Low and Highly Variable Exposure to Prophylactic LMWH Nadroparin in Critically Ill Patients: Back to the Drawing Board for Prophylactic Dosing?

Background and Objective: Low-molecular-weight heparins are routinely administered to patients in the intensive care unit to prevent venous thromboembolisms. There is considerable evidence that low-molecular-weight heparin doses should be personalised based on anti-Xa levels, but pharmacokinetic data in intensive care unit patients are lacking. This study aimed to characterise the pharmacokinetics and associated variability of the low-molecular-weight heparin nadroparin in critically ill patients. Methods: Critically ill adult patients who were admitted to the intensive care unit and received nadroparin for prophylaxis of venous thromboembolism were included in a study. Population pharmacokinetic analysis was performed by means of parametric non-linear mixed-effects modelling (NONMEM). Results: A total of 30 patients were enrolled with 12 patients undergoing continuous veno-venous hemodialysis and 18 patients not undergoing continuous veno-venous hemodialysis. Very high variability in pharmacokinetics was observed with an inter-individual variability in the volume of distribution of 63.7% (95% confidence interval 46.5–90.6), clearance of 166% (95% confidence interval 84.7–280) and relative bioavailability of 40.2% (95% confidence interval 29.5–52.6). We found that standard doses of 2850 IE and 5700 IE of nadroparin resulted in sub-prophylactic exposure in critically ill patients. Conclusions: Low exposure and highly variable pharmacokinetics of nadroparin were observed in intensive care unit patients treated with a prophylactic dose. It can be debated whether nadroparin is currently dosed optimally in intensive care unit patients and our findings encourage the investigation of higher and tailored dosing of nadroparin in the critically ill

Ventilation management and clinical outcomes in invasively ventilated patients with COVID-19 (PRoVENT-COVID): a national, multicentre, observational cohort study

Background: Little is known about the practice of ventilation management in patients with COVID-19. We aimed to describe the practice of ventilation management and to establish outcomes in invasively ventilated patients with COVID-19 in a single country during the first month of the outbreak. Methods: PRoVENT-COVID is a national, multicentre, retrospective observational study done at 18 intensive care units (ICUs) in the Netherlands. Consecutive patients aged at least 18 years were eligible for participation if they had received invasive ventilation for COVID-19 at a participating ICU during the first month of the national outbreak in the Netherlands. The primary outcome was a combination of ventilator variables and parameters over the first 4 calendar days of ventilation: tidal volume, positive end-expiratory pressure (PEEP), respiratory system compliance, and driving pressure. Secondary outcomes included the use of adjunctive treatments for refractory hypoxaemia and ICU complications. Patient-centred outcomes were ventilator-free days at day 28, duration of ventilation, duration of ICU and hospital stay, and mortality. PRoVENT-COVID is registered at ClinicalTrials.gov (NCT04346342). Findings: Between March 1 and April 1, 2020, 553 patients were included in the study. Median tidal volume was 6·3 mL/kg predicted bodyweight (IQR 5·7–7·1), PEEP was 14·0 cm H2O (IQR 11·0–15·0), and driving pressure was 14·0 cm H2O (11·2–16·0). Median respiratory system compliance was 31·9 mL/cm H2O (26·0–39·9). Of the adjunctive treatments for refractory hypoxaemia, prone positioning was most often used in the first 4 days of ventilation (283 [53%] of 530 patients). The median number of ventilator-free days at day 28 was 0 (IQR 0–15); 186 (35%) of 530 patients had died by day 28. Predictors of 28-day mortality were gender, age, tidal volume, respiratory system compliance, arterial pH, and heart rate on the first day of invasive ventilation. Interpretation: In patients with COVID-19 who were invasively ventilated during the first month of the outbreak in the Netherlands, lung-protective ventilation with low tidal volume and low driving pressure was broadly applied and prone positioning was often used. The applied PEEP varied widely, despite an invariably low respiratory system compliance. The findings of this national study provide a basis for new hypotheses and sample size calculations for future trials of invasive ventilation for COVID-19. These data could also help in the interpretation of findings from other studies of ventilation practice and outcomes in invasively ventilated patients with COVID-19. Funding: Amsterdam University Medical Centers, location Academic Medical Center