Neurologic Complications of Cardiac Arrest

Keywords

cardiac arrest, anoxic-ischemic encephalopathy, EEG, myoclonus status epilepticus, neuron specific enolase, somatosensory evoked potentials, therapeutic hypothermia, prognosis

Introduction

Despite advances in the management of cardiac arrest, patients continue to have high mortality, exceeding 90 percent. Following the return of spontaneous circulation, dysfunction of multiple organ systems along with a systemic inflammatory response, collectively termed the “post-arrest syndrome,” can lead to substantial morbidity. The diagnosis of primary anoxic-ischemic brain injury and the prevention of secondary neurologic injury are primary goals of early management. Persistence of coma or the prediction of long-term severe neurologic deficits commonly leads to withdrawal of life support; therefore, accurate prediction of neurologic outcome early after resuscitation is important. This chapter reviews the pathophysiology of anoxic-ischemic brain injury and the neuroprotective mechanisms of therapeutic hypothermia. In addition, the clinical, biochemical, radiographic, and electrophysiologic tests used to predict neurologic outcome following cardiac arrest are reviewed, as are the ethical implications that follow prognostication.

Anoxic-Ischemic Encephalopathy

There is a delay between the time of ischemic cell injury and the manifestation of cell death. This delay may be hours, or up to 4 days following the initial insult. During cardiac arrest, oxygen levels decline and cerebral blood flow ceases, and cells must switch to anaerobic metabolism in order to produce adenosine triphosphate (ATP). Anaerobic glycolysis leads to an accumulation of hydrogen ions, phosphate, and lactate, all of which result in intracellular acidosis. The resulting excess of hydrogen ions displaces calcium from intracellular proteins, increasing its intracellular concentration. Dysfunction of the Na ⁺/K ⁺ATP pump and ATP-dependent channels leads to further increases in intracellular calcium. In addition, hypoxia results in the release of excitatory neurotransmitters, such as glutamate, that cause the endoplasmic reticulum to release calcium stores. This excess calcium activates intracellular proteases and leads to further release of excitatory neurotransmitters following depolarization of the cell membrane. Activation of N -methyl- d -aspartate (NMDA) glutamate receptors results in sodium and chloride influx, leading to hyperosmolarity that causes water influx and neuronal death. Restoration of the circulation can lead to further glutamate release and the formation of oxygen-derived free radicals and reperfusion injury, which can cause additional damage. In addition, apoptosis, due to caspase-3 activation in neurons and oligodendroglia in the cerebral neocortex, hippocampus, and striatum, can contribute to cell death, at least in perinatal models of anoxia-ischemia.

Different brain regions and specific neuronal populations appear more susceptible to hypoxic-ischemic injury, probably due to their location in a vascular border-zone or to higher metabolic rates requiring increased oxygen or density of various glutamate receptors on neuronal membranes. The CA1 neurons of the hippocampus are the most sensitive to ischemia, and injury commonly results in memory dysfunction. The Purkinje cells of the cerebellum, the pyramidal neurons in layers 3, 5, and 6 of the neocortex, and the reticular neurons of the thalamus are also commonly affected. In addition, three vascular border-zones are susceptible to a reduction in blood flow due to their distance from the parent vessel; these areas become clinically important in cases of severe hypotension and incomplete cardiopulmonary arrest. The cortical border-zones are the anterior border-zone between the anterior cerebral artery and the middle cerebral artery territories, and the posterior border-zone between the middle cerebral artery and posterior cerebral artery territories. Infarction of the anterior border-zone results in brachial diplegia, or “man-in-a-barrel” syndrome. Infarction of the posterior border-zone results in visual deficits including cortical blindness if bilateral. The internal, or subcortical, border-zone is found at the junctions between the branches of the anterior, middle, and posterior cerebral arteries with the deep perforating vessels, including the lenticulostriate and anterior choroidal arteries.

Therapeutic Hypothermia

The use of therapeutic hypothermia (TH) in patients after cardiac arrest was first reported in the 1950s, but the complication rate was high and results were inconclusive. In 2002, two landmark studies were published showing that TH improves neurologic outcomes following cardiac arrest when the initial rhythm was ventricular fibrillation (or possibly pulseless ventricular tachycardia). Bernard and colleagues randomized 77 patients to either moderate hypothermia (33°C) or normothermia. Among the hypothermia group, 49 percent survived and were able to be discharged home or to a rehabilitation facility, compared to 26 percent of controls. In the second study, in which patients were randomized to mild hypothermia (32° to 34°C) or standard of care, mortality was 41 percent in the TH group and 55 percent in the control group. In addition, 55 percent of patients treated with TH had favorable neurologic outcome, defined as Cerebral Performance Category 1 (normal) or 2 (moderate disability), compared to 39 percent of controls. No significant differences were found between the groups with respect to complications, including bleeding, infection, and arrhythmias, and the number needed to treat in these trials was impressively in the single digits. Follow-up studies investigating the implementation of TH at multiple centers confirmed the benefit and feasibility of TH.

There are many postulated mechanisms to explain the neurologic benefits that occur with TH, including a decrease of the extracellular levels of excitatory neurotransmitters such as glutamate and dopamine. The NMDA receptor is glycine dependent, and TH has been shown to decrease cerebral levels of glycine following ischemia, and thus to lessen glutamate-related hyperexcitability. TH reduces the proliferation of astroglial cells and their release of inflammatory cytokines and free radicals. TH also results in decreased cerebral blood flow, as well as decreased metabolism and oxygen and glucose utilization. A study investigating hypothermia and brain metabolism in rats revealed that decreases in metabolism of 5 to 10 percent occur for every decline in temperature of 1°C.

Prognostic Determination

Following return of spontaneous circulation, neurologists are often consulted to determine prognosis, specifically the probability of regaining consciousness and of the likely presence, severity, and extent of any persistent neurologic deficits. While prognostication with 100 percent certainty is not possible, a reasonable goal is to identify, with virtually no false positives, those patients who will have severe neurologic deficits with complete dependency at 6 months following the arrest. Much of the published literature attempts to predict which patients will have a Glasgow outcome score of 3 or less at 6 months after cardiac arrest, such an outcome includes death, vegetative state (defined as wakefulness without awareness), and severe disability with total dependency. However, a growing body of evidence suggests that some patients previously diagnosed as being in vegetative state may have some degree of preserved awareness (the “minimally conscious state”) and thus this definition is being challenged. To avoid this controversy, our preference is to define a poor outcome generally as severe disability with total dependency at 6 months after the arrest. As many patients and their families would likely not choose to continue aggressive measures in the face of such a dismal prognosis, withdrawal of life support often follows. It is essential that the combination of clinical, radiographic, and electrophysiologic tests used to arrive at this conclusion therefore have a false-positive rate (FPR) that is essentially zero.

The neurologic examination following stabilization of the patient should include assessment of the pupillary reaction to light, corneal reflexes, and motor response to command and noxious stimuli. As the brainstem is more resilient than the cortex to anoxic-ischemic injury, brainstem dysfunction usually implies severe cortical injury. Axial myoclonus, defined as bilateral synchronous jerks of the face, trunk, shoulders, or hips, should be noted as it portends a poor prognosis, and these movements should be distinguished from multifocal myoclonus, which is distal, asynchronous, and of no prognostic value. Patients with a purely anoxic insult, as opposed to anoxic-ischemic injury, may recover despite having symmetric myoclonus, perhaps due to a reversible synaptic injury affecting γ-aminobutyric acid type A (GABA-A)-mediated neurotransmission. No neurologic prognostication should occur until a minimum of 24 hours after the arrest; in patients treated with hypothermia, it may take days to establish a prognosis because the lowered temperature affects the clinical and electrophysiologic findings.

Prognostication in the Absence of Therapeutic Hypothermia

Prognostication following cardiac arrest has largely been based on the work of Levy and colleagues, who analyzed a single cohort of 210 patients and identified factors that could accurately predict at various times the development of a poor neurologic outcome. Systematic reviews on the topic have been published. In 2006, the American Academy of Neurology (AAN) published practice parameters that summarized the available literature and provided an algorithm to establish prognosis. After 24 hours, if a patient has absence of all brainstem reflexes, motor responses, and is apneic, ancillary testing can be used to confirm a diagnosis of brain death. In patients who remain comatose but have a less severe neurologic insult, clinical signs and electrophysiologic tests can be used to establish a poor prognosis. The clinical signs that predicted poor neurologic outcome were myoclonus status epilepticus on day 1 (FPR 0%, CI 0–8.8), absence of the pupillary light reflex or corneal reflex on day 3 (FPR 0%, CI 0–3), and best motor response of extension or worse on day 3 (FPR 0%, CI 0–3). Somatosensory evoked potentials (SSEPs) recorded between days 1 and 3 demonstrating bilaterally absent N20 responses also predicted poor outcome (FPR of 0.7%, CI 0–3.7). Serum neuron-specific enolase (NSE) levels greater than 33 μg/L on day 1 to 3 were also a negative prognosticator (FPR 0%, CI 0–3). The practice parameters allow a physician to identify patients who will definitively have a poor neurologic outcome, but it is important to note that many other patients not meeting these criteria will also have a poor outcome.

Caution must be exercised when applying these prognostic criteria to patients who have undergone TH, a well-established confounder of the neurologic and electrophysiologic examination, as the practice parameters were based on literature published before its widespread adoption.

Therapeutic Hypothermia and the Neurologic Examination

In patients treated with TH, the pupillary light reflexes, corneal reflexes, motor responses, serum NSE levels, and presence of axial myoclonus have all been shown to have reduced accuracy for predicting poor neurologic outcome. Rossetti and colleagues prospectively studied a cohort of post-arrest patients undergoing TH in order to evaluate the application of established AAN practice parameters for prognostication. When these patients were examined 72 hours after the arrest, they found higher FPRs for predicting mortality when using the absence of pupillary reactivity (FPR 4%), the presence of axial myoclonus (FPR 3%) and best motor response of extensor posturing or worse (FPR 24%). Al Thenayan and colleagues found that motor response, specifically extensor posturing or worse, was not prognostically reliable at day 3 following TH. In their prospective review, 14 patients had delayed return of the motor response as late as 6 days after cardiac arrest, and two of these patients had favorable outcomes. We have also encountered a patient treated with TH who lacked motor response until day 21 after cardiac arrest.

Axial myoclonus may arise from the cerebral cortex or brainstem. The cortical form, unlike the brainstem form, has a reliable correlate on the electroencephalogram (EEG). Until recently, the presence of axial myoclonus was considered uniformly fatal based on studies in the prehypothermic era, including a series of 11 patients with postarrest axial myoclonus who all died. These patients all had severe damage to various gray matter structures in the brain and spinal cord, demonstrating the cause of death to be anoxic-ischemic insult rather than status epilepticus. Six more recently published cases of good outcome despite axial myoclonus suggest that TH may modify the outcome of a small but significant number of patients who develop axial myoclonus after resuscitation from cardiac arrest. Thus, the presence of this sign is still suggestive of a poor neurologic outcome but should not be used in isolation to prognosticate.

After cardiac arrest many patients have other confounders of the neurologic examination than hypothermia, including cardiogenic shock, metabolic acidosis, and other metabolic derangements. Organ failure, especially hepatic and renal dysfunction, may cause reversible encephalopathy and cloud the predictive power of the neurologic examination. Comatose patients require sedation for presumed pain or distress, ventilator asynchrony, or as part of many hypothermia protocols, and clearance of these drugs may be delayed due to organ dysfunction. TH itself can also result in increased serum concentrations of certain drugs, increased duration of action, and decreased clearance, including with fentanyl, midazolam, propofol, and neuromuscular blocking agents. Use of these types of drugs is indeed common in TH protocols. Samaniego and colleagues found that 83 percent of patients undergoing a hypothermia protocol after cardiac arrest were still receiving at least one sedating agent 72 hours later, in comparison to 60 percent of normothermic patients; both the corneal reflexes and motor responses became unreliable at predicting outcome at 72 hours after arrest if a patient had received a sedating drug within 12 hours of the neurologic examination, regardless of whether they had been treated with TH.

Specifics of the Cardiac Arrest

Characteristics of the cardiac arrest, including anoxia time (the time from onset to initiation of cardiopulmonary resuscitation) and total arrest duration, have been explored as predictors of prognosis. A retrospective review of a cohort of 64,339 patients with in-hospital cardiac arrest identified 8,724 patients with available neurologic outcome data. The duration of resuscitation did not affect neurologic outcome: favorable outcome occurred in 81 percent of patients with a resuscitation time of less than 15 minutes, 80 percent for durations between 15 and 30 minutes, and 78 percent for resuscitation lasting greater than 30 minutes. The Brain Resuscitation Clinical Trial and Study Group found that anoxia time greater than 5 minutes and total resuscitation time exceeding 20 minutes independently predicted mortality. However, even in this study, the presence of prolonged anoxia time or cardiopulmonary resuscitation exceeding 20 minutes did not preclude a favorable neurologic outcome. Among 245 patients, 41 (17%) with anoxia time exceeding 5 minutes had a cerebral performance category of 1 or 2 at outcome assessment but, similarly, 48 of 311 patients (15%) with resuscitation times exceeding 20 minutes also had this favorable outcome. Increased age was associated with increased mortality, but was not an independent predictor of poor neurologic outcome. Although arrest features such as longer anoxia time and duration of resuscitation are associated with poorer outcomes, the false-positive rates are too high to be useful for prognostication purposes.

Electrophysiologic Tests

Electrophysiologic tests, including SSEPs and EEG, can aid in prognostication after cardiac arrest. The most common SSEP measured involves stimulation of the median nerve at the wrist and recording the response over the contralateral scalp, specifically over the primary somatosensory cortex. In a normal adult this response occurs 20 msec from the time of median nerve stimulation and is therefore called the N20 response ( Fig. 9-1 ). During this test, additional electrodes are placed over Erb point (over the brachial plexus) and high on the posterior neck (over the dorsal columns of the spinal cord); stimulation of the median nerve results in responses at these electrodes at approximately 9 msec and 13 msec, respectively. These N9 and N13 responses, along with the N20, examine the continuity of the nervous system from the median nerve through the brachial plexus and high cervical cord to the cortex and reduce false-positive results from conduction problems below the cranium. The AAN practice parameter found that bilaterally absent N20 responses on SSEPs accurately predicted poor outcome with an FPR of 0.7 percent when performed between day 1 and day 3 following arrest. Tiainen and colleagues evaluated SSEPs in post-arrest patients randomized to TH or standard care and found that although TH resulted in delayed latencies of the waveforms, 100 percent of patients with bilaterally absent N20 responses, regardless of whether they had undergone TH, had poor neurologic outcomes. Leithner and colleagues found a slightly lower predictive value in the setting of TH, identifying 1 of 36 patients who, despite bilaterally absent N20 responses after cardiac arrest, eventually regained consciousness. While median nerve SSEPs can still be used to accurately predict outcome, the false-positive rate is not zero, again emphasizing that in patients who have undergone TH, no test should be used in isolation to determine prognosis.