The use of beta(β)-blockers during septic shock aimed at countering peripheral adrenergic stress may be justified by the early reduction in deleterious effects resulting from sympathetic overactivation, and could improve the prognosis of patients in septic shock. Animal studies have demonstrated either a maintenance or increase in cardiac output (CO) despite the decrease in heart rate (HR) associated with improved myocardial performance. The mechanism by which β-blockers alter hemodynamics in septic shock is debated; however, preclinical and clinical data show that β-blockers are safe when started at a low dose. Recent publications (2019-2021) on adrenergic β1 receptor antagonists used in septic shock indicate that esmolol and landiolol should not be used in the early phase. While there is no optimal timing for their administration, a minimum of 12 h after the initiation of vasopressor therapy in stabilized euvolemic patients is a reasonable option. Patients should have a normal cardiac function, although a slight depression is compatible with landiolol use under hemodynamic monitoring. Slow titration in patients who remain tachycardic is preferable to rapid titration. When used to decrease HR, landiolol is also effective in reducing the incidence of new arrhythmias. Results of a well-performed and well-powered randomized controlled trial (RCT) demonstrating a positive effect on survival - or at least on hard surrogates such as the incidence/duration of organ failure - are pending.

Background: Adjusting drug therapy under veno-venous extracorporeal membrane oxygenation (VV ECMO) is challenging. Although impaired pharmacokinetics (PK) under VV ECMO have been reported for sedative drugs and antibiotics, data about amiodarone are lacking. We evaluated the pharmacokinetics of amiodarone under VV ECMO both in vitro and in vivo. Methods: In vitro: Amiodarone concentration decays were compared between closed-loop ECMO and control stirring containers over a 24 h period. In vivo: Potassium-induced cardiac arrest in 10 pigs with ARDS, assigned to either control or VV ECMO groups, was treated with 300 mg amiodarone injection under continuous cardiopulmonary resuscitation. Pharmacokinetic parameters C_max, T_max AUC and F were determined from both direct amiodarone plasma concentrations observation and non-linear mixed effects modeling estimation. Results: An in vitro study revealed a rapid and significant decrease in amiodarone concentrations in the closed-loop ECMO circuitry whereas it remained stable in control experiment. In vivo study revealed a 32% decrease in the AUC and a significant 42% drop of C_max in the VV ECMO group as compared to controls. No difference in T_max was observed. VV ECMO significantly modified both central distribution volume and amiodarone clearance. Monte Carlo simulations predicted that a 600 mg bolus of amiodarone under VV ECMO would achieve the amiodarone bioavailability observed in the control group. Conclusions: This is the first study to report decreased amiodarone bioavailability under VV ECMO. Higher doses of amiodarone should be considered for effective amiodarone exposure under VV ECMO.

Background: Refractory cardiac arrest management relies on extracorporeal cardiopulmonary resuscitation (ECPR), requiring the use of veno-arterial extracorporeal membrane oxygenation (VA-ECMO). Circulatory flow recovery can be associated with an ischemia–reperfusion injury, leading to vasoplegia and vasopressor requirement. The aim of this work was to evaluate the impact on hemodynamics of a methylene blue bolus infusion in a porcine model of ischemic refractory cardiac arrest. Methods: Ischemic refractory cardiac arrest was induced in 20 pigs. After a low flow period of 30 min, VA-ECMO was initiated and the pigs were randomly assigned to the standard care group (norepinephrine + crystalloids) or methylene blue group (IV 2 mg·kg⁻¹ bolus of methylene blue over 30 min + norepinephrine and crystalloids). Macrocirculatory parameters and lactate clearance were measured. Sublingual microcirculation was evaluated with sidestream dark field (SDF) imaging. The severity of the ischemic digestive lesions was assessed according to the histologic Chiu/Park scale. Results: Eighteen pigs were included. The total crystalloid load (5000 (6000–8000) mL vs. 17,000 (10,000–19,000) mL, p = 0.007, methylene blue vs. standard care group) and catecholamine requirements (0.31 (0.14–0.44) μg·kg⁻¹·min⁻¹ vs. 2.32 (1.17–5.55) μg·kg⁻¹·min⁻¹, methylene blue vs. standard care group, p = 0.004) were significantly reduced in the methylene blue group. There were no significant between-group differences in lactate clearance, sublingual capillary microvascular parameters assessed by SDF or histologic Chiu/Park scale. Conclusions: In our refractory cardiac arrest porcine model treated with ECPR, methylene blue markedly reduced fluid loading and norepinephrine requirements in comparison to standard care during the first 6 h of VA-ECMO.

Objectives: Practice concerning post-transplant Pneumocystis prophylaxis remains heterogeneous. SXT benefits must be balanced with frequent toxicity. We aimed to assess whether a low-dose SXT strategy might limit toxicities while maintaining an undisrupted prophylaxis compared with a standard dose in a retrospective cohort of heart transplant population. Methods: Patients undergoing heart transplant from two distinct centres, receiving daily SXT 20/100 mg versus daily SXT 80/400 mg between 2018 and 2020, were retrospectively included in the study. Demographic, immunosuppression and survival characteristics were collected to ensure group comparability. The occurrence of adverse effects and the rate of SXT discontinuation were compared between the two groups. Results: Overall, 359 patients were recruited in the study, 108 patients for the standard-dose group and 251 patients for the low-dose group. The leading cause of prophylaxis discontinuation was cytopenia. We observed significantly more discontinuation in the standard-dose compared with the low-dose group (24.1% and 6.4%, respectively, P < 0.001). No patient with ongoing prophylaxis presented Pneumocystis pneumonia or toxoplasmosis during the 2-year follow-up. Two Pneumocystis infections in the low-dose group occurred during prophylaxis breaks. The rate of toxoplasmosis seroconversion was similar in both groups. Conclusions: This retrospective study suggests that a low-dose SXT Pneumocystis prophylaxis strategy might offer a more favourable safety/efficacy profile than standard-dose prophylaxis after heart transplantation. These results should be confirmed in an interventional trial. Caution remains for toxoplasmosis serology D+/R− profiles.