Anesth Analg 1999;89:1331
© 1999 International Anesthesia Research Society
LETTERS TO THE EDITOR
Conclusions Regarding Propofol/Lidocaine Admixture May Be Misleading
Richard P. Driver, Jr., MD
Department of Anesthesiology , West Virginia University , Morgantown, WV 26506
Wachowski et al. (1) stated "We conclude that clinically relevant concentrations of lidocaine, when mixed with the propofol emulsion, do not prevent the growth of S. aureus, E. coli, and C. albicans." This broad generalization may be misleading. As noted in the article, growth inhibition of bacteria and fungi by lidocaine is altered by pH, concentration, and temperature. Wachowski et al. (1) failed to demonstrate growth inhibition of S. aureus in mixtures of propofol containing 5 mg/mL lidocaine hydrochloride at 20°C (68°F). This temperature was used to mimic conditions within an operating room. In a similar study, we determined that an admixture of propofol with a lidocaine hydrochloride concentration of 5 mg/mL resulted in significant growth inhibition of S. aureus at 37°C (2). Although many operating room sites are kept at reduced temperatures, other operating room sites such as those for pediatric surgery or trauma surgery are maintained at temperatures significantly higher than normal room temperatures. The admixture of 5 mg/mL to 10 mg/mL lidocaine hydrochloride with propofol may increase safety by inhibiting the growth of some microorganisms at temperatures >20°C. The mean inhibitory concentration of lidocaine hydrochloride ranges between 2.5 mg/mL to 40 mg/mL (3–5). This range in concentrations may reflect variations in temperature, pH, and the variability of resistance by different organisms. In addition, the pKa (pH at which the concentration of ionized and unionized forms are equal) of lidocaine hydrochloride is 7.9, and only the nonionized fraction appears to be active in microbial growth inhibition. Wachowski et al. (1) determined the mean pH of the solutions in the study and found that the lidocaine/propofol admixtures were as acidic as 0.5% lidocaine alone. In our study, we used 4% lidocaine to formulate the propofol lidocaine admixtures to minimize the volume of the acidic lidocaine in the final mixture. Because we (2) did not determine the pH of our solutions and Wachowski et al. (1) did not describe the formulations of their mixtures, no direct comparison of the effect of pH on the ability of lidocaine hydrochloride to inhibit microbial growth can be ascertained between the studies. A detailed analysis of the effects of temperature, concentration, and pH on inhibition of microbial growth with lidocaine hydrochloride and propofol admixtures would help determine the differing findings of these two studies.
References
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Wachowski I, Jolly DT, Hrazdil J, et al. The growth of microorganisms in propofol and mixtures of propofol and lidocaine. Analg 1999;88:209–12.[Abstract/Free Full Text]
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Driver RP, Granus VA, Yassa YJ. Growth inhibition of Staphylococcus aureus by propofol/lidocaine admixture. Anesth Analg 1998;86:S166.
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Ohsuka S, Ohta M, Masuda K, et al. Lidocaine hydrochloride and acetylsalicylate kill bacteria by disrupting the bacterial membrane potential in different ways. Microbiol Immunol 1994;38:429–34.[Web of Science][Medline]
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Thompson KD, Welykyj S, Massa MC. Antibacterial activity of lidocaine in combination with a bicarbonate buffer. J Dermatol Surg Oncol 1993;19:216–20.[Web of Science][Medline]
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Ravin CE, Latimer JM, Matsen JM. In vitro effects of lidocaine on anaerobic respiratory pathogens and strains of Hemophilus influenza. Chest 1977;72:439–41.[Abstract/Free Full Text]
Response
Donald T. Jolly, MD, FRCPC,
Ireneusz Wachowski, MD, FRCPC, and
Jiri Hrazdil, MD, FRCPC
Department of Anaesthesia , Capital Health Authority , University of Alberta Hospital Site , Edmonton, Alberta, Canada T6G 2C7
John C. Galbraith, MD, FRCPC
Department of Laboratory Medicine , Capital Health Authority , University of Alberta Hospital Site , Edmonton, Alberta, Canada T6G 2C7
We thank Dr. Driver for his observations and comments. Dr. Driver correctly identifies two of the factors that are potentially confounding variables in microbial studies of this nature, pH and temperature.
We highlighted the relationship between temperature and the growth of S. aureus in the paper by Crowther et al. (1). In that study, we were not able to document a significant growth of S. aureus in propofol at 20°C in contrast to the report of Sosis and Braverman (2), which clearly documented significant growth in propofol after 6 h at 27°C. We had used the same S. aureus strain (ATCC 25923) and similar methodology. Temperature was the only variable that accounted for this discrepancy.
Taki et al. (3) addressed the issues of temperature and lidocaine concentration on the growth of S. aureus. They demonstrated that at 37°C, a lidocaine concentration of 0.5% (5 mg/mL) was the highest concentration of lidocaine that permitted S. aureus to grow after 6 h. Concentrations of lidocaine greater than this resulted in the decline of bacterial viability. They also observed that, at 10°C, a lidocaine concentration of 1.0% resulted in no decline of the viability of S. aureus. Furthermore, at 40°C, lidocaine 0.25% produced a conspicuous decline of bacterial viability. This work confirms that the inhibitory actions of lidocaine toward S. aureus are concentration and temperature dependent.
The report of Berry et al. (4) speculated that pH is a mechanism of the bactericidal activity of thiopentone. The high alkalinity of thiopentone accounted for its bactericidal activity, a property that Crowther et al. (1) demonstrated could be transferred to an admixture of thiopentone and propofol.
Although our generalization in the paper by Wachowski et al. (5) was broad, it remains accurate. It is also supported by the recent work by Vidovich et al. (6), who concluded that the addition of lidocaine to propofol in concentrations clinically effective in reducing pain on injection had no effect on microbial growth. As Dr. Driver correctly proposes, studies with any admixture involving propofol must be carefully conceived and executed. Not only must pH and temperature be carefully documented, but the strain of bacteria used must be clearly identified, because not all strains of S. aureus are inhibited by even 2% lidocaine (7). Likewise, methodological differences can confound comparisons between studies. In Dr. Driver’s abstract (8), baseline colony counts in the various mixtures are not presented. Therefore, conclusions regarding relative growth between the mixtures should be interpreted with caution. We chose a methodology similar to Sosis and Braverman (2) to compare our results. As it turned out, this allowed us to consider the role of pH and temperature on microbial growth in our papers by Crowther et al. (1) and Wachowski et al. (5).
We concur with Dr. Driver that a detailed analysis of the effects of temperature, concentration, and pH on the inhibition of microbial growth with any admixture involving the propofol emulsion is necessary. However, we suggest that any conclusion that implies that an admixture of lidocaine with propofol may increase patient safety by inhibiting the growth of some microorganisms at temperatures >20°C is intrinsically flawed. Inhibition of microbial growth is not the same as microbial destruction. Any inhibitory effects of the admixture may rapidly dissipate after introduction into the patient. Once introduced into the circulating blood volume, the concentration of lidocaine would become barely detectable. As has been documented with E. coli, those bacteria not irreversibly damaged would again be able to propagate and pose a life-threatening risk to the patient (9). Consequently, any alteration of the propofol emulsion that does not confer bactericidal properties to the resulting admixture cannot be assumed to provide the patient with an added margin of safety.
References
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Crowther J, Hrazdil J, Jolly DT, et al. Growth of microorganisms in propofol, thiopental, and a 1:1 mixture of propofol and thiopental. Anesth Analg 1996;82:475–8.[Abstract]
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Sosis MB, Braverman B. Growth of Staphylococcus aureus in four intravenous anesthetics. Anesth Analg 1993;77:766–8.[Abstract/Free Full Text]
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Taki Y, Keiko S, Hajime I, et al. Effect of temperature on antibacterial activity of lidocaine to Staphylococcus aureus and Pseudomonas aeruginosa. Microbiol Immunol 1988;32:429–34.[Web of Science][Medline]
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Berry CB, Gillespie T, Hood J, et al. Growth of micro-organisms in solutions of intravenous anaesthetic agents. Anaesthesia 1993;48:30–2.[Web of Science][Medline]
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Wachowski I, Jolly DT, Hrazdil J, et al. The growth of microorganisms in propofol and mixtures of propofol and lidocaine. Analg 1999;88:209–12.
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Vidovich MI, Peterson LR, Wong HY. The effect of lidocaine on bacterial growth in propofol. Anesth Analg 1999;88:936–8.[Abstract/Free Full Text]
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Schmidt RM, Rosenkranz HS. Antimicrobial activity of local anesthetics: lidocaine and procaine. J Infect Dis 1970;121:597–607.[Web of Science][Medline]
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Driver RP, Granus VA, Yassa YJ. Growth inhibition of Staphylococcus aureus by propofol/lidocaine admixture. Anesth Analg 1998;86:S166.
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Fazly Bazaz BS, Salt WG. Local anaesthetics as antimicrobial agents: structure-action considerations. Microbios 1983;37:45–64.[Web of Science][Medline]
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