Cerebral resuscitation: Advances and controversies

CPR BLOOD FLOW Niemann

proved regional blood flow and resuscitation in dogs. Ann Emerg Med 1984;13:79-86.

9. Niemann JT, Rosborough JP, Ung S, et ah Coronary perfusion pressure during experimental cardiopulmonary resuscitation. Ann Emerg Med 1982;11:127-131.

10. Niemann J, Rosborough J, Criley JM: Coronary perfusion pressure during cardiopulmonary resuscitation: A determinant of successful defibrillation, abstract. Clin Res 1983;3h208A.

11. Guerci AD, Chandra N, Tsitlik J, et ah Intracranial pressure during CPR: Demonstration of transmission of intrathoracic pressure along non-valved venous channels, abstract. Clin Res 1984;32:172A. 12. Klocke FJ, Ellis AK: Control of coronary blood flow. Annual Review of Medicine 1980;31:489-508.

13. Sundt TM, Sharbrough FW, Piepgras DG, et ah Correlation of cerebral blood flow and electroencephalographic changes during carotid endarterectomy: With results of surgery and hemodynamics of cerebral isehemia. Mayo Clin Proc 1981;56:533-543.

14. McKeever WP~ Gregg DE, Canney PC: Oxygen uptake of the nonworking left ventricle. Circ Res 1958;6:612-623. 15. Monroe RG, French G: Ventricular pressure-volume rela- tionships and oxygen consumption in fibrillation and arrest. Circ Res 1960;8:260-266.

16. Hashimoto K, Shigei T, Imai S, et ah Oxygen consumption and coronary vascular tone in the isolated fibrillating dog heart. Am J Physiol 1960;198:965-970. 17. Kohn RM: Myocardial oxygen uptake during ventricular fibrillation and electromechanical dissociation. Am I Cardiol

1963;11:483-486.

18. Gibbs CL, Papdoyannis DE, Drake AJ, et ah Oxygen consumption of the nonworking and potassium chloride-arrest dog heart. Circ Res 1980;47:408-417.

19. Downey JM, Chagrasulis RW, Hemphill V: Quantitative study of intramyocardial compression in the fibrillating heart. Am J Physiol 1979;237:H191-H196. 20. Voorhees WD, Babbs CF, Tacker WA: Regional blood flow during cardiopuhnonary resuscitation in dogs. Crit Care Med 1980; 8:134-136.

21. Bellamy RF: Blood flow during experimental cardiac massage, abstract. Circulatory Shock 1981;8:191.

22. Bellamy RF, DeGuzman LR, Pedersen DC: Coronary blood flow during cardiopulmonary resuscitation in swine. Circulation 1984;69:174-180.

23. Maier GW, Olsen CO, Tyson GS, et al: The physiology of external cardiac massage in the intact dog, abstract. Circulation 1981;64{Suppl IV):IV-303.

24. Ralston SH, Babbs CF, Niebauer MJ: Cardiopulmonary resuscitation with interposed abdominal compression in dogs. Anesth Analg 1982;61:645-651.

25. Michael JR, Guerci AD, Koehler RC, et ah Mechanisms by which epinephrine augments cerebral and myocardial perfusion during cardiopulmonary resuscitation in dogs. Circulation 1984; 69:822-835.

26. Thompson RG, Hallstrom AP, Cobb LA: Bystander-initiated cardiopulmonary resuscitation in the management of ventricular fibrillation. Ann Intern Med 1979;90:737-740.

Cerebral Resuscitation: Advances and Controversies Leslie A Newberg, MD / Rochester, Minnesota

Brain protection is the prevention or amelioration of neuronal damage occurring after a hypoxic or ischemic event. Controversies in this field focus on whether incomplete global ischemia may produce a worse insult than does complete global ischemia; whether barbiturates provide protection fol lowing complete global ischemia; and whether the calcium entry blockers have a role in brain protection. Current knowledge dictates that incomplete ischemia coupled with hyperglycemia will cause a severe cerebral lactic acidosis and produce a worse insult than does complete ischemia. In the absence of hyperglycemia complete cerebral ischemia produces more neuronal damage. The barbiturates have been shown to provide protection in focal ischemia and incomplete global ischemia in which neuronal function is still present, but have not been shown to provide protection following complete global ischemia.

From the Department of Anesthesiology, Mayo Clinic and Mayo Foundation, Rochester, Minnesota. Address for reprints: Leslie A Newberg, MD, Department of Anesthesiology, Mayo Clinic, Rochester, Minnesota 55905.

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Those calcium entry blockers with cerebral vascular selec- tivity may well provide some brain protection following complete cerebral ischemia by ameliorating the postischemic hypoperfusion state. [Newberg LA: Cerebral resuscitation: Advances and controversies. Ann Emerg Med September 1984 (Part 2);13:853-856. Key words: barbiturates; calcium blockers; cerebral resuscitation.]

Introduction Brain protection may be defined as prevention or ame-

lioration of neuronal damage, as evidenced by abnormalities in cerebral metabolism or neurologic function, occurring after a hypoxic or i schemic event. Because the patho- physiology in each of these forms of reduced oxygen deliv- ely is different, therapeutic interventions that provide protection in one form should not be assumed to be effective in other forms.

Trickle Flow versus No Flow Theoretically complete interruption of oxygen (and sub-

stratel supply should represent the max imum insult. In

Annals of Emergency Medicine 13:9 September 1984 (Part 2)

1973, however, Hossman et all observed that there was less functional recovery [spontaneous return of electroencephalographic [EEG] activity) following incomplete ischemia {trickle flow) than following complete ischemia for 60 minutes.

This paradox was studied by Nordstrom et al in 1978. 2 Following complete ischemia, there was extensive recovery of the cerebral energy state {normal phosph0creatine [PCr], ATP, and energy charge and only mildly elevated lactate concentration), whereas following incomplete ischemia, the cerebral metabolites were markedly abnormal. The explana- tion for this seemingly improved outcome with no flow lies in the fact that the animals were fed. When ischemia is sufficiently severe to disrupt the cerebral energy state (as in both the complete and incomplete ischemia groups) and the ischemia is sufficiently prolonged to allow appreciable amounts of glucose {which is continually delivered with incomplete ischemia, although at a lesser rate) to be translo- cated from blood to tissue, the continued metabolic activity gives rise to excessive acidosis. This results In detrimental alterations in metabolism.

This theory has been substantiated by Rehncrona3 in a study demonstrating an inverse correlation between the de- gree of lactic acidosis (associated with hyperglycemia) during ischemia and the extent of metabolic recovery. Animals made hyperglycemic prior to complete ischemia had abnormal metabolic recovery. Fasted animals subjected to incomplete ischemia had excellent recovers, but fed animals demonstrated extensive deterioration of the cerebral energy state.

Kalimo 4 demonstrated that fasted animals subiected to incomplete ischemia had better recovery than did those exposed to complete ischemia. Marshall demonstrated earlier return of EEG activity and better return of neurologic function in animals subjected to incomplete ischemia over animals with no cerebral blood flow {CBF).5 A study by Steen et al6 of cerebral metabolites and return of neurologic be- havioral function also demonstrated that fasted dogs subjected to incomplete ischemia had a faster return of EEG activity and returned with normal neurologic function after longer periods of ischemia than did fasted animals subiected to complete ischemia. Cerebral metabolites, which were also measured, were not a good index of return of neurologic function.

Thus complete ischemia produces a more severe insult to neurologic function than does incomplete ischemia, except in the presence of hyperglycemia.

Barbiturate Protection The barbiturates were first shown to prolong survival

time in hypoxic or asphyxiated animals--quite a crude measure of brain protection for incomplete global ischemia. In 1962 Arrffred and Secher z demonstrated that mice anes- thetized with thiopental survived longer than did control mice when exposed to gas mixtures containing 0% to 5% oxygen. It was assumed that the prolonged survival by the thiopental group was due to Increased tolerance of hypoxia because of reduced cerebral oxygen consumption due to the barbiturate anesthesia. In addition the nonanesthetized mice exposed tO hypoxia developed seizures with a conse- quent excessive rise in metabolic rate before death. That thiopental prevents the seizures and at tendant hyper- metabolism with increased oxygen demand provides an- other mechanism for protection. This "protective" action of the barbiturates seems to be related to its anesthetic effect.

In a similar study in which mice were exposed to 5% oxygen, Steen and Michenfelder8 showed that mice pretreated with the anesthetically active isomer or the racemic mix- ture of mephobarbital survived two to three times longer than did untreated mice or mice pretreated with the anesthetically inactive isomer.

The major mechanism of action is presumed to be im- provement of the ratio of oxygen supply to oxygen demand. The barbiturates can reduce cerebral oxygen metabolism to 40% of normal because they reduce or suppress neuronal electrical function as measured by EEG. The barbiturates are unable to affect the cerebral metabolism required for cellular function, such as biosynthesis or maintenance of ion gradients. This mechanism explains protection in In- stances of incomplete global ischemia (as in the hypoxic mouse model) in which some basal nutrient supply to cerebral tissues is still maintained.

Nilsson9 found evidence of cerebral protection (maintenance of cerebral metabolites and less lactate accumulation) by barbiturates during hemorrhagic shock in rats {incomplete global ischemia), but no evidence of protection following abrupt onset of asphyxia [complete global ischemia). Michenfelder and Theye lo demonstrated that the rate of depletion of cerebral metabolites and lactate accumulation was slowed in dogs treated with thiopental and subjected to hemorrhagic shock [incomplete ischemia) when compared to untreated animalsj however, no difference was found between the thiopental and the untreated groups when the animals were subjected to complete ischemia.

All these circumstances demonstrate brain protection by barbiturates only in incomplete global ischemia. Oxygen delivery, although inadequate, does continue and therapeutic intervention is aimed at decreasing oxygen needs. To date there are no confirmed studies that the barbiturates provide any protection following complete global ischemia, as occurs following cardiac arrest. In 1966 Goldstein and Keats n subjected dogs to ten-minute periods of arrest of the cerebral circulation by temporary ligation of ascending aorta and venae cavae. Prior administration of pentobarbital prevented severe neurologic damage as judged 48 hours postischemia {grades III and IV) when compared to dogs treated with local anesthetic alone. Steen et all2 in 1979 were unable to reproduce this study. They found no difference in neurologic recovery assessed at 48 hours between barbiturate-treated and untreated dogs following eight to ten minutes of complete global ischemia.

In 1978 BleYaert et a113 reported that massive doses of thiopental given to primates after 16 minutes of complete global ischemia of the brain decreased the incidence and severity of neuropathol0gic abnormalities and improved neurologic fimction. The model of complete cerebral ischemia was complicated, however, and the protocol required meticulous postischemic resuscitation and intensive care. Complete cerebral ischemia was induced by a combination of systemic hypotension produced by trimethaphan and rapid inflation of a neck toumiquet to 1,500 mm Hg. Un- controlled differences in care occurred between the untreated and thiopental groups, which may have influenced outcome. Immediate postischemic blood pressures were different; the majority of control experiments were con- ducted before the treatment group; and subtle differences in the quality of intensive care occurred.

Because of criticisms raised, this study was repeated by Gisvold et alx4 in the same laboratory using pigtail monkeys, running concurrent experiments of control and thio-

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CEREBRAL RESUSCITATION Newberg

pental-treated animals, and met iculous ly controll ing postischemic resuscitation and intensive care. No signifi- cant differences in mortality or neurologic outcome were found between the control and thiopenta ! groups.

The only other well-controlled study of complete global ischemia, a ventricular fibrillation model of cardiac arrest in cats, demonstrated that post-treatment with thiopental prevented seizures and improved survival when compared to untreated animals, but that treatment with thiopental failed to significantly improve neurologic function in the survivors. 15

The only controlle d clinical trial of the use of barbiturates following cardiac arrest has failed to demonstrate any advantage over conventional therapy. 16 Thus the barbiturates do not provide any protection following complete global ischemia. They may provide protection in instances of focal or incomplete ischemia.

Protection from Calcium Entry Blockers Ionic calcium shifts are related tO abnormalities in cel-

lular metabolism, intracellular release of free fatty acids, production of oxidative free radicals, and the no reflow phe- nomenon-al l of which can take place in the brain in the postischemic period and might lead to ultimate neuronal injury. There is increasing evidence that calcium entry blockers might modify these processes3Z, lS

With restoration of blood flow following complete global ischemia, there is a transient 10- to 20-minute period of hy- perperfusion associated with vasomotor paralysis with possible breakdown of the blood brain barrier and edema for- mation, followed by a prolonged period of hypoperfusion (the length of which seems to depend on the duration of ischemia, but it can last from 6 to 18 hours). Several calcium entry blockers are potent cerebral vasodilators I and they are currently being investigated for their role in brain protection because they may ameliorate this postischemic hypoperfusion.

Nimodipine, a dihydropyridine derivative, selectively de- creases the tone of cerebral vessels, resulting in an increase in cerebral blood flow. When given by mouth to cats 15 minutes prior to seven minutes of complete cerebral ischemia produced by neck tourniquet inflation, nimodipine 1 mg/kg ameliorated the postischemic hypoperfusion39

Steen et a117 subsequently studied the effects of nimodipine on CBF, cerebral metabolism, and neuro!ogic recovery in a canine model of complete cerebral ischemia produced by temporary ligation of the ascending aorta and venae cavae. Immediately before the ischemic event, the dogs received nimodipine 10 ~g/kg intravenously. Following ischemia, the dogs received a constant infusion of nimodipine I ~g/kg/min for two hours. Nimodipine nearly dou- bled the cerebral blood flow in the delayed postischemic hypoperfusion period, when compared with untreated dogs. In an additional set of experiments, dogs were pretreated with nimodipine, underwent ten minutes of ischemia, and then were allowed to recover. The extent of neurologic damage was judged at 48 hours. Dogs treated with nimodipine before the ischemic event had significantly better neurologic recovery. Four of five were normal and one exhibited ataxia. In comparison five of the seven untreated animals had severe neurologic damage and one died. 17

The observation that nimodipine improved neurologic outcome suggests that it may be a useful therapeutic agent in situations of complete cerebral ischemia. It also provides evidence that the delayed postischemic hypoperfusion state

contributes to ultimate neurologic damage, and that any increase made in CBF during this time might improve outcome.

To be clinically useful, however, such treatment must be shown to be effective when given only after the ischemic event. Thus the studies described were repeated, with the exception that the dogs were treated with nimodipine only after the ischemic event J8 When nimodipine was given only after ischemia, the postischemic hypoperfusion was ameliorated (again twice that in untreated animals), but neurologic recovery was intermediate and not significantly different from either the control group or the nimodipine- pretreated group.

Because the results of the neurologic functional recovery study were equivocal, the importance of the delayed hypoperfusion state in contributing to ult imate neurologic damage and the possible clinical benefit of therapy with nim0dipine following complete cerebral ischemia was con- sidered unresolved. We, therefore, investigated neurologic recovery following ischemia and nimodipine therapy in the primate model, which was used extensively to study barbiturate therapy. 13,14

Twenty-seven pigtailed monkeys were studied, but six were excluded for failure to meet protocol criteria. They underwent 17 minutes of complete cerebral ischemia produced by a combination of systemic hypotension from trimethaphan and neck tourniquet inflation. Five minutes postischemia 11 monkeys received nimodipine (10 ~g/kg) foUowed by an infusion of 1 ~g/kg/min for ten hours. Ten monkeys received an equal vo lume of placebo. The monkeys were cared for in an intensive care setting for 24 hours or longer as needed. Detailed neurologic evaluations were done by a blinded observer periodically over 96 hours. The monkeys treated wi th nimodipine had significantly better neurologic function at 96 hours than did the untreated monkeys. Four monkeys receiving nimodipine appeared absolutely normal, and one was only mildly apraxic. None of the placebo-treated monkeys was normal; all were pri- marily obtunded and responsive only to noxious stimuli.

Conclusion From these results we conclude that nimodipine, when

given after complete cerebral ischemia, can improve neurologic recovery. These promising results demonstrating some brain protection with nimodipine must be accepted with caution until confirmatory studies are done.

References L Hossman KA, Kleihues P: Reversibility of ischemic brain damage. Arch Neurol 1973;29:375-384.

2. Nordstrom CH, Rehncrona S, Siesjo BK: Effects of phenobar- bital in cerebral ischemia. Part II. Restitution of cerebral energy state as well as glyc0tic metabo!ites, citric acid cycle intermedi- ates, and associated amino acids after pronounced incomplete ischemia. Stroke 1978;9:335-343. 3. Rehncrona S, Rosen I, Siesjo BK: Excessive cellular acidosis: An important mechanism of neuronal damage in the brain Acta Physiol Scand 1980;110:435-437. 4. Kalimo H, Rehncrona S, Soderfelt B: The role of lactic acidosis in the ischemic nerve cell injury. Acta Neuropathol 1981;(Suppl VII):20-22. 5. Marshall LF, Durity F, Lounsbury R, et al: Experimental cerebral oligemia and isChemia produced by intracranial hyperten- sion. Part 1. J Neurosurg 1975;43:308-317.

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6. Steen PA, Michenfelder JD, Milde JH: Incomplete vs complete cerebral ischemia: Improved outcome with a minimal blood flow. Ann Neurol 1979;6:389-398.

7. Arnfred I, Secher O: Anoxia and barbiturates: Tolerance to anoxia in mice influenced by barbiturates. Arch Int Pharmaco- dyn Ther 1962;139:67-74.

8. Steen PA, Michenfelder JD: Cerebral protection with barbiturates: Relation to anesthetic effect. Stroke 1978;9:140-142.

9. Nilsson L: The influence of barbiturate anesthesia upon the energy state and upon acid-base parameters of the brain in ar- terial hypotension and in asphyxia. Acta Neurol Seand 1971;47: 233-253.

10. Michenfelder JD, Theye RA: Cerebral protection by thiopental during hypoxia. Anesthesiology 1973;39:510-517.

11. Goldstein A, Wells BA, Keats AS: Increased tolerance to cerebral anoxia by pentobarbital. Arch Int Pharmacodyn Ther 1966; 161:138-143.

12. Steen PA, Milde JH, Michenfelder JD: No barbiturate protection in a dog model of complete cerebral ischemia. Ann Neurol 1979; 5:343 -349.

13. Bleyaert AL, Nemoto EM, Safar P, et al: Thiopental ameliora-

tion of brain damage after global ischemia in monkeys. Anesthe- siology 1978;49:390-398.

14. Gisvold SE, Safar P, Hendrickx HHL, et al: Thiopental treatment after global brain ischemia in pigtailed monkeys. Anesthe- siology 1984;60:88-96.

15. Todd MM, Chadwick HS, Shapiro HM, et al: The neurologic effects of thiopental therapy following experimental cardiac arrest in cats. Anesthesiology 1982;57:76-86.

16. Abramson NS, Safar P, Detre K, et al: Results of a randomized clinical trial of brain resuscitation with thiopental, abstract. Anesthesiology 1983;59:A101.

17. Steen PA, Newberg LA, Milde JH, et al: Nimodipine improves cerebral blood flow and neurologic recovery after complete cerebral ischemia in the dog. J Cereb Blood Flow Metabol 1983; 3:38-43.

18. Steen PA, Newberg LA, Milde JH, et al: Cerebral blood flow and neurologic outcome when nimodipine is given after complete cerebral ischemia in the dog. J Cereb Blood Flow Metabol 1984;4:82-88.

19. Kazda S, Garthoff B, Krause HP, et al: Cerebrovascular effects of the calcium antagonistic dihydropyridine derivative nimodipine in animal experiments. Arzheim Forsch 1982;32:331-338.

Recent Advances in Cardiopulmonary.Cerebral Resuscitation: A Review Peter Safar, MD / Pittsburgh, Pennsylvania

Standard external CPR (SECPR) steps A, B, and C can maintain the brain's viability if started immediately, but not after prolonged arrest times. "New CPR" (simultaneous ventilation-compression CPR, SVC-CPR) is not suitable for basic life support, and may not be physiologically superior to optimally performed SECPR. The superiority of interposed abdominal compression CPR (IAC-CPR) over SECPR for basic life support is also uncertain. Open-chest CPR is physiologically superior to all external CPR methods studied thus far. Open-chest CPR should again be taught to physicians, and used more often after prolonged cardiac arrest. In intractable cases of cardiac arrest, particularly after prolonged arrest times or cold water drowning, cardiopulmonary bypass appears promising. After restoration of normal perfusion pressures and blood gases, a brain-oriented intensive care protocol for the support of extracerebraI organs leads to better outcome than "usual care." Reflow promoting measures, particularly intracarotid hypertensive

From the Resuscitation Research Center and Department of Anes- thesiology/Critical Care Medicine, University of Pittsburgh School of Medicine, and Presbyterian-University Hospital, Pittsburgh, Pennsyl- vania. Address for reprints: Peter Safar, MD, Resuscitation Research Center, 3434 Fifth Avenue, Pittsburgh, Pennsylvania 15260. This pa- per is excerpted from a similar presentation given at the 4th Belgian Congress of Anesthesiology, September 1983, in Brussels, and one to be presented at the 12th General Meeting of the Japanese Asso- ciation for Acute Medicine, November 22-24, 1984, in Hiroshima.

13:9 September 1984 (Part 2)

hemodilution, ameliorate postarrest brain damage and should be developed for clinical use. Barbiturates have been shown to exert no breakthrough effect on outcome after cardiac arrest, but are safe in the hands of those skilled in advanced intensive care. Barbiturates may be of adjunctive value after prolonged cardiac arrest, particularly when used to suppress seizures, facilitate controlled ventilation, and reduce intracranial pressure. Calcium entry blockers have been shown in animal models to improve hemodynamics and cerebral outcome postarrest, but not consistently. Needed are systematic studies of the multiple organ systems failure of the postresuscitation syndrome, as well as development and testing of etiology-specific multi- faceted therapies. Treatments effective after cardiac arrest also might benefit patients with other acute insults. [Safar P: Recent advances in cardiopulmonary-cerebral resuscitation: A review. Ann Emerg Med September 1984 (Part 2);13:856-862. Key words: cardiopulmonary resuscitation; cerebral resuscitation.]

Introduction In the 1960s, all the necessary steps for cardiopulmonary

resuscitation (CPR) became available through decisive research on backward tilt of the head and forward displace- men t of the mandible for airway control (Step A); 1 exhaled air artificial ven t i l a t ion (Step B);2, 3 closed-chest cardiac massage (Step C); 4 epinephrine,5 electrocardiography, and

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Cerebral resuscitation: Advances and controversies