Clinical impact of stress dose steroids in patients with septic shock: insights from the PROWESS-Shock trial

We found no benefits from the use of intravenous steroids for treatment of septic shock at baseline either in patients randomized to DrotAA or placebo. In addition, we observed that intravenous steroids did not seem to influence the clinical course of septic shock, expressed by the cardiovascular SOFA, vasopressor-free days, and death from refractory shock.

The role of steroids as an adjunctive therapy in the treatment of septic shock has been a controversial issue for many decades [24]. A large meta-analysis including 17 randomized controlled trials (RCT) and 3 quasi-RCTs suggested some survival benefit of prolonged low-dose corticosteroid therapy in septic shock patients [25]. However, the analysis of the impact of low-dose corticosteroids in septic shock mortality assessed in large clinical registries showed little or no effect [7] or a significant increase in mortality [26], even after adjusting for clinical severity. Similarly, a recent meta-analysis found no statistically significant difference in mortality (relative risk 1.00, 95% CI, 0.84, 1.18) [27]. Recently, Dellinger and coworkers [8] found that hydrocortisone failed to show any benefit on outcome (relative risk 1.06) if the meta-analysis included only the six high-level RCTs with low risk of bias [11,14,28-31] and excluded studies with placebo mortality >60%.

In the midst of these conflicting results, two recent observational studies were published [32,33] that brought a little light to these issues [34,35]. The first study from Katsenos et al. [32], showed a potential mortality benefit from early initiation of steroids (in the first 9 hours after vasopressors). However, these results are compromised by several limitations, namely the small and asymmetric sample size, the fact that the impact of steroid therapy was not adjusted for clinical severity nor organ dysfunction, and the very high mortality rate at 28 days (almost 70% in patients with late steroid initiation) [34]. The study from Funk et al. [33] was a large retrospective multicenter propensity-matched cohort study that showed no benefit from low-dose corticosteroids in septic shock patients either in 30-day mortality or vasopressor dependence. However, in those with higher severity, with APACHE II ≥30, there might be a benefit, whereas in the lower clinical-severity quartiles there might be potential harm. Similarly, this study has also several limitations, in particular the very long period of patient inclusion (11 years) during which a marked change in mortality was expectable [6,7,9], and the propensity score did not include variables associated with shock severity, namely the SOFA score or the number and dose of vasopressors. Finally, almost 16% of low-dose corticosteroids given to septic shock patients did not have APACHE II score recorded.

Conversely, when the two largest RCTs [11,14] of low-dose corticosteroids were analyzed, one (n = 300) suggests a marked positive impact of steroids on mortality in septic shock only in the patients who did not respond to the short corticotropin test, whereas the second (n = 499) found no beneficial effect irrespective of the response to the short corticotropin test [14].

However, these two RCTs are not totally comparable. Septic shock patients in the positive trial had a higher Simplified Acute Physiology Score II at baseline, were unresponsive to vasopressors, were all under mechanical ventilation (compared to 86% in CORTICUS and 82% in PROWESS-Shock) and there was a much higher rate of death at 28 days in the placebo group (61% compared with 32% in the CORTICUS trial). The enrolment of patients in the positive trial was allowed only within 8 hours after fulfilling inclusion criteria, as compared with a 72-hour window in the negative trial. Therefore, some authors perceive that results of the negative trial represent the randomization of patients whose clinicians decided not to treat with corticosteroids, that is, those with less severe clinical presentation [17,18]. Taken together, these findings might suggest a potential benefit of steroids for the most severe cases at the earliest stages of septic shock.

In the present analysis of PROWESS-Shock trial, we confirmed that steroid use in usual care was indeed reserved for more critically ill individuals. However, we could not confirm such benefit from this practice, even when steroids were administered early in the course of shock, with or without concomitant DrotAA. The same was true in the different subgroup analyses, namely of patients with lung infection, abdominal infection, Gram-positive infection or Gram-negative infection.

Both trials that assessed the efficacy of DrotAA [10,15] allowed the use of intravenous steroids at the discretion of the attending physician. In line with the original recommendations of the Surviving Sepsis Campaign [12], as well as the 2008 revision [13], the administration of intravenous steroids for treatment of septic shock was recommended and as a result its prescription increased from 36.0% in the original PROWESS trial to 49.5% in the PROWESS-Shock trial.

The potential synergies in the concomitant use of corticosteroids and DrotAA were evaluated in only one recent study, and this analysis was limited by the discontinuation of the DrotAA [16]. However, the authors found no significant interaction between corticosteroids and DrotAA (P = 0.47). Similarly, in our analysis we were unable to find any significant interaction between these two drugs among the total patient group, or in the different subgroups, namely of patients with lung infection, abdominal infection, Gram-positive or Gram-negative sepsis.

In addition, we were unable to demonstrate any significant improvement in hemodynamic stability associated with the use of corticosteroids [11,14]. Nonetheless we could not evaluate the response to the short corticotropin test, as it was not routinely performed and if performed those data were not collected in the PROWESS-Shock trial. However, in the past decade a significant amount of data have questioned the validity of the results of such a test in this setting [36,37]. First, there is a great variability of cortisol measurements observed between different methods and laboratories [36]. Also, the relationship between total and free cortisol levels had also been shown to be poor [38]. Finally, it has been shown in critically ill patients that cortisol production was 83% higher and cortisol clearance was 50% lower in comparison to matched controls. These factors account for a 3.5 times greater cortisol level in these patients [39].

In our study there are also several limitations that need to be acknowledged. The present study was not designed to stratify by the use of corticosteroids a priori and unmeasured confounders may have been missed or incompletely accounted for in our propensity adjustments. Enroled patients must have survived the initial resuscitation period to be randomized, which was on average 17 hours from the onset of vasopressor use [15]. As a result only septic shock patients that survived to that time point were analyzed, excluding very sick septic shock patients. As a result patients with early refractory shock and early deaths during this period were not included. We were unable to analyze the type, the dose of corticosteroid drug administered and the duration of steroid therapy, as these data were not collected. Only the prescription of intravenous steroid therapy for septic shock during the pretreatment period (before study drug infusion) was recorded. In addition, data on etomidate and fludrocortisone prescription was not collected in the PROWESS-Shock database. Similarly the steroid-related complications namely myopathy, nosocomial infections, and metabolic alteration were not fully available. However, if we consider endpoints such as all-cause mortality and duration of mechanical ventilation as surrogates for these complications, we did not find significant differences among the groups. Nonetheless, we acknowledge that these safety issues deserve in-depth analysis with specific and robust data collection in future studies.

The present study does have several strengths. Our analyses utilized data from a large multicenter and well-conducted RCT collected during a 25-month period and with a 90-day follow up. In addition, the inverse probability of treatment weighting using the propensity score to perform our analysis balances measured covariates between those prescribed steroids and those not prescribed steroids [23].