Effect of Midazolam on Vestibular Signs in Two Geriatric Dogs with Vestibular Disease
ABSTRACT
An abrupt balance impairment, including leaning, falling, and rolling, occurred after IV administration of 0.2 mg/kg midazolam as a preanesthetic medication in two geriatric dogs with a history of nystagmus and head tilt. In the second case, leaning, falling, and rolling recurred after recovery from general anesthesia but gradually ceased after IV administration of 0.01 mg/kg flumazenil. These two cases suggest that the IV administration of midazolam was responsible for the balance impairment in dogs who were suspected to have idiopathic peripheral vestibular disease.
Introduction
The vestibular system is the major sensory system that functions to maintain balance.1 Nystagmus, head tilt, leaning, falling, and rolling are common signs of a problem in the vestibular system.2 In geriatric dogs, idiopathic peripheral vestibular disease is a common cause of peripheral vestibular dysfunction.1 Evidence suggests that midazolam may impair postural control in humans, with more pronounced effects in older individuals.3 This report describes two cases of sudden development of leaning, falling, and rolling in geriatric dogs with vestibular disease after administration of midazolam.
Case Reports
Case 1
A 15 yr old 5.6 kg spayed female shih tzu with a history of acute right head tilt was referred to the diagnostic imaging center for MRI of the brain. The dog’s head tilt was reported by the owner to have begun 2 days previously. Values reported on a complete blood count were within normal limits. Abnormalities on a serum biochemistry profile included increased alkaline phosphatase activity (2163 U/L; reference interval, 47–254 U/L).
On presentation, the dog was alert and responsive. A complete neurological examination revealed a right-sided head tilt and bilateral horizontal nystagmus (fast-phase to the left). No detectable paresis and proprioceptive deficits were noted. The dog's heart rate (HR) was 100 beats/min and respiratory rate (RR) was 48 breaths/min. Systolic blood pressure was 150 mm Hg measured by Doppler ultrasonic flow probe method. The dog was premedicated with 0.2 mg/kg butorphanola IV. Following preoxygenation, midazolamb (0.2 mg/kg IV) was administered. Immediately afterward, the dog began to show an abrupt balance impairment characterized by leaning, falling, and rolling (Supplementary Video I). Anesthesia was induced with propofolc (4 mg/kg IV) and the dog’s leaning, falling, and rolling ceased. After intubation, general anesthesia was maintained with 2% sevofluraned in 2 L/min oxygen delivered through a semi–closed circle system. The dog breathed spontaneously throughout the anesthetic period. Isotonic saline (0.9% NaCl) was administered at a rate of 5 mL/kg/hr IV. Initial readings during the MRIe procedure were HR of 150 beats/min, oscillometric mean arterial pressure of 68 mm Hg, RR of 29 breaths/min, end-tidal CO2 partial pressure of 43 mm Hg, pulse oximetry of 98%, and end-tidal sevoflurane concentration of 1.6% as recorded by a monitorf. The MRI procedure was performed without complications, and cerebrospinal fluid tap was not performed. Fifty-five minutes after the midazolam premedication was administered, the dog was extubated and recovered from anesthesia. No abnormalities were noted in the tympanic or intracranial cavities on MRI to explain the signs of vestibular dysfunction. On the basis of these results, management of idiopathic peripheral vestibular disease was performed by the primary care veterinarian.
Case 2
A 15 yr old 8.5 kg neutered male mixed-breed dog with a history of acute right head tilt was referred to the diagnostic imaging center for MRI of the brain. Two days prior to referral, the dog was presented to a primary care veterinarian for evaluation of head tilt and nystagmus. A complete blood count and serum chemistry were within normal reference intervals.
Upon neurological examination, abnormalities included a right-sided head tilt and bilateral horizontal nystagmus (fast-phase to the left). No detectable paresis and proprioceptive deficits were noted. Ten minutes after butorphanol (0.2 mg/kg IV) premedication, midazolam (0.2 mg/kg IV) was administered. Immediately following midazolam administration, the dog was unable to maintain postural control and began leaning and falling. Anesthesia was induced with propofol (4 mg/kg IV) and maintained with 2% sevoflurane in 2 L/min oxygen. During anesthesia, measured vital parameters included HR of 87 beats/min, oscillometric mean arterial pressure of 82 mm Hg, RR of 16 breaths/min, end-tidal CO2 partial pressure of 42 mm Hg, pulse oximetry of 99%, and end-tidal sevoflurane concentration of 1.8%. The MRI procedure was performed without complications, and cerebrospinal fluid tap was not performed. After the anesthetic vaporizer was turned off, which was 60 min after the midazolam premedication was administered, the dog was extubated. During recovery from general anesthesia, which was 15 min after extubation, the dog was unable to maintain postural control and leaning, falling and rolling were again observed (Supplementary Video II). Flumazenilg (10 μg/kg IV) was administered at this time. Within 5 min of flumazenil administration, the dog’s vestibular signs had gradually ceased, and the dog regained the ability to balance himself and maintain an upright posture. The dog’s vestibular signs were back to the status on presentation. No abnormalities were noted in the tympanic or intracranial cavities on MRI to explain the signs of vestibular dysfunction. The dog was transferred back to the primary care veterinarian for management of idiopathic peripheral vestibular disease.
Discussion
In the two dogs of the present report, sudden balance impairments occurred after the administration of midazolam, and leaning and rolling recurred during recovery from general anesthesia in the second case. Sedative drugs and volatile anesthetic agents are known to affect balance control as well as the vestibulo-ocular reflex and also influence central sensory processing.4–6 In human medicine, evidence suggests that midazolam and other benzodiazepines can influence postural control, especially in older individuals.3,7 Although the mechanisms of balance impairment are still not fully understood, the effects of benzodiazepines on the central nervous system (CNS) may be assumed to impair psychomotor function, which potentially causes falls in older people.3,5 Benzodiazepines may also affect ambulation and posture through its effects on the peripheral musculature where it affects contraction of skeletal muscle.5,7,8
There is little information regarding the effect of anesthetic drugs on vestibular function in dogs with vestibular disease. Some suggest that short-acting anesthetic drugs and low-dose dexmedetomidine are advisable for smooth, rapid, and complete recovery.9 The dogs described in this study were 15 yr old, so they could be classified as geriatric patients.10 In geriatric patients, the use of benzodiazepines and opioids, which are reversible and relatively short-acting drugs, is commonly recommended, and they are known to reduce induction and inhalation agent requirements.10 The information provided in this case report suggests that when midazolam is used as a premedication for general anesthesia in geriatric dogs with vestibular disease, sudden onset of balance impairment is possible.
Idiopathic vestibular disease is a common cause of vestibular disturbance in dogs with diagnosis made by the absence of any detectable structural, metabolic, or inflammatory disease as well as lack of evidence of central vestibular disease.11 The onset of clinical signs is often peracute to acute, and affected animals may present with nystagmus, head tilt, ataxia, leaning, and rolling.1 In the two dogs of the present report, leaning, falling, and rolling occurred after administration of midazolam as a preanesthetic medication at 0.2 mg/kg IV. At presentation both dogs were observed to have nystagmus and head tilt but were able to walk and maintain an upright posture. However, sudden abrupt loss of postural control occurred after administration of midazolam. In the second case, leaning, falling, and rolling recurred after recovery from general anesthesia but ceased after administration of flumazenil. Therefore, these two cases illustrate that administration of midazolam to dogs with idiopathic vestibular disease may induce an abrupt balance impairment.
Midazolam is a water-soluble imidazole benzodiazepine that acts selectively at gamma-aminobutyric acid receptors on the CNS by enhancing the response to gamma-aminobutyric acid, resulting in increased frequency of chloride channel opening and hyperpolarization of postsynaptic cell membranes.12,13 In human and veterinary medicine, midazolam is widely used for providing sedative, anxiolytic, anticonvulsant, and muscle relaxant effects.14,15 Although it is difficult to induce sedation with midazolam alone in healthy dogs, the drug can cause sedation when used with opioids or in sick or depressed patients.12 In the dogs of the present report, butorphanol and midazolam were administered for premedication. In both cases, butorphanol was administered first and the noted balance impairments were only observed following midazolam administration. Although there is little information regarding the effect of midazolam on vestibular function in dogs, midazolam is associated with an increased risk of impairments related to postural control in older people.3,16 In addition, in the second case, the administration of flumazenil resolved the balance impairments observed during recovery from anesthesia. Flumazenil is a specific competitive benzodiazepine receptor antagonist that effectively reverses amnestic, anxiolytic, and hypnotic effects of benzodiazepines on the CNS.17,18 In the second case reported here, falling and rolling ceased after the administration of flumazenil. Although there is little information about the veterinary use of flumazenil,12 the reversal of abnormal vestibular signs following general anesthesia after flumazenil administration has been reported in a dog that received midazolam and butorphanol as a premedicant drug.19 In addition, flumazenil does not reverse the effects of midazolam on skeletal muscle contraction.8 The observation that balance impairment resolved after flumazenil administration strengthens the hypothesis that midazolam’s central effects were of primary importance. This strongly suggests that some characteristic of midazolam, aside from its sedative properties, was responsible for the leaning and rolling in the dogs of this report, who were subsequently diagnosed with idiopathic vestibular disease.
The present case report had a limitation. It was not clear how the butorphanol that was administered affected the balance impairments because there were no notable changes observed after premedication with butorphanol. There is little information about the effect of butorphanol and opioids on postural control in dogs. However, high-dose opioids were associated with a significant sedation and compromised coordination in older people.20 Although the dogs of the present report received butorphanol and it might be associated with these balance impairments, sudden balance impairments occurred immediately after the administration of midazolam, and the administration of flumazenil resolved these signs in the second case. Therefore, recognizing that there is little information available regarding the effect of midazolam and butorphanol on balance impairments in dogs, the authors suspected that some characteristic of midazolam could have contributed to the sudden onset of balance impairments during the anesthetic period.
Conclusion
The authors report the onset of abrupt balance impairment in two geriatric dogs with idiopathic peripheral vestibular disease following administration of 0.2 mg/kg midazolam IV. The leaning, falling, and rolling observed in one of these dogs did not recur following general anesthesia. However, in the second case, these signs did recur during the recovery period but ceased following administration of flumazenil at 0.01 mg/kg IV. This information may prove useful to practitioners who use midazolam as a premedication because such neurological signs are generally not expected following midazolam administration in geriatric dogs with idiopathic peripheral vestibular disease.
Contributor Notes
CNS (central nervous system); HR (heart rate); RR (respiratory rate)
M. Jang’s present affiliation is the Department of Veterinary Surgery, Haemaru Referral Animal Hospital, Seongnam, Republic of Korea.
