Acta anaesth. scand. 1975, 19, 260-264
A Rational Approach to Dosage and Preparation of Parenteral Glucocorticoid Substitution Therapy During Surgical Procedures A Short Review
H. KEHLET Hvidore Hospital and Medical Department F and Surgical Department D, Gentofte Hospital, Copenhagen, Denmark
A rational, physiological schedule for parenteral glucocorticoid substitution therapy during surgical procedures is proposed based on the principle of imitating the normal hypothalamic-pituitary-adrenocortical response to surgery. T h e schedule includes the injection of 25 mg cortisol intravenously in all patients together with induction of anaesthesia. Following major mrgery, 100 mg cortisol dissolved in saline or glucose is continuously infused intravenously every 24 hours until gastrointestinal function permits oral intake of usual glucocorticoid substitution therapy. I n case continuous cortisol infusion is undesirable, 25 mg cortisol is injected intravenously every four hours. Following minor Jurgery, usual oral glucocorticoid therapy is started immediately after the operation. It is recommended to use water-soluble cortisol preparations and not cortisone acetate, which results in limited plasma cortisol levels.
Received I4 January, acceptedfor Publication 18January 1975
Parenteral glucocorticoid substitution therapy to infection (PRAKASH& TANGA1968 is indicated during surgical procedures in STEPHENS et al. 1971) and retarding wound Addisonian and adrenalectomized subjects, healing (SANDBERG 1964). This paper is during and following bilateral adrenalectomy an attempt to attain a rational, physiological and in glucocorticoid treated patients with schedule for glucocorticoid therapy during depressed hypothalamic-pituitary-adrenocor- surgery based upon the principle of imitating tical (HPA) function. A great number of dif- the normal HPA response to surgery. ferent schedules for this supplementary glucocorticoid administration have been I. Choice of Glucocorticoid Preparation and Route 1969, PLUMP- o f Administration proposed (PARIS1961, OYAMA TON et al. 196913, Rains et al. 1971, GABRILOVEThe aim of supplementary glucocorticoid & NICOLIS 1972, WILLIAMSet al. 1974). administration is to provide the patient However, the majority of these schedules with sufficient glucocorticoid. Of the natural have been founded on an empirical basis, glucocorticoids, cortisol is the biological not considering glucocorticoid dosage, prep- active hormone and cortisone must be aration and route of administration on a converted to cortisol to mediate its glucoet al. 1951, clinical-pharmacological basis. Furthermore, corticoid effect (HOLLANDER et al. 1957). I t is usually recomglucocorticoid should only be given in a PETERSON necessary and adequate dose due to its mended that cortisone acetate or cortisone undesirable side effects in lowering resistance acetate plus cortisol should be employed
GLUCOCORTICOID SUBSTITUTION THERAPY
261
in parenteral glucocorticoid substitution and loss from overlooked venous emuents therapy (PARIS1961, OYAMA 1969, RAINS et cannot be excluded. Based upon repeated al. 1971, GABRILOVE& NICOLIS 1972, plasma cortisol determinations and assuming WILLIAMS et al. 1974).However, recent studies a constant volume of distribution of cortisol, (PLUMPTON et al. 1969b, KEHLETet al. 1974), WISE et al. (1972) calculated the amount of together with sporadic observations (NELSON cortisol secreted during surgery to be 60 mg et al. 1952, RAILEet al. 1953, BANKS1970) per 24 hours. However, the apparent volume have revealed that very limited and variable of distribution of cortisol changes markedly plasma cortisol levels may be obtained during surgery (KEHLET& BINDER1973a), following intramuscular cortisone acetate, as and the above-mentioned value, therefore, compared to intramuscular cortisol (PLUMP- represents an approximate and minimal estimate. KEHLET& BINUER(1 973a), using TON et al. 1969b, KEHLETet al. 1974). This is probably due both to deficient repeated injections of labelled cortisol in absorption (SILBER& MORGAN1956) and measuring cortisol metabolism, calculated to only partial conversion of cortisone to cortisol secretion during and after surgery cortisol (JENKINS & SAMPSON1967). No and found values about 10 and 5 mg per major difference in efficacy exists between hour, respectively. However, these values the various water-soluble cortisol-esters, represent an overestimation amounting to although the phosphate-esters may give a about 25% due to the one-compartment & little higher plasma cortisol level (MELBY model used in the calculations (BRADLEY 1966, DAZORDet al. 1972, & ST. CYR 1961). Intravenous cortisol WATERHOUSE gives the highest plasma cortisol concentra- GOLD& CRIGLER1972). Thus, based upon et al. 1969b). the available data, a reasonable estimate of tions (PLUMPTON Therefore, parenteral glucocorticoid sub- cortisol secretion during the 24 hours followstitution therapy is most safely administered ing surgery amounts to about 75-150 mg. by intravenous or intramuscular injection This is not contradictory to observations made during maximal stimulation with of a water-soluble cortisol preparation. exogenous ACTH showing average values 11.Dosage o f Glucocorticoids of about 200 mg per 24 hours (PETERSON a. Major surgery (abdominal, thoracic and major 1959, PETERSON et al. 1960, ICHIKAWA 1966, orthobaedic operations) THOMAS &. EL-SHABOURY 1971) . Postoperatively, cortisol secretion is often Obviously, the amount of glucocorticoid to be administered for total substitution normalised 24 hours after skin incision as should correspond to the amount of gluco- reflected by a normal plasma cortisol level et al. 1956, SAMPSON et al. 1962), corticoid secreted during major surgery (STEENBURG but on an average a normal value is gained in normal individuals. Various approaches to determine cortisol 36 to 72 hours after skin incision (SAMPSON et al. 1969a, HAMANsecretion during major surgery have been et al. 1962, PLUMPTON used. Thus, HARDY & TURNER (1957) and AKA et al. 1970). This is due to continued HUMEet al. (1962) found values of 72 and increased cortisol secretion in patients with et al. 95 mg per 24 hours, respectively, by direct surgical complications (STEENBURG 1959) (fever, peritonitis, measurement using adrenocortical vein 1956, THOMASSON catheterisation. These observations, based on intestinal paralysis). Thus, in case of postmeasurements during or immediately follow- operative complications, glucocorticoid subing surgery during supposed maximal cortisol stitution therapy should also remain at an secretion (HUMEet al. 1962), represent only elevated dosage. As a parameter of posta rough estimate, as cortisol secretion is operative complications gastrointestinal funcnot maximal during the entire 24-hour tion is suitable. Normal function will exclude postoperative period (HUME et al. 1962), serious complications and thereby the indica-
262
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tion for continued supplementary glucocorticoid and will also permit peroral glucocorticoids to be given safely. Accordingly, a reasonable schedule for glucocorticoid substitution therapy in connection with major surgery may be the following : With induction of anaesthesia 25 mg cortisol is injected intravenously, resulting in plasma cortisol levels >30 pg/lOO ml (PLUMPTON et al. 1969b) and providing the patient with immediate sufficient gluco& BINDER1973b). During corticoid (KEHLET or a t the end of the operation, intravenous infusion of 100 mg cortisol dissolved in saline or glucose is started and continued during the first 24 postoperative hours and recontinued every 24 hours until gastrointestinal function permits oral intake of usual glucocorticoid substitution therapy. I n case continuous cortisol infusion is undesirable, 25 mg cortisol is injected intravenously every four hours.
incision (PLUMPTON et al. 1969a, KEHLET& BINDER197313). Accordingly, a reasonable schedule for glucocorticoid substitution therapy in connection with minor surgery may be intravenous injection of 25 mg cortisol with induction of anaesthesia, providing the patient with sufficient glucocorticoid during surgery. Postoperatively, usual oral glucocorticoid substitution therapy is administered as soon as the patient is able to drink. I n case oral intake is prevented, the schedule proposed for major surgery is followed until gastrointestinal function is normalised. ZUSAMMENFASSUNG
Es wird ein rationelles, physiologisches Schema fur die parenterale Glukokortikoid-Substitutionstherapie vorgeschlagen, das auf dem Prinzip beruht, die normale hypothalamisch-hypophysar-adrenocorticaleReaktion auf die Operation nachzuahmen. Zusammen mit der Anaesthesie-Einleitung erhalten alle Patienten 25 mg Cortisol i.v. Nach groBen Eingriffen werden uber 24 Stunden 100 mg Cortisol, in Glukose- oder Kochsalzlosung aufgelost, als i.v. b. Minor surgery (hand surgery, haemorrhoidectomy, Tropfinfusion verabreicht, bis die Magen-Darmuterine curettage, etc.) Tatigkeit eine orale Gluko-Kortikoid-SubstitutionsThe HPA response to minor surgery as therapie gestattet. Fur den Fall, daB die kontinuierliche reflected by plasma cortisol is poor (PLUMPTONZufuhr von Cortisol unerwunscht sein sollte, werden et al. 1969a, KEHLET& BINDER 197313) 25 m g Cortisol alle 6 Stnnden i.v. injiziert. Nach kleinen operativen Eingriffen kann ublicherweise and often even absent. Cortisol secretion schon unmittelbar anschlieknd die Cortisoltherapie in connection with minor surgery has only oral begonnen werden. been investigated by QUERIDO & VAN Es wird empfohlen, wasserlosliche Cortisol-Praparate SETERS(1967), who found values of about und nicht Cortison-Acetate zu verwenden, mit denen 130 mg cortisol secreted during the first nur beschrankte Plasma-Cortisol-Spiegel erzielt werden konnen.
48 postoperative hours following inguinal herniotomy. However, the urinary isotopic dilution method used has recently been REFERENCES seriously questioned (GALLAGHER et al. BANKS,P. (1970) T h e adreno-cortical response to oral 1970, KELLY 1970). Based upon repeated surgery. Brit. 3. Oral Surg. 8, 32. BRADLEY, E. ILI. & MJATERHOUSE, C. (1966) Effect of plasma cortisol determinations (PLUMPTON estrogen administration on extravascular cortisol. et al. 1969a, KEHLET & BINDER 1973b) 3. elin. Endocr. 26, 705. and compared to data from studies in major DAZORD,A,, S A E Z ~& J . BERTRAND, J. (1972) Metabolic surgery (KEHLET& BINDER1973a), a reasonclearance rates and interconversion of cortisol and able estimate of cortisol secretion in concortisone. 3. clin. Endocr. 35, 24. J. L. & NICOLIS,G. L. (1972) Adrenonection with minor surgery amounts to GABRILOVE, cortical function and the glucocorticoids. Surg. about 50 mg during the first 24 postoperative Clin. .N. Amer. 52, 951. hours. Hereafter, cortisol secretion is expected GALLAGHER, T. F., FUKUSHIMA, D. K. & HELLMAN, L. to be normal according to the normal plasma (1970) Clarification of discrepancies in cortisol cortisol values detected 24 hours after skin secretion rate. J . elin. Endocr. 31, 625.
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263
GOLD,N. I. & CRIGLER, J. F., Jr. (1972) Suggested in R. L. (1960) Estrogen and adrenocortical function vivo irreversible metabolism of labelled cortisol in man. 3. elin. Endocr. 20,495. during distribution : effects on kinetic measurements PETERSON, R. E., PIERCE,@. E., WYNGAARDEN, ,J. B., and role of modes and sites of administration. BUNIM,J. J. & BRODIE, B. B. (1957) The physiological 3. elin. Endow. 34, 1025. disposition and metabolic fate of cortisone in man. HAMANAKA, Y., MANABE, H., TANAKA, H., PIONDEN, 3. elin. Invest. 36, 1301. Y . , UOZUMI,T. & MATSUMOTO, K. (1970) Effects PLUMPTON, F. S., BESSER, G. M. & COLE,P. V. (1969a) of surgery on plasma levels of cortisol, corticosterone Corticosteroid treatmcnt and surgery. An investigaand non-protein-bound cortisol. Acta endocrinol. tion of the indications for steroid cover. Anaesthesia (Kbh.) 64, 439. 24, 3. HARDY, J. D. & TURNER, M. D. (1957) Hydrocortisone PLUMPTON, F. S., BESSER, G. M. & COLE,P. V. secretion in man: studies of adrenal vein blood. (196913) Corticosteroid treatment and surgery. Surgery 42, 194. The management of steroid cover. Anaesthesia 24, HOLLANDER, J. L., BROWN, E. M., Jr., JESSAR, R. A. & 12. BROWN,C. Y . (1951) Hydrocortisone and cortisone PRAKASH, A. & TANGA, M. C. (1968) Surgery and injected into arthritic joints: comparative effects corticosteroids. Int. 3. Surg. 49, 143. of and use of hydrocortisone as local antiarthritic QUERIDO, A. & VAN SErERS, A . P. (1967) The function agent. 3. Amer. med. Ass. 147, 1629. of the adrenal cortex in old age. The Human HUME,D. M., BELL,C. C. & BARTER, F. C. (1962) Adrenal Cortex, ed. G. E. W. WOLSTENHOLME & Direct measurement of adrenal secretion during R. PORTER,p. 119. Ciba Foundation Study Group operative trauma and convalescence. Surgery 52, 174. 27, Churchill Ltd., London. ICHIKAWA, Y . (1966) Metabolism of cortisol-4-CI4 in RAILE,R. B., ELY, R. S. & KELLY,V. C. (1953) patients with infection and collagen diseases. Studies of 17-hydroxycorticosteroids in children Metabolism 15, 613. II. Response of blood levels to the injection of JENKINS, J. S. & SAMPSON, P. A. (1967) Conversion of certain hormones. 3. Pediat. 42, 46. cortisone to cortisol and prednisone to prednisolone. RAINS, G., CLELAND, A.J. H., CAPPER, W. M., KNIGHT, Brit. med. 3. 1, 205. W. P. & FREEMAN, M. A . R. (1971) Management KEHLET,H. & BINDER,C. (1973a) .4lterations in after adrenalectomy, Bailey and Love’s Short Practice distribution volume and biological halflife of corOfSurgery, ed. A. J. H. RAINS,W. M. CAPPER,G. KNIGHT,W. P. CLELAND & M. A. R. FREEMAN, tisol during major surgery. 3. elin. Endocr. 36, 330. KEHLET,H. & BINDER,C. (1973b) Adrenocortical p. 602. Lewis & Co. Ltd, London. function and clinical course during and after surgery SAMPSON, P. A,, WINSTONE, N. E. & BROOKE,B. N. in unsupplemented glucocorticoid treated patients. (1962) Adrenal function in surgical patients after Brit. 3. Anaesth. 45, 1043. steroid therapy. Lancet ii, 322. KEHLET, N. (1964) Time relationship between adH., NISTRUP MADSEN, S. & BINDER, C. (1974) SANDBERG, ministration of cortisone and wound hcaling in rats. Cortisol or cortisone acetate in parenteral glucocorticoid therapy? Acta. med. scand. 195, 421. Acta chir. scand. 127, 446. KELLY, W. G. (1970) Questions concerning the SILBER,R. H. & MORGAN, E. R. (1956) Absorption validity of one of the assumptions underlying the and excretion of 17,2 1-dihydroxy-20-kctosteroidsin determination of the secretion rate of cortisol. dogs. Clin. Chenz. 2, 170. Steroids 16, 579. R. W., LENNIHAN, R. & MOORE,F. D. STEENBURG, MELBY,J. C. & ST. CYR, M. (1961) Comparative (1956) The free blood 17-hydroxycorticosteroids in surgical patients; their relation to urine steroids, studies on absorption and metabolic disposal of metabolism and convalescence. Ann. Surg. 143, water-soluble corticosteroid esters. Metabolism 10, 180. 75. NELSON, D. H., SANDBERG, A. A., PALMER, J. G. & STEPHENS, F. O., HUNT,T. K., JAWETZ, E., SONNE, TYLER, F. H . (1952) Blood levels of 17-hydroxyM. & DUNPHY, J. E. (1971) Effect of cortisone and corticosteroids following the administration of vitamin A on wound infection. Amer. 3. Surg. 121, 569. adrenal steroid and their relation to levels of THOMAS, J. P. & EL-SHABOURY, A. H. (1971) Aldocirculating leucocytes. 3. elin. Invest. 13, 843. OYAMA,T. (1969) Hazards of steroids in association sterone secretion in steroid-treated patients with adrenal suppression. Lancet i, 623. with anaesthesia. Canad. Anaesth. Soc. 3. 16, 361. B. (1959) Studies on the content of 17PARIS,J. (1961) Pituitary-adrenal suppression after THOMASSON, protracted administration of adrenal cortical horhydroxycortisteroids and its diurnal rhythm in the mones. Proc. M a y Clin. 36, 305. plasma of surgical patients. Scand. 3. elin. Lab. Invest., Suppl. 42, 104. PETERSON, R. E. (1959) The miscible pool turnover rate of adrenocortical steroids in man. Rec. Progr. WILLIAMS, G. H., DLUHY,R. G. & THORN, G. W. (1 974) Diseases of the adrenal rortex. Harrison’s Hormone Res. 15, 231. PETERSON, R . E., NOKES,G., CHEN,P. S. & BLACK, Principles of Internal Medicine, ed. M. M. WINTROBE,
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G. W. THORN,R. D. ADAMS,I. L. BENNET,E. BRAUNWALD, K. J. ISSELBACKER & R. G. PETERSDORF. D. 519. McGraw-Hill. New York. WISE,L., MARGRAF, H . W. & BALLINGER, W. F. (1972) A new concept on the pre- and postoperative regulation of cortisol secretion. Surgery 72, 290.
Address: Henrik Kehlet, M.D.
, l
Hvidnre Hospital DK-2930 Klampenborg Denmark
A Rational Approach to Dosage and Preparation of Parenteral Glucocorticoid Substitution Therapy During Surgical Procedures A Short Review
H. KEHLET Hvidore Hospital and Medical Department F and Surgical Department D, Gentofte Hospital, Copenhagen, Denmark
A rational, physiological schedule for parenteral glucocorticoid substitution therapy during surgical procedures is proposed based on the principle of imitating the normal hypothalamic-pituitary-adrenocortical response to surgery. T h e schedule includes the injection of 25 mg cortisol intravenously in all patients together with induction of anaesthesia. Following major mrgery, 100 mg cortisol dissolved in saline or glucose is continuously infused intravenously every 24 hours until gastrointestinal function permits oral intake of usual glucocorticoid substitution therapy. I n case continuous cortisol infusion is undesirable, 25 mg cortisol is injected intravenously every four hours. Following minor Jurgery, usual oral glucocorticoid therapy is started immediately after the operation. It is recommended to use water-soluble cortisol preparations and not cortisone acetate, which results in limited plasma cortisol levels.
Received I4 January, acceptedfor Publication 18January 1975
Parenteral glucocorticoid substitution therapy to infection (PRAKASH& TANGA1968 is indicated during surgical procedures in STEPHENS et al. 1971) and retarding wound Addisonian and adrenalectomized subjects, healing (SANDBERG 1964). This paper is during and following bilateral adrenalectomy an attempt to attain a rational, physiological and in glucocorticoid treated patients with schedule for glucocorticoid therapy during depressed hypothalamic-pituitary-adrenocor- surgery based upon the principle of imitating tical (HPA) function. A great number of dif- the normal HPA response to surgery. ferent schedules for this supplementary glucocorticoid administration have been I. Choice of Glucocorticoid Preparation and Route 1969, PLUMP- o f Administration proposed (PARIS1961, OYAMA TON et al. 196913, Rains et al. 1971, GABRILOVEThe aim of supplementary glucocorticoid & NICOLIS 1972, WILLIAMSet al. 1974). administration is to provide the patient However, the majority of these schedules with sufficient glucocorticoid. Of the natural have been founded on an empirical basis, glucocorticoids, cortisol is the biological not considering glucocorticoid dosage, prep- active hormone and cortisone must be aration and route of administration on a converted to cortisol to mediate its glucoet al. 1951, clinical-pharmacological basis. Furthermore, corticoid effect (HOLLANDER et al. 1957). I t is usually recomglucocorticoid should only be given in a PETERSON necessary and adequate dose due to its mended that cortisone acetate or cortisone undesirable side effects in lowering resistance acetate plus cortisol should be employed
GLUCOCORTICOID SUBSTITUTION THERAPY
261
in parenteral glucocorticoid substitution and loss from overlooked venous emuents therapy (PARIS1961, OYAMA 1969, RAINS et cannot be excluded. Based upon repeated al. 1971, GABRILOVE& NICOLIS 1972, plasma cortisol determinations and assuming WILLIAMS et al. 1974).However, recent studies a constant volume of distribution of cortisol, (PLUMPTON et al. 1969b, KEHLETet al. 1974), WISE et al. (1972) calculated the amount of together with sporadic observations (NELSON cortisol secreted during surgery to be 60 mg et al. 1952, RAILEet al. 1953, BANKS1970) per 24 hours. However, the apparent volume have revealed that very limited and variable of distribution of cortisol changes markedly plasma cortisol levels may be obtained during surgery (KEHLET& BINDER1973a), following intramuscular cortisone acetate, as and the above-mentioned value, therefore, compared to intramuscular cortisol (PLUMP- represents an approximate and minimal estimate. KEHLET& BINUER(1 973a), using TON et al. 1969b, KEHLETet al. 1974). This is probably due both to deficient repeated injections of labelled cortisol in absorption (SILBER& MORGAN1956) and measuring cortisol metabolism, calculated to only partial conversion of cortisone to cortisol secretion during and after surgery cortisol (JENKINS & SAMPSON1967). No and found values about 10 and 5 mg per major difference in efficacy exists between hour, respectively. However, these values the various water-soluble cortisol-esters, represent an overestimation amounting to although the phosphate-esters may give a about 25% due to the one-compartment & little higher plasma cortisol level (MELBY model used in the calculations (BRADLEY 1966, DAZORDet al. 1972, & ST. CYR 1961). Intravenous cortisol WATERHOUSE gives the highest plasma cortisol concentra- GOLD& CRIGLER1972). Thus, based upon et al. 1969b). the available data, a reasonable estimate of tions (PLUMPTON Therefore, parenteral glucocorticoid sub- cortisol secretion during the 24 hours followstitution therapy is most safely administered ing surgery amounts to about 75-150 mg. by intravenous or intramuscular injection This is not contradictory to observations made during maximal stimulation with of a water-soluble cortisol preparation. exogenous ACTH showing average values 11.Dosage o f Glucocorticoids of about 200 mg per 24 hours (PETERSON a. Major surgery (abdominal, thoracic and major 1959, PETERSON et al. 1960, ICHIKAWA 1966, orthobaedic operations) THOMAS &. EL-SHABOURY 1971) . Postoperatively, cortisol secretion is often Obviously, the amount of glucocorticoid to be administered for total substitution normalised 24 hours after skin incision as should correspond to the amount of gluco- reflected by a normal plasma cortisol level et al. 1956, SAMPSON et al. 1962), corticoid secreted during major surgery (STEENBURG but on an average a normal value is gained in normal individuals. Various approaches to determine cortisol 36 to 72 hours after skin incision (SAMPSON et al. 1969a, HAMANsecretion during major surgery have been et al. 1962, PLUMPTON used. Thus, HARDY & TURNER (1957) and AKA et al. 1970). This is due to continued HUMEet al. (1962) found values of 72 and increased cortisol secretion in patients with et al. 95 mg per 24 hours, respectively, by direct surgical complications (STEENBURG 1959) (fever, peritonitis, measurement using adrenocortical vein 1956, THOMASSON catheterisation. These observations, based on intestinal paralysis). Thus, in case of postmeasurements during or immediately follow- operative complications, glucocorticoid subing surgery during supposed maximal cortisol stitution therapy should also remain at an secretion (HUMEet al. 1962), represent only elevated dosage. As a parameter of posta rough estimate, as cortisol secretion is operative complications gastrointestinal funcnot maximal during the entire 24-hour tion is suitable. Normal function will exclude postoperative period (HUME et al. 1962), serious complications and thereby the indica-
262
H. KEHLET
tion for continued supplementary glucocorticoid and will also permit peroral glucocorticoids to be given safely. Accordingly, a reasonable schedule for glucocorticoid substitution therapy in connection with major surgery may be the following : With induction of anaesthesia 25 mg cortisol is injected intravenously, resulting in plasma cortisol levels >30 pg/lOO ml (PLUMPTON et al. 1969b) and providing the patient with immediate sufficient gluco& BINDER1973b). During corticoid (KEHLET or a t the end of the operation, intravenous infusion of 100 mg cortisol dissolved in saline or glucose is started and continued during the first 24 postoperative hours and recontinued every 24 hours until gastrointestinal function permits oral intake of usual glucocorticoid substitution therapy. I n case continuous cortisol infusion is undesirable, 25 mg cortisol is injected intravenously every four hours.
incision (PLUMPTON et al. 1969a, KEHLET& BINDER197313). Accordingly, a reasonable schedule for glucocorticoid substitution therapy in connection with minor surgery may be intravenous injection of 25 mg cortisol with induction of anaesthesia, providing the patient with sufficient glucocorticoid during surgery. Postoperatively, usual oral glucocorticoid substitution therapy is administered as soon as the patient is able to drink. I n case oral intake is prevented, the schedule proposed for major surgery is followed until gastrointestinal function is normalised. ZUSAMMENFASSUNG
Es wird ein rationelles, physiologisches Schema fur die parenterale Glukokortikoid-Substitutionstherapie vorgeschlagen, das auf dem Prinzip beruht, die normale hypothalamisch-hypophysar-adrenocorticaleReaktion auf die Operation nachzuahmen. Zusammen mit der Anaesthesie-Einleitung erhalten alle Patienten 25 mg Cortisol i.v. Nach groBen Eingriffen werden uber 24 Stunden 100 mg Cortisol, in Glukose- oder Kochsalzlosung aufgelost, als i.v. b. Minor surgery (hand surgery, haemorrhoidectomy, Tropfinfusion verabreicht, bis die Magen-Darmuterine curettage, etc.) Tatigkeit eine orale Gluko-Kortikoid-SubstitutionsThe HPA response to minor surgery as therapie gestattet. Fur den Fall, daB die kontinuierliche reflected by plasma cortisol is poor (PLUMPTONZufuhr von Cortisol unerwunscht sein sollte, werden et al. 1969a, KEHLET& BINDER 197313) 25 m g Cortisol alle 6 Stnnden i.v. injiziert. Nach kleinen operativen Eingriffen kann ublicherweise and often even absent. Cortisol secretion schon unmittelbar anschlieknd die Cortisoltherapie in connection with minor surgery has only oral begonnen werden. been investigated by QUERIDO & VAN Es wird empfohlen, wasserlosliche Cortisol-Praparate SETERS(1967), who found values of about und nicht Cortison-Acetate zu verwenden, mit denen 130 mg cortisol secreted during the first nur beschrankte Plasma-Cortisol-Spiegel erzielt werden konnen.
48 postoperative hours following inguinal herniotomy. However, the urinary isotopic dilution method used has recently been REFERENCES seriously questioned (GALLAGHER et al. BANKS,P. (1970) T h e adreno-cortical response to oral 1970, KELLY 1970). Based upon repeated surgery. Brit. 3. Oral Surg. 8, 32. BRADLEY, E. ILI. & MJATERHOUSE, C. (1966) Effect of plasma cortisol determinations (PLUMPTON estrogen administration on extravascular cortisol. et al. 1969a, KEHLET & BINDER 1973b) 3. elin. Endocr. 26, 705. and compared to data from studies in major DAZORD,A,, S A E Z ~& J . BERTRAND, J. (1972) Metabolic surgery (KEHLET& BINDER1973a), a reasonclearance rates and interconversion of cortisol and able estimate of cortisol secretion in concortisone. 3. clin. Endocr. 35, 24. J. L. & NICOLIS,G. L. (1972) Adrenonection with minor surgery amounts to GABRILOVE, cortical function and the glucocorticoids. Surg. about 50 mg during the first 24 postoperative Clin. .N. Amer. 52, 951. hours. Hereafter, cortisol secretion is expected GALLAGHER, T. F., FUKUSHIMA, D. K. & HELLMAN, L. to be normal according to the normal plasma (1970) Clarification of discrepancies in cortisol cortisol values detected 24 hours after skin secretion rate. J . elin. Endocr. 31, 625.
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263
GOLD,N. I. & CRIGLER, J. F., Jr. (1972) Suggested in R. L. (1960) Estrogen and adrenocortical function vivo irreversible metabolism of labelled cortisol in man. 3. elin. Endocr. 20,495. during distribution : effects on kinetic measurements PETERSON, R. E., PIERCE,@. E., WYNGAARDEN, ,J. B., and role of modes and sites of administration. BUNIM,J. J. & BRODIE, B. B. (1957) The physiological 3. elin. Endow. 34, 1025. disposition and metabolic fate of cortisone in man. HAMANAKA, Y., MANABE, H., TANAKA, H., PIONDEN, 3. elin. Invest. 36, 1301. Y . , UOZUMI,T. & MATSUMOTO, K. (1970) Effects PLUMPTON, F. S., BESSER, G. M. & COLE,P. V. (1969a) of surgery on plasma levels of cortisol, corticosterone Corticosteroid treatmcnt and surgery. An investigaand non-protein-bound cortisol. Acta endocrinol. tion of the indications for steroid cover. Anaesthesia (Kbh.) 64, 439. 24, 3. HARDY, J. D. & TURNER, M. D. (1957) Hydrocortisone PLUMPTON, F. S., BESSER, G. M. & COLE,P. V. secretion in man: studies of adrenal vein blood. (196913) Corticosteroid treatment and surgery. Surgery 42, 194. The management of steroid cover. Anaesthesia 24, HOLLANDER, J. L., BROWN, E. M., Jr., JESSAR, R. A. & 12. BROWN,C. Y . (1951) Hydrocortisone and cortisone PRAKASH, A. & TANGA, M. C. (1968) Surgery and injected into arthritic joints: comparative effects corticosteroids. Int. 3. Surg. 49, 143. of and use of hydrocortisone as local antiarthritic QUERIDO, A. & VAN SErERS, A . P. (1967) The function agent. 3. Amer. med. Ass. 147, 1629. of the adrenal cortex in old age. The Human HUME,D. M., BELL,C. C. & BARTER, F. C. (1962) Adrenal Cortex, ed. G. E. W. WOLSTENHOLME & Direct measurement of adrenal secretion during R. PORTER,p. 119. Ciba Foundation Study Group operative trauma and convalescence. Surgery 52, 174. 27, Churchill Ltd., London. ICHIKAWA, Y . (1966) Metabolism of cortisol-4-CI4 in RAILE,R. B., ELY, R. S. & KELLY,V. C. (1953) patients with infection and collagen diseases. Studies of 17-hydroxycorticosteroids in children Metabolism 15, 613. II. Response of blood levels to the injection of JENKINS, J. S. & SAMPSON, P. A. (1967) Conversion of certain hormones. 3. Pediat. 42, 46. cortisone to cortisol and prednisone to prednisolone. RAINS, G., CLELAND, A.J. H., CAPPER, W. M., KNIGHT, Brit. med. 3. 1, 205. W. P. & FREEMAN, M. A . R. (1971) Management KEHLET,H. & BINDER,C. (1973a) .4lterations in after adrenalectomy, Bailey and Love’s Short Practice distribution volume and biological halflife of corOfSurgery, ed. A. J. H. RAINS,W. M. CAPPER,G. KNIGHT,W. P. CLELAND & M. A. R. FREEMAN, tisol during major surgery. 3. elin. Endocr. 36, 330. KEHLET,H. & BINDER,C. (1973b) Adrenocortical p. 602. Lewis & Co. Ltd, London. function and clinical course during and after surgery SAMPSON, P. A,, WINSTONE, N. E. & BROOKE,B. N. in unsupplemented glucocorticoid treated patients. 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Address: Henrik Kehlet, M.D.
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Hvidnre Hospital DK-2930 Klampenborg Denmark
