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ORIGINAL ARTICLE
Year : 2019  |  Volume : 13  |  Issue : 1  |  Page : 44-49  

Evaluation of neuromuscular blockade with vecuronium during general anesthesia with oxygen, nitrous oxide, isoflurane versus oxygen, air, isoflurane: A randomized controlled study


Department of Anaesthesiology and Critical Care, JIPMER, Puducherry, India

Date of Web Publication7-Mar-2019

Correspondence Address:
Srinivasan Swaminathan
DH2, Maragatham Apartments, Ellaipillaichavady, Puducherry - 605 005
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0259-1162.252574

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   Abstract 

Background: The use of air oxygen mixture with isoflurane has become more common in the place of nitrous oxide, especially in laparoscopic and abdominal surgeries. With a varied mixture of gases and isoflurane used in general anesthesia, the exact dosing requirement and time duration of action have not been precisely studied with vecuronium when given as a bolus, as is given routinely. Purpose: This study was undertaken to evaluate and compare the neuromuscular effect of vecuronium during anesthesia with oxygen, nitrous oxide and isoflurane versus oxygen, air and isoflurane. Methodology: The study was a prospective, randomized controlled trial on 70 patients allocated into two groups as follows: Group N (nitrous oxide group) and Group A (medical air group). The primary objective was to measure and compare the posttetanic count (PTC1) – train of four (TOF1) interval, to evaluate the time taken for recovery from the intense blockade in both groups. The secondary objectives were to compare time duration for twitch height depression to be 30% of baseline after administering vecuronium, time duration from vecuronium administration to appearance of the first PTC1, PTC (n) at the reappearance of the 1st twitch, time interval between TOF1 and TOF3 and time from vecuronium administration to appearance of TOF3 in both the groups. Results: There is no significant difference between both the groups with reference to the block onset time using 30% depression of single twitch and recovery time from neuromuscular blockade using PTC, PTC1-TOF1 and TOF1-TOF3 time intervals. Conclusion: Measuring and comparing neuromuscular transmission monitoring parameters such as the onset time(ST depression to 30%), and recovery using PTC, PTC1-TOF1 and TOF1-TOF3 time intervals, it is concluded that the character of neuromuscular block with vecuronium is unaffected and not prolonged with or without nitrous oxide when used with isoflurane.

Keywords: Air, isoflurane, neuromuscular blockade, nitrous oxide, oxygen, vecuonium


How to cite this article:
Boddu V, Swaminathan S, Balachander H, Sivakumar RK. Evaluation of neuromuscular blockade with vecuronium during general anesthesia with oxygen, nitrous oxide, isoflurane versus oxygen, air, isoflurane: A randomized controlled study. Anesth Essays Res 2019;13:44-9

How to cite this URL:
Boddu V, Swaminathan S, Balachander H, Sivakumar RK. Evaluation of neuromuscular blockade with vecuronium during general anesthesia with oxygen, nitrous oxide, isoflurane versus oxygen, air, isoflurane: A randomized controlled study. Anesth Essays Res [serial online] 2019 [cited 2019 Dec 13];13:44-9. Available from: http://www.aeronline.org/text.asp?2019/13/1/44/252574


   Introduction Top


Balanced anesthesia involves the use of inhalational agents and nondepolarizing agents. Isoflurane is added to nitrous oxide at 66% to act as a carrier gas. However as nitrous oxide can cause distension of bowel due to its low solubility, the use of air with oxygen and isoflurane has become common, particularly in abdominal and laparoscopic surgeries.[1],[2],[3],[4]

Isoflurane is one of the commonly used volatile agents in laparoscopic surgeries since it is cardiostable and less arrhythmogenic.[1] When nitrous oxide is replaced by air, the percentage of isoflurane is kept higher to ensure adequate depth of anesthesia. Inhalational agents have a variable effect on muscle relaxants and by themselves are also known to have an effect on neuromuscular junction.[5],[6],[7],[8],[9] Nitrous oxide is conventionally considered to have no effect on relaxant effect, but one study observed that it potentiates neuromuscular blockers.[10] With a varied mixture of gases and isoflurane used in general anesthesia, the exact dosing requirement and time duration of action have not been precisely studied with vecuronium when given as a bolus, as is given routinely. Hence, this study was undertaken to evaluate and compare the neuromuscular effect of vecuronium during anesthesia with oxygen, nitrous oxide (O2: N2O), isoflurane versus oxygen, air (O2: Air) isoflurane. Even though studies have been done to evaluate the potentiation of vecuronium by various volatile agents, comparison of the neuromuscular blocking effect of vecuronium at varied isoflurane concentration with and without nitrous oxide are few. Quantifying the character of the block using neuromuscular monitoring by measuring single twitch (ST), posttetanic count (PTC), and train of four (TOF) precise information regarding the onset and duration of various degrees of the block was evaluated and compared.


   Methodology Top


The study participants included all adult patients undergoing elective surgical procedures of >1 h duration, requiring general anesthesia with muscle relaxation. The exclusion criteria include patient refusal, patients with hepatic or renal dysfunction, patients with neuromuscular disorders, patients on medication that may alter neuromuscular transmission, pregnancy and patients >65 years of age. The study was undertaken over a period of 2 years.

The study population was divided into two groups as follows: Group N: They received anesthesia with nitrous oxide, oxygen, and isoflurane and Group A: They received anesthesia with oxygen, medical air, and isoflurane. The time from PTC1 to TOF1 was used to calculate sample size, as this time interval is the time taken for recovery from intense block and is considered a reflection of duration of intermediate block which is maintained for most surgeries and significant prolongation of this time could result in delayed recovery and implies a need to reduce the dose of vecuronium. The sample size was estimated using a statistical formula for comparing two independent means with equal variance. The sample size was calculated to detect a 20% difference in the time from PTC1 to TOF1 between the two groups with a type 1 error of 0.05 and a power of 0.8. Then, n = 33 in each group.

After approval from the Institutional Review Board, 70 patients of ASA physical status Classes I and II admitted to undergo elective surgery under general anesthesia, and satisfying the inclusion and exclusion criteria, were enrolled in this study [Figure 1]. Informed consent was obtained from all patients. Patients were randomly allocated into two groups using block randomization technique into either Group N (nitrous oxide group) or Group A (medical air group). Allocation concealment was done using sealed envelope technique. The study was single-blinded. All patients were premedicated orally on the preoperative night with tablet diazepam 0.2 mg/kg. Tablet famotidine 20 mg and tablet perinorm 10 mg were given orally 2 h before the scheduled time of operation on the day of surgery. In the operation theater, patients were explained about the procedure. Then, monitors were attached and intravenous (IV) access was established and after measuring baseline heart rate (HR), saturation and blood pressure, injection fentanyl 2 μg/kg IV was given. Neuromuscular monitoring was set up and ulnar nerve was stimulated using surface electrodes at wrist and response was recorded in adductor pollicis using accelerographic transducer. Using supramaximal stimulus ST stimulus at 1 Hz was given and control twitch height obtained. Later, after vecuronium administration, ST stimulus at 0.1 Hz to determine the onset time, the PTC to determine the duration of intense block and TOF stimuli to determine the recovery times were used.
Figure 1: Consort diagram for the trial

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Following preoxygenation for 3 min, anesthesia was induced with thiopentone 4–5 mg/kg, and after checking for the adequacy of mask ventilation, injection vecuronium 0.1 mg/kg was given IV and mask ventilation continued with oxygen: Air or oxygen: Nitrous oxide with isoflurane targeting a minimum alveolar concentration (MAC) of 1.3. When twitch height suppression of 30% was reached airway was secured and anesthesia maintained with high flows for 20 min. In Group N, anesthesia was maintained on 33% oxygen and 66% nitrous oxide at a flow rate of 1.5 L/min with isoflurane, titrated to a MAC maintained at 1–1.3 and patients of Group A were maintained on oxygen 50% in medical air with isoflurane (MAC 1–1.3) at a flow rate of 1.5 L/min during the study period.

Parameters monitored were electrocardiography, HR, SpO2, noninvasive blood pressure, FiO2, end-tidal oxygen, the fraction of inspired nitrous oxide, end-tidal nitrous oxide, the fraction of inspired isoflurane, end-tidal isoflurane, fraction of inspired carbon dioxide, end-tidal carbon dioxide, MAC of isoflurane and the dial concentration of isoflurane. These were noted every 5 min during the surgery.

After administration of injection vecuronium, the response to ST stimulus at 0.1 Hz was monitored and the trachea was intubated when the twitch height became 30% of control value. This was taken as the onset time of neuromuscular blockade. PTC was monitored every 5 min, after the abolition of ST. The time from vecuronium administration to first recorded PTC is defined as the duration of the intense block. Monitoring using PTC was continued every 5 min until the response to the TOF1 stimulus was observed. This is defined as the recovery from the intense blockade. The TOF stimuli were monitored every 15 s at 2 Hz till the appearance of TOF3 response. The time interval between the appearance of TOF1 and TOF3 is defined as recovery interval. The time interval between vecuronium administration and the appearance of TOF3 response was taken as the duration of action of vecuronium. During anesthetic maintenance, opioids and vasopressors were administered as per patient requirement. After completion of the surgery, agents were discontinued, reversal was administered and when spontaneous eye opening with the adequate respiratory effort was observed airway was extubated.

The statistical analysis was performed using the SPSS 19 (IBM SPSS statistics 19) statistical software. The demographic data and duration of various types of the blockade were analyzed using unpaired Student's t-test. All statistical analysis was carried out at 5% level of significance and value of P < 0.05 was considered statistically significant.


   Results Top


A total of 70 patients were enrolled in this trial and all were included in the study [Figure 1]. Thirty-five patients each were randomly allocated to A and N group. None of the patients were excluded after randomization. Data from all 70 patients were included for final analysis. Demographic characteristics such as distribution of age, sex, and weight among the groups are represented in [Table 1]. All parameters mentioned above were comparable between the groups.
Table 1: Demographic Characteristics

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Independent sample t-test was used to test the null hypothesis for descriptive data such as time to 30% twitch depression, time to first PTC1, PTC at appearance of first twitch in TOF1, time from PTC1 to TOF1, time from TOF1 to TOF3 and vecuronium administration to TOF3, all of which are represented in [Table 2]. All the parameters were comparable among the groups.
Table 2: Onset and recovery profile of neuromuscular blockade

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Comparison of end-tidal concentrations of isoflurane and systolic blood pressure is shown in [Figure 2] and [Figure 3], respectively. Lesser concentrations of isoflurane were used in Group N, and the changes in systolic blood pressure were similar in both groups which included an initial fall followed by a stable maintenance phase.
Figure 2: Comparison of end tidal concentration of isoflurane in Group N and Group A

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Figure 3: Comparison of systolic blood pressure among the groups

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   Discussion Top


This study was undertaken to evaluate and compare the neuromuscular effect of vecuronium during general anesthesia using isoflurane with either nitrous oxide and oxygen or air and oxygen. The present study has revealed that is there are no significant differences in the character of the block with vecuronium when isoflurane is administered with nitrous oxide: O2 or with air: O2 combination. This was regardless of the fact that isoflurane concentrations were higher in the group nitrous oxide was not used.

Previous studies have used preblock twitch height as a control to judge the recovery and studies utilizing PTC as a tool to quantify the recovery from intense blockade are few. We chose to study the PTC1 to TOF1 interval for the following reasons: PTC could be both a prejunctional and postjunctional event while TOF a postjunctional event. Inhalational agents may have effect only on the postjunctional receptors, thus altering only the TOF response while PTC may be unaltered.[7] To ensure the parameter we chose would reflect the events in both the pre- and post-junctional regions we studied the PTC1-TOF1 duration. This duration also reflects the period of intermediate block and recovery from the intense block.[11],[12]

Regardless of the postulated mechanism of action of the agents used and parameters studied, we observed that there was no difference in the onset and duration of action of the administered dose of vecuronium (1 mg/kg) in both the groups. This is against our hypothesis which was that as isoflurane used will be more in the oxygen air group to ensure adequate depth of anesthesia the relaxant effect will be prolonged with a faster onset in this group. Isoflurane has an effect on the neuro muscle blockade, and desensitization of postjunctional membrane seems to be the major factor in potentiating neuromuscular blockade by volatile agent.[9] The inhalational anesthetic agents decrease the release of acetylcholine presynaptically, but their main effect is on the ion channels of the postsynaptic membrane. Rather than binding at the acetylcholine binding site, they dissolve in the lipid membrane, thereby effecting the channel function. Other mechanisms include binding to the receptor proteins at sites different from the acetylcholine binding sites. By decreasing the frequency of gap junction channel opening and increasing gap junctional channel closing, thereby reduction in junctional conductance is another possible mechanism.[13]

Since the main effect of inhalational agents is on the postjunctional region of the neuromuscular junction, ST response may be affected, but not the PTC.[14],[15] Hence, PTC1 recovery values were expected to be the same and were the same in both groups, as we have used vecuronium which blocks prejunctional Ach receptors,[16] at the same dose in both groups.

In both the groups, time to return of TOF1, TOF1-TOF3 and the total duration of the blockade was comparable and this could be because both groups received isoflurane. Postulating that higher isoflurane concentrations may have a more significant effect on the duration of action of vecuronium, we hypothesized that the return of TOF1 response will be delayed. However, the parameters studied were unaffected by either the addition of nitrous oxide or the use of isoflurane in two different concentrations. One possible explanation could be that the isoflurane concentration at the muscle and neuromuscular junction had yet to attain equilibrium with the end-tidal concentrations as the study period was restricted to <1 h and increasing the concentration of volatile anesthetic has less effect on neuromuscular blockade. The latter findings, i.e., increasing concentration of volatile anesthetics has less effect on neuromuscular blockade has been noted in earlier studies.[17],[18],[19]

The other possible reason for our finding could be related to the effect of nitrous oxide. A study by Fiset et al. had shown that nitrous oxide potentiates neuromuscular blockade.[10] Hence when nitrous oxide is used even with lesser concentrations of isoflurane, we hypothesize that it would add up to the neuromuscular blockade potentiation, and as observed in our study, possibly contributes to the effect of isoflurane.

Accleromyography is a cheap, practically easy to use quantitative neuromuscular monitoring technique, hence has become very popular.[20] Using acceleromyography, ST, PTC1, and TOF1 patterns of nerve stimulation were monitored. ST was used to determine the onset of the blockade, PTC and TOF to determine the intensity of blockade and recovery times, respectively [Figure 4]. We have monitored PTC every 5 min, because each tetanus will distort the posttetanic state of neuromuscular transmission for at least 5 min, sometimes up to 30 min and therefore, repeated unnecessary tetanus was avoided, to prevent a false picture of the degree of neuromuscular block, with recovery appearing to be more rapid than it really is.[20] TOF was monitored every 15 s, as first twitch would serve as an accurate control only if a minimum of 10 s had elapsed after the previous stimulation.[21] The study was done till TOF3, as the reversal of neuromuscular block has to be done, which is usually administered at this stage.[7],[22]
Figure 4: Overview of methodology

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PTC is monitored by applying tetanic stimulation (50 Hz for 5 s) and then the post-tetanic response to single-twitch stimulation was given at 1 Hz starting 3 s after the end of tetanic stimulation. PTC 8-10 implies the return of TOF1 which is 9.14 ± 1.8 in N2O group and 8.3 ± 1.8 in the air group, respectively. This was in accordance with the previous study done by Erikkson.[14] PTC indicates a prejunctional effect of the nondepolarizing neuromuscular blocking agent, whereas the ST or TOF twitch height is thought to reflect postjunctional effects.

Since the main effect of inhalational agents is on the postjunctional region of the neuromuscular junction, there is a delay in the onset of the ST response, but not the PTC.[15] This might be the reason, why PTC1 recovery values are the same in both groups, as we have used vecuronium in both groups, which blocks prejunctional Ach receptors.[16]

In both the groups, TOF1-TOF3 and the total duration of the blockade was comparable and this could be because both groups received isoflurane in varied concentrations and increasing the concentration of volatile anesthetic has less effect on neuromuscular blockade.[18]

Limitations of the study could be the following: intraoperative opioids administered may play a role in potentiation of neuromuscular blockade, and their effects on neuromuscular junction are not clear. Cumulative effects of doses of vecuronium and its effects have not been studied.

Regardless of the possible mechanism, during general anesthesia, the character and duration of neuromuscular blockade of vecuronium at 0.1 mg/kg, when administered during anesthesia using isoflurane with air oxygen mixture or nitrous oxide-oxygen mixture appears to be similar. Use of nitrous oxide with lesser isoflurane or the increase in isoflurane concentration when used without nitrous oxide to maintain adequate depth do not seem to affect the onset or duration of the standard intubating dose of vecuronium. Hence, we can safely administer the standard dose of vecuronium with either anesthetic mixtures for surgeries <1-h duration.


   Conclusion Top


Measuring and comparing neuromuscular transmission monitoring parameters such as the onset time (ST depression to 30%), and recovery using PTC, PTC1-TOF1 and TOF1-TOF3 time intervals, it could be concluded that the character of neuromuscular block with vecuronium is unaffected and not prolonged with or without nitrous oxide when used with isoflurane.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

 
   References Top

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Akca O, Lenhardt R, Fleischmann E, Treschan T, Greif R, Fleischhackl R, et al. Nitrous oxide increases the incidence of bowel distension in patients undergoing elective colon resection. Acta Anaesthesiol Scand 2004;48:894-8.  Back to cited text no. 2
    
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El-Galley R, Hammontree L, Urban D, Pierce A, Sakawi Y. Anesthesia for laparoscopic donor nephrectomy: Is nitrous oxide contraindicated? J Urol 2007;178:225-7.  Back to cited text no. 3
    
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Scheinin B, Lindgren L, Scheinin TM. Peroperative nitrous oxide delays bowel function after colonic surgery. Br J Anaesth 1990;64:154-8.  Back to cited text no. 4
    
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Wright PM, Hart P, Lau M, Brown R, Sharma ML, Gruenke L, et al. The magnitude and time course of vecuronium potentiation by desflurane versus isoflurane. Anesthesiology 1995;82:404-11.  Back to cited text no. 5
    
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Paul M, Fokt RM, Kindler CH, Dipp NC, Yost CS. Characterization of the interactions between volatile anesthetics and neuromuscular blockers at the muscle nicotinic acetylcholine receptor. Anesth Analg 2002;95:362-7.  Back to cited text no. 6
    
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Sudhakar S, Hemavathi B, Ravishankar M. Effect of sevoflurane on vecuronium induced neuro muscular blockade. J Anesth Clin Pharmacol 2007:23:59-64.  Back to cited text no. 7
    
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Baurain MJ, d'Hollander AA, Melot C, Dernovoi BS, Barvais L. Effects of residual concentrations of isoflurane on the reversal of vecuronium-induced neuromuscular blockade. Anesthesiology 1991;74:474-8.  Back to cited text no. 8
    
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Vanlinthout LE, Booij LH, van Egmond J, Robertson EN. Effect of isoflurane and sevoflurane on the magnitude and time course of neuromuscular block produced by vecuronium, pancuronium and atracurium. Br J Anaesth 1996;76:389-95.  Back to cited text no. 9
    
10.
Fiset P, Balendran P, Bevan DR, Donati F. Nitrous oxide potentiates vecuronium neuromuscular blockade in humans. Can J Anaesth 1991;38:866-9.  Back to cited text no. 10
    
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Padmaja D, Srinivas M. Monitoring of the neuromuscular junction. Indian J Anaesth 2002;46:279-88.  Back to cited text no. 11
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12.
Viby-Mogensen J, Howardy-Hansen P, Chraemmer-Jørgensen B, Ording H, Engbaek J, Nielsen A, et al. Posttetanic count (PTC): A new method of evaluating an intense nondepolarizing neuromuscular blockade. Anesthesiology 1981;55:458-61.  Back to cited text no. 12
    
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Zwer F. Factors affect neuromuscular transmission and block. J Anesth Crit Care Open Access 2016;6:216.  Back to cited text no. 13
    
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Eriksson LI, Lennmarken C, Staun P, Viby-Mogensen J. Use of post-tetanic count in assessment of a repetitive vecuronium-induced neuromuscular block. Br J Anaesth 1990;65:487-93.  Back to cited text no. 14
    
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Saitoh Y, Toyooka H, Amaha K. Relationship between post-tetanic twitch and single twitch response after administration of vecuronium. Br J Anaesth 1993;71:443-4.  Back to cited text no. 15
    
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Appiah-Ankam J, Hunter JM. Pharmacology of neuromuscular blocking drugs. Contin Educ Anaesth Crit Care Pain 2004;4:2-7.  Back to cited text no. 16
    
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Quill TJ, Glass PS, Beach CA. Efficacy of vecuronium by continuous infusion with either isoflurane or fentanyl-nitrous oxide anesthesia. Anesth Analg 1988;67:176.  Back to cited text no. 17
    
18.
Rupp SM, Miller RD, Gencarelli PJ. Vecuronium-induced neuromuscular blockade during enflurane, isoflurane, and halothane anesthesia in humans. Anesthesiology 1984;60:102-5.  Back to cited text no. 18
    
19.
Gissen AJ, Karis JH, Nastuk WL. Effect of halothane on neuromuscular transmission. JAMA 1966;197:770-4.  Back to cited text no. 19
    
20.
Fuchs-Buder T, Schreiber JU, Meistelman C. Monitoring neuromuscular block: An update. Anaesthesia 2009;64 Suppl 1:82-9.  Back to cited text no. 20
    
21.
Lee C, Katz RL. Neuromuscular pharmacology. A clinical update and commentary. Br J Anaesth 1980;52:173-88.  Back to cited text no. 21
    
22.
Miller RD, Ward TA. Monitoring and pharmacologic reversal of a nondepolarizing neuromuscular blockade should be routine. Anesth Analg 2010;111:3-5.  Back to cited text no. 22
    


    Figures

  [Figure 1], [Figure 2], [Figure 3], [Figure 4]
 
 
    Tables

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