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ORIGINAL ARTICLE
Year : 2015  |  Volume : 28  |  Issue : 4  |  Page : 838-844

Evaluation of the effect of transdermal nitroglycerin and intravenous neostigmine added to lignocaine for intravenous regional anesthesia


1 Department of Anesthesia, Faculty of Medicine, Menoufia University, Shibin Elkom, Menoufia, Egypt
2 Neurosurgery Department, Shebin El Kom Hospital, Shebin El Kom, Egypt

Date of Submission30-Jan-2015
Date of Acceptance26-Feb-2015
Date of Web Publication12-Jan-2016

Correspondence Address:
Mohamed Abd El Hamid
Quesna, 41517, Menoufia
Egypt
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/1110-2098.173601

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  Abstract 

Objective
This study aimed to determine the advantage of a combination of transdermal nitroglycerine and neostigmine in intravenous regional anesthesia (IVRA).
Background
The aim of this study was to evaluate the effect of transdermal nitroglycerine, neostigmine, or both when added to lidocaine compared with lidocaine alone in the IVRA technique.
Patients and methods
Eighty patients (ASA grade I and II, aged 18-60 years) of both sexes were enrolled. The patients were divided randomly into groups as follows: group 1: the neostigmine group: a dose of 2.5 mg/kg lidocaine 0.5% (0.5 ml/kg) with the addition of 0.5 mg neostigmine was administered (n = 20). Group 2: nitroglycerine group: a dose of 2.5 mg/kg lidocaine 0.5% (0.5 ml/kg) with the addition of 5 mg of transdermal nitroglycerine (a nitroglycerine patch was applied 2 h before the start of IVRA) was administered (n = 20). Group 3: nitroglycerine-neostigmine group: a dose of 2.5 mg/kg lidocaine 0.5% (0.5 ml/kg) with the addition of 5 mg of transdermal nitroglycerine (a nitroglycerine patch was applied 2 h before the start of IVRA) and 0.5 mg neostigmine was administered (n = 20). Group 4: lidocaine only (control group): participants received IVRA with 2 ml saline added to lidocaine (0.5 ml/kg) (n = 20).
Exclusion criteria
Patients with ischemic heart disease, heart block, second or third degree, severe sinoatrial block, serious adverse drug reaction to lidocaine or amide local anesthetics, concurrent treatment with quinidine, flecainide, disopyramide, procainamide, Adams-Stokes syndrome, Wolff-Parkinson-White syndrome, allergic reactions to organic nitrates, allergy to nitroglycerin, allergy to the adhesive patches, hypersensitivity to neostigmine, myasthenia graves, a history of reaction to bromides, peritonitis, mechanical gastrointestinal, or urinary tract obstruction were excluded.
Results
Sensory and motor block onset times were shorter in the neostigmine-nitroglycerine group compared with all the other groups (P < 0.05). Sensory block recovery time was significantly prolonged and the quality of anesthesia was better in the neostigmine-nitroglycerine group compared with all the other groups (P < 0.05).
Conclusion
We found that the addition of 0.5 mg neostigmine to a dose of 2.5 mg/kg of 0.5% lidocaine for IVRA with a 5 mg transdermal nitroglycerine patch improved the operating conditions and the quality of anesthesia and prolonged postoperative relief, with no adverse effects.

Keywords: intravenous regional anesthesia, neostigmine, transdermal nitroglycerine


How to cite this article:
El Sharkawy O, Mahamed S, Mostafa N, El Hamid MA. Evaluation of the effect of transdermal nitroglycerin and intravenous neostigmine added to lignocaine for intravenous regional anesthesia. Menoufia Med J 2015;28:838-44

How to cite this URL:
El Sharkawy O, Mahamed S, Mostafa N, El Hamid MA. Evaluation of the effect of transdermal nitroglycerin and intravenous neostigmine added to lignocaine for intravenous regional anesthesia. Menoufia Med J [serial online] 2015 [cited 2020 Feb 17];28:838-44. Available from: http://www.mmj.eg.net/text.asp?2015/28/4/838/173601


  Introduction Top


In 1908, Karl August Bier, Professor of Surgery in Berlin, described a new method of producing analgesia of a limb that he named vein anesthesia; the technique did not become popular until the 1960s, when it was reintroduced by Holmes [1],[2] .

Intravenous regional anesthesia (IVRA) is one of the most frequently used maneuvers for short procedures of the upper extremities that do not exceed 90 min [3],[4],[5],[6],[7] .

Previously, there was a focus on the cholinergic system, which modulates pain perception and transmission. It was shown that the spinal or the epidural administration of the acetylcholine (ACH) esterase inhibitor neostigmine resulted in dose-dependent analgesia by inhibition of the breakdown of ACH in the spinal cord. There are ACH receptors in the peripheral nerves [8] , and when neostigmine was added as an adjunct to prilocaine during IVRA, the quality of anesthesia was improved, with prolonged postoperative analgesia. Data from the literature suggest that in humans, high-dose nitroglycerine is hyperalgesic, whereas doses less than 6 mg/day are analgesic under different conditions. Moreover, transdermal nitroglycerine was found to enhance spinal sufentanil postoperative analgesia following orthopedic surgery, and it prolonged the analgesic effect of intrathecal neostigmine [9] .

The present study will compare the onset and duration of sensory and motor block, intraoperative, and postoperative pain measured by the visual analog scale (VAS), the analgesic requirement during intraoperatively and postoperatively, side effects, and the hemodynamic variables during addition of either neostigmine or transdermal nitroglycerine or both to lidocaine in IVRA [10],[11] .


  Patients and methods Top


The present study was a prospective randomized and controlled study carried out in the orthopedic surgery department of Menoufiya University Hospitals, after receiving the approval of the ethical committee, on eighty patients of both sexes, ASA I or II, between 18 and 60 years of age, undergoing minor surgical operations of the upper limb (CTS, tendon repair, tendon release nerve release, and ganglion excision); all the patients underwent elective surgery. The mean weight of the patients was 76.80 ± 10.13 kg, with no significant P value. All patients had two cannulas: one for anesthesia in the operated limb and the other in the other arm for the administration of any drug and intravenous fluids, if needed. Two tourniquets (each 6 cm wide) were applied on the arm with generous layers of padding, ensuring that no wrinkles were formed and that the tourniquet edges do not touch the skin. The arm was exsanguinated using an Esmarch bandage. First, the distal tourniquet was inflated to at least 100 mmHg higher than the patient's systolic blood pressure (250-300 mmHg). Then, the proximal tourniquet was inflated to the same pressure. After ensuring inflation, the distal cuff was deflated. Before a local anesthetic (with or without an adjuvant) was injected, it was confirmed that there was no palpable radial pulse. The local anesthetic (with or without an adjuvant) was then injected slowly. Standard IVRA involves the administration of a 0.5% lidocaine solution using a dosing scheme of 1.5-3 mg/kg body weight (0.3-0.6 ml/kg). The distal tourniquet, which overlies part of the anesthetized arm, can then be inflated and the proximal one can be deflated to relieve tourniquet pain. The cuff should not be deflated until 30 min after the injection of the local anesthetic because systemic toxic doses of local anesthetic may occur. Then, surgery is performed under close monitoring and documentation of parameters of the trial. Cuff deflation is performed in cycles with deflation/inflation times of not less than 10 s until the patient no longer shows symptoms of systemic toxicity (e.g. tingling of the lips, tinnitus, and drowsiness). The patient should be monitored closely for 30 min following tourniquet release. Signs of systemic toxicity will be monitored and managed accordingly.

Groups

The trial was designed as a randomized and prospective clinical trial. The 80 patients included were divided into four equal groups:

Group 1: Neostigmine group: a dose of 2.5 mg/kg lidocaine 0.5% (0.5 ml/kg) with the addition of 0.5 mg neostigmine was administered. (n = 20).

Group 2: Nitroglycerine group: a dose of 2.5 mg/kg lidocaine 0.5% (0.5 ml/kg) with the addition of 5 mg of transdermal nitroglycerine was administered (a nitroglycerine patch was applied 2 h before the start of IVRA and removed before the patient was transferred to the ward) (n = 20).

Group 3: Nitroglycerine-neostigmine group: a dose of 2.5 mg/kg lidocaine 0.5% (0.5 ml/kg) with the addition of 5 mg of transdermal nitroglycerine (a nitroglycerine patch was applied 2 h before the start of IVRA and removed before the patient was transferred to the ward) and 0.5 mg neostigmine was administered (n = 20).

Group 4: Lidocaine only (control group): received IVRA with 2 ml saline added to lidocaine (0.5 ml/kg) to a total dose of 40 ml (n = 20).

The solution was administered by the anesthetist who was unaware of the content of the syringe over 3 min.

Assessment and measurements

Motor and sensory block: the sensory block was assessed every 30 s after the injection of lidocaine. Motor function was assessed by asking the patient to flex and extend their wrist and fingers at 30-s intervals. The onset time of sensory and motor block was recorded as the time elapsed from the injection of the study drug to the onset of both blocks. The mean arterial blood pressure (MAP), heart rate (HR), and oxygen saturation (SPO 2 ) values were recorded before inflation of tourniquet as baseline, 1 min after inflation of tourniquet, (10, 20, and 30 min) after the injection of drugs, and (1, 10, 20, and 30 min) after deflation of tourniquet. The assessment of tourniquet pain was performed using a 10 cm VAS, with anchors of 0 = no pain and 10 = worst pain imaginable. Onset of tourniquet pain was defined as the duration between inflation of tourniquet and until the time when the patient cannot tolerate tourniquet pain (VAS >3). The number of patients complaining of tourniquet pain was recorded for each group. The analgesic requirements intraoperatively and 24 h during the postoperative period were evaluated. When the VAS score of tourniquet pain was reported to be more than 3, the patient was administered pethidine 0.5 mg/kg intravenous boluses, and consumption was recorded during the intraoperative period; patients were administered ketorolac 30 mg (NSAID) (ASA I patients and in whom it was confirmed that there was no renal impairment or known allergy) over a 24 h postoperative period as postoperative analgesia. Intravenous bolus pethidine was administered in the PACU whenever VAS was higher than 3. Recovery time: the distal tourniquet was not deflated until a minimum of 30 min after the lidocaine injection, and was performed using the cyclic deflation technique. Sensory and motor block recovery times were noted as the time elapsed after tourniquet deflation until the return of pain sensation and movement in the fingers.

Duration of effectiveness of analgesic effect of IVRA in minutes: it is the time from the time of deflation until the time when the patient cannot tolerate postoperative pain (VAS >3).

Patient satisfaction

Patients were asked to rate the operative conditions according to the following numerical scale: unsuccessful = 0, poor = 1, moderate (pain required supplemental analgesia) = 2, good (minor pain with no need of supplemental analgesia) = 3, excellent (no pain) = 4.

Surgeon opinion

The surgeon was asked to rate the score during the operative conditions such as movement of limb or bleeding. The surgeon was blinded to patient randomization. The score was assigned according to the following numerical scale: 0 = unsuccessful, 1=poor, 2=acceptable (moderate), 3 = good, 4 = excellent.

Complications

Complications were recorded if present.

Statistical analysis

Data were collected, tabulated, and analyzed statistically. t-Tests were used to compare continuous variables between the two groups. A P value of less than 0.05 was considered statistically significant. A P value of less than 0.01 was considered highly significant.


  Results Top


All 80 patients completed the study. There were no significant differences in patients' characteristics. The operation time was similar in the four groups, indicating similar operative conditions. Sensory and motor block onset times were statistically shorter in the neostigmine-nitroglycerine group compared with all the other groups (P < 0.05), and they were shorter in the neostigmine group compared with the control group (P < 0.05). Patients in the neostigmine-nitroglycerine group had a significantly prolonged sensory block recovery time compared with all the other groups (P < 0.05) ([Table 1] and [Table 2]) ([Figure 1] and [Figure 2]). The sensory and motor block recovery time was similar in the neostigmine and the neostigmine-nitroglycerine groups (P > 0.05), but it was prolonged in these two groups compared with the control group (P < 0.05) ([Table 3] and [Table 4]) ([Figure 3] and [Figure 4]).
Figure 1 Sensory block onset among the groups studied.



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Figure 2 Motor block onset time.



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Figure 3 Deflation to sensory recovery time (min).



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Figure 4 Deflation to motor recovery time.



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Table 1 Sensory block onset among the groups studied


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Table 2 Motor block onset time


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Table 3 Deflation to sensory recovery time (min)


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Table 4 Deflation to motor recovery time


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The VAS values of the operative conditions, assessed by the surgeon, were similar in the neostigmine and the neostigmine-nitroglycerine groups and these were statistically higher in those groups compared with the control group. The quality of anesthesia determined by the anesthesiologist was significantly better in the neostigmine-nitroglycerine group compared with all the other groups (P < 0.005).

There was no statistical difference between groups when compared for MAP, SPO 2 , and HR at any time point of measurement (P > 0.05). The first analgesic requirement time was longer for the neostigmine-nitroglycerine group compared with all the other groups (P < 0.005), and it was longer for the neostigmine group compared with the control group (P < 0.05). The pain VAS at the time of first rescue analgesic medication was similar among the four groups.

No adverse effects were observed in this study either intraoperatively or throughout the 24-h postoperative period in any group as we asked the surgeon to admit cases for this period.


  Discussion Top


In our study, we found that there no statistically significant differences were observed between the four groups in the demographic data, type of operation, and duration of operations.

Also, there were no statistically significant differences between the four groups in the vital signs (MAP, HR, and SPO 2 ) during the operations and 30 min after deflation; this may have been because the drugs exerted limited effects systemically as the limb was isolated by the tourniquet.

Statistically, there was a highly significant decrease in sensory block onset time in group 1, group 2, and group 3 compared with group 4. There was a highly significant decrease in the sensory block onset time in groups 1 and 3 compared with group 2. There was a highly significant decrease in motor block onset time in group 1, group 2, and group 3 compared with 4. There was a significant decrease in the motor block onset time in group 1 compared with group 2. There was a highly significant decrease in the motor block onset time in group 3 compared with group 1 and group 2.

Also, our study showed that the time between tourniquet deflation and recovery of sensory and motor function was significantly delayed in group 3, which was a highly significant delay in the sensory recovery compared with group 1, group 2, and group 4. Also, group 1 and group 2 showed a highly significant delay in the sensory recovery time compared with group 4 and group 1 showed a highly significant delay in the sensory recovery time compared with group 2. Group 3 showed a highly significant delay in the motor recovery compared with both group 2 and group 4. Also, group 1 showed a highly significant delay in the motor recovery time compared with both group 2 and group 4. Group 2 showed a highly significant delay in motor recovery compared with group 4.

In terms of the VAS score for tourniquet and surgical pain during the intraoperative and postoperative period, our results showed that on comparing the groups, there was a highly significant difference between group 3 and both of group 1 and group 2 in the VAS through the intraoperative period, but there were highly significant differences between groups 1, 2, and 3 compared with groups 4 in the same period as they showed significantly lower VAS scores than group 4. Also, in the postoperative period, there were significant differences between the four groups in the VAS score for postoperative pain, with groups 1, 2, and 3 having highly significant lower VAS scores than group 4 in the postoperative period after tourniquet deflation. However, on comparing group 3 with group 1 and group 2, we observed that in the postoperative period, group 3 showed highly significantly lower VAS scores than group 1 and group 2.

There was no significant difference in the onset of the tourniquet pain between the four groups.

There was a statistically significant reduction in the number of patients who complained of tourniquet pain in group 3 than in the group 4. Also, the number of patients who complained of tourniquet pain in group 3 was significantly lower than group 1 and the number of patients who complained of tourniquet pain in group 1 and group 2 was significantly lower than that in group 4.

During the operation, the numbers of patients who needed pethidine (systemic analgesic) in group 3 were highly significantly lower than those in groups 1, 2, and 4. In groups 1 and 2, significantly lower number of patients needed systemic analgesia compared with group 4.

Postoperative analgesia provided by IVRA was prolonged in patients in group 3, with a highly significantly longer time than the patients in group 1, group 2, and group 4. Also, group 1 and group 2 had highly significant longer time in than group 4.

The dose of ketorolac required in patients in group 4 was higher than that needed for patients in group 1, group 2, and group 3.

Neither patients' opinion of the experience of the operation nor the surgical opinion in the operative condition showed a statistically significant difference between the four groups.

In our study, neither neostigmine nor transdermal nitroglycerine caused any side effects when added to lidocaine as no side effects were recorded in any of the groups studied.

Jain et al. [8] , in agreement with our results, found that the addition of neostigmine to prilocaine in IVRA shortened sensory and motor block onset times and prolonged the time to first analgesic requirement.

Yang et al. [12] concluded that an intra-articular injection of neostigmine after knee arthroscopy produced a significant analgesic effect.

Sen et al. [13] studied the effect of adding nitroglycerin to lidocaine for IVRA on 30 patients in two groups. In agreement with our results, they found that the addition of nitroglycerine to lidocaine in IVRA shortened the time of onset of sensory and motor blocks, prolonged the time between deflation of tourniquet and recovery of sensory and motor power, delayed onset of tourniquet pain, and decreased the number of patients who needed systemic analgesia. Also, VAS scores were lower intraoperatively and postoperatively, the first postoperative analgesic required was delayed, the dose of analgesia needed postoperatively was decreased, and the patients did not experience any significant side effects.

The analgesic effects of transdermal nitroglycerin have been reported in several studies. The beneficial effects of nitroglycerin seem to be influenced by a direct potent vasodilator effect that promotes the distribution of lidocaine to nerves that is mainly dose dependent and can be increased by increasing drug dosages. The details of the pain-relieving mechanism of nitroglycerin have been well understood. Nitroglycerin exerts its analgesic effect as it is metabolized to nitric oxide (NO) in the cell. NO causes an increase in the intracellular concentration of cyclic GMP, 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 [14],[15],[16],[17] .

The presence of ACH receptors in peripheral nerves is responsible for the action of neostigmine in peripheral analgesia, and ACH plays a role in the sensory regulatory mechanisms controlled by the motor system [18] .

Moreover, Chiou-Tan et al. [19] had reported the presence of ACH receptors in the soma of many petrosal ganglion neurons, thus supporting the idea that under normal conditions, peripheral sensory processes may be associated with ACH.

Our results also showed that a 5 mg transdermal nitroglycerine patch (which releases ~250 μg of nitroglycerine/h) enhanced the analgesic effect of neostigmine. Their combination resulted in improved operative conditions, with better quality of anesthesia and prolonged postoperative analgesia. The transdermal patch was applied on the operative arm 2 h before the start of IVRA as the plasma concentration of nitroglycerine reaches a plateau within 2 h and is maintained throughout the application period [20] .

How nitroglycerine would enhance the analgesic effect of neostigmine is not known, and some explanations are possible. Several studies had reported the synergistic interaction between nitroglycerine and the μ-opioid receptor agonists. Nitroglycerine was found to enhance morphine after intravenous or spinal administration [21] . In addition, systemic morphine increased spinal cord NO metabolite concentrations, and behavioral analgesia in healthy animals from systemic morphine is blocked by NO synthetase inhibitors [22] .

Thus, because of the similarities in the different pain-modulating systems (opioid, α2 adrenergic, and cholinergic receptors) [23] , we could assume a similar synergistic interaction between nitroglycerine and the muscarinic agents peripherally; NO produces neither nociceptive nor antinociceptive effects on the receptors [20] . However, it modulates the anti-inflammatory process and formation of edema. Its vasodilator action on the venous system decreases the vasoconstrictor tone induced by the inflammatory process and further reduces the formation of edema [24] . Finally, nitroglycerine may exert an analgesic effect through the direct stimulation of peripheral fibers, mimicking the actions of locally applied ACH [25] . Therefore, the most probable explanation for our findings is that the administration of the ACH esterase inhibitor neostigmine might exert an analgesic effect by increasing endogenous ACH levels at the peripheral nociceptors. Because of its chemical structure, neostigmine might show longer stability [12] , thereby insuring a longer analgesic effect. Thus, it might enhance the availability of more ACH at the assumed peripherally distributed ACH receptors. Putative mechanisms of a peripheral cholinergic-mediated antinociception at the peripheral nerve endings are the hyperpolarization of neurons [26] , the reduction of pronociceptive neurotransmitter, and the activation of the NO-cyclic GMP pathway [27] . In addition, Durate et al. [25] previously reported that ACH induces analgesia by increasing cyclic GMP by the generation of NO. Therefore, application of a transdermal nitroglycerine patch (a NO donor) could enhance the analgesic effect of neostigmine [28] .

No adverse effects were encountered in this study. This could be because of the relatively long operative time in all patients (>40 min) and the deflation of tourniquet by the cyclic deflation technique.

The main results of our study were that the adjuvant drugs (neostigmine and transdermal nitroglycerine), when added to lidocaine in 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, and decreased the total amount of analgesic consumption without any side effects. Also, the combination of neostigmine and transdermal nitroglycerine is better than neostigmine or transdermal nitroglycerine alone in terms of all the parameters measured.


  Acknowledgements Top


Conflicts of interest

There are no conflicts of interest.

 
  References Top

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    Figures

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

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



 

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