ORIGINAL RESEARCH CONTRIBUTIONS

L-Carnitine Increases Survival in a MurineModel of Severe Verapamil ToxicityEric Perez, MD, Jason Chu, MD, Theodore Bania, MD, and Kamal Medlej, MD

AbstractObjectives: L-Carnitine is an essential compound involved in cellular energy production through freefatty acid metabolism. It has been theorized that severe verapamil toxicity ‘‘shifts’’ heart energy produc-tion away from free fatty acids and toward other sources, contributing to profound cardiogenic shock.The primary study objective was to determine whether intravenous (IV) L-carnitine affects survival insevere verapamil toxicity. Secondary objectives were to determine the effects on hemodynamic parame-ters. The authors hypothesized that IV L-carnitine would increase both survival and hemodynamicparameters in severe verapamil toxicity.

Methods: This was a controlled, blinded animal investigation. Sixteen male rats were anesthetized, ven-tilated, and instrumented to record mean arterial pressure (MAP) and heart rate. Verapamil toxicity wasachieved by a constant infusion of 5 mg ⁄ kg ⁄ hr. After 5 minutes a bolus of 50 mg ⁄ kg of either L-carnitineor normal saline was given. The experiment concluded when either 10% of baseline MAP was achievedor 150 minutes had elapsed. The data were analyzed using Kaplan-Meier analysis, log rank test, andanalysis of variance.

Results: The median survival for the animals in the L-carnitine group was 140.75 minutes (interquartilerange [IQR] = 98.6 to 150 minutes), and for those in the normal saline group it was 49.19 minutes(IQR = 39.02 to 70.97 minutes; p = 0.0001). At 15 minutes the MAP was 20.45 mm Hg greater in the ani-mals in the L-carnitine group than in the animals in the normal saline group (95% confidence interval[CI] = 0.25 to 40.65; p = 0.047).

Conclusions: When compared with saline, IV L-carnitine increases survival and MAP in a murine modelof severe verapamil toxicity.

ACADEMIC EMERGENCY MEDICINE 2011; 18:1135–1140 ª 2011 by the Society for AcademicEmergency Medicine

C arnitine is a compound initially isolated frommeat (carnus) in 1905. It was mistakenly catego-rized as a nutritional vitamin until further inves-

tigation revealed that it could be synthesized in severalorgans of the human body including the liver and kid-neys. There it is produced from the combination of theamino acids lysine and methionine, in two opticalisomeric forms, of which only the isomer L-carnitine isbiologically active.

Carnitine is essential for cellular energy productionfrom the breakdown of free fatty acids. It serves to

transport fatty acids from the cellular cytoplasm intothe mitochondrial matrix via the carnitine shuttle. Oncein the mitochondrial matrix, the fatty acids undergobeta-oxidation to form acetyl-CoA, which subsequentlyenters the Krebs cycle to satisfy cellular energydemands.

Carnitine has drawn interest as an adjunctive treat-ment for a wide range of medical conditions. Amongthem, there is evidence that chronic daily supplementa-tion with carnitine can improve the symptoms of inter-mittent claudication in peripheral vascular disease andimprove exercise tolerance in both angina pectoris andcongestive heart failure patients.1,2 In addition, carni-tine has been recommended by some for treatment ofthe acute toxicity of valproic acid, as well as the chronictoxicities of some human immunodeficiency virus andchemotherapy agents.3,4

Severe calcium channel antagonist toxicity continuesto be a clinical concern without a universally standardmedical treatment. Clinically, this toxicity manifests assevere cardiogenic shock that is unresponsive to tradi-tional medical therapies for shock. The reason for thisis likely multifactorial. Calcium channel antagonist

ª 2011 by the Society for Academic Emergency Medicine ISSN 1069-6563doi: 10.1111/j.1553-2712.2011.01217.x PII ISSN 1069-6563583 1135

From the Department of Emergency Medicine, St Luke’s ⁄Roosevelt Hospital, New York, NY.Received March 2, 2011; revisions received May 16, June 3, andJune 15, 2011; accepted June 15, 2011.Presented at the Society for Academic Emergency Medicineannual meeting, Phoenix, AZ, June 2010.The authors have no relevant financial information or potentialconflicts of interest to disclose.Supervising Editor: Mark B. Mycyk, MD.Address for correspondence and reprints: Eric Perez, MD;e-mail: eperez95@yahoo.com.

toxicity, like other cardiac stressors, switches cardiacmetabolism from free fatty acids to glucose.5 However,unlike other cardiac stressors, calcium channel antago-nists block the utilization of glucose by both inhibitinginsulin release from the pancreas and inhibiting thestress-regulated entry of glucose into cells for energyconsumption.6,7 Consequently, cardiac myocytes aredeprived of both free fatty acids and glucose as energysources, leading to shock.

High-dose insulin euglycemia has become an effec-tive method of treating calcium channel antagonist tox-icity. It improves glucose utilization in this toxicity byovercoming the insulin resistance. Consequently, glu-cose is delivered intracellularly, providing myocytes anenergy source for contraction while overcomingshock.5,8

Likewise, intravenous (IV) fat emulsions have suc-cessfully reversed the effects of verapamil toxicity inseveral animal models and recently one human casereport.9-12 The mechanism of action of this treatment isstill not completely understood. It is thought to work bycreating a lipid compartment in the serum that seques-ters lipid-soluble drugs. However, it remains possiblethat it reverses cardiogenic shock by providing a sub-strate for cellular energy production in cardiac tissue.10

Given the success of other metabolic agents in cal-cium channel antagonist toxicity, we focused on carni-tine as a possible treatment. Fatty acids are thepreferential source of energy for cardiac myocytes, andcardiac tissue appears to be overwhelmingly affected insevere verapamil poisoning. Since carnitine is an essen-tial component of fatty acid utilization, it is possible thatcarnitine could reverse the acute toxicity of calciumchannel antagonists.

The objective of this study was to evaluate the effectsof IV L-carnitine on survival in a murine model ofsevere verapamil toxicity. We hypothesized that L-carni-tine would increase survival and improve hemodynamicparameters in this model.

METHODS

Study DesignThis was a controlled, blinded laboratory investigationin a murine model. The animal care and use committeeof our institution approved this protocol, and the careand handling of the animals were in accordance withthe National Institutes of Health guidelines.

Animal SubjectsSixteen adult male Sprague-Dawley rats ranging inweight from 300 to 420 g were used in this protocol(Taconic Farms, Inc., Hudson, NY). Adult male Spra-gue-Dawley rats were used in this study because of ourprevious experience using this species in models ofsevere verapamil toxicity. All animals were allowed freeaccess to food and water and housed in plastic cageswith 12-hour light and dark cycles. Rats were randomlyassigned to one of the two study groups.

Study ProtocolEach animal was weighed, and then anesthesia wasinduced with 5% isoflurane through a nose cone. Once

asleep, each animal was placed on a heating pad(Model T ⁄ Pump, Gaymar Industries Inc., Orchard Park,NY) to control body temperature. While still underanesthesia, the neck was instrumented and a 14-gaugecatheter was inserted into the trachea under directvisualization and secured with a suture. Anesthesia wasthen maintained with 1.5% isoflurane while a rodentventilator (Model 683, Harvard Apparatus Inc., Holliston,MA) supplied each animal with 100% oxygen via thetracheostomy tube at a rate of 60 breaths ⁄ min and with atidal volume of 3L ⁄ min. The neck was further instrumen-ted to expose the right carotid artery and a 22-gaugecatheter was inserted for continuous blood pressuremeasurements. A 24-gauge catheter was inserted andsecured in each femoral vein using open ‘‘cut-down’’techniques. The right femoral catheter was used for infu-sion of verapamil solution, and the left femoral catheterwas used for the administration of our investigationalsubstance. McGaw infusion pumps (Model 360infuser,B. Braun Medical Inc., Bethlehem, PA) were used forboth the administration of investigational substance aswell as the verapamil infusion.

After instrumentation was complete, surface elec-trodes were placed on the rat’s chest to capture contin-ual electrocardiogram (ECG) tracings. A PowerLab4 ⁄ 20 data acquisition system (Model ML840, ADInstru-ments Inc., Colorado Springs, CO) recorded both theECG readings and the continual arterial blood pressurereadings using PowerLab software (Chart 5, ADInstru-ments). At this time, baseline measurements of heartrate and blood pressure were recorded, and all linesand equipment were checked prior to the start of theexperiment.

After baseline measurements were completed, theexperiment was begun. At the start (time 0), a constantinfusion of 5 mg ⁄ kg ⁄ hr verapamil was initiated. Thisinfusion would run until the end of the experiment. Theverapamil was prepared in a concentration of2.5 mg ⁄ mL, which allowed us a manageable volume ofinfusion of less than 1 mL ⁄ hr that would not beexpected to affect the animal’s intravascular volume sta-tus. This particular dose of verapamil infusion was cho-sen because of our previous unpublished experience inverapamil murine models. Based on this experience,this dose was expected to produce survival times of 40to 50 minutes in untreated animals.

Five minutes after the verapamil infusion was begun,the investigational substance was infused over 5 min-utes in a blinded manner. Either 50 mg ⁄ kg IV L-carnitineor a similar volume of 0.9% normal saline was infused.The dose of 50 mg ⁄ kg was chosen as it has previouslybeen advocated for human treatment of acute valproicacid toxicity as well as infant carnitine deficiencies.13,14

After the investigational agent was infused, hemody-namic parameters were followed until the conclusion ofthe experiment. Likewise, during data analysis, theinvestigator interpreting the data was blinded to thetreatment group.

MeasurementsSurvival time was defined as the length of time in min-utes from the initiation of verapamil (time 0) until thefirst of the following conditions was met: either the

1136 Perez et al. • L-CARNITINE INCREASES SURVIVAL IN VERAPAMIL TOXICITY

mean arterial pressure (MAP) had reached 10% of base-line values or 150 minutes had elapsed without a suit-able decrease in blood pressure. At this time, the animalwas euthanized with 100 mg ⁄ kg IV pentobarbital.

Continuous MAP and heart rate measurements wereobtained. For the purposes of comparison, measure-ments were recorded at 15 and 30 minutes after thestart of the experiment for exploring differences in sec-ondary outcomes between both groups. Any particularanimal that had died prior to the 15- or 30-minute per-iod was excluded from the statistical analysis andgraphs of that particular group. No comparisons weremade after 30 minutes, since a significant proportionof the control animals had already expired prior to the45-minute mark.

Data AnalysisOur primary objective (survival) was analyzed with timeto event: Kaplan-Meier survival curves and log ranktest. Secondary endpoints (heart rate and MAP) wereanalyzed by repeated-measures analysis of variancewith post hoc testing. Post hoc testing was done foreach secondary endpoint at both the 15- and the30-minute time periods. Significance was determinedvia 95% confidence intervals (CIs). Data were analyzedusing SPSS 8.0 (SPSS Inc., Chicago, IL).

The following a priori sample size calculation wasperformed to test the null hypothesis. A two-tailed testwas performed with the criterion for significance(alpha) set at 0.05. Based on assumptions of intergroupvariability, a sample size of 16 (eight per group) wascalculated to be necessary to detect a 50% differencebetween groups with a power of 0.85. The 50% differ-ence chosen for this study was purposely large for thispilot work with carnitine. We recognize appropriatelyused high-dose insulin is an excellent treatment for tox-icity, and IV fat emulsion has also shown to be anexcellent noninferior treatment in animal models. Thus,we felt future investigations with carnitine worthpursuing only if its effect size should be large.

RESULTS

At the beginning of the experiment we were unable todetect any significant difference in hemodynamicparameters between groups. The carnitine group beganthe experiment with a MAP of 92.7 mm Hg (standarddeviation [SD] ± 20.08 mm Hg, 95% CI = 79.8 to106.6 mm Hg), while the normal saline group had aMAP of 94 mm Hg (SD ± 21.53 mmHg, 95% CI = 79.1to 108.9 mm Hg). Likewise, the carnitine group beganthe experiment with a mean heart rate of 323 beats ⁄ min(SD ± 30.27 beats ⁄ min, 95% CI = 312 to 334 beats ⁄ min),while the normal saline group had a mean heart rate of307 beats ⁄ min (SD ± 35.37 mm Hg, 95% CI = 282 to 333beats ⁄ min).

Primary Outcome (Survival)Median survival in the carnitine group was 140.75 min-utes (IQR = 98.60 to 150 minutes, 95% CI = 112.59 to168.89 minutes), while the median survival for the nor-mal saline group was 49.19 minutes (IQR = 39.02 to70.97 minutes, 95% CI = 30.16 to 68.22 minutes).

All animals in the carnitine group lived over 90 min-utes, compared to only one in the normal saline group(see Figure 1). In addition, half the animals in the carni-tine group (four) survived the 150-minute protocol andwere euthanized as per protocol.

Secondary OutcomesHeart Rate (Figure 2). At 15 minutes, the carnitinegroup had a median heart rate of 297 beats ⁄ min(IQR = 273 to 313 beats ⁄ min) versus the normal salinegroup’s median heart rate of 161 beats ⁄ min(IQR = 108.5 to 295 beats ⁄ min). The difference of 136beats ⁄ min was not significant (p = 0.18).

At 30 minutes, the carnitine group had a median heartrate of 280 beats ⁄ min (IQR = 198 to 306.5 beats ⁄ min) asopposed to the normal saline group’s heart rate of 96beats ⁄ min (IQR = 74 to 241 beats ⁄ min). The difference of184 beats ⁄ min was again not significant (p = 0.228).

MAP (Figure 3). At 15 minutes, the carnitine grouphad a mean MAP of 63 mm Hg (SD ± 19.4 mm Hg),

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Figure 1. Kaplan-Meier survival curve.

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Figure 2. Carnitine versus heart rate.

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while the normal saline group had a MAP of 42.6 mmHg (SD ± 22.9 mm Hg). The difference of 20.4 mm Hg(95% CI = 0.25 to 40.65 mm Hg) was statistically signifi-cant (p = 0.047).

At 30 minutes, the mean MAP for the carnitine groupwas 52.9 mm Hg (SD ± 17.9 mm Hg) versus the normalsaline group’s MAP of 34.3 mm Hg (SD ± 17.6 mm Hg).The difference of 18.6 mm Hg (95 CI = )9.3 to 46.4 mmHg) was not significant (p = 0.08).

DISCUSSION

This study tested the hypothesis that IV L-carnitinecould improve hemodynamics and increase survival inan animal setting of severe verapamil toxicity. Theseresults are important because clinically, calcium chan-nel antagonist poisonings continue to be deadly despiterecent advances and aggressive therapies.

Outcomes of calcium channel antagonist toxicity haveimproved over the past decade while the overall inci-dence of reported ingestions has increased. In fact,according to the latest report by the American Associa-tion of Poison Control Centers in 2009, there were 16deaths and 62 major complications associated with cal-cium channel antagonists out of a reported 5,027 singleexposures in that year.13 Contrast that with the 1998report, where 61 deaths and 277 major complicationswere observed from only 2,197 single exposures.14

There is no standardized treatment for significantingestions of calcium channel antagonists. Rather, therecontinues to be variability among clinicians as to whatconstitutes standard treatment. This does not imply thateffective treatments do not exist, but rather that theirimplementation varies among clinicians, especiallyamongst different specialties. Oftentimes multipleagents are used in concert. Given these divergent treat-ment patterns for a potentially deadly ingestion, weaimed to investigate a novel treatment for this toxicity.

We designed our preliminary experiment testingL-carnitine’s effects on survival in severe verapamil tox-icity using a rat model. Our experiment demonstratesthat IV L-carnitine increases survival in this setting. Toour knowledge, this is the first experiment that demon-strates carnitine’s ability to clinically improve verapamiltoxicity. In addition, carnitine’s effect on survival in this

experiment was likely muted by our experimentaldesign. By design, our experiment was terminated andthe animal killed at 150 minutes, if it had not previouslysuccumbed to severe verapamil toxicity as described inour methods. This resulted in four out of eight animalsin the carnitine group being euthanized at the 150-minutemark, despite having a relatively robust hemodynamicprofile. Consequently, the true difference in survivalbetween both groups may actually be larger than statedin our results. With this in mind, it seems that morework needs to be done in evaluating carnitine’s use-fulness as an antidote in calcium channel antagonisttoxicity.

Carnitine’s mechanism of action in reversing severeverapamil toxicity is unknown, although several possi-bilities exist. First, biochemistry experiments demon-strate that verapamil inhibits absorption of carnitinefrom the plasma into myocardial and skeletal cells.15,16

Myocardial and skeletal cells do not produce their owncarnitine supplies and are consequently dependent onuptake from plasma supplies generated from the liverand kidneys and to some extent absorbed from dietarysupplies.17 It is therefore possible that carnitinereverses verapamil toxicity by overcoming this blockadethrough mass effect, resulting in intracellular carnitinelevels capable of maintaining energy supplies throughbeta-oxidation.

Another possibility is that IV L-carnitine results in thedirect activation of calcium channels, thereby reducingverapamil’s calcium channel antagonism. Palmitoyl car-nitine and other acylcarnitines have been shown to beendogenous in vitro ligands for calcium channel activa-tion.18,19 This activation of myocardial calcium channelshas been used to explain the positive inotropic effectsof palmitoyl carnitine on chick heart cell aggregates.20

It is therefore possible in our model that the IV L-carnitineis being transported into myocytes and bound to freefatty acids with acetyl-CoA to form higher concentra-tions of acylcarnitines. These acylcarnitines in turn couldtheoretically increase the activation of voltage-gatedcalcium channels and increase inotropy.

A third possibility is that IV L-carnitine could increasefree fatty acid utilization during verapamil toxicity. Pre-vious work in models of congestive heart failure andcardiac ischemia have shown that impaired hearts withdecreased oxygenation have a markedly decreased myo-cardial free carnitine concentration, as well as adecrease in beta-oxidation.2 This in turn leads to anaccumulation of fatty acylcarnitines and acyl-CoA in thecytoplasm, which inhibits the transporter responsiblefor transporting ATP out of the mitochondria, effec-tively trapping ATP in the mitochondria.21 The overalleffect is decreased contractility due to lack of a physio-logic energy source. In these models, L-carnitine hasbeen shown to reverse the inhibition of the adenine-nucleotide transferase, essentially unlocking ATP frommitochondria and transferring it to the cytoplasm whereit can be used as an energy source for contractility.

It has also been hypothesized that verapamil toxicityshifts cardiac metabolism from free fatty acids, its pref-erential source of energy, to carbohydrate metabo-lism.7,22,23 This in part is used for the explanation as towhy high-dose insulin euglycemia reverses verapamil’s

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1138 Perez et al. • L-CARNITINE INCREASES SURVIVAL IN VERAPAMIL TOXICITY

toxicity; it in essence provides a myocardial energysource that sustains cardiac contractility in a situationwhere cardiac starvation might otherwise occur. It istherefore possible that in our model of verapamil toxic-ity, IV carnitine shifts cardiac metabolism back to itspreferential source of energy: free fatty acids. By sup-plying an energy source to the myocardium, the myo-cardium avoids a state of starvation and consequentlycontractility is maintained.

Finally, it is entirely possible that the effects of IVL-carnitine are multifactorial or that another explanationexists. Further studies are needed to explore these pos-sible mechanisms as well as further delineate the roleof carnitine in other similar toxicities as well as incombination with other treatments.

To the best of our knowledge, there have been nohuman data on IV L-carnitine use in verapamil toxicity.However, there is substantial evidence documenting IVcarnitine’s safety in treating other conditions. In fact,the dose of carnitine used in this experiment (50 mg ⁄ kg)was obtained from reviewing the literature on valproicacid toxicity in humans. It seems that this dose is safeand free of any significant side effects, save for the pro-pensity of the patient to develop a ‘‘fishy odor.’’3 Thatbeing said, it is too early to suggest using this excitingfinding in human cases.

LIMITATIONS

This was a small model animal study, and how wellthese results would translate to humans is unknown.Although IV L-carnitine has been previously studied inhumans, it has never been used for this indication. It isunknown if the improvements in survival and hemody-namic parameters seen in this experiment could be rep-licated in a real-life clinical scenario.

Our experiment employed small sample sizes. Conse-quently, our results had wide variability. Larger studiesare necessary to determine the true effect size ofL-carnitine.

Our experiment creates verapamil toxicity through acontinual infusion of IV verapamil. This model may notaccurately represent the toxicity achieved through amassive oral ingestion of verapamil. Our serum verapa-mil concentrations may therefore differ from those seenin a human ingestion. Consequently, carnitine could beexpected to have different if any efficacy in humaningestions. In addition, our model was intentionallydesigned to be extremely toxic. Most control animalsdied within an hour of the onset of verapamil toxicity.This too may differ from a massive oral ingestion.

Our experiment used L-carnitine as the sole treatmentfor verapamil toxicity. As described earlier, there areseveral treatments for verapamil toxicity including butnot limited to calcium, atropine, glucagon, high-doseinsulin euglycemia, inotropes, and IV fat emulsions. Itwould be unreasonable to suspect that L-carnitinewould ever be used as the sole treatment for the rever-sal of verapamil toxicity in a real-world setting. Carni-tine’s effect in the presence of some or all of theseother antidotes is unknown. It is possible that otherantidotes could dilute the effect of carnitine producedin this experiment or alternatively augment it.

Our experiment used a single dose bolus of L-carnitineto reverse verapamil toxicity. It is unknown whetherhigher dose boluses of carnitine would provide anybenefit over the dose chosen. Likewise it is unknownwhether repeated doses or a constant infusion ofcarnitine would be more effective in improving hemody-namic parameters and survival.

CONCLUSIONS

When compared with saline, intravenous L-carnitineincreases survival and mean arterial pressure in a mur-ine model of severe verapamil toxicity.

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1140 Perez et al. • L-CARNITINE INCREASES SURVIVAL IN VERAPAMIL TOXICITY