Traumatic Brain Injury and Effects of Altitude: An Analysis of the Literature

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1 Traumatic Brain Injury and Effects of Altitude: September 14, 2010

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3 TABLE OF CONTENTS Executive Summary... 1 Introduction... 4 Background... 4 Secondary brain injury due to TBI... 7 Clinical Parameters of TBI at Altitude... 9 Neuropsychological effects of altitude exposure Military Concerns and Operational Constraints Objectives TBI at Altitude: Risk Factors Altitude-related brain damage Aeromedical transport Hypoxia Intra-cranial pressure/blood pressure Hydration Temperature Conclusions Clinical considerations Research Considerations References Appendix FIGURES Figure 1. Neurological symptoms and cognitive impairments associated with high altitudes... 7 Figure 2. Events and processes underlying primary and secondary brain injury... 8 Figure 3. Proposed pathogenesis of ACE and HACE TABLES Table 1. Overview of altitude-related risk factors for adverse TBI outcome... 5 Table 2. Studies of altitude-related brain damage Table 3. Studies of aeromedical transport of TBI Table 4. Studies of hypoxia effects on TBI outcome Table 5. Studies of ICP and/or blood pressure effects on TBI Table 6. Studies of hydration effects on TBI Table 7. Studies of temperature effects on TBI September 14, 2010 i

4 ABBREVIATIONS AMS ADH BBB BINT CPP CT DCoE DCS GCS HACE HAPE ICP MAP mmhg MRI mtbi PaO 2 P0 2 SpO 2 TBI acute mountain sickness antidiuretic hormone (vasopressin) blood-brain barrier blast-induced neurotrauma cerebral perfusion pressure computed tomography Defense Centers of Excellence decompression sickness Glasgow Coma Scale high-altitude cerebral edema high-altitude pulmonary edema intra-cranial pressure mean arterial pressure millimeters of mercury magnetic resonance image mild traumatic brain injury partial pressure of oxygen in arterial blood partial pressure of oxygen saturation of peripheral oxygen (pulse oximeter saturation) traumatic brain injury September 14, 2010 ii

5 Traumatic Brain Injury (TBI) and Effects of Altitude: Executive Summary The mission of the Defense Centers of Excellence (DCoE) for Psychological Health and Traumatic Brain Injury is to assess, validate, oversee and facilitate the prevention, resilience, identification, treatment, outreach, rehabilitation and reintegration programs for psychological health and traumatic brain injury to ensure the Department of Defense meets the needs of the nation s military communities, warriors, and families. In support of these objectives, we performed a literature review and analysis of recent and relevant research to inform the care and treatment of military TBI involving high-altitude settings. The scope and methodology for this analysis were developed in collaboration with the DCoE Traumatic Brain Injury Clinical Standards of Care Directorate. Although relatively uncommon in civilian settings, the potentially adverse effects of high ( meters), very high ( meters) or extreme altitude (above 5500 meters) exposure must be weighed in treating head injuries sustained by mountain climbers, aviators, and military personnel involved in conflicts at high elevations. It is well-known that rapid ascent to high altitude can cause acute mountain sickness (AMS) and, more rarely but more seriously, high-altitude cerebral edema (HACE). These syndromes can cause brain swelling and increased intracranial pressure (ICP). Due to a combination of low temperature and hypoxia, exposure to high altitude can have significant effects upon brain function even in otherwise healthy individuals. Many of the same factors that affect healthy brains at high altitude are also implicated in secondary brain injury processes common within the minutes, hours and days following TBI. For example, mean arterial pressure, fluid balance and ICP are potentially important variables in determining the outcome of TBI generally. Therefore, it is important to consider how these factors might complicate the care and treatment of TBI patients at altitude and in the course of aeromedical evacuation and transport. The purpose of this report was to consider how altitude-related factors might complicate or confound military traumatic brain injury (TBI) and its care and treatment. Specifically, we examine the potentially complicating effects of conditions that can occur as direct or indirect effects of exposure to high altitude. These include hypoxia, hypotension, elevated intracranial pressure (ICP), dehydration and hypothermia/hyperthermia. Each of these variables can play a role in secondary brain injury and/or altitude-related illness, and each has been demonstrated to adversely affect TBI patient survival and/or functional recovery. As many as 40% of TBI patients deteriorate not as the direct result of their primary injuries, but rather due to the damaging effects of secondary physiologic, mechanistic, and neuroinflammatory processes. Based on the available scientific medical literature, we find clear basis for concern that exposure to high altitude may tend to increase TBI patients vulnerability to secondary brain injury and compromise their outcome. In addition, there is an obvious and compelling need for additional research in this area, to identify and document the potential effects and extent of these risks in military medical settings, September 14,

6 especially in the context of aeromedical evacuation that may require rapid ascent in unpressurized aircraft. Clinical research to date emphasizes the need for efficient medical evacuation as well as early mitigation of hypoxia, hypotension, ICP, dehydration and uncontrolled temperature abnormalities. Specifically, our review and analysis finds that: Exposure to very high altitudes can induce brain damage and impair cognitive functioning. Hypoxia, which is correlated with poor TBI outcome, likely plays a major role in altitude-related brain injury. Elevated ICP and hypotension play an important role in determining outcome from brain injury. Fluid resuscitation and management is important to prevent hypotension and prevent adverse effects of secondary brain injury and/or altitude exposure. Hyperthermia is a risk factor for secondary brain injury. Hyperthermia is common in post-acute TBI, and can be the result of environmental high temperatures, strenuous physical activity, infection, or injury-related hypothalamic damage and impaired thermoregulation. Hypothermia has been linked to increased mortality in general trauma patients, including those with TBI. Hypothermia is a concern in military operational settings and in military aeromedical evacuation, where the average interior temperature of a military cargo plane is around 59 F. To reduce the risks associated with hyperthermia and hypothermia, it is important to assess and stabilize temperature in the pre-hospital setting. Retrospective clinical studies suggest that preventing hypoxia, controlling high ICP and temperature stabilization are beneficial to TBI patient outcome. Therefore, it is important that TBI patients avoid exposure to hypoxia, hypotension, and extreme temperatures in the immediate aftermath of injury. Through this analysis, several key knowledge gaps are apparent. Primarily, there is a pressing need for clinical studies and/or case reports of military aeromedical evacuation and transport involving TBI casualties. Virtually no research has yet been published to address the unique injury and treatment experiences of military TBI casualties in high-altitude settings. Clinical findings are crucial to inform the development of risk and injury profiles and protocols which can address timing and interventions needed to prevent adverse outcomes from exposure to altitude-related factors, as well as secondary brain injury events. Specifically, additional research is needed to address the following concerns: Identify risks, benefits, intervention strategies and outcomes associated with military aeromedical transport of TBI casualties This information is needed to identify the ideal time to fly and to inform risk profiles and injury protocols to address the timing and use of interventions to mitigate adverse effects of altitude and/or secondary brain injury events. Document the effects of altitude exposure on mild TBI (mtbi) and blast-induced neurotrauma (BINT) Although mtbi can involve structural neurological damage, little if any research to date has addressed the potential impact of secondary brain injury processes on mtbi. Most military TBIs are classified as mild, related to the effects of blast or explosion. The potential impact of altitude on these injuries is largely unknown. September 14,

7 Determine what, if any, health risks or performance effects might occur among post-tbi/postconcussion military personnel who return to duty at high altitudes Operational performance at altitude introduces physiologic stress, which may reveal lingering functional post-tbi or repeated concussion-related deficits otherwise not clinically apparent at sea level. It is essential to determine how the return to duty in high-altitude and mountainous terrain might affect the health or performance of military personnel who are classified as recovered from TBI. Investigate the efficacy of pharmacotherapeutic interventions for the prevention of altituderelated and secondary brain injuries Medications effective in treating altitude illness can improve oxygenation and reduce inflammatory responses. To the extent that these processes also mediate secondary brain injury, altitude medications may be useful to mitigate effects of altitude and secondary injury on TBI outcome. Conversely, it is important to identify medications that are contraindicated for use in TBI at altitude. TBI is a persistent challenge in civilian and military settings, due to the inherent difficulties of preventing secondary brain injury and controlling for environmental factors that may provoke or aggravate secondary injury. Practical challenges are most pronounced in the combat casualty environment, where military medical practitioners are expected to deliver care in austere and sometimes hostile environments. This review hopes to inform these efforts, and to catalyze additional research as needed to determine optimal solution sets and treatment strategies. September 14,

8 Introduction BACKGROUND Traumatic brain injury (TBI) can occur as the result of external force due to blunt impact (being struck by or striking an object); foreign body penetration of the brain, sudden; brain acceleration or deceleration movement; or concussive forces from an explosion or blast (see Taber et al., 2006). Depending on the severity of the underlying injury, TBIs are classified as mild, moderate or severe. Most (75-90%) are classified as mild TBI (mtbi) or as concussion 1 (Cassidy et al., 2004). TBI is a significant public health concern. An estimated two percent of Americans currently live with TBIrelated disability and related costs (Rutland-Brown et al., 2006; Thurman et al., 1999). The Centers for Disease Control (CDC) estimates that each year, 1.7 million people in the United States sustain traumatic brain injuries (TBI). These injuries represent nearly one-third of all injury-related deaths in the U.S. annually, and are the leading cause of death and disability among young adults (CDC, 2006). Importantly, statistics reported by the CDC do not include deployed service member or veteran TBIs from federal, military, or Veterans Administration (VA) hospitals which face a variety of unique challenges associated with the diagnosis, care and treatment of TBI sustained in recent military conflicts. In cooperation with the Armed Forces Health Surveillance Center, the Defense and Veterans Brain Injury Center (DVBIC) tracks and analyzes the incidence of military TBI based on actual medical diagnoses of TBI within the U.S. armed forces. Their findings show that military TBI incident diagnoses have more than doubled since Calendar Year * TBI Incident diagnoses 10, , , , , , , , , , 862 * Numbers updated as of 31 December Information available at DVBIC, Broadly recognized as a signature injury of conflicts in Iraq and Afghanistan, TBI is a significant concern for the U.S. military. Head, face and neck injuries have been reported to account for 22-52% of all battle injuries sustained by U.S. troops in Iraq and Afghanistan (Okie, 2005; Owens et al., 2008; Wade et al., 2007). In these conflicts, it has been estimated that TBI occurs in approximately 60% of blast casualties (Galarneau et al., 2008). In a recent study of soldiers deployed to Iraq, clinician-confirmed TBI history (primarily mtbi) was identified in more than one of every five (22.8%) soldiers from a Brigade Combat Team (Terrio et al., 2009). Other studies have found that as many as 28% of military personnel have sustained at least mtbi while deployed to conflicts in Iraq and Afghanistan (Warden, 2006). As the individual and operational costs of these injuries become increasingly obvious, so does our recognition 1 In 1997, the American Academy of Neurology (AAN, 1997) identified its criteria for three grades of concussion severity. The least severe of these (Grade 1) is sometimes described as minor concussion, but typically would not meet the diagnostic standards for mtbi. Therefore, the terms mtbi and concussion overlap, but are not necessarily always interchangeable. Although it is common for the two terms to be used interchangeably, it may not always be appropriate to do so in the diagnostic setting. September 14,

9 of the need to reduce the vulnerability and improve the survivability of military personnel who face a variety of unique risks in the course of their work. Military TBI patients follow a system of trauma care that begins with triage in the war zone and proceeds to acute care, rehabilitation, and reintegration into their homes and communities (for a description of TBI clinical care in the Department of Defense, see Jaffe et al., 2009). In 2005, the Brain Trauma Foundation ( published Guidelines for the Field Management of Combat- Related Head Trauma (Knuth et al., 2005) as an evidence-based guide to address the specific needs of head injury assessment, treatment and triage/transport decisions in military settings with attention to military operational concerns. However, these guidelines did not specifically address head injury in the context of high altitude. Although relatively uncommon in civilian settings, the potentially adverse effects of high ( meters), very high ( meters) or extreme altitude (above 5500 meters) exposure must be weighed in treating head injuries sustained by mountain climbers, aviators, and military personnel involved in conflicts at high elevations. The potentially adverse effects of altitude-related factors on TBI outcome are not fully understood, but have been documented in the published scientific and medical literature. Table 1 presents a summary overview of factors and events that are known to threaten the condition, outcome or survival of TBI patients. Although these events can occur in uncontrolled settings before, during or after TBI, research to date primarily documents the effects of these conditions when they occur during the pre-hospital, acute, and/or early post-acute stages of TBI. The information presented in Table 1 represents findings published to date, and is not intended to exclude other effects, exposure settings or injury severity levels not yet studied. Table 1. Overview of altitude-related risk factors for adverse TBI outcome Variable Hypoxia (brain po 2 < 15, PaO 2 < 60, SpO 2 < 90%) Hypotension (systolic B/P < 90) Adverse Outcomes Reported Morbidity Hosp/ICU length of stay Disability Mortality Cognitive Functional Hosp length of stay Disability Mortality Cognitive TBI severity levels studied Moderate Severe Moderate Severe Times of exposure considered Pre-hospital Acute Post-acute Pre-hospital Acute Post-acute Selected References Ariza et al., 2004 ; Chang et al., 2009 ; Chestnut et al., 1993; Chi et al., 2006 ; Davis et al., 2009 ; Geeraerts et al., 2008; Ghajar, 2000; Grissom, 2006; Jiang et al., 2002 ; Kiening, 1996; Mendeloff et al., 1991; Miller, 1978; Schreiber et al., 2002; Stochetti et al., 1996 Ariza et al., 2004 ; Chan et al., 1992; Chestnut et al., 1993; Chi et al., 2006 ; Clifton et al., 2002 ; Graham et al., 1989; Letarte et al., 1999;Manley et al., 2001 ; Marion et al., 1991; Marmarou et al., 1991; Morris, 1992; Schreiber et al., 2002 ; Stiver & Manley, 2008 September 14,

10 Variable ICP (> 20 mmhg) Dehydration (fluid balance < -594 ml; Clifton et al., 2002) Hyperthermia (> 37.5 C /100 F) Hypothermia (unmanaged) (< 35 C/95 F) Adverse Outcomes Reported Morbidity Mortality Cognitive Morbidity Mortality Hosp/ICU length of stay Morbidity Mortality Cognitive Morbidity mortality TBI severity levels studied Moderate Severe Severe Moderate Severe Severe Times of exposure considered Pre-hospital Acute Post-acute Pre-injury Pre-hospital Acute Pre-hospital Acute Post-acute Pre-hospital Acute Selected References Chan et al., 1992; Clifton et al., 2002 ; Cortbus et al., 1994; Graham et al., 1989; Jiang et al., 2002 ; Juul et al., 2000; Marion et al., 1991; Rosner et al., 1995; Schreiber et al., 2002 ; Stochetti et al, 1991 Badjatia et al., 2008; Clifton et al., 2002 ; Dickson et al., 2005; Eker et al., 1998; Shackford et al., 1992 Albrecht et al., 1998; Badjatia, 2009; Busto et al., 1987, 1989; Cairns & Andrews, 2002; Dietrich, 1992; Dietrich et al., 1990; Diringer et al., 2004 ; Geffroy et al., 2004 ; Jiang et al., 2002 ; Minamisawa et al., 1990 Coleshaw et al., 1982; Imray & Jurkovich et al., 1987; Luna et al., 1987; Oakley, 2005; Shurtleff et al., 1994; Wang et al., 2005 The possible adverse effects of altitude exposure on health, performance, and injury outcome are a current concern for military personnel in Afghanistan, where the average elevation is about 1200 meters (4000 feet) above sea level (Figure 1). Bagram Air Base sits at 1491 meters (4894 feet) above sea level. Kabul is one of the world s highest capital cities and is located at an altitude of 1800 meters (6000) feet. Afghanistan s highest mountain ranges rise to heights well above 7000 meters (23,000 feet). In general, many military land operations in Afghanistan occur at meters ( ,000 feet). U.S. military operations in Afghanistan sometimes involve ground personnel working and fighting in passes and hillsides at altitudes above 3000 meters (10,000 feet). Without the aid of supplemental oxygen, at 10,000-12,000 feet above sea level a healthy, acclimatized individual s blood typically has about 90 percent of its normal oxygen level (Grissom et al., 2006). In the unacclimatized individual, this is the altitude at which early signs of hypoxia typically begin. Even a single episode of hypoxia is a predictor of poor outcome in severely head-injured patients whose resulting mortality and disability rates may be as high as 50% (Chestnut et al., 1993; Miller, 1978). September 14,

11 Figure 1. Neurological symptoms and cognitive impairments associated with high altitudes. (Map image created by DACAAR.ORG using public domain Shuttle Radar Topography Mission (SRTM) dataset.) SECONDARY BRAIN INJURY DUE TO TBI The potentially devastating effects of altitude-related risk factors can be best understood in the context of secondary brain injury. Even at sea level, the injured brain is uniquely susceptible to secondary injuries which may result from various physiologic, metabolic, mechanistic, and neuroinflammatory cascade events that can occur within minutes, hours, days and months of TBI (Figure 2). It is also important to recognize that post-traumatic neuro-metabolic alteration (depressed glucose metabolism) can occur as the result of mild brain trauma and has been observed in mtbi patients who are otherwise relatively asymptomatic (Bergsneider et al., 2000; Giza & Hovda, 2001). In the injured brain, secondary injury cascades predict poor outcome in TBI patients (Doberstein et al., 1993; Ghajar, 2000; McHugh et al., 2007). As many as 40% of TBI patients deteriorate not as the direct result of their primary injuries, but rather due to the damaging effects of secondary processes (Byrnes & Faden, 2007; Cernak & Noble-Haeusslein, 2010; Narayan et al., 2002; Sauaia et al., 1995; Stoica & Faden, 2010). Potential effects of these disturbances include intra-cranial hemorrhage; infection; cerebral edema (fluid accumulation in brain tissue); hypoxia (insufficient oxygen); ischemia (insufficient blood flow); hydrocephalus (fluid accumulation inside the skull); hypotension (reduced blood pressure); elevated intra-cranial pressure (ICP; pressure within the skull); and brain herniation (displacement of neural tissue due to compression). September 14,

12 Figure 2. Events and processes underlying primary and secondary brain injury Secondary brain damage can also be induced by breakdown of the blood-brain barrier (BBB) 2, which in turn leads to edema, neuroinflammation and increased ICP (Goodman, 2009). As ICP increases, reduced cerebral perfusion leads to ischemia. Consequently, it is crucial to avoid conditions and circumstances that can aggravate primary brain injury, accelerate secondary injury processes, or introduce additional sources of physiologic stress that may directly or indirectly compromise brain health and function. The most commonly reported causes of secondary injury are hypoxia and/or hypotension, which are estimated to occur in 30-50% of headinjured patients before they reach the hospital (Chestnut et al., 1993; Ghajar, 2000). TBI patients who experience hypoxia or hypotension in the pre-hospital setting are at substantially greater risk of death or disability due to secondary brain injury (Chestnut et al., 1993; Chi et al., 2006; Ghajar, 2000). Because high altitude is often associated with hypoxic conditions, it is reasonable to consider that exposure to altitude may aggravate or increase the risk of secondary brain injury. Although the processes underlying brain response to altitude exposure are not yet fully understood, the effects of altitude exposure on neurologically healthy individuals are well-documented. 2 The BBB normally prevents certain blood proteins and water from entering the cerebral space. Dysfunction of the BBB can occur as the result of physical disruption, hypertension, and/or the release pass through of destructive compounds that can bind to glutamate and kainate receptors and initiate excitotoxic events, including free radical release and neuronal apoptosis or necrosis, excitatory neurotransmitters and free radicals. When the BBB breaks down, water enters the brain and causes edema, which can spread quickly and bring about a dangerous increase in ICP. September 14,

13 Clinical Parameters of TBI at Altitude Neurons respond to oxygen deprivation in the order of milliseconds. Because the brain is the most oxygen-dependent organ in the body, it is the first organ to be affected by reduced oxygen delivery at high altitude. The concentration of oxygen in air is constant at 20.9% up to about 12, 000 meters, but as one ascends in altitude, barometric pressure decreases and causes a reduction in the partial pressure 3 of oxygen. This is referred to as hypobaric hypoxia. At 5500 meters (about 18,000 feet) above sea level, the partial pressure of oxygen is reduced to about half its value at sea level; at 8800 meters (about 29,000 feet) it is reduced to a third of its sea level value. When the body is subjected to hypobaric hypoxia, less oxygen can move from the airspace of the lungs into the blood. Low arterial PO 2 causes vasodilation in the brain (Borgstrom et al., 1975), which alters cerebral blood flow. The precise underlying mechanisms and processes 4 of altitude-related changes in the brain are not yet fully understood, but the results are similar to the events that trigger secondary injury cascades following TBI. These include cerebral edema, increased ICP, compromised perfusion, ischemic injury, and apoptosis 5. Therefore, individuals who sustain TBI at high altitude, or who must be transported at high altitude, are placed at additional risk for secondary hypoxic tissue injury. This presents a unique challenge for those who provide acute medical care and transport. High-altitude illness refers to a spectrum of syndromes that can develop in otherwise healthy individuals shortly after ascent to high ( meters), very high ( meters) or extreme (above 5500 meters) altitudes. Neurological effects vary widely among individuals. Symptoms such as headache and altered night vision can develop in some individuals at as little as 1500 meters (approximately 5000 feet), which is the altitude equivalent inside a pressurized commercial aircraft. In general, though, neurological effects are more likely to occur at altitudes above 2500 meters (approximately 8000 feet). Prevention of altitude illness depends on slow ascent, prompt recognition of signs and symptoms, supplementary oxygen and descent to lower altitude to avoid worsening effects. Three altitude-related syndromes have been identified: acute mountain sickness; high altitude cerebral edema; and high altitude pulmonary cerebral edema. Acute mountain sickness (AMS) involves a variety of non-specific symptoms such as headache, fatigue, dizziness, nausea, vomiting, and/or sleep disturbance. Typically, one or more of these symptoms develop 6-12 hours after arrival at altitude; they are easily confused with effects of exhaustion, migraine, dehydration or hypothermia. Some individuals experience discomfort and/or AMS at as low as 2400 meters (8000 feet) (Muhm et al., 2007). Without the benefit of supplemental oxygen, AMS affects about half (53%) of those who trek (walk) to heights of meters (13, , 000 feet; Hackett et al., 1976; Verdy & Judge, 2006). Rapid ascent dramatically increases the risk of developing altitude-related high-altitude illness (Hackett et al., 1976), 3 In a gas mixture (in this case, air), partial pressure of oxygen refers to the pressure it would have if it occupied the same volume, alone, at the same temperature. 4 A detailed analysis of the cellular basis and pathophysiological mechanisms underlying these and related effects is beyond the scope of this report; these have been discussed at length by other authors (Bailey et al., 2009; Basnyat & Murdoch, 2003; Finnoff, 2008; Goodman et al., 2009; Kushi et al., 2003; Schmidt et al., 2005; Wilson et al., 2009). 5 Apoptosis is a type of programmed cell death involving a series of biochemical events which lead to the death of cells. The processes associated with apoptosis do not damage the organism. By contrast, necrosis is a form of traumatic cell death that results from acute cellular injury. September 14,

14 with AMS affecting more than four out of five individuals who fly directly to above 3800 meters (about 12, 500 feet) (Basnyat & Murdoch, 2003). Individuals who develop symptoms of AMS should not ascend further, and should descend if their symptoms worsen or fail to improve. Immediate descent is critical if cerebral or pulmonary symptoms appear. Supplemental oxygen may help to relieve AMS symptoms. High-altitude cerebral edema (HACE) is relatively unusual, with prevalence estimated at between 0.5% and 4.0% of individuals who climb to altitudes above 2500 meters (8000 feet). However, because the precise pathophysiology of neither syndrome is fully understood and because the incidence of HACE is dramatically less than that of AMS, it is not clear that the two syndromes reflect identical processes or vulnerabilities. Signs and symptoms of HACE may include dizziness, intense weakness, tingling, ataxia, altered consciousness, papilloedema (optic disc swelling), retinal hemorrhages and focal neurological deficits. These symptoms can develop very quickly and are potentially fatal. As symptoms develop, the time to loss of consciousness may be as little as 1-10 minutes (Clarke, 2006). Treatment requires immediate descent and oxygen supplementation. If HACE is not promptly managed and relieved, it can lead to brain herniation, coma, and death. Because HACE is usually preceded by AMS symptoms, it is often regarded as the end stage of AMS. The precise pathophysiological bases of AMS and HACE are not known, and are difficult to ascertain partly due to individual differences. When these syndromes occur, they appear to follow from a series of systemic and cerebral changes that may involve increased cerebral blood flow (due to hypoxia) and/or vasogenic edema, both of which can cause to brain swelling and raised ICP (see Figure 3, below). Vasogenic edema has been observed in cases of moderate to severe AMS and HACE, perhaps due to disruption of BBB permeability. These and related hypotheses are the focus of continuing research, analysis, and review (Basnyat & Murdoch, 2003; Hackett, 1999a, 1999b; Hackett & Roach, 2001; Roach & Hackett, 2001; West, 2004; Wilson et al., 2009). Treatment with dexamethasone (anti-inflammatory steroid) is sometimes recommended to treat HACE (Schoene, 2005). However, recent clinical research suggests that steroids have no clear beneficial effect on TBI and may even have deleterious effects; therefore, steroids are NOT recommended for reducing ICP in individuals who have sustained traumatic brain injury (TBI) (Bullock & Povlishock, 2007). Other pharmacotherapeutic options for the prevention and treatment of altitude-related illnesses in otherwise healthy individuals are reviewed elsewhere (Wilson et al., 2009; Wright et al., 2008). A third altitude-related illness is known as high-altitude pulmonary edema (HAPE), which usually presents in the first hours after arrival at altitudes higher than 2500 meters (approximately 8000 feet). HAPE may or may not follow AMS, but often co-occurs with signs of HACE. HAPE is a cardiopulmonary syndrome that usually appears first as dyspnea (shortness of breath) and reduced tolerance for exercise. This can lead to dry cough (which can later become productive), tachypnea (rapid breathing), tachycardia (rapid heart rate) and fever. Cold is a risk factor for HAPE. HAPE is more common in men than in women, and in individuals with pre-existing cardiopulmonary circulation abnormalities. Again, descent and supplemental oxygen are the recommended treatments. September 14,

15 Figure 3. Proposed pathogenesis of ACE and HACE Finally, exposure to high altitude may be associated with other focal neurological disturbances that can present separately from AMS or HACE; these include transient ischemic attacks, double vision, scotomas, 6 and cerebral venous thrombosis. While these neurological impairments may accompany HACE and be related to hypoxia, they do not necessarily follow the same course (Basnyat et al., 2004). NEUROPSYCHOLOGICAL EFFECTS OF ALTITUDE EXPOSURE Neuropsychological impairments have been observed in climbers exposed to extreme altitudes with and without the use of supplemental oxygen (Virues-Ortega et al., 2004). In particular, several investigators have found evidence for persistent cognitive functional impairment in climbers exposed to extreme altitudes without oxygen assistance. Regard et al. (1989) performed comprehensive neuropsychological testing on eight mountaineers who had previously reached summits higher than 8500 meters (above 27, 000 feet) on multiple occasions without supplementary oxygen. Five of the eight climbers showed persisting mild cognitive impairments in their concentration, short-term memory, cognitive flexibility and control of errors. Although the degree of impairment did not correlate with length of exposure to 6 Areas of partial alteration in the visual field. September 14,

16 extreme altitude, the three climbers who were most severely impaired also demonstrated EEG abnormalities suggestive of irreversible hypoxic damage in fronto-temporal limbic (hippocampal) brain structures. Other investigators have reported similar evidence of lasting effects of extreme altitude exposure on cognitive function (Garrido et al., 1993, 1996; Hornbein et al., 1989). Temporary neuropsychological impairments have also been observed in climbers who have reached extreme altitudes with the use of supplemental oxygen (Clark et al., 1983; Lowe et al., 2007; Townes et al., 1984), and in volunteers subjected to artificial altitude in the laboratory setting (Ledwith, 1968). This suggests that effects of altitude on cognitive performance are probably mediated by hypoxia and that supplemental oxygen may play a critical role in preventing permanent damage from sustained or repeated hypoxic insult to the brain. Military Concerns and Operational Constraints Military medics, physicians and surgeons must be aware of many direct and indirect environmental threats to the survival of injured soldiers. Because the human brain is susceptible and sensitive to physiological change, medical caregivers need to know what, if anything can be done to avoid or mitigate the potentially harmful effects of time and environment on military casualties in whom TBI is known or suspected. The Guidelines for the Field Management of Combat-Related Head Trauma (Knuth et al., 2005) emphasized the importance of monitoring and preventing hypoxemia and hypotension, both of which have been identified in different studies as independent predictors of poor outcome in brain-injured patients (Chestnut et al., 1993; Manley et al., 2001). There is also a need to better understand the possible long-term health and performance implications for warfighters who recover from concussion or TBI and then return to duty in high-altitude settings. TBI can be uniquely difficult to manage effectively in combat settings, which introduce myriad additional risks to the survival of injured military personnel and those who provide for their acute medical care and transport. For example, operational constraints may make it impossible to provide immediate or direct transport from the battlefield to a trauma center with neurosurgical capabilities. Delay itself can increase the risk of secondary injuries. In addition, the potentially harmful effects of rapid ascent to high altitude on critically ill and injured patients introduce yet another complex hazard for casualties who are evacuated by aeromedical transport, and for the flight crews who care for them. Military medical flights transporting warfighters from combat zones to medical care centers in Europe or the U.S. can last for many hours. During this time, patients are exposed to multiple sources of physiologic stress, including hypoxia, dehydration and cold temperatures. Even with the benefit of training and redundant protective systems in place, fliers of military aircraft do sometimes experience potentially deadly hypoxia (Cable, 2003). Although the risks associated with aeromedical transport are not new to those who practice emergency and military medicine, mitigating and controlling their potentially dangerous effects requires knowledgeable preparation and management, adequate resources and careful attention to patient status (Argyros & Cassimatis, 2002; Barnes et al., 2008; Helling & McKinlay, 2005; Johannigman, 2007, 2008; Letarte et al., 1999; Morris, 1992; Reddick, 1977; Turkan et al., 2006). Military personnel who have experienced multiple concussions or are considered to have recovered from TBI are often returned to active duty, where they may fly in non-pressurized aircraft and/or be re- September 14,

17 deployed to high-altitude mission environments such as Afghanistan. It is not clear whether, or how, reexposure to high-altitude settings might affect these individuals physical and cognitive performance. There is a pressing need for additional research in this area, given previous evidence that persisting effects of even minor head injury may cause subtle but persistent cognitive deficits that can emerge under mildly hypoxic conditions. Ewing et al. (1980) observed vigilance and memory decrements in previously concussed (vs. non-concussed) individuals when exposed to simulated high altitude (3800 meters). In addition, preliminary data suggests that individuals with disabilities performing as athletes at high altitude (> 2500 meters) may be more susceptible to AMS, with fatigue and weakness being the most common symptoms (Dicianno et al., 2008). The study included military personnel with a variety of disabilities, including paraplegia, tetraplegia, multiple sclerosis, and TBI. The incidence of AMS among disabled soldier athletes was not significantly different for those with neurological (vs. non-neurological) disabilities, which raises the concern that prior significant injury in general may be a risk factor for those who return to duty at high altitude. Objectives The mission of the Defense Centers of Excellence (DCoE) for Psychological Health and Traumatic Brain Injury is to assess, validate, oversee, and facilitate the prevention, resilience, identification, treatment, outreach, rehabilitation, and reintegration programs for psychological health and traumatic brain injury to ensure the Department of Defense meets the needs of the nation s military communities, warriors and families. In keeping with these objectives, DCoE requested a review and analysis of recent research to inform the care and treatment of military TBI in high-altitude settings. The overarching intent of this review is to address the question of how altitude-related factors might complicate or confound military TBI or its care and treatment. Core concerns of this analysis are (1) the acute stages of care, when the injured brain is most vulnerable to environmental effects associated with altitude and (2) whether exposure to high altitude may compromise the neurological health or performance of those who return to duty after recovering from TBI. Our analysis was focused to address three component questions: 1. How is TBI affected by altitude and related/co-occurring changes in oxygenation, intra-cranial pressure (ICP), edema, temperature, blood pressure or fluid balance? 2. How can altitude-related effects on the brain inform the transport, care and treatment of TBI in military settings? 3. Do altitude-related effects on TBI vary by injury severity level and/or acute vs. chronic injury phase? To address these questions, we conducted a broad search of the medical scientific literature relevant to TBI, altitude-related illness, and secondary brain injury. In addition, we also performed a targeted search using Google Scholar and PubMed to capture clinical studies published in English within a 10-year period from 2000 to April, 2010, inclusive. We used any combination of the primary search terms; traumatic brain injury, TBI, mild traumatic brain injury, mtbi, moderate TBI, severe TBI, concussion, repeat concussion, multiple concussion, and blast injury in any combination with the secondary search terms; altitude, high altitude cerebral edema, HACE, brain volume, aeromedical, temperature, September 14,

18 intracranial, acute, chronic, hydration, hyperbaric, hypertonic saline, acute mountain sickness, and AMS; as well as the tertiary search terms, hypertension, hypotension, hypothermia, hyperthermia, perfusion, oxygen, hemoglobin, edema, blood pressure, intra cranial pressure, ICP, hypoxia, military, defense, DoD, soldier, and veteran. In addition, we searched the reference lists of discovered articles for references that may have been missed in the original search. The targeted 10-year search strategy described above yielded a total of 16 clinical articles describing human clinical studies ( ) of factors that can threaten the outcome or survival of TBI patients: altitude-related brain damage, aeromedical evacuation, hypoxia, ICP/blood pressure, hydration and temperature. In each case, we describe key findings from the available research literature and consider potential interventions and management strategies that may be employed to monitor or reduce negative effects on neurological health. Finally, we consider implications unique to military TBI and identify knowledge gaps that need to be addressed by future research. TBI at Altitude: Risk Factors ALTITUDE-RELATED BRAIN DAMAGE There is a small but compelling literature that demonstrates lasting adverse neurological effects from exposure to extremely high altitude, as evinced by irreversible structural MRI abnormalities. Garrido et al. (1993, 1996) found evidence of persistent cortical atrophy in elite climbers who had ascended multiple times to altitudes above 8000 meters without supplemental oxygen; interestingly, only one among a comparison group of seven Himilayan Sherpas showed similar evidence of neurological damage (Garrido et al., 1996). We also identified three more recent articles documenting evidence of brain damage after exposure to extreme altitude (Appendix: Appendix Table 2). One of these was a case study (Jersey, 2010) reporting a rare, near-fatal example of decompression sickness (DCS) in a U.S. Air Force pilot while flying a high-altitude surveillance aircraft (cabin pressure = 28, 000 feet). Decompression sickness is the result of exposure to changes in environmental pressure, either as the result of deep scuba diving or high-altitude aviation. In high-altitude situations, DCS may occur if an unpressurized aircraft ascends rapidly or if its pressurization fails at high altitude. Inert gas (nitrogen) in the body is released as bubbles, which can enter the arterial bloodstream and damage the brain. In the case reported by Jersey, MRI images revealed that as a result of DCS, the pilot had developed bilateral frontal and right cerebellar abnormalities consistent with ischemia and hypoxia; he was also left with persistent cognitive impairments (confusion, amnesia, personality changes) and balance deficits (ataxia, impaired equilibrium). These clinical findings were described as similar to those of traumatic brain injury or stroke. Fayed et al. (2006) and Paola (2008) observed MRI abnormalities in civilian mountain climbers who had been exposed to very high/extreme altitudes without the benefit of supplementary oxygen. The larger of the two studies observed 35 climbers, finding irreversible frontal and parietal lesions in the amateur climbers and diffuse cortical atrophy in professional climbers (Fayed et al., 2006). The smaller study, comprised only of world-class climbers, observed focal areas of cortical atrophy in climbers motor cortices (Paola, 2008). September 14,

19 AEROMEDICAL TRANSPORT By reducing the time between injury and definitive medical care, air transport can mitigate the impact of secondary cerebral injuries that would otherwise jeopardize TBI patient survival (Malacrida et al., 1993). Davis et al. (2005a) reported significantly better outcomes for moderate to severe TBI patients who are transported by air vs. ground, with the clearest benefit observed among those with the most severe TBIs. However, air transport also introduces certain unique risks which have the potential to aggravate or increase the risk of secondary brain injury. Evacuation by air can expose head injury patients to multiple sources of additional physiologic stress, including cold, hypobaric hypoxia, expansion of trapped gases, changes in temperature, noise, vibration, acceleration/deceleration and sometimes rapid tactical ascent (Barnes et al., 2008; Reddick, 1977). Military medical aircrews operate in austere environments, under demanding and sometimes dangerous circumstances. They must be prepared to ascend to higherthan-normal altitudes not only to avoid weather systems and high terrain, but also to avoid detection or attack by military enemies on the ground. Letarte et al. (1999) reviews clinical recommendations for managing head injury in the flight environment, emphasizing that the two critical predictors of outcome from head injury, hypoxia and hypotension, may depend primarily on early and effective prevention and management by flight crews. Failure to avoid these well-established risks can have fatal consequences (Turkan et al., 2006). Supplemental oxygen treatment is indicated for patients with moderate to severe TBI (Glasgow Coma Scale score/gcs < 14), hemorrhagic shock and/or other injuries that may be associated with impaired oxygenation such as chest trauma, neck/facial trauma and airway obstruction (Grissom et al., 2006; Sumann et al., 2009). Healthy individuals taken to an aircraft cabin altitude of about 2500 meters (8000 feet) can experience an average drop in saturation of blood oxygen (SpO 2 ) of 4% or more (Cottrell et al., 1995; Muhm et al., 2007). Unfortunately, there is little empirical evidence available to inform risk assessment as relates to air transport of TBI casualties. We found two recent clinical studies that specifically address this question (Appendix: Table 3). Neither study reported negative effects of pre-hospital care on TBI outcome in a flight environment. To the contrary, findings in each case described overall potential benefits of aeromedical transport. Although some studies report adverse effects of pre-hospital ventilation by intubation on TBI patient outcome (e.g., Davis et al., 2005b; Murray et al., 2000; Wang et al., 2004), airway management is generally considered fundamental to the acute care and oxygenation of severely head-injured patients (Winchell & Hoyt, 1997). Davis et al. (2005a) document improved survival among TBI patients who are intubated in flight compared to those who receive ground transport and subsequent intubation in the hospital emergency department. Recent evidence suggests that improved outcomes in patients transported by air may depend on the effective use of monitoring procedures, resources, and avoidance of hyperventilation (Argyros & Cassimatis, 2002; Austin, 2000; Barnes et al., 2008; Carrel et al., 1994; Davis et al., 2004; Poste et al., 2004). Donovan et al. (2008) examined the outcome of aeromedically transported patients with head injuries in relation to intracranial air, which expands at high altitude and can lead to subdural hematoma and brain herniation. All patients underwent air transport without neurological deterioration. The authors conclude that the presence of intracranial air in the head-injured patient is not an absolute contraindication to air evacuation. However, it should be noted that only three of the military patients September 14,

20 reported in the retrospective study by Donovan et al. (2008) had intracranial air volumes above 14 ml at the time of air transport. Using a computer model to simulate the pressure effects of expanding intracranial air, Andersson et al. (2003) consider worst case results of intracranial air volume increase during aeromedical transport. Based on their theoretical modeling, the authors conclude that intracranial air volume will increase by 30% at a maximum cabin altitude of 8000 feet and that resulting ICP depends on initial air volume and the rate of cabin pressure change. They considered that for an intracranial air volume of 30 ml, ICP could increase by approximately 11 mmhg, which is potentially high enough to impair a patient s clinical condition. HYPOXIA Although the concentration of oxygen in the air remains constant up to the limits of the troposphere, atmospheric pressure decreases exponentially with altitude. This causes a reduction in the partial pressure of oxygen, which in turn causes tissue hypoxia. Normal brain tissue oxygen pressure (P0 2 ) is between 20 and 40 mmhg. When brain tissue P0 2 falls to 15 mmhg or below, it is considered hypoxic (Kiening, 1996). When brain cells are deprived of oxygen, this initiates a cascade of damaging biochemical and physiologic events. A dramatic increase in excitatory neurotransmitters (e.g., glutamate, aspartate) causes a massive, unregulated influx of calcium which in turn triggers the release of enzymes. Affected neurons begin to catabolize themselves to maintain energy and activity. An accumulation of catabolic waste products such as lactic acid causes irreversible damage to neurons, eventually resulting in cell death. This contributes to secondary brain injury, and to the worsening of outcome in patients with moderate and severe TBI (Chestnut et al., 1993; Miller et al., 1978; Schreiber, et al., 2002; Stocchetti et al., 1996). To prevent secondary damage by hypoxia, TBI patients (GCS < 14) at high altitude should be treated with supplemental oxygen 7. Grissom (2006) recommends oxygen treatment of combat casualties at high altitude under the following circumstances: SpO 2 < 90% at altitudes up to 10, 000 feet; SpO 2 < 85% at 12, 000 feet; and SpO 2 < 80% at 14, 000 feet Injuries associated with impaired oxygenation including blunt or penetrating chest trauma, or neck or facial trauma associated with airway obstruction Unconscious patient Traumatic brain injury with a Glasgow Coma Scale score < 13 Hemorrhagic shock as identified by systolic blood pressure less than 90 mmhg or heart rate greater than systolic blood pressure Oxygen treatment should be titrated to achieve an SpO 2 > 90% or applied empirically by highflow face mask when SpO 2 is not available or obtainable because of decreased peripheral perfusion 7 Oxygen treatment also provides the additional benefit of reducing ICP and increasing CPP. September 14,

21 All of the hypoxia studies identified and included for this review involved patients with moderate and/or severe TBI. None included patients with mild TBI, and none found reported differential effects of hypoxia based on level of TBI severity. Our search captured six recent studies of hypoxia as a risk factor in TBI outcome (Appendix: Table 4). Of these, four retrospective studies and one prospective study found a strong association between hypoxia and TBI outcome. Three identified a significant relationship between hypoxic episodes and patient morbidity, disability and/or mortality (Chi et al., 2006; Davis et al., 2009; Jiang et al., 2002), while two reported an association between hypoxia and functional outcome. Ariza et al. (2004) observed a relationship between pre-hospital hypoxia and prefrontal outcome, evinced by impaired attention, reaction time, mental flexibility, fluency and verbal memory. Chang et al. (2009) found that the frequency and duration of brain tissue hypoxia in the intensive care setting was related to subsequent poor functional outcome as assessed in various domains such as personal care, home management, social integration, work/school activity, ambulation and executive functioning. While Manley s (2001) prospective study found no relationship between hypoxia and TBI outcome, the authors identified several limitations of this study to include data recording artifact from the data collection environment. Of particular relevance to this review is the observation that both hypoxemia and hyperoxemia (increased arterial blood oxygen saturation) are potentially dangerous to patients with TBI (Davis et al., 2009). This is consistent with contemporary practice that cautions against aggressive hyperventilation during acute phases of severe TBI and pre-hospital care (Bullock & Povlishock, 2007). Hyperventilation can cause hypocapnia -- a reduction in the arterial pressure of carbon dioxide (PaCO 2 ) which leads to vasoconstriction in the brain. This restricts circulation and oxygenation, which in turn exacerbates ischemia and hypoxia. Hyperventilation can be effective to reduce ICP in some patients (Letarte, 1999). However, its use is recommended only in patients with clear signs and symptoms of brain herniation and oxygen delivery should be monitored. Prophylactic hyperventilation (PaCO2 of 25 mm HG or less) is not recommended for severe TBI patients, and should be avoided during the first 24 hours post-injury when CBF may be critically reduced (Bullock & Povlishock, 2007). Papadimos (2008) proposes that inhaled nitrous oxide (INO) may be an effective intervention to support oxygenation while reducing the risk of inflammation and intracranial pressure, especially in patients who have TBI in combination with acute respiratory distress. Rodent studies show results from this technique with potential translational value, as have at least two clinical case reports (Papadimos et al., 2009; Vavilala et al., 2001). INTRA-CRANIAL PRESSURE/BLOOD PRESSURE Alterations in blood pressure and oxygenation that could normally be tolerated well by the uninjured brain are potentially damaging to the injured brain. Secondary ischemic damage is more common in patients who have sustained hypoxia, hypotension, or elevated ICP. It is also more common and severe in more severe TBI and is found in the majority of patients who die of head injury (Chan et al., 1992; Graham et al., 1989; Marion et al., 1991). September 14,