History

A 1.5-year-old castrated male ferret was evaluated because of a 6-week history of melena, bruxism, and decreased appetite. A CBC was performed by the referring veterinarian, and results were unremarkable. Hyperproteinemia (11.8 g/dL) was found on serum biochemical analysis, but no other abnormalities were noted. Results of a PCR assay for influenza virus were negative. The ferret was empirically treated with amoxicillin-clavulanate, metronidazole, sucralfate, chloramphenicol, buprenorphine, and prednisolone. There was no improvement in response to treatment, so the patient was referred to the Zoological Medicine Service at the University of Georgia.

On initial evaluation, the ferret was quiet, alert, and responsive with a body condition of 3 on a scale from 1 to 5 and a body weight of 1.2 kg (2.64 lb). Rectal temperature was 37.5°C (99.6°F; reference range,^1,2 37.8° to 40°C [100° to 104°F]). The femoral pulses were strong and synchronous, with a rate of 210 beats/min. Results of cardiothoracic auscultation were unremarkable. Abdominal palpation revealed cranial abdominal organomegaly.

Abdominal ultrasonography was performed, and a mass adjacent to the portal vein was found in the mid-cranial portion of the abdomen. The gastric, colic, and jejunal lymph nodes were moderately enlarged. Cytologic examination of a fine-needle aspirate of the cranial abdominal mass revealed a population of malignant cells of unknown origin. Examination of an aspirate from the jejunal lymph nodes revealed a similar population of malignant cells, consistent with metastatic neoplasia.

Two days later, an exploratory laparotomy for biopsy and potential surgical mass removal was planned. Results of a serum biochemical profile, including measurement of electrolyte concentrations,^a were unremarkable. On preanesthetic evaluation, the patient was dehydrated and appeared lethargic. Heart and lung sounds were normal. The ferret was assigned an American Society of Anesthesiologists status of III because of dehydration and the presence of malignant neoplasia. The patient was premedicated with oxymorphone (0.1 mg/kg [0.045 mg/lb], IM) and midazolam (0.2 mg/kg [0.09 mg/lb], IM), which resulted in profound sedation. A 22-gauge catheter was placed in the left cephalic vein. An ultrasonic Doppler probe was positioned over the metatarsal artery, and a size 2 cuff was placed proximal to the probe to allow for indirect blood pressure monitoring. Anesthesia was induced 20 minutes following premedication with propofol administered to effect (4 mg/kg [1.8 mg/lb], IV). A 3-mm cuffed endotracheal tube was inserted in the trachea by means of direct visualization of the larynx. Anesthesia was then maintained with isoflurane administered in oxygen (1 L/min) with a Mapleson F (nonrebreathing) system. To monitor heart rhythm, ECG leads were placed. A second 22-gauge IV catheter was placed in the right cephalic vein. A lumbosacral epidural injection of preservative-free morphine (0.1 mg/kg; total volume, 0.15 mL) was administered to provide additional analgesia. The ventral aspect of the abdomen was clipped of hair and prepared for surgery. Ten minutes after anesthetic induction, a precipitous decrease in heart rate was observed (from 200 to 90 beats/min) and atropine (0.02 mg/kg [0.009 mg/lb], IV) was administered. After 20 minutes of inhalation anesthesia, the ferret became hypotensive and a dopamine infusion was started (5 μg/kg/min [2.27 μg/lb/min], IV). Additionally, a fentanyl infusion (5 μg/kg/h, IV) was instituted to allow the inhalation anesthetic requirement to be reduced.

Thirty minutes after anesthetic induction, the ferret was transferred to the operating theater. At this time, the patient was connected to a circle circuit with a time-cycled volume ventilator designed for animals with a body weight < 7 kg (15.4 lb; Figure 1).^b Temperature and ECG were monitored with a multiparameter monitor.^c A separate monitor⁴ was used to record Petco₂, oxygen saturation (measured via pulse oximetry), and inspiratory and expiratory isoflurane concentrations. End-tidal isoflurane concentration was maintained between 0.5% and 1.0% for approximately 50 minutes following transport to the operating room.

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Photograph of an anesthesia workstation used to provide inhalation anesthesia and intermittent positive-pressure ventilation in a 1.5-year-old castrated male ferret evaluated because of a 6-week history of melena, bruxism, and decreased appetite.

Citation: Journal of the American Veterinary Medical Association 241, 12; 10.2460/javma.241.12.1577

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Surgery began 15 minutes after the ferret was transported to the operating theater. Fifty-five minutes after anesthetic induction (10 minutes after surgery began), the Petco₂ increased from 28 to 66 mm Hg. In response to the hypercarbia, the minute ventilation was increased by increasing the tidal volume, which resulted in an accompanying increase in peak inspiratory pressure to 15 cm H₂O. An abrupt increase in temperature from 39° to 39.5°C (102.3° to 103.1°F) occurred within 5 minutes after the increase in Petco₂ was identified. The room temperature was decreased, and all sources of external heat (recirculating hot water pad^e and forced warm air blanket^f) were discontinued. The Petco₂ did not respond to the increased ventilation and peaked at 70 mm Hg. The temperature continued to increase over the next 10 minutes and reached a maximum of 40.7°C (105.3°F). In addition, blood pressure (measured indirectly) increased from approximately 80 to 140 mm Hg.

Question

What are the likely causes of the hyperthermia and hypercarbia in this ferret?

Answer

Possible causes for the concurrent hyperthermia and hypercarbia in this case include malignant hyperthermia, decreased heat loss (ie, heat stroke),³ tumor manipulation (ie, pheochromocytoma),⁴ and equipment failure,⁵ such as a malfunctioning thermometer or faulty inspiratory 1-way valve.

Initially, the hyperthermia was thought to be due to excessive warming from the forced warm air blanket^f and circulating hot water blanket.^e However, despite discontinuation of all exogenous heat sources and a decrease in ambient temperature to 15.6°C (60°F), the ferret's temperature continued to increase, making overzealous patient warming unlikely.

Because the Petco₂ continued to increase, a hypermetabolic condition, such as malignant hyperthermia, was considered, despite the lack of reports of malignant hyperthermia in ferrets. Inhalation anesthetic administration was discontinued, and anesthesia was maintained by means of a total IV anesthetic protocol. At this time, hypercarbia and hyperthermia secondary to tumor manipulation could not be ruled out.

Three days following this anesthetic episode, a small 6-week-old puppy with a vascular ring anomaly was anesthetized with the same circle anesthetic system. In addition to inhalation anesthesia, a fentanyl infusion (10 μg/kg/h [4.55 μg/lb/h], IV) was administered to the puppy. After the puppy was transported to the operating theater, a high inspired Pco₂ and elevated capnogram baseline were noted. Causes of the high inspired Pco₂ that were considered included excessive dead space (eg, an overly long endotracheal tube), exhaustion of the CO₂ (soda lime) absorbent, or 1-way valve malfunction. The endotracheal tube was cut to shorten the tube and decrease the dead space. However, the high inspired Pco₂ persisted. Also during this time, the patient became hyperthermic and hypercarbic. The circle circuit was replaced with a Mapleson F (nonrebreathing) system (Ayres T piece with Jackson Rees modification). The circle circuit was then examined, and a faulty 1-way valve (Figure 2) was found on the inspiratory limb of the circle circuit.

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Photograph of the unidirectional valves on the anesthesia workstation in Figure 1. The inspiratory 1-way valve on the right was determined to be stuck in the open position when excessive moisture developed in the system.

Citation: Journal of the American Veterinary Medical Association 241, 12; 10.2460/javma.241.12.1577

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Following identification of the faulty 1-way valve, the hypercarbia and hyperthermia that had developed in the ferret anesthetized with the same anesthesia system 3 days earlier were considered to most likely also be a result of this faulty valve. We believe that the 1-way valve was functioning normally for the first 20 minutes in the operating room but became stuck in the open position when excessive moisture developed in the system. When this valve becomes stuck in the open position, expired CO₂ enters the inspiratory limb of the circuit and is rebreathed during subsequent breaths. The circuit then effectively acts as a to-and-fro circuit, and the most common complication of to-and-fro systems is hyperthermia.⁶

Outcome

Active cooling was initiated by applying ice packs to the fluid line and breathing circuit. The ambient temperature was decreased to approximately 15.6°C. In addition, isoflurane administration was discontinued and the patient was transitioned to a propofol CRI (0.3 mg/kg/h [0.14 mg/lb/h], IV). The rate of the fentanyl CRI was increased from 5 to 10 μg/kg/h (2.27 to 4.55 μg/lb/h). The patient was disconnected from the circle circuit and connected to a nonrebreathing system. Manual ventilation at approximately 40 breaths/min was commenced. The Petco₂ decreased from 70 to approximately 40 mm Hg over a 20-minute time period, and the temperature decreased to 38.7°C (101.6°F). Following closure of the abdominal cavity, the propofol CRI was discontinued and the fentanyl administration rate was decreased to 3 μg/kg/h.

The ferret recovered well from anesthesia, with a rectal temperature of 38.7°C, and was transferred to the intensive care unit. The rectal temperature continued to remain normal for the duration of hospitalization. Postoperative treatments included orbofloxacin, sucralfate, famotidine, and lactated Ringer's solution. Two days after surgery, vomiting and bruxism were noted, and ultrasonography revealed free abdominal fluid. Results of cytologic examination of the fluid were consistent with a nonseptic purulent exudate. Antimicrobial treatment was changed from orbofloxacin to enrofloxacin and metronidazole. The ferret's condition continued to worsen, and 7 days after surgery, the patient was euthanized. Necropsy revealed septic peritonitis secondary to gastric suture line failure. In addition, multiple pyogranulomatous lesions consistent with ferret coronavirus infection were found throughout the peritoneal cavity.

Discussion

Causes of hypercarbia during general anesthesia include pulmonary parenchymal or pleural space disease, thoracic or abdominal restrictive disease, inappropriate ventilator settings, hypermetabolic states,⁷ neoplasia,⁴ exhaustion of the CO₂ absorbent (eg, soda lime canister),⁵ and equipment failure.⁵ The ferret of this report had no evidence of pulmonary or pleural space disease. In addition, abdominal and thoracic restrictive disease was not found on necropsy. The initially set minute ventilation maintained a normal Petco₂ for 20 minutes; therefore, the initial settings appeared appropriate.

Pheochromocytoma has been found to cause acute profound hyperthermia and hypercarbia in people. The clinical findings are similar to those seen with malignant hyperthermia. However, no muscle rigidity is seen with pheochromocytoma.⁴ To our knowledge, there are no published reports of a pheochromocytoma causing hyperthermia or hypercarbia in ferrets, and necropsy of the ferret did not reveal any neoplastic processes. The abdominal masses that precipitated the exploratory laparotomy were granulomas consistent with ferret coronavirus infection, and there are no reports of coronavirus inducing a malignant hyperthermia–like syndrome in ferrets. Additionally, the same clinical signs of hyperthermia and hypercarbia were noted in a 6-week-old puppy with a vascular ring anomaly anesthetized with the same anesthesia system 3 days later.

Exhausted soda lime canisters and faulty 1-way valves are common machine-related causes of hypercarbia. In both instances, expired CO₂ is rebreathed.⁵ On further examination of the anesthetic circuit, a faulty inspiratory 1-way valve stuck in the open position was found. Severe hypercarbia following inspiratory valve malfunction has been reported in dogs and horses.^8,9 With a malfunctioning inspiratory valve, expired CO₂ is allowed to enter the inspiratory limb of the circuit, so that CO₂ is rebreathed.⁸ Because there is some degree of rebreathing of CO₂, an elevation of the capnogram baseline and inspired Pco₂ should be evident.⁷ The 1-way valve failure was the most likely cause of the severe hypercarbia seen in this ferret. The machine was leak- and function-tested thoroughly prior to use. The hypercarbia and hyperthermia did not develop until the patient had been connected to the circle circuit for 20 minutes, during which time the system appeared to be functioning appropriately. However, condensation likely developed within the valve, causing the valve to stick in the open position.

The hyperthermia in this case was also suspected to be secondary to the malfunctioning inspiratory 1-way valve. High temperatures have been measured in soda lime canisters during absorption of CO₂. The temperature increase within the canister is secondary to the chemical reaction that occurs when CO₂ reacts with soda lime.^9,10 Temperatures as high as 40°C in circle systems have been reported.¹⁰ Owing to the close proximity of the inspiratory limb to the soda lime canister, it is reasonable to believe that the hyperthermia in this case was secondary to the malfunctioning 1-way valve. Furthermore, given the arrangement of the circuit, the failure of the valve may have caused the circuit to function similar to a to-and-fro system. A reported disadvantage of the to-and-fro system is hyperthermia, secondary to the close proximity of the soda lime canister to the patient.^9,11

Malignant hyperthermia, a muscular disorder, can cause hyperthermia and hypercarbia. Malignant hyperthermia is caused by a mutation of the RYR1 gene. This gene is responsible for causing calcium release into the skeletal muscle. The mutation causes altered skeletal muscle calcium metabolism and is the cause of the hypermetabolic state seen with malignant hyperthermia.¹² Because this syndrome may be triggered by inhalation anesthetics and depolarizing neuromuscular blocking agents, immediate treatment involves discontinuation of the triggering agent.^12,13 Additionally, a new, unused circuit or bag valve mask should be used to deliver 100% oxygen. If a new, unused circuit is unavailable, the machine should be flushed with 100% O₂ in an attempt to remove any volatile anesthetic from the circuit. In this case, isoflurane administration was discontinued and a Mapleson F circuit was used to deliver oxygen. Anesthesia was then maintained via infusions of propofol and fentanyl. Specific treatment of malignant hyperthermia involves administering dantrolene, a drug that prevents calcium release and has skeletal muscle relaxant properties.¹³ Most muscle relaxants work centrally or at the neuromuscular junction; however, dantrolene is unique in that it works directly on the muscle. This drug prevents calcium ion flux across the sarcoplasmic reticulum and leads to calcium ion sequestration within the sarcoplasmic reticulum. This leads to excitation-contraction uncoupling within the muscle fibers.¹⁴ Because clinical signs of malignant hyperthermia can be nonspecific, diagnosis relies on identifying consistent clinical signs and ruling out other potential causes of the clinical signs.¹² In the ferret of the present report, other causes of hypercarbia and hyperthermia could not be eliminated, and there are no published reports of malignant hyperthermia in ferrets. Also, malignant hyperthermia often causes a precipitous increase in temperature, which can rapidly reach 42.2° to 42.8°C (108° to 109°F), and the temperature increases in both cases in the present report were not as rapid or as extreme as would be expected with malignant hyperthermia. Finally, arrhythmias are common clinical signs of malignant hyperthermia¹² but were not seen in either the ferret or the puppy of this report.

Opioid administration has been shown to cause hyperthermia in cats.^15,16 However, fentanyl was considered to be an unlikely cause of the hyperthermia in the ferret or puppy of this report, and to the authors' knowledge, there are no reports of opioids causing hyperthermia in ferrets or dogs. In addition, studies of pure μ-opioid receptor agonists in cats have found that the hyperthermia associated with these agents is mild to moderate (< 40.5°C [104.9°F]) and self-limiting.¹⁵ The ferret of this report had a peak temperature of 40.7°C. Cats that become hyperthermic secondary to opioid administration tend to become hyperthermic after surgery, and higher postoperative temperatures are associated with lower intraoperative temperatures.¹⁶ The ferret of this report was hyperthermic intraoperatively and was never hypothermic, making opioid-induced hyperthermia unlikely.

Clinically important complications can arise in anesthetized patients secondary to equipment failure. In human medicine, equipment failure is associated with negative outcomes in a reasonable number of patients.¹⁷ Thorough inspection of anesthesia equipment prior to use is important for patient safety and a positive outcome. Although inspection prior to use is important, equipment problems may develop during the course of the anesthetic event. Monitoring the anesthetic circuit during each anesthetic event may help reduce or eliminate equipment-related anesthetic complications.