Do metoclopramide and ondansetrone alter mivacurium-induced neuromuscular blockade? - a randomised trial

Abstracts

Experiência:

Objetivamos investigar os efeitos de metoclopramida e ondansetrona no bloqueio neuromuscular por mivacúrio.

Métodos:

Foram incluídos no estudo 75 pacientes ASA I-II, com idades entre 18 e 65 anos e agendados para cirurgia eletiva necessitando de intubação traqueal. Os pacientes receberam metoclopramida 10 mg, ondansetrona 4 mg ou salina normal 5 mL; grupo M, grupo O e grupo SN (n = 25) respectivamente. Antes da anestesia, os medicamentos em estudo foram administrados em um volume de 5 mL. O nível de colinesterase plasmática foram obtidos antes e 5 minutos depois da administração dos medicamentos em estudo e 5 minutos depois da administração de mivacúrio. Os tempos até o início e os níveis T25, T75, T25-75 e T90 foram comparados entre si, tendo sido investigadas as diferenças entre cada paciente. Depois de registrar T90, o estudo foi terminado, tendo início a cirurgia.

Resultados:

O tempo até o início foi significativamente mais breve no Grupo M versus os outros dois grupos. O tempo até o início no Grupo O foi significativamente mais breve versus grupo SN. No grupo M, T25, T75, T90 e os índices de recuperação foram significativamente maiores versus Grupo NS (p < 0,001). No Grupo O, T25 e T75 foram maiores versus Grupo NS (p < 0,01 e p < 0,05,respectivamente). No Grupo M, T75, T90 e índices de retorno da anestesia foram significativamente maiores versus Grupo O (p < 0,001, p < 0,01, p < 0,001, respectivamente). Nos Grupos M e O, os níveis plasmáticos de colinesterase diminuíram significativamente (p < 0,001). Depois da administração dos medicamentos em estudo e de mivacúrio. Houve também redução na colinesterase plasmática no Grupo NS 5 minutos após a administração de mivacúrio (p < 0,001).

Conclusão:

Consideramos que ondansetrona seja agente mais confiável do que metoclopramida, quando utilizada com mivacúrio.

Mivacúrio; Metoclopramida; Ondansetrona; Neuromuscular; Bloqueio; Anestesia

Experiencia:

deseamos investigar los efectos de la metoclopramida y la ondansetrona en el bloqueo neuromuscular por mivacurio.

Métodos:

se incluyeron en el estudio 75 pacientes ASA I-II, con edades entre 18 y 65 anos, programados para la cirurgia electiva necesitando intubación traqueal. Los pacientes recibieron metoclopramida 10 mg, ondansetrona 4 mg o salina normal 5 mL; grupo M, grupo O y grupo SN (n = 25) respectivamente. Antes de la anestesia, los medicamentos en estudio se administraron en un volumen de 5 mL. El nivel de colinesterasa plasmática se obtuvo antes y 5 minutos después de la administración de los medicamentos en estudio y 5 minutos después de la administración del mivacurio. Los tiempos hasta el inicio y los niveles T25, T75, T25-75 y T90, fueron comparados entre si y se investigaron las diferencias entre cada paciente. Después de registrar T90, el estudio se concluyó y se inició la cirugía.

Resultados:

el tiempo hasta el inicio fue significativamente más corto en el Grupo M versus los otros dos grupos. El tiempo hasta el Grupo O fue significativamente más corto versus grupo SN. En el grupo M, T25, T75, T90 y los indices de recuperación, fueron significativamente mayores versus Grupo NS (p<0,001). En el Grupo O, T25 y T75 fueron mayores versus Grupo NS (p<0,01 y p<0,05, respectivamente). En el Grupo M, T75, T90 y los indices de resultado de la anestesia fueron significativamente mayores versus Grupo O (p< 0,001, p<0,01, p< 0,001, respectivamente). En los Grupos M y O, los niveles plasmáticos de colinesterasa se redujeron significativamente (p < 0,001) después de administrar los medicamentos en estudio y del mivacurio. También hubo una reducción en la colinesterasa plasmática en el Grupo NS 5 minutos después de la administración de mivacurio (p< 0,001).

Conclusiones:

consideramos que la ondansetrona es un agente más confiable que la metoclopramida cuando se usa con el mivacurio.

Introduction

Mivacurium chloride is a short acting non-depolarizing neuromuscular blocking agent rapidly hydrolised by plasma cholinesterase (pCHE). Drugs which inhibit pCHE prolong mivacurium neuromuscular block.^1,2 Delayed recovery from neuromuscular block may compromise respiratory effort and airway integrity during emergence from anesthesia. Metoclopramide, which hastens gastric emptying and decreases gastroesophageal reflux, is commonly used for prevention of nausea and vomiting in the early postoperative period.^3-6 Metoclopramide inhibits Pche,⁷ and giving it before mivacurium can prolong recovery time by 30%, probably via increased bioavailability caused by decreased plasma clearance of mivacurium.^8,9 Ondansetrone, a serotonin type-3 receptor antagonist, is also used to prevent nausea and vomiting.¹⁰ The serotonin type-3 receptor is found in both peripheral and central nervous systems. Ondansetrone may also affect neuromuscular blockade by possible inhibiting of Ach releasing to neuromuscular junction.^11-14 In this placebo controlled, prospective, randomised and double blind study, we aimed to investigate the effects of metoclopramide and ondansetrone on mivacurium neuromuscular blockade.

Materials and methods

After Hospital Ethics Committee approval and receipt of written informed consent, seventy five ASA I-II status patients, aged 18-65 and scheduled for elective surgery requiring tracheal intubation were included in the study. Patients with neuromuscular, liver and kidney diseases, or under medication known to affect neuromuscular transmission, with history of difficult intubation, malnutrition, alcohol abuse, fluid electrolyte disturbances, or BMI > 35 were rejected. The patients were randomly assigned according to computer-generated random number sequence into one of three groups to receive metoclopramide, ondansetrone or normal saline; group M (n = 25), group O (n = 25) and group NS (n = 25), respectively.

In the operating room monitoring of D_II derivated ECG, pulse oximetry and non-invasive arterial pressure was performed by Datex-Ohmeda Cardiocap^TM/5 (GE, Finland). A peripheric intravenous line was inserted with 20 gauge catheter and 0.9 NaCl infusion was started.

Metoclopramide 10 mg, ondansetrone 4 mg or normal saline were administered in a volume of 5 mL, 5 minutes before anesthesia induction. The study drugs were prepared by another physician so all drugs were administered blindly. Blood samples were obtained to measure the level of plasma cholinesterase activity, before and 5 minutes after the administration of study drugs and 5 minutes after the administration of mivacurium. During two hours, these samples were sent to be centrifuged in gel contained tubes at 5,000 rpm for five minutes. One ml of obtained serum were inserted to the eppendorf. Those samples were labeled as 1, 2, 3 in order. They were kept in -20 ºC in biochemistry laboratory. Plasma cholinesterase levels were measured colorimetrically with Vitros 250 Chemistry System (Ortho-Clinical Diagnostics, a Johnson Johnson Company). Plasma cholinesterase reference level was considered as 4-12 U.mL^-1.

Anesthesia was induced with 2 μg.kg^-1 fentanyl and 2.5 mg.kg^-1 propofol and patient was ventilated manually by mask with %100 oxygen until the intubation. During this time using TOF-Watch^® SX (Organon, Ireland) and ulnar nerve of the non-cannulated arm was stimulated with supramaximal (50 mA) train of four stimulation to 1 Hz mode to obtain a %100 control level (EMAX).

After obtaining a neuromuscular block control level, 0.2 mg.kg^-1 mivacurium was administered and the patient was intubated. Anesthesia was maintained by MAC 1 sevoflurane in an equal parts O₂/N₂O mixture during operation and patient was ventilated to maintain normocapnia. Forearm skin temperature was kept greater than 32 ºC.

The time from mivacurium injection up to performing 100% neuromusculary blockade was recorded as onset time. For assessment of neuromuscular transmission, TOF impulse with 50 mA current was used at 5 minutes intervals in first 10 minutes and once every minute after 10 minutes. T₂₅, T₇₅, T_25-75, T₉₀ were recorded during the study. Onset time, T₂₅, T₇₅, T_25-75, T₉₀ levels were compared with each other and differences between each patients were investigated. After recording T₉₀, the study was terminated and surgery was started.

At 1^st, 3^rd, 5^th, 10^th, 20^th and 30^th minutes after intubation, mean arterial pressure (MAP), heart rate (HR), ETCO₂, SPO₂ were recorded. 0.5 μg.kg^-1 IV fentanyl and 10 mg IV efedrin were planned to be administered at the time of 20% increase or decrease of MAP respectively.

The data were statistically analyzed using SPSS version 13.0 (SPSS Inc., Chicago, IL). The Kruskal-Wallis test was used to assess differences among the three groups with respect to non-parametric variables. If this revealed significant differences, the Mann-Whitney U test was used to analyze differences between the groups in pairs. Nominal non-parametric data were analyzed using the Chi-square test and Fisher's exact test. Data were presented as mean ± SD, median (range), and number of patients (percentage) per category. P values < 0.05 were considered to indicate statistical significance.

Results

The three study groups did not differ significantly in gender, ASA, age, weight, height and BMI (p > 0.05) (Table 1).

Table 1
Demographic data (number, mean ± standard deviation or number).

	Group M	Group O	Group SN
	n = 25	n = 25	n = 25
Gender (M/F)	4/21	5/20	4/21
ASA (I/II)	18/7	20/5	22/3
Age (year)	44.24 ± 10.38	33.52 ± 10.57	41.32 ± 12.24
Weight (kg)	66.16 ± 9.46	68.08 ± 9.61	65.48 ± 8.52
Height (cm)	163.84 ± 5.41	166.36 ± 7.33	162.92 ± 5.6
BMI	24.60 ± 2.96	24.50 ± 2.00	24.60 ± 2.36

• ASA, American Society of Anesthesiologists; BMI, Body mass index; F, female; M, male; M, metoclopramide; NS, normal saline; O,ondansetrone.

There were no differences in hemodynamic parameters between groups. Onset time was significantly shorter in group M than the other two groups. Onset time in group O was significantly shorter than in group NS. There was no significant difference in EMAX values (p > 0.05) (Table 2).

Table 2
MAX and onset time (mean ± standard deviation).

	EMAX	Onset time (sec)
Group M	99.6 ± 0.48	138.8 ± 5.82a
Group O	99.4 ± 0.50	162.0 ± 9.89b
Group SF	99.3 ± 0.47	168.8 ± 7.67

In Group M T₂₅, T₇₅, T₉₀ and recovery indices were significantly greater than in Group NS (p < 0.001). In Group O T₂₅, T₇₅ were greater than Group NS (p < 0.01 and p < 0.05, respectively). In Group M T₇₅, T₉₀ and emergence indices were significantly higher than Group O (p < 0.001, p < 0.01, p < 0.001 respectively) (Table 3).

Table 3
T₂₅, T₇₅, T₉₀ and recovery indices (minute) (mean ± standard deviation).

	T25	T75	T90	Recovery index
Group M	20.92 ± 1.70a	27.92 ± 1.75a,b	33.40 ± 1.77a,c	7.00 ± 0.70a,b
Group O	19.80 ± 2.12d	25.04 ±2.38e	30.44 ± 2.88	5.48 ± 0.87
Group SN	17.56 ± 2.45	23.12 ± 2.83	29.72 ± 3.03	5.24 ± 0.87

• ^a
  p < 0,001; comparing with Group SN.
• ^b
  p < 0,001; comparing with Group O.
• ^c
  p < 0,01; comparing with Group O.
• ^d
  p < 0,01; comparing with Group SN.
• ^e
  p < 0,05; comparing with Group SN.

Although plasma cholinesterase levels were all in the normal range, there were significant differences in groups (Table 4). In Groups M and O, plasma cholinesterase levels decreased significantly (p < 0.001) after administration of study drugs and mivacurium. In Group NS, plasma cholinesterase level was found to reduce 5 minutes after the administration of mivacurium (p < 0.001).

Table 4
Plasma cholinesterase levels (med ± standar deviation).

	PC1	PC2	PC3
Group M	6.502 ± 0.922	5.674 ± 0.817a	5.033 ± 0.790a
Group O	6.124 ± 1.418	5.634 ± 1.387a	4.884 ± 1.203a
Group SN	5.895 ± 1.204	5.894 ± 1.204	4.998 ± 1.190a

• M, metoclopramide; NS, normal saline; O, ondansetrone; PC1, plasma cholinesterase level in first blood sample; PC2, plasmacholinesterase level 5 min after administration of study drug; PC3, plasma cholinesterase level 5 min after administration of mivacurium.
• ^a
  p < 0.001 evaluation in group.

Discussion

Metoclopramide and ondansetrone are commonly given to prevent nausea and vomiting but their possible interactions with mivacurium are not fully understood. Metoclopramide prolongs the action of succinylcholine, suggesting possible depression of pCHE activity,^15-17 and indeed, it has been shown to prolong the effect of mivacurium.⁸ The 5-HT₃ antagonist ondansetrone may cause increased sensitivity to the competitive neuromuscular blockade induced by non-depolarising muscle relaxants by reducing the release of Ach.¹⁴

We found that metoclopramide reduced the onset time of mivacurium significantly compared to ondansetrone and saline; ondansetrone reduced onset time significantly but to a lesser extent. Metoclopramide also reduced neuromuscular transmission more than ondansetrone, but there was no difference between the two drugs in their effects on pCHE after giving mivacurium.

Motamed et al.¹⁶ studied the effect of 10 and 20 mg metoclopramide on mivacurium-induced neuromuscular blockade. Ten or 20 mg metoclopramide before an intubating dose of mivacurium hastened the onset of maximum blockade by 30% and prolonged recovery by at least 50%. Time to 25% recovery was significantly greater in both metoclopramide groups compared to saline. A slight but significant reduction in cholinesterase activity was detected 2 minutes after the administration of 20 mg metoclopramide. In our study only 10 mg metoclopramide decreased pCHE activity significantly.

El Ayass and Hendrickx found a reduction of mivacurium infusion rate and a delay in neuromuscular recovery after metoclopramide 10 or 20 mg in their randomised double blind placebo-controlled study of 45 patients.¹⁸ There was no significant change in the onset time compared to saline, probably due to an inadequate number of patients. Plasma cholinesterase level decreased in both metoclopramide groups. The recovery indices were greater with metoclopramide compared to saline. While there were significant increases in the time to recovery at 25%, 50%, 75% and 90% with 20 mg, there was only 75% and 90% increase in the time of recovery with 10 mg, compared to saline. We had similar results with this study; 10 mg metoclopramide prolonged the recovery time and indices by 25%, 75% and 90% and decreased pCHE level significantly.

Skinner et al.⁸ investigated the influence of 15 mg.kg^-1 metoclopramide on pCHE and the duration of action of mivacurium in a randomised double-blind study of 30 patients. Onset time and recovery index were not affected, but there was a reduction of pCHE activity at the time of maximum blockade with both metoclopramide and saline. An increased time to recovery of T₁ to 25%, 75% and 90% was seen in the metoclopramide group.

Lien et al.¹⁴ found that 8 and 16 mg ondansetron did not affect the neuromuscular blockade induced by atracurium in their study of 30 patients; ondansetron may thus be preferable as an antiemetic agent when used with other muscle relaxant agents other than mivacurium. We found that 4 mg ondansetrone did not affect mivacurium-induced neuromuscular blockade.

Mivacurium is hydrolyzed by pCHE, an enzyme whose activity is known to be affected by age, gender, ethnic groups and by some physiologic and pathologic situations. Lepage et al.¹⁹ studied factors affecting biological variations in total pCHE in 3,372 apparently healthy subjects more than four years old. They concluded that genetic factors, hormonal status, age and some medications and, especially in males, BMI, affected pCHE. In our study we excluded patients who were more than 65 years old and with BMI > 35. In our study it was important to show that pCHE activity was indeed in the normal range, because low pCHE activity causes prolongation of mivacurium induced neuromuscular blockade.^20,21 After giving metoclopramide and ondansetrone, enzyme levels decreased in different ratios. After mivacurium, enzyme levels decreased significantly in all groups but stayed within the normal range, with no significant difference between groups.

Considering that 10 mg metoclopramide prolonged mivacurium-induced neuromuscular block, we believe that neuromuscular function should be monitored during surgery in order to avoid the complications of excessive dosage. Because ondansetrone did not prolong T₉₀ or recovery indices, and affected other parameters of neuromuscular blockade less than metoclopramide, we believe that it is a more reliable agent than metoclopramide when used with mivacurium.

Referências

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Publication Dates

• Publication in this collection
  Jan-Feb 2014

History

• Received
  27 Jan 2013
• Accepted
  01 Apr 2013