Bonnie Hay Kraus1 and Philip Johnson2 1 Department of Veterinary Clinical Sciences, College of Veterinary Medicine, Iowa State University, 1809 South Riverside Drive, Ames, IA, 50011, USA 2 Department of Veterinary Medicine and Surgery, College of Veterinary Medicine, University of Missouri, 900 East Campus Drive, Columbia, MO, 65211, USA The understanding and recognition of equine endocrine disease has expanded significantly over the past decade. Endocrine disorders may have a primary cause or may be secondary to other systemic disease. Many of these disorders can be interlinked and affect multiple body systems. Aging horses are at increased risk for endocrine disease. The two most common endocrine diseases are pituitary pars intermedia dysfunction (PPID) and insulin dysregulation/equine metabolic syndrome (EMS/ID). Other endocrine diseases in aged horses may be associated with neoplasia (diabetes mellitus [DM], thyroid, parathyroid, and adrenal disease). PPID is the most common endocrine disorder in geriatric horses, with a reported prevalence of ~21% in horses aged 15 years or older (McGowan et al. 2013; Miller et al. 2016). It is a clinical syndrome associated with hypertrichosis (hirsutism), chronic laminitis, epaxial muscle atrophy, weight loss, polyuria/polydipsia, and lethargy (Figure 11.1). PPID was originally and erroneously referred to as an equine manifestation of Cushing Disease due to similarities with humans and canine conditions. In those species, pituitary adenomas of the pars distalis (adenohypophysis) secrete excessive proopiomelano(lipo)cortin (POMC)‐derived peptides, primarily ACTH (adrenocorticotropic hormone or corticotropin) and lead to secondary hyperadrenocorticism. In horses, increased secretion of POMC‐peptides arises from melanotropes in the pars intermedia (PI) and results in increased secretion of numerous melanocortins with ACTH being a relatively minor product. Normally, melanocortin secretion by the PI is inhibited by dopamine from the hypothalamus. PPID is a neurodegenerative disease in which there is loss of the normal dopaminergic inhibition, leading to secondary endocrinopathy (McFarlane 2011; McFarlane and Toribio 2010). The pituitary gland (hypophysis) lies within a bony cavity (the sella turcica) of the sphenoid bone in the base of the skull (McFarlane 2011). The gland is divided into anterior and posterior lobes which have different embryological origins and functions. The posterior pituitary lobe (neurohypophysis or pars nervosa) consists of a collection of axons and nerve terminals originating in the hypothalamus (McFarlane 2011). The pars nervosa stores and secretes oxytocin and vasopressin (also known as antidiuretic hormone or ADH) (McFarlane 2011). The anterior pituitary (adenohypophysis) includes the pars tuberalis and the pars distalis (also called the pars ventralis). The pars distalis contains endocrine cells that synthesize, store, and release six different hormones in response to stimulating or inhibiting factors from the hypothalamus: growth hormone (GH, somatotropin), follicle stimulating hormone (FSH), luteinizing hormone (LH), prolactin (PRL), thyroid stimulating hormone (TSH, thyrotropin), and adrenocorticotrophic hormone (ACTH, corticotropin). The corticotropes of the pars distalis produce the pre‐pro‐hormone POMC which is converted into beta‐lipotropin and ACTH, which are subsequently released into the circulation. Figure 11.1 A 22‐year‐old pony with hypertrichosis as a result of pituitary pars intermedia dysfunction (PPID). The PI lies between the anterior and posterior pituitary lobes. The primary endocrine cells are melanotropes, which also produce POMC. PI‐derived POMC undergoes further peptide cleavage and modification resulting in the secretory products (melanocortins): alpha melanocyte‐stimulating hormone (α‐MSH), beta‐endorphin (β‐END), corticotropin‐like intermediate lobe peptide (CLIP), and ACTH (McFarlane 2011). Alpha‐MSH exerts potent anti‐inflammatory activity through inhibition of cytokine production and plays a role in metabolism and obesity (McFarlane 2011). The function of CLIP is not completely understood but it may enhance pancreatic insulin release, thus promoting hyperinsulinemia, a risk factor for endocrinopathic laminitis. β‐END is a potent endogenous opioid agonist. Melanotrope‐derived ACTH represents a significant minority (~2%) of the secreted output from the normal pituitary gland. For further detailed information on normal and pathologic equine pituitary function, the reader is referred to the referenced textbooks. Overproduction of melanocortins is the endocrinological basis of PPID. In health, melanocortin secretion is tonically inhibited by dopamine released from the periventricular nuclei of the hypothalamus. PPID results from loss of this normal dopaminergic inhibition. Therefore, PPID is a primary neurodegenerative disease with secondary endocrinopathic consequences. Macroscopic enlargement of the pituitary gland is evident in some but not all cases of PPID, and histological examination is needed to identify small (micro) adenoma formation in the PI of affected pituitary glands. The overall clinical picture for PPID varies quite significantly between affected individuals due to heterogeneity in the PI‐derived melanocortins produced by a given patient. For example, elevated levels of secreted β‐END with enhanced opioid effectiveness in PPID cases may contribute to the lethargy and somnolence seen in some individuals. Horses affected with PPID develop diminished systemic inflammatory responsiveness, possibly explained by the anti‐inflammatory actions of elevated circulating melanocortin concentrations. Inhibited pain expression in the face of laminitis may lead to detrimental disruption of the digital lamellae in physically active PPID‐affected individuals due to repeated uninhibited mechanical loading. Immunosenescence and inhibited inflammatory responsiveness also contribute to an increased risk of infection in PPID‐affected horses. A recent study suggested that age is the only risk factor for PPID (Ireland and McGowan 2018). Clinical manifestations, including laminitis, are reported to be more severe in the fall (autumn) season. Diagnosis of PPID in older horses that have developed inappropriate hirsutism (hypertrichosis, retention of the haircoat) is often presumptively made without corroborative endocrinological testing. PPID also occurs to an extent greater than previously recognized in younger horses (especially, ponies), and the clinical expression of PPID in these younger horses may not be so pathognomonic. Although it is most commonly diagnosed in horses and ponies aged over 18 years, PPID has been diagnosed in ponies less than seven years of age. A diagnosis of PPID in the absence of inappropriate hirsutism can be challenging because several aspects of the clinical appearance of PPID could be attributed to other primary diseases (e.g. laminitis resulting from any cause) or the effects of advancing age. However, with time, horses affected with PPID eventually develop a characteristic physical appearance. Clinical abnormalities observed in younger horses include endocrinopathic laminitis, reduced athletic performance, lethargy, changed personality, and reduced shedding of haircoat and regional hypertrichosis, and changes in body morphology, including regional adiposity. PPID should be suspected in mature and geriatric horses and ponies that are presented for diminishing athletic performance, ill‐thrift, changing body condition (skeletal muscle atrophy, abdominal rotundity, regional adiposity), chronic laminitis, polyuria/polydipsia (PU/PD), and haircoat abnormalities. PPID‐affected equids tend to lose skeletal muscle mass (especially from the gluteal and epaxial musculature), and to acquire a characteristic “regional” distribution of body fat. Paradoxically, some younger PPID‐affected horses may be in normal or generally obese bodily condition. Endocrinopathic laminitis is usually recognized in horses and ponies with concomitant EMS/ID and presents as abnormalities of hoof structure and growth rather than lameness. Signs of laminitic pain (stiffness, lameness, etc.) may be diminished as a result of the combined anti‐inflammatory (α‐MSH) and analgesic (β‐endorphin) actions of elevated circulating melanocortins in PPID. However, PPID‐associated endocrinopathic laminitis can certainly cause very severe pain and lameness in some cases. Other clinical problems that develop as a result of PPID include abnormalities of thermoregulation (inappropriate sweating or “hyperhidrosis,” hypohidrosis, or anhidrosis), lethargy, infertility or inappropriate lactation (galactorrhea) in mares, suspensory ligament degeneration, blindness, and seizures. Ophthalmic (corneal) health is often compromised because the combination of increasing age and PPID elevates the risk of nonhealing or recurrent corneal ulcers in horses and lead to the development of corneal degeneration and calcific band keratopathy (Miller et al. 2013; Berryhill et al. 2017). Reduced immune function due to elevated circulating levels of immunosuppressive factors (α‐MSH, β‐endorphin, and cortisol) can result in affected horses that are presented with opportunistic infections including equine protozoal myeloencephalitis, chronic dermatitis, tooth root infection, bronchopneumonia, and infection of the urinary tract. Although the diagnosis of PPID is commonly made based on the development of a characteristic clinical appearance, endocrine testing is important to establish the diagnosis in less advanced, less certain cases. Moreover, it is necessary to discriminate the clinical effects of PPID from those associated with advancing age in general. Many horses with PPID are often concomitantly affected with EMS/ID. EMS/ID requires its own specific testing and has its own line of specific treatment (see section on EMS/ID). Endocrinological tests are utilized for establishing a diagnosis of PPID. The most straightforward test for PPID is to determine the plasma ACTH concentration and evaluate the result in light of seasonally appropriate reference intervals. An elevated plasma ACTH concentration is diagnostic for PPID in resting horses that are not concomitantly affected with either severe pain or systemic disease. Specific information on currently recommended testing methodologies can be found in the findings from the Equine Endocrinology Working Group (https://sites.tufts.edu/equineendogroup). Previously, endocrinopathic laminitis was thought to be a clinical abnormality in early cases of PPID. However, recent recognition that insulin causes endocrinopathic laminitis has led to a revision of our understanding regarding the relationship between PPID and laminitis. Endocrinopathic laminitis is now attributed to a manifestation of hyperinsulinemia/ID and not directly to PPID. Thus, the endocrinopathic condition associated with insulin‐mediated laminitis is equine metabolic syndrome or insulin dysregulation. These two conditions (PPID and EMS/ID) are regarded as independent diseases though some horses and ponies may develop both conditions. The development of PPID in EMS/ID‐affected individuals is associated with more severe manifestations of endocrinopathic laminitis that may severely cripple horses. A complete blood count (CBC) and serum/plasma biochemical analysis should be included in the pre‐anesthetic work‐up of all PPID‐affected horses and ponies to provide information regarding overall health and evidence of significant co‐morbidities that may or may not be evident upon review of the patient’s medical history or following physical examination. There are usually no specific hematologic or serum/plasma biochemical abnormalities associated with the diagnosis of PPID, and abnormalities identified in geriatric horses may be interpreted as indicators of inflammation or disease due to age or co‐morbidities, rather than PPID. Commonly identified but nonspecific abnormalities include leukocytosis (neutrophilia, lymphopenia), hyperfibrinogenemia, anemia, hypertriglyceridemia (more common in ponies), hyperglycemia, and increased liver enzymes. Hyperglycemia is the most commonly identified abnormality on serum/plasma biochemical analysis in these cases (McFarlane 2011). Elevated liver enzyme activities may be consistent with histopathologic hepatopathy in >70% of horses with PPID (Glover et al. 2009). Glycosuria is a common finding on urinalysis in horses with both PPID and hyperglycemia (Toribio 2010). Hyperglycemia in an aged horse, although nonspecific, should trigger consideration of PPID as it is present in 45–95% of horses with PPID (Toribio 2010). Horses and ponies with both PPID and hyperglycemia are also commonly affected with EMS/ID; hyperinsulinemia has been documented in ~32% of horses with PPID (McGowan et al. 2013). Clinically, hyperinsulinemia associated with normoglycemia is referred to as “compensated” insulin resistance (IR), and hyperinsulinemia with hyperglycemia is “decompensated” IR (or type‐2 DM). Insulin resistance, EMS/ID, and diabetes are discussed in a separate section (see the following text). Human beings and dogs with endocrine abnormalities associated with glucose dysregulation (usually DM and/or IR) have higher complication and mortality rates attributed to the effects of altered glucose homeostasis on the cardiovascular, renal and central, peripheral, and autonomic nervous systems. The pathophysiology of many of these effects involves damage to the vascular endothelium throughout the body. Persistent hyperglycemia results in glycosylation of amino acids and stimulation of diacylglycerol synthesis and activation of protein kinase C causing blood vessel dysfunction (Frank and Tadros 2014). To date, there is little information regarding these effects in horses. It is unknown/undocumented whether horses develop hypertension and associated nephropathy, retinopathy, or peripheral or autonomic neuropathy. Systemic hypertension and left ventricular hypertrophy have been identified in ponies affected with chronic endocrinopathic laminitis (Rugh et al. 1987). Autonomic neuropathy has been documented in humans and dogs and results in altered parasympathetic and vasomotor tone, hypotension, decreased respiratory response to hypoxemia, and impaired thermoregulation, all of which provide concern during general anesthesia (Kadoi 2010a, b). When identified in PPID‐affected horses, hyperglycemia is usually mild and not sufficiently elevated to result in osmotic diuresis. With more severe degrees of hyperglycemia, osmotic diuresis and concomitant urinary loss of sodium and potassium may lead to hypovolemia. Some reports have suggested that polyuria/polydipsia occurs in ~30% of horses with PPID, perhaps a result of reduced antidiuretic hormone secretion, increased thirst due to hypercortisolism, or osmotic diuresis due to hyperglycemia/glycosuria. Moreover, inappropriate hyperhidrosis is commonly identified in PPID‐affected individuals and is believed to result from melanocortin‐induced abnormalities of thermoregulation. These abnormalities may contribute to alterations in body fluid and electrolyte abnormalities or imbalances. Therefore, it is important to assess the patient’s hydration and electrolyte status and correct any abnormalities prior to anesthesia whenever possible. Muscle wasting (sarcopenia) and weakness are common features of PPID and are most evident in the gluteal and epaxial musculature. Recently, a postmortem study comparing histopathologic changes in the suspensory ligaments of horses with PPID to old horses without PPID, and young horses revealed a possible association between PPID and degeneration of the suspensory ligament (Hofberger et al. 2015). Approximately 30% of horses with PPID develop chronic hypercortisolism. Chronic hypercortisolism leads to osteoporosis in humans and therefore the risk of complicating pathological fractures should be considered when PPID‐affected patients are being recovered from general anesthesia. Weight loss, ligament degeneration, sarcopenia, myasthenia, and neurologic impairment represent significant risk factors for injury during anesthetic recovery for PPID patients. Careful attention should be paid to proper positioning and padding of these horses in an effort to prevent post‐anesthetic myopathy/neuropathy. Anesthesia durations exceeding two hours, and especially greater than three hours, are associated with significantly higher mortality and so it is imperative to limit anesthesia duration to obviate these risks (Johnston et al. 1995). Rope assistance (tail or head and tail) during recovery may reduce mortality associated with musculoskeletal injuries (Bidwell et al. 2007; Niimura Del Barrio et al. 2018). When painful, laminitis may also contribute to difficulty achieving and maintaining a standing position following anesthesia. Providing appropriate analgesia and support during the recovery period may be helpful in reducing injury. Pergolide is the only drug presently approved for the treatment of PPID. It is used to support or re‐establish dopaminergic control of melanotropes in the PI. Pergolide is a potent dopamine (D2) agonist that also may exert some adrenergic and 5‐hydroxytryptamine effects. The administration of drugs that are antagonistic to the action of dopamine, such as phenothiazine tranquilizers (acepromazine), in horses being treated with pergolide may alter drug effectiveness. Two of the melanocortins, α‐MSH and β‐END, may diminish PPID patients’ responses to painful stimuli. Alpha‐MSH decreases cytokine production and therefore exerts a potent anti‐inflammatory effect, and β‐END is a potent endogenous opioid receptor agonist. Butorphanol is a mu‐antagonist, kappa agonist opioid commonly used in equine anesthetic patients as a premedication and as part of a multi‐modal analgesia protocol. However, since it is a mu‐antagonist, it may interact with endogenous β‐endorphins to partially reverse analgesic effects. Morphine (0.05–0.15 mg/kg intravenous [IV]) loading doses followed by a constant rate infusion (CRI) (0.03–0.1 mg/kg/h [0.5–1.7 μg/kg/min]) have been safely used for analgesia in horses without adverse behavioral or disrupted locomotor functions that could adversely affect recovery (Valverde 2013). Use of mu‐agonists at the lower end of the dose range, along with reliance on alternative classes of analgesic drugs for balanced anesthesia/analgesia techniques, may be warranted in these cases. Lidocaine, alpha‐2 agonists (xylazine, detomidine, romifidine, dexmedetomidine), and ketamine have all been used alone or in combination to provide balanced anesthesia and have been reviewed elsewhere (Valverde 2013). As noted above, PPID is most commonly diagnosed in geriatric horses (≥15 years of age) which now make up ~1/3 of the equine population (Ireland 2016). Along with the clinical and metabolic disturbances due to PPID, geriatric patients may also have additional significant age‐related co‐morbidities, including other endocrine, dental, musculoskeletal, respiratory, and cardiovascular disorders (Ireland 2016). These may serve as co‐morbidities that require consideration for anesthetic management or they may be a primary presenting complaint requiring general anesthesia. A complete and detailed physical examination, supported by appropriate diagnostic testing, will assist in identifying these co‐morbidities and allow for peri‐anesthetic planning and improved post‐anesthetic outcomes. For example, the addition of a CBC and serum biochemical analysis should be included in the pre‐anesthetic work‐up of all geriatric horses to provide information regarding general health and for evidence of co‐morbidities that may not be evident on physical examination. A thorough review of anesthesia in geriatric equine patients is beyond the scope of this chapter, and the reader is referred to other sources (Donaldson 2005). Musculoskeletal disease and lameness, specifically osteoarthritis, represent the second most frequent cause for referral and a major reason for euthanasia of geriatric horses (Ireland 2016). Laminitis is also a common lameness diagnosis in geriatric horses and has been reported in 24–82% of horses with PPID (Ireland 2016). Geriatric horses with lameness may present for advanced imaging, surgical intervention, or another primary complaint. Special care and attention should be taken with respect to proper positioning and padding, making sure that limbs are supported and that weight is evenly distributed. Use of multi‐modal analgesia, even if the procedure itself is not painful (e.g. MRI), may help alleviate patient discomfort, pain, and disability during recovery. Assisted rope recovery may also be beneficial since painful osteoarthritis and/or laminitis may affect the ability of geriatric patients to stand during recovery. Dental disorders, including tooth loss, diastemata, periodontal disease, and wear abnormalities affect a high proportion of geriatric horses. These horses may require general anesthesia for advanced imaging (e.g. computed tomography) and/or dental extractions. Some procedures may be accomplished standing using combinations of an alpha‐2 agonist, an opioid such as butorphanol or morphine, and locoregional anesthesia/analgesia (mental, inferior alveolar, infraorbital, and maxillary blocks). This multi‐modal approach provides synergistic effects and enables the use of lower doses of each individual drug. This approach would be especially advantageous in geriatric horses since they may have increased sensitivity to sedative drugs and altered clearance. Further information on anesthesia and sedation for sinus and dental disease can be found in Chapter 1. Colic is the most frequent reason for referral of horses ≥20 years old (Brosnahan and Paradis 2003; Silva and Furr 2013) and, depending on the study, is the most or second most common reason for euthanasia in geriatric horses (Ireland 2016; Miller et al. 2016). Geriatric horses referred to a surgical facility are more likely to have a surgical lesion compared to mature horses (Southwood et al. 2010). The etiologies of colic in geriatric horses tend to differ from those reported for younger horses. Geriatric horses have a higher frequency of cecal and large colon impactions which may be partly attributed to poor dentition (Ireland 2016). Horses ≥16 years of age are twice as likely to be diagnosed with a strangulating small intestinal lesion compared to horses aged 4–15 years with strangulating pedunculated mesenteric lipoma being the most common diagnosis. Current studies indicate that there is no significant difference regarding complications or short‐term survival between geriatric horses and mature horses (4–15 years) for small or large intestinal surgical lesions (Southwood et al. 2010; Gazzerro et al. 2015). For additional information on gastrointestinal disease, the reader is directed to the Chapter 10. Equine asthma or “heaves” is the most prevalent respiratory disease of geriatric horses (Ireland 2016; Marr 2016). Anesthetic management strategies of horses with equine asthma and other respiratory diseases are described in other chapters. It should be noted that PPID is an important predisposing cause of bronchopneumonia in older horses. Up to ~35% of PPID horses have opportunistic or secondary infections due to their inability to mount a satisfactory inflammatory response to pathogens. These infections may be recurrent and occult and not necessarily associated with obvious signs of respiratory disease; therefore, clinicians should adopt a high level of suspicion and pursue thorough physical examination and diagnostic tests such as cytological examination and microbiological culturing of airway fluid, thoracic radiography, and thoracic ultrasonography (Marr 2016). Cardiac murmurs are detected in ~20% of horses aged 15 years or older. Aortic valve degeneration is the most common of the valvular disorders and is associated with a pan‐, holo‐, or early diastolic, decrescendo murmur heard loudest over the aortic valve in the left fifth intercostal space and radiating toward the heart base (Marr 2016). Mitral regurgitation (MR) is also common in older horses and is associated with a systolic murmur heard loudest over the fifth intercostal space on the left side and radiating caudodorsally (Marr 2016). MR and AR are collectively referred to as left‐sided valvular regurgitation (LSVR). The prevalence of LSVR increases with age; 13.5% in horses 15–23 years old and 14.8% in horses ≥24 years (Stevens et al. 2009). Clinically important tricuspid regurgitation is not as common (~5%) in geriatric horses and always occurs in conjunction with LSVR. Irregular cardiac rhythm consistent with atrial fibrillation (AF) was detected in 2% of horses ≥15 years of age and 4.4% of horses ≥30 years of age (Ireland et al. 2012) and is likely associated with underlying structural cardiac changes in geriatric horses. Anesthetic management of horses with cardiac disease is described in a separate chapter. Neurologic impairment, including ataxia, blindness, seizures, and ‘narcolepsy’ (sleep deprivation) are more common in horses with PPID than aged horses without PPID (McFarlane 2011). Geriatric horses with PPID should be assessed for neurologic function prior to general anesthesia as neurological impediments may especially lead to serious complications during anesthetic recovery. EMS or ID represents a clustering of risk factors for endocrinopathic laminitis. Emphasis should be placed on the early identification of EMS/ID‐affected individuals that are at risk for laminitis and the institution of effective preventive measures because effective treatment of laminitis is often not possible. Endocrinopathic laminitis results directly from the influence of elevated circulating plasma insulin levels and any factor that might cause hyperinsulinemia likely increases the risk. Horses and ponies were traditionally characterized as being affected by EMS/ID when they had developed generalized obesity or regional adiposity, IR, and endocrinopathic laminitis. Other abnormalities that have also been identified in EMS/ID‐affected equids include hypertriglyceridemia (hepatic lipidosis in Miniature Horses), estrous cycling abnormalities, and abnormalities in the concentrations of some circulating plasma adipocytokines (hyperleptinemia, hypoadiponectinemia). EMS should be suspected in mature horses and ponies that develop either generalized obesity or regional adiposity. Regional adiposity refers to the gradual accumulation of subcutaneous adipose tissue deposits along the nuchal ligament and in proximity to the base of the tail. It should be emphasized that EMS/ID does not arise in all obese individuals and that EMS/ID is sometimes present in lean individuals. EMS/ID is regarded as the most common cause of laminitis in mature horses and ponies; thus, lameness is a common presenting complaint in EMS/ID‐affected individuals. Other less well‐characterized clinical manifestations include abnormalities of reproductive cycling in mature broodmares and seasonal hypertension. Recent studies further demonstrated that ponies with EMS/ID may be affected with myocardial hypertrophy (Heliczer et al. 2017). Insulin resistance is an important component of the hyperlipemia syndrome and hepatic lipidosis that develops in obese Miniature Horses and British pony breeds (and other breeds) when food intake has been diminished or discontinued. Although diagnosis of EMS may be suspected based on consideration of a patient’s breed, signalment, medical history, and results of physical/radiographic examination, corroborative endocrine testing should be undertaken to confirm the diagnosis and to establish a baseline characterization for future comparisons. The importance of endocrine testing is further appreciated when one considers that not all obese equids are affected by EMS/ID and that EMS/ID may develop in some relatively lean individuals. Diagnostic tests for EMS/ID may be categorized into those that evaluate the enteroinsular axis, those that evaluate IR, and those that evaluate related co‐morbidities. For routine clinical practice, it is recommended that diagnosis of EMS/ID should be undertaken in a stepwise manner, beginning with measurement of baseline values of insulin and glucose. A complete review of the different testing methods for EMS/ID is beyond the scope of this chapter. Specific information on currently recommended testing methodologies can be found in the findings from the Equine Endocrinology Working Group. The reader is also directed to published reviews (Bertin and de Laat 2017). Demonstration of an elevated resting plasma insulin concentration (resting hyperinsulinemia) when being fed hay or during pasture grazing (>50 μU/ml) is diagnostically supportive for EMS/ID. However, simply measuring plasma insulin concentration is an insensitive test for this condition as it produced many false negatives. Practical diagnosis of EMS/ID/IR is presently based on two applied dynamic tests, the oral sugar test (OST) and the insulin sensitivity test (IST). The OST consists of evaluating the plasma insulin concentration at 60 minutes following an oral dose of light corn Syrup (0.45 ml/kg of body weight). Diagnostic corroboration for EMS/ID is supported if the insulin concentration exceeds 63 μU/ml. The IST presently specifically recommended for the purpose of establishing whether an equine patient is affected with IR (Bertin and Sojka‐Kritchevsky 2013). Blood glucose concentration is measured before and at +30 minutes following IV administration of regular insulin (0.1 U/kg of body weight). In normal patients, the blood glucose concentration should decrease to below 50% of the baseline by 30 minutes. IR‐affected patients fail to reduce blood glucose to less than 50% of the starting concentration under the influence of insulin. In some instances, especially in older horses (>15 years of age), individuals may be affected by both EMS/ID and PPID. Although unproven, it has also been suggested that the presence of EMS/ID increases the likelihood that PPID will eventually develop. Currently, EMS/ID and PPID are regarded as independent conditions and the relationship between them is not fully understood. PPID‐affected horses that are not affected with EMS/ID are thought to be less likely to be affected by clinical laminitis. However, PPID may carry its own risk regarding hyperinsulinemia (the melanocortin CLIP stimulates pancreatic insulin secretion). Since PPID is readily treated with pergolide, it is recommended that older horses (>15 years) and ponies affected by EMS/ID be evaluated for PPID. If PPID is present, the risk of laminitis may be mitigated by pergolide treatment. The principles of treatment for EMS/ID fall into the following categories: As a defining component of EMS, obesity is associated with both IR and increased risk of laminitis. It is logical that the reversal of obesity should minimize the risk of laminitis and promote insulin sensitivity. Obese horses and ponies should not be “starved” for purposes of weight loss because severe calorie restriction leads to the activation of physiological mechanisms that promote worsening IR. Moreover, obese ponies, donkeys, and Miniature Horses are especially predisposed to hyperlipemia and hepatic lipidosis (potentially fatal) when subjected to a severely calorie restricted ration. Strategies intended to reverse obesity should include both increased physical activity and a reasonable, gradual restriction of dietary energy intake. Unfortunately, the development of painful laminitis in some EMS/ID‐affected equids precludes the prescribed exercise for purposes of promoting weight reduction. In those patients, dietary adjustments and the specific management of laminitis, including pain management, must be undertaken to better address both obesity and EMS/ID. For detailed information on feeding strategies for weight loss in EMS/ID horses, readers are directed to veterinary nutrition resources. In all cases, management of EMS/ID should be primarily centered on nutrition and exercise recommendations. Oral levothyroxine sodium appears to be helpful for the management of refractory cases of obesity and EMS/ID but should not be used as a lifelong management strategy. Levothyroxine sodium is usually administered daily (0.05–0.20 mg/kg, commonly 0.1 mg/kg) for a period of approximately three to six months. This treatment helps with initiation of weight loss in obese individuals and also promotes insulin sensitivity. The biguanide, metformin, is also recommended for treatment of EMS/ID (30 mg/kg, PO, q12 hours). In horses, metformin probably exerts a local pharmacological action at the epithelial lining of the small intestine and acts to inhibit glucose absorption, thus preventing both post‐prandial hyperglycemia and hyperinsulinemia. Orally administered metformin also promotes weight loss in obese equine patients. If the EMS/ID patient is concomitantly affected with PPID, treatment for PPID using pergolide mesylate (0.5–3.0 mg/day, PO, per 450 kg horse) should also be instituted. More recently, there has been increase in the use of sodium‐glucose co‐transporter 2 (SGLT2) inhibitors, such as velagliflozin, for the management of refractory cases of EMS/ID (Meier et al. 2018). SGLT2 inhibitors are showing promise as safe and effective drugs for the management of EMS/ID and prevention of laminitis by lessening hyperinsulinemic responses to dietary sugars and starch. Many horses and ponies afflicted with EMS/ID are also geriatric and may have concomitant PPID. The reader is referred to the above section which addresses the anesthetic concerns associated with these disorders and co‐morbidities. The primary remaining factor that has implications for general anesthesia is obesity. Several recent studies have documented the prevalence of obesity in horses in a variety of countries: 31.2% (Great Britain), 24% (Denmark), 24.5% (Australia), 28.6% (Canada) (Robin et al. 2015; Jensen et al. 2016; Potter et al. 2016; Kosolofski et al. 2017). Despite such a high prevalence of overweight/obesity in the horse populations of the world, there is little information regarding the implications or risk associated with anesthesia in these horses. Recently, a study suggested that a higher body mass index in horses may increase the risk for development of incisional complications (Hill et al. 2020). The veterinary literature regarding obesity and its relevance to anesthesia is in its infancy, and very little information is available even in small animal patients, despite an even higher prevalence of obesity of ~45% (Love and Cline 2015). Therefore, physiologic alterations and anesthetic management strategies are extrapolated from human and the few small animal references available. The reader is referred to comprehensive human texts for more complete review of the physiologic changes and anesthetic management of the obese anesthetic patient (Brodsky and Lemmens 2012; Leykin and Brodsky 2013). Obesity increases metabolic oxygen requirements and one of the earliest changes to compensate for this is an increase in circulating blood volume caused by fluid and sodium retention. Hypervolemia leads to increased preload, stroke volume, and cardiac output. Increased left ventricular preload causes chamber dilation and, eventually, eccentric left ventricular hypertrophy. Activation of the renin‐angiotensin‐aldosterone system leads to systemic hypertension and the development of concentric left ventricular hypertrophy. Ventricular dysfunction progresses and may lead to congestive heart failure known as “obesity cardiomyopathy” in people. Tissue pathology associated with obesity cardiomyopathy includes myocardial fibrosis, fatty infiltration of the myocardium, and abnormal accumulation of free fatty acids and lipids in cardiac myocytes. Both hyperaldosteronism and type‐2 DM predispose to fibrosis of the myocardial electrical conduction system leading to cardiac dysrhythmias. The extent to which obese horses develop any of these cardiovascular abnormalities is presently unknown. However, it has been shown that obese ponies with chronic laminitis often develop systemic hypertension (Rugh et al. 1987). Therefore, an important first step when considering general anesthesia for obese equine patients is to identify cardiac or cardiovascular abnormalities if they exist. To this end, careful evaluation of the cardiovascular system is warranted in all obese (and geriatric) horses. Although not routinely performed preoperatively in horses, indirect blood pressure measurement may identify hypertension in obese patients and may be a sentinel of cardiovascular dysfunction. Indirect blood pressure is readily measured using a blood pressure cuff placed around the tail or metatarsus (Garner et al. 1975; Olsen et al. 2016). Preoperative ECG
11
Anesthetic Management for Endocrine Diseases and Geriatric Horses
Introduction
Pituitary Pars Intermedia Dysfunction (PPID, Equine Cushing Disease)
Normal Anatomy/Physiology/Pathophysiology
Clinical Signs
Diagnosis
Endocrinopathic Laminitis
PPID – Specific Implications for Anesthesia
Hyperglycemia
Musculoskeletal Considerations
Drug Interactions in PPID Horses
Geriatric Co‐morbidities That May Affect Anesthetic Management
Musculoskeletal and Lameness Anesthetic Considerations in Geriatric Horses
Dental Anesthetic Considerations in Geriatric Horses
Gastrointestinal Anesthetic Considerations in Geriatric Horses
Respiratory Anesthetic Considerations in Geriatric Horses
Cardiac Anesthetic Considerations in Geriatric Horses
Neurological Anesthetic Considerations in Geriatric Horses
Equine Metabolic Syndrome/Insulin Dysregulation
Clinical Signs
Endocrine Tests for the Diagnostic Corroboration of EMS
Diagnostic Tests for IR
Testing EMS/ID Candidates for PPID
Treatment and Management of EMS/ID
Strategies for Reversal of Obesity
Pharmacological Strategies for the Management of Refractory EMS/ID
Implications for Anesthesia
Cardiovascular Effects of Obesity
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