Abstract
Objectives
Injection pain and hypotension are two main adverse effects of propofol that discourage uniform acceptation. The aim of this study was to compare the effect of ephedrine-lidocaine combination with lidocaine and ephedrine alone on injection pain and hemodynamic changes caused by propofol injection.
Methods
One hundred and sixty five patients were randomly allocated to five groups to receive either lidocaine 0.5 mg/kg (Group L) alone, ephedrine 30 μg/kg (Group E30) alone, ephedrine 70 μg/kg (Group E70) alone, lidocaine 0.5 mg/kg-ephedrine 30 μg/kg Group LE, or 2 mL saline (Group S). One minute after the respective study solution was given propofol 2 mg/kg was injected. Face pain scale and verbal rating scale were then evaluated. The mean arterial blood pressure (MAP) and heart rate (HR) were recorded before injection of the test solution, just before the intubation, and 1 minute after intubation.
Results
Patients in the Group L and Group LE showed significantly smaller pain scores compared with the saline group (Group S) [95% confidence interval (CI) 0.50–1.50; p = 0.003 and 95% CI 1.000–1.500; p = 0.004, respectively). The pain scores in Group E30 and Group E70 failed to show a significant difference with that of the Group S (p = 0.193 and p = 0.184, respectively). The changes of MAP before and after propofol injection between the Group L versus Group E30, Group E70, and Group LE were found to be significant (95% CI 5.27–14.49; p = 0.000), (95% CI 4.72–16.39; p = 0.001), and (95% CI 5.94–16.47; p = 0.001), respectively. The HR changes, before and after propofol injection, tended to be smaller in ephedrine groups than in Group L and Group S (p < 0.05).
Conclusion
Pretreatment with combination of small-dose ephedrine and lidocaine could reduce the incidence and intensity of propofol-induced pain and also result in more stable hemodynamic profile, but however, the combination of two drugs failed to work better in further reduction of pain.
Keywords
ephedrine; lidocaine; pain; propofol;
1. Introduction
Propofol has gained popularity, principally because of its rapid recovery, safety, and minimal organ toxicity.1 Pain from propofol injection occurs in 80% to 90% of patients, if a vein on the dorsum of the hand is used.2 The etiology of this pain is uncertain, but two causes have been suggested. First, the phenol may cause immediate pain from a local irritant effect on the vein. This effect could be decreased when aqueous solution is phased with fat emulsion of propofol for further dilution.3 Second, an indirect action on the endothelium-releasing kininogens may trigger painful stimuli at the nerve endings between the intima and the media of the vessel wall causing delayed pain (after 10–20 seconds).4 Several techniques have been applied to alleviate the propofol-induced pain, such as: adding lidocaine,4, 5 cooling, warming,5 or diluting the propofol solution,6 injection of propofol into a large vein,4 and prior injection of metoclopramide,7 clonidine,8 ephedrine,9 magnesium sulfate,10 opioids,11 thiopental,12, 13 ketamine,14, 15 paracetamol,16 and flurbiprofen axetil before giving propofol.17, 18, 19 However, the incidence of pain from propofol is still high. In a recent study by Fujji et al19 it was declared that the combination of flurbiprofen/lidocaine could significantly decrease the pain caused by propofol injection compared with flurbiprofen or lidocaine alone. However, the effect of flurbiprofen on hemodynamic changes of propofol is unknown. Furthermore, the main adverse drug reactions associated with administration of NSAIDs (non steroidal anti-inflammatory drugs) are related to direct and indirect irritation of the gastrointestinal tract.20 Lidocaine pretreatment has been commonly proposed to decrease propofol-induced pain. The exact mechanism by which lidocaine reduces pain on injection of propofol is unknown, but there is a possibility that lidocaine, a local anesthetic, reversibly blocks peripheral nerve pathways through the action on excitable membranes.21 Propofol can cause hypotension and an initial increase in heart rate (HR) and cardiac output, with a subsequent decrease than the baseline.22 This effect may be augmented by lidocaine but the addition of ephedrine to lidocaine may overcome this disadvantage.23
In a previous study by Cheong et al it is suggested that the endogenous norepinephrine release by ephedrine may reduce the effect of bradykinin.9 It also causes venous dilation and hyperpermeability and increases the contact between the aqueous phase of propofol and free nerve endings.4 Therefore ephedrine may reduce the pain caused by propofol injection.9 Tekol et al found that ephedrine might enhance the analgesic effect of opioids in both experimental and clinical parts of their study.24 The alpha-adrenergic stimulating action of ephedrine may play a role in this interaction as the spinal administration of norepinephrine and other alpha-adrenergic agonists produces or enhances analgesia in man and in experimental animal. In contrast, Gordon et al25 demonstrated the lack of any potentiating effect of ephedrine on pentazocine analgesia, although another adrenomimetic drug, amphetamine, was previously shown to affect the opioid analgesia. In general, a synergistic effect of two agents would allow a reduction in dose for both agents and therefore limit the side effects while improving efficacy. Our hypothesis is that ephedrine may also enhance analgesic effect of lidocaine. Therefore, coadministration of lidocaine and ephedrine before the induction of anesthesia with propofol may favorably prevent propofol-induced pain and hypotension. To date, no study has been conducted to assess the efficacy of combined ephedrine-lidocaine specifically in reducing the adverse effect on propofol injection. To test our hypothesis, a randomized double-blind, placebo-controlled study was designed to evaluate the effect of combined ephedrine-lidocaine (two drugs easily available in our operating room) on pain and hemodynamic changes caused by propofol injection compared with lidocaine and ephedrine alone.
2. Methods
This clinical trial was registered at the United States National Institutes of Health (www.clinicaltrials.gov), with the number NCT01186549. After obtaining approval from the institutional Ethics Committee and patient informed consent, 180 adult patients, irrespective of sex, aged 20–60 years, of American Society Anesthesiologists physical Status I and II, undergoing elective surgery under general anesthesia were enrolled for study. Patients with difficulty in communication, with a history of adverse response to propofol, lidocaine or ephedrine with allergy, neurologic, or cardiovascular disease and patients who had received an analgesic medication within 24 hours before surgery were excluded from the study. Randomization was performed based on computer-generated codes. A 20 gauge Teflon catheter was inserted into a vein of the dorsum of the hand without prior subcutaneous lidocaine infiltration, before the conduct of anesthesia. The present study was a double-blinded clinical trial with both the patient and the administrating practitioner being ignorant of the anesthetic type. We dealt with the blinding through application of equal volumes of the pretreatment drugs (2 mL) with each syringe labeled as A, B, C, D, or E according to its code name. The coded syringes were identical and the drugs were prepared and stored at room temperature (21–23°C) by the personnel not involved in the study, who randomly handed over to the anesthetists for pretreatment who were unaware of the identity of the drug, so that the investigator who assessed the patient response was also ignorant of the nature of the solution. All drugs were used within 15 minutes after preparation. Patients were randomly assigned into five groups (33 patients per group) to receive either intravenous lidocaine 0.5 mg/kg (Group L), ephedrine 30 μg/kg (Group E30), ephedrine 70 μg/kg (Group E70), ephedrine 30 μg/kg plus lidocaine 0.5 mg/kg (Group LE) or 2 mL saline (Group S). Ephedrine was diluted into a final 2-ml solution with distilled water.
One minute after the administration of the test solution, the 1% solution of propofol at 2 mg/kg was given through the IV catheter at 1 mL/s9, 14 while the running of IV infusion was temporarily ceased. After the injection of propofol the crystalloids was administered at maximal gravity flow at uniform height. Patients were informed regarding the possible stinging sensation on administration of a drug at the start of the anesthesia and they would be asked the mean level score of their pain during the injection period before the loss of consciousness according to the verbal rating scale (VRS) explained to patients at the preoperative visit. Furthermore, a blinded anesthesiologist evaluated the face pain score26 every 5 seconds during propofol injection. The grading criteria of VRS was as follows: 0 = no pain experienced (negative response to questioning), 1 = mild pain (pain reported only in response to questioning without any behavioral signs), 2 = moderate pain (pain reported in response to questioning and accompanied by a behavioral sign or pain reported spontaneously without questioning), 3 = severe pain (strong vocal response or response accompanied by facial grimacing, arm withdrawal or tears). The face pain score26 was expressed by seven schematic facial configurations depicting the severity of pain from no pain (1 on the scale) to the most pain possible (7 on the scale). After propofol injection and the loss of consciousness, midazolam 0.03 mg/kg, fentanyl 2 μg/kg, and atracurium 0.5 mg/kg were administered. Supplemental oxygen at a rate of 6 L/min was delivered by means of a face mask to all patients. Three minutes after atracurium injection, the trachea was intubated and anesthesia was maintained with 1.0–2.0% isoflurane and 50% N2O in oxygen. The mean arterial blood pressure (MAP) and HR were recorded before administration of the test solution, just before intubation, and one minute after intubation. Based on previously published data, 7, 8, 9, 10, 11, 12, 13, 14, 15 the incidence of pain on injection of propofol is approximately 80%. An absolute reduction of 40% (from 80% to 40%) with lidocaine or ephedrine would be considered to be of clinical importance.
A sample size of 30 patients per group was estimated to provide an 80% power to detect such difference using a two-sided test with α = 0.05. Parametric data were analyzed using analysis of variance, independent sample t-test, and paired sample test. HRs and blood pressures were tested for normal distribution by one sample Kolmogorov-Smirnov test and further compared with baseline values using the two tailed paired t-test. The within-group comparisons in MAP and HR were performed using analysis of independent sample t-test. The nonparametric data for pain scores were analyzed using the Kruskal-Wallis test and the Mann-Whitney U test. SPSS version 16.0 (SPSS Inc., Chicago, IL, USA) was used for statistical analyses. Data are presented as mean ± standard deviation, number (%), or median ± interquartile range. A p value <0.05 was considered to be significant.
3. Results
Among 180 patients initially enrolled in this study, 15 patients had to be excluded because of logistic reasons or other causes violating the study protocol. Hence, 165 patients were included and randomly assigned to the treatment groups (Fig. 1).
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There were no significant differences in sex, age, height, and weight among the five groups (Table 1).
The overall incidence and severity of pain scores for patients (median and interquartile range) during injection of propofol among the five groups are shown in Table 2. The respective incidence of pain in patients receiving lidocaine was 39.4%, lidocaine-ephedrine 45.4%, ephedrine30 63.6%, ephedrine70 75.8%, and saline 72.7%. The patients in the Group L and Group LE had significantly smaller pain scores compared with the Group S [95% confidence interval (CI) 0.50–1.50; p = 0.003 and 95% CI 1.000–1.500; p = 0.004, respectively]. Likewise, the patients in the Group L and Group LE had significantly smaller pain scores (VRS) compared with the Group E70 (95% CI 0.500–1.000; p = 0.013 and 95% CI 0.500–1.000; p = 0.019 respectively). The pain scores (VRS) in the Group E30 and Group E70 were found to have no significant difference compared with the Group S (p = 0.193 and p = 0.184 respectively).
As shown in Table 3, although the mean arterial pressures (MAP) in all five groups decreased significantly after the injection of propofol (p = 0.000), the blood pressure levels remained significantly higher in the ephedrine groups than in the Group L and Group S. The MAP following the propofol injection was reduced by 22.06 ± 9.16 mmHg in Group S, by 23.84 ± 9.63 mmHg in Group L, and by 13.95 ± 9.10 mmHg in Group E30 before tracheal intubation, as shown in Table 4. This difference between the Group E30 and Group L (95% CI 5.27–14.49; p = 0.00) and also the Group E30 and Group S (95% CI 5.27–14.49; p = 0.00) was shown to be significant, statistically. Furthermore, the fall of MAP after propofol in Group E70 was 13.29 ± 13.74 mmHg (Table 4). The difference (MAP1,2) between the Group E70 and Group L (95% CI 4.72–16.39; p = 0.001) and also between the Group E70 and Group S (95% CI 3.02–14.51; p = 0.003) was found to be significant. Furthermore, as shown in Table 4, the MAP was reduced by 12.63 ± 11.68 mmHg after propofol in Group LE. This difference between the Group LE and Group L (95% CI 5.94–16.47; p = 0.000) and also between the Group LE and Group S (95% CI 4.25–14.58; p = 0.001) was significant. As shown in Table 4, although the HR in Group L and Group S decreased significantly following the propofol injection (p <0.05) the levels remained noticeably constant in the ephedrine groups. Similarly, the HR was significantly reduced by 9.30 ± 8.88/min following the propofol injection in Group S (95% CI 6.15–12.45; p = 0.000) and 6.21 ± 11.39/min in Group L (95% CI 2.17–10.25; p = 0.004) whereas in Group E30, Group E70, and Group LE it was 1.09 ± 14.94, −0.424 ± 12.68, and 4.90 ± 14.04, respectively. The changes of HR before propofol injection and just before tracheal intubation (HR1, HR2) in ephedrine groups were insignificant (Table 3). The hemodynamic changes among the five study groups after intubation were insignificant (Table 3).
According to our data, the smaller dose of ephedrine (30 μg/kg) could reduce the propofol-induced hemodynamic changes before intubation and failed to produce significant hemodynamic changes after intubation compared with other groups (Table 4). Hypotension that required treatment (>30% fall), bradycardia, dysrhythmias, severe hypertension (>200 mmHg) or an increase of >30% of preinduction value for >60 seconds, allergic reactions or cardiovascular collapse were not observed in any of our patients.
4. Discussion
We have demonstrated that the pretreatment with a combination of small-dose ephedrine and lidocaine could reduce the incidence and intensity of propofol-induced pain and result in more stable hemodynamic profile. However, the combination of these two drugs failed to work better in further reduction of pain. In the present study, the incidence of pain in patients of Group L was 39.4%, Group LE 45.4%, Group E30 63.6%, Group E70 75.8%, and Group S 72.7% was consistent with the data reported by Agarwal et al27 in which 87% of ephedrine pretreatment patients were described of having pain during intravenous injection of propofol compared with 77% in the normal Group S and 42% in Group L.27 Furthermore, in a report by Ozkoçak et al14 the incidence of pain in placebo and ephedrine and ketamine groups were similar, which was again in agreement with our findings. In the present study, the incidence of pain in the Group L and Group LE was comparable yet the combination of ephedrine and lidocaine showed disability in further reduction of the pain. These results are also supported by a study carried out by Kau et al28 in which it was reported that a combination of ephedrine and either lidocaine or bupivacaine was unlikely to allow significant dose reduction for rat sciatic nerve block because of lack of synergy.28 Furthermore, in another study by Hennery et al29 it was declared that when phenylephrine or ephedrine was used to prevent the postspinal hypotension, the dosing requirement of hyperbaric bupivacaine (ED95) was similar for intrathecal anesthesia, a finding in accordance with that obtained in our study. There are several possible explanations for the finding that why ephedrine failed to further reduce the pain. First, although ephedrine has potent vasoactive properties, its overall effect on nerve blood flow is unknown because of the complexity of the vascular supply of peripheral nerves.28, 30 Second, local anesthetics severely reduce the nerve blood flow as assessed by a laser Doppler flow meter.28 Therefore ephedrine may be unable to further reduce the nerve blood flow leading to a reduction in the level of pain. The dose of ephedrine was selected based on the previous study.9, 14, 31 Cheong et al reported that ephedrine 30 μg/kg could reduce the pain caused by propofol injection as effectively as lidocaine and that the larger doses of ephedrine (110 μg/kg and 150 μg/kg) could produce severe hypertension, tachycardia, and arrhythmias especially in patients with cardiovascular disorders.9
Furthermore, Faridi et al31 reported that in patients undergoing cesarean section under spinal anesthesia, the incidence of hypotension was reduced to 65% by administration of ephedrine 25 μg/kg compared with the Group S in which the incidence of hypotension was 90%. However, it was described that the smallest effective dose of ephedrine to significantly reduce the incidence of hypotension was 40 μg/kg.31 Although there are different factors such as solution temperature, vein size, and the speed of injection known as possible causes of pain induced by propofol injection, these factors were controlled among the treatment groups in our study. Therefore, it could be inferred that the difference between our results and that reported by Cheong et al9 may be because of either population differences or solving ephedrine in distilled water (in our study) with different pH solution compared with that of Cheong’s study in which ephedrine was solved in normal saline. Furthermore, Autsin et al32 reported that the addition of 30 mg of ephedrine to 20 mL of 1% propofol was as effective as adding lidocaine in preventing injection pain and also leading to a more stable hemodynamic profile.32 Their dose of the admixed ephedrine was equal to 380 μg/kg, a dose much higher than those published previously and that of the present study. Furthermore, Eriksson et al33 suggested that a mixture of lidocaine and propofol works through reducing the pH of the emulsion, rendering more of the propofol un-ionized although driving it from the aqueous phase into the lipid phase.33 Autsin et al32 also declared that ephedrine is buffered with HCl, and both lidocaine and ephedrine have a pH of 6–7. Hence, the pain-reducing effect of ephedrine-propofol admixture is not only based on its peripheral effect, but also a decrease in pH of the propofol-ephedrine mixture on basis.
Furthermore, the present study also supports the previously published hemodynamic findings.9, 14, 31 Ephedrine has two mechanisms of action: A direct action through both α and β receptors and an indirect effect by means of releasing endogenous norepinephrine. Because of its β1 adrenergic stimulating effects, ephedrine is helpful in treating moderate hypotension, particularly if accompanied by bradycardia.23 Chong et al9 declared that an ephedrine pretreatment dose of 30 μg/kg or 70 μg/kg results in an optimum hemodynamics, which is in harmony with our finding. Our results are also supported by the study of Faridi et al,31 in which it was reported that in patients undergoing cesarean section under spinal anesthesia, hypotension was reduced to 65% by administration of ephedrine 25 μg/kg compared with Group S in which the incidence of hypotension was 90%. Furthermore, Ozkocak et al14 found that a dose of 70 μg/kg ephedrine pretreatment was capable of preventing hypotension induced by propofol injection. On the contrary, Agarwal et al27 showed that pretreatment with 30 μg/kg of ephedrine failed to improve the hemodynamic instability. The difference between these results could be explained by differences in population (age, gender) or methodologies.
5. Conclusion
Based on data found in our study, it could be concluded that pretreatment with a combination of small-dose ephedrine and lidocaine reduces the incidence and intensity of propofol-induced pain and results in a more stable hemodynamic profile. However, because of the lack of synergistic effect between lidocaine and ephedrine, pretreatment with combination of these two drugs failed to work better in further reduction of pain. Further studies are needed to evaluate the analgesic efficacy of combination of lidocaine-ephedrine admixture with propofol for minimizing its injection pain with more stable hemodynamic profile.
Acknowledgment
The authors gratefully acknowledge the assistance given by Dr Hamideh Yari and Zahra Mohamadi for their help in the preparation of this manuscript.