History

An 11-month-old 3.8-kg male domestic shorthair cat was anesthetized for a right femur fracture repair and neuter at the University of California-Davis William R. Pritchard Veterinary Medical Teaching Hospital. The cat was presumably hit by a car approximately 2 weeks before presentation, and no other medical history was known.

The cat was assigned an American Society of Anesthesiologists physical status I based on preanesthetic physical examination and blood work.

After subcutaneous methadone (0.4 mg/kg, once) and atropine (0.02 mg/kg, once), an IV catheter was placed. General anesthesia was induced with IV ketamine (5 mg/kg, once) and midazolam (0.25 mg/kg, once) and maintained with isoflurane in 100% oxygen for 3.3 hours after orotracheal intubation. Lactated Ringer solution was infused at 5 mL/kg/h during anesthesia. Cephazolin (22 mg/kg) IV was administered every 90 minutes during surgery.

The cat was allowed to breath spontaneously. The end-tidal carbon dioxide, hemoglobin oxygen saturation, respiratory rate, heart rate, systolic arterial blood pressure (SAP) measured with a doppler device and body temperature were monitored every 5 minutes.

After induction of anesthesia, an epidural injection was attempted at the L7-S1 intervertebral space with a 22-gauge 3.81 cm short-bevel spinal needle guided by the hanging drop technique.¹ Cerebrospinal fluid (CSF) was appreciated in the needle hub upon aspiration and half of the volume intended for the epidural administration was injected over 30 seconds in the subarachnoid space. The drugs injected in the subarachnoid space were preservative free (PF) morphine (0.05 mg/kg) mixed with PF bupivacaine 0.5% (0.5 mg/kg) diluted to a total volume of 0.15 mL/kg with PF sodium chloride 0.9%.

Complications encountered during anesthesia were transient hypotension (SAP 80 mmHg) and hypothermia (35.4°C), which were treated by reducing the delivered concentration of isoflurane and with external heating devices, respectively.

About 50 minutes after administration of the intra-thecal injection, intermittent muscular activity of the fractured limb was observed during the procedure, both concomitant and not to surgical manipulation. Anesthetic depth was judged to be adequate at that time. Myoclonus persisted, but its degree was deemed mild, so no treatment was instituted, and surgery was successfully completed. Postoperatively, soon after tracheal extubation, myoclonic contractions became more frequent and progressed to myoclonic seizure-like activity characterized by repetitive, involuntary, rhythmic contractions of both hind limbs, accompanied by whole-body contractions involving the trunk and thoracic limbs that lasted around 2 seconds each (Supplementary Video S1). Respiratory muscle function was not apparently affected, as the patient’s respiratory pattern was normal. At this time, the anesthetist assigned to the case mentioned that mild focal contraction of the tail had been noticed soon after the spinal injection, before surgery began. Body temperature during recovery increased from 37.8 °C to 40.5 °C at about 2.5hours after tracheal extubation. Electrolytes and venous blood gas analysis showed mixed acidosis with hypercapnia, hyperlactatemia and hyperkalemia (Table 1).

Case Management and Outcome

Based on clinical signs and history of intrathecal anesthesia, a presumptive diagnosis of morphine-induced spinal myoclonus was made, despite the inability to perform either a full neurologic exam or electrophysiology studies to confirm the spinal origin due to limited finances of the client.

The increase in carbon dioxide, hyperlactatemia, and the resultant acidosis were attributed to the increased muscle activity exhibited by the patient. In cases of acidemia, excess hydrogen ions are buffered into cells, and electroneutrality is maintained in part by the movement of intracellular potassium into the extracellular fluid, resulting in elevation of plasma potassium concentration.

In an attempt to alleviate clinical signs and provide muscle relaxation, a total amount of dexmedetomidine 0.007 mg/kg and midazolam 0.4 mg/kg were titrated IV over a period of about 30 minutes in recovery, however this was unsuccessful. To rule out local anesthetic central nervous system toxicity, intralipid was administered IV at 0.25 mL/kg/min for 60 minutes without resolution of the myoclonic activity. To treat the hyperkalemia, dextrose 50% (400 mg/kg dilute 50:50 with PF sodium chloride 0.9%), and regular insulin (1 IU) were administered IV once. No electrocardiographic changes were noted. Active cooling was instituted once the animal became hyperthermic. Lactated Ringer solution, 60 mL, was administered over 2.5 hours during recovery and oxygen supplementation was provided via facemask at 5 L/min as well.

The patient’s myoclonus only stopped when general anesthesia was induced again with a single IV injection of ketamine and midazolam (dose not recorded on the anesthesia record). The patient was kept intubated and anesthetized overnight in the ICU with isoflurane in 55% oxygen and was mechanically ventilated. No additional ketamine was administered. Plasmalyte with 2.5% dextrose supplementation was infused at 4 mL/kg/h while the patient was anesthetized in ICU. Anesthesia was uneventful, isoflurane was discontinued the next morning and the patient discharged the following day without further complications. Follow-up examination 2 months after discharge was normal.

Comments

In cats, the dural sac can extend caudally as far as the first sacral segment and inadvertent subarachnoid puncture during epidural injection is likely.¹ If this occurs, the intrathecal doses for opioids and local anesthetics have not been established in controlled studies in small animals, and the often recommended 40% to 50% volume reduction of the intended epidural dose might result in higher CSF concentrations than necessary.¹

Spinal myoclonus is characterized by myoclonic activity spreading up and down the spinal cord through propriospinal pathways, and it has been described as a rare adverse effect of epidural or intrathecal administration of morphine in several species, including cats at dosages similar to those reported in this case.^2–5

High doses of morphine seem to be an important risk factor in the causation of spinal myoclonus.^2,3 Although the responsible pharmacological mechanisms have not yet been detected, the inability to block myoclonic seizure-like activity with naloxone after neuraxial morphine strongly implies these actions are not mediated through traditional opioid receptors.^2,3 Moreover, other commonly used opioids such methadone, fentanyl and pethidine did not produce myoclonic activity when injected intrathecally in rats.²

Systemic administration of N-methyl-D-aspartate receptor (NMDAR) antagonists like ketamine attenuates the clonic seizure–like excitatory effects induced by intrathecal morphine in a dose-dependent manner in mice,³ suggesting the implication of NMDARs. Ketamine was also effective at alleviating, but not completely resolving, myoclonus following intrathecal morphine and bupivacaine in a cat.⁴

In this case, despite multiple attempts to treat the myoclonic contractions, myoclonus only ceased after ketamine administration, supporting the theory that NMDARs may play a role in the pathogenesis of morphine-induced spinal myoclonus. Midazolam was also co-administered with ketamine to reinduce general anesthesia in this case. Because midazolam was ineffective at stopping myoclonus when previously administered to this patient, the author believes that ketamine was most likely responsible for the cessation of myoclonus, as previously suggested in other species.³ A ketamine infusion was not started, and the cat was kept under isoflurane anesthesia overnight. The patient did not show any further myoclonic activity and it is possible that isoflurane’s inhibitory effects on NMDA currents contributed to the resolution of clinical signs as well. To the author’s knowledge, this is the third report of spinal myoclonus after spinal injection of morphine and bupivacaine in cats.^4,5

Although the underlying mechanism still remain unknown, excessively high concentration of morphine in the CSF might be implicated, and careful consideration of intrathecal doses for morphine is warranted.

Supplementary Materials

Supplementary materials are posted online at the journal website: avmajournals.avma.org

Disclosures

The authors have nothing to disclose. No AI-assisted technologies were used in the generation of this manuscript.

Funding

The authors have nothing to disclose.