Traumatic Brain Injury and Effects of Altitude - Human Performance ...

Traumatic Brain Injuryand Effects of Altitude:An Analysis of the LiteratureSeptember 14, 2010

Traumatic Brain Injury (TBI) and Effects of Altitude:An Analysis of the LiteratureTraumatic Brain Injury (TBI) and Effects of Altitude:An Analysis of the LiteratureExecutive SummaryThe mission of the Defense Centers of Excellence (DCoE) for Psychological Health and Traumatic BrainInjury is to assess, validate, oversee and facilitate the prevention, resilience, identification, treatment,outreach, rehabilitation and reintegration programs for psychological health and traumatic brain injuryto 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 andrelevant research to inform the care and treatment of military TBI involving high-altitude settings. Thescope and methodology for this analysis were developed in collaboration with the DCoE Traumatic BrainInjury Clinical Standards of Care Directorate.Although relatively uncommon in civilian settings, the potentially adverse effects of high (1500-3500meters), very high (3500-5500 meters) or extreme altitude (above 5500 meters) exposure must beweighed in treating head injuries sustained by mountain climbers, aviators, and military personnelinvolved in conflicts at high elevations.It is well-known that rapid ascent to high altitude can cause acute mountain sickness (AMS) and, morerarely but more seriously, high-altitude cerebral edema (HACE). These syndromes can cause brainswelling and increased intracranial pressure (ICP). Due to a combination of low temperature andhypoxia, exposure to high altitude can have significant effects upon brain function even in otherwisehealthy individuals. Many of the same factors that affect healthy brains at high altitude are alsoimplicated in secondary brain injury processes common within the minutes, hours and days followingTBI. For example, mean arterial pressure, fluid balance and ICP are potentially important variables indetermining the outcome of TBI generally. Therefore, it is important to consider how these factorsmight complicate the care and treatment of TBI patients at altitude and in the course of aeromedicalevacuation and transport.The purpose of this report was to consider how altitude-related factors might complicate or confoundmilitary traumatic brain injury (TBI) and its care and treatment. Specifically, we examine the potentiallycomplicating effects of conditions that can occur as direct or indirect effects of exposure to highaltitude. These include hypoxia, hypotension, elevated intracranial pressure (ICP), dehydration andhypothermia/hyperthermia. Each of these variables can play a role in secondary brain injury and/oraltitude-related illness, and each has been demonstrated to adversely affect TBI patient survival and/orfunctional recovery. As many as 40% of TBI patients deteriorate not as the direct result of their primaryinjuries, but rather due to the damaging effects of secondary physiologic, mechanistic, andneuroinflammatory processes.Based on the available scientific medical literature, we find clear basis for concern that exposure to highaltitude may tend to increase TBI patients’ vulnerability to secondary brain injury and compromise theiroutcome. In addition, there is an obvious and compelling need for additional research in this area, toidentify and document the potential effects and extent of these risks in military medical settings,September 14, 2010 1

Traumatic Brain Injury (TBI) and Effects of Altitude:An Analysis of the Literatureespecially in the context of aeromedical evacuation that may require rapid ascent in unpressurizedaircraft. Clinical research to date emphasizes the need for efficient medical evacuation as well as earlymitigation 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-relatedbrain 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 adverseeffects of secondary brain injury and/or altitude exposure.Hyperthermia is a risk factor for secondary brain injury. Hyperthermia is common in post-acuteTBI, 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 thosewith TBI. Hypothermia is a concern in military operational settings and in military aeromedicalevacuation, 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 andstabilize temperature in the pre-hospital setting.Retrospective clinical studies suggest that preventing hypoxia, controlling high ICP and temperaturestabilization are beneficial to TBI patient outcome. Therefore, it is important that TBI patients avoidexposure 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 forclinical studies and/or case reports of military aeromedical evacuation and transport involving TBIcasualties. Virtually no research has yet been published to address the unique injury and treatmentexperiences of military TBI casualties in high-altitude settings. Clinical findings are crucial to inform thedevelopment of risk and injury profiles and protocols which can address timing and interventionsneeded to prevent adverse outcomes from exposure to altitude-related factors, as well as secondarybrain injury events. Specifically, additional research is needed to address the following concerns:Identify risks, benefits, intervention strategies and outcomes associated with militaryaeromedical transport of TBI casualtiesThis information is needed to identify the “ideal time to fly” and to inform risk profiles andinjury protocols to address the timing and use of interventions to mitigate adverse effects ofaltitude 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 hasaddressed the potential impact of secondary brain injury processes on mTBI. Most military TBIsare classified as mild, related to the effects of blast or explosion. The potential impact of altitudeon these injuries is largely unknown.September 14, 2010 2

Traumatic Brain Injury (TBI) and Effects of Altitude:An Analysis of the LiteratureDetermine what, if any, health risks or performance effects might occur among post-TBI/postconcussionmilitary personnel who return to duty at high altitudesOperational performance at altitude introduces physiologic stress, which may reveal lingeringfunctional post-TBI or repeated concussion-related deficits otherwise not clinically apparent atsea level. It is essential to determine how the return to duty in high-altitude and mountainousterrain might affect the health or performance of military personnel who are classified asrecovered from TBI.Investigate the efficacy of pharmacotherapeutic interventions for the prevention of altituderelatedand secondary brain injuriesMedications effective in treating altitude illness can improve oxygenation and reduceinflammatory responses. To the extent that these processes also mediate secondary braininjury, altitude medications may be useful to mitigate effects of altitude and secondary injury onTBI outcome. Conversely, it is important to identify medications that are contraindicated for usein TBI at altitude.TBI is a persistent challenge in civilian and military settings, due to the inherent difficulties of preventingsecondary brain injury and controlling for environmental factors that may provoke or aggravatesecondary injury. Practical challenges are most pronounced in the combat casualty environment, wheremilitary medical practitioners are expected to deliver care in austere and sometimes hostileenvironments. This review hopes to inform these efforts, and to catalyze additional research as neededto determine optimal solution sets and treatment strategies.September 14, 2010 3

Traumatic Brain Injury (TBI) and Effects of Altitude:An Analysis of the LiteratureIntroductionBACKGROUNDTraumatic brain injury (TBI) can occur as the result of external force due to blunt impact (being struck byor striking an object); foreign body penetration of the brain, sudden; brain acceleration or decelerationmovement; or concussive forces from an explosion or blast (see Taber et al., 2006). Depending on theseverity of the underlying injury, TBIs are classified as mild, moderate or severe. Most (75-90%) areclassified 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 TBIrelateddisability and related costs (Rutland-Brown et al., 2006; Thurman et al., 1999). The Centers forDisease Control (CDC) estimates that each year, 1.7 million people in the United States sustain traumaticbrain 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 TBIsfrom federal, military, or Veterans Administration (VA) hospitals which face a variety of uniquechallenges 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 InjuryCenter (DVBIC) tracks and analyzes the incidence of military TBI based on actual medical diagnoses ofTBI within the U.S. armed forces. Their findings show that military TBI incident diagnoses have morethan doubled since 2005.Calendar Year 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009*TBI Incident diagnoses 10, 963 11, 830 12, 469 12, 886 13, 271 12, 025 16, 873 23, 002 28, 557 27, 862* Numbers updated as of 31 December 2009.Information available at DVBIC, http://www.dvbic.org/TBI-Numbers.aspxBroadly recognized as a signature injury of conflicts in Iraq and Afghanistan, TBI is a significant concernfor the U.S. military. Head, face and neck injuries have been reported to account for 22-52% of all battleinjuries 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 CombatTeam (Terrio et al., 2009). Other studies have found that as many as 28% of military personnel havesustained at least mTBI while deployed to conflicts in Iraq and Afghanistan (Warden, 2006). As theindividual and operational costs of these injuries become increasingly obvious, so does our recognition1 In 1997, the American Academy of Neurology (AAN, 1997) identified its criteria for three grades of concussion severity. Theleast severe of these (Grade 1) is sometimes described as “minor concussion, ” but typically would not meet the diagnosticstandards 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 thediagnostic setting.September 14, 2010 4

Traumatic Brain Injury (TBI) and Effects of Altitude:An Analysis of the Literatureof the need to reduce the vulnerability and improve the survivability of military personnel who face avariety 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 andproceeds to acute care, rehabilitation, and reintegration into their homes and communities (for adescription of TBI clinical care in the Department of Defense, see Jaffe et al., 2009). In 2005, the BrainTrauma Foundation (www.braintrauma.org) 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 ofhead injury assessment, treatment and triage/transport decisions in military settings with attention tomilitary operational concerns. However, these guidelines did not specifically address head injury in thecontext of high altitude.Although relatively uncommon in civilian settings, the potentially adverse effects of high (1500-3500meters), very high (3500-5500 meters) or extreme altitude (above 5500 meters) exposure must beweighed in treating head injuries sustained by mountain climbers, aviators, and military personnelinvolved in conflicts at high elevations. The potentially adverse effects of altitude-related factors on TBIoutcome are not fully understood, but have been documented in the published scientific and medicalliterature. Table 1 presents a summary overview of factors and events that are known to threaten thecondition, outcome or survival of TBI patients. Although these events can occur in uncontrolled settingsbefore, during or after TBI, research to date primarily documents the effects of these conditions whenthey occur during the pre-hospital, acute, and/or early post-acute stages of TBI. The informationpresented 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 outcomeVariableHypoxia(brain pO 2 < 15,PaO 2 < 60, SpO 2< 90%)Hypotension(systolic B/P < 90)Adverse OutcomesReportedMorbidityHosp/ICU length of stayDisabilityMortalityCognitiveFunctionalHosp length of stayDisabilityMortalityCognitiveTBI severitylevels studiedModerateSevereModerateSevereTimes of exposureconsideredPre-hospitalAcutePost-acutePre-hospitalAcutePost-acuteSelected ReferencesAriza et al., 2004 ; Chang et al.,2009 ; Chestnut et al., 1993; Chi etal., 2006 ; Davis et al., 2009 ;Geeraerts et al., 2008; Ghajar,2000; Grissom, 2006; Jiang et al.,2002 ; Kiening, 1996; Mendeloff etal., 1991; Miller, 1978; Schreiberet al., 2002; Stochetti et al., 1996Ariza et al., 2004 ; Chan et al.,1992; Chestnut et al., 1993; Chi etal., 2006 ; Clifton et al., 2002 ;Graham et al., 1989; Letarte et al.,1999;Manley et al., 2001 ; Marionet al., 1991; Marmarou et al.,1991; Morris, 1992; Schreiber etal., 2002 ; Stiver & Manley, 2008September 14, 2010 5

Traumatic Brain Injury (TBI) and Effects of Altitude:An Analysis of the LiteratureVariableICP(> 20 mmHg)Dehydration(fluid balance 37.5 °C /100 °F)Hypothermia(unmanaged)(< 35 °C/95 °F)Adverse OutcomesReportedMorbidityMortalityCognitiveMorbidityMortalityHosp/ICU length of stayMorbidityMortalityCognitiveMorbiditymortalityTBI severitylevels studiedModerateSevereSevereModerateSevereSevereTimes of exposureconsideredPre-hospitalAcutePost-acutePre-injuryPre-hospitalAcutePre-hospitalAcutePost-acutePre-hospitalAcuteSelected ReferencesChan et al., 1992; Clifton et al.,2002 ; Cortbus et al., 1994;Graham et al., 1989; Jiang et al.,2002 ; Juul et al., 2000; Marion etal., 1991; Rosner et al., 1995;Schreiber et al., 2002 ; Stochetti etal, 1991Badjatia et al., 2008; Clifton et al.,2002 ; Dickson et al., 2005; Eker etal., 1998; Shackford et al., 1992Albrecht et al., 1998; Badjatia,2009; Busto et al., 1987, 1989;Cairns & Andrews, 2002; Dietrich,1992; Dietrich et al., 1990;Diringer et al., 2004 ; Geffroy etal., 2004 ; Jiang et al., 2002 ;Minamisawa et al., 1990Coleshaw et al., 1982; Imray &Jurkovich et al., 1987; Luna et al.,1987; Oakley, 2005; Shurtleff etal., 1994; Wang et al., 2005The possible adverse effects of altitude exposure on health, performance, and injury outcome are acurrent 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 2000-3000 meters (7000-10,000 feet). U.S.military operations in Afghanistan sometimes involve ground personnel working and fighting in passesand hillsides at altitudes above 3000 meters (10,000 feet). Without the aid of supplemental oxygen, at10,000-12,000 feet above sea level a healthy, acclimatized individual’s blood typically has about 90percent of its normal oxygen level (Grissom et al., 2006). In the unacclimatized individual, this is thealtitude at which early signs of hypoxia typically begin. Even a single episode of hypoxia is a predictor ofpoor outcome in severely head-injured patients whose resulting mortality and disability rates may be ashigh as 50% (Chestnut et al., 1993; Miller, 1978).September 14, 2010 6

Traumatic Brain Injury (TBI) and Effects of Altitude:An Analysis of the LiteratureFigure 1. Neurological symptoms and cognitive impairments associated with high altitudes. (Map image created byDACAAR.ORG using public domain Shuttle Radar Topography Mission (SRTM) dataset.)SECONDARY BRAIN INJURY DUE TO TBIThe potentially devastating effects of altitude-related risk factors can be best understood in the contextof secondary brain injury. Even at sea level, the injured brain is uniquely susceptible to secondaryinjuries which may result from various physiologic, metabolic, mechanistic, and neuroinflammatorycascade events that can occur within minutes, hours, days and months of TBI (Figure 2). It is alsoimportant 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 otherwiserelatively 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 directresult 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; cerebraledema (fluid accumulation in brain tissue); hypoxia (insufficient oxygen); ischemia (insufficient bloodflow); hydrocephalus (fluid accumulation inside the skull); hypotension (reduced blood pressure);elevated intra-cranial pressure (ICP; pressure within the skull); and brain herniation (displacement ofneural tissue due to compression).September 14, 2010 7

Traumatic Brain Injury (TBI) and Effects of Altitude:An Analysis of the LiteratureFigure 2. Events and processes underlying primary and secondary brain injurySecondary brain damage can also be induced by breakdown of the blood-brain barrier (BBB) 2 , which inturn leads to edema, neuroinflammation and increased ICP (Goodman, 2009). As ICP increases, reducedcerebral 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 maydirectly or indirectly compromise brain health and function. The most commonly reported causes ofsecondary injury are hypoxia and/or hypotension, which are estimated to occur in 30-50% of headinjuredpatients before they reach the hospital (Chestnut et al., 1993; Ghajar, 2000). TBI patients whoexperience hypoxia or hypotension in the pre-hospital setting are at substantially greater risk of death ordisability due to secondary brain injury (Chestnut et al., 1993; Chi et al., 2006; Ghajar, 2000). Becausehigh altitude is often associated with hypoxic conditions, it is reasonable to consider that exposure toaltitude may aggravate or increase the risk of secondary brain injury. Although the processes underlyingbrain response to altitude exposure are not yet fully understood, the effects of altitude exposure onneurologically healthy individuals are well-documented.2 The BBB normally prevents certain blood proteins and water from entering the cerebral space. Dysfunction of the BBB canoccur as the result of physical disruption, hypertension, and/or the release pass through of destructive compounds that canbind to glutamate and kainate receptors and initiate excitotoxic events, including free radical release and neuronal apoptosis ornecrosis, 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, 2010 8

Traumatic Brain Injury (TBI) and Effects of Altitude:An Analysis of the LiteratureClinical Parameters of TBI at AltitudeNeurons respond to oxygen deprivation in the order of milliseconds. Because the brain is the mostoxygen-dependent organ in the body, it is the first organ to be affected by reduced oxygen delivery athigh altitude. The concentration of oxygen in air is constant at 20.9% up to about 12, 000 meters, but asone ascends in altitude, barometric pressure decreases and causes a reduction in the partial pressure 3 ofoxygen. This is referred to as hypobaric hypoxia. At 5500 meters (about 18,000 feet) above sea level, thepartial pressure of oxygen is reduced to about half its value at sea level; at 8800 meters (about 29,000feet) 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 lungsinto the blood. Low arterial PO 2 causes vasodilation in the brain (Borgstrom et al., 1975), which alterscerebral blood flow. The precise underlying mechanisms and processes 4 of altitude-related changes inthe brain are not yet fully understood, but the results are similar to the events that trigger secondaryinjury 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 betransported at high altitude, are placed at additional risk for secondary hypoxic tissue injury. Thispresents 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 individualsshortly after ascent to high (1500-3500 meters), very high (3500-5500 meters) or extreme (above 5500meters) altitudes. Neurological effects vary widely among individuals. Symptoms such as headache andaltered night vision can develop in some individuals at as little as 1500 meters (approximately 5000feet), 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 cerebraledema; and high altitude pulmonary cerebral edema. Acute mountain sickness (AMS) involves a varietyof non-specific symptoms such as headache, fatigue, dizziness, nausea, vomiting, and/or sleepdisturbance. Typically, one or more of these symptoms develop 6-12 hours after arrival at altitude; theyare easily confused with effects of exhaustion, migraine, dehydration or hypothermia. Some individualsexperience discomfort and/or AMS at as low as 2400 meters (8000 feet) (Muhm et al., 2007). Withoutthe benefit of supplemental oxygen, AMS affects about half (53%) of those who trek (walk) to heights of4000 - 5000 meters (13, 000-16, 000 feet; Hackett et al., 1976; Verdy & Judge, 2006). Rapid ascentdramatically 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 samevolume, alone, at the same temperature.4 A detailed analysis of the cellular basis and pathophysiological mechanisms underlying these and related effects is beyond thescope 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. Theprocesses associated with apoptosis do not damage the organism. By contrast, necrosis is a form of traumatic cell death thatresults from acute cellular injury.September 14, 2010 9

Traumatic Brain Injury (TBI) and Effects of Altitude:An Analysis of the Literaturewith AMS affecting more than four out of five individuals who fly directly to above 3800 meters (about12, 500 feet) (Basnyat & Murdoch, 2003).Individuals who develop symptoms of AMS should not ascend further, and should descend if theirsymptoms worsen or fail to improve. Immediate descent is critical if cerebral or pulmonary symptomsappear. 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 theprecise pathophysiology of neither syndrome is fully understood and because the incidence of HACE isdramatically less than that of AMS, it is not clear that the two syndromes reflect identical processes orvulnerabilities. Signs and symptoms of HACE may include dizziness, intense weakness, tingling, ataxia,altered consciousness, papilloedema (optic disc swelling), retinal hemorrhages and focal neurologicaldeficits. These symptoms can develop very quickly and are potentially fatal. As symptoms develop, thetime to loss of consciousness may be as little as 1-10 minutes (Clarke, 2006). Treatment requiresimmediate descent and oxygen supplementation. If HACE is not promptly managed and relieved, it canlead to brain herniation, coma, and death. Because HACE is usually preceded by AMS symptoms, it isoften regarded as the “end stage” of AMS.The precise pathophysiological bases of AMS and HACE are not known, and are difficult to ascertainpartly due to individual differences. When these syndromes occur, they appear to follow from a seriesof 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 todisruption 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 effecton TBI and may even have deleterious effects; therefore, steroids are NOT recommended for reducingICP in individuals who have sustained traumatic brain injury (TBI) (Bullock & Povlishock, 2007). Otherpharmacotherapeutic options for the prevention and treatment of altitude-related illnesses in otherwisehealthy 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 usuallypresents in the first 24-48 hours after arrival at altitudes higher than 2500 meters (approximately 8000feet). HAPE may or may not follow AMS, but often co-occurs with signs of HACE. HAPE is a cardiopulmonarysyndrome that usually appears first as dyspnea (shortness of breath) and reduced tolerance forexercise. 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 menthan in women, and in individuals with pre-existing cardiopulmonary circulation abnormalities. Again,descent and supplemental oxygen are the recommended treatments.September 14, 2010 10

Traumatic Brain Injury (TBI) and Effects of Altitude:An Analysis of the LiteratureFigure 3. Proposed pathogenesis of ACE and HACEFinally, exposure to high altitude may be associated with other focal neurological disturbances that canpresent separately from AMS or HACE; these include transient ischemic attacks, double vision,scotomas, 6 and cerebral venous thrombosis. While these neurological impairments may accompanyHACE and be related to hypoxia, they do not necessarily follow the same course (Basnyat et al., 2004).NEUROPSYCHOLOGICAL EFFECTS OF ALTITUDE EXPOSURENeuropsychological impairments have been observed in climbers exposed to extreme altitudes with andwithout the use of supplemental oxygen (Virues-Ortega et al., 2004). In particular, several investigatorshave found evidence for persistent cognitive functional impairment in climbers exposed to extremealtitudes without oxygen assistance. Regard et al. (1989) performed comprehensive neuropsychologicaltesting 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 showedpersisting mild cognitive impairments in their concentration, short-term memory, cognitive flexibilityand control of errors. Although the degree of impairment did not correlate with length of exposure to6 Areas of partial alteration in the visual field.September 14, 2010 11

Traumatic Brain Injury (TBI) and Effects of Altitude:An Analysis of the Literatureextreme altitude, the three climbers who were most severely impaired also demonstrated EEGabnormalities suggestive of irreversible hypoxic damage in fronto-temporal limbic (hippocampal) brainstructures. Other investigators have reported similar evidence of lasting effects of extreme altitudeexposure on cognitive function (Garrido et al., 1993, 1996; Hornbein et al., 1989).Temporary neuropsychological impairments have also been observed in climbers who have reachedextreme altitudes with the use of supplemental oxygen (Clark et al., 1983; Lowe et al., 2007; Townes etal., 1984), and in volunteers subjected to artificial altitude in the laboratory setting (Ledwith, 1968). Thissuggests that effects of altitude on cognitive performance are probably mediated by hypoxia and thatsupplemental oxygen may play a critical role in preventing permanent damage from sustained orrepeated hypoxic insult to the brain.Military Concerns and Operational ConstraintsMilitary medics, physicians and surgeons must be aware of many direct and indirect environmentalthreats to the survival of injured soldiers. Because the human brain is susceptible and sensitive tophysiological change, medical caregivers need to know what, if anything can be done to avoid ormitigate the potentially harmful effects of time and environment on military casualties in whom TBI isknown or suspected. The Guidelines for the Field Management of Combat-Related Head Trauma (Knuthet 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 inbrain-injured patients (Chestnut et al., 1993; Manley et al., 2001). There is also a need to betterunderstand the possible long-term health and performance implications for warfighters who recoverfrom 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 additionalrisks to the survival of injured military personnel and those who provide for their acute medical care andtransport. For example, operational constraints may make it impossible to provide immediate or directtransport from the battlefield to a trauma center with neurosurgical capabilities. Delay itself canincrease the risk of secondary injuries. In addition, the potentially harmful effects of rapid ascent to highaltitude on critically ill and injured patients introduce yet another complex hazard for casualties who areevacuated 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 orthe U.S. can last for many hours. During this time, patients are exposed to multiple sources ofphysiologic stress, including hypoxia, dehydration and cold temperatures. Even with the benefit oftraining and redundant protective systems in place, fliers of military aircraft do sometimes experiencepotentially deadly hypoxia (Cable, 2003). Although the risks associated with aeromedical transport arenot new to those who practice emergency and military medicine, mitigating and controlling theirpotentially dangerous effects requires knowledgeable preparation and management, adequateresources 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 recoveredfrom TBI are often returned to active duty, where they may fly in non-pressurized aircraft and/or be re-September 14, 2010 12

Traumatic Brain Injury (TBI) and Effects of Altitude:An Analysis of the Literaturedeployed to high-altitude mission environments such as Afghanistan. It is not clear whether, or how, reexposureto 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 persistingeffects of even minor head injury may cause subtle but persistent cognitive deficits that can emergeunder mildly hypoxic conditions. Ewing et al. (1980) observed vigilance and memory decrements inpreviously concussed (vs. non-concussed) individuals when exposed to simulated high altitude (3800meters). In addition, preliminary data suggests that individuals with disabilities performing as athletes athigh altitude (> 2500 meters) may be more susceptible to AMS, with fatigue and weakness being themost common symptoms (Dicianno et al., 2008). The study included military personnel with a variety ofdisabilities, including paraplegia, tetraplegia, multiple sclerosis, and TBI. The incidence of AMS amongdisabled 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 thosewho return to duty at high altitude.ObjectivesThe mission of the Defense Centers of Excellence (DCoE) for Psychological Health and Traumatic BrainInjury is to assess, validate, oversee, and facilitate the prevention, resilience, identification, treatment,outreach, rehabilitation, and reintegration programs for psychological health and traumatic brain injuryto ensure the Department of Defense meets the needs of the nation’s military communities, warriorsand families. In keeping with these objectives, DCoE requested a review and analysis of recent researchto inform the care and treatment of military TBI in high-altitude settings. The overarching intent of thisreview is to address the question of how altitude-related factors might complicate or confound militaryTBI or its care and treatment. Core concerns of this analysis are (1) the acute stages of care, when theinjured brain is most vulnerable to environmental effects associated with altitude and (2) whetherexposure to high altitude may compromise the neurological health or performance of those who returnto 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-cranialpressure (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 inmilitary settings?3. Do altitude-related effects on TBI vary by injury severity level and/or acute vs. chronic injuryphase?To address these questions, we conducted a broad search of the medical scientific literature relevant toTBI, altitude-related illness, and secondary brain injury. In addition, we also performed a targetedsearch using Google Scholar and PubMed to capture clinical studies published in English within a 10-yearperiod 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 searchterms; altitude, high altitude cerebral edema, HACE, brain volume, aeromedical, temperature,September 14, 2010 13

Traumatic Brain Injury (TBI) and Effects of Altitude:An Analysis of the Literatureintracranial, 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 referencesthat may have been missed in the original search.The targeted 10-year search strategy described above yielded a total of 16 clinical articles describinghuman clinical studies (2000-2010) of factors that can threaten the outcome or survival of TBI patients:altitude-related brain damage, aeromedical evacuation, hypoxia, ICP/blood pressure, hydration andtemperature. In each case, we describe key findings from the available research literature and considerpotential interventions and management strategies that may be employed to monitor or reducenegative effects on neurological health. Finally, we consider implications unique to military TBI andidentify knowledge gaps that need to be addressed by future research.TBI at Altitude: Risk FactorsALTITUDE-RELATED BRAIN DAMAGEThere is a small but compelling literature that demonstrates lasting adverse neurological effects fromexposure to extremely high altitude, as evinced by irreversible structural MRI abnormalities. Garrido etal. (1993, 1996) found evidence of persistent cortical atrophy in elite climbers who had ascendedmultiple times to altitudes above 8000 meters without supplemental oxygen; interestingly, only oneamong 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 toextreme altitude (Appendix: AppendixTable 2). One of these was a case study (Jersey, 2010) reporting a rare, near-fatal example ofdecompression 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 inenvironmental pressure, either as the result of deep scuba diving or high-altitude aviation. In high-altitudesituations, DCS may occur if an unpressurized aircraft ascends rapidly or if its pressurization fails at highaltitude. Inert gas (nitrogen) in the body is released as bubbles, which can enter the arterial bloodstreamand damage the brain. In the case reported by Jersey, MRI images revealed that as a result of DCS, thepilot had developed bilateral frontal and right cerebellar abnormalities consistent with ischemia andhypoxia; 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 tothose of traumatic brain injury or stroke.Fayed et al. (2006) and Paola (2008) observed MRI abnormalities in civilian mountain climbers who hadbeen exposed to very high/extreme altitudes without the benefit of supplementary oxygen. The largerof the two studies observed 35 climbers, finding irreversible frontal and parietal lesions in the amateurclimbers 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’ motorcortices (Paola, 2008).September 14, 2010 14

Traumatic Brain Injury (TBI) and Effects of Altitude:An Analysis of the LiteratureAEROMEDICAL TRANSPORTBy reducing the time between injury and definitive medical care, air transport can mitigate the impact ofsecondary 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 aretransported by air vs. ground, with the clearest benefit observed among those with the most severeTBIs. However, air transport also introduces certain unique risks which have the potential to aggravateor increase the risk of secondary brain injury. Evacuation by air can expose head injury patients tomultiple sources of additional physiologic stress, including cold, hypobaric hypoxia, expansion of trappedgases, changes in temperature, noise, vibration, acceleration/deceleration and sometimes rapid tacticalascent (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-normalaltitudes not only to avoid weather systems and high terrain, but also to avoid detection orattack by military enemies on the ground.Letarte et al. (1999) reviews clinical recommendations for managing head injury in the flightenvironment, emphasizing that the two critical predictors of outcome from head injury, hypoxia andhypotension, 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 ComaScale score/GCS < 14), hemorrhagic shock and/or other injuries that may be associated with impairedoxygenation 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 experiencean 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 toair transport of TBI casualties. We found two recent clinical studies that specifically address thisquestion (Appendix: Table 3). Neither study reported negative effects of pre-hospital care on TBIoutcome in a flight environment. To the contrary, findings in each case described overall potentialbenefits of aeromedical transport.Although some studies report adverse effects of pre-hospital ventilation by intubation on TBI patientoutcome (e.g., Davis et al., 2005b; Murray et al., 2000; Wang et al., 2004), airway management isgenerally 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 areintubated in flight compared to those who receive ground transport and subsequent intubation in thehospital emergency department. Recent evidence suggests that improved outcomes in patientstransported by air may depend on the effective use of monitoring procedures, resources, and avoidanceof 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 inrelation to intracranial air, which expands at high altitude and can lead to subdural hematoma and brainherniation. All patients underwent air transport without neurological deterioration. The authorsconclude that the presence of intracranial air in the head-injured patient is not an absolute contraindicationto air evacuation. However, it should be noted that only three of the military patientsSeptember 14, 2010 15

Traumatic Brain Injury (TBI) and Effects of Altitude:An Analysis of the Literaturereported in the retrospective study by Donovan et al. (2008) had intracranial air volumes above 14 ml atthe time of air transport. Using a computer model to simulate the pressure effects of expandingintracranial air, Andersson et al. (2003) consider worst case results of intracranial air volume increaseduring aeromedical transport. Based on their theoretical modeling, the authors conclude thatintracranial air volume will increase by 30% at a maximum cabin altitude of 8000 feet and that resultingICP depends on initial air volume and the rate of cabin pressure change. They considered that for anintracranial air volume of 30 ml, ICP could increase by approximately 11 mmHg, which is potentially highenough to impair a patient’s clinical condition.HYPOXIAAlthough 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 partialpressure of oxygen, which in turn causes tissue hypoxia. Normal brain tissue oxygen pressure (P0 2 ) isbetween 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 andphysiologic 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. Affectedneurons begin to catabolize themselves to maintain energy and activity. An accumulation of catabolicwaste products such as lactic acid causes irreversible damage to neurons, eventually resulting in celldeath. This contributes to secondary brain injury, and to the worsening of outcome in patients withmoderate and severe TBI (Chestnut et al., 1993; Miller et al., 1978; Schreiber, et al., 2002; Stocchetti etal., 1996).To prevent secondary damage by hypoxia, TBI patients (GCS < 14) at high altitude should be treated withsupplemental oxygen 7 . Grissom (2006) recommends oxygen treatment of combat casualties at highaltitude 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 feetInjuries associated with impaired oxygenation including blunt or penetrating chest trauma, orneck or facial trauma associated with airway obstructionUnconscious patientTraumatic brain injury with a Glasgow Coma Scale score < 13Hemorrhagic shock as identified by systolic blood pressure less than 90 mmHg or heart rategreater than systolic blood pressureOxygen treatment should be titrated to achieve an SpO 2 > 90% or applied empirically by highflowface mask when SpO 2 is not available or obtainable because of decreased peripheralperfusion7 Oxygen treatment also provides the additional benefit of reducing ICP and increasing CPP.September 14, 2010 16

Traumatic Brain Injury (TBI) and Effects of Altitude:An Analysis of the LiteratureAll of the hypoxia studies identified and included for this review involved patients with moderate and/orsevere TBI. None included patients with mild TBI, and none found reported differential effects ofhypoxia based on level of TBI severity.Our search captured six recent studies of hypoxia as a risk factor in TBI outcome (Appendix: Table 4). Ofthese, four retrospective studies and one prospective study found a strong association between hypoxiaand TBI outcome. Three identified a significant relationship between hypoxic episodes and patientmorbidity, disability and/or mortality (Chi et al., 2006; Davis et al., 2009; Jiang et al., 2002), while tworeported an association between hypoxia and functional outcome. Ariza et al. (2004) observed arelationship 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 thefrequency and duration of brain tissue hypoxia in the intensive care setting was related to subsequentpoor 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, theauthors identified several limitations of this study to include data recording artifact from the datacollection 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 hyperventilationduring acute phases of severe TBI and pre-hospital care (Bullock & Povlishock, 2007). Hyperventilationcan cause hypocapnia -- a reduction in the arterial pressure of carbon dioxide (PaCO 2 ) – which leads tovasoconstriction in the brain. This restricts circulation and oxygenation, which in turn exacerbatesischemia 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 andoxygen delivery should be monitored. Prophylactic hyperventilation (PaCO2 of 25 mm HG or less) is notrecommended for severe TBI patients, and should be avoided during the first 24 hours post-injury whenCBF may be critically reduced (Bullock & Povlishock, 2007).Papadimos (2008) proposes that inhaled nitrous oxide (INO) may be an effective intervention to supportoxygenation while reducing the risk of inflammation and intracranial pressure, especially in patients whohave TBI in combination with acute respiratory distress. Rodent studies show results from this techniquewith potential translational value, as have at least two clinical case reports (Papadimos et al., 2009;Vavilala et al., 2001).INTRA-CRANIAL PRESSURE/BLOOD PRESSUREAlterations in blood pressure and oxygenation that could normally be tolerated well by the uninjuredbrain are potentially damaging to the injured brain. Secondary ischemic damage is more common inpatients who have sustained hypoxia, hypotension, or elevated ICP. It is also more common and severein 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, 2010 17

Traumatic Brain Injury (TBI) and Effects of Altitude:An Analysis of the LiteratureLow systolic blood pressure and increased ICP have been identified as the two most critical factors indetermining outcome from severe brain injury (Marmarou et al., 1991). It is estimated that as many as13% of severe TBI patients experience hypotension at the scene or in the emergency department(Chestnut et al., 1993). Hypotension is not caused by isolated head injury, but head-injured patients withlow systolic blood pressure (< 90 mmHg) or increased ICP tend to have poorer outcomes, probably dueto reduced cerebral blood flow (hypoperfusion, ischemia) (Chestnut et al., 1993). Normal adult ICP istypically 5-15 mmHg. ICP values above 20 mmHg indicate mild intracranial hypertension and usuallyrequire treatment. ICP sustained above 40 mmHg is severe, and may be life-threatening. 8 Elevated ICPcan occur due to lesions, hypoxia, or to edema which can develop as the result of changes in arterialpressure, vasodilation, or obstruction of venous outflow.Changes in cerebral blood flow due to head injury also make the injured brain relatively moresusceptible to hypoxia. On exposure to high altitude, cerebral blood flow increases (20-60%)immediately in response to hypoxia and vasodilation (Grissom, 2006). This occurs despite the competingeffect of cerebral vasoconstriction (due to hyperventilation and hypocapnia), suggesting that normalcerebrovascular autoregulation is fundamentally altered by hypoxia. Although the underlyingmechanisms of this disruption are not fully understood, the effect can be rapidly reversed by return tolow altitude. The alteration of cerebral blood flow autoregulation at high altitude has also beenproposed as a possible basis for AMS (Van Osta et al., 2005).As long as cerebral perfusion is maintained, the uninjured brain can protect itself from hypoxia byextracting oxygen from the blood. However, when cerebrovascular autoregulation is impaired – eitheras the result of brain damage, high altitude exposure or both – cerebral perfusion becomes dependentupon systemic blood pressure. Arterial hypotension then leads to brain hypoperfusion. Therefore, in theimmediate aftermath of head injury, adequate oxygenation and perfusion are essential to goodoutcome. It is recommended that in the pre-hospital setting, systolic blood pressure should bemaintained well above 90 mmHg, and PaO 2 should be maintained well above 60 (Letarte et al., 1999;Morris, 1992; Stiver & Manley, 2008).Our search captured six studies of ICP and/or arterial blood pressure effects on TBI (Appendix: Table 5).None included mild TBI patients as subjects. In five of the studies, hypotension was independentlyassociated with a greater likelihood of poor TBI outcome or mortality (Ariza et al., 2004; Clifton et al.,2002; Jiang et al., 2002; Manley et al., 2001; Schrieber et al., 2002). Three studies observed TBI severitylevel as an independent predictor of mortality, but only one (Manley et al., 2001) found that the effectof hypotension on outcome varied by TBI severity level (moderate vs. severe). Four studies included ICPas a variable, and three of these found an adverse effect of increased ICP on TBI outcome (Clifton et al.,2002; Jiang et al., 2002; Schrieber et al., 2002).Chi et al. (2006) found that mortality was increased by hypoxia, but did not observe a relationshipbetween hypotensive episodes and TBI outcome. Because this study excluded patients who died within12 hours post-injury, its results may fail to account for the full range of head-injured patients sufferingfrom fatal hypotension in the immediate post-acute phase of TBI. The authors of this study8 The intracranial space is occupied by cerebral tissue, cerebrospinal fluid, and blood. Together, these comprise total brainvolume. Because the skull is an inflexible container, any increase in brain volume brings about a potentially dangerous increasein ICP. Normal adult ICP is typically 5-15 mmHg. ICP values above 20 mmHg indicate mild intracranial hypertension and usuallyrequire treatment. ICP sustained above 40 mmHg is severe, and may be life-threatening.September 14, 2010 18

Traumatic Brain Injury (TBI) and Effects of Altitude:An Analysis of the Literatureacknowledged that their findings are specific to the subset of patients who survive the first 12 hourspost-TBI.Finally, although Ariza et al. (2006) observed significant adverse effects of hypotension onneuropsychological outcome and cerebral atrophy they found no significant effect of ICP or CPP onthese same variables. Correlational analysis showed only a tendency toward association between thehighest values of ICP and reduced verbal memory performance. Lack of significant ICP effects in thisstudy may also be attributable to the subject sample, which included only TBI patients recovered to atestable level.TBI at altitude presents a potentially complicated pre-hospital treatment challenge requiresmanagement of brain oxygenation, blood pressure, ICP, and cerebral perfusion pressure (CPP) 9 . Thus,while it is important to maintain adequate blood pressure and cerebral perfusion immediately followingTBI, it is also important to avoid increases that can cause or aggravate increased ICP (Rangel-Castillo etal., 2008).CPP can be calculated by subtracting the patient’s ICP from mean arterial pressure 10 (MAP).The clinical challenge is to maintain cerebral CPP within narrow limits. Too little perfusion pressure canlead to ischemia, while too much can raise ICP. CPP can be reduced by increasing ICP, decreasing bloodpressure, or both. In adults, normal CPP is between 70 and 90 mmHg; ischemic brain damage can occurif CPP falls below 70 mmHg for a sustained period of time (Rosner et al., 1995). CPP less than 60 mmHgis associated with inadequate perfusion (Stochetti et al, 1991) and poorer outcomes (Cortbus et al.,1994; Juul et al., 2000). Based on these and similar findings, Brain Trauma Foundation Guidelinesindicate that CPP should be maintained about 60 mmHg (Bullock & Povlishock, 2007).HYDRATIONModerate to severe dehydration can cause hypotension, rapid heart rate, increased body temperature,dizziness, fainting, seizures, unconsciousness, and even death. Dehydration happens faster at higheraltitudes due to lower air pressure and humidity, which cause more rapid evaporation of moisture fromthe skin and lungs. Dehydration may also be caused by increased energy expenditure and reducedaccess to water at high altitude. When dehydration occurs, it causes physiological changes aimed atconserving fluid in the body through the production of sodium and hormones. At high altitude, thesechanges can reduce the ability of the kidneys to excrete bicarbonate, which is a process important toacclimatization at high altitude. Dehydration has been identified as a possible risk factor for thedevelopment of AMS in climbers (Cumbo et al., 2002).There is also some evidence that pre-injury dehydration can contribute to reduction in the volume ofintra-cranial compartments, which in turn could render dehydrated TBI patients relatively morevulnerable to secondary brain injury (Dickson et al., 2005; Eker et al., 1998). As noted in the BrainTrauma Foundation’s Guidelines for the Field Management of Combat-Related Head Trauma (Knuth etal., 2005), pre-injury dehydration may also compromise the ability of the human body to compensate for9 Cerebral perfusion pressure (CPP) is the difference between mean arterial blood pressure and ICP.10 At normal resting heart rates, MAP is approximated as MAP ≈ DP + 1/3 (SP – DP), where SP is systolic pressure and DP isdiastolic pressure. At high heart rates, MAP is more closely approximated as the arithmetic mean of the systolic and diastolicpressures.September 14, 2010 19

Traumatic Brain Injury (TBI) and Effects of Altitude:An Analysis of the Literaturefluid loss after injury. Whether hypotonic (due to loss of electrolytes), hypertonic (due to loss of water)or isotonic (due to loss of water and electrolytes), dehydration can interfere with central nervous systemfunction.Fluid management is thus an important and challenging aspect of TBI patient care. Although fluidrestriction has traditionally prevailed as the clinical protocol for preventing edema after brain injury(Shenkin et al., 1976), this practice is not supported by experimental findings (Gaab et al., 1979; Morseet al., 1985). Today, effective fluid balance management is widely accepted as a cornerstone formaintaining adequate blood pressure; in turn, optimal fluid management may help to reduce secondarybrain injury by reducing ICP and improving cerebral blood flow (Badjatia et al., 2008; Shackford et al.,1992).Fluid resuscitation and management may also be important to correct for electrolyte derangements thatcan compromise TBI patient status and outcome. 11 For example, TBI-related injury and/or secondaryeffects are often associated with blood sodium imbalance. Hyponatremia (low blood sodium, < 135mEq/L) is common after TBI, causing water retention by an increased volume of extracellular fluid. Thismay indicate TBI-related pituitary dysfunction and related anti-diuretic hormone (ADH/vasopressin)abnormality. If not treated, hyponatremia can cause confusion, convulsions, stupor, or even coma.However, it is likewise important to prevent blood sodium excess. Hypernatremia (elevated bloodsodium, > 145 mEq/L) can also occur after TBI and is equally important to monitor and treat. Earlysymptoms of hypernatremia are often subtle, including lethargy, weakness, and irritability. In severeform, hypernatremia can also cause seizures and coma.We identified just two studies that specifically addressed the effects of fluid volume on TBI outcome(Appendix: Table 6). An analysis of data from the National Acute Brain Injury Study of 392 severe TBIpatients found that low fluid balance (< - 594 mL) was an independent predictor of poor TBI outcome,and was an even more powerful a predictor than ICP (> 25 mmHg) (Clifton et al., 2002). Although theexact basis for this relationship was not clear, the authors’ analyses indicated that the low fluid balanceeffect was not related to ICP, MAP or CPP. The study emphasized the need for careful attention to TBIpatient fluid balance, noting that some of the most severely affected patients did not receive adequatefluid replacement.The importance of effective fluid management is reinforced by the finding that even a mildderangement of electrolyte balance (sodium disorder) can have potentially serious implications forpatients with severe TBI. In the immediate aftermath of TBI, mild hypernatremia (Na > 145 mmol/l) wasindependently associated with a higher risk of mortality (Maggiore et al., 2009). Hypernatremiaoccurred in more than half of the 130 severe TBI patients in this study and was due to TBI-relatedcentral diabetes insipidus in a subset of them.There are several treatment options available for fluid resuscitation/management. Mannitol (a sugaralcohol solution) is generally safe, effective, and has been commonly used to reduce ICP, and improveCPP and cerebral oxygenation. However, mannitol has several known limitations including the possibilitythat it may cause hypotension in already hypovolemic (dehydrated) patients. An alternative approachinvolves the use of hypertonic saline (Schmoker et al., 1991), which has been well-supported by the11 A detailed review of underlying mechanisms is beyond the scope of this review, and can be found elsewhere (Rhoney et al.,2006).September 14, 2010 20

Traumatic Brain Injury (TBI) and Effects of Altitude:An Analysis of the Literatureclinical literature for use in TBI patients (Anderson et al., 1997; Gemma et al., 1996; Oddo et al., 2009;Sandhu et al., 2004; Soreide & Deakin, 2005). Very recent evidence suggests that pre-hospital treatmentof severe TBI patients with hypertonic saline solution can serve to attenuate cell inflammatory processesand edema associated with secondary brain injury (Rhind et al., 2010). The Institute of Medicine hasrecommended hypertonic saline as the fluid treatment of choice for combat and civilian casualties(Committee on Fluid Resuscitation for Combat Casualties, 1999). Hypertonic saline administration is nowalso recommended as optimal for fluid resuscitation on the battlefield under current Guidelines for theField Management of Combat-related Head Trauma (Knuth et al., 2005) and has also been specified asappropriate for use in the treatment of TBI patients in mountain rescue settings (Sumann et al., 2009).White et al. (2006) present an informative review of hypertonic saline treatment effects, benefits andpotential complications.TEMPERATURENormal human body temperature is (37 °C or 98.6 °F) is maintained by the preoptic hypothalamus.When this area of the brain detects a change in body temperature, it triggers the autonomic nervoussystem to respond accordingly to provide for cooling (sweat production) or warming (shivering). If thisresponse is not adequate to correct for heat loss or production, thermal injury can occur withneurological manifestations. Temperature-related changes in the brain can affect secondary injuryrelated processes including oxygen requirements, inflammation, ischemia and edema (Mcilvoy, 2005).Hyperthermia (elevated core body temperature, 37.5-38.3 °C or 100-101 °F) causes an increase in brainmetabolism and reduces cerebral blood flow, probably as the result of cerebral vasoconstriction due tohyperventilation (hypocapnia). Early symptoms include confusion, altered affect and impaired workperformance. Hyperthermia may be associated with altered brain wave activity consistent with reducedarousal (Nielsen et al., 2001). If core body temperature is not reduced, the individual may experiencecoordination problems, seizures and coma. Numerous experimental animal studies show thathyperthermia can exacerbate the secondary processes and effects associated with brain injury (Busto etal., 1987, 1989; Dietrich, 1992; Dietrich et al., 1990; Minamisawa et al., 1990). Whether due toenvironmental factors, infection or hypothalamic dysfunction, hyperthermia is a common problem in TBIpatients. Incidence has been reported as high as 68% within 72 hours of injury (Albrecht et al., 1998).Hyperthermia early after TBI has been associated with lower GCS, diffuse axonal injury, cerebral edemaand hypotension (Cairns & Andrews, 2002). Badjatia (2009) has written a detailed and informativereview of the pathophysiology and clinical care considerations in TBI with hyperthermia.Hypothermia is marked by a core body temperature at or below 35 °C (95 °F). In addition to obviousenvironmental risk factors such as cold and wind, other risk factors for hypothermia include highaltitude, fatigue, hypoxia, dehydration, trauma, hypopituitarism 12 , and central nervous systemdysfunction (Imray & Oakley, 2005). Even mild hypothermia can affect cognitive functions includingmemory, learning and reasoning. These impairments are likely due to direct effects of cold on the brainitself (Coleshaw et al., 1983; Shurtleff et al., 1994). Moderate hypothermia (28-32 °C or 82.5-89.5 °F) isassociated with progressively reduced consciousness, decreased blood pressure, heart rate andmetabolism. With severe hypothermia (< 28 °C or 82.4 °F), the affected individual usually becomesunresponsive with cardiac arrhythmias. Brain wave activity declines and cerebral autoregulation andpupillary dilation stop at core body temperatures below 26 °C (78.8 °F).12 Hypopituitarism is the abnormal reduced secretion of hormones produced by the pituitary gland.September 14, 2010 21

Traumatic Brain Injury (TBI) and Effects of Altitude:An Analysis of the LiteratureHypothermia has been linked to increased mortality in general trauma patients, including those withsevere TBI (Jurkovich et al., 1987; Luna et al., 1987; Wang et al., 2005). This is a potential concern inmilitary operational settings and in the context of military aeromedical evacuation, where the averageinterior temperature of a military cargo plane is around 59 °F. Schmelz et al. (2007) provide an overviewof these and related concerns for military trauma casualties. The authors also report their findings froma comparison of three hypothermia intervention (blanket warming) strategies tested on an animal (pig)model to address the constraints of an aeromedical evacuation setting.However, there is also evidence to indicate that controlled, targeted hypothermia may exertneuroprotective effects during the acute phase of TBI (Clifton et al., 2002; Marion et al., 1997;Polderman et al., 2002; Shiozaki et al., 1993; Sinclair & Andrews, 2010). In a study of severe head injurypatients, reducing body temperature to 35-35.5 °C (95-95.9 °F) was found to reduce intracranialhypertension while maintaining CPP without cardiac dysfunction or oxygen debt (Tokutomi et al., 2003).Induced/therapeutic hypothermia is now sometimes used to treat TBI and other conditions known tocause ischemic tissue damage. The effectiveness of induced hypothermia may depend on careful tissuetemperature management prior to or soon after injury, and on slow re-warming. Clinical findings aboutthe potential benefits of therapeutic hypothermia have been inconsistent, likely due to the use ofinconsistent methodologies, treatment and timing protocols, and experimental populations. As a result,the most recent edition of the Brain Trauma Foundation’s Guidelines for Management of SevereTraumatic Brain Injury concluded that there is insufficient data to support Level I or Level II treatmentrecommendations. Detailed reviews of the physiological basis, clinical factors, and methodologies ofinduced hypothermia have been presented elsewhere (Diller & Zhu, 2009; Fritz & Bauer, 2004; Sinclair &Andrews, 2010).Of primary interest to the current review was the question of how exposure to altitude-relatedenvironmental variables such as temperature might affect TBI. We found three recent studies that metour inclusion criteria to address this question (Appendix: Table 7). All three studies examined the effectof hyperthermia on patient outcome. Two of these studies included only severe TBI patients (Geffroy etal., 2004; Jiang et al., 2002). One included a subset of TBI patients (GCS 9-13) within a large cohort ofneurological ICU patients (Diringer et al., 2004). In each case, hyperthermia predicted longer hospitalstays, poorer recovery, increased disability and/or increased risk of mortality. Geffroy et al. (2004)identified risk factors for early post-TBI hyperthermia to include gender, body temperature onadmission, white blood cell (WBC) count on admission and diabetes insipidus within two days of injury.Of these, body temperature and WBC count on admission were the two most powerful predictors ofearly (w/in 48 hrs) hyperthermia. Acetaminophen was identified as having potential prophylactic valuein preventing early hyperthermia if administered before patients’ temperatures reached 38.5 °C/101.3°F (Geffroy et al., 2004).In addition to the clinical group studies reported above, we identified a recent case report describing amilitary casualty of severe TBI (GCS = 3) who received U.S. Army medical care after prolonged exposureto high environmental temperatures (115-120 °F) and hyperthermia (core temperature > 108 °F).Hermstad & Adams (2010) reported on the case of an Iraqi soldier whose condition illustrated thecombined and cumulatively fatal effects of environmental heat and TBI involving hypothalamic damage.The patient received aggressive cooling treatment by ice bags, removed when the patient’s temperaturewas reduced to 100 °F. Despite all attempts to reduce this patient’s body temperature, maintain hisoxygenation, systolic blood pressure and controlled ICP, the patient ultimately died as a result of theSeptember 14, 2010 22

Traumatic Brain Injury (TBI) and Effects of Altitude:An Analysis of the Literatureextensive injuries. This case report illustrates the devastating combined effects of heatstroke and TBIwith damage to the hypothalamus and impaired thermoregulation. The authors emphasize theimportance of early recognition and treatment of hyperthermia and the relevance of this problem tocurrent conflicts in hostile and extreme climates where military casualties are sometimes not evaluatedfor temperature until arrival at a military medical facility. This can introduce a delay of several criticalhours. Hermstad & Adams recommend that future editions of Brain Trauma Foundation prehospital andfield management guidelines for TBI consider protocols for early core temperature measurement andtreatment of hypothermia and hyperthermia.Arcure and Harrison (2009) describe a new ice water immersion system that can reduce a patient’s corebody temperature to therapeutic level (33 °C/91.4 °F) within 20 minutes. This extremely rapid newdevice can counter hyperthermia much faster than is currently possible by other methods such as watercirculatingblankets, gel pads, intravenous cooling, and air-circulating cooling systems (Hoedemaekers etal., 2007). The authors suggest that this new device, if its use is supported by clinical data, could beimplemented as a field-ready system for use in military settings.ConclusionsIn a recently published account of the story now known as the “Miracle of the Andes, ” Estol (2009)describes the experience of Fernando Parrado, who survived severe head injuries after a 1972 planecrash in the mountains of South America. Parrado’s ordeal began with the plane crash itself, at analtitude of nearly 4000 meters without acclimatization. He was suddenly exposed to between – 15 and 0°C. His own account indicates that he sustained multiple skull fractures, experienced edema, loss ofconsciousness and coma, during which time he lost nearly 90 pounds. More than two months later,Parrado would lead a 10-day trip to secure a rescue for his fellow surviving passengers. More than 30years later, a CT scan of Parrado’s head revealed no sign of brain injury. Estol attributes Parrado’samazing survival and recovery to the “accidental best care” of circumstances surrounding him,speculating that his skull fractures enabled decompression and his hypothermia exertedneuroprotective benefit against secondary brain injury. Estrol concludes:Had the same accident occurred without disruption to the skull, in an environment withnormal or high temperatures, and without the associated dehydration, survival withoutsequelae would have been unlikely. Even under the best care, modern measures ofneurointensive treatment, such as cranial decompression and hypothermia, wouldprobably not have been implemented at any medical centre in the early 1970s, and theoutcome for Parrado would probably have been quite different.Parrado’s experience was, indeed, unique. Although Parrado’s two-day coma and resulting temporarydehydration may have helped to mitigate edema, without sustained hypothermia and decompressingskull fractures he likely would have succumbed to multiple effects of secondary brain injury.The purpose of the current review was to identify, document, review and analyze recent research toaddress altitude and related factors that might complicate or confound military TBI or its care andtreatment. Specifically, we considered how TBI may be affected by altitude and/or secondary braininjury processes associated with altitude-related factors and events such as hypoxia, hypotension, ICP,September 14, 2010 23

Traumatic Brain Injury (TBI) and Effects of Altitude:An Analysis of the Literaturedehydration, and extreme temperatures. We reviewed the available clinical literature to capturecontemporary findings, strategies, and recommendations relevant to these concerns.Although the overall body of research literature remains limited, when taken together it providescompelling evidence that altitude exposure itself is a risk factor for some degree of potentiallypermanent neurological damage as evident on MRI. Although such damage might not later be clinicallyobservable as functional impairment at sea level, it represents the effects of processes consistent withthose which underlie secondary brain injury after TBI. As such, altitude-related neurological changessuggest that TBI patients may be relatively more vulnerable to secondary brain injuries at high altitude.Whether by exacerbation of underlying pathophysiological processes or by cumulative effect, TBIrelatedsequelae are probably worsened to some degree by exposure to high altitude and resultinghypoxia.This reinforces the importance of rapid evacuation and descent with careful attention to mitigatingother sources of physiologic stress. Military medical air crews are highly experienced in trauma casualtycare and management, but sometimes are forced to perform under very demanding and sometimesunexpected circumstances. To avoid complications, minimize secondary injury and promote goodoutcome, it is especially critical that TBI patients avoid exposure to hypoxia, hypotension, andhyperthermia in the immediate aftermath of injury. There is a pressing need for additional research andinstructive case reports to document risks, benefits, interventions and outcomes associated withmilitary aeromedical transport of TBI casualties.Based on our review, there is little question that hypoxia itself – whether as the result of high altitude ortraumatic injury processes – is a strong predictor of poor outcome in TBI. Studies included in this reviewidentified clear adverse effects of hypoxia on morbidity, disability, neuropsychological/cognitivefunction, daily life functional status and morbidity among TBI patients. Taken together, they underscorethat a single episode of hypoxia is potentially dangerous and should be avoided by treatment withsupplemental oxygen. However, it is important to note that hypocapnia and hyperoxemia are alsopotentially dangerous to TBI patients. Recent findings indicate that while careful airway managementand controlled oxygenation are important, TBI patients should not be hyperventilated in the pre-hospitalsetting unless there are clear signs and symptoms of brain herniation due to elevated ICP.With rare exception, clinical studies show that elevated ICP (> 20 mmHg) and hypotension (< 90 mmHg)also play a critical role in determining outcome from brain injury. Both events reduce cerebral bloodflow, leading to hypoperfusion and ischemia. Therefore, CPP (MAP minus ICP) may be the mostinformative variable for study. Ischemic brain damage can occur if CPP falls below 70 mmHg and CPPless than 60 mmHg is associated with poor outcome. Additional research is needed to determinewhether the incidence or impact of these alterations might vary by TBI severity level. We found onestudy (Manley et al., 2001) indicating a potential correlation between hypotension and brain traumaseverity. Our search on these variables revealed no clinical studies involving mild TBI (mTBI) patientcohorts.Hypotension can be provoked or aggravated by dehydration, which progresses faster at higher altitudes.Dehydration can compromise the body’s ability to compensate for injury-related fluid loss. In one study,low fluid balance (< 594 mL) was found to be an even more powerful independent predictor of poor TBIoutcome than ICP (Clifton et al., 2002). Fluid resuscitation and management is thus important not onlyto prevent hypotension itself, but also to correct for potentially dangerous blood sodium abnormalities,September 14, 2010 24

Traumatic Brain Injury (TBI) and Effects of Altitude:An Analysis of the Literaturereduce ICP, and improve cerebral blood flow to mitigate or prevent adverse effects of secondary braininjury and/or altitude exposure. The most current available guidelines available for fluid management ofmilitary casualties recommend treatment with hypertonic saline, which in addition to restoring fluidbalance may also reduce secondary injury processes such as inflammatory processes and edema.Temperature-related changes in the brain can affect secondary injury processes such as oxygenrequirements, inflammation, ischemia and edema. In particular, hyperthermia is a risk factor forsecondary brain injury because it both increases metabolism (elevated oxygen requirements) anddecreases cerebral blood flow (hypoperfusion). It has also been linked to edema, hypotension anddiffuse axonal injury. Hyperthermia is common in post-acute TBI, and can be the result of environmentalhigh temperatures, infection or injury-related hypothalamic dysfunction. TBI patients with earlyhyperthermia are at risk for longer hospital stays, poor recovery, and increased disability and death. Onestudy (Geffroy et al., 2004) found evidence suggesting that prophylactic use of acetaminophen may behelpful to reduce hyperthermia without adverse complications. Such an effect would be reasonable toexpect, but additional studies are needed to confirm effectiveness.CLINICAL CONSIDERATIONSThe objectives of pre-hospital TBI care are to stabilize and triage patients and to prevent secondarybrain injury. Those who provide pre-hospital TBI care, including transport, can mitigate the potentiallylife-threatening effects of secondary damage by preventing potentially dangerous changes in brainoxygenation, blood pressure, ICP and cerebral perfusion (blood flow to the brain). In particular, earlyhypoxia and hypotension should be monitored and prevented to the extent possible (Chestnut et al.,1993; Hartl et al., 2006; Manley et al., 2001; Mendeloff et al., 1991; Stiver & Manley, 2008). The resultsof at least one rodent study indicate that damaging effects of hypoxia and hypotension on the posttraumaticbrain may depend on the time interval between primary and secondary insults (Geeraerts etal., 2008).Careful monitoring and control of ICP, blood pressure and cerebral perfusion pressure (CPP) areassociated with marked reductions in TBI-related mortality (Fakhry et al., 2004; Ghajar, 2000; Hesdorfferet al., 2007; Palmer et al., 2001; Patel et al., 2002), as is direct and efficient transport of severe TBIpatients to a Level I or Level II trauma center (Hartl et al., 2006; Rudehill et al., 2002; Wright et al.,1996). These factors are considered within recommendations issued in the Guidelines for Managementof Severe Traumatic Brain Injury (Bullock & Povlishock, 2007) and Guidelines for Prehospital Managementof Traumatic Brain Injury (Badjatia et al., 2008). These Guidelines recommend that blood pressureand oxygenation be monitored and maintained at 90 mmHg and PaO 2 < 60 mmHg, respectively, to avoidhypotension and hypoxemia (reduction in oxygen saturation in the arterial blood as the result ofhypoxia). Adherence to these guidelines (prior editions not cited here) were shown to support improvedTBI outcome through the prevention and treatment of secondary injury in the early phases after primaryinjury (Watts et al., 2004).Although therapeutic and carefully managed hypothermia may serve to mitigate early secondary braindamage, its effectiveness has not yet been consistently demonstrated in clinical settings and specificparameters and procedures have not yet been clearly established. Uncontrolled hypothermia has beenassociated with impaired neurological and systemic function, and has been linked to increased mortalityamong trauma patients in general and TBI patients among them. These findings indicate the generalSeptember 14, 2010 25

Traumatic Brain Injury (TBI) and Effects of Altitude:An Analysis of the Literatureimportance of temperature assessment and stabilization in the pre-hospital setting, especially in militaryoperational settings where casualties may be exposed to extreme hot or cold temperatures and/or highlevels of physical activity for prolonged periods of time.RESEARCH CONSIDERATIONSBased on this review, several key knowledge gap areas are apparent. First and foremost, there is apressing need for additional clinical studies and/or case reports of military aeromedical evacuation andtransport involving TBI casualties. This work is needed to inform the development of risk and injuryprofiles and protocols which address timing and interventions needed to prevent adverse outcomesfrom exposure to altitude-related factors, as well as secondary brain injury events. Goodman et al.(2009) have specified the need for studies to delineate the course of neuro-inflammation during airtransport. Such research may help to identify an “ideal time to fly” so as to avoid exacerbation of post-TBI secondary injury (neuro-inflammatory) events.This review focused on moderate-to-severe TBI patients; none of the studies we identified through thisreview included mTBI patient cohorts for comparison. This is understandable, given that the majority ofmTBI patients recover well over a period of weeks or months without hospitalization. However, itbecomes more difficult to identify severity-related differences across studies that do not wholly addressthe full spectrum of injuries and impact. Observed relationships between severity and altitude-relatedfactors were few (Davis et al., 2005; Diringer et al., 2004; Maggiore et al., 2009; Manley et al., 2001).Military conflicts in high-altitude and mountainous terrain underscore the need for renewed emphasisto determine what if any health risks or performance effects might occur in military personnel whorecover from mTBI, concussion, or multiple concussions and then return to duty at high altitudes.Though recovery from mild head injury is common, mTBI can involve cerebral tissue damage resulting innerve axon degeneration, neurotransmission impairment, and the loss of neural connections (Povlishocket al., 1992; Raghupathi et al., 2002; Smith et al., 2003; Iverson, 2005; Kraus et al., 2007). Quantitatively,the severity of such damage can be conceived as “proportional to the numbers of dead and damagedneurons, their relative functional importance, and their capacity for self-repair” (Gualtieri, 1995). It isreasonable, then, to consider that mTBI also may be adversely affected by exposure to altitude-relatedsecondary injury processes. Most military TBIs are closed-head injuries due to blast or explosion and areclassified as mTBI (Warden, 2006; Galarneau et al., 2008). Many military personnel who sustain mTBI orconcussion will recover and return to duty. Lew et al. (2007) present an informative review of postconcussionreturn-to-action criteria based on research and experience from within the field of sportsmedicine. However, little research has addressed the question of lingering, subclinical functionalimpairments since the early work of Ewing, et.al. (1980). Military conflicts in high-altitude andmountainous terrain underscore the need for renewed emphasis to determine what if any health risksor performance effects might occur in military personnel who recover from mTBI, concussion or multipleconcussions and then return to duty at high altitudes.Finally, research is needed to investigate the prophylactic and/or therapeutic effects of drug therapiescommonly used to treat altitude-related illness, to determine their potential efficacy in preventingaltitude-related illness or injury in TBI casualties. To the extent that such medications improveoxygenation or reduce inflammatory responses, they may also be helpful to prevent or mitigatesecondary brain injury generally. Likewise, it is important to identify any such formulations that may beSeptember 14, 2010 26

Traumatic Brain Injury (TBI) and Effects of Altitude:An Analysis of the Literaturecontraindicated for use in TBI patients. A detailed exploration of pharmaceutical interventions is beyondthe scope of this review, but can be found elsewhere (Wright et al., 2008).Military operational medicine provides unique settings and opportunities for medical scientific researchand development. TBI is a persistent challenge in civilian and military settings, due in large part tomultiple difficulties inherent to the prevention and control of secondary brain injury. Associatedpractical challenges are most pronounced in the combat casualty environment, where military medics,flight crews and surgeons often must perform heroic acts of medical care in austere, complex andsometimes hostile conditions. In the combat setting where multiple environmental and operationalvariables are brought to bear on human health and performance, the possible effects of high altitude onmilitary TBI may be more difficult to specify than to prevent. It is hoped that this review will spuradditional research as needed to delineate best available solutions and treatments.September 14, 2010 27

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Traumatic Brain Injury (TBI) and Effects of Altitude:An Analysis of the LiteratureAppendixTable 2. Studies of altitude-related brain damageAuthor(s), Journal Title Population (N) FindingsFayed et al. (2006)Am J Med, 119,168.e1-168.e6Jersey (2010) AviatSpace EnvironMed, 82, 64-68Paola et al. (2008)European JNeurology, 15,1050-1057Evidence of braindamage after highaltitudeclimbing bymeans of magneticresonance imagingSevere neurologicaldecompression sicknessin a U-2 pilotReduced oxygen due tohigh-altitude exposurerelates to atrophy inmotor function brainareasCivilianN=35 climbers (12professional, 23 amateur)N=20 controlsCase report (N=1)CivilianN=9 world-class climbersN=19 non-exposed controlsMRI evidence of irreversible lesions(frontal, parietal) in amateurs and diffusecortical atrophy in professionals afterclimbing to 4810-8848 meters w/osupplementary oxygen.Pilot who experienced DCS at very highaltitude (cabin pressure 8500 meters).Examination revealed bilateral frontal andright cerebellar evidence of hypoxia andischemia, as well as persistent cognitiveimpairments and balance deficits.Climbers showed subtle white and greymatter MRI abnormalities in brain motorcortices after climbing to > 7500 metersw/o supplementary oxygen. Repeatedextreme altitude exposure was associatedwith changes in left primary andsupplemental motor cortices (right handcontrol). Single exposure was associatedwith changes in left angular gyrus (motorplanning).Table 3. Studies of aeromedical transport of TBIAuthor(s),Journal Title Population (N)Davis et al.(2005)Annals ofEmergencyMedicine, 46,115-122Donovan etal. (2008)Aviat SpaceEnviron Med,79, 30-35The impact ofaeromedicalresponse topatients withmoderate to severetraumatic braininjuryAeromedicalevacuation ofpatients withpneumocephalus:outcomes in 21casesCivilianN = 10,314 totalN = 3,017 local Aeromedtransport by helicoptermoderate & severe TBImean GCS = 9.5MilitaryN=21 head injuries +intracranial air (N=19post-craniotomy)Long-range air transportin pressurized aircraftTBI severity not specifiedOutcome xTBI severityStatisticallysignificantbenefit ofairtransportfor severeTBI patients(GCS < 9)NRFindingsRetrospective study of outcomes foraeromedical vs. ground transport ofmoderate and severe TBI patients.Transport altitude not specified.Outcomes were significantly betteroverall for aeromedically transportedTBI patients. Greatest benefitobserved for more severe TBIs (meanGCS = 4.1). Survival improved forpatients intubated during air transportvs. ground transported patientsintubated in emergency department.Retrospective study of outcomesamong 21 head injury patients withintracranial air (mean volume 9.3 ml)who underwent long-range airevacuation in pressurized equivalent5000-8000 feet. No patients showedclinical neurological deterioration intransport or within 24 hours of arrival.September 14, 2010 38

Traumatic Brain Injury (TBI) and Effects of Altitude:An Analysis of the LiteratureTable 4. Studies of hypoxia effects on TBI outcomeAuthor(s),Journal Title Population (N)Ariza et al.(2004)J Neurotrauma,21, 864-876Chang et al.(2009) Crit CareMed, 37, 283-290Chi et al. (2006)J Trauma, 61,1134-1141Davis et al.(2009) JNeurotrauma,26, 2217-2223Jiang et al.(2002)J Neurotrauma,19, 869-874Manley et al.(2001) ArchSurg, 136, 1118-1123Influence ofextraneurologicalinsults on ventricularenlargement andneuropsychologicalfunctioning aftermoderate and severetraumatic brain injuryPhysiologic andfunctional outcomecorrelates of braintissue hypoxia intraumatic brain injuryPrehospital hypoxiaaffects outcome inpatients withtraumatic brain injury:a prospectivemulticenter studyBoth hypoxemia andextreme hyperoxemiamay be detrimental inpatients with severetraumatic brain injuryEarly indicators ofprognosis in 846 casesof severe traumaticbrain injuryHypotension, hypoxia,and head injury:frequency, duration,and consequencesCivilianN=57Moderate TBI(N=18)Severe TBI (N=39)CivilianN=27Severe TBIGCS < 7CivilianN=150Moderate & severeTBIGCS < 13CivilianN = 3420Moderate tosevere TBIMean GCS = 11.6CivilianN = 864Severe TBIGCS < 9CivilianN = 107Moderate tosevere TBIGCS < 13Outcome xTBI severityEffects ofhypoxiawereindependentof TBIseverityN/ANRNRN/ANo effect ofhypoxiaFindingsRegardless of TBI severity, episodes ofhypoxia (and hypotension) were relatedto neuropsychological outcome andlong-term ventricular enlargement. Prehospitalhypoxia was related to thirdventricle dilatation and neurological andcognitive impairments of attention,motor speed, mental flexibility, fluency,and verbal memory.Retrospective review of severe TBIpatients in an intensive care unit. Braintissue oxygen levels were monitoredand measured hourly. Hypoxic episodeswere common, usually associated withnormal ICP. Frequency and duration ofbrain tissue hypoxia were related topoor functional outcome.Prospective study found that withmultiple other variables controlled,hypoxia in the prehospital setting wasassociated with significantly highermortality after brain injury. Mortalityfor patients with hypoxic episodes was37% (vs. 20%); of the 43 (29%) patientswho had hypoxic episodes, 36% died.Patients with prehospital episodes ofhypoxia (and/or hypotension) requiredlonger hospital stays and had a greaterdegree of disability at discharge.Retrospective analysis found that bothhypoxemia and extreme hyperoxemiawere related to a decrease in goodoutcome and increase in mortality formoderate-to-severe TBI patients.Authors concluded that there may be atherapeutic range for oxygen, withoptimal PO2 range 110-487 mmHg.Retrospective study of 864 severe TBIpatients found that in addition to age,GCS, and pupillary response/size, thepresence of hyperthermia, hypoxia, andhigh ICP were also strongly correlatedwith patient outcome.Prospective study reported nosignificant effect of hypoxia during earlyresuscitation in the emergencydepartment. Authors noted lack ofhypoxia effect may have been due torecording artifacts.September 14, 2010 39

Traumatic Brain Injury (TBI) and Effects of Altitude:An Analysis of the LiteratureTable 5. Studies of ICP and/or blood pressure effects on TBIAuthor(s),Journal Title Population (N)Ariza et al.(2004)J Neurotrauma,21, 864-876Chi et al. (2006)J Trauma, 61,1134-1141Clifton et al.(2002) Crit CareMed, 30, 739-745Jiang et al.(2002)J Neurotrauma,19, 869-874Manley et al.(2001) ArchSurg, 136, 1118-1123Schreiber et al.(2002) ArchSurg, 137, 285-290Influence ofextraneurologicalinsults on ventricularenlargement andneuropsychologicalfunctioning aftermoderate and severetraumatic brain injuryPrehospital hypoxiaaffects outcome inpatients withtraumatic braininjury: a prospectivemulticenter studyFluid thresholds andoutcome from severebrain injuryEarly indicators ofprognosis in 846 casesof severe traumaticbrain injuryHypotension, hypoxia,and head injury:frequency, duration,and consequencesDeterminants ofmortality in patientswith severe blunthead injuryCivilianN = 57Moderate TBI (N =18; GCS = 9-13)Severe TBI (N = 39;GCS < 8)CivilianN = 150Moderate & severeTBIGCS < 13CivilianN = 392Severe TBIGCS = 3-8CivilianN = 864severe TBIGCS < 9CivilianN = 107Moderate tosevere TBIGCS < 13CivilianN = 368Moderate-tosevereMean GCS = 6.4Outcome xTBI severityGCSassociatedwith pooroutcome.ICP/BP xseverity notreportedNRFindingsPatients with episodes of hypotension 20 mmHg) or reducedCPP (< 60 mmHg) and those without.Prospective study found patients withpre-hospital episodes of hypoxia and/orhypotension had a greater degree ofdisability and longer hospital stays thanthose with no secondary insults.However, hypotension (< 90 mmHg)alone was not an independent predictorof outcome or mortality. This study didnot include patients who died within 12hrs. of injury.N/A Retrospective study found that ICP (>25mmHg), MAP (< 70mmHg) and CPP ( 15 mmHg was alsoindependently associated withmortality, as was GCS and age (> 55 yrs).September 14, 2010 40

Traumatic Brain Injury (TBI) and Effects of Altitude:An Analysis of the LiteratureTable 6. Studies of hydration effects on TBIAuthor(s),Journal Title Population (N)Clifton et al.(2002) CritCare Med,30, 739-745Maggiore etal. (2009)Critical Care,13, R110Fluid thresholds andoutcome fromsevere brain injuryThe relationbetween theincidence ofhypernatremia andmortality in patientswith severetraumatic braininjuryCivilianN = 392Severe TBIGCS = 3-8CivilianN = 130Severe TBIGCS = 3-8Outcome x TBIseverityFindingsN/A Retrospective study found that ICP (>25mmHg), MAP (< 70mmHg), or CPP ( 50% of TBI patients in ICU,which was more than double the incidenceof central diabetes insipidus.September 14, 2010 41

Traumatic Brain Injury (TBI) and Effects of Altitude:An Analysis of the LiteratureTable 7. Studies of temperature effects on TBIAuthor(s),Journal Title Population (N)Diringer et al.(2004) Crit CareMed, 32, 1489-1495Geffroy et al.(2004) IntensiveCare Med, 30,785-790Jiang et al.(2002)J Neurotrauma,19, 869-874Elevated bodytemperatureindependentlycontributes toincreased length ofstay in neurologicintensive care unitpatientsSevere traumatichead injury inadults:Which patients areat risk of earlyhyperthermia?Early indicators ofprognosis in 846cases of severetraumatic braininjuryCivilianN = 4295 neuro ptsIncludedN = 617 TBI ptsMean GCS = 9-13CivilianN = 101Severe TBIGCS < 8CivilianN = 864severe TBIGCS < 9Outcome x TBIseverityIllness severitysignificantlyassociatedw/fever andcomplicationsN/AN/AFindingsRetrospective review of largeneurological ICU cohort withmultiple diagnoses including tumor,stroke, subarachnoid hemorrhage,and TBI. Episode(s) of elevatedtemperature were associated withdose-dependent increase in ICU andhospital lengths of stay, worseoutcome, and increased mortalityrate for all diagnoses. Fever was thesecond most predictive factor, twiceas powerful a predictor of hospitallength of stay as severity of illness.Retrospective review found 44 of101 (44%) severe TBI patientsexperienced early hyperthermia,which was associated with 1) poorerrecovery and 2) moderate or severedisability. Strong risk factors forearly hyperthermia within 2 dayswere WBC count (> 14.5) onadmission and body temperature >36 C on admission. Prophylactic useof acetaminophen was negativelyassociated with early hyperthermia.Retrospective study of 864 severeTBI patients found hyperthermiaw/in 72 hrs post-injury to bestrongly correlated with morenegative patient outcome.September 14, 2010 42