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Detection of endogenous gas phase formation in humans at
altitude
by Dr. Jolie Bookspan, PhD

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Bookspan, J. Detection of endogenous gas phase formation in humans at altitude. Medicine & Science in Sports & Exercise Suppl. Vol. 35, Num 5, May
2003 # 901, p S164.

DETECTION OF ENDOGENOUS GAS PHASE FORMATION IN HUMANS AT ALTITUDE
Investigators   
Jolie Bookspan, Ph.D.   Research Associate, Institute for Environmental Medicine (IFEM) University of Pennsylvania School of Medicine
G. Golden Bell Labs.

ABSTRACT
That endogenous gas bubbles form after decompression from saturation at depth appears to be well founded. Data from preliminary work for this study (1) suggest the decompression required to produce bubbles in 50% of male subjects is from air saturation at only 10 fswg. Extrapolation to altitude suggests that pressure reductions commonly attained in commercial and military aircraft may be sufficient to form a gas phase in humans. We examined the magnitude and duration of gas phase production in human male volunteers at altitudes up to 10,000 feet in an altitude chamber to establish a dose response relationship between bubble formation and hypobaric exposures using Doppler ultrasound. This study has the benefits of identifying potentially preventable decompression stress during flying after diving in what is often considered routine cabin pressures. Individual factors that predispose to bubble formation were examined. The data may be applicable to flying after diving schedules.

 INTRODUCTION
Delaying flying after recreational diving is an important issue requiring more objective data. That gas bubbles form in the body after decompression from saturation at depth is well founded. Recent data from preliminary work for this study by co-investigator of previous work Eckenhoff showed bubbles in 50% of male subjects after decompression from saturation in an underwater habitat at only 10 feet (fswg). Extrapolation to altitude suggests that pressure reductions commonly attained in commercial and military aircraft may be sufficient to form a gas phase in humans. Air travel routinely exposes passengers to ambient pressure transients. Work in decompression during undersea operations has established that these pressure changes may produce small, mostly inert gas bubbles which become widespread throughout tissues and blood. It was previously thought that bubbles would not form unless a specific supersaturation ratio of tissue pressure to ambient pressure was exceeded.  However, detectable gas phases develop in humans after surprisingly small decompressions (1,2).  Since this small decompression is substantially less than previously thought required for these gas phases to evolve (3,4) it is possible that humans have stable pre-existing gas spaces (5, 6) which with reduced pressure, enlarge according to Boyle's Law and bud-off bubbles into the tissues and blood stream.

Inert gas bubbles are generally accepted as the mechanism behind decompression sickness (DCS), also called dysbarism or bends. Manifestations of DCS range from itching to death, although more often the gas phase is asymptomatic (silent bubbles) or noticeable only as fatigue. Long term exposure to silent bubbles may be associated with health risks in commercial divers such as osteobaric necrosis.  Conditions analogous to decompression from undersea are encountered in altitude exposure.  Grover et al. (7) considered bubble formation a factor in acute altitude sickness. Significant and ongoing work done in this area by Eckenhoff (1,2) suggests that a gas phase may form at pressure reductions commonly attained in commercial and military aircraft, a prediction consistent with a recent case report of DCI occurring after decompression to 8000 feet (8), but no study has examined if this extrapolation is valid. We examined the magnitude, duration, and latency of gas phase production in human male volunteers at (chamber) altitudes of 2000 to 14,000 feet to establish a dose response relationship between hypobaric exposure and bubble formation.

STATEMENT OF PROBLEM
No study to date has examined gas phase formation at routine flight altitudes.  The purpose of the study is to identify the magnitude and duration of gas phase production at altitude to establish a dose response relationship between bubble formation and hypobaric exposures using Doppler ultrasound.


OBJECTIVES
-    To establish if tissue bubbles form in humans at altitude, and gather information toward developing a dose-response curve.

-    To gather information toward developing a dose-response curve. This curve can be applied to information regarding flying after diving schedules.

-    To identify individual factors which predispose to tissue bubble formation at altitude
-    Elimination or modification of bubble production, a known health risk, using a physical or pharmacologic approach is a long range goal of this research.


SIGNIFICANCE OF THE PROJECT
The expected dose response curve will help identify acceptable schedules of flying after recreational diving, as well as potentially preventable decompression stresses during flying after diving for all divers. This study was the first to investigate gas phase formation with exposure to routine flight altitude. 

 DESCRIPTION OF EXPERIMENTAL WORK
Human subject approval was obtained. Subjects were recruited from the general population with no restriction on age or physical stature.  Physical examination by a physician familiar with diving medicine was required before exposures.  Subjects were free of hyper or hypobaric exposures for three days prior to exposure.
Decompression to altitude from one atmosphere was studied at the Institute For Environmental Medicine (IFEM) altitude chambers at the University of Penn School of Medicine. Subjects were divided randomly into groups and exposed to hypobaric conditions from 4000 to 10,000 ft. (1000 ft increments). At each altitude Doppler ultrasound (9,10) was used to detect a mobile gas phase at several venous sites over each twelve hour run. Dose response relationships were constructed and contrasted to results from simpler systems (in vivo and in vitro IFEM counter diffusion model) and differences will be used as the basis for future studies. Data from many human subjects will allow correlations between outcome of the Doppler monitoring and age, gender, height, weight, body fat, previous injuries, etc.  Preliminary data from Eckenhoff (11) on 170 subjects showed a significant correlation between age and bubbles but not between weight, body fat or gender and bubbles. Individual factors that may predispose to bubble formation (age, gender, height, weight, body fat, previous injuries, etc.) will be examined. The chamber system is certified for safety by the Naval Facilities Engineering Command under NAVMAT P-9290 and has been under continuous certification since 1975.

CONSTRAINTS AND RISKS
Potential hazards to investigative staff and subjects are those ordinarily encountered in work involving reduced ambient pressures including decompression sickness and ear and other air space equalization problems. Risk of air embolism from lung barotrauma is greatly reduced by breathing normally and continuously at all times. Although decompression sickness is possible the relatively low pressure reduction makes the likelihood remote.

 RESULTS
We found bubbling in 75% of male subjects at 10,000 feet which is sometimes reached as an equivalent cabin pressure in commercial air flights, and is routinely achieved in unpressurized passenger flights and some military aircraft. The rate of ascent was found to relate to diving decompression stops. The data may be applicable to flying after diving schedules and may contribute to understanding of a bubble component to altitude sickness.

MORE STILL TO DO
From this preliminary work we make the tentative conclusion that civilian airline cabin pressure may be sufficient to form a gas phase in humans, even with no prior diving. It is hoped to continue this study with additional runs from 2,000 to 12,000 to establish a dose response relationship between altitude exposure at airplane cabin pressures and bubble formation.

In a previous study we did with 170 subjects coming up from saturation underwater we found a relationship between age and bubbles. That may not mean that getting older causes more bubbles, but that older subjects tended to bubble more than younger subjects for reasons we don¹t yet know. The dividing age for 'older¹ was age thirty. We didn¹t find any trends between weight, body fat, or gender and bubbles. That means we didn¹t find any bubble difference between larger or smaller subjects, fatter or thinner, or between females and males. Another question is why some people are more likely to form bubbles than others.  Are things like age, gender, height, weight, body fat, and previous injuries really predisposing factors? Predisposing factors are important to know about, but little is yet known.
This work will add important information to the flying after diving puzzle.
Thanks to Dr. Peter Bennett and 'The Recreational Diving Research Foundation' for funding this work.


LITERATURE CITED
1.    Eckenhoff RG, Olstad CE, Carrod GE. Human dose response relationship for decompression and endogenous bubble formation. J Appl Physiol
69:914-918, 1990.
2.    Eckenhoff RG, Osborne SF, Parker JW, Bondi KR. Direct ascent from shallow air saturation exposures. Undersea Biomed Res 13:305-316, 1986.
3.    Weathersby PK, Homer LD, Flynn ET Homogeneous nucleation of gas bubbles in vivo. J Appl Physiol  53:940-956, 1982;
4.    Yount DE & Kunkle DE. Gas nucleation in the vicinity of solid hydrophobic spheres. J Appl Physiol  46:4484-4486, 1975.
5.    Evans A & Walder DN. Significance of gas micronuclei in the aetiology of decompression sickness. Nature 222:251-252, 1969.
6.    Tikusis P. Modeling the observations of in vivo bubble formation with hydrophobic crevices. Undersea Biomed Res 13:165-180, 1986.
7.    Grover RF. Tucker A & Reeves JT.  Hypobaria: an etiologic factor in acute mountain sickness?   in: Loeppky JA & M.L. Riedesl (eds.) Oxygen Transport to Human Tissues. New York: Elsevier/North Holland, 1982.
8.    Rudge FW. A case of decompression sickness at 2437 meters (8000 feet). Aviat Space Environ Med 1990; 61:1026-7.
9.    Kisman KE & Masurel G. Bubble evaluation code for Doppler Ultrasonic decompression data. Undersea Biomed Res 5:A28,1978.
10.     Spencer MP. Decompression limits for compressed air determined by ultrasonically detected blood bubbles. J Appl Physiol  40: 229-235,1976.
11.    Eckenhoff RG, Olstad CE. Gender effect on venous bubble formation after decompression from prolonged 16 fswg exposures. Undersea Biomed Res
(abstract).