Resuscitation, 9 (1981) 18+196 o Elsevier/North-Holland Scientific Publishers Ltd.

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BARBITURATE RESUSCITATION FROM FOCAL CEREBRAL ISCHEMIA - A REVIEW

WARREN R. SELMAN, ROBERT F. SPETZLER* and RICHARD A. ROSKI

Division of Neurosurgery, Case Western Reserve University, University Hospitals of Cleveland, 2074 Abington Road, Cleveland, Ohio 44106 (U.S.A.)

SUMMARY

Barbiturate therapy has been shown to be of benefit in certain instances for focal cerebral ischemia. This therapy can, however, result in a deleterious outcome. Early institution in combination with revascularization appears to be important for successful barbiturate application. Whether combina- tions of agents designed to act on different mechanisms in the patho- physiology of cerebral &hernia can prolong the ‘therapeutic window’ of barbiturate application is an area for future investigation.

INTRODUCTION

Barbiturates have attracted interest as agents for resuscitation in brain injury from various insults. These insults include head trauma, cardiac arrest, near-drowning, Reye’s Syndrome and stroke. The pathophysiology of brain injury from each of these mechanisms is quite different. As a result, barbiturate therapy for these pathological conditions has met with various degrees of success. One of the most promising areas of barbiturate applica- tion is in the treatment of focal cerebral ischemia. This review will discuss barbiturate resuscitation for focal cerebral ischemia.

PATHOPHYSIOLOGY

It is essential to understand the pathophysiology of ischemic brain injury to understand the possible benefits of barbiturate therapy (Selman and Spetzler, 1981). With respect to hemodynamics, there are two general models with which to study cerebral ischemia: global ischemia, simulating circulatory arrest in humans, and regional ischemia, modeling clinical cerebrovascular occlusive disease. Focal ischemia differs importantly from global ischemia in that there exists the potential for collateral circulation. The result is that focal ischemia is not in fact a homogenous entity, but can

*To whom all correspondence should be addressed.

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best be described as suggested by Symon as an ‘ischemic penumbra’. His study of the regional cerebral blood flow in baboons after middle cerebral artery occlusion revealed varying densities of ischemia (Symon, Pasztor and Bran&on, 1974).

In this regard the concept of ischemic thresholds for neuronal function and viability bears significance. There exist different tolerances to reduc- tion in cerebral blood flow for various cellular functions. Experimental models of focal ischemia in anesthetized baboons revealed the following thresholds (Branston, Symon and Crockard, 1976; A&up, Symon, Branston and Lasse, 1977). Neurons maintain electrophysiological function, as evidenced by normal evoked potentials, from flows of approximately 50 ml/100 g/mm to 20 ml/100 g/min. Between 20 ml/100 g/min and 12 ml/100 g/min synaptic transmission fails. Below 12 ml/100 g/min evidence of impending cell death and membrane dysfunction is apparent. The precise level of flow necessary for survival may be higher in unanesthe- tized humans (Scharbrough, Messick and Sundt, 1973), but the concept of ischemic thresholds has been confirmed by other investigators (Sundt and Waltz, 1971; Crowell, pers. comm., 1981).

Thus, viable but non-functioning neurons, so called ‘idling neurons’, exist in the area of a clinically evident stroke. The viability of these neurons was demonstrated by Symon who showed that three years after middle cerebral artery occlusion in baboons, the area of infarction was much less than the area of clinically evident dysfunction (Symon, Crockard, Dorsch, Branston and Juhasz, 1975). Of particular interest in this regard is Crowell’s findings that the functional threshold for diminished flow is independent of time, whereas the infarction threshold is time-dependent. (R. Crowell, pers. comm., 1981) The protection of these idling neurons, to prevent permanent damage, by alteration of these thresholds, or improvement in blood flow is thus a primary therapeutic goal in the management of ischemic cerebro- vascular disease.

The exact nature of the ischemic insult is probably the result of many processes. Certain metabolic disorders are characteristic subsequent to an ischemic event. Nordstrom and co-workers studied the effects of both complete and incomplete ,ischemia (Nordstrom, Rhencrona and Siesjii, 1978; Nordstrom and Siesjo, 1978). They noted that changes in the concen- tration of glucose 6-phosphate, fructose 6-phosphate, fructose diphosphate, and dihydroxyacetone phosphate are similar in both. situations. These changes are compatible with a facilitation of the phosphofructokinase reaction. A shift in the redox state, towards increased reduction, is also apparent. The results of incomplete ischemia, which may be similar to the ischemia present in the ‘watershed areas’ after focal ischemia, differed from those of complete &hernia in that a profound and progressive acetate accumulation was noted (Nordstrom et al., 1978). These authors suggested that incomplete ischemia is more deleterious to cellular mechanisms than is complete ischemia (Nordstrom et al., 1978; Nordstrom and Siesjo, 1978).

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In their review of the molecular pathophysiology of stroke, Shaller and his colleagues suggested that incomplete ischemia also would result in a greater pool of peroxidation products (Shaller, Jacques and Shelden, 1980). These products, as will be discussed later, are believed to be primary factors in membrane damage (Tappel, 1973). Steen and Michenfelder, however, emphasized that cerebral metabolic levels are not a good index to predict the return of neurological function, They reported no difference in outcome between complete and incomplete ischemia (Steen, Michenfelder and Milde, 1979).

Microcirculatory obstruction has also been reported after focal ischemia. The concept of ‘no-reflow’ was originally used in the context of global &hernia (Ames, Wright, Kowada, Thurston and Majno, 1968). Crowell and Olsson (1972) extended its application to focal ischemia by noting impaired microvascular filling with restoration of flow after temporary middle cerebral artery occlusion. Possible mediators of this reperfusion failure include precapillary shunting (Fischer, Ames, Hedley-White and O’Gorman, 1977), intravascular sludging and coagulation at low flow rates (Ginsberg and Meyers, 1972), and increased extracellular potassium concen- tration with vascular spasm (Wade, Amtorp and Sorensen, 1975). The role of reperfusion failure in the genesis of infarction is not firmly established. It has not been resolved whether ischemia primarily damages neurons or the microcirculation (Levy, Brierly, Silverman and Plum, 1975; Little, Kerr and Sundt, 1975).

Whether neuronal damage or microcirculatory damage is primarily responsible for infarction, the resulting ischemic edema can contribute to further damage. Ischemic edema has been defined as a combination of both cytotoxic and vasogenic components (Bartko, Reulen, Koch and Schurmann, 1972). Furthermore, ischemic edema has a biphasic quality; initially the cytotoxic element predominates, which is followed by a ‘maturation’ over the ensuing hours to the vasogenic component (Anderson and Cranford, 1979).

The pathogenesis of the cytotoxic component may be related to either free radical or free fatty acid action. With an abrupt loss of oxygen there is an accumulation of flavin adenine dinucleotide and coenzyme Q radicals from the mitochondrial respiratory chain; these highly reactive molecules may initiate widespread alterations of membrane lipids (Butterfield and McGraw, 1978). The liberation of fatty acid peroxidation products can further damage cell membranes with resultant cytotoxic edema. Fatty acid moieties are also involved in the production of free radicals. These compounds and their peroxidation products can also interact with membrane lipids to destroy the normal cytoarchitecture (Shaller et al., 1980; Tappel, 1973). Accumulation of such free fatty acids has been observed after ischemia in the gerbil model (Yoshida, Inoh, Asana, Sane, Kubota, Shimazaki and Veta, 1980).

It is important to stress that local increases in tissue pressure, which may

not be reflected in gross measures of intracranial pressure, may compromise local blood flow leading to a vicious circle of increased tissue damage.

It is of interest in this regard that Bran&on and his colleagues noted that edema formation can occur at flow reductions initially above the threshold for synaptic transmission (Branston, Hope and Symon, 1979). Thus early therapeutic intervention may allow protection of areas not yet clinically affected.

MECHANISM OF BARBITURATE ACTION

The precise mechanism of barbiturate protection is not clearly defined. Reports in the literature have stressed one or more of the following actions: a reduction of cerebral metabolism, an antioxidant effect, and a specific anesthetic effect. While barbiturates have been shown to decrease the cerebral metabolic rate of oxygen consumption (CMR02) (Smith and Wollman, 1972; Smith and Marque, 1976), other anesthetic agents that lower CMROz fail to protect the brain from ischemia (Wilhjelm and Arnfred, 1965; Michenfelder and Milde, 1975).

Astrup and co-workers noted that, in rats, barbiturates prevented the rise in extracellular potassium ions after ischemia (A&up, Nordstrom and Rhencrona, 1977). These researchers suggested that barbiturates had a ‘sealing’ effect on membranes in the cerebral cortex. Recent investigation indicates that this action may be mediated through inhibition of free radical and free fatty acid effect on cell membranes (Tappel, 1973; Demopoulus, Flamm, Seligman, Jorgenseill and Ranshoff, 1977; Flamm, Demopoulus, Seligman and Ranshoff, 1977; Butterfield and McGraw, 1978; Shaller, Jacques and Shelden, 1980).

Flamm et al. (1977) postulate that barbiturates exert a protective effect through inhibition of electron transport between flavin adenine dinucleotide and coenzyme Q, thus controlling the accumulation of free radicals during ischemia.

Steen and Michenfelder (1978) have suggested that a specific anesthetic effect is necessary to explain the protection of barbiturates. These investi- gators studied the effect of racemic mephobarbital and determined that a stereospecific locus is present, which is the same for ischemia protection and anesthesia. Only the enantiomer that gave adequate anesthesia was protective during ischemia. Further studies were done by these investigators to confirm the importance of the anesthetic effect of barbiturates. Mice made tolerant to barbiturates, with the same brain tissue level of drug, were more damaged by hypoxia than were a similar group of animals who were anesthetized by an equal dose of barbiturates (Steen and Michenfelder, 1979). Thus these investigators concluded that it is the specific anesthetic effect of barbiturates, not the presence of the barbiturate molecule alone, that is necessary for protection.

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EXPERIMENTALRESULTS

While the mechanism of action, optimal dose and method of administra- tion have not been clearly delineated, the evidence for barbiturate protection from ischemia is well documented. Hoff and Smith (1977) correlated infarct size and neurological deficit score with and without barbiturate treatment after focal &hernia. Both parameters showed evidence of protection in dogs and primates. Hoff and his co-workers also compared various doses of barbiturates given before middle cerebral artery occlusion in baboons. With permanent middle cerebral artery occlusion 90 mg/kg provided a significant reduction in infarct size, whereas 60 mg/kg was not effective, and 120 mg/ kg, although protective, was associated with severe hypotension (Hoff, Smith, Hankinson and Nielsen, 1975). In this study, single dose barbiturate injection was used, and monitoring and support was continued for 7.5 h. These studies indicated that barbiturate protection may be greatest with the largest dose not complicated by cardiovascular depression.

Subsequent studies demonstrated that barbiturates could still confer protection when administered after the ischemic insult. Moseley and his co-workers demonstrated protection with pentobarbital, 4 mg/kg bolus/h, initiated 30 min after permanent middle cerebral artery embolization when therapy was continued for 12 h (Moseley, Laurent and Molinari, 1978). Michenfelder used a regimen of 14 mg/kg pentobarbital as a loading dose and 7 mg/kg bolus every 2 h for 48 h to achieve a reduction in infarct size and improved neurological scores in Java monkeys treated 0.5 h after permanent middle cerebral artery occlusion (Michenfelder, Mildt and Sundt, 1976). These studies demonstrated barbiturate protection, but varied greatly in their method of barbiturate administration.

We examined prolonged barbiturate anesthesia in baboons. The greatest barbiturate dose with the most stable cardiovascular environment was achieved with continuous barbiturate infusion to maintain an isoelectric EEG (Selman, Spetzler, Anton and Crumrine, 1980).

The ischemic lesions which respond best to barbiturate therapy have not been delineated. Several investigators have demonstrated that reperfusion after 5 h of ischemia results in a worse outcome secondary to aggrevated edema (Dujovny, Osgood, Barrionuevo, Hellstrom and Lahra, 1976;Dujovny, Lahra, Barrionuevo, Solis and Corkill, 1979; Levinthal, Moseley, Brown and Stern, 1979). Since the natural history of permanent and temporary occlusion is markedly different, it is not unreasonable to consider that the response to therapy might similarly be different.

In our series, barbiturate therapy initiated after 30 min with permanent occlusion resulted in a worse outcome compared to no therapy (Selman, Spetzler, Roessmann, Rosenblatt and Crumrine, 1981). Similar treatment in temporary, 6 h, middle cerebral artery occlusion provided nearly complete protection from the otherwise poor outcome of this insult (Selman et al., 1981). Thus reperfusion appears to be critical for barbiturate protection.

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Corkill, Chikovani, McLeish, Donald and Youmans (1976) examined the time constraints on effective barbiturate protection. No benefit was seen when therapy was initiated after 1 h. With our regimen we noted a signifi- cant decrease in barbiturate protection for temporary occlusion when therapy was delayed more than 30 min (Sellman et al., 1981). Thus increased dose and more prolonged therapy alone cannot extend the limits of barbiturate protection with respect to time of initiation.

CLINICAL INVESTIGATION

Only a few reports document the use of barbiturate therapy in humans. Hoff, Pitts, Spetzler and Wilson (1977) and Hoff and Smith (1977) examined barbiturate therapy for intraoperative vessel occlusion. Of interest in this regard is that massive edema and death occurred with per- manent occlusion; no deaths were reported with temporary occlusion. Lawner and Simeone (1979) similarly reported the successful combination of revascularization and barbiturate therapy for intraoperative sacrifice of a major vessel. Rockoff, Marshall and Shapiro (1979) reported four deaths among four patients in whom high dose barbiturate therapy was used with- out revascularization after major vessel occlusion.

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