Sepsis is a syndrome that is defined by organ dysfunction because of a dysregulated host immune response to the presence of infection. Sepsis has high mortality rates, particularly in low-income countries, and is associated with significant long-term morbidity and health care costs.1,2 Septic shock is a more severe form of the sepsis syndrome that is characterized by the presence of sepsis together with persistent hypotension requiring vasopressors after adequate fluid resuscitation and hyperlactemia (serum lactate ≥2.0 mmol/L).3
The cornerstones of the management of septic shock are prompt recognition, resuscitation including early adequate antimicrobial therapy, and perhaps most importantly, source control. In addition to these broadly accepted therapies for septic shock, a variety of adjunctive therapies have been used.4–15 Some of these adjuncts target the immune dysregulation, which is a defining characteristic of septic shock, whereas others target metabolic pathways. Corticosteroids are one group of drugs that have been used to attenuate and modify the inflammatory response in septic shock. There have been numerous trials testing the use of corticosteroids in septic shock over the last 40 years. The use of corticosteroids in septic shock has waxed and waned in response to conflicting results from the various trials.
This chapter reviews the role of adjunctive corticosteroids in the treatment of septic shock. We first discuss the biological rationale for the use of corticosteroids in septic shock and then describe the evolution of the clinical evidence culminating in the recently published ADRENAL and APROCCHSS trials and the subsequent meta-analyses. Finally, we outline the unresolved questions that continue to prompt debate in the critical care community.
Endogenous corticosteroids are a critical component of the host response to sepsis. Cortisol is the principal corticosteroid secreted by the adrenal cortex. It has both glucocorticoid and mineralocorticoid actions. The synthetic corticosteroids commonly used in clinical practice (prednisolone, methylprednisolone, dexamethasone, hydrocortisone) have varying potencies of glucocorticoid and mineralocorticoid action (Table 1).
Corticosteroids have effects on the immunological and cardiovascular systems that are of potential benefit in the treatment of septic shock. They also have wide-ranging effects on other body systems that contribute to their adverse effects profile.
Corticosteroids exert their effects by modulation of gene transcription. The intracellular corticosteroid receptor, which is expressed in all nucleated cells, binds to corticosteroids and the steroid-receptor complex penetrates the nucleus, where it binds to certain genes and modulates transcription.16,17 In addition, there are “non-genomic” effects of corticosteroids that are not mediated by transcription. These effects include rapid inhibition of ACTH release, disruption of the T-cell receptor complex, and hippocampal stimulation, among others.18
Corticosteroids exert wide immunosuppressive and anti-inflammatory effects through the inhibition of nuclear factor kappa beta (NFkb). The synthesis of proinflammatory cytokines such as tumor necrosis factor alpha (TNF-alpha), interleukin 1 (IL-1), and interleukin 6 (IL-6) is inhibited.19 Lymphocyte count decreases through redistribution and steroid-mediated apoptosis and neutrophil count increases through increased release from bone marrow and reduced removal of old neutrophils.20,21 Corticosteroids reduce the migration of inflammatory cells to sites of injury or infection by reducing the expression of endothelial adhesion molecules, intercellular adhesion molecules, prostaglandins (mediated through phospholipase A2 inhibition), and chemokines.22–24
Corticosteroids reduce the production of inducible nitric oxide synthase (iNOS), thereby reducing the endothelial production of nitric oxide, a potent endogenous vasodilator that is upregulated in sepsis. The vasopressor response to catecholamines such as epinephrine and norepinephrine is enhanced by exogenous corticosteroids,25 as is the release of endogenous catecholamines by neural cells.26
Thus, the rationale for the use of corticosteroids in septic shock is that the host inflammatory response is attenuated, and cardiovascular hemodynamics and tissue perfusion are improved.
Evolution of Clinical Evidence
The first randomized-controlled trial (RCT) of corticosteroids in septic shock was published in 1976.27 This trial, using 2 different types of corticosteroids (3 mg/kg dexamethasone or 30 mg/kg methylprednisolone), showed a significant reduction in mortality in patients treated with corticosteroids from 42.5% to 14%. The use of corticosteroids in septic shock gained popularity after this publication. Two major RCTs were published in 1984 and 1987.28,29 Both these trials used 30 mg/kg methylprednisolone as the intervention and both showed no improvement in mortality compared with placebo. Although both RCTs showed the efficacy of corticosteroids in reversing the shock state, one29 showed an increase in mortality in the subgroup of patients with elevated creatinine who received corticosteroids. The early enthusiasm for corticosteroids in septic shock dissipated after the publication of these results.
Despite a failure to replicate a mortality benefit, small RCTs conducted in the 1990s showed that lower dose corticosteroids (200 to 300 mg of hydrocortisone/d) improved shock reversal30,31 and the pressor response to vasoactive agents.32 In addition, the concept of relative adrenal insufficiency (RAI)33 emerged, whereby the endogenous cortisol release in response to sepsis was theorized to be insufficient for the magnitude of the stressor. This syndrome was identified by a “blunted” cortisol response to exogenously administered corticotropin. It was hypothesized that patients diagnosed with RAI would be more likely to respond to adjunctive corticosteroid treatment than would those with a “normal” adrenal response. RAI was broadened to include dysfunction of the hypothalamic-pituitary-adrenal axis and tissue insensitivity to glucocorticoids that occurs in critical illness. The term critical illness-related corticosteroid insufficiency was coined to describe this phenomenon.34
This led to 2 major RCTs that were published in the 2000s. The Ger-Inf-05 trial35 published in 2002 recruited 299 patients and compared a 7-day course of IV hydrocortisone 200 mg plus oral fludrocortisone 50 mcg to placebo. Shock reversal was improved in the steroids group, but overall mortality was not significantly improved. However, mortality was significantly reduced in steroid-treated patients who had a blunted cortisol response to corticotropin, seemingly adding weight to the RAI theory. The CORTICUS trial36 compared a 5-day course of hydrocortisone 200 mg (followed by a 6 d taper) to placebo. Recruitment was ceased early at 499 patients because of slow recruitment, leading to withdrawal of funding. This trial failed to show mortality benefit overall or in the corticotropin nonresponder subgroup. Secondary infections were higher in the corticosteroid group.
Despite being larger than previous trials of low-dose corticosteroids, both the Ger-Inf-05 and CORTICUS trials were ultimately underpowered to answer the question of mortality benefit. Both trials were potentially confounded by the use of etomidate, an induction agent that is a known inhibitor of corticosteroid synthesis in the adrenal glands.37,38 There were conflicting results with respect to corticotropin responders, who had a higher mortality with corticosteroid treatment in the Ger-Inf-05 trial and no difference in mortality in the CORTICUS trial. The proportion of corticotropin responders was much higher than anticipated in Ger-Inf-05 and the exact significance of this was unknown. Overall, the debate on corticosteroids in septic shock continued. There was a high degree of uncertainty among clinicians on the role of corticosteroids as indicated by global surveys.39 Between 2009 and 2017, several small RCTs40–46 (sample sizes 38 to 206) were published. None were powered adequately to satisfactorily determine whether corticosteroids reduced mortality in patients with septic shock.
In early 2018, 2 large RCTs examining the role of corticosteroids in septic shock were reported. The ADRENAL trial47,48 randomized 3800 patients with septic shock in 69 intensive care units (ICUs) from 5 countries (Australia, New Zealand, UK, Denmark, and Saudi Arabia) to hydrocortisone 200 mg administered daily by continuous infusion or placebo for 7 days, and reported no significant difference in 90-day mortality between the 2 groups (27.9% vs. 28.8%, P=0.5). In patients assigned to receive hydrocortisone, there were significant improvements in some of the secondary outcomes including faster shock resolution, shorter duration of mechanical ventilation, reduced length of stay in ICU, and reduced need for blood transfusion. However, there were no significant differences in other secondary outcomes such as time to hospital discharge, recurrence of shock, recurrence of mechanical ventilation, new bacteremia/fungemia, receipt of renal replacement therapy, and 6-month mortality.48 The APROCCHSS trial49 (n=1241) was conducted in 34 French ICUs and was originally designed as a 2-by-2 factorial RCT comparing the effect of hydrocortisone plus fludrocortisone, drotrecogin alfa, and their respective placebos on mortality in septic shock. After the removal of drotrecogin alfa from the market in 2011, APROCCHSS continued as a parallel-group trial of hydrocortisone plus fludrocortisone versus placebo. Patients assigned to hydrocortisone plus fludrocortisone had significantly reduced 90-day mortality (43% vs. 49.1, P=0.03). Among the secondary outcomes, ICU-related, hospital-related, and 180-day mortality were significantly reduced, but not 28-day mortality. Patients in the hydrocortisone plus fludrocortisone group also had a significantly shorter time to weaning from mechanical ventilation, vasopressors, and reaching a Sequential Organ Failure Score <6.
The adverse event rate was higher in the hydrocortisone group in ADRENAL, but this was driven largely by hyperglycemia. The serious adverse event rate was higher in APROCCHSS compared with ADRENAL, but not significantly different between the 2 groups. Overall, both trials confirmed the safety of 200 mg hydrocortisone daily in patients with septic shock. Earlier concerns related to superinfection were not replicated in these larger and adequately powered RCTs.
Three meta-analyses50–52 have been reported since the publication of ADRENAL and APROCCHSS. They have used slightly different methodologies and inclusion criteria and have hence reported slightly divergent results. The largest meta-analysis51 included data from 42 RCTs and found no difference in short-term mortality and possibly a small benefit in long-term mortality (relative risk, 0.94; 95% confidence interval, 0.89-1.00). The meta-analyses50,52 that included only RCTs of low-dose corticosteroids found no differences in either short-term or long-term mortality. ICU length of stay was reduced significantly in all 3 meta-analyses, whereas the duration of shock and mechanical ventilation was reduced in 2.
In summary, the evidence base for corticosteroids in septic shock has evolved from small studies of short-course, high-dose corticosteroids in the 1970s and 1980s to small studies of longer course, low-dose corticosteroids in the 1990s and 2000s. In 2018, the 2 largest RCTs of corticosteroids in septic shock were published and some of the unresolved questions from previous decades have been answered (Table 2). There is no, or at best a small, mortality benefit with the use of low-dose corticosteroids in septic shock. Corticosteroids lead to faster resolution of shock and reduced duration of mechanical ventilation and ICU length of stay. These secondary outcomes are important even in the absence of a mortality benefit as they are both patient centered and likely to be beneficial from a health resource usage perspective. The safety of hydrocortisone at a dose of 200 mg per day has also been confirmed.
The Debate Continues
There are, however, unresolved questions that remain and will continue to be debated by the critical care community (Table 3).
Differences in Mortality Benefit Between ADRENAL and APROCCHSS
An important distinction between the results of ADRENAL and APROCCHSS was the divergent observation of a mortality benefit. There were differences between the 2 trials with respect to trial design, inclusion-exclusion criteria, and the interventions. A potential explanation may lie in differences in the inclusion criteria, mainly the minimum vasopressor dose (0.25 mcg/kg/min norepinephrine equivalent) and Sequential Organ Failure Score (of 3 or 4 in 2 organs) required for randomization into APROCCHSS. The need for mechanical ventilation was an inclusion criterion in ADRENAL, but not in APROCCHSS. The patients in APROCCHSS had a higher mean lactate concentration at baseline, a greater proportion of patients requiring renal replacement therapy at randomization, and higher baseline mortality compared with ADRENAL, raising the question of whether the APROCCHSS trial recruited a sicker cohort of patients. However, a priori subgroup analyses of ADRENAL showed no treatment effect on mortality in patients with a higher Acute Physiology and Chronic Health Evaluation II score (APACHE >or<25) or with a higher norepinephrine equivalent dose (>15 or<15 mcg/min) at randomization.
It is unclear whether corticosteroids have a mortality benefit in sicker patients. However, the secondary outcome benefits, which are of some importance, were observed in both APROCCHSS and ADRENAL, and many of them were confirmed in meta-analyses incorporating earlier trials. Thus, corticosteroids, if they are to be used, should not be withheld in patients with septic shock perceived to be less sick, or requiring less than an arbitrary threshold dose of vasopressors. The other key difference between the 2 trials is the use of fludrocortisone in the APROCCHSS trial. Its potential role is discussed in more detail below.
Role of Fludrocortisone
It has been shown that the administration of aldosterone can restore vascular endothelial alpha-1 receptor expression in septic shock models.53 Fludrocortisone is a synthetic mineralocorticoid receptor agonist that may be used to upregulate alpha-1 receptors and hence improve sensitivity to exogenously administered catecholamines. It is available only for enteral administration. The efficacy of fludrocortisone in septic shock has been evaluated in 3 trials: Ger-Inf-05, COIITTS,54 and APROCCHSS. Of these, only one trial (APROCCHSS) reported a mortality benefit in the intention-to-treat analysis; in the Ger-Inf-05 trial, a reduction in mortality was observed in the corticotropin nonresponders, although this differential treatment effect was not reported in the APROCCHSS trial. However, pharmacodynamic and pharmacokinetic considerations suggest that it is unlikely that the mortality benefits observed were driven by fludrocortisone. The mineralocorticoid receptor has equal affinity for glucocorticoids and mineralocorticoids in vitro, and hence should be activated by circulating cortisol or administered hydrocortisone.55 Hydrocortisone administered at a supraphysiological dose of 200 mg per day has sufficient mineralocorticoid activity that exogenous fludrocortisone should not be necessary. Pharmacokinetic studies have shown that fludrocortisone has a plasma half-life of 1.4 hours.56 Once-daily dosing, as was used in both Ger-Inf-05 and APROCCHSS, is unlikely to have resulted in sufficient fludrocortisone levels throughout the treatment period. The absorption of fludrocortisone in patients with septic shock is unreliable, with 1 in 3 patients having undetectable fludrocortisone plasma levels after enteral administration.57 Although a beneficial effect of fludrocortisone cannot be excluded, an RCT comparing hydrocortisone versus hydrocortisone and fludrocortisone is necessary to answer this question.
Relevance of Corticotropin Responsiveness
Sepsis has long been recognized as a heterogeneous entity.33 The concept of RAI has been used to identify a subgroup of patients with septic shock who may be more likely to respond to corticosteroid treatment. Despite early evidence from Ger-Inf-05 that corticotropin nonresponders may benefit from corticosteroids, subsequent larger trials (CORTICUS and APROCCHSS) failed to replicate this differential effect. It should now be accepted that corticotropin response is not a clinically useful test to select septic shock patients for corticosteroid administration. Recent reviews including that of an international task force on critical illness-related corticosteroid insufficiency concluded that there was no reliable test to diagnose adrenal insufficiency in critically ill patients.58,59 However, there may be other methods of phenotyping sepsis that could be used to determine which patients benefit from corticosteroids. Biomarkers and genetic tests may in the future be able to identify inflammatory phenotypes where corticosteroids are beneficial.60
Dosage and Mode of Administration of Hydrocortisone
The current evidence supports the use of hydrocortisone at a dose of 200 mg per day for 7 days without tapering. Additional hydrocortisone (300 mg compared with 200 mg) does not seem to have any benefits and may increase the rate of shock recurrence after cessation of hydrocortisone.61 Longer courses, as used in CORTICUS because of the 4-day taper after the 7-day course, also do not have any proven benefit. It is unknown whether even lower doses of hydrocortisone, and courses shorter than 7 days, could be used safely in septic shock. This is one of the potential topics for future research.
The ADRENAL trial used a continuous infusion of hydrocortisone, whereas most of the other trials have used bolus doses, typically hydrocortisone 50 mg administered 6-hourly. There are few direct comparisons of bolus versus infusion of hydrocortisone. One trial showed no difference in shock reversal, but fewer episodes of hyperglycemia with hydrocortisone infusion. A meta-analysis50 concluded that infusion versus bolus did not have any differential effect on mortality. It is possible that the lower adverse event rate in ADRENAL compared with APROCCHSS was at least partially driven by the use of hydrocortisone infusion. Although there may be some minor benefits with the use of infusion, the requirement for dedicated venous access makes infusions less practical, and in the absence of a clear benefit, hydrocortisone infusion cannot specifically be recommended over bolus dosing.
Tapering of corticosteroids has been used, for example in CORTICUS, as it has been observed that inflammatory markers can increase after the cessation of corticosteroids.62 However, neither of the recent large trials (ADRENAL and APROCCHSS) used a tapering strategy. Recurrence of shock was not different between the hydrocortisone and placebo groups in ADRENAL. A recent meta-analysis50 also did not find any beneficial effect from a tapering strategy. Current evidence does not support the use of tapering.
Time From Onset of Shock to Corticosteroid Administration
There are no RCTs directly comparing the different times at which corticosteroids were first administered after the onset of septic shock. Two small cohort studies, 1 retrospective63 and 1 prospective,64 both suggested that earlier administration of corticosteroids after the onset of shock was associated with improved survival. In addition, the study by Katsenos et al,64 reported a reduction in cytokine production among those patients receiving steroids <9 hours of the onset of shock. In the 2 largest RCTs, ADRENAL and APROCCHSS, the duration of septic shock had to be at least 4 and 6 hours, respectively, to be eligible for enrollment, but not >24 hours. In the CORTICUS and Ger-Inf-05 trials, patients had to be in septic shock for only 1 hour to be included. However, CORTICUS enrolled patients who had a shock duration up to 72 hours, whereas Ger-Inf-05 only included patients whose shock duration was <8 hours. The observed mortality benefit in the treatment group in the Ger-Inf-05 trial was restricted to the corticotropin responders. A post hoc analysis in CORTICUS showed no difference in mortality rates in patients who received the study drug within 12 hours of recruitment. An analysis of the Surviving Sepsis Campaign database of 8992 patients who received steroids for septic shock suggested that there was an association with increased adjusted hospital mortality when prescribed within 8 hours, but no significant difference in hospital mortality when prescribed between 8 and 24 hours.65 Current evidence therefore does not support a strong recommendation to guide the timing of corticosteroid therapy initiation for patients with septic shock.
Health Economic Benefits
Hydrocortisone is a relatively inexpensive and safe drug. Although it may not have a mortality benefit in septic shock, it does have several benefits from a health resources utilization perspective: shorter ICU stay, shorter time on mechanical ventilation, and faster shock resolution. An ICU bed can cost several thousands of dollars per day depending on the individual health system, whereas a 7-day course of hydrocortisone costs <$150. Rigorous health economic analyses of data from trials such as ADRENAL and APROCCHSS are required as evidence of health economic and resource utilizations benefits are likely to have a major impact on clinical practice and sepsis guidelines.
Several avenues for further investigation are likely to be pursued in the coming years. Distinguishing corticosteroid-responsive phenotypes from nonresponsive phenotypes, on the basis of genetic or biochemical markers, is one such example. The underlying mechanisms that determine vascular responsiveness in the individual and variability in vascular responsiveness are yet to be elucidated. The role of fludrocortisone, the duration of corticosteroid therapy, and the potential synergy between ascorbic acid, thiamine, and hydrocortisone are all areas where further research is required.
Septic shock is a heterogeneous syndrome for which there are some widely accepted and evidence-based treatment strategies. Corticosteroids are an adjunctive therapy for septic shock that have been studied extensively and generated significant debate in the critical care community. With new evidence from large multicenter RCTs and subsequent meta-analyses, we can conclude that hydrocortisone is safe, and results in faster resolution of shock, reduced duration of mechanical ventilation, and reduced ICU length of stay. Its role in the reduction of mortality remains unclear. Significant unresolved issues including the role of mineralocorticoid therapy, dose, duration, and administration method of hydrocortisone, determining steroid-responsive septic shock phenotypes and health economic benefits, among others, will continue to fuel debate.
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