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Anti-activated factor X response to enoxaparin in critically ill patients

Introduction

Low molecular weight heparin (LMWH) dosing protocols for deep vein thrombosis prophylaxis in critically ill patients (CIPs) are not based on pharmacologic studies in these patients. Antithrombotic LMWH activity correlates with peak anti-activated factor × (aFXa) levels (4 hours post injection) of 0.1 to 0.2 IU/ml. The hypothesis of this study is that most CIPs do not achieve therapeutic levels for prevention of DVT.

Methods

A prospective study of CIPs randomized to receive enoxaparin once daily intravenously 0.5 mg/kg, subcutaneously 0.5 mg/kg or subcutaneously 40 mg. Blood was sampled for peak and trough aFXa levels (5 days). Inclusion criteria: CIPs aged ≥ 18 years, expected to require mechanical ventilation >3 days. Exclusion criteria: full anticoagulation, platelets <75,000, creatinine clearance <30 ml/min/m2, BMI >30, International Normalized Ratio >1.7, contraindication to anticoagulation. Outcome measures: primary, achievement of target peak/trough levels of aFXa; secondary, monitoring the effect of concomitant administration of noradrenalin on aFXa levels.

Results

Included were 35 patients (5, 15 and 15 accordingly). Mostly male (n = 23, 66%), nonsmokers (n = 23,66%) aged 68 ± 15 years (range 25 to 92) with a BMI of 25 ± 3 (range 17 to 30). Most were admitted for diseases of the digestive/respiratory systems (ICD-9). APACHE scores were 19 ± 4 (range 12 to 29). Forty percent underwent surgery before ICU admission (n = 14). Upon inclusion, 34% (n = 12) were receiving noradrenalin, blood pressures averaged 83 ± 6 mmHg, blood creatinine 1.08 ± 0.27, platelets 206,942 ± 95,128 and International Normalized Ratio 1.3 ± 0.16. No protocol resulted in aFXa levels within the therapeutic range; peak levels were too high and trough levels too low. The only significant difference between patients receiving/not-receiving noradrenalin was found in the trough levels of the SQ 0.5 mg/kg protocol. Hemorrhagic/thorombotic complications included: one gastrointestinal bleeding (SQ 40 mg) and two distal inferior limb DVTs (SQ 0.5 mg/kg and intravenous 0.5 mg/kg protocols). ICU length of stays averaged 9 ± 6 days (median 8, range 4 to 33). Three patients died for causes seemingly unrelated to the study (overwhelming fungal sepsis, severe pneumonia and malignant reperfusion syndrome post carotid endarterectomy).

Conclusion

Current DVT prophylaxis protocols do not result in peak aFXa levels within the recommended antithrombotic range in CIPs. This suggests subtherapeutic levels of LMWH activity and should lead to further studies on optimal dosing in these patients.

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Einav, S., Dezigibker, I., Naamad, M. et al. Anti-activated factor X response to enoxaparin in critically ill patients. Crit Care 13, P439 (2009). https://doi.org/10.1186/cc7603

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Keywords

  • International Normalize Ratio
  • Enoxaparin
  • Trough Level
  • Apache Score
  • Inferior Limb