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Intravenous lipid emulsion therapy – The fat of the land
Trends in Anaesthesia and Critical Care 3 (2013) 336e341
Contents lists available at SciVerse ScienceDirect
Trends in Anaesthesia and Critical Care journal homepage: www.elsevier.com/locate/tacc
REVIEW
Intravenous lipid emulsion therapy e The fat of the land Rebecca Garrett a, *, Vikas Kaura b, Sheridan Kathawaroo c a
Intensive Care Unit, St Mary’s Hospital, Praed Street, London W2 1N, UK Hull York Medical School, UK c North Cumbria University Hospitals NHS Trust, UK b
s u m m a r y Keywords: Intravenous lipid emulsion Local anaesthetic toxicity Calcium channel antagonist overdose Tri-cyclic antidepressant overdose
Local anaesthetic agents are utilised ubiquitously in clinical practice, and as such potentially grave adverse events such as systemic toxicity can occur. Although the use of ultrasound, and nerve stimulator guided administration have reduced the risk of such adversities, they unfortunately have not been eliminated. This review examines the pharmacology and toxicology of local anaesthetic agents and the use of Intravenous Lipid Emulsion (ILE) to counteract the systemic toxic effects. The research underpinning the ‘Lipid Sink’ and ‘Lipid Flux’ theories of ILE mechanism of action are explored, as is the novel and successful use of ILE in other lipophilic drug toxidromes, such as overdoses of tri-cyclic antidepressants and calcium channel antagonists. Also discussed are the potential direct and indirect risks associated with the use of intravenous lipid treatments and the possibility for reporting bias in the literature. Despite this, case reports of the successful use of ILE are certainly compelling, and have led to the rapid adoption of ILE in clinical practice and the recommendation for its use by anaesthetic associations worldwide. Ó 2013 Elsevier Ltd. All rights reserved.
1. Introduction The first report of the successful utilisation of lipid emulsion to counteract a drug toxidrome was in 1962, whereby researchers demonstrated an enhanced recovery from barbiturate induced neurological depression in rats.1 However, it was the pioneering studies of Weinberg et al. over three decades later that initiated the translation of academic research into accepted clinical practice. In 1997 Weinberg and colleagues published a case report of a low dose of sub-cutaneous bupivacaine eliciting cardiotoxic effects in a carnitine-deficient patient.2 This chance observation was the catalyst behind research into the interplay between lipid administration and local anaesthetic toxicity. Ultimately, the findings from these early experiments, that lipid pre-treatment confers protective effects from local anaesthetic toxicity have brought about a significant development in clinical practice through the use of Intravenous Lipid Emulsion (ILE) in local anaesthetic toxicity. Moreover, as the wealth of knowledge and experience with the utilisation of ILE mounts so too does the number of possibilities for use. Whilst clinical familiarity with ILE is strengthening, there still remains scientific uncertainty as to the precise mechanism of * Corresponding author. Tel.: þ44 (0)7868648014. E-mail addresses: [email protected] (R. Garrett), [email protected] (V. Kaura), [email protected] (S. Kathawaroo). 2210-8440/$ e see front matter Ó 2013 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.tacc.2013.04.001
action. In the next section these issues will be addressed by outlining the currently held theories. However, it is first necessary to look at the nature of the toxicity in order to discuss the antidote. 1.1. The pharmacology of local anaesthetic agents It has been well over a century since Carl Koller, at the suggestion of Sigmund Freud, utilised the topical anaesthetic properties of cocaine to perform surgery on the insensate eye. In the decades that followed, the use of cocaine and subsequently other local anaesthetic agents, such as procaine and benzocaine became more commonplace. Unfortunately however, so too did the number of reports of fatal toxicity.3 Subsequently modification of existing agents and the development of new compounds have dramatically increased the safety profile of local anaesthetic agents. Furthermore, universal access to monitoring equipment and the advent of ultrasound guidance technology have provided additional, indispensable levels of protection against potential systemic toxicity. Nevertheless, adverse events are inevitable when one considers the vast number of procedures performed, thus the potential for grave consequences means that this should be an area of ongoing research and optimisation of practice. Local anaesthetic agents are used ubiquitously in clinical practice to reversibly block the action of sensory, motor and autonomic neurons. They can be divided into two groups dependent on whether an amide or an ester links the core aromatic and amino
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portions common to all local anaesthetics. The esters include procaine and cocaine, whilst the amides constitute lidocaine, prilocaine, bupivacaine and ropivacaine. It is the amino portion of the molecule which, dependent on its pKa value will dictate the degree of ionisation when in contact with a substance of particular pH. When pH is equal to pKa, the molecule is 50% ionised. At a higher pKa, the ionised and therefore water soluble molecule prevails, with a resultant slower onset of action, as illustrated by bupivacaine. With a lower pKa, the non-ionised, lipid soluble species predominates. This facilitates diffusion through lipid membranes, thereby hastening the speed of onset.4 Central nerve fibres, which are responsible for distal limb innervation, are the last to be reached and therefore anaesthetised, during this process of diffusion. Conversely however, the vascular core fibres are anaesthetised preferentially during intravenous regional anaesthesia.5 The duration of block is dependent upon the degree of protein binding by the molecule in question as well as the vascularity of the area anaesthetised. This latter facet is exploited clinically by the addition of vasoactive agents such as adrenaline to local anaesthetics, which via reduction in blood flow, prolong the duration of action. Once the unionised molecule has diffused across the neuronal membrane the lower pH of the intracellular environment promotes dissociation into the ionised form, which then reversibly binds to, and inactivates the sodium channel. Once a sufficient degree of channel blockade is achieved, membrane depolarisation and hence transmission of nerve impulses is impeded, thereby eliciting local anaesthetic effects.6 However, this channel-blocking property is not restricted to sodium channels within neurons, or even to sodium channels in general. Thus, in sufficient concentration and/or distribution local anaesthetics will block sodium, potassium and calcium channels within cardiac myocytes as well as sodium and potassium channels within the central nervous system. It is such disseminated effects which account for the severe and potentially fatal cardiac and neurological toxicity associated with local anaesthetics. 2. Local anaesthetic toxicity
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excitation-contraction coupling, thereby reducing contractility and exerting negative inotropic effects.3 Oxidative phosphorylation within myocytes is impaired by local anaesthetics as they cause the uncoupling of complexes I and II in the electron transport chain. The resultant low levels of ATP cause myocardial depression.3,8 ATP stores are further depleted by the inhibition of free fatty acid transfer into the cell and mitochondria. Specifically, local anaesthetics inhibit an intracellular enzyme known as carnitine-acylcarnitine translocase (CACT), which is vital for the transfer of long-chain fatty acids into the mitochondria. As only short- and medium-chain fatty acids can reach the inner mitochondrial membrane by passive diffusion, this inhibition significantly limits an important energy source.8 Indirect cardiotoxic effects arise from inhibition of the nucleus tractus solitarius in the medulla oblongata. The resultant modulation of intrinsic activity and sympathetic tone decreases cardiac output and blood pressure and provokes arrhythmias.10 2.2. Neurotoxicity Local anaesthetics exert a bi-phasic effect within the central nervous system. Disinhibition of excitatory interneurons, via sodium channel inactivation on inhibitory interneurons, elicits an excitatory neurological state typified by circumoral paraesthesia, metallic taste, tinnitus, visual disturbance, tremors, dizziness and ultimately, convulsions. At sufficient concentrations, both inhibitory and excitatory neurons are blocked producing profound neurological depression, which is manifest clinically as respiratory depression, loss of consciousness, coma and death. 3. Mechanism of action of intravenous lipid emulsion The precise mechanism of action of lipid emulsion in the treatment of local anaesthetic toxicity has yet to be conclusively defined. However, there are two principle theories which have evolved alongside the ever mounting clinical and biochemical exploration into this field.
2.1. Cardiac toxicity 3.1. ‘Lipid Sink’ theory Local anaesthetic agents are capable of inducing dysrhythmias, myocardial depression and hypotension. Such disturbance in functioning can be elicited by direct and indirect mechanisms. Sodium channel blockade within the myocardium impedes membrane depolarisation and hence cardiac action potential propagation.3 This slowing of cardiac conduction can be used for clinical benefit, as is typified by the antiarrhythmic effects of lidocaine. However, it is crucially dependent on the ability of lidocaine to not only bind rapidly, but more importantly dissociate rapidly from sodium channels. Other local anaesthetics such as bupivacaine and ropivacaine are slow to dissociate, thereby resulting in a prolonged impedance to conduction, manifest clinically as prolongation of the PR interval, widening of the QRS complex and bradyarrhythmias, which can subsequently predispose to reentrant arrhythmias and ventricular fibrillation.7 Exacerbation of such arrhythmogenic effects are elicited via blockade of cardiac potassium channels. Thus, inhibition of the transient outward potassium current prolongs the action potential and impedes repolarisation,8 whilst blockade of two pore domain potassium channels (delayed rectifier channels) within the conduction system increases the possibility of spontaneous depolarisation and re-entry phenomenon.9 Local anaesthetics bind to and inhibit L-type calcium channels which prolongs the cardiac action potential,10 as well as reducing calcium release from the sarcoplasmic reticulum. Diminished cytosolic calcium impedes the Naþ/Ca2þ exchange pump and
The Lipid Sink theory holds that administration of lipid emulsion provides an expanded lipid compartment separate from the plasma aqueous phase, which attracts and sequesters lipophilic drugs, thereby reducing the amount of free molecules capable of eliciting toxicity.11 Furthermore, this could also expedite the removal of toxins already bound to tissue.12 Conceptual support for the Lipid Sink arises from two main observations. Firstly, lipid emulsion is capable of counteracting both the cardiac and neurological sequelae of lipophilic drug toxicity. In contrast to the heart, the brain is not dependent on fatty acid metabolism for energy requirements and this would suggest that, at least with respect to neurotoxicity, it is this partitioning (and not metabolic) effect which prevails.13 Secondly, lipid emulsion has been demonstrated to exert beneficial effects on toxicity associated with a variety of drugs with disparate sites and mechanisms of action. Their commonality lies in a high lipid solubility, favouring their extraction to a lipid phase.13 Direct experimental support has been demonstrated in numerous in vitro and in vivo studies. In the initial work by Weinberg et al. examining the effects of ILE on bupivacaine toxicity in rats, they demonstrated a statistically significant rise in plasma (both lipid and aqueous phase combined) concentration of bupivacaine with increasing doses of ILE. Furthermore, they established a lipid:aqueous partition coefficient for bupivacaine of 11.9, with over 75% of bupivacaine being dissolved in the lipid phase.11 French
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et al. have recently demonstrated the in vitro extraction of bupivacaine, ropivacaine and mepivacaine into a lipid partition in quantities proportional to the degree of lipophilicity of the anaesthetic agent.14 Animal studies have also demonstrated an enhanced rate of bupivacaine removal from rat hearts following lipid infusion.15 Moreover, significant partition into the lipid phase has also been demonstrated with the lipophilic drugs chlorpromazine and phenytoin.16,17 Results from recent in vitro studies have also highlighted how the lipid partition constant and volume of distribution of a drug (such as local anaesthetics) can be utilised to evaluate the degree of efficacy of lipid infusion in ameliorating cardiotoxicity.14 Interestingly, Papadopoulou et al. have recently published what they refer to as a visual representation of the lipid sink effect by way of dye surrogates to demonstrate local anaesthetic sequestration by lipid emulsions.18 Despite such decisive outcomes from animal studies, human case reports have been somewhat more ambiguous in their findings. Thus, Litz et al.19 and Ludot et al.20 reported reductions in plasma local anaesthetic concentrations post ILE infusion. However, the former authors proposed that the rate of clearance was greater than would be expected from conventional pharmacokinetics, and have led to suggestions that the lipid infusion alters the metabolism of the toxins involved.6 Certainly, Weinberg noted low bupivacaine concentrations after lipid treatment in some instances and suggested that modulation of pharmacodynamics, such as uptake of toxin by lipid-storing organs could account for these findings.11 Indeed, lipid delivery to the liver would augment clearance of toxins which undergo hepatic metabolism.21 Also of consideration is the demonstration that lipid therapy itself can interfere with results obtained from the laboratory analysis of samples.22 3.2. ‘Lipid Flux’ theory This theory is based on the aforementioned ability of local anaesthetics to inhibit the action of the intracellular enzyme carnitine-acylcarnitine translocase (CACT) and thus the transfer of long chain fatty acids into the mitochondria for oxidative metabolism. It is held that lipid treatment overcomes this barrier to ATP and energy production by providing an influx of fatty acids, which via mass action surmount local anaesthetic-induced cardiac depression. Ultimately, this renders the heart more responsive to resuscitation.8 The serendipitous origin of this theory arose when Weinberg noted ventricular dysrhythmias in a ‘carnitine deficient’ patient administered subcutaneous low dose bupivacaine.2 The group went on to demonstrate inhibition of CACT and long chain fatty acid transport by bupivacaine in isolated mitochondria.23 Furthermore, it has been observed that administration of ILE improves cardiac contractility in a rat model of bupivacaine cardiotoxicity24 and a canine model of myocardial stunning.25 Of note, is the finding that the potential for a particular local anaesthetic to elicit cardiotoxicity is comparable to its ability to impair carnitine-dependent fatty acid transport.23
such that the LD50 was increased by 48% in the group receiving lipid.11 They subsequently reproduced the cardioprotective effects of lipid emulsions in a canine model of local anaesthetic toxicity, thereby permitting correlation of the findings more appropriately to the complexities of human physiology.26 A treatment algorithm for the use of lipid emulsion in human cardiac arrest attributed to local anaesthetic toxicity was proposed by Weinberg in 2004.27 This regime was extrapolated solely from information acquired from animal studies, and as such lipid rescue therapy was initially recommended for use only after exhaustion of standard advanced life support techniques. Of course, the infrequent but potentially catastrophic effects of systemic local anaesthetic toxicity have precluded it from being the subject of human randomised controlled trials. The first case report of ILE being used to successfully resuscitate a patient after presumed bupivacaine related cardiac arrest was published in 2006.28 The patient was a 58 year old male who developed seizures, ventricular dysrrhythmias and ultimately asystole, post administration of a bupivacaine and mepivacaine interscalene block. After 20 min of advanced life support, at a point when cardio-pulmonary bypass was being considered, the use of ILE was proposed. The patient received a bolus of ILE followed by a defibrillation shock at 360 Joules at which time a sinus beat was noted on monitoring. Atropine and adrenaline were given and were followed 15 s later by return of spontaneous circulation. The patient was subsequently discharged with no neurological sequelae. This initial case report has paved the way for numerous publications detailing the successful utilisation of ILE in treating refractory cardiac arrest due to local anaesthetic toxicity. Indeed, as of 2012 there had been 21 published case reports of successful use of ILE in local anaesthetic toxicity.29 Furthermore, given the not too infrequent alterations to local anaesthetic packaging it seems unfortunately inevitable that inadvertent local anaesthetic toxicity will continue to mar clinical practice; a point eloquently highlighted in a recent letter in the Royal College of Anaesthesia bulletin (see Fig. 1). In 2005 Dalgish and Kathawaroo highlighted the exciting findings from the Weinberg team in Anaesthesia.30 Subsequent correspondences and publications regarding ILE led to the Association of Anaesthetists of Great Britain and Ireland (AAGBI) releasing recommendations for the use of lipid rescue in severe local anaesthetic toxicity in 2007.31 Furthermore, the accumulating evidence base and clinical experience with ILE has led commentators in the field to propose a more timely use of ILE; that is, at the point of recognition of toxicity.32 There are certainly case reports to support this recommendation, as evidenced by the termination of abnormal ECG morphology and arrhythmias with ILE, prior to degeneration into clinically significant physiological decompensation. Thus, Ludot et al. report a case of ventricular arrhythmia in a 13 year old female post lumbar plexus block with lidocaine and ropivacaine.20 An immediate bolus of 20% lipid emulsion was given, with normalisation of the QRS complex within 2 min and resolution of all ECG changes within 30 min. 4.2. Lipophilic drugs
4. Clinical use of intravenous lipid emulsion 4.1. Local anaesthetics The preliminary hypothesis of Weinberg and colleagues that lipid pre-treatment would exacerbate local anaesthetic toxicity was not born out. Indeed these initial findings led to the tailoring of specific experimental designs to prove just the opposite. Thus, Weinberg et al. eloquently demonstrated that pretreatment or resuscitation with a lipid infusion shifts the doseeresponse curve to bupivacaine-induced asystole in rats in an impressive manner,
Having secured its role as an antidote to local anaesthetic toxicity, the successful use of lipid rescue therapy to combat toxicity associated with other lipophilic drugs has been published. Thus, both animal studies and human case reports demonstrate beneficial effects of lipid rescue against verapamil,21,33 bupropion and lamotrigine,34 quetiapine and sertraline,35 as well as tricyclic antidepressants.36 Given the potential for abuse and overdose of these medications, particularly the antidepressants, ILE offers a valuable tool in the battle to counteract toxicity associated with these drugs.
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Fig. 1. A recent letter in the Royal College of Anaesthesia bulletin highlights the new non-sterile packed ampoule of bupivacaine hydrochloride (top in A, and bottom in B). Note the similarity between saline and the new bupivacaine vials; this may increase the risk of inadvertent intravenous injection of bupivacaine. Image with permission from.55 [The Royal College of Anaesthetists (UK), Bulletin 76, page 58, November 2012].
4.2.1. Calcium channel antagonists 4.2.1.1. Verapamil. Verapamil is a lipophilic calcium channel antagonist which is associated with profound toxicity in overdose, typified by bradycardia, hypotension, bowel ischaemia and cardiac arrest.37 In 2007 the American Poison’s Association reported that whilst verapamil accounted for only 12% of all cardiovascular toxic drug exposures, it was responsible for almost half the deaths (47%) in the same category.38 Management in overdose, has primarily relied upon physiological support until the drug is eliminated. This includes, gastric decontamination, intravenous calcium, preload enhancement and inotropic support, euglycaemic hyperinsulinaemia and as a last resort, cardiac bypass. However, over recent years animal studies and human case reports have begun to detail the successful use of ILE as a specific antidote to verapamil toxicity.21,39 Thus Tebbutt et al. demonstrated impressive results in a rat model of verapamil toxicity, whereby infusion of ILE conferred a near doubling of survival time, mean lethal dose and LD50 in this group as compared to saline treated controls.21 Such favourable outcomes have also been established in a canine model of verapamil toxicity, in which 100% animals receiving standard resuscitation plus lipid treatment survived to 120 min compared to only 14% in the group receiving standard resuscitation and saline alone.12 With respect to human case reports, Young et al. reported the rapid stabilisation of a 32 year old male who had ingested 13.44 g verapamil (plus other medications) following ILE administration,33 whilst Liang et al.39 described the physiological improvement post ILE of a 41 year old female who had ingested 19.2 g verapamil. Whilst in such anecdotal reports it remains difficult to prove causality, in both cases the temporal relationship between ILE administration and improvement in physiological parameters is certainly persuasive. 4.2.1.2. Diltiazem. Encouraging outcomes have also been achieved using ILE in diltiazem overdose.40,41 Montiel et al. reported a positive outcome following the use of ILE in an 18 year old female who had ingested 3.6 g sustained release Diltiazem.42 The initial blood diltiazem level was 7893 ng/mL. Such levels have in the past proven to be fatal, but the patient continued to improve post ILE bolus and infusion, with no reported complications from the therapy. It is apparent that both the aforementioned Lipid Sink and Lipid Flux theories could underlie the clinical benefit of ILE utilisation in calcium channel toxicity. However, alternative propositions specific to calcium channel antagonism have also been voiced. Thus it is known that in overdose, calcium channel antagonists inhibit pancreatic calcium channels, thereby reducing insulin secretion. ILE
promotes production of nitric oxide and b-ketoacids,43 which in turn stimulate insulin secretion and hence augmentation of intracellular energy production.21 Furthermore, it has also been proposed that fatty acids from lipid emulsion could directly stimulate calcium channels.44 4.2.2. Antidepressants: tri-cyclic antidepressants TCA toxicity is elicited via myocardial sodium-channel blockage, with resultant ventricular dysrhythmias, myocardial depression and eventual cardiovascular collapse analogous to that observed with local anaesthetic toxicity. This capacity for severe toxicity in overdose has led to the development of, and preference in prescribing alternate antidepressants with safer side effect profiles; nevertheless TCA overdose remains a contributor to drug overdose mortality.45 Established therapy comprises decontamination, antidysrhythmic agents, sodium bicarbonate and supportive measures. The beneficial effects of ILE in TCA toxicity have been demonstrated in both animal studies and case reports. Thus, in a rabbit model of clomipramine toxicity Harvey et al. eloquently demonstrated the superiority of ILE over sodium bicarbonate in reversal of clomipramine-induced hypotension.46 Moreover, in their protocol for severe clomipramine toxicity all rabbits treated with ILE survived, whilst all those receiving sodium bicarbonate perished. Similarly persuasive findings have also been demonstrated in human case reports. Blaber et al. report a 36 year old woman who ingested 2.25 g of the TCA dothiepin.36 On arrival to the Emergency Department GCS was 4/15, BP 53/35, pulse 130 (broad complex tachycardia) and pH 6.75. Despite mechanical ventilation and multiple boluses of sodium bicarbonate the patient developed a cardiac arrest of 11 min duration. Further sodium bicarbonate as well as amiodarone and transvenous pacing were administered to no avail. At this point ILE was commenced as per the ‘bolus-infusion’ protocol, resulting in restoration of sinus rhythm within minutes. After 24 hours ventilator and inotropic support was withdrawn, with the patient being later discharged with no neurological sequelae. 4.3. Other uses Lipid emulsion has several other uses and in various species, these range from a dietary source of lipid in total parenteral nutrition, the treatment of certain drug toxicities in dogs, to its potential use in women with recurrent failure of embryonic implantation.47 Interestingly, older studies have also shown the survival advantage of ILE therapy following lethal injections of endotoxin in rats.48,49
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5. ILE reporting
7. Conclusion
Whilst such case reports provide persuasive accounts of the beneficial effects of ILE, one must of course, be aware of the potential biases associated with the literature. Due to the relative novel nature of using ILE following drug overdoses, reports are at risk of being self-selecting, such that cases where the therapy has been effective are reported and published, whereas those cases where resuscitation attempts have failed are not communicated. Proponents of ILE therapy have tried to overcome this through the development of self-reporting websites where a database can be assimilated of all cases where ILE has been used. However there may not be sufficient publicity to allow such databases to capture the majority of cases, especially given the voluntary nature of reporting. Furthermore, the utility of various multimodal rescue drugs and techniques during the resuscitation of patients following drug overdoses poses challenges in ascertaining the success of the intravenous lipid therapy component in the resuscitation.
Throughout this article we have chronicled the use of intravenous lipid emulsion, from its serendipitous inception to ever accumulating case reports of successful resuscitation in current clinical practice. Not only does ILE have demonstrable efficacy as an antidote to local anaesthetic toxicity, its spectrum of use now clearly lies beyond this to encompass the treatment of other lipid soluble drug toxidromes. While the mechanism of action is not clearly elucidated, we surmise that the high dose lipid leaches the toxic drug from inactivated ion channels - either by reducing the intravenous drug concentration or directly from the ion channels themselves. No doubt, as clinical familiarity and confidence with its use continues to grow, we expect to see more case reports of successful resuscitation from the use of intravenous lipid emulsion.
6. Complications of intravenous lipid emulsion
References
Paracelsus has previously written ‘all things are poison, and nothing is without poison; only the dose permits something not to be poisonous’. This may run true with ILE therapy, as previous studies have shown large volumes of high concentration of lipid infusion during parenteral nutrition have resulted in pulmonary complications.13 Furthermore there are some theoretical and animal experimental data which highlight some of the risks associated with ILE therapy. Studies in rodents have shown reduced resistance to bacterial pathogens with parenteral lipid administration.50 However, part of the explanation may be due to the experimental methodology as a parenteral lipid infusion is likely to have a greater risk of bacterial contamination/colonisation than saline infusions. Furthermore some of the infective risks associated with parenteral lipid infusion may be related to the long duration of infusions over days-weeks, in contrast ILE therapy is an infusion utilised for minutes to hours. A systematic review of lipid therapy for acute drug poisoning in animal and human studies reported that although there is some benefit of ILE utilisation in certain drug toxicities, the evidence is weak, with human data based on case reports. Furthermore it found no trials examining the safety of ILE in acute poisoning.51 However, whilst there has been one case report detailing the occurrence of asymptomatic hyperamylasemia post ILE use, most authors have not reported any adverse events associated with lipid therapy.52 Nevertheless, the AAGBI recommend the monitoring of the patient and biochemical markers for the development of pancreatitis post treatment with intravenous lipids. The maximum dose that can be administered to humans is unknown; experiments in rats have shown the lethal dose required to kill 50% of the animals (LD50) to be 68 ml/kg of rapidly infused 20% intravenous lipid.53 In humans, the recommended upper limit of 20% intravenous lipid is 10 ml/kg.51 It is not only the direct effects of the lipid therapy that can perturb the clinical management of a case. ILE can cause analytical interference with the various tests including haematological and biochemistry assays, the extent of the interference depends on the test and analyser used.22 High lipid content can result in reports of a falsely elevated haemoglobin and platelet count.54 Thus ideally samples should be taken prior to intravenous lipid therapy, and for those taken after, they should be fully discussed with the pathology laboratory.
1. Russel R, Westfall B. Alleviation of barbiturate depression by fat emulsion. Anaesthesia Analgesia 1962;41:582e5. 2. Weinberg GL, Laurito CE, Geldner P, Pygon BH, Burton BK. Malignant ventricular dysrhythmias in a patient with isovaleric acidemia receiving general and local anaesthesia for suction lipectomy. Journal of Clinical Anaesthesia 1997;9(8):668e70. 3. Dippenaar JM. Local anaesthetic toxicity. South African Journal of Anaesthesia and Analgesia 2007;13(3):23e8. 4. Covino BG. Pharmacology of local anaesthetic agents. British Journal of Anaesthesia 1986;58:701e16. 5. Raj PP, Garcia CE, Burleson JW, Jenkins MT. The site of action of intravenous regional anaesthesia. Anaesthesia Analgesia 1972;51:776e86. 6. Odedra D, Lyons G. Local anaesthetic toxicity. Current Anaesthesia and Critical Care 2010;21:52e4. 7. Johnson ME. Potential neurotoxicity of spinial anaesthesia with lognocaine. Mayo Clinic Proceedings 2000;75(9):921e32. 8. Kruger CJ, Marwick PC, Levin AL. Lipid rescue: the use of lipid emulsions to treat local anaesthetic toxicity. South African Journal of Anaesthesia and Analgesia 2009;15(5):20e8. 9. Kinder C, Yost CS. Two pore potassium channels: new sites for local anaesthetic action and toxicity. Regional Anaesthesia and Pain Medicine 2005;30(3):260e74. 10. Graf B. The cardiotoxicity of local anaesthetics: the place of ropivocaine. Current Topics in Medicinal Chemistry 2001;1:207e14. 11. Weinberg GL, VandeBoncouer T, Ramaraju GA, Garcia-Amaro MF, Cwik MJ. Pretreatment or resuscitation with a lipid infusion shifts the dose-response to bupivocaine-induced asystole in rats. Anaesthesiology 1998;88(4):1071e5. 12. Bania TC, Chu J, Perez E, Su M, Hahn IH. Haemodynamic effects of intravenous fat emulsion in an animal model of severe verapamil toxicity resuscitated with atropine, calcium and saline. Academic Emergency Medicine 2007:105e11. 13. Weinberg GL. Lipid emulsion infusion. Resusitation for local anaesthetic and other drug overdoses. Anaesthesiology 2012;117:180e7. 14. French D, Smollin C, Ruan W, Wong A, Drasner K, Wu AHB. Partition constant and volume of distribution as predictors of clinical efficacy of lipid rescue for toxicological emergencies. Clinical Toxicology 2011;49(9):801e9. 15. Weinberg GL, Ripper R, Murphy P. Lipid infusion accelerates removal of bupivocaine and recovery from bupivocaine toxicity in the isolated rat heart. Regional Anesthesia and Pain Medicine 2006;31:296e303. 16. Krieglstein J, Meffer A, Niemeyer D. Influence of emulsified fat on chlorpromazine availability in rat blood. Experientia 1974;30:924e6. 17. Straathof D, Driessen O, Meyer W. Influence of intralipid infusion on elimination of phenytoin. Archives Internationales de Pharmacodynamie et de Therapie 1984;267:180e6. 18. Papadopoulou A, Willers JW, Samuels TL, Uncles DR. The use of dye surrogates to illustrate local anaesthetic drug sequestration by lipid emulsion: a visual demonstration of the lipid sink effect. Regional Anesthesia and Pain Medicine 2012;37(2):183e7. 19. Litz RJ, Roessel T, Heller AR, Stehr AN. Reversal of central nervous system and cardiac toxicity after local anaesthetic intoxication by lipid emulsion. Anaesthesia and Analgesia 2008;106(5):1575e7. 20. Ludot H, Tharin J-Y, Belouadah M, Maziot J-X, Malinovsky J-M. Successful resuscitation after ropivacaine and lidocaine-induced ventricular arrhythmia following posterior lumbar plexus block in a child. Anesthesia and Analgesia 2008;106(5):1572e4. 21. Tebbutt S, Harvery M, Nicholson T, Cave G. Intralipid prolongs survival in a rat model of verapamil toxicity. Academic Emergency Medicine 2008;13(2):134e9.
Conflict of interest None.
R. Garrett et al. / Trends in Anaesthesia and Critical Care 3 (2013) 336e341 22. Dimeski G. A commentary on the effect of lipid emulsions on pathology tests. Anaesthesia 2009;64:1033e5. 23. Weinberg GL, Palmer JW, VadeBoncouer TR, Zuechner MB, Edelman G, Hoppel CL. Bupivacaine inhibits acylcarnitine exchange in cardiac mitochondria. Anesthesiology 2000;92(2):523e8. 24. Stehr SN, Ziegeler JC, Pexa A. The effects of lipid infusion on myocardial function and bioenergetics in l-bupivacaine toxicity in the isolated rat heart. Anesthesia Analgesia 2007;104(1):186e92. 25. Van de Velde M, Wouters PF, Rolf N, Van Aken H, Flameng W, Vandermeersch E. Long-chain triglycerides improve recovery from myocardial stunning in conscious dogs. Cardiovascular Research 1996;32:1008e15. 26. Weinberg GL, Ripper R, Feinstein DL, Hoffman W. Lipid emulsion infusion rescues dogs from bupivacaine-induced cardiac toxicity. Regional Anesthesia and Pain Medicine 2003;28(3):198e202. 27. Weinberg G. Lipid rescue: caveats and recommendations for the “Silver Bullet” [letter]. Regional Anesthesia and Pain Medicine 2004;29:74e5. 28. Rosenblatt MA, Abel M, Fischer GW, Itzkovich CJ, Eisenkraft JB. Successful use of a 20% lipid emulsion to resuscitate a patient after a presumed bupivacainerelated cardiac arrest. Anesthesiology 2006;105:217e8. 29. Lipid rescue resuscitation in the peer reviewed medical literature. www. lipidrescue.org. [accessed 11.03.13]. 30. Dalgleish D, Kathawaroo S. Lipid emulsion to treat bupivacaine toxicity. Anaesthesia 2005;60(8):822. 31. Association of Anaesthetists of Great Britain and Ireland. Guidelines for the management of severe local anaesthetic toxicity 2007. 32. Weinberg G. Lipid infusion therapy: translation to clinical practice. Anesthesia and Analgesia 2008;106(5):1340e2. 33. Young AC, Velez LI, Kleinschmidt KC. Intravenous fat emulsion therapy for sustained-release verapamil overdose. Resuscitation 2009:591e3. 34. Sirianni AJ, Osterhoudt KC, Calello DP, Muller AA, Waterhous MR, Goodkin MB, et al. Use of lipid emulsion in the resuscitation of a patient with prolonged cardiovascular collapse after overdose of bupropion and lamotrigine. Annals of Emergency Medicine 2008;51(4):412e5. 35. Finn SDH, Uncles DR, Willers J, Sable N. Early treatment of a quetiapine and sertraline overdose with intralipid. Anaesthesia 2009;64:191e4. 36. Blaber MS, Khan JN, Brebner JA, McColm R. “Lipid Rescue” for tricyclic antidepressant cardiotoxicity. The Journal of Emergency Medicine 2012;43(3): 465e7. 37. Derlet RW, Horowitz BZ. Cardiotoxic drugs. Emergency Medicine Clinics of North America 1995;13(4):771e91. 38. Bronstein AC, Spyker DA, Cantilena Jr LR, Green JL, Rumack BH, Heard SE. 2007 annual report of the American Association of Poison Control Centers’ National poison data system (NPDS): 25th Annual report. Clinical Toxicology (Phiadelphia) 2008;46:927e1057. 39. Liang CW, Diamond SJ, Hagg DS. Lipid rescue of massive verapamil overdose: a case report. Journal of Medical Case Reports 2011;5:399e404.
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40. Oakes J, Piquette C, Barthold C. Successful use of intravenous lipid as adjunctive therapy in severe calcium channel antagonist poisoning [Abstract]. Clinical Toxicology 2009;47:720e30. 41. Cooper G, Dyas J, Krishna C, Thompson J. Successful use of intravenous fat emulsion in severe poisoning following ingestion of lipid soluble drugs [Abstract]. Clinical Toxicology 2010;48:298. 42. Montiel V, Gougnard T, Hanston P. Diltiazem poisoning treated with hyperinsulinaemic euglycaemia therapy and intravenous lipid emulsion. European Journal of Emergency Medicine 2011;18(2):121e3. 43. Chelly JE, Oguchi T, Liang YY, Hartley CJ, Doursout M-F. Role of the intra lipid solvent in the propofol-induced nitric oxide stimulation [Abstract]. Anesthesiology 1996;85:A555. 44. Gueret G, Pennec JP, Arvieux CC. Haemodynamic effects of intralipid after verapamil intoxication may be due to a direct effect of fatty acids on myocardial calcium channels [Letter]. Academic Emergency Medicine 2007;14(8):761. 45. Office for National Statistics. Deaths related to drug poisoning in England and Wales. Statistical Bulletin. Available at: http://www.ons.gov.uk/ons/rel/ subnational-health3/deaths-related-to-drug-poisoning/2011/stb-deaths-relatedto-drug-poisoning-2011.html#tab-Antidepressants; 2011 [accessed 11.03.13]. 46. Harvey M, Cave G. Intralipid outperforms sodium bicarbonate in a rabbit model of clomipramine toxicity. Annals of Emergency Medicine 2007;49(2): 178e85. 47. Shreeve N, Sadek K. Intralipid therapy for recurrent implantation failure: new hope or false dawn? Journal of Reproductive Immunology 2012;93(1): 38e40. 48. Read TE, Grunfeld C, Kumwenda Z, Calhoun MC, Kane JP, Feingold KR, et al. Triglyceride-rich lipoproteins improve survival when given after endotoxin in rats. Surgery 1995;117(1):62e7. 49. Read TE, Grunfeld C, Kumwenda ZL, Calhoun MC, Kane JP, Feingold KR, et al. Triglyceride-rich lipoproteins prevent septic death in rats. The Journal of Experimental Medicine 1995;182(1):267e72. 50. Wanten GJA. Parenteral lipids in nutritional support and immune modulation. Clinical Nutrition Supplements 2009;4(1):13e7. 51. Jamaty C, Bailey B, Larocque A, Notebaert E, Sanogo K, Chauny JM. Lipid emulsions in the treatment of acute poisoning: a systematic review of human and animal studies. Clinical Toxicology (Philadelphia) 2010;48(1):1e27. 52. Marwick PC, Levin AI, Coetzee AR. Recurrence of cardiotoxicity after lipid rescue from bupivacaine-induced cardiac arrest. Anesthesia and Analgesia 2009;108:1344e6. 53. Hiller DB, Di Gregorio G, Kelly K, Ripper R, Edelman L, Boumendjel R, et al. Safety of high volume lipid emulsion infusion: a first approximation of LD50 in rats. Regional Anesthesia and Pain Medicine 2010;35(2):140e4. 54. Cantero M, Conejo JR, Jimenez A. Interference from lipemia in cell count by hematology analysers. Clinical Chemistry 1996;42:987e8. 55. The Royal College of Anaesthetists (UK). Bulletin November 2012;76:58.
Contents lists available at SciVerse ScienceDirect
Trends in Anaesthesia and Critical Care journal homepage: www.elsevier.com/locate/tacc
REVIEW
Intravenous lipid emulsion therapy e The fat of the land Rebecca Garrett a, *, Vikas Kaura b, Sheridan Kathawaroo c a
Intensive Care Unit, St Mary’s Hospital, Praed Street, London W2 1N, UK Hull York Medical School, UK c North Cumbria University Hospitals NHS Trust, UK b
s u m m a r y Keywords: Intravenous lipid emulsion Local anaesthetic toxicity Calcium channel antagonist overdose Tri-cyclic antidepressant overdose
Local anaesthetic agents are utilised ubiquitously in clinical practice, and as such potentially grave adverse events such as systemic toxicity can occur. Although the use of ultrasound, and nerve stimulator guided administration have reduced the risk of such adversities, they unfortunately have not been eliminated. This review examines the pharmacology and toxicology of local anaesthetic agents and the use of Intravenous Lipid Emulsion (ILE) to counteract the systemic toxic effects. The research underpinning the ‘Lipid Sink’ and ‘Lipid Flux’ theories of ILE mechanism of action are explored, as is the novel and successful use of ILE in other lipophilic drug toxidromes, such as overdoses of tri-cyclic antidepressants and calcium channel antagonists. Also discussed are the potential direct and indirect risks associated with the use of intravenous lipid treatments and the possibility for reporting bias in the literature. Despite this, case reports of the successful use of ILE are certainly compelling, and have led to the rapid adoption of ILE in clinical practice and the recommendation for its use by anaesthetic associations worldwide. Ó 2013 Elsevier Ltd. All rights reserved.
1. Introduction The first report of the successful utilisation of lipid emulsion to counteract a drug toxidrome was in 1962, whereby researchers demonstrated an enhanced recovery from barbiturate induced neurological depression in rats.1 However, it was the pioneering studies of Weinberg et al. over three decades later that initiated the translation of academic research into accepted clinical practice. In 1997 Weinberg and colleagues published a case report of a low dose of sub-cutaneous bupivacaine eliciting cardiotoxic effects in a carnitine-deficient patient.2 This chance observation was the catalyst behind research into the interplay between lipid administration and local anaesthetic toxicity. Ultimately, the findings from these early experiments, that lipid pre-treatment confers protective effects from local anaesthetic toxicity have brought about a significant development in clinical practice through the use of Intravenous Lipid Emulsion (ILE) in local anaesthetic toxicity. Moreover, as the wealth of knowledge and experience with the utilisation of ILE mounts so too does the number of possibilities for use. Whilst clinical familiarity with ILE is strengthening, there still remains scientific uncertainty as to the precise mechanism of * Corresponding author. Tel.: þ44 (0)7868648014. E-mail addresses: [email protected] (R. Garrett), [email protected] (V. Kaura), [email protected] (S. Kathawaroo). 2210-8440/$ e see front matter Ó 2013 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.tacc.2013.04.001
action. In the next section these issues will be addressed by outlining the currently held theories. However, it is first necessary to look at the nature of the toxicity in order to discuss the antidote. 1.1. The pharmacology of local anaesthetic agents It has been well over a century since Carl Koller, at the suggestion of Sigmund Freud, utilised the topical anaesthetic properties of cocaine to perform surgery on the insensate eye. In the decades that followed, the use of cocaine and subsequently other local anaesthetic agents, such as procaine and benzocaine became more commonplace. Unfortunately however, so too did the number of reports of fatal toxicity.3 Subsequently modification of existing agents and the development of new compounds have dramatically increased the safety profile of local anaesthetic agents. Furthermore, universal access to monitoring equipment and the advent of ultrasound guidance technology have provided additional, indispensable levels of protection against potential systemic toxicity. Nevertheless, adverse events are inevitable when one considers the vast number of procedures performed, thus the potential for grave consequences means that this should be an area of ongoing research and optimisation of practice. Local anaesthetic agents are used ubiquitously in clinical practice to reversibly block the action of sensory, motor and autonomic neurons. They can be divided into two groups dependent on whether an amide or an ester links the core aromatic and amino
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portions common to all local anaesthetics. The esters include procaine and cocaine, whilst the amides constitute lidocaine, prilocaine, bupivacaine and ropivacaine. It is the amino portion of the molecule which, dependent on its pKa value will dictate the degree of ionisation when in contact with a substance of particular pH. When pH is equal to pKa, the molecule is 50% ionised. At a higher pKa, the ionised and therefore water soluble molecule prevails, with a resultant slower onset of action, as illustrated by bupivacaine. With a lower pKa, the non-ionised, lipid soluble species predominates. This facilitates diffusion through lipid membranes, thereby hastening the speed of onset.4 Central nerve fibres, which are responsible for distal limb innervation, are the last to be reached and therefore anaesthetised, during this process of diffusion. Conversely however, the vascular core fibres are anaesthetised preferentially during intravenous regional anaesthesia.5 The duration of block is dependent upon the degree of protein binding by the molecule in question as well as the vascularity of the area anaesthetised. This latter facet is exploited clinically by the addition of vasoactive agents such as adrenaline to local anaesthetics, which via reduction in blood flow, prolong the duration of action. Once the unionised molecule has diffused across the neuronal membrane the lower pH of the intracellular environment promotes dissociation into the ionised form, which then reversibly binds to, and inactivates the sodium channel. Once a sufficient degree of channel blockade is achieved, membrane depolarisation and hence transmission of nerve impulses is impeded, thereby eliciting local anaesthetic effects.6 However, this channel-blocking property is not restricted to sodium channels within neurons, or even to sodium channels in general. Thus, in sufficient concentration and/or distribution local anaesthetics will block sodium, potassium and calcium channels within cardiac myocytes as well as sodium and potassium channels within the central nervous system. It is such disseminated effects which account for the severe and potentially fatal cardiac and neurological toxicity associated with local anaesthetics. 2. Local anaesthetic toxicity
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excitation-contraction coupling, thereby reducing contractility and exerting negative inotropic effects.3 Oxidative phosphorylation within myocytes is impaired by local anaesthetics as they cause the uncoupling of complexes I and II in the electron transport chain. The resultant low levels of ATP cause myocardial depression.3,8 ATP stores are further depleted by the inhibition of free fatty acid transfer into the cell and mitochondria. Specifically, local anaesthetics inhibit an intracellular enzyme known as carnitine-acylcarnitine translocase (CACT), which is vital for the transfer of long-chain fatty acids into the mitochondria. As only short- and medium-chain fatty acids can reach the inner mitochondrial membrane by passive diffusion, this inhibition significantly limits an important energy source.8 Indirect cardiotoxic effects arise from inhibition of the nucleus tractus solitarius in the medulla oblongata. The resultant modulation of intrinsic activity and sympathetic tone decreases cardiac output and blood pressure and provokes arrhythmias.10 2.2. Neurotoxicity Local anaesthetics exert a bi-phasic effect within the central nervous system. Disinhibition of excitatory interneurons, via sodium channel inactivation on inhibitory interneurons, elicits an excitatory neurological state typified by circumoral paraesthesia, metallic taste, tinnitus, visual disturbance, tremors, dizziness and ultimately, convulsions. At sufficient concentrations, both inhibitory and excitatory neurons are blocked producing profound neurological depression, which is manifest clinically as respiratory depression, loss of consciousness, coma and death. 3. Mechanism of action of intravenous lipid emulsion The precise mechanism of action of lipid emulsion in the treatment of local anaesthetic toxicity has yet to be conclusively defined. However, there are two principle theories which have evolved alongside the ever mounting clinical and biochemical exploration into this field.
2.1. Cardiac toxicity 3.1. ‘Lipid Sink’ theory Local anaesthetic agents are capable of inducing dysrhythmias, myocardial depression and hypotension. Such disturbance in functioning can be elicited by direct and indirect mechanisms. Sodium channel blockade within the myocardium impedes membrane depolarisation and hence cardiac action potential propagation.3 This slowing of cardiac conduction can be used for clinical benefit, as is typified by the antiarrhythmic effects of lidocaine. However, it is crucially dependent on the ability of lidocaine to not only bind rapidly, but more importantly dissociate rapidly from sodium channels. Other local anaesthetics such as bupivacaine and ropivacaine are slow to dissociate, thereby resulting in a prolonged impedance to conduction, manifest clinically as prolongation of the PR interval, widening of the QRS complex and bradyarrhythmias, which can subsequently predispose to reentrant arrhythmias and ventricular fibrillation.7 Exacerbation of such arrhythmogenic effects are elicited via blockade of cardiac potassium channels. Thus, inhibition of the transient outward potassium current prolongs the action potential and impedes repolarisation,8 whilst blockade of two pore domain potassium channels (delayed rectifier channels) within the conduction system increases the possibility of spontaneous depolarisation and re-entry phenomenon.9 Local anaesthetics bind to and inhibit L-type calcium channels which prolongs the cardiac action potential,10 as well as reducing calcium release from the sarcoplasmic reticulum. Diminished cytosolic calcium impedes the Naþ/Ca2þ exchange pump and
The Lipid Sink theory holds that administration of lipid emulsion provides an expanded lipid compartment separate from the plasma aqueous phase, which attracts and sequesters lipophilic drugs, thereby reducing the amount of free molecules capable of eliciting toxicity.11 Furthermore, this could also expedite the removal of toxins already bound to tissue.12 Conceptual support for the Lipid Sink arises from two main observations. Firstly, lipid emulsion is capable of counteracting both the cardiac and neurological sequelae of lipophilic drug toxicity. In contrast to the heart, the brain is not dependent on fatty acid metabolism for energy requirements and this would suggest that, at least with respect to neurotoxicity, it is this partitioning (and not metabolic) effect which prevails.13 Secondly, lipid emulsion has been demonstrated to exert beneficial effects on toxicity associated with a variety of drugs with disparate sites and mechanisms of action. Their commonality lies in a high lipid solubility, favouring their extraction to a lipid phase.13 Direct experimental support has been demonstrated in numerous in vitro and in vivo studies. In the initial work by Weinberg et al. examining the effects of ILE on bupivacaine toxicity in rats, they demonstrated a statistically significant rise in plasma (both lipid and aqueous phase combined) concentration of bupivacaine with increasing doses of ILE. Furthermore, they established a lipid:aqueous partition coefficient for bupivacaine of 11.9, with over 75% of bupivacaine being dissolved in the lipid phase.11 French
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et al. have recently demonstrated the in vitro extraction of bupivacaine, ropivacaine and mepivacaine into a lipid partition in quantities proportional to the degree of lipophilicity of the anaesthetic agent.14 Animal studies have also demonstrated an enhanced rate of bupivacaine removal from rat hearts following lipid infusion.15 Moreover, significant partition into the lipid phase has also been demonstrated with the lipophilic drugs chlorpromazine and phenytoin.16,17 Results from recent in vitro studies have also highlighted how the lipid partition constant and volume of distribution of a drug (such as local anaesthetics) can be utilised to evaluate the degree of efficacy of lipid infusion in ameliorating cardiotoxicity.14 Interestingly, Papadopoulou et al. have recently published what they refer to as a visual representation of the lipid sink effect by way of dye surrogates to demonstrate local anaesthetic sequestration by lipid emulsions.18 Despite such decisive outcomes from animal studies, human case reports have been somewhat more ambiguous in their findings. Thus, Litz et al.19 and Ludot et al.20 reported reductions in plasma local anaesthetic concentrations post ILE infusion. However, the former authors proposed that the rate of clearance was greater than would be expected from conventional pharmacokinetics, and have led to suggestions that the lipid infusion alters the metabolism of the toxins involved.6 Certainly, Weinberg noted low bupivacaine concentrations after lipid treatment in some instances and suggested that modulation of pharmacodynamics, such as uptake of toxin by lipid-storing organs could account for these findings.11 Indeed, lipid delivery to the liver would augment clearance of toxins which undergo hepatic metabolism.21 Also of consideration is the demonstration that lipid therapy itself can interfere with results obtained from the laboratory analysis of samples.22 3.2. ‘Lipid Flux’ theory This theory is based on the aforementioned ability of local anaesthetics to inhibit the action of the intracellular enzyme carnitine-acylcarnitine translocase (CACT) and thus the transfer of long chain fatty acids into the mitochondria for oxidative metabolism. It is held that lipid treatment overcomes this barrier to ATP and energy production by providing an influx of fatty acids, which via mass action surmount local anaesthetic-induced cardiac depression. Ultimately, this renders the heart more responsive to resuscitation.8 The serendipitous origin of this theory arose when Weinberg noted ventricular dysrhythmias in a ‘carnitine deficient’ patient administered subcutaneous low dose bupivacaine.2 The group went on to demonstrate inhibition of CACT and long chain fatty acid transport by bupivacaine in isolated mitochondria.23 Furthermore, it has been observed that administration of ILE improves cardiac contractility in a rat model of bupivacaine cardiotoxicity24 and a canine model of myocardial stunning.25 Of note, is the finding that the potential for a particular local anaesthetic to elicit cardiotoxicity is comparable to its ability to impair carnitine-dependent fatty acid transport.23
such that the LD50 was increased by 48% in the group receiving lipid.11 They subsequently reproduced the cardioprotective effects of lipid emulsions in a canine model of local anaesthetic toxicity, thereby permitting correlation of the findings more appropriately to the complexities of human physiology.26 A treatment algorithm for the use of lipid emulsion in human cardiac arrest attributed to local anaesthetic toxicity was proposed by Weinberg in 2004.27 This regime was extrapolated solely from information acquired from animal studies, and as such lipid rescue therapy was initially recommended for use only after exhaustion of standard advanced life support techniques. Of course, the infrequent but potentially catastrophic effects of systemic local anaesthetic toxicity have precluded it from being the subject of human randomised controlled trials. The first case report of ILE being used to successfully resuscitate a patient after presumed bupivacaine related cardiac arrest was published in 2006.28 The patient was a 58 year old male who developed seizures, ventricular dysrrhythmias and ultimately asystole, post administration of a bupivacaine and mepivacaine interscalene block. After 20 min of advanced life support, at a point when cardio-pulmonary bypass was being considered, the use of ILE was proposed. The patient received a bolus of ILE followed by a defibrillation shock at 360 Joules at which time a sinus beat was noted on monitoring. Atropine and adrenaline were given and were followed 15 s later by return of spontaneous circulation. The patient was subsequently discharged with no neurological sequelae. This initial case report has paved the way for numerous publications detailing the successful utilisation of ILE in treating refractory cardiac arrest due to local anaesthetic toxicity. Indeed, as of 2012 there had been 21 published case reports of successful use of ILE in local anaesthetic toxicity.29 Furthermore, given the not too infrequent alterations to local anaesthetic packaging it seems unfortunately inevitable that inadvertent local anaesthetic toxicity will continue to mar clinical practice; a point eloquently highlighted in a recent letter in the Royal College of Anaesthesia bulletin (see Fig. 1). In 2005 Dalgish and Kathawaroo highlighted the exciting findings from the Weinberg team in Anaesthesia.30 Subsequent correspondences and publications regarding ILE led to the Association of Anaesthetists of Great Britain and Ireland (AAGBI) releasing recommendations for the use of lipid rescue in severe local anaesthetic toxicity in 2007.31 Furthermore, the accumulating evidence base and clinical experience with ILE has led commentators in the field to propose a more timely use of ILE; that is, at the point of recognition of toxicity.32 There are certainly case reports to support this recommendation, as evidenced by the termination of abnormal ECG morphology and arrhythmias with ILE, prior to degeneration into clinically significant physiological decompensation. Thus, Ludot et al. report a case of ventricular arrhythmia in a 13 year old female post lumbar plexus block with lidocaine and ropivacaine.20 An immediate bolus of 20% lipid emulsion was given, with normalisation of the QRS complex within 2 min and resolution of all ECG changes within 30 min. 4.2. Lipophilic drugs
4. Clinical use of intravenous lipid emulsion 4.1. Local anaesthetics The preliminary hypothesis of Weinberg and colleagues that lipid pre-treatment would exacerbate local anaesthetic toxicity was not born out. Indeed these initial findings led to the tailoring of specific experimental designs to prove just the opposite. Thus, Weinberg et al. eloquently demonstrated that pretreatment or resuscitation with a lipid infusion shifts the doseeresponse curve to bupivacaine-induced asystole in rats in an impressive manner,
Having secured its role as an antidote to local anaesthetic toxicity, the successful use of lipid rescue therapy to combat toxicity associated with other lipophilic drugs has been published. Thus, both animal studies and human case reports demonstrate beneficial effects of lipid rescue against verapamil,21,33 bupropion and lamotrigine,34 quetiapine and sertraline,35 as well as tricyclic antidepressants.36 Given the potential for abuse and overdose of these medications, particularly the antidepressants, ILE offers a valuable tool in the battle to counteract toxicity associated with these drugs.
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Fig. 1. A recent letter in the Royal College of Anaesthesia bulletin highlights the new non-sterile packed ampoule of bupivacaine hydrochloride (top in A, and bottom in B). Note the similarity between saline and the new bupivacaine vials; this may increase the risk of inadvertent intravenous injection of bupivacaine. Image with permission from.55 [The Royal College of Anaesthetists (UK), Bulletin 76, page 58, November 2012].
4.2.1. Calcium channel antagonists 4.2.1.1. Verapamil. Verapamil is a lipophilic calcium channel antagonist which is associated with profound toxicity in overdose, typified by bradycardia, hypotension, bowel ischaemia and cardiac arrest.37 In 2007 the American Poison’s Association reported that whilst verapamil accounted for only 12% of all cardiovascular toxic drug exposures, it was responsible for almost half the deaths (47%) in the same category.38 Management in overdose, has primarily relied upon physiological support until the drug is eliminated. This includes, gastric decontamination, intravenous calcium, preload enhancement and inotropic support, euglycaemic hyperinsulinaemia and as a last resort, cardiac bypass. However, over recent years animal studies and human case reports have begun to detail the successful use of ILE as a specific antidote to verapamil toxicity.21,39 Thus Tebbutt et al. demonstrated impressive results in a rat model of verapamil toxicity, whereby infusion of ILE conferred a near doubling of survival time, mean lethal dose and LD50 in this group as compared to saline treated controls.21 Such favourable outcomes have also been established in a canine model of verapamil toxicity, in which 100% animals receiving standard resuscitation plus lipid treatment survived to 120 min compared to only 14% in the group receiving standard resuscitation and saline alone.12 With respect to human case reports, Young et al. reported the rapid stabilisation of a 32 year old male who had ingested 13.44 g verapamil (plus other medications) following ILE administration,33 whilst Liang et al.39 described the physiological improvement post ILE of a 41 year old female who had ingested 19.2 g verapamil. Whilst in such anecdotal reports it remains difficult to prove causality, in both cases the temporal relationship between ILE administration and improvement in physiological parameters is certainly persuasive. 4.2.1.2. Diltiazem. Encouraging outcomes have also been achieved using ILE in diltiazem overdose.40,41 Montiel et al. reported a positive outcome following the use of ILE in an 18 year old female who had ingested 3.6 g sustained release Diltiazem.42 The initial blood diltiazem level was 7893 ng/mL. Such levels have in the past proven to be fatal, but the patient continued to improve post ILE bolus and infusion, with no reported complications from the therapy. It is apparent that both the aforementioned Lipid Sink and Lipid Flux theories could underlie the clinical benefit of ILE utilisation in calcium channel toxicity. However, alternative propositions specific to calcium channel antagonism have also been voiced. Thus it is known that in overdose, calcium channel antagonists inhibit pancreatic calcium channels, thereby reducing insulin secretion. ILE
promotes production of nitric oxide and b-ketoacids,43 which in turn stimulate insulin secretion and hence augmentation of intracellular energy production.21 Furthermore, it has also been proposed that fatty acids from lipid emulsion could directly stimulate calcium channels.44 4.2.2. Antidepressants: tri-cyclic antidepressants TCA toxicity is elicited via myocardial sodium-channel blockage, with resultant ventricular dysrhythmias, myocardial depression and eventual cardiovascular collapse analogous to that observed with local anaesthetic toxicity. This capacity for severe toxicity in overdose has led to the development of, and preference in prescribing alternate antidepressants with safer side effect profiles; nevertheless TCA overdose remains a contributor to drug overdose mortality.45 Established therapy comprises decontamination, antidysrhythmic agents, sodium bicarbonate and supportive measures. The beneficial effects of ILE in TCA toxicity have been demonstrated in both animal studies and case reports. Thus, in a rabbit model of clomipramine toxicity Harvey et al. eloquently demonstrated the superiority of ILE over sodium bicarbonate in reversal of clomipramine-induced hypotension.46 Moreover, in their protocol for severe clomipramine toxicity all rabbits treated with ILE survived, whilst all those receiving sodium bicarbonate perished. Similarly persuasive findings have also been demonstrated in human case reports. Blaber et al. report a 36 year old woman who ingested 2.25 g of the TCA dothiepin.36 On arrival to the Emergency Department GCS was 4/15, BP 53/35, pulse 130 (broad complex tachycardia) and pH 6.75. Despite mechanical ventilation and multiple boluses of sodium bicarbonate the patient developed a cardiac arrest of 11 min duration. Further sodium bicarbonate as well as amiodarone and transvenous pacing were administered to no avail. At this point ILE was commenced as per the ‘bolus-infusion’ protocol, resulting in restoration of sinus rhythm within minutes. After 24 hours ventilator and inotropic support was withdrawn, with the patient being later discharged with no neurological sequelae. 4.3. Other uses Lipid emulsion has several other uses and in various species, these range from a dietary source of lipid in total parenteral nutrition, the treatment of certain drug toxicities in dogs, to its potential use in women with recurrent failure of embryonic implantation.47 Interestingly, older studies have also shown the survival advantage of ILE therapy following lethal injections of endotoxin in rats.48,49
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5. ILE reporting
7. Conclusion
Whilst such case reports provide persuasive accounts of the beneficial effects of ILE, one must of course, be aware of the potential biases associated with the literature. Due to the relative novel nature of using ILE following drug overdoses, reports are at risk of being self-selecting, such that cases where the therapy has been effective are reported and published, whereas those cases where resuscitation attempts have failed are not communicated. Proponents of ILE therapy have tried to overcome this through the development of self-reporting websites where a database can be assimilated of all cases where ILE has been used. However there may not be sufficient publicity to allow such databases to capture the majority of cases, especially given the voluntary nature of reporting. Furthermore, the utility of various multimodal rescue drugs and techniques during the resuscitation of patients following drug overdoses poses challenges in ascertaining the success of the intravenous lipid therapy component in the resuscitation.
Throughout this article we have chronicled the use of intravenous lipid emulsion, from its serendipitous inception to ever accumulating case reports of successful resuscitation in current clinical practice. Not only does ILE have demonstrable efficacy as an antidote to local anaesthetic toxicity, its spectrum of use now clearly lies beyond this to encompass the treatment of other lipid soluble drug toxidromes. While the mechanism of action is not clearly elucidated, we surmise that the high dose lipid leaches the toxic drug from inactivated ion channels - either by reducing the intravenous drug concentration or directly from the ion channels themselves. No doubt, as clinical familiarity and confidence with its use continues to grow, we expect to see more case reports of successful resuscitation from the use of intravenous lipid emulsion.
6. Complications of intravenous lipid emulsion
References
Paracelsus has previously written ‘all things are poison, and nothing is without poison; only the dose permits something not to be poisonous’. This may run true with ILE therapy, as previous studies have shown large volumes of high concentration of lipid infusion during parenteral nutrition have resulted in pulmonary complications.13 Furthermore there are some theoretical and animal experimental data which highlight some of the risks associated with ILE therapy. Studies in rodents have shown reduced resistance to bacterial pathogens with parenteral lipid administration.50 However, part of the explanation may be due to the experimental methodology as a parenteral lipid infusion is likely to have a greater risk of bacterial contamination/colonisation than saline infusions. Furthermore some of the infective risks associated with parenteral lipid infusion may be related to the long duration of infusions over days-weeks, in contrast ILE therapy is an infusion utilised for minutes to hours. A systematic review of lipid therapy for acute drug poisoning in animal and human studies reported that although there is some benefit of ILE utilisation in certain drug toxicities, the evidence is weak, with human data based on case reports. Furthermore it found no trials examining the safety of ILE in acute poisoning.51 However, whilst there has been one case report detailing the occurrence of asymptomatic hyperamylasemia post ILE use, most authors have not reported any adverse events associated with lipid therapy.52 Nevertheless, the AAGBI recommend the monitoring of the patient and biochemical markers for the development of pancreatitis post treatment with intravenous lipids. The maximum dose that can be administered to humans is unknown; experiments in rats have shown the lethal dose required to kill 50% of the animals (LD50) to be 68 ml/kg of rapidly infused 20% intravenous lipid.53 In humans, the recommended upper limit of 20% intravenous lipid is 10 ml/kg.51 It is not only the direct effects of the lipid therapy that can perturb the clinical management of a case. ILE can cause analytical interference with the various tests including haematological and biochemistry assays, the extent of the interference depends on the test and analyser used.22 High lipid content can result in reports of a falsely elevated haemoglobin and platelet count.54 Thus ideally samples should be taken prior to intravenous lipid therapy, and for those taken after, they should be fully discussed with the pathology laboratory.
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Conflict of interest None.
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