BASIC INVESTIGATION

Determining the Optimal Dose of IntravenousFat Emulsion for the Treatment of SevereVerapamil Toxicity in a Rodent ModelEric Perez, MD, Theodore C. Bania, MD, Kamal Medlej, MD, Jason Chu, MD

AbstractObjectives: Recent animal studies have shown that intravenous fat emulsion (IFE) increases survival andhemodynamics in severe verapamil toxicity. However, the optimal dose of IFE is unknown. The primaryobjective was to determine the optimal dose of IFE based on survival in severe verapamil toxicity. Second-ary objectives were to determine the effects on hemodynamic and metabolic parameters. The hypothesiswas that there is a dose-dependent effect of IFE on survival until a maximum dose is reached.

Methods: This was a controlled dose-escalation study. Thirty male rats were anesthetized, ventilated,and instrumented to record mean arterial pressure (MAP) and heart rate (HR). Verapamil toxicity wasachieved by a constant infusion of 15 mg ⁄ kg ⁄ hr. After 5 minutes, a bolus of 20% IFE was given. Animalswere divided into six groups based on differing doses of IFE. Arterial base excess (ABE) was measuredevery 30 minutes. Data were analyzed with analysis of variance.

Results: The mean survival time for each dose of IFE was 0 mL ⁄ kg = 34 minutes, 6.2 mL ⁄ kg = 58 minutes,12.4 mL ⁄ kg = 63 minutes, 18.6 mL ⁄ kg = 143.8 minutes, 24.8 mL ⁄ kg = 125.6 minutes, and 37.6 mL ⁄ kg =130 minutes. Post hoc testing determined that the 18.6 mL ⁄ kg dose resulted in the greatest survival whencompared to other doses. It increased survival 107.2 minutes (p = 0.004), 91.2 minutes (p = 0.001), and80.8 minutes (p = 0.023) when compared to the lower doses of 0, 6.2, and 12.4 mL ⁄ kg, respectively. Therewas no added benefit to survival for doses greater than 18.6 mL ⁄ kg. The secondary outcomes of HR, MAP,and ABE showed the most benefit with 24.8 mL ⁄ kg of IFE at both 30 and 60 minutes.

Conclusions: The greatest benefit to survival occurs with 18.6 mL ⁄ kg IFE, while the greatest benefit toHR, MAP, and BE occurs at 24.8 mL ⁄ kg IFE. The optimal dose for the treatment of severe verapamil tox-icity in this murine model was 18.6 mL ⁄ kg.

ACADEMIC EMERGENCY MEDICINE 2008; 15:1284–1289 ª 2008 by the Society for Academic Emer-gency Medicine

Keywords: intravenous fat emulsion, verapamil toxicity

I ntravenous fat emulsions (IFEs) have traditionallybeen used as a source of calories in parenteral nutri-tion. Another familiar use of IFE is as a solvent in

medications such as propofol and amphotericin.Recently, a new nontraditional use of IFE has emerged.IFE has been investigated and reported as a novel anti-dote in treating several drug toxicities.

Among these medications, IFE has recently beenstudied as a treatment for calcium channel antagonisttoxicity. A murine model has demonstrated that IFEscan increase survival and heart rate (HR) in the settingof severe verapamil toxicity.1 A large animal modelstudy demonstrated that both survival and blood pres-sure are increased in animals resuscitated with IFE pluscalcium, atropine, and saline versus those resuscitatedwith calcium, atropine, and saline alone.2

These recent experimental models using IFE areencouraging, but little is known about how to dose IFEas an antidote. It is uncertain whether greater benefitsexist with higher doses or if smaller doses are just aseffective.

The purpose of this study was to determine if there isa dose-dependent beneficial effect of IFE in severeverapamil toxicity. We also wanted to determine if a

ISSN 1069-6563 ª 2008 by the Society for Academic Emergency Medicine1284 PII ISSN 1069-6563583 doi: 10.1111/j.1553-2712.2008.00259.x

From the St. Luke’s Roosevelt Hospital Center, Columbia Uni-versity, College of Physicians and Surgeons (EP, TCB, KM, JC),New York, NY.Presented at the 2008 SAEM National Meeting, WashingtonDC, May 27, 2008, and the SAEM NY regional meeting.Received March 24, 2008; revision received June 3, 2008;accepted June 4, 2008.Address for correspondence and reprints: Eric Perez, MD;e-mail: eperez95@yahoo.com.

maximal beneficial effect of IFE in severe verapamiltoxicity existed.

METHODS

Study DesignThis was a controlled murine laboratory investigationusing a dose-escalation study design. The primaryobjective was to determine the dose of 20% IFE thatconferred the longest survival (measured in minutes) torats with severe verapamil toxicity. Secondary objec-tives were to determine the effect of varying doses ofIFE on blood pressure, HR, and arterial blood gas anal-ysis in rats with severe verapamil toxicity. The animalcare and use committee of the institution approved thisprotocol, and the care and handling of the animalswere in accordance with National Institutes of Healthguidelines.

Animal SubjectsThirty adult male Sprague-Dawley rats ranging from445 to 630 g were used in the study. Adult male Spra-gue-Dawley rats were chosen because they were previ-ously used to study verapamil toxicity. The animalswere housed in plastic cages with 12-hour light anddark cycles and were allowed free access to food andwater.

Study ProtocolAll animals were prepared in a similar manner. The ani-mals were first placed on a Gaymar heating pad (ModelT ⁄ Pump, Gaymar Industries Inc., Orchard Park, NY)and induced with 5% isoflurane anesthesia via nosecone. While under anesthesia, the neck was dissectedand a catheter (14-gauge) was inserted into the tracheaand secured with a suture. At that point, the isofluranewas decreased to 1.5% and maintained for the durationof the protocol. A Harvard rodent ventilator (Model683, Harvard Apparatus Inc., Holliston, MA) suppliedthe animals with 100% oxygen via the tracheostomytube at a rate of 60 breaths ⁄ min and a tidal volume of6 mL ⁄ kg.

The animals’ right carotid artery was directly visual-ized and a catheter (22-gauge) was placed and securedwith suture. This catheter was used for continuousblood pressure monitoring as well as blood gas sam-pling using a Radiometer blood gas analyzer (ModelABL505, Radiometer America Inc., Westlake, OH).Bilateral femoral venous catheters (24-gauge) were thenplaced under direct visualization using a ‘‘cut-down’’technique. One was used exclusively for verapamil infu-sion, and the other exclusively for IFE infusion usingMcGaw infusion pumps (Model 360infuser, B. BraunMedical Inc., Bethlehem, PA). Surface pin electrodeswere placed to capture ongoing electrocardiogram(ECG) rhythm strips. A PowerLab 4 ⁄ 20 data acquisitionsystem (Model ML840, ADInstruments Inc., ColoradoSprings, CO) recorded both the continuous blood pres-sure and the ECG readings using PowerLab software(Chart 5, ADInstruments Inc.).

Following instrumentation and baseline blood gasmeasurement, all animals received a constant infusionof verapamil (15 mg ⁄ kg ⁄ hr) using a verapamil solution

of 10 mg ⁄ mL in normal saline. This infusion rate waschosen based on our previous unpublished experiencewith verapamil toxicity in a murine model. This rateproduced survival rates of approximately 35 minutes inuntreated animals in our model. This concentration ofverapamil limited the volume delivered to the rats toless than 1 mL ⁄ hr. The beginning of the verapamil infu-sion constituted the start of the experiment (Time 0).Five minutes after the start of the verapamil infusion,one of the following doses of 20% IFE (20% Intralipid,Sigma-Aldrich Co., St. Louis, MO) was given: 0 mL ⁄ kg,6.2 mL ⁄ kg over 2.5 minutes, 12.4 mL ⁄ kg over 5 minutes,18.6 mL ⁄ kg over 7.5 minutes, 24.8 mL ⁄ kg over 10 min-utes, and 37.6 mL ⁄ kg over 15 minutes. Five animalswere assigned to each dose of IFE. This design pro-vided a constant rate of infusion of IFE equal to2.48 mL ⁄ min to each animal. These nonstandard doseswere chosen based on a previous murine model investi-gating the effects of IFE on verapamil toxicity.1 In thisprevious model, the authors demonstrated significanteffect at a dose of 12.4 mL ⁄ kg. Our current study wasdesigned to investigate the effects on survival for doseshigher and lower than 12.4 mL ⁄ kg using increments of6.2 mL ⁄ kg (or 50%) of the previously studied value. A31 mL ⁄ kg dose was purposely omitted and replacedwith the 37.6 mL ⁄ kg dose. This was designed to repre-sent what we believed to be an extremely high dosethat would likely cause systemic toxicity.

MeasurementsArterial blood gases were measured at baseline toensure a properly ventilated animal and then every30 minutes from the start of the experiment. Arterialpressures and ECG were recorded continuouslythroughout the duration of the protocol. Animals weremonitored until asystole or pulseless electrical activity(PEA) occurred. Survival was measured from the begin-ning of verapamil infusion until asystole or PEA. Mea-surements of mean arterial pressure (MAP), HR, andarterial base excess (ABE) taken at 30 and 60 minutesafter IFE infusion were used for data analysis. Any ani-mal that had died prior to the 30- or 60-minute timeperiod was excluded from that particular graph andanalysis of MAP, HR, and ABE (Figure 1).

Data AnalysisTo determine the relationship between the dose of IFEgiven and primary outcome (survival) as well as second-ary outcomes, data were analyzed using analysis of var-iance and Fishers least significant difference (LSD) post

Figure 1. Study flow. ABG = arterial blood gas; IL = Intralipid;PEA = pulseless electrical activity.

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hoc testing. These secondary outcomes were HR, MAP,and ABE. Post hoc testing for each secondary outcomewere done at both 30 and 60 minutes after the begin-ning of the experiment. Data were analyzed using SPSS8.0 (SPSS Inc., Chicago, IL). The alpha level was set at0.05.

RESULTS

Primary OutcomeSurvival. Increasing IFE doses resulted in increasedmean survival times. The greatest increase occurred inthe 18.6 mL ⁄ kg group. LSD post hoc testing demon-strated that the 18.6 mL ⁄ kg dose of IFE was superior toall lower doses (see Figure 2). Specifically, it conferreda survival advantage of 107.2 minutes versus the0 mL ⁄ kg dose (p = 0.004; 95% confidence interval[CI] = 38.6 to 176 minutes), a 91.2-minute advantageover the 6.2 mL ⁄ kg dose (p = 0.001; 95% CI = 22.6 to160 minutes), and an 80.8-minute advantage over the12.4 mL ⁄ kg dose (p = 0.023; 95% CI = 12.2 to 149 min-utes). There was no significant difference in survivalbetween the 18.6 mL ⁄ kg dose and higher doses (24.8and 37.6 mL ⁄ kg).

Both higher doses significantly increased survivalwhen compared to the 0 and 6.2 mL ⁄ kg dose of IFE,but showed no difference when compared to the12.4 mL ⁄ kg dose (Figure 2). In addition, this experimentwas unable to show a difference in survival among the0, 6.2, and 12.4 mL ⁄ kg doses of IFE.

Secondary OutcomesMAP. At 30 minutes, the 24.8 mL ⁄ kg dose of IFEresulted in a significantly greater MAP than the 0, 12.4,and 18.6 mL ⁄ kg dose. Specifically it resulted in anincrease of 43 mm Hg versus the 0 mL ⁄ kg dose(p = 0.009; 95% CI = 16 to 70 mmHg), an increase of36 mm Hg versus the 12.4 mL ⁄ kg dose (p = 0.011; 95%CI = 9 to 63 mm Hg), and an increase of 37 mm Hg ver-sus the 18.6 mL ⁄ kg dose (p = 0.09; 95% CI = 10 to 64).No other dose of IFE showed an advantage in MAPversus the zero dose or other doses of IFE at this timepoint.

At 60 minutes, the 24.8 mL ⁄ kg dose of IFE resulted ingreater MAP than both the 6.2 and the 12.4 mL ⁄ kgdoses of IFE (see Figure 3). Specifically, it resulted in an

increase of 52 mm Hg versus the 6.2 mL ⁄ kg dose(p = 0.006; 95% CI = 18 to 86 mm Hg) and an increaseof 31 mm Hg versus the 12.4 mL ⁄ kg dose (p = 0.04; 95%CI = 2 to 60 mm Hg). The highest dose of IFE,37 mL ⁄ kg, resulted in an increase of 50 mm Hg versusthe 6.2 mL ⁄ kg dose (p = 0.02; 95% CI = 9 to 90 mm Hg).No other dose of IFE showed an advantage in MAP atthis time point.

HR. At 30 minutes, the 24.8 mL ⁄ kg dose resulted in asignificantly greater HR than all other doses. Specifi-cally, it resulted in an increase in HR of 162 beats ⁄ minversus the 0.0 mL ⁄ kg dose (p < 0.001; 95% CI = 93 to230 beats ⁄ min), an increase of 127 beats ⁄ min versus the6.2 mL ⁄ kg dose (p = 0.002; 95% CI = 54 to 200 beats ⁄ -min), an increase of 146 beats ⁄ min versus the12.4 mL ⁄ kg dose (p < 0.001; 95% CI = 78 to 215 beats ⁄ -min), an increase of 127 beats ⁄ min versus the18.6 mL ⁄ kg dose (p = 0.001; 95% CI = 58 to 196 beats ⁄ -min), and an increase of 89 beats ⁄ min versus the37.6 mL ⁄ kg dose (p = 0.019; 95% CI = 16 to 161). Noother dose of IFE showed an advantage in HR at thistime point.

At 60 minutes, the 24.8 mL ⁄ kg dose resulted in agreater HR than both the 6.2 and the 12.4 mL ⁄ kg dose(see Figure 4). Specifically it resulted in an increase of132 beats ⁄ min versus the 6.2 mL ⁄ kg dose (p = 0.035;95% CI = 11 to 252 beats ⁄ min) and an increase of124 beats ⁄ min versus the 12.4 mL ⁄ kg dose (p = 0.04;95% CI = 4 to 244 beats ⁄ min). No other dose of IFEshowed an advantage in HR at this time point.

ABE. At 30 minutes, all doses showed significantlygreater ABE than the 0 mL ⁄ kg dose. The 24.8 mL ⁄ kgdose showed the most benefit being greater than the 0,6.2, and 12.4 mL ⁄ kg doses, respectively. Specifically, itresulted in an increase of 16.0 mEq ⁄ L versus the0 mL ⁄ kg dose (p < 0.001; 95% CI = 10.7 to 21.4 mEq ⁄ L),an increase of 8.2 mEq ⁄ L versus the 6.2 mL ⁄ kg dose(p = 0.007; 95% CI = 2.5 to 13.9 mEq ⁄ L), and an increaseof 9.7 mEq ⁄ L versus the 12.4 mL ⁄ kg dose (p = 0.002;95% CI = 4.0 to 15.4 units). Both the 18.6 and37.6 mL ⁄ kg doses were significantly greater than theFigure 2. Mean survival.

Figure 3. Mean arterial pressure (MAP) at 60 minutes.IFE = intravenous fat emulsion. Note: Whiskers are 95% confi-dence intervals (CIs). This graph does not contain data fromanimals that expired before the 60-minute mark.

1286 Perez et al. • IV FAT EMULSION IN VERAPAMIL TOXICITY

0 mL ⁄ kg dose, but unlike the 24.8 mL ⁄ kg dose, theyshowed no advantage versus any other dose.

At 60 minutes, the 24.8 mL ⁄ kg dose of IFE was signifi-cantly greater than all other doses other than 37.6 mL ⁄ kg(see Figure 5). Specifically it resulted in an increase of13.4 mEq ⁄ L versus the 6.2 mL ⁄ kg dose (p < 0.001; 95%CI = 8.1 to 18.7 mEq ⁄ L), an increase of 11 mEq ⁄ L versusthe 12.4 mL ⁄ kg dose (p = 0.002; 95% CI = 5.1 to17.0 mEq ⁄ L), and an increase of 6.2 mEq ⁄ L versus the18.6 mL ⁄ kg dose (p = 0.013; 95% CI = 1.6 to 10.9 mEq ⁄ L).By contrast, the 37.6 mL ⁄ kg dose was significantlygreater than the 6.2 and 12.4 mL ⁄ kg doses, but not the18.6 mL ⁄ kg dose. The 18.6 mL ⁄ kg dose on the other handwas only greater than the 6.2 mL ⁄ kg dose.

DISCUSSION

This experiment adds to our knowledge of IFE as atreatment for severe verapamil toxicity. Specifically itdemonstrates that higher doses of IFE infusion thanthose previously studied result in a significant increasein survival, hemodynamic parameters, and ABE.1,2

The idea of IFE as a treatment for drug toxicity is notnew. It has previously been hypothesized to reduce thetoxicity of lipophilic drugs by sequestering these drugsin the serum, away from their target organs.2,3 It hasalso been speculated to improve toxicity by increasingmyocardial energy supplies.2,3 Finally, it has been sug-gested that IFE may have a direct influence on calciumchannels, producing a dose-dependent increase in cal-cium current that reverses cardiac toxicity.4

Although its mechanism of action remains unclear,IFE has been shown to resuscitate bupivacaine-inducedcardiac arrest in both a canine model and most recentlyhuman case reports.5,6 IFE has also been shown toreverse bupivacaine-induced seizures.7,8 Case reportshave similarly described IFE’s role in resuscitating ropi-vacaine-induced cardiac arrest.9 It has also been shownto decrease mortality following clomipramine overdosein a rabbit model.10 Despite evidence of its effect, littleresearch has been performed establishing optimal IFEdoses or ranges in reversing drug toxicity.

Before this experiment, the optimal dose of IFE totreat verapamil toxicity was unknown. The only twostudies that investigated IFE in verapamil toxicity used12.4 and 7 mL ⁄ kg, respectively.1,2 Both were effective,and it was uncertain as to which dose was superior andif higher doses would have more benefit. Tebbutt et al.1

showed that both HR and survival increased when12.4 mL ⁄ kg IFE was used to treat severe verapamil tox-icity in a rodent model. Likewise, our group previouslyshowed that survival and blood pressure improved with7 mL ⁄ kg IFE in an anesthetized canine model.2

Our experiment helps clarify IFE dosing in severeverapamil toxicity. The results show that IFE has a maxi-mum effect on survival at a dose of 18.6 mL ⁄ kg. At thisdose, survival is increased 107.2, 91.2, and 80.8 minutes,respectively, versus the lower doses of 0, 6.2, and12.4 mL ⁄ kg IFE. Using higher dose of IFE greater than18.6 mL ⁄ kg did not result in any improvement in sur-vival. This likely represents a ‘‘plateau effect’’ in the bene-fits of IFE. Unlike previous studies, we were unable todetect a difference between the lower doses of IFE (6.2and 12.4 mL ⁄ kg) and the 0 mL ⁄ kg dose. This is likely sec-ondary to the small sample size of our study.

We also showed that IFE had a beneficial effect onhemodynamic variables, namely HR and MAPs. Themaximal effect for IFE in these outcomes was seen atthe 24.8 mL ⁄ kg dose at both 30 and 60 minutes. Thisfinding is important because it confirmed the findingsof Tebbutt et al. finding that IFE increases HR in verap-amil toxicity and also confirmed our previous findingsthat IFE increased MAP in verapamil toxicity.1,2 In addi-tion, this finding suggests that doses of IFE greaterthan those previously studied have the maximal benefi-cial effect on hemodynamic parameters.

To the best of our knowledge, this experiment is thefirst to show that IFE improves ABE in verapamil toxic-ity. It does so with a maximal effect at 24.8 mL ⁄ kg.Arterial base deficit has been used a marker of perfu-sion in multiple shock models.11,12 We believe that animproved base excess with IFE treatment representsimproved end-organ perfusion. This is consistent withour findings of increased blood pressure and HR athigher doses of IFE.

Figure 4. Heart rate (HR) at 60 minutes. IFE = intravenous fatemulsion. Note: Whiskers are 95% confidence intervals (CIs).This graph does not contain data from animals that expiredbefore the 60-minute mark.

Figure 5. Arterial base excess (ABE) at 60 minutes. IFE = intra-venous fat emulsion. Note: Whiskers are 95% confidence inter-vals (CIs). This graph does not contain data from animals thatexpired before the 60-minute mark.

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Although this experiment showed multiple beneficialeffects of IFE in severe verapamil toxicity, an optimaldose is difficult to determine. Survival increased maxi-mally up to 18.6 mL ⁄ kg, while hemodynamic parame-ters and ABE increased maximally up to 24.8 mL ⁄ kg ofIFE. This difference may be accounted for by severalreasons. First, our sample size of five animals per groupmay not be sufficient to adequately differentiatebetween the two doses. Second, these results mayreflect a survival bias. While the majority of animals inthe 24.8 mL ⁄ kg group lived past 60 minutes, one didnot. This could negatively impact survival while posi-tively impacting hemodynamic and metabolic parame-ters at 60 minutes. Last, it is possible that a lessersurvival at 24.8 mL ⁄ kg IFE, in spite of improved hemo-dynamics and metabolic parameters, represents thebeginning of toxicity of IFE itself. In other words, it ispossible that at high doses the antidote itself may betoxic. This could explain why there was deterioration insurvival in the ultrahigh IFE group (37.6 mL ⁄ kg). Ani-mals in that group had either extremely long survivaltimes or, paradoxically, short ones. Since survival wasour primary outcome, and concerns exist about admin-istering high doses of IFE, we suggest that 18.6 mL ⁄ kgis a superior dose to 24.8 mL ⁄ kg in this murine model.

Reported acute human toxicity from IFE includesallergic reactions (in persons sensitive to eggs) andsymptoms consistent with fat emboli and fat overloadsyndromes. In addition, problems with elevated livertransaminases, increased coagulability, and symptomsof headache, fatigue, nausea, and vomiting have beenreported. Most of the complications, other than allergy,are caused by long-term IFE administration.13,14 Toxic-ity from one-time rapid infusion of these substances islargely unknown.

Concerns over fat emboli and other complicationslimit the amount of IFE humans currently receive. Cur-rent maximal recommended doses of IFE for the pur-poses of artificial nutrition are approximately theequivalent of 10 mL ⁄ kg ⁄ day 20% IFE.2,15 Little informa-tion is reported on short-term, rapid administration ofIFE in humans. The little information available comesfrom regional anesthesia case reports of resuscitationof bupivacaine and ropivacaine cardiac arrest. Authorsof these case reports suggest bolus doses ranging from1 mL ⁄ kg given three times to 1.2 mL ⁄ kg given as a sin-gle dose. The recommendations go on to suggest infu-sion rates of 0.2 mL ⁄ kg ⁄ min to 0.5 mL ⁄ kg ⁄ minfollowing the initial bolus or boluses.14 The highestreported dose comes from Spence,8 who infused a totalof 500 mL of 20% IFE in a rapid succession withoutcomplications in an 86-kg gravid female to reverse bup-ivacaine-induced seizure. In fact, the patient underwentgeneral anesthesia directly after the infusion.

Our results from this murine model suggest thatdoses higher than those previously reported in humancase reports and animal studies may be of most benefitin severe verapamil overdose. It is impossible to quan-tify, recommend, or suggest human doses from thisexperiment. However, this experiment opens the possi-bility that relatively large doses of IFE could be benefi-cial in severe verapamil overdose. More investigationon the safety of large, short-term dose administration

of these substances is needed prior to fully endorsingthese higher doses.

LIMITATIONS

This was an animal experiment, and it is unclear howapplicable these results would be in cases of humanverapamil toxicity. Although high doses of IFE (up to18.6 mL ⁄ kg) showed substantial increases in survivaland hemodynamics, these doses have never been testedin humans. In fact, these doses are above the recom-mendations for administration given by the manufac-turers of IFE.10 Further studies would be needed toclarify the toxicity from higher doses of IFE prior touse in humans.

We adapted a previously studied model that createsverapamil toxicity by continually infusing a constantdose of verapamil intravenously. This model may notaccurately reflect the serum and tissue concentrationsof verapamil during a massive oral ingestion. Conse-quently, the dose of IFE needed to reverse toxicity afteroral ingestion may differ from our results. Our modelwas also extremely toxic. Control animals lived lessthan 40 minutes from the start of the verapamil infu-sion. This may also not reflect the reality of a massiveoral verapamil ingestion. For this reason it is possiblethat the dose of IFE with maximum efficacy in ourstudy may be higher than the dose of maximal efficacyneeded in human oral ingestion.

This experiment had no means to determine themechanism of toxicity from IFE itself. No autopsieswere performed to look for evidence of fat emboli, andno other attempts to obtain direct evidence of IFE tox-icity were included in the methods. In our discussionwe suggest that toxicity may have occurred in the ultra-high (37.6 mL ⁄ kg) group. We did so because of thewide variability in survival times caused by two animalsthat died suddenly soon after the infusion of IFE. Thesudden deaths may have been due to other unforeseenfactors or combination of factors. It is possible that IFEtoxicity had no role in the deaths of these two animals.Likewise, it is also possible that other lower groupsincluding the 18.6 mL ⁄ kg group experienced toxicityfrom IFE that was not immediately apparent to us.

Finally, our experiment looks only at single IFEboluses given at one specific rate. It is impossible for usto speculate on what effects slower or faster rateswould produce. Likewise, it is impossible for us to com-ment on the effectiveness of starting with a small bolusof IFE and either repeating or escalating the dose ifclinical deterioration continued or in refractory cases.Our results on dosing are only valid in this murinemodel of verapamil toxicity. Toxicities from other drugsmay optimally respond to either higher or lower dosesof IFE.

CONCLUSIONS

IFEs improve survival, HR, MAP, and ABE in severeverapamil toxicity in a rodent model. The greatest bene-fit to survival occurs with 18.6 mL ⁄ kg IFE, while thegreatest benefit to HR, MAP, and BE occurs at24.8 mL ⁄ kg IFE. We believe 18.6 mL ⁄ kg IFE to be the

1288 Perez et al. • IV FAT EMULSION IN VERAPAMIL TOXICITY

optimal dose for the treatment of severe verapamil tox-icity in this rodent model.

References

1. Tebbutt S, Harvey M, Nicholson T, Cave G. Intrali-pid prolongs survival in a rat model of verapamiltoxicity. Acad Emerg Med. 2006; 13:134–9.

2. Bania TC, Chu J, Perez E, Su M, Hahn IH. Hem-odynamic effects of intravenous fat emulsion in ananimal model of severe verapamil toxicity resusci-tated with atropine, calcium and normal saline.Acad Emerg Med. 2007; 14:105–11.

3. Picard J, Meek T. Lipid emulsion to treat overdoseof local anaesthetic: the gift of glob. Anaesthesia.2006; 61:107–9.

4. Gueret G, Pennec JP, Arvieux CC. Hemodynamiceffects of Intralipid after verapamil intoxication maybe due to a direct effect of fatty acids on myocardialcalcium channels [letter]. Acad Emerg Med. 2007;14:761.

5. Weinberg G, Ripper R, Feinstein DL, Hoffman W.Lipid emulsion infusion rescues dogs from bupiva-caine-induced cardiac toxicity. Reg Anesth PainMed. 2003; 28:198–202.

6. Rosenblatt MA, Abel M, Fischer GW, Itzkovich CJ,Eisenkraft JB. Successful use of a 20% lipid emul-sion to resuscitate a patient after a presumedrelated-related cardiac arrest. Anesthesiology. 2006;105:217–8.

7. Foxall G, McCahon R, Lamb J, Hardman JG,Bedforth NM. Levobupivacaine-induced seizure andcardiovascular collapse treated with Intralipid.Anaesthesia. 2007; 62:516–8.

8. Spence AG. Lipid reversal of central nervous symp-toms of bupivacaine toxicity. Anesthesiology. 2007;107:516–7.

9. Litz RJ, Popp M, Stehr SN, Koch T. Successfulresuscitation of a patient with ropivacaine-inducedasystole after axillary plexus block using lipid infu-sion. Anaesthesia. 2006; 61:800–1.

10. Harvey M, Cage G. Intralipid outperforms sodiumbicarbonate in a rabbit model of clomipramine tox-icity. Ann Emerg Med. 2007; 49:178–85.

11. Rixen D, Raum M, Holzgraefe B, Sauerland S. A pighemorrhagic shock model: oxygen debt and meta-bolic acidemia as indicators of severity. Shock.2001; 16:239–44.

12. Baron BJ, Sinert RH, Sinha AK, Buckley MC.Effects of traditional versus delayed resuscitationon serum lactate and base deficit. Resuscitation.1999; 43:39–46.

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14. Corman SL, Skledar SJ. Use of lipid emulsion toreverse local anesthetic-induced toxicity. AnnPaharmacother. 2007; 41:1873–4.

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ERRATUM

The following table in the October 2008 issue, Asaro PV, Lewis LM. Effects of a Triage Process Conversion onthe Triage of High-Risk Presentations. Acad Emerg Med. 2008; 15: DOI: 10.1111/j.1553-2712.2008.00236.x waspublished incorrectly. We apologize to the authors for this error.

The correct Table 2:

Table 2Test Characteristics for Specific Presentations and Outcomes*

Presentation:outcome CTAS vs. ESI TP TN FP FN Sensitivity (95% CI) Specificity (95% CI)

Abdominal pain:admit,transfer, or ED death�

CTAS 1742 3435 1536 494 77.9% (76.1, 79.6) 69.1% (67.8, 70.4)ESI 775 4890 536 1356 36.4% (34.3, 38.5) 90.1% (89.3, 90.9)

Abdominal pain:ICU ⁄OR admit or ED death

CTAS 121 3893 3157 29 80.7% (73.2, 86.5) 55.2% (54.0, 56.4)ESI 96 6143 1208 93 50.8% (43.5, 58.1) 83.6% (82.7, 84.4)

Chest pain age 55 years:ED diagnosis MI

CTAS 75 69 2147 0 100.0% (93.9, 100.0) 3.1% (2.4, 3.9)ESI 95 1420 2420 19 83.3% (74.9, 89.4) 37.0% (35.5, 38.5)

Chest pain ⁄ SOB� age 55 years:ED diagnosis MI

CTAS 96 212 4105 1 99.0% (93.6, 99.9) 4.9% (4.3, 5.6)ESI 133 3133 4731 33 80.1% (73.1, 85.7) 39.8% (38.8, 40.9)

*AMA ⁄ LWBS excluded from analysis.�Versus patients who were discharged from the ED.�Patients presenting with either chest pain or SOB.AMA = against medical advice; CI = confidence interval; CTAS = Canadian Triage and Acuity Scale; ED = emergency department;ESI = emergency severity index; ICU = intensive care unit; FN = false negative; FP = false positive; LWBS = left without beingseen; MI = myocardial infarction; OR = operating room; SOB = shortness of breath; TP = true positive.

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