Lipid rescue: does the sink hold water? And other controversies
2014; Elsevier BV; Volume: 112; Issue: 4 Linguagem: Inglês
10.1093/bja/aeu010
ISSN1471-6771
Autores Tópico(s)Anesthesia and Sedative Agents
ResumoThe very first reports of successful use of i.v. lipid emulsion (ILE) preparations to ameliorate local anaesthetic toxicity originated from the laboratory of Guy Weinberg MD in 1998.1Weinberg G VadeBoncouer T Ramaraju G Garcia-Amaro M Cwik M Pretreatment or resuscitation with a lipid infusion shifts the dose–response to bupivacaine-induced asystole in rats.Anaesthesiology. 1998; 88: 1071-1075Crossref PubMed Scopus (512) Google Scholar Demonstration of a significant increase in the LD50 for bupivacaine after ILE application in a rodent model rapidly beget an explosion of experimental, and more latterly clinical, interest in the use of lipid preparations as antidote. Largely driven by the 'sink' theory positing sequestration of lipophilic xenobiotics to an expanded intravascular lipid phase,2Weinberg G Ripper R Feinstein D Hoffman W Lipid emulsion infusion rescues dogs from bupivacaine induced cardiac toxicity.Reg Anesth Pain Med. 2003; 28: 198-202Crossref PubMed Google Scholar new researchers have extended the profiling of lipid rescue beyond lipid-soluble local anaesthetics and demonstrated the effect for ILE in animal models of lipophillic calcium channel blockers,3Tebbutt S Harvey M Nicholson T Cave G Intralipid prolongs survival in a rat model of verapamil toxicity.Acad Emerg Med. 2006; 13: 134-139Crossref PubMed Google Scholar 4Bania T Chu J Perez E Hemodynamic effects of intravenous fat emulsion in an animal model of severe verapamil toxicity resuscitated with atropine, calcium, and saline.Acad Emerg Med. 2007; 14: 105-111Crossref PubMed Google Scholar tricyclic antidepressants,5Bania T Chu J Hemodynamic effect of intralipid in amitriptyline toxicity.Acad Emerg Med. 2006; 13: 117Google Scholar 6Harvey M Cave G Intralipid outperforms sodium bicarbonate in a rabbit model of clomipramine toxicity.Ann Emerg Med. 2007; 49: 178-185Abstract Full Text Full Text PDF PubMed Scopus (142) Google Scholar antipsychotics,7Krieglstein J Meffert A Niemeyer D Influence of emulsified fat on chlorpromazine availability in rabbit blood.Experientia. 1974; 15: 924-926Crossref Scopus (51) Google Scholar and antiarrhythmics8Bania T Chu J Wesolowski M The hemodynamic effect of Intralipid on propranolol toxicity.Acad Emerg Med. 2006; 13: 109Crossref PubMed Google Scholar 9Niiya T Litonius E Petaja L Neuvonen P Rosenburg P Intravenous lipid emulsion sequesters amiodarone in plasma and eliminates its hypotensive action in pigs.Ann Emerg Med. 2010; 56: 402-408Abstract Full Text Full Text PDF PubMed Scopus (55) Google Scholar to name but a few. Successful resuscitation in clinical cases of local anaesthetic systemic toxicity (LAST) with lipid infusion have been well documented10Rosenblatt M Abel M Fischer G Itzkovich C Eisenkraft J Successful use of a 20% lipid emulsion to resuscitate a patient after a presumed bupivacaine-related cardiac arrest.Anesthesiology. 2006; 105: 217-218Crossref PubMed Scopus (483) Google Scholar, 11Foxall G McCahon R Lamb J Hardman J Bedforth N Levobupivacaine-induced seizures and cardiovascular collapse treated with Intralipid.Anaesthesia. 2007; 62: 516-518Crossref PubMed Scopus (195) Google Scholar, 12Lin E, Aronson L. Successful resuscitation of bupivacaine induced cardiotoxicity in a neonate. Paediatr Anaesth 2101; 20: 955–7.Google Scholar, 13Shah S Gopalakrishnan S Apuya J Shah S Martin T Use of intralipid in an infant with impending cardiovascular collapse due to local anesthetic toxicity.J Anesth. 2009; 23: 439-441Crossref PubMed Scopus (56) Google Scholar and anecdotal instances of seemingly dramatic recovery for non-local anaesthetic drug poisonings likewise reported.14Weinberg G Di Gregorio G Hiller D Hewett A Sirianni A Reversal of haloperidol induced cardiac arrest by using lipid emulsion.Ann Intern Med. 2009; 19: 737-738Crossref Scopus (44) Google Scholar 15Sirianni A Osterhoudt K Calello D et al.Use of Intralipid in the resuscitation of a patient with prolonged cardiovascular collapse after overdose of bupropion and lamotrigine.Ann Emerg Med. 2007; 51: 412-415Abstract Full Text Full Text PDF PubMed Scopus (225) Google Scholar Confirmation of clinical efficacy has seen ILE endorsed by anaesthetic societies on both sides of the Atlantic16Guidelines for the Management of Severe Local-Anaesthetic Toxicity, The Association of Anaesthestists of Great Britain and Ireland http://www.aagbi.org/publications/guidelines/docs/latoxicity07.pdf accessed September 2013.Google Scholar 17Neal JM Bernards CM Butterworth JF et al.ASRA practice advisory on local anesthetic systemic toxicity.Reg Anesth Pain Med. 2010; 35: 152-161Crossref PubMed Scopus (415) Google Scholar with support also forthcoming from toxicologic forums18American College of Medical ToxicologyACMT Position statement: Interim guidance for the use of lipid resuscitation therapy.J Med Tox. 2011; 7: 81-82Crossref PubMed Scopus (72) Google Scholar endorsing ILE use as potential adjuvant to resuscitation in lipophilic drug poisonings. And so lipid emulsion smoothly transitions from parenteral nutritional supplement to established antidote. If only it were that simple. The rapid ascent of ILE as rescue therapy in LAST, and indeed toxicology in general, provides a case study in adoption of novel therapies when data pertaining to both the scope and mechanism of action remain incomplete. For there is much about ILE that remains unknown. Indeed despite significant research effort over the last decade and-a-half, the exact mechanism, or perhaps more rightly mechanisms, of action for ILE are only just beginning to be fully elucidated. Similarly, the scope of indications for utilization of lipid, particularly beyond that in LAST, remains the subject of significant controversy.19Buckley N Dawson A The intralipid genie is out of the bottle—spin and wishful thinking.Anaesth Intensive Care. 2013; 41: 154-156PubMed Google Scholar It is into such a background that the present edition of the journal publishes two pre-clinical investigations further exploring ILE use in local anaesthetic toxicity—two more pieces in the puzzle. They ask: does ILE therapy confer benefit in the paediatric population suffering LAST? The answer in the model interrogated at least appears in the affirmative. The answers to the more fundamental questions posed, however, are less clear. How do we integrate ILE into standard APLS resuscitation algorithms? And what is the fundamental mechanism of action of ILE in LAST anyway? By examining some of these unanswered questions pertaining to ILE, the authors serve to bring us incrementally closer to a complete understanding of this novel therapy. In the first paper, De Queiroz Siqueira and colleagues20De Queiroz Siqueira M Chassard D Musard H et al.Resuscitation with lipid, epinephrine, or both in levobupivacaine-induced cardiac toxicity in newborn piglets.Br J Anaesth. 2014; 112: 729-734Abstract Full Text Full Text PDF PubMed Scopus (14) Google Scholar address the issue of ILE use in the paediatric population suffering LAST, and furthermore attempt to clarify the role of epinephrine co-administration in the neonate arrested secondary to local anaesthetic cardiotoxicity. The intrinsic susceptibility of this population to complications of regional anaesthesia with cardiotoxic local anaesthetics, coupled with the profound impact of preventable paediatric death on all involved, render this an important issue for investigators and clinicians alike. In their model, sedated instrumented neonatal piglets were infused with levobupivacaine to 50% of baseline mean arterial pressure. Resuscitation was undertaken with saline control, 20% lipid emulsion, repeated dose epinephrine, or a combination of ILE and epinephrine, coupled with external chest compressions and mechanical ventilation. No difference was observed in rates of ROSC between active treatment groups. However, epinephrine administered alone or in combination with ILE resulted in increased cardiac arrhythmogenesis. These results are at once encouraging and perplexing. Lipid injection itself, or in combination with epinephrine, resulted in circulatory return in keeping with the positive clinical experience reported with ILE adult10Rosenblatt M Abel M Fischer G Itzkovich C Eisenkraft J Successful use of a 20% lipid emulsion to resuscitate a patient after a presumed bupivacaine-related cardiac arrest.Anesthesiology. 2006; 105: 217-218Crossref PubMed Scopus (483) Google Scholar 11Foxall G McCahon R Lamb J Hardman J Bedforth N Levobupivacaine-induced seizures and cardiovascular collapse treated with Intralipid.Anaesthesia. 2007; 62: 516-518Crossref PubMed Scopus (195) Google Scholar and also paediatric12Lin E, Aronson L. Successful resuscitation of bupivacaine induced cardiotoxicity in a neonate. Paediatr Anaesth 2101; 20: 955–7.Google Scholar 13Shah S Gopalakrishnan S Apuya J Shah S Martin T Use of intralipid in an infant with impending cardiovascular collapse due to local anesthetic toxicity.J Anesth. 2009; 23: 439-441Crossref PubMed Scopus (56) Google Scholar patients exhibiting LAST, thereby endorsing ILE in this proxy model of paediatric practice. The issue of concurrent vasopressor administration, however, remains much more vexing. Comparison of vasopressor use in ILE-based resuscitation from LAST in animal models has been extensively studied. Drawing definitive conclusions from the available data set is nevertheless limited by variation in animal models used, resuscitation regimes, and small sample sizes in the majority of trials. ILE has been demonstrated to result in superior haemodynamic and metabolic recovery compared with epinephrine either alone,21Weinberg G Di Gregorio G Ripper R et al.Resuscitation with lipid versus epinephrine in a rat model of bupivacaine overdose.Anesthesiology. 2008; 108: 907-913Crossref PubMed Scopus (145) Google Scholar or in combination with vasopressin,22Di Gregorio G Schwartz D Ripper R et al.Lipid emulsion is superior to vasopressin in a rodent model of resuscitation from toxin induced cardiac arrest.Crit Care Med. 2009; 37: 993-999Crossref PubMed Scopus (91) Google Scholar in rodents resuscitated from bupivacaine-induced asystole. In a similar rat model, the same research group subsequently demonstrated numerically identical rates of ROSC when ILE was co-administered with or without low-dose epinephrine in bupivacaine-induced cardiac arrest,23Hiller D Gregorio G Ripper R et al.Epinephrine impairs lipid resuscitation from bupivacaine overdose: a threshold effect.Anesthesiology. 2009; 111: 498-505Crossref PubMed Scopus (127) Google Scholar albeit epinephrine was associated with more rapid circulatory return. Epinephrine at doses above 10 µg kg−1 in conjunction with ILE, however, resulted in lesser rates of ROSC and deteriorating metabolic parameters characterized by hyperlactatemia, thus suggesting a threshold effect to any benefit of administered exogenous catecholamines. Additional researchers exploring epinephrine co-treatment with ILE in LAST have reported mixed results. Li and colleagues24Li B Yan J Shen Y Li B Hu Z Ma Z Association of sustained cardiovascular recovery with epinephrine in the delayed lipid-based resuscitation from cardiac arrest induced by bupivacaine overdose in rats.Br J Anaesth. 2012; 108: 857-863Abstract Full Text Full Text PDF PubMed Scopus (14) Google Scholar in a rat model of bupivacaine-induced asystole have shown superior outcomes with epinephrine plus lipid emulsion administered after 10 min of BLS, but greater metabolic recovery in surviving animals that received lipid only. Similarly, in a piglet model of bupivacaine-induced circulatory arrest, Mauch and colleagues25Mauch J Jurado O Spielmann N Bettschart-Wolfensberger R Weiss M Resuscitation strategies from bupivacaine induced cardiac arrest.Paediatr Anaesth. 2012; 22: 124-129Crossref PubMed Scopus (17) Google Scholar report greatest survival (86%) with a combination of lipid and epinephrine-augmented ACLS, compared with just 29% with lipid only treated animals. Vasopressor (epinephrine and vasopressin)-treated animals returned intermediate results. Epinephrine/vasopressin combination was conversely demonstrated superior in achieving ROSC in an adult porcine model of bupivacaine-induced cardiac arrest when compared with ILE alone by Mayr and colleagues.26Mayr V Mitterschiffhaler L Neurauter A et al.A comparison of the combination of epinephrine and vasopressin with lipid emulsion in a porcine model of asphyxial cardiac arrest after intravenous injection of bupivacaine.Anesth Analg. 2008; 106: 1566-1571Crossref PubMed Scopus (82) Google Scholar This study design differed markedly from the former in that induction of cardiac arrest was associated with induced asphyxia, and resuscitative efforts were associated with significantly lesser coronary perfusion pressure in the lipid-treated group. In direct contrast to the work of De Queiroz Siqueira, Mauch and colleagues27Mauch J Martin Jurado O Spielmann N Bettschart-Wolfensberger R Weiss M Comparison of epinephrine vs lipid rescue to treat severe local anesthetic toxicity—an experimental study in piglets.Paediatr Anaesth. 2011; 21: 1103-1108Crossref PubMed Scopus (22) Google Scholar in a near identical model of bupivacaine-induced cardiovascular collapse (again infused to 50% baseline MAP in instrumented piglets), reported greatest survival in epinephrine-treated groups when compared with two different ILE regimens. Significantly, the most fundamental difference between study designs was the absence of external chest compressions in the latter, having been instituted at target MAP in the former. The question of epinephrine co-administration with lipid emulsion in an isolated heart model of LA toxicity has been investigated by one group in an effort to separate the systemic circulatory effects of vasopressor activity from its direct cardiotonic effect.28Liu L Xia Y Chen Y The comparative effects of lipid, epinephrine, and their combination in the reversal of bupivacaine induced asystole in the isolated rat heart.Anesth Analg. 2012; 114: 886-893Crossref PubMed Scopus (24) Google Scholar In a non-recirculating Langendorff preparation, isolated rat hearts were perfused with bupivacaine until 3 min after asystole. Continuous perfusion was then undertaken with control, lipid, epinephrine, or lipid plus epinephrine-spiked perfuslate. Time to heartbeat recovery was significantly shorter in both the lipid- and combination-treated groups, with the mean rate pressure product greatest in the combination group. Cardiac tissue bupivacaine concentration was noted to be significantly higher in the control and epinephrine-treated groups, suggesting augmented myocardial washout with ILE-containing perfuslate. To complicate things still further, interactions between ILE and epinephrine have been reported in some animal models. ILE pre-treatment was shown to delay the peak effect on mean arterial pressure (MAP), and prolong its duration, without altering the peak increase in either MAP or heart rate response in rats administered i.v. epinephrine at 15 µg kg−1.29Carreiro S Blum J Jay G Hack J Intravenous lipid emulsion alters the hemodynamic response to epinephrine in a rat model.J Med Toxicol. 2013; 9: 220-225Crossref PubMed Scopus (8) Google Scholar It would seem likely that some interaction between ILE and additional lipophillic resuscitation drugs30Niiya T Litonius E Petaja L Neuvonen P Rosenberg P Intravenous lipid emulsion sequesters amiodarone in plasma and eliminates its hypotensive action in pigs.Ann Emerg Med. 2010; 56: 401-408Abstract Full Text Full Text PDF Scopus (43) Google Scholar likewise may occur potentially limiting their intended utility. The sum of available pre-clinical data appears to be that ILE alone may confer equivalent resuscitation outcome, with lesser arrhythmogenesis and improved post-arrest metabolic parameters, in models where coronary perfusion (CP) can be assured. In models where cardiopulmonary resuscitation returned lesser CP pressures, ROSC and survival proved more dependent on epinephrine administration. Therefore, until studies of significantly greater power exist comparing resuscitation outcome in lipid alone and lipid/epinephrine-treated animals in appropriate models, clinical recommendation must continue for early APLS, including epinephrine co-administration with immediate ILE injection in local anaesthetic cardiotoxicity. In the second paper, Aumeier and colleagues31Aumeier C Kasdorf B Gruber M et al.Lipid emulsion pretreatment has different effects on mepivacaine and bupivacaine cardiac toxicity in an isolated rat heart model.Br J Anaesth. 2014; 112: 735-741Abstract Full Text Full Text PDF PubMed Scopus (20) Google Scholar explore the effect of lipid pre-treatment on recovery from local anaesthetic-induced asystole in an isolated heart model. Two local anaesthetics with disparate physicochemical properties [the relatively hydrophilic mepivacaine (logP1.9), and highly lipophilic bupivacaine (logP3.65)] are interrogated with two underlying postulates. First, can pre-treatment with a lipid emulsion ameliorate developed local anaesthetic-induced cardiac toxicity, and secondly, does the postulated 'sink' hypothesis explain any observed benefits. These very questions are not new having been posed since discovery of lipid rescue.32Weinberg G Lipid rescue resuscitation from local anaesthetic cardiac toxicity.Toxicol Rev. 2006; 25: 139-145Crossref PubMed Scopus (107) Google Scholar They nevertheless manifest some unresolved mechanistic tension, for if the pre-treatment strategy proves efficacious by definition some advantage has occurred before any juncture whereby lipid-enhanced pharmacokinetic washout were to occur. The results are informative. ILE-containing perfuslate prolonged time to developed asystole and speeded recovery of rate–pressure product (RPP) in bupivacaine intoxicated hearts. No such difference was seen in the mepivacaine group with ILE seemingly worsening recovery of RPP. In many ways, these findings mirror those of the earliest reports of Weinberg and colleagues,1Weinberg G VadeBoncouer T Ramaraju G Garcia-Amaro M Cwik M Pretreatment or resuscitation with a lipid infusion shifts the dose–response to bupivacaine-induced asystole in rats.Anaesthesiology. 1998; 88: 1071-1075Crossref PubMed Scopus (512) Google Scholar who demonstrated ILE pre-treatment to initiate a rightward shift in survival curves after bupivacaine-induced cardiac arrest in whole rats. Subsequent work from the same study group demonstrated increased bupivacaine washout from isolated hearts perfused with lipid-containing perfuslate consistent with myocardial drug detoxification.33Weinberg G Ripper R Murphy P et al.Lipid infusion accelerates removal of bupivacaine and recovery from bupivacaine toxicity in the isolated rat heart.Reg Anesth Pain Med. 2006; 31: 296-303Crossref PubMed Google Scholar The absence of effect in the mepivacaine group seemingly supports such a pharmacokinetic explanation based on lipophilicity alone. Such findings are further supported by the work of Ruan and colleagues who demonstrated in vitro that the local anaesthetics bupivacaine, ropivacaine, and mepivacaine are sequestered to lipid-spiked plasma consistent with their intrinsic octanol:water partition constants.34Ruan W French D Wong A Drasner K Wu A A mixed (long and medium chain) triglyceride lipid emulsion extracts local anesthetic from human serum in vitro more effectively than a long chain emulsion.Anesthesiology. 2012; 116: 334-339Crossref PubMed Scopus (44) Google Scholar Similarly, Shi and colleagues35Shi K Xia Y Wand Q et al.The effect of lipid emulsion on pharmacokinetics and tissue distribution of bupivacaine in rats.Aneth Analg. 2013; 116: 804-809Crossref PubMed Scopus (62) Google Scholar have demonstrated modulation of bupivacaine redistribution kinetics in favour of accelerated elimination in an intact rodent model of bupivacaine intoxication treated with lipid emulsion. While attractive in its simplicity, the sink/redistribution hypothesis has been increasingly questioned as the sole cause for the observed benefits in drug-induced cardiotoxicity. In 2007, Stehr and colleagues36Stehr S Ziegeler J Pexa A et al.The effects of lipid infusion on myocardial function and bioenergetics in l-bupivacaine toxicity in the isolated rat heart.Anesth Analg. 2007; 104: 186-192Crossref PubMed Scopus (131) Google Scholar demonstrated a positive inotropic effect of lipid on isolated heart preparations subjected to bupivacaine at doses lower than required to effect changes in plasma concentration of the local anaesthetic. Similarly, Fettiplace and colleagues37Fettiplace M Ripper R Lis K et al.Rapid cardiotonic effects of lipid emulsion infusion.Crit Care Med. 2013; 41: 156-162Crossref PubMed Scopus (93) Google Scholar have shown positive inotropic and positive lusitropic effects for lipid emulsion in both intact rodents and isolated heart models citing this as one potential beneficial mechanism of action for ILE in LAST. Notwithstanding these, augmentation of free fatty acid oxidation,38Bania T Chu J Lyon T Yoon J The role of cardiac free fatty acid metabolism in verapamil toxicity treated with intravenous fat emulsions.Acad Emerg Med. 2007; 14: 196-197Crossref Google Scholar 39Partownavid P Umar S Li J Rahman S Eghbali M Fatty-acid oxidation and calcium homeostasis are involved in the rescue of bupivacaine induced cardiotoxicity by lipid emulsion in rats.Crit Care Med. 2012; 40: 2431-2437Crossref PubMed Scopus (83) Google Scholar altered calcium homeostasis,39Partownavid P Umar S Li J Rahman S Eghbali M Fatty-acid oxidation and calcium homeostasis are involved in the rescue of bupivacaine induced cardiotoxicity by lipid emulsion in rats.Crit Care Med. 2012; 40: 2431-2437Crossref PubMed Scopus (83) Google Scholar and direct ion-channel effects40Nadrowitz F Stoetzer C Foadi N et al.The distinct effects of lipid emulsions used for lipid resuscitation on gating and bupivacaine induced inhibition of the cardiac sodium channel Nav1.5.Anesth Analg. 2013; 117: 1101-1108Crossref PubMed Scopus (27) Google Scholar have all been investigated and gained support as potential origins of the beneficial effects for ILE in animal models of lipid rescue from drug-induced cardiotoxicity. The work of Aumeier and colleagues poses yet more questions. If the sink alone is responsible for more rapid cardiac recovery then why is that very recovery manifest when lipid perfusion has ceased? Conversely, if some advantage is conferred through pre-treatment with lipid via metabolic means, then why is the benefit confined to bupivacaine alone? More broadly, it would appear that while a single beneficial mechanism may dominate in effecting recovery from myocardial intoxication for any drug, it is perhaps more likely that a number of mechanisms are acting in concert with synergistic antidotal effect. Potential even exists for varying contributions from any given mechanism at differing stages in the course of poisoning for the same agent, and indeed for differing mechanisms to predominate across classes of agent of intoxication. What appears clear from both models is that application of lipid emulsion results in amelioration of cardiotoxicity from lipophillic local anaesthetic overdose. The next stage in our understanding of this (increasingly complex) antidote is likely to come from animal models incorporating concurrent investigation into both pharmacokinetic and pharmacodynamic mechanisms of action. Then we will be in a position to start putting more pieces of the puzzle together. None declared.
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