Early adjunctive methylene blue in patients with septic shock: a randomized controlled trial.

PURPOSE: Methylene blue (MB) has been tested as a rescue therapy for patients with refractory septic shock. However, there is a lack of evidence on MB as an adjuvant therapy, its' optimal timing, dosing and safety profile. We aimed to assess whether early adjunctive MB can reduce time to vasopressor discontinuation in patients with septic shock. METHODS: In this single-center randomized controlled trial, we assigned patients with septic shock according to Sepsis-3 criteria to MB or placebo. Primary outcome was time to vasopressor discontinuation at 28 days. Secondary outcomes included vasopressor-free days at 28 days, days on mechanical ventilator, length of stay in ICU and hospital, and mortality at 28 days. RESULTS: Among 91 randomized patients, forty-five were assigned to MB and 46 to placebo. The MB group had a shorter time to vasopressor discontinuation (69 h [IQR 59-83] vs 94 h [IQR 74-141]; p < 0.001), one more day of vasopressor-free days at day 28 (p = 0.008), a shorter ICU length of stay by 1.5 days (p = 0.039) and shorter hospital length of stay by 2.7 days (p = 0.027) compared to patients in the control group. Days on mechanical ventilator and mortality were similar. There were no serious adverse effects related to MB administration. CONCLUSION: In patients with septic shock, MB initiated within 24 h reduced time to vasopressor discontinuation and increased vasopressor-free days at 28 days. It also reduced length of stay in ICU and hospital without adverse effects. Our study supports further research regarding MB in larger randomized clinical trials. Trial registration ClinicalTrials.gov registration number NCT04446871 , June 25, 2020, retrospectively registered.

Timing, method and discontinuation of hydrocortisone administration for septic shock patients.

AIM: To characterize the prescribing patterns for hydrocortisone for patients with septic shock and perform an exploratory analysis in order to identify the variables associated with better outcomes. METHODS: This prospective cohort study included 59 patients with septic shock who received stress-dose hydrocortisone. It was performed at 2 critical care units in academic hospitals from June 1st, 2015, to July 31st, 2016. Demographic data, comorbidities, medical management details, adverse effects related to corticosteroids, and outcomes were collected after the critical care physician indicated initiation of hydrocortisone. Univariate comparison between continuous and bolus administration of hydrocortisone was performed, including multivariate analysis, as well as Kaplan-Meier analysis to compare the proportion of shock reversal at 7 d after presentation. Receiver operating characteristic (ROC) curves determined the best cut-off criteria for initiation of hydrocortisone associated with the highest probability of shock reversal. We addressed the effects of the taper strategy for discontinuation of hydrocortisone, noting risk of shock relapse and adverse effects. RESULTS: All-cause 30-d mortality was 42%. Hydrocortisone was administered as a continuous infusion in 54.2% of patients; time to reversal of shock was 49 h longer in patients who were given a bolus administration [59 h (range, 47.5-90.5) vs 108 h (range, 63.2-189); P = 0.001]. The maximal dose of norepinephrine after initiation of hydrocortisone was lower in patients on continuous infusion [0.19 µg/kg per minute (range, 0.11-0.28 µg)] compared with patients who were given bolus [0.34 µg/kg per minute (range, 0.16-0.49); P = 0.004]. Kaplan-Meier analysis revealed a higher proportion of shock reversal at 7 d in patients with continuous infusion compared to those given bolus (83% vs 63%; P = 0.004). There was a good correlation between time to initiation of hydrocortisone and time to reversal of shock (r = 0.80; P < 0.0001); ROC curve analysis revealed that the best criteria for prediction of shock reversal was a time to initiation of hydrocortisone of ≤ 13 h after administration of norepinephrine, with an area under the curve of 0.81 (P < 0.001). The maximal dose of norepinephrine at initiation of hydrocortisone with the highest association with shock reversal was ≤ 0.28 µg/kg per minute, with an area under the curve of 0.75 (P = 0.0002). On a logistic regression model, hydrocortisone taper was not associated with a lower risk of shock relapse (RR = 1.29; P = 0.17) but was related to a higher probability of hyperglycemia [odds ratio (OR), 5.3; P = 0.04] and hypokalemia (OR = 10.6; P = 0.01). CONCLUSION: Continuous infusion of hydrocortisone could hasten the resolution of septic shock compared to bolus administration. Earlier initiation corresponds with a higher probability of shock reversal. Tapering strategy is unnecessary.