ORIGINAL RESEARCH CONTRIBUTION

Intralipid Fat Emulsion Decreases RespiratoryFailure in a Rat Model of Parathion ExposureCourtney Dunn, Steven B. Bird, MD, and Romolo Gaspari, MD, PhD

AbstractBackground: Therapies exist for acute organophosphate (OP) exposure but mortality rates remain high(10% to 20%). Currently, treatment focuses on reversing the resultant cholinergic excess effects throughthe use of atropine. Intralipid fat emulsion (IFE) has been used to treat lipophilic drug ingestions andtheoretically would be beneficial for some OP agents.

Objectives: The hypothesis was that IFE would decrease the acute respiratory depressant effects follow-ing lethal OP exposure using a lipophilic OP agent (parathion).

Methods: The authors used a previously validated animal model of OP poisoning with detailed physio-logic respiratory recordings. The model consisted of Wistar rats anesthetized but spontaneously breath-ing 100% oxygen. Airflow, respiratory rate, tidal volume, mean arterial pressure, and pulse rate weredigitally recorded for 120 minutes following OP exposure or until respiratory failure. Three study groupsincluded parathion alone (n = 6), parathion and IFE 5 minutes after poisoning (n = 6), and parathion andIFE 20 minutes after poisoning (n = 6). In all groups, parathion was given as a single oral dose of54 mg ⁄ kg (four times the rat oral 50% population lethal dose [LD50]). Three boluses of IFE(15 mg ⁄ kg ⁄ min) were given over 3 minutes, 20 minutes apart, starting either 5 or 20 minutes after poi-soning. Timing of IFE was based on parathion kinetics. In one study group IFE was initiated 5 minutesafter poisoning to coincide with initial absorption of parathion. In another study group IFE was given at20 minutes to coincide with peak intravenous (IV) parathion concentration. Primary outcome waspercentage of animals with apnea. Secondary outcome was time to apnea.

Results: Animals exposed to parathion alone demonstrated a steady decline in respiratory rate and tidalvolume postexposure, with apnea occurring a mean of 51.6 minutes after poisoning (95% confidenceinterval [CI] = 35.8 to 53.2 minutes). Animals treated with IFE 5 minutes postexposure demonstrated nodifference in mean time to apnea (44.5 minutes vs. 51.6 minutes, p = 0.29) or number of animals withrespiratory arrest (100% vs. 100%, p = 1.00). Animals treated with IFE 20 minutes postexposure demon-strated a significantly prolonged mean time to apnea (95.3 minutes vs. 51.6 minutes, p = 0.002), but therewas no difference in number of animals with respiratory arrest (100% vs. 66.7%, p = 0.45).

Conclusions: All animals exposed to 4 · LD50 of oral parathion demonstrate apnea and respiratoryarrest. IFE given immediately after oral parathion does not prolong time to apnea. IFE given 20 minutesafter oral exposure to parathion decreases the acute effects of the OP and prolongs the time to apnea.

ACADEMIC EMERGENCY MEDICINE 2012; 19:504–509 ª 2012 by the Society for Academic EmergencyMedicine

O rganophosphate (OP) pesticide exposure isresponsible for more than three million poison-ings worldwide each year and results in an esti-

mated 250,000 deaths annually.1,2 Mortality from OPexposure is multifactorial, but both central apnea andpulmonary failure occur following lethal exposure to OPagents.3 OP compounds are used globally in agriculture,and the intentional ingestion of these chemicals is a sig-nificant public concern, particularly in developing coun-tries in and around Asia.4 Related compounds also posea risk from terrorist attacks, such as the 1995 sarin gasattack on the Tokyo city subway.5 Although treatmentsexist for OP poisoning, the mortality rate remains unac-ceptably high, with rates of up to 40% in even the most

ISSN 1069-6563 ª 2012 by the Society for Academic Emergency Medicine504 PII ISSN 1069-6563583 doi: 10.1111/j.1553-2712.2012.01337.x

From the Department of Emergency Medicine, University ofMassachusetts School of Medicine, Worcester, MA.Received September 30, 2011; revision received October 28,2011; accepted October 29, 2011.Presented at the Society for Academic Emergency Medicineannual meeting, Boston, MA, June 2011.This study was supported in part by the National Institutes ofHealth (grant 1K08NSO48857).The authors have no relevant financial information or potentialconflicts of interest to disclose.Supervising Editor: Mark B. Mycyk, MD.Address for correspondence and reprints: Courtney Dunn;e-mail: courtney.dunn@umassmed.edu.

sophisticated intensive care hospital.6 The effects of OPexposure disproportionally affect developing worldcountries, where availability of OP agents is high andmedical care may be less available.

Despite advances in other areas of medicine, thetreatment of acute OP poisoning has not changed sub-stantially in over 50 years. OPs function by inhibitingacetylcholinesterase. Currently, treatment focuses onreversing the resultant cholinergic excess effectsthrough the use of atropine. Adjunctive treatmentsinclude reversing cholinesterase inhibition through theuse of oximes and suppressing OP-induced neuroto-xicity via benzodiazepines. Medical therapy alone iscommonly insufficient for severe OP poisoning, aspatients often require mechanical ventilation followingprimary resuscitation.7,8 One promising alternative totreating the postexposure effects is to reduce the effectsof the OP by increasing the elimination or degradationof the pesticide. Such enzymatic degradation of OPshas been successful in animal models,9,10 but thisresearch is still in the preclinical stage. Another possi-ble alternative is the use of an agent such as intralipidfat emulsion (IFE) to sequester the OP intravenouslyafter ingestion.

Although the specific mechanism of IFE action isunknown, it has been suggested that IFE acts as a‘‘lipid sink,’’ absorbing lipophilic drugs and separatingthem from the primary site of toxicity.11,12 IFE has con-ventionally been used to administer calories in the formof fatty acids to patients requiring parenteral nutritionor as a vehicle for the delivery of highly lipid solubledrugs such as propofol, paclitaxel, etomidate, and diaz-epam.13,14 More recently, it has been found to be bene-ficial in treating severe overdoses of some lipophilicdrugs such as local anesthetics and calcium channelblockers.15 As many OP agents are lipophilic, IFEpotentially represents a novel therapeutic agent for OPingestions. We hypothesized that IFE would decreasethe acute respiratory depressant effects following lethalOP exposure using a lipophilic OP agent (parathion).

METHODS

Study DesignThis was a laboratory study using a murine model ofOP poisoning. The study protocol was approved by theInstitutional Animal Care and Use Committee of theUniversity of Massachusetts Medical School.

Animal Handling and PreparationMale Wistar rats obtained from Charles River Labora-tories (Wilmington, MA) were pair housed and main-tained on a 12-hour light and dark cycle. Food andwater was available ad libitum prior to sedation at thestart of the study. All animals were housed and caredfor in accordance with the guidelines of the NationalInstitutes of Health. We used a previously validated ani-mal model of OP poisoning with detailed physiologicrespiratory recordings, which are described in thefollowing sections.

Anesthesia. All animals were anesthetized, spontane-ously breathing 100% oxygen via a 3 ⁄ 32-inch Kynar

barbed y-fitting (Small Parts, Inc., Miami Lakes, FL).The gas mixture was delivered through one arm (inspi-ratory), while the second (exhalatory) was connected toa low-pressure scavenger system (Surgivet, Waukesha,WI). An end-tidal CO2 detector (Columbus Instruments,Columbus, OH) and pneumotach (HSE, March-Hugstetten,Germany) were connected in series with the trachealtube. The dead space of the entire system totaled0.33 cm3 or approximately 10% of the animals’ tidalvolume.

Animals were anesthetized using a titrated dose ofisoflurane (Webster Veterinary, Sterling, MA) between1.5 and 2.5%. Anesthetic efficacy was determined bythe lack of withdrawal from painful stimulus on the footor tail. Anesthesia was titrated prior to initiating theexperimental protocol to a level sufficient to sustain arespiratory rate between 45 and 60 breaths ⁄ min. Nochanges in anesthesia occurred from 10 minutesprior to the OP exposure to termination of the studyprotocol.

Study ProtocolSurgical Setup. A midcervical tracheostomy was per-formed using polyethylene tubing (0.24 mm). Polyethyl-ene tubing (PE50) was placed under direct visualizationinto the femoral artery and connected to a pressuretransducer. Polyethylene tubing (PE50) was placedunder direct visualization into the femoral vein andconnected to a stopcock. A rigid gavage tube (0.05-mminner diameter) was temporarily inserted into thestomach through the mouth to administer the para-thion. The gavage tube was removed immediatelyfollowing administration of the parathion.

Respiratory and Hemodynamic Recordings. End-tidal pressure of CO2 (PCO2), airflow, and mean arterialpressure were recorded continuously during the experi-ment. Respiratory rate was calculated from the airflowsignal using peak of inspiration as the mark of an indi-vidual breath. Volume of expired gas was calculatedthrough integration of the airflow tracing. Minute venti-lation was calculated by multiplying the respiratory rateand volume of expiration. Pulse rate was calculatedfrom the arterial tracing. A noninvasive pulse oximeter(MouseOx, Starr Life Sciences Corp., Oakmont, PA)attached to the right back paw measured arterialoxygen saturation.

Data Acquisition. Signals were digitally recorded anddisplayed in real time using a data acquisition system(PowerLab, ADInstruments, Inc., Colorado Springs,CO) and a computer (Dell, Round Rock, TX). Airflowrecordings were filtered and amplified using the Cyber-Amp (AutoMate Scientific, Berkeley, CA), and all datawere sampled at 400 Hz. A separate amplifier (ADIns-truments) filtered and amplified the arterial pressuresignal. Data were recorded for later analysis.

Drug Exposure. Animals were divided into threestudy groups: parathion (Sigma-Aldrich, St. Louis, MO)alone (Group 1, n = 6), parathion followed by IFE5 minutes postexposure (Group 2, n = 6), and parathionfollowed by IFE 20 minutes postexposure (Group 3,

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n = 6). Parathion was given as a single oral dose of54 mg ⁄ kg (approximately 4 · rat oral 50% populationlethal dose [LD50]), over 20 seconds. Parathion was sus-pended in peanut oil to a concentration of 10 mg ⁄ mL.Each dose of IFE consisted of 20% IFE (Fresenius Kabi,Uppsala, Sweden) given intravenously at a rate of15 mL ⁄ kg via syringe pump (CMA 402, CMA Microdial-ysis, North Chelmsford, MA) over an average of 3 min-utes. The dose of IFE is based on previous experimentsusing IFE in rats.14,16 Animals in Group 2 receivedthree doses of IFE separated by 20 minutes, starting5 minutes postexposure (i.e., at 5, 25, and 45 minutespostexposure). Animals in Group 3 received three dosesof IFE separated by 20 minutes, starting 20 minutespostexposure (i.e., at 20, 40, and 60 minutes postexpo-sure). The timing of the administration of the IFE waschosen to coincide with either the initial effects of para-thion following oral exposure (5 minutes)17 or the peakconcentrations of parathion following oral exposure(20 minutes).18 According to Yamamoto et al.,17 the ini-tial measurable levels of parathion following oral expo-sure to parathion occur 6 to 8 minutes after ingestion.According to Miyamoto et al.,18 the peak effect follow-ing oral parathion occurs 30 minutes postexposure. Wechose to start the IFE infusion before these times toensure serum levels of IFE at the stated initial and peaklevels. The peak concentration of ethyl-parathion (thecompound used in this study) following oral exposureis unknown, so the peak concentration of methyl-parathion was used. The primary endpoint was thepercentage of animals with apnea.

Data AnalysisA review of our data using the Shapiro-Wilk test fornormality demonstrated that our data were nonpara-metric. Comparison between groups was performedusing a Mann-Whitney test or a Kruskal-Wallis testwhere appropriate. In comparisons that involved multi-ple groups, the Kruskal-Wallis test was followed by aDunn’s multiple comparison test to compare each indi-vidual study group. Respiratory variables were analyzedwith analysis of variance (ANOVA) techniques.

Assuming 100% respiratory failure following para-thion exposure with an alpha of 0.05 and a beta of 0.2,our study was powered to detect an absolute difference

of 60% between any two groups. As there are no previ-ously published data to use for our power calculation,we used a 60% difference between groups based on theeffect of IFE in previous studies of verapamil poisoning,another lipophilic compound.16 We assume a family-wise error rate of 0.0975% and did not adjust formultiple comparisons. A further data analysis was per-formed to calculate the rate of decline of the respiratoryrate for each group of animals. Using a best-fit curve ofbreaths ⁄ min versus time, a constant for each animal’srate of respiratory decline was determined and definedas breaths ⁄ min.

RESULTS

Baseline respiratory and circulatory parameters weresimilar between groups at baseline (Table 1). Animalsexposed to parathion alone (Group 1) demonstratedapnea characterized by a steady decline in respiratoryrate, tidal volume, and minute ventilation postexposure.Apnea occurred a mean 44.5 minutes after parathionexposure (range = 31 to 54 minutes). No animals dem-onstrated a decrease of pulse or blood pressure belowbaseline values postexposure and prior to apnea. Ani-mals treated with IFE 5 minutes postexposure (Group2) demonstrated a similar clinical course with all ani-mals demonstrating apnea followed by circulatory col-lapse and death. Animals in Group 2 demonstrated nodifference in mean time to apnea (44.5 minutes, 95%confidence interval [CI] = 35.78 to 53.22 vs. 51.6 min-utes, 95% CI = 43.55 to 59.79; p = 0.29) or number ofanimals with respiratory arrest (100% in both groups).Animals treated with IFE 20 minutes postexposure(Group 3) demonstrated no difference in mortality com-pared to control (100% vs. 66.7%, p = 0.45). The meantime to apnea in these animals was prolonged com-pared to Group 1 (51.6 minutes, 95% CI = 43.55 to 59.79vs. 95.3 minutes, 95% CI = 71.65 to 119.02; p = 0.002).The times to apnea for all animals in Group 1 with notreatment (range = 31 to 54 minutes) and Group 2 withIFE at 5 minutes (range = 41 to 65 minutes) were lessthan for any individual animal treated with IFE at20 minutes (range = 68 to 120 minutes).

Respiratory variables demonstrated no differencebetween animals that received no therapy and animals

Table 1Baseline Parameters of Study Groups

Variable

Group 1,Parathion

Alone (n = 6)

Group 2,Parathion Then IFEat 5 Minutes (n = 6)

Group 3,Parathion Then IFE

at 20 Minutes (n = 6)

Respiratory rate 49.3 50.9 49.5Tidal volume 3.1 2.7 2.7Minute ventilation 153.3 138.9 135.4Mean arterial pressure 88.1 73.8 90.9Pulse rate 372.0 376.9 357.0Pulse oxygenation 92.0 98.5 98.6

There were no significant differences of respiratory or cardiovascular values at baseline between groups (p = NS all com-parisons). Due to technical failures, one animal in the control group did not have an arterial pressure recording and a separateanimal in an experimental group did not have a pulse oximetry recording.

506 Dunn et al. • IFE DECREASES RESPIRATORY FAILURE IN PARATHION EXPOSURE

that were treated with IFE 5 minutes postexposure(p = NS, by ANOVA), but animals treated with IFE20 minutes postexposure demonstrated a prolongedtime to respiratory failure compared to either group(p < 0.001, by ANOVA). All three groups demonstratedsimilar changes in respiratory variables until roughly30 minutes postexposure (Figures 1–3). The rate ofrespiratory decline was significantly steeper in animalswith no treatment and those treated with IFE at 5 min-utes postexposure when compared to animals treatedwith IFE 20 minutes postexposure (Table 2).

DISCUSSION

Data from this study indicate that administration of IFEat 20, 40, and 60 minutes after exposure mitigates therespiratory depressant effects of acute parathion poi-soning in a rat model. When IFE was given 5, 25, and45 minutes after oral parathion, there were no statisti-cally significant differences in any cardiopulmonarymeasures. However, none of the study groups (initialIFE at 5 or 20 minutes postexposure) demonstrated anyincrease in survival. It is possible that this is related todose, timing, or the inability of IFE to fully protectagainst OP exposure. Further studies are required.

The mechanism of action of IFE in decreasing OP-induced respiratory depression is unknown. Because ofthe lipophilic nature of the parathion (log octanol ⁄ waterpartition coefficient [log Kow] of 3.83), it is possible thatthe IFE absorbed a portion of the circulating parathion,thereby sequestering the OP and preventing its inhibi-

tion of acetylcholinesterase. This speculative mecha-nism has been described as a lipid sink and was initiallydescribed by Weinberg et al.14 The IFE may effectivelyprovide a circulating intravenous (IV) lipid compart-ment that produces a gradient for diffusion of lipophilicsubstances out of surrounding tissue. The concept of alipid sink, although unproven, provides a possibleexplanation for the increased effectiveness of IFE when

Figure 1. Decline in respiratory rate after parathion exposure.The data were averaged into 5-minute bins starting from thetime of OP introduction to the 2-hour endpoint of the study.Data are presented as mean (dot) with standard deviation (errorbars). IFE = intralipid fat emulsion; OP = organophosphate.

Table 2Rate of Respiratory Decline of Study Groups

Parameters Group 1, Control Group 2, IFE at 5 Minutes Group 3, IFE at 20 Minutes

Rate of respiratory decline, mean )2.65 )2.295 )0.795Standard deviation ±1.35 ±0.58 ±0.55p-value — 0.661 0.0179

Rate of respiratory decline was found by calculating a constant for each animal’s rate of respiratory decline in breaths ⁄ min usinga best-fit curve of breaths per minute versus time.

Figure 3. Decline in minute ventilation after parathion expo-sure. The decrease in minute ventilation is shown as percentageof baseline to normalize differences between individual animalswithin groups. The data were averaged into 5-minute bins start-ing from the time of OP introduction to the 2-hour endpoint ofthe study. Data are presented as mean (dot) with standard devi-ation (error bars). IFE = intralipid fat emulsion; OP = organo-phosphate.

Figure 2. Decline in tidal volume after parathion exposure. Thedata were averaged into 5-minute bins starting from the time ofOP introduction to the 2-hour endpoint of the study. Data arepresented as mean (dot) with standard deviation (error bars).IFE = intralipid fat emulsion; OP = organophosphate.

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given at the time of peak parathion effect. It raises aninteresting question concerning the clinical dosing ofIFE, because if true, the time of maximal efficacy of IFEwould vary depending on the specific compound, routeof poisoning, and possibly the presence of othercoingestants.

It is not clear why IFE first given 5 minutes afterparathion poisoning demonstrated no effect on therespiratory decline postexposure, but IFE initially given20 minutes after parathion poisoning demonstrated aneffect. IFE for both treatment groups was administeredevery 20 minutes, so at 30 minutes postexposure, bothgroups had received IFE. Animals receiving IFE start-ing at 5 minutes postexposure had received twice theIFE as animals with IFE starting 20 minutes postexpo-sure. There were no respiratory effects from parathiondemonstrated prior to 30 minutes, so it is possible thatIFE given at 5 minutes was given too early, whenserum levels were lower. Animals with IFE started at5 minutes received one dose when serum levels ofparathion were presumably higher, while animals withIFE started at 20 minutes received two doses. This,however, does not explain why animals with IFEstarted at 5 minutes died before they could receive asecond dose. This raises the possibility that the IFE isonly effective when given at a specific time related topeak concentration.

Alternatively, the IFE may have contributed to higherserum levels of parathion, accelerating OP-inducedrespiratory depression. It is possible that the earlyadministration of IFE provides a higher gradient of dif-fusion from the stomach to a circulating lipid compart-ment in the vasculature, resulting in increased earlytissue exposure to parathion. This theory is less likely,as we demonstrated no early respiratory depression inanimals treated with IFE at 5 minutes postexposurewhen compared to controls.

Limited previous work has been published on theeffect of IFE on OP toxicity, with only a single pub-lished abstract found on the subject. Bania et al.19

investigated the use of IFE on paraoxon (the activemetabolite of parathion) toxicity in mice. While theirresults failed to demonstrate an increase in the LD50 ofparaoxon with the use of IFE, it is possible that theextreme rapidity of paraoxon’s toxicity, as well as dif-ferences in kinetics between parathion and paraoxon,account for the differences between the currentstudy and that of Bania et al. Parathion requires P450-mediated metabolism to paraoxon in the liver before itis able to inhibit acetylcholinesterase.17 This metabolicstep provides a period of time where a medication thatmitigates tissue exposure can be administered. Becauseparaoxon requires no metabolic conversion to be physi-ologically active, there may be insufficient time toadminister IFE for it to have any beneficial effectsfollowing paraoxon exposure.

Despite several decades of research, no methodshave been proven effective in reducing the amount ofOPs absorbed after poisoning in humans.20 Becausestandard treatment with anticholinergics and oximeshas severe limitations (as demonstrated by the highmorbidity and mortality post-OP ingestion despiteaggressive therapy) alternative therapies are urgently

needed.20,21 A novel strategy such as sequestering theOP after ingestion has the potential to fundamentallychange the management of acute OP poisoning. Ourresults demonstrate a potential role for IFE post-OPexposure, but more research is needed to determinethe timing of administration and the role of IFE in otherOP agents.

LIMITATIONS

We did not quantify parathion concentrations in plasmain any group of animals. If IFE truly sequesters OPs (asis theorized for other lipophilic drugs19), then anincrease in parathion within the intravascular compart-ment would be expected. In addition, quantifying theconcentration of IV parathion during IFE administra-tion may have helped elucidate the mechanism of actionof IFE. Quantification of IV parathion could help deter-mine if early IFE increases the exposure of parathionafter oral ingestion.

The use of an anesthetized model to monitor OP-induced respiratory effects produces significant limita-tions. Isoflurane causes respiratory depression andcould have contributed to the OP-induced apnea. It isunlikely that the use of isoflurane is responsible for dif-ferences in respiratory effects between study groupsfor a number of reasons. First, each group of animalsreceived a similar level of isoflurane, so differences inrespiratory changes should not be attributed to theanesthetic. Second, in previously published animalmodels of OP poisoning with isoflurane from our labo-ratory, we demonstrated longer periods of anesthesiawithout respiratory depression. Third, isoflurane canprevent seizures, a known effect of OP ingestion. Theseeffects of isoflurane limit the generalizability of ourfindings.

It is unclear what effect IFE has on the traditionaltherapies for acute OP exposure. The current mainstayof therapy includes anticholinergic agents, oximes, andbenzodiazepines. In an effort to study the isolatedeffects of IFE, we intentionally did not include standardtherapeutic agents, so it remains unclear if IFE affectsthe efficacy of these agents. Studies of combinationtreatment with all of these agents should be consideredprior to recommending the clinical use of IFE inpatients exposed to OP agents.

The use of IFE for acute OP poisoning is also compli-cated by the fact that there are hundreds of unique OPagents with a wide range of physiochemical properties.OP pesticides are a group of physicochemically distinctcompounds. They can differ substantially in such prop-erties as potency,20 lipophilicity, need for bioactivation,response to oximes,20 and persistence in the environ-ment. Future trials with alternative OP agents shouldbe considered.

CONCLUSIONS

The use of intralipid fat emulsion postexposure partiallymitigates the respiratory depressant effects of para-thion. Further research is required before intralipid fatemulsion therapy should be considered for clinical useafter organophosphate pesticide exposure. Optimal

508 Dunn et al. • IFE DECREASES RESPIRATORY FAILURE IN PARATHION EXPOSURE

intralipid fat emulsion dosing, rate of administration,total or duration of dosing, and the pharmacokineticand pharmacodynamic effects of intralipid fat emulsionon atropine and oximes remain unknown.

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