Solumedrol Treatment for Severe Sepsis in Humans with a Blunted Adrenocorticotropic Hormone-Cortisol Response: A Prospective Randomized Double-Blind Placebo-Controlled Pilot Clinical Trial

Abstract

Purpose

To test the benefits of Solumedrol treatment in sepsis patients with a blunted adrenocorticotropic hormone (ACTH)-cortisol response (delta <13 µg/dL) with regard to the number of days on ventilator, days on intravenous blood pressure support, length of time in an intensive care unit (ICU), 14-day mortality, and 28-day mortality. The trial was prospective, randomized, and double-blind. As part of a larger sepsis trial, 54 patients with sepsis had an intravenous ACTH stimulation test using 250 µg of ACTH, and serum cortisol was measured at times 0, 30, and 60 min. Eleven patients failed to increase their cortisol concentration above 19.9 µg/dL and were excluded from the clinical trial as they were considered to have adrenal insufficiency. The remaining 43 patients had a baseline cortisol of 32 ± 1 µg/dL increased to 38 ± 3 µg/dL at 30 min and 40 ± 3 at 60 min. All cortisol responses were <12.9 µg/dL between time 0 and time 60, which is defined as a blunted cortisol response to intravenous ACTH administration. Twenty-one were randomized to receive 20 mg of intravenous Solumedrol and 22 were randomized to receive a matching placebo every 8 h for 7-days. There was no significant difference between the two randomized groups. Data analysis was carried out bya two-tailed test and P < .05 as significant.

Results

Results: The mean age was 51 ± 2 (mean ± SEM) with 61% female. Groups were well matched with regard to APACHE III score in Solumedrol versus placebo (59 ± 6 vs 59 ± 6), white blood cell count (18.8 ± 2.2 vs 18.6 ± 2.6), and incidence of bacteremia (29 vs 39%). The 28-day mortality rate was reduced in the Solumedrol treated arm (43 ± 11 vs 73 ± 10%; P < .05). There was no change in days in ICU, days on blood pressure agents, or days on ventilator. Seven days of high-dose intravenous Solumedrol treatment (20 mg every 8 h) in patients with a blunted cortisol response to ACTH was associated with an improved 28-day survival. This small study suggests that an inability to increase endogenous cortisol production in patients with sepsis who are then provided steroid treatment could improve survival.

Keywords

clinical research critical care hospital mortality

Introduction

Sepsis mortality remains very high over an extended period despite new approaches to treatment.¹ Dexamethasone treatment has recently been shown to reduce mortality in patients with coronavirus disease 2019 (COVID-19) infections.² This may be due to a reduction in the inflammatory response seen in COVID-19 when given steroids. We have evaluated 106 cases of systemic inflammatory response syndrome (SIRS) at our institution³ and have identified that the mortality is inversely related to the delta cortisol response (r = −.815, P < .05). The highest hospital mortality was seen in the group with the delta cortisol response of <13 µg/dL at 40%. This was a rationale to use a delta cutoff of <13 µg/dL response in this randomized clinical trial. The mortality was 24% with the delta cortisol response of 13 to 25.9 µg/dL and only 7% with the delta cortisol response of ≥26 µg/dL, P < .05). Interestingly, cortisol concentrations were not elevated in these SIRS patients with bacteremic versus nonbacteremic patients (25.4 ± 1.9 vs 25.1 ± 2.5 µg/dL). The only cortisol abnormality noted in the bacteremia patients was a smaller delta cortisol response to Adrenocorticotropic hormone (ACTH; 14.7 ± 2.2 vs 18.9 ± 1.2 µg/dL, P < .05).Ref 3 (not 2) is the correct reference.³ The smaller delta cortisol response seen in bacteremia suggests that bacteremia may blunt the endogenous cortisol response to a system infection. In septic shock, a delta cortisol response <13 µg/dL had a threefold increase in mortality (75% vs 25%).⁴

Earlier research has demonstrated that a significant reduction in mortality is noted in septic patients who have an ACTH stimulation test with a serum delta cortisol response of >12 µg/dL versus those with a blunted cortisol response (<12 µg/dL; Sibbald et al⁵). The mortality rate was 73% in those patients with a blunted cortisol response to ACTH as compared to 43% in those with a robust cortisol response to the ACTH stimulation test (P < .05).

Additional research tested if mineralocorticoid and corticoid treatment improved septic shock survival in patients with a severely blunted delta cortisol response <9 µg/dL to 250 µg of intravenous ACTH. Seven days of hydrocortisone and fludrocortisone reduced 28-day mortality from 61% to 53%.⁶ There was no mortality benefit in responders to 250 µg of ACTH as defined as a delta cortisol response of >9.0 µg/dL. Based on our SIRS data and other work, our objective was to test if providing 7 days of Solumedrol treatment every 8 h to patients with severe sepsis with a delta cortisol response <13 µg/dL would improve 28-day survival.

Methods

Prospective, randomized, double-blind, placebo-controlled clinical trial was conducted at Harbor-UCLA Medical Center with the Internal Review Board (IRB) approval. Simplified Acute Physiology Score (APACHE III) was obtained on the day of entry into the study and on day 14. The principal investigator (Tayek) or study coordinator obtained the informed consent for the clinical trial. Waiver of consent was approved for this study with patients who did not have the capacity to consent and next of kin obtained consent.

ACTH (Cortropin) stimulation test (250 µg) was administered intravenously (IV) at time 0 and samples were drawn for cortisol at times 0, 30, and 60 min. Lab samples were obtained on entry into the study and prior to the first dose of blinded medication. Cortisol level, ACTH, and other assays were determined by radioimmunoassay and routine labs by the hospital laboratory.

Entry criteria required that patients over the age of 18 years who meet the criteria for severe sepsis or septic shock. Patients were excluded if they had human immunodeficiency virus, pregnant, do not resuscitate (DNR), chronic steroid use, or adrenal insufficiency as defined as all serum cortisol concentrations <20 µg/dL before and after the 60 min ACTH stimulation test. The cutoff number of <20 was obtained by consultation with 3 international experts who recommended <15, <18, and <20 as cut points to exclude from a randomized clinical trial. We adopted the most conservative estimate of the potential for adrenal insufficiency by selecting that all 3 cortisol values <20 µg/dL would be excluded from entry into the trial. Eleven patients met this criterion during the 124 patients’ consent for the entire clinical trial. The Vitamin A-arm of the study, where all patients had a delta cortisol response of >13 µg/dL to intravenous 250 µg of ACTH was recently published.⁷

Forty-four patients were randomized by the pharmacist based on a random table of numbers in the block size of 10. She used continuous numbering for each person who consented. Solumedrol 20 mg (NDC 0009-0047-22) or placebo was administered IV every 8 h for the first 7 days of study entry. The research pharmacist did the randomization, coding, preparing the IV Solumedrol and Placebo bags, and covering the IV bags so only she knew which product was provided to each patient. She administered the product to each patient. There was no reason to break the randomization code during the study trial.

Bloodstream infection, days in the intensive care unit (ICU), days on ventilator, and days on blood pressure agents were measured both before entry into the study and during the stay in the ICU. Solumedrol or placebo was administered in piggyback plastic bags every 8 h for 7 days. One of the 44 patients was mistakenly randomized with a normal cortisol response to ACTH (time 0 baseline of 33 µg/dL, which increased to 69 µg/dL at time 60 for a delta cortisol response of 36 µg/dL. He was randomized to receive a placebo. This person was the only one with a delta cortisol response >13 µg/dL in the clinical trial with sepsis, so his data were excluded from the analysis.

Statistical analysis was performed by analysis of variance with correction for multiple comparisons. Comorbidities were compared between groups for age, gender, number of intensive care unit (ICU) days before randomization, number of ventilatory days, number of days on blood pressure agents, temperature, blood pressure, pulse, respiratory rate, white blood cell (WBC), creatinine, glucose, albumin, bilirubin total, and body weight. Nearly 50% of patients required ventilator support. Mortality data were reported for both day 14 and day 28 of the hospital stay. A two-tailed P-value <.05 was used for determining significance, with correction for multiple comparisons. Data were expressed as mean ± SEM.

Results

The mean age was 51 ± 2 years (mean ± SEM) with 62% male. Heart rate (107 ± 4 vs 107 ± 4), systolic blood pressure (115 ± 5 vs 110 ± 4), diastolic blood pressure (59 ± 3 vs 55 ± 3), respiratory rate (24.5 ± 1.3 vs 24.7 ± 1.3), temperature (37.8 ± 0.2 vs 38.1 ± 0.3), Hematocrit (HCT, %) (22.2 ± 3.1 vs 25.4 ± 2.2), and sodium (137 ± 1 vs 137 ± 1) were similar in the Solumedrol versus Placebo groups. All patients had an ACTH stimulation test using 250 µg of ACTH IV and serum cortisol was measured at times 0, 30, and 60 min. Baseline cortisol of 32 ± 3 µg/dL increased to 37 ± 3 µg/dL at 30 min and 39 ± 2 at 60 min. There was no significant difference between the groups. All but one of the cortisol responses were <13 µg/dL. The one with a normal cortisol response to ACTH was removed from the study. Baseline urinary cortisol was measured and found to be similar in Solumedrol and Placebo groups (176 ± 23 vs 130 ± 26 µg/g creatinine), respectively.

Table 1 describes the two groups’ baseline APACHE III score, baseline labs, days in ICU, days on blood pressure agents, days on ventilator, and percent of patients with bacteremia. There was no significant difference between the two groups for any of the measured variables prior to administration of the Solumedrol or Placebo.

Table 1.

Baseline Data on Day 1 of Study.

Groups	APACHE III	WBC (1000)	Creatinine (mg/dL)	Entry day	Glucose (mg/dL)	Bacteremia	Days in ICU	Days on blood pressure agents	Days on ventilator
Solumedrol	59 ± 6	18.8 ± 2.2	2.7 ± 0.6	6.0 ± 1.4	138 ± 10	29%	5.3 ± 1.1	2.2 ± 0.7	4.2 ± 1.0
Placebo	59 ± 6	18.6 ± 2.6	1.9 ± 0.4	8.6 ± 4.0	168 ± 22	39%	7.2 ± 2.9	0.9 ± 0.3	6.8 ± 3.1

Abbreviations: WBC, white blood cell; ICU, intensive care unit.

After randomization, 20 mg of Solumedrol was given every 8 h for 7 days to 21 patients and a placebo was given to 22 patients. This was administered as a 1 cc IV piggyback infusion over 30 min of either medication or placebo and was blinded from all but the research pharmacist. Table 2 lists the outcome measurements. The APACHE III score and 14-day mortality were slightly but not significantly reduced in the steroid-treated group on day 14 (see Table 2). The serum albumin, number of days in the ICU, number of days on blood pressure agents, and days of ventilator were similar between the Solumedrol- and Placebo-treated groups. The 28-day mortality was lower in the Solumedrol group than the placebo-treated group (43 ± 11 vs 73 ± 10%, P < .05). (Please put the * for 28-day mortality on the 43 + 11% and not 73 + 10% in Table 2). In this pilot trial, patients with severe sepsis who had a blunted cortisol response to ACTH (<13 µg/dL) who were randomized to receive intravenous Solumedrol every 8 h for 7 days had a reduced 28-day mortality.

Table 2.

Days 14 and 28 Study Data (End of Study).

Groups	APACHE III (day 14)	14-day mortality	Day 14 albumin (g/dL)	Days in intensive care unit (ICU)	Days on blood pressure agents	Days on ventilator	28-Day mortality
Solumedrol	45 ± 7	43 ± 11%	2.3 ± 0.1	6.1 ± 1.1	3.0 ± 0.9	5.1 ± 1.1	43 ± 11%
Placebo	55 ± 6	59 ± 11%	2.1 ± 0.2	6.6 ± 1.2	2.6 ± 0.5	6.2 ± 1.4	73 ± 10%*

*P < .05.

Discussion

The following is a proposed mechanism behind the blunted or absent cortisol response to ACTH in sepsis. Proopiolmelanocortin production, via an increase in free cortisol results in a dissociation of the ACTH-cortisol axis.⁸ Approximately 9% of septic patients fail traditional ACTH-cortisol stimulation testing with 4% due to secondary adrenal insufficiency (AI) and 5% due to sepsis-related AI.⁹ In comparison, ∼50% to 70% of patients with septic shock have a <9 µg/dL increase in cortisol and/or serum cortisol <10 µg/dL after ACTH testing which is known as critically illness-related cortisol insufficiency (CIRCI).⁶ Seven days of hydrocortisone and fludrocortisone treatment in septic shock patients with CIRCI reduced 28-day mortality from 61% to 53%.⁶ Recent guidelines suggest that hydrocortisone given to patients with a CIRCI can reduce mortality.¹⁰ The reduction in sepsis mortality seen in this study may have been due to early treatment of CIRCI.⁶ A recent review suggests that corticosterone treatment of sepsis can improve 28-day mortality.¹¹ Newer machine learning models may help identify those who will benefit the most from corticosteroid treatment.¹²

Corticosteroid treatment in patients with COVID and acute respiratory distress syndrome (ARDS) has shown some benefits.^2,13,14 Low dose corticosteroid treatment reduces C-reactive protein (CRP) concentrations and improves oxygenation which may reduce the ARDS process seen in patients with COVID.¹⁵ The reduction in the inflammatory process may be one mechanism reducing mortality in COVID and ARDS.^2,13,14 Providing additional corticosteroid treatment, when the adrenal gland cannot produce adequate glucocorticoids for lung tissue, may reduce the degree of injury, inflammation, or infection as reflected by the reduced CRP levels and improve oxygen saturation.¹⁵ There are data to suggest that a dose of methylprednisolone to increase to normal plasma levels may be associated with reduction in intracellular bacterial growth and inflammatory cytokine (tumor necrosis factor-alpha, interleukin-1 beta, and interleukin-6) expressions.¹⁶ While a recent meta-analysis suggests that corticosteroids probably reduce mortality in ARDS patients,¹⁷ a better understanding of the host-tissue response to injury, infection, and inflammation is needed.

A limitation of this study was its small size which is subject to beta error. As part of a larger clinical trial, we demonstrated that ∼9% of septic patients have primary or secondary AI.⁸ Interestingly, the lack of steroid treatment in those patients did not alter their expected mortality. These data support the Society of Critical Care Medicine 2017 Guideline recommendation that steroid treatment should be considered when baseline cortisol is <10 µg/dL and/or when the delta cortisol response of <9 µg/dL. Our clinical trial provides supportive data for the treatment of CIRCI in patients with sepsis. Patients without an adrenal–cortical reserve may benefit from additional glucocorticoids in certain disease states such as COVID and ARDS.

Conclusion

In this pilot study, 28-day mortality was reduced in patients with a blunted cortisol response to ACTH who were randomized to receive 7 days of 20 mg of Solumedrol every 8 h versus matching placebo (43% vs 73%, P < .05). The number of days in the ICU, days on blood pressure agents, the number of days on the ventilator, and the 14-day mortality rate were not reduced in patients randomized to receive intravenous Solumedrol. Blunted serum cortisol response to ACTH testing of <13 µg/dL may be a marker of poor outcome like that seen in those with <9 µg/dL cortisol response. However, our pilot data do not support a change in clinical treatment decisions until these data can be confirmed in larger randomized clinical trials.

Authors’ Note

Sajad Hamel was responsible for the data management, analysis, and interpretation of the abstract presentation. Divya Birudaraju contributed to the writing of the draft manuscript. Dr. John A. Tayek was responsible for the design, funding, IRB approval, implementation, completion, statistical analysis, and manuscript completion.

Footnotes

Acknowledgments

We especially thank Roxanne Tanoviceanu, PharmD for her help with this research study. We also want to thank Vince Atienza for his help to identify two female patients with secondary adrenal insuffency during after hours (cortisols <1.0 μg/dL during their ACTH stimulation test) who were provided timely glucorticoid replacement therapy which likley saved their lives.

Declaration of Conflicting Interests

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work was partly funded by Pharmacia & UpJohn Company (grant number 7680).

ORCID iD

John A. Tayek

Supplemental Material

Supplemental material for this article is available online.

Appendix 1: Flowchart

Flowchart: 200 hospitalized patients were screened for sepsis and 124 consented to the study (76 did not meet entry criteria or refused to give consent).

A 250 µg ACTH stimulation test was performed in 124 patients and 63 were considered to have a normal ACTH-cortisol axis (43 patients had a baseline plasma cortisol level above 19.9 µg/dL and the increase was <13 µg/dL after 30 and 60 min of ACTH administration).

Of the 43 patients who started the study, 22 were randomized to treatment and 21 to placebo.

See supplement image.

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