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Rev. Bras. Anestesiol. vol.57 no.5 Campinas Sept./Oct. 2007
Prospective study on the repercussions of low doses of remifentanil on sinoatrial function and in cardiac conduction and refractory period*
Estudio prospectivo de las repercusiones de bajas dosis de remifentanil en la función sinoatrial en la conducción y refractariedad cardiaca
Simone Soares Leite, TSAI; Elizabeth Bessadas Penna Firme, TSAII; Márcia Santana Bevilaqua, TSAIII; Leonel dos Santos Pereira, TSAIV; Jacob AtiéV
IMédica Assistente do Serviço de Anestesia do HUCFF/UFRJ;
Co-Responsável pelo CET do HUCFF/UFRJ; Chefe do Serviço de Anestesia
do Hospital Maternidade Carmela Dutra
IIMédica Assistente do Serviço de Anestesia do HUCFF/UFRJ; Co-Responsável pelo CET do Hospital dos Servidores do Estado do Rio de Janeiro
IIIMédica Assistente do Serviço de Anestesia do HUCFF/UFRJ; Co-Responsável pelo CET do Hospital dos Servidores do Estado do Rio de Janeiro
IVCo-Responsável pelo CET do HUCFF/UFRJ; Doutor em Medicina do Departamento de Cirurgia (Setor Anestesiologia) da FM/UFRJ; Professor Adjunto do Departamento de Cirurgia (Especialidade Anestesia) da UFRJ; Chefe do Serviço de Anestesia do HUCFF/UFRJ
VChefe do Setor de Arritmias Cardíacas do HUCFF/UFRJ e da Clínica São Vicente da Gávea; Professor Adjunto do Departamento de Cardiologia da UFRJ
BACKGROUND AND OBJECTIVES: Remifentanil is an opiod with fast onset
of action and short acting, and its use in short-duration procedures has increased
in the last few years. Bradycardia and asystole are among the side effects reported.
The objective of this study was to evaluate the effects of this drug in cardiac
conduction and refractory period in human beings.
METHODS: A prospective study with 16 patients, ages 18 to 65, both genders, ASA I to III, undergoing elective intracardiac electrophysiological study, was undertaken. Patients with disorders of the sinoatrial node and those with severe cardiac blocks were excluded. In the laboratory of electrophysiology, patients were sedated with midazolam (0.03 mg.kg-1) after 5 minutes the degree of sedation and degree of pain, systolic and diastolic blood pressure, heart rate and respiratory rate, and oxygen saturation were evaluated. The electrophysiologist evaluated cardiac conduction (duration of the QRS complex, and AA, AH, HV, and PA intervals), duration of sinoatrial node recovery, and cardiac refractory period (refractory period of the right atrium, right ventricle, and atrioventricular node). After the initial measurements, remifentanil was administered (bolus of 0.5 µg.kg-1 + infusion of 0.05 µg.kg-1.min-1) and, after 20 minutes, the same parameters were evaluated.
RESULTS: There was a reduction in systolic and diastolic blood pressure (p = 0.0001) between M0 and M1, and significant differences in respiratory rate and oxygen saturation, which were not statistically significant. The atrium-His interval (p = 0.006), recovery time of the sinoatrial node (p = 0.0004), refractory period of the right atrium (p = 0.001), and refractory period of the sinoatrial node (p = 0.0001) were all increased; however, there were no differences in heart rate between M0 and M1.
CONCLUSIONS: Remifentanil changes cardiac electrophysiological parameters and, in doses higher than the ones used in this study, can cause sinus bradycardia, asystole, and conduction defects.
Key Words: ANALGESICS, Opioid: remifentanil; COMPLICATIONS, Heart Arrest; Arrhythmia: Bradycardia; PHYSIOLOGY, Cardiovascular system: Heart conduction system; SURGERY, Cardiac; Catheter ablation.
JUSTIFICATIVA Y OBJETIVOS: El remifentanil es un opioide con inicio
y fin de acción rápidos, cuyo uso en procedimientos de corta duración
se ha venido propagando en los últimos años. Entre los efectos
colaterales descritos, hay relatos de bradicardia y asistolia. El objetivo de
este estudio fue evaluar los efectos de este fármaco en la conducción
y refractariedad cardíaca, en humanos.
MÉTODO: Estudio prospectivo de 16 pacientes, entre 18 y 65 años, de ambos sexos, ASA I a III, que se sometieron a estudio electrofisiológico intra cardiaco electivo. Se excluyeron pacientes con enfermedades del nódulo sino-atrial y los portadores de bloqueos cardíacos graves. En el laboratorio de electrofisiologia, los pacientes fueron inicialmente sedados con midazolam (0,03 mg.kg-1), 5 minutos después (M0) se evaluó el grado de sedación e intensidad de dolor, presiones arteriales sistólica y diastólica, frecuencias cardíaca y respiratoria y saturación de oxígeno. El electrofisiologista evaluó las variables de conducción cardíaca (duración del QRS, intervalos AA, AH, HV y PA), el tiempo de recuperación del nódulo sino-atrial y las variables de refractariedad cardíaca (período refractario del atrio derecho, período refractario del ventrículo derecho y período refractario del nódulo atrio ventricular). Después de las medidas iniciales el remifentanil fue introducido (bolo de 0,5 µg.kg-1 + infusión de 0,05 µg.kg-1.min-1) y después de 20 minutos las mismas variables fueron evaluadas nuevamente (M1).
RESULTADOS: Se observó disminución de las presiones sistólica y diastólica (p = 0.0001) entre M0 y M1, sin diferencia estadística significativa de la frecuencia respiratoria o de la saturación de oxígeno. Hubo aumento del intervalo atrio-His (p = 0,006) y del tiempo de recuperación del nódulo sino-atrial (p = 0,0004), del período refractario del atrio derecho (p = 0,001) y del período refractario del nódulo atrio ventricular (p = 0,0001), pero no hubo disminución de la frecuencia cardíaca basal entre M0 e M1.
CONCLUSIONES: El remifentanil altero las variables electrofisiológicas cardíacas, lo que en dosis mayores que las estudiadas podría causar bradicardia sinusal, asistolia y disturbios de conducción.
Remifentanil is a selective mu receptor agonist, and its potency is similar to that of fentanyl. It has a methyl ester propanoic bond in its chemical structure that is hydrolyzed by non-specific plasma and tissue esterases (carboxy esterase), resulting in predictable and short action, which does not accumulate with repeated doses or when administered by continuous intravenous infusion (context-dependent half-life of 3 minutes). Its volume of distribution in central and total compartments is also very low, with a beta half-life much lower than other opioids, besides a small Ke0 half-live, responsible for its fast onset of action 1-9.
This pharmacokinetic and pharmacodynamic profile is very attractive, especially in cases of short-duration procedures. However, its use is associated with hemodynamic instability, with hypotension and bradycardia 10-14. Besides, there is a report in the literature of two cases of asystole after the use of remifentanil in anesthetic induction 15,16.
Bradycardia has been reported, especially in patients taking beta-adrenergic receptor antagonists, patients with preexisting bradycardia, and in those who received a bolus dose of the drug (> 1 µg.kg-1 in 30 seconds) 12,13. However, one of the cases of asystole described affected a young patient without associated diseases who did not receive a bolus of the drug 16.
The objective of this study was to evaluate, in human beings, whether the effects of remifentanil on cardiac conduction and refractoriness explains the bradycardia observed by other authors.
After approval by the Ethics Committee on Research of the Hospital Universitário Clementino Fraga Filho, and after patients signed an informed consent, a prospective study was conducted with 16 adult patients, both genders, scheduled for elective, percutaneous, intracardiac electrophysiologic study, ablation of arrhythmias by radiofrequency catheter, or both.
Patients received sedation and analgesia in which the sedative chosen was midazolam.
Inclusion criteria included: ages ranging from 18 and 65 years, physical status ASA I to III, and weighing less than 100% above the ideal body weight.
Exclusion criteria included patients: taking benzodiazepines, antidepressants, illegal drugs, or central nervous system stimulants; beta-receptor antagonists or alfa2-receptor agonists; who were anesthetized or took opioids during the prior 48 hours; taking amiodarone (or when the drug was discontinued in the prior 45 days); with Myasthenia Gravis, closed angle glaucoma, or those who were not "on an empty stomach"; with psychiatric problems, severe pulmonary disease, congestive heart failure, unstable angina, or myocardial infarction in the prior six weeks; with severe cardiac blocks; patients with nephropathy or liver disease.
Antiarrhythmic drugs were discontinued for at least five half-lives (except amiodarone) in all patients.
The intracardiac electrophysiological study was performed at the cardiac electrophysiology laboratory of the Hospital Clementino Fraga Filho.
Patients did not receive any pre-anesthetic medication.
After monitoring with a 12-lead electrocardiogram with the EPTRACER V0.73 system (ECG), pulse oximetry, non-invasive blood pressure (NIBP), capnograph (calibrated by the Cardiocap Ultima Datex Ohmeda monitor), and venipuncture in the left upper limb with an 18G catheter, 20 mL.kg-1 of Ringer's lactate were administered over 10 to 15 minutes. Infusion was reduced to keep patent vein. A Y connector (Polifix®-B Braun) was attached to the IV tubing and a 3-way tap (TAP-3 Embramed) was placed between the connector and the IV catheter.
Midazolam, 0.03 mg.kg-1 (ideal weight), was administered before the femoral punctures performed by the electrophysiologist.
At M0 (5 minutes after the administration of midazolam), the degree of sedation (Ramsay scale), severity of pain using a subjective scale from 0 to 4 (0 = no pain, 4 = the worst pain ever felt), systolic (SBP) and diastolic (DBP) blood pressures, heart rate (HR) without electrical stimulation, respiratory rate (RR), arterial oxygen saturation (SpO2) by pulse oximetry with supplementary oxygen therapy (5 L.min-1 O2 with a Hudson mask), expired CO2 by capnography (PETCO2), cardiac conduction (duration of the QRS complex, and AA, AH, HV and PA intervals), sinoatrial node function (recovery of the sinoatrial node), and cardiac refractory period (refractory period of the right atrium, right ventricle, and atrioventricular node) were evaluated. Refer to the glossary for definitions.
Basal electrophysiological study was done with the simultaneous recording of the 12-lead electrocardiogram and intracavitary signs (EPTRACER V0.73) that were capture by three or four intravenous catheter-electrodes (quadripolar 6F Biosense Webster®) placed in the upper region of the right atrium, adjacent to the His bundle, at the tip of the right ventricle, and in the coronary sinus. The basal duration of the QRS complex and basal intervals (AA, PR, PA, AH, HV, and QT intervals) were evaluated during sinus rhythm with a recording speed of 100 mm.seg-1. ERPRA, ERPRV, and ERAVN were determined by decrescent extra-stimuli inserted over the continuous stimulation in cycles of 600, 500, and 430 ms. The time of recovery of the sinoatrial node (TRSN) was determined by direct right atrium stimulation with cycles of 600, 550, 430, and 380 ms for 1 minute in each level and a recording speed of 100 mm.seg-1. Ten cycles were analyzed after the end of the stimulation, and the greatest post-stimulation interval was used to calculate TRSN. The configuration of the P wave on the surface ECG and intraatrial electrocardiograms were used to determine whether the origin of the first beat after the end of the stimulation really originated in the sinoatrial node.
At M0, patients who did not present PA, AH, and HV intervals within the normal limits standardized by the laboratory, were excluded from the study, as well as patients with WPW whose anterograde PRE of the accessory pathway was smaller than that of the AVN.
After the initial measurements, a bolus of remifentanil, 0.5 µg.kg-1 (ideal body weight) was administered over 30 seconds, followed by a continuous intravenous infusion (0.05 µg.kg-1 of ideal body weight), in order to maintain a grade 2 to 4 sedation, by the Ramsay scale, and severity of pain from 0 to 1. The dose of remifentanil could be adjusted in up to ± 50% to reach these goals. Patients who did not achieve these results received a continuous infusion of propofol, with or without a bolus of 0.5 mg.kg-1 (ideal body weight), and were excluded from the study.
After evaluating hemodynamic and respiratory parameters (NIBP, HR, RR, PETCO2, and SpO2), the dose of remifentanil was decreased in up to 50% of the initial dose, when systolic BP had decreased by more than 15 mmHg or it was below 80 mmHg, when the respiratory rate was below 8 bpm, SpO2 was less than 94% (with supplementary oxygen), or when the heart rate was below 40 bpm.
The same parameters were evaluated at M1 (after 20 minutes of the adjusted infusion of remifentanil).
After evaluating all parameters, continuation of the anesthesia was at the discretion of the anesthesiologist. The capability to induce sustained tachycardia was not evaluated.
Paired Student t test was used for comparative analysis of the parameters at M0 and M1; levels of p < 0.05 were considered significant.
Table I shows the demographic data of patients in the study.
The procedure was indicated for diagnosis of and ablation of AV nodal reentrant tachycardia (AVNRT), in seven cases, and Wolf-Parkinson-White syndrome, in the remaining nine patients, using a radiofrequency catheter.
The procedure lasted a mean of 78 ± 25 minutes (maximum of 128 and minimum of 40 minutes), and the mean total dose of remifentanil per procedure was 276 ± 115 µg (maximum of 520 and minimum of 140 µg), with a mean of 3.45 ± 0.12 µg.min-1.
The degree of sedation was satisfactory in every case, with a grade 2 to 3 by the Ramsay scale at M0 and 3 to 4 at M1 (Table II).
The severity of pain by the subjective scale varied from 0 to 2 at M0 and 0 to 1 at M1 (Table III). Those parameters were considered satisfactory and it was not necessary to administer propofol to any patient.
Of the hemodynamic parameters evaluated (NIBP, HR, PETCO2, and SpO2) at M0 and M1, only systolic and diastolic blood pressures showed statistically significant differences (Table IV). There were no significant differences in HR between M0 and M1.
Among the parameters of cardiac conduction (duration of the QRS complex, AA, HA, HV, and PA intervals), we observed an increase in the duration of the QRS complex and AH interval (Tables V and VI). The other parameters did not show statistically significant differences between M0 and M1.
There was also increase in TRNS (Table VII).
Regarding the parameters of cardiac refractoriness (refractory period of the right atrium, right ventricle, and atrioventricular node), there was an increase in the refractory period of the right atrium (p = 0.001) and atrioventricular node (p = 0.0001). There were no statistically significant differences in the refractory period of the right ventricle.
Similar to other opioids, remifentanil can cause bradycardia and asystole, before or during laryngoscopy and tracheal intubation 10-21.
Initially, it was attributed to a central-mediated mechanism; however, Morphine is known to exert a direct effect on the sinoatrial node and atrioventricular conduction 22,23. On the other hand, sufentanil prolongs the duration of the action potential in Purkinje fibers in dogs 24-26.
Reitan et al. attributed 10% of the bradycardia caused by sufentanil in dogs to its peripheral effects, and not only to its central vagotonic effect 27. Saeki et al. demonstrated, in mice, the activation of opioid mu receptors in the sinoatrial node and, therefore, proving a direct negative chronotropic action 28. However, these direct electrophysiological effects of fentanyl were not observed in human beings 29.
Sharpe et al. also did not demonstrate direct effects of alfentanil and sufentanil on cardiac conduction and refractoriness (in human beings), which is contrary to the effects of inhalational anesthetics that increase the refractoriness of atrioventricular conduction pathways 30,31.
As for remifentanil, some mechanisms have been proposed to explain the bradycardia and hypotension caused by this drug; among them, we can include the possible release of histamine after fast administration of the drug, a centrally-mediated vagal stimulus, central inhibition of the sympathetic tone, a direct effect on cardiac conduction and refractory period, or a multifactorial cause 10.
However, Sebel et al. demonstrated that the hemodynamic changes observed are not related with changes in plasma levels of histamine 32.
Currently, it is believed that the reduction in mean arterial blood pressure caused by remifentanil is secondary to the peripheral vasodilation, and consequent reduction in systemic vascular resistance, by an endothelium-dependent mechanism related to the release of prostacyclin and nitric oxide 33.
Sinohara et al. showed that, in mice with intact neuron axis (preserved response to baroreceptor reflex), sudden and easily corrected hypotension and bradycardia are due to the central vagotonic action of remifentanil 3,4. However, slowly developing hypotension and bradycardia were also observed on denervated animals (without active baroreceptor reflex), which showed that the vagotonic central effect is not the only cause of bradycardia. Since these animals did not show a reduction in sympathetic tone, this hypothesis was also ruled out. The authors proposed that bradycardia would be caused by a direct negative chronotropic effect secondary to direct stimulation of mu receptors in the sinoatrial node. This hypothesis is supported by the prior administration of Naloxone (a mu receptor antagonist), which abolishes bradycardia in baro-denervated and vagotomized animals 3,4.
Thompson et al., studying the effects of remifentanil on hemodynamic response to tracheal intubation, also evaluated the effects of prior administration of a vagolytic agent (glycopyrrolate 200 µg), in an attempt to avoid the onset of bradycardia. The authors concluded that glycopyrrolate did not increase basal cardiac frequency, but it attenuated the bradycardia associated with the administration of remifentanil (50% incidence in the remifentanil group ´ 10% in the remifentanil and glycopyrrolate group) 11.
Sebel et al. observed a mean reduction of 20% in blood pressure and heart rate after the intravenous administration of remifentanil, in doses ranging from 2 to 30 µg.kg-1 (administered over 1 minute), in patients who received glycopyrrolate before remifentanil 32.
The current study proved that remifentanil depresses the function of the sinoatrial node (reflected in an increase in the recovery period of the sinoatrial node) and in intra-atrial conduction (by an increase in the atrium-His interval) justifying, therefore, the bradycardia associated with the administration of this drug 35.
However, we did not observe changes in basal heart rate, probably due to the small doses of remifentanil used in this study (the variations in AH interval and in TRSN were statistically significant but, in absolute numbers, within the normal range) or to the size of the study group. The second hypothesis is unlikely to be true, i.e., changes in A-H interval and TRSN were very different statistically (p = 0.006 and 0.0004, respectively).
Remifentanil also caused an increase in the refractory period of the right atrium and atrioventricular node, suggesting an arrhythmogenic potential of this drug 36. However, the changes observed in refractory periods are within normal limits.
Compared to other opioids studied 30,31, even small doses of remifentanil (doses for awake sedation) caused changes in electrophysiological parameters, and the changes observed in the current study can be attributed to this drug since Sharpe et al. demonstrated that midazolam does not change cardiac conduction and refractoriness 30.
Additionally, these results proved that remifentanil is capable of causing hypotension, as had been shown before 10,11.
Regarding sedation and analgesia, other studies have demonstrated that the association of remifentanil (bolus of 0.5 µg.kg-1.min-1 over 30 seconds, followed by continuous intravenous infusion, 0.05 µg.min-1) and midazolam (2 mg IV) is effective, since 66% of the patients did not experience pain or discomfort during the procedures, and provided light sedation. Besides, few side effects were observed (16% of nausea and 2% of vomiting) 37,38.
Therefore, remifentanil would be the ideal analgesic component in sedations and analgesia for percutaneous intracardiac electrophysiological studies, ablation of arrhythmias with radiofrequency catheter, or both, if it were not for the results of our study. These results suggest that remifentanil should not be used in those procedures, because it can interfere with the precision of electrophysiological measurements.
From what has been exposed, we concluded that remifentanil had an electrophysiological effect in the function of the sinoatrial node and in cardiac conduction and refractoriness (it increased the recovery time of the sinoatrial node, the duration of the QRS complex, AH interval, and refractory periods of the right atrium and atrioventricular node), and, in higher doses that the ones used in this study, it could cause sinus bradycardia and conduction defects.
Therefore, its use should be avoided in patients with known disorders of the sinoatrial node, prior conduction disturbances, and in patients who take regularly drugs that affect cardiac chronotropism, such as beta-blockers.
We also concluded that remifentanil is not a good drug to be used as the analgesic component in sedation and analgesia for intracardiac electrophysiological studies because it can interfere with the interpretation of the results.
In this study, we did not observe changes in basal heart rate, but further studies should be performed in the future, with higher doses of the drug, to evaluate its safety.
1) Atrium-His interval (AH) Estimates the time of internodal atrioventricular conduction, measuring from the atrial electrogram to the electrogram of the bundle of His. Normal values in adults vary from 35 to 150 ms.
2) PA interval An approximation of the intraatrial conduction time. It is measured from the beginning of the P wave to the beginning of atrial activation in the His electrogram (beginning of the A potential). Normal values in adults in sinus rhythm vary from 9 to 150 ms.
3) His-ventricle interval (HV) It is the conduction time between the place where the His potential is recorded (proximal bundle of His) and the beginning of ventricular activation. Normal values in adults vary from 10 to 55 ms.
4) Time of recovery of the sinoatrial node (TRSN) Time required for recovery of sinus signal formation after a super-stimulation of the atrial pacemaker. Normal values in adults vary from < or = 1207 to < or = 1500.
5) Effective refractory period of the right atrium (ERPRA) The longest S1-S2 interval (artifact stimulus) that does not result in atrial depolarization. Normal values in adults vary from 150 to 360 ms (dependent on the amplitude of the cycle used).
6) Effective refractory period of the right ventricle (ERPRV) The longest S1-S2 interval that cannot evoke a ventricular response. Normal values for adults vary from 170 to 290 ms.
7) Effective refractory period of the atrioventricular node (ERPAVN) The longest A1-A2 interval measured on the His electrogram that does not propagate through the bundle of His. Normal values for adults vary from 230 to 430 ms.
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Simone Soares Leite
Rua Marques de Paraná, 128/706 Flamengo
22230-030 Rio de Janeiro, RJ
Submitted em 15 de maio de 2006
Accepted para publicação em 12 de junho de 2007
* Pesquisa realizada no Hospital Clementino Fraga Filho (HUCFF) da Faculdade de Medicina da Universidade Federal do Rio de Janeiro (FM/UFRJ), Rio de Janeiro, RJ