Correspondence Heparin half-life in normal and impaired renal function
To the Editor: I read with great interest the article by Dr. Paul Perry and associates entitled "Heparin half-life in normal and impaired renal function," which appeared in the September, 1974, issue of the JOURNAL. It appears that the heparin infusion rate equation as derived by Dr. Perry is not substantiated by the half-life values obtained from the study patients. A half-life of 37 min is reported for normal patients given a dose of heparin sufficient to produce a plasma concentration of 0.6 VlmI. A half-life of 37 min can be converted to a plasma elimination constant of 1.13 hr- l . An elimination constant for heparin in normal patients can be determined from Fig. 1, page 516, by utilizing the heparin rate equation. Theoretically, r = Cp • k.i . Vd, where Cp is the therapeutic concentration, kd is the elimination constant, and Vd is the distribution volume. The slope of either of these equations, when r is plotted against Vd or blood volume, is equal to Cp • k.i. Therefore,
k.J
= slope (Fig. I) = 0.47 Vlml/hr = 0.767 hc l Cp 0.60 Vlml '
which is equivalent to a half-life of 54 min. This kd from Dr. Perry's equation represents a much slower elimination and a longer half-life than 37 min. The difference in half-lives from Dr. Perry's data is due to a miscalculation in the slope of the heparin rate equation. The true slope of this line is calculated below: Since slope = Cp x k.J (from a TV2 of 37 min), Then slope = 0.6 Vlml x 1.13 hc l = 0.67 Vlml/hr
Fig. I shows the straight line relationships for heparin infusion rate vs blood volume for the two slopes of 0.46 and 0.67 U/ml/hr. Observe in Fig. 1 the difference in heparin infusion rate for a patient with a blood volume
of 4,800 mi. Curve A gives 1,700 Vlhr vs 2,800 U/hr from Curve B. Thus, an infusion rate obtained from the true Curve B is certainly too high and would probably result in bleeding. Thomas/ Gurewich,3 and Sullivan6 have separately reported that the usual dose of heparin required to elevate a clotting time, be it Lee-White, activated partial thromboplastin time, or activated clotting time, is from 1,000 to 1,500 U/hr. In normal patients, Estes2 demonstrated that the minimum effective dose to raise a clotting time to therapeutic levels is 35 U/kg. For a 70-kg patient, a loading dose of 2,500 U may be given, followed by 1,000 U/hr (r = 2,500 U x 0.4 he l ), where the anticoagulant half-life is 1.7 hr and does not vary with dose. The relative doses which Estes 2 evaluated kinetically ranged from 40 to 150 U/kg. Dr. Perry and associates appear to have evaluated relative doses 3,000 uno kg or 43 U/kg (for a blood volume of 5,000 ml). Thus, it appears that the anticoagulant half-life from Dr. Perry's kinetic data should correlate more closely with Estes'2 half-life of 1.5 to 1.7 hr. An explanation for this disparity should be entertained. Another important consideration that Dr. Perry and others have reported is the variability among patients in heparin anticoagulant responsiveness. Even an individual patient has dayto-day variability in response to heparin. In addition, patients who sustain a thromboembolic phenomenon generally require relatively larger amounts of heparin for the first two to three days of therapy.4 Thus, with heparin sensitivity changing on a day-to-day basis, the use of a structured equation that takes only blood volume into account will not truly represent a patient's heparin requirement. I realize that a correlation of infusion rate and blood volume may have been established
249
250
Correspondence
by Dr. Perry and associates, but the clinical usefulness of the derived equations for the treatment of pulmonary embolus or deep vein thrombophlebitis remains to be established in this group of patients.
Clinical Pharmacology and Therapeutics
To the Editor: I read with great interest the article by Dr. Paul Perry and associates entitled "Heparin half-life in normal and impaired renal function," which appeared in the September, 1974, issue of the JOURNAL. It appears that the heparin infusion rate equation as derived by Dr. Perry is not substantiated by the half-life values obtained from the study patients. A half-life of 37 min is reported for normal patients given a dose of heparin sufficient to produce a plasma concentration of 0.6 VlmI. A half-life of 37 min can be converted to a plasma elimination constant of 1.13 hr- l . An elimination constant for heparin in normal patients can be determined from Fig. 1, page 516, by utilizing the heparin rate equation. Theoretically, r = Cp • k.i . Vd, where Cp is the therapeutic concentration, kd is the elimination constant, and Vd is the distribution volume. The slope of either of these equations, when r is plotted against Vd or blood volume, is equal to Cp • k.i. Therefore,
k.J
= slope (Fig. I) = 0.47 Vlml/hr = 0.767 hc l Cp 0.60 Vlml '
which is equivalent to a half-life of 54 min. This kd from Dr. Perry's equation represents a much slower elimination and a longer half-life than 37 min. The difference in half-lives from Dr. Perry's data is due to a miscalculation in the slope of the heparin rate equation. The true slope of this line is calculated below: Since slope = Cp x k.J (from a TV2 of 37 min), Then slope = 0.6 Vlml x 1.13 hc l = 0.67 Vlml/hr
Fig. I shows the straight line relationships for heparin infusion rate vs blood volume for the two slopes of 0.46 and 0.67 U/ml/hr. Observe in Fig. 1 the difference in heparin infusion rate for a patient with a blood volume
of 4,800 mi. Curve A gives 1,700 Vlhr vs 2,800 U/hr from Curve B. Thus, an infusion rate obtained from the true Curve B is certainly too high and would probably result in bleeding. Thomas/ Gurewich,3 and Sullivan6 have separately reported that the usual dose of heparin required to elevate a clotting time, be it Lee-White, activated partial thromboplastin time, or activated clotting time, is from 1,000 to 1,500 U/hr. In normal patients, Estes2 demonstrated that the minimum effective dose to raise a clotting time to therapeutic levels is 35 U/kg. For a 70-kg patient, a loading dose of 2,500 U may be given, followed by 1,000 U/hr (r = 2,500 U x 0.4 he l ), where the anticoagulant half-life is 1.7 hr and does not vary with dose. The relative doses which Estes 2 evaluated kinetically ranged from 40 to 150 U/kg. Dr. Perry and associates appear to have evaluated relative doses 3,000 uno kg or 43 U/kg (for a blood volume of 5,000 ml). Thus, it appears that the anticoagulant half-life from Dr. Perry's kinetic data should correlate more closely with Estes'2 half-life of 1.5 to 1.7 hr. An explanation for this disparity should be entertained. Another important consideration that Dr. Perry and others have reported is the variability among patients in heparin anticoagulant responsiveness. Even an individual patient has dayto-day variability in response to heparin. In addition, patients who sustain a thromboembolic phenomenon generally require relatively larger amounts of heparin for the first two to three days of therapy.4 Thus, with heparin sensitivity changing on a day-to-day basis, the use of a structured equation that takes only blood volume into account will not truly represent a patient's heparin requirement. I realize that a correlation of infusion rate and blood volume may have been established
249
250
Correspondence
by Dr. Perry and associates, but the clinical usefulness of the derived equations for the treatment of pulmonary embolus or deep vein thrombophlebitis remains to be established in this group of patients.
Clinical Pharmacology and Therapeutics
