Propofol and rocuronium are associated with pain or discomfort on injection (25–100% for propofol and 22–84% for rocuronium) in most of the patients [1-3]. Propofol is frequently preferred for anaesthesia induction for its properties of fast onset and fast recovery. Rocuronium is also used in anaesthesia induction, especially when rapid control of the airway is required, because of its fast onset of action. However, injection pain due to these drugs results in problems like hand withdrawal and dislodging of venous cannula.
Dexmedetomidine is a potent α2-adrenoceptor agonist that has beneficial analgesic effects for anaesthetic procedures. The anaesthetic and analgesic sparing effects of dexmedetomidine are well established . The analgesic effects of dexmedetomidine in the clinical setting have been investigated, primarily with regard to its opioid-sparing action . We designed this double-blind, placebo-controlled study to compare the efficacy of dexmedetomidine with lidocaine in reducing the pain of both propofol and rocuronium injection during anaesthesia induction.
With the approval of the Hospital Ethics Committee of The Zonguldak Karaelmas University School of Medicine and after obtaining written informed consents, 150 patients, 18–65-yr old, (ASA I–II), scheduled to undergo minor elective surgery, were included in the study. Exclusion criteria included the presence of neurological or psychiatric diseases, difficulty with communication, history of renal or hepatic insufficiency and hypersensitivity to the study drugs. The patients were randomly assigned into five groups.
Patients were allowed to receive 0.07 mg kg−1 of midazolam intramuscularly, given 1 h before the induction of anaesthesia. On arrival in the operating room, patients were instructed to inform the investigator about the amount of pain they experienced by use of a 10-point verbal rating scale (VRS). A 20-G intravenous (i.v.) cannula was inserted into a vein on the dorsum of the hand for administration of study drugs. Another cannula was placed in the other hand for infusion of i.v. fluids. Mean arterial pressure, SPO2 and heart rate (HR) were monitored. All pretreatment drugs were prepared in 3 mL saline in a 5-mL syringe that was covered by red tape. An independent anaesthesiologist prepared the pretreatment solutions, and the investigator did not know the contents of the solutions. All study drugs were maintained at room temperature and were used within 30 min of preparation. Another anaesthesiologist, who was unaware of the study groups, assessed the intensity of pain after propofol and rocuronium injections. Following the elevation of the arm for 15 s, a tourniquet was applied on the forearm up to 70 mmHg. Then, the patients were administered saline (3 mL) (Group 1, n = 30), dexmedetomidine 0.25 μg kg−1 (Group 2, n = 30), lidocaine 0.5 mg kg−1 (Group 3, n = 30), dexmedetomidine 0.25 μg kg−1 plus lidocaine 0.25 mg kg−1 (Group 4, n = 30) or dexmedetomidine 0.25 μg kg−1 plus lidocaine 0.5 mg kg−1 (Group 5, n = 30), diluted into 3 mL of saline and injected at a rate of 0.5 mL s−1. The tourniquet was released after 1 min and 5 mL of propofol was injected over 20 s.
The patients were observed and asked immediately if they had pain in the arm, and their responses were assessed. Then, the rest of the induction dose of propofol, 3 mL of saline bolus and 0.6 mg kg−1 of rocuronium, respectively, were injected over 10 s. The response of the patients to the injection of rocuronium was assessed with a four-point scale by an independent observer. The score was graded as 0 for no response, 1 for movement at the wrist only, 2 for movement involving the arm only (elbow or shoulder) and 3 for generalized response or movement in more than one extremity and reactions such as discomfort and pain (Table 1).
After tracheal intubation, anaesthesia was maintained with 50% N2O in oxygen and sevoflurane. Within the first 24 h after the operation, the injection site was checked for any complications, such as pain, swelling or allergic reactions by an anaesthesiologist who did not know which drug was administered.
The results were analysed with one way ANOVA and Bonferroni's post hoc test for age, body weight and propofol injection pain. The occurrences of withdrawal movements and gender were analysed by the χ2-test. Statistical significance was set at a P value of <0.05.
There were no significant differences in terms of patient charecteristics data (Table 2). The mean propofol pain score of Group 1 was 8.0 ± 1.4. Groups 1 and 2 were found to have higher propofol injection pain scores than Groups 3, 4 and 5 (P < 0.05). Although there was no difference between the pain scores of Groups 1 and 2, Group 2 was found to be different from Groups 3, 4 and 5 (P < 0.05) (Fig. 1). When the groups were compared according to the overall incidence of withdrawal movements due to rocuronium (≥1 response), the incidences were found to be 86.7% in Group 1, 60% in Group 2, 36.7% in Group 3, 50% in Group 4 and 40% in Group 5 (P < 0.05) (Table 3). Group 1 was found to be significantly different when compared with other groups, according to the number of patients who had withdrawal score of 0. Group 1 was different from Groups 3 and 5 when the patients with withdrawal score 2 were compared (P < 0.05). When we compared the study groups except Group 1, we found no significant difference between the groups according to the incidence of withdrawal movement after rocuronium injection (P = 0.325). SPO2 was always within the clinically acceptable range. No complications, such as pain, oedema, wheal, bradycardia, hypotension in need of treatment or flare response were observed at the injection site within the first 24 h after the operation.
Pain, emotional stress and stimulation during anaesthesia induction may cause bronchospasm, asthma and even myocardial ischaemic attack [3,6]. In addition, withdrawal movements can dislodge the venous catheter, causing injury during induction of anaesthesia .
Peripheral veins are innervated with polymodal nociceptors, which mediate the pain response to the injection of certain anaesthetic agents . Aetiology of the injection pain caused by i.v. administration of propofol and rocuronium is not clear. It has been reported that the pain may be due to the activation of nociceptors by the osmolality or pH of the solution, amount of free agent in the aqueous phase of emulsion or activation by the release of endogenous mediators, such as histamine, bradykinin and other substances mediating inflamation [1,2,8-10].
Adding lidocaine to propofol with or without tourniquet, injection of propofol into a large vein, cooling or warming of propofol, oral administration of clonidine, pretreatment with i.v. injection of lidocaine, ondansetron, metoclopramide, opioid, thiopental, magnesium sulphate, tramadol, ketamine, 5% glucose solution or butorphanol have all been tried for minimizing propofol-induced pain with varying results [11-15]. Venous retention with a tourniquet to keep the drug within the vein has often been used for pretreatment of propofol injection pain . In our study, we also used this tourniquet technique.
We compared lidocaine and dexmedetomidine along with different doses of lidocaine added to dexmedetomidine in this study. Dexmedetomidine alone has been found to be insufficient on prevention for propofol pain; however, it had a similar analgesic effect to lidocaine on rocuronium pain. Turan and colleagues suggested a possible mechanism of dexmedetomidine in decreasing propofol pain, which might be venous α1- and α2-stimulation, resulting in release of vasodilator prostaglandins that antagonize the venoconstrictor response . In that study, i.v. 0.25 μg kg−1 dexmedetomidine was found to be equally effective in reducing the pain associated with the i.v. injection of propofol when compared with 0.5 mg kg−1 lidocaine . In our study, the dexmedetomidine dose was chosen as 0.25 μg kg−1 based on Turan's paper. Unfortunately, dexmedetomidine was not found to be effective in reducing propofol injection pain even when used alone in our study. This may be due to the differences between the methods of both studies (e.g. no premedication, different assessment method of the intensity of propofol pain and rates of injection of the study drugs).
Lidocaine works as a local anaesthetic on the venous nociceptors and decreases the percentage of free propofol in the aqueous phase of the emulsion, thus reducing pain on injection . The suggestion about an effective dose ranges from 10 mg of lidocaine to 30 mg of lidocaine in 200 mg of propofol . We used lidocaine in two different doses. We found out that dexmedetomidine added to different doses of lidocaine had a similar effect with pure lidocaine in prevention of injection pain. Dexmedetomidine has been reported to increase the local anaesthetic effect and activation time of lidocaine when added to i.v. regional anaesthesia . However, we demonstrated that the addition of dexmedetomidine to lidocaine had no advantage on the prevention of propofol injection pain. On the other hand, lidocaine doses of 0.25 and 0.5 mg kg−1 had demonstrated similar analgesic effects.
I.v. injection of rocuronium, after the induction of anaesthesia, is often associated with a localized withdrawal of the arm or generalized movement. Such movements are presumed to be secondary to discomfort at the site of injection . The withdrawal rate in our study is 86.7% in the saline group. Klement and Arndt showed that acidic and alkaline solutions elicited pain at pH values less than 4 and more than 11, respectively . Pain latency also decreased with increasing osmolality, acidity and alkalinity. However, rocuronium is an isotonic solution with a pH of 4. Blunk and colleagues showed that the pain produced by aminosteroidal neuromuscular-blocking drugs can be attributed to a direct activation of C-nociceptors . Tramadol, midazolam, fentanyl, ondansetron, lidocaine, alfentanil, magnesium sulphate, ketamine and sodium bicarbonate have been used for prevention of rocuronium injection pain and withdrawal movements [7,9,20-22]. Also, Memis and colleagues concluded that dexmedetomidine 0.2 μg kg−1 may be useful in prevention of rocuronium injection pain . Lockey and Coleman reported a reduction in significant limb withdrawal or generalized movement in patients who received 0.6 mg kg−1 rocuronium after an induction dose of propofol mixed with 20 mg of lidocaine . Cheong and Wong compared the effect of lidocaine on rocuronium injection pain in bolus doses of 10 and 30 mg, and found out that the lidocaine dose of 30 mg was more effective . In this study, we found no difference between the groups of dexmedetomidine, lidocaine and dexmedetomidine with lidocaine groups in prevention of rocuronium injection pain.
In conclusion, pretreatment with dexmedetomidine is not as effective as lidocaine in reducing injection pain of propofol, but may attenuate the hand withdrawal associated to rocuronium.
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