The brain consumes a significant amount of energy compared to its weight and size.
It is highly metabolically active, and exquisitely sensitive to hypoxia and hypoperfusion. Cellular injury can begin within minutes, and permanent brain injury will follow if prompt intervention does not occur. For that reason, it is critical to understand the clinical presentation, pathophysiology, and management options.
Anoxic and hypoxic brain injury can occur whenever oxygen delivery to the brain is compromised. Oxygen delivery is a function of the blood flow to the brain and the oxygen content of the blood. Consequently, hypoxic brain injury can result from interruption of blood flow to the brain, such as cardiac arrest or strangulation, or from systemic derangements that affect the oxygen content of the blood. Severe anemia, systemic hypotension, and systemic hypoxia can result in hypoxic brain injury if left untreated. In the United States, cardiac arrest is the most common cause of hypoxic brain injury. Other causes include traumatic vascular injuries; near-drowning; smoke inhalation or carbon monoxide poisoning; shock, including hemorrhagic and septic shock; drug overdoses; and acute lung injury.
Because the potential causes of hypoxic brain injury are diverse, the precise incidence is difficult to quantify. The best data comes from cardiac arrest and resuscitation literature. According to data from the American Heart Association, over half a million patients in the U. S. suffer a cardiac arrest each year. Unfortunately, the vast majority of patients who experience a cardiac arrest do not survive to hospital discharge; of those who do, the majority (50-83%) experienced clinically significant cognitive symptoms. Among those who do not survive hospitalization, death often results when families make the decision to limit life-sustaining interventions due to concern for severe brain injury. Clinical outcomes among survivors are variable, but some degree of neurological disability is common; even with state-of-the-art post-resuscitation care, only about 10% of cardiac arrest survivors presenting with non-shockable rhythm achieved a good neurological outcome, defined as neurological function adequate to perform activities of daily living, at 90 days.  A recent European study indicated that only 5% of cardiac arrest survivors achieved full neurological recovery at 30 days. 
The brain depends on a constant energy supply provided by glucose and oxygen but is unable to store energy. With the cessation of blood flow, intracellular production of adenosine triphosphate is diminished. This results in dysfunction of energy-dependent ion channels, which contributes to intracellular sodium accumulation and cytotoxic edema. Ongoing ischemia results in the release of glutamate, an excitatory neurotransmitter, which promotes calcium influx through N-methyl-D-aspartate (NMDA) receptors. Calcium influx exacerbates neuronal injury by activating lytic enzymes, precipitating free radical formation, and interfering with mitochondrial function. This process, known as excitotoxicity, can ultimately lead to cell death. 
The mechanisms that lead to delayed cell death following hypoxic-ischemic injury in the brain are complex. Ischemic cell death occurs via two different pathways: necrosis and apoptosis. During hypoxia-ischemia of the brain, acute energy failure leads to loss of ion homeostasis where intracellular sodium and calcium accumulate creating osmotic swelling which, can lead to cell lysis. This process releases glutamate and free radicals which are cytotoxic and exacerbate the injury. A secondary phase of neuronal death can occur hours later.
Moderate global ischemia leads to infarcts in watershed areas (e.g., the area lying between regions fed by the anterior and middle cerebral artery). These infarcts can damage the highly vulnerable areas such as pyramidal neurons of the hippocampus (CA1 region), pyramidal neurons of the cerebral cortex (layers 3, 5, and 6) which leads to laminar necrosis, the death of neurons in the basal ganglia (caudate nucleus and putamen), and the Purkinje cell layer of the cerebellum.
The cells of these areas are high in metabolic demand and contain a high concentration of excitatory neurotransmitter receptors. Other histologic findings include a shrunken eosinophilic neuron (anoxic neuron) and a red neuron which represents neuronal cells that die because of hypoxia.
Hypoxic or anoxic brain injury often results in an impaired level of consciousness. Patients are often unable to follow verbal commands and may present with coma. For that reason, relevant history must typically be obtained from emergency personnel, family members, or other bystanders who may have witnessed the event. Information regarding the circumstances of brain injury is critical. For example, victims of strangulation may suffer from associated injuries to the cervical spine; the same may be true for patients suffering a near-drowning event after diving into shallow water. For cardiac arrest patients, in particular, information about the initial rhythm, whether or not the arrest was witnessed, and the duration of resuscitation efforts will be important to note. A focused medical history, including medication use, chronic medical conditions, and exposure to toxins or illicit substances, should be obtained if feasible.
Although obtaining a thorough neurological exam is important, the first priority for patients with hypoxic brain injury is adequate resuscitation. Specific therapeutic interventions should be targeted at the underlying cause of the injury, with the goal of returning normal cerebral blood flow and oxygen delivery. Systemic hypotension, hypoxia, and hypovolemia should be corrected prior to attempting a neurological evaluation.
After appropriate resuscitation, factors that may confound an adequate assessment of neurological function must be excluded. The most prevalent confounder is drug exposure, including both illicit substances and medications that may have been administered during resuscitation efforts. Sedative agents and neuromuscular blockade are common, but toxic levels of certain antibiotics, anticholinergic medications, and antiepileptic drugs may also lead to a depressed level of consciousness. Significant metabolic derangements, such as severe acidosis, acute kidney failure, and acute liver injury may also preclude an accurate assessment.
Once confounders have been excluded, the first step of the neurological assessment is an evaluation of the level of consciousness, which involves determining if the patient is arousable. Observe for eye-opening in response to voice, and determine whether the patient follows verbal commands. If not, gentle tactile stimuli may be employed. If this does not result in eye-opening, noxious stimulation is required. This may entail supraorbital pressure, pressure on the temporal-mandibular joint, or other methods of eliciting central pain. Sternal rub and nail-bed pressure are not recommended, because these techniques may precipitate spinal reflexes. While applying noxious stimulation, the examiner observes the patient for eye-opening and motor response. Motor response in the setting of noxious stimulation can be described as localizing, i.e. the patient reaches for the source of pain, withdrawal, flexor posturing, extensor posturing, or no response. Cranial nerve examination should be performed, including an assessment of pupillary reactivity, corneal reflexes, and oculocephalics. Importantly, testing of oculocephalic reflexes is contraindicated if there is a suspected injury to the cervical spine. The position of the eyes at rest should be evaluated, as a dysconjugate gaze or gaze deviation may indicate a focal brain injury. A full examination of the cranial nerves may not be possible for patients with an endotracheal tube, but the gag and cough reflexes should be assessed. Repeating the neurological assessment at intervals can be valuable for determining prognosis; this is discussed in detail below.
In the acute period after the presentation to the hospital, laboratory, and radiological evaluation of a patient with hypoxic brain injury are dictated by the underlying cause of the injury. Initial studies should include basic blood work, including blood glucose, electrolyte panel, a complete blood count, a blood urea nitrogen, serum creatinine, and liver function studies. An arterial blood gas is often indicated in order to evaluate the acid-base status and rule out hypercarbia. A urine drug screen and/or blood alcohol level is useful, but it is important to note that many medications and drugs of abuse are not detected by routine urine tests; consequently, a negative UDS is not sufficient to exclude the possibility of drug intoxication or overdose. A non-contrast head CT should be performed in all patients with depressed level of consciousness, in order to evaluate for structural lesions. Head CT is sufficient to detect acute hemorrhage, hydrocephalus, and evidence of traumatic injuries such as skull fractures. The primary indication for obtaining a head CT is to detect a structural lesion that may require intervention, such as a subdural hematoma or acute hydrocephalus. Often in the setting of an acute hypoxic brain injury, the CT may be relatively unremarkable. However, the loss of gray-white differentiation may be appreciated. This can be quantified by measuring the Hounsfield units of the cerebral cortex and underlying white matter; the ratio of these values has been shown to correlate with prognosis. 
For patients who remain comatose after resuscitation, further evaluation may be required. CT angiography and/or CT perfusion may be performed if an acute stroke is suspected, and may also be valuable to rule out vascular injuries in patients who have experienced cervical trauma. Electroencephalography is valuable to rule out nonconvulsive status epilepticus. MRI is more sensitive for hypoxic injury than CT, and has been correlated with prognosis; this is discussed in more detail in subsequent sections.
In the setting of brain anoxia due to cardiac arrest, resuscitation efforts, optimizing blood pressure, and maintaining systemic perfusion are the critical component of treatment. Clinical management is focused on supportive care, treatment of the underlying cause of the hypoxia, and prevention of ongoing brain injury. A variety of neuroprotective strategies have been evaluated in an effort to prevent cell death by interrupting or attenuating the cascade of events by which hypoxia precipitates neuronal apoptosis and necrosis. The most promising of these is therapeutic hypothermia or targeted temperature management, which has become the standard of care for comatose survivors of cardiac arrest. Initial trials evaluated the utility of induced hypothermia, to a target of 32-34 degrees Celsius, for patients with cardiac arrest due to ventricular fibrillation or pulseless ventricular tachycardia. These randomized controlled trials indicated that patients who received hypothermia had lower mortality rates and improved neurological outcome. In a 2006 meta-analysis including roughly 400 patients, authors calculated a number needed to treat of 5 patients to present 1 poor neurological outcome. Subsequent observational studies have confirmed that therapeutic hypothermia can be implemented successfully in clinical practice, low rates of adverse events.  A subsequent, larger trial evaluated the benefits of mild hypothermia, with a target temperature of 33 degrees Celsius, as opposed to targeted temperature management with a goal of 36 degrees Celsius. In this study, investigators were unable to detect a statistically significant benefit in either arm of the trial, leading some researchers to hypothesize that avoiding hyperthermia is the key to improving neurological recovery. In the latest version of the Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiac Care, the American Heart Association recommends that all comatose adult patients after cardiac arrest should receive targeted temperature management, with a goal temperature between 32-36 degrees Celsius, maintained for 24 hours after the arrest.
Although a complete discussion targeted temperature management is outside the scope of this document, there are few important points to note. Mild hypothermia acts via a number of mechanisms to inhibit apoptosis, excitotoxicity, and mitochondrial dysfunction. Lowering the body temperature also acts to decrease the cerebral metabolic rate, leading to a reduction in oxygen consumption and cerebral blood flow, and stabilizes the blood-brain-barrier, which decreases edema formation. In order to optimize the clinical benefit, treatment must be initiated as soon as possible following the hypoxic brain injury, ideally within 6 hours. Furthermore, clinicians must be aware of the various physiological effects of mild to moderate hypothermia, including hemodynamic effects, effects on glucose and electrolyte homeostasis, renal function, and drug metabolism. Mild to moderate hypothermia often results in bradycardia, and can sometimes result in hypotension. Although bradycardia is often well-tolerated, pressors may be required in order to maintain organ perfusion. If clinically significant bradyarrhythmias occur, often careful rewarming by 1-2 degrees Celsius--i.e., from 33 degrees to 34 degrees--is sufficient to resolve the issue. Hypothermic patients are often hyperglycemic, due to decreased insulin secretion and relative insulin resistance. Additionally, induction of hypothermia results in an intracellular influx of potassium, which can result in hypokalemia. In addition, hypothermia may produce a "cold diuresis," which can contribute to electrolyte abnormalities and result in volume depletion. During the rewarming phase, the sequestration of potassium is reversed, which may result in hyperkalemia, especially if hypokalemia was overtreated during induction and maintenance of hypothermia. For this reason, frequent monitoring of blood glucose and electrolyte levels are required during the induction and rewarming phases. Adequate sedation and analgesia are critical during targeted temperature management, often requiring continuous infusions of sedative agents such as propofol or midazolam as well as opiate medications. However, these agents can confound neurological assessment. Furthermore, seizures are a common complication of anoxic brain injury. Electroencephalography can, therefore, be very valuable.
Finally, shivering is a common complication of induced hypothermia or targeted temperature management. Shivering is problematic because it increases the metabolic rate, slows the rate of cooling, and can increase intracranial pressure. Consequently, shivering can seriously undercut the beneficial effects of therapeutic hypothermia. Several methods for treatment and prevention of shivering have been described in the literature. Adequate analgesia and sedation are important; opiates, in particular, have been shown to decrease the shivering threshold. Counterwarming of the hands face, and upper chest can be very effective. Other pharmacological interventions including antipyretics, such as acetaminophen; magnesium sulfate; and central alpha-2 blockers, such as dexmedetomidine, have been shown to be valuable. It is recommended that patients undergoing therapeutic hypothermia be monitored for shivering on an ongoing basis, and treated accordingly.
Patients with anoxic brain injury have a dismal prognosis despite our understanding of the complex of pathways leading to anoxic brain injury. More clinical and basic science research are necessary to determine ways to slow down the anoxic and hypoxic brain injury. Overall, the best treatment solution is prevention.
Anoxic brain injury can be devastating after prolonged cerebral hypoxia; further, it is often challenging to predict the prognosis based on clinical findings. Although the clinical exam provides valuable prognostic information, much of the literature on exam findings pre-dates the advent of therapeutic hypothermia and targeted temperature management. It is also important to recognize that induced hypothermia can have significant effects on the pharmacokinetics of many commonly used sedative and analgesic medications, including propofol and fentanyl. Consequently, it is important that examiners ensure that the patient is normothermic, and that sedating medications have been held for an adequate period prior to performing a neurological assessment for prognostic purposes. It has long been appreciated that patients who demonstrate one or more absent brainstem reflexes in the hours immediately following an arrest can often be observed to improve with time. For that reason, it was often recommended to delay prognostication until 72 hours after the arrest; in particular, the absence of corneal and/or pupillary reflexes at 72 hours has been established as a reliable sign of poor neurological outcome. The motor exam at 72 hours has also been noted to correlate with prognosis in non-hypothermic patients. Specifically, an absent or extensor response to central pain at 72 hours has a high positive predictive value for poor outcomes. In the era of therapeutic hypothermia, some investigators have attempted to validate these findings. In one such study, bilateral absence of pupillary light reflexes was found to be a reliable indicator of poor neurological outcome in patients treated with hypothermia; however, the authors note that it is necessary to exclude surgical pupils and pre-existing pupillary abnormalities. Unfortunately, corneal reflexes and motor examination appear to be somewhat less reliable.
In addition to the clinical assessment, electrophysiological studies have been shown to be useful for prognostication. Somatosensory evoked potentials (SSEPs) can be useful because they can typically be evaluated even in the setting of hypothermia and/or moderate sedation. Specifically, bilaterally absent cortical N20 responses following median nerve stimulation SSEPs are highly specific for poor prognosis. It is important to note that the absence of cortical responses is unreliable unless peripheral and spinal responses are preserved. If this is not the case, the possibility of a confounding spine or peripheral nerve process cannot be excluded. Unfortunately, SSEPs are not very sensitive, as this finding is present in a relatively low percentage of patients who go on to have a poor outcome. In contrast, electroencephalography (EEG) can be valuable for identifying patients who may be more likely to recover. EEG monitoring is often used in patients with anoxic brain injury to identify status epilepticus. The presence of post-anoxic status epilepticus is associated with an increased likelihood of poor neurological outcome, but increasing evidence suggests that this entity may respond to aggressive antiepileptic therapy. In addition, investigators have identified several EEG patters with prognostic implications. Malignant patterns such as generalized suppression, alpha coma, and burst suppression not attributable to medication effect have been demonstrated to correlate with poor outcome. Conversely, reactive, and continuous EEG patterns have been shown to predict awakening from coma.
The value of magnetic resonance imaging (MRI) in survivors after cardiac arrest has been investigated thoroughly. The literature describes magnetic resonance imaging (MRI) findings in anoxic brain injury in four phases: an acute phase which lasts 24 hours after anoxia or hypoxia; an early subacute phase lasting from one to thirteen days, a late subacute phase lasting from fourteen to twenty days; and a chronic phase, starting at day twenty-one. MRI will show swelling, a hyper signal of basal ganglia, delayed white matter degeneration, cortical laminar necrosis, and atrophy occurring in succession. From a practical standpoint, an MRI obtained at 2-7 days after the arrest is likely to provide the highest yield. Diffusion restriction and/or hyperintensity on Fluid-Attenuated Inversion Recovery (FLAIR) sequences have been shown to correlate with poor prognosis; involvement of cortical gray matter is more specific than similar findings in the deep nuclei.
Although there is considerable interest in identifying serum biomarkers for prognostication in the setting of brian injury, these have not been widely adopted in practice. Neuron-specific enolase (NSE) has been evaluated extensively for this purpose, and levels > 33 micrograms/liter have been correlated with poor prognosis. However, studies have shown that hypothermia attenuates neuron-specific enolase levels, leading to higher false-positive rates in patients treated with hypothermia when established cutoff values are used. Neuron-specific enolase is also released in the setting of hemolysis, and it can be elevated in patients with other mechanisms of brain injury, including trauma. Consequently, NSE levels should not be used in isolation and should be interpreted with caution in patients treated with therapeutic hypothermia.
Anoxic brain injury often results in a prolonged coma, but the pattern of recovery ranges from recovery to mild cognitive deficits to coma and possibly death. Trials show that 27% of patients with post-hypoxic coma regained consciousness within 28 days, Nearly 9% remained comatose or in a vegetative state, and unfortunately, 64% died. Common sequelae can occur after sustaining an anoxic brain injury and may vary from persistent vegetative states, seizures, myoclonus, movement disorder, cognitive dysfunction, and other neurological abnormalities.
The patient and family should receive education and counseling about the prognosis and sequelae of an anoxic brain injury. Patients with anoxic brain injury secondary to drug overdose should receive extensive use disorder counseling. Patients with anoxic brain injury secondary to a cardiac arrest should receive education about lifestyle modification such as diet, exercise, and adherence to medications.
Patients with hypoxic brain injury benefit from receiving coordinated care from interdisciplinary teams. In addition to physicians experienced in dealing with brain injury, patients require skilled nursing staff who are trained to recognize neurological complications such as seizures, herniation syndromes, etc. Furthermore, nursing care is instrumental in preventing complications of immobility, including aspiration, skin breakdown, and deep venous thrombosis. Clinical pharmacists can be helpful, especially for patients undergoing therapeutic hypothermia, because of the impact that low body temperature can have on glucose management, drug absorption, and pharmacokinetics. Consultation with rehabilitation specialists, including physical therapy, occupational therapy, and speech-language pathologists are important for stable patients in order to maximize the potential for recovery. Finally, case management and social work personnel play an important role in discharge planning and transitions of care.
|||Arora S,Tantia P, Physiology of Oxygen Transport and its Determinants in Intensive Care Unit. Indian journal of critical care medicine : peer-reviewed, official publication of Indian Society of Critical Care Medicine. 2019 Sep; [PubMed PMID: 31656372]|
|||Howell K,Grill E,Klein AM,Straube A,Bender A, Rehabilitation outcome of anoxic-ischaemic encephalopathy survivors with prolonged disorders of consciousness. Resuscitation. 2013 Oct [PubMed PMID: 23747956]|
|||Laver S,Farrow C,Turner D,Nolan J, Mode of death after admission to an intensive care unit following cardiac arrest. Intensive care medicine. 2004 Nov [PubMed PMID: 15365608]|
|||Lascarrou JB,Merdji H,Le Gouge A,Colin G,Grillet G,Girardie P,Coupez E,Dequin PF,Cariou A,Boulain T,Brule N,Frat JP,Asfar P,Pichon N,Landais M,Plantefeve G,Quenot JP,Chakarian JC,Sirodot M,Legriel S,Letheulle J,Thevenin D,Desachy A,Delahaye A,Botoc V,Vimeux S,Martino F,Giraudeau B,Reignier J, Targeted Temperature Management for Cardiac Arrest with Nonshockable Rhythm. The New England journal of medicine. 2019 Dec 12 [PubMed PMID: 31577396]|
|||Gräsner JT,Lefering R,Koster RW,Masterson S,Böttiger BW,Herlitz J,Wnent J,Tjelmeland IB,Ortiz FR,Maurer H,Baubin M,Mols P,Hadžibegović I,Ioannides M,Škulec R,Wissenberg M,Salo A,Hubert H,Nikolaou NI,Lóczi G,Svavarsdóttir H,Semeraro F,Wright PJ,Clarens C,Pijls R,Cebula G,Correia VG,Cimpoesu D,Raffay V,Trenkler S,Markota A,Strömsöe A,Burkart R,Perkins GD,Bossaert LL, EuReCa ONE-27 Nations, ONE Europe, ONE Registry: A prospective one month analysis of out-of-hospital cardiac arrest outcomes in 27 countries in Europe. Resuscitation. 2016 Aug [PubMed PMID: 27321577]|
|||[PubMed PMID: 18514823]|
|||[PubMed PMID: 28403909]|
|||Beilharz EJ,Williams CE,Dragunow M,Sirimanne ES,Gluckman PD, Mechanisms of delayed cell death following hypoxic-ischemic injury in the immature rat: evidence for apoptosis during selective neuronal loss. Brain research. Molecular brain research. 1995 Mar [PubMed PMID: 7769986]|
|||Fugate JE, Anoxic-Ischemic Brain Injury. Neurologic clinics. 2017 Nov [PubMed PMID: 28962803]|
|||[PubMed PMID: 23672736]|
|||Donnino MW,Andersen LW,Berg KM,Reynolds JC,Nolan JP,Morley PT,Lang E,Cocchi MN,Xanthos T,Callaway CW,Soar J, Temperature Management After Cardiac Arrest: An Advisory Statement by the Advanced Life Support Task Force of the International Liaison Committee on Resuscitation and the American Heart Association Emergency Cardiovascular Care Committee and the Council on Cardiopulmonary, Critical Care, Perioperative and Resuscitation. Resuscitation. 2016 Jan [PubMed PMID: 26449873]|
|||Bernard SA,Gray TW,Buist MD,Jones BM,Silvester W,Gutteridge G,Smith K, Treatment of comatose survivors of out-of-hospital cardiac arrest with induced hypothermia. The New England journal of medicine. 2002 Feb 21 [PubMed PMID: 11856794]|
|||Mild therapeutic hypothermia to improve the neurologic outcome after cardiac arrest. The New England journal of medicine. 2002 Feb 21 [PubMed PMID: 11856793]|
|||[PubMed PMID: 17338844]|
|||[PubMed PMID: 17334257]|
|||[PubMed PMID: 24237006]|
|||Callaway CW,Donnino MW,Fink EL,Geocadin RG,Golan E,Kern KB,Leary M,Meurer WJ,Peberdy MA,Thompson TM,Zimmerman JL, Part 8: Post-Cardiac Arrest Care: 2015 American Heart Association Guidelines Update for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. Circulation. 2015 Nov 3 [PubMed PMID: 26472996]|
|||Polderman KH, Mechanisms of action, physiological effects, and complications of hypothermia. Critical care medicine. 2009 Jul [PubMed PMID: 19535947]|
|||Silverman MG,Scirica BM, Cardiac arrest and therapeutic hypothermia. Trends in cardiovascular medicine. 2016 May [PubMed PMID: 26603661]|
|||[PubMed PMID: 32084066]|
|||Oddo M,Rossetti AO, Predicting neurological outcome after cardiac arrest. Current opinion in critical care. 2011 Jun [PubMed PMID: 21346563]|
|||[PubMed PMID: 22810246]|
|||[PubMed PMID: 20927660]|
|||Taccone F,Cronberg T,Friberg H,Greer D,Horn J,Oddo M,Scolletta S,Vincent JL, How to assess prognosis after cardiac arrest and therapeutic hypothermia. Critical care (London, England). 2014 Jan 14 [PubMed PMID: 24417885]|
|||Weiss N,Galanaud D,Carpentier A,Naccache L,Puybasset L, Clinical review: Prognostic value of magnetic resonance imaging in acute brain injury and coma. Critical care (London, England). 2007 [PubMed PMID: 17980050]|
|||Hirsch KG,Mlynash M,Jansen S,Persoon S,Eyngorn I,Krasnokutsky MV,Wijman CA,Fischbein NJ, Prognostic value of a qualitative brain MRI scoring system after cardiac arrest. Journal of neuroimaging : official journal of the American Society of Neuroimaging. 2015 May-Jun [PubMed PMID: 25040353]|
|||Wijdicks EF,Hijdra A,Young GB,Bassetti CL,Wiebe S, Practice parameter: prediction of outcome in comatose survivors after cardiopulmonary resuscitation (an evidence-based review): report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology. 2006 Jul 25 [PubMed PMID: 16864809]|
|||Khot S,Tirschwell DL, Long-term neurological complications after hypoxic-ischemic encephalopathy. Seminars in neurology. 2006 Sep [PubMed PMID: 16969743]|