A Critical Appraisal of the Effects of Anesthetics on Immune-system Modulation in Critically Ill Patients With COVID-19.

PURPOSE: The aim of the present article was to briefly summarize current knowledge about the immunomodulatory effects of general anesthetics and the possible clinical effects of this immunomodulation in patients with COVID-19. METHODS: The PubMed, Scopus, and Google Scholar databases were comprehensively searched for relevant studies. FINDINGS: The novel coronavirus causes a wide spectrum of clinical manifestations, with a large absolute number of patients experiencing severe pneumonia and rapid progression to acute respiratory distress syndrome and multiple organ failure. In these patients, the equilibrium of the inflammatory response is a major determinant of survival. The impact of anesthetics on immune-system modulation may vary and includes both pro-inflammatory and anti-inflammatory effects. IMPLICATIONS: Inhibition of the development of severe inflammation and/or the enhancement of inflammation resolution by anesthetics may limit organ damage and improve outcomes in patients with COVID-19.

A Pharmacokinetics-Informed Approach to Navigating Hydroxychloroquine Shortages in Patients With Rheumatic Disease During the COVID-19 Pandemic.

OBJECTIVE: The recent hydroxychloroquine (HCQ) shortage due to use in coronavirus disease 2019 (COVID-19) has forced some rheumatic disease patients to choose between continuing their current dose of HCQ but exhaust their supply early or ration it in order to prolong its use. Blood HCQ concentrations are directly correlated with disease activity in rheumatic diseases such as systemic lupus erythematosus. We sought to model how changes in HCQ dosage will best maintain sufficient blood HCQ concentrations for the longest period of time in order to avoid potential future flares. METHODS: A one-compartment pharmacokinetic model was used to predict mean blood HCQ concentrations. Monte Carlo simulations with 10-fold inflated model parameter variance was utilized to assess the impact of variability. RESULTS: Maintenance of 400 mg/d resulted in mean therapeutic whole-blood HCQ concentrations that exceeded 700 ng/ml for 10.5 days, whereas HCQ rationing by reducing the dose by half resulted in the mean concentration remaining above 700 ng/ml for 2.4 days (net gain = 8 days). Variability analysis demonstrates that results may differ at the individual level, dependent on baseline blood HCQ concentrations. CONCLUSION: Although mean blood concentrations exceed 700 ng/ml for a longer time if patients maintain their full dose of HCQ, more information is needed to fully understand the elimination of HCQ at the patient level, particularly the contribution of tissue stores of HCQ transiting back into the blood.

The Pharmacokinetic and Pharmacodynamic Properties of Hydroxychloroquine and Dose Selection for COVID-19: Putting the Cart Before the Horse.

Coronavirus disease 2019 (COVID-19), caused by the 2019 novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is currently responsible for a global pandemic. To date, only remdesivir and dexamethasone have demonstrated a positive response in a prospective, randomized trial for the treatment of patients with COVID-19. Hydroxychloroquine (HCQ) is an agent available in an oral formulation with in vitro activity against SARS-CoV-2 that has been suggested as a potential agent. Unfortunately, results of randomized trials evaluating HCQ as treatment against a control group are lacking, and little is known about its pharmacokinetic/pharmacodynamic (PK/PD) profile against SARS-CoV-2. The objective of this review was to describe the current understanding of the PK/PD and dose selection of HCQ against SARS-CoV-2, discuss knowledge gaps, and identify future studies that are needed to optimize the efficacy and safety of treatments against COVID-19.