Anti-Xa activity after subcutaneous administration of dalteparin in intensive care unit patients with and without subcutaneous oedema

Introduction

Subcutaneous administration of low molecular weight heparins (LMWHs) is efficient in the prevention of venous thromboembolism (VTE), which is a frequent complication in critically ill patients. ICU patients often suffer from subcutaneous oedema, due to the pathophysiology and large volumes of fluid they require. Subcutaneous oedema may impair the absorption of dalteparin, a LMWH, which is given by subcutaneous administration for VTE. To investigate whether indeed the absorption of dalteparin is impaired because of subcutaneous oedema, we compared the anti-Xa activity after subcutaneous injection of dalteparin in ICU patients with subcutaneous oedema with ICU patients without subcutaneous oedema.

Methods

The study design is a non-randomised open parallel group follow-up study. The study was conducted at the ICUs (mixed medical–surgical) of two teaching hospitals in The Netherlands, from January 2003 until November 2004. The inclusion criteria were ICU patients with age >18 years, subcutaneous administration of dalteparin 2500 IU once daily for VTE prophylaxis. The exclusion criteria were use of vitamin K antagonists, use of therapeutic doses of LMWHs or UFH, severe liver failure, renal insufficiency, signs of disseminated intravascular coagulation, use of vasopressors and/or inotropics. Anti-Xa activities were determined at 0, 3, 4, 6, 8, 12 and 24 hours after subcutaneous administration of dalteparin. Both the Cmax and AUC(0–24 hours) values of anti-Xa activity were compared. Comparison of continuous variables was done by Student's t test. The anti-Xa activity (Cmax and AUC(0–24 hours)) was compared by the non-parametric Mann–Whitney test (mean ± standard error of the mean). A P value of 0.05 is taken as the cut-off for statistical significance.

Results

Six ICU patients with and six ICU patients without subcutaneous oedema were studied. The characteristics of the index group were: age 57 years, male/female ratio 5/1, body mass index at admission 22.7 kg/m². The characteristics of the reference group were: age 48 years, male/female ratio 5/1, body mass index at admission 23.9 kg/m². In the index group creatinine clearance was lower compared with the reference group (81 vs 127 ml/min, P = 0.57). Both mean creatinine clearances were within the normal range. Sequential organ failure assessment score did not differ between the index and reference groups (4 vs 5). Mean arterial pressure was comparable between the index and reference group (87 vs 90 mmHg) and within the normal range. Mean plasma concentrations of factor anti-Xa activity were comparable in both groups. The mean Cmax value was not different between ICU patients with and without subcutaneous oedema (0.15 ± 0.02 vs 0.13 ± 0.03 IU/ml, P = 0.30). In the ICU patients with subcutaneous oedema the mean AUC(0–24 hours) value was higher (1.41 ± 0.34 vs 0.92 ± 0.11 hours IU/ml, P = 0.23).

Conclusions

There is no difference in anti-Xa activity after subcutaneous administration of 2500 IU dalteparin between ICU patients with and without subcutaneous oedema. When compared with values in healthy volunteers, critically ill patients seem to have lower anti-Xa activity levels. This is found in recent studies as well. More research is necessary to identify the proper dose and route of LMWHs for VTE prophylaxis in ICU patients.