Robert J. Kandrotas

Carbamazepine Clearance in Hemodialysis and Hemoperfusion

A 47–year-old woman with endstage renal disease and dialysis-induced encephalopathy was being treated with carbamazepine for myoclonus. Her carbamazepine serum concentration appeared to be therapeutic at 5.1 μg/ml. She experienced a seizure while on hemodialysis/hemoperfusion that was possibly related to the removal of carbamazepine during dialysis. The elimination of carbamazepine on a dialysis day was compared with elimination on a nondialysis day. The half-life and apparent clearance were the same for each day, indicating that hemodialysis/hemoperfusion had little effect on the overall removal of carbamazepine from the body. The possible reasons for this lack of effect are discussed.

The effect of hemodialysis and hemoperfusion on serum valproic acid concentration

We report a patient with dialysis-induced encephalopathy who was taking divalproex sodium for a seizure disorder. Her serum valproic acid concentration appeared to be in the low therapeutic range at 54 mg/1 yet she continued to have seizure activity. The elimination half-life and apparent clearance of valproic acid were the same for both a dialysis and nondialysis day, indicating that hemodialysis/hemoperfusion has little effect on the overall removal of valmoic acid from the body.

The Impact of Changing Ventilator Parameters on Availability of Nebulized Drugs in an in Vitro Neonatal Lung System

An in vitro model was developed to assess nebulized drug delivery. The model simulated the intubated neonate and examined the effect of changes in a variety of parameters commonly confronted in the clinical setting. Theophylline was nebulized for 15 minutes and captured in an artificial lung system (a 1000-mL intravenous bag). Variables were: Peak pressure (20, 24, 28 cm H2O), ventilator rate (40, 60, 80 breaths/min), nebulizer flow rate (5, 7, 10 L/min), endotracheal tube size (2.5, 3.0, 3.5 mm), and ventilator type (Servo 900C, Bourns BP 200, Bear Cub BP 2001). The amount of drug actually captured in the bag ranged from 0.009 to 12.59 percent (mean 2.08). A multivariate analysis showed that only nebulizer flow rate had a statistically significant effect on drug delivery with 10 L/min delivering the most drug. All factors combined only accounted for 11.5 percent of the variability in drug delivery. In light of the wide and unpredictable amounts of drug delivered through ventilators, dosing to pharmacologic effect rather than staying within narrow dosing guidelines may be more rational in patients responding poorly to standard doses.

Rapid Determination of Maintenance Heparin Infusion Rates with the Use of Non-Steady-State Heparin Concentrations

OBJECTIVE: To compare heparin dosage adjustment using only activated partial thromboplastin time (APTT) with a method using non-steady-state heparin concentrations (HCs) to rapidly achieve and maintain an APTT ratio greater than or equal to 1.5 times baseline throughout the first 24 hours of therapy. DESIGN: Randomized, blind, parallel comparison of an empiric dosing method based only on APTT with a dosing method based on the calculation of heparin clearance using non-steady-state HCs. SETTING: A private community teaching hospital. The patient, physician, nurses, and investigators were blinded to the dosing method. Only the clinical staff pharmacist, who received the consult and made all dosage adjustments, was not blinded. PATIENTS: All patients requiring heparin for the treatment of thromboembolic disease were evaluated for potential inclusion in the study. Patients were enrolled in the study if they had a clinical diagnosis of deep venous thrombosis confirmed by objective means such as venography or ultrasonography. Patients were excluded if they had active bleeding, platelet dysfunction, thrombocytopenia, severe hepatic disease (total bilirubin >25.7 μmol/L), renal disease, or evidence of stroke. Patients were also excluded if they were receiving heparin prior to enrollment. MAIN OUTCOME MEASURE: Maintenance of an APTT ratio greater than or equal to 1.5 times baseline throughout the first 24 hours of heparin therapy. RESULTS: Thirty-four patients were enrolled in the study; 17 in each group. The groups were not significantly different with regard to gender, age, baseline APTT, or mean loading dose (p>0.5). Mean initial infusion rates for the control and HC groups were 1042 ± 194 and 1071 ± 143 units/h, respectively (p>0.5). After the first rate adjustment at 4 hours, the difference achieved significance at 1032 ± 232 and 1367 ± 317 units/h for the control and HC groups, respectively (p<0.01). At 12 hours, 18.8 percent of the patients in the control group were subtherapeutic; by 24 hours, 33.3 percent were subtherapeutic. No patients became subtherapeutic in the HCs group during the first 24 hours. CONCLUSIONS: This study demonstrates that, in contrast to standard heparin dosing methods, the use of non-steady-state HCs allows patients with deep venous thrombosis to rapidly achieve and maintain therapeutic APTT ratios throughout the critical first 24 hours of therapy.

Heparin pharmacokinetics during hemodialysis

The disposition of heparin was studied in 21 chronic hemodialysis patients. Heparin was administered as a bolus injection in doses of 3,000–12,000 U. Combined zero and first-order elimination was demonstrated, with heparin half-life declining by 74% over 3.5 h during dialysis. Assumption of a first-order pharmacokinetic model of elimination resulted in a mean difference of 0.001 U/ml between actual and predicted heparin concentrations. Mean first-order pharmacokinetic parameters were: half-life, 117 min; heparin volume of distribution (V), 68 ml/kg; clearance, 28 ml/min. A high degree of interpatient variability was also observed. A comparison of V and plasma volume (PV) revealed V to be significantly greater than PV (p < 0.001), indicating distribution outside the plasma compartment. When compared to blood volume, there was no significant difference (p > 0.1), indicating that blood volume may be used to approximate V. The nonlinear component of the elimination process is not clinically significant within the range of therapeutic plasma concentrations used during hemodialysis, but the high degree of interpatient variability indicates that dosage individualization may be useful.

Effect of phenobarbital administration on theophylline clearance in premature neonates.

Summary: The effect of phenobarbital administration on theophylline clearance was studied in 24 premature neonates. Aminophylline was administered according to a standard protocol of 6 mg/kg loading dose followed by a maintenance dose of 2.5–5 mg/kg/12 h. Of the 24 neonates studied, 12 received a mean phenobarbital dose of 26.34 mg/kg/d (ranging from 2 mg every 24 h to 25 mg every 12 h) and the mean phenobarbital concentration was 56.12 mUg/ml (range 22–112 mUg/ml). The remaining 12 patients did not require phenobarbital therapy but did receive aminophylline alone. The two groups were closely matched for gestational age, 5-min Apgar scores, and sex (p > 0.2). Steady-state theophylline clearance was determined at least once a week for four or more separate weeks. The study lasted a minimum of 8 wk and if more than one theophylline clearance was determined in any given week, the mean of these clearances was used. Both groups demonstrated an increase in mean theophylline clearance over time (from 15.75 and 16.67 ml/h/kg to 30.33 and 35.42 ml/h/kg for the aminophylline and aminophylline plus phenobarbital groups, respectively). The mean slope, an indicator of the average change in theophylline clearance, was 2.19 for the aminophylline group and 3.27 for the aminophylline plus phenobarbital group (p > 0.2), indicating that the theophylline clearance for neonates receiving phenobarbital was not significantly different from that for neonates receiving aminophylline alone. Based on this information, aminophylline does not need to be adjusted solely based on concomitant phenobarbital administration; however, theophylline concentrations should be monitored since theophylline clearance can change rapidly and unpredictably in neonates.

Altered heparin pharmacodynamics in patients with pulmonary embolism.

Heparin clearance and pharmacodynamic response were examined in 12 patients being treated for deep venous thrombosis (DVT, 6 patients) or pulmonary embolism (PE, 6 patients). A loading dose of 70 units/kg was administered to DVT patients and 100 units/kg to PE patients followed by an initial infusion rate of 15 or 25 units/kg/h for DVT or PE patients, respectively. Heparin clearance was determined at 4, 12, and 24 h after initiating heparin therapy. The mean heparin clearance in the DVT group was 2,164 ± 1,024 ml/h at 4 h, 2,591 ± 1,239 ml/h at 12 h, and 2,795 ± 1,863 m/h at 24 h. The PE patients had clearances of 1,775 ± 494, 2,004 ± 321, and 2,843 ± 1,000 ml/h at 4, 12, and 24 h, respectively. The difference between the two groups was not statistically significant (p > 0.50). The activated partial thromboplastin time (aPTT) was used as a measure of heparin effect. The maximum effect (EMAX) and concentration required to attain 50% of the maximum effect (EC50) were determined for each group using the Lineweaver-Burke linearization method. The mean EMAX and EC50 for the DVT patients were 130 ± 40.99 s and 1.01 ± 0.70 units/ml, respectively. For the PE patients, the mean EMAX was 418 ± 200 s and the mean EC50 was 4.32 ± 2.81 units/ml. The difference between both groups for each parameter was statistically significant (p < 0.05). The results of the present study indicate that PE patients do not have a higher clearance than DVT patients; however, PE patients do have a lower sensitivity to heparin at higher concentrations than DVT patients. This supports the concept that comparable heparin doses can be used for anticoagulation at the lower aPTT range, but in the higher range of aPTTs, higher doses are required to treat PE patients compared to DVT patients.

The effect of total parenteral nutrition-induced cholestasis on theophylline clearance in neonates.

The effect of total parenteral nutrition (TPN) induced cholestasis on theophylline clearance was examined in premature neonates. Thirty-six neonates receiving TPN and theophylline concurrently were reviewed. Aminophylline was administered according to a standard protocol of 6 mg/kg loading dose, followed by a maintenance dose of 2.5–5 mg/kg every 12 h. Of the 36 neonates reviewed, 18 developed cholestasis (direct bilirubin le 1 mg/100 ml and direct bilirubin le60% of total bilirubin). The remaining 18 did not develop cholestasis. The two groups were closely matched for gestational age, 5-min apgar score, and sex. The neonates with cholestasis had a mean maximum direct bilirubin of 5.19 mg/100 ml (range 1–13.8 mg/100 ml) as compared to the patients without cholestasis who had a mean maximum direct bilirubin of 0.54 mg/100 ml (range 0.3–0.8 mg/100 ml). Steady-state theophylline clearance was determined at least once a week for at least 4 separate weeks. The study lasted a minimum of 8 weeks, and if more than one theophylline clearance was determined in any given week, the mean of these clearances was used. Both groups demonstrated a significant increase in mean theophylline clearance over time (from 16.09 and 18.60 ml/h/kg to 28.65 and 24.73 ml/h/kg for the cholestatic and noncholestatic groups, respectively). The mean slope, an indicator of the average rate of change of theophylline clearance, was 1.4 for the noncholestatic group and 2.5 for the cholestatic group, indicating that the theophylline clearance for neonates with cholestasis was not significantly different from that for neonates with normal liver function (p = 0.61) over time.

Book Review: Techniques of Patient-Oriented ResearchTechniques of Patient-Oriented Research Edited by PakCharles Y.C., M.D. and AdamsPerrie M., Ph.D. Published by Raven Press, New York, 1994. ISBN 0-78170107-4. Hardbound, ix + 205 pp. (24 × 16 cm),

The amount of information necessary to practice in the clinical environment continues to increase daily. As a result, curricula in clinical programs have become increasingly strained and the amount of time devoted to teaching basic research skills has steadily declined. Techniques of Patient-Oriented Research attempts to fill this gap by providing an introduction to the basic principles of clinical research. It is written for medical students, residents, and fellows; however, the principles outlined are useful for any clinician who is beginning to conduct clinical research. The book is based on a series of seminars on an Introduction to Clinical Research presented at the University of Texas Southwestern Medical School. The authors cover the basics of clinical research, starting with a review of the decline in the number of physicians trained to do research and what this means to the future of clinical research. The subsequent chapters discuss various aspects of clinical research, including grantsmanship, study design, laboratory techniques, and statistical analysis. More in-depth discussions of these topics can be found elsewhere; however, these chapters provide an adequate introduction to the topics with some basic guidelines. One of the strengths of this book is its coverage of topics that are typically covered only briefly or not at all in other publications of this nature. Examples include chapters on the role of the Investigational Review Board in protecting human subjects and its implications for writing protocols, nutritional aspects of clinical research, and the basics of how to write a scientific paper, all of which are important to the novice investigator. The first section of the chapter on statistics is largely repetitive of material presented in previous chapters. The remainder of the chapter presents brief overviews of various statistical considerations, such as blinding, data collection forms, and various statistical methods. Two highlights of this chapter are the discussions of sample size determination and confidence intervals. Finally, the last chapter reviews the importance of submitting the results of clinical research for publication and outlines the steps involved in writing a scientific paper. This chapter should be particularly useful to the inexperienced writer. The experienced researcher will not find detailed discussions of research techniques in this text; however, that is not the intent of this book. Techniques ofPatient-Oriented Research is an easy-to-read introduction to the steps involved in basic clinical research and will be useful to anyone interested in becoming involved in clinical research.