Effect of erythromycin base on theophylline kinetics.

Because of several recent reports describing altered theophylline elimination in the presence of salts of erythromycin, the effect of a 10-day course of erythromycin base on theophylline kinetics was studied in eight healthy adult men. Theophylline (4 mg/kg) was given on four separate study days: (1) prior to starting erythromycin, (2) on the third day of erythromycin administration, (3) on the tenth day of erythromycin administration, and (4) 2 weeks after the course of erythromycin was completed. Mean theophylline kinetic parameter values on each of the 4 study days were: apparent volume of distribution (Vd), 0.466, 0.466, 0.472, and 0.470 1/kg; elimination half-life (t1/2), 7.4, 7.8, 8.5, and 7.0 hr; and total body clearance (ClB), 0.747, 0.723, 0.683, and 0.821 ml/min/kg. A maximum decrease of 20.7% in theophylline ClB was noted by the third study day. Two weeks after erythromycin was discontinued, the greatest increase in ClB observed was 45.7%. Differences in t1/2 and ClB between the third and fourth study days were statistically significant (p less than 0.05).

Disposition of digoxin immune Fab in patients with kidney failure.

Digoxin and digoxin immune Fab, its antidote, are eliminated renally. However, the disposition of Fab in severe kidney disease is poorly described. Therefore, the disposition of Fab and its relationship to total and free digoxin were studied in five digoxin-toxic patients with end-stage renal disease (n = 4) or severe renal dysfunction (n = 1) with a mean (+/- SD) serum creatinine of 5.9 +/- 1.2 mg/dl (four patients were receiving long-term hemodialysis). Serum was drawn after a clinically neutralizing Fab dose (80 to 160 mg) every 12 to 24 hours for 204 to 327 hours. Fab concentrations were assessed by radioimmunoassay, whereas total digoxin concentrations were assessed with a modified radioimmunoassay or fluorescence polarization immunoassay. The concentration-time profile of Fab appeared to be similar to the concentration-time profile of total digoxin. The mean (+/- SD) half-lives of the alpha and beta disposition phases of Fab were 13 +/- 5 hours and 96 +/- 31 hours, respectively, which were similar to the alpha and beta parameter estimates of total digoxin (14 +/- 4 and 123 +/- 16 hours, respectively). Steady-state volume of distribution and systemic clearance of Fab were 0.29 +/- 0.11 L/kg and 0.057 +/- 0.022 ml/min/kg, respectively. Thus, in comparison to values reported in patients with normal renal function, the elimination of Fab and total digoxin are markedly delayed in patients with end-stage renal disease, which may necessitate prolonged clinical monitoring.

Bioelectrical impedance analysis measurements for drug pharmacokinetics.

I review the rationale, methods, and existing data for using bioelectrical impedance to determine drug pharmacokinetics. Because drugs distribute into body compartments after absorption, it is expected that bioelectrical impedance measurements may correlate with drug pharmacokinetics (absorption, distribution, metabolism, and excretion). Authors have examined correlations between total body water, extracellular fluid, and body cell mass and the drug volume of distribution or clearance and the elimination rate constant. Multiple-regression models with the all-subsets technique provided the most accurate equations with the lowest prediction errors and the highest correlation coefficients. Application of bioelectrical impedance-derived equations to a different set of patients allows prediction of pharmacokinetics. However, bioelectrical impedance equations do not yield more accurate dosing estimates than do standard dosing methods, and large dosing errors are possible in patients with aberrant physiology. Therefore, until multicenter trials in large subject populations can provide stable, accurate equations applicable to a wide variety of patient populations, bioelectrical impedance offers no advantage over standard pharmacokinetic dosing methods for the drugs studied.

Bioelectrical impedance assessment of nutritional status in critically ill patients.

The objective of this study was to assess the utility of bioelectrical impedance analysis (BIA) in determining nutritional status in critically ill patients in the intensive care unit (ICU). Data were collected prospectively in 33 mechanically ventilated medical and surgical ICU patients requiring nutrition as part of their care. BIA, with subsequent calculation of body-composition indexes, was performed every other day for the duration of ICU stay. Body cell mass (BCM) changes correlated with energy and protein intakes (r2 = 0.87, P < 0.001 and r2 = 0.67, P < 0.001, respectively). Maintenance of BCM was achieved by a daily provision of 125.5 kJ.kg-1.d-1 (30 kcal.kg-1.d-1) and 1.5 g protein/kg whereas greater intakes allowed restoration of BCM. The mean ratios of exchangeable sodium to potassium (Nae:Ke) improved only in patients achieving positive nitrogen balance (P = 0.013). Body-composition changes determined by BIA represent a feasible adjunctive method for evaluating and monitoring nutritional status in ICU patients.

Relationship of bioelectrical impedance to pharmacokinetic parameters of theophylline in healthy males.

Bioelectrical impedance is a reliable, safe, non-invasive and valid method of determining body composition, using measures of resistance and reactance by passing a low voltage alternating current through the body. This study investigates relationships between the pharmacokinetics of theophylline and parameters of bioelectrical impedance in 15 non-smoking, healthy, adult male volunteers. After an overnight fast, subjects received 5 mg/kg of aminophylline intravenously over 30 minutes. Blood samples were obtained serially over a period of 12 hours. Bioelectrical impedance measurements were made in triplicate, using a 4-electrode plethysmograph. Sera were assayed in duplicate by enzyme-mediated immunoassay (coefficient of variation less than 5%), and data were fitted to a non-compartmental regression program. An all-subsets multiple-regression technique was employed to arrive at predictive equations for theophylline clearance (CL) and volume of distribution at steady-state (Vss) using age, height, weight and mean bioelectrical impedance parameters. Equations for Vss and CL revealed p-values of less than 0.001 and coefficients of variation of 8.5 and 13.33% respectively. Although the equations display some degree of colinearity they account for 95 and 86.5% of the variability in Vss and CL respectively, and represent an innovative approach to the estimation of pharmacokinetic parameters.

Population pharmacokinetics of gentamicin. Use of the nonparametric expectation maximisation (NPEM) algorithm.

A new nonparametric expectation maximisation (NPEM) algorithm for the estimation of population pharmacokinetic parameter values was evaluated. The algorithm, in the form of a personal computer program, was used to compute population pharmacokinetic parameter densities of gentamicin in a group of 9 patients with indicators of malnutrition. The 1-compartment parameter values for clearance (CL), volume of distribution (Vd) and elimination rate constant (k) were compared with values generated using a standard 2-stage (STS) approach. NPEM was used with a full data set (72 gentamicin concentrations) and a sparse data set (only peak and trough concentrations for each patient; 18 in total). There were no differences in parameter value estimations between the STS and NPEM with all the data (p greater than 0.05) or with the sparse data (p greater than 0.05). Mean parameter value estimates from the STS and NPEM (with sparse data) were used as a priori data sets in the USC*PACK gentamicin Bayesian program to predict concentrations in 8 subsequent patients with similar indicators of malnutrition. There were no differences in predicted gentamicin concentrations between STS (3.75 +/- 2.06 mg/L) and NPEM (3.75 +/- 2.17 mg/L). NPEM was able to generate population pharmacokinetic parameter values for gentamicin in a defined population of patients using sparse routine clinical data. It was also shown to function with only a single data point per patient.

Review of randomized trials of digoxin therapy in patients with chronic heart failure.

Although digitalis glycosides were introduced in the treatment of cardiac maladies greater than 200 years ago, controversy persists regarding the precise role of digoxin in any multidrug approach to the treatment of congestive heart failure (CHF). Despite its widespread use for more than 2 centuries, only recently have double-blind, randomized, placebo-controlled trials of digoxin therapy been conducted in patients with moderate CHF and sinus rhythm. These trials demonstrate that digoxin is superior to placebo in improving left ventricular (LV) ejection fraction, increasing exercise capacity, and preventing CHF worsening. Digoxin produces benefits similar to those seen with angiotensin converting enzyme (ACE) inhibitors with regard to clinical compensation and improvement in LV function. However, improved survival is demonstrated only in response to ACE inhibitors. The recently completed RADIANCE study addresses the value of combining digoxin with ACE inhibitor therapy in patients with mild-to-moderate CHF. Because increased mortality has been reported with the newer oral inotropic agents, it currently appears that digoxin is the only oral inotropic agent useful in clinical practice in the treatment of CHF. However, the effects of digoxin on mortality in patients with CHF remain unknown. In the large, double-blind, randomized trial conducted by the National Heart, Lung, and Blood Institute, the effects of digoxin on mortality in patients with CHF and already being treated with ACE inhibitors are currently being evaluated. Presently, based on the results of placebo-controlled studies, it appears that digoxin, alone or in combination with ACE inhibitors, is beneficial in patients with any signs or symptoms of CHF due to systolic LV dysfunction.

Variability in theophylline volume of distribution and clearance in patients with acute respiratory failure requiring mechanical ventilation.

This study examines the intrasubject variability in theophylline volume of distribution (V) and clearance (CL) in critically ill, mechanically ventilated adults. Fifteen patients received two intravenous doses of theophylline approximately ten hours apart. Although there was no statistical difference between the mean VI (first dose, 0.51 L/kg) and V2 (second dose, 0.47 L/kg), the absolute difference between measurements of 0.15 L/kg was statistically significant (p less than .05). Range of differences follows: between VI and V2, 3.8 to 72.4 percent (mean, 33.5 percent); between CL1 and CL2, 6.1 to 100 percent (mean, 32.2 percent). Absolute difference between clearances was 0.019 L/kg/hr. A comparative error analysis revealed an absolute difference for V of 27.9 percent and for CL of 37 percent. Considerable intra-subject variability was shown for theophylline V and CL in these critically ill adults. Variability in V was not significantly different than variability in CL, and may result in severe underdosing or overdosing.

Determination of gentamicin pharmacokinetics by bioelectrical impedance in critically ill adults.

This investigation compares the accuracy of calculating gentamicin pharmacokinetic parameters by a noninvasive body composition technique (bioelectrical impedance analysis; BIA) with an empiric method, against the two-point method as the criterion standard. A prospective concurrent open label design was used. The 32 medical and surgical intensive care unit beds at Henry Ford Hospital, a not-for-profit, university-affiliated teaching hospital, served as the setting. Twenty critical ill adults, Therapeutic Index Scoring System (TISS) = 4, who required gentamicin as part of their normal course of therapy for gram-negative bacillary infections, were evaluated. Gentamicin Vd and k were calculated by three methods. After measurement of body composition parameters by BIA, previously derived gentamicin dosing equations were used to predict gentamicin volume of distribution (Vd) and elimination rate constant (k) (BIA method). Empiric estimates of these parameters (Vd = 0.3L/kg and k derived from creatinine clearance) were compared with the BIA parameters against a criterion standard Vd and k determined from a two-point sampling of gentamicin serum concentrations. Measurements of BIA parameters and gentamicin serum concentrations were made in duplicate with coefficients of variation, < or = 2% and < or = 3%, respectively. The BIA and empiric methods produced resultant pharmacokinetic parameters (Vd and k) not different than those measured by the two-point method. There were no statistically significant differences in mean error (bias), or mean squared error (precision) for both Vd and k assessed by the empiric or BIA methods.(ABSTRACT TRUNCATED AT 250 WORDS)

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.

Inhibition of N-acetylation of procainamide and renal clearance of N-acetylprocainamide by para-aminobenzoic acid in humans.

Procainamide administration often results in excessively high serum N-acetylprocainamide (NAPA) concentrations and subtherapeutic serum procainamide concentrations. Inhibition of N-acetylation of procainamide may prevent accumulation of excessive NAPA while maintaining therapeutic serum procainamide concentrations. The purpose of this randomized, two-way crossover study was to determine if para-aminobenzoic acid (PABA) inhibits N-acetylation of procainamide in healthy volunteers. Eleven (7 female, 4 male) fast acetylators of caffeine received, in random order, PABA 1.5 g orally every 6 hours for 5 days, with a single intravenous dose of procainamide 750 mg administered over 30 minutes on the third day, or intravenous procainamide alone. Blood samples were collected during a 48-hour period after initiation of the infusion. Urine was collected over a 72-hour period. Serum procainamide and NAPA concentrations were analyzed using fluorescence polarization immunoassay. Urine procainamide and NAPA concentrations were measured with high performance liquid chromatography. PABA did not significantly influence total or renal procainamide clearance, elimination rate constant, AUC0-00, amount of procainamide excreted unchanged in the urine, or volume of distribution. However, concomitant PABA administration with procainamide resulted in increases in NAPA AUC0-00 and t1/2 and reductions in NAPA Ke, procainamide acetylation (NAPA formation) clearance, and NAPA renal clearance. Although PABA inhibits metabolic conversion of procainamide to NAPA, it also impairs the renal clearance of NAPA (but not procainamide) in healthy subjects. Therefore, PABA may not be useful for optimizing the safety of efficacy of procainamide in patients.

Disposition of procainamide in patients with chronic congestive heart failure receiving medical therapy.

Dosage reduction of procainamide has been recommended in patients with congestive heart failure (CHF). However, these recommendations are based primarily on studies with unmatched control groups, suboptimal blood sampling, and in patients not receiving angiotensin-converting enzyme (ACE) inhibitors. These agents increase renal blood flow, which theoretically may offset alterations in drug disposition in patients with CHF. The pharmacokinetics of procainamide in patients with chronic CHF and in matched controls were compared. A single intravenous dose of 750 mg of procainamide was administered to 9 patients with chronic New York Heart Association (NYHA) class II or III CHF (mean +/- SD left ventricular ejection fraction 22 +/- 9%) receiving medical therapy and 7 control subjects matched for age and gender. Blood and urine samples were collected at intervals over a period of 48 and 72 hours, respectively. Patients with CHF and control subjects were demographically similar, with the exception of concomitant medications, including ACE inhibitors (8/9 versus 1/7, respectively). There were no significant differences between patients with CHF and control subjects in mean +/- SD peak serum concentrations (Cmax), area under the serum concentration-time curve (AUC0-infinity), total clearance, renal clearance, half-life (t1/2), or volume of distribution (Vd) of procainamide. Similarly, there were no significant differences between patients with CHF and control subjects in the mean +/- SD Cmax, AUC0-infinity, renal clearance, or t1/2 of N-acetylprocainamide (NAPA). Procainamide dosage reduction may not be necessary in patients with chronic stable CHF who are receiving medical therapy.

Body composition analysis by bioelectrical impedance: the effects of time of day and body side on estimated gentamicin pharmacokinetics.

To assess if repetitive measures are useful in a clinical setting, the effects of time of day and body side on bioelectrical impedance (BI) measurements were evaluated. Fifteen healthy, male volunteers underwent serial BI measurements at 0, 3, 6, 9, 24, and 48 hours on both sides of the body using a four-electrode plethysmograph. Analysis of variance for repeated measures indicated that the mean resistance (R) value of the right side was statistically lower from that of the left side (447 +/- 27.9 vs 457 +/- 29.1 ohms; p = 0.006). Both R and reactance (Xc) varied significantly over time. For R, the mean response at 0, 6, 9, and 48 hours was different from the overall mean of the remaining time points (p less than 0.007). Only times 6 and 24 hours were significantly different for Xc (p less than 0.006). No relevant time and side effects were noted in calculated gentamicin pharmacokinetic parameters on incorporation of BI measurements into impedance-derived predictive equations for clearance, volume of distribution, and elimination constant. Correlation coefficients of reliability were high within 1 day and across days (R greater than or equal to 0.8407). These data suggest that under normal conditions, BI analysis provides reliable results, and that time and side standardizations in its measurements are not necessary.

Relationship between values of bioelectrical impedance and creatinine clearance.

This investigation was conducted to determine if measurements of bioelectrical impedance in conjunction with serum creatinine concentrations are useful in predicting creatinine clearance. Twenty-eight healthy volunteers between 23 and 50 years of age followed an individualized protein diet to provide 1.2 g protein/kg/day for 3 consecutive days. At the beginning of day 3, a 24-hour urine collection was initiated. At the midpoint of urine collection, bioelectrical impedance measurements of resistance and reactance were taken, together with a single blood sample for assessment of serum creatinine concentration. Multiple linear regression techniques were used to identify significant values for predicting creatinine clearance. Resistance and serum creatinine concentration were identified as significant predictors. The measured creatinine clearance was compared to that predicted by the impedance-derived model that we developed, as well as other established estimation methods. Mean absolute prediction errors in creatinine clearance using this model were significantly lower than those obtained using four empiric methods. Bioelectrical impedance may provide a noninvasive, quick, and accurate method for predicting creatinine clearance from serum creatinine concentration values.

Bar code documentation of pharmacotherapy services in intensive care units.

Bar code technology has been used for 5 years to improve the efficiency of identifying and documenting clinical pharmacy services at our institution. Data for an entire year (1993) were analyzed to quantify the nature and magnitude of pharmacy services provided for critically ill patients in intensive care units (ICU). Patients in the medical (MICU), respiratory (RICU), intermediate (IMU), and surgical (SICU) units (3234/3743 patients, 86%) were reviewed. Clinical interventions and expected outcomes were documented by pharmacists using an automated bar code system. There were 11,628 pharmacotherapy interventions, 3.6/patient; 12/pharmacist work day. Of patients whose drug therapy was reviewed at least once, 50% (1610/3234) received at least one intervention. The mean number of interventions/patient was 7.2 in the MICU, 6.1 in RICU, 3.4 in IMU, and 2.4 in the SICU, corresponding to APACHE III scores of 71.2, 66.2, 42.8, and 43.3, respectively. The majority of interventions were to modify dosages of antimicrobial agents, and were performed to achieve optimum efficacy (42%) and to minimize toxicity (46.2%). These data support the necessity for pharmacists to provide individualized care to critically ill patients.

Retrospective pharmacoeconomic evaluation of dosing vecuronium by peripheral nerve stimulation versus standard clinical assessment in critically ill patients.

Adjusting the dosage of vecuronium by peripheral nerve stimulation versus standard clinical dosing in critically ill patients reduces drug requirements to maintain a desired depth of paralysis and, on average, produces faster recovery of neuromuscular function. We retrospectively analyzed the health and economic outcomes of using train-of-four (TOF) end points by peripheral nerve stimulation in dosing neuromuscular blocking agents during continuous infusion in a medical intensive care unit (ICU). A decision-analytic model was used to calculate outcomes and costs of treatment using and not using TOF end points of dosing vecuronium. Data from our TOF trial provided the difference in neuromuscular and functional recovery time. Charges billed by the Patient Financial Services Department were used to determine hourly costs of ICU stay for recovery from neuromuscular blockade using costs:charges ratios estimated from a sample of 20 patients. The cost of vecuronium was determined using the hospital acquisition cost and the actual number of milligrams of drug given to each patient in the TOF trial. The cost of performing one TOF event was determined by timing six events performed by six pharmacists, and randomly selecting 60% of these to calculate a mean time/TOF event. The economic impact of dosing by TOF was determined by calculating the cost savings/patient dosed by TOF compared with those who had doses individualized by standard clinical assessment. One-way and multiway sensitivity analyses were performed to assess model uncertainty. The mean drug cost was $286 in the TOF group versus $580 in the standard dosing group. With a mean time/TOF assessment of 5.8 +/- 1.6 minutes, each episode cost $2.92 for a total TOF cost/patient of $23. At $54/hour of recovery time in the ICU, the estimated cost of ICU care for the TOF group was $34,214 versus $118,681 for the standard group. The estimated costs/patient were $459 and $1197, respectively, for a total cost savings/patient of $738. Sensitivity analyses showed the model to be robust. Estimated annual savings of $146,103 are projected by using TOF to individualize vecuronium doses in patients in the ICU. Individualizing vecuronium doses to TOF end points has both therapeutic and economic advantages. When considering costs of drug, TOF monitoring, and ICU, the total cost/patient was 40% of that in the control group.

Critical pathways: the time is here for pharmacist involvement. American College of Clinical Pharmacy.

Successful development, implementation, and assessment of the effectiveness of critical pathways involves many processes and tools. Numerous pathways have been developed and the value of this tool in improving patient care has been demonstrated in some patient groups.27,29 Pharmacists are becoming more involved, but the window of opportunity is small. Critical pathways are routinely being utilized to optimally sequence time-appropriate interventions of the interdisciplinary plan of care set forth to achieve patient satisfaction and desired outcomes. Pharmacists must seize the chance to provide pharmaceutical care and assure their participation in the development and implementation of critical pathways.

Pharmacotherapy specialty certification examination. IV. 1992 results and process modifications, including recertification. The 1992 Specialty Council on Pharmacotherapy, Board of Pharmaceutical Specialties.

Certification of pharmacotherapy specialists is proceeding smoothly. Modifications to the examination process, which include reapportioning domains, offering the examination at several sites, and establishing the recertification process, have occurred. The guidelines for petitioners and structure of specialization continue to receive the attention and interest of prospective candidates, pharmacy organizations, and the BPS. To date, 674 specialists have been certified in the approved specialties: 175 nuclear pharmacists, 236 nutrition pharmacists, and 263 pharmacotherapy specialists.

Epidemiology of atrial fibrillation in patients hospitalized in a large hospital.

The prevalence of atrial fibrillation varies widely depending on the population studied. To understand the incidence of atrial fibrillation and its significance in relation to other diseases, 3 years (1989 through 1991) of consecutive hospital discharges from the neurology and internal medicine services at Henry Ford Hospital were studied. Of the 26,964 patients who qualified for analysis, 1346 (5%) had atrial fibrillation as 1 of their 5 recorded discharge diagnoses. Comparing the group without atrial fibrillation to those with atrial fibrillation, there were 51% males in both groups (p = 0.88). African-Americans comprised 33% of the patients with atrial fibrillation and 50% of the patients without atrial fibrillation (p < 0.001). The average age of those with atrial fibrillation was 72 +/- 13 years, and 58 +/- 18 years for those without atrial fibrillation (p < 0.001). Length of hospital stay was 9.6 +/- 8.6 days with atrial fibrillation and 7.6 +/- 9.2 days for those without atrial fibrillation (p < 0.001). After adjusting for the effects of age, significant positive associations were noted in those patients with atrial fibrillation whose co-existing condition was either stroke, heart failure, myocardial infarction, hyperthyroidism, or mitral valve disease. There was also a significant negative relationship between hypertension and atrial fibrillation. The most common of the 5 discharge diagnoses observed in patients with atrial fibrillation was congestive heart failure (40%), followed by hypertension (23%) and ischemic heart disease (21%). The existence of a comorbid disease in patients with atrial fibrillation is important, as it can influence medical management and prognosis.(ABSTRACT TRUNCATED AT 250 WORDS)

Evaluation of gentamicin premixed admixtures: cost and clinical utility.

An objective of this study was to evaluate the cost effectiveness of employing gentamicin premixed admixtures compared to using exact, individualized compounded doses. Gentamicin use and waste data were collected over a 2-month period. Annualized institutional savings (300 beds) were projected to be $8,802. A second objective was to compare predicted to measured peak and trough serum gentamicin concentrations when premixed admixtures are used (rounding off computer generated doses to the nearest 10 mg) and when individually compounded exact doses are delivered. Twenty adults were randomized to receive premixed or compounded doses. Blood levels drawn at steady state were compared to predicted levels for the delivered dose. Differences between measured and predicted levels were not significant by performance of an independent t test on the mean square prediction errors. We conclude that it is cost effective and clinically valid to employ premixed intravenous admixtures in a large teaching hospital.