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 Table of Contents  
ORIGINAL ARTICLE
Year : 2017  |  Volume : 30  |  Issue : 4  |  Page : 1232-1237

Effects of transdermal nitroglycerin and intravenous pancuronium added to lidocaine for intravenous regional anesthesia


1 Department of Anesthesia and PSICUD, Faculty of Medicine, Tanta University, Tanta, Egypt
2 Department of Anesthesiology, Damanhour Medical National Institute, Damanhur, Egypt

Date of Submission04-Mar-2017
Date of Acceptance11-May-2017
Date of Web Publication04-Apr-2018

Correspondence Address:
Ahmed S Elgebaly
Department of Anesthesia and ICU, Faculty of Medicine, Tanta University, Tanta
Egypt
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/mmj.mmj_163_17

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  Abstract 


Objective
The aim of this study was to evaluate the effects of transdermal nitroglycerin patch, pancuronium, or a combination of both when added to low-dose lidocaine compared with standard-dose lidocaine alone in the intravenous regional anesthesia (IVRA) technique in adult healthy participants.
Background
Administration of neuromuscular blocking agents or nitroglycerin with local anesthetics in the upper limb during IVRA improves surgical conditions in adults.
Patients and methods
A total of 100 patients of both sexes aged 18 years or older undergoing elective forearm and hand surgeries were divided into four groups: group A received only lidocaine, group B received lidocaine + pancuronium, group C received lidocaine + nitroglycerin patch, and group D received lidocaine + pancuronium + nitroglycerin patch. Sensory and motor block onset and recovery times, Visual Analog Scale for Pain (VAS scores) for tourniquet pain, postoperative VAS score, and analgesic requirements were recorded.
Results
Sensory block onset times were shorter in groups D and C. Motor block onset times were shorter in groups D and B. Sensory block recovery time prolonged in group D. Motor block recovery time was prolonged in group D. There was a significant difference between the four groups in intraoperative pethidine requirements. The lowest dose of pethidine needed was in group D. Postoperative VAS scores showed significant differences between groups. Postoperative analgesic effect was the longest in group D.
Conclusion
A combination of 0.5 mg of pancuronium and 5 mg of transdermal nitroglycerin patch as adjuvant to 1.5 mg/kg lidocaine 0.25% improves the quality of IVRA without any side effects.

Keywords: anesthesia, lidocaine, nitroglycerin, pancuronium, prospective studies


How to cite this article:
Elgebaly AS, Elmorad MB, Elhawary S, Elhalafawy M. Effects of transdermal nitroglycerin and intravenous pancuronium added to lidocaine for intravenous regional anesthesia. Menoufia Med J 2017;30:1232-7

How to cite this URL:
Elgebaly AS, Elmorad MB, Elhawary S, Elhalafawy M. Effects of transdermal nitroglycerin and intravenous pancuronium added to lidocaine for intravenous regional anesthesia. Menoufia Med J [serial online] 2017 [cited 2020 Apr 2];30:1232-7. Available from: http://www.mmj.eg.net/text.asp?2017/30/4/1232/229204




  Introduction Top


Intravenous regional anesthesia (IVRA) is a reliable, simple, and cost-effective technique of regional anesthesia that is used for performing short surgical procedures in the extremities[1]. It is a widely accepted technique, which is well suited for brief minor surgeries[2]. It provides easy application, effective anesthesia with rapid onset and termination of the effect, the avoidance of certain risk factors that are inherent to general anesthesia, particularly those of airway obstruction and pulmonary aspiration, and short durations of the perioperative morbidity and postoperative hospital stay[3].

There are a few limitations associated with IVRA and those concerns regarding its use must be considered. These concerns include local anesthetic (LA) toxicity, delayed onset of action, poor muscle relaxation, tourniquet pain, and minimal postoperative analgesia [4–6].

It was proved that transdermal nitroglycerin (NTG), nitric oxide (NO) generator, helps in distribution of LA agents to neuron trunks by vasodilatation and also it has been demonstrated that, when transdermal NTG is used with other drugs, analgesic effect is increased[5]. Transdermal NTG has been reported in several studies as an adjuvant in IVRA and its effects on tourniquet pain and intraoperative and postoperative analgesia were promising[7].

Various neuromuscular blocking agents have been used with IVRA to improve the operating conditions and reduce the LA dose and possible systemic toxicity. No complications were reported from using adjuvant neuromuscular blocking drugs in IVRA[8].

The aim of this study is to compare the onset and duration of sensory and motor block, intraoperatively and postoperatively, and the analgesic requirement during and after the operation when adding either pancuronium or transdermal NTG patch or a combination of both to low-dose lidocaine compared with standard-dose lidocaine alone for elective upper limb surgery.


  Patients and Methods Top


This study was carried out on 100 patients of both sexes aged 18 years or older belonging to American Society of Anesthesiologists I and II undergoing elective surgeries of the forearm and hand from January 2015 to December 2015, after obtaining approval of the local ethics committee, and written consent was obtained from the patients after they were adequately informed about the procedure. This study was designed as a prospective, double-blinded, randomized and controlled clinical trial. Randomization was done using a sealed envelope technique according to the dose of lidocaine and addition of transdermal NTG patch and intravenous pancuronium or both. A blinded doctor who did not participate in the study or data collection read the numbers contained in the envelope and made group assignment; another doctor prepared identical syringes containing drugs of the study according to randomization list. The 100 patients were randomly divided into four equal groups:

  1. Lidocaine group (A): 40 ml of 3 mg/kg of 0.5% lidocaine diluted in normal saline (0.9% NaCl) was used for administering IVRA. Empty NTG patch was applied on the ventral aspect of the proximal forearm of the operative arm 2 h preoperatively
  2. Lidocaine and pancuronium group (B): 40 ml of 1.5 mg/kg of 0.25% lidocaine diluted in normal saline (0.9% NaCl) with addition of 0.5 mg pancuronium was used for administering IVRA. Empty NTG patch was applied on the ventral aspect of the proximal forearm of the operative arm 2 h preoperatively
  3. Lidocaine and transdermal nitroglycerin group (C): 40 ml of 1.5 mg/kg of 0.25% lidocaine diluted in normal saline (0.9% NaCl) with application of 5 mg of transdermal NTG patch was used for administering IVRA. NTG patch was applied on the ventral aspect of the proximal forearm of the operative arm 2 h preoperatively
  4. Lidocaine, pancuronium, and transdermal nitroglycerin group (D): 40 ml of 1.5 mg/kg of 0.25% lidocaine diluted in normal saline (0.9% NaCl) with application of 5 mg of transdermal NTG patch and 0.5 mg of pancuronium was used simultaneously for administering IVRA. NTG patch was applied on the ventral aspect of the proximal forearm of the operative arm 2 h preoperatively.


Patient refusal, Reynaud's disease, sickle cell disease, crush injuries, swelling or skin infection at the site of injection, patients with contraindications to NSAIDs, patients with history of allergy to NTG, pancuronium, or lidocaine, and surgeries more than 60 min or less than 30 min were excluded from the study.

After history taking, complete clinical examination, and laboratory investigations, monitoring of the patient with noninvasive blood pressure, ECG, and peripheral oxygen saturation was performed. A 22 G intravenous cannula was inserted in the dorsum of the operative hand (as distal as possible) for injection of the study drugs; another 20 G intravenous cannula was inserted in the contralateral hand for crystalloid infusion.

A double pneumatic tourniquet was placed on the upper arm with generous layers of cotton padding on the operative side, ensuring that no wrinkles are formed and the tourniquet edges do not touch the skin, and then it was exsanguinated by 2 min. Elevation and wrapping were done with an Esmarch bandage. If it is impossible because of infection or fracture, exsanguinations can be achieved by elevating the arm for 2–3 min while compressing the axillary artery.

The proximal tourniquet was then inflated to 100 mmHg above the systolic blood pressure or to a minimum of 250 mmHg. Before LA (with or without adjuvant) was injected, circulatory isolation of the arm was verified by inspection, absence of radial pulse, and loss of pulse oximetry tracing in the ipsilateral index finger, and then the LA solution was injected.

Ten minutes were allowed after injection of LA for block onset. After 15 min of injection in all patients, distal tourniquet was inflated to 250 mmHg and the proximal tourniquet was deflated after taking out transdermal NTG patch. If no block occurs up to 15 min, the patient was excluded and replaced with another matched one. The cuff was not deflated until 30 min after LA injection because systemic toxicity of LA may occur and was not inflated for more than 1.5 h.

Assessment of demographic data, duration of surgery, mean arterial blood pressure, heart rate, peripheral oxygen saturation, sensory (pinprick test) and motor block (asking the patient to flex and extend the wrist and fingers) onset and recovery times, onset time of tourniquet pain and number of patients complaining from it, intraoperative and 24-h postoperative analgesic requirements, postoperative Visual Analog Scale (VAS) score, and first time of analgesic requirement and complications were recorded.

Statistical analysis

Data were fed to the computer and analyzed using IBM SPSS Statistics for Windows, version 20.0, released 2011 (IBM Corp., Armonk, New York, USA). Qualitative data were described using number and percent. Quantitative data were described using range (minimum and maximum), mean, and SD. Comparison between different groups regarding categorical variables was tested using χ2-test. When more than 20% of the cells have expected count less than 5, correction for χ2 was conducted using Fisher's exact test or Monte Carlo correction. The distributions of quantitative variables were tested for normality using Kolmogorov–Smirnov test, Shapiro–Wilk's test, and D'Agstino test. If it reveals normal data distribution, parametric tests were applied. If the data were abnormally distributed, nonparametric tests were used. For normally distributed data, comparison between more than two population were analyzed F-test (analysis of variance) to be used and post-hoc test (Tukey), comparison between different periods using analysis of variance with repeated measures and post-hoc test (least significant difference) was assessed using. For abnormally distributed data, Kruskal–Wallis test was used to compare between different groups and pairwise comparison was assessed using Mann–Whitney test. To compare between the different periods, Wilcoxon signed-ranks test was applied. Significance of the obtained results was judged at the 5% level.


  Results Top


The patient flow diagram is illustrated, and it shows that 108 parturients were evaluated for eligibility. Eight parturients were excluded: two patients because of refusal, two patients of liver disease, two patients for inadequate block, and two patients for vasovagal attack at baseline. The remaining 100 parturients (25/group) completed the study.

Demographic data were comparable with insignificant difference in age, sex, weight, American Society of Anesthesiologists physical status, duration, and type of surgery [Table 1].
Table 1: Demographic data

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Sensory block onset times were shorter in group D (3.76 ± 0.93) and group C (3.80 ± 1.0) followed by group A (5.72 ± 1.46) and group B (6.32 ± 1.63), and motor block onset times were shorter in group D (7.44 ± 1.23) and group B (8.12 ± 1.17) followed by group C (10.72 ± 1.93) and group A (13.56 ± 1.26). Sensory block recovery time was prolonged in group D (11.44 ± 1.33), followed by group C (10.56 ± 1.12) and then by group B (6.96 ± 1.10) and group A (6.88 ± 1.45), and motor block recovery time was prolonged in group D (21.44 ± 2.08), followed by group B (19.36 ± 2.53) and then by group C (13.04 ± 1.57) and group A (11.96 ± 1.72) [Table 2].
Table 2: Sensory and motor block onset and recovery times

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VAS scores for tourniquet pain showed significant differences between the four groups at the following points of measurement: 10, 15, 20, and 30 min after tourniquet inflation. By comparing two groups at a time, there were highly significant differences with lower VAS scores between group C (0.68 ± 0.63, 1.04 ± 0.35, 1.44 ± 0.58, 2.12 ± 0.78, and 2.96 ± 0.61, respectively) and group D (0.68 ± 0.63, 1.04 ± 0.35, 1.32 ± 0.48, 1.92 ± 0.64, and 2.84 ± 0.69, respectively) when compared with either group A (1.44 ± 0.77, 2.24 ± 0.52, 3.28 ± 0.79, 2.68 ± 0.69, and 2.44 ± 0.58, respectively) or group B (1.72 ± 0.54, 2.0 ± 0.50, 3.32 ± 0.75, 2.88 ± 0.67, and 2.32 ± 0.48, respectively). In addition, there was a significant difference in the number of patients who complained of tourniquet pain between the four groups: in group A 13 (52%) patients complained of tourniquet pain, in group B 14 (56%) patients complained of tourniquet pain, in group C six (24%) patients complained of tourniquet pain, and in group D only five (20%) patients complained of tourniquet pain. Onset time of tourniquet pain was the longest in group C (29.17 ± 2.04 min) and group D (29.00 ± 2.24 min) followed by group A (21.54 ± 3.15 min) and group B (20.71 ± 1.82 min) [Table 3].
Table 3: Visual Analog Scale scores for tourniquet pain

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Postoperative VAS scores showed significant differences between the four groups at the following points of measurement: 30 min, 1 h, and 4 h after tourniquet deflation with lower VAS scores in group C (1.36 ± 0.81, 1.92 ± 0.40) and group D (1.12 ± 0.93, 2.04 ± 0.35) at 30 min and 1 h (P< 0.001); there was no significant difference between study groups at 2 h, and there was a significant difference with lower VAS scores in group A (2.16 ± 0.47) and group B (2.20 ± 0.41) at 4 h (P< 0.001) [Table 4].
Table 4: Postoperative Visual Analog Scale score

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Postoperative analgesic effect was the longest in group D (196.80 ± 58.79 min) followed by group C (187.20 ± 60.79 min), and the shortest in group A (51.60 ± 25.28 min) and group B (46.80 ± 26.10 min). Postoperative analgesic requirement was the lowest in group D (32.40 ± 8.31 mg), followed by group C (33.60 ± 9.95 mg), and the highest requirement was in group B (42.0 ± 15.0 mg) and then group A (40.80 ± 14.70 mg) [Table 5].
Table 5: Analgesic requirements

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There was a significant difference between the four groups in intraoperative pethidine requirements. The lowest dose of pethidine needed was in group D (30.00 ± 3.54) followed by group C (31.67 ± 5.16), and then group B (38.93 ± 5.25) and group A (39.23 ± 6.07) [Table 5].

No adverse effects or complications were seen in this study. No evidence of central nervous system complications (as circumoral numbness, headache, convulsions, or coma) or cardiac complications (such as arrhythmias, hypotension, or bradycardia) were seen after LA administration, before and during surgery and after release of the tourniquet.


  Discussion Top


Providing satisfactory and prolonged analgesia is an important goal in the management of postoperative pain. IVRA is a technique that is mostly used for providing anesthesia and analgesia during the operation. Using additives with lidocaine may prolong the duration of postoperative analgesia.

Our study results showed that the addition of 0.5 mg of pancuronium and 5 mg of transdermal NTG patch as adjuvant to 1.5 mg/kg lidocaine 0.25% for IVRA reduced the dose of lidocaine used for IVRA, shortened the sensory and motor block onset times, prolonged the sensory and motor block recovery times, decreased VAS scores and analgesic consumption intraoperatively and postoperatively, prolonged the duration of postoperative analgesic effect of IVRA, and delayed the first time to analgesic requirement and improved the quality of IVRA without any side effects.

The analgesic effects of transdermal NTG have been reported in several studies [9–11]. The beneficial effects of NTG seem to be influenced by a direct potent vasodilatory effect that promotes distribution of lidocaine to nerves that is mainly dose dependent and can be increased by elevating drug dosages[10]. The details of the pain-relieving mechanism of NTG have been well understood. NTG exerts its analgesic effect as it is metabolized to NO in the cell. NO causes an increase in the intracellular concentration of cyclic guanosine monophosphate, which produces pain modulation in the central and peripheral nervous systems. NO generators also induce anti-inflammatory effects and analgesia by blocking hyperalgesia and the neurogenic component of inflammatory edema by topical application[12].

The first study on adding NTG to lidocaine for IVRA for hand and forearm surgery was performed by Sen et al.[13], who studied the effect of adding NTG to lidocaine for IVRA on 30 patients undergoing hand surgery in two groups. The control group (group C, n = 15) received a total dose of 40 ml with 3 mg/kg of lidocaine diluted with saline, and the NTG group (group NTG, n = 15) received an additional 200 μg NTG, and this treatment led to hemodynamic stability in the perioperative period, shortened the onset time of sensory block with prolonged sensory block recovery time, shortened the onset time of motor block with prolonged recovery time, shortened VAS scores of tourniquet pain, and improved the quality of anesthesia in group NTG; VAS scores were lower in group NTG after tourniquet release and in the postoperative period. First analgesic requirement time was longer in group NTG than in group C. Postoperative analgesic requirements were significantly smaller in group NTG.

Asadi et al.[1] studied the analgesic effect of NTG when added to lidocaine for IVRA on 40 patients scheduled for elective forearm and hand surgery, and the results of this study were in agreement with our results: it reported shorter sensory block onset time and delay in sensory block recovery time after tourniquet release in the NTG group with shorter motor block onset time and delay in recovery time after tourniquet release in the first group; the frequency of opioid injections was significantly lower in those who were administered lidocaine and NTG.

Postoperative VAS scores were higher in groups A and B at 30 min and 1 h and lower than groups C and D at 4 h, which can be attributed to the analgesic effect of ketorolac, which was given to patients for relief from postoperative pain. Elmetwaly et al.[6] studied the effect of adding ketamine or NTG to lidocaine for IVRA on 75 patients undergoing hand surgery and found that postoperative VAS scores were higher for the first 4 h in the control group compared with the other study groups.

Muscle relaxants act at the level of the muscle spindle and reduce the central input from these structures resulting in loss of muscle tone and spasm[12]. Addition of muscle relaxants to lidocaine for IVRA has shown to shorten the motor block onset time, prolong the motor block recovery time, and improve the muscle relaxation and operative conditions[14]. Although LAs can only produce neuromuscular blockade at high doses, interactions with neuromuscular blockers, particularly nondepolarizing, become clinically relevant, and careful observation is required when using these agents simultaneously, or in situ ations in which the safety margin of neuromuscular transmission is reduced[15],[16].

Flamer et al.[4] evaluated thirty-one studies with data collected on 1523 patients and use of muscle relaxants (pancuronium, atracurium, mivacurium, and cisatracurium) and reported that the use of muscle relaxants as adjuvant in IVRA enhances motor block and shortens its onset time with delay of its recovery time. In addition to making the surgery easier, addition of muscle relaxant as an adjuvant in IVRA reduces the dose of LA to a nontoxic range. Evidence indicates that an equivalent quality of block can be achieved with the addition of these adjuncts to a dilute solution of LA, but at the expense of a potentially slower onset of sensory block. Aujla et al.[12] evaluated the effect of lignocaine alone versus a mixture of lignocaine, fentanyl, and pancuronium for IVRA on 100 patients divided into two equal groups of 50 each scheduled for elective upper limb surgery; they revealed that the addition of muscle relaxant (0.5 mg of pancuronium) to IVRA anesthetic solution improved the muscle relaxation and operative conditions.

The primary outcomes of our study were that the combination of pancuronium and transdermal NTG patch is better than pancuronium or transdermal NTG patch alone without any side effects. Secondary outcomes were that the adjuvant drugs (pancuronium or transdermal NTG patch), when added to lidocaine in IVRA, reduced the dose of lidocaine used for IVRA, shortened sensory and motor block onset times, prolonged sensory and motor block recovery times, delayed the onset of tourniquet pain, prolonged the time for first analgesic requirement, decreased VAS scores, and decreased the total amount of analgesic consumption intraoperatively and postoperatively without any side effects.

Limitations

Some limitations of this study should be noted. First, although no major complications were observed and some parturients required conversion to general anesthesia, we did not assess the parturients' satisfaction. Second, when testing the anesthetic effects, we only checked the pain sensation (pinprick test) and did not check the sympathetic level (i.e., cold test), which may have more of a relationship with hypotension. However, we assumed that both would have a close correlation. The third limitation was the small sample size. The study included only 100 participants who fulfilled all the inclusion criteria and had undergone elective surgeries of the forearm and hand. The sample size was restricted to 100 cases because of logistical reasons, short duration of the operation, which ranged from 30 to 60 min, and limited operation type varieties; we could only schedule elective surgery for our study. Fourth, the correlation between the dose of the drugs injected and the duration of IVRA anesthesia and postoperative analgesia was out of the scope of our study.


  Conclusion Top


From our study results we conclude that the addition a combination of 0.5 mg of pancuronium and 5 mg of transdermal NTG patch as adjuvant to 1.5 mg/kg lidocaine 0.25% for IVRA reduced the dose of lidocaine used for IVRA, shortened the sensory and motor block onset times, prolonged the sensory and motor block recovery times, decreased VAS scores and analgesic consumption intraoperatively and postoperatively, prolonged the duration of postoperative analgesic effect of IVRA, and delayed the first time to analgesic requirement and improved the quality of IVRA without any side effects.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

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Asadi HK, Mehri D. The analgesic effect of nitroglycerin added to lidocaine on quality of intravenous regional anesthesia in patients undergoing elective forearm and hand surgery. Acta Cir Bras 2013; 28:19–25.  Back to cited text no. 1
    
2.
Choyce A, Peng P. A systematic review of adjuncts for intravenous regional anesthesia for surgical procedures. Can J Anesth 2002; 49:32–45.  Back to cited text no. 2
    
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Marashi S, Yazdanifard A, Shoeibi G. The analgesic effect of intravenous neostigmine and transdermal nitroglycerin added to lidocaine on intravenous regional anesthesia (Bier's block): a randomized, controlled study in hand surgery. Inter J of Pharmacol 2008; 4:218–222.  Back to cited text no. 3
    
4.
Flamer D, Peng PW. Intravenous regional anesthesia: a review of common local anesthetic options and the use of opioids and muscle relaxants as adjuncts. Local Reg Anesth 2011; 4:57–76.  Back to cited text no. 4
    
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Sen H, Kulahci Y, Bicerer E, Ozkan S, Dagli G, Turan A. The analgesic effect of paracetamol when added to lidocaine for intravenous regional anesthesia. Anesth Analg 2009; 109:1327–1330.  Back to cited text no. 5
    
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Elmetwaly KF, Hegazy NA, Aboelseoud AA, Alshaer AA. Does the use of ketamine or nitroglycerin as an adjuvant to lidocaine improve the quality of intravenous regional anesthesia? Saudi J Anesth. 2010; 4:55–62.  Back to cited text no. 6
    
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Lauretti GR, Perez MV, ReIs MP, PereIra NL. Double-blind evaluation of transdermal nitroglycerine as adjuvant to oral morphine for cancer pain management. J Clin Anesth 2002; 14:83–86.  Back to cited text no. 7
    
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Dominic A, Barry A. Complications of intravenous regional anesthesia. In: Finucane BT, editor. Complications of regional anesthesia. 2nd ed. New York, NY: Springer; 2007. pp. 211–223.  Back to cited text no. 8
    
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Glantz L, Godovic G, Lekar M, Kramer M, Eidelman LA. Efficacy of transdermal nitroglycerin combined with etodolac for the treatment of chronic post-thoracotomy pain: an open-label prospective clinical trial. J Pain Symptom Manage 2004; 27:277–281.  Back to cited text no. 9
    
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Jorge LL, Feres CC, Teles VE. Topical preparations for pain relief: efficacy and patient adherence. J Pain Res 2010; 4:11–24.  Back to cited text no. 10
    
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Aujla KS, Gupta R, Singh J. Plain lignocaine versus mixture of lignocaine, fentanyl and pancuronium for intravenous regional anesthesia. J Anesth Clin Pharmacol 2009; 25:301–304.  Back to cited text no. 12
    
13.
Sen S, Ugur B, Aydin ON, Ogurlu M, Gursoy F, Savk O. The analgesic effect of nitroglycerin added to lidocaine on intravenous regional anesthesia. Anesth Analg 2006; 102:916–920.  Back to cited text no. 13
    
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Esmaoglu A, Akin A, Mizrak A, Turk Y, Boyaci A. Addition of cisatracurium to lidocaine for intravenous regional anesthesia. J Clinical Anesth 2006; 18:194–197.  Back to cited text no. 14
    
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Suzuki T, Mizutani H, Ishikawa K, Miyake E, Saeki S, Ogawa S. Epidurally administered mepivacaine delays recovery of train-of-four ratio from vecuronium-induced neuromuscular block. Br J Anesth 2007; 99:721–725.  Back to cited text no. 16
    



 
 
    Tables

  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5]



 

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