Harry G. McCoy

Effect of cardiopulmonary bypass on cefazolin disposition

Cefazolin kinetics was studied in 8 patients the day before (PREOP), during (SURG), and the day after (POSTOP) cardiopulmonary bypass (CPB) surgery. PREOP (48.6 ml/min) and POSTOP (46.6 ml/min) total body clearances were of the same order and both were greater than the SURG (27.4 ml/min) total body clearance. Since cefazolin is almost entirely eliminated by the kidney, the lower SURG clearance is a result of reduced renal elimination, as confirmed by measuring cefazolin SURG (28.7 ml/min) and POSTOP (52.9 ml/min) renal clearance. The reduction in cefazolin renal elimination was the same throughout the surgical procedure, including the period of extracorporeal circulation. Cefazolin distribution was altered by the operative procedure as evidenced by a higher SURG steady‐state volume of distribution. This increase in apparent cefazolin distribution volume brought about by surgery was not seen with cephalothin, which was investigated by us in a similar group of patients. The different effect of CPB surgery on cefazolin and cephalothin distribution may be due to differences in plasma protein binding.

Cephalothin kinetics: Before, during, and after cardiopulmonary bypass surgery

Cephalothin kinetics was studied in 5 patients the day before (PREOP), during (SURG), and the day after (POSTOP) cardiopulmonary bypass surgery. The PREOP (114 ml/min) and SURG (94 ml/min) renal clearances were of the same order but both were less than POSTOP renal clearance (248 ml/min). Cephalothin total body clearance during operation was lower (p < 0.01) than PREOP or POSTOP clearance, with decreased metabolic clearance the primary cause. There was reduction in cephalothin elimination throughout the surgical procedure, not only in the period of extracorporeal circulation, indicating that general anesthesia had a significant influence on drug disposition. The metabolite deacetylcephalothin was rapidly formed on all 3 days and its kinetic behavior paralleled that of the parent drug.

Stability and delivery of vancomycin hydrochloride when admixed in a total parenteral nutrition solution

Vancomycin hydrochloride, 400 mg/liter was mixed in six standard pediatric parenteral nutrition solutions with and without heparin added. The solutions were stored over a period of 8 days (192 hr) under refrigeration and at room temperature. Aliquots from all six solutions were assayed in duplicate for vancomycin at time 0, 24, 96, and 192 hr. All samples were run through an Ivex 0.22-micron filter, observed for physical incompatibilities, and frozen at -70 degrees C until assay. Our results indicate that vancomycin was stable and was delivered with loss in concentration of less than 5% with and without storage under refrigeration. This study suggests an alternative method for delivering vancomycin when treating a catheter-related infection. If vancomycin is delivered in this fashion, less manipulations of the line would be required. In addition, there may be a theoretical advantage of constantly bathing the catheter with vancomycin when the catheter is suspected of harboring the infecting organism.

Variable first-pass elimination of propranolol following single and multiple oral doses in hypertensive patients

SummaryThe disposition of orally administered propranolol has been studied in twelve patients with mild to moderate hypertension. Each patient received single doses of 40, 80, and 160 mg. Serial blood samples were obtained and quantitated using a sensitive gas chromatographic analytical technique. Ten of the twelve patients received 40 mg doses of propranolol every 6 hours for 5 doses. Blood samples were obtained after administration of the first, second, third, and fifth doses. Substantial intersubject variability in the areas under the bloodconcentration-time profiles (AUC) was observed. p ]Evidence for a nonlinear first-pass effect was not obtained in all patients. The patients displaying a nonlinear relationship between dose and AUC for single propranolol doses consistently showed a similar relationship during multiple dosing. Blood levels obtained following the evening dose (08h00 to 14h00) appeared to be lower than expected based on multiple-dosing pharmacokinetic principles. These findings suggest that monitoring propranolol blood levels is the most viable way to ascertain therapeutic concentrations of this drug.

Supraventricular tachycardia treated with continuous infusions of propranolol

Because oral therapy is often contraindicated in hospitalized patients we assessed the safety and efficacy of continuous intravenous propranolol infusions in nine patients with refractory supraventricular tachycardia. Standard pharmacokinetic formulas predicted a loading dose (52.2 ± 38.3 μg/kg), steady‐state plasma concentration, and the initial maintenance dose (16.1 ± 16.2 μg/kg/hr; range 6.1 to 56.0 μg/kg/hr) to control heart rate. Subsequent maintenance doses (3.9 to 74.9 μg/kg/hr) were determined by clinical response. Heart rate decreased from 146 ± 22 to 98 ± 16 beats/min (p < 0.0001). This decrease persisted throughout the infusion. Measured propranolol levels (28 ±21 ng/ml) did not differ significantly from the predicted levels (23 ± 17 ng/ml). The duration of the infusion averaged 97 ± 77 hours. A side effect, transient wheezing, occurred in only one patient. This resolved when the infusion rate was decreased. We conclude that continuous propranolol infusions appear safe and effective in treating these patients with supraventricular tachycardia.

Nitroglycerin Adsorption to a Combination Polyvinyl Chloride, Polyethylene Intravenous Administration Set:

Loss of nitroglycerin (NTG) from intravenous solutions to intravenous bags and administration sets has been well documented. This study was designed to examine a commercially available low adsorption administration set that was compatible with a volumetric infusion pump. A solution of NTG 100 μg/ml in dextrose 5% in glass bottles was used. Six study administration sets were tested. The infusion sets were connected to the NTG-containing glass bottles, filled as rapidly as possible, placed in the infusion pump, and set at the appropriate rate. Effluent was collected for NTG assay initially, and at 20 and 40 minutes, and 1, 1.5, 2, 3, 6, and 24 hours. The effects of flow rate were studied at 0.2 and 1.0 ml/min. The tubing performed similarly to other polyvinyl chloride (PVC)-containing sets at 0.2 ml/min and similar to non-PVC sets at 1.0 ml/min. The effect of an initial flush with 20–100 ml of 100 μg/ml NTG was also examined. An initial flush of 20 ml of 100 μg/ml NTG solution was found to enhance delivery of NTG immediately. NTG aliquots were stored frozen in glass vials prior to assay by high performance liquid chromatography.

Laboratory Analysis of Cyclosporine

There is little question that monitoring cyclosporine concentrations can improve patient outcome after organ transplantation. The procedure is very important to ensure the optimal therapeutic outcome for each patient, with minimal toxicities. One of the questions that remains revolves around how best to monitor cyclosporine levels. Even before the drug was released to the United States market, an editorial described the many problems entailed in providing consistent analysis of cyclosporine.’ That editorial did not question whether monitoring was a good idea, it simply expressed pessimism as to whether all the incumbent analytical problems could ever be overcome. Seven years later the problems are still not completely solved. The history of drug analysis is the story of a continuing search for simple-to-perform, specific laboratory methods. This, too, is the story of cyclosporine analysis. Monitoring is complicated, however, by the drug’s many metabolites, and difficulty with the stability of measurable drug in biologic fluids.

Toward optimal drug therapy. Benefits of therapeutic drug monitoring.

Over the past two decades, therapeutic drug monitoring has repeatedly been found to improve efficacy and minimize toxicity. Monitoring is needed in patients with conditions that alter their responses to drugs, such as congestive heart failure or old age. It is also necessitated by such drug factors as variable distribution or elimination and by such clinical situations as when compliance or efficacy is questioned. For drug monitoring to achieve its potential benefits, serum concentrations of drug must be measured at the appropriate time. In most clinical situations, a single trough measurement at steady state is adequate to assess therapy.

State of the Art: Measurement of Drug Concentrations for Therapeutic Drug Monitoring

THIS OVERVIEW of laboratory analysis will emphasize the procedures used to measure serum concentrations of drugs that are in common clinical use today. The goals of this review are to provide the reader with an understanding of current analytical procedures, the ability to interpret analytical results more accurately, and to solve clinical problems more readily. The review is not intended to instruct the reader