Efficacy and safety of corticosteroids in immunocompetent patients with septic shock

doi:10.5847/wjem.j.1920-8642.2021.02.007

Abstract

Abstract:

BACKGROUND: The use of corticosteroids in septic shock has been studied for many decades but yielded conflicting results. We conducted a systematic review to evaluate the efficacy and the safety of corticosteroids in immunocompetent patients with septic shock.

METHODS: Medline via PubMed, Cochrane Central Register of Controlled Trials (CENTRAL) in the Cochrane Library, and EMBASE were searched from inception to March 2020. Two reviewers independently identified randomized controlled trials (RCTs) comparing corticosteroids with a control group for immunocompetent patients with septic shock. Data were abstracted and reported following the Cochrane Handbook for Systematic Review of Intervention and Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. The efficacy outcome included mortality and shock reversal. The safety outcomes were infection, gastrointestinal bleeding, and hyperglycemia.

RESULTS: Nine RCTs with a total of 1,298 patients were included. Compared with the control group, corticosteroid group did not lower the short-term (28 or 30 days) mortality (risk ratio [RR] 0.95, 95% confidence interval (CI) 0.85 to 1.06, inconsistency [I ²]=0%, trial sequential analysis [TSA]-adjusted CI 0.83 to 1.09, moderate-certainty evidence). Corticosteroids significantly shortened the time to shock reversal compared with the control group (mean difference [MD] -21.56 hours; 95% CI -32.95 to -10.16, I ²=0%; TSA-adjusted CI -33.33 to -9.78, moderate-certainty evidence). The corticosteroid treatment was associated with an increased risk of hyperglycemia but not the infection or gastrointestinal bleeding.

CONCLUSIONS: The corticosteroid treatment is not associated with lower short- or long- term mortality compared with placebo in immunocompetent patients with septic shock. However, corticosteroids significantly shorten the time to shock reversal without increasing the risk of infection. The patient’s immune status should also be considered during clinical treatment and clinical trials in future.

Key words: Corticosteroids, Septic shock, Immunocompetent patients, Systematic review, Meta-analysis

Xin Lu, Wei Han, Yan-xia Gao, Shi-gong Guo, Shi-yuan Yu, Xue-zhong Yu, Hua-dong Zhu, Yi Li. Efficacy and safety of corticosteroids in immunocompetent patients with septic shock[J]. World Journal of Emergency Medicine, 2021, 12(2): 124-130.

Figures/Tables 5

Figure 1.

Table 1

Characteristics of included RCTs comparing corticosteroids versus control in immunocompetent patients with septic shock

Study	Design and study place	Sample size (corticosteroids /control)	Excluded population (major selection criteria)	Intervention	Outcomes^a
Annane et al^[29] (2002)	Multicenter (19 sites), France	150/149	Advanced form of cancer or AIDS infection	IV hydrocortisone 50 mg bolus q6h and po fludrocortisone 50 μg qd versus placebo for seven days	ICU mortality, 28-day mortality, hospital mortality, one-year mortality, seven-day mortality,^b shock reversal, and safety outcomes
Briegel et al^[30] (1999)	One center, Germany	20/20	End-stage neoplasm, organ transplant recipients	IV hydrocortisone 100 mg loading, followed by 0.18 mg/(kg·h) continuous infusion until shock reversal, then reduced to 0.08 mg/(kg·h) for six days, then tapered off versus placebo (physiologic saline solution)	Shock reversal, 28-day mortality,^b ICU mortality, hospital mortality, one-year mortality, seven-day mortality,^b and safety outcomes
Cicarelli et al^[27] (2007)	One center, Brazil	14/15	Immunosuppression therapy, end stage neoplasm with a life expectancy of less than three months	IV dexamethasone 0.2 mg/kg q36h for three doses versus placebo (0.9% physiological saline solution)	Seven-day mortality, 28-day mortality, and shock reversal
Doluee et al^[32] (2018)	One center, Iran	56/52	Malignancy	IV hydrocortisone 50 mg q6h versus placebo (saline in the same volume) for seven days	Twenty-eight-day mortality
Luce et al^[31] (1988)	One center, USA	38/37	Severe immunodeficiency and AIDS	IV methylprednisolone 30 mg/kg q6h for four doses versus mannitol placebo	Incidence of ARDS, hospital mortality, and safety outcomes
Lv et al^[24] (2017)	One center, China	58/60	Immunosuppression	IV hydrocortisone 200 mg/d for six days, then tapered off versus placebo (normal saline)	Hospital mortality, 28-day mortality, shock reversal, and length of stay in ICU and hospital
Oppert et al^[28] (2005)	One center, Germany	18/23	HIV positive or recipients of organ transplants	IV hydrocortisone 50 mg bolus, followed by 0.18 mg/(kg·h) continuous infusion until shock reversal, then tapered off versus placebo	Time to cessation of vasopressor support, 28-day mortality, and shock reversal
Sprung et al^[26] (2008)	Multicenter (52 sites), Europe and Israel	251/248	Immunosuppression	IV hydrocortisone 50 mg q6h for five days, then tapered to 50 mg q12h for three days, then 50 mg QD for three days versus placebo	Mortality in ICU and hospital, 28-day mortality, one-year mortality, shock reversal, length of stay in ICU and hospital, and safety outcomes
Wan et al^[25] (2014)	One center, China	62/27	Advanced form of cancer or HIV infection	IV hydrocortisone 50 mg q6h for seven days or five days versus saline	Shock reversal, 28-day mortality, seven-day mortality, length of stay in ICU, and safety outcomes

Table 1

Figure 2.

Figure 3.

Table 2

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Outcomes	Anticipated absolute effects ^a (95% CI)		Relative effect (95% CI)	Number of participants (studies)	Quality of the evidence (GRADE)
Outcomes	Risk with control	Risk with corticosteroids	Relative effect (95% CI)	Number of participants (studies)	Quality of the evidence (GRADE)
Short-term mortality	452 per 1,000	429 per 1,000 (384-479)	RR 0.95 (0.85-1.06)	1,298 (nine RCTs)	⊕⊕⊕? moderate^b
Long-term mortality	606 per 1,000	582 per 1,000 (528-649)	RR 0.96 (0.87-1.07)	816 (three RCTs)	⊕⊕⊕⊕ high
Seven-day mortality	412 per 1,000	280 per 1,000 (210-371)	RR 0.68 (0.51-0.90)	457 (four RCTs)	⊕⊕?? low^{b, c}
Time to shock reversal	Ranging from 75.81 to 91.2 hours	MD -21.56 (-32.95 to -10.16)		263 (four RCTs)	⊕⊕⊕? moderate^b
Shock reversal	648 per 1,000	700-1,000 (642-765)	RR 1.08 (0.99-1.18)	997 (five RCTs)	⊕⊕⊕? moderate^b
Infection	257 per 1,000	280 per 1,000 (224-352)	RR 1.09 (0.87-1.37)	894 (four RCTs)	⊕⊕⊕? moderate^c
Gastrointestinal bleeding	88 per 1,000	100 per 1,000 (69-143)	RR 1.14 (0.79-1.63)	927 (four RCTs)	⊕⊕?? low^{b, c}
Hyperglycemia	657 per 1,000	749 per 1,000 (676-834)	RR 1.14 (1.03-1.27)	539 (two RCTs)	⊕⊕⊕? moderate^b

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