100 µm) and large (100–200 µm) arterioles dilated in response to hemorrhagic hypotension.

During hypothermia, vasodilatory responses of pial arterioles to hemorrhagic hypotension were abolished. Verhaegen et al. (20) investigated the effect of moderate hypothermia with a pericranial temperature of 30.5°C on cerebral autoregulation by using a laser-Dopper flowmeter in halothane-anesthetized rats. When {alpha}-stat management (i.e., uncorrected for temperature) was used to monitor PaCO2 and pHa, CBF autoregulation was impaired; however, it was at least partially preserved during moderate hypothermia. By contrast, when pH-stat (i.e., corrected for temperature) management was used, autoregulation was abolished, indicating the importance of the acid-base management scheme chosen during hypothermia. Irikura et al. (21) also investigated the effects of moderate hypothermia (30°C) on the vasodilatory response of pial arterioles to hemorrhagic hypotension in rats anesthetized with {alpha}-chloralose and urethane. Vasodilation was significantly reduced in the hypothermic animals. Moreover, hypotensive vasodilation was more attenuated with pH-stat than {alpha}-stat management. Niwa et al. (23) examined the effects of mild hypothermia (33°C) with an {alpha}-stat management on autoregulation of regional CBF by using an autoradiographic technique in awake and spontaneously breathing rats. In the normothermic control, regional CBF in most of the supratentorial cortical regions was maintained down to a MAP of 50 mm Hg. In contrast, regional CBF in all brain regions declined significantly in proportion to decreasing MAP in the hypothermic group, suggesting that mild hypothermia disturbs cerebrovascular autoregulation in awake rats. Because an {alpha}-stat management is frequently used during deliberate mild hypothermia for neurosurgical procedures, we only examined the effect of hypothermia with an {alpha}-stat management. However, considering the results from the previous studies and our study, hypothermia impairs CBF autoregulation, even with an {alpha}-stat management, although the effect of hypothermia on CBF autoregulation is more prominent with a pH-stat management than {alpha}-stat management.

During hemorrhagic hypotension, hematocrit was significantly reduced in both groups. Hemodilution has been reported to induce constriction of pial arterioles (22,24). Therefore, we cannot deny the possibility that autoregulatory vasodilation of pial arterioles was underestimated and hypothermia affected vasoconstriction of pial arterioles induced by a reduction of hematocrit. However, because the extent of reduction of hematocrit was similar between the normothermic and hypothermic groups, we believe that the influence of hematocrit would be similar.

We used pentobarbital for anesthesia in both groups. However, hypothermia might affect drug kinetics. Leslie et al. (25) demonstrated that a temperature reduction of 3°C increased blood propofol concentration by 30% during a constant rate infusion. Although the effect of hypothermia on pentobarbital kinetics is not defined in cats, hypothermia might attenuate the metabolism of barbiturates, resulting in a larger concentration of pentobarbital. There is a possibility that this difference between groups might have affected our results. However, Donegan et al. (26) investigated the effect of different doses of pentobarbital on autoregulatory responses of CBF to hypotension in sheep and demonstrated autoregulatory responses were similar among the sheep, either awake or anesthetized with pentobarbital (lightly or deeply). Therefore, it is unlikely that relatively small increases in pentobarbital concentration caused by hypothermia abolished vasodilatory responses of pial arterioles.

In summary, vasodilatory responses of pial arterioles to hemorrhagic hypotension were attenuated by hypothermia (32°C). These results suggest that CBF autoregulatory responses to hypotension may be impaired during mild hypothermic therapy, indicating that maintenance of cerebral perfusion pressure would be important to prevent cerebral ischemia during mild hypothermic therapy for neurosurgical procedures. Further study is required to clarify the effect of mild hypothermia on autoregulatory response in a clinical situation.


   References
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 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 

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Accepted for publication March 20, 2000.





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Lippincott, Williams & Wilkins Anesthesia & Analgesia® is published for the International Anesthesia Research Society® by Lippincott Williams & Wilkins with the assistance of Stanford University Libraries' HighWire Press®. Copyright 2006 by the International Anesthesia Research Society. Online ISSN: 1526-7598   Print ISSN: 0003-2999 HighWire Press