Intensive care unit mortality and length of stay among critically ill patients with sepsis treated with corticosteroids: A retrospective cohort study

INTRODUCTION

Sepsis is a major contributor to mortality rates in the United States, and the standard pharmacologic treatment involves antibiotics, fluids, and vasopressors as needed.^[1,2] Despite tremendous progress in understanding its underlying mechanisms of sepsis, drugs targeting specific cytokine cascade pathways have not conclusively improved patient survival.^[3,4] As a result, corticosteroids have been used as adjuvant therapy for sepsis for decades.^[5] However, their safety and effectiveness in patients admitted to the intensive care units (ICUs) remain uncertain.^[6,7]

The previous randomized clinical trials (RCTs) have linked high-dose corticosteroid use with increased morbidity and mortality.^[8,9] However, the results of studies examining the effects of lower-dose corticosteroids on sepsis mortality are mixed.^[3,10] Systematic reviews of several observational studies and RCTs have not provided compelling evidence for or against the use of corticosteroids in patients with sepsis or septic shock.^[11] Some studies suggest that the use of corticosteroids is associated with reduced mortality and ICU length of stay (LOS).^[6] others did not.^[7,12]

Lu et al. used a publicly available clinical database to investigate corticosteroid use in patients with sepsis admitted to the ICU. They found no association between corticosteroid use and a decreased risk of infection, ICU LOS, or mortality.^[7] Conversely, Britt et al. found that corticosteroid use was associated with an increased risk of infection, ICU LOS, prolonged ventilator LOS, and mortality.^[12] Current clinical practice guidelines recommend using corticosteroids in patients with septic shock only after adequate fluid resuscitation and vasopressor treatment have failed to restore hemodynamic stability. However, the guidelines classified the recommendation as weak due to the low quality of available evidence.^[13]

Given the lack of consensus on the usefulness of corticosteroids for reducing sepsis mortality, clinical practices vary widely. Therefore, real-world studies are needed to add to the totality of evidence regarding the outcomes of corticosteroid use in patients with sepsis. As a result, we conducted a retrospective cohort study of patients with sepsis admitted to the ICU to evaluate the treatment effect of corticosteroids on 30-day ICU mortality and ICU LOS.

MATERIALS AND METHODS

Sepsis patients selection and definition

This study is designed as a diagnosis-based cohort entry restricted to admission into the ICU as shown in [Figure 1]. We defined patients with sepsis using the modified Angus abstraction criteria and relevant ICD-9-CM and ICD-10-CM codes. The abstraction process and programming was performed as described in Horng et al. and Iwashyna et al.^[16,17] and as programmed in the MIMIC Laboratory for Computational Physiology retrieved from mimic GitHub, Inc website (https://github.com/MIT-LCP/mimiccode/blob/master/concepts/sepsis/angus.sql). Specifically, we utilized a set of ICD-9-CM and ICD-10-CM codes and procedure codes for infection, acute organ dysfunction, and mechanical ventilation to retrospectively identify patients with severe sepsis. The Angus abstraction was then modified by including additional new ICD-9-CM and ICD-10-CM codes for sepsis, severe sepsis, septic shock and codes indicative of viral meningitis, cholangitis, and orbital cellulitis.^[16,17] A total of 13,425 patients with their first ICU admission for first sepsis diagnosis between 2008 and 2019 or latest data available were identified. Patients with zero (0) or missing sequential organ failure assessment (SOFA) score were excluded from the study. Patients younger than 18 years of age and with missing data or without documented laboratory tests and vital signs taken within the first 24 h of ICU admission were excluded from the study. For patients with multiple vital signs or laboratory tests records in the first 24 h, average record was considered.

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Figure 1:

Sepsis diagnosis-based cohort entry restricted to ICU admitted patients where the cohort entry date is selected after application of exclusion criteria. ICU: Intensive care unit; SOFA score: The Sequential Organ Failure Assessment.

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RESULTS

We restricted patient population to adult patients with first sepsis diagnosis and the corresponding ICU admission as shown in [Figure 1]. In [Figure 2], we present the flow chart of the cohort selection process including application of various inclusion and exclusion criteria as well as the final analytical sample. From the MIMIC-IV v0.4 database, a total of 54,911 hospitalized patients diagnosed with sepsis based on modified angus abstraction between 2008 and 2019 were identified. We identified 13,425 adult patients with first diagnosis of sepsis and first ICU admission. After, applying exclusion and inclusion criteria, we identified in the final sample, 1,235 who were treated with steroids (steroid users) and 8,863 who were not treated with steroids (non-users).

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Figure 2:

Flow chart on the cohort selection process.

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[Table 1] provides an overview of the baseline characteristics of the individuals included in the study, categorized by their steroid prescription status. The table includes both unweighted and weighted standardized differences calculated using the AIPW method. The weighted standardized differences were below 0.10 and were smaller than the values obtained for unweighted standardized differences, indicating a balanced distribution of characteristics between steroid users and non-users.

[Table 2] shows crude estimates of steroid use on 30-day ICU mortality, ICU LOS, mechanical ventilation, new onset of infection, and incidence of hyperglycemia. A total of 1,732 patients died in the ICU within 30 days of admission of which 324 patients were treated with steroids. 30-day ICU mortality was significantly different between steroid users versus non-users (P < 0.0001). Average ICU LOS was higher among steroids users compared with non-users (7.08 vs. 5.20 days; P < 0.0001). Crude assessment shows that steroid users had higher average ICU LOS than non-users by 2.6 fractional days on average. A total of 3,166 patients were incident users of mechanical ventilation after index date.

Crude estimation shows that incident use of mechanical ventilation was significantly lower in steroids users versus non-users (P < 0.0001). A total of 8,161 patients experienced hyperglycemia following index date. Crude estimation shows that new diagnosis of hyperglycemia was significantly lower in steroids users versus non-users (P < 0.0001).

The result in [Table 3] shows the ATE of steroids on various primary and secondary outcomes after adjusting for confounders. Steroid use significantly increased average 30-day ICU mortality compared to non-use (ATE, 0.127; 95% confidence interval [CI], 0.083–0.171; P < 0.0001). Steroid use significantly increased average ICU LOS of patients with sepsis compared to non-use (ATE, 1.773; 95% CI, 1.036–2.510; P < 0.0001). Considering the secondary outcomes, steroid use significantly increased the incidence of mechanical ventilation use compared to non-users (ATE, 0.181; 95% CI, 0.130–0.233; P < 0.0001). Steroid use significantly increased new onset of infection compared to non-steroid use (ATE, 0.063; 95% CI, 0.032–0.094; P < 0.0001). Steroid use significantly increased the incidence of hyperglycemia compared to non-steroid use (ATE, 0.024; 95% CI, 0.013–0.035; p = 0.0004).

The sensitivity analysis revealed that there was no significant difference in the ATEs when comparing subgroups of individuals who received low-dose, long-duration corticosteroid treatment with those who did not receive any corticosteroid treatment [Supplementary table 1]. Specifically, the ATEs generated were similar in magnitude and direction to those obtained when corticosteroid prescription was dichotomized into “yes” or “no” categories.

DISCUSSION

Among patients admitted to the ICU and who were diagnosed with sepsis, we found that, the use of corticosteroids significantly increased average 30-day ICU mortality, average ICU LOS, incidence of mechanical ventilation use, new onset of infection and incidence of hyperglycemia. Our findings are consistent with previous studies that examined impact of corticosteroid on patients with sepsis or septic shock admitted in the ICU. Britt and colleagues conducted a case-control study of patients treated with corticosteroids in the ICU and reported similar findings, including increased ICU LOS, increased ventilator LOS, increased new onset of infection, and an upward trend in mortality rates.^[12] Similarly, Lu et al. conducted a study using data from MIMIC-III (an earlier version of MIMIC-IV) and determined that administering systemic corticosteroids to patients with septic shock resulted in higher 30-day mortality rates among those with metastatic cancer, while it did not improve mortality rates in immunocompromised patients.^[7] They also observed that use of systemic corticosteroids was associated with hemodynamic stability, long ICU and hospital LOS and an increased risk of hyperglycemia.^[7] Collectively, these results indicate that corticosteroid use in patients with sepsis may result in noteworthy negative consequences and should be employed with careful consideration.

The findings of this research are a valuable addition to the ongoing discourse regarding the mortality implications of utilizing corticosteroids to treat patients with sepsis and septic shock. The two most recent RCTs on corticosteroid treatment for sepsis reported contradictory conclusions on 90-day mortality.^[22,23] The ADRENAL trial, which included 3,658 patients with septic shock, found no statistically significant difference between hydrocortisone and placebo in terms of 90-day mortality.^[22] In contrast, the APROCCHSS trial, which included 1,241 patients with septic shock, reported that hydrocortisone and fludrocortisone combination reduced 90-day mortality compared to placebo.^[23] These trials were included in a linked systematic review with other RCTs comparing corticosteroids with placebo in patients with sepsis and/or septic shock. The BMJ Rapid Panel of Recommendation carefully reviewed and translated the evidence using GRADE methodology for trustworthy guidelines and concluded that while corticosteroids may have a positive effect on mortality, the evidence was considered uncertain due to the inconsistency of results across RCTs.^[24,25] Although recent meta-analyses have been conducted, a conclusive consensus has yet to be reached regarding the use of corticosteroids in patients with sepsis or septic shock.^[6,24,26-31] Our study examined patients admitted to the ICU with sepsis or septic shock and found that administering corticosteroids was associated with increased ICU mortality rates. However, other investigations have reported no reduction in mortality or LOS in the ICU.^[3,10,32]

Corticosteroids are known to have immunosuppressive effects, as documented in previous studies.^[33] Severe depression of the immune system due to circulating inflammatory mediators during trauma and infection is also well understood.^[34] The combination of these two effects on the immune system could explain the increased onset of new infections and ICU mortality found in our study. Furthermore, all-cause immunosuppression has been associated with an increased risk of mortality.^[35-38] Our study found that the mean ICU LOS was prolonged by 2 days in the corticosteroid user group, and a higher percentage of patients in this group required mechanical ventilation (41.7%). These results could be attributed to the secondary effect of the increased infection rate in the corticosteroid group. In addition, hyperglycemia is a well-known adverse effect of corticosteroids,^[7] which could explain why the percentage of patients with incident hyperglycemia (5.18%) was higher in the corticosteroid group. Overall, these findings provide important insights into the potential adverse effects of corticosteroids in patients with sepsis and suggest that clinicians should carefully consider their use in this population.

This study has several strengths and limitations. The MIMIC-IV data are the most recent version of the MIMIC database which included large patient population size with updated real-world electronic medical records. As a result, evidence generated is updated evidence among ICU patients and which represents the critical care practice reality within the most recent decade. This study utilized the novel AIPW approach to account for the inherent selection bias resulting from “self-selection” toward treatment with corticosteroids to generate doubly robust estimates which are considered unbiased ATEs of corticosteroids use.^[20] Specifically, AIPW approach generates an unbiased ATE of corticosteroid use in terms of 30-day ICU mortality, ICU LOS, new onset of infection, diagnosis of hyperglycemia and use of mechanical ventilation.

While interpreting the results of this study, it is important to consider its limitations. The MIMIC-IV database, which was the source of the data used, is a real-world data collected from a single center, which may limit external validity and generalizability beyond BIDMC centers in Massachusetts. However, as intensivists and other clinicians are expected to be guided by similar clinical practice guidelines, we do not anticipate a significant difference in practice across ICUs in the United States. Nevertheless, the included variables were limited to those available in the data, which may have resulted in unmeasured residual confounding factors. The MIMIC-IV data did not include a date of death variable, only a 30-day mortality variable, which limited our ability to assess mortality for longer periods, such as 60-day or 90-day mortality. Therefore, the study only provides evidence on short-term mortality assessment. Finally, the study utilized data from 2008 to 2019, and treatment guidelines may have changed over time. While it may be helpful to adjust for calendar year in the propensity score model in future studies, this limitation should be considered when interpreting the current findings.

CONCLUSION

This study’s findings highlight that administering systemic corticosteroids, such as dexamethasone, hydrocortisone, and methylprednisolone, to treat sepsis in ICU patients is associated with increased rates of 30-day ICU mortality, ICU LOS, mechanical ventilation use, new onset of infection, and hyperglycemia diagnosis. While there are clinical practice guidelines in place for the use of corticosteroids in sepsis patients, the evidence supporting their use remains weak and uncertain. In light of the findings presented in this study and the current literature, we recommend that clinicians treating sepsis patients in the ICU remain diligent in their decision-making process when prescribing corticosteroids, taking into account all available evidence and patient preferences.