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19 July 2013 No. 24 LOCAL ANAESTHETIC TOXICITY Veena Ramson Commentator: D Pillay Moderator: L Padayachee DISCIPLINE OF ANAESTHETICS CONTENTS INTRODUCTION ................................................................................................... 3 INCIDENCE OF LA TOXICITY ............................................................................. 3 MECHANISMS OF LA TOXICITY ......................................................................... 4 CLINICAL PRESENTATION OF LAST ................................................................ 7 TREATMENT OF LAST ........................................................................................ 8 LIPID EMULSION THERAPY ............................................................................... 9 TYPES OF LIPID EMULSIONS ............................................................................ 9 TIMING OF THERAPY AND SAFETY ................................................................ 10 USE OF LIPID EMULSION IN CHILDREN ......................................................... 10 USE OF LIPID EMULSION IN PREGNANCY ..................................................... 11 THE PROTOCOL ................................................................................................ 11 CONCLUSION .................................................................................................... 16 APPENDIX 3 ....................................................................................................... 17 REFERENCES ................................................................................................... 18 Page 2 of 19 LOCAL ANAESTHETIC TOXICITY INTRODUCTION The resurgence of regional and neuroaxial anaesthesia in our current practice has prompted the avid use of local anesthetic drugs (LA). Inasmuch as these drugs produce beneficial analgesic and anaesthetic effects; in high enough doses; these drugs are much feared for its toxicity.In recent years, there has been much interest in interrogating and explaining the underlying mechanisms of LA toxicity in attempt to adequately treat and prevent the disastrous effects of overdose. The much-dreaded cardiovascular collapse that is seen in human beings has led to most experiments and evidence being demonstrated in animal models. The purpose of this review is to elucidate on the mechanisms of LA toxicity, discuss the clinical presentation and formulate a concise management plan, based on current evidence. INCIDENCE OF LA TOXICITY The latest literature quotes Local Anaesthetic Systemic Toxicity (LAST) as occurring between 7.5 to 20X per 10000 peripheral nerve blocks and 4X per 10000 epidurals.[1]However, there are certain individual nerve blocks that have been associated with higher rates of toxicity: interscalene and supraclavicular blocks may cause a n incidence of toxicity be as high as 79 per 10000. [2] Agarwal et al, listed patients associated with a higher risk of developing LA toxicity even within normal therapeutic dosage ranges. [3] These are: Extremes of age Cardiac Conduction Deficits Ischaemic Heart Disease Liver disease Metabolic or respiratory acidosis Cardiac disease resulting in decreased ejection fraction Higher risk type of block and location of block Older LA compound Higher total dose administered Page 3 of 19 MECHANISMS OF LA TOXICITY LA toxicity can be divided into 2 broad categories: A. LA in situ toxicity – affecting local muscle and nerves B. LA systemic toxicity (LAST) – manifesting as CNS and CVS collapse A. LA “In Situ” Toxicity The infiltration of LA’s during peripheral nerve blocks has been shown to be cytotoxic to both neighboring myocytes as well as neurons. LA myotoxicity was very robustly demonstrated in ophthalmic surgery, where the use of bupivacaine in retro- and peribulbar blocks resulted in persistent diplopia from direct damage to the affected extraocular muscles.[4, 5] They cause damage in 2 main ways: 1. Destruction of the tissue ultrastructure with concomitant inflammatory reaction 2. Interference with cellular energy metabolism at a mitochondrial level 1.1. Destruction of the tissue ultrastructure: Myocytes High dose of LA injected directly into muscle (16mg/kg bupivacaine) or a bolus dose (3-5mg/kg of bupivacaine) followed by an infusion yielded the following microscopic changes: [6] interstitial oedema disjointed muscle fibres and subsequent disruption of the myofilaments lysis of the sarcoplasmic reticulum mitochondrial lysis pycnosis of nuclei 1.2 Destruction of the tissue ultrastructure: Neurons[7] Axonal tissue that was incubated in LA for prolonged periods showed the following changes: Axonal swelling and necrosis Loss of normal myelin architecture an axonal demyelination Formation of myelin globules and vacuoles Neuronal apoptosis with subsequent macrophage phagocytosis of epineural and endoneural collagen A recent study has shown that bupivacaine (and all other LA’s) cause time and dose dependent death of schwann cells; with brief exposure of high doses of the drug being just as dangerous as prolonged exposure of intermediate and low concentrations of bupivaciane [8] 2.1. Interference with cellular energy metabolism : calcium homeostasis [9] LA’s have been shown to result in increased intracellular calcium concentration: Page 4 of 19 Increased entry of calcium through the plasma membrane; and increased calcium release from the sarcoplasmic reticulum (SR) via activation of calcium ryanodine receptors (RyR) Decreased calcium reuptake into the SR via inhibition of calcium ATPase. Production of reactive oxygen species The result of the above is depletion of calcium in the SR, while the sustained increase in intracellular calcium concentrations result in cell death. 2.2. LA-induced inhibition of cellular ATP production [10] Due to the following mechanisms: Direct destruction and depletion of mitochondria and mitochondrial network Direct inhibition of mitochondrial respiratory chain complex I Uncoupling of oxidative phosphorylation Inhibition of mitochondrial ATP synthase Decreased mitochondrial resting membrane potential Production of ROS B. LA Systemic Toxicity (LAST) Systemic toxicity is a result of delayed absorption of LA from site of injection into the systemic circulation; or direct infusion of the drug into the vasculature- either deliberately (Bier’s Block) or inadvertently. This leads to interference of a number of ionic and non-ionic pathways at a cellular level. Page 5 of 19 The voltage-gated sodium (Nav) channel is primarily involved when local anaesthetics bind; which leads to decreased electrophysiological conduction. There are 9 isoforms of these channels, and it has been postulated that different LA’s have different affinities for these isoforms and thus manifest as varying degrees of toxicity clinically [11] In addition to the Nav channels, LA’s affect cardiomyocytes at other channels and receptors. Bupivacaine inhibition of calcium channels are implicated in myocardial depression as a result of decreased muscular contractility. Many authors have also shown that LA affect the transient outward potassium (K) channels as well; thereby slowing repolarization and impairing conduction. [12, 13] There has been numerous studies that have also demonstrated other biochemical mechanisms causing cardiovascular collapse, including: Inhibition of NA/K ATPase pump Decrease in the Mg-ATP concentration (which is important for actin-myosin cross-bridging, and hence, muscle contraction) [14] Uncoupling of oxidative phosphorylation: Bupivacaine inhibits carnitine acylcarnitine transferase (CACT) in cardiac mitochondria of rats. CACT is the only enzyme that transports acylcarnitines across mitochondrial membranes in the fatty acid transport chain during phase I mitochondrial respiration. [15] This is important for aerobic metabolism. and may be implicit in inducing the severity of LA-induced toxicity that is unresponsive to ACLS techniques. (Other biochemical mechanisms of LA toxicity- Appendix 1) Based on the above mechanisms, the questions that logically follow are: 1. Does LAST occur due to its electrophysiological effects on cardiac conductivity; that is: do affected patients die from arrhythmias? 2. Is LAST a consequence of depressed cardiac contractility? 3. Is it drug/compound specific? A summary of the evidence has shown that CVS collapse is due to a combination of both pathologies, and it is drug specific. Multiple studies have shown that bupivacaine has a greater predilection toward producing arrhythmias by delaying conduction; and may or may not cause concomitant depression in myocyte contractility (de Jong, et al; groban et al). [16-18] Bupivacaine’s effect on conduction ranges from premature depolarization, causing fibrillation to AV block (and potential to cause reentrant arrhythmias), complete heart block and even pacemaker-resistant bradycardia and asystole. Page 6 of 19 Block and Cavino have also shown bupivacaine was 8-15 times more potent than lignocaine in inhibiting or delaying AV node conduction, QRS duration and QT interval. [19] Furthermore, there is consistent evidence that the R(+) enantiomer of bupivacaine produces much more profound AV conduction delay than the S(-) enantiomer or the racemic mixture. [20, 21] Lignocaine, on the other hand, tends to produce myocardial depression without causing malignant arrhythmias (hence its use as an antiarrhythmic agent); and if arrhythmias do occur, they are less persistent or resistant to treatment than those caused by ropivacaine or bupivacaine. Other indirect mechanisms that contribute to cardiovascular collapse that of hypotension secondary to vasodilatation, and inhibition of autonomic reflexes. [22] Of note, is that bupivacaine causes vasoconstriction at low doses (ropivacaine and levobupivacaine to a lesser extent). [23] The implication of this is that in addition to the negative inotropy, there is also an increase in ventricular afterload leading to decreased cardiac output. This effect is mediated by α1 adrenoreceptors. CLINICAL PRESENTATION OF LAST The clinical presentation of LAST is typically a biphasic one, involving the CNS and CVS; by initially causing excitation and then depression. The reason for this is that these two organ systems are especially sensitive to electrophysiological changes; and are also most vulnerable to hypoxia due to high mitochondrial metabolic activity. Usually (but not always) neurological signs appear first, which is then followed by cardiovascular excitation and then depression. As previously mentioned, this collapse leads to cardiac arrest that can be resistant to standard resuscitation efforts. If extremely high plasma concentrations of LA is achieved, or if bupivacaine is injected intravascularly, cardiovascular compromise may ensue without any preceding CNS involvement. The added quandary of general anaesthesia and its depressant effects exacerbate hypotension and ventricular contractility. Hypotension that is resistant to fluid administration or the use of vasopressors may be the only discernable sign of LAST under GA. Unfortunately, at this point these findings may herald imminent cardiac arrest. Page 7 of 19 The typical progression of signs are as follows: TREATMENT OF LAST While it is intuitively accepted that successful resuscitation in any medical emergency involves rapid ACLS measures of securing and supporting the circulation, airway, oxygenation and ventilation; there are a few key features that need to be considered in treating LAST. Immediate suppression of seizures using benzodiazepines (midazolam) or boluses of propofol is vital in preventing intracellular acidosis. In terms of CVS support: maintaining coronary perfusion, attenuating tissue acidosis and reversing the negative inotropy are key principles in management. Prior to the advent of lipid emulsions, cardiopulmonary bypass had been the only successful intervention in rescuing patients from LA cardiovascular toxicity. That, in itself, is wrought with logistic and practical issues, which precludes most patients from its use. Since its introduction in 2001, lipid emulsion therapy has now been consistently shown to improve cardiac contractility and re-establish coronary perfusion, by binding and removing the LA from the myocardial tissue. Page 8 of 19 LIPID EMULSION THERAPY The exact mechanism of action of lipid emulsion is unknown, and in fact its discovery in use as a therapeutic agent was a paradoxical finding. Researchers based their hypothesis that lipid emulsion will worsen LA-induced arrhythmias (more specifically bupivacaine); based on the fact that FFA’s cause accumulation of intracellular toxic metabolites, and also cause uncoupling of oxidative phosphorylation which exacerbates tissue damage during periods of myocardial ischaemia and low flow states. When this theory was tested out on rats, the protective effects of lipid infusions were discovered, and reproduced in several further studies. [24] (appendix 2) The “Lipid sink” theory is the most widely quoted of mechanism of action of lipid emulsions. [14] The lipid emulsion literally acts like a sink that “drains” the LA from plasma after selectively binding to these highly lipophilic drugs. Other theories also postulated include lipid possibly increasing LA metabolism and distribution [25] lipid releases FFA’s which are important in restoring the oxidative phosphorylation pathways that bupivacaine interferes with [15] TYPES OF LIPID EMULSIONS Most lipid emulsions are composed of soya bean, egg and differing lengths of triglyceride chains. Intralipid: composed solely of long chain triglycerides Medialipid: has equal amounts of long-chain and medium chain triglycerides (50/50) Structolipid: 64% long chain triglycerides and 34% medium chain triglycerides Most recent evidence by Candela et al has shown that there is no significant difference in outcome between the use of intralipid versus an agent with a mixture of long and medium chain triglycerides [26]. Thus, anaesthetists need to be aware that their hospital may choose to stock agents other than Intralipid. Further studies are needed to validate the efficacy and supremacy of one agent over the other in human cohorts; as the evidence is ultimately conflicting. Van de Velde et al showed that acute administration of Medialipid in dogs was associated with decreased myocardial contractility and increase in the systemic vascular resistance; both of which could prove to be disastrous in the face of LA cardiotoxicity. [27] Propofol, by virtue of also being a lipid emulsion, has been purported to be an effective therapeutic agent. However, the dose and volume needed for effective treatment of LAST can actually be lethal. Propofol is, thus, reserved for treatment of convulsions associated with LAST. Page 9 of 19 TIMING OF THERAPY AND SAFETY Intralipid was initially recommended as a last resort after failure of response to standard resuscitation, but the trend has now moved to early use of the drug in order to prevent progression to cardiac arrest; and case reports have even associated the use of lipid with reversal of altered mentation and convulsions in addition to the reversal of cardiotoxicity. [28-30] This approach gives rise to 3 issues: Lipid emulsion is not an innocuous agent. The exact consequences of high dose and volumes of lipid therapy is not known. While long term lipid infusions have been associated with cytokine production and increased infection risk as well as thrombolytic effects and pulmonary emboli (if the lipid particles are very large), short term use of lipid in LAST evokes the possibility of allergy or anaphylaxis. The use of lipid therapy cannot be a prophylactic measure by any means; as the risk : benefit ratio of large doses of lipid use versus LAST is not known. Bolus doses of intralipid seem to be inadequate in treatment of LAST, as initial studies showed a transient improvement in cardiovascular profile, followed by a steady decline. This problem has been ameliorated by a concomitant infusion; and it has been suggested that this infusion be continued for at least 12 hours. A recent study looked at the effects of an adrenaline injection during concomitant lipid resuscitation in a rat model with bupivacaine overdose. Interestingly, they found a threshold effect with adrenaline. Adrenaline doses higher than 10mg/kg were found to impair lipid resuscitation from bupivacaine toxicity, possibly by causing acidosis and hyperlactatemia. [31] Seeing that LAST and effective safe dosing ranges cannot be elicited by performing RCT’s in human cohorts, the guidelines that have been published by the Association of Anaesthetists of Great Britain and Ireland. USE OF LIPID EMULSION IN CHILDREN There have been case reports of successful intralipid use in children and neonates [32], however there is no consensus on maximum safe doses. Mirtallo et al examined the use of parenteral lipid infusions and noted that fat overload syndrome only occurred with very large daily doses of between 3.0 – 5.4g/kg/day over a mean period of 28-114 days. [33] Christensen et al did a cohort analysis of 1366 neonates. After minimal of lipid for 14 days, they showed the incidence of adverse effects. [34] Neonates receiving lipid for 14–28 days had a 14% incidence of parenteral nutrition associate liver disease (PNALD); 29–56 days of therapy was associated with a 43% incidence; while 57–100 days of therapy had a 72% incidence. Those neonates receiving lipid for >100 days had an 86% incidence. Page 10 of 19 Patients identified with the highest risk of developing PNALD were extremely low birth weight babies of <500 g or 500–749 g, gastroschisis and jejunal atresia. USE OF LIPID EMULSION IN PREGNANCY Pregnancy is thought to be associated with enhanced sensitivity to local anaesthetic systemic toxicity. Several mechanisms have been postulated to account for this. Entrainment of local anesthetic and catheter migration more likely due to epidural vein distention. Uptake of local anesthetic from the epidural space and distribution to potential target sites are altered by the increased cardiac output state. Pregnancy results in decreased plasma protein, thereby increasing the free drug concentration in the vascular compartment. Oestrogen and progesterone also appear to alter cardiomyocyte electrophysiology to increase arrhythmogenic risk and cardiotoxicity. [35] Increased neuronal susceptibility to LA’s may also occur decreasing convulsion threshold. Weinberg and Bern, in their review, have postulated that lipid works similarly in pregnant women as in non-pregnant patients, but they also brought up some important unanswered questions regarding lipid use in parturients. It is possible that the lipid sink effect could demonstrate different characteristics due to pregnancy-associated changes in circulating blood volume, cardiac output, protein composition and binding, and overall metabolism. The effects- if any- of rapid intralipid infusion on uteroplacental circulation and drug exchange are not known. Again, high quality BLS/ACLS is advocated, with early recognition of LA toxicity or high index of suspicion. Early airway management in paturients cannot be overemphasized, especially with a gravid uterus causing splinting of the diaphragm and decreasing FRC. The current ACLS guidelines for resuscitation of pregnant women need to be adhered to; paying particular attention to early expedition of caesarian section as soon as CVS instability is identified. Delivery of the fetus should be achieved within 4-5min after the mother’s heart has stopped. Several studies have shown return of spontaneous circulation and improved maternal hemodynamics only after evacuation of the uterus; hence prompt perimortem cesarean delivery not only improves infant survival rate, but may also prove lifesaving to the mother. [36, 37] THE PROTOCOL Both ASRA and the AAGBI have published protocols to guide management of LAST. I have includes both as a quick reference. Page 11 of 19 Page 12 of 19 Page 13 of 19 Page 14 of 19 Page 15 of 19 CONCLUSION Local anaesthetic in situ toxicity and LAST are anaesthetic emergencies that require prompt early recognition and decisive management strategy. All hospitals that use local anaesthetics should have Lipid emulsion readily available for overdose situations, and the current evidence makes it difficult for us to justify its absence in some of our hospitals. Lipid rescue therapy has emerged as a lifesaving modality in adults, children and pregnant women, but exact mechanism of action; safe dosing strategy and safety profiles still have yet to be validated. Types of lipid emulsions and their efficacy and potential harmful effects are also areas that are being investigated in an aim to refine current guidelines and implement universal protocols. That being said, I cannot overstate the importance of exemplary ACLS technique as the basis of lifesaving strategy in these patients. APPENDIX 1 [38] TABLE 4. Biochemical Actions of Local Anesthetics Possibly Linked to Cardiac Toxicity Author Year Local Anesthetic Sperelakis and Lee78 Chapman and Miller79 de Boland et al80 Katz et al81 Suko et al82 1971 1974 1975 1975 1976 T P D, T, L, P L, PA T, D, P, L Singh et al83 Voeikov et al84 Chazotte and Vanderkooi85 1977 1980 1981 Vanderkooi et al87 Dorris88 Dabadie et al89 Schönfeld et al90 Butterworth et al91 1981 1983 1987 1992 1993 Butterworth et al92 Sztark et al93 McCaslin and Butterworth74 Weinberg et al94 Unami et al95 1997 1998 2000 2000 2003 Joseph et al96 2005 Enzyme or Process Na-K ATPase of chicken heart Antagonism of caffeine contracture in Na-free solution D + T Antagonize ATPase and Ca transport in rabbit skeletal muscle SR Antagonize calcium transport in canine cardiac SR Antagonize Ca uptake, Ca-ATPase, Ca-dependant ATP-ADP phosphate exchange in rabbit skeletal muscle SR T Antagonize Ach-medicated positive cardiac inotropy in frogs D, L, T, B Antagonize catecholamine-stimulated adenylyl cyclase in frog erythrocytes P, T, D Antagonizes cytochrome c oxidase, durohydroquinone oxidase, succinate oxidase, reduced nicotinamide adenine dinucleotide oxidase, succinate dehydrogenase, succinate-cytochrome c oxidoreductase, NADH-cytochrome c oxidoreductase in beef heart Tanaka and Hidaka86 1981 L, T, D Antagonize Cacalmodulin activation of cyclic nucleotide phosphodiesterase, myosin light chain kinase in chicken gizzard T Antagonizes mitochondrial F1-ATPase in bovine heart P, 2-CP, T Antagonize monoamine oxidase in rat and mouse myocardium L, B Uncouple oxidative phosphorylation in rat liver B, QX-572 B is a protonophore in rat heart mitochondria M, R, B Antagonize basal, epinephrine-stimulated, and forskolin-stimulated cyclic AMP production in human lymphocyte adenylyl cyclase M, R, B and others Antagonize binding to A2-receptors in human lymphocytes B, R Uncoupling of oxygen consumption from phosphorylation in rat heart B Antagonizes calcium oscillations in cardiomyocytes from rat B Antagonizes acylcarnitine exchange in myocardial mitochondria from rat B Induce apoptosis in promyelocytic leukemia cells from human B Antagonizes norepinephrine release from adrenergic nerve terminals in rat atria B indicates bupivacaine; 2-CP, 2-chloroprocaine; D, dibucaine; L, lidocaine; M, mepivacaine; P, procaine; PA, procainamide; R, ropivacaine; T, tetracaine. Page 16 of 19 APPENDIX 2 [14] y APPENDIX 3 DRUG LIGNOCAINE PRILOCAINE BUPIVACAINE LEVOBUPIVACAINE ROPIVACAINE 2 2 8 8 6 Onset 5-10 min 5-10 min 10-15 min 10-15 min 10-15 mins Duration without adrenaline 1-2 hours 1-2 hours 3-12 hours 3-12 hours 3-12 hours Duration with adrenaline 2-4 hours 2-4 hours 4-12 hours 4-12 hours 4-12 hours Max dose without adrenaline 3 mg/kg 6 mg/kg 2 mg/kg 2.5 mg/kg 3 mg / kg Max dose with adrenaline 7 mg/kg 9 mg/kg 2.5 mg/kg 3 mg/kg 4 mg / kg Relative potency Page 17 of 19 REFERENCES 1 X) Weinberg GL, Palmer JW, VadeBoncouer TR, Zuechner MB, Edelman G, Hoppel CL. Bupivacaine inhibits acylcarnitine exchange in cardiac mitochondria. Anesthesiology. 2000;92(2):523–528 Y) Bourne E, Wright W, Royse C.A review of local anesthetic cardiotoxicity and treatment with lipid emulsion.Local Reg Anesth. 2010; 3: 11–19. z) Candela D, Louart G, Bousquet PJ, et al. Reversal of bupivacaine-induced cardiac electrophysiologic changes by two lipid emulsions in anesthetized and mechanically ventilated piglets. Anesth Analg 2010; 110:1473–1479. Hiller) Hiller DB, Gregorio GD, Ripper R, et al. Epinephrine impairs lipid resuscitation from bupivacaine overdose: a threshold effect. Anesthesiology 2009;111:498–505. Mirtallo) Mirtallo J. State of the art review: intravenous fat emulsions: current applications,safety profile, and clinical implications. Ann Pharmacother 2010; 44: 688–700. Christensen) Christensen RD. Identifying patients, on the first day of life, at highrisk of developing parenteral nutrition–associated liver disease.J Perinatol 2007; 27: 284–290. Progesterone) Moller RA, Datta S, Fox J, et al. Effects of progesterone on the cardiac electrophysiologic action of bupivacaine and lidocaine. Anesthesiology 1992; 76:604–608. McDon) McDonnell NJ. Cardiopulmonary arrest in pregnancy: two case reports of successful outcomes in association with perimortem Caesarean delivery. Br J Anaesth 2009; 103:406–409. Katz V, Balderston K, DeFreest M. Perimortem cesarean delivery: were our assumptions correct? Am J Obstet Gynecol 2005; 192:1916–1920; discussion 1920–1921. Page 18 of 19 REFERENCES 2 1. 2. Dillane D FB: Local anesthetic systemic toxicity. Can J Anaesth 2010, 57(4):368-380. doi: 310.1007/s12630-12010-19275-12637. Epub 12010 Feb 12612. Ciechanowicz S, Patil V: Lipid Emulsion for Local Anesthetic Systemic Toxicity. Anesthesiology Research and Practice 2012, 2012:11. 3. Agarwal J MA, Jafa S, Wahal R, Kapoor R, Awasthi A Management of local anaesthetictoxicity. Anaesthesia Update 2011, . 14(2):19-24. 4. Han SK, Kim JH, Hwang JM: Persistent diplopia after retrobulbar anesthesia. Journal of cataract and refractive surgery 2004, 30(6):12481253. 5. Gómez‐Arnau JI, Yangüela J, González A, Andrés Y, García del Valle S, Gili P, Fernández‐Guisasola J, Arias A: Anaesthesia‐related diplopia after cataract surgery. British Journal of Anaesthesia 2003, 90(2):189-193. 6. Perez-Castro R, Patel S, Garavito-Aguilar ZV, Rosenberg A, Recio-Pinto E, Zhang J, Blanck TJ, Xu F: Cytotoxicity of local anesthetics in human neuronal cells. Anesthesia and analgesia 2009, 108(3):997-1007. 7. Zink W, Graf BM, Sinner B, Martin E, Fink RH, Kunst G: Differential effects of bupivacaine on intracellular Ca2+ regulation: potential mechanisms of its myotoxicity. Anesthesiology 2002, 97(3):710-716. 8. Nouette-Gaulain K, Dadure C, Morau D, Pertuiset C, Galbes O, Hayot M, Mercier J, Sztark F, Rossignol R, Capdevila X: Age-dependent bupivacaine-induced muscle toxicity during continuous peripheral nerve block in rats. Anesthesiology 2009, 111(5):1120-1127. Page 19 of 19