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Lipid Emulsion Therapy in Lipophilic Drug Toxicity
CORRESPONDENCE
Guidelines for Letters to the Editor Annals welcomes letters to the editor, including observations, opinions, corrections, very brief reports, and comments on published articles. Letters to the editor should not exceed 500 words and 5 references. They should be submitted using Annals’ Web-based peer review system, Editorial Manager™ (http://www. editorialmanager.com/annemergmed). Annals no longer accepts submissions by mail. Letters should not contain abbreviations. A Manuscript Submission Agreement (MSA), signed by all authors, must be faxed to the Annals office at the time of submission. Financial association or other possible conflicts of interest should always be disclosed, as documented on the MSA, and their presence or absence will be published with the correspondence. Letters discussing an Annals article must be received within 8 weeks of the article’s publication. Published letters will be edited and may be shortened. Authors of articles for which comments are received will be given the opportunity to reply. If those authors wish to respond, their reply will not be shared with the author of the letter before publication. Neither Annals of Emergency Medicine nor the Publisher accepts responsibility for statements made by contributors or advertisers.
0196-0644/$-see front matter Copyright © 2008 by the American College of Emergency Physicians.
Lipid Emulsion Therapy in Lipophilic Drug Toxicity To the Editor: We wish to congratulate Sirianni et al on their case publication “Use of Lipid Emulsion in the Resuscitation of a Patient With Prolonged Cardiovascular Collapse After Overdose of Bupropion and Lamotrigine.”1 This represents a major step in the evolution of lipid emulsion as antidotal therapy in lipid-soluble drug cardiotoxicity, and is the first to demonstrate effect in an enteric overdose of lipid soluble drug. Application of lipid infusion in local anesthetic-induced cardiotoxicity follows pioneering work by Weinberg and others demonstrating efficacy in animal models,2 and subsequently successful case publications.3 Re-establishment of new plasma equibrilium favoring sequestration of lipophilic drugs into a newly created intravascular compartment is the currently proposed mechanism of action. We have additionally demonstrated efficacy for lipid infusion in animal models of clomipramine4 and verapamil5 toxicity, suggesting potential benefit in deliberate overdose from these lipid soluble agents. Guidelines advocating lipid emulsion as therapy for local anesthetic cardiotoxocity have recently been published by The Association of Anaesthetists of Great Britain and Ireland.6 We would endeavor to contribute to the “bringing over” of lipid therapy for lipophilic drug toxidromes from the anesthetic domain to the general toxicologic domain wherein we believe the greatest benefit is likely to be manifest. The use of lipid emulsion as antidote should, however, progress with some caution. Enthusiasm and imprudence are Volume , . : April
common bedfellows in the commendation and application of novel medical therapies. The special setting encountered by Sirianni et al, that of refractory arrest despite all conventional therapy, is one where use of lipid emulsion is rational. The only potential alteration to outcome is benefit. Indiscriminate application of this therapy at the expense of validated antidotal therapies is unwarranted at this point. We would echo the call of the anesthetic literature for the use of lipid emulsion in the setting of lipophilic drug cardiotoxicity where death is adjudged inevitable despite all available alternative therapies. Finally, as the nature and presentation of life-threatening lipophilic drug intoxication renders systemic human study impractical, animal modelling and case publication are likely to represent the avenues by which lipid therapy may advance. It is therefore the responsibility of individual clinicians to disseminate their experience with lipid therapy, both successes and otherwise. Moreover we would implore editors to publish such case reports both positive and negative. In time a major new therapy may be available to severely intoxicated patients. Grant Cave, BHB, MBChB Emergency Medical Systems Australia Melbourne Victoria, Australia Martyn Harvey, BHB, MBChB Department of Emergency Medicine Waikato Hospital Hamilton, New Zealand doi:10.1016/j.annemergmed.2007.10.014
Annals of Emergency Medicine 449
Correspondence Funding and support: By Annals policy, all authors are required to disclose any and all commercial, financial, and other relationships in any way related to the subject of this article, that might create any potential conflict of interest. The authors have stated that no such relationships exist. See the Manuscript Submission Agreement in this issue for examples of specific conflicts covered by this statement. 1. Henretig et al. Use of lipid emulsion in the resuscitation of a patient with prolonged cardiovascular collapse after overdose of bupropion and lamotrigine. Ann Emerg Med. 2008;51:412-415. 2. Weinberg G, Ripper R, Feinstein D, et al. Lipid emulsion infusion rescues dogs from bupivacaine induced cardiac toxicity. Reg Anesth Pain Med. 2003;28:198-202. 3. Rosenblatt M, Abel M, Fischer G, et al. Successful use of a 20% lipid emulsion to resuscitate a patient after presumed bupivacaine related cardiac arrest. Anaesthesia. 2006;105:217-218. 4. Harvey M, Cave G. Intralipid outperfroms sodium bicarbonate in a rabbit model of clomipramine toxicity. Ann Emerg Med. 2007;49: 178-185. 5. Tebbutt S, Harvey M, Nicholson T, et al. Intralipid prolongs survival in a rat model of verapamil toxicity. Acad Emerg Med. 2006;13: 134-139. 6. The Association of Anaesthetists of Great Britain and Ireland. Guidelines for the management of severe local anaesthetic toxicity. The Association of Anaesthetists of Great Britain and Ireland Website. Available at http://www.aagbi.org/ publications/guidelines/docs/latoxicity07.pdf. Accessed October 2, 2007.
In reply: We thank Drs. Harvey and Cave for their positive comments regarding our case report. We recognize their important contributions to this nascent field and agree that use of lipid infusion therapy in the emergency management of appropriate intoxications has significant potential to yield more positive outcomes in the future. We also agree that continued reporting of such cases, whether successful or not, is necessary given that each event is unique and helps to further inform our general understanding of the method. When publication in a peer-reviewed journal is not possible, physicians can post their cases at the educational Web site, www.lipidrescue.org, where there is a forum to vent and discuss their experiences. In the meantime, we believe further basic research into the mechanism of lipid infusion therapy is needed to optimize the method and better understand the scope and limits to its clinical use. Finally, we would like to convey that primary credit for the patient’s remarkable recovery goes to our first author, Dr. Archie Sirianni, an anesthesiologist at Riddle Memorial Hospital in Media, PA. Dr. Sirianni was called to assist the resuscitation team in airway support, and after doing so, personally consulted Philadelphia’s regional poison control center, conveyed its advice to consider sodium bicarbonate as an antidotal therapy for bupropion’s sodium channelblocking properties, and then, as the patient remained refractory to advanced life support, made the novel, intellectual leap of considering lipid infusion in this setting. 450 Annals of Emergency Medicine
In addition, we recognize the staff of the pediatric intensive care unit at Children’s Hospital of Philadelphia, whose dedication to the patient’s post-resuscitation care made her recovery a reality. Guy L. Weinberg, MD Department of Anesthesiology University of Illinois College of Medicine at Chicago Jessie Brown VA Medical Center Chicago, IL Fred M. Henretig, MD Department of Pediatrics University of Pennsylvania School of Medicine Division of Emergency Medicine Children’s Hospital of Philadelphia Philadelphia, PA doi:10.1016/j.annemergmed.2007.10.015
Funding and support: By Annals policy, all authors are required to disclose any and all commercial, financial, and other relationships in any way related to the subject of this article, that might create any potential conflict of interest. See the Manuscript Submission Agreement in this issue for examples of specific conflicts covered by this statement. Since acceptance of the paper, GW was awarded US patent 7,261,903 B1, “Lipid emulsion in the treatment of systemic poisoning.” GW has no equity interest or financial agreements with any company or commercial entity related to this method and has never received salary or support from any company related to the method. GW does not intend to prohibit or restrict the practice of this method on any patient.
Speaking in Plain Language To the Editor: As a member of my institution’s internal review board (IRB) responsible for reviewing research proposals, I find that there is a constant need to “dummy down” the verbiage found on project consent forms in order to increase their clarity and comprehension. Our IRB strives for the use of plain, everyday language whenever possible, at an 8th grade readability level, where the average adult comprehends at the 6-8th grade level.1 When working a busy emergency department shift, I may sometimes fail to obtain a “written” informed consent for a minor procedure or test, and unfortunately, I know that I am not alone in this practice pattern. Regardless, no matter how trivial a procedure may seem, I always make sure to discuss with the patient (or their proxy) what to expect, giving them the opportunity to have their questions answered, as part of a “verbal” informed consent process. In the “Patient Communication” section of the evidencebased emergency medicine review article entitled “Prevention of Contrast-Induced Nephropathy in the Emergency Department” Volume , . : April
Guidelines for Letters to the Editor Annals welcomes letters to the editor, including observations, opinions, corrections, very brief reports, and comments on published articles. Letters to the editor should not exceed 500 words and 5 references. They should be submitted using Annals’ Web-based peer review system, Editorial Manager™ (http://www. editorialmanager.com/annemergmed). Annals no longer accepts submissions by mail. Letters should not contain abbreviations. A Manuscript Submission Agreement (MSA), signed by all authors, must be faxed to the Annals office at the time of submission. Financial association or other possible conflicts of interest should always be disclosed, as documented on the MSA, and their presence or absence will be published with the correspondence. Letters discussing an Annals article must be received within 8 weeks of the article’s publication. Published letters will be edited and may be shortened. Authors of articles for which comments are received will be given the opportunity to reply. If those authors wish to respond, their reply will not be shared with the author of the letter before publication. Neither Annals of Emergency Medicine nor the Publisher accepts responsibility for statements made by contributors or advertisers.
0196-0644/$-see front matter Copyright © 2008 by the American College of Emergency Physicians.
Lipid Emulsion Therapy in Lipophilic Drug Toxicity To the Editor: We wish to congratulate Sirianni et al on their case publication “Use of Lipid Emulsion in the Resuscitation of a Patient With Prolonged Cardiovascular Collapse After Overdose of Bupropion and Lamotrigine.”1 This represents a major step in the evolution of lipid emulsion as antidotal therapy in lipid-soluble drug cardiotoxicity, and is the first to demonstrate effect in an enteric overdose of lipid soluble drug. Application of lipid infusion in local anesthetic-induced cardiotoxicity follows pioneering work by Weinberg and others demonstrating efficacy in animal models,2 and subsequently successful case publications.3 Re-establishment of new plasma equibrilium favoring sequestration of lipophilic drugs into a newly created intravascular compartment is the currently proposed mechanism of action. We have additionally demonstrated efficacy for lipid infusion in animal models of clomipramine4 and verapamil5 toxicity, suggesting potential benefit in deliberate overdose from these lipid soluble agents. Guidelines advocating lipid emulsion as therapy for local anesthetic cardiotoxocity have recently been published by The Association of Anaesthetists of Great Britain and Ireland.6 We would endeavor to contribute to the “bringing over” of lipid therapy for lipophilic drug toxidromes from the anesthetic domain to the general toxicologic domain wherein we believe the greatest benefit is likely to be manifest. The use of lipid emulsion as antidote should, however, progress with some caution. Enthusiasm and imprudence are Volume , . : April
common bedfellows in the commendation and application of novel medical therapies. The special setting encountered by Sirianni et al, that of refractory arrest despite all conventional therapy, is one where use of lipid emulsion is rational. The only potential alteration to outcome is benefit. Indiscriminate application of this therapy at the expense of validated antidotal therapies is unwarranted at this point. We would echo the call of the anesthetic literature for the use of lipid emulsion in the setting of lipophilic drug cardiotoxicity where death is adjudged inevitable despite all available alternative therapies. Finally, as the nature and presentation of life-threatening lipophilic drug intoxication renders systemic human study impractical, animal modelling and case publication are likely to represent the avenues by which lipid therapy may advance. It is therefore the responsibility of individual clinicians to disseminate their experience with lipid therapy, both successes and otherwise. Moreover we would implore editors to publish such case reports both positive and negative. In time a major new therapy may be available to severely intoxicated patients. Grant Cave, BHB, MBChB Emergency Medical Systems Australia Melbourne Victoria, Australia Martyn Harvey, BHB, MBChB Department of Emergency Medicine Waikato Hospital Hamilton, New Zealand doi:10.1016/j.annemergmed.2007.10.014
Annals of Emergency Medicine 449
Correspondence Funding and support: By Annals policy, all authors are required to disclose any and all commercial, financial, and other relationships in any way related to the subject of this article, that might create any potential conflict of interest. The authors have stated that no such relationships exist. See the Manuscript Submission Agreement in this issue for examples of specific conflicts covered by this statement. 1. Henretig et al. Use of lipid emulsion in the resuscitation of a patient with prolonged cardiovascular collapse after overdose of bupropion and lamotrigine. Ann Emerg Med. 2008;51:412-415. 2. Weinberg G, Ripper R, Feinstein D, et al. Lipid emulsion infusion rescues dogs from bupivacaine induced cardiac toxicity. Reg Anesth Pain Med. 2003;28:198-202. 3. Rosenblatt M, Abel M, Fischer G, et al. Successful use of a 20% lipid emulsion to resuscitate a patient after presumed bupivacaine related cardiac arrest. Anaesthesia. 2006;105:217-218. 4. Harvey M, Cave G. Intralipid outperfroms sodium bicarbonate in a rabbit model of clomipramine toxicity. Ann Emerg Med. 2007;49: 178-185. 5. Tebbutt S, Harvey M, Nicholson T, et al. Intralipid prolongs survival in a rat model of verapamil toxicity. Acad Emerg Med. 2006;13: 134-139. 6. The Association of Anaesthetists of Great Britain and Ireland. Guidelines for the management of severe local anaesthetic toxicity. The Association of Anaesthetists of Great Britain and Ireland Website. Available at http://www.aagbi.org/ publications/guidelines/docs/latoxicity07.pdf. Accessed October 2, 2007.
In reply: We thank Drs. Harvey and Cave for their positive comments regarding our case report. We recognize their important contributions to this nascent field and agree that use of lipid infusion therapy in the emergency management of appropriate intoxications has significant potential to yield more positive outcomes in the future. We also agree that continued reporting of such cases, whether successful or not, is necessary given that each event is unique and helps to further inform our general understanding of the method. When publication in a peer-reviewed journal is not possible, physicians can post their cases at the educational Web site, www.lipidrescue.org, where there is a forum to vent and discuss their experiences. In the meantime, we believe further basic research into the mechanism of lipid infusion therapy is needed to optimize the method and better understand the scope and limits to its clinical use. Finally, we would like to convey that primary credit for the patient’s remarkable recovery goes to our first author, Dr. Archie Sirianni, an anesthesiologist at Riddle Memorial Hospital in Media, PA. Dr. Sirianni was called to assist the resuscitation team in airway support, and after doing so, personally consulted Philadelphia’s regional poison control center, conveyed its advice to consider sodium bicarbonate as an antidotal therapy for bupropion’s sodium channelblocking properties, and then, as the patient remained refractory to advanced life support, made the novel, intellectual leap of considering lipid infusion in this setting. 450 Annals of Emergency Medicine
In addition, we recognize the staff of the pediatric intensive care unit at Children’s Hospital of Philadelphia, whose dedication to the patient’s post-resuscitation care made her recovery a reality. Guy L. Weinberg, MD Department of Anesthesiology University of Illinois College of Medicine at Chicago Jessie Brown VA Medical Center Chicago, IL Fred M. Henretig, MD Department of Pediatrics University of Pennsylvania School of Medicine Division of Emergency Medicine Children’s Hospital of Philadelphia Philadelphia, PA doi:10.1016/j.annemergmed.2007.10.015
Funding and support: By Annals policy, all authors are required to disclose any and all commercial, financial, and other relationships in any way related to the subject of this article, that might create any potential conflict of interest. See the Manuscript Submission Agreement in this issue for examples of specific conflicts covered by this statement. Since acceptance of the paper, GW was awarded US patent 7,261,903 B1, “Lipid emulsion in the treatment of systemic poisoning.” GW has no equity interest or financial agreements with any company or commercial entity related to this method and has never received salary or support from any company related to the method. GW does not intend to prohibit or restrict the practice of this method on any patient.
Speaking in Plain Language To the Editor: As a member of my institution’s internal review board (IRB) responsible for reviewing research proposals, I find that there is a constant need to “dummy down” the verbiage found on project consent forms in order to increase their clarity and comprehension. Our IRB strives for the use of plain, everyday language whenever possible, at an 8th grade readability level, where the average adult comprehends at the 6-8th grade level.1 When working a busy emergency department shift, I may sometimes fail to obtain a “written” informed consent for a minor procedure or test, and unfortunately, I know that I am not alone in this practice pattern. Regardless, no matter how trivial a procedure may seem, I always make sure to discuss with the patient (or their proxy) what to expect, giving them the opportunity to have their questions answered, as part of a “verbal” informed consent process. In the “Patient Communication” section of the evidencebased emergency medicine review article entitled “Prevention of Contrast-Induced Nephropathy in the Emergency Department” Volume , . : April