- Email: [email protected]
The metabolic response to adrenalectomy and hypophysectomy
VOL. I (1956)
THE
CLINICA
METABOLIC
CHIMICA ACTX
REZP3NSE
AND
533
TO ADRENALECTOMY
HY PJPHYSECTOMY bY
J. S. ROBSOS, The De@zrtnzents
H. A. DUDLXY,
of Clinical
&hen&try
1.~.B. HORN
dud Swgery,
AND C. P. STEWART
Uniwrsity
ofEdinburgh
(Scotland)
INTRODUCTION
Injury or surgical operation in human subjects is followed by certain biochemical phenomena collectively called the metabolic response to surgery or trauma. The most prominent of these events are a diminution in the excretion by the kidney of sodium and chloride and an increase in the excretion of potassium and nitrogen l,z*S. Although the factors responsible for the occurrence of these changes in human subjects are undoubtedly complex, many workers have accepted the view originally put forward by ALBRIGHT 4 that the changes in electrolyte and nitrogen excretion are brought about by an increase in the secretory activity of the adrenal cortex consequent upon the stress of the operative procedure 5$6. This view has gained support from the finding that increased amounts of corticosteroids, determined by a variety ot procedures, occur in the urine and blood after operation ‘-I*. On the other hand, as MOORE et n2. I3 have recently acknowledged, an increased amount of adrenocorticosteroids in the urine does not constitute proof that increased secretion of the adrenal cortex is the cause of the post-operative metabolic response, and it has been suggested that the rise in the blood concentration of adrenocorticosteroids after surgical operation might be partly due to other factors lo, Previous experimental work by ENGEL 15 and INGLE I6 had shown occurred
that a retention
maintained The
of sodium
in adrenalectomised on a constant use of bilateral
has provided
rats
chloride subjected
dose of cortical adrenalectomy
the opportunity
for defining
and an increased to
experimental
excretion bone
of nitrogen
fracture
while
extract. and of hypophysectomy
in human
subjects
more precisely the relation of the adrenal gland to the metabolic response after injury in man. It is difficult to interpret the majority of studies of patients undergoing such operations since it has been customary to alter the dose of cortisone given to the patients during the day of operation and for the ensuing few days Fy17, x8, a step which by itself is capable of producing changes in electrolyte and nitrogen excretion qualitatively similar to the changes seen in a metabolic response to trauma Is. Only by keeping the patient undergoing adrenalectomy on a constant dose of cortisone before and after the operation is it possible to assess the influence on the metabolic response to injury of factors other than change in the absolute amount of corticosteroids available to the body. In a preliminary communication 3n we reported the occurrence of alterations in the renal excretion of electrolytes and nitrogen after a second stage adrenalectomy in a patient maintained on a constant dose of cortisone throughout the period of observation. Similar results have also been reported by MASON 2z. The purpose of this paper is to extend these observations, and to include data on urinary corticosteroids in patients undergoing bilateral adrenalectomy or hypophysectomy. Refewwes
p. ~$4
J. S. KOBSON t$ al.
534
vo1;. 1 (1956)
Estimations have been made of the 24-hour urinary excretion of sodium, potassium, chloride, nitrogen and corticosteroids in two subjects subjected to second stage adrenalectomy and splanchnicectomy, one patient subjected to bilateral adrenalectomy and splanchnicectomy carried out in two steps, and two patients subjected to hypophysectomy. With the exception of the day of operation and first three days thereafter, all the patients received a diet constant for each one and containing adcquate calories within the range 1400 to 2000. The basic diet contained 0.5 g sodium chloride and 1.2 to 2.0 g potassium. The greater part of the potassium was derived from canned fruit juice, each patient receiving a fixed daily allowance from a single batch. The diet was supplemented with 4.5 g sodium chloride per day given by mouth as cachets. On the day of operation food was not eaten, and a slow intravenous infusion of 500 ml of 0.9”/:, saline was given to ensure an intake of 4.5 g sodium chloride. In some of the cases, as indicated in the legends to the figures, 400 to 1200 ml of blood were given on this day. On the first three post-operative days, the intake of potassium and nitrogen was estimated from the actual amount of the diet consumed, and the salt intake of 4.5 g was maintained either by infusion or by oral administration. Thereafter the basic diet, supplemented by 4.5 g sodium chloride, was once more given. The patients undergoing adrenalectomy received 200 mg of cortisone acetate per day in div ded doses by intramuscmar injection, and 75 n.g per day was given to one of the patients undergoing hypophysectomy. The cortisone was begun from five to twelve days before the operations, and the patients were in sodium, potassium and nitrogen equilibrium for some days before the operation. Cortisone was not given to the other patient who underwent hypophysectomy. The doses were more than the minimum necessary for recovery from adrenalectomy, and were considered ample to ensure the uncomplicated convalescence desirable for a satisfactory balance study. This indeed proved to be the case. The relevant clinical data of the patients studied are shown in Table I. Chemical methods Sodium and potassium were determined in the urine using a Barclay Flame Photometer with lithium internal standard. Urinary chloride was determined titrimetrically by the method of VAN SLYKE 22,and urinary nitrogen was estimated by the TABLE
I
--.-.--Patient
A@ years
Sex
-.. qf cortisone acetate mg per day _.-. ~-_.. -
Disease
M.G.
47
F
Carcinoma of breast
rst and 2nd stage adrenalectomy and splanchnicectomy
1I.B.
47
F
Malignant hypertension
2nd stage adrenalectomy and splanchnicectomy
D. McK.
37
M
Malignant hypertension
2nd stage adrenalectomy and splanchnicectomy
M.H.
48
F
Carcinoma of breast
Hypophysectomy
75
E.W.
A0
F
Carcinoma of breast
Hypophysectomy
0
References p. 5’44
200
200
VOL. 1 (1956) micro-Kjeldahl were measured hydroxy
~IETABOLIC
method.
RESPOIG:SE TO .~DRENALECTO~IY
Urinary
using the method
steroids by the method
acid-stable
etc.
formaldehydogenic
535 steroids
of TOMPSETT AND SMITH 11, and urinary
(ASFS) total
17-
of REDDY, JENKINS AND THORN 23.
Results The results are shown graphically in Figs. 1-5. The data on sodium, chloride, nitrogen and potassium are plotted by the method of REIFENSTEIN, ALBRIGHT AND
123456789K)12345678910111213!41234 Day5 t
OpeAtion 1” staqe
t
Operation 2nd staqe
Fig. I. M.G. First and second stage adrenalectomy and splanchnicectomy. Cortisone acetate zoo mgper day i.m.i. (intramuscular injection) over period of observations. I pint of blood given on day of both stages of operation. Black area above or below the balance line represents loss or accumulation respectively.
WELLS 24, in which the intake
for each constituent
is measured
down from the base
line, and urinary excretion upwards from the intake level. The small and nearly constant losses in the faeces and sweat have been ignored. Accumulation and loss from the body are therefore represented by black areas below or above the balance line respectively. Urinary corticosteroids are shown on the diagram as mg excreted per 24 hours. In the cases in which blood was given on the day of operation, the sodium, chloride and potassium in the “plasma” of the blood have been included in the intake in computing the balance. In short term studies it is legitimate to exclude the red blood cell and the plasma proteins from the balance. References
p. 544
536
J. S. ROBSOX ei n/.
\‘()I.. 1 (I()@)
In the patients subjected to adrenalectomy (Figs. I-3), whether first or second stage, a retention of sodium and of chloride occurred over the first six to eight days after operation. The amount of sodium and chloride retained corresponded to that seen in other operations of similar magnitude which do not involve the adrenal glands”. Similarly, 1.6 g to 5.2 g of body potassium was lost during the first two to five postoperative days. A loss of body nitrogen also occurred for the first three to nine days after op?ratiDn,
the cumulative
deficit rang+
Balance line Chloride g (as NaCl 1
from 15 g to 56 g.
+2 -S
I{ 1;‘:
Nitrogen g Batonce line
:: +2 -S v-4 1:
(IS mg/24hours desoxycorticosterone 0 12312345678 Days
Fig. 2. K.B. Second stage adrenalectomy and splanchniccctomy. Cortisone acetate Loo ITi)? per day i.m.i. over period of observations. 3 pints of blood gi\-en on day of operation. Black arca above or below the balance line represents loss or accumulation respectively.
In the patient M.G. (Fig. I) in whom observations were made over bothstagesof bilateral adrenalectomy, the excretion of acid-stabie formaidehydogenic steroids (ASFS) in the urine showed an increase after the first stage but not after the second. No increase in urinary excretion of corticosteroids was evident in the other two cases undergoing second stage adrenalectomy (Figs. 2 and 3). This is shown graphically for patient K.B. (Fig. z) in whom ASFS was measured, and for patient D. McK. {Fig. 3) who showed no increase in urinary I?-hydroxy steroids during the post-operative period. TheresultsobtainedinthetwocasesundergoinghypophysectomyareshowninFigs. 4 and 5. In the post-operative period in both subjects sodium and chloride retention occurredalongwithlossofpotassiumandnitrogen. Urinarycorticosteroids(ASFS)rosewell above their pre-operative level for from one to four days after theoperation in both cases. DISCUSSION
Our results confirm the finding that certain features of the post-operative metabolic response in man occur after the removal of the second adrenal gland in a twoR~$W~BCCS fi,,j&t
VOL. 1
(1956)
JIETAUOLIC
RESPONSE
TO ADRENALECTOJIY
etc.
537
stage adrenalectomy 2ot 21. No estimation was made of urinary corticosteroids on the patients studied by MASON and it seemed possible from his observations that the anaesthesia and the trauma of the operative procedure before the actual exclusion of the adrenal gland from the circulation might result in enough stimulation of the adrenal cortex to produce some of the alterations in metabolic balance during the post-operative period. This possibility can be finally eliminated only if post-operative metabolic changes are shown to occur in patients both of whose adrenal glands have been previously removed and who are subjected after an interval of time to another Sodium g Balanceline
+2 +l :j
Potassium
+3 +2 Cl
Bohr% line -7 -2 +2 +1 Balance line Chloride 4 (as NoClj
-c: IJ’ 1; +20 +16
Nitr:gen Balance line
+ +8l2 +4 -s -182
123456712345676 Days
II
Fig. 3. D.McK. Second stage adrenalectomy and splanchnicectomy. Cortisone acetate zoo mg per day i.m.i. over period of obserrations. No blood given. Black area above or below the balance line represents loss or accumulation respectively. operation while on a constant dose of cortisone. However, our observation that there is no increase in the urinary corticosteroids (acid-stable formaldehydogenic and 17hydroxy steroids) after the second stage of the adrenalectomy provides no evidence that stimulation of the adrenal cortex occurs during this part of the operation. The absence of any measurable alteration in corticosteroid excretion is in striking contrast to the increase seen in Case M.G. (Fig. I) after the first stage adrenalectomy and splanchnicectomy, a difference which can be attributed only to the presence of the other, intact, adrenal gland at that time. SANDBERG et al. lo have recently shown that in man an increase in r7-hydroxy corticosteroids in the blood occurs during the early stage of anaesthesia and a similar transient rise has been shown to take place in normal dogs during the first few hours of anaesthesia *6. However, such short-lived increases in blood hormone concentration would seem an unlikely cause for metabolic events which continue for several days after second stage adrenalectomy. References 9. 544
J. S. ROBSOX et c&!.
538
VOL.
1 (19j6)
On the basis of experiments with adrenalectomised rats INGLE I6suggested that a~enocort~cal hormones played a “permissive” role in the metabolic response to injury in these animals. Although our observations on adrenalectomy in human subjects are consistent with this view, the extent to which the observed alterations in
i-4 +3 +2 +t EkY’ance Chbride‘inc
-‘:
(as &a,
I; 12 1: +12 78
Nitmgen Eblo9nceline
Ifi +2 -x I;
ASfS excretion 12 in urine 05 mg/24 hour% : desoxywrticosteront O 123456123456789lo
Fig. 4. MR. Black
Hypophysectomy. Cortisone acetate 75 mg per day i.m.i. given over period of observations. I pint of blood given on day of operation. area above or below the balance line represents loss or accumulation respectively.
electrolyte and nitrogen balance represent a tissue and renal response to trauma in which the administered hormone plays a direct and active part is still open to question. STEENBURG AND GANONG a6 have shown in adren~ectomised dogs that the metabolism of hydrocortisone given by intravenous infusion is altered by anaesthesia and by anaesthesia $&VSoperation. The concentration of free corticosteroid in the blood of the anaesthetised animals, whether operation has been performed or not, was higher than that in the control non-anaesthetised animals. It is possible that a similar increase in blood concentration may occur in anaesthetised human subjects, given a constant dose of cortisone acetate by mouth or by intramuscular injection, even when increased secretory production of adrenocortical hormones is impossible. However, this could be the cause of the metabolic response which we have observed following second stage adrenalectomy only if it is assumed that the higher blood levels persist for some days after the patient recovers from the anaesthetic at the end of the operReferences
p. 544
VOL.
1 (1956)
METABOLIC
RESPONSE
To ADRENALE~TOMY
ation. STEENBURGAND GANONG’S observations
on adrenalectomised
period of only four hours after the end of the anaesthetic
539
etc.
animals cover a
or operation.
The shape of
the curves for blood corticosteroids which they published suggests that a possible explanation for the rise in circulating corticosteroids is the transient depression in renal blood flow and filtration rate known to be associated with anaesthesia 26, 27. Definite conclusions on the concentration, in the blood, of corticosteroids following the adSodium 9 Balance line
+2 +l 19
Potassium B&A
line
+* +l 19
Balance line Chloride g (as NaCI)
+2 +1 -7 1; 145
t10 +8 Nitrogen Balon:e line
I$ +2 -: 1; -8
‘!I 05 mg/24hours 2 desoxycorticosterone0
=;;;J,b
Fig. 5. E.W. Hypophysectomy. No cortisone acetate given. No blood given. Black area above or below the balance line represents loss or accumulation respectively.
of cortisone acetate cannot be drawn from measurements of corticoin the urine because only a small proportion of administered cortisone is
ministration
steroids
detectable in the urine either as acid-stable formaldehydogenic metabolite or as 17hydroxysteroid. Nevertheless, the data on urinary corticosteroids after second stage adrenalectomy do not suggest that an increase in the blood concentration of hormone occurs during the period when the alterations in electrolyte and nitrogen balance take place, and when renal function has recovered from the effects of anaesthesia. However, if there is an alteration in the metabolism and rate of disposal of the biologically effective hormone for some days after second stage adrenalectomy, and if this alteration is sufficiently large to increase the concentration of steroid in the blood and to bring about the changes in electrolyte and nitrogen balance, then the rise in concentration must occur without an increase in urinary content of steroid metabolites normally detectable as acid-stable formaldehydogenic and r7-hydroxy steroids after operations not involving the adrenal glands. Useful information on the role of exogenous cortisone acetate in the metabolic response after second stage adrenalectomy might be obtained by comparing the magnitude of the response to different but constant References
p. 544
J. S.
540
VOL. 1 (1956)
RoBSOK et cd.
levels of dosage of cortisone and by the determination for some days before and after the operation.
of corticosteroids
in the blood
Irrespective of the part played by the administered hormone, neither the results of INGLE in animals nor our own observations in human subjects exclude the possibility that injury normally results in adrenocortical stimulation. However, the results we have obtained, in man, do indicate that those parts of the metabolic response which we have measured cannot be accepted as evidence of such stimulation, an d that they can occur in the absence secretion by the adrenal cortex. In the observations alterations in electrolyte
of any significant
change in the rate of hormone
made upon patients subjected to hypophysectomy, the and nitrogen balance are qualitatively similar to those
reported by 1fASON 21.However, after this operation there is a significant increase in the excretion of corticosteroids in the urine. Therefore the metabolic response resembles that seen after 1st stage adrenalectomy and after operations that do not involve the adrenal gland, and the observations of MASON on alterations in electrolyte and nitrogen balance after hypophysectomy cannot be used as evidence to support the theory of the “permissive” action of adrenocortical hormones. Unlike the patients studied by MASON, our own subjects received no corticotrophin over the period of observation, and neither the magnitude of the metabolic response nor the increase in the excretion of corticosteroids were detectably influenced by the fact that cortisone was not given to patient E.W. (Fig. 5) before or after the hypophysectomy. The reason for the rise in urinary steroids, measured by TOMPSETT'S method, following hypophysectomy
remains
unknown
and its occurrence
is surprising.
At least
four explanations are possible. First, the pituitary-adrenal axis may be stimulated by that part of the operative procedure which takes place before removal of the hypophysis from the circulation, so that the increase in urinary corticosteroids is in fact evidence of an increase in adrenocortical activity brought about by the adrenocorticotrophic hormone. This explanation seems unlikely in view of the absence of a rise in urinary corticosteroids in the case of second stage adrenalectomy, where the trauma up to the point of removal of the gland is of a similar order of severity though not of duration. Secondly, it may be that in both patients studied the hypophysectomy was in fact only partial and that functioning pituitary tissue was left behind; up to the present time we have not had the opportunity of verifying this. Thirdly, the increase in corticosteroids in the urine might reflect some alteration in the metabolism of adrenocorticosteroids secreted by the adrenal cortex rather than a change in rate of secretion; evidence has already been quoted that trauma and operative procedures alter the rate of metabolism and of excretion of r7-hydroxy corticosteroids, though the absence of a similar rise in the urinary excretion of corticosteroids after second stage adrenalectomy while cortisone acetate is being given by mouth would not make this a likely suggestion. Finally there remains the possibility of general adrenocorticdl stimulation being brought about through channels other than that of the pituitary adrenocorticotrophic hormone, as seems to be the case for aldosterone 28. At present it is not possible to decide which of these four explanations is correct. In discussing these observations, we have accepted the view that post-operative ttlterations in the urinary excretion of sodium, potassium, chloride and nitrogen represent a more or less definite and unified response to trauma. This itself may prove to be an over-simplification because there can be little doubt that numerous factors References p..j.#
VOL.
METABOLIC
1 (I’)$)
RESF’OSSE
TO ADRENALECTOJIY
&.
54
may modify the series of events which follow trauma 2s. Balance studies are among the most important methods available for definition of the metabolic events after surgery. However, the results of such studies are dependent upon the calculation of intake and the measurement of rates of excretion in the urine. Interpretation of results obtained by this technique is made more difficult by the introduction of additional factors, such as the infusion of large quantities of blood 3o which complicate the computation of intake and also alter renal function. It is clear that the metabolic response demonstrated by balance study represents a combination of actual changes in cellular activity after injury and the results of treatment. Until a more sensitive indicator of such metabolic activity than the balance technique is found, caution must be observed in drawing up any hypothesis which describes the metabolic response to injury as being due to particular causes. However, our conclusion that those features of the response which we have observed may occur in the absence of increased adrenocortical secretion is independent of whatever hypothesis of the metabolic response, Unitarian or other, may ultimately prove to be correct. ACKNOWLEDGEMENTS Our thanks
are due to Sir JAMES LEAHMONTH and Professor
NORMAN DOTT for
their kindness in giving us the opportunity to study patients under their care, and to the Scottish Hospital Endowments Research Trust for a grant which allowed D. B. H. to take part in these investigations. We are also grateful to Xiss MAUREEN SMITH who carried out some of the steroid estimations. SUMMARY I. Observations have been made upon the balance of sodium, potassium, chloride and nitrogen and the excretion of corticosteroids in the urine in three patients subjected to bilateral adrenalectomy and given constant doses of cortisone acetate, and in two patients undergoing
hypophysectomy,
only one of whomreceived
cortisone acetate.
2. The usual post-operative metabolic changes of sodium and chloride retention with loss of potassium and nitrogen in the urine occurred in all patients. In the three patients subjected to second stage adrenalectomy,
the metabolic response was not
associated with a rise in the urinary excretion of adrenocorticosteroids (acid-stable formaldehydogenic or r7-hydroxy-steroids). Increase in urinary corticosteroids occurred in both patients after hypophysectomy and in the one patient studied on whom a first stage adrenalectomy was performed. 3* It is concluded that the metabolic responses observed after second stage adrenalectomy occurred in the absence of significant alterations in the rate of adrenocortical secretion. The observations we have made do not eliminate the possibility that trauma and surgical operation in patients with intact adrenal glands increase the secretory activity of the adrenal cortex. However the occurrence of alterations in electrolyte and nitrogen balance following surgical trauma may not be used as evidence that such an increase in secretion occurs. 4. The role of the cortisone acetate given to the patients before and after removal of the adrenal glands in the metabolic response is discussed. Although the results are not inconsistent with the “permissive” action of the hormone as suggested by INGLE, the possibility that alterations in metabolism and the rate of excretion of the References
p.
544
542
J. S. XOBSOS
YOL. 1
et cd.
a rise
a une
a une A une d’adr~nocorticost~ro~des (stero’ides stables a eu
& glandes a la
a lieu
VOL.
1 (1956)
METABOLIC
RESPONSE
543
etc.
TO ADRENALECTOMY
ZUSAMMENFASSUNG I. Die Natrium-, Kalium-, Chlorid-und Stickstoffbilanz und die Ausscheidung von Corticosteroiden im Urin wurden bei drei an bilaterale Adrenalectomie unterworfenen Patienten, die konstante Dosen von Cortisonacetat erhielten, und bei zwei Patienten nach Hypophysectomie, von denen nur einer Cortisonacetat erhielt, beobachtet. 2. Die iiblichen post-operativen metabolischen Vergnderungen von Natriumund Chlorid-Retention mit Verlust von Kalium und Stickstoff durch den Harn kamen bei allen Patienten vor. Bei den drei Patienten deren zweite Nebenniere entfernt worden war, war die metabolische Reaktion nicht mit einer Zunahme der Ausscheidung von Adrenocorticosteroiden (sgure-stabilen formaldehydbildenden oder 17Hydroxysteroiden) im Urin verbunden. Eine Zunahme der Corticosteroide im Urin kam vor: bei beiden Patienten nach Hypophysectomie und bei dem einen untersuchten Patienten, bei welchem eine einseitige Adrenalectomie ausgefiihrt worden war. 3. Es wird geschlossen, dass die nach Resektion der zweiten Nebenniere beobachteten metabolischen Reaktionen ohne signifikante Anderungen der adrenocorticalen Sekretion stattfanden. Die gemachten Beobachtungen schliessen die Mijglichkeit nicht aus, dass Trauma und chirurgische Operation bei Patienten mit intakten Nebennieren die Sekretionsaktivitgt der Nebennierenrinde erhiihen. Jedoch darf das Auftreten von _&nderungen der Elektrolyt- und Stickstoffbilanz nach einem chirurgischen Trauma nicht als Beweis einer derartigen Sekretionserhdhung benutzt werden. 4. Die Rolle, welche das vor und nach Entfernung der Nebennieren an Patienten verabreichte Cortisonacetat bei der metabolischen Reaktion spielt, wird eriirtert. Obwohl die Ergebnisse nicht mit der “permissive action” des Hormons von INGLE im Streit sind, kann die Mijglichkeit nicht ausgeschlossen werden, dass linderungen des Metabolismus und der Ausscheidungsgeschwindigkeit des Hormons eine Zunahme der Blutkonzentration des biologisch wirksamen Hormons mit hiermit zusammenhgngenden Anderungen der Elektrolytund Stickstoffbilanz, zur Folge haben. Nichtsdestoweniger muss eine derartige linderung der Verwertungsgeschwindigkeit des biologisch aktiven Hormons, wenn sie wghrend einiger Tage nach der Operation auftritt, doch ohne ErhGhung des im Urin gemessenen Gehaltes an Steroidmetaboliten stattfinden, wie diese normalerweise nach Operationen die sich nicht auf die Nebenniere beziehen, gefunden wird. 5. Vier verschiedene Auslegungen der Zunahme an Corticosteroiden im Harn nach Hypophysectomie werden vorgeschlagen aber es ist nicht miiglich zu entscheiden, welche von diesen Erklgrungen die Richtige ist.
PE3IOME I. npOu3BO,@iAOCb BbI6pOC pC3CKguU
B
MO¶y
nauueHToB
anpeHahOBbIX
xeAe3
~~0p0t
cTa,qm
y
TpeX
u nOA~aBI,IuX
c pe3eKaeP
naIJueHTb1 o6HapymiAu 3anepxcaHr.m HaTpm wa
~a,q 6aAaHcoM
KOpTuKOCTepOWOB
H y asyx naguemoB UCAbIti KOpTuSOH. 2. Bee HeHm B
Ha6AmaeHue
wno@f3br,
u
KaAbyuK,
naJJUeHTOB
HaTpus,
XAopuna
nO~eprH)rrbIX
u a3OTa
nOCTOIIHHbIe aO3bI yKCyCHOKHCAOrOKOpTu3OHa, u3 KOTOP~IX
ToAbKo
onu~noA)n1aAyKcycH0~-
HopMaAbHbIe nocAe-onepa~uoHHbIeMeTa6OAU~eCKueM3~exnopu,qa c noTepeii KaAu* u a3oTa B Moqe. Y
pe3eKgm.f
EI
DyX-CTOpOHHeii
aApeHanosblx
xeAe3,
MeTa6OAmeCKaR
Tpex
xapaKTep-
UCTUKa He 6mAa CBII3aHa C BbI6pOCOM B MOYy a,ZJpeHOKOpTElKOCTepOPldOB. ~OBbIIIIC!H~e KOpTuKOCTepOH~OB B MOge UMeAO MeCTO y &(ByX naIJUCHTOB C pe3CK&@&i I'UnO$,u3bI u y odHor0 nauuenTa Ha nepaofi cTa,quu peseKgus4 aapeHaAoBoii xceAe3bI. 3. 4eAaCTCK
BbIBO&
¶TO MeTa6OAWIeCKaK
XapaKTeptlCTUKa
Ha6AIO&sBmaKCK
nOCAt! BTOpOii
J. S. ROBSON
544 cra,zwn
pe3eKgIwI
anpeHaAosoii
II3MeHeHMfi a aeAwIkIHe B03MOXHOCTX
po~yToti
TOTO,
>KeAesbr. OaHaKo 6aAaHCe
He
BCAeACTBMII
IwIeAa
TpaBMa
XIlpyprwIecKoe
II
II~II ~TC~~CTBIIII 3HawITeAbHbI* Harukl HaGAIo,qewnI He HcKAwIaIoI
aMeInaTenbcTa0
3KeAesoii yckI*ImaIoT ceKpegHoHHyn3 peKoMeHnyeTc3
paccMaTpm3aTb
XIIpyprIIYcCKOt
TpaaMbI
KaK
1 (1956)
VOL.
MecTo
a,zIpeHoKopTwIecKoii ceepeuma.
YTO
anpeHanonofi
XeAe3bI
et al
Ha
aKTmzHocTb
nayMeHTax
c HTT-
KopbIaape~ahoaoii
II3bIeHeHHa a sncKTpo,~Te
II a3oTHoM
_?IOKa3aTeAbcTaO HaAII9IIX TaKOIO
yae,,II-
4e~118 ceKpeI_pIkI.
4. y
06cyxaaexx
nautteHToe
pesaT
cl0
amfume nocne
II
~KC~CEI~KMCA~~~
K~OBM,
,,AOnyCTRMOMy"
RbI3bIBaKIT yBeAHseHMe
9~0
CCAH TaKOe HeCKOAbKO
BAegeT
nocne
I13MeHeHMe
onepagaii nocne
He
3aBIKXMOCTb
II3MeHeHIIa I3 MeTa6oAI.IaMe II MHTeHcIIBHOCTb
M3McHeIiHa
B aAeKTpoAmTe
noche
onepagIwI,
IIpOayKTOB
II BSOTHOM
6aAaHCe.
6ElonorIIsecKM aKTMBHbIx OH0
CTepOII,ZIHOTO MeTaGOAIIaMa,
3aTparImaIoxyr?x anpeHaAosbIx rMno@3bI,
O,&HaKO He
TeM
rop~o~oa
abI6poca
IOpMOHOB
a
He MeHer,
IIMeeTMecTo
+'IONKHO IIpOIICXO,!QlrTb6~3
IIOBbIIIIeHIIR
KaK 06bIYHo IIpOIICXO~IIT
jl(ehe3.
'IeTbIpeB03MO)KHbIX 06bKCHeHIIiiaBAeHIIii )IBeAllYeHZUI
pe3eKgnII
113 HIIX JIBARCTCX
mxa6onmecKym
KOHI&eHTpaIJZIll 6lroAorwsecKII a@eKTIIBHbIX
CKO~OCTII BbI6pOCa
II3MepeHHbIX
5. npeAAaraeTCa B MoYe
31 co608
aIIeti cnycra
COAepmaHlla
Ha
aApeHanosbIx xeAe3. XOTR pe3yAbTaTbI Ire npo~vmoKaK 6bIAo IIpc&AOXceIIO MHTAC (LNGLE),HeAbSa ,?(etiCTBLItO ropMoHa,
IICKAIOYaTb TOti BOBMO)KHOCTII, YTO I'OpMOHa
KopTm3oHa
yAaneHwI
KOpTIIKOCTepOII,!IOB
IIMeeTCR B03MO)f(HOCTII yCTaHOBIITb,
KaKOe
IIpaBIIAbHbIM.
I D. P. CUTHBERTSOK, B&hem. J,, 23 (1929) 1x28. L D. P. CUTHBERTSON, Rzoclzena.J., 24 (1930) Iz44. 3 A. W. WILKINSON,B. H. BILLING, G. NAC~Y AND C. P. STEIVART, Lanret, 256 (1949) 640. 4 F. ALBRIGHT, Proc. rst Co?$ I?one and m’ound Hcalzng. Josiah ivracey Jr. Foundation, New lTorlr,'942. 5 H. SELYE, .I.Clin. Exdocvinol., 6 (1946) I I 7. 6 F. D. ~UOORE AND RI. K. BALL, The Netabolic Respome to Surgery, Charles C.Thomas, Springfield,1952, p, III. 7 C. I'.STEWART, J. S. ROBSON AND S. L. TOMPSETT, 281ne Congr. intern.biochiwz., Paris, 19.52, Res. Cowmuns., p. 138. 8 G. W. THORN, D. JENKINS, J. C. LAIDLAW, F. C. COETZ AN;D 14:.REDDY, Trans. Assoc. Am. Physicians, 66 (1953) 48. 9 C. L. COPE AND B. HURLOCK, Clin. Sci.,13 (1954) 69. IO A.A.SANDBERG,K.EII<-NES,L.T.SA~MUELSANDF.H.TYLER,J.C~~~. Inz’est.,33(Igjq) 15I7. II S. L. TOMPSETT AND D. C. SMITH, J. Clin. Endorrinol. and ~Vletabolisnz, 14 (1954) 922. 12 J. G. LLAURUDO, Lancet, 268 (1955) 1295. 13 F. D. MOORE, Ii.W. STEENBURG, 1\1.Ii.BALL, G. XI. W~ILSON AND J. A. MYSDE?I, Ann. Surg., I&(I955) 145. 14 E. H. V'ENNING, I. DYRENFORTH, ‘5 16 17 18 19
LO 21 2~
23 24 25
26
C. S. P. GIROUD
AND
J. C. BECK,
PUG.
Montreal
Physiul.
SoC., (1955) 13. F. L. ENGEL, Recent Progr. Hormone Research, 6 (1951) ~77. D. J. INGLE, J. Endocrinol., 8 (1952) 23. G. HUGGINS AND D. BERGENSTAL, J. ,4nz. Med. Assoc., 147 (1951) IOI. A. V%".WILKINSON, Lancet, 270 (1956) 184. 13. iX, CAMPBELL, G. 31. E. SHARP, -4.W. BOYNE AND D. P. CUTHBERTSON, Nature, 17.5 (1953) 158. J. S. ROBSON, D. B. HORN, H. A. DUDLEY AND C. P. STEWART, Lancet, 269 (1955) 325. A. S. MASON. Lancet, 269 (1955) 632. D. D. VAN SLYKE, Quantitative Clinical Chemistry. Balliere. Tindall & Co., 1932, p. 833. W. J. REDDY, D. JENKINS AND G. W.THORN, Metabolism, I (1952) 511. EC. REIFENSTEIN, F. ALBRIGHT AND S. L. WELLS, J.Clin.Endocrinol., 5(Ig45) 232. K. W. STEENBURG AND W. F. GANONG, Swgery, 38 (1955) 92. B. E. >~ILES, H. E. DE \VARDENER,H.C.CHURCHILL-DAVIDSON AND W.D. WYLIE,CZ~VZ. Sci.,
II (1952) 73. ~7 G. DE J, LEE, H.C. CHURCHILL-DAVIDSON, B. E.&LES AND H. E. DE ~'ARDENER, 12 (1953) 169. r8 S. A. SIMPSON AND J. F. TAIT, Recent Prop. Hormme Research, 12 (1955) 183. 29 C. P. STEWART, 30 G. T. G. FLEAR
Clin. Sci.,
16th Intern. Cony. Surgery, Copenhagsn, 1955. AND R.CLARKE, Clzn..'?ci., 14 (1955) 576. Received
September
Ist,
1956
THE
CLINICA
METABOLIC
CHIMICA ACTX
REZP3NSE
AND
533
TO ADRENALECTOMY
HY PJPHYSECTOMY bY
J. S. ROBSOS, The De@zrtnzents
H. A. DUDLXY,
of Clinical
&hen&try
1.~.B. HORN
dud Swgery,
AND C. P. STEWART
Uniwrsity
ofEdinburgh
(Scotland)
INTRODUCTION
Injury or surgical operation in human subjects is followed by certain biochemical phenomena collectively called the metabolic response to surgery or trauma. The most prominent of these events are a diminution in the excretion by the kidney of sodium and chloride and an increase in the excretion of potassium and nitrogen l,z*S. Although the factors responsible for the occurrence of these changes in human subjects are undoubtedly complex, many workers have accepted the view originally put forward by ALBRIGHT 4 that the changes in electrolyte and nitrogen excretion are brought about by an increase in the secretory activity of the adrenal cortex consequent upon the stress of the operative procedure 5$6. This view has gained support from the finding that increased amounts of corticosteroids, determined by a variety ot procedures, occur in the urine and blood after operation ‘-I*. On the other hand, as MOORE et n2. I3 have recently acknowledged, an increased amount of adrenocorticosteroids in the urine does not constitute proof that increased secretion of the adrenal cortex is the cause of the post-operative metabolic response, and it has been suggested that the rise in the blood concentration of adrenocorticosteroids after surgical operation might be partly due to other factors lo, Previous experimental work by ENGEL 15 and INGLE I6 had shown occurred
that a retention
maintained The
of sodium
in adrenalectomised on a constant use of bilateral
has provided
rats
chloride subjected
dose of cortical adrenalectomy
the opportunity
for defining
and an increased to
experimental
excretion bone
of nitrogen
fracture
while
extract. and of hypophysectomy
in human
subjects
more precisely the relation of the adrenal gland to the metabolic response after injury in man. It is difficult to interpret the majority of studies of patients undergoing such operations since it has been customary to alter the dose of cortisone given to the patients during the day of operation and for the ensuing few days Fy17, x8, a step which by itself is capable of producing changes in electrolyte and nitrogen excretion qualitatively similar to the changes seen in a metabolic response to trauma Is. Only by keeping the patient undergoing adrenalectomy on a constant dose of cortisone before and after the operation is it possible to assess the influence on the metabolic response to injury of factors other than change in the absolute amount of corticosteroids available to the body. In a preliminary communication 3n we reported the occurrence of alterations in the renal excretion of electrolytes and nitrogen after a second stage adrenalectomy in a patient maintained on a constant dose of cortisone throughout the period of observation. Similar results have also been reported by MASON 2z. The purpose of this paper is to extend these observations, and to include data on urinary corticosteroids in patients undergoing bilateral adrenalectomy or hypophysectomy. Refewwes
p. ~$4
J. S. KOBSON t$ al.
534
vo1;. 1 (1956)
Estimations have been made of the 24-hour urinary excretion of sodium, potassium, chloride, nitrogen and corticosteroids in two subjects subjected to second stage adrenalectomy and splanchnicectomy, one patient subjected to bilateral adrenalectomy and splanchnicectomy carried out in two steps, and two patients subjected to hypophysectomy. With the exception of the day of operation and first three days thereafter, all the patients received a diet constant for each one and containing adcquate calories within the range 1400 to 2000. The basic diet contained 0.5 g sodium chloride and 1.2 to 2.0 g potassium. The greater part of the potassium was derived from canned fruit juice, each patient receiving a fixed daily allowance from a single batch. The diet was supplemented with 4.5 g sodium chloride per day given by mouth as cachets. On the day of operation food was not eaten, and a slow intravenous infusion of 500 ml of 0.9”/:, saline was given to ensure an intake of 4.5 g sodium chloride. In some of the cases, as indicated in the legends to the figures, 400 to 1200 ml of blood were given on this day. On the first three post-operative days, the intake of potassium and nitrogen was estimated from the actual amount of the diet consumed, and the salt intake of 4.5 g was maintained either by infusion or by oral administration. Thereafter the basic diet, supplemented by 4.5 g sodium chloride, was once more given. The patients undergoing adrenalectomy received 200 mg of cortisone acetate per day in div ded doses by intramuscmar injection, and 75 n.g per day was given to one of the patients undergoing hypophysectomy. The cortisone was begun from five to twelve days before the operations, and the patients were in sodium, potassium and nitrogen equilibrium for some days before the operation. Cortisone was not given to the other patient who underwent hypophysectomy. The doses were more than the minimum necessary for recovery from adrenalectomy, and were considered ample to ensure the uncomplicated convalescence desirable for a satisfactory balance study. This indeed proved to be the case. The relevant clinical data of the patients studied are shown in Table I. Chemical methods Sodium and potassium were determined in the urine using a Barclay Flame Photometer with lithium internal standard. Urinary chloride was determined titrimetrically by the method of VAN SLYKE 22,and urinary nitrogen was estimated by the TABLE
I
--.-.--Patient
A@ years
Sex
-.. qf cortisone acetate mg per day _.-. ~-_.. -
Disease
M.G.
47
F
Carcinoma of breast
rst and 2nd stage adrenalectomy and splanchnicectomy
1I.B.
47
F
Malignant hypertension
2nd stage adrenalectomy and splanchnicectomy
D. McK.
37
M
Malignant hypertension
2nd stage adrenalectomy and splanchnicectomy
M.H.
48
F
Carcinoma of breast
Hypophysectomy
75
E.W.
A0
F
Carcinoma of breast
Hypophysectomy
0
References p. 5’44
200
200
VOL. 1 (1956) micro-Kjeldahl were measured hydroxy
~IETABOLIC
method.
RESPOIG:SE TO .~DRENALECTO~IY
Urinary
using the method
steroids by the method
acid-stable
etc.
formaldehydogenic
535 steroids
of TOMPSETT AND SMITH 11, and urinary
(ASFS) total
17-
of REDDY, JENKINS AND THORN 23.
Results The results are shown graphically in Figs. 1-5. The data on sodium, chloride, nitrogen and potassium are plotted by the method of REIFENSTEIN, ALBRIGHT AND
123456789K)12345678910111213!41234 Day5 t
OpeAtion 1” staqe
t
Operation 2nd staqe
Fig. I. M.G. First and second stage adrenalectomy and splanchnicectomy. Cortisone acetate zoo mgper day i.m.i. (intramuscular injection) over period of observations. I pint of blood given on day of both stages of operation. Black area above or below the balance line represents loss or accumulation respectively.
WELLS 24, in which the intake
for each constituent
is measured
down from the base
line, and urinary excretion upwards from the intake level. The small and nearly constant losses in the faeces and sweat have been ignored. Accumulation and loss from the body are therefore represented by black areas below or above the balance line respectively. Urinary corticosteroids are shown on the diagram as mg excreted per 24 hours. In the cases in which blood was given on the day of operation, the sodium, chloride and potassium in the “plasma” of the blood have been included in the intake in computing the balance. In short term studies it is legitimate to exclude the red blood cell and the plasma proteins from the balance. References
p. 544
536
J. S. ROBSOX ei n/.
\‘()I.. 1 (I()@)
In the patients subjected to adrenalectomy (Figs. I-3), whether first or second stage, a retention of sodium and of chloride occurred over the first six to eight days after operation. The amount of sodium and chloride retained corresponded to that seen in other operations of similar magnitude which do not involve the adrenal glands”. Similarly, 1.6 g to 5.2 g of body potassium was lost during the first two to five postoperative days. A loss of body nitrogen also occurred for the first three to nine days after op?ratiDn,
the cumulative
deficit rang+
Balance line Chloride g (as NaCl 1
from 15 g to 56 g.
+2 -S
I{ 1;‘:
Nitrogen g Batonce line
:: +2 -S v-4 1:
(IS mg/24hours desoxycorticosterone 0 12312345678 Days
Fig. 2. K.B. Second stage adrenalectomy and splanchniccctomy. Cortisone acetate Loo ITi)? per day i.m.i. over period of observations. 3 pints of blood gi\-en on day of operation. Black arca above or below the balance line represents loss or accumulation respectively.
In the patient M.G. (Fig. I) in whom observations were made over bothstagesof bilateral adrenalectomy, the excretion of acid-stabie formaidehydogenic steroids (ASFS) in the urine showed an increase after the first stage but not after the second. No increase in urinary excretion of corticosteroids was evident in the other two cases undergoing second stage adrenalectomy (Figs. 2 and 3). This is shown graphically for patient K.B. (Fig. z) in whom ASFS was measured, and for patient D. McK. {Fig. 3) who showed no increase in urinary I?-hydroxy steroids during the post-operative period. TheresultsobtainedinthetwocasesundergoinghypophysectomyareshowninFigs. 4 and 5. In the post-operative period in both subjects sodium and chloride retention occurredalongwithlossofpotassiumandnitrogen. Urinarycorticosteroids(ASFS)rosewell above their pre-operative level for from one to four days after theoperation in both cases. DISCUSSION
Our results confirm the finding that certain features of the post-operative metabolic response in man occur after the removal of the second adrenal gland in a twoR~$W~BCCS fi,,j&t
VOL. 1
(1956)
JIETAUOLIC
RESPONSE
TO ADRENALECTOJIY
etc.
537
stage adrenalectomy 2ot 21. No estimation was made of urinary corticosteroids on the patients studied by MASON and it seemed possible from his observations that the anaesthesia and the trauma of the operative procedure before the actual exclusion of the adrenal gland from the circulation might result in enough stimulation of the adrenal cortex to produce some of the alterations in metabolic balance during the post-operative period. This possibility can be finally eliminated only if post-operative metabolic changes are shown to occur in patients both of whose adrenal glands have been previously removed and who are subjected after an interval of time to another Sodium g Balanceline
+2 +l :j
Potassium
+3 +2 Cl
Bohr% line -7 -2 +2 +1 Balance line Chloride 4 (as NoClj
-c: IJ’ 1; +20 +16
Nitr:gen Balance line
+ +8l2 +4 -s -182
123456712345676 Days
II
Fig. 3. D.McK. Second stage adrenalectomy and splanchnicectomy. Cortisone acetate zoo mg per day i.m.i. over period of obserrations. No blood given. Black area above or below the balance line represents loss or accumulation respectively. operation while on a constant dose of cortisone. However, our observation that there is no increase in the urinary corticosteroids (acid-stable formaldehydogenic and 17hydroxy steroids) after the second stage of the adrenalectomy provides no evidence that stimulation of the adrenal cortex occurs during this part of the operation. The absence of any measurable alteration in corticosteroid excretion is in striking contrast to the increase seen in Case M.G. (Fig. I) after the first stage adrenalectomy and splanchnicectomy, a difference which can be attributed only to the presence of the other, intact, adrenal gland at that time. SANDBERG et al. lo have recently shown that in man an increase in r7-hydroxy corticosteroids in the blood occurs during the early stage of anaesthesia and a similar transient rise has been shown to take place in normal dogs during the first few hours of anaesthesia *6. However, such short-lived increases in blood hormone concentration would seem an unlikely cause for metabolic events which continue for several days after second stage adrenalectomy. References 9. 544
J. S. ROBSOX et c&!.
538
VOL.
1 (19j6)
On the basis of experiments with adrenalectomised rats INGLE I6suggested that a~enocort~cal hormones played a “permissive” role in the metabolic response to injury in these animals. Although our observations on adrenalectomy in human subjects are consistent with this view, the extent to which the observed alterations in
i-4 +3 +2 +t EkY’ance Chbride‘inc
-‘:
(as &a,
I; 12 1: +12 78
Nitmgen Eblo9nceline
Ifi +2 -x I;
ASfS excretion 12 in urine 05 mg/24 hour% : desoxywrticosteront O 123456123456789lo
Fig. 4. MR. Black
Hypophysectomy. Cortisone acetate 75 mg per day i.m.i. given over period of observations. I pint of blood given on day of operation. area above or below the balance line represents loss or accumulation respectively.
electrolyte and nitrogen balance represent a tissue and renal response to trauma in which the administered hormone plays a direct and active part is still open to question. STEENBURG AND GANONG a6 have shown in adren~ectomised dogs that the metabolism of hydrocortisone given by intravenous infusion is altered by anaesthesia and by anaesthesia $&VSoperation. The concentration of free corticosteroid in the blood of the anaesthetised animals, whether operation has been performed or not, was higher than that in the control non-anaesthetised animals. It is possible that a similar increase in blood concentration may occur in anaesthetised human subjects, given a constant dose of cortisone acetate by mouth or by intramuscular injection, even when increased secretory production of adrenocortical hormones is impossible. However, this could be the cause of the metabolic response which we have observed following second stage adrenalectomy only if it is assumed that the higher blood levels persist for some days after the patient recovers from the anaesthetic at the end of the operReferences
p. 544
VOL.
1 (1956)
METABOLIC
RESPONSE
To ADRENALE~TOMY
ation. STEENBURGAND GANONG’S observations
on adrenalectomised
period of only four hours after the end of the anaesthetic
539
etc.
animals cover a
or operation.
The shape of
the curves for blood corticosteroids which they published suggests that a possible explanation for the rise in circulating corticosteroids is the transient depression in renal blood flow and filtration rate known to be associated with anaesthesia 26, 27. Definite conclusions on the concentration, in the blood, of corticosteroids following the adSodium 9 Balance line
+2 +l 19
Potassium B&A
line
+* +l 19
Balance line Chloride g (as NaCI)
+2 +1 -7 1; 145
t10 +8 Nitrogen Balon:e line
I$ +2 -: 1; -8
‘!I 05 mg/24hours 2 desoxycorticosterone0
=;;;J,b
Fig. 5. E.W. Hypophysectomy. No cortisone acetate given. No blood given. Black area above or below the balance line represents loss or accumulation respectively.
of cortisone acetate cannot be drawn from measurements of corticoin the urine because only a small proportion of administered cortisone is
ministration
steroids
detectable in the urine either as acid-stable formaldehydogenic metabolite or as 17hydroxysteroid. Nevertheless, the data on urinary corticosteroids after second stage adrenalectomy do not suggest that an increase in the blood concentration of hormone occurs during the period when the alterations in electrolyte and nitrogen balance take place, and when renal function has recovered from the effects of anaesthesia. However, if there is an alteration in the metabolism and rate of disposal of the biologically effective hormone for some days after second stage adrenalectomy, and if this alteration is sufficiently large to increase the concentration of steroid in the blood and to bring about the changes in electrolyte and nitrogen balance, then the rise in concentration must occur without an increase in urinary content of steroid metabolites normally detectable as acid-stable formaldehydogenic and r7-hydroxy steroids after operations not involving the adrenal glands. Useful information on the role of exogenous cortisone acetate in the metabolic response after second stage adrenalectomy might be obtained by comparing the magnitude of the response to different but constant References
p. 544
J. S.
540
VOL. 1 (1956)
RoBSOK et cd.
levels of dosage of cortisone and by the determination for some days before and after the operation.
of corticosteroids
in the blood
Irrespective of the part played by the administered hormone, neither the results of INGLE in animals nor our own observations in human subjects exclude the possibility that injury normally results in adrenocortical stimulation. However, the results we have obtained, in man, do indicate that those parts of the metabolic response which we have measured cannot be accepted as evidence of such stimulation, an d that they can occur in the absence secretion by the adrenal cortex. In the observations alterations in electrolyte
of any significant
change in the rate of hormone
made upon patients subjected to hypophysectomy, the and nitrogen balance are qualitatively similar to those
reported by 1fASON 21.However, after this operation there is a significant increase in the excretion of corticosteroids in the urine. Therefore the metabolic response resembles that seen after 1st stage adrenalectomy and after operations that do not involve the adrenal gland, and the observations of MASON on alterations in electrolyte and nitrogen balance after hypophysectomy cannot be used as evidence to support the theory of the “permissive” action of adrenocortical hormones. Unlike the patients studied by MASON, our own subjects received no corticotrophin over the period of observation, and neither the magnitude of the metabolic response nor the increase in the excretion of corticosteroids were detectably influenced by the fact that cortisone was not given to patient E.W. (Fig. 5) before or after the hypophysectomy. The reason for the rise in urinary steroids, measured by TOMPSETT'S method, following hypophysectomy
remains
unknown
and its occurrence
is surprising.
At least
four explanations are possible. First, the pituitary-adrenal axis may be stimulated by that part of the operative procedure which takes place before removal of the hypophysis from the circulation, so that the increase in urinary corticosteroids is in fact evidence of an increase in adrenocortical activity brought about by the adrenocorticotrophic hormone. This explanation seems unlikely in view of the absence of a rise in urinary corticosteroids in the case of second stage adrenalectomy, where the trauma up to the point of removal of the gland is of a similar order of severity though not of duration. Secondly, it may be that in both patients studied the hypophysectomy was in fact only partial and that functioning pituitary tissue was left behind; up to the present time we have not had the opportunity of verifying this. Thirdly, the increase in corticosteroids in the urine might reflect some alteration in the metabolism of adrenocorticosteroids secreted by the adrenal cortex rather than a change in rate of secretion; evidence has already been quoted that trauma and operative procedures alter the rate of metabolism and of excretion of r7-hydroxy corticosteroids, though the absence of a similar rise in the urinary excretion of corticosteroids after second stage adrenalectomy while cortisone acetate is being given by mouth would not make this a likely suggestion. Finally there remains the possibility of general adrenocorticdl stimulation being brought about through channels other than that of the pituitary adrenocorticotrophic hormone, as seems to be the case for aldosterone 28. At present it is not possible to decide which of these four explanations is correct. In discussing these observations, we have accepted the view that post-operative ttlterations in the urinary excretion of sodium, potassium, chloride and nitrogen represent a more or less definite and unified response to trauma. This itself may prove to be an over-simplification because there can be little doubt that numerous factors References p..j.#
VOL.
METABOLIC
1 (I’)$)
RESF’OSSE
TO ADRENALECTOJIY
&.
54
may modify the series of events which follow trauma 2s. Balance studies are among the most important methods available for definition of the metabolic events after surgery. However, the results of such studies are dependent upon the calculation of intake and the measurement of rates of excretion in the urine. Interpretation of results obtained by this technique is made more difficult by the introduction of additional factors, such as the infusion of large quantities of blood 3o which complicate the computation of intake and also alter renal function. It is clear that the metabolic response demonstrated by balance study represents a combination of actual changes in cellular activity after injury and the results of treatment. Until a more sensitive indicator of such metabolic activity than the balance technique is found, caution must be observed in drawing up any hypothesis which describes the metabolic response to injury as being due to particular causes. However, our conclusion that those features of the response which we have observed may occur in the absence of increased adrenocortical secretion is independent of whatever hypothesis of the metabolic response, Unitarian or other, may ultimately prove to be correct. ACKNOWLEDGEMENTS Our thanks
are due to Sir JAMES LEAHMONTH and Professor
NORMAN DOTT for
their kindness in giving us the opportunity to study patients under their care, and to the Scottish Hospital Endowments Research Trust for a grant which allowed D. B. H. to take part in these investigations. We are also grateful to Xiss MAUREEN SMITH who carried out some of the steroid estimations. SUMMARY I. Observations have been made upon the balance of sodium, potassium, chloride and nitrogen and the excretion of corticosteroids in the urine in three patients subjected to bilateral adrenalectomy and given constant doses of cortisone acetate, and in two patients undergoing
hypophysectomy,
only one of whomreceived
cortisone acetate.
2. The usual post-operative metabolic changes of sodium and chloride retention with loss of potassium and nitrogen in the urine occurred in all patients. In the three patients subjected to second stage adrenalectomy,
the metabolic response was not
associated with a rise in the urinary excretion of adrenocorticosteroids (acid-stable formaldehydogenic or r7-hydroxy-steroids). Increase in urinary corticosteroids occurred in both patients after hypophysectomy and in the one patient studied on whom a first stage adrenalectomy was performed. 3* It is concluded that the metabolic responses observed after second stage adrenalectomy occurred in the absence of significant alterations in the rate of adrenocortical secretion. The observations we have made do not eliminate the possibility that trauma and surgical operation in patients with intact adrenal glands increase the secretory activity of the adrenal cortex. However the occurrence of alterations in electrolyte and nitrogen balance following surgical trauma may not be used as evidence that such an increase in secretion occurs. 4. The role of the cortisone acetate given to the patients before and after removal of the adrenal glands in the metabolic response is discussed. Although the results are not inconsistent with the “permissive” action of the hormone as suggested by INGLE, the possibility that alterations in metabolism and the rate of excretion of the References
p.
544
542
J. S. XOBSOS
YOL. 1
et cd.
a rise
a une
a une A une d’adr~nocorticost~ro~des (stero’ides stables a eu
& glandes a la
a lieu
VOL.
1 (1956)
METABOLIC
RESPONSE
543
etc.
TO ADRENALECTOMY
ZUSAMMENFASSUNG I. Die Natrium-, Kalium-, Chlorid-und Stickstoffbilanz und die Ausscheidung von Corticosteroiden im Urin wurden bei drei an bilaterale Adrenalectomie unterworfenen Patienten, die konstante Dosen von Cortisonacetat erhielten, und bei zwei Patienten nach Hypophysectomie, von denen nur einer Cortisonacetat erhielt, beobachtet. 2. Die iiblichen post-operativen metabolischen Vergnderungen von Natriumund Chlorid-Retention mit Verlust von Kalium und Stickstoff durch den Harn kamen bei allen Patienten vor. Bei den drei Patienten deren zweite Nebenniere entfernt worden war, war die metabolische Reaktion nicht mit einer Zunahme der Ausscheidung von Adrenocorticosteroiden (sgure-stabilen formaldehydbildenden oder 17Hydroxysteroiden) im Urin verbunden. Eine Zunahme der Corticosteroide im Urin kam vor: bei beiden Patienten nach Hypophysectomie und bei dem einen untersuchten Patienten, bei welchem eine einseitige Adrenalectomie ausgefiihrt worden war. 3. Es wird geschlossen, dass die nach Resektion der zweiten Nebenniere beobachteten metabolischen Reaktionen ohne signifikante Anderungen der adrenocorticalen Sekretion stattfanden. Die gemachten Beobachtungen schliessen die Mijglichkeit nicht aus, dass Trauma und chirurgische Operation bei Patienten mit intakten Nebennieren die Sekretionsaktivitgt der Nebennierenrinde erhiihen. Jedoch darf das Auftreten von _&nderungen der Elektrolyt- und Stickstoffbilanz nach einem chirurgischen Trauma nicht als Beweis einer derartigen Sekretionserhdhung benutzt werden. 4. Die Rolle, welche das vor und nach Entfernung der Nebennieren an Patienten verabreichte Cortisonacetat bei der metabolischen Reaktion spielt, wird eriirtert. Obwohl die Ergebnisse nicht mit der “permissive action” des Hormons von INGLE im Streit sind, kann die Mijglichkeit nicht ausgeschlossen werden, dass linderungen des Metabolismus und der Ausscheidungsgeschwindigkeit des Hormons eine Zunahme der Blutkonzentration des biologisch wirksamen Hormons mit hiermit zusammenhgngenden Anderungen der Elektrolytund Stickstoffbilanz, zur Folge haben. Nichtsdestoweniger muss eine derartige linderung der Verwertungsgeschwindigkeit des biologisch aktiven Hormons, wenn sie wghrend einiger Tage nach der Operation auftritt, doch ohne ErhGhung des im Urin gemessenen Gehaltes an Steroidmetaboliten stattfinden, wie diese normalerweise nach Operationen die sich nicht auf die Nebenniere beziehen, gefunden wird. 5. Vier verschiedene Auslegungen der Zunahme an Corticosteroiden im Harn nach Hypophysectomie werden vorgeschlagen aber es ist nicht miiglich zu entscheiden, welche von diesen Erklgrungen die Richtige ist.
PE3IOME I. npOu3BO,@iAOCb BbI6pOC pC3CKguU
B
MO¶y
nauueHToB
anpeHahOBbIX
xeAe3
~~0p0t
cTa,qm
y
TpeX
u nOA~aBI,IuX
c pe3eKaeP
naIJueHTb1 o6HapymiAu 3anepxcaHr.m HaTpm wa
~a,q 6aAaHcoM
KOpTuKOCTepOWOB
H y asyx naguemoB UCAbIti KOpTuSOH. 2. Bee HeHm B
Ha6AmaeHue
wno@f3br,
u
KaAbyuK,
naJJUeHTOB
HaTpus,
XAopuna
nO~eprH)rrbIX
u a3OTa
nOCTOIIHHbIe aO3bI yKCyCHOKHCAOrOKOpTu3OHa, u3 KOTOP~IX
ToAbKo
onu~noA)n1aAyKcycH0~-
HopMaAbHbIe nocAe-onepa~uoHHbIeMeTa6OAU~eCKueM3~exnopu,qa c noTepeii KaAu* u a3oTa B Moqe. Y
pe3eKgm.f
EI
DyX-CTOpOHHeii
aApeHanosblx
xeAe3,
MeTa6OAmeCKaR
Tpex
xapaKTep-
UCTUKa He 6mAa CBII3aHa C BbI6pOCOM B MOYy a,ZJpeHOKOpTElKOCTepOPldOB. ~OBbIIIIC!H~e KOpTuKOCTepOH~OB B MOge UMeAO MeCTO y &(ByX naIJUCHTOB C pe3CK&@&i I'UnO$,u3bI u y odHor0 nauuenTa Ha nepaofi cTa,quu peseKgus4 aapeHaAoBoii xceAe3bI. 3. 4eAaCTCK
BbIBO&
¶TO MeTa6OAWIeCKaK
XapaKTeptlCTUKa
Ha6AIO&sBmaKCK
nOCAt! BTOpOii
J. S. ROBSON
544 cra,zwn
pe3eKgIwI
anpeHaAosoii
II3MeHeHMfi a aeAwIkIHe B03MOXHOCTX
po~yToti
TOTO,
>KeAesbr. OaHaKo 6aAaHCe
He
BCAeACTBMII
IwIeAa
TpaBMa
XIlpyprwIecKoe
II
II~II ~TC~~CTBIIII 3HawITeAbHbI* Harukl HaGAIo,qewnI He HcKAwIaIoI
aMeInaTenbcTa0
3KeAesoii yckI*ImaIoT ceKpegHoHHyn3 peKoMeHnyeTc3
paccMaTpm3aTb
XIIpyprIIYcCKOt
TpaaMbI
KaK
1 (1956)
VOL.
MecTo
a,zIpeHoKopTwIecKoii ceepeuma.
YTO
anpeHanonofi
XeAe3bI
et al
Ha
aKTmzHocTb
nayMeHTax
c HTT-
KopbIaape~ahoaoii
II3bIeHeHHa a sncKTpo,~Te
II a3oTHoM
_?IOKa3aTeAbcTaO HaAII9IIX TaKOIO
yae,,II-
4e~118 ceKpeI_pIkI.
4. y
06cyxaaexx
nautteHToe
pesaT
cl0
amfume nocne
II
~KC~CEI~KMCA~~~
K~OBM,
,,AOnyCTRMOMy"
RbI3bIBaKIT yBeAHseHMe
9~0
CCAH TaKOe HeCKOAbKO
BAegeT
nocne
I13MeHeHMe
onepagaii nocne
He
3aBIKXMOCTb
II3MeHeHIIa I3 MeTa6oAI.IaMe II MHTeHcIIBHOCTb
M3McHeIiHa
B aAeKTpoAmTe
noche
onepagIwI,
IIpOayKTOB
II BSOTHOM
6aAaHCe.
6ElonorIIsecKM aKTMBHbIx OH0
CTepOII,ZIHOTO MeTaGOAIIaMa,
3aTparImaIoxyr?x anpeHaAosbIx rMno@3bI,
O,&HaKO He
TeM
rop~o~oa
abI6poca
IOpMOHOB
a
He MeHer,
IIMeeTMecTo
+'IONKHO IIpOIICXO,!QlrTb6~3
IIOBbIIIIeHIIR
KaK 06bIYHo IIpOIICXO~IIT
jl(ehe3.
'IeTbIpeB03MO)KHbIX 06bKCHeHIIiiaBAeHIIii )IBeAllYeHZUI
pe3eKgnII
113 HIIX JIBARCTCX
mxa6onmecKym
KOHI&eHTpaIJZIll 6lroAorwsecKII a@eKTIIBHbIX
CKO~OCTII BbI6pOCa
II3MepeHHbIX
5. npeAAaraeTCa B MoYe
31 co608
aIIeti cnycra
COAepmaHlla
Ha
aApeHanosbIx xeAe3. XOTR pe3yAbTaTbI Ire npo~vmoKaK 6bIAo IIpc&AOXceIIO MHTAC (LNGLE),HeAbSa ,?(etiCTBLItO ropMoHa,
IICKAIOYaTb TOti BOBMO)KHOCTII, YTO I'OpMOHa
KopTm3oHa
yAaneHwI
KOpTIIKOCTepOII,!IOB
IIMeeTCR B03MO)f(HOCTII yCTaHOBIITb,
KaKOe
IIpaBIIAbHbIM.
I D. P. CUTHBERTSOK, B&hem. J,, 23 (1929) 1x28. L D. P. CUTHBERTSON, Rzoclzena.J., 24 (1930) Iz44. 3 A. W. WILKINSON,B. H. BILLING, G. NAC~Y AND C. P. STEIVART, Lanret, 256 (1949) 640. 4 F. ALBRIGHT, Proc. rst Co?$ I?one and m’ound Hcalzng. Josiah ivracey Jr. Foundation, New lTorlr,'942. 5 H. SELYE, .I.Clin. Exdocvinol., 6 (1946) I I 7. 6 F. D. ~UOORE AND RI. K. BALL, The Netabolic Respome to Surgery, Charles C.Thomas, Springfield,1952, p, III. 7 C. I'.STEWART, J. S. ROBSON AND S. L. TOMPSETT, 281ne Congr. intern.biochiwz., Paris, 19.52, Res. Cowmuns., p. 138. 8 G. W. THORN, D. JENKINS, J. C. LAIDLAW, F. C. COETZ AN;D 14:.REDDY, Trans. Assoc. Am. Physicians, 66 (1953) 48. 9 C. L. COPE AND B. HURLOCK, Clin. Sci.,13 (1954) 69. IO A.A.SANDBERG,K.EII<-NES,L.T.SA~MUELSANDF.H.TYLER,J.C~~~. Inz’est.,33(Igjq) 15I7. II S. L. TOMPSETT AND D. C. SMITH, J. Clin. Endorrinol. and ~Vletabolisnz, 14 (1954) 922. 12 J. G. LLAURUDO, Lancet, 268 (1955) 1295. 13 F. D. MOORE, Ii.W. STEENBURG, 1\1.Ii.BALL, G. XI. W~ILSON AND J. A. MYSDE?I, Ann. Surg., I&(I955) 145. 14 E. H. V'ENNING, I. DYRENFORTH, ‘5 16 17 18 19
LO 21 2~
23 24 25
26
C. S. P. GIROUD
AND
J. C. BECK,
PUG.
Montreal
Physiul.
SoC., (1955) 13. F. L. ENGEL, Recent Progr. Hormone Research, 6 (1951) ~77. D. J. INGLE, J. Endocrinol., 8 (1952) 23. G. HUGGINS AND D. BERGENSTAL, J. ,4nz. Med. Assoc., 147 (1951) IOI. A. V%".WILKINSON, Lancet, 270 (1956) 184. 13. iX, CAMPBELL, G. 31. E. SHARP, -4.W. BOYNE AND D. P. CUTHBERTSON, Nature, 17.5 (1953) 158. J. S. ROBSON, D. B. HORN, H. A. DUDLEY AND C. P. STEWART, Lancet, 269 (1955) 325. A. S. MASON. Lancet, 269 (1955) 632. D. D. VAN SLYKE, Quantitative Clinical Chemistry. Balliere. Tindall & Co., 1932, p. 833. W. J. REDDY, D. JENKINS AND G. W.THORN, Metabolism, I (1952) 511. EC. REIFENSTEIN, F. ALBRIGHT AND S. L. WELLS, J.Clin.Endocrinol., 5(Ig45) 232. K. W. STEENBURG AND W. F. GANONG, Swgery, 38 (1955) 92. B. E. >~ILES, H. E. DE \VARDENER,H.C.CHURCHILL-DAVIDSON AND W.D. WYLIE,CZ~VZ. Sci.,
II (1952) 73. ~7 G. DE J, LEE, H.C. CHURCHILL-DAVIDSON, B. E.&LES AND H. E. DE ~'ARDENER, 12 (1953) 169. r8 S. A. SIMPSON AND J. F. TAIT, Recent Prop. Hormme Research, 12 (1955) 183. 29 C. P. STEWART, 30 G. T. G. FLEAR
Clin. Sci.,
16th Intern. Cony. Surgery, Copenhagsn, 1955. AND R.CLARKE, Clzn..'?ci., 14 (1955) 576. Received
September
Ist,
1956