Pharmacokinetics and Pharmacodynamics of Vecuronium in the Obese Surgical Patient Arthur E. Schwartz, MD, IClchard S. Matteo, Jonathan D. Halevy, MD, and Jaime Diaz
MD,
Eugene Ornstein,
PhD, MD,
Department of Anesthesiology, College of Physicians and Surgeons, Columbia University, New York, New York
The effect of obesity on the disposition and action of vecuronium was studied in 14 surgical patients. After induction of anesthesia with thiopental and maintenance of anesthesia by inhalation of nitrous oxide and halothane, seven obese patients (93.4 13.9 kg, 166% 30% of ideal body weight, mean 2 SD) and seven control patients (60.9 12.3 kg, 93% 6% of ideal body weight) received 0.1 mgikg of vecuronium. Plasma arterial concentrations of muscle relaxant were determined at 1, 3, 5, 10, 15, 20, 30, 45, 60, 90, 120, 150, 180, 210, 240, 300, and 360 min by a spectrofluorometric method. Simultaneously, neuromuscular blockade was assessed by stimulation of the ulnar nerve and quantification of thumb adductor response. Times to 50% recovery of twitch were longer in the obese than in the control patients (75 t 8 versus 46 8 min) as were 5%-25% recovery times (14.9 4.0 versus 10.0 i 1.7 min) and 25%-75% recovery times (38.4 13.8 versus 16.7 10.3 min). However, vecuronium pharmacokinetics were simi-
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*
*
*
*
besity is associated with changes in body composition and function that may alter drug disposition. Obese individuals have an increased proportion of body fat to total body mass and a decreased proportion of muscle mass and body water (1,2). Cardiac output, glomerular filtration rate, and intravascular volume are all increased (3,4). In addition, there is evidence that obesity may alter both liver function and protein binding (5,6). We previously found a slower recovery from vecuronium neuromuscular blockade in obese surgical patients when compared with controls (7). The duration of neuromuscular blockade was strongly correlated with degree of obesity. We sought to determine
Presented in part at the Congress of the International Anesthesia Research Society, Orlando, Florida, March 1989. Accepted for publication December 6, 1991. Address correspondence to Dr. Schwartz, NeuroanesthesiaRoom 901, Columbia University, 161 Fort Washington Avenue, New York, NY 10032. 01992 by the International Anesthesia Research Society 0003-2999/92/$5.00
lar for both groups. When the data were calculated on the basis of ideal body weight (IBW) for obese and control patients, total volume of distribution (791 303 versus 919 360 mLikg IBW), plasma clearance (4.65 t 0.89 versus 5.02 t 1.13 mL.min-'.kg IBW-'), and elimination half-life (119 2 43 versus 133 ? 57 min) were not different between groups. Only when total volume of distribution and clearance are divided by patient weight (a larger value for the obese) and expressed per kilogram of actual body weight do these values appear smaller in the obese (473 142 versus 993 401 mLikg and 2.83 0.54 versus 5.36 t 1.14 mL.min-'.kg-', respectively). As obesity did not alter the distribution or elimination of vecuronium, the prolonged action seen at 0.1 mg/kg is due to an overdose when vecuronium is administered on the basis of total body weight. Clinically, ideal body weight should be used for dose calculation in the obese patient.
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*
*
*
(Anesth Analg 1992;74:5158)
if altered pharmacokinetics may account for the prolonged action of vecuronium with obesity.
Methods After Institutional Review Board approval, informed consent was obtained from seven obese and seven control patients undergoing elective neurosurgical procedures. Patients with evidence of cardiac, hepatic, renal, or neuromuscular disease were excluded from the study, as were patients taking medications known to affect neuromuscular blockade. Obese patients were at least 30% above ideal body weight (IBW), whereas control patients were within 10% of IBW. Ideal body weight was defined as follows (5-7): IBW (males)
=
110 Ib
+
5 lbiinch above 5 foot height,
IBW (females)
=
100 lb
+
5 lb/inch above 5 foot height.
Anesth Analg 1992;74:5158
515
516
ANESTH ANALG 1992;74:5158
5CtfWARTZ ET AL \'FCL!IIONICM Ih THE OBESE
Percentage IBW was defined as the ratio of total body weight to IBW. General anesthesia was induced with thiopental (4-7 mglkg IV) and continued with nitrous oxidel oxygen (2:l) and halothane via a mask. During this time, baseline twitch tension of the thumb adductor was quantified by a Grass force displacement transducer (FT-10) with ulnar nerve stimulation of the wrist by surface electrodes using supramaximal stimuli from a Grass Stimulator (model S8) in conjunction with Grass stimulation isolation units. Responses to single stimuli of 0.15-ms duration delivered at a rate of 0.1 Hz were recorded. After 10 min of steady baseline twitch tension, 0.1 mgikg of vecuronium was administered as an intravenous bolus and the trachea was intubated. Thereafter, ventilation was controlled to maintain end-tidal carbon dioxide tension between 26 and 36 mm Hg as measured by infrared analysis. Nitrous oxide was continued and halothane was administered to maintain an end-tidal concentration of 0.5%-0.7% as measured by infrared analysis. Esophageal temperature was kept at 35.4" to 36.9"C with the aid of warming blankets. Blood samples were obtained from arterial catheters at 1, 3, 5, 10, 15, 20, 30, 45, 60, 90, 120, 150, 180, 210, 240, 300, and 360 min. Additional samples were obtained between these fixed times during recovery of neuromuscular blockade at 5% and 75% of control twitch tension. Plasma was separated and frozen until assayed for vecuronium concentration. One molar sodium phosphate buffer (pH = 4.0) was added to plasma samples to achieve a volume ratio of 1:4. Anion exchange columns (Bakerbond STE) were used for analysis, and vecuronium concentration was determined by a spectrofluorometric method. The coefficient of variation was 5.8%, and the sensitivity was 10 ngimL (8). The times to 5%, 25%, 50%, and 75% recovery of twitch tension were recorded. Both biexponential and triexponential equations were fitted to the plasma concentration-versus-time data for each patient using nonlinear least-squares regression (9). A weighting function of l/X,' was used. The best fit for the data was determined using the F ratio test (10). The method of Wagner was used to calculate pharmacokinetic parameters (11). Total volume of distribution was determined by the area method. Volumes of distribution and clearances per kilogram of IBW were determined by dividing the volume of distribution (in mL) or clearance (in mLimin) by IBW to permit meaningful comparisons between obese and control patients. Comparison of demographic data, coefficients and exponents of the pharmacokinetic equations, pharmacokinetic parameters, times to 50% recovery, recovery indexes (25%-75% and 5'/c-25'% ), and vecuronium concentrations a t
Table 1. Demographic Data Obese (If =
Agt, ( v r ) Height (cm) Sex (M F) Weight (kg) 1BLY (kg) ' i IBW
Control ( n = 7)
7)
49.6 f 13 8 165 2 9 215
93.4 f 13 9 57.0 2 9.5 166 2 30
45.1 f 11.0 172 f 10 314 60 9 12.3 65.1 2 11.9 93 f 6
*
P C0.60 c0.20
MD,
Eugene Ornstein,
PhD, MD,
Department of Anesthesiology, College of Physicians and Surgeons, Columbia University, New York, New York
The effect of obesity on the disposition and action of vecuronium was studied in 14 surgical patients. After induction of anesthesia with thiopental and maintenance of anesthesia by inhalation of nitrous oxide and halothane, seven obese patients (93.4 13.9 kg, 166% 30% of ideal body weight, mean 2 SD) and seven control patients (60.9 12.3 kg, 93% 6% of ideal body weight) received 0.1 mgikg of vecuronium. Plasma arterial concentrations of muscle relaxant were determined at 1, 3, 5, 10, 15, 20, 30, 45, 60, 90, 120, 150, 180, 210, 240, 300, and 360 min by a spectrofluorometric method. Simultaneously, neuromuscular blockade was assessed by stimulation of the ulnar nerve and quantification of thumb adductor response. Times to 50% recovery of twitch were longer in the obese than in the control patients (75 t 8 versus 46 8 min) as were 5%-25% recovery times (14.9 4.0 versus 10.0 i 1.7 min) and 25%-75% recovery times (38.4 13.8 versus 16.7 10.3 min). However, vecuronium pharmacokinetics were simi-
*
*
*
*
*
*
*
*
besity is associated with changes in body composition and function that may alter drug disposition. Obese individuals have an increased proportion of body fat to total body mass and a decreased proportion of muscle mass and body water (1,2). Cardiac output, glomerular filtration rate, and intravascular volume are all increased (3,4). In addition, there is evidence that obesity may alter both liver function and protein binding (5,6). We previously found a slower recovery from vecuronium neuromuscular blockade in obese surgical patients when compared with controls (7). The duration of neuromuscular blockade was strongly correlated with degree of obesity. We sought to determine
Presented in part at the Congress of the International Anesthesia Research Society, Orlando, Florida, March 1989. Accepted for publication December 6, 1991. Address correspondence to Dr. Schwartz, NeuroanesthesiaRoom 901, Columbia University, 161 Fort Washington Avenue, New York, NY 10032. 01992 by the International Anesthesia Research Society 0003-2999/92/$5.00
lar for both groups. When the data were calculated on the basis of ideal body weight (IBW) for obese and control patients, total volume of distribution (791 303 versus 919 360 mLikg IBW), plasma clearance (4.65 t 0.89 versus 5.02 t 1.13 mL.min-'.kg IBW-'), and elimination half-life (119 2 43 versus 133 ? 57 min) were not different between groups. Only when total volume of distribution and clearance are divided by patient weight (a larger value for the obese) and expressed per kilogram of actual body weight do these values appear smaller in the obese (473 142 versus 993 401 mLikg and 2.83 0.54 versus 5.36 t 1.14 mL.min-'.kg-', respectively). As obesity did not alter the distribution or elimination of vecuronium, the prolonged action seen at 0.1 mg/kg is due to an overdose when vecuronium is administered on the basis of total body weight. Clinically, ideal body weight should be used for dose calculation in the obese patient.
*
*
*
*
(Anesth Analg 1992;74:5158)
if altered pharmacokinetics may account for the prolonged action of vecuronium with obesity.
Methods After Institutional Review Board approval, informed consent was obtained from seven obese and seven control patients undergoing elective neurosurgical procedures. Patients with evidence of cardiac, hepatic, renal, or neuromuscular disease were excluded from the study, as were patients taking medications known to affect neuromuscular blockade. Obese patients were at least 30% above ideal body weight (IBW), whereas control patients were within 10% of IBW. Ideal body weight was defined as follows (5-7): IBW (males)
=
110 Ib
+
5 lbiinch above 5 foot height,
IBW (females)
=
100 lb
+
5 lb/inch above 5 foot height.
Anesth Analg 1992;74:5158
515
516
ANESTH ANALG 1992;74:5158
5CtfWARTZ ET AL \'FCL!IIONICM Ih THE OBESE
Percentage IBW was defined as the ratio of total body weight to IBW. General anesthesia was induced with thiopental (4-7 mglkg IV) and continued with nitrous oxidel oxygen (2:l) and halothane via a mask. During this time, baseline twitch tension of the thumb adductor was quantified by a Grass force displacement transducer (FT-10) with ulnar nerve stimulation of the wrist by surface electrodes using supramaximal stimuli from a Grass Stimulator (model S8) in conjunction with Grass stimulation isolation units. Responses to single stimuli of 0.15-ms duration delivered at a rate of 0.1 Hz were recorded. After 10 min of steady baseline twitch tension, 0.1 mgikg of vecuronium was administered as an intravenous bolus and the trachea was intubated. Thereafter, ventilation was controlled to maintain end-tidal carbon dioxide tension between 26 and 36 mm Hg as measured by infrared analysis. Nitrous oxide was continued and halothane was administered to maintain an end-tidal concentration of 0.5%-0.7% as measured by infrared analysis. Esophageal temperature was kept at 35.4" to 36.9"C with the aid of warming blankets. Blood samples were obtained from arterial catheters at 1, 3, 5, 10, 15, 20, 30, 45, 60, 90, 120, 150, 180, 210, 240, 300, and 360 min. Additional samples were obtained between these fixed times during recovery of neuromuscular blockade at 5% and 75% of control twitch tension. Plasma was separated and frozen until assayed for vecuronium concentration. One molar sodium phosphate buffer (pH = 4.0) was added to plasma samples to achieve a volume ratio of 1:4. Anion exchange columns (Bakerbond STE) were used for analysis, and vecuronium concentration was determined by a spectrofluorometric method. The coefficient of variation was 5.8%, and the sensitivity was 10 ngimL (8). The times to 5%, 25%, 50%, and 75% recovery of twitch tension were recorded. Both biexponential and triexponential equations were fitted to the plasma concentration-versus-time data for each patient using nonlinear least-squares regression (9). A weighting function of l/X,' was used. The best fit for the data was determined using the F ratio test (10). The method of Wagner was used to calculate pharmacokinetic parameters (11). Total volume of distribution was determined by the area method. Volumes of distribution and clearances per kilogram of IBW were determined by dividing the volume of distribution (in mL) or clearance (in mLimin) by IBW to permit meaningful comparisons between obese and control patients. Comparison of demographic data, coefficients and exponents of the pharmacokinetic equations, pharmacokinetic parameters, times to 50% recovery, recovery indexes (25%-75% and 5'/c-25'% ), and vecuronium concentrations a t
Table 1. Demographic Data Obese (If =
Agt, ( v r ) Height (cm) Sex (M F) Weight (kg) 1BLY (kg) ' i IBW
Control ( n = 7)
7)
49.6 f 13 8 165 2 9 215
93.4 f 13 9 57.0 2 9.5 166 2 30
45.1 f 11.0 172 f 10 314 60 9 12.3 65.1 2 11.9 93 f 6
*
P C0.60 c0.20
