Brain Hypoperfusion Post-Resuscitation

Critical Care

0195-5616/89 $0.00 + .20

Brain Hypoperfusion Post-Resuscitation William W. Muir, DVM, PhD*

Far too often, veterinarians are faced with clinical situations in which a dog or cat has been successfully resuscitated from a severe hypotensive episode or cardiac arrest only to begin to show signs of progressive neurologic deterioration culminating in respiratory arrest and death. The deterioration of neurologic status occurs regardless of the ability to restore heart rate, mucous membrane color, capillary refill time (CRT), and arterial blood pressure to near normal values. This clinical scenario is now known to be due to postresuscitation brain hypoperfusion and is triggered by the initial ischemic event and subsequent reperfusion. Brain blood flow during the postresuscitation period may average less than ~5 per cent of normal and may last for longer than 24 h, depending upon the duration a:qd-severity of the initial ischemic episode (fig. 1). 1• 53 The dramatic decrease in brain blood flow is caused by an increase in cerebral vascular resistance, which appears to be linked to an ischemia-induced increase in vascular tissue intracellular calcium. Regardless of cause, the development of post-resuscitation brain hypoperfusion is life-threatening and has been termed post-resuscitation syndrome. This brief review describes the normal brain physiology and anatomy required for a conceptual understanding of the pathophysiology ofbrain ischemia and reperfusion. Various therapeutic modalities are detailed prior to discussing predictors of outcome.

BRAIN ANATOMY AND PHYSIOLOGY The brain occupies 80 per cent of the cranium and is composed of neurons (60 to 70 per cent) as well as mechanical and metabolic supportive tissues, termed glial cells. The carotid and vertebral arteries are the principle sources of blood supply, and although anastomotic branches have been identified, *Diplomate, American College of Veterinary Anesthesiologists; Charter Diplomate, American College of Veterinary Emergency and Critical Care; Chairman and Professor, Department of Veterinary Clinical Sciences and Professor, Department of Veterinary Physiology and Pharmacology, College of Veterinary Medicine; Professor, Division of Cardiology, College of Medicine; The Ohio State University, Columbus, Ohio Veterinary Clinics of North America: Small Animal Practice- Vol. 19, No. 6, November 1989

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most vessels in the brain are end arteries, thereby increasing their vulnerability to ischemia. Astrocytes are a special type of glial cell that surround cerebral capillaries and, together with the capillary endothelium, comprise the bloodbrain barrier. Under normal conditions this barrier provides a relatively formidable obstacle to most blood-borne a.nd polar chemical substances having low permeability and filtration coefficients and a high electrical resistance. The blood-brain barrier also possesses carrier-mediated and energy (adenosine triphosphate [ATP]) dependent transport processes that are responsible for maintaining the brain's fluid, acid-base, and electrolyte homeostasis. 7 The cerebrospinal fluid (CSF) surrounds and cushions the brain and is in close association with the blood, owing to the tremendous vascularity of its major site of production, the choroid plexus. Additional amounts ofCSF are secreted by the ependymal surfaces of the brain's ventricles. Normally, the blood-CSF and blood-brain barriers are highly permeable to water, carbon dioxide, oxygen, and most lipid-soluble substances, minimally soluble to electrolytes (sodium, chloride, and potassium), and totally impermeable to plasma proteins and large molecules. CSF pressure is dependent upon brain blood flow and the continuity of the blood-brain barrier. Increases in arteriolar and particularly venous pressure can cause disruption of the blood-brain barrier and increases in CSF pressure. The importance of increases in arteriolar pressure are made even more important with the realization that the brain has no lymphatic drainage. The brain, an obligate aerobe with a relatively high metabolic rate. (3 to 5 mil 100 g), consumes up to 20 per cent of the total oxygen used by the body. Since all cellular work is ultimately done at the expense of ATP formed in the

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BRAIN HYPOPERFUSION PosT-REsusciTATION

cytoplasm or mitochondria, the brain is extremely dependent upon an energy source-glucose-and the uninterrupted delivery of oxygenated blood. Anaerobic glycolysis cannot supply the brain's energy requirements. These unique characteristics, combined with extremely limited oxygen and energy storage capabilities, increase the brain's vulnerability to decreases or discontinuation of blood flow. The blood flow to the brain (cerebral blood flow [CBF]) accounts for approximately 10 to 15 per cent of the cardiac output and is normally regulated by the brain's metabolic rate and extrinsic factors such as arterial blood pressure, the partial pressure of oxygen (Pao 2) and carbon dioxide (Paco2), and the sympathetic nervous system (CNS). CBF of 40 to 50 ml/min/100 g of brain tissue are maintained relatively constant at mean arterial pressures between 60 and 150 mm Hg but can be modified by increases in intracranial pressure (ICP) and increases in vascular resistance. Under normal conditions ICP averages 5 to 10 mm Hg and plays little, if any, role in regulating CBF. Increases in intracranial volume associated with excessive fluid administration, tumors, or decreased CSF outflow, however, can dramatically increase ICP within the unyielding skull and severely limit CBF. Decreases in Pao2 below 30 to 40 mm Hg and increases of Paco2 can lead to dramatic increases in CBF. CBF is so sensitive to an increase in Paco2 that a change in Paco2 from 40 to 60 mm doubles CBF, with maximal vasodilation occurring at Paco2 values greater than 60 to 70 mm Hg. Decreases in Paco2 below 20 to 25 mm Hg, by contrast, can cause cerebral hypoxia, each 1 mm Hg decrease in Paco2 causing a 1 to 2 ml/mm/100 g decrease in CBF (Fig. 2). Finally, increases in sympathetic tone (shock, volume depletion) can cause vascular spasm leading to a differential distribution of blood flow, which may deprive relatively vulnerable areas of the brain of an adequate blood supply.

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PATHOPHYSIOLOGY

Although seriously investigated, the pathophysiologic processes responsible for the development of post-resuscitation syndrome remain poorly understood. It is clear, however, that the cascade of detrimental processes that do occur are triggered by brain ischemia and hypoxia42 (Fig. 3). Surprisingly, isolated brain cells maintained under physiologic yet artificial conditions can resume near-normal activity following periods of ischemia and hypoxia that last for up to 60 min. 51 This observation is in total contrast to studies conducted in intact animals, which indicate that periods of complete ischemia lasting for more than 5 min are usually fatal. Taken together, these studies suggest that one or more pathologic events are initiated by reducing brain perfusion and that, if not stopped, are ultimately responsible for cell death. Under conditions of adequate blood flow, ATP and the blood brain barrier provide a stable environment characterized by the maintenance of normal intracellular ion (K+, Na +, Ca2 +, cl-, H+) concentrations and low interstitial fluid K+ concentrations. An intact blood brain barrier prevents increases in serum K+ concentrations of up to two times normal or increases in circulating substances such as epinephrine, norepinephrine, dopamine, and acetycholine from entering the brain. Partial or complete ischemia, however, severely depresses ATP-dependent membrane pumps, leading to cellular membrane depolarizaton and a sudden increase in membrane permeability to all ions, which Ischemia

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initiates water uptake (edema). The disruption of the blood-brain barrier, with its carrier-mediated transport system for K+, leads to an increase in CSF and brain interstitial fluid concentrations of K+, further depolarizing neurons and exposing the brain to synaptic transmitters that initiate spontaneous and uncoordinated activity. Intracellular H+ concentration increases significantly, owing to the development of lactic acidosis caused by anaerobic glycolysis. Recent investigations suggest that hyperglycemia or the maintenance of brain blood flow at a value less than 10 per cent of normal ("trickle flow") produces more tissue swelling and infarction than complete ischemia because of the development of a more severe intracellular lactic acidosis. 1• 51 Lactic acidosis is exaggerated further, owing to the continued delivery of glucose in the remaining blood supply. An acute rise in tissue carbon dioxide (P1co2 ) concentrations due to decreased tissue washout also contributes to the decrease in intracellular pH. The increase in P 1co2 is also greater in hyperglycemic than normoglycemic animals. 42 The central damaging event caused by ischemia and hypoxia is ATP depletion. Produced by glycolysis in the cytoplasm and oxidative phosphorylation in the mitochondria, ATP is the energy source for all cellular work. As previously pointed out, the brain has limited energy and oxygen storage capabilities. A sudden interruption of the brain's blood supply leads to total oxygen consumption within 10 sec and complete depletion of ATP stores within 2 to 4 min. Anaerobic glycolysis produces inadequate quantities of ATP and permits the simultaneous release of lactate and H+, leading to lactic acidosis. Without adequate concentrations of ATP, cellular ion gradients are lost, intracellular communication becomes deranged, enzyme-catalyzed reactions are inhibited, and cellular membrane permeability is increased. If brain blood flow can be reinstated to values above 20 to 30 per cent of normal in less than 5 min, cellular function can be restored without compromise. Interestingly, conventional closed-chest cardiopulmonary resuscitation (CPR) provides only 3 to 10 per cent of the normal brain blood flow. One of the key factors now believed to be responsible for cellular disruption and permanent neurological injury is the loss of intracellular calcium ion (Ca; 2 +) homeostasis and the compartmental control of intracellular iron. Ischemia increases Ca; 2 + concentration, owing to inhibition of the Ca2 +-ATP dependent pump and opening of membrane voltage and receptor operated channels. Loss of ATP and oxygen during ischemia also prevents the mitochondria and sarcoplasmic reticulum from sequestering Ca; 2 +. Increases in Ca; 2 + concentration may be further enhanced by the increased release and/or exposure of brain neurons to the excitatory neurotransmitters glutamate and aspartate. These and other excitatory amino acids are released in increased amounts during ischemia and are known to predispose to neuronal necrosis, possibly by increasing Ca;2 +. Excess Ca; 2 + uncouples intercellular communication, enhances the breakdown of proteins and lipids, inhibits axonal transport, and disrupts membrane structure, eventually leading to cell death. Lipolysis and the accumulation of free fatty acids are the substrates for thromboxanes and leukotrienes, the metabolites of arachidonic acid after cyclooxygenase and lipoxygenase metabolism, respectively. 18 Furthermore, calcium-potentiated proteolysis initiates the conversion of xanthine dehydrogenase to xanthine oxidase, allowing oxidation of hypothanthine and oxygen free radical (·0 2-) production (Fig. 4). 19• 27 • 47 Calcium-mediated mitochondrial injury also releases a readily exchangeable pool of mitochondrial iron, which catalyzes the reaction of ·0 2- and hydrogen peroxide (H 2 0 2 ) to form hydroxyl anion (·OH-). The pathologic effects of free radical production include damage to nucleic acids (DNA, RNA), lipid peroxidation of me.mbranes,

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connective and supportive tissue injury, and enhanced prostaglandin production. Notably, there are no enzyme systems that can scavenge excessive quantities of hydroxyl radicals. 19 In summary, the production of global brain ischemia produces a cascade of events at the cellular level that begins with a loss of energy (ATP) and the development of intracellular acidosis. Within minutes, the cell begins to accumulate excessive quantities ofNa+, Ca2 +, and H+, as well as to depolarize and to absorb water and swell. Neuroexcitatory and potentially neuron-damaging amino acids are released in increased amounts. Loss of Ca2 + homeostasis activates proteases and phospholipases that injure mitochondria, liberating a labile pool of mitochondrial iron. Phospholipases release free fatty acids, which are metabolized by the ischemia-induced activation of phospholipase C to thromboxanes and leukotrienes. Phospholipases also act as detergents, injuring cell membranes. Iron released from mitochondria acts as a catalyst for hydroxyl anion production causing further derangements in cellular function and membrane integrity. All of these events are potentially reversible, providing that adequate concentrations of oxygen and nutrients can be restored early enough. Severe incomplete ischemia produces greater mitochondrial injury, cellular structural damage and functional neurologic injurythan does complete ischemia. Hyperglycemia (>200 mg/dl) exacerbates this damage, probably because of the development of a more severe lactic acidosis. Finally, although it is the obvious endpoint of therapy, reperfusion oftentimes acceler-. ates free radical development and oxidative injury mechanisms following ischemia, making cell injury irreversible. CLINICAL MANIFESTATIONS OF BRAIN ISCHEMIA The clinical sequelae of partial or complete brain ischemia include movement disorders, sensory deficits, cerebral edema, seizures, and coma, culminating in respiratory arrest and cardiovascular collapse. These signs can be used to determine the progression of neurologic status and emphasize the importance of monitoring (1) level of consciousness, (2) voluntary and involuntary body movements, (3) extraocular reflexes, (4) pupil position and response to light, (5) respiratory rate and pattern, and (6) heart rate and rhythm (see Dayrell-Hart and Klide). Large differences exist among various neurons in their sensitivity to hypoxia.U· 12 Neurons in the hippocampus and neocortex, caudoputamen, thalamus, and other subcortical nuclei are very sensitive to short periods of ischemia and anoxia. Clinically, injury to these areas causes memory loss, movement disorders, weakness, and mild sensory deficits. Release of neurotransmitters, the accumulation of intracellular H+ due to lactic acidosis, and neuronal depolarization predispose to epileptic seizures. Loss of corneal reflexes indicates brain stem herniation and is usually followed by respiratory arrest. 22 Bilateral pupillary dilation occurs with complete cerebral ischemia and brain death. Bilateral pupillary constriction is an early response to brain ischemia and suggests interruption of sympathetic tracts. Altered respiratory patterns of breathing, including Cheyne-Stokes respiration, suggest respiratory center depression. Prolonged periods of ischemia can cause temporary or permanent blindness, total loss of coordinated movement, seizures, and coma. Long-term recovery of normal brain function is likely after resuscitation from a period of cardiac arrest lasting up to 10 to 12 min only if conditions for recovery are initiated early (within 1 to 3 min) and optimized. The development of clinical manifestations of neurologic injury following resuscitation

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from severe hypotension or cardiac arrest is frequently delayed. Clinical signs of neurologic injury may not become apparent for several hours after successful resuscitation and has developed up to 72 h post-resuscitation in experimental animals. 53 The delay in onset of clinical signs is difficult to explain and suggests that the transient restoration of near-normal brain function followed by gradual deterioration is due to the maturation or continuation of mechanisms responsible for cellular injury. The initial period of ischemia causes cytotoxic or cellular edema due to failure of the ATP-dependent pumps (Na+-K+, Ca2 +). The blood brain barrier may be disrupted by increases in intracranial pressure associated with chest compression and increases in postcapillary venular pressure. 28 Following successful resuscitation and reperfusion, brain water increases, water and protein cross the blood brain barrier and enter the interstitial space, and fluid accumulates in astrocytes and the capillary endothelium. Cerebral edema caused by this net gain in brain water may eventually impede cerebral blood flow, causing delayed clinical signs. Arachidonic acid metabolites (thromboxanes, leukotrienes), highly reactive free radicals (·OH-, ·0 2-), and excitatory neurotransmitters are vasoactive and potentiate the development of cerebral edema and vasoconstriction following the ischemic period (see Fig. 3). Capillary vasospasm and abnormal vasoconstrictive activity are responsible for large increases in postischemic vascular resistance and are believed to be responsible for the delayed onset of hypoperfusion of the cerebral cortex and for clinical signs following cardiac arrest and resuscitation in dogs and cats. 42 The hematologic and blood chemical evaluation of patients successfully resuscitated from a hypotensive episode or cardiac arrest is relatively standard and is oriented towards defining blood glucose, electrolyte, acid-base, and fluid volume (PCV, total protein) abnormalities. Low or elevated serum blood glucose levels may have a detrimental effect upon outcome and long-term survival following resuscitation. Hyperkalemia and severe metabolic acidosis prolong the return to normal neurologic activity and increase the brain's vulnerability to seizures. Reductions in the effective circulating blood volume may prolong the period of cerebral hypoperfusion and worsen ischemia, whereas overhydration predisposes the patient to cerebral edema.

THERAPY OF BRAIN ISCHEMIA AND POST-RESUSCITATION SYNDROME Successful treatment and prevention of post-resuscitation syndrome is dependent upon the rapid reestablishment of brain blood flow, the control of intracranial pressure, and the inhibition of those detrimental processes triggered by brain ischemia and/or reperfusion 55 (Table 1). Clinical experience reminds us that the duration of circulatory arrest prior to the initiation of CPR and the time required to reestablish an adequate hemodynamic response are paramount in determining outcome. This experience also suggests that when conventional closed-chest cardiac massage is used, neurologic prognosis is poor if resuscitation takes longer than 10 min. The reason for this is that conventional closed-chest massage (C-CPR) provides only 5 to 10 per cent of the brain's normal blood flow. These values (5 to 10 per cent) produce what was earlier described (see Pathophysiology) as "trickle flow," which is believed to be more damaging than complete global ischemia because of elevation in intracranial lactic acid concentrations, prostaglandin formation, and free radical production. Recent studies in dogs and cats suggest that modified methods of external cardiac massage that include simultaneous lung inflation-

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Table l. PROBLEM

Brain-Oriented Resuscitation THERAPY/DRUG

DOSE

Hypotension

Lactated Ringer's 6% Dextran 70 7% NaCl 7% NaCl in 6% Dextran 70 Dopamine Dobutamine

35-70 ml!kg IV 10 ml/kg IV 5 ml/kg IV 5 ml/kg IV 2-5 1-tg/kg/min IV 1-3 ~-tg/kg/min IV

Seizures

Pentobarbital Thiamylal, Thiopental Phenytoin Diazepam

1-3 mg/kg IV 1-3 mg/kg IV 10-20 mg/kg IV O.l-0.2 mg/kg IV

Cerebral edema or increased ICP

Hyperventilation Oxygenahon Furosemide Mannitol Methylprednisolone sodium succinate Elevate head

Paco2 25-35 mm Hg Pao2 > 60 mm Hg l mg/kg IV 0.5-l.O g/kg IV 5-10 mg/kg IV

Toxic cellular products*

Verapamil Desferoxamine Superoxide dismutase Dimethyl sulfoxide Allopurinol

0.05 mg/kg IV 25-50 mg/kg IV slowly 5-50-mg SQ 250-500 mg/kg IV 10 mg/kg PO

* These therapies await clinical verification of efficacy. compression (SVC-CPR) with intermittent abdominal binding produce significantly greater brain blood flow than C-CPR. 17• 20 · 21 • 23 - 26 • 35 • 38 Furthermore, compression rates of 120/min are more effective than previously prescribed (60 to 90/min) rates. 12 Finally, open-chest cardiac massage (OC-CPR) at compression rates of 120/min produces the greatest increases in mean aortic, coronary, and carotid artery perfusion pressures and substantially improves brain blood flow to values greater than 50 per cent of normaJ.3 5 The increase in perfusion pressures during OC-CPR is accomplished with minimum increases in central venous pressure. Central venous pressure is increased during C-CPR and SVC-CPR and could lead to damage of the blood-brain barrier. 37 The intravenous (IV) administration of epinephrine (0.2 mg/kg) concurrent with SVC-CPP or OC-CPR maintains high levels of blood Bow to the brain by preventing run-off of blood to peripheral tissues. 8 • 29 • 31 • 36 Taken together, these studies suggest that (1) CPR should begin promptly, (2) SVC-CPR and OC-CPR are superior to C-CPR, (3) compression rates closer to 120/min are preferred, (4) OC-CPR produces the best brain blood flow and does so without significantly elevating venous pressures, and (5) the administration of epinephrine during CPR significantly improves brain blood flow by intensely vasoconstricting peripheral vascular beds.

Fluids No one would argue that the single most important therapy for the restoration of the circulation or for the treatment of shock is administration of fluids. Both crystalloid and colloid administration have been advocated as a method

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to increase mean arterial blood pressure and cardiac output. 33• 49 Their effects on ICP and CBF when administered during the post-resuscitation period, however, remains controversial. Crystalloid solutions rapidly diffuse into the extravascular space and are believed to impair pulmonary function by causing subclinical pulmonary edema. Brain swelling may also occur when administered to patients with hypovolemic shock. Crystalloids or colloids are also known to cause dramatic increases in ICP when given at shock doses (35 to 70 ml!kg) to dogs and cats. The increase in interstitial fluid volume and ICP is exacerbated because the brain does not have lymphatic drainage and is enclosed in a rigid container. Isovolemic hemodilution induced by isooncotic crystalloid administration to produce hematocrit values of20 to 30 per cent has been shown to increase cardiac output and CBF in normal dogs. 32 Similar studies using isooncotic and hyperoncotic (6 per cent hetastarch) solutions for resuscitation of hemorrhagic shock in dogs demonstrate variable effects (no change; increase) on CBF without significant increases in ICP. 33 Recent experiments using hypertonic saline (7 per cent NaCl) to resuscitate hypovolemic dogs have demonstrated rapid but transient restoration of hemodynamics, increases in CBF, and decreases in ICP. 33 These studies suggest that fluid therapy must first restore systemic hemodynamics in order to return CBF to normal and that hyperoncotic or hyperosmotic solutions may minimize increases in ICP. Perhaps the administration of5 ml!kg of7 per cent NaCl in 6 per cent dextran 70 would be ideal for this purpose. Mannitol, a hyperosmotic inert sugar, removes water from the brain by creating an osmotic gradient between the intravascular and extravascular compartments. Current dosage recommendations are 0.5 to 1.0 g/kg administered twice, 1 to 2 h apart. 3 Additional benefits of mannitol infusions include increases in CBF, hemodilution and scavenging of oxygen and hydroxyl free radicals. The administration of hyperosmotic or hyperoncotic solutions is not recommended, however, if cerebral hemorrhage is suspected (head trauma). The presence of a hyperosmotic or hyperoncotic solution in the extravascular space would increase interstitial fluid accumulation and ICP. Hyperventilation, Oxygenation, and Positioning One of the most important yet oftentimes overlooked therapeutic considerations in the treatment and prevention of post-resuscitation syndrome is the maintenance of adequate breathing and gas exchange. 16 Brain blood flow is increased by elevations in Paco 2 and decreases in Pao 2 (see Fig. 2). Maximal vasodilation occurs at Paco2 of 60 mm Hg, whereas Pao2 values less than 50 mm Hg are required to increase brain blood flow. Oxygen tensions ofless than 25 mm Hg may increase brain blood flow as much as five times. Increases in brain blood flow increase the vascular to interstitial compartment fluid flux, increasing ICP, predisposing to or causing cerebral edema. Nasal oxygen or jet ventilation can be used to maintain Pao 2 above 100 mm Hg. 13 • 46 Hyperventilation, using an Ambu bag, anesthetic machine, or respirator will help to prevent potentially detrimental increases in brain blood flow by normalizing Paco2 and maintaining values for Pao2 above 100 mm Hg (FI0 2 = 50 to 90 per cent). Currently, Paco 2 values between 25 and 35 mm Hg and Pao 2 values greater than 60 mm Hg are recommended. This generally requires an increase of minute volume (V) by 15 to 20 per cent. A 15-kg dog having a tidal volume (V1) of 12 to 14 ml!kg and a respiratory rate (f) of 12/min would normally have a minute volume of approximately 2200 ml (15[kg] x 12[V1 ] x 12[f] = V). Increasing V1 by 5 ml!kg and fby 5/min would increase V by 375 ml (17 per cent), which should prevent deleterious increases in brain blood flow and help to maintain adequate oxygenation. Head elevation and neck extension during

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spontaneous or controlled ventilation may also help to alleviate increases in ICP and ensure a patent airway. Hyperventilation and increases in V are not without problems, however, because they may lead to overventilation and increases in cerebral venous pressure. Values of Paco 2 below 20 mm Hg can cause cerebral hypoxia and increase CSF lactate concentrations. Large increases in V during controlled ventilation may adversely increase cerebral venous pressure, causing disruption of the blood brain barrier and increases in intrathoracic pressure, limiting venous return and cardiac output. The detrimental effects of low Paco 2 (less than 20 mm Hg) and increased intrathoracic pressure are exacerbated by systemic hypotension. Normalizing Acid-Base Imbalance Most patients resuscitated from an acute hypotensive crisis or cardiac arrest have developed some degree of metabolic acidosis due to the accumulation of lactic acid. Providing that resuscitative efforts are initiated early and are able to restore reasonable systemic hemodynamics within a reasonable time (less than 10 min), bicarbonate therapy may not be necessary. The determination of blood gases (Paco 2 , Pao 2 ) and pH using an automated blood gas machine is the most accurate method of assessing acid-base disorders. 43 Furthermore, venous blood samples are superior to arterial blood samples for assessing the severity of the acid-base abnormality. Empirically, the administration of0.5 to 1.0 mEq/kg for every 10 min of resuscitation effort has proven satisfactory for normalizing acid-base disorders due to metabolic acidosis. Diuresis Highly potent loop (furosemide, bumetanide) and osmotic (20 per cent mannitol) diuretics are used to rapidly decrease ICP. Both furosemide and bumetanide inhibit Cl- and N a+ reabsorption in the ascending limb of the loop of Henle, producing immediate large volume diuresis. Bumetanide is approximately 50 times as potent as furosemide. These drugs also redistribute blood to peripheral vascular beds by dilating venules. The net effect of this diuresis and redistribution of blood favors the movement of fluid from the brain (or lung) to the intravascular space, decreasing brain water and ICP. Furosemide has also been shown to be a carbonic anhydrase inhibitor, decreasing Na+ uptake by the brain and decreasing brain swelling. Neither furosemide nor bumetanide decrease brain blood flow unless cardiac output decreases. Furosemide is initially administered at 1 mg/kg IV or 2 mg/kg IM followed by 0.5 mg/kg IV every 2 to 4 h if required. Although both furosemide and bumetanide have the potential to produce hypokalemic metabolic alkalosis, this is generally not of concern during acute therapy. Mannitol produces its diuretic actions by establishing an osmotic gradient that moves water from the brain to the intravascular space, using the blood brain barrier as a semipermeable membrane. 3 This property, combined with its ability to promote reperfusion and scavenge free radicals, makes it an ideal choice for the prevention and treatment of increases in ICP and cerebral edema. As previously detailed, total IV dosages of 0.5 to 1.0 g/kg are recommended and can be repeated at 0.5 g/kg IV at approximately 2-4 h. Corticosteroids The use of glucocorticosteroids for the treatment of shock and prevention of cerebral edema in the immediate post-resuscitative period remains controversial.2· ·34 Although purported to preserve membrane integrity, prevent the formation of prostaglandins and free radicals, stabilize lysosomal mem-

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branes, inhibit histamine release, and preserve vascular membrane permeability, the ability of glucocorticoids to inhibit or reduce post-ischemic cerebral edema or improve long-term survival after cardiac arrest has not been documented. Clinical experience, however, suggests that the use of corticosteroids may be useful as adjunctive therapy and is safe when used for short periods. Large doses of glucocorticosteroids are recommended for the treatment of cerebral edema. Intravenous dosages of 5 to 10 mg/kg methylprednisolone sodium succinate or 1 to 3 mg/kg water-soluble dexamethasone are recommended. These dosages can be repeated every 6 h for up to 48 h. Sedatives/ Anesthetics Barbiturates are not recommended as routine therapy during the postresuscitation period but are useful for the control of seizures (see Dayrell-Hart and Klide). Both sodium pentobarbital (5 to 15 mg/kg IV) and sodium thiamylal (2 to 5 mg/kg IV) given to effect are useful for seizure control. 6 In addition to suppressing seizures, barbiturates also decrease cerebral metabolic rate (0 2 consumption) by decreasing neuronal activity, protect membranes from free radicals and other noxious stimuli, decrease intracranial blood volume and ICP, and increase tolerance to brief periods of complete brain ischemia. Recently isoflurane or ketamine have been advocated as an alternative to barbiturates for acute seizure control in dogs and cats. 10• 15• 30 Reduced concentration of isoflurane anesthesia (1 to 2 per cent) provides stable hemodynamics, maintains brain blood flow, and does not increase ICP. Phenytoin (10 to 20 mg/kg) may be an excellent alternative to the barbiturates for long-term seizure control in dogs. Finally, lidocaine and other local anesthetics are known to significantly reduce brain metabolic rate and stabilize cell membranes when administered in subepileptogenic doses:50 Although potentially beneficial for the treatment of complete global ischemia, recent studies demonstrate no effect in preventing early post-ischemic cerebral edema or delayed neuronal necrosis.

Unverified Therapy New, unproven, co.ntroversial and practically difficult therapeutic interventions are included under the heading of Unverified Therapy. As a group or individually, these therapies may offer immediate benefits or some hope for the future. They include calcium entry blockers, iron chelators, free radical scavengers, and heparinization. Additional therapeutic modalities are sure to be developed but await clinical verification before they can be advocated. Calcium Entry Blockers Very simply, calcium entry blockers are believed to produce their beneficial effects by preventing or reducing large increases in the concentration of Cai 2 +, thereby inducing vasodilation and increases in brain blood flow. 41 A wide variety of compounds with a variety of pharmacologic effects, including verapamil, nifedipine, nimodipine, diltiazem, flunarizine, and lidoflazine have been investigated for their ability to prevent post-resuscitation brain hypoperfusion and to improve outcome. 41 • 44 • 48 • 52 • 54 Many of these drugs are currently under clinical investigation for use in humans and are not available. Only nimodipine (10 ~-tg/kg IV, 1 ~-tg/kg/min for 10 h), a drug currently not available for clinical use, has been demonstrated to improve neurologic outcome in dogs and cats. 44 · 45 Verapamil, diltiazem, and nifedipine are available but have not been studied in clinical post-arrest resuscitation situations. Experimental studies administering verapamil at 0.1 mg/kg IV to dogs have not been encouraging, since it did not produce long-term increases in brain blood flow or improve outcome. Furthermore, many calcium entry blocking drugs

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produce hypotension, owing to their vasodilatory and negative inotropic effects. Because of their questionable effects, the absence of certainty as to safe and effective dosages, and potential deleterious hemodynamic actions, the clinical use of currently available calcium entry blocking drugs for the treatment or prevention of post-resuscitation brain hypoperfusion cannot be recommended at this time. Iron Chelators Increases in intracellular "free iron" is known to occur following brief periods of ischemia (Fig. 4). Iron is probably released by Ca2 + mediated injury of mitochondria, causing the liberation of ferrous iron from ferritin in association with xanthine oxidase activity during reperfusion, or by the release of ferrous iron from ferratin by reducing equivalents produced during ischemia.51 Free iron induces lipid peroxidation and oxygen and hydroxyl free radical formation. Infusion of small quantities of FeCl 2 have been shown to worsen tissue injury. Desferoxamine, a selective chelator of ferric iron, readily crosses the blood brain barrier to form a ferroxamine complex, which is readily excreted in the urine. The administration of 25 to 50 mg/kg desferoxamine either IM or IV has been shown to improve neurologic outcome in dogs subjected to a brief period of cardiac arrest. Free Radical Scavengers The continued investigation and clinical use of oxygen and hydroxyl free radical scavengers is warranted based upon their ahility to prevent the chemical reactions leading to membrane damage and cellular necrosis. Superoxide dismutase (5 to 50 mg, SQ), dimethyl sulfoxide (250 to 500 g/kg IV), allopurinol (10 mg/kg PO), tromethamine (THAM) (0.5 to 1.0 mg/kg IV) mannitol, and glucocorticosteroids are just a few of the compounds currently being examined in animal models for their therape~tic or protective effects against oxygenderived free radicals. No convincing evidence that they improve neurologic outcome or survival is available at this time. Heparinization The cessation of blood flow caused by cardiac arrest and shock predisposes to blood stasis and initiates clotting mechanisms. Heparinization may help to prevent the clotting cascade initiated by ischemia. The administration of 1 mg/kg (100 U) at 2 to 4 h intervals for 24 h in patients with severe shock should provide adequate heparinization. PREDICTORS OF OUTCOME Potentially, one of the most useful yet least investigated aspects of the post-resuscitation period is the development of criteria for predicting outcome. The period of brain ischemia, time required to restore the circulation, and the ability to successfully treat shock are of obvious prognostic value. 4· 4 Clinical experience suggests that when complete brain ischemia lasts for longer than 5 min and the cardiac resuscitative effort lasts in excess of 10 min, a progressively worse neurologic outcome and reduced long-term survival can be expected. 14 The patient's age, concurrent disease, and current medical or surgical complications are all important factors that must be considered. 9 The author's clinical experience suggests that up to 40 per cent of most dogs and cats can be expected to recover fully if they are in reasonably good health at the time of cardiac arrest and if resuscitation is instituted immediately. Additional important prognostic indicators include the level of consciousness, pupil,

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eyelid, and upper airway reflexes, breathing pattern, and the ability to maintain normal body temperature. The use of the oculocephalic (Doll's eye) and oculovestibular (caloric) reflexes are potentially useful as indicators of prognosis but are markedly suppressed by sedatives, anesthetics, and hypothermia. These reflexes are generally absent at body temperatures below 97°F in the dog and cat. The determination of the time to return of spontaneous breathing, pupil size, and evaluation of isolated motor reflexes has little or no demonstrated predictive value. Rapid recovery of eyelid and swallowing reflexes, resumption of a normal breathing pattern, increasing levels of consciousness, and the maintenance of normal body temperature should be considered good prognostic signs. Most dogs and cats that show signs of recovery within 5 to 10 min of restoration of spontaneous circulation recover with normal brain function. Progressive mental deterioration, seizures, or unconsciousness, particularly after initial partial recovery, dilated fixed pupils, loss of eyelid and swallowing reflexes, prolonged respiratory arrest, and gradual decreases in body temperature should be considered poor prognostic signs. The inability to maintain adequate arterial blood pressure and cardiac output to support life, regardless of specific therapies, is a reliable indicator of impending death. Close monitoring and nursing care should be continued for at least 24 h when cardiorespiratory function is rapidly restored and easily maintained, regardless oflevel of the consciousness and reflex responses. Common sense should be used when deciding to terminate therapy or euthanatize the patient. 39 Resuscitation should not be attempted in dogs or cats with incurable diseases, in the terminal stages of a prolonged illness, or when there is no hope for a favorable outcome.

CONCLUSION Investigations into those factors responsible for post-resuscitation brain hypoperfusion are continuously generating new data that are being used to improve our understanding and increase therapeutic modalities for the treatment of brain ischemia. Recent experimental investigations in dogs suggest that successful recovery from cardiac arrest with complete neurologic recovery is possible even after 20 to 30 min of cessation of brain blood flow. The future for brain- resuscitation is exciting and awaits documented identification and verification of the many new therapeutic modalities currently being investigated.

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55. Winegar CP, Henderson 0, White BC, et al: Early amelioration of neurologic deficit by lidoflazine after fifteen minutes of cardiopulmonary arrest in dogs. Ann Emerg Med 12:471, 1983 56. Winegar CP, White BC: Physiology of resuscitation. Emerg Med Clin North Am 1:479, 1983 . Department of Veterinary Clinical Sciences The Ohio State University 1935 Coffey Road Columbus, OH 43210