Effect of priming in shortening onset of pipecuronium, a new nondepolarizing neuromuscular blocker

Abstracts

JUSTIFICATIVA E OBJETIVOS: Uma das mais importantes propriedades dos bloqueadores neuromusculares é o rápido início de ação, possibilitando intubação traqueal precoce. A administração de pequena dose de bloqueador não-despolarizante antes da dose plena é sabidamente redutora da latência da maioria dos bloqueadores neuromusculares utilizados. O brometo de pipecurônio é um agente aminoesteróide de longa duração com grande estabilidade cardiovascular, porém, com início de ação tardio. O objetivo desse estudo foi avaliar o efeito do priming do pipecurônio em pacientes adultos submetidos a cirurgias eletivas sob anestesia geral. MÉTODO: Foram estudados 33 pacientes adultos de ambos os sexos, com idade entre 20 e 65 anos, estado físico ASA I ou II, submetidos a cirurgias eletivas sob anestesia geral. Foram excluídos do estudo pacientes com insuficiência renal ou hepática, neuromiopatia, uso concomitante de drogas que influenciem a sua farmacocinética ou pacientes com histórico familiar de hipertermia maligna. Foram divididos em dois grupos: Grupo 1 onde foi utilizado o priming com 0,01 mg.kg-1 e três minutos depois completada a dose de 0,08 mg.kg-1 e o Grupo 2, sem dose priming (Grupo Controle). O relaxamento neuromuscular foi controlado pela aceleromiografia (Aparelho TOF-Guard) e no momento em que T1 < 10% era realizada a laringoscopia. A análise estatística foi feita pelos testes T para amostras independentes e a normalidade pelo Shapiro Wilks. RESULTADOS: Os grupos foram homogêneos e observou-se que o tempo para T1 < 10% no Grupo 1 foi de 161,4 ± 13,7 segundos e no Grupo 2 foi 217,8 ± 23,4 segundos, com p < 0,001, havendo diferença estatística significativa entre os grupos. CONCLUSÕES: Os resultados do estudo mostraram diferença estatística significativa entre os grupos com e sem priming, indicando que o pipecurônio também tem latência reduzida, assim como os demais bloqueadores neuromusculares conhecidos.

BLOQUEADORES NEUROMUSCULARES; BLOQUEADORES NEUROMUSCULARES

SCIENTIFIC ARTICLE

Effect of priming in shortening onset of pipecuronium, a new nondepolarizing neuromuscular blocker^*

Efecto del priming en la reducción de la latencia del pipecuronio, nuevo bloqueador neuromuscular no despolarizante

José Carlos Canga, TSA, M.D.^I; Carlos Neutzling Lehn, M.D.^II; Deoclécio Tonelli, TSA, M.D.^III; Paula de Camargo Neves Sacco, TSA, M.D.^IV; Danielle Beltrão, M.D.^V; Marcelo Kirsch, M.D.^V; Fernando César Serralheiro, M.D.^V; Gustavo Cimerman, M.D.^VI

^IAnestesiologista, Co-Responsável pelo CET Integrado de Anestesiologia da Faculdade de Medicina ABC

^IIChefe do Serviço de Cabeça e Pescoço do Hospital Heliópolis. Doutor em Medicina pela UNIFESP. Professor do Curso de Pós-Graduação do Complexo Hospitalar Heliópolis

^IIIAnestesiologista, Responsável pelo CET Integrado de Anestesiologia da Faculdade de Medicina ABC

^IVAnestesiologista, Instrutora do CET Integrado de Anestesia da Faculdade de Medicina ABC

^VAnestesiologista, Ex-Residente do CET Integrado de Anestesia da Faculdade de Medicina ABC

^VIME₃ do CET Integrado de Anestesia da Faculdade de Medicina ABC

^{Correspondence}

SUMMARY

BACKGROUND AND OBJECTIVES: One of the most important neuromuscular blockers property is short onset, allowing early tracheal intubation. Low nondepolarizing blocker dose before the full dose is known to decrease the onset of most neuromuscular blockers. Pipecuronium bromide is a long-lasting aminosteroid with major cardiovascular stability, however, with late onset. This study aimed at evaluating pipecuronium priming effect in adult patients submitted to elective surgeries under general anesthesia.

METHODS: Participated in this study 33 adult patients of both genders, aged 20 to 65 years, physical status ASA I or II, to be submitted to elective surgeries under general anesthesia. Exclusion criteria were patients with kidney or liver failure, neuromuscular diseases, in concurrent use of drugs influencing pipecuronium pharmacokinetics, and patients with family history of malignant hyperthermia. Patients were divided in 2 groups: Group 1 = priming with 0.01 mg.kg^-1 and 3 minutes later the remaining 0.07 mg.kg^-1 (total 0.08 mg.kg^-1); Group 2 = no priming dose (group control). Neuromuscular relaxation was controlled by acceleromyography (TOF-Guard device) and laryngoscopy was accomplished when T₁ < 10%. T test for independent samples was used for statistical analysis and Shapiro Wilks was used to test normality.

RESULTS: Groups were homogeneous. Time for T₁ < 10% was 161.4 ± 13.7 seconds for Group 1 and 217.8 ± 23.4 seconds for Group 2, with p < 0.001 and statistically significant differences between groups.

CONCLUSIONS: Our results have shown statistically significant differences between groups with and without priming, indicating that pipecuronium also has its onset decreased, similarly to other known neuromuscular blockers.

Key Words: NEUROMUSCULAR BLOCKERS, Nondepolarizing: pipecuronium

RESUMEN

JUSTIFICATIVA Y OBJETIVOS: Una de las más importantes propiedades de los bloqueadores neuromusculares es el rápido inicio de acción, posibilitando intubación orotraqueal precoz. La administración de pequeña dosis del bloqueador no despolarizante antes de la dosis completa es consabidamente reductora de la latencia de la mayoría de los bloqueadores neuromusculares utilizados. El bromuro de pipecuronio es un agente aminoesteroide de larga duración con grande estabilidad cardiovascular, sin embargo, con inicio de acción tardía. El objetivo de ese estudio es evaluar el efecto del priming del pipecuronio en pacientes adultos sometidos a cirugías electivas bajo anestesia general.

MÉTODO: Fueron estudiados 32 pacientes adultos de ambos sexos, con edad entre 20 y 65 años, estado físico ASA I ó II, a ser sometidos a cirugías electivas bajo anestesia general. Fueron excluidos del estudio pacientes con insuficiencia renal o hepática, neuromiopatia, uso concomitante de drogas que influencien la farmacocinética de la droga o pacientes con histórico familiar de hipertermia maligna. Fueron divididos en dos grupos: Grupo 1 donde fue utilizada el priming con 0,01 mg.kg^-1 3 minutos después de completada la dosis de 0,08 mg.kg-1 y el Grupo 2, sin dosis priming (Grupo Control). El relajamiento neuromuscular fue controlado por la aceleromiografía (Aparato TOF-Guard) y en el momento en que T₁ < 10% era realizada la laringoscopia. El análisis estadístico fue hecha por la prueba T para muestras independientes y la normalidad testada por el Shapiro Wilks.

RESULTADOS: Los grupos fueron homogéneos y se observó que el tiempo para T₁ < 10% en el Grupo 1 fue de 161,4 ± 13,7 segundos y en el Grupo 2 fue 217,8 ± 23,4 segundos, con p < 0,001, habiendo diferencia estadísticamente significativa entre los grupos.

CONCLUSIONES: Los resultados del estudio mostraron diferencia estadísticamente significativa entre los grupos con y sin priming, indicando que el pipecuronio también tiene latencia reducida, así como también los demás bloqueadores neuromusculares conocidos.

INTRODUCTION

Fast onset allowing early tracheal intubation is one of the most important neuromuscular blocker properties ^1-3.

A low nondepolarizing blocker dose before its full dose is recommended to obtain ideal tracheal intubation conditions in a shorter period of time ^1,4,5.

Pipecuronium bromide is a long-lasting aminosteroid neuromuscular blocker, with negligible cardiovascular effects until DE 95 (0.15 mg.kg^-1) ^4,6,7.

This study aimed at evaluating the effects of low pipecuronium priming dose (0.01 mg.kg^-1) before the remaining dose (0.07 mg.kg^-1) on onset, as compared to bolus injection of the same drug (0.08 mg.kg^-1).

METHODS

After the Ethics Committee, Hospital de Ensino Padre Anchieta, Hospital de Ensino Faculdade de Medicina ABC, participated in this randomized double-blind study 33 adult patients of both genders, aged 20 to 65 years, physical status ASA I and II, to be submitted to elective surgeries under general anesthesia with tracheal intubation and lasting more than 60 minutes. Exclusion criteria were patients with kidney or renal failure, body mass index above 30, neuromuscular disease, family history of malignant hyperthermia or under drugs interfering with neuromuscular transmission.

After preanesthetic evaluation the day before surgery, patients were premedicated with oral midazolam (15 mg) one hour before surgery.

Monitoring in the operating room consisted of ECG at D_II lead to evaluate cardiac rhythm and heart rate (HR), pulse oximetry (SpO₂), capnography and noninvasive blood pressure (NIBP).

Neuromuscular transmission was monitored by acceleromyography (TOF-Guard) every 15 seconds to evaluate adductor pollicis muscle response with stimulating electrodes on wrist ulnar nerve.

Anesthesia was induced with intravenous fentanyl (2 to 5 µg.kg^-1), propofol (3 mg.kg^-1) or etomidate (0.2 mg.kg^-1) and was maintained with 1:1 N₂O/O₂ and sevoflurane in enough concentration to maintain anesthetic depth, observing heart rate, blood pressure, pupil diameter changes and tearing. Breathing was controlled with tidal volume and respiratory rate adjusted according to P_ETCO₂. TOF-Guard was installed after anesthetic induction and ulnar nerve stimulation was only started when patients were asleep.

Patients received intravenous neuromuscular blocker and were divided in two groups of 16 patients:

Group 1 - pipecuronium with priming: patients were given 0.01 mg.kg^-1 and 3 minutes later the remaining drug was added (0.07 mg.kg^-1) to complete 0.08 mg.kg^-1.

Group 2 - pipecuronium without priming: patients were given a bolus 0.08 mg.kg^-1 dose.

Laryngoscopy was accomplished when T₁ < 10% (T10%) and this period was considered neuromuscular blocker onset (O).

Excel 97 and Statistic v. 6 were the pieces of software used for statistical treatment of data.

RESULTS

Data were analyzed by descriptive statistics and represented in central trend measurements and error, mean and standard deviation and percentage count, as shown in table I.

Brazilian Journal of Anesthesiology, 2005; 55: 4: 381-386

Effect of priming in shortening onset of pipecuronium, a new nondepolarizing neuromuscular blocker

José Carlos Canga; Carlos Neutzling Lehn; Deoclécio Tonelli; Paula de Camargo Neves Sacco;

Danielle Beltrão; Marcelo Kirsch; Fernando César Serralheiro; Gustavo Cimerman

T test for independent samples was used to compare parametric variables between groups (age, body mass and onset) (Table I), considering significant p < 0.05. Table I show means, percentage distributions and differences between groups in demographics, physical status and onset.

Parametric variables were defined as those with continuous ratio scale and distributed within the normality curve, confirmed by Shapiro Wilk test.

Groups were similar in age, body mass, physical status and gender, indicating homogeneity and parity among studied subjects characteristics (Table I).

Group receiving pipecuronium without priming (Group 2) had significant longer onset as compared to the group induced with the same drug, however without priming (p < 0.05) (Table I).

DISCUSSION

Pipecuronium bromide is a long-lasting nondepolarizing neuromuscular blocker. Its chemical formulation is C35 H62 N 4 O4 BR 2 2H2 O (b-diacetoxi-aridostrane) with 798.74 molecular weight and low liposolubility ^1,2,8.

As with other neuromuscular blockers, its phamarcokinetics and pharmacodynamics are influenced by age, obesity, kidney and liver failure, drugs and neuromuscular diseases ^4,5,9. Volatile inhalational anesthetics associated to pipecuronium usually prolong its duration. The association with isoflurane increases blocker duration in 12%; associated to enflurane there is approximately 50% increase ^3,6,9. Parenteral antibiotics, such as neomycin, streptomycin and gentamycin, in high doses, exacerbate neuromuscular block ^1-3.

In myasthenia gravis patients, low nondepolarizing neuromuscular blocker doses may have exaggerated effects, being indicated short-lasting agents for those patients and counterindicated pipecuronium ¹².

Priming action mechanism may be explained by the wide safety margin in neuromuscular transmission. Approximately 75% of neuromuscular receptors have to be occupied for any neuromuscular function change evaluated by acceleromyography to be detected ¹³. If a low nondepolarizing neuromuscular blocker dose is given and occupies a small portion of 75% of neuromuscular receptors, the second higher dose will provide shorter onset ^1-3,13,14.

Our study has evaluated pipecuronium onset by two different techniques: control group (Group 2) without priming and group 1 with priming before total blocker dose.

The study has shown that the priming technique was statistically acceptable in shortening onset, as compared to the other technique. Similar observations were reported by other authors using different neuromuscular blockers, such as vecuronium ⁸, pancuronium ⁹ and atracurium ¹⁰.

Some authors ¹¹ have studied the priming effect of pipecuronium as compared to bolus injection of the same drug and have observed results similar to ours. Onset time after bolus pipecuronium injection (0.08 mg.kg^-1) was 217 seconds, similar to other authors' results ^7,12,14,15 and longer than those reported by others ¹¹.

With priming, onset was 161 seconds, slightly higher that those reported in the literature ^11,15.

Our conclusion was that, similar to other nondepolarizing neuromuscular blockers, pipecuronium also has its onset shortened if priming dose is administered three minutes before total dose.

So, it could be observed that priming was effective in shortening pipecuronium onset in our patients.

ACKNOWLEDGMENTS

We acknowledge Isabel de Camargo Neves Sacco for the excellent statistical analysis of this study.

REFERENCES

Submitted for publication November 18, 2004

Accepted for publication April 13, 2004

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  Swen J, Rashkovsky OM, Ket J et al - Interactions between nondepolarizing neuromuscular blocking agents and inhalational anesthetics. Anesth Analg, 1989;69:752-755
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  Paton WD, Waud DR - The margin of safety of neuromuscular transmission. J Physiol, 1967;191:59-90.
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  Atherton DP, Hunter JM - Clinical pharmacokinetics of the newer neuromuscular blocking drugs. Clin Pharmacokinet, 1999;36: 169-189.
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Correspondence to

Dra. Paula de Camargo Neves Sacco

Address: Avenida Portugal, 723/72

ZIP: 09040-011 City: Santo André, Brazil

*

Received from CET Integrado de Anestesiologia da Faculdade de Medicina ABC, Santo André, SP

Publication Dates

• Publication in this collection
  24 Oct 2005
• Date of issue
  Aug 2005

History

• Accepted
  13 Apr 2004
• Received
  18 Nov 2004