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On-line version ISSN 1806-907X
Rev. Bras. Anestesiol. vol.52 no.2 Campinas Mar./Apr. 2002
Onset time and duration of rocuronium, atracurium and mivacurium in pediatric patients*
Tiempo de latencia y duración del efecto del rocuronio, atracúrio y mivacúrio en pacientes pediátricos
Norma Sueli Pinheiro Módolo, TSA, M.D.I; Paulo do Nascimento Júnior, TSA, M.D.I; Lorena Brito da Justa Croitor, TSA, M.D.II; Pedro Thadeu Galvão Vianna, TSA, M.D.III; Yara Marcondes Machado Castiglia, TSA, M.D.III; Eliana Marisa Ganem, TSA, M.D.I; José Reinaldo Cerqueira Braz, TSA, M.D.III; Daniela Suemi Takito, M.D.IV; Luciano Akira Takaesu, M.D.V
IProfessor Assistente Doutor do CET/SBA
da FMB - UNESP
IIAnestesiologista do Departamento de Anestesiologia da FMB - UNESP
IIIProfessor Titular do CET/SBA do Departamento de Anestesiologia da FMB - UNESP
IVME3 do CET/SBA da FMB - UNESP
VDoutorando da FMB - UNESP
BACKGROUND AND OBJECTIVES : Neuromuscular
blockers (NMB) are widely used in pediatric anesthesia, but there is no ideal
NMB. This study aimed at evaluating onset and recovery time, hemodynamic changes
and tracheal intubation conditions of rocuronium, atracurium and mivacurium
in pediatric patients.
METHODS: Participated in this study 67 children aged 30 months to 12 years, physical status ASA I and II, who were allocated into three groups: G1 = 0.9 mg.kg-1 rocuronium (n = 22); G2 = 0.5 mg.kg-1 atracurium (n = 22); G3 = 0.15 mg.kg-1 mivacurium (n = 23). Anesthesia was induced with 50 µg.kg-1 alfentanil, 3 mg.kg-1 propofol, sevoflurane and N2O/O2. Neuromuscular block was monitored by acceleromyography on the ulnar nerve pathway. The following parameters were evaluated: onset time (OT), clinical duration (T25) relaxation time (T75) and recovery time (T25-75). Heart rate (HR) and mean blood pressure (MBP) were recorded in 6 moments, as well as tracheal intubation conditions.
RESULTS: Median OT was: G1 = 0.6 min, G2 = 1.3 min, G3 = 1.9 min. Median T25 was: G1 = 38 min, G2 = 41.5, G3 = 8.8 min. Median T75 was: G1 = 57.7 min; G2 = 54.6 min, G3 = 13.6 min. Median T25-75 was: G1 = 19.7 min, G2 = 13.1 min and G3 = 4.8 min. Tracheal intubation conditions were excellent for most children in all groups. There were no significant MBP and HR clinical changes.
CONCLUSIONS: Rocuronium (0.9 mg.kg-1) had the fastest onset time and mivacurium (0.15 mg.kg-1) the shortest recovery time in pediatric patients anesthetized with sevoflurane. Rocuronium, mivacurium and atracurium had also not determined significant hemodynamic changes and allowed for excellent tracheal intubation conditions.
Key words: ANESTHESIA, Pediatric; MONITORING: acceleromyography; NEUROMUSCULAR BLOCKERS, Nondepolarizing: atracurium, mivacurium, rocuronium
JUSTIFICATIVA Y OBJETIVOS:
Os bloqueadores neuromusculares (BNM) son frecuentemente utilizados en anestesia
pediátrica y no existe aquel que sea considerado ideal. El objetivo de
este trabajo fue evaluar el rocuronio, el atracúrio y el mivacúrio,
en niños, cuanto al tiempo de latencia y de recuperación, a la interferencia
sobre las variables hemodinámicas y las condiciones de intubación
MÉTODO: Sesenta y siete niños, estado físico ASA I y II, con edad variando de 2 años y 6 meses a 12 años, fueron anestesiadas con alfentanil (50 µg.kg-1), propofol (3 mg.kg-1), sevoflurano y N2O/O2 y divididas en tres grupos: G1 = rocuronio 0,9 mg.kg-1 (n = 22); G2 = atracúrio 0,5 mg.kg-1 (n = 22) y G3 = mivacúrio 0,15 mg.kg-1 (n = 23). La monitorización del bloqueo neuromuscular fue realizada con el método de aceleromiografia en el trayecto del nervio ulnar. Fueron estudiados: el tiempo de latencia (TL), la duración clínica (T25), el tiempo de relajamiento (T75) y el índice de recuperación (T25-75). La presión arterial media (PAM) y la frecuencia cardíaca (FC) fueron registradas en seis momentos, bien como las condiciones encontradas en el momento de la intubación traqueal.
RESULTADOS: La mediana del TL fue de 0,6 minutos en G1, 1,3 minutos en G2 e 1,9 minutos en G3. La mediana del T25 fue en G1 = 38,0 minutos, G2 = 41,5 minutos y G3 = 8,8 minutos. La mediana de T75 fue en G1 = 57,7 minutos, G2 = 54,6 minutos y G3 = 13,6 minutos. La mediana del índice de recuperación (T25-75) fue en G1 = 19,7 minutos, G2 = 13,1 minutos y G3 = 4,8 minutos. Las condiciones de intubación traqueal fueron consideradas excelentes en la mayoría de los pacientes de ambos los grupos. No hubo modificaciones clínicas importantes de la PAM y de la FC.
CONCLUSIONES: El rocurónio, 0,9 mg.kg-1, tuvo el menor tiempo de latencia y el mivacúrio, 0,15 mg.kg-1, el menor tiempo de recuperación en los pacientes pediátricos anestesiados con sevoflurano. También, el rocuronio, el mivacúrio y el atracúrio no determinaron alteraciones hemodinamicas de importancia clínica relevante y proporcionaran excelentes condiciones de intubación traqueal.
Neuromuscular blockers are widely used to help tracheal intubation. For paralyzing vocal cords and relaxing muscles, especially oropharyngeal muscles, they decrease the incidence of complications at tracheal intubation. As general anesthesia adjuvants for pediatric patients they help the surgical procedure for causing muscle relaxation. Used in bolus or continuous infusion they help mechanical ventilation in intensive care units 1-4.
Neuromuscular blockers may also be used to temporarily prevent childrens sudden movements during diagnostic or minor surgical procedures (CT, MRI, bronchoscopy, etc.) 1,2,4.
The ideal neuromuscular blocker should have the following characteristics: fast onset, short duration, absence of cardiovascular effects (tachycardia, hypotension secondary to histamine release) and foreseeable action time. However, there is still no ideal neuromuscular blocker and, among those available for clinical use, all of them have advantages and disadvantages 2,4.
This study aimed at evaluating onset and recovery time, hemodynamic changes and tracheal intubation conditions of three neuromuscular blockers widely used in pediatrics.
After the Clinical Research Ethical Committee, Faculdade de Medicina de Botucatu, UNESP approval and the written consent of parents or guardians, participated in this randomized double-blind study 67 children aged 30 months to 12 years, physical status ASA I and II, not receiving medication and without diseases affecting neuromuscular function, to be submitted to procedures lasting 60 minutes or above. Children where submitted to general anesthesia and tracheal intubation for urologic, gastrointestinal and ophthalmologic surgeries. After pre-anesthetic evaluation the day before surgery, children were premedicated with 0.3 to 0.5 mg.kg-1 oral midazolam, one hour before surgery.
Monitoring in the operating room consisted of ECG at DII to evaluate heart rhythm and rate, pulse oximetry to evaluate hemoglobin peripheral saturation (SpO2), capnometry and capnography to evaluate CO2 expired pressure (PETCO2) and its corresponding curve, non-invasive blood pressure (BP) and esophageal temperature (T) readings with a digital thermometer. Neuromuscular transmission was monitored with acceleromyography (TOF-Guard) to evaluate at 15-second intervals adductor muscle of thumb response with stimulating electrodes placed on the ulnar nerve on the wrist.
Anesthesia was induced with intravenous alfentanil (50 µg.kg-1) and propofol (3 mg.kg-1) and was maintained with 50% N2O/O2 and sevoflurane in a concentration enough to maintain anesthetic depth. Heart rate, blood pressure, changes in pupil diameter and lacrimation were monitored. Breathing was controlled with tidal volume and respiratory rate adjusted according to PETCO2.
TOF-Guard was installed after anesthetic induction and ulnar nerve stimulation was only started after patients were asleep. Neuromuscular blockers were administered after completion of the first TOF stimulation response. The same neuromuscular blocker volume was used for all patients. Patients received intravenous NMB and were distributed as follows:
G1 = 0.9 mg.kg-1 rocuronium;
G2 = 0.5 mg.kg-1 atracurium;
G3 = 0.15 mg.kg-1 mivacurium.
Laryngoscopy was performed when T1 < 10% (T10%) and this was considered the neuromuscular blocker onset time (OT). The use of a simple stimulation at every second during this period allows for a more accurate OT calculation. Laryngoscopy conditions were observed and recorded, according to figure 1 5 and the criteria proposed by Goldberg et al. 6: 1 - excellent (easy tracheal tube insertion without coughing and with relaxed vocal cords); 2 - good (minor reaction to tracheal tube); 3 - poor (tracheal tube insertion with moderate coughing or bucking, vocal cord movements); 4 - impossible (adducted or non visualized vocal cords without mandible relaxation). Additional data, such as difficult intubation or the use of a mandrel were also recorded in an adequate protocol.
Neuromuscular transmission monitoring was performed until T1 = 25% and 75% and time elapsed was recorded. Neuromuscular blockers clinical duration was considered as time elapsed between OT and T1 recovery to 25% of control (T25). Relaxation time was measured in minutes between the end of OT and recovery to 75% of control (T75). Time elapsed between T25 and T75 was considered as relaxation recovery time (T25-75).
Mean blood pressure (MBP) and heart rate (HR) were evaluated in the following moments: at operating room arrival (M0 = control), one minute after induction (M1), during intubation (M2), one minute after intubation (M3), three minutes after intubation (M4), and five minutes after intubation (M5).
Analysis of variance, chi-square test and non-parametric Kruskall-Wallis test were used for statistical analysis. Significance level was p < 0.05.
Groups were homogeneous in age, weight, height, gender and physical status (Table I).
Statistical MBP analysis has shown significant differences in M1 for the mivacurium group as compared to other groups (Figure 2) (G3 < G2 = G1; p = 0.02). HR in the mivacurium group has shown a significant decrease only in M1 but returned to control values and stabilization in the remaining moments (Figure 3). Moment M4 has shown more significant values for the rocuronium group as compared to other groups.
Onset time (OT) was significantly shorter for G1 (0.5 mg.kg-1 rocuronium) with median of 0.6 minute, as compared to other groups, G2 (0.5 mg.kg-1 atracurium) with median of 1.3 minute and G3 (0.15 mg.kg-1 mivacurium) with median of 1.96 minute (G1 < G2 = G3; p < 0.001) (Table II and Figure 4).
T25 was considered blockers clinical duration and groups had the following behaviors: G3 - shortest clinical duration with median of 8.8 minutes, as compared to G1, with median of 38 minutes and G2, with median of 41.5 minutes (G3 < G1 = G2; p < 0.001) (Table II and Figure 5).
Relaxation time (T25) was shorter for G3 (median of 13.6 minutes) as compared to other groups (G1 with median of 57.7 minutes and G2 with median of 54.6 minutes) (G3 < G1 = G2; p < 0.001) (Table II and Figure 6).
All groups had totally satisfactory tracheal intubation conditions by direct laryngoscopy (grade I and open vocal cords). Hence, there were no differences in intubation difficulty and no patient needed a guide wire.
This study has evaluated hemodynamic and tracheal intubation conditions, onset and recovery time of three pediatric neuromuscular blockers. Acceleromyography was used because it is based on the fact that if the mass is kept constant, thumb acceleration in response to neurostimu- lation is proportional to contraction strength.
Patients age has varied from 30 months to 12 years (mean of approximately 5 years), thus with similar extracellular fluid composition and adequate renal and liver function. Other factors, such as neuromuscular junction maturity, the rate between slow and fast contraction fibers and muscle mass size must have been also equivalent in the studied population 3,4,7,8.
In general, blood pressure decrease associated to neuromuscular blockers is due to histamine release by such compounds. In low concentrations they cause skin erythema and in high concentrations they may cause systemic vasodilation with hypotension and bronchomotor tone increase 8,9. Vasodilation may be attributed to histamine stimulation of vascular endothelium H1 receptors with subsequent changes in vasodilating prostaglandin. When histamine release is compared among neuromuscular blockers, atracurium and mivacurium are considered of mild or moderate release and rocuronium as minimum or nonexistent release 8.
Mivacurium-induced blood pressure decrease did not impair anesthesia safety because there has been a prompt recovery in the following moments. Several papers have shown that atracurium and mivacurium release less histamine in children as compared to adults 7,9-11 and do not cause significant changes in blood pressure, heart rate and pulse 9,12. It is generally accepted that mivacurium, atracurium and rocuronium do not significantly change cardiocirculatory parameters in pediatric patients 7,8,13,14.
Heart rate decrease in M1 in the mivacurium group, and its increase in M4 in the rocuronium group represented minor changes without any clinical consequence. In addition, this parameter was completely stabilized in the following moments.
When comparing the neuromuscular blockers object of this study, rocuronium (0.9 mg.kg-1) has shown a shorter onset time as compared to other groups. Neuromuscular blockers onset time is influenced by several factors, such as cardiac output, muscle blood flow, distance between injection site and heart, distribution volume, non-specific bindings, blood-tissue participation coefficient, drug potency and dose 8,15.
Since rocuronium is a low potency drug, it needs a higher number of feasible molecules to bind to the receptor and help diffusion to a small neuromuscular junction space. So, the dose of 0.9 mg.kg-1 used in our study justifies a shorter onset time. Several authors have used the same dose in children or adults, especially when the administration route is a peripheral vein 15-17. This same dose has been used when a fast onset is desired, such as in patients needing a rapid sequence intubation 15,17,19.
Fuchs-Buder et al. 19 have compared two rocuronium doses: 0.6 mg.kg-1 (2 x ED95) and 0.9 mg.kg-1 (3 x ED95) in children aged 3 to 7 years and submitted to rapid sequence intubation. Intubation conditions were considered excellent in 33 children and good in 2 children with the higher NMB dose (0.9 mg.kg-1). Onset time was 188 seconds for the 0.9 mg.kg-1 dose and 193 seconds for the 0.6 mg.kg-1 dose.
Other authors have found in children onset times of 1.1 to 1.5 minutes with 0.6 mg.kg-1 rocuronium 20-22. With a dose of 1.2 mg.kg-1, Wolf et al. 22 have found a 0.7-minute onset time for rocuronium. So, the dose used was an important parameter to determine rocuronium onset time. Considering other factors interfering with this parameter, such as distribution volume, one may say that it has been similar for all neuromuscular blockers object of this study. Since they are polar substances, they do not cross lipidic membranes and do not distribute in fat or enter the cells. Distribution volume in balance state corresponds approximately to extracellular volume fluid 8.
Atracurium (1.3 min) and mivacurium (1.9 min) onset times were not significantly different. Several authors have determined mivacurium onset time in children with doses varying from 0.1 to 0.3 mg.kg-1 and have found a decrease in onset time with an increase in dose (3.2, 1.5 and 1.2 minutes, respectively). However, the increase to 0.4 mg.kg-1 has not further decreased onset time, although prolonging recovery 23,24.
Kaplan et al. 25 have administered 0.2 mg mivacurium in children who were anesthetized with sevoflurane or halothane. Onset time was 2.4 minutes with halothane and 1.8 minutes with sevoflurane.
With 0.5 mg.kg-1 atracurium, onset time was 1.3 minutes, which is also not so different from most papers in the literature. Goudsouzian et al. 26, in a study with babies anesthetized with halothane and receiving 0.4 mg.kg-1 atracurium, observed an onset time of 1.6 minutes. In this same study onset time was 1.5 minutes for children receiving 0.5 mg.kg-1 atracurium and anesthetized with N2O/O2.
Other authors have found a similar onset time (1.50 minutes) in children receiving 0.5 mg.kg-1 atracurium 27.
Recovery time (T25-75) is a comparison standard largely independent of neuromuscular blocker dose and is inversely correlated to drug metabolization 8,28. However, for a drug where redistribution plays a major role in recovery, this ratio (T25-75) may increase after high doses, serial doses or continuous infusion. A cumulative effect has been described after high mivacurium doses, however without clinical significance 8.
Neuromuscular block duration and recovery depend on factors such as redistribution and potentiation by other drugs.
Redistribution (fastest a phase) is the major reason for the apparent disappearance of clinical effects. Afterwards there is a slow return to the central compartment and clearance becomes in charge of subsequent NMB plasma and neuromuscular junction removal. Redistribution is more effective in decreasing neuromuscular blockers effects after a single dose 8.
Several papers have shown that volatile anesthetics potentiate neuromuscular blockers action, thus prolonging their duration. This phenomenon is not yet well understood, but some factors might be involved, such as an action on acetylcholine receptors, action on the central nervous system with reflex medullary depression, decreased post-junctional membrane sensitivity to acetylcholine-induced depolarization, or even increased muscle blood flow 28-30.
Among the neuromuscular blockers object of this study, mivacurium had the shortest clinical duration, the shortest relaxation time and the fastest recovery time. Rocuronium and atracurium did not differ in clinical duration, relaxation time or recovery time.
Mivacurium, considered a short-duration neuromuscular blocker, is a blend of three optic isomers. From these, two are active (trans-trans and cis-trans), although with short half-life and fast clearance due to enzymatic hydrolysis. The cis-cis isomer is metabolized more slowly and has minimum effects as a neuromuscular blocker 3,8,9. There are papers in the literature describing prolonged recovery times in children receiving mivacurium and relating them to butyrylcholine esterase enzyme or plasma cholinesterase which are responsible for its hyodrolysis 7,31,32. Some authors have determined mivacurium recovery times in different age brackets and concluded that they were shorter in children as compared to adults 13,14, and that even with increased doses spontaneous neuromuscular junction function recovery was not prolonged 4,24.
Mivacurium duration seems to be influenced by the anesthetic technique. Studies comparing the need for mivacurium in children anesthetized with halothane or sevoflurane have shown a lower neuromuscular blocker need in 37% and 70%, respectively 23.
Kaplan et al. 25 have studied children aged 1 to 12 years anesthetized with halothane or sevoflurane and have found a 75% contraction recovery 19.5 and 15.0 minutes, respectively, after the administration of 0.2 mg.kg-1 mivacurium.
A different study has shown a 70% decrease in mivacurium dose in children anesthetized with isoflurane as compared to those anesthetized with halothane 23.
A period of 30 to 45 minutes is taken into account when studying the influence of volatile anesthetics on neuromuscular blockers, that is, enough time for its diffusion in the muscle compartment and to establish a balance among inhaled alveolar, plasma and muscular concentrations 28,33-35. Sevoflurane was the volatile anesthetic drug used in this study and was administered for more than 30 to 45 minutes. So, it does not seem to have influenced mivacurium duration.
Atracurium and rocuronium are considered neuromuscular blockers of intermediate duration and our study has confirmed such classification. Atracurium metabolization by non-specific estearases and its spontaneous decomposition by Hofmanns breakdown are sensitive to pH and temperature changes. Its clinical duration (T25-75) is 33 minutes in small children and 44 minutes in adults 7, and the recovery time (T25-75) is 10-15 minutes 8.
By increasing atracurium doses some authors have found an increase in neuromuscular function recovery in children when recovery time was compared among neonates 27,36.
Other authors 37 have shown an increase in atracurium infusion when anesthesia was induced with N2O/O2 and fentanyl, as opposed to halothane or sevoflurane.
So, atracurium duration found in our study is in line with existing data. Rocuronium, in the dose used in this study, is considered an alternative to succinylcholine for tracheal intubation.
Fuchs-Buder et al. 19 have compared 0.6 mg.kg-1 and 0.9 mg.kg-1 rocuronium in children. Clinical duration (T25-75) was 34 and 21 minutes and relaxation time was 44 and 30 minutes, respectively. Increasing rocuronium dose to 1.2 mg.kg-1, Woolf et al. 22 have found in children a clinical duration of 41 minutes. Other authors have used 0.6 mg.kg-1 and clinical duration was 26.7 and 24.2 minutes 21,22.
Rocuronium recovery time (T25-75) is of approximately 10 to 15 minutes 5,6. Prolonged neuromuscular junction recovery time depending on the type of anesthetics has been studied for rocuronium.
Some authors have found a prolonged T25-75 in adults with rocuronium and sevoflurane as compared to isoflurane (26.3 and 14.7 minutes, respectively) 28. The slower recovery time observed by some authors may be due to lower rocuronium doses or the association of intravenous anesthetics 20,34,35.
Rocuronium recovery time of 19.7 minutes found in our study was not different from that obtained for atracurium, which was 13.1 minutes. So, 0.9 mg.kg-1 associated to sevoflurane has not significantly changed this time.
In conclusion, our results as compared to other authors have shown that 0.9 mg.kg-1 rocuronium had the shortest onset time and that 0.15 mg.kg-1 mivacurium had the shortest recovery time. Atracurium and rocuronium were not different in recovery time in pediatric patients anesthetized with sevoflurane. Rocuronium, mivacurium and atracurium offer good conditions for direct laryngoscopy and have not determined clinically relevant hemodynamic changes. So, in pediatric patients, rocuronium is the drug of choice when a fast onset time is desired, and mivacurium is the best option for short procedures.
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Dra. Norma Sueli Pinheiro Módolo
Deptº de Anestesiologia da FMB - UNESP
Distrito de Rubião Junior
18618-970 Botucatu, SP
Submitted for publication July 11, 2001
Accepted for publication October 02, 2001