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Physiological-dose steroid therapy in sepsis [ISRCTN36253388]

Orhan Yildiz1*, Mehmet Doğanay2, Bilgehan Aygen2, Muhammet Güven3, Fahrettin Keleştimur4 and Ahmet Tutuş5

Author Affiliations

1 Consultant, Department of Infectious Diseases, School of Medicine, Erciyes University, Kayseri, Turkey

2 Lecturer, Department of Infectious Diseases, School of Medicine, Erciyes University, Kayseri, Turkey

3 Lecturer, Division of Critical Care, Department of Internal Medicine, School of Medicine, Erciyes University, Kayseri, Turkey

4 Lecturer, Division of Endocrinology, Department of Internal Medicine, School of Medicine, Erciyes University, Kayseri, Turkey

5 Lecturer, Department of Nuclear Medicine, School of Medicine, Erciyes University, Kayseri, Turkey

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Critical Care 2002, 6:251-259  doi:10.1186/cc1498


See related Commentary: http://ccforum.com/content/6/3/190


The electronic version of this article is the complete one and can be found online at:


Received:5 October 2001
Revisions received:27 January 2002
Accepted:2 April 2002
Published:19 April 2002

© 2002 BioMed Central Ltd

Abstract

Introduction

The aim of the study was to assess the prognostic importance of basal cortisol concentrations and cortisol response to corticotropin, and to determine the effects of physiological dose steroid therapy on mortality in patients with sepsis.

Methods

Basal cortisol level and corticotropin stimulation test were performed within 24 hours in all patients. One group (20 patients) received standard therapy for sepsis and physiological-dose steroid therapy for 10 days; the other group (20 patients) received only standard therapy for sepsis. Basal cortisol level was measured on the 14th day in patients who recovered. The outcome of sepsis was compared.

Results

Only Sequential Organ Failure Assessment (SOFA) score was found related to mortality, independent from other factors in multivariate analysis. No significant difference was found between the changes in the percentage of SOFA scores of the steroid therapy group and the standard therapy group in survivors, nor between the groups in basal and peak cortisol levels, cortisol response to corticotropin test and mortality. The mortality rates among patients with occult adrenal insufficiencies were 40% in the steroid therapy group and 55.6% in the standard therapy group.

Discussion

There was a trend towards a decrease in the mortality rates of the patients with sepsis who received physiological-dose steroid therapy. In the advancing process from sepsis to septic shock, adrenal insufficiency was not frequent as supposed. There was a trend (that did not reach significance) towards a decrease in the mortality rates of the patients with sepsis who received physiological-dose steroid therapy.

Keywords:
adrenal insufficiencies; cortisol; occult adrenal insufficiencies; physiological-dose steroid therapy; sepsis

Introduction

This paper was presented at the 10th European Congress of Clinical Microbiology and Infectious Diseases (28–31 May 2000, Stockholm, Sweden).

Sepsis can be defined as a systemic response to infection [1]. The incidence of sepsis worldwide is on the increase. Sepsis and its sequels are the leading causes of death in intensive care units. Mortality rates are higher for patients with pre-existing disease, medical conditions, care in the intensive care unit, and multiple organ failure [2,3]. Despite steady improvements in antibiotic therapy and intensive care management during the past decade, mortality has remained close to 50%. This high mortality rate has continued to stimulate interest in pharmacological agents that might reduce morbidity and mortality [4,5,6,7].

Steroid therapy in patients with sepsis is still controversial. In the 1960s, stress doses of hydrocortisone for the treatment of sepsis were investigated, but no advantages could be shown in a double-blind multicenter study [8]. This led to the discontinuation of steroid replacement therapy for sepsis. In the 1970s, therapy with pharmacological doses of glucocorticoids was widely used in patients with sepsis and septic shock. The most compelling evidence in favor of corticosteroid treatment was reported by Schumer [9] in his prospective randomized study of steroid administration to patients with septic shock. These data indicate that methylprednisolone (30 mg/kg) or dexamethasone (3 mg/kg) reduced the mortality rate from 38.4% to 10.5%. However, later in the mid-1980s, pharmacological doses of glucocorticoids for the treatment of sepsis were investigated extensively until several clinical trials gave negative results [10,11,12]. Moreover, there is some evidence that the use of high-dose glucocorticoids in sepsis might be harmful [11].

Many studies have demonstrated that elevated cortisol levels in sepsis and the degree of elevation are related to the severity of illness [13]. Basal and corticotropin (ACTH)-stimulated cortisol levels correlate with the severity of illness, and very high cortisol levels often signify a poor prognosis [14]. In sepsis, the hypothalamic–pituitary–adrenal axis is activated through systemic and neural pathways. Circulating cytokines such as tumor necrosis factor α, interleukin-1 and interleukin-6 activate the hypothalamic–pituitary–adrenal axis independently and, when combined, have synergistic effects [15].

Sepsis can also cause adrenal insufficiency (AI), which is associated with increased mortality [16]. In recent years, several authors have proposed a syndrome of occult AI in septic shock in the presence of normal or even elevated serum cortisol concentrations. This hypothesis is based on many studies investigating the adrenocortical response of patients with septic shock to 0.25 mg of ACTH. Up to 28% of seriously ill patients have been suggested to have occult or unrecognized AI [14]. The prevalence of occult AI (a cortisol increment after a short ACTH test of less than 9 mg/dl) in severe sepsis was estimated at about 50% and the 28-day mortality rate at about 75% [17]. A few studies have indicated that stress doses of hydrocortisone improve hemody-namics in patients with hyperdynamic septic shock, which is unresponsive to conventional therapy [18,19]. However, the use of a physiological dose of steroid in patients with sepsis, severe sepsis, and septic shock has not yet been completely evaluated. We therefore performed a placebo-controlled, randomized, double-blind, single-center study.

The aim of this study was to assess basal cortisol concentrations and the cortisol response to ACTH stimulation as well as their prognostic importance, and also to determine the effects of the physiological-dose steroid therapy on mortality in patients with sepsis.

Methods

Study design

The study protocol was approved by the Institutional Review Board of Erciyes University and informed consent was obtained from the patients' relatives. This placebo-controlled, randomized, double-blind, single-center study was performed at the Department of Medical Intensive Care Unit and the Department of Infectious Diseases of Erciyes University Medical School during a 2-year period (from May 1997 to April 1999).

Patient selection

Patients over 17 years old and diagnosed with sepsis were included consecutively in the study. The diagnosis of sepsis was based on the definition of the American College of Chest Physicians/Society of Critical Care Medicine Consensus Conference Report [1]. The severity of illness was classified according to this definition (Table 1).

Table 1. Consensus conference group definitions of the stages of sepsis [1]

Criteria for exclusion from the study were as follows: already known pre-existing adrenal disease or adrenalectomy, known malignancies, tuberculosis that might have involved the adrenal gland, and administration of steroids within the 3 months before the admission. In addition, patients with burns, hemorrhagic shock or those who had suffered myocar-dial infarction were not included.

Treatment protocol

Patients enrolled in the study were treated with standard therapy used in the treatment of sepsis and septic shock. This therapy could include the following: administration of antibiotics, fluid replacement, vasoactive drugs, mechanical ventila-tory support, and any other form of supportive therapy deemed necessary by the primary physicians. Soon after the presumptive diagnosis of severe sepsis, initial laboratory specimens were obtained and within 2 hours the patients were randomized to treatment with prednisolone or placebo groups. The treatment groups were determined by a computer-generated randomization procedure. The steroid therapy group received prednisolone at a physiological dose. Prednisolone was given intravenously at 06.00 (5 mg) and 18.00 (2.5 mg) for 10 days. The standard therapy group received a placebo infusion containing physiological saline solution in an identical manner. Patients and their primary physicians were blinded as to which therapy was administered.

Data collection

An ACTH stimulation test was performed with 250 g of tetracosactrin (synacthene; Ciba Geigy, Germany) given intravenously. Blood samples were taken immediately before the test and at 30 and 60 minutes afterwards. After centrifugation, plasma samples were stored at -20°C until assayed. ACTH stimulation test was repeated on the 14th day in the patients who survived. Plasma cortisol concentrations were determined by radioimmunoassay with a commercially available kit (ICN Biomedicals, Inc, Costa Mesa, California, USA). Intra-assay coefficients of variation were for control A 7.0%, control B 5.8%, and control C 5.1%. Inter-assay coefficients of variation were for control A 7.9%, control B 6.5%, control C 6.0%. The cortisol response was defined as the difference between the basal and peak cortisol concentrations. Normal adrenal function was defined as a plasma cortisol level (before or at 30 or 60 minutes after the injection of ACTH) above 20 μg/dl. The cases with peak cortisol levels lower than 20 μg/dl were considered to be AI [13,20,21,22]. Occult AI was defined as an increase in cortisol after a ACTH test of less than 9 g/dl (a cortisol response of no more than 9 μg/dl) [17,23,24].

Community-acquired sepsis had its onset within 72 hours of the patients' admission to the hospital, whereas hospital-acquired sepsis began 72 hours or later after admission. The estimated prognosis of any pre-existing underlying diseases had been classified according to the classification of McCabe and Jackson [25].

Observed initial findings that related to disseminated intravas-cular coagulation, respiratory insufficiency, altered mental status, and renal, cardiac, and liver failure were noted [26,27]. The severity of the illness was assessed with the Acute Physiology and Chronic Health Evaluation II (APACHEII) scoring system [28]. The Sequential Organ Failure Assessment (SOFA) score [29] was added to the study protocol by amendment and retrospectively from the raw data. Infections were diagnosed according to clinical and microbiological criteria. Blood samples for cultures were obtained by the same investigator (O Yildiz) and inoculated into a standard culture medium (BACTEC 9240). Patients were evaluated at enrollment and at the 24th hour, and on the 3rd, 7th, 10th, 14th, 21st, and 28th days, and followed for 1 month after discharge from hospital.

Body temperature, respiratory rate, heart rate, blood pressure, the use of vasopressor drugs, urine output, complete blood counts, urinalysis with microscopic examination, erythrocytes sedimentation rate, blood chemistry, prothrombin time, partial thromboplastin time, fibrinogen, fibrin debranch-ing product, blood gases, electrocardiogram, and chest roentgenogram were recorded for each patient individually.

Study endpoints

The primary endpoint of the study was 28-day mortality from all causes. The secondary endpoint consisted of adverse occurrences including possible complications of drug therapy and morbid events such as the progression of initial infection and the development of secondary infection. Secondary infection was defined as the identification of a new site of infection or the emergence of a different organism at the same site, generally requiring a change in antibiotic management.

All medications given to the patients, any complications, the duration of hospitalization, the mortality rate, and the causes of death were recorded and compared between the groups. We also compared average values of basal cortisol, peak cortisol and cortisol responses to ACTH between survivors and non-survivors on the first day. Moreover, basal cortisol levels on the 1st and 14th days were compared in patients who recovered in each group.

Statistical analysis

Student's t-test and the Mann-Whitney U multivariate analysis test were used for continuous variables, χ2 and Fisher's χ2 tests were used for proportions, and logistic regression was used for effects of factors on mortality. Values are expressed as means ± SD, odds ratio (OR) and 95% confidence interval (CI) or proportion.

Results

Description of study population

Forty patients with sepsis, severe sepsis and septic shock were included in this study. The mean age of patients was 56.5 ± 16.4 years in the standard therapy group and 57.8 ± 17.7 years in the steroid therapy group. There was no significant difference in demographic characteristics, the severity of underlying diseases, the APACHE II and SOFA scores, the median time to hospital and median time to death, the acquisition of infection, and the sepsis categories between the groups (Table 2).

Table 2. Characteristics of patients

The 28-day mortality

There were eight deaths (40%) in the steroid therapy group and 12 (60%) deaths in the standard therapy group (P = 0.343). The mortality rate in the patients with hospital-acquired sepsis was higher than that in the patients with community-acquired sepsis in both groups, but this difference was not statistically significant. The relationship between mortality and age, the presence of an underlying disease, vasopressor and steroid therapy, and APACHE II and SOFA scores was assessed. Age, the presence of an underlying disease, steroid therapy, basal plasma cortisol levels, and cortisol response to ACTH below 9 g/dl were not associated with mortality. Although a univariate analysis found vasopressor therapy (OR 4.64, 95% CI 1.02–21.00), APACHE II (OR 1.18, 95% CI 1.04–1.34) and maximum SOFA (OR 1.63, 95% CI 1.23–2.16) to be effective on mortality, only the SOFA score was found related to mortality, independently of other factors (OR 2.09, 95% CI 1.01–4.30) in a multivariate analysis (Fig. 1 and Table 3).

thumbnailFigure 1. Comparison of mortality rates for (a) basal cortisol (μg/dl), (b) cortisol response to ACTH (μg/dl), (c) APACHE II and (d) maximum SOFA scores in both groups.

Table 3. Average values (means ± SD) of basal cortisol, peak cortisol, cortisol responses to corticotropin, APACHE II and maximum SOFA scores according to survivors and non-survivors in both groups on the first day

Variations of treatment effects on the 28-day mortality among subgroups

The mortality rates among patients with a cortisol level over 60 μg/dl were 29% (2 of 7) in the steroid therapy group and 78% (7 of 9) in the standard therapy group (χ2 = 3.874, P = 0.126). Although there was an increase in the level of basal cortisol in patients with sepsis, 14 of 40 patients (35%) had occult AI. The mortality rates in patients with occult AI were 40% (2 of 5) in the steroid therapy group and 55.6% (5 of 9) in the standard therapy group, respectively (χ2 = 0.311, P = 1). Only one patient had both basal and peak cortisol levels lower than 20 g/dl; this patient was in the standard therapy group and died on the 7th day of treatment. This case was accepted as adrenal failure. A comparison of mortality rates for basal cortisol and cortisol responses to ACTH in both groups is shown in Figure 1. The median time to death was 5 days (95% CI 2.55–8.20) in the steroid therapy group and 5.5 days (95% CI 2.19–13) in the standard therapy group (P = 0.496). The reason for death in all patients was attributed to sepsis. The median stay in hospital was 14 days (95% CI 11.09–20.08) in the steroid therapy group and 13 days (95% CI 10.13–16.37) in the standard therapy group (P = 0.406).

Sepsis-related organ dysfunction

Organ dysfunction and failure rates of the patients on admission were 40% and 45% in the steroid therapy and the standard therapy groups, respectively (Table 4). No statistically significant difference was found between the changes in the percentage of SOFA scores of the steroid therapy group (43.1 ± 26.5%) and the standard therapy group (45.4 ± 12.7%) in survivors (P = 0.624).

Table 4. Organ failure in groups at baseline

Cortisol levels and cortisol responses to ACTH

Basal and peak cortisol levels and cortisol responses to ACTH in the steroid therapy group were not significantly different from those in the standard therapy group (Table 5). The average values of basal cortisol, peak cortisol and cortisol responses to ACTH in survivors and non-survivors in both groups for the first day are shown in Table 3. There was no significant difference between the values for survivors and non-survivors. The mean basal cortisol level was 47.6 ± 26.9 g/dl on the first day in all survivors and 17.2 ± 8.6 g/dl on the 14th day in patients who recovered (P = 0.0003). In the steroid therapy group, the mean basal cortisol level was 52.5 ± 30.5 g/dl on the first day and 17.6 ± 10.3 g/dl on the 14th day (P = 0.003). In the standard therapy group, the mean basal cortisol level was 40.3 ± 19.9 g/dl on the first day and 16.4 ± 4.6 g/dl on the 14th day (P = 0.028) (Table 6).

Table 5. Average values (means ± SD) of basal cortisol, peak cortisol and cortisol responses of all patients on the first day

Table 6. Comparison of basal cortisol levels (μg/dl; means ± SD) on the 1st and 14th days in recovering patients

Adverse events

There were no adverse effects due to steroid therapy. Only one patient, in the standard therapy group, had a secondary infection.

Discussion

Sepsis is a severe and life-threatening disease. Septic shock is associated with a mortality rate of more than 50%. Despite improvements in the overall management of such patients, including intensive fluid resuscitation, broad-spectrum antibiotic therapy, and life-support devices, mortality rates have not improved during the past decade [4]. In this randomized, double-blind study of the physiological dose of intravenous prednisolone or placebo in the treatment of sepsis, we observed an important difference in mortality rates between both groups. The mortality rates were 40% in the steroid therapy group and 60% in the standard treatment group. There was a trend towards a decrease in the mortality rate of the patients with sepsis who received physiological-dose steroid therapy. However, the differences were not statisti-μ cally significant (P = 0.343). Several factors were suspected to be associated with mortality in sepsis [30,31]. Annane et al. [17] reported that SOFA score, high plasma cortisol levels and weak response of cortisol to ACTH were also associated with mortality. However, we found that only SOFA score was related to mortality, independently of other factors (OR 2.07, 95% CI 1.02–4.22) in the multivariate analysis.

Briegel et al. [19] showed that stress doses of hydrocorti-sone reduce the time for the reversal of shock, the number of organ system failures, and the length of mechanical ventilation in patients with septic shock. This finding underlines the fact that an impaired adrenocortical function contributes to vascular hyporesponsiveness in septic shock. In contrast to other studies, our study was performed in patients with sepsis, severe sepsis and septic shock with the use of physiological-dose prednisolone with or without vasopressor support. Because the administration of prednisolone does not affect the circadian adrenocortical patterns and the results of an ACTH stimulation test in adults, we preferred to use this drug [32]. In this study we did not completely evaluate the effect of the steroid on patients with vasopressor-dependent septic shock. However, in a few patients, a physiological dose of prednisolone reduces the time for the reversal of shock as defined by the cessation of vasopressor therapy.

It is known that the plasma cortisol level increases in critical illnesses and that basal cortisol levels have a positive correlation with severity of illness and prognosis. However, some investigators [16,23,33,34,35] showed that patients with sepsis and high baseline cortisol levels had a lower cortisol response to the ACTH stimulation test. Our entire study group had higher mean random basal and stimulated cortisol levels than those seen in outpatients. The difference between the basal cortisol levels on the 1st and 14th days in patients who recovered was statistically significant (P < 0.0001) (Table 5). We have also shown that basal cortisol levels correlate with the severity of the illness, and that very high corti-sol levels signify a poor prognosis in the standard therapy group (Fig. 1).

Clinically significant AI is unusual in outpatients. The studies of adrenal function in critically ill patients report conflicting incidences of AI ranging from 0% to 28% [35,36,37]. Our results show a low incidence of AI in septic patients. One of our 40 patients had abnormal basal and peak cortisol levels (less than 20 g/dl) and died. This condition was evaluated as AI. In the advancing process from sepsis to septic shock, we concluded that AI was not so frequent as supposed.

In recent years, several authors have proposed a syndrome of occult AI in septic shock in the presence of normal or even elevated serum cortisol concentrations. Annane et al. [17] reported that 50% of patients with severe sepsis had occult AI. In the present study, 14 (35%) of the 40 patients had a subnormal cortisol response (occult AI). Five patients in the steroid treatment group had an inadequate cortisol response; two of them died. However, five of nine patients in the standard treatment group who showed inadequate cortisol response died. No statistical differences were observed in mortality rates between the patients who had occult AI (χ2 = 0.311, P = 1) (Fig. 1).

In conclusion, a physiological dose of intravenous pred-nisolone had a tendency towards a decrease in mortality in the patients with sepsis, but the difference between the two groups was not significant. Because our study had a small sample size and showed heterogeneity in population in terms of clinical severity, treatment with physiological-dose steroid in sepsis should be evaluated in a larger group of patients.

Key messages

· There was an increase in the level of basal cortisol in patients with sepsis.

· In the advancing process from sepsis to septic shock, adrenal insufficiency was not so frequent as supposed.

· Sepsis can cause occult adrenal insufficiency in the presence of normal or even elevated serum cortisol concentrations.

· Physiological-dose prednisolone therapy had a tendency towards a decrease in mortality in the patients with sepsis.

Competing interests

None declared.

Abbreviations

AI = adrenal insufficiency; APACHE = Acute Physiology and Chronic Health Evaluation; ACTH = corticotropin; CI = confidence interval; OR = odds ratio; SOFA = Sequential Organ Failure Assessment.

References

  1. 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.

    Chest 1992, 101:1644-1655. PubMed Abstract OpenURL

  2. Centers for Disease Control: Increase in national hospital discharge survey rates for septicemia – United States, 1979–1987.

    JAMA 1990, 263:937-938. PubMed Abstract OpenURL

  3. Angus DC, Wax RS: Epidemiology of sepsis: an update.

    Crit Care Med 2001, 29:S109-S116. PubMed Abstract | Publisher Full Text OpenURL

  4. Wheeler AP, Bernard GR: Treating patients with severe sepsis.

    N Engl JMed 1999, 340:207-214. Publisher Full Text OpenURL

  5. Natanson C, Hofmann WD, Suffredini AF, Eichacker PQ, Danner RL: Selected treatment strategies for septic shock based on proposed mechanism of pathogenesis.

    Ann Intern Med 1994, 120:771-783. PubMed Abstract | Publisher Full Text OpenURL

  6. Matthay M: A severe sepsis – a new treatment with both anticoagulant and antiinflammatory properties.

    N Engl J Med 2001, 344:759-762. PubMed Abstract | Publisher Full Text OpenURL

  7. Bernard GR, Vincent J-L, Laterre P-F, LaRosa SP, Dhainaut J-F, Rodriguez AL, Stein grub JS, Garber GE, Helterbrand JD, Ely EW, Fisher CJ: Efficacy and safety of recombinant human activated protein Cfor severe sepsis.

    N Engl JMed 2001, 344:699-709. Publisher Full Text OpenURL

  8. Bennet IL Jr, Finland M, Hamburger M, Kass EH, Lepper M, Wais-bren BA: The effectiveness of hydrocortisone in the management of severe infections.

    JAMA 1963, 183:462-465. OpenURL

  9. Schumer W: Steroids in the treatment of clinical septic shock.

    Ann Surg 1976, 184:333-341. PubMed Abstract | Publisher Full Text OpenURL

  10. The Veterans Administration Systemic Sepsis Cooperative Study Group: Effect of high-dose glucocorticoid therapy on mortality in patients with clinical signs of systemic sepsis.

    N Engl JMed 1987, 317:659-665. OpenURL

  11. Bone RC, Fisher CJ, Clemmer TP, Slotman GJ, Metz CA, Balk RA: A controlled clinical trial of high-dose methylprednisolone in the treatment of severe sepsis and septic shock.

    N Engl JMed 1987, 317:653-658. OpenURL

  12. Sprung CL, Caralis PV, Marcial EH, Pierce M, Gelhard MA, Long WM, Duncan RC, Tendler MD, Karpf M: The effect of high-dose corticosteroids in patients with septic shock: a prospective, controlled study.

    N Engl JMed 1984, 311:1137-1143. OpenURL

  13. Jenkins RC, Ross RJM: The endocrinology of the critically ill: current Opinion.

    Curr OpinEndocrinol Diab 1996, 3:138-145. OpenURL

  14. Jurney TH, Cockrell JL Jr, Lindberg JS, Lamiell JM, Wade CE: Spectrum of serum cortisol response to ACTH in ICU patients: correlation with degree of illness and mortality.

    Chest 1987, 92:292-295. PubMed Abstract OpenURL

  15. Chrousos GP: The hypothalamic–pituitary–adrenal axis and immune mediated inflammation.

    N Engl J Med 1995, 332:1351-1362. PubMed Abstract | Publisher Full Text OpenURL

  16. Aygen B, Inan M, Doganay M, Kelestimur F: Adrenal functions in patients with sepsis.

    Exp Clin Endocrinol Diab 1997, 105:182-186. OpenURL

  17. Annane D, Sebille V, Troche G, Raphael J-C, Gajdos P, Bellissant E: A 3-level prognostic classification in septic shock based on cortisol levels and cortisol response to corticotropin.

    JAMA 2000, 283:1038-1045. PubMed Abstract | Publisher Full Text OpenURL

  18. Bollaert PE, Charpentier C, Levy B, Debouverie M, Audibert G, Larcan A: Reversal of late septic shock with supraphysiologic doses of hydrocortisone.

    Crit Care Med 1998, 26(4):645-50. PubMed Abstract | Publisher Full Text OpenURL

  19. Briegel J, Forst H, Haller M, Schelling G, Kilger E, Kuprat G, Hemmer B, Hummel T, Lenhart A, Heyduck M, Stoll C, Peter K: Stress doses of hydrocortisone reverse hyperdynamic septic shock: a prospective, randomized, double-blind, single-center study.

    Crit Care Med 1999, 27:723-732. PubMed Abstract | Publisher Full Text OpenURL

  20. Oelkers W: Adrenal insufficiency.

    N Engl J Med 1996, 335:1206-1212. PubMed Abstract | Publisher Full Text OpenURL

  21. Oelkers W: Dose-response aspects in the clinical assessment of the hypothalamo-pituitary-adrenal axis, and the low-dose adrenocorticotropin test.

    Eur J Endocrinol 1996, 135:27-33. PubMed Abstract OpenURL

  22. Kelestimur F, Akgün A, Günay O: A comparison between short synacthen test and depot synacthen test in the evaluation of cortisol reserve of adrenal gland in normal subject.

    J Endocrinol Invest 1995, 18:823-826. PubMed Abstract OpenURL

  23. Rothwell PM, Udwadia ZF, Lawler PG: Cortisol response to corticotropin and survival in septic shock.

    Lancet 1991, 337:582-583. PubMed Abstract | Publisher Full Text OpenURL

  24. Grinspoon SK, Biller BM: Clinical review 62 laboratory assessment of adrenal insufficiency.

    J Clin Endocrinol Metab 1994, 79:923-931. PubMed Abstract OpenURL

  25. McCabe WR, Jackson GG: Gram-negative bacteremia I: etiology and ecology.

    Arch Intern Med 1962, 110:847-863. OpenURL

  26. Geerdes HF, Ziegler D, Lode H, Hund M, Loehr A, Fangmann W, Wagner J: Septicemia in 980 patients at a university hospital in Berlin: prospective studies during 4 selected years between 1979 and 1989.

    Clin Infect Dis 1992, 15:991-1002. PubMed Abstract OpenURL

  27. Valles J, Leon C, Lerma FA: Nosocomial bacteremia in critically ill patients: a multicenter study evaluating epidemiology and prognosis.

    Clin Infect Dis 1997, 24:387-395. PubMed Abstract OpenURL

  28. Knaus WA, Draper EA, Wagner DP, Zimmerman JE: APACHE II: a severity of the disease classification system.

    Crit Care Med 1985, 13:818-829. PubMed Abstract OpenURL

  29. Vincent JL, Moreno R, Takala J: The SOFA (Sepsis-related Organ Failure Assessment) score to describe organ dysfunction/failure.

    Intensive Care Med 1996, 22:707-710. PubMed Abstract | Publisher Full Text OpenURL

  30. Calandra T, Baumgartner JD, Grau GE, Wu MM, Lambert PH, Schellekens J, Verhoef J, Glauser MP: Prognostic values of tumor necrosis factor/cachectin, interleukin 1, interferon α, interferon γ in the serum of patients with septic shock.

    J Infect Dis 1990, 161:982-987. PubMed Abstract OpenURL

  31. Bone RC, Fisher CJ Jr, Clemmer TP, Slotman GJ, Metz CA, Balk RA: Sepsis syndrome.

    Crit Care Med 1989, 17:389-393. PubMed Abstract OpenURL

  32. Carella MJ, Srivastava LS, Gossain VV, Rovner DR: Hypothalamic–pituitary–adrenal function one week after a short burst of steroid therapy.

    J Clin Endocrinol Metab 1993, 76(5):1188-1191. PubMed Abstract OpenURL

  33. Wade CE, Lindberg JS, Cockrell JL, Lamiell JM, Hunt MM, Ducey J, Jurney TH: Upon-admission adrenal steroidogenesis is adapted to the degree of illness in intensive care unit patients.

    J Clin Endocrinol Metab 1988, 67:223-227. PubMed Abstract OpenURL

  34. Reincke M, Allolio B, Würth G, Winkelman W: The hypothalamic–pituitary–adrenal axis in critical illness: response to dex-amethasone and corticotropin releasing hormone.

    J Clin Endocrinol Metab 1993, 77:151-156. PubMed Abstract OpenURL

  35. Sibbald WJ, Short A, Cohen MP, Wilson RF: Variations in adrenocortical responsiveness during severe bacterial infections. Unrecognized adrenocortical insufficiency in severe bacterial infections.

    Ann Surg 1977, 186:29-33. PubMed Abstract OpenURL

  36. Finlay WEI, McKee JI: Serum cortisol levels in severely stressed patients.

    Lancet 1982, 1:1414-1415. PubMed Abstract | Publisher Full Text OpenURL

  37. McKee JI, Finlay WE: Cortisol replacement in severely stressed patients.

    Lancet 1983, 1:484. PubMed Abstract | Publisher Full Text OpenURL