A fixed dose approach to thrombosis chemoprophylaxis may be inadequate in heavier critically ill patients

In Australia and New Zealand, overweight and obese adults represent about two-thirds of the adult population, and the mean body mass index (BMI) of critically ill patients has almost reached the obese category.1,2 Patients who are overweight or obese are at greater risk of complications, including venous thromboembolism (VTE).3 For unselected patients requiring intensive care unit (ICU) admission, the prophylactic administration of low molecular weight heparin (LMWH) mitigates VTE risk.4,5 For patients in the normal weight range, the effect of LMWH is predictable; however, in otherwise healthy individuals, excessive weight is known to affect the pharmacokinetics of LMWH.6,7 In ICUs, conditions such as shock, frequently administered therapies such as vasopressors and complications such as oedema also substantially affect the pharmacokinetics of subcutaneously administered drugs.8,9 Data evaluating the use of LMWH for VTE prophylaxis in heavier critically ill patients are limited.This has led to uncertainty regarding optimal dosing regimens for this group.10 While inadequate dosing will increase the risk of thrombosis, excessive dosing will increase the risk of bleeding, and both conditions can have catastrophic consequences for a patient.11,12 Accordingly, inadequate evidence and concerns about underdosing or overdosing may lead to considerable variation in practice between clinicians.The effect of LMWH may be quantified using the biomarker of plasma anti-factor Xa concentration -the so-called anti-Xa level.In healthy individuals, anti-Xa levels peak 4-6 hours after subcutaneous administration of enoxaparin, with steady state concentrations achieved after three or more doses.13 Despite uncertainty about target anti-Xa levels for effective prophylaxis in critically ill patients, it is generally agreed that peak levels in the range 0.2-0.5 IU/mL and trough levels ≥ 0.1 IU/mL are appropriate targets for minimising risk of thrombosis without increasing risk of bleeding.10,[14][15][16][17] Indeed, in a sequential period study of 205 patients after trauma, an intervention of increasing enoxaparin dose based on trough anti-Xa levels (ie, if a trough anti-Xa level was < 0.1 IU/mL after three doses, enoxaparin dose was increased) reduced rates of venous thrombosis by sevenfold.18 ABSTRACT Objectives: Overweight patients are at greater risk of venous thromboembolism.We aimed to describe prescribing patterns of thrombosis chemoprophylaxis in critically ill patients weighing ≥ 100 kg and quantify the effectiveness of these regimens using the surrogate biomarker of plasma anti-Xa level.Design, setting and patients: A prospective singlecentre cohort study was conducted over a 6-month period.Patients weighing ≥ 100 kg who were prescribed enoxaparin for chemoprophylaxis and expected to remain in the intensive care unit for > 48 hours were eligible.Anti-Xa levels were measured once a patient had received at least three consecutive doses of enoxaparin.Peak levels were measured 4-6 hours after the third dose and trough levels were measured before the fourth dose.Anti-Xa levels were compared with established target ranges for peak and trough anti-Xa levels (0.2-0.5 IU/mL and > 0.1 IU/mL, respectively).Results: Eighty-eight patients met the eligibility criteria, and anti-Xa levels for 42 patients were obtained.Fixed dose chemoprophylaxis approaches varied considerably, with 40 mg once daily (54/88 [61%]) and 40 mg twice daily (20/88 [23%]) being the most frequently prescribed regimens.No patient had a peak anti-Xa level > 0.5 IU/mL.When comparing 40 mg once daily versus twice daily, the once daily regimen had lower median trough levels (0.01 IU/mL [interquartile range (IQR), 0.00-0.04]v 0.09 IU/mL [IQR, 0.05-0.13];P < 0.001) and greater proportions of patients with levels below the established range (< 0.1 IU/mL) (15/16 [95%] v 7/14 [50%]; P = 0.002) and levels that were undetectable (0.00 IU/mL) (8/16 [50%] v 1/14 [7%]; P = 0.01). Conclusions:At a single centre, thrombosis chemoprophylaxis prescribing patterns for heavier critically ill patients varied considerably.Current fixed dose approaches may be inadequate in this cohort.