SHOCK, Vol. 36, No. 4, pp.

345Y349, 2011

PROGNOSTIC SIGNIFICANCE OF DIFFERENT SUBGROUP CLASSIFICATIONS OF CRITICAL ILLNESSYRELATED CORTICOSTEROID INSUFFICIENCY IN PATIENTS WITH SEPTIC SHOCK
So Yeon Lim,* Yong Soo Kwon, Maeng Real Park, Seo Goo Han,* Kyeongman Jeon,* Sang-Won Um,* Won-Jung Koh,* Man Pyo Chung,* Hojoong Kim,* O. Jung Kwon,* and Gee Young Suh*
*Division of Pulmonary and Critical Care Medicine, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul; Chonnam National University Hospital, Gwangju; and Department of Emergency Medicine, Pusan National University Yangsan Hospital, Pusan National University School of Medicine, Busan, Korea
Received 26 May 2011; first review completed 7 Jun 2011; accepted in final form 10 Jun 2011 ABSTRACTThe purpose of this study was to evaluate the prognostic significance of classification of patients with septic shock into different critical illnessYrelated corticosteroid insufficiency subgroups. A retrospective observational study was conducted in patients with septic shock who underwent a short corticotropin stimulation test within 72 h of the onset of shock. Patients were classified into normal adrenal function (NOM), low basal cortisol (LBC) (basal cortisol, G10 2g/dL), or low $ cortisol (LDC) (basal cortisol, Q10 2g/dL; cortisol, G9 2g/dL) groups. A total of 168 septic shock patients were recruited. Forty-two patients (25%) were assigned to the NOM group, 39 (23.2%) to the LBC group, and 87 (51.8%) to the LDC group. All of the patients received hydrocortisone therapy. Patients in the LDC group had significantly higher Simplified Acute Physiology Score 3 (P G 0.001) and Sequential Organ Failure Assessment score (P G 0.001) than did patients in the NOM group. The 28-day mortalities of the NOM, LBC, and LDC groups were 40.5%, 38.5%, and 63.2%, respectively (P = 0.007). Classification into the LDC group significantly increased the odds of 28-day mortality (odds ratio, 2.717; 95% confidence interval, 1.452Y5.082; P = 0.002) and remained an independent risk factor for mortality even after controlling for all the other potential risk factors identified (odds ratio, 3.638; 95% confidence interval, 1.418Y9.028; P = 0.006). Classification into the LDC group is an independent risk factor for mortality in hydrocortisone-treated septic shock patients. KEYWORDSCorticosteroid insufficiency, corticotropin, cortisol, critical illness, septic shock

INTRODUCTION The integrity of the hypothalamic-pituitary-adrenal (HPA) axis is important for maintaining physiologic balance in critically ill patients (1Y3). Several studies have shown that dysregulation of the HPA axis is a poor prognostic factor in patients with septic shock (4Y8), but corticosteroid therapy to correct HPA axis abnormalities has produced mixed results (3, 4, 9, 10). A recent consensus statement proposed two critical illnessY related corticosteroid insufficiency (CIRCI) subgroups based on cortisol response to a short corticotropin stimulation test (11). However, it is not known whether the two CIRCI subgroups diagnosed according to this criterion have similar clinical characteristics or prognoses. Recently, Kwon et al. (12). demonstrated that patients in the two CIRCI subgroups have significantly different cytokine profiles, suggesting that the pathogenesis of CIRCI may be different in these two subgroups. Therefore, we undertook this study to assess whether the two CIRCI subgroups have different clinical characteristics and prognoses, with a focus on 28-day mortality in patients with septic shock.

MATERIALS AND METHODS

Study population
This study was approved by our institutional review board, and the requirement for informed consent was waived because of the retrospective nature of the study. All consecutive patients admitted to the two medical ICUs of Samsung Medical Center, a 1,900-bed tertiary referral center in Seoul, Korea, between August 2008 and May 2010 were retrospectively recruited for the study if they met the definition of septic shock and had undergone the short corticotropin stimulation test within 72 h of the onset of shock. In our treatment protocol, we recommend hydrocortisone therapy in refractory septic shock, and before beginning hydrocortisone treatment, short corticotropin stimulation test was done at the discretion of the attending physician. All patients included received hydrocortisone therapy until the results of the short corticotropin stimulation test were obtained. The hydrocortisone was tapered according to the results of the short corticotropin stimulation test and clinical response. Patients were excluded if they had been treated with any dose of corticosteroid or any drug interfering with the HPA axis within the last month, had known previous conditions that may have disrupted the HPA axis, or if they were younger than 18 years of age.

Definitions
A short corticotropin stimulation test was performed within 72 h of the onset of septic shock. Blood samples were collected immediately before the test and 30 and 60 min after corticotropin administration. $ Cortisol was defined as the difference between the basal cortisol level and the highest cortisol concentration measured. Patients were classified into three groups according to the results of the short corticotropin stimulation test. The normal group (NOM) comprised patients with normal adrenal function, the low basal cortisol (LBC) group is composed of patients with a basal cortisol level of less than 10 2g/dL regardless of cortisol, and the low $ cortisol (LDC) group comprised patients with a basal cortisol level 10 2g/dL or greater and cortisol of less than 9 2g/dL. Septic shock was defined as sepsis with arterial hypotension, despite adequate fluid resuscitation (13). Hypotension was defined as a systolic arterial pressure less than 90 mmHg, a mean arterial pressure less than 65 mmHg, or a reduction in systolic blood pressure of more than 40 mmHg from baseline, despite adequate volume resuscitation (13). Reversal of shock was defined as the maintenance of 345

Address reprint requests to Gee Young Suh, MD, Division of Pulmonary and Critical Care Medicine, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, 50 Irwon-dong, Gangnam-gu, Seoul, 135-710, South Korea. E-mail: suhgy@skku.edu. DOI: 10.1097/SHK.0b013e318228ed18 Copyright 2011 by the Shock Society

Copyright 2011 by the Shock Society. Unauthorized reproduction of this article is prohibited.

346

SHOCK VOL. 36, NO. 4

LIM

ET AL.

a systolic blood pressure of at least 90 mmHg without vasopressors for at least 24 h (9). Shock-free day was defined as the day of patients being alive and not being in shock over a 28-day follow up period after the onset of septic shock. ICU-free day was defined as the day of patients being alive and not being in the ICU over the same period.

Data collection
At the onset of septic shock, the following variables were recorded: (a) general characteristics including age, sex, and preexisting underlying disease; (b) severity of illness as assessed by the Simplified Acute Physiology Score 3 (SAPS 3) and the Sequential Organ Failure Assessment (SOFA) score; and (c) interventions including corticosteroid therapy, need for mechanical ventilation, and continuous renal replacement therapy. At the onset of septic shock, hematologic and chemistry data, arterial lactate, and arterial blood gas determinations were recorded. The results of the short corticotropin stimulation test were also recorded.

Statistical analysis
For statistical analysis, SPSS PAWS 17.0; SPSS Inc., Chicago, Ill) and STATA 11.0 (StataCorp LP, College Station, Tex) were used. For continuous variables, data are shown as mean (SD) if the data were normally distributed or as median and interquartile range (IQR) if the data were not normally distributed unless specified otherwise. Categorical data are shown as count (percentage). Continuous variables were analyzed using one-way ANOVA, with t tests to determine the significance of between-group differences, or the Kruskal-Wallis test with the Mann-Whitney U test, as appropriate. The chisquare test or Fisher exact test was used to compare categorical data. Univariate logistic regression model was used to identify significant predictors of 28-day mortality. Multivariate logistic regression analysis was performed to evaluate the effect of classification into the LDC group on 28-day mortality. Two models were evaluated. Model 1 was adjusted for age, sex, and SAPS 3; model 2 was adjusted for all variables that had P G 0.25 in the univariate analysis, in addition to age, sex, and SAPS 3. For survival analysis, KaplanMeier analysis with the log-rank method was performed. P G 0.05 was considered statistically significant. Bonferroni correction was used to adjust for multiple comparisons, with P G 0.0167 considered statistically significant where appropriate.

RESULTS
Baseline characteristics, clinical features, and outcomes of the septic shock patients

patients were included in the LDC group than were in the NOM group (P = 0.009). The clinical features and outcomes of the 168 septic shock patients are shown in Table 2. The LDC group had significantly higher SAPS 3 (84.3 [SD, 14.3] vs. 73.0 [SD, 19.0], P G 0.001) and SOFA scores (10.8 [SD, 3.3] vs. 7.9 [SD, 3.6], P G 0.001) than did those in the NOM group. The albumin concentration was significantly higher in the NOM group than it was in the LBC or LDC group (P G 0.016). None of the other measurements were significantly different among the three groups. All patients were treated with hydrocortisone, and the peak dose, total cumulative dose, and duration of steroid treatment were not significantly different among the three groups (Table 2). The rates of shock reversal were not different among the three groups; however, shock-free days differed among the three groups (P = 0.035), and mean shock-free days were 13.5 (SD, 13.1), 14.2 (SD, 12.8), and 9.9 (SD, 12.0 days) for NOM, LBC, and LDC groups, respectively. ICU-free days also differed significantly among the three groups (P = 0.012). The 28-day mortality of the LDC group was 63.2%, significantly higher than that of the LBC group (38.5%) or NOM group (40.5%) (P G 0.016). The Kaplan-Meier survival curves for each group are shown in Fig. 1, illustrating that there were significant differences among the three groups (P = 0.0139). The LDC group tended to have a lower 28-day survival rate than did the NOM group (P = 0.0387) and had a significantly lower 28-day survival rate than did the LBC group (P = 0.0108). The median time to death from onset of septic shock was not different among the three groups, with median values of 10 (IQR, 3Y19) days for NOM, 20 (IQR, 3Y28) days for LBC, and 6 (IQR, 3Y9) days for LDC (P = 0.364).
The effects of classification into the LDC group on the odds ratio of 28-day mortality

Among the 168 patients included in the analysis, 42 patients (25%) were classified into the NOM group, 39 patients (23.2%) into the LBC group, and 87 patients (51.8%) into the LDC group (Table 1). There were no differences in age or sex among the three groups (Table 1). Significantly more cancer

Univariate logistic regression analysis was performed to determine if there were any associations between various risk

TABLE 1. Baseline characteristics of the 168 septic shock patients according to the results of the short corticotropin stimulation test P Characteristic Age, y Male sex Preexisting disease Diabetes mellitus Cardiovascular disease Chronic renal failure Chronic liver disease Neurologic disease Cancer 1 (2.4) 11 (26.2) 6 (14.3) 0 (0) 1 (2.4) 12 (28.6) 1 (2.6) 4 (10.3) 5 (12.8) 1 (2.6) 2 (5.1) 13 (33.3) 3 (3.4) 12 (13.8) 7 (8) 4 (4.6) 3 (3.4) 46 (52.9) 1.000 0.127 0.512 0.429 0.749 0.012 V V V V V 0.810 V V V V V 0.053 V V V V V 0.009 NOM (n = 42) 67 (49Y77) 27 (64.3) LBC (n = 39) 64 (57Y70) 20 (51.3) LDC (n = 87) 65 (51Y72) 58 (66.7) NOM vs LBC vs LDC 0.584 0.149 NOM vs. LBC V V LBC vs. LDC V V LDC vs. NOM V V

Data are presented as median (IQR) or number (percentage). To compare continuous variables, the Kruskal-Wallis test with the Mann-Whitney U test was used to compare differences between groups, and P G 0.0167 was considered statistically significant. To compare categorical variables, chi-square analysis or Fisher exact test was used, and P G 0.05 was considered statistically significant. LBC indicates low basal cortisol (basal cortisol G 10 2g/dL); LDC, low delta cortisol (basal cortisol Q 10 2g/dL and $ cortisol G 9 2g/dL); NOM, normal adrenal function.

Copyright 2011 by the Shock Society. Unauthorized reproduction of this article is prohibited.

SHOCK OCTOBER 2011

PROGNOSIS

AND

CIRCI

347

TABLE 2. Clinical features and outcomes of the 168 septic shock patients according to the results of the short corticotropin stimulation test P Characteristic
Temperature, median (IQR), -C Heart rate, mean (SD), beats/min SAPS 3, mean (SD) SOFA, mean (SD) Hematocrit, mean (SD), % Leukocytes, median (IQR), 109/L Platelets, median (IQR), 103/2L Albumin, mean (SD), g/dL Total bilirubin, median (IQR), mg/dL Creatinine, median (IQR), mg/dL Lactate, median (IQR), mmol/L CRP, median (IQR), mg/dL Arterial pH, median (IQR) Short corticotropin test ACTH, median (IQR), pg/mL Cortisol0, median (IQR), 2g/mL Cortisol30, median (IQR), 2g/mL Cortisol60, median (IQR), 2g/mL PaO2/Fio2, median (IQR), mmHg Hydrocortisone (peak dose), median (IQR), mg Hydrocortisone (total cumulative dose), median (IQR), mg Hydrocortisone (duration), median (IQR), d Mechanical ventilation, n (%) CRRT, n (%) Shock reversal, n (%)l No. shock-free days, median (IQR) No. ICU-free days, median (IQR) ICU mortality, n (%) 28-d Mortality, n (%) 16 (8.7Y23.2) 18.8 (13.4Y27.4) 31.1 (23.3Y56.9) 36.4 (28.6Y64.8) 106 (60.8Y167.3) 200 (200Y200) 825 (400Y1,499) 4 (2Y15) 33 (78.6) 12 (28.6) 25 (59.5) 20 (0Y27) 5 (0Y21) 17 (40.5) 17 (40.5) 13.1 (9.8Y27.0) 7.3 (4.6Y8.9) 10.7 (8.6Y13.4) 11.9 (8.5Y15.3) 126.2 (70Y246.7) 200 (200Y200) 1,050 (450Y1,600) 7 (4Y10) 28 (71.8) 9 (23.1) 22 (56.4) 22 (0Y26) 8 (0Y22) 17 (43.6) 15 (38.5) 31 (16Y113) 21.1(13.3Y31.2) 24.4 (15.9Y31.3) 23.5 (16.7Y31.6) 119 (75.7Y174) 200 (200Y200) 1,000 (510Y1,510) 7 (3Y13) 66 (75.9) 21 (24.1) 35 (40.2) 0 (0Y24) 0 (0Y8) 49 (56.3) 55 (63.2) G0.001 G0.001 G0.001 G0.001 0.333 0.931 0.931 0.838 0..770 0.842 0.085 0.035 0.012 0.150 0.007 0.967 G0.001 G0.001 G0.001 V V V V V V V 0.886 0.936 V 1.000 G0.001 G0.001 G0.001 G0.001 V V V V V V V 0.033 0.036 V 0.011 G0.001 0.603 G0.001 G0.001 V V V V V V V 0.035 0.084 V 0.014

NOM (n = 42)
37.6 (36.0Y38.7) 125 (28.4) 73.0 (19.0) 7.9 (3.6) 30.9 (6.8) 11.7 (5.8Y21.9) 150 (45Y242) 2.9 (0.6) 1 (0.6Y1.4) 1.1 (0.8Y1.7) 2.3 (1.6Y3.9) 9.4 (3.4Y20.5) 7.3 (7.1Y7.5)

LBC (n = 39)
37.4 (35.8Y38.4) 126 (22.7) 79.8 (17.3) 9.6 (3.9) 29.5 (5.9) 11.4 (6.6Y22.9) 70 (32Y162) 2.5 (0.4) 1.5 (0.7Y3.3) 1.1 (0.7Y2.8) 2.7 (1.8Y6.3) 13.5 (7.8Y17.2) 7.3 (7.2Y7.5)

LDC (n = 87)
38 (36.4Y38.8) 131.7 (24.8) 84.3 (14.3) 10.8 (3.3) 30.8 (6.3) 10 (1.1Y15.9) 85 (38Y186) 2.6 (0.5) 1.4 (0.7Y3.0) 1.4 (0.9Y2.2) 3.9 (2.0Y7.0) 16.1 (4.8Y24.9) 7.3 (7.2Y7.5)

NOM vs LBC vs LDC NOM vs. LBC LBC vs. LDC LDC vs. NOM
0.107 0.203 G0.001 G0.001 0.885 0.058 0.040 0.014 0.021 0.308 0.079 0.263 0.806 V V 0.103 0.045 V V V 0.001 0.022 V V V V V V 0.143 0.073 V V V 0.161 0.741 V V V V V V G0.001 G0.001 V V V 0.014 0.010 V V V V

To compare continuous variables, one-way ANOVA or a Kruskal-Wallis test using the t test or the Mann-Whitney U test to assess the significance of between-group differences was used. To compare categorical variables, chi-square analysis or Fisher exact test using Bonferroni correction was used. A P G 0.0167 was considered statistically significant. CRP indicates C-reactive protein; ACTH, adrenocorticotropin hormone; cortisol0, basal cortisol; cortisol30, cortisol at 30 min; cortisol60, cortisol at 60 min; PaO2, arterial oxygen pressure; FIO2, inspired oxygen fraction; CRRT, continuous renal replacement therapy; LBC, low basal cortisol (basal cortisol G 10 2g/dL); LDC, low delta cortisol (basal cortisol Q 10 2g/dL and $ cortisol G 9 2g/dL); NOM, normal adrenal function.

factors and 28-day mortality in the 168 septic shock patients (Table 3). The unadjusted odds ratio (OR) of being classified into the LDC group compared with other groups with regard to 28-day mortality was 2.717 (95% confidence interval [CI], 1.452Y5.082; P = 0.002) (Table 4). When adjusted for age, sex, and SAPS 3 (model 1), being classified into the LDC group significantly increased the odds of 28-day mortality (OR, 2.667; 95% CI, 1.341Y5.305; P = 0.005). Even after adjusting for all of the variables with P G 0.25 in univariate analysis, being classified into the LDC group remained a significant risk factor for mortality (model 2) (OR, 3.638; 95% CI, 1.438Y9.203; P = 0.006) (Table 4). DISCUSSION The main finding of this study is that, in septic shock patients treated with hydrocortisone, subgroups of CIRCI have different clinical characteristics and prognoses. The LDC

group (basal cortisol, Q10 2g/dL; $ cortisol, G9 2g/dL) had a higher severity score than did the NOM group, and being classified into the LDC group was associated with poor outcome. Patients in the LDC group had a 3.6-fold increased OR of 28-day mortality compared with those of the other groups even after adjusting for all relevant confounding variables. The diagnosis of dysfunction of the HPA axis is difficult, especially in the critically ill, because there are no universally accepted standard diagnostic criteria that can be used in the bedside in the ICU. Recently, new diagnostic criteria for CIRCI were proposed based on the results of a study that compared the results of the short corticotropin test with the metyrapone test, that is, a basal cortisol of less than 10 2g/dL or an increase in cortisol levels of less than 9 2g/dL from baseline (11). However, these definitions have not been validated against clinically important end points or in specific populations of patients.

Copyright 2011 by the Shock Society. Unauthorized reproduction of this article is prohibited.

348

SHOCK VOL. 36, NO. 4

LIM

ET AL.

TABLE 4. Relationship between being classified as LDC group and 28-day mortality in the 168 septic shock patients LDC Unadjusted OR (95% CI, P) Adjusted OR (95% CI, P) Model 1 Model 2 2.667 (1.341Y5.305, 0.005) 3.638 (1.438Y9.203, 0.006) 2.717 (1.452Y5.082, 0.002)

LDC, low $ cortisol (basal cortisol, Q10 2g/dL; $ cortisol, G9 2g/dL). Model 1 was adjusted for age, sex, and SAPS 3, and model 2 was additionally adjusted for cancer, temperature G 35-C, hematocrit, platelets, albumin, total bilirubin, lactate, arterial pH, PaO2/FiO2, mechanical ventilation, and CRRT.

FIG. 1. Kaplan-Meier survival curves over 28 days. The survival curves for the three groups (NOM, LBC, LDC) with septic shock who received hydrocortisone therapy were significantly different (P = 0.0139). There was no significant difference between the NOM and LBC groups (P = 0.7071). However, the probability of survival was significantly different between the LDC and NOM groups (P = 0.0387). The survival of the LDC group also tended to be lower than that of the LBC group (P = 0.0108).

Our data confirm that the two CIRCI subgroups of septic shock patients have different clinical characteristics and prognoses. This is consistent with the results of a recent study by Kwon et al. (12), who reported that the two CIRCI groups had different serum cytokine profiles. In that study, serum cytokines, including IL-6 and TNF-!, were significantly elevated in the LDC group compared with those in the LBC group (12). The cytokine profile of the LBC group was similar to that of the group of patients with normal HPA axis function (12).

TABLE 3. Univariate analysis of the effects of various clinical parameters on the OR for 28-day mortality in 168 septic shock patients Characteristic Age Male sex SAPS 3 Cancer Temperature G35-C Heart rate Hematocrit Leukocytes Platelets Albumin Total bilirubin Creatinine Lactate CRP Arterial pH LDC PaO2/Fio2 Mechanical ventilation CRRT OR 1.010 0.722 1.034 1.963 3.083 1.004 0.940 1.000 0.995 0.670 1.230 1.042 1.229 1.007 0.157 2.717 0.997 1.765 4.821 95% CI 0.990Y1.030 0.384Y1.355 1.013Y1.056 1.048Y3.676 1.065Y8.925 0.992Y1.016 0.894Y0.989 1.000Y1.000 0.992Y0.998 0.379Y1.183 1.060Y1.426 0.881Y1.233 1.099Y1.374 0.978Y1.036 0.030Y0.826 1.452Y5.082 0.994Y1.000 0.864Y3.603 2.128Y10.920 P 0.323 0.310 0.002 0.035 0.038 0.555 0.017 0.446 0.002 0.167 0.006 0.628 G0.001 0.650 0.029 0.002 0.068 0.119 G0.001

LDC, low $ cortisol (basal cortisol, Q10 2g/dL; $ cortisol, G9 2g/dL).

In this study of septic shock patients treated with hydrocortisone, 28-day mortality was significantly higher in the LDC group than it was in the other two groups. When we performed a simple analysis of relationship between 28-day mortality and Bresponse to corticotropin[ in only the patients who received hydrocortisone using the data presented in table 3 of the CORTICUS manuscript (14), there was a trend of increasing of mortality in patients with Bno response to corticotropin[ (49/125 patients; mortality, 39.2%) compared with patients with Bresponse to corticotropin[ (34/118 patients; mortality, 28.8%, P = 0.088 according to the chi-square test), although that results did not reach statistical significance (14). The differences seen in these two studies might be explained by contamination in Bno response to corticotropin[ group in the CORTICUS study by the LBC group patients in this study. Of the 39 patients assigned to the LBC group in this study, 32 patients would have been classified as Bno response to corticotropin[ in that previous study because their $ cortisol was less than 9 2g/dL. The mortality rate of these 32 patients was 37.5% (12/32 patients), very similar to the mortality rate of patients with low basal cortisol and a higher $ cortisol (3/7 patients, 42.9%). This suggests that, even in patients with no response to corticotropin, the basal cortisol level may be important in stratifying the risk of mortality and possibly the response to corticosteroid therapy. Some authors have suggested that different subgroups of CIRCI may be useful for predicting the benefits of corticosteroid therapy and that only patients in the LDC group may benefit from corticosteroid therapy (15). Our study results suggest the opposite: Only patients with a low basal cortisol level regardless of $ cortisol may benefit from corticosteroid therapy. In our study, all patients were treated with hydrocortisone, and the 28-day mortality rate was significantly higher in the LDC group. One possible explanation for this observation is that patients with low basal cortisol may be suffering from an absolute lack of cortisol, which is correctable by the addition of exogenous corticosteroids, whereas patients with high basal cortisol levels and a low $ cortisol have HPA axis dysfunction that is uncorrectable with exogenous corticosteroids. Randomized trials of corticosteroids in septic shock patients stratified according to CIRCI subgroups are needed to confirm these hypotheses. The present study had several limitations. First, it was a retrospective analysis of data; thus, we could not fully account for selection bias. Second, we used the results of the short

Copyright 2011 by the Shock Society. Unauthorized reproduction of this article is prohibited.

SHOCK OCTOBER 2011

corticotropin stimulation test, which does not directly assess the integrity of the HPA axis (11, 16). However, direct tests of the HPA axis such as insulin-induced hypoglycemia or the metyrapone test are dangerous or impractical in the critically ill. Furthermore, this study was a single-center study, and so the results may not be generalizable to other patient populations. However, our study has several strengths. First, this is the first study that tried to investigate whether patients classified into different subgroups of CIRCI have different prognoses. Second, our data suggest that steroid therapy may not be beneficial in patients in the LDC group, which had a higher mortality compared with other groups in these hydrocortisonetreated septic shock patients. Thus, risk and benefits of steroids should be carefully considered when considering initiation or continuation of steroid therapy in patients classified into LDC group until the results of a prospective trial of steroids stratified according to subgroups of CIRCI can give clinicians more definitive answers. CONCLUSIONS Classification into the LDC group based on the results of the short corticotropin stimulation test was an independent risk factor for mortality in hydrocortisone-treated septic shock patients. Further investigations should be conducted to gain a better understanding of the potential therapeutic and risk stratification implications of CIRCI subgroup classification. REFERENCES
1. Dimopoulou I, Tsagarakis S: Hypothalamic-pituitary dysfunction in critically ill patients with traumatic and nontraumatic brain injury. Intensive Care Med 31:1020Y1028, 2005.

PROGNOSIS

AND

CIRCI

349

2. Marik PE, Zaloga GP: Adrenal insufficiency during septic shock. Crit Care Med 31:141Y145, 2003. 3. Bollaert PE, Fieux F, Charpentier C, Levy B: Baseline cortisol levels, cortisol response to corticotropin, and prognosis in late septic shock. Shock 19:13Y15, 2003. 4. Finlay WE, McKee JI: Serum cortisol levels in severely stressed patients. Lancet 1:1414Y1415, 1982. 5. McKee JI, Finlay WE: Cortisol replacement in severely stressed patients. Lancet 1:484, 1983. 6. Drucker D, Shandling M: Variable adrenocortical function in acute medical illness. Crit Care Med 13:477Y479, 1985. 7. Rothwell PM, Udwadia ZF, Lawler PG: Cortisol response to corticotropin and survival in septic shock. Lancet 337:582Y583, 1991. 8. American College of Chest Physicians/Society of Critical Care Medicine Consensus Conference: definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis. Crit Care Med 20:864Y874, 1992. 9. Annane D, Bellissant E, Bollaert PE, Briegel J, Keh D, Kupfer Y: Corticosteroids for severe sepsis and septic shock: a systematic review and metaanalysis. BMJ 329:480, 2004. 10. Annane D, Maxime V, Ibrahim F, Alvarez JC, Abe E, Boudou P: Diagnosis of adrenal insufficiency in severe sepsis and septic shock. Am J Respir Crit Care Med 174:1319Y1326, 2006. 11. Marik PE, Pastores SM, Annane D, Meduri GU, Sprung CL, Arlt W, Keh D, Briegel J, Beishuizen A, Dimopoulou I, et al.: Recommendations for the diagnosis and management of corticosteroid insufficiency in critically ill adult patients: consensus statements from an international task force by the American College of Critical Care Medicine. Crit Care Med 36:1937Y1949, 2008. 12. Kwon YS, Suh GY, Jeon K, Park SY, Lim SY, Koh WJ, Chung MP, Kim H, Kwon OJ: Serum cytokines and critical illnessYrelated corticosteroid insufficiency. Intensive Care Med 36:1845Y1851, 2010. 13. Levy MM, Fink MP, Marshall JC, Abraham E, Angus D, Cook D, Cohen J, Opal SM, Vincent JL, Ramsay G: 2001 CCM/ESICM/ACCP/ATS/SIS International Sepsis Definitions Conference. Crit Care Med 31:1250Y1256, 2003. 14. Sprung CL, Annane D, Keh D, Moreno R, Singer M, Freivogel K, Weiss YG, Benbenishty J, Kalenka A, Forst H, et al.: Hydrocortisone therapy for patients with septic shock. N Engl J Med 358:111Y124, 2008. 15. Marik PE, Levitov A: The Bkoala stress syndrome[ and adrenal responsiveness in the critically ill. Intensive Care Med 36:1805Y1806, 2010. 16. Bouachour G, Roy PM, Guiraud MP: The repetitive short corticotropin stimulation test in patients with septic shock. Ann Intern Med 123:962Y963, 1995.

Copyright 2011 by the Shock Society. Unauthorized reproduction of this article is prohibited.