Basic Principles of Cerebral Protection in Humans William L. Lanier oe ee tice, the greatest evidence for cerebral prot tion occurs in the setting of cerebral ischemia, Because the mechanisms responsible for ischemic injury may be shared, in part, with other types of cerebral insults, ischemia serves as a model for discussing the general principles of cerebral protec- tion, Limiting the Duration and Extent of Cerebral Oxygen Deprivation Corebral ischemic injury begins when the brain is deprived of oxygen-rich blood. Thus, it is not surprising that in many types of brain injury, the extent of injury is directly proportional to the duration and extent of interrupted oxygen deli ery! Outcome can be improved simply by reducing the period of insult.! Improving the delivery of oxygen-rich blood t0 the brain is accomplished by first addressing car- diae performance, blood pressure, and blood oxy- genation. In general, such therapy is best directed by following the guidelines for advanced cardiac life support, as outlined by the American Heart Association. It should be remembered that the driving force for the delivery of blood flow to the brain, cerebral perfusion pressure (CPP), is dependent on both ‘mean arterial blood pressure (MAP) and intracra- nial pressure (ICP).* Isolated increases in ICP uncompensated by increases in MAP will reduce CPP and increase the risk for ischemic brain injury. Conversely, a rapid reduction in MAP not accompa- nied by a reduction in ICP will also reduce CPP. In the worst of all circumstances, vasodilating drugs, such as nitroglycerin and nitroprusside, adminis- tered (0 a patient with intracranial hypertension will reduce MAP as they increase ICP? This com- pound effect on CPP will greatly increase the likelihood of ischemic injury. Control of Seizures Seizures are commonly associated with brain i sults and injury. If left untreated, prolonged sei- Zures (i.e, status epilepticus) ean metabolically Liver Transplantation ard Surgery Vol 5, No 4 (July), 1999: pp 347-350 etch brain pathways and produce irreversible brain injury! Drug therapies that control seizures will attenuate or prevent seizure-induced brain injury; however, these same drug therapies may have little or no effect on outcome resulting from coexisting seizure-independent cerebral insults, Control of Blood Glucose Concentrations Increases in blood and brain glucose levels wil worsen outcome after cerebral ischemia and per- haps after other insults (e.g, trauma). The mecha- m underlying this effect is as follows: during periods of cellular hypoxia or anoxia, the anaerobic metabolism of brain glucose contributes to an intracellular lactic acidosis that is injurious to neurons and glia? Hyperglycemia will exacerbate ischemic brain injury regardless of the source of the hyperglyce- ‘mia.’ In previously hyperglycemic subjects, insulin therapy will reduce both blood and brain glucose concentrations and improve postischemic out- Patients at risk for ongoing or new-onset is- chemic injury are best maintained at normoglyce- mia or near normoglycemia as long as the period of risk persists.» However, hypoglycemia should be avoided because severe hypoglycemia can cause cerebral dysfunction and irreversible brain injury regardless of whether there is ongoing cerebral ischemia.s Use of Corticosteroid Drugs Traditional corticosteroid drugs are generally not indicated for cerebral protection. Instead, there is a growing body of experimental evidence that sug- ‘From the Deparment of Anesthesiology, Mayo Chink, Roches- fer Ades eprint rquests to Wallon L ante, MD, Department of Anesth, Myo Clans, 200 Firat SYS, Rochester, AE ss005 CCopright © 1999 bythe dmercan association forthe Sy of Liver Disses 1074-3022/99 0501001783 00 347348, ll L. Lair gests corticosteroids may actually enhance brain injury, largely as a result of their effect on blood glucose concentrations.°9 Fortunately, the majority of the corticosteroids toxic effect on the ischemic brain can be relieved simply by using insulin to control blood glucose concentrations.°* Ifcorticosteroids are legitimately indicated (e.g, to treat liver failure or peritumoral brain edema) in the treatment of critically ill patients with coexist- ing primary brain injury (e.g., cerebral ischemia), then blood glucose concentrations should be closely monitored, and any episodes of hyperglycemia should be promptly treated Temperature Manipulation It has long been recognized that alterations in temperature can modulate brain injury; however, only recently has the power of this effect been fully understood. Numerous studies have now shown that temperature reductions of a mere 2°C to 6°C will improve postischemic neurological outcome, ‘and temperature increases of a mere 1°C ot 2°C will worsen outcome.” The physiological basis of this phenomenon is multifactorial; it clearly involves factors other than a reduction in basal metabolic rate for oxygen consumption and high-energy phosphate depletion.” Based on presently available data, it is possible to conclude that in patients at high risk for brain injury, fever and hyperthermia should be avoided, Mild induced hypothermia may be of benefit However, at temperatures less than 35°C, the systemic side effects of hypothermia (in patients with endogenous circulation) may override any direct beneficial effects of hypothermia on the brain.” Anesthetics, Barbiturates have by far the most experimental support for cerebral protection, and they are the only class of anesthetics identified as cerebroprotec- tive in humans Recent research has determined that the protection is not solely because of a reduetion in basal metabolic rate, as has long been theorized.* The property of cerebral protection by barbitu- rates is not consistently shared with other anesthet- ies. For example, etomidate, which has a metabolic profile similar 10 barbiturates, exacerbates ische- ‘mic neurological injury in animal models (presum- ably as a result of interference with nitric oxide ‘metabolism).* Propofol, which has much utility in the treatment of critically ill patients (as a result of its fast onset-fast offSet pharmacodynamics) prob- ably has no meaningful protective or detrimental cffect in adults. However, in children, prolonged administration of propofol has been reported to produce a fatal metabolic acidosis, perhaps as a result of the drugs carrier® Nimodipine The calcium entry blocker, nimodipine, will pro- tect the brain from vasospasm-related neurological deficits Nimodipine’s cerebroprotective proper- ties are unproven outside the setting of vasospasm, and nimodipines protective properties are not generally shared by other caleium entry blockers. The drug is discussed here only to emphasize that drug-induced cerebroprotection is an elusive en- tity ‘Summary Although a variety of therapies have been shown in laboratory animals to improve neurological out- come after cerebral ischemia and other insults, few hhave been proven to benefit humans. Of the few beneficial therapies, the mechanisms of protection are often poorly understood. References 1. Wass CT, Lanier WL. Improving neurologic outcome following craiac ares In: Rothenberg DM (ed), Anesthe- siology Clnies of North America: Curent concepts in cardiac resuscitation. Philadelphia: Saunders, 1996:868- 903. 2, American Heart Association. Advanced cardiac Ife sup- port Dalias: American Heart Associaton, 1987. 3, Lanier WL, Weglinskt MR. Inacranal pressure. In: Cue- chiara RF. Michentelder JO (eds). Neuroanestnesia. New York: ChurchillLivingstone, 1990:77-115, 4. SoderfelatB, KalimoH, Olsson Y, Siesjo BK. Sieveuline- Induced epileptic brain injury. Acta Neuropathol (Ber) 1989:6287-96. ‘5, Wass CT, Lanier WL. Glucose modulation of ischemic brain injury. Review and enial recommendations. Mayo Cin Proc 199671'801-812, 6, Wass CT, Schelthaver BMV, Bronk JT, Wison RM. Lanier WL. Insulin treatment of cortcosterod-associated hyper- alycemia and is efect on outcome after forebrain Is- chemia in rats, Anesthesiology 1996 84°644.651Fulminant Hepate Faure 349 7, Wass CT, Lanier WL, Hypothermia-associated protection from ischemic brain injury. Implications for patient man- ‘agement, Int Anesthesiol Clin 1996;34.95-111 8, Pols TZ, Lanier WL.A reevaluation of cerebral protection byenesthtics, wit specalreferenceto metabolic depres- sion. In: Heyer EJ, Young WL (eds). Anesthesiology Clinics of North America: Anesthesia forthe patent with Neurologic disease. Philadelphia: Saunders, 1997:631- 77. 9. Lanier WL. Cerebral vasospasm. In-Allee J (ed). Compl- Cations in anesthesiology. Phiadelphia: Saunders, 1998: 733-726. Case Presentation: Fulminant Hepatic Failure Michelle ¥. Braunfeld Case Report 2i-yearold white woman was transferred to the University of California, Los Angeles (UCLA) in fulminant hepatic failure for evaluation for liver transplantation. She had been admitted to the referring hospital | day before with a history of acetaminophen overdose, Laboratory test results there were remarkable for profound acidosis, with ‘an arterial pH of 6.85, and an acetaminophen level (of 20 ug/ml. 24 to 36 hours postingestion. ‘The patient arrived at UCLA and was electively intubated and sedated with diprivan, Additional laboratory tests showed a prothrombin time greater than 100 seconds and factor V activity of 4.8%. She was oliguric. A pulmonary artery catheter was placed and hemofiltration was started. Head com- puted tomographic (CT) scans were unremarkable ‘on admission and repeated every 12 hours. The patient’ father was considered as a donor for living related liver transplantation but was rejected be- cause of inadequate liver volume. Over the second and third hospital days at UCLA, the diprivan sedation was stopped and the patients coma progressed from stage 3 to 4. An intracranial pressure (ICP) monitor was placed, with pressures ranging between 15 and 20 mmHg, Frum the Deparinent af Avestlsilo, University of Cfo. rin at Los dngeles Madico! Conte Loses, CA “dress reprint request NéchlleY Brome, Department ofdnsthesiolog UCLA Meal Comer 10833 Le Come Ave, Los Angeles, C4 90098, ‘Copyright ©1999 by te merc Aasoition fr the Stabs of Ener Disoses| 1074-3022990804-001883 000 Nonetheless, serial head CT scans showed the development of cerebral edema. ‘On the fourth hospital day, the patient was taken to the operating room for liver transplantation, Her blood pressure and ICP, up to now stable, destabi- lized during hepatic dissection. The sodium thio- ppental infusion for brain protection was stopped. and the patients blood pressure was supported with phenylephrine, During the anhepatic phase, her cerebral perfusion pressure (CPP) was 30 t0 40 mmHg. Just before reperfusion, her ICP increased acutely to 80 mmHg and remained there uatil the termination of the surgery. A postoperative head CT scan showed small lateral ventricles with loss of gray/white matter differentiation. The basal cis- terns were completely eflaced, and the pons was believed to be compressed. Serial neurological examinations were consistent with brain death, (On the fifth hospital day, the patient was taken to the operating room for organ procurement. The liver was harvested and transplanted into a 42-year- old Hispanic woman with Wilson's disease, The liver functioned well, and that patient was dis- charged home on the 26th hospital day. Discussion The defining feature of fulminant hepatic failure is ‘the rapid onset and progression of hepatic encepha~ lopathy in the setting of acute liver disease. Unlike the encephalopathy of patients with chronic liver isease, this encephalopathy is often associated ‘with cerebral edema and increases in ICP that may lead to cerebral death. The challenge of these patients is to decide: (1) who requires transplanta- tion and who will spontaneously recover, (2) who ‘may no longer be a candidate because neurological350 Michelle ¥ Brownfeld recovery is unlikely, and (3) how to manage the ‘operative care of the transplant recipient. In these times of massive mismatch between supply and demand of transplantable organs, a fourth chal- lenge also appears, which is the management of those patients ia fulminant hepatic failure awaiting transplantation, There is no doubt that the patient described here ‘was unlikely to recover spontaneously. Her acetami- nophen level on admission, if plotted on a drug nomogram, was consistent with an ingestion dose expected to lead to severe hepatic damage.’ Further- more, her acidosis on admission to the referring hospital, renal insufficiency, INR greater than 10, and factor V activity of 4.8% are all criteria believed to be indicative of the need for transplantation in the setting ofacetaminophen toxicity ‘There are several clinical issues that may render 1 patient @ noncandidate for liver transplantation, Strictly from a neurological point of view, in the absence of an unacceptable, fixed, central nervous system lesion, the CPP has prognostic significance, A University of Nebraska study suggested that in patients who underwent transplantation for fulmi- nant hepatic failure, a CPP maintained at greater than 50 mmHg was associated with neurological recovery, Whereas a CPP less than 40. mmHg sustained for greater than 2 hours was associated ‘with brain death.+ Although there have since been reports of neurological recovery in patients with sustained CPP less than 40 mmHg, 50 mmHg remains the benchmark for expected neurological recovery. Certainly up until the anhepatie phase of our patient, there was good reason to expect neurological recovery. Even up until reperfusion, it was not clear whether her low CPP was sustained long enough to produce permanent damage. Is there anything in this patients preoperative ‘management that might have made a difference in her outcome? She appears to have been appropri- ately treated and referved in a timely fashion by the outside hospital. She was aggressively managed at UCLA with serial head CT scans and early place- ment of an ICP monitor. Probably the single intervention that could have made a difference was an immediate transplant or, failing that, an effective bridging therapy. Although a porcine hepatocyte- based bioartificial liver had been on clinical tral at UCLA, this patient presented during a hiatus of that trial. Previous data suggest, however, that if she had been randomized to receive treatment, she could have been expected to be bridged success- fully to transplant with neurological recovery.°* References 1. lennom MJ, Barceloux OG. Medical toxicology. New York: Elsevier, 1988 2. Willams R, Wendon JA. Acute Wer falure—Clincal syndrome and terminology. In: Proceedings ofthe Ninth Biennial Scentfic Meeting, Asian Pacific Associaton for the Study ofthe Liver, January 1994 3, Perera LM, Langley PO, et al. Coagulation factor V and VIIUV ratio ‘8s predictors of outcome in paracetamal- Induced fulminant hepate falure. Gut 1982;38:98-102 4. Inagaki M, Shaw 8, at al, Advantages of intracranial Pressure monitoring in patents with fulminant iver failure [abstract), Gastroenterology 1992;102:4828. '5, Watanabe FO, Mullon C et al. Cinical experience with & bioartiical iver in the veatment of severe liver fare. ‘Ann Surg 1987:228:484.484 6. Cottman KL, Hoffman A, et al. Neurological and psycho- logical sequelae in transplant recipients after bridging th the biearificial ver. Gen Hosp Psychiatry 1986;78: 208-248.