When given in prophylactic doses, LMWH has not been shown to increase the risk of bleeding complica- tions, irrespective of the degree of impairment of renal function. Although higher anti-Xa levels were found in patients with renal failure who received repeated once-daily prophylactic doses of enoxaparin, the mean peak anti-Xa level was only 0.6 units/mL, the trough was,0.2 units/mL, and no increased bleeding was observed.156,164 In a prospective cohort study of critically ill patients with a wide range of renal function, including some with acute renal fail- ure who required hemodialysis, dalteparin bioaccu- mulation was not observed despite repeated dosing.165 In a more recent study, subcutaneous dalteparin (5,000 International Units) was given daily to consec- utive ICU patients who had an estimated creatinine clearance,30 mL/min. There was no evidence of drug accumulation nor was the risk of bleeding increased.166 For patients with a CrCl,30 mL/min who require pharmacologic VTE prophylaxis, manu- facturer of enoxaparin recommends that 30 mg once daily be used. In a small comparative study of enox- aparin (40 mg once daily) or tinzaparin (4,500 units once daily), bioaccumulation of enoxaparin, but not tinzaparin, was seen over 8 days of exposure.167 For other LMWHs, dosing recommendations cannot be made in the setting of renal insuf ciency. 1.2.5 Reversing the Anticoagulant Effects of LMWH: There is no proven method for neutralizing LMWH. Studies in vitro and in animals have demon- strated that protamine sulfate neutralizes the anti-IIa activity of LMWH, thereby normalizing the aPTT and the thrombin time. 