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Anesth Analg 2001;93:697-702
© 2001 International Anesthesia Research Society

NEUROSURGICAL ANESTHESIA

The Effects of Topical and Intravenous Ketamine on Cerebral Arterioles in Dogs Receiving Pentobarbital or Isoflurane Anesthesia

Hiroto Ohata, MD, Hiroki Iida, MD, Kiyoshi Nagase, MD, and Shuji Dohi, MD

Department of Anesthesiology and Critical Care Medicine, Gifu University School of Medicine, Gifu City, Gifu 500-8705, Japan

Address correspondence and reprint requests to Hiroki Iida, MD, Department of Anesthesiology and Critical Care Medicine, Gifu University School of Medicine, Gifu City, Gifu 500-8705, Japan. Address e-mail to iida{at}cc.gifu-u.ac.jp


   Abstract
Top
 Abstract
Introduction
 Material and Methods
 Results
 Discussion
 References
 
To evaluate the effects of ketamine on cerebral arterioles, we used a closed cranial window technique in mechanically ventilated, anesthetized dogs. Fourteen dogs were assigned to one of the following two basal-anesthesia groups: pentobarbital 2 mg · kg-1 · h-1 or isoflurane 0.5 MAC (n = 7 each). We administered three different concentrations of ketamine (10-7, 10-5, and 10-3 M) under the window and measured arteriolar diameters. For comparison, in another 14 dogs we examined the effect of systemic (IV) ketamine (1 mg/kg and 5 mg/kg) using the same two basal anesthetics. We measured diameters before and after ketamine administration, and we evaluated the effect of ketamine on CO2 reactivity of the cerebral arterioles. Neither topical nor systemic ketamine dilated pial arterioles in either basal-anesthesia group. CO2 reactivity of pial arterioles was reduced under systemic ketamine in both basal-anesthesia groups. The results indicate that although ketamine does not dilate pial arteriolar diameters when topically or IV administered, IV ketamine does attenuate hypercapnic vasodilation in dogs under basal pentobarbital or isoflurane anesthesia. These results provide some insight that ketamine is suitable for supplementary neurosurgical anesthesia.

IMPLICATIONS: In cerebral arterioles in dogs under pentobarbital or isoflurane anesthesia, neither topical nor IV ketamine induced vasodilation. However, IV ketamine did attenuate hypercapnia-induced vasodilation. These findings provide some insight into the safety and suitability of ketamine as a supplement for neurosurgical anesthesia.


   Introduction
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 Abstract
 Introduction
Material and Methods
 Results
 Discussion
 References
 
Ketamine is generally considered to be contraindicated in patients with an increased intracranial pressure (ICP) or at risk for increases in ICP because of its reported effects on ICP and cerebral blood flow (CBF) (1–3). However, the truth is that the reports of the effects of ketamine on cerebral hemodynamics are conflicting; it has been said to increase, decrease, or have no effect on CBF (1–9). This lack of consistency may be, in part, attributable to differences in experimental design among the published studies, such as the absence or presence of other medication (including background anesthetics) or mechanical ventilation. For example, in dogs under controlled ventilation, ketamine (2 mg/kg) increased CBF in the presence of nitrous oxide (N2O) except when the animals were pretreated with thiopental (6). However, in ventilated pigs anesthetized with fentanyl and N2O, ketamine (2 mg/kg) had no significant effects on CBF or on the cerebral metabolic rate of oxygen (CMRO2) (7). This made us think that under controlled ventilation, the cerebrovascular effects of ketamine may be modulated by the preexisting cerebrovascular tone, which in turn may be affected by the presence of other drugs, such as background anesthetics.

Clinical studies performed under general anesthesia with controlled ventilation have suggested that ketamine does not affect ICP in humans with intracranial pathology (8,9). Further, ketamine has been reported to have neuroprotective properties as a result of its N-methyl-D-aspartate (NMDA) receptor antagonism (10,11). Because ketamine is the only NMDA receptor antagonist currently approved for clinical use as an anesthetic, it is important to know whether its use can be recommended for neurosurgical anesthesia alone or in combination with other anesthetics. We thought that useful information might be obtained by reevaluating the effects of ketamine on the cerebral arterioles under background anesthesia produced using two drugs often used in the perioperative period in neurosurgical patients (pentobarbital and isoflurane). We performed the present study using a closed cranial window technique in dogs.


   Material and Methods
Top
 Abstract
 Introduction
 Material and Methods
Results
 Discussion
 References
 
The experimental protocols were approved by our Institutional Committee for Animal Care. Twenty-eight dogs weighing 8–12 kg were anesthetized with IV pentobarbital sodium (20 mg/kg) and subsequently maintained on either a continuous infusion of pentobarbital sodium (2 mg · kg-1 · h-1) or inhaled isoflurane (1–1.2 MAC) for the entire preparation period. After tracheal intubation, the lungs were mechanically ventilated with oxygen-enriched room air (50 vol% oxygen). The tidal volume and respiratory rate were adjusted to maintain a PaCO2 of 35–40 mm Hg. Polyvinyl chloride catheters were placed in the left femoral vein and artery for administration of drugs and fluid (lactated Ringer’s solution; 6 mL · kg-1 · h-1), as well as for arterial blood-pressure measurements and blood sampling. Rectal temperature was maintained between 36.5°C and 37.5°C with the aid of a water-circulated warming blanket.

A closed cranial window was used to observe the pial arterioles. Each anesthetized animal was placed in the sphinx position, with the head immobilized in a stereotaxic frame. Another catheter was placed in the sagittal sinus for blood sampling. The scalp was retracted, the temporal muscle removed, and a hole 2 cm in diameter made in the parietal bone. After coagulation of dural vessels using a bipolar electrocoagulator, the dura and arachnoid membrane were cut and retracted over the bone. A ring fitted with a cover glass was secured over the hole with the aid of bone wax and dental acrylic, and the space under the window was filled with artificial cerebrospinal fluid (aCSF). The composition of the aCSF was: Na+, 151 mEq/L; K+, 4 mEq/L; Ca2+, 3 mEq/L; Cl-, 110 mEq/L; and glucose, 100 mg/dL; pH was adjusted to 7.48, and the solution was bubbled with 5% CO2 in air at 37.0°C. The volume of fluid below the window was between 0.5 and 1.0 mL. Four polyvinyl chloride catheters were inserted through the ring. One catheter was attached to a reservoir bottle containing aCSF, which allowed adjustment of intrawindow pressure. Two catheters were used for infusing and draining aCSF and experimental drug solutions, and the last one was used for continuous monitoring of intrawindow pressure. Intrawindow temperature was monitored using a thermistor (Model 6510; Mallinckrodt Medical; St. Louis, MO) and was between 36.5°C and 37.5°C.

All experiments were performed in vivo using the following protocols. After instrumentation, dogs were assigned to one of the following basal-anesthesia groups–pentobarbital 2 mg · kg-1 · h-1 or isoflurane 0.5 MAC (n = 14 each). The animals were allowed at least 45 min to recover from the surgical procedures.

Protocol 1
To assess its direct effect on cerebral arterioles, we introduced 3 different concentrations of ketamine (in aCSF) into the window. First, aCSF was infused continuously at 1 mL/min into the cranial window in both anesthetic groups (n = 7 each). To establish baseline values, pial arteriolar diameters, mean arterial pressure (MAP), heart rate, and arterial blood gas tensions and pH were measured. Dogs were assigned to receive 3 concentrations of ketamine (10-7, 10-5, and 10-3 M) in a randomized manner. The variables listed above were measured before and after topical administration of each solution. For washout, the window was continuously flushed with drug-free aCSF at 1 mL/min for 30 min after each measurement.

Protocol 2
To examine the cerebrovascular response to systemically administered ketamine, we gave two different doses (1 mg/kg and 5 mg/kg) IV in a sequential manner to another 14 instrumented dogs (7 of which received each basal anesthetic). First, we established the control hypercapnic response of the cerebral arterioles by adding CO2 to the inspired gas mixture. At 30 min after the hypercapnic challenge, the pial vascular diameters had returned to baseline. In each group, the smaller dose of ketamine (1 mg/kg) was given and 5 min later diameter measurements were taken. Then, <10 min after injecting the dose of ketamine, we measured the response of the pial arterioles to a hypercapnic challenge, as we had done before. Finally, to evaluate the response to the larger dose of ketamine (5 mg/kg), the experiment was repeated using this dose 60 min after the administration of the smaller dose.

In each dog, the inner diameters of four pial arterioles (2 >=100 µm and 2 <100 µm) were measured by another investigator blinded to the procedures just described by using an Olympus Flovel videomicrometer (Model VM-20; Flovel, Tokyo, Japan) attached to a microscope (Model OMK-1; Olympus, Tokyo, Japan). The data from each pial view were stored on videotape for later playback and analysis. The percentage changes recorded for individual arteriolar segments were averaged for each size of vessel in each dog, and this average value was used in the statistical analysis. Gas tensions and pH in arterial and sagittal sinus blood were measured at 37°C immediately after withdrawal by using a STAT Profile-5® (NOVA Biomedicals, Waltham, MA). Oxygen saturation and hemoglobin were measured spectrophotometrically by using a Radiometer Hemoximeter OSM-3® (Radiometer, Copenhagen, Denmark). Arterial and cerebral venous oxygen contents were calculated from the measured oxygen saturation and hemoglobin concentration and corrected for dissolved oxygen. The cerebral oxygen extraction ratio was calculated by dividing the arterial to sagittal sinus oxygen-content difference by the arterial oxygen content. The cerebral arteriolar CO2 reactivity was calculated by dividing the percentage change in diameter by the difference of PaCO2 between before administration of CO2 and after administration of CO2.

Statistical Analysis
Values are given as mean ± SD. A two-way analysis of variance within anesthetic groups and within treatment-drug groups was used to compare pial vessel diameters, percentage change in diameter with respect to baseline diameter, and blood gas and hemodynamic variables induced by the various maneuvers. P < 0.05 was considered significant. If a significant anesthetic or treatment-drug effect was demonstrated, a subsequent one-way repeated-measures analysis of variance followed by a paired Student’s t-test with Bonferroni’s correction was performed to assess the effect within a group, and a one-way analysis of variance followed by an unpaired Student’s t-test with Bonferroni’s correction was performed to assess the difference between groups.


   Results
Top
 Abstract
 Introduction
 Material and Methods
 Results
Discussion
 References
 
Table 1 shows the baseline diameters of the pial vessels examined in the present study; there were no significant differences between anesthetic groups in either type of experiment. Rectal temperature remained between 36.5°C and 37.5°C throughout each experiment.


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  		Table 1. Mean Diameter (µm) of Pial Arterioles at Baseline Stage in Each Protocol
 
Topical Administration of Ketamine (Protocol 1)
Table 2 gives baseline physiologic data, and shows that there were no significant differences between the basal-anesthetic groups. In both of these groups, topical administration of ketamine induced no changes in diameter in pial arterioles at any concentration (<0.5% changes; data not shown). In addition, MAP, heart rate, and arterial gas tensions and pH all remained unchanged throughout the experiments (Table 2).


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  		Table 2. Hemodynamic and Physiological Measurements at Pre- and Posttreatment (Topical Administration of Ketamine) in Pentobarbital and Isoflurane Groups
 
Systemic Administration of Ketamine (Protocol 2)
Systemic administration of ketamine at 1 and 5 mg/kg did not alter any hemodynamic values significantly in either of the basal-anesthetic groups (Table 3). Systemic ketamine did not induce significant changes in diameter in pial arterioles, but it tended to increased vasoconstriction in the Isoflurane group compared with the Pentobarbital group (Fig. 1). This difference between the groups reached statistical significance in larger arterioles after 1 mg/kg ketamine and in smaller arterioles after 5 mg/kg ketamine. Although administration of CO2 increased PaCO2, it did not significantly alter any hemodynamic measurements. The changes in PaCO2 induced by the hypercapnic challenge under control (no ketamine) conditions were as follows: from 38 ± 1 to 61 ± 2 mm Hg versus from 39 ± 2 to 58 ± 2 mm Hg (Pentobarbital group versus Isoflurane group). After 1 mg/kg ketamine, the corresponding data were: from 38 ± 2 to 60 ± 3 mm Hg versus from 39 ± 2 to 59 ± 4 mm Hg, and after 5 mg/kg ketamine: from 39 ± 3 to 61 ± 3 mm Hg versus from 40 ± 2 to 57 ± 3 mm Hg. The hypercapnia-induced pial arteriolar reactivity seen under control conditions was significantly attenuated after ketamine in both large and small arterioles, but a difference in magnitude of attenuation was not observed between 1 and 5 mg/kg of ketamine in either basal-anesthetic group (Fig. 2).


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  		Table 3. Hemodynamic and Physiological Measurements at Pre- and Posttreatment (Systemic Administration of Ketamine) in Pentobarbital and Isoflurane Groups
 


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  		Figure 1. Percentage change in diameter in large (>=100 µm) and small (<100 µm) pial arterioles after systemic administration of ketamine (1 mg/kg or 5 mg/kg) under pentobarbital (A) or isoflurane (B) anesthesia. *P <0.05 versus corresponding pentobarbital group value. Values are mean ± SD.

 


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  		Figure 2. Cerebrovascular CO2 reactivity (% change in diameter/mm Hg) in large (>=100 µm) and small (<100 µm) pial arterioles under pentobarbital (A) or isoflurane (B) anesthesia. *p < 0.05 vs corresponding control. Values are mean ± SD.

 

   Discussion
Top
 Abstract
 Introduction
 Material and Methods
 Results
 Discussion
References
 
Our major findings were that in anesthetized (pentobarbital or isoflurane) and mechanically ventilated dogs, topical administration of ketamine (10-7, 10-5, and 10-3 M) did not induce any change in pial arteriolar diameter and systemic administration of ketamine (1 and 5 mg/kg) neither dilated pial arterioles nor induced any significant increases in hemodynamic variables. However, systemic administration of ketamine significantly attenuated the cerebral arteriolar dilation induced by hypercapnia.

Several reports have shown that the increases in CBF or ICP associated with ketamine are blunted or eliminated by the presence of other anesthetics used with it (5–9). For example, Dawson et al. (6) studying ventilated dogs anesthetized with N2O, demonstrated that although ketamine (2 mg/kg) significantly increased both CBF and CMRO2, these effects were blocked by pretreatment with thiopental (5 mg/kg). In humans, Strebel et al. (5) indicated that during normoventilation and light steady-state anesthesia with isoflurane 0.3%, IV ketamine (2 mg/kg) increased blood velocity in the middle cerebral artery, but this effect was prevented by prior administration of midazolam. Furthermore, Mayberg et al. (8) demonstrated that in patients with mildly increased ICP resulting from intracranial pathology, ketamine (1 mg/kg) did not increase ICP; moreover, ketamine decreased electroencephalogram activity under isoflurane and N2O anesthesia. Thus, the present results are consistent with this general picture; that is, the effects of ketamine on the cerebral arterioles seem to be modulated (probably by the preexisting cerebrovascular tone) under anesthetics such as isoflurane that cause "uncoupling" of blood flow and metabolism and under anesthetics such as pentobarbital, which produces a deep depression of metabolic activity and a decrease in ICP.

In the present study, we found that systemic administration of ketamine did not increase MAP or cerebral oxygen extraction significantly. Gardner et al. (12) have reported that the increase in CBF induced by ketamine depended on the increase in MAP. Cavazzuti et al. (4) suggested that the effect of ketamine on the cerebral circulation was a result of an induced increase in CMRO2. However, when ketamine is administered with other anesthetics, MAP or CMRO2 may be maintained (4–9). Hence, one possible explanation for the present results is that when ketamine is added to a background level of anesthesia produced by other drugs, its property of central nervous excitation is blunted and thus the cerebral circulation is relatively unaffected.

Our data also demonstrated that although topical application of ketamine did not change pial arteriolar diameter, IV ketamine had a tendency to induce vasoconstriction. Interestingly, Faraci and Breece (13) found that topical application of MK-801, an NMDA receptor antagonist, had no significant vasoactive effect on cerebral arterioles. Shortly afterward, Meng et al. (14) found that IV administration of MK-801 caused a slight but nonsignificant decrease in pial arteriolar diameter. Our findings are consistent with the above results, as ketamine too is an NMDA receptor antagonist. Because NMDA receptors are not present in cerebral blood vessels (13,15), the different effects observed between topical and IV administrations of ketamine in the present study may reflect the distribution of NMDA receptors throughout the body.

In general, previous data have indicated that the CBF reactivity to CO2 is preserved under ketamine (1–3). However, little is known about the effect of ketamine on CO2 reactivity in the presence of other anesthetics (16–18). Our data revealed that ketamine directly inhibited hypercapnia-induced cerebral arteriolar vasodilation even though the background anesthetics, pentobarbital and isoflurane, leave the CO2 responsiveness of the cerebral circulation unchanged or even enhance it (19,20). Nagase et al. (16,17), who measured blood velocity in the middle cerebral artery in humans using transcranial Doppler ultrasonography, indicated that ketamine decreased CO2 reactivity during isoflurane and propofol/fentanyl anesthesia. However, Sakai et al. (18) demonstrated that ketamine did not alter the cerebrovascular CO2 response in humans under anesthesia produced by propofol alone. Therefore, it is possible that the modulation observed with ketamine may depend on the identity of the other anesthetics used, the region in which observations are made, and the species.

Because the basal anesthetic state with pentobarbital or isoflurane might affect the tone of cerebral arterioles and there are no data about how pentobarbital or isoflurane affect the vascular effect of ketamine, we cannot exclude the possibility that the effects we observed on pial arteriolar tone after ketamine administration could be modulated, at least in part, by the presence of pentobarbital or isoflurane.

In summary, our data indicate that (a) topical administration of ketamine does not induce cerebral arteriolar vasodilation and (b) systemic administration of ketamine does not induce cerebral arteriolar vasodilation nor a significant change in MAP and cerebral oxygen extraction, whereas (c) systemic ketamine does attenuate hypercapnia-induced cerebral arteriolar vasodilation. Because ketamine has little or no effect on cerebral hemodynamics when used with other anesthetics, these results provide some insight into the safety and suitability of ketamine administration in the presence of general anesthetics during neurosurgical anesthesia.


   Acknowledgments
 
Supported, in part, by the Fund for Scientific Research in Gifu University School of Medicine in 1998 (Gifu University School of Medicine, Gifu, Japan), and by Grant-in Aid #11671489 and #13671570 for Scientific Research from the Ministry of Education, Science, and Culture, Japan.


   Footnotes
 
Presented, in part, at the annual meeting of International Symposium on Cerebral Blood Flow, Metabolism and Function, Copenhagen, Denmark, June 13-17, 1999.


   References
Top
 Abstract
 Introduction
 Material and Methods
 Results
 Discussion
 References
 

  1. Takeshita H, Okuda Y, Sari A. The effects of ketamine on cerebral circulation and metabolism in man. Anesthesiology 1972; 36: 69–75.[Web of Science][Medline]
  2. Sari A, Okuda Y, Takeshita H. The effect of ketamine on cerebrospinal fluid pressure. Anesth Analg 1972; 51: 560–5.[Free Full Text]
  3. Shapiro HM, Wyte SR, Harris AB. Ketamine anaesthesia in patients with intracranial pathology. Br J Anaesth 1972; 44: 1200–4.[Abstract/Free Full Text]
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  6. Dawson B, Michenfelder JD, Theye RA. Effects of ketamine on canine cerebral blood flow and metabolism: modification by prior administration of thiopental. Anesth Analg 1971; 50: 443–77.[Free Full Text]
  7. Akeson J, Bjorkeman S, Messeter K, et al. Cerebral pharmacodynamics of anaesthetic and subanaesthetic doses of ketamine in the normoventilated pig. Acta Anaesthesiol Scand 1993; 37: 211–8.[Web of Science][Medline]
  8. Mayberg TS, Lam AM, Matta BF, et al. Ketamine dose not increase cerebral blood flow velocity or intracranial pressure during isoflurane/nitrous oxide anesthesia in patients undergoing craniotomy. Anesth Analg 1995; 81: 84–9.[Abstract]
  9. Albanese J, Arnaud S, Thomachot L, et al. Ketamine decreases intracranial pressure and electroencephalographic activity in traumatic brain injury patients during propofol sedation. Anesthesiology 1997; 87: 1328–34.[Web of Science][Medline]
  10. Hoffman WE, Pelligrino D, Werner C, et al. Ketamine decreases plasma catecholamines and improves neurologic outcome from incomplete cerebral ischemia in rats. Anesthesiology 1992; 76: 755–62.[Web of Science][Medline]
  11. Shapira Y, Lam AM, Engl CC, et al. Therapeutic time window and dose response of the beneficial effects of ketamine in experimental head injury. Stroke 1994; 25: 1637–43.[Abstract]
  12. Gardner AE, Olson BE, Lichtiger M. Cerebrospinal-fluid pressure during dissociative anesthesia with ketamine. Anesthesiology 1971; 35: 226–8.[Web of Science][Medline]
  13. Faraci FM, Breese KR. Nitric oxide mediates vasodilatation in response to activation of N-methyl-D-aspartate receptors in brain. Circ Res 1993; 72: 476–80.[Abstract/Free Full Text]
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  15. Beart PM, Sheehaan KAM, Manallack DT. Absence of N-methyl-D-aspartate receptors on ovine cerebral microvessels. J Cereb Blood Flow Metab 1988; 8: 879–82.[Web of Science][Medline]
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  17. Nagase K, Iida H, Ohata H, et al. Ketamine, but not propofol, attenuates cerebrovascular carbon dioxide response during isoflurane anesthesia. J Cereb Blood Flow Metab 1999; 19: S642.
  18. Sakai K, Cho S, Fukusaki M, et al. The effects of propofol with and without ketamine on human cerebral blood flow velocity and CO2 response. Anesth Analg 2000; 90: 377–82.[Abstract/Free Full Text]
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  20. Drummond JC, Todd MM. The response of the feline cerebral circulation to PaCO2 during anesthesia with isoflurane and halothane and during sedation with nitrous oxide. Anesthesiology 1985; 62: 268–73.[Web of Science][Medline]
Accepted for publication May 1, 2001.




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Lippincott, Williams & Wilkins Anesthesia & Analgesia® is published for the International Anesthesia Research Society® by Lippincott Williams & Wilkins and Stanford University Libraries' HighWire Press®. Copyright 2001 by the International Anesthesia Research Society. Online ISSN: 1526-7598   Print ISSN: 0003-2999 HighWire Press