Methocarbamol CRI for Symptomatic Treatment of ...

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called pyrethrins. Pyrethrins are naturally occurring compounds derived from a combination of insecticidal esters (pyrethrins, cinerins, and jasmolins) that are ...
CASE REPORTS

Methocarbamol CRI for Symptomatic Treatment of Pyrethroid Intoxication: A Report of Three Cases William E. Draper, DVM*, Luiz Bolfer, DVM, Emily Cottam, DVM, Maureen McMichael, DVM, Thomas Schubert, DVM

ABSTRACT Pyrethroids are popular for use in companion animals due to their relatively low mammalian toxicity and efficacy against arthropods. Nonetheless, pyrethroid intoxication has been reported in cats and dogs, and cats appear to be more susceptible due to difficulty in biotransformation and excretion of pyrethroids. Pyrethroid intoxications are generally due to either the improper use or accidental ingestion of approved products. Methocarbamol, given as intermittent injections, is a common first-line treatment choice for the tremors associated with pyrethroid intoxication. Two cats and one dog were treated with a methocarbamol continuous rate infusion (CRI) for pyrethroid intoxication. Clinical signs of toxicity resolved within a few hr in all three cases, with no adverse drug effects. A methocarbamol CRI can be considered in animals presenting with pyrethroid intoxication. (J Am Anim Hosp Assoc 2013; 49:---–---. DOI 10.5326/JAAHA-MS-5835)

Introduction

delayed for up to 72 hr postexposure.3,7,9 Symptomatic treatment

Pyrethrum is a combination of six natural insecticidal esters

regimens are based on control of the muscle tremors and/or

called pyrethrins. Pyrethrins are naturally occurring compounds

seizures, supportive care, and decontamination.5,10 Traditionally,

derived from a combination of insecticidal esters (pyrethrins,

it is recommended to control the muscle tremors with IV boluses

cinerins, and jasmolins) that are isolated from the flowers of

of methocarbamol, a centrally acting muscle relaxant, and to treat

Chrysanthemum cinerariaefolium and related species.

1,2

Pyre-

seizures with IV diazepam and/or barbiturates.

thrins are poisons that act on the nervous system. Products

In this report, three cases of pyrethroid toxicity successfully

containing 45–65% permethrin intended for use in dogs only

treated with methocarbamol using a continuous rate infusion

are particularly concerning. Pets may be adversely affected after

(CRI) technique are described. To the authors’ knowledge, there

either oral ingestion or by topical application of such concen-

have not been any studies previously published regarding the use

trated products.1,3,4

of a methocarbamol CRI in animals presenting with pyrethroid

The clinical signs most commonly reported with pyrethroid

intoxication.

toxicity in the veterinary literature include hypersalivation, muscle tremors/fasciculations, hyperthermia, hyperesthesia, ataxia, hy-

Case Report

perexcitability, mydriasis, and seizures.3,5–8 The onset of clinical

The two cats described in the following section were treated at

signs is usually within a few hr of exposure, with some being

the College of Veterinary Medicine, University of Illinois between

From the Department of Small Animal Clinical Sciences, College of Veterinary Medicine, University of Florida, Gainesville, FL (W.D., T.S.); and Department of Veterinary Clinical Medicine, College of Veterinary Medicine, University of Illinois at Urbana-Champaign, Urbana, IL (L.B., E.C., M.M).

CRI continuous rate infusion; ICU intensive care unit; PO per os *W. Draper’s present affiliation is VCA Animal Specialty Center of South Carolina, Columbia, SC.

Correspondence: [email protected] (W.D.)

ª 2013 by American Animal Hospital Association

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February 2009 and March 2009. The dog described below presented

information, the cat was then bathed with soap and given an IV

in June 2010 to the University of Florida’s College of Veterinary

bolus of methocarbamolf at a dose of 89.3 mg/kg. The tremors

Medicine. Before transfer to the authors’ institution and/or clinical

were reduced shortly after that treatment. The cat was then

service all three animals were treated with diazepam, and two of them

placed on IV lactated Ringer’s solutiong (2.7 mL/kg/hr) and

were treated with phenobarbital. Both of those treatments achieved

a methocarbamol CRI (8.8 mg/kg/hr). After a few hr, the muscle

only minimal control of muscle tremors. All three patients responded

tremors had ceased. After 8 hr, the methocarbamol CRI was de-

well to methocarbamol IV boluses, and a complete resolution of

creased to 4.7 mg/kg/hr for an additional 4 hr, and minimal

muscle tremors was achieved after starting a methocarbamol CRI.

tremors were noted. The cat was discharged on the same day with minimal tremors and was prescribed methocarbamol (45 mg/kg

Case 1

per os [PO] q 8 hr for 2 days). No muscle tremors were present at

A 3 yr old castrated male domestic shorthair weighing 5.6 kg

a follow-up appointment 3 days after discharge.

presented to the University of Illinois Veterinary Teaching Hospital in lateral recumbency and with severe, generalized,

Case 2

muscle tremors after being found in a ditch by the owners’

A 2 yr old spayed female domestic longhair weighing 4.6 kg

neighbors in the morning. The neighbors were not able to

presented to the University of Illinois’ Veterinary Teaching Hos-

contact the owners at the time of presentation to collect more

pital with generalized tremors that started approximately 12 hr

information about the cat’s history. On physical examination,

after the owner applied one tube of flea medication labeled for

a mild tachypnea was noted. Due to the severity of the muscle

dogs containing imidacloprid (8.8%), permethrin (44.0%), and

tremors, a full neurologic examination and evaluation for ap-

pyripoxyfen (0.44%)e. The cat had been bathed and treated with

propriate mentation were not possible. The remaining vital

an unknown dose of diazepam administered rectally by the re-

parameters were within normal limits (Table 1). Given the

ferring veterinarian. Physical exam findings at the time of referral

clinical presentation and inability to obtain additional historic

included a mild tachypnea (Table 1). Blood was submitted for

information, seizures and possible head trauma were initially

packed cell volume and total solids, and a hand-held glucometer

suspected. An IV catheter was placed, and the cat was treated

revealed hypoglycemia (Table 1). Diazepam (1 mg/kg) was ad-

a

b

with IV diazepam (1 mg/kg) followed by phenobarbital (6 mg/kg

ministered rectally at the time of presentation. An IV catheter was

IV), which did not reduce the clinical signs. The cat was ad-

placed, and the cat was started on 2.5% dextroseh in lactated

ministered 25% mannitolc (10 mL IV slowly over 20 min) and

Ringer solution at a rate of 3.2 mL/kg/hr. Methocarbamol was

was maintained on flow-by oxygen at 2 L/min via a face mask.

administered (43.5 mg/kg) as an IV bolus, followed by a CRI

A packed cell volume, total plasma protein, and blood gas

(11.6 mg/kg/hr). During the first day of hospitalization, the cat

analysisd was performed, and no major abnormalities were

had muscle tremors only when aroused. No muscle tremors

identified (Table 1). The owners were eventually contacted, and

were observed on the second day of hospitalization, so the

they stated that the cat was healthy and normal before they left

methocarbamol CRI was discontinued over 4 hr, and the cat

for work that morning. Because of a flea infestation, the owners

was switched to oral methocarbamol (54 mg/kg PO q 12 hr for

had applied their dog’s flea prevention, which contained imid-

3 days following discharge). The owner reported no muscle

e

tremors after discharge during follow-up contact several days after

acloprid (8.8%), permethrin (44.0%), and pyripoxyfen

(0.44%), on the cat early that morning. Based on that

the incident.

TABLE 1 Summary of Vital Parameters and Blood Work in the Three Described Cases Body temperature (8C)

Heart rate (beats/min)

Respiratory rate (breaths/min)

PCV* (41–55%)

TS (6.0–7.4 g/dL)

Na1 (144–151 mmol/L)

K1 (3.7–4.91 mmol/L)

Cl2 (110–117 mmol/L)

iCa11 (1.1–1.5 mmol/L)

1

38.4

186

44

30

6.5

154.4

3.15

125.6

2 3

38.5 37.2

200 118

52 28

39 42

7.7 6.5

N/A 151

N/A 3.65

N/A 115

Case

* Reference ranges and units are provided in parentheses. BUN, blood urea nitrogen; Cl, chloride; iCa; ionized Ca; K, potassium; N/A, not available; PCV, packed cell volume; TS, total solids.

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49:3 May/Jun 2013

BUN (9.1–24 mg/dl.5)

Glucose (77–192 mg/dL)

1.12

36

N/A

N/A 1.20

N/A 24

62 135

Methocarbamol CRI for Pyrethroid Intoxication

Case 3

function. Methocarbamol has a greater effect in the spinal cord

A 5 yr old castrated male miniature schnauzer weighing 8.2 kg

compared with the brain. This is displayed in its ability to protect

presented for tremors and generalized ataxia that started ap-

against the convulsant effects of strychnine (a spinal cord stim-

proximately 4 hr after the owner witnessed him licking a flea and

ulant), but not pentylenetetrazol (a stimulant that produces ex-

tick preventative containing cyphenothrin (40%) and pyriproxyfen

citation in the central nervous system rostral to the foramen

(2%) off of another animal residing in the household. The physical

magnum).11 Methocarbamol, given as intermittent injections, is

examination showed severe whole-body tremors and generalized

often a first-line treatment for the control of increased muscular

ataxia. Vital parameters were unremarkable (Table 1). A venous

activity associated with pyrethroid intoxication.1,5,10 To the authors’

i

j

blood sample was submitted for blood gas analysis , which revealed

knowledge, methocarbamol has not been used as a CRI in humans,

no abnormalities (Table 1). The dog was bathed to remove any

dogs, or cats; therefore, specific information regarding pharma-

possible dermal contamination and was monitored throughout

codynamics and pharmacokinetics of a CRI are lacking at this

the day. The muscle tremors increased, and diazepam (0.3 mg/kg)

point. At clinically relevant doses, methocarbamol reportedly

and methocarbamol (61 mg/kg) were administered PO 10 hr after

prolongs the refractory period of skeletal muscle by a direct action

admission. No resolution of the tremors was noted. An IV cath-

on the fibers.12 That same study showed that diazepam did not

eter was placed, and 0.9% NaClk was started 12 hr after admission

have that direct effect on the muscles.12 That additional mecha-

at a rate of 3.7 mL/kg/hr. Diazepam (0.5 mg/kg IV), midazolaml

nism could also be helpful in controlling the spasms related to

(0.2 mg/kg IV), and methocarbamol (50 mg/kg IV) were given as

pyrethroid intoxication.

boluses q 4 hr starting 12 hr after admission. Resolution of the

The dose of methocarbamol used by the authors was based on

tremors was noted shortly after the boluses, but the resolution was

the published maximum safe dose of 330 mg/kg/day. The initial

described as short-lived by the attending technicians in the in-

bolus of methocarbamol administered to the patient was sub-

tensive care unit (ICU). Three phenobarbital boluses (2 mg/kg

tracted from the total daily dose, and the remainder was ad-

IV) were administered overnight as well. The tremors were still

ministered as a CRI. The CRI can be administered either as the

quite severe 22 hr after admission. At that time, methocarbamol

drug alone on a syringe pump (as described in case 3) or as the drug

was administered as a 12.2 mg/kg bolus. Immediately after that

added to a fluid bag (e.g., methocarbamol added to 240 mL of 0.9%

bolus, a 12.2 mg/kg/hr methocarbamol CRI was maintained for

NaCl) and given as a CRI (10 mL/hr to start, then tapered as

4 hr. After 4 hr the rate was reduced to 9.1 mg/kg/hr for 10 hr,

necessary) as described in cases 1 and 2. The decision of when to

3mg/kg/hr for 7 hr, and then stopped. Oral methocarbamol

taper, and by how much, is dependent on the clinician and patient.

(61 mg/kg q 8 hr) was started at the same time as the 3 mg/kg/hr

The decision to use a CRI instead of multiple boluses is made for

CRI. The muscle tremors were controlled immediately after the

a number of reasons, including reduced stress on the patient

methocarbamol bolus, and no muscle tremors were observed after

(because the tremors rarely return), reduced need for the ICU staff

starting the methocarbamol CRI. The dog was monitored in the

to monitor for recurrence of tremors, and the routine need for less

ICU for the rest of the day and overnight. The dog was discharged

total medication when given as a CRI.

with oral methocarbamol (61 mg/kg PO q 8 hr for 8 days). When

Methocarbamol, given intermittently, is often considered

contacted the day after discharge, the owner reported no muscle

a first-line treatment of muscle tremors due to pyrethroid in-

tremors.

toxication. Although seizures are rarely a sequela of pyrethroid intoxication (and can be difficult to differentiate from severe

Discussion

tremors), a wide variety of pharmacologic treatments have been

This case series documents the use of methocarbamol as a CRI for

reported, including intermittent boluses of diazepam and phe-

control of muscle tremors due to pyrethroid toxicosis in two cats

nobarbital. Those drugs are sometimes followed by a CRI of either

and one dog. The prognosis for recovery from intoxication due to

a benzodiazepine (i.e., diazepam, midazolam) or propofol. Given

pyrethroids is good, presuming therapy is instituted early in the

a lack of historical information at the time of presentation for case

course of the disease. The majority of animals that receive prompt

1, the authors suspected seizures and possible head trauma. After

and aggressive treatment recover within 48–72 hr with few per-

collecting additional information, treatment with methocarbamol

manent sequelae.

1,2,5,9

was initiated, which controlled the muscle tremors when ad-

Methocarbamol is a propanediol, and this class of drug has its

ministered as an IV bolus followed by a CRI. In retrospect, all three

therapeutic value in abolishing abnormal muscle tone and in-

of the cases should have been treated with a methocarbamol bolus

voluntary movement without impairing normal neuromuscular

followed by a CRI immediately after presentation. It is likely that

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this would have controlled any tremors due to the pyrethroid intoxication, obviating the need for other medications with more

d e f

side effects.6

g

General supportive care for pyrethroid intoxication was

h

provided for all three cases described in this report, including

i

bathing the animals in a dilute solution of liquid dishwashing

j

detergent to help remove residual drug from the skin and coat,

k

maintenance of normothermia, IV fluid therapy to support cir-

l

Blood gas analysis; Nova Biomedical, Waltham, MA K9 Advantix; Bayer HealthCare, KA Methocarmabol; Baxter Healthcare Corp., Deerfield, IL Lactated Ringer’s solution; Hospira Inc., Lake Forest, IL Dextrose; Hospira Inc., Lake Forest, IL Sentry Pro XFC; Sergeant Pet Care Products Inc., Omaha, NE Blood gas analysis; Radiometer Medical ApS, Bronshoj, Denmark 0.9% NaCl; Abbott Laboratories, North Chicago, IL Midazolam; Hospira Inc., Lake Forest, IL

culation, and monitoring in the ICU. In this small case series, there did not appear to be any side effects associated with using a methocarbamol CRI, and all three patients had resolution of clinical signs. Because all three patients were treated with diazepam and/or phenobarbital, it is not entirely clear that the resolution was due to methocarbamol alone. When giving IV boluses of methocarbamol, the muscle tremors should become less intense but the action appears to be short lived. To avoid using multiple drugs that can cause side effects and promote little muscle relaxation effect (as was performed in the three cases described herein), a CRI of methocarbamol should be started immediately after the IV bolus. As described above, the methocarbamol CRIs were not initiated without an initial IV bolus.

Conclusion The use of methocarbamol as a CRI for pyrethroid intoxication appeared beneficial in this report; however, further studies regarding the pharmacology of methocarbamol (in general and as a CRI) and to examine the efficacy of methocarbamol for tremorogenic diseases are necessary. FOOTNOTES a Diazepam; Hospira Inc., Lake Forest, IL b Phenobarbitol; Baxter Healthcare, Corp., Deerfield, IL c Mannitol; Hospira Inc., Lake Forest, IL

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