Pharmacokinetics of bumetanide in critically ill infants*

Pharmacokinetics of bumetanide in critically ill infants

Object&: Define the pharmacokinetics of bumetanide after single intravenous doses in volume-overloaded critically ill infants. Methods: A prospective, open-label study was carried out in a group of 58 infants aged 0 to 6 months who required diuretic therapy. Each patient received a single dose of intravenous bumetanide. Doses selected in sequential order ranged from 0.005 to 0.10 mg/kg. Hematologic and serum chemistry studies were performed before and at 6 and 24 hours after bumetanide administration. Determinations of urine volume and chemistries were performed before (collected from - 2 to -4 hours to time 0) and at 1,2,3,4,6, and 12 hours after bumetanide dosing. Serum samples collected at time 0 and at 5,15,30,60,120,180,240, 360, and 480 minutes and urine collected at time 0 and at 0 to 1, 1 to 2, 2 to 3, 3 to 4,4 to 6, and 6 to 12 hours were analyzed for bumetanide concentration. Data were evaluated by standard noncompartmental pharmacokinetic techniques. Resdts: Peak serum bumetanide concentrations occurred at 5 minutes after bumetanide administration. Area under the curve and peak serum bumetanide concentrations showed linear increases over the twentyfold dose range; whereas beta volume of distribution, volume of distribution at steady state, clearance, renal clearance, half-life, and mean residence time values were independent of dose. Peak urinary excretion rates of bumetanide increased linearly with increasing doses. The mean percent of bumetanide recovered in the urine from 0 to 12 hours was 40% + 15% of the administered dose. Conclwions: Distribution and elimination kinetics of bumetanide were similar in all patients. Elimination kinetics were first order over the dose range of 0.005 to 0.10 mg/kg. Pharmacokinetic parameter estimates (beta volume of distribution, volume of distribution at steady state, clearance, renal clearance, half-life, and mean residence time) were independent of the dose of bumetanide administered. Single doses of bumetanide up to 0.10 mg/kg appear to be well tolerated in acutely ill volume-overloaded infants aged 0 to 6 months. (Clin Pharmacol Ther 1996;60:405-13.)

Janice E. Sullivan, MD,” Madolin K. Witte, MD,b Toyoko S. Yamashita, PhD, Carolyn M. Myers, PhD, and Jeffrey L. Blumer, PhD, MD Cleveland, Ohio

From the Departments of Pediatrics, Pharmacology, and Epide- miology and Biostatistics, Case Western Reserve University; and the Division of Pediatric Pharmacology and Critical Care, Rainbow Babies and Childrens Hospital.

Supported in part by a grant from Roche Laboratories, through the Children’s Research Foundation of Cleveland and Pediat- ric Pharmacology Research Unit Grant (HD 31323-02).

Portions of this work were presented at Society for Pediatric Research (Washington, D.C., 1986), International Congress of Pharmacology (Stockholm, 1986 and Montreal, 1994), and American Society for Clinical Pharmacology and Therapeutics (New Orleans, 1994 and San Diego, 1995).

Received for publication June 27, 1995; accepted May 20, 1996. Reprint requests: Jeffrey L. Blumer, PhD, MD, Rainbow Babies

and Childrens Hospital, Department of Pediatrics, Division of Pediatric Pharmacology and Critical Care, Mailstop 6010, 11100 Euclid Ave., Cleveland, OH 44106.

aPresent address: Department of Pediatrics, University of Louis- ville, Louisville, KY 40292.

Pathologic fluid retention in critically ill infants is frequently associated with congestive heart failure, pulmonary disease, renal disease, or sepsis with cap- illary 1eak.l Diuresis is often required to improve hemodynamics, facilitate weaning a patient from mechanical ventilation, and maintain or establish adequate urinary output in a patient with oliguria. Although medical treatment should focus primarily on correcting the underlying disorder causing fluid retention, judicious administration of diuretic agents is often needed to supplement meticulous

bPresent address: Department of Pediatrics, University of Utah Medical Center, Salt Lake City, UT 84132.

Copyright 0 1996 by Mosby-Year Book, Inc. 0009-9236/96/$5.00 + 0 13/l/75214

405

406 Sullivan et al. CLINICAL PHAPAfACOLOGY &THERAPEUTICS

OCTOBER 1996

fluid and electrolyte management to attain or maintain homeostasis in these patients.‘,’

Loop diuretics are the most frequently administered diuretic agents in volume-overloaded infants because they prevent reabsorption of ~15% of fil- tered sodium and produce a greater diuresis than other types of diuretics.3 The prototype of this class, furosemide, is used most commonly to treat fluid overload in infants and children.2 However, bumetanide (3-n-butylamino-4-phenoxy-5-sulfamoyl- benzoic acid), a loop diuretic chemically related to furosemide, may be less toxic4 Other potential therapeutic advantages of bumetanide include greater potency than furosemide,5,6 decreased displacement of bilirubin from albumin at presumed therapeutic concentrations of each drug,7-9 less potential for ototoxicity,lO~ll and significantly lower potassium excretion.5,12 Except for one study of infants receiving extracorporeal membrane oxygenation,13 the pharmacokinetics of bumetanide in children are de- scribed only in abstracts of studies performed in preterm or term newborn infants.14’15 Present published data are inadequate to permit design of an effective, safe diuretic regimen for infants.

This is the first of three articles describing the pharmacokinetics and pharmacodynamics of bumetanide and factors affecting the response to this agent in acutely ill, fluid-overloaded infants up to 6 months of age. Here, we report the pharmacokinet- its of bumetanide over a twentyfold dosage range.

METHODS Patients. Critically ill infants from birth to 6

months of age with fluid retention and clinical indications for diuretic therapy were considered for enrollment. Fluid retention was evidenced by the presence of edema, excessive weight gain, signs of congestive heart failure, or pulmonary edema. Primary physicians determined the need for diuretic therapy before patient enrollment. Patients were screened by an investigator who obtained written consent for participation from their parents or legal guardians. Exclusion criteria included: treatment with a diuretic agent within the previous 24 hours, New York Heart Associa- tion cardiac status/prognosis Class IV,16 history of hearing impairment or concurrent exposure to other ototoxic agents (e.g., aminoglycosides, am- photericin), clinically significant hypotension (~2 standard deviations below normal for age), poly- cythemia (hematocrit r60%), allergy to sulfon- amide derivatives, significant acid-base or electro-

lyte imbalance, clinical and laboratory evidence of significant renal impairment (serum creatinine ~2.5 mg/dl, anuria, or both), or evidence of mul- tiorgan system failure. After approval of the protocol by the Institutional Review Board of the University Hospitals of Cleveland, this study was performed in the Pediatric Intensive Care Unit at Rain- bow Babies and Childrens Hospital, Cleveland, Ohio.

Study design. In this open-label, dose-ranging study protocol, each patient received a single dose of bumetanide intravenously over 1 to 2 minutes. Doses were selected in a sequential order starting with 0.005 mg/kg and proceeding sequentially to 0.01, 0.015, 0.02, 0.025, 0.03, 0.035, 0.05, and 0.10 mg/kg. The maximal dose (0.10 mg/kg) was based on the usual pediatric dose of furosemide (1 to 2 mg/ kg), reportedly twentyfold to fortyfold less potent than bumetanide in adults.5

Blood samples for serum chemistries and hematologic studies were drawn before the administration of bumetanide and repeated 6 and 24 hours thereafter to assess renal and hepatic status and drug safety. Analyses included a complete blood count with differential and determinations of serum sodium, potassium, chloride, bicarbonate, urea nitrogen, creatinine, aspartate aminotransferase, ala- nine aminotransferase, lactate dehydrogenase, alka- line phosphatase, total and direct bilirubin, total protein, albumin, calcium, magnesium, glucose, and uric acid levels and osmolality.

Serial blood samples for analysis of serum bumetanide concentration were drawn from an indwelling arterial or venous catheter before and at 5, 15, 30, 60, 120, 180, 240, 360, and 480 minutes after the bumetanide bolus injection. Serum obtained after centrifugation of these samples was stored at -70” C for later processing and assay.

Urine was collected for a 2- to 4-hour period before the bumetanide dose and for timed intervals thereafter (0 to 1, 1 to 2, 2 to 3, 3 to 4, 4 to 6, and 6 to 12 hours). Urine volumes were recorded, and aliquots were analyzed for sodium, potassium, chloride, calcium, magnesium, and creatinine levels and osmolality. Aliquots of urine for bumetanide concentration determination were stored at -70” C un- til they were analyzed. Most patients had Foley catheters in place during the study. Diapers from each patient were weighed before and after use to assure accurate urine collection.

Creatinine clearance (CL,,) was used to estimate the glomerular filtration rate for each patient ac- cording to the following formula:

CLINICAL PHARMACOLOGY &THERAPEUTICS VOLUME 60, NUMBER4 Sullivan et al. 407

[UCR] CkR (ml/min/1.73 m’) = ,ScRl X

Urine output X 1.73 TXBSA

in which [U,,] and [S,,] represent urine and serum concentrations of creatinine (in milligrams per de- ciliter), respectively, T is the collection time (in minutes), and BSA is body surface area (in square meters). Creatinine clearance was calculated on the basis of both body weight and body surface area. Creatinine clearances determined by using pretreatment, posttreatment, and combined pretreatment and posttreatment urine samples did not differ significantly from each other (p > 0.05); accordingly, CL,, was calculated from the combined pretreatment and posttreatment urine samples for each patient. Timed urine samples for CL,, determination were collected for a minimum of 6 hours. Values calculated for CL, were compared with normal values reported for infants of the same age.17’18

Blood pressure, heart rate, and respiratory rate were monitored continuously in each patient and recorded hourly for 2 to 4 hours before the dose of bumetanide was administered and for at least 6 hours after bumetanide administration. Fluid management for each patient before and during the study period was determined by the primary physi- cian.

Determination of bumetanide concentrations in serum and urine. Bumetanide analyses were performed by HPLC. Serum samples (0.4 ml) were combined with 0.1 ml of internal standard (0.5 @ml R021-1825 supplied by Roche Laboratories, Nutley, N.J.) and 1.0 ml of 1.0 mol/L potassium citrate, pH 5.0, in 13 X 100 mm screw cap borosili- cate tubes. Mixtures were vortexed and allowed to sit for 1 minute, after which 4.0 ml of ethyl acetate/ cyclohexane (70:30) was added. The contents were mixed for 10 minutes on a Rototorque mixer (Cole Parmer Instrument Co., Niles, Ill.) at 60 rpm and centrifuged at 11508 for 1 minute. The upper or- ganic layer was removed and evaporated to dryness under reduced pressure. The solid residue was re- dissolved in 0.125 ml of mobile phase, and 0.05 ml was injected onto the HPLC column for analysis. The assay was standardized against identically pro- cessed sera to which known amounts of bumetanide were added.

Urine samples were centrifuged for 1 minute at 16,OOOg in an Eppendorf microcentrifuge (Eppen- dorf North America Inc., Madison, Wis.) to remove particulate matter. One volume of urine supernatant was mixed with 1 volume of 0.8 mol/L potassium

formate, pH 3.9, and the resulting solution was analyzed for bumetanide concentration. This assay was standardized by processing urine samples to which known amounts of bumetanide were added before storage at -70” C.

Bumetanide concentrations were determined by chromatography on a Varian Instruments model 5500 liquid chromatograph (Varian Sample Prepa- ration Products, Harbor City, Calif.) equipped with a 30 cm X 4 mm Zorbax C-8 reversed-phase column (MAC-MOD Analytical Inc., Chadds Ford, Pa.) maintained at 40” C. Peaks were eluted with a mobile phase of methanol (0.03 mol/L potassium phos- phate, pH 2.5 [63:37, vol/vol] at a flow rate of 1 ml/min) and detected with a Varian 9070 fluores- cence detector set at a wavelength of 340 nm for excitation and 440 nm for emission. Peak areas were integrated by a DS 604 computer (Varian Analytical Instruments, San Fernando, Calif.) and printed on a Hewlett-Packard Think Jet recorder (Hewlett- Packard Co., Palo Alto, Calif.). Retention times were approximately 6.8 and 8.6 minutes for bumetanide and the internal standard, respectively.

Serum and urine assays were linear with respect to bumetanide concentrations from 3 to 200 rig/ml (r = 0.999) and from 10 to 500 rig/ml (Y = 0.997), respectively. Bumetanide recovery was 74.3% + 5.9% from serum and 97.1% 2 7.2% from urine. The mean intraassay and interassay coefficients of variation were 4.6% and 6.3% for serum and 5.6% and 4.7% for urine.

Pharmacokinetic analysis. The time-dependent disposition of bumetanide was subjected to standard noncompartmental pharmacokinetic analysis.” Se- rum bumetanide concentration versus 0- to g-hour time curves were plotted for each patient on a semi- logarithmic scale. To compare the serum concentration versus time patterns of the nine dose groups of bumetanide, a composite serum concentration versus time curve was constructed. To accomplish this, the peak bumetanide concentration for each patient was arbitrarily assigned the value of 100%. Each subsequent serum concentration was then expressed as a percentage of the peak for that patient, after which the mean percent for each dose group at each time point was determined. The mean percent of maximal bumetanide concentration for each dose group at each time point was then used to determine the mean t SD for the entire study population at each time point, and these values were then plotted on a graph as a function of time. This graph was not used to derive pharmacokinetic parameters but sim-

408 Sdlivan et al. CLINICAL PJSARMA COLOGY & THERAPEUTICS

OCTOBER 1996

Table I. Patient characteristics (n = 58) 1400 1 1200-

" lOOO- E B 5 800-

ii E 600- .

0

I 0.02 0.04 0.06 0.08 0.10 0.12

Dose (mglkg)

Fig. 1. Dose-dependence of peak bumetanide serum concentrations. Bumetanide serum concentration was maximal in all patients when the first sample was obtained 5 minutes after bumetanide administration. Peak serum concentrations (C,,) were plotted against dose of bumetanide administered (in milligrams per kilogram) for each patient. The number of points is actually the same as the number of patients shown in Table II for each dose group but may appear to be lower because of substantial overlap of similar C,, values. C,, was linear and proportional to dose over the entire dose range (R2 = 0.66;~ < 0.001).

ply to illustrate the serum concentration versus time curve for all patients.

Pharmacokinetic parameters were estimated for each patient by the following methods. The area under the serum drug concentration-time curve (AUC) was determined for each patient by the linear trapezoidal rule up to the time that the final concentration was measured and was then extrapo- lated to infinity [AUC(,_,)]. Linear regression was used to estimate the elimination rate constant (k,) from the postdistributive terminal slope of the log serum concentration versus time plot. Elimination half-life (t& and mean residence time (MRT) were calculated as 0.693/k, and AUMC/AUC, respectively, in which AUMC represents the area under the moment curve.

Total (CLr) and renal (C&J clearances of bumetanide were determined for each patient by the following equations:

CL, = Dose/[AUC(O-m)]

and

Parameters Mean + SD Range

Age (mo> 2.16 5 1.63 0.13-5.78 Sex (M/F) 38120 NA Weight (kg) 4.0 + 1.3 2.3-7.5 BUN (mgidl) 10 ? 6 1-24 Creatinine (mg/dl) 0.5 2 0.2 0.1-1.3 Albumin (mg/dl) 3.2 r 0.7 1.8-5.1 CL,, (ml/minikg) 2.2 + 1.7 0.5-8.1 CL,, (ml/min/1.73 m2) 64 -+ 50 15-248

NA, Not applicable; BUN, Blood urea nitrogen; CL,,, creatinine clearance.

CL, = AJ[AUC(O-a)]

in which A, represents the cumulative amount excreted during the sampling interval. A, was interpo- lated for the S-hour time point because urine was collected from 6 to 12 hours, whereas serum bumetanide concentration was determined at 8 hours after the dose was given. Nonrenal clearance (CL& was estimated by subtracting renal clearance from total clearance. Beta volume of distribution (VP) and volume of distribution at steady state (V,,) were estimated, respectively, from the following equations:

and v, = C&/k,

V,, = (Dose X AUMC)/AUC2

Values for Cl+ CL,, CL,,, V,, and Vss were corrected for body weight.

The excretion rate of bumetanide (in micrograms per kilogram per hour) for each collection interval was determined by dividing the amount of bumetanide in the urine during the sampling interval by the collection time and weight of each patient. The cumulative amount of drug eliminated in the urine from 0 to 12 hours was divided by the total intravenous dose to determine the percent of the dose excreted in the urine over that time interval.

Statistical analysis. Pharmacokinetic parameter estimates (V,, Vss, tm+, MRT, CLr, CLn, and CL& for each patient were graphed as a function of dose and evaluated by regression and one-way analysis of variance to determine their relationship to dose. The accepted level of significance wasp < 0.05. By using power analysis2’ and on the basis of our pharmacokinetic data, we estimated that six patients were required per dose group (80% power to detect a difference of 20% between the 9 treatment groups, (Y = 0.05).

CLINICAL PHARMA COLOGY &THERAPEUTICS VOLUME 60, NUMBER4 Sullivan etal. 409

1 I 0 2 4 6 a

Time (hours)

Fig. 2. Composite serum bumetanide concentration versus time curve. Peak bumetanide concentrations for each patient (from Fig. 1) were assigned the value of lOO%, and the curve was constructed as explained in Methods. Bu- metanide elimination appeared to follow first-order kinetics over the dose range studied.

RESULTS Study population. Of the 71 patients initially en-

rolled in the study, 13 were eliminated for the following reasons: inadequate urine collections (n = 9), age >6 months (TZ = l), oliguria with worsening congestive heart failure requiring additional diuretic therapy during the sampling period (n = l), pharmacokinetic data >3 standard deviations from the mean of other patients in the same dose group (n = l), and inadvertent double enrollment (n = 1). In the last instance, only data from the first study are included.

The final study group consisted of 58 infants (Ta- ble I) who fell into three categories: postoperative repair or palliation of congenital heart defects (n = 31), pulmonary disorders (n = 22), or other disorders (n = 5), each associated with volume overload requiring parenteral diuretic therapy. However, all patients had normal renal and hepatic function on entry into the study as determined by CL,,, serum transaminase, bilirubin values, and hepatic synthetic function (prothrombin time and partial thrombo- plastin time). The study population was also nutri- tionally replete, as evidenced by normal values for serum albumin and total protein. Four patients had serum albumin values ~2.5 mg/dl, but only one of these patients had a value ~2.0 mg/dl; low serum

0.02 0.04 0.06 0.08 0.10 0.12

Dose (mglkg)

Fig. 3. Dose dependence of peak urinary bumetanide excretion, rate. Peak bumetanide urinary excretion rate for each patient was plotted against dose of bumetanide administered (in milligrams per kilogram). Peak bumetanide excretion rates appeared linear and proportional to dose (P = 0.74; p < 0.001).

albumin concentrations were attributed to volume overload rather than to poor nutritional status. No adverse effects of bumetanide (e.g., hemodynamic instability, serum electrolyte abnormalities, significant elevations of bilirubin, or allergic reactions) were noted in any patient.

Pharmacokinetics. Both peak serum concentrations of bumetanide (Fig. 1; R2 = 0.66, p < 0.001) and AUC (data not shown) showed linear and proportional increases with respect to dose over the twentyfold dose range. Serum bumetanide concentrations were maximal in all patients 5 minutes after bumetanide administration and decreased rapidly, irrespective of the dose administered, to approximately 25% of the peak concentration by 1 hour after the dose (Fig. 2). Bumetanide elimination fol- lowed first-order kinetics in all patients over the dosage range studied.

Pharmacokinetic parameter estimates for V,, Vss, Cb, Ch, tliz, and MRT did not differ significantly among dose groups (Table II). Peak serum concentrations and V, did not differ significantly among patients with serum albumin ~2.5 mg/dl compared with those with serum albumin >2.5 mg/dl (p > 0.65). Estimates of pharmacokinetic parameters showed marked interpatient and intergroup variations, which did not reach statistical significance.

Urinary excretion of bumetanide achieved maximal values in all patients by 3 hours after the dose,

4 10 Sullivan et al. CLINICAL PHARMA COLOGY & THERAPEUTICS

OCTOBER 1996

Table II. Estimates of pharmacokinetic parameters by dose group after a single intravenous dose of bumetanide

Subjects Dose (4 h&d (L2g)

CL, (mllminlkg)

CL, (mllminlkg)

t1/2

(W MRT @r)

6 0.005 0.34 t 0.14 0.25 ? 0.11 2.63 ? 1.23 1.04 + 0.45 1.62 2 0.47 1.71 2 0.51 6 0.010 0.26 ? 0.07 0.20 2 0.07 1.40 +- 0.75 0.72 2 0.69 2.65 + 1.41 2.92 k 2.05 6 0.015 0.30 2 0.10 0.25 2 0.10 1.63 ? 0.84 0.63 2 0.36 3.03 + 2.48 3.73 + 3.34 6 0.020 0.24 k 0.04 0.20 i. 0.02 1.94 t 1.24 0.85 2 0.81 2.03 + 1.35 2.72 + 2.26 6 0.025 0.43 t 0.21 0.35 + 0.14 2.68 k 1.44 1.30 If: 0.76 2.06 2 0.78 2.59 +- 1.35 6 0.030 0.42 2 0.15 0.35 + 0.12 3.14 k 2.55 1.10 t 0.77 2.52 k 1.73 3.23 2 2.40 7 0.035 0.39 2 0.10 0.32 !I 0.09 3.34 2 1.54 1.09 2 0.90 1.57 + 0.75 1.84 2 0.90 8 0.050 0.60 t 0.42 0.39 2 0.17 3.82 2 3.14 1.61 21 1.46 2.55 2 1.49 3.05 c 2.38 7 0.100 0.43 2 0.17 0.28 ? 0.07 3.49 2 2.27 1.33 t 0.83 2.12 2 1.47 2.43 5 2.28

Mean 2 SD 0.39 t 0.21 0.29 + 0.12 2.74 2 1.95 1.10 2 0.86 2.34 2 1.41 2.68 -t- 2.04

V,, Beta volume of distribution; Ch, total clearance; CL, renal clearance; t,,2, half-life; MRT, mean residence time.

and in the majority of patients, by 1 or 2 hours after the dose. Peak urinary bumetanide excretion rates (in micrograms per kilogram per hour) demonstrated a linear relationship to dose (I?’ = 0.74;~ < O.OOl), and showed no evidence of approaching a maximum (Fig. 3). The greatest percentage of the administered dose of bumetanide was recovered in the urine within the first hour after bumetanide administration and declined steadily thereafter. The mean percent of bumetanide recovered in the urine for all patients by 12 hours was 40% ? 15% of the administered dose with a range of 10% to 83% (Fig. 4). No relationship was evident between the dose administered and the total percent of bumetanide recovered by 12 hours.

DISCUSSION This is the first study of the effect of dose on the

pharmacokinetics of bumetanide in volume- overloaded critically ill infants during the first 6 months of life. The large size of our patient population and the number of patients in each dosage group permit identification of certain pharmacokinetic patterns despite large interindividual and intergroup variations in estimates of pharmacokinetic parameters in this heterogeneous population. The primary findings were that peak serum concentration, AUC, and bumetanide excretion rate increased linearly with increasing doses of bumetanide; whereas V,, Vss, CLr, CL,, t,,,, and MRT did not vary significantly. Elimination kinetics of bumetanide were first order. About 40% of the drug was cleared through renal elimination, and 10% to 83% of the administered dose was recovered in the urine during the 12 hours immediately after the dose.

Studies in adult patients have demonstrated about 50% to 70% recovery of unchanged bumetanide in the urine over 24 to 48 hours after intravenous administration of bumetanide.21‘23 Because bumetanide was still detected in the 6- to 12-hour urine sample from most of our patients, total urinary recovery of bumetanide may have been underesti- mated. The percent of drug recovered might have been similar to that reported for adults if we had collected urine for 24 hours after administration of bumetanide.

Estimates of certain pharmacokinetic parameters in our study differ from others published in abstract form. Lopez et a1.15 reported serum concentrations of bumetanide twofold to sixfold higher than we found with comparable doses and identical sampling intervals during the bumetanide elimination phase. Their values are also much greater than those reported by Cook et a1.24 in adults who received an average of 0.045 mg/kg. Estimated CLcu was 30% of adult values, and CL, of bumetanide was much less (range, 0.2 to 1.1 ml/minikg) in the infants studied by Lopez et al. l5 than in either our patients or adults24 (2.74 t 1.95 ml/min/kg and 2.55 + 0.54 ml/mm/kg, respectively). A reduction in clearance (about fourfold) may account for the large differences in reported serum concentrations between groups. Similar to our findings, Lopez et a1.13 also reported large interpatient variability in serum bumetanide concentrations in their infant population. Peak serum bumetanide concentrations in our patients showed a linear increase with increasing dose and substantial variability within each dose group. Other investigators14715 found values for V, and Vs, similar to those found in our patients, but their

CLINICAL P HARMACOLOGY &THERAPEUTICS VOLUME 60, NUMBER4 Sullivan etal. 411

o-1 l-2 2-3 3-4 4-6 6-12 o-12

Time (hours)

Fig. 4. Urinary recovery of bumetanide. Light bars on the left represent percentages of total dose of administered bumetanide recovered per hour for each collection interval. The dark bar on the right depicts the mean t SD of the total percentage of bumetanide dose recovered from 0 to 12 hours (40% +- 15%) after administration of bumetanide (n = 58).

bumetanide clearances were reduced (0.83 2 0.83 ml/min/kg versus 2.74 + 1.95 ml/min/kg, respectively), and plasma t,,, values were increased (5.8 t 0.7 versus 2.34 t 1.41 hours, respectively). These differences may reflect the relative immaturity of bumetanide clearance mechanisms manifested by preterm infants included in their studies. The actual dose of bumetanide administered in their studies was not validated by measurement of bumetanide excretion rates, as was done in our study.

Bumetanide clearances for infants in our study were similar to those reported for healthy adults (2.74 + 1.95 ml/mm/kg versus 2.55 + 0.54 mUmin/ kg), 21,24,25 although the variability was much greater. This may reflect the ontogeny of renal and hepatic function. However, the volume of distribution (Vs,) was about twofold greater in our infants (0.29 ? 0.12 L/kg versus 0.13 +- 0.03 L/kg), thereby largely ac- counting for the longer observed elimination t,,, (2.34 t 1.41 hours versus 0.8 + 0.2 hours). The reason for the larger volume of distribution for bumetanide in infants as compared with adults is not known. Protein binding of bumetanide (97%) is reportedly similar in the two populations, but even an experimentally undetectable decrease in bumetanide binding to plasma proteins could substantially increase values for this parameter in our patients.26 Also, the greater volume of extracellular fluid per kilogram of body weight available for bumetanide distribution in infants as compared with adults (350

to 440 ml/kg versus 200 ml/kg, respectively)27 may contribute to the larger volume of bumetanide distribution in infants.

In infants major differences exist between the pharmacokinetics of bumetanide and furosemide, the prototype of loop diuretics. The t,,, of bumetanide (2.34 + 1.41 hours) is much shorter than that of furosemide (13.4 +- 8.6 hours).28 This nearly sixfold difference is largely due to a greater clearance of bumetanide (2.74 2 1.95 ml/min/kg versus 0.20 t 0.16 ml/min/kg for furosemide28), even though smaller V, (0.39 + 0.21 versus 0.52 2 0.42 L/kg for furosemide2’) contributes to it.29”1 This suggests that more frequent drug administration is needed with bumetanide than furosemide, depending on their relative pharmacodynamic effects.

The highest single dose of bumetanide chosen for our study, 0.10 mg/kg, produced no adverse effects attributable to the drug, namely electrolyte abnormalities, hemodynamic instability, hypovolemia, or significant elevations in bilirubin. Long-term management (2 to 40 weeks) with oral doses of bumetanide up to 0.1 mg/kg/day has been reported to be an effective adjunct to therapy designed to control congestive heart failure in pediatric patients, and without demonstrable toxicity.32 However, possible ototoxicity was not evaluated in either study.

In conclusion, bumetanide exhibited first-order elimination kinetics after single doses ranging from 0.005 to 0.10 mg/kg in acutely ill, fluid-overloaded

412 Sadivan et al,

infants aged 4 days to 6 months. Pharmacokinetic parameter estimates were independent of the bumetanide dose administered, whereas peak urinary excretion rates of bumetanide were proportional to dose over the range studied with no evidence for saturation of bumetanide excretion mechanisms. No toxicity attributable to bumetanide was observed. The large interpatient and intergroup variability found for pharmacokinetic parameter estimates may, at least in part, reflect different disease states and the ontogeny of hepatic and renal excretory mechanisms in this patient population.

We thank Dr. Leslie T. Webster, Jr., Dr. Lia Lowrie, and Dr. Michael D. Reed for their contributions during the performance of this study and the preparation of this manuscript. We also thank the research nurses for assist- ing in patient enrollment, data collection, and collection and storage of serum and urine specimens; and Anita Pettigrew for performing HPLC bumetanide analyses.

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Pharmacokinetics of bumetanide in critically ill infants*