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Anoxic Encephalopathy
Introduction
Anoxic encephalopathy, or hypoxic-ischemic brain injury, is a process that begins with the cessation of cerebral blood flow to brain tissue, which most commonly results from poisoning (for example, carbon monoxide or drug overdose), vascular injury or insult, or cardiac arrest. Many patients who suffer anoxic brain injury expire without regaining full consciousness, and many patients have significantly poor neurologic outcomes. However, some advances are beginning to demonstrate the preservation of brain tissue, and there is a focus on identifying patients with the prospect of improving neurologic morbidity and mortality.[1] Data has been published to indicate that there are predictors for poor outcomes. However, evidence of factors suggestive of good prognosis or outcome has lagged. This topic reviews the literature and practices concerning anoxic encephalopathy and brain injury.
Etiology
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Etiology
Patients experience anoxic brain injury due to decreased oxygen delivery to the various regions of the brain; this may be due to cardiac arrest, where global hypoxia is a common observation, or vascular injury or insult, where a more localized area may be affected. In the case of post-arrest patients, an increase in body temperature, which may be neurologically mediated, beyond 37 degrees Celsius is associated with less favorable neurologic outcomes and appears to also worsen with every degree beyond 37 degrees Celsius.[2]
Epidemiology
Epidemiology, as it concerns gender, age, or race, has not been shown to have a predominance due to the variable outcome from the primary causation leading to anoxic injury. Most commonly, the cause of anoxic injury is due to cardiac arrest and includes either in-hospital cardiac arrest (IHCA) or out-of-hospital cardiac arrest (OHCA). Though surveillance of statistics regarding cardiac arrest and the neurologic outcome is varied, further studies are needed to determine the differences between IHCA and OHCA. The all-cause post-arrest anoxic injury is the most researched etiology at this time.
Pathophysiology
When the blood supply to the brain is reduced, oxygen and glucose delivery are impaired. This stimulates an anaerobic type of respiration and reduces the production of adenosine triphosphate. The sodium-potassium pump fails, and there is an increased production of lactate. An influx of sodium into the cell results in massive depolarization, leading to an increased concentration of intracellular calcium.[3] The latter leads to cellular death by the following mechanisms:
- Mitochondrial injury leads to the generation of reactive oxygen species
- Activation of nitric oxide, caspases, and calpains
- Disruption of protein synthesis
History and Physical
A thorough history is the most helpful initial aspect but usually must be obtained from several sources. Because patients with anoxic brain injury are typically unresponsive upon initial presentation, sources such as family members, individuals who were part of the initial resuscitation of the patient, or outpatient care providers can provide information regarding the patient's medical history and witnessed events or interventions performed. A full understanding of baseline neurologic status is essential, utilizing the resources that may have known the patient before the event. If possible, information such as prodromal symptoms, medication use, substance abuse, time of onset, and, if applicable, duration of CPR should also be ascertained.
The elimination of confounding factors is also necessary for a reliable neurologic examination. These factors include, but are not limited to, sedating medications, anticholinergic medications, paralytic drugs, metabolic abnormalities such as acute hepatic or renal failure, shock or continued irreversible hypoperfusion state, therapeutic hypothermia from targeted temperature management, and pathologic hypothermia. These conditions potentially impact cerebral consciousness and brainstem reflexes and can demonstrate false findings on detailed neurologic examination. Particularly on the initial evaluation of the patient, these considerations are paramount and should be actively pursued when considering the neurologic examination of an obtunded patient.
There may be physical findings of myoclonic activity or myoclonic status epilepticus in the setting of anoxic encephalopathy. While this may produce confounding examination findings, this does not exclude anoxic injury. Post-hypoxic myoclonus findings may be observed within 24 hours after a hypoxic insult has occurred. However, there are case reports available that describe delayed myoclonus even 48 hours after hypoxic insult due to sedation or paralytic medication use.[4] One factor to consider is that post-hypoxic myoclonus is typically generalized and does not demonstrate particular focality.[5]
Evaluation
In evaluating the suspected anoxic injury, there should always be a thorough investigation of confounding metabolic abnormalities. Testing should include a comprehensive metabolic workup including serum electrolytes, hepatic studies including ammonia, blood gas analysis for acid-base disturbances, and hemoglobin measurement to ensure adequate delivery capacity for oxygen. Potential causes such as infection or drug overdose should also be considered using cultures and drug and toxicology screens, respectively. A cardiac evaluation, including an echocardiogram and cardiac biomarkers, could be considered if the precipitating event was cardiac arrest. Discussing a further toxicology or cardiology evaluation with the team is essential.
Computed tomography (CT) imaging of the brain is typically performed, which may demonstrate acute findings of subarachnoid or intracranial hemorrhage as the source of the patient's decreased level of consciousness. In cases without intracerebral hemorrhage where there is cardiac arrest-related hypoxic injury, initial CT imaging of the brain is frequently normal. However, repeat CT imaging is recommended by post-arrest day 3 as this often shows manifestations of anoxic injury such as cerebral edema or inversion of gray-white matter density.[6] Magnetic resonance imaging (MRI) has also been shown to play a role in diagnosing anoxic injuries using diffusion-weighted MRI.[7] A nuclear medicine cerebral diffusion study can be considered to evaluate cerebral blood flow concerning global anoxic injury resulting in brain death.
The utility of electroencephalogram (EEG) is somewhat unclear in the routine diagnosis of anoxic encephalopathy due to the potential for interpretation variability due to sedation or drug use, metabolic abnormalities, or sepsis. There are specific findings that may suggest the presence of anoxic injury. However, the extent remains unclear. These findings include alpha-theta pattern, intermittent or continuous seizures, burst suppression, generalized periodic complexes, complete or near-complete suppression, and generalized or focal low-voltage output.[8][9]
Knowing the limitations, there are EEG classification systems for anoxic encephalopathy that have been proposed. One system classifies encephalopathy into 4 grades utilizing global waveform patterns on EEG. Grade I anoxic encephalopathy has the most favorable prognosis and consists of alpha-wave activity. Grade II anoxic encephalopathy consists of predominantly theta wave activity on EEG. For grade III, a predominant delta wave pattern is typical, and this extends into grade IV, where the low amplitude delta waves approach an isoelectric EEG.[10] A delta wave pattern is associated with a worse prognosis, and the isoelectric EEG suggests a poor outcome. Continuous EEG monitoring is preferred to single static EEG to evaluate these findings fully. Continuous EEG with therapeutic hypothermia can also be performed, and malignant changes observed during re-warming are associated with poor prognosis.[8]
Treatment / Management
The initial course of management is the stabilization of the patient upon presentation; this includes correction of metabolic abnormalities, initiation of antibiotics if septic, stabilization of hemodynamics, and a reversal of any possible toxic ingestions or overdose. Potential interventions regarding anoxic encephalopathy include post-arrest targeted temperature management as well as management of seizures should they present. It is also essential to commence discussion with family members regarding the potential for anoxic insult in preparation for permanent neurological damage or death.
Targeted temperature management involves maintaining the temperature at or below 36 degrees Celsius, whereas therapeutic hypothermia involves maintaining the temperature within the range of 32 to 34 degrees Celsius. Historically, the suggested temperature range was 32 to 34 degrees Celsius;[11] however, newer trials suggest similar benefits at 36 degrees when compared to 33 degrees, giving rise to targeted temperature management.[12] While temperature management may be accomplished using external cooling, therapeutic hypothermia may require invasive cooling measures. The indication for temperature management is any patient who, after cardiac arrest, does not demonstrate purposeful movements or follow commands. Both therapeutic hypothermia and temperature management can also be useful in patients undergoing coronary catheterization or receiving thrombolytic medications, as well as pregnant patients; however, there is an increased risk of bleeding in these populations.[13] Therapeutic hypothermia is not recommended in patients with active, non-compressible bleeding; however, targeted temperature management is an option.(A1)
Initiation of temperature management is suggested after initial resuscitation in individuals with non-purposeful motor responses, no evidence of cerebral edema on CT imaging, and, if available immediately, no malignant features on EEG. The duration should be at least 24 hours, although studies demonstrate a slight advantage to 48 hours, albeit with a higher risk of adverse effects.[14] Therapeutic hypothermia should be a possible therapy in patients who, after initial resuscitation, demonstrate CT imaging evidence for the development of cerebral edema, lack motor function or brainstem reflexes, or have malignant EEG patterns if available. The recommended duration is consistent with temperature management. In both targeted temperature management and therapeutic hypothermia, shivering may cause a delay in obtaining temperature goals. Sedation may suppress the shivering response. However, neuromuscular blockade may ultimately be required. Neuromuscular blockades may mask the physical manifestations of seizures, and it is recommended that they be used with continuous EEG monitoring.[15][16](A1)
After meeting the therapeutic hypothermia timeframe, the rewarming portion of the intervention begins. If automated devices controlling intravascular or surface cooling are implemented, temperature changes can be adjusted for specific targets. Rates of warming should not exceed 0.5 degrees Celsius per hour. The rate should be maintained at 0.25 degrees Celsius per hour instead.[17] If automated devices are not in use, manual rewarming is an option. Changing the temperature on cooling blankets or gradually removing ice packs are examples of manual rewarming. The goal rate of rewarming is 0.5 degrees Celsius every 3 hours, and monitoring is done by checking the core temperature.(B2)
Differential Diagnosis
When considering a diagnosis of anoxic encephalopathy, examination, and observation are required to ensure no confounding factors contribute to the current neurologic presentation. Therefore, metabolic abnormalities such as hypernatremia, hyponatremia, and hypoglycemia, among others, must be considered and corrected before the diagnosis of anoxic encephalopathy. Sepsis also merits consideration. Drug overdose or alcohol intoxication can also present with neurologic findings that may mimic anoxic injury. Sedation medication or neuromuscular blocking agents also demonstrate neurologic findings and deficits that may be mistaken for anoxic injury.
Anoxic encephalopathy and neurologic injury can also have various presentations. Anoxic injury can present as an initial comatose state, where self-awareness and sleep-wake cycles are absent. Typically, in 2 to 4 weeks, a comatose patient either shows some recovery or may progress to a persistent vegetative state or brain death. The persistent vegetative state (PVS) lacks self-awareness but maintains the sleep-wake cycle.[18] PVS does require meeting a set of diagnostic criteria for formal diagnosis from numerous repeat neurologic examinations.[19] The term 'minimally conscious state' describes the current neurological condition if the requirements are not completely satisfied.[20]
Locked-in syndrome is a state where self-awareness is likely to present in addition to preserving the sleep-wake cycle. Typically, this results in persistent quadriplegia, although it does have the potential for prolonged survivability. Akinetic mutism, a condition where damage to the frontal lobe of the brain results in a lack of movement or speech initiation, is also a potential condition that may be the result of anoxic injury, among other causes. Dementia, particularly advanced dementia, should also be considered, especially with a known history.[18] A physical feature that may be present is post-hypoxic myoclonus.[4][5] While this suggests hypoxic insult likely from anoxic injury, consideration of status epilepticus or other seizure activity is warranted. Evaluation with continuous EEG is ideal if available. A bispectral index can also be utilized; it is more limited in terms of surveillance of multiple regions of the brain. In addition to seizure disorders, the Lance-Adams syndrome also correlates with myoclonus but has a favorable neurologic outcome. Neurology consultation may help to distinguish post-hypoxic myoclonus from Lance-Adams syndrome.
Prognosis
Prognosis is often a crucial question that providers handle routinely in the setting of anoxic encephalopathy. However, studies regarding accurate prognosis have not validated a solitary evaluation or scoring system. Currently, several scoring systems based on imaging, testing, and exam findings exist and may be of more benefit in discussions of current neurologic status and potential outcomes with families. Factors such as shorter time to initiation of CPR, shorter duration of CPR, and ventricular tachycardia or ventricular fibrillation as the identified arrest rhythm are associated with improved outcomes. However, the evaluation and findings of the provider are still the choices over scoring systems for routine practice. Several scoring systems that attempt to predict prognosis relate to post-arrest anoxic encephalopathy. The GO-FAR score is a tool that retrospectively analyzed in-hospital cardiac arrest patients and predicted the likelihood of survival with good neurologic outcomes based on 13 clinical variables.[21] According to the study, the scoring system drafted may have the utility of predicting a low or very low likelihood of survival with good neurologic outcomes after in-hospital cardiac arrest. It may aid in the discussions of advance directives with the family.
The prognosis after resuscitation score is another post-arrest score that aims to predict survival. It was also a retrospective analysis of in-hospital cardiac arrest patients.[22] It may also serve a role in advance directive discussions with families; however, it has not been validated for routine use in clinical decision-making. The brain arrest neurological outcome scale (BrANOS) was formulated using retrospective data that incorporates radiologic findings into prognosis in addition to the Glasgow Coma Scale and duration of cardiac arrest. Combining these data, the prognosis of severe neurologic disability and mortality was estimated at up to 90% accuracy.[23] However, these data did not include patients who underwent therapeutic hypothermia; therefore, this scale has not yet been fully validated and is not recommended for routine use.
In addition to prognostic scales, a physical test can provide prognostic information using bilateral stimulation of the median nerve. This testing evaluates for somatosensory evoked potentials (SSEP), which are averaged electrical responses in the central nervous system to somatosensory stimulation peripherally to remove the possibility of peripheral nervous system damage confounding exam findings. This testing does require expert consultation for implementation and interpretation. SSEP evaluation aims to evaluate the presence of N20 response from the primary somatosensory cortex bilaterally.[24] If absent bilaterally within the first week, often tested 24 to 72 hours post-arrest, there is likely no outcome better than a persistent vegetative state.[25] In addition, SSEP testing has also been demonstrated to be the least susceptible to metabolic change, as well as drugs.[24] If the N20 response is present upon initial testing, consideration should be given to testing a second time after the first week, as the N20 response may be extinguished at that time. Ultimately, the area of predicting prognosis continues to develop, and at this time, there is no fully validated prognostic scale. However, the combination of initial testing continued neurologic evaluation, and ancillary testing can provide information regarding the likelihood and assist surrogate decision-makers in determining the extent of treatment.
Complications
The complications of anoxic encephalopathy most commonly present as seizures, myoclonus, or permanent disability. Other complications may be due to the inability to treat effectively, such as difficulty maintaining temperature management or therapeutic hypothermia, or iatrogenic, such as rapid rewarming, infusion of excessive crystalloid causing metabolic abnormalities, or edema. Therapeutic hypothermia is known to cause changes in coagulation and hemostasis; therefore, there is a risk of bleeding due to decreased platelet function and coagulation factor activity.[26][27] Rarely does this cause significant bleeding to alter hemodynamics; however, if present, therapeutic hypothermia should be abandoned in favor of temperature management. Therapeutic hypothermia has also been shown to cause bradycardia. However, this is often transient and is often acceptable with normal blood pressure.[28] Drug metabolism is also impacted by therapeutic hypothermia, which may delay the metabolism of drugs that could cause physical exam changes.[29] In contrast, rapid rewarming can occur with inadequate monitoring of temperature, particularly a core temperature. The consequences of rapid rewarming include seizures, cerebral edema, and electrolyte disturbances, particularly hyperkalemia. The ideal core temperature monitor is with the use of a central venous probe. However, surrogate temperature monitoring using esophageal, rectal, or bladder probes is available.[30] The esophageal probe is thought to be the most reliable surrogate for temperature monitoring.
Deterrence and Patient Education
The focus of education is routinely the education of family members or surrogate decision-makers. Early summarization of events leading to the current presentation and the likelihood of survival with good neurologic outcome and prognosis is essential. Because of involuntary reflexes that may appear as crying, facial grimacing, or other expressions of suffering, an explanation of the lack of consciousness and suffering in a coma can provide relief. Early discussion of prognosis, with reinforcement and updates regarding clinical findings, can significantly aid surrogate decision-makers in considering goals of care and re-evaluating whether the current care regimen is consistent with the patient’s values and goals.
Enhancing Healthcare Team Outcomes
The management and care of patients with suspected anoxic encephalopathy or anoxic injury are challenging. They should involve individuals from medical teams and supportive roles, functioning as a coordinated interprofessional team. This interprofessional team approach includes care management, nursing, pharmacy staff, dieticians, palliative care, and neurology consultation. Daily collaboration as a team to discuss further management and findings to inform surrogate decision-makers is essential and may best be performed collaboratively to ensure no gaps in information. Pharmacists review medications prescribed, detect drug-drug interactions, and counsel patients and their families. Specialty-trained critical care and neuroscience nurses provide prescribed treatments, monitor patients, educate family members, and give status updates to the team. The outcomes for patients with anoxic encephalopathy depend on the age of the patient, the extent of brain injury, the presence of neuropsychiatric deficits at the time of diagnosis, and comorbidity. For most patients, recovery is prolonged and requires extensive rehabilitation. The interprofessional paradigm with open communication yields the best patient outcomes.
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