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BJA Advance Access originally published online on January 16, 2007
British Journal of Anaesthesia 2007 98(3):342-346; doi:10.1093/bja/ael362
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© The Board of Management and Trustees of the British Journal of Anaesthesia 2007. All rights reserved. For Permissions, please e-mail: journals.permissions@oxfordjournals.org

Influence of acute normovolaemic haemodilution on the dose–response relationship and time course of action of cisatracurium besylate

A. A. Dahaba1,*, G. Wang2, X. Xu2, X. Liu2, X. Wu2, H. Bornemann1 and H. Metzler1

1 Department of Anaesthesiology and Intensive Care Medicine, Medical University of Graz, Graz, Austria
2 Department of Anaesthesiology, Peking University First Hospital, Beijing, People's Republic of China

* Corresponding author: Department of Anaesthesiology and Intensive Care Medicine, Medical University of Graz, Auenbruggerplatz 29, A-8036, Graz, Austria. E-mail: ashraf.dahaba{at}meduni-graz.at

Accepted for publication December 1, 2006.


   Abstract
Top
 Abstract
Introduction
 Patients and methods
 Statistical analysis
 Results
 Discussion
 References
 
BACKGROUND: Acute normovolaemic haemodilution (ANH) is an efficacious blood conservation strategy aiming at avoiding allogeneic blood transfusion. ANH was shown to increase the potency of vecuronium, atracurium, and rocuronium. The aim of our study was to investigate whether cisatracurium potency is altered with ANH.

METHODS: Using the Relaxometer mechanomyograph, we compared cisatracurium dose–response relationship and time course of action in 60 patients randomly allocated to the ANH or control groups. Patients in each group were randomly allocated to receive one of three cisatracurium doses (30, 40, 50 µg kg–1) followed by a second supplemental dose to reach a total of 100 µg kg–1.

RESULTS: ANH did not result in a significant shift in cisatracurium log dose–probit dose–response curve. There was no significant difference in mean (95% confidence intervals) ED50, ED90, and ED95 (effective doses required for 50, 90, and 95% first twitch depression) between the ANH group [29.5 (27–32), 50.4 (47.4–53.4), 58.7 (55.3–62) µg kg–1] and the control group [28.2 (25.3–31), 47.6 (44.9–50.3), 55.3 (52.5–58.1) µg kg–1], whereas there was no difference in mean (SD) Dur25 and Dur0.8 (time until 25% first twitch and 0.8 train-of-four ratio recoveries) between the ANH group [40.8 (5.9), 64.7 (8.4) min] and the control group [42.2 (7.6), 66.5 (10.7) min].

CONCLUSIONS: Our results demonstrated that unlike other previously reported neuromuscular blocking drugs, ANH did not alter cisatracurium potency. Thus, cisatracurium would be the neuromuscular blocking drug of choice in patients who undergo surgery with ANH, as no dose adjustments are required.

Keywords: monitoring; neuromuscular block; neuromuscular blocking agent


   Introduction
Top
 Abstract
 Introduction
Patients and methods
 Statistical analysis
 Results
 Discussion
 References
 
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 an efficacious cost-effective2 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. Since the first report by Schuh4 of a significant increase in the potency of succinylcholine and pancuronium with ANH, several publications demonstrated a similar augmentation of vecuronium,5 atracurium,6 and rocuronium7 potencies. Cisatracurium besylate, a benzylisoquinolinium neuromuscular blocking drug, is a purified preparation of 1 of the 10 stereoisomers of atracurium, which retained atracurium's advantage of Hofmann elimination but not atracurium's elimination via the non-specific plasma esterases hydrolysis pathway.8 The aim of our study was to investigate whether cisatracurium's potency is altered with ANH.

In that regard, a neuromuscular blocking drug that is not influenced by ANH, thus requiring no dose adjustments, could be beneficial in patients undergoing surgery with ANH. We assessed cisatracurium's dose–response relationship and time course of action in patients undergoing surgery with and without ANH.


   Patients and methods
Top
 Abstract
 Introduction
 Patients and methods
Statistical analysis
 Results
 Discussion
 References
 
A prospective, controlled, clinical, consecutive study was conducted in conformity with the guidelines of ‘Good clinical research practice (GCRP) in pharmacodynamic studies of neuromuscular blocking agents’9 and the ‘Consolidated standards of reporting trials (CONSORT) statement’.10

After ethics committee approval, all patients who agreed to participate in the study gave written informed consent. Exclusion criteria were history of neuromuscular disease, small joint arthritis, haemoglobin (Hb) less than 12 g dl–1, body mass index of less than 20 or more than 26 kg m–2, or treatment with drugs thought to interfere with neuromuscular transmission.

Based upon a previous study,6 our a priori power analysis showed that a subgroup size of 10 patients would be required to reveal a statistically significant difference between the two groups. Using a computer-generated randomization list, 60 patients with American Society of Anesthesiologists (ASA) classification I–III undergoing radical cystectomy, radical hysterectomy, or retropubic radical prostatectomy were randomly allocated to the ANH or control groups and were stratified by gender and ASA classification. Patients in each group were randomly allocated to receive one of three initial cisatracurium doses (30, 40, 50 µg kg–1), followed by a second supplemental dose to reach a total dose of 100 µg kg–1.

A radial artery cannula was placed under local anaesthetic, before anaesthesia induction. Arterial Hb, haematocrit (Hct), and total plasma proteins were measured before and after ANH. A volume of 15 ml kg–1 blood (approximately 20% of blood volume) was 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 ideally re-infused towards the end of the operation after the phase of major blood loss, or sooner if clinically indicated primarily for persistent hypotension or if the Hb less than 7 g dl–1 threshold was reached.

After blood procurement and HES fluid replacement, anaesthesia was induced with fentanyl (1.5 µg kg–1) and propofol (2–3 mg kg–1). Patients were ventilated via a facemask, and after lidocaine 2% topical spray of the laryngeal region and when anaesthesia was 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. Patients were ventilated mechanically with 40% oxygen in air and adjusted to maintain 30–40 mm Hg end-tidal carbon dioxide. Patients were warmed using a forced hot-air blanket to maintain core temperature >36°C and skin temperature >32°C.

Neuromuscular block at the adductor pollicis muscle was evaluated using the Relaxometer mechanomyograph (Groningen University, Groningen, Holland).11 The force transducer of the Relaxometer was attached to the thumb, and the ulnar nerve was stimulated supramaximally at the wrist (pulse width 200 µs, square wave) 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 until all patients fully recovered from neuromuscular block. T1 (first twitch of the TOF) expressed as percentage of control response and TOF ratio (T4:T1) were used to evaluate the neuromuscular block.

After T1(%) baseline stabilization, the designated cisatracurium dose of 30, 40, or 50 µg kg–1 was administered into a rapidly running infusion and the maximum neuromuscular block, defined as three consecutive T1 responses that did not register a decline, was recorded. Cisatracurium dose–response curves were obtained according to Donlon's single-dose method12 using the ordinary least-squares regression of the probit transformation of T1(%) maximum twitch suppression against the common logarithm of each dose. Mean regression lines representing the two groups were plotted using the slopes and intercepts, from which the doses required for 50, 90, and 95% T1 depression (ED50, ED90 and ED95, respectively) were calculated.

This was followed by a second supplemental dose to reach a total dose of 100 µg kg–1. Patients were allowed to recover spontaneously from the neuromuscular block. Dur25 (time from beginning of cisatracurium first 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 beginning of cisatracurium first dose administration until 0.8 TOF ratio recovery) time course of action variables were calculated.9


   Statistical analysis
Top
 Abstract
 Introduction
 Patients and methods
 Statistical analysis
Results
 Discussion
 References
 
The primary endpoint of our study was to compare cisatracurium ED95 in patients who underwent ANH with control subjects. Based upon a previous study, in which atracurium ED95 was 208 (37) µg kg–1 in patients who underwent ANH and 309 (88) µg kg–1 in control subjects, our a priori power analysis ({alpha} = 0.05) with 101 (51) µg kg–1 difference between the two groups,6 showed that a subgroup size of 10 patients would be required to reveal a statistically significant difference between the two groups with >80% power. Analysis of covariance (two-way ANOVA) was used for intergroup analysis. Data were expressed as means (SD or 95% confidence intervals). P < 0.05 was considered statistically significant.


   Results
Top
 Abstract
 Introduction
 Patients and methods
 Statistical analysis
 Results
Discussion
 References
 
Patients' characteristics are presented in Table 1. There was no significant blood loss during the neuromuscular monitoring period of the study. Haemoglobin, Hct, and plasma proteins declined significantly with ANH (Table 1). There were no significant differences between the two groups in the T1 stabilization period, anaesthesia induction period, skin and core temperature, mean arterial pressure, estimated blood loss, fluid replacements, and propofol and remifentanil requirements during the neuromuscular monitoring period of the study.


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  		Table 1 Patients' characteristics and blood investigations. Means (SD or range). ANH, acute normovolaemic haemodilution; BMI, body mass index; Hb, haemoglobin; Hct, haematocrit

 
Our study showed that ANH did not result in a significant shift in the cisatracurium dose–response curve (Fig. 1). There were no significant differences between the two groups in cisatracurium onset time or maximum T1 block (Table 2). Although cisatracurium ED50, ED90, and ED95 were slightly higher in the ANH group indicating a minor decrease in potency, still the differences between the two groups did not reach statistical significance (Table 3). The duration of action (Dur25 and Dur0.8) and the rate of recovery (Dur25–75, Dur25–0.8) parameters were similar between the two groups (Table 4).


Figure 1
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  		Fig 1 Cisatracurium log dose–probit curves (upper and lower 95% confidence intervals) in the acute normovolaemic haemodilution (ANH) and control groups.

 


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  		Table 2 Time to T1 baseline stabilization, anaesthesia induction, cisatracurium onset, and maximum T1 block. Means (SD), n = 30. ANH, acute normovolaemic haemodilution; onset time, time from beginning of cisatracurium first dose administration until first response of train-of-four (T1) maximum suppression

 


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  		Table 3 Cisatracurium effective doses 50, 90, and 95%. Means (95% confidence intervals), n = 30. ANH, acute normovolaemic haemodilution; ED50, ED90, ED95, effective dose 50, 90, 95%

 


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  		Table 4 Cisatracurium time course of action. Means (SD), n = 30. ANH, acute normovolaemic haemodilution; Dur25, time from beginning of cisatracurium first dose administration until first response of train-of-four (T1) 25% recovery; Dur25–75, time of T1 recovery from 25 to 75%; Dur0.8, time from beginning of cisatracurium first dose administration until 0.8 train-of-four ratio recovery; Dur25–0.8, time from T1 25% until 0.8 train-of-four ratio recovery

 

   Discussion
Top
 Abstract
 Introduction
 Patients and methods
 Statistical analysis
 Results
 Discussion
References
 
The principal dose–response relationship finding of our study was that unlike other previously reported neuromuscular blocking drugs, in which ANH was shown to increase their potency thus requiring lower doses,4–7 ANH did not significantly alter the potency of cisatracurium as evident by the similar ED50, ED90, and ED95 in the two groups. Although we did not specifically assess the above-mentioned neuromuscular blocking drugs under the exactly same ANH conditions, we can speculate that the observed differences between cisatracurium and other neuromuscular blocking drugs including atracurium could arise from their significantly different distribution characteristics, because dose–response relationships depend mainly on the initial concentration of a drug rather than the disposition process that follows. Cisatracurium is only 1 of the 10 stereoisomers that constitute atracurium and makes up just 15% of the atracurium mixture.13 Smith and colleagues13 demonstrated that cisatracurium possesses a significantly different distribution profile than the other three geometric isomer groups that constitute the atracurium mixture.13 Furthermore, atracurium's volume of distribution at steady state (Vdss) and distribution half-life (t1/2{alpha}) [87.4 (31) ml kg–1, 2.1 (0.4) min]1415 are different from cisatracurium's Vdss and t1/2{alpha} [168 (44) ml kg–1, 6.4 (0.5) min].8 13 Whereas, the previously reported succinylcholine,4 pancuronium,4 vecuronium,5 and rocuronium7 were either depolarizing4 or aminosteroid neuromuscular blocking drug,4 5 7 all with distribution features completely different from cisatracurium.

In our study, Hct declined to 28.6 (–31%), indicating significant haemodilution. A recent study in patients who underwent ANH with HES demonstrated that haemodilution fluids increased the extracellular fluid volume by 600–800 ml;16 this would consequently result in cisatracurium dilution as cisatracurium is rapidly distributed into the extracellular space.15 Unlike other neuromuscular blocking drugs in which ANH was shown to significantly increase their potency and shift their dose–response curves to the left,4–7 in our study, cisatracurium's dose–response curve was actually shifted to the right, indicting a decrease, albeit not statistically significant, in its potency (Fig. 1, Table 3). This could be attributed to the fact that because ANH did not significantly influence the potency of cisatracurium, our dose–response curve just reflected the initial dilution of cisatracurium plasma concentrations.

The principal time course of action finding of our study was that cisatracurium's duration of action (Dur25 and Dur0.8) and recovery rate parameters (Dur25–75 and Dur25–0.8) were not prolonged in the ANH group compared with the control group. However, Xue and colleagues6 showed that ANH prolonged atracurium's time course of action. In addition to the fact that recovery parameters are crude measurements of the elimination process and might not detect minor differences between groups, still the differences between cisatracurium and atracurium could be attributed to the differences in the disposition process. Fisher and colleagues14 found that more than 60% of atracurium clearance was organ-based through pathways other than Hofmann degradation and ester hydrolysis.14 Although, cisatracurium retained atracurium's advantage of spontaneous organ-independent, base catalysed, temperature-dependent Hofmann degradation, but unlike atracurium, cisatracurium is not eliminated via the non-specific plasma esterases hydrolysis pathway.8 The clinical implications of our results are that no adjustment in cisatracurium's initial and repeat doses is necessary in patients who undergo surgery with ANH.

The protein bound fraction of cisatracurium was recently reported to be 38%.17 In our study, there was a significant decline in total plasma proteins with ANH. The decreased protein-binding capacity could have purportedly resulted in higher concentrations of cisatracurium's pharmacologically active free fraction. However, plasma protein-binding changes were recently shown to have little clinical relevance.18 Benet and Hoener18 demonstrated that except drugs with very high extraction ratio, changes in plasma protein binding do not influence the clinical exposure of a patient to parenterally administered drugs such as cisatracurium. They found that the concept that effective concentrations of drugs are dependent on protein binding is incorrect, as the effective concentrations of drugs are mainly dependent on the disposition process.18

The ED50 (28.2 µg kg–1) of our control group closely matched the previously reported 29,19 30,20 and 31.1 µg kg–1 21 ED50 using the single-dose method. Similarly, the ED95 of our control group (55.3 µg kg–1) was comparable with the previously reported 48,19 53,20 and 57.6 µg kg–1 22 ED95.

Our study has limitations, because our study design did not enable us to explore the effect of the diverse ANH conditions used in other studies that could have influenced the outcome. First, whether there is a critical threshold for ANH volume to alter the potency of cisatracurium, as we only used the recommended 15 ml kg–1 volume of blood (20% of blood volume).3 Second, does the type of replacement fluid make a difference: we used HES as opposed to a mixture of Ringer's lactate and dextran in Xue and colleagues' studies.5 6 Furthermore, if blood was procured before the induction of anaesthesia as opposed to ANH after induction of anaesthesia and administration of cisatracurium intubating dose, obviously ANH would only influence cisatracurium's repeat dose administrations.

In conclusion, our results demonstrated that unlike other previously reported neuromuscular blocking drugs, cisatracurium dose–response relationship and time course of action were not influenced by ANH, thus requiring no dosing adjustments. This would render cisatracurium as the neuromuscular blocking drug of choice in patients who undergo surgery with ANH.


   References
Top
 Abstract
 Introduction
 Patients and methods
 Statistical analysis
 Results
 Discussion
 References
 
1 Consensus Conference. (1988) Perioperative red blood cell transfusion. JAMA 260:2700–3.[Abstract/Free Full Text]

2 Monk TG, Goodnough LT, Brecher ME, Colberg JW, Andriole GL, Catalona WJ. (1999) A prospective randomized comparison of three blood conservation strategies for radical prostatectomy. Anesthesiology 91:24–33.[CrossRef][Web of Science][Medline]

3 Napier JAF, Bruce M, Chapman J, et al. (1997) Guidelines for autologous transfusion. II. Perioperative haemodilution and cell salvage. Br J Anaesth 78:768–71.[Free Full Text]

4 Schuh FT. (1981) Influence of haemodilution on the potency of neuromuscular blocking drugs. Br J Anaesth 53:263–5.[Abstract/Free Full Text]

5 Xue FS, Liu JH, Liao X, et al. (1998) The influence of acute normovolemic hemodilution on the dose-response and time course of action of vecuronium. Anesth Analg 86:861–6.[Abstract]

6 Xue FS, Liao X, Liu JH, Zhang YM, An G, Luo LK. (2000) Influence of acute normovolaemic haemodilution on the dose-response and time-course of action of atracurium. Acta Anaesthesiol Scand 44:163–9.[CrossRef][Web of Science][Medline]

7 Dahaba AA, Perelman SI, Moskowitz DM, et al. (2006) Influence of acute normovolaemic haemodilution on the dose-response relationship, time-course of action and pharmacokinetics of rocuronium bromide. Br J Anaesth 97:482–8.[Abstract/Free Full Text]

8 Kisor DF, Schmith VD, Wargin WA, Lien CA, Ornstein E, Cook DR. (1996) Importance of the organ-independent elimination of cisatracurium. Anesth Analg 83:1065–71.[Abstract]

9 Viby-Mogensen J, Engbaek J, Eriksson I, et al. (1996) Good clinical research practice (GCRP) in pharmacodynamic studies of neuromuscular blocking agents. Acta Anaesthesiol Scand 40:59–74.[Web of Science][Medline]

10 Moher D, Schulz KF, Altman DG, for the CONSORT group. (2001) The CONSORT statement: revised recommendations for improving the quality of reports of parallel-group randomised trials. Lancet 357:1191–4.[CrossRef][Web of Science][Medline]

11 Rowaan CJ, Vandenbrom RHG, Wierda JMKH. (1993) The Relaxometer: a complete and comprehensive computer-controlled neuromuscular transmission measurement system developed for clinical research on muscle relaxants. J Clin Monit 9:38–44.[CrossRef][Web of Science][Medline]

12 Donlon JV, Savarese JJ, Ali HH, Teplik RS. (1980) Human dose-response curves for neuromuscular blocking drugs: a comparison of two methods of construction and analysis. Anesthesiology 53:161–6.[Web of Science][Medline]

13 Smith CE, Van Miert MM, Parker CJR, Hunter JM. (1997) A comparison of the infusion pharmacokinetics and pharmacodynamics of cisatracurium, the 1R-cis 1'R-cis isomer of atracurium, with atracurium besylate in healthy patients. Anaesthesia 52:833–41.[CrossRef][Web of Science][Medline]

14 Fisher DM, Canfell PC, Fahey MR, et al. (1986) Elimination of atracurium in humans: contribution of Hofmann elimination and ester hydrolysis versus organ-based elimination. Anesthesiology 65:6–12.[CrossRef][Web of Science][Medline]

15 Hull CJ. (1995) Pharmacokinetics and pharmacodynamics of the benzylisoquinolinium muscle relaxants. Acta Anaesthesiol Scand 39:suppl 106, 13–7.

16 Rehm M, Orth V, Scheingraber S, Kreimeier U, Brechtelsbauer H, Finsterer U. (2000) Acid–base changes caused by 5% albumen versus 6% hydroxyethyl starch solution in patients undergoing acute normovolemic hemodilution. A randomized prospective study. Anesthesiology 93:1174–83.[CrossRef][Web of Science][Medline]

17 Roy JJ and Varin F. (2004) Physicochemical properties of neuromuscular blocking agents and their impact on the pharmacokinetic-pharmacodynamic relationship. Br J Anaesth 93:241–8.[Abstract/Free Full Text]

18 Benet LZ and Hoener BA. (2002) Changes in plasma protein binding have little clinical relevance. Clin Pharmacol Ther 71:115–21.[CrossRef][Web of Science][Medline]

19 Belmont MR, Lien CA, Quessy S, et al. (1995) The clinical neuromuscular pharmacology of 51W89 in patients receiving nitrous oxide/opioid/barbiturate anesthesia. Anesthesiology 82:1139–45.[CrossRef][Web of Science][Medline]

20 Lepage JY, Malinovsky JM, Malinge M, et al. (1996) Pharmacodynamic dose-response and safety study of cisatracurium (51W89) in adult surgical patients during N2O-O2-opioid anesthesia. Anesth Analg 83:823–9.[Abstract]

21 Kim KS, Chung CW, Shin WJ. (1999) Cisatracurium neuromuscular block at the adductor pollicis and the laryngeal adductor muscles in humans. Br J Anaesth 83:483–4.[Abstract/Free Full Text]

22 Kim KS, Chun YS, Chon SU, Suh JK. (1998) Neuromuscular interaction between cisatracurium and mivacurium, atracurium, vecuronium or rocuronium administered in combination. Anaesthesia 53:872–8.[CrossRef][Web of Science][Medline]


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