Variations in Adrenocortical Responsiveness During Severe Bacterial Infections Unrecognized Adrenocortical Insufficiency in Severe Bacterial Infections WILLIAM J. SIBBALD, M.D., F.R.C.P. (C),* ALLISTIR SHORT, M.B., Ch.B. (Edin.), MARGO P. COHEN, M.D., ROBERT F. WILSON, M.D.
From the Robert S. Marx Surgical Laboratories, Department of Surgery, Wayne State University School of Medicine; and the Detroit General Hospital, Detroit
Plasma cortisol levels and their response to .25 mg synthetic A.C.T.H. (CortrosynR) were studied in 26 septic patients. Four (15.4%) of these patients appeared to have greatly increased adrenocortical activity with plasma cortisol levels averaging 65.4 + 14.8 ,ug/dl (normal = 8-18 ,ug/dl. All four of these patients were agonal and died within five days. Seventeen (65.4%) of these 26 patients appeared to have an appropriate adrenocortical response to severe infection in that their plasma cortisol levels increased (averaging 19.2 ± 6.0 Ag/dl) following synthetic A.C.T.H. The remaining five patients, who constituted 19.2%o of the 26 patients studied, appeared to have some impairment of adrenocortical function. In spite of severe bacterial infections and no history to support Addison's disease, their plasma cortisol levels (averaging 13.8 ± 3.3 ,ug/dl) were not increased above normal and their response to CortrosynR was much less than would be expected; the increase in plasma cortisol levels in these patients following the synthetic A.C.T.H. averaged 1.1 ± 3.6 jig/dl. It is reemphasized that patients with severe sepsis who are not responding adequately to standard therapy should be suspected of having adrenocortical insufficiency and treated accordingly.
intravenous corticotropin in 6 patients with bacteremic shock.13 Therefore in most instances of severe infection, adrenal reserve appears sufficient to further augment secretion in response to A.C.T.H. However, adrenocortical insufficiency has been documented during severe infections, most notably with disseminated meningococcemia. 14 Similarly, Jacobs and Nabarro described one patient with acute severe infection, who had unexpectedly low plasma cortisol levels.9 Our experience in managing critically ill septic patients has suggested the presence of a small group of patients, not suspected of having Addison's disease, who responded with rapid clinical improvement to intravenous glucocorticoid preparations. This observation has led us to wonder if adrenocortical insufficiency may occasionally exist in severe bacterial infections, in individuals not previously demonstrating any evidence of Addison's disease. Consequently, a prospective study was carried out to examine the function of the adrenal cortex in critically ill patients with sepsis. This was done by measuring basal plasma cortisol levels and examining their response to the administration of synthetic adrenocorticotrophic hormone (ACTH) [a 1-24 corticotropin; CortrosynR].
I T IS WELL RECOGNIZED that the presence of enhanced adrenal cortical secretion is a concomitant of severe bacterial infections. The response of the adrenal cortex to the stress of severe infection includes an increased secretion of all major corticosteroid
hormones, 14 manifested by elevated plasma cortisol levels, elevated urinary 17-hydroxysteroid levels and elevated cortisol secretory rates.4 The exact mechanism whereby severe infections cause an augmented cortisol secretory rate is not clear at present.2 Further, Melby and Spink demonstrated an enhanced secretion of adrenocortical hormones in response to Submitted for publication: July 20, 1976. *Current address and Reprint Requests: Department of Medicine, Victoria Hospital and the University of Western Ontario, London, Ontario, Canada. Supported by Detroit General Hospital Research Corporation and Michigan Association for Regional Medical Programs.
Patients and Methods Twenty-six patients critically ill with severe infections admitted to the Intensive Care Unit of Detroit General Hospital from September 1, 1974 to August 30,
29
30
SIBBALD AND OTHERS TABLE 1. Plasma Cortisol Response after Administration of CortrosynR to Normal and Septic Patients
Subjects Normal: Sepsis: Group I Group II Group III
9
5 17 4
Base Line (ug/dl) 9.97 ± 5
Maximum within 1 hour (ug/dl) 25.4 ± 6.3
13.8 3.3* 14.9 ± 2.2t 19.2 ± 5.1t 32.4 ± 9.3* 65.4 ± 14.8t 88.25 ± 30.3
Increment (ug/dl)
with the Technicon Auto-Analizer SMA-12/60. Results are expressed as the mean + the standard deviation (S.D.). Statistical analysis was done by the students-t test for independent variables. Results
15.4 ± 4
1.1 ± 3.6t 13.2 ± 5.95t 22.9 ± 34
Mean values + standard deviation. Significance (compared to normal), * P < .005; t P < .0005; NS.
1975 were studied as closely as possible to the time of initial diagnosis. The diagnosis of severe infection was established by clinical findings, including the identification of a major focus of infection, usually pneumonia or peritonitis, and/or positive blood cultures. Of the 26 patients studied, the primary site of infection included pneumonia (9), peritonitis (10), pneumonia complicating burns (4) and mediastinitis (3). Eighteen of the 26 patients had a positive blood culture at time of study and in none was N. meningitis isolated. Patients with a previous history of exogenous steroid therapy, or known malignancies or tuberculosis which might have involved the adrenal gland, were excluded from the study. All studies were done in the morning. Blood samples were drawn from a central venous catheter, with a basal sample for plasma cortisol determination being drawn and then followed by .25 mg of CortrosynR injected intravenously. Blood was then drawn at 5, 10, 15, 30, 45, and 60 minutes for determination of plasma cortisol. The highest value measured during the one hour following injection of CortrosynR was utilized as being indicative of the maximal response of the adrenal gland. In addition, human growth hormone (HGH) was assayed in the control samples and at 15, 30 and 60 minutes after CortrosynR. Blood glucose, electrolytes, and creatinine were measured initially and 60 minutes following CortrosynR. Normals for comparison consisted of nine patients on the general medicine service, without any clinical or laboratory evidence of an endocrine disorder, in whom CortrosynR was administered intramuscularly. Plasma cortisol was measured by the Schwartz/Mann radioimmunoassay kit utilizing the methods of Murphy15 and Nugent and Mayes.Y Growth hormone (HGH) was measured by the method of Pennisi18 also utilizing a Schwartz/Mann radioimmunoassay kit. Normal H.G.H. levels in our laboratory are 1-5 ng/ml. Serum electrolytes were measured by the Technicon Auto-Analizer SMA-12/60. Creatinine was measured by the creatinine reduction method in conjunction
Ann. Surg. * July 1977
Normals The mean baseline morning plasma cortisol was 9.97 + 5 ug/dl with a maximal rise to 25.4 + 6.3 ,ig/dl following intramuscular CortrosynR within one hour, representing a mean increment of 15.4 + 4.0 ,ug/dl (Table 1). Sepsis
Of the 26 patients studied, four were identified (Group III) on retrospective review of clinical data and the time to death, as being in the agonal state (Table 1). Three of the four were hypotensive at time of study (defined as: systolic BP < 90 mm Hg or a fall of 30 mm Hg from previously recorded levels; urine output < 20 cc/hr and/or requirement of vasopressors to maintain blood pressure) and only one survived greater than one day following study. The mean baseline cortisol in this group was 65.4 + 14.8 ,ug/dl (range 55 to 86.4 ug/dl) and the patients showed a variable response to intravenous CortrosynR. Two of the four did not elevate plasma cortisol greater than 7 ug/dl following CortrosynR. The remaining 22 patients exhibited baseline plasma cortisols of 18.0 + 3.4 ,ug/dl), a significant elevation above normal (P
From the Robert S. Marx Surgical Laboratories, Department of Surgery, Wayne State University School of Medicine; and the Detroit General Hospital, Detroit
Plasma cortisol levels and their response to .25 mg synthetic A.C.T.H. (CortrosynR) were studied in 26 septic patients. Four (15.4%) of these patients appeared to have greatly increased adrenocortical activity with plasma cortisol levels averaging 65.4 + 14.8 ,ug/dl (normal = 8-18 ,ug/dl. All four of these patients were agonal and died within five days. Seventeen (65.4%) of these 26 patients appeared to have an appropriate adrenocortical response to severe infection in that their plasma cortisol levels increased (averaging 19.2 ± 6.0 Ag/dl) following synthetic A.C.T.H. The remaining five patients, who constituted 19.2%o of the 26 patients studied, appeared to have some impairment of adrenocortical function. In spite of severe bacterial infections and no history to support Addison's disease, their plasma cortisol levels (averaging 13.8 ± 3.3 ,ug/dl) were not increased above normal and their response to CortrosynR was much less than would be expected; the increase in plasma cortisol levels in these patients following the synthetic A.C.T.H. averaged 1.1 ± 3.6 jig/dl. It is reemphasized that patients with severe sepsis who are not responding adequately to standard therapy should be suspected of having adrenocortical insufficiency and treated accordingly.
intravenous corticotropin in 6 patients with bacteremic shock.13 Therefore in most instances of severe infection, adrenal reserve appears sufficient to further augment secretion in response to A.C.T.H. However, adrenocortical insufficiency has been documented during severe infections, most notably with disseminated meningococcemia. 14 Similarly, Jacobs and Nabarro described one patient with acute severe infection, who had unexpectedly low plasma cortisol levels.9 Our experience in managing critically ill septic patients has suggested the presence of a small group of patients, not suspected of having Addison's disease, who responded with rapid clinical improvement to intravenous glucocorticoid preparations. This observation has led us to wonder if adrenocortical insufficiency may occasionally exist in severe bacterial infections, in individuals not previously demonstrating any evidence of Addison's disease. Consequently, a prospective study was carried out to examine the function of the adrenal cortex in critically ill patients with sepsis. This was done by measuring basal plasma cortisol levels and examining their response to the administration of synthetic adrenocorticotrophic hormone (ACTH) [a 1-24 corticotropin; CortrosynR].
I T IS WELL RECOGNIZED that the presence of enhanced adrenal cortical secretion is a concomitant of severe bacterial infections. The response of the adrenal cortex to the stress of severe infection includes an increased secretion of all major corticosteroid
hormones, 14 manifested by elevated plasma cortisol levels, elevated urinary 17-hydroxysteroid levels and elevated cortisol secretory rates.4 The exact mechanism whereby severe infections cause an augmented cortisol secretory rate is not clear at present.2 Further, Melby and Spink demonstrated an enhanced secretion of adrenocortical hormones in response to Submitted for publication: July 20, 1976. *Current address and Reprint Requests: Department of Medicine, Victoria Hospital and the University of Western Ontario, London, Ontario, Canada. Supported by Detroit General Hospital Research Corporation and Michigan Association for Regional Medical Programs.
Patients and Methods Twenty-six patients critically ill with severe infections admitted to the Intensive Care Unit of Detroit General Hospital from September 1, 1974 to August 30,
29
30
SIBBALD AND OTHERS TABLE 1. Plasma Cortisol Response after Administration of CortrosynR to Normal and Septic Patients
Subjects Normal: Sepsis: Group I Group II Group III
9
5 17 4
Base Line (ug/dl) 9.97 ± 5
Maximum within 1 hour (ug/dl) 25.4 ± 6.3
13.8 3.3* 14.9 ± 2.2t 19.2 ± 5.1t 32.4 ± 9.3* 65.4 ± 14.8t 88.25 ± 30.3
Increment (ug/dl)
with the Technicon Auto-Analizer SMA-12/60. Results are expressed as the mean + the standard deviation (S.D.). Statistical analysis was done by the students-t test for independent variables. Results
15.4 ± 4
1.1 ± 3.6t 13.2 ± 5.95t 22.9 ± 34
Mean values + standard deviation. Significance (compared to normal), * P < .005; t P < .0005; NS.
1975 were studied as closely as possible to the time of initial diagnosis. The diagnosis of severe infection was established by clinical findings, including the identification of a major focus of infection, usually pneumonia or peritonitis, and/or positive blood cultures. Of the 26 patients studied, the primary site of infection included pneumonia (9), peritonitis (10), pneumonia complicating burns (4) and mediastinitis (3). Eighteen of the 26 patients had a positive blood culture at time of study and in none was N. meningitis isolated. Patients with a previous history of exogenous steroid therapy, or known malignancies or tuberculosis which might have involved the adrenal gland, were excluded from the study. All studies were done in the morning. Blood samples were drawn from a central venous catheter, with a basal sample for plasma cortisol determination being drawn and then followed by .25 mg of CortrosynR injected intravenously. Blood was then drawn at 5, 10, 15, 30, 45, and 60 minutes for determination of plasma cortisol. The highest value measured during the one hour following injection of CortrosynR was utilized as being indicative of the maximal response of the adrenal gland. In addition, human growth hormone (HGH) was assayed in the control samples and at 15, 30 and 60 minutes after CortrosynR. Blood glucose, electrolytes, and creatinine were measured initially and 60 minutes following CortrosynR. Normals for comparison consisted of nine patients on the general medicine service, without any clinical or laboratory evidence of an endocrine disorder, in whom CortrosynR was administered intramuscularly. Plasma cortisol was measured by the Schwartz/Mann radioimmunoassay kit utilizing the methods of Murphy15 and Nugent and Mayes.Y Growth hormone (HGH) was measured by the method of Pennisi18 also utilizing a Schwartz/Mann radioimmunoassay kit. Normal H.G.H. levels in our laboratory are 1-5 ng/ml. Serum electrolytes were measured by the Technicon Auto-Analizer SMA-12/60. Creatinine was measured by the creatinine reduction method in conjunction
Ann. Surg. * July 1977
Normals The mean baseline morning plasma cortisol was 9.97 + 5 ug/dl with a maximal rise to 25.4 + 6.3 ,ig/dl following intramuscular CortrosynR within one hour, representing a mean increment of 15.4 + 4.0 ,ug/dl (Table 1). Sepsis
Of the 26 patients studied, four were identified (Group III) on retrospective review of clinical data and the time to death, as being in the agonal state (Table 1). Three of the four were hypotensive at time of study (defined as: systolic BP < 90 mm Hg or a fall of 30 mm Hg from previously recorded levels; urine output < 20 cc/hr and/or requirement of vasopressors to maintain blood pressure) and only one survived greater than one day following study. The mean baseline cortisol in this group was 65.4 + 14.8 ,ug/dl (range 55 to 86.4 ug/dl) and the patients showed a variable response to intravenous CortrosynR. Two of the four did not elevate plasma cortisol greater than 7 ug/dl following CortrosynR. The remaining 22 patients exhibited baseline plasma cortisols of 18.0 + 3.4 ,ug/dl), a significant elevation above normal (P
