Binding of Long-Lasting Local Anesthetics to Lipid Emulsions

Ⅵ PAIN MEDICINE

Anesthesiology 2009; 110:380–6 Copyright © 2009, the American Society of Anesthesiologists, Inc. Lippincott Williams & Wilkins, Inc. Binding of Long-lasting Local Anesthetics to Lipid Emulsions Jean-Xavier Mazoit, M.D., Ph.D.,* Re´ gine Le Guen, B.S.,† He´le` ne Beloeil, M.D., Ph.D.,* Dan Benhamou, M.D.‡

Background: Rapid infusion of lipid emulsion has been pro- acaine and levobupivacaine seem to clear more rapidly than posed to treat local anesthetic toxicity. The authors wanted to test ropivacaine. the buffering properties of two commercially available emulsions made of long- and of long- and medium-chain triglycerides. TOXICITY of long-acting local anesthetics (LA) remains

Methods: Using the shake-flask method, the authors measured Downloaded from http://pubs.asahq.org/anesthesiology/article-pdf/110/2/380/491208/0000542-200902000-00030.pdf by guest on 25 September 2021 the solubility and binding of racemic bupivacaine, levobupiva- an important problem, despite the availability of new 1 caine, and ropivacaine to diluted Intralipid (Fresenius Kabi, Paris, S-enantiomers of LAs. Indeed, both ropivacaine and France) and Medialipide (B-Braun, Boulogne, France). levobupivacaine appear to be less cardiotoxic than race- Results: The apparent distribution coefficient expressed as the mic bupivacaine (rac-bupivacaine),2,3 but life-threaten- ratio of mole fraction was 823 ؎ 198 and 320 ؎ 65 for racemic ing events still occur.4,5 Rapid infusion of lipid emulsion bupivacaine and levobupivacaine, and ropivacaine, respectively, has recently been proposed to treat such toxic events at 500 mg in the Medialipide/buffer emulsion; and 1,870 ؎ 92 and 6,7 initially in animal studies and, more recently, in human ؎ 1,240 14 for racemic bupivacaine and levobupivacaine, and 8,9 ropivacaine, respectively, in the Intralipid/buffer emulsion. De- patients with success. The mechanism of action of creasing the pH from 7.40 to 7.00 of the Medialipide/buffer emul- lipid emulsions is not fully established, but the binding sion led to a decrease in ratio of molar concentration from 121 ؎ property of the emulsion is likely to be the major, if not to 46 ؎ 2.8 for bupivacaine, and to a lesser extent from 51 ؎ 4.0 the only, mechanism by which lipid emulsion reverses 3.8 to 31 ؎ 1.6 for ropivacaine. The capacity of the 1% emulsions was the adverse effects of LAs.6,10 Rapid infusion of lipid ␮ 871 and 2,200 M for the 1% Medialipide and Intralipid emulsions, emulsion has also been used to successfully treat other ␮ respectively. The dissociation constant was 818 and 2,120 M for intoxications in humans11 and in animal models.12–14 racemic bupivacaine and levobupivacaine, and ropivacaine, respectively. Increasing the temperature from 20 to 37°C led to a Lipid emulsions used for intravenous parenteral nutrition greater increase in affinity for ropivacaine (55%) than for bupiv- are composed of chylomicron-like particles and lipo- 15 acaine (27%). When the pH of the buffer was decreased from 7.40 somes. These emulsions are also used to deliver hydro- to 7.00, the affinity was decreased by a factor of 1.68, similar for phobic drugs such as propofol.16 It is then likely that lipid both anesthetics. emulsions rapidly adsorb hydrophobic drugs such as bu- Conclusions: The solubility of long-acting local anesthetics pivacaine or ropivacaine. The long-chain fatty acid emul- in lipid emulsions and the high capacity of binding of these sion Intralipid (Fresenius Kabi, Paris, France) has been emulsions most probably explain their clinical efficacy in case of toxicity. The long-chain triglyceride emulsion In- almost exclusively used in the context of LA toxicity. An tralipid appears to be about 2.5 times more efficacious than emulsion including medium-chain fatty acids (Medialipide; B- 4 the 50/50 medium-chain/long-chain Medialipide emulsion. Braun, Boulogne, France) has been also used successfully. Also, because of their higher hydrophobicity, racemic bupiv- We then measured the binding capacity of two commercially available emulsions made of long- and of Supplemental digital content is available for this article. Direct long- and medium-chain triglycerides to test our hy- URL citations appear in the printed text and are available in pothesis that lipid emulsions mainly act by binding both the HTML and PDF versions of this article. Links to the local anesthetic molecules. digital files are provided in the HTML text of this article on the Journal’s Web site (www.anesthesiology.org). Materials and Methods

* Staff anesthesiologist, † Laboratory Technician, ‡ Professor of Anesthesiol- The solubility of LAs in two commercially available lipid ogy; Universite´ Paris-Sud, Laboratoire d’Anesthe´sie, Faculte´deMe´decine, Le emulsions was measured using the classic shake-flask method; Kremlin Biceˆtre, France. i.e., by mixing the solutions by continuous agitation. The Received from the Universite´ Paris-Sud, Laboratoire d’Anesthe´sie, Faculte´de Me´decine, Le Kremlin Biceˆtre, France. Submitted for publication May 26, 2008. validity of this technique was also confirmed by using a Accepted for publication October 22, 2008. Supported by grants from the method of cobinding with activated charcoal.17 University Paris-Sud, Orsay Cedex, France, and from Association Mises au Point en Anesthe´sie et Reánimation, Hoˆpital Biceˆtre, Biceˆtre Cedex, France. Associa- tion Mises au Point en Anesthe´sie et Reánimation received funding from Astra- Drugs and Chemicals Zeneca Laboratories (Rueil-Malmaison France) and from Abbott Laboratories (Rungis France). Presented in part at the American Society of Anesthesiologists The LAs used were rac-bupivacaine (Sigma, Saint annual meeting, San Francisco, California, October 13–17, 2007. Quentin-Fallavier, France), ropivacaine (Naropeine; As- Address correspondence to: Dr. Mazoit, Laboratoire d’Anesthe´sie, Faculte´de Me´decine, 94276 Le Kremlin Biceˆtre, France. [email protected]. In- traZeneca, Rueil-Malmaison, France), and levobupiva- formation on purchasing reprints may be found at www.anesthesiology.org or on caine (Chirocaine; Abbott, Rungis, France). The lipid the masthead page at the beginning of this issue. ANESTHESIOLOGY’s articles are made freely accessible to all readers, for personal use only, 6 months from the emulsions were a long-chain triglyceride emulsion (In- cover date of the issue. tralipid 20%) and a medium- and long-chain triglyceride

Anesthesiology, V 110, No 2, Feb 2009 380 LOCAL ANESTHETIC BINDING TO LIPID EMULSIONS 381

Fig. 1. Binding of bupivacaine and ropivacaine (125 mg/l) to Intralipid 1% (Fre- senius Kabi; Paris, France) and to Medi- alipide 1% (B-Braun; Boulogne, France) according to the duration of mixing (0.2,

1, 3, 5, 10, 20 min). The points represent Downloaded from http://pubs.asahq.org/anesthesiology/article-pdf/110/2/380/491208/0000542-200902000-00030.pdf by guest on 25 September 2021 the mean of three measurements. The values measured at 0.2 min and at 1 min are given with great care, because there is a large uncertainty in the time measurement.

(50/50) emulsion (Medialipide 20%). Medialipide is also 125, 250, 500, and 1,000 mg/l in 1% and 2% Medialip- known as Lipofundin in Germany and as Vasolipid in ide and 1% Intralipid emulsions. The accuracy of the Denmark, Norway, and Sweden. All experiments were shake-ﬂask method was checked using cobinding with conducted using a buffer solution containing (in mM) dextran-coated charcoal (Sigma, St. Quentin-Fallavier,

NaCl 120, NaH2PO4 10, Na2HPO4 10, and CaCl2 1, pH France) at a final concentration of 2 mg/ml and a 5% lipid 7.4. The lipid emulsions were diluted in buffer at the emulsion. In addition, rac-bupivacaine and ropivacaine following final concentrations: 0.5, 1, and 2%. A prelim- binding were measured at 2, 4, 8, 15.60, 31.25, 62.50, 125, inary experiment with Medialipide emulsion diluted to a 250, 500, and 1,000 mg/l in 2% Medialipide emulsion at pH 10% concentration was also performed with 64, 128, 7.00 and pH 7.40. The effect of temperature on rac-bupiv- 256, and 512 mg/l rac-bupivacaine. acaine and ropivacaine binding was also tested on a sepa- rate set of data at 15.60, 31.25, 62.50, 125, 250, 500, and Experiments 1,000 mg/l in 1% Medialipide and 1% Intralipid at 20 and at All experiments were done in triplicate at 20°C. To 37°C, respectively. The data are reported as molar concen- 19 minimize problems related to emulsion stability with trations. LAs were assayed using gas chromatography. time and dilution,18 the emulsion was diluted in buffer Statistics immediately before use. The LA was then added and the The distribution coefficient was calculated as ␳, the emulsion was mixed by shaking for a 20-min period. A ratio of the mole fraction in lipid and in buffer§ and as D, measure of binding according to the duration of shak- the ratio of molar concentration. The relationship be- ing, done with rac-bupivacaine and ropivacaine, tween free concentration (concentration in the aqueous showed that steady state was nearly attained after 1–3 phase) and bound concentration (concentration in the min (fig. 1). The aqueous phase was then separated by lipid phase) was also analyzed using nonlinear regres- 2 centrifugation steps (15,000 g, 10 min). LAs were sion. This bound (B) versus free (F) drug concentration added at the following concentrations (considering Bmax Lip F the hydrochloride salt for all LAs): 1, 2, 4, 8 16, and 32 ϭ was modeled as B ϩ , considering a one-site mg/l in the 0.5, 1, and 2% Medialipide emulsions; at 8, Kd F model. Bmax is the maximum binding capacity, Kd is the 16, 32, and 64 mg/l in 1% Medialipide and 1% In- dissociation constant, and Lip is the concentration of tralipid emulsions; and at 2, 4, 8, 15.60, 31.25, 62.50, lipid in the emulsion. The whole data set was simulta- neously fitted using mixed-effect modeling with the § The mole fraction in lipid emulsion is the proportion of anesthetic molecules NONMEM software (version 6, level 1; GloboMax, LLC, to the total number of molecules of lipids and anesthetics in the emulsion. The ratio of mole fraction is then the ratio of the mole fraction of local anesthetic Hanover, MD).࿣ We added a random parameter to each molecules in lipids to the mole fraction of anesthetic molecules in buffer. of the fixed (structural) parameters (Bmax and Kd) to ࿣ Sheiner LB, Beal SL, Boeckmann AJ. NONMEM Project Group, University of California at San Francisco, San Francisco, California 1990 (at http://www.globomax. account for interbatch variability. These random param- net/products/nonmem.cfm accessed 10/23/2008). eters were modeled according to an exponential equa-

Anesthesiology, V 110, No 2, Feb 2009 382 MAZOIT ET AL.

Table 1. Distribution Coefﬁcient of Racemic Bupivacaine, Levobupivacaine, and Ropivacaine between Emulsion and Buffer

Medialipide* Intralipid†

Total Concentration (mg/l) Rac-bupivacaine Ropivacaine Rac-bupivacaine/Levobupivacaine Ropivacaine

20°C 8 ␳ 1,390 Ϯ 235 615 Ϯ 150 3,770 Ϯ 298 1,470 Ϯ 24 D 113 Ϯ 21 51 Ϯ 12 283 Ϯ 22 111 Ϯ 1.8 62.5‡ ␳ 1,130 Ϯ 470 498 Ϯ 154 2,510 Ϯ 220 1,420 Ϯ 24 D94Ϯ 23 41 Ϯ 13 189 Ϯ 16 107 Ϯ 1.6 500 Downloaded from http://pubs.asahq.org/anesthesiology/article-pdf/110/2/380/491208/0000542-200902000-00030.pdf by guest on 25 September 2021 ␳ 823 Ϯ 198 320 Ϯ 65 1,870 Ϯ 92 1,240 Ϯ 14 D69Ϯ 16 27 Ϯ 5.5 144 Ϯ 6.1 95 Ϯ 1.0 37°C 62.5 ␳ 1,570 Ϯ 113 904 Ϯ 155 3,110 Ϯ 295 2,530 Ϯ 165 D 132 Ϯ 9.5 76 Ϯ 13 258 Ϯ 25 210 Ϯ 14 500 ␳ 1,020 Ϯ 95 512 Ϯ 94 2,280 Ϯ 107 1,560 Ϯ 150 D85Ϯ 843Ϯ 7.9 193 Ϯ 9.1 131 Ϯ 13 pH 7.00 62.5 ␳ 550 Ϯ 130 456 Ϯ 102 D46Ϯ 11 38 Ϯ 8.5 500 ␳ 515 Ϯ 52 360 Ϯ 82 D43Ϯ 4.4 30 Ϯ 6.9

␳ in the first line represents the ratio of the mole fraction, and D in the second line represents the ratio of molar concentrations. * B-Braun; Boulogne, France. † Fresenius Kabi; Paris, France. ‡ 62.5 or 64 mg/l, depending on the batch. Rac-Bupivacaine ϭ racemic bupivacaine. tion (we made the usual assumption that fixed parame- performed with the software R (version 2.5.1; The R ters were log-normally distributed). A combined additive Foundation for Statistical Computing, Vienna, Austria)#, and constant coefficient residual (intraindividual) error and the normalized prediction distribution errors proce- model was used. The significance of random parameters dure.20 Data are reported as the mean Ϯ SD, or as the and of Bmax and Kd for each LA and each emulsion was fitted value and 95% CI. tested using the log-likelihood ratio test. Fitting was performed using the first order conditional estimation method with interaction. Because of the asymptotic na- Results ture of fitting, P Ͻ 0.01 was considered the minimum level of significance for this part of the study. The full The preliminary experiment done with a 20% Medi- (initial) model was based on the hypothesis that each LA alipide emulsion diluted to 10% showed similar results as and each emulsion had different binding properties. In those obtained with more diluted emulsions, but the the final model, Bmax was only dependent on the emul- coefficient of variation was exceedingly high. The shake- sion, and Kd was only dependent on the anesthetics. Kd flask technique was also compared to a technique of was also similar for levobupivacaine and rac-bupiva- cobinding with activated charcoal. The two techniques caine. Random parameters associated with all of these yielded similar results. It was not possible to differentiate fixed parameters were always significant. The data sets between rac-bupivacaine and levobupivacaine; i.e., ste- corresponding to the effect of pH and to the effect of reospecificity was not observed. Binding was rapid, temperature were separately fitted using a full model since steady state was nearly attained after 3 min of considering different Bmax and different Kd for each mixing. emulsion and each LA. The precision (95% CI) and ac- Binding of LAs was almost linear, from 2 to 125 mg/l in curacy (bias) of fitting were estimated using a nonpara- the 0.5, 1 and 2% emulsions; i.e., from 6.16 to 385 ␮M for metric bootstrap with 1,000 replicates, and by a visual bupivacaine and from 6.42 to 401 ␮M for ropivacaine. predictive check. The bootstrap was stratified by batch. The apparent distribution coefficients calculated in dif- In addition to NONMEM, this part of modeling was ferent ranges of concentrations are reported in table 1. Decreasing the pH of the Medialipide/buffer emulsion

# The R Foundation for Statistical Computing, Vienna University of Technol- from 7.40 to 7.00 led to an average 40–60% decrease in ogy, Vienna Austria (at http://www.r-project.org/ accessed 10/23/2008). the apparent distribution coefﬁcient (table 1). Increasing

Anesthesiology, V 110, No 2, Feb 2009 LOCAL ANESTHETIC BINDING TO LIPID EMULSIONS 383

Fig. 2. Binding of racemic bupivacaine (circles), levobupivacaine (diamonds) and ropivacaine (triangles)toIn- tralipid (Fresenius Kabi; Paris, France) (dark ﬁlled symbols), and to Medialip- ide (B-Braun; Boulogne, France) (light ﬁlled symbols). Data are those of the 2

to 1,000 mg/l binding to 1% emulsions Downloaded from http://pubs.asahq.org/anesthesiology/article-pdf/110/2/380/491208/0000542-200902000-00030.pdf by guest on 25 September 2021 experiment.

the temperature from 20 to 37°C led to an increase in the and the Intralipid emulsions. (See table, Supplemental Dig- apparent distribution coefficient (table 1). At higher con- ital Content 1, which shows Bayesian estimates of the centrations, saturation occurred progressively (fig. 2). A parameters, http://links.lww.com/A678.) Decreasing the one-site binding model was used to fit the free versus pH of the 2% Medialipide emulsion from 7.40 to 7.00 led to bound concentrations. Fitting was excellent; the visual a decrease in the affinity (1/Kd), but without any significant predictive check did not show any departure of the effect on the capacity: Kd was increased by a factor of 1.68 residuals from normality (the Shapiro-Wilk test was (95% CI 1.65–1.75) similar for bupivacaine and ropiva- Ͼ 0.2). As with the calculation of ␳ and the ratio of molar caine. Increasing the temperature from 20°C to 37°C led to concentration, it was not possible to differentiate be- an increase in affinity. Bmax was similar, whether the tween rac-bupivacaine and levobupivacaine. Bmax, the experiment was performed at 20°C or at 37°C. Conversely, binding capacity, was different for the two emulsions, Kd was significantly lower at 37°C than at 20°C, but the but similar for the three drugs in each emulsion group decrease was significantly higher with bupivacaine (rac-bupiv- (table 2). Conversely, Kd, the dissociation constant, was acaine or levobupivacaine) than ropivacaine (table 2) (fig. 3). different between drugs (bupivacaine vs. ropivacaine) Since binding was linear in the range 0.5–2%, and but similar for the same drug between the Medialipide because a preliminary study done with the 10% Medi-

Table 2. Binding of Levobupivacaine, Racemic Bupivacaine, and Ropivacaine to Medialipide or Intralipid

Bmax (␮M)Kd(␮M)

Medialipide* Intralipid† Rac-bupivacaine/Levobupivacaine Ropivacaine

871 2,200 818 2,120 Bias 7 0 3 70 95% CI 781–955 2,030–2,370 724–916 1,860–2,340 Effect of temperature 20 °C 855 2,130 915 2,060 Bias Ϫ10 Ϫ18 17 54 95% CI 822–894 1,970–2,280 682–1,020 1,820–2,290 37 °C 855 2,130 665 936 Bias Ϫ10 Ϫ18 9 18 95% CI 822–894 1,970–2,280 496–765 745–1,110 Effect of pH§ pH 7.40 860‡ 765 1,780 Bias 0 Ϫ39 Ϫ140 95% CI 855–869 696–946 1700–2249 pH 7.00 Kd is increased by 1.68 (bias 0.02, 95% CI 1.67–1.75)

All parameters are for the 1% emulsion. Parameters are the estimates of the structural parameters obtained by fitting the original data set. Bmax is the binding capacity (reported for an arbitrary concentration of 1 % Medialipide or Intralipid). Kd is the dissociation constant. Bias is the bias of fitting calculated as the difference between the value obtained by fitting the original data set and the median value of the 1,000 bootstrap replicates. 95% CI is the 95% confidence interval of the parameter obtained by the bootstrap. * B-Braun; Boulogne, France. † Fresenius Kabi; Paris, France. ‡ The random effect was not significant. § The effect of pH was measured only for the Medialipide emulsion.

Anesthesiology, V 110, No 2, Feb 2009 384 MAZOIT ET AL.

Fig. 3. Binding of racemic bupivacaine (circles) and ropivacaine (triangles)to Intralipid 1% (Fresenius Kabi; Paris, France) at 20°C (dark ﬁlled symbols) and at 37°C (light ﬁlled symbols). Downloaded from http://pubs.asahq.org/anesthesiology/article-pdf/110/2/380/491208/0000542-200902000-00030.pdf by guest on 25 September 2021

alipide emulsion had given approximate distribution co- potential to a point where flocculation begins.18 How- efficients and parameters of binding similar to those ever, this may also occur in vivo. Mixing time was measured with the low concentrated emulsions, we may limited to 20 min to reduce this phenomenon. A mea- speculate that the binding capacity is approximately 17 sure of binding according to the duration of shaking mM for the 20% Medialipide emulsion and 44 mM for the showed that steady state was attained after 1–3 min 20% Intralipid® emulsion. (fig. 1). This expected rapid binding process demon- strates that in clinical situations, an infusion of the emulsion may rapidly trap the circulating anesthetic Discussion molecules. The main finding of the study was that the two lipid We calculated the distribution coefficient as the ratio emulsions were capable of binding each of the three of molar concentration in the two solvents, but also as local anesthetics tested in vitro. However, no stereospe- the ratio of the mole fraction:1lofwater contains Ϸ55.6 cific difference between the two enantiomers of bupiv- moles, whereas1lofthelipid fraction of Intralipid and acaine was observed. Bupivacaine was more bound than Medialipide contains Ϸ4.19 and Ϸ4.61 moles of the ropivacaine and the difference was in close relation to mixture of phospholipids, lecithins, and glycerol, re- the octanol/water distribution coefficient of each LA. spectively; similarly, 1 l octanol contains Ϸ7.68 moles. The binding capacity of Intralipid was 2–3 times greater Calculated in this way, the classic octanol/buffer distri- than that of Medialipide. bution coefficient of ropivacaine (5 mM) and of bupiva- Lipid emulsions were diluted in an ionic buffer to caine (1 mM) at 25°C is then approximately 1,000 and accurately measure the concentration of LAs in the aque- 3,000 for ropivacaine and bupivacaine, respectively;22 ous phase. Indeed, dilution in buffer is known to modify similar to the distribution coefficient of ropivacaine and the physicochemical properties of the lipid emulsion, of bupivacaine in Intralipid at 20°C (approximately but these conditions were close to those encountered in 1,200 and 2,000, respectively) (table 1). The ratio of the the clinical situation, where dilution of the emulsion mole fraction at saturation calculated from the one-site occurs rapidly in the blood stream. Both emulsions are binding model was Ϸ3 for the Intralipid emulsion and made of chylomicron-like particles. The volume of dis- Ϸ1 for the Medialipide emulsion. However, there is a tribution of chylomicrons has been shown to be slightly large confidence interval of the estimated capacity, and greater than the plasma volume (Ϸ4,500 ml), with a these numbers need to be interpreted with care. half-life between 5 and 7 min.21 The concentration of The drugs distribute more in Intralipid than in Medi- intact droplets in plasma during a rapid infusion of lipid alipide. For both drugs, the distribution ratio is 2.4–3.0 emulsion is then expected not to exceed 1%, even if greater in Intralipid than in Medialipide, suggesting that large amounts are infused. The stability of the chylomi- Intralipid might be preferable to Medialipide in a clinical cron-like droplets depends on their surface charge. The situation. Also, bupivacaine distributes 2.0–2.6 times zeta potential (the zeta potential, which stabilizes the more than ropivacaine in Intralipid and in Medialipide. emulsion, is the potential surrounding the droplet at its This is close to the distribution ratio of 3 of both drugs interface with the solvent) of both Intralipid and Medi- in octanol.22 Then, the clearance of the drug exerted by alipide is between -50 and -45 mV, and the use of ionic infusion of a lipid emulsion is expected to be lower for buffer to dilute the emulsion may have increased the ropivacaine than for bupivacaine.

Anesthesiology, V 110, No 2, Feb 2009 LOCAL ANESTHETIC BINDING TO LIPID EMULSIONS 385

At concentrations greater than 400 ␮M, saturation be- amines bupivacaine and ropivacaine increases. In addi- comes significant and a one-site binding model ade- tion to the difference in phospholipid composition, the quately fitted the data. Interestingly, the binding capac- two emulsions differ also by the size of the droplets,** ity of the emulsion was similar for bupivacaine and which may possibly explain the difference in capacity. ropivacaine, but about 2.5 times greater with Intralipid However, the marked decrease in affinity when ioniza- than with Medialipide. This ratio is similar to the distri- tion increases, together with the temperature-depen- bution ratio calculated at lower concentrations. The af- dence of binding and the close relationship between finity of the emulsion for the drug (1/Kd) was compara- affinity and hydrophobicity of the molecules, tends to ble for both emulsions, but about 2.6 times greater for favor the hypothesis of a predominant hydrophobic bupivacaine than for ropivacaine. Like the distribution uptake.

ratio calculated at lower concentrations, this ratio of In conclusion, the solubility of long-acting LAs in lipid Downloaded from http://pubs.asahq.org/anesthesiology/article-pdf/110/2/380/491208/0000542-200902000-00030.pdf by guest on 25 September 2021 affinity is not very different from the ratio of 3 (bupiva- emulsions and the high capacity of binding presented by caine/ropivacaine) observed for the distribution in octa- these emulsions most probably explain the clinical efficacy nol.22 In serum, bupivacaine binds to apha-1 acid glyco- presented by a rapid infusion in case of LA toxicity. The protein and to albumin. The affinity of bupivacaine to long-chain triglyceride emulsion Intralipid appears to be apha-1 acid glycoprotein is very high (Kd ϭ 1.62–3.69 about 2.5 times more efficacious than the 50/50 medium- ␮M), depending on experimental conditions and the en- chain/long-chain Medialipide emulsion. Also, because of antiomer considered.22–24 The affinity of ropivacaine to their higher hydrophobicity, rac-bupivacaine and levobupi- apha-1 acid glycoprotein is similar to that of bupivacaine vacaine seem to be more rapidly cleared than ropivacaine. 25 (Kd ϭ 2.78 ␮M). However, because apha-1 acid glyco- Acidosis likely lowers the binding capacity of the emul- protein is not very abundant in the human plasma (Ϸ20 sions, and this fact needs to be kept in mind. Intoxication 23–25 with other drugs might also be effectively treated if their ␮M), the capacity is low (42–45 ␮M). Conversely, lipid solubility is in the same range of values, but further serum albumin is abundant in plasma (Ϸ640 ␮M), and its studies are needed to ascertain this potential. capacity to bind bupivacaine is large (898–1510 ␮M), but the affinity of bupivacaine for albumin is relatively low 23,24 (Kd ϭ 680–1200 ␮M). The affinity of bupivacaine References and ropivacaine to Intralipid and Medialipide is close to 1. 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Ludot H, Tharin JY, Belouadah M, Mazoit JX, Malinovsky JM: Successful to 12 l of serum. resuscitation after ropivacaine and lidocaine-induced ventricular arrhythmia fol- Increasing the temperature from 20 to 37°C led to an lowing posterior lumbar plexus block in a child. Anesth Analg 2008; 106:1572–4 5. Warren JA, Thoma RB, Georgescu A, Shah SJ: Intravenous lipid infusion in important increase in affinity and thermal energy (diffu- the successful resuscitation of local anesthetic-induced cardiovascular collapse sion) seems to drive the uptake. The capacity of both after supraclavicular brachial plexus block. Anesth Analg 2008; 106:1578–80 6. Weinberg GL, VadeBoncouer T, Ramaraju GA, Garcia-Amaro MF, Cwik MJ: emulsions remained unchanged (tables 1 and 2). In this Pretreatment or resuscitation with a lipid infusion shifts the dose-response to case, the decrease in Kd (increase in affinity) was signif- bupivacaine-induced asystole in rats. ANESTHESIOLOGY 1998; 88:1071–5 7. Weinberg GL, Di Gregorio G, Ripper R, Kelly K, Massad M, Edelman L, icantly greater for ropivacaine (55%) than for bupiva- Schwartz D, Shah N, Zheng S, Feinstein DL: Resuscitation with lipid versus caine (27%). Both emulsions have a similar negatively epinephrine in a rat model of bupivacaine overdose. ANESTHESIOLOGY 2008; 108: 907–13 charged double-layer interface (the zeta potential is be- 8. Rosenblatt MA, Abel M, Fischer GW, Itzkovich CJ, Eisenkraft JB: Successful tween -45 and -50 mV at pH 7.40). Then, part of the use of a 20% lipid emulsion to resuscitate a patient after a presumed bupivacaine- related cardiac arrest. ANESTHESIOLOGY 2006; 105:217–8 adsorption process of the positively charged tertiary 9. Litz RJ, Popp M, Stehr SN, Koch T: Successful resuscitation of a patient with ropivacaine-induced asystole after axillary plexus block using lipid infusion. amines may also occur at the shear plane that surrounds Anaesthesia 2006; 61:800–1 the droplets. When the pH of the buffer was decreased 10. Weinberg GL, Ripper R, Murphy P, Edelman LB, Hoffman W, Strichartz G, Feinstein DL: Lipid infusion accelerates removal of bupivacaine and recovery from 7.40 to 7.00, the capacity remained also un- from bupivacaine toxicity in the isolated rat heart. Reg Anesth Pain Med 2006; changed, but the affinity decreased by a factor of 1.68, 31:296–303 11. Sirianni AJ, Osterhoudt KC, Calello DP, Muller AA, Waterhouse MR, Goodkin similar for both anesthetics. Indeed, when the pH of the MB, Weinberg GL, Henretig FM: Use of lipid emulsion in the resuscitation of a patient buffer decreases, the zeta potential increases (the drop- with prolonged cardiovascular collapse after overdose of bupropion and lamotrigine. Ann Emerg Med 2008; 51:412–5 lets are less charged), but ionization of the tertiary 12. Tebbutt S, Harvey M, Nicholson T, Cave G: Intralipid prolongs survival in a rat model of verapamil toxicity. Acad Emerg Med 2006; 13:134–9 13. Cave G, Harvey MG, Castle CD: The role of fat emulsion therapy in a ** Wabel C. Influence of Lecithin on Structure and Stability of Parenteral Fat rodent model of propranolol toxicity: A preliminary study. J Med Toxicol 2006; Emulsions. Ph D dissertation. 07 1998. Friedrich-Alexander-Universita¨t Erlangen- 2:4–7 Nu¨rnberg. (at http://www2.chemie.uni-erlangen.de/services/dissonline/data/ 14. Harvey M, Cave G: Intralipid outperforms sodium bicarbonate in a rabbit dissertation/Christoph_Wabel/html/ accessed 10/23/2008). model of clomipramine toxicity. Ann Emerg Med 2007; 49:178–85

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Beta-Eucaine Bottle

While searching for antiques in Lahaska, Pennsylvania, near the artists’ colony of New Hope, Mrs. Ramona Bause happened upon this early bottle of Beta-Eucaine. An early synthetic substitute for cocaine as a local or topical anesthetic, beta-eucaine was much less irritating than alpha-eucaine for dental, ophthalmic, or urethral procedures. After both alpha- and beta-formulations were listed alongside opium, cocaine, and heroin in the Pure Food and Drug Act of 1906, both eucaines fell out of favor. Their popularity declined even further with the synthesis of less toxic local anesthetics, such as procaine (Novocain௡). (Copyright © the American Society of Anesthesiologists, Inc. This image appears in the Anesthesiology Reﬂec- tions online collection available at www.anesthesiology.org.) George S. Bause, M.D., M.P.H., Honorary Curator, ASA’s Wood Library-Museum of Anesthe- siology, Park Ridge, Illinois, and Clinical Associate Professor, Case Western Reserve Univer- sity, Cleveland, Ohio. [email protected].

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