INTRODUCTION
The incidence of cardiac arrest with anoxia and cerebral ischemia occurs in more than 400,000 cases per year in the United States, of which more than 80% of these patients are likely to have poor neurological outcomes (Geocadin et al., Reference Geocadin, Buitrago, Torbey, Chandra-Strobos, Williams and Kaplan2006; Zheng et al., Reference Zheng, Croft, Giles and Mensah2001). Recent improvements in emergency and critical care medicine have resulted in approximately 200,000 cardiac resuscitations per year of which over 70,000 patients survive but constitute only 1% of those admitted to brain injury rehabilitation centers (Bachman & Katz, Reference Bachman, Katz, Mills, Cassidy and Katz1997). Anoxia and ischemia can occur because of cardiac or respiratory arrest, open heart surgery, attempted hanging, complications of anesthesia, and near drowning.
Some brain regions are more vulnerable to the effects of anoxia/ischemia, particularly structures at the end of the vascular supply, with high metabolic rates (Brierley & Graham, Reference Brierley and Graham1984), and/or proximity to structures that contain excitatory amino acids such as glutamate (Martin et al., Reference Martin, Lloyd and Cowan1994; Siesjo et al., Reference Siesjo, Bengtsson, Grampp and Theander1989). Vulnerable brain regions include the neocortex, hippocampus, basal ganglia, cerebellum, primary visual cortex, frontal regions, and thalamus (Chalela et al., Reference Chalela, Wolf, Maldjian and Kasner2001). Anoxic brain injury results in focal and diffuse neuropathologic lesions and atrophy (Bachevalier & Meunier, Reference Bachevalier and Meunier1996; Caine & Watson, Reference Caine and Watson2000; Gale et al., Reference Gale, Hopkins, Weaver, Bigler, Booth and Blatter1999; Hopkins et al., Reference Hopkins, Kesner and Goldstein1995b) including lesions in the hippocampus (Manns et al., Reference Manns, Hopkins, Reed, Kitchener and Squire2003a; Manns et al., Reference Manns, Hopkins and Squire2003b), basal ganglia, cerebellum (Mascalchi et al., Reference Mascalchi, Petruzzi and Zampa1996), subcortical and periventricular white matter lesions (Parkinson et al., Reference Parkinson, Hopkins, Cleavinger, Weaver, Victoroff, Foley and Bigler2002) and atrophy of the corpus callosum (Porter et al., Reference Porter, Hopkins, Weaver, Bigler and Blatter2002). Generalized brain volume loss leading to ventricular enlargement and sulcal widening (Caine & Watson, Reference Caine and Watson2000) and hippocampal atrophy are also common (Hopkins et al., Reference Hopkins, Kesner and Goldstein1995b; Press et al., Reference Press, Amaral and Squire1989). A review of anoxic brain injury (N = 90) found that 44% of individuals had cortical edema or atrophy, 33% had cerebellar lesions, 22% had basal ganglia lesions, 21% had hippocampal atrophy, and 3% had thalamic lesions (Caine & Watson, Reference Caine and Watson2000).
Neurological and Neuropsychological Sequelae
Poor neurological outcomes after brain injury include death, coma, vegetative state, severe neurologic disability (Jennett & Bond, Reference Jennett and Bond1975), cognitive sequelae, and development of new psychiatric disorders (Bachevalier & Meunier, Reference Bachevalier and Meunier1996; Caine & Watson, Reference Caine and Watson2000). Neuropsychological deficits after anoxia or ischemia are heterogeneous and include agnosia (Farah, Reference Farah1990), impaired memory (Hopkins et al., Reference Hopkins, Myers, Shohamy, Grossman and Gluck2004; Manns et al., Reference Manns, Hopkins, Reed, Kitchener and Squire2003a; Zola-Morgan et al., Reference Zola-Morgan, Squire and Amaral1986), executive dysfunction (Hopkins et al., Reference Hopkins, Gale, Johnson, Anderson, Bigler, Blatter and Weaver1995a; Lezak, Reference Lezak1995), impaired visual-spatial skills (Barat et al., Reference Barat, Blanchard and Carriet1989), generalized cognitive impairments (Wilson, Reference Wilson1996), and motor disturbances (Lishman, Reference Lishman1998). Psychological and behavioral changes following anoxic brain injury often include euphoria, irritability, emotional volatility, depression, and anxiety (Bahrke & Schukitt-Hale, Reference Bahrke and Schukitt-Hale1993; Li et al., Reference Li, Wu, Fu, Shen, Wu and Wang2000).
Mechanisms of Brain Injury
Anoxia or ischemia causes a pathophysiological cascade that leads to neuronal damage and death (for reviews of the mechanisms see Biagas, Reference Biagas1999; Johnston et al., Reference Johnston, Nakajima and Hagberg2002). Mechanisms of anoxic induced neuronal injury include: (1) decreased ATP production without decreasing ATP utilization, resulting in energy depletion, ionic pump failure, K+ outflow, and inflow of Ca2+ (Lutz & Nilsson, Reference Lutz and Nilsson1994); (2) lactic acidosis caused by anaerobic metabolism (Siesjo, Reference Siesjo1981); (3) excitotoxic damage caused by excessive glutamate release leading to increased neuronal firing, calcium influx, and neuronal death (Johnston et al., Reference Johnston, Nakajima and Hagberg2002); (4) increased calcium influx and intracellular accumulation of calcium due to ionic pump failure (Schurr et al., Reference Schurr, Lipton, West, Rigor and Krieglstein1990); (5) the formation of oxygen radicals during reperfusion or reoxygenation (Biagas, Reference Biagas1999); (6) nitric oxide synthase leads to impaired neurotransmission, protein synthesis, and membrane peroxidation (Biagas, Reference Biagas1999); and (7) anoxia or ischemia also results in neuronal necrosis and/or apoptosis or programmed cell death (Beilharz et al., Reference Beilharz, Williams, Dragunow, Sirimanne and Gluckman1995; Steller, Reference Steller1995).
Therapeutic Hypothermia
Recent research has generated considerable hope for better recovery following anoxia and ischemia using a variety of treatments. One such treatment is therapeutic hypothermia, which has shown improved neurological outcomes in 1 out of every 6 patients after cardiac arrest and cardiopulmonary resuscitation (Bernard et al., Reference Bernard, Gray, Buist, Jones, Silvester, Gutteridge and Smith2002; The Hypothermia after Cardiac Arrest Study Group, 2002). In principle a reduction in brain metabolic demands lead to decreased oxygen requirements and therefore reduced vulnerability to the neural effects of anoxia/ischemia. Animal models show that hypothermia inhibits multiple steps in the reperfusion phase of anoxic injury, including ATP consumption (Erecinska et al., Reference Erecinska, Thoresen and Silver2003), reduced neuronal depolarization (Sick et al., Reference Sick, Xu and Perez-Pinzon1999), decreased extra cellular glutamate concentrations (Busto et al., Reference Busto, Globus, Dietrich, Martinez, Valdes and Ginsberg1989), and decreased free radical production (Globus et al., Reference Globus, Alonso, Dietrich, Busto and Ginsberg1995). A meta-analysis of 3 randomized controlled clinical trails in humans evaluated therapeutic hypothermia compared to normothermia found that therapeutic hypothermia was associated with good neurologic outcomes [relative risk of 1.68 (95% CI 1.29–2.07)] (Holzer et al., Reference Holzer, Bernard, Hachimi-Idrissi, Roine, Sterz and Mullner2005). The data mentioned earlier raise questions as to what if any role accidental hypothermia caused by cold-water immersion may play in preventing or reducing neuropsychological and psychiatric sequelae following near drowning.
Cold Water Near-Drowning
Cold water near-drowning is often believed to be neuroprotective in individuals with anoxia of a longer duration than that usually required to produce irreversible neurologic damage (Chochinov et al., Reference Chochinov, Baydock, Bristow and Giesbrecht1998). Such neuroprotection is attributed to low core body temperatures, which reduce cerebral metabolic oxygen requirements and the mammalian dive reflex, which is believed to enhance the delivery of limited available oxygen stores to the brain (Chochinov et al., Reference Chochinov, Baydock, Bristow and Giesbrecht1998). Most studies to date that assess outcome following cold water near-drowning have been conducted in children. A review of near-drowning and ice-water submersion in pediatric patients (13 less than 19 years of age) found 15 patients had a good outcome and 2 patients had a “fair to good outcome”, but outcome was not defined and neuropsychological tests were not administered to these patients (Orlowski, Reference Orlowski1987). There are few cases of near-drowning with cold-water submersion with poor outcomes reported in the literature (Orlowski, Reference Orlowski1987). Orlowski suggests that cases with poor outcome are probably not reported whereas cases with good outcome are more commonly reported, resulting in a bias of good outcomes in the literature (Orlowski, Reference Orlowski1987). One case of note, is that of R.D. who at 2.5 years of age was submerged in frigid water for 66 minutes with reportedly “good neurologic recovery” (Bolte et al., Reference Bolte, Black, Bowers, Thorne and Corneli1988). However, a neuropsychological evaluation 13 years later in this same individual found broad neurodevelopmental compromise, impaired memory, and executive function, despite a normal brain imaging (Hughes et al., Reference Hughes, Nilsson, Boyer, Bolte, Hoffman, Lewine and Bigler2002).
There is a paucity of data in adults with cold water near-drowning that assess outcome and only one study assessed neuropsychological function (Huckabee et al., Reference Huckabee, Craig and Williams1996). The two cases of cold water near-drowning reported in this issue of JINS by Samuelson and colleagues assessed short term (a few days to months) and long-term (1.5 to 3.5 years) neuropsychological outcomes. Both cases had neuropsychological impairments that persisted over time. The neuropsychological findings of these two individuals with anoxic brain injury following cold water near-drowning are similar to those reported after anoxia from other etiologies (Bachevalier & Meunier, Reference Bachevalier and Meunier1996; Caine & Watson, Reference Caine and Watson2000; Hopkins et al., Reference Hopkins, Myers, Shohamy, Grossman and Gluck2004; Manns et al., Reference Manns, Hopkins, Reed, Kitchener and Squire2003a; Zola-Morgan et al., Reference Zola-Morgan, Squire and Amaral1986). Further, these two individuals had symptoms of depression and behavioral changes. The rate of mood disorders after anoxic brain injury varies from 24% to 60% of cases, which is significantly higher than the prevalence rate in the general population (2% to 9% major depression and 3% generalized anxiety), and the 12% rate observed in medical populations.
Case 1 had a normal brain MRI scan 1.5 years after the accident, a finding that is similar to that reported by Orlowski (Reference Orlowski1987). However, brain imaging findings in near-drowning survivors are heterogeneous with abnormalities ranging from hemorrhageic infarctions to global atrophy (Fitch et al., Reference Fitch, Gerald, Magill and Tonkin1985). Similarly, brain MRI findings in anoxic patients who were not near-drowning accidents include lesions in gray (e.g., basal ganglia, hippocampus, etc) and white matter, and global and focal atrophy (Bachevalier & Meunier, Reference Bachevalier and Meunier1996; Caine & Watson, Reference Caine and Watson2000; Hopkins et al., Reference Hopkins, Myers, Shohamy, Grossman and Gluck2004; Manns et al., Reference Manns, Hopkins, Reed, Kitchener and Squire2003a; Zola-Morgan et al., Reference Zola-Morgan, Squire and Amaral1986). Whereas braining imaging was normal by radiologic report in Case 1, quantitative neuroimaging was not carried out (Bachevalier & Meunier, Reference Bachevalier and Meunier1996; Caine & Watson, Reference Caine and Watson2000; Gale et al., Reference Gale, Hopkins, Weaver, Bigler, Booth and Blatter1999; Hopkins et al., Reference Hopkins, Kesner and Goldstein1995b). Nonspecific brain damage may result in general volume reduction manifested by reduced gyral volume, increased sulcal space, passive increase in ventricular volume (i.e., hydrocephalus ex vacuo), increase in whole brain cerebral spinal fluid (CSF; Graham et al., Reference Graham, Gennarelli, McIntosh, Graham and Lantos2002), and structural atrophy (e.g. hippocampus, basal ganglia, etc.). These changes may not be apparent visually but can be readily documented using quantitative MR analyses (Bigler, Reference Bigler2001). Thus, quantitative neuroimaging may detect important neuropathological changes in these cases that otherwise may not be detected.
The accidental hypothermia in these two cases likely contributed to preservation of life, but was not entirely neuroprotective, because both individuals had long-term neuropsychological and behavioral changes. The neuropsychological and neurobehavioral changes are similar to that observed after anoxia because of other etiologies. It is unclear if the accidental hypothermia reduced the extent and severity of the neuropsycholgoical and behavioral changes in these two cases, but it is certainly possible given the long duration of anoxia experienced by these two individuals. Research on the long-term effects of anoxia with and without cold water near-drowning on neuropathology, neuropsychological, and neurobehavioral outcomes is needed to better elucidate the effects of and possible benefits of accidental hypothermia.
