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Print version ISSN 0034-7094
Rev. Bras. Anestesiol. vol.55 no.4 Campinas July/Aug. 2005
Effects of intravenous lidocaine on the pharmacodynamics of rocuronium*
Efectos de la lidocaína por vía venosa sobre la farmacodinámica del rocuronio
Leandro Sotto Maior Cardoso, TSA, M.D.I; César Romão Martins, TSA, M.D.II; Maria Angela Tardelli, TSA, M.D.III
IAnestesiologista, Universidade Federal
de São Paulo - Escola Paulista de Medicina
IIAnestesiologista, Preceptor dos Residentes do CET da UNIFESP - EPM
IIIProfessora Adjunta da Disciplina de Anestesiologia, Dor e Terapia Intensiva da UNIFESP - EPM
BACKGROUND AND OBJECTIVES: Rocuronium
is an intermediate nondepolarizing neuromuscular blocker (NMB) with faster onset
and indicated in situations requiring rapid tracheal intubation. Intravenous
lidocaine is often used to decrease hemodynamic responses to tracheal intubation.
The association of NMB to local anesthetics results in potentiation of NMB effects.
The purpose of this study was to evaluate the influence of lidocaine on rocuronium's
pharmacodynamics determined by acceleromyography.
METHODS: Forty-six ASA I-II patients, aged 18 to 65 years, were randomly distributed in two groups (CG: control and LG: lidocaine). Rocuronium was given to all patients for neuromuscular block. LG received lidocaine (1.5 mg.kg-1) 3 minutes before rocuronium. Neuromuscular function was evaluated by adductor pollicis muscle response to TOF. After NMB injection, times for first TOF response (T1) to reach 10 and 0% of baseline value and recover 25%, 75% and 95% of contraction height (Dur25%, Dur75%, Dur95%) were recorded. Recovery time of T4/T1 = 0.8 and intervals Dur75%-Dur25% (IR25-75) and T4/T1 = 0.8 - Dur25% were also recorded.
RESULTS: This study has not shown statistically significant differences between groups when T1= 10%, T1 = 0, RI25-75, T4/T1 = 0.8 - Dur25% were compared. Times for Dur25%, Dur75%, Dur95% in LG were significantly higher as compared to CG.
CONCLUSIONS: Lidocaine associated to rocuronium has prolonged early blockade recovery stage without interfering with onset or late recovery stage.
Key Words: ANESTHETICS, Local: lidocaine; NEUROMUSCULAR BLOCKERS: Nondepolarizing: rocuronium
JUSTIFICATIVA Y OBJETIVOS: El rocuronio
es un bloqueador neuromuscular (BNM) no despolarizante de acción intermediaria
que presenta un inicio de acción más rápido, indicado para situaciones
donde hay necesidad de rápida intubación traqueal. La lidocaína
es frecuentemente utilizada por vía venosa para disminuir las respuestas
hemodinámicas asociadas a la intubación traqueal. La asociación
de un BNM a un anestésico local resulta en potencialización de los
efectos bloqueadores neuromusculares. El objetivo de este estudio es evaluar
la interacción entre la lidocaína y a farmacodinámica del rocuronio
evaluada por aceleromiografia.
MÉTODO: Pacientes estado físico ASA I y II, con edad entre 18 y 65 años, eventualmente distribuidos en dos grupos (GC: control y GL: lidocaína), recibieron rocuronio como bloqueador neuromuscular. El GL recibió lidocaína (1,5 mg.kg-1) 3 minutos antes del rocuronio. La función neuromuscular fue evaluada por la respuesta del músculo aductor del pulgar a la secuencia de cuatro estímulos (SQE). Después de la inyección del BNM se anotaron los tiempos para la primera respuesta (T1) a la SQE alcanzar 10 y 0% del valor control, y recobrar 25%, 75% y 95% de la altura de la contracción (Dur25%, Dur75%, Dur95%). Se anotó también el tiempo de recuperación de T4/T1 = 0,8) y los intervalos Dur75%-Dur25% (IR25-75) y T4/T1 = 0,8 - Dur25%.
RESULTADOS: Este estudio no demostró diferencia estadísticamente significativa entre los grupos cuando comparados T1= 10%, T1 = 0, IR25-75, T4/T1 = 0,8 - Dur25%. Los tiempos para Dur25%, Dur75%, Dur95% en el GL fueron estadísticamente superiores a los del GC.
CONCLUSIONES: La asociación de lidocaína al rocuronio prolongó la parte inicial de recuperación del bloqueo sin interferir con el inicio de acción o con la parte de recuperación final.
Rocuronium bromide is an intermediate nondepolarizing aminosteroid neuromuscular blocker (NMB) 1-5. Among current nondepolarizing MNBs, rocuronium has the shortest onset 6, being indicated when rapid tracheal intubation without the inconveniences of succinylcholine is desired 7.
Lidocaine is a popular intravenous agent for anesthetic induction, which decreases hemodynamic responses associated to tracheal intubation 8.
There are evidences that local anesthetics decrease neuromuscular transmission with effects on motor neurons and muscle fibers. In vitro studies have shown that the association of these agents to NMB results in improved NMB effects 9,10. In clinical practice, this synergistic effect of NMB and local anesthetics could be useful if it resulted in early neuromuscular block installation, which would provide faster tracheal intubation and protection against cardiovascular effects inherent of the technique.
This study aimed at evaluating whether intravenous lidocaine preceding rocuronium for tracheal intubation would change the pharmacodynamics of this neuromuscular blocker.
This clinical prospective study was approved by the Research Ethics Committee, Universidade Federal de São Paulo, Escola Paulista de Medicina (UNIFESP - EPM) and involved 46 patients aged 18 to 65 years, physical status ASA I and II, with body mass index between 20 and 25 kg.m-2, submitted to elective surgical procedures under general anesthesia with tracheal intubation and mechanically controlled ventilation.
After their written and informed consent, patients were randomly distributed in two groups: CG (control) and LG (lidocaine). All patients were given rocuronium for neuromuscular block. LG patients received lidocaine 3 minutes before rocuronium, while GC patients received equal volume of saline solution. Exclusion criteria were situations interfering with neuromuscular blocker action, such as hypo or hyperproteinemia, renal failure, liver diseases, hypo or hyperthermia, changes in acid-base and hydroelectrolytic balance, pregnancy, neuromuscular diseases, chronic alcoholism and drugs affecting NMB pharmacology.
Patients were given no premedication. Venous access was obtained in the arm with 18G catheter for hydration and drug administration. A tap was directly connected to the catheter to allow drugs to directly reach blood flow and rule out the influence of catheter size and length on lidocaine and rocuronium infusion time.
Monitoring consisted of cardioscopy, pulse oximetry, capnography, blood gases analyzer, noninvasive blood pressure, neuromuscular transmission monitoring by acceleromyography (TOF GUARD®), and esophageal and cutaneous thermometers.
Anesthesia was induced with fentanyl (5 µg.kg-1) and etomidate (0.3 mg.kg-1), followed three minutes later by rocuronium. Patients were maintained under manual ventilation with 100% oxygen and isoflurane and expired fraction up to 0.5% until stabilization of adductor pollicis response to electric ulnar nerve stimulation. Induction went on with 1.5 mg.kg-1 lidocaine (LG) or equivalent volume of saline (CG). Rocuronium (0.6 mg.kg-1) was administered three minutes later during 15 seconds. Laryngoscopy and tracheal intubation was performed after abolishment of TOF responses.
Anesthesia was maintained with isoflurane to a maximum of 1% expired fraction, mixed in oxygen and 50% nitrous oxide. Additional 2 µg.kg-1 fentanyl was administered whenever blood pressure or heart rate would go beyond 20% of baseline values. Central temperature was maintained between 36.5 and 37 ºC and peripheral temperature was maintained above 34 ºC throughout the procedure with the aid of thermal blanket with convection heat. Mechanical ventilation was adjusted to maintain end tidal CO2 (PETCO2) between 32 and 36 mmHg.
Neuromuscular function (NMF) was continuously monitored in the arm contralateral to intravenous access with TOF Guard (Denmark) monitor, using TOF stimulation (train of four), through supramaximal stimulation of the ulnar nerve with two surface electrodes on the wrist. This stimulation was maintained for at least 5 minutes to stabilize adductor pollicis muscle response. Neuromuscular block was quantified as the percentage of standard initial T1/T0 response, where T1 is the amplitude of first TOF response and T0 is the amplitude of the first response before NMB administration.
After rocuronium administration, time needed to abolish 90% of muscle response (T1 = 10%), time needed for total muscle response abolishment (T1 = 0) and 25%, 75% and 95% recovery time for T1 were registered. Time for T4/T1 ratio to reach 0.8 (T4/T1 = 0,8) was also recorded.
Mean blood pressure, heart rate, peripheral and central temperature were recorded simultaneously to data on neuromuscular function monitoring.
Definitions of the evaluated parameters were:
1. Onset: time for 100% muscle response abolishment, T1 = 0, after end of neuromuscular blocker injection;
2. Clinical duration (Dur25%): time in minutes between end of rocuronium injection and spontaneous recovery of 25% of first TOF response;
3. Dur75%: time in minutes between rocuronium injection and 75% recovery of first TOF response;
4. Total duration of action (Dur95%): time in minutes between rocuronium injection and 95% recovery of first TOF response;
5. Recovery index (RI25-75%): time between 25% and 75% spontaneous recovery of first TOF response height;
6. Ratio T4/T1 = 0.8: time in minutes between rocuronium injection and 80% recovery of fourth TOF response as compared to first response;
7. Interval T4/T1 = 0.8: - Dur25%: interval between Dur25% and 0.8 TOF.
Student's t test was used to evaluate body mass index, age, heart rate and blood pressure. Fisher's proportion test was used to compare gender distribution. Mann-Whitney's non-parametric test was used for statistical analysis of neuromuscular function monitoring. For all variables, significance level was 5% (p <0.05).
There were 23 patients in each group. Demographic data means and standard deviations (age, body mass index and gender) are shown in table I, and were statistically similar.
Figure 1 shows mean and standard deviation of neuromuscular block installation variables. Time for 90% muscle response abolishment (T1 = 10%), in seconds, for groups CG and LG were 83.83 ± 35.31 and 78.74 ± 20.37 respectively, without statistically significant differences (p = 0.8175). Onset (T1 = 0), in seconds, for groups CG and LG was 123.17 ± 55.57 and 107.79 ± 34.70 respectively, without statistically significant differences (p = 0.5530).
Figure 2 shows neuromuscular block recovery data.
Clinical duration (Dur25%), in minutes for groups CG and LG was 32.35 ± 6.26 and 36.48 ± 6.69 respectively, with statistically significant difference (p = 0.0449).
Values of 75% duration (Dur75%), in minutes, for groups GC and LG were 44.09 ± 11.16 and 53.83 ± 12.49, respectively, with statistically significant difference (p = 0.0029).
Duration of action (Dur95%), in minutes, for groups GC and LG was 49.66 ± 13.94 and 60.69 ± 13.82, with statistically significant difference (p = 0.0060).
Recovery index (RI25-75) means and standard deviations, in minutes, were 11.74 ± 6.50 for CG and 17.35 ± 9.90 for LG, without statistically significant differences (p = 0.2531).
Means and standard deviations of time for T4/T1 ratio to reach 0.8, in minutes, were 62.52 ± 15.31 for CG and 72.87 ± 17.21 for LG, without statistically significant differences (p = 0.0558).
Means and standard deviations of time intervals between T4/T1 ratio to reach 0.8 and Dur25%, in minutes, were 30.17 ± 11.21 for CG and 36.39 ± 14.17 for LG, without statistically significant differences (p = 0.1378).
Figure 3 shows mean blood pressure and heart rate in the moments in which neuromuscular function monitoring parameters were recorded. There were no statistically significant differences between groups.
This study has followed the guidelines of GCRP (Good Clinical Research Practice in pharmacodynamic studies of neuromuscular blocking agents) 11.
We have tried to standardize factors, which could interfere with neuromuscular block during anesthesia.
No benzodiazepine was used as premedication because they may promote muscle relaxation, thus potentiating NMBs 12. Intraoperatively, we have tried to use drugs prioritizing hemodynamic stability and assuring adequate muscle perfusion, so that there would be no interference in neuromuscular blocker distribution to its biophase 13. This way, etomidate was chosen as hypnotic for the anesthetic induction.
Inhalational anesthetics also potentiate neuromuscular blockers by different mechanisms. They depress central nervous system, increase muscle blood flow, decrease glomerular filtration, decrease liver blood flow, and decrease post-junctional membrane sensitivity to depolarization and have direct action on muscle fibers 14-16. Among inhalational anesthetic agents, nitrous oxide presents the lowest interaction with neuromuscular block. Isoflurane below 1% associated to nitrous oxide was used because, up to this concentration, its effect on neuromuscular function is similar to that of intravenous anesthesia, which is the standard for NMB trials 17.
Hypothermia is common during surgical procedures 18,19. Strict control of central and peripheral temperature is particularly important since NMBs pharmacology and neuromuscular function monitoring are affected by central and peripheral hypothermia, respectively 11,20. Hypothermia potentiates NMB action by decreasing nervous conduction, urinary and billiary excretion and enzymes activity 21,22. It is known that during neuromuscular function monitoring, decreased skin temperature to below 32 ºC reduces evoked responses amplitude, while local heat decreases electrode impedance 23-25. Care taken by the protocol to maintain central and peripheral temperature allows us to rule out the interference of this factor on results.
After anesthetic induction, patients were submitted to manual ventilation for at least 5 minutes before receiving NMB, to stabilize muscle response to electric stimulation. This is important because the level of neuromuscular block is estimated by comparing the amplitude of muscle contraction and a control value measured in the absence of neuromuscular block.
Practically, this control value is in general difficult to determine because repetitive motor nerve stimulation increases mechanical evoked response of the corresponding muscle, resulting in increased response to isolated stimulation. This is known as staircase phenomenon. Possible explanation for such finding is phosphorilation of the light myosin chain increasing isolated contraction strength to a certain amount of calcium released at each action potential. Practical implication of this event is that an anesthesiologists unfamiliar with this potentiation may consider that, when isolated stimulation response reaches pre-blockade levels, recovery is complete 26.
End tidal CO2 concentration was maintained within a narrow range because respiratory alkalosis antagonizes NMB effects, while respiratory acidosis precipitate them 27.
By controlling these variables and making groups homogeneous, it was possible to evaluate, as a single variable, the effects of intravenous lidocaine on the pharmacodynamics of rocuronium.
When rapid muscle relaxation is desired, succinylcholine is being increasingly replaced by other techniques due to its adverse effects 28. Techniques to shorten nondepolarizing NMB onset includes higher dose (more than twice DE95) 29 and priming dose 30. These techniques, however, may involve undesirable effects, like prolonged neuromuscular block length, which is associated to possible cardiovascular effects or risk of bronchial aspiration, when increased dose or priming dose are used, respectively 31.
The search for neuromuscular blockers to replace succinylcholine has resulted in the development of rocuronium, nondepolarizing NMB with the fastest onset 32. To further shorten onset, the higher dose technique has been used (3 to 4 times DE95) 31, allowing tracheal intubation in approximately 60 seconds, however with considerable increase in duration, making this intermediate NMB behave as long duration NMB 1.
Our study tried to evaluate the effects of the interaction of lidocaine and rocuronium.
Different studies have shown synergistic interaction of local anesthetics and NMBs in vitro and in vivo, both intravenously 33,34 and epidurally 35,36.
Local anesthetics may interfere with neuromuscular function by acting on different myoneural junction components, both in pre and post-synaptic membrane. In the pre-synaptic membrane, local anesthetics block motor nerve terminal fibers conduction 9,37, decrease the quantal content of acetylcholine or the number of quanta released at rest or after nervous stimulation 9,38, and prolong the absolute refractory period and the fatigue to tetanic stimulation 37. In the post-synaptic membrane, they bind to specific areas of nicotinic receptors different from ACh, promoting loss of sensitization of such receptors 39,40, block open nicotinic receptors channels, where they seem to bind to a specific area located at ¾ of the transmembrane pathway 41,42, and directly interfere with muscle fibers by blocking sodium channels (procaine) 43 or sodium and potassium channels (lidocaine) 44.
It is assumed that during neuromuscular function monitoring, depression and recovery of contraction strength to first TOF stimulation (T1 or twitch) is a consequence of effects on post-synaptic membrane, while fatigue is related to pre-synaptic effects 45.
Although our study design does not allow for the evaluation of actual mechanisms of lidocaine/rocuronium interaction, results do allow some speculations on possible actions on pre and post-synaptic areas.
A recent study 46 has compared intubation conditions provided by succinylcholine with those after rocuronium (0.6 mg.kg-1) associated or not to lidocaine (1.5 mg.kg-1), 60 and 90 seconds after NMB administration. They have shown that the association lidocaine/rocuronium provides adequate tracheal intubation conditions in 60 seconds, similarly to succinylcholine and better than rocuronium alone. All groups presented adequate intubation conditions 90 seconds later.
These authors were based on clinical criteria to define intubation conditions, without monitoring neuromuscular function. In our study, lidocaine was unable to shorten rocuronium onset (T1 = 10% and T1 = 0), what does not necessarily contradicts the previous study since adequate intubation conditions may be obtained even in the absence of neuromuscular blockers 47. Authors stress that this association has the advantage of shortening rocuronium onset without increasing its duration. However, it should be highlighted that these authors have not included in their method any objective evaluation of blockade duration.
In our study, the association lidocaine/rocuronium has promoted increased 25%, 75% and 95% blockade duration. Since the effects of the association of lidocaine to different rocuronium doses were not evaluated, the method does not allow us to verify whether the effect of both drugs association is similar to the one of an increased NMB dose. However, considering our results, the association has promoted delay in early neuromuscular block recovery, without prolonging its late recovery.
In a different study with a method similar to ours, authors have shown that lidocaine (1.5 mg.kg-1) 3 minutes before NMB was able to shorten vecuronium onset. However, these authors have not investigated the impact of the co-administration of both drugs on NMB duration 48.
As to neuromuscular block recovery phase, and in line with data in the literature, our study showed that lidocaine prolonged recovery time for first TOF response, represented by Dur25%, Dur75% and Dur95%, which confirms its post-synaptic effects. Lidocaine prolonged recovery by uniformly shifting values as from Dur25%, what can be seen by the lack of difference in recovery index (RI25-75%).
On the other hand, our study has not detected significant pre-synaptic action of the interaction of lidocaine and rocuronium, evidenced by the lack of difference between times for final neuromuscular function recovery, represented by times for T4/T1 to reach 0.8 and the difference between times for T4/T1 = 0.8 and Dur25%, which has been proposed as final recovery speed index 11.
Considering that nondepolarizing NMBs have different affinities for pre and post synaptic receptors, and that lidocaine acts by impairing neuromuscular transmission in the pre-synaptic terminal and muscle fibers, one may conclude, in the conditions of our study, that the local anesthetic agent has more intensively interfered with post-synaptic effects.
In our conditions, intravenous lidocaine administered before rocuronium was unable to shorten its onset, but prolonged its pharmacological duration without prolonging total neuromuscular function recovery.
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Dra. Maria Angela Tardelli
Disciplina de Anestesiologia, Dor e Terapia Intensiva
Address: Rua Napoleão de Barros, 715, 4º A
ZIP: 04024-002 City: São Paulo, Brazil
Submitted for publication September 20, 2004
Accepted for publication March 10, 2005
* Received from Universidade Federal de São Paulo - Escola Paulista de Medicina (UNIFESP - EPM), São Paulo, SP