preoperative psychological state and the adrenal response to
TRANSCRIPT
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Yale Medicine Thesis Digital Library School of Medicine
1964
Preoperative psychological state and the adrenalresponse to surgeryJonathan Jay RussYale University
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Recommended CitationRuss, Jonathan Jay, "Preoperative psychological state and the adrenal response to surgery" (1964). Yale Medicine Thesis Digital Library.3113.http://elischolar.library.yale.edu/ymtdl/3113
PREOPEFATIVE PSYCHOLOGICAL STATE AND THE ADRENAL RESPONSE
TO SURGERY
JONATHAN J. RUSS
YALE
MEDICAL LIBRARY
Digitized by the Internet Archive in 2017 with funding from
The National Endowment for the Humanities and the Arcadia Fund
https://archive.org/details/preoperativepsycOOruss
Preoperative Psychological State
and the
Adrenal Response to Surgery
by
Jonathan J„ Russ, A.B.
A Thesis
Submitted to the Faculty
of the
Yale University School of Medicine
In Candidacy for the Degree of
Doctor of Medicine
The Department of Psychiatry
School of Medicine, Yale University
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ACKNOWLEDGMENTS
This study could not have been executed without the assistance and co-operation of a number of individuals.
I should like to thank Dr. Ben Bursten for his supervision and guidance from the inception of the planning of this work to the com¬ pletion of its writing, and also for obtaining financial support for the typing of the interviews. Without his persistent adherence to rigorous standards of proceedure and thought, this thesis could not have reached its present form.
Dr. Thomas T. Amatruda was unstinting of his advice concerning the metabolic problems involved in this research, and also in supply¬ ing laboratory facilities with which to carry out the necessary lab¬ oratory work. The staff of his metabolic research laboratory was most helpful in aiding the author in learning the proceedures of the plasma cortisol determination, and in carrying out themselves the urine keto- genic steroid determinations.
Dr. Robert K. Marvin and the Department of Anesthesiology at the West Haven V. A. Hospital were of great help in controlling the type and length of anesthesia, and in assisting in drawing the blood sample taken while the patient was ungoing surgery.
finally, I should like to thank Dr. W. W. Lindemuth and the surgi¬ cal staff at the West Haven V. A. Hospital for consenting to this work with their patients and for whenever possible predicting herniorraphies several days in advance of operation. The nursing staff was instrumental in achieving a remarkably high proportion of successful 2U hour urine collections.
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CONTENTS
Introduction.............. • ••.<>.. 1
Hypothesis .....3.4
Materials and Methods......14
Results ....... ® 22
Discussion. ............... 30
Summary. .. 41
Bibliography...42
Appendix I... .1'
Appendix II. .....7 *
Appendix III. ....S'
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PREOPERATIVE PSYCHOLOGICAL STATE AND THE
ADRENAL RESPONSE TO SURGERY
INTRODUCTION
It is well known that the physical stress of surgical operation
can induce an increase in adrenocortical activity to many times the
basal levels in patients with normal endocrine systems,(15*21,27*28,35
lil,31j53a57,62) a2,so known that emotional stress, including pre¬
operative emotional state, is capable of affecting corticosteroid
levels independently of physical trauma,(U,8,19,22,26,37>h7*!'rd,5>0,5>2)
although values remain "within the normal physiological range.It
is the purpose of this thesis to investigate the possibility that pre¬
operative psychological states affect adrenocortical activity during
and after surgical proceedures.
Steroids and Psychological Factors
Although other substances present in the body have been found
to correlate well with measurements of certain emotional states, in
recent years investigators have tended to concentrate their attention
on the hormones synthesized by the adrenal cortex, particularly hydro-
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cortisone (compound F, cortisol). Even before techniques for deter¬
mining corticosteroid concentrations were widely available, it was
known that parameters dependent on adrenocortical function such as
salivary NaA ratio-^ and blood eosinophil levels-^ were affected
by psychological stresses. Dreyfuss and Feldman^ found a hh% drop
in the average eosinophil level in medical students awaiting examina¬
tion, and hypothesized that emotions act through the hypothalamic-
pituitary-adrenocortical route to produce an increase in corticosteroid
levels in the body analogous to that attained as a result of physical
stresses.
More direct estimations of adrenocortical activity have been
made using techniques capable of measuring the concentration of cor¬
ticosteroids and their metabolic products in the urine (17-GH cortico¬
steroids, 17-ketogenic steroids) and in the blood (17-OHCS, IIOHCS).^
In all of the blood determinations, cortisol is the major component
measured, but the absolute concentrations recorded vary with the par¬
ticular method used (acid fluorescence, phenylhydrazine reaction, etc.)
and it is therefore not possible to compare directly the levels measured
by various investigators.
There is evidence that even the process of collecting blood
samples may cause a significant elevation of cortisol levels in the
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blood of subjects. Davis and co-workers0 found mean serum cortisol
levels in the blood of subjects undergoing an anticipated unknown pro-
ceedure (venipuncture) to be significantly higher than the second time
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the same—by then familiar-- proceedure was performed* Although they
relate this finding to a "first time effect," it would seem more
accurate to attribute it to anxiety over the concealed nature of the
proceedure, rather than to the fact that it was a new esqperience.
They did, in fact, find a correlation of +.6U, significant at the
0*02 level, between the cortisol levels of the individual subjects
and their scores on the Sarason general anxiety test.
Many workers have found that anxious subjects tend to have
higher corticosteroid levels than non-anxious controls. Persky et. al.^7
found plasma and urinary hydrocortisone concentrations to average 60-
70$ greater in subjects judged anxious by psychiatric interview than
in those not considered anxious. Florica and Muehl1^ compared the
plasma cortisol levels of nineteen subjects achieving high scores on
the TajSor Manifest Anxiety Scale with the cortisol levels of thirty-
one low-scoring subjects, and found the former to be significantly
higher (Q.Q05> level) than the latter. The relationship between ele¬
vated corticosteroid levels and anxiety is widely accepted#(ii*22,U8,52)
There is less evidence to indicate that corticoid levels may
be lowered, as well as elevated, by psychological factors. Handlon
et. al. °found that subjects viewing certain dull and relaxing films
responded with a lowering of steroid levels, and suggested that the
adrenal cortex responds to events of emotional significance in ordinary
experience by raising or lowering of plasma corticosteroids. Occasional
fall of these corticoids to extremely low levels (0-3|$) has been more
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recently noted to occur in deep hypnotic trances,^ tending to return
to normal levels within 90 minutes after termination of the trance.
There is no agreement among experimenters about factors that may de¬
li press steroid levels, Bliss^ found that monotonous and repetitive
tasks did not significantly change plasma cortisol concentrations.
Depression and psychomotor retardation have been found to be asso¬
ciated with elevated, rather than decreased, corticosteroid concen¬
trations
As evidence accumulates it appears that psychological turmoil,
rather than anxiety alone, is the psychic state that is best correlated
with steroid level elevations. Eosinopenia— a sensitive indication
of cortisol elevation— has been reported to occur in manic-depressive
patients during depression, as well as agitation.^ Sachar et. al.,^
in a psychiatric and endocrine study of four acutely psychotic patients
extending over a period of months, found elevations of steroid levels
in blood and urine to occur during periods of excitement and depression,
and reported normal levels during recovery and “psychotic equilibrium,•»
These findings are consistent with the fact that steroid levels are
generally normal in chronic schizophrenic patients.-^ It seems that
corticosteroid concentrations are more influenced by the effectiveness
of the psychological defenses used by the individual than by the par¬
ticular type of psychological defense used. Previous work (Burster^)
has shown that inadequacy of coping mechanisms may be associated with a
predictable physiological response, whether the psychological distress
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is manifested by agitation or by depression.
Psychological factors may cause changes in patterns of corti¬
costeroid levels in the blood as well as changes in the levels alone,
33 Kral"^ found that abnormal diurnal patterns of steroid-dependent valuefe
(eosinophil count and salivary NaA) were most likely to occur in patients
for whom there was difficulty in making a psychiatric diagnosis. Persky,
Grinker and co-workers^? noted that patients with high levels of anxiety
showed less of an adrenocortical effect of additional psychological
stress than did patients who were less anxious.
The general hypothesis of the workers in the study of these
psychoendocrine relationships seems to have been that a psychological-
cortical disturbance affects the adrenals by way of the hypothalamus
and pituitary (ACTH)U* with a tendency toward a direct relationship
between the extent of the psychological stimulus and the adrenal re¬
sponse, This hypothesis cannot yet be regarded as proven, in the ab-
scence of measured changes in ACTH secretion concomitant with psycho¬
logical stress. The possible individual variations in steroid con¬
jugation (liver), excretion (kidney), and even in physiological re¬
sponsiveness to a psychological stimulus must also be borne in mind,
although there is no way to allow for their effects in evaluating
data. That these factors may be significant is shown by the impossi¬
bility of predicting in any single case what the steroid response to J
psychological stress will be. Bliss et. al. persistently found a
proportion of patients who were marked exceptions to their expectations.
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as in those subjects who had extremely low steroid levels at a time
when they appeared extremely anxious. The cortical-hypothalamic-
pituitary-adrenal explanation nevertheless is adequate to account for
most of the data most of the time.
Steroids and Surgical Stress
Any consideration of variation of normal corticosteroids with
stresses such as surgery must necessarily be evaluated against the back¬
ground of normal variations in unstressed individuals. There are two
types of variation involving blood cortisol levels ordinarily. The
first is that of normal biological variation from individual to indi¬
vidual, which in the case of plasma cortisol determinations may en¬
compass a normal range (8 a.m. samples) of about 10%» where the mean
normal level is about 2Q$% (see method section for further details).
The second type of normal variation is temporal, consists of a diurnal
variation in blood levels of cortisol, and seems to represent actual
changes In the activity of the adrenals during each 2k hour period.^
Normally, cortical activity of the adrenal is highest at 6-8 a.m. and
11 lowest at about midnight. This cyclic pattern is remarkably constant
and resistant to change, and is usually unaltered by working night hours
or by blindness.^ Perkoff et. al.^ found that in 5>1 normal subjects
plasma 17-QH corticosteroids were lower at U a.m. than at 8 a.m. in all
but ohej lower at it p.m. than 8 a.m. in all but five; and lower at noon
than at 8 a.m. in all but seven. These same workers found the daily
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. . • .: c . t • arid- ' . '. : '-oo . . i
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variation to average about 8.5 in a group of subjects that averaged
about l6J$>$ 8 a.m. levels. Thus it can be seen that the daily variation
in plasma cortisol levels in a normal individual is about as great as
the range of values among the majority of normal individuals. It is
therefore obviously important to allow for the diurnal variation in
attempting to draw conclusions about the significance of differences
in the adrenal activity of experimental subjects. It has been demon¬
ic strated^7 that steroid levels elevated due to stress are still suscep¬
tible to the effects of diurnal changes, and the data of Sachar et. al.^4
show the same diurnal variation in patients with elevated plasma cor¬
tisol concomitant with psychosis.
After surgical trauma, burns, shock or other severe physical
stress there is usually an increase in the concentration of cortico¬
steroids circulating in the plasma. The length and extent of the oper¬
ative proceedure tend to be related directly to the maximum plasma
57 steroid concentrations reached after surgery. Maximum levels are
usually reached between four and twelve hours after operation,-'^ but
pronounced rises have been observed as early as one-half hour after
66 incision. Most workers have not taken blood samples between incision
and one hour afterwards. Early uniform increase in plasma corticoids
has been observed in patients undergoing severe operative trauma (thora¬
cotomies and cholecystectomies). It is currently believed by most
investigators that this response to surgery is caused by increased
corticosteroid secretion under the influence of a greater AGTH stimulus.
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perhaps aided by retardation of the normal mechanisms of corticosteroid
removal from the bloodActual increases In blood levels of AGTH have
been measured during operation, and it has been found that in most
patients maximal levels are found early in the course of the operation
7 (one-half hour postincision). Adrenal capacity does not limit the mag¬
nitude of the response, since it has been observed that administration
of AGTH after operation will almost always cause an additional rise
in plasma corticoids.^*^ The corticosteroid response is also mani¬
fested in rises in urinary excretion of 17-OHGS which follow and are
more prolonged than the changes in the blood, as well as in secondary
effects of elevated steroid levels, including negative nitrogen balance,
eosinopenia, and changes in caloric consumption.15*27jU1,62 p^aslna cor„
tisol levels are generally again back to normal levels within 2U hours
after operation. 9 Although the typical response to operation has
been described above, it should be noted that some workers* data indicate
that not all patients elevate their plasma corticosteroids in response
to surgery;36j5-7j67,71 some 0f them even show a drop. Most, but not
all, of the patients who failed to show a rise in steroid level under-
67 went a relatively minor operation such as herniorraphy. Failure to
show a rise was most common among, but not unique to, patients given
spinal anesthesia.
The anesthesia used in preparing the patient for operation has,
in itself, a significant effect on plasma corticosteroid concentrations,
and one which varies with the agent used. The time elapsed from the
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onset of anesthesia to time of operation tends to be directly related
to the presurgical steroid level if ether is used* and to a lesser ex¬
tent with N2O and Halothane also.^6 There is apparently no blocking
effect of deep surgical anesthesia on the neurohumoral reflexes in¬
volved in the elevation of corticosteroid levels, but spinal anes¬
thesia probably blocks some of the afferent impulses necessary for
1 1 /C7 7*1
a typical response to surgery (see above). 99 (Some authors re-
35 57 port a good steroid response with spinal anesthesia, * but the
reason for this discrepancy is unclear.) According to Viikari and
Thomasson^ all general anesthetic agents except ether cause a slight
fall in corticosteroid concentration when the length of presurgical
anesthesia is short. Data obtained after an hour of uninterrupted
67 anesthesia ' reveal a significant rise with ether, but only slight
and inconsistent changes with cyclopropane, thiopental-^0 and spinal
anesthesias. In summarizing the effects of anesthesia on corticosteroid
levels, it may be said that ether stimulates a marked rise, spinal
probably interferes with the neurohumoral reflexes necessary for a
normal response to surgery, and no other anesthetic agents cause a
pronounced change, although there seems to be a tendency for an early
drop in cortisol levels. Individual response to anesthesias other
than ether varies, and cortisol levels in some patients may rise under
36 66 the same conditions in which those in other patients fall." 9 ' It
is at least theoretically possible that the changes ©ccmrLng in cor¬
ticosteroid levels during anesthesia are not a direct result of the
effects of anesthesia itself, but may be due to interference with other
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factors that tend to either elevate or depress steroid concentrations
in the blood„ Such an explanation would help to account for variations
in individual responses to the same anesthesia.
The importance of the corticosteroid response to surgery is
clear only in the uncommon case of its inadequacy, when the patient
21 may go into irreversible shock. In animals, a vigorous response has
been associated with a good postoperative course, but in humans it is
felt that a very wide range of responses is compatible with an uneventful
5l convalescence. Some workers believe that persistent postoperative
elevation is related to an increased incidence of complications,-^
but no clear relationship between adrenal physiology and convalescent
course has been established.
Psychological Factors and Surgery; Relation to Steroids
The relationships of psychological factors to surgical illness
and operation are manifold, and may range from why a patient chooses to
J 6h undergo operation to why his symptoms may persist after he has been
29 successfully operated on. The segment of this subject with which this
thesis is concerned is the psychological state of the patient during
the preoperative period.
While awaiting surgery, the patient must face many types of
30 threats, some actual and others symbolic. Janis describes three
major forms of actual imminent dangers acute pain, mutilation, and
dying. Since there is little that the patient can do to directly influ¬
ence or alter the nature of his actual danger, he is in the position of
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having to cope with it by psychological mechanisms, rather than by
30 39 69 action. 9 9 Illness, hospitalization, and the passivity of the
patient’s role in surgery tend to foster functional and psychological
39 regression, and the degree of dependency may be little related to
the patient’s prior behavior or the degree of his actual danger.
The patient's preoperative psychological state is apt to be
more a result of fantasied dangers than of the actual dangers of an¬
esthesia and operation. These more intrapsychic threats are dependent
on (l)the patient’s premorbid personality, (2)the meaning of the im¬
pending operation to the patient. Including his feelings about anes-
rtlaiii i
thesia and ’’incisional attack,” and (3)the patient’s emotional/^to the
surgeon,10 as well as temporary changes in his economic, domestic, social
39 and sexual patterns. Both the anticipated anesthesia and operation
lend themselves to unconscious ideation, with anesthesia often equated
39 with death or loss of control of impulses-^ and operation itself with
30 39 sadomasochistic fantasies. The patient may have more specific
69 fears of castration, separation or delivery, particularly if the op¬
eration involves relevant areas of the body. Janis^0 notes that ”a
high level of preoperative fear appears especially likely if one faces
hernia repair or hemorrhoidectomy and less likely if one faces an ap-
pendectongr,”
As the result of the threats to the patient occasioned by the
operation, real and imagined, conscious and unconscious, he experiences
an anxiety signal.10 This is usually dealt with by some degree of denial
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65 of the danger* As listed by Titchner the levels of this denial
aret (l)Suppressionj The patient is aware of his operation and of
his danger, but endeavors not to think about it. (2)Constriction of
ego functions The patient will go to great lengths to avoid doing any¬
thing that might bring his tru<| physical condition with its implications
to his attention. (3Repressions The patient becomes unaware of his
physical state and/or impending treatment. (U)Complete denials The patient
actively denies his illness and asserts his health. Janis'0 lists four
similar levels, but emphasizes the psychological means by which the
patient achieves denials (l)suppression of unpleasant thoughts, (2)
isolation and repression, (3Rationalization and displacement, and (U)
defensive dominance and negativism. The relationship of anxiety sig¬
nal and successful denial to psychological stress in the preoperative
patient is the key problem in the evaluation of patients with respect
to the effect of psychological state on corticosteroid responses.
Elevated plasma corticoids have been found in preoperative pa-
22 tients. Franksson and Gemzell took blood samples on the morning of
surgery, and on the mornings of the two days before in 33 surgical
patients. Twenty-six out of the group had a higher 17-OHCS level on
the morning of operation than on either of the two days before, and
only three failed to raise their level in the last 2h hour period.
37 Mason obtained similar results, and remarked that the elevations
are "physiologically significant elevations which seem to characterize
the response of healthy ^subjects to psychological stress.15 Not all
-12-
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investigators have corroborated these findings, however, and some have
reported that plasma cortisol levels on the morning of operation are
36 66 not significantly higher than those of their control groups. 9
In rating the psychological stress of preoperative patients most
workers have evaluated anxiety. Price, Thaler and Mason-’’0 found that
"anxiety” was not an adequate description of the psychological state
of their preoperative patients, whose "emotional responses were di¬
verse," including states of resentful anger, active hostility—"high
states of emotionality, but not always anxious ones."5° They also
demonstrated that other characteristics (as measured by Rorschach)
including "unpleasant content" and "neutral content" (inverse cor¬
relation) correlated better with preoperative steroid levels than did
"anxious content," They rated their patients on the basis of "discomfort-
invivement" rather than anxiety, "Discomfort-involvement" was defined
as a measure of emotional involvement including agitated depression as
well as anxiety, a class of states in which "the clinical diagnosis was
of relatively little importance when contrasted with the amount of
50 feeling evidenced in the current situation." Discomfort-involvement
ratings made by psychiatrists and psychologists correlated with corti¬
sol levels drawn on the day before operation at a better than $% con¬
fidence level. The concept of discomfort-involvement would appear to
be a reasonable description of the state of emotional turmoil found by
other workers to be better correlated with elevated steroid levels than
any single emotional state.
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b.b t: ,• ?.jixc-^ds ovidsxaqor-xq rid.fr: lodded badGlai'ioo (cioxd da'i
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icy , . » -x
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t d ■ to* dd« • #ie•'-0' ’ •
.ed-,dc Xanoidowa aiqn-fr. £na
HYPOTHESIS
Review of the literature reveals no previous study attempting
to relate preoperative psychological state to changes in adrenal function
during and after surgery. It was expected that the effects of surgery
and psychological stress on steroid levels would tend to summate, and
the hypotheses were therefores
I Patients with higher degrees of discomfort-involvement
(and/or with higher scores on a test of anxiety) will
have a greater production of steroids during and after
surgery than those with less discomfort-involvement
or anxiety.
II Patients with higher degrees of ’'apathy-withdrawal'*
(essentially the reverse of discomfort-involvement, and
16 partially derived from Engel's concept of "depression-
withdrawal" as a primary affect) and/or with higher
scores on a test of depression, will have a lesser pro¬
duction of steroids during and after surgery than those
with lower degrees of these psychological states.
MATERIAL AND METHODS
The Patients N-10
All patients were white males scheduled to undergo a unilateral
.. ' : ' • ^ ■
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■ ■■ :o ■ • . ' 1 ."
j-v...jj:. oJ- ivt >y o.Lxrov; a. .ova'. bioisda no au id's . .bo.-:;;.o.' ov.q ,«?*; hub
te'so'i&J&tii' i-r: ■: isuodco'. /• eud-
■ i as j j:u fladi ■
, ; ' ■ )
, j ' .‘ti'jU •’ SbJtO'.SJdv. ‘.to 'XOX'+.i.'f Q'xCl ’ISvi’iiOIQ 0 9v.»it
oei i[«±± - a ■ / ■ 1 '■ . ' cwb
. 'o ox.iriB ■ o
io'.cvf” o aop'if'.w ) 'lori','- e'.,\ f.v*xu aJcxoj-v/c IX
• o .u.u-d-';:o‘J .ooaxb lo aev.eva-a or'J- ■ ,I.; f-cduoaiy ,
c\f ,iy> ‘..o oonoa a’. o;- iii\ ov.:. !.->©••/X'ao; •^xXeio -B',
o\bn (do • 8
... oil JLljfcw tiioXi’- ■ > -'O daed s no esnoot
Otitf l7<3ud ;jt/:j u ..i"C iijC'Itfb SbXO‘. 'fids .'.O fiOXduifb
0 , : . 5 : '• ■
■ >lk uIASi T
m ■ aboif od lbslx/bsrios aeien odxrfw a'low adiioidsq XXA
inguinal herniorraphy. They were screened by history and laboratory
examinations for abscence of endocrine, liver and renal disease likely
to interfere with normal production, metabolism and excretion of cor-
23 tic©steroids.
The age of the patients was not limited. According to Samuels,-^
hormone levels (corticosteroids) in the blood are not significantly
altered by aging, although there is a slight decrease in the maximal
capacity to both produce and metabolize adrenal steroids in men over
65. Pincus confirms this statement,^ but Nilsson et. al.^ found
patients over the age of 70 to have the same order of rises in plasma
corticosteroids due to operation as younger ones.
Patient #s 123U56789 10 mean age
Ages 6 9 35> 30 6l 31 S3 71 U8 k9 57
The rank-order coefficient comparing ages of the patients with the
change in plasma cortisol levels from just before the operation until
the last sample taken (three hours later) is r1 = +.19* statistically
insignificant, indicating that the age of the subjects did not affect
their response to surgery as manifested by plasma cortisol levels.
The Physical Stress
The patients were usually informed of the date of their operation
on the day prior to it. They were routinely premedicated with seconal
-15-
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. . ii ,9/xtioo re "to 90i»9«d» tot anoWanlM**
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, llOT-iiGOoj..)'
'<■-,8 .ui .g:. oi- .li’ -reoo, .ba*jtedtf. *on »» ainaWsq «B lo •&»
ion o-ib bool- stl* ni (a6tow»*>oii-a>t-) alavaX anomton
± m ii! » irisiJ » * it •»<» <•*»*« ■ « '-■■■1 1
JV;, at EDlnied-a Jjmwi »ilXoda#aB 6m sooboiq rfiod o» y?l9«V»
iobbJ n it t* II »i ' ; ■ ■'•■■■ ■ ? ■ • ■
sresslq ni eosi-t to tebuo aras 9.X avsd oi' OV to ago onJ w» ataixir.q
. o as no-t oX awf) a b£o*if>XaooiX'iOO
, isor.L jl o 8 . T ^ c ^ ^
,rn XV £'<i Xc: Ot c& V-'
X : v; XiteiXjvi
.J X ..ii; aXn Xd-' • oriJ Vo aa&s ^ni^GqroOO Xnaioiliooo ioh%o->JtBi 9(ir£
id .• c X rx« .. - • ' - • 1 BBi ‘ 3 a '
.. ...^iXsiXBXa t". .+ - W a± (?aXaX vsjjod e-ait) neJifiX «Xqw6« *»®X
oat r(X *3 a; ■ •■■■■ c,: - -
. . >X l±ns ifi ' ■ ■ « ’Ltt -i'/
o xXc .;.>-.o.CP/-;flci otiT
,toiJ XrjiiX lo aXsb ariX 'io bat/iolai: tflBURU w»w aXaeiXsq sc?i
ifIO{ * r/ ^ ao
and atropine* known not to cause significant changes in steroid
levels^-5 Premedication was usually administered about one-half
hour before the beginning of anesthesia, and although in some
patients (those operated on early in the morning) it preceeded the
drawing of blood for the d a.m„ sample of the morning of operation, the
data (appendix II, figo 1) do not support the hypothesis that it may
have lowered the cortisol levels in this sample from these patients
due to sedation.
Anesthesias Induction was achieved with pentothal, and the patient was
then maintained with cyclopropane for the duration of the operation.
Patients received succinyl choline during endotracheal intubation. One
patient (#li) received maintainence intravenous insulin in a slow drip
during operation. The time of presurgical anesthesia was always be¬
tween 10 and 15 minutes.
Operations The operative repairs were all unilateral, uncomplicated, and
lasted between 1 hour 20 minutes and 1 hour b$ minutes. In the opinion
of the surgeons, there was no unusual surgical trauma in any of the
operations.
Herniorraphy was chosen because of (l)the relatively standard
degree of physical trauma involved,(2)the relatively high degree of
psychological stress likely to occur,J (3) the generally good state
of health of the patients undergoing this elective proceedure, and (U)
the frequency of the operation. Pentothal-cyclopropane anesthesia was
chosen because it is not known to cause any significant change in corti¬
sol levels (as does ether) or any interference with the typical adrenal
-16-
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JB : Jj fan ■»» <“>-W*otl .»
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„ voio s xit aHanai auoaava-Btal aoneittotiiiaB bovieoa* W taett.-aj
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.BodMilm <iX job 01 neavAt
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t, , o <o::j ni .a»taxta cl I boa aodirxt.au 02 iwori 1 ao&vtea beJesl
• o • m i: r, ur. -J JLaol&suB Saaemus on asw •‘xeftt tanoosiua on<> lo
. cno.cJ’s'-xoqo
• sbfxi d-fci ^Levirfalei arid-(I) lo aaifisoac fl«norio anw ^dqs'fioxineti
(s)* - ; ■ u •rS3
oi-Rd-a oo . «* CO °C^ooo o* <*«**£ araut* laoiaoloiiow
. -nr. to'inbot>oo'iq avjrfoala exxid ^nlo^obnn x&noidrsq art lo Mlted lo
. ; : , - - toi w* ■ • • ' ' 0 COaauprA *&
-jtteoo id 3sn*suo daBotlJtasis yns oei/so oJ- riwokt>: *oa si j.fc aanuoacf noaoiio
. :, yi art rtxv sono'. ol'irtnt y.nc -xo (mitt* «»ob as) alovsJ .Coa
-61-
response to surgery (as does spinal anesthesia)
The Psychological Parameters
Interview? The patients were interviewed on the evening before
their scheduled operation, (In no case was the operation postponed.)
They were encouraged to talk about the operation, particularly feelings
of discomfort or uncertainty about it, and also about their terifencies
to be ’’nervous,'9 although the interviews were not rigidly structured,
nor was there a fixed set of questions asked. The interviews were
about 35 minutes average length, and an attempt was made not to intensify
or allay the patient’s feelings about the operation during the course of
the interview. The interviews were recorded on tape, typed in duplicate,
and evaluated as a group by two judges after all data had been gathered.
Ratings? The interviews were ranked by the two judges on the
5o basis of discomfort-involvement as described by Price, et. al. Patients
were assigned no score, but simply a rank relative to the other patients.
The judges did not consult over the ratings, but proceeded independently.
An original intent to also rank the patients on the basis of "apathy-
withdrawal” was not carried out, because of the lack of evidence of
this affect in the interviews.
Judges? The judges varied in experience. Judge #1 was also the
interviewer and the author of this thesis, and was a medical student
with limited experience in interview rating. Judge #2 was an experienced
research psychiatrist. The judges had previously discussed the ratings
-17-
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j 3'VOjCV' )d'I(.C JiiT » ' .:. '.cj i3iiOJCCi’w3i/f* XO S <J10* to ofc»T. >U
'iiibiu.'oii£ oo* ./on obaei affw dtj^adds a& w. a- eiuvs M&niba «iv. ovjoug
'..o ... uoo arid1 ;; >f: a nold’unst o Hid ' ••• ' '■ •: '• • -°
: j J; t 0 ~ 1 '■
. . . ■ wad bad Bdfi > X/; • tv: • > , .v, o*: ov ■ ' ■ » • 1 •
add- no Bogbui. owd add ^d no oan ersmt smiv'sed-ni: oil'..: ta-jfifctek
oJ-j•, .. .. • Cl . : .. ® ■ iO< ci '-0 :.: . 1
. . It
. jMn9brloqahcit, b&b&ooQ'ici dud *i. • 1 d o ■ - 'J 1
.. ; ; • io aissaf arid- n< id seidcq e J w o sis od h u fat I«n. o at
:.o eon»birvo :'osl arid- lo oaufload tduo bolrriBO don anu §IiWB*ibrid.fcw
. ;uo±vnf"d ..J: mix ai dcoVxe a£dd
laJtiJtt * aswr boa ^ajfcaorid aixld io k d ra iid ■. c. .:
. •. ■ - C b ...
... . ■ sjfc dairis ton
of five other pilot patients on the basis of discomfort-involvement.
Neither of the judges was aware of the steroid values or test scores
of the patients at the time of rating.
Anxiety test and Depression inventory's Immediately after the
interview, the patients answered a paper-and-pencil test (see Appendix I)
consisting of (l)a depression inventory developed by Beck, et, al.
comprising 21 multiple-choice items, and (2) a condensed form of the
Taylor Manifest Anxiety Scale. The questionnaires were not perused
or scored until evaluation of the interviews had been completed.
Comments It was chosen to rank the patients on the basis of dis¬
comfort-involvement because of the association that had been demonstrated
50 with preoperative cortisol levels. The Taylor MAS was used because of
31 its tendency to correlate with physiological variables, particularly
steroids.^ The depression inventory was considered a reasonable ex¬
ample of tests of its type.
Abbreviationst On occasion in the balance of this paper the
following abbreviations will be used*
D-I]_ = Discomfort-involvement of patient, ranked by judge #1.
B-I2 * Discomfort-involvement of patient, ranked by judge #2.
MA s Score of patient on Taylor Manifest Anxiety Scale.
DP s Score of patient on depression inventory (Beck),
The Physical Parameters
Blood Sampless Five blood samples were drawn from each patient, as
-18-
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. ,•;■ •'niioo 21 . >• relvne'tiiJfc and j.o no .i6i/j.sv9 Xidnt/ ba^oot* io
‘•aJ: .to .,:••• ai.d ;o ad* ■. iter e>«,t :iasi od* neeo»:.o ar.u dl :on»vmoO
. , . . ... - : ■ iid* lo jBxrsoac iaexnsvlovfii-d .
'^.slevel loeld-ioo •▼X#B*X0qoertq ricMw
> < wt»- -■ ■ "
... ■ i *:. eiiT . ••5
«oqv;d* ao*± to ad ood* lo 9-IqiviB
[.•]• ,1/td* t o . g -.a o;•.. xi joiusroo cr* »y^5*i*AV‘*
: .r iss ed I.:..c .• tv(c>id*siv9iduft oI.: ot.
xi • lo > ■ IffiOi :
:c . >vn±-d* ol/no: * : -
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. t, ; ,:oo ,f /rtJc lio.ceso’sqs. xto ineid-sq lo 91008 3 it).
_ . oil.
: BSlcJpIBB JO 9 - . j .J.
described belows
#1 The first sample was drawn, when possible, 8 a.m. on the
morning of the day before operation (six patients). On occasion, the
decision to operate was made by the surgeons late on the day before op¬
eration, and an 8 a.m. sample drawn earlier in the patient's hospital
stay was substituted. In two cases this was drawn five days before
operation, in two other cases, eight days before. The patients were
never certain of the date of their operation until the afternoon of
the day before surgery, so it might be expected that their psychological
state would not be too dissimilar on the morning of the day before op¬
eration and on several mornings before. There is no statistically
significant difference between the means of the cortisol values of
the subjects having the sample taken one day before operation and
those having it drawn five or eight days before. (Festinger's x non-
parametric test for the significance of differences between meansj
ncU , m s 6 , d ® .25, where it would have to be equal to or greater
than 2.50 to indicate a difference significant at the $% level of con¬
fidence.)
#2 The second sample was drawn at 8 a.m. on the morning of
the day of operation.
#3 The third sample was drawn in the operating room while
the patient was anesthetized, and immediately before surgical incision.
#U The fourth sample was drawn in the operating room while the
patient was still undergoing surgery, Jj.5 minutes after sample #3.
#5 The fifth sample was drawn in the recovery room, three hours
after sample #3. At this time the patient was usually conscious, but
quite drowsy.
-19-
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■:.c. od L '.u > oc od aver! blno. dx o- arlrf . a b t d ~ . * J » n
) id
(♦ooxieblH
jr/r^no; a..d :o ... *s .• dr. nrnb as;. eI<jr'S8 bnoooa oxfT S-:,\
. iO.;:d ;'.o qo Ho ;;e.i arid
. nidsneqo odd tit iwenb saw alcpiBB y.xnd ariT
. .'.sox^'iiJR anoHed -^XadBibantoi brjs t. »i fcdadda ns .• - '
([o d . , . a.. -i x i*3 aril
. ;.. s ; di I < . v. jjc jnxognobnu .Clide iusw dni Ida -
. . .. d t ooi ••x&voxoi axld n.t xa-,3*xb alqpxse ridHXH sriT
t - cd ■ . ' i- . ., o.
. ..cjT.-o'in adiifjt
At each sampling blood was drawn into two 10ml, tubes (Vacutainer)
each containing 10 mg. of powdered EDTA (ethylene diamine tetraacetic
acid). The blood was centrifuged immediately, and the plasma frozen
at 0o to 10° F. until determination of plasma cortisol.
The cortisol determination used was a modification of the De Moor^
fluorometric analysis, and measures 11-OH corticosteroids (cortisol +
corticosterone in approximately Usl ratio). Nevertheless, the readings
are generally considered “plasma cortisol,,n Duplicate samples were run,
and had to agree within 10$ of each other before they were accepted. The
final eluate was read on a Farrand Photoelectric Fluorometer, with a
U00-800 mjl primary wavelength, and a secondary filter passing 535-570
ir^i. Normal 8 a.m. samples range from about 15-25Q% using this method.
In order to rule out the possibility that medications or other
impurities might have been influencing the cortisol reading, selected,
samples were analyzed using a Keirs Spectrophosphorimeter, scanning from
200 to 800 n^i. No evidence of contaminating fluorescence or interfering
substances was noted (fig. 2).
Urine Sampless Twenty-four hour urine specimens were also col¬
lected from each patient on the day of surgery and the day afterwards?
I#1 from 8 a.m. on the day of surgery until 8 a.m. on the next day.
I#2 from 8 a.m. on the day after surgery until 2li hours later.
The urine was frozen and later determinations of urine 17-ketogenic steroids
(KGS) were done by the regular laboratory staff of the metabolic research
laboratory at the West Haven V. A. Hospital, using a method derived from
-20-
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' 4 sxltjlU
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. rio*il
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-OS
the work of Norymberski,^ and utilizing the Zimmerman reaction.12*^0
Normal standards are not established for this determination at this
laboratory, but probably range about 8-22 mg/2li hours.
Proceedure
Care was taken to avoid bias in rating of D-I manifested in the
interviews. None of the physical data was known to the judges at the
time of rating. Plasma cortisol values had already been determined by
judge #1, but the tubes had been randomly mixed and coded by another
person. The urine KGS values were recorded by the laboratory personnel
in a notebook, but were not read until after the ratings were made. The
psychological tests (MA and DP) were not scored until after rating of the
interviews was completed. In addition, the order of the interviews was,
of. course, known to judge #1 (the interviewer) but was concealed from
judge #2, who was unaware of the patient numbers until after rating
was finished. As a result, the judges read the interview transcripts
in different orders.
Statistical Proceedures
Because some of the major data (D-I) was present only in the
form of ranks, and also because of the unjustifiability of assuming
a normal population distribution in a group subjected to an acute and
similar stress, it was decided to use the rank correlation coefficient to
test possible associations. The rank correlation coefficient is com-
-21-
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. • .. d. ■ )!
**i' do ax dm
i. s-i'ioo Dinm exld sen od bobiosb aow d.c ^aaendu 10.
00 IT . anoidaiooBaa oicfiaecM d
_
puted from the formula5^
r} =
n (n2 - 1)
where r* = the rank correlation coefficient
D = the difference between a pair of ranks for a given subject
n = the number of pairs of ranks (= the number of subjects)
Significance of the correlation coefficients was evaluated using a
table computed from the data of E.G. Olds (Annals of Mathematical
Statistics, 1938, £, 133-1^8). Olds® tables show the distributions
of sums of squares of rank differences for small numbers of individuals.
(The t-distribution is an inadequate approximation of the rank difference
distribution for n of 10 and below.) The use of this statistical
technique does not require the assumption of a normal population
distribution.^
62q2
RESULTS
The data measured during the course of the experiment are re¬
corded in appendix II. Certain useful values derived from this pri¬
mary information are presented in appendix III A-C, and the changes
occuring in the plasma cortisol levels of each patient are charted
against the time of day in figure le It is important to note that
values standardized to an 8 a.m. level (by compensating for the normal
-22-
a t
rsJjjF’col &>id fijO'/Jt ; odxrq
(j- ** ~*0 n
i \ io loddsla'rxoo lusi arid => *1 9'xerfw
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(ad; jj ?•> . ) jj { and ») ar'. i v : 'io ai.f:G< io twmim arid 53 n
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. :d .9 i v . io -u' abJ.O .1 .b 'io sdnb © id- »• o*/i oadtf<y.voo aloud
. 1 . ■ . ... id. id
h,': (j: io s^e.i u. t IXsao '..o'. i.v o \I'/eil.i i tr.x io aoiBi/pa ‘io a ur. io
iiio V( •*. o J- . o o.';J . o', o od j/ 9 sax ns ox noJ:di/< ..irdoxL-d or .)
.'. d io 881/ sdT (•wolsd . io Ttoi ■ ■ V . .': I■ .
j'XtzJji or rsmron . '. o acidt^ x/c ;n aid oxfci/po-j: doa &«oo ai/pjfcnriood
.aoidadir^dciib
8Tt'i ueaa
s ' i io ob roo arid ban/asai sdsb aril'
ii< -l id .ox! • o/jt'ioi aw/Inv .u/loajj nxnd . <.■ ,.□! xxbnoqqu njfc bob'ioo
ti-A XXX • .xbnoq- ,s :lc bod'it -*:.q omk ao±d&»< • coin.! ^ty
i.ic fi,\ d. fvcdsc riosa io a.CovoX . o xdnoo 'V-tasIq arid njfc ^niurooo
» • ■'! njt vfib io or-, id add
- o; ) ... .in od i ’ ; 0’.;jj ■■■■
drop in plasma cortisol during the daylight hours^—see also fig* 1)
were used in calculating most of the derived data. The reasons for
using standardized values rather than measured values in comparing
samples drawn at different J-iraes of day have already been discussed.
In describing implications of the descriptive statistical values that
will be presented, those corresponding to the commonly used level of
p<*05 will be called "significant," those with a p^.Ol will be called
"highly significant," and those with a p between .05 and ,10 will be
called "suggestive" or "tendencies."
The average of the four (#2-#5) plasma cortisol samples drawn
on the day of operation may be considered indicative of relative
adrenocortical activity during the portion of the day including the
immediate preoperative, operative, and early postoperative periods.
Since the half-life of cortisol in the plasma is usually less than
23 one hour it might be expected that the relative elevations in plasma
cortisol levels would be reflected in relative differences in 2k hour
urinary KGS excretion, providing plasma cortisol levels during the com¬
plete 2k hour period were proportional to those during the sampled
periods. Rank-order correlation of the average of standardized samples
#2-#5 with urinary KGS excretion on the day of operation yields an
r* of +.28, however, not significant.
The correlations of the psychological measures used with each
other are recoreded in table 1. All of the tests of significance used
were two-tailed —as are all the tests in this thesis unless otherwise noted
-23-
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_oC_
except for that comparing the two D-i ratings. It is felt that a
TABLE 1. Rank-order correlations of the psychological measures with each other (for abbreviations see p.18)
D-Ix with D-I2 r« s +.h9 P<.08 *
D-Ij_ with MA r» S3 +.U6 NS
D-I2 with MA ri s +.U8 NS -8-one-tailed
+.5U test; all others
D-I-j. with DP r1 s NS are two-tailed.
D-I2 with DP r9 - +.U1 NS
one-tailed test is appropriate in this instance, because only a pos¬
itive correlation would have been accepted as indicating that both
judges were rating the same phenomenon in the same manner. It can
be seen that there is a tendency for the ratings of discomfort-involve¬
ment made by judge #1 to correspond to those made by judge #2. None
of the other psychological measures are even suggestively correlated.
Scores on the Mfi. scale showed a wide distribution (range 1-31
out of a maximum possible score of 5>0) with an average score of 12,
but the depression inventory (DP) yielded a narrow range of scores,
running only from 0 to 6, and were very low, averaging 2.8 out of a
possible maximum of 62. (appendices I, II)
Correlations of the individual plasma cortisol samples with
psychological measures are shown in table 2. Although sample #1 was
taken prior to the time of interview in all patients, and very much
prior to interview in four of them (for justification for combinging
v • •> jS vi • j. .fl • 3 aid' I-( *j - v.- lid : ■ too d’sdd*
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. o AI . _ £*i: ;a p'A ;:A xorio :onm*n air8 e/iA J:Asn OAaw ae^Awi,
-o i.': ..y.1-. ooaxf' A.o •/ A:A ... yriA ':o‘i prtebiifsA c gJfc aieiiA AsrfA noou gef
- o . >jfc . ubsi a 93o-'A oA bno; t .. :. oo oA o^ou^ vc. d\fta •.
. :.A .Aaff-'-'iWa u&.e . ; ao'x/jBsopi 1 scI;;o.-..o.':o-'A'-'. '.cox.to ruiA Ao
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■ - • 'A loAni lo araxA -.A oA 'xoir'xq naxifiA
l- '"o.. V -r.A. A i. '■x'Tl) *i*A '..o M/o'i nx 'slv’y.. Anx oA tojtocq
these samples* see p. 19) it can be seen that there is a marked re-
TABLE 2. RANK-ORDER CORRELATIONS OF INDIVIDUAL CORTISOL SAMPLES " WITH PSYCHOLOGICAL MEASURES —
D-Ii d-i2 MA DP
(#1) d a.m. one, five or eight days preop*
+.32(NS) +.86(p<,01) +.Ui(NS) +.25(NS)
($2) 0 a,m, on morning of op. -.08(NS) -.06(NS) -.59( PC.08) -,iiO(NS)
(#3) just before incision +.31(NS) +.31(NS) +.05(NS) -*39(NS)
(#1;) U5 minutes after #3 -,21(NS) -,23(NS) +.07(NS) -.U5(NS)
(#!>) 3 hours after #3 -,26(NS) -*36(NS) -*65(p<.06) -.15(NS)
lationship between D-I2 and the level of plasma cortisol in the first
blood sample. Also to be noted is the tendency for MA to inversely
related to the second and fifth blood samples (the first and the last
on the day of operation,)
Correlations of the 2h hour urine ketogenic steroid excretion with
the psychological measures are presented in table 3* It can be seen that
TABLE 3 Rank-order correlations of 1? KGS (2it hour) on op, day witfo psychological measures
KGS with D-Ix r» ■ +.29 NS KGS with D-I2 r1 =» +.01 NS KGS with MA r» ”■ +*5U NS KGS with DP r» = -.13 NS
-25-
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-. :c;_
none of the correlations is significant.
Use of the average of samples #2 through as an indication of
the relative adrenocortical activity during the operative and immediate
preoperative and postoperative periods has been discussed above. Cor¬
relation of this average with the psychological measures (table h) shows
TABLE Ij. Rank-order correlation of average standardized cortisol levels {#£+$34$k+$5/k) on op day with psychological measures
Average with D-Iq_ r» = -.02 NS Average with D-I2 r» = -.19 NS Average with MA r* = -.5>9 p<.08 Average with DP r» = -.23 NS
a suggestive inverse relationship to the scores on the Taylor MAS.
It can be seen in appendix III that 8 a.m. plasma cortisol levels
on the morning of operation average 5>.2^$ lower than those from 8 a.m.
on the day(s) before operation. This calculated difference is not,
however, statistically significant (t = 1.79; pXlO).
Other changes in plasma cortisol levels, those on the day of
operation, may be derived from the data in appendices III A, B, and
C. The only highly consistent change in adrenal activity found was
a net rise, usually pronounced, between sample number 3 (just before
operation) and sample number f? (three hours after the beginning of
operation). Only one out of the ten patients showed a drop in plasma
cortisol over this period (patient #3). Including all patients, the
change in plasma cortisol during this three hour period averaged an
actual rise of +l£.0^ %f and an effective change of +l8.it$ % (when
-26-
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jxd'.o. o . . c * > ■ ■
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., . c; i - d) diiaollxa ;i,1.1 Gold-axdcd’G tiovo :o/I
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• - . Ill qs >d Id- . .o .1 beviiob 9 if jam tnoxd rxoqo
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• ...
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standardized values are used in the calculation)* Both changes
are statistically highly significant! using the t-test corrected
for correlated data, the results are:
for actual change: t = 3*36 p^o01
for effective change: t = 3.94 p<<,01 „
It is of interest that patient #3, apart from being the only patient
•who did not raise his plasma cortisol levels from sample #3 to sam¬
ple #5, was also unique in having the highest actual cortisol level
at the onset of operation. This preponderant tendency toward ele¬
vated plasma corticosteroids after surgery is fully in accord with
the findings of the research described in the Introduction.
None of the other changes observed in cortisol levels on
the day of operation was consistent. During the period between
8 a.ra. on the morning of operation (sample #2) and the beginning
of operation (sample #3) the cortisol levels may either rise or
fall, but the change during the wait for surgery may be shown to
be significantly related to the length of time the patient had
to wait: r* - 4-*68 (p<i04). The longer the patient has to wait
for the beginning of surgery on the day of operation, then, the
more probable it is that his plasma cortisol levels will rise
higher (or fall less) by the time the operation begins. No pre¬
vious report of this relationship has been found in the literature0
During the first 45 minutes after the onset of operation
(sample #3 to sample #4) the plasma cortisol levels may again
either rise or fall over a wide range of values (+15«0^,? to
—8<>9 &$) • It can be demonstrated that subjects having higher
-27-
orfd- , *>***! 9T*>* to'i
*' - „ i
J
■ • .8 « - **“ *asi®i*« % I Jl
■ t- 0 -f odi •;■ _ • ■
• .... ... ■ 9 m *
’
10 f. . L 1
J
0 ■?;. i©i r\* o ' fte**!-'-* #&
, ' c ■"•-■ ■ m c k 3 ' i : * ' '■
. a . ■ ■ •> i .. ( »* »i ' ' "■
.. •
3 '■ '• ! ' :
, f f ‘ '
'* ■■ • l^V' '• -
-; -
cortisol levels at the beginning of operation tend to drop their
levels more during this period, while those beginning with lower
levels have a greater tendency toward elevation. The rank—order
correlation of sample #3 with this initial change during oper¬
ation is highly significant? r* = -„91 (p^o0l)o This same initial
steroid change is unrelated to the cortisol levels on the morning
of operation (sample #2): r' = -c38 (NS).
Correlations of changes in plasma cortisol on the day of
operation and changes in 24 hour urine KGS excretion with the psy¬
chological measures are shown in table 5. Although none of the
TABLE 5 Rank-order correlations of steroid changes with psy¬ chological ratings and tests
waiting change
(#2 to #3)
"~A1
+ol3(NS)
u— i ^ —-2-—-—
-o03(NS)
JUA
+.37(NS)
Vr
-<,29 (NS)
rate of waiting change(app. IIIB)
+.30(NS) +o23(NS) +.50(NS) .00(ns)
initial op. change
(#3 to #4) -.53(NS) -,55(p<ol0) -oOl(NS) +. ix(ns)
three—hour change (#3 to ;^5)
-.32(NS) -o54(NS) -.27(NS) +o09(NS)
fo three hour change(app. IIIC)
-.41(NS) -.46(NS) -.43(NS) +.21(NS)
drop (—) in 24 hr. KGS, op. day to
next
+.41(NS) +o10(NS) +.12(NS) -.06(NS)
correlations «*|s statistically significant, one relationship is sug¬
gestive, that of the inverse correlation between B-I as rated by
n. 91
Oi'to is ?*I9v91
Bg “Jo IK*i<tJ8-r- 91100
. — r. ' ■ :
7, ' r-.r jIoHOO
'■ oi
10 9 9 J
'
; o'jit
•-
o a tiov
.
'
t
’Vi'. 0 9 ailJ- 10
judge -#2 and the initial change in steroid levels -with operation.
Correlations that are statistically significant or suggestive
are summarized below (table 6).
TABLE 6 Summary of significant and suggestive statistical data
Items related relationship
(+ or -) * value P<
D-Il and D-I0 + r ' - +.49 o08
samples #3 and #5 (th^ee^hour)
actual effective
+15.ojfe +1&,4q%
.01
.01
waiting time and waiting rise + r1 = +068 .04
preincision level "(#3) with initial change (#3 to #4)
- r * = -.91 o01
sample #1 with D—In + r' =4.86 .01
sample #2 with MA ' - r ' = -.59 .08
sample #5 with MA - r' = -.65 o06
a,verage plasma cortisol on op da,y with MA
- r» = -.59 .08
D-I0 with initial change (#32to #4)
- r' = -.55 .10
■29-
. snoO
'
J ;• X 6 ’ t at: :*. J
■ . i--’ , ' —•
■’ v-v oi *' , *>£nti-ifo j
F c; •
- t\ ■■■,." v c o
c1 —i.i
(4^S o<J,“’‘S%)
_
DISCUSSION
It is -well known that physiological changes often accom¬
pany intense emotional states. V/hether emotion originates in
16 the mind, and is only secondarily manifested physically or is
on the other hand ’’cortically perceived but physiologica iiy <le-
32 termined” £ is an unsolved problem, but it is certainly possible
at this time to study the changes that take place in the body
concomitant with emotional expression.
One such association was the starting-point of this study,
namely, the demonstrated association of elevated steroid levels
22 50 with preoperative emotional states.1" 9 Because both psychological
and surgical stress cause increased levels of plasma cortisol, it
was the expectation in beginning this work that they would tend to
summate, or perhaps even act synergistically, and it was antici¬
pated that the more anxious, involved, or generally distressed
preoperative patients would tend to have a greater production of
steroids in response to surgery than less disturbed patients. It
62 has been demonstrated by Steenberg that a postoperative stimulus
to cortisol production (ACTH injection) appeared to be affected
synergistically by the proceeding surgery, and resulted in a greater
response to stimulus than in unoperated patients. If an ACTE
stimulus could suEimate with alreadjr elevated cortisol levels as
the result of preceeding surgery, then it seemed at least possible
-30-
avrocc . w ex il
.
ref oiq f’vAoartij ei
• oJ wi.w aidJ1
j;.. J- ■ -o M" i: -- j ; tUit o;ic o
.• j o: - t • •. gc 1i X^inr
; £ ■•. ■ .
.. ..iiu';, . i nx it. icf o-sqxs a bit
t
e,9i hi .'/••ioiei'a
. iJ' >.n : .q{> iig-’.-cI a ad
:. 109 ©3
.
!i.(b9<j09if, lo Jf.Cuesi edJ’
that a precceding ACTH stimulus due to greater emotional dis¬
turbance might summate with the subsequent adrenocortical re¬
sponse to surgical trauma.
One of the subsidiary expectations, based on the data of
22 Franksson and Gemzell'"" was that steroid levels would be higher
on the morning of operation than they were on the mornings of
earlier days. Although the measurements made in this experiment
do not directly contradict their findings (since the drop of average
steroid levels occurring between the earlier samples and the morning
of surgery was not statistically significant) they do fail to sup¬
port their results. No obvious explanation of this discrepancy
is apparent, but it should be remembered that other workers also have
failed to find cortisol levels on the morning of operation elevated
, , 36 ,66 above normal.
The association of high degrees of disconfort-involvement
with elevated cortisol levels on the day before operation re-
50 ported by price .et. _al. ^ was strongly supported by the highly
significant correlation of sample #1 with the B-I ratings of the
more experienced judge. It is interesting that despite differences
in method of rating (relative ranking used here, eight—point scale
used by Price) and in collection of samples (four out of ten of
this study's first samples taken earlier than one day before op¬
eration) such a strong confirmation of the earlier findings is
obtained. In both instances, the blood samples were drawn before
-31-
. -KtU. '( JO Oi O • <
-
»? ■
.
<)■ ,
0,T ■
- . ■... > 1 . J 9*ri< o »a ciu;_;-ie.
.
-
„ , , . . >»« ' o.i.tdO
_ _
the interview, and it may be that the precise number of days be¬
fore surgery is not an important factor as long as the patient's
state of anticipation is approximately the same. Also strfading
is the lack of correlation of D-I with the cortisol levels on the
morning of operation, in contrast to the strong relationship noted
with levels just one to several days before. The possibility of
anticipated relief, or some other change of attitude towards the
impending surgery occurring on the morning of surgery might be
responsible. The feeling of a measure of relief at finally facing
a feared event with the expectation of having it over with is a
common one, and may be shared by surgical patients on the morning
of their operation.
2 The depression inventory used did not correlatCat even
suggestive levels with any other measures, and the scores were
so low and clustered as to make it unlikely that it would be of
much help in differentiating the psychological state of one patient
from another. This may in part have been the result of an actual
low incidence and degree of depression among the preoperative
patients. Indeed, it was originally planned to include an ap¬
praisal of "apathy—withdrawal” in the ratings of the interviews,
but this was abandoned because of lack of occurrence in the inter¬
view data. But this, in turn, may have been influenced by the con¬
duct of the interviews, which were more geared to reveal anxiety
than depression.
The data indicate that in response to inguinal herniorraphy
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under cyclopropane anesthesia, there is a highly significant and
relatively uniform elevation of plasma cortisol levels within
three hours, that does not correlate significantly with any of
the psychological measurements. In the abscence of evidence to
the contrary, it may be concluded that this elevation is the
result of anesthesia and surgical trauma, probably primarily the
latter. The lack of any even suggestive correlations with psy¬
chological data of the three hour steroid change, and of both
individual steroid samples (#3 and #&) taken while the patient
was unconscious, suggests that the narcosis of anesthesia inter¬
rupts direct psychological effects on the adrenal cortices during
operation. It might be interesting to compare these data with
similar information obtained from patients undergoing operation
under spinal anesthesia, which might be expected to block some
of the effects of physical trauma on adrenocortical activity, but
not to interfere with psychological influences on ACTH secretion.
Psychological factors may help to account for some of the diverse
findings concerning the adrenal response of spinal-anesthetized
patients to surgery.
The data also show a significant correlation of waiting time
with the rise (or lack of fall) in steroid levels during that
time. -Since no blood samples were taken at the beginning of
anesthesia, it is not possible absolutely to rule out anesthesia
as the cause of these "waiting time" changes, or to separate any
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changes occurring during the wait from those in the first 10
minutes of anesthesia. It is felt that it is quite unlikely,
however, that a large proportion of these changes (in two cases,
rises even larger than the rise in three hours after incision )
could have been the result of anesthesia itself, because (l) the
time involved in presurgical anesthesia was probably too short to
allow a great change to occur, (2) pentothal and cyclopropane are
not known to cause any significant changes in steroid levels, par-
ticularly in the first 20 minutes, and (3) in none of the patients
operated on within 45 minutes of the 8 a.m. sample (five out of ten)
was there more than a minimal rise in steroids by the time surgery
was begun, even though the anesthesia was identical. These results
suggest that any person, irrespective of his normal tendency toward
anxiety or discomfort—involvement, will be likely to have elevations
of his plasma cortisol at the beginning of operation if he has
to wait for surgery for a relatively long time on the day of operation.
The change occurring in the cortisol levels during the first
45 minutes of surgery (#3 to #i) showed a marked inverse correlation
(r* = -09l) with the level at the beginning of surgery (:!&)• These
69 findings conform almost literally to Wilder 's Law of Initial Values,
which states that the higher a prestimulus level, the smaller the
tendency to rise with exciting stimuli, and the greater the ten¬
dency to drop with inhibiting stimuli. Uthough the Law of Initial
69 . Values is generally considered an "empirical law," ~ in this specific
-34-
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case there is probably enough known about regulatory factors
to enable a more specific explanation to be suggested. .Assuming
normal metabolism and excretion of cortisol during early surgery,
there are three main factors that may determine what the initial
steroid response will be: (l) a central, psychologic ally-influenced
action on the pituitary to promote the release of ACTH, (2) the
normal inhibitory effects of circulating cortisol, which can com-
pletely halt the release of ACTH temporarily if high enough, ' (3)
the early physical trauma of anesthesia and surgery, tending to
cause the release of ACTH —found to be maximal about one-half
7 hour after the beginning of surgery--* by neurohuaoral reflexes.
(1) and (3) tend to cause elevation of cortisol levels in the blood,
while (2) tends to cause a drop. (Since the half-life of cortisol
03 in the blood is short, normally about one hour, " it is possible
for a considerable drop to occur within 45 minutes as a result of
inhibited stimuli alone, without postulating abnormally rapid re¬
moval from the bloodstream.) At the beginning of surgery, factor
(1) will most likely no longer be operative, because of the nar¬
cosis of anesthesia. Factor (3) will depend on the severity of
the operation, and will probably not be initially very great in
a herniorraphy. Therefore ^t might be expected that the initial
change in pla-sma cortisol levels will tend to be dependent to a
significant degree on the levels of cortisol already present, which
is precisely what is found. The suggestive correle/tion of the
-35
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initial change with D—I0 (also inverse) may reflect the contribution
of D-I to the individual's preoperative cortisol level (sample #3),
even though correlation of D-I -with the preincisional level it¬
self may have been mashed by individual variations in basal physio¬
logical activity and reactiveness0 Thus the drop (if it occurs) in
the initial period of surgery may reflect t-wo factors, both suggested
by the statistical data* First, a drop primarily determined by the
inhibiting levels of cortisol present in the blood when other factors
ere relatively minimal, and second, a drop directly related to the
strength of the D-I stimulus that is lost with the narcosis of sur¬
gical anesthesia.
idditional evidence suggesting the importance of psychological
factors in affecting the preincisional cortisol level, at least po¬
tentially, may be found in the case of the one patient in the series
who did not show a net rise in cortisol levels by three hours after
incision (patient #3). This patient described a morbid fear of
hypodermic needles, and also had extraordinarily high levels of
cortisol when he was conscious. Although it was felt at the time
of interview that the patient's assertion that he would "rather
get an operation than a needle" was just another example of dis-
30 placement as a means of denial, further study of the transcript
of the interview shows this fear to be rather deep-rooted, going
back to terrifying experiences of inoculation while living in the
"county home," Although a causal relationship cannot be proven, this
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case may at least serve as a model of a hypothetical means by which
preoperative emotional state may alter the adrenal response to phy¬
sical trauma.
It remains to account for the suggestive inverse corre¬
lations of the TMAS with cortisol levels in samples $2, #5, and
average plasma cortisol on the day of operation (r#24#3-4#4+#5/4) e
The fact that there are no similar correlations with the individual
samples dr awn when the patient was unconscious emphasizes tile pos¬
sibility that there may be a significant relationship between
some psychological function reflected in the TMAS and plasma cor¬
tisol.
At this point it may be worthwhile to raise the question of
what psychological functions are measured by a test such as the
TMAS, and what its relation to the evaluation of interview material
may be. Can it be assumed that the test measures "anxiety” merely
because it includes the word in its title? According to Taylor,
the scores on the TMAS "tend to remain constant over relatively
63 long periods of time.” This, in itself, would tend to refute
the assumption, since anxiety in most persons is a considerably
variable state. Upon examining the questions in the test (ap¬
pendix I, pp. 5*—6*) it can be seen that they deal with habitual
feelings and reaction-patterns of the individual, rather than with
the way he is feeling at the time he takes the test. Can the test,
then, be said to show how easily and often an individual manifests
anxiety (as implied in its title) rather than anxiety itself? Sven
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this statement would be inaccurate, for most of the questions
deal with manifestations hardly unique to anxiety, such as sleep
disturbance, crying, feeling inadequate, and restlessness, as we 11
as sixteen questions (out of fifty) that seem to reflect the degree
of physiologic responsiveness (tiredness, blushing, headache, tremor,
bowel disturbances, vasomotor instability) to psychological states
rather than the ra nifestation of any particular emotion. It can
thus be seen that one should not expect the scores on the TMAS
to reflect what might be rated as anxiety on the basis of an inter¬
view. It would seem that Taylor's test is as much a test of the
ease of developing mental and physical manifestations of "disconifort-
involvement" as it is anything else.
With the realization that the TMAS tests something different
from what it purports to test, together with the idea of anticipated
relief, mentioned above, it may be possible to suggest an explanation
of the correlations with MA that were found. It may be that individuals
with higher scores on the TMAS are those who tend to resolve psycho¬
logical conflicts by psychosomatic means, and thereby subconsciously
become accustomed to expect release of psychological tensions by phy¬
sical routes. Thus it might he expected that individuals with high¬
er scores on the TMAS might paradoxically become batter able to
cope with the nature of their danger as the physic I threat becomes
more imminent. From what is known about psychological states and
steroid levels, it is likely that an individual will have 1c ;r
-38-
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steroid levels as his ability to cope with his situation improves,
even if the increased security is at the expense of using "patho¬
54
logical" mechanisms.
The overall findings of changes in plasma cortisol levels
on the day of operation do not support the expected relationship
of summation of the effects of preoperative psychological stress
and surgical stress on the adrenal cortex. It would be justifiable,
on the basis of the results of this study, to reject Hypothesis I
(p. 14) but Hypothesis II cannot be considered to have been adequately
tested, because of insufficient data gathered by the test of de¬
pression and techniques of interview used. The results do support
the concept that psychological factors may inf^ience the adreno¬
cortical response to physical trauma, although in a taore compli¬
cated fashion than had been anticipated. It appears that Wilder's
Law of Initial Values, in this instance explainable by what is known
of pituitary—adrenal relationships, is a pivotal factor, and perhaps
the only means by which psychological state can modify physiological
responses when the individual is unconscious. If the psyche "leaves"
the body in a state of excitement relative to the function being dis-
cussed, it is then less capable of responding to additional stimuli
that would ordinarily be effective in causing a more pronounced re-
69 sponse. "Inhibition by excitation""' is the key concept. Of course,
this thesis reports no date that would indicate broader application
-39-
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of the Lew of Initial Values than to adrenal-cortical function,
but it should serve to re-emphasize the importance of this concept
in psychophysiologic research.
If an impending surgical operation always represents a
real or imagined danger (or both) it also represents a stimulus
that can possibly modify the physiologic response to the intervention
itself. Whether or not the modification of the physiologic response
may be in itself physiologically significant it is not possible
to say. Patient #3—possibly because of psychological causes—
hod an inversion of the usual response to operation, yet similar
responses are known to occur in uncomplicated operations, and this
patient's convalescence was quite uneventful. The modification of
the adrenal response might be of more concern in more extensive and
hazardous surgery, but it is quite possible that it would be overcome
45 completely by a greater physical trauma. Gken and Heath have
recently written, "there is a definite possibility that the initial-
values effect operates as a determinent of prolonged stress response."
This study tends to support their conjecture, and to underscore their
opinion that it "deserves further study."
-40'
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SUMMARY
The literature dealing with psychological factors and steroids,
surgery and steroids, and psychology of preoperative surgical state
is reviewed briefly. It is noted that current evidence indicates
that elevated steroid levels occur with psychic turmoil of any type*
The experiment is described: ten white male patients undergoing
elective unilateral inguinal herniorraphy were studied psychologically
by preoperative interview and tests of ” anxiety ” and depression, and
studied physiologically by serial plasma, cortisol samples and 24 hour
urinary corticosteroid (KGS) excretion. Interviews were rated on the
basis of ‘’discomfort-involvement” and without foreknowleclge of any of
the other experimental measurements.
All patients except one showed a marked rise in plasma cortisol
levels by three hours after incision. The average rise was highly
significant. Highly significant correlations were also notec' between
the level of the plasma ©ortisol at the beginning of operation and
a tendency for the steroid levels to drop during the first 45 minutes
of operation, as well as between one judge’s rating of discomfort-
involvement and the steroid levels of the patients on the days be¬
fore surgery. The longer a patient waited for operation on the
day of surgery, the greater tendency there ms for him to have ele¬
vated cortisol levels when it b©gan0 Discomfort-involvement was
suggestively related to a fall in steroids during the initial op¬
erative period, "Anxiety” test scores tended to be higher in patients
with lower first and last cortisol levels on the day of operation.
The results are discussed and explanations of the results
attempted. Attention is called to T/ilder's concept of the Law of
Initial Values, and the process of "inhibition by excitation” is
discussed as central to the findings of this study, and easily ex¬
plainable in this instance on the basis of known endocrine physiology.
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BIBLIOGRAPHY
1. BASOWITZ, H, PERSKY, H., KORCHIN, S., AND GR1NKER, R., Anxiety and Stress, McGraw-Hill, New York, 1955*
2. BECK, A.I. ET. AL., An Inventory for the Measurement of Depression, Arch, Genl. Psychiat,, U:56l, 1961.
3. BLISS, E,L., Adrenalcortical Function in Schizophrenia, Am, J, Psychiat., 112:358, 1955-56.
li. BLISS, E.L., MIGEON, C.J., BRANCH, C.H.H., AND SAMUELS, L.T., Reaction of the Adrenal Cortex to Emotional Stress, Psychosom. Med., 18j56, 1956.
5* BURSTEN, B., Psychological State and Sputum Eosinophilia, Psychosom. Med., l£: 529, 1962.
6. BOARD, F., ET. AL., Depressive Affect and Endocrine Functions, Arch. Neuro. & Psychiat., 78:612, 1957.
7. COOPER, C.E., AND NELSON, D.H., ACTH Levels in Plasma in Preoperative and Surgically Stressed Patients, J. Clin. Invest., Ul:l599, 1962.
8. DAVIS, J., MORRILL, R., FAWCETT, J., UPTON, U., BONDI, P.K., AND SPIRO, H.M., Apprehension and Elevated Serum Cortisol Levels, J. of Psychosom. Resrch., 6:83, 1962.
9* DE MOOR, P., STEERO, 0., ET. AL., Fluorimetric Determinations of Free Plasma 11-OHGS in Man, Acta Endocrinol., 33: 297, I960.
10. DEUTSK, H., Some Psychoanalytic Observations in Surgery, Psychosom. ted., k,105, 191,2. -J—--
11. DOE, R.P., ET. AL., Correlation of Diurnal Variations In Eosinophils and 17-OHCS in Plasma and Urine, J. Clin. Endoerin. & Me tab., li;:77U, 195U.
12. DREKTER, I.J., ET. AT., The Determination of Urinary Steroids, J. Clin. Endoerin. & Metab., 12:55* 1952.
13. DREY FUSS, F., AND FELDMAN, S., Eosinopenia Induced by Emotional Stress, Acta Med. Scand., lUI(.:107, 1952.
lit. EDWARDS, ALIEN L., Statistical Methods for the Behavioral Sciences, Rinehart, New York, l£5Iu
”42”
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■ .. . . , .0 t:.. ;/ lTS .. . A- f':': :■ . f .on£ •.oooflfo s£p>. n.C GOHj-xX a jo*A
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15>. ELMAN, R., ET. AL., Adrenal Cortical Steroids Following Elective Operations, Arch. Surg., 71:697, 1955.
16. ENGEL, G.L., Anxiety and Depression-Withdrawal: the Primary Affects of Unpleasure, Int. Jourril. of Psycho-Anal., 1*3:89, 1962.
17. ESTABROGKS, R.A., ET. AL., The Effect of Surgical Operation on the Adrenocortical Response to ACTH, Ann. Surg., I50s9hl, 1959.
18. FESTINGER, L., The Significance of Difference between Means Without Reference to the Frequency Distribution Function, Psychometrika, 11:97, 19U6.
19. FIORIGA, V., AND MUEHL, S., The Relationship Between Plasma Levels of 17-OHCS and a Psychological Measure of Manifest Anxiety, Psychosom. Med., 2U:596, 1962.
20. FOX, H.M., ET. AL., Adrenal Steroid Excretion Patterns in Eighteen Healthy Subjects, Psychosom. Med., 23:33, 1961.
21. FRANKSSON, C. AND GEMZELL, C.A., Blood Levels of 170HCS in Surgery and Allied Conditions, Acta Chir. Scand., 106:2i*, 1953.
22. FRANKSSON, C., AND GEMZELL, C.A., Adrenocortical Activity in the Preoperative Period, J. Clin. Endocrin. & Metab., 15:1069, 1955.
23. GRAY, C.H., AND BACHAR AGH, A.L., (EDS.) Hormones in Blood, Academic Press, London, 1961.
2lu GRINKER, R., The Psychosomatic Approach to Anxiety, Am. J. of Psychiat., 113:1*1*3, 1956.
25. GRINKER, R., ET. AL., The Phenomena of Depressions , Paul B. Hoeber, New York, 1961.
26. HANDLON, J.H., AND OTHERS, Psychological Factors Lowering Plasma 17-OHCS Concentrations, Psychosom. Med., 2b, 1962.
27. HEIMREICH, M.L., ET. AL., The Adrenal Cortical Response to Surgery, II, Surgery, Ul:895, 1957.
28. HUME, D.M., Direct Measurement of Adrenal Secretion During Operative Trauma and Convalescence, Surgery, 52:l?Ii, 1962.
29. IMBODEN, J.B., ET. AL., Symptomatic Recovery From Medical Disorders, the Influence Psychological Factors, Journl. of the A.M.A., 178:1182, 1961.
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30, JANIS, I.L., Psychological Stress; Psychoanalytic and Behavioral Studies of Surgical Patients, John Wiley & Sones, New YorkTl5?B.
31, JOHANNSEN, W. J., ET. AL.,A Re-examination of the Hippuric Acid Anxiety RelationsKip, Psychosom. Med., 2kt569, 1962.
32, KRAJNES, S.J., Emotions: A Physiologic Process, Psychosomatics, lu313, 1963.
33• KRAL, V.A., ET, AL., Diurnal Variation Patterns of Circulating Eosinophil Counts and Salivary Na/K in Psychiatric Patients, J. Nerv. & Ment. Disease,129:69, 19^9.
3k• LAIDLOW, J.C,, ET. AL., The Diurnal Variation in Adrenocortical Secretion, J. oT"Clin. Invest., 33s950» 195U*
35* LEFEMINE, A.A., ET. AL., The Adrenocortical Response to Surgery,Ann. Surg., 150: 9kl, 1957. ““ “
36. LEWIS, R.N., Plasma Hydrocortison Concentrations in Relation to Anes¬ thesia and Surgery, Brit. Journl. Anesth., 35s8ii, 1963.
37. MASON, J.W., ET. AL., Psychological Influences on the Pituitary- Ad renalcor tic a 1 System, in Recent Progress in Hormone Research (ed. Pincus, G.) vol. 15, Academic Press, New Yorlc, 1959.
38. MENNINGER,G., Psychological Aspects of the Organism Under Stress, J. Amer. Psychoanal. As00c., 2:280, 195U.
39. METER, B.C., Some Psychiatric Aspects of Surgical Practice, Psychosom. Med., 20:203, 1958.
1*0. MIGEGN, G., The Diurnal Variation of the Plasma Levels and Urinary Excretion of 17-GHGS in Normal Subjects, Night Workers, and Blind Subjects, J. Clin. Endocrin. & Metab., 16:622, 1956.
Ul. MOORE, F.D., ET. AL., Studies in Surgical Endocrinology, Ann. Surg., 1)41:145» 19557”
U2. MURRAY, J., ET. AL., The Effect of Surgical Operation on the Plasma Clearance of Infused Cortisol, Ann. Surg., 1148:951, 1958.
k3• NILSSON, EV, ET. AL., Corticosteroid Concentration in Plasma During Anesthesia and at Operation, Acta Chir. Scand., 126:281, 1963.
hh* NORYMBERSKI, J.K., ET. AL., The Assessment of Adrenocortical Activity by Assay of 17 KG Steroids in the Urine, Lancet, 2614:1276, 1953®
U5. OKEN, D., AND HEATH, H.A., The Law of Initial Values: Some Further Considerations, Psychosom. Med., 25:3, 1963®
I46. PERKOFF, G.T. AND OTHERS, Studies of the Diurnal Variation of Plasma 17 OHGS in Man, J. Clin. Endocrin. & Me tab., 19sit,32, 1959.
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U7o PERSKY, H. ET. AL., Adrenal Cortical Function in Anxious Human Subjects, AMA ARCH of Neurol, & Psychiat., 76:5U9, 1956,
I4.8, PERSKY, H* ET* AL., Blood Corticotropin & AWMF Levels of Anxious Patients and Normal Subjects, Psychosom, Med., 21:379, 1959.
k9» PINCUS, G., Effects of Acute Stress on Adrenocortical Hormones, in Hormones and the Aging Process (ed. Engle, E.T., & Pincus, G.) Academic Press, New York,
50. PRICE, D.B., THALER, M., AND MASON, J.W., Preoperative Emotional State and Adrenocortical Activity, AMA Arch, of Neurol. & Psychiat., 77s6ii6, 1957.
5>1. REECE. M.W., ET. AL.. Adrenocortical Response to Surgery, Surgery, U2s669, "" 19^7.
52. RIOGH, D. MCK., Experimental Aspects of Anxiety, Am. J. Psychiat., 113:U35, 1956.
53• ROCHE, AND OTHERS, The Levels of Circulating Eosinophils and Their Response to ACTH in Surgery, in Proc. of the 1st Clinical ACTH Conn, p. 55, 1950.
5U. SACHAR, E.J., MASON, J.W. ET. AL., Psychoendocrine Aspects of Acute Schizophrenic Reactions, Psychosom. Med., 25:510, 1963.
55* SACHAR, E.J., ET. AL., The Influence of the Hypnotic Trance on Plasma 17-OHCS Concentration, paper presented at theannual meeting oFtKe American Psychosomatic Society, April 196iu
56. SAMUELS, L.T., ET. AL., Age and 17-OHCS in CIBA Foundation Colloquia on Endocrinology, Vol 11, Hormones in the Blood, (ed. Wolstenholme, G.E.W.) Little Brown & co., Boston, 1^57.
57. SANDBERG, A.A., ET. AL., The Effects of Surgery on the Blood Levels and Metabolism oFl7-QHGS in Man, J. of Clin. Invest., 33:1509, 1951..
58. SELYE, H., Stress and Psychiatry, Am. Journl. of Psychiat., 113:^23,1956.
59. SHANNON, I.L. AND ISBELL, G.M., The Effect of Time of Day on Adreno¬ cortical Response to Oral Surgery, J. Oral Surgery, 21:101, 1963.
60. SOBEL, C., ET. AL., Study of the Norymberski Methods For Determination of 17 KGS in Urine, J. Clin. Endocrin. & Metab., 18:208, 1958.
61. SPROWIS, R.S., Elementary Statistics, McGraw-Hill, New York, 1955.
-45-
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62. STEENBERG, R.W., LENNIHAN, R., AND MOORE, F.D., Studies in Surgical Endocrinology II: Free Blood 17-OHGS and their Relation to Urine Steroids, Metabolism, and Convalescence, Ann. Surg., 1^3:180, 1956.
63. TAILOR, J., A Personality Scale of Manifest Anxiety, J. of Abn. & Social Psychology, U8:285, 1953.
6U. TITCHENER, J. ET. AL., The Problem of Delay in Seeking Surgical Care, Journal of the~AMA, 160:1187, 1956.
65. TITCHENER, J., AND LEVINE, M., Surgery as a Human Experience; the Psychodynamics of Surgical Practice, QxfforT'TC" P res s, New I orkT"T96Q.
66. VIIKARI, S.J. AND THuMASSON, B.H., On the Changes in Plasma 17-OHCS Levels During Surgical Proceedures, Acta Endocrinol., 2U:36l, 1957.
67. VIRTUE, R.W., AND OTHERS, The Adrenocortical Response to Surgery: The Effect of Anesthesia on Plasma 17-OHCS Levels, Surgery, Ul:5ii9, 1957*
68. WALDRON, S., Plasma 17-OHGS Levels in Newly Admitted Psychiatric Patients, Thesii7~TaTendi^ersity, T5>6£T””
69. WILDER, J., Modem Psychophysiology and the Law of Initial Values, Am. J. Psychotherapy, 12:199, 1958.
70. WITTENSTEIN AND HUME, Relationship of the Hypothalamus to Pituitary- Adrenocortical Function, in Proc. 1st Clin. ACTH conf., Phila,, 1950.
71. WOLFF, H., Stress and Disease, C.C. Thomas, Springfield, 1953.
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APPENDIX I PAPER-AND-PENCIL TEST ADMINISTERED FOLLOWING
INTERVIEW ON NIGHT BEFORE SURGERY
THIS IS A CONFIDENTIAL OtlSST 1ONNAIRE» Tom*
aasvers will be sased for research purposes
and will not h® aescei»t®d witfo jmr
naiMS #
Nasse
Age _Birth date
Date
THE DEPRESSION INVENTORY WAS SCORED BY ADDING THE NUMBERS THAT WERE CIRCLED IN ANSWERING THE QUESTIONS. MAXIMUM POSSIBLE: W 62 ffl
THE TMAS WAS SCORED BY ADDING THE NUMBER OF ANSWERS CO-INCINDENT WITH THE KEY (SEE LAST TWO PAGES OF TEST). MAXIMUM POSSIBLE: M 50ffi
0 i
Part lo Circle the one statement in each group that is closest
to your o’cra feelings*
A. 0 1 do not feel, sad*
t X feel Ifbae or sad®
2a I am blue or sad all the time and 1 casi'i snap out of it®
2b I am so sad or unhappy that it is very painful*
3 I as so sad or unhappy that I caa8t stand it*
B* 0 I am not particularly pessimistic or discouraged about the future
la I feel discouraged about the future»
2a 1 feel I have nothing to look forward to®
2b I fa©1 that I won't ever get over ray troubles„
3 I feel -that the future is hopeless and that things cannot improve
C* 0 I do not feel like a failure*
I I feel I have failed acre -than the average person*
2a I feel 2 have accomplished very little that is worthwhile or that means anything*
2fe As 1 look hack on my life all 1 can see is a lot of failures*.
3 1 feel I aia a complete failure as a person (parent;hushand)*
D. 0 1 am not particularly dissatisfied*
la I feel bored most of the time®
lb 1 don't, esajoy things the way 1 used to®
8 1 desist get satisfaction out of anything any more«
3 1 am dissatisfied with everything*
E* 0 I don't feel particularly guilty*
1 1 feel bad or unworthy a good part of the time*
2& 1 feel quits guilty*
2b I feel ted or unworthy practically all the tisse sow®
3 I feel as though 1 air* very ted or worthless«
Fo 0 I don't feel I ara being punished*
1 1 have a feeling that something bad may happen to me*
2 I feel 1 a® being punished or will fe© punished*
3a I feel l deserve to be punished*
3b 1 mint to be punished®
i
G, 0
la
lb
2
3
I don't feel disappointed in sayself*
1 am disappointed in myself©
1 d©Kct like myself*
2 a&s disgusted ■with myself©
1 Hate myself®
Q
1
2a
2h
I dob81 feel I asa any worse than anybody else©
1 asa very critical of rayself for ray weaknesses or mistakes,
] blame rayself for everything that goes wrong*
I feel J have assay bad faults*.
0 I don't have any thoughts of harming rayself*
1 1 have thoughts of harming rayself but 1 would not carry them ont»
2a I feel 1 would be better off dead*
2b 1 have (‘©finite plans about ceEsaiitisg suicide®
2c 1 feel ray faraily would be better off if 1 were dead*.
3 1 would kill rayself if I could*
0
1
9
s
I don't cry &nj more than usual*
I cry more now than i used to**
1 cry all the time now* I can't stop it©
I used to be able to cry but now I can't cry at all oven, though I want to®
K0 0 I am no more irritated now than 1 ever am*
1 1 get annoyed or irritated more easily than I used to*
2 I feel irritated all the time*
3 I don't get irritated at all at the things th-t used to irritate to*
L® 0 I have not lost interest in other people*
1 I am less interested in other people now than 1 used to be*
2 1 have lost most of ray interest in other people and have little feeling for theme
3 1 have lost all my interest in other people and don't
care about them at all*
(2)
m„ o I sake decisions about as well as era?*
i I a« less sore of rayself sow and try to put off saak.i ng dec is i ons ®
2 I can’t raake decisions any more without help®
8 I can’t make any d9c.isio.BS at oil anymore®
N. 0 I don't feel I look any wore© than 1 used to®
1 I am worried that I as looking old or unattractive®
2
8
I feel that there are permanent changes in my appearance and they make na look unattractive®
I feel that 3 am ugly or repulsive looking®
0* 0 I can work about as well as before®
la It takes extra effort to get started at doing something®
lh I don ’t work as well a® I used to®
2 1 have to push myself very hard to do anything®
8 1 c.an’t do any rork at all®,
© I can sleep as well as usual*
i 1 wake up more tired la the morning that? 1 use' to®
2 I wake up 1-2 hours earlier than usual and find it hard to get back tc sleep®
3 I wake up. early every day and can’t get more than five hours sleep®
0® 0 1 don't get any mere tired than usual®,
1 1 get tired more easily than J ns a cl to®
2 I get tired from doing anything®
3 I get too tired to c'o anything®
R. 0 My appetite is no erorse than usual*
1 My appetite is not as good as it used to foe®
2 My appetite is much worse bow®
3 I have ao appetite at all any more®
0/
I haven*! lost much weight,, if any* lately*
I have lest more than five pounds®*
I have lest more than tea pounds*
1 have lost more than fifteen pounds*
1 am no more concerned about oy health than usual*
2 am concerned about aches and pains or upset stomach or constipation or other unpleasant feelings in say body*
I am so concerned with how I feel or what I feel that it*s hard to think of oush else®
1 am completely absorbed in what 1 feel*
1 ha-re not noticed any recent change in my interest in sex*
I am loss interested in ses than I used to be*
1 am ouch less interested in sex now*
I have lost interest in sex eorapl©tely®
END OF PART ONE
Fart I!® Mark after each statement holm Aether it is tr?B© about ym (f) ore false (F)»
1.
21
3o
4e
60
Go
fo
8.
9e
10 a
lie
12 a
13*
14 «
15*
16.
17.
18*
19®
20o
21*
<rt€% *
23®
m»
25 a
20 o
2? ©
28 a
29o
31*
32®
<3
I da not tire >iUickly. F
I a® often ©iek to BSjf stomachy T
1 a® about as nervous a® other people«^F
I have very few headaches® p
1 work under s great deal of s train T
1 cannot keep say mind oa osse thing;® t
I worry ever som©y and business ^.T .-
I fre<£uenfy notice siy head shakes when I try to do soseihiiag*, T
I blush as often a® others* F tSMSEMBURH*
I have diarrhea^"the nm»H) once a month or more., T
I worry <|uit@ a bit over possible trouble®* «p
1 practically never blwshqJF
I as often afraid that I as going to bluafe^JF
I have nightmares every few night® T
My hands and feet are usually warm enough
I sweat trery easily si?en on cool days. T
When embarrassed I often break out in a sweat which is very annoying.T
1 do not often notice my heart pounding and 1 am soldo® short of
I feel hungry almost all the time® y <
Often my bowel© don't move for several days at a time, T
I have a great deal of stomach troublea T
At times I !os& sleep over worry. 3?
My sleep is restless and disturbed. T T
I often dream about things i don’t like to toll other people.
I as e&ailjs embarrassed *. t " ’ •'isa.«S3WfcBrili4
My feeling® are hurt easier than most peoplee T
1 often find myself worrying about something. T
1 wish 1 could by as happy a® others. T
I am ismlly calm and oot easily upset, j*
I cry easily® T
1 feel ansi'jus about something or ©oris on® almost all of the time
I ass happy most of the time*
It makes m nervous to have to wait. T
i
34 c
36.
38*
39*
40 o
4 i a>
42*
43 «
44 •
45 .>
46 8
47*
48a
49©
50*
At MOM 1 Siis so milw that I cantsot «H is * ‘haijr for very ioas.__*
Sonetioe* I becom so excited thut 1 find it hard i, get to sleep._JL
I have often felt that 1 fee® so i»ny difficulties tint 1 could not over* eras T
.* «», X have been worried beyond reason about soaring that really .. 2.0 hlSQt oji v'OX* &
F I do sot have as o&ny fears as sy i'rldncls»„^...
1 have been afraid of things or people that 1 toon could not ha.t «,._f
i certainly feel nselees at time*<w>T ^
1 find it hard to keep say mad on a task or
i ass ©ore eelf-e cause lour* than most people •JL—.
I am the kind of person who takes things .
I am a very nervous person
Life is often a strain for a»*_JL
At times I think 1 am no good at all*_JL-
1 am aot at '*11 confident o£ ayselx
I times 1 feel that I am going to crwsk spaJj^,
I don't like to fac© a difficulty or make ass important F
] am very confident of
CWE
END OF £0S ST I 0N8AIRE ttw re*c «wo ozea^nz- <«w *«**• «aw> *asr>
WPS «*•«>' «!K''
DO MOT WRITE BELOW THIS LIME
MAXIMUM SCORES
-
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- • J r -
APPENDIX II: : PRIMARY DATA (RANKS ARE IN PARENTHESIS)
patient & sample time(EST) plasma 28 hr. ■urine KGS date of & days before op cortisol (mg/28 hr.) operation of sample #1 (if« 8#1 m D-I], d-i2 MA DP
1 #1 CD
»»
o
o
a) . 3 . H
22.0 29.7 26.0 (8) (2) 18 6
(2/6/68) #2 8:00 a.m. 9.7 (8) (5) (3) (1.5) #3 2:12 p.m. 22.9 #1+ 2:57 p.m. 18.9 #5 5*12 p.m. 38.2
£ #1 d:0U a.m.^i; lV.2 21.2 10.9 (l) (7) 6 "ITT” (2/12/68) #2 8:00 a.m. 20.9 (6) (10) (8.5) (8)
#3 8:31+ a.m. 19.U #1+ 9*19 a.m. 18.0 #5 11:31+ a.m. 85.1+
3“ #1 6:00 a.m.(jL)" JL+l+.B 35.1 25.0 (3) (3) ~T3— T" (2/13/6U) #2 8:00 a.m. 89.3 (3) (6) (8) (5.5)
#3 8:30 a.m. 88.8 #1+ 9:15 a.m. 39.8 #5 11:30 a.m. 26.9
IT" #1 8:00 a.m.(5) 18.6 2 6.6 " 18.1 (9) (9) 12 i $2/17/610 #2 8:00 a.m. 18.9 (5) (8) (5) (7.5)
#3 8:36 a.m. 12.9 #1+ 9*21 a.m. 23.9 #5 11:36 a.m. 28.3
5“ #1 d:0u a.m. uT" 37.3 38.8 31t.li (6) (5) 10 0 (2/28/68) #2 8:00 a.m. 23.8 (2) (2.5) (6) (9.5)
#3 1:12 p.m. 8o.o #1+ 1:57 p.m. 30.6 #5 1+*12 p.m. 58.3
5" #1 8:00 a.m.(8) 2o.£ i8.5 33.2 (7) (8) 8 ~T~
(3/3/61+) #2 8:00 a.m. 19.8 (8) (8) (7) d.5) #3 11:17 a.m. 9.2 #1+ 12:02 p.m. 23.1 #5 2:17 P.m. +5.0
7 #1 8:00 a.m.(8) 21.8 18.9 lU.i (10) (8) 1 i (3/3M) #2 8:00 a.m. 22.7 (10) (9) (10) (7.5)
#3 8:35 a.m. 16.5 #1+ 9:20 a.m. 19.9 #5 11:35 a.m. 80.5
(T“ #1 8:00 a.m. (1J l9.o --- 39.6 38.8 (5) (8) 31 3 (3/26/61+) #2 8:00a.m. 11.9 (1) (2.5) (1) (5.5)
#3 12:06 p.m. 13.5 #1+ 12:51 p.m. 22.6 #5 3:06 p.m. 35.3
9 #1 8:00 a.m. (5) 38.8 "T57T” 20.3 (2) (i) 17 "TT (3/30/61+) #2 8:00 a.m. 18.0 {9) (7) (2) (3)
#3 8:31 a.m. 16,5 #1+ 9:16 a.m. 17.3 #5 11:31 a.m. 22.6 #1 8:00 a.m.(1} 15.7 17.5 39.6 (8) (10) T" 0
(3/30/61+) #2 8:00 a.m. 17.3 (7) (1) (8.5) (9.5) #3 11:52 a.m. 28.3 #1+ 12:37 p.m. 26.2 #5 2:52 p.m. 37.2
AVERAGES #i:£5«6 #8 .'*23.6 25.6 25.6 12 2.8 #2:20.8 #5*36.9 #3*21.9
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APPENDIX III (A-C) CALCULATED DATA (RANKS IN PARENTHESIS)
A.
patient number
plasma steroid standardized to b a.m. (irA %)
average standardized cortisol on op day
fj - #1 #2 #3 #4 (#2-#5A) k%) 1 , 22.0
(W 9.7 (10)
30.5 (3)
23.1 (7)
“Ui.4 (6)
26.9 (6.5)
T~ 1?.4 (p),
' 20.9
(0
20.2
(5) 19.9 (9)
50.7 (3)
27.9 ft) ... .
T~ W.B (1)
49.3 (1)
1*5.1 (2) .
41.6
wu 34.2 (?) ......
42,1 (2)
44 IB.6
-
14.9 (7)
ill. 7 (9)
25.B (6)
33.7 (?)
22.5 (9)
5 57.5 (3)
23. b (2)
L6.9 (1)
38.0
(2) 63.5 ft)
0.1 (1)
TT 5o.£ (6)
19. B (5)
iu (1°)
29.1 ft),
52.7 (2)
28.$ (!•)
T~ 2l.Ii ft)
22.7 (3)
17.3 (7)
21. B (8)
45.6 ft)
26.9 (6.5). .
b 19.a (7)
11.5 (9)
19.6 (6)
59.2 ft).
43.6 (7)
25.6 (8)
9 3b.b
(2) 1U.0 (8)
11.2 (8) .
19.1 27.$ (10)
19.6 (10)
10 15.? (10)
17.3 (6)
30.1 (it).
32.6 (3)
£5.3 (g)
31.3 (3)
Average 25.6 20.L 25.6 2b.0 0.9
B. (STANDARDIZED VALUES ARE USED IN CALCULATIONS)
PATIENT NUMBER
waiting time(min) (8 a.m. to time #3)
waiting change (#2 to #3)&0
rate of waiting initial op change change &$/100min) (#3 to #0{&$)
1 372(1) +20.b(2) +5.6(3) 17.4(9)
2 34(6) - 0.7(7)" -2.1(7) ““^7T(77
T“ 30(10) -4.2(b) -100(9) -3.5(B)
IT 36(6} -0.2(6) 1 -0.6(6) "Tiirrr^r-
5 3l2(0 +23.1(1) +7.7ft) -6.9(10)
6 W(5) ” -Wdo')1 -2.9(b) ' +15.0(1)“
7 35(7) -5.4(9) -i5ft(lo) +05(0
a 20(3) +7.7(h) "+JTT7TT ‘ “ ~+9T6U1
9
—
3l(9) +3.2(5) +10.5(1) +1.5(6)
~ $Mh) +12.8(3) “+5.5(0 +2,5(5)
AVERAGE 153 +5.1
(S')
V « l .). .. , . - ■ J • V ' » . . . i / i ‘h» jT^Vi i'K I •£» ... ■
.
A*;*.r*uT: -.-jv sieve • * • f> u OO - - ’ * ’ , r ~
r*rJ raw;a ; a .. . j ; j . » » •» •> it K * • P ». ;Iq xfh * .ieq
SL ,'C HO iO-AolOO _GlX ;'v . •iaui j/a
i\j UV..-: \'L ~ . K , • • 'l. J •, • > _ . • vi ■ • %
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. V.'j-. __ _r- „ rr^r-/_ - - i * \
MM ^ • V. , . - O i \ « ■: ii \' / (Q) ..... ,>dvV- CY) _ , J,, „ u . „
-. • c. . ) • c. C*Y£ U) _,o)—
r o\ ;-•) _IS) . —
. • : .l« ■, j • : 0
_La_ iS) {' V*' -. •/. _ ( . . ^.
. . -ara—” ' • • i * . ... . - ,^7'r— | • .1-4 • - *T
.._. X-:vix _... {■■>L __iv. J_ O. t'
........ • . n •XX • „ 1 0
...... jll). .., .. .A. vv lv \ t) « <J. irfc . • i - r ^ r • n- s*v
. _____ TV ^ . _ __ ..... ,y . / . . . „ f f ‘ ** ^
.A." nj.- . ... \>:>y _ly. _ ...M...... C • -'.v. „ e ■•. . i.lt j..or t . C-L
__m.- U) ( c\ - - ur'^iftm
c n C ) r ,vQ^,_ » *
... • A 'T* ' oKg*:*:vA
xfcHOrj?. ..V ..’l .DC l.-. ■ Mi A SaUdAV M Mi IAC MX) .. .
;o n.ov.ar;; :.'.v .,•.< ■ M, aM ^^""To^^TDTru-: ~::o* .otcKxaW "
) . :.■ \ '/■->: a-no id. , CCv; ht " j (£'.. ar.Lfcj- Ox\ «b • ) EAtaJJA
:■) v-JM.:-:- Ml .oT+ UTSyT T
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-^
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( V - ■^Torjrr^-t
X / X* i~ x ■'•') *'• • '.: '!‘ ' —r^r™’ c
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APPENDIX III (CONTINUED) CALCULATED PITA (RANKS IN PARENTHESIS)
C.
tmos iw a* hr. PATIENT
NUMBER
LATER OP. CHANGE
m to #$){%%) TOTAL CHANGE (3 HR.),
(#3 to #5) (*$) TOTAL CHANGE AS $
OF VALUE #3 KGS (OP DAY TO
POSTOP DAY)(MG/D)
I +21.3(5) ! +13.9(8)
i +1*6$ (8)
' -3.7 (6) *
2 +32.8(1) ;+30.5(2) +15W(3) -10.3(1)
3 -9.il (10) -12.9(10) 1. i
-29$ (10) -10.1(2)
k +7.9 (9) +19.0(5) +129$ (it) -8.5 (3)
5 +25.5(2) +16.6(6) +35? (9) -U.U (8)
6 +23.6(10 +38.6(1) +278$(1) .... . . .a
+16.7(9)
7 +2l*.0(3) U28.5(3) | +165$(2) -0.8 (7)
8 +1U.U(6) j+2l*.0(l*) +122$(5) -5.2 (5)
9 +8.8 (8) '+10.7(9) i
+62$ (6) J+8.7 (8) %
10 +12.7(7) |+15.2(7) l*S& (7) +22.1(10)
AVERAGE
-—
! +18.1* k°o? “ I 1
if hi ^kiu <A»ix+i jntewf ^fy
(9’)
)
(uy. Jxi-'{
*■ a r -or * it . AWW r {* < x • U .) CllAHD i TOT
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■ <xrr«M *■"*•**»•
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x •; -• , ) i*$Z+ - 5 . fX
w; • X \.r,r>
x'■’••/ ^ ... J \ •- «i- £
.; ( « ■U
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w; . '(•)-. iS+ • *■ V
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YALE MEDICAL LIBRARY
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deposited in the Yale Medical Library are to be used only with due regard to the
rights of the authors. Bibliographical references may be noted, but passages
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This thesis by has been
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