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Survival from out-of-hospital cardiac arrest is becoming an increasingly common occurrence, because of defibrillation initiatives and increased public awareness of basic life support skills.1-4 Two main factors determine survival from an out-of-hospital cardiac arrest: prompt administration of effective cardiopulmonary resuscitation (CPR); and early defibrillation. In addition to increasing the number of victims who survive to discharge, these interventions also allow some individuals to survive who would have otherwise succumbed immediately, only for them to die later because of the sequelae of cerebral hypoxia. Thus, there is an increasing population of cardiac arrest victims who survive with neurological injury. For those who avoid lethal brain injury, the initial priority is the assessment of the risk of further arrhythmic events. This is important because treatments such as revascularisation, antiarrhythmic drugs, and implantable cardioverter defibrillators (ICDs) reduce the risk of subsequent death in some subgroups. Resuscitated cardiac arrest victims present a challenge on two fronts: assessment and treatment of neurological injury, and assessment and intervention to minimise risk of further arrhythmic events. This first article focuses on early management and neurological sequelae of cardiac arrest. The second article in this series focuses on investigating the substrate for cardiac arrest, and interventions that reduce the risk of further arrhythmic events.
After admission, resuscitated cardiac arrest victims may be unstable for several reasons. Nearly half require mechanical ventilation, and aspiration of gastric contents may exacerbate respiratory compromise. Peri-arrest arrhythmias are common, and management guidelines are published by the Resuscitation Council (UK).5 Hypotension can result from the process that leads to the cardiac arrest (for example, myocardial infarction) and from post-resuscitation myocardial stunning, necessitating the use of inotropes or mechanical circulatory support, or both. Many resuscitated cardiac arrest victims are elderly and have serious underlying comorbidity. Essential to their management is involvement of their family at this stage in discussion about treatment. In this way, patients can be managed at a level appropriate to their overall prognosis and quality of life. Age alone should not dictate whether or not intensive treatment is given, since the elderly have almost as good a prospect of survival to discharge as younger patients after initially successful resuscitation.6
Management of specific triggering pathologies (for example, acute myocardial infarction) will be discussed in the second article in this series.
Mechanisms of brain injury during and after cardiac arrest
Data from animal models, and limited human studies of neonatal hypoxia and cerebral hypoperfusion during cardiopulmonary bypass, indicate that brain injury occurs through several mechanisms. Hypoxia itself is the main factor—failure of ATP dependent cell membrane ion transporters leads to influx of calcium into the neuronal cytoplasm, causing cell death. In addition, oxidative stress occurs after resuscitation due to abrupt restoration of tissue blood flow and administration of supraphysiological concentrations of oxygen.7 Free radical mediated tissue injury occurs, leading to microvascular damage and impaired reflow, similar to that seen after coronary reperfusion.8 9 Cerebral oedema may follow, caused by movement of fluid from the intravascular compartment into the hyperosmotic interstitial space.10 Infiltration of tissue by neutrophils may result from release of chemotactic factors and expression of integrins (for example, CD11b/CD18 and ICAM-1), and further tissue injury may occur.11 Finally, neuronal injury may also result from cerebral hypoperfusion after resuscitation caused by reduction in cardiac output. “Watershed” zones (for example, the hippocampus) may be especially prone to injury during and after resuscitation because of their relatively poor blood supply, potentially leading to memory and visio-spatial deficits.
Assessment and management of hypoxic brain injury
Accurate prognostic assessment of cardiac arrest survivors is important because treatment decisions are partly governed by the patient's prognosis. If a given patient is assessed as having zero probability of survival to discharge, treatments such as CPR, antibiotic therapy or organ support may be inappropriate. Conversely, it is important not to deprive patients of these treatments if their prospect of survival is real. Knowledge about the patient's prognosis also helps when counselling their family about the likely outcome.
SPECIFICITY: THE KEY TO PROGNOSTIC ASSESSMENT
Many cardiac arrest victims are admitted to hospital unconscious, with an uncertain prognosis, and are difficult to assess and manage. More than 75% of initially comatose patients die during hospital admission.12 When assessing a patient's prognosis, an important issue is the specificity of the tests used. In other words, it is important for that test to be as certain as possible when it predicts in-hospital death, otherwise the patient could be denied treatment when their prospect of survival is not hopeless. Sensitivity is less important; no prognostic test can identify all patients who will die in hospital, because death occurs from many causes—cerebral hypoxia, arrhythmias, pump failure, sepsis, etc. Many methods have been evaluated for assessing the prognosis of cardiac arrest victims. These include clinical algorithms, neurophysiological tests, and tests which quantify structural brain injury.
Clinical assessment aids risk stratification of cardiac arrest victims. The Glasgow coma score (GCS) has been evaluated in several studies.12 Although a low admission GCS identifies patients at greatest risk of in-hospital death, in most studies high specificity is only achieved when the GCS is measured three to five days after admission. Even then, patients with an intermediate GCS have an indeterminate prognosis. Its utility is limited in ventilated patients and in patients treated with sedation and neuromuscular blockade. A more sophisticated scoring system, incorporating variables such as pupil response, doll's eyes reflex, blink reflex, and presence or absence of seizures, was developed by Levy, based on data from more than 200 patients with hypoxic-ischaemic coma. From these data a flow chart algorithm has been developed to predict prognosis at different time points after cardiac arrest (fig 1).13 In particular, persistent absence of the pupillary reflex predicted either death or severe neurological disability with absolute specificity. This type of algorithm is useful, and requires consistency in examination technique, but it is also of limited use in patients receiving sedation or neuromuscular blockade.
The two main techniques for neurophysiological assessment are electroencephalography (EEG), which measures cerebral electrical activity at rest, and cerebral evoked potentials, measured in response to defined stimuli. Specific EEG findings, such as the alpha coma, burst suppression, and isoelectric patterns, have been identified with an adverse prognosis.14 These lack specificity, with some patients surviving despite their presence. In contrast cerebral evoked potentials, such as the cortical response to median nerve stimulation, can reliably identify subgroups with a poor prognosis with a specificity that is superior to clinical algorithms and to the EEG.
QUANTITATION OF BRAIN INJURY
Clinical and neurophysiological techniques rely on assessing brain function. An alternative approach is to estimate the magnitude of the brain injury caused by cardiac arrest. Magnetic resonance imaging and computerised tomography are of limited use, and can usually only detect gross abnormalities such as watershed infarcts or intracranial haemorrhage. Brain injury can also be measured using biochemical markers in a manner analogous to that of cardiac enzymes in myocardial infarction. Two markers appear promising from recent trials—protein S-100 (a glial protein), and neuron-specific enolase (NSE). One early report indicated that a serum NSE concentration greater than 33 μg/l measured within a week of cardiac arrest had a sensitivity of 80% and a specificity of 100% for persistent coma.15 Estimation of serum S-100 concentration as early as 24 hours after cardiac arrest identifies a subgroup with an apparently hopeless prognosis (S-100 concentration ⩾ 0.7 μg/l).16 These findings are based on small cohorts and require confirmation in a larger scale study before they can be applied to clinical decision making.
DO ADJUNCTIVE TREATMENTS IMPROVE PROGNOSIS?
Several adjunctive treatments have been evaluated in attempts to limit brain injury after cardiac arrest. These include administration of glucose (as a substrate for brain metabolism), dexamethasone and mannitol (to reduce osmotic load and cerebral oedema), barbiturates (to reduce cerebral oxygen demand), and nimodipine (to improve cerebral blood flow and to reduce entry of calcium into neurons). None of these agents has been conclusively shown to improve outcome. Preliminary data suggest that induction of mild hypothermia during cardiac arrest affords a degree of cerebral protection, but it is difficult to envisage how this could be practically applied.17 Perhaps the most encouraging development in neuroprotection relates to experimental evidence of limitation of brain injury with antioxidant agents, notably the 21-aminosteroid tirilazad.18 Since oxidative stress can persist for several hours after cardiac arrest, such agents may in future have a role in neuroprotection.
QUALITY OF SURVIVAL: IS RESUSCITATION WORTH THE EFFORT?
Cardiac arrest victims may survive after a prolonged but non-lethal period of cerebral hypoxia. The resulting neurological injury can be severe enough to affect cognitive function and to compromise patients' independence. Overt neurological deficits are surprisingly uncommon, affecting less than 5% of patients. Cognitive dysfunction is more prevalent, affecting between 20–50% of patients.19 Memory impairment is common and may affect the patient's ability to return to work and to perform daily activities. Despite this, most out-of-hospital cardiac arrest survivors are functionally independent and have intact cognitive function.
Cardiologists and intensivists can expect to care for a growing population of out-of-hospital cardiac arrest survivors. Most are unconscious on admission to hospital. Although early awakening is associated with a good neurological prognosis, the prognosis of those who remain comatose is difficult to assess, and management decisions are difficult. Clinical prognostic scoring systems and cortical evoked potentials help in their evaluation, and can assist when planning counselling of relatives. Figure 2 summarises the key elements of early management. There is a need to develop more reliable methods of prognostic assessment that are specific at identifying patients who have a hopeless prognosis at an early stage, ideally on the first day of admission. For those who survive, identification of the cause of cardiac arrest is central to assessment of future risk and in planning their management.