Meersseman, Philippe

ABSTRACT Background and Aims Steroid supplementation remains controversial in septic shock, partly due to the heterogeneity of the populations studied. Cirrhotic patients with sepsis frequently develop relative adrenal insufficiency, showing poor response to vasopressors and poor prognosis. Early administration of low‐dose hydrocortisone might facilitate shock reversal and reduce mortality in this population. Methods Double‐blind, randomised, placebo‐controlled multicentre trial, enrolling adult cirrhotic patients with septic shock. Patients were assigned to receive i.v. hydrocortisone (100 mg followed by a continuous infusion of 200 mg/24 h) or placebo, for at least 3 days, followed by a tapering period of 3–7 days, depending on the time of shock resolution. Primary endpoint was 28‐day all‐cause mortality. Results After enrolment of 83 patients the trial was stopped early due to slow inclusions. Most patients required low‐to‐moderate doses of vasopressors. There was no difference in 28‐day mortality (35% vs. 39.5%; p = 0.84) between hydrocortisone and placebo groups. Shock resolution (85% vs. 72.1%; p = 0.25) and days to shock resolution [3 days (2.2–4; IQR) vs. 4 (2–7.5; IQR)] were also similar between groups. More patients receiving placebo died of refractory shock (47.6% vs. 8.7%). No significant differences between treatment arms were observed in shock relapse, new shock episodes or bacterial or fungal superinfections during hospital stay. Hypo‐ and hyperglycaemias were more frequent in the hydrocortisone arm. Severity of ACLF at inclusion and inadequacy of empirical antibiotic therapy (HR = 6.40; 95% CI: 3.21–12.79) independently predicted 28‐day mortality. Conclusions Supplemental hydrocortisone did not improve short‐term survival in cirrhotic patients with septic shock requiring low‐to‐moderate doses of vasopressors. Trial Registration S‐number University Hospitals Leuven, Belgium: S55168; EUDRACT: 2010–024273‐38; Clinicaltrials.gov id: NCT02602210

Background and Aims: Acute-on-chronic liver failure (ACLF) is a complication of cirrhosis characterized by multiple organ failure and high short-term mortality. The pathophysiology of ACLF involves elevated systemic inflammation leading to organ failure, along with immune dysfunction that heightens susceptibility to bacterial infections. However, it is unclear how these aspects are associated with recovery and nonrecovery in ACLF. Approach and Results: Here, we mapped the single-cell transcriptome of circulating immune cells from patients with ACLF and acute decompensated (AD) cirrhosis and healthy individuals. We further interrogate how these findings, as well as immunometabolic and functional profiles, associate with ACLF-recovery (ACLF-R) or nonrecovery (ACLF-NR). Our analysis unveiled 2 distinct states of classical monocytes (cMons). Hereto, ACLF-R cMons were characterized by transcripts associated with immune and stress tolerance, including anti-inflammatory genes such as RETN and LGALS1. Additional metabolomic and functional validation experiments implicated an elevated oxidative phosphorylation metabolic program as well as an impaired ACLF-R cMon functionality. Interestingly, we observed a common stress-induced tolerant state, oxidative phosphorylation program, and blunted activation among lymphoid populations in patients with ACLF-R. Conversely, ACLF-NR cMon featured elevated expression of inflammatory and stress response genes such as VIM, LGALS2, and TREM1, along with blunted metabolic activity and increased functionality. Conclusions: This study identifies distinct immunometabolic cellular states that contribute to disease outcomes in patients with ACLF. Our findings provide valuable insights into the pathogenesis of ACLF, shedding light on factors driving either recovery or nonrecovery phenotypes, which may be harnessed as potential therapeutic targets in the future.

Recently, during critical illness, cortisol metabolism was found to be reduced. We hypothesize that such reduced cortisol breakdown may suppress pulsatile ACTH and cortisol secretion via feedback inhibition. To test this hypothesis, nocturnal ACTH and cortisol secretory profiles were constructed by deconvolution analysis from plasma concentration time series in 40 matched critically ill patients and eight healthy controls, excluding diseases or drugs that affect the hypothalamic-pituitary-adrenal axis. Blood was sampled every 10 min between 2100 and 0600 to quantify plasma concentrations of ACTH and (free) cortisol. Approximate entropy, an estimation of process irregularity, cross-approximate entropy, a measure of ACTH-cortisol asynchrony, and ACTH-cortisol dose-response relationships were calculated. Total and free plasma cortisol concentrations were higher at all times in patients than in controls (all P < 0.04). Pulsatile cortisol secretion was 54% lower in patients than in controls ( P = 0.005), explained by reduced cortisol burst mass ( P = 0.03), whereas cortisol pulse frequency ( P = 0.35) and nonpulsatile cortisol secretion ( P = 0.80) were unaltered. Pulsatile ACTH secretion was 31% lower in patients than in controls ( P = 0.03), again explained by a lower ACTH burst mass ( P = 0.02), whereas ACTH pulse frequency ( P = 0.50) and nonpulsatile ACTH secretion ( P = 0.80) were unchanged. ACTH-cortisol dose response estimates were similar in patients and controls. ACTH and cortisol approximate entropy were higher in patients ( P ≤ 0.03), as was ACTH-cortisol cross-approximate entropy ( P ≤ 0.001). We conclude that hypercortisolism during critical illness coincided with suppressed pulsatile ACTH and cortisol secretion and a normal ACTH-cortisol dose response. Increased irregularity and asynchrony of the ACTH and cortisol time series supported non-ACTH-dependent mechanisms driving hypercortisolism during critical illness.