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Anesth Analg 2005;100:841-846
© 2005 International Anesthesia Research Society
doi: 10.1213/01.ANE.0000146519.85312.21

NEUROSURGICAL ANESTHESIA

The Role of Nitric Oxide Synthase Inhibition in the Adverse Effects of Etomidate in the Setting of Focal Cerebral Ischemia in Rats

John C. Drummond, MD*{dagger}, Lorne D. McKay, MD{ddagger}, Daniel J. Cole, MD§, and Piyush M. Patel, MD*{dagger}

*Departments of Anesthesiology, University of California, San Diego, La Jolla; {dagger}VA Medical Center, San Diego; {ddagger}Loma Linda University, Loma Linda, California; and §Mayo Clinic College of Medicine, Rochester, Minnesota

Address correspondence and reprint requests to John C. Drummond, MD, VA Medical Center, Anesthesia Service-125, 3350 La Jolla Village Dr., San Diego, CA 92161. Address e-mail to jdrummond{at}ucsd.edu.


   Abstract
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We evaluated the effect of NG-nitro-l-arginine-methyl-ester (l-NAME, a nitric oxide synthase [NOS] inhibitor) and l-arginine (nitric oxide substrate) on cerebral mitochondrial dysfunction (hereafter referred to as "injury") after temporary middle cerebral artery occlusion (MCAo) during halothane or etomidate anesthesia in spontaneously hypertensive rats. Sixty minutes before MCAo, rats were randomized to 1 of 5 regimens (n = 8 per group): h/control, 1.2 minimum alveolar anesthetic concentration of halothane; h/l-NAME, 1.2 minimum alveolar anesthetic concentration of halothane and l-NAME (30 mg/kg); etomidate, an electroencephalographic (EEG) burst suppression dose of etomidate; e/l-NAME, an EEG burst suppression dose of etomidate and l-NAME (30 mg/kg); or e/l-NAME/arg, an EEG burst suppression dose of etomidate, l-NAME (30 mg/kg), and l-arginine (bolus of 300 mg/kg with an infusion at 35 mg · kg–1 · min–1). After 180 min of MCAo and 120 min of reperfusion, volume of injury was determined using 2,3,5-triphenytetrazolium stain. Injury volume (mm3, mean ± sd) was larger in the etomidate group (153 ± 17) than the halothane anesthetized h/control group (93 ± 16) (P < 0.05) but did not differ between the e/l-NAME (162 ± 17) and h/l-NAME groups (155 ± 26). Injury volume in the e/l-NAME/arg group (88 ± 15) was not different from the h/control group (93 ± 16) and was less than that in either the etomidate or the e/l-NAME groups (P < 0.05). The data reproduce our previous observation that, relative to a halothane-anesthetized control state, etomidate has an adverse effect on ischemic injury in the setting of temporary focal cerebral ischemia. Prior inhibition of NOS with l-NAME resulted in no difference in the volume of injury between groups receiving etomidate or halothane (162 ± 17 versus 155 ± 26). Administration of a large dose of l-arginine prevented the adverse effect of etomidate. The data were obtained after only 2 h of reperfusion and therefore cannot be construed as representative of final neurologic outcome. They nonetheless suggest that etomidate produces an adverse effect on mitochondrial function early in the course of focal cerebral ischemia, in part, by inhibition of NOS.


   Introduction
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Etomidate has been promoted for use as a cerebral protective drug, particularly during intracranial aneurysm surgery. The neurosurgical literature contains reports of etomidate’s use in that context (1,2) and etomidate was used as a cerebral protectant in some of the patients entered in the recently completed International Hypothermia in Aneurysm Surgery Trial II (M. Todd, MD, personal communication). Advocacy of its use was initially based on the premise that etomidate has cerebral metabolic rate suppressing properties that are similar to those of the barbiturates. Our laboratory has performed previous investigations in an attempt to provide preclinical confirmation of the protective advocacy of etomidate. In our initial investigation, we demonstrated improved tolerance of the hippocampus (3,4) in a model of moderately severe forebrain ischemia in rats in association with the administration of etomidate. However, in a subsequent investigation, using a model of focal ischemia, a model more representative of the focal occlusions that occur during aneurysm surgery, we were unable to demonstrate any protective efficacy of etomidate relative to other anesthetic regimens (5). Those investigations, in fact, yielded the then remarkable observation that etomidate actually seemed to be deleterious in the setting of temporary occlusion of the middle cerebral artery (MCAo).

Etomidate is a carboxylated imidazole. Many imidazoles are inhibitors of nitric oxide synthase (NOS) (6). In addition, etomidate is recognized to cause some degree of hemolysis in humans (7) and hemoglobin is also an effective scavenger of nitric oxide (NO) (8). As a consequence, we theorized that the deleterious effect of etomidate in our preclinical model was a function of NO inhibition and that the adverse effect was occurring as a result of the reduced availability of an important cerebral vasodilating substance, NO, during a period of flow restriction.

We undertook the experiments described herein to determine whether effects mediated via NO were involved in the apparently deleterious effect of etomidate in the setting of temporary focal cerebral ischemia.


   Methods
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The protocol was approved by the Animal Research Committee of Loma Linda University in accordance with the standards for the care of laboratory animals of the National Institutes of Health (publication no. 96-208, 1996). Male, spontaneously hypertensive rats (n = 40, 375–425 g, 16–20 wk; Harlan, Indianapolis, IN) were anesthetized with isoflurane and orotracheally intubated. Spontaneously hypertensive rats were used because the homogeneity of the response to MCAo permits the use of relatively smaller group sizes. Mechanical ventilation was maintained (Harvard Co., Boston, MA) with isoflurane (1.44%, end-tidal) in an oxygen/air mixture (fractional inspired oxygen 0.4). The volatile anesthetic concentration was measured with a Datex Capnomac (Datex Co., Helsinki, Finland). The femoral vessels and left internal jugular vein were cannulated for arterial blood pressure monitoring, blood sampling, and fluid administration. Mean arterial blood pressure (MABP) was recorded using a Micro-Med Blood Pressure Analyzer (Micro-Med, Inc., Louisville, KY). That device continuously records blood arterial pressure and averages MABP over user-determined intervals. Average MABPs were determined for each 15-min interval, beginning at the time of MCAo. MABP was supported at ≥130 mm Hg by IV infusion of phenylephrine, as required. On the basis of our experience with halothane-anesthetized spontaneously hypertensive rats, we identified 130 mm Hg as the baseline MABP. After randomization of the animals, if MABP was <130 mm Hg, phenylephrine was administered IV to restore MABP.

Maintenance fluids consisted of 0.9% NaCl at 4 mL · kg–1 · h–1 IV. Temperature was measured under the temporalis muscle (Mon-a-Therm temperature sensor; Mallinckrodt Anesthesia Products, St. Louis, MO) and servo-controlled at 37°C by a heating blanket. At 30-min intervals, arterial blood (125 µL) was analyzed for arterial pH, arterial carbon dioxide partial pressure (Paco2), arterial oxygen partial pressure (Pao2), glucose, and hematocrit (IL-1306 pH Blood Gas Analyzer [Instrumentation Laboratory, Lexington, MA]; YSI Model 23-A Glucose Analyzer [Yellow Springs Instruments, Yellow Springs, OH]; IEC MB Centrifuge Microhematocrit [DAMON/IEC Division, Needham Heights, MA]). The electroencephalogram (EEG) was continuously recorded between platinum needle electrodes placed in a bitemporal configuration. Sixty minutes before MCAo, the isoflurane was discontinued and each rat was assigned, at random, to one of the following regimens, each of which was maintained for the duration of the experiment:

h/control (n = 8). Each rat received 1.2 minimum alveolar anesthetic concentration (MAC) of halothane (9) (Abbott Laboratories, North Chicago, IL) throughout MCAo and reperfusion.
h/l-NAME (n = 8). Each rat received 1.2 MAC halothane throughout MCAo and reperfusion, and NG-nitro-l-arginine-methyl-ester (l-NAME, 30 mg/kg) was given, intraperitoneally.
etomidate (n = 8). Etomidate (HypnomidateTM, Janssen Pharmaceutica, Beerse, Belgium) (see Appendix 1) was infused at a dose sufficient to yield a burst-suppression (3–5 bursts/min) pattern on the EEG.
e/l-NAME (n = 8). Etomidate was infused at a dose sufficient to yield a burst-suppression (3–5 bursts/min) pattern on the EEG, and l-NAME (30 mg/kg) was given, intraperitoneally.
e/l-NAME/arg (n = 8). Etomidate was infused at a dose that provided a burst-suppression (3–5 bursts/min) pattern on the EEG, l-NAME (30 mg/kg) was given intraperitoneally 60 min before MCAo, and l-arginine was administered IV in a bolus dose of 300 mg/kg, followed immediately by an infusion at 35 mg · kg–1 · min–1 that was continued until the time of death.

In the latter 3 groups, anesthetic administration was titrated to achieve 3–5 bursts/min on the EEG. The burst-suppression pattern was maintained for 60 min before MCAo and throughout the period of MCAo and reperfusion.

The dose of l-NAME and the period of administration were chosen to ensure that the inhibitory effects of l-NAME on vascular and parenchymal NOS were maximal during the period of occlusion and reperfusion. They were based on previous pharmacokinetic studies that demonstrated that the onset of l-NAME effect begins within 30 min of dosing (10,11). The dose of l-arginine administration was based on our own observations of the dose of l-arginine that was required to prevent the hemodynamic effect of l-NAME.

A left temporal craniectomy was performed, and the MCA was occluded in with a 10-0 monofilament nylon suture to achieve ischemia of both cortical and subcortical tissue (12,13). After 180 min of MCAo, the sutures were released, and a 120-min period of reperfusion ensued. During MCAo and reperfusion, the craniotomy site was bathed in mock cerebrospinal fluid at 37°C. Immediately after the 120-min period of reperfusion, perfusion fixation was performed. Normal saline was first infused via the ascending aorta until the effluent from the incised right atrium was clear. Thereafter, 200 mL of 2% 2,3,5-triphenyltetrazolium chloride (TTC, 37°C) was infused over 15 min followed by 50 mL of 10% buffered formalin delivered over 5 min. All fluids were infused from a height of 106 cm. The brains were harvested immediately and embedded in an egg/albumin-gelatin media and mounted on a vibratome (Vibratome Series 1000; Technical Products International, Inc., St. Louis, MO). Ten serial coronal sections were cut in 1.0-mm increments, spanning the area of MCA distribution (2.0–11.0 mm from the frontal pole). The 10 brain sections were photographed with color slide film (Ektachrome, tungsten 160 ASA). The area of each section with deficient TTC staining was determined with a Drexel/DUMAS Image Analysis System (Drexel University, Philadelphia, PA), and the volume of injured tissue in the hemisphere ipsilateral to MCAo was calculated from the consecutive sums of infarct area multiplied by the interval between sections (1.0 mm) over the extent of the lesion (14). The corpus callosum does not routinely stain with TTC in normal tissue; accordingly, the rim of tissue representing the corpus callosum was excluded from analysis. All image analyses were performed by an independent observer who was blinded to study protocol.

The physiologic data were analyzed by repeated-measures analysis of variance, and volume of injury data by a one-way analysis of variance. Where differences were identified, pairwise comparisons were performed using Student’s t-test with appropriate Bonferroni corrections. P < 0.05 was considered significant. All data are presented as mean ± sd.


   Results
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The physiologic and pharmacologic data are presented in Table 1. There were no between-group differences at any measurement interval for the physiologic indices. Accordingly, these data are presented as averages during the study period. Phenylephrine was required in the control and e/l-NAME/arg groups.


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  		Table 1. Physiologic and Pharmacologic Data

 

The volume of cerebral ischemic injury is presented in Figure 1. There were no abnormalities in TTC staining for the hemisphere contralateral to MCAo. Ischemic injury volume (mm3) was larger for the h/l-NAME group (155 ± 26) than the h/control group (93 ± 16) (P < 0.05), but did not differ from the etomidate (153 ± 17) and e/l-NAME groups (162 ± 17). Lesion volume was less in the e/l-NAME/arg group (88 ± 15) than in the h/l-NAME, etomidate, and e/l-NAME groups (P < 0.05).



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  		Figure 1. Volume of brain injury (mm3, mean ± sd) as determined by triphenyl tetrazolium chloride staining for each group. The control group (halothane control) received 1.2 minimum alveolar anesthetic concentration of halothane, the halothane/l-NAME group received halothane and NG-nitro-l-arginine-methyl-ester (l-NAME, 30 mg/kg), the etomidate group received etomidate at a burst-suppression dose, the etomidate/l-NAME group received etomidate and l-NAME (30 mg/kg), and the etomidate/l-NAME/arg group received etomidate, l-NAME, and l-arginine (bolus of 300 mg/kg, and an infusion at 35 mg · kg–1 · min–1. *P < 0.05 versus the halothane control group. **P < 0.05 versus the halothane/l-NAME, etomidate, and etomidate/l-NAME groups.

 


   Discussion
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The protocol included five study groups. The intention for including the h/control and the etomidate groups was to verify the findings of the previous experiment (5) in which it was observed that etomidate worsened focal cerebral ischemic injury. Once again, TTC staining after 2 hours of reperfusion after 3 hours of MCAo revealed a larger volume of metabolically compromised brain in the animals that received etomidate than in those that received halothane. The group that received l-NAME during halothane anesthesia was included to establish, in essence, an additional "control" state. Because of the prior administration of the NO inhibitor l-NAME, any effects of subsequently administered etomidate mediated by NO inhibition would be largely eliminated, thereby revealing only etomidate’s NO-independent effects. The addition of l-NAME in halothane-anesthetized animals (h/l-NAME) resulted in an increase in the volume of injured tissue relative to those animals that received halothane only (h/control). The volume of injury in the group that received l-NAME and etomidate (e/l-NAME) was no different from that observed in the h/l-NAME animals. These observations are consistent with our hypothesis that the apparent adverse effect of etomidate observed in both our previous investigation and the current etomidate group is mediated by inhibition of NO. In addition, they suggest that, absent the NO-mediated effect, etomidate has neither beneficial nor deleterious cerebral outcome effects (relative to anesthesia with 1.2 MAC halothane) in the setting of temporary focal ischemia. Confirmation of NO’s contribution to the results of the present study would have required measurement of tissue levels of either NO or markers of its synthesis. These measurements were not performed as part of this investigation.

The effects of etomidate on NOS are not completely defined. Etomidate is an imidazole and many imidazoles are inhibitors of NOS (6,15,16). Etomidate has been shown to be an inhibitor of NO-mediated vasodilation in canine pulmonary arteries (17). With respect to the brain, the specificity of etomidate’s NOS inhibition (endothelial versus neuronal versus inducible) is entirely undefined. However, there is a second mechanism by which etomidate might inhibit NO. That is by direct scavenging by hemoglobin. Etomidate causes a minor degree of hemolysis (7) and free hemoglobin is an effective scavenger of NO (18–20). The e/l-NAME/arg group was included to provide insight into the mechanism by which etomidate’s effect on NO is mediated. The adverse of effects of l-NAME and etomidate were not apparent in the e/l-NAME/arg group. That suggests that the inhibition of NO caused by etomidate was competitive [as that of l-NAME is also (21)]. A competitive inhibition of NOS would be predicted from the behavior of some other imidazoles (22). Because reversal of the adverse effect of etomidate by l-arginine implies a competitive effect, the mechanism of etomidate’s adverse effect is more likely to be by inhibition of NOS than by the NO scavenging mechanism that was suggested above.

Although the literature regarding the effects of NOS inhibition on outcome after cerebral ischemia includes many investigations demonstrating both protective and deleterious effects, the overview that has evolved is that early inhibition, especially inhibition of endothelial NOS exacerbates injury and late inhibition of neuronal and/or inducible NOS, lessens injury (23,24). The rationale (with substantial supporting evidence) is that during ischemia NO is normally elaborated in increased amounts (25) and is critical to penumbral flow (26) and that early inhibition of endothelial NOS denies the brain a critically important endogenous vasodilator at a time when flow is marginal or inadequate (27). There is, in addition, evidence that NO reduces the adherence of leukocytes to vascular endothelium early in the course of an ischemic episode (28–30). Later in the postischemic period, NO of neuronal origin has deleterious effects, possibly through its effects as a free radical, and inhibition has a favorable effect on outcome (23). An adverse effect of etomidate on cerebral blood flow (CBF) during periods of restricted flow has been demonstrated in both animals (31) and humans (32,33) and is consistent with the NOS-mediated effects we postulate. The effects of etomidate observed in humans (32,33) are in turn consistent with investigations confirming that NO is one of the influences that determine basal CBF in humans (34–36). Note that in the present investigation, CBF measurements were not performed. Accordingly, our suggestion that the adverse effects of etomidate were CBF-mediated must be viewed as speculation.

Although TTC has been used extensively in investigations of cerebral ischemia, its limitations should be fully understood. Absence of TTC staining indicates regions of impaired mitochondrial function but does not give certain delineation of areas of inevitable infarction. We have previously demonstrated that injury as defined by TTC can be at least in part reversible (37). Nonetheless, it probably does provide an indication of regions in which physiologic function is substantially impaired at a given point in time.

This investigation was performed in rats and the results cannot justify an assertion that etomidate has an adverse effect in the ischemic human brain. However, before proceeding with even tentative exploration of beneficial effects in humans, it is customary to obtain preclinical evidence of efficacy. This investigation does not lend support in that quarter. While the early adverse effect we have demonstrated is not proof of an adverse effect on final outcome it may, in addition, not be applicable in humans. However, the experimental group in the present investigation in which NO was eliminated as a variable did not indicate any beneficial effect relative to a volatile anesthetic at clinically relevant concentrations. The present results, combined with the CBF observations of Edelman et al. (32) and Hoffman et al. (33) and obtained in the context of temporary vessel occlusion during aneurysm surgery do not provide support for the use of etomidate for cerebral protection that has been described in the clinical literature (1,2). Additional investigation that provides some preclinical evidence of protective efficacy seems warranted before advocacy of human use as a neuroprotective drug.

The authors gratefully acknowledge the technical assistance of Suzzanne Marcantonio.


   Appendix 1: Preparation of the Etomidate Infusion
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In the preliminary experiments, the etomidate preparation used was Amidate (Abbott Laboratories) which is prepared at a concentration of 2 mg/mL in a propylene glycol vehicle. Our attempts to maintain a burst-suppression pattern for a 5-h period resulted in a delayed deterioration in cardiopulmonary performance. We attributed that deterioration to a combination of volume overload and possible propylene glycol toxicity (38,39). We next obtained the Janssen preparation of etomidate (Hypnomidate). This preparation contains etomidate in a concentration of 125 mg/mL in an ethanol vehicle. The use of this preparation would have entailed the administration of a substantial amount of ethanol, with its own potential intercurrent effects on neuronal survival. Accordingly, immediately before each study requiring etomidate, the Hypnomidate preparation was lyophilized and immediately resuspended in saline to produce a preparation with a concentration of 12.5 mg/mL. The osmolality of the resuspended etomidate in saline was between 319 and 327, as measured by freezing point depression. In the next series of preliminary experiments, we observed that we could achieve and maintain the desired EEG end point (3–5 bursts/min) with an infusion requiring approximately 10% more etomidate (assuming no degradation) than was required with the propylene glycol preparation. Our observations implied little or no degradation of the etomidate by the lyophilization-resuspension process. The Director of Research for Abbott Laboratories was contacted, and after consultation, he reported that it was the opinion of Abbott’s biochemists that our procedure would not be expected to lead to immediate degradation of the etomidate (William Houghton, MD, Director of Research, Abbott Laboratories, personal communication).


   References
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W. Li, J. Xue, C. Niu, H. Fu, C. S. C. Lam, J. Luo, H. H. N. Chan, H. Xue, K. K. W. Kan, N. T. K. Lee, et al.
Synergistic Neuroprotection by Bis(7)-tacrine via Concurrent Blockade of N-Methyl-D-aspartate Receptors and Neuronal Nitric-Oxide Synthase
Mol. Pharmacol., May 1, 2007; 71(5): 1258 - 1267.
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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 2005 by the International Anesthesia Research Society. Online ISSN: 1526-7598   Print ISSN: 0003-2999 HighWire Press