Coma After Global Ischemic Brain Injury: Pathophysiology and Emerging Therapies

Crit Care Clin 24 (2008) 25–44

Coma After Global Ischemic Brain Injury: Pathophysiology and Emerging Therapies Robert E. Hoesch, MD, PhDa,b,*, Matthew A. Koenig, MDa,b,c, Romergryko G. Geocadin, MDa,b,c a

Department of Neurology, Johns Hopkins University School of Medicine, 600 North Wolfe Street, Meyer 8-140, Baltimore, MD 21287, USA b Department of Anesthesiology Critical Care Medicine, Johns Hopkins University School of Medicine, 600 North Wolfe Street, Meyer 8-140, Baltimore, MD 21287, USA c Department of Neurosurgery, Johns Hopkins University School of Medicine, 600 North Wolfe Street, Meyer 8-140, Baltimore, MD 21287, USA

Brain injury from global cerebral ischemia is a significant worldwide clinical problem. Global cerebral ischemia can occur in the setting of cardiac arrest, open heart surgery, prolonged hypoxia or hypoglycemia, pathologically elevated cerebral metabolic rate, or decreased cerebral perfusion pressure [1,2]. The annual incidence of cardiac arrest alone, with concomitant global cerebral ischemia, is in excess of 400,000, and more than 80% of these patients are expected to have poor neurological outcomes [1,2]. Thus, the medical, financial, and emotional burdens of global cerebral ischemia are enormous. Poor neurological outcomes after brain injury include death, coma, the vegetative state (VS), minimally conscious state (MCS), and severe disability with chronic dependence on nursing care [3]. Thus, a preponderance of poor outcomes after global ischemia is accounted for by disorders of arousal and consciousness. Arousal refers to the process of waking or becoming more vigilant, and can occur in response to external or internal stimuli. An important difference between arousal and consciousness is that consciousness comprises both arousal and awareness: awareness requires intact cortical

Dr. Geocadin is supported in part by NIH grants R44-NS-38016 and RO1-HL-EB-71568. * Corresponding author. E-mail address: [email protected] (R.E. Hoesch). 0749-0704/08/$ - see front matter Ó 2008 Elsevier Inc. All rights reserved. doi:10.1016/j.ccc.2007.11.003 criticalcare.theclinics.com

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function, whereas arousal requires intact subcortical and brainstem function. Coma is defined as a state of complete unresponsiveness to external or internal stimuli, and is characterized by a failure of arousal [4]. Patients in coma have no spontaneous eye opening and do not arouse to sensory stimuli [4]. Coma usually results from damage to the brainstem, thalamus, or both cerebral hemispheres, and represents the leading cause of morbidity and disability after cardiac arrest [5]. Patients in a VS may present with periodic episodes of spontaneous arousal, and also arouse to external stimuli, but all other components of consciousness and cognition are absent [6]. In a VS, arousal occurs in the absence of consciousness because awareness is absent. Not surprisingly, a VS usually results from extensive bilateral cortical, subcortical white matter, or thalamic injuries, with relative sparing of the brainstem, which accounts for preservation of arousal mechanisms [7]. A VS may represent a transitional state from the unarousable unresponsiveness of a coma to a partially responsive state. By definition, a VS persisting for longer than 1 month is referred to as a ‘‘persistent’’ VS, whereas the persistence of VS for more than 3 months following nontraumatic brain injury is called a ‘‘permanent’’ VS, in light of the low likelihood of recovery of independent function [6]. In the MCS, responses to both environmental and internal stimuli are present, but this state differs from the VS in that intermittent, inconsistent behavioral evidence of consciousness is discernible, suggesting awareness [8]. Recent research has generated considerable hope for better chances of recovery following global ischemia. First, therapeutic hypothermia (TH) applied to comatose survivors of cardiac arrest was shown to significantly improve neurological outcomes in approximately one of every six patients [9,10]. This intervention has provided the most substantial improvement in neurological outcomes after cardiac arrest since the advent of modern cardiopulmonary resuscitation (CPR). Second, considerable interest has developed around the possibility of deep brain stimulation for patients who have disorders of consciousness, as evidenced by a recent case report in which stimulation of central thalamic nuclei was reported to improve arousal in a patient who had MCS after traumatic brain injury (TBI) [11]. Together, these two interventions provide hope that with a better pathophysiological understanding of global ischemic brain injury and consequent impaired arousal and unresponsiveness, new clinical applications can be developed toward an even greater impact on neurological outcomes. This article presents a pathophysiological model for states of unresponsiveness after global ischemia. First, the authors describe the physiology of normal arousal mechanisms, which provide the substrate for responses to internal and external stimuli that lead to arousal. Next, we describe the pathophysiology of ischemic brain injury, followed by a description of how anatomy and physiology altered by ischemic injury could impact arousal. We conclude with a brief description of the potential therapeutic mechanisms of hypothermia and deep brain stimulation. The primary

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goal of this summary is to generate scientific interest in coma within the general critical care community as a stimulus for further basic, translational, and clinical investigation. Arousal systems Arousal or vigilance is mediated by a complex interaction of cortical and subcortical networks. Cortical activation is required for arousal, but anatomic and physiological data suggest that the cortex does not contain an intrinsic mechanism for the generation and maintenance of arousal [12,13]. As such, a number of subcortical networks participate in the process of arousal. These networks include arousal systems located in the brainstem, the thalamus, the basal forebrain, and the hypothalamus (Box 1). Brainstem arousal systems The brainstem arousal systems comprise the reticular formation, the pedunculopontine tegmental and laterodorsal (PPT/LDT) nuclei, the locus coeruleus (LC), the substantia nigra pars compacta (SNPC), and the midline raphe nuclei (RN). These nuclei are located in disparate anatomical sites Box 1. Brain arousal systems Brainstem arousal systems Reticular activating system (RAS) Pedunculopontine tegmental and laterodorsal nuclei (PPT/LDT) Locus ceruleus (LC) Substantia nigra pars compacta and ventral tegmental area (SNPC-VTA) Raphe nucleus (RN) Thalamic arousal systems Specific thalamocortical system Nonspecific thalamocortical system Basal forebrain arousal systems Substantia innominata Nucleus basalis of Meynert Diagonal band of Broca Magnocellular preoptic nucleus Median septum Globus pallidus Hypothalamic arousal system Posterior hypothalamus Anterior hypothalamus

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in the brainstem, but each is optimally positioned to send and receive information broadly. Because of their anatomical positioning and their broad rostral projections, these nuclei may serve as sentries for the arousal system. An understanding of the brainstem arousal system began in 1949, with the work of Moruzzi and Magoun [14], who demonstrated in cats that stimulation of the midbrain near the cerebral aqueduct resulted in immediate wakefulness and activation of the electroencephalogram (EEG). Further work by Moruzzi and colleagues [15] demonstrated that a surgical transection through the rostral midbrain of the cat resulted in continuous sleep, whereas a more caudal section through the pons or medulla did not affect arousal. These studies coalesced into the notion that a group of neurons in the core of the midbrain, called the reticular formation, are part of an activating system required for cortical arousal. Subsequent anatomical data revealed that this reticular activating system (RAS) comprises neurons in core nuclei located near the cerebral aqueduct of the midbrain, and near the fourth ventricle in the pons and medulla [15,16]. These neurons are interspersed in a weblike reticulum between ascending and descending fibers, and have long dendrites that interdigitate those fibers [16]. Thus, reticular neurons are optimally situated to integrate information from a wide variety of sources, including sensory input from visual, somatosensory, auditory, and vestibular systems, as well as sensory and motor output from the cerebral cortex, thalamus, and basal ganglia [17,18]. As a result of these anatomical relationships, reticular neurons may be well-suited to play a critical role in arousal, in addition to other tasks such as the regulation of muscle tone and integration of afferent pain signals through descending, efferent signals to the spinal cord [19]. Reticular neurons employ glutamate almost exclusively [20,21], with the exception of a set of interneurons that produce gamma-aminobutyric acid (GABA), which exert local control over reticular neuron firing [22]. Ascending arousal signals from the reticular formation to the forebrain are conveyed through two systems: the dorsal system traverses the thalamus and transmits diffusely to the cortex through thalamocortical projections, and the ventral system comprises the basal forebrain and hypothalamus as key relay components [23]. PPT/LDT nuclei are located in the rostral pons and caudal midbrain and contain mostly cholinergic neurons, which contribute substantially to arousal [24]. These neurons also have long dendrites, which are interdigitated with ascending and descending fibers, and are thus may also monitor neurotransmission within a wide variety of systems [16]. These neurons also employ the dorsal and ventral cortical arousal systems, and the ascending cholinergic synapses are excitatory, as demonstrated in cats, where stimulation of PPT/LDT nuclei leads to cortical activation and arousal [25]. The LC is located in the midpons in the periventricular gray matter and uses norepinephrine as the principal neurotransmitter [19]. Both ascending and descending LC outputs are excitatory, and the LC can stimulate the cortex both indirectly, through the dorsal and ventral cortical arousal systems,

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and through direct cortical projections [19,26]. LC activation is strongly associated with conditions of heightened arousal [27,28], but in cats that have LC lesions, after an initial period of hypersomnolence, normal wakefulness returned after several days [29]. These data suggest that the LC is part of the arousal system, but is not imperative for arousal. The SNPC and the ventral tegmental area (VTA) are dopaminergic nuclei within the ventral midbrain [16]. These neurons release dopamine synaptically within the dorsal striatum via the nigrostriatal system, and also within the ventral striatum, basal forebrain, and cortex via the meso-limo-cortical system, in addition to forming dopaminergic synapses with other nuclei within the brainstem arousal system, such as the dorsal raphe nucleus, the PPT/LDT, and the LC [16]. Lesions of midbrain dopaminergic nuclei in cats led to an akinetic state characterized by a failure to arouse [30], although SNPC and VTA neurons do not change their firing rate across the sleep-wake cycle [31,32]. The precise role of the SNPC and VTA neurons in the brainstem arousal system is still being explored. Brainstem RN are located in the midline in two major groups: (1) a rostral group in the midbrain and pons, consisting of the nucleus centralis superior and the dorsal raphe nucleus, which provide serotonergic output to the cortex and forebrain; and (2) a caudal group of nuclei in the medulla, which provide serotonergic output to the spinal cord [33]. Serotonergic neurons have a regular 3 Hz tonic action potential firing pattern in awake, unstimulated animals. During sleep, the firing rate drops and becomes less regular, whereas in the setting of heightened arousal, the firing rate can increase by up to 50% [34–36]. In animal studies, serotonin release tends to promote a quiet satiety, whereas lesioning of the RN results in agitation and a persistently vigilant state [37]. Thalamic arousal systems The thalamus is crucial for achieving and maintaining arousal through its connections with the cortex [12,13]. The thalamus receives and sends data to and from virtually all central nervous system structures. Functionally, thalamic nuclei have been classified into ‘‘specific’’ and ‘‘nonspecific’’ thalamocortical systems, whereby the thalamus projects to the cortex [38]. Specific thalamocortical projections convey information within the sensory, visual, auditory, or motor systems, which have precise neuroanatomical localizations within the cortex and thalamus, and include such thalamic nuclei as the medial and lateral geniculate nuclei and the group of ventral nuclei. In contrast, nonspecific thalamocortical projections transmit information from multiple subcortical nuclei, including the reticular nuclei, LC, dorsal raphe, PPT/LDN, basal forebrain, and hypothalamus, to multiple cortical regions. Nonspecific thalamocortical projections originate from midline, medial, and intralaminar groups of thalamic nuclei, which are located in the central thalamus. Contrary to initial reports, these central thalamic

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nuclei actually have a specific neuroanatomical localization, which has drawn into question their identification as nonspecific [39]. Because of their connection with the cortex, each of the thalamocortical projection systems can play a role in cortical activation. Thalamocortical neurons have two distinct firing modes: burst and tonic. A burst firing mode is associated with sleep and unresponsiveness, and is triggered by membrane hyperpolarization [13]. In response to a stimulus, hyperpolarized thalamocortical neurons fire high-frequency bursts of action potentials followed by relative quiescence [13]. In contrast, a tonic mode of thalamocortical neuron firing is associated with wakefulness, and is triggered by membrane depolarization [13]. In response to a stimulus, depolarized thalamocortical neurons repetitively fire single action potentials, separated by a constant interval [13]. Thalamocortical neurons receive a wide variety of depolarizing glutamatergic, cholinergic, and adrenergic inputs, including those from the visual, auditory, sensory, and motor sensory systems, as well as from the brainstem arousal system [38]. Thalamocortical neurons also receive hyperpolarizing serotonergic inputs [40]. Neurons in both the thalamic reticular nucleus and local interneurons are GABAergic and also likely play a role in arousal [41,42]. These neurons form inhibitory synapses and provide hyperpolarizing input to thalamocortical neurons [43]. Thalamic reticular neurons receive inputs from and send efferents to almost all thalamic nuclei and, like thalamocortical neurons, also have burst and tonic firing modes. Thalamic reticular neurons were previously hypothesized to gate the firing of thalamocortical neurons [41]; however, the firing patterns of thalamic reticular neurons are slightly different than those of thalamocortical neurons, and thalamic reticular neurons, which form inhibitory synapses with thalamocortical neurons, are paradoxically activated during arousal [41]. Thus, a clear-cut regulatory role for thalamic reticular neurons has not yet been elucidated, although a modulatory influence of reticular neurons on local GABAergic interneurons is conceivable [41]. Basal forebrain arousal systems Basal forebrain structures include the substantia innominata, the nucleus basalis of Meynert, the diagonal band of Broca, the magnocellular preoptic nucleus, the medial septum, and the globus pallidus [44]. Neurons in the basal forebrain are a major source of acetylcholine release throughout the brain, and thus play a major excitatory role in cortical activation and arousal [45]. In guinea pigs, neurons in the basal forebrain arousal system were demonstrated to receive both excitatory (glutamate, histamine, orexins, acetylcholine) and inhibitory (serotonin) inputs from the brainstem and hypothalamic arousal systems [46]. In rats, neurons in the basal forebrain arousal system discharge tonically during wakefulness, leading either to direct activation of cortical neurons or to indirect cortical activation via depolarization of thalamocortical neurons [45]. Unlike thalamocortical

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neurons, however, intact basal forebrain activity is not required for arousal: destruction of the basal forebrain in cats does not abolish cortical activation [47]. Hypothalamic arousal systems The hypothalamus also plays a vital role in both arousal and sleep generation. In cats, when posterior hypothalamus neuronal activity was inhibited by infusion of muscimol, a GABA receptor agonist, hypersomnia resulted [48]. When muscimol was infused into the anterior hypothalamus, hypervigilance resulted [48]. Further, anatomic lesions in the anterior hypothalamus led to insomnia in cats, but sleep was transiently restored by pharmacological blockade of posterior hypothalamus activity by muscimol [48]. Thus the posterior hypothalamus appears to be the most important hypothalamic center for arousal behaviors, whereas the anterior hypothalamus and hypothalamic-mesencephalic junction promote sleep [48]. Studies of the cellular physiology mediating the influence of the hypothalamus on arousal and vigilance are ongoing. Hypothalamic nuclei comprise many types of neurons, including histaminergic neurons and peptidergic neurons that produce orexins. Histaminergic neurons are found primarily in the tuberomammillary nucleus and posterior hypothalamus, and can influence arousal via projections to the anterior hypothalamus, the dorsal raphe nuclei, the mesopontine tegmentum, the thalamus, the substantia innominata, and directly to the cortex [49]. Histaminergic neurons have a tonic firing rate of approximately 2 Hz during wakefulness, which disappears during sleep [50]. Postsynaptic binding of histamine to H1 receptors on thalamocortical neurons leads to membrane depolarization through blockade of a potassium conductance [51], whereas binding of histamine to H2 receptors activates a chloride conductance resulting in membrane hyperpolarization [52]. Thus, histaminergic neurons can influence the firing mode of thalamocortical neurons depending on the relative distribution and activation of H1 and H2 receptors [53]. Furthermore, histidine decarboxylase knock-out mice have impaired arousal [54]. Orexins (hypocretins) are neuropeptides that promote arousal [55]. An orexin deficiency has been hypothesized as a cause of narcolepsy, a disease characterized by hypersomnolence [56–58]. Orexin-producing neurons, located within the posterior and lateral hypothalamic areas in the region of the fornix, are known to have widespread excitatory central nervous system projections, with densest projections to the locus ceruleus, in addition to other regions of the hypothalamus, the basal forebrain, the thalamocortical system, and to multiple brainstem nuclei [59]. Summary of arousal systems The cortex lacks an intrinsic mechanism to promote awakening and is dependent on subcortical structures to generate and maintain arousal. Signals

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from peripheral sensory organs such as the eyes, ears, or skin are detected by sentinel arousal systems within the brainstem, which in turn excite thalamocortical neurons. Sensory transmission within the thalamus also directly excites thalamocortical neurons. As a result, thalamocortical neurons are progressively more depolarized, which promotes a mode of excitation that is supportive of arousal. The hypothalamus and basal forebrain also play roles in arousal, although the precise identities of those roles are still under investigation. Given its participation in generating circadian rhythms, the hypothalamus might help to produce or respond to internal stimuli, which can also trigger arousal. As the preceding sections demonstrate, cerebral arousal systems are multiple, widely distributed, mechanistically diverse, and still not fully understood. New insight into the physiology of arousal is paramount for the development of new therapies to treat disorders of consciousness. Pathophysiology of global cerebral ischemia Because of the limited capacity of neurons to store energy and the high metabolic demands required to maintain a polarized neurolemma, support synaptic activity, and conduct action potentials, neurons are vulnerable to even very short periods of ischemia. Global cerebral ischemia quickly leads to failure of synaptic transmission, axonal conduction, and action potential firing in a sequential manner. Neuronal susceptibility to ischemic injury is not uniform; particularly vulnerable are the CA1 and CA4 regions of the hippocampus, the middle laminae of the neocortex, the reticular nucleus of the thalamus, the amygdala, the cerebellar vermis, select neurons in the caudate nucleus, and certain brain stem nuclei, such as the pars reticulata of the substantia nigra [60,61]. This sensitivity appears to be caused by the inherent properties of neurons in those brain regions, and not by uneven circulation. This is illustrated by the example that the CA3 region of the hippocampus is less vulnerable to ischemia than the CA1 and CA4 regions, but is served by the same vascular supply [61]. Hypotheses for the differential susceptibilities of certain brain regions to ischemia include nonuniform cellular energy requirements, or the induction of certain enzyme systems, such as heat shock proteins, or c-fos or c-jun gene products, which confer a relative sensitivity to ischemia [62]. At the cellular level, ischemic brain injury unfolds in a two-part process: the initial ischemic cascade; and reperfusion injury [63]. During cerebral ischemia, cessation of blood flow to a region of the brain, and consequent local hypoxia, triggers a complex set of metabolic and biochemical processes that compose the ischemic cascade. Depletion of adenosine triphosphate (ATP) leads to collapse of transmembrane Naþ and Kþ gradients and neurolemma depolarization, with accumulation of intracellular Ca2þ from both Ca2þ influx and from intracellular Ca2þ stores [64,65]. Ischemic injury is also associated with a marked increase in extracellular glutamate, and activation of glutamate receptors, leading to additional Ca2þ influx. Elevation

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of intracellular Ca2þ triggers activation of multiple intracellular enzyme systems, including protein kinase C, protein kinase B, calcium/calmodulindependent protein kinase II, mitogen-activated protein kinases (MAPKs), and phospholipases A2, C, and D [66]. Although the restoration of brain perfusion (as occurs with successful CPR) will re-establish energy stores, cell injury and death continue in a process known as reperfusion injury [63]. Mechanisms of reperfusion injury include lipid peroxidation and other damage caused by oxygen free radicals that accumulate after reintroduction of oxygen to the ischemic region, and neuronal damage mediated by inflammatory cells. Reperfusion is also characterized by continued activation of extracellular glutamate- and intracellular calcium-dependent enzyme systems, calcium-dependent gene expression, caspase activation, and immune-mediated damage by microglia [63,65,67]. One important consequence of this pathophysiological signaling cascade is the activation of apoptosis, or programmed cell death. Reperfusion facilitates oxidative and inflammatory injury; however, it may have a role in minimizing apoptosis [68]. Because reperfusion always occurs in survivors of global ischemia, reperfusion injury likely plays a major neurotoxic role in global ischemic brain injury [63]. Pathophysiology of unresponsiveness following global ischemia Although surprisingly little research has been conducted into the exact mechanism whereby global cerebral ischemia leads to coma, or the mechanisms involved in restoration of arousal or consciousness, a number of studies have explored the clinical electrophysiological consequences of ischemia, and the evolution of electrophysiological markers during brain recovery. Given the strong association between frequency and reactivity of electroencephalogram (EEG) with various stages of arousal, and the prognostic accuracy of EEG and evoked potentials in predicting coma emergence, mechanistic information about coma and recovery can be gleaned from electrophysiological monitoring. In humans, EEG activity is completely suppressed within seconds of cardiac arrest, and rapidly returns to baseline after resuscitation if cardiac arrest is brief [69–73]. In an important clinical series, EEG and neurological examination were continuously monitored during and after CPR in cardiac arrest survivors [74,75]. Among patients who ultimately regained consciousness, electrical activity resumed after a period of EEG silence lasting 10 minutes to 8 hours [75]. In most cases, an initial pattern of EEG burst suppression occurred before restitution of continuous activity. EEG recordings during experimental cardiac arrest in animals closely mirror these findings, with arousal preceded by a variable period of EEG burst suppression [76–79]. A ‘‘burst-suppression pattern’’ is characterized by periodic bursts of generalized, sharply-contoured electrical activity interrupted by periods of EEG silence. Emergence from burst suppression and restitution of continuous EEG activity often preceded

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arousal by hours to days [75]. Among the patients who never regained consciousness in this series, burst suppression persisted longer [74]. Prognosis for neurological recovery in humans and animals is inversely correlated with the duration of burst suppression, and patients who have persistent burst suppression beyond 24 hours almost never emerge from coma [79–82]. Somatosensory evoked potentials (SSEPs) can also be used to test the functional integrity of the neuraxis after cardiac arrest, by tracing an electrical stimulus originating in the periphery through the brainstem, thalamus, and cortex. Like EEG, recovery of evoked potentials also follows a wellcharacterized time course after cardiac arrest [83,84]. In animal models of cardiac arrest, cortical signals (potentials) are lost within seconds of ischemia [85]. ‘‘Short-latency potentials’’ are then sequentially lost over the ensuing minutes, first involving the thalamic potentials, then brainstem potentials. After resuscitation, short-latency potentials (brainstem and thalamus) recover over the first hour, followed by restitution of baseline amplitude in the cortical potentials over several hours [85–87]. In adult humans, persistent loss of cortical potentials beyond 48 hours accurately predicts death or the VS. Because arousal is produced and maintained through a complex interplay between the brainstem reticular formation, cholinergic projections from the basal forebrain, the hypothalamus, and the thalamocortical circuitry, ischemia-induced derangements in these structures or their interplay could lead to impaired consciousness or arousal. As such, the SSEP and EEG data suggest that relatively short durations of ischemia produce cortical injury alone, which would lead to loss of consciousness. Over time, if subcortical and brainstem structures are preserved, then arousal can recover, and consciousness can return, if the cortex is able to generate awareness. With progressively more severe ischemic brain injury from longer periods of ischemia, subcortical and brainstem structures are compromised in addition to the cortex, and both arousal and awareness are impaired. Necrotic and apoptotic cell death involving thalamocortical neurons and the reticular thalamus have been extensively documented after cardiac arrest in animals [87–89] and humans [90]. Injury to the thalamocortical network has also been directly implicated in the generation of burst-suppression EEG patterns, especially when cortical neurons are deafferented from tonic thalamic firing [91–93]. The pervasiveness of burst suppression in coma after cardiac arrest, therefore, suggests roles for cortical deafferentation and the loss of thalamo-cortical rhythmicity in producing ischemic coma. Evoked potential studies corroborate this hypothesis in showing dissociated recovery of thalamic and cortical potentials after resuscitation [87]. In addition, large pyramidal neurons in cortical lamina V have selective vulnerability to global hypoxia/ischemia [89]. These neurons are important for the generation of cortical rhythms detectable by scalp EEG [94] and represent the major source of corticothalamic projections involved in widespread cortical and thalamic activation associated with arousal [38]. Injury to this pathway

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and loss of thalamocortical rhythmicity is speculated to result in coma and burst-suppression EEG through the disinhibition of intrinsic cortical ‘‘pacemaker’’ rhythms [92]. In summary, histopathological and electrophysiological data suggest that postischemic coma is produced by selective injury to the cortical and thalamic neurons that produce and maintain arousal through complex thalamo-cortical rhythmic firing. Ischemia results in decoupling of thalamo-cortical processesdas evidenced by EEG burst suppression and asynchronous recovery of cortical and thalamic potentials after cardiac arrestdand recovery of consciousness occurs when thalamo-cortical synchrony is re-established. Therapeutic hypothermia for global cerebral ischemia In animal models of ischemia, hypothermia inhibits multiple steps in the ischemic and reperfusion phases of cerebral injury. The rates of chemical reactions decrease by approximately one half for every 10 C decrement in temperature [95], leading to a slowing of energy-dependent, enzyme-catalyzed processes, such as synaptic transmission, gene expression, and protein assembly. In principle, a reduction in the brain’s metabolic demand leads to a decreased oxygen requirement and less vulnerability to ischemia. Although hypothermia also leads to a decrease in ATP production, this decrement is far outweighed by increased stability of ATP molecules in the setting of hypothermia, which, with concurrently decreased metabolic demand, leads to greatly decreased net ATP consumption [96]. Overall, improved ATP economy, in addition to less intracellular acidosis and more efficient glucose metabolism, are among the initial potentially therapeutic biochemical effects of hypothermia [96]. Additional possible therapeutic effects of hypothermia on the ischemic cascade include reduced neuronal depolarization by improving resolution of deranged Kþ gradients [97], and by decreasing extracellular glutamate concentrations [98], leading to a reduced intracellular Ca2þ concentration and decreased intracellular Ca2þ-dependent kinase activity [99]. Perhaps more significantly, hypothermia also inhibits many of the steps leading to reperfusion injury by decreasing free radical production [100,101] and impairing endothelial adhesion molecule expression and leukocyte invasion [102]. Under hypothermic conditions, neuronal caspase-3 activation is reduced [103] and fewer neurons undergo apoptosis [104], leading to less ongoing neuronal injury. Based on these studies, TH was tested in animal models of global cerebral ischemia. Six studies employed an induced cardiac arrest model of global ischemia in dogs, with the duration of hypoperfusion ranging from 10 to 20 minutes [105–110]. In these studies, TH (range 32 C–36 C) applied before and during [105,107] or after [106,108–110] cardiac arrest, improved neurological recovery compared with normothermic controls. In one example, dogs underwent 16 to 20 minutes of cardiac arrest secondary to ventricular fibrillation, followed by standard CPR, epinephrine, and defibrillation [108].

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In this study, there were three groups: one group was maintained at 37.5 C, the second group was maintained at 34 C after initiation of normal systemic pressure (after about 16–20 minutes of hypoperfusion), and the third was maintained at 34 C from the beginning of CPR. The authors found that, compared with normothermia, dogs in both TH groups had significantly less histopathological damage and better overall performance [108]. Most importantly, these dogs had better neurological outcomes, which were defined by level of consciousness, breathing patterns, cranial nerve function, spinal nerve function, and behavior [108]. These data suggested that TH was neuroprotective in animal models of global cerebral ischemia and led to subsequent clinical trials [111]. Three randomized, controlled clinical trials [112–114], evaluated the role of TH after global ischemia from cardiac arrest. The two largest of the clinical trials enrolled patients who had global ischemic brain injury in Europe (N ¼ 237) and in Australia (N ¼ 77) who were comatose after successful resuscitation from cardiac arrest, and if ventricular fibrillation was the initial post-resuscitation rhythm. In these studies, patients were randomized to receive either normothermia or TH (32 C–34 C). In a third, smaller Class I clinical trial performed in Belgium (N ¼ 30), patients were resuscitated in the field after asystolic or pulseless electrical activity (PEA) arrest, and were randomized to receive either normothermia or TH to a core temperature of 34 C using a helmet device that cooled the head and neck [112]. A meta-analysis combining these data found that TH was associated with a risk ratio of 1.68 (95% CI, 1.29–2.07), favoring a good neurological outcome when compared with normothermia [113]. Furthermore, the number-needed-to-treat (NNT) to generate one favorable neurological recovery was 6 (95% CI, 4–13). If TH were implemented in all cardiac arrest patients who have a potentially poor neurological outcome, these data suggest that hypothermia could improve the neurological recovery of more than 10,000 patients per year [1,2]. Because most patients in these Class I studies had an initial rhythm of ventricular fibrillation, the 2005 Guidelines for Post-Resuscitative Support issued by the American Heart Association recommended ‘‘cooling unconscious survivors after out-of-hospital cardiac arrest to 32 C–34 C for 12– 24 hours when the initial rhythm is ventricular fibrillation’’ [114]. This advisory statement adds that TH may also be beneficial for other cardiac rhythms or in-hospital cardiac arrest [114]. Although additional studies are required to delineate the role of TH in other forms of global cerebral ischemia, such as PEA or asystolic arrest, a therapeutic benefit is believed to be likely based on the clear neuroprotective effect after cardiac arrest caused by ventricular fibrillation. Deep brain stimulation after global cerebral ischemia Electrophysiological recordings in the acute phase after resuscitation from cardiac arrest have demonstrated uncoupling of thalamic and cortical

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rhythms, resulting in asynchronous thalamic and cortical evoked potentials and EEG burst suppression. As discussed above, the intrinsic arousal network involves ascending projections from reticular nuclei in the brainstem that project diffusely throughout the deep cortical layers and more focally to thalamic relay neurons. Increased activity of the ascending reticular activation centers results in heightened thalamo-cortical transmission and desynchronization of EEG signals, both of which correspond to heightened arousal. In experimental models of functional thalamocortical dissociation caused by inhalational anesthetic agents, EEG burst-suppression patterns similar to those seen after resuscitation from cardiac arrest can be produced. In these animal models, despite continuous inhalation of anesthetic gases, electrical stimulation of mesencephalic and pontine reticular nuclei results in rapid production of arousal EEG patterns [115,116]. If the ascending projections from the brainstem and thalamocortical relay neurons remains intact after cardiac arrest and activity of this network can be recruited by electrical stimulation, there may be a therapeutic opportunity for patients who have chronic impairment of consciousness (persistent vegetative state or minimally conscious state) using implantable deep brain stimulators. In fact, several case reports and case series have been published over the last decade that detail use of deep brain stimulators in these patients [117–121]. The largest series comes from Japan, reporting 10-year follow-up data from 26 patients who had deep brain stimulators implanted in either the central thalamic nuclei or the mesencephalic reticular nuclei [118]. Although many patients remained in a vegetative state after stimulation, meaningful behaviors and interaction with the external environment were observed in several patients after several months of stimulation. In the United States, similar results were reported with deep brain stimulation of a traumatic brain injury patient who had MCS [11]. Although deep brain stimulation remains experimental in survivors of cardiac arrest with impairment of arousal, there is strong biological plausibility supporting recruitment of cortical arousal patterns by stimulation of deeper nuclei in the thalamus and brainstem. Initial optimism for this potential therapeutic option, however, must be tempered by lack of any control group in existing studies. Confirmation in preclinical and clinical studies is needed before such a therapy can be adopted in more widespread fashion. Summary Global ischemic brain injury after cardiac arrest is a major cause of morbidity and mortality worldwide. Foremost among the complications of global ischemic brain injury is impaired consciousness, characterized by loss of awareness or failure of arousal. A number of cerebral systems contribute to the physiological mechanisms responsible for normal awareness and arousal, including the neocortex, the thalamus, the basal forebrain, the hypothalamus, and the brainstem. Acute and delayed neuronal death

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occur after cardiac arrest, and specific neuronal populations in the cortex, thalamus, and brainstem are selectively vulnerable to ischemia. Clinical electrophysiology studies have concluded that short durations of global cerebral ischemia affect primarily cortical structures, whereas progressively longer cerebral ischemia damages subcortical and brainstem structures. Therapies aimed at improving neurological outcomes after cardiac arrest could have an enormous clinical impact. Mechanistically, TH inhibits the ischemic cascade and reperfusion injury after global ischemia at multiple steps, and clinical trials have shown that TH improves neurological outcomes. Despite the data supporting hypothermia as a therapy for global cerebral ischemia, implementation of TH remains suboptimal. According to four recent surveys of mostly emergency room and intensive care physicians in the United States and Europe [122–125], the implementation rate of TH for cardiac arrest is 13% to 28% The implementation rate is slightly higher in the United Kingdom and Finland (36%) than in the United States (26%) [123]. The most common reasons cited for not implementing TH were perceived lack of evidence, cumbersome logistics of cooling patients, and lack of integration of cooling protocols into advanced cardiac life support (ACLS) algorithms [122–124]. Clearly, global education is needed regarding the strength of the clinical data supporting TH for cardiac arrest. Furthermore, additional data supporting TH for global cerebral ischemia resulting from all etiologies will facilitate general acceptance of TH as standard of care. Mechanistically, deep brain stimulation for impaired arousal seeks to reconnect the complex electrophysiological interplay between the cortex, the thalamus, and the brainstem. This technique has shown promise in promoting consciousness in patients in a VS and MCS after traumatic brain injury. Further investigations will examine the role of deep brain stimulation for coma after global ischemic brain injury wherein the structural integrity of cerebral arousal systems might be compromised. In conclusion, coma after global cerebral ischemic brain injury is a common, serious complication of cardiac arrest. Although anatomical and physiological studies in animals have begun to define normal arousal systems, the pathophysiology of coma and the physiology of coma emergence are still poorly understood. It is hoped that with a focused, multidisciplinary, worldwide effort to study and understand the mechanisms underlying coma and other disorders of consciousness, existing therapeutic interventions will be more broadly applied and new therapies will be developed.

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