Characterization of gentamicin pharmacokinetics in patients hemodialyzed with high-flux polysulfone membranes.

To characterize the pharmacokinetics of gentamicin during and after hemodialysis (using polysulfone Fresenius F-80 membranes (Fresenius USA, Inc, Walnut Creek, CA), surface area 1.6 m(2)), eight patients with end-stage renal disease undergoing chronic hemodialysis receiving the drug for therapeutic indications were enrolled. Intradialytic gentamicin half-life, clearance, and amount of gentamicin recovered during a hemodialysis session were also determined. Serum gentamicin concentrations were analyzed using fluorescence polarization immunoassay. The amount of gentamicin recovered was 64.3 +/- 14.4 mg, whereas the intradialytic gentamicin half-life was 2.24 +/- 0.83 hours, with a clearance of 116 +/- 9 mL/min. Gentamicin concentrations rebounded by 27.86% +/- 16.4% at 1. 5 +/- 0.52 hours after the end of the hemodialysis session. The decrease in gentamicin concentrations comparing maximum rebound to prehemodialysis concentrations was 53.54% +/- 9.97%. A variable yet substantial amount of gentamicin is removed during hemodialysis using F-80 membranes; hence, supplemental doses are necessary to avoid potential treatment failures. The supplemental doses of gentamicin calculated based on gentamicin concentrations obtained immediately postdialysis could be overestimated if the postdialysis rebound concentrations are not considered. A dosing regimen is suggested using the pharmacokinetic parameters defined by the present study and population estimate of volume of distribution.

Continuous arteriovenous hemofiltration of aminoglycoside antibiotics in critically ill patients.

The effect of continuous arteriovenous hemofiltration on the clearance of either tobramycin or gentamicin (mean dose, 1.65 +/- 0.36 mg/kg) was studied in eight critically ill patients. Mean aminoglycoside clearance by hemofiltration was 3.47 +/- 1.93 mL/min and total body clearance was 11.92 +/- 3.51 mL/min. Hemofiltration clearance (HFCL) was directly correlated with hemofiltration flow rate (HFQR): HFCL (mL/min) = 1.03 HFQR (mL/min)-0.88 (R = .89). Mean volume of distribution was 0.31 +/- 0.08 L/kg, and the elimination rate constant was 0.020 +/- 0.01 hr-1. Continuous arteriovenous hemofiltration was responsible for the removal of between 3% and 36% of each aminoglycoside dose in 24 hours. In critically ill patients with changing hemofiltration flow rates, measurement of multiple serum aminoglycoside concentrations is necessary to accurately assess dosing requirements and avoid ototoxicity and nephrotoxicity.

Reducing the number of formulary theophylline preparations.

Cost reduction resulting from decreasing the number of theophylline products on a hospital formulary is reported. A special review subcommittee of the pharmacy and therapeutics (P&T) committee of a 1049-bed hospital was appointed to study tee literature on theophylline preparations. Bids were requested on all theophylline preparations. Bids were requested on all theophylline products. The subcommittee recommended one liquid preparation, one combination product, two sustained-release products, and two rapid-release solid oral theophylline products for inclusion in the formulary. The P&T committee approved the action, and all other oral and rectal theophylline products were deleted. In 1978 (before the product reduction), the hospital purchased 357,551 doses of theophylline at a cost of $27,926.10. In 1979, this cost was reduced to $11.624.39 for 309.069 doses, a savings of over $16,000. Substantial cost savings can be achieved by reducing the number of therapeutically equivalent products and by using teh bid system.

Nephropathy as a hazard of analgesic abuse.

Analgesic nephropathy is discussed. It has been estimated that 5-7% of all patients with chronic renal failure have a history of excessive analgesic use. Chronic analgesic abusers are predominantly women (3:1), and the peak incidence is between the ages of 40-60. Most analgesic abusers have some psychoneurosis with a history of headaches, backaches, arthritis, or ulcers. Several mechanisms for this nephrotoxicity have been proposed. It is thought that the ingestion of aspirin with phenacetin modifies the metabolism or alters the renal tissue response to one of these two drugs in such a manner as to increase toxicity. It has been proposed that the oxidative metabolites of phenacetin act in conjunction with aspirin to cause papillary necrosis. Chronic renal failure, a history of excessive analgesic use, radiological evidence of papillary necrosis, and clinical evidence of hematuria and mild proteinuria may confirm the diagnosis of analgesic nephropathy. Pharmacists should be aware of the indicence of analgesic nephropathy, and the general profile of patients who abuse analgesics. Early detection and cessation of analgesic use may avert progressive renal failure. Pharmacists should advise patients on the long-term complications of chronic analgesic use.

Fee structure for investigational drug studies.

The development and implementation of a fee structure for a pharmacy-coordinated investigational drug service is described. A pilot task and time study established specific time and cost elements for investigational drug services provided by the pharmacy department. To fully assess the costs in dispensing investigational drugs, each research study that used the investigational drug service was broken down into five phases of service. Each phase was further categorized by specific tasks or activities, and a time element to perform each activity or task was determined. Since some studies could require more elaborate randomization of patients, more extensive review of protocols, or more individualized dispensing procedures than others, a range of charges was derived: $2800 for standard protocols to $5700 for more complicated studies. An institutional drug therapy newsletter describing the services and costs was distributed to all medical staff members and principal investigators. The development of a fee structure for an investigational drug service coordinated by the pharmacy department has ensured that pharmacy services are adequately reimbursed and has allowed the department to allocate appropriate personnel to provide the services.

A prospective study of the incidence of the purple glove syndrome.

PURPOSE: Phenytoin (PHT) has been widely used intravenously for the treatment of seizures since 1956, and for many years, it has been considered first-line therapy for status epilepticus. It is routinely administered intravenously in emergency departments and hospitals for patients who have had isolated seizures and for many patients undergoing neurosurgical procedures who are unable to receive oral medication. Adverse reactions from PHT have been widely studied for years, but in the past decade, new adverse reactions have been identified. One of these adverse reactions is the purple glove syndrome (PGS), characterized by edema, discoloration, and pain distal to the site of i.v. administration of PHT. Because there have been no prospective reports of the incidence of PGS, the objective of the study was to report the incidence of this syndrome. METHODS: We enrolled 179 consecutive exposures to i.v. PHT at Henry Ford Hospital. Distal portions of the upper extremities were examined and digitally photographed by one of the authors (J.G.B.). The photos were blindly evaluated by the third author (G.L.B.) for PGS. Demographic and pertinent medical history was recorded for all patients, and outcome for those who experienced PGS was recorded. Associations between PGS, demographic, and medical history information were assessed. RESULTS: In only three of the 179 exposures did PGS develop. In both patients, the severity of the clinical picture was mild and did not required prolonged hospitalization or specialized treatment. CONCLUSIONS: PGS is an infrequent and mild adverse effect of i.v. PHT administration.

Interaction between tacrolimus and erythromycin.

A 40-year-old Asian man, 6 months post renal transplant and receiving tacrolimus therapy, presented to the emergency department with a complaint of sudden-onset left eye pain with blurred vision, headache on the left side, and nausea and vomiting. On being admitted, the patient was intubated for respiratory depression, and erythromycin was initiated for suspected atypical pneumonia. Tacrolimus concentrations (whole blood) drawn on the 3rd day of hospitalization were reported to be > 60.0 ng/ml. Before hospitalization, tacrolimus concentrations were reported to be 9.8 ng/ml on a maintenance dose of 7 mg twice daily. Six days after discontinuation of erythromycin and a decrease in tacrolimus dose, the concentration decreased to 11.5 ng/ml and the original dose of tacrolimus was restarted. It is recommended that concurrent administration of erythromycin and tacrolimus be avoided. However, if concomitant therapy is necessary, tacrolimus concentrations, serum creatinine, blood urea nitrogen, and urine output should be monitored.

Vancomycin removal by high-flux polysulfone hemodialysis membranes in critically ill patients with end-stage renal disease.

To define the pharmacokinetics of vancomycin in patients undergoing maintenance hemodialysis in an acute care setting and to characterize the rebound phenomenon occurring after hemodialysis, vancomycin t1/2 during the interdialytic and intradialytic phases and intradialytic clearance were measured in eight critically ill patients undergoing high-flux hemodialysis using F-80 or F-60 polysulfone dialyzers. Intradialytic clearance was determined using the recovery method. In patients dialyzed with F-80 dialyzers, interdialytic and intradialytic t1/2 for vancomycin were 162 +/- 69.8 hours and 4.7 +/- 1.3 hours, respectively. Intradialytic clearance was 108.5 +/- 16.3 mL/min, and 238 +/- 55 mg of vancomycin was recovered in the dialysate. In patients dialyzed with F-60 dialyzers, interdialytic and intradialytic t1/2 were 211.0 +/- 166.8 and 4.6 +/- 0.4 hours, respectively. Intradialytic clearance was 100.6 +/- 18.3 mL/min and the amount of vancomycin recovered was 252 +/- 79 mg. Vancomycin concentrations rebounded by 16% to 37% between 3 and 6 hours in patients dialyzed with the F-80 dialyzer and 15% to 38% between 2 and 3 hours in patient dialyzed with F-60 dialyzers. Hemodialysis with high-flux polysulfone dialyzers removes significant amounts of vancomycin in patients dialyzed in an acute care setting. A suggested scheme for vancomycin dosage adjustments in these patients is presented.

The transition to medication system performance indicators.

Economic and competitive pressures in the health care market are causing hospitals and other health care providers to seek more effective ways to improve the quality of care and to decrease costs. Integrating total quality management and continuous quality improvement techniques into traditional drug use evaluation methodology allows for the development of critical performance indicators. These indicators integrate the selection, use, delivery methods, and outcomes of drug therapy with other operational therapeutic modalities. The article describes the development of medication system performance indicators using heparin dosing as a model.

Dialysate iron therapy: infusion of soluble ferric pyrophosphate via the dialysate during hemodialysis.

BACKGROUND: Soluble iron salts are toxic for parenteral administration because free iron catalyzes free radical generation. Pyrophosphate strongly complexes iron and enhances iron transport between transferrin, ferritin, and tissues. Hemodialysis patients need iron to replenish ongoing losses. We evaluated the short-term safety and efficacy of infusing soluble ferric pyrophosphate by dialysate. METHODS: Maintenance hemodialysis patients receiving erythropoietin were stabilized on regular doses of intravenous (i.v.) iron dextran after oral iron supplements were discontinued. During the treatment phase, 10 patients received ferric pyrophosphate via hemodialysis as monthly dialysate iron concentrations were progressively increased from 2, 4, 8, to 12 micrograms/dl and were then sustained for two additional months at 12 micrograms/dl (dialysate iron group); 11 control patients were continued on i.v. iron dextran (i.v. iron group). RESULTS: Hemoglobin, serum iron parameters, and the erythropoietin dose did not change significantly from month 0 to month 6, both within and between the two groups. The weekly dose of i.v. iron (mean +/- SD) needed to maintain iron balance during month 6 was 56 +/- 37 mg in the i.v. iron group compared with 10 +/- 23 mg in the dialysate iron group (P = 0.001). Intravenous iron was required by all 11 patients in the i.v. iron group compared with only 2 of the 10 patients receiving 12 micrograms/dl dialysate iron. The incidence of adverse effects was similar in both groups. CONCLUSIONS: Slow infusion of soluble iron pyrophosphate by hemodialysis may be a safe and effective alternative to the i.v. administration of colloidal iron dextran in maintenance hemodialysis patients.

Optimization of epoetin therapy with intravenous iron therapy in hemodialysis patients.

Iron deficiency limits the efficacy of recombinant human erythropoietin (rhEPO) therapy in end-stage renal disease (ESRD) patients. Functional iron deficiency occurs with serum ferritin >500 ng/ml and/or transferrin saturation (TSAT) of 20 to 30%. This study examines the effects of a maintenance intravenous iron dextran (ivID) protocol that increased TSAT in ESRD hemodialysis patients from conventional levels of 20 to 30% (control group) to those of 30 to 50% (study group) for a period of 6 mo. Forty-two patients receiving chronic hemodialysis completed a 16- to 20-wk run-in period, during which maintenance ivID and rhEPO were administered in amounts to achieve average TSAT of 20 to 30% and baseline levels of hemoglobin of 9.5 to 12.0 g/dl. After the run-in period, 19 patients randomized to the control group received ivID doses of 25 to 150 mg/wk for 6 mo. Twenty-three patients randomized to the study group received four to six loading doses of ivID, 100 mg each, over a 2-wk period to achieve a TSAT >30% followed by 25 to 150 mg weekly to maintain TSAT between 30 and 50% for 6 mo. Both regimens were effective in maintaining targeted hemoglobin levels. Fifteen patients in the control group and 17 patients in the study group finished the study in which the primary outcome parameter by intention to treat analysis was the rhEPO dose needed to maintain prestudy hemoglobin levels. Maintenance ivID requirements in the study group increased from 176 to 501 mg/mo and were associated with a progressive increase in serum ferritin to 658 ng/ml. Epoetin dose requirements for the study group decreased by the third month and remained 40% lower than for the control group, resulting in an overall cost savings in managing the anemia. Secondary indicators of iron-deficient erythropoiesis were also assessed. Zinc protoporphyrin did not change in either group. Reticulocyte hemoglobin content increased only in the study group from 28.5 to 30.1 pg. It is concluded that maintenance of TSAT between 30 and 50% reduces rhEPO requirements significantly over a 6-mo period.