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<HTML> <HEAD> <META NAME="GENERATOR" CONTENT="Adobe PageMill 2.0 Win"> <TITLE>ACLS Chapter 15</TITLE> </HEAD> <BODY TEXT="#bafddc" LINK="#ffcc66" VLINK="#5cf373" BGCOLOR="#006666" ALINK= "#fb1814"> <H1>Chapter 15 Cerebral Resuscitation: Treatment of the Brain After Cardiac Resuscitation</H1> <H2><HR ALIGN=LEFT></H2> <H1><A NAME="anchor161800"></A>15.1 Pathophysiology</H1> The human brain is a complex organ. It consists of some 10 billion neurons, each with multiple axonal and dendritic connections to other cells, totaling an estimated 500 trillion synapses. Although the brain represents only 2% of body weight, because of its high metabolic activity it receives 15% of the body's cardiac output and accounts for 20% of the body's oxygen use. Although no mechanical and little secretory work is performed, energy expenditures include the synthesis of cellular constituents (eg, an estimated 2000 mitochondria are reproduced each day by each cell) and neurotransmitter substances as well as the axoplasmic transport of these substances and the transmembrane pumping of ions. <A NAME="anchor1"></A> During cardiac arrest the brain converts to anaerobic metabolism. This energy production is inadequate to supply the high metabolic needs of the brain. Thus, during total circulatory arrest, brain function quickly deteriorates as the brain "turns itself off." This "turning off" may occur in a progressive stepwise fashion if perfusion and oxygen delivery are compromised gradually <A HREF="http://localhost:8032/servlet/lp?url=Book_ACLS/ACLS_ch15/ta15_01.htx" TARGET="_blank">(Table 1)<IMG SRC= "Book_ACLS/ACLS_Source_Art/ACLS_table_icon.GIF" ALIGN="BOTTOM" WIDTH="32" HEIGHT= "23" NATURALSIZEFLAG="3"></A>. <A NAME="anchor2"></A> With the onset of cardiac arrest, people quickly lose consciousness, usually within 15 seconds. By the end of 1 minute, brain stem function ceases, respirations become agonal, and pupils are fixed or dilated. This clinical picture corresponds to the biochemical changes of oxygen depletion that occur over 15 seconds. In these 15 seconds the patient loses consciousness. Glucose and adenosine triphosphate are exhausted within 4 to 5 minutes. <A NAME="anchor3"></A> While irreversible brain damage is commonly believed to occur after 4 to 6 minutes of cardiac arrest,<A HREF="http://localhost:8032/servlet/lp?url=Book_ACLS/ACLS_ch15/ch15_ref.htx#anchor0001" TARGET="Footnote #1">1</A> current evidence suggests that neurons are more resistant to ischemia than was previously thought.<A HREF="http://localhost:8032/servlet/lp?url=Book_ACLS/ACLS_ch15/ch15_ref.htx#anchor0002" TARGET="Footnote #2">2</A>,<A HREF="http://localhost:8032/servlet/lp?url=Book_ACLS/ACLS_ch15/ch15_ref.htx#anchor0003" TARGET="Footnote #3">3</A> Even after as many as 60 minutes of complete ischemia (without reperfusion), neurons maintain some electrical and biochemical activity.<A HREF="http://localhost:8032/servlet/lp?url=Book_ACLS/ACLS_ch15/ch15_ref.htx#anchor0004" TARGET="Footnote #4">4</A>,<A HREF="http://localhost:8032/servlet/lp?url=Book_ACLS/ACLS_ch15/ch15_ref.htx#anchor0005" TARGET="Footnote #5">5</A> <A NAME="anchor4"></A> Reperfusion of the brain after cardiac arrest produces additional brain damage. This "postresuscitation syndrome" includes variable but persistent hypoperfusion thought to be caused by vasoconstriction, decreased red blood cell deformability, platelet aggregation, pericapillary cellular edema, and abnormal calcium ion fluxes. Increased intracranial pressure has not been implicated.<A HREF="http://localhost:8032/servlet/lp?url=Book_ACLS/ACLS_ch15/ch15_ref.htx#anchor0006" TARGET="Footnote #6">6-10</A> The inability to regain cerebral blood flow after a significant period of flow interruption has also been called the "no-reflow phenomenon."<A HREF= "http://localhost:8032/servlet/lp?url=Book_ACLS/ACLS_ch15/ch15_ref.htx#anchor0011" TARGET="Footnote #11">11</A>,<A HREF="http://localhost:8032/servlet/lp?url=Book_ACLS/ACLS_ch15/ch15_ref.htx#anchor0012" TARGET="Footnote #12">12</A> It may last for 18 to 24 hours. Following this, regional cerebral blood flow may improve, leading to functional recovery, or decline, leading to progressive ischemic damage and cell death.<A HREF="http://localhost:8032/servlet/lp?url=Book_ACLS/ACLS_ch15/ch15_ref.htx#anchor0011" TARGET="Footnote #11">11</A>,<A HREF="http://localhost:8032/servlet/lp?url=Book_ACLS/ACLS_ch15/ch15_ref.htx#anchor0013" TARGET="Footnote #13">13</A> <A NAME="anchor5"></A> Also implicated in the postresuscitation syndrome are the effects of ischemia-induced intracellular calcium overload. Calcium overload is hypothesized to precipitate vasospasm, uncouple oxidative phosphorylation, destroy cellular membranes, and produce a wide variety of toxic chemicals, including prostaglandins, leukotrienes, and free radicals.<A HREF="http://localhost:8032/servlet/lp?url=Book_ACLS/ACLS_ch15/ch15_ref.htx#anchor0014" TARGET="Footnote #14">14</A>,<A HREF="http://localhost:8032/servlet/lp?url=Book_ACLS/ACLS_ch15/ch15_ref.htx#anchor0015" TARGET="Footnote #15">15</A> Although the unfolding story of the pathophysiology of the postresuscitation syndrome reveals previously unknown mechanisms of tissue damage, there are also reasons for increasing optimism. First, neurons have recently been demonstrated to be more resistant to ischemia than was previously believed. Second, the secondary mechanisms of tissue injury occur during postischemic reperfusion. Consequently, interventions can be used to mitigate this tissue injury. Increasing numbers of potentially beneficial agents are being identified in the continuing search for effective therapies for resuscitation of the brain. <A NAME="anchor6"></A> Both the brain and noncerebral organs must be supported during the postischemic period. <A HREF="http://localhost:8032/servlet/lp?url=Book_ACLS/ACLS_ch15/ta15_02.htx" TARGET="_blank">Table 2<IMG SRC="Book_ACLS/ACLS_Source_Art/ACLS_table_icon.GIF" ALIGN="BOTTOM" WIDTH="32" HEIGHT="23" NATURALSIZEFLAG="3"></A>presents brain-oriented intensive care for survivors of cardiac arrest.<HR ALIGN=LEFT> <A NAME="anchor7"></A> <H1><A NAME="anchor224211"></A>15.2 Brain-Oriented Treatment of the Patient After Resuscitation From Cardiac Arrest</H1> <H2>15.2.1 Noncerebral Organ Systems After Cardiac Arrest</H2> <H3>Perfusion Pressures</H3> Maintenance of adequate cerebral perfusion pressure (ie, normal to high normal standard range as determined by the individual patient's baseline prearrest blood pressure) is a mainstay of treatment. Normally cerebral blood flow is autoregulated, so flow is independent of perfusion pressure over a wide range of blood pressures (between approximately 50 and 150 mm Hg mean arterial pressure). During ischemia, however, accumulation of tissue metabolites and abnormal calcium ion fluxes cause autoregulation to be compromised (false autoregulation) if not lost.<A HREF="http://localhost:8032/servlet/lp?url=Book_ACLS/ACLS_ch15/ch15_ref.htx#anchor0016" TARGET="Footnote #16">16</A> Perfusion of ischemic tissue then becomes dependent on arterial pressure. The occurrence of postischemic hypotension can cause severe compromise of cerebral blood flow and result in significant additional brain damage.<A HREF="http://localhost:8032/servlet/lp?url=Book_ACLS/ACLS_ch15/ch15_ref.htx#anchor0017" TARGET="Footnote #17">17</A> Therefore, following restoration of spontaneous circulation, arterial pressure should be rapidly normalized, using intravascular volume administration and vasopressors.<A HREF="http://localhost:8032/servlet/lp?url=Book_ACLS/ACLS_ch15/ch15_ref.htx#anchor0018" TARGET="Footnote #18">18</A> <A NAME="anchor8"></A> In experimental studies a transient period of vasopressor-induced moderate hypertension improved postischemic brain reperfusion and neurological recovery.<A HREF="http://localhost:8032/servlet/lp?url=Book_ACLS/ACLS_ch15/ch15_ref.htx#anchor0019" TARGET="Footnote #19">19-22</A> Such transient hypertensive reperfusion may occur after CPR because of epinephrine loading during resuscitation. <A NAME="anchor9"></A> <H3>Oxygenation</H3> Adequate tissue oxygenation is necessary to preserve cellular function and to allow postischemic reparative processes to occur. Moderate hyperoxia (PO2 greater than 100 mm Hg) should be maintained. This prevents transient pulmonary problems from causing a significant deterioration of oxygenation in already compromised tissues. Adequate arterial PO2 levels should be maintained using the lowest FIO2 possible with carefully titrated positive end-expiratory pressure (PEEP). Some controversy exists concerning a possible role of high arterial oxygen levels in the generation of postischemic, reperfusion-induced free radicals. These concerns are speculative and should not affect current clinical practice. <A NAME="anchor10"></A> <H3>Hyperventilation</H3> By lowering intracranial blood volume through cerebral vasoconstriction, passive hyperventilation can effectively lower intracranial pressure (in patients in whom it is elevated). This may result in improved cerebral perfusion. Although cytotoxic cellular edema occurs after ischemic brain insults,<A HREF="http://localhost:8032/servlet/lp?url=Book_ACLS/ACLS_ch15/ch15_ref.htx#anchor0023" TARGET="Footnote #23">23-25</A> it does not usually accumulate enough to cause continued elevation of intracranial pressure following cardiac arrest.<A HREF="http://localhost:8032/servlet/lp?url=Book_ACLS/ACLS_ch15/ch15_ref.htx#anchor0006" TARGET="Footnote #6">6-10</A> Thus, if hyperventilation is beneficial after cardiac arrest, it is not through this mechanism. <A NAME="anchor11"></A> Hyperventilation may correct postischemic tissue acidosis and helps excretion of the carbon dioxide load generated from bicarbonate administration during CPR. As hyperventilation continues, however, cerebrospinal fluid and renal ion transport mechanisms attempt to compensate.<A HREF= "http://localhost:8032/servlet/lp?url=Book_ACLS/ACLS_ch15/ch15_ref.htx#anchor0026" TARGET="Footnote #26">26</A> After approximately 4 hours, the effectiveness of hyperventilation may decline.<A HREF="http://localhost:8032/servlet/lp?url=Book_ACLS/ACLS_ch15/ch15_ref.htx#anchor0027" TARGET="Footnote #27">27</A> Passive hyperventilation is of unproven value for the comatose cardiac arrest survivor,<A HREF="http://localhost:8032/servlet/lp?url=Book_ACLS/ACLS_ch15/ch15_ref.htx#anchor0024" TARGET="Footnote #24">24</A>,<A HREF="http://localhost:8032/servlet/lp?url=Book_ACLS/ACLS_ch15/ch15_ref.htx#anchor0027" TARGET="Footnote #27">27</A> with the possible exception of benefit for the hypothesized vasogenic edema and intracranial hypertension of late secondary neurological deterioration (24 hours or more after insult). <A NAME="anchor12"></A> <H3>Correction of Acidosis</H3> Severe tissue lactic acidosis limits cell survival after brain ischemia.<A HREF="http://localhost:8032/servlet/lp?url=Book_ACLS/ACLS_ch15/ch15_ref.htx#anchor0016" TARGET="Footnote #16">16</A>,<A HREF="http://localhost:8032/servlet/lp?url=Book_ACLS/ACLS_ch15/ch15_ref.htx#anchor0028" TARGET="Footnote #28">28</A> Experimental data strongly suggest that therapeutic measures aimed at preventing or ameliorating tissue acidosis are of significant clinical benefit.<A HREF="http://localhost:8032/servlet/lp?url=Book_ACLS/ACLS_ch15/ch15_ref.htx#anchor0028" TARGET="Footnote #28">28</A> Accumulation of metabolic acids during ischemia is in part compensated by a decrease in PCO2; however, respiratory compensation for a metabolic acid load is limited.<A HREF="http://localhost:8032/servlet/lp?url=Book_ACLS/ACLS_ch15/ch15_ref.htx#anchor0028" TARGET="Footnote #28">28</A> Unfortunately correction of intracellular acidosis remains a clinical challenge. <A NAME="anchor13"></A> <H3>Temperature Control</H3> Cerebral metabolic rate increases about 8% per degree centigrade of body temperature elevation. The regional cerebral metabolic rate determines the regional blood flow requirements. Thus elevation of temperature above normal can create significant imbalance between oxygen supply and demand, and it should be aggressively treated in the postischemic period. <A NAME="anchor14"></A> Hypothermia, on the other hand, is an effective method of suppression of cerebral metabolic activity. Although widely used during cardiovascular surgery, hypothermia has significant detrimental effects that might adversely affect the post-cardiac arrest patient, including increased blood viscosity, decreased cardiac output, and increased susceptibility to infection.<A HREF="http://localhost:8032/servlet/lp?url=Book_ACLS/ACLS_ch15/ch15_ref.htx#anchor0029" TARGET="Footnote #29">29</A> Many reports indicate benefit after brain ischemia,<A HREF="http://localhost:8032/servlet/lp?url=Book_ACLS/ACLS_ch15/ch15_ref.htx#anchor0030" TARGET="Footnote #30">30-32</A> although some document detrimental effects or lack of improvement.<A HREF="http://localhost:8032/servlet/lp?url=Book_ACLS/ACLS_ch15/ch15_ref.htx#anchor0033" TARGET="Footnote #33">33</A>,<A HREF="http://localhost:8032/servlet/lp?url=Book_ACLS/ACLS_ch15/ch15_ref.htx#anchor0034" TARGET="Footnote #34">34</A> Recent evidence indicates that mild levels of hypothermia (eg, 34°C) are effective in mitigating postischemic brain damage without inducing detrimental side effects.<A HREF="http://localhost:8032/servlet/lp?url=Book_ACLS/ACLS_ch15/ch15_ref.htx#anchor0035" TARGET= "Footnote #35">35</A>,<A HREF="http://localhost:8032/servlet/lp?url=Book_ACLS/ACLS_ch15/ch15_ref.htx#anchor0036" TARGET="Footnote #36">36</A> <A NAME="anchor15"></A> The delayed hypermetabolism believed to occur after normothermic cardiac arrest, with its attendant potential imbalance of cerebral oxygen supply and demand, also suggests a possible clinical role for induced hypothermia.<A HREF="http://localhost:8032/servlet/lp?url=Book_ACLS/ACLS_ch15/ch15_ref.htx#anchor0016" TARGET="Footnote #16">16</A>,<A HREF="http://localhost:8032/servlet/lp?url=Book_ACLS/ACLS_ch15/ch15_ref.htx#anchor0037" TARGET="Footnote #37">37</A> Clinical investigation seems indicated, but at present therapeutic hypothermia cannot be recommended for routine clinical use after cardiac arrest. <A NAME="anchor16"></A> <H3>Other Biochemical Parameters</H3> Alteration of hematocrit (hemodilution). The balance between improving blood flow by reducing viscosity with hemodilution and the associated compromise of oxygen-carrying capacity has not been resolved. <A NAME="anchor17"></A> Glucose. Continued supply of glucose to ischemic tissues, either through high pre-cardiac arrest tissue stores or because of continued trickle blood flow, allows continued anaerobic metabolism. This results in excessive lactate production. As a result, tissue lactic acidosis becomes more severe, exacerbating tissue damage. Although high preischemic blood glucose levels can exacerbate brain damage, adequate nutritional support and at least normal blood glucose levels should be maintained after resuscitation to supply needed metabolic substrates for tissue repair.<A HREF="http://localhost:8032/servlet/lp?url=Book_ACLS/ACLS_ch15/ch15_ref.htx#anchor0038" TARGET="Footnote #38">38</A>,<A HREF="http://localhost:8032/servlet/lp?url=Book_ACLS/ACLS_ch15/ch15_ref.htx#anchor0039" TARGET="Footnote #39">39</A> <A NAME="anchor18"></A> <H3>Immobilization/Sedation</H3> The comatose brain can respond to external stimuli, such as physical examination and airway suctioning, and this can increase cerebral metabolism. This elevated regional brain metabolism requires increased regional cerebral blood flow at a time when the oxygen demand-perfusion rates may be precariously balanced. Protection from afferent sensory stimuli with administration of titrated doses of sedative-anesthetic drugs and muscle relaxants may prevent oxygen supply-demand imbalance and improve the chances for neuronal recovery. <A NAME="anchor19"></A> <H3>Anticonvulsant Therapy</H3> Seizure activity can increase brain metabolism by 300% to 400%.<A HREF="http://localhost:8032/servlet/lp?url=Book_ACLS/ACLS_ch15/ch15_ref.htx#anchor0040" TARGET="Footnote #40">40</A> This extreme increase in metabolic demand may tip the tissue oxygen supply-demand balance unfavorably with catastrophic neurological consequences. Conflicting evidence about the effects of postischemic seizures on neurological recovery has been reported. Some report exacerbation of postischemic brain damage,<A HREF="http://localhost:8032/servlet/lp?url=Book_ACLS/ACLS_ch15/ch15_ref.htx#anchor0041" TARGET="Footnote #41">41-43</A> whereas others report no effect on neurological recovery.<A HREF="http://localhost:8032/servlet/lp?url=Book_ACLS/ACLS_ch15/ch15_ref.htx#anchor0044" TARGET="Footnote #44">44-46</A> Although there is disagreement about the prophylactic use of anticonvulsant drugs, ie, treatment before a seizure occurs, there is general agreement that a postischemic seizure should be quickly and effectively treated. Commonly used drugs include barbiturates, phenytoin, and diazepam. <A NAME="anchor20"></A> <H3>Corticosteroids</H3> Although corticosteroids are commonly administered to patients with intracranial pathology of any cause, their value is largely unproved. Evidence does support a benefit in patients with intracranial tumor-related cerebral edema,<A HREF="http://localhost:8032/servlet/lp?url=Book_ACLS/ACLS_ch15/ch15_ref.htx#anchor0047" TARGET="Footnote #47">47</A> but there is no benefit in patients with other types of cerebral pathology.<A HREF="http://localhost:8032/servlet/lp?url=Book_ACLS/ACLS_ch15/ch15_ref.htx#anchor0048" TARGET="Footnote #48">48</A>,<A HREF="http://localhost:8032/servlet/lp?url=Book_ACLS/ACLS_ch15/ch15_ref.htx#anchor0049" TARGET="Footnote #49">49</A> <A NAME="anchor21"></A> <H2>15.2.2 Brain-Specific Therapies After Cardiac Arrest</H2> Researchers are investigating brain resuscitation measures specifically aimed at reversing the secondary postreperfusion pathophysiology that occurs after prolonged cardiac arrest. Among the first to look promising in studies of laboratory animals were the barbiturates. However, a randomized clinical trial of thiopental loading after cardiac arrest did not indicate benefit in humans.<A HREF="http://localhost:8032/servlet/lp?url=Book_ACLS/ACLS_ch15/ch15_ref.htx#anchor0044" TARGET="Footnote #44">44</A> On the basis of this study, high-dose thiopental loading cannot be recommended for routine clinical use after cardiac arrest. Nonetheless, for specific therapeutic effects in, eg, sedation, anticonvulsant therapy, or intracranial pressure reduction, barbiturates can be safely administered to patients resuscitated from cardiac arrest. <A NAME="anchor22"></A> <H3>Calcium Entry Blocking Drugs</H3> In the wake of the unfolding theory of calcium-related pathophysiology of brain ischemia, investigators have been examining the potential usefulness of these drugs after circulatory arrest. With the support of the National Institutes of Health, 20 hospitals in eight countries tested the effects of lidoflazine, an investigational calcium entry blocker, on neurological recovery in comatose cardiac arrest survivors. No differences in outcomes between patients treated with lidoflazine or standard therapy were found.<A HREF="http://localhost:8032/servlet/lp?url=Book_ACLS/ACLS_ch15/ch15_ref.htx#anchor0050" TARGET="Footnote #50">50</A> Clinical trials of nimodipine<A HREF="http://localhost:8032/servlet/lp?url=Book_ACLS/ACLS_ch15/ch15_ref.htx#anchor0051" TARGET="Footnote #51">51</A> and flunarizine similarly did not show benefit of treatment. No drug of this type has yet proved beneficial for clinical treatment of post-cardiac arrest brain damage. <A NAME="anchor23"></A> <H3>Other Experimental Modalities</H3> A number of experimental brain resuscitation therapies of varying potential promise, eg, prostaglandin synthesis inhibitors, free radical scavengers, free iron chelators, excitatory amino acid receptor blockers, and combinations of these therapies, are still awaiting definitive investigation. None is yet ready for clinical use.<HR ALIGN=LEFT> <A NAME="anchor24"></A> <H1><A NAME="anchor223206"></A>15.3 Summary</H1> Rapidly expanding knowledge about the pathophysiology of postischemic encephalopathy is leading to new avenues of research for developing effective therapies for brain resuscitation. Experimental work suggests many promising therapies. Unfortunately, varying animal models and research protocols make comparison and synthesis of experimental results difficult. Currently no single drug or therapeutic modality has conclusively proved to be of benefit after global brain ischemia. The most effective therapeutic regimen available is meticulous adherence to a standard, brain-oriented therapeutic protocol, such as previously described in this chapter. <A NAME="anchor25"></A> Adapted from Abramson NS. Brain resuscitation after cardiac arrest. In: Rosen P, ed. Emergency Medicine: Concepts and Clinical Practice. St Louis, Mo: Mosby Year Book Co; 1992.<HR ALIGN=LEFT> <A NAME="anchor26"></A> end of Chapter 15 </BODY> </HTML>