0.3493/90/1803-025902.00/0, CCrmeat Cate Meoiene {Copy © 1990 y The Witians & Wakins Co, Vol 18,No.3 Panicdin USA Plasma cortisol levels in patients with septic shock ROLAND M. H. SCHEIN, MD; CHARLES L. SPRUNG, MD, JD; EILEEN MARCIAL, RRT: LENA NAPOLITANO, MD: BART CHERNOW, MD To investigate the endogenous adrenocortical re- sponse to sepsis, plasma cortisol concentrations were measured in 37 patients (53 * 3 yr of age) with septic shock. Patients were studied 11 + 2 h after shock commenced. Vasopressor therapy was required in 35 of 37 patients (median dopamine infusion rate of 11 ug/ ikg-min, range 3 to 74). ‘Plasma cortisol concentrations were increased mark- edly (median 50.7 upidl, range 15.6 to 400) above ‘normal values (10 to 20 g/dl) in patients with septic shock. Neither patients who reversed their shock nor those who survived to hospital discharge had signifi- cantly different plasma cortisol concentrations from those who did not. Patients with Gram-positive infec- tions had increased cortisol levels compared with those ‘who had Gram-negative infections (median 83 st/dl, range 32 to 400 vs. median 44 g/dl, range 16 to 81, respectively; p < .05). The source of infection, amount ‘of vasopressors infused, and severity of shock were not associated with differences in cortisol concentrations. ‘The length of time in shock before collection of the blood sample for measurements of cortisol and mean arterial pressure at the time of blood collection had significant but weak negative correlations with corti concentrations (p < .05, r, = —.37 and p < 05, r, = 40, respectively) ‘We conclude that plasma cortisol concentrations are increased in patients with sept degree of increase is variable. This variability may, in part, be related to type of infection, length of time in shock, and BP at the time of blood sampling, There is 10 indication that plasma cortisol concentrations may be used in the prediction of patient outcome. Based on this study, adrenal insufficiency as judged by absolute cortisol concentrations is probably rare in septic shock. (Crit Care Med 1990; 18:259) Plasma cortisol concentrations increase with the de- velopment of the sepsis syndrome in adults (1-5), chil dren (6), and neonates (7). Sepsis-induced hypercort- From the Seton of Critical Care Medicine, Department of Med: icine, Veterans Administration Medical Center, Unversity of Miami School of Medicine Miami, FL (Drs. Schein and Sprung, and Ms Marca) and the Department of Anesthesia, Masschusets Genera Hoop, Harvard Medial School, Boston, MA (Drs. Napolitano and Chemo). ‘This study was supported in part, by funds fom Henry K. Beecher ‘Avestesa Research Laboratories a the Masschusets General Hos Dita and the Veterans Administration ‘Adéres eauess for reprints to: Roland MH, Schein, MD, Sec tion of Creal Care Medicine, Veterans Adminisration Medical (Center (11), 1201 NW. th Siret, Miami, FL 33125. solism is pantally due to decreased rate of cortisol extraction from the blood (1, 2, 4) and decreased bind- ing of cortisol to transcortin, resulting in an increase in the circulating free cortisol concentration (8, 9). Septic shock is also associated with an increase in the half-life of cortisol (1, 2) ‘Adrenalectomy reduces the tolerance of animals to ‘experimentally induced septic shock. Administered doses of endotoxin or live Escherichia coli which are sublethal in normal animals produce mortality when administered to adrenalectomized animals (10-14), ‘These studies suggest that normal adrenal gland func- tion is vital to survival from septic insults, and that pplasma cortisol increases in septic shock may be a protective homeostatic response. The objectives of this study were: a) to measure plasma cortisol concentrations in patients with septic shock, b) to determine whether either an absolute or relative adrenal insufficiency might account for differ- ‘ences in shock reversal or survival, and c) to identify any clinical features of patients in septic shock that ‘might be associated with gradations in plasma cortisol levels PATIENTS AND METHODS ‘Study Design ‘The clinical characteristics of the patients described in this report have been reported previously (15). Patients with a clinical diagnosis of septic shock who fulfilled the following four criteria were considered eligible for inclusion in the study: a) systolic BP <90 mm Hg, b) signs of decreased organ perfusion as evi- denced by altered mental status and/or oliguria (urine ‘output <20 mi/h), c) continued hypotension despite 2500 mi 0.9% NaCl administered iv, and d) bacteremia or an identified source of infection. Severity of shock ‘was defined as mild, moderate, or severe. Patients with mild shock either required <5 g/kg-min of dopamine to maintain adequate perfusion or had <5 mmol/L of lactate, or both. Patients with moderate shock required 5 10 19.9 ug/kg-min of dopamine or had lactate levels, between 5 and 10 mmol/L, or both, Patients were ‘considered to be in severe shock when they required >20 ug/kg-min of dopamine, had lactate levels >10 ‘mmol/L, or both. Shock state reversal was defined as a sustained systolic BP >90 mm Hg without vasopressor therapy and reversal of the oliguric state. Survival was defined as survival to hospital discharge.260 CRITICAL CARE MEDICINE Patients were categorized by severity of underlying disease and by the presence of hepatic or renal disease Patients with rapidly fatal underiying diseases were predicted to have a >50% likelihood of dying from their underlying disease during hospitalization, Patients with ultimately fatal disorders had a >50% chance of dying within 5 yr. Those with nonfatal disease either had 2 <50% chance of dying from their underlying disease or had no known disorder. A clinical diagnosis of acute or chronic hepatic or renal disease was also used to categorize patients. Infections were characterized as Gram-positive (ex- clusively Gram-positive organisms} cultured from the suspected site of infection), Gram-negative (exclusively Gram-negative organisms] cultured from the suspected site of infection), other (cultures positive for either ced Gram-positive and Gram-negative organisms or ‘nonbacterial organisms), or no growth (culture of sus- pected site negative). ‘Immediately after patient enrollment in the study, a blood specimen was obtained for determination of plasma cortisol concentration. Plasma cortisol concen- trations were determined by a sensitive and specific radioimmunoassay. The coefficient of variation within assay was 4% and the coefficient of variation between assays was 5% in our laboratory. Because the assay accuracy declines significantly after eight serial dilu- tions (required for concentrations =400 g/dl), cortisol concentrations 2400 g/dl are reported as values of 400 e/a Statistics Descriptive statistics are reported as mean + sem for normally distributed variables, and as a median and range for nonparametric data. Comparisons of categor- ical data were made using the chi-square test and Fisher's exact test. Nonparametric data for multiple groups were compared by computing the Kruskal- Wallis statistic; pairwise comparisons were made by using the Mann-Whitney rank-sum test with levels of significance adjusted to control for multiplicity (Bon- ferroni). Correlation between variables was assessed by the Spearman rank correlation coefficient. For all comparisons and correlations, differences ‘were considered significant when p <.05. RESULTS ‘Thirty-seven patients were studied (mean age 55 + 3 yr). Shock was characterized as severe in 13 (35%) Patients, moderate in 21 (57%), and mild in 3 (8%). Thirty-five (95%) patients were receiving dopamine at the time of plasma cortisol sampling, with a median dopamine infusion rate of 11 ug/kg-min (range 3 to 74). Shock reversal occurred in 20 (54%) patients. Underlying disease was classified as rapidly fatal in four MaxcH, 1990 (11%) patients, ultimately fatal in 16 (43%) patients, and nonfatal in 17 (46%) patients. Ten (27%) patients survived until hospital discharge. Relevant clinical data are shown in Table 1. Plasma cortisol levels were increased markedly above normal values in patients with septic shock, with a median value of 50.7 ug/dl (range 15.6 to 400). The extent of this sepsis-associated increase in plasma cor- tisol concentration was, however, variable (Fig. 1). ‘There were no statistically significant differences in cortisol concentrations when severity of shock at the time of cortisol measurement, severity of underlying disease, reversal of shock, survival, the presence of hepatic disease, or the presence of renal disease were considered (p <.05 for all comparisons). Statistical significance was achieved when plasma cortisol concentrations were analyzed with respect to type of infection (p <.05). This difference (p <.05 with Bonferroni adjustment) could be attributed to the dif- ferences between patients with Gram-positive and Gram-negative infections. The median plasma cortisol for patients with Gram-positive infections was 83 g/ dl (n = 9, range 32.3 0 400) and 43.7 g/dl for patients with Gram-negative infections (n = 13, range 15.6 to 80.9). Patients with Gram-positive-related septic shock were also less likely to reverse their shock (0/9 Gram- positive and 9/13 Gram-negative, p <_.005) or survive (0/9 Gram-positive and 7/13 Gram-negative, p <_.05) than patients with other etiologies for their shock de- spite similar distributions of underlying disease and severity of shock, ‘The correlations between plasma cortisol concentra- tion and factors such as patient age, length of time in shock, BP, amount of dopamine being infused, and total protein in patient's serum are shown in Table 2 ‘The length of time in shock and mean arterial pressure (MAP) were significantly (although weakly) negatively correlated with plasma cortisol concentrations (p <.0S; +, values ~.37 and ~.40, respectively). DISCUSSION We determined plasma cortisol concentrations in a group of patients with rigorously defined septic shock. ‘We found cortisol concentrations to be increased in the ‘majority of such patients, but the degree of this increase varies considerably with values ranging from “high normal” to 20 times a high normal value. As far as we are aware, these high values exceed previously reported plasma cortisol values associated with infection, This finding may be a reflection of the severity of illness and relative uniformity of the patients we selected for study, although we did not collect data on other groups of septic patients for comparison. Earlier studies of in- fected patients had generally found some degree of increase, but this finding was not consistent for allVol. 18, No. 3 ‘Tame 1. Clinical data for 37 patients pase AE Hout sos of Shack Soure ENS ‘Schein et al—coRTISOL LEVELS IN SHOCK. 261 eral MAP Dopamine Cadac nes COM yy oo _ "Sheek Diane _Daewe img) angi) (L/min) ald T aes ‘a a ° 27 593968 2 a os Modente Ling Jes Jes 00 ‘ 2 a) fe 3 se Ser Bos te See » fy sje a ea Modene Lung jes te 8 3 Mate 5 38S Moseme Unmet oD 5 a ss ‘ so wi rm 8 8 % é 7 he : ne! Nils Se 5 Hae ‘ Bod Moteme mom Re 2 32 5 a 8 Moderate = m8 a Me oe 6 BO Ser sm 8 Fr ee ti 5 OF See moo A a rye a moo Shee ee at a 00 ye 5 SF Shee 3 © i = Eran’ a a Shee es % 32 000 es is mo Moderate Soo i a 338 je ‘6 so Moderate moms a 20 Ys ° eG Moser rn) A se Ble i xf Moderate js om 5 = moe 8 & ow Moser = oS of o a ‘39 ye FA = Mover re) i 3 tas 0 2 ot Moderate om 0 ‘ sa M3 fe = 8 2 a M3 fe a) > amd fe ne) ® "4 09 es OS u i Bs ie = @ Bh 00 ee = OS ‘ = y2 te E * 3 Bie ss G ° 2 soo Ses % oetetete te ete Puma Cortel Concentration (p}) Fr, 1, Distbution of plasma consol! concentrations (/€l in 37 tints with septi shock Patients examined. The studies of Melby and Spink (1) and Cornil et al. (5) first documented the increase in plasma cortisol in infection both with and without shock. In a group of 20 patients with hypotension and bacterial infections, cortisol levels of 30 to 160 yg/dl (1) were seen. Sibbald et al. (3) reported 26 patients with the diagnosis of severe sepsis. Although the overall group means were above the normal range, 14 had ‘Tanus 2. Comation coefcients and. significance levels for asociations between plasma cortisol and clinical variables" Variable eValue pValue ‘Time from onset of shock to =a73 oO measurement (2) ‘Time from measurement. re 096 sr ‘ers of shock (b) Age) 060 n MAP (mm He) 401 2 Dose of vasopressor (uh 28 14 ‘min) ‘Tal protein era) (ei) 232 20 Albumin (serum) (ay =215 25 * Goefcients determined by Spearman rank method with core. tion fo es, initial cortisol levels <20 yg/dl. A retrospectively de- fined group of four “agonal” patients showed higher levels, ranging from $5 to 86 ug/l. As implied by these studies, while cortisol levels are generally increased in infection, extreme increases are associated with a preterminal state, We have been un- able to confirm a statistically significant difference be- tween cortisol levels of patients who reversed their shock or survived to hospital discharge and those of patients who did not. In addition, doses of vasopressors ‘were not correlated with cortisol concentrations. Simi-262 CRITICAL CARE MEDICINE larly, we (15) found that cortisol levels did not vary significantly with our prospectively determined criteria. for severity of shock, while reversal of shock did corre- late with severity of shock. Thus, it appears that plasma cortisol concentrations, per se, are not predictive ofthe clinical outcome of septic shock. A second area for consideration is the possibility that there may be a relative adrenal insufficiency in sepsis and septic shock, ie, “normal” or “high normal” plasma cortisol concentrations may actually represent an insufficient response to the stresses of sepsis and septic shock. To define such a state, patients would havetobe found tohave either noora minimal increase in cortisol to cosyntropin challenge and a definable, Positive clinical response to moderate doses of exoge- nous corticosteroids. The results of two double-blind, placebo-controlled studies (16, 17) of the use of co costeoids in sepsis and septic shock support the argu- ‘ment that the latter requirement is not routinely met. Neither study ofthe administration of high dose co costerods showed improved survival in the experimen: tal group, and one (16) showed no differences in the reversal or prevention of shock. In contradistnction to the findings of Sibbald et al. (3) of five patients in 26 with a mean plasma cortisol concentration of 14 ne/dt and no response to iv cosyntropin, the lowest vales of our series comprised three patients with cortisol levels between 15.6 and 25 yg/dl, considered to be in the high range for normal circadian variation or typical of pa- tients undergoing minor surgical procedures (18). This diference may have been due to different patient pop- ulations, since our study considered only patients with shock. Unfortunately, we did not perform stimulation tests, However, with & median cortisol concentration of 50.7 wa/l, a blunted or nonexistent response to cosyn- ‘tropin would be uninterpretable. Although there were no differences in survival, these patients, as previously reported (15), did show a greater incidence of shock reversal within 24 h when treated with corticosteroids. Temay be speculated tha this improvement was due to the physiologic effects of corticosteroid administration, although it should be noted that because of additional physiologic effects, responses to exogenous steroid ad- ‘ministration may not be a reliable means for evaluating adrenal insufficiency. Therefore, while it appears that absolute hypocortsolism is rarity in septic shock and that the majority of patients do not benefit from treat- ment with corticosteroids, the possibilty exists that a minority of patients may be hypoadrenal and respond to corticosteroid therapy. The incidence of such a state in other infected patients may be greater, but it still remains to be shown that such patients will benefit from corticosteroid therapy. “Two factors which were negatively correlated with cortisol concentrations were the length oftime a patent Marcu, 1990 was in shock before sampling the plasma cortisol and the patient’s MAP at the time of cortisol sampling. While both of these factors were statistically significant, we do not feel that the correlations were sufficiently hhigh to justify speculation. Similarly, we find it of interest that patients with Gram-positive infections should have higher cortisol levels than those with Gram-negative infections. However, the relatively small numbers of patients in these groups, and their differing ‘outcomes and severity of shock suggest that this be a topic for further study rather than being taken as a proven relationship. What is the “normal” value for plasma cortisol in septic shock? While our data are not normally distrib- ‘uted, 90% of our patients had values >27 yg/dl, and all have values >15 g/dl. While we believe that a plasma cortisol concentration >20 ug/dl is appropriate and adequate for these crticaly ill patients, no one has tested the hypothesis that lower levels, eg., 15 to 20 ug/ dl, are insufficient for tissue requirements. A clinical investigation for hypoadrenalism might reasonably be pursued for patients at the lower end of this spectrum, It is possible that any of these patients not responding to Cortrosyn should be considered for corticosteroid replacement therapy. The importance of inadequate adrenal production of glucocorticoids is especially im- portant today. The use of exogenous glucocorticoids for sepsis and septic shock is decreasing since the publica- tion of two double-blind, placebo-controlled trials (16, 17) Itis conceivable that patients who several years ago might have inadvertently received treatment for adrenal insufficiency will now not be treated. Our data, in conjunction with other studies, suggest that this will at most be a rare event, but practitioners should remain alert to the possibility REFERENCES 1. Melby JC, Spink WW: Comparative studies on adrenal cota fuostonandcorso metabotsm fealty adlsandipasens with shook due to meson 4 Clin vest (998 37.1791 2. 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