History

A 9.5-year-old 20.4-kg spayed female Border Collie was referred to the oncology service of Washington State University Veterinary Teaching Hospital for evaluation of a right anal gland mass and hypercalcemia. The referring veterinarian had evaluated the dog 3 weeks earlier for a 1- to 2-year history of alopecia, polydipsia, polyuria, and polyphagia; noticed a right anal gland mass; and then performed a CBC, serum biochemical analyses, serum thyroid and parathyroid panels, and abdominal ultrasonography. The CBC and thyroid panel results were within reference limits; however, the biochemical analyses revealed mildly high serum alanine aminotransferase (141 U/L; reference range, 18 to 121 U/L) and creatine kinase (478 U/L; reference range, 10 to 200 U/L) activities, hypercholesterolemia (455 mg/dL; reference range, 131 to 345 mg/dL), and hypercalcemia (total calcium, 13.7 mg/dL; reference range, 8.8 to 11.2 mg/dL; ionized calcium, 1.94 mmol/L; reference range, 1.25 to 1.45 mmol/L). The serum parathyroid hormone concentration was 5.80 pmol/L (reference range, 0.50 to 5.80 pmol/L) and parathyroid hormone–related protein concentration was 0.0 pmol/L (reference range, 0.0 to 1.0 pmol/L). Abdominal ultrasonography revealed an enlarged right iliac lymph node, and cytologic examination of aspirate samples obtained from it revealed epithelial neoplasia, presumed metastatic. The dog was treated for hypercalcemia with IV administration of 30 mg of pamidronate in 1 L of saline (0.9% NaCl) solution and then referred.

On referral examination, the dog was bright, alert, and responsive and had a body condition score of 5 (on a scale from 1 to 5, with 3 considered clinically normal). The dog was panting and had moist and pink mucous membranes, a capillary refill time of < 2 seconds, rectal temperature of 38.6 °C (reference range, 37.8 to 39.2 °C), and heart rate of 110 beats/min (reference range, 60 to 140 beats/min). Thoracic auscultation revealed no abnormal lung sounds but a grade 3/6 heart murmur with the point of maximum intensity at the left apex. Mandibular lymph nodes were enlarged, and the remaining lymph nodes palpated were soft, symmetric, and clinically normal in size. Abdominal palpation and ambulation were unremarkable. Transrectal palpation revealed a small nodule on the right anal sac. The dog’s coat was dry and thin.

Results of a CBC were within reference limits, whereas serum biochemical analyses revealed mildly high serum alanine aminotransferase (162 U/L; reference limit < 113 U/L) and alkaline phosphatase (164 U/L; reference range, 4 to 113 U/L) activities, hypercholesterolemia (456 mg/dL; reference range, 134 to 359 mg/dL), and hypercalcemia (total calcium, 14.2 mg/dL; reference range, 9 to 11.3 mg/dL). Thoracic and abdominal CT revealed 2 small soft tissue–attenuating nodules in the lungs, marked sublumbar lymphadenopathy, a soft tissue–attenuating and contrast-enhancing nodule (approx 6 mm in diameter) in the dorsal aspect of the right anal sac, a hypoattenuating and contrast-enhancing nodule (approx 3 mm wide × 1.5 cm tall) in the left ventral aspect of the liver, enlarged and rounded right medial iliac (4.5 × 4 × 5-cm) and sacral (2.1 × 1.7 × 4-cm) lymph nodes, and calculi and sediment in the urinary bladder. Ultrasonography of the thyroid gland, parathyroid glands, and liver revealed an enlarged left cranial parathyroid gland (4 mm wide × 5 mm tall) and a solitary hyperechoic liver nodule. Cytologic examination of ultrasound-guided fine-needle aspirate samples of the liver nodule revealed marked hepatic vacuolar degeneration. The owner opted for surgical removal of the right medial iliac and hypogastric lymph nodes (to remove lymph nodes with metastatic disease), partial right medial liver lobectomy (to remove the liver nodule), cystotomy (to remove uroliths), and right anal sacculectomy (to remove anal sac adenocarcinoma), with later ethanol ablation of the parathyroid gland. Surgery was scheduled for the following day.

On the day of surgery, the dog was bright and alert and had vital signs within reference limits, with findings on physical examination unchanged from the previous day. The dog had a clinically normal hydration status (as assessed by skin turgor, moistness of mucous membranes, and capillary refill time), prothrombin time and partial thromboplastin time within reference limits, PCV of 50% (reference range, 36% to 56%), and plasma total solids concentration of 8.8 g/dL (reference range, 5.5 to 7.5 g/dL) and was assigned an American Society of Anesthesiologists status of II on the basis of the underlying disease process. Blood typing and cross matching were performed, and the dog was premedicated with dexmedetomidine (0.005 mg/kg, IM) and morphine (0.25 mg/kg, IM). About 20 minutes later, an 18-gauge, 1.8-inch-long IV catheter was placed in the left cephalic vein and a 20-gauge, 1.13-inch-long IV catheter was placed in the right cephalic vein. Lead II ECG was used for assessment of heart rhythm, and a size 3 cuff placed around the right forelimb was used for oscillometric blood pressure measurement via a multiparameter monitor (DPM 6; Mindray DS). The dog was preoxygenated with 100% O₂ delivered by face mask for 5 minutes. Thirty-five minutes after premedication, anesthesia was induced with propofol (1.5 mg/kg, IV, to effect), intubation was achieved with the use of a laryngoscope for direct visualization of the glottis and placement of a 10-mm-internal-diameter cuffed endotracheal tube, and the free end of the endotracheal tube was connected to a previously leak-tested anesthesia machine with a circle breathing system that allowed partial rebreathing of inhaled gases. The cuff of the endotracheal tube was inflated to achieve an effective seal with tracheal mucosa so that no leak was detected when the anesthesia circuit was pressurized to 20 cm H₂O. Anesthesia was maintained with sevoflurane delivered in O₂ (3 L/min), and fluid therapy with physiologic saline solution (10 mL/kg/h, IV) was initiated. A lumbosacral epidural injection of preservative-free morphine (0.1 mg/kg) and ropivacaine (0.5 mg/kg) for a total volume of approximately 0.2 mL/kg was administered through a 20-gauge, 2.5-inch-long spinal needle. While the surgical sites were being prepared, a 22-gauge catheter was placed in the right dorsal pedal artery for direct blood pressure monitoring and intermittent arterial blood gas analysis intraoperatively.

The dog was moved to the surgery suite, positioned on the surgery table in dorsal recumbency, and equipped for anesthetic monitoring. A transducer (Transpac IV; Hospira Inc) to measure direct blood pressure was positioned at the level of the right atrium and zeroed to the atmospheric pressure before arterial blood pressure was measured. The dog was connected to a mechanical ventilator (Veterinary Anesthesia Ventilator Model 2000; Hallowell EMC), and tidal volume and rate were adjusted on the basis of the end-tidal CO₂ concentration.

The total duration of anesthesia was 5 hours and 40 minutes. Approximately 15 minutes after the start of surgery, the dog’s heart rate and blood pressure started to increase and kept increasing slowly for about 10 minutes. These changes were attributed to surgical stimulation; thus, fentanyl (2.5 µg/kg bolus followed by 0.3 μg/kg/min constant rate infusion) was administered. The first arterial blood gas analysis (Epocal Inc) was performed approximately 20 minutes after anesthetic induction and revealed moderate hyperlactatemia (6.29 mmol/L; Table 1). The mean arterial blood pressure (MAP) at that time was 83 mm Hg (MAP < 60 mm Hg considered hypotension). Six arterial blood samples were analyzed intraoperatively at approximately 1-hour intervals, and each showed mild to moderate hyperlactatemia (4.67 to 6.29 mmol/L). The dog was not hypotensive but had intraoperative MAPs between 65 and 105 mm Hg. After the third arterial blood gas analyses and to improve any perfusion deficits that might have been causing hyperlactatemia, a synthetic colloid (VetStarch; 100 mL; 5 mL/kg) bolus followed by glycopyrrolate (0.1 mg; 0.005 mg/kg) were administered IV. The MAP and heart rate increased by 20 mm Hg and 15 beats/min, respectively, over the next 15 minutes. Subsequent arterial blood sample evaluations revealed reduced lactate concentrations.

After surgery, the dog recovered uneventfully in the small animal intensive care unit and received fentanyl (3 μg/kg/h, IV) and isotonic crystalloid fluids (Plasma-Lyte 148 injection; 3.7 mL/kg/h [1.5 times the maintenance requirement]). The dog’s venous blood lactate concentration (Lactate Plus; Nova Biomedical) was 3.4 mmol/L at 20 minutes and 2.4 mmol/L (clinically normal) at 6 hours and 20 minutes after the final intraoperative blood sample assessment. No further lactate measurements were performed.

Question

What likely caused hyperlactatemia in this dog?

Answer

The most likely cause of hyperlactatemia in this dog was neoplastic disease.

Discussion

The dog of the present report had mild to moderate hyperlactatemia intraoperatively. Type A (vs type B) hyperlactatemia is a common reason for increased blood lactate concentration in anesthetized patients due to dose-dependent effects of anesthetics on cardiac output and systemic vascular resistance, characterized by decreased delivery of O₂ (Do₂) to tissues.¹ The main causes of decreased Do₂ and thus type A hyperlactatemia are low arterial O₂ content (Cao₂), hypoperfusion, and hypotension, alone or in combination. The Cao₂ is the sum of O₂ bound to hemoglobin (Hb) and O₂ dissolved in plasma and is calculated from the Hb content, arterial O₂ saturation of Hb (Sao₂), and arterial partial pressure of O₂ (Pao₂), as follows: (Hb content × 1.34 × Sao₂) + (Pao₂ × 0.003).² The Do₂ is then calculated by multiplying the Cao₂ by cardiac output.² The intraoperative Cao₂ for this dog varied from 16.01 to 19.75 mL/dL (reference range,² 15.5 to 20.1 mL/dL) and thus did not seem to contribute to this dog’s hyperlactatemia.

In addition, physiologic saline solution was used as a crystalloid fluid to maintain organ perfusion in this dog intraoperatively because high Na⁺ content promotes calciuresis by competitively inhibiting Ca²⁺ reabsorption in the renal tubules, and this solution is thus the fluid of choice in hypercalcemic patients.³ Dogs with anal sac adenocarcinoma may have hypercalcemia^4,5; however, in the dog of the present report, hypercalcemia was attributed to primary hyperparathyroidism on the basis of findings from ultrasonography of the parathyroid gland, circulating parathyroid hormone concentration at the upper limit of the reference range in the face of hypercalcemia, and a circulating parathyroid hormone–related protein concentration of 0 pmol/L. Patients with hypercalcemia sometimes have dehydration due to polyuria. The dog in the present report had polyuria and polydipsia but also had unrestricted access to water up until the time of premedication for surgery. Although no evidence of dehydration was noticed on physical examination, the slightly high plasma total protein concentration before surgery could have been due to preexisting volume deficit. Furthermore, although cardiac output was not measured directly, measurements of the dog’s MAP did not indicate hypotension. Still, to rule out any occult hypoperfusion, a bolus of synthetic colloid solution and a muscarinic receptor antagonist (glycopyrrolate) were used to increase preload and heart rate, respectively, and further improve cardiac output and tissue perfusion. The resultant increase in cardiac output was observed as increased MAP for this dog. We used a synthetic colloid for the bolus because colloids have been shown to be more efficacious than crystalloids to improve perfusion in dogs during inhalation anesthesia.^6,7 Despite this increase in perfusion, no clinically meaningful decrease in blood lactate concentration was noticed, a finding that indicated hyperlactatemia in this dog was not due to hypoperfusion.

Type B hyperlactatemia occurs due to various etiologies, such as neoplastic disease, acute hepatic disease, chronic renal disease, hyperthyroidism, diabetes mellitus, sepsis, alkalosis, and various drugs or toxins,⁸ many of which were ruled out on the basis of findings from the dog’s history, physical examination, and preoperative blood work. Mildly high activities of alanine aminotransferase and alkaline phosphatase and the presence of 1 small nodule in the liver parenchyma made it difficult to conclude that hepatic clearance of lactate was altered in this dog. Although hypercalcemia can cause renal dysfunction, no such evidence was found in this dog based on serum biochemical analyses. However, malignant cells exhibit the Warburg effect, or aerobic glycolysis characterized by altered carbohydrate metabolism in which glucose is converted to lactate rather than being processed through oxidative phosphorylation even in the presence of O₂,⁹ and this high rate of glycolysis can result in hyperlactatemia in patients with neoplastic diseases. In human medicine, hyperlactatemia has been documented in people with hematopoietic tumors,^10–13 but evidence in veterinary medicine is lacking.^14–16 A retrospective study of dogs¹⁴ with lymphoma identified clinically relevant hyperlactatemia (> 2.5 mmol/L) in 40% (20/50) of the dogs, but only 10% (5/50) of the dogs had hyperlactatemia solely ascribed to their tumor pathology. The mean circulating lactate concentration for these 5 dogs was 3.8 mmol/L (range, 2.7 to 5.7 mmol/L). A prospective study¹⁵ looked at 37 dogs with neoplasia (15 with solid tumors and 22 with hematopoietic neoplasia) but failed to demonstrate clinically relevant hyperlactatemia (> 2.5 mmol/L) in either group, and there was no difference between groups. Although tumor type was reported (1 dog had anal sac adenocarcinoma),¹⁵ the extent of metastasis or size of solid tumors was not. The authors of these studies^14,15 concluded that clinically substantial hyperlactatemia in dogs may be uncommon or appreciated only in complicated neoplastic cases that might also have impaired lactate clearance. Another retrospective study¹⁶ of dogs revealed higher circulating lactate concentrations in dogs with intracranial neoplasia (meningiomas), compared with dogs with intervertebral disease. Furthermore, steroid administration could influence dogs’ lactate concentrations.^17,18

The dog of the present report had anal sac apocrine adenocarcinoma histologically diagnosed, metastases to abdominal lymph nodes histologically confirmed, and suspected metastatic origin for the 2 pulmonary nodules. The liver nodule was diagnosed as chronic, multifocal hepatocellular degeneration. The dog’s neoplastic load was considered sufficient to have led to the moderate hyperlactatemia evident on the first intraoperative arterial blood sample analyses. This was further supported by the observation that the blood lactate concentration returned to a clinically normal value (at 2.4 mmol/L) within approximately 6 hours of completion of surgery.

Clinically, blood lactate concentration is used commonly as an index of microvascular perfusion, and fluid therapy is often the key to improve perfusion; however, findings for the dog of the present report illustrated the importance of type B hyperlactatemia in dogs with neoplastic disease undergoing anesthesia. It is important for anesthetists to consider other causes of hyperlactatemia, especially if indices of Do₂ are clinically normal, to avoid unnecessary use of fluids that could cause fluid overload, particularly in patients with cardiac or renal disease. Additionally, on the basis of observations of the dog of the present report, it would be desirable to evaluate a preoperative blood lactate concentration as part of the diagnostic workup in patients with clinically substantial neoplastic disease to rule out the presence of type B hyperlactatemia in dogs that need general anesthesia for various surgical or diagnostic interventions to help differentiate it from type A hyperlactatemia that may occur due to poor perfusion under general anesthesia.