Strategies to improve performance at high altitude

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.


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


Easy Access to High Altitude Creates a Health and Performance Problem

Colorado Collegiate Range

5000

4000

3000

2000

1000

0

DEN

Camp 1

Camp 2

Camp 3 Camp 4

RDU

0 20 40 60 80

ELAPSED TIME (hr)

100 120


9000

8000

7000

6000

5000

4000

3000

2000

1000

0

20

Biophysics of High Altitude

Mt. Everest, Nepal

Mt. Mckinley, AK

30000

25000

20000

Pikes Peak, CO

15000

Leadville, CO 10000

Colorado Spgs, CO

Salt Lake City, UT

5000

Boston, MA

160

0

40 60 80 100 120 140

Inspired Oxygen Partial Pressure (mmHg)

Human Performance Physiology and Environmental Medicine at Terrestrial Extremes, 1988

Medical Aspects of Harsh Environments, 2002


Biophysics of High Altitude

100

80

60

40

20

0

0

Sea Level

1850 m (Colorado Spgs, CO)

4300 m (Pikes Peak, CO)

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

%

20 40 60 80 100 120 140

PaO

2

(mmHg)


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


PIO

2


Acute Physiological Responses

PAO

2

PaO

2

Disruption in Homeostasis

• 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 a up regulates >100 genes: EPO, VEGF, HSP(s)

• ???



Acute Physiological Responses: HIF Target Genes

Bernhardt, W.M. et al 2007



<1% of All Genes Changed Over Acclimatization



Acute Physiological Responses

PIO

2

PAO

2

PaO

2

Disruption in Homeostasis e.g.: Increased Alveolar Ventilation Causes Respiratory Alkalosis



Summary of Acute Physiological State

PIO

2

PAO

2

PaO

2

Disruption in Homeostasis

• 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

• ???

Table 2 –4


Altitude Acclimatization

A series of physiological adjustments that compensate for the reduction in ambient oxygen, and restores homeostasis

Benefits of 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

Table 2 –4



Summary of major physiological adaptations characteristic of altitude acclimatization

Increase Oxygen Delivery

Increased Ventilation: Raises partial pressure of arterial O

2

(PO

2

) and arterial oxyhemoglobin saturation (SaO

2

)

Decreased Plasma Volume: Raises arterial O

2 content via increased hemoglobin concentration [Hb]

Increased 2,3-diphosphoglycerate and Renal

Bicarbonate Excretion: Promotes O

2 unloading from hemoglobin

Increased Sympathetic Activity: Sustains blood flow and blood pressure

Erythropoietin Mediated Increase in Red

Blood Cell Mass: Raises arterial O

2 content

Increase Oxygen Utilization

Increased Tissue Extraction of O

2

Capillary Blood from

Increased Carbohydrate Transport and

Utilization

Hypoxia-Inducible Factor (HIF)-Mediated

Increased Oxidative Enzyme Function

Table 2 –4


Time Course of Altitude Acclimatization

Table 2 –4



Summary of major physiological adaptations characteristic of altitude acclimatization

Increase Oxygen Delivery

Increased Ventilation: Raises partial pressure of arterial O

2

(PO

2

) and arterial oxyhemoglobin saturation (SaO

2

)

Decreased Plasma Volume: Raises arterial O

2 content via increased hemoglobin concentration [Hb]

Increased 2,3-diphosphoglycerate and Renal

Bicarbonate Excretion: Promotes O

2 unloading from hemoglobin

Increased Sympathetic Activity: Sustains blood flow and blood pressure

Erythropoietin Mediated Increase in Red

Blood Cell Mass: Raises arterial O

2 content

Increase Oxygen Utilization

Increased Tissue Extraction of O

2

Capillary Blood from

Increased Carbohydrate Transport and

Utilization

Hypoxia-Inducible Factor (HIF)-Mediated

Increased Oxidative Enzyme Function



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

44

42

40

38

36

34

32

30

28

26

22 Women

37 Men

SL 1 2 3 4 5 7

Altitude Exposure (days)

10

100

95

90

22 Women (Muza et al. 2001)

37 Men (Reeves et al. 1993)

85

80

75

SL 1 2 3 4 5 7 10 12

4,300 m Altitude Exposure (days)

19



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

100

95

90

85

80

75

70

SL 1 2 3 6 9 11 13


Lyons et al. 1995

Sawka et al. 1996

Wolfel et al. 1991

21

15

14

13

12

18

17

16

SL 1 2 3 6 9 11 13


Lyons et al. 1995

Sawka et al. 1996

Wolfel et al. 1991

Reeves et al. 2001

21



Long-term Adaptation:

Tibetans:

High HVR,

Low PHPR

Larger TLC

Ward, Milledge & West, 2000



Procedures

• 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

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)


Staged Ascent Acclimatization Strategies

Ascend high enough to induce acclimatization, but to avoid developing

AMS, do not ascend too high or too fast.

2400

2200

2000

1800

Effective

Acclimatization

Marginal

Acclimatization

1600

1400

0 1 2 3 4 5 6 7 8 9 10 11 12 13 14

Staging Days

After staging, single day ascent up to 2,000 m above staging altitude has low risk of AMS.


Graded Ascent Acclimatization Strategies

Ascend high enough to induce acclimatization, but to avoid developing

AMS, do not ascend too high or too fast.

4500

Recommendations: above 2,400 m no more than 300 m/d.

Add a rest day every

900-1,200 m.

4000

300 m/day

3500

3000 Slow Ascents Above 2,400 m

Reduces AMS Incidence

2500

Unacclimatized Personnel

Rapid Ascent to 2,400 m

2000

0 1 2 3 4 5 6 7 8 9 10 11 12 13 14

Days



Acute Physiological State

PAO

2

PaO

2

Disruption in Homeostasis PIO

2

• Medical Issues:

Altitude Sickness and Deterioration

• Performance Issues:

Physical and Neuropsychological


Altitude Sickness

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



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



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


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

Beidleman, B.A.. et al., Med. Sci. Sports Exerc.:45, 2013



Time Course

2.0

32 men and women lowlanders

AMS incidence >80%

1.5

1.0

0.5

AMS Criterion

0.0

SL 1 2 3 4 5 6 7 8 9 10 11 12

Days at 4,300 m Altitude



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)


High Altitude Cerebral Edema (HACE)

Pathophysiology

Prevailing theory: continuum of AMS progressing to vasogenic edema

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)

33 yr male, SL to 5200 m in 6 days,

MRI day 2 and 11 months later


High Altitude Pulmonary Edema (HAPE)

Pathophysiology

SNS

(HVR, A-a O

2

, exercise, sleep)

Altitude Hypoxia Pulmonary Venoconstriction

Vascular Permeability

Agents?

PaO

2

(exercise, cold)

(Endothelin-1, NO)

Uneven HPVR

120

100

80

Pulmonary Htn

Pulmonary Pcap

60

40

20

Capillary Stress Failure

0

Pulmonary Capillary Leak

R S (well) S (sick)

HAPE Status

( Alveolar Fluid Absorption)

High Altitude Pulmonary Edema

Swenson, E. et.al. JAMA 2002



Prevention

80

Day 1

Unacclimatized Sea

Level Residents

60

Day 3

40

Day 1

"Staged" Sea

Level Residents

Altitude acclimatization above 1,200 m

20

0

80

For AMS consider Diamox (Acetazolamide)

- carbonic anhydrase Inhibitor facilitates HCO -

3 diuresis

For HACE consider Dexamethasone (corticosteroid)

82

For HAPE consider Nifedipine (calcium channel blocker),

Sildenafil, Tadalafil (5-PDE Inhibitor),

Salmeterol ( b

2

-adrenergic agonist)

Day 3

Day 1

84

SaO2 (%)

86

Moderate Altitude

Residents

Day 3

88



Treatment

Stop ascent

Descend (most efficacious treatment)

Rest

Medications listed for prevention

Oxygen

Hyperbaric treatment bag (>2 psi)


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



Acute Physiological State

PAO

2

PaO

2

Disruption in Homeostasis PIO

2

• Medical Issues:

Altitude Sickness and Deterioration

• Performance Issues:

Physical and Neuropsychological


Altitude Impact on Physical Work Performance

Maximal Aerobic Exercise Performance

0

-5

-10

-15

-20

-25

-30

-35

-40

-45

-50

-55

-60

-65

-70

-75

-80

0

146 mean data points from 67 studies

1000 2000 3000 4000 5000 6000 7000 8000 9000

Altitude (meters)

Fulco CS, et al., Aviat Space Environ Med 69: 793-801, 1998



Decreased Maximal Arterial Oxygen Delivery

100

80

60

40

20

0

0

Sea Level

1850 m (Colorado Spgs, CO)

4300 m (Pikes Peak, CO)

20

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

%

40 60 80 100 120 140

PaO

2

(mmHg)

.

.

VO

2 max = Qmax x (CaO

2

– CvO

2

)

(ml/min) (L/min) (ml/L)

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)



Endurance Exercise Performance

5

4

3

2

1

.

50 %VO

2 max 73

.

~31% decrease VO

2 max

150 W steady-state exercise

0

Sea Level 4,300 m




5

4

3

2

1

.

50 %VO

2 max 50

.

~31% decrease VO

2 max

150 W decreased to

105 W steady-state exercise

0

Sea Level 4,300 m




135

130

125

120

115

110

105

100

95

0

1 to 3 hours

20 to 30 minutes

2 to 5 minutes

< 2 minutes

1000 2000 3000

Altitude (meters)

4000



Acclimatization Improves Submax Exercise Performance

70

60

Maher et al, J Appl Physiol 1974

Horstman et al, J Appl Physiol 1980

Fulco et al, Aviat Space Environ Med 1994

Performance Metric:

Endurance Time at a

Fixed Work Intensity

50

40

30

20

10

0

81% VO

2 max

Cycle n=8

77% VO

2 max

Cycle n=8

83% VO

2 max

Run n=8

2 h-12 d 2-12 d 2-16 d

Continuous Residence at 4300 M



Performance Improvement is Strongly Correlated to

Ventilatory Acclimatization

50

40

30

20

10

0

-1 0 1 2

SaO2 increase (%)

3 4


Optimizing Exercise Performance At High Altitude:

What’s the fuss?

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


100

Altitude Impact on Neuropsychological

Neuropsychological Impairment with Acute

Performance

-5% light sensitivity

95

90

-30% visual acuity

-25% light sensitivity

-25% attention

85

80

75

70

-33% postural stability

-15% cognition

-25% pursuit tracking

-20% recall

-25% reaction time

-25% decoding

65

60

0 2000 6000 4000

Altitude (m)

8000

Kryskow et al., ASEM, 2013


160

Altitude Impact on Neuropsychological

Performance

ANAM Reaction Time-2 Choice (RT2)

Sea Level 4500 m Altitude Sea Level

140 *

120

M A E M A

Time of Day

E M A

Take home message: immediate impairment, but rapid recovery


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


Questions?

Mt. Kilimanjaro Crater

Pikes Peak Sunset

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