Article, Critical Care

Early initiation of low-dose hydrocortisone treatment for septic shock in adults: A randomized clinical trial

a b s t r a c t

Background: Physiologic dose hydrocortisone is part of the suggested adjuvant therapies for patients with septic shock. However, the association between the corticosteroid therapy and mortality in patients with septic shock is still not clear. Some authors considered that the mortality is related to the time frame between development of septic shock and start of low dose hydrocortisone. Thus we designed a placebo-controlled, randomized clinical trial to assess the importance of early initiation of low dose hydrocortisone for the final outcome.

Methods: A total of 118 patients with septic shock were recruited in the study. All eligible patients were randomized

to receive hydrocortisone (n = 58) or normal saline (n = 60). The study medication (hydrocortisone and normal saline) was initiated simultaneously with vasopressors. The primary end-point was 28-day mortality. The secondary end-points were the reversal of shock, in-hospital mortality and the duration of ICU and hospital stay.

Results: The proportion of patients with reversal of shock was similar in the two groups (P = 0.602); There were no significant differences in 28-day or hospital all-cause mortality; length of stay in the ICU or hospital between pa- tients treated with hydrocortisone or normal saline.

Conclusion: The early initiation of low-dose of hydrocortisone did not decrease the risk of mortality, and the length of stay in the ICU or hospital in adults with septic shock.

Trial registration: www.clinicaltrials.gov NCT02580240.

(C) 2017

Introduction

Septic shock is common in the critically ill, with an increasing inci- dence ranging from 5% to 19% [1] and mortality rate varies from 30% to 60% [2]. Ongoing vasopressor-refractory hypotension is a major con- tributor to the high mortality [3].

Both Surviving Sepsis Campaign [4] and American College of Critical Care Medicine (ACCCM) [5] recommend the application of hydrocortisone in adult septic shock patients who have responded poorly to fluid resuscitation and vasopressor therapy. However, the rec- ommendations are too general. What exactly “poorly responsive to fluid resuscitation and vasopressor therapy” means is ambiguous. Different physicians may treat or not treat the same patient with septic shock. A multicenter, electronic survey of US critical care practitioners showed that criteria used to initiate corticosteroid therapy in septic shock patients and opinions regarding their impact vary. About 19% of the practitioners

* Corresponding author at: Department of Critical Care Medicine, Subei People’s Hospital, Clinical Medical School of Yangzhou University, 98 West Nantong Road, 225001 Yangzhou, China.

E-mail address: [email protected] (R. Zheng).

1 These authors contributed equally to the study and they should be regarded as joint

first authors.

do not prescribe corticosteroids for patients with septic shock, and the most common reason was lack of proven Survival benefit [6].

Controversies on the association between the corticosteroid therapy

and mortality in patients with septic shock always exist. Some authors attributed the significant variability in mortality to the time frame between development of septic shock and start of low dose hydrocorti- sone [7,8].A retrospective study [9] demonstrated a significant associa- tion between early initiation (administered within 6 h after the onset of septic shock) of low-dose corticosteroid therapy and decreased mortality rate in patients with septic shock. A survival benefit was also observed in patients with septic shock treated with low doses of hydro- cortisone, when hydrocortisone was administrated within 9 h after shock development [7]. Thus we designed a placebo-controlled, dou- ble-blind randomized clinical trial (RCT) to assess the importance of early initiation of low dose hydrocortisone for the final outcome.

Methods

Study design and participants

This study was approved by the Human Research Ethics Committee of Subei People’s Hospital and was registered at clinicaltrial.gov (NCT02580240).

http://dx.doi.org/10.1016/j.ajem.2017.06.004

0735-6757/(C) 2017

From September 2015 to September 2016, 118 patients admitted to the 35-bed intensive care unit (ICU) of the Subei People’s Hospital (Yangzhou), were recruited according to the following inclusion criteria: 1) age 18 years old or older; 2) onset of septic shock within 6 h. The exclusion criterion was the presence of any of the following:

1) Systemic corticosteroid therapy within the last 3 months before sep- tic shock; 2) high-dose steroid therapy; 3) immunosuppression; 4) re- fusal of the attending staff or patient family (Fig. 1).

Randomization

Patients were randomly assigned to receive hydrocortisone or nor- mal saline (placebo). The randomization was stratified according to a table of computer-generated random numbers. Patients as well as in- vestigators remained blinded to the allocated therapy throughout the study. At the end of the study, clinical evaluations were performed by a staff member who was unaware of the study group assignments and the appropriateness of treatment.

Treatment

Patients were treated with Standard therapy for septic shock, ac- cording to international guidelines [10]: empiric antimicrobials were administered within the first hour of recognition of septic shock; the empiric drug was chosen as epidemic and endemic ecologies dictate. Emergent source control was sought and diagnosed or excluded as rap- idly as possible and intervention was undertaken for source control within the first 12 h after the diagnosis is made. For Fluid replacement, patients were to receive at least 1000 to 1500 mL (20 to 30 mL per kilogram) of crystalloids over 30 to 60 min. The use of hydroxyethyl starch preparations was forbidden due to possible harmful effects on renal function [11,12]. isotonic crystalloid was used to achieve a CVP of 8 to 12 mm Hg. Vasopressors were added if necessary to reach the tar- get MAP of 65 mm Hg. For the use of vasoactive drugs, norepinephrine was the first choice. Packed red blood cells and/or dobutamine were given when needed to reach the target ScvO2 of 70%.

Once the vasoactive drugs were initiated, the study medication (hydrocortisone or normal saline) started with vasopressors simul- taneously. Hydrocortisone was administered 200 mg/d as a contin- uous infusion for 6 days, and then tapered off. Once all vasopressors were discontinued, the taper protocol was initiated (half dose for three days, then quarter dose for three days and then stopped). Vials containing normal saline as placebo were identical to those containing hydrocortisone. Placebo administration procedures were similar.

Definitions

Septic shock was defined as sepsis-induced hypotension (systolic blood pressure b 90 mm Hg or a systolic blood pressure decrease N 40 mm Hg, or b 2 standard deviations below normal for age in the ab- sence of other causes of hypotension) despite adequate volume resusci- tation [4]. Failure of major organ systems was defined as a Sequential Organ Failure Assessment score of 4 points [13]. Reversal of shock was defined as the maintenance of a systolic blood pressure of at least 90 mm Hg without vasopressor support for at least 24 h [14]. Ap- propriate antibiotic therapy was considered if the initially prescribed antibiotics were active against the identified pathogens, based on In vitro susceptibility testing.

Data collection

The following information was collected and analyzed for every en- rolled patient: demographics, amount of fluid administered before initi- ation of vasopressor, doses of vasopressor (norepinephrine), and organ failure. Hematological and biochemical data and arterial lactate levels were measured, and blood culture and cultures of specimens from the site of infection were routinely performed. Disease severity was assessed by Acute Physiology and Chronic Health Evaluation II (APACHE II) [15,16] and Sepsis-related Organ Failure Assessment (SOFA) scores [17].

Fig. 1. Patient enrollment, randomization, and treatment flow.

End-points

The primary end-point was 28-day mortality. The secondary end- points were the reversal of shock, in-hospital mortality and the duration of ICU and hospital stay.

Statistical analysis

Categorical variables are reported as percentages and continuous or discrete variables are reported as means +- standard deviation (SD). The unpaired Student t-test or Mann-Whitney U test for continuous vari- ables and the chi-square test or the Fisher exact test for categorical var- iables were used for comparisons between the groups. Univariate analysis was done for the effect of variables on final outcome. A binary logistic regression model was used to adjust for potential confounding factors in the association between low-dose corticosteroid therapy and 28-day mortality. Data are presented as odds ratios (OR) with 95% confidence intervals (CI). Significant variables were also entered in forward stepwise Cox, hazard ratio and 95% CI were calculated. SPSS version11.0 was used for statistical analyses. Unless otherwise stated, all statistical evaluations were made assuming a two-sided test with a significance level of value P b 0.05.

Results

There were 118 patients enrolled in this study; each patient was assigned to either the hydrocortisone group (n = 58) or the placebo group (n = 60). The baseline characteristics of the two groups are

presented in Table 1. Briefly, there were no differences between the groups with respect to gender, age, locale before ICU admission, comor- bidities, culture results, appropriateness of antimicrobials and organ failure on admission to the ICU. The initial APACHE II score and SOFA score was higher in the hydrocortisone group compared to the placebo group, and both the differences were statistically significant (P = 0.007 and P b 0.001, respectively). Abdominal infections were significantly more frequent in the placebo group (P = 0.026).

Baseline clinical and Laboratory measurements are presented in Table 2. The two groups did not significantly differ in any of the biolog- ical variables considered. Both groups had similar characteristics, such as norepinephrine duration, maximum norepinephrine quantity, time to shock reversal, need for mechanical ventilation and need for renal re- placement therapy (P N 0.05). The amount of fluid administered before vasopressor in the placebo group (1.5 L, IQR 1.00-2.98 L) was signifi- cantly larger than that in the hydrocortisone group (1.0 L, IQR 0.70- 1.60 L) (P = 0.013).

The proportion of patients with reversal of shock was similar in the two groups (P = 0.602); There were no significant differences in 28- day or hospital all-cause mortality; length of stay in the ICU or hospital between patients treated with hydrocortisone or placebo (Table 3). After adjusting for potential confounding factors, APACHE II score (OR 1.147, 95% CI 1.053 to 1.250, P = 0.002), appropriateness of antimicro- bials (OR 0.219, 95% CI 0.052 to 0.916, P = 0.038), maximum norepi- nephrine quantity (OR 2.879, 95% CI 1.732 to 4.787, P b 0.001) and the need for renal replacement therapy (OR 5.241, 95% CI 1.424 to 19.294, P = 0.013) were independent factors influencing 28-day mortality in patients (Table 4).

Table 1

Baseline characteristics of patients enrolled in the study.

Variables

Hydrocortisone

Placebo

P value

(N = 58)

(N = 60)

Gender, male: female

33/25

37/23

0.598

Age (years, mean +- SD)

68.8 +- 12.6

64.8 +- 16.7

0.141

APACHE II score (M, P25-P75)

25.5 +- 9.5

21.3 +- 6.9

0.007

SOFA score (mean +- SD)

11.9 +- 3.3

9.9 +- 3.0

b0.001

Locale before ICU admission, Emergency department: General ward

17/41

22/38

0.396

Patients with comorbidities, n (%)

54 (93.1)

49 (81.7)

0.062

Hypertension

25 (43.1)

26 (43.3)

0.980

COPD

2 (3.4)

4 (6.7)

0.707a

CAD

7 (12.1)

8 (13.3)

0.837

DM

14 (24.1)

12 (20.0)

0.588

CRD

2 (3.4)

1 (1.7)

0.976a

Malignancy

9 (15.5)

13 (21.7)

0.391

Site of infection n (%) Lung

22 (37.9)

22 (36.7)

0.887

Abdominal cavity

21 (36.2)

34 (56.7)

0.026

Urinary tract

10 (17.2)

7 (11.7)

0.389

Skin and soft tissue

2 (3.4)

1 (1.7)

0.976a

Others

7 (12.1)

4 (6.7)

0.313

Bacteremia

18 (31.0)

13 (21.7)

0.225

Culture results, n (%)

42 (72.4)

44 (73.3)

0.911

Klebsiella pneumoniae

11 (19.0)

9 (15.0)

0.566

Acinetobacter baumannii

4 (6.9)

10 (16.7)

0.101

Pseudomonas aeruginosa

3 (5.2)

2 (3.3)

0.969a

Escherichia coli

8 (13.8)

10 (16.7)

0.664

MRSA

4 (6.9)

4 (6.7)

1.000

Others

14 (24.1)

25 (41.7)

0.043

Appropriateness of antimicrobials, n (%)

48 (82.8)

47 (78.3)

0.544

Organ failure n (%)

10 (17.2)

6 (10.0)

0.251

Respiratory

7 (12.1)

4 (6.7)

0.313

Liver

1 (1.7)

1 (1.7)

1.000b

Renal

3 (5.2)

1 (1.7)

0.587a

Coagulation

3 (5.2)

1 (1.7)

0.587a

APACHE II, Acute Physiology and Chronic Health Evaluation II; SOFA, Sequential Organ Failure Assessment. COPD, Chronic obstructive pulmonary disease; CAD, Coronary artery disease; DM, Diabetes mellitus; CRD, Chronic renal disease; MRSA, Methicillin resistant Staphylococcus aureus.

a Chi-square test.

b Fisher exact test.

Table 2

Baseline clinical and laboratory measurements for the patients who received hydrocorti- sone or placebo.

Table 4

Logistic regression analysis of factors influencing 28-day mortality in patients. Variables OR 95% CI for OR P value

Variables

Hydrocortisone (N = 58)

Placebo (N = 60)

P value

Age (years, mean +- SD) APACHE II score

1.055

1.147

0.999-1.115

1.053-1.250

0.056

0.002

Leukocytes, 103/mm3

13.2 (7.0-20.0)

13.0 (9.3-18.2)

0.651a

Appropriateness of antimicrobials, n (%)

0.219

0.052-0.916

0.038

Platelet, 103/mm3

123.3 +- 106.3

149.5 +- 113.8

0.200

Maximum norepinephrine quantity (ug/kg * min)

2.879

1.732-4.787

b 0.001

Total bilirubin, umol/L

36.7 +- 47.2

28.3 +- 38.3

0.285

Need for RRT

5.241

1.424-19.294

0.013

Creatinine, mg/dL

Prothrombin time, s

1.9 +- 1.3

22.7 +- 21.2

1.5 +- 0.9

18.6 +- 6.0

0.097

0.154

RRT, renal replacement therapy.

Albumin, g/L

25.8 +- 6.8

27.7 +- 7.9

0.166

Initial lactate, mmol/L

5.7 +- 3.8

4.4 +- 3.2

0.051

on mortality at maximal follow-up [19]. In addition, the results are

also in agreement with the HYPRESS trial that found the use of hydro- cortisone compared with placebo did not reduce the risk of septic

Procalcitonin, ng/mL

Amount of fluid administered

32.8 +- 42.2

1.0 (0.70-1.60)

24.5 +- 36.3

1.50 (1.00-2.98)

0.252

0.013a

before vasopressor, L

Norepinephrine duration, days

2.5 +- 2.4

2.8 +- 4.0

0.639

shock [20].

Maximum norepinephrine

1.7 +- 2.1

1.2 +- 1.4

0.089

It is worth mentioning that in the current study, patients’ severity of

quantity, ug/kg * min

Time to shock reversal, days

3.5 +- 2.4

3.8 +- 4.0

0.639

Need for mechanical ventilation

52 (89.7)

51 (85.0)

0.448

Need for RRT

24 (41.4)

18 (30.0)

0.197

RRT, renal replacement therapy.

a Mann-Whitney U test.

Discussion

Stress dose of hydrocortisone is part of the suggested adjuvant ther- apies for patients with septic shock. However, this treatment strategy has been controversial and conflicting due to the inconsistent results of conducted clinical trials. Some authors think that contradictions in survival studies may be explained by differences in the time elapsed be- tween development of septic shock and initiation of corticosteroid therapy.

In the study by Annane et al. [18], hydrocortisone was started within 3 to 8 h after diagnosis of septic shock, the 28-day mortality was signif- icantly decreased by corticosteroid therapy in patients (61% vs. 55%); whereas in the largest randomized control trial, CORTICUS, hydrocorti- sone was started within 12 h for 77% of the patients, results demonstrat- ed no significant difference in 28 mortality between patients treated with corticosteroids and those receiving placebo (39.2% and 36.1% mor- tality, respectively, P = 0.69), regardless of the patients’ adrenal respon- siveness to corticotropin [14]. In a recent retrospective observational study, Park et al. [9] found that early administration (within 6 h from the initial onset of septic shock)of low-dose corticosteroid therapy is significantly associated with decreased mortality in patients with septic shock.

In this RCT, hydrocortisone was administrated simultaneously with vasopressors. Similar to CORTICUS [14], there were no significant differ- ences between treatment groups with regard to mortality or length of stay in the ICU or hospital in our study. The proportion of patients in whom reversal of shock was achieved was similar in the two groups; however, this goal was achieved earlier in patients who received hydro- cortisone (3.5 d vs. 3.8 d, P = 0.639).

The presented findings are consistent with the recently published results of a meta-analysis including 35 randomized trials with 4682 patients, which demonstrated no statistically significant effect for low dose hydrocortisone (or equivalent) versus placebo or no intervention

Table 3

The clinical course in patients with septic shock who received hydrocortisone or placebo.

Variables

Hydrocortisone (N = 58)

Placebo (N = 60)

P value

Reversal of shock

38 (65.6)

42 (70.0)

0.602

28-day mortality

23 (39.7)

19 (31.7)

0.365

LOS in ICU, days

10.9 +- 17.5

10.2 +- 13.1

0.799

In-hospital mortality

23 (39.7)

19 (31.7)

0.365

LOS in hospital, days

23.7 +- 36.8

21.7 +- 21.7

0.711

LOS, length of stay.

illness, as assessed by APACHE II score and SOFA score was greater in the hydrocortisone group compared to the placebo group, and both the dif- ferences were statistically significant (P = 0.007 and P b 0.001, respec- tively). However, after adjusting for potential confounding factors, still, the hydrocortisone therapy has no significant impact on mortality rate. Of note, according to our findings, early administration of hydrocor- tisone in septic shock is being able to titrate patients off vasoactive therapy earlier. This more rapid shock reversal with steroid therapy is consistent with previous reports [21-25]. This may be related to increased sensitization of the vasculature to vasopressors caused by hydrocortisone or with the mineralocorticoid properties of hydrocorti- sone [26]. Decreased exposure to vasoactive therapy is potentially ben- eficial for Organ function and peripheral vascular circulation recovery [2,27,28]. Nevertheless, there is no proven link between faster resolu-

tion of shock with corticosteroids and improved mortality.

Lack of the overall survival benefit of low-dose hydrocortisone ther- apy is likely attributable to its adverse events such as hyperglycemia, secondary infection from immune suppression, delayed healing, and muscle weakness [27]. Further studies are needed to clarify the involved mechanisms of action of hydrocortisone.

Strengths of our study included: 1) this is the first study to start the application of low-dose corticosteroid therapy simultaneously with va- sopressors. Therefore, it is possible to rule out the effect of time delay in hydrocortisone application on the mortality of septic shock. 2) In this study, the administration of hydrocortisone was accomplished via con- tinuous infusion. Unlike the rapid Intermittent boluses, the continuous infusion of hydrocortisone mimics a more natural physiologic response without causing high spikes in the serum level and dramatic changes in Blood sugar [27,29]. And 3) our protocolized slow tapering of the study medication after achieving predefined parameters of hemodynamic sta- bility was more physiologically appropriate than use of a predefined schedule with abrupt discontinuation or tapering irrespective of hemo- dynamic status.

The limitations of our study warrant consideration: 1) only short time outcomes, 28-day and in-hospital mortality were collected, and therefore any long-term differences between treatment groups cannot be assessed. 2) Our study was likely to be underpowered to detect a sta- tistical significant difference by the recruitment of patients with lower mortality. While the original sample size calculation was based on a control mortality of 60%, originating from the findings of the largest prior study [2], our control 28-day mortality was almost half that. 3) The sample size was relatively small, and only one center was involved, which may affect its generalizability. Additional large-scale studies are needed to confirm our findings.

Conclusions

In this randomized controlled trial, the early initiation of low-dose hydrocortisone did not decrease the risk of mortality, and the length of stay in the ICU or hospital in adults with septic shock. These findings

do not support the use of hydrocortisone in these patients, even though they hastened reversal of shock.

Competing interests

The authors declare that they have no competing interests.

Acknowledgments

None.

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