Pharmacokinetics and pharmacodynamics of bumetanide in neonates treated with extracorporeal membrane oxygenation T h o m a s G. Wells, MD, J a m e s W, Fasules, MD, Bonne J. Taylor, MD, a n d G r e g o r y L. Kearns, PharmD From the Divisions of Clinical Pharmacology, Nephrology, Cardiology, and Neonatology, Department of Pediatrics, University of Arkansas for Medical Sciences and the Arkansas Children's Hospital, Little Rock
Eleven term neonates treated with extracorporeal membrane oxygenation received bumetanide to treat volume overload. All patients had stable renal function, no history of prior diuretic therapy, and no overt evidence of hepatobiliary disease or hypoalbuminemia. Pretreatment creatinine c l e a r a n c e was 35.2 • 4.5 ml/min per 1.73 m 2 (range, 20.3 to 57.5). Bumetanide, 0.095 +_ 0.003 mg/kg, was administered for 2 minutes into the postmembrane side of the extracorporeal membrane oxygenation circuit. Serial plasma and urine samples were collected for measurement of bumetanide and electrolyte concentrations. Total plasma and renal clearances for bumetanide were 0.63 • 0.11 and 0.16 • 0.04 ml/min per kilogram, respectively. The steady-state volume of distribution (0.44 • 0.03 L/kg) and the elimination half-life (13.2 • 3.8 hours) were greater than similar values reported in previous studies of bumetanide disposition in premature and term neonates who were not treated with extracorporeal membrane oxygenation. At observed rates of bumetanide excretion, the diuretic, natriuretic, and kaliuretic responses were linear. Significant diuresis, natriuresis, and kaliuresis were observed, although the duration of these effects was less than expected given the prolonged renal elimination of bumetanide. Nonrenal elimination of bumetanide was variable (47.2% to 96.9%) but higher than expected; this may explain the relatively brief diuretic and kaliuretic response. (J PEDIATR1992;121:974-80)
In neonates treated with extracorporeal membrane oxygenation, clinically significant fluid retention frequently develops despite adequate blood pressure and lack of overt signs of intrinsic or obstructive renal disease. Mobilization of excess fluid is often desired and may be achieved with diuretics. However, several characteristics of ECMO therapy may
Portions of the data were previously,.published in abstract form: Wells TG, Taylor BJ, Fasules JW, Nearns GL. Pediatr Res 1991;29:67A. Submitted for publication April 24, 1992; accepted July 28, 1992. Reprint requests: Thomas G. Wells, MD, Assistant Professor of Pediatrics, S-450 Sturgis Bldg., Arkansas Children's Hospital, 800 Marshall St., Little Rock, AR 72202. 9/25/41391 974
alter drug disposition. The large surface area of the ECMO circuit potentially allows significant drug-circuit binding, resulting in an increase in the volume of distribution. The volume of the extracorporeal circuit often equals or exceeds ECMO FeK FeNa PCA
Extracorporeal membrane oxygenation Fractional excretion of potassium Fractional excretion of sodium Postconceptional age
the expected blood volume of neonates and small infants; this substantial increase in blood volume may significantly increase the distribution volume of drugs with a normally small volume of distribution.l Furthermore, for drugs that undergo significant renal elimination, the effects of exter-
Volume 121 Number 6
nally determined, pump-driven blood flow and altered renal hemodynamics may modify drug elimination. Bumetanide is a potent inhibitor of Na+-K+-2C1cotransport in the thick ascending limb of the loop of Henle. 2 It has been used to treat a variety of conditions associated with fluid retention in children. 3 Bumetanide disposition has been studied in neonates and infants 49 but has not, to our knowledge, been evaluated in neonates treated with ECMO. In this article, we report the pharmacokinetics and pharmacodynamic response to bumetanide in neonates treated with ECMO. METHODS ECMO methods. Vascular access for ECMO was achieved by means of venoarterial cannulation of the right carotid artery and the ipsilateral internal jugular vein. A standard perfusion system (St6ckert-Shiley perfusion system; Shiley, Inc., Irvine, Calif.) and membrane oxygenator (0800 ECMO extended-capacity membrane oxygenator; Avecor Cardiovascular, Inc., Plymouth, Minn.) were used. In all cases the membrane oxygenator surface area was 0.8 m 2. The standard initial blood flow rate in neonates was 120 ml/min per kilogram. Subsequent adjustments in the flow rate were made at the discretion of the ECMO perfusionist and physician. Patient selection. Term neonates (less than 1 month of age) with fluid retention and potentially reversible cardiac or pulmonary failure requiring treatment with ECMO were considered for enrollment. Gestational age was determined by using a standar d Dubowitz examination. All patients had a minimal mean arterial pressure of 45 mm Hg, oxygen tension of >60 mm Hg, and a Foley catheter in place for medical management. Fluids, including blood products, were administered at the discretion of each patient's physician. Patients were excluded from the study if any of the following criteria were present: anuria, an estimated creatinine clearance 1~of less than 20 ml/min per 1.73 m 2, a serum albumin concentration of less than 25 gm/L, overt hepatic failure, or administration of any diuretic within 48 hours before entry into the study. The study protocol was approved by the human research advisory committee of the University of Arkansas for Medical Sciences. Written informed consent was obtained from the parents of each subject before enrollment. Study design. A baseline urine sample was collected for 2 to 4 hours before administration of bumetanide. This sample was used to determine pretreatment urine flow rate and concentrations of sodium, potassium, calcium, magnesium, and creatinine. During collection of the baseline urine sample, a blood sample was drawn for measurement of serum concentrations of sodium, potassium, calcium, magnesium, and creatinine. After collection of the pretreatment urine sample was
B u m e t a n i d e in neonates treated with E C M O
975
completed, bumetanide, 0.10 mg/kg, was administered intravenously for 2 minutes into the postmembrane side of the ECMO circuit. Blood samples (1 ml each) for measurement of bumetanide were obtained before and at the following times after administration of bumetanide: 5, 10, 15, 30, 45, 60, 90, 120, 180, 360, 720, and 1440 minutes. Blood samples collected for measurement of bumetanide were centrifuged and the plasma was stored at - 7 0 ~ C for later extraction and assay. As part of the routine care for these patients, blood also was drawn every 12 hours for serial measurement of serum sodium, potassium, chloride, calcium, magnesium, and creatinine concentrations. Timed urine samples were collected at hourly intervals during the first 6 hours after bumetanide was administered. Subsequent samples were collected during the following time intervals: 6 to 8, 8 to 10, 10 to 12, 12 to 16, 16 to 20, and 20 to 24 hours. For each time interval, urine volume and flow rate were determined and an aliquot was frozen at - 7 0 ~ C for later measurement of bumetanide, sodium, potassium, calcium, magnesium, and creatinine concentrations. Laboratory methods. Serum electrolyte and creatinine concentrations were measured by using standard methods in the clinical laboratory (Ektachem 700, Eastman Kodak Co., Rochester, N.Y.). Urine creatinine concentrations were determined by using a Beckman analyzer (Beckman Instruments, Inc., Brea, Calif.) after appropriate dilution. A Perkin-Elmer atomic absorption spectrophotometer (model 2380; Perkin-Elmer Corp., Norwalk, Conn.) was used to measure levels of sodium, potassium, calcium, and magnesium from urine samples. Bumetanide concentrations in plasma and urine were determined after solid-phase extraction by high-performance liquid chromatography. 11 Pharmacokinetie data analysis. Individual plasma concentration-time data were evaluated by using Siphar/Base (Simed, Creteil, France). Initial polyexponential parameter estimates were generated with a peeling algorithm.12 Final parameter estimates were obtained from curve fitting of individual data sets by using a nonlinear, weighted least squares algorithm, with the weight set as the reciprocal of the calculated plasma concentration.13 Compartment model selection was made after application of the Akaike information criterion. 14 Finally, compartment model-dependent pharmacokinetic parameters were calculated by previously described methods. 15 Bumetanide renal clearance (Clrenal) was calculated from the following equation: Clrenal = Ae/ AUC, where Ae represents the total amount of drug excreted unchanged in the urine and AUC is the area under the concentration versus time curve from 0 to 24 hours. Pharmacokinetic parameters are expressed as mean-+ SEM. Pharmaeodynamie data analysis. Fractional excretion of electrolytes was calculated from the following general
976
W e l l s et al.
The Journal o f Pediatrics December 1992
Table I. Pharmacokinetic parameters for 11
least-squares linear regression. 17 The significance limit accepted for all statistical analyses was defined as ~ = 0.05.
ECMO-treated term neonates Pharmacokinetic parameters
Bumetanide dose (mg/kg) AUC (0-24 hr) (~g/ml 9 hr) Cltotat (ml/min/kg) Clrenal (ml/min/kg) Vd~s (L/kg) Vdl3 (L/kg) Vc (L/kg) Kel/3 (1/hr) t89 (hr) t89 (hr) Recovery (0-24 hr) (%)*
Patient clata Mean _+ $EM
Range
0.095 _+ 0.003 (0.077-0.105) 2.39 +_0 . 2 8 (1.25-4.48) 0.63 +_ 0.ll (0.14-l.33) 0.16 _+ 0 . 0 4 (0.02-0.41) 0.44 +_ 0 . 0 3 (0.32-0.57) 0.45 +_ 0.03 (0.33-0.57) 0.16 _+ 0 . 0 2 (0.13-0.25) 0.086 +_ 0.015 (0.029-0.156) 0.35 _+ 0 . 1 2 (0.06-1.23) 13.2 +_ 3.8 (4.5-45,9) 20 -+ 5 (3.1-52.8)
AUC (0-24 hr), Areaunderthe concentrationversustimecurvefrom0 to 24 hours; Clwtat,totalbodyclearance;ClrenaI,renalclearance;Vd,s, steady-state volumeof distribution;Vd[3, elimination-phasevolumeof distribution;Vc, votumeof the centralcompartment;Kelfl, eliminationrate constant;t89
distributionhalf-life;t89 eliminationhalf-life. *Recovery represents the urinaryrecovery of bumetanide,expressed as mean _+SEM, from baselineto 24 hours.
equation: Fractional excretion = ([Ux] • [Screatinine])§ ([Ucreatinine] X [Sx]), where [Ux] and [Sx] are urine and serum concentrations of sodium or potassium. Creatinine is both filtered by the glomerulus and secreted by the renal tubule; thus the calculated fractional excretions of sodium and potassium may slightly underestimate the true values. All pharmacodynamic data are expressed as mean + SEM. Pharmacokinetic-pharmacodynamic relationships were assessed by using individual patient data. Because of apparent linearity in the response to bumetanide, a linear pharmacodynamic model was used to examine potential relationships between the rate of urinary excretion of bumetanide and the change from baseline for urine flow rate, FeNa and FeK, magnesium and calcium excretion, and urine calcium/creatinine ratio. In addition, concentration-effect profiles were generated by using a sigmoid Emax model as described by Holford and Sheiner. 16 Statistical analysis. Relationships among pretreatment creatinine clearance, postconceptional age, and pharmaeokinetic parameters (total, renal, and nonrenal bumetanide clearance; elimination rate constant; distribution and elimination half-lives; volume of distribution at steady state and in the elimination phase; and volume of the central compartment) were examined byusing least-squares linear r egression. 17 Differences ' between pretherapy and posttherapy urine flow rate and electrolyte excretion (FeNa, FeK, magnesium and calcium excretion, and urine calcium/creatinine ratio) were examined by using single-factor repeated measures analysis of variance. 17 Relationships between the bumetanide excretion rate and the urine flow and electrolyte excretion rates were characterized by using
RESULTS Bumetanide was administered to 11 term neonates (gestational ages, 37 to 41 weeks) on postnatal days 1 to 7 during ECMO therapy. Primary diagnoses included persistent pulmonary hypertension (six neonates), sepsis and pneumonia (three), respiratory distress syndrome (one), and congenital diaphragmatic hernia (one). Mean patient weight at the time ECMO therapy was started was 3.81 ___ 0.22 kg (range, 3.20 to 5.67 kg), and the mean creatinine clearance, calculatedfromthebaselinedata, was35.2 _+ 4.5 ml/min per 1.73 m 2 (range, 20.3 to 57.5 mL/min per 1.73 m2). None of the 11 patients had received prior diuretic therapy. Pharmacokinetlcs of bumetanide. First-dose pharmacokinetic parameters were estimated in all 11 patients (Table I). Data were best fit to a two-compartment open model. Relationships between PCA and calculated pharmacokinetic parameters were examined. Over the range studied, PCA strongly correlated with elimination parameters but not with distribution parameters or the urinary recovery of bumetanide (Table II). Pretreatment creatinine clearance correlated well with total plasma clearance (r = 0.72, p = 0.019) but not with renal clearance (r = 0.63, p = 0.052) of bumetanide. The elimination rate constant and the elimination half-life were extremely variable and did not correlate with ereatinine clearance (r = 0.53, p = 0.11; r = 0.25, p = 0.48, respectively). Elimination half-life was extremely prolonged in two patients (24.2 and 45.9 hours). The urinary recovery of bumetanide did not correlate with pretreatment creatinine clearance (r = 0.24, p = 0.50).
Pharmaeodynamic data and pharmacokinetic-pharmaeodynamic relationships. The response to bumetanide is shown in Fig. 1. All p~ttients had a transient increase in urine flow rate of more than 100% within the first 6 hours after bumetanide was administered. Mean urine flow rate and bumetanide excretion rate peaked at 0.75 ml/min and 0.13 ug/min, respectively, within the first hour after administration of bumetanide, and then decreased. The mean urine flow rate was significantly increased above baseline only during the first 3 hours after administration of bumetanide. Despite maintenance of adequate blood pressure and continued urinary excretion of bumetanide, only two patients had a sustained increase in urine flow rate throughout the 24-hour study period. In the two patients with elimination half-lives greater than 24 hours, initial urine flow rates (both 0.11 ml/min) and the maximum absolute increase in urine flow rates (0.16 and 0.31 ml/min) were among the lowest of the entire group. The relationships between the urinary excretion rate of
Volume 121 Number 6
Bumetanide in neonates treated with E C M O
977
1.0 1.0"
0.8
0.8-
0.6
Urine Flow 0.6 Ra~ (mL/min) 0.4
Urine Flow Rate (mL/rnin)
9
~176
9
0.4
0.2
0.2 84
0.0
6
A
12
18
0.0 0.00
24
l ~-~-~'~11
~"
i
0.05
0. I0
0.15
Time (h)
A
Bumetanide Excretion Rate (pg/min)
0.15 0"121
1
0.I0
0'08 t
FeNa
I !
0.05
I
i
T
" .
~
FeNa
I
0.04-
[ ~2o~o p : o . ~ 0.00 0
6
B
12
18
24
0.(30 0.00
Time (h)
B
0.05 Bumeta~lde
0.10 Excretion
0.15
Rate (pg/mln)
0.8 0.6
0.4
FeK FeK
0.2
0.0 C
0.2 84
0
6
12
18
y = 0.203 + 3.33 x r = 0.875 p = 0.0004
24
Time (h)
Fig. t. Mean (_+SEM) data for measured responses to bumetanide (urine flow rate, FeNa, FeK) are plotted against time. Baseline for each measured response is indicated by horizontal solid line. Urine flow rate, FeNa, and FeK are significantly elevated through 3, 20, and 5 hours, respectively (* = p
Eleven term neonates treated with extracorporeal membrane oxygenation received bumetanide to treat volume overload. All patients had stable renal function, no history of prior diuretic therapy, and no overt evidence of hepatobiliary disease or hypoalbuminemia. Pretreatment creatinine c l e a r a n c e was 35.2 • 4.5 ml/min per 1.73 m 2 (range, 20.3 to 57.5). Bumetanide, 0.095 +_ 0.003 mg/kg, was administered for 2 minutes into the postmembrane side of the extracorporeal membrane oxygenation circuit. Serial plasma and urine samples were collected for measurement of bumetanide and electrolyte concentrations. Total plasma and renal clearances for bumetanide were 0.63 • 0.11 and 0.16 • 0.04 ml/min per kilogram, respectively. The steady-state volume of distribution (0.44 • 0.03 L/kg) and the elimination half-life (13.2 • 3.8 hours) were greater than similar values reported in previous studies of bumetanide disposition in premature and term neonates who were not treated with extracorporeal membrane oxygenation. At observed rates of bumetanide excretion, the diuretic, natriuretic, and kaliuretic responses were linear. Significant diuresis, natriuresis, and kaliuresis were observed, although the duration of these effects was less than expected given the prolonged renal elimination of bumetanide. Nonrenal elimination of bumetanide was variable (47.2% to 96.9%) but higher than expected; this may explain the relatively brief diuretic and kaliuretic response. (J PEDIATR1992;121:974-80)
In neonates treated with extracorporeal membrane oxygenation, clinically significant fluid retention frequently develops despite adequate blood pressure and lack of overt signs of intrinsic or obstructive renal disease. Mobilization of excess fluid is often desired and may be achieved with diuretics. However, several characteristics of ECMO therapy may
Portions of the data were previously,.published in abstract form: Wells TG, Taylor BJ, Fasules JW, Nearns GL. Pediatr Res 1991;29:67A. Submitted for publication April 24, 1992; accepted July 28, 1992. Reprint requests: Thomas G. Wells, MD, Assistant Professor of Pediatrics, S-450 Sturgis Bldg., Arkansas Children's Hospital, 800 Marshall St., Little Rock, AR 72202. 9/25/41391 974
alter drug disposition. The large surface area of the ECMO circuit potentially allows significant drug-circuit binding, resulting in an increase in the volume of distribution. The volume of the extracorporeal circuit often equals or exceeds ECMO FeK FeNa PCA
Extracorporeal membrane oxygenation Fractional excretion of potassium Fractional excretion of sodium Postconceptional age
the expected blood volume of neonates and small infants; this substantial increase in blood volume may significantly increase the distribution volume of drugs with a normally small volume of distribution.l Furthermore, for drugs that undergo significant renal elimination, the effects of exter-
Volume 121 Number 6
nally determined, pump-driven blood flow and altered renal hemodynamics may modify drug elimination. Bumetanide is a potent inhibitor of Na+-K+-2C1cotransport in the thick ascending limb of the loop of Henle. 2 It has been used to treat a variety of conditions associated with fluid retention in children. 3 Bumetanide disposition has been studied in neonates and infants 49 but has not, to our knowledge, been evaluated in neonates treated with ECMO. In this article, we report the pharmacokinetics and pharmacodynamic response to bumetanide in neonates treated with ECMO. METHODS ECMO methods. Vascular access for ECMO was achieved by means of venoarterial cannulation of the right carotid artery and the ipsilateral internal jugular vein. A standard perfusion system (St6ckert-Shiley perfusion system; Shiley, Inc., Irvine, Calif.) and membrane oxygenator (0800 ECMO extended-capacity membrane oxygenator; Avecor Cardiovascular, Inc., Plymouth, Minn.) were used. In all cases the membrane oxygenator surface area was 0.8 m 2. The standard initial blood flow rate in neonates was 120 ml/min per kilogram. Subsequent adjustments in the flow rate were made at the discretion of the ECMO perfusionist and physician. Patient selection. Term neonates (less than 1 month of age) with fluid retention and potentially reversible cardiac or pulmonary failure requiring treatment with ECMO were considered for enrollment. Gestational age was determined by using a standar d Dubowitz examination. All patients had a minimal mean arterial pressure of 45 mm Hg, oxygen tension of >60 mm Hg, and a Foley catheter in place for medical management. Fluids, including blood products, were administered at the discretion of each patient's physician. Patients were excluded from the study if any of the following criteria were present: anuria, an estimated creatinine clearance 1~of less than 20 ml/min per 1.73 m 2, a serum albumin concentration of less than 25 gm/L, overt hepatic failure, or administration of any diuretic within 48 hours before entry into the study. The study protocol was approved by the human research advisory committee of the University of Arkansas for Medical Sciences. Written informed consent was obtained from the parents of each subject before enrollment. Study design. A baseline urine sample was collected for 2 to 4 hours before administration of bumetanide. This sample was used to determine pretreatment urine flow rate and concentrations of sodium, potassium, calcium, magnesium, and creatinine. During collection of the baseline urine sample, a blood sample was drawn for measurement of serum concentrations of sodium, potassium, calcium, magnesium, and creatinine. After collection of the pretreatment urine sample was
B u m e t a n i d e in neonates treated with E C M O
975
completed, bumetanide, 0.10 mg/kg, was administered intravenously for 2 minutes into the postmembrane side of the ECMO circuit. Blood samples (1 ml each) for measurement of bumetanide were obtained before and at the following times after administration of bumetanide: 5, 10, 15, 30, 45, 60, 90, 120, 180, 360, 720, and 1440 minutes. Blood samples collected for measurement of bumetanide were centrifuged and the plasma was stored at - 7 0 ~ C for later extraction and assay. As part of the routine care for these patients, blood also was drawn every 12 hours for serial measurement of serum sodium, potassium, chloride, calcium, magnesium, and creatinine concentrations. Timed urine samples were collected at hourly intervals during the first 6 hours after bumetanide was administered. Subsequent samples were collected during the following time intervals: 6 to 8, 8 to 10, 10 to 12, 12 to 16, 16 to 20, and 20 to 24 hours. For each time interval, urine volume and flow rate were determined and an aliquot was frozen at - 7 0 ~ C for later measurement of bumetanide, sodium, potassium, calcium, magnesium, and creatinine concentrations. Laboratory methods. Serum electrolyte and creatinine concentrations were measured by using standard methods in the clinical laboratory (Ektachem 700, Eastman Kodak Co., Rochester, N.Y.). Urine creatinine concentrations were determined by using a Beckman analyzer (Beckman Instruments, Inc., Brea, Calif.) after appropriate dilution. A Perkin-Elmer atomic absorption spectrophotometer (model 2380; Perkin-Elmer Corp., Norwalk, Conn.) was used to measure levels of sodium, potassium, calcium, and magnesium from urine samples. Bumetanide concentrations in plasma and urine were determined after solid-phase extraction by high-performance liquid chromatography. 11 Pharmacokinetie data analysis. Individual plasma concentration-time data were evaluated by using Siphar/Base (Simed, Creteil, France). Initial polyexponential parameter estimates were generated with a peeling algorithm.12 Final parameter estimates were obtained from curve fitting of individual data sets by using a nonlinear, weighted least squares algorithm, with the weight set as the reciprocal of the calculated plasma concentration.13 Compartment model selection was made after application of the Akaike information criterion. 14 Finally, compartment model-dependent pharmacokinetic parameters were calculated by previously described methods. 15 Bumetanide renal clearance (Clrenal) was calculated from the following equation: Clrenal = Ae/ AUC, where Ae represents the total amount of drug excreted unchanged in the urine and AUC is the area under the concentration versus time curve from 0 to 24 hours. Pharmacokinetic parameters are expressed as mean-+ SEM. Pharmaeodynamie data analysis. Fractional excretion of electrolytes was calculated from the following general
976
W e l l s et al.
The Journal o f Pediatrics December 1992
Table I. Pharmacokinetic parameters for 11
least-squares linear regression. 17 The significance limit accepted for all statistical analyses was defined as ~ = 0.05.
ECMO-treated term neonates Pharmacokinetic parameters
Bumetanide dose (mg/kg) AUC (0-24 hr) (~g/ml 9 hr) Cltotat (ml/min/kg) Clrenal (ml/min/kg) Vd~s (L/kg) Vdl3 (L/kg) Vc (L/kg) Kel/3 (1/hr) t89 (hr) t89 (hr) Recovery (0-24 hr) (%)*
Patient clata Mean _+ $EM
Range
0.095 _+ 0.003 (0.077-0.105) 2.39 +_0 . 2 8 (1.25-4.48) 0.63 +_ 0.ll (0.14-l.33) 0.16 _+ 0 . 0 4 (0.02-0.41) 0.44 +_ 0 . 0 3 (0.32-0.57) 0.45 +_ 0.03 (0.33-0.57) 0.16 _+ 0 . 0 2 (0.13-0.25) 0.086 +_ 0.015 (0.029-0.156) 0.35 _+ 0 . 1 2 (0.06-1.23) 13.2 +_ 3.8 (4.5-45,9) 20 -+ 5 (3.1-52.8)
AUC (0-24 hr), Areaunderthe concentrationversustimecurvefrom0 to 24 hours; Clwtat,totalbodyclearance;ClrenaI,renalclearance;Vd,s, steady-state volumeof distribution;Vd[3, elimination-phasevolumeof distribution;Vc, votumeof the centralcompartment;Kelfl, eliminationrate constant;t89
distributionhalf-life;t89 eliminationhalf-life. *Recovery represents the urinaryrecovery of bumetanide,expressed as mean _+SEM, from baselineto 24 hours.
equation: Fractional excretion = ([Ux] • [Screatinine])§ ([Ucreatinine] X [Sx]), where [Ux] and [Sx] are urine and serum concentrations of sodium or potassium. Creatinine is both filtered by the glomerulus and secreted by the renal tubule; thus the calculated fractional excretions of sodium and potassium may slightly underestimate the true values. All pharmacodynamic data are expressed as mean + SEM. Pharmacokinetic-pharmacodynamic relationships were assessed by using individual patient data. Because of apparent linearity in the response to bumetanide, a linear pharmacodynamic model was used to examine potential relationships between the rate of urinary excretion of bumetanide and the change from baseline for urine flow rate, FeNa and FeK, magnesium and calcium excretion, and urine calcium/creatinine ratio. In addition, concentration-effect profiles were generated by using a sigmoid Emax model as described by Holford and Sheiner. 16 Statistical analysis. Relationships among pretreatment creatinine clearance, postconceptional age, and pharmaeokinetic parameters (total, renal, and nonrenal bumetanide clearance; elimination rate constant; distribution and elimination half-lives; volume of distribution at steady state and in the elimination phase; and volume of the central compartment) were examined byusing least-squares linear r egression. 17 Differences ' between pretherapy and posttherapy urine flow rate and electrolyte excretion (FeNa, FeK, magnesium and calcium excretion, and urine calcium/creatinine ratio) were examined by using single-factor repeated measures analysis of variance. 17 Relationships between the bumetanide excretion rate and the urine flow and electrolyte excretion rates were characterized by using
RESULTS Bumetanide was administered to 11 term neonates (gestational ages, 37 to 41 weeks) on postnatal days 1 to 7 during ECMO therapy. Primary diagnoses included persistent pulmonary hypertension (six neonates), sepsis and pneumonia (three), respiratory distress syndrome (one), and congenital diaphragmatic hernia (one). Mean patient weight at the time ECMO therapy was started was 3.81 ___ 0.22 kg (range, 3.20 to 5.67 kg), and the mean creatinine clearance, calculatedfromthebaselinedata, was35.2 _+ 4.5 ml/min per 1.73 m 2 (range, 20.3 to 57.5 mL/min per 1.73 m2). None of the 11 patients had received prior diuretic therapy. Pharmacokinetlcs of bumetanide. First-dose pharmacokinetic parameters were estimated in all 11 patients (Table I). Data were best fit to a two-compartment open model. Relationships between PCA and calculated pharmacokinetic parameters were examined. Over the range studied, PCA strongly correlated with elimination parameters but not with distribution parameters or the urinary recovery of bumetanide (Table II). Pretreatment creatinine clearance correlated well with total plasma clearance (r = 0.72, p = 0.019) but not with renal clearance (r = 0.63, p = 0.052) of bumetanide. The elimination rate constant and the elimination half-life were extremely variable and did not correlate with ereatinine clearance (r = 0.53, p = 0.11; r = 0.25, p = 0.48, respectively). Elimination half-life was extremely prolonged in two patients (24.2 and 45.9 hours). The urinary recovery of bumetanide did not correlate with pretreatment creatinine clearance (r = 0.24, p = 0.50).
Pharmaeodynamic data and pharmacokinetic-pharmaeodynamic relationships. The response to bumetanide is shown in Fig. 1. All p~ttients had a transient increase in urine flow rate of more than 100% within the first 6 hours after bumetanide was administered. Mean urine flow rate and bumetanide excretion rate peaked at 0.75 ml/min and 0.13 ug/min, respectively, within the first hour after administration of bumetanide, and then decreased. The mean urine flow rate was significantly increased above baseline only during the first 3 hours after administration of bumetanide. Despite maintenance of adequate blood pressure and continued urinary excretion of bumetanide, only two patients had a sustained increase in urine flow rate throughout the 24-hour study period. In the two patients with elimination half-lives greater than 24 hours, initial urine flow rates (both 0.11 ml/min) and the maximum absolute increase in urine flow rates (0.16 and 0.31 ml/min) were among the lowest of the entire group. The relationships between the urinary excretion rate of
Volume 121 Number 6
Bumetanide in neonates treated with E C M O
977
1.0 1.0"
0.8
0.8-
0.6
Urine Flow 0.6 Ra~ (mL/min) 0.4
Urine Flow Rate (mL/rnin)
9
~176
9
0.4
0.2
0.2 84
0.0
6
A
12
18
0.0 0.00
24
l ~-~-~'~11
~"
i
0.05
0. I0
0.15
Time (h)
A
Bumetanide Excretion Rate (pg/min)
0.15 0"121
1
0.I0
0'08 t
FeNa
I !
0.05
I
i
T
" .
~
FeNa
I
0.04-
[ ~2o~o p : o . ~ 0.00 0
6
B
12
18
24
0.(30 0.00
Time (h)
B
0.05 Bumeta~lde
0.10 Excretion
0.15
Rate (pg/mln)
0.8 0.6
0.4
FeK FeK
0.2
0.0 C
0.2 84
0
6
12
18
y = 0.203 + 3.33 x r = 0.875 p = 0.0004
24
Time (h)
Fig. t. Mean (_+SEM) data for measured responses to bumetanide (urine flow rate, FeNa, FeK) are plotted against time. Baseline for each measured response is indicated by horizontal solid line. Urine flow rate, FeNa, and FeK are significantly elevated through 3, 20, and 5 hours, respectively (* = p
