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.

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 micrograms/kg), steady-state plasma concentration, and the initial maintenance dose (16.1 +/- 16.2 micrograms/kg/hr; range 6.1 to 56.0 micrograms/kg/hr) to control heart rate. Subsequent maintenance doses (3.9 to 74.9 micrograms/kg/hr) were determined by clinical response. Heart rate decreased from 146 +/- 22 to 98 +/- 16 beats/min (p less than 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.

Reliability of antidepressant assays: a reference laboratory perspective on antidepressant monitoring.

Chromatography (gas and liquid) and immunoassays are used for monitoring the commonly prescribed tricyclic antidepressants. Many commercially available immunoassays are known to cross react with structurally similar compounds. Chromatographic methods make it possible simultaneously to resolve and quantify amitriptyline, nortriptyline, imipramine, desipramine, trimipramine, doxepin, desmethyldoxepin, protriptyline, and maprotiline-and potentially crossreactive compounds can be separated from the tricyclics. Immunoassays may have a valuable role in initial toxicological screening for the presence of a tricyclic-like compound, and they also may be helpful in a laboratory dedicated to a well-controlled patient group. However, 10% of our specimens contain more or different antidepressants than we are requested to analyze for. With our analysis, we are able to report which antidepressants are present, and in what concentrations. Further, in the case of a potential overdose of tricyclic, the primary purpose for early toxicological analysis to anticipate subsequent clinical complications. Therefore, even in the case of toxicological analysis, it is important to know exactly what tricyclic antidepressant is present rather than just the semiquantitative presence of one or more structurally related compounds, because these various compounds differ markedly in their potential for adverse effects. There are too many potential, and possibly yet unknown, interactions for a reference laboratory routinely to rely on immunoassays for therapeutic drug monitoring or toxicological identification of antidepressants.

Problems+Solutions.

Readers are invited to submit questions relating to problem cases. Inquiries will be answered by qualified consultants and replies forwarded by mail promptly. Selected problems and solutions are published every month in this section.

Is serum creatine kinase-MB in electrically injured patients predictive of myocardial injury?

We undertook a retrospective study of 36 victims of high-voltage electrical contact injuries to determine the incidence and possible source of elevated creatine kinase (CK)-MB enzyme in their serum. Only two sustained myocardial infarctions (one late) according to history, electrocardiographic findings, and clinical course. Serum lactate dehydrogenase isoenzyme levels were abnormal but revealed no myocardial infarction patterns. Creatine kinase total activity, however, reached 1.5 to 1,140 times normal in 92% and the CK-MB level was abnormal in 50% despite the low incidence of myocardial damage. Skeletal muscle CK and CK-MB levels in four nonelectrically injured patients were comparable to those in normal muscle while CK and CK-MB activity was elevated in six such electrical injuries. There was a gradient in CK-MB activity with greatest CK-MB activity in "normal" muscle near the injury site, lesser amounts in border tissue, and least in the worst-injured site. We conclude that myocardial injury is uncommon in high-voltage electrical injury and skeletal muscle injured by high electrical voltage is stimulated to produce, as well as release, CK-MB.

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 micrograms/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 micrograms/ml NTG was also examined. An initial flush of 20 ml of 100 micrograms/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.

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.

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

The 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. 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.

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 evidence 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.

Severe methanol poisoning. Application of a pharmacokinetic model for ethanol therapy and hemodialysis.

Two patients with extremely high blood methanol concentrations (260 and 282 mg/dl) were successfully treated using pharmacokinetic dosing of ethanol, hemodialysis and supportive measures. Both patients recovered completely without residual ophthalmologic deficits. Early hemodialysis and inhibition of methanol metabolism with effective ethanol concentrations were attributed to the patients' full recovery. Methanol elimination was enhanced by hemodialysis as evidenced by a decrease in half-life from eight to two and a half hours. Methanol dialysance was 98 ml/min. A dosage regimen for ethanol was devised, utilizing dose-dependent pharmacokinetic parameters and the ethanol dialysance (100 to 120 ml/min) from these two patients. An ethanol loading dose of 0.6 g/kg should be administered to an adult with an acute methanol ingestion. This dose will produce a blood ethanol concentration of approximately 100 mg/dl which can be maintained by an ethanol infusion of 66 mg/kg/hour for nondrinkers to 154 mg/kg/hour for chronic ethanol drinkers. Hemodialysis should be initiated if the blood methanol concentration is greater than 50 mg/dl. If hemodialysis is initiated, the ethanol infusion should be increased by 7.2 g/hour.

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 less than 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.