Marilynn C. Frederiksen

Single-dose methotrexate for the treatment of ectopic pregnancy: Northwestern Memorial Hospital three-year experience

OBJECTIVE Our purpose was to evaluate the effectiveness of single-dose intramuscular methotrexate in the treatment of ectopic pregnancies by physicians in the Department of Obstetrics and Gynecology of Northwestern Memorial Hospital and to compare the results with those of previously published studies. STUDY DESIGN A retrospective chart review was performed of 50 patients with ectopic pregnancies treated with single-dose methotrexate according to the protocol of Stovall et al. from January 1992 to February 1995. RESULTS The mean pretreatment level of beta-human chorionic gonadotropin was 1896.4 +/- 2399 mlU/ml. Only 32 women (64%) were successfully treated with a single dose of methotrexate. An additional 7 women required a second or third injection. The combined success rate for medical management of ectopic pregnancy with one to three doses of methotrexate was 78% (39 women). Pretreatment beta-human chorionic gonadotropin levels were significantly lower in women who responded to single-dose therapy than in those who required either two or three doses or who had failure of medical management (p = 0.0011). The mean time to resolution of beta-human chorionic gonadotropin was 26.5 +/- 17 days. Higher pretreatment levels correlated with longer resolution time (r = 0.83, p < 0.001). Eleven women (22%) with failure of medical management required surgery. CONCLUSIONS In our series single-dose methotrexate was only 64% successful. Women with a pretreatment beta-human chorionic gonadotropin level >5000 mlU/ml had a greater probability of requiring either surgical intervention or multiple doses of methotrexate. The potential for emergency surgery remains an important risk.

Placenta previa: A 22-year analysis

OBJECTIVE Our purpose was to identify what anesthetic method is safer for women with a placenta previa. STUDY DESIGN We retrospectively reviewed all women with placenta previa who underwent cesarean delivery during the period January 1, 1976-December 31, 1997 at Northwestern Memorial Hospital. RESULTS Of 93,384 deliveries, placenta previa was found in 514 women. Identifiable trends with time included an increasing incidence of placenta previa (r = 0.54, P <.01); cesarean hysterectomy (r = 0.54, P <.01); placenta accreta (r = 0.45, P <.03); and regional anesthesia (r = 0.84, P <.0001). The mean gestational age at delivery was 35.3 +/- 3.4 weeks and did not change with time. General anesthesia was used for delivery in 380 women and regional anesthesia was used for 134 women. Prior cesarean delivery and general anesthesia were independent predictors of the need for blood transfusion, but only prior cesarean delivery was a predictor of the need for hysterectomy. General anesthesia increased the estimated blood loss, was associated with a lower postoperative hemoglobin concentration, and increased the need for blood transfusion. Elective and emergent deliveries did not differ in estimated blood loss, in postoperative hemoglobin concentrations, or in the incidence of intraoperative and anesthesia complications. Regional and general anesthesia did not differ in the incidence of intraoperative and anesthesia complications. CONCLUSIONS In women with placenta previa, general anesthesia increased intraoperative blood loss and the need for blood transfusion. Regional anesthesia appears to be a safe alternative.

Pharmacokinetics of prednisolone transfer to breast milk

Prednisolone transfer to breast milk was studied in three nursing women who required oral steroid therapy for asthma. Each patient received a 50 mg intravenous dose of prednisolone phosphate, and blood and breast milk were sampled for 6 hours. Concentrations of prednisolone in milk declined more rapidly than in serum but were similar to expected unbound serum concentrations, suggesting that exchange between unbound prednisolone in serum and breast milk is relatively rapid and bidirectional. Because an average of 0.025% (range, 0.010% to 0.049%) of the prednisolone dose was recovered in milk, prednisolone transfer to breast milk does not appear to pose a clinically significant risk to nursing infants.

Theophylline pharmacokinetics in pregnancy.

Theophylline pharmacokinetics were studied serially in five women during and after pregnancy. Theophylline protein binding was reduced to 11.1% ± 4.7% (P < 0.01) and 13.0% ± 5.9% (P < 0.01) during the second and third trimesters of pregnancy, respectively, compared with 28.1% ± 2.8% when the patients were more than 6 months postpartum. Similar comparisons indicate that theophylline distribution volume and elimination t1/2 were increased from 30.7 ± 4.4 L and 262 ±57 minutes to 36.8 ± 4.2 L (P < 0.05) and 389 ± 73 minutes (P < 0.01) in the third trimester of pregnancy. In the second and third trimesters, intrinsic nonrenal clearance was reduced to 0.82 ± 0.25 ml/min · kg (P < 0.05) and 0.67 ± 0.18 ml/min • kg (P < 0.01) compared with a remote postpartum value of 1.25 ± 0.37 ml/min · kg. However, these reductions were offset by increases in theophylline intrinsic renal clearance so that apparent reductions in the overall unbound clearance of this drug did not reach statistical significance either during pregnancy or in the early postpartum period.

Effects of dietary protein on theophylline pharmacokinetics and caffeine and aminopyrine breath tests

The effects of low‐ and high‐protein diets on theophylline kinetics and the time course of changes in 13C‐labeled caffeine and aminopyrine CO2 breath tests were examined in six young men. With a low‐protein diet, mean theophylline clearance fell 21% (P < 0.04) and the t1/2 rose from 8.0 to 10.6 hours (P < 0.02). With a high‐protein diet, mean theophylline clearance rose 26% (P < 0.004) and the t1/2 shortened to 7.4 hours (P < 0.03). Theophylline volume of distribution and protein binding did not change. Renal clearance of theophylline was lowered during the low‐protein diet. Theophylline clearance correlated with caffeine breath test values during the low‐ (r = 0.73) and high‐ (r = 0.70) protein diets. Theophylline clearance correlated less well with the aminopyrine breath test values during the low‐ (r = 0.47) and high‐ (r = 0.55) protein diets. Thus dietary protein significantly influenced theophylline clearance, but the caffeine and aminopyrine breath tests showed a differential response to this important environmental factor.

A comparison of once-daily and 8-hour gentamicin dosing in the treatment of postpartum endometritis.

Objective To evaluate whether once-daily gentamicin dosing is as effective as the traditional 8-hour regimen for the treatment of postpartum endometritis. Methods Postpartum women with endometritis were randomized to receive gentamicin 5 mg/kg as a single daily dose or 1.75 mg/kg every 8 hours. All subjects also received clindamycin. Each participant had a peak serum gentamicin level of at least 5.0 μg/mL within the first 24 hours. The dosing regimens were compared by analyzing the number of hours that patients were febrile, the length of hospital stay, occurrence of complications, pharmacy costs, and nursing time required to administer the regimens. Results The study group (n = 62) and the control group (n = 65) were similar in demographic characteristics and the presence of endometritis risk factors. No differences were found between the groups in the number of patients who completed therapy without complications, required changes in antibiotics, or required readmission for endometritis. The groups did not differ in the number of hours that patients remained febrile after the start of therapy or in the length of hospital stay. No patient in the study group had an initial peak serum concentration less than 5.0 μg/mL, whereas 24 patients in the control group had initial peak serum concentrations less than 5.0 μg/mL and required dose adjustment, a statistically significant difference (P < .001). Pharmacy costs averaged

Kinetics of epsilon-aminocaproic acid distribution, elimination, and antifibrinolytic effects in normal subjects

16.12 ± 5.68 for the study group and

Simultaneous analysis of inulin and 15N2-urea kinetics in humans

41.75 ± 17.41 for the control group, also a significant difference (P < .001). Nurse tasking time averaged 13.62 ± 2.56 minutes for the study group and 28.06 ± 8.77 minutes for the control group (P < .001). Conclusion In patients with postpartum endometritis, once-daily gentamicin dosing provides consistently high peak serum levels of gentamicin, requires less nurse tasking time, costs less, and is as effective as the 8-hour dosing regimen.

Characterization of theophylline binding to serum proteins in pregnant and nonpregnant women

The kinetics of €‐aminocaproic acid (EACA) distribution and elimination were studied in six normal subjects after a single 10‐gm iv dose. Steady‐state distribution volume averaged 30.0 l or 0.39 l/kg. Mean elimination t½ was 294 min and the elimination clearance was 0.19 l/min. Renal excretion of unchanged EACA accounted for 68% of its elimination and renal EACA clearance averaged 115% of creatinine clearance. EACA antifibrinolytic effect kinetics were also characterized in five of the subjects by the monitoring of clot lysis times in whole blood and platelet‐rich plasma. Peak antifibrinolytic effects were observed 15 to 60 min after peak EACA plasma concentrations were attained. A model of maximal fibrinolysis inhibition (Emax) was used to estimate a half‐maximal inhibition (IC50) of 63 ±19.7 µg/ml. This agrees with the value of 0.55 mM or 72 µg/ml that has been reported for the dissociation constant of the EACA‐plasminogen complex and is consistent with the proposed biochemical mechanism of EACA action.

PHYSIOLOGICAL BASIS OF MULTICOMPARTMENTAL MODELS OF DRUG DISTRIBUTION

To elucidate the physiologic basis of multicompartmental systems used to model drug distribution, we studied inulin and 15N2‐urea kinetics after simultaneous intravenous injection in five normal subjects. Distribution of both compounds was characterized by three‐compartment models in which the central compartment corresponded to intravascular space. The mean distribution volumes of 0.164 ± 0.009 L/kg (± SD) for inulin and of 0.670 ± 0.143 L/kg for urea were similar to expected values for extracellular space and total body water, respectively. Distribution from intravascular space was kinetically heterogeneous, presumably reflecting differences in vascular beds supplied by either fenestrated and discontinuous capillaries or capillaries with a continuous basement membrane. Intercompartmental clearances of inulin and urea and the ratio of their free water diffusion coefficients were used to estimate blood flows and permeability coefficient‐surface area products for the peripheral compartments. The sum of compartmental blood flows averaged 5.39 ± 0.49 L/min and was similar to dual‐beam Doppler measurements of cardiac output (5.47 ± 0.40 L/min).