A prospective evaluation of elevated serum theophylline concentrations to determine if high concentrations are predictable.

PURPOSE: To evaluate prospectively whether serum theophylline concentrations of 25 mg/L and greater were predictable (and presumably preventable) by use of basic pharmacokinetic calculations. DESIGN: Prospective study. PATIENTS: Fifty-five patients with a serum theophylline concentration of at least 25.0 mg/L were evaluated initially and if subsequent elevated theophylline concentrations occurred. INTERVENTIONS: The predicted steady-state serum theophylline concentration was calculated from the dosage rate divided by the predicted clearance to determine how many elevated concentrations (greater than 20 mg/L) were predictable. Predicted clearances were 0.04 L/kg/hour for normal subjects less than 70 years of age and 0.02 L/kg/hour for patients with congestive heart failure, chronic obstructive pulmonary disease, or liver disease. Estimated clearances were determined and compared with predicted clearances. If patients did not have steady-state concentrations, additional calculations were made. MAIN RESULTS: From 6,368 consecutive theophylline determinations, 69 (1.08%) samples from 55 patients were 25 mg/L or higher. Predictably high concentrations occurred in 23 of 33 (69.7%) fully evaluable cases. These concentrations occurred because of a failure to consider decreased elimination clearance from congestive heart failure, chronic obstructive pulmonary disease, or hepatic disease. Five fatalities occurred, and in two cases, theophylline appeared to contribute to the patient's death. Three other patients experienced syncope. The predicted elimination clearance of theophylline of 0.02 L/kg/hour was too high in eight patients over 70 years old with cardiac or pulmonary disease. Nursing and pharmacy oversights were identified as three patients were given two theophylline products simultaneously. CONCLUSIONS: Most elevated theophylline concentrations are predictable (and preventable) by basic pharmacokinetic calculations. Patients experiencing elevated theophylline concentrations often had comorbid conditions and were greater than 60 years of age. The dosage rate of theophylline (mg/hour) can be estimated from predicted clearance (L/kg/hour) times desired steady-state serum concentration (mg/L).

Activation of renin-angiotensin system does not cause skeletal muscle cramps during hemodialysis.

Activation of the renin-angiotensin system usually occurs during hemodialysis and in hemodialyzed normal dogs parallels reductions in blood flow to a tissue group that is largely composed of skeletal muscle. To determine if excessive activation of this system might cause dialysis-associated skeletal muscle cramps in some patients, we conducted a double-blind, randomized and balanced trial in which 5 patients with frequent dialysis-associated cramps were each given either a 25 mg oral dose of captopril or placebo 1 h before 8 consecutive dialyses. Captopril increased the frequency of dialyses complicated by skeletal muscle cramps in 1 patient and did not affect cramp frequency in the other 4 patients. Predialysis plasma renin activity (PRA) averaged 3.9 ng/ml/h (+/- SD) and was the same as in unselected hemodialysis patients. Following captopril, PRA increased by an average of 2.2 +/- 0.7 times, similar to the 2.6-fold increase that was reported when this drug was used to prevent dialysis-associated hypertensive crises. However, hemodialysis by itself did not activate the renin-angiotensin system as consistently in patients with frequent dialysis-associated skeletal muscle cramps as in unselected hemodialysis patients and the ratio of post- to predialysis PRA averaged 1.0 +/- 0.6. We conclude that the renin-angiotensin system does not mediate, and that its activation during hemodialysis may actually help prevent, dialysis-associated skeletal muscle cramps.

Pharmacokinetics of N-acetylprocainamide in patients profiled with a stable isotope method.

N-Acetylprocainamide (NAPA) absorption and disposition were profiled in five patients with ventricular arrhythmias by the simultaneous intravenous administration of NAPA-13C and oral administration of a 500 mg NAPA hydrochloride tablet. NAPA distribution was modeled with a three compartment mammillary system. The central compartment volume of 14.1 +/- 2.6 L (mean +/- SD) was similar to expected intravascular space, corrected for NAPA partitioning between erythrocytes and plasma. Other compartment volumes, intercompartmental and nonrenal clearances, and the steady-state distribution volume of 1.45 +/- 0.09 L/kg were similar to normal subject values. The least-squares estimate of 1.67 for the NAPA renal clearance/creatinine clearance ratio was similar to the value of 1.68 previously reported for functionally anephric patients and showed the expected age-associated decrease. The oral NAPA dose was 78.0% +/- 11.7% absorbed and interindividual variation in NAPA absorption was correlated with fast intercompartmental clearance (r = 0.89, p = 0.045). Because fast intercompartmental clearance partly reflects splanchnic blood flow, hemodynamic changes may affect NAPA bioavailability, as has been found for procainamide.

D-xylose absorption and disposition in patients with moderately impaired renal function.

D-Xylose kinetics were studied after oral and intravenous administration to 10 patients with impaired renal function, three of whom were being evaluated for intestinal malabsorption. The 0.32 +/- 0.06 L/kg (mean +/- SD) distribution volume of D-xylose in patients with uncomplicated renal impairment was larger than the value of 0.23 +/- 0.04 L/kg that we reported previously for normal subjects (P less than 0.01). Renal clearance was also reduced, averaging 87% of glomerular filtration rate estimated from creatinine clearance, so that the elimination-phase half-life was prolonged to 138 +/- 39 minutes from 75 +/- 11 minutes in normal individuals (P less than 0.01). The 25 gm oral D-xylose dose was 77.4% +/- 14.8% absorbed in the patients with uncomplicated renal impairment, similar to the 69.4% +/- 13.6% absorption reported in normal individuals. However, the absorption half-life was prolonged from 31 +/- 12 minutes in normal subjects to a value of 62 +/- 23 minutes (P less than 0.02). Of the usual clinical indexes of D-xylose absorption, the serum concentration measured 1 hour after the oral dose was best correlated with the extent of D-xylose absorption (r = 0.76; P less than 0.01), and the standard lower normal limit of 0.2 mg/ml was satisfactory.