Neurologic complications of cardiac arrest.

Handbook of Clinical Neurology, Vol. 119 (3rd series) Neurologic Aspects of Systemic Disease Part I Jose Biller and Jose M. Ferro, Editors © 2014 Elsevier B.V. All rights reserved

Chapter 3

Neurologic complications of cardiac arrest MATTHEW McCOYD1* AND THOMAS McKIERNAN2 Department of Neurology, Loyola University Healthcare Center, Maywood, IL, USA

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Center for Heart and Vascular Medicine, Loyola University Healthcare Center, Maywood, IL, USA

NEUROLOGIC COMPLICATIONS OF CARDIAC ARREST In the US, about 350 000–450 000 lives per year will suffer cardiac arrest (Callans, 2004). Cardiac arrest is defined as cessation of cardiac mechanical activity and is confirmed by the absence of signs of circulation (Thom et al., 2006). Approximately 80% of cardiac arrests occur at home (Callans, 2004; Young, 2009). Many will receive cardiopulmonary resuscitation (CPR) by well-trained emergency medical service providers (60%) (Thom et al., 2006; Hess and White, 2010). The disappointment is that 69% of patients who have cardiac arrest will not receive bystander assistance (Thom et al., 2006). If a patient does not receive bystander CPR then the chances of survival fall approximately 7% for every minute until defibrillation (Callans, 2004). The survival to hospital discharge for out-of-hospital cardiac arrest is 6.4% and for in-hospital cardiac arrest is a little better at 17.6% (Peberdy et al., 2003; Cooper et al., 2006; Thom et al., 2006; Sandroni et al., 2007). For those who suffered an in-hospital arrest, 95% were monitored or witnessed events and if in ventricular fibrillation (VF), 78% received a defibrillation attempt within 3 minutes. More discouragingly, the survivors of cardiac arrest often suffer severe anoxic-hypoxic brain injury related to prolonged anoxia and the inability of rescuers to restore spontaneous circulation in an acceptable amount of time. Cardiac arrest presents global ischemic insult to the brain. The neurologic complications of cardiac arrest are closely related to anoxic-hypoxic time. Brain anoxic injury is a complex process that begins early after cardiopulmonary arrest and includes transient global hyperemia with delayed prolonged global and multifocal hypoperfusion and reoxygenation injuries that can lead to primary necrosis and triggering of apoptosis

(Holzer et al., 2005). The brain depends on uninterrupted oxidative metabolism to uphold neuronal function, for cellular detoxification and for the maintenance of membrane integrity (Bouch et al., 2008). Cerebral perfusion accounts for approximately 20% of total cardiac output (Bouch et al., 2008). During circulatory arrest, both cerebral blood flow and oxygen delivery rapidly cease, and neither can help compensate for the other (Bass, 1985). Brain damage and subsequent neuronal degeneration is due to both immediate cytotoxicity producing necrosis for up to 72 hours after cardiac arrest and delayed apoptosis leading to neuronal death up to 21 days after the arrest (Bouch et al., 2008; Horstmann et al., 2010). Reperfusion injury causes delayed neuronal death by apoptosis and autophagocytosis (Bouch et al., 2008). The extent of cerebral damage is influenced by the duration of interrupted cerebral blood flow. There are virtually no cerebral stores of oxygen (Bouch et al., 2008). Cerebral oxygen stores and consciousness are lost within 20 seconds of the onset of cardiac arrest. Glucose and adenosine stores are lost within 5 minutes (Booth et al., 2004). Irreversible brain damage occurs within 5–10 minutes of complete circulatory arrest (Bass, 1985). The halt of cerebral activity that occurs within seconds after arrest indicates cessation of synaptic transmission, which may possibly occur as a protective measure employed by the brain to preserve energy and maintain cell survival (Bass, 1985). Without restoration of perfusion/oxygenation, cell injury begins to occur as calcium and lactate levels rise within cells (Bass, 1985). The most vulnerable areas are the large projection neurons of the cerebral cortex, cerebellar Purkinje cells, and the CA-1 area of the hippocampus. Subcortical areas including the brainstem, thalamus, and hypothalamus are more resistant to injury (Geocadin et al., 2008).

*Correspondence to: Matthew McCoyd, M.D., Loyola University Healthcare Center, Building 105, Room 2700, 2160 S. First Avenue, Maywood, IL 60153, USA. Tel: þ1-708-216-2127, Fax: þ1-708-216-5617, E-mail: [email protected]

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M. McCOYD AND T. McKIERNAN

Prolonged cardiac arrest can also be followed by fixed or dynamic failure of cerebral microcirculatory reperfusion despite adequate cerebral perfusion pressure. Impaired reflow can cause persistent ischemia and microinfarcts in some brain regions (Nolan et al., 2008). A generalized inflammatory response also occurs following arrest, which has been referred to as the postcardiac arrest syndrome (Busto et al., 1989). The brain–heart connection remains a poorly understood but real physiological phenomenon that has long been recognized by neurologists and neurosurgeons and is now acknowledged by cardiologists with the description of the takotsubo syndrome. This syndrome presents as a severe cardiomyopathy that is associated with catastrophic life events or stress, such as the death of a loved one, or being “scared to death.” Despite significantly elevated troponin levels, the patients demonstrate normal coronary arteries at coronary angiography and complete recovery of left ventricular function in approximately 1–2 weeks (Kawai et al., 2000). A similar event occurs in the heart when severe cerebral damage occurs, particularly following subarachnoid hemorrhage. This cardiac dysfunction is probably related to excess catecholamine stimulation or some other cerebral–cardiac relation and is not as yet well delineated (Wittstein et al., 2005). Over 50 years ago, Kouvenhouven and Safar reported their work on, respectively, chest compression and mouthto-mouth pulmonary resuscitation, and modern CPR was born. Kouvenhoven et al. reported the results of chest compression on 20 hospitalized patients, of whom 14 were successfully resuscitated (Kouwenhoven et al., 1960; Eisenberg and Psaty, 2010). At the same time, Safar reported his data on the benefit of mouth-to-mouth ventilation (Eisenberg and Psaty, 2010). In 1947, Claude Beck performed the first successful open human defibrillation with recovery of the patient (Beck et al., 1947; Cooper et al., 2006). Paul Zoll recorded the first successful closed chest defibrillation in 1955 (Zoll et al., 1956; Cooper et al., 2006). Many lives since have been saved by CPR due to training in the use of this technique under the support and guidance of the American Heart Association. Currently, specific guidelines are published every 5 years to advise rescuers on the best practices for CPR. There is a current paradigm shift, however, in CPR technique that is expected to be outlined in the next set of CPR guidelines. This shift is toward cardiocerebral resuscitation (CCR) and away from cardiopulmonary resuscitation and has been spearheaded by Gordon Ewy and his colleagues at the Sarver Institute at the University of Arizona. Ewy and colleagues designed a study to compare 24 hour neurologically normal survival between continuous chest compressions (CCC) without assisted ventilations and 30 compressions to 2 breaths (CPR) as recommended in the 2005 American Heart Association guidelines in a

swine model of witnessed out-of-hospital cardiac arrest. They showed that continuous compression resuscitation was better at producing neurologically normal survivors than classic CPR (Ewy, 2005; Ewy et al., 2007). In a human retrospective observational cohort study by Garza et al., they found improved survival to discharge when a protocol that optimized chest compressions was used for outof-hospital ventricular fibrillation/ventricular tachycardia cardiac arrest (Garza et al., 2009). Subsequently, papers simultaneously published by Svensson and Rea reported opposite results, with Svensson concluding no benefit or advantage to CCC and Rea favoring the technique by showing a trend toward benefit in certain subgroups for CCC. However, these important papers viewed in context support the hypothesis that compression only resuscitation (CCC), which is easier to learn and perform, should be the preferred and instructed method of CPR (Rea et al., 2010; Svensson et al., 2010). Likewise, the increasing use of hypothermia for cerebral function preservation as established by the work of Bernard, the Hypothermia After Cardiac Arrest (HACA) group in Europe, and others has finally helped to improve neurologic outcomes in cardiac arrest patients (Hachimi-Idrissi et al., 2002; Bernard et al., 2003; Hypothermia After Cardiac Arrest Study Group, 2003). In discussing neurologic complications of cardiac arrest, the focus will be on preventing anoxic-hypoxic complications and will include the epidemiology of cardiac arrest, the neuropathology and physiology of anoxic-hypoxic brain damage, neurologic clinical syndromes after cardiac arrest, diagnosis and prognostic indicators, and finally, treatment of the post-cardiac arrest patient. In the 1970s, Negovsky described the effects of resuscitation and anoxia-hypoxia and labeled it “postresuscitation disease” (Negovsky, 1972). Now, Neumar et al. have described a “post-cardiac arrest syndrome” and its treatment, and how we can limit neurologic damage after cardiac arrest by aggressive treatment including therapeutic hypothermia (Neumar et al., 2008).

EPIDEMIOLOGY OF CARDIAC ARREST In-hospital cardiac arrest The incidence of in-hospital cardiac arrest has been well tracked since 2000 with the advent of the National CPR (NCPR) registry sponsored by the American Heart Association (Peberdy et al., 2003). This registry uses Utstein outcome criteria to follow in-hospital arrest at over 500 institutions (Cummins et al., 1997). As far back as 1987, McGrath and colleagues looked at in-hospital cardiac arrest in 13 000 patients and noted an overall survival to discharge of 14%. While this overall survival rate is low, neurologic recovery in survivors was

NEUROLOGIC COMPLICATIONS OF CARDIAC ARREST 27 approximately 60% (McGrath et al., 1987; Weil and Fries, outcome included sepsis, malignancy, renal failure, 2005). The NCPR initial data in 2003 on resuscitation of homebound status, and age, which was felt to be a boradults and children in the hospital had 14 720 cardiac derline predictor. Predictors of good outcome included arrests that were evaluated with an overall survival to early resuscitation, early defibrillation, mild hypotherdischarge of 17%. If the initial rhythm was VF, survival mia, and out-of-hospital arrests from VT/VF (Sandroni to discharge was 34% (Peberdy et al., 2003). This same et al., 2007). registry reported again in 2006 and at that time included These data give a much clearer picture of in-hospital 253 centers and 36 902 adults and 880 children with pulcardiac arrest outcomes, especially with the inception of seless cardiac arrest. They excluded peripartum, neonathe National Registry of Cardiopulmonary Resuscitation tal, and out-of-hospital arrests. The endpoint was (NRCPR) database. The sad fact is that for overall sursurvival to hospital discharge. Overall survival was vival we have not improved significantly. 27% in children and 18% in adults. VT/VF was the initial rhythm in 14% of children and 23% of adults. Survival to Out-of-hospital cardiac arrest discharge was 29% in children and 36% in adults, and good neurologic outcome occurred in 62.9% of children The outcomes of out-of-hospital cardiac arrest are worse than the in-hospital data, and the reporting and collection and 75.3% of adults. Asystole was the initial rhythm in of outcome data is particularly problematic. There is 40% of children and 35% of adults. Survival to discharge was 22.3% in children and 10.6% in adults and good wide variation in the reported incidence of out-ofneurologic outcome occurred in 55% of children and hospital cardiac arrest. Death certificate reporting in 61% of adults. PEA was the initial rhythm in 24% of chilmany US states will not allow for “cardiac arrest” or dren and 32% of adults. Survival to discharge was 26.6% “sudden cardiac arrest” as a diagnosis, and therefore in children and 11.2% in adults and good neurologic outsurrogate diagnoses are used, thus decreasing the accucome was 63.2% in children and 62.2% in adults. They racy of epidemiologic data. These surrogate data often include death due to coronary artery disease that concluded that asystole and PEA were the most common occurred within 1 hour of symptom onset and without initial rhythms and that children had better outcomes (Nadkarni et al., 2006). Patient characteristics included other probable cause of death (Thom et al., 2006). a mean age of 65, male sex predominance (57% versus In 1994, Lombardi published the New York City out43%); only 11% of in-hospital codes occurred in the emercomes for out-of-hospital arrest as part of the PHASE gency room (ER); illness categories included cardiac in study. This observational cohort study interviewed para38% and medical noncardiac in 41%, surgical cardiac medics about postarrest therapy. The endpoint for this in 7% and surgical noncardiac in 11%. The event was wittrial was discharge to home. They studied 3243 patients of whom 72% suffered primary cardiac events. The nessed and/or monitored in 88% of cases. In adult caroverall survival rate was 1.4%. Witnessed arrest survival diac arrest the mean interval to initiation of CPR was 0.5 minutes, mean interval to first attempted defibrillawas 5.3%. They noted 32% received bystander CPR, of tion was 2.1 minutes, mean duration of CPR was 22.3 whom 2.9% survived; among those without bystander minutes, and mean duration of CPR in survivors to hosCPR, 0.8% survived (Lombardi et al., 1994). Comparipital discharge was 16 minutes (Nadkarni et al., 2006). sons with other large urban areas were similar but midWhat is also apparent is that there is little improvement size towns and rural areas did better, particularly the in survival to discharge overall since McGrath’s data in highly organized King County, Washington (Eisenberg and Mengert, 2001). 1987. In a study from the Netherlands in 1999 that looked In Scotland, a 1996 study of initially resuscitated outat in-hospital CPR and tried to find predictors of survival of cardiac arrest, 553 patients were studied. Overall surof-hospital cardiac arrests in 1476 patients showed that vival to hospital discharge was 21.7%. Independent pre46% were discharged alive. In this group, 89% had good dictors of poor outcome included age > 70, stroke, renal neurologic function (Cobbe et al., 1996). In 2004, the failure, and congestive heart failure. Independent preOntario Prehospital Advanced Life Support Study studdictors of good outcome included angina pectoris and ied the rate of survival to discharge in 5638 cardiac VT/VF (de Vos et al., 1999). Saklayen et al. reported a arrests. The investigators noted survival to discharge in patients with rapid defibrillation of 5%, with advanced worldwide survival to discharge of 15.2% in 1995. This life support 5.1%, after a witnessed arrest by a bystander included survival by world regions as follows: US 15%, Canada 16%, UK 17%, and Europe 14% (Saklayen 4.4%, after CPR by a bystander 3.7%, and after rapid et al., 1995). In 2007, Sandroni et al., from Italy, reported defibrillation by a bystander 3.4% (Stiell et al., 2004). an overall survival to discharge from 0 to 42% in a Valenzuela noted a 74% survival to hospital discharge literature search and review of cardiac arrest. They also in out-of-hospital cardiac arrest when on-site lay listed predictors of outcome. Predictors of poor responders provided defibrillation in < 3 minutes, and

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Caffrey et al. reported overall survival rates of 66% in VT/VF arrest in the Chicago Airport System (Valenzuela et al., 2000; Caffrey et al., 2002). Bunch and his colleagues at Mayo Clinic studied long-term outcomes of out-of-hospital cardiac arrest after successful early defibrillation. In Olmstead County, Minnesota, they studied 200 patients with VF and noted excellent long-term survival in these patients. Some 72% survived to hospital admission and 40% were neurologically intact at discharge. The long-term 5 year survival was 79% and as good as age and sex matched controls with a similar disease processes. Bystander CPR was performed in 48% of this group (Bunch et al., 2003). In 2008, Sasson et al. reviewed 142 740 patients with out-of-hospital cardiac arrest and noted an overall survival to discharge of 7.6%. Bystander CPR occurred in 32%. If the patient’s arrest was witnessed by emergency medical services (EMS) the survival was 4.9– 18.2%. If the arrest was VT/VF, the survival was 14.8– 23%. If the arrest had return of spontaneous circulation (ROSC), then survival was best (15–33%). Overall, the conclusion of the authors was that survival in out-ofhospital cardiac arrest has been stable and little improved for almost 30 years (Sasson et al., 2010). In 2010, Svensson and his colleagues, in a lead New England Journal of Medicine article, studied 1226 cardiac arrests that took place outside hospital and reported a 30 day survival of 7.0–8.7%. Rea and colleagues, in the same issue, reported survival to discharge of 11.0–12.5% (Rea et al., 2010; Svensson et al., 2010). The lack of improvement in survival, especially for out-of-hospital cardiac arrest, carries significant implications for the neurologist. Almost all of these patients’ survival relates to the anoxic-hypoxic damage occurring during cardiac arrest.

TREATMENT OF CARDIAC ARREST The initial resuscitation of cardiac arrest is well outlined in the 2005 AHA Guidelines and includes specific algorithms for pulseless VF/VT, PEA, and asystole (Committee, Subcommittees and Task Forces of the American Heart Association, 2005). These measures are beyond the scope of this chapter and can be reviewed in detail in the 2010 AHA Guidelines (Field et al., 2010). The purpose of our review is to focus on the postresuscitative care of these patients, specifically a brain-oriented therapeutic approach. Neumar et al., in the 2008 International Liaison Committee on Resuscitation (ILCOR) consensus statement on post-cardiac arrest syndrome, have described five stages of postresuscitative care. These include immediate (the first 20 minutes after return of spontaneous circulation)

stabilization; early (the first 20 minutes to 12 hours after ROSC) interventions; intermediate (12–72 hours after ROSC) paths of treatment; recovery (72 hours plus) and prognostic indicators; rehabilitation-disposition and long-term care and rehabilitation (Neumar et al., 2008). It is during these first three phases that the focus is primarily on brain preservation. It is this period that we wish to focus on in terms of treatment post-cardiac arrest. Our goal is preservation of neurologic function. This is commonly measured in the hypothermia literature using the cerebral performance categories (CPC). These categories are as follows: CPC 1: good: the patient is alert and can live independently and has normal cerebral function; CPC 2: moderate disability: the patient is alert and can live independently and work part-time; such patients may have seizures and ataxia, etc.; CPC 3: severe disability: the patient is conscious but dependent on others for daily support (impaired cerebral function); CPC 4: vegetative state (Jennett and Bond, 1975; Cummins et al., 1997). Best outcomes for the cardiac arrest patient will be CPC 1 or 2. This section will review postresuscitative care basic measures, early diagnosis and treatment of the cause of cardiac arrest, temperature regulation therapy (hypothermia), seizure management, and long-term neurologic and cardiac management.

Basic measures The postarrest patient should be cared for in the critical care setting whether it be the medical intensive care unit (MICU) or cardiac care unit (CCU). The 2005 American Heart Association guidelines emphasize optimization of hemodynamic, ventilatory, and neurologic support. It is equally important to correct the underlying cause of the arrest, which is coronary artery disease in approximately 80% of cases (Chugh et al., 2008). Acute myocardial infarction (AMI) caused cardiac arrest in 68% in a study by Herlitz et al. (1995). Adequate airway and breathing, ventilator support, arterial line, ABG, pulse oximetry, CVP, MVO2, lactate levels, frequent vital signs, telemetry, central lines, Foley catheter, and general critical care measures are needed (Neumar et al., 2008). Echocardiography and EKG are necessary to evaluate the heart, and emergent cardiac catheterization and coronary angiography should be undertaken if ST elevation myocardial infarction is present. Knafelj et al. have shown the safety and potential benefit to neurologic survival in combining mild induced hypothermia with percutaneous intervention (PCI) to comatose survivors of cardiac arrest (Knafelj et al., 2007). Likewise, Wolfrum et al. studied 33 consecutive patients after VF cardiac arrest who remained comatose after ROSC and had acute myocardial infarction. Some 16 patients received immediate

NEUROLOGIC COMPLICATIONS OF CARDIAC ARREST induced hypothermia and it was continued during PCI. This group was compared to a similar group not receiving induced hypothermia. They found that initiation of hypothermia did not delay door-to-balloon times and that patients receiving induced hypothermia had a lower mortality (25% versus 35%) and an improved neurologic outcome (Wolfrum et al., 2008). An organized approach to the cardiac arrest patient’s postresuscitation treatment is recommended. Sunde and colleagues reported on a standardized treatment protocol for postresuscitation care after out-of-hospital cardiac arrest and compared a protocol using early reperfusion treatment (PCI), therapeutic hypothermia, a standardized treatment protocol (particular goals for seizure control, temperature regulation, glucose control and PaCO2), maintenance of an adequate arterial blood pressure, and prehospital CPR, and compared their results to a time before these standards were implemented. They found a survival-to-hospital discharge with a good neurologic outcome of 26% in the control period and 56% with the current plan including PCI and hypothermia (Sunde et al., 2006). The approach to the postcardiac arrest patient is really dependent on aggressive interventions in this early time period postarrest. Laurent et al. (2002) noted that most postresuscitation deaths occur in the first 24 hours. Perhaps the most important therapeutic intervention since Gorelick and Kelly reviewed this topic in 1993 has been the use of therapeutic hypothermia (Gorelick and Kelly, 1993).

Therapeutic hypothermia for cardiac arrest Hypothermia for brain preservation is not a new idea. In the November 1950 Annals of Surgery, Bigelow described the possible role of hypothermia in future cardiac surgery on the basis of experiments he performed on dogs. He described a state in which the body temperature is lowered and the oxygen requirements of the tissues are reduced. He foresaw this allowing exclusion of the organs from the circulation for prolonged periods and thus allowing surgeons to operate on the bloodless heart (Bigelow, 1950). In 1997, Marion et al. reported on the treatment of traumatic brain injury with moderate hypothermia. They randomized 82 patients with severe closed head injuries (Glasgow Coma Score (GCS) 3–7) to hypothermia at 33 C for 24 hours against normothermia. The patients were reevaluated using the Glasgow scale at 3, 6, and 12 months. At 12 months 62% of the patients in the hypothermia group and 38% in the normothermia group had good outcomes (moderate, mild, or no disabilities). The authors concluded that treatment with moderate hypothermia for 24 hours in patients with severe traumatic brain injury and with coma scores of 5–7 on admission may have improved neurologic

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outcome (Marion et al., 1997). Conflicting data were published by Clifton and colleagues in 2001 when they investigated the induction of hypothermia after brain injury. They studied 392 patients with coma after closed head injury and compared hypothermia to normothermia. Their study concluded that hypothermia is not effective in improving neurologic outcomes or mortality (Clifton et al., 2001). Despite this controversy, the interest in this treatment continued and has as its basis fundamental physiologic mechanisms that give it appeal for neurologic injury. Hypothermia may preserve brain function in several ways. In the normal brain, hypothermia reduces the cerebral metabolic rate for oxygen by 6% for every 1 C reduction in brain temperature. Cooling also reduces electrical activity and may increase the seizure threshold. Hypothermia has been reported to suppress reperfusion injury (free radical production, excitatory amino acids release, calcium shifts that lead to mitochondrial destruction and apoptosis). It also reduces tissue lactate and may decrease blood–brain barrier disruption and lead to less cerebral edema (Nolan et al., 2003; Holzer et al., 2005; Greer, 2006). Although the protective mechanism of hypothermia remains to be clearly defined, the above mechanisms should have merit and consideration. Several studies in laboratory animals show that hypothermia induced shortly after cardiac arrest may improve neurologic outcome (Greer, 2006). The breakthrough for the current practice of hypothermic therapy came through two key human randomized controlled studies published in the February 21, 2002 issue of the New England Journal of Medicine. The Hypothermia After Cardiac Arrest (HACA) Study Group in Europe published a paper entitled “Mild therapeutic hypothermia to improve neurologic outcome after cardiac arrest.” In this multicenter trial they studied comatose patients who had been resuscitated after cardiac arrest due to ventricular fibrillation. Patients were randomized to undergo therapeutic hypothermia (32–34 C) over 24 hours or normothermia. The primary endpoint was favorable neurologic outcome at 6 months after cardiac arrest. The study found 55% favorable outcome in the hypothermia group and 39% favorable outcome in the normothermia group. Suprisingly, mortality at 6 months was 41% in the hypothermia group and 55% in the normothermia group. The complication rate was the same for the two groups (Hypothermia After Cardiac Arrest Study Group, 2002). A second study was published from Australia by Bernard et al. and assessed treatment of comatose survivors of out-of-hospital cardiac arrest with induced hypothermia. They randomized 77 patients who remained unconscious after cardiac arrest to treatment with hypothermia (core temperature reduced to 33 C within 2 hours after ROSC and maintained

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for 12 hours) or normothermia. They had a good neurologic outcome in 49% of the hypothermia group and in 26% of the normothermia group. The Australian investigators did not show a difference in mortality had been shown in Europe, but they concluded that treatment with moderate hypothermia appears to improve neurologic outcomes in patients with coma after cardiac arrest. There were no differences in complications in this study between the two groups (Bernard et al., 2002). Hachimi-Idrissi and his group studied 33 patients with coma after cardiac arrest and a primary electrocardiographic rhythm of asystole or pulseless electrical activity. Systemic cooling was achieved using a helmet device with a cooling solution. The patients were cooled to 34 C for 4 hours. It was found that 19% of the patients in the hypothermia group were alive at hospital discharge with a favorable neurologic outcome while none of the normothermia group had a favorable outcome. This was the only study to feature asystole and PEA treated with hypothermia (Hachimi-Idrissi et al., 2001). Potential complications of hypothermia involve all organ systems. Cardiovascular complications include sinus bradycardia, prolonged electrocardiographic intervals (QTc especially), atrial fibrillation, and ventricular dysrhythmias. Hematologic complications involve prolonged PT and PTT, thrombocytopenia and platelet dysfunction, impaired granulocyte function, and impaired granulocyte release. Metabolic effects include hypokalemia and hyperkalemia with rewarming, hyperglycemia, and shivering. Gastrointestinal effects are pancreatitis and ileus. Infections are increased, especially pneumonitis and bacteremia (Bernard et al., 2002; Hypothermia After Cardiac Arrest Study Group, 2002; Holzer et al., 2005; Greer, 2006; Seder and Jarrah, 2008). Skin care is crucial and cold-induced skin changes can occur. Following these human randomized controlled studies, the Advanced Life Support Task Force of the International Liaison Committee on Resuscitation made strong recommendations regarding the use of hypothermia. They recommended that unconscious adult patients with spontaneous circulation after out-of-hospital cardiac arrest should be cooled to 32–34 C for 12–24 hours when the initial rhythm was ventricular fibrillation. Such cooling may also be beneficial for other rhythms or in-hospital cardiac arrest (Nolan et al., 2003). This statement was in 2003 and subsequently, in 2005, the American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Care made hypothermia for these two categories in the ILCOR statement a Class IIa and Class IIb recommendation, respectively (Guidelines, 2005a, b, c). Despite these strong recommendations by authoritative bodies, the treatment of hypothermia was not

universally adopted. In a survey of physicians’ utilization of hypothermia in published, Abella et al found that use of hypothermia had yet to be broadly incorporated into physician practice. Reasons for nonuse included that it was too difficult, that there was not enough support in the literature, and that they did not know about it (Abella et al., 2005). Slowly these trends are changing and more and more medical centers have active hypothermia protocols. Many questions still remain as areas of future research regarding hypothermia for cardiac arrest. We still need to determine who are the best candidates for this treatment and who should be excluded. What is the target temperature, and for how long should we cool? Many of the studies have variable time periods of cooling. The HACA group cooled for 24 hours, Bernard in Australia for 12 hours, and Hachimi for 4 hours. What is the best way to cool, internal or external, and by what technology? Current cooling techniques vary from iced saline bags around the head to topical cooling blankets to sophisticated chaps and vests systems, and even a cooling helmet. Internal cooling can be accomplished with intravenous iced saline or internal catheters that will cool the body core. When is it best to use neuromuscular blockade for shivering? How soon should cooling take place after cardiac arrest? When is it too late to cool? Abella et al., in a study of a murine arrest model, found that the timing of hypothermia was a crucial element of survival. They demonstrated that early intra-arrest cooling appears to be significantly better than delayed post-ROSC cooling or normothermic resuscitation (Abella et al., 2004). This would dictate in-the-field cooling, as was done in Bernard’s study in Australia (Bernard et al., 2002). How do we determine neurologic prognosis in the presence of hypothermia and sedation and often neuromuscular blockade (Young, 2009)? All these questions need answers before we can optimize this promising treatment for anoxic brain injury.

Sedation and neuromuscular blockade After cardiac arrest, the intubated comatose patient will require sedation and often neuromuscular blockade. Neuromuscular blockade may facilitate induction of hypothermia by blocking shivering and depth of blockade can be assessed by using train-of-four muscle twitch assessment in the intensive care unit (ICU). Deep sedation alone may suppress shivering and there is a movement in hypothermia protocols to use bolus neuromuscular blockade only rather than mandatory blockade in each case (Neumar et al., 2008). Sedation and neuromuscular blockade both affect prognostic neurologic assessment of the patient, as does hypothermia itself

NEUROLOGIC COMPLICATIONS OF CARDIAC ARREST (Young, 2009). Because of the relatively high incidence of seizures after cardiac arrest, continuous EEG recording is recommended when neuromuscular blockade is in place (Neumar et al., 2008).

Seizure control and prevention Seizures, myoclonus, or both occur in 10–40% of adults who remain comatose after cardiac arrest (Neumar et al., 2008). No studies have directly addressed the use of prophylactic anticonvulsant drugs after cardiac arrest in adults. Myoclonus can be difficult to treat and clonazepam remains the most effective antimyoclonic drug. Prolonged seizures can cause cerebral injury and should be treated promptly by standard drugs such as benzodiazepines or phenytoin. Prospective studies to determine the benefit of prophylactic seizure treatment and the benefit of continuous EEG monitoring remain to be done. A recent prospective observational study by Rundgren studied comatose cardiac arrest survivors using a continuous amplitude integrated EEG during hypothermia until the patient regained consciousness or 120 hours had elapsed. The study looked at 34 patients and at normothermia the EEG pattern was discriminative for outcome. They found that a continuous EEG pattern at normothermia was predictive of regaining consciousness whereas a pathologic pattern (flat, burstsuppression, or status epilepticus) was not. Seven patients (21%) developed clinical seizures and electrographic status epilepticus during hypothermia. None of these patients regained consciousness and all died in the hospital (Rundgren et al., 2006).

Neuroprotective pharmacology A number of trials have investigated neuroprotective mechanisms in the immediate postarrest period (Geocadin et al., 2008). With the exception of therapeutic hypothermia, few have proven successful. Treatment strategies that have shown promise in experimental studies, but whose success could not replicated in larger or controlled trials, have included barbiturates such as thiopental (Brain Resuscitation Clinical Trial I Study Group, 1986), glucorticoids (Jastremski et al., 1989), calcium channel blockers such as lidoflazine (Brain Resuscitation Clinical Trial II Study Group, 1991), nimodipine (Roine et al., 1990; Safar, 1993), resuscitation with 0.45% NaCl versus 5% glucose (Longstreth et al., 1986), intravenous magnesium alone (Thel et al., 1997) or with diazepam (Longstreth et al., 2002). The use of tenecteplase in the Thrombolyisis in Cardiac Arrest (TROICA) trial for patients with out-of-hospital cardiac arrest of presumed cardiac etiology did not increase 30 day survival compared with placebo (Bottiger et al., 2008). A recent retrospective, nonrandomized study of 227

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patients following cardiac arrest suggested that the early administration of intravenous selenium for 5 days following arrest was a significant predictor of regaining consciousness. Overall survival at 6 months was not significantly influenced (Reisinger, 2009). Coenzyme Q10, whose potential benefit has been speculated on in diseases ranging from congestive heart failure to amyotrophic lateral sclerosis, has also been studied as a therapy for cardiac arrest. Coenzyme Q10 combined with mild hypothermia in a small study of 49 patients appeared to improve survival at 3 months (68% versus 29%) and was associated with a lower mean serum S100 protein level (Damian et al., 2004). Several protective measures have demonstrated some benefit in the postarrest patient, including management of intracranial pressure, fever, and seizures. Maintenance of an adequate mean arterial pressure (MAP) between 80 and 100 mmHg has been suggested to ensure adequate cerebral blood flow (Bell et al., 2005). In one retrospective study of 136 patients, good neurologic recovery was independently and directly related to a MAP > 100 mmHg during the first 2 hours after the return of spontaneous circulation, but not associated with hypertensive reperfusion within the first 5 minutes after the return of spontaneous circulation (Mullner et al., 1996).

PROGNOSIS In addition to attempting to minimize brain injury in the immediate postarrest period, one of the most common questions for neurologists is to predict the longterm prognosis for these patients. Approximately 18% of patients who have an inpatient cardiac arrest survive to discharge while only 2–9% of those who experience an out-of-hospital arrest survive to discharge (Geocadin et al., 2008). In those that survive cardiac arrest, only 3–7% are able to return to their previous level of functioning (Geocadin et al., 2008). In those that survive cardiac arrest, brain injury is common. In one study of patients who survived to ICU admission but subsequently died in the hospital, brain injury was the cause of death in 68% after out-of-hospital cardiac arrest and 23% after in-hospital arrest (Laver et al., 2004; Nolan et al., 2008). In 1985, Levy et al. published a report on predicting outcome from hypoxic-ischemic coma (Levy et al., 1985). Poor prognostic signs included absent pupillary light reflexes, motor responses at 24 hours that were absent, extensor, or flexor, and by spontaneous eye movements that were neither orienting nor roving conjugate. The ensuing two and half decades of clinical experience and research data have largely validated their findings. Awakening generally occurs within 3 days in

32 M. McCOYD AND T. McKIERNAN patients who are comatose due to anoxic-ischemic epilepticus, characterized by bilaterally synchronous encephalopathy following resuscitation, if patients twitches of limb, trunk, or facial muscles, occurring awaken at all. Neurologic impairment is expected in within the first 24 hours in patients with primary circulathose that fail to do so (Wijdicks et al., 2006). Most studtory arrest is invariably associated with in-hospital death ies that assess predictors of poor outcome in patients or poor outcome, even in patients with intact brainstem with anoxic-ischemic encephalopathy have as their prime reflexes or some motor responses (Wijdicks et al., 2006; objective the reliable prediction of an outcome no better Young, 2009). In a prospective study of 407 patients, than a vegetative state or severe disability with total myoclonic status epilepticus at 24 hours after arrest dependency at 3–6 months after arrest (Young, 2009). was associated with no false-positive predictors of poor The circumstances of the arrest, including time between outcome (Zandbergen et al., 2006a; Young, 2009). collapse and initiation of CPR, duration of CPR, cause Information derived from electroencephalograms of the arrest (cardiac versus noncardiac), and type of (EEG) has been difficult to apply broadly owing to difarrhythmia are related to poor outcome but cannot disferences in interpretation and categorization. It is genercriminate accurately between patients with poor and ally accepted that generalized suppression to 20 mV, favorable outcomes (Wijdicks et al., 2006). The presence burst-suppression pattern with generalized epileptiform or absence of any single specific clinical sign observed activity, or generalized periodic complexes on a flat immediately after cardiac arrest has not been shown background are strongly but not invariably associated accurately to predict outcome either. However, patients with poor outcome (Wijdicks et al., 2006). Burst suppreswho lack pupillary and corneal reflexes at 24 hours and sion on isoelectric pattern on EEG within the first week have no motor response at 72 hours have an extremely had a 100% specificity for poor outcome in most studies small chance of meaningful recovery (Booth et al., (Zandbergen et al., 1998). In one older study, only two of 2004). Absent pupillary light reflexes 24–72 hours after 18 patients with a seriously impaired EEG had a relatively CPR and absent corneal reflexes after 3 days has consisgood outcome (Cloche et al., 1968). A recent study by tently shown a 0% false-positive prediction rate for poor Thenayan et al. looked at EEG reactivity as an indicator outcome in multiple studies (Wijdicks et al., 2006). In of recovery (Thenayan et al., 2010). The study found a several prospective studies, 108 patients identified with strong association between the presence of reactivity absent pupillary light responses 3 days after cardiac on EEG and the comatose patient regaining awareness. arrest all had poor outcomes (Young, 2009). FalseTen of 11 patients with EEG reactivity regained conpositive predictions of poor outcome based on motor sciousness; the one that did not had life support withresponse may occur with a GCS motor score of < 2 drawn on day 5 after cardiac arrest in part due to (i.e., extensor or absent motor responses) 24–48 hours absent somatosensory evoked potential (SSEP) response after CPR, but no false predictions have occurred after and poor prognostic clinical features. Seventeen of 18 72 hours other than in patients who have undergone therpatients with no reactivity on EEG did not regain conapeutic hypothermia (Wijdicks et al., 2006). sciousness (Thenayan et al., 2010). Clinical predictors should be treated with some Short-latency SSEPs have proven to be the most degree of caution in patients who undergo therapeutic robust predictor of poor outcome following cardiac hypothermia. One study by Al Thenayan et al. of 37 arrest (Bleck, 2006). Early cortical responses are generpatients showed recovery of awareness on day 6 in ated in the somatosensory cortex and can help identify two of 14 patients who had motor responses no better patients with severe brain damage (Allison et al., 1991). than extensor posturing on day 3. However, none of SSEPs are less influenced by drugs and metabolic the patients without pupillary reactivity on day 3 and derangements than EEG and are therefore more accunone with absent corneal reflexes recovered awareness rate than EEG in prognostication (Wijdicks et al., (Al Thenayan et al., 2008; Young, 2009). These findings 2006). The bilateral absence of the N20 of the SSEP were confirmed in a second study by Rossetti et al. of 111 in patients with postanoxic coma of at least 24 hours patients that also showed that motor response to pain duration is invariably associated with poor outcome was a less reliable predictor of poor outcome in coma(Zandbergen et al., 2006b). Loss of the cortical response tose cardiac arrest survivors after therapeutic hypotherto median nerve stimulation (the N20 potential) when the mia, with a false-positive mortality prediction of 24% earlier potentials (those recorded over the brachial (Rosetti et al., 2010). plexus and the dorsal root entry zone near C7) are intact Though seizures are often considered to portend a carries an almost certain prognosis of death or poor poor outcome, no individual studies or summary meafunctional recovery (Bleck, 2006). Of 187 patients with sures have established that single seizures or sporadic absent N20 responses, 179 died and the remaining eight myoclonus accurately predict outcome (Booth et al., were in a vegetative state. The chance of recovery of con2004; Wijdicks et al., 2006). However, myoclonic status sciousness in patients with absent N20 responses in the

NEUROLOGIC COMPLICATIONS OF CARDIAC ARREST 33 first week who are in a vegetative state after 1 month is occurring potentials are generated by thalamocortical virtually nil, indicating irreversible brain damage severe interactions and are modulated by the reticular activatenough to justify its combination with death as an outing system (Pfurtscheller et al., 1985). Smaller studies come measure (Zandbergen et al., 1998). Bilateral were supportive of the use of long-term latencies to absence of the N20 component of the SSEP with median improve the sensitivity of SSEPs in predicting poor outnerve stimulation had good predictive value for poor come. In one study by Madl et al., the preservation of the outcome with almost all studies showing false-positive N70 SSEP had a sensitivity of 94% and a specificity of rates of 0% (Wijdicks et al., 2006). Absent SSEP has 97% for predicting good outcome in patients with prebeen found more often than any other neurophysiologic served N20 potentials (Madl et al., 2000). In another or clinical predictor with 100% predictive value small study, by Young et al., all five patients with pre(Zandbergen et al., 2006b). served N70 responses recovered awareness out of 33 The presence of N20 potentials does not select a comatose cardiac arrest survivors (Young et al., 2005). group who will do well, however. The prevalence of A larger study by Prohl et al. found that the long-latency absent short-latency SSEP is rather low. Its sensitivity N70 on day 4 correlated more strongly with the outcome as a test for poor outcome is only moderate (Zandbergen groups than short-latency SSEPs. If SSEP N70 could be et al., 2006b). Many patients who fail to recover will have recorded (which it was in 30 out of 47 examinations), the preserved N20 responses (Wijdicks et al., 2006). In one prediction of a favorable outcome was successful in 87% study, 40% (13/32) of the patients with preserved early of patients (n ¼ 26) (Prohl et al., 2007). However, in a cortical responses achieved a good recovery (Daubin multicenter study by Zandbergen et al., the presence et al., 2008). or absence of the N70 in patients with postanoxic coma It has generally been accepted that once lost, N20 was not found to be precise enough to base treatment responses are not regained, especially if absent 72 hours decisions solely on its absence (Zandbergen et al., after arrest (Young, 2009). Absent SSEPs have rarely 2006b). In the study of 407 patients, poor outcome been associated with recovery of consciousness and in occurred more often when N70 was absent 72 hours after those cases, SSEPs were typically performed in the first CPR compared with earlier recordings. However, there 24 hours, possibly representing a “shock phase” early was a substantial increase of false-positive predictions after the insult from which the brain can recover (4–15%). The presence of the N70 response resulted in (Guerit et al., 1993; Zandbergen et al., 1998). Studies have an outcome better than death in only 28% of patients. suggested that hypothermia, even cooling to 30 C, may There was also a high percentage of failures to classify influence the latencies of the cortical responses but not the N70 response, caused by equivocal readings or techthe responses themselves (Stecker et al., 2001; nically insufficient recordings. The authors concluded Kottenberg-Assenmacher et al., 2003). However, more that the false prediction of poor outcome occurs in a recent data suggest that hypothermia treatment may number of patients when N70 is used (Zandbergen affect the predictive value of clinical findings and N20 et al., 2006b). responses. In a study by Leithner et al., one patient At least one study looked at brainstem auditory had absent N20 3 days after arrest, good outcome, and evoked potentials for predictive value in postanoxic recovery of N20 responses on follow-up, and one patient encephalopathy. The middle latency auditory evoked with barely detectable N20 on day 3 who also had good response was absent in all 13 patients who died or outcome and recovery of N20 on follow-up. Both remained in a persistent vegetative state (with a sensitivpatients’ SSEP recordings were performed 3 days after ity of 34%) (Young, 2009). However, there is only a limcardiac arrest and 2 days after the beginning of rewarmited amount of data to support its routine use. ing at core body temperatures of 36 C and 37 C. These The use of serum biochemical markers has been of findings suggest that the prediction of poor outcome by interest, in part due to the possibility of simplifying the bilateral absent N20 might not be 100% certain and that acquisition of prognostic information, but their poor relevant recovery of N20 might occur beyond 24 hours in sensitivity has limited their use (Bunch et al., 2007). cardiac arrest patients treated with hypothermia Neuron-specific enolase (NSE) is localized primarily in (Leithner et al., 2010). The other 35 patients who had the neuronal cytoplasm and is released into the cerebrospibilateral absent N20 recordings had poor outcomes nal fluid and serum with neural tissue injury (Bunch et al., (Leithner et al., 2010). However, in the study by Rossetti 2007). NSE serum concentration level of > 33 mg/L samet al., no patients with absent N20 responses had favorpled between 1 and 3 days after cardiac arrest was strongly able outcomes despite therapeutic hypothermia (Rosetti predictive of poor outcome with no false positives. Some et al., 2010). 60% of 231 patients in a study by Zandbergen et al. had There has been interest in the use of long-term latenNSE > 33 mg/L at day 1–3 after CPR and all had a poor cies (N70) as well, with mixed results. These later outcome (Zandbergen et al., 2006b). Similar findings

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were reported by Prohl et al., who found that the median values of NSE on days 2–4 were higher among patients with a poor neurologic outcome as compared to those with a favorable outcome. Those who died or remained in a persistent vegetative state had a median NSE of 28.60 on day 4. Those who regained consciousness had a median NSE of 9.75 on day 4. NSE values tended to rise from day 2 to day 4 in those who did poorly and decreased in those who regained consciousness. The authors concluded that NSE can reliably distinguish between patients with favorable and unfavorable neurologic outcomes at an early stage, though biomarkers alone cannot replace a systematic neurologic examination (Prohl et al., 2007). Previous studies have not been as convincing for the validity of timing and cutoff values for biomarkers such as NSE (Schoerkhuber et al., 1999; Rech et al., 2006; Young, 2009). Some patients with NSE values > 33 mg/L have been reported who survived (Zandbergen et al., 2006b). NSE values were found to be significantly lower in patients who underwent therapeutic hypothermia versus those who did not in one study (Tiainen et al., 2003). A limiting factor may be the availability of the assay in North America (Young, 2009). The greatest predictive value of biomarkers such as NSE may be in combination with other variables such as the clinical examination and electrophysiologic testing (Bunch et al., 2007; Prohl et al., 2007). Protein S100B has also been a serum biochemical marker of interest in postarrest patients. Protein S100B is a calcium-binding astroglial protein that is released after stroke and cardiac arrest. Elevated levels of S100B might cause neuronal apoptosis, suggesting that S100B may play a role as a cytokine in brain inflammatory responses (Van Eldik et al., 2003; Bianchi et al., 2007; Shinozaki et al., 2009). The available data seem to indicate that protein S100B is not superior to NSE for predicting poor outcome, in part due to its low sensitivity. A study by Grubb et al. found that a S100B cutoff of > 1.2 mgL1 drawn between 24 and 48 hours after return of spontaneous circulation was required to achieve a false-positive rate of 0% with a sensitivity of 45% (Grubb et al., 1996). Zandbergen et al. found the sensitivity of NSE to be “clearly superior” to that of S100B testing (Zandbergen et al., 2006b). Mild therapeutic hypothermia was not found to significantly influence serum levels of S100B in patients surviving non-traumatic out-of-hospital cardiac arrest (Derwall et al., 2009). The predictive quality of S100B levels was best on admission but not on later time points. S100B levels at baseline were significantly lower in patients with good neurologic outcome at 14 days (Derwall et al., 2009). In a systematic review of the available literature, Shinozaki et al. also found that serum levels of S100B may be the most clinically useful within 24 hours of cardiac arrest in predicting neurologic outcomes such as regaining consciousness and returning to

independent daily life (Shinozaki et al., 2009). In the 2006 American Academy of Neurology Practice Parameter, S100B was felt to be a poor prognostic indicator with inadequate data to support or refute its value (Wijdicks et al., 2006). Imaging studies, particularly CT, in the immediate postarrest period are typically normal. Diffuse brain swelling may occur as early as 3 days after CPR (Wijdicks et al., 2006). There are two CT signs associated with ischemic brain damage: loss of boundary (LOB) between gray matter and white matter, and cortical sulcal effacement. An inversed gray/white matter ratio in Hounsfield units on CT was found in patients who failed to awaken after CPR in at least one study (Torbey et al., 2000; Wijdicks et al., 2006). A recent study by Inamasu et al. found that when the cardiac arrest–return of spontaneous circulation interval exceeded 20 minutes, patients developed a positive LOB sign, and those with an interval of > 30 minutes did so invariably. The signs were recognizable on CT as early as 1 hour after cardiac arrest. Sulcal effacement was not found to be as timedependent or predictable as the LOB sign, but was a more specific sign of fatal brain injury when present (Inamasu et al., 2010). MRI data as a tool for prognostication have been limited (Wijdicks et al., 2006). Diffusion-weighted imaging abnormalities have correlated with poor outcome in several smaller studies of no more than 12 patients (Wijdicks et al., 2001). A larger, more recent retrospective study of 80 patients found that whole brain median ADC was a significant predictor of poor outcome with lower ADCs for patients with poor outcomes. Severe ADC depression within the first few days of global anoxia was highly specific for permanent brain injury (Wu et al., 2009). The ideal time window for prognostication appears to be between 49 and 108 hours after the arrest, when ADC reductions are the most apparent. No patients with > 10% of brain tissue with an ADC value < 650 106 mm2/s to 700 106 mm2/s during this time window regained consciousness. ADC changes due to global ischemic brain injury are delayed compared to changes caused by focal ischemia. Changes in postarrest patients with poor prognosis are the most severe in cortical gray regions and the most prominent between days 3 and 5 after the arrest (Mlynash et al., 2010).

LONG-TERM COMPLICATIONS OF CARDIAC ARREST Approximately 18% of patients who have an inpatient cardiac arrest survive to discharge and only 2–9% of those who experience an out-of-hospital arrest survive to discharge (Geocadin et al., 2008). In those that survive cardiac arrest, only 3–7% are able to return to their

NEUROLOGIC COMPLICATIONS OF CARDIAC ARREST previous level of functioning (Geocadin et al., 2008). In those that survive cardiac arrest, brain injury is common. In one study of patients who survived to ICU admission but subsequently died in the hospital, brain injury was the cause of death in 68% after out-of-hospital cardiac arrest and 23% after in-hospital arrest (Laver et al., 2004; Nolan et al., 2008). There are several common immediate and delayed neurologic syndromes associated with cardiac arrest. An amnestic syndrome is common after brief periods of arrest, including both retrograde and anterograde amnesia, which may include a component of confabulation (Bass, 1985). Cortical blindness – an inability to see despite intact anterior visual pathways – has been described. In such cases, pupillary reflexes will remain intact but patients will not blink to threat and will not track. Denial of blindness (Anton syndrome) may occur (Bass, 1985). Bibrachial weakness may occur due to bilateral watershed infarctions related to the close junction of the anterior and middle cerebral arterial zones (Bass, 1985). Bilateral flaccid leg weakness may occur due to hypoperfusion of the poorly vascularized watershed regions of the spinal cord. Delayed postanoxic leukoencephalopathy may occur 2–3 weeks after arrest in patients who appear to be recovering well (Bass, 1985). Movement disorders may arise from metabolic disturbances from hypoxic-ischemic injury to the liver and/or kidney, medications, or brain ischemia (Venkatesan et al., 2006). Posthypoxic myoclonus (PHM) is perhaps the most common, and can occur acutely or begin after a period of delay (the Lance–Adams syndrome) (Venkatesan et al., 2006). Acute PHM occurs in 30– 40% of comatose arrest survivors within 24 hours of the arrest and is characterized by violent flexion movements, usually of the face and limb muscles. Acute PHM lasting > 30 minutes or occurring for most of the first postresuscitation day is termed myoclonic status epilepticus, though the movement may not represent true “epileptic” activity, and is associated with an extremely poor prognosis (Venkatesan et al., 2006). Autopsied patients have evidence of neuronal ischemia and cell death in the cerebral cortex, deep gray nuclei (basal ganglia and thalamus), hippocampus, and cerebellum that is more severe than those who did not have myoclonus (Venkatesan et al., 2006). Chronic PHM occurs within days to weeks of the arrest, and typically while the patient is still in coma. Patients are noted to have action myoclonus involving the limbs and occur on attempting to move or position a limb. Clonazepam and valproate have demonstrated an efficacy in 50% of patients with chronic PHM (Venkatesan et al., 2006). At least half of those who survive cardiac arrest have evidence of neuropsychological impairments, including memory difficulties and problems with planning,

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perception, and language, as well as personality changes (Caine et al., 2000; Lim et al., 2004; Horstmann et al., 2010). Perhaps as many as a third of patients who survive to discharge have cognitive deficits which are severe enough to hinder daily activities (Grubb et al., 1996, 2007). “Isolated amnesia” in the absence of other cognitive or motor deficits is reported but rare. Recovery of memory and visuospatial deficits likely occurs only in the first 3 months after arrest with little recovery beyond that time. Executive disturbances may improve over 3–10 months (Lim et al., 2004). Reductions in gray matter volumes have been noted in the anterior, medial, and posterior cingulated cortex, the precuneus, the insular cortex, the posterior hippocampus, and the dorsomedial thalamus on MRI, correlating with neuropsychological impairments such as amnestic deficits and apathy (Horstmann et al., 2010). Mild therapeutic hypothermia has not been noted to have a negative impact on cognition (Tiainen et al., 2007). In a study of 70 patients randomized to therapeutic hypothermia or normothermia, 67% of the survivors in the hypothermia group and 44% in the normothermia group were cognitively intact or had only subtle cognitive deficits 3 months after the arrest (the difference was not statistically significant) (Tiainen et al., 2007). Protein S100, an astroglial protein that is released after stroke and cardiac arrest, may be associated with cognitive deficits. A study by Grubb et al. found that S100 estimation at 24–48 hours may provide useful prognostic information, correlating with memory indices. S100 concentrations > 0.29 mg/L identified a subgroup of patients with significant impairment in working memory at time of discharge from the hospital (Grubb et al., 2007).

CONCLUSION The management and complications of cardiac arrest pose a significant challenge for the medical community in general and neurologists specifically. Despite intense efforts to optimize care for these patients, prognosis has remained poor for the majority of individuals. Therapeutic hypothermia has emerged as the most promising neuroprotective therapy, validated in multiple studies in appropriately selected patients. The implementation of hypothermia protocols in many centers has established a trend toward better outcomes. The two and a half decades of clinical experience have served to confirm the published work of Levy et al. (1985) in regards to prognosis following cardiac arrest. However, in addition to clinical findings, data have consistently shown that prognosis can also be guided by ancillary studies such as somatosensory evoked potentials, electroencephalography, and brain imaging. The use of serum and CSF biomarkers as an aid to prognosis continues to evolve.

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The hope remains that progress will continue toward effective therapies to reduce the likelihood of death or disability following cardiac arrest, as well as diagnostic modalities to aid the clinician in identifying patients expected to recover.

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