Neurologic Complications of Cardiac Arrest

Hypoxic-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, 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.

Distinct 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.

Targeted Temperature Management

The use of 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). Patients randomized to moderate hypothermia (32° to 34°C) had a more favorable neurologic outcome, defined as Cerebral Performance Category (CPC) 1 (normal) or 2 (moderate disability), compared with controls randomized to standard care. 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.

However, whether the therapeutic benefit observed in these trials was due to TH or fever prevention remained unclear until publication of the targeted temperature management (TTM) trial in 2013. This study randomized patients to moderate hypothermia (32° to 34°C) or 36°C for 24 hours, followed by 48 hours of fever prevention using acetaminophen and surface cooling in both groups. No difference was observed in outcome, with 46 to 48 percent of patients in both groups achieving a CPC of 1 or 2 at 6 months, a rate similar to that observed in the treatment arms of both 2002 TH studies. This study is the basis for current guidelines that recommend a target temperature of 32° to 36°C for 24 hours, followed by 48 hours of fever prevention.

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. Conversely, fever may exacerbate brain injury following cardiac arrest due to increased glutamate production and excitotoxicity, increased cerebral metabolism, blood–brain barrier permeability leading to hyperemia, cerebral edema, and increased intracranial pressure.

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 those patients who will have severe neurologic deficits with complete dependency at 6 months. Because many patients and their families choose withdrawal of life support when faced with this unfavorable prognosis, it is essential that the combination of clinical, radiographic, and electrophysiologic tests used to arrive at this conclusion therefore have a positive predictive value (PPV) as close to 100 percent as possible.

Much of the published literature attempts to predict which patients will have a CPC of 3 or greater 6 months after cardiac arrest. Such an outcome includes death, vegetative state, and severe disability with dependency on caregivers for daily support. However, because studies of prognosis after cardiac arrest include patients whose families elected to withdraw life support, the true range of long-term functional outcomes remains unknown and the prognostication algorithms discussed in this chapter suffer from the risk of self-fulfilling prophecy. In addition, because studies tend to group CPC 3 to 5 and label them all “unfavorable,” distinguishing between the possibility of severe disability with dependency but some retained ability to communicate or even ambulate (CPC 3) and a persistent vegetative state or death (CPC 4 or 5) remains difficult. Further complicating prognosis and blurring the lines of what some consider meaningful recovery is the discovery through functional brain imaging techniques that some patients in a persistent vegetative state retain awareness and potentially even comprehension of spoken language.

Most studies of prognosis after cardiac arrest report false-positive rates (FPRs), yet this is a difficult number to translate for families. In prognostic studies, true positives are generally defined as patients with a poor prognostic sign who have a poor outcome, and false positives are those with a poor prognostic sign who have a good outcome. The FPR (or 1-specificity) is determined by dividing the number of false positives by the number of patients who had a good outcome. In lay terms this can be stated as the percentage of patients with good outcome who had the poor prognostic sign, a number that carries little practical meaning. The PPV provides more clinically relevant information: the percentage of patients with a poor prognostic sign who have a poor outcome. Surrogate decision-makers want to know (1–PPV), or the chance that a patient with the poor prognostic sign will still have a good outcome. When there are more patients with a good outcome than patients with a specific poor prognostic sign, (1–PPV) is often larger than the FPR, and thus the FPR can be misleadingly low.

No neurologic prognostication should occur until a minimum of 24 hours after the arrest; in patients treated with TTM, it may take days to establish a prognosis because both the lowered temperature and associated sedation required may profoundly affect clinical and electrophysiologic findings. The neurologic examination should be performed approximately 72 hours after the arrest and all sedatives should be discontinued with enough time for them to have reliably cleared from the body. The examination should focus on the level of consciousness, the pupillary light reflex, corneal reflex, spontaneous eye movements, the oculocephalic reflex, and the motor response to central and peripheral painful stimuli. Quantitative pupillometry is less likely to mistake minimally reactive pupils for unreactive pupils and is therefore preferred to the standard pupillary light reflex. The presence of status myoclonus, defined as spontaneous, repetitive, unrelenting, and generalized myoclonus affecting the face, limbs, and axial musculature lasting more than 30 minutes should be noted. Electroencephalography and somatosensory evoked potentials (SSEPs) are performed after rewarming, between 24 and 72 hours after the arrest, and serum neuron-specific enolase can be measured at 24, 48, and 72 hours. The combination of clinical, electrophysiologic, and serum biomarker data derived from these tests forms the basis of the modern multimodal approach to prognostication.