|Year : 2014 | Volume
| Issue : 2 | Page : 80-84
Incidence of adrenal insufficiency and its relation to mortality in patients with septic shock
Jugendra Singh1, Avinash Agrawal1, Manish Gutch2, Shuchi Consul3, Ali Abbas Mahdi4, Ajai Singh5, Sukriti Kumar6
1 Department of Internal Medicine, King George's Medical University, Lucknow, Uttar Pradesh, India
2 Department of Endocrinology and Metabolism, LLRM Medical College, Meerut, Uttar Pradesh, India
3 Casualty Medical Officer, King George's Medical University, Lucknow, Uttar Pradesh, India
4 Department of Biochemistry, King George's Medical University, Lucknow, Uttar Pradesh, India
5 Department of Orthopedics, King George's Medical University, Lucknow, Uttar Pradesh, India
6 Department of Radiodiagnosis, SGPGI, Lucknow, Uttar Pradesh, India
|Date of Web Publication||13-Nov-2014|
Dr. Manish Gutch
Department of Endocrinology and Metabolism, LLRM Medical College, Meerut, Uttar Pradesh
Source of Support: None, Conflict of Interest: None
Background: The hypothalamic pituitary adrenal axis has a pivotal role in combating acute insults. Glucocorticoids play a role directly or indirectly in the maintenance of normal vascular tone and in potentiating the vasoconstrictor action of catecholamine, associated with septic shock. Aims: The aim was to determine the incidence of adrenal insufficiency (AI) and its relation to mortality in patients with septic shock. Settings and Design: A prospective observational study carried out at Tertiary Care Center. Materials and Methods: In patients of septic shock, acute physiology and chronic health evaluation II (APACHE II) score was calculated and serum cortisol was measured at the time of admission and 1 h after giving 250 μg adrenocorticotrophin hormone (ACTH). Hydrocortisone was added to inotropics in all patients after drawing second blood sample for serum cortisol and was continued till 7 days or less. In our study, the patients with inadequate adrenal response were divided into two groups: (1) Absolute AI - baseline cortisol <20 μg/dL and increment ≤9 μg/dL after the ACTH stimulation test; (2) relative AI - patients with baseline cortisol ≥20 μg/dL and increment ≤9 μg/dL. Statistical Analysis Used: Data were analyzed with SPSS version 17 and were presented in the values of mean, median, and percentages. P < 0.05 was considered to be significant. Results: The incidence of AI in septic shock was (N = 100) was 42% (in absolute 14%, relative 28%).The incidence of AI in septic shock was 42% (absolute 14%, relative 28%). The mortality rate was 48%, and it was higher in patients with AI than in patients without AI (P = 0.017). The APACHE II score >25 carried higher mortality rate than a score of ≤25 (P ≤ 0.001). Baseline serum cortisol >45 μg/dl had exceptionally high likelihood of mortality (OR: 50, P ≤ 0.001). Among those who survived, inotropic support was required for a longer period in relative when compared to absolute AI and to non-AI. Conclusions: AI is prevalent among patients with septic shock. We found that higher APACHE scores were associated with higher rates of adrenal failure and mortality in patients with septic shock. There also appears to be a bimodal distribution of mortality with adrenal status in patients with septic shock.
Keywords: Adrenal insufficiency, hydrocortisone, septic shock, serum cortisol
|How to cite this article:|
Singh J, Agrawal A, Gutch M, Consul S, Mahdi AA, Singh A, Kumar S. Incidence of adrenal insufficiency and its relation to mortality in patients with septic shock. Afr J Med Health Sci 2014;13:80-4
|How to cite this URL:|
Singh J, Agrawal A, Gutch M, Consul S, Mahdi AA, Singh A, Kumar S. Incidence of adrenal insufficiency and its relation to mortality in patients with septic shock. Afr J Med Health Sci [serial online] 2014 [cited 2019 Jul 24];13:80-4. Available from: http://www.ajmhs.org/text.asp?2014/13/2/80/144566
| Introduction|| |
Adrenal insufficiency (AI) should be suspected in critically ill hypotensive patients who respond poorly to fluid resuscitation and vasopressor therapy. Occult AI is independently associated with increased mortality in Intensive Care Unit (ICU) irrespective of the normal baseline serum cortisol, and it could be an important aspect of shock in sepsis, which is frequently overlooked in the most of the protocols used in the management of septic shock. ,,
| Pathogenesis|| |
Many factors can impair the cortisol response to adrenocorticotrophin hormone (ACTH) in patients with critical illness. Cortisol synthesis can be hampered due to (preexisting) disease of the hypothalamus, pituitary or adrenals, by drug administration, due to inflammatory cytokines and infection, by increased tissue resistance to cortisol, by substrate deficiency, or by decreased cortisol delivery to tissues. Hypothalamic/pituitary gland necrosis has been reported in patients with sepsis with resultant decreased synthesis of corticotropin-releasing hormone (CRH) and ACTH. Other than this, high levels of inflammatory cytokines in state of critical illness can lead to impaired cortisol synthesis. ,, For example, tumor necrosis factor alpha impairs CRH-stimulated ACTH-release and inhibits the stimulatory actions of ACTH on the adrenals in cortisol synthesis. , Proinflammatory cytokines and sepsis have been demonstrated to modulate numbers, expression and function of the glucocorticoid receptor. , Relative adrenal insufficiency may also arise due to altered binding activity of the receptor and altered uptake of cortisol by its receptor in peripheral target organs or due to impaired activity of the glucocorticoid receptor at the nuclear level of the target cell. Peripheral tissue resistance to glucocorticoids may also result from the use of drugs.  Overall, loss of function of the glucocorticoid receptor mainly exaggerates the systemic inflammatory response.
The normal protective response of hypothalamic pituitary adrenal (HPA) axis is to raise the level of stress hormones such as glucocorticoids, epinephrine, and norepinephrine during the stress. There are a number of unexplained factors, which may contribute to the development of AI in septic shock. The various mechanisms hypothesized for AI to occur in septic shock are the inflammatory cytokines-mediated suppression of HPA axis , and tissue corticosteroid resistance, etc. 
It has been observed that despite high-plasma cortisol level, low-corticotropin response in sepsis is associated with higher risks of morbidity and mortality.  In some previous studies, benefit of treatment with corticosteroids was observed in patients of vasopressor-dependent shock.  It has also been observed that corticosteroids have mortality benefits in patients of severe sepsis and septic shock because corticosteroids increase the responsiveness to adrenaline and noradrenaline and also modulate the inflammatory response towards the protective mode. , Therefore, it would be prudent to identify those who would have AI and could have the benefit with hydrocortisone therapy. This endeavor was undertaken to determine the incidence of AI and its relation to mortality in patients with septic shock.
| Materials and Methods|| |
The patients with septic shock admitted to the medical ICU of our institute in between July 2010 and June 2011 were studied. The diagnosis of septic shock was made in accordance with the criteria proposed by American College of Chest Physicians.
All patients had their serum cortisol measured at the time of admission and 1 h after giving 250 μg adrenocorticotropic hormone ACTH; then hydrocortisone (50 mg intravenously every 6 hourly) was started, and it was continued for 7 days or less according to the hemodynamic response in patients who were found to have AI. In those patients who did not have AI, hydrocortisone was discontinued on the next day. Two criteria were used to make a diagnosis of AI: Basal serum cortisol levels <20 μg/dL and increment ≤9 μg/dL after the ACTH stimulation test. Patients with baseline cortisol ≥20 μg/dL and increment ≤9 μg/dl after the ACTH stimulation test was used to diagnose relative AI. , The acute physiology and chronic health evaluation II (APACHE II) score was used to monitor the progress of critical illness of patients.  APACHE II score was evaluated at the time of admission, and patients were categorized into three groups; 1 st with score <10, 2 nd with score 10-25, and 3 rd with score >25. The mortality rate at the end of 28 days after hospitalization was compared between patients with AI to patients without AI. Data were analyzed by Statistical Package for the Social Sciences (SPSS) version 17, and results were interpreted in the values of mean, median, and percentages. P < 0.05 was considered to be significant.
| Results|| |
Of total 100 admitted patients, 58 patients were in the age group of 21-60 years. Males were 42, and females were 58. AI was found in 42% patients (absolute AI in 14, relative AI in 28). AI was more common in female when compared to male (26/58 vs. 16/42, P = 0.002). In our study, 50% of the patients with relative AI were from age group 21 to 40, and 72% of absolute AI were in the age group of 41-60 years (P = 0.001). As shown in [Table 1], the most common etiology attributed to septic shock was a lung infection (38%) followed by central nervous system infections (18%). The maximum numbers of patients had APACHE II score in between 10 and 25 [Table 2]. In 28 patients, APACHE II score was >25 and in 72 patients, it was <25 (P = 0.004). The mean serum cortisol value of first measurement taken at the time of admission was 29.6 ± 17.7 μg/dl and second after 1 h of giving 250 μg of ACTH was 36.75 ± 17 μg/dl. At the time of admission, the baseline serum cortisol value <10 μg/dl was found in 8 patients and all of them expired. Absolute AI was seen more commonly when APACHE score was >25, whereas most of the patients with relative AI had APACHE II score in between 10 and 25. The total mortality rate was 48% and was significantly higher in patients with AI than in those with non-AI (26/42 vs. 22/58, P = 0.018). However, the mortality was not significantly varied between absolute AI and relative AI (10/14 vs. 16/28, P = 0.37). The patients with absolute AI had a high likelihood of mortality than non-AI (odds ratio 4.09, P = 0.035), but the trend for relative AI was not significant [Table 3]. The APACHE II score of >25 carried a higher mortality rate than a score of ≤25 (26/ 28 vs. 22/72, P ≤ 0.001). In the survivor group, the requirement of inotropic support for days was in the order of: Non AI < absolute AI < relative AI (2.17 ± 0.4 in non-AI, 3.50 ± 2.9 in absolute AI, 9.29 ± 3.2 in relative AI, P ≤ 0.001).
|Table 1: Distribution of adrenal insuffi ciency according to etiology of sepsis|
Click here to view
|Table 2: Distribution of adrenal insuffi ciency according to APACHE II score|
Click here to view
|Table 3: The variables affecting the primary end point (mortality at the end of 28 days) in septic shock|
Click here to view
| Discussion|| |
In our study, the occurrence of AI in septic shock is similar to that reported in previous studies. Shenker and Skatrud  reported AI in 59% (relative AI 70% and absolute AI 13%). In a study by Rivers et al.,  the prevalence of relative AI and absolute AI were 54% and 21%, respectively, while AI with shock was found in 76%. The present study showed that the high mortality (around half of the patients) occurred in patients with septic shock. The mortality rate was significantly higher in patients with AI than in those without AI (P = 0.018). Moreover, the patients with absolute AI had a higher likelihood of mortality compared with non-AI (odds ratio [OR] 4.09, P = 0.035), but not significantly higher compared to relative AI (OR: 2.18, P = 0.10).
We have found that relative AI was more common in younger the age group, whereas absolute AI was more common in the older age group. In most of the studies, age could not be related with AI in patients with septic shock. ,, However, in a few reports AI was more common in the older age group,  and one study, the mean age was 64 years.  The lower mean age in our study could be due to more number of young patients being admitted to ICU or to geographical or racial factors. Another reason for this disparity could be fewer elderly patients having access to tertiary care facilities.
In this study, male patients predominantly presented with relative AI in contrast with females, who mainly presented with absolute AI (P = 0.002). This could be a social factor rather than a coincidence as decision making and finance lies with the males. This would appear to be a coincidental finding.
Earlier studies by Venkatesh et al., Marik et al., and Annane et al.  have not shown any relationship with the different etiologies of sepsis or any preponderance for having AI. In contrast, Chen et al. showed a positive correlation of AI with pneumonia. Bornstein et al.  have tried to correlate predisposing factors with AI and found that intra-abdominal sepsis was associated with relative AI.
Absolute AI was more common when APACHE II score was >25, whereas, most of the patients with relative AI had APACHE II score of 10-25. APACHE II score >25 was associated invariably with fatal outcome. The odds of 19 were seen when compared for outcome in between APACHE II score of >25 and to a score of 10-25. This was concordant to the study conducted by Mpe et al.  Non-survivors had significantly higher APACHE II score (27 ± 4) than the survivors where APACHE II score was 16 ± 4. Similar study conducted by Krishna and Shivakumar  found that the APACHE II score was higher among non-survivors than survivors. In a study by Annane et al.,  where 90% of the patients of severe sepsis and septic shock had high APACHE II score of 29 ± 5.
Of interest, 26 patients had high-baseline serum cortisol (>45 μg/dl), out of whom, 84.6% (22/26) patients had APACHE II score of >25 with a mortality rate of 77% (20/26). Mpe et al., have also shown that patients with "adequate" adrenal function had higher illness severity scores when compared with those with adrenal failure (15.42 vs. 12.58, P = 0.023). Marik and Zaloga  believes that the conflicting reports reflect a bimodal distribution of mortality in relationship to the random cortisol level during sepsis, that is, patients having extremely low (<25 μg/dl) or high levels (>45 μg/dl) having the highest mortality rates.
A multicenter French study published by Annane et al.  in 2002, demonstrated the benefit of hydrocortisone 200 mg/day with enteral fludrocortisone in vasopressor-refractory septic shock patients. However, the 2008 corticosteroid therapy of septic shock (CORTICUS) study found that a similar population of septic shock patients failed to demonstrate a reduction in mortality with corticosteroids, but the shock resolved faster in these patients.  There are several key differences between these studies. Both studies enrolled patients with persistent hypotension despite vasopressor therapy, but patients in the French study were enrolled within 8 h of septic shock onset, whereas patients in the CORTICUS study were enrolled up to 72 h. A greater proportion of surgical patients was in the CORTICUS study, suggesting that primary site control may be more important for reversal of septic shock in surgical patients.
Additionally, dosing was slightly different; the French study administered hydrocortisone 50 mg intravenously every 6 h for 7 days and did not taper, but the CORTICUS trial used the same dosing strategy for 5 days and tapered over 6 days. Tapering is not typically necessary for steroid treatments lasting shorter than 7 days, but there is an increased likelihood of a rebound in inflammatory mediators with abrupt discontinuation. 
Conversely, if patients have been receiving corticosteroids chronically, a taper should be considered as patients may exhibit long-term HPA axis suppression. While fixed duration and symptom-driven duration of corticosteroids have been advocated, the guidelines recommend tapering slowly in patients with critical illness-related corticosteroid insufficiency.  Therapy duration should be guided by the resolution of symptoms initially leading to the diagnosis of critical illness-related corticosteroid insufficiency.
Based on the available evidence, the critical illness-related corticosteroid insufficiency guidelines recommend that, when initiated early, hydrocortisone 200-300 mg/day may be beneficial in reducing mortality in septic shock patients who remain hypotensive despite adequate resuscitation and vasopressor therapy; this intervention was also recommended in the 2008 surviving sepsis campaign. 
Benefits of corticosteroid replacement during critical illness has been demonstrated in a number of other patient populations including acute respiratory distress syndrome, severe community-acquired pneumonia, high-risk cardiac surgery, weaning from mechanical ventilation and post-traumatic stress disorder. ,,,
Methylprednisolone use is recommended in patients with early severe acute respiratory distress syndrome or in persistent acute respiratory distress syndrome prior to day 14, as one study showed no benefit in late acute respiratory distress syndrome when started after 14 days duration. ,
We have observed that patients with AI required vasopressor support for a longer time than patients without AI. Only the patients with absolute AI insufficiency and patients of non-AI, with a high level of serum cortisol (>45 μg/dl) showed a response to vasopressor therapy. There was no response in patients with relative AI in septic shock. The study has one important limitation as it is comprised of a small number of subjects. We would like to conclude that AI was prevalent among patients with septic shock, and it lead to a prolonged duration of a shock and a prolonged requirement of vasopressors. In septic shock with AI, despite treatment with hydrocortisone, these patients had higher mortality compared to those who did not have AI; the higher mortality risk was most likely with absolute AI. The mortality risk was also high when baseline serum cortisol was more than >45 μg/dl. We would like to recommend evaluating the adrenal status in patients with septic shock because it would entail prognosis.
| References|| |
Beishuizen A, Thijs LG. Relative adrenal failure in intensive care: An identifiable problem requiring treatment? Best Pract Res Clin Endocrinol Metab 2001;15:513-31.
Prigent H, Maxime V, Annane D. Clinical review: Corticotherapy in sepsis. Crit Care 2004;8:122-9.
Cooper MS, Stewart PM. Corticosteroid insufficiency in acutely ill patients. N Engl J Med 2003;348:727-34.
Ehrhart-Bornstein M, Hinson JP, Bornstein SR, Scherba um WA, Vinson GP. Intraadrenal interactions in the regulation of adrenocortical steroidogenesis. Endocr Rev 1998;19:101-43.
Arlt W, Allolio B. Adrenal insufficiency. Lancet 2003;361:1881-93.
Paolo WF Jr, Nosanchuk JD. Adrenal infections. Int J Infect Dis 2006;10:343-53.
Pariante CM, Pearce BD, Pisell TL, Sanchez CI, Po C, Su C, et al.
The proinflammatory cytokine, interleukin-1alpha, reduces glucocorticoid receptor translocation and function. Endocrinology 1999;140:4359-66.
Sun X, Fischer DR, Pritts TA, Wray CJ, Hasselgren PO. Expression and binding activity of the glucocorticoid receptor are upregulated in septic muscle. Am J Physiol Regul Integr Comp Physiol 2002;282:R509-18.
Szumita PM, Enfanto CM, Greenwood B, Wechsler ME. Vasopressin for vasopressor-dependent septic shock. Am J Health Syst Pharm 2005;62:1931-6.
Levy MM, Fink MP, Marshall JC, Abraham E, Angus D, Cook D, et al.
2001 SCCM/ESICM/ACCP/ATS/SIS International Sepsis Definitions Conference. Crit Care Med 2003;31:1250-6.
Bouachour G, Tirot P, Gouello JP, Mathieu E, Vincent JF, Alquier P. Adrenocortical function during septic shock. Intensive Care Med 1995;21:57-62.
Rothwell PM, Udwadia ZF, Lawler PG. Cortisol response to corticotropin and survival in septic shock. Lancet 1991;337:582-3.
Waters M, Nightingale P, Edwards JD. A critical study of the APACHE II scoring system using earlier data collection. Arch Emerg Med 1990;7:16-20.
Shenker Y, Skatrud JB. Adrenal insufficiency in critically ill patients. Am J Respir Crit Care Med 2001;163:1520-3.
Rivers EP, Gaspari M, Saad GA, Mlynarek M, Fath J, Horst HM, et al.
Adrenal insufficiency in high-risk surgical ICU patients. Chest 2001;119:889-96.
Venkatesh B, Prins J, Torpy D, Chapman M, Joyce C, Cooper DJ, et al.
Relative adrenal insufficiency in sepsis: Match point or deuce? Crit Care Resusc 2006;8:376-80.
Marik PE. The diagnosis of adrenal insufficiency in the critically ill patient: Does it really matter? Crit Care 2006;10:176.
Mohammad Z, Afessa B, Finkielman JD. The incidence of relative adrenal insufficiency in patients with septic shock after the administration of etomidate. Crit Care 2006;10:R105.
Chen YC, Chen YC, Chou LF, Chen TJ, Hwang SJ. Adrenal insufficiency in the elderly: A nationwide study of hospitalizations in Taiwan. Tohoku J Exp Med 2010;221:281-5.
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 2006;174:1319-26.
Bornstein SR. Predisposing factors for adrenal insufficiency. N Engl J Med 2009;360:2328-39.
Mpe MJ, Muleba NC, Selepe EM, Mothabeng TG. Adrenal insufficiency in critically ill septic patients at George Mukhari Hospital. South Afr J Anaesth Analg 2006;12:135-8.
Krishna MV, Shivakumar NS. Hypothalamo-pituitary-adrenal axis in septic shock. J Indian Acad Clin Med 2007;8:42-4.
Marik PE, Zaloga GP. Adrenal insufficiency during septic shock. Crit Care Med 2003;31:141-5.
Annane D, Sébille V, Charpentier C, Bollaert PE, François B, Korach JM, et al.
Effect of treatment with low doses of hydrocortisone and fludrocortisone on mortality in patients with septic shock. JAMA 2002;288:862-71.
Sprung CL, Annane D, Keh D, Moreno R, Singer M, Freivogel K, et al
. Hydrocortisone therapy for patients with septic shock. N Engl J Med 2008;358:111-24.
Weis F, Beiras-Fernandez A, Schelling G, Briegel J, Lang P, Hauer D, et al.
Stress doses of hydrocortisone in high-risk patients undergoing cardiac surgery: Effects on interleukin-6 to interleukin-10 ratio and early outcome. Crit Care Med 2009;37:1685-90.
Marik PE, Pastores SM, Annane D, Meduri GU, Sprung CL, Arlt W, 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 2008;36:1937-49.
Dellinger RP, Levy MM, Carlet JM, Bion J, Parker MM, Jaeschke R, et al.
Surviving Sepsis Campaign: International guidelines for management of severe sepsis and septic shock: 2008. Crit Care Med 2008;36:296-327.
Confalonieri M, Urbino R, Potena A, Piattella M, Parigi P, Puccio G, et al.
Hydrocortisone infusion for severe community-acquired pneumonia: A preliminary randomized study. Am J Respir Crit Care Med 2005;171:242-8.
Salem M, Tainsh RE Jr, Bromberg J, Loriaux DL, Chernow B. Perioperative glucocorticoid coverage. A reassessment 42 years after emergence of a problem. Ann Surg 1994;219:416-25.
Meduri GU, Golden E, Freire AX, Taylor E, Zaman M, Carson SJ, et al.
Methylprednisolone infusion in early severe ARDS: Results of a randomized controlled trial. Chest 2007;131:954-63.
Meduri GU, Headley AS, Golden E, Carson SJ, Umberger RA, Kelso T, et al.
Effect of prolonged methylprednisolone therapy in unresolving acute respiratory distress syndrome: A randomized controlled trial. JAMA 1998;280:159-65.
[Table 1], [Table 2], [Table 3]