Prognostication after cardiac arrest (CA) can be a challenging and complex task. Many patients and their surrogates would consider limiting care if there is no hope for meaningful neurologic recovery. Therefore, it is important for medical providers to be aware of the prognostic possibilities at all stages of care so that accurate information can be provided to family and informed decisions can be made. Ideally, variables used for prognostication should accurately predict with high specificity which patients have a universally poor prognosis. In other words, we want to make sure that close to 100% of those labeled as having a poor prognosis do in fact have no chance of meaningful recovery.

Unfortunately, most elements of the neurologic examination immediately after CA lack sufficient predictive value to provide accurate outcome prediction.^1-3 Prognostication based solely on a clinical examination within hours after CA is not recommended.

After a complete cessation of cerebral perfusion, cerebral oxygen is rapidly depleted. Within 20 seconds, electroencephalography (EEG) shows electrocerebral silence.^4,5 Cerebral adenosine triphosphate (ATP) and glucose stores are consumed within 5 minutes, resulting in dysfunction of ion pumps and channels, and loss of transmembrane sodium, potassium, and calcium gradients.^5-7 Membrane depolarization results in excessive release of excitatory neurotransmitters, which in turn leads to further accumulation of intracellular calcium. Calcium overload results in the activation of lipases, proteases, nucleases, and other destructive enzymes.⁸ Bulk inflow of ions brings with it water, which results in cell swelling. Free-radical production dramatically increases.⁸ Systemic and local anaerobic metabolism results in neuronal acidosis, leading to deranged function of a wide variety of proteins.⁹ Hyperglycemia can worsen this acidosis.^10,11 The process of cell death can begin as little as 1.5 to 5 minutes after complete cessation of cerebral blood flow (CBF), particularly within sensitive cell populations such as the CA1 hippocampal pyramidal neurons, cerebellar Purkinje neurons, medium spiny striatal neurons, and pyramidal neurons in layers 3, 5, and 6 of the neocortex.^12-14

Reperfusion is essential for the continued survival of neurons and leads to a rapid increase in ATP levels and re-establishment of ionic gradients.¹⁵ Unfortunately, reperfusion also results in further damage. Arachidonic acid and other free fatty acids, which are released by lipases during ischemia, undergo rapid oxidation. This leads to the production of superoxide radicals.^16-18 Xanthine dehydrogenase is converted to xanthine oxidase, which results in additional superoxide radical production.¹⁹ Free iron released from damaged proteins catalyzes the destructive peroxidation of membrane lipids by superoxide radicals.^20,21 Superoxide also reacts with nitric oxide to form peroxynitrite, which is not a free radical but is a potent oxidizer. The damaging effects of peroxynitrite and xanthine oxidase may be particularly important in vascular endothelium, leading to increased permeability of the blood-brain barrier and impairment of vascular reactivity.^22,23

Numerous interventions have been studied to block the neurotoxic cascade after both global and local ischemic cerebral insults. Most of these have targeted specific steps in the cascade; for example, free-radical scavenging or calcium channel blockade. Despite promising animal studies, all drugs studied in humans have failed to show any clear benefit, including calcium channel blockers, barbiturates, benzodiazepines, magnesium, and glucocorticoids.^24-29 To date, only hypothermia has been shown to improve outcome after CA.

Hypothermia after cardiac arrest (HACA) was initially studied in humans in the late 1950s, with some degree of possible success.^30,31 Peter Safar documented his use of HACA to 30°C in routine clinical practice during the 1950s and 1960s.³² Despite this, additional human trials with HACA were not performed until the 1990s, when 3 small pilot studies showed mild HACA to be safe and feasible.^33-35

In 2002, an Australian group published the results of a 77-patient controlled trial of hypothermia vs normothermia after out-of-hospital cardiac arrest (OHCA).³⁶ They included men older than 18 years and women older than 50 years whose initial rhythm was VF and who remained comatose after spontaneous circulation was successfully re-established. Coma was not defined. Patients were excluded if they had a systolic pressure < 90 mm Hg despite vasopressors or if there was another possible cause of coma. There was no true randomization—on odd-numbered days, patients were assigned to hypothermia. Paramedics applied ice packs to the head and torso in the field. On arrival at the ED, all patients received initial doses of midazolam and vecuronium as well as lidocaine infusion to prevent recurrent ventricular arrhythmia. They maintained a mean arterial pressure (MAP) of 90 to 100 mm Hg, partial pressure of oxygen in blood (Pao₂) of 100 mm Hg, partial pressure of carbon dioxide in blood (Paco₂) of 40 mm Hg, and blood glucose < 180 mg/dL. Hypothermia patients had additional ice packs applied and maintained until core temperature reached 33°C. Additional midazolam and vecuronium were given as needed for shivering. At 18 hours, the patients began to be actively rewarmed with heated-air blankets. Normothermia patients were maintained at 37°C throughout this period.

The primary outcome measure was good neurologic outcome, defined as discharge home or to an acute rehabilitation facility. Significantly fewer patients in the hypothermia group received bystander CPR. Despite this, 49% of hypothermia patients had a good outcome compared with 26% of normothermia patients (P = .046). Mortality (51% vs 68%) was not significantly different. There were no reported deleterious consequences of hypothermia.

Holzer et al carried out a larger, more rigorous 275-patient trial of HACA conducted through 9 centers in 5 European countries.³⁷ Patients 18 to 75 years old who had a witnessed OHCA were included if they had VF or nonperfusing ventricular tachycardia (VT) on the arrival of the paramedics, 5 to 15 minutes of downtime before commencement of CPR, and no more than 60 minutes from CA to ROSC. Patents were excluded if they had a temperature below 30°C, sustained hypoxia or hypotension before randomization, or known impediments to long-term follow-up. No specific treatment was initiated before ED arrival. Randomization was via envelope-concealed, computer-generated treatment assignments. All patients received pancuronium, fentanyl, and midazolam for 32 hours. Hypothermia patients were placed in an air-cooling device that enveloped their body, with a goal temperature of 32°C to 34°C. Ice packs were added if needed. Hypothermia was maintained for 24 hours from initiation, and then patients were allowed to passively rewarm. Control patients were maintained at a goal of normothermia.

The primary outcome measure was good neurologic outcome at 6 months, as defined by a Cerebral Performance Category (CPC) (Table 11-1) of 1 or 2. CPC scoring was determined by a blinded examiner. Just as in the Australian HACA trial, bystander CPR was performed on significantly fewer hypothermia patients. Good outcome was attained by 55% of hypothermia patients compared with 39% of normothermia patients (P = .009). Fewer hypothermia patients were dead at 6 months (41% vs 55%; P = .02). There was no significant difference in any of the tracked complications.

After the publication of these two controlled trials, the International Liaison Committee on Resuscitation (ILCOR) Advanced Life Support Task Force published the following recommendations³⁸:

Similar recommendations remain in the 2010 ILCOR CPR guidelines.³⁹ A Cochrane review pooling individual data from the above two randomized controlled trials (RCTs), plus data from a 30-patient RCT of helmet cooling,⁴⁰ found an odds ratio of 1.55 (95% confidence interval, 1.22 to 1.96) for good outcome at hospital discharge, with no significant difference in complications.⁴¹

The results of another influential trial on targeted temperature management (TTM) were released in 2013. Nielsen et al⁴² sought to investigate whether TTM to 36°C would be as effective as mild hypothermia to 33°C. Adult patients (N = 950) presenting after OHCA to 36 centers in Europe and Australia were randomized to the two different temperature targets. In contrast to previous trials, any initial cardiac rhythm was included. Patients were maintained at the target temperature for 36 hours after randomization, and then all patients were rewarmed to 37°C and maintained at < 37.5°C until 72 hours after CA. At the end of the trial, there was no significant difference in mortality between the 33°C (50%) and 36°C (48%; P = .51) groups. There were also no differences in poor neurologic outcome based on CPC score 3-5 or modified Rankin Scale 4-6 at 180 days. Of note, 20% of patients in this trial presented with nonshockable rhythms, in contrast to the previously mentioned hypothermia trials.

Key features of the TTM trial included mandatory sedation during the intervention period to reduce bias based on clinical exam, as well as a protocolized approach by a blinded evaluator for prognostication and recommendation for withdrawal of care. Perhaps most importantly, this trial was more effective in preventing fever than the previous HACA trials. There were no differences in serious adverse events or causes of mortality between the two groups; hypokalemia was more common in the 33°C group. Although this does not negate the neuroprotective effect of hypothermia in comatose survivors of CA, it does suggest that a more liberal goal of 36°C with aggressive fever control may have a similarly beneficial effect.

Hypothermia has multiple effects on the brain and the toxic cascades after hypoxia-ischemia, which differentiates it from prior failed therapies. Polderman described the numerous, interrelated effects of hypothermia on the injured brain, observed primarily in animal studies.⁴³ These are divided into early and late mechanisms of action, as summarized in Figure 11-1. At 33°C, cerebral metabolic rate (CMR) is reduced by nearly 50%. The reduction in CMR leads to decreases in the CBF threshold for ischemia, cerebral volume, and free-radical production. More energy is available for restoration and maintenance of neuronal ionic gradients, in turn reducing calcium overload, intracellular acidosis, and continued accumulation of glutamate. Oxidation from free radicals and peroxynitrite proceeds at a slower rate. Hypothermia reduces disruption of the blood-brain barrier and improves endothelial function, thereby attenuating cerebral edema and intracranial hypertension. Thromboxane A₂ and endothelin-1 levels are decreased, lessening vasoconstriction. A systemic inflammatory response and activation of coagulation normally occur after ROSC, and these are both attenuated by hypothermia.⁴⁴ This may reduce cerebral microvascular thrombosis, in turn reducing ongoing ischemia. Activation of caspases is reduced, resulting in improved mitochondrial function and sparing some neurons from apoptosis. Finally, convulsive and nonconvulsive seizures occur commonly after CA, and hypothermia has been observed to have an antiepileptic effect in both animals and humans.⁴⁵

Table 11-2 lists some methods of cooling and TTM. Some modalities are more suitable for either induction (eg, ice-cold saline) or maintenance (eg, conventional cooling blankets). Some modalities are more likely to result in overcooling (eg, ice packs), which can lead to treatment complications such as bleeding and arrhythmias.⁴⁶ Cost, convenience, and effectiveness of each method need to be taken into consideration. Automated systems with patient temperature feedback are ideal from a convenience and effectiveness standpoint, but may carry greater cost.

The majority of studies on temperature management after CA have initiated therapy upon arrival at the hospital.^36,37,42 In theory, starting therapy as early as possible before the patient even arrives at the hospital could potentially prevent early injury after ROSC. Bernard et al investigated whether early prehospital induction of hypothermia could improve outcomes after VF⁴⁷ and non-VF⁴⁸ OHCA. Paramedics administered ice-cold IV saline infusion in the field prior to hospital arrival, at which time all patients were cooled according to the same hypothermia protocol. Although prehospital cooling was effective at significantly lowering patient temperature at the time of arrival at the ED, there were no observed differences in favorable outcome at the time of hospital discharge. A larger trial of 1359 patients with OHCA of all causes found similar results; prehospital cooling successfully lowered the temperature at the time of presentation, but was not associated with improved neurologic outcome or survival.⁴⁹ However, the treatment group had a higher rate of repeat CA in the field, longer time to ED arrival, and greater incidence of early pulmonary edema and diuretic use. At this time, a safe and reasonable approach is to start TTM at the time of hospital arrival.

The optimal duration of TTM has not been clearly defined. At a goal of 33°C, 24 hours is a generally accepted time frame. The Safar group attained its best brain histology results with a 12-hour protocol of mild hypothermia.⁵⁰ Colbourne and Corbett conducted a series of experiments with gerbils, in which the best long-term histologic and functional outcomes were attained with 24 hours of mild hypothermia.^51,52 Prolonged hypothermia was also safe and efficacious in rats.⁵³ The aforementioned human pilot studies and subsequent phase III trials were based on these temperatures and durations.^33-37 The European HACA trial,³⁷ the larger and more rigorously conducted of the two pivotal trials, maintained mild hypothermia for 24 hours.

On the other hand, fever control appears to be vitally important in recovery, and a TTM goal of normothermia could be easily maintained for a longer duration of time. In the Nielsen trial, rewarming began at 28 hours, but TTM of < 37.5°C was continued for 72 hours.⁴² As this has been shown to be as effective as hypothermia to 33°C, this is a reasonable alternative approach. It is unknown at this time if there is any benefit to continuing TTM for longer periods of time.

RCTs of mild HACA have not shown any significant complications.^36,37 Hypokalemia, hyperglycemia, and cold diuresis are known to occur with mild hypothermia. Hypothermia < 32°C can lead to bradycardia and ventricular arrhythmias, low cardiac function, immunocompromise, coagulopathy, and increased blood viscosity.⁵⁴