Neuromuscular and cardiovascular effects of pipecuronium: a comparative study between different dose

Abstracts

JUSTIFICATIVA E OBJETIVOS: O pipecurônio é um bloqueador neuromuscular não-despolarizante, com propriedades similares as do pancurônio, mas desprovido de efeitos cardiovasculares. Foram avaliados os efeitos neuromusculares, as condições de intubação traqueal e as repercussões hemodinâmicas de duas diferentes doses de pipecurônio. MÉTODO: Pacientes foram distribuídos em dois grupos de acordo com a dose de pipecurônio: Grupo I (0,04 mg.kg-1) e Grupo II (0,05 mg.kg-1). A medicação pré-anestésica consistiu em midazolam (0,1 mg.kg-1) por via muscular, 30 minutos antes da operação. A indução anestésica foi obtida com propofol (2,5 mg.kg-1) precedido de fentanil (5 µg.kg-1) e pipecurônio nas doses de 0,04 e 0,05 mg.kg-1 para os Grupos I e II, respectivamente. Os pacientes foram ventilados com O2 a 100% sob máscara até a redução de 75% da amplitude da resposta a estímulo isolado (1 Hz), quando foram realizadas a laringoscopia e intubação traqueal. O isoflurano (0,5 a 1%) em mistura de O2 e N(2)0 a 50% para a manutenção da anestesia, foi introduzido logo após a intubação traqueal. Os pacientes foram ventilados mecanicamente para manter P ET CO2 entre 32 e 36 mmHg. A farmacodinâmica do pipecurônio foi avaliada por aceleromiografia. RESULTADOS: Os tempos médios e desvios-padrão para o início de ação, duração clínica (T1(25%)) e índice de recuperação (T1(25-75%)) foram: Grupo I (122,10 ± 4,18 s, 49,63 ± 9,54 min e 48,21 ± 6,72 min) e Grupo II (95,78 ± 8,91 s, 64,84 ± 13,13 min e 48,52 ± 4,95 min). O início de ação, a duração clínica e as condições de intubação traqueal foram significativamente diferentes entre os grupos. CONCLUSÕES: O pipecurônio na dose 0,05 mg.kg-1 pode ser usado em procedimentos de longa duração, nos quais é desejável evitar alterações cardiocirculatórias.

BLOQUEADORES NEUROMUSCULARES, Não-Despolarizantes; FARMACOLOGIA; FARMACOLOGIA

SCIENTIFIC ARTICLE

Neuromuscular and cardiovascular effects of pipecuronium. A comparative study between different doses^*

Efectos neuromusculares y cardiovasculares del pipecuronio. Estudio comparativo entre diferentes dosis

Angélica de Fátima de Assunção Braga, TSA, M.D.^I; Leandro Yoshioka, M.D.^II; Franklin Sarmento da Silva Braga, M.D.^III; Gloria Maria Braga Potério, TSA, M.D.^I; José Aristeu F. Frias, TSA, M.D.^IV; Rita de Cássia Rodrigues, TSA, M.D.^V

^IProfessora Livre-Docente em Anestesiologia; Professora-Associada do Departamento de Anestesiologia da FCM/UNICAMP

^IIAnestesiologista

^IIIProfessor-Assistente Doutor do Departamento de Anestesiologia da FCM/UNICAMP

^IVAnestesiologista CAISM - UNICAMP

^VProfessora Adjunta Disciplina de Anestesiologia, Dor e Terapia Intensiva Cirúrgica da Escola Paulista de Medicina da Universidade Federal de São Paulo, UNIFESP

Correspondence to

SUMMARY

BACKGROUND AND OBJECTIVES: Pipecuronium is a non-depolarizing neuromuscular blocker with similar properties to pancuronium, but without cardiovascular effects. Neuromuscular effects, conditions of tracheal intubation, and hemodynamic repercussions of two different doses of pipecuronium were evaluated.

METHOD: Patients were divided into two groups according to the dose of pipecuronium: Group I (0.04 mg.kg^-1) and Group II (0.05 mg.kg^-1). Intramuscular midazolam (0.1 mg.kg^-1) was administered 30 minutes before the surgery. Propofol (2.5 mg.kg^-1), preceded by fentanyl (5 µg.kg^-1) and pipecuronium (0.04 and 0.05 mg.kg^-1 for Groups I and II, respectively), was administered for anesthetic induction. Patients were ventilated with 100% oxygen via a face mask until a 75% reduction in the amplitude of the response to an isolated stimulus (1 Hz) is achieved, at which time laryngoscopy and intubation were carried out. Anesthetic maintenance was achieved with isoflurane (0.5 to 1%) with a mixture of 50% O₂ and N₂O. Mechanical ventilation was used to maintain P_ETCO₂ between 32 and 36 mmHg. The pharmacodynamics of pipecuronium was evaluated by acceleromyography.

RESULTS: Mean times and standard deviation for the onset of action, clinical duration (T1_25%), and recovery index (T1_25-75%) were: Group I (122.10 ± 4.18 sec, 49.63 ± 9.54 min, and 48.21 ± 6.72 min), and Group II (95.78 ± 8.91 sec, 64.84 ± 13.13 min, and 48.52 ± 4.95 min). Onset of action, clinical duration, and conditions of tracheal intubation were significantly different for both groups.

CONCLUSIONS: Pipecuronium at a dose of 0.05 mg.kg^-1 can be used in prolonged procedures in which cardiovascular changes should be avoided.

Key Words: NEUROMUSCULAR BLOCKERS, Non-depolarizing, Pipecuronium; PHARMACOLOGY: Pharmacodynamics, Pharmacokinetics.

RESUMEN

JUSTIFICATIVA Y OBJETIVOS: El pipecuronio es un bloqueador neuromuscular no despolarizador, con propiedades similares a las del pancuronio, pero desprovisto de efectos cardiovasculares. Se evaluaron los efectos neuromusculares, condiciones de intubación traqueal y las repercusiones hemodinámicas de de los diferentes dosis de pipecuronio.

MÉTODO: Los pacientes fueron distribuidos en de los grupos de acuerdo a la dosis de pipecuronio: Grupo I (0,04 mg.kg^-1) y Grupo II (0,05 mg.kg^-1). La medicación preanestésica consistió en midazolam (0,1 mg.kg^-1) por vía muscular, 30 minutos antes de la operación. La inducción anestésica se obtuvo con propofol (2,5 mg.kg^-1) precedido del fentanil (5 µg.kg^-1) y del pipecuronio en las dosis de 0,04 y 0,05 mg.kg^-1 para los Grupos I y II, respectivamente. Los pacientes se ventilaron con O₂ a 100% bajo máscara hasta la reducción de un 75% de la amplitud de la respuesta al estímulo aislado (1 Hz), cuando fueron realizadas la laringoscopía y la intubación traqueal. El isoflurano (0,5 a 1%) en mezcla de O₂ y N₂0 a un 50% para el mantenimiento de la anestesia, fue introducido a continuación de la intubación traqueal. Los pacientes fueron ventilados mecánicamente para mantener el P_ETCO₂ entre 32 y 36 mmHg. La farmacodinámica del pipecuronio se evaluó por aceleromiografía.

RESULTADOS: Los tiempos promedios y desviaciones estándar para el inicio de acción, duración clínica (T1_25%) e índice de recuperación (T1_25-75%) fueron los siguientes: Grupo I (122,10 ± 4,18 seg, 49,63 ± 9,54 min y 48,21 ± 6,72 min) y Grupo II (95,78 ± 8,91 seg, 64,84 ± 13,13 min y 48,52 ± 4,95 min). El inicio de acción, la duración clínica y las condiciones de intubación traqueal fueron significativamente diferentes entre los grupos.

CONCLUSIONES: El pipecuronio, en la dosis 0,05 mg.kg^-1 puede ser usado en procedimientos de larga duración donde se desee evitar alteraciones cardiocirculatorias.

INTRODUCTION

Pipecuronium is an aminosteroid, bisquaternary, non-depolarizing neuromuscular blocker. It resulted from modifications in the molecule of pancuronium, substituting the piperidinic ring, bound to positions 2 and 16 of the steroidal nucleus, by a piperazinic ring. Those modifications increased potency by 20% to 30% (ED₉₅ = 35 µg.kg^-1 to 50 µg.kg^-1 during balanced anesthesia) and reduced by about ten times its vagolytic activity, with reduced affinity for cardiac receptors. Duration of action and latency depend on the dose and are similar to pancuronium. It is eliminated mainly by the kidneys (70% to 80%), and a small fraction is eliminated through the bile after being metabolized in the liver. Similarly to other neuromuscular blockers with a steroid ring, it has minimal ganglionic blocking and release of histamine activities. For this reason, the cardiovascular effects of pipecuronium are not evident even with doses above 4 ED₉₅^1-10. The objective of this study was to evaluate the neuromuscular and cardiovascular effects as well as the conditions of tracheal intubation of different doses of pipecuronium.

METHODS

After approval by the Ethics Commission of the hospital and signing of the informed consent, 38 adult patients, physical status ASA I and II, ages varying from 26 to 63 years, and weight between 51 and 90 kg, scheduled for elective surgeries under general anesthesia with indication of tracheal intubation and controlled mechanical ventilation were included in this study. Patients were randomly divided into two groups (n = 19) according to the dose of pipecuronium administered: Group I (0.04 mg.kg^-1) and Group II (0.05 mg.kg^-1). Exclusion criteria included history of neuromuscular, renal, or liver disease, water and electrolyte and acid-base imbalances, temperature changes, indicative signs of difficult laryngoscopy and tracheal intubation maneuvers (Mallampati II and IV) ¹¹, history of gastroesophageal reflux, and use of drugs that interact with neuromuscular blockers.

Intramuscular midazolam (0.1 mg.kg^-1) was administered 30 minutes before the surgery. In the operating room, a peripheral venous access was established for hydration and administration of drugs. Anesthetic induction was achieved with fentanyl (5 µg.kg^-1) followed by propofol (2.5 mg.kg^-1) and pipecuronium, 0.04 and 0.05 mg.kg^-1 for Groups I and II respectively. Patients were ventilated with oxygen via a face mask, and laryngoscopy and tracheal intubation were carried out when a 75% reduction in the amplitude of muscular responses to isolated stimulus (1 Hz) was achieved. In both groups, isoflurane (0.5 to 1.0%) in a mixture of 50% O₂ and N₂O, instituted immediately after the intubation, was used for anesthetic maintenance. Additional doses of fentanyl (2 µg.kg^-1) were administered whenever signs of superficial anesthesia were evident (blood pressure and heart rate above baseline levels). Mechanical ventilation was instituted to maintain P_ETCO₂ between 32 and 36 mmHg.

Patients were monitored with continuous cardioscopy in D_II, pulse oximetry, capnography, non-invasive blood pressure, and acceleromyography. The temperature of the skin above the monitored muscle (adductor pollicis) was measured and maintained at 32°C. Before anesthetic induction, supramaximal stimuli (1 Hz) were applied for 3 minutes to stabilize the neuromuscular response of the adductor pollicis muscle, using surface electrodes on the route of the ulnar nerve in the wrist. An acceleration transducer (piezoelectric) was placed on the distal phalange of the monitored limb. Stimulation with isolated stimuli was maintained during anesthetic induction until tracheal intubation to record the latency time of the neuromuscular blocker. After tracheal intubation, ulnar nerve stimulation continued with train-of-four (TOF) stimuli every 15 seconds. The response of the adductor pollicis muscle, shown in charts and digital numbers, were stored in a memory card and reproduced later in a previously programmed computer. In the tracing recordings of the muscular responses (Figures 1 and 2), one can observe in both groups: 1) onset of action of pipecuronium - time in seconds between the administration of pipecuronium and a 75% reduction in the amplitude of the muscular response to isolated stimuli; 2) clinical duration of pipecuronium (T1_25%) - time in minutes between the administration of pipecuronium and a 25% recovery in the amplitude of the first response to TOF; and 3) recovery index (RI = T1_25-75%) - time in minutes until the recovery from 25% to 75% in the amplitude of the response to the first response to TOF. The conditions of tracheal intubation were analyzed according to the method proposed by Goldberg et al. ¹², including the degree of difficulty of laryngoscopy, presence and severity of cough, and position and movement of the vocal cords, which received a score of one to four (Chart I). A score equal to or below two for the three parameters corresponded to satisfactory intubation conditions, and scores above 2 for one of the parameters were consider unsatisfactory. Cardiovascular parameters (heart rate - bpm, and mean arterial pressure - mmHg) were recorded at the following moments for analysis: after administration of pre-anesthetic medication and immediately before anesthetic induction (M0); five minutes after the administration of fentanyl (M1); immediately before tracheal intubation (M2); and one minute after intubation (M3).

Results are expressed in means and standard deviation. ANOVA was used to test the homogeneity between groups and hemodynamic parameters; the Kruskal-Wallis test was used to analyze neuromuscular parameters; and the Chi-square test for the conditions of tracheal intubation. It was established a level of statistical significance of 5% (p < 0.05).

RESULTS

Groups did not show significant differences in demographic data, and were deemed homogenous. This was also observed for the temperature in the tenar region (adductor pollicis muscle) and pressure of expired CO₂ (Table I).

The onset of action was significantly shorter in Group II (pipecuronium - 0.05 mg.kg^-1) than in Group I (pipecuronium - 0.04 mg.kg^-1). Clinical duration (T1_25%) was significantly longer in Group II, and the recovery index was similar in both groups (Table II and Figures 1 and 2).

Clinical conditions for intubation in Group 1 were considered satisfactory in six patients (31.57%) and unsatisfactory in 13 patients (68.42%). In Group II, they were satisfactory in 15 cases (78.94%) and unsatisfactory in four (21.05%). The difference between both groups was statistically significant.

Hemodynamic changes were similar in both groups; mean MAP and HR did not show statistically significance differences at all evaluation moments. Table III shows mean values and standard deviation of cardiovascular parameters. Both groups needed and extra dose of fentanyl intraoperatively, which ranged from 200 to 300 µg.

DISCUSSION

The objective of this study was to evaluate the pharmacodynamic characteristics of pipecuronium in conditions similar to those in which this drug is normally used. In anesthesia induction is one of the critical moments due to the risk of hypoxia and aspiration, especially in specific clinical situations, with a high risk of vomiting and/or aspiration of gastric contents. Those problems are solved by immediate intubation and mechanical ventilation, and the reduction in the time between anesthetic induction and the development of safe airways conditions is extremely important since in this period the airways are unprotected. However, the latency period to achieve adequate muscle relaxation for laryngoscopy and tracheal intubation varies according to the neuromuscular blocker used ¹³.

The search for new non-depolarizing neuromuscular blockers has been successful in accelerating the onset of action, as well as improving the duration and decreasing collateral effects, but, unfortunately, the ideal has not yet been achieved, i.e., a drug that provides intubation conditions as quickly as succinylcholline associated to a long-acting profile.

Some pharmacokinetic characteristics of neuromuscular blockers such as diffusion, affinity, rate receptor binding and potency can influence the development of the blockade. The same is true for patient-related factors such as age, cardiac output, circulatory time, and muscular blood flow ^13-14.

According to some authors, the potency of the neuromuscular blocker is inversely related with the onset of action. It is also influenced by the dose administered, decreasing with the increase in dose or by a priming dose ^13,15-17.

At a dose of 2 ED₉₅, the neuromuscular blockade produced by pipecuronium develops in approximately 2.5 minutes, which is similar to that of pancuronium ^2,3,7. As described for most non-depolarizing neuromuscular blockers, the onset of action of pipecuronium can be accelerated if a priming dose is used a few minutes before the full dose or after the administration of higher doses ^2,6,13,15-17. In the present study, patients who received 0.05 mg.kg^-1 of pipecuronium presented a 75% reduction in the amplitude of the response to an isolated stimulus (1 Hz) significantly faster (95 seconds) than patients who received 0.04 mg.kg^-1 (122 seconds). The significantly faster onset of action with higher doses is similar to that reported by other authors⁶, but contrary to the results reported by Larinjani et al. ² Those authors, using different doses of pipecuronium (0.07 and 0.1 mg.kg^-1) observed that although the time necessary to obtain 90% of motor blockade was inversely proportional to the dose, the difference was not statistically significant. Other authors ¹⁸ observed a greater latency period (5 minutes) with a 0.04 mg.kg^-1 of pipecuronium; however, the blockade was also greater (93.7%).

Conditions for tracheal intubation with 75% blockade of the aplitude of the responses to isolated stimulus (1 Hz) were significantly better in the group of patients who received higher doses. Other studies reported similar results but, unlike the present study, the doses of pipecuronium were higher and ranged from 70 to 100 µg.kg^{-1 2,19,20}.

It is known that the duration of action of neuromuscular blockers is affected by several factors, such as changes in temperature, acid-base balance, and drugs, among which volatile anesthetics should be mentioned because they prolong recovery from the neuromuscular blockade even with low concentration leading, consequently, to a reduction in the consumption of those drugs ^3,7,21-26. It is known that skin temperature below 32°C decreases the amplitude of the evoked muscular response, while an increase in temperature decreases electrode impedance, overestimating or underestimating, respectively, the neuromuscular blockade ^26,27. Ventilatory changes and the resulting respiratory acidosis or alkalosis can also affect the response to neuromuscular blockers, increasing or reducing the blockade ^23,26. In the present study, the temperature of the skin above the muscle and end-expiratory CO₂ concentration were monitored continuously and maintained around 33.6°C and 34 mmHG, respectively, and therefore one can rule out their influence on the results.

The clinical duration of the blockade, i.e., to recover 25% of T₁, varied according to the dose, being significantly longer in patients who received 0.05 mg.kg^-1 (64.84 minutes) than in those who received 0.04 mg.kg^-1 (49.63 minutes). Longer duration of action associated with higher doses and the use of volatile agents has also been reported by other authors ^2,19,20.

In the present study, isoflurane, which might increase the duration of the blockade, was used for anesthesia maintenance. Prior studies indicated that isoflurane is twice effective increasing the potency of neuromuscular blockers and decreasing the ED95 of pipecuronium by 30% ^3,28. This property of volatile agents can be attributed to changes in the kinetic properties of the channels of acetylcholine receptors in the neuromuscular synapse, similar to what is observed with local anesthetics; effects on the central nervous system, which cause reflex spinal cord depression and contribute to reduce muscle tone leading to relaxation of skeletal muscles; reduction in the sensitivity of post-synaptic membrane to the depolarization caused by acetylcholine; and the increase of muscular blood flow, increasing the concentration of the neuromuscular blocker in the muscles ^29-31. It has also been argued that volatile agents and non-depolarizing neuromuscular blockers may have synergic pre-synaptic activity. Although all neuromuscular blockers affect pre- and post-synaptic receptors, their affinity for those receptors may vary, which would explain the different degrees by which different volatile anesthetics affect the potency of neuromuscular blockers ^3,32.

Mean recuperation indexes - RI (T1_25-75%) after different doses of pipecuronium were similar. This pharmacodynamic parameter results from the analysis of T₁, representing an independent comparison standard that is not influenced by the total dose of non-depolarizing neuromuscular blocker. It is inversely related to the elimination of the drug, and it can be changed by drugs that interfere with the regression of the neuromuscular blockade ^33-35. Similar to other reports ^{2,6,9,10,36,37}, in the present study changes in blood pressure and heart rate, or other adverse effects that could be attributed to pipecuronium, were not observed. In a similar way as vecuronium, but unlike pancuronium, pipecuronium does not have cardiovascular actions. This difference occurs because pipecuronium has minimal or no inhibitory effects on muscarinic receptors in noradrenergic nerve endings; therefore, it does not cause an increase in blood pressure and heart rate, which are commonly observed with pancuronium ^38,39. Pipecuronium at a dose of 0.05 mg.kg^-1 can be considered an acceptable alternative in prolonged procedures in which one needs to avoid an elevation in blood pressure as well as in heart rate.

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*

Recebido do Departamento de Anestesiologia da Faculdade de Ciências Médicas (FCM) da Universidade de Campinas (UNICAMP), Campinas, SP

Publication Dates

• Publication in this collection
  14 Nov 2008
• Date of issue
  Dec 2008

History

• Accepted
  18 Aug 2008
• Received
  22 Jan 2008