Severe propofol-associated dystonia in a dog

Abstract

A 2-year-old castrated dog was presented for chronic coughing that was evaluated with bronchoscopy following intravenous boluses of propofol. During recovery the dog developed severe rigidity of muscles of the neck and thoracic limbs, which was unresponsive to treatment but subsided over 25 minutes. A presumptive diagnosis of propofol-associated dystonia was made. The clinical characteristics and theorized pathophysiology of propofol-associated dystonia are discussed.

Dystonia after propofol administration is a rare phenomenon that has been well-documented in humans (1–3). It is characterized by sustained, arrhythmic contractions of the muscles of the thoracic limbs and involuntary twitching after administration of propofol (1). This case report describes an occurrence of propofol-associated dystonia in a dog and discusses the pathophysiology of the condition.

Case description

A 2-year-old male neutered golden retriever and poodle cross-bred dog weighing 31 kg was referred to the Small Animal Medicine Service of the Veterinary Teaching Hospital at the University of Illinois. The dog had a 1-year history of coughing and vomiting that were unresponsive to treatment. There were no other abnormalities, including seizures or neuromuscular diseases, noted in the dog’s history. Previously prescribed medications included doxycycline, ciprofloxacin, hydrocodone, hydrocodone and homatropine syrup, famotidine, and fenbendazole. At the time of admission and subsequent anesthesia, only famotidine was administered to the dog. Physical examination of the dog revealed a rectal temperature of 39°C (102.2°F), a heart rate of 80 beats/min, a respiratory rate of 24 breaths/min, and a body condition score of 5 out of 9. The dog was bright, alert and responsive, and had pink mucous membranes and a capillary refill time of 2 s. Thoracic auscultation revealed no abnormalities. The dog had normal mentation but was very anxious. Initial diagnostics involved taking a jugular blood sample for packed cell volume and total protein concentration, venous blood gas analysis, and quantification of electrolytes, blood urea nitrogen, creatinine, and lactate, which were all within normal ranges. A blastomycosis urine antigen test was negative. Thoracic radiographs revealed a bronchial pattern in the caudodorsal lung fields. Differential diagnoses included acute-on-chronic bronchitis of infectious or inflammatory etiology. A barium esophogram was performed and revealed no abnormalities. Anesthesia to facilitate bronchoscopy, bronchoalveolar lavage, and gastroscopy was scheduled for the following day to further investigate the presenting complaints. Food was withheld from the dog overnight, and water was withheld for 2 h prior to anesthesia.

The dog was administered dexmedetomidine (Dexmedetomidine hydrochloride; Pfizer Animal Health, New York, New York, USA), 4 μg/kg body weight (BW), IM and butorphanol (Fort Dodge, Fort Dodge, Iowa, USA), 0.4 mg/kg, IM as an anesthetic premedication. After 10 min, the dog was moderately sedate, and a 20-gauge cephalic indwelling catheter was placed. Nasal flow-by oxygen was administered via an appropriately sized facemask from an anesthesia machine at a rate of 2 L/min for 5 min prior to induction to increase the fraction of inspired oxygen. Anesthesia was induced with propofol (Novaplus, Schaumburg, Illinois, USA), 4 mg/kg, BW, IV. The dog continued to spontaneously ventilate and did not respond to insertion of a bronchoscope or performance of a bronchoalveolar lavage. Nasal flow-by oxygen was continued at a rate of 2 L/min during the procedure by placing the end of an anesthesia breathing circuit close to the dog’s mouth and nose. To maintain adequate depth of anesthesia, intermittent boluses of propofol were administered over the 30-minute period necessary to complete the procedure, resulting in a total dose of 10.6 mg/kg BW. The dog received lactated Ringer’s solution at 10 mL/kg BW per hour, IV throughout the procedure. Vital parameters, including pulse rate, respiratory rate, indirect blood pressure, electrocardiogram (ECG), and hemoglobin oxygen saturation (SPO₂) were continuously monitored. Vital parameters remained normal probe placed throughout the duration of anesthesia. The SPO₂ on the tongue of the dog was dislodged several times during the procedure which resulted in intermittent measurements; however, no abnormalities were noted in the measurements that were obtained. After completion of bronchoscopy and bronchoalveolar lavage, the dog was intubated and administered 100% oxygen at 2 L/min from a circle system attached to an anesthesia machine. Anesthesia maintenance was continued with intermittent boluses of propofol.

Gastroscopy was performed and completed in 5 min. Propofol administration was discontinued, and the dog was allowed to recover from anesthesia. Five minutes later, the dog began to move and demonstrated an opisthotonus-like position of severe extension confined to the cervical region. The forelimbs of the dog became rigidly extended, and the musculature of the forelimbs and cervical spine began to contract repetitively. The muscles of the pelvic limbs, abdomen, and lumbar epaxial musculature were not affected and remained relaxed. Initially, the muscular contractions were mild but increased in intensity over the next several minutes. The patient remained intubated and unconscious while displaying the abnormal muscle movements. Palpation of the forelimbs revealed tightly contracted, rigid muscles, and it was difficult to flex the carpi and elbows. When the forelimbs were forced into complete flexion so that the limbs were pressed to the thorax, the muscle contractions ceased and the affected muscles relaxed. However, when the limbs were straightened, the muscle rigidity and contracting reoccurred. Within 2 min of the initiation of the abnormal muscle movements, midazolam (Hospira, Lake Forest, Illinois, USA), 0.3 mg/kg BW was administered IV for muscle relaxation. The myoclonus continued to progress with no apparent response to the midazolam. Atipamezole (Atipamezole hydrochloride; Pfizer Animal Health), 0.04 mg/kg BW, IM was administered to antagonize the previously administered dexmedetomidine. The alpha-2 agonist was antagonized because it is standard protocol of our hospital to antagonize, when possible, medications that may have significant cardiovascular side-effects when an unexpected anesthetic complication arises, particularly if the complication may progress towards a life-threatening event. In this case, the dexmedetomidine was antagonized due to continuing progression of clinical signs.

Ten minutes later, there was no decrease in the abnormal movements and muscle contraction, and a second dose of 0.3 mg/kg of midazolam was administered IV. The abnormal muscle contraction continued and seemed to be refractory to benzodiazepine therapy. Isoflurane (Isothesia; Butler Schein Animal Health, Dublin, Ohio, USA) administration at 2% was initiated in expectation that general anesthesia might help decrease the muscle contractions. However, after 5 min of isoflurane administration, the muscle contraction subsided only minimally. Isoflurane was therefore discontinued. The dog continued to exhibit abnormal muscle extension, which slowly began to decrease in frequency and severity and eventually ceased over the next 25 min. During the entire episode, capnography, pulse oximetry, ECG, and blood pressure monitoring were continually performed on the dog. The dog remained unconscious and displayed no evidence of awakening from anesthesia during the event. Blood pressure and SPO₂ remained within normal parameters. Eventually, the dog started showing signs of emerging from anesthesia and was extubated once it began to demonstrate swallowing movements and control of its airway. Recovery continued uneventfully, except for a mild horizontal nystagmus, which continued for an additional 30 min. The dog demonstrated normal mentation and was bright, alert, and responsive. Ten minutes after extubation, the dog was able to walk and urinated without difficulty or any evidence of neurologic deficits. A jugular venous blood sample was obtained and submitted for complete blood (cell) count (CBC) and chemistry profile, which were within normal parameters. Post-anesthetic pulse rate, respiratory rate, and temperature were 86 beats/min, 56 breaths/min, and 38.6°C (101.5°F), respectively. Based on the clinical signs and course of the observed muscle disorder, a presumptive diagnosis of propofol-associated dystonia was made.

The remainder of the recovery was uneventful, and the dog was discharged to its owner. The dog was diagnosed with mycoplasma pneumonitis and treated with doxycycline and prednisone. One month later, the owner reported that the dog had some response to treatment but was still having episodes of coughing.

Discussion

The classification of involuntary muscle movements and disorders is challenging because differentiation of neurologic and muscular diseases can be difficult. For example, differentiating movement disorders, such as dystonia, from simple partial seizures requires advanced diagnostic modalities such as an electroencephalogram (EEG). Involuntary muscle contractions originate from either a primary muscular or primary nervous system disorder. If the contractions are a result of a primary muscle disorder, which was not thought to be likely in this case, the contractions are termed myotonia; a persistent, repetitive muscle cell contraction without relaxation after a physiologic stimulus (4). Electromyography and biopsy can be used to diagnose specific muscle disorders. In contrast, muscle contractions caused by abnormalities of the nervous system are termed tetanus, tetany, or myoclonus. These result from spontaneous uncontrolled discharge of motor neurons. Myoclonus is defined as a clinical sign of a sudden contraction of a group of muscle cells followed by immediate relaxation; both sporadic and repetitive forms have been observed (4). Dystonia is a syndrome that falls under the category of a movement disorder (4).

According to the National Institutes of Health, and Institute of Neurological Disorders and Stroke, dystonia is defined as involuntary muscle contractions causing repetitive movements and/or abnormal postures. Some patients with dystonia may also experience tremors or other neurological signs. Depending upon the specific type of dystonia affecting the patient, 1 muscle (focal dystonia), groups of muscles (segmental or multifocal dystonia), or muscles throughout the entire body (generalized dystonia) may contract involuntarily (5). The dog described in this report displayed dystonia that would be classified as segmental or multifocal. Regardless of the type of dystonia, it is hypothesized that abnormal activity in the basal ganglia results in the clinical disorder (5). Differentiating seizure activity from dystonia can be difficult. An EEG performed during the episode is the only way to definitively rule out epileptic activity (3). However, distinct clinical signs can lead to a diagnosis of dystonia. We concluded that the dog described in this report was displaying dystonia, and not seizure activity, for several reasons. First, the dog did not respond to 2 doses of midazolam, a benzodiazepine that is the first line of treatment for most seizure disorders due to its high lipophilicity and rapid brain penetration (6). Second, this dog had been administered propofol prior to the onset of the abnormal muscle activity and propofol can reduce or abolish seizure activity in patients with seizure disorders (7). Third, initiation of isoflurane anesthesia at a 2% concentration in oxygen did not decrease the severity or frequency of abnormal activity. With seizures, general anesthesia can reduce or eliminate clinical signs of seizure activity when an animal is at an appropriate plane of anesthesia (8). Fourth, one of the hallmarks of dystonia is sustained abnormal positioning, which is not observed with pure seizure activity (5). At times, our patient exhibited opisthotonus with sustained muscle rigidity and extension confined to the forelimbs and neck.

The balance between inhibitory dopamine receptors and excitatory cholinergic receptors in the basal ganglia is hypothesized to control neuromuscular coordination (9). With dystonic reactions, this delicate balance is lost. Propofol can disrupt the balance through increases in excitatory cholinergic output (1). Sustained muscle contractions and abnormal posturing seen in propofol-associated dystonia are thought to be caused by an imbalance of cholinergic-dopaminergic neurotransmitters (1). Interestingly, in schizophrenic patients receiving antipsychotics, dystonia can occur and is linked to dopamine antagonism. Therefore, either an increase in excitatory cholinergic output, or a blockade of inhibitory dopamine receptors may cause dystonia (10).

Since propofol was introduced nearly 30 years ago, it has been documented to cause a range of excitatory neurological reactions (ENR) that appear during induction, maintenance, and emergence, including grand mal seizures, unbalanced, involuntary muscle movements, myoclonic jerks, generalized tonic-clonic seizures, opisthotonus, and dystonia after administration in humans (11–14). Excitatory neurological reactions after propofol administration are more likely to occur during induction and emergence and rarely occur during maintenance of anesthesia; therefore, it is thought that seizure-like phenomena (generalized tonic-clonic seizures, increased tone with twitching and rhythmic movements, and involuntary movements) are more likely when propofol levels in the brain change rapidly (15). Schramm and Orser (1) proposed that ENR related to propofol fit into 2 categories: seizure-like reactions and dystonic reactions. Seizure-like reactions were defined as intermittent contractions with muscles alternatively contracting and relaxing. Dystonic movements were defined as abnormal hypertonicity in the limbs, including opisthotonus (1).

Reports of excitatory movements after propofol administration in veterinary medicine are limited and do not specifically discuss dystonia or treatment options for canine patients. In 1 study comparing propofol total intravenous anesthesia (TIVA) to isoflurane anesthesia, the authors described the occurrence of abnormal movements, but they were present in both groups and the occurrence was not different between groups (16). Excitatory neurologic reactions were described in a 2-year-old neutered male dog anesthetized with intravenous propofol for bronchoscopy (17). However, this dog had been previously diagnosed with idiopathic epilepsy and experienced generalized grand mal seizures on a routine basis. Thus, it could not be determined if the ENRs were a result of the seizure disorder or associated with propofol. In a 1991 report of 148 dogs anesthetized with propofol, 12 dogs developed signs of central nervous system excitement (including panting, muscle twitching, opisthotonus, and limb rigidity) (18). These dogs were administered diazepam which resulted in cessation of all abnormal movements. This report differs from the case reported here in that this dog was administered a benzodiazepine (midazolam) which had no apparent effect on reducing the abnormal movements.

There have been several case reports in humans describing dystonia after propofol administration. In a report of a young woman who received propofol, dystonia developed 6 h after surgery; subsequently, the patient experienced symptoms intermittently for 3 mo, which necessitated treatment with sodium valproate (3). The authors state that EEG monitoring may be necessary to define the type of ENR observed. In the dog reported here, EEG was not available. In another report, an adult male began to involuntarily twitch his upper limbs arrhythmically immediately after a bolus of propofol (1). Similar to the case reported here, the dystonia was refractory to midazolam; however, administration of 2 mg of benztropine IV eliminated the dystonic movements. This patient had previously received a 5-hour propofol infusion for cardiac surgery and recovery with no dystonia noted. It is unknown why this patient exhibited dystonia after a propofol bolus but not during the previous infusion.

Dystonia has also been reported to occur after administration of opioid medications. Iselin-Chaves et al (19) reported dystonia and parkinsonism which they attributed to morphine administration, following general anesthesia. The patient was administered paracetamol and morphine post-operatively, which resulted in increased severity of abnormal muscle movements. Clonidine and midazolam administration did not reduce the dystonia and parkinsonian signs. However, naloxone administration immediately and completely inhibited the abnormal movements (19). Naloxone was not administered to the dog in this report, and it is unknown if the preanesthetic butorphanol had any involvement in the dystonia.

Benztropine is an anticholinergic that has been reported to successfully treat propofol-induced dystonia in a single human case report (1). Benztropine is used to treat Parkinson’s disease. It has mixed anticholinergic, antihistaminic, and dopaminergic properties. By blocking intrastriatal cholinergic activity, benztropine is hypothesized to restore neurotransmitter balance in the central nervous system. To treat extrapyramidal side effects, the recommended dose is 2 mg IV in humans (20). The dose can be repeated every 30 min until dystonia symptoms cease.

To date, only relatively sparse reports of human and veterinary cases of propofol-associated dystonia are present in the literature, and thus, a consensus for treatment has not been developed. However, in most cases, it seems clinical signs abate over time after discontinuation of propofol administration.

In veterinary medicine, dystonia after the administration of propofol is probably a rare occurrence. However, veterinarians should be aware that propofol administration can be associated with neuroexcitatory events, including dystonia. CVJ