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Thiopentone and methohexital, but not pentobarbitone, reduce early focal cerebral ischemic injury in rats

[Le thiopental et le méthohexital, mais non le pentobarbital, réduisent la lésion ischémique cérébrale focale précoce chez les rats]

Daniel J. Cole, MD^*, Lorne M. Cross, MD^*, John C. Drummond, MD, Piyush M. Patel, MD and Wayne K. Jacobsen, MD^*

^* From the Departments of Anesthesiology, Loma Linda University, Loma Linda, the University of California and the VA Medical Center,
San Diego, California, USA.

Address correspondence to: Dr. Daniel J. Cole, Department of Anesthesiology, Loma Linda University, Loma Linda, CA 92354, USA. Phone: 909-558-4475; Fax: 909-558-4143; E-mail: djcole{at}som.llu.edu

	Abstract

TOP Abstract Introduction Methods Part A Part B Results Discussion References

 
Purpose: Although barbiturates are considered to be cerebral protectants, little is known regarding the relative efficacy of different barbiturates to reduce ischemic brain injury. In a model of middle cerebral artery occlusion (MCAo), we compared the relative effects of 1.0 and 0.4 burst-suppression doses of thiopentone, methohexital, and pentobarbitone on cerebral infarct.

Methods: During isoflurane anesthesia, MCAo was achieved via a temporal craniotomy. Thirty minutes before MCAo the rats were randomized to receive one of the following which was maintained throughout the study. Halothane (n=20)-1.2 MAC halothane, thiopentone (n=20), methohexital (n=20), or pentobarbitone (n=20). The first ten animals in each barbiturate group received the respective barbiturate in a dose sufficient to maintain burst-suppression of the electroencephalogram (3–5 bursts•min^–1). The subsequent ten animals in each barbiturate group received 40% of the burst-suppression dose. After 180 min of MCAo and 120 min of reperfusion, cerebral injury was assessed.

Results: For the burst-suppression animals, injury volume (mm³, mean ± SD) was less in the thiopentone group (88 ± 14) than the halothane (133 ± 17), methohexital (126 ± 19), or pentobarbitone (130 ± 17) groups (P <0.05). For 0.4 burst-suppression animals, injury volume was less for the methohexital group (70 ± 22) than the halothane (124 ± 24), thiopentone (118 ± 15), or pentobarbitone (121 ± 20) groups (P <0.05).

Conclusions: These data are inconsistent with the longstanding assumption that electrophysiologically comparable doses of the various classes of barbiturates have equivalent protective efficacy. They in turn suggest that mechanisms other than, or at least in addition to, metabolic suppression may contribute to the protective effect of barbiturates.

	Introduction

TOP Abstract Introduction Methods Part A Part B Results Discussion References

 
SPECIFIC substitutions on the pyrimidine ring of barbituric acid have resulted in several clinically applicable barbiturates with distinct pharmacophysiologic profiles. There is abundant experimental evidence that barbiturates can decrease the extent of neurologic injury caused by an episode of temporary focal cerebral ischemia,^1–4 and seminal experiments by Michenfelder and colleagues provided data that led many to conclude that this protection was mediated primarily by reduction of cerebral metabolic rate (CMR).^4,5 More recently, however, this belief has been challenged because of the observation that a comparable reduction of CMR produced by other anesthetic agents (e.g., isoflurane, etomidate) does not have an equivalent protective effect.^3,6 Furthermore, a recent investigation by Warner et al.⁷ demonstrated that pentobarbitone administered in the two dose regimens used in this investigation, i.e., electroencephalographic (EEG) burst-suppression and 40% burst-suppression doses, resulted in indistinguishable degrees of neuronal injury after middle cerebral artery occlusion (MCAo) in spite of significant differences in CMR.

A second widely held assumption is that, if the same metabolic end-point is established (as suggested by a quiescent EEG), there is protective equivalence among the barbiturates. This assumption seemed reasonable when the accepted dogma was that CMR suppression was the basis for barbiturate-induced cerebral protection. However, if non-CMR mechanisms contribute to barbiturate-induced cerebral protection,⁷ it is not necessarily reasonable to assume that all barbiturates are equivalent with respect to these other, undefined protective properties.

In view of this potential for a therapeutic difference in the efficacy of various barbiturates in ameliorating cerebral ischemic injury, we performed a comparison of the effect of thiopentone, methohexital, and pentobarbitone on the extent of early ischemic injury following temporary MCAo in rats. Pentobarbitone is a widely used oxybarbiturate, while thiopentone is its thioanalog, and methohexital is an oxybarbiturate with excitatory properties. Each barbiturate was given in two dose regimens to provide insight into dose-response relationships for the three barbiturates.

	Methods

TOP Abstract Introduction Methods Part A Part B Results Discussion References

 
The protocol was approved by the Animal Investigation 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=80, 375–425 g, 16–20 weeks) were anesthetized with isoflurane and orotracheally intubated. Mechanical ventilation was maintained (Harvard Co., Boston, MA, USA) with isoflurane (1.44%, end-tidal) in an oxygen: air mixture (fractional inspired oxygen 0.4). The femoral vessels were cannulated for 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, USA). The device continuously records blood pressure and averaged MABP over 15-min intervals, beginning with the moment of MCAo. Mean arterial blood pressure was supported at 120 mmHg by iv infusion of phenylephrine, as required.

Maintenance fluids consisted of 0.9% NaCl at 4 mL•kg^–1•hr^–1. Temperature was measured under the temporalis muscle (Mon-a-Therm temperature sensor; Mallinckrodt Anesthesia Products, St. Louis, MO, USA) and servo-controlled at 37°C by a heating blanket. At 30-min intervals, arterial blood (125 µL) was analyzed for pHa, PaCO₂, PaO₂, glucose, and hematocrit (IL-1306 pH blood gas analyzer [Instrumentation Laboratory, Lexington, MA, USA]; YSI Model 23-A glucose analyzer [Yellow Springs Instruments, Yellow Springs, OH, USA]; IEC MB centrifuge microhematocrit [DAMON/IEC Division, Needham Heights, MA, USA]). The EEG was continuously recorded between platinum needle electrodes placed in a bitemporal configuration. Thirty minutes before MCAo, the isoflurane was discontinued and each rat randomized to receive one of the following regimens, each of which was maintained for the duration of the experiment:

	Part A

TOP Abstract Introduction Methods Part A Part B Results Discussion References

 
Control (n=10):Each rat received 1.2 MAC⁸ halothane (Abbott Laboratories, North Chicago, IL, USA) while 0.9% NaCl was adminis- tered intravenously.

Thiopentone (n=10):Thiopentone sodium (Abbott Laboratories, North Chicago, IL, USA) was infused at a dose which provided a burst-suppres- sion (3–5 bursts•min^–1) pat- tern on the EEG.

Methohexital (n=10):Methohexital sodium (Jones Pharma, St. Louis, MO, USA) was infused at a dose which provided a burst-suppression (3–5 bursts•min^–1) pattern on the EEG.

Pentobarbitone (n=10):Pentobarbitone sodium (Abbott Laboratories, North Chicago, IL, USA) was infused at a dose which provided a burst-suppres- sion (3–5 bursts•min^–1) pat- tern on the EEG.

	Part B

TOP Abstract Introduction Methods Part A Part B Results Discussion References

 
Control (n=10): Each rat received 1.2 MAC halothane.

Thiopentone (n=10):Thiopentone sodium was infused at 40% of the dose required in Part A.

Methohexital (n=10):Methohexital sodium was infused at 40% of the dose required in Part A.

Pentobarbitone (n=10):Pentobarbitone sodium was infused at 40% of the dose required in Part A.

The volume of infused barbiturate was deducted from the maintenance fluid in each group such that all animals received equivalent amounts of fluid throughout the experiment.

A left temporal craniectomy was performed, and the middle cerebral artery was occluded in two locations with 10-O monofilament nylon suture to achieve ischemia of both cortical and subcortical tissue.^9,10 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 following the 120-min period of reperfusion, perfusion fixation was performed. This was accomplished by infusion, via the ascending aorta, of 200 mL of 2% 2,3,5-triphenyltetrazolium chloride (TTC, 37°C) over 15-min followed by 50 mL of 10% buffered formalin over five minutes. The brains were immediately harvested and embedded in an egg: albumin-gelatin media and mounted on a vibratome (Vibratome Series 1000; Technical Products International, Inc., St. Louis, MO, USA). Ten serial coronal sections were cut in 1.0-mm increments, spanning the area of middle cerebral artery distribution (2.0–11.0 mm from the frontal pole). The ten brain sections were photographed with colour 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, USA), and the volume of injured tissue in the hemisphere ipsilateral to MCAo calculated from the consecutive sums of infarct area multiplied by the interval between sections (1.0 mm) over the extent of the infarct.¹¹

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 the study protocol.

The physiological 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 tests with appropriate Bonferroni correction. P <0.05 was considered significant. All data are presented as means ± SD.

	Results

TOP Abstract Introduction Methods Part A Part B Results Discussion References

 
The physiologic and pharmacologic data are presented in Table I. The physiologic data were similar between groups. In general, a greater amount of phenylephrine was required during the reperfusion period, than during MCAo. For Part A, phenylephrine was required in all barbiturate groups, but not the control group. The amount of phenylephrine was greater for the methohexital group vs the other three groups. For Part B, phenylephrine was required only in four methohexital animals.

Part B (40% of the barbiturate dose required to maintain EEG burst-suppression)
The volume of cerebral injury was not different for the control (124 ± 22), thiopentone (118 ± 15) or pentobarbitone groups (121 ± 20); but was less (P <0.05) in the methohexital group (70 ± 22) than in the other three groups.

	Discussion

TOP Abstract Introduction Methods Part A Part B Results Discussion References

 
These data confirm previous reports that thiopentone, in a dose which induces EEG burst-suppression, results in a reduction in infarct volume following temporary focal cerebral ischemia.^1,3–5,12 However, the novel observation is that neither methohexital nor pentobarbitone, in burst-suppression doses, had a comparable effect on cerebral injury volume. Moreover, at a barbiturate dose that was 40% of a burst-suppression dose, thiopentone did not exhibit a significant effect on volume of injury while methohexital reduced injury to an extent comparable to that achieved in Part A for thiopentone. This latter observation, however, is subject to the limitation that Parts A and B of this experiment were not performed concurrently.

With few exceptions^7,13 most studies evaluating barbiturate-induced cerebral protection have been conducted on the premise that optimal outcome is dependent on maximum CMR suppression. Barbiturates are known to reduce CMR in a dose-dependent manner that occurs in parallel with suppression of the EEG.^5,7 It has been assumed that complete suppression of the EEG is required to achieve maximal cerebral protection from barbiturates. Few studies have attempted to examine the dose-response relationship between barbiturates and neurologic outcome following focal cerebral ischemia.^7,13–15 In the most detailed of these studies, Warner et al.⁷ assessed the effect of an active EEG dose and a burst-suppression EEG dose of pentobarbitone on infarct volume after temporary MCAo in rats. They confirmed that the degree of CMR suppression was significantly different at the two doses but, nonetheless, observed no difference in infarct volume. The results for the two pentobarbitone groups in the present study are similar to those of Warner et al. in that the protective efficacy was apparently not different for the burst-suppression and 40% burst-suppression doses.

The present data suggest that for some, if not all, barbiturates, mechanisms other than CMR suppression contribute to protective efficacy. The properties critical to the protective effect are yet to be identified and barbiturates have numerous effects that might be relevant. Mechanisms of note include effects on free radical scavenging, vascular tone, cellular ionic gradients, and excitotoxicity.^16–21 In most instances, there are insufficient data to conclude that these properties are shared equally by all of the available barbiturates. In addition, if these mechanisms contribute to barbiturate-mediated cerebral protection, there is no confirmation that their activity parallels the reductions in CMR caused by barbiturates.

The second assumption mentioned previously is the apparent acceptance of the protective equivalence of the various clinically available barbiturates. The present data are inconsistent with that assumption. Thiopentone and methohexital in specific doses (i.e., the former at a full burst-suppression dose and the latter at 40% of the burst-suppression dose) appeared more effective than pentobarbitone. These observations should not necessarily be unexpected because as noted above, if non-CMR mechanisms are involved, there is no basis for assuming that all barbiturates share the critical properties or that the dose-response relationship for the critical properties is such that maximal effect is achieved at complete CMR suppression. Some of the properties of barbiturates that might contribute to a protective effect are listed below.

Free radicals
There are data that suggest a differential ability of barbiturates to scavenge free radicals.^19,22,23 In a human neuronal cell preparation, Almaas, et al.,¹⁹ observed that pentobarbitone, phenobarbital, methohexital, and thiopentone dose-dependently inhibited formation of hydroxyl radicals and lipid peroxidation by-products. Thiopentone was more effective than the other barbiturates in inhibiting formation of hydroxyl radicals at equimolar concentrations; while thiopentone and methohexital were more effective than pentobarbitone and phenobarbital in inhibiting lipid peroxidation. Moreover, phenobarbital and pentobarbitone effected an increase in markers of cell damage, while thiopentone and methohexital decreased cell injury.

Nitric oxide neurotoxicity
Although controversial, there is evidence that nitric oxide contributes to ischemic brain injury.^24,25 Nitric oxide is synthesized by endothelial cells, glia and several types of neurons. Synthesis of nitric oxide from vascular endothelium is accomplished by an isoform of nitric oxide synthase that is expressed constitutively.²⁵ Two other isoforms of nitric oxide synthase have also been described (neuronal and inducible) which may contribute to ischemic neuronal injury.^25–27 During cerebral ischemia, neuronal nitric oxide synthase is activated²⁵ which can result in cytotoxicity by mechanisms which include free radical damage, inactivation of enzymes involved in mitochondrial respiration, and energy depletion subsequent to activation of poly-ADP ribose synthase.²⁸ In a neuronal cell culture model of nitric oxide induced cytotoxicity, Shibuta et al.²⁹ assessed the effect of thiopentone and pentobarbitone on cell death. They observed that cell death was reduced by thiopentone but not pentobarbitone. They hypothesized that it was the sulphhydryl group on thiopentone, with its augmented free radical scavenging properties, which effected this result.

Vasoactive properties
Although limited, there are data which demonstrate that specific barbiturates have unique contractile responses in cerebral vessels.^30,31 Hatano et al.,³⁰ assessed the effect of thiamylal, thiopentone, secobarbital, and pentobarbitone on helical strips of canine cerebral arteries. They observed greater vessel contraction for thiamylal than thiopentone, and a relaxation response for secobarbital and pentobarbitone. The extent to which this data applies to the present in vivo study is speculative. However, they raise the possibility that a barbiturate will have differential effects on vasomotor tone and therefore blood flow distribution during ischemia.

Calcium entry
It has long been known that barbiturates effect voltage-gated neuronal calcium channels^32,33 and this may have implications in the evolution of excitotoxic brain injury. Although the evidence is limited, Zhan et al.³⁴ observed, in a rat hippocampal slice model, a differential ability of barbiturates to block voltage-gated neuronal calcium channels, with the potency—thiamylal > thiopentone >>> phenobarbital. Conversely, Miao et al.,²⁰ in a rat culture neuron preparation, observed a greater potency of methohexital than thiopentone in the inhibition of both the intracellular calcium peak and glutamate release in response to depolarization.

Glutamate
Barbiturates are considered to be antagonists of excitotoxic neuronal injury.³⁵ A potential mechanism is blockade of glutamate receptors, including the kainate, N-methyl-D-aspartate (NMDA), and -amino-3-hydroxy-5-methyl- 4-isoxazole propionic acid (AMPA) sub-types.³⁶ Relevant to the present results is the data of Cai et al.,³⁷ who observed a differential ability, in a neuronal culture, of barbiturates to block these receptors. Thiamylal was the most effective followed by secobarbital, while pentobarbitone and phenobarbital were without effect. In addition, in an in vitro preparation of rat spinal cord, Zeman and Lodge³⁸ observed a differential effect of barbiturates at the kainate receptor with methohexital being the most potent, followed by secobarbital, thiopentone, pentobarbitone, and phenobarbital.

Conversely, there may be properties of certain barbiturates that act to counter the overall benefit that has been observed during neurotoxic injury. Following an episode of cerebral ischemia, glutamate uptake by astrocytes is a critical function that acts to maintain neuronal survival. There is evidence that glutamate uptake by astrocytes may be inhibited in a dose-dependent manner by barbiturates.^39–42 Swanson et al.,³⁹ in rat astrocyte cell cultures, assessed the effect of barbiturates on the inhibition of glutamate uptake. They observed that thiopentone and thiamylal were the most potent in inhibiting glutamate uptake, while secobarbital, amobarbital, and pentobarbitone had negligible effects.

The preceding discussion of the differences among barbiturates does not provide a definitive explanation of the findings of the present study. While the apparent dose-related ability of thiopentone to reduce ischemic injury is intuitively reasonable, the inverse dose-response relationship of methohexital to ischemic injury is difficult to explain. The latter requires either the assumption of an inverted U-shaped dose-response for some beneficial effect or the assumption of an adverse effect that becomes apparent at higher doses. There are no data to support or refute these possibilities. The unresolved issues notwithstanding, the results of the present investigation are consistent with our initial premise that non CMR related mechanisms may contribute to barbiturate-induced cerebral protection in a manner that is not necessarily equivalent among the barbiturates.

Limitations of this study include some uncertainty as to the specificity of TTC stain to identify brain infarction. During normal aerobic metabolism, TTC is converted by mitochondrial oxidative enzymes to a formazan product which effects a red staining of brain tissue. With prolonged ischemia these enzymes are rendered dysfunctional, and because of the resulting failure of TTC conversion to its red derivative, a pale area of brain is identifiable. Thus, TTC stain defines areas of enzymatic dysfunction, not necessarily neuronal necrosis. However, our methodology is validated by data that have shown reasonable correlation between TTC stain and conventional histologic markers of infarct.^43,44 Another limitation is the delineation of cerebral infarction at an early time period following MCAo. Recent data suggests that ischemic brain injury is a dynamic process that requires at least 14 days to evolve fully.^45,46 Accordingly, the present findings should ideally be validated in a long term model of infarct assessment to confirm the outcome differences between barbiturates that we observed.

In summary, we evaluated the effect of three different barbiturates on early brain injury following temporary MCAo in rats. Two different doses of each barbiturate were administered: a dose which achieved a burst-suppression pattern on the EEG, and 40% of that dose. For the burst-suppression groups, thiopentone was the only barbiturate that significantly reduced the volume of injury as compared to a halothane anesthetized control group. For the 40% barbiturate dose groups, only methohexital reduced infarct volume. These data provoke further examination of both the commonly held tenet that a burst-suppression pattern on the EEG is necessary to achieve maximal barbiturate-induced cerebral protection, as well as tacit assumptions about the protective equivalence of different barbiturates.

	Acknowledgments

 
The authors gratefully acknowledge the technical assistance of Suzzanne Marcantonio.

	Footnotes

 
Support for this study was provided by the Department of Anesthesiology, Loma Linda University-School of Medicine.

Revision received May 2, 2001. Accepted for publication March 2, 2001.

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TOP Abstract Introduction Methods Part A Part B Results Discussion References

 
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