IV regional anesthesia (IVRA) is one of the safest and most reliable forms of regional anesthesia for short procedures on the upper extremity. However, it has been limited by tourniquet pain, inability to provide postoperative analgesia, and lack of a bloodless field for microsurgical repairs (1). It is also associated with a more favorable patient recovery profile than general anesthesia (2). Patients undergoing regional anesthesia for outpatient hand surgery are less likely to require analgesic and antiemetic medication during the recovery period than those receiving general anesthesia. IVRA also offers reduced nursing time demand in the postanesthesia care unit and expedited hospital discharge, resulting in decreased hospital costs (2).
The ideal IVRA solution should have the following features: rapid onset, reduced dose of local anesthetic, reduced tourniquet pain, and prolonged postdeflation analgesia (3). At present, this may only be achieved by the addition of various adjuncts including morphine, meperidine, fentanyl, sufentanil, and clonidine to the local anesthetics (4–8).
Neostigmine is a drug that has been used to antagonize muscle relaxants. Intrathecal administration of neostigmine in animals and humans caused analgesia by inhibition of the breakdown of acetylcholine (ACh) in the spinal cord (9,10). There are ACh receptors in peripheral nerves (11). Animal and human studies showed significant analgesic effects from intraarticular neostigmine (12,13), but a recent study in patients undergoing carpal tunnel release showed that neostigmine added to lidocaine for axillary plexus block lacked an analgesic action (14). Therefore, this study was designed to evaluate the effect of neostigmine when added to prilocaine in IVRA.
Materials and Methods
After ethics committee approval and informed written consent, 30 ASA physical status I-II patients scheduled for hand surgery were included in the study. Patients with Raynaud disease, sickle cell anemia, and a history of allergy to any drug used were excluded from study. The cases were randomized to 2 groups with 15 patients in each. A randomization list was generated, and identical syringes containing each drug were prepared by an anesthesia assistant not involved in the study.
Patients were premedicated with 0.07 mg/kg of midazolam and 0.01 mg/kg of atropine, which were intramuscularly administered 45 min before the surgical procedure. Patients were monitored (Drager Cato PM 8040, Lübeck, Germany) for mean arterial blood pressure (MAP), oxygen saturation (Spo2), and heart rate (HR) in the operating room. Two cannulae were placed; one was in a vein on the dorsum of the operative hand and the other in the opposite hand for crystalloid infusion. The operative arm was elevated for 2 min then exsanguinated with an Esmarch bandage; a pneumatic tourniquet was then placed around the upper arm, and the proximal cuff was inflated to 250 mm Hg. Circulatory isolation of the arm was verified by inspection, absence of radial pulse, and loss of pulse oximetry tracing in the ipsilateral index finger. IVRA was achieved using 1 mL of saline plus 3 mg/kg of prilocaine (Citanest 2%, AstraZeneca) diluted with saline to a total dose of 40 mL in the control group (n = 15) or 0.5 mg of neostigmine (Neostigmine, Adeka Ïlaç San) plus 3 mg/kg of prilocaine diluted with saline to a total dose of 40 mL in the neostigmine group. The solution was injected over 60 s by an anesthesiologist blinded to the injection.
Sensory block was assessed by a pinprick performed with a 22-gauge short-beveled needle continuously every 30 s. Patient response was evaluated in the dermatomal sensory distribution of the medial and lateral antebranchial cutaneous, ulnar, median, and radial nerves. Motor function was assessed by asking the subject to flex and extend his wrist and fingers; complete motor block was noted when no voluntary movement was possible. Sensory block onset time was noted as the time elapsed from injection of study drug to sensory block achieved in all dermatomes, and motor block onset time was the time elapsed from injection of study drug to complete motor block.
After sensory and motor block onset, the operative tourniquet (distal cuff) was inflated to 250 mm Hg, the proximal tourniquet was released, and surgery was started. MAP, HR, and Spo2 were monitored before and after tourniquet application, 5, 10, 15, 20, and 40 min after the injection of anesthetic, and after release of the tourniquet by an anesthesiology resident, who did not know which medication was administered.
At the end of the operation, this resident was asked to qualify the operative conditions according to following numeric scale: excellent (4) = no complaint from patient, good (3) = minor complaint with no need for supplemental analgesics, moderate (2) = complaint which required supplemental analgesic, and unsuccessful (1) = patient given general anesthesia.
At the end of the operation, the surgeon, who did not know what medication was given, was asked to qualify the operative conditions and dryness of the operative field according to the following numeric scale: 0 = unsuccessful, 1 = poor, 2 = acceptable, and 3 = perfect.
The tourniquet was not deflated before 30 min and was not inflated for more than 2 h. At the end of surgery, the tourniquet deflation was performed by the cyclic deflation technique. Sensory recovery time was noted (time elapsed after tourniquet deflation up to recovery of pain in all dermatomes determined by pinprick test). Motor block recovery time was noted (the time elapsed after tourniquet deflation up to movement of fingers). First analgesic requirement time was also noted (the time elapsed after tourniquet release to first patient request of analgesic).
Patients were questioned during the first 2 h in the postanesthesia care unit and later in the ward every 2 h by an anesthesiology resident not involved in study for nausea and vomiting. Skin rash, tachycardia, bradycardia, hypotension, hypertension, dizziness, tinnitus, hypoxemia, and other side effects were noted if encountered during the 24 postoperative h in the ward. Statistical analyses were performed by Student’s t-test, χ2, and Mann-Whitney tests. Significance was determined at the P < 0.05 level.
Thirty patients (n = 15; eight women and seven men in each group) were enrolled in the study. The mean age (34 ± 12 yr and 34 ± 12 yr), weight (70 ± 9 kg and 68 ± 7 kg), duration of surgery (45 ± 10 min and 48 ± 15 min), and duration of tourniquet (51 ± 11 min and 52 ± 13 min), respectively, were not different between groups.
Sensory and motor block onset times were statistically shorter in the neostigmine group (P < 0.05). Sensory and motor block recovery times were statistically prolonged in this group also (P < 0.05) (Table 1).
Anesthesia quality determined by the anesthesiologist and the surgeon and dryness of the operative field were found statistically better in the neostigmine group (P < 0.05) (Table 2). Four patients in the control group received additional analgesics in the preoperative period, whereas no patients were given additional analgesics in the neostigmine group, and this was statistically insignificant (P > 0.05).
There was no statistical difference between groups when compared for MAP and Spo2 at any time (Table 3). There was also no statistical difference between groups when compared for HR before and after tourniquet inflation, after anesthetic injection, and at 1 and 5 min, but at 10, 15, 20, and 40 min, there was a statistically significant decrease in the neostigmine group when compared with the control group (P < 0.05) (Table 3).
Time to first analgesic request in the control group was 15 ± 9 min and 35 ± 8 min in the neostigmine group, which was statistically significant (P < 0.05).
There were no dropouts because of insufficient anesthesia or complications. There was no adverse effect seen through the 24-h postoperative period in either group; only one patient in the neostigmine group had nausea that required treatment.
Studies have shown that there are ACh receptors in peripheral nerves, and in vitro studies have shown that peripheral cholinergic antinociception is caused by neuronal hyperpolarization and by modulation of nitric oxide pathways. ACh induces analgesia via increasing cyclic GMP by generation of nitric oxide (11,15). Spinal endogenous ACh plays an important role in mediating the analgesic effect of systemic morphine through both muscarinic and nicotinic receptors (16) that are also present in the peripheral tissue. The peripheral analgesic effect of neostigmine has been demonstrated in an animal model of inflamed knee joint in rats (12). Another study of intraarticular administration revealed peripheral analgesic effects in humans (13).
However, a recent study performed by Van Elstraete et al. (14) in patients undergoing carpal tunnel release showed that neostigmine added to lidocaine for axillary plexus block lacked an analgesic action. Peripheral inflammatory conditions, when present, enhance analgesic actions of locally administered opioids and cholinergic drugs (14,17). The reason for neostigmine’s lack of analgesic action may be the lack of an inflammatory process and intact dense lipid coverings of nerves (14). Yet, controversy persists. In a study performed by Bouaziz et al. (18), neostigmine lacked analgesic effects in a carrageenan-induced hyperalgesia rat model with inflamed tissue.
Therefore, we used neostigmine in a block with a very different mechanism of action. IVRA local anesthetic and adjuvants are injected very near to the surgical site, and the tourniquet causes ischemia, which distorts nerve penetration by oxidative stress and affects the blood-nerve barrier (19). Existing ACh receptors in peripheral nerves are also responsible for the action of neostigmine in peripheral analgesia, and ACh plays a role in newly discovered sensory regulatory mechanisms controlled by the motor system (20). Study results indicate that ACh receptors are present in the soma of many petrosal ganglion neurons, thus supporting the idea that under normal conditions, peripheral sensory processes may be associated with ACh (21).
The most frequent side effect seen in our study was bradycardia, which may have been because of systemic absorption of neostigmine or its escape during tourniquet inflation. Tourniquet release did not further decrease HR. Nausea seen in one patient may also have been due to systemic absorption.
Results of a systematic review by Choyce and Peng (3) suggested that nonsteroidal antiinflammatory drugs (NSAIDs) have the most to offer as adjuncts to IVRA when compared with others. NSAIDs, either as part of IVRA or wound infiltration, resulted in an analgesic benefit lasting longer than the same dose parenterally administrated. Our results revealed a clinically minor postoperative analgesia effect when compared with NSAIDs. Muscle relaxants (3) improve muscle relaxation, facilitate fracture reduction, and improve overall analgesia. However, there is a risk of residual muscle weakness that can last several hours. Neostigmine improved muscle relaxation with residual weakness lasting for only a few minutes. Our study presents information about the clinical use of neostigmine as an adjunct in IVRA, however it may also be a useful model for studying the peripheral action of neostigmine in the absence of central effects.
In conclusion, the addition of neostigmine to prilocaine in IVRA shortened sensory and motor block onset times, prolonged sensory and motor block recovery times, and improved quality of anesthesia while prolonging the time to first analgesic requirement. The side effects seen with neostigmine were usually associated with systemic absorption but did not require treatment. The addition of neostigmine to local anesthetics in IVRA is effective in increasing the quality of anesthesia; therefore, further studies are required to determine the effect in different peripheral techniques.
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