BJA Advance Access originally published online on July 27, 2006
British Journal of Anaesthesia 2006 97(4):482-488; doi:10.1093/bja/ael207
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Influence of acute normovolaemic haemodilution on the dose–response relationship, time-course of action and pharmacokinetics of rocuronium bromide
1 Department of Anaesthesiology and Intensive Care Medicine, Graz Medical University Graz, Austria.
2 Department of Anesthesiology, Critical Care Medicine, Pain Management and Hyperbaric Medicine Englewood Hospital and Medical Center, Englewood, NJ, USA
3 Institute of Medical Chemistry and Pregl Laboratory Graz Medical University, Graz, Austria
*Corresponding author. E-mail: ashraf.dahaba{at}meduni-graz.at
Accepted for publication June 7, 2006.
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Abstract |
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Background. Acute normovolaemic haemodilution (ANH) is an effective strategy for avoiding or reducing allogeneic blood transfusion. We aimed to study its effect on the pharmacological profile of rocuronium.
Methods. In two study centres, 28 patients undergoing major surgery with ANH were matched with 28 control patients. In the dose–response groups, using the mechanomyograph, neuromuscular block of six consecutive incremental doses of rocuronium 50 µg kg–1, followed by 300 µg kg–1, was evaluated. In the pharmacokinetics groups, serial arterial blood samples were withdrawn for rocuronium assay after a single dose of rocuronium 600 µg kg–1.
Results. ANH resulted in a shift to the left of rocuronium dose–response curve. Rocuronium effective dose95 (ED95) was 26% lower (P<0.05) in the ANH group [283.4 (92.0) µg kg–1] compared with the control group [383.5 (127.3) µg kg–1]. Times from administration of last incremental dose until 25% of first response of train-of-four (TOF) recovery (Dur25) and 0.8 TOF ratio recovery (Dur0.8) were 28% longer in the ANH group [39.9 (8.4), 66.7 (14.2) min] compared with the control group [31.1 (6.6), 52.1 (15.8) min] (P<0.01, P<0.05), respectively. Volume of distribution was higher (P<0.01), central clearance was lower (P<0.05) and terminal elimination half-life was longer (P<0.0001) in the ANH group [234.97 (47.11) ml kg–1, 4.70 (0.94) ml kg–1 min–1, 77.29 (12.25) min] compared with the control group [181.22 (35.73) ml kg–1, 5.71 (1.29) ml kg–1 min–1, 56.86 (10.05) min, respectively].
Conclusion. ANH resulted in prolongation of rocuronium time-course of action, thus careful monitoring of neuromuscular block is recommended in patients who undergo ANH.
Keywords: complications, acute normovolaemic haemodilution; neuromuscular block, rocuronium
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Introduction |
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TopAbstractIntroductionPatients and methodsResultsDiscussionReferences |
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Blood conservation techniques aiming at avoiding or reducing allogeneic blood transfusion during major surgery include preoperative autologous blood donation, intraoperative cell salvage and acute normovolaemic haemodilution (ANH). ANH autologous blood procurement technique, recommended by the National Institute of Health Consensus Conference,1 is a cost-effective2 and effective blood conservation strategy in procedures with expected blood loss of more than 1 litre.3 With ANH the amount of red blood cells and other plasma constituents lost during surgical bleeding are reduced through preoperative dilution of the circulating blood volume. However, ANH is associated with considerable haemodynamic and blood chemistry changes that might alter the pharmacokinetics and pharmacodynamics of neuromuscular blocking drugs. Schuh4 demonstrated that ANH significantly increased the potency of succinylcholine, pancuronium and tubocurarine. Whereas Xue and colleagues5 demonstrated alterations of the pharmacokinetics of vecuronium and prolongation in the time-course of action of atracurium6 with ANH.
Rocuronium bromide, a monoquaternary aminosteroid with a short onset and an intermediate duration of action,7 is currently one of the most commonly used neuromuscular blocking drugs. The aim of our study was to compare dose–response relationship, time-course of action and pharmacokinetic variables of rocuronium in patients who underwent ANH to the matched control patients.
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Patients and methods |
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A prospective controlled study was carried out in two centres. Both centres adhered to the guidelines of ‘Good clinical research practice (GCRP) in pharmacodynamic studies of neuromuscular blocking agents’8 and the ‘Consolidated standards of reporting trials (CONSORT)-statement’.9
After approvals from Englewood Medical Center institutional review board and Graz Medical University ethics committee, a written informed consent was obtained from all patients who agreed to participate in the study. Potential participants with a history of neuromuscular disease, small joint arthritis, with haemoglobin (Hb) <12 g dl–1, body mass index <20 or >26 kg m–2,10 or patients on treatment with drugs thought to interfere with neuromuscular transmission were excluded from the study.
Figure 1 illustrates the design and flow of the study. Twenty-eight consecutive, ASA I–III patients undergoing radical cystectomy, radical hysterectomy or retropubic radical prostatectomy with ANH were recruited in the two study centres: 14 patients for the dose–response relationship part of the study in Englewood Medical Center and 14 patients for the pharmacokinetics part of the study in Graz Medical University. In the two centres, each recruited ANH patient was matched for gender, ASA classification, approximate age and approximate body weight with a control patient undergoing major elective abdominal surgical procedures without ANH.
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Oral midazolam 3.75–7.5 mg was the only premedication given 1 h before surgery. Anaesthesia was induced with fentanyl 1.5 µg kg–1 and propofol 2–3 mg kg–1. Lungs were ventilated using a facemask, and after topical spray of larynx using lidocaine 2% and when anaesthesia was considered deep enough, the trachea was intubated without using neuromuscular blocking drugs. Anaesthesia was maintained with propofol 100–150 µg kg–1 min–1 and remifentanil 0.1–0.3 µg kg–1 min–1 infusions. The lungs were ventilated mechanically with 40% oxygen in air and adjusted to maintain end-tidal carbon dioxide between 4.5–5.5 kPa. Patients were warmed using a forced hot air blanket to maintain core temperature >36°C and skin temperature >32°C.
In the two dose–response groups, neuromuscular block at the adductor pollicis muscle was evaluated using the relaxometer mechanomyograph (Groningen University, The Netherlands).11 After induction of anaesthesia, ANH was carried out in accordance with recently published guidelines.3 A volume of 15 ml kg–1 blood (approximately 20% of blood volume) were procured from the cubital vein and stored in an acid–citrate–dextrose reservoir bag to be simultaneously replaced by an equal volume of 6% hydroxyethyl starch (HES) 130/0.4 solution rapidly infused via a cubital vein cannula in the other arm. The patient's blood was to be re-infused towards the end of the operation after major blood loss had occurred, or sooner if clinically indicated for persistent hypotension, or if Hb <8 g dl–1 threshold was reached.
After the conclusion of blood procurement and HES fluid replacement, the force transducer was attached to the thumb and the ulnar nerve was stimulated supramaximally at the wrist (pulse width 200 µs, square wave) via surface electrodes with train-of-four (TOF) stimuli (2 Hz for 2 s) at 12 s intervals. Data were continuously recorded using the ‘AZG-Relaxometer 5.0’ program. T1% (first twitch of the TOF expressed as percentage of control response) and the TOF ratio (T4:T1) were used for the evaluation of neuromuscular block.
After T1% baseline stabilization, six consecutive incremental doses of rocuronium 50 µg kg–1 were administered into a rapidly running infusion. Each incremental dose was given after three consecutive T1 responses did not register a decline. T1% achieved after each rocuronium bolus was recorded. Rocuronium dose–response curves were created according to Donlon's cumulative dose method.12 Individual dose–response relationships for each patient were examined by least squares linear regression of the logarithm of each dose against a probit transformation of T1%. Because of the fact that probit values for 0 and 100% do not exist, 0 and 100% T1 depression were considered missing values. Regression lines representing the two groups were constructed from the means of the intercepts and slopes of individual regression lines, from which the doses required for 50, 90 and 95% T1 depression (ED50, ED90 and ED95, respectively) were calculated.12
After all six incremental doses, or if 100% twitch depression was achieved after any of the incremental doses, rocuronium 300 µg kg–1 together with the remainder of the incremental doses (if any) was administered. Patients were allowed to recover spontaneously from the neuromuscular block and Dur25 (time from last incremental dose administration until 25% T1 recovery), Dur25–75 (time from 25 to 75% T1 recovery), Dur25–0.8 (time from 25% T1 to 0.8 TOF ratio recovery) and Dur0.8 (time from last incremental dose administration until 0.8 TOF ratio recovery) were calculated.8 Neuromuscular measurements were completed before the surgical incision.
In the two groups for pharmacokinetic studies, after induction of anaesthesia and after the conclusion of blood procurement and HES fluid replacement, patients received a single bolus dose of rocuronium 600 µg kg–1. Serial arterial blood samples (5 ml) were withdrawn in lithium heparin tubes before rocuronium administration and at 1, 3, 5, 7, 10, 15, 20, 30, 40, 50, 60 min after rocuronium administration and then every 30 min up to 180 min. Samples were kept on ice. During the blood samples acquisition part of the study, the levels of anaesthesia and analgesia were deepened to avoid additional rocuronium doses administration. Ephedrine 10–20 mg bolus doses were administered if hypotension occurred. Within 30 min of samples acquisition, plasma was isolated by 3000 g centrifugation for 10 min. Blood samples were immediately acidified to prevent rocuronium degradation by adding 200 µl of 1 M dihydrogen phosphate buffer (NaH2PO4 d.h. 138 g litre–1)to 1 ml plasma, carefully mixed and subsequently stored at –20°C.
After all samples were collected, 10 µl (1.3 mg ml–1) of 3-desacetylvecuronium (Org 7268) as internal standard were added to each set of plasma samples that was used to rectify any variations in recovery and stability among samples. Blood samples were assayed in duplicate according to Gao and colleagues13 using gas chromatograph/mass spectrometer (Voyager GC/MS, ThermoQuest, Austria). The method involved iodide ion pair formation and a single-step liquid–liquid extraction with dichloromethane (DB-5 chemical bonded silica capillary column 15 m x0.25 mm i.d., film 0.25 µm). The carrier gas was helium. The lower quantification limit of sensitivity was 30 ng ml–1. Precision of the assay expressed as relative standard deviation for rocuronium concentrations less than 400 ng ml–1 was 3.9%.
Rocuronium pharmacokinetic analysis was performed using the ‘SCIENTIST’ program (MicroMath Scientific Software Inc.).14 Compartmental statistical analysis of the goodness of fit for a parametric non-linear mixed effects multicompartment model for each individual patient's data was constructed. Goodness of fit was evaluated using Akaike's information criterion (AIC). Alpha, beta and pi are the hybrid rate constants, because each comprises elements of distribution and elimination. Volumes of distribution (Vd), clearances (Cl), distribution half-life (t1/2 alpha), elimination half-life (t1/2 beta) and terminal elimination half-life (t1/2 pi) were calculated.
The primary endpoint of our study was to compare rocuronium ED95 in patients who underwent ANH with control subjects. Based upon a previous study, our a priori t-test power analysis (alpha=0.05) with a 140 (69) µg kg–1 difference in rocuronium ED95 between patients who underwent ANH and control subjects15 showed that a group size of 14 patients would be required to reveal a statistically significant difference between the two groups with >90% power. One way analysis of variance (ANOVA) was used for intergroup analysis. Data were expressed as mean (SD). P<0.05 was considered statistically significant.
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Results |
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Patients' characteristics are presented in Table 1. There were no significant differences between the two dose–response groups regarding T1 stabilization period, and skin and core temperature during neuromuscular monitoring period of the study. There were no significant differences between the two pharmacokinetic groups regarding mean arterial pressure, estimated blood losses, fluid replacements, propofol and remifentanil doses during blood sample acquisition part of the study. Haemoglobin, haematocrit, total plasma proteins, albumin, ionized calcium and potassium plasma concentrations decreased after ANH by 34, 35, 31, 31, 13 and 10%, respectively (Table 1).
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Our study showed that ANH resulted in a shift to the left of rocuronium dose–response curve (Fig. 2). In all ANH patients, and in nine control patients, maximal neuromuscular block was achieved with fewer than six incremental doses (Fig. 2). Rocuronium ED95 was 26% lower in the ANH group compared with the control group (Table 2). ANH resulted in 28% prolongation of Dur25 and Dur0.8, with no difference in the rate of recovery (Dur25–75, Dur25–0.8) between the two groups (Table 3).
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Rocuronium plasma concentrations of the two groups are illustrated in Figure 3. Volumes of distribution were higher, plasma clearance lower, and distribution and elimination half-lives significantly longer in the ANH group compared with the control group (Table 4).
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Discussion |
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TopAbstractIntroductionPatients and methodsResultsDiscussionReferences |
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The principal finding of our study was that, when compared with controls, rocuronium is more potent in ANH patients, as evident by the 26% reduction in the ED95. This difference was still considerably less than the 39% decrease in rocuronium ED95 with ANH previously reported by Xue and colleagues.15 We also demonstrated that the time-course of rocuronium neuromuscular block was prolonged, as Dur25 and Dur0.8 were 28% longer in the ANH group compared with control group. The time-course of action was not assessed in the Xue and colleagues15 study. Although Dur25–75 and Dur25–0.8 in our study were 25–30% longer, still the differences did not reach statistical significance, which could be simply attributed to the fact that the Dur25–75 and Dur25–0.8 were not specifically powered to determine if differences in the speed of recovery existed, as P-values (P=0.061, P=0.057, respectively) closely approached statistical significance.
A recent study in patients who underwent ANH with HES demonstrated that rapid infusion of haemodilution fluids enlarged the extracellular fluid volume by 600–800 ml.16 Because rocuronium is a water-soluble neuromuscular blocking drug that distributes mainly in extracellular fluid,17 the enlarged volumes of distribution in the ANH group of our study that resulted in rocuronium dilution and lower plasma concentrations should have consequently decreased rocuronium potency. However, this seems to be irrelevant as rocuronium potency was increased with ANH. On the other hand, the significant reduction in rocuronium clearances (central, fast and slow) with ANH resulted in a prolongation of the elimination half-lives in our study patients, clearly indicating that the slower disposition process significantly prolonged the offset of rocuronium.
Haemodilution was shown to be associated with increases in cardiac output in humans.18 Furthermore, assessing skeletal muscle blood flow using radioactive microspheres in animals undergoing ANH with HES showed that skeletal muscle blood flow homogenously increased by 27%,19 and a fractional redistribution of blood flow in favour of skeletal muscle capillaries at the expense of adjacent connective tissue supplied by the same arterioles.20 An increase in cardiac output and skeletal muscle blood flow could result in a more rapid initial uptake of rocuronium into the biophase for receptor interaction and consequently a shorter onset time. However, this does not seem to be the case as our results demonstrated an almost identical onset time among the two groups.
The protein-bound fraction of rocuronium was recently reported to be 46%,21 considerably higher than earlier reports of 25%.22 In our study, there was a 31% decline in total plasma proteins with haemodilution that might have decreased rocuronium protein binding capacity resulting in higher concentrations of the pharmacologically active free fraction at the receptor sites. However, this does not seem to be the case as plasma protein binding changes were recently shown to have little clinical relevance.23
Potassium and calcium ions play an influential role in the excitatory transmission at the neuromuscular junction. Potassium concentrations are of prime importance in determining the postjunctional transmembrane potential,24 whereas calcium enhances excitation–contraction coupling in muscles.25 Hypokalaemia and hypocalcaemia were shown to augment neuromuscular block, as a recent report laid emphases to the fact that hypokalaemia and hypocalcaemia could have significantly contributed to rocuronium prolonged paralysis that lasted for several hours after surgery.26 In our study, patients manifested dilutional hypokalaemia and hypocalcaemia as a result of the rapid infusion of relatively large amounts of potassium/calcium-free replacement solutions (HES in 0.9 NaCl), thereby possibly contributing to the prolonged rocuronium neuromuscular block.
Because the aim of our study was to simply compare the dose–response relationship with and without ANH and was not intended as an absolute potency estimate, thus we used the cumulative dose technique rather than the single dose method, the gold standard for creating dose–response curves8 that would have required a far larger sample size of 84 patients. According to the consensus conference8 recommendations the cumulative dose technique could be used for intermediate acting neuromuscular blocking drugs such as rocuronium, provided that the incremental doses were given within a brief period of time8 12 such as the 36 s of three consecutive T1 responses that we used in our study. This allowed no significant recovery between the incremental doses as indicated by the short and almost identical onset time among the two groups (Table 3). The difference in the methods used for the creation of the dose–response curves could explain the differences between the ED90 (332 µg kg–1) and ED95 (384 µg kg–1) of our control group using the cumulative dose method and the previously reported 300 µg kg–1 ED9027 and 305 µg kg–1 ED957. On the other hand, our ED90 and ED95 closely matched the reported 328 µg kg–1 ED9028 and the 398 µg kg–1 ED9529 using the single dose method and was almost identical to the 329 µg kg–1 ED9030 and 390 µg kg–1 ED9530 using the cumulative dose method.
Our results demonstrated that rocuronium time-course of action and elimination half-lives were prolonged with ANH. Thus, careful monitoring of neuromuscular block and reversal of residual block, if needed, is recommended in patients who undergo ANH.
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Acknowledgments |
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The authors would like to thank Professor Peter H. Rehak, Biomedical and Engineering and Computing Unit of the Department of Surgery, Graz Medical University for the statistical analysis and Engineer Andreas Meinitzer, Department of Medical Chemistry, Graz Medical University for the rocuronium assay. Their work was indeed a valuable contribution to the study.
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References |
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