European Journal of Cardiovascular Medicine

Sepsis is a spectrum of disease, where there is a systemic and dysregulated host response to an infection. The presentation may range from non-specific or non-localizing symptoms to severe signs with evidence of multi-organ dysfunction and septic shock.¹

The data from the Western world reveals an incidence of septic shock to be 8.2 per 100 intensive care admissions, with a mortality of 55-62.1%. Septic shock remains the most common cause of death in the ICU with a mortality rate of 30-50% despite conventional treatment methods and effective antibiotic therapy.^2,3 Sepsis has had a changing definition throughout the decades. Sepsis was defined as a host’s systemic inflammatory response syndrome (SIRS) to infection.⁴ Septic shock was defined as a bunch of clinical symptoms in which fluid/vasopressor-resistant hypotension (mean artery blood pressure ≤70 mmHg) and hypoperfusion are observed.⁵

In 2016 SCCM/ESICM task force defined sepsis as a life-threatening organ dysfunction caused by a dysregulated host response to infection. Organ dysfunction is defined by the 2016 SCCM/ESICM task force as an increase of two or more points in the SOFA score and now there is no more term known as severe sepsis.

Sepsis leads to activation of these multiple signalling pathways ultimately leading to the expression of several common gene classes that are involved in inflammation, adaptive immunity and cellular metabolism due to the simultaneous recognition of multiple infection-derived microbial products. Septic inflammatory response leads to vascular and ischemic damage, inflammation, and apoptosis within the hypothalamic-pituitary-adrenal axis leaving it severely impaired.⁶ This adrenal insufficiency is a well-described complication during sepsis.⁷ Glucocorticoid insufficiency may result in an imbalanced T-cell response with uncontrolled systemic inflammation⁸ which could be lethal. Treatment with lower doses of hydrocortisone (200-300 mg per day) documented an increase in baseline cortisol levels above the normal physiologic levels.⁹

Corticosteroids enhance the vasoconstrictor response to vasopressor drugs, exogenous catecholamines. It inhibits cyclooxygenase-2 and inducible nitric-oxide synthase which are likely to play a role in maintaining hemodynamic stability. Corticosteroids also mediate catecholamine release from neural cells which may partly explain the effect of corticosteroids on the vasculature.¹⁰ Corticosteroids suppress proinflammatory cytokines, and improve circulatory dynamics and immunomodulation which will help to increase tissue perfusion that ultimately reduces mortality.

The Annane trial in 2002, and the Corticus trial in 2008 who used low dose of hydrocortisone along with fludrocortisone saw a reversal of shock early as compared to the placebo group, but overall mortality was not reduced. The investigators reported improved survival in patients with a reduced response to corticotropin.¹¹

In our study, we took 90 patients who were in sepsis and septic shock and needed mechanical ventilation. These patients couldn’t maintain their mean arterial pressure above 65 mmHg even after fluid resuscitation. The control group 1 was given vasopressors, and the other group 2 was given vasopressors along with a continuous infusion of 50 mg of hydrocortisone 6 hourly. We have not added fludrocortisone like the previous studies because in vitro mineralocorticoid receptors have an equal affinity for both mineralocorticoid as well as glucocorticoid and as such would be activated by circulating cortisone which is found in far higher circulating concentration than aldosterone.¹²

The study was conducted at the Intensive Care Unit, Sir Sundar Lal Hospital, Banaras Hindu University, Varanasi during January to June 2020, written and informed consent were taken from the patient’s relatives. The study was approved by the Ethical Committee of the Institute of Medical Sciences, Banaras Hindu University-Dean/2019/EC/1788. This study is a prospective, randomized, comparative parallel-group, single-center study.

The study was conducted on 90 patients, aged between 18-60 years of age of either sex, who were admitted at Sir Sunder Lal ICU with septic shock with hypotension. Patients were randomized into two groups using computer generated random numbers and allocated into 2 groups each with 45 patients for a total duration of seven days.

Group 1 (n=45) was the control group which included patients with septic shock who were administered vasopressors. Group 2 (n=45) had patients with septic shock who were administered vasopressors with 50 mg hydrocortisone infusion every 6 hours.

We included patients of both sexes with septic shock for less than 24 hours fulfilling the criteria of SIRS, aged between 18-60 years, and attendants giving informed written consent. We excluded patients with septic shock for more than 24 hours, pregnancy, lactations, prior treatment with hydrocortisone, high risk of bleeding, diabetic mellitus, hypersensitivity to steroids, patients with known adrenal insufficiency, and immunodeficient patients.

On admission, all the patients were monitored for heart rate, invasive blood pressure, pulse oximetry, ECG, random blood sugar, and temperature. Routine baseline investigations including complete blood count, liver function test, renal function test, arterial blood gas, and procalcitonin were sent before starting the study and then a blood culture was done to confirm sepsis. ICU scoring was done with the Glasgow coma scale, APACHE Ⅱ (Acute Physiology and Chronic Health Evaluation II) and SOFA (sequential organ dysfunction assessment) score.

All patients were managed according to the standard protocol of ICU, which includes fluid infusion, vasopressors administration, mechanical ventilation, antibiotic therapy and support of renal function such as artificial CRRT and/or hemodialysis, strict input output monitoring.

Patients with septic shock got initial fluid resuscitation of 20-30 ml/kg of 0.9% normal saline (1000-1500 ml) and those with systolic blood pressure of less than 90 mmHg were started on noradrenaline (2.5µg/min). The blood pressure was noninvasively monitored every 3 min and the rate of infusion was increased by 2µg/min, the systolic blood pressure achieved was 90 mmHg or 1hour since the start of vasopressor. Whose systolic blood pressure still less than 90 mmHg was defined as refractory shock and the patients were eligible for corticosteroid therapy and were enrolled in the study. Subsequently, the dose of noradrenaline was increased as described above till the desired blood pressure was achieved or the maximum dose (20 mcg/min) has reached. Among patients who are still hypotensive despite a maximum dose of a single vasopressor (noradrenaline), the second agent (vasopressin at rate of 2 U/hour) was added. Once a patient has attained hemodynamic stability (mean arterial pressure of 65 mmHg or systolic blood pressure of 100 mmHg, heart rate of 100/min, urine output of at least 0.5ml/kg/hr) for at least 6 hours, the tapering of vasopressors was done at the dose of 2µg/min noradrenaline. Reversal of shock was defined as the maintenance of mean arterial pressure of 65 mmHg for at least 1hour after cessation of vasopressor. The duration of the vasopressor requirement was recorded in micrograms per day. Blood sugar level checked every 4 hours. Hyperglycaemia will be defined as blood sugar 150 mg/dl and organ dysfunction was assessed by SOFA score for 7 days.

Statistical Analysis

The data obtained from the study was subjected to statistical analysis using SPSS version 28.0. The p-value < 0.05 was considered statistically significant. The data was presented as mean ± standard deviation for continuous variables and frequency for categorical variables. Chi-square test was done for categorical data, and for continuous data, independent student’s t test was performed.

Sample size was calculated so as to maintain the overall alpha error < 0.05 and power (1-beta) > 0.9. The sample size required was 80 patients, so total of 90 patients were enrolled, with 45 patients in each group of the study considering for any dropouts during the study period.

Among the 90 patients without any dropouts (Figure 1), there was a significant difference in the length of ICU stay showing a shorter ICU stay of Group 2 (12.09 ± 5.180 days) compared to Group 1 (14.71 ± 5.983 days) (Table 1). There was a significant decrease in noradrenaline dose in group 2 (p < 0.05) (Table 2), but no difference in the dose of vasopressin (Table 3). There was no significant difference in the duration of mechanical ventilation except on day 7 which was comparable (Table 4). Regarding hemodynamic stability, significant changes were seen on day 2 and day 3 but no change from day 4 to day 7, however, there was no change in mortality rate (P = 0.077) (Table 1), which remained almost the same in both groups. The changes in glycaemic index were not vary significant till day 7.

The primary outcome of the study was significant where the dose of vasopressors (norepinephrine) was reduced on day 1 (P = 0.010), day 2 (P = 0.008) and in day 4 (P = 0.025), day 6 (P < 0.001), day 7 (P = 0.003) in group 2 in whom vasopressors were given along with hydrocortisone but the dose of vasopressin didn’t show any reduction. However, 7 days mortality was not significant (P = 0.777), amongst the two groups.

There was a decrease in the length of ICU stay in group 2 (12.09 ± 5.180 days) than in group 1 (14.71 ± 5.983 days) with (P < 0.028). There was no significant difference between the two groups on days of mechanical ventilation (P > 0.05) and SOFA score. The rise in blood sugar level was not significant (P > 0.05). During the study, there were 11 cases of peripheral cyanosis observed and 2 cases of peripheral gangrene were also seen.

Septic shock arises due to inflammation and vasoplegia from a complex biological cascade dependent on inter and intracellular signaling. The role of the adrenal cortex in recovery from septic shock dates back nearly 100 years.¹³ Corticosteroids are steroid hormones synthesized by adrenal glands from cholesterol. They are divided into mineralocorticoids and glucocorticoids. Mineralocorticoids have a greater effect on salt and water balance and have a narrower focus of action than glucocorticoids.

They are used for their role in immune modulation, effects on cardiovascular tone and anti-inflammatory effects. Corticosteroids modulate the transcription of nuclear factor ⱪβ-regulated genes leading to inflammation. The synthesis of interleukin-1, interleukin-6, and tumour necrosis factor-α is inhibited along with cyclooxygenase-2 and nitric-oxide synthase.¹⁴ Corticosteroids also enhance the vasoconstrictor response to vasopressor drugs, exogenous catecholamines. Corticosteroid mediates catecholamine release from neural cells which explains its effects on vasculatures, it also suppresses proinflammatory cytokines and improves circulatory dynamics, so it is said to maintain tissue perfusion and metabolic functions thus reducing mortality.

Hydrocortisone was given to the patients by continuous infusion of 200mg/day (50mg over 6 hours) because infusion had been shown to attenuate the inflammatory response.⁹ The continuous infusion may decrease the metabolic side effects of corticosteroids.^15,16 Dose tapering of glucocorticoids was not done as it was seen to have a beneficial effect even without tapering.¹¹ We didn’t do corticotropin testing to determine which patient should be given hydrocortisone as studies had described a poor relationship between total and free cortisol¹⁷ as well as other issues concerning dose, timing and types of corticotropins.¹⁸

Randomized controlled trials were done in the 1980s using high-dose corticosteroids for septic shock which was effective in reversing shock but did not provide mortality benefit.¹⁹ This encouraged the use of lower doses (200 to 300mg of hydrocortisone/day) which was near to the physiological dose. The normal daily output of cortisol is 40 to 80 µmol/day (i.e.,15 to 30mg/day). Treatment with low-dose hydrocortisone increases the baseline cortisol levels by a factor of 5, reaching above-normal physiologic levels.⁹

Limitations

The study was a single-center study and was conducted with limited sample size. Thus, future studies are required to be conducted with a greater number of patients. The study didn’t focus on increased risk of infections due to steroids and other adverse effects like neuromuscular weakness, and gastrointestinal bleeding.

Therefore, our study findings suggested that the use of continuous infusion of low-dose hydrocortisone in patients with septic shock who are not responsive to initial fluid resuscitation will lead to a decrease in the dose of noradrenaline as well as hasten the reversal of shock. There was also decrease in the duration of ICU stay and continuous infusion doesn’t lead to increase in glycaemic index.

Acknowledgement: None.

Source of Funding: None.

Conflict of Interest: None.

1. Singer M, Deutschman CS, Seymour CW, Shankar-Hari M, Annane D, Bauer M, et al. The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3). JAMA 2016;315(8):801.
2. Angus DC, Linde-Zwirble WT, Lidicker J, Clermont G, Carcillo J, Pinsky MR. Epidemiology of severe sepsis in the United States: analysis of incidence, outcome, and associated costs of care. Crit Care Med 2001;29(7):1303-10.
3. Angus DC, Wax RS. Epidemiology of sepsis: an update. Crit Care Med 2001;29(7 Suppl):S109-16.
4. Bone RC, Balk RA, Cerra FB, et al. 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 1992;20(6):864-74.
5. Vincent JL. Dear SIRS, I’m sorry to say that I don’t like you. Crit Care Med 1997;25:372-4.
6. Sharshar T, Gray F, Lorin de la Grandmaison G, Hopkinson NS, Ross E, Dorandeu A, et al. Apoptosis of neurons in cardiovascular autonomic centres triggered by inducible nitric oxide synthase after death from septic shock. Lancet Lond Engl 2003;29:1799-805.
7. Annane D. Adrenal insufficiency in sepsis. Curr Pharm Des 2008;14(19):1882-6.
8. Annane D, Sébille V, Bellissant E, Group GI 05 S. Effect of low doses of corticosteroids in septic shock patients with or without early acute respiratory distress syndrome. Crit Care Med 2006;34(1):22-30.
9. Keh D, Boehnke T, Weber-Carstens S, Schulz C, Ahlers O, Bercker S, et al. Immunologic and hemodynamic effects of “low-dose” hydrocortisone in septic shock: a double-blind, randomized, placebo-controlled, crossover study. Am J Respir Crit Care Med 2003;167:512-20.
10. Shi LJ, He HY, Liu LA, Wang CA. Rapid nongenomic effect of corticosterone on neuronal nicotinic acetylcholine receptor in PC12 cells. Arch Biochem Biophys 2001;394(2):145-50.
11. 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(7):862-71.
12. Arriza JL, Weinberger C, Cerelli G, Glaser TM, Handelin BL, Housman DE, et al. Cloning of human mineralocorticoid receptor complementary DNA: structural and functional kinship with the glucocorticoid receptor. Science 1987;237(4812):268-75.
13. Cohen J, Venkatesh B. Adjunctive Corticosteroid Treatment in Septic Shock. Anesthesiology 2019;131(2):410-9.
14. Annane D. Glucocorticoids in the treatment of severe sepsis and septic shock. Curr Opin Crit Care 2005;11(5):449-53.
15. Loisa P, Parviainen I, Tenhunen J, Hovilehto S, Ruokonen E. Effect of mode of hydrocortisone administration on glycemic control in patients with septic shock: a prospective randomized trial. Crit Care Lond Engl 2007;11(1):R21.
16. Rhodes A, Evans L, Alhazzani W, Levy M, Antonelli M, Ferrer R, et al. Surviving Sepsis Campaign: International Guidelines for Management of Sepsis and Septic Shock: 2016. Intensive Care Med 2017;18:43.
17. Sprung CL, Singer M, Kalenka A, Cuthbertson BH. Hydrocortisone therapy for patients with septic shock. N Engl J Med 2008;14.
18. Arafah BM. Hypothalamic pituitary adrenal function during critical illness: limitations of current assessment methods. J Clin Endocrinol Metab 2006;91:3725-45.
19. 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 J Med 1987;317(11):653-8