Bayesian forecasting of aminoglycoside dosing requirements in obese patients: influence of subpopulation versus general population pharmacokinetic parameters as the internal estimates.

An aminoglycoside Bayesian forecaster was evaluated in obese patients. This study assessed the influence of replacing the program-supplied general population parameters (GPP) with obese population parameters (OPP) determined from the study population (n = 26). After entering the required patient information and the first peak and trough levels, patient-specific pharmacokinetic parameters were generated by the Bayesian program based on GPP. These parameters were used to predict peak and trough levels for a second dosage regimen. Next, average OPP determined from a study population were substituted for the GPP, and the peak and trough levels were predicted again. Finally, Bayesian predictions of peak and trough levels were made in a validation population (n = 10), first with GPP, then with OPP. The accuracy of the predictions were evaluated through a prediction error analysis in which mean error indicates bias and mean absolute error and root mean-squared error indicate precision. Means were statistically compared through a Student's t test, with the significance level set at p less than 0.05. For the study and validation populations, peak level predictions based on the OPP had less bias and greater precision than those predicted with GPP. Peaks predicted with GPP were statistically different from the observed peaks as well as the peaks predicted using the OPP. There was no statistical difference between the observed peaks and the predicted peaks using the OPP. The trough level predictions using GPP in the study population had less bias than those predicted using OPP; however, the OPP predictions had less bias in the validation population.(ABSTRACT TRUNCATED AT 250 WORDS)

Predicting need for pharmacokinetic consultation follow-up using discriminant analysis.

A discriminant function that predicts whether a patient will require more than one intervention by the pharmacokinetic consultation service (PCS) was derived and evaluated prospectively. In phase 1, peak and trough serum aminoglycoside concentrations were evaluated for each of the 150 patients. The patients were then classified into either group 1 or group 2. Group 1 patients required a change in regimen after the initial recommended regimen was begun, while patients in group 2 did not require a change in regimen. Forty-seven variables of group 1 and group 2 were compared by univariate analysis. Stepwise discriminant analysis was then used to develop a model for classifying patients into either group 1 or group 2. In phase 2, the discriminant function derived in phase 1 was applied to a new group of 47 patients. In phase 1, significant variables of the derived discriminant function, in decreasing order of significance, were leukemia, serum creatinine concentration, location in an intensive-care unit (ICU), male sex, actual volume of distribution, therapeutic trough concentration, and number of days in the ICU before consultation. In phase 2, 6 (23%) of the 26 patients who actually required a change were classified into group 2, and 8 (38%) of the 21 patients who were assigned to group 1 for continuous monitoring did not actually require a regimen change. Although the results of the derived discriminant function were significant, the function's clinical utility in predicting the need for a second dosing intervention was poor.

Clinical assessment of a two-compartment Bayesian forecasting method for lidocaine.

The predictive performance of a two-compartment Bayesian forecasting method for lidocaine (L) was evaluated concurrently with lidocaine therapy in 46 hospitalized patients; 14 of these patients presented with congestive heart failure (CHF). Using an HP-85 microcomputer, demographic and dose-concentration information obtained during continuous lidocaine therapy was used to forecast subsequent lidocaine concentrations. One lidocaine concentration was obtained within each of the three intervals following initiation of lidocaine infusions: I1 (1-6 h), I2 (6-12 h), and I3 (greater than 12 h). Patients were categorized into 4 groups: (a) short-term infusions (less than 24 h) without CHF, (b) short-term infusions with CHF, (c) long-term infusions (greater than 24 h) without CHF, and (d) long-term infusions with CHF. The mean prediction errors (range -0.60-0.27) included zero (95% confidence limits) in all groups and suggested no bias. Forecasts of the I3 lidocaine concentrations were consistently more precise [lower mean absolute errors (MAE) and root mean squared errors] using the lidocaine concentration obtained during the 6-12-h interval (I2) than when the lidocaine concentration obtained at the earlier interval (I1) was used. The MAE was reduced by 20-40% when a single lidocaine concentration obtained during I2 was used as compared to I1. Precision was only slightly improved with the use of two lidocaine concentrations. We conclude that this Bayesian algorithm is unbiased and delivers acceptable precision in forecasting lidocaine concentrations.

Accuracy of three methods for predicting concentrations of free phenytoin.

Predictions of free (unbound) serum phenytoin concentration by three methods were compared with results obtained by the Abbott TDx Free Phenytoin ultrafiltration and fluorescence-polarization immunoassay technique. Data were obtained for hospitalized adults who had been receiving phenytoin for at least five days and were free of renal or hepatic disease. Total phenytoin concentration was determined, and free phenytoin concentration was measured in ultrafiltrate at 25 degrees C. For each patient, measured concentrations of total phenytoin and albumin were used to predict free phenytoin concentrations by the Gugler method, the Sheiner-Tozer nomogram, and the Sheiner-Tozer equation. Mean measured percentages of free phenytoin were 17.79%, 12.13%, and 8.73%, respectively, for patients with albumin concentrations of less than 2 g/dL (n = 5), 2-3 g/dL (n = 18), and greater than 3 g/dL (n = 26). There was a strong correlation between actual and predicted free phenytoin concentrations for each of the methods, but all methods were found to lack precision. All methods also exhibited bias, as demonstrated by overprediction of the free concentration; however, none of the methods exhibited bias when the difference between the in vitro temperature of 25 degrees C and the in vivo temperature of 37 degrees C was considered. Because of their poor precision, the three methods evaluated in this study are not recommended for predicting free phenytoin concentration.

An aggressive surgical approach to bile duct cancer.

Fifty-five patients with bile duct carcinoma have been treated at the Vanderbilt University, Metropolitan Nashville General, and Baptist Hospitals since 1957. Thirty-eight per cent (21) of the patients had tumors arising in the upper third of the bile duct; eight (15%) were in the middle third, and ten (18%) were in the lower third. In 12 instances, the malignant process involved both the middle and lower thirds of the bile duct, and in four cases, the extent of the tumor was too great to determine its origin. Most patients (49) presented with jaundice. Thirty (54%) also had pain, and 43 (24%) had experienced some weight loss. Fifteen had hepatomegaly, but only eight were found to have an enlarged gallbladder upon physical exam. Four patients (7%) had a positive history for hepatitis. Resection of the tumor was possible in 19 patients (35%). Decompressive procedures and biopsies were done in 25 of the others. Decompression was not possible in 11 patients. Survival for the 11 patients whose tumors were only biopsied averaged 4.6 months. Of the 25 patients who had palliative decompression, average survival has been 7.7 months. The 19 patients who had resection of their tumors survived an average of 2.08 years. Six of these patients are alive from 1-9 years post-diagnosis. Recently, a more aggressive surgical approach to bile duct carcinoma has been successful and has affected possible cure in ten patients of 19 in whom resection was possible and offered prolonged palliation to many of the other patients.

Experience with intrainstitutional clinical evaluations of newly marketed preparations as a basis for drug-product selection to hospital formularies.

The decision to admit a new drug-product formulation (NDPF) to a hospital pharmacy formulary is a difficult task, particularly when minimal pharmacokinetic or clinical efficacy data are available. To provide objective information to the Pharmacy and Therapeutics (P&T) Committee, we implemented a procedure to evaluate these NDPFs at our institution. This procedure, termed clinical evaluation, was initiated at our institution in 1981. The clinical evaluations of two NDPFs were performed. The two NDPFs studied were a transdermal nitroglycerin preparation and a sustained-release procainamide preparation. The clinical assessment of the therapeutic and the pharmacokinetic performance of each preparation was made by clinical pharmacists. Following completion of the clinical evaluation, the data were presented at a regular meeting of the P&T committee. The presentation of clinical data derived from our patient population facilitated objective assessment by the P&T committee regarding formulary status. We conclude that the clinical evaluation represents a novel approach to acquire data necessary for objective decisions on NDPFs by the P&T committee.

Carcinoma of the gallbladder and bile ducts. A retrospective review.

In retrospective review, 31 patients with carcinoma of the gallbladder and 39 patients with carcinoma of the extrahepatic bile ducts (excluding ampullary tumors) were identified. Case records and operative reports of patients seen between 1955 and 1980 were reviewed for the purpose of evaluating clinical features, preoperative studies, and operative treatment of these two disease processes. Similarities and differences between the two malignancies are highlighted. Demographic features of these patients supported findings of previous studies. Preoperative symptoms were typical of calculus disease often with the stigmata of malignancy superimposed. Laboratory findings provided a rather nonspecific confirmation of cholestasis. Roentgenogram examinations proved to be of little value in differentiating either disease process. A variety of surgical procedures was used by several surgeons to attempt cure or palliation in these tumors. Cholecystectomy was the most frequent procedure performed for patients with gallbladder carcinoma (18 cases). Curative cholecystectomy yielded an average 17.8 month survival. More radical procedures produced higher survival rates although the study size is of questionable statistical significance. Biliary-enteric bypass (choledochojejunostomy) was performed most often for patients with bile duct carcinoma (12 cases). The magnitude of the operation failed to affect the duration of patient survival except in patients with carcinomas of the distal common bile duct. Three Whipple procedures were performed for distal bile duct lesions yielding the one five-year survivor of this study but with an associated 30 per cent operative mortality. Operative strategy and options are discussed. The current literature dealing with these two malignancies is reviewed.

Operative cholangiography. Review of 7,529 operations on the biliary tree in a community hospital.

Primary operation for cholelithiasis ranks third in frequency among general surgical procedures performed in this country each year [16]. The mortality and morbidity associated with retained common duct stones are apparent to all biliary surgeons. Although operative cholangiography is a standard procedure in many centers, some still use this adjunct to biliary surgery infrequently, as shown by the 51 percent performance rate in the present study. However, the literature is replete with evidence supporting the routine use of cholangiography. In the present report positive findings on common duct exploration almost doubled when operative cholangiography was added to the clinical and operative criteria for common duct exploration. Our experience indicates that common duct exploration is not always required when the patient has jaundice if normal operative cholangiograms support the patient's history and other laboratory findings. Cholangiography was also found to be accurate in the five cases in which a secondary biliary procedure had to be performed.

Pilonidal cyst: an operative approach.

An operative technic is presented which has been used on fifty-four patients with pilonidal cyst. This technic has resulted in primary union and complete healing within six weeks in 89 per cent of cases. The use of an incision that crosses the vertical gluteal fold at an angle and eliminates the suture line in the gluteal fold has been beneficial in all patients on whom it was used.

Thyroid cancer. Twenty-three years' experience at Baptist and St. Thomas Hospitals.

One hundred fifty-six patients with thyroid cancer were diagnosed and treated at Baptist and St. Thomas Hospitals from 1952 through 1955. Papillary carcinoma, representing 65 to 70 per cent of the total, occurs in all age groups and is the most readily curable of all carcinomas. Slightly more than 50 per cent of our series presented with multinodular goiters. When a male patient has nontoxic nodular goiter, it is three times more likely that he will have cancer of the thyroid than a female patient with a similar goiter. Definitive thyroid surgery was performed by over fifty different surgeons in 143 patients and simultaneous neck dissection in twenty-five. The histologic types ranged from papillary (9 per cent mortality) to anaplastic carcinoma (nearly 100 per cent mortality). Age and sex were shown in our series to affect survival. The female survival figures were better than the male, and older patients fared far worse then younger ones. Survival rates are much improved in patients with cervical node metastases when radical neck dissection is done. Patients reoperated for enlarged nodes located lateral to posterior triangle were found not to have metastatic cancer. Hyperthyroidism was confirmed in 0.25 per cent.