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Anesth Analg 2002;95:1293-1296 © 2002 International Anesthesia Research Society
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Abstract |
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One hundred seventy-six patients (ASA physical status I or II) presenting for elective surgery were randomly allocated into six study groups to compare the incidence of propofol-induced pain after pretreatment with different doses of ephedrine as compared with lidocaine. Patients in Group P (n = 30) received saline placebo; patients in Group L (n = 30) received 2% lidocaine 40 mg; patients received ephedrine 30 µg/kg (Group E30, n = 28), 70 µg/kg (Group E70, n = 30), 110 µg/kg (Group E110, n = 30), and 150 µg/kg (Group E150, n = 28), respectively, followed 30 s later by propofol 2.5 mg/kg. A blinded anesthesiologist asked the patient to evaluate the pain score (verbal rating scale and face pain scale). The incidence and intensity of pain was less in the lidocaine and ephedrine groups than in the placebo group (P < 0.01). Before tracheal intubation, the arterial blood pressure was decreased in the P and L groups, and after intubation, hemodynamics were increased in the E110 and E150 groups, respectively (P < 0.05). We concluded that pretreatment with a small dose of ephedrine (30 and 70 µg/kg) reduced the incidence and intensity of propofol-induced pain with a lesser decrease in arterial blood pressure than from propofol alone in lidocaine pretreatment.
IMPLICATIONS. Propofol is a widely used IV anesthetic for the induction of anesthesia, but it often causes local pain when administered into peripheral veins. A small dose of ephedrine reduces the incidence and intensity of the pain without significant adverse hemodynamic effects during induction.
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Introduction |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Propofol is a popular drug to induce anesthesia, but it causes pain when given IV, the incidence of which is between 40% and 86% (1). Several methods have been used to try to reduce this pain: adding lidocaine, cooling or warming, diluting the propofol solution, injection of propofol into a large vein, previous injection of ondansetron, metoclopramide, and opioids or thiopental (2–5). Lidocaine pretreatment has been commonly proposed to decrease injection-related pain; unfortunately, the failure rate is between 13% and 32% (2,3). Propofol can cause hypotension and an initial increase in heart rate and cardiac output, with a subsequent decrease to less than baseline (6).
Ephedrine, which acts directly at both the 
and ß receptor and indirectly by releasing endogenous norepinephrine, has been used for many years to counteract hypotension and bradycardia in spinal and epidural anesthesia (7). There were no studies about ephedrine’s effect on propofol-induced pain from injection. In this study, our aim was to evaluate the effects of different doses of ephedrine on injection pain during the induction sequence.
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Methods |
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This randomized, placebo-controlled, double-blinded study was approved by the institutional ethics committee of Hanyang University Hospital. One hundred seventy-six patients (ASA physical status I or II, aged 19–59 yr) undergoing elective surgery signed informed consent before enrollment. Patients taking sedatives or analgesics and those with allergic, neurologic, or cardiovascular disease were excluded from the study. No patient received analgesics during the 24 h preceding the surgery. A 20-gauge Teflon catheter was inserted into a vein of the dorsum or wrist of the hand without subcutaneous lidocaine infiltration at approximately 180 min before the induction of anesthesia when the patient was still in the ward on the day of surgery. The catheter was used for IV infusion of Ringer’s lactate solution.
Patients were randomly allocated to receive one of six treatments. Randomization was based on computer-generated codes that were maintained in sequentially numbered opaque envelopes. Subjects received 0.9% normal saline 2 mL (Group P, n = 30), 2% lidocaine 2 mL (Group L, n = 30), ephedrine 30 µg/kg (Group E30, n = 28), 70 µg/kg (Group E70, n = 30), 110 µg/kg (Group E110, n = 30), and 150 µg/kg (Group E150, n = 28), respectively. Ephedrine was diluted with 0.9% normal saline into a 2-mL solution. All syringes of test solution were prepared by another investigator and covered so that the investigator who assessed the patient response was unaware of the nature of the solution. Thirty seconds after the administration of the test solution, 1% solution of propofol 2.5 mg/kg was given through the catheter and injected through a 3-way tap directly connected to the IV catheter at 1 mL/s, with the IV infusion line closed. After the injection of propofol, crystalloids were administered at maximal gravity flow. All drugs were kept at room temperature and used within 30 min of preparation.
Before the administration of propofol, the patient was requested to rate immediately any sensation of pain during injection. Also, a blinded anesthesiologist asked the patient to evaluate the pain score (verbal rating scale [VRS]) every 5 s during propofol injection graded as 0–3 in accordance with the scale advocated by McCrirrick and Hunter (4) and then recorded the highest degree of pain. The grading criteria of VRS was as follows: 0 = no pain experienced, 1 = patients complained of mild pain or soreness, 2 = moderate pain complaint by patients, and 3 = severe pain associated with grimacing, withdrawal movement of forearm, or both. We also used the face pain scale (FPS) advocated by Bieri et al. (8), which is seven schematic faces depicting changes in severity of expressed pain from no pain (1 on the scale) to the most pain possible (7 on the scale). After the propofol was injected and the patient lost consciousness, vecuronium 0.15 mg/kg was administered to facilitate controlled ventilation and 8 L/min oxygen with isoflurane 2.5 vol% were given during ventilation via a facemask. Three minutes after vecuronium injection, the trachea was intubated and anesthesia was maintained with isoflurane 1.0–2.0 vol% and N2O 50% in oxygen. Noninvasive mean arterial blood pressure (MAP) and heart rate were recorded before induction, just before intubation, and 1, 2, and 3 min after intubation, respectively.
Before beginning the study, a power analysis indicated that 25 patents in each group would be required to detect an improvement in injection pain of 20% with a power of 0.8 ( = 0.05). Of the 180 patients who consented for the study, 4 were excluded because of difficult intubation. Data were expressed as mean ± SD. Statistical comparison between groups was made with 
2 and one-way analysis of variance by using SPSS (version 10.0). Post hoc testing was performed according to the Tukey’s method. Within groups, comparisons were performed by using repeated measures of analysis of variance using Sigma Stat (version 2.0). Nonparametric data of pain scores were analyzed by using the Kruskal-Wallis test. A P value < 0.05 was considered significant.
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Results |
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There were no significant differences in sex, age, height, and weight among the six groups (Table 1). The number of patients in each group who experienced pain or discomfort is shown in Table 2. The incidence of pain was 86.6% in P, 43.3% in L, 35.6% in E30, 43.3% in E70, 40% in E110, and 42.8% in E150, respectively. The patients in the L and ephedrine groups had significantly smaller pain scores (VRS and FPS) compared with the P group (P < 0.01), and there was no difference of incidence and intensity of pain between lidocaine and each dose of ephedrine. The Gamma statistics between VRS and FPS was 0.94, which was closely correlated.
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Before intubation, MAP was significantly decreased in the P and L groups compared with values before induction (P < 0.05); however, it was maintained in all ephedrine groups (Fig. 1). After intubation, MAP and heart rate variables in the E110 and E150 groups were significantly higher than in the P and L groups, respectively (P < 0.05) (Figs. 1 and 2). A small dose of ephedrine (30 and 70 µg/kg) could prevent propofol-induced hypotension before intubation, and did not produce significant hemodynamic changes compared with the other groups after intubation. None of the patients developed profound hypotension or bradycardia that required treatment, and there were no adverse events such as dysrhythmias, severe hypertension defined as systolic arterial blood pressure >200 mm Hg or increase of >30% of preinduction value for >60 s (9), allergic reactions, or cardiovascular collapse during induction.
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Discussion |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Small doses of ephedrine given before propofol reduced the incidence and intensity of propofol-induced pain without significant adverse hemodynamic effects during induction. Also, propofol-induced hypotension was attenuated before tracheal intubation.
The incidence of propofol injection pain is between 28% and 91% in adults (2,3) and specifically between 40% and 86% in a hand vein (1) during the induction of anesthesia, and 86.6% in the present study. The mechanism responsible for the pain is unknown; however, the activation of pain mediators such as the kinin cascade system has been suggested (2). Pain on injection of propofol can be immediate or delayed, and delayed pain has a latency of between 10 and 20 seconds (10). In the present study, a blinded anesthesiologist asked the patient to evaluate the pain score every 5 seconds during propofol injection and then recorded the highest degree of pain.
Although the etiology of this pain remains obscure, numerous methods have been used to reduce its incidence and intensity. Among them, the most popular is the use of lidocaine either by mixing lidocaine with propofol or by pretreatment with a bolus injection of lidocaine (2,3,5). However, even in patients who received lidocaine treatment, the incidence of pain has been reported to be as frequent as 32% (3) or 48% (11). In our patients who received lidocaine only, the incidence of pain was 43.3%. In the current study, MAP was reduced by 27% by both the propofol in placebo and lidocaine groups before tracheal intubation, respectively (Fig. 1).
The propofol-ephedrine combination is chemically compatible and stable, and maintains blood pressure and cardiac output without tachycardia or other adverse effects (12). An added benefit of using the propofol-ephedrine combination with rocuronium is that it produces good intubating conditions in a timescale appropriate for rapid sequence induction (13). However, the propofol-induced pain has not been evaluated during the injection of the propofol-ephedrine combination.
Each dose of ephedrine reduced the pain from the propofol injection as effectively as lidocaine. Greenberg et al. (14) reported that bradykinin inhibited norepinephrine efflux from sympathetic nerve terminals innervating canine mesenteric and pulmonary arteries. We suggest that endogenous norepinephrine released by ephedrine might be reduced by the effect of bradykinin.
Although we did not find adverse hemodynamic effects after tracheal intubation with pretreatment of ephedrine, such as severe hypertension, tachycardia, and arrhythmias, larger doses of ephedrine (110 and 150 µg/kg) could produce these adverse effects. Their incidence might be more frequent in patients with cardiovascular disease or with a different induction technique. Therefore, when we considered the hemodynamic effects of propofol, we recommended a small dose of ephedrine (30 and 70 µg/kg) suitable to reduce the propofol-induced pain compared with lidocaine or a large dose of ephedrine.
The visual analog scale and VRS (4) were commonly used for assessing acute pain. The visual analog scale is the most sensitive for pain detection and evaluation of analgesic efficacy. But during propofol injection, capacities for abstraction were poor, reading tasks were difficult, and motor coordination was disturbed. We therefore used VRS and FPS for assessing pain scores.
We concluded that pretreatment with a small dose of ephedrine (30 and 70 µg/kg) reduced the incidence and intensity of propofol-induced pain without significant adverse hemodynamic effects.
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References |
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- Angst MS, Mackey SC, Zupfer GH, et al. Reduction of propofol injection pain with a double lumen i.v. set. J Clin Anesth 1997; 9: 462–6.[Web of Science][Medline]
- Scott RP, Saunders DA, Norman J. Propofol: clinical strategies for preventing the pain of injection. Anaesthesia 1988; 43: 492–4.[Web of Science][Medline]
- King SY, Davis FM, Wells JE, et al. Lidocaine for the prevention of pain due to injection of propofol. Anesth Analg 1992; 74: 246–9.[Web of Science][Medline]
- McCrirrick A, Hunter S. Pain on injection of propofol: the effect of injectate temperature. Anaesthesia 1990; 45: 443–4.[Web of Science][Medline]
- Picard P, Tramer MR. Prevention of pain on injection with propofol: a quantitative systematic review. Anesth Analg 2000; 90: 963–9.
[Abstract/Free Full Text] - Fairfield JE, Dritsas A, Beale RJ. Haemodynamic effects of propofol: induction with 2.5 mg kg-1. Br J Anaesth 1991; 67: 618–20.
[Abstract/Free Full Text] - Hemmingsen C, Poulsen JA, Risbo A. Prophylactic ephedrine during spinal anaesthesia: double-blind study in patients in ASA groups I–III. Br J Anaesth 1989; 63: 340–2.
[Abstract/Free Full Text] - Bieri D, Reeve RA, Champion GD, et al. The Faces Pain Scale for the self-assessment of the severity of pain experienced by children: development, initial validation, and preliminary investigation for ratio scale properties. Pain 1990; 41: 139–50.[Web of Science][Medline]
- Maguire AM, Kumar N, Parker JL, et al. Comparison of effects of remifentanil and alfentanil on cardiovascular response to tracheal intubation in hypertensive patients. Br J Anaesth 2001; 86: 90–3.
[Abstract/Free Full Text] - Briggs LP, Clarke RS, Dundee JW, et al. Use of di-isopropyl phenol as main agent for short procedures. Br J Anaesth 1981; 53: 1197–202.
[Abstract/Free Full Text] - O’Hara JR Jr, Sprung J, Laseter JT, et al. Effects of topical nitroglycerin and intravenous lidocaine on propofol-induced pain on injection. Anesth Analg 1997; 84: 865–9.[Abstract]
- Gamlin F, Vucevic M, Winslow L, Berridge J. The haemodynamic effects of propofol in combination with ephedrine. Anaesthesia 1996; 51: 488–91.[Web of Science][Medline]
- Munoz HR, Gonzalez AG, Dagnino JA, et al. The effect of ephedrine on the onset time of rocuronium. Anesth Analg 1997; 85: 437–40.[Web of Science][Medline]
- Greenberg SS, Peevy K, Tanaka TP. Endothelium-derived and intraneuronal nitric oxide-dependent inhibition of norepinephrine efflux from sympathetic nerves by bradykinin. Am J Hypertens 1991; 4: 464–7.[Web of Science][Medline]
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