Renata S. Costa1, Teela Jones2, and Thomas K. Graves3 1 Section of Anaesthesia and Analgesia, School of Veterinary Medicine, Murdoch University, Murdoch, Western Australia, Australia 2 Summit Veterinary Referral Center, Tacoma, Washington, USA 3 Professor and Dean Emeritus, College of Veterinary Medicine, Midwestern University, Glendale, Arizona, USA The endocrine system plays an important role in homeostasis through secretion of hormones that function in metabolism, growth, reproduction, and digestion. In patients with endocrine disorders, an understanding of the physiology and pathophysiology of the disease process is imperative to provide adequate perianesthetic management. The endocrine system regulates the secretion of hormones from several peripheral organs under the direction of the hypothalamus together with the hypophysis (pituitary gland) (Fig. 42.1). Hormones are substances secreted into the circulation in small amounts to produce a biologic effect at distant target organs or cells. Hormones may be proteins (corticotropin, growth hormone, and insulin), peptides (oxytocin and vasopressin), steroids (glucocorticoids, mineralocorticoids, and sex hormones), or amines (dopamine, melatonin, and epinephrine). Other hypothalamic hormones include oxytocin, and prolactin‐releasing hormone, while other pituitary hormones include gonadotropin (GH), somatostatin, prolactin, luteinizing hormone, and follicle‐stimulating hormone. The hypothalamus is a small area located in the ventral aspect of the diencephalon flanking each side of the third ventricle, almost directly above the caudal pharynx. In addition to endocrine control of metabolism, growth, and reproduction, the hypothalamus helps to coordinate other vital aspects of mammalian physiology including the autonomic nervous system, behavior, emotion, and digestion [1]. A physiologic stress response may be activated during sedation, anesthesia, or following noxious stimuli ultimately activating the hypothalamic–pituitary–adrenal axis [2]. Activation of this axis leads to release of cortisol and catecholamines from the adrenal gland resulting in increases in heart rate, blood pressure, and systemic vascular resistance. Increases in metabolic rate, oxygen consumption, and hyperglycemia, as well as release of cytokines, vasopressin, and insulin also occur [2]. The pituitary gland is located just below the hypothalamus. It has two main lobes, distinct in both anatomic composition and function: the adenohypophysis or anterior pituitary (AP) and the neurohypophysis or posterior pituitary (PP). The AP functions like a true endocrine gland, producing and secreting peptide and glycoprotein hormones that target the pancreas, thyroid gland, adrenal glands, reproductive organs, and the intestine. These hormones regulate various cellular processes including growth, metabolism, reproduction, and response to stress. The AP has three distinct areas – the pars tuberalis, the pars intermedia, and the pars distalis. Hypothalamic‐releasing hormones, such as thyrotropin‐releasing hormone and corticotropin‐releasing hormone, regulate AP hormonal secretion. Once the hypothalamic hormones reach their target cells in the AP, they may stimulate or inhibit the synthesis and secretion of AP hormones (e.g., thyroid‐stimulating hormone [TSH]). The PP is primarily a conduit between the hypothalamus and the peripheral circulation. It is composed of the pars nervosa and infundibular stalk. Axons in the supraoptic and paraventricular nuclei of the hypothalamus extend into the pars nervosa. Hormones that are produced by the hypothalamus, such as oxytocin and vasopressin, are secreted into the peripheral circulation by these specialized neurosecretory cells [1]. In contrast to the AP that produces hormones that stimulate the production of other hormones, the PP secretes hormones that directly affect target tissues [1]. For example, vasopressin or antidiuretic hormone (ADH) acts on the kidneys to control water reabsorption. Figure 42.1 Summary of important hormones in the hypothalamic–pituitary axis, target tissues, and physiologic responses [1–3]. 1. Hypothalamus; 2. Anterior pituitary gland (AP); 3. Posterior pituitary gland; 4. Parathyroid gland; 5. Thyroid gland; 6. Pancreas; 7. Kidney; 8. Adrenal gland. TRH, thyrotropin‐releasing hormone; CRH, corticotropin‐releasing hormone; ADH, antidiuretic hormone; TSH, thyroid‐stimulating hormone (thyrotropin); ACTH, adrenocorticotropic hormone (corticotropin); PTH, parathyroid hormone. Source: Dr. Teela Jones; with permission. Relevant anatomy, physiology, and pathophysiology of common endocrine disorders affecting the adrenal gland, pancreas, kidney, thyroid gland, and parathyroid glands are described below. Specific anesthetic considerations and appropriate perianesthetic management of small animals presenting with endocrinopathies are also discussed. The two adrenal glands are located retroperitoneally; each gland is craniomedial to the kidney. They are composed of a central medulla and outer cortex. The medulla is densely innervated with preganglionic sympathetic fibers and is considered part of the autonomic nervous system. Its main cell type, the chromaffin cell, produces epinephrine and norepinephrine, which are important in emergent and stressful circumstances [3]. The adrenal cortex is an important endocrine organ with three distinct zones (zona glomerulosa, zona fasciculata, and zona reticularis). The zona glomerulosa is the most superficial, and it secretes mineralocorticoids, mainly aldosterone. Deep to this area is the zona fasciculata, which secretes glucocorticoid hormones, primarily cortisol in the dog and cat. The deepest zone of the adrenal cortex is the zona reticularis, which secretes sex hormones (Fig. 42.2) [3]. Aldosterone, secreted by the zona glomerulosa, stimulates sodium and chloride reabsorption and potassium excretion in the cortical collecting ducts of the renal tubules. Because water follows sodium, it is also reabsorbed, which promotes plasma volume expansion [4]. Cortisol, secreted by the zona fasciculata, affects endothelial integrity, vascular permeability, and sensitivity to catecholamines, ultimately regulating vascular tone and blood pressure. Cortisol is also involved in the modulation of inflammation by stabilizing lysosomal membranes, decreasing leukocyte migration, reducing capillary permeability, and altering circulating leukocyte levels and antibody production. Diminished function of the adrenal cortex resulting in glucocorticoid and/or mineralocorticoid deficiency produces hypoadrenocorticism or Addison’s disease. Dogs with Addison’s disease are usually presented for complications associated with deficiency of both aldosterone and cortisol. However, a form of the disease characterized by signs of cortisol deficiency only (“atypical” hypoadrenocorticism) has been recognized [5]. Primary hypoadrenocorticism due to failure of the adrenal gland is the most common form of the disease and most likely occurs due to immune‐mediated destruction of the adrenal cortex [6,7]. Causes of secondary hypoadrenocorticism include lack of production of adrenocorticotropic hormone (ACTH) by the pituitary gland, iatrogenic disease following treatment for hyperadrenocorticism, or when high‐dose steroid therapy is abruptly withdrawn. Tertiary hypoadrenocorticism caused by hypothalamic malfunction also exists. Hypoadrenocorticism occurs most often in young‐ to middle‐aged female dogs (median age 4 years). Most commonly affected purebred dogs include Standard Poodles, West Highland White Terriers, Great Danes, Rottweilers, and Portuguese Water Dogs. There are no known breed predilections in cats, but most are also middle‐aged at the time of diagnosis [8]. Clinical signs of hypoadrenocorticism are usually non‐specific and may include anorexia, lethargy, vomiting, diarrhea, weight loss, and polyuria/polydipsia (PU/PD). Whenever a patient, especially a middle‐aged female dog, is presented with vague gastrointestinal clinical signs and/or lethargy, Addison’s disease should be suspected. Signs of the disease range from mild to severe, and those patients presenting in an acute Addisonian crisis are at risk of death. Glucocorticoid deficiency is responsible for many of the vague, chronic, waxing and waning clinical signs. Mineralocorticoid (e.g., aldosterone) deficiency leads to potassium retention and urinary sodium and water loss. Hyperkalemia due to potassium retention can lead to myocardial excitability, muscle weakness, inability to retain bicarbonate and chloride, and loss of renal concentrating ability. Impaired sodium retention can result in decreased extracellular fluid and plasma volume, low cardiac output, and impaired renal blood flow. When severe, these changes result in dehydration, azotemia, hypotension, bradycardia, collapse, and hypovolemic shock. Figure 42.2 Diagrammatic cross‐section of the adrenal gland [3]. Source: Dr. Teela Jones; with permission. Anemia, lymphocytosis, or eosinophilia may be present on a complete blood count (CBC). The lack of a stress leukogram in an ill patient should also lead the clinician to suspect glucocorticoid deficiency and possibly hypoadrenocorticism [9]. Serum biochemistry findings can include hyperkalemia and hyponatremia (Na+:K+ < 27:1), hypoalbuminemia, mild hypercalcemia, and, in dehydrated patients, prerenal azotemia due to decreased blood flow to the kidneys [9]. Even though the azotemia is prerenal in origin, a low urine specific gravity (i.e., < 1.030 in the dog and < 1.040 in the cat) may be evident owing to the inability to retain sodium [10,11]. Mild to moderate hypoglycemia may also be apparent in some animals. This is mainly due to decreased levels of glucocorticoid resulting in a reduction of gluconeogenesis and an increased sensitivity to insulin. Definitive diagnosis of hypoadrenocorticism requires measurement of serum concentrations of cortisol before and after stimulation with ACTH [12]; however, the CBC and serum biochemistry findings listed above are helpful when a diagnosis of hypoadrenocorticism is suspected. Once the diagnosis is made, treatment carries a good prognosis [6,7,13]. Dogs and cats in non‐critical condition are treated with mineralocorticoid and glucocorticoid supplementation. Mineralocorticoid treatment can be with injectable desoxycorticosterone pivalate (DOCP) or oral fludrocortisone. Fludrocortisone has mild glucocorticoid activity; thus, glucocorticoid supplementation is not always needed. Patients treated with DOCP should also receive low maintenance doses of a glucocorticoid. Addisonian patients in adrenal crisis require intravenous (IV) fluid therapy and monitoring of electrolytes. Normal saline ([Na+] 154 mEq/L) is commonly administered for the initial treatment to replace circulatory volume and sodium deficits [10,11]. However, sodium concentrations should be raised gradually, not exceeding 0.5 mEq/kg/h, to avoid neurological signs caused by osmotic demyelination syndrome [14,15]. Note that the most appropriate fluid or fluid combination to administer should be based on each animal’s baseline sodium concentration. In cases of severe hyponatremia, a balanced electrolyte solution such as Lactated Ringer’s solution (LRS) ([Na+] 130 mEq/L) may be a more appropriate treatment. Although balanced electrolyte solutions such as LRS contain potassium (4 mEq/L), it appears that fluid resuscitation and the increase in glomerular filtration rate alone will still initiate kaliuresis [11]. Another important aspect of stabilization of an animal in Addisonian crisis is evaluation of the electrocardiogram (ECG) and management of hyperkalemia if necessary. Common treatments for life‐threatening hyperkalemia include administration of IV calcium gluconate (as a cardioprotective agent) and dextrose, insulin, and sodium bicarbonate (to lower serum potassium) [16]. Suggested management of hyperkalemia is presented in Table 42.1. Dexamethasone, 0.25 mg/kg IV, can be administered before the completion of the ACTH stimulation test [16]. Hydrocortisone and prednisolone cross‐react with some cortisol assays and should be withheld until after ACTH stimulation testing is complete. Unstable or poorly controlled animals with hypoadrenocorticism may require anesthesia for emergency procedures. These animals must be evaluated for hyperkalemia and hyponatremia, prerenal azotemia, hypovolemia and hypotension, metabolic acidosis, and hypoglycemia [17–19]. These abnormalities should be managed prior to anesthesia. A baseline blood pressure and ECG should also be obtained. Goal‐directed volume replacement can be accomplished with IV isotonic crystalloids, and this may be adequate to correct electrolyte abnormalities and stabilize vascular volume and blood pressure. Electrocardiography may show evidence of hyperkalemia including tall, narrow T waves, prolonged QRS complexes, and atrial standstill, usually when serum concentrations exceed 5.5 mEq/L, although this is variable [20]. If hyperkalemia persists, especially if bradycardia and/or arrhythmias are present, specific therapy as described in the previous section is warranted. After initial stabilization, sedation and anesthesia are performed utilizing balanced anesthetic protocols and multimodal analgesia. Premedication with intravenous opioids is commonly recommended. Butorphanol is often administered for non‐painful procedures, whereas full μ‐opioid receptor agonists are preferred for invasive or painful procedures. In these cases, short‐acting full μ‐opioid receptor agonists may also be administered as a constant rate infusion (CRI) to provide analgesia, dose‐dependent sedation, and minimum alveolar concentration (MAC)‐sparing effects. Anesthesia may be induced with drugs such as propofol, alfaxalone, ketamine–benzodiazepine, and other combinations such as propofol and midazolam. It is important to note that induction of anesthesia with etomidate is usually avoided in animals with hypoadrenocorticism, especially when critically ill, as cortisol synthesis may be depressed from inhibition of 11β‐hydroxylase in dogs and cats [21–26]. Table 42.1 Suggested management of hyperkalemia. Source: Koenig [4]; Lathan and Thompson [16]; Kintzer and Peterson [17]; Stafford and Bartges [18]; Koenig [19]. CRI, constant rate infusion. Many animals with hypoadrenocorticism will undergo anesthesia for surgical procedures unrelated to the disease and have been previously managed with medical therapy at the time of surgery [2,17]. The choice of anesthetic protocol in these patients is not as critical as the perioperative medical management. However, anesthetic protocol selection should reflect the patient’s health status and stability, and procedure being performed. Provision of locoregional anesthesia whenever possible is recommended due to desirable effects such as reliable analgesia, decreased systemic drug requirements, and MAC‐sparing effects, which may help maintain normal blood pressure intraoperatively. Even for animals with well‐controlled hypoadrenocorticism, it is recommended to assess hydration status, blood pressure, and ECG prior to anesthesia. The normal mineralocorticoid supplementation regimen of animals with Addison’s disease undergoing anesthesia should be continued. Glucocorticoid doses, however, may require adjustment because these animals have inappropriate responses to stressful situations including hospitalization, surgery, and anesthesia. In addition to baseline steroid therapy, several preoperative glucocorticoid supplementation protocols have been recommended for people with hypoadrenocorticism to prevent adrenal crisis and refractory hypotension in the perioperative period [27]. There have been no studies proving the benefits of additional preoperative steroid supplementation in dogs undergoing surgery; however, it has been suggested that prednisone is doubled the day before and 1–2 days following the stressful event [16]. Recommended doses of glucocorticoids include 0.1–0.5 mg/kg of dexamethasone sodium phosphate IV or up to 1–2 mg/kg of prednisolone sodium succinate IV, with lower doses repeated as necessary [4,28]. Postoperatively, additional glucocorticoids are administered as needed. Due to the negative fluid balance and electrolyte abnormalities, hypotension is a common intraoperative complication of animals with hypoadrenocorticism. Addisonian patients may not respond adequately to basic interventions or may present in hypovolemic shock; therefore, advanced monitoring techniques including invasive (direct) blood pressure may be beneficial. If invasive blood pressure is measured, variation in the amplitude of the systolic pressure waveform during positive‐pressure ventilation may be seen when hypovolemia is present [29]. A balanced electrolyte solution should be administered intraoperatively at a rate of 5–10 mL/kg/h. This rate should be adjusted or supplemental boluses administered depending on the patient’s hydration status [27,30]. Positive inotropes may also be necessary to maintain adequate blood pressure intraoperatively [27,30]. As previously discussed, insufficient glucocorticoid secretion may result in cardiovascular consequences including hypotension. Although there is little evidence in veterinary medicine, hypotension refractory to vasopressor administration has been successfully treated with hydrocortisone in a dog [31]. Excess circulating concentrations of cortisol produces hyperadrenocorticism (HAC) or Cushing’s syndrome [32]. In 80–85% of spontaneous or naturally occurring cases, the disease is due to increased secretion of ACTH from a pituitary tumor, usually an adenoma of the corticotropes in the pars distalis of the pituitary, resulting in bilateral adrenocortical hyperplasia and excessive cortisol secretion. This is known as “pituitary‐dependent hyperadrenocorticism.” Albeit less common, a cortisol‐secreting tumor of the adrenal gland can also lead to hyperadrenocorticism. Chronic administration of glucocorticoids may result in iatrogenic Cushing’s syndrome [33,34]. Spontaneous HAC generally occurs in middle‐aged and older dogs. Although the literature is conflicting, female and neutered dogs appear to be at a higher risk [35]. Any purebred or mixed‐breed dog can be affected, but Standard Schnauzers and Fox Terriers appear to be predisposed. Although this chapter focuses on small animal patients, it is important to note that HAC is also a common endocrine disease of older horses and ponies and is referred to as “pituitary pars intermedia dysfunction” (PPID) [36]. There is no sex predilection, and the incidence has been reported as 15–30% in older horses [37]. Clinical signs of dogs with hyperadrenocorticism include bilaterally symmetrical alopecia, comedones, recurrent skin infections, thin skin, dermal hyperpigmentation, dermal and muscle atrophy, PU/PD, polyphagia, pendulous abdomen, hepatomegaly, panting, hypertension, and lethargy (Fig. 42.3) [32]. Albeit not common, large pituitary tumors can result in neurological signs. The clinical signs observed are due to the increased circulating concentrations of cortisol. Cortisol stimulates gluconeogenesis, protein and fat catabolism, leading to redistribution of adipose tissue both dorsally and within the abdomen and the resultant pendulous abdomen. Polyuria occurs because cortisol inhibits ADH release. Systemic hypertension may occur due to increased vascular responsiveness to catecholamines, increased activation of the renin–angiotensin system and increased angiotensin II, and decreased release of vasodilatory prostaglandins and hyperaldosteronism [38,39]. Findings on CBC are non‐specific, however, dogs with HAC often exhibit changes consistent with a stress leukogram (neutrophilia, monocytosis, lymphopenia, and eosinopenia) [32]. Serum biochemistry findings include increased alkaline phosphatase (ALP) activity in 90% or more of cases, increased alanine aminotransferase (ALT) activity, hypercholesterolemia, and hyperglycemia [32,40]. ALP activity increases as a result of a steroid‐induced isoform of the enzyme. This steroid‐induced ALP isoform has not been demonstrated in cats. Hyperglycemia may be due to increased gluconeogenesis and decreased peripheral tissue utilization through insulin antagonists [38]. Excess glucocorticoid secretion may result in concurrent diabetes mellitus characterized by insulin resistance [41]. Serum phosphorus may be decreased due to polyuria. Urinalysis typically reveals low urine specific gravity with or without mild proteinuria. Concurrent urinary tract infection is common in dogs with HAC [42]. The diagnosis of HAC should be based on history and clinical findings and can be confirmed by one or a combination of the following screening tests: ACTH stimulation test, low‐dose dexamethasone suppression test (LDDS), urine cortisol:creatinine ratio (UCCR), and dexamethasone‐suppressed UCCR [43,44]. According to some reports, the diagnostic accuracies of the dexamethasone‐suppressed UCCR and LDDS are greater than that of the ACTH stimulation test and may, therefore, be preferred [45]. In addition to screening tests for HAC, tests to differentiate the cause of the condition are also recommended. High‐dose dexamethasone suppression test can confirm pituitary‐dependent HAC, and adrenal tumors can be investigated by abdominal ultrasound. Diagnostic imaging modalities such as computed tomography (CT) or magnetic resonance imaging (MRI) can confirm the presence of a pituitary tumor. Figure 42.3 A. Mixed‐breed dog diagnosed with hyperadrenocorticism and diabetes mellitus with alopecia and abdominal distension. Patient is placed on a conductive heating device and is being preoxygenated in preparation for induction of anesthesia. Source: Dr. Tanya Duke‐Novakovski; with permission. B. Mixed‐breed dog with diabetes mellitus and hyperadrenocorticism exhibiting classic signs of pendulous abdomen, organomegaly, and panting. Source: Dr. Renata S. Costa, with permission. Most canine patients with pituitary‐dependent disease are treated with the adrenocorticostatic drug, trilostane. Trilostane causes reversible, competitive inhibition of the 3β‐hydroxysteroid dehydrogenase enzyme necessary for the production of cortisol, aldosterone, and androgens in the adrenal cortex. The adrencorticolytic drug, mitotane, is still prescribed in some cases [46,47]. Mitotane causes necrosis of the deeper zones of the adrenal cortex, sparing the superficial mineralocorticoid‐producing zone. Both treatments can precipitate an acute Addisonian crisis (see hypoadrenocorticism). In addition to medical management, surgical resection of tumors by transsphenoidal hypophysectomy [48] or adrenalectomy [49] has been successful. For elective procedures, animals should be treated with trilostane for 3–4 weeks prior to surgery in an effort to reverse the metabolic derangements of HAC and minimize the risk of complications associated with adrenalectomy [50]. Treating HAC in cats is challenging and less predictable. Optimal treatments for HAC in cats have not been established [51]. Animals with HAC are predisposed to hypertension [52], which should be managed with antihypertensive drugs such as angiotensin‐converting enzyme (ACE) inhibitors, in conjunction with trilostane or mitotane prior to surgery [2,53]. Hypertension may lead to cardiac changes including pressure and volume overload, left ventricular hypertrophy, and congestive heart failure. Persistent high blood pressure can cause kidney injury, and volume overload may occur due to renal sodium retention and increased circulating volume. Hypercoagulability and subsequent pulmonary thromboembolism resulting from excess production of vitamin K‐dependent clotting factors is a potentially life‐threatening complication of HAC [38]. However, it appears that only a small subset of dogs with HAC develop thrombosis and current guidelines only support antithrombotic therapy (i.e., heparin and clopidogrel) if HAC is accompanied by other risk factors for thrombosis [54]. Dogs with pituitary‐dependent HAC often require anesthesia for other concurrent diseases [2], elective procedures, and diagnostic imaging. These animals should be carefully evaluated and stabilized prior to sedation or any anesthetic event. A CBC and serum biochemistry are recommended to assess hydration status, electrolytes, and hepatic and renal function, especially when dealing with geriatric patients. A thorough physical examination should be performed and baseline blood pressure measured to determine if concurrent hypertension is present. When adrenal neoplasia is suspected, the extent of local vascular invasion is usually determined with abdominal ultrasound and/or CT prior to the surgical procedure. Animals with cortisol‐secreting adrenocortical tumors may undergo adrenalectomy [17]. Blood type should be determined and a crossmatch performed if the animal is to undergo an invasive procedure such as an adrenalectomy, especially if the tumor is in close proximity to or is invading the aorta or vena cava. Blood or packed red blood cells (RBCs) should be available as excessive intraoperative hemorrhage may occur [55,56]. Animals with HAC may be prothrombotic and hypercoagulable and if hypercoagulability is suspected, thromboelastography (TEG) can help guide the most appropriate treatment perioperatively. When an antithrombotic agent is being administered, clotting times should also be evaluated. Measurement of activated partial thromboplastin time (aPTT) may be indicated to ensure that the patient is receiving an appropriate dose and is not at increased risk for excessive bleeding during surgery. The goal is an (aPTT) that is increased by no more than 1.5–2‐fold [2,55,57–59]. If the patient is hypertensive and the planned procedure is elective, it should be postponed until this comorbidity is further assessed and managed. Hypertensive dogs may be treated with ACE inhibitors and, although there have been no studies investigating the effects of withholding these agents prior to anesthesia, a study with 12 healthy female Beagle dogs receiving oral enalapril 90 min prior to isoflurane anesthesia showed an increase in the severity of intraoperative hypotension [60]. Therefore, some anesthesiologists discontinue ACE inhibitors 24 h prior to the scheduled procedure. Animals with Cushing’s syndrome, even those undergoing medical management, may develop PU/PD. Reduced total water intake attributed to both the stress of an unusual environment and fasting could result in rapid dehydration in those animals. Hydration status should be carefully assessed using both physical examination and laboratory parameters (e.g., capillary refill time, mucous membrane color, skin turgor, heart rate, blood pressure, and PCV/TS). Goal‐directed perianesthetic fluid therapy should be instituted to prevent or treat dehydration and hypotension [2]. Animals treated with mitotane or trilostane may lack functional adrenocortical reserve, and their lower cortisol levels may impair their ability to handle stressful anesthetic or surgical events appropriately. These cases should be managed as iatrogenic Addisonians and may require preoperative glucocorticoid supplementation with 0.1–0.2 mg/kg of dexamethasone sodium phosphate IV [4,28]. In addition, serum sodium and potassium concentrations should be monitored in these patients [2,16]. No specific anesthetic protocol is contraindicated for patients with Cushing’s syndrome; however, drug choices should be based on the patient’s health status and concurrent comorbidities. Patients may be geriatric and/or in poor condition and lethargy is common [2]; therefore, intense sedation may not be required. The anesthesiologist should aim to select drugs and dosages that allow for a smooth and quick recovery to promote movement within 4 h of surgery to improve blood flow. This is particularly important when thrombosis is a concern [52]. Opioids are generally administered to provide analgesia and because they induce minimal dose‐dependent cardiorespiratory effects. Sedatives and tranquilizers may not be needed, but a benzodiazepine or a low dose of acepromazine may be administered in conjunction with the opioid. Note that acepromazine may result in worsening of intraoperative hypotension due to its vasodilatory effects, especially in dogs managed with antihypertensive drugs; thus, the authors usually reserve its administration to otherwise healthy but nervous animals. α2‐Adrenergic receptor agonists inhibit pancreatic β‐cells resulting in a transient increase in blood glucose [61–63]. Although their use is unlikely to cause clinically relevant adverse effects, there are no published, evidence‐based guidelines for use of α2‐adrenergic receptor agonists in animals with HAC or diabetes mellitus. As pain and stress will also result in a physiological and transient increase in blood glucose, a balanced anesthetic protocol is recommended. If α2‐adrenergic receptor agonists are used in patients with concurrent diabetes mellitus, judicious use of additional insulin is warranted to avoid hypoglycemia once the effects of the α2‐adrenergic receptor agonists have waned. For patients undergoing adrenalectomies, administration of hydrocortisone 2 mg/kg IV or dexamethasone 0.07–0.2 mg/kg IV has been recommended immediately after induction of anesthesia [64,65]. Administration of non‐steroidal anti‐inflammatory drugs (NSAIDs) is often avoided in HAC patients owing to the potential risk of gastrointestinal ulceration, nephropathy, and hepatopathy in dogs with high endogenous cortisol concentrations [2,66,67]. Use of NSAIDs must be carefully considered based on how well‐controlled the disease is, the patient’s clinical signs and cortisol levels, and potential concurrent renal or hepatic disease. If a dog with uncontrolled HAC and hypertension presents for an emergency procedure, a balanced anesthetic and multimodal analgesic protocol may reduce fluctuations in blood pressure intraoperatively. Additionally, as in cases of pheochromocytomas, sodium nitroprusside, β‐adrenergic blockers, magnesium sulfate, or increasing inhalant concentrations may be used to control fluctuations in heart rate and blood pressure (see pheochromocytoma) [68]. Animals with HAC often have thin skin and fragile veins, which may present challenges for intravenous catheterization. They may also have delayed primary wound healing and should be handled gently. Minimal hair clipping is advised to reduce the risk of skin trauma, which could become a source of infection, and to minimize heat loss. However, there is limited evidence demonstrating the correlation of area shaved and rectal temperature during anesthesia [69]. Preoxygenation is indicated prior to induction, especially in patients with large pendulous abdomens (Fig. 42.3A). Studies in healthy patients have demonstrated prolongation of the time to desaturation when oxygen is supplemented via face mask [70,71]. Dogs with HAC commonly hypoventilate during anesthesia due to increased abdominal fat, hepatomegaly, respiratory muscle weakness, and bladder distension [2]. Hypoventilation and poor respiratory function may lead to ventilation–perfusion mismatch, atelectasis, hypercapnia, and respiratory acidosis. Hypoxemia may result if oxygen is not supplemented, especially during recovery. These animals may also develop pulmonary mineralization and pulmonary thromboembolism [38,72–74]. Animals with HAC may also be more prone to developing hypothermia under anesthesia due to muscle and dermal atrophy and alopecia. During anesthesia, ventilatory support is often required using intermittent positive‐pressure ventilation, especially in animals positioned in dorsal recumbency. Close monitoring of ventilation and oxygenation via end‐tidal carbon dioxide, pulse oximetry, and/or arterial blood gas analysis is warranted. In the postoperative period, ventilation and hemoglobin saturation should continue to be monitored, especially if the animal is hypothermic. Severe hypothermia decreases cellular metabolism and lowers carbon dioxide production, resulting in diminished stimulation of ventilation and reduced respiratory rate and tidal volume [75]. Rewarming results in increased metabolic rate and oxygen consumption [76,77]; thus, oxygen supplementation is recommended. Temperature should be monitored and supplemental warming devices employed, but care must be taken to avoid thermal burns. Blood pressure should be monitored, and direct measurement via an arterial line is recommended for animals anesthetized for invasive procedures such as an adrenalectomy due to the high risk of hemorrhage [2,27]. Furthermore, when an enlarged abdomen and/or hepatomegaly is present, venous return to the heart may be compromised, which could result in intraoperative hypotension. Hypotension may be exacerbated by the presence of hypovolemia, the use of positive‐pressure ventilation, and positioning in dorsal recumbency [29]. Following adrenalectomy, especially with invasion of the vena cava, animals are at even greater risk of thromboembolic complications in recovery. Based on the rational use of antithrombotics in veterinary critical care (CURATIVE) guidelines [54], antithrombotic drugs should not be discontinued prior to invasive procedures in animals at high risk for thrombosis; however, these drugs may be withheld in animals at low‐to‐moderate risk for thrombosis. In animals where antithrombotic therapy was discontinued prior to surgery, therapy can be restarted immediately after the procedure as long as there is no evidence of ongoing bleeding. If signs of thrombosis develop at any point, antithrombotic therapy should be initiated immediately. Clinical signs of thromboembolic events are often non‐specific and highly variable [78]; however, acute onset of dyspnea, tachypnea, cyanosis, and collapse should prompt suspicion of pulmonary thromboembolism. Arterial blood gas analysis usually reveals hypoxemia, hypocapnia, and an increased alveolar to arterial oxygen gradient. Treatment is symptomatic and should be instituted immediately, with increased inspired oxygen concentrations and cardiovascular support as needed [2]. Postoperative dexamethasone 0.05–0.15 mg/kg IV has been administered to prevent the development of hypoadrenocorticism [64,79]. Sodium and potassium should also be monitored and mineralocorticoid therapy instituted if the sodium:potassium ratio decreases dramatically [56]. Pheochromocytoma (PHEO) is a catecholamine‐secreting tumor that arises from chromaffin cells of the adrenal medulla. Chromaffin cells synthesize, store, and release catecholamines in response to sympathetic stimulation. In PHEO, catecholamine release may be episodic or continuous and may or may not be related to physiologic stressors such as fear, stress, tumor manipulation, and drugs [80]. This malignant or locally invasive tumor has been reported in several species including dogs, cats, and people [81–83]. Approximately 15–38% of dogs with PHEO have neoplastic invasion of the caudal vena cava; however, clinical signs are not associated with the extent or presence of vena caval invasion (Fig. 42.4) [79,84,85]. Invasive PHEOs have been reported to affect not only the vena cava, but also the aorta, renal veins, and hepatic veins [4,86]. In veterinary species, there are limited data regarding the specific catecholamines released from these tumors. Higher concentrations of plasma metabolites of norepinephrine in comparison to epinephrine have been reported in dogs [86]. In cats, norepinephrine is typically the catecholamine released by PHEO [80]. Figure 42.4 A 12‐year‐old Siberian husky with a pheochromocytoma (10 cm × 7 cm × 6 cm) of the right adrenal gland severely compressing and invading the caudal vena cava. Source: Dr. Jung Keun Lee, Diagnostic Pathology Center, Midwestern University, Glendale, AZ; with permission. PHEO tends to occur in older dogs (10–12 years), and there is no known breed or sex predilection [82,86–89]. Note that many small animals with PHEO may be asymptomatic, which explains the high number of cases (48–80%) diagnosed postmortem or as an incidental finding on abdominal ultrasound [81,82]. Clinical signs of PHEO may be dramatic but are often intermittent and paroxysmal due to the episodic release of catecholamines [17]. The most common signs are weakness, syncope, tachypnea, tachyarrhythmia, hypertension, and seizures [4]. Underlying disorders secondary to chronic hypertension may be observed including retinal detachment, pulmonary venous congestion or pulmonary edema, and congestive heart failure (82,83). Animals with PHEO may also have other concurrent endocrinopathies such as hyperadrenocorticism (HAC). Therefore, this disorder should be ruled out and/or managed, especially in dogs where HAC is more commonly seen (see hyperadrenocorticism) [88,90]. Findings on CBC and serum biochemistry are usually non‐specific. Urinalysis in 10 out of 20 dogs with PHEO showed proteinuria, likely caused by a hypertensive glomerulopathy [91]. If HAC is also present, liver enzymes may be elevated, and a stress leukogram may be present (see hyperadrenocorticism). Clinical signs of episodic weakness, collapse, hypertension, and arrhythmias are suggestive of PHEO. Abdominal ultrasound is commonly used to diagnose the presence of an adrenal mass, local metastasis, and thrombi, as it is readily available and does not require general anesthesia [91–94]. Contrast‐enhanced ultrasonography may aid in the differentiation of adrenal tumors [95]. Advanced imaging including CT and MRI can also be used and are useful in evaluation of tumor architecture, metastasis, degree of invasion, and thrombi [80,92,93]. Diagnosis of PHEO can be determined via biopsy, but this is rarely performed owing to the difficulty in obtaining good samples and the risk of hemorrhage or a hypertensive crisis. Additionally, there is not clear evidence of histopathological features predictive of metastasis [93]. Other diagnostic tools used to confirm PHEO in dogs and cats include urinary catecholamines and the metanephrine‐to‐creatinine ratio, and plasma metanephrine and normetanephrine analysis [96,97]. However, these biomarkers may also be elevated in dogs with HAC, due to non‐adrenal illness, and other factors such as excitement [97]. Definitive treatment for PHEO is surgical resection of the tumor. To determine the feasibility and complexity of the surgery, it is advised to assess the origin, architecture, vascularity, and invasiveness of the mass via CT or MRI [55,56,86,91–93]. Preoperative evaluation and stabilization is of the utmost importance in animals with suspected PHEO. Thoracic radiographs prior to surgery should be considered as metastasis to the lung may occur [88]. Further advanced diagnostic imaging will help determine the feasibility of surgical removal in addition to the probable need for crossmatching and blood transfusion [55,56,86,91]. Preanesthetic blood pressure and ECG evaluation is indicated, and medical management to stabilize these animals should be performed prior to anesthesia. Catecholamine‐induced hypertension can be managed with phenoxybenzamine, a long‐acting non‐competitive α1‐adrenergic receptor antagonist with some α2‐adrenergic receptor antagonism. It is recommended to start phenoxybenzamine treatment 1–2 weeks before surgery. An oral dose of 0.25 mg/kg twice daily is often prescribed, but higher doses may be required, up to 2.5 mg/kg twice daily. Serial blood pressure measurements should be performed to evaluate response to therapy [4,55,56,86,89,98,99]. It has been reported that although preoperative administration of phenoxybenzamine did not decrease the frequency or severity of perioperative hypertension in dogs with PHEO, the mortality rate decreased from 43% to 13%. This improved outcome may be due to the reduction in vasoconstriction and improvement of intravascular volume [89]. Prazosin, a competitive, reversible α1‐adrenergic receptor antagonist, is an alternative agent to manage catecholamine‐induced hypertension when phenoxybenzamine is not available [100]. Oral doses range from 0.25 to 1 mg/kg twice daily. In contrast to phenoxybenzamine, prazosin’s effects can be overcome by high concentrations of catecholamines. Therefore, phenoxybenzamine is considered the drug of choice for animals undergoing surgery for PHEO excision. Doxazosin is another alternative to phenoxybenzamine, but reports of its clinical use in veterinary medicine are limited. [101,102]. Doxazosin has been used at a dosage of 0.5 mg/kg orally every 24 h to manage hypertension in an HAC dog with a PHEO [103]. Atrial and ventricular tachycardia and, less often, atrioventricular block may occur with these tumors [2,86,104]. Severe tachycardia can be treated with oral β‐adrenergic receptor antagonists, such as propranolol (0.2–1 mg/kg every 8 h) or atenolol (0.2–1 mg/kg every 12 h). However, better results are seen when α‐adrenergic receptor blockade, usually with phenoxybenzamine, is instituted first because administration of a β‐adrenergic receptor blocker alone may lead to unopposed α‐adrenergic receptor‐mediated vasoconstriction, which may exacerbate hypertension [2,17,27,86,105]. The risk of bradyarrhythmias may also be reduced by preoperative management of hypertension. Cardiac evaluation is an important determinant of whether surgical treatment for PHEO should be pursued. Third‐degree atrioventricular block in dogs with PHEO has been related to myocardial damage and atrioventricular nodal fibrosis from chronic catecholamine exposure [104]. Animals undergoing adrenalectomy are often classified as ASA III, IV, or V, and risk factors associated with the surgical procedure include significant hemorrhage, precipitation of a hypertensive crisis, cardiac arrhythmias, and intraoperative/postoperative hypotension following tumor excision. A minimum database consisting of a CBC, serum biochemistry profile, urinalysis, baseline ECG, and blood pressure should be evaluated prior to anesthesia. Hydration status should be assessed and appropriate preoperative fluid therapy instituted to correct any signs of dehydration or hypovolemia. Chronic sympathetic stimulation and vasoconstriction seen with PHEO may cause intravascular volume depletion [17,86]. Factors that could stimulate further catecholamine release such as fear, stress, pain, hypothermia, shivering, hypoxia, and hypercapnia should be minimized as much as possible. Blood type should be determined and crossmatch considered prior to surgery. There is significant potential for intraoperative blood loss, particularly for tumors involving the right adrenal gland due to its proximity to the caudal vena cava. Therefore, packed RBCs, fresh frozen plasma, or whole blood should be available for immediate volume resuscitation if needed [2,55,56,86,91,106]. LRS and hypertonic saline can be used in the initial resuscitation of hemorrhagic shock and may stabilize cardiovascular parameters until a blood transfusion can be initiated [107,108]. Effects of hypertonic saline outlast those of LRS [108]. Continuous ECG and invasive arterial blood pressure measurement should be performed to identify and manage cardiac arrhythmias and abrupt changes in blood pressure [17,86]. Multiple intravenous access sites should be available to promptly manage intraoperative complications. Central venous access may be beneficial for intraoperative and postoperative management. Although most anesthetic drugs have been used in animals with PHEO with some success, drugs with sympathomimetic or vagolytic effects, such as ketamine and anticholinergics, are often avoided to prevent possible adverse hemodynamic responses. Histamine release associated with morphine and atracurium administration may result in sympathetic stimulation in response to vasodilation. Thiobarbiturates and halothane, though no longer available in many countries, have historically been avoided owing to their tendency to cause ventricular arrhythmias, especially in the presence of high catecholamine levels. Acepromazine may complicate the treatment of hypotension due to its α‐adrenergic receptor blocking effects, particularly if the animal has been pretreated with phenoxybenzamine [2,27,56,86]. Case reports in humans and dogs suggest that dexmedetomidine could aid in controlling hypertensive surges during anesthesia of patients undergoing PHEO excision. Catecholamine release and sympathetic response may be reduced by dexmedetomidine binding to presynaptic α2‐adrenergic receptors resulting in inhibition of norepinephrine release [109]. Based on the authors’ experience, administration of dexmedetomidine (0.5–1 μg/kg/h) IV as a CRI is helpful to stabilize blood pressure changes intraoperatively. There is, however, a lack of controlled studies investigating the effects of dexmedetomidine on physiological variables and perioperative outcomes of animals undergoing adrenalectomies [110–113]. A suggested balanced anesthetic protocol for animals with PHEO includes IV premedication with an opioid that does not promote histamine release (e.g., hydromorphone, methadone, or fentanyl) combined with a benzodiazepine. Induction of anesthesia may be accomplished with IV propofol, alfaxalone, or etomidate [55,89,98]. Isoflurane or sevoflurane is preferred for anesthetic maintenance as opposed to desflurane, which can cause sympathetic stimulation [114]. Inhalant agents should be supplemented with a potent, rapid‐acting opioid CRI (e.g., fentanyl, sulfentanil, or remifentanil) and potentially other MAC‐sparing agents combined in a balanced anesthetic protocol [2,86,89]. Drugs for the treatment of perioperative complications must be readily available for administration when an emergency arises, especially during induction of anesthesia or tumor manipulation. The authors recommend calculation of all emergency drugs prior to anesthesia, and it may be beneficial to prepare syringes of those most likely to be needed in advance. Table 42.2 provides drug dosages for antiarrhythmic therapy and blood pressure support. Profound fluctuations in blood pressure are often observed during PHEO surgery. Sodium nitroprusside, a direct‐acting vasodilator, is the agent of choice to treat severe hypertension due to its potency, rapid onset, and short duration of action. Phentolamine, a short‐acting competitive α‐adrenergic receptor antagonist and direct vasodilator, is an alternative for the treatment of intraoperative hypertension [17,27,55,86,89]. Another commonly administered agent is magnesium sulfate (MgSO4). In human patients, MgSO4 has been used for the treatment of hypertension and arrhythmias during anesthesia. MgSO4 inhibits the release of catecholamines from the adrenal medulla and peripheral nerve terminals, reduces the sensitivity of α‐adrenergic receptors to catecholamines, is a direct vasodilator, and has antiarrhythmic effects [4,27]. Table 42.2 Treatments for intraoperative complications in animals with pheochromocytoma. Source: Veres‐Nyéki [2]; Koenig [4]; Kyles et al. [55]; Santoro‐Beer and Mandell [86]; Viilman and Vettorato [113]; Robinson [115]; Pedro et al. [116]; Nazari et al. [117]. BP, blood pressure; CRI, constant rate infusion. Arrhythmias are another common perioperative complication of animals with PHEO. Tachyarrhythmias are usually managed with lidocaine or β‐adrenergic receptor antagonists. Esmolol, a β‐adrenergic blocker, has a rapid onset, a short duration of action, and readily controls heart rate [2,4,17,27,86]. Supraventricular and ventricular rhythm disturbances are sometimes managed with the class III antiarrhythmic agent, amiodarone, that blocks potassium channels but also inhibits β‐adrenergic receptors, calcium channels, and sodium channels [115–117]. Reflex bradycardia may also occur secondary to hypertension. Appropriate management of blood pressure usually corrects the changes in heart rate. However, if bradycardia is accompanied by hypotension, anticholinergics may be required. Intraoperative and postoperative hypotension following PHEO excision is common. It is multifactorial due to an immediate decrease in catecholamine concentrations, vasodilation from residual α‐adrenergic receptor blockade caused by phenoxybenzamine, impaired sympathetic reflexes, and hypovolemia. Treatment includes reduction of inhalant concentration, reduction or discontinuation of nitroprusside/phentolamine/magnesium sulfate, and volume expansion with isotonic crystalloid or colloid fluids. Vasopressor (e.g., phenylephrine and norepinephrine) and inotropic drugs are used to treat refractory hypotension, although patients treated with phenoxybenzamine may be less responsive to vasopressor therapy [2,17,27,86,118]. Treatment with a non‐catecholamine pressor, such as vasopressin, may be necessary to maintain adequate blood pressure [118]. To protect vital organs from reduced oxygen delivery, surface‐induced hypothermia to a temperature of 32 °C (89.6 °F) has been advocated for animals requiring temporary vascular occlusion during PHEO resection [55,89,119]. Additionally, during anesthesia, blood pressure values should be maintained close to the animal’s baseline blood pressure to prevent renal hypoperfusion and ischemia. If bilateral adrenalectomy has been performed, glucocorticoid and mineralocorticoid replacement therapy will be necessary. In addition, blood glucose should be monitored postoperatively because hypoglycemia may occur when plasma catecholamine concentrations decrease suddenly. Continuous ECG and blood pressure monitoring should be maintained for at least 24 h postoperatively [27,86]. During the recovery period, thromboembolic events may occur. Antithrombotic drugs should not be discontinued in animals at high risk for thrombosis; however, they may be withheld in cases of low to moderate risk. In these cases, antithrombotic drugs can be restarted immediately after the procedure if there is no evidence of ongoing bleeding or if development of a thrombosis occurs [54]. The pancreas is a nodular, bilobed gland located within the mesentery at the angle where the duodenum meets the stomach. The pancreas is composed of acini and pancreatic islets, previously known as “islets of Langerhans.” The acinar cells produce and secrete digestive enzymes via the pancreatic duct into the duodenum. Two pancreatic ducts are usually found in the dog but only one in the cat. The pancreatic or dorsal duct drains the left lobe and joins the main bile duct before entering the duodenum at the major duodenal papilla; the ventral or accessory duct drains the right lobe into the duodenum at the minor duodenal papilla. The cat has only the dorsal duct to drain both areas [120]. The pancreatic islets secrete hormones such as insulin (β‐cells), glucagon (α‐cells), somatostatin (δ‐cells), and pancreatic polypeptide (pancreatic polypeptide cells) into the bloodstream, thereby exerting critical endocrine effects. Pancreatic endocrine disorders involving insulin include diabetes mellitus and insulinoma. The kidneys are essential for maintenance of extracellular fluid homeostasis. When they are unable to adequately concentrate urine and maintain fluid balance either due to impaired production of ADH or impaired renal response to ADH, the resulting endocrine disorder is known as “diabetes insipidus.” Diabetes mellitus (DM) occurs due to inadequate insulin secretion or resistance to the effects of insulin, which culminates in the development of hyperglycemia. Hyperglycemia occurs following impairment of glucose uptake into tissues and increased hepatic gluconeogenesis. It results in fluid shifting from the intracellular space into the intravascular space thus causing cellular dehydration. In dogs, the predominant form of DM is caused by β‐cell destruction resulting in insulin deficiency and hyperglycemia. This is homologous to type 1 DM in people [121,122]. In cats, insulin resistance is most common. Insulin is available, but target tissues have an impaired ability to respond to its metabolic effects, and eventual exhaustion of β‐cells ensues [123]. This is homologous to type 2 DM in humans [121,123–125]. In approximately ¼ of cats, DM is secondary to hypersomatotropism. DM occurs most often in middle‐aged or older animals. In dogs, there is a female sex predilection, whereas in cats, it is more frequently diagnosed in neutered males [121,123,126]. There are several canine breeds at increased risk for DM, including the Australian Terrier, Miniature and Standard Schnauzers, Samoyed, Miniature and Toy Poodles, Cairn Terrier, Keeshond, Bichon Frise, and Finnish Spitz [127]. Reports indicate that Burmese cats may be at a higher risk in some geographical areas [123]. Because cats primarily have the type 2 form, obesity increases the risk of diabetes dramatically in this species [123,128]. The clinical presentation of animals with DM may be non‐specific, but a common reported sign is polyuria/polydipsia (PU/PD). When the concentration of glucose in the plasma exceeds the renal threshold for proximal tubular reabsorption of glucose from the filtrate, glucosuria ensues, causing osmotic diuresis and PU/PD. Animals may also be dehydrated or hypovolemic. Because DM is a catabolic condition, dogs with insulin deficiency may have severe depletion of both energy stores and protein mass. Clinical signs such as lethargy, polyphagia, and weight loss may be seen. Older cats (> 7 years) with weight loss and polyphagia should be tested for hyperthyroidism as clinical signs of both diseases are similar and can occur concurrently [129]. Other signs of DM depend on the severity and chronicity of hyperglycemia. Cataracts are common in dogs with DM due to disruption of normal lens metabolism (Fig. 42.5), and some cats with chronic DM develop a peripheral neuropathy that results in a plantigrade posture (Fig. 42.6). In severe manifestations of DM such as diabetic ketoacidosis (DKA) or hyperglycemic hyperosmolar syndrome (HHS), patients can present in critical condition with clinical signs of vomiting, anorexia, severe dehydration, depression, coma, or death. Ketones are synthesized from fatty acids as a substitute form of energy because glucose is not transported into the cells. Excess ketoacids results in acidosis and severe electrolyte abnormalities, which can be life‐threatening. HHS is an uncommon form of diabetic crisis marked by severe hyperglycemia, minimal or no urine ketones, hypovolemia, decreased glomerular filtration rate (GFR), weakness, and possible coma. Animals with DKA often have other concurrent diseases such as acute pancreatitis, urinary tract infection, and hyperadrenocorticism [130]. Animals with DKA and HHS should be stabilized prior to undergoing sedation or anesthesia. Figure 42.5 A 9‐year‐old diabetic Schnauzer with cataract‐associated uveitis. The dog required general anesthesia for phacoemulsification. Source: Dr. Stephanie Pumphrey, Veterinary Ophthalmology, Cummings School of Veterinary Medicine at Tufts University, North Grafton, MA; with permission. Figure 42.6 Plantigrade posture in a cat with DM is caused by peripheral neuropathy. The posture itself may not represent a complicating factor for anesthesia; however, it does suggest chronic and/or uncontrolled diabetes. Serial measurements of blood glucose during anesthesia, ± insulin/dextrose administration, are warranted perioperatively. Source: Dr. Todd Green, Department of Small Animal Medicine and Surgery, St. George’s University, St. George’s, Grenada; with permission. Findings on CBC are often normal, but dogs and cats with DKA may present with a non‐regenerative anemia. Leukocytosis may occur in animals with concurrent infection, which is common in DM and DKA. The most important serum biochemistry finding in animals with DM is hyperglycemia, but elevated liver enzyme activity and hypercholesterolemia may also occur [131]. In dehydrated patients, azotemia and electrolyte disorders including hypokalemia, hypernatremia, hyponatremia, hypophosphatemia, and hypochloremia can be observed. Pseudohyponatremia may be caused by hyperglycemia resulting in increased water retention in the intravascular space. Urinalysis should also be performed and glucosuria can be identified when the blood glucose (BG) exceeds the renal threshold, approximately 200 mg/dL in dogs and 250 mg/dL in cats [129,132]. Proteinuria and ketonuria may also be seen. Nitroprusside reagent urine test strips do not detect the dominant ketone produced in DKA, 3‐hydroxybutyrate (3‐HB); therefore, ketonuria may not be detected [133]. A 3‐HB ketone meter or serum 3‐HB could be used to identify the presence of this ketone. In dogs and cats with DKA, blood gas analysis reveals a low concentration of bicarbonate and, with the increased production of ketoacid anions, a high anion gap [134]. The hallmarks of diagnosis of DM are persistent hyperglycemia (BG > 200 mg/dL in dogs and > 270 mg/dL in cats with classic clinical signs of hyperglycemia) and glucosuria. In cats, stress hyperglycemia should be ruled out by reassessing BG in a calmer environment and/or measuring serum fructosamine concentrations [129]. Although treatment protocols are constantly evolving, dogs are commonly treated with either porcine lente (Vetsulin®) or neutral protamine Hagedorn (NPH) insulin, and cats with either glargine (Lantus®) or NPH insulin [129]. In cats, dietary management with diets low in carbohydrates and high in protein has been advocated [135]. Oral hypoglycemic drugs have been advocated to control hyperglycemia in diabetic cats, but the use of these drugs is not commonplace [136]. Treatment of DKA often requires hospitalization and critical care, including IV fluid therapy, insulin CRI, and intensive monitoring of acid–base status, fluid balance, glucose, and electrolytes [123,137,138]. Fluid therapy usually involves administration of an isotonic crystalloid. In animals with hypernatremia, 0.9% sodium chloride could be administered to minimize the risk of rapid sodium changes (> 0.5 mEq/h) and transcellular fluid shifts; however, it may result in increased chloride concentration and may not correct acidemia as well as other balanced electrolyte solutions [133,139]. Fluids such as Hartmann’s solution or polyionic hypotonic maintenance solution may be advantageous due to a resultant increase in bicarbonate and base excess [139]. LRS is avoided by some clinicians due to the hepatic conversion of lactate to ketones, whereas the buffers in Plasma‐Lyte® and Normosol‐R® are acetate and gluconate, which are metabolized by skeletal muscle [133,139]. Rapid‐acting insulins, such as regular insulin, are usually administered as CRIs, and close and regular monitoring of BG is required. Monitoring treatment success is somewhat controversial, but measurement of serum fructosamine concentrations may be used to evaluate long‐term control of hyperglycemia. Although serial BG curves have traditionally been recommended to assess the effects of insulin therapy, their use is called into question by studies in both dogs and cats showing their poor reliability for predicting glycemic control [140,141]. In cases of DKA and during anesthesia of animals with DM, serial BG measurements should be performed. Continuous glucose monitors that measure rapid changes in interstitial glucose levels have been used with success in dogs with DKA. In well‐regulated diabetic dogs, the BG concentration measured within 1–4 h of insulin administration should be between 150 and 250 mg/dL. An early morning BG concentration greater than 300 mg/dL could suggest poor glycemic control. However, a single measurement does not confirm this because BG concentrations even in well‐controlled diabetic dogs may vary throughout the day and excursions of 400–600 mg/dL could be observed. In cases of high BG levels, inadequate glycemic control is more likely present if the fructosamine concentration is greater than 500 mg/dL [142]. Hyperglycemia has been associated with higher morbidity, depression of leukocyte function, increased wound infections, and decreased tissue perfusion in dogs and people [143,144]. Additionally, animals with unregulated diabetes can have marked fluctuation of BG concentrations during anesthesia. Anesthesia for elective procedures should be postponed in patients with poorly regulated DM. One exception to this recommendation is intact females with insulin resistance that require ovariohysterectomy before the disease can be controlled [142]. Fluid therapy to correct water losses and electrolyte imbalances should be instituted before anesthesia. In any hyperglycemic and DKA animal, hydration status, acid–base status, and electrolyte imbalances should be assessed and corrected as preoperative hyperglycemia can contribute to hyperosmolar diuresis with subsequent dehydration, hypovolemia, and increased risk for intraoperative hypotension [2,30,145]. When dogs and cats with diabetes require anesthesia for medical and surgical procedures, these may not be directly related to DM or may be due to comorbidities secondary to DM. For example, many diabetic dogs develop cataracts, which require removal via phacoemulsification under anesthesia [2]. Timely monitoring of serum BG during the perioperative period and appropriate intervention (e.g., with regular insulin or dextrose administration) can help prevent severe hyper‐ and hypoglycemia during the perioperative period. Patients with DKA should not be anesthetized until clinical signs have subsided and the animal has been stabilized. Whenever possible, anesthetic procedures for patients with DM should be performed early in the day to reduce the need for prolonged fasting times, to allow for a rapid return to normal activity and insulin regimen, and to allow for close monitoring postoperatively. Although preoperative fasting times can vary, food is often withheld after 10 pm for morning procedures. On the day of anesthesia, numerous fasting and insulin administration protocols have been recommended (Table 42.3). Although glycemic control was achieved with most protocols, withholding insulin completely was associated with greater increases in intraoperative BG levels [146,147]. In animals receiving basal insulin, dose reduction prior to anesthesia may not be necessary. However, intermediate‐acting insulin dose may need to be decreased pending fasting duration. Note that there is no consensus statement in veterinary medicine on fasting times and insulin regimens preoperatively. Additionally, there are no data on the association between level of glycemic control and postprocedural or long‐term outcome. Serial BG measurements before and after induction of anesthesia, every 30–60 min throughout anesthesia, and postoperatively are often required. However, the time and frequency of rechecks may vary depending on the BG results obtained. If BG values are consistently stable, measurements may be performed less often. If BG fluctuations are moderate to severe, this should prompt the clinician to monitor the values closely and undertake more frequent sampling. Dextrose solutions may be provided to maintain BG levels within the patient’s normal or clinically acceptable range. It is important to remember that stress‐induced increases in BG may occur due to anesthesia and surgery and should also be taken into consideration when evaluating BG levels. Table 42.3 Summary of suggested guidelines for preoperative insulin management of diabetic patients based on retrospective studies, clinical studies, and textbooks.
42
Physiology, Pathophysiology, and Anesthetic Management of Patients with Endocrine Disease
Introduction
Anatomy and physiology
Adrenal gland
Hypoadrenocorticism
Clinical presentation
Clinical pathology
Diagnosis and treatment
Anesthetic considerations and management
Treatment
Dose
Mechanism
Comments
Replacement crystalloid fluids
Shock dose (dogs 90 mL/kg; cats 60 mL/kg) in aliquots of ⅓ of total dose based on patient reassessment
Correction of hypovolemia, dilution of K+, and diuresis
K+ in balanced crystalloids has not been reported to exacerbate hyperkalemia
Calcium gluconate 10% solution
0.5–1.5 mL/kg IV over 10–20 min
Increases cardiac myocyte threshold potential, restores normal gradient between threshold potential and resting membrane potential, reduces myocardial irritability
Monitor ECG and slow/discontinue if bradycardia or arrhythmias occur
Does not lower K+; antagonizes effect of hyperkalemia on myocardium
Rapid onset of action
Regular insulin followed by dextrose
0.2–0.5 U/kg insulin IV followed by 4 mL dextrose (12.5–25%) IV per unit of insulin
Insulin stimulates transport of glucose and K+ into cells
Rapid onset of action
Monitor blood glucose levels
Dextrose
0.5–1 mL/kg IV bolus followed by dextrose (2.5%–5%) IV CRI
May stimulate endogenous insulin secretion
Monitor blood glucose levels
Sodium bicarbonate
1–3 mEq/kg IV over 30 min
Corrects metabolic acidosis; promotes K+ uptake into cell in exchange for H+ via Na+‐K+ ATPase
Reserved for severe metabolic acidosis; controversial as first‐line therapy
Hyperadrenocorticism
Clinical presentation
Clinical pathology
Diagnosis and treatment
Anesthetic considerations
Anesthetic management
Pheochromocytoma
Clinical presentation
Clinical pathology
Diagnosis and treatment
Anesthetic considerations
Anesthetic management
Complication
Drug
Dose
Comments
Hypertension
Nitroprusside
Phentolamine
Magnesium sulfate (MgSO4)
0.1–10 μg/kg/min IV
0.1 mg/kg IV followed by at 1–2 μg/kg/min CRI
50 mg/kg (diluted) over 15 min, followed by 15 mg/kg/h CRI
Dilates arterioles and veins independent of catecholamines; direct BP monitoring preferred
Induces short‐acting α‐adrenergic blockade
Inhibits catecholamine release, induces α‐adrenergic blockade, directly dilates arterioles
Tachyarrhythmia
Lidocaine
Esmolol
2 mg/kg IV, followed by 50–80 μg/kg/min CRI
0.25–0.5 mg/kg IV over 1–2 min followed by 10–200 μg/kg/min CRI
For management of ventricular arrhythmias
Only after α‐adrenergic blockade or may precipitate hypertensive crisis; induces short‐acting β1‐adrenergic blockade; for sinus or supraventricular tachycardia
Refractory hypotension
Phenylephrine
Norepinephrine
Vasopressin
0.4–4 μg/kg/min CRI
0.05–1 μg/kg/min CRI
0.2–0.8 IU/kg IV and/or 0.002–0.006 IU/kg/min CRI
Induces potent α1‐adrenergic agonism; may cause vagally mediated bradycardia; use lowest effective dose
Use lowest effective dose
Indicated if patient has reduced sensitivity to catecholamines; works in acidic environment; use lowest effective dose
Pancreas and kidney
Diabetes mellitus
Clinical presentation
Clinical pathology
Diagnosis and treatment
Anesthetic considerations
Anesthetic management
Fasting time
Preoperative insulin regimen
Dextrose administration
Outcome and/or comments
Reference
6 and 12 h
½ usual insulin dose SC morning of surgery
No dextrose administered
Lower intraoperative increases in BG in groups receiving insulin compared to group where insulin was withheld;
No dogs became hypoglycemic
Adami C, et al., 2020 [146]; retrospective study
12 h
Full insulin dose SC morning of surgery
12 h
No insulin morning of surgery
7–7.5 h
¼ usual insulin dose SC morning of surgery
ND or not administered
No dogs became hypoglycemic;
Normoglycemia in 4% of samples;
Severe hyperglycemia in 58% of samples
Kronen P, et al., 2001 [147]; prospective clinical study
Full insulin dose SC morning of surgery
Hypoglycemia in 25% of dogs;
Normoglycemia in 15% of samples;
Severe hyperglycemia in 57% of samples
6 h
Full usual intermediate‐acting insulin dose SC in the afternoon prior to surgery
No dextrose administered
No dogs became hypoglycemic intraoperatively;
hyperglycemia (> 300 mg/dL) in 65% of dogs
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