Pharmacokinetics of flucytosine in a critically ill patient on continuous venovenous hemodiafiltration.

PURPOSE: To describe the pharmacokinetics of flucytosine in a critically ill patient undergoing continuous venovenous hemodiafiltration (CVVHDF) treated for cryptococcal meningitis. SUMMARY: A 20-year-old female weighing 93.4 kg with a body mass index of 34.3 kg/m2 with a past medical history of systemic lupus erythematous with diffuse proliferative lupus nephritis (class IV) was admitted to the hospital after several months of worsening dyspnea, fatigue, myalgia, vomiting, and diarrhea. The patient developed worsening renal function and volume overload requiring CVVHDF on hospital day 7. She was diagnosed with cryptococcal meningitis on hospital day 8, and flucytosine 2,500 mg enterally every 12 hours and liposomal amphotericin B 500 mg intravenously every 24 hours were initiated. Flucytosine serum concentrations were collected on day 4 of therapy, and pharmacokinetics were performed on 2 sequential levels. Pharmacokinetic calculations displayed an elimination rate constant of 0.0338 h-1, a volume of distribution between 0.42 and 0.43 L/kg, a half-life of 20.5 hours, and a total drug clearance between 1.32 and 1.36 L/h while on CVVHDF. The nonsequential levels displayed good correlation, and no further monitoring or dosage adjustment was required. The patient completed therapy, with clinical resolution of her infection, and no toxicities due to flucytosine were noted. CONCLUSION: Flucytosine dosed at 25 mg/kg of actual body weight every 12 hours during CVVHDF conferred therapeutic levels with no appreciable toxicities. Because of its narrow therapeutic index and risk of toxicity, additional pharmacokinetic studies are needed to determine optimal drug dosing of this medication in patients requiring renal replacement therapy.

Effect of Best Practice Advisories on Sedation Protocol Compliance and Drug-Related Hazardous Condition Mitigation Among Critical Care Patients.

OBJECTIVES: To determine whether best practice advisories improved sedation protocol compliance and could mitigate potential propofol-related hazardous conditions. DESIGN: Retrospective observational cohort study. SETTING: Two adult ICUs at two academic medical centers that share the same sedation protocol. PATIENTS: Adults 18 years old or older admitted to the ICU between January 1, 2016, and January 31, 2018, who received a continuous infusion of propofol. INTERVENTIONS: Two concurrent best practice advisories built in the electronic health record as a clinical decision support tool to enforce protocol compliance with triglyceride and lipase level monitoring and mitigate propofol-related hazardous conditions. MEASUREMENTS AND MAIN RESULTS: The primary outcomes were baseline and day 3 compliance with triglyceride and lipase laboratory monitoring per protocol and time to discontinuation of propofol in the setting of triglyceride and/or lipase levels exceeding protocol cutoffs. A total of 1,394 patients were included in the study cohort (n = 700 in the pre-best practice advisory group; n = 694 in the post-best practice advisory group). In inverse probability weighted regression analyses, implementing the best practice advisory was associated with a 56.6% (95% CI, 52.6-60.9) absolute increase and a 173% relative increase (risk ratio, 2.73; 95% CI, 2.45-3.04) in baseline laboratory monitoring. The best practice advisory was associated with a 34.0% (95% CI, 20.9-47.1) absolute increase and a 74% (95% CI, 1.39-2.19) relative increase in day 3 laboratory monitoring after inverse probability weighted analyses. Among patients with laboratory values exceeding protocol cutoffs, implementation of the best practice advisory resulted in providers discontinuing propofol an average of 16.6 hours (95% CI, 4.8-28.3) sooner than pre-best practice advisory. Findings from alternate analyses using interrupted time series were consistent with the inverse probability weighted analyses. CONCLUSIONS: Best practice advisories can be effectively used in ICUs to improve sedation protocol compliance and may mitigate potential propofol-related hazardous conditions. Best practice advisories should undergo continuous quality assurance and optimizations to maximize clinical utility and minimize alert fatigue.

Exogenous supplementation of antithrombin III in adult and pediatric patients receiving extracorporeal membrane oxygenation.

BACKGROUND: Antithrombin III deficiency can occur with heparin anticoagulation during extracorporeal membrane oxygenation leading to heparin resistance. Antithrombin III supplementation has been shown to improve anticoagulation; however, there is no consensus on appropriate administration. We described the effect of antithrombin III supplementation on coagulation parameters in adult and pediatric extracorporeal membrane oxygenation patients. METHODS: We conducted a retrospective cohort study using electronic medical records of patients who received ⩾1 dose of antithrombin III during extracorporeal membrane oxygenation while on continuous heparin. Endpoints included the change in anti-Xa levels and antithrombin III activity at -6 versus 6 h relative to antithrombin III supplementation, and heparin infusion rates at 6 versus 12 h after antithrombin III supplementation. RESULTS: Eighteen patients receiving 36 antithrombin III administrations were analyzed. Mean (standard deviation) anti-Xa values at -6 versus 6 h were 0.15 (0.07) versus 0.24 (0.15) IU/mL (p-value: 0.250) for pediatrics and 0.19 (0.22) versus 0.31 (0.27) IU/mL (p-value: 0.052) for adults. Mean (standard deviation) plasma antithrombin III activity at the same intervals were 32% (14.2%) versus 66.8% (25.1%; p-value: 0.062) for pediatrics and 30.3% (14%) versus 52.8% (8.1%; p-value: 0.094) for adults. Mean (standard deviation) heparin rates at 6 versus 12 h after antithrombin III for pediatrics were 23.6 (6) versus 23.5 (6.5) units/kg/h (p-value: 0.728), and 15.3 (6.6) versus 13.5 (8) units/kg/h (p-value: 0.188) for adults. CONCLUSION: Administration of antithrombin III improved anti-Xa levels in both populations, however, did not significantly reduce heparin rates. Our findings suggest that the use of antithrombin III restores heparin responsiveness in patients with low antithrombin III activity and low anti-Xa activity.