JOURNAL HOME CME HOME THIS MONTH PAST ISSUES ETOC COLLECTIONS
AUTHORS REVIEWERS EDITORIAL BOARD FEEDBACK RSS HELP
A&A International Anesthesia Research Society
QUICK SEARCH:   [advanced]


     

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a colleague
Right arrow Similar articles in this journal
Right arrow Similar articles in Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrowRequest Permissions
Citing Articles
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Takayama, R.
Right arrow Articles by Mori, H.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Takayama, R.
Right arrow Articles by Mori, H.
Related Collections
Right arrow Neuroanesthesia
Right arrow Anesthetic Techniques

Anesth Analg 2005;100:1458-1462
© 2005 International Anesthesia Research Society
doi: 10.1213/01.ANE.0000148659.04168.DB

NEUROSURGICAL ANESTHESIA

Section Editor:
David S. Warner

Selective Brain Hypothermia Suppresses Noxious-Evoked Movement in Canines

Ryukichi Takayama, MD*, Rumiko Uda, MD*, Naofumi Isono, MD{dagger}, Motomasa Furuse, MD{dagger}, Tomio Ohta, MD{dagger}, Toshihiko Kuroiwa, MD{dagger}, and Hidemaro Mori, MD*

Department of *Anesthesiology and {dagger}Neurosurgery, Osaka Medical College, Japan

Address correspondence and reprint requests to Ryukichi Takayama, MD, Department of Anesthesiology, Osaka Medical College, 2-7 Daigaku-machi, Takatsuki, Osaka 569-8686, Japan. Address e-mail to ane030{at}poh.osaka-med.ac.jp.


   Abstract
Top
 Abstract
Introduction
 Methods
 Results
 Discussion
 References
 
Systemic hypothermia suppresses noxious-evoked movement, but its main site of action is unknown. We examined the effect of hypothermia in the brain on noxious-evoked movement by selectively cooling the brain. Sixteen beagles were randomly divided into two groups and anesthetized with isoflurane/oxygen. After being deeply anesthetized, the dogs’ lungs were artificially ventilated, and several major vessels were cannulated for perfusion and monitoring. Cold lactate Ringer’s solution was infused into the right vertebral artery to cool the brain while maintaining the trunk temperature relatively warmer. When the brain temperature decreased to 20°C or 25°C, isoflurane administration was discontinued; the trunk temperatures at this stage were approximately 34.7°C and 34.6°C, respectively. After the end-tidal isoflurane concentration reached 0%, the base of the tail was stimulated with an electric current through 2 25-gauge needles. None of the dogs reacted to tail stimulation when the brain temperature was at 20°C, whereas 7 of 8 reacted at 25°C. These results indicate that selective brain hypothermia (20°C) results in suppressing noxious-evoked movement in canines.


   Introduction
Top
 Abstract
 Introduction
Methods
 Results
 Discussion
 References
 
Anesthetic requirements are known to be dependent on body temperature (1–6). Systemic hypothermia suppresses movement to a noxious stimulus at 20°C in animals (7), but the mechanism is not clear. The spinal cord is now recognized as an important site of anesthetic action. In particular, anesthetics produce immobility in response to a noxious stimulus via action in the spinal cord (8,9), but the effect of hypothermia on the spinal cord remains unknown. We hypothesized that controlled brain hypothermia, by differential cooling at normothermic trunk temperature, suppresses noxious-evoked movement. A technique is presented for isolated cooling of the brain in canines by selective hypothermic perfusion (10–12).


   Methods
Top
 Abstract
 Introduction
 Methods
Results
 Discussion
 References
 
Our institutional animal care and use committee approved this study. Sixteen female beagles weighing 9 to 11 kg were each anesthetized with a mask using isoflurane (Abbott, Tokyo, Japan) in oxygen. Tracheal intubation was performed after the anesthesia induction. Anesthesia was maintained by isoflurane in oxygen delivered via a calibrated vaporizer (TEC3; Ohmeda, England, United Kingdom). The canines were randomly assigned to one of 2 groups (n = 8 per group): group A (brain cooling at 20°C) and group B (brain cooling at 25°C).

A 12F triple-lumen catheter (CS-15123-E; Arrow, Tokyo, Japan) was inserted into the inferior vena cava (IVC) via the right femoral vein for venous access and for infusion of venous blood from the ultrafiltration and rewarming circuit. A 16-gauge needle was inserted into the right femoral artery (FA) for mean arterial blood pressure (MAP) and blood gas determination.

The common carotid arteries (CCAs), vertebral arteries (VAs), and jugular veins (JVs) were surgically and bilaterally exposed in the neck, and a 7F double-lumen catheter (AK-17702-J; Arrow) was inserted into the distal right VA to infuse cooled Ringer’s lactate solution (Otsuka, Tokyo, Japan) into the brain. The 12F triple-lumen catheter was also inserted into the distal right JV to extract blood for blood gas measurement, ultrafiltration, and rewarming.

A flow-directed pulmonary artery catheter (AI-7365H; Arrow) was inserted into the pulmonary artery via the right JV to measure pulmonary artery blood temperature (PAT). This was continuously recorded on an Oximetrix-3 monitor (Abbott). The temperature was recorded at the tip of the pulmonary artery catheter and the rectum.

The bilateral CCAs, left JV, and left VA were occluded with open-close control of the vessels, which was accomplished using vascular loops with rubber tubing occluders. A burr hole was made 1.5 cm lateral to the midline in the left frontal bone, and a needle thermistor (Type NST; Shibaura Electronics, Tokyo, Japan) was inserted into the brain to monitor brain temperature at a depth of 1 cm. Core temperature was measured using a thermistor placed in the pulmonary artery, and a rectal thermometer (ER400–12; Nihon Medico, Nagoya, Japan) was used for peripheral temperature determination. Small burr holes were made in two places 1.5 cm lateral to the midline in the left parietal bone, and needle electrodes were placed in the epidural space to obtain an electroencephalogram (EEG), which was continuously monitored with an OEE-7204 monitor (Nihon Kohden, Tokyo, Japan). The circuit for selective brain cooling (SBC) was the same (Nikkiso CO, Ltd., Tokyo, Japan) as that of Ohta et al. (10) (Fig. 1).



View larger version (34K):
[in this window]
[in a new window]
  		Figure 1. Schematic drawing of selective brain cooling using a cooling circuit and ultrafiltration-rewarming circuit. CCA = common carotid artery; rt.VA = right vertebral artery; lt.VA = left vertebral artery; rt.JV = right jugular vein; lt.JV = left jugular vein; rt.FV = right femoral vein; SVC = superior vena cava; IVC = inferior vena cava.

 

The minimum alveolar anesthetic concentration (MAC) for isoflurane was determined with a noxious stimulus. The lung isoflurane concentration was determined from end-tidal samples aspirated using an OMA-8103 monitor (Nihon Kohden, Tokyo, Japan). End-tidal isoflurane was maintained for 15–20 min, and an electric current (60 mA at 100 Hz, 0.2 ms per pulse for 60 s) (SEN-3301; Nihon Kohden), delivered via 2 25-gauge needles placed at the base of the tail, was used as the noxious stimulus (13,14). The needles were subcutaneously inserted 2–3 cm apart. Depending on whether the dog moved, isoflurane was either increased or decreased by 0.2%, then stabilized, and the process was repeated. Between stimuli, the needles were moved to different sites at the base of the tail to minimize the possibility of damage. In several instances, the dog moved while equilibration was being attempted at the smaller concentration, and thus, the noxious stimulus was applied sooner than 15 min; if the dog did not exhibit a gross, purposeful movement, then the stimulus was repeated after 15 min. The concentrations of isoflurane that just permitted and just prevented movement were averaged to determine MAC.

After control MAC determination, the bilateral CCAs, left JV, and left VA were occluded soon after systemic heparinization (50 IU/kg), and cold Ringer’s lactate solution (5.0°C ± 0.5°C) was infused into the right VA at a rate of 60–100 mL/min. The total dose of heparin used was approximately 100 IU/kg. At the same time, jugular venous blood was withdrawn from the right JV at a rate of 20–60 mL/min. The withdrawn venous blood was ultrafiltrated and rewarmed to 38°C and then returned to the IVC via the right femoral vein. The ultrafiltration and rewarming circuit was composed of a dialyzer (FLX-08GW: Nikkiso) for ultrafiltration (Fig. 1). After the brain temperature had decreased to 20°C or 25°C, the infusion rate was reduced to 20–40 mL/min to maintain this temperature for ~60 min.

The brains were cooled to approximately 20°C or 25°C, and the isoflurane was suspended during this period. It was switched off for approximately 40–50 min, and the end-tidal isoflurane concentration became 0%. After cooling for 60 min, the reactions to noxious stimuli were assessed.

After the brain temperature had been maintained at 20°C or 25°C for 60 min, both the cooling and ultrafiltration circuits were turned off. The occlusions on the bilateral CCAs, left JV, and left VA were then released to spontaneously warm the brain. Venous blood in the ultrafiltration and rewarming circuits was all returned to the body. Isoflurane was then re-started, and after the rectal temperature (RT) returned to approximately 37°C and the respiratory status was stabilized, the MAC was measured after the termination of SBC. Throughout the experiment, the EEG was continuously monitored. Blood gas values for the FA and JV blood were measured before, during, and after cooling. Blood gas analysis was performed with electrodes at 37°C (Rapidlab850 pH/blood gas electrolyte analyzer; Bayer Diagnostics Manufacturing Ltd, Sudbury, United Kingdom); the reported values were not corrected for temperature. Before and after the experiment, antibiotic solutions containing 40 mg/kg of cefotiam dihydrochloride (Takeda Chemical Industries, Ltd, Osaka, Japan) were infused IV into the dogs. After the experiment, tracheal extubation was performed, and the canines were carefully nursed for a few hours. Each dog was IM treated with 0.01 mg/kg of buprenorphine as required during that time. After the canines recovered to stable general status, daily neurological examinations (15) were performed.

All values are shown as mean ± sd. Repeated-measures analysis of variance and Student’s t-test were used to determine significant changes in the brain temperature, RT, PAT, MAC, MAP, hematocrit (Hct), and blood gases. A probability of <0.05 was considered to be statistically significant.


   Results
Top
 Abstract
 Introduction
 Methods
 Results
Discussion
 References
 
Before cooling, the brain temperatures and MAC were 38.3°C ± 0.7°C and 1.2% ± 0.2% for group A and 38.1°C ± 0.4°C and 1.2% ± 0.1% for group B. During cooling, the brain temperature and MAC were 20.8°C ± 0.8°C and 0% for group A. The brain temperature for group B was 25.0°C ± 0.5°C. Because the duration of brain hypothermia was only 60 min, the MAC for isoflurane could not be determined during cooling for group B. The brain temperature reached 25°C within 10 ± 7 min and 20°C within 13 ± 9 min. After rewarming, the brain temperature and MAC were 36.6°C ± 0.5°C and 1.0% ± 0.2% for group A and 37.2°C ± 0.5°C and 1.0% ± 0.1% for group B.

During cooling, no canine reacted to noxious stimulation in group A. In contrast, 7 of 8 canines moved in response to noxious stimuli in group B. One canine that did not react to noxious stimuli did not recover from anesthesia and died after rewarming.

When the brain temperature decreased to 20.8°C ± 0.8°C, the RT and PAT were 34.7°C ± 0.9°C and 34.3°C ± 1.9°C, respectively, for group A, and when the brain temperature decreased to 25.0°C ± 0.5°C, these respective temperatures were 34.6°C ± 1.5°C and 34.4°C ± 1.7°C for group B. Before and after cooling, the brain temperature, RT, and PAT were approximately the same for each group.

The MAP were 109 ± 12, 86 ± 12, and 102 ± 15 mm Hg for the pre-SBC, SBC, and post-SBC periods, respectively, for group A and were 116 ± 10, 103 ± 7, and 114 ± 9 mm Hg, respectively, for group B. During cooling, the MAP exhibited almost no change in response to noxious stimuli for group A, whereas it showed a tendency to increase for group B. It significantly decreased during SBC for each group, but there was no statistical significance between the groups.

Arterial and jugular venous blood gases and Hct are shown in Tables 1 and 2. These data show that Hct decreased and metabolic acidosis occurred during and after SBC, but these tendencies were not progressive.


View this table:
[in this window]
[in a new window]
  		Table 1. Acid-Base and Hematocrit (Hct) Changes in the Femoral Artery in Beagles Undergoing Selective Brain Cooling (SBC) at 20°C or 25°C

 


View this table:
[in this window]
[in a new window]
  		Table 2. Acid-Base and Hematocrit (Hct) Changes in the Jugular Vein in Beagles Undergoing Selective Brain Cooling (SBC) at 20°C or 25°C

 
The EEG changed into a slow wave pattern soon after injecting cold Ringer’s lactate solution and changed from burst and suppression to isoelectric-only pattern a few minutes after SBC initiation. The brain temperature was more than 30°C as EEG pattern became isoelectric, and the maximum temperature was approximately 34°C. The EEG again showed burst suppression during rewarming, when the brain temperature increased to more than 30°C. It normalized when the brain temperature increased to more than 32°C (20–30 min after SBC termination). All canines survived for 10 wk after the experiment with no neurological deficits except one from group B, which died after rewarming.


   Discussion
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
References
 
The blockade of movement is a central feature of general anesthesia. Most movements during anesthesia are reflexes to stimulation (mainly a noxious stimulus) and are generated in the spinal cord and probably not in the brain (8,9,16). MAC, used as an index of anesthetic potency, is determined from the presence of movement evoked by a noxious stimulus. However, MAC is unrelated to the action of the anesthetic on the cortex. This is supported by studies by Antognini et al. (9) and Rampil et al. (8,16). Some studies suggest that anesthetics such as isoflurane act on the spinal cord to suppress movements that occur after noxious stimuli. This suggests that immobility caused by anesthetics may be related to depression of motoneuron activity in the spinal cord instead of depression of supraspinal sites, such as the cerebral cortex. In contrast, thiopental has a more potent supraspinal effect (17). These reports may not always mean that only the spinal cord emerges as the site of anesthetic action. Antognini (7) found that hypothermia suppresses movement that occurs after a noxious stimulus at 20°C. In his series, however, we cannot determine whether hypothermia acts on the spinal cord or the brain to suppress movement that occurs after a noxious stimulus because of systemic hypothermia. The mechanism by which hypothermia suppresses noxious-evoked movement at 20°C is not clear.

We examined the effect of controlled brain hypothermia at normothermic trunk temperature on noxious-evoked movement by SBC. The results indicate that brain hypothermia eliminates the need for isoflurane at 20°C, but not at 25°C.

In our study, we tried to determine by how much the spinal cord temperature was decreased by SBC. We could not take the spinal cord temperature technically, nor could we find a report on brain and spinal cord temperatures taken during brain/spinal cord cooling. The PAT and RT were preserved at more than 34°C during SBC to 20°C and 25°C. Between these brain temperatures, there was a critical point of anesthetic effect, whereas there were no significant changes in the two temperatures. Direct epidural cooling performed by Marsala et al. (18) decreased the spinal cord temperature to 26°C–28°C and maintained the core temperature at around 34°C using superficial warming such as heating and blankets. We did not cool the spinal cord directly and even returned rewarmed venous blood to the IVC. We assumed from these results that the spinal cord temperatures in our SBC were higher than 26°C–28°C but were never less than 25°C, even when the brain temperature was 20°C.

It has been shown that isoflurane acts on the spinal cord to immobilize animals (17,19). Isoflurane was required for immobilization when the brain temperature was at 25°C. This supports the idea that the spinal cord was not sufficiently cold, and the motor neuron activities are maintained when the brain is cooled. If the brain temperature is 20°C and the spinal cord still exhibits motor activity, movement should occur without isoflurane. However, we found no reaction to noxious stimuli at 20°C, which may have resulted from the more potent anesthetic effect of selective brain hypothermia in suppressing traces of motor neuron activity in the spinal cord. We speculate that brain temperature at 20°C produces a supraspinal anesthetic effect preventing spinal reflex.

The crystalloid (cold Ringer’s lactate solution) infused into the brain undoubtedly contributed to the acidosis and anemia of the brain (Table 2). However, acidosis, anemia, and the length of the experiment were unlikely to have affected the results (1,20–22).

What we found from these results is that brain hypothermia has an anesthetic effect similar to systemic hypothermia at 20°C. In other words, this suggests that brain hypothermia might depress not only supraspinal sites such as the cerebral cortex but also motoneuron activity in the spinal cord.

We believe that this blunting effect of noxious-evoked movement is useful for elucidating the mechanism of hypothermia to depress nociceptive transmission in supraspinal and spinal targets.

The authors wish to thank Yoshihiko Kinoshita at the Medical Intelligence Department of the Medical Equipment Unit at Nikkiso CO, Ltd, for his contribution to this study.


   Footnotes
 
Supported, in part, by the Proposal-Based Immediate-Effect R&D Promotion Program from the New Energy and Industrial Technology Development Organization (NEDO) of Japan.

Accepted for publication October 6, 2004.


   References
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 

  1. Eger EI II, Johnson BH. MAC of I-653 in rats, including a test of the effect of body temperature and anesthetic duration. Anesth Analg 1987;66:974–6.[Abstract/Free Full Text]
  2. Vitez TS, White PF, Eger EI II. Effects of hypothermia on halothane MAC and isoflurane MAC in the rat. Anesthesiology 1974;41:80–1.[Web of Science][Medline]
  3. Munson ES. Effect of hypothermia on anesthetic requirement in rats. Lab Anim Care 1970;20:1109–13.[Web of Science][Medline]
  4. Regan MJ, Eger EI II. Effect of hypothermia in dogs on anesthetizing and apneic doses of inhalation agents: determination of the anesthetic index (Apnea/MAC). Anesthesiology 1967;28:689–700.[Web of Science][Medline]
  5. Eger EI II, Saidman LJ, Brandstater B. Temperature dependence of halothane and cyclopropane anesthesia in dogs: correlation with some theories of anesthetic action. Anesthesiology 1965;26:764–70.[Web of Science][Medline]
  6. Cherkin A, Catchpool JF. Temperature dependence of anesthesia in goldfish. Science 1964;144:1460–2.[Abstract/Free Full Text]
  7. Antognini JF. Hypothermia eliminates isoflurane requirements at 20°C. Anesthesiology 1993;78:1152–6.[Web of Science][Medline]
  8. Rampil IJ. Anesthetic potency is not altered after hypothermic spinal cord transection in rats. Anesthesiology 1994;80:606–10.[Web of Science][Medline]
  9. Antognini JF, Schwartz K. Exaggerated anesthetic requirements in the preferentially anesthetized brain. Anesthesiology 1993;79:1244–9.[Web of Science][Medline]
  10. Ohta T, Kuroiwa T, Sakaguchi I, et al. Selective hypothermic perfusion of canine brain. Neurosurgery 1996;38:1211–5.[Web of Science][Medline]
  11. Ohta T, Sakaguchi I, Liu WD, et al. Selective cooling of brain using profound hemodilution in dogs. Neurosurgery 1992;31:1049–55.[Web of Science][Medline]
  12. Ohta T, Sagarminaga J, Baldwin M. Profound hypotension with differential cooling of the brain in dogs. J Neurosurg 1966;24:993–1001.[Web of Science][Medline]
  13. Antognini JF, Kien ND. Potency (minimum alveolar anesthetic concentration) of isoflurane is independent of peripheral anesthetic effects. Anesth Analg 1995;81:69–72.[Abstract]
  14. Laster MJ, Liu J, Eger EI II, Taheri S. Electrical stimulation as a substitute for the tail clamp in the determination of minimum alveolar concentration. Anesth Analg 1993;76:1310–2.[Web of Science][Medline]
  15. Leonov Y, Sterz F, Safar P, et al. Mild cerebral hypothermia during and after cardiac arrest improves neurologic outcome in dogs. J Cereb Blood Flow Metab 1990;10:57–70.[Web of Science][Medline]
  16. Rampil IJ, Mason P, Singh H. Anesthetic potency (MAC) is independent of forebrain structures in the rat. Anesthesiology 1993;78:707–12.[Web of Science][Medline]
  17. Antognini JF, Carstens E, Atherley R. Does the immobilizing effect of thiopental in brain exceed that of halothane? Anesthesiology 2002;96:980–6.[Web of Science][Medline]
  18. Marsala M, Vanicky I, Galik J, et al. Panmyelic epidural cooling protects against ischemic spinal cord damage. J Surg Res 1993;55:21–31.[Web of Science][Medline]
  19. Jinks SL, Martin JT, Carstens E, et al. Peri-MAC depression of a nociceptive withdrawal reflex is accompanied by reduced dorsal horn activity with halothane but not isoflurane. Anesthesiology 2003;98:1128–38.[Web of Science][Medline]
  20. Cullen DJ, Eger EI II. The effects of hypoxia and isovolemic anemia on the halothane requirement (MAC) of dogs. III. The effects of acute isovolemic anemia. Anesthesiology 1970;32:46–50.[Web of Science][Medline]
  21. Eisele JH, Eger EI II, Muallem M. Narcotic properties of carbon dioxide in the dog. Anesthesiology 1967;28:856–65.[Web of Science][Medline]
  22. Eger EI II, Saidman LJ, Brandstater B. Minimum alveolar anesthetic concentration: a standard of anesthetic potency. Anesthesiology 1965;26:756–63.[Web of Science][Medline]




This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a colleague
Right arrow Similar articles in this journal
Right arrow Similar articles in Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrowRequest Permissions
Citing Articles
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Takayama, R.
Right arrow Articles by Mori, H.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Takayama, R.
Right arrow Articles by Mori, H.
Related Collections
Right arrow Neuroanesthesia
Right arrow Anesthetic Techniques

Lippincott, Williams & Wilkins Anesthesia & Analgesia® is published for the International Anesthesia Research Society® by Lippincott Williams & Wilkins and Stanford University Libraries' HighWire Press®. Copyright 2005 by the International Anesthesia Research Society. Online ISSN: 1526-7598   Print ISSN: 0003-2999 HighWire Press