British Journal of Anaesthesia 1990; 65: 675-683
PHARMACODYNAMICS OF ATRACURIUM DURING PROPOFOL, THIOPENTONE AND OPIOID ANAESTHESIA G. H. BEEMER, A. R. BJORKSTEN AND D. P. CRANKSHAW SUMMARY
KEY WORDS Anaesthetics, intravenous: propofol, thiopentone. Anaesthetic techniques: infusion. Neuromuscular relaxants: atracurium. Pharmacodynamics: atracurium.
G. H. BEEMER, F.F.A.R.A.CS., Department of Anaesthesia, Post Office, The Royal Melbourne Hospital, Victoria 3050, Australia.
A. R. BJORKSTEN,
PH.D. ;
D. P. CHANWHAW,
F.F.A.R.A.CS., PH.D.; Department of Surgery (R.M.H.), University of Melbourne, Victoria, Australia. Accepted for Publication: May 23, 1990. Correspondence to G.H.B.
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We have assessed in 20 patients the accuracy and precision of an infusion profile for atracurium, which continually set the infusion rate to maintain stable muscle paralysis and a target steady state plasma concentration, when equilibrium between the biophase and plasma had occurred. Muscle paralysis was stable after 20 min, with a mean absolute drift in muscle paralysis in the succeeding 40 min of 0.13 (SD 0.07)% Tl/Tc (height of first twitch/height of control twitch) per min. The plasma samples after 30 min, which were assessed empirically as being in equilibrium with the biophase, had an overall mean bias of 8.0 (SEM 3.7) % (? < 0.05) and an overall mean absolute prediction error of 16.4 (SEM 2.5) % from the target steady state concentration being delivered by the infusion. The profile was then used to estimate the steady state plasma concentration of atracurium required to maintain 90% paralysis (Cp"^, by manually adjusting the delivered target concentration of the infusion until muscle paralysis was stable at 88-92% inhibition of Tl/Tc for 15-20 min, with three plasma samples taken over the next 10 min. Measurements were completed within 60-90 min. The mean Cp"x of atracurium with propofol was 1.039 (so 0.224) fig ml~' (n = 10), with thiopentone 1.334 (0.378) fig mf~' (n = 10), and with opioidanaesthesia 0.915 (0.221) ng ml-' (n=10). These differences in the Cpt>90 explain some of the variability in response which occurs with neuromuscular blocking drugs. The technique enables the CP"90 of a myoneural blocker to be determined by a simple model-independent method.
The magnitude and duration of muscle paralysis following administration of a given dose of a competitive neuromuscular blocking drug in an individual patient is unpredictable. Katz found that tubocurarine 0.1 mg kg"1 caused no block in 6%, and 100% block in 7% of patients [1]. This variability in response is probably the chief contributing factor in anaesthetic morbidity and mortality associated with neuromuscular blocking drugs. Pharmacokinetic and pharmacodynamic studies allow the identification of the sources of this variability, enabling the anaesthetist better to anticipate patient responses, and thus reduce the likelihood of excessive paralysis and residual curarization [2]. Accurate estimation of the pharmacodynamics of myoneural blockers, in particular, is difficult with current research techniques. Combined pharmacokinetic-dynamic models have been developed to make allowance for the temporal disequilibrium between the plasma and the biophase (neuromuscular effector site), to enable pharmacodynamics to be studied under nonsteady state conditions [3-8]. The technical difficulties associated with these methods have resulted in a limited number of patients having been studied, with only two pharmacokineticdynamic models for normal patients, based on a study of eight patients and four patients, developed for atracurium [7, 8]. The aim of this study was to develop a simple alternative technique to characterize the pharmacodynamics of a neuromuscular blocker by estimating the effective steady state plasma concentration for 90% paralysis (CP"00) using an
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infusion regimen to maintain constant muscle paralysis. The method was utilized to determine the Cp"^ of atracurium during propofol, thiopentone and opioid anaesthesia. PATENTS AND METHODS
TABLE I. The infusion profile used in this study. The profile was adjusted to achieve a target plasma concentration of atracurium, after equilibrium between the biophase and plasma had occurred, of 1.0 fig ml'1 in a "patient" of 1 kg lean body mass (LBM) Time (min) 0-1 1-2 2-3 3-4 4-5 5-6 6-7 7-8 8-9 £-10 10-11 11-12 12-13 13-14 14-15 15-16 16-17 17-18 18-19 19-20 20-21
Infusion profile (^g min"1 kgLBM-1) 200 8.68 8.68 8.68 8.68 8.68 8.68 8.41 8.15 7.88 7.83 7.78 7.72 7.67 7.62 7.62 7.62 7.62 7.62 7.62 7.52
Time (min)
Infusion profile (ng min-1 kgLBM-1)
21-22 22-23 23-24 24-25 25-26 26-27 27-28 28-29 29-30 30-31 31-32 32-33 33-34 34-35 35-36 36-37 37-38 38-39 39-40 40-oo
7.40 7.30 7.20 7.10 7.00 6.88 6.78 6.68 6.58 6.47 6.35 6.23 6.12 6.02 5.90 5.78 5.67 5.55 5.43 5.43
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Fifty adult patients undergoing major surgery gave informed consent to participate in the study, which was approved by the Hospital Board of Medical Research. Routine preoperative biochemical tests were used to exclude patients with evidence of hepatic or renal dysfunction. The electromyogram (EMG) of the first dorsal interosseous muscle to supramaximal stimulation of the ulnar nerve was measured and recorded with a Datex Relaxograph. The test hand was immobilized with no resting tension and wrapped in a towel with Medi-trace pellet electrodes placed 10-15 min before induction of anaesthesia. After anaesthesia was induced and before atracurium was administered, control twitch height (Tc) and a train-of-four fade ratio (T4:T1) were established. Subsequently, a train-of-four stimulation was delivered every 12 s with the single twitch inhibition (Tl/Tc) and T4:T1 recorded. Baseline
was stabilized for 3-5 min, with T l / T c and T4:T1 at 100% before the onset of muscle paralysis. A specially built syringe pump capable of reading successive memory locations, containing the infusion rate data, at specific times and adjusting the infusion rate according to patient size and the target plasma concentration, was used to infuse atracurium [9]. Atracurium was infused according to a profile defined in table I, which continually set the infusion rate to maintain a constant biophase concentration, as assessed by stable muscle paralysis. When equilibrium had occurred between the biophase and plasma, a target steady state plasma concentration was maintained thereafter by the infusion. The technique used to develop the profile is briefly outlined in the Appendix, and is based on a modification of the plasma drug efflux method [9]. The infusion rate was adjusted for by patient lean body mass (LBM), estimation of which, for each patient, was based on the method of James [10]. The precise infusion rate delivered to an individual patient for a specific time interval (Q,) is the rate defined in the profile for that interval adjusted for patient LBM and the target
PHARMACODYNAMICS OF ATRACURIUM steady state concentration of atracurium (CPt) and is given by: Qi = QPiCpt.LBM. (1)
Anaesthesia was maintained with 70% nitrous oxide in oxygen and continuous infusion of pro-
TABLE II. Patient characteristics (mean (SD)). LBM = lean
body mass Age
Sex
Study
n
(yr)
(M/F)
Weight (kg)
LBM (kg)
Pan 1 Part 2 Propofol Thiopentone Opioid
20
56 (13)
11/9
69(13)
50(8)
10 10 10
62(11) 49 (12) 54(10)
7/3 6/4 6/4
68(20) 76(22) 76(8)
51(11) 52(11) 58(5)
pofol (maintenance infusion rate 0.05-0.15 mg kg"1 min"1), continuous infusion of thiopentone (to maintain an arterial plasma concentration of thiopentone 10 ug ml"1 [9], maintenance infusion rate 55-95 ug kg"1 min"1), or incremental doses of fentanyl 5-10 ug kg"1 (total dose 30-50 |ig kg"1 within the first 60 min). Plasma concentrations of atracurium were measured by a high pressure liquid chromatography (HPLC) technique. The assay was sensitive to 0.03 ug ml"1 of plasma atracurium and was linear over the range of the standard curve (0.05—10 ug ml"1 in plasma) with a coefficient of variation of 4.1 % at 0.06 ug ml"1. Data atialysis
The accuracy and precision of the profile in achieving the target steady state plasma concentration of atracurium was assessed by the bias and mean absolute prediction error. These were calculated from the prediction error (PE, as a percentage) using the method described by Maitre and colleagues [11]. The prediction error was modified as follows: CPt
(2)
where Cpm was the measured arterial concentration. Student's t test was used to assess if the mean bias estimates for the group differed from zero. Student's t test with Bonferroni correction for multiple comparisons was used to assess the significance of the effect of anaesthetic agents on the CP°00 of atracurium. P < 0.05 was considered significant. Data are presented as mean (SD) unless stated otherwise. RESULTS
Patient data are presented in table II. Figure 1 shows the results of the infusion of atracurium according to the infusion profile in a represen-
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In the first part of the study, the accuracy of the profile in maintaining both stable muscle paralysis and the target plasma concentration was assessed in 20 patients. Anaesthesia was induced with thiopentone 1-4 mg kg"1 and fentanyl 5-20 ug kg"1 and maintained with 70 % nitrous oxide and incremental doses of fentanyl. Atracurium was infused for 1 h according to a profile to maintain stable muscle paralysis and a target steady state plasma concentration of 1.0 ug ml"1 when equilibrium between the biophase and plasma had occurred. Arterial blood samples were obtained at 0, 2, 4, 7, 10, 15, 20, 30, 40, 50 and 60 min. The patients received other adjuvants, including diazepam and droperidol, but excluding volatile anaesthetic agents, on the basis of clinical signs and in accordance with current practice. Ventilation was controlled throughout the study to maintain PaCOt in the range 4.7-5.3 kPa. Nasopharyngeal temperature was kept at 35.5-37 °C. In the second part of the study, the C P " M of atracurium was assessed during propofol, thiopentone and fentanyl anaesthesia with 10 patients in each group. Atracurium was infused initially according to the profile to achieve a target steady state plasma concentration of 1.0-1.5 ug ml"1 when equilibrium between the biophase and plasma had occurred. Following the onset of stable muscle paralysis, within 15-20 min of commencing the infusion, the target steady state plasma concentration delivered by the infusion was adjusted to maintain 90% inhibition of T l / T c , within a range of 88-92 %. If the paralysis was less than 90%, the patient was administered a small bolus of atracurium (1-3 mg) and the target concentration increased. If the paralysis was greater than 90%, the infusion was stopped and was recommenced at a lesser concentration when T l / T c inhibition was 95%. This process was repeated until inhibition of T l / T c was stable at 88-92% for 15-20 min. Three arterial blood samples were obtained at 5-min intervals, with the first sample being a minimum of 20 min after the final alteration of the infusion rate. Variation in the plasma concentration of atracurium of less than 5% confirmed steady state conditions for estimation of CPMW.
677
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tative patient from the first part of the study. The mean plasma concentration of atracurium with 95% confidence limits in the 20 patients is illustrated in figure 2. Figure 3 shows the resultant muscle paralysis with 95% confidence intervals. The mean muscle paralysis in the 20 patients at 60 min was 11.5 % T l / T c , 95 % of patients falling within the range 3-20%. The infusion profile maintained a relatively constant biophase concentration following onset of maximum muscle
ii
21-
O-i
50-
100-" 10
20
30
40
50
60
Time (mm) FIG. 1. Upper graph: measured plasma concentrations of atracurium in a 67-yr-old patient (total body weight 63 kg, LBM 44 kg) in whom atracurium was infused according to the profile in the first part of the study, along with the target plasma concentration of atracurium which was to be maintained after 30 min (dashed line). Lower graph: resulting muscle paralysis (% inhibition of T l / T c assessed by EMG).
4-1
I 32-
8 H
10
20
30
40
50
60
Time (min) FIG. 2. Mean plasma concentration of atracurium ( # ) and 95 % confidence intervals (vertical bars) for the 20 patients in whom atracurium was infused in the first pan of the study. The dashed line represents the target plasma concentration of l.Ongml" 1 which was to be maintained after 30min, after equilibrium between the plasma and biophase had occurred.
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5 8
paralysis 15-20 min after commencing the infusion, as shown by a mean absolute drift in muscle paralysis in the succeeding 40 min of 0.13 (0.07)% T l / T c min"1, with most of this drift occurring between 20 and 30 min (fig. 3). The plasma concentration became constant 30 min after starting the infusion, with a mean absolute drift of 0.51 (0.40)% min"1 between 30 and 60 min. Thus plasma samples taken 30 min after starting the infusion were assessed empirically as
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679
100-r
FIG. 3. Mean muscle paralysis as % inhibition of T l / T c assessed by EMG (thick line) with 95% confidence interval (fine lines) in the 20 patients in whom atracurium was infused in the first part of the study.
Target: 1.7mg litre' Bolus:2 mg
Target :1 9 mg litre' 1 Bolus: 1mg
100-1
E
*•=
1-
0J 10
20
30 40 Time (min)
50
60
70
FIG. 4. Upper graph: muscle paralysis as % inhibition of T l / T c assessed by EMG during estimation of C P M M of atracurium during propofol anaesthesia in a representative male patient. The initial target steady state plasma concentration of atracurium was 1.3 ug ml"1, which was changed to 1.5 ug ml"1 at 22 min and to 1.9 ug ml"1 at 35 min. Lower graph: plasma concentration of atracurium at 55, 60 and 65 min, when muscle paralysis was stable at 11% inhibition T l / T c . CP"te of atracurium during propofol anaesthesia was estimated to be 1.851 ug ml"1 in this patient.
in equilibrium with the biophase. The overall mean bias for these plasma samples was 8.0 (SEM 3.7) % (P < 0.05) and the overall mean absolute prediction error was 16.4 (SEM 2.5) % in achieving the target steady state plasma concentration. The method of estimation of CPra80 of atracurium, as used in the second part of the study, is illustrated in figure 4 for a representative patient. The infusion rate was adjusted twice until in-
hibition of T l / T c was stable at 88-92% for 20 min, with blood samples taken to measure the steady state plasma concentration of atracurium. The concentration was relatively constant during this sampling period in all patients, with less than the maximum allowable variation of 5%. The overall mean bias of these plasma samples from the target steady state plasma concentration being delivered by the infusion profile was —2.5
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30 Time (min)
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TABLE I I I . Individual estimates of the CP" w of atracurium during propofol anaesthesia, together with the individual arterial plasma concentrations of atracurium and the mean measured twitch depression during the sampling period Plasma arterial concn Gig ml"1)
No.
Sample 2
Sample 3
1
2
0.844 0.894 1.020 0.732 0.877 1.452 1.110 1.020 1.174 1.263
0.844 0.872 0.988 0.711 0.840 1.460 1.158 1.053 1.187 1.228
0.831 0.876 0.996 0.752 0.861 1.488 1.160 1.026 1.214 1.246
90 89 89 88 92 91 90 90 89 89
3 4 5 6 7 8 9 10
Mean (so)
°p to Gig ml"') 0.840 0.881 1.001 0.732 0.859 1.467 1.143 1.033 1.192 1.246 1.039 (0.224)
TABLE IV. Individual estimates of the CP" M of atracurium during thiopentone anaesthesia, together with the individual arterial plasma concentrations of atracurium and the mean measured twitch depression during the sampling period
Plasma arterial concn (ug ml"1) Sample 1
Sample 2
Sample 3
Twitch depression (% of control)
1.191 1.846 1.333 0.917 2.000 0.921 1.065 1.499 1.460 1.079
1.208 1.857 1.354 0.953 2.071 0.919 1.029 1.541 1.430 1.075
1.174 1.850 1.381 0.949 1.995 0.923 1.048 1.481 1.446 1.027
89 89 91 91 90 91 91 89 92 90
Patient
No. 1 2 3 4 5 6 7 8 9 10
Mean (so)
(SEM 5.6)% (ns), and the overall mean absolute prediction error was 24.1 (SEM 3.4)%. Measurements were completed within 60-90 min. The individual estimates of the CP"90 of atracurium in 10 patients during propofol, thiopentone and opioid anaesthesia are listed in tables III-V. The Cp^w of atracurium during propofol anaesthesia was 1.039 (0.224) ug ml"1, during thiopentone anaesthesia 1.334 (0.378) ug ml"1, and during fentanyl anaesthesia 0.915 (0.221) Ug ml"1 (fentanyl vs thiopentone, P < 0.05; others ns). The maintenance infusion rate of atracurium required to maintain 90% inhibition of T l / T c with propofol was 4.44 (0.78) ug kg"1 min"1, with thiopentone 5.62 (1.23) ug kg"1 min"1, and with opioid anaesthesia 3.86 (0.51) ug kg"1 min"1.
° P 80
(Ug ml"1) 1.191 1.851 1.356 0.940 :2.022 0.921 .047 .507 .445 .060 .334 (0.378)
DISCUSSION
Pharmacodynamic investigation of neuromuscular blocking drugs attempts to define the relationship between the concentration of the agent in the biophase and the degree of muscle paralysis. Unfortunately, the concentration of the drug in the biophase cannot be measured directly. The use of plasma concentration induces a distributional hysteresis because of delay in equilibrium between the biophase and plasma; this obscures the pharmacodynamic relationship [3]. The hysteresis can be corrected either by the development of a pharmacokinetic-dynamic model or by performing multiple steady state experiments. The complex technical requirements
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Sample 1
Twitch depression (% of control)
Patient
681
PHARMACODYNAMICS OF ATRACURIUM TABLE V. Individual estimates of the CH" Kof atracurium during fentanyl anaesthesia, together with the individual arterial plasma concentrations of atracurium and the mean measured twitch depression during the sampling period
Plasma arterial concn Gig ml-1) No.
Sample 2
Sample 3
1 2 3 4 5 6 7 8 9 10
0.900 0.903 0.700 1.215 1.283 0.981 0.734 1.019 0.835 0.555
0.930 0.864 0.750 1.190 1.290 0.970 0.709 1.050 0.838 0.542
0.942 0.928 0.730 1.202 1.255 1.002 0.726 1.004 0.844 0.555
90 90 90 89 90 88 90 90 88 91
Mean (SD)
of pharmacokinetic—dynamic models and their many inherent limitations [12] have restricted their usefulness. For steady state conditions to apply, measurements must be performed when the biophase and plasma are in equilibrium. At steady state the plasma concentration, although not equal to the biophase concentration, uniquely reflects it and may be used to estimate the pharmacodynamics of myoneural blockers [5]. In this study we have characterized the pharmacodynamics of atracurium at only one level of paralysis, by estimation of the Cp"^. This represents the steady state plasma concentration of the blocker which is desirable for surgical relaxation in normal patients [13]; 90% paralysis of adductor pollicis is considered optimal for intra-abdominal surgery [14]. A critical requirement for this method was that equilibrium between the plasma and biophase must have occurred at the time of estimation of CPraj0. A first order rate constant (k^) characterizes the rate at which the biophase equilibrates with the plasma. The half-time for equilibration between the plasma and biophase (7j*«>) has been estimated to be 4.7 min for tubocurarine [3], 3.3 min for pancuronium [4] and 4.8 min for fazadinium during nitrous oxide—opioid anaesthesia [4]. We have observed similar values for atracurium [unpublished observation]. Theoretically, the time required for equilibration between the plasma and biophase following a change in the plasma concentration of a neuromuscular blocker is approximately four times the 7j*«>, and hence is approximately 20 min for blocking drugs under nitrous oxide-opioid anaesthesia. We confirmed
W » Gig ml"1) 0.924 0.898 0.727 1.202 1.276 0.984 0.723 1.024 0.839 0.551 0.915 (0.221)
this estimation empirically in the first part of this study, where, in the presence of stable muscle paralysis for 20 min, and hence a constant biophase concentration, the arterial concentration became constant. Therefore, in the second part of the study, to ensure equilibrium between the biophase and plasma, CPMB0 was estimated only after the biophase concentration had remained constant for 20 min as indicated by stable muscle paralysis. In addition, a constant arterial concentration was assessed by serial estimation of plasma concentration of atracurium over the measurement interval. All patients were within the maximum allowable drift of 5 % in the plasma concentration of atracurium over the 10-min measurement interval which we considered compatible with equilibrium conditions. This criterion is quite strict, given that the HPLC assay has a coefficient of variation of approximately 4 %. The infusion profile developed for this study is a useful research tool as it facilitates study under steady state conditions. Equilibrium between the biophase and plasma occurred 30 min after commencing the infusion, compared with 80-100 min for a constant rate infusion of atracurium. This enabled estimation of the CPM90 within 60-90 min under relatively stable conditions before other factors which may modify the pharmacodynamics of neuromuscular blocking drugs occurred, such as hypothermia or fluid and electrolyte changes. The maintenance of a constant biophase concentration by the infusion profile resulted in adequate muscle paralysis after 5-10 min, compared with 15-25 min for an infusion profile which maintained a constant plasma concen-
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Sample 1
Twitch depression (% of control)
Patient
682
variability in response which occurs with neuromuscular blockers. In particular, this may explain the previous observation that the pharmacodynamics of such drugs are less variable during volatile anaesthesia than i.v. anaesthesia [3]. In that study, patients during i.v. anaesthesia received highly variable incremental doses of thiopentone [3]. In contrast with fentanyl and perhaps other i.v. agents, thiopentone appears to have a relatively antagonistic effect on the pharmacodynamics of neuromuscular blocking drugs, as suggested by the greater Cp10^ of atracurium. In conclusion, this study has utilized an infusion profile to estimate the CP**B0 of atracurium under various anaesthetic conditions. The technique enables the CPM,0 to be determined by a model-independent method and its simplicity allows large numbers of patients to be studied, in contrast to existing research techniques. Such data should permit the design of more accurate infusion regimens for neuromuscular blocking drugs. APPENDIX In this Appendix, we present the method used to develop the infusion profile used in this study. The profile was designed to maintain a constant biophase concentration of atracurium, as indicated by stable muscle paralysis, and a target steady state plasma concentration after equilibrium between the biophase and plasma had occurred. An iterative approach was used, whereby an initial arbitrary infusion profile was modified in successive groups of patients to produce an infusion profile with the desired characteristics. The initial arbitrary profile was infused to a small group of patients, with serial estimations of the plasma concentration of atracurium and continuous measurement of the degree of muscle paralysis. The profile was modified using two criteria. First, the shape of the profile was adjusted to maintain stable muscle paralysis. The loading dose was decreased to avoid 100% muscle paralysis, with the profile in turn adjusted to maintain the degree of paralysis achieved by the loading dose in that patient. The infusion rate was altered by assuming a linear relationship between the infusion rate and paralysis, and empirically allowing for the delay in equilibrium between the plasma and biophase by altering the infusion rate 5-10 min before the change in muscle paralysis occurred in the previous iteration. A new infusion profile was thus generated for each patient (/a(t)). A line of best fit was produced for the group to generate an interim profile (/ag(r)), empirically shaped to maintain stable paralysis. Second, the infusion profile was modified to achieve the target plasma concentration, when equilibrium had occurred between the biophase and plasma, using a modification of the plasma drug efflux method [9]. Equilibrium between the plasma and biophase was considered to have occurred when, in the presence of constant muscle paralysis, the plasma concentration of atracurium became constant. If equilibration could not be assessed empirically, equilibrium was considered to occur 30 min after starting the infusion [3, 4]. A dimen-
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tration. The overall simplicity of the method allows the CpM90 of a neuromuscular blocking drug to be estimated in large patient numbers. The accuracy of the infusion profile in maintaining a target steady state plasma concentration, after equilibrium between the biophase and plasma had occurred, appears to be comparable to advanced drug delivery systems which utilize a computer-controlled infusion pump [15-17]. This suggests that an infusion profile for a myoneural blocker may be useful also in routine clinical practice, by allowing more precise control of drug delivery. While the* profile developed for this study is not suitable, because of slow onset of muscle paralysis as the initial dose was limited to avoid marked overshoot in the desired degree of paralysis, a profile for clinical use could be developed readily using the method outlined in the Appendix. The positive bias of 8 % with this profile suggests that its accuracy could be improved by further iteration. Neuromuscular block in this study was measured by the EMG of the first dorsal interosseous muscle following supramaximal stimulation of the ulnar nerve at the wrist. This has been shown to be equivalent to the isometric recording of the mechanical response of adductor pollicis under nitrous oxide-opioid anaesthesia [18, 19]. Baseline drift of the EMG was minimized by not administering volatile anaesthetic agents, careful preparation and placement of recording electrodes 10 min before establishing the control reading (Tc), and by keeping the hand warm and immobile. Stability was confirmed further by allowing baseline to be stabilized for 3-5 min before onset of muscle paralysis [20]. The CPMM of atracurium estimated in this study appears to be comparable to that derived from complex pharmacokinetic-dynamic models. The estimated Cp88^ of atracurium during halothane anaesthesia was 1.09 ug ml"1 from a pharmacokinetic-dynamic model developed in eight patients [7], and 1.08 ug ml"1 during nitrous oxide-fentanyl anaesthesia from a study of four patients [8]. Our estimate of the CPM,0 under nitrous oxide-opioid anaesthesia is 0.92 ug ml"1. This is consistent with clinical observations that the pharmacodynamics of atracurium are similar during opioid and halothane anaesthesia [21, 22]. The statistically significant difference in the estimated Cp"^, found in this study during thiopentone and fentanyl anaesthesia has not been reported previously, but does explain some of the
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7. Weatherley BC, Williams SG, Neill EAM. Pharmacokinetics, pharmacodynamics and dose-response relationships of atracurium administered i.v. British Journal of Anaesthesia 1983; 55: 39S-^J6S. 8. Marathe PH, Dwersteg JF, Pavlin EG, Haschke RH, Heimbach DM, Slattery JT. Effect of thermal injury on the pharmacokinetics and pharmacodynamics of atracurium in humans. Anesthesiology 1989; 70: 752-755. where CPt = target steady state plasma concentration; Cpin, = the measured arterial concentration at the ith sampling point; 9. Crankshaw DP, Boyd MD, Bjorksten AR. Plasma Drug /, = corresponding infusion rate at that time; 7a, = infusion Efflux—A new approach to optimization of drug infusions rate at the corresponding time in the new profile developed for constant blood concentration of thiopental and methousing the first criterion in this patient. Individual values of Ft hexital. Anesthesiology 1987; 67: 32^11. were averaged to produce a mean scaling factor for the patient 10. James WPT. Research on Obesity. London: Her Majesty's and for the group (Fg). Fg was used to scale the entire Stationery Office, 1976. modified profile (7ag(r)), up or down as appropriate, to achieve 11. Maitre PO, Ausems ME, Vozeh S, Stanski DR. Evaluathe target plasma concentration without changing its shape. ting the accuracy of using population pharmacokinetic The new profile (7n(r)) was derived as follows: data to predict plasma concentrations of alfentanil. Anesthesiology 1988; 68: 59-67. = 7ag(r).Fg (2) 12. Hull CJ. Pharmacokinetics and clinical anaesthesia. Canadian Anaesthetists' Society Journal 1985; 32: S12-S15. This new profile was administered to a further group of patients as the next iteration, and the process repeated until a 13. Shanks CA. Design of therapeutic regimens. Clinics in Anaesthesiology 1985; 3: 283-291. profile with the desired characteristics was developed. Five iterations, in a total of 16 patients, were required to develop 14. Ali HH, Savarese JJ. Monitoring of neuromuscular the profile used in this study and presented in table I. function. Anesthesiology 1976; 45: 218-251. 15. Glass P, Jacobs JR, Hawkins ED, Ginsberg B, Quil TJ, Reves JG. Accuracy and efficacy of a pharmacokinctic ACKNOWLEDGEMENTS model-driven device to infuse fentanyl for anesthesia during surgery. Anesthesiology 1988; 69: A290. Supported in part by Faculty of Anaesthetists RACS Foundation Research Grant, Wellcome Australia Limited and the 16. Ausems ME, Vuyk J, Hug CC, Stanski DR. Comparison of computer-assisted infusion versus intermittent bolus National Health & Medical Research Council of Australia administration of alfentanil as a supplement to nitrous (Grant 870439). oxide for lower abdominal surgery. Anesthesiology 1988; 68: 851-861. REFERENCES 17. Shafer SL, Varvel JR, AzizN, Scott JC. The performance 1. Katz RL. Ncuromuscular effects of d-tubocurarine, of pharmacokinetic parameters derived from a computer cdrophonium and neostigmine in man. Anesthesiology controlled infusion pump. Anesthesiology 1988; 69: A460. 1967; 28: 327-336. 18. Kopman AF. The dose-effect relationship of metocurine: 2. Stanski DR, Sheiner LB. Pharmacokinetics and dynamics The integrated elcctromyogram of the first dorsal interof muscle relaxants. Anesthesiology 1979; 51: 103-105. osseous muscle and the mechanomyogram of the adductor 3. Stanski DR, Ham J, Miller RD, Sheiner LB. Pharmacopollicis compared. Anesthesiology 1988; 68: 604-607. kinetics and pharmacodynamics of d-tubocurarine during 19. Ali HH, DeCesare R. Evoked EMG, integrated EMG nitrous oxide—narcotic and halothane anesthesia in man. (IEMG) and mechanical responses. Anesthesiology 1989; Anesthesiology 1979; 51: 235-241. 71: A396. 4. Hull CJ, English MJM, Sibbald A. Fazadinium and 20. Meretoja OA, Brown TCK. Drift of the evoked thenar pancuronium: A pharmacodynamic study. British Journal EMG-signal. Anesthesiology 1989; 71: A825. of Anaesthesia 1980; 52: 1209-1220. 21. Rupp SM, McChristian JW, Miller RD. Atracurium 5. Hull CJ. Pharmacodynamics of non-depolarizing neuroneuromuscular blockade during halothane/N,0 and enmuscular blocking agents. British Journal of Anaesthesia flurane/N,O anesthesia in humans. Anesthesiology 1984; 1982; 54: 169-182. 61: A288. 6. Sheiner LB, Stanski DR, Vozeh S, Miller RD, Ham J. 22. Rupp SM, Fahey MR, Miller RD. Neuromuscular and Simultaneous modelling of pharmacokinetics and pharcardiovascular effects of atracurium during nitrous oxidemacodynamics: application to d-tubocurarinc. Clinical fentanyl and nitrous oxide—isoflurane anaesthesia. British Pharmacology and Therapeutics 1979; 25: 358-371. Journal of Anaesthesia 1983; 55: 67S-70S.
sionless scaling factor (F) was derived to modify the infusion profile developed using the first criterion. For each sampling point at equilibrium between the biophase and plasma, F, was calculated as follows:
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PHARMACODYNAMICS OF ATRACURIUM DURING PROPOFOL, THIOPENTONE AND OPIOID ANAESTHESIA G. H. BEEMER, A. R. BJORKSTEN AND D. P. CRANKSHAW SUMMARY
KEY WORDS Anaesthetics, intravenous: propofol, thiopentone. Anaesthetic techniques: infusion. Neuromuscular relaxants: atracurium. Pharmacodynamics: atracurium.
G. H. BEEMER, F.F.A.R.A.CS., Department of Anaesthesia, Post Office, The Royal Melbourne Hospital, Victoria 3050, Australia.
A. R. BJORKSTEN,
PH.D. ;
D. P. CHANWHAW,
F.F.A.R.A.CS., PH.D.; Department of Surgery (R.M.H.), University of Melbourne, Victoria, Australia. Accepted for Publication: May 23, 1990. Correspondence to G.H.B.
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We have assessed in 20 patients the accuracy and precision of an infusion profile for atracurium, which continually set the infusion rate to maintain stable muscle paralysis and a target steady state plasma concentration, when equilibrium between the biophase and plasma had occurred. Muscle paralysis was stable after 20 min, with a mean absolute drift in muscle paralysis in the succeeding 40 min of 0.13 (SD 0.07)% Tl/Tc (height of first twitch/height of control twitch) per min. The plasma samples after 30 min, which were assessed empirically as being in equilibrium with the biophase, had an overall mean bias of 8.0 (SEM 3.7) % (? < 0.05) and an overall mean absolute prediction error of 16.4 (SEM 2.5) % from the target steady state concentration being delivered by the infusion. The profile was then used to estimate the steady state plasma concentration of atracurium required to maintain 90% paralysis (Cp"^, by manually adjusting the delivered target concentration of the infusion until muscle paralysis was stable at 88-92% inhibition of Tl/Tc for 15-20 min, with three plasma samples taken over the next 10 min. Measurements were completed within 60-90 min. The mean Cp"x of atracurium with propofol was 1.039 (so 0.224) fig ml~' (n = 10), with thiopentone 1.334 (0.378) fig mf~' (n = 10), and with opioidanaesthesia 0.915 (0.221) ng ml-' (n=10). These differences in the Cpt>90 explain some of the variability in response which occurs with neuromuscular blocking drugs. The technique enables the CP"90 of a myoneural blocker to be determined by a simple model-independent method.
The magnitude and duration of muscle paralysis following administration of a given dose of a competitive neuromuscular blocking drug in an individual patient is unpredictable. Katz found that tubocurarine 0.1 mg kg"1 caused no block in 6%, and 100% block in 7% of patients [1]. This variability in response is probably the chief contributing factor in anaesthetic morbidity and mortality associated with neuromuscular blocking drugs. Pharmacokinetic and pharmacodynamic studies allow the identification of the sources of this variability, enabling the anaesthetist better to anticipate patient responses, and thus reduce the likelihood of excessive paralysis and residual curarization [2]. Accurate estimation of the pharmacodynamics of myoneural blockers, in particular, is difficult with current research techniques. Combined pharmacokinetic-dynamic models have been developed to make allowance for the temporal disequilibrium between the plasma and the biophase (neuromuscular effector site), to enable pharmacodynamics to be studied under nonsteady state conditions [3-8]. The technical difficulties associated with these methods have resulted in a limited number of patients having been studied, with only two pharmacokineticdynamic models for normal patients, based on a study of eight patients and four patients, developed for atracurium [7, 8]. The aim of this study was to develop a simple alternative technique to characterize the pharmacodynamics of a neuromuscular blocker by estimating the effective steady state plasma concentration for 90% paralysis (CP"00) using an
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infusion regimen to maintain constant muscle paralysis. The method was utilized to determine the Cp"^ of atracurium during propofol, thiopentone and opioid anaesthesia. PATENTS AND METHODS
TABLE I. The infusion profile used in this study. The profile was adjusted to achieve a target plasma concentration of atracurium, after equilibrium between the biophase and plasma had occurred, of 1.0 fig ml'1 in a "patient" of 1 kg lean body mass (LBM) Time (min) 0-1 1-2 2-3 3-4 4-5 5-6 6-7 7-8 8-9 £-10 10-11 11-12 12-13 13-14 14-15 15-16 16-17 17-18 18-19 19-20 20-21
Infusion profile (^g min"1 kgLBM-1) 200 8.68 8.68 8.68 8.68 8.68 8.68 8.41 8.15 7.88 7.83 7.78 7.72 7.67 7.62 7.62 7.62 7.62 7.62 7.62 7.52
Time (min)
Infusion profile (ng min-1 kgLBM-1)
21-22 22-23 23-24 24-25 25-26 26-27 27-28 28-29 29-30 30-31 31-32 32-33 33-34 34-35 35-36 36-37 37-38 38-39 39-40 40-oo
7.40 7.30 7.20 7.10 7.00 6.88 6.78 6.68 6.58 6.47 6.35 6.23 6.12 6.02 5.90 5.78 5.67 5.55 5.43 5.43
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Fifty adult patients undergoing major surgery gave informed consent to participate in the study, which was approved by the Hospital Board of Medical Research. Routine preoperative biochemical tests were used to exclude patients with evidence of hepatic or renal dysfunction. The electromyogram (EMG) of the first dorsal interosseous muscle to supramaximal stimulation of the ulnar nerve was measured and recorded with a Datex Relaxograph. The test hand was immobilized with no resting tension and wrapped in a towel with Medi-trace pellet electrodes placed 10-15 min before induction of anaesthesia. After anaesthesia was induced and before atracurium was administered, control twitch height (Tc) and a train-of-four fade ratio (T4:T1) were established. Subsequently, a train-of-four stimulation was delivered every 12 s with the single twitch inhibition (Tl/Tc) and T4:T1 recorded. Baseline
was stabilized for 3-5 min, with T l / T c and T4:T1 at 100% before the onset of muscle paralysis. A specially built syringe pump capable of reading successive memory locations, containing the infusion rate data, at specific times and adjusting the infusion rate according to patient size and the target plasma concentration, was used to infuse atracurium [9]. Atracurium was infused according to a profile defined in table I, which continually set the infusion rate to maintain a constant biophase concentration, as assessed by stable muscle paralysis. When equilibrium had occurred between the biophase and plasma, a target steady state plasma concentration was maintained thereafter by the infusion. The technique used to develop the profile is briefly outlined in the Appendix, and is based on a modification of the plasma drug efflux method [9]. The infusion rate was adjusted for by patient lean body mass (LBM), estimation of which, for each patient, was based on the method of James [10]. The precise infusion rate delivered to an individual patient for a specific time interval (Q,) is the rate defined in the profile for that interval adjusted for patient LBM and the target
PHARMACODYNAMICS OF ATRACURIUM steady state concentration of atracurium (CPt) and is given by: Qi = QPiCpt.LBM. (1)
Anaesthesia was maintained with 70% nitrous oxide in oxygen and continuous infusion of pro-
TABLE II. Patient characteristics (mean (SD)). LBM = lean
body mass Age
Sex
Study
n
(yr)
(M/F)
Weight (kg)
LBM (kg)
Pan 1 Part 2 Propofol Thiopentone Opioid
20
56 (13)
11/9
69(13)
50(8)
10 10 10
62(11) 49 (12) 54(10)
7/3 6/4 6/4
68(20) 76(22) 76(8)
51(11) 52(11) 58(5)
pofol (maintenance infusion rate 0.05-0.15 mg kg"1 min"1), continuous infusion of thiopentone (to maintain an arterial plasma concentration of thiopentone 10 ug ml"1 [9], maintenance infusion rate 55-95 ug kg"1 min"1), or incremental doses of fentanyl 5-10 ug kg"1 (total dose 30-50 |ig kg"1 within the first 60 min). Plasma concentrations of atracurium were measured by a high pressure liquid chromatography (HPLC) technique. The assay was sensitive to 0.03 ug ml"1 of plasma atracurium and was linear over the range of the standard curve (0.05—10 ug ml"1 in plasma) with a coefficient of variation of 4.1 % at 0.06 ug ml"1. Data atialysis
The accuracy and precision of the profile in achieving the target steady state plasma concentration of atracurium was assessed by the bias and mean absolute prediction error. These were calculated from the prediction error (PE, as a percentage) using the method described by Maitre and colleagues [11]. The prediction error was modified as follows: CPt
(2)
where Cpm was the measured arterial concentration. Student's t test was used to assess if the mean bias estimates for the group differed from zero. Student's t test with Bonferroni correction for multiple comparisons was used to assess the significance of the effect of anaesthetic agents on the CP°00 of atracurium. P < 0.05 was considered significant. Data are presented as mean (SD) unless stated otherwise. RESULTS
Patient data are presented in table II. Figure 1 shows the results of the infusion of atracurium according to the infusion profile in a represen-
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In the first part of the study, the accuracy of the profile in maintaining both stable muscle paralysis and the target plasma concentration was assessed in 20 patients. Anaesthesia was induced with thiopentone 1-4 mg kg"1 and fentanyl 5-20 ug kg"1 and maintained with 70 % nitrous oxide and incremental doses of fentanyl. Atracurium was infused for 1 h according to a profile to maintain stable muscle paralysis and a target steady state plasma concentration of 1.0 ug ml"1 when equilibrium between the biophase and plasma had occurred. Arterial blood samples were obtained at 0, 2, 4, 7, 10, 15, 20, 30, 40, 50 and 60 min. The patients received other adjuvants, including diazepam and droperidol, but excluding volatile anaesthetic agents, on the basis of clinical signs and in accordance with current practice. Ventilation was controlled throughout the study to maintain PaCOt in the range 4.7-5.3 kPa. Nasopharyngeal temperature was kept at 35.5-37 °C. In the second part of the study, the C P " M of atracurium was assessed during propofol, thiopentone and fentanyl anaesthesia with 10 patients in each group. Atracurium was infused initially according to the profile to achieve a target steady state plasma concentration of 1.0-1.5 ug ml"1 when equilibrium between the biophase and plasma had occurred. Following the onset of stable muscle paralysis, within 15-20 min of commencing the infusion, the target steady state plasma concentration delivered by the infusion was adjusted to maintain 90% inhibition of T l / T c , within a range of 88-92 %. If the paralysis was less than 90%, the patient was administered a small bolus of atracurium (1-3 mg) and the target concentration increased. If the paralysis was greater than 90%, the infusion was stopped and was recommenced at a lesser concentration when T l / T c inhibition was 95%. This process was repeated until inhibition of T l / T c was stable at 88-92% for 15-20 min. Three arterial blood samples were obtained at 5-min intervals, with the first sample being a minimum of 20 min after the final alteration of the infusion rate. Variation in the plasma concentration of atracurium of less than 5% confirmed steady state conditions for estimation of CPMW.
677
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tative patient from the first part of the study. The mean plasma concentration of atracurium with 95% confidence limits in the 20 patients is illustrated in figure 2. Figure 3 shows the resultant muscle paralysis with 95% confidence intervals. The mean muscle paralysis in the 20 patients at 60 min was 11.5 % T l / T c , 95 % of patients falling within the range 3-20%. The infusion profile maintained a relatively constant biophase concentration following onset of maximum muscle
ii
21-
O-i
50-
100-" 10
20
30
40
50
60
Time (mm) FIG. 1. Upper graph: measured plasma concentrations of atracurium in a 67-yr-old patient (total body weight 63 kg, LBM 44 kg) in whom atracurium was infused according to the profile in the first part of the study, along with the target plasma concentration of atracurium which was to be maintained after 30 min (dashed line). Lower graph: resulting muscle paralysis (% inhibition of T l / T c assessed by EMG).
4-1
I 32-
8 H
10
20
30
40
50
60
Time (min) FIG. 2. Mean plasma concentration of atracurium ( # ) and 95 % confidence intervals (vertical bars) for the 20 patients in whom atracurium was infused in the first pan of the study. The dashed line represents the target plasma concentration of l.Ongml" 1 which was to be maintained after 30min, after equilibrium between the plasma and biophase had occurred.
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5 8
paralysis 15-20 min after commencing the infusion, as shown by a mean absolute drift in muscle paralysis in the succeeding 40 min of 0.13 (0.07)% T l / T c min"1, with most of this drift occurring between 20 and 30 min (fig. 3). The plasma concentration became constant 30 min after starting the infusion, with a mean absolute drift of 0.51 (0.40)% min"1 between 30 and 60 min. Thus plasma samples taken 30 min after starting the infusion were assessed empirically as
PHARMACODYNAMICS OF ATRACURIUM
679
100-r
FIG. 3. Mean muscle paralysis as % inhibition of T l / T c assessed by EMG (thick line) with 95% confidence interval (fine lines) in the 20 patients in whom atracurium was infused in the first part of the study.
Target: 1.7mg litre' Bolus:2 mg
Target :1 9 mg litre' 1 Bolus: 1mg
100-1
E
*•=
1-
0J 10
20
30 40 Time (min)
50
60
70
FIG. 4. Upper graph: muscle paralysis as % inhibition of T l / T c assessed by EMG during estimation of C P M M of atracurium during propofol anaesthesia in a representative male patient. The initial target steady state plasma concentration of atracurium was 1.3 ug ml"1, which was changed to 1.5 ug ml"1 at 22 min and to 1.9 ug ml"1 at 35 min. Lower graph: plasma concentration of atracurium at 55, 60 and 65 min, when muscle paralysis was stable at 11% inhibition T l / T c . CP"te of atracurium during propofol anaesthesia was estimated to be 1.851 ug ml"1 in this patient.
in equilibrium with the biophase. The overall mean bias for these plasma samples was 8.0 (SEM 3.7) % (P < 0.05) and the overall mean absolute prediction error was 16.4 (SEM 2.5) % in achieving the target steady state plasma concentration. The method of estimation of CPra80 of atracurium, as used in the second part of the study, is illustrated in figure 4 for a representative patient. The infusion rate was adjusted twice until in-
hibition of T l / T c was stable at 88-92% for 20 min, with blood samples taken to measure the steady state plasma concentration of atracurium. The concentration was relatively constant during this sampling period in all patients, with less than the maximum allowable variation of 5%. The overall mean bias of these plasma samples from the target steady state plasma concentration being delivered by the infusion profile was —2.5
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30 Time (min)
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TABLE I I I . Individual estimates of the CP" w of atracurium during propofol anaesthesia, together with the individual arterial plasma concentrations of atracurium and the mean measured twitch depression during the sampling period Plasma arterial concn Gig ml"1)
No.
Sample 2
Sample 3
1
2
0.844 0.894 1.020 0.732 0.877 1.452 1.110 1.020 1.174 1.263
0.844 0.872 0.988 0.711 0.840 1.460 1.158 1.053 1.187 1.228
0.831 0.876 0.996 0.752 0.861 1.488 1.160 1.026 1.214 1.246
90 89 89 88 92 91 90 90 89 89
3 4 5 6 7 8 9 10
Mean (so)
°p to Gig ml"') 0.840 0.881 1.001 0.732 0.859 1.467 1.143 1.033 1.192 1.246 1.039 (0.224)
TABLE IV. Individual estimates of the CP" M of atracurium during thiopentone anaesthesia, together with the individual arterial plasma concentrations of atracurium and the mean measured twitch depression during the sampling period
Plasma arterial concn (ug ml"1) Sample 1
Sample 2
Sample 3
Twitch depression (% of control)
1.191 1.846 1.333 0.917 2.000 0.921 1.065 1.499 1.460 1.079
1.208 1.857 1.354 0.953 2.071 0.919 1.029 1.541 1.430 1.075
1.174 1.850 1.381 0.949 1.995 0.923 1.048 1.481 1.446 1.027
89 89 91 91 90 91 91 89 92 90
Patient
No. 1 2 3 4 5 6 7 8 9 10
Mean (so)
(SEM 5.6)% (ns), and the overall mean absolute prediction error was 24.1 (SEM 3.4)%. Measurements were completed within 60-90 min. The individual estimates of the CP"90 of atracurium in 10 patients during propofol, thiopentone and opioid anaesthesia are listed in tables III-V. The Cp^w of atracurium during propofol anaesthesia was 1.039 (0.224) ug ml"1, during thiopentone anaesthesia 1.334 (0.378) ug ml"1, and during fentanyl anaesthesia 0.915 (0.221) Ug ml"1 (fentanyl vs thiopentone, P < 0.05; others ns). The maintenance infusion rate of atracurium required to maintain 90% inhibition of T l / T c with propofol was 4.44 (0.78) ug kg"1 min"1, with thiopentone 5.62 (1.23) ug kg"1 min"1, and with opioid anaesthesia 3.86 (0.51) ug kg"1 min"1.
° P 80
(Ug ml"1) 1.191 1.851 1.356 0.940 :2.022 0.921 .047 .507 .445 .060 .334 (0.378)
DISCUSSION
Pharmacodynamic investigation of neuromuscular blocking drugs attempts to define the relationship between the concentration of the agent in the biophase and the degree of muscle paralysis. Unfortunately, the concentration of the drug in the biophase cannot be measured directly. The use of plasma concentration induces a distributional hysteresis because of delay in equilibrium between the biophase and plasma; this obscures the pharmacodynamic relationship [3]. The hysteresis can be corrected either by the development of a pharmacokinetic-dynamic model or by performing multiple steady state experiments. The complex technical requirements
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Sample 1
Twitch depression (% of control)
Patient
681
PHARMACODYNAMICS OF ATRACURIUM TABLE V. Individual estimates of the CH" Kof atracurium during fentanyl anaesthesia, together with the individual arterial plasma concentrations of atracurium and the mean measured twitch depression during the sampling period
Plasma arterial concn Gig ml-1) No.
Sample 2
Sample 3
1 2 3 4 5 6 7 8 9 10
0.900 0.903 0.700 1.215 1.283 0.981 0.734 1.019 0.835 0.555
0.930 0.864 0.750 1.190 1.290 0.970 0.709 1.050 0.838 0.542
0.942 0.928 0.730 1.202 1.255 1.002 0.726 1.004 0.844 0.555
90 90 90 89 90 88 90 90 88 91
Mean (SD)
of pharmacokinetic—dynamic models and their many inherent limitations [12] have restricted their usefulness. For steady state conditions to apply, measurements must be performed when the biophase and plasma are in equilibrium. At steady state the plasma concentration, although not equal to the biophase concentration, uniquely reflects it and may be used to estimate the pharmacodynamics of myoneural blockers [5]. In this study we have characterized the pharmacodynamics of atracurium at only one level of paralysis, by estimation of the Cp"^. This represents the steady state plasma concentration of the blocker which is desirable for surgical relaxation in normal patients [13]; 90% paralysis of adductor pollicis is considered optimal for intra-abdominal surgery [14]. A critical requirement for this method was that equilibrium between the plasma and biophase must have occurred at the time of estimation of CPraj0. A first order rate constant (k^) characterizes the rate at which the biophase equilibrates with the plasma. The half-time for equilibration between the plasma and biophase (7j*«>) has been estimated to be 4.7 min for tubocurarine [3], 3.3 min for pancuronium [4] and 4.8 min for fazadinium during nitrous oxide—opioid anaesthesia [4]. We have observed similar values for atracurium [unpublished observation]. Theoretically, the time required for equilibration between the plasma and biophase following a change in the plasma concentration of a neuromuscular blocker is approximately four times the 7j*«>, and hence is approximately 20 min for blocking drugs under nitrous oxide-opioid anaesthesia. We confirmed
W » Gig ml"1) 0.924 0.898 0.727 1.202 1.276 0.984 0.723 1.024 0.839 0.551 0.915 (0.221)
this estimation empirically in the first part of this study, where, in the presence of stable muscle paralysis for 20 min, and hence a constant biophase concentration, the arterial concentration became constant. Therefore, in the second part of the study, to ensure equilibrium between the biophase and plasma, CPMB0 was estimated only after the biophase concentration had remained constant for 20 min as indicated by stable muscle paralysis. In addition, a constant arterial concentration was assessed by serial estimation of plasma concentration of atracurium over the measurement interval. All patients were within the maximum allowable drift of 5 % in the plasma concentration of atracurium over the 10-min measurement interval which we considered compatible with equilibrium conditions. This criterion is quite strict, given that the HPLC assay has a coefficient of variation of approximately 4 %. The infusion profile developed for this study is a useful research tool as it facilitates study under steady state conditions. Equilibrium between the biophase and plasma occurred 30 min after commencing the infusion, compared with 80-100 min for a constant rate infusion of atracurium. This enabled estimation of the CPM90 within 60-90 min under relatively stable conditions before other factors which may modify the pharmacodynamics of neuromuscular blocking drugs occurred, such as hypothermia or fluid and electrolyte changes. The maintenance of a constant biophase concentration by the infusion profile resulted in adequate muscle paralysis after 5-10 min, compared with 15-25 min for an infusion profile which maintained a constant plasma concen-
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Sample 1
Twitch depression (% of control)
Patient
682
variability in response which occurs with neuromuscular blockers. In particular, this may explain the previous observation that the pharmacodynamics of such drugs are less variable during volatile anaesthesia than i.v. anaesthesia [3]. In that study, patients during i.v. anaesthesia received highly variable incremental doses of thiopentone [3]. In contrast with fentanyl and perhaps other i.v. agents, thiopentone appears to have a relatively antagonistic effect on the pharmacodynamics of neuromuscular blocking drugs, as suggested by the greater Cp10^ of atracurium. In conclusion, this study has utilized an infusion profile to estimate the CP**B0 of atracurium under various anaesthetic conditions. The technique enables the CPM,0 to be determined by a model-independent method and its simplicity allows large numbers of patients to be studied, in contrast to existing research techniques. Such data should permit the design of more accurate infusion regimens for neuromuscular blocking drugs. APPENDIX In this Appendix, we present the method used to develop the infusion profile used in this study. The profile was designed to maintain a constant biophase concentration of atracurium, as indicated by stable muscle paralysis, and a target steady state plasma concentration after equilibrium between the biophase and plasma had occurred. An iterative approach was used, whereby an initial arbitrary infusion profile was modified in successive groups of patients to produce an infusion profile with the desired characteristics. The initial arbitrary profile was infused to a small group of patients, with serial estimations of the plasma concentration of atracurium and continuous measurement of the degree of muscle paralysis. The profile was modified using two criteria. First, the shape of the profile was adjusted to maintain stable muscle paralysis. The loading dose was decreased to avoid 100% muscle paralysis, with the profile in turn adjusted to maintain the degree of paralysis achieved by the loading dose in that patient. The infusion rate was altered by assuming a linear relationship between the infusion rate and paralysis, and empirically allowing for the delay in equilibrium between the plasma and biophase by altering the infusion rate 5-10 min before the change in muscle paralysis occurred in the previous iteration. A new infusion profile was thus generated for each patient (/a(t)). A line of best fit was produced for the group to generate an interim profile (/ag(r)), empirically shaped to maintain stable paralysis. Second, the infusion profile was modified to achieve the target plasma concentration, when equilibrium had occurred between the biophase and plasma, using a modification of the plasma drug efflux method [9]. Equilibrium between the plasma and biophase was considered to have occurred when, in the presence of constant muscle paralysis, the plasma concentration of atracurium became constant. If equilibration could not be assessed empirically, equilibrium was considered to occur 30 min after starting the infusion [3, 4]. A dimen-
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tration. The overall simplicity of the method allows the CpM90 of a neuromuscular blocking drug to be estimated in large patient numbers. The accuracy of the infusion profile in maintaining a target steady state plasma concentration, after equilibrium between the biophase and plasma had occurred, appears to be comparable to advanced drug delivery systems which utilize a computer-controlled infusion pump [15-17]. This suggests that an infusion profile for a myoneural blocker may be useful also in routine clinical practice, by allowing more precise control of drug delivery. While the* profile developed for this study is not suitable, because of slow onset of muscle paralysis as the initial dose was limited to avoid marked overshoot in the desired degree of paralysis, a profile for clinical use could be developed readily using the method outlined in the Appendix. The positive bias of 8 % with this profile suggests that its accuracy could be improved by further iteration. Neuromuscular block in this study was measured by the EMG of the first dorsal interosseous muscle following supramaximal stimulation of the ulnar nerve at the wrist. This has been shown to be equivalent to the isometric recording of the mechanical response of adductor pollicis under nitrous oxide-opioid anaesthesia [18, 19]. Baseline drift of the EMG was minimized by not administering volatile anaesthetic agents, careful preparation and placement of recording electrodes 10 min before establishing the control reading (Tc), and by keeping the hand warm and immobile. Stability was confirmed further by allowing baseline to be stabilized for 3-5 min before onset of muscle paralysis [20]. The CPMM of atracurium estimated in this study appears to be comparable to that derived from complex pharmacokinetic-dynamic models. The estimated Cp88^ of atracurium during halothane anaesthesia was 1.09 ug ml"1 from a pharmacokinetic-dynamic model developed in eight patients [7], and 1.08 ug ml"1 during nitrous oxide-fentanyl anaesthesia from a study of four patients [8]. Our estimate of the CPM,0 under nitrous oxide-opioid anaesthesia is 0.92 ug ml"1. This is consistent with clinical observations that the pharmacodynamics of atracurium are similar during opioid and halothane anaesthesia [21, 22]. The statistically significant difference in the estimated Cp"^, found in this study during thiopentone and fentanyl anaesthesia has not been reported previously, but does explain some of the
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7. Weatherley BC, Williams SG, Neill EAM. Pharmacokinetics, pharmacodynamics and dose-response relationships of atracurium administered i.v. British Journal of Anaesthesia 1983; 55: 39S-^J6S. 8. Marathe PH, Dwersteg JF, Pavlin EG, Haschke RH, Heimbach DM, Slattery JT. Effect of thermal injury on the pharmacokinetics and pharmacodynamics of atracurium in humans. Anesthesiology 1989; 70: 752-755. where CPt = target steady state plasma concentration; Cpin, = the measured arterial concentration at the ith sampling point; 9. Crankshaw DP, Boyd MD, Bjorksten AR. Plasma Drug /, = corresponding infusion rate at that time; 7a, = infusion Efflux—A new approach to optimization of drug infusions rate at the corresponding time in the new profile developed for constant blood concentration of thiopental and methousing the first criterion in this patient. Individual values of Ft hexital. Anesthesiology 1987; 67: 32^11. were averaged to produce a mean scaling factor for the patient 10. James WPT. Research on Obesity. London: Her Majesty's and for the group (Fg). Fg was used to scale the entire Stationery Office, 1976. modified profile (7ag(r)), up or down as appropriate, to achieve 11. Maitre PO, Ausems ME, Vozeh S, Stanski DR. Evaluathe target plasma concentration without changing its shape. ting the accuracy of using population pharmacokinetic The new profile (7n(r)) was derived as follows: data to predict plasma concentrations of alfentanil. Anesthesiology 1988; 68: 59-67. = 7ag(r).Fg (2) 12. Hull CJ. Pharmacokinetics and clinical anaesthesia. Canadian Anaesthetists' Society Journal 1985; 32: S12-S15. This new profile was administered to a further group of patients as the next iteration, and the process repeated until a 13. Shanks CA. Design of therapeutic regimens. Clinics in Anaesthesiology 1985; 3: 283-291. profile with the desired characteristics was developed. Five iterations, in a total of 16 patients, were required to develop 14. Ali HH, Savarese JJ. Monitoring of neuromuscular the profile used in this study and presented in table I. function. Anesthesiology 1976; 45: 218-251. 15. Glass P, Jacobs JR, Hawkins ED, Ginsberg B, Quil TJ, Reves JG. Accuracy and efficacy of a pharmacokinctic ACKNOWLEDGEMENTS model-driven device to infuse fentanyl for anesthesia during surgery. Anesthesiology 1988; 69: A290. Supported in part by Faculty of Anaesthetists RACS Foundation Research Grant, Wellcome Australia Limited and the 16. Ausems ME, Vuyk J, Hug CC, Stanski DR. Comparison of computer-assisted infusion versus intermittent bolus National Health & Medical Research Council of Australia administration of alfentanil as a supplement to nitrous (Grant 870439). oxide for lower abdominal surgery. Anesthesiology 1988; 68: 851-861. REFERENCES 17. Shafer SL, Varvel JR, AzizN, Scott JC. The performance 1. Katz RL. Ncuromuscular effects of d-tubocurarine, of pharmacokinetic parameters derived from a computer cdrophonium and neostigmine in man. Anesthesiology controlled infusion pump. Anesthesiology 1988; 69: A460. 1967; 28: 327-336. 18. Kopman AF. The dose-effect relationship of metocurine: 2. Stanski DR, Sheiner LB. Pharmacokinetics and dynamics The integrated elcctromyogram of the first dorsal interof muscle relaxants. Anesthesiology 1979; 51: 103-105. osseous muscle and the mechanomyogram of the adductor 3. Stanski DR, Ham J, Miller RD, Sheiner LB. Pharmacopollicis compared. Anesthesiology 1988; 68: 604-607. kinetics and pharmacodynamics of d-tubocurarine during 19. Ali HH, DeCesare R. Evoked EMG, integrated EMG nitrous oxide—narcotic and halothane anesthesia in man. (IEMG) and mechanical responses. Anesthesiology 1989; Anesthesiology 1979; 51: 235-241. 71: A396. 4. Hull CJ, English MJM, Sibbald A. Fazadinium and 20. Meretoja OA, Brown TCK. Drift of the evoked thenar pancuronium: A pharmacodynamic study. British Journal EMG-signal. Anesthesiology 1989; 71: A825. of Anaesthesia 1980; 52: 1209-1220. 21. Rupp SM, McChristian JW, Miller RD. Atracurium 5. Hull CJ. Pharmacodynamics of non-depolarizing neuroneuromuscular blockade during halothane/N,0 and enmuscular blocking agents. British Journal of Anaesthesia flurane/N,O anesthesia in humans. Anesthesiology 1984; 1982; 54: 169-182. 61: A288. 6. Sheiner LB, Stanski DR, Vozeh S, Miller RD, Ham J. 22. Rupp SM, Fahey MR, Miller RD. Neuromuscular and Simultaneous modelling of pharmacokinetics and pharcardiovascular effects of atracurium during nitrous oxidemacodynamics: application to d-tubocurarinc. Clinical fentanyl and nitrous oxide—isoflurane anaesthesia. British Pharmacology and Therapeutics 1979; 25: 358-371. Journal of Anaesthesia 1983; 55: 67S-70S.
sionless scaling factor (F) was derived to modify the infusion profile developed using the first criterion. For each sampling point at equilibrium between the biophase and plasma, F, was calculated as follows:
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