Corticosteroids have been used for more than 60 years to treat various forms of severe infection. Yet, corticotherapy remains one of the most controversial treatments for sepsis. The past 2 years, guidelines for clinical practices about corticosteroids for sepsis have been released by at least five entities (1–5). All but one (2) of these guidelines recommended the use of corticosteroids only in patients with septic shock who are poorly responsive to fluid replacement and vasopressor therapy. One group suggested that corticosteroids should be given in patients with sepsis (weak recommendation) with or without shock (2). In 2018, five systematic reviews addressing the effects of corticosteroids in sepsis were published (6–10). The number of included trials differed between systematic reviews and ranged from 14 to 42. The relative risk (RR) of death in the short-term varied from 0.91 to 0.96 and the upper limit of its 95% CI varied from 0.98 to 1.03. Then, the magnitude and direction of the pooled RR of dying in the short-term favoring corticosteroids were consistent across these five meta-analyses which differed mainly by the presence of some imprecision in the point estimate. Among the trials of corticosteroids for sepsis, five trials deserve specific attention for three main reasons (11–15). First, they account for more than 60% of all participants in trials of corticosteroids for sepsis. Second, they were at moderate to low risk of bias in the five domains of allocation, blinding, incomplete data, selective reporting, and other potential sources of bias. Third, they were conducted after the first consensus definition for sepsis (16) and their target population was septic shock. Two of these trials found survival benefits from corticosteroids (11,15) and three did not (12–14), and will be referred to as “positive” and “negative” trials, respectively. This article explores potential explanations for discrepancies in trials’ findings in four domains, that is, study population, experimental interventions, outcomes, and risk of bias.
COMPARISON OF TRIALS’ POPULATION
Eligibility criteria and main observed basal characteristics of patients are displayed for the five trials in Supplemental Table 1 (Supplemental Digital Content 1, http://links.lww.com/CCM/E729). Both “positive” (11,15) and “negative” trials (12–14) included adults at the early phase of septic shock. There was no evidence for difference between trials in the characteristics of infection with predominantly community-acquired nonsurgical sepsis related to lung infection and slightly higher proportion of infections caused by Gram-negative than Gram-positive bacteria. The main differences in terms of eligibility criteria between the “positive” and “negative” trials were for the definition of shock and organ failures. Although for all trials entry criteria requested the participants to be refractory to fluid therapy and to receive vasopressors, only the “positive” trials required a minimal dose of catecholamines (11,15). This difference in the definition of shock translated into greater vasopressor-dependency in “positive” versus “negative” trials’ participants. On average, the dose of norepinephrine was 1.0 μg/kg/min in the “positive” trials and 0.4 μg/kg/min in the “negative” trials. Likewise, “positive” trials’ patients had values for baseline mean blood pressure roughly 10 points lower than those included in the “negative” trials. The “positive” trials required as entry criteria that participants had more severe and numerically more organ failures than it was requested in the “negative” trials. This difference resulted in higher severity of illness scores with about plus 9 points of Simplified Acute Physiology Score II scores. Likewise, arterial lactate concentrations were higher by roughly 22%.
COMPARISON OF TRIALS’ INTERVENTIONS
Trials used different formulations for hydrocortisone that is hydrocortisone succinate/hemisuccinate (11,12,14,15) or phosphate (13) (Table 1). There is no evidence for any difference in pharmacokinetics and pharmacodynamics between these formulations that may be relevant for the management of sepsis. All trials used IV hydrocortisone as a daily dose of 200 mg, and cumulated dose was grossly similar. Hydrocortisone was administered as intermittent bolus in all except one trial (14) and without taper off except in two trials (12,13). A recent systematic review and meta-analysis found no evidence for difference in survival between continuous infusions versus intermittent bolus administration of corticosteroids (17). Indirect comparison of the two modes of corticosteroids administration (50 trials, 11,233 participants) found a p value of 0.52 for subgroup difference in all-cause 28-day mortality. Likewise, direct comparison of continuous versus bolus administration of hydrocortisone found no evidence for difference in the risk of death at 28-day (p = 0.82; three trials; 310 participants). By contrast, the reduction in the risk of death at 28-day was significantly greater in trials where corticosteroid treatment were not tapered off (test for subgroup differences: χ2 = 3.94; p = 0.05; I2 = 74.6%) (17). In keeping, in the three trials that did not taper off corticosteroids (11,14,15) the direction of the absolute reduction in mortality favored active treatment versus placebo, albeit some imprecision in one trial (14) (Supplemental Table 1, Supplemental Digital Content 1, http://links.lww.com/CCM/E729).
The main difference with regard to experimental interventions between the “positive” and “negative” trials was the administration of fludrocortisone on top of hydrocortisone therapy (Table 1). Fludrocortisone has glucocorticoid and mineralocorticoid activities that are respectively 10- and 125-fold greater than that of hydrocortisone (18). Albeit cortisol and aldosterone bind the mineralocorticoid receptor (MR) with equal affinity, the transcriptional response of the MR is approximately 100-fold higher for aldosterone than for cortisol (19). Furthermore, the MR has several isoforms of which some bind exclusively mineralocorticoids (20). Thus, the mineralocorticoid activity of hydrocortisone is qualitatively and quantitatively different from that of fludrocortisone. Finally, the MR is expressed in many other tissues than the kidney and its agonists may have pleiotropic effects beyond salt and water regulation, and in particular effects on innate immunity (18). Then, studies in both small and large animals provided evidence that MR agonists attenuate endotoxin and bacterial infections related systemic and tissues inflammation. The MR agonists also improved survival time and survival rates in these models of sepsis (18). One trial (500 participants) has compared hydrocortisone plus fludrocortisone versus hydrocortisone alone in adults with septic shock (21). The primary comparison in this 2 × 2 factorial trial was about intensive insulin therapy versus usual care in corticosteroid-treated adults with septic shock. To minimize heterogeneity in the administration of corticotherapy, participants were allocated at random to receive open labeled fludrocortisone (50 μg/d) in addition to hydrocortisone or hydrocortisone alone. In this trial, there was a –3% (nonstatistically significant) absolute difference in in-hospital mortality rates (primary outcome) between patients treated with hydrocortisone plus fludrocortisone versus those treated with hydrocortisone alone. Taken together preclinical and trials (11,15,21) findings suggested that, in septic shock, the combination hydrocortisone plus fludrocortisone is more likely to be associated to survival benefits than hydrocortisone alone.
COMPARISON OF TRIALS’ OUTCOMES
The primary outcome was survival time in one trial (11), all-cause mortality at 28-day in one trial (12) and at 90-day in two trials (14,15), and the number of days alive and free of kidney failure in one trial (13). Two trials used modified intent-to-treat analysis to assess the primary outcome in the subset of patients who were nonresponders to 250 μg IV bolus of adrencorticotrophin (11,12). The direction of the point estimate for the primary outcome favored corticosteroids in three trials (11,14,15), albeit the reduction in all-cause mortality was not statistically significant in one (14) of these trials. These differences in the measurements of corticosteroids effects on survival are unlikely to account for “positive” versus “negative” trials.
All trials except one (13) found similar substantial benefits from corticosteroids in secondary outcomes. Then, corticosteroids hastened the weaning of patients from vasopressor and from mechanical ventilation, accelerated the recovery from organs’ failure, and shortened length of stay at hospital. These trials found roughly similar safety profiles for corticosteroids with no evidence for increased risk of gastrointestinal bleeding or superinfection, and increased risk of metabolic complications and acquired muscle weakness.
COMPARISON OF TRIALS’ RISK OF BIAS
The five trials (11–15) were very well designed, conducted, and reported and could be considered at low risk of bias (Table 2). They used high standard methods for random sequence generation, appropriate allocation concealment, and robust masking of study drugs. Trials had no-to-few patients lost to follow-up. There was no remarkable difference in risk of bias between “positive” and “negative” trials.
In summary, sepsis trials that found survival benefits from corticosteroids differed from trials that did not find such survival benefits, mainly in two domains related to population and intervention (Table 3). Then, factors that increase the chance of patients with sepsis to respond to corticotherapy include high vasopressor-dependency (norepinephrine dose of 1 μg/kg/min or more) and sustained organs failure (Sequential Organ Failure Assessment score > 6 for > 6 hr), the use of fludrocortisone in addition to hydrocortisone, a maximal duration of treatment of 7 days (or up to ICU discharge) and termination of treatment without taper off.
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