Sweet dreams: Use of low-dose dexmedetomidine for perioperative management of canine insulinoma

Insulinomas are a neuroendocrine tumors of the pancreatic beta islet cells, which compose a large portion of the islets of Langerhans and are responsible for insulin production. Insulinomas lead to overproduction of insulin and disrupt normal glucose homeostasis, leading to chronic hypoglycemia. Insulinoma is the most common pancreatic tumor in dogs, although the overall incidence is low. The tumor is rarely seen in cats.

Patients presenting with insulinomas often show clinical signs associated with severe hypoglycemia, including trembling, weakness, seizures, collapse, stupor, and/or ataxia.¹ These signs are exacerbated by events that trigger a drop in blood glucose (BG), such as fasting, stress, exercise, or excitement.² Blood work in these patients often shows severe hypoglycemia (30-50 mg/dL; normal range, 70-143 mm Hg) and high levels of insulin if a glucose: insulin ratio panel is performed. Because of the chronicity of hypoglycemia in these patients, they often have a higher tolerance for severe hypoglycemia and need less supplementation than acutely hypoglycemic patients.¹ These tumors are usually malignant in dogs, and surgical resection is often necessary for therapeutic management.

Anesthesia challenges

Anesthetic management of these patients can be tricky. Careful assessment of BG changes should be paramount during the perioperative period for insulinoma removal. To avoid insulin surges, BG management during anesthesia should be aimed at keeping changes within 20 to 30 mg/dL of starting values.²

Intraoperative insulin surges can predispose patients to developing hyperglycemia or diabetes in the recovery period. Severe hypoglycemia must be addressed because anesthesia can mask the signs associated with hypoglycemia (seizure, abnormal mentation, coma). Dextrose solutions are a treatment option, but they must be administered slowly and at low concentrations to avoid overcorrection. Glucagon may be administered to raise circulating BG concentrations by increasing the rates of both glycogenolysis and gluconeogenesis in the liver, but it is generally not a cost-effective treatment and results may be variable.³ Prednisone therapy can be initiated prior to surgery to increase BG by stimulating glucagon secretion, decreasing insulin sensitivity, and increasing gluconeogenesis.⁴ According to correspondence with James A. Perry, DVM, PhD, from the University of Pennsylvania College of Veterinary Medicine in Philadelphia, results of a 2015 retrospective study showed that animals receiving prednisone prior to surgery were significantly less likely to develop diabetes following insulinoma removal.

Goals of anesthesia should aim to minimize stress and the associated sympathomimetic increases in circulating blood glucose to prevent an insulin surge that may worsen hypoglycemia. Anesthetic drugs that have similar effects, such as ketamine, may also need to be avoided.² This can pose a difficult challenge in otherwise healthy patients that require more than an opioid or midazolam to facilitate catheterization and safe induction.

So, what other safe options are available? A 2013 study investigated the effect of medetomidine on plasma glucose and insulin levels in dogs with insulinomas and healthy dogs. The study showed that preanesthetic administration of medetomidine significantly suppressed insulin secretion and increased plasma glucose concentration in dogs with insulinomas.⁵

Case report

Enter Biscuit, a 13-year-old, neutered terrier mix. This feisty dog was diagnosed with an insulinoma in December 2019, but because of owner finances and COVID-19 was unable to have a partial pancreatectomy until July 2020. Biscuit presented to his primary care veterinarian for routine dental care and on preoperative bloodwork was noted to have a BG of 41 mg/dL. His preoperative diagnostics were otherwise unremarkable, and he had no clinical signs of hypoglycemia at the time of the appointment. The dental procedure was postponed after verifying the results throughout the day and confirming persistent hypoglycemia. A glucose: insulin panel was submitted with results suggestive of insulinoma (Figure 1). An abdominal ultrasound a few months later confirmed the presence of a pancreatic tumor, and surgery was scheduled.

Figure 1. Results of Biscuit’s glucose: insulin panel were suggestive of insulinoma. (All images are courtesy of the author)

Biscuit was a finicky eater, so feeding several small meals a day was difficult for the owner. Ideal fasting times for patients with insulinoma are 6 to 8 hours. The owner was also unable to give a small meal after midnight, so the fasting time for this patient was longer than ideal. On presentation the morning of surgery, Biscuit’s bloodwork showed a BG of 38 mg/dL and lactate level of 4.3 mmol/L, but no other abnormalities or clinical signs of hypoglycemia were noted. With a severely low glucose level, it is reasonable to think that dextrose should be administered prior to anesthesia to provide a higher starting glucose level. However, this may prove deleterious because a bolus or high dose of dextrose intravenously (IV) may precipitate an insulin surge and worsen hypoglycemia.

Gastrointestinal (GI) issues and pancreatitis are also common postoperative complications of partial pancreatectomy, so premedications should aim to minimize GI adverse effects and ease return to spontaneous feeding. Biscuit was a nervous dog, and premedication with an opioid, either alone or with a benzodiazepine, was unlikely to facilitate low-stress catheter placement and induction. Therefore, Biscuit was premedicated with 1 mg/kg maropitant subcutaneously (SC), 1 µg/kg of dexmedetomidine intramuscularly (IM), and 0.3 mg/kg butorphanol IM. This allowed stress-free placement of an IV catheter, connection to monitors, and easy preoxygenation.

The anesthetic protocol

Biscuit was induced with a midazolam and propofol to reduce sympathomimetic increases in BG, decrease cerebral metabolic oxygen consumption, and reduce glucose utilization. He was maintained on isoflurane in 100% oxygen. BG measured immediately after induction showed only a slight increase to 69 mg/dL. Loading doses of lidocaine and fentanyl at 1 mg/kg and 5 µg/kg, respectively, were administered, and a constant-rate infusion (CRI)with fentanyl (7.5 µg/kg/hr), lidocaine (25 µg/kg/min), and dexmedetomidine (0.5 µg/kg/hr) was initiated.

Figure 2. During surgery there were no signs of hypertension, and cardiac output was adequate.

Figure 3. Standard glucometer for serial blood glucose monitoring.

At higher doses, dexmedetomidine causes significant vasoconstriction and bradycardia in most patients. However, at lower rates (0.5-1 µg/kg/hr), hypertension and reflex bradycardia are often minimized, as occurred with Biscuit (Figure 2). An arterial catheter was placed to allow invasive blood pressure monitoring and serial blood glucose sampling. BG measurements were obtained every 30 minutes during surgery and every hour postoperatively via glucometer (Figure 3). Changes in BG were as follows:

• 58 mg/dL 30 min after initiation of CRI
• 81 mg/dL 1 hour after initiation of CRI
• 120 mg/dL 1.5 hours after initiation of CRI
• 183 mg/dL 2.5 hours after initiation of CRI, immediately before discontinuing CRI
• 220 mg/dL 2.5 hours after discontinuing CRI
• 130 mg/dL 3.5 hours after discontinuing CRI
• 112 mg/dL 8.5 hours after discontinuing CRI
• 139 mg/dL 14.5 hours after discontinuing CRI

Surgical outcome and recovery

Surgery and anesthesia were uneventful. Biscuit was placed on a ventilator due to hypercapnia (end-tidal carbon dioxide, 52 mm Hg) and had mild hypothermia intraoperatively (lowest temperature 95.3 ˚F). The tumor was visualized and extended to the head of the pancreas (Figure 4). A partial pancreatectomy and abdominal exploratory procedure were performed. The dexmedetomidine/fentanyl/lidocaine CRI was decreased while the surgeon was closing the abdomen and discontinued postoperatively, after which Biscuit received 0.03 mg/kg buprenorphine IV and was maintained on a lidocaine CRI for continued analgesia. For prophylactic GI support, 0.4 mg/kg metoclopramide SC and 1 mg/kg pantoprazole IV were administered in recovery. The goal was to minimize GI adverse effects and prevent breakthrough pain that may cause stress-related increases in BG.

Figure 4. The insulinoma extended to the head of the pancreas.

Postoperative nursing care in these patients is crucial, because some patients may have refractory hyperglycemia or even become transiently diabetic after insulinoma removal, necessitating exogenous insulin supplementation. In this case, the use of low-dose dexmedetomidine may have prevented the need for hypoglycemia treatment with a dextrose CRI, and the resulting insulin surge and refractory hypoglycemia. By decreasing plasma insulin level with dexmedetomidine, Biscuit’s blood glucose levels remained within an ideal therapeutic range in the peri- and postoperative periods. Biscuit’s stress level and pain were well controlled throughout the process and, with the help of a single dose of capromorelin oral solution (Entyce; Elanco), he returned to spontaneous feeding the next day and was able to go home on oral medications. Since surgery, Biscuit’s recovery has been uneventful with no signs of hypoglycemia, hyperglycemia, or pancreatitis. Recent bloodwork showed a return to normal glucose (BG 89 mg/dL), with no other abnormalities noted at his recheck exam. He will continue to be monitored every 2 to 3 months for signs of metastatic disease.

Conclusion

Insulinoma cases present unique challenges in anesthetic management and glucose homeostasis. Biscuit was one of several cases in which the use of low-dose dexmedetomidine has proven to be a useful tool in the perioperative management of canine insulinomas. More research is needed to discover all the effects of dexmedetomidine as an adjunct in the management of insulinoma cases, but so far it has a promising start.

References

1. Adams JG, Figueiredo JP, Graves TK. Physiology, pathophysiology, and anesthetic management of patients with gastrointestinal and endocrine disease. In: Grimm KA, Lamont LA, Tranquilli WJ, Greene SA, Robertson SA, eds. Lumb and Jones’ Veterinary Anesthesia and Analgesia, 5th ed. Wiley-Blackwell; 2015:645-647.
2. Mama K. Ask the expert: anesthesia for pancreatic disease. Clin Brief. 2013;June:91-94.
3. Goswami J, Somkuwar P, Naik Y. Insulinoma and anaesthetic implications. Indian J Anaesth. 2012;56(2):117-122. doi:10.4103/0019-5049.96301
4. Grant ER, Burgess KE. Canine insulinoma: diagnosis, treatment, & staging. Today’s Vet Pract. 2016;6(6):60-64.
5. Guedes AGP, Rude EP. Effects of pre-operative administration of medetomidine on plasma insulin and glucose concentrations in healthy dogs with insulinoma. Vet Anaesth Analg. 2013;40(5):472-481. doi:10.1111/vaa.12047