Anesthesia Case of the Month

Alicia M. Skelding 404 Veterinary Emergency & Referral Hospital, 510 Harry Walker Pkwy S, Newmarket, ON L3Y 0B3, Canada.

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Alexander Valverde Department of Clinical Studies, Ontario Veterinary College, University of Guelph, Guelph, ON NIG 2WI, Canada.

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History

A 4-year-old 24-kg (53-lb) spayed female mixed-breed dog was examined for removal of porcupine quills. The patient had no other pertinent medical history, and no abnormalities were noted on physical examination other than the presence of porcupine quills within the mouth, on the muzzle and face, and above the eyes. The patient was classified as American Society of Anesthesiologists physical status I (healthy patient). The patient was premedicated with hydromorphone (0.05 mg/kg [0.023 mg/lb], IM) and dexmedetomidine (5 μg/kg [2.3 μg/lb], IM), and general anesthesia was induced with propofol (2 mg/kg [0.9 mg/lb], IV) administered via a 20-gauge catheter placed in a cephalic vein. Anesthesia was maintained by means of total IV anesthesia with propofol (total dose, 10 mg/kg [4.5 mg/lb], IV, over a 60-minute period). Anesthesia and recovery were uneventful. The patient received meloxicam (0.1 mg/kg [0.045 mg/lb], SC) and was discharged the same day with a 10-day course of amoxicillin-clavulanic acid (15.6 mg/kg [7.1 mg/lb], PO, q 12 h). However, the patient was readmitted to the hospital the following day for removal of additional porcupine quills that had not been noticed previously. No abnormalities were noted on physical examination other than a few remaining porcupine quills on the muzzle and in the mouth. The patient was again classified as American Society of Anesthesiologists physical status I. On this occasion, the patient was premedicated with a combination of dexmedetomidine (5 μg/kg, IM) and butorphanol (0.2 mg/kg [0.09 mg/lb], IM), which provided moderate sedation. A 20-gauge IV catheter was again placed in a cephalic vein, and general anesthesia was induced with propofol (2 mg/kg, IV) 20 minutes later. The patient received flow-by oxygen supplementation at a rate of 4 L/min via an F circuit. Because of the short duration of the procedure and so that the oral cavity could be thoroughly evaluated, endotracheal intubation was not performed, but was readily available if deemed necessary. Anesthesia was maintained via total IV anesthesia with propofol boluses to effect (total dose, 6 mg/kg [2.7 mg/lb], IV, over a 30-minute period). Arterial blood pressure (measured noninvasively with an oscillometric method), ECG, oxygen saturation as measured with pulse oximetry, and rectal temperature were monitored with a multiparameter monitor.a Palpebral reflexes and jaw tone were frequently evaluated, and respiratory rate was recorded by observation of thoracic excursions. The patient was stable throughout the procedure with a respiratory rate of 12 to 16 breaths/min, oxygen saturation of 98% to 100%, heart rate of 65 to 77 beats/min, mean arterial pressure of 130 to 150 mm Hg, and rectal temperature of 37.9° to 38.3°C (100.2° to 100.9°F). The remaining quills were removed without complications. The total procedure time was 30 minutes. It was initially noticed that the patient had developed mild, intermittent generalized muscle trembling and mild forelimb extensor rigidity during the last 5 minutes of the procedure, approximately 45 minutes after the premedication had been administered (approx 25 minutes after the initial dose of propofol had been administered). In an effort to shorten time for recovery from general anesthesia, atipamezole (0.05 mg/kg, IM) was administered to reverse the dexmedetomidine that had been given as a premedicant. However, 15 minutes later, the patient had not regained consciousness, although the cardiovascular changes attributable to dexmedetomidine had returned to the patient's baseline values (heart rate, 90 to 120 beats/min; mean arterial pressure, 80 to 110 mm Hg; and rectal temperature, 38.7°C [101.7°F]), and the patient was placed on a large mat. The rigidity progressed to sustained severe extensor rigidity in all 4 limbs and severe opisthotonus. The patient remained unconscious and displayed bilateral miosis with the pupils in a ventral position. To treat the rigidity and opisthotonus, diazepam (0.1 mg/kg, IV) was administered, with no appreciable response. A venous blood sample was obtained for a CBC and serum biochemical analyses, including measurement of serum ionized calcium concentration. Fluid therapy with a balanced electrolyte solution was initiated (20 mL/kg [9 mL/lb], IV bolus over 15 minutes) and continued at a rate of 5 mL/kg/h. Over the same 15-minute period, 3 additional doses of diazepam (0.2 mg/kg, IV) were administered, but no clinical response was observed. Because of the posturing the patient was exhibiting, concerns existed about the possibility of an increase in intracranial pressure, although the history, preprocedural physical examination findings, and cardiorespiratory parameters at the time (respiratory rate, 12 to 16 breaths/min; oxygen saturation, 97% to 100%; heart rate, 90 to 120 beats/min; mean arterial pressure, 80 to 110 mm Hg; and ECG demon-strating sinus rhythm, apart from intermittent interference because of muscle tremors) did not support this differential diagnosis. The patient was then given a bolus of hypertonic saline (7.2% NaCl) solution (2 mL/kg, IV) over a 20-minute period, but the clinical signs did not resolve. Results of laboratory testing were within reference limits, suggesting there was no hepatic or renal disease and no electrolyte disturbances or associated pathological changes in muscle tissue. Approximately 45 minutes after the initial onset (90 minutes after premedication and 70 minutes after the initial propofol dose), the patient's clinical signs started to abate, with the rigidity resolving in the pelvic limbs first, then the forelimbs, followed by a gradual return to consciousness. Clinical signs resolved, including an apparent return to consciousness, with normal ambulation occurring over 15 minutes while sedation was still apparent. The patient was maintained in the hospital overnight for monitoring and was discharged the following day when results of physical and neurologic examinations were normal. During a follow-up examination 10 months later, the owner reported that the patient had been apparently healthy with no further neurologic episodes. The owner reported that 14 months after the episode, the patient required sedation with dexmedetomidine and butorphanol for a minor procedure. The patient experienced no adverse reactions and recovered without complications.

Question

What is the mostly likely cause of this patient's neurologic signs, including opisthotonus, muscle tremors, extensor rigidity, and prolonged return to consciousness following total IV anesthesia?

Answer

Together, this patient's involuntary postural signs and muscle tremors were indicative of dystonia. Dystonia-like signs in veterinary and human patients have been attributed to a variety of anesthetic drugs.1–4 Two cases of propofol-associated dystonia in dogs following total IV anesthesia have been reported.1,2 In addition to propofol, phenothiazines3 and opioids4 have also been implicated in affected human patients. In the patient of the present report, we believe anesthetic drug-associated dystonia likely resulted from interactions among several of the drugs administered. The only other likely explanation for the dog's signs was seizure-like activity. However, the dog did not respond to multiple doses of diazepam, and this is generally the benzodiazepine of choice for the initial treatment of acute seizure activity in dogs. Additionally, the patient had received butorphanol and propofol prior to the onset of clinical signs, and both of these drugs have been associated with dystonic reactions. Finally, dystonia results in sustained abnormal posturing, whereas seizure-like activity causes abnormal posturing only during the seizure episode.

Discussion

Dystonia is a syndrome characterized by involuntary posturing and muscular spasm occurring as a result of neurologic disease or as an adverse effect of drug administration.5 Acute drug-induced dystonia can be caused by a variety of drugs, including levodopa, dopamine agonists, antipsychotics (phenothiazines), anticonvulsants, selective serotonin-reuptake inhibitors, and, rarely, other miscellaneous drugs, including propofol, opioids, and antihistamines. The involuntary muscle contractions can be localized (ie, focal and affecting a single muscle), multifocal (ie, affecting a group of muscles), or generalized (ie, affecting the entire body).5 The patient described in the present report initially developed signs of localized dystonia, with muscle trembling and mild forelimb extensor rigidity that progressed to sustained opisthotonus with generalized muscle rigidity and continuous extension of the thoracic and pelvic limbs.

Normal neuromuscular function is the result of a balance between central inhibitory and excitatory output via cholinergic and dopaminergic pathways resulting from modulation of the nuclei of the basal ganglia through γ-aminobutyric acid (GABA) inhibitory actions. The basal ganglia are a group of nuclei located in the subcortical white matter of the frontal lobes of the brain. These are strongly interconnected with the cerebral cortex, thalamus, and brainstem via direct and indirect pathways from which impulses are relayed to the spinal cord and muscles, allowing for voluntary muscle movement through activation of neuromuscular junctions.6–8 Abnormal muscle movements can be the result of impaired voluntary movement, the presence of involuntary movements, or a combination of both of these. Movement can be decreased (hypokinesis) or increased (hyperkinesis). Dystonia is characterized by hyperkinetic involuntary movement resulting from a reduction in the normal inhibitory output from the basal ganglia.9

Dopamine released by the substantia nigra through axons reaching the basal ganglia stimulates the direct pathway and inhibits the indirect pathway, which results in motor activity and a hyperkinetic state such as dystonia,7,9 whereas acetylcholine released by cholinergic neurons located in the basal ganglia has the opposite effect, inhibiting the direct pathway and stimulating the indirect pathway. This decreases motor activity and produces a hypokinetic state (eg, Parkinsonian syndrome).7 The pathophysiology of dystonia is poorly understood. It has been suggested that drug-induced disruptions in the basal ganglia can result in a motor circuit disorder that offsets the balance between the release of excitatory (ie, dopamine) and inhibitory (ie, cholinergic) neurotransmitters affecting the direct pathway or inhibitory (ie, dopamine) and excitatory (ie, cholinergic) actions in the indirect pathway.7 Either a lack of or an excess of dopamine could produce dystonia, depending on its relative influence on the direct and indirect pathways10 and the type of dopamine receptor affected; this explains why so many different drugs can cause dystonia and why drugs that are used for its treatment can also cause hyper- or hypokinetic muscle disorders.

It is possible that > 1 mechanism and various preexisting conditions are involved in the etiology of dystonia. In the 2 previously reported cases involving dogs,1,2 both were 2-year-old neutered males. One patient was undergoing bronchoscopy,1 and the other was undergoing bronchoscopy and gastroscopy,2 both under propofol anesthesia. One patient had preexisting idiopathic epilepsy and received diazepam PO and meperidine IM as premedications1; the other dog was premedicated with a combination of dexmedetomidine and butorphanol IM.2 Both patients developed signs consisting of forelimb extensor rigidity and opisthotonus, occurring shortly after induction of general anesthesia in one dog and during recovery in the other. The dog with idiopathic epilepsy also showed paddling, bilateral horizontal nystagmus, and facial twitching during the episode and was refractory to treatment with diazepam.1 Propofol was the common factor for the dystonia observed in the 2 patients in these published reports and the patient described in the present report; however, other drugs cannot be ruled out as contributing factors.

Propofol is widely used for sedation and anesthesia in human and veterinary patients. Propofol modulates the actions of GABA, more specifically at the GABAA receptor, but it can also activate the receptor directly in the absence of GABA.11,12 Propofol has been reported to have the potential to cause a wide range of excitatory reactions including involuntary muscle movements, myoclonic jerks, generalized tonic-clonic seizures, opisthotonus, and dystonia.2,12,13 Dystoniclike reactions (eg, paddling of limbs, muscle twitching, opisthotonus) have been reported13 in client-owned dogs undergoing total IV anesthesia with propofol for surgical or diagnostic procedures, with a reported incidence of 10.3% (6/58 dogs) after premedication with acepromazine or diazepam IV, and are also well documented in human patients.14–16 In a study17 of 148 dogs anesthetized (induced and sometimes maintained) with propofol, 12 (8.1%) developed signs of CNS excitement including panting, muscle twitching, opisthotonus, and limb rigidity. Of interest is that some dogs with signs of excitement may have had a history of uncomplicated propofol general anesthesia, as for the patient of the present report, which had undergone propofol anesthesia the prior day without incident.

Several mechanisms have been suggested for propofol's adverse neuromuscular effects, which may occur independently or in combination. These mechanisms include spinal antagonistic effects to glycine,18 decreased chloride conductance at the GABA receptor,19 and potentiation of seizure activity.20,21 Unlike GABA, which has inhibitory actions in both the cerebral cortex and spinal cord, glycine acts as an inhibitory neurotransmitter at subcortical levels of the spinal cord only. Propofol has an antagonistic effect on glycine at a subcortical level in the spinal cord, similar to the action of strychnine, which can result in clonic seizure-like movements.18 Normally, propofol increases chloride conductance, activating the GABAA receptor-chloride ionophore complex and facilitating the inhibitory actions of GABA.19 However, high concentrations of propofol can desensitize chloride channels, producing the opposite effects and promoting the excitatory actions of dopaminergic pathways, altering the balance with inhibitory cholinergic pathways, and leading to dystonia.7,16,19 Propofol has anticonvulsant activity via sedation and unconsciousness as a result of potentiation of GABAergic interneurons in the cerebral cortex, the thalamic reticular nucleus, and the arousal centers that enhance inhibitory actions.20 Conversely, propofol can also potentiate GABAergic interneurons locally in the cerebral cortex and induce seizure activity when administered at anesthetic doses.18,20,21 Therefore, although generally considered an anticonvulsant, propofol also has a weaker convulsant effect. It is hypothesized that excitatory reactions following propofol administration are more likely to occur during periods when the concentration of propofol in the brain is changing rapidly; therefore, these reactions are most commonly observed during induction or recovery.2 However, intermittent signs may persist for hours1 to days, even after a single IV dose.16 It should be noted, though, that in an experimental study of mice,18 when propofol was injected intraperitoneally, seizure-like clonic movements during anesthesia were frequent and persistent, likely as a result of more sustained propofol concentrations in the brain associated with IP administration.

In a study13 of 149 client-owned dogs, the reported incidence of signs of dystonia for patients given propofol was similar to the incidence among patients in which anesthesia was maintained with isoflurane (10.3% [6/58 cases] vs 8.8% [8/91 cases]). However, we suggest that a valid comparison may be difficult because all patients received propofol for anesthetic induction and acepromazine was administered to some dogs in both groups. Additionally, other drugs used as part of the premedication and anesthetic protocols may have contributed. Antipsychotic (neuroleptic) drugs, such as acepromazine, have antidopaminergic and anticholinergic effects. These actions occur at the basal ganglia, where they specifically block dopamine 2 receptors, which may allow for overactivation of unblocked dopamine 1 receptors, whereas anticholinergic actions are related to blockade of muscarinic receptors.3,22 Activation of dopamine receptors can result in dystonia-like reactions via dopamine 1 receptors’ excitatory effect on the direct pathway and dopamine 2 receptors’ inhibitory effect on the indirect pathway of the basal ganglia. Inhibition of dopamine 2 receptors and overactivation of dopamine 1 receptors may lead to increased signaling of the motor thalamus and cerebral cortex, producing increased motor activity. Antipsychotic drugs with greater anticholinergic properties have the fewest dystonic-like adverse effects,23 whereas drugs such as chlorpromazine, which is very similar to acepromazine, have antidopaminergic potency in excess of anticholinergic potency and have a high incidence of adverse effects, including extrapyramidal reactions.3 Acepromazine administration has been reported in some cases involving dogs that have dystonia-like reactions,13 and we speculate that this could be a predisposing factor in combination with propofol anesthesia.

Opioids are also implicated in dystonic reactions.4 The mechanism of action involves postsynaptic μ-opioid receptors stimulating GABAergic input of neurons in the basal ganglia, likely via indirect mechanisms,24 with activation of the direct pathway and inactivation of the indirect pathway of the basal ganglia, resulting in increased motor activity, whereas presynaptic κ-opioid receptors inhibit dopamine 2 receptors,24 which allows for potential inhibition of the indirect pathway of the basal ganglia and increased motor activity. Butorphanol, a κ-agonist, was used in our patient and was also reportedly used in another dog that developed signs of propofol-associated dystonia,2 whereas meperidine, a μ-agonist, has also been reported1 to potentially have contributed to dystonic signs.

Treatment options have not been developed for patients that exhibit dystonic reactions secondary to propofol administration. Supportive measures and diagnostic testing to rule out the possibility of other underlying disease mechanisms are always warranted in these patients. Propofol-associated dystonia appears to be refractory to benzodiazepine administration and unresponsive to administration of inhalant anesthetics.2 Benzodiazepines are reportedly also only partly efficacious in human patients with dystonia.5,16 Anticholinergics with antimuscarinic central actions are considered antiparkinsonian medications because they can favor dopaminergic activity by blocking cholinergic activity, which may help reestablish the equilibrium between the 2 systems. Anticholinergics such as benztropine and trihexyphenidyl have been used successfully for treatment of dystonia in humans,5,25,26 but these have not been used in dogs with propofol-associated dystonia. Benztropine was also reported to cause a dystonic reaction in a human patient following an overdose,26 which was thought to be secondary to increased dopamine presence in the basal ganglia that resulted in enhanced excitatory output.

Mild dystonia-like signs (eg, involuntary paddling of limbs and myoclonic jerks) associated with anesthetic drugs are reportedly relatively common in dogs (8% to 10%), and the signs generally resolve without specific treatment.13,17 Conversely, severe signs of dystonia (eg, generalized tonic-clonic seizures, opisthotonus, and generalized hyperkinetic movements) are apparently uncommon but require immediate attention, including ensuring a patent airway, ruling out an underlying disease process, and providing patient support.

Footnotes

a.

SurgiVet Advisor, Smiths Medical, Dublin, Ohio.

References

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