Myxedema coma leading to respiratory depression in a dog

Abstract

A 10-year-old, intact male, cocker spaniel was presented with hypothermia, without shivering, and progressive stupor leading to coma. Myxedema coma, potentially precipitated by diuretic therapy, was tentatively diagnosed and treatment initiated, but progressive respiratory depression led to the decision to euthanize. Postmortem findings supported the diagnosis of myxedema coma.

A 10-year-old, intact male, cocker spaniel was presented to the Veterinary Teaching Hospital (VTH), Ontario Veterinary College in the autumn with a history of profound lethargy of 2 wk duration.

A tentative diagnosis of congestive heart failure, based on moderate cardiomegaly noted on thoracic radiographs, had been made prior to presentation to the VTH. The dog had been medicated with furosemide (Apo-Furosemide; Apotex, Toronto, Ontario), 3 mg/kg body weight (BW), PO, q12h, and enalapril (Enacard; Merial, Baie d’Urfe, Quebec), 1 mg/kg BW, PO, q24h for 7 d preceding presentation. Prior to initiating diuretic therapy, the referring veterinarian had performed a complete blood cell (CBC) count and serum biochemical profile. The only abnormalities at that time were a nonregenerative anemia (Hematocrit (Hct) 0.32 L/L; reference range, 0.39 to 0.56 L/L) and hypercholesterolemia (24.5 mmol/L; reference range, 3.0 to 9.9 mmol/L).

On presentation to the VTH, the dog was recumbent. Rectal temperature (36.3°C), heart rate (66 beats/min), and systemic blood pressure (systolic 92 mmHg, diastolic 54 mmHg, mean 64 mmHg) were abnormally low. Rectal examination revealed melena. The animal was estimated to be 10% dehydrated. No cardiac murmur was detected and thoracic auscultation did not reveal any abnormalities. A CBC count, serum biochemical panel, and venous blood gases were obtained. The CBC count revealed a mild, nonregenerative anemia (Hct. 0.35 L/L). Abnormalities on venous blood gas included overall acidosis (pH 7.12; reference range, 7.32 to 7.38) due to a metabolic (adjusted base excess -11.9; reference range, −6.4 bolic to −0.4) and respiratory acidosis (hypercapnea 58.0 mmHg; reference range, 36.0 to 52.0 mmHg). Results from the serum biochemical profile indicated hyponatremia (sodium 143 mmol/L; reference range, 145 to 158 mmol/L), hyperkalemia (potassium 6.6 mmol/L; reference range, 3.7 to 5.8 mmol/L), hypochloremia (chloride 94 mmol/L; reference range, 105 to 122 mmol/L), elevated creatinine (1096 μmol/L; reference range, 27 to 124 μmol/L), elevated blood urea nitrogen (>64.3 mol/L; reference range, 2.5 to 8.9 mmol/L), and hypercholesterolemia (>13.5 mmol/L; reference range, 3.2 to 7.0 mmol/L). The urine specific gravity of a sample obtained via catheterization was 1.014. Lateral and dorsoventral thoracic radiographs were taken and revealed mild right-sided cardiomegaly. No evidence of pulmonary edema was detected. Left lateral and ventrodorsal abdominal radiographs did not reveal any abnormalities. Initial differential diagnoses included acute or chronic renal failure, and hypoadrenocorticism. A 20-mL/kg BW bolus of IV crystalloid solution was administered, and IV fluid therapy was continued with 175 mL/kg BW, q24h. A 1-mL/kg BW bolus of 50% dextrose was given in an effort to correct the hyperkalemia. Intravenous ampicillin (Ampicillin sodium; Novopharm, Toronto, Ontario), 22 mg/kg BW, q8h, was given, as well as IV dexamethasone (Uni-Dex; Univet, Milton, Ontario), 0.25 mg/kg BW. Since the dog was presented over a weekend, samples for an adrenocorticotropic hormone stimulation test, leptospirosis titer, and urine culture were held for submission during regular business hours, but the animal’s eventual demise precluded these samples being analyzed. Within several hours of hospitalization, the findings of severe mental depression, hypothermia without shivering, bradycardia, and thickened, edematous skin led to a tentative diagnosis of severe, chronic hypothyroidism leading to myxedema coma. Treatment was initiated with levothyroxine sodium (Eltroxin; GlaxoSmithKline, Oakville, Ontario), 0.025 mg/kg BW, PO, q12h.

Twenty-four hours after presentation, the dog was unable to maintain a body temperature over 37.0°C. Hypoventilation persisted. An arterial blood gas analysis indicated an ongoing acidosis (pH 7.22; reference range, 7.41 to 7.44) with an improved metabolic component (adjusted base excess −3.2; reference range, −2.5 to −10.3), but hypercarbia (PCO₂ 63.5 mmHg; reference range, 23.0 to 42.0 mmHg), and hypoxemia (PO₂ 59 mmHg; reference range, 80 to 112 mmHg) were evident. The dog exhibited a slow and shallow respiratory rate of 12 breaths/min, with no crackles noted on thoracic auscultation. Electrolytes had returned to within reference ranges. Azotemia was partially corrected (creatinine 585 umol/L) with fluid therapy. A nasal oxygen line was placed. Intravenous levothyroxine sodium (Thyroid Hormone; Pfizer, Toronto, Ontario), 0.005 mg/kg BW was administered as soon as it could be obtained. As hypoventilation continued, hypercarbia worsened (PCO₂ 83 mmHg). The dog became increasingly comatose, and hypothermic. Mechanical ventilation was recommended. The owners elected euthanasia.

The thyroid panel results were reported postmortem. Free serum total thyroxine measured by equilibrium dialysis (fT4) was low (0 pmol/L; reference range, 6 to 36 pmol/L), as was total T4 level (<13 nmol/L; reference range, 13 to 50 nmol/L), while cTSH was elevated (3.7 ng/mL; reference range 0.0 to 0.70 ng/mL). Necropsy findings indicated an obese body condition. The right atrium and ventricle were moderately dilated, and there was no evidence of pulmonary edema or ascites. The adrenal gland was normal. Grossly, the thyroid glands, bilaterally, were small and shrunken, and approximately less than 25% of normal size. On histological examination, aggregates of mononuclear inflammatory cells were observed and isolated individual follicles contained little colloid, consistent with lymphoplasmacytic thyroiditis. The kidneys were normal in size and shape, and displayed periglomerular fibrosis, consistent with aging. Regenerative repair of tubular epithelium consistent with a recent ischemic insult was detected. The bone marrow was hypoplastic with adequate iron stores. No gross or microscopic lesions were detected in the brain that could account for the mental depression.

Myxedema coma is a rare and life-threatening variant of severe, chronic hypothyroidism. In humans, it is associated with a mortality rate of 15% to 50% (1,2). It is characterized by lethargy, stupor progressing to coma, respiratory failure, and hypothermia. It can be precipitated by drug therapy, including diuretics, prolonged cold exposure, and infection. Myxedema coma is extremely rare in dogs (3–6). Affected dogs typically present with bradycardia, hypoventilation, mental depression, thickened skin, and severe hypothermia without shivering. Biochemical abnormalities include hyponatremia, hypercholesterolemia, and a mild, nonregenerative anemia. The hyponatremia is attributable to a diminished ability to excrete water, secondary to decreased renal blood flow and glomerular filtration rate, and excessive antidiuretic hormone secretion (2). The anemia is due to decreased erythropoiesis and lower erythropoietin levels. Iron stores are normal and the bone marrow is hypoplastic (7). Hypothyroidism results in hypercholesterolemia due to decreased cholesterol utilization and a decrease in the number of low density lipoproteins (LDL) receptors of the liver, which decreases clearance of cholesterol from the circulation (7). Thyroid hormone acts on the cellular membrane sodium-potassium adenosine triphosphatase to stimulate the cell’s sodium pump, increase oxygen consumption, and raise basal metabolic rate in many cell types (8). Similarly, the activity of calcium ATP-ase in the sarcoplasmic reticulum is increased by thyroid hormone. In the hypothyroid state, activity of these enzymes is thought to be decreased, leading to decreased ATP utilization and a decrease in substrates needed for ATP synthesis. This results in a decrease in substrate utilization, oxygen consumption, and heat generation in hypothyroidism. Dysfunction in the thermoregulatory center of the hypothalmus also contributes to hypothermia (1). Reduction in the body’s core temperature leads to reflex vasoconstriction of the skin and shunting of blood into the central circulation. The myxedematous changes to the skin are due to deposition of hydrophilic glycosaminoglycans in the interstitial space. Cells and tissues become less responsive to catecholamines, possibly through decreases in the beta-adrenergic receptors (2), in spite of enhanced central sympathetic stimulation of the tissues and intact alpha-adrenergic receptors. Cardiovascular changes include bradycardia, decreased stroke volume, and a decreased cardiac output (8). Sympathetic stimulation of the heart is increased, but the contractility and the functional reserve are decreased because of reduced sympathetic responsiveness of the heart and lack of the chronotropic effect of thyroid hormone on the sinoatrial node.

Hypothyroidism results in a decreased ventilatory response to hypoxia and hypercarbia (9). Weakness of the respiratory muscles and diaphragm, obesity, myxedematous swelling of the upper airway, and concurrent pneumonia may also contribute to hypoventilation and hypercarbia (2,8,10). Hypercarbia contributes to the stuporous mental state of these patients. In humans, treatment for myxedema coma often requires ventilatory support for 24 to 48 h, although some patients require support for weeks (2).

Other goals of treatment include controlled, passive rewarming to avoid vasodilation and hypotension. Replacement of endogenous thyroid hormone can be accomplished with oral thyroxine supplementation. As decreased gastrointestinal motility is seen in hypothyroidism and thus absorption of oral medications may be roidism reduced, the IV route of administration is preferred. Published doses in dogs vary, from 0.001 mg/kg BW (3) to 0.020 mg/kg BW (5) to 6.6 mg/kg BW (4). A conservative dose was chosen in this particular patient due to concerns about the cardiovascular function. If IV thyroxine is not available, oral levothyroxine may be administered via orogastric tube. As some human patients with primary hypothyroidism also have primary adrenal insufficiency, short-term glucocorticoid supplementation is recommended (1). As infection is a common precipitating factor in myxedema coma in humans, broad spectrum antibiotic administration may be indicated (10).

Overzealous diuretic therapy has been reported in humans to cause hypothyroidism to decompensate into a myxedema coma (10). In the kidney, furosemide decreases the reabsorption of sodium and chloride, increases the excretion of potassium, and changes electrolyte absorption and transport leading to increased excretion of water, sodium, potassium, chloride, calcium, and bicarbonate. Initiation of aggressive diuretic therapy without evidence of congestive heart failure may have led to the electrolyte imbalances and dehydration seen in this dog, and may have precipitated its decline. Chronic hypothyroidism would have resulted in a decreased intravascular volume, and the furosemide therapy may have decreased the intravascular volume further, leading to hypotension and decompensation.

Fluid therapy in myxedema coma must be judicious, as these patients may have underlying cardiac dysfunction and may be at risk for developing congestive heart failure. Fluid therapy is aimed at reduction of the underlying hyponatremia, which may contribute to worsening mental dullness through cerebral edema, remembering that free water clearance is reduced in the hypothyroid state. In retrospect, the original differential diagnoses in this case led us to choose a initial fluid rate that was overly aggressive. This case highlights the fact that myxedema coma is an important differential diagnosis for any patient presenting for severe lethargy or collapse. It is a medical emergency and should be recognized by its hallmarks of hypothermia without shivering, depression, nonpitting edema, and bradycardia. Once a presumptive diagnosis has been made on the basis of signalment, clinical signs, and supporting clinicopathological features, supplementation should be started immediately, without waiting for the results of a T4 analysis. CVJ