The Brain in Shock

The Brain In Shock* secondary Disturbances of cerebral Function A BaethmtJnn, M.D.; and Q Kempski, M.D.

• n important determinant of the clinical outcome of lowflow conditions, such as protracted arterial hypotension and cardiovascular shock, is irreversible damage to the brain. Yet under experimental conditions considerable periods of arrest of the cerebral circulation can be followed by an impressive functional recovery,I.1 whereas in man, interruption of blood flow to the brain or cerebral hypoperfusion of relatively short duration more often than not is associated with a poor outcome. 3 The development of brain damage under these conditions must be attributed to a variety of mechanisms, many of them of a secondary nature.4-6 The following discussion explores various aspects ofthis problem, such as cerebral blood 80w (CBF) and flow distribution in general circulatory failure, ischemic flow thresholds associated with functional and structural alterations in the brain, plstiscbemic brain edema, and, particularly important, the phenomenon of selective vulnerability of the brain.

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CEREBRAL BLOOD FLOW IN SYSTEMIC

HYPOTENSION AND SHOCK

The brain has an effective autoregulation system providing maintenance of blood flow within narrow limits despite variable perfusion pressures. This phenomenon, however, is operative only in nondamaged brain tissue. 7 In damaged brain, blood flow is at the mercy of the cerebral perfusion pressure. Then, high blood pressure may result in hyperperfusion of the brain with its adverse sequelae, such as extravasation of edema,8,9 while low blood pressure results in cerebral ischemia. 10 Figure 1 shows the effect on CBF of gradually decreasing the circulating blood· volume in dogs by bleeding. Initially this measure led to a steady decline in cardiac output and consequently in the systemic blood pressure, whereas blood Bow to the brain remained largely stable up to a withdrawal of blood of 30 mllkg body weight. At this level of hypovolemia, cardiac output and systemic blood pressure bad fallen to 60% of normal. Further reduction of the blood volume, decreasing cardiac output below 50% or arterial blood pressure to 50 mm Hg or belo~ was associated with the beginning of hypoperfusion of the brain. Mean CBF then fell to approximately 50% of normal. II The regional distribution of the remaining CBF was studied in multiple tissue samples with the use of radioactively labeled microspheres 15 IJ.m in diameter. With impairment of CBF, the flow distribution became rather heterogeneous between different areas, such as the cerebral cortex, white matter, and basal ganglia, and brain-stem regions, such as the medulla oblongata and pons. The hemispheric brain tissue areas were more or less uniformly *From the Institute for Surgical Research, Ludwig-MaximiliansUniversity, Klinikum GroBbadem, Munich, Germany. Reprint ~uut.: Prof. Dr. Baethmann, Institute for SurgU;al Research, KlifUkum Grosahadem, D-8OOO Munich 70, Germany.

hypoperfused, whereas the central ar~ such as the pons, medulla oblongata, and cervical spinal cord, appeared able to sustain blood 80w at an almost normal level. 11 It was concluded, therefore, that under boundary conditions of the general circulation, blood flow is preferentially protected in brain areas that control the cardiovascular system. FLOW THRESHOLDS IN CEREBRAL ISCHEMIA

Our understanding of cerebral hypoperfusion has been improved by experimental findings on blood flow threshold levels associated with onset of dysfunction or failures of the central nervous system (CNS). Impressive data on the subject have been contributed by the laboratories ofSymon l2 and Morawetz et al. 13 Regional CBF and function were studied in a model of chronic focal cerebral ischemia in

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AMOUNT OF HEMORRHAGE (mllkg) FIGURE 1. Response of mean arterial blood pressure (A) and mean cerebral blood Bow (radioactively labeled 15 J1.m microspberes) and cardiac output (B) in dogs subjected to a gradually increasing degree ofhemorrhagic hypovolemia. Cerebral blood Row started to decline once cardiac output fell below 50% of normal or arterial blood pressure feU to 50 mm Hg. (From Chen, et ale Stroke 1984; 15:34350, Reproduced by permission.) CHEST I 100 I 3 I SEPTEMBER, 1991 I Supplement

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baboons subjected to permanent occlusion of the middle cerebral artery. Reduction of blood How below a threshold of 20 mVlOO g x min, or to approximately 40% of normal, leads to disappearance of the spontaneous electrical activity of the brain on the EEG, while evoked potentials, albeit increasingly abnormal, may still be recorded. A flow threshold at 40% of normal is also associated with the beginning of ischemic brain edema. Even more important, reduction of blood flow to 20% or below correlates with the development of irreversible tissue damage, such as infarction, if maintained over extended periods. 13 In general, extinction of viable brain tissue can be considered as a function of the level of ischemia times its duration, ie, the more severe the curtailment of flovv, the more rapid the development of infarction. Disappearance of spontaneous electrical activity or of evoked responses in cerebral ischemia cannot be attributed to the breakdown of the extracellular/intracellular Na+, K+, or Cal + ion distribution. The extracellular K + concentration increased only after CBF fell to a threshold of 20% of normal, which is definitely below the threshold associated with electrical failure. II On the other hand, the closeness of flow thresholds associated with irreversible tissue damage and development of brain edema may suggest a pathophysiologic relationship between the latter and the former. In other words, formation of brain edema may commence once brain tissue elements, including the cerebrovascular endothelium, have been structurally damaged. Survival and quality of CNS function after a period of cerebral ischemia depend on the quality of postischemic reperfusion ofthe brain. 14 Periods of global cerebral ischemia or of low-flow conditions followed by recirculation are characterized by initial hyperemia of limited duration and a subsequent period of delayed hypoperfusion of the brain. 15 Whereas postischemic hyperemia is likely to be the result of excessive dilatory mechanisms, such as acidosis and accumulation ofvasodilatory compounds (eg, adenosine), the ensuing phase of hypoperfusion is more difficult to explain at the moment. During the latter, CBF may fall to as low as 50% of normal. 11 Obviousl~ the more severe the delayed hypoperfusion, the dimmer the chances for a reasonable recovery. Attempts to bolster the general circulation, for example, by hypervolemic hemodilution with mild systolic hypertension to increase the cerebral perfusion pr~ssure, might be of therapeutic benefit. 17 ISCHEMIC BRAIN EDEMA

Brain edema is an important manifestation of secondary brain damage from cerebral ischemia. 18 It cannot evolve during complete interruption of blood flovv, since an uptake of fluid and electrolytes into the cerebral parenchyma is not possible then: at least a trickle of flow is required. Ie Ischemic brain edema does develop, however, immediately after reinstatement of the cerebral circulation during the early postischemic reperfusion period. Experimental studies have demonstrated a marked increase in brain tissue osmolality during the circulatory arrest period." This process must be considered a powerful mechanism drawing water into the tissue as soon as isotonic blood is reperfusing the hyperosmotic brain parenchyma. It may be recalled in this context that a difference in the osmotic concentration between tissue 208S

and blood of only 1 mOsm is equivalent to a pressure differential of 19.3 mm Hg.II Since brain tissue osmolality from ischemia may increase by no less than 40 to 50 mOsm,1O the resulting osmotic pressure gradient between blood and tissue driving water into the ischemic parenchyma upon postischemic recirculation may transiently increase to as high as I,()()() mm Hg. Yet, if the recirculation is adequate and well maintained, ischemic brain edema and, consequently, intracranial hypertension may resolve within hours, together with the electrolyte and osmotic abnormalities of the tissue. Ie On the other hand, in focal cerebral ischemia leading to the formation of cerebral infarction, brain edema may have a variable, often unpredictable course, either resolving in a period of days (or longer)B or resulting in lethal secondary complications, such as malignant brain swelling with tentorial or foramen magnum herniation. i3 SELECOVE VULNERABIUTY OF THE BRAIN:

A

SECONDARY PHENOMENON?

It is a frequent neuropathologic observation that periods of low flow or complete arrest of the cerebral circulation that are survived are followed by disseminated hemorrhagic infarction and destruction of nerve cells in selectively vulnerable areas, such as the hippocampal formation. 3 Hemorrhagic infarction under those conditions preferentially affects brain areas of the boundary zones between the territories supplied by the larger cerebral arteries. 3 ,14 Disseminated ischemic damage, such as neuronal necrosis, may affect, among other structures, the basal ganglia, thalamus, hippocampus, and layers III and V of the cerebral cortex. It is a safe assumption that the outcome of ischemia depends on the development and extent of this process. A phenomenon attracting wide interest in this context is the delayed extinction ofnerve cells in the selectively vulnerable tissue, such as the hippocampal formation. IS Short periods (2 min) of circulatory arrest or low Bow suffice to induce selective destruction of nerve cells in these areas, apparently without injury to other cell elements. IS, . The pyramidal cells of the cornu ammonis, particularly in the CAl sector of the hippocampus, appear to be the most vulnerable neurons. IS These nerve cells are heavily innervated by g1utamatergic excitatory fibers. The g1utamatergic afferences reach the pyramidal cells of the CAl layer from the contralateral hippocampus via the commissural6bers, from the entorhinal cortex via the perforant path, or from the dentate gyrus via Schaffer's collateral fibers. J7 Although recently disputed,· it has been assumed that even brief ischemia triggers a state of hyperexcitation of the selectively vulnerable nerve cells, which subsequently becomes autonomous, with the neurons seemingly unable to terminate this abnormal behavior until their own demise. 18 A marked increase in spontaneous firing of CAl neurons in the brain of gerbils exposed to 5 min of global cerebral ischemia was observed by Suzuki et al. 18 Firing increased within 10 h after ischemia to three to four times the rate found prior to interruption of blood Hovv, whereas the nerve cells of the cerebral cortex were only marginally excited. Hyperactive Bring of the pyramidal cells in the cornu ammonis continued through the next day, but the nerve cell activity had completely disappeared by the 2nd day after ischemia, when the neurons of the cerebral cortex were still The Brain in Shock (Baethmann, Ksmpsk/)

alive and active.-

The development of electrical silence of the previously hyperactive neurons 2 d later was not associated at that time postischemia with any stroctural abnormalities in histologic preparations. Nevertheless, it bas been frequently reported that 15 min of global cerebral ischemia suffices for nearly complete destruction of CAl nerve cells after a delay of some days.·.. The delayed destroction of selectively vulnerable nerve cells subjected to brief ischemia is a wellrecognized histologic phenomenon that can be quantified. Thus, counting of dead pyramidal cells in the hippocampus bas become a widely employed method to analyze pathomechanisms of ischemia as well as methods of inhibition at an advanced level of subtlet)r. Although it is not yet known whether the development of hemorrhagic infarction in vascular boundary territories of the brain from transient cerebral ischemia is a secondary phenomenon that could be inhibited by appropriate therapeutic methods, it bas been shown that the delayed destruction of selectively vulnerable nerve cells can be prevented. Prevention or attenuation of delayed neuronal death from global cerebral ischemia can be accomplished b~ among others, Cat+ channel blockers, glutamate receptor antagonists, and glutamate receptoNlependent channel blockers. 30 The powerful methods of molecular biology are increasingly employed for exploring mechanisms of cerebral ischemia. Studies utilizing in situ hybridization for assessment of the formation of mRNA as a measure of gene activation may be mentioned in this context. Valuable information might be obtained thereby on fundamental aspects of gene regulation and activation that either permit ultimate survival or lead to extinction of nerve cells previously rendered ischemic. For example, it bas been reported that the c-j08 protooncogene is activated in the cornu ammonis layer in the hippocampus by periods of cerebral ischemia, apparently in relation with the development ofdelayed neuronal necrosis. 31 Activation ofthe gene occurred after a similar delay ofhours or days after the insult, raising the possibility of a causal Bfsociation between this process and the phenomenon of selective vulnerabili~ Activation of the c-j08 oncogene bas also been reported to occur in epilep~· Thus, we may witness the development of a molecular biologic understanding of acute pathophysiologic states of the brain which may have therapeutic perspectives for the future. REFERENCES

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G, ed. Therapie der Hirndurchblutungsst6nmgen. ~inbeim, Germany: Edition Medizin, 1984:37-84 8 Johansson B, Olsson Y, KIatzo I. The effect of acute arterial hypertension on the BBB to protein tracers. Acta Neuropatbol 1970; 16:117-24 9 Johansson B, Strandgaard S, Lassen NA. On the pathogenesis of hypertensive encepbaIopath~Cire Res 1974; suppll:167-74 10 K1eihues ~ Kiessling M. Patbologie der Hirndurcbblutungsst6nmgen. In: Paal G, ed. Therapie der HirndurchblutuDgssNJnmgen. Weinheim, Germany: Edition Medizin, 1984:3-35 11 Chen RYZ, Fan F-e, Schuessler GB, Simcbon S, Kim S, Chien S. Regional cerebral blood Bow and oxygen consumption of the canine brain during hemorrhagic hypotension. Stroke 1984; 15:343-50 12 Symon L. Progression and irreversibility in brain ischemia. In: Baethmann A, Go ICG, Unterberg A, eds. Mechanisms of secondary brain damage. NATO ASI series A. Life Sci 1986; 115:221-37 13 Morawetz RD, De Girolami U, Ojemann RG, Marcoux ~ CroweD RD. Cerebral blood Sow determined by hydrogen clearance during middle cerebral artery occlusion in unanesthetized monkeys. Stroke 1978; 9:143-49 14 Hossmann KA. Resuscitation potentials after prolonged global cerebral ischemia in cats. Crit Care Med 1988; 16:964-71 15 Hossman KA. The role of recirculation for functional and metabolic recovery after cerebral ischemia. In: 8aetbmann A, Go ICG, Unterberg, eels. Mechanisms of secondary brain damage. NATO ASI series A. Ufe Sci 1986; 115:239-48 16 Hossmann KA. ExperimenteDe Gnmdlagen der Iscbimietoleranz des Hims. Z KardioII987; 76(suppI4):47-66 17 Meyer FB, Sundt TM Jr, Yanagihara T, Anderson RE. Focal cerebral ischemia: pathophysiologic mechanisms and rationale for future avenues of treatment. Mayo Clin Proc 1987; 62:35-55 18 Baethmann A, Kempski O. Ischemic brain edema. Progr Appl Microcirc 1989; 13:38-53 19 Hossmann KA. Development and resolution of ischemic brain swelling. In: Pappius 8M, Feindel ~ eds. Dynamics of brain edema. Berlin: Springe~Verlag, 1976:219-27 20 Hossmann KA, Takagi S. Osmolality of brain in cerebral ischemia. Exp Neuroll976; 51:124-31 21 Guyton A. Textbook of medical physiology. 4th ed. Philadelphia: WB Saunders, 1971 22 Golob 0, Asano T, ICoide 1: 18bkura K. Ischemic brain edema foDowing occlusion of the middle cerebral artery in the rat: I. The time courses of the brain water, sodium and potassium contents and blood-brain barrier penneability to 125-I-albumin. Stroke 1985; 16:101-09 23 Shaw CM, Alvord EC, Berry RC. Swelling of the brain following ischemic infarction with arterial occlusion. Arch Neurol 1959; 1:161-77 24 Brierley JB, Brown A'W, ExceD BJ, Meldrum BS. Brain damage in the rhesus monkey resulting from profOund arterial hypotension: I. Its nature, disbibution and general physiological correlates. Brain Res 1969; 13:68-100. 25 Kirino R. Delayed neuronal death in the gerbil hippocampus following ischemia. Brain Res 1982; 239:57-69 26 Smith ML, Auer RN, Siesjfi BIC. The density and distribution of ischemic brain injury in the rat following 2-10 min offorebrain ischemia. Acta Neuropatboll984; 64:319-32 27 Wieloch 1: Neurochemical correlates to selective neuronal vulnerabili~ Prog Brain Res 1985; 63:69-85 28 Buzslk G, Freund TF, Bayardo F, Somogyi E Ischemia-induced changes in the electrical activity of the hippocampus. Exp Brain Res 1989; 78:268-78 29 Suzuki R, Yamaguchi T, Li CL, IClatzo I. The effects of 5-minute ischemia in mongolian gerbils: II. Changes of spontaneous neuronal activity in cerebral cortex and CAl sector ofhippocamCHEST I 100 I 3 I SEPTEMBER. 1991 I SUpplement

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pus. Acta Neuropatholl983; 60:217-22 30 Baethmann A. Secondary brain damage from severe bead injury and cerebral ischemia: the role of glutamate. Carr Opinion Anaestbesioll989; 2:567-71 31 Jorgensen MB, Deckert J, Wright DC, Gehlert DR. Delayed c-fos p~ncogene expression in the rat hippocampus induced

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by transient global cerebral ischemia: an in situ hybridization stud}'. Brain Res 1989; 484:393-98 32 Dragunow M, Robertson RA. Kindling stimulation induces e-fos protein(s) in granule ceUs of the rat dentate gyrus. Nature 1981; 329:441-42

The IbIn In Shock (Baethmann, KsmpakJ