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Hypoxic-ischemic brain injury in adults: Evaluation and prognosis

Hypoxic-ischemic brain injury in adults: Evaluation and prognosis
Authors:
Gerald L Weinhouse, MD
G Bryan Young, MD, FRCPC
Section Editors:
Michael J Aminoff, MD, DSc
R Sean Morrison, MD
Deputy Editor:
Janet L Wilterdink, MD
Literature review current through: Nov 2022. | This topic last updated: Jun 02, 2020.

INTRODUCTION — Hypoxic-ischemic brain injury most often results from insults such as cardiac arrest, vascular catastrophe, poisoning (such as carbon monoxide intoxication or drug overdose), or head trauma. While many patients expire without recovering awareness, improved techniques in resuscitation and artificial life support have resulted in greater numbers of patients surviving with variable degrees of brain injury. The evolution of hypothermic treatment for comatose survivors of cardiac arrest has furthered the potential to improve neurologic morbidity and lessen mortality following anoxic brain injury [1-3].

While progress has also been made in the early identification of patients at greatest risk of poor neurologic outcome after cardiac arrest, reliable prediction of good outcomes, with intact memory and independence, has lagged. The evaluation and prognosis of patients with nontraumatic hypoxic-ischemic brain injury are reviewed here.

CLINICAL STATE AND TERMINOLOGY — Coma is defined as a state of pathologic unconsciousness; patients are unaware of their environment and are unarousable. It is caused by either dysfunction of the reticular activating system above the level of the mid-pons or dysfunction of both cerebral hemispheres. Physical examination permits localization of the level of central nervous system dysfunction [4,5]. (See 'Prognosis assessed on clinical features' below.)

Coma must be distinguished from the persistent vegetative state (PVS), which is also characterized by unawareness, but in which patients have normal sleep-wake cycles and are arousable. Patients in a coma may progress to a vegetative state, but this may not be associated with an improvement in their overall functional outcome. Both coma and PVS must be distinguished from brain death, locked-in syndrome (a condition in which the patient is awake and aware but cannot move or communicate due to muscle paralysis), akinetic mutism (a condition resulting from frontal lobe injury in which the patient does not initiate speech or movements), and dementia (table 1) [4,6]. (See "Stupor and coma in adults", section on 'Conditions mistaken for coma'.)

The vegetative and minimally conscious states (MCS) are clinically defined syndromes. Importantly, prognosis for recovery can vary depending on the underlying etiology and differs between patients who have hypoxic-ischemic versus traumatic brain injury [7].

Brain death — Brain death (death by brain criteria) is defined as the irreversible cessation of cerebral and brainstem function. There is no respiratory drive, and thus there are no spontaneous breaths regardless of hypercarbia or hypoxemia. There are no responses arising from the brain (including cranial nerve reflexes and motor responses) to stimuli, although spinal reflexes may persist [8]. One is legally dead in the United States when criteria for brain death have been demonstrated. (See "Diagnosis of brain death".)

In some cases, patients who meet brain death criteria may be potential organ donors; issues specific to the management of these individuals are discussed separately. (See "Management of the deceased organ donor".)

Persistent vegetative state — Patients in a PVS represent a subgroup of patients who suffer severe anoxic brain injury and progress to a state of wakefulness without awareness. A vegetative state may represent a transition between coma and recovery or between coma and death. The term was first used in 1972 and is defined as [4,6,9-12]:

No evidence of awareness of self or environment and an inability to interact with others

No evidence of sustained, reproducible, purposeful, or voluntary behavioral responses to visual, auditory, tactile, or noxious stimuli

No evidence of language comprehension or expression

Intermittent wakefulness manifested by the presence of sleep-wake cycles

Sufficiently preserved hypothalamic and brainstem autonomic function to permit survival with medical and nursing care

Bowel and bladder incontinence

Variably preserved cranial nerve reflexes and spinal reflexes

If a patient remains comatose, the usual outcome is recovery, PVS, or death within two weeks. On the basis of available clinical data, PVS is judged to be permanent after three months if induced nontraumatically. For traumatic brain injury, a year in this state is generally required to be considered permanent [7]. Most data indicate that after three months in a PVS related to hypoxic-ischemic injury, recovery is rare and is associated with moderate to severe disability at best [13,14]. With the use of ancillary testing it is often possible to arrive at reliable prognostic conclusions in much shorter intervals of time following cardiac arrest. (See 'Ancillary testing' below.)

The distinction between PVS and MCS can be difficult. Careful and repeated bedside testing has been reported to reveal evidence of awareness and voluntary responses in patients originally believed to be in a PVS.

Functional magnetic resonance imaging (fMRI) studies have revealed that a small proportion of patients with traumatic brain injury who satisfied the above criteria for vegetative state show evidence of awareness [15-19]. In these studies, patients were verbally instructed to imagine either a motor activity (playing tennis) or a visual exercise (alternately looking at rooms in their homes). Patients who responded showed increased blood oxygen level determination (BOLD) signal in the motor or visual centers in the cerebral hemispheres to the appropriate question [16]. These binary responses were also used to generate yes/no answers to questions [15]. Similarly, another study found electrophysiologic responses to an auditory cognitive paradigm in two patients with PVS after traumatic brain injury and acute disseminated encephalomyelitis [20]. Another small case series found that 3 of 16 patients with PVS were able to repeatedly and reliably generate appropriate electroencephalography (EEG) responses to two distinct commands, despite being behaviorally unresponsive [21]. While these signs of awareness are more often observed in patients with PVS after traumatic brain injury, they have been described in nontrauma cases as well, including at least one case of hypoxic-ischemic injury [21,22]. These studies have raised concern about the possibility of awareness in patients who are diagnosed with PVS, and it may be more appropriate to communicate predictions regarding outcome in terms of levels of disability, which can be reliably determined using clinical, radiologic, and electrophysiologic evaluation [23].

In patients who continue in PVS, life expectancy is approximately two to five years, and most patients die from infection of the lungs or urinary tract, multiorgan system failure, sudden death of unknown cause, respiratory failure, or underlying disease. It is estimated that there are 10,000 to 25,000 adult patients in PVS in the United States, generating an estimated annual cost of care of up to seven billion dollars.

Minimally conscious state — The term "minimally conscious state" has been proposed to describe patients who do not meet criteria for PVS [24]. As with PVS, these patients have a severe alteration in consciousness. In contrast to PVS, they may intermittently demonstrate limited interaction with the environment by visually tracking, following simple commands, signaling yes or no (not necessarily accurately), or having intelligible verbalization or restricted purposeful behavior. In one series, patients in an MCS demonstrated sleep-wake cycles with both slow-wave and rapid eye movement (REM) sleep, while patients in PVS did not [25]. The Coma Recovery Scale-Revised (CRS-R) appears to be a useful tool to aid clinicians in soliciting responses to stimuli that distinguish patients in PVS from those in MCS [22,26,27]. (See 'Predictive features in the subacute setting' below.)

Follow-up data on this group of patients are limited; they are believed to have a somewhat less severe injury and less dire prognosis than patients with PVS [28,29]. However, data on late recovery of patients in MCS are largely reported in traumatic, rather than anoxic, brain injury [30-32]. One case series of 39 minimally conscious patients included seven with a primary etiology of hypoxic-ischemic encephalopathy [13]. Five years after coma onset, only one of these seven patients had emerged from this state compared with one-third of the patient group overall. In this case series, the best recovery from the MCS was characterized as severe disability.

Because MCS may represent a group of patients with a better prognosis after brain injury, clinical investigations have been undertaken to ascertain specific clinical and diagnostic test features that might reliably distinguish between patients with MCS and PVS, and also that might identify patients in both groups that have either a better or a worse prognosis for late recovery [33]. While these require further study, those that show promise include advanced neuroimaging techniques (including positron emission tomography [PET], fMRI, and diffusion tensor imaging) [34,35] and electrophysiologic studies [21,22,36,37], as well as clinical scales such as the CRS-R [36,38].

PROGNOSIS ASSESSED ON CLINICAL FEATURES

Clinical setting — A thorough history from the patient's family members or health care providers is essential to the assessment, although in some cases it may be impossible to obtain. The time and pace of onset, history of drug and medication use, prodromal symptoms, and duration of resuscitation and presumed cerebral hypoxia assist in determining both the etiology and the prognosis of a given patient's condition [39]. However, none of these factors are sufficiently reliable to differentiate those with poor outcomes (no greater than persistent vegetative state [PVS]) from those patients who regain awareness.

The circumstances of cardiopulmonary resuscitation (CPR) can affect prognosis after a cardiac arrest in terms of both survival and quality of life. In one study of out-of-hospital cardiac arrest, 44 percent of patients receiving CPR survived initially, 30 percent were alive at 24 hours, 13 percent at one month, and only 6 percent were alive after six months. The duration of CPR significantly correlated with outcome; no patient who required more than 15 minutes of CPR survived more than six weeks [40]. (See "Prognosis and outcomes following sudden cardiac arrest in adults".)

In other studies, variables such as age >70, stroke or renal failure prior to admission, fever within the first 48 hours, and recent congestive heart failure were associated with a poor prognosis; by contrast, factors such as a witnessed arrest and an initial rhythm of ventricular fibrillation (VF) or tachycardia have correlated with a better prognosis [39,41,42].

Prognosis based on clinical findings — Some features of the physical and neurologic examinations are helpful in determining prognosis (table 2 and table 3) [40,43,44]. (See "The detailed neurologic examination in adults" and "Stupor and coma in adults", section on 'Neurologic examination'.)

Predictive features in the acute setting — Physical assessment should include documentation of:

Presence or absence of spontaneous movements

Response to voice, light touch, and painful stimuli

Pupillary size and response to light

Other cranial nerve function, including corneal and oculovestibular reflexes

Respiratory pattern (spontaneous, ataxic, etc)

A number of clinical series and systematic reviews have assessed the utility of specific clinical findings in predicting outcome from anoxic brain injury. A Glasgow Coma Scale (GCS) score (table 4) of ≤4 within the first 48 hours has been associated with poor outcome (death, persistent coma) [45,46]. In other series, absent corneal or pupillary light reflexes at 24 hours and absent motor responses at 24 or 72 hours have also been associated with poor prognosis (severe neurologic disability or death) [39,43].

For making decisions regarding withdrawal of life support, statistically significant associations are inadequate. Two systematic reviews have concluded that two clinical criteria have each been found to be 100 percent specific for poor outcome in the absence of confounding factors [39,47]:

Absent or extensor motor response on day 3

Absent pupillary or corneal reflexes on day 3

Confounding factors — These assessments may be confounded, and their sensitivity and specificity for prognosis reduced, in the setting of specific treatments and comorbid conditions:

Medications (eg, anticholinergics used in resuscitation or sedative, paralytic agents used after arrest)

Acute metabolic derangements, especially acute renal or liver failure or shock

Induced hypothermia may also impact test reliability (see "Initial assessment and management of the adult post-cardiac arrest patient", section on 'Temperature management')

As an example, in a series of 111 patients treated with therapeutic hypothermia, neither of the clinical criteria were 100 percent specific for poor outcome [48]. The presence of both of these criteria was specific for poor outcome. Additional studies and a meta-analysis have shown that loss of motor responses better than extension on day 3 was not prognostically reliable in this setting (with a false-positive rate of 21 percent), while absent pupillary and corneal reflexes on day 3 remained predictive of no recovery [49-52].

In patients with one of these confounding variables, ancillary testing may be helpful. (See 'Ancillary testing' below.)

Predictive features in the subacute setting — The Coma Recovery Scale-Revised (CRS-R), a revision of the original Coma Recovery Scale (CRS) comprises six subscales addressing auditory, visual, motor, oromotor, communication, and arousal functions [53,54]. The subscales are arranged hierarchically with the lowest scores for no or reflexive responses; the highest scores indicate cognitively mediated behaviors. Scoring is done in a standardized fashion. The CRS-R and guidelines on its use are available at the Center for Outcome Measurement in Brain Injury.

The CRS and CRS-R have been validated in studies of patients who have survived traumatic brain injury as well as hypoxic-ischemic or ischemic brain damage and provide prognostic information [55-59]. For example, the change in aggregate CRS score from insult to four weeks out showed a stronger association with outcome at one year than did the Disability Rating Scale or the GCS [57]. It thus has a potential application in the acute phase of illness and recovery [36,60].

Myoclonic status epilepticus — Persistent bilaterally synchronous myoclonus in the face, limbs, and axial musculature is usually associated with in-hospital death or poor outcome, even in patients with intact brainstem reflexes or some motor response [61-64]. In a postmortem study, myoclonic status epilepticus (MSE) was associated with severe ischemic brain, brainstem, and spinal cord damage, a pattern that is distinct from the neuropathology of status epilepticus [65]. Clinicians should be careful to distinguish MSE (bilaterally synchronous twitching of axial structures, often with eye-opening and upward deviation of the eyes) from multifocal myoclonus and generalized tonic-clonic seizures, which are not reliably helpful in prognostication.

However, increasing evidence suggests that the presence of MSE has insufficient negative prognostic power when considered in isolation. Cases with good recovery have been reported in patients with MSE in whom circulatory arrest was secondary to respiratory failure [39,66-68]. In some of these, accumulation of sedative agents could have been confounders, and in others, the myoclonus was not clearly generalized and persistent, and may have been sporadic. One systematic review of three series that examined MSE as a prognostic factor found that it did not have sufficient predictive ability for poor outcome [43], while another concluded that in the setting of primary circulatory arrest, MSE within the first day reliably identifies patients with a poor neurologic outcome [39]. In another case series, the authors report functional recovery in six patients with MSE; all had received hypothermia treatment and had intact brainstem function at 36 hours, reactive background activity on electroencephalography (EEG), and intact cortical responses on somatosensory evoked potential (SSEP) [69]. In addition, two of four patients with only EEG evidence of MSE recovered, while 23 of 24 patients with electroclinical MSE did not awaken. Thus, the presence of MSE should be considered in the context of other clinical features in making decisions to withdraw or maintain care.

ANCILLARY TESTING — Several tests have been studied in the period after anoxic injury; these are often helpful at arriving at an earlier prognostic determination than would be possible with clinical testing alone. Of the available tests, bilaterally absent somatosensory evoked responses at 24 to 72 hours appears to be most useful to identify those with a poor prognosis. While very specific, these signs are not very sensitive for poor neurologic outcome.

No single evaluation or finding should be considered in isolation; most experts recommend a multimodal approach to assessment that considers the clinical setting and findings on physical examination, along with the results of available testing, particularly somatosensory evoked potentials (SSEPs) and electroencephalography (EEG) [70,71].

Somatosensory evoked potentials — SSEPs are the averaged electrical responses in the central nervous system to somatosensory stimulation. Bilateral absence of the N20 component of the SSEP with median nerve stimulation at the wrist in the first week (usually between 24 and 72 hours) from the arrest has a pooled likelihood ratio of 12.0 (95% CI 5.3-26.6) and a false-positive rate of 0 percent for an outcome no better than PVS [36,39,47,62,72-77]. Repeated testing should be considered when the N20 responses are present in the first two to three days from the cardiac arrest, as they may later disappear.

In a multicenter cohort, the interobserver agreement of SSEP interpretation in patients with hypoxic-ischemic coma was only moderate [78]. Noise level strongly influenced interobserver disagreement. Despite this finding, an absent N20 was still 100 percent predictive of a dismal outcome (ie, no better than persistent coma) [76].

The presence of the N20 responses, however, does not assure a good outcome. Approximately one-half of patients with a preserved N20 response on SSEP testing still die without recovering consciousness [39]. Although some studies have suggested that the presence or absence of the long latency response, N70, on SSEP can add to the prognostic ability of SSEP in this group of patients [79], a multicenter cohort study did not confirm this finding [76].

Induced hypothermia may slow conduction velocities and alter the predictive ability of SSEP findings in patients with anoxic brain injury [39,80]. While three studies have found that bilaterally absent N20 responses remain predictive of poor outcome in this setting [48,50,51,81], another found that neurologic recovery was possible in a small number of patients (1 of 36 patients) who had absent N20 responses in the setting of cardiac arrest treated with induced hypothermia [82]. (See "Initial assessment and management of the adult post-cardiac arrest patient", section on 'Temperature management'.)

The clinical operating characteristics of other evoked potentials (brainstem, auditory, visual, middle latency, and event-related) have not been adequately evaluated. SSEPs are the best validated and most reliable of the ancillary tests currently available for clinical use.

In the subacute setting, electrophysiologic testing shows promise in predicting late recovery in patients who remain in an unresponsive state after an anoxic injury. In one study, the presence of N20 responses in persistently unresponsive patients one month after anoxic injury was predictive of recovery of responsiveness within the following 24 months [36]. In another study, a positive EEG response potential to a speech stimulus (N400) was associated with a higher rate of neurologic recovery in patients unresponsive (in either minimally conscious state [MCS] or persistent vegetative state [PCS]) after traumatic or hypoxic-ischemic brain injury [83].

Electroencephalography

Assessment of prognosis — The clinical value of the EEG is unclear in the assessment of prognosis of anoxic brain injury because investigators have used different classification systems and variable intervals of recordings after resuscitation. Furthermore, the EEG is susceptible to subjective interpretation, the effects of sedative drugs, metabolic disturbances, and sepsis, which can invalidate the results. As a result, while EEG findings can be useful, they should be used in the context of other prognostic indicators [70]. (See "Electroencephalography (EEG) in the diagnosis of seizures and epilepsy", section on 'Routine EEG technique'.)

EEG categories can be crudely classified into malignant and benign types. The former includes complete or near-complete suppression, burst suppression, generalized periodic complexes, low-voltage output pattern (≤10 microvolts), intermittent or continuous seizures, lack of reaction to stimuli and the alpha-theta pattern [64,84]. In one series, these malignant EEG findings were associated with a higher mortality (91 versus 54 percent) compared with those who did not have these findings [84]. Of these findings, complete, generalized suppression (<20 microvolts) is the most specific for poor outcome; other patterns are less reliable for prognosis [36,39,48,73,85,86]. In another series of 51 patients who had EEG monitoring during therapeutic hypothermia and again during subsequent rewarming, EEG findings remained stable in most (75 percent) and worsened in 8 percent; malignant EEG findings during normothermia were associated with poor outcome in all patients [64]. The presence of variability and reactivity are relatively favorable features for recovery of awareness [48,64,87].

Seizure detection — An EEG can also be helpful to evaluate for the possibility of status epilepticus, which may be clinically suppressed by sedation or neuromuscular junction blockade, medications sometimes used to control shivering in induced-hypothermia therapy [88]. In different series, nonconvulsive seizures (NCS) have been detected in 9 to 30 percent of patients after cardiac arrest [64,89,90]. Therapeutic hypothermia may precipitate NCS. Severe brain injury of any mechanism is associated with NCS. (See "Nonconvulsive status epilepticus: Classification, clinical features, and diagnosis".)

NCS are associated with poor prognosis and near universal mortality [70]. In one case series, detection of seizures in 5 of 51 patients was associated with poor outcome, which was not improved by antiseizure drug therapy [64]. However, there are also reports of recovery after NCS, highlighting the importance of considering EEG evidence in the context of other available data [69,70].

Biochemistry — At present, biochemical tests do not have sufficient clinical predictive accuracy to be recommended in routine clinical practice. The predictive value of several chemical tests including neuron-specific enolase (NSE), the glial S-100 protein, creatine kinase, and lactate in blood and cerebrospinal fluid (CSF) has been evaluated after anoxic brain injury in a number of studies [91-96]. Smaller studies have also examined the utility of CSF adenylate kinase, lactate dehydrogenase, acid phosphatase, and glutathione concentrations predicting neurologic outcome [97]. A meta-analysis of all reported biochemical tests in blood and CSF concluded that the combined results were not sufficiently predictive for clinical use [47,98].

Subsequent studies have confirmed that markedly elevated serum levels of NSE and S-100 are associated with poor outcomes, but cutoff values vary among series [62,98-102]. A prospective study of 407 consecutive patients after cardiopulmonary resuscitation (CPR) used cutoff values derived from a previous meta-analysis [62,98]. In this study, NSE >33 mcg/L was found to perform similarly to SSEP as a test of poor outcome with 0 percent false-positive rate and a positive likelihood ratio of 23 (95% CI 2-357) [98]. When combined with SSEP, the prevalence of an abnormal test result (either NSE or SSEP) was extended from 45 to 66 percent.

The effect of induced hypothermia on the predictive value of these laboratory studies is uncertain. One study compared 97 cardiac arrest patients treated with hypothermia and 133 historical control patients who did not receive hypothermia [103]. NSE did not correlate with adverse outcome in the hypothermia patients until a cutoff of nearly 80 mcg/L at the 72 hour mark. In other studies, NSE >33 mcg/L has had false-positive rates of 8 to 29 percent in the prediction of poor outcome in the setting of hypothermia [50,51,86]. By contrast, a smaller study found that NSE >33 mcg/L was associated with failure to regain consciousness in 17 of 17 patients treated with hypothermia, while 6 of 17 patients with lower NSE levels were later able to obey verbal commands [104]. Further studies are needed before NSE or other biologic markers can be used prognostically in cardiac arrest patients treated with hypothermia.

Neuroimaging — Computed tomography (CT) and/or magnetic resonance imaging (MRI) can identify an intracranial hemorrhage, especially subarachnoid hemorrhage, which is sometimes the cause of the arrest. CT images are usually normal immediately after a cardiac arrest, but by day 3, they often show brain swelling and inversion of the gray-white densities (with the use of quantitative measures) in patients with a poor outcome [100].

MRI, especially with apparent diffusion coefficient (ADC) mapping, can add greater precision in predicting a poor outcome [105,106]. There is a strong correlation between MRI findings and long-term outcome in infants suffering hypoxic-ischemic encephalopathy [107]. It appears to have best prognostic power when performed approximately five days after cardiac arrest [71]. (See "Clinical features, diagnosis, and treatment of neonatal encephalopathy", section on 'Neuroimaging predictors'.)

An area of active investigation is the role of functional neuroimaging studies (positron emission tomography [PET] and functional MRI [fMRI]) in the prognostic assessment of adults with anoxic-ischemic brain injury [108-110]. As mentioned above, fMRI studies have the potential to detect network processing of sensory and motor responses, showing some evidence of awareness in a small proportion of behaviorally unresponsive patients [15,16,23,111]. One study evaluated the role of fMRI and PET in the evaluation of patients after hypoxic-ischemic and traumatic brain injury; PET was superior to fMRI in predicting neurologic outcomes (74 versus 56 percent) in behaviorally unresponsive patients [35]. However, the performance and interpretation of these studies remains complex and is still investigational [4]. There are also ethical issues regarding quality of life in decision-making that need to be resolved, namely whether patients who can generate such binary responses can participate in a decision-making process. (See 'Persistent vegetative state' above.)

MANAGEMENT — Supportive and preventive care remains the mainstay of therapy in all forms of anoxic brain injury [9,10,112]. Efforts should be focused upon providing adequate nutritional support, reducing the potential for nosocomial infection, and providing adequate prophylaxis against venous thromboembolism and gastric stress ulceration. (See "Prevention of venous thromboembolic disease in adult nonorthopedic surgical patients" and "Stress ulcers in the intensive care unit: Diagnosis, management, and prevention".)

Although pharmacologic stimulant therapy is recommended for some patients in a vegetative or minimally conscious state (MCS) from traumatic and nontraumatic brain injury, there is no evidence to support their use in anoxic brain injury. Transcranial direct current stimulation and other techniques are also being investigated in such patients [113].

Therapeutic (induced) hypothermia — The induction of mild to moderate hypothermia (chill therapy) to a target temperature 32 to 34ºC in the initial hours after cardiac arrest improves the neurologic outcome of resuscitated patients. This topic is discussed in detail separately. (See "Initial assessment and management of the adult post-cardiac arrest patient", section on 'Temperature management'.)

Accumulating reports suggest that induced-hypothermia therapy impacts the prognostic utility of clinical examination findings and ancillary testing (such as somatosensory evoked potentials [SSEPs] and neuron-specific enolase [NSE]) [39,48,80]. Validated protocols for assessing prognosis in the setting of therapeutic hypothermia are needed [114]. (See 'Prognosis assessed on clinical features' above and 'Ancillary testing' above.)

Seizures — Myoclonic seizures may respond to valproate or clonazepam [115]. In one case series, intravenous propofol was successful in eliminating clinical myoclonus and suppressing the electroencephalography (EEG) manifestations in all 60 patients treated [116]. Given the overall poor prognosis associated with MSE following primary cardiac arrest, it does not seem justified to resort to general anesthesia to stop the seizures. Stopping the myoclonus does not improve the dismal outcome.

Similarly, limited evidence suggests that treating subclinical seizures detected on continuous EEG monitoring does not improve outcome in patients with hypoxic-ischemic encephalopathy [64].

Family counseling — Family members of patients with severe neurologic injuries should be kept well informed about prognosis. They should be informed that patients in a coma are thought to experience no pain because there is no sense of awareness of self or environment, despite what may appear as grimaces, crying, or other expressions of discomfort. The perception of pain and suffering are conscious experiences governed by the cerebral cortex, while the expression of pain may be elicited at any level of the nervous system, including the motor/behavioral, endocrinologic, and autonomic responses that may occur as reflexes in the absence of consciousness.

Decision-making regarding withdrawal of various levels of treatment is dependent on accurate prognostication as discussed above. Once this is established, discussions with surrogate decision makers should focus on the patient's known stated preferences or advance directives (ie, whether ongoing life-supporting treatments are consistent with their prior stated wishes, or, in the absence of known wishes or directives, whether ongoing treatments are consistent with the patient's known values and goals). (See "Ethics in the intensive care unit: Informed consent" and "Ethical issues in palliative care".)

Uncertainty about the prognosis should be communicated with family members. In a survey of 179 surrogate decision makers of incapacitated patients, 87 percent wanted to know the degree of prognostic uncertainty to help with decision-making [117]. In some cases more time or additional tests may help to reduce uncertainty.

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Brain death and disorders of consciousness".)

SUMMARY AND RECOMMENDATIONS — Resuscitation from cardiac arrest or other cardiopulmonary catastrophe may be complicated by hypoxic-ischemic brain injury. Obtundation or coma are frequent early on, followed by recovery or evolution to brain death or persistent vegetative state (PVS).

Certain clinical criteria have been demonstrated to be reliable in identifying individuals with a very poor prognosis. Absent pupillary or corneal reflexes at three days after cardiac arrest are invariably associated with a poor outcome. Motor responses at day 3 are not reliable indicators in patients treated with hypothermia. (See 'Prognosis assessed on clinical features' above.)

Bilaterally absent somatosensory evoked responses at 24 to 72 hours may be useful to identify those with a poor prognosis. While very specific, these signs are not very sensitive for poor neurologic outcome. (See 'Somatosensory evoked potentials' above.)

Biomarkers (eg, neuron-specific enolase [NSE]) appear to be promising indicators of poor outcome, but have uncertain predictive value at least for those patients treated with hypothermia. Further research is needed to better define their cutoff values and sensitivity. (See 'Biochemistry' above.)

It is helpful to have two indicators of poor outcome before concluding that the patient will be severely disabled. (See 'Ancillary testing' above.)

Potential confounding factors in the clinical assessment of patients in hypoxic-ischemic coma include acute metabolic derangements (eg, renal failure, liver failure, shock), the administration of sedative or neuromuscular agents, and induced-hypothermia therapy. (See 'Prognosis assessed on clinical features' above and 'Ancillary testing' above.)

If no negative prognostic criteria apply, the patient should continue to be supported until a more definitive prognosis can be reached. (See 'Management' above.)

Regular information sessions with substitute decision maker(s) and family are advisable. (See 'Family counseling' above.)

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