Sepsis is the appearance of systemic signs and symptoms of the infection, in the presence of the infection. Severe sepsis is sepsis complicated by deterioration of tissue perfusion and organ dysfunction. Septic shock occurs when hypotension in patients with sepsis does not improve despite the proper hydration (1).
Approximately one-quarter of sepsis cases are fatal (2,3). Therefore quick and accurate sepsis management is crucial.
The first animal experiments published nearly forty years ago showed that steroid therapy improved survival in endotoxic shock. As a result of those studies, steroid therapy was started to be addressed in clinical trials (4,5).
Steroid dose used in some of the clinical trials was increased up to 30-120 mg/kg/day of methylprednisolone or equivalent. However, the negative results of the treatment at this dose were observed as well. In fact, a meta-analysis has proved that high-dose steroids increases mortality in septic patients (6). But in subsequent years, clinical studies have revealed ample evidence on the benefits of physiological doses of steroids (7,8,9,10,11).
Exposure to stress starts a series of responses that are interrelated in organism, but also complex, and have central and peripheral terminals. These responses are intended to increase survival. This phenomenon, known as stress response, is governed by two principal systems; sympathetic nervous system and the hypothalamic-pituitary-adrenal axis (HPA) (12). Due to the activation of the HPA axis, steroid synthesis increases and as such, steroid regulates immune, cardiovascular and metabolic changes in order to cope with stress.
The primary glucocorticoid secreting by the adrenal cortex is cortisol. Cortisol is not a hormone stored in the adrenal and it has a half-life of 70 to 120 minutes (13). In the circulation, 90% of cortisol is transported by cortisol-binding globulin (CBG) (13). In the cell, cortisol binds to the intracellular glucocorticoid receptor (GR). With this binding, steroid-receptor complex gets activated and moves to the nucleus. In the nucleus, steroid-receptor complex binds to the particular regions in DNA that are called glucocorticoid response elements (GRE). Consequently, the transcription of the related genes and protein synthesis are carried out as such (15) (Figure 1). Besides managing the transcription process in thousands of genes, cortisol may intervene with other transcription factors as well. The most significant of these is nuclear factor kappa beta (NF-κB). NF-κB is responsible for the synthesis of important cytokines such as the interleukins and tumor necrosis factor, and inhibits cortisol NF-κB (16).
It was found that, in acute disease, some changes occurred in cortisol’s production, transportation and cellular effects. In acute disease, CBG levels are decreased by almost half and the free cortisol levels are increased (17). In experimental models, pro-inflammatory cytokines and endotoxins have been shown to decrease the number of GR, GR’s translocation, and the affinity of the steroid receptor complex to DNA. This situation indicates that steroid resistance, usually observed during chronic inflammatory conditions like chronic obstructive pulmonary disease, might be present in the acute inflammation as well. In another study, it has been proven that cortisol, measured from the interstitium by microdialysis method, only moderately correlates with plasma cortisol (18). This means that cortisol levels in the circulation are not necessarily a direct indicator of its effects in the tissue.
These changes complicate the task of defining the adrenal insufficiency in sepsis. But the challenges facing clinicians are not limited with these. Usually, adrenal insufficiency is diagnosed through the ACTH stimulation test. 9 mcg/dl or more increase in cortisol (delta cortisol) following a 250 mcg intravenous ACTH excludes the diagnosis of adrenal insufficiency (19). Studies shows that steroid therapy reduces mortality in patients with sepsis, who were diagnosed with adrenal insufficiency by using this test (7,9). However, study results published recently has suggested that this test might not be reliable. Investigating the effects of steroid therapy in patients with sepsis, this multicenter, randomized, controlled study has been shown that steroid therapy has no effect on mortality whether or not the patient responds to ACTH (20). ACTH stimulation test might give an idea about the function of the adrenal glands but does not reveal whether the HPA axis is normal or not. For this reason, manuals do not recommend steroid therapy to be planned based on the ACTH stimulation test in septic patients (21,22).
Likewise, the measurements of free cortisol levels are not recommended in the manuals (21,22). The reason behind this is the fact that the free cortisol measurement cannot be performed in every laboratory. In addition, the normal level of free cortisol in septic patients has not yet been clearly established. Etomidate, that is used in the intensive care for induction of anesthesia prior to the intubation, is also known to suppress the HPA axis (23).
All of these factors clearly show that, there is no good laboratory test in the hands of clinicians to diagnose the relative or absolute adrenal insufficiency. A guide published in 2008 has been proposed the “critical illness associated adrenal insufficiency” as a definition instead of “relative or absolute adrenal insufficiency” (22).
This definition includes both the lack of adrenal steroid production and the immeasurable changes in tissue levels; and does not specify a threshold laboratory value.
Regarding the use of steroids in sepsis, there are numerous clinical studies with different results. In recent years these studies have been examined through meta-analyses. In a compilation including 12 studies, Annane et al. report that low-dose hydrocortisone accelerates the recovery time from the shock and remarkably reduces 28-day mortality rate (RR, 0.84; 95% CI, 0.72-0.97, p=0.02). (6) Minecci et al. has obtained similar results in their meta-analysis (24). In another meta-analysis, Sligl et al. was more selective in choosing the cases and evaluated 8 studies (6 of them being good level randomized, controlled studies), and argued that steroid accelerates the recovery from the shock but it has no effect on mortality (RR, 1.00; 95% CI, 0.84 to 1.18) (25). In sepsis manual published in 2013, according to an assessment among evidences, in three of the 6 selected studies which used hydrocortisone for sepsis treatment, mortality was relatively lower than the others but in these studies hydrocortisone therapy had no effect on mortality. In the other three studies with higher mortality, a non-significant reduction in mortality was observed (22).
Out of the two most comprehensive studies regarding the use of steroids in sepsis, the first one is the multicenter study of Annane and colleagues held in France, and the other is a multicenter study called CORTICUS that was conducted in Europe. Both studies were designed as randomized, double-blind, and placebo controlled.
Annane et al. worked with 300 patients with sepsis. To septic shock patients, who are not responding to vasopressors, 4x50 mg hydrocortisone and 50 mcg fludrocortisone treatment was administered for five days. This treatment had started within 8 hours after patients were diagnosed with sepsis. In this study, patients with delta cortisol lower than 9mcg/dl after ACTH stimulation test had been considered as non-responders. In ACTH non-responder cases, hydrocortisone treatment had been shown to accelerate the recovery time from the shock and reduce mortality (7). According to this study, there was no infection or an increased incidence of gastrointestinal bleeding in the steroid receiving group.
In CORTICUS, 500 patients with septic shock were included in the study. The use of hydrocortisone was started in the first 72 hours at a dose of 4x50 mcg. But in this study, it was proven that steroid has no effect on the mortality in any cases, whether responded to ACTH or not. Shock recovery appeared faster in the steroid receiving group despite their ACTH response. In the steroid group, the recurrence of shock and the risk of infection was increased, though statistically insignificant. CORTICUS authors do not recommend steroid therapy in septic shock (20).
The comparative summary of these two studies is shown in Table 1. In CORTICUS, the 28-day mortality rate is lower in the placebo cases, that is, it can be said that this study includes sepsis patients in relatively good conditions. In CORTICUS, the ratio of surgical patients is higher. Between this study and the one held in France, the main differences are the latter’s inclusion of only sepsis patients with no vasopressors response, the rapid initiation of the treatment and the high mortality in the placebo group.
Current clinical approach to the diagnosis and treatment of adrenal insufficiency associated with sepsis:
The American Critical Care Medicine Manual was published in 2008. This manual proposes the consideration of hydrocortisone treatment in patients with septic shock who have no response to fluid and vasopressor therapy. Authors have been described this proposal as a recommendation based on weak and/or moderate evidence (22). Recommended diagnostic threshold of this guide is 10 mcg/dl or lower cortisol level or a cortisol increase (delta cortisol) of lower than 9 mcg/dl after the cosintrophyn test. As the threshold in sepsis patients is not known, free cortisol measurement is not recommended. Regarding the dose, this guide recommandes a 200 mg/day of hydrocortisone in four divided doses or 10mg/hour infusion after 100mg bolus hydrocortisone (240 mg).
The sepsis manual of Canadian Association of Emergency Physicians, that was published in the same year, repeats the same recommendations regarding which patient should be given steroids. This is a Level D recommendation, which means that it was based on contradictory results (26). Hydrocortisone dose recommended by this manual is 200-300 mg/day. Administration of an ACTH stimulation test before medical treatment is optional, but steroids should be given based on the clinical requirements prior to the test results. Canadian manual recommends 4-6 mg intravenous dexamethasone to emergency physicians as another option. In this situation, tests can be administered later as dexamethasone does not affect ACTH and serum cortisol.
In 2010, the German Hematology Oncology Association published a guide not recommending the steroid use for sepsis in neutropenic patients, a suggestion based on moderate contradictory evidence (27).
The most comprehensive and up to date manual about sepsis was published in February 2013. This guide proposes the consideration of hydrocortisone in septic shock patients with no response to fluid and inotropic agents. This is a Level C recommendation, that means a low-level evidence-based, weak suggestion (21). Recommended dose is 200 mg/day hydrocortisone. Authors argue that in patients with sepsis, cortisol measurement tests conducted anytime in patient’s history would not reveal accurate results and ACTH stimulation test is unnecessary. Steroid therapy should be tapered slowly after the elimination of the need for vasopressors.
Sepsis is a complex process affecting many systems and involves different response mechanisms. In septic patients, steroids, both in the HPA axis and intracellularly, are dissimilar to a healthy person. Thus there is no reliable test to detect the steroid sufficiency in sepsis. Clinical studies give conflicting information about the effects of steroids in sepsis mortality. In the light of current manuals, steroid therapy is thought to be appropriate to sepsis patients whose hypotension does not improve despite proper support for vasopressor and the proper hydration. Yet stronger evidence derived from randomized controlled trials are necesssary to define this treatment as conclusive.
1. Dellinger RP, Levy MM, Rhodes A, et al. Surviving Sepsis Campaign Guidelines Committee including the Pediatric Subgroup. Surviving sepsis campaign: international guidelines for management of severe sepsis and septic shock: 2012. Crit Care Med 2013;41:580-637.
2. Dellinger RP. Cardiovascular management of septic shock. Crit Care Med 2003;31:946-55.
3. Uyar M. ARDS and Sepsis: Current Evaluation and Treatment. Turkiye Klinikleri J Orthop & Traumatol-Special Topics 2012;5:26-32.
4. Hinshaw LB, Coalson JJ, Benjamin BA et al. Escherichia coli shock in the baboon and the response to adrenocorticosteroid treatment. Surg Gynecol Obstet 1978;147:545-57.
5. Pingleton WW, Coalson JJ, Hinshaw LB, Guenter CA. Effects of steroid pretreatment on development of shock lung. Hemodynamic, respiratory, and morphologic studies. Lab Invest 1972;27:445-56.
6. Zeni F, Freeman B, Natanson C. Anti-inflammatory therapies to treat sepsis and septic shock: a reassessment. Crit Care Med 1997;25:1095-100.
7. Annane D, Sébille V, Charpentier C,et al. Effect of treatment with low doses of hydrocortisone and fludrocortisone on mortality in patients with septic shock. JAMA 2002;288:862-71.
8. Briegel J, Forst H, Haller M, et al. Stress doses of hydrocortisone reverse hyperdynamic septic shock: a prospective, randomized, double-blind, single-center study. Crit Care Med 1999;27:723-32.
9. Bollaert PE, Charpentier C, Levy B, Debouverie M, Audibert G, Larcan A.Reversal of late septic shock with supraphysiologic doses of hydrocortisone. CritCare Med 1998;26:645-50.
10. Oppert M, Schindler R, Husung C, Offermann K, Gräf KJ, Boenisch O, et al. Low-dose hydrocortisone improves shock reversal and reduces cytokine levels in early hyperdynamic septic shock. Crit Care Med 2005;33:2457-64.
11. Yildiz O, Doganay M, Aygen B, ve ark. Physiological-dose steroid therapy in sepsis. Crit Care 2002;6:251-59.
12. Carrasco GA, Van de Kar LD. Neuroendocrine pharmacology of stress. Eur J Pharmacol 2003;463:235-72.
13. Arlt W, Stewart PM. Adrenal corticosteroid biosynthesis, metabolism, and action. Endocrinol Metab Clin North Am 2005;34:293-313.
14. Mueller UW, Potter JM. Binding of cortisol to human albumin and serum: the effect of protein concentration. Biochem Pharmacol. 1981;30:727-33.
15. Rhen T, Cidlowski JA. Antiinflammatory action of glucocorticoids--new mechanisms for old drugs. N Engl J Med 2005;353:1711-23
16. Barnes PJ, Adcock I. Anti-inflammatory actions of steroids: molecular mechanisms. Trends Pharmacol Sci 1993;14:436-41
17. Dimopoulou I, Alevizopoulou P, Dafni,et al. Pituitary-adrenal responses to humancorticotropin-releasing hormone in critically ill patients. Intensive Care Med 2007;33:454-9.
18. Vassiliadi DA, Ilias I, Tzanela M, et al. Interstitial cortisol obtained by microdialysisin mechanically ventilated septic patients: correlations with total and free serum cortisol. J Crit Care 2013;28:158-65.
19. Marik PE, Zaloga GP. Adrenal insufficiency in the critically ill: a new look at an old problem. Chest 2002122:1784-96.
20. Sprung CL, Annane D, Keh D, Moreno R, Singer M, Freivogel K, et al. CORTICUS Study Group. Hydrocortisone therapy for patients with septic shock. N Engl J Med 2008;358:111-24.
21. Dellinger RP, Levy MM, Rhodes A, et al. Surviving Sepsis Campaign Guidelines Committee including the Pediatric Subgroup. Surviving sepsis campaign: international guidelines for management of severe sepsis and septic shock: 2012. Crit Care Med 2013;41:580-637.
22. Marik PE, Pastores SM, Annane D, et al. American College of Critical Care Medicine. 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 2008;36:1937-49.
23. Allolio B, Dörr H, Stuttmann R, et al. Effect of a single bolus of etomidate upon eight major corticosteroid hormones and plasma ACTH. Clin Endocrinol (Oxf) 1985;22:281-6.
24. Minneci PC, Deans KJ, Banks SM, Eichacker PQ, Natanson C. Meta-analysis: the effect of steroids on survival and shock during sepsis depends on the dose. Ann Intern Med 2004;141:47-56.
25. Sligl WI, Milner DA Jr, Sundar S,et al. Safety and efficacyof corticosteroids for the treatment of septic shock: A systematic review and meta-analysis. Clin Infect Dis 2009;49:93-101.
26. Green RS, Djogovic D, Gray S, et al. CAEP Critical Care Interest Group. Canadian Association of Emergency Physicians Sepsis Guidelines: the optimal management of severe sepsis in Canadian emergency departments. CJEM 2008;10:443-59.
27. Penack O, Buchheidt D, Christopeit M, von Lilienfeld-Toal M, Massenkeil G, Hentrich M, et al; German Society of Hematology and Oncology. Management of sepsis in neutropenic patients: guidelines from the infectious diseases working party of the German Society of Hematology and Oncology. Ann Oncol 2011;22:1019-29.