Comparison of recovery time of bolus and continuous infusion mivacurium

Abstracts

JUSTIFICATIVA E OBJETIVOS: O mivacúrio é um bloqueador neuromuscular (BNM) de ação curta, que apresenta uma duração total não ultrapassando 24 minutos. As primeiras comunicações científicas relataram não haver diferenças significativas no tempo de recuperação, independentemente da forma de administração. No entanto, a experiência clínica aponta para recuperações mais prolongadas quando se administra o fármaco em infusão contínua. Este trabalho tem por objetivo comparar o tempo de recuperação do mivacúrio quando administrado em bolus e em forma contínua, em um grupo de pacientes jovens e adultos. MÉTODO: Foram analisados 40 pacientes jovens sem doenças neuromusculares. Após receberem midazolam como medicação pré-anestésica, foram monitorizados na sala de operação com ECG na derivação D II e realizada a aferição da pressão arterial indireta por método automático. Todos receberam propofol e fentanil, e a anestesia foi mantida com isoflurano, óxido nitroso e oxigênio. Após a indução, foram instalados o monitor da transmissão neuromuscular por acelerometria e, após a intubação, o capnógrafo e o analisador de gases. Foram divididos em 2 grupos iguais de acordo com o regime de administração de mivacúrio: os do grupo 1 receberam somente dose inicial em bolus e os do grupo 2, após a dose inicial e terem recuperado 10% de T1, receberam infusão contínua para manter uma T1 nesse valor. Foram anotados em ambos os grupos os valores de T1 e T4/T1 na fase de recuperação, a partir de T1 em 10% da resposta inicial, de minuto a minuto, até 30 minutos. RESULTADOS: Os grupos foram homogêneos em relação às variáveis antropométricas. O grupo 2 apresentou tempo de recuperação mais lenta do que os pacientes que receberam somente a dose inicial em bolus. Houve grande variação de doses de infusão entre pacientes e no próprio paciente no decorrer da infusão. CONCLUSÕES: Em pacientes jovens e adultos sem evidências de doenças, a recuperação do mivacúrio é mais lenta após infusão contínua do que sob forma única em bolus. Em decorrência das variações de dose de infusão entre os pacientes e em cada paciente em si, para manter um relaxamento constante e estável, recomenda-se o uso de monitor da transmissão neuromuscular.

BLOQUEADORES NEUROMUSCULARES, Não-despolarizante; MONITORIZAÇÃO; TÉCNICAS DE ADMINISTRAÇÃO

SCIENTIFIC ARTICLE

Comparison of recovery time of bolus and continuous infusion mivacurium^*

Comparación del tiempo de recuperación del mivacúrio en bolus y en infusión continuada

Maria Cristina Simões de Almeida, TSA, M.D.

Doutor em Medicina pela Universidade Johannes Gutenberg-Alemanha, Professora Adjunta da Universidade Federal de Santa Catarina (UFSC), Florianópolis, SC

^{Correspondence}

SUMMARY

BACKGROUND AND OBJECTIVES: Mivacurium is a short-acting neuromuscular blocker (NMB), with total duration not exceeding 24 minutes. Early publications have reported no significant differences in recovery time, regardless of the route administration. However, clinical experience points out to longer recovery times when the drug is administered in continuous infusion. This study aimed at comparing recovery time of bolus administration and continuous infusion of mivacurium in a group of young adult patients.

METHODS: Forty young patients with no neuromuscular disease were enrolled in the study. Patients were premedicated with midazolam and monitored in the OR with ECG in D_II and non-invasive automatic blood pressure. All patients received propofol and fentanyl and anesthesia was maintained with isoflurane, nitrous oxide and oxygen. Accelerometric neuromuscular transmission monitor was installed after induction and capnograph and gases analyzer were installed after intubation. Patients were divided in 2 equal groups according to mivacurium administration regimen: group 1 received initial bolus dose alone, and group 2, after the initial bolus dose and having recovered 10% of T₁, received continuous infusion to maintain T₁ within this value. For both groups, T₁ and T₄/T₁ values were recorded during recovery, as from T₁ in 10% of initial response, every minute up to 30 minutes.

RESULTS: Demographics were homogeneous between groups. Group 2 had slower recovery as compared to group 1. There have been major variations in infusion doses among patients and for the same patient during infusion.

CONCLUSION: In young adult patients without evidences of disease, mivacurium recovery is longer after continuous infusion as compared to bolus infusion. As a consequence of infusion dose variation among patients and for each patient, we recommend the use of neuromuscular transmission monitor to maintain constant and stable relaxation.

Key words: ADMINISTRATION TECHNIQUES, continuous intravenous infusion; MONITORING: neuromuscular transmission; NEUROMUSCULAR BLOCKERS, Non-depolarizing: mivacurium

RESUMEN

JUSTIFICATIVA Y OBJETIVOS: El mivacúrio es un bloqueador neuromuscular (BNM) de corta acción, que presenta una duración total no sobrepasando a 24 minutos. Las primeras comunicaciones científicas relataron que no hay diferencias significativas en el tiempo de recuperación, independientemente de la forma de administración. Sin embargo, la experiencia clínica apunta para recuperaciones más prolongadas cuando se administra el fármaco en infusión continuada. Este trabajo tiene por objetivo comparar el tiempo de recuperación del mivacúrio cuando administrado en bolus y en forma continuada, en un grupo de pacientes jóvenes y adultos.

MÉTODO: Fueron analizados 40 pacientes jóvenes sin enfermedades neuromusculares. Después de recibir midazolam como medicación pre-anestésica, fueron monitorizados en la sala de operación con ECG en D_II y realizada la aferición de la presión arterial indirecta por método automático. Todos recibieron propofol y fentanil, y la anestesia fue mantenida con isoflurano, óxido nitroso y oxígeno. Después de la inducción, fueron instalados el monitor de la transmisión neuromuscular por acelerometria y después de la intubación el capnógrafo y el analisador de gases. Fueron divididos en 2 grupos iguales de acuerdo con el régimen de administración de mivacúrio: los del grupo 1 recibieron solamente dosis inicial en bolus y los del grupo 2, después de la dosis inicial y de haber recuperado 10% de T₁,recibieron infusión continuada para mantener una T₁ en ese valor. Fueron anotados en ambos grupos los valores de T₁ y T₄/T₁ en la fase de recuperación, a partir de T₁ en un 10% de la respuesta inicial, de minuto a minuto, hasta 30 minutos.

RESULTADOS: Los grupos fueron homogéneos con relación a las variables antropométricas. El grupo 2 presentó tiempo de recuperación más lenta que los pacientes que recibieron solamente la dosis inicial en bolus. Hubo grande variación de dosis de infusión entre pacientes y en el propio paciente en el decorrer de la infusión.

CONCLUSIONES: En pacientes jóvenes y adultos sin evidencias de enfermedades, la recuperación del mivacúrio es más lenta después de infusión continuada de que bajo forma única en bolus. En decurrencia de las variaciones de dosis de infusión entre los pacientes y en cada paciente en sí, para mantener un relajamiento constante y estable, se recomienda el uso de monitor de la transmisión neuromuscular.

INTRODUCTION

Mivacurium is a biquartenary benzylisoquinolonium with adult 95 effective dose (DE₉₅) of 0.08 mg.kg^-1. With 0.1 mg.kg^-1 there is neuromuscular block in 95% of patients within 3.8 minutes and total duration does not exceed 24 minutes, characterizing it as a short-acting neuromuscular blocker (NMB) ¹. In continuous infusion, and maintenance infusion to achieve depression of T₁ to 5%, the T₄/T₁ recovery time to 0.7 is recorded of approximately 3.4 minutes. So, mivacurium is well indicated in continuous infusion for long procedures or for those with unexpected duration, since spontaneous is fast and devoid of clinical evidences of cumulative effect ².

Early publications have reported no significant differences in recovery time, regardless of the administration regimen ¹. However, clinical experience points out to longer recovery times when the drug is administered in continuous infusion. This study aimed at comparing recovery time of mivacurium in bolus and continuous infusion in a group of young adult patients with no history of neuromuscular diseases.

METHODS

After the Ethics Committee for Human Research approval and their informed consent, participated of this study 40 patients of both genders, aged 18 to 65 years, physical status ASA I and II, submitted to elective surgeries. Exclusion criteria were pregnancy or breast-feeding, patients with diseases or under medication knowingly interfering with neuromuscular transmission, in addition to history of hypersensitivity to studied drugs. Patients whose mivacurium infusion time has not reached 40 minutes were dropped out from the study.

All patients received 7.5 to 15 mg oral midazolam 90 minutes before surgery. Monitoring in the operating room consisted of ECG in D_II, pulse oximetry and noninvasive blood pressure. After oxygenation under facial mask for 3 minutes, patients were given propofol (maximum 3 mg.kg^-1) and fentanyl (maximum 200 µg) and anesthesia was maintained with isoflurane and up to 2% nitrous oxide and oxygen expired fraction. Immediately after loss of consciousness, neuromuscular transmission monitor by accelerography was installed (TOF Guard^®) on the thumb and stimulating electrodes were placed on the wrist with supramaximal stimulations every 12 seconds. Capnograph, esophageal thermometer and anesthetic gases analyzer were installed after tracheal intubation.

Tracheal intubation conditions at 3 minutes were analyzed by clinical scale described by Viby-Mogensen et al. ³.

Patients were then randomly distributed in two equal groups (n = 20), according to mivacurium administration regimen. Group 1 received initial bolus dose alone and group 2 received, after initial bolus dose, mivacurium continuous infusion to maintain T₁ relaxation in 10% and started when T₁ was within this value.

The following parameters were recorded during infusion at 1, 3, 5 intervals and at every 5 subsequent minutes: T₁, T₄/T₁, infusion dose, blood pressure and pulse. Continuous infusion was withdrawn at surgery completion. For both groups, spontaneous T₁ and T₄/T₁ recovery was recorded from 10% of T₁. This recovery was recorded every minute for 30 minutes. In this same frequency, blood pressure and pulse values were recorded. Halogenate agent was withdrawn in all cases only after 0.9 T₄/T₁ recovery.

Chi-square test was used for demographics, body mass index (BMI) and supramaximal response milliamperage (mA), and Kruskal-Wallis test was used for T₁,T₄/T₁, blood pressure and pulse variables, considering significant p < 0.05.

RESULTS

Groups were homogeneous in demographics data, ASA physical status, BMI and mA (Table I).

Brazilian Journal of Anesthesiology, 2005; 55: 1: 50 - 58

Comparison of recovery time of bolus and continuous infusion mivacurium

Maria Cristina Simões de Almeida

Tracheal intubation conditions at 3 minutes are shown in table II. All patients were intubated in "clinically acceptable" conditions.

Brazilian Journal of Anesthesiology, 2005; 55: 1: 50 - 58

Comparison of recovery time of bolus and continuous infusion mivacurium

Maria Cristina Simões de Almeida

T₄/T₁ and T₁ recovery times are shown in figure 1 and figure 2, respectively. There were significant differences between groups in T₄/T₁ with slower recovery in group 2 (p = 0.021).

Brazilian Journal of Anesthesiology, 2005; 55: 1: 50 - 58

Comparison of recovery time of bolus and continuous infusion mivacurium

Maria Cristina Simões de Almeida

Brazilian Journal of Anesthesiology, 2005; 55: 1: 50 - 58

Comparison of recovery time of bolus and continuous infusion mivacurium

Maria Cristina Simões de Almeida

Continuous infusion dose variation as a function of time is shown in figure 3. Mean dose was 8 ± 3.15 mg.kg^-1.min^-1.

Brazilian Journal of Anesthesiology, 2005; 55: 1: 50 - 58

Comparison of recovery time of bolus and continuous infusion mivacurium

Maria Cristina Simões de Almeida

Pulse variations during infusion, and systolic blood pressure and pulse variations for groups 1 and 2 during recovery are shown in figure 4, figure 5 and figure 6, respectively. There were no significant changes in those hemodynamic variables.

Brazilian Journal of Anesthesiology, 2005; 55: 1: 50 - 58

Comparison of recovery time of bolus and continuous infusion mivacurium

Maria Cristina Simões de Almeida

Brazilian Journal of Anesthesiology, 2005; 55: 1: 50 - 58

Comparison of recovery time of bolus and continuous infusion mivacurium

Maria Cristina Simões de Almeida

Brazilian Journal of Anesthesiology, 2005; 55: 1: 50 - 58

Comparison of recovery time of bolus and continuous infusion mivacurium

Maria Cristina Simões de Almeida

DISCUSSION

The most important result of our study is that mivacurium recovery is significantly slower in continuous infusion. This result differs from others in which there have been no differences in recovery rate for different administration regimens ^1,4,5. At a first sight, slower recovery suggests that mivacurium may have a certain degree of accumulation, or that the association with inhalational agents have some residual effect.

Commercial mivacurium presentation is a mixture of 3 stereoisomers: trans-trans, trans-cis and cis-cis. The two formers contribute with 60% and 30% respectively for drug potency and are excreted in approximately 2 minutes. Cis-cis isomer has a different kinetic profile. It is responsible for just 8% of potency and is excreted in approximately 52 minutes ⁶. So, clinical behavior of the drug is predominantly determined by trans-trans and cis-trans isomers, thus characterizing the drug as short-acting neuromuscular blocker. For this reason, it is not recommended to use anticholinesterase drugs during single injection regimen because spontaneous recovery in patients with normal pseudocholinesterase is a rapid process ^1,7. If the decision is to revert with neostigmine or edrophonium, although inhibiting pseudocholinesterase, they satisfactorily revert mivacurium action ^1,8, but the magnitude of the benefit is limited ⁹.

As opposed to early publications ¹, a mivacurium pharmacological study has shown that after a second infusion regimen there is a certain level of cis-cis isomer build up in plasma ¹⁰. This gives the drug a different profile in infusion regimen; in terms of spontaneous recovery, that is, when the idea is not administering neostigmine at procedure completion, longer recovery time would be a limitation of the technique.

Another observation of this study, and to which other authors have noticed, is the different recovery rate of T₁ and 4^th TOF response. This fact is known as fatigue and is a characteristic of non-depolarizing neuromuscular blockers, such as mivacurium. A challenge to this fact is based on the quantal acetylcholine release theory. Scientific evidences show that after nerve stimulation there is physiological release of 20 to 30 times the necessary amount of neurotransmitter - acetylcholine - to promote depolarization. When non-depolarizing NMBs are used, in addition to post-synaptic effect, they also occupy pre-synaptic nicotinic receptors decreasing acetylcholine release. The discussion is whether this lower acetylcholine release caused by the action of the blocker on pre-synaptic receptor would be enough to promote such significant decrease in muscle contraction. The basis for this discussion is an experimental study by Wessler et al. ¹¹ who have only found decreased acetylcholine release after partial blockade with d-tubocurarine after 10 to 15 nervous stimulations.

Another curious fatigue phenomenon fact is the behavior of myasthenic syndrome patients who present fatigue in the absence of neuromuscular blockers. It is known that this pathology presents post-synaptic receptor changes, and evidences with mutant genes point to changes in a or b subunits depending on the type of myasthenic syndrome. It is interesting to observe that g subunit synthesis is not present in this auto-immune disease ^12,13. These patients have an increase in the number of acetylcholine molecules in response to changes in muscle nicotinic receptors. Intriguingly, there is fatigue even with increased numbers of agonist molecules (acetylcholine). This and other evidences suggest that mechanisms might be involved in fatigue, other than pre-synaptic occupation of neuronal nicotinic receptors ¹⁴.

Intubation conditions evaluated by clinical scale ³, where considered excellent or good at 3 minutes, with some patients presenting diaphragmatic movements after cuff inflation. These good results with 0.2 mg.kg^-1 have already been described by Shanks et al. ¹⁰. There has been wide variation in infusion doses among patients and constant infusion during procedure was virtually not achieved. Convincing explanations were not found in the literature about variations in the same patient. Dose variation among patients is known by the literature and authors relate it to differences in plasma cholinesterase activity ^5,15,16.

Mivacurium is enzymatically hydrolyzed by pseudocholinesterase at 88% rate as compared to succinylcholine, resulting in quaternary aminoalcohol compounds and quaternary monoester, both also hydrolyzed in plasma ^1,5,17.

There have also been wide infusion dose variations in the same patient throughout the procedure, either needing up to 15 µg.kg^-1.min^-1 or periods without mivacurium infusion. No convincing explanation for this phenomenon was found in the literature since neither drugs which could potentiate blockade were used nor there have been situations of major intraoperative blood losses or thermal variations.

Mean infusion dose of 8 ± 3.15 mg.kg^-1.min^-1 is in line with previous results, emphasizing that volatile agents potentiate blockade level in approximately 20% to 30% ^10,18.

In conclusion, there is longer recovery time when mivacurium is administered in continuous infusion as compared to bolus injection. Equally important is to report major mean dose variation among patients receiving continuous infusion and variations for the same patient during infusion. These factors suggest cautiousness with continuous infusion and the need to assess muscle relaxation with neuromuscular transmission monitors.

REFERENCES

Submitted for publication April 22, 2004

Accepted for publication September 13 de setembro de 2004

• 01. 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;68:723-732.
• 02. Savarese JJ - Mivacurium: a comparison with other benzylisoquinolinium non-depolarising muscle relaxants. J Drug Dev, 1993;5:1-5.
• 03. Viby-Mogensen J, Engbaek J, Eriksson LI et al - Good clinical research practice (GCRP) in pharmacodynamic studies of neuromuscular blocking agents. Acta Anaesthesiol Scand, 1996;40:59-74.
• 04. Goudsouzian N, Chakravorti S, Denman W et al - Prolonged mivacurium infusion in young and elderly adults. Can J Anaesth, 1997;44:955-962.
• 05. Ali HH, Savarese JJ, Embree PB et al - Clinical pharmacology of mivacurium chloride (BW B1090U) infusion: comparison with vecuronium and atracurium. Br J Anaesth, 1988;61:541-546.
• 06. 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;80:1296-1302.
• 07. Goldhill DR, Whitehead JP, Emmott RS et al - Neuromuscular and clinical effects of mivacurium chloride in healthy adult patients during nitrous oxide-enflurane anaesthesia. Br J Anaesth, 1991;67:289-295.
• 08. Savarese JJ, Ginsburg S, Braswell L et al - Actions at neuromuscular and esteratic cholinoceptive sites of some phenylene diacryloyl bis-cholinium esters. J Pharmacol Exp Ther, 1979;208:436-445.
• 09. Szenohradszky J, Fogarty D, Kirkegaard-Nielsen H et al - Effect of edrophonium and neostigmine on the pharmacokinetics and neuromuscular effects of mivacurium. Anesthesiology, 2000;92:708-714.
• 10. Shanks CA, Fragen RJ, Pemberton D et al - Mivacurium-induced neuromuscular blockade following single bolus doses and with continuous infusion during either balanced or enflurane anesthesia. Anesthesiology, 1989;71:362-366.
• 11. Wessler I, Rasbach J, Scheuer B et al - Effects of (+)-tubocurarine on [3H]acetylcholine release from the rat phrenic nerve at different stimulation frequencies and train lengths. Naunyn Schmiedebergs Arch Pharmacol, 1987;335:496-501.
• 12. Guyon T, Wakkach A, Poea S et al - Regulation of acetylcholine receptor gene expression in human myasthenia gravis muscles. Evidences for a compensatory mechanism triggered by receptor loss. J Clin Invest, 1998;102:249-263.
• 13. Milone M, Wang HL, Ohno K et al - Mode switching kinetics produced by a naturally occurring mutation in the cytoplasmic loop of the human acetylcholine receptor epsilon subunit. Neuron, 1998;20:575-588.
• 14. Feldman S - Second thoughts on the train-of-four. Anaesthesia, 1993;48:1-2.
• 15. Hart PS, McCarthy GJ, Brown R et al - The effect of plasma cholinesterase activity on mivacurium infusion rates. Anesth Analg, 1995;80:760-763.
• 16. Markakis DA, Hart PS, Lau M et al - Does age or pseudocholinesterase activity predict mivacurium infusion rate in children? Anesth Analg, 1996;82:39-43.
• 17. Cook DR, Stiller RL, Weakly JN et al - In vitro metabolism of mivacurium chloride (BW B1090U) and succinylcholine. Anesth Analg, 1989;68:452-456.
• 18. Maddineni VR, Mirakhur RK - Prolonged neuromuscular block following mivacurium. Anesthesiology, 1993;78:1181-1184.

Correspondence to

Dra. Maria Cristina Simões de Almeida

Address: Rua Renato Barbosa, 227 Jurerê Tradicional

ZIP: 88053-640 City: Florianópolis, Brazil

*

Received from Hospital Governador Celso Ramos, CET Integrado da SES/SC, Florianópolis, SC

Publication Dates

• Publication in this collection
  01 Mar 2005
• Date of issue
  Feb 2005

History

• Accepted
  13 Sept 2004
• Received
  22 Apr 2004