Treatment of Local Anesthetic Induced Cardiotoxicity

Treatment of Local AnestheticInduced Cardiotoxicity Using Drug Scavenging Nanoparticles Journal Club Presentation Sept. 2006 Kelly Shinkaruk Morey et al Basic science research paper Undertaken to determine the ability of emulsion based nanoparticles to remove Bupivicaine molecules from various solutions and compared to a standardized macroemulsion The hypothesis was that nanoparticles would more effectively partition local anesthetics than would a macroemulsion Morey et al Initially, a nanoparticle emulsion was synthesized as described in a previous paper (von Corswant, C; Thoren, P; Engstrom, S. J. Pharm Sci. 1998, 88, 1071) Intralipid, a commercially available macroemulsion (Baxter) derived from soybean phosphatidylcholine was obtained for use as the control lipid emulsion The particle population diameter densities were analyzed using a submicron particle size analyzer Morey et al The mean diameters of the nano- and macroemulsions were compared using a three parameter Gaussian distribution equation Each emulsion was found to be normally distributed and significantly different Morey et al There are three parts in this particular experiment The initial part was used to determine several binding parameters of nanoemulsion or macroemulsion for bupivacaine The second part then went on to analyze the extraction of bupivacaine from human blood samples Finally, the last part looked at the extent to which the nanoemulsion attenuated the cardiotoxicity bupivacaine caused in guinea pig heart Extraction of Bupivacaine in PBS Bupivacaine was spiked into PBS solution (the composition of which is defined in the article) and samples containing three concentrations were made Then the nanoemulsion and macroemulsions were added to the samples, allowed to equilibrate and then the emulsions were removed by ultrafiltration Finally, the amount of bupivacaine sequestered by each emulsion was analyzed and the nanoemulsion was found to have sequestered a greater fraction of bupivacaine Attenuation of Cardiotoxicity in Guinea Pig Heart Using guinea pig hearts, the QRS interval was measured as a representation of the summation of all sodium ionic currents in the ventricles An n=5 for each of the nanoemulsion and macroemulsion groups was used Bupivacaine was noted to increase the QRS interval for both groups of hearts Attenuation (cont) Treatment of the intoxicated hearts with the emulsions was found to significantly reduce the QRS interval The effect of the nanoemulsion was significantly greater and more rapid In fact, the difference between the two sets of emulsions was greater than expected based on the initial experiments Extraction of Bupivicaine from Human Blood In this part, bupivacaine was spiked into blood samples Once equilibration was attained, the plasma was separated from the cells and was centrifuged to obtain a protein/particle free supernatant The extraction of bupivacaine was analyzed and found to be extracted to a greater extent based on increasing concentrations of nanoemulsion Critical Analysis The author clearly defines a research problem and explains its significance with regards to the practice of medicine The author addresses core issues and variables; furthermore, he defines specialized terminology An small but adequate literature review is included and past research into the field of nanotechnology is sited Critical Analysis (2) A clear hypothesis is stated: “We hypothesize that smaller emulsion particles (ie: nanoemulsions) will even more effectively partition local anesthetics from an aqueous environment into the lipid core or onto the surface interface.” Critical Analysis - Methodology Methodology is outlined in each of the three parts of the study No limitations are noted by the author All solutions/samples used are outlined and the method in which guinea pig hearts are obtained is noted as a reference all instruments used in the study are adequately described The methods for measuring the results are clearly outlined and easy to understand Critical Analysis - Results The results for each part of the study are clearly presented though graphs were only given for the third part The research objectives are addressed The graphs utilized are easy to decipher and clearly demonstrate the differences between nano and macroemulsions Critical Analysis - Discussion The discussion does not appear under its own heading thereby making it difficult to localize in the text The results do, in fact, validate the author’s hypothesis Only one local anesthetic was tested in this study and the author clearly identifies that this is a limitation but indicates that further research should be undertaken Critical Analysis – Discussion The author suggests that this research could be further applied to include nanoemulsions for the detoxification of other classes of drugs The author does not suggest that this research should alter current practice Critical Analysis – Personal Perspectives I believe that this research is very applicable in this age of increasing use of regional anesthetic techniques The research is relevant and touches on a field that is in its infancy but promises to revolutionize the way in which medical professionals deal with drug overdose Critical Analysis – Personal Perspectives As this study was basic science oriented, it provides an excellent background for further research ultimately leading to clinical trials The difficulty is that clinical trials will be unethical to undertake in RCT in true overdose situations therefore, inevitably, the use of nanoparticles in acute overdose situations will rely on anecdotal evidence Critical Analysis – Personal Perspectives In conclusion, I feel that this research is incredibly relevant and, given the significant mortality associated with bupivicaine toxicity, it would be reasonable to administer a nanoemulsion in acute situations