1. US Army Research Institute of Environmental Medicine Medicine and Work Performance at High Altitude Stephen R. Muza, Ph.D. U.S. Army Research Institute of Environmental Medicine Natick, MA, USA 01760 The opinions or assertions contained herein are the private views of the author(s) and are not to be construed as official or as reflecting the views of the Army or the Department of Defense.

2. US Army Research Institute of Environmental Medicine Overview 1. Biophysics of the Altitude Environment 2. Altitude Acclimatization: Key Physiological Adaptations Time-Course 3. High Altitude Stress: Medical Problems - Altitude Illness Performance – Physical & Neuropsychological

3. US Army Research Institute of Environmental Medicine Easy Access to High Altitude Creates a Health and Performance Problem

4. US Army Research Institute of Environmental Medicine Biophysics of High Altitude Human Performance Physiology and Environmental Medicine at Terrestrial Extremes, 1988 Medical Aspects of Harsh Environments, 2002

5. US Army Research Institute of Environmental Medicine Biophysics of High Altitude SL:CaO 2 = 19.6 ml O 2 % 1850 m:CaO 2 = 19.2 ml O 2 % 4300 m:CaO 2 = 16.5 ml O 2 %

6. US Army Research Institute of Environmental Medicine High Altitude Stress: Impact on Low Altitude Residents Decreased Physical Performance (>1,200 m) Risk of Altitude Sickness (>2,400 m) Decreased Neuropsychological Performances (>2,400 m) Medical Aspects of Harsh Environments, 2002

7. US Army Research Institute of Environmental Medicine High Altitude Stress: Acute Physiological Responses Increased alveolar ventilation Increased heart rate, and cardiac output Peripheral vasodilation Pulmonary arterial vasoconstriction Increased 2,3-diphosphoglycerate Increased epinephrine release from adrenal medulla Increased HIF-1  up regulates >100 genes: EPO, VEGF, HSP(s) ??? PIO 2 PAO 2 PaO 2 Disruption in Homeostasis

8. US Army Research Institute of Environmental Medicine High Altitude Stress: Acute Physiological Responses: HIF Target Genes Bernhardt, W.M. et al 2007

9. US Army Research Institute of Environmental Medicine High Altitude Stress: <1% of All Genes Changed Over Acclimatization

10. US Army Research Institute of Environmental Medicine High Altitude Stress: Acute Physiological Responses PIO 2 PAO 2 PaO 2 Disruption in Homeostasis e.g.: Increased Alveolar Ventilation Causes Respiratory Alkalosis

11. US Army Research Institute of Environmental Medicine High Altitude Stress: Summary of Acute Physiological State Systemic hypoxia Respiratory alkalosis (disrupted acid-base balance) Orthostatic intolerant (light-headed, syncope) Pulmonary arterial hypertension (impaired gas exchange) Altered body fluid regulation: vascular space is leaking, some tissues develop edema ??? PIO 2 PAO 2 PaO 2 Disruption in Homeostasis

12. US Army Research Institute of Environmental Medicine Altitude Acclimatization A series of physiological adjustments that compensate for the reduction in ambient oxygen, and restores homeostasis Table 2–4 Summary of major physiological adaptations characteristic of altitude acclimatization Restored Mental Performance: 1-2 Days Decreased Susceptibility to Altitude Illness: 2-5 Days Improved Sleep Quality: 5-7 Days Improved Physical Work Performance: 5-14 Days Overall, improved Resilience Benefits of Acclimatization:

13. US Army Research Institute of Environmental Medicine Altitude Acclimatization Increase Oxygen DeliveryIncrease Oxygen Utilization Increased Ventilation: Raises partial pressure of arterial O 2 (PO 2 ) and arterial oxyhemoglobin saturation (SaO 2 ) Increased Tissue Extraction of O 2 from Capillary Blood Decreased Plasma Volume: Raises arterial O 2 content via increased hemoglobin concentration [Hb] Increased Carbohydrate Transport and Utilization Increased 2,3-diphosphoglycerate and Renal Bicarbonate Excretion: Promotes O 2 unloading from hemoglobin Hypoxia-Inducible Factor (HIF)-Mediated Increased Oxidative Enzyme Function Increased Sympathetic Activity: Sustains blood flow and blood pressure Erythropoietin Mediated Increase in Red Blood Cell Mass: Raises arterial O 2 content Table 2–4 Summary of major physiological adaptations characteristic of altitude acclimatization Summary of major physiological adaptations characteristic of altitude acclimatization

14. US Army Research Institute of Environmental Medicine Time Course of Altitude Acclimatization Table 2–4 Summary of major physiological adaptations characteristic of altitude acclimatization

15. US Army Research Institute of Environmental Medicine Altitude Acclimatization Increase Oxygen DeliveryIncrease Oxygen Utilization Increased Ventilation: Raises partial pressure of arterial O 2 (PO 2 ) and arterial oxyhemoglobin saturation (SaO 2 ) Increased Tissue Extraction of O 2 from Capillary Blood Decreased Plasma Volume: Raises arterial O 2 content via increased hemoglobin concentration [Hb] Increased Carbohydrate Transport and Utilization Increased 2,3-diphosphoglycerate and Renal Bicarbonate Excretion: Promotes O 2 unloading from hemoglobin Hypoxia-Inducible Factor (HIF)-Mediated Increased Oxidative Enzyme Function Increased Sympathetic Activity: Sustains blood flow and blood pressure Erythropoietin Mediated Increase in Red Blood Cell Mass: Raises arterial O 2 content Table 2–4 Summary of major physiological adaptations characteristic of altitude acclimatization Summary of major physiological adaptations characteristic of altitude acclimatization

16. US Army Research Institute of Environmental Medicine Altitude Acclimatization Ventilatory Acclimatization: Increased Hypoxic Ventilatory Response (HVR) Decreased PaCO 2 set point Near normalization of pHa Compensated Respiratory Alkalosis Elevated PaO 2, SaO 2, and CaO 2

17. US Army Research Institute of Environmental Medicine Altitude Acclimatization Hematological Acclimatization: Early Response: Decreased Plasma Volume Increases [HB] Long-term Response (up to 18 months): Stimulation of Erythropoietin Increases RBC mass Near normalization of CaO 2

18. US Army Research Institute of Environmental Medicine Altitude Acclimatization Ward, Milledge & West, 2000 Long-term Adaptation: Tibetans: High HVR, Low PHPR Larger TLC

19. US Army Research Institute of Environmental Medicine ABOVE 8,000 ft (2,400 m): Slow ascent (no greater than 1,000 ft/day) Staged ascent (4 - 10 days at 6,000 - 8,500 ft) Intermittent Altitude Exposures (4+ hr exposure to high altitude each day for 1 or more weeks) Ascend High Enough to Induce Acclimatization, but Not Too High Reside at High Altitude for a Sufficient Length of Time Methods For Inducing Acclimatization: Staged or Gradual Ascent Profiles Intermittent Altitude Exposure Protocols Altitude Acclimatization Procedures

20. US Army Research Institute of Environmental Medicine Staged Ascent Acclimatization Strategies Ascend high enough to induce acclimatization, but to avoid developing AMS, do not ascend too high or too fast. After staging, single day ascent up to 2,000 m above staging altitude has low risk of AMS.

21. US Army Research Institute of Environmental Medicine Graded Ascent Acclimatization Strategies Ascend high enough to induce acclimatization, but to avoid developing AMS, do not ascend too high or too fast. Recommendations: above 2,400 m no more than 300 m/d. Add a rest day every 900-1,200 m.

22. US Army Research Institute of Environmental Medicine High Altitude Stress: Acute Physiological State Medical Issues: Altitude Sickness and Deterioration Performance Issues: Physical and Neuropsychological PIO 2 PAO 2 PaO 2 Disruption in Homeostasis

23. US Army Research Institute of Environmental Medicine Acute Mountain Sickness High Altitude Cerebral Edema High Altitude Pulmonary Edema High Altitude Retinal Hemorrhage High Altitude Peripheral Edema High Altitude Bronchitis Chronic Mountain Sickness Altitude Sickness

24. US Army Research Institute of Environmental Medicine Susceptibiity: Currently not predictable, but maybe? Individual susceptibility is reproducible Men greater susceptibility than women Risk Factors: Unacclimatized state Rapid ascent >2400 m Exercise or heavy physical work Hypohydration Very, very low HVR Cold Exposure Obesity Compromised cardiopulmonary function Age < 50 yrs Altitude Sickness

25. US Army Research Institute of Environmental Medicine Altitude Sickness Acute Mountain Sickness (AMS) – “most common” Incidence: 20 – 90% Symptom Complex:Headache, Nausea, Vomiting, Lassitude, Dizziness, Insomnia High Altitude Cerebral Edema (HACE) – “rare below the death zone” Incidence: ~1% Symptom Complex:Severe Headache, Impaired Mental Status, Truncal Ataxia, Coma High Altitude Pulmonary Edema (HAPE) – “leading cause of death” Incidence: 5-15% Symptom Complex:Dyspnea, Severe Fatigue, Non-productive Cough, becoming productive, Pink & Frothy, Coma Roach, R.C. et al., Medical Aspects of Harsh Environments, 2002

26. US Army Research Institute of Environmental Medicine Beidleman, B.A.. et al., Med. Sci. Sports Exerc.:45, 2013 Acute Mountain Sickness (AMS) Prediction of AMS: Time and altitude are key factors AMS increases 145% every 1000 m AMS severity peaks 18-24 h Physical activity increases AMS Physical activity delays recovery from AMS Women have lower AMS severity

27. US Army Research Institute of Environmental Medicine Acute Mountain Sickness (AMS) Time Course

28. US Army Research Institute of Environmental Medicine Acute Mountain Sickness (AMS) Pathophysiology Prevailing theory: hypoxia-induced mild edema of both cytotoxic (intracellular) and vasogenic (extracellular) origin Evidence: DW-MRI, volumetric MRI, CSF volume, IR-NIR scattering Problem: everyone affected, no correlation with AMS symptoms, no evidence of BBB failure Recent controversial theory: hypoxia-induced cerebral oxidative-nitrative stress releases noxious biomolecules that activate trigeminovascular nocioceptors to cause headache and AMS (Bailey, D.M. et al, 2009)

29. US Army Research Institute of Environmental Medicine High Altitude Cerebral Edema (HACE) Pathophysiology Prevailing theory: continuum of AMS progressing to vasogenic edema 33 yr male, SL to 5200 m in 6 days, MRI day 2 and 11 months later MRI of acute and recovered phases of HACE. 7 of 9 patients with HACE showed intense T2 signal in white matter areas, especially the splenium of the corpus callosum. (Hackett, P. et al., JAMA 1998)

30. US Army Research Institute of Environmental Medicine Altitude Hypoxia PaO 2 Uneven HPVR Pulmonary Htn Pulmonary Pcap Capillary Stress Failure Pulmonary Capillary Leak High Altitude Pulmonary Edema SNS Pulmonary Venoconstriction Vascular Permeability Agents? (exercise, cold) (Endothelin-1, NO) (HVR, A-a O 2, exercise, sleep) ( Alveolar Fluid Absorption) High Altitude Pulmonary Edema (HAPE) Pathophysiology Swenson, E. et.al. JAMA 2002

31. US Army Research Institute of Environmental Medicine Altitude acclimatization above 1,200 m For AMS consider Diamox (Acetazolamide) - carbonic anhydrase Inhibitor facilitates HCO - 3 diuresis For HACE consider Dexamethasone (corticosteroid) For HAPE consider Nifedipine (calcium channel blocker), Sildenafil, Tadalafil (5-PDE Inhibitor), Salmeterol (  2 -adrenergic agonist) Altitude Sickness Prevention

32. US Army Research Institute of Environmental Medicine Stop ascent Descend (most efficacious treatment) Rest Medications listed for prevention Oxygen Hyperbaric treatment bag (>2 psi) Altitude Sickness Treatment

33. US Army Research Institute of Environmental Medicine HIGH ALTITUDE DETERIORATION Key Features: >5000 m long-duration exposures Excessive weight loss Poor appetite Slow recovery from fatigue Poor wound healing Lethargy Irritability Lack of willpower Possible permanent brain damage

34. US Army Research Institute of Environmental Medicine High Altitude Stress: Acute Physiological State Medical Issues: Altitude Sickness and Deterioration Performance Issues: Physical and Neuropsychological PIO 2 PAO 2 PaO 2 Disruption in Homeostasis

35. US Army Research Institute of Environmental Medicine Altitude Impact on Physical Work Performance Maximal Aerobic Exercise Performance Fulco CS, et al., Aviat Space Environ Med 69: 793-801, 1998 146 mean data points from 67 studies

36. US Army Research Institute of Environmental Medicine Decreased Maximal Arterial Oxygen Delivery SL:CaO 2 = 19.6 ml O 2 % 1850 m:CaO 2 = 19.2 ml O 2 % 4300 m:CaO 2 = 16.5 ml O 2 % Altitude Impact on Physical Work Performance At Sea Level (SaO 2 =97%): 4200 ml/min = 25 L/min x (196-28 ml/L) At 4300 m (SaO 2 =80%): 3425 ml/min = 25 L/min x (165-28 ml/L) VO 2 max = Qmax x (CaO 2 – CvO 2 ) (ml/min) (L/min) (ml/L)..

37. US Army Research Institute of Environmental Medicine Altitude Impact on Physical Work Performance 150 W steady-state exercise ~31% decrease VO 2 max. 50 %VO 2 max 73. Endurance Exercise Performance

38. US Army Research Institute of Environmental Medicine Altitude Impact on Physical Work Performance ~31% decrease VO 2 max. 50 %VO 2 max 50. 150 W decreased to 105 W steady-state exercise Endurance Exercise Performance

39. US Army Research Institute of Environmental Medicine Endurance Exercise Performance Altitude Impact on Physical Work Performance

40. US Army Research Institute of Environmental Medicine Acclimatization Improves Submax Exercise Performance Performance Metric: Endurance Time at a Fixed Work Intensity Altitude Impact on Physical Work Performance

41. US Army Research Institute of Environmental Medicine Performance Improvement is Strongly Correlated to Ventilatory Acclimatization Altitude Impact on Physical Work Performance

42. US Army Research Institute of Environmental Medicine Sanctioned Competitions: 2010 FIFA World Cup (~5,000 ft) 2002 Winter Olympics (4,675 – 5,742 ft) Pikes Peak Marathon (7,000 – 14,110 ft) Leadville 100 (9,200 – 12,600 ft) 2014 Winter Olympics (5,000 ft) Recreational Activities: Trekking & Mountaineering Snow Sports Hunting & Fishing Occupational Activities: Military & Law Enforcement Forestry & Mining Civil Engineering Optimizing Exercise Performance At High Altitude: What’s the fuss?

43. US Army Research Institute of Environmental Medicine Altitude Impact on Neuropsychological Performance Kryskow et al., ASEM, 2013

44. US Army Research Institute of Environmental Medicine Altitude Impact on Neuropsychological Performance Take home message: immediate impairment, but rapid recovery

45. US Army Research Institute of Environmental Medicine Summary 1. Biophysics of the Altitude Environment 2. Altitude Acclimatization: Key Physiological Adaptations Time-Course 3. High Altitude Stress: Medical Problems - Altitude Illness Performance – Physical & Neuropsychological

46. US Army Research Institute of Environmental Medicine Questions? Pikes Peak Sunset Mt. Kilimanjaro Crater