JILL Z. STUART
THOMAS J. FARRER
ALEX L. HEINTZELMAN
Hypoxic and anoxic brain injuries can damage many different organ systems, and some organs are particularly vulnerable due to their high oxygen consumption. For example, although the brain constitutes only a mere 2% of the total body mass, it uses 20% of the body’s total oxygen consumption (Hopkins & Bigler, 2008). Hypoxic brain injury refers to a reduction of oxygen to the brain tissue, and anoxia refers to total absence of oxygen. Isolated hypoxia/anoxia refers strictly to lack of oxygen, whereas ischemia refers to a restriction of blood supply to tissues, which causes not only a shortage of oxygen, but also a shortage of essential cellular metabolites (i.e., glucose) (Howard, Holmes, & Koutroumanidis, 2011). Neurons in particular are sensitive to oxygen deprivation because they are not capable of storing oxygen and glucose for later use (Hopkins & Bigler, 2008). In fact, brain cells can begin to die within 5 minutes after oxygen supply has been cut off.
Advances in medicine make it increasingly likely that a significant number of individuals will have a hypoxic or anoxic event. For example, cardiac or pulmonary crises are no longer the death sentence they used to be, but surviving these events can lead to other medical and/or psychosocial complications. A large percentage of patients who have had hypoxic or anoxic brain injuries are unable to return to their premorbid level of functioning and many will be unable to return to work. Therefore, hypoxic/anoxic brain injuries have the potential to become a significant public health concern.
This chapter will describe the pathophysiology behind anoxic and hypoxic brain injuries, common etiologies, and the epidemiology of such events. We will also discuss clinical presentations, diagnostic considerations, and treatment recommendations for neurotrauma and neurorehabilitation professionals. Finally, a clinical case of anoxic brain injury following an episode of cardiac arrest will be presented with a brief discussion highlighting the relevant medical, cognitive, and treatment needs of the patient.
Both research and clinical examination of hypoxic and anoxic injury have evolved with time. In fact, a PubMed search of “anoxic brain injury” indicates that the number of indexed publications has increased from 599 in 2000 to 783 in 2005, 936 in 2010, and 1,014 in 2015 (National Library of Medicine [pubmed.gov]). This increase in research related to hypoxic and anoxic injury is likely related to multiple factors, including diet, obesity, environmental pollutants, and increasing rates of chronic obstructive pulmonary disease (COPD) and asthma. Cardiovascular and pulmonary diseases continue to be common public health concerns. There are also increased incidence rates of obstructive sleep apnea (OSA), COPD, and acute respiratory distress syndrome (ARDS), all of which correlate with lifestyle factors such as alcohol consumption, sedentary living, and tobacco use (Franklin & Lindberg, 2015; Raherison & Girodet, 2009). This is especially true among older adults. Specifically, the elderly are particularly vulnerable to lifestyle risks and other injuries, which is a significant public health concern given people are more likely to live to an older age and due to the fact that the average age of the adult population is increasing. In addition, the increased rates of obesity in the United States correlate in a rise in rates of COPD and OSA (Franklin & Lindberg, 2015; Raherison & Girodet, 2009). Second, as critical care medicine has advanced, mortality rates have declined following such emergencies as cardiac arrest, stroke, and carbon monoxide poisoning (Rab et al., 2015; Wilson, Staniforth, Till, das Nair, & Vesey, 2014). With high survival rates, more individuals experience long-term deficits from oxygen deprivation to the brain.
Overall, the extent of brain damage is directly linked to the length of time without oxygen (Busl & Greer, 2010). Once circulation is interrupted, cell death occurs in several ways: necrosis, apoptosis, autophagy, excitotoxicity, decreased ATP production, and calcium influx (Hopkins & Bigler, 2008; Northington, Chavez-Valdez, & Martin, 2011). In purely hypoxic brain injuries, with sustained circulation, glucose is still supplied to the brain and toxic metabolites are able to be washed away (Busl & Greer, 2010). During hypoxia or anoxia, there is a decrease of adenosine triphosphate (ATP) production, which ultimately results in a pathophysiological cascade that leads to neuronal death (Hopkins & Haaland, 2004). One of the first results is anoxic depolarization, which leads to changes in electrolyte composition both inside and outside of cells and a decrease in ATP (Busl & Greer, 2010). This change in electrolyte composition causes a decrease in cell membrane function and ultimately an approximate 25% increase in total cell calcium (Busl & Greer, 2010). This high intracellular calcium results in mitochondrial damage that causes further ATP depletion (Busl & Greer, 2010). Ultimately, the cytoskeleton is damaged and therefore cells cannot maintain their structure, which is a crucial factor in the process of cell death (Busl & Greer, 2010). This mechanism is referred to as “death by calcium” and can cause protein degradation (Biagas, 1999). In addition to the aforementioned processes, which occur from the initial oxygen deprivation, ischemic reperfusion injury can also cause neuronal damage (Hopkins & Bigler, 2008).
Although neuroanatomical damage can often be widespread (Hopkins, Kesner, & Goldstein, 1995), the hippocampus, a structure that plays a crucial role in memory and storage of semantic knowledge, is one of the most vulnerable structures and widely known structures to be damaged by hypoxic/anoxic injury. In addition, the cerebral cortex neurons, cerebellum, deep white matter, corpus callosum, fornix, mammillary bodies, and basal ganglia are particularly susceptible to the drop in cerebral blood flow and therefore are less resistant to oxygen deprivation (Garcia-Molina et al., 2006; Hopkins & Bigler, 2012). Deficits in memory due to hippocampal damage is perhaps one of the most common neuropathological outcomes of hypoxic injury; however, some researchers have suggested that changes in watershed areas and the basal ganglia are even more common (Caine & Watson, 2000). A study comparing the effects of hypoxia on the brain due to either carbon monoxide poisoning or OSA revealed hippocampal atrophy in both groups, whereas generalized brain atrophy was more prevalent in the carbon monoxide group (Gale & Hopkins, 2004). The amount of neuronal tissue loss has been suggested as an important factor in neuropsychological outcome in the absence of focal lesions (Hopkins, Tate, & Bigler, 2005).
The most common cause of hypoxic–ischemic brain injury is cardiac arrest. Other causes of hypoxic (not necessarily ischemic) injuries include profound hypotension (associated with pulmonary embolism, surgery, shock, sepsis, metabolic encephalopathy, and drug overdose), as well as hypovolemia due to blood loss, drowning, stroke, and neonatal injuries (Howard et al., 2011). Isolated hypoxic brain injuries include any situation that results in decreased oxygen flow, such as suffocation, airway obstruction, strangulation, drowning, or poisoning. According to the National Institutes of Health (NIH), common causes of hypoxia include smoke inhalation, carbon monoxide poisoning, choking, high altitudes, compression of the trachea, and suffocation or strangulation, including as a result of attempted suicide. Other causes include asthma, OSA, and COPD (Hopkins & Bigler, 2008; Howard et al., 2011). Isolated hypoxia is more common in children as they are more likely to suffer from asphyxia, whereas adults are more likely to have cardiac arrest and suffer from ischemia (Biagas, 1999). Children who survive asphyxia at birth often develop problems such as cerebral palsy, mental retardation, and learning difficulties (Bryce, Boschi-Pinto, Shibuya, Black, & WHO Child Health Epidemiology Reference Group, 2005).
Cardiac death is the leading cause of mortality in the United States (Chiota, Freeman, & Barrett, 2011), with only a 10% survival rate if occurring outside the hospital setting (Hinduja, Gupta, Yang, & Onteddu, 2014). The survival rate of an in-hospital cardiac arrest is between 2.4% and 18.1% (Hinduja et al., 2014). An autopsy study of patients with cardiopulmonary arrest revealed 21% with hypoxic brain damage (Hinduja et al., 2014). One study of anoxic brain injury revealed interesting age/sex differences, with incidents of anoxic injury in men peaking around age 60 related to cardiac causes, whereas for women there was a peak in the 20- to 30-year-old age group related to a higher prevalence of suicide or parasuicide (Fitzgerald, Aditya, Prior, McNeill, & Pentland, 2010). According to Franklin and Lindberg (2015), the prevalence of OSA, a condition causing intermittent hypoxia, in general population–based studies is roughly 22% in men and 17% in women. Carbon monoxide poisoning in the United States has resulted in extremely large numbers of patients diagnosed but a relatively low death rate. Specifically, carbon monoxide poisoning accounts for 50,000 emergency department visits and 2,700 deaths annually in the United States (Ruth-Sahd, Zulkosky, & Fetter, 2011). Hypoxia due to carbon monoxide poisoning has an increased incidence in colder months, when use of furnaces and fireplaces increases.
As the incidence of hypoxic and anoxic injuries rise, more information is needed on the public health impact of hypoxia/anoxia, including the financial burden as a result of the functional impact of these brain injuries. Cullen and Weisz (2011) note that research on patients with anoxic brain injuries pales in comparison to the research on patients with traumatic brain injury (TBI); however, there is a trend in the literature showing worse functional outcomes in patients with anoxic brain injuries compared with TBI. Of the studies that do exist, most studies do not include older adults with nontraumatic brain injuries such as anoxia. Certainly, the variability in etiology, age ranges, and severity of brain injury can make it difficult to set up direct comparisons between groups.
Pure hypoxic brain injury does not always cause severe brain injury if systemic circulation is maintained (Busl & Greer, 2010); however, hypoxic/anoxic brain injuries often result in neurocognitive deficits. In their review, Caine and Watson (2000) found that hypoxic brain injury resulted in amnestic memory impairment in over half (54%) of the individual case reports they analyzed; executive deficits or personality changes (i.e., frontal symptoms) were the second most commonly reported neuropsychological sequela, followed by visuospatial deficits. A similar pattern emerged in their review of group studies. Garcia-Molina et al. (2006) investigated cognitive outcomes across two different groups of patients with cerebral anoxic injuries. Although deficits in multiple domains of cognition were reported, the authors found more significant verbal memory deficits with episodes of ischemic anoxia than in patients with hypoxemic anoxia. In general, the degree of neurocognitive impairment tends to mirror the degree of neuropathological damage (Hopkins & Bigler, 2008).
Brain imaging for anoxic/hypoxic injuries often reveals both focal and diffuse neuropathologic lesions and atrophy (Hopkins & Bigler, 2008). Hopkins and Bigler (2008) note that commonly ordered scans (e.g., CT and MR) may appear to be normal or show only subtle changes during the acute period; however, newer imaging techniques (e.g., diffusion-weighted magnetic resonance imaging [MRI]), can reveal more extensive changes even in the acute phase. Damage is commonly reported in the hippocampus, white matter, cerebellum, and corpus callosum, as noted previously in this chapter. For example, using voxel-based morphometry, Di Paola et al. (2008) found a bilateral reduction of hippocampal gray matter in persons who had anoxic/hypoxic injuries as compared with healthy subjects. In terms of diffuse damage, common findings may include generalized cerebral atrophy and enlargement of the ventricles, with enlarged ventricle to brain ratios (Hopkins & Bigler, 2008). Diffuse damage is likely to appear over time, not acutely following hypoxic injury.
Psychosocial impairments are important considerations in overall quality of life post hypoxic brain injury. Not surprisingly, quality of life may vary significantly depending on the extent of the hypoxic/anoxic injury, particularly with greater cognitive impairments that affect one’s ability to work, independence for ADLs, or interpersonal relationships. Psychological and behavioral changes often occur following hypoxic/anoxic brain injuries. Symptoms can vary widely and may include symptoms of euphoria, irritability, hostility, emotional lability, apathy, depression, anxiety, and occasionally mania (Hopkins & Bigler, 2008). Emotional and personality changes can be difficult for the patient, as well as for loved ones or caregivers. In a study of psychosocial outcomes of anoxic brain injury following cardiac arrest, Wilson et al. (2014) found that patients who had anoxia following cardiac arrest demonstrated more significant psychosocial difficulties, including anxiety, depression, PTSD, and social problems. Social difficulties were associated with subjective ratings of memory and executive dysfunction.