0021-972X/91/7301-0111$03.00/0 Journal of Clinical Endocrinology and Metabolism Copyright © 1991 by The Endocrine Society
Vol. 73, No. 1 Printed in U.S.A.
Biphasic Changes in Hypothalamo-Pituitary-Adrenal Function during the Early Recovery Period after Major Abdominal Surgery* YOSHIYUKI NAITO, JUNICHI FUKATA, SUNAO TAMAI, NORIMASA SEOf, YOSHIKATSU NAKAI, KENJIRO MORI, AND HIROO IMURA Department of Anesthesia (Y.Nai., S.T., N.S., KM.), Second Division, Department of Internal Medicine (J.F., Y.Nak, H.I.), Kyoto University School of Medicine, Kyoto 606, Japan
higher than those during the preoperative period. The exogenously administered hydrocortisone clearance rate in phase II did not differ from that observed on the day before surgery. Dexamethasone administration resulted in a decrease in plasma cortisol levels similar to that observed preoperatively. Conversely, the ACTH-stimulated cortisol increase was significantly greater in phase II than that observed preoperatively. These results suggest that during and after major surgical stress, the H-P-A axis undergoes a biphasic change in the pattern of the stress response and during the second phase, not the continuous hypothalamo-pituitary drive but the increased adrenal responsiveness to ACTH is responsible at least in part for maintaining the elevated plasma cortisol level. (J Clin Endocrinol Metab 73: 111-117,1991)
ABSTRACT. Regulatory nechanisms of the hypothalamo-pituitary-adrenal (H-P-A) axis during and after major abdominal surgery were studied in a group of patients who underwent upper abdominal surgery. We first examined the general profile of the changes of the H-P-A axis from the day before surgery to the seventh day after surgery. On the day of surgery, plasma levels of CRH, ACTH, and cortisol were all significantly elevated after skin incision (phase I). During the next 2 days, plasma cortisol levels remained significantly elevated, and the both plasma CRH and ACTH levels were suppressed below the control levels obtained on the day before surgery (phase II). Several additional studies, carried out to analyze the mechanism that maintains the high plasma cortisol levels, revealed the following features of the H-P-A axis during phase II. Plasma free cortisol levels in this phase were
I
the surgical procedure performed (5, 6). Although McIntosh et al. (6) observed a disturbance of the circadian rhythm with prolonged elevation of cortisol levels on the second postoperative day, they did not further study the mechanism responsible for the elevation of plasma cortisol levels. Recently, immunoreactive CRH levels in peripheral plasma were measured under several conditions and were suggested to reflect hypophyseal plasma levels under certain conditions (7-9). It remains controversial, however, whether peripheral plasma CRH levels could become an indicator of hypothalamic function during stressful conditions, including surgery (10-12). To further clarify the mechanism controlling the HP-A axis during and after major surgical stress, we observed the changes in plasma ACTH, cortisol, and CRH levels in a group of patients who underwent upper abdominal surgery over a period of 7 postoperative days and also evaluated the changes in the H-P-A axis by several additional indices of the H-P-A function.
T IS WELL known that major stress, like a surgical procedure, results in a profound activation of the hypothalamo-pituitary-adrenal (H-P-A) axis and induces a marked elevation in both plasma ACTH and cortisol levels. It has, however, not been well elucidated how the H-P-A axis is stimulated by surgical procedures and how long the stimulation persists during the period of recovery. Several investigators have reported that perioperative stress responses of ACTH and corticosteroid are rapid and transient in nature and that the elevated plasma levels of these hormones usually return to normal within 24 h after surgery (1-4). On the other hand, some recent publications have indicated that after major surgery, changes in the H-P-A axis persisted for more than 24 h, of which the profile varies depending on Received October 4,1990. Address all correspondence and requests for reprints to: Dr. Junichi Fukata, Second Division, Department of Internal Medicine, Kyoto University Faculty of Medicine, Sakyo-ku, Kyoto 606, Japan. * This work was supported in part by grants from the Ministry of Health and Welfare and the Ministry of Education, Science, and Culture, the Yanase Memorial Foundation, and the Fujiwara Memorial Foundation. t Present address; Department of Anesthesiology, Jichi Medical School, Omiya Medical Center, Saitama 330, Japan.
Subjects and Methods Patients and experimental design Forty-nine adult patients (aged 21-75 yr) were scheduled to undergo elective upper abdominal surgeries, such as total gasIll
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112
NAITO ET AL.
trectomy, pancreatoduodenectomy, and colectomy. None of the patients had endocrine disorders, liver diseases, or kidney dysfunction, as judged by routine laboratory tests. Anesthesia usually began at 0830 h. To all of the patients premedicated with 0.01 mg/kg BW atropine, im, surgical procedures began at 0930 h and were performed under neuroleptanesthesia (diazepam, 0.2 mg/kg BW; fentanyl, 10 Mg/kg BW; 66% N2O) with or without supplementary administration of 0.5-2.0% enflurane. For the purpose of postoperative pain relief, 15 mg pentazocin and 25 mg hydroxydine were administered im upon the patient's request. During the perioperative period of study, none of the patients experienced surgical complications or received glucocorticoid treatment. The investigation reported below was approved by the ethical committee of our university, and informed consent was obtained from each patient. Patients were randomly assigned to one of the six studies. First, four patients were used to obtain a general view of the perioperative changes in plasma ACTH and cortisol levels. Blood samples (2 L) were drawn at a 1-h interval starting at 0900 h for the 24 h before surgery, the day of surgery, and the first, second, third, fifth, and seventh postoperative days. To analyze the regulatory mechanisms of the H-P-A axis during the early period after surgery, the following studies were performed. In the second study, perioperative changes in plasma CRH levels were studied in 15 patients and compared with changes in plasma ACTH and cortisol levels. For this study, blood samples (10 mL) were collected on the day before surgery, the day of surgery, and the second and seventh postoperative days at 1100 h. Thirdly, in 10 patients, the changes in the biologically active fraction of plasma cortisol, i.e. cortisol-binding globulin (CBG)-unbound or free cortisol, were studied by comparison of the free cortisol index (13) during the period of prolonged elevation of plasma cortisol levels after upper abdominal surgery. For this study, 2 mL blood were obtained at 1000 h on the day before surgery and on the second postoperative day. Fourthly, we compared the kinetics of glucocorticoid exogenously administered to patients before and after surgery. In 5 patients, 25 mg hydrocortisone (Hydrocortone phosphate injection, Banyu Pharmaceutical Co., Ltd., Tokyo, Japan), which was reported to be deesterified to cortisol rapidly and completely after iv administration (14), was given as a bolus iv injection, and changes in plasma cortisol levels were observed for 180 min on the morning of the day before surgery and on the second postoperative day. In the fifth study, we compared the suppressibility of plasma cortisol levels by the administration of dexamethasone phosphate before and after surgery. Plasma cortisol levels were measured in five patients on the morning of the day before surgery and on the second postoperative day over a period of 360 min after the iv administration of 8 mg dexamethasone (Decadron phosphate injection, Banyu Pharmaceutical Co.). To ensure adequate blood levels throughout the experimental period, dexamethasone was administered in a divided dose, i.e. iv administration of dexamethasone (6 mg) was followed by administration of 1 mg every 120 min. A preliminary study (n = 3) revealed that dexamethasone
JCE & M • 1991 Vol 73 • No 1
administered in this manner resulted in plasma concentratrations (73.9 nmol/L) that were considered high enough to suppress cortisol secretion (15) throughout the 360-min sampling period. Finally, we compared responsiveness of the adrenal cortex to exogenously administered ACTH before and after surgery. For this study, 0.25 mg ACTH-(1-24) (Cortrosyn, Daiichi Pharmaceutical Co., Ltd., Tokyo, Japan) was administered iv to another 10 patients on the morning of the day before surgery and of the second postoperative day, after which plasma samples were obtained over 120 min to measure cortisol levels. Blood sample preparation and hormone assay Blood samples were withdrawn through an indwelling catheter inserted into a forearm vein in all studies, except in the second and third studies, in which venopuncture was used. Blood samples were collected in prechilled tubes containing EDTA and centrifuged at 4 C. Separated plasma samples were stored at -20 C until assay. CRH-like immunoreactivity (LI) was extracted from 4 mL plasma with a Baker 10 SPE WP 1 butyl (C4) column (J. T. Baker Chemical Co., Philipsbury, NJ) and eluted with acetonitrile-0.9% saline (1:1). The extracts were lyophilized, reconstituted in assay buffer, and subjected to CRH RIA (16). The mean (±SD) recovery rate of synthetic human/rat CRH (h/ rCRH) added to the plasma was 81.2 ± 9.5% (n = 24). The minimal detectable quantity of this RIA system was 0.8 pmol/ L, and intra- and interassay coefficients of variation were both less than 10%. CRH-LI extracted from plasma was characterized as follows. CRH-LI extracted from 350 mL pooled plasma obtained from the 70 patients who underwent upper abdominal surgery (sampled on the day of surgery at 1000 h) was chromatographed on a 0.7 x 50-cm Sephadex G-50 (fine) column equilibrated and eluted with 0.1 N HC1 containing 0.1% BSA, 0.02% NaN3, and 2 M urea. CRH-LI in each eluted fraction was extracted as described for plasma samples and assayed by RIA. The column was calibrated with synthetic h/rCRH. The plasma cortisol concentration was determined with a solid phase RIA kit (Daiichi Radioisotope Laboratories, Ltd., Tokyo, Japan), as previously described (17). The minimal detectable limit of this assay was 30 nmol/L, and intra- and interassay coefficients of variation were both less than 10%. Plasma free cortisol levels were assessed by the free cortisol index, which was calculated from the total plasma cortisol, and percent free steroid was measured by the charcoal adsorption technique, using [l,2-3H]hydrocortisone (New England Nuclear Corp., Boston, MA) (13). The plasma ACTH concentration was measured by RIA without extraction, using an anti-ACTH antiserum, IgGACTH-1 (IgG Corp., Nashville, TN), as previously described (17). The minimal detectable limit of this assay was 1 pmol/L, and intra- and interassay coefficients of variation were both less than 10%. Statistical analysis Statistical analysis was performed with analysis of variance or repeat measurements analysis of variance and subsequently
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113
GLUCOCORTICOID REGULATORY MECHANISMS AFTER SURGERY with the Bonferroni method (18), and P < 0.05 was considered significant.
Results A profile of perioperative hormone levels Figure 1 shows the typical patterns of the perioperative changes in plasma ACTH and cortisol levels observed in two patients. In all four patients who participated in the
first study, normal patterns of plasma ACTH and cortisol levels were observed on the day before surgery. During the course of surgery, a prompt and marked elevation of plasma ACTH levels, followed by a steep elevation of plasma cortisol levels, was observed in all patients. After the surgery, plasma ACTH levels decreased gradually and became almost undetectable (
Vol. 73, No. 1 Printed in U.S.A.
Biphasic Changes in Hypothalamo-Pituitary-Adrenal Function during the Early Recovery Period after Major Abdominal Surgery* YOSHIYUKI NAITO, JUNICHI FUKATA, SUNAO TAMAI, NORIMASA SEOf, YOSHIKATSU NAKAI, KENJIRO MORI, AND HIROO IMURA Department of Anesthesia (Y.Nai., S.T., N.S., KM.), Second Division, Department of Internal Medicine (J.F., Y.Nak, H.I.), Kyoto University School of Medicine, Kyoto 606, Japan
higher than those during the preoperative period. The exogenously administered hydrocortisone clearance rate in phase II did not differ from that observed on the day before surgery. Dexamethasone administration resulted in a decrease in plasma cortisol levels similar to that observed preoperatively. Conversely, the ACTH-stimulated cortisol increase was significantly greater in phase II than that observed preoperatively. These results suggest that during and after major surgical stress, the H-P-A axis undergoes a biphasic change in the pattern of the stress response and during the second phase, not the continuous hypothalamo-pituitary drive but the increased adrenal responsiveness to ACTH is responsible at least in part for maintaining the elevated plasma cortisol level. (J Clin Endocrinol Metab 73: 111-117,1991)
ABSTRACT. Regulatory nechanisms of the hypothalamo-pituitary-adrenal (H-P-A) axis during and after major abdominal surgery were studied in a group of patients who underwent upper abdominal surgery. We first examined the general profile of the changes of the H-P-A axis from the day before surgery to the seventh day after surgery. On the day of surgery, plasma levels of CRH, ACTH, and cortisol were all significantly elevated after skin incision (phase I). During the next 2 days, plasma cortisol levels remained significantly elevated, and the both plasma CRH and ACTH levels were suppressed below the control levels obtained on the day before surgery (phase II). Several additional studies, carried out to analyze the mechanism that maintains the high plasma cortisol levels, revealed the following features of the H-P-A axis during phase II. Plasma free cortisol levels in this phase were
I
the surgical procedure performed (5, 6). Although McIntosh et al. (6) observed a disturbance of the circadian rhythm with prolonged elevation of cortisol levels on the second postoperative day, they did not further study the mechanism responsible for the elevation of plasma cortisol levels. Recently, immunoreactive CRH levels in peripheral plasma were measured under several conditions and were suggested to reflect hypophyseal plasma levels under certain conditions (7-9). It remains controversial, however, whether peripheral plasma CRH levels could become an indicator of hypothalamic function during stressful conditions, including surgery (10-12). To further clarify the mechanism controlling the HP-A axis during and after major surgical stress, we observed the changes in plasma ACTH, cortisol, and CRH levels in a group of patients who underwent upper abdominal surgery over a period of 7 postoperative days and also evaluated the changes in the H-P-A axis by several additional indices of the H-P-A function.
T IS WELL known that major stress, like a surgical procedure, results in a profound activation of the hypothalamo-pituitary-adrenal (H-P-A) axis and induces a marked elevation in both plasma ACTH and cortisol levels. It has, however, not been well elucidated how the H-P-A axis is stimulated by surgical procedures and how long the stimulation persists during the period of recovery. Several investigators have reported that perioperative stress responses of ACTH and corticosteroid are rapid and transient in nature and that the elevated plasma levels of these hormones usually return to normal within 24 h after surgery (1-4). On the other hand, some recent publications have indicated that after major surgery, changes in the H-P-A axis persisted for more than 24 h, of which the profile varies depending on Received October 4,1990. Address all correspondence and requests for reprints to: Dr. Junichi Fukata, Second Division, Department of Internal Medicine, Kyoto University Faculty of Medicine, Sakyo-ku, Kyoto 606, Japan. * This work was supported in part by grants from the Ministry of Health and Welfare and the Ministry of Education, Science, and Culture, the Yanase Memorial Foundation, and the Fujiwara Memorial Foundation. t Present address; Department of Anesthesiology, Jichi Medical School, Omiya Medical Center, Saitama 330, Japan.
Subjects and Methods Patients and experimental design Forty-nine adult patients (aged 21-75 yr) were scheduled to undergo elective upper abdominal surgeries, such as total gasIll
The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 14 November 2015. at 09:32 For personal use only. No other uses without permission. . All rights reserved.
112
NAITO ET AL.
trectomy, pancreatoduodenectomy, and colectomy. None of the patients had endocrine disorders, liver diseases, or kidney dysfunction, as judged by routine laboratory tests. Anesthesia usually began at 0830 h. To all of the patients premedicated with 0.01 mg/kg BW atropine, im, surgical procedures began at 0930 h and were performed under neuroleptanesthesia (diazepam, 0.2 mg/kg BW; fentanyl, 10 Mg/kg BW; 66% N2O) with or without supplementary administration of 0.5-2.0% enflurane. For the purpose of postoperative pain relief, 15 mg pentazocin and 25 mg hydroxydine were administered im upon the patient's request. During the perioperative period of study, none of the patients experienced surgical complications or received glucocorticoid treatment. The investigation reported below was approved by the ethical committee of our university, and informed consent was obtained from each patient. Patients were randomly assigned to one of the six studies. First, four patients were used to obtain a general view of the perioperative changes in plasma ACTH and cortisol levels. Blood samples (2 L) were drawn at a 1-h interval starting at 0900 h for the 24 h before surgery, the day of surgery, and the first, second, third, fifth, and seventh postoperative days. To analyze the regulatory mechanisms of the H-P-A axis during the early period after surgery, the following studies were performed. In the second study, perioperative changes in plasma CRH levels were studied in 15 patients and compared with changes in plasma ACTH and cortisol levels. For this study, blood samples (10 mL) were collected on the day before surgery, the day of surgery, and the second and seventh postoperative days at 1100 h. Thirdly, in 10 patients, the changes in the biologically active fraction of plasma cortisol, i.e. cortisol-binding globulin (CBG)-unbound or free cortisol, were studied by comparison of the free cortisol index (13) during the period of prolonged elevation of plasma cortisol levels after upper abdominal surgery. For this study, 2 mL blood were obtained at 1000 h on the day before surgery and on the second postoperative day. Fourthly, we compared the kinetics of glucocorticoid exogenously administered to patients before and after surgery. In 5 patients, 25 mg hydrocortisone (Hydrocortone phosphate injection, Banyu Pharmaceutical Co., Ltd., Tokyo, Japan), which was reported to be deesterified to cortisol rapidly and completely after iv administration (14), was given as a bolus iv injection, and changes in plasma cortisol levels were observed for 180 min on the morning of the day before surgery and on the second postoperative day. In the fifth study, we compared the suppressibility of plasma cortisol levels by the administration of dexamethasone phosphate before and after surgery. Plasma cortisol levels were measured in five patients on the morning of the day before surgery and on the second postoperative day over a period of 360 min after the iv administration of 8 mg dexamethasone (Decadron phosphate injection, Banyu Pharmaceutical Co.). To ensure adequate blood levels throughout the experimental period, dexamethasone was administered in a divided dose, i.e. iv administration of dexamethasone (6 mg) was followed by administration of 1 mg every 120 min. A preliminary study (n = 3) revealed that dexamethasone
JCE & M • 1991 Vol 73 • No 1
administered in this manner resulted in plasma concentratrations (73.9 nmol/L) that were considered high enough to suppress cortisol secretion (15) throughout the 360-min sampling period. Finally, we compared responsiveness of the adrenal cortex to exogenously administered ACTH before and after surgery. For this study, 0.25 mg ACTH-(1-24) (Cortrosyn, Daiichi Pharmaceutical Co., Ltd., Tokyo, Japan) was administered iv to another 10 patients on the morning of the day before surgery and of the second postoperative day, after which plasma samples were obtained over 120 min to measure cortisol levels. Blood sample preparation and hormone assay Blood samples were withdrawn through an indwelling catheter inserted into a forearm vein in all studies, except in the second and third studies, in which venopuncture was used. Blood samples were collected in prechilled tubes containing EDTA and centrifuged at 4 C. Separated plasma samples were stored at -20 C until assay. CRH-like immunoreactivity (LI) was extracted from 4 mL plasma with a Baker 10 SPE WP 1 butyl (C4) column (J. T. Baker Chemical Co., Philipsbury, NJ) and eluted with acetonitrile-0.9% saline (1:1). The extracts were lyophilized, reconstituted in assay buffer, and subjected to CRH RIA (16). The mean (±SD) recovery rate of synthetic human/rat CRH (h/ rCRH) added to the plasma was 81.2 ± 9.5% (n = 24). The minimal detectable quantity of this RIA system was 0.8 pmol/ L, and intra- and interassay coefficients of variation were both less than 10%. CRH-LI extracted from plasma was characterized as follows. CRH-LI extracted from 350 mL pooled plasma obtained from the 70 patients who underwent upper abdominal surgery (sampled on the day of surgery at 1000 h) was chromatographed on a 0.7 x 50-cm Sephadex G-50 (fine) column equilibrated and eluted with 0.1 N HC1 containing 0.1% BSA, 0.02% NaN3, and 2 M urea. CRH-LI in each eluted fraction was extracted as described for plasma samples and assayed by RIA. The column was calibrated with synthetic h/rCRH. The plasma cortisol concentration was determined with a solid phase RIA kit (Daiichi Radioisotope Laboratories, Ltd., Tokyo, Japan), as previously described (17). The minimal detectable limit of this assay was 30 nmol/L, and intra- and interassay coefficients of variation were both less than 10%. Plasma free cortisol levels were assessed by the free cortisol index, which was calculated from the total plasma cortisol, and percent free steroid was measured by the charcoal adsorption technique, using [l,2-3H]hydrocortisone (New England Nuclear Corp., Boston, MA) (13). The plasma ACTH concentration was measured by RIA without extraction, using an anti-ACTH antiserum, IgGACTH-1 (IgG Corp., Nashville, TN), as previously described (17). The minimal detectable limit of this assay was 1 pmol/L, and intra- and interassay coefficients of variation were both less than 10%. Statistical analysis Statistical analysis was performed with analysis of variance or repeat measurements analysis of variance and subsequently
The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 14 November 2015. at 09:32 For personal use only. No other uses without permission. . All rights reserved.
113
GLUCOCORTICOID REGULATORY MECHANISMS AFTER SURGERY with the Bonferroni method (18), and P < 0.05 was considered significant.
Results A profile of perioperative hormone levels Figure 1 shows the typical patterns of the perioperative changes in plasma ACTH and cortisol levels observed in two patients. In all four patients who participated in the
first study, normal patterns of plasma ACTH and cortisol levels were observed on the day before surgery. During the course of surgery, a prompt and marked elevation of plasma ACTH levels, followed by a steep elevation of plasma cortisol levels, was observed in all patients. After the surgery, plasma ACTH levels decreased gradually and became almost undetectable (
