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REGIONAL ANESTHESIA

The Analgesic Effect of Nitroglycerin Added to Lidocaine on Intravenous Regional Anesthesia

Selda Sen, MD, Bakiye Ugur, MD, Osman N. Aydn, MD, Mustafa Ogurlu, MD, Feray Gursoy, MD, and Oner Savk, MD

Department of Anesthesiology and Reanimation, Department of Orthopedics, and Traumatology Adnan Menderes University, Medical Faculty, Aydin, Turkey

Address correspondence and reprint requests to Selda Sen, MD, Adnan Menderes Üniversitesi Tp Fakültesi, Anesteziyoloji ve Reanimasyon A.D., 09100 Aydin, Turkey. Address e-mail to drseldasen{at}yahoo.com or uzmdrsenselda{at}mynet.com.

	Abstract

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We evaluated the analgesic effect of nitroglycerine (NTG) when added to lidocaine in IV regional anesthesia. Thirty patients undergoing hand surgery were randomly assigned to 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. Hemodynamic variables, tourniquet pain measured before and 1, 5, 10, 20, and 30 min after tourniquet inflation, and analgesic requirements were recorded during the operation. After the tourniquet deflation, at 1 and 30 min and 2 and 4 h, visual analog scale (VAS) score, time to first analgesic requirement, total analgesic consumption in the first 24 h after operation, and side effects were noted. Shortened sensory and motor block onset time (3.2 ± 1.1 versus 4.5 ± 1.2 min; P = 0.01 and 3.3 ± 1.6 versus 5.2 ± 1.8; P = 0.009 in group NTG and group C, respectively), prolonged sensory and motor block recovery times (6.8 ± 1.6 versus 3.1 ± 1.2 min P < 0.0001 and 7.3 ± 1.3 versus 3.6 ± 0.8 P < 0.0001 in group NTG and group C, respectively), shortened VAS scores of tourniquet pain (P = 0.023), and improved quality of anesthesia were found in group NTG (P < 0.05). VAS scores were lower in group NTG after tourniquet release and in the postoperative period (P = 0.001). First analgesic requirement time was longer in group NTG (225 ± 74 min versus 39 ± 33 min) than in group C (P < 0.0001). Postoperative analgesic requirements were significantly smaller in group NTG (P < 0.0001) but the side effects were similar in both groups. We conclude that the addition of NTG to lidocaine for IV regional anesthesia improves sensory and motor block, tourniquet pain, and postoperative analgesia without side effects.

	Introduction

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IV regional anesthesia (IVRA) is easy to administer, reliable, and cost-effective. It is ideal for short operative procedures of extremities performed on an ambulatory basis (1,2). Disadvantages include concerns about local anesthetic (LA) toxicity, slow onset, poor muscle relaxation, tourniquet pain, and minimal postoperative pain relief (1,3). The ideal IVRA solution should have the following features: rapid onset, reduced dose of LA, reduced tourniquet pain, and prolonged postdeflation analgesia. At present, this is achieved by the addition of adjuncts, including opioids, tramadol, nonsteroidal antiinflammatory drugs, dexmedetomidine, muscle relaxants, alkalinization with sodium bicarbonate, potassium, and temperature of LA (1–4).

Although several studies support the use of transdermal nitroglycerine (NTG) for various analgesic effects (5–11), the addition of IV NTG to lidocaine for IVRA has not been studied.

We evaluated the effect of NTG on intraoperative and postoperative analgesia, sensorial and motor block onset times, and tourniquet pain when added to lidocaine for IVRA.

	Methods

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Thirty ASA physical status I–II patients scheduled for hand or forearm surgery (i.e., carpal tunnel, trigger finger, and tendon release) were included in this prospective, randomized, double-blind study. Informed patient consent and ethical committee approval was obtained. Patients with sickle cell anemia, history of drug allergy, or Reynaud disease were excluded from the study. An anesthesia resident blinded to the study group assignments randomly selected prepared identical syringes containing each drug. As premedication, midazolam 0.15 mg/kg and atropine 0.01 mg/kg were administered IM before the surgical procedure. After the patients had been taken to the surgery room, mean arterial blood pressure (MAP), peripheral oxygen saturation (Spo₂), and heart rate (HR) were monitored (AS-3; Datex-Ohmeda, Helsinki, Finland). Two cannulae were placed; one was in a dorsal vein 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 administered with 3 mg/kg 2% lidocaine (Aritmal; TEMS, Istanbul, Turkey) diluted with saline to a total dose of 40 mL in the control group (group C, n = 15) or with 200 µg NTG (Perlinganit, Adeka Ilac San, Istanbul, Turkey) plus 3 mg/kg 2% lidocaine diluted with saline to a total dose of 40 mL in the NTG group (group NTG; n = 15). The solution was injected over 90 s by an anesthesiologist blinded as to group assignments. The sensory block was assessed by a pinprick performed with a 22-gauge short-beveled needle taken out every 30 s. Patient response was evaluated in the dermatomal sensory distribution of the medial and lateral antebrachial cutaneous, ulnar, median, and radial nerves. Motor function was assessed by asking the subject to flex and extend his/her wrist and fingers, and complete motor block was noted when no voluntary movement was possible.

Sensory block onset time was noted as the time elapsed from injection of drug to sensory block achieved in all dermatomes. Motor block onset time was the time elapsed from injection of drug to complete motor block.

After sensory and motor block onset, the operative tourniquet (distal cuff) was inflated to 250 mm Hg, and the proximal tourniquet was released. MAP, HR, Spo₂, and visual analog scale (VAS) scores (0 = no pain and 10 = worst pain imaginable) were monitored before and 1, 5, 10, 20, and 30 min after tourniquet inflation. Data were measured after release of the tourniquet; and postoperatively at 1 and 30 min and 2, 4, 6, and 24 h by an anesthesiology resident who was blinded as to the study group assignments. When tourniquet pain was >3 on the VAS, patients were given IV fentanyl 1 µg/kg (fentanyl citrate; Abbott, North Chicago, IL). Total administered fentanyl dose and time of administration were noted. Surgery was started 10 min after tourniquet inflation in all patients.

At the end of the operation, the patient was asked to rate the operative conditions such as tourniquet pain or incisional pain according to the following numeric scale: excellent, 4 = no pain; good, 3 = minor pain with no need for supplemental analgesics; moderate, 2 = pain which required supplemental analgesic; and unsuccessful, 1 = patient did not tolerate IVRA.

At the end of the operation, the surgeon, who was blinded as to patient randomization, was asked to score operative conditions such as disturbing movement of the arm and excessive bleeding according to the following numeric scale: 0 = unsuccessful, 1 = poor, 2 = acceptable, 3 = good, and 4 = excellent (4).

The tourniquet was not deflated before 30 min and was not inflated for more than 1 h postoperatively. 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).

Patients received 75 mg of IM diclofenac (Voltaren; Ciba-Geigy, Istanbul, Turkey) when the VAS score was >3, and total diclofenac consumption was recorded in the first 8 h postoperatively. Patients were given oral paracetamol (Parol tablet 500 mg; Atabay, Istanbul, Turkey), 8–24 h postoperatively, when the VAS score was >3. The total administered paracetamol dose was noted. All evaluations were performed by an anesthesiology resident blinded as to the study group assignments.

First analgesic requirement time (the time elapsed after tourniquet release to first patient request of analgesic) was also noted. Patients were questioned about side effects during the first 2 h in the postanesthesia care unit and later in the ward every 2 h by an anesthesiology resident who was blinded as to the study group assignments. Skin rash, tachycardia, hypotension, hypertension, tinnitus, hypoxemia, headache, nausea, and other side effects were noted during the first 24 h postoperatively in the ward.

The statistical power of the matched analysis was computed in a pilot study performed before this study (10 cases in each group). We found a 70% clinically significant chance of the time to first analgesic requirement in the pilot study. We also found approximately 50% clinically significant changes of the sensory block onset and recovery times, motor block onset and recovery times, postoperative analgesic consumption and tourniquet pain in the pilot study. Based on these estimates, we calculated a sample size that would permit a type I error of = 0.05 and power of 90%. Enrollment of 15 patients in each group was required.

Independent samples Student's t-test were used for evaluation of the demographic data, intraoperative and postoperative hemodynamic data, the time of the onset and recovery of sensory and motor block, the duration of the operation and tourniquet, the duration of analgesia, and intraoperative and postoperative analgesic use. The Mann-Whitney U-test was used for intraoperative and postoperative VAS scores and the quality of anesthesia. Complications and operation type were compared with Fischer's exact ² test. Significance was determined at P < 0.05.

	Results

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The demographic data for both groups were similar (P > 0.05) (Table 1). Duration of tourniquet and surgery times (41.7 ± 9.9, 42.3 ± 8.2, and 30.2 ± 11.2, 31.4 ± 10.3 in group NTG and group C, respectively) were also similar in both groups. There was no significant difference in types of surgical procedure (Table 1). There was no exclusion from the study because of technical failure.

MAP, HR, and Spo₂ were similar between the groups at any intraoperative or postoperative period (P > 0.05) (Table 2).

Sensory and motor block onset times were statistically shorter in group NTG (Table 3). Sensory and motor block recovery times were also statistically prolonged in this group (Table 3).

No patient suffered from incisional pain during the intraoperative period. VAS scores for tourniquet pain were lower at 10, 20, and 30 min in group NTG during the intraoperative period. The time to complaint of tourniquet pain (the time of fentanyl requirement for tourniquet pain) was prolonged in group NTG compared with group C (31 ± 9 min, 19.3 ± 7 min; P = 0.044, respectively). Two patients in group NTG and 6 patients in group C required fentanyl for tourniquet pain (P = 0.023). The amount of fentanyl requirement was also smaller in group NTG compared with group C during the intraoperative period (3.5 ± 13.3 µg, 21.4 ± 25.6 µg; P = 0.029, respectively). Postoperative VAS scores were significantly higher for the first 4 h postoperatively in group C compared with group NTG.

Anesthesia quality, as determined by the patient and the surgeon, was better in NTG group (P = 0.024 and P = 0.001, respectively) (Table 4). The time to first postoperative analgesic request in group C and group NTG was 39 ± 33 min and 225 ± 74 min, respectively (P < 0.0001). Diclofenac was used in 8 patients in group NTG and 15 patients in group C (P = 0.0029). Paracetamol was also used for 11 patients in group NTG and 15 patients in group C (P = 0.001). Diclofenac consumption was smaller in group NTG (37 ± 38 mg) compared with group C (101 ± 37 mg) (P < 0.0001). Paracetamol consumption was also smaller in group NTG (535 ± 307 mg) compared with group C (1392 ± 212 mg) (P < 0.0001).

No patient developed low MAP, tachycardia, or nausea in both groups. One patient in group C and two patients in group NTG developed headache (P > 0.05).

	Discussion

Top Abstract Introduction Methods Results Discussion References

 
The main result of our study was that the addition of NTG to lidocaine for IVRA improved the speed of onset and the quality of anesthesia, decreased tourniquet pain and intraoperative and postoperative analgesic consumption, and caused no side effects.

There are various proposed sites of action of IVRA. Raj et al. (12) reported that the action of LA is on major nerve trunks, possibly reaching to the nerve trunk via small venules within the nerve core, whereas Rosenberg (13) provided strong evidence concerning a peripheral site. It is now accepted that both the nerve endings and trunks are affected (14).

The beneficial effects of NTG, which we showed in this study, might depend on a direct strong vasodilatory effect that promotes distribution of lidocaine to nerves. This would explain the rapid onset of sensory and motor block.

NTG is metabolized to nitric oxide (NO) in the cell (6,15). NO causes an increase in the intracellular concentration of cyclic guanosine monophosphate, which produces pain modulation in the central and peripheral nervous system (5,6). NO generators also induce antiinflammatory effects and analgesia by blocking hyperalgesia and the neurogenic component of inflammatory edema by topical application (7). Another possible mechanism includes an analgesic effect through the direct stimulation of peripheral fibers mimicking the actions of locally applied acetylcholine (6,16). Mechanisms mentioned above, or their combinations, might contribute to the analgesic effects of NTG added to lidocaine in IVRA.

The clinical efficacy of transdermal NTG for acute pain relief has been documented in several studies (6–11). NTG was found to be useful for the treatment of shoulder pain (17) and thrombophlebitis (7,18) and for enhancing the effect of spinal sufentanil or neostigmine (6,19). Lauretti et al. (5) also showed that delivery of NO donors (transdermal NTG) together with opioids may be of significant benefit in cancer pain management, delaying morphine tolerance and decreasing the frequency of adverse effects related to large doses of opioid.

Data from the literature suggest that in humans, large doses of transdermal NTG, such as 30 mg daily, are hyperalgesic, whereas doses <6 mg daily are analgesic under various circumstances (17–19). Because of these data, we chose to add small dose (200 µg) NTG to lidocaine for an analgesic effect.

Sensory and motor block onset times were statistically shorter in group NTG in our study. This is an advantage for the surgeon and anesthesiologist. There were also lower VAS scores for tourniquet pain and prolonged first analgesic requirement time in group NTG.

Turan et al. (11) investigated the effects of transdermal NTG in IVRA. They used 2% prilocaine and a nitroderm TTS 10 (NTG transdermal patch) 2 hours before surgery in their study. They suggested that transdermal NTG exerts beneficial effects on sensory and motor block without side effects in IVRA. However, they did not evaluate postoperative analgesia in their study.

Although various adjuvants have been suggested for improving intraoperative and postoperative analgesia and maintaining better operative conditions, these adjuvants may cause side effects such as nausea, vomiting, sedation, dizziness, wound hematoma, skin rash, and hypotension (1–4,20). NTG may also cause dose-dependent side effects such as hypotension, tachycardia, or headache (15,21). In our study, there was no significant difference in side effects between groups. The tourniquet was not deflated before 30 min and the tourniquet deflation was performed by the cyclic deflation technique at the end of surgery. NTG has a very short half-life (15). These techniques, combined with the short half-life of NTG, may reduce the frequency and severity of unwanted side effects.

In conclusion, the addition of NTG to lidocaine in IVRA shortened sensory and motor block onset times, prolonged sensory and motor block recovery times, and improved tourniquet pain while prolonging the time for first analgesic requirement and decreasing total amount of analgesic without side effects. Further studies must be performed with experimental models and different doses to determine a relevant conclusion before NTG's routine use.

	Footnotes

 
Accepted for publication October 6, 2005.

	References

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This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Web of Science (3) Citing Articles via Google Scholar Google Scholar Articles by Sen, S. Articles by Savk, O. Search for Related Content PubMed PubMed Citation Articles by Sen, S. Articles by Savk, O. Related Collections Regional Anesthesia Pain Pharmacology