Journal of Veterinary Emergency and Critical Care 25(5) 2015, pp 597–605 doi: 10.1111/vec.12322
A randomized, controlled clinical trial of intravenous lipid emulsion as an adjunctive treatment for permethrin toxicosis in cats Rachel E. Peacock, BVSc, MVMedSc, MVS, MANZCVS, DACVECC; Giselle Hosgood, BVSc, MS, PhD, FANZCVS, DACVS; Katrin L. Swindells, BVSc, MANZCVS, DACVECC and Lisa Smart, BVSc, DACVECC
Objective – To assess for any clinical benefit of intravenous lipid emulsion (ILE) for permethrin toxicosis in cats by comparing the progression of clinical signs of cats before and after treatment with ILE to cats treated with a saline control. To accomplish this objective, a clinical staging system for cats with permethrin toxicosis was developed and validated. Design – Prospective, multicenter, randomized, controlled clinical trial. Setting – University veterinary teaching hospital and 12 private veterinary emergency hospitals. Animals – Thirty-four client-owned cats with permethrin toxicosis. Interventions – A clinical staging system was designed based on abnormalities found on physical examination of cats with permethrin toxicosis. The clinical staging system had 6 stages, ranging from Stage A for cats with no abnormalities to Stage F for cats with grand mal seizures. The system was validated for intraviewer and interviewer variability. Cats in the clinical trial were randomized to receive 15 mL/kg of either intravenous 0.9% saline (control) or 20% ILE over 60 minutes. For each cat, a clinical stage was recorded at set time points before and after the randomized treatment was administered. The distribution of clinical stage stratified over time was compared across treatment groups. Measurements and Main Results – The clinical staging system showed excellent repeatability (P = 1.0) and reliability (P = 1.0). In the clinical trial, there was a significant difference in the distribution of clinical stages over time (P < 0.001) and from presentation stage to Stage B (P = 0.006), with ILE-treated cats (n = 20) having lower clinical stages earlier than control cats (n = 14). There was no significant difference in signalment, body weight, or supportive treatment between the groups. Conclusions – The clinical staging system was repeatable and reliable. Clinical stages of permethrin toxicosis in ILE-treated cats improved earlier compared to control cats, suggesting ILE may be a useful adjunctive therapy in the treatment of permethrin toxicosis in cats. (J Vet Emerg Crit Care 2015; 25(5): 597–605) doi: 10.1111/vec.12322 Keywords: feline, intralipid therapy, methocarbamol, toxicology
ILE intravenous lipid emulsion
From the School of Veterinary and Life Sciences, Murdoch University, 90 South Street, Murdoch, 6150, Western Australia. The authors declare no conflict of interests. Address correspondence and reprint requests to Dr. Rachel E. Peacock, 37 Blackburn Road, Mount Waverley, Victoria 3130, Australia. Email: [email protected]
Submitted April 04, 2013; Accepted March 22, 2015. C Veterinary Emergency and Critical Care Society 2015
Intravenous lipid emulsion (ILE) therapy has been shown to improve signs of toxicosis in people and animals with lipid-soluble drug toxicoses. Initial interest in the therapy was prompted after Weinberg et al demonstrated that both preemptive treatment and resuscitation with ILE resulted in amelioration of bupivacaineinduced cardiotoxicity in rats.1 ILEs have since been included in treatment guidelines for local anesthetic systemic toxicosis.2,3 An increase in the rate of resolution of clinical signs, or augmentation of cardiopulmonary resuscitation efforts, has also been reported after ILE administration in experimental models of other 597
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lipophilic drug toxicoses including beta blockers,4 antidepressants,5–7 calcium channel blockers,a,8,9 and thiopentone.10 Numerous human and animal case reports have reported apparent beneficial effects of ILE in clinical toxicosis due to beta blockers,b antidepressants,11,12 antipsychotics,13,14 calcium channel blockers,15 sodium channel blockers,c antimalarials,c baclofen,16 and insecticides.17–20 However, these case reports need to be interpreted with caution as blood drug levels were not confirmed and response to ILE treatment was based on subjective clinical assessment. The mechanisms of action of ILE in the treatment of lipophilic drug toxicoses have not been fully elucidated. One proposed mechanism of action is the formation of an intravascular lipid sink where lipid-soluble drugs are sequestered away from their sites of toxicity and are then redistributed to biologically inert sites.21–23 Ex vivo and in vitro experimental models have been successfully used to demonstrate this theory.23–26 In addition, increases in the blood concentration of lipophilic drugs after ILE administration have been reported in live animal experiments and in human and veterinary case reports, suggesting that lipid partitioning of lipophilic drugs does occur in vivo.7,18,27,28 However, confirmation of lipid partitioning does not necessarily translate into an improvement in clinical signs of toxicosis in vivo. Permethrin is a lipid-soluble insecticide common in spot-on flea treatments for dogs, and permethrinassociated toxicosis in cats exposed to these products is frequently reported.29,30 Permethrin binds to the voltage-gated sodium channels of myelinated nerves, slowing their closure and resulting in repetitive neuronal discharge.31,32 Clinical signs of permethrin toxicosis are therefore neuroexcitatory in nature and can cause substantial morbidity and mortality.29,33–36 Mortality rates have been reported to be between 2.4% and 16.9%.30,33,36 In 1 study, it was reported that 5.2% of cats with permethrin toxicosis were euthanized due to owner financial constraints.30 Diagnosis of permethrin toxicosis in cats is based on exposure history and consistent clinical signs. Studies have shown that permethrin and its metabolites can be detected in human blood and urine;37,38 however, no studies have reported blood permethrin concentrations in cats with permethrin toxicosis, or correlated such concentrations with clinical signs. In addition, the technology for such assays is not widely available. Therefore, at this time, measurement of the concentration of permethrin or its metabolites in biological samples is not routinely performed to confirm exposure or assess the severity of permethrin toxicosis in cats in the clinical setting.
There are 2 published case reports describing a total of 5 cats with permethrin toxicosis where ILE was used as an adjunctive treatment.19,39 Despite its clinical use, no prospective clinical trials have been published to support its efficacy. The aim of this study was to assess for any clinical benefit of ILE for permethrin toxicosis in cats by comparing the progression of clinical signs before and after treatment with ILE compared to a saline control. To accomplish this objective, a clinical staging system was developed and validated in order to standardize the assessment of clinical signs in cats with permethrin toxicosis. Our hypothesis was that clinical stages of permethrin toxicosis in ILE-treated cats would improve earlier compared to cats receiving a saline control.
Materials and Methods The study protocol had approval from the Murdoch University’s Animal Ethics Committee and a license for the use of animals for scientific procedures was obtained in each state where required. Clinical staging system Design A clinical staging system was designed using the dichotomous outcomes “yes” and “no” to questions based on abnormalities found on physical examination (Figure 1). The order of the observations was based on expert clinical opinion of the anticipated deterioration or improvement of common clinical signs in cats with permethrin toxicosis. The clinical staging system had 6 stages, ranging from Stage A for cats that had no abnormalities detected to Stage F for cats with grand mal seizures. Validation Thirteen cats with permethrin toxicosis were video recorded for 1–3 minutes. Each clinical stage, as defined by the staging system, was represented at least once. The series of video footage was then shown to 5 veterinarians and 5 veterinary nurses individually (Trial 1), with each cat shown in a random order to each observer, as determined by random number generation.d Each observer assigned a clinical stage to each of the cats shown in the video footage. One month later, the same observers were shown the same footage of each cat in another random order (Trial 2) and each observer assigned a clinical stage to each of the cats viewed. Statistical analysis: clinical staging The stage for each video was assessed for both intraviewer variability (repeatability), controlling for
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Intravenous lipid emulsion therapy for permethrin toxicosis
Figure 1: Clinical staging system used to assess cats with permethrin toxicoses.
video, and interviewer variability (reliability), controlling for trial. A Cochran–Mantel–Haenszel test of conditional independence was used to test for association; with failure to reject the null hypothesis of independence indicative of no intra- or interviewer variability. A P < 0.05 was used as criteria for determination of association. All analyses were performed with a commercially available statistical software package.e Clinical trial Design The clinical trial was prospective, multicenter, randomized, and controlled, involving 1 university veterinary teaching hospital and 12 private veterinary emergency hospitals across 4 states within Australia. Client-owned cats were enrolled between March 2011 and June 2012. The clinical trial was planned based on a power of 80% and an effect size of 1 (difference in means/standard deviation). That is, it was estimated that control cats would take twice as long to recover with a variance of 100%. With significance at 0.05, a total sample size of 130 was estimated for this result. Since this estimate was very C Veterinary Emergency and Critical Care Society 2015, doi: 10.1111/vec.12322
conservative, and for ethical reasons, an interim statistical analysis was planned to be performed after enrolment of 30 cats to determine if either there was a significant beneficial effect or unforeseen adverse events were occurring. A box of study materials was delivered to each veterinary hospital. Each box contained 6 treatment envelopes and a folder that contained study information for the client, client consent forms, and information for the attending veterinarians. Each of the 6 treatment envelopes contained a study method and a prerandomized treatment of either a 500 mL bag of 0.9% sodium chloride,f which served as the control treatment, or a 500 mL bag of a 20% ILEg as the intervention treatment. Prerandomization was performed by random number generation.d Veterinarians were not blinded to the treatment. Inclusion and exclusion criteria Cats were included in the study if they had direct application of a “spot on” permethrin product by their owner, had clinical signs of permethrin toxicosis at presentation with a clinical Stage C, D, E, or F, and their owner had 599
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signed a client consent form. Cats were excluded from the study if they had already received treatment for their toxicosis prior to presentation or were clinical Stage A or B at presentation as treatment may not have been indicated. Additional exclusion criteria included obesity (body condition score ࣙ7 of 9) or a previous diagnosis of diabetes mellitus, cardiac, or renal disease, in order to minimize potential risks associated with fluid therapy or ILE therapy. Treatment Initial emergency stabilization was performed using intravenous methocarbamol to effect for tremors and intravenous diazepam to effect for seizures. Recommendations for initial doses were 40 mg/kg for methocarbamol and 0.5–1 mg/kg for diazepam. Dermal decontamination was then performed, which included clipping of the patch of fur where the permethrin product had been applied followed by bathing of the cat in tepid water with a dishwashing liquid detergent. After bathing, 15 mL/kg of the randomized treatment was administered over 60 minutes, which is the equivalent of 0.25 mL/kg/min for 60 minutes. The use of additional open-label drugs or fluid therapy was permitted at the discretion of the clinician and details were recorded. Assessment and monitoring The time from application of the permethrin product to presentation was recorded. Clinical stage, heart rate, respiratory rate, and rectal temperature were recorded at presentation (t = Pre), after bathing (t = Bath), immediately after the randomized treatment was administered (t = 0 hour), then every 3 hours for 12 hours, followed by every 6 hours for the duration of the hospitalized period. The time from presentation to clinical Stage B (or A if faster improvement occurred between the set time points) was then calculated, as the authors agreed that this would be the stage at which discharge home could reasonably occur. Adverse events detected on physical examination were recorded during the infusion and at each time point from t = 0 hour. Clinicians were specifically asked to monitor for clinical signs of nausea, abdominal pain, hypersensitivity reaction, or volume overload. Outcome was recorded as death, euthanasia, discharge to primary care veterinarian, or discharge home. The length of hospitalization was recorded.
stratified at each time point. The distribution of clinical stage categories stratified over time was compared across treatment groups using the Friedman’s test for repeated categorical data. All other categorical data that described the characteristics of the treatment groups were summarized as relative frequencies across groups. Differences in the relative frequencies of these categorical variables were compared across treatment groups using a Fisher’s exact test. All categorical tests were performed using a two-sided hypothesis with significance declared at P < 0.05. Numerical data were tested for normality based on the Shapiro–Wilk test with the null hypothesis of normality rejected at P < 0.05. Non-normal numerical data were summarized as median and quartiles and normal numerical data were summarized as mean and 95% confidence intervals. Selected non-normal numerical data were compared across treatment groups using the Wilcoxon rank-sum test and normal numerical data were compared across treatment groups using a t-test adjusting for equal or unequal variances. A twosided hypothesis was tested with significance declared at P < 0.05. All analyses were performed with a commercially available statistical software package.e
Results Clinical staging Visual assessment of the scores showed almost perfect agreement (repeatability) of scores across videos regardless of viewer and almost perfect reliability across viewers. In Trial 1, there was discrepancy for 2 viewers for video 5 (Stage B), 1 viewer for video 6 (Stage C), and 1 viewer in video 10 (Stage B). In Trial 2, there was discrepancy for 2 viewers for video 5 (Stage B) and 2 viewers for video 6 (Stage B). One viewer had the same discrepancy in both trials for videos 5 and 6. There was no association of trial by video, controlling for viewer (P = 1.0), indicative of no significant intraviewer variability, and hence excellent repeatability. There was no association of viewer by video, controlling for trial (P = 1.0) indicative of no significant interviewer variability, and hence excellent reliability. Clinical trial Analysis of data was performed after enrollment of 36 cats. At this time, a significant benefit of the ILE was detected and the trial was prematurely stopped.
Statistical analysis: Clinical trial The clinical stages assigned at each time point were treated as ordinal categorical data and were summarized as relative frequencies within each treatment group, 600
Population characteristics Two of the 36 cats were excluded from data analysis as they had received treatment from their primary C Veterinary Emergency and Critical Care Society 2015, doi: 10.1111/vec.12322
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Table 1: Age, sex, breed, and weight of 34 cats with permethrin toxicosis randomized to receive 0.9% saline or intravenous lipid emulsion (ILE) treatment
Control (n = 14) ILE (n = 20) Age, median years (1st quartile, 3rd quartile)∗ Sex, frequency† Male Female Breed, frequency† DSH DMH DLH Other Weight, median kilogram (1st quartile, 3rd quartile)∗ ∗ †
3.3 (1.3, 4.5)
4.0 (1.4, 5.1)
13 0 0 1 4.2 (3.7, 4.8)
12 1 5 2 4.5 (3.5, 4.9)
P 0.324 0.487
Analysis with Wilcoxon rank-sum test. Analysis with Fisher’s exact test.
Table 2: Relative frequency (n) of clinical stages at presentation in 34 cats with permethrin toxicosis randomized to receive 0.9% saline or intravenous lipid emulsion (ILE) treatment∗
C D E F ∗
Control (n = 14)
ILE (n = 20)
0.36 (5) 0.29 (4) 0.21 (3) 0.14 (2)
0.45 (9) 0.10 (2) 0.25 (5) 0.20 (4)
Analysis with Fisher’s exact test.
veterinarian prior to enrolment. Fourteen cats received the control treatment and 20 cats received the ILE treatment. Cats were enrolled from 9 of the 13 veterinary hospitals participating in the study. There was no significant difference in age, frequency of sex, or frequency of breed or weight between the control and ILE-treated cats (Table 1). The median time from application of the permethrin product to presentation for the control and ILE-treated cats were not significantly different (P = 0.180), with a median time of 14 hours (1st quartile 7.0 hours, 3rd quartile 24.0 hours) and 13.5 hours (1st quartile 3.0 hours, 3rd quartile 18.0 hours), respectively. The relative frequency of clinical stages at presentation of the control and ILE-treated cats were not significantly different (P = 0.684, Table 2). Effect of ILE treatment on clinical stages There was a significant difference (P < 0.001) in the distribution of relative frequencies (Figure 2) of clinical stages over time between control cats and ILE-treated cats, with cats receiving a 20% ILE displaying lower clinical stages earlier. There was a significant difference (P = 0.006) between control and ILE-treated cats in the time from C Veterinary Emergency and Critical Care Society 2015, doi: 10.1111/vec.12322
Figure 2: Relative frequencies of clinical stages at each time point in cats with permethrin toxicoses randomized to receive 0.9% sodium chloride (control) or intravenous lipid emulsion (ILE) treatment. The distribution of relative frequencies between the 2 groups was significantly different (P < 0.001).
presentation to achievement of clinical Stage B (or A), with a mean time of 16.2 hours (95% CI 9.1–23.3 hours) and 5.5 hours (95% CI 1.6–9.5 hours), respectively. There was no significant difference (P = 0.087) between control and ILE-treated cats in duration of hospitalization, with a mean time of 27.5 hours (95% CI 18.8–36.2 hours) and 19.4 hours (95% CI 14.1–24.8 hours), respectively. No cats had worsening of their clinical stage while in hospital. Other treatments administered A range of drugs was administered to the study population. There was no significant difference in the dose of methocarbamol (P = 0.187), diazepam (P = 0.820), or intravenous fluid (P = 0.650) administered to control or ILE-treated cats (Table 3). Alphaxalone was administered intravenously to 1 control cat (5.0 mg/kg) and 3 ILE-treated cats (1.25, 1.85, and 12.36 mg/kg). Butorphanol was administered intravenously to 1 control cat (0.39 mg/kg) and 2 ILE-treated cats (0.20 and 601
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Table 3: Median dose of drugs administered to 34 cats with permethrin toxicosis randomized to receive 0.9% saline or intravenous lipid emulsion (ILE) treatment
Methocarbamol (mg/kg) (1st quartile, 3rd quartile)∗ Diazepam (mg/kg) (1st quartile, 3rd quartile)∗ Intravenous fluid therapy (mL/kg) (1st quartile, 3rd quartile)∗ ∗
Control (n = 14)
ILE (n = 20)
111.4 (14) (80.0, 171.9) 0.9 (7) (0.7, 2.0) 110.4 (6) (55.9, 165.9)
63.9 (20) (46.3, 131.8) 0.8 (10) (0.6, 2.6) 143.0 (10) (39.0, 320.0)
P 0.187 0.820 0.650
Analysis with Wilcoxon rank-sum test.
0.25 mg/kg). Midazolam was administered intravenously as a continuous rate infusion to 2 control cats (total doses 2.99 mg/kg over 8 hours and 5.63 mg/kg over 22 hours). Acepromazine (0.06 mg/kg), medetomidine (4.0 g/kg), phenobarbitone (2.0 mg/kg) and propofol (7.41 mg/kg) were administered intravenously to 1 cat each among the ILE-treated cats. Adverse effects No adverse events as assessed by a physical examination were recorded for any control cats. One of the ILE-treated cats had signs of pruritus of the right side of its face that began 10 hours after the end of the ILE infusion. Chlorpheniramine (0.30 mg/kg, intramuscularly) was administered and the signs resolved over the following 8 hours. Outcome All cats survived to discharge. One control and 2 ILE-treated cats were discharged to their referring veterinarians and later discharged home. One of these ILE-treated cats represented to a veterinary emergency hospital the same night for reoccurrence of permethrin toxicosis, after having been clinically normal at its referring veterinarian throughout the day. Follow-up information was available for all cats for between 5 and 19 months after treatment. No cats had presented to a veterinarian for clinical disease of any kind in that time frame. Eight cats had presented for vaccination and were reported as clinically normal at that visit.
Discussion The results of this study demonstrate that the clinical signs of permethrin toxicosis in cats treated with ILE improved earlier compared to cats receiving a saline control. By decreasing the severity of clinical signs earlier in the course of treatment, administration of an ILE reduced 602
the morbidity of cats in this study. This result supports the use of ILE as an adjunctive therapy in the treatment of this toxicosis. The clinical trial was stopped after what was intended to be an interim statistical analysis as a significant benefit was detected and the research team did not want to deprive owners the option of an efficacious treatment for their cat. A difference in hospitalization time between the control and ILE-treated cats was not detected in this study despite the demonstrated earlier improvement in clinical signs of ILE-treated cats. This highlights the variable nature of relatively short hospitalization times, since the duration is dependent on factors other than clinical status of the animal, including availability of owners to collect their cat. A significant difference may have become apparent if more cats had been enrolled. However, it was more important to the authors to determine when a cat reached a point at which it may be stable enough for discharge (Stage B) and the clinical staging system was useful in this regard. Using this analysis a significant difference was detected between control and ILE-treated cats. The clinical staging system validated for this study showed excellent repeatability and reliability. The system was simple to use for both veterinarians and nursing staff as it included easily recognizable clinical signs. A limitation of this system is the possible effect of drugs administered by the clinicians, and timing of those drugs, in relation to the assignment of clinical stages. Treatment with diazepam or methocarbamol immediately before the assessment of clinical stage in a cat that was seizuring may reduce the stage assigned. Conversely, such treatment in an ambulatory cat with tremors may cause recumbency and thus increase the stage assigned. However, as there was no difference in the drugs or drug doses used between groups and there was a large number of clinical stage assessments performed in this study, any confounding effects due to the timing of drug administration are considered minimal. ILE therapy should not be the first line treatment for permethrin toxicosis. Instead, immediate stabilization of neuroexcitatory signs is required using drugs such as methocarbamol. Mephenesin and its derivative methocarbamol have been shown in rats to reduce the clinical signs and mortality of permethrin and other pyrethroid toxicoses.40–42 Methocarbamol was the first line treatment for muscle tremors in this study as it is regarded in the authors’ experience to be the most efficacious drug for this clinical sign. Although commonly used by the authors, the efficacy of IV methocarbamol for permethrin toxicoses in cats has not been fully evaluated and it is not available in many countries. The use of IV methocarbamol in this study may be why this study reported shorter hospitalization times compared to other C Veterinary Emergency and Critical Care Society 2015, doi: 10.1111/vec.12322
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published reports.33,36 Because of the empirical clinical efficacy of methocarbamol in the treatment of permethrin toxicosis, it was considered appropriate that treatment with ILE or saline in this study be administered after methocarbamol. There was no difference in the dose of methocarbamol used in the cats of either group and hence it is unlikely to have had an effect on the results. In this study, veterinarians were at liberty to use any supportive treatment thought best for their case; however, suggestions regarding emergency stabilization and treatment options were provided. This did not appear to be a confounding factor in the statistical analysis, with the 2 groups having no significant difference between them in regard to the dose of methocarbamol, diazepam, or IV fluids administered. All other treatments were used to control neuroexcitatory signs and were unable to be evaluated due to the low numbers of cats in each group receiving them. The lipid sink theory is one of the proposed mechanisms of action for the increased rate of resolution of clinical signs of lipophilic drug toxicosis.21–23 Drugs are considered lipophilic if their octanol/water partition coefficient (log P) is >1.0. Permethrin has a log P of 6.1 at 20°C and therefore is considered highly lipophilic.42 However, the log P value alone cannot predict the likely response to ILE administration in an animal with toxicosis since other factors such as pH, temperature, and a drug’s volume of distribution influence ILE sequestration of a drug.23,25,43 The creation of a lipid sink may affect other drugs administered concurrently with ILE. In regards to this study, it is possible that higher doses of methocarbamol may have been required to control clinical signs in the ILE-treated cats. However, there was no significant difference in the dose of methocarbamol between the control and ILE-treated cats, which may be due to the comparatively low log P of methocarbamol (0.5 at 25°C).44 Similarly, higher doses of diazepam were not used in ILE-treated cats compared to control cats despite the log P value of diazepam being higher (3.0 at 25°C) than that of methocarbamol.44 An optimal dosing regime of ILE for lipophilic drug toxicosis has not been established. A commonly reported dose of a 20% ILE is a bolus of 1.5 mL/kg followed by a continuous rate infusion of 0.25 mL/kg/min for 30–60 minutes.45,46 A bolus was not used in this study; however, a bolus may be of benefit in toxicoses producing life-threatening cardiotoxicity such as with local anesthetic overdose. In such cases, ILE may overcome the toxic effects of impairment of fatty acid transport into the myocardium.47 ILEs may also improve myocardial function by increasing intramyocyte calcium concentration in drug toxicoses such as calcium channel blocker overdose.48,49 Permethrin does not have C Veterinary Emergency and Critical Care Society 2015, doi: 10.1111/vec.12322
significant cardiotoxic effects and therefore an ILE bolus for cats in this study was considered unnecessary. Also, given the short half-life of exogenous lipids,50–52 it is likely that bolus therapy would not significantly affect the size of the intravascular lipid sink created, therefore a continuous rate infusion was considered to be sufficient. Further investigation is required to determine the optimal dosing of ILE in lipophilic drug toxicoses. Adverse events associated with the administration of ILE were only assessed based on physical examination in this study, as permission for nonroutine monitoring of the cats was not sought from owners. Only one possible adverse event was reported for a cat that developed facial pruritis. The cat had also received a number of other drugs before and after the ILE was administered, therefore it is difficult to attribute this observation directly to ILE administration. Adverse effects reported in people administered ILE as a component of parenteral nutrition are rare and include anaphylaxis, fever, vomiting, tachypnea, dyspnea, acute lung injury, phlebitis, fat embolism, and hyperlipidemia.51–55 Adverse events that have been reported after ILE administration for drug toxicoses include gross hyperlipidemia, mottling of the skin in a group of pigs, and mild phlebitis.16,27 Experimental studies to date have not been specifically designed to assess for ILE-related adverse events at doses used for drug toxicoses.6,17–20,56–61 This study was not powered to investigate adverse events, nor designed to assess for all possible adverse events. A Stage IV clinical trial is necessary to specifically address the incidence of adverse events and clinicians should remain vigilant in monitoring for adverse events when administering ILE. The ILE-treated cat that returned for reevaluation of worsening tremors had been discharged to its regular veterinarian for monitoring throughout the day. It did not receive any additional medications, was assessed as clinically normal, and was subsequently discharged after 7 hours. During the period at home the cat had been grooming herself, and had been lying on a bed that she and the family dogs had used after having the permethrin applied to them. It is highly plausible that the reoccurrence of this cat’s clinical signs was due to reexposure to permethrin. Release of permethrin from a lipid sink during its metabolism cannot be excluded, but is considered less likely given the time from ILE administration to the reoccurrence of clinical signs, and the at-home conditions in the interim period. No animals died in this study, which is in contrast to the study by Malik et al where 16.9% of cats died and 5% were euthanized.30 Other studies have shown lower proportions of deaths or euthanasia;33,35,36 however, the samples sizes for these retrospective studies were much smaller than in the study by Malik et al.30 The zero mortality in this study may be a factor of a higher 603
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standard of care available from 24-hour emergency hospitals, a general improvement in the standard of care since data collection in the other studies or the effect of bias, as animals presenting to 24-hour emergency hospitals may be more likely to have committed owners that are financially able to provide for their care. This study was not blinded, which may have created bias in clinical stage assignment. Blinding may have been performed by using opaque fluid bags and giving sets or by having a person administer the treatment who was not involved in the assessment of the cat. A further limitation of the study was that blood permethrin concentration was not measured before or after ILE treatment. This information may have helped characterize the lipid sink as the mechanism of action in permethrin toxicoses; however, this was not an objective of this study. In addition, measurement of blood permethrin concentration in each cat would have confirmed exposure to permethrin. It would have been interesting to determine the relationship between clinical stages and blood permethrin concentrations and this may be an area for future research.
Conclusions The clinical staging system developed was repeatable and reliable and was a useful tool to standardize the clinical assessment of cats in this study. In the clinical trial, the clinical stages of permethrin toxicosis in ILEtreated cats improved earlier compared to control cats. Clinically, this means that the signs of permethrin toxicosis in ILE-treated cats improved earlier compared to the control cats, making ILE a useful adjunctive therapy in the treatment of this toxicosis in cats. Conducting a phase IV clinical trial, where the administration of ILE is monitored over a large cohort of cats, will be important to capture any adverse effects.
Acknowledgements This study was supported by grant number 2010/2/2 from the Feline Health Research Fund. The authors thank the veterinarians, support staff, and clients of the following participating veterinary emergency hospitals: Advanced Vet Care, Animal Accident and Emergency, Animal Referral Hospital Baulkham Hills, Animal Referral Hospital Homebush, Balcatta Veterinary Hospital, Brisbane Veterinary Emergency and Critical Care Services, Frankston Animal Emergency Centre, Hallam Animal Emergency Centre, Lort Smith Animal Hospital, Mount Waverley Animal Emergency Centre, Newcastle Animal Emergency Centre, and Veterinary Emergency and Intensive Care Unit. The authors would also like 604
to thank Drs. Richard Malik and Stephen Page for their technical advice on the study design.
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