Population Pharmacokinetics of Isavuconazole in Critical Care Patients with COVID-19-Associated Pulmonary Aspergillosis and Monte Carlo Simulations of High Off-Label Doses.

Isavuconazole is a triazole antifungal agent recently recommended as first-line therapy for invasive pulmonary aspergillosis. With the COVID-19 pandemic, cases of COVID-19-associated pulmonary aspergillosis (CAPA) have been described with a prevalence ranging from 5 to 30%. We developed and validated a population pharmacokinetic (PKpop) model of isavuconazole plasma concentrations in intensive care unit patients with CAPA. Nonlinear mixed-effect modeling Monolix software were used for PK analysis of 65 plasma trough concentrations from 18 patients. PK parameters were best estimated with a one-compartment model. The mean of ISA plasma concentrations was 1.87 [1.29-2.25] mg/L despite prolonged loading dose (72 h for one-third) and a mean maintenance dose of 300 mg per day. Pharmacokinetics (PK) modeling showed that renal replacement therapy (RRT) was significantly associated with under exposure, explaining a part of clearance variability. The Monte Carlo simulations suggested that the recommended dosing regimen did not achieve the trough target of 2 mg/L in a timely manner (72 h). This is the first isavuconazole PKpop model developed for CAPA critical care patients underlying the need of therapeutic drug monitoring, especially for patients under RRT.

Continuous peripheral nerve blocks for analgesia of ventilated critically ill patients with multiple trauma: a prospective randomized study.

BACKGROUND: Sedation of ventilated critically ill trauma patients requires high doses of opioids and hypnotics. We aimed to compare the consumption of opioids and hypnotics, and patient outcomes using sedation with or without continuous regional analgesia (CRA). METHODS: Multiple trauma-ventilated patients were included. The patients were randomized to receive an intravenous analgesia (control group) or an addition of CRA within 24h of admission. A traumatic brain injury (TBI) patients group was analyzed. The primary endpoint was the cumulative consumption of sufentanil at 2 days of admission. Secondary endpoints were cumulative and daily consumption of sufentanil and midazolam, duration of mechanical ventilation, intensive care unit (ICU) stay, and safety of CRA management. RESULTS: Seventy six patients were analyzed: 40 (67.5% males) in the control group and 36 (72% males) in the CRA group, respectively. The median [IQR] Injury Severity Score was 30.5 [23.5-38.5] and 26.0 [22.0-41.0]. The consumption of sufentanil at 48h was 725 [465-960] µg/48h versus 670 [510-940] µg/48h (p = 0.16). Daily consumption did not differ between the groups except on day 1 when consumption of sufentanil was 360 [270-480] µg vs. 480 [352-535] µg (p = 0.03). Consumptions of midazolam did not differ between the groups. No difference was noted between the groups according to the secondary endpoints. CONCLUSIONS: CRA does not decrease significantly sufentanil and midazolam consumption within the first 5 days after ICU admission in multiple trauma-ventilated patients. The use of peripheral nerve blocks in heavily sedated and ventilated trauma patients in the ICU seems safe.

Comparison of the visualisation of the subclavian and axillary veins: An ultrasound study in healthy volunteers.

OBJECTIVE: To compare the area of the lumen of the axillary and subclavian veins using ultrasound (US) in 50 healthy volunteers. METHODS: Using an ultrasound device, depth, area, short axis vein length and long axis vein, vein-artery and vein-pleura distances were measured for axillary and subclavian approaches. RESULTS: The mean cross-sectional area of the axillary vein was greater than the mean cross-sectional area of the subclavian vein (327±89 mm2 versus 124±46 mm2, P<0.001). Both the mean transverse (10±2mm versus 9±2mm) and longitudinal axes (39±8mm versus 17±7mm) of the axillary vein were greater than those of subclavian vein (P<0.01, P<0.001, respectively). The depths of the axillary and subclavian veins were similar (21±6mm versus 20±6mm, P=0.43). The axillary and subclavian arteries were visualised in 3 and 45 volunteers, respectively (P<0.001). The pleura was seen in 25 and 37 volunteers with the axillary and subclavian approaches, respectively (P=0.01). The distance between the pleura and the subclavian vein was smaller (6±2mm versus 8±3mm, P<0.04). CONCLUSION: The present US study shows that visualisation of the axillary vein under US is greater than that for the subclavian vein, mainly due to a better alignment with the long axis of the axillary vein leading to a greater cross-sectional area of the axillary vein. TRIAL REGISTER NUMBER: NCT01647815.

The Influence of Arm Positioning on Ultrasonic Visualization of the Subclavian Vein: An Anatomical Ultrasound Study in Healthy Volunteers.

We hypothesized that placing the arm in 90° abduction, through 90° flexion and 90° external rotation, could improve ultrasound visualization of the subclavian vein. In 49 healthy volunteers, a single operator performed a view of the subclavian vein in neutral position and abduction position. A second blinded operator measured the cross-sectional area of the subclavian vein. Abduction position increased the cross-sectional area of the subclavian vein from 124 ± 46 (mean ± SD) to 162 ± 58 mm (P = 0.001). An increase of the cross-sectional area of ≥50% was observed in 41% volunteers (95% confidence interval, 27%-56%, n = 20); this technique offers an alternative approach (maybe safer) for ultrasound-guided catheterization of the subclavian vein.