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Comparing Resuscitative Measures for Bupivacaine Toxicity Utilizing Lipid Emulsions in a swine model (Sus scrofa)
1LT Andrea Hudson, BSN
CPT Sarah Bolin, BSN
CPT Mark Bishop, BSN
1LT Randall Schmidt, BSN 
Arthur D Johnson, PhD
Joseph O�Sullivan, PhD




Corresponding Author: Joseph O�Sullivan, 3490 Forage Rd, Dunlap Hall, Ft Sam Houston, TX 78234. (o) 210-295-4769
Institution: AMEDD Center and School, Academy of Health Sciences, Graduate School 
Financial grant: Tri-Service Nursing Research Program, Bethesda MD.








ABSTRACT
Introduction: A toxic dose of bupivacaine causes cardiac arrhythmias and ultimately asystole. Resuscitation is difficult and almost always unsuccessful. Until recently, cardiopulmonary bypass was the only effective treatment. Anecdotal evidence suggests that infusion of lipid emulsion may be an effective treatment. No studies have determined the optimal combination of lipid rescue and traditional Advanced Cardiac Life Support (ACLS) therapy for a toxic dose of bupivacaine. The purpose was to determine the optimal combination of lipid rescue and traditional ACLS therapy for treatment overdose of bupivacaine.
Methods: This study was a prospective, experimental, mixed research design. Seven swine were assigned to eight ACLS or BLS protocol resuscitation groups: Vasopressin/Lipid; Epinephrine/Lipid; Lipid; Epinephrine; Vasopressin; Epineprine/Vasopressin; Epinephrine/Lipid/Vasopressin; and CPR.  Each subject was administered a toxic dose of bupivacaine (10mg/kg) until there was a non-perfusing arrhythmia.  Each resuscitation protocol was implemented.  Survival was defined as return of spontaneous circulation to a systolic blood pressure e" 60 mm/Hg. A chi-square and odds ratio was used to analyze the data. 
Results: Seventy one percent of the epinephrine/lipid group survived compared to 19% of all the groups without lipid therapy. The chances of survival for the epinephrine with lipids group was 6.2 fold greater than the groups with standard ACLS protocol. Epinephrine with lipid group had a 2.5 times greater chances for survival compared to epinephrine with vasopressin. Epinephrine with lipid  offered a 15 times greater chance of survival when compared to the group that received lipid alone. No swine in the CPR or vasopressin group survived. 
Conclusions: The combination of epinephrine with lipid emulsion infusion was the best resuscitation method to restore spontaneous circulation with bupivacaine toxicity in this swine model. Epinephrine alone was 43% effective, and lipid only was only 14% effective. The synergistic effect of the two combined drugs may warrant changes in ACLS protocol when there is bupivacaine toxicity. 
Source of Funding: TriService Nursing Research Program






Introduction
     Toxic doses of highly lipophilic drugs, specifically local anesthetics, are usually deadly.  The most devastating complication of such drugs is a non-perfusing cardiac arrhythmia, ultimately asystole.     An accidental overdose of local anesthetics (or other lipid soluable drugs) have been treated with 20% lipid emulsion infusions.1-6  Most of these anecdotal letters  have  stated that the last ditch effort to save the patients by starting lipid infusion was effective.  These patients were not responding effectively to standard ACLS resuscitation protocols but recovered shortly after lipid infusions.7 However, a comparison of different resuscitation techniques with and without lipid emulsion infusion have not been performed on an adult size model to determine if lipid emulsion or ACLS protocol or possibly a combination of the two is the most effective treatment.8  However, Mauch and associates recently published a similar study using piglets in their model.9  Another study had used lipid emulsion  and Advanced Cardiac Life Support ( ACLS) protocols had used hypoxia to induce cardiovascular collapse as well as toxic dose of bupivacaine. 10  When cardiac toxicity occurs, resuscitation is difficult, prolonged, and almost always fatal.11  Utilizing newer technologies for peripheral regional anesthesia (ultrasound) does not prevent intravascular injection.12 With widespread use of local anesthetics in the military or civilian for acute and chronic pain control, it is of paramount importance to find methods for effective resuscitation. 
Until recently, cardiopulmonary bypass was the only method to effectively treat cardiac arrest from these drugs13-14   Infusion of lipid emulsion may be effective in treating an otherwise fatal complication.  The proposed mechanism of action of lipid therapy is not known but is thought to be a combination of reduced tissue binding by re-established equilibrium in the plasma lipid phase and possibly a beneficial energetic-metabolic effect.15   Previous research stresses that future areas of investigation should focus on improved treatment regimes and better understanding of the mechanism of lipid therapy16.  	
The optimal combination of lipid rescue and traditional ACLS therapy for treatment of bupivacaine toxicity has not been performed.  The hypothesis of this study is to determine is there a significant increase in survival when combining lipid emulsion infusion with standard ACLS protocols in the face of bupivacaine toxicity. (Figure 1 is a graphical depiction of the theoretical framework.) Current research into the effectiveness of lipid emulsion in animal models has had mixed results.  Figure 2 depicts graphically the mixed results that have been obtained regarding optimal treatment of bupivacaine drug toxicity. Moreover, studies are lacking in determining  the optimal combination of lipid rescue and traditional ACLS therapy for treatment of overdose of bupivacaine.  This study examined the comparative effectiveness of eight resuscitation strategies given a toxic dose of bupivacaine. In accordance with other studies investigating local anesthetic toxicity and resuscitation, our sample size was determined to be 7 in each group.17-19  The eight groups tested (with 7 in each group) were CPR only and CPR with the following drug combinations: epinephrine alone; vasopressin alone; lipid alone; epinephrine and vasopressin; epinephrine and lipid; vasopressin and lipid; and finally, epinephrine, vasopressin, and lipid. 
Materials and Methods
     Study design: This study used a prospective, experimental, between subjects design with a swine model. The study was approved by our institutional IACUC committee.  The animals received care in compliance with the Animal Welfare Act and the Guide for the Use of Laboratory animals.
     Setting:  Fifty-four Male Yorkshire swine weighing approximately 55-75 kgs. were acclimated to the research facility for 4-7 days to ensure good state of health, fed a standard diet and remained NPO after midnight the day of the experiment. The weight and size of the swine approximates the average weight of an adult male. Male swine were used to decrease the possible confounding variables related to female hormones. 
     Procedure:  Intramuscular sedation was provided with Telezol (4-8 mg/kg) and Glycopyrrolate  (0.2 mg) 30 minutes prior to instrumentation by a veterinary technologist or qualified technician.  Anesthesia was induced by snout mask with oxygen and isoflurane (2-4%).  An ear vein was cannulated and infused with lactated ringers at 10 ml/kg/hr for the remainder of the procedure. Standard ECG pads were applied. Body temperature was monitored with a rectal temperature probe to maintain euthermia with a heating blanket. The trachea was intubated with a cuffed endotracheal tube and the animals were ventilated (tidal volume 8-10 cc/kg, respiratory rate 8-14 breaths per minute) with a standard Narkomed anesthesia machine (Drager, Telford, PA) and continuously monitored with the following standard monitors: HR, SBP, MAP, DBP, ECG, SpO2, CO, ETCO2, Isoflurane end tidal concentration. Tidal volume was adjusted (10 ml/kg) to ensure normocapnia (32-36 mmHg end tidal carbon dioxide). A large bore venous catheter was inserted into the left jugular vein and another catheter was inserted into the left carotid artery.  These two catheters were used for blood sampling, fluid/ lipid emulsion infusions and cardiac output monitoring via the Vigileo cardiac output monitor (Edwards Lifesciences).  Another arterial catheter was inserted into the femoral artery and attached to the Marquette Solar 800 system for continuous BP pressure monitoring.  The animals were allowed to stabilize for 10 minutes following instrumentation prior to beginning the procedure.
     Methods: Following completion of preparatory procedures, a toxic dose of bupivacaine (10 mg/kg) was given via the jugular catheter followed by 20 ml normal saline flush.  Upon confirmation of a non-perfusing rhythm, CPR was initiated, isoflurane terminated and an injection of 0.1mg/kg of Midazolam and 0.6mg of Buprenex was given IV.   The external cardiac compressions were delivered by a pneumatic compression device (Life-Stat Cardiopulmonary Resuscitator, Model 1008) we have called the �Thumper�.  The Thumper was set at a 30:2 compression ventilation ratio with a rate of 100 compressions per minute and a sternal depth of 20% of the measured thoracic anterior to posterior diameter and a 50:50 compression relaxation ratio. Compressions were only halted every 2 minutes for cardiac rhythm analysis.  At the first 2 minute mark, intravenous resuscitation drugs were given to each animal according to its group designation via peripheral IV followed by a 20 ml NS flush. Table 1 displays the drug doses given according to group designation. Ventilation was maintained with 100% oxygen. Blood pressure, HR, pulse oximetry, end-tidal carbon dioxide and cardiac output were recorded every two minutes
After every two minutes of cardiopulmonary resuscitation, pulse and cardiac rhythm were checked. Ventricular fibrillation or tachycardia was defibrillated with 200J for the initial shock and 360J for subsequent shocks.  Treatment ended after 30 minutes with an additional 10 min for those swine that had a return of spontaneous circulation (total 40 min).  If a sustainable, perfusing rhythm occurred anytime during the experiment (systolic BP over 60 mm/hg), CPR ended but monitoring continued. Survival for this experiment is defined as a perfusing rhythm that maintains a SBP over 60 mm/hg. Figure 3 presents a graphic overview of the experimental procedure.   All animals were euthanized by a veterinarian, veterinary technician, or qualified technician without emergence from general anesthesia. 
A multivariate analyses of variance was used to determine if the groups were equally distributed with regards to pre-intervention data.  The post-intervention data was analyzed using an odds ratio (chance to survival) to determine differences in survivability between the groups. Additionally, a Fisher�s Exact test was used to examine for statistical significance among groups. Means and standard deviations from a previous study were used to calculate an effect size.16 The investigators also used G-Power 3.0.10 to determine the sample sizes needed in the bupivacaine experiment.  Using an alpha of 0.05, power of .80, and a large effect size, 0.6, the number needed was determined to be 7 per group.  
     Results:  The minimum number of swine was used to obtain a statistically valid result. A total of 54 animals were included in the research. A MANOVA was used to analyze the pretest variables of all laboratory values, weight, vital signs and NPO deficit replacement. There were no statistically differences between the groups (p>.05) indicating all 54 swine were equivalent within these stated parameters.  The CPR only group was purposely reduced to 5 swine (instead of 7) due to the lethality of the model and zero probability that any swine in that group would recover in order to reduce the number of swine used. 
 The epinephrine and lipid emulsion group had the greatest amount of survivors with five of the seven swine surviving. The Epinephrine only group yielded three survivors and the Lipid emulsion only group yielded one survivor. No swine in the CPR only or Vasopressin only groups survived.  Graph 1 outlines the results of survivability between intervention groups. 
The impact of Epinephrine and Lipid emulsion, both alone and in combination, with regard to treatment of bupivacaine toxicity is depicted in Graph 2.  Seventy one percent of the animals in the Epinephrine/Lipid emulsion group survived compared to 19% of all the groups without Lipid emulsion therapy (p=0.008).The chances of survival for the Epinephrine/Lipid emulsion group was 3.7 fold greater than all the groups without Lipid emulsion therapy. Furthermore, there was a statistically significant difference relevant to survival between the Epinephrine/Lipid emulsion group and the CPR only group (p=0.028); and when compared with the Vasopressin group (p=0.05).
Comparison of the chances of survival of different ACLS regimes given a toxic dose of bupivacaine is listed in Table 2.  In comparing the group that represents group 1 to the group the represents group 2, group 1 has a greater likelihood of survival, which is represented by the chances of survival number. For example, there is a 5 times greater odds ratio of survival of bupivacaine toxicity if one used epinephrine and lipid emulsion vs. using lipid emulsion alone. 
One other notable result of the study was the time of return to spontaneous circulation for the swine that did survive.  As shown in Table 3 it also appears that not only did the Epinephrine/ Lipid group have the greatest number of swine that returned to spontaneous circulation, but they did it much faster. The mean time for return of spontaneous circulation for that group was 4 minutes. Although this rapid response is two-seven times faster than the other survivors in the other groups, the small number of survivors overall (small n) may be an issue. However, the trend is apparent that this drug combination not only offers increased survivability, but may also deliver quicker onset to return of spontaneous circulation. 
Discussion
This study investigated eight different rescue methods incorporating ACLS as the basis to survival in the face of bupivacaine toxicity.  Our major finding was that epinephrine with lipid emulsion had the highest survivability (71%) and possibly the quickest return to spontaneous circulation in a very lethal swine model. 
 Based on the anecdotal evidence regarding the benefit of incorporating lipid emulsion for treatment of bupivacaine toxicity3,20-22, and animal studies14-16 , it is currently recommended by Dr Weinberg at Lipid Rescue (HYPERLINK "http://www.lipidrescue.com"www.lipidrescue.com) that lipid emulsion be available during any regional anesthetic block with local anesthetic. This treatment protocol has seen wide acceptance in many hospitals and countries.23  
The results of this study showed that lipid emulsion and Epinephrine in combination was the single best treatment as far as survival was concerned, being effective 71% of the time when treating a fixed (mg/kg) bupivacaine overdose. A recent study by Mauch 9 utilizing piglets had similar results with the epinephrine / lipid group having the best survivability (86%) although they used a variable dose of bupivacaine. (Questions arise because of the variable bupivacaine dose as the epinephrine /lipid group had the highest survivability but also had the lowest bupivacaine blood concentration levels.)  Without the inclusion of lipid emulsion, traditional ACLS therapy with Epinephrine alone was the second most effective treatment group, which was 43% of the time. However, evidence has indicated that epinephrine in high doses offers no or little benefit when combined with lipid infusion in local anesthetic induced cardiac arrest. 24 
Surprisingly, lipid emulsion alone was not as effective as predicted based on the anecdotal evidence available prior to beginning this study. Lipid emulsion alone was effective only 14% of the time. As similar to the study done by Mauch, lipid alone rarely resulted in ROSC.  However, those swine with lipid emulsion infusion with adrenergic support required much less epinephrine to maintain ROSC than the epinephrine alone group. Epinephrine has been known to cause significant rhythm disturbances especially in higher doses. Combining lower dose epinephrine with lipid emulsion may lead to less post-code sequlea than frequent doses of epinephrine25
In our study it was expected that the best response to the lethal dose of bupivacaine would be lipid emulsion with epinephrine with vasopressin. Surprisingly, that group had a decreased survival rate as compared to lipid emulsion/ epinephrine group and none of the swine that received vasopressin alone survived. Gregorio et al had similar results in a rat model as vasopressin was associated with adverse outcomes. 26   In a study by Hicks lipid with epinephrine with vasopressin likewise did not improve survival in a swine model.17 In the study by Mauch, the lipid only and lipid/vasopressin groups had the lowest survivability.9 However in another swine study done by Mayr et al, their epinephrine and vasopressin group had 100% survival. However, they used a lower dose bupivacaine toxicity model, no lipid infusion, and they had a hypoxic variable. 18      It is suggested by this author that vasopressin may be avoided in patients exposed to a toxic dose of bupivacaine until further definitive studies can be done. 
Swine are physically and anatomically very similar to humans and their ease of use has made them used widely in resuscitation protocols. With that stated, it should be noted that recently there has been some issues related to using swine in lipid resuscitation models. In our study, as well as the study by Niiya and colleagues, some of our swine exhibited a transient red mottling rash after administration of the lipid infusion.27 Therefore, before initiating this study we performed a small study examining IgE, IgG, c-reactive protein, blood gas analysis and cardiovascular parameters to determine if there are any changes before and after lipid infusions. Our published paper showed there were no significant changes in any of our measured parameters before and after lipid emulsion infusions.28 Although these tests were not �CARPA� specific,29 there was no CARPA like reactions with major cardiovascular changes.  Swine have been shown to have consistent major cardiovascular changes after liposome / nanoparticle infusions. It has been hypothesized that swine may also have CARPA like reactions after lipid infusions. A transient increase in pulmonary hypertension has occurred with a all swine exposed to liposomes with significant decreases in systemic arterial pressures.30 This decrease in SBP did not occur with our infusion of lipids, therefore offering the possibility that this swine model may be suitable for lipid infusion experiments. 
Further research is necessary to validate the findings of this study. Larger study groups and a larger number of subjects may also be helpful to further prove significance of the results, especially to confirm if time to onset of ROSC is indeed quicker with the lipid emulsion/ epinephrine group.  Additionally, it is not known if these results are generalizable to other animal species, hence, study replication using another species of animal, such as sheep or rabbits, could reinforce the findings of this study. Likewise, it is not known if these results are applicable to other local anesthetics; therefore, research pertaining to toxicity of other local anesthetics could prove invaluable for treatment of local anesthetic toxicity.

Conclusion
Based on the results of this study, the synergistic effect of the two combined drugs (epinephrine and lipid emulsion) may warrant permanent changes in ACLS protocol when there is local anesthetic toxicity. Also the use of vasopressin in this scenario should be used cautiously, if at all, until further research is completed.    This finding could have significant implications for improving survival rates following overdose of lipophilic drugs, specifically the local anesthetic bupivacaine.
References
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2.  Finn S, Uncles D, Willers J, Sable N (2009) Early treatment of a quetiapine and sertraline overdose with Intralipid. Anaesthesia, 64, 191-194
3.  Sirianni A, Osterhoudt K, Calello D, Muller A, Waterhouse M, Goodkin M, Weinberg G (2008) Use of Lipid Emulsion in the Resuscitation of a Patient With Prolonged Cardiovascular Collapse After Overdose of Bupropion and Lamotrigine. Annals of Emergency Medicine, 51(4), 412-15
4.  Foxall G, McCahon R, Lamb J, Hardman JG, Bedforth NM (2007) Levobupivacaine induced seizures and cardiovascular collapse treated with Intralipid. Anaesthesia, 62, 516-518
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8.  Rothschild L, Bern S, Oswald S, Weinberg G (2010) Intravenous Lipid Emulsion in Clinical Toxicology. Scandinavian Journal of Trauma, Resuscitation, and Emergency Medicine, 18, (51), 1-8
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11.  Albright GA (1979) Cardiac arrest following regional anesthesia Anesthesiology, 51(4), 285-7
12. Zetiaoui  P, Labbe JP, Benhamou D (2008), Ultrasound Guidance for Axillary Plexus Block Does Not
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Prevention. Review Article. Drug Safety, 24, (6), 413-442
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15. Weinberg G, Ripper R, Murphy P, Edelman L, Hoffman W, Strichartz G, Feinstein D (2006A) Lipid Infusion Accelerates Removal of Bupivacaine and Recovery from Bupivacaine Toxicity in the Isolated Rat Heart. Regional Anesthesia and Pain Medicine, 31, (4), 296-303
16. Weinberg G,  Gregorio  G, Ripper R, Kelly  K, Massad  M, Edelman  L, Schwartz D, Shah  N,  Zheng S,  Feinstein D (2008) Resuscitation with Lipid vs Epinephrine in a Rat Model of Bupivacaine Overdose. Anesthesiology, 108(5), 907-913.
17.  Hicks S, Salcido D, Logue E, Suffoletto B, Empey P, Poloyac S, Miller D, Callaway C (2009) Lipid Emulsion Combined with Epinephrine and Vasopressin Does Not Improve Survival in a Swine Model of Bupivacaine-induced Cardiac Arrest. Aneshtesiology, 111,138-46
18. Mayr V, Mitterschiffthaler L, Neurauter A, Gritsch C, Wenzel V, Muller T, Luckner G, Lindner K, Strohmenger H (2008) A comparison of the combination of epinephrine and vasopressin with lipid emulsion in a porcine model of asphyxia cardiac arrest after intravenous injection of bupivacaine. Anesthesia and Analgesia, 106(5), 1566-71
19.  Weinberg G, Ripper R, Feinstein DL, et al. (2003) Lipid emulsion infusion rescues dogs from bupivacaine-induced cardiac toxicity. Reg Anesth Pain Med. 28, 198-202
20.  Corman S, Skledar S (2007) Use of Lipid Emulsion to Reverse Local Anesthetic-Induced Toxicity. The Annals of Pharmacotherapy. 41, 1873-1877.
21.  Weinberg G (2008) Lipid Infusion Therapy: Translation to Clinical Practice. Anesthesia and Analgesia. 106(5), 1340-42.
22. Stoelting R, Miller R (2007) Basics of Anesthesia, Philadelphia, PA: Churchill, Livingstone Susino D, Fishler M (2009) Immediate Intravenous Lipid Infusion in the Successful Resuscitation of Ropivacaine-Induced Cardiac Arrest After Infraclavicular Brachial Plexus Block. Regional Anesthesia and Pain Medicine, 34(3), 276-277.
23.  Picard J, Ward SC, Zumpe R (2009) Guidelines and the adoption of �lipid rescue� therapy for local anesthetic  toxicity. Anesthesiology, 64; 122-125
24. Hiller D, Di Gregorio G, Ripper R, Kelly K, Massad M, Edelman L, Edelman G, Feinstein D, Weinberg G (2009) Epinephrine Impairs Lipid Resuscitation from Bupivacaine Overdose. Anesthesiology,111, 498-505
25. Harvey M (2009) Bupivacaine-induced Cardiac Arrest. Fat is Good- Is Epinephrine Really Bad? Anesthesiology, 111(3), 467-68.
26.  Gregorio G, Schwartz D, Ripper R, Kelly K, Feinstein D, Minshall R, Massad M, Ori C, Weinberg G (2009) Lipid emulsion is superior to vasopressin in a rodent model of resuscitation from toxin-induced cardiac arrest. Critical Care Medicince, 37 (3); 993-999
27. Niiya T, Litonius E, Petaja L, et al. (2010) Intravenous lipid emulsion sequesters amiodarone in plasma and eliminates its hypotensive action in pigs. Annals of Emergency Med, 56(4), 402-408
28. Crane C, Sagini E, Johnson A, O�Sullivan J (2012) Utilization of a swine (sus scrofa) model for lipid emulsion resuscitation studies. ISRN Anesthesiology, DOI: 10.5402/2012/905034, 5 pages
29. Szebeni J, Bedocs P, Csukas D, et al (2012) A porcine model of complement- mediated infusion reactions to drug carrier nanosystems and other medicines. Adv Drug Delivery Reviews, 64: 1706-1716
30. Szebeni J, Baranyi L, Savay S, et al (2005) Complement activation- related cardiac anaphylaxis in pigs: role of C5a anaphylatoxin and adenosine in liposome- induced abnormalities n EKG and heart function. Amer Journal Physio Circ Physio, 290, H1050-H1058

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