NASA/TP–2008–214759 

Risk Assessment of Acute Mountain Sickness 

in the Crew Exploration Vehicle 

Johnny Conkin, Ph.D. 

Universities Space Research Association 

January 2008 
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NASA/TP–2008–214759 

Risk Assessment of Acute Mountain Sickness 

in the Crew Exploration Vehicle 

Johnny Conkin, Ph.D. 

Universities Space Research Association 

 

National Aeronautics and 

Space Administration 

Lyndon B. Johnson Space Center 

Houston, Texas 77058 

January 2008 
Acknowledgment 

 I sincerely appreciate the thorough manuscript review by Mr. James H. Wessel, 

III. His effort improved my review of what is a complex interdisciplinary topic. Special 

thanks to Dr. Noah Walman, an October 2006 Aerospace Medicine Clerk, and Dr. Wyche 

T. Coleman, III, an April 2007 Aerospace Medicine Clerk, for educating NASA Flight 

Surgeons on this topic. Drs. Jeffrey A. Jones, Richard A. Scheuring, and Michael L. 

Gernhardt contributed substantially to the Executive Summary. My views and opinions 

do not reflect official NASA policy. This work was possible through the NASA 

Cooperative Agreement NNJ06HG25A with the Universities Space Research 

Association. 

 
Abstract

To limit the risk of fire, reduce the risk of decompression sickness and reduce the 

prebreathe (denitrogenation) time to support frequent extravehicular activities on the 

moon and later Mars, a hypobaric and mildly hypoxic living environment is considered 

for the Crew Exploration Vehicle (CEV), the Lunar Surface Access Module, and longterm surface habitats. Superimposed on physiological adjustments to living in a 

hypobaric hypoxia (HH) environment are also physiological adjustments associated with 

adaptation to microgravity (μG). The outward manifestations of these physiological 

adaptations may present as unexpected signs and symptoms of Acute Mountain Sickness 

(AMS). There is a medical concern that combining these stresses will degrade the health 

and performance of astronauts who must maintain a high level of proficiency to 

accomplish mission goals. The concern comes from a lack of mechanistic understanding 

of the changes induced by each of the above conditions. Therefore, there is a lack of 

mechanistic understanding of the integrated response. In particular, signs and symptoms 

of AMS are undesirable, as they would impact crew health and performance. A review 

of the research literature suggests that: (1) there is an absolute pressure (PB) effect per se

on AMS, so the higher the altitude for a given computed hypoxic alveolar oxygen (O2) 

partial pressure (PAO2) the greater the AMS response; (2) about 25% of adults would 

experience AMS near 2,000 m (6,600 ft, PAO2 = 75 mmHg) altitude; (3) there is no 

direct evidence from 6 research reports that HH synergizes with adaptive changes during 

simulated μG to dramatically increase hematocrit (HCT) and blood viscosity, and (4) 

only susceptible astronauts would develop mild and transient AMS with exposure to 8.0 

pounds per square inch, absolute (psia) (16,000 ft) while breathing 32% O2 (PAO2 = 77 

mmHg) and simultaneously adapting to μG. No clinically significant increase in HCT or 

blood viscosity is expected as red blood cell mass, plasma, and total body water volumes 

adjust to the combined HH and μG environment. Good operational experience with the 

shuttle staged denitrogenation protocol at 10.2 psia (10,000 ft) while breathing 26.5% O2

(PAO2 = 85 mmHg) in μG-adapted astronauts suggests that a similar good experience is 

expected for the proposed CEV environment. The uncertainties in the above conclusions 

due to limited research data require a risk mitigation plan that includes some of the 

following: (1) developing the rationale and procedures to increase PB as needed in the 

CEV, plus using medications, including supplemental O2, to effectively treat AMS; (2) 

consider pre-selection of astronauts who are resistant to AMS; (3) pre-adapting the crew 

to a hypoxic environment prior to launch; (4) considering breathing 100% O2 at 

prescribed intervals, or as needed, during the initial adaptive phase to the new 

environment to prevent AMS; (5) developing an acclimatization plan through a gradual 

reduction in PAO2 during the initial phase of the mission; or (6) conducting a detailed 

validation test of the extreme limit of the proposed CEV living environment (7.8 psia 

with 30% O2, PAO2 = 68) in a large representative sample of subjects during 6-deg head 

down bedrest over several days to characterize the risk of anticipated AMS. 

 i
Contents 

Section Page 

Executive Summary .......................................................................... 1 

 Concerns Relevant to Constellation Vehicle .................................... 2 

 The Risk of Acute Mountain Sickness ........................................... 2 

 Quality and Quantity of Research Data .......................................... 3 

 Risk Mitigation Plan ................................................................ 4 

Risk Assessment of Acute Mountain Sickness in the Crew Exploration Vehicle ... 6 

 Introduction .......................................................................... 6 

 Purpose ............................................................................... 6 

 Rationale for Mild Hypoxic Spacecraft Atmosphere .................................. 8 

 First Issue: Hypoxia and Acute Mountain Sickness................................ 9 

 Carbonic Anhydrase and Action of Acetazolamide ..................................... 11 

Is Acute Mountain Sickness a Function of Absolute Pressure 

and Hypoxic Stress? .................................................................................... 14 

 Concept of Equivalent Air Altitude Exposure ............................................ 16 

 Variability to Acute Mountain Sickness ..................................................... 18 

 Data for Pressure Effect per se on Acute Mountain Sickness .................... 22 

Do Venous Gas Emboli have a Role in Acute Mountain Sickness? ........ 32 

Partial Pressure of Nitrogen, Oxygen, and Carbon Dioxide in the 

Cerebrospinal Fluid .................................................................................... 33 

 Second Issue: Body Fluid and Red Blood Cell Changes in Microgravity . 68 

 Third Issue: Potential Integrated Response ..................................... 73 

Conclusions ................................................................................. 84 

 Quality and Quantity of Literature Data ....................................... 84 

Risk Mitigation Plan ....................................................................... 89 

Notes ...................................................................................................................... 91 

References ................................................................................... 92 

Appendix: Standard Atmosphere ........................................................... 98 

 ii
Tables 

Table Page 

I Range of Atmospheric Conditions in Proposed Living Environments ...... 1, 7 

 iii
Figures 

Figure Page 

1 Two examples of EAAs as a function of CEV atmospheric pressure. ...... 17 

2 Matrix of combinations of PB and O2 concentration that have been 

 evaluated. ............................................................................ 23 

 3 A PB effect per se appears at work on physiological responses 

 and signs and symptoms of AMS based on a review of literature 

 from 1980 to the present. ........................................................... 24 

4 The average Lake Louise AMS score from 6 and 9 hrs of hypoxic 

exposure in 9 subjects associated with the computed PAO2 

from the AOE. ..................................................................... 26 

5 Tucker’s (1983) summary results supports a PB effect at work 

 on the signs and symptoms of AMS. ........................................... 28 

6 Best-fit statistical DCS dose - VGE response curve for 52 different 

 tests at altitude that involved 1,009 men who were physically active 

 at altitude. .......................................................................... 33 

7 Change in metabolic rate and N2 kinetics within the lung modifies 

 PAO2 and PACO2. ............................................................... 36 

8 Eight PIO2 isopleths from 80 to 150 mmHg. ................................. 39 

9 Grover’s (1982) summary results. .............................................. 41 

10 Curves created from an equation published by Grover (1982). ............ 42 

11 Levine’s (1988) summary results for 8,500 ft exposure. ................. 44 

12 Levine’s (1988) summary results for 15,100 ft exposure. ............... 45 

13 Levine’s (1988) summary results for 21,500 ft exposure. ............... 46 

14 Loeppky (2005a) summary results describe classic edema formation 

 with AMS. ........................................................................ 49 

15 Savourey’s (2003) summary results. .......................................... 50 

16 Loeppky’s (1996) summary results. ........................................... 54 

17 Loeppky’s (1997) summary results. ........................................... 55 

18 There appears to be a consensus of opinion of a PB effect at 

 work on the signs and symptoms of AMS, but no one knows a 

 mechanism as of 2008. .......................................................... 60 

19 Epstein’s (1972) summary results. ............................................. 61 

20 The experimental data presented allows comparisons and then 

 conclusions about the risk of AMS given the nominal and extreme 

 breathing gas environment on the CEV. ....................................... 66 

21 A visual comparison of the difference in physiological and actual 

 altitude in 3 vehicles: the shuttle, proposed CEV and LSAM, 

 and proposed moon and Mars habitats. ........................................ 67 

22 Ge’s (2002) summary results. ................................................... 69 

23 Increase in absolute viscosity of blood with an increase in HCT. .......... 71 

24 Summary results from extended BR for 28 days in very young men 

 (19 years old average). ............................................................ 76 

 iv
25 Waligora’s (1982) summary results. ............................................ 78 

26 Fulco’s (1985) summary results. ................................................ 79 

27 Loeppky’s (1990) summary results. ............................................ 80 

28 Loeppky’s (1993a and 1993b) summary results. ............................. 82 

29 Plot shows the position of several tests in this report by the test 

 altitude and computed PAO2 compared to the position of successful 

 NASA human space programs and the proposed CEV program. ........... 88 

 v
Acronyms and Nomenlature

ADH antidiuretic hormone 

ALD aldosterone 

AMS Acute Mountain Sickness 

ANP atrial naturetic peptide 

AOE alveolar oxygen equation 

ATA atmosphere pressure absolute 

AZ acetazolamide 

BBB blood brain barrier 

BR bedrest 

BTPS body temperature, pressure, saturated with water vapor 

C Celsius 

Ccr creatinin clearance 

CA carbonic anhydrase 

CEV crew exploration vehicle 

Cl- chloride ion 

CNS central nervous system 

CO cardiac output 

CO2 carbon dioxide 

CSF cerebrospinal fluid 

DBP diastolic blood pressure 

DCS decompression sickness 

EAA Equivalent Air Altitude 

EP erythropoietin 

EPI epinephrine 

EVA extravehicular activity 

FEN2 expired nitrogen fraction 

FICO2 inspired carbon dioxide fraction 

FIO2 inspired oxygen fraction 

FIN2 inspired nitrogen fraction 

ft feet 

GRF glomerular filtration rate

H+ hydrogen ion 

HACE high altitude cerebral edema 

HAPE high altitude pulmonary edema 

HB hemoglobin 

HCT hematocrit 

 vi
HCO3- bicarbonate ion 

HH hypobaric hypoxia 

HN hypobaric normoxia 

HR heart rate 

hr hour 

HVR hypoxic ventilatory response 

JSC Johnson Space Center 

K+ potassium ion 

kg kilogram 

LSAM lunar surface access module 

m meter 

MAP mean arterial pressure 

ml milliliter 

μG microgravity 

min minute 

mmHg millimeter of mercury 

N2 nitrogen 

Na+ sodium ion 

NH normobaric hypoxia 

NN normobaric normoxia 

NOR norepinephrine 

O2 oxygen 

PaCO2 arterial blood carbon dioxide partial pressure 

PACO2 alveolar carbon dioxide partial pressure 

PaO2 arterial blood oxygen partial pressure 

PAO2 alveolar oxygen partial pressure 

PaN2 arterial blood nitrogen partial pressure 

PB atmospheric pressure 

PB prebreathe 

PCSFN2 cerebrospinal fluid nitrogen partial pressure 

PCSFO2 cerebrospinal fluid oxygen partial pressure 

pH hydrogen ion concentration 

PECO2 end-tidal carbon dioxide partial pressure 

PEO2 end-tidal oxygen partial pressure 

PICO2 inspired carbon dioxide partial pressure 

PIN2 inspired nitrogen partial pressure 

 vii
PIO2 inspired oxygen partial pressure 

ppO2 oxygen partial pressure 

ppN2 nitrogen partial pressure 

psia pounds per square inch absolute 

P(VGE) probability of venous gas emboli 

PV plasma volume 

Q cardiac output, pulmonary perfusion rate 

RBC red blood cell 

RER respiratory exchange ratio 

SaO2% arterial blood oxygen saturation 

SBP systolic blood pressure 

SMEAT Skylab Medical Experiments Altitude Test 

STPD standard temperature (37 c), pressure (760 mmHg), dry gas 

VA alveolar ventilation rate 

VCO2 carbon dioxide production rate 

VE minute ventilation rate 

VO2 oxygen consumption rate 

VGE venous gas emboli 

Vt tidal volume 

 viii
Executive Summary 

 This is a summary of a longer report that was written for medical operations, 

specifically the Flight Surgeons. It will summarize an analysis of risk of crew symptoms 

associated with the proposed Constellation vehicle oxygen (O2) partial pressure (ppO2). 

The goal of any trade process is an integrated product, and each stakeholder accepts a less 

than ideal outcome. Each stakeholder then develops a strategy to minimize the impacts 

of their less than ideal outcome. From the medical and physiological perspective, we 

need to minimize any risk of altitude transition symptoms, otherwise known as Acute 

Mountain Sickness (AMS). 

To limit the risk of fire, reduce the risk of decompression sickness and reduce the 

prebreathe time to support frequent extravehicular activities (EVAs) on the moon and 

Mars, a hypobaric and mildly hypoxic living environment is proposed for the Crew 

Exploration Vehicle (CEV), the Lunar Surface Access Module (LSAM), and long-term 

planetary surface habitats. 

Two living environments recommended by the Exploration Atmospheres 

Working Group at the Johnson Space Center in 2006 are seen in Table I. 

Table I. Range of Atmospheric Conditions in Proposed Living Environments 

Environment PB FIO2 PIO2 PAO2* Actual Altitude Equivalent 

Air Altitude (EAA)

psia mmHg (%) mmHg mmHg m ft m ft 

CEV + LSAM 

normal 8.0 414 32.0 117 77 4,877 16,000 1,829 6,000 

best case 8.2 424 34.0 128 86 4,816 15,800 1,158 3,800 

worse case 7.8 403 30.0 107 68 5,029 16,500 2,438 8,000 

Habitat 

normal 7.6 393 32.0 111 71 5,182 17,000 2,286 7,500 

best case 7.8 403 34.0 121 80 5,029 16,500 1,524 5,000 

worse case 7.4 383 30.0 101 63 5,364 17,600 2,895 9,500 

PB is ambient pressure; PIO2 is inspired oxygen partial pressure, computed as (PB mmHg – 47) * FIO2 (as 

decimal percent); and FIO2 is inspired oxygen fraction. 

* computed alveolar oxygen partial pressure (PAO2) is for an acute altitude exposure with a “typical” adult 

exhibiting a “typical” response to mild hypoxia. When breathing an atmosphere that does not contain FIO2

= 20.9% O2, it is helpful to determine the EAA by using the Alveolar O2 Equation since most experience 

with hypoxia is with ascent to altitude while breathing air. 

The expected EAAs of 1,829 and 2,286 m (6,000 and 7,500 ft) do not reflect the 

complete hypoxic stress since current literature indicates that AMS results from a 

complex interaction between both PAO2 and PB. Therefore, there is uncertainty as to 

how to fully evaluate the combination of the 2 components of hypoxic stress to estimate 

the true risk of AMS. 

 1
Superimposed on physiological adjustments to living in a hypobaric hypoxia 

(HH) environment are physiological adjustments associated with adaptation to 

microgravity (μG). The outward manifestations of these physiological adaptations may 

present as unexpected signs and symptoms of AMS. There is some uncertainty about the 

full impact that the combination of these stresses will have on the health and performance 

of astronauts who must maintain a high level of proficiency to accomplish exploration 

mission goals. Therefore, it is prudent to recommend operational ppO2 that do not fall 

into a physiological area of uncertainty, and to have a risk mitigation strategy for cases 

when operations push towards the limits of the known safe operational range. 

Concerns Relevant to Constellation Vehicles 

There is a PB effect per se on the risk of AMS, in addition to the AMS risk induced 

by the HH, but to what degree is uncertain. 

There may be an increased risk of AMS when HH is combined with adaptations to 

μG. 

Associated with 2 above, there may be an amplified increase in blood viscosity when 

HH is combined with adaptation to μG. 

 Since significant uncertainties exist to resolve these concerns, a risk mitigation 

plan should be developed to minimize the impact of mild hypoxia combined with 

adaptation to μG. 

The Risk of Acute Mountain Sickness 

 Quick ascent to altitudes over 2,590 m (8,500 ft) often results in symptoms of 

AMS. Nearly 25% of individuals are affected from a rapid ascent (< 24 hrs), even to 

2,000 m (6,600 ft). Many factors modify the risk of AMS between 2,000 and 3,048 m 

(6,600 and 10,000 ft), particularly the rate of ascent to altitude, the activity level at 

altitude, and individual susceptibility. 

AMS is a constellation of signs and symptoms including headache, nausea, 

dizziness, fatigue, and sleeplessness that develops over a 6 to 24 hr stay in a hypoxic 

environment, usually from rapid ascent to altitude while breathing ambient air. The 

headache, for example, is usually throbbing, bitemporal or occipital, typically worse 

during the night and on awakening, and made worse by Valsalva’s maneuver; when 

combined with nausea, it can be likened to an alcohol hangover. Additional clinical 

findings that confirm a diagnosis of AMS include changes in mental status, ataxia, 

peripheral edema, or changes in performance. A change in performance means that any 

of the above symptoms or clinical findings have caused a reduction in normal activities. 

 2
Quality and Quantity of Research Data 

Any factor that could reduce crew health and performance should be minimized. 

There is not an abundance of data specific to that required for the spaceflight AMS risk 

assessment. There are only 4 reports about a PB effect per se on the risk of AMS 

induced by HH and 6 reports on the combined effects of HH and simulated μG adaptation 

that have some application here. So, all of the conclusions listed in this summary are 

based on extrapolation or interpolation from limited information. 

Although initial signs and symptoms of AMS in susceptible subjects are expected 

after acute exposure to between 2,000 m (6,600 ft at PAO2 = 75 mmHg) and 2,590 m 

(8,500 ft at PAO2 = 67 mmHg) while breathing air, it is likely that these would be 

self-limiting once acclimatization occurs. 

At 8.0 pounds per square inch, absolute (psia) (4,876 m or 16,000 ft) with a nominal 

PAO2 = 77 mmHg, it is likely that susceptible astronauts breathing O2-enriched air 

and simultaneously undergoing adaptation to μG will experience signs and symptoms 

of AMS. 

No clinically significant increase in hematocrit or blood viscosity is expected as red 

blood cell mass, plasma, and total body water volumes adjust to the combined HH 

and μG environment. A transient increase to a mean hematocrit of about 50%, 

possibly as high as 55% in a particular crewperson, would be predicted based on the 

data for the combined effects of HH and adaptation to μG as envisioned for the CEV 

program. However, typical μG-adapted spaceflight hematocrit values are in the low 

normal range, from 36 to 40% depending on gender. 

The repeatedly validated operational experience with the shuttle staged 

denitrogenation protocol at 10.2 psia (10,000 ft) while breathing 26.5% O2 (PAO2 = 

85 mmHg) in μG-adapted astronauts suggests that a similar low risk of AMS can be 

expected for the proposed CEV environment. 

On balance, there is no definitive evidence for an exaggerated (negatively synergistic) 

response to the combination of HH and adaptation to μG. On the contrary, the limited 

evidence suggests that one stressor tends to counteract the other. 

 All events associated with the CEV/LSAM mission to the moon are on a short 

timescale compared to weeks and months needed to achieve a new steady state 

adaptation. So, physiological compensation, accommodation, or acclimatization 

processes are under way in the CEV immediately after orbital insertion, on the way to the 

moon, during EVA on the moon, and during the return to Earth over a 10 to 15 day 

mission. Individual susceptibility to μG adaptation in a HH environment will likely play 

a role in mission success (including an absence of medical problems) in these short-term 

missions with high EVA-rate scenarios. Some peak performance degradation could be 

expected in crewmembers, if ppO2 is reduced acutely to less than 2.8 psia, until 

 3
compensation occurs. The magnitude of the performance affect will depend on the ppO2, 

the metabolic demands of the task, and individual (genetic) factors. Current threshold for 

mandatory supplemental O2 during spaceflight operations is 2.2 psia. For lunar outpost 

missions (approximately 6 months surface stays), full acclimatization to reduced ppO2

can be expected after 30 to 45 days, allowing crews to function at high performance 

levels in the face of reduced O2 tension. 

Risk Mitigation Plan

 There is no single study that addresses the exact conditions for the proposed 

nominal Constellation vehicle environment: adaptation to μG with a breathing 

environment at 8.0 psia (16,000 ft altitude) with 32% O2 and 68% N2, resulting in an 

acute PAO2 of about 77 mmHg. Therefore, the recommendations that follow are not 

only based on extrapolations and judgment from an exhaustive literature review, but also 

from tests that differ from the proposed CEV, LSAM, and long-duration surface habitat 

environments. 

We expect no significant negative synergistic interaction between HH exposure with 

μG adaptation for the proposed CEV environment. Any AMS signs and symptoms 

would be mild, and transient. 

Develop the rationale and procedures to easily increase ambient PB plus use 

medications such as prophylactic or, as-needed, acetazolamide, dexamethasone, and 

supplemental O2 to reduce AMS risk or provide effective treatment if required. 

Caution is warranted here for several reasons: acetazolamide may be prescribed for 

diagnosed AMS when, in fact, signs and symptoms are from motion sickness. Or, 

medication for motion sickness may be incorrectly prescribed for AMS. AMS and 

motion sickness share many of the same signs and symptoms, and may appear along a 

similar time course. Often sleep medication is prescribed due to the many 

distractions in a small space vehicle. However, sleep medications may be 

contraindicated if AMS is suspected. A sleep medication would likely worsen the 

signs and symptoms of AMS. 

Consider preflight testing to identify astronauts who are susceptible to atmospheric 

changes in the CEV environment, and provide special training and risk mitigation 

plans for those who are identified as susceptible, versus reassignment to a different 

mission. 

Pre-adapt crews to a hypoxic environment prior to launch to blunt any combined 

negative effects of HH exposure with μG adaptation shortly after launch. But, this 

intervention to reduce the risk of AMS is contraindicated if the resulting increase in 

HCT significantly adds to the increased HCT transiently observed during the acute 

phase of μG adaptation, possibly leading to impaired circulation and O2 delivery. 

Consider phlebotomy, if warranted. 

 4
Develop an acclimatization plan through the gradual reduction in PAO2 during the 

initial phase of the missions, which should significantly reduce the likelihood of AMS 

signs and symptoms. 

Consider inclusion of a plan to breathe 100% O2 by mask over several intervals of 

time during the acclimatization to the μG plus HH exposure. Breathing 100% O2 is 

shown to blunt the negative physiological effects of subsequent HH exposure. 

 5
Risk Assessment of Acute Mountain Sickness in the 

Crew Exploration Vehicle 

Introduction 

 This report was written for the medical operations community at the Johnson 

Space Center (JSC), specifically the Flight Surgeons. It summarizes an analysis of risk of 

crew symptoms associated with the proposed Constellation vehicle oxygen (O2) partial 

pressure (ppO2). Extended exposures to even mild hypoxic stress can lead some to signs 

and symptoms of Acute Mountain Sickness (AMS). This is a concern in any aerospace 

application where mild hypoxia is deemed an acceptable trade. The goal of any trade 

process is an integrated product, and each stakeholder accepts a less-than-ideal outcome. 

Each stakeholder then develops a strategy to minimize the impacts of their less-than-ideal 

outcome. Our goal is to understand the risk of AMS, and then develop strategies to 

minimize any perceived risk. 

 

 The brain and spinal cord, which are the central nervous system (CNS), constitute 

2% of body mass in adults. Yet, this organ system under basal conditions commands 

14% of the cardiac output (CO) and consumes 20% of the O2 at any given time. The 

CNS is the system to preserve in a crisis and at some point hypoxia caused by a reduction 

in breathing gas ppO2 becomes a crisis. O2 is not stored in the body, so a reduction in 

supply quickly becomes apparent. For example, the rods of the eye lose the ability to 

respond in dim light with ascent to as little as 1,524 m (5,000 ft) altitude. 

In situations that threaten O2 supply to the CNS, compensatory measures are 

taken to maintain adequate cerebral blood flow. Cerebral blood flow appears to be 

regulated almost entirely by local mechanisms. The brain initiates various actions in 

response to peripheral and central detection of a changed O2 and acid-base environment. 

The long-term adjustments (adaptation) to hypoxia either return the internal environment 

to near normal or various organ systems tolerate (accommodation) the new hypoxic 

conditions with some loss of function. Hypoxic stress impacts the function of any 

aerobic tissue, and a common first response is to consider the changes in the peripheral 

lungs, kidneys, or even gut. But, the brain is central and an understanding of the 

integrated response to hypoxia is no small task. In this vein, it is ultimately necessary to 

focus on the CNS as the target of and responder to hypoxic stress.

 

Purpose 

This report addresses, through a comprehensive literature search and evaluation of 

those data, 3 important questions related to AMS. These questions were raised during the 

development of 2 proposed living environments for continued space exploration, as 

recommended by the Exploration Atmospheres Working Group at JSC in 2006 

(Campbell 2006). 

 6
Is there evidence for an absolute pressure (PB) effect per se on the risk of AMS 

induced by hypobaric hypoxia (HH)? 

Is there evidence for an increased risk of AMS when HH is combined with 

adaptations to microgravity (μG)? 

Is there evidence for an amplified increase in blood viscosity when HH is combined 

with adaptations to μG? 

 

 Since significant uncertainties do exist to resolve the above questions, a risk 

mitigation plan must be developed to minimize the impact of mild hypoxia combined 

with adaptation to μG. 

The 2 proposed living environments are in the (1) Crew Exploration Vehicle 

(CEV) plus Lunar Surface Access Module (LSAM), and (2) long-duration moon and 

Mars surface habitats. The proposed nominal living environment for the CEV and 

LSAM are at 8.0 pounds per square inch, absolute (psia) (16,000 ft) with 32% O2

compared to 7.6 psia (17,000 ft) and 32% O2 for the long-duration moon and Mars 

surface habitats. The environmental control and life support system will operate within a 

control range; the minimum, normal, and maximum control range for PB and O2

concentration (the inspired oxygen fraction, FIO2), plus an estimate of the acute alveolar 

oxygen partial pressure (PAO2) from the alveolar oxygen equation (AOE) are shown in 

Table I. 

Table I. Range of Atmospheric Conditions in Proposed Living Environments 

Environment PB FIO2 PIO2 PAO2* Actual Altitude Equivalent 

Air Altitude (EAA)

psia mmHg (%) mmHg mmHg m ft m ft 

CEV + LSAM 

normal 8.0 414 32.0 117 77 4,877 16,000 1,829 6,000 

best case 8.2 424 34.0 128 86 4,816 15,800 1,158 3,800 

worse case 7.8 403 30.0 107 68 5,029 16,500 2,438 8,000 

Habitat 

normal 7.6 393 32.0 111 71 5,182 17,000 2,286 7,500 

best case 7.8 403 34.0 121 80 5,029 16,500 1,524 5,000 

worse case 7.4 383 30.0 101 63 5,364 17,600 2,895 9,500 

PB is ambient pressure; PIO2 is inspired oxygen partial pressure, computed as (PB mmHg – 47) * FIO2 (as 

decimal percent); and FIO2 is inspired oxygen fraction. 

* computed alveolar oxygen partial pressure (PAO2) is for an acute altitude exposure with a “typical” adult 

exhibiting a “typical” response to mild hypoxia. The exact value for PAO2 seen in the table would not 

likely be measured in a small sample of adults exposed to the conditions listed in the table. When 

breathing an atmosphere that does not contain FIO2 = 20.9% O2, it is helpful to estimate the EAA since 

most experience with hypoxia is with ascent to altitude while breathing air. With a given PAO2 from the 

AOE one can consult published “altitude tables” (DeHart 1996 in Appendix) to find the altitude while 

 7
breathing air that corresponds to the acute PAO2 value, regardless of the combination of PB and FIO2 that 

is used to achieve the value. 

Rationale for Mild Hypoxic Spacecraft Atmosphere 

 Future vehicles for space exploration will have less than atmospheric PB, with a 

ppO2 less than a sea level equivalent of 3.07 psia, or 160 mmHg. What is the rationale 

for this statement? A hypobaric and mildly hypoxic environment will be the product of a 

complex integration of safety, engineering, operational, and medical concerns where the 

goal is routine and safe exploration of the lunar and martian surfaces. An efficient 

exploration program requires that extravehicular activity (EVA) be efficient. The time to 

prepare for EVA should be minimal, and the suit pressure should be low to accommodate 

EVA tasks without undue fatigue, physical discomfort, or even suit-related trauma. 

Currently, a long prebreathe (PB) time is used prior to EVA from the shuttle and the 

International Space Station to prevent decompression sickness (DCS) and significant 

venous gas emboli (VGE) insult of the lungs at 4.3 psia. To shorten the PB time, the 

habitat atmosphere should not have a high nitrogen (N2) partial pressure (ppN2). One 

practical approach to reduce the ppN2 is to increase the ppO2 while also reducing the PB. 

A balance must be achieved between the increased risk of fire at high O2 concentration 

and the decreased risk of DCS as ppN2 is reduced in the habitat. The concentration of 

O2 and, therefore, the risk of fire for a given PB can be reduced further if PIO2 is less 

than 149 mmHg, but not so low as to cause significant hypoxia. A candidate atmosphere 

for the CEV is 8.0 psia (414 mmHg) with O2 concentration between 30% and 34% 

(ppO2 = 124 to 140 mmHg), with balance N2. So, for good reasons, a modest HH 

environment with crews adapted to μG is one option for future moon and Mars 

exploration. How will the body accommodate or adapt to this new living environment? 

Will the accommodation or adaptation lead to a new functional state for the crew and, 

therefore, a significant change in health and performance? 

It is known that deconditioning and fluid redistribution occurs during extended 

bedrest (BR), BR with head down tilt, and exposure to μG. There is a decrease in total 

blood volume through a combined loss in plasma volume (PV) and red blood cell (RBC) 

mass (Alfrey 1996, Buckey 2006, Bungo 1989, Johnson 1977). Hematocrit (HCT) 

transiently changes during this period of adaptation, but returns to near-baseline values 

over several weeks in a normobaric normoxia (NN) environment. Exposure to significant 

HH leads to an increase in RBC mass with an expected increase in HCT (Ge 2002, 

Murray 1986) and blood viscosity (Martin 1986, Neuman 1976). An increase in HCT 

above 55% increases blood viscosity where the decrease in CO more than offsets the gain 

in O2 capacity of the blood. This combination leads to a decrease in O2 transport 

(Murray 1986, Burton 1972). 

A small environmental perturbation is expected to produce a small transient 

physiological change until the original equilibrium or new equilibrium condition is 

 8
established. There are situations where several small physiological adjustments, which 

by themselves are inconsequential, synergize to induce an amplified positive feedback 

change. For example, hyperventilation is a CNS-mediated response to increase PAO2 to 

preserve CNS function. But this action also reduces arterial blood carbon dioxide (CO2) 

partial pressure (PaCO2) that, in turn, leads to vasoconstriction of cerebral blood vessels 

and that further exacerbates O2 delivery to the CNS that in turn leads to a greater CNSmediated drive to increase hyperventilation. In the short term, the new condition may not 

be favorable to the organism but buys time so that longer-term adjustments can bring a 

new functional equilibrium. So, time is taken to survey the literature to understand the 

integrated physiological response to HH and adaptation to μG. Our interest is primarily 

during the acute physiological compensatory phase, the first 3 or 4 days of a 15-day sortie 

mission back to the moon. 

Our physiology, with individual sensitivities, has the ability to integrate multiple 

environmental changes to achieve a new “functional” sustained balance. As long as this 

new functional balance does not degrade significant health and performance, then 

engineers should take advantage of human adaptability when designing life support 

systems. The key is to understand what is meant by a “significant decrease in health and 

performance”. 

First Issue: Hypoxia and Acute Mountain Sickness 

 Ascent to altitude without supplemental O2 results in decreased PIO2 and PAO2

along with a decrease in gas density. Alveolar hypoxia is immediately sensed by the 

lungs, leading to increased pulmonary vasoconstriction with a corresponding increase in 

pulmonary artery pressure (McMurtry 1982, Hultgren 1982, Moudgil 2005). Peripheral 

(carotid and aortic bodies) and CNS (medulla) respond to arterial oxygen (PaO2) and 

PaCO2 partial pressure, and hydrogen ion (H+) concentration (pH). O2 delivery must 

fundamentally match tissue demand, leading to increased pulmonary ventilation as a 

means by which to increase O2 supply to the body. This is a breath-by-breath response 

on the order of seconds since the body needs an uninterrupted source of O2. The CNS 

consumes about 20% of available O2, and is exquisitely sensitive to the lack of O2. 

Hyperventilation in response to significant hypoxia simultaneously reduces alveolar 

carbon dioxide partial pressure (PACO2), leading to transient alkalosis. The body’s 

response to the alkalosis and hypoxic milieu triggers numerous physiological 

adjustments: rapid responses in the blood buffer system and pulmonary mechanics to 

increase PAO2 with adjusted acid-base and fluid balance by the kidneys much later to 

reestablish homeostasis. AMS signs and symptoms are ultimately linked to poorly 

understood disruptions of the CNS. 

 This report covers a substantial amount of physiology on adaptation to hypoxia 

and μG even before addressing adaptation to the combination of these stressors. But, it is 

necessary to limit the scope of this report since decades of interest in hypoxia, from many 

 9
perspectives, has led to thousands of reports and hundreds of books. Humans now 

routinely live in space for long periods, and a substantial amount of information has 

accumulated about adaptation to μG from simulated μG as well as actual exposure. 

Without precisely defining the terms below (see Fulco 1988 for additional discussion), 

this report is restricted to the conditions between the brackets. 

seconds – [minutes – hours – days] – weeks – months – years 

responses – [adjustments – acclimatization] – adaptation 

[acute ]------------------- chronic

 

AMS is a constellation of signs and symptoms including headache, nausea, 

dizziness, fatigue, and sleeplessness that develops over a 6 to 24 hr stay in a hypoxic 

environment, usually from rapid ascent to altitude while breathing air. The headache, for 

example, is usually throbbing, bitemporal or occipital, typically worse during the night 

and on awakening, and made worse by Valsalva’s maneuver; when combined with 

nausea, it can be likened to an alcohol hangover. In one of the earliest efforts to 

understand the interaction between prolonged BR and HH, Lynch (1967) and Stevens 

(1966) exposed young men to 3,658 m (12,000 ft) in an altitude chamber for 28 days. 

Lynch writes, “In the altitude subjects, headache of moderate severity was not uncommon 

during the first 24 hrs of BR at simulated altitude, particularly in the 3,658 m groups”. 

This was at a time when AMS was not well characterized. In retrospect, it appears to this 

reviewer that an acute PAO2 = 54 mmHg at 3,658 m altitude is sufficient to precipitate a 

necessary symptom for a diagnosis of AMS. 

Roach (1998) says that a quick ascent to altitudes over 2,590 m (8,500 ft) often 

results in symptoms of AMS. Nearly 25% of people are affected even at 2,000 m (6,600 

ft) (Roach 1998, Houston 1982, Montgomery 1989). Montgomery (1989) observes that 

half of the 12% of tourists afflicted with symptoms of AMS at 2,000 m (6,600 ft) seek 

relief of symptoms through medication. Others (Vardy 2006) find no significant 

symptoms below 3,048 m (10,000 ft). Many factors modify the risk of AMS between 

2,000 to 3,048 m (6,600 to 10,000 ft), particularly the rate of ascent to altitude, activity 

level at altitude, and individual susceptibility. One reality about NASA space vehicles is 

that depressurization to a final hypobaric PB is on the order of minutes and not hours or 

days. 

AMS, as opposed to the immediate response to hypoxia, evolves over a timecourse that suggests changes in hormones are also involved in its final expression. There 

is a wide range of susceptibility to AMS. If you are susceptible, then the risk of AMS 

increases the longer you stay and the higher you go, until you adapt to the new conditions 

or return to higher PB. Mild forms of AMS are transient but can impact crew health and 

performance, certainly on short missions. Serious manifestations of AMS lead to high 

altitude pulmonary edema (HAPE) and high altitude cerebral edema (HACE), both 

 10
debilitating and life threatening conditions. This report considers only the milder forms 

of AMS that may impact the success of a mission more so than threaten life. The 

operation of the environmental control and life support system, even at the extreme of the 

control range, will not place the crew in an extreme hypoxic environment. 

The “normal” response to acute hypobaric exposure is extremely variable but is 

characterized by an increase in the rate and depth of respiration as compensation for 

detected hypoxemia. But, the resulting respiratory alkalosis stimulates the CNS to reduce 

respiration as a means to preserve the pH in the cerebrospinal fluid (CSF). There is also 

an expected hypoxia-induced diuresis through the loss of bicarbonate (HCO3-) and 

sodium (Na+) ions from the plasma through the kidneys as compensation for the 

respiratory alkalosis and through activation of the peripheral chemoreceptors. In those 

individuals who go on to experience AMS, the normal hyperventilation response to HH is 

modified such that the minute ventilation rate (VE) is reduced relative to the VE of 

someone who will not go on to develop AMS (Roach 1992 and 1994). It appears that a 

reduced sensitivity to the HH environment effectively increases the deadspace ventilation 

with all of the attending disruptive consequences of those who go on to develop AMS, 

but there are contrary interpretation of data (Savourey 2003, Loeppky 1997). Those who 

are prone to subsequent AMS have a slightly greater hypoxemia compared to those who 

have acclimatized well. A greater alveolar-arterial O2 difference (PAO2 - PaO2) is 

associated with AMS, suggesting that impaired gas exchange due to pulmonary edema 

begins prior to the onset of clinical symptoms. Also, there is an absence of the typical 

hypoxia-induced diuresis and natriuresis. PV moves into the interstitial space leading to 

edema in those who go on to develop AMS (Auerbach 1995, Sutton 1976, Hackett 1982, 

Hildebrandt 2000). In severe exposures, the resulting pulmonary and cerebral edema can 

lead to death if either a return to higher PB or supplemental O2 is delayed (Severinghaus 

1995). Finally, no one knows the integrated physiological mechanisms that precipitate 

signs and symptoms of AMS, but progress is being made (Leaf 2006). 

The diagnosis of AMS has been standardized using the Lake Louise AMS Scoring 

System (Roach 1993, The Lake Louise consensus 1992). You have AMS if you have 

been at altitude for an extended period greater than 2 hrs and you develop a headache 

plus one or more of the following conditions: nausea, dizziness, fatigue, or sleeplessness. 

Additional clinical findings that confirm a diagnosis of AMS include changes in mental 

status, ataxia, peripheral edema, or changes in performance. A change in performance 

means that any of the above symptoms or clinical findings have caused you to reduce 

your normal activities. 

Carbonic Anhydrase and Action of Acetazolamide 

 The prevention and treatment of AMS with acetazolamide (AZ, DIAMOX), a 

potent carbonic anhydrase (CA) inhibitor, is very effective. Some understanding of this 

interaction is helpful to grasp the multiple causes and effects from hypoxia leading to 

AMS. Carbonic anhydrase in its several isozyme forms is a ubiquitous and highly 

conserved enzyme that is found in RBCs, pulmonary endothelial cells, the kidney, acid 

 11
secreting cells in the stomach, the brain, and even within the peripheral chemosensors. 

The isozyme form CAIV is located on the luminal aspect of nearly all capillary beds. 

 Carbonic acid formed by the hydration of CO2 quickly dissociates to H+ and 

HCO3- ions, but this reversible reaction is too slow to process the 13 to 20 moles of CO2

(volatile acid) produced per day. 

CO2 + H2O ↔ H2CO3 ↔ H+ + HCO3- 

Valtin (1983) shows that the hydroxylation of CO2 through the action of CA is the 

significant reversible reaction that moves CO2 into its main transportable form. 

 HOH ↔ H+ 

 ↑↓ 

CO2 + OH- ↔ HCO3- 

 CA

Inhibiting this reaction prevents CO2 from being managed by the lungs and kidneys 

leading to global tissue metabolic acidosis, so proper dosing of AZ is key to efficacy. 

The inhibition of CA in RBCs and vascular endothelial cells increases CO2 retention in 

all tissues, which is an additional stimulus to increase VE associated with CA inhibition. 

 As tissue CO2 diffuses into plasma and then into RBCs, the reactions shown 

previously are driven to the right, and about 63% of the CO2 is carried to the lungs as 

plasma bicarbonate, with 7% carried as dissolved CO2 and 30% as CO2 bound to 

hemoglobin (HB). The reactions are reversed in the lungs, and HCO3- moves from the 

plasma into the RBCs and CO2 leaves the body. Bicarbonate from CO2 in the parietal 

cells of the stomach is conserved while the H+ and Cl- ions are pumped into the gastric 

lumen. The similar action in the brain returns H+ ions to the circulation, leaving HCO3- 

in the CSF. CA in the membrane and cytosol of cells in the proximal tubules of the 

kidney promotes about 99.9% of HCO3- reabsorption and H+ secretion. 

 The main action of AZ is the reversible inhibition of CA. However, Swenson 

(2006) shows that AZ also reduces hypoxic pulmonary vasoconstriction independent of 

CA inhibition. AZ can, to a limited degree, cross the blood brain barrier (BBB). In the 

brain, the effect is to reduce the production of CSF and the HCO3- content in the CSF. 

This is certainly beneficial if cerebral edema is present. The reduction of HCO3- tends to 

restore the H+ concentration, returning CSF toward its near-normal pH of 7.33 compared 

to 7.40 for arterial blood. This then reduces the hypoventilation response mediated by the 

medullary respiratory center due to high CSF HCO3- concentration. Ventilation is 

improved, particularly during sleep, leading to enhanced O2 delivery in a hypoxic 

environment. Inhibition of CA in the proximal tubules of the kidneys prevents the 

 12
reabsorption of HCO3- and distal tubular H+ secretion (Swenson 1998). An osmotic 

diuresis with natriuresis ensues, reducing the magnitude of tissue edema seen in AMS. 

 The extent of AZ interaction with several isozyme forms of CA (I, II, IV, XII, 

XIV) in central and peripheral tissues is not known, so how it reduces the signs and 

symptoms of AMS is unclear. Leaf (2006) provides a review and summary figure for the 

known and suspected actions of AZ on the physiology and how these actions reduce the 

consequences of hypoxia. Much of what he summarizes in his figure 5, which is shown 

below, is now described. 

The metabolic acidosis that results from HCO3- loss from the kidneys due to AZ 

counters the respiratory alkalosis from increased VE in response to hypoxia detected by 

peripheral and central chemosensors. In effect, the resulting metabolic acidosis increases 

VE for a given PaCO2, improving O2 supply to the tissues. There is a leftward shift in 

the ventilation-CO2 response curve after AZ administration. A critical observation is that 

AZ actually inhibits the sensitivity of the carotid body chemoreceptor response to CO2. 

A decreased sensitivity of the peripheral chemosensors is thought to reduce periodic 

breathing during sleep at high altitude, thus increasing blood O2 saturation. Inhibition of 

 13
the CO2 hydration reaction within the carotid body would limit the increase in H+ 

following a hypercapnic stimulus. Since VE is increased at any PaCO2 under hypoxic 

stress given AZ, the effect is principally mediated by central chemosensors. This 

mediation appears to be indirect in that AZ does not cross the BBB to a significant 

degree. So, interaction with CA within the central chemosensors or the CNS is limited. 

However, metabolic acidosis from the action of AZ on the kidneys ultimately reduces 

HCO3- in the CSF over many hrs since a diffusion gradient for HCO3- from the CSF to 

plasma is established. The restricted movement of ions through the BBB is a hallmark of 

this system, so a mechanism that depends on diffusion would certainly be slow to reach 

equilibrium _ much like the slow onset of AMS. The reduction in CSF HCO3- plus the 

increase in CO2 due to global tissue respiratory acidosis effectively reduces the inhibition 

to respiration, and VE increases. The central chemosensors profoundly change VE given 

their high CO2 ventilatory responsiveness (1 to 3 L/min/mmHg, Swenson 1998). 

 There are side effects to AZ that may be as significant in some individuals as the 

symptoms of AMS. In those sensitive to sulfonamide drugs, a severe allergic reaction is 

possible. There are reports of tingling of the lips and fingertips, blurred vision, malaise, 

anorexia, weakness, nausea, diarrhea, and alteration of taste, just to list a few. The 

medical management of AMS with AZ and the efficacy of this drug in μG are not the 

thrust of this report, but deserve serious consideration. 

Is Acute Mountain Sickness a Function of Absolute Pressure and Hypoxic Stress? 

The complex cardiovascular-pulmonary-cerebral-renal-hematological-endocrine 

response to a hypoxic environment is assumed to be identical whether you are hypoxic 

while at altitude in an altitude chamber or whether you breathe an equivalent hypoxic 

mixture at sea level PB. It is also assumed that if you maintain sea level equivalent 

conditions at all altitudes given the correct supplemental O2, no AMS signs and 

symptoms are expected. The first assumption (accepted truth) is called into question with 

data in this report, and the second assumption has not been systematically tested as of 

2008. 

For example, in an experiment where the subjects are their own controls, the 

hypothesis is that there are no signs or symptoms of AMS if PAO2 is made equivalent to 

sea level conditions (PAO2 = 103 mmHg from AOE if ppO2 = 160 mmHg) at any 

reduced PB. So, a subject exposed to 5.45 psia (282 mmHg, 25,000 ft altitude) in an 

altitude chamber would have no signs or symptoms of AMS if the atmosphere was 63% 

O2 (177 mmHg/282 mmHg = 63%) for PAO2 = 103 mmHg from the AOE. All other 

variables would be identical to the sea level control in the altitude chamber, except the 

density of the atmosphere would decrease from 1.177 g/liter to 0.431 g/liter at 50% 

relative humidity, using 25° C for ambient temperature and 15° C for dew point. 

 14
To eliminate the confounding influence of DCS and VGE, the subject would PB 

100% O2 for 4 hrs prior to a slow 1,000 ft/min ascent to 5.45 psia. Noninvasive 

monitoring for VGE in the pulmonary artery using an ultrasound Doppler bubble detector 

would verify that no gas phase is present in the venous return due to the depressurization. 

If signs or symptoms of AMS or a change in any physiological measurement are 

observed while exposed to 5.45 psia, then the explanatory variables associated with the 

observations are the changes in breathing gas density and decrease in absolute PB. It is 

stated this way because gas density could be reduced (changed) independent of PB by 

substituting helium for N2; for example, in the breathing mixture. Other physical 

changes occur with a change in PB beyond a change in breathing gas density, such as 

changing the capacity of a fluid to hold gas in solution. 

The AOE (DeHart 1996) will be referenced and used often in the remainder of 

this report. It is the key physiological variable to associate changes in the breathing 

environment to changes in other physiological systems. Acute respiratory changes, such 

as hyperventilation that increases the respiratory exchange ratio (RER), make it difficult 

to understand the resulting PAO2 without the aid of an equation. Also, the 

disproportionate contribution of water vapor toward decreasing PAO2 as PB decreases is 

managed in the AOE: 

PAO2 = FIO2 * (PB - 47) - PACO2 * [FIO2 + ((1 - FIO2)/RER)] (1) 

where PAO2 is alveolar oxygen partial pressure (mmHg), FIO2 is inspired oxygen 

fraction (decimal percent), PB is atmospheric pressure (mmHg), 47 is the vapor pressure 

of water at 37 C (mmHg), PACO2 is alveolar carbon dioxide partial pressure (mmHg), 

and RER is the respiratory exchange ratio (unitless), which is equal to 1.0 when breathing 

100% O2. The contribution of RER to PAO2 and PACO2 is complex when PB, for 

example, changes. This important topic is explored in the section entitled “Partial 

Pressure of Nitrogen, Oxygen, and Carbon Dioxide in the Cerebrospinal Fluid” but for 

now we move forward as if RER is a particular value fixed in time, but modified by at 

least hypoxia-induced hyperventilation. Another often reported variable is the inspired 

oxygen partial pressure (PIO2) defined as FIO2 * (PB - 47). 

 Algebraic manipulation of the AOE provides a useful form where ppO2 is 

computed for a particular constant PAO2 plus other inputs to the equation. Since 

engineers deal with the control of a life support system with O2 sensors that monitor the 

cabin environment, it is convenient to express a desired PAO2 in terms of ppO2, which 

can easily be measured in the breathing environment. 

 Since FIO2 = ppO2/PB, you can rearrange the AOE to solve for ppO2: 

ppO2 = [PAO2 + (PACO2/RER)]/[1 - ((47 + PACO2 - (PACO2/RER))/PB)]. (2) 

 15
 As an example, the medical community at JSC decides, after various engineering, 

operational, and medical trades, that a long-term exposure to a mild hypoxic condition in 

a hypobaric living environment for astronauts is desirable for mission efficiency. The 

target PAO2 is 77 mmHg. The habitat PB is 414 mmHg (8.0 psia). Physiological 

acclimatization and adaptation will occur, so average PACO2 and RER return to nearnormal sea level values of 40 mmHg and 0.85 after a period of respiratory compensation 

where mild hyperventilation resulted in a PACO2 = 37 mmHg and an RER = 0.88. 

Given the inputs after adaptation, the life support engineer computes a ppO2 of 137 

mmHg, meaning that the concentration of O2 in the 8.0 psia habitat should be no lower 

than 33% (137/414 = 33%) to maintain PAO2 at 77 mmHg under resting, steady state 

conditions. 

 Another helpful equation computes PB in mmHg for an altitude exposure 

expressed in kilometers (H): 

PB = 760 * [288.15/(288.15 - 6.5 * H)] -5.256. (3) 

Concept of Equivalent Air Altitude Exposure 

Figure 1 is an example of the application of the AOE, which demonstrates the 

concept of EAA exposure. The concept of an EAA exposure is that there is no difference 

in hypoxic response at any altitude as long as the same PAO2 is achieved at 2 different 

altitudes by breathing the proper supplemental O2. It also follows that there should be no 

hypoxic response at all as long as sea level equivalent PAO2 is maintained at any 

altitude. The routinely applied notion of an EAA exposure is invalid for higher altitude if 

it is true that there is an absolute PB effect on the risk of AMS. The validity of an 

absolute PB effect on the risk of AMS would be easier to confirm if the 2 different test 

altitudes are supposedly equivalently hypoxic. For example, a PAO2 of 77 mmHg in 

people just arriving from sea level to 1,829 m (6,000 ft) could induce a low incidence of 

mild AMS symptoms. These same people breathing 100% O2 at 11,278 m (37,000 ft) 

would have the same PAO2 but the incidence of AMS might double. This PB effect on 

AMS would not likely be observed when a PAO2 of 103 mmHg for air breathing at sea 

level is compared to the same PAO2 while breathing 100% O2 at 10,211 m (33,500 ft), 

even though the difference in PB is substantial. In the second example, a degree of 

hypoxia was not initially present, so a PB effect could not manifest itself. 

 16
4 5 6 7 8 9 10 11 12 13 14 15

CEV pressure (psia)

12.0

20.8

29.6

38.4

47.2

56.0

64.8

73.6

82.4

91.2

100.0

C

E

V

O

2

c

o

n

c

e

ntratio

n

%( )

A

B

Fig. 1. Two examples of EAAs as a function of CEV atmospheric pressure. Curve A is 

the minimum required inspired oxygen fraction (FIO2) for a specific CEV atmosphere 

PB for a 5,000 ft EAA exposure. Curve B is the minimum FIO2 for a specific CEV 

atmosphere PB for a 2,000 ft EAA exposure. The further left you go from Curve A the 

more hypoxia you accept; and the further right you go, the less hypoxia you accept. For 

Curve A, PAO2 = 81 mmHg, PACO2 = 37 mmHg, and RER = 0.87, all for the 5,000 ft 

EAA condition. For Curve B, PAO2 = 94 mmHg, PACO2 = 39 mmHg, and RER = 0.86, 

all for the 2,000 ft EAA condition (see Appendix for these data). 

The earliest known record of altitude sickness was a report by Chinese official 

Too Kin in 37 to 32 BCE. He described the perils of a route over or near the Karakoram 

Range of the western Himalya: “Next one comes to Big Headache and Little Headache 

Mountains ... They make a man so hot that his face turns pale, his head aches, and he 

begins to vomit... Even the donkeys and swine react this way”. Big Headache Mountain 

is believed to be the apex of the Kilik Pass at an altitude of 4,827 m (15,837 ft). Paul 

Bert, as long ago as 1878, is recognized as the first person to show that AMS is prevented 

at any altitude if PAO2 is maintained at a sea level EAA (ppO2 = 160 mmHg and PAO2

= 103 mmHg). But, there are recent data to suggest there could be a PB effect that works 

independent of the change in PAO2 that contributes to the signs and symptoms of AMS 

(Roach 1996, Tucker 1983). So, the question is: Is absolute PB per se an explanatory 

variable for AMS? But, even this question is not specific enough since the majority of 

the information in this report has an overlay of hypoxic stress. The more appropriate 

question is, therefore: Is absolute PB per se an explanatory variable for AMS on the 

 17
condition that significant hypoxic stress is present? The assumption here is that there is 

no absolute PB effect if PAO2 under all hypobaric conditions is > 103 mmHg. This 

question deserves serious attention since we move forward with habitat atmosphere 

selection for moon and Mars exploration on the assumption that PAO2, and not PB and 

PAO2, is the only consideration to avoid the signs and symptoms of AMS. 

Variability to Acute Mountain Sickness 

The challenge to understanding AMS, regardless of additional complicating 

factors from μG adaptation, is that there is no single predictive variable associated with 

AMS. There is no one dominant cause associated with one dominant effect; even the 

most significant environmental stress of hypoxia affects some individuals more than 

others. By definition, AMS has a component of hypoxia that itself produces signs and 

symptoms that are included in the description of AMS; for example, headache, nausea, 

dizziness, fatigue, and sleeplessness are sure signs and symptoms of AMS. But, many 

would be dizzy and fatigued while breathing 12% O2 at sea level if they also scaled a 

flight of stairs. In fact, it is not possible to induce AMS unless hypoxia is a factor. But 

there does seem to be a component to AMS that is in addition to just chronic hypoxic 

stress. A component of AMS is that it takes from 6 to 24 hrs to manifest (Milledge 

1984). Changes secondary to the immediate effects of hypoxia suggest that hormones 

such as renin, aldosterone (ALD), atrial naturetic peptide (ANP), catecholamines, and 

antidiuretic hormone (ADH), which change fluid balance and microvascular function, are 

linked to AMS (Loeppky 2005a, Loeppky 2005b, Hackett 1982). 

Yet individual variability to AMS makes this a difficult malady to study, even 

when studied in a controlled laboratory setting where cold, fatigue, variable ascent rates, 

dehydration, etc., from mountain trekking are not confounding factors. AMS seems to be 

a cluster of many subtle physiological changes in response to the ambient PB per se and 

the degree of hypoxic stress that, by themselves, are meaningless to the malady. But, in 

combination these subtle physiological changes drive susceptible people to modest signs 

and symptoms under modest HH conditions. Extreme HH conditions drive susceptible 

and not-so-susceptible people all the way to serious pulmonary and cerebral edema, 

leading to cardiopulmonary and neurological collapse, and even death. 

Figures from Schoene (1984), on the following pages, show a wide range of 

integrated physiological response between subjects to significant hypoxia where exercise 

while hypoxic is an additional stress. Schoene’s figure 6 shows the extreme range of the 

integrated physiological reaction to hypoxic stress, expressed as the hypoxic ventilatory 

response (VE/VO2) to exercise. As O2 consumption and CO2 production increase with 

exercise, the pattern of integrated response expressed as the ratio of VE/VO2 is consistent 

across the 3 subjects at sea level PB and under extreme hypoxic stress. But, it is clear 

that the low responder (L) is very insensitive to hypoxic stimulation of the peripheral and 

CNS at low and higher exercise intensity. Figure 7, also from Schoene (1984), is another 

example of the extreme variability between subjects in their response to hypoxia. Subject 

CP increases ventilation in response to breathing 10% O2 at 750 mmHg (computed 

 18
PAO2 = 49 mmHg for resting condition) while at rest and during mild exercise much 

more than subject RS. As a result, the HB saturation for subject CP shows a modest 

decrease compared to subject RS under a significant hypoxic stress. 

A lower ventilatory response to HH is linked to AMS (Schoene 1984, King 1972, 

Sutton 1976), so this between-subject variability can be the basis of a selection protocol if 

AMS is to be avoided when exposure to a significant hypoxic environment is 

unavoidable. However, Sutton (1976) found no relation between the degree of 

ventilatory response to hypoxia at site PB and the development of AMS at 5,364 m 

(17,600 ft). He did not control for PACO2, and the test was done at site PB, both of 

which could mask a better relationship between the decreased hypoxic ventilatory 

response and the subsequent AMS. 

 19
 

 20
 

 21
 

 Finally, the figure below from Ge (2002) provides an excellent example of the 

variability in erythropoietin (EP) change after 24 hrs of mild (1,780 m or about 5,850 ft) 

to modest (2,805 m or about 9,200 ft) hypoxic challenge from ascent in an altitude 

chamber. Ge makes the point that individual variability to increased EP production 

increases with increasing altitude. 

Data for Pressure Effect per se on Acute Mountain Sickness 

There are hundreds of reports about HH and hundreds of reports about NH, but 

unfortunately there are fewer than 9 reports where the combination of HH and NH was 

tested together or HH, NH, and HN were tested together to specifically look for a PB

effect on AMS. The sum total are listed here in ascending chronological order: Tucker 

(1981 [abstract] and 1983), Grover (1982), Levine (1988), Roach (1995), Roach (1996), 

Loeppky (1996), Loeppky (1997), Savourey (2003), and Leoppky (2005a). 

Three of these report: Grover (1982), Leoppky (1996), and Savourey (2003), were 

looking for a mechanism to account for a decreased VE response under HH compared to 

NH conditions. Their tests were of very short duration of less than 120 min, so AMS was 

not the primary focus. One study was with sheep (Levine 1988), so no direct application 

here. Only 4 of these studies (Tucker 1983, Roach 1996, Loeppky 1997, and Loeppky 

 22
2005a) have some direct application here. The others, plus Epstein’s (1972) evaluation 

of HN, provide helpful insight into mechanisms. 

Figures 2 and 3 show a data presentation format used extensively for the remainer 

of this report. The PB and O2 exposure matrix (4 quadrant box) provides a convenient 

way to summarize the main experimental conditions and to show selected data. It is not 

possible to summarize all available data, so only data that show magnitude and direction 

deemed relevant to this report are shown. This is a practical, although incomplete, 

approach to show what would otherwise be an unmanageable amount of information. 

PB and O2 Exposure Matrix 

“assumes no ambient pressure effect”

Normobaric, 

PB = 760 

mmHg 

Hypobaric, 

PB < 760 

mmHg 

Normoxic, PAO2

= 103 mmHg 

Hypoxic, PAO2 < 

103 mmHg 

PB = 760 mmHg 

with PAO2 = 103 

mmHg (21% O2). 

No AMS 

symptoms. 

PB < 760 mmHg 

with PAO2 = 103 

mmHg (>21% O2). 

No AMS 

symptoms. 

PB = 760 mmHg 

with PAO2< 103 

mmHg (<21% O2). 

AMS symptoms ƒ

PAO2. 

PB < 760 mmHg 

with PAO2< 103 

mmHg. 

AMS symptoms ƒ

PAO2. 

NN – normobaric normoxia, NH – normobaric hypoxia, HN – hypobaric normoxia, HH – 

hypobaric hypoxia 

Fig. 2. Matrix of combinations of PB and O2 concentration that have been evaluated. 

Hyperbaric PB exposures are not covered here. The higher the altitude, the greater the 

O2 concentration needed to provide a particular PAO2 < 103 mmHg. So, there are 

infinite combinations of altitudes and O2 concentrations that can set a particular PAO2 < 

103 mmHg, with the assumption that the consequences are equivalent to ascent on air 

(21% O2) to a particular PAO2 < 103 mmHg; a notion accepted, since the time of Paul 

Bert in 1878, about AMS symptoms. 

 23
PB and O2 Exposure Matrix

“assumes an ambient pressure effect” 

Normobaric, 

PB = 760 

mmHg 

Hypobaric, 

PB < 760 

mmHg 

Normoxic, PAO2

= 103 mmHg 

Hypoxic, PAO2 < 

103 mmHg 

PB = 760 mmHg with 

PAO2 = 103 mmHg (21% 

O2). 

No AMS symptoms. 

No DCS/VGE possible.

PB < 760 mmHg with 

PAO2 = 103 mmHg 

(>21% O2). 

Some AMS symptoms. 

DCS/VGE is possible.

PB = 760 mmHg with 

PAO2< 103 mmHg 

(<21% O2). 

Some AMS symptoms ƒ

PAO2. 

No DCS/VGE possible.

PB < 760 mmHg with 

PAO2< 103 mmHg. 

More still AMS 

symptoms ƒ PAO2. 

DCS/VGE is possible.

Fig. 3. A PB effect per se appears at work on physiological responses and signs and 

symptoms of AMS based on a review of literature from 1980 to the present. Notice that 

this statement is “conditional” on the fact that hypoxia is present. The current research 

says that you should not assume all AMS outcomes would be equivalent given only 

equivalent hypoxic PIO2 or PAO2. This confirms anecdotal observations that the most 

effective treatment for AMS is the application of increased PB to achieve a particular 

treatment PAO2 instead of increasing the percentage of O2 at the current lower PB to 

achieve the same treatment PAO2 (Kasic 1991). What is needed are data that show little 

or no physiological changes when ambient PB is reduced but PAO2 > 103 mmHg. These 

data, and there are thousands of exposures to altitude while breathing 100% O2, would 

indirectly support the idea that both hypoxia and hypobaria have a negative synergistic 

effect on the body. One confounding reality that has not been carefully controlled in 

early studies was the potential for bubble formation and subsequent embolization of the 

lungs due to HN and HH exposures. 

 Notice that under steady state conditions, data in the 2 verticals of the PB and O2

exposure matrix allow you to understand the contribution of changes in PB (physics 

about gas density, gas viscosity, work of breathing, etc.) on the data, irrespective of the 

physiology. Data in the 2 horizontals allow you to understand the physiology of hypoxia, 

irrespective of the PB. The data in the 2 diagonals combine gas physics and the 

 24
physiology of hypoxia, allowing you to understand the interaction of both variables. The 

interactions can be additive in the same direction, additive in opposite directions, cancel 

each other, or some other complex nonlinear interaction. 

 By way of introduction, and for economy of space, we list several related figures 

now that display summary data about a PB effect on AMS. Figure 4 shows results from 

Roach (1996), figure 5 is Tucker (1983), figures 9 and 10 are Grover (1982), figures 11 

to 13 are Levine (1988), figure 14 is Leoppky (2005a), figure 15 is Savourey (2003), 

figure 16 is Loeppky (1996), figure 17 is Loeppky (1997), figure 18 is Meehan (1986), 

Swenson (1995), and Knight (1991), and figure 19 is Epstein (1972). 

 

 25
Summary of Roach (1996) Results (acute PAO2)

Normobaric, 

PB = 760 

mmHg 

Hypobaric, 

PB < 760 

mmHg 

Normoxic, PAO2

= 103 mmHg 

Hypoxic, PAO2 < 

103 mmHg 

PAO2 = 76* 

no AMS

PAO2 = 74.5 

mean AMS = 0.4 

SaO2% = 96

PAO2 = 45.9 

mean AMS = 2.0 

SaO2% = 83

PAO2 = 46.0 

mean AMS = 3.7 

SaO2% = 83

15,000 ft on air 

*See Note 1 at end of report. 

AMS – Acute Mountain Sickness score using the Lake Louise system (Roach 1993). 

SaO2% - arterial blood oxygen saturation (%). 

Fig. 4. The average Lake Louise AMS score from 6 and 9 hrs of hypoxic exposure in 9 

subjects associated with the computed PAO2 from the AOE. These data are from figure 

1 in Roach (1996); see next page. An earlier review by Roach (1995) expands on data 

from others that he references in the 1996 paper. Roach concludes that symptoms of 

AMS are less severe and occur later during NH compared to HH, given the same inspired 

ppO2. Based on the data above, there appears to be a PB effect at work on the signs and 

symptoms of AMS. Note that there was no clear cause-and-effect relationship between 

SaO2% and AMS with PB, except that hypoxia reduces SaO2%. Results in this report 

suggest that you should not assume that all AMS outcomes would be equivalent given 

only equivalent PAO2. 

 26
 27
Summary of Tucker (1983) Results (acute PAO2) 

Normobaric, 

PB = 760 

mmHg 

Hypobaric, 

PB < 760 

mmHg 

Normoxic, PAO2

= 103 mmHg 

Hypoxic, PAO2 < 

103 mmHg 

PAO2 = 77* 

no AMS 

SaO2% ≅ 94 for 

all

PAO2 = 47.1 

mean AMS = 3.2 

SaO2% = 80.2

PAO2 = 45.0 

mean AMS1 = 6.3 

mean AMS2 = 8.3 

mean AMS3 = 5.7 

SaO2% ≅ 81 for all 15,000 ft on air 

*See Note 2 at end of report. 

AMS – Acute Mountain Sickness score not based on the Lake Louise system. 

SaO2% - arterial blood oxygen saturation (%). 

Fig. 5. Tucker’s (1983) summary results supports a PB effect at work on the signs and 

symptoms of AMS (see his figures 1 and 2 below). A 2-hr exposure time was sufficient 

to measure acute changes, but not sufficient enough to track any adaptive changes in VE

seen by Grover (1982) in 4 hrs. AMS1 was with subjects in a normal water balance, 

AMS2 was with subjects in a positive water balance (no statistical difference between 

AMS1 and AMS2), and AMS3 was with subjects in a normal water balance plus a 1.5-hr 

PB prior to ascent (no statistical difference between AMS1 and AMS3). 

 There was no significant difference in any measured variables between normal 

and overhydrated subjects. Prior PB did not change the AMS score between NH and HH 

(3.2 vs. 5.7). The difference between an AMS of 3.2 for NH and 8.3 for HH in subjects 

with positive water balance was not statistically evaluated. But PB did reduce 

hyperventilation and alkalotic response to HH. This was a reduction in VE relative to 

what was observed under NH. There was a 27% greater VE in NH relative to HH in 6 

subjects, a change similar to that reported by Loeppky (1997) in 9 subjects over a longer 

measurement period. The smaller increase in VE response under HH relative to NH was 

further reduced (blunted) when O2 was breathed for 1.5 hrs in 11 subjects. Since 

 28
subjects maintained arterial O2 saturation after PB, despite the relative hypoventilation at 

4,572 m (15,000 ft), the gas exchange must have improved, possibly through an 

improved ventilation - perfusion (VA/Q) matching. Increased ppO2 during PB may also 

decrease ADH secretion from the pituitary gland. This would, in turn, encourage a 

diuresis, which is associated with fewer signs and symptoms of AMS. It appears that 

there is renal dysfunction leading to fluid shifts and water retention as an important 

component of AMS with both hypoxic stress (Hackett 1982) and hypobaria (Epstein 

1972) implicated in this dysfunction. 

 Heart rate (HR) did not increase as much with prior PB and subsequent HH 

exposure compared to just HH exposure. Systolic and diastolic blood pressure (SBP, 

DBP) were actually lower than control values with prior PB and subsequent HH exposure 

compared to just HH exposure. HH by itself increased both SBP and DBP from baseline. 

PB tended to “blunt” the classic cardiopulmonary response seen in HH exposure. Tucker 

(1983) proposes a decrease in chemosensitivity to hypoxia due to 100% O2 PB at site PB, 

and it persisted for the 2-hr duration of his test. O2 can be considered a drug with doseresponse relationships. During a 3 hr PB, Conkin (1984) measured an increase in DBP 

with a reduction in CO, and no change in SBP. These changes increased mean arterial 

pressure (MAP) and computed peripheral vascular resistance. One atmosphere ppO2 has 

a vasoconstrictive effect on the vasculature, and the persistent reduction in SBP and DBP 

during subsequent hypoxic exposure following O2 PB in Tucker’s experiment is curious. 

 The decrease in VE, increase in pH and end-tidal CO2 partial pressure (PECO2), 

and decrease in urine flow with expected increase in urine osmolality in the HH exposure 

relative to the NH exposure is consistent with a hypobaric PB effect, given that hypoxia 

is present. SBP and DBP were also higher in the NH exposure compared to the HH 

exposure. So, Tucker also proposes a decrease in chemosensitivity caused by just the 

hypobaric exposure since VE was actually higher in the NH exposure. There appears to 

be some benefit to PB above and beyond reducing the chance of VGE as a confounder. 

Periods of PB prior to and following ascent are easy to implement and should make the 

acclimatization to HH easier. 

 29
 30
 31
Do Venous Gas Emboli have a Role in Acute Mountain Sickness? 

 The topic of VGE, in conjunction with O2 PB and subsequent HN or HH 

exposures, needs some discussion. The lungs are an excellent filter of bubbles in the 

venous return. The microscopic to macroscopic impacts that VGE have on modifications 

to pulmonary blood flow, subsequent pulmonary vasoreactivity, and gas exchange is not 

covered here. It is certain that VGE form with very little provocation during ascent to 

even modest altitudes; especially if the ascent to a final PB is within minutes, there is 

little or no O2 PB, subjects are physically active at altitude, and the altitude exposure is 

longer than a couple of hours. All of these conditions are present in most of the research 

on AMS performed in altitude chambers. In addition, hypoxia is present that may or may 

not contribute to the incidence or consequences of VGE. 

 Figure 6 shows the probability of venous gas emboli [P(VGE)] as a function of 

the DCS dose (Conkin 1994). The figure is helpful to show the magnitude of the “VGE 

potential” given some of the exposure conditions documented in the reports on HH. But, 

the data shown in the figure were collected in experiments about DCS where subjects 

routinely performed hours of PB, breathed 100% O2 from a mask while at altitude, and 

were physically active during the 3 to 6-hr tests. In the case of Tucker’s experiment, a 

1.5 hr PB reduces the computed ppN2 in a theoretical tissue compartment with a 380 min 

half-time from 9.7 to 8.2 psia. Tucker performed his experiment with subjects living at 

12.2 psia, so the initial tissue ppN2 is simply taken as 12.2 * FIN2 (0.79) = 9.7 psia. The 

DCS dose on the x-axis is defined as [(PN2380/P2) - 0.95], where PN2380 is the 

computed 8.2 psia, and P2 is the final exposure altitude of 8.3 psia (15,000 ft) used in 

Tucker’s experiment. The DCS dose is therefore computed as 0.037, indicating a very 

low probability of VGE from figure 6. 

Discounting the influence of hypoxia on the incidence of VGE, the computed P( 

VGE) for Tucker’s experiment with PB is [0.0371.576/(0.0371.576 + 0.48)] = 0.01, or 

1%. A direct ascent to 8.3 psia without the benefit of O2 PB gives a DCS Dose of 

[(9.7/8.3) - 0.95] = 0.218, and a computed P(VGE) of [0.2181.576/(0.2181.576 + 0.48)] = 

0.16, or 16%. There is a potential for VGE to influence the lungs of subjects exposed for 

2 hrs, but the impact is unclear on how this might affect gas exchange in hypoxic 

subjects. There is a latency time for the onset of detectable VGE in the pulmonary artery 

and a response pattern (Conkin 1996) that is a function of the DCS dose, and in most 

studies about HH the DCS dose is small. This is because ascents in altitude chambers 

without supplemental O2 are limited because of hypoxia. Changes in pulmonary gas 

kinetics ascribed to VGE in HH occur on time scales that do not match the latency times 

or response patterns for VGE embolization of the lung. So, it is unlikely that VGE are 

the “magic bullets” to understand differences between NH and HH. Other HH 

experiments to be described are similar to Tucker’s except O2 PB was never considered, 

so the confounding role of VGE in those results must be acknowledged. 

 32
Fig. 6. Best-fit statistical DCS dose - VGE response curve for 52 different tests at 

altitude that involved 1,009 men who were physically active at altitude. The duration of 

exposures was greater than 1 hr, but usually less than 6 hrs. VGE were or were not 

detected in the pulmonary artery during the test using a Doppler ultrasound bubble 

detector with the sensor placed in the precordial position. The presence of any VGE, 

regardless of Doppler signal intensity, was coded as a “yes (1)” response for VGE. The 

absence of VGE was coded as a “no (0)” response, and a DCS dose and dichotomous 

VGE response curve was constructed for the 1,009 records. See explanation above for 

the definition of DCS dose. 

Partial Pressure of Nitrogen, Oxygen, and Carbon Dioxide in the Cerebrospinal 

Fluid 

 As just described, evolved N2 contributes to VGE that could alter VA/Q in the 

lungs or cause the release of vasoactive compounds from pulmonary endothelium under 

both HH and HN. But, the movement of dissolved N2 under HH and NH should also be 

discussed. Differences in the outward manifestations of hypoxia, such as the incidence or 

severity of AMS, in what is an identical hypoxic stress as defined by PIO2 for both NH 

and HH would be reconciled if there is a true difference in hypoxic stress within the 

CNS. An understanding of this difference defines the PB effect. 

 33
 The mechanism for a PB effect on AMS starts with the transport of O2 from the 

atmosphere to the blood. The effectiveness of alveolar ventilation is influenced by the 

density of the breathing gas since flow is proportional to the reciprocal of the square root 

of gas density, the work of breathing is proportional to the relative density times the 

minute volume cubed, and the diffusivity of a gas, including water vapor, is inversely 

proportional to the density of the breathing gas. These effects are small in resting 

subjects in our circumstances. Logic dictates that even subtle changes in the breathing 

environment affects physiology, as most investigators conclude. Gas density in 

conjunction with other factors about a change and rate of change in PB contributes to 

differences in the body that do matter. 

 One could reason, farther into the body, that both the numerator and the 

denominator of the VA/Q ratio are affected differently under NH and HH conditions. 

Alveolar ventilation is affected by gas density, while pulmonary perfusion is affected by 

regional time-varying responses to hypoxia within the lung. Careful measurements show 

lower VE with HH relative to NH in some subjects. But, there is disagreement 

concerning whether these data support a decrease or an increase in alveolar deadspace 

(wasted ventilation) under the HH condition. Savourey (2003) speaks of the “specific 

response to HH” and concludes the lower tidal volume and higher breathing rate in his 

HH condition supports an increase in deadspace ventilation. Loeppky (1997), in contrast, 

used fewer subjects but collected data over several hours compared to Savourey, says 

there is a decrease in deadspace ventilation in his HH results. There was a suspected 

decrease in O2 consumption and CO2 production rate of about 80 ml/min attributable to a 

decreased work of breathing in HH. Loeppky shows no difference in SpO2 from finger 

oximetry between NH and HH conditions, about 83%, while Savourey shows an SaO2

from arterial blood of 88% for NH and 85% for the HH condition. Even though in both 

experiments HH was from an ascent on air in an altitude chamber to 4,572 m (15,000 ft), 

subjects in Loeppky’s study lived in Albuquerque, New Mexico at an altitude of about 

1,524 m (5,000 ft). 

 We will now go farther into the body, to the system that interprets, integrates, and 

responds to peripheral and central chemoreceptors. The premise to explore is that 

differences in AMS to identical hypoxic PIO2 under NH and HH conditions are due to 

proper responses of the CNS to the true hypoxic condition. The proper CNS response is 

due to different constituents of the CSF that are due finally to the different metabolic rate 

and N2 kinetics leading to different quantities of dissolved O2 and CO2 in the CSF under 

NH and HH conditions. The differences in these gases within the CSF are our 

hypothesized cause-and-effect of the PB effect on AMS. We focus on the role of the 

CSF as an acellular capacitance reservoir through which the medulla senses H+ and a 

medium through which O2 and CO2 interact with brain cells. The medulla as a central 

chemoreceptor has been established (Leaf 2006, Murray 1986). Small pockets of CSF 

are found within the subarachnoid space, particularly around the base of the brain. The 

largest of these pockets is the cisterna magna between the inferior surface of the 

cerebellum and the medulla. 

 34
 The solubility of N2, O2, and CO2 in CSF is 0.01, 0.02, and 0.5 ml (STPD)/ml 

CSF * ATA-1 respectively, with CO2 about 25 times more soluble than O2. The 

absolute quantity (moles) of these gases is small owing to the small volume (130 to 150 

ml) of the CSF and the low solubility of O2 and N2. CSF is an extension of the 

extracellular fluid of brain cells; a unique system that transiently buffers extremes in 

PaO2 (Kazemi 1968). Depending on the conditions, the CSF is either a sink or a source 

of dissolved O2. An increase in PaO2 moves excess O2 from brain cells into the 

acellular CSF until a new, higher equilibrium is established. A decrease in PaO2 moves 

excess (relative) O2 from the CSF into brain cells until a new, lower equilibrium is 

established. The flux is large for O2 (about 50 ml/min) and CO2 (about 50 ml/min) to 

meet the high metabolic demand of brain cells at 3.5 ml/100 gm/min. So, small 

differences in PAO2 and PACO2 between non-equivalent NH and HH conditions 

combined with the required flux rate through the CSF have the potential for large effects 

in the brain, particularly the cerebral blood flow. There would be no hindrance to the 

diffusion of gases through the BBB. The barrier serves to protect the CNS from ionic 

disturbances in the plasma, and protects the brain and vascular smooth muscle cells in 

brain vessels from circulating hormones. 

 

 A study by Tucker (1983) points to the importance of N2 in the development of 

AMS. Depending on the duration of 100% O2 breathing, the ppN2 gradient across the 

alveoli is less compared to the gradient when a hypoxic mixture is breathed at the start of 

a NH or HH exposure. The reduction in the N2 diffusion gradient across the alveoli due 

to a 1.5 hr denitrogenation at site pressure correlated with a reduction in AMS scores 

between the NH and HH conditions where SpO2 from ear oximetry was about 81% for 

both conditions. As in Loeppky’s studies (1996, 1997), subjects in Tucker’s study lived 

at about 1,524 m (5,000 ft), but in Fort Collins, Colorado, prior to ascent to 4,570 m 

(15,000 ft). The score (Environmental Symptoms Questionnaire) for the NH condition 

was 3.2 compared to 5.7 after denitrogenation under HH conditions, which was lower 

compared to 6.3 and 8.3 units in 2 other HH experimental conditions that did not include 

prior denitrogenation. We will focus on the movement of dissolved gases as opposed to 

evolved gas, as Tucker suggested, and how this movement influences hypoxic stress 

within the CNS. 

 The transient ppN2 concentration gradient in NH causes N2 to diffuse from the 

alveoli into oxygenated blood, and this gradient is reversed in HH. The small change in 

volume affects other alveolar gases as a function of the direction and amount of N2

movement through time. The effect must be small since the removal of N2 from the 

body after about 90 min of resting denitrogenation with 100% O2 breathing is in the 

range of 2 to 3 ml/min. In NH the FEN2/FIN2 ratio is initially less than one as N2 enters 

the tissues, and then increases toward one, modified by actual VO2 and VCO2, as a new 

equilibrium PaN2 is established. The combination of a changing metabolic rate and N2

 35
kinetics, reflected in the RER and FEN2/FIN2 ratio, change PAO2 and PACO2 through 

time between NH and HH; both Savourey (2003) and Loeppky (1997) show trends in 

lower end-tidal O2 partial pressure (PEO2) and PECO2 in HH relative to NH. 

 We propose that PAO2 and PACO2 in NH are always initially higher relative to 

HH given that PIO2 is identical in both conditions when metabolic rate and N2 kinetics 

are considered. PAO2 and PACO2 in NH falls to a final steady state value reflected 

through a stable FEN2/FIN2 ratio. PAO2 and PACO2 in HH are always initially lower

than in NH, and increases to a final steady state value, again reflected through a stable 

FEN2/FIN2 ratio. For the same hypoxic PIO2, the N2 gradient is larger in the HH 

condition. Therefore it takes longer to come to the new PaN2 equilibrium thus keeping 

PAO2 and PACO2 lower in HH than NH. By our reasoning, investigators who rely on 

PIO2 to establish identical hypoxic equivalency between NH and HH exposures should 

instead refer to this method as establishing similar hypoxic equivalency. 

 Figure 7 is our conceptual construct for the cause of the differences in CNS 

hypoxic stress between NH and HH. PIO2 is 80 mmHg at both 760 mmHg for the NH 

case with RER of 0.92 and 428 mmHg (15,000 ft altitude) for the HH case with RER of 

0.86 (see Loeppky 1997). 

Fig. 7. Change in metabolic rate due to work of breathing and N2 kinetics within the 

lung modifies PAO2 and PACO2. At some future time both situations approach a steady 

state PAO2 of 45 mmHg and PACO2 of 32 mmHg. But the outcome for AMS between 

 36
NH and HH is not the same due to earlier differences in the transport of O2 and CO2 to 

and from the CNS. 

The concept, but not the magnitude of the effect, applies to other comparisons at different 

PIO2s. Note that there is no unit for time and only steady state PAO2 and PACO2 is 

shown since only the direction, but not the magnitude or duration of this effect is clear. 

The time to reach a new equilibrium for the PaO2 and PCSFO2 gradient following a 

switch to a hypoxic condition depends how quickly the O2 partial pressure in the CSF 

falls and how quickly the reduced supply at a reduced partial pressure can diffuse through 

out the CSF as an extension of the extracellular fluid of neural tissues. PB does not 

change in NH but PIN2 increases in the breathing gas, by 74 mmHg in our example 

where 88.8% N2 is breathed at sea level to simulate a hypoxic ascent to 4,572 m (15,000 

ft) on air. PCSFO2 falls to match the new reality of an acute PAO2, about 45 mmHg after 

a new steady state FEN2/FIN2 is established. Oxygen, N2 and CO2 reach equilibrium 

gradients with the arterial source once the capacity of the CSF to accept these gases is 

reached. The hypothesis is that NH provides medullary tissues in contact with the CSF a 

greater net flux of O2; the gradient between PCSFO2 and mixed venous ppO2 from the 

jugular vein is larger for a time in NH than in HH. There is a shorter delay to achieve the 

lower steady state PCSFO2 in NH compared to HH. In concert with this process is a 

slower decrease in CSF H+ since there is a higher PaCO2 in NH compared to HH. This 

delays a change in CSF pH thus delays hypoxia-induced hypoventilation caused by the 

alkalization of the CSF. There is less inhibition on the ventilatory drive to hypoxia due to 

the alkalization of the CSF, so VE is higher in NH relative to HH. A higher PaCO2 also 

increases cerebral blood flow relative to HH at a time when local autoregulation is active. 

 PB is reduced in HH leading to a lower PIN2 and PIO2 in the lungs, a large 

decrease of 262 mmHg for N2 in our example. PAO2 decreases to 45 mmHg after a new 

steady state FEN2/FIN2 ratio is established. The CSF at a lower PB initially has N2 in 

excess of what can be held in solution, so a greater amount of N2 leaves the CSF and 

body tissues than enters the body in NH. It takes longer to achieve a new PaN2

equilibrium in our HH example where PIO2 is 80 mmHg in both conditions. The O2 in 

excess of what is held in solution in the CSF is quickly consumed by neural tissues, or 

lost to the venous return. The HH condition provides medullary tissues in contact with 

the CSF a reduced net flux of O2; the gradient between PCSFO2 and mixed venous ppO2

from the jugular vein is smaller for a time in HH than in NH. There is a longer delay to 

achieve the lower steady state PCSFO2 in HH compared to NH. There is also a faster 

decrease in CSF H+ since there is a lower PaCO2 in HH compared to NH. This leads to 

a faster alkalization of the CSF, a potent stimulus within the CNS to transiently suppress 

(Grover 1982) the ventilatory response to hypoxia, so VE is lower in HH relative to NH. 

A lower PaCO2 would suppress cerebral blood flow relative to NH. 

 37
 In summary, the change in metabolic rate and opposite direction of N2 movement 

and different times to achieve a new PaN2 equilibrium have the net effect of making 

more O2 and a slower decrease of H+ transiently available to the CSF in NH relative to 

HH. Savourey (2003) shows a mean PaO2 of 6.90 kPa (47.5 mmHg) and PaCO2 of 5.06 

kPa (34.9 mmHg) for an NH condition in 15 subjects after a 40 min exposure compared 

to significantly lower (p <0.05) values of 6.38 kPa (43.0 mmHg) and 4.65 kPa (32.0 

mmHg) for the HH condition where PIO2 was 81 mmHg for both experiments. This 

result is consistent with Loeppky’s observations on how changes in O2 consumption and 

CO2 production influences the partial pressure of gases in the alveoli and, by extension, 

the partial pressure of gases in the CSF. It follows from this hypothesis that under NH 

the onset of signs and symptoms of AMS occur later, the incidence of AMS is lower, and 

the severity of signs and symptoms is less compared to HH. In effect, the body is 

responding properly under both NH and HH but the responses are not equivalent. 

 To achieve the same AMS response as in NH the PAO2 and PACO2 must 

increase in HH by an amount computed from a precise model (not yet available) that 

quantifies how changes in metabolic rate, PIN2, and direction of movement of N2 affects 

O2 and CO2 in the CSF. Figure 8 shows our application of a iso-hypoxic model through 

a range of hypobaric and hyperbaric pressures. A contrast is made between the current 

EAA (iso-PIO2) model and a future iso-hypoxic model using an example for an 

atmosphere currently selected for the NASA CEV where FIO2 is 0.32 at a PB of 414 

mmHg (PIO2 = 117 mmHg). 

 38
Fig. 8. Eight PIO2 isopleths from 80 to 150 mmHg. Dashed curve A is the x% AMS 

isopleth and dashed curve B is the larger y% AMS isopleth; the actual incidence of AMS 

for the true isopleths is unknown. Each curve demonstrates that an increasingly larger 

PIO2 is needed to achieve the same probability of AMS as ambient pressure decreases, or 

conversely a smaller PIO2 is needed as ambient pressure increases. Upper point near the 

x% AMS isopleth is PIO2 of 117 at a CEV pressure of 414 mmHg, middle point further 

from the x% AMS isopleth is also PIO2 of 117 at a sea level pressure of 760 mmHg, and 

finally lowest point farthest from the x% AMS isopleth is again PIO2 of 117 at 1,050 

mmHg (1.38 ATA). Therefore, the signs and symptoms of AMS are not identical 

(hypothesis) between the 3 conditions. Difference in time to achieve a new equilibrium 

FEN2/FIN2 ratio is a factor that defines the AMS isopleth. 

A point at PB of 609 mmHg and FIO2 of 0.209 on figure 8 represents an ascent on air to 

1,829 m (6,000 ft), and is also a PIO2 of 117 mmHg. This point is slightly further from 

the x% AMS isopleth than the upper most point representing the CEV breathing 

environment. Therefore, we hypothesize that the CEV breathing environment has 

 39
slightly more hypoxic stress than would otherwise be observed for a direct ascent on air 

to 1,829 m, but how much more hypoxic stress is unclear. A future iso-hypoxic model 

that creates precise AMS isopleths would be a refinement to the current EAA (iso-PIO2) 

model, which empirical data suggests needs to be refined. 

 Kazemi (1968) measured PCSFO2 in dogs breathing 14% O2, a typical NH 

condition evaluated in humans, and showed a rapid reduction and equilibration of 

PCSFO2, on the order of 30 minutes. Our working hypothesis requires that PCSFO2 and 

pH be effective inputs to the medulla and other brain cells over an extended period, 

certainly hours, roughly matching the different times it takes for FEN2/FIN2 to come to a 

new equilibrium under NH and HH conditions where hypoxic PIO2 are identical. 

Kazemi also shows that an increased cerebral blood flow accelerated the equilibration of 

the PaO2 - PCSFO2 gradient by using 30% CO2 and 70% O2 in mechanically ventilated 

dogs to induce vasodilatation of cerebral blood vessels. In humans, hyperventilation in 

response to hypoxia leads to hypocapnia that, in turn, causes vasoconstriction of cerebral 

blood vessels. So, the combination of hypoxia and hypocapnia in spontaneously 

breathing humans under both NH and HH conditions is expected to increase the time to 

reach an equilibration of the PaO2 - PCSFO2 gradient; there would be a significant 

difference in time to reach an equilibrium O2 gradient in a comparison of NH and HH. 

We conclude that there is a PB effect on AMS. It is the difference in PIO2 and 

PICO2 needed to achieve the same AMS response in a large number of subjects between 

HH and NH. This difference changes as a function of the imposed hypoxic stress, the 

PB, and rate of change of PB. One only needs to measure PCSFO2 and pH through time, 

given identical PIO2 in both NH and HH, to test the basic hypothesis. 

 

 40
Summary of Grover (1982) Results (acute PAO2)

Normobaric, 

PB = 760 

mmHg 

Hypobaric, 

PB < 760 

mmHg 

Normoxic, PAO2

= 103 mmHg 

Hypoxic, PAO2 < 

103 mmHg 

PAO2 = 140 to 

40, HVR = 133 

PAO2 = 140 to 

40, HVR = 53 

after 30 min, and 

124 after 240 

min

12,000 ft 

HVR - hypoxic ventilatory response. Values shown above are coefficients (A) that relates the HVR (l/min, 

BTPS) to PEO2 under isocapnic rebreathing in the equation: VE (BTPS) = Vo + A/(PAO2 - 32), and BTPS 

is body temperature, pressure, saturated with water vapor. 

Fig. 9. Grover’s (1982) summary results. He had subjects breathe supplemental O2 at 

750 mmHg such that PEO2 was at 140 mmHg at the start of the HVR measurement. The 

O2 concentration in the rebreather system decreased over 10 min so that PEO2 fell from 

140 to 40 mmHg. As hyperventilation ensued, he increased CO2 concentration in the 

rebreather to maintain constant PECO2. The resulting HVR was compared to the 

response at 480 mmHg (12,000 ft) after 30- and 240-min exposures in an altitude 

chamber. Subjects breathed 40% O2 during ascent to 3,657 m (12,000 ft), which 

provides a computed PAO2 of 129 mmHg from the AOE for the start of the experiment. 

But during the time at site PB (750 mmHg) on 40% O2, the PAO2 is estimated at 237 

mmHg. The time from the end of the first experiment to the second while at 3,657 m was 

spent breathing ambient air (PAO2 = 54 mmHg) before once again breathing 40% O2 for 

the 10-min duration of the HVR measurement. During the first measurement, HVR was 

suppressed; but by the second measurement, the HVR had returned to a pre-test response 

(see figure 10 below for the HVR curves). 

 41
30 40 50 60 70 80 90 100 110 120 130 140 150

PAO2 (mmHg)

8.0

10.2

12.4

14.6

16.8

19.0

21.2

23.4

25.6

27.8

30.0

V

E (l m/ in, B

T

P

S) h

y

p

o

xic

v

e

ntilatory re

s

p

o

n

s

e

Fig. 10. Curves created from an equation published by Grover (1982). Upper solid curve 

shows the increase in VE as PEO2 (similar to PAO2) is reduced at a total PB of 750 

mmHg by subjects breathing a hypoxic mixture with PACO2 held constant at about 40 

mmHg. So, this curve shows just the hypoxic ventilatory response at 750 mmHg without 

the confounding interaction of a decreasing PACO2 in the face of increased VE. The 

lower solid curve is the same experiment performed at 480 mmHg (12,000 ft altitude) 

during the first 30 mins of the altitude exposure. Note the decreased response in VE

caused by a decrease in absolute PB (or other factors) over the same change in PAO2. A 

mechanism to describe what appears to be a transient reduced sensitivity to hypoxic 

challenge at altitude is not known. The dashed curve shows the change in VE in response 

to a normocapnic hypoxic challenge after 4 hrs at 480 mmHg. The change seen after the 

first 30 mins is not evident after 4 hrs, and the changes after 4 hrs at 480 mmHg are no 

different than the changes at 750 mmHg. 

 Grover (1982) concludes that hypobaria per se, at least transiently, was the cause 

of blunted respiratory chemosensitivity to hypoxia. Since air enriched with O2 was used 

at site PB and at 3,657 m to achieve an initial PEO2 of 140 mmHg, it is likely that the 

brief exposures to enriched O2 equally desensitized the respiratory chemoreceptors in 

both experiments, so the effect of hypobaria could be understood without a bias from the 

procedure. But, the use of O2-enriched air does add some uncertainty as to the cause of 

the blunted HVR immediately on arrival at 3,657 m altitude. He discusses earlier work 

that he and Tucker (1981 and 1983) performed where 1.5 hrs of 100% O2 PB were 

 42
performed before an exposure to 430 mmHg. Tucker shows that the smaller increase in 

VE response after 2 hrs under HH relative to NH was further reduced (blunted) when O2

was breathed for 1.5 hrs in 11 subjects. So, it is strange that Grover does not discuss that 

his brief period of hyperoxia (40% O2 at site PB) was not a contributor to his blunted 

HVR response after 30 min at 3,657 m. He attributes his observation only to a hypobaric 

PB effect. Finally, Loeppky (1996) conducts a pilot test of a PB effect for only 30 min at 

430 mmHg to understand whether sensitivity (chemoresponsiveness) to hypoxia was 

altered by hypobaric exposure. He measured pulmonary changes the last 2 mins of a 30-

min exposure, and then had subjects breathe 100% O2 for 1 min. He shows, on a short 

time scale, that there was no decrease in hypoxic sensitivity, which did not accord with 

Grover (1982). Tucker (1983) and even Loeppky (1997) show a greater VE in NH than 

HH. The reduction in VE with 100% O2 suggests that reduced PB did not markedly alter 

hypoxic chemosensitivity within 30 mins. 

 Before leaving the discussion of HVR by Grover (1982), it is helpful to include 

observations from Prisk (2000) to understand more about factors that modify HVR. Prisk 

shows that sustained μG and supine body position in normal gravity reduce the 

ventilatory response to hypoxia but not to hypercapnia under NH conditions. The HVR 

response, as measured from the slope of ventilation against arterial O2 saturation from a 

rebreather device that maintained normocapnia, was reduced about 50% compared to 

subjects in a standing position. Prisk concludes that inhibition of the hypoxic drive, but 

not the hypercapnic drive, was mediated through stimulation of carotid baroreceptors in 

response to an increase in blood pressure. The point being that there could be a 

combined reduction in HVR due to μG exposure and hypobaria anticipated in the CEV, 

leading to a greater risk of AMS. 

 

 43
Summary of Levine (1988) Results for 8,500 

ft exposure (acute PAO2) 

Normobaric, 

PB = 760 

mmHg 

Hypobaric, 

PB < 760 

mmHg 

Normoxic, PAO2

= 103 mmHg 

Hypoxic, PAO2 < 

103 mmHg 

PAO2 = 95* 

PAO2 = 95.0 

mean lymph 

flow as % 

change from 

baseline = 95% 

PAO2 = 67.2 

mean lymph 

flow as % 

change from 

baseline = 105% 

PAO2 = 67.0 

mean lymph 

flow as % 

change from 

baseline = 139% 8,500 ft on air 

*See Note 3 at end of report. 

Fig. 11. Levine’s (1988) summary results for 8,500 ft exposure. It was expected that any 

effect of HN and NH on increased pulmonary lymph flow would be additive in the results 

from the HH condition. This was not the case, however, suggesting that there was a 

complex negative synergy between HN and NH leading to the HH results. See figure 13 

description for more information. 

 44
Summary of Levine (1988) Results for 15,100 

ft exposure (acute PAO2) 

Normobaric, 

PB = 760 

mmHg 

Hypobaric, 

PB < 760 

mmHg 

Normoxic, PAO2

= 103 mmHg 

Hypoxic, PAO2 < 

103 mmHg 

PAO2 = 95.7 

mean lymph 

flow as % 

change from 

baseline = 88% 

PAO2 = 46.0 

mean lymph 

flow as % 

change from 

baseline = 108% 

PAO2 = 45.0 

mean lymph 

flow as % 

change from 

baseline = 153% 15,100 ft on air 

Fig.12. Levine’s (1988) summary results for 15,100 ft exposure. Again, the HH results 

far exceed the combined effects of the HN and the NH conditions. See figure 13 

description for more information. 

 45
Summary of Levine (1988) Results for 21,500 

ft exposure (acute PAO2) 

Normobaric, 

PB = 760 

mmHg 

Hypobaric, 

PB < 760 

mmHg 

Normoxic, PAO2

= 103 mmHg 

Hypoxic, PAO2 < 

103 mmHg 

PAO2 = 95.9 

mean lymph 

flow as % 

change from 

baseline = 83% 

PAO2 = 32.0 

mean lymph 

flow as % 

change from 

baseline = 105% 

PAO2 = 33.1 

mean lymph 

flow as % 

change from 

baseline = 173% 21,500 ft on air 

Fig. 13. Levine’s (1988) summary results for 21,500 ft exposure. Figures 11, 12, and 13 

show important results from Levine (1988) taken from his figure 3 (see below). He used 

a sheep model to understand pulmonary edema caused by substantial hypoxic insult. 

Classic pulmonary edema formation in HH AMS is evident. Pulmonary and cerebral 

edema in extreme cases leads to death. There appears to be a PB effect at work. Since 

no change in lymph flow occurred under HN conditions, he concludes that hypobaria is a 

necessary, but not sufficient, condition for change in pulmonary fluid balance under HH 

conditions. He demonstrates an increased lymph flow and protein clearance (not shown 

here) only under conditions of combined (synergized) HH, not under equivalent degrees 

of alveolar hypoxia or hypobaria alone. Only under HH was there a clear and highly 

significant increase in lymph flow. Levine hypothesizes that ambient PB in the alveoli 

significantly alters the Starling forces (delta hydrostatic pressure and delta oncotic 

pressure) governing transcapillary fluid flux in the lung, which in turn may affect the 

PAO2 - PaO2 gradient for O2 diffusion. 

 Levine’s results logically lead to this conclusion, but it is completely contrary to 

the dogma that absolute PB is communicated equally throughout the body. In essence, 

the body can be considered a bag of water. Any PB applied to the bag is equally 

distributed. This is easy to visualize if the bag is taken 30 m underwater. The additional 

hydrostatic PB is transmitted through the bag of water such that there is no pressure 

 46
difference at any location. So, the bag maintains the original shape. The same applies if 

the increase in PB is caused by compressing gas. If this were not so, we would certainly 

notice significant effects with just a few mmHg change in pressure, such as you 

experience when trying to equalize pressure across the ear drum when going from a lowpressure airplane cabin to the higher pressure at the airport. So, in the absence of 

additional hypoxic stress leading to some change in epithelial or endothelial membrane 

properties, it is not reasonable to accept that PB over a few hundred mmHg can influence 

membrane permeability to water. If this were so, a simple SCUBA dive should always 

cause some significant fluid imbalance in the lungs, and this is certainly not the case. 

The amount of extravascular liquid in the lung depends on the balance between the rate 

of fluid formation and the rate of its removal. 

 Levine suggests that PB is not communicated equally within the lungs and the 

body such that there are areas of significant pressure difference (delta or transmural 

pressure) that would affect the balance of Startling forces. This hypothesis is suspect. 

The alternative is to think that oncotic pressure, or the filtration coefficient, is somehow 

modified after hypoxic stress, but to a greater extent when ambient PB is reduced, or to a 

lesser extent when ambient PB is increased. The fact that Levine shows no change in 

lymph flow under NH condition equivalent to 6,553 m (21,500 ft) altitude is compelling 

evidence that high PB, even in the presence of hypoxic stress, is protective. 

 

 47
 48
Summary of Loeppky (2005a) Results (acute PAO2) 

Normobaric, 

PB = 760 

mmHg 

Hypobaric, 

PB < 760 

mmHg 

Normoxic, PAO2

= 103 mmHg 

Hypoxic, PAO2 < 

103 mmHg 

PAO2 = 75* 

K+ = 3.9

PAO2 = 74.5 

mean PV = - 2.5, 

Na+ = 138, ADH 

= 2.4, K+ = 4.2 

PAO2 = 45.9 

mean PV = - 5.0, 

Na+ = 138, ADH 

= 2.6 

PAO2 = 46.0 

mean PV = 2.5, 

Na+ = 136, ADH 

= 2.9 15,000 ft on air 

*See Note 1 at end of report. 

PV - plasma volume as % change from baseline 

K+ - potassium ion concentration in plasma (mmol/l) 

Na+ - sodium ion concentration in plasma (mmol/l) 

ADH - antidiuretic hormone in plasma (pg/ml) 

Fig. 14. Loeppky (2005a) summary results describe classic edema formation with AMS. 

Urine volume decreased over 10 hrs in HH while PV increased relative to NH. Plasma 

Na+ decreased at HH due to increased PV, and ADH was greatest in HH even in the 

presence of increased PV. Loeppky concludes that fluid retention under HH conditions 

in AMS-susceptible subjects appears related to a synergistic interaction between reduced 

PB and ADH and ALD. Plasma K+ was significantly elevated in HN compared to NN. 

This peculiar observation was noted by Epstein (1972) and Leach (1973) while testing 

the NH environment proposed for Skylab, which each attributed to increased ALD 

production while living normoxic at 5.0 psia. Glomerular filtration rate (GFR), through 

creatinine clearance, did not decrease over just 9 hrs under HN as it did progressively 

over 9 days from Epstein (1972). But GFR was reduced transiently in HH. The changes 

cited above are modest, but pulmonary and cerebral edema in extreme cases lead to 

death. There appears to be a PB effect at work. More AMS was reported in HH (3.7 

mean score) than NH (2.0 mean score), and even symptoms in HN (0.4 mean score) as 

reported by Roach (1996) for these same experiments. 

 49
Summary of Savourey (2003) Results

(acute PAO2 only 40 min) 

Normobaric, 

PB = 760 

mmHg 

Hypobaric, 

PB < 760 

mmHg 

Normoxic, PAO2

= 103 mmHg 

Hypoxic, PAO2 < 

103 mmHg 

PAO2 = 98* PAO2 = 49.0 

mean Vt = 0.8, f = 12, 

VE = 9.5, HR = 70, 

SaO2% = 88, PaCO2 = 

34.9, PaO2 = 47.5 

PAO2 = 46.1 

mean Vt = 0.6, f = 14, 

VE = 8.5, HR = 75, 

SaO2% = 84, PaCO2 = 

32, PaO2 = 43 15,000 ft on air 

*See Note 4 at end of report. 

Vt - tidal volume (l/min, BTPS) 

f - breathing rate (breaths/min) 

VE - min ventilation (l/min, BTPS) 

HR - heart rate (beats/min) 

SaO2% - arterial blood oxygen saturation (%) 

PaCO2 - arterial blood carbon dioxide partial pressure (mmHg) 

PaO2 - arterial blood oxygen partial pressure (mmHg) 

Fig. 15. Savourey’s (2003) summary results. This example shows changes in pulmonary 

mechanics for the same PAO2 under NH and HH conditions (see Savourey’s figures 1 

and 2 below). There appears to be a PB effect at work in the control of pulmonary 

mechanics. Others also show a decrease in VE at altitude given the same degree of 

hypoxic stress as simulated at sea level with a hypoxic breathing mixture. The author 

concludes that the lower Vt and higher breathing rate in HH results indicates an increase 

in deadspace ventilation (Van Liew in a personal communication says that there is a 

decrease in deadspace ventilation in HH, but warns there are different definitions for 

deadspace), and Loeppky (1997) says that there is a decrease in deadspace ventilation in 

his HH vs. NH results; his experiment was over 10 hrs, not 40 min seen with Savourey. 

 50
Loeppky (1997) used half the subjects (9) and started the experiment with subjects living 

at 636 mmHg (5,270 ft) compared to 733 mmHg (1,000 ft) in Savourey’s work. 

 Compared to NH, HH leads to a greater hypoxemia, hypocapnia, and blood 

alkalosis, and to lower O2 arterial saturation. 

 A working hypothesis to account for these and similar observations is that there is 

an increased alveolar deadspace through a mismatch in VA/Q secondary to regional 

pulmonary vasoconstriction as a function of gas density plus hypoxic stress. And, both 

synergize to create a greater response than either in isolation of the other. You must have 

both at once, not just hypoxic stress and not just reduced gas density. Savourey refers to 

this as a “specific response to HH” in that it is a unique response, one that is not possible 

to simulate with an NH analog. 

 It is difficult to reconcile only small changes in gas density as a significant 

contribution to these changes, since the magnitude of differences in breathing gas density 

routinely encountered in normoxic and even hyperoxic SCUBA diving does not lead to 

any clinical consequences. It must be a synergistic interaction through a poorly 

understood mechanism between gas density and hypoxic stress within the CNS (see 

Partial Pressure of Nitrogen, Oxygen, and Carbon Dioxide in the Cerebrospinal Fluid). 

 One could hypothesize that a direct ascent to 4,572 m (15,000 ft) while breathing 

100% O2 or a mixture that brings PAO2 to a normoxic 103 mmHg (39.0% O2) will not 

elicit the changes seen during Savourey’s HH exposure, even though the breathing gas is 

at the same lower density. One caveat to this test is that there is some risk of forming 

VGE that embolize the lung given the magnitude of this depressurization if some prior 

denitrogenation is not done and the exposure time exceeds about 60 mins (see Do Venous 

Gas Emboli have a Role in Acute Mountain Sickness?). 

Another interesting experiment would be to repeat the work done by Savourey, 

except to provide the identical hypoxic stress under hyperbaric conditions. Take the 

same pressure difference used in his study (740 mmHg - 430 mmHg = 310 mmHg) and 

add the difference to his 740 mmHg ambient PB to produce a modest hyperbaric PB of 

1,050 mmHg. Have the subjects breathe 7.9% O2, which provides a computed PAO2 of 

45 mmHg, to produce the same hypoxic stress in his 2 comparisons. 

The results from the 2 experiments above would help to understand a PB effect on 

the physiological response to hypoxia. 

 51
 52
 

 53
Summary of Loeppky (1996) Results (acute PAO2 only 30 min) 

Normobaric, 

PB = 760 

mmHg 

Hypobaric, 

PB < 760 

mmHg 

Normoxic, PAO2

= 103 mmHg 

Hypoxic, PAO2 < 

103 mmHg 

PAO2 = 75*, VE = 

10.8, ETCO2 = 27.3, f

= 17, Vt = 0.60, SaO2

= 95.6, HR = 72 

PAO2 = 74 

VE = 11.6, ETCO2 = 

29.3, f = 18, Vt = 

0.69, SaO2 = 95.0, HR 

= 72 

PAO2 = 49 

VE = 12.3, ETCO2 = 

26.8, f = 18, Vt = 

0.72, SaO2 = 80.7, HR 

= 81 

PAO2 = 45 

VE = 12.9, ETCO2 = 

25.5, f = 20, Vt = 

0.67, SaO2 = 77.4, HR 

= 85 

NN = 5,270 ft on air, 

HN = 15,000 ft on 

29.8% O2, NH = 6,000 

ft on 14.1% O2, and HH 

= 15,000 ft on air

*See Note 1 at end of report. 

VE - min ventilation (l/min, BTPS) 

ETCO2 - partial pressure of end-tidal carbon dioxide - inspired oxygen - PECO2 - PICO2 (mmHg) 

f - breathing rate (breaths/min) 

Vt - tidal volume (l/min, BTPS) 

HR - heart rate (beats/min) 

SaO2% - arterial blood oxygen saturation (%) 

Fig. 16. Loeppky’s (1996) summary results. He conducted a pilot test of a PB effect for 

only 30 min at 430 mmHg to understand whether sensitivity (chemoresponsiveness) to 

hypoxia was altered by hypobaric exposure. He measured pulmonary changes the last 2 

mins of a 30 min exposure, and then had subjects breathe 100% O2 for 1 min. He shows, 

on a short time scale, that there was no decrease in hypoxic sensitivity, which did not 

accord with Grover (1982). Tucker (1983) and even Loeppky (1997) show a greater VE

in NH than HH. The reduction in VE with 100% O2 suggested that reduced PB did not 

markedly alter hypoxic chemosensitivity within 30 mins. 

 54
Summary of Loeppky (1997) Results (acute PAO2) 

Normobaric, 

PB = 760 

mmHg 

Hypobaric, 

PB < 760 

mmHg 

Normoxic, PAO2

= 103 mmHg 

Hypoxic, PAO2 < 

103 mmHg 

PAO2 = 75* 

VE = 9.5, ETCO2 = 

32, f = 12, Vt = 0.85, 

SaO2 = 95.7 

PAO2 = 74 

VE = 10.0, ETCO2 = 

31, PEO2 = 82, f = 15, 

Vt = 0.75, SaO2 = 95.7 

PAO2 = 47 

VE = 13.0, ETCO2 = 

28, PEO2 = 51, f = 16, 

Vt = 0.90, SaO2 = 82.7 

PAO2 = 46 

VE = 10.5, ETCO2 = 

26, PEO2 = 50, f = 13, 

Vt = 0.85, SaO2 = 82.7 NN = 5,270 ft on air, 

HN = 15,000 ft on 

29.6% O2, NH = 6,000 

ft on 14.2% O2, and HH 

= 15,000 ft on air 

*See Note 1 at end of report. 

VE - min ventilation (l/min, BTPS) 

ETCO2 - partial pressure of end-tidal carbon dioxide - inspired oxygen = PECO2 - PICO2 (mmHg) 

PEO2 - partial pressure of end-tidal oxygen (mmHg) 

f = breathing rate (breaths/min) 

Vt - tidal volume (l/min, BTPS) 

SaO2% - arterial blood oxygen saturation (%) 

Fig. 17. Loeppky’s (1997) summary results. He conducted a detailed analysis of a PB

effect on respiratory dynamics by comparing results for all 4 O2 and PB options (see 

Loeppk’s figures 1 and 2 below). Nine subjects had pulmonary measurements taken 

about 1, 4, 7, and 10 hrs into each of the 3 experimental conditions, plus baseline values 

for the NN condition about 2 hrs after the experimental conditions. Shown above are the 

means for his 4-, 7-, and 10-hr experimental results and his 2-hr post-test controls at 636 

mmHg (5,270 ft). 

It is best to list Loeppky’s main results and conclusions: 

1. There was a greater VE and higher PETCO2 during NH as compared to HH, about a 

31% increase for NH and a 20% increase for HH for VE when compared to the NN 

baseline. A high PETCO2 in relation to a high VE for NH suggested that there was 

 55
an increased physiological deadspace in NH relative to HN and HH, assuming no 

change in O2 consumption and CO2 production. If you assume there was a change in 

O2 consumption and CO2 production in NH relative to HN and HH, the work of 

breathing and not an increase in physiological deadspace could explain the 

observations. 

2. There was no difference between NN and HN, so a decrease in PB (gas density) 

without hypoxic stress did not affect the pulmonary measures even when the physics 

of gas density and gas flow is present. You need the combination of reduced gas 

density and hypoxic pulmonary vasoconstriction to get a better VA/Q matching, 

which manifests as a reduced alveolar deadspace in HH relative to NH. 

3. Loeppky posits that a decreased work of breathing (less CO2 production and less O2

consumption) and/or an improved VA/Q in HH relative to NH would explain the HH 

results relative to NH, but you still need hypoxic stress to make this conclusion. 

4. What seems plausible is that respiratory dynamics do change as a function of PB

since dense gas requires more respiratory effort for the same flow. As the dynamics 

of respiration change as a function of PB, maybe VA/Q changes. But, only in the 

presence of hypoxic stress do the synchronized effects of decreased PB and altered 

VA/Q plus pulmonary vasoconstriction explain the differences seen in all 3 

experimental conditions. 

5. Loeppky says an increase in physiological deadspace in NH due to a less ideal VA/Q 

relation relative to HH could be an explanation for the results if you assume CO2

production was constant over all experiments. 

6. A reduced gas density does reduce the pressure swings (driving delta pressure for 

ventilation) to ventilate the lungs, so ventilation dynamics change. These changes 

coupled with pulmonary vasoconstriction due to hypoxic stress may improve VA/Q, 

which manifests as a reduced alveolar deadspace relative to NH. VE is not stimulated 

to increase relative to NH. In NH, the pulmonary vasoconstriction is not associated 

with a reduced gas density, so VA/Q is not improved as much, which manifests as an 

increased alveolar deadspace relative to HH. VE is stimulated to increase relative to 

HH. 

7. Loeppky (1997) was the first to rigorously evaluate mechanisms to account for his 

observations, so a portion of his important Discussion is paraphrased here as follows: 

 Perhaps more interesting and important in considering these results is 

how alveolar deadspace may be altered by the change in VA/Q ratio to 

account for the difference in VE between HH and NH. The reduction in 

PIO2 was essentially identical in these two situations. A number of acute 

measurements in humans have demonstrated that the initial increase in 

mean pulmonary arterial pressure is approximately 5 mmHg within 10 

min. If this response is equal under both conditions, then at altitude this 

would be associated with a synchronous and significant reduction in the 

airway or alveolar pressure swing during the breathing cycle because of 

 56
the reduction in gas density. This reduction in alveolar pressure at a given 

air flow at altitude was impressively demonstrated by Otis (1949) in 

humans breathing 100% O2. An increase in pulmonary artery pressure 

(due to hypoxia) simultaneous to a reduction in airway pressure at altitude 

would be expected to (through a better matching of ventilation to 

perfusion) result in an improved VA/Q distribution and a reduction in 

equivalent alveolar deadspace (because pulmonary artery mean pressure 

exceeds alveolar pressure) as compared to NH, where an increase in 

pulmonary artery pressure is not associated with changes in airway 

pressure. The PaO2 would fall and PaCO2 rise more in the case of a 

synchronous enlargement of alveolar deadspace, this would stimulate VE

by chemoreceptors. In HN, the reduction in density was not accompanied 

by hypoxic pulmonary vasoconstriction and no change in deadspace or VE

resulted. 

 57
 58
 59
Summary of Meehan (1986), Swenson (1995), and Knight 

(1991) Results (acute PAO2) 

Normobaric, 

PB = 760 

mmHg 

Hypobaric, 

PB < 760 

mmHg 

Normoxic, PAO2

= 103 mmHg 

Hypoxic, PAO2 < 

103 mmHg 

PAO2 = 52.9 with 

no AMS, PAO2 = 

50.1 with minimal 

AMS, and PAO2 = 

50 with no AMS 

PAO2 = 51 

others predict 

this would give 

significant AMS 13,000 ft on air 

Fig. 18. There appears to be a consensus of opinion of a PB effect at work on the signs 

and symptoms of AMS, but no one knows a mechanism as of 2008. No one knows why 

AMS occurs, except that the trigger is hypoxia. Hypoxia affects every system in the 

body instantly, since you need O2 on a breath-by-breath basis. There appears to be direct 

peripheral effects on the kidneys and the pulmonary vasculature in response to hypoxia as 

well as a centrally-mediated response from the CNS as it receives a plethora of inputs 

about changes induced by hypoxia. There is a decreased hypobaric diuresis, an increased 

edema, and a decreased hypoxic ventilatory response in subjects that go on to exhibit 

AMS. No mechanism for AMS is available from which to interpolate or extrapolate to a 

new set of environmental conditions. Meehan (1986), Swenson (1995), and Knight 

(1991) published results from NH exposures where computed PAO2 was about 51 

mmHg, and there was little or no AMS. Based on observations of significant AMS with 

HH exposures that produce PAO2 around 50 mmHg (13,000 ft), it is reasonable to 

conclude, although indirectly, that there is a PB effect at work on the signs and symptoms 

of AMS. 

 60
Summary of Epstein (1972) Results (chronic PAO2) 

Normobaric, 

PB = 760 

mmHg 

Hypobaric, 

PB < 760 

mmHg 

Normoxic, PAO2

= 103 mmHg 

Hypoxic, PAO2 < 

103 mmHg 

PAO2 = 102, ALD = 

74, BW = -2.6, Na 

t

1/2 = 0.70, HR = 

70, Ccr = 100 

PAO2 = 105.6, ALD 

= 82, BW = -1.1, Na 

t

1/2 = 0.57, HR = 

62, Ccr = 57 

Na+ - sodium ion concentration in plasma or urine 

K+ - potassium ion concentration in plasma or urine 

ALD - aldosterone concentration (μg/24 hr) 

BW - body weight (% change in body weight following dietary Na+ restriction) 

HR - heart rate (beats/min) 

Na t1/2 - half-time in days to achieve a new lower urinary Na+ balance following dietary Na+ restriction. 

Ccr - Creatinin clearance (ml/min), a measure of kidney glomerular filtration rate (GFR) 

Note: Comparison data between NN and HN shown in table are generally after 7 or more days after the 

start of the restricted Na+ diet (see Epstein 1972 for details). 

Fig. 19. Epstein’s (1972) summary results. He shows a PB effect on Na+ balance in 

subjects with significant dietary Na+ restriction. He reproduced the 70% O2 at 5.0 psia 

(258 mmHg) Skylab atmosphere in an altitude chamber for 9 days. He wanted to 

understand the effect of hypobaria alone without the confounding role of hypoxia on the 

responsiveness of the renin-angiotensin-ALD system given a diet deficient in Na+ as a 

means to stimulate Na+ conservation. 

 About 99.5% of the filtered load of Na+ is reabsorbed by the kidneys. Given a 

normal dietary intake of about 155 mEq per day, any change in the GFR or in the rate of 

tubular Na+ reabsorption could seriously threaten Na+ balance and, hence, the 

maintenance of body fluid compartments. Or, a change in the dietary intake of Na+ 

would pose a similar threat unless the GFR or tubular reabsorption rate were quickly 

adjusted. Plasma Na+ is carefully maintained between 136 and 146 mEq/L. Plasma 

 61
sodium chloride is sensed by the kidney, specifically the juxtaglomerular apparatus, 

where renin is secreted when Na+ is reduced, ultimately leading in several steps to the 

production of ALD. As plasma Na+ decreases, ALD concentration increases, leading to 

increased tubular reabsorption of Na+. Epstein reduced Na+ in the diet of 8 men from a 

10-day control period of 200 mEq to 10 mEq over 9 days to understand how the reninangiotensin-ALD system would respond to the HN in the absence of μG. 

 There was a small, but insignificant, decrease in plasma Na+ in pooled data from 

days 7 through 9 in both NN and HN (142 mEq/L vs. 145 mEq/L) compared to the first 

day of Na+ restriction. So, plasma Na+ concentration was preserved. The increase in 

plasma renin activity was the same for NN and HN. Urinary ALD excretion over days 7 

and 9 was significantly greater in HN compared to NN over days 8, 9, and 10 (82 μg/24 

hr vs. 74 μg/24 hr). The significant decrease in body weight of 1.1% over 9 days for HN 

was less than the decrease of 2.6% in NN. So, more body water was retained relative to 

controls during a diet restricted in Na+. As expected, urinary Na+ fell. Subjects under 

NN lost 134 mEq of Na+ during the 3.1 days required to achieve a new, lower Na+ 

balance after the start of Na+ restriction. The half-time to achieve a new lower Na+ 

balance under NN was 0.70 day. Subjects under HN lost 100 mEq of Na+ during the 2.6 

days required to achieve a new, lower Na+ balance after the start of Na+ restriction. The 

half-time to achieve a new lower Na+ balance under HN was 0.57 days So, it appears 

that the conservation of Na+ under HN responds faster than under NN conditions. 

Creatinine clearance (Ccr) decreased progressively from about 100 ml/min to 57 ml/min 

(a 40% reduction) after 8 days in HN compared to NN, and returned to pre-test level after 

about 3 days after the test (see Epstein’s figure 2 below). Although serum creatinine 

increased from a mean of 1.22 to 1.46 on day 8 of HN, the decrease in Ccr was primarily 

attributed to the decrease in urinary creatinine excretion. 

 Epstein says the highly significant decrease in Ccr during HN suggests that the 

changes in renal Na+ handling may have been mediated by changes in the filtered load of 

Na+, and points to the decrease in HR as evidence that CO may have decreased during 

HN. Blood pressure did not change under NN or HN conditions in the Na+ deprived 

matched subjects, but HR was consistently lower in HN compared to NN (see Epstein’s 

figure 4 below). If you assume that renal blood flow was constant between HN and NN, 

then an increase in afferent renal arteriolar resistance or a decrease in efferent renal 

arteriolar resistance would decrease Ccr (GFR). This does not explain the difference in 

Ccr between HN and NN, but it does offer a possible effector site in the kidneys to 

account for this interesting observation. 

 Epstein concludes that subjects exposed to HN attained Na+ balance more 

rapidly, with a smaller decrement in body weight, in response to dietary Na+ deprivation. 

The early positive Na+ balance in HN may be related to reduced PB, but he offers no 

mechanism whereby reduced PB alters renal Na+ handling. HH-induced diuresis is 

associated with less risk of AMS while antidiuresis is associated with more risk. Epstein 

shows that reduced PB alone may contribute to antidiuresis, at least in a situation where 

Na+ is being conserved due to a restricted Na+ diet. 

 62
 Finally, in contrast to the above, Leach (1973) reports very modest changes in 

fluid and electrolyte balance in 3 subjects over 56 days during the Skylab Medical 

Experiments Altitude Test (SMEAT). These 3 subjects did not change body weight over 

the first 10 days of a HN environmental exposure that was identical to Epstein (1972). 

Urinary ALD and plasma Angiotensin I, which was used as a direct measure of renin 

activity, showed increases in the 3 subjects. There was a slight, but significant, decrease 

in K+ excretion attributed to the slight increase in plasma ALD; Epstein (1972) also 

reports a positive K+ balance. It is possible that the dietary Na+ restriction by Epstein 

(1972) revealed a subtle contribution of PB in the HN condition that otherwise goes 

unnoticed given a normal diet, even after 56 days in a HN environment. 

 This ends the summary of data for our first issue, Hypoxia and Acute Mountain 

Sickness. Figures 20 and 21 compare and contrast the PAO2 and PB in some past, 

present, and future NASA vehicles. A comparison is started between the literature results 

about a PB effect on AMS and the mild hypoxic atmospheres proposed for the CEV, 

LSAM, and surface habitats. 

 63
 64
 65
Skylab, Shuttle, and Proposed Crew Exploration Vehicle, 

Lunar Surface Access Module and Habitat Results 

(acute PAO2) 

Normobaric, 

PB = 760 

mmHg 

Hypobaric, 

PB < 760 

mmHg 

Normoxic, PAO2

= 103 mmHg 

Hypoxic, PAO2 < 

103 mmHg 

PAO2 = 105.6 

For Skylab 

PAO2 = 85.2 for 

Shuttle, PAO2 = 

77.0 for CEV 

nominal, and 68.0 

for CEV extreme 

Skylab - 70.0% O2 at 5.0 psia (27,000 ft, 8,229 m) 

shuttle - 26.5% O2 at 10.2 psia (10,000 ft, 3,048 m) 

CEV/LSAM nominal - 32.0% O2 at 8.0 psia (16,000 ft, 4,877 m) 

CEV/LSAM extreme - 30.0% O2 at 7.8 psia (16,500 ft, 5,029 m) 

Habitat nominal - 32.0% O2 at 7.6 psia (17,000 ft, 5,181 m) 

Habitat extreme - 30.0% O2 at 7.4 psia (17,600 ft, 5,364 m) 

Fig. 20. The experimental data presented allow comparisons and then conclusions about 

the risk of AMS given the nominal and extreme breathing gas environment on the CEV. 

With 10.2 psia PB (10,000 ft) and 26.5% O2 on the shuttle, the ppO2 is 140 mmHg with 

PAO2 = 85 mmHg from the AOE. For the proposed nominal CEV, LSAM, and moon 

habitat with an 8.0 psia PB (16,000 ft) and 32.0% O2, the ppO2 is 132 mmHg with PAO2

= 77 mmHg from the AOE. These conditions are equivalent to an ascent on 21% O2 to 

11.8 psia. Since AMS signs and symptoms do not start at less than 11.5 psia (6,500 ft, 

ppO2 = 125 mmHg with PAO2 = 75 mmHg from the AOE), it is unlikely that anyone on 

the shuttle would experience AMS. The conditions on the CEV, especially the worse 

case extreme of the control box for the life support system, could drop PAO2 to about 68 

mmHg. Months of living in the moon and Mars habitats will likely be well tolerated 

even when the worse case acute PAO2 to about 63 mmHg. See Conclusions for a 

 66
summary of expectations about this degree of HH plus adaptation to μG on the risk of 

AMS. 

0 1 2 3 4 5 6 7

shuttle, CEV, habitat comparisons

0

2000

4000

6000

8000

10000

12000

14000

16000

18000

20000

p

h

y

siolo

gic

al a

n

d

a

c

ut al alti ut d

e ( ef et)

Fig. 21. A visual comparison of the difference in physiological and actual altitude in 3 

vehicles: the shuttle, the proposed CEV and LSAM, and the proposed moon and Mars 

habitats. The increase in physiological altitude from 4,000 (1) to 6,000 (3) to 7,500 (5) ft 

shows a desire to exploit mild hypoxia as a means to reduce denitrogenation time and 

reduce the risk of DCS during EVAs from these vehicles. The increase in actual altitudes 

from 9,800 (2) to 16,000 (4), to 17,000 (6) ft is possible because the O2 concentration is 

increased from 26.5% in the shuttle to 32.0% in the other vehicles. One goal of this 

report is to understand whether the difference between physiological and actual altitude 

significantly increases the risk or nature of AMS. 

 

 67
Second Issue: Body Fluid Balance and Red Blood Cell Changes in Microgravity 

The adaptive response to μG exposure is a rapid reduction in total body fluid 

(Leach 1977), followed by a gradual reduction in RBC mass, but with little change in 

HCT in the absence of hypoxic stress (Johnson 1977). Prior to the reduction in body 

fluid, there is a cephalic shift of fluid leading to a loss of leg fluid volume, with excess 

fluid distributed into the face and chest. Pulmonary capillary blood volume increases by 

about 25%. The initial fluid shift increases stroke volume. Stretch receptors in the 

arterial circulation and the heart sense changes in the central blood volume, so water 

immersion, supine or head down BR, and exposure to μG are all sensed as an increase in 

central blood volume. In response, there is a decreased renal sympathetic drive, a 

decrease in renin activity from the kidneys leading to decreased ALD secretion (Buckey 

2006). 

Although urine output does not appear to increase on the first day in orbit, PV 

drops rapidly by about 17% (Buckey 2006). Part of this reduction is due to the loss of 

fluid to the extravascular space. There is a transient increase in HCT that would reduce 

EP secretion, which does decrease in space (Srinivasan, 1996). The net result in a 

normoxic environment is a reduction in RBC mass. In a significant hypoxic 

environment, EP production would be stimulated. EP secretion requires an altitude of 

about 2,500 m (8,200 ft) or greater, and exposures longer than 6 hrs (Ge 2002). Figure 

22 is a summary from Ge (2002) that shows EP production as a function of PB. The 

combined PV and RBC mass loss contribute to a reduction in total blood volume of about 

11%. This new fluid volume appears to provide a central blood volume similar to what is 

seen on Earth in an upright posture. The HN condition during SMEAT was not expected 

to, and did not, down-regulate RBC production (Johnson 1973). Total blood volume in 3 

subjects after 56 days in the SMEAT did not change. So, the loss of RBCs in Skylab was 

attributable to μG adaptation and not to a HN environment of 70% O2 at 5 psia (Johnson 

1977). Erythrocytes are the most abundant cells in the body, and their numbers are 

exquisitely regulated in a normal physiology to match O2 supply with O2 demand. 

 68
Summary of Ge (2002) Results (acute PAO2) 

Normobaric, 

PB = 760 

mmHg 

Hypobaric, 

PB < 760 

mmHg 

Normoxic, PAO2

= 103 mmHg 

Hypoxic, PAO2 < 

103 mmHg 

PAO2 = 103 

EP = 14.3 

mU/ml

PAO2 = 77, 19.6 EP 

PAO2 = 73, 19.4 EP 

PAO2 = 69, 25.4 EP 

PAO2 = 65, 27.2 EP 

6,000 ft on air 

7,000 ft on air 

8,000 ft on air 

9,000 ft on air

EP - plasma erythropoietin (mU/ml) under 1 atmosphere pressure absolute (ATA) control, or after 24 hrs at 

altitude 

Fig. 22. Ge’s (2002) summary results. EP is dose-dependent on a renal hypoxia 

trigger. It is expected to increase at > 2,100 m (7,000 ft). Since the nominal CEV 

environment is close to PAO2 = 77, there is some HH-induced increase in EP expected 

even in the face of fluid redistribution and reduction in μG adaptation. We used discrete 

data published in Ge (2001) in a regression model to summarize the mean response to EP 

over the tested range of altitude and time. The model computes the central tendency in 

these data, well within the standard error of tabulated data. The regression is: EP 

concentration (μm/l) = 14.3/(1 – 0.000091 * altitude (meters) * time (hrs)0.2104). If 

time = 0 hr regardless of altitude, the function computes 14.3 μm/l, the mean EP 

concentration at 1 ATA in 32 men and 16 women. 

 69
A dysfunction in the body’s handling of water is proposed as one factor in the 

development of AMS. Individuals who show diuresis upon arrival at high altitude fare 

better than those who exhibit an antidiuresis response. The most affected subjects show a 

marked reduction in urine flow associated with elevated levels of ADH (Loeppky 2005a, 

Loeppky 2005b). It is unclear whether the increase in ADH is a response to net fluid loss 

into the extravascular space or whether the cause is initiated by an unknown mechanism 

triggered by HH. Fluid shifts from the intravascular space to the extravascular space 

leads to edema, with significant problems if the result is cerebral edema or pulmonary 

edema. As mentioned in the previous section, there is a hypoxic component as well as a 

hypobaric component to AMS. There is no mechanism available to pull all of the 

observations together about changes in the neural, cardiopulmonary, renal, and endocrine 

systems. 

 Certainly fluid retention and redistribution leading to edema seen in AMS could 

be exacerbated (synergized) if these processes were superimposed on fluid redistribution 

and net fluid loss seen in early adaptation to μG. It is not possible to practically alter 

fluid changes during μG adaptation; but with the judicious use of O2 and/or AZ, it may 

be possible to reduce any negative synergy by reducing the risk of AMS. Periods of 

breathing 100% O2 prior to and following orbital insertion of the CEV and reduction of 

cabin PB to 8.0 psia with 32% O2 would be needed to avoid VGE formation, and would 

also ease the transition to the hypobaric and mild hypoxic environment during the early 

stages of μG adaptation. Two hours of PB would be effective to reduce the risk of VGE, 

thus removing one confounding condition that some suggest contributes to AMS. 

Breathing 100% O2 for 30 mins every 8 hrs for 2 days during early adaptation to μG may 

be effective to reduce the risk of AMS. Previous studies show the benefits of O2

breathing above and beyond the benefit through denitrogenation to reduce the risk of 

VGE. 

 Tucker (1983) shows that O2 prebreathing reduced sympathoadrenal sensitivity. 

If hypoxia-induced secretion of epinephrine (EPI) and norepinephrine (NOR) were 

reduced, the cardiovascular response to these hormones would be reduced. He observed 

less tachycardia and no increase in systemic blood pressure in those who breathed O2

(see Tucker’s figure 2 in this report). There was also more diuresis with the 

accompanying decrease in urine osmolarity. His observations were similar to those of 

Hesse (1981), who showed a decreased NOR response during 100% O2 breathing at sea 

level compared to breathing 21% O2. Hesse (1981) concludes that these data 

demonstrated a causal relationship between O2 and sympathetic nervous activity. During 

exercise, a reduced HR and plasma EPI concentration was additional evidence that the 

sympathetic nervous system was responding to 100% O2 breathing. It does appear that 

prebreathing O2 modifies some physiological responses to subsequent HH in the results 

from Tucker (1983) and Grover (1982). There was an improvement in pulmonary gas 

exchange implicating less VA/Q mismatching, plus antidiuresis was prevented. The 1.5 

 70
hr dose of O2 at sea level PB appears to have a protracted benefit for several hours, 

which makes it viable as a therapeutic intervention to reduce the risk of AMS. 

A concern with any decrease in PV, with or without an accompanying edema, is 

that the rheological properties of the blood will change, ultimately leading to impaired 

cardiopulmonary performance. So, a brief discussion about HCT and blood viscosity is 

provided. 

Viscosity is a property of fluid related to the internal friction of adjacent fluid 

layers sliding past one another as well as the friction generated between the fluid and the 

wall of the vessel. This internal friction contributes to resistance to flow. The viscosity 

of plasma is about 1.8 times the viscosity of water (termed relative viscosity) at 37° C 

and is related to the protein composition of the plasma. Whole blood has a relative 

viscosity of 3 to 4, depending upon HCT, temperature, and flow rate. 

HCT is an important determinant of blood viscosity. Figure 23 shows that as 

HCT increases, there is a disproportionate increase in viscosity. For example, at a HCT 

of 40%, the absolute viscosity is 2.3 centipoise. At an HCT of 60%, the viscosity is 3.7 

centipoise. Therefore, a 50% increase in HCT from a normal value increases absolute 

blood viscosity by 63%. Such changes in HCT and blood viscosity occur in patients with 

polycythemia. 

 71
Fig. 23. Increase in absolute viscosity of blood with an increase in HCT. A 63% 

increase [(3.75 – 2.30)/2.3] in absolute viscosity by a 50% increase in HCT from 40 to 60 

[(60 – 40)/40]. A second-degree polynomial curve fit for absolute viscosity as a function 

of HCT is: viscosity (centipoise) = 1.803 - 0.032 * HCT + ((1.071 * HCT2 )/1000). 

Temperature also has a significant effect on viscosity. As temperature decreases, 

viscosity increases. Viscosity increases approximate 2% for each °C decrease in 

temperature. This effect has several implications. For example, when a persons hand is 

cooled the increase in blood viscosity contributes to the decrease in blood flow, along 

with neural-mediated thermoregulatory mechanisms that constrict the vessels. 

Blood flow rate also affects viscosity. At very low flow states in the 

microcirculation, as occurs during circulatory shock, the blood viscosity can increase 

significantly. This occurs because at low flow states, there are increased cell-to-cell and 

protein-to-cell adhesive interactions that can cause erythrocytes to adhere to one another 

and increase the blood viscosity. 

An example is helpful to understand the optimal HCT for O2 transport per unit 

time by the circulation. The size, shape, and flexibility of RBCs are different for 

different species, and evolution has set an optimum ratio of RBC volume to PV to deliver 

O2 to the tissues. The optimal HCT for a camel is 27%, 32% for a sheep, and 47% for a 

man (Burton 1972). Figure 5-5 below from Burton (1972) shows the curves of relative 

viscosity versus HCT for a camel and a man in panel A and the rate of flow of HB 

through a glass tube with a constant driving pressure for a camel and a man in panel B. 

The highest HB flow is associated with the optimum HCT for each species. Crowell 

(1967), with a different methodology, places the optimal HCT for a man at 40%. 

 72
 

Papers by Martin (1986) and Neuman (1976) are helpful to understand the change 

in blood and plasma viscosity in relation to changes in HCT and plasma protein content. 

Results from Martin (1986) are shown in the next section as an introduction to the 

“typical” changes expected during NN extended 6-deg head down BR. 

Third Issue: Potential Integrated Response 

 There are hundreds of reports about HH without μG simulation, and hundreds of 

reports about μG simulation under NN conditions. But, the unfortunate reality is that 

there are fewer than 10 reports in the United States where the combination of HH and 

adaptation to μG were tested together. And in some of these reports, the degree of μG 

adaptation was limited to just hours on a tilt table, so have limited application here. The 

sum total are listed here in ascending chronological order: Stevens (1966), Lynch (1967), 

Waligora (1982), Fulco (1985), Loeppky (1990), Loeppky (1993a), Loeppky (1993b), 

and Whitson (1994). Two of these reports have minimal application here: (Loeppky 

(1990), Whitson (1994), since the μG simulation was from short-duration tilt table studies 

with subjects breathing a hypoxic mixture through a mask. 

 73
 Before providing a summary about these reports, it is helpful to understand the 

“typical” changes expected during NN extended 6-deg head down BR, as reported by 

Martin (1986). His figure 1 below is very descriptive. Data during BR 1 and BR 2 

intervals are from day 6 of a 10-day BR. The intervening control period was 14 days. 

 

 The data from Martin (1986) shows changes after 6 days of BR simply by taking 

an active person moving in a gravity field and making that person less active by placing 

them in 6-deg head down BR. Total plasma protein increased from 7.2 to 7.7 g/dl with 

the decrease in PV from 3,704 to 3,271 ml. HCT increased from 42.0 to 45.7%, and 

plasma viscosity increased from 1.32 to 1.39 centipoise after 6 days in the first 10-day 

BR period. Martin says that the increase in plasma fibrinogen from 324 to 396 mg/dl is 

greater than can be explained by hemoconcentration alone, so the increase in blood 

viscosity is without an enhancement of O2 carrying capacity that you would expect if the 

increase in HCT was due to new RBC production. The changes seen after 6 days in the 

second 10-day BR period after the intervening 14 days of recovery were similar to the 

first BR results. 

 74
 Martin (1986) was the first to directly measure changes in plasma viscosity during 

simulated μG, so a portion of his important Discussion is paraphrased here as follows: 

Viscosity of blood is a function of several factors: RBC concentration 

(HCT), plasma viscosity, RBC aggregation, and RBC deformability. HCT 

is the single most important determinant of blood viscosity. At a constant 

plasma viscosity and shear rate (vessel size and flow rate), an exponential 

increase in blood viscosity is observed with elevations in HCT. At an 

HCT of 20%, plasma viscosity is the primary determinant of blood 

viscosity. As shown in this study, there is a strong relationship between 

plasma viscosity and total plasma proteins, with fibrinogen having the 

greatest influence. Because of their marked axial asymmetry, fibrinogen 

molecules produce a greater hydrodynamic effect on fluid streamlines and 

influence plasma viscosity more than albumin and globulins. The final 

two determinants of whole blood viscosity, RBC deformability and 

aggregability were not directly measured in this study. RBC aggregability 

is dependent on shear rates, inter-cellular bridging by fibrinogen 

molecules as well as packing or closeness of the cells, a function of HCT. 

In vitro a 20% elevation in fibrinogen concentration results in elevations 

in RBC aggregability and whole blood viscosity of 70 - 85 centipoise at 

low shear rates (0.1 s-1). Thus, the increases in fibrinogen concentration 

and HCT we observed in this study should markedly elevate viscosity in 

low shear fields. Given the > 20% elevation in fibrinogen concentration 

and the 5 - 8% increase in HCT in this study, it is reasonable to suspect 

that RBC aggregability and whole blood viscosity in venous beds may 

have risen markedly in our volunteers during BR. This suggests a 

potential for increased venous stasis during BR. 

By way of introduction, and for economy of space, we list several related figures 

now that display summary data about the potential integrated response between HH and 

adaptation to μG. Figure 24 shows results from Stevens (1966) and Lynch (1967), figure 

25 is Waligora (1982), figure 26 is Fulco (1985), figure 27 is Loeppky (1990) and 

Whitson (1994), and figure 28 is Loeppky (1993a and 1993b). 

 75
Summary of Stevens (1966) and Lynch (1967) 

Results (chronic PAO2)

Normobaric, 

PB = 760 

mmHg 

Hypobaric, 

PB < 760 

mmHg 

Normoxic, PAO2

= 103 mmHg 

Hypoxic, PAO2 < 

103 mmHg 

PAO2 = 103 

PV = 2928, HCT 

= 43.6, RBC = 

2265, TBV = 

5193 

PAO2 = 58 

PV = 2318, HCT = 

50.9, RBC = 2396, 

TBV = 4716 

10,000 to 12,000 ft plus 

extended BR, use 

11,000 ft average for 

combined data. Data are 

from day 26. 

PV - plasma volume (ml) 

HCT - hematocrit (%) 

RBC – red blood cell volume (ml) 

TBV - total blood volume (ml) 

Fig. 24. Summary results from extended BR for 28 days in very young men (19 years old 

average). No difference in results from 10,000 ft and 12,000 ft exposures allowed the 

author to combine his data. He wanted to understand the benefit of lower body negative 

pressure to reverse the deconditioning effects of BR, and possibly the benefits of a HH 

exposure to counter the effects of BR. The study detected the expected changes in 

respiration and fluid redistribution and regulation associated with extended BR plus 

exposure to 3,353 m (11,000 ft) altitude (PAO2 = 58 mmHg). The issue was a potential 

negative synergistic effect of HH exposure and fluid redistribution during a 28 day 

simulated μG adaptation. There was no negative synergy over 28 days of exposure, 

which included modest exercise during BR. HCT increased from 44% to 51% over 28 

days. Hypoxia prevented the loss in RBC mass experienced in extended BR, but the 

augmented RBC mass induced by hypoxia was less than anticipated. So, Stevens 

suspected that BR interfered with the response to increased RBC mass by hypoxia. 

This study suggests that the proposed nominal CEV operating environment 

(16,000 ft with PAO2 = 77 mmHg) would be acceptable from an AMS perspective and 

increased blood viscosity perspective. HCT increased to 51% on average, with 54% at 

the extreme range. Lynch writes, “In the altitude subjects, headache of moderate severity 

 76
was not uncommon during the first 24 hrs of BR at simulated altitude, particularly in the 

12,000 ft groups”. This was at a time when AMS was not well characterized. In 

retrospect, it appears that an acute PAO2 = 54 mmHg at 3,657 m (12,000 ft) altitu

sufficient to precipitate AMS. 

de is 

 77
Summary of Waligora (1982) Results (acute PAO2) 

Normobaric, 

PB = 760 

mmHg 

Hypobaric, 

PB < 760 

mmHg 

Normoxic, PAO2

= 103 mmHg 

Hypoxic, PAO2 < 

103 mmHg 

PAO2 = 103 

HCT = 43 

PAO2 = 69 

HCT = 46 

8,000 ft on air plus 

head down tilt 

HCT - hematocrit (%) 

Fig. 25. Waligora’s (1982) summary results. The study detected the expected changes in 

respiration associated with an 8 hr exposure to 2,438 m (8,000 ft) altitude (PAO2 = 69 

mmHg). Waligora detected the expected changes in fluid redistribution seen in extended 

head down BR. The issue was a potential negative synergistic effect of HH exposure and 

fluid redistribution during a 28 hr simulated μG adaptation (6-deg head down BR). There 

was no negative synergy over 8 hrs of resting exposure with these 2 interventions; in 

particular, there was no difference in effective O2 transport across the lungs with the 

combination of stressors. HCT increased from 43% to 46% over 28 hrs in 6-deg head 

down BR; the control group started with 46%, and this did not change during 8 hrs at 

altitude. Hemoglobin O2 saturation decreased 6.8% in BR and 4.1% in control, PaO2

decreased 25.8 mmHg in BR and 27.4 mmHg in control (absolute value of 60 mmHg for 

the combined BR and control at altitude), and PaCO2 decreased 3.1 mmHg in BR and 5.5 

mmHg in control. The PEO2 - PaO2 difference was 20 mmHg for the combined BR and 

control at altitude. 

 CEV will be at a lower absolute PB of 4,876 m (16,000 ft) compared to this study 

at 2,438 m (8,000 ft), but PAO2 will be higher at 77 mmHg compared to 69 mmHg. If 6-

deg head down BR is a reasonable analog for early changes and adaptation to μG, then it 

is reasonable to expect, based on the observations from Waligora (1982), that negative 

synergy between HH exposure plus μG adaptation might not be anticipated for the CEV. 

 78
Summary of Fulco (1985) and Results (chronic PAO2) 

Normobaric, 

PB = 760 

mmHg 

Hypobaric, 

PB < 760 

mmHg 

Normoxic, PAO2

= 103 mmHg 

Hypoxic, PAO2 < 

103 mmHg 

PAO2 = 103, CO = 

5.7, TPR = 15.2, 

MAP = 83, HCT = 

42, HB = 15.1, TBV 

= 100, PV = 100, 

NOR = 227 

PAO2 = 48, CO = 4.6, 

TPR = 20.9, MAP = 

94, HCT = 48, HB = 

16.8, TBV = 90, PV = 

81, NOR = 334 

14,000 ft plus extended 

supine BR, used 60-deg 

head up tilt as challenge, 

1, 18, 66, and 114 hrs. 

Data from 114 hrs, 

except NOR at 66 hrs. 

PV - plasma volume (%) NOR - norepinephrine (pg/ml) 

HCT - hematocrit (%) CO - cardiac output (l/min) 

TBV - total blood volume (%) TPR - total peripheral resistance (mmHg/l/min) 

HB - hemoglobin (g/dl) MAP - mean arterial pressure (mmHg) 

Fig. 26. Fulco’s (1985) summary results. Changes show typical magnitudes for 

combined supine and HH, with no exacerbated negative synergy. Fulco hypothesized 

that pre-activation of the sympathetic drive through hypoxia-induced increased 

catecholamine release would decrease subsequent changes elicited by 60-deg head up tilt 

from supine position. This response should change as “adaptation” to supine and hypoxia 

continues from 1 to 114 hrs. With continued altitude exposure, the difference between 

supine and upright values for stroke volume, CO, TPR, and calf blood flow decreased. 

Less response to tilt at altitude was attributed to 10% less BV and a 40% increase in NOR 

release. There is an increased sympathetic (adrenergic) drive relative to parasympathetic 

(cholinergic, Vegas nerve) on exposure to HH as evidenced by increased catecholamines 

(Malhorta 1976, 1977), particularly NOR (Fulco 1988). Even mild hypoxia while 

breathing 15% O2 at sea level for 10 mins increases HR without a significant increase in 

respiration rate (Iwasaki 2006). 

 

 79
Summary of Loeppky (1990) Results (acute PAO2) 

Summary of Whitson (1994) Results (acute PAO2) 

Normobaric, 

PB = 760 

mmHg 

Hypobaric, 

PB < 760 

mmHg 

Normoxic, PAO2

= 103 mmHg 

Hypoxic, PAO2 < 

103 mmHg 

PAO2 = 75* 

SaO2 = 95.5, VA

= 5.69, PAO2 – 

PaO2 = 16 

PAO2 = 48 

SaO2 = 80.6, VA

= 6.18, PAO2 – 

PaO2 = 8 

14,828 ft with 13.9% O2

at 5,000 ft plus 28-deg 

head down tilt for both 

reports. Data from 51 

min into head down tilt 

from Loeppky. 

*See Note 5 at end of report. 

SaO2 - arterial blood oxygen saturation (%) 

VA - alveolar ventilation rate (l/min, BTSP) 

PAO2 – PaO2 - alveolar - arterial ppO2 difference (mmHg) 

Fig. 27. Loeppky’s (1990) summary results. Loeppky found no exacerbated reaction to 

the changes expected with 28-deg head down tilt and the changes expected with acute 

NH. The 2 combined conditions did not create any unexpected synergistic outcomes. 

 Short-duration 28-deg head down tilt is an extreme input to initiate fluid and 

hormone changes, and the addition of a hypoxic breathing mixture by mask adds another 

variable. But this type of experimental intervention is not similar to the conditions 

expected on the CEV, so these results have limited application here. Loeppky noted that 

there were no gross indications of pulmonary congestion or interstitial edema with this 

level of hypoxia in subjects who were pre-adapted to 1,649 m (5,400 ft). The increase in 

HR, decrease in SBP, DBP, MAP, increase in CO, and decrease in systemic resistance 

with NH and 60 mins of 28-deg head down tilt is different from what you expect from 

just NH or HH. The combination of stresses seems to decrease systemic resistance more 

than expected, such that Loeppky feels the risk of orthostatic intolerance is increased. An 

acute exposure to NH or HH is expected to increase sympathetic drive (Malhorta 1976, 

Fulco 1988, Iwasaki 2006). 

 80
 Whitson (1994) continues the work on ANP that Loeppky started. Loeppky 

(1993b) shows twice the ANP in a 5-deg head down BR after 4 days at 3,261 m (10,700 

ft) compared to altitude exposure without head down BR. HH decreases plasma renin 

activity and ALD levels (Bouissou 1989). Bouissou (1989) shows no change in ANP on 

initial exposure to 4206 m (14,000 ft) with a computed PAO2 = 48 mmHg. Whitson also 

shows an increase in ANP with NH and head down tilt. The acute exposure to NH did 

not significantly alter the ANP response to head down tilt, but suggested attenuation 

during the NH. 

 81
Summary of Loeppky (1993a and b) Results (acute PAO2) 

Normobaric, 

PB = 760 

mmHg 

Hypobaric, 

PB < 760 

mmHg 

Normoxic, PAO2

= 103 mmHg 

Hypoxic, PAO2 < 

103 mmHg 

PAO2 = 75*, HB 

= 16.5, HCT = 

47 

PAO2 = 59, HB = 

17.5, HCT = 49, PV = 

-5, PaO2 = 67 with HH 

HB = 19.0, HCT = 52, 

PV = -20, PaO2 = 62 

with HH + BR 

10,700 ft on air and 

HH plus head down 

tilt BR 

* See Note 1 at end of report. 

HB - hemoglobin (g/dl) 

HCT - hematocrit (%) 

PV - plasma volume (% from baseline) 

PaO2 - arterial oxygen partial pressure (mmHg) 

Fig. 28. Loeppky’s (1993a and 1993b) summary results. The study detected the 

expected changes in respiration associated with an 8 day exposure to a 3,254 m (10,678 

ft) altitude (PAO2 = 59 mmHg) with subjects pre-adapted to 1,646 m (PAO2 = 75 

mmHg). These results should be considered conservative since subjects exposed to 3,254 

m from sea level would be expected to show greater changes. The study detected the 

expected changes in fluid redistribution seen in extended head down BR. The issue was a 

potential negative synergistic effect of HH exposure and fluid redistribution during 8 

days of simulated μG adaptation (5-deg head down BR). HH plus head down BR did 

show an additive effect on changes over 8 days. 

 Changes associated with adaptation to mild hypoxia include an increased HB 

from 16.5% to 17.5%, an increased HCT from 47% to 49%, and a decrease in PV over 

the 8 days of about 5%. This compared to adaptive changes caused by mild hypoxia plus 

head down BR with an increased HB from 16.5% to 19.0%, an increased HCT from 47% 

to 52%, and an impressive decrease in PV over the 8 days of about 20%. He mentions 

from another study that the decrease in PV just from head down BR at sea level is about 

 82
10%. PaO2 in BR plus hypoxia after 7 days was 62 mmHg compared to 67 mmHg for 

hypoxia only. The PEO2 - PaO2 difference in BR plus hypoxia was 6 mmHg compared 

to 4 mmHg for hypoxia only. An elevated ANP and catecholamines together account for 

the enhanced fluid shift with head down BR during HH exposure. 

 Loeppky concludes that head down BR and HH exposure accentuated the loss of 

fluids and electrolytes and reduced PV. There were no negative impacts resulting from 

these fluid changes in terms of pulmonary mechanics or gas exchange, suggesting no 

evidence of pulmonary interstitial edema. He notes that symptoms of AMS were more 

prevalent, but not marked, and arterial blood gases and oxygenation were not seriously 

affected by the fluid shifts associated with adaptations to head down BR given that HH 

exposure was present. 

 CEV will be at a lower absolute PB of 4,877 m (16,000 ft) compared to this study 

at 3,254 m (10,678 ft) with subjects pre-adapted to 1,646 m (5,400 ft), but PAO2 will be 

higher at 77 mmHg compared to 59 mmHg in this study. It is assumed that extended 5-

deg head down BR is a reasonable analog for changes and adaptation to μG, so it is 

reasonable to expect, based on the observations from Loeppky (1993), that there would 

be no negative synergy between HH exposure plus μG adaptation anticipated for CEV. 

 The increase in HCT from about 42 to 45% during 10 days of 6-deg head down 

BR from Martin (1986) was similar to the increase from 43 to 46% for 6-deg head down 

BR after 28 hrs reported by Waligora (1982) with subjects exposed to 2,438 m (8,000 ft) 

altitude for 8 hrs, and the increase from 42 to 48% for supine subjects after 114 hrs at 

4,300 m (14,000 ft) reported by Fulco (1985). The results from Fulco (1985) are similar 

to Stevens (1966) and Loeppky (1993a, 1993b). They show increases from 43.6% to 

50.9% and from 47% to 52% when head down BR over many days was combined with 

HH from ascent to between 3,048 and 3,657 m (10,000 and 12,000 ft). It is important to 

note that the baseline data from Loeppky with 47% HCT are from subjects pre-adapted to 

living at about 1,524 m (5,000 ft), but the difference of 5% from the combined head 

down BR and HH is comparable to the 6% difference from Stevens (1966) and the 6% 

difference from Fulco (1985). 

 In summary, there is no obvious negative synergistic interaction between HH 

exposure with μG adaptation that appears across the experimental conditions in 6 

applicable reports. There was no test done under the specific conditions proposed for the 

CEV. In light of the limited research data, the good operational experience from the 10.2 

psia staged denitrogenation protocol from the shuttle is considered relevant to this 

discussion since it is close to the living environment proposed for the CEV. 

 83
Conclusions 

Quality and Quantity of Research Data 

Any factor that reduces crew health and performance should be minimized. But,

we now measure smaller changes with better instruments and, at the end of the day, are 

left to decide how much change is acceptable. There was not an abundance of data or 

even a small amount of data specific to our needs. There were only 4 reports about a PB

effect on the risk of AMS induced by HH, and 6 reports on the combined effects of HH 

and simulated μG adaptation that have some application here. The absence of 

information is not proof that a problem does not exist. So, all conclusions made here are 

based on extrapolation or interpolation from limited information. Knowing that you do 

not know something is often as important as knowing something. In this regard, it was 

verified, with confidence, that there is an absence of data specific to our needs. Even the 

small amount of best data is not directly applicable. Data from Roach, Loeppky, and 

Tucker are specific to subjects who lived for years at about 1,524 m (5,000 ft) altitude in 

New Mexico and Colorado prior to tests conducted at 3,261 and 4,572 m (10,700 and 

15,000 ft). Changes associated with these tests are certainly less than expected if applied 

to subjects who ascend from sea level to 4,572 m (15,000 ft) altitude. In addition to the 

lack of applicable data, there is also a lack of data for women exposed to HH, to 

simulated μG adaptation, and to the combination of HH and simulated μG adaptation. 

There are extensive data, not summarized here, about good outcomes from ascent 

to altitude while breathing 100% O2. The Apollo and Skylab missions, as well as 

associated ground-based validation and baseline data collection, showed that weeks to 

months could be spent at an altitude of 27,000 ft (5.0 psia) while breathing 100% O2

(Apollo) or 70% O2 (Skylab), certainly without gross indications of hypoxic stress in 

astronauts adapting to μG. So, it appears that as long as normoxic or slight hyperoxic 

conditions are maintained, the absolute ambient PB is a secondary concern. It is only 

when a hypoxic condition is combined with a hypobaric condition that an ambient PB

become a concern. 

 All the reports here used 21% O2 in air plus hypobaric PB or less than 21% O2 at 

site PB to achieve a degree of hypoxia. It is important to point out that the atmosphere – 

one that is mildly hypoxic to reduce the risk of fire - proposed for the CEV, LSAM, and 

long-duration surface habitats will be enriched with O2 to between 30 and 34%. This 

method to produce HH may have some net advantage to the body than by producing the 

same HH using 21% O2 in air. But, there is an absence of data to evaluate hypoxia 

produced through the combination of enriched O2 (>21%) under hypobaric conditions 

(PB <760 mmHg). If the effort is made to enrich the breathing gas with O2, then the goal 

is often to provide a normoxic environment, such as was done with the breathing 

environment for Skylab. 

 84
There is one example where mild hypoxia is produced through the combination of 

enriched O2 (>21%) under hypobaric conditions (PB <760 mmHg) and has been used 

with hundreds of subjects over several days, with and without adaptation to μG. These 

data are from the ground testing and good operation experience of the shuttle staged 

denitrogenation protocol. The data are marginally applicable here since good operational 

experience is not equivalent to quality research data, and the shuttle conditions are not 

identical to those currently planned for the CEV and beyond. Subjects in an altitude 

chamber and later astronauts on the shuttle spent hours to days at 10.2 psia (10,000 ft) 

breathing 26.5% O2 as a means to partially denitrogenate body tissues prior to 

depressurization to 4.3 psia with 100% O2. The PAO2 is computed at 85 mmHg during 

the staged protocol, which is equivalent to breathing air at 1,219 m (4,000 ft) if we 

discount the current discussion about the validity of applying the idea of an EAA 

exposure. The point is that the good testing and operational experience with this protocol 

suggests that there is no significant negative synergy between very mild HH and μG. But, 

it is an extrapolation to conclude anything about the worse case PAO2 of 68 mmHg at 

5,029 m (16,500 ft) in astronauts adapted to μG in the CEV based on the literature 

reviewed for this report. 

It is unlikely that being restricted to the fourth box in the PB and O2 exposure 

matrix (see figure 20 for example) will provide enough difference in exposure conditions 

to show a difference in AMS outcomes given the same PAO2 but different ambient PBs. 

The shuttle and future habitat atmospheres are contained in this fourth box. With 10.2 

psia PB and 26.5% O2 on the shuttle, the ppO2 is 140 mmHg with PAO2 = 85 mmHg 

from the AOE. For the proposed nominal CEV, LSAM, and moon habitat an 8.0 psia PB

and 32.0% O2 the ppO2 is 132 mmHg with PAO2 = 77 mmHg from the AOE. These 

conditions are close to an ascent on 21% O2 to 11.8 psia. Since AMS signs and 

symptoms do not begin at less than 11.5 psia (6,500 ft, ppO2 = 125 mmHg with PAO2 = 

75 mmHg from the AOE), it is unlikely that anyone on the shuttle will experience AMS. 

The conditions on the CEV, especially the worse case extreme of the control box for the 

life support system, could drop PAO2 to about 68 mmHg. 

 Although initial signs and symptoms of AMS in susceptible subjects are expected 

after prolonged exposure to between 2,000 m (6,600 at PAO2 = 75 mmHg) and 2,590 m 

(8,500 ft at PAO2 = 67 mmHg), it is likely that these would be self-limiting once 

acclimatization proceeds (Roach 1998). Roach (1996) and Tucker (1983) have the best 

data from which to conclude that AMS is very likely for some people who are exposed to 

4,572 m (15,000 ft) with a PAO2 of about 45 mmHg and who are pre-adapted to living at 

1,524 m (5,000 ft). Therefore, at 8.0 psia (4,877 m or 16,000 ft) with a nominal PAO2 = 

77 mmHg in astronauts not pre-adapted to living at 1,524 m altitude, it is likely that 

susceptible astronauts simultaneously undergoing adaptation to μG (Loeppky 1993a and 

1993b) will experience the signs and symptoms of AMS. It is unlikely that a clinically 

significant increase in HCT will occur. A transient increase to a mean HCT of about 

50%, possibly as high as 55% in a particular crewperson, would be predicted based on 

 85
the data (Stevens 1966, Loeppky 1993a, 1993b) for the combined effects of HH and 

adaptation to μG as envisioned for the CEV program. However, typical μG adapted 

spaceflight HCT values are in the low normal range, from 36 to 40% depending on 

gender. 

 There are several examples where the physiological changes initiated by HH and 

adaptation to μG are in opposite directions. Therefore, the net effect is a blunted 

response when both conditions occur simultaneously. For example, HH increases 

sympathetic drive through the release of catecholamines (Fulco 1985, 1988, Malhotra 

1976, 1977) while supine or head down BR reduces sympathetic drive (Volicer 1976). 

HH increases RBC mass that is opposite the decrease seen in extended BR and exposure 

to μG (Alfrey 1996). Some even propose that the compensations for HH provide a 

beneficial therapy for cardiovascular deconditioning associated with extended BR (Lamb 

1965, Lynch 1967, Shvartz 1990). One example for a negative synergy is a possible 

enhanced reduction of the ventilatory response to hypoxia. The classic response to 

hypoxia is to increase VE, but the increase is slightly less if the hypoxia is caused by a 

hypobaric exposure compared to the same hypoxia caused in a normobaric condition 

(Savourey 2003). Prisk (2000) shows a reduction in ventilatory response to hypoxia in 

normocapnic subjects during supine and μG exposure compared to standing subjects. 

The notion is that increase in blood pressure due to body position modifies the ventilatory 

response to hypoxic challenge. The 2 studies are not directly comparable, but this may 

be a case where HH and adaptation to μG lead to a greater reduction in ventilatory 

response to hypoxia that either in isolation would cause. This is not an ideal situation if 

the goal is to avoid AMS associated with a suppressed ventilatory response to hypoxia. 

Rahn (1954) shows that hyperventilation on standing after being supine increases PAO2

as PACO2 drops from about 42 mmHg to 37 mmHg in response to the hyperventilation. 

So, body position modifies PAO2, and it is unclear how μG influences PAO2, given that 

body position is irrelevant. Finally, you can argue from the work of Loeppky (1993a and 

1993b) that HH and μG simulation produced changes that are additive. He shows an 

additional loss of PV, with an additional increase in HB and HCT given a PAO2 = 59 

mmHg at 3,261 m (10,700 ft) altitude in subjects exposed 8 days to 5-deg head down BR 

compared to the loss of PV and increase in HB and HCT in subjects just exposed to 3,261 

m altitude. On balance, there is no definitive evidence for an exaggerated (negative 

synergistic) response to the combination of HH and adaptation to μG. On the contrary, 

the limited evidence suggests that one stressor tends to counteract the other. 

 All events associated with the CEV mission to the moon are on a short time scale 

compared to the weeks and months needed to achieve a new steady state adaptation. So, 

physiological compensation, accommodation, or acclimatization processes are underway 

in the CEV immediately after orbital insertion, on the way to the moon, during EVA on 

the moon, and during the return to Earth over a 10 to 15 day mission. It is unclear how 

the cyclical pattern of mild hyperoxia (EVA environment) and mild hypoxia (habitat 

environment) caused by an ambitious EVA schedule on the moon would influence 

physiology. The up and down regulation of various antioxidant enzyme systems due to 

the changing ppO2 may exhaust the ability to scavenge reactive O2 species. 

 86
 Individual susceptibility to μG adaptation in a HH environment will likely play a 

role in mission success (including an absence of medical problems) in these short-term 

missions with high EVA-rate scenarios. Some peak performance degradation could be 

expected in crewmembers if ppO2 is reduced acutely to less than 2.8 psia until 

compensation occurs. The magnitude of the performance affect will depend on the ppO2, 

the metabolic demands of the task, and individual (genetic) factors. The current 

threshold for mandatory supplemental ppO2 during spaceflight operations is 2.2 psia. 

For lunar outpost missions (approximately 6 months surface stays), full acclimatization to 

reduced ppO2 can be expected after 30 to 45 days, allowing crews to function at high 

performance levels in the face of reduced O2 tension. Figure 29 is a plot of several tests 

in this report by the test altitude and computed PAO2 compared to the position of 

successful NASA human space programs and the proposed CEV program. 

 87
Fig. 29. Plot shows the position of several tests in this report by the test altitude and 

computed PAO2 compared to the position of successful NASA human space programs 

and the proposed CEV program. Solid circles connected by the curve are studies done 

where HH was induced by ascent to altitude on air, but are HH exposures without 

simulated μG. The open boxes are exposures where μG adaptation through simulation or 

actual exposure is present as part of the HH. The 2 least stressful points along the curve 

at 6,000 and 7,000 ft are from Ge (2002) where he shows a slight increase in plasma EP 

concentration. The third point at 8,000 ft from Ge (2002) is within the open box from 

Waligora (1982). Ge showed a substantial increase in plasma EP concentration at this 

altitude after 24 hrs. Waligora had subjects in 6-deg head down BR for 28 hrs with 8 of 

the hours spent at 8,000 ft. No differences were noted that could not be attributed to 

those expected for acute exposure to 8,000 ft and those attributed to acute head down BR. 

The most stressful point along the curve is from Levine (1988) and his work with sheep 

that produced significant pulmonary edema. If you accept that mission-impact AMS 

after hours of exposure to HH can start at altitudes between 2,000 and 2,590 m (6,600 

and 8,500 ft) (Roach 1998) given a mean PAO2 of 71 mmHg for 2,286 m (7,500 ft), then 

the question to ponder is whether the risk of AMS dramatically increases in the CEV 

given a worse case PAO2 of about 68 mmHg, and with an additional 2,743 m (9,000 ft) 

altitude (5,029 – 2,286 = 2,743 m) in astronauts adapting to μG. 

 88
Risk Mitigation Plan 

 There is no single study that addresses the exact conditions for the proposed 

nominal Constellation vehicle environment: adaptation to μG with a breathing 

environment at 8.0 psia (16,000 ft altitude) with 32% O2 and 68% N2, resulting in an 

acute PAO2 of about 77 mmHg. Therefore, the recommendations that follow are not 

only based on extrapolations and judgment from an exhaustive literature review, but also 

from tests that differ from the proposed CEV, LSAM, and long-duration surface habitat 

environments. No global mechanism yet exists to describe the observations from these 

experiments, so you cannot predict changes expected for CEV based on an understanding 

of a mechanism that describes the empirical data. So, uncertainty prevails; and at least 7 

options are offered as part of an integrated risk mitigation plan: 

Accept a conclusion based on a literature review that no significant negative 

synergistic interaction between HH exposure with μG adaptation is expected for the 

proposed CEV environment. Any AMS signs and symptoms would be mild, and 

transient. 

Develop the rationale and procedures to easily increase ambient PB plus use 

medications such as prophylactic or, as-needed, AZ, dexamethasone, and 

supplemental O2 to reduce AMS risk or provide effective treatment if required. 

Caution is warranted here for several reasons: AZ may be prescribed for diagnosed 

AMS when, in fact, the signs and symptoms are from motion sickness. Or, 

medication for motion sickness may be incorrectly prescribed for AMS. AMS and 

motion sickness share many of the same signs and symptoms, and may appear along a 

similar time course. Often sleep medication is prescribed due to the many 

distractions in a small space vehicle. However, sleep medications may be 

contraindicated if AMS is suspected. A sleep medication would likely worsen the 

signs and symptoms of AMS. 

Consider preflight testing to identify astronauts who are susceptible to atmospheric 

changes in the CEV environment, and provide special training and risk mitigation 

plans for those who are identified as susceptible, versus reassignment to a different 

mission. 

Pre-adapt crews to a hypoxic environment, either NH or HH, prior to launch to blunt 

any combined negative effects of HH exposure with μG adaptation shortly after 

launch. But, this intervention to reduce the risk of AMS is contraindicated if the 

resulting increase in HCT significantly adds to the increased HCT transiently 

observed during the acute phase of μG adaptation, possibly leading to impaired 

circulation and O2 delivery. Consider phlebotomy, if warranted. 

Develop an acclimatization plan through the gradual reduction in PAO2 during the 

initial phase of the mission, which should significantly reduce the likelihood of AMS 

signs and symptoms. 

 89
In addition to 100% O2 PB to prevent VGE on initial depressurization to 8.0 psia in 

the CEV, consider a plan to breathe 100% O2 by mask over several intervals of time 

during the acclimatization to the μG plus HH exposure. Breathing 100% O2 is shown 

to blunt the negative physiological effects of subsequent HH exposure. 

Perform a 5-day study in 10 subjects representative of the astronaut corps simulating 

the extreme control box environmental parameters of the CEV (7.8 psia with 30% 

O2, PAO2 = 68) plus a head down BR analog for μG adaptation after a 2-hr O2 PB. 

Collect some or all of the following measurements to characterize the risk of AMS: 

• Hematology: HCT, RBC mass, plasma globin, HB, plasma EP, total plasma 

protein, plasma albumin, plasma fibrinogen, PV 

• Endocrinology: ADH, ANP, ALD 

• Renal: Fluid intake, urine output 

• Serum and Urine Electrolytes: Na+, K+, Ca++, Cl-, PO4-, H+ (pH) 

• Performance measures: AMS score, visual acuity, 75% VO2 max 

• Pulmonary: Oximetry for SaO2 (expect about 93% saturation), PaO2, PaCO2, 

PAO2, PACO2, ETPO2 and ETPCO2, Vt (l/min, BTPS), VE (l/min, BPTS), 

breathing frequency, a measure of pulmonary edema, a measure of effective O2

transport, i.e., PAO2 - PaO2

• Compute VA/Q, alveolar and physiological deadspace 

• Cardiovascular Measures: Stroke volume, HR, SBP, DBP, CO via 

echocardiography, and ECG 

• Body Weight 

• Other: Precordial VGE monitoring with a Doppler ultrasound bubble detector, or 

transthoracic echocardiography 

 90
Notes 

1. Roach and Loeppky performed their extensive research on AMS at the University of 

New Mexico in Albuquerque. The average PB in this city is 630 + 10 mmHg, or 

equivalent to an altitude of about 1,524 m (5,000 ft); they quote closer to 1,646 m (5,400 

ft). So, physiological changes for subsequent HH, NH, or HN exposures, when compared 

to other studies that started at sea level, must be considered “conservative”. Their 

observations are conservative since subjects were pre-adapted to living at about 1,524 m 

(5,000 ft) before the experiment began. 

2. Tucker performed his research on AMS at Colorado State University in Fort Collins. 

The average PB in this city is 632 mmHg, or equivalent to an altitude of about 1,524 m 

(5,000 ft). So, physiological changes for subsequent HH, NH, or HN exposures, when 

compared to other studies that started at sea level, must be considered “conservative”. 

His observations are conservative since subjects were pre-adapted to living at about 1,524 

m (5,000 ft) before the experiment began. 

3. Levine performed his research in Matsumoto, Japan. The average PB in this city is 

708 mmHg, or equivalent to an altitude of about 579 m (1,900 ft). 

4. Savourey performed his research in La Tronche, France. The average PB in this city 

is 733 mmHg, or equivalent to an altitude of about 305 m (1,000 ft). 

5. Loeppky and Whitson did their research at the University of New Mexico in 

Albuquerque. The average PB in this city is 630 ± 10 mmHg, or equivalent to an altitude 

of about 1,524 m (5,000 ft). So, physiological changes for subsequent NH exposures, 

when compared to other studies that started at sea level, must be considered 

“conservative”. Their observations are conservative since subjects were pre-adapted to 

living at about 1,524 m (5,000 ft) before the experiment began. 

 91
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Appendix: Standard Atmosphere 

 When breathing an atmosphere that does not contain 20.9% O2, it is helpful to 

estimate the EAA since most experience with hypoxia is with ascent to altitude while 

breathing air (FIO2 = 20.9%). With a given PAO2 from the AOE one can consult a 

published “altitude table”, like the one reproduced here from DeHart (1996) to find the 

altitude while breathing air that corresponds to the acute PAO2 value, regardless of the 

combination of PB and FIO2 that is used to achieve the value. 

 

 98
 Notice that to achieve a normoxic PAO2 of about 103 mmHg, a person can 

breathe 100% O2 at 10,058 m (33,000 ft). However, the ambient ppO2 must be about 

200 mmHg compared to 160 mmHg at sea level to achieve this equivalency. This is due 

to the greater contribution of water vapor pressure toward total pressure as pressure is 

reduced. The PIO2 defined as (PB - 47) * FIO2 is 150 mmHg in the first case and 149 

mmHg for the second case. So to use this table to determine the EAA you must first 

compute PIO2 for the breathing gas where FIO2 ≠ 0.209, and then find the PIO2 that 

corresponds to your computed value. Unfortunately, the table above does not show 

PIO2, only ppO2. So, you must compute several PIO2s from the PBs and the FIO2 of 

0.209 until you find the PIO2 that matches your PIO2. For example, the PIO2 for 

breathing 32% O2 at 413 mmHg (about 16,000 ft altitude) is (413 - 47) * 0.32 = 117 

mmHg. Through trial and error you find that the entry for an EAA of 6,000 ft gives a 

PIO2 of 118 mmHg [(609 - 47) * 0.209 = 118 mmHg], so you conclude that breathing 

32% O2 at 16,000 ft altitude is equivalent to breathing air at 6,000 ft altitude. 

 Since the AOE accounts for water vapor pressure, you can also use this equation 

to compute PAO2 and find the corresponding PAO2 in the above table to determine the 

Equivalent Air Altitude. Using the same example, the Alveolar Oxygen Equation 

computes a PAO2 of 77 mmHg given the PACO2 of 37 mmHg, the RER of 0.88, the PB

of 413 mmHg, and the FIO2 of 0.32. The PAO2 of 77 mmHg is compared to the 77 

mmHg seen in the table, so you once again conclude that breathing 32% O2 at 16,000 ft 

altitude is equivalent to breathing air at 6,000 ft altitude. 

 A final caveat. A large portion of this report evaluates results from tests where 

PIO2 or computed hypoxic PAO2 were very similar between 2 tests with different PBs. 

Two assumptions are that identical hypoxic PIO2 or PAO2, computed between 2 

different tests, results in an equivalent hypoxic response, and that computed PAO2 is the 

correct PAO2 experienced by the subjects. So, if an equivalent hypoxic response is not 

observed, and we accept the 2 assumptions, it follows that the differences in hypoxic 

response must be linked to something in addition to a reduced PAO2. But, Rahn (1954, 

1956) shows us that PAO2 is extremely dynamic, even when people change posture, 

certainly when they go to altitude, when they change the composition of the breathing 

gas, if they exercise, if they stay for short or long periods at altitude, etc. And then, there 

is individual variability in how the CNS in conjunction with the respiratory system reacts 

to mild hypoxia, both during an acute and chronic exposure. So, the caveat is to consider 

computed PAO2 as a “best estimate” not as an absolute. Always consider the possibility 

that there is a true difference in PAO2 in 2 experiments that purport to be equivalent 

hypoxic exposures when identical PIO2 or computed PAO2 are offered as evidence of 

their equivalency. 

 

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 January 2008 NASA Technical Paper 

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Risk Assessment of Acute Mountain Sickness in the Crew Exploration Vehicles 

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Johnny Conkin, Universities Space Research Association 

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Lyndon B. Johnson Space Center 

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13. ABSTRACT (Maximum 200 words)

To limit the risk of fire and reduce the risk of decompression sickness and prebreathe time to support frequent activities on the moon 

and Mars, a hypobaric and mildly hypoxic living environment is considered for the Crew Exploration Vehicle, Lunar Surface Access 

Module, and long-term surface habitats. Superimposed on physiological adjustments to living in a hypobaric hypoxia (HH) 

environment are those associated with adaptation to microgravity (μG). Outward manifestations of physiological adaptations may 

present as signs and symptoms of Acute Mountain Sickness (AMS). The signs and symptoms of AMS are undesirable, as they would 

impact crew health and performance. A literature review suggests that: (1) there is an absolute pressure effect per se on AMS, so the 

higher the altitude for a given computed hypoxic alveolar oxygen (O2) partial pressure (PAO2) the greater the AMS response; (2)

about 25% of adults would experience AMS near 2,000 m altitude; (3) there is no direct evidence that HH synergizes with adaptive 

changes during simulated μG to dramatically increase hematocrit and blood viscosity, and (4) only susceptible astronauts would 

develop mild and transient AMS with exposure to 8.0 psia (16,000 ft) while breathing 32% O2 and simultaneously adapting to μG. 

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decompression sickness, extravehicular activity, Crew Exploration Vehicle; Lunar 

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