Hydrocortisone treatment in early sepsis-associated acute respiratory distress syndrome: results of a randomized controlled trial

This is the first prospective trial investigating a 7-day course of low-dose hydrocortisone treatment in patients with sepsis-associated early ARDS. Hydrocortisone treatment was associated with rapid and sustained improvement in pulmonary physiology and a nonsignificant increase (65.3 % vs. 55.6 %; p?=?0.19) in patients alive on day 28 without organ support. The significant physiological improvements did not translate into an overall survival benefit for the whole group (HR 0.80, 95 % CI 0.46–1.41; p?=?0.44), however, and for the largest subgroup of patients with APACHE II score 25 (HR 0.57, 95 % CI 0.24–1.36; p?=?0.20). Importantly, in agreement with the literature on sepsis [21] and ARDS [10], we did not find an increased risk of complications, with the exception of hyperglycemia, and hyperglycemia did not affect outcome. Our findings are placed in the context of the limitations of the trial and the updated literature.

Our study has several limitations. First, and most important, our study was significantly underpowered by the recruitment of patients with less severe illness and lower mortality. While the original sample size calculation was based on a control mortality of 60 %, originating from the findings of the largest prior trial [6], our control 28-day mortality was almost half that and similar to the most recent report [5]. This is partly attributable to two main factors: (1) exclusion of a large number of patients who, during the screening process, were already receiving hydrocortisone treatment for refractory septic shock [14]; and (2) improved outcome as a result of implementing the international guidelines of the Surviving Sepsis Campaign [14]. In comparison with prior RCTs, our trial differs by not including longitudinal measurements of systemic inflammatory response syndrome parameters or markers of systemic inflammation [6, 22–27] and an assessment of adrenal function [6, 26].

Seven RCTs published in the English language investigated prolonged glucocorticoid treatment in ARDS [6, 22–27]. In each trial, glucocorticoid treatment was associated with a significant reduction in markers of systemic inflammation (inflammatory cytokines and/or C-reactive protein levels) and improvement in lung function. Three trials investigated hydrocortisone treatment in sepsis [22, 23] or septic shock-associated ARDS [6]. The largest study [6] is a post hoc analysis of 177 patients with ARDS from a trial of vasopressor-dependent septic shock investigating hydrocortisone (dosage similar to our trial) and fludrocortisone (50 ?g daily) treatment [28]. In the largest trial [6], among those randomized to receive the active drug, the larger subgroup (n?=?129) of nonresponders to a short corticotropin test, contrary to responders (n?=?48), had more days alive and off a mechanical ventilator (5.6?±?8.8 days vs. 2.6?±?6.6 days; p?=?0.006) and improved survival (47 % vs. 25 %; p?=?0.021). Two other trials [22, 23] of patients with severe community-acquired pneumonia included 94 patients on MV with early ARDS (16 % with shock). In both trials [22, 23], a hydrocortisone bolus (200 mg) followed by an infusion (240–300 mg/24 h) was associated with a significant reduction in duration of MV; one research group reported improved survival [22].

Four trials investigated prolonged methylprednisolone treatment in early [26, 27] and late [24, 25] ARDS and were the subject of a recent individual patient data (IPD) meta-analysis (n?=?322) [10]. By study day 28, the methylprednisolone group had fewer patients dying while on MV (12 % vs. 29 %; p??0.001) and more patients successfully extubated (80 % vs. 50 %; p??0.001); hospital mortality was decreased (20 % vs. 33 %; p?=?0.006). Importantly, each trial [24–27] consistently reported a 9- to 10-day reduction in duration of MV during methylprednisolone administration (Table S3 supplementary material in [10]). All but one trial [25] incorporated slow tapering of the study drug after extubation; lack of slow tapering contributed to increased return to MV [25].

Our trial is a single-center RCT, which may raise concerns regarding the generalization of the results based on participants’ characteristics and the intervention tested. In comparison with our study, severity of illness scores and LISs were higher in five RCTs [6, 24–27] and similar in two RCTs [22, 23]. Fundamental variables of the treatment protocol that may significantly affect overall response to glucocorticoid treatment in ARDS include study drug, dosage, and duration of administration, including tapering [7]. Our treatment intervention was comparable to the one investigated in the two RCTs with lower severity of illness [22, 23] and differed from the other five RCTs by study drug (hydrocortisone vs. hydrocortisone plus fludrocortisone [6] or methylprednisolone [24–27]), duration of treatment (7 days vs. 14–28 days [24–27]), and tapering (lack of tapering vs. slow tapering [24, 26, 27]).

In the past exogenous glucocorticoids were thought to be qualitatively indistinguishable because they act via the same receptor, but qualitative differences have been discovered, and one glucocorticoid cannot be simply replaced by another [29]. In reference to the RCTs described above [6, 24–27], hydrocortisone has (1) less anti-inflammatory potency when it is not combined with fludrocortisone (a drug with both mineralocorticoid and glucocorticoid activities) and (2) lesser direct inhibitory NF-?B activity than methylprednisolone (half-maximal inhibitory concentration for NF-?B inhibition 16 and 2.8, respectively) [30]. Methylprednisolone, because of its greater penetration in lung tissue and longer residence time [31], is the most frequently used intravenous glucocorticoid for the treatment of severe acute inflammatory lung diseases [32].

New understanding of the central role played by glucocorticoids in resolution of inflammation and restoration of tissue homeostasis [33] provides support for longer duration of treatment incorporating slow tapering (up to 4 weeks). A recent IPD meta-analysis demonstrates that lack of glucocorticoid tapering after extubation of patients with ARDS is frequently associated with clinical deterioration and return to MV [10]. Similarly, researchers in a comparison study of two concurrent RCTs—hydrocortisone 7-day infusion vs. prolonged methylprednisolone—reported that removing hydrocortisone without tapering led to a rebound of systemic inflammation with worsening organ dysfunction requiring reintubation [34]. In our study, we did not measure markers of inflammation and cannot comment on the presence of rebound inflammation. After completion of study treatment, however, the hydrocortisone group continued to demonstrate improved gas exchange and LIS, and the two groups had a similar rate of reintubation by day 28. While these findings may suggest that a clinically significant rebound effect is less likely, most patients (n?=?55) had hydrocortisone treatment discontinued prior to extubation, masking a possible rebound.

Our trial does not confirm the benefits reported on the basis of prior RCTs for reduction in duration of MV and intensive care unit stay [22–27] or survival [22–24, 26, 27]. Our study is underpowered for the exploratory analysis to demonstrate a survival benefit in patients with APACHE II scores 25. It is likely that this cohort had a lesser degree of systemic inflammation than patients with APACHE II scores ?25. Lacking measurement of markers of systemic inflammation over time, we cannot comment on whether our treatment protocol was less effective in achieving a significant anti-inflammatory effect in those with APACHE II scores ?25.