No abstract

No abstract

Nitric oxide (NO) is a gaseous signaling molecule and a key endogenous mediator of vascular tone. Hydroxocobalamin (HCB) affects NO-mediated vasoplegia as (1) a direct inhibitor of nitric oxide synthase (NOS), thereby decreasing its production, and (2) by binding directly to NO and acting as a scavenger. HCB has been increasingly used in the treatment of refractory vasoplegia, particularly in cardiac surgery and liver transplant patients. Sepsis and septic shock are characterized by an increase in inducible NOS expression and activity with excessive NO production, resulting in endothelial dysfunction and profound systemic vasodilation. Therefore, a careful sustained reduction in NO burden represents a potential therapeutic target. Here, we present a case of refractory septic shock, which resolved after an extended duration infusion of high-dose HCB. We hope to foster further exploration regarding the safety, dosing, and efficacy of HCB when administered for vasopressor refractory septic shock.

Extracorporeal membrane oxygenation (ECMO) poses unique thrombotic and hemorrhagic risks, and the optimal anticoagulant choice is unknown. We systematically searched Ovid EBM Reviews, Ovid Embase, Ovid Medline, Scopus, and Web of Science Core Collection for randomized-, crossover-, retrospective cohort-, or parallel-designed clinical studies of adult patients receiving ECMO that compared heparin recipients with bivalirudin recipients. Meta-analysis was performed with random-effects models. The ROBINS-I tool was used to assess the risk of bias. Six retrospective observational studies met the inclusion criteria for the qualitative summary. Five studies were suitable for meta-analysis. Those who received heparin were more likely to experience circuit-related thrombosis (odds ratio [OR] 2.05, 95% confidence interval [CI] 1.25-3.37, p = 0.005, I 2 = 0%) and die (OR 1.62, 95% CI 1.19-2.21, p = 0.002, I 2 = 0%) compared with those who received bivalirudin. There were no differences in major bleeding events between heparin and bivalirudin recipients (OR 1.83, 95% CI 0.55-6.09, p = 0.33, I 2 = 82.7%). In retrospective settings compared with heparin anticoagulation, bivalirudin was associated with less circuit-related thrombotic events and greater survival in adults supported on ECMO, without contributing to more bleeding complications. Prospective controlled studies comparing heparin and bivalirudin in adult ECMO patients are warranted to corroborate these findings.

We read with interest the article by Mang et al. 1 Indeed, oxygenator thrombosis remains a common reason for circuit exchange, the risk of which increases with the duration of extracorporeal membrane oxygenation (ECMO) support. 2 Coinciding with the pandemic's unprecedented increase of ECMO disposable demand, judicious use of limited supply was warranted. While we applaud the authors for their clever approach, we would like to add words of caution regarding their strategy.Catheter-directed regional thrombolysis using a slow thrombolytic infusion is well established, and similarly, the strategy of Mang et al. 1 is to deliver the thrombolytic to the site of the thrombus to maximize its local exposure, while minimizing systemic effects. 3 This strategy achieves a favorable risk-benefit profile by 1) maximizing thrombus-drug exposure through heightened local drug concentrations; 2) reducing nonlocal side effects as the half-life of alteplase is short (~5 minutes) and agent washout is limited due to vascular occlusion; and 3) limit bleeding complications as compared to bolus thrombolytics application. 3 In the absence of detailed thrombolytic dosing rates by Mang et al. 1 it is not possible to ascertain whether a sustained extended infusion or a bolus strategy was employed. If the rapid administration of alteplase was applied, it may provide an explanation for why three of the four patients required multiple thrombolytic administrations and one patient receiving nine separate administrations. This presumed bolus administration pattern may increase the risk of devastating bleeding complications. Of additional concern was that patient 1, the lone discharge survivor, had ECMO circuit flow adjusted lower by over 50% throughout the course of eight injections, which may have clouded the pressure drop effects of thrombolysis. This is due to the physical effects of a decreased pressure drop with decreasing flows across the oxygenator.Further, we ask: should the approach to membrane lung preservation rely on rescuing an exhausted device, or rather focus on implementing preventative strategies? Mang et al. reported heparin anticoagulation titrated to an activated partial thromboplastin time of 45-55 seconds, a modest level of anticoagulation. In standard venovenous (VV)-ECMO circuits, this may be sufficient, however, higher anticoagulation levels may be needed in coronavirus disease 2019 (COVID-19) patients due to an underlying hypercoagulable state. 4 Furthermore, Mang et al. 1 do not report any intensification of anticoagulation in an attempt slow the increasing rate of pressure drop. Finally, one might consider direct thrombin inhibitors as first-line anticoagulants in VV-ECMO patients to mitigate these deposits. Indeed, in aggregate analyses of non-COVID-19 ECMO patients, bivalirudin use was associated with reduced circuitrelated thrombotic events when compared to heparin. 5 This may be due to pharmacologic differences between the agents. Specifically, heparin only exerts an antithrombotic effect on freely circulating throm...