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Anesth Analg 1999;88:787
© 1999 International Anesthesia Research Society

NEUROSURGICAL ANESTHESIA

Effects of Isoflurane, Ketamine, and Fentanyl/N2O on Concentrations of Brain and Plasma Catecholamines During Near-Complete Cerebral Ischemia in the Rat

Yoshihide Miura, MD, G. Burkhard Mackensen, MD, Bengt Nellgård, MD, PhD, Robert D. Pearlstein, PhD, Robert D. Bart, MD, Franklin Dexter, MD, PhD, and David S. Warner, MD

Neuroanesthesia Research Laboratory, Department of Anesthesiology, Duke University Medical Center, Durham, North Carolina

Address correspondence to David S. Warner, MD, Department of Anesthesiology, Box 3094, Duke University Medical Center, Durham, NC 27710. Address e-mail to warne002{at}mc.duke.edu


   Abstract
Top
 Abstract
Introduction
 Methods
 Results
 Discussion
 References
 
We postulated that adrenergic responses to global cerebral ischemia are anesthetic-dependent and similar in both brain and arterial blood. Rats were anesthetized with isoflurane (1.4%), ketamine (1 mg · kg-1 · min-1), or fentanyl (25 µg · kg-1 · h-1)/70% N2O. The carotid arteries were occluded for either 20 min with mean arterial pressure (MAP) 50 mm Hg (incomplete ischemia) or 10 min with MAP 30 mm Hg (near-complete ischemia). Norepinephrine was measured in hippocampal microdialysate. Norepinephrine and epinephrine were measured in arterial plasma. In both hippocampus and plasma, basal norepinephrine was similar among anesthetics. During incomplete ischemia, hippocampal norepinephrine was twofold greater with fentanyl/N2O than with isoflurane (P = 0.037), but plasma norepinephrine and epinephrine were similar and unchanged among all three anesthetics. During near-complete ischemia, hippocampal norepinephrine was threefold greater with ketamine than fentanyl/N2O (P = 0.005), whereas plasma norepinephrine and epinephrine were markedly greater with fentanyl/N2O than with ketamine (P < 0.0005) or isoflurane (P = 0.05). There was no correlation between norepinephrine concentrations in hippocampus and plasma for either incomplete or near-complete ischemia. This study demonstrates that adrenergic responses to global ischemia are anesthetic-dependent, particularly during more severe insults. The absence of a correlation between plasma and brain catecholamine concentrations indicates that adrenergic responses to ischemia are independent in brain and blood.

Implications: It has been proposed that anesthetics modulate cerebral ischemic outcome by influencing peripheral adrenergic responses to ischemia. This experiment demonstrates that anesthetics differentially modulate adrenergic responses to ischemia but that effects in plasma and brain are independent. This suggests that events detected in the peripheral circulation do not implicate direct mechanisms of action of catecholamines at the neuronal/glial level.


   Introduction
Top
 Abstract
 Introduction
Methods
 Results
 Discussion
 References
 
Anesthetics improve outcome from some forms of cerebral ischemia (1,2). Although the magnitude of this protection is dependent on the severity of the ischemic insult (3), the mechanistic basis for understanding anesthetic-mediated neuroprotection is incomplete (4). Anesthetics have variously been reported to reduce cerebral metabolic rate (5,6), antagonize glutamatergic excitotoxicity (7–9), scavenge free radicals (10), improve cerebral blood flow (11), and inhibit spontaneous ischemic depolarizations (12). Others have suggested that adrenergic responses to cerebral ischemia also play an important role in histologic and behavioral outcome and that anesthetics may modulate these adrenergic events. For example, pharmacologic sympathetic ganglionic blockade alters outcome from global ischemia in the rat, whereas co-administration of exogenous epinephrine and/or norepinephrine reverses this effect (13,14). In a rat model of hemispheric cerebral ischemia, ketamine anesthesia also decreased plasma catecholamine concentrations compared with N2O, and this has been associated with improved neurologic outcome (15).

During global cerebral ischemia, there are large increases in brain extracellular catecholamines (16,17). If and how anesthetics modulate these events is unknown. We postulated that adrenergic responses to global ischemia are anesthetic-dependent in both brain and arterial blood and that the effects of anesthetics in these two compartments are similar. To examine this, we subjected rats to different severities of global cerebral ischemia while anesthetized with distinctly different anesthetic regimens. Hippocampal microdialysate and arterial plasma were sequentially analyzed for norepinephrine and epinephrine concentrations in the periischemic interval.


   Methods
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 Abstract
 Introduction
 Methods
Results
 Discussion
 References
 
These studies were approved by our animal care and use committee. Male Sprague-Dawley rats (8–10 wk) were fasted from food for 12–16 h but were allowed free access to water. The animals were then anesthetized with 5% isoflurane in oxygen. After tracheal intubation, the lungs were mechanically ventilated with a gas mixture of isoflurane (2.0%–2.5%) in 30% O2/70% N2. The inspired isoflurane concentration was adjusted to maintain mean arterial pressure (MAP) within 80–120 mm Hg. All surgical fields were infiltrated with 1% lidocaine. The tail artery was cannulated and used for blood pressure monitoring and arterial blood sampling. The right jugular vein was cannulated for drug infusion and blood withdrawal. The common carotid arteries were encircled with suture. The vagus nerves and cervical sympathetic plexus were left intact. Heparin (30 IU) was given IV. Minute ventilation was adjusted to maintain normocapnia throughout the experiment.

Animals were then positioned in a stereotactic head frame. A midline scalp incision was made, and the skull was exposed. Using a 2-mm trephine drill with continuous saline irrigation, a burr hole was drilled over the left hemisphere above the dorsal hippocampus (bregma -4.2 mm, lateral 2.0 mm). The dura was opened. A guide cannula was inserted through the cranial opening and stereotactically positioned with the tip at the brain surface (10o lateral to perpendicular). The guide was fixed in place with a cranial screw, and the burr hole was sealed with orthodontic cement. The wound was closed with sutures. The animal was unmounted from the head frame and placed in the lateral decubitus position.

A 22-gauge needle thermistor was placed underneath the right temporalis muscle, and pericranial temperature was monitored and servoregulated to 37.5 ± 0.1°C with a heat lamp and cooling fan controlled by a temperature-regulation system. A subdermal scalp electrode was positioned over each parietal cortex for continuous monitoring of hemispheric electroencephalographic (EEG) activity relative to a reference electrode placed on the nasion and a ground lead positioned in the tail.

A 2.0-mm membrane microdialysis probe was connected to a microinfusion pump and perfused at a flow rate of 2 µL/min with artificial cerebrospinal fluid. Membrane efficiency was determined before each use by dialyzing against a 1-ng/mL norepinephrine standard solution in 0.2N perchloric acid. The probe was inserted through the guide cannula into the dorsal hippocampus with the tip of the probe positioned at a depth of 4 mm from the brain surface. Pilot studies were performed to verify the accuracy of these stereotactic coordinates by perfusing a 0.1% fluorescein solution through the microdialysis probe. The distribution of the fluorescein dye in coronal sections from the brain was visualized by illumination with a Wood’s lamp. The highest concentration of the dye was found in the dorsal hippocampus, with modest dye accumulation in the overlying cerebral cortex.

After positioning the microdialysis probe in the brain, artificial cerebrospinal fluid was perfused through the probe for 2 h. No dialysate samples were collected during this interval to allow recovery from the trauma of probe insertion. Pilot studies were performed to confirm the adequacy of this 2-h recovery interval. The norepinephrine concentration in the dialysate decreased over the first 90 min after probe insertion and remained stable thereafter. At the end of the 2-h stabilization period, the dialysate was collected into microcentrifuge tubes containing 0.2N perchloric acid to stabilize the recovered catecholamines as described below.

Rats were then randomly assigned to one of three anesthetic regimens. A 30-min stabilization interval was allowed to establish each of the following anesthetic states:

    1. Isoflurane: 1.4% isoflurane inspired in 30% O2/balance N2;

    2. Fentanyl/N2O: Isoflurane was discontinued. An IV infusion of fentanyl was begun (10 µg/kg bolus followed by 25 µg · kg-1 · h-1). The inspiratory gas mixture was changed to 30% O2/70% N2O;

    3. Ketamine: Isoflurane was discontinued. The inspiratory gas mixture was maintained at 30% O2/70% N2. Ketamine was infused IV at a rate of 1.0 mg · kg-1 · min-1.

Muscle paralysis was provided by a 1-mg IV bolus of succinylcholine 5–10 min before the onset of ischemia. Pilot studies were performed to assure that rats would not exhibit an escape response in the absence of succinylcholine given the respective anesthetic regimens. Ischemia was initiated by reducing MAP with exsanguination (typically 5–8 mL of blood withdrawn) to either 50 mm Hg for 20 min (incomplete ischemia) or 30 mm Hg for 10 min (near-complete ischemia) (18,19). In both experiments, the reduction in MAP was followed by bilateral carotid occlusion using temporary aneurysm clips. Animals with active EEG during ischemia in the near-complete model or isoelectric EEG in the incomplete model were excluded from the analysis. To terminate ischemia, shed blood was reinfused, and the aneurysm clips were removed. NaHCO3 (0.1 mEq IV) was administered to minimize systemic acidosis. Eight rats were studied in each anesthetic group for each severity of ischemia. Two microdialysate samples were taken before ischemia at 15-min intervals, one sample was taken during ischemia (10 min after carotid occlusion for the near-complete group and 20 min after carotid occlusion for the incomplete group), and five samples were taken after restoring circulation. Blood samples were taken for determination of plasma catecholamine concentrations 5 min before ischemia, at the midpoint of the ischemic interval, and 20 min postischemia. Physiologic values were recorded 10 min preischemia, 10 min postischemia, and 1 h postischemia. At the conclusion of the experiment, rats were killed with large-dose isoflurane. The brains were removed, and hippocampal probe placement was verified at necropsy. Animals having significant intracerebral hemorrhage caused by microdialysis probe insertion were excluded from the study. Catecholamine concentrations were measured by using high-performance liquid chromatography. Microdialysate samples were directly injected (no extraction) into the chromatographic column. Blood samples (200 µL volume) were collected into tubes containing sodium metabisulfite (0.5 mg/mL of blood) and EDTA (1.8 mg/mL of blood) to stabilize the catecholamine and were immediately centrifuged at 10,000g for 1 min. Plasma catecholamines were extracted on aluminum and eluted into 0.2N perchloric acid for analysis by high-performance liquid chromatography. Microdialysate norepinephrine concentrations were corrected for membrane efficiency (9.8%–20.4%) and are reported as fmol/µL dialysate. Epinephrine was not measured in the microdialysis samples because of a co-eluting contaminant present in the microdialysate buffer. Values for plasma catecholamines were corrected for extraction efficiency (65%–80%) and are reported as ng/mL plasma. The incomplete and near-complete ischemia studies were performed concurrently but were statistically analyzed independently. Differences among anesthetics in concentrations of norepinephrine in the hippocampus were compared using Tukey’s method. Plasma concentrations of epinephrine and norepinephrine were transformed logarithmically before statistical analysis to achieve normal distributions. Differences in concentrations among anesthetics were then tested by using analysis of variance and Tukey’s method. Analysis of covariance was used to test for effects of physiologic values on differences among groups. Pearson correlation coefficients were calculated between the peak concentrations of norepinephrine in the hippocampus and the logarithms of the peak concentrations of norepinephrine in the plasma. Statistical significance was assumed when P <= 0.05. Data are reported as mean ± SEM.


   Results
Top
 Abstract
 Introduction
 Methods
 Results
Discussion
 References
 
In the incomplete ischemia study, two rats were excluded from the isoflurane group and one from the ketamine group because the EEG became isoelectric during ischemia. These animals were replaced. One rat in the fentanyl/N2O group had a plasma norepinephrine concentration >4 SD from the mean; this datum was not included in the statistical analysis. Pericranial temperature was maintained at 37.5 ± 0.1°C for all animals. Physiologic values are summarized in Table 1. During incomplete ischemia, hippocampal norepinephrine concentrations were significantly higher with fentanyl/N2O than with isoflurane (P = 0.037). We did not detect a significant difference between fentanyl/N2O and ketamine (P = 0.86) or isoflurane and ketamine (P = 0.11) (Figure 1A). No physiologic values were found to be a significant covariate in this assay. There were no significant differences in the concentrations of plasma norepinephrine (P = 0.22) or epinephrine (P = 0.32) among the anesthetic groups (Figure 2, A and B). No physiologic values were found to be a significant covariate. There was no correlation between peak norepinephrine concentrations in the hippocampus and plasma during incomplete ischemia (Pearson r = 0.06, n = 22, P = 0.76, 95% confidence interval -0.22 to 0.36, Kendall’s {tau} = -0.03). In the near-complete ischemia study, pericranial temperature was successfully maintained at 37.5 ± 0.1°C for all animals. Physiologic values for the respective treatment groups are summarized in Table 2. During near-complete ischemia, hippocampal norepinephrine concentrations were significantly lower with fentanyl/N2O than with ketamine (P = 0.005). We did not detect a significant difference between fentanyl/N2O and isoflurane (P = 0.50) or isoflurane and ketamine (P = 0.06) (Figure 1B). Concentrations of plasma norepinephrine were significantly greater with fentanyl/N2O than with ketamine (P = 0.0005) or isoflurane (P = 0.05). We did not detect a significant difference between ketamine and isoflurane (P = 0.12) (Figure 2C). Likewise, plasma concentrations of epinephrine during ischemia were significantly higher with fentanyl/N2O than with ketamine (P < 0.0001) or isoflurane (P = 0.012). We did not detect a significant difference between ketamine and isoflurane (P = 0.6) (Figure 2D). There was a significant correlation between the base excess 60 min after reperfusion and both plasma norepinephrine and epinephrine (P = 0.005), with increasing concentrations of plasma norepinephrine and epinephrine being associated with decreasing base excess. There was no correlation between peak concentrations of norepinephrine in the hippocampus and plasma during near-complete ischemia (Pearson r = -0.26, n = 24, P = 0.22, 95% confidence interval -0.55 to 0.03, Kendall’s {tau} = -0.11).


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  		Table 1. Physiologic Values for Incomplete Ischemia
 


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  		Figure 1. Rats were subjected to either (A) incomplete (attenuated electroencephalogram) or (B) near-complete (isoelectric electroencephalogram) forebrain ischemia. Throughout the periischemic interval, the dorsal hippocampus was microdialyzed for concentrations of norepinephrine as a function of anesthetics. {uparrow} = onset of ischemia, {downarrow} = onset of recirculation. Values are mean ± SEM. *P = 0.037 for fentanyl/N2O versus isoflurane. **P = 0.0005 for fentanyl/N2O versus ketamine.

 


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  		Figure 2. Rats were subjected to either incomplete (A and B) or near-complete (C and D) forebrain ischemia. Arterial plasma was sampled for norepinephrine and epinephrine concentrations 5 min before ischemia, during ischemia, and 20 min after the onset of recirculation as a function of anesthetics. {uparrow} = onset of ischemia, {downarrow} = onset of recirculation. Values are mean ± SEM. *P <= 0.05 for fentanyl/N2O versus ketamine or isoflurane during near-complete ischemia.

 

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  		Table 2. Physiologic Values for Near-Complete Ischemia
 

   Discussion
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 Abstract
 Introduction
 Methods
 Results
 Discussion
References
 
The findings from this experiment are consistent with previous reports that the extracellular concentration of norepinephrine increases during global cerebral ischemia and returns to baseline concentrations with reperfusion (16,17,20). This was extended in the current study by the observation that the magnitude of the response was dependent on both the anesthetic administered and the severity of the ischemic insult. Plasma concentrations of norepinephrine and epinephrine also increased during near-complete ischemia, consistent with previous observations (18). However, in the current study, we demonstrated that large changes in plasma catecholamines occur only in the context of near-complete ischemia induced with more severe arterial hypotension and that the magnitude of adrenergic response is also dependent on the anesthetic. We previously reported that histologic and behavioral outcome from near-complete global ischemia is also anesthetic-dependent in rats whose brain temperature is strictly maintained normothermic during the periischemic interval (21). Rats anesthetized with isoflurane during ischemia had substantial decreases in hippocampal CA1 and neocortical neuronal necrosis (associated with improved motor function) compared with rats anesthetized with fentanyl/N2O. The effect of ketamine was intermediate. In contrast, for rats subjected to incomplete global ischemia, no anesthetic-dependent effects on histologic outcome were observed. In both cases, doses of anesthetic (i.e., isoflurane, fentanyl/N2O, and ketamine) and severities of ischemia were identical to those used in the current study. Several factors caused us to consider adrenergic events as potential explanations for these histological/behavioral findings. The two-vessel occlusion model of forebrain ischemia requires induced systemic hypotension to diminish circulation from the vertebrobasilar system to the forebrain during carotid artery occlusion. The magnitude of arterial hypotension can be associated with both the magnitude of cerebral blood flow reduction and the severity of histologic injury (19). Rats subjected to near-complete ischemia, as defined by an isoelectric EEG, are subjected to severe hemorrhagic shock (MAP 30 mm Hg) in which adrenergic responses would be expected to be more profound than those observed during incomplete ischemia (MAP 50 mm Hg). The extent to which anesthetics modulate the cerebral adrenergic response to ischemia and the extent to which plasma catecholamine concentrations represent concentrations in brain interstitium during the hypotensive ischemic challenges had not been previously examined. Others have questioned the role of adrenergic events in global ischemia and whether anesthetics provide differential effects on circulating catecholamines. Ketamine has been examined in a model of hemispheric cerebral ischemia caused by unilateral carotid occlusion combined with systemic hypotension (15). Although blood was sampled only at the end of ischemia, ketamine inhibited the increases of plasma norepinephrine and epinephrine observed in rats that received fentanyl/N2O, and neurologic outcome was improved. This is consistent with other work performed using the same model, in which ganglionic blockade caused by hexamethonium (14) reduced circulating catecholamine concentrations and improved neurologic injury when given to rats anesthetized with fentanyl/N2O. Brain extracellular catecholamine concentrations were not examined in either of these studies. No correlation was observed between plasma and brain catecholamine concentrations in the current study. The blood-brain barrier is normally resistant to the transfer of catecholamines (22) and remains impermeable to at least macromolecules after severe forebrain ischemia in the rat (23). Our study suggests that the blood-brain barrier remains impermeable to catecholamines after near-complete ischemia. Although rats anesthetized with fentanyl/N2O had the greatest increase in plasma norepinephrine, the same group had the smallest increase in hippocampal norepinephrine. Similarly, rats anesthetized with ketamine had little or no change in plasma norepinephrine, whereas hippocampal norepinephrine was increased >100-fold. These findings make it unlikely that differential effects of anesthetics on global ischemic outcome can be explained by the transit of catecholamines from plasma to cause direct effects at the neuronal/glial level (15, 21,24). It is plausible, however, that high concentrations of circulating catecholamines alter the function of other organ systems, which might have adverse consequences for postischemic neurons. This would be consistent with the greater increases in both plasma catecholamines and histologic injury observed in rats anesthetized with fentanyl/N2O. There is reason to believe that brain parenchymal catecholamines play a role in the eventual histologic/behavioral outcome from ischemia. In the gerbil, a reduced number of brain {alpha}1-, {alpha}2-, and ß-adrenergic receptors has been demonstrated as early as 24 h after unilateral carotid artery occlusion (25). The magnitude of this effect is both anatomically and receptor-subtype specific. Consistent with this, {alpha}1-adrenergic receptor binding is reduced by approximately 50% in forebrain homogenates of postischemic gerbils, whereas ß1 and ß2 binding undergoes little or no change (26). However, there is conflicting evidence for the qualitative effects of central catecholamines in ischemic neuronal injury. Lesions of the locus ceruleus made before cardiac arrest in the rat resulted in a 90% reduction of brain norepinephrine concentration and worsened histologic outcome (27). Similarly, postischemic administration of idazoxan (a central {alpha}2-adrenergic antagonist) reduced histologic damage in the rat (28). It was hypothesized that antagonism of noradrenergic afferents to the locus ceruleus by idazoxan increased the tonic activity of this region, resulting in an upregulated inhibition of postischemic neuronal hyperactivity in regions of the brain selectively vulnerable to global ischemia. Conversely, treatment with dexmedetomidine, which is a central {alpha}2-adrenoreceptor agonist, also improves neurologic outcome in the rat and reduces histologic injury in the rabbit (29,30). Unfortunately, the data provided in our study do not help in defining either the beneficial or detrimental contributions of increased hippocampal norepinephrine to eventual histologic outcome. As shown in Figure 1B, animals anesthetized with isoflurane had an intermediate adrenergic response. This is in contrast to our previous study examining histologic outcome under the same ischemic conditions in which isoflurane-anesthetized rats had substantially better outcomes than rats anesthetized with either fentanyl/N2O or ketamine (21). Accordingly, we postulate that central adrenergic responses to global ischemia do not play a dominant role in ischemic injury but might act in concert with other mechanisms at the cellular level. In conclusion, we examined the response of both blood and brain catecholamine concentrations to different severities of global brain ischemia as a function of anesthetic during ischemic insult. Moderate (incomplete) ischemia caused no change in plasma catecholamines in any anesthetic group. In the brain, the concentration of norepinephrine was highest in rats anesthetized with fentanyl/N2O. During severe (near-complete) ischemia, plasma epinephrine and norepinephrine were substantively increased only in rats anesthetized with fentanyl/N2O. In contrast, brain norepinephrine increases were the least in that group (compared with either isoflurane or ketamine). The absence of a correlation between plasma and brain catecholamine concentrations is consistent with the belief that adrenergic responses to ischemia are independent in the blood and brain and that these compartmental changes contribute to ischemic outcome by different mechanisms of action.


   Acknowledgments
 
This work was supported by NIH Grant RO1 GM39771–12. GBM was supported by a postdoctoral stipend through the German Academic Exchange Service. BN was supported by postdoctoral stipends provided by The Laerdal Foundation for Acute Medicine and The Swedish Society of Physicians.


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 Introduction
 Methods
 Results
 Discussion
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Accepted for publication December 21, 1998.




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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 1999 by the International Anesthesia Research Society. Online ISSN: 1526-7598   Print ISSN: 0003-2999 HighWire Press