Jvim_17_303.304_310.tp

J Vet Intern Med 2003;17:304–310 Diazepam as a Treatment for Metronidazole Toxicosis in Dogs:
A Retrospective Study of 21 Cases
Jason Evans, Donald Levesque, Kim Knowles, Randy Longshore, and Scott Plummer The currently recommended treatment for metronidazole toxicosis is drug discontinuation and supportive therapy. Reported recoverytimes are 1–2 weeks. The records of 21 dogs with metronidazole toxicosis were retrospectively analyzed to determine whetherdiazepam improved recovery. The dosage and duration of metronidazole therapy and the response and recovery times of 13 dogstreated with diazepam were compared to those of 8 dogs receiving only supportive care. Response time was defined as the timeto resolution of the debilitating clinical signs. Recovery time was the time to resolution of all residual clinical signs. The averagedosage and duration of metronidazole administration for the diazepam-treated and untreated groups were 60.3 mg/kg/d for 44.9days and 65.1 mg/kg/d for 37.25 days. The protocol for diazepam administration consisted of an initial IV bolus and then diazepamPO q8h for 3 days. The average dosage of both the IV and PO diazepam was 0.43 mg/kg. The average response time for thediazepam-treated dogs was 13.4 hours compared to 4.25 days for the untreated group. Recovery time also was markedly shorterfor the diazepam-treated dogs (38.8 hours) compared to the untreated group (11 days). Results of this study showed that dogs withmetronidazole toxicosis recover faster when treated with diazepam. Although the mechanism of metronidazole toxicosis or howdiazepam exerts its favorable effect is not known, it is likely related to modulation of the ␥-aminobutyric acid (GABA) receptorwithin the cerebellar and vestibular systems.
Key words: Benzodiazepine; Cerebellar disease; Drug toxicity; ␥-Aminobutyric acid; Vestibular syndrome.
Metronidazolea is a nitroimidazole antibacterial and an-
In humans, the centrally acting benzodiazepine diaze- tiprotozoal compound1 used routinely in the treat- pamb has long been used in the symptomatic treatment of ment of giardiasis,2 anaerobic infections,3,4 and inflamma- vertigo or disequilibrium secondary to diseases of the ves- tory bowel disease.5 It has high bioavailability for most tibular system such as benign paroxysmal vertigo (BPV)13,14 tissues, including bone and the central nervous system.
and endolymphatic hydrops (Meniere’s disease).15 Diaze- Metronidazole is metabolized by the liver and has a half- pam is believed to exert its antivertiginous effects by fa- life of 3–13 hours in the dog.1 The adverse effects of met- cilitating the effects of the inhibitory neurotransmitter ronidazole in humans, which include seizures, ataxia, pe- ␥-aminobutyric acid (GABA) within the vestibular sys- ripheral neuropathy, and hematuria, are well document- tem.16–21 Diazepam is principally used in veterinary medi- ed.1,6,7 Adverse effects of metronidazole in the dog8,9 and cine for its anticonvulsant, muscle-relaxant, sedative, an- cat10,11 have been reported and include vomiting, hepato- xiolytic, and appetite-stimulating properties.22,23 It has been toxicity, neutropenia, and neurologic signs such as seizures, suggested for use as a sedative in animals with severe dis- head tilt, falling, paresis, ataxia, vertical nystagmus, trem- equilibrium secondary to vestibular syndromes,24 but re- ors, and rigidity.8–10 Neurologic adverse effects in cats have ports suggesting its application as an antidote to a specific a greater tendency to reflect forebrain dysfunction (disori- entation and seizures) than brain stem dysfunction.10,11 At the Veterinary Neurological Center (VNC), dogs pre- Neurologic toxicity from metronidazole has been report- senting with signs of metronidazole toxicosis that were ed in dogs receiving Ͼ60 mg/kg/d for an average of 3–14 treated symptomatically with diazepam appeared to have a days,8 but reports of toxicity at lower dosages have been more rapid resolution of clinical signs than dogs in various cited.10,11 The mechanism of the toxic effects of metroni- published reports that had been treated with conservative dazole has not been identified. The currently recommended therapy alone. To evaluate potential differences in the re- therapy for treating metronidazole toxicosis is discontinu- covery time between dogs with metronidazole toxicosis ation of the drug and supportive therapy. No specific treat- treated with diazepam and a similar group that did not re- ment to counteract the toxic effects of metronidazole has ceive diazepam as part of the therapy, the following param- been reported. Reported recovery times of dogs with neu- eters were compared: dosage of metronidazole, duration of rologic manifestations of metronidazole toxicosis are 1–2 therapy, time to resolution of the debilitating clinical signs (response time), and time to final resolution of all residualclinical signs (recovery time).
Although the exact mechanism of metronidazole toxicity From the Veterinary Neurological Center, Las Vegas, NV (Evans, Levesque); and the Veterinary Neurological Center, Phoenix, AZ is not known, the neurologic adverse effects are indicative (Knowles, Longshore, Plummer). The work was performed at both of of cerebellar and central vestibular dysfunction. The neu- the above addresses. A poster abstract was presented at the 2002 roinhibitory actions of benzodiazepines on the brain have been shown to be mediated by GABA. Because GABA is Reprint requests: Jason Evans, DVM, MS, Veterinary Neurological the major inhibitory neurotransmitter of the cerebellar and Center, 4445 N Rainbow Boulevard, Las Vegas, NV 89108; e-mail: vestibular systems25–27 and because benzodiazepines such as diazepam have their major effect on this neurotransmit- Submitted July 12, 2002; Revised September 12, 2002; Accepted ter,16–21 a possible relationship between metronidazole and Copyright ᭧ 2003 by the American College of Veterinary Internal diazepam was postulated. Further speculation for metroni- dazole’s affinity for the GABA receptor site was based on the similarity of both the chemical structure and clinical Summary statistics of dogs with metronidazole toxicosis in the treated and untreated groups.a N/A, not applicable.
a Mean Ϯ standard deviation.
b The response and recovery times for the untreated group are listed in days, and the response and recovery times for the treated group are signs of toxicity of metronidazole and the benzodiazepine Statistical Analysis
antagonist flumazenil,c which also is known to attach to the All statistical comparisons between the 2 groups were made by the Student’s t-test. The level of significance was chosen as P Ͻ .05.
Correlation analysis was applied to the scatterplot (Fig 1) to measure Materials and Methods
the correlation coefficient (r) of the relationship between dosage and Criteria for Case Selection
duration of metronidazole administration and the onset of clinical signsof metronidazole toxicosis.
Medical records of 33 dogs at the VNC with a diagnosis of met- ronidazole toxicosis between 1997 and 2001 were reviewed. Twenty- one dogs were selected for this study on the basis of the availabilityof data regarding metronidazole dosage and duration of therapy before The ages of the dogs in this study ranged from 10 months the onset of clinical signs, response time, and recovery time. Thirteen to 13 years, and the weight of the dogs ranged from 4.1 to of the 21 dogs had been treated with diazepam, whereas the other 8 47.3 kg. Only 1 breed of dog (Shih Tzu) was represented dogs had not received diazepam as part of their therapy. Response more than once (twice) in this study.
time was defined as the time to resolution of debilitating clinical signs The results of routine physical examinations did not iden- and was determined by physical examination. For the purpose of thisstudy, debilitating clinical signs were those signs that resulted in the tify any other major abnormality except for the neurologic loss of vestibular function, motor function, or both to the degree that signs. Nearly all of the neurologic problems were acute, ambulation, eating, or drinking could not be performed. Debilitating and the dogs were presented to a veterinarian within 24 clinical signs typically were related to the profound disequilibrium hours of the onset of signs. Additionally, the final dose of often associated with vestibular syndromes. Recovery time was de- metronidazole had been given to all dogs within 24 hours fined as the time to resolution of residual clinical signs of metroni- of presentation to the VNC for examination. CBCs and se- dazole toxicosis, which was the point at which the dog was considered rum biochemistry were performed in 11 of 21 dogs, and normal by either clinical examination or owner evaluation. Data con- the most common abnormalities were mild-to-moderate in- cerning breed, age, history, manifestations of metronidazole toxicosis, creases in alkaline phosphatase activity and stress leuko- and previous treatments were collected but not considered in the sta- grams. Serum titers for Coccidioides immitis and Ehrlichia canis had been performed on 7 and 8 dogs, respectively, Treatment
and were negative. In addition, serum bile acid concentra-tions had been measured in 3 dogs, whereas computed tom- The treatment for 13 patients with a tentative diagnosis of metro- ographyd brain scans and cerebrospinal fluid analyses were nidazole toxicosis at the VNC included an initial bolus of diazepam performed on 2 dogs. All results were within normal limits.
administered IV and then PO q8h for 3 days. Metronidazole was dis- The most common neurological signs were vertical nys- continued in all animals, and supportive care including IV fluid ad- tagmus (17 of 21), truncal ataxia (15 of 21), inability to ministration was given to animals that were admitted to the hospital.
walk (10 of 21), upper motor neuron (UMN) paraparesis Treatment for the group of dogs that did not receive diazepam after adiagnosis of metronidazole toxicosis primarily consisted of discontin- (7 of 21), hypermetria (5 of 21), extensor rigidity of all 4 uation of the drug and supportive care. Summary information of the limbs (5 of 21), UMN tetraparesis (5 of 21), intention trem- dosages of both IV and PO diazepam administered is listed in Table 1.
ors (4 of 21), right head tilt (2 of 21), left head tilt (1 of21), right torticollis (2 of 21), and opisthotonos (2 of 21).
Diagnosis of Metronidazole Toxicosis
Of the 10 dogs that were nonambulatory, 5 were unable towalk without assistance because of cerebellovestibular dys- Blood concentrations of metronidazole were not measured, but all function, but these dogs were not tetraparetic.
dogs in this study were diagnosed with metronidazole toxicosis on thebasis of a history of having received metronidazole, clinical signs The most common reasons for administration of metro- compatible with metronidazole toxicosis, absence of other clinical dis- nidazole were for treatment of gastrointestinal signs such ease, and eventual recovery of all dogs upon discontinuation of met- as diarrhea (7 of 21) or vomiting (4 of 21), for suspected inflammatory bowel disease (5 of 21), for high liver en- A scatterplot analysis of the doses and durations of metronidazole therapy for the dogs in this investigation. Higher dosages generally require shorter duration of administration to produce clinical signs of metronidazole toxicosis (r ϭ Ϫ.56). The data from dog 13 of the treatedgroup were omitted from this chart because the dog had been on metronidazole therapy for 1,099 days, which was, individually, markedly differentfrom the other dogs in this study.
zyme activities (2 of 21), for giardiasis (2 of 21), and for diazepam was 0.2–0.625 and 0.31–0.69 mg/kg, respective- dental disease (1 of 21). Before the diagnosis of metroni- dazole toxicosis, medical treatments for the neurologic Dogs treated with diazepam had an average response signs consisted of one or more of the following: corticoste- time of 13 hours and an average recovery time of 38.7 roids (16 of 21), antibiotics (8 of 21), methocarbamole (5 hours. The response times for dogs treated with diazepam of 21), carprofenf (3 of 21), meclizineg (2 of 21), and bu- ranged from 20 minutes to 24 hours, and the recovery times ranged from 24 to 72 hours. Dogs that were not treated Table 1 lists the summary statistics of dosages and du- with diazepam had an average response time of 4.25 days ration of metronidazole administration, dosages of IV and and an average recovery time of 11.6 days. Response times PO diazepam, if applicable, and response and recovery for the dogs in the untreated group ranged from 2 to 10 times for dogs in the untreated and treated groups.
days, and recovery times ranged from 5 to 21 days. Both The average daily dosage of metronidazole for dogs that the response and recovery times for the animals treated with received diazepam was 60.3 mg/kg/d; for dogs that were diazepam were significantly shorter than those for the un- not treated with diazepam, the average daily dosage of met- ronidazole was 65.1 mg/kg/d. The range of the individualdosages of metronidazole for dogs that were given diaze- Discussion
pam was 33–83 mg/kg/d. The range of the metronidazoledosages for dogs in the untreated group was 45–110 mg/ The neurologic adverse effects of metronidazole are well kg/d. The average daily dosage of metronidazole was not documented in humans1,7 and companion animals.8–11 There significantly different between the 2 groups (P Ͼ .05).
is currently no recommended treatment other than with- The average duration of metronidazole administration for drawing the drug and providing supportive care. Diazepam, dogs treated with diazepam was 127 days, with a range of a centrally acting benzodiazepine, is used in human medi- 7–1,099 days. The average duration of metronidazole ad- cine for symptomatic treatment of signs of vestibular sys- ministration was 37 days for animals in the untreated group, tem dysfunction,13–15,28,29 but reports have not indicated any with a range of 10–120 days. If the data from dog 13 of curative effect for an underlying disease or toxicity. In one the diazepam-treated group that had been on metronidazole study, guinea pigs undergoing unilateral labyrinthectomy therapy for 1,099 days are disregarded, the average duration and treated with diazepam had milder signs than the un- of metronidazole use for the diazepam-treated group be- treated group, but there was no marked difference between comes 44 days. The resulting calculation is closer to the the groups in the time to complete vestibular compensa- 37-day average of the untreated group; however, including tion.28 Similar findings regarding vestibular compensation the data from this dog does not alter the statistical analysis are reported in humans with BPV treated with diazepam.14,29 in comparing the 2 groups. The duration of metronidazole Diazepam has been recommended for alleviating signs of administration was not significantly different between the 2 vestibular dysfunction in humans and animals, but indica- tions for the use of diazepam other than for palliative ther- The average single, initial IV dosage of diazepam was 0.43 mg/kg, and the average subsequent PO dosage was The results of this investigation demonstrate that diaze- 0.43 mg/kg. The range for IV and PO administration of pam dramatically improves recovery times for dogs with metronidazole toxicosis. Recovery times for dogs in thisstudy that did not receive diazepam were consistent withprevious reports. Dogs 1 and 3 in the untreated group hadprolonged recovery times, which greatly increased the av-erage overall recovery time for animals in this group. Bothof these dogs suffered pronounced paraparesis, which lin-gered long past the resolution of the acute vestibular signs.
Although these 2 dogs may have adversely influenced theaverage overall time to clinical resolution for the untreatedgroup, there still was a marked difference in the responseand recovery times compared to the diazepam-treated ani-mals if data from these 2 dogs are discarded.
The results of this investigation show a positive corre- lation between dosage and duration of treatment relative tothe time of onset of signs of metronidazole toxicosis (Fig Diagrammatic representation of a ␥-aminobutyric acid 1). There did not appear to be an increased susceptibility (GABA) receptor. The GABA receptor is a multisubunit ligand-gatedchloride (ClϪ) ion channel composed of to adverse effects of metronidazole administration on the increase in chloride conductance from the release of GABA from the basis of either age or breed. The average dosage of met- presynaptic membrane results in the inhibitory modulation of neural ronidazole that induced toxicity in the dogs of this study activity through membrane hyperpolarization.
(60.3 and 65.1 mg/kg/d for diazepam-treated and untreatedgroups, respectively) was consistent with published reports.
Ours was a retrospective study, and a specific protocol for the administration of diazepam was not used. All ani- facilitates inhibitory transmission in the cerebral cortex and mals in the diazepam-treated group, however, received an between the substantia nigra and caudate nucleus.27,34 initial, single IV bolus and then diazepam PO q8h for 3 Because of the prevalence of GABA-minergic receptors days. The average dosage of both the IV and PO diazepam in those tracts damaged by metronidazole and the knownrelationship of GABA receptors and benzodiazepines, the was 0.43 mg/kg, but there was no apparent correlation be- following mechanism may be postulated: benzodiazepines, tween the dosages of either the IV or PO routes and the such as diazepam, potentiate GABA influence on chloride conductance, thereby enhancing an inhibitory effect on ex- Neither the mechanism of metronidazole toxicity nor the citatory neurons.38–40 Conversely, inhibition of GABA re- precise mechanism of action of diazepam in the reversal of lease, such as seen in the neurological adverse effects of signs is known. Because the neurological effects of met- enrofloxacin,i ciprofloxacin,j and imipenem,k can lead to hy- ronidazole are referable to both cerebellar and central ves- perexcitability of the central nervous system, resulting in tibular dysfunction, literature regarding the histology and seizures or tremors.41,42 It may therefore be speculated that physiology of these systems was reviewed for a relationship interference of the GABA receptor at the postsynaptic membrane also may result in central nervous system hy- Histological examinations of brain tissue in dogs with metronidazole toxicosis have demonstrated Purkinje cell The benzodiazepines have specific binding sites on loss8,30 and axonal degeneration in vestibular tracts.8 His- GABA receptors within the brain, particularly in the cere- topathologic studies in mice given toxic dosages of met- bellum, cerebral cortex, and limbic system.41,43 The imida- ronidazole showed cerebellar Purkinje cell loss and degen- zobenzodiazepine flumazenil is a selective, competitive an- erative changes in the vestibular, cochlear, deep cerebellar, tagonist (also known as an inverse agonist) of the benzo- and olivary nuclei as well as in the rostral colliculi.31 These diazepine receptor.40,41,44–47 Both flumazenil and metronida- nuclei and their associated tracts are involved primarily zole have an imidazole component, and it is possible that with equilibrium, hearing, and fine motor control.32,33 These metronidazole also may bind specifically to benzodiazepine nuclei, particularly the Purkinje cells, mediate an inhibitory sites on GABA receptors in the cerebellar and central ves- influence on postsynaptic receptors,34,35 and their principal tibular systems, resulting in loss of inhibition, similar in neurotransmitter is GABA,25,26,34 which is the major inhib- effect to flumazenil (Fig 3). That the adverse reactions of itory neurotransmitter of the central nervous system.25–27,36 flumazenil in humans, such as seizures, vertigo, and atax- Activation of the GABA receptor by GABA or GABA mi- ia,45–47 are similar to the neurological adverse effects of metics, such as benzodiazepines, increases chloride (ClϪ) metronidazole in dogs lends additional credence to this pro- conductance at the postsynaptic membrane, resulting in hy- posed mechanism of metronidazole toxicity. Regardless of perpolarization (Fig 2).37 The majority of GABA-minergic whether metronidazole specifically binds to the benzodi- receptors in the central nervous system are located between azepine receptor inhibiting the effects of GABA or selec- the neurons of the cerebellum and their associated brain- tively destroys these cells by another mechanism, it is the stem nuclei, especially the Purkinje cells and the lateral GABA-dependent interactions of the cerebellar and central vestibular nuclei. Other major sites of GABA receptors are vestibular systems that are affected. It can be therefore pos- in the tracts between the vestibular nuclei and the trochlear tulated that diazepam either competes with metronidazole motor neurons and within the olfactory bulbs, cuneate nu- for the benzodiazepine receptor site or supplements GABA clei, hippocampus, and lateral septal nuclei.27 GABA also propagation via unaffected receptors, whereas the remain- Diagrammatic representation of the proposed mechanism of Diagram of the proposed mechanism for the therapeutic effect metronidazole toxicity. Metronidazole binds to the ␥-aminobutyric of diazepam in metronidazole toxicosis. Metronidazole produces its acid (GABA) receptor on the postsynaptic membrane and disrupts the toxic effects by binding to the benzodiazepine site on the ␥-amino- inhibitory influence of GABA. Benzodiazepine antagonists, such as butyric acid (GABA) receptor on the postsynaptic membrane, dis- flumazenil, bind to the benzodiazepine site, competitively inhibiting rupting inhibitory neurotransmission. We postulate that diazepam has the actions of benzodiazepines. Metronidazole and flumazenil share a higher affinity for the benzodiazepine site than metronidazole and both similar chemical structure and toxic adverse effects such as ataxia therefore displaces metronidazole. Removal of metronidazole not only restores normal chloride conductance but also increases benzodiaze-pine-induced chloride conductance (inhibition).
der of the metronidazole in the system is metabolized. It ismore likely that diazepam at therapeutic concentrations existent. The 2 dogs that had received the H -antagonist competitively reverses the binding of metronidazole to the meclizine, which generally is used to treat signs of motion benzodiazepine site on the GABA receptor, because re- sickness in humans,48 and the 2 dogs that underwent general bound manifestations of metronidazole toxicosis were not anesthesia all were in the untreated group. Four dogs from observed in the dogs of this study (Fig 4).
each group had been given either an aminopenicillin or a The average response time for the resolution of debili- 1st-generation cephalosporin; methocarbamol had been giv- tating clinical signs in animals receiving diazepam in this en to 3 dogs of the treated group and 2 dogs of the untreated study was 13 hours, with a final resolution of the remaining group; and butorphanol had been administered to 1 dog clinical signs (usually mild ataxia) over the next 24–48 from each group. Neurological adverse effects such as sei- hours. The plasma half-life of metronidazole in the dog is zures, sedation, and ataxia have been described for each of 3–13 hours1; given this fact, the question of why the clinical these medications, but these adverse effects have been re- signs of metronidazole toxicosis are not resolved in this ported rarely and only with prolonged use or very high time simply after discontinuation of the drug also is raised.
dosages.42,49–51 Corticosteroids, which had been adminis- It is possible that metronidazole at toxic doses either alters tered to 6 of 8 dogs in the untreated group and to 10 of 13 the GABA receptor sufficiently to prevent a return to nor- dogs in the diazepam-treated group, could theoretically mal function within the anticipated time or firmly binds to have induced the oxidative metabolism of metronidazole,52 the receptor and therefore is not subject to normal metab- but the effect of corticosteroids was not believed to be im- olism. From the similarities in the plasma half-life of met- portant because their use was common in both groups, and ronidazole and the average response time of the diazepam- only 1–2 doses had been given. All dogs in this study had treated group, it could be speculated that once metronida- neurological manifestations consistent with metronidazole zole is displaced from the benzodiazepine receptor by di- toxicosis before administration of any of these drugs and azepam, normal metabolism of the displaced drug then were diagnosed with metronidazole toxicosis within 24 occurs, resulting in the rapid clinical improvement ob- hours of the onset of the neurological signs. Administration served. Furthermore, once metronidazole is displaced, the of the above ancillary medications was discontinued after exogenous benzodiazepine not only restores but also en- the diagnosis was established, making it unlikely any med- hances normal benzodiazepine-induced chloride conduc- ication other than diazepam influenced the outcome of these tance. Blood metronidazole concentrations were not mea- sured in the dogs of this study but may have been useful A dose-dependent or duration-dependent relationship be- as an ancillary test to further confirm the diagnosis of met- tween actual neuronal cell death or leukomalacia of the ronidazole toxicosis; additionally, serial posttreatment con- vestibulocerebellar tracts and metronidazole administration centrations could give additional insight into the metabolic could not be determined from this study because no histo- fate of metronidazole after administration of diazepam.
pathologic evaluations were performed. Clinical and exper- Nineteen of the 21 dogs of this investigation received 1 imental studies reported neuronal changes in subjects re- or more medications as treatment for the acute onset of ceiving much higher dosages than the 60.3-mg/kg/d dosage neurological signs before definitive diagnosis of metroni- received by dogs in this investigation.8,30,31 Vestibulocere- dazole toxicosis, but the influence of these medications on bellar axonal degeneration with no loss of neurons, how- the results of this study was thought to be minimal to non- ever, has been reported in dogs receiving 63 mg/kg/d.8 Al- though the animals in this investigation recovered, the po- 12. Dow SW. Management of anaerobic infections. Vet Clin North tential for permanent, subclinical damage to neurons and white matter tracts in all cases of metronidazole toxicosis 13. McClure JA, Lycett P, Baskerville JC. Diazepam as an anti- exists, thereby increasing the probability that these animals motion sickness drug. J Otolaryngol 1982;4:253–259.
will be more susceptible to the adverse effects of metro- 14. McClure JA, Willett JM. Lorazepam and diazepam in the treat- ment of benign paroxysmal vertigo. J Otolaryngol 1980;6:472–477.
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use of diazepam for the treatment of metronidazole toxi- 17. Pettorossi VE, Troiani D, Petrosini L. Diazepam enhances cer- ebellar inhibition on vestibular neurons. Acta Otolaryngol 1982;93:363–373.
18. Matsuoka I, Takahashi H, Sasa M, Takaori S. Experimental ves- tibular pharmacology: A minireview with special reference to neuro- Footnotes
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