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Lu B, Wei L, Shi G, Du J. Nanotherapeutics for Alleviating Anesthesia-Associated Complications. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2024; 11:e2308241. [PMID: 38342603 PMCID: PMC11022745 DOI: 10.1002/advs.202308241] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/30/2023] [Revised: 12/22/2023] [Indexed: 02/13/2024]
Abstract
Current management of anesthesia-associated complications falls short in terms of both efficacy and safety. Nanomaterials with versatile properties and unique nano-bio interactions hold substantial promise as therapeutics for addressing these complications. This review conducts a thorough examination of the existing nanotherapeutics and highlights the strategies for developing prospective nanomedicines to mitigate anesthetics-related toxicity. Initially, general, regional, and local anesthesia along with the commonly used anesthetics and related prevalent side effects are introduced. Furthermore, employing nanotechnology to prevent and alleviate the complications of anesthetics is systematically demonstrated from three aspects, that is, developing 1) safe nano-formulization for anesthetics; 2) nano-antidotes to sequester overdosed anesthetics and alter their pharmacokinetics; 3) nanomedicines with pharmacodynamic activities to treat anesthetics toxicity. Finally, the prospects and challenges facing the clinical translation of nanotherapeutics for anesthesia-related complications are discussed. This work provides a comprehensive roadmap for developing effective nanotherapeutics to prevent and mitigate anesthesia-associated toxicity, which can potentially revolutionize the management of anesthesia complications.
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Affiliation(s)
- Bin Lu
- Department of AnesthesiologyThird Hospital of Shanxi Medical UniversityShanxi Bethune HospitalShanxi Academy of Medical SciencesTongji Shanxi HospitalTaiyuan030032China
- Key Laboratory of Cellular Physiology at Shanxi Medical UniversityMinistry of EducationTaiyuanShanxi Province030001China
| | - Ling Wei
- Shanxi Bethune Hospital Center Surgery DepartmentShanxi Academy of Medical SciencesTongji Shanxi HospitalThird Hospital of Shanxi Medical UniversityTaiyuan030032China
| | - Gaoxiang Shi
- Department of AnesthesiologyThird Hospital of Shanxi Medical UniversityShanxi Bethune HospitalShanxi Academy of Medical SciencesTongji Shanxi HospitalTaiyuan030032China
| | - Jiangfeng Du
- Key Laboratory of Cellular Physiology at Shanxi Medical UniversityMinistry of EducationTaiyuanShanxi Province030001China
- Department of Medical ImagingShanxi Key Laboratory of Intelligent Imaging and NanomedicineFirst Hospital of Shanxi Medical UniversityTaiyuanShanxi Province030001China
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Wang L, Wang Y, Zhang RY, Wang Y, Liang W, Li TG. Management of acute carbamazepine poisoning: A narrative review. World J Psychiatry 2023; 13:816-830. [DOI: 10.5498/wjp.v13.i11.816] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/05/2023] [Revised: 09/23/2023] [Accepted: 10/11/2023] [Indexed: 11/17/2023] Open
Abstract
Standard management protocols are lacking and specific antidotes are unavailable for acute carbamazepine (CBZ) poisoning. The objective of this review is to provide currently available information on acute CBZ poisoning, including its management, by describing and summarizing various therapeutic methods for its treatment according to previously published studies. Several treatment methods for CBZ poisoning will be briefly introduced, their advantages and disadvantages will be analyzed and compared, and suggestions for the clinical treatment of CBZ poisoning will be provided. A literature search was performed in various English and Chinese databases. In addition, the reference lists of identified articles were screened for additional relevant studies, including non-indexed reports. Non-peer-reviewed sources were also included. In the present review, 154 articles met the inclusion criteria including case reports, case series, descriptive cohorts, pharmacokinetic studies, and in vitro studies. Data on 67 patients, including 4 fatalities, were reviewed. Based on the summary of cases reported in the included articles, the cure rate of CBZ poisoning after symptomatic treatment was 82% and the efficiency of hemoperfusion was 58.2%. Based on the literature review, CBZ is moderately dialyzable and the recommendation for CBZ poisoning is supportive management and gastric lavage. In severe cases, extracorporeal treatment is recommended, with hemodialysis as the first choice.
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Affiliation(s)
- Luan Wang
- Department of Emergency Medicine, Shengjing Hospital of China Medical University, Shenyang 110004, Liaoning Province, China
| | - Yang Wang
- Department of General Surgery, The 4th Affiliated Hospital of China Medical University, Shenyang 110032, Liaoning Province, China
| | - Ruo-Ying Zhang
- Department of Emergency Medicine, Shengjing Hospital of China Medical University, Shenyang 110004, Liaoning Province, China
| | - Yao Wang
- Department of Emergency Medicine, Shengjing Hospital of China Medical University, Shenyang 110004, Liaoning Province, China
| | - Wei Liang
- Department of Emergency Medicine, Shengjing Hospital of China Medical University, Shenyang 110004, Liaoning Province, China
| | - Tie-Gang Li
- Department of Emergency Medicine, Shengjing Hospital of China Medical University, Shenyang 110004, Liaoning Province, China
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Gerner P, Vlassakov K, Stone A. Lipid emulsion for reversal of acute cannabinoid toxicity? Reg Anesth Pain Med 2023; 48:532-533. [PMID: 36858481 DOI: 10.1136/rapm-2023-104429] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2023] [Accepted: 02/21/2023] [Indexed: 03/03/2023]
Affiliation(s)
- Philipp Gerner
- Department of Anesthesiology, Perioperative, and Pain Medicine, Brigham and Women's Hospital, Boston, Massachusetts, USA
| | - Kamen Vlassakov
- Department of Anesthesiology, Perioperative, and Pain Medicine, Brigham and Women's Hospital, Boston, Massachusetts, USA
| | - Alexander Stone
- Department of Anesthesiology, Perioperative, and Pain Medicine, Brigham and Women's Hospital, Boston, Massachusetts, USA
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Pashirova TN, Shaihutdinova ZM, Mironov VF, Masson P. Biomedical Nanosystems for In Vivo Detoxification: From Passive Delivery Systems to Functional Nanodevices and Nanorobots. Acta Naturae 2023; 15:4-12. [PMID: 37153510 PMCID: PMC10154777 DOI: 10.32607/actanaturae.15681] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2023] [Accepted: 03/21/2023] [Indexed: 05/09/2023] Open
Abstract
The problem of low efficiency of nanotherapeutic drugs challenges the creation of new alternative biomedical nanosystems known as robotic nanodevices. In addition to encapsulating properties, nanodevices can perform different biomedical functions, such as precision surgery, in vivo detection and imaging, biosensing, targeted delivery, and, more recently, detoxification of endogenous and xenobiotic compounds. Nanodevices for detoxification are aimed at removing toxic molecules from biological tissues, using a chemical- and/or enzyme-containing nanocarrier for the toxicant to diffuse inside the nanobody. This strategy is opposite to drug delivery systems that focus on encapsulating drugs and releasing them under the influence of external factors. The review describes various kinds of nanodevices intended for detoxification that differ by the type of poisoning treatment they provide, as well as the type of materials and toxicants. The final part of the review is devoted to enzyme nanosystems, an emerging area of research that provides fast and effective neutralization of toxins in vivo.
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Affiliation(s)
- T. N. Pashirova
- Arbuzov Institute of Organic and Physical Chemistry, FRC Kazan Scientific Center of RAS, Kazan, 420088 Russian Federation
| | - Z. M. Shaihutdinova
- Arbuzov Institute of Organic and Physical Chemistry, FRC Kazan Scientific Center of RAS, Kazan, 420088 Russian Federation
- Kazan (Volga Region) Federal University, Kazan, 420008 Russian Federation
| | - V. F. Mironov
- Arbuzov Institute of Organic and Physical Chemistry, FRC Kazan Scientific Center of RAS, Kazan, 420088 Russian Federation
| | - P. Masson
- Kazan (Volga Region) Federal University, Kazan, 420008 Russian Federation
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Tikhomirov M, Jajor P, Śniegocki T, Poźniak B. Predicting the efficacy of opioid sequestration by intravenous lipid emulsion using biologically relevant in vitro models of drug distribution. Sci Rep 2022; 12:18683. [PMID: 36333363 PMCID: PMC9636243 DOI: 10.1038/s41598-022-21790-4] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2022] [Accepted: 10/04/2022] [Indexed: 11/06/2022] Open
Abstract
Intravenous lipid emulsions (ILE), among other uses, are utilized in the treatment of poisonings caused by lipophilic substances. The body of evidence regarding the benefits of this treatment is growing but information about opioids-ILE interaction is still very scarce. In this work, the impact of ILE on the distribution of buprenorphine, fentanyl and butorphanol used in various concentrations (100-500 ng/ml) was investigated. Two different in vitro models were used: disposition of the drugs in plasma after ultracentrifugation and distribution into the simulated biophase (cell monolayer of 3T3 fibroblasts or J774.E macrophages). We confirmed the ability of ILE to sequester the three drugs of interest which results in their decrease in the aqueous part of the plasma by 34.2-38.2%, 11.7-28.5% and 6.0-15.5% for buprenorphine, fentanyl and butorphanol, respectively. Moreover, ILE affected the drug distribution to the biophase in vitro, however, in this case the drug concentration in cells decreased by 97.3 ± 3.1%, 28.6 ± 5.4% and 13.0 ± 7.5% for buprenorphine, fentanyl and butorphanol, respectively. The two models revealed notable differences in ILE's potential for drug sequestration, especially for buprenorphine. Similar, but not as pronounced tendencies were observed for the two other drugs. These discrepancies may result from the difference in protein abundance and resulting drug-protein binding in both systems. Nevertheless, the results obtained with both in vitro models correlated well with the partition coefficient (logP) values for these drugs.
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Affiliation(s)
- Marta Tikhomirov
- Faculty of Veterinary Medicine, Department of Pharmacology and Toxicology, Wroclaw University of Environmental and Life Sciences, 50-375, Wrocław, Poland
| | - Paweł Jajor
- Faculty of Veterinary Medicine, Department of Pharmacology and Toxicology, Wroclaw University of Environmental and Life Sciences, 50-375, Wrocław, Poland
| | - Tomasz Śniegocki
- Department of Pharmacology and Toxicology, National Veterinary Research Institute, 24-100, Puławy, Poland
| | - Błażej Poźniak
- Faculty of Veterinary Medicine, Department of Pharmacology and Toxicology, Wroclaw University of Environmental and Life Sciences, 50-375, Wrocław, Poland.
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Oung SW, Kremer N, Ben Amara S, Zaidi A, Koslowski T. Protonation and orientation: a computational approach to cocaine diffusion through a model membrane. Phys Chem Chem Phys 2022; 24:14219-14227. [DOI: 10.1039/d2cp01140a] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
We study the diffusion of cocaine through a DMPC lipid bilayer as an example of a protonable, amphiphilic molecule passing a biological membrane. Using classical molecular dynamics simulations, the free...
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Saasouh W, Nikam A, Hachwa B. Intravenous Lipid Emulsion for the Treatment of Perioperative Cocaine Intoxication. Cureus 2021; 13:e19146. [PMID: 34868781 PMCID: PMC8629685 DOI: 10.7759/cureus.19146] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/29/2021] [Indexed: 11/17/2022] Open
Abstract
Symptomatic cocaine intoxication in the preoperative period is a potentially life-threatening condition, especially before emergent surgery. The anesthesiologist is faced with a dilemma where the patient is deemed unsafe for induction of general anesthesia but also in need of immediate surgical intervention. Cocaine is a local anesthetic and, as such, has been proposed to respond to lipid emulsion treatment as other local anesthetics would. We present a case supporting this statement and review the relevant published literature on the topic.
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Affiliation(s)
- Wael Saasouh
- Anesthesiology, Detroit Medical Center, NorthStar Anesthesia, Detroit, USA
| | - Anuja Nikam
- Medicine, Michigan State University, Detroit, USA
| | - Bachar Hachwa
- Anesthesiology, Detroit Medical Center, NorthStar Anesthesia, Detroit, USA
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Paneta M, Waring WS. Literature review of the evidence regarding intravenous lipid administration in drug-induced cardiotoxicity. Expert Rev Clin Pharmacol 2019; 12:591-602. [PMID: 31106655 DOI: 10.1080/17512433.2019.1621163] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/26/2022]
Abstract
Introduction: Intravenous lipid emulsion (ILE) administration is capable of reversing the acute cardiac and neurological toxicity caused by local anesthetic agents. In recent years, ILE has also been explored as a potential antidote for cardiotoxicity caused by non-anesthetic agents too. Areas covered: The potential mechanisms, safety, and efficacy of this approach are considered. Data were sought from published reports listed in PubMed and EMBASE, and abstracts of meetings of the North American Congress of Clinical Toxicology and European Association of Poisons Centres and Clinical Toxicologists. There were reports involving 298 patients where ILE has been administered for severe drug toxicity. Clinical improvement was observed in 57 of 59 patients with local anesthetic toxicity (96.6%); there were 239 patients where toxicity was due to non-anesthetic agents, and ILE apparently improved clinical outcome in 215 (72.1%). Expert opinion: Response rates were similar between ILE treated toxicity caused by lipid soluble and non-lipid soluble drugs. Potential adverse effects of ILE include interference with laboratory assays, acute pancreatitis, and adult respiratory distress syndrome, although the rate of occurrence is difficult to ascertain.
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Affiliation(s)
- Maria Paneta
- a Acute Medical Unit , York Teaching Hospital NHS Foundation Trust , York , UK
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Nicholson HL, Ford JA. Sociodemographic, neighborhood, psychosocial, and substance use correlates of cocaine use among Black adults: Findings from a pooled analysis of national data. Addict Behav 2019; 88:182-186. [PMID: 30218941 DOI: 10.1016/j.addbeh.2018.08.042] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2018] [Revised: 08/31/2018] [Accepted: 08/31/2018] [Indexed: 11/30/2022]
Abstract
OBJECTIVE Cocaine use (CU) is serious a public health issue affecting U.S. adults, including Blacks. Cocaine-related overdose deaths have also trended upwards among this population. However, there remains a lack of research on correlates of CU among a nationally representative sample of Black adults. METHODS The current study examines the prevalence and correlates of past-year CU among Black adults aged 18 and older (N = 9,821). Data from the National Survey on Drug Use and Health (2015-2016) were used and a weighted logistic regression model was estimated. RESULTS Findings showed 2.4% of Black adults reported past-year CU-significantly higher than rates of CU among other assessed racial groups. Opioid use/misuse, encounters with drug dealers, easier access to cocaine, unemployment, and being 35 or older were associated with increased odds of CU. Greater risk perception of CU and religiosity were associated decreased odds of CU. CONCLUSION Results identified several correlates associated with past-year CU among Black adults. Findings suggest addressing CU among this population will likely require the development of multilevel prevention and intervention strategies and an increased focus on opioid use/misuse as opioids have been recently implicated in cocaine-related overdose deaths.
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Affiliation(s)
| | - Jason A Ford
- University of Central Florida, Department of Sociology, United States
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Bikhazi N, Atkins JH. Office-Based Procedures for Nasal Airway Obstruction. Otolaryngol Clin North Am 2018; 51:957-969. [PMID: 30017095 DOI: 10.1016/j.otc.2018.05.006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/28/2022]
Abstract
Treatment of common rhinologic problems with in-office surgical procedures has increased dramatically in response to patient preference, evolving insurance patterns, and changes in coding and reimbursement. Because this is an emerging practice, there is not a lot of evidence published about how to best perform these techniques. This article provides practical advice from experienced surgeons related to logistics and anesthetic techniques for conducting in-office surgical treatment of nasal airway obstruction; an overview of office set-up and necessary equipment; and specific procedural considerations. Attention also is paid to pharmacologic issues. Logistics and clinical considerations for common office-based procedures for obstructive pathology are reviewed.
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Affiliation(s)
- Nadim Bikhazi
- Ogden Clinic, 4650 Harrison Boulevard, Ogden, UT 84403, USA
| | - James H Atkins
- Texas Sinus Center, 15900 La Cantera Parkway, Suite 20210, San Antonio, TX 78256, USA.
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A cohort study of unstable overdose patients treated with intravenous lipid emulsion therapy. CAN J EMERG MED 2016; 19:256-264. [DOI: 10.1017/cem.2016.396] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
Abstract
AbstractObjectivesIntravenous lipid emulsion (ILE) has been used increasingly over the last decade for a range of drug overdoses. Although the use of ILE in local anesthetic toxicity (LAST) is well established, the hemodynamic effectiveness of ILE in non-LAST poisonings is still unclear. Thus, the primary objective of this study was to examine a cohort of poisoned patients in whom ILE was administered.MethodsConsecutive patients were identified by calls to a regional poison center from May 1, 2012 to May 30, 2014. Patients were enrolled if they ingested a drug, developed hemodynamic instability, failed conventional treatment, and received ILE therapy. Data were collected by medical record review. The primary outcome was the change in mean arterial pressure (MAP) in the first hour after ILE administration. Secondary outcomes included survival, length of stay, and the effect of drug class on patient outcome.ResultsThirty-six patients were enrolled. Agents ingested included calcium channel blockers and beta blockers (10/36, 27.8%), tricyclic antidepressants (5/36, 13.9%), bupropion (3/36, 8.3%), and antiepileptic agents (1/36, 2.8%). Seventeen patients (47.2%) ingested multiple agents. Twenty-five patients survived (69.0%). Overall, MAP increased by 13.79 mm Hg (95% CI 1.43–26.15); this did not meet oura prioridefinition of clinical significance.ConclusionsOur study did not find a clinically important improvement in MAP after ILE administration. Until future research is done to more definitively study its efficacy, ILE should remain a potential treatment option for hemodynamically unstable overdose patients only after conventional therapy has failed.
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Lam SH, Majlesi N, Vilke GM. Use of Intravenous Fat Emulsion in the Emergency Department for the Critically Ill Poisoned Patient. J Emerg Med 2016; 51:203-14. [DOI: 10.1016/j.jemermed.2016.02.008] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2016] [Accepted: 02/05/2016] [Indexed: 11/25/2022]
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Tse J, Ferguson K, Whitlow KS, Erickson K. The use of intravenous lipid emulsion therapy in acute methamphetamine toxicity. Am J Emerg Med 2016; 34:1732.e3-4. [DOI: 10.1016/j.ajem.2015.12.055] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2015] [Accepted: 12/18/2015] [Indexed: 12/19/2022] Open
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Intravenous lipid emulsion in the resuscitation of cocaine-induced cardiovascular arrest in a rat model. Am J Emerg Med 2016; 34:1452-4. [PMID: 27142757 DOI: 10.1016/j.ajem.2016.04.026] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2016] [Revised: 04/09/2016] [Accepted: 04/17/2016] [Indexed: 11/23/2022] Open
Abstract
CONTEXT Intravenous lipid emulsion (ILE) is a potential antidote for severe overdose of certain lipophilic drugs. Cocaine overdose is often fatal and has no antidote. The use of ILE after cocaine-induced cardiac arrest has been suggested but is not well characterized. OBJECTIVE The objective of the study is to determine if ILE would reverse cocaine-induced cardiac arrest in a rat model. MATERIALS AND METHODS Twelve Sprague-Dawley rats with intra-arterial and intravenous access were sedated with isoflurane and split into 2 cocaine dose groups, then given either ILE or normal saline (NS) intravenously (IV)-group A, 7 animals received cocaine (10 mg/kg IV) with 6 of 7 given ILE (15 mg/kg IV) and 1 of 7 given NS (equal volume); group B, 5 animals received cocaine (5 mg/kg IV) with 3 of 5 given ILE (15 mg/kg IV) and 2 of 5 given NS (equal volume). Closed chest compressions were initiated for asystole and continued for 15 minutes with rhythm checks every minute. RESULTS All 12 rats experienced cardiac arrest after cocaine bolus. Resuscitation was successful in 1 of 7 rats in group A and 0 of 5 in group B. CONCLUSIONS Intravenous lipid emulsion administration did not affect outcome of cocaine-induced cardiac arrest compared with control in this model.
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Hayes BD, Gosselin S, Calello DP, Nacca N, Rollins CJ, Abourbih D, Morris M, Nesbitt-Miller A, Morais JA, Lavergne V. Systematic review of clinical adverse events reported after acute intravenous lipid emulsion administration. Clin Toxicol (Phila) 2016; 54:365-404. [PMID: 27035513 DOI: 10.3109/15563650.2016.1151528] [Citation(s) in RCA: 104] [Impact Index Per Article: 11.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
Abstract
BACKGROUND Intravenous lipid emulsions (ILEs) were initially developed to provide parenteral nutrition. In recent years, ILE has emerged as a treatment for poisoning by local anesthetics and various other drugs. The dosing regimen for the clinical toxicology indications differs significantly from those used for parenteral nutrition. The evidence on the efficacy of ILE to reverse acute toxicity of diverse substances consists mainly of case reports and animal experiments. Adverse events to ILE are important to consider when clinicians need to make a risk/benefit analysis for this therapy. METHODS Multiple publication databases were searched to identify reports of adverse effects associated with acute ILE administration for either treatment of acute poisoning or parenteral nutrition. Articles were selected based on pre-defined criteria to reflect acute use of ILE. Experimental studies and reports of adverse effects as a complication of long-term therapy exceeding 14 days were excluded. RESULTS The search identified 789 full-text articles, of which 114 met the study criteria. 27 were animal studies, and 87 were human studies. The adverse effects associated with acute ILE administration included acute kidney injury, cardiac arrest, ventilation perfusion mismatch, acute lung injury, venous thromboembolism, hypersensitivity, fat embolism, fat overload syndrome, pancreatitis, extracorporeal circulation machine circuit obstruction, allergic reaction, and increased susceptibility to infection. CONCLUSION The emerging use of ILE administration in clinical toxicology warrants careful attention to its potential adverse effects. The dosing regimen and context of administration leading to the adverse events documented in this review are not generalizable to all clinical toxicology scenarios. Adverse effects seem to be proportional to the rate of infusion as well as total dose received. Further safety studies in humans and reporting of adverse events associated with ILE administration at the doses advocated in current clinical toxicology literature are needed.
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Affiliation(s)
- Bryan D Hayes
- a Department of Pharmacy , University of Maryland Medical Center and Department of Emergency Medicine, University of Maryland School of Medicine , Baltimore , MD , USA
| | - Sophie Gosselin
- b Department of Medicine, McGill Faculty of Medicine, Emergency Medicine , McGill University Health Centre , Montréal , Canada ;,c Province of Alberta Drug Information Services , Alberta , Canada ;,d Centre antipoison du Québec , Québec , Canada
| | - Diane P Calello
- e Medical Toxicology, Department of Emergency Medicine , Morristown Medical Center, Emergency Medical Associates , Morristown , NJ , USA
| | - Nicholas Nacca
- f Department of Surgery, Division of Emergency Medicine , University of Vermont , Burlington , VT , USA
| | - Carol J Rollins
- g Banner-University Medical Center Tucson, University of Arizona College of Pharmacy , Tucson , AZ , USA
| | - Daniel Abourbih
- h Department of Medicine, Division of Emergency Medicine , University of Toronto , Toronto , Canada
| | - Martin Morris
- i Life Sciences Library , McGill University , Montréal , Canada
| | | | - José A Morais
- j Division of Geriatric Medicine , McGill University , Montréal , Québec , Canada
| | - Valéry Lavergne
- k Department of Medical Biology , Sacré-Coeur Hospital, University of Montréal , Montréal , Canada
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Richards JR, Garber D, Laurin EG, Albertson TE, Derlet RW, Amsterdam EA, Olson KR, Ramoska EA, Lange RA. Treatment of cocaine cardiovascular toxicity: a systematic review. Clin Toxicol (Phila) 2016; 54:345-64. [PMID: 26919414 DOI: 10.3109/15563650.2016.1142090] [Citation(s) in RCA: 59] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/24/2023]
Abstract
INTRODUCTION Cocaine abuse is a major worldwide health problem. Patients with acute cocaine toxicity presenting to the emergency department may require urgent treatment for tachycardia, dysrhythmia, hypertension, and coronary vasospasm, leading to pathological sequelae such as acute coronary syndrome, stroke, and death. OBJECTIVE The objective of this study is to review the current evidence for pharmacological treatment of cardiovascular toxicity resulting from cocaine abuse. METHODS MEDLINE, PsycINFO, Database of Abstracts of Reviews of Effects (DARE), OpenGrey, Google Scholar, and the Cochrane Library were searched from inception to November 2015. Articles on pharmacological treatment involving human subjects and cocaine were selected and reviewed. Evidence was graded using Oxford Centre for Evidence-Based Medicine guidelines. Treatment recommendations were compared to current American College of Cardiology/American Heart Association guidelines. Special attention was given to adverse drug events or treatment failure. The search resulted in 2376 articles with 120 eligible involving 2358 human subjects. Benzodiazepines and other GABA-active agents: There were five high-quality (CEBM Level I/II) studies, three retrospective (Level III), and 25 case series/reports (Level IV/V) supporting the use of benzodiazepines and other GABA-active agents in 234 subjects with eight treatment failures. Benzodiazepines may not always effectively mitigate tachycardia, hypertension, and vasospasm from cocaine toxicity. Calcium channel blockers: There were seven Level I/II, one Level III, and seven Level IV/V studies involving 107 subjects and one treatment failure. Calcium channel blockers may decrease hypertension and coronary vasospasm, but not necessarily tachycardia. Nitric oxide-mediated vasodilators: There were six Level I/II, one Level III, and 25 Level IV/V studies conducted in 246 subjects with 11 treatment failures and two adverse drug events. Nitroglycerin may lead to severe hypotension and reflex tachycardia. Alpha-adrenoceptor blocking drugs: There were two Level I studies and three case reports. Alpha-1 blockers may improve hypertension and vasospasm, but not tachycardia, although evidence is limited. Alpha-2-adrenoceptor agonists: There were two high-quality studies and one case report detailing the successful use of dexmedetomidine. Beta-blockers and β/α-blockers: There were nine Level I/II, seven Level III, and 34 Level IV/V studies of β-blockers, with 1744 subjects, seven adverse drug events, and three treatment failures. No adverse events were reported for use of combined β/α-blockers such as labetalol and carvedilol, which were effective in attenuating both hypertension and tachycardia. Antipsychotics: Seven Level I/II studies, three Level III studies, and seven Level IV/V case series and reports involving 168 subjects have been published. Antipsychotics may improve agitation and psychosis, but with inconsistent reduction in tachycardia and hypertension and risk of extrapyramidal adverse effects. Other agents: There was only one high level study of morphine, which reversed cocaine-induced coronary vasoconstriction but increased heart rate. Other agents reviewed included lidocaine, sodium bicarbonate, amiodarone, procainamide, propofol, intravenous lipid emulsion, propofol, and ketamine. CONCLUSIONS High-quality evidence for pharmacological treatment of cocaine cardiovascular toxicity is limited but can guide acute management of associated tachycardia, dysrhythmia, hypertension, and coronary vasospasm. Future randomized prospective trials are needed to evaluate new agents and further define optimal treatment of cocaine-toxic patients.
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Affiliation(s)
- John R Richards
- a Department of Emergency Medicine , University of California Davis Medical Center , Sacramento , CA , USA
| | - Dariush Garber
- a Department of Emergency Medicine , University of California Davis Medical Center , Sacramento , CA , USA
| | - Erik G Laurin
- a Department of Emergency Medicine , University of California Davis Medical Center , Sacramento , CA , USA
| | - Timothy E Albertson
- b Department of Internal Medicine, Divisions of Toxicology, Pulmonary and Critical Care , University of California Davis Medical Center , Sacramento , CA , USA
| | - Robert W Derlet
- a Department of Emergency Medicine , University of California Davis Medical Center , Sacramento , CA , USA
| | - Ezra A Amsterdam
- c Department of Internal Medicine, Division of Cardiology , University of California Davis Medical Center , Sacramento , CA , USA
| | - Kent R Olson
- d Departments of Medicine and Clinical Pharmacy , University of California, San Francisco, Medical Director, California Poison Control System, San Francisco Division , San Francisco , CA , USA
| | - Edward A Ramoska
- e Department of Emergency Medicine , Drexel University , Philadelphia , PA , USA
| | - Richard A Lange
- f Department of Internal Medicine, Division of Cardiology , Texas Tech University Health Sciences Center , El Paso , TX , USA
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Levine M, Hoffman RS, Lavergne V, Stork CM, Graudins A, Chuang R, Stellpflug SJ, Morris M, Miller-Nesbitt A, Gosselin S. Systematic review of the effect of intravenous lipid emulsion therapy for non-local anesthetics toxicity. Clin Toxicol (Phila) 2016; 54:194-221. [DOI: 10.3109/15563650.2015.1126286] [Citation(s) in RCA: 73] [Impact Index Per Article: 8.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
Affiliation(s)
- Michael Levine
- Department of Emergency Medicine, Section of Medical Toxicology, University of Southern California, Los Angeles, CA, USA
| | - Robert S. Hoffman
- Division of Medical Toxicology, Ronald O. Perelman Department of Emergency Medicine, New York University School of Medicine, New York, NY, USA
| | - Valéry Lavergne
- Department of Medical Biology, Sacré-Coeur Hospital, University of Montreal, Montreal, Canada
| | - Christine M. Stork
- Department of Emergency Medicine, Upstate Medical University, New York and Upstate New York Poison Center, New York, NY, USA
| | - Andis Graudins
- Department of Medicine, School of Clinical Sciences at Monash Health, Clinical Toxicology Service at Monash Health and Monash Emergency Translational Research Group, Monash University, Clayton, Victoria, Australia
| | - Ryan Chuang
- Department of Emergency Medicine, University of Calgary, Poison and Drug Information Service, Calgary, Canada
| | | | - Martin Morris
- Schulich Library of Science and Engineering, McGill University, Montreal, Canada; and
| | - Andrea Miller-Nesbitt
- Schulich Library of Science and Engineering, McGill University, Montreal, Canada; and
| | - Sophie Gosselin
- Department of Emergency Medicine, McGill University Health Centre & Department of Medicine, McGill University, Montreal, Canada
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18
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Johnston AJ, Busch S, Pardo LC, Callear SK, Biggin PC, McLain SE. On the atomic structure of cocaine in solution. Phys Chem Chem Phys 2016; 18:991-9. [DOI: 10.1039/c5cp06090g] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/27/2023]
Abstract
A combination of neutron diffraction and computation has been used to investigate the atomic scale structure of cocaine in aqueous solutions.
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Affiliation(s)
| | - Sebastian Busch
- German Engineering Materials Science Centre (GEMS) at Heinz Maier-Leibnitz Zentrum (MLZ)
- Helmholtz-Zentrum Geesthacht GmbH
- 85747 Garching bei München
- Germany
| | - Luis Carlos Pardo
- Departament de Física i Enginyeria Nuclear
- Escola Tècnica Superior d'Enginyeria Industrial de Barcelona (ETSEIB)
- Universitat Politècnica de Catalunya
- 08028 Barcelona
- Spain
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19
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Stankowski RV, Kloner RA, Rezkalla SH. Cardiovascular consequences of cocaine use. Trends Cardiovasc Med 2015; 25:517-26. [DOI: 10.1016/j.tcm.2014.12.013] [Citation(s) in RCA: 63] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/21/2014] [Revised: 12/03/2014] [Accepted: 12/17/2014] [Indexed: 11/28/2022]
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Fettiplace MR, Weinberg G. Past, Present, and Future of Lipid Resuscitation Therapy. JPEN J Parenter Enteral Nutr 2015; 39:72S-83S. [DOI: 10.1177/0148607115595979] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2015] [Accepted: 06/22/2015] [Indexed: 01/18/2023]
Affiliation(s)
- Michael R. Fettiplace
- Department of Anesthesiology, University of Illinois College of Medicine, Chicago, Illinois
- Research & Development Service, Jesse Brown Veterans Affairs Medical Center, Chicago, Illinois
- Neuroscience Program, University of Illinois at Chicago, Chicago, Illinois
| | - Guy Weinberg
- Department of Anesthesiology, University of Illinois College of Medicine, Chicago, Illinois
- Research & Development Service, Jesse Brown Veterans Affairs Medical Center, Chicago, Illinois
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21
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Fettiplace MR, Pichurko A, Ripper R, Lin B, Kowal K, Lis K, Schwartz D, Feinstein DL, Rubinstein I, Weinberg G. Cardiac depression induced by cocaine or cocaethylene is alleviated by lipid emulsion more effectively than by sulfobutylether-β-cyclodextrin. Acad Emerg Med 2015; 22:508-17. [PMID: 25908403 DOI: 10.1111/acem.12657] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2014] [Revised: 11/24/2014] [Accepted: 11/29/2014] [Indexed: 12/28/2022]
Abstract
OBJECTIVES Cocaine intoxication leads to over 500,000 emergency department visits annually in the United States and ethanol cointoxication occurs in 34% of those cases. Cardiotoxicity is an ominous complication of cocaine and cocaethylene overdose for which no specific antidote exists. Because infusion of lipid emulsion (Intralipid) can treat lipophilic local anesthetic toxicity and cocaine is an amphipathic local anesthetic, the authors tested whether lipid emulsion could attenuate cocaine cardiotoxicity in vivo. The effects of lipid emulsion were compared with the metabolically inert sulfobutylether-β-cyclodextrin (SBE-β-CD; Captisol) in an isolated heart model of cocaine and cocaethylene toxicity to determine if capture alone could exert similar benefit as lipid emulsion, which exhibits multimodal effects. The authors then tested if cocaine and cocaethylene, like bupivacaine, inhibit lipid-based metabolism in isolated cardiac mitochondria. METHODS For whole animal experiments, Sprague-Dawley rats were anesthetized, instrumented, and pretreated with lipid emulsion followed by a continuous infusion of cocaine to assess time of onset of cocaine toxicity. For ex vivo experiments, rat hearts were placed onto a nonrecirculating Langendorff system perfused with Krebs-Henseleit solution. Heart rate, left ventricle maximum developed pressure (LVdevP), left ventricle diastolic pressure, maximum rate of contraction (+dP/dtmax), maximum rate of relaxation (-dP/dtmax), rate-pressure product (RPP = heart rate × LVdevP), and line pressure were monitored continuously during the experiment. A dose response to cocaine (10, 30, 50, and 100 μmol/L) and cocaethylene (10, 30, and 50 μmol/L) was generated in the absence or presence of either 0.25% lipid emulsion or SBE-β-CD. Substrate-specific rates of oxygen consumption were measured in interfibrillar cardiac mitochondria in the presence of cocaine, cocaethylene, ecgonine, and benzoylecgonine. RESULTS Treatment with lipid emulsion delayed onset of hypotension (140 seconds vs. 279 seconds; p = 0.008) and asystole (369 seconds vs. 607 seconds; p = 0.02) in whole animals. Cocaine and cocaethylene induced dose-dependent decreases in RPP, +dP/dtmax, and -dP/dtmaxabs (p < 0.0001) in Langendorff hearts; line pressure was increased by cocaine and cocaethylene infusion, but not altered by treatment. Lipid emulsion attenuated cocaine- and cocaethylene-induced cardiac depression. SBE-β-CD alone evoked a mild cardiodepressant effect (p < 0.0001) but attenuated further cocaine- and cocaethylene-induced decrements in cardiac contractility at high concentrations of drug (100 μmol/L; p < 0.001). Finally, both cocaine and cocaethylene, but not ecgonine and benzoylecgonine, inhibited lipid-dependent mitochondrial respiration by blocking carnitine exchange (p < 0.05). CONCLUSIONS A commercially available lipid emulsion was able to delay progression of cocaine cardiac toxicity in vivo. Further, it improved acute cocaine- and cocaethylene-induced cardiac toxicity in rat isolated heart while SBE-β-CD was effective only at the highest cocaine concentration. Further, both cocaine and cocaethylene inhibited lipid-dependent mitochondrial respiration. Collectively, this suggests that scavenging-independent effects of lipid emulsion may contribute to reversal of acute cocaine and cocaethylene cardiotoxicity, and the beneficial effects may involve mitochondrial lipid processing.
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Affiliation(s)
- Michael R. Fettiplace
- Department of Anesthesiology; University of Illinois College of Medicine; Chicago IL
- Research & Development Service; Jesse Brown Veterans' Affairs Medical Center; Chicago IL
- Neuroscience Program; University of Illinois at Chicago; Chicago IL
| | - Adrian Pichurko
- Department of Anesthesiology; University of Illinois College of Medicine; Chicago IL
- Research & Development Service; Jesse Brown Veterans' Affairs Medical Center; Chicago IL
| | - Richard Ripper
- Department of Anesthesiology; University of Illinois College of Medicine; Chicago IL
- Research & Development Service; Jesse Brown Veterans' Affairs Medical Center; Chicago IL
| | - Bocheng Lin
- Department of Anesthesiology; University of Illinois College of Medicine; Chicago IL
- Research & Development Service; Jesse Brown Veterans' Affairs Medical Center; Chicago IL
| | - Katarzyna Kowal
- Department of Anesthesiology; University of Illinois College of Medicine; Chicago IL
- Research & Development Service; Jesse Brown Veterans' Affairs Medical Center; Chicago IL
| | - Kinga Lis
- Department of Anesthesiology; University of Illinois College of Medicine; Chicago IL
- Research & Development Service; Jesse Brown Veterans' Affairs Medical Center; Chicago IL
| | - David Schwartz
- Department of Anesthesiology; University of Illinois College of Medicine; Chicago IL
| | - Douglas L. Feinstein
- Department of Anesthesiology; University of Illinois College of Medicine; Chicago IL
- Research & Development Service; Jesse Brown Veterans' Affairs Medical Center; Chicago IL
| | - Israel Rubinstein
- Research & Development Service; Jesse Brown Veterans' Affairs Medical Center; Chicago IL
- Section of Pulmonary, Critical Care, Sleep and Allergy Medicine; Department of Medicine, University of Illinois College of Medicine; Chicago IL
| | - Guy Weinberg
- Department of Anesthesiology; University of Illinois College of Medicine; Chicago IL
- Research & Development Service; Jesse Brown Veterans' Affairs Medical Center; Chicago IL
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22
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Cao D, Heard K, Foran M, Koyfman A. Intravenous Lipid Emulsion in the Emergency Department: A Systematic Review of Recent Literature. J Emerg Med 2015; 48:387-97. [DOI: 10.1016/j.jemermed.2014.10.009] [Citation(s) in RCA: 69] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2014] [Revised: 10/01/2014] [Accepted: 10/12/2014] [Indexed: 10/24/2022]
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23
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Thomas EK, Drobatz KJ, Mandell DC. Presumptive cocaine toxicosis in 19 dogs: 2004-2012. J Vet Emerg Crit Care (San Antonio) 2014; 24:201-7. [PMID: 24739034 DOI: 10.1111/vec.12159] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2012] [Accepted: 12/30/2013] [Indexed: 11/29/2022]
Abstract
OBJECTIVE To characterize the incidence, signalment, presenting complaint, history, clinical signs, diagnostic test results, complications, treatment, length of hospitalization, and outcome of dogs presenting with presumptive cocaine toxicosis. DESIGN Retrospective study from March 1, 2004 to March 1, 2012. SETTING Twenty-four hour urban university veterinary teaching hospital. ANIMALS Nineteen dogs presenting with clinical signs consistent with cocaine toxicosis and having a positive urine cocaine test. INTERVENTIONS None. MEASUREMENTS AND MAIN RESULTS All dogs had neurological abnormalities including bilateral mydriasis (11/19 [58%]), hyperexcitability/hyperesthesia (10/19 [53%]), ataxia (8/19 [42%]), focal or generalized muscle tremors (8/19 [42%]), reduced mental awareness (6/19 [32%]), and seizures (3/19 [16%]). Other signs included weakness (7/19 [37%]), vomiting (6/19 [32%]), and lethargy (3/19 [16%]). Tachycardia was apparent in 10/19 (53%) dogs, hypertension in 4/19 (21%), and hyperthermia in 5/19 (26%). Sinus tachycardia was the only reported cardiac arrhythmia. Bloodwork findings included hyperglycemia in 4/19 (21%) dogs, and increased plasma lactate concentration in 9/19 (47%). Most dogs (16/19 [84%]) were hospitalized for supportive care, which generally included isotonic crystalloid fluid administration, and treatment with sedative or anxiolytic drugs including diazepam, midazolam, acepromazine, and chlorpromazine. Two dogs required further anticonvulsant therapy (phenobarbital and propofol) and 1 dog was treated with a constant rate infusion of esmolol. All dogs survived to discharge, and the median length of hospitalization was 15 hours (10-30 h). CONCLUSIONS Cocaine toxicosis was infrequently suspected. Neurological signs predominated, but cardiovascular alterations were also frequently reported. Hospitalization for monitoring and supportive care is recommended given the potential for life-threatening complications such as seizures, hypertensive crisis, and tachyarrhythmias. The prognosis for survival to hospital discharge can be good with the appropriate supportive care.
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Affiliation(s)
- Emily K Thomas
- Department of Clinical Studies-Philadelphia, School of Veterinary Medicine, University of Pennsylvania, PA, 19104-6010
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24
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Cave G, Harvey MG. Should we consider the infusion of lipid emulsion in the resuscitation of poisoned patients? CRITICAL CARE : THE OFFICIAL JOURNAL OF THE CRITICAL CARE FORUM 2014; 18:457. [PMID: 25673255 PMCID: PMC4331416 DOI: 10.1186/s13054-014-0457-5] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 02/03/2023]
Abstract
The use of intravenous lipid emulsions (ILEs) as antidote in local anaesthetic systemic toxicity has gained widespread support following convincing data from animal models, and successful case reports in humans. Proposed beneficial mechanisms of action for ILEs include intravascular sequestration of intoxicant and subsequent enhanced redistribution to biologically inert tissues, augmentation of fatty acid utilisation for ATP synthesis in the context of metabolic poisoning, and direct cardiotonic and ion channel effects. The evidence base for use of ILEs in acute drug intoxication is evolving. The present evidence supports use of ILEs only in local anaesthetic systemic toxicity and in lipophilic cardiotoxin intoxication when there is an immediate threat to life, and other therapies have proven ineffective.
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25
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Carreiro S, Blum J, Hack JB. Pretreatment With Intravenous Lipid Emulsion Reduces Mortality From Cocaine Toxicity in a Rat Model. Ann Emerg Med 2014; 64:32-7. [DOI: 10.1016/j.annemergmed.2013.11.017] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2013] [Revised: 11/11/2013] [Accepted: 11/22/2013] [Indexed: 10/25/2022]
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Abstract
Intravenous lipid emulsion (ILE) has been used widely for the treatment of poisoning due to local anesthetic agent and is increasingly reported as a therapy for other forms of poisoning. This article will review the proposed mechanisms of action for ILE in poisoning and the evidence from animal studies and human experience supporting the use of ILE for poisoning due to nonlocal anesthetic agents.
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27
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Fettiplace MR, Akpa BS, Ripper R, Zider B, Lang J, Rubinstein I, Weinberg G. Resuscitation with lipid emulsion: dose-dependent recovery from cardiac pharmacotoxicity requires a cardiotonic effect. Anesthesiology 2014; 120:915-25. [PMID: 24496123 PMCID: PMC4077021 DOI: 10.1097/aln.0000000000000142] [Citation(s) in RCA: 44] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
BACKGROUND Recent publications have questioned the validity of the "lipid sink" theory of lipid resuscitation while others have identified sink-independent effects and posed alternative mechanisms such as hemodilution. To address these issues, the authors tested the dose-dependent response to intravenous lipid emulsion during reversal of bupivacaine-induced cardiovascular toxicity in vivo. Subsequently, the authors modeled the relative contribution of volume resuscitation, drug sequestration, inotropy and combined drug sequestration, and inotropy to this response with the use of an in silico model. METHODS Rats were surgically prepared to monitor cardiovascular metrics and deliver drugs. After catheterization and instrumentation, animals received a nonlethal dose of bupivacaine to produce transient cardiovascular toxicity, then were randomized to receive one of the four treatments: 30% intravenous lipid emulsion, 20% intravenous lipid emulsion, intravenous saline, or no treatment (n = 7 per condition; 28 total animals). Recovery responses were compared with the predictions of a pharmacokinetic-pharmacodynamic model parameterized using previously published laboratory data. RESULTS Rats treated with lipid emulsions recovered faster than did rats treated with saline or no treatment. Intravenous lipid emulsion of 30% elicited the fastest hemodynamic recovery followed in order by 20% intravenous lipid emulsion, saline, and no treatment. An increase in arterial blood pressure underlay the recovery in both lipid emulsion-treated groups. Heart rates remained depressed in all four groups throughout the observation period. Model predictions mirrored the experimental recovery, and the model that combined volume, sequestration, and inotropy predicted in vivo results most accurately. CONCLUSION Intravenous lipid emulsion accelerates cardiovascular recovery from bupivacaine toxicity in a dose-dependent manner, which is driven by a cardiotonic response that complements the previously reported sequestration effect.
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Affiliation(s)
- Michael R Fettiplace
- From the Department of Anesthesiology, University of Illinois College of Medicine, Chicago, Illinois (M.R.F., R.R., and G.W.); Research and Development Service, Jesse Brown Veterans Affairs Medical Center, Chicago, Illinois (M.R.F., R.R., I.R., and G.W.); University of Illinois College of Medicine, Chicago, Illinois (M.R.F. and B.Z.); Department of Chemical Engineering, University of Illinois at Chicago, Chicago, Illinois (B.S.A.); University of Illinois College of Medicine, Peoria, Illinois (J.L.); and Section of Pulmonary, Critical Care, Sleep, and Allergy Medicine, Department of Medicine, University of Illinois College of Medicine, Chicago, Illinois (I.R.)
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28
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Connors NJ, Hoffman RS. Experimental treatments for cocaine toxicity: a difficult transition to the bedside. J Pharmacol Exp Ther 2013; 347:251-7. [PMID: 23978563 DOI: 10.1124/jpet.113.206383] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/08/2025] Open
Abstract
Cocaine is a commonly abused illicit drug that causes significant morbidity and mortality. Although there is no true antidote to cocaine toxicity, current management strategies address the life-threatening systemic effects, namely hyperthermia, vasospasm, and severe hypertension. Clinicians rely on rapid cooling, benzodiazepines, and α-adrenergic antagonists for management, with years of proven benefit. Experimental agents have been developed to more effectively treat acute toxicity. Pharmacodynamic approaches include antipsychotics that are thought to interfere with cocaine's actions at several neurotransmitter receptors. However, these medications may worsen the consequences of cocaine toxicity as they can interfere with heat dissipation, cause arrhythmias, and lower the seizure threshold. Pharmacokinetic approaches use cocaine-metabolizing enzymes, such as butyrylcholinesterase (BChE), cocaine hydrolase (CocH), and bacterial cocaine esterase (CocE). Experimental models with these therapies improve survival, primarily when administered before cocaine, although newer evidence demonstrates beneficial effects shortly after cocaine toxicity has manifested. CocE, a foreign protein, can induce an immune response with antibody formation. When enzyme administration was combined with vaccination against the cocaine molecule, improvement in cocaine-induced locomotor activity was observed. Finally, lipid emulsion rescue has been described in human case reports as an effective treatment in patients with hemodynamic compromise because of cocaine, which correlates well with its documented benefit in toxicity due to other local anesthetics. A pharmaceutical developed from these concepts will need to be expedient in onset and effective with minimal adverse effects while at the same time being economical.
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Affiliation(s)
- Nicholas J Connors
- Division of Medical Toxicology, Department of Emergency Medicine, New York University School of Medicine, Bellevue Hospital Center, New York, New York
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29
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Abstract
OBJECTIVES Bolus infusion of lipid emulsion can reverse cardiac pharmacotoxicity caused by local anesthetics and other lipophilic drugs. The mechanisms of this effect are not completely elucidated. The authors test the hypothesis that lipid emulsion infusion exerts direct, positive inotropic effects. DESIGN Prospective, randomized animal study. SETTING University research laboratory. SUBJECTS Adult male Sprague-Dawley rats. INTERVENTIONS Rats anesthetized with isoflurane were given intravenous infusions (9 mL/kg over 1 min) of either 20% soybean oil-based emulsion or saline. MEASUREMENTS AND MAIN RESULTS Arterial pressure and aortic flow were measured continuously in intact animals. Lipid infusion increased aortic flow and arterial pressure faster and to a greater degree than did the same volume of saline infusion. Isolated rat hearts were studied using an isovolumetric, constant flow, nonrecirculating system. Left ventricular pressure was monitored. The infusion of lipid emulsion in the isolated heart dose-dependently increased rate pressure product, dP/dt, -dP/dt, and myocardial oxygen demand. CONCLUSIONS Lipid emulsion exerts rapid, positive inotropic and positive lusitropic effects in both intact animal and isolated heart models. We hypothesize that this inotropy and the resulting increase in tissue blood flow contribute to the phenomenon of lipid reversal of cardiac toxicity caused by drug overdose.
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30
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Abstract
The investigators describe the clinical course of a 26-year-old-man who was brought to the emergency department in a comatose state with status epilepticus after smoking a large amount of crack cocaine. In the emergency department, he was intubated because of depressed mental status and respiratory acidosis. His troponin I remained negative, and electrocardiography showed wide-complex tachycardia with a prolonged corrected QT interval. Because of the corrected QT interval prolongation and wide-complex tachycardia, the patient was started on intravenous magnesium sulfate and sodium bicarbonate. Despite these interventions, no improvement in cardiac rhythm was observed, and electrocardiography continued to show wide-complex tachycardia. The patient became more unstable from a cardiovascular standpoint, with a decrease in blood pressure to 85/60 mm Hg. He was then given 100 ml of 20% lipid emulsion (Intralipid). Within 10 minutes of starting the infusion of 20% lipid emulsion, wide-complex tachycardia disappeared, with an improvement in systemic blood pressure to 120/70 mm Hg. Repeat electrocardiography after the infusion of intravenous lipid emulsion showed regular sinus rhythm with normal QRS and corrected QT intervals. The patient was successfully extubated on day 8 of hospitalization and discharged home on day 10. His cardiac rhythm and blood pressure remained stable throughout his further stay in the hospital.
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Affiliation(s)
- Natasha Purai Arora
- Department of Internal Medicine, Wayne State University School of Medicine, Detroit Medical Center, Michigan, USA
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31
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Wong GTC, Irwin MG. Poisoning with illicit substances: toxicology for the anaesthetist. Anaesthesia 2013; 68 Suppl 1:117-24. [PMID: 23210561 DOI: 10.1111/anae.12053] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Abstract
The consumption of illicit substances represents a considerable threat to the health and wellbeing of particular sectors of our communities. Hospitalisation is sometimes required for the treatment of the direct toxic effects of the drugs as well as for injuries sustained while under their influence. Although poisoning with 'traditional' substances of abuse such as opioids, cocaine and cannabis still predominate in terms of numbers, the availability and use of new psychoactive substances are on the rise. These latter agents, some of which began life as failed pharmaceutical products, have enjoyed renewed status as recreational stimulants, entactogens or hallucinogens, properties that originally precluded them from legitimate use. These drugs may act by enhancing endogenous release of neurotransmitters, inhibiting their reuptake back into neurons or having direct effects on receptors, and may involve adrenergic, dopaminergic or serotonergic systems. The use of intravenous lipid emulsion for the symptomatic treatment of drug overdose has become a fertile ground for research and may hold promise as a non-specific treatment for poisoning with illicit substances. Dexmedetomidine, an α(2)-receptor agonist with a central sympatholytic effect, may be able to counteract the cardiovascular and central nervous system overstimulation that may accompany stimulant toxicity.
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Affiliation(s)
- G T C Wong
- Department of Anaesthesiology, University of Hong Kong, Hong Kong.
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32
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Waring WS. Intravenous lipid administration for drug-induced toxicity: a critical review of the existing data. Expert Rev Clin Pharmacol 2013; 5:437-44. [PMID: 22943123 DOI: 10.1586/ecp.12.27] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Abstract
Following the discovery that administration of intravenous lipid emulsion (ILE) may reverse the cardiac and neurological toxicity of certain local anesthetic agents, ILE's potential role has recently been explored in the setting of toxicity attributed to a variety of different drugs. The potential mechanisms, safety and efficacy of this approach are considered in this review. Data are reviewed from 76 published reports involving ILE administration for severe drug toxicity, including 55 where toxicity was due to nonanesthetic agents. ILE was reported to exert a positive therapeutic effect in only a proportion of the reported cases, with greatest evidence of efficacy concerning local anesthetic agents. Administration has typically involved bolus administration followed by continuous maintenance infusion, and a number of different mechanisms are proposed, from preferential partitioning of the drug from cardiac tissue to the circulating lipid fraction and direct inotropic effects related to carnitine pathways and fatty acid oxidative metabolism. No major adverse effects have been encountered, but too few data exist to adequately address the safety profile of ILE.
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Affiliation(s)
- W Stephen Waring
- Acute Medical Unit, York Teaching Hospital NHS Foundation Trust, York, UK.
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33
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Samuels TL, Papadopoulou A, Willers JW, Uncles DR. Logging the delivery of intravenous lipid emulsion for cocaine and other lipophilic drug overdoses. Anaesthesia 2012; 67:437-8. [DOI: 10.1111/j.1365-2044.2012.07097.x] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
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