Anesth Analg 2005;100:683-686
© 2005 International Anesthesia Research Society
doi: 10.1213/01.ANE.0000148617.98716.EB
AMBULATORY ANESTHESIA
Bacteriostatic Saline Containing Benzyl Alcohol Decreases the Pain Associated with the Injection of Propofol
Sean C. Minogue, FCARCSI, and
Deidre A. Sun, FANZCA
Department of Anesthesia, Vancouver General Hospital and the University of British Columbia, Canada
Address correspondence and reprint requests to Dr. Sean Minogue, Department of Anaesthesia, The Adelaide & Meath Hospital Dublin Incorporating The National Children's Hospital Tallaght, Dublin 24, Republic of Ireland. Address e-mail to minogues{at}indigo.ie.
 |
Abstract
|
|---|
Bacteriostatic saline is a physiological saline solution containing the bacteriostatic agent benzyl alcohol as a 0.9% solution. It is used mostly for diluting and dissolving drugs for IV injection and as a flush for intravascular catheters. It also has local anesthetic properties. We studied its efficacy in decreasing the pain associated with IV administration of propofol and compared it with mixing lidocaine with propofol. One-hundred-twenty patients were randomly allocated into three groups. All patients received propofol 50 mg. The benzyl alcohol group received bacteriostatic saline as a preinjection, and the lidocaine group received propofol containing lidocaine. The placebo group did not receive bacteriostatic saline or lidocaine. Fifteen of 39 patients (38%) in the benzyl alcohol group complained of pain on injection compared to 33 of 39 (84%) in the placebo group and 22 of 42 (52%) in the lidocaine group. Differences were significant between the benzyl alcohol and placebo groups (P < 0.01) and the lidocaine and placebo groups (P < 0.01). Preinjection with bacteriostatic saline decreases the incidence of pain associated with IV administration of propofol and is comparable to that of mixing lidocaine with propofol.
|
Introduction
|
|---|
The incidence of pain associated with the IV administration of propofol ranges between 30% and 90% (1,2). This pain can, in some cases, be quite severe and distressing for the patient. The cause of pain may be a direct irritant effect of the aqueous phase phenol on the vein or may be caused indirectly by the release of kinins on contact with the endothelial wall (3–5). The exact mechanism remains unclear. The modifying effect of different drugs such as opioids and local anesthetics on this pain has been studied, as has the effect of variations in the site of injection, duration of injection, and temperature and pH of the injectant (6). The addition of lidocaine to propofol and the injection of lidocaine before propofol have consistently been shown to decrease the incidence and severity of injection pain. However, both methods are still associated with frequent failure (28%–47%) (7–10).
Bacteriostatic saline 0.9% (Abbott Laboratories, Limited, Saint Laurent, Qc, Canada) is a widely available physiological saline solution containing the bacteriostatic agent benzyl alcohol. Each milliliter contains sodium chloride 9 mg and benzyl alcohol 9 mg. Although used mostly for diluting and dissolving drugs for IV injection and as a flush for intravascular catheters, the active ingredient benzyl alcohol is also a weak local anesthetic, and its use as an intradermal anesthetic has been reported (11). We postulated that as an agent used for IV injection and one with local anesthetic properties, it could modulate the pain associated with propofol injection. We performed a prospective double-blind, placebo-controlled study to see if preinjection with bacteriostatic saline could decrease the pain associated with IV administration of propofol and to compare it with mixing lidocaine with propofol in terms of efficacy.
|
Methods
|
|---|
After university and institutional ethics approval and having obtained written informed consent from each subject, we enrolled 120 ASA physical status I and II adult patients presenting over a 2 mo period for elective surgery under general anesthesia at our ambulatory center.
Before transfer to the operating room, each patient had a 20-gauge IV cannula inserted on the dorsum of the hand. This was secured and flushed with normal saline. No other drugs were administered through the IV line until the study drugs had been administered. Premedication was not given.
For the study, we used a formulation of propofol (Diprivan®, AstraZeneca, Wilmington, DE) containing 2,6 diisopropylphenol 1%, soya bean oil 10%, glycerol 2.2%, and egg phosphatide 1.2%. The formulation did not contain antimicrobial preservatives. Using a randomly generated computer assignment, patients were allocated to one of three study groups: benzyl alcohol, lidocaine, or placebo. The benzyl alcohol group received 10 mL of bacteriostatic saline followed by 5 mL (50 mg) of propofol. For the lidocaine group, 1 mL of 2% lidocaine (20 mg) was mixed with 19 mL of propofol (190 mg). Ten mL of preservative-free normal saline was then administered followed by 5 mL of the propofol and lidocaine mixture. The placebo group received 10 mL of preservative-free normal saline followed by 5 mL of propofol. The amount of propofol administered in each case was limited to 5 mL to ensure patients were awake and able to report the degree of pain. The agents were prepared by the investigator and given to the attending anesthesiologist who was blinded as to the contents. The attending anesthesiologist also acted as the observer for the study. After establishing standard monitoring, both study drugs were injected in sequence over a 10- to 15-s period. After the first and the second injection, subjects were asked if they experienced any pain. If they answered "yes," they were then asked to grade the pain as mild, moderate, or severe. The cannula was then flushed with normal saline from a free-running IV line, and the anesthetic induction then proceeded as normal.
A previous study showed a 73% incidence of pain on injection of propofol and a 32% incidence when lidocaine was used as a pretreatment (7). To be considered as a worthwhile pretreatment, a comparable reduction using bacteriostatic saline needs to be shown. Power analysis indicated that at least 30 patients would be required per group to detect a difference with a power of 90% in this study. Data were analyzed using analysis of variance and  2 test as appropriate. After using the Bonferroni correction for multiple comparisons, the P value was adjusted to P < 0.018 to compare the groups for differences.
|
Results
|
|---|
Patients were selected on an intention-to-treat basis. Of the 120 patients studied, 39 were in the benzyl alcohol group, 39 in the placebo group, and 42 in the lidocaine group. Eight patients who had cannulas sited in positions other then the dorsum of the hand (because of difficult access) were included in the study: four from the benzyl alcohol group, one from the placebo group, and three from the lidocaine group. The study groups were comparable in terms of age, ASA grading, and body mass index but not sex distribution, where the placebo group had a larger proportion of men to women (46% compared to 25% in the benzyl alcohol group and 17% in the lidocaine group; Table 1). Fifteen of the 39 patients (38%) in the benzyl alcohol group complained of pain on injection of propofol compared to 33 of 39 (84%) in the placebo group and 22 of 42 (52%) in the lidocaine group. There was no difference in the incidence of pain between the benzyl alcohol and lidocaine groups, but there was a significant difference between the benzyl alcohol and placebo groups (P < 0.01) and placebo and lidocaine groups (P < 0.01) (Tables 2 and 3). Eight of 39 patients in the benzyl alcohol group complained of mild pain on injection of bacteriostatic saline compared to 1 patient in the placebo group and 1 in the lidocaine group.
|
Discussion
|
|---|
Although its properties as a local anesthetic are not widely known, bacteriostatic saline has been used for intradermal anesthesia for IV line placement, and its safety and efficacy has been validated in different studies (12–14). A short duration of action when injected intradermally (less then 5 minutes) has considerably limited further clinical applications. The addition of epinephrine increased the duration of action and enabled it to be used as an alternative to lidocaine for simple laceration repairs (15,16). Benzyl alcohol is an aromatic alcohol with a structure dissimilar to either the amide or ester local anesthetics. Toxicity studies performed on animals suggest that the contents of a 30-mL vial of 0.9% benzyl alcohol could be given to healthy adult patients without any problems and that toxic effects are less than other local anesthetics (12,17,18). There have been reports of neurotoxicity in preterm or very small birth weight babies who repeatedly received large doses of bacteriostatic saline, and its use in this population is contraindicated (19). Benzyl alcohol is frequently found as a bacteriostatic agent in premixed injectable drugs, and there are case reports of suspected hypersensitivity reactions to drugs containing benzyl alcohol as a preservative (20,21). Case reports of toxicity associated with intrathecal use have also been reported, and its intrathecal use is not recommended (22).
In our study, we mixed 1 mL of 2% lidocaine (20 mg) with propofol. The use of this amount has been shown to decrease the incidence of pain on injection compared with propofol alone (7). The effect of increasing or decreasing the dose of lidocaine is unclear. King et al. (7) examined the effect of different doses of lidocaine mixed with propofol on the incidence of pain in 368 women. They were able to show a strong negative dose response between the dose of lidocaine and the severity of pain over the range 0–20 mg. However, Gehan et al. (23) conducted a similar study in 310 patients undergoing general anesthesia and concluded that a dose of lidocaine 0.1 mg/kg significantly reduced the incidence of pain but noted no improvement when the dose was increased.
Thirty-eight percent of patients in the benzyl alcohol group complained of pain on injection of propofol. Picard and Tramèr (6), in a quantitative analysis of different methods of alleviating propofol pain, found incidences of pain ranging between 54% and 76% for patients administered lidocaine before propofol. However, relevant information regarding the time interval between the administration of lidocaine and propofol was not available. Mangar and Holak (2) studied the effect of the application of a tourniquet followed by the injection of lidocaine 100 mg on the incidence of pain associated with propofol injection. The incidence of pain in the group where a tourniquet was applied was comparable to our figure, i.e., 37%. However, in the group where lidocaine was injected without it the incidence of pain was significantly more frequent at 90%. They concluded that the free flow of lidocaine provided some analgesia but was not sufficient to predictably prevent pain and that the application of a tourniquet, by obstructing the venous return, increased the duration of contact of lidocaine in the venous system distal to the occlusion thus enhancing the analgesic effect of lidocaine. A difference in methodologies in our study is that propofol was injected immediately after benzyl alcohol, whereas propofol was administered one minute after the lidocaine administration in the group where the tourniquet was not applied in their study. Work performed by Scott et al. (4) suggests a relationship between timing of administration of the drugs and the incidence of pain. As part of a study investigating different modes of the administration of propofol, they examined the effect on the incidence of pain of different intervals between the administration of lidocaine and propofol. Although the difference was not significant, they found a 40% incidence of pain when lidocaine was administered 30 seconds before propofol compared to a 73% incidence of pain when lidocaine was administered 120 seconds before propofol. The effect of obstructing venous return before the lidocaine administration was also investigated by Johnson et al. (24). They compared preinjection of lidocaine with mixing lidocaine and propofol. In the case of patients administered lidocaine, the venous return was occluded for 20 seconds. They were unable to find a significant difference between the two methods of administration. However, because they did not have a control group where lidocaine was administered without obstructing the venous return, it is not possible to say whether the application of a tourniquet actually increases efficacy.
We used a large volume of benzyl alcohol solution, whereas in most studies where lidocaine was preinjected, 2 mL or less of 1% or 2% lidocaine was used. A limitation of our study is that we did not include a group containing lidocaine diluted to the same volume as the benzyl alcohol solution to see whether pretreatment with a larger volume of lidocaine solution would have made a difference in terms of efficacy. Whereas it would also have been of interest to administer benzyl alcohol as a mixture with propofol, it is only available for medical use as a 0.9% solution. Administration of a similar volume in this manner would have required significant dilution of propofol, and this could be regarded as a confounding factor.
The incidence of pain on injection of propofol experienced by the placebo group is frequent (84%). This is similar to the results of other studies where venous access was established using veins on the dorsum of the hand (1,8) and is in keeping with the opinion that increased contact between the drug and the endothelium using small veins is responsible for the increased incidence of pain. Eight patients from the benzyl alcohol group complained of pain on injection of bacteriostatic saline compared to one patient in the placebo group and one in the lidocaine group, who complained of pain on injection of normal saline. This was an unexpected finding of the study because it has not been reported, and although all patients reported the pain as mild, it is a potential drawback to its use.
Although we were not able to show a significant difference in efficacy between the lidocaine and benzyl alcohol groups, benzyl alcohol in a solution as 0.9% bacteriostatic saline is inexpensive and, in quantities used in this study, has the advantage of being more cost-effective than lidocaine.
In conclusion, preinjection of bacteriostatic saline decreases the incidence and severity of pain associated with IV injection of propofol. The decreased incidence is comparable to that found with mixing lidocaine and propofol and makes it a useful alternative. However, its use is not recommended in a neonatal or pediatric population.
|
References
|
|---|
- Briggs L, White M. The effect of premedication on anaesthesia with propofol (Diprivan). Postgrad Med J 1985;61:35–7.[Abstract/Free Full Text]
- Mangar D, Holak EJ. Tourniquet at 50 mm Hg followed by intravenous lidocaine diminishes hand pain associated with propofol injection. Anesth Analg 1992;74:250–2.[Web of Science][Medline]
- Doenicke AW, Roizen MF, Rau J, et al. Reducing pain during propofol injection: the role of the solvent. Anesth Analg 1996;82:472–4.[Abstract]
- Scott RP, Saunders DA, Norman J. Propofol: clinical strategies for preventing the pain of injection. Anaesthesia 1988;43:492–4.[Web of Science][Medline]
- Klement W, Arndt JO. Pain on injection of propofol: effects of concentration and diluent. Br J Anaesth 1991;67:281–4.[Abstract/Free Full Text]
- Picard P, Tramèr M. Prevention of pain on injection with propofol: a quantitative systematic review. Anesth Analg 2000;90:963–9.[Abstract/Free Full Text]
- 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]
- Parmar AK, Koay CK. Pain on injection of propofol: a comparison of cold propofol with propofol premixed with lignocaine. Anaesthesia 1998;53:79–83.[Web of Science][Medline]
- Lyons B, Lohan D, Flynn C, McCarroll M. Modification of pain on injection with propofol. Anaesthesia 1996;51:394–5.[Web of Science][Medline]
- Lee T, Loewenthal A, Strachan J. Pain during injection of propofol: the effect of prior administration of thiopentone. Anaesthesia 1994;49:817–8.[Web of Science][Medline]
- Macht DI. A pharmacological and therapeutic study of benzyl alcohol as a local anesthetic. J Pharmacol Exp Ther 1918;11:263–79.[Abstract/Free Full Text]
- Wightman MA, Vaughan RW. Comparison of compounds used for intradermal anesthesia. Anesthesiology 1976;45:687–9.[Web of Science][Medline]
- Fein JA, Boardman CR, Stevenson S, et al. Saline with benzyl alcohol as intradermal anesthesia for intravenous line placement in children. Pediatr Emerg Care 1998;14:119–22.[Web of Science][Medline]
- Nuttall GA, Barnett MR, Smith RL, et al. Establishing intravenous access: a study of local anesthetic efficacy. Anesth Analg 1993;77:950–3.[Abstract/Free Full Text]
- Bartfield JM, May-Wheeling HE, Raccio-Robak N, et al. Benzyl alcohol with epinephrine as an alternative to lidocaine with epinephrine. J Emerg Med 2001;21:375–9.[Web of Science][Medline]
- Martin S, Wilson L. Benzyl alcohol with epinephrine as an alternative local anesthetic. Ann Emerg Med 1999;33:495.[Web of Science][Medline]
- Kimura ET, Darby TD, Krause RA, Brondyk HD. Parenteral toxicity studies with benzyl alcohol. Toxicol Appl Pharmacol 1971;18:60-8.[Web of Science][Medline]
- Novak E, Stubbs SS, Sanborn EC, Eustice RM. The tolerance and safety of intravenously administered benzyl alcohol in methylprednisolone sodium succinate formulations in normal human subjects. Toxicol Appl Pharmacol 1972;23:54–61.[Web of Science][Medline]
- Benzyl alcohol: toxic agent in neonatal units. Pediatrics 1983;72:356–8.[Abstract/Free Full Text]
- Wilson J, Solimando D, Edwards M. Parenteral benzyl alcohol induced hypersensitivity reaction. Drug Intell Clin Pharm 1986;20:689–91.[Abstract]
- Shmunes E. Allergic dermatitis to benzyl alcohol in an injectable solution. Arch Dermatol 1984;120:1200–1.[Abstract/Free Full Text]
- Hetherington N, Dooley M. Potential for patient harm from intrathecal administration of preserved solutions. Med J Aust 2000;173:141–3.[Web of Science][Medline]
- Gehan G, Karoubi F, Quinet A, et al. Optimal dose of lidocaine for preventing pain on injection of propofol. Br J Anaesth 1991;66:324–6.[Abstract/Free Full Text]
- Johnson RA, Harper NJN, Chadwick S. Pain on injection of propofol: methods of alleviation. Anaesthesia 1990;45:439–42.[Web of Science][Medline]
|
Top
Abstract
Introduction
