Share this article on:

The Quantitative Distinction Between Train-of-Four “Counts of 2” and Posttetanic “Counts of 2” Evidenced by a Stable Paralysis/Stable Infusion Rate Method in Anesthetized Patients Receiving Mivacurium

d’Hollander, A A. MD, PhD; Pytel, A V. MD; Merzouga, B M. MD; Klopfenstein, C -E. MD

doi: 10.1213/01.ANE.0000148693.12874.22
Anesthetic Pharmacology: Research Report

In this study we quantitatively evaluated, by a stable paralysis/stable infusion rate method, the difference between two standardized paralysis levels—train-of-four (TOF) count of 2 responses and posttetanic count (PTC) of 2. Ten ASA physical status I–II consenting adult patients scheduled for elective surgery were anesthetized (sufentanil/propofol), tracheally intubated, mechanically normoventilated with a fixed O2/air mixture, and normothermic; oropharynx and thenar temperatures were maintained above 36° and 32.5°C, respectively. After partial recovery from 200 μg/kg mivacurium (MIV), stable tactile TOF and PTC counts of 2 paralysis levels were induced on the adductor pollicis muscle by manual adjustments of an infusion pump containing MIV. The paralysis levels and the infusion rates were considered as stable once they remained constant at 4 consecutive time points separated by 5 min each. Infusion rates observed were: TOF count 2–6 (2–11) and PTC 2–17 (3–18) μg · kg−1 · min−1 (P < 0.001; Wilcoxon’s paired comparison test). Under the present conditions, obtaining and maintaining a PTC of 2 requires MIV infusion rates far in excess of the “standard” recommendations mentioned in the literature for MIV infusion management.

IMPLICATIONS: In anesthetized patients receiving mivacurium (MIV) infusion, the use of the stable paralysis/stable infusion rate method established that, for obtaining and maintaining a posttetanic count of 2, MIV administration must be far more (>200%) than the recommendations mentioned in the literature for MIV infusion management.

Service d’ Anesthésiologie, Hôpital Universitaire de Genève, Genève, Switzerland

Accepted for publication October 6, 2004.

Address correspondence to A. A. d’Hollander, Service d’ Anesthésiologie, Hôpital Universitaire de Genève, 24 Rue Micheli-du-Crest, 1211 Genève, Suisse. Address e-mail to dhollanderalain@yahoo.fr.

The use of the train-of-four (TOF) stimulation for controlling clinical paralysis has become extremely popular since its introduction by Ali et al. (1). Nevertheless, the various paralysis levels monitored by this stimulation pattern are quite often not profound enough to satisfy some special clinical situations—such as a “no cough maneuver” during tracheal suctioning or an immediate “full hiccup control” during delicate intraabdominal surgery—very often requiring additional muscle relaxant administration (2). Viby-Mogensen et al. (3) proposed a very elegant practical solution—the posttetanic count (PTC) methodology—based on the posttetanic facilitation phenomenon for managing deeper paralysis levels than those monitored with the sole TOF stimulation.

The present study was thus designed to make this quantitative distinction using a previously described method for stabilizing precise targeted paralysis levels by a constant or adjusted muscle relaxant infusion rate (4–8).

To optimize the quality of the scheduled observations, the following approaches were preselected: first, the use of a noncumulative muscle relaxant with short duration of action—mivacurium (MIV) (5–8); second, an anesthetic drug regimen providing time-independent observation conditions (7); and third, the choice of precise targeted paralysis levels, TOF and PTC counts of 2, monitored on an adductor pollicis maintained in normal conditions.

Back to Top | Article Outline

Methods

After local ethical committee approval of the study design and conditions, 10 ASA physical status I–II adult patients scheduled for elective abdominal surgery were enrolled. Written informed consent was obtained from all subjects. Patients exceeding 130% of ideal body weight, those with clinical biochemical evidence of hepatic, renal, electrolyte, and neuromuscular disorders or those taking medications known to interfere with neuromuscular transmission were excluded. Moreover, total pseudocholinesterases together with dibucaine and fluoride numbers were screened to eliminate the patients with grossly abnormal plasma cholinesterase patterns (9,10).

The patients received 7.5 mg of midazolam orally, 1 h before their arrival in the anesthesia room where they were equipped for monitoring with a 3-lead electrocardiogram, upper extremity noninvasive arterial blood pressure, and pulse oximetry. An infusion line, with a 3-way stopcock, loaded with Ringer’s lactate solution, was placed in a large forearm vein. After 3 min of 100% oxygen administration, anesthesia was induced with sufentanil 0.04 μg/kg IV followed by propofol administered to provide effect compartment target concentrations between 4–5 μg/mL (Diprifusor™; Vial Medical, Brezins, France). After loss of consciousness, assessed verbally, ventilation was controlled manually. Tracheal intubation was performed after the administration of MIV 200 μg/kg. Thereafter, ventilation was controlled mechanically (semiclosed circuit, 35%–45% oxygen in air) and adjusted to produce an end-tidal carbon dioxide concentration in the range of 4.1–4.7 kPa. According to the patient’s reactions to surgical stimulations (modification of arterial blood pressure and/or heart rate of >15%), the targeted effect site compartment propofol concentration was changed and an additional bolus of sufentanil 0.01 μg/kg was injected when requested.

The skin thenar temperature was measured with a surface electrothermometer and the oropharyngeal temperature was obtained with a bulb electrothermometer. Heat loss from the body surface and the arms was controlled by using a hot-air warming mattress placed on the upper trunk, face, and arms of the patient. Occasionally, the IV infusion line was warmed. Oropharyngeal temperature was maintained between 36° and 36.5°C and thenar skin temperatures above 32.5°C during the entire study period.

For eliciting adductor pollicis movements, the ulnar nerve was stimulated by surface electrodes placed at the wrist. The paralysis levels targeted were assessed by gentle contact between the patient’s freely moving thumb and the index finger of the investigator applied during either a TOF or a PTC stimulation (11). TOF and PTC count stimulation patterns (50 mA, 0.2-ms duration of constant rectangular current) were provided by a peripheral nerve stimulator (TOF-Watch™; Organon Ireland Ltd., Dublin, Ireland). After recovery from the initial MIV dose with 2 responses to TOF stimulation, a 50-mL electrically driven syringe of 2 mg/mL native MIV solution was started. Manual flow adjustments of the syringe were allowed every 5 min to produce 2 predetermined paralysis levels: first, stable TOF counts of 2 and second, a constant PTC of 2. An interval of about 5 min was considered sufficient between repeated PTC stimulations to minimize the interference of the posttetanic facilitation phenomenon (11) on the thumb movements observed. The sequence TOF/PTC stimulations was always performed in that order. These paralysis levels noted every 5 min were considered as stable if they remained constant during 4 consecutive determinations, thus after at least a 15-min period; similarly, MIV infusion rates, calculated in μg · kg−1 · min−1, were considered stable if they remained constant during 3 consecutive periods of 5 min (12).

Statistical analysis of the data was performed with Wilcoxon’s test for paired comparisons. Data were noted as: median (min–max).

Back to Top | Article Outline

Results

Patient characteristics including pseudocholinesterases, dibucaine number, fluoride number, durations of MIV exposure, end-tidal carbon dioxide, and central and thenar temperatures are summarized in Table 1.

Table 1

Table 1

MIV infusion rates observed varied from 6 (2–11) for maintaining a TOF count of 2 to 17 (3–18) μg · kg−1 · min−1 for obtaining a PTC of 2 (P < 0.001; Wilcoxon’s paired comparison test). Evolutions of individual MIV infusion rates noted for the TOF count of 2 and the PTC of 2 are illustrated in Figure 1.

Figure 1

Figure 1

Back to Top | Article Outline

Discussion

When a stable paralysis/stable infusion rate method is used, there is a clear quantitative distinction between a TOF count of 2 and a PTC of 2. This implies that a marked MIV infusion rate increase (>200%) is necessary to progress from a TOF count of 2 paralysis level to the PTC of 2.

TOF and PTC stimulations applied to the ulnar nerve to elicit adductor pollicis reactions are popular approaches for monitoring various clinical paralysis levels (11,13–17). Both stimulation patterns could be complementary for correct management of the various paralysis levels needed by the serial phases of a surgical procedure. Whereas PTC-based paralysis levels were termed “intense” by the first authors describing this particular pattern (3), TOF counts of 1 or 2 are often referred to as the “standard” paralysis level. This objective, but purely qualitative, distinction has remained largely accepted. The goal of this study was to provide more practical quantitative information under very basic conditions, including tactile detection of the paralysis levels observed and manual adjustments of an electrical syringe containing a noncumulative short-acting muscle relaxant. This design provides immediately useful data for those clinicians working in cost-contained professional environments.

Numerous authors have designed clinical studies relying partly or totally on tactile or visual detection of muscle movements after standardized stimulation patterns (11,13–17). More recently, the sole use of a tactile TOF count monitoring was advocated, by Pedersen et al. (17), for the management of atracurium and MIV infusions in daily practice. This study confirms their previous conclusions about the feasibility of such a “naked hand” clinical monitoring approach for maintaining stable paralysis levels. The administration of an initial dose followed by an adjustable infusion, once partial recovery is identified, seems to be a very practical method for efficient control of muscle relaxant management because it avoids the occurrence of any major overdosing and limits paralysis level variations. Among the available clinical muscle relaxants, some (i.e., atracurium, cisatracurium, MIV) clearly exhibit noncumulative effects even during long lasting infusions (4–8,12). MIV was selected in this study because its short duration of action offered a rapid resolution of an “intense” PTC of 2 once the study was completed.

Closed level-loop MIV infusions have been described during anesthesia using various drug regimens. In many situations, the servo-controlled infusion rate was influenced either by the magnitude of volatile drug concentrations (18,19) or, in the presence of a constant inhaled concentration, by the duration of volatile drug exposure (7). In the present study, inhaled drugs were not used and anesthesia was maintained with coadministration of propofol and sufentanil providing stable conditions for the observed variables: adductor pollicis activity and MIV infusion rates. It is interesting that the median MIV infusion rate required to maintain stable a clinically assessed TOF count of 2 level, representing approximately an 80% reduction of initial twitch height (15), is not very different than that observed previously with the use of a more sophisticated monitoring method such as close-loop control of MIV infusion on a reduced fraction (circa 5%) of the initial or reference twitch (7,8,18–25) (Table 2).

Table 2

Table 2

In anesthetized patients receiving MIV infusion, the use of the stable paralysis/stable infusion rate method established that, for obtaining and maintaining a PTC of 2, MIV infusion rates must be far in excess of the recommendations suggested by the existing literature.

The authors thank Pr. F. Clergue and Dr. A. Foster for their support of this clinical study and Prs. R. Smiley and M. Baurain for their very kind help in editing the manuscript. The expert assistance, for patient testing, provided by the staff members (Mr. N. Mensi and Dr. O. Gollaz) of the institutional clinical chemistry laboratory (Pr. D. Hochstrasser) was also particularly appreciated.

Back to Top | Article Outline

References

1. Ali HH, Utting JE, Gray C. Stimulus frequency in the detection of neuromuscular block in humans. Br J Anaesth 1970;42:967–78.
2. Fernando PU, Viby-Mogensen J, Bonsu AK, et al. Relationship between posttetanic count and response to carinal stimulation during vecuronium-induced neuromuscular blockade. Acta Anaesthesiol Scand 1987;31:593–6.
3. Viby-Mogensen J, Howardy-Hansen P, Chraemmer-Jorgensen B, et al. Posttetanic count (PTC): a new method of evaluating an intense nondepolarizing neuromuscular blockade. Anesthesiology 1981;55:458–61.
4. d’Hollander AA, Luyckx C, Barvais L, De Ville A. Clinical evaluation of atracurium besylate requirement for a stable muscle relaxation during surgery: lack of age-related effects. Anesthesiology 1983;59:237–40.
5. Savarese JJ, Ali HH, Basta SJ, et al. The clinical neuromuscular pharmacology of mivacurium chloride (BW B1090U): a short-acting nondepolarizing ester neuromuscular blocking drug. Anesthesiology 1988;68:723–32.
6. Lien CA, Schmith VD, Embree PB, et al. The pharmacokinetics and pharmacodynamics of the stereoisomers of mivacurium in patients receiving nitrous oxide/opioid/barbiturate anesthesia. Anesthesiology 1994;80:1296–302.
7. Motamed C, Donati F. Sevoflurane and isoflurane, but not propofol, decrease mivacurium requirements over time. Can J Anaesth 2002;49:907–12.
8. Goudsouzian N, Chakravorti S, Denman W, et al. Prolonged mivacurium infusion in young and elderly adults. Can J Anaesth 1997;44:955–62.
9. Dietz AA, Rubinstein HM, Lubrano T. Colorimetric determination of serum cholinesterase and its genetic variants by the proprionylthiocholindithio-bis(nitrobenzoic acid) procedure. Clin Chem 1973;19:1309–13.
10. Jensen FS, Skovgaard LT, Viby-Mogensen J. Identification of human plasma cholinesterase variants in 6,688 individuals using biochemical analysis. Acta Anaesthesiol Scand 1995;39:157–62.
11. Howardy-Hansen P, Viby-Mogensen J, Gottschau A, et al. Tactile evaluation of the posttetanic count (PTC). Anesthesiology 1984;60:372–4.
12. Hart PS, McCarthy GJ, Brown R, et al. The effect of plasma cholinesterase activity on mivacurium infusion rates. Anesth Analg 1995;80:760–3.
13. Viby-Mogensen J, Jensen NH, Englbaek J, et al. Tactile and visual evaluation of the response to train-of-four nerve stimulation. Anesthesiology 1985;63:440–3.
14. Debaene B, Meistelman C, Beaussier M, Lienhart A. Visual estimation of train-of-four responses at the orbicularis oculi and posttetanic count at the adductor pollicis during intense neuromuscular block. Anesth Analg 1994;78:697–700.
15. Kopman AF, Mallhi MU, Justo MD, et al. Antagonism of mivacurium-induced neuromuscular blockade in humans: edrophonium dose requirements at threshold train-of-four count of 4. Anesthesiology 1994;81:1394–400.
16. Kopman AF, Ng J, Zank LM, et al. Residual postoperative paralysis: pancuronium versus mivacurium, does it matter? Anesthesiology 1996;85:1253–9.
17. Pedersen NA, Ostergaard D, Olsen JS, et al. Infusion of mivacurium and atracurium guided by manual tactile evaluation. Ugeskr Laeger 2000;162:6532–5.
18. Kansanaho M, Olkkola KT. Quantifying the effect of isoflurane on mivacurium infusion requirements. Anaesthesia 1996;51:133–6.
19. Kansanaho M, Olkkola KT. The effect of halothane on mivacurium infusion requirements in adult surgical patients. Acta Anaesthesiol Scand 1997;41:754–9.
20. Brandom BW, Woelfel SK, Cook DR, et al. Comparison of mivacurium and suxamethonium administered by bolus and infusion. Br J Anaesth 1989;62:488–93.
21. Diefenbach C, Mellinghoff H, Lynch J, Buzello W. Mivacurium: dose-response relationship and administration by repeated injection or infusion. Anesth Analg 1992;74:420–3.
22. Miller DR, Bryson G, Martineau RJ, et al. Edrophonium requirements for reversal of deep neuromuscular block following infusion of mivacurium. Can J Anaesth 1995;42:996–1002.
23. Bevan JC, Reimer EJ, Smith MF, et al. Decreased mivacurium requirements and delayed neuromuscular recovery during sevoflurane anesthesia in children and adults. Anesth Analg 1998;87:772–8.
24. Lien C, Belmont M, Wray R, et al. Pharmacodynamics and the plasma concentrations of mivacurium during spontaneous recovery and neostigmine-facilitated recovery. Anesthesiology 1999;91:119–26.
25. Østergaard D, Viby-Mogensen J, Pedersen NA, et al. Pharmacokinetics and pharmacodynamics of mivacurium in young adult and elderly patients. Acta Anaesthesiol Scand 2002;46:684–91.
© 2005 International Anesthesia Research Society