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Cuenca Cage Mec ‘Copright © 1992 by Wiliams & Wikine Dobutamine pharmacokinetics and pharmacodynamics in pediatric intensive care patients DAVID M. HABIB, MD; JAMES F, PADBURY, MD; NICK G. ANAS, MD; RONALD M. PERKIN, MD, FCC CRAIG MINEGAR, BS Objective: To evaluate the pharmacokinetics and pharmacodynamics of dobutamine in criti- cally ill children. ‘Design: A prospective study of pediatric pa- tients receiving continuous infusions of dobutamine in a stepwise format from 2.510 10.0 pa/kg/min. ‘Setting: A pediatric critical care unit. Patients: ‘Twelve children ranging in age from 1 month to 17 yrs with primary medical conditions. ‘Measurements: Plasma dobutamine concen- trations and hemodynamic responses were mea- sured at each infusion rate at stendy state. Dose response data were analyzed to determine the threshold or minimum plasma dobutamine con- centration necessary for discernible hemody- namic effects. ‘Main Results: Dobutamine plasma clearance rates ranged from 40 to 130 mL/kg/min. Each patient presented alinear increasein the plasma dobutamine concentration at each infusion rate (2.97,p<.001). Plasma clearance rate vs. actual dobutamine concentration did not vary. Car- diac output, BP, and heart rate increased 30%, 17%, and 7%, respectively, at maximal dose. The dobutamine concentration thresholds for changes in cardiac output, BP, and heart rate were 13 + 6, 23 ¢ 14, and 65 + 30 ng/mL, respectively. Conclusions: There was no effect of plasma dobutamine concentration or infusion rate on From the Harbor-UCLA Medical Center, UCLA School of Medi- cine, Torrance, CA (Dr. Padbury), and Children's Hospital of Orange County, Orange, CA, ‘Ths study was supported, in part, by a grant from the USPHS. ‘HD48014, an Investigative Group Fellowship Award from the ‘American Heart Assocation, Los Angeles Afiiate, and the Ei Lilly Research Laboraterien ‘Adress for requeata for reprints to: David M. Habib, MD, Medical Univesity of South Caraline Children's Hospital, 171 Athley Avenue, Charlestan, SC 29425-3306. 07a. 349882/205-0601803.000 601 plasma clearance rate. For this group of pa- tients, over the range of the intravenous doses studied, dobutamine pharmacokineticsfollowed a first-order kinetic model. Threshold values for dobutamine usually show increases in cardiac ‘output before changes in heart rate. These data demonstrate that dobutamine is an effective inotropic agent in critically ill pediatric patients and has minimal chronotropic action, (Crit Care ‘Med 1992; 20:601-608) Key Wonns: dobutamine; pharmacokinetics intensive care unit, pediatric; hemodynamics; pulmonary artery occlusion pressure; inotropic agents; cardiac output; catecholamine echocardiography; catheterization, central Dobutamine is a synthetic, inotropic agent that was first developed for clinical use by Tuttle and Mills in 1975 (1), Dobutamine was designed to produce positive cardiac inotropic responses with a minimum change in heart rate or rhythm (2). Studies performed in adult animals and in humans support dose-dependent in- ‘creases in myocardial contractility, stroke volume, and cardiac output, with a lowering of pulmonary artery ‘occlusion pressure. Dobutamine has less arrhythmic effects than isoproterenol or dopamine (3-7). Since dobutamine has no agonist effect on dopamine recep tors, it improves renal function only as a result of improved cardiac output and renal blood flow. The plasma half-life is generally 2 to 3 mins, with the principal metabolic pathway being extraneuronal 3- O-methylation by the enzyme catechol-O- methyltransferase, followed by hepatic conjugation and exeretion into the urine and bile (8, 9). Limited pharmacokineticor pharmacodynamicdata (10-13) exist to support the use of inotropic agents in critically ill pediatric patients. The rationale for use of individual agents has largely been based on adult studies and extrapolated to the pediatric age group, where cardiac failure usually results from sepsis or 602 Carrcas, Cans Mepicive cardiogenic etiologies other than primary coronary artery disease. Previous pediatric investigations (14-17) on the efficacy of dobutamine have compared infusion dose with the observed hemodynamic re- sponse, These studies have suggested that both age or diagnostic condition may affect response. We hypoth- ‘sized that these observations may be the result of differences in dobutamine metabolism or responsive ness. For pediatric patients, limited pharmacokinetic or pharmacodynamic data are based on measured plasma dobutamine concentrations and derived hemo- dynamic parameters. To test this hypothesis, we per- formed a prospective study that is designed to deter- minea)the pharmacokinetics of dobutamineincritically ill children; b) the minimum plasma dobutamine con- centration and corresponding dose associated with clinically important hemodynamic improvement; and ©) the effect of the underlying clinical condition or diagnosis on the clearance and/or responsiveness to dobutamine. MATERIALS AND METHODS Patient selection and enrollment were approved by the Institutional Review Board, to administer dobutamine by a controlled infusion protocol, to criti- cally ill children who had been identified by their clinical physicians asbeingin need of inotropic support. Blood samples were removed for measurement of plasma dobutamine concentration during different in- fusion rates. All study subjects were patients in the pediatric ICU at Children's Hospital of Orange County {in Orange, CA. The decision to initiate inotropic sup- port rested solely with the clinical staff at Children's Hospital of Orange County. Clinical indications for dobutamine administration included hypotension, poor peripheral perfusion, oliguria, metabolic acidosis, and echocardiographic ejection fraction (<55%). All pa- tients had received volume resuscitation before the initiation ofdobutamine and had shown transient or no improvement in these clinical indicators. The majority ‘of patients did not have pulmonary artery pressure or central venous pressure catheters in place. We consid- ered all patients who were treated with dobutamine to be potential candidates for this study. However, to avoid confounding alteration of the pharmacokinetic and pharmacodynamic responses under evaluation, wwe chose to exclude patients if they were clinically unstable; ifthey had the necessity for large amounts of additional volume administration duringthe2-hr course ofour investigational drug infusion; ifthey had been on chronic inotropic support; or, if in the opinion of the clinical staff, rapid changes in dobutamine infusion rates became necessary. There were also nochangesin ‘May, 1992 administration ofsedation/analgesicagents duringthe course of the study. Thus, our purpose was to examine pharmacokinetic and pharmacodynamic responses when the only variable being modified was the dobutamine dose. Informed consent was obtained for all patients, Dobutamine Administration, Allpatientshad intra- arterial catheters inserted for clinical management before enrollment in the study. Dobutamine was in- fused into peripheral or central venous catheter. The dobutamine infusate was prepared immediately befare infusion, with the concentration adjusted to deliverthe desired dobutamine dosage. All infusions were done by using the same precalibrated syringe pump (A520A, ‘Travenol Laboratories, Hooksett, NH). An aliquot of the infusate was obtained and frozen for later assay of dobutamine concentration. We used the measured dobutamine infusate concentration and the plasma clearance rate of each patient to calculate the actual dobutamine infusion rate. Dobutamine was adminis- tered at a nominal dose of 2.5 pg/kg/min, followed by 5.0, 7.5, and 10.0 pg/kg/'min. Each dose was infused for 30 to 40 mins. Data Collection. Duplicate measurements of BP, heart rate, cardiae output, and blood for determina: tions of endogenous plasma catecholamine concentra- tions were obtained before beginning the dobutamine infusions, Repeat measurements of systemic BP, heart rate, cardiac output, and plasma for dobutamine con- centration were obtained every 15 to 20 mins of each infusion. Blood samples for measurement. of plasma catecholamine concentration were also obtained at the same time points, Ten blood samples a total of 10 mL) ‘were removed from each patient. For patients weigh- ing <10 kg, sampled blood was replaced incrementally with cross-matched RBCs. All patients had received transfusion support from the same donor before enrollment. Analytical Techniques. Heart rate and BP were measured continuously and displayed both digitally and as an oseilloscopie waveform on bedside monitors (78532B, Hewlett-Packard, Palo Alto, CA). Cardiac output was measured by pulsed Doppler echocardiography (77020A color low Doppler, Hewlett- Packard Waltham, MA), using a 2.5, 3.5, or 5.0 MHz short or medium focus transducer. By using the suprasternal notch, the transducer was focused to the area of highest blood flow velocity within the ascending aorta, as indicated by the color scale. The internal aortic root diameter was measured from the two- dimension, long-axis view during systole before init tion of the infusions. Data for cardiac output represent, the mean of two sequential measurements, each deter- ‘mined from at least three cardiac cycles. Previous Vol. 20, No. 5 investigators (18) have shown that Doppler ‘measurements provide reliable estimates of cardiac ‘output when compared with thermodilution and dye dilution techniques in human subjects. Intrapatient variation in echocardiographic estimation of cardiac output is also low, coefficient of variation <2.5% (19). ‘Thus, itis a suitable estimate in our study where each, patient served as his or her own control. Blood taken at each sample point was transferred immediately to chilled test tubes that contained EGTA, 4-mM and reduced glutathione 3 mM. All tubes were immediately mixed and then centrifuged for 5 mins at. 4°C. Plasma was separated, frozen, andstored at 70°C until assay. Plasma catecholamine and dobutamine concentrations were measured simultaneously by a radioenzymatic assay that was recently developed in ‘our laboratory (20). The assay is sensitive to 10to20 pe/ mL of norepinephrine or epinephrine, and 100 to 125 pg/ml, of dobutamine. The cross-reactivity of 100 ng/ mL of dobutamine with catecholamines is 0.3 + 29 for norepinephrine and 0.3 + 0.2% for epinephrine. The inter- and intra-assay variabilities for dobutamine were 10% and 8.7%, respectively. For endogenous catecholamines, these variabilities are both at <5%. Data Analysis. The dose-response curves comparing hemodynamiemeasurements with plasma dobutamine concentration were analyzed by computer-ascisted graphic analysis. Previous investigations (10, 21-25) in adult animals and in humans have suggested that there is no change in a particular response over a certain range of plasma catecholamines, until thresh- oldisreached or exceeded. Beyond the threshold value, there is a log-linear relationship between a given response and increases in eatecholamine concentra- tion. A computer-based graphic analysis that uses a nonlinear, least squares method was developed to fit experimental hemodynamic and biochemical data to this model. Below the threshold, data were fit toa zero- order equation (y = a). Beyond the threshold, we assumed a linear inerease in the response for logarith- ‘ic increases in plasma catecholamine concentrations (y=minx +). The threshold, or the minimum eonce tration necessary to produce a discernible change, -derived from the intersection of these two lines. The program determined a) the average baseline value of each hemodynamic response, b) the threshold for dobutamine-induced increases in this response, and ¢) the slope and correlation coefficient of the log-linear regression line beyond the threshold concentration. Goodness-of-fit of the data to the theoretical model is, ‘assessed by the method of Glejser (26). This method ‘uses a regression of the difference between the ex- pected and the observed physiologic value vs. the logof the dobutamine concentration. Agreement with the Donvrawne Puarsacoxinerics in Pepiarnic PaTiers 603 ‘models indicated by aslope for this comparison, which isnot statistically different from zero. The customized program for threshold estimation is available on request (JF-P)) ‘To compare dobutamine clearance at each dose and between patients, we determined the plasmaclearance rate by using the following standard equation: plasma clearance rate (mL/kg/min) = ({infusion rate mL/min] (infusate concentration ng/mL.)\({plasma steady-state concentration ng/mL] x [weight kg). Plasma dobutamine concentration and clearance rate were compared at each time point and ateach dose by one-way analysis of variance. All mean data are shown as mean = se. RESULTS Patient Data. Twelve pediatric ICU patients were enrolled (Table 1). Their individual characteristics included @ mean age of 4 yrs (range 0.1 to 17) and a ‘mean weight of 21 kg (range 3.2 to 72). Four patients, were <1 yr of age. Clinicel diagnoses included cardiomyopathy, hypoxia-ischemia, sepsis, cor pulmonale, and adult respiratory distress syndrome. All patients had clinical and/or echocardiographic evi- dence of cardiovascular compromise, such as hypotension, tachycardia, poor perfusion, oliguria, al- tered neurologic status, metabolic acidosis, inereased ventricular diameter, decreased left or right ventricu- lar wall motion, abnormal septal wall motion, or de- creased ejection fraction. All patients had received volume support before initiation of dobutamine infu- sion. One patient was maintained on a prior dopamine infusion at 5.0 pg/kg/min throughout the study. children required assisted ventilation at the time of study. Mean baseline blood gas values were pH of 7.40 (range 7.23 to 7.49), Pao, of 112 torr (15 kPa) (range 35, to 198 torr [4.7026 kPal), and Paco, of 40torr(5.3 kPa) (range 18 to 68 torr (2.4 to 9.0 kPal). Analgesic and sedative medications werenotchanged during the 2-hr protocol. Baselinecatecholamineconcentrations were ignifi- cantly increased (above thenormal range)before initia- tion of dobutamine, Mean epinephrine (471 + 110 pg/ mL) and norepinephrine (1880 + 280 pg/mL) concen- trations were seven- to 20-fold above reported resting concentrations for children and adults (22, 27). Dur- ing dobutamine infusion, mean epinephrine and norepinephrine concentrations declined in a gradual ‘manner by 11% and 23%, respectively. Pharmacokinetics. The mean plasma dobutamine concentration achieved at each infusion rate is shown in Figure 1. Each patient studied showed a linear inerease in the plasma dobutamine concentration at