RESPONSE TO LBNP STRESS

GND=Ground; ALT=Altitude

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2
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=
Oo
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Figure 14. Plots of diastolic middle cerebral artery flow velocity between rest and peak LBNP at
ground and altitude in tolerant and intolerant subjects.

At altitude, tolerant and intolerant subjects had simi-
lar resting heart rates (84 + 17 vs 72 + 15, P=ns) and
systolic blood pressures (133 + 17.4 vs 125 + 18.2, P=ns).
At peak exercise, significant differences were found be-
tween heart rates (136 + 18.7 vs 111 + 14.2, P< .001),
and systolic blood pressure (190 + 22 vs 156 + 27, P<
-001) in tolerant and intolerant subjects, probably re-
flecting the prevalence of beta-blockers in the intolerant

group.

Transcranial Doppler Responses (Table V)

A. Tolerance to lower body negative pressure

The transcranial Doppler flow velocity in the middle
cerebral artery was indexed by the peak systolic velocity
(Figure 13), diastolic velocity (Figure 14), the mean
velocity (Figure 15), and the systolic to diastolic velocity
ratio (Figure 16).

These 4 parameters were measured at rest and at 2
minute intervals as lower body negative pressure pro-
gressed,


SVR RESPONSES
beta blocked vs placebo
-~ 1600
fe)
| oO P
€ 15004
Oo es
*
14004 oT
& GROUND,
3% 13004 A
— ALTITUDE ee
1200 “a
cw 1100 a8
A
1000 + +
REST PEAK

Figure 7. Group mean systemic vascular resistance (SVR) responses are plotted between rest and peak lower
body negative pressure at ground andataltitude. Both placebo and beta-blocked subjects had arise in systemic
vascular resistance between rest and peak tolerated lower body negative pressure at ground, but at altitude

the resistance fell (P=ns).

Ataltitude, resting values for heart rate were higher in
both beta-blocker and placebo-controlled subjects, com-
pared to those at ground (62 + 7.8 and 82 + 15.8 vs 67
+6.5 and 88 + 13.4, P=ns both). Values for mean arterial
pressure were similar to ground measurement (91 + 9.5
and 104 + 11.6 vs 92 + 10.6 and 103 + 12.5). Stroke
volume values were higher at altitude for both groups,
compared to stroke volume at ground (74 + 19 and 61 +
19 vs 100 + 26 and 84 + 27, P< .001 both).

Asa result, systemic vascular resistance was lower at
altitude for both groups, compared to ground measure-
ments (1,368 + 317 and 1,418 + 365 vs 1,203 + 384 and
1,294 + 502, P=ns both). With the stress of lower-body
negative pressure, the placebo-treated group had a rise in

heart rate (88 + 13.4 to 98 + 17.1, P=ns), a fall in mean
arterial pressure (103 + 12.5 to 94 + 16.4, P=ns), anda
fall in stroke volume (84 + 27 to 76 + 34, P=ns). These
parameters caused an insignificant decline in systemic
vascular resistance to peak tolerated lower body negative
pressure, and this peak value was lower than correspond-
ing measurements at ground (1,294 + 502 to 1,182 +
445, P=ns). Beta-blocked responses showed similar trends
in heart rate (66 + 6.5 to71 + 5.7, P=ns), arterial pressure
(92 + 10.6 t0 84 + 13.0, P=ns), stroke volume (100 + 26.4
to 95 + 27, P=ns) and vascular resistance (1,203 + 384 to
1,113 + 449, P=ns). Heart rate and pressure data were
significantly lower at peak LBNP for beta-blocker vs.
placebo subjects (P < .001).


Figure 18. Examples of intolerant responses during lower body negative pressure as revealed by
transcranial Doppler monitoring of middle cerebral artery flow. Nonbradycardiac intolerance is

illustrated. Into

lerance (bottom view) was marked by a fall in diastolic flow velocity between rest

and the intolerant endpoint. Often this depression of diastolic velocity would persist long into
recovery. Systolic velocity was often higher than that measured at rest. Intolerance was marked by
extreme widening of the systolic-to-diastolic ratio, to ratios of nine or higher.

B. Intolerance to lower body negative pressure

Resting transcranial velocity profiles were indistin-
guishable in tolerant and intolerant subjects. However,
intolerance was marked by a progressive and significant
fall in both the diastolic (44.12 + 8.9 to 33.6 + 11.6 cm/
s, P< .05) and mean (56.7 + 10.5 to 42.9 + 11.9 cm/s,
P <..05) transcranial velocities, with subsequent signifi-

19

cant widening of the systolic to diastolic ratio from rest-
to-peak tolerated stress (2.03 + 0.20 2.32 + .38, P<.01).
Often, but not always, this widening of the S to D ratio
correlated with systemic hypotension and bradycardia.


LEGEND ABBREVIATIONS IN FIGURES AND TABLES

ALT... .. altitude

AVG... average

BAT. .. battery

BPD... .. diastolic blood pressure
BPM... .. mean blood pressure

BPS... .. systolic blood pressure

... diastolic velocity

.. ground

hematocrit

++. heart rate

... intolerant

.. lower body negative pressure
.» mean arterial pressure

... mean velocity

group number

-. patient

.. peak velocity

.+. Systolic-to-diastolic ratio

.. standard deviation

... stroke volume

systemic vascular resistance
+ time

... bioimpedance thoracic fluid index

... tolerant


a

33.

34.

35.

36.

37.
38.

39.

Lababidi Z, Enmke DA, Durnin RE, Leaverton PE,
Lauer RM. The first derivative thoracic impedance
cardiogram. Circulation 41:651-658,1970.

Ebert TJ, Smith JJ, Barney JA, Merrill DC, Smith
GK. The use of thoracic impedance for determining
thoracic blood volume changes in man. Aviat Space
Environ Med 57(1):49-53,1986.

Padayachee TS, Kirkham FJ, Lewis RR, Gillard J,
Hutchinson MC, Gosling RG. Transcranial mea-
surement of blood velocities in the basal cerebral
arteries using pulsed Doppler ultrasound:a method of
assessing the Circle of Willis. Ultrasound Med Biol
12(1):5-14,1986.

Markwalder TM, Grolimund P, Seiler RW, Roth F,
Aaslid R. Dependency of blood flow velocity in the
middle cerebral artery on end-tidal carbon dioxide
partial pressure—a transcranial ultrasound Doppler
study. J Cereb Flow Metab 4(3):368-72,1984.

Bishop CCR, Powell S, Rutt D, Browse NL.
Transcranial Doppler measurement of middle cere-
bral artery blood flow velocity:A validation study.
Stroke Vol 17, No 5,1986,

Fundamentals of Aerospace Medicine.R.L.DeHart,
ed. Philadelphia, Lea & Febiger, p.211,1985.

Fundamentals of Aerospace Medicine.R.L.DeHart,
ed. Philadelphia, Lea & Febiger, pp.225-226,1985.

Stevens PM, Lamb LE. Effects oflower body negative
pressure on the cardiovascular system. Am J Cardiol
16:506-515,1965.

*U.S.GPO:1992-661-063/40046

4,

45,

46.

Wolthius RA, Hoffler GW, Johnson RL. Lower body
negative pressure as an assay technique for othostatic
tolerance. The individual response to a constant level
(40mmHg) of LBNP. Aerospace Med 41:29-
35,1970.

Murray RH, Thompson LJ, Bowers JA, Albright
CD. Hemodymanic effects of graded hypovolemia
and vasodepressor syncope induced by lower body
negative pressure.Am Heart J 76:799-811,1968.

Montgomery LD, Kirk PJ, Payne PA, Guber RL,
Newton SD, Williams BA. Cardiovascular responses
of men and women to lower body negative pressure.-
Aviat Space Environ Med 48:138-145,1977.

Ahmad M, Blomqvist CG, Mullins CB, Willerson
JT. Left ventricular function during lower body nega-
tive pressure, Aviat Space Environ Med 48(6):512-
515,1977.

Fundamentals of Aerospace Medicine.R.L.DeHart,
ed. Philadelphia, Lea & Febiger, pp.238-239,1985.

Sather TM; ‘Goldwater DJ, Montgomery LD,
Convertino VA. Cardiovascular dynamics associated.
with tolerance to lower body negative pressure. Aviat
Space Environ Med 57:413-9,1986.

Goldstein DS, Keiser HR. Pressor and depressor
responses after cholinergic blockade in humans. AM
Heart J 107:974,1984.



RESPONSE TO LBNP STRESS
GND=Ground; ALT=Altitude

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Rest Peak Rest Peak

TOLERANT INTOLERANT

Figure 15. Plots of mean middle cerebral artery flow velocity between rest and peak tolerated
lower negative pressure at ground and altitude in tolerant and intolerant subjects.


FIRST STRESS ORDER

g 28 o—o Placebo
~ e——e Beta
2 4—6 Learning |
= 264 an
: r |
& ©
S 244 ] °.
8 : p=.001
z | °

22 °
i I .
<
ia
uw
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G GL A AL
STRESS ORDER

Figure 19, Cognitive response of placebo and beta-blocked subjects during ground unstressed (G),
pround lower body negative pressure testing (GL), altitude unstressed (A) and altitude plus lower
ody negative pressure stress (AL) conditions. Only during AL stress was cognitive function im-

paired compared to the learning curve.

B. Stress order #1 (Figure 19)

The first order of stressors was applied on testing days
1 and 3. The order was unstressed. cognitive testing,
exercise, and then cognitive testing during lower body
negative pressure, first at ground and then at altitude.
Responses under these four conditions can be compared
to the four sequential applications of the battery under
unstressed conditions characterizing the learning curve.
Average throughput responses for both beta-blocker and
placebo treated subjects were no different than the
learning curve for administrations 1 thru 3. Thus, at
ground there was no detectable effect from lower body
negative pressure, and at altitude there was no detectable
effect without LBNP. However, when lower body nega-
tive pressure was applied at altitude, both placebo and
beta-blocker subjects showed an equivalent departure
from the learning curve (22.5 + 7.4and 21.3 + 8.4 vs 26.3
+ 11.7) with impaired cognitive performance significant
at the’P <.001 level.

22

C. Stress order #2 (Figure 20)

On test days 2 and 4, the subjects underwent lower-
body negative pressure with cognitive testing, and then
unstressed cognitive testing first at altitude and then at
ground. The responses during this sequence were com-
pared to the learning curve. The first application of the
battery was in the most stressed condition, consisting of
both altitude and lower body negative pressure. This
combination of stressors showed a marked decrement in
cognitive performance, compared to the learning curve
(P< .001). However, this decrement was no different for
beta-blocker or placebo-treated subjects (17.2 + 6.8 vs
18.5 + 7.4). In the second administration, unstressed at
altitude, the cognitive performance of both placebo and
beta-blocker subjects returned within the range of the
learning curve.


Figure 17. Transcranial monitoring of middle cerebral flow velocity during a tolerant response to
lower body negative pressure. Minus 40 mmHg lower body negative pressure (photo on right)

produced an increase in the heart rate, and a decrement in Doppler systolic and diastolic velocity,
ut the systolic-to-diastolic ratio was unchanged.

Figure 17 demonstrates a characteristic tolerant sub-
ject tracing. In tolerant subjects, the systolic velocity
decreased from rest to peak orthostaticstress (85.6 + 17.5
to 75.7 + 17.8 cm/s, P=ns).

The diastolic velocity also decreased in response to
orthostatic stress (41.8 + 9.9 to 37.5 + 10.9 cm/s P=ns).

18

A minor, and insignificant decrease in mean flow veloc-
ity, which correlates with cerebral blood flow, was ob-
served (54 + 12 to 47.3 + 12.3 cm/s). The
systolic-to-diastolic (S to D) ratio remained constant
between rest and peak orthostatic stress (2.08 + 0.25 to
2.07 + 31).


EXERCISE RESPONSES

J
5 200
B |
n ap ap |
ra
Biot | Kas so
ai :
e | on 4 @p
2 100, Ss ep sBP a /
ir 4, B WA oB
., Ve ° V4 |
uw §=80+ e
s HR MR |
5
= 40 i + + + + i
= REST PEAK REST PEAK

GROUND ALTITUDE

Figure 12. Exercise performance of placebo treated and beta-blocked subjects between rest and
peak exercise at ground and at a simulated altitude of 12,500 feet. Means are plotted for heart rate
(HR) and systolic blood pressure (SBP) during the various test conditions.

Exercise Responses (Table IV, Figure 12)

A. Beta-Blockade vs. Placebo

All subjects were capable of pedaliiig to 100 watts for
3 minutes on the seated bicycle at ground and at altitude.
At ground, heart rates were significantly lower in the
beta-blocked subjects at rest (60 + 12.1 vs 78 + 16.9, P
<.001), and at peak exercise (102 + 11.2 vs 126 + 17.9,
P < .001) compared to placebo treated subjects. In
addition, systolic blood pressures were lower at rest (124
+ 14.9 vs 137 + 16.3, P<.04), arid at peak exercise (156
+ 21.1 vs 183 + 26.2, P<.01).

As a result, beta-blocked subjects had lower rate-
pressure products, calculated as HR X SBP/100, at peak
exercise than their placebo-treated counterparts (166 +
35 vs 231 + 58.5, P<.001). Ataltitude, resting heart rates
were higher compared to ground prior to exercise (68 +
9.5 and 87 + 19.9, both P=ns), but systolic blood
pressures were similar. Both placebo and beta-blocked

13

subjects achieved similar rate pressure products at
exercise at altitude compared to ground (249 + 46 vs 169
+35). Rate-pressure products were significantly lower in
beta-blocker subjects (P <. 01).

B. Tolerance vs Intolerance

At ground, resting values for heart rate and systolic
blood pressure were similar in tolerant and intolerant
groups (73.7 + 18.3 vs 70 + 14.5). With exercise, systolic
pressure (132.9 + 17.4 and 123.2 + 15.8 to 171.5 + 28.9
and 167.7 + 23.1) and heart rate (to 118.2 + 21 and 115
+ 18.2) rose in both groups, with differences being
insignificant. The peak double product achieved in
intolerant and tolerant subjects exercising at ground to
100 watts was not significantly different (206.6 + 65 vs
195.2 +52). .


EKG RATE & RHYTHM

BP BPS BPD BPM
co SV HR LVET
Qaorta SV MA PV
Vvmca Vs Vd vm

HP
HR Paramed 9300
TFI Evi BOMED NCCOM3
QUINTON EXERDOP
$/D CME TC DOPPLER

Table I. Instrumentation

Statistical Methods

Statistical methods consisted of group means and
standard deviations, with level of significance being
established between group means using Student's t tests
on paired or unpaired variables. Chi-square analysis
established significance of treatment effects. Standard
deviation (SD), and standard error of the mean (SEM)
were calculated in the usual fashion.

REsuLts
Tolerance

Atotal of 160 lower body negative pressure tests were
performed, 80 at ground and 80 at altitude. In turn, 40
of the ground runs were done with subjects taking
placebo, and 40 with atenolol. Correspondingly, at
altitude 40 runs were done on beta-blockers and 40 on
placebo. At ground, only 5 of the 80 lower body negative
pressure tests were terminated for intolerance (Figure 4).

Intolerance was defined as declining blood pressure to
levels below 90/60, declining heart rate to rates below 60,
adrop in diastolic middle cerebral artery diastolic blood
flow, or profound functional impairment. Only 2 of the
35 intolerant responses were terminated due to symp-
toms, and the remainder were terminated for hemody-
namic compromise. Symptoms during intolerance
included dizziness in 18, nausea in 18, lightheadedness
in 11, epigastric fullness in 9, chest pressure in 4, loss of
concentration in 10, and a distant, detached feeling in 9.
Of the 5 intolerant runs at ground, all were associated
with beta-blockade. The remaining 30 intolerant re-
sponses were observed at altitude. Of these 30 intolerant
responses, 18 were observed with beta-blockade treat-
ment, while 12 were observed with placebo treatment.
The effect of altitude was significant (P<.01), and the
effect of beta-blockade was significant (P<.05).

Figure 4. Graphical
_, fepresentationofin-

INTOLERANT RES

. tolerant responses,
S as influenced by
. ground or altitude
conditions and pla-
ceboorbeta-blocker
treatment. Of 35 in-
tolerantresponses, 5
wereexperiencedat
proun on beta-

lockade. Eighteen
wereexperiencedat
altitude on beta-
blockade, and 12 at
altitude on placebo.
No intolerant re-
sponses were ob-
served at ground
level testing during
lower body negative

-ONS

pressure during pla-
cebo treatment.


aircraft who are treated for hypertension with beta-
blocking drugs. Further study of drugs that deplete the
vascular space, block the renin-angiotensin system, in-
hibit the central vasomotor center, or act as
noncardioselective beta-blockers may be warranted.

Asecond finding of clinical revelance is the existence
of a high-risk subgroup with provokable orthostatic
intolerance within the general hypertensive population.
These individuals have no prior history of syncope or
orthostatic intolerance. Such individuals have reproduc-
ible intolerance to lower body negative pressure testing.
Should other pharmacologic agents prove to be less
provocative of orthostatic intolerance than beta-blockers,
orthostatic testing of the hypertensive aviator may be
warranted to tailor antihypertensive medications ac-
cording to orthostatic tolerance.

‘The final implication of the study is that the param-
eter most likely to enhance orthostatic tolerance is un-
controlled systemic hypertension. Although not
statistically significant, we observed that the most toler-
ant subjects had the highest blood pressures at the
initiation of lower body negative pressure testing. This
finding may warrant further investigation. If corrobo-
rated, the implication would be that some trade-off
between antihypertensive control and orthostatic toler-
ance may be needed.

Future Work in This Area

In an attempt to improve the economics and prolif-
eration potential of such testing, a study aimed at the
evaluation of a hypoxic gas mixture and tilt table ortho-
static testing might be considered. Such a streamlined
testing protocol would obviate the need for a hypobaric
chamber as well as a lower body negative pressure device.
It may be possible to achieve similar physiologic stress by
breathing a mixture of gases approximating the atmo-
sphere at 12,500 feet, and performing orthostatic stress
on atilt table rather than a lower body negative pressure
device. It would be possible to maintain noninvasive
monitoring of hemodynamic and cerebral blood flow
parameters in such a system and avoid the cost of a
hypobaric chamber and lower body negative pressure
testing equipment.

Regarding hemodynamic monitoring, the essential
elements must be heart rate, mean arterial pressure, and
stroke volume. A beat-to-beat method for the assessment
for mean arterial pressure would enhance the hemody-
namic monitoring of orthostatic stress testing. From
these prime independent variables, hemodynamic char-
acterization of cardiac performance and performance of
the peripheral autonomic nervous system can be deter-

28

mined, Accessory and useful monitoring includes
transcranial middle cerebral blood flow, and some esti-
mate of pooling in the lower extremities in response to
lower body negative pressure stress testing. We did not
find Doppler assessment of left ventricular ejection an
easy procedure to perform, and it offered no further
information beyond the assessment of cardiac stroke
volume already available from bioimpedarice. Morework
appears justified for the development of cognitive batter-
ies that are more sensitive to minor cognitive impair-
ments induced by aviation specific stressors.

Of basic importance is a more general physiologic
understanding of the phenomenon of orthostatic intol-
erance, and the development of pharmacologic means of
ameliorating or abating such a response. Such research
would aim at selecting antihypertensive agents that do
not inhibit orthostatic reflexes, possibly in combination
with other agents that enhance the vasoconstrictive
response of the peripheral autonomic nervous system in
response to orthostatic stress.

REFERENCES
1, Kulak LL, Wick RLJR, Billings CE. Epidemiological
study of in-flight airline pilot incapacitation. Aero-
space Med 42:670-72,1971.

IATA Medical Committee - Annual statistics on in-
flight incapacitation. Montreal:International Air Trans-
port Association, Montreal, Canada.

Cardiovascular problems associated with aviation
safety:Eighth Bethesda Conference of the American
College of Cardiology. Am J Cardiol 36:573-
628,1975.

Engleberg AL, Gibbons HL, Doege TC. A review of
the medical standands for civilian airmen:Synopsis of
a two-year study. JAMA 255(12):1589-1599,1986.

Bennett G.Aviation accident and aircrew licensing.-
Eur Heart J 5(suppl A):9-13,1984.

Bulpitt CJ. Risk indicators fordeath in patients treated
for hypertension:Emphasis on consequences for air-
line pilots.Eur Heart J 5(Suppl A):33-35,1984.

Krannel WB, Doyle JT, McNamara PM, et al. Pre-
cursor of sudden cardiac death:Factors related to the
incidence of sudden death. Circulation 51:606-
614,1975.



24 HR AMBULATORY MONITORING
# MEAN MEAN MEAN. SDEV_ SDEV SDEV

FRACTIONAL

PT BAT DRG TOL BPS BPD HR BPS _.BPD.- HR

HCT SODIUM _

TOLERANT GROUP
BON1 PY 80 27
BON2 PY 73 ibd
BON3 BY 79 12
BON4 BY 70 12
BOU2 BY 83 18
BOU4 PY 86 27
BURT PY” 100 iI
BUR2 PY a9 7
BUR4 BY 91 9
CAT PY 91 12
CIA2_ PY 96 12
CIA4_ BY 92 16
GART PY 78 22
GAR2_ PY 81 13
GAR4 BY 78 17
GRIT =B SY 92 32
Gris PY 74 19
GRi4_ PY 72 20
HART PY 83 32
HAR4 BY 78 Ti
HENT PY 80 24
HEN2 PY 82 13
HEN3 BY 66 9
McG2 BY 76 14
McG4 PY 77 i
ODET BY 68 9
ODE2 BY 67 14
ODES PY 7 17
ODE4 PY 86 87 15
PNKT PY 89 9
PNK2 PY 87 15
PNK3. BY 69 12
PNK4 BY 73 16
PINT PY 83 16
POM3 PY 86 16
POM4 PY 88 15
SEL2. BY 76 13
SEL3. PY 80 12
SEL4. PY 84 18 :
WALT BY 9% vt 20. 19"
WAL2 BY 7 ~~ B.S~<CS~«~SrTC:C“(<i‘<‘

Table Vill. Poststress Clinical Monitoring. (Sorted By Tolerance To LBNP.)

25


EEE EE SISSSSSSSSCSICNC“N:~CS:=CSC

study. Subjects exited the study on prestudy medica-
tions. All 20 subjects entering the protocol exited the
protocol, and no subject failed to complete any test
battery.

researchers, the research subject proceeded through the
battery, which lasted. approximately 20 minutes. The test
could be scored as total iput, or correct hits per
minute for the 20-minute period. An additional param-
eter, average throughput, was also calculated, defined as

DOUBLE BLIND, RANDOMIZED,
PLACEBO CONTROLLED TRIAL

ATENOLOL
100 mg

SCREENING

PLACEBO

Figure 1. Schematic representation of the double-

Test Battery

The test battery consisted of § components (Table I),
The first component included a brief interval historyand
physical examination on the morning of the testing.
Blood pressureand pulse was tecorded supine and stand-
ing, and a blood specimen was drawn for hematocrit,
sodium, and creatinine.

The second component consisted of cognitive perfor-
mance evaluation. We modified the cognitive perfor-
mance battery developed by Dr. David Thorn at Walter
Reed Medical Center for this purpose." ‘The test
battery is a computer-based modular assessment of spa-
tial reasoning, logical reasoning, short-term memory,
and reaction time. Each module can be scored in a
quantitative fashion. Following instruction by one of the

blind, randomized placebo crossover trial of
atenolol used in this study. T=test; M=Month; LBNP=lower body negative pressure.

TEST BATTERY
1. Prestress Interview, Physical, Bloodwork

2. Unstressed Cognitive Testing (Walter Reed)

3. Bicycle Exercise (graded) to 100 W for 3
minutes

4. Seated Lower Body Stress Testing to - 40
mmHg in 20 minutes

5. Poststress Monitoring, Blood and Urine
Assays

_

Table 1. Test Battery



TOLERANCE OF BETA BLOCKED HYPERTENSIVES DURING
ORTHOSTATIC AND ALTITUDE STRESSES

INTRODUCTION

Sudden incapacitation poses the greatest medical risks
to commercial and private air travel.'4 Thechief medical
concerns causing sudden incapacitation include acute
myocardial infarction, cerebral vascular thrombosis, and
seizure. In the adult population, common etiologic
factors responsible for these acute medical syndromes
include uncontrolled hypertension and advanced
atherosclerosis. The previous 2 decades have shown
remarkable reductions in the incidence of myocardial
infarction and stroke in the general population** The
reasons for these reductions include a heightened public
awareness of the cardiovascular complications of tobacco
use, uncontrolled hypertension, and uncontrolled hyper-
cholesterolemia.

Effective antihypertensive agents have made the con-
trol of hypertension possible in every hypertensive. In
addition, newer anticholesterol agents have made cho-
lesterol control possible for many patients untreatable
with previous drugs or diet alone. Thus, it is probable
that continued reductions in myocardial infarction and
stroke will be experienced in the ensuing decades. It is
plausible that civilian aviation medical research should
now turn from the study of myocardial infarction and
stroke in the aviation environment to the evaluation of
potentially deleterious hemodynamic consequences of
the drugs that control hypertension and atherosclerosis.

The antihypertensives, particularly, deserve special
attention in that they block the central vasomotor cen-
ters, inhibit peripheral vasoconstriction, or deplete the
vascular space of sodium and water. In many hyperten-
sive patients, these therapies result in mild orthostatic
intolerance, as manifested by dizziness upon stand-
ing." Civilian aviators are also routinely exposed to
orthostatic stresses." In addition, evasive maneuvers
or emergency situations could expose crew and passen-
gers to accelerations of greater degree and duration. The
FAA has licensed over 15,000 aviators to fly with the
diagnosis of hypertension." It remains to be estab-
lished whether the orthostatic tolerance of treated hyper-
tensive airmen would be sufficient to maintain functional
status during routine or unusual orthostatic stress.

Moreover, the aviation environment often imposes
the effects of altitude, namely hypobaria and hypoxia.
These physical stresses could heighten orthostatic intol-
erance, and potentiate deleterious effects of agents that
are used to alter vascular responses.'?°

These issues led us to pose the following key ques-

tions:

1. Does beta-blockade compromise orthostatic tol-
erance?

2. Does altitude compromise orthostatic tolerance?

3. Do the combined effects of beta-blockade and
altitude impair exercise performance?

4. Do the combined effects of beta-blockade and
altitude compromise cognitive performance?

5. Can a stress protocol be designed to answer ques-
tions 1-4?

6. Cananoninvasive physiologic monitoring system
be developed to assess hemodynamic and cogni-
tive responses to the stresses in questions 1-4?

7. What physiologic factors predict orthostatic in-
tolerance?

Stupy Desicn
Subjects

We reeruited fifteen males and five females from the
general population with a mean age of 34 (range 18 to
52). Individuals were qualified for the study by meeting
physical standards as specified for the FAA class 3 certifi-
cate, achieving age predicted target heart rate during
treadmill exercise, and an entry blood pressure of 140/90
or greater. All subjects had been advised by their personal
physicians of hypertension, and 12 subjects were under
active treatment with antihypertensive agents. No sub-
ject had a history of fainting, syncope, or orthostatic
intolerance.

Protocol

The protocol design was a placebo controlled double-
blind, crossover study of atenolol, 100mg, daily (Figure
1). This study lasted 6 months. At time 0, the subjects
discontinued all medications and half were randomized
to atenolol, and half to placebo. At the end of 1 month,
both groups underwent the first test battery (Table 1). At
the end of month 3, subjects underwent the second test
battery. At that time, each half group crossed over to the
opposite medication, and were tested in 1 month at test
battery number 3. At month 6, the fourth and final test
battery was applied. The subjects were then removed
from test drugs, the drug code was broken, and the
subjects were counseled regarding findings during the


TOLERANT GROUP, N=50 INTOLERANT GROUP, N=30
MEANS, MEANS

LBNP
MIN MV s/D PV DV MV s/D PV DV
REST 54.05 2.08 85.58 41.80 56.75 2.03 88.53 44.12

7 53.63 2.13 85.00 40.91 53.10 2.13 85.68 41.68
12 51.95 2.11 82.11 39.97 52.24 2.09 84.45 40.97
17 49.42 2.10 78.32 37.97 48.07 2.28 81.21 37.52
22 47.32 2.07 75.71 37.51 42.95 2.32 78.56 33.59

STANDARD DEVIATIONS STANDARD DEVIATIONS

LBNP
MIN MV s/D PV DV MV s/D PV DV
REST 11.91 0.25 17.49 9.85 10.53 0.20 16.44 8.99

7 13.45 0.34 19.03 11.15 12.80 0.35 17.15 11,73
12 14.29 0.30 20.01 11.87 10.55 0.24 14.79 8.87
17 13.11 0.28 18.08 10.16 12.23 0.53 15.28 11.24
22 12.29 0.31 17.75 10.91 11,92 0.38 10.99 11.59

Table V. Transcranial Monitoring at Altitude During LBNP.
Ir
RESPONSE TO LBNP STRESS
GND=Ground; ALT=Altitude

=~
on
~
E
5)
LY
2
‘oO
x
©
>
<
{S)
=
2
xo)
2
o
>
7)

Rest Peak

NTOLERANT

Figure 13. Transcranial Doppler monitoring of the systolic middle cerebral artery flow velocity
(MCA) in subjects tolerant and intolerant to lower body negative pressure between rest and peak
LBNP effect, at ground (GND) and altitude (ALT).

14



ee |

TEST SEQUENCING

STUDIES 1 & S

Figure 3. Schematic representation
of test sequencing studies 1
& 3, and 2 & 4. The arrows indicate
the order of progression.
COG=cognitive testing, EX=exercise
testing, LBNP=lower body negative
pressure testing.

GROUND | coc EX

ALTITUDE | coc EX

LBNP+COG

LBNP+COG

with the battery protocol being lower body
negative. pressure, exercise, and unstressed
cognitivetesting. We did this because we felt
that reversing the sequence of the stress
orders would eliminate learning effects in
the responses.

Instrumentation

STUDIES 2 & 4

Noninvasive hemodynamic monitoring
was employed to ensure the safety of the test
subject and to assess hemodynamic responses
to the various stresses (Table II). The elec-
trocardiogram was monitored in limb lead I
utilizing a Hewlett Packard continuous
monitor. The automated blood pressure cuff
was inflated at least every 2 minutes to assess
systolic (BPS), diastolic (BPD) and mean

ALTITUDE | LBNP+COG EX
4 4 4

GROUND LBNP+COG Ex

Le _.

(BPM) blood pressure (Paramed 6300,
Paramed Technology, Irvine, CA).
Suprasternal transcutaneous Doppler ultra-
sound was employed to assess left ventricu-
+ ; | lar function in terms of maximal ejection
acceleration (MA), peak ejection velocity
coc |] (PV), and stroke distance (SD) (Exerdop,
j Quinton Instruments, Seattle, WA).?&8
' | Transthoracic bioimpedance techniques

CoG

were utilized to determine stroke volume

ambulatory blood pressure monitor, which inflated ev-
ery 15 minutes, affording up to 100 samples of systolic
and diastolic pressure with heart rate in the 24-hour
period. In addition, the subject collected a 24-hour
urine specimen for sodium and creatinine to assess
hydration status.

The test battery, consisting of unstressed cognitive
testing, exercise, and lower body negative pressure, was
repeated at ground and ata simulated altitude of 12,500,
utilizing a hypobaric chamber at the Civil Aeromedical
Institute, Oklahoma City, Oklahoma. The test battery
was administered on 4 occasions (Figure 3). On occa-
sions 1 and 3, the sequence was ground and then altitude,
with the battery sequence being unstressed cognitive,
exercise, and lower body negative pressure. On testing
days 2 and 4, the order was first altitude and then ground,

(SV), heart rate (HR), and cardiac output
(NCCOM 3, BoMed Medical, Irvine, CA).2922

The transthoracic impedance (TFI) reflected theelec-
trolyte volume of the thorax? To measure cerebral
blood flow, transcutaneous pulsed Doppler ultrasonic
measurements in the right middle cerebral artery were
performed at rest, every 2 minutes into the LBNP stress
protocol, and at peak tolerated stress. Measurements
included peak systolic (Vs), diastolic (Vd), mean (Vm)
and ratio (S/D) velocities (TC 64, Carolina Medical
Electronics, King, NC).4 The Doppler probe was
held stationary in a helmet worn by the subject. All data
but the transcranial monitoring were digitized and trans-
mitted over an RS232 port to a host AT class personal
computer for data logging and analysis in Lotus spread-
sheets.



AVERAGE THROUGHPUT SUM THROUGHPUTS
(learning curve) (learning curve)
PT 1.0 2.0 3.0 4.0 1.0 2.0 3.0 4.0
BAK 14.2.°19.1 23.1 18.7 85.5 114.3 138.5 112.0
BUR 15.9 18.7 22.9 25.6 95.6 412.1 137.5 153.5
HAR 9.6 19.2 13.2 12.4 57.4 115.0 79.4 74.4
MCG 11.6 9.5 12.1 10.7 69.3 56.9 72.5 64.2
ODE 34.1 31.1 32.3 30.4 204.7 186.5 193.7 182.6
PIN 38.9 45.3 41.5 54.0 233.6 271.7 249.0 323.8
RUS 22.2. 21.0 24.1 23.4 132.9 126.0 144.4 140.3
SEL 28.3 27.4 24.0 23.5 169.6 164.2 143.8 141.0
WEG 21.1 21.1 31.6 33.0 126.4 126.6 189.8 198.0
WES 24.7 24.9 33.5 31.3 148.2 149.5 201.1 187.6
AVG 22.05 23.71 25.83 26.29 132.31 142.29 154.97 157.73
sTD 9.18 9.05 8.66 11.68 55.05 54.29 51.98 70.06
STUDY #1 (AV THROUGHPUT) STUDY #2 (AV THROUGHPUT)

PT DRG G1 GLI Al ALi AL2 A2 GL2 G2

BAK P 19.9 204 25.5 263 15.6 17.2 18.0 18.9
BON P 16.5 17.0 32.5 28.2 17.6 16.3 18.1 20.9
BUR P 35.6 34.2 40.1 283 21.9 20.4 27.1 25.9
CLA P 18.5 28.9 28.3 27.7 14.0 14.8 11.7 14.1
GAR P 23.0 32.1. 32.8 42.9 18.9 27.8 26.7 33.3
HAR P 13.6 19.1 22.4 26.2 14.2 12.4 12.0 10.8
HEN P 38.8 37.7 40.9 38.8 27.9 29.6 26.8 26.3
PIN P 52.4 59.7 60.8 67.1 28.4 34.7 28.8 31.5
PNK P 30.5 33.8 40.4 39.0 26.0 35.3 25.5 30.8
RUS P 34.6 27.0 42.1 28.6 11.6 20.5 18.8 32.0
PLACEBO AVG 22.0 24.7 25.2 23.3 19.6 22.9 21.3 24.4
PLACEBO STD 11.6 11.7 10.4 12.1 5.8 7.9 6.1 7.5
BIR B 18.4 206 31.7 31.0 4.6 19.2 20.3 22.8
BOU 8B 15.6 21.4 21.0 188 11.7 12.2 13.7 13.2
GR} B 244 19.8 23.8 21.9 10.8 15.8 16.4 14.8
MCG B 10.1 19.9 15.0 13.9 11.6 17.6 11.5 27.8
ODE B 42.2 48.0 55.9 37.2 27.0 31.9 37.5 36.6
POM B 22.9 209 21.6 21.4 16.2 21.0 19.5 27.4
SEL B 22.4 18.2 26.3 25.6 14.8 20.4 18.1 17.6
WAL B 19.1 21.7 23.5 27.6 17.6 19.4 17.5 23.4
WEG B 21.0 23.1 284 23.7 14.7 26.7 25.6 20.9
WES B 27.0 49.5 38.9 38.7 24.5 32.6 29.7 80.8
BETA AVG 22.3. 21.2 22.6 20.0 15.3 21.7 21.0 23.5
BETA sTD 8.0 12.0 11.0 75 6.2 6.4 7.5 6.9

Table VI. Cognitive Responses. (Sorted By Treatment And Test Conditions.)

20





GROUND RESPONSES
beta blocked vs placebo

9S
=x
P 3
2
4
o

cc,

BPM,

Figure 5. Responses of mean arterial pressure (MAP:squares), stroke volume (SV:triangles), and heart rate

(HR:circles) between rest and peak tolerated lower

ly negative pressure for placebo (P) and beta-blocker

(B) treatment groups at ground. The lower body negative pressure stress augmented heart rate significantly
(P <.001) in the placebo treated group compared to the beta-blocked group.

Hemodynamic Responses (Table III)

A. Beta-blockade versus Placebo (Figures 5 8& 6)

Before the initiation of lower body negative pressure,
beta-blocker subjects had lower heart rates (62 + 7.8 vs
82 + 15.8, P<.001), mean arterial pressure (91 + 9.5 vs
104 + 11.6, P < .001), and higher bioimpedance stroke
volume (91 + 22 vs 78 + 21, P=ns), as compared to
placebo treated subjects (n=40), At the end oflower body
negative pressure, heart rates (70 +7 vs 99 + 18, P<.001)
and mean arterial pressures (89 + 12 vs 103 + 17, P<
.001) were lower and stroke volumes (74 + 19 vs 61 + 19,
P=ns) were higher compared to placebo treatment.

‘The stress-induced rise in heart rate was lower in the
beta-blocker subjects. Both beta-blocker and control
subjects manifested a decrement in mean arterial pres-
sure with lower body negative pressure, and the degree of
decrement was not significant between the 2 treatments.
Stroke volume declined proportionally in both the beta-
blocker and placebo groups. Systemic vascular resis-
tance, defined as 80 times the mean arterial pressure
divided by the cardiac output, was similar in both groups
at rest (1,368 + 317 vs 1,418 + 365, P=ns).


GROUND

**MEANS** N HR Tri sv MAP SvR
TOL REST 75 73.40 33.80 84.30 98.00 1383
TOL PEAK 75 85.30 34.60 67.00 97.00 1511
INTOL REST 5 59.00 36.00 93.50 88.50 1322
INTOL PEAK 5 71.50 36.00 74.50 76.70 1020
PLACEBO REST 40 82.51 33.05 78.33 103.63 1406
PLACEBO PEAK 40 98.71 34,13 60.62 103.19 1534
BETA REST 40 62.30 34.88 91.18 90.75 1361
BETA PEAK 40 69.95 35.59 74.77 88.66 1452
**STD DEV** N HRSD TFISD SVSD MAPSD SVRSD
TOL REST 75 15.70 8.00 20.70 11.70 325.0
TOL PEAK 75 20.00 5.70 19.30 19.00 431.0
INTOL REST 5 5.80 4.80 18.60 8.90 229.0
INTOL PEAK 5 7.10 4.50 12.00 7.70 328.0
PLACEBO REST 40 15.83 5.31 21.49 11.61 36.58
PLACEBO PEAK 40 18.28 5.33 18.86 17.11 48.16
BETA REST 40 7.83 5.88 22.00 9.47 31.76
BETA PEAK 40 FAT 5.70 18.92 12.44 39.42
ALTITUDE
**MEANS** N HR TF sv MAP SVR
TOL REST 50 76.70 31.30 92.70 98.70 1289
TOL PEAK 50 87.30 32.60 77.70 95.70 1420
INTOL REST 30 78.00 29.20 90.90 95.80 1177
INTOL PEAK 30 79.70 28.30 98.30 77.00 949
PLACEBO REST 40 87.76 29.97 83.78 103.40 1294
PLACEBO PEAK 40 97.86 30.21 75.77 93.87 1182
BETA REST 40 66.60 31.09 100.09 92.40 1203
BETA PEAK 40 70.73 30.91 95.11 84.04 1113
**STD DEV** N HRSD TFISD SvVSD MAPSD SVRSD
TOL REST 50 14.30 6.00 26.00 12.70 390.0
TOL PEAK 50 18.00 6.10 23.00 12.50 364.0
INTOL REST 30 13.30 5.90 21.00 12.70 325.0
INTOL PEAK 30 15.00 5.90 30.00 12.30 247.0
PLACEBO REST 40 13.44 6.24 28.68 12.45 50.19
PLACEBO PEAK 40 17.14 6.34 34,30 16.43 44,52
BETA REST 40 6.51 6.51 26.37 10.62 38.44
BETA PEAK 40 5.66 7.37 27.46 12.97 44.94

Table Hl. Summary of Hemodynamic Responses During LBNP. (Sorted By Treatment Tolerance.)
6


5. Itdoes appear feasible to simulate the stresses of
aviation, namely vertical acceleration and altitude, in a
controlled ground-level testing environment utilizing
hypobaric hypoxia and seated lower body negative pres-
sure stress. Utilizing modest levels oflower body negative
Pressure meant to simulate 2G of sustained vertical
acceleration at a simulated altitude of 12,500 feet, 30%
(placebo cases) to 45% (betablocker cases) of trials can be
expected to cause sudden incapacitation and intolerance.

6. Utilizing current technology, it is very possible
to perform noninvasive hemodynamic monitoring in
subjects undergoing altitude and orthostatic stress.
Noninvasive monitoring of mean arterial pressure, heart
tate, and stroke volume is necessary for quantitative
analysis of hemodynamic responses to these stressors.
‘These parameters demonstrate progressive decrements
in systemic vascular resistance in intolerant subjects,
implicating a defective peripheral autonomic nervous
system response. In intolerant subjects, the peripheral
autonomic nervous system appears to be incapable of
increasing vascular tone in response to increasing
orthostasis. Intolerance is not due to a cardiodepressor
reflex, as commonly believed. Moreover, monitoring of
systemic vascular resistance, blood pressure, and
transcranial middle cerebral artery flow velocities allows
prediction of impending cognitive and hemodynamic
collapse. Collapse is marked by falling middle cerebral
diastolic flow velocity, a widening of the systolic-to-
diastolic ratio, and systemic hypotension. Simultaneous
cognitive testing with a quantitative performance battery
mirrors orthostatic intolerance by a profound reduction
in correct responses per minute.

7. Nocommon clinical parameter, such as hema-
tocrit, state of hydration, average 24-hour blood pres-
sure, or supine-to-standing blood pressure or pulse rate
predicts subsequent intolerance. The most predictive
index of orthostatic tolerance is prior proven ability to
withstand orthostatic stress.“ “In the current study, 5
subjects accounted for over 50% of the intolerant re-
sponses. Thus, within the hypertensive population at
large, there exists a subpopulation at high risk for ortho-
static intolerance during beta-blockade and altitude ex-
posure, It appears that only formal stress testing will
uncover these orthostatis-prone individuals.

Limitations

The duration and rate of increase of the orthostatic
stress imposed by LBNP were not representative of the
stresses encountered in the general aviation environ-
ment. Although +2 Gz is commonly experienced in the
aviation environment, usually this level of acceleration is
reached much more rapidly and is of much shorter

duration. It is possible that our lower body negative
pressure protocol caused more extensive pooling in the
lower extremities over the 20-minute stress period, re-
sulting in more pronounced orthostasis than might be
experienced during nominal civilian flight. Moreover,
lower body negative pressure testing only approximates
the full orthostatic stress of vertical acceleration. The
augmented stress is simulated by the production of
vascular pooling in response to negative pressures ap-
plied to the lower extremities. This regional effect may be
different from a distributed effect of augmented accel-
eration forces acting on every unit of blood within the
vascular tree. Nonetheless, anticipated falls in mean
arterial pressure, rises in heart rates, and falls in stroke
volume were produced that mimic the +2Gz responses
seen in human centrifuge runs.

Asecond limitation of this study was the lack of abeat-
to-beat methodology for monitoring blood pressure. It
was possible to monitor all other physiologic parameters
such as heart rate, stroke volume, and Doppler ejection
indices in a continuous and uniform fashion so that clear
trends were apparent long before hemodynamic collapse
occurred. The addition of beat-to-beat assessment of
noninvasive blood pressure would be a welcome addi-
tion, as it would afford early warning of falling blood
pressure.

The third limitation of the study was the apparent
insensitivity of the cognitive battery to the potentially
potent effects of lower body negative pressure and alti-
tude. Significant reductions in cognitive performance
were found only during periods of orthostatic intoler-
ance induced by lower body negative pressure at altitude
and ground. These findings may warrant a closer look at
thescoring scheme or test design of such batteries for the
assessment of performance in the aviation environment.

The final limitation of this study was the essential cost
and complexity of the testing protocol. Duplication of
this protocol would require access to a hypobaric cham-
ber capable of at least 12,500 feet altitude, a custom
lower body negative pressure stress testing plethysmo-
graph, and approximately $40,000 worth of noninvasive
hemodynamic monitoring equipment, as well as the cost
of personnel to staff the hypobaric chamber and perform
the stress protocol. Safety reasons mandate that the
hemodynamic monitoring must be maintained.

Clinical Implications

‘These data implicate the synergistic deleterious effects
of beta-blockade and altitude in the potentiation of
intolerance to orthostatic stress. These findings may
have most revelance to the personnel of unpressurized



24 Hr AMBULATORY MONITORING
# MEAN MEAN MEAN SDEV SDEV SDEV FRACT.
PTBATDRGTOL BPS __ BPD H BPS __ BPD HR _HCT SODIUM
WAL3 PY 97 10 13
WAL4 PY 89 22 29
WEG3 PY 84 10 12
WEST BY 79 15 6
WES2 BY 68 13 13
WES3. PY 85 12 16
Wes4 PY 61 13 NW
TOL=49__ MEANS 81.58 15.41 14.02
SD 9.167 5.670 5.018
INTOLERANT GROUP
# MEAN MEAN MEAN SDEV SDEV  SDEV FRACT.
PTBATDRG TOL T BPS BPD HR BPS __ BPD
BAKT_P_N 32 8675 OB
BAK2__ PN 89. 70 3
BAK3 BN BB 72 5
BAK4_B_N “8466 4
BIRT BN 83.77 20
BIRZ BN Bt 70 5
BIR3_P_N : 86 13
BIR4_P__N 9678 3
BOUT BN "78 73 5 TZ
BOUS_P__N~ "84 76 1810
BUR3 BN 4 CE TT
CIA3_B__N- BB TT
CARS BN wae 34 310
HARZ_P__N 77 76 a 2
HAR3__BN i 60 TT 5
HEN4 _B__N 68 66 9.8
MécGT_B__N 82 82 7 5
McG 3__P__N Ba 85 “8 7
PINZ P__N 9 64 2 13
PIN3_B__N 71 50 12 3
PIN4 _B7_N : 69. 50 17 3
POMTB~_N_ 1830127 69 6T 15 15
POM2ZB__N_19:30 126 80" 63 3 TT
RUST PN 17:00 T30 66 68 24 TO
RUSZ PN 15330 119 70 73 B TO
RUS3 BN 1830. ‘116 62 355 7 7
RUS4 BN 13:20. 118 67 38 7 B
SELT BN 19:40. 115 71 62 Ey 7
WEGT BN 15:00. 125 $2 72 12 TT
WEG? BN 17:30 T22 74 62 TT 9
WEG4_P__N_ 16:30 147 ELS 69 TO TT
INTOL MEANS 125.3 78.12. 67.80 13.80. 11.35 14.48: 47.74° 0.730548
=31___ 5D 10.09 7.857 9.215 4.631 «3.676 5098 3.918 . 0.176848

Table VIII (Continued). Poststress Clinical Monitoring. (Sorted By Tolerance To LBNP.)

26


LBNP PROTOCOL

5 10

15 20 25 30

TIME INTO LBNP, min

Figure 2. The lower negative pressure stress test is described in terms of the vacuum applied to the
lower body as a function of time. The first 5 minutes were defined as a resting prestress measure-
ment, and the ensuing 20 minutes were the stress protocol, and the final 5 minutes were a post test

monitoring period.

responses per minute divided by the total number of
minutes completed.

The third component consisted of bicycle exercise.
Subjects performed seated bicycle exercise initiated at 50
watts, and then advanced to75 and 100 watts at 3 minute
intervals during hemodynamic monitoring.

The fourth component consisted of lower body nega-
tive pressure testing (LBNP).” This method was used to
apply orthostatic stress to the subjects. The subject is
sealed about the waist into a plethysmograph in a seated
posture. Progressive vacuum can be applied, which re-
sults in blood pooling in the venous capacitance vessels
ofthe lower extremities. This stress, if mild, simulates the
stress of standing, and if greater, simulates the accelera-
tion stress achieved in a human centrifuge.TM After a 5
minute resting session, 10mmHg vacuum was applied to
the lower extremities for the first 5 minutes, and then
advanced to 20mmH for the second 5 minutes (Figure
2).

The subsequent 5 minute periods had vacuums of 30
and 40mmHg. It was anticipated that the 40 mmHg
vacuum would apply a total of +2G to the subject, when
coupled with the 1G afforded by gravity alone. After the
20 minute LBNP protocol was complete, the vacuum
was released to ambient conditions slowly over the
ensuing 90 seconds. Endpoints for the stress test in-
cluded the subject’s request to terminate, significant
bradycardia to rates less than 60 beats per minute,
significant hypotension to blood pressures of 90/60 or
lower, or evidence of impaired cerebral blood flow
utilizing transcutaneous Doppler ultrasound.

Throughout the LBNP protocol, the subject repeated
the computerized cognitive battery to examine the indi-
vidual and combined effects of LBNP, beta-blockade,
and altitude upon cognitive performance.

The fifth component of the test battery included post-
stress monitoring. The subject was fitted with a 24-hour


RESPONSE TO LBNP STRESS

GND ; ALT=Altitude

S/D MCA Velocity Ratio

Rest Peak Rest Peak

TOLERANT INTOLERANT

Figure 16. Plots of the systolic-to-diastolic middle cerebral artery flow velocity ratio between rest
and peak tolerated lower body negative pressure at altitude and ground in tolerant and intolerant

subjects.

17



SECOND STRESS ORDER

= 26 o-——o Placebo

~ e—e Beta ] |

YP 26 4—ao Learning |

5 374 i p=.001 8

a I :

® 22+ a —_ ~e

g i —=

£ 204 p=.001

a

lu °o

Oo 18+

zz e

$

= 16 ' A :
AL A GL G

STRESS ORDER

Figure 20. Cognitive performance, as expressed by average throughput, plotted as a function of the

second stress order and compared to the learning curve. Lower b

negative pressure stress both

at altitude and ground onditions significantly impaired cognitive performance in the second stress

order.

However, the third application, at ground during
lower-body negative pressure, again showed a marked
reduction in cognitive throughput for both beta-blocker
and placebo-treated subjects (21.7 + 6.4 and 20.8 + 7.8
ys 25.8 + 8.7, P<.001). This effect may be ascribed to the
stresses of lower-body negative pressure, or it may repre-
sent the cumulative fatigue experienced in the prior
altitude testing. However, the fatigue hypothesis is thrown
into doubt by the fourth administration of the test, at
ground and without the stress of lower body negative
pressure. Both placebo-treated subjects and beta-blocker
subjects were within 1 standard deviation from the mean
of learning curve during this condition.

23

Correlates of Intolerance

A. Pretest measurements. (Table VII)

Supine resting blood pressure was higher in placebo
treated versus beta-blocker subjects for all 80 testing
sessions (140/92.5 + 15.8/15.9 vs 130/83 + 15.9/9.9,
P=ns). The orthostatic rise in pulse rate going from
supine to standing positions was lower in beta-blocker
subjects (64.5 + 7.5 1067.8 + 8.4 vs 80+ 10.6 1085 + 9.8,
P < .001). However, sorting these data on the basis of
tolerance or intolerance to subsequent lower body nega-
tive pressure, the pretest orthostatic blood pressure and
pulse measurements of the 35 intolerant subjects were
not predictive.


‘The computer-based cognitive testing in this avia-
tion-specific stress environment permits quantitative
assessment of individual and cumulative effects of the
stressors; however, this cognitive impairment was prin-
cipally the end result of significant central hemodynamic
compromise, rather than premonitory decrement in
cognitive function prior to onset of cardiovascular
symptomatology.

Conclusions

‘Thus, for the medication studied, we would predict
substantive physiological and performance decrement if
a pilot on such medication is exposed to orthostatic
stressors equivalent to or higher than the +2 Gz equiva-
lent herein studied, and, especially, orthostatic stressors
combined with altitude exposure.

Extrapolating to other dosages of atenolol and to
other beta-blockers can only be effected cautiously.
However,a systematic methodology has been developed
and introduced that can demonstrate the pattern of
physiological and performance decrement induced by
any class of antihypertensive medication and perhaps
even by many other classes of cardiovascular and central
nervous system active medications. New entrants into
the pharmacological armamentarium can be evaluated
for specific civil aviation medicine relevance using this
protocol.

The final contract report of this research submitted by
Dr. Steve Teague is presented. Dr. Teague completed
this work while at the University of Oklahoma; he
currently is affiliated with Case Western Reserve Univer-
sity in Cleveland, Ohio.



GROUND RESPONSES
105
© MAP ye ee T
Ss 954 i °
Ss PN
a 354 Sv ft
S a p = .05
o
_ 75 °
=
a HR
657
¢
55
REST PEAK

Figure 8. Hemodynamic parameters MAP, SV, and HRare plotted between rest and peak tolerated lower body

ne
to lower

tive presure at ground. Subject responses are stratified on the basis of tolerance (T) or intolerance (1)
Y

negative pressure. The intolerant fall in MAP at ground was significant (P <.05).
ALTITUDE RESPONSES
100
(2) i = .05
s MAP tor pao
S 954 -o UT
SV
a
Oo 90+
o oT
O 85+
oO
« _é |
2 80 . Se | p= 001
aa) HR 6 “OT
75 + +
REST PEAK

Figure 9. Hemodynamic responses

MAP, SV, and HR are plotted between rest and peak tolerated

lower body negative pressure administered at altitude. Tolerant (T) and intolerant (I) responses are
illustrated. Altitude intolerant responses were marked by a significant (P < .001) fall in mean arterial
pressure (squares) and rise in stroke volume (triangles) (P < .05) at the point of intolerance to lower

body negative pressure.

10


ree

I

| se mEANS** **REST** **EXERCISE**
N HR BPS BPD HR BPS BPD RPP
GROUND
BETA 40 60.46 124.10 79.08 102.36 156.56 84.97 166.72
PLACEBO 40 77.68 137.63 90.00 126.63 182.83 92.83 230.68
ALTITUDE
BETA 40 68.15 123.03 79.41 106.90 156.62 79.77 168.77
PLACEBO 40 86.75 138.40 89.15 134.15 186.23 83.30 248.93
**STANDARD DEVIATIONS**
GROUND
BETA 40 12.08 14.85 11.49 11.21 21.07. 18.35 35.00
PLACEBO 40 16.94 16.27 12.78 17.87 26.16 14.25 58.46
ALTITUDE
BETA 40 9.54 16.02 11.99 13.71 29.35 16.90 60.96
PLACEBO 40 19.90 17.45 13.46 17.90 18.03 15.03 46.26

Table 1V. Exercise at Ground and Altitude.

B. Tolerant versus Intolerant Responses (Figures 8 &

)

Only 5 of the 80 lower body negative pressure testing

runs at ground were complicated by intolerance, and all
5 intolerant runs were associated with beta-blockade.
Since intolerance was uniformly associated with beta-
blockade, it is not surprising that heart rate responses
between rest and peak LBNP at ground were blunted in
theintolerant subjects, compared to tolerant subjects (59
+ 5.8 to 71 + 7.1 vs 73 + 15.7 to 85 + 20.0, P=ns).
Likewise, mean arterial pressure fell to a greater degree
during LBNP stress in the intolerant subjects, compared
to tolerant subjects (88.5 + 8.9 1076.7 + 7-7 vs98 + 11.7
to 97 + 19, P< .05). Stroke volume fell in both groups,
and the difference between intolerant and tolerant sub-
jects was insignificant (93.5 + 18.6 to 74.5 + 12 vs 84.3
‘+ 20.7 1067 + 19.3). Systemic vascular resistance (Figure
10) increased in tolerant subjects, and decreased in
intolerant subjects with increasing lower-body negative
pressure (1,383 + 325 to 1,511 + 431 vs 1,322 + 229 to
1,020 +328, P<.01).Insummary, intoleranceat ground
during beta-blockade was most associated with an im-
paired rise in heart rate and progressive peripheral va-
sodilation in response to the orthostatic stress. These
responses are comparable to intolerant responses at alti-
tude.

Compared to ground, both tolerant and intolerant
subjects had higher heart rates resting at altitude (76.6 +
14.3 and 78 + 13.3 vs 73.4 + 15.7 and 59 + 5.8, P=ns).
Similar insignificant differences were returned for mean
arterial pressure and stroke volume. With lower-body
negative pressure, tolerant subjects showed a slightly
exaggerated rise in heart rate (76.7 + 14.3 to 87.3 + 18.0,
P < .05), fall in mean arterial pressure (98.7 + 12.7 to
95.7 + 12.5, P=ns), and fall in stroke volume (92.7 + 26
1077.7 + 23, P< .05), compared to ground level testing.
Asa result, systemic vascular resistance (Figure 11) rose
in tolerant subjects between rest and. peak tolerated
lower-body negative pressure (1,289 + 390 to 1,420 +
364, P=ns). In contradistinction, intolerant subjects had
a blunted rise in heart rate (78 + 133 to 79.7 + 15), 4
significant fall in mean arterial pressure (95.8 + 12.7 to
77 + 12.3, P < 001), and a paradoxical rise in stroke
volume (90 + 21 to 98.3 + 30, P=ns) between restand
peak tolerated lower body negative pressure. Examining
individual alterations in stroke volume, the response of
intolerant subjects to increasing lower body negative
pressure was a progressive decrement in systemic vascu-
far resistance, culminating in a vascular resistance much
lower at peak LBNP than it was at rest (1,177 + 325 to
949 + 247, P < .05).

12


Executive SUMMARY

Background

A study was initiated by the University of Oklahoma
in October of 1986 that addressed a long-range Federal
Aviation Administration (FAA) need to develop a stan-
dardized aviation-stress-specific human testing proto-
col, which could be used to assist in assessing the safety
of specific medications employed by civilian pilots. De-
cisions to permit use of medications are currently based
largely on non-aviation related clinical data; and, al-
though very thoroughly executed, such decisions would
be improved by the availability of relevant performance
data. Additionally, the National Transportation Safety
Board’s Class III, Longer Term Action, #A-84-96, rec-
ommended attention to research addressing potential
effects of both licit and illicit drugs on human perfor-
mance in all transportation modes.

The study herein described was defined to address a
subset of overall FAA research needs and NTSB research
recommendations. Specifically, the University of Okla-
homa, represented by the principal investigator, Dr.
Steve Teague, developed a testing protocol adaptable
primarily to cardiovascular-acting drugs; and, to the
antihypertensive atenolol (a beta-blocking agent that is
the most prevalent of those beta-blocking agents certi-
fied by the FAA for use in civilian pilots).

Methods

The protocol, which is described in detail in the
attached primary report, exposed the test subjects to
stressors considered representative of “maximum” civil
aviation stressors, defined for the purposes of this study
as (a) 12,500 feet altitude exposure in a hypobaric
chamber, (b) = 2.0 Gz accelerative stress simulated in a
seated lower body negative pressure (LBNP) device, (c)
75-100 watts exercise output ona bicycle ergometer, and
(d) part-task simulation of required flying skills using a
computer screen presentation and keyboard. These lev-
els of stress are normally exceeded only in emergencies or
in unique subsets of civilian aviation duties. For ex-
ample, altitude exposures above 12,500 feet are normally
compensated with supplemental oxygen, and higher Gz
levels are developed normally only in aerobatic or in high
maneuvering applications, such as agricultural spraying.

This protocol that was followed can be characterized
as a double-blind randomized placebo controlled inves-
tigation of responses to atenolol. All subjects (15 males
and 5 females) qualified for the study via physical exami-
nations based on FAA Class III certification standards,
and also had entry blood pressures of 140/90 mm Hg or

greater.

During the approximately 8 months of hypobaric
chamber-based testing, which was carried out by the
University of Oklahoma staff in a collaborative effort
with FAA Civil Aeromedical Research and Education
Divisions at CAMI, each subject was exposed to the
multi-stressor sequence at approximately 1 and 3 months
of both the placebo and drug phases of the study.
Appropriate crossover time was factored into the study
design. The noninvasive methodologies employed in the
study included continuous electrocardiography, an au-
tomated differential transducer sphygmomanometer, a
transthoracic bio-impedance monitoring device (to evalu-
ate cardiac pump function), continuous wave Doppler
monitoring (to further assess cardiac function), and a
transcranial Doppler (to evaluate cerebral blood flow
velocities).

Results

Each subject had 4 test days, with 1 at ground level
and 1 altitude test session per test day; thus the entire
collective of test sessions numbered 160 (20 subjects X4
test days X 2 test sessions per day). The monitoring
methodology permitted successful delineation of physi-
ological and performance decrement in this test collec-
tive. All subjects completed the extended testing sequence.

Of the 160 test sessions, 35 were terminated for
hemodynamic intolerance. Only 5 intolerant responses
were recorded at ground, and theses were attributed to
beta-blockade. The remaining 30 intolerant responses
were seen at altitude, and 60% of these were attributed
to the combined effects of altitude and beta-blockade.
Intolerance to hemodynamic stress (lower body negative
pressure) at altitude appears to be accompanied by
progressive vasodilation in which the heart remains
relatively unimpaired and progressive augmentation of
stroke volume is observed. This cannot be described a
cardiovascular presyncope, but rather a phenomenon of
arteriolar resistance.


STUDY #3 (AV THROUGHPUT) STUDY #4 (AV THROUGHPUT)

PT DRG G3 _GL3_—A3_—sCAL AL4 A4 GL4 G4

BAK 8B 16.0 17.4 13.9 18.0 14.1 15.1 17.2 20.9
BON B 10.3 13.8 21.3 24.9 18.2 14.4 20.0 21.9
BUR B 13.2. 185 19.5 16.8 20.9 15.6 22.8 18.9
CLA B 16.0 19.6 145 15.1 21.9 17.3 16.6 19.8
GAR B 22.6 42.4 26.6 22.6 25.6 32.6 24.9 34.6
HAR B 126 11.8 23.7 13.6 13.7 14.5 15.7 19.9
HEN B 24.4 24.2 27.3 20.8 19.2 24.8 21.8 26.1
PIN B 40.4 45.0 49.9 48.7 21.6 44.6 40.6 40.1
PNK B 32.3 34.6 29.1 33.8 20.2 32.4 27.2 27.8
RUS B 16.3 22.7 29.6 13.5 20.6 21,7 21.8 23.7
BETA AVG 20.4 25.0 25.5 22.8 19.6 23.3 22.9 25.4
BETA sTD 9.1 11.1 9.7 10.4 3.4 9.7 69 6.7
BIR P 25.0 27.3 30.6 22.0 18.9 20.9 25.4 20.4
BOU P 1.9 12.9 14.6 17.5 12.2 18.5 14.2 14.7
GRI P 15.2 15.1 25.5 18.9 14,1 18.2 16.7 27.4
MCG P 19.2, 188 187 11.2 9.8 18.5 9.2 20.8
ODE P 31.7 33.6 34.6 32.2 32.5 31.2 28.7 29.6
POM P 15.5 19.2 15.0 17.3 16.8 21.4 22.2 21.6
SEL P 19.1 17.4 23.2 19.5 16.2 22.8 25.7 29.7
WAL P 13.6 15.8 19.0 20.9 15.2 16.4 18.5 21.0
WEG P 16.6 20.4 28.9 24.4 14.3 20.9 27.2 26.8
WES P 27.5 25.5 29.8 29.5 28.4 31.0 20.1 26.7
PLACEBO AVG 21.9 20.6 24.0 21.3 17.8 22.0 20.8 23.9
PLACEBO _—STD 62 60 66 5.8 6.8 49 5.9 4.6

Table Vi (Continued). Cognitive Responses. (Sorted By Treatment And Test Conditions.)

However, some responses were recorded with no
bradycardia, but a widening in the S to D ratio (Figure
18).

Frequently, the intolerant endpoint was preceded 2 to
3 minutes by a detectable increase in the S to D ratio of
the transcranial velocity profile. Frequently, the investi-
gators were warned of impending intolerance by pro-
gressive widening of this ratio from resting values.

Cognitive Responses (Table VI)

A. The learning curve

All subjects manifest a distinct learning curve during
administration of this abbreviated Walter Reed perfor-

21

mance battery. Average throughput values (correct re-
sponses/minute) for subjects representing the upper,
middle, and lower terciles of performance on the battery
showed average throughput values of 22.05 + 9.2, 23.8
+9.1, 25.8 + 8.7, 26.3 + 11.7 for repeated administra-
tions spaced by 40 minutes, respectively. These data
showed a gradual improvement of response from appli-
cations 1 to 2, and 2 to 3, then with a slower rate of
response from 3 to 4. This slowing of the rate of
improvement appeared to indicate either fatigue or a
plateau in the learning curve.


Technical Report Documentation Page

T. Report No. 7. Government Accession No. 3. Recipient's Catalog No.
DOT/FAA/AM-92/19
@._ Title ond Subtitle 3. Report Date

September 1991

TOLERANCE OF BETA BLOCKED HYPERTENSIVES DURING 3. Perlarming Orgonization Code

ORTHOSTATIC AND ALTITUDE STRESSES

8. Performing Organization Report No.

7. Authors) Steven M. Teague, M.D. and
Jerry R. Hordinsky, M.D.

9. Performing Orgonization Name ond Address 10. Work Unit No. (TRAIS)

FAA Civil Aeromedical Institute
TV. Contract or Geont No.

P. 0. Box 25082 DTFA-02-86-85098
Oklahoma City, OK 73125

13. Type of Report and Period Covered

72. Sponsoring Agency Nome and Address

Office of Aviation Medicine
Federal Aviation Administration
800 Independence Avenue, S.W. Td. Sponsoring Agency Code
Washington, D.C. 20591

15. Supplementary Notes

16. Abstract

To evaluate the effects of orthostatic, altitude, and pharmacologic stresses upon civil aviation-specific performance,
a double-blind, randomized, crossover trial of ‘atenolol, 100mg, was designed and executed. Hypertensive males and
females qualifying for the FAA class 3 certificate with mean age of 34 were studied during simulated altitude exposure
to 12,500 ft, orthostatic stress, and moderate exercise. Seated lower body Negative pressure to -40 mmig supplied
orthostatic stress simulating +2G vertical acceleration. A total of 160 lower body negative pressure tests were
performed, 80 at ground and 80 at altitude. Beta-blockade caused 9 modest impairment in orthostatic tolerance. Five
‘of the 80 lower body negative pressure runs at ground Level were marked by intolerance, and all of those responses were
in beta-blocked subjects. Of the 80 altitude runs, 30 were terminated for intolerance, of which 18 included beta-
blockade. These findings had a Chi-square significance value of P< .05. The effect of altitude was significant at
P< .01. Ina modest exercise protocol (100 watts for 3 minutes) meant to be no more stressful than the exertional
requirements of piloting an aircraft during adverse conditions, neither beta-blockade or altitude appeared to limit
performance.Quantitative performance on a computerized cognitive battery clearly demonstrated impaired performance
during lower body negative pressure stress at altitude. The degree of impairment was significant compared to a
learning curve response at the P < 001 level. The degree of impairment was similar for placebo treated and beta-
blocked subjects.

Monitoring of mean arterial pressure, heart rate, and stroke volume was necessary for quantitative analysis of
hemodynamic responses to these stressors. These parameters demons: ‘ed progressive decrements in systemic vascular
Teciscance in intolerant subjects, implicating a defective peripheral autonomic nervous system response. Moreover,
monitoring of systemic vascular resistance, blood pressure, and transcranial Doppler middle cerebral artery flow
velocities allowed prediction of impending cognitive and hemodynamic collapse.

These data implicate the synergistic deleterious effects of beta-blockade and altitude in the potentiation of
intolerance to orthostatic stress. These findings may have most revelance to the personnel of unpressurized aircraft
who are being treated with beta-blocking drugs for hypertension. No common clinical parameter predicts subsequent
intolerance. It appears that only formal stress testing will uncover orthostatic-prone individuals.

17. Key Words 18. Distribution Statement

Hypertension, Beta-blockers, Document is available to the public through

Orthostatic Tolerance, Hypoxia, the National Technical Information Service,

Medical Certification Springfield, Virginia 22161

19. Security Classi. (of this report) 0. Security Clossif. (of this pege) Zi. No, of Pages | 22. Price
Unclassified Unclassified 36

Form DOT F 1700.7 (8-72) Reproduction of completed page outhorized


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Fundamentals of Aerospace Medicine.R.L.DeHart,
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nn

SUPINE STANDING

MEANS BPS BPD BPM HR BPS PD BPM HR
N = 40 PLACEBO 140. 92.5 108.0 80.0 141, 95.5 110. 85.0
N= 40 BETA 130. 83.3 98.8 64.5 129. 88.7 102. 67.8
N=55 TOL 138. 88.7 105.0 72.9 139. 93.8 108. 76.8
N=35INTOL 1317, 86.6 101.0 71.3 130. 89.6 103. 75.7
STANDARD DEVIATIONS

N= 40 PLACEBO 15.8 8.41 9.55 10.6 17.9 6.74 9.25 9.82
N= 40 BETA 15.9 995 11.2 746 17.2 11,1 11.5 8.38
N= 55 TOL 17.8 9.32 11,1 11.9 18.6 7.99 10.0 12.2
N = 35 INTOL 14.2 11.50 11.6 12.0 16.9 11.6 12.1 12.8

Table VII. Prestress Orthostatic Blood Pressure and Pulse. (Sorted By Treatment And Tolerance.)

B. Post-test measurements (Table VIII)

After the altitude chamber runs and ground level
testing, the subjects collected 24-hour urine for the
determination of the fractional excretion of sodium.
Sodium excretion values were no different between
placebo and beta-blocker subjects. In addition, frac-
tional excretion of sodium failed to discriminate subjects
that had been intolerant to lower body negative pressure
from those who were tolerant (.73 + .18 vs .67 + .19).
‘Twenty-four hour ambulatory blood pressure monitor-
ing showed lower values for systolic blood pressure (122
+ 10.6 vs 130 + 19.8, P=ns), diastolic blood pressure
(77.2 + 8.9 vs 82 + 8, P=ns), and mean heart rate (64 +
7.3 vs 74 + 9.2, P< .001) in beta-blocker versus placebo-
treated individuals, Sorting the data on the basis of
tolerance or intolerance to lower body negative pressure,
the tolerant subjects had insignificantly higher values for
systolic blood pressure (126 + 19 vs 125 + 11), diastolic
blood pressure (82 + 9 vs 78 + 8), and heart rate (70 + 10
vs 68 + 9) than those of intolerant subjects. In view of the
lack of statistical significance, these mean 24-hour blood
pressure and heart rate values cannot account for the 35
orthostatic intolerant runs, Hematocrit did not predict
intolerance either (46.6 + 3.4 vs 47.7 + 3.9).

SUMMARY

In summary, the following answers to the key ques-
tions presented in the introduction were provided.

1, Beta-blockade in this double-blind randomized
placebo controlled cross-over study caused a modest
impairment in orthostatic tolerance. Five of the 80
lower-body negative pressure runs at ground level were
marked by intolerance, and all of those responses were in

24

beta-blocker subjects. Of the 80 altitude runs, 30 were
terminated for intolerance, and 18 were attributable to
beta-blockade. These findings had a Chi-square signifi-
cance value of P < .05.

2. Altitude is a potent factor, potentiating orthos-
tatic intolerance, Of the 35 intolerant runs, 30 of those
were recorded at altitude, The effect of altitude was
significant at P < .01 level.

3. Ina modest exercise protocol, meant to be no
more stressful than the exertional requirements of pilot-
ing an aircraft during adverse conditions, neither beta-
blockade nor altitude appeared to limit performance. All
subjects were capable of exercising to 100 watts, and
maintaining that exercise level for 3 minutes, even at a
simulated altitude of 12,500 feet.

4. Quantitative performance on the Walter Reed
cognitive battery clearly demonstrated impaired perfor-
mance during lower body negative pressure stress at
altitude. The degree of impairment was significant com-
pared with a learning curve response at the P< .001 level.
‘The degree of impairment was similar for placebo-
treated and beta-blocker subjects. The significant con-
tributing factor to cognitive dysfunction during LBNP
at altitude was sudden incapacitation. This phenom-
enon often resulted in cognitive collapse and inability to
continue cognitive testing even though the orthostatic
stress had been released. In no set of testing conditions
could a cognitive impairment effect be demonstrated
due to beta-blockade alone.



ALTITUDE RESPONSES
beta blocked vs placebo

<)
x=
2
> 3
a
o

oon

BPM,

REST

Figure 6. The hemodynamic descriptors MAP, SV, and HR are

PEAK

plotted between rest and peak tolerated lower

body negative pressure while at a simulated altitude of 12,500 feet. Means are plotted. Placebo treated

responses are compared to

Both beta-blocker and placebo-treated subjects aug-
mented systemic vascular resistance during lower body
negative pressure, with values rising to 1,534 + 481 inthe
placebo group versus 1,458 + 394 in the beta-blocker
group. These differences were not statistically significant-
(Figure 7).

‘Thus, the minus 40 mmHg seated lower body nega-
tive pressure stress test induced typical physiologic re-
sponses to orthostatic stress in the subjects, with
decrements in mean arterial pressure and stroke volume,
accompanied. by a rise in heart rate.”

beta blocked responses. Beta-blocked patients had significantly lower mean
arterial pressure and heart rate at rest and peak tolerated LBNP (P < .001).

‘The only significant beta-blocker effect seen at ground
lower-body negative pressure stress testing was the blunted.
rise in heart rate. This appeared to be offset by a higher
stroke volume at any given level of lower body negative
pressure stress, such that adequate cardiac output and
systemic vascular resistance were maintained.'*""

As already mentioned, 30 of the 80 lower body
negative pressure runs at altitude were complicated by
intolerance. Since the majority of these responses, which
are characterized by hypotension and bradycardia, are in
the beta-blocker group, the intolerant physiologic state
heavily biases the group altitude data.


GROUND SVR RESPONSES
1600
om oT
E 1400+ goo
v4 e
3 i p=.01
£ 1200+
Ss I
« 1000+ a
a
800 t +
REST PEAK

Figure 10. Systemic vascular resistance responses between rest and peak tolerated lower body
negative pressure for intolerant (I) and tolerant (T) subjects. The intolerant response was marked by
significant depression in systemic vascular resistance in response to orthostatic stress (P < .01).

ALTITUDE SVR RESPONSES
1600
~ OT
ive)
14004 goo
: e
9 i p = .01
= 1200+
Cc
& 1
~ 1000+ e1
B |
800 + '
REST PEAK

Figure 11, Responses of systemic vascular resistance between rest and peak tolerated lower body
negative pressure for tolerant (T) and intolerant (1) subjects tested at altitude. Intolerance was
marked by a significant decline in systemic vascular resistance between rest and peak tolerated
lower body negative pressure (P < .01).

ll