Diabetic Ketoacidosis PDF

PART VII ENDOCRINE DISORDERS CHAPTER 64 DIABETIC KETOACIDOSIS Rebecka S. Hess, DVM, DACVIM KEY POINTS Diabetic ketoacidosis (DKA) is a severe form of complicated diabetes mellitus that requires emergency care. Acidosis and electrolyte abnormalities can be life threatening. Fluid therapy and correcti...

PART VII ENDOCRINE DISORDERS CHAPTER 64 DIABETIC KETOACIDOSIS Rebecka S. Hess, DVM, DACVIM KEY POINTS Diabetic ketoacidosis (DKA) is a severe form of complicated diabetes mellitus that requires emergency care. Acidosis and electrolyte abnormalities can be life threatening. Fluid therapy and correction of electrolyte abnormalities are the two most important components of therapy. Concurrent disease increases the risk for DKA and must be addressed as part of the diagnostic and therapeutic plan. Bicarbonate therapy usually is not needed, and its use is controversial. About 70% of treated dogs and cats are discharged from the hospital after 5 to 6 days of hospitalization. The degree of base deficit is associated with outcome in dogs with DKA. Additionally, dogs that have concurrent hyperadrenocorticism are less likely to be discharged from the hospital. Diabetic ketoacidosis (DKA) is a severe form of complicated diabetes mellitus that requires emergency care. 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. Copyright © 2014. Elsevier. All rights reserved. PATHOPHYSIOLOGY Ketone bodies are synthesized as an alternative source of energy when intracellular glucose concentration cannot meet metabolic demands. Ketone bodies are synthesized from acetyl-coenzyme A (acetyl-CoA), which is a product of mitochondrial β-oxidation of fatty acids. This adenosine triphosphate (ATP)–dependent catabolism of fatty acids is associated with breakdown of two carbon fragments at a time and results in formation of acetyl-CoA. Synthesis of acetyl-CoA is facilitated by decreased insulin concentration and increased glucagon concentration. The anabolic effects of insulin include conversion of glucose to glycogen, storage of amino acids as protein, and storage of fatty acids in adipose tissue. Similarly, the catabolic effects of glucagon include glycogenolysis, proteolysis, and lipolysis. Therefore a low insulin concentration and increased glucagon concentration contribute to decreased mobilization of fatty acids into adipose tissue and increased lipolysis, resulting in increased acetyl-CoA concentration. In nondiabetics, acetyl-CoA and pyruvate enter the citric acid cycle to form ATP. However, in diabetic patients, glucose does not enter the cells in adequate amounts and production of pyruvate by glycolysis is decreased. The activity of the citric acid cycle is therefore diminished, resulting in decreased utilization of acetyl-CoA. The net effect of increased production and decreased utilization of acetylCoA is an increase in the concentration of acetyl-CoA, which is the precursor of ketone body synthesis.1 The three ketone bodies synthesized in the liver from acetyl-CoA are acetoacetate, β-hydroxybutyrate, and acetone. Acetyl-CoA is converted to acetoacetate by two metabolic pathways, and acetoacetate is then metabolized to β-hydroxybutyrate or acetone. One of the pathways for acetoacetate synthesis involves condensation of two acetyl-CoA units and the other utilizes three units of acetyl-CoA.1 Acetoacetate and β-hydroxybutyrate are anions of moderately strong acids. Therefore accumulation of these ketone bodies results in ketotic acidosis. Metabolic acidosis may be worsened by vomiting, dehydration, and renal hypoperfusion (see Chapter 54).1 Metabolic acidosis and the electrolyte abnormalities that ensue are important determinants in the outcome of patients with DKA.2 It was previously believed that DKA patients have zero or undetectable endogenous insulin. However, in a study that included 7 dogs with DKA, 5 had detectable endogenous serum insulin concentrations, and 2 of these dogs had endogenous serum insulin concentration within the normal range.3 Similarly, a study documenting resolution of diabetes mellitus in 7 of 12 cats with DKA suggested that in some cats, DKA can develop despite residual and ultimately adequate insulin concentrations.4 Therefore it is possible that other factors, such as an increased glucagon, cortisol, or catecholamine concentrations, contribute to DKA. The concentration of these hormones may be increased because of concurrent disease. Cytokine dysregulation is likely also involved in the pathophysiology of DKA. A recent study in dogs found that interleukin 18 (IL-18), resistin, and granulocyte-monocyte colony-stimulating factor concentrations were significantly higher in dogs with DKA before treatment compared with after resolution of ketoacidosis, and keratinocyte chemoattractant was significantly higher in dogs with DKA compared with dogs with uncomplicated diabetes. Additionally, IL-8 and monocyte chemoattractant protein 1 were significantly higher in dogs with uncomplicated diabetes compared with healthy controls. It is not yet known whether the cytokine dysregulation observed in patients with DKA is due to presence of concurrent disorders or other reasons. Interestingly, in this study the changes in cytokine concentrations were more pronounced than the changes noted in glucagon concentration.5 RISK FACTORS The median age of dogs with DKA is 8 years (range 8 months to 16 years).2 The mean age of cats with DKA is 9 years (range 2 to 343 Silverstein, D., & Hopper, K. (2014). Small animal critical care medicine. Elsevier. Created from purdue on 2024-02-13 21:44:55. 344 PART VII ENDOCRINE DISORDERS 6 16 years). Breed or sex has not been shown to increase the risk of DKA in dogs or cats.2,6,7 Concurrent disease has been documented in about 70% of dogs with DKA and 90% of cats with DKA. The most common concurrent diseases noted in dogs with DKA are acute pancreatitis, bacterial urinary tract infection, and hyperadrenocorticism.2 The most common concurrent diseases noted in cats with DKA are hepatic lipidosis, chronic renal failure, acute pancreatitis, bacterial or viral infections, and neoplasia.6 It is possible that concurrent disease results in increased glucagon, cortisol, or catecholamine concentration and increased risk of DKA. Most dogs and cats with DKA are newly diagnosed diabetics. Insulin treatment may reduce the risk of DKA in dogs and cats.2,6 CLINICAL SIGNS AND PHYSICAL EXAMINATION FINDINGS Clinical signs and physical examination findings may be attributed to chronic unmanaged diabetes mellitus, concurrent disease, or the acute onset of DKA. The most common clinical signs in dogs or cats with DKA are polyuria and polydipsia, lethargy, inappetence or anorexia, vomiting, and weight loss.2,6,8 Common abnormalities noted on physical examination of dogs with DKA are subjectively overweight or underweight body condition, dehydration, cranial organomegaly, abdominal pain, cardiac murmur, mental dullness, dermatologic abnormalities, dyspnea, coughing, abnormal lung sounds, and cataracts.2 Common abnormalities noted in cats with DKA are subjectively underweight body condition, dehydration, icterus, and hepatomegaly.6 Copyright © 2014. Elsevier. All rights reserved. CLINICAL PATHOLOGY Approximately 50% of dogs with DKA have a nonregenerative anemia (which is not associated with hypophosphatemia), neutrophilia with a left shift, or thrombocytosis.2 Anemia and neutrophilia with a left shift are also common features of feline DKA.6 Cats with DKA also have significantly more red blood cell Heinz body formation than do normal cats, and the degree of Heinz body formation is correlated with plasma β-hydroxybutyrate concentration.9 Persistent hyperglycemia is apparent in all dogs and cats diagnosed with DKA unless they have received insulin.2,6 Alkaline phosphatase activity is increased in almost all dogs with DKA.2 Alanine aminotransferase activity, aspartate aminotransferase activity, and cholesterol concentration are increased in about half of dogs with DKA.2 Increases in alanine aminotransferase activity and cholesterol concentration are also commonly observed in cats with DKA.6 Azotemia is reported more commonly in cats than in dogs with DKA.2,6,8 Electrolyte abnormalities are common in both dogs and cats with DKA.2,6,8 Initially an animal with DKA may appear to have extracellular hyperkalemia caused by dehydration, decreased renal excretion, hypoinsulinemia, decreased insulin function, hyperglycemia, and acidemia (leading to movement of hydrogen ions into the cells and potassium ions out to maintain cellular electronegativity). However, with rehydration, potassium ions are lost from the extracellular fluid and a true hypokalemia from depletion of total body potassium stores often becomes apparent. Hypokalemia may be exacerbated by binding of potassium to ketoacids, vomiting, anorexia, and osmotic diuresis. Insulin therapy may worsen extracellular hypokalemia as insulin shifts potassium into cells.10 The most important clinical manifestation of hypokalemia in patients with DKA is profound muscle weakness, which can result in respiratory paralysis in extreme cases. A total body phosphorous depletion often develops when phosphate shifts from the intracellular space to the extracellular space as a result of hyperglycemia, acidosis, and hypoinsulinemia; the Silverstein, D., & Hopper, K. (2014). Small animal critical care medicine. Elsevier. Created from purdue on 2024-02-13 21:44:55. phosphorous is then excreted as a result of the osmotic diuresis. Dehydration and decreased phosphorus excretion in the later stages of the disease may cause the serum phosphorous concentration to be normal or increased. Once fluid therapy is initiated, along with insulin therapy, a rapid decline in phosphorous often occurs secondary to extracellular and whole body phosphate depletion.10 Hypophosphatemia related to DKA has been associated with hemolysis (in a cat) and seizures (in a dog).11 Additional clinical signs that may develop because of hypophosphatemia include weakness, myocardial depression, and arrhythmias. Decreased plasma ionized magnesium (iMg) concentration has been documented in four of seven cats with DKA and may be due to increased urinary excretion of magnesium.12 The clinical significance of hypomagnesemia in cats is unknown. The clinical consequence of hypomagnesemia in humans with diabetes includes insulin resistance, hypertension, hyperlipidemia, and increased platelet aggregation. Dogs with DKA usually do not have low iMg concentrations at the time of initial examination.2,13 In one study of 78 dogs with uncomplicated diabetes mellitus, 32 dogs with DKA, and 22 control dogs, plasma iMg concentration at the time of initial examination was significantly higher in dogs with DKA than in dogs with uncomplicated diabetes mellitus and control dogs.13 Hyponatremia, hypochloremia, and decreased ionized calcium concentration have also been documented in about 50% of dogs with DKA. Low sodium concentration may develop secondary to hyperglycemia as intra­ cellular fluid shifts to the extracellular compartment because of hyperglycemia (this is also known as pseudohyponatremia). Other explanations for hyponatremia, proposed in humans and experimental models of rodents, include ingestion of large amounts of water or retention of free water as a result of increased antidiuretic hormone secretion. In humans it is suggested that there is a decrease of 1 mEq/L in sodium concentration for every 62 mg/dl increase in glucose concentration. Venous pH is less than 7.35 in all dogs and cats with DKA. Lactate concentration is increased in about one third of dogs with DKA and is not correlated with the degree of acidosis.2 Urinalysis is usually indicative of glucosuria. Proteinuria or ketonuria may also be apparent. However, ketonuria may not be detected because the nitroprusside reagent in the urine dipstick reacts with acetoacetate and not with β-hydroxybutyrate, which is the dominant ketone body in DKA. Measurement of serum β-hydroxybutyrate is more sensitive than measurement of urine ketones.14,15 The number of white blood cells per high-power field is usually 5 or fewer in the urine sediment, although 20% of dogs with DKA have aerobic bacterial growth on culture of urine obtained by cystocentesis.2 This is likely a result of diabetic immunosuppression and decreased ability to mobilize white blood cells to the site of infection. Results of additional clinicopathologic or imaging tests such as urine culture, abdominal ultrasonography, thoracic radiographs, adrenal or thyroid axis testing, pancreatic lipase immunoreactivity, liver function tests, or liver biopsy depend on concurrent disorders. DIFFERENTIAL DIAGNOSIS Differential diagnoses for ketonemia include DKA, acute pancreatitis, starvation, low-carbohydrate diet, persistent hypoglycemia, persistent fever, or pregnancy. Differential diagnoses for a primary metabolic acidosis include DKA, renal failure, lactic acidosis, toxin exposure, severe tissue destruction, renal tubular acidosis, and hyperchloremia. TREATMENT Administration and careful monitoring of intravenous (IV) fluid therapy is the most important component of treatment (see Chapters CHAPTER 64 59 and 60). Any commercially available isotonic crystalloid solution may be used. The use of 0.9% saline has been advocated because of its relatively high sodium concentration10; however, it may be contraindicated in hyperosmolar diabetics. Additionally, 0.9% saline may contribute further to the acidosis because of the high chloride concentration and lack of a buffer. Lactate (contained in lactated Ringer’s solution) and acetate/gluconate (contained in Plasma-Lyte and Normosol-R) are converted to bicarbonate and may contribute to management of acidosis. Another advantage of these buffercontaining crystalloids is that they contain a small amount of potassium, which may blunt the acute decline in potassium concentration that the animal could suffer with initiation of fluid and insulin treatment. As long as the patient is monitored carefully, particularly in regard to hydration, mental status, and electrolyte concentrations, any of the above crystalloids can be used. Fluid therapy alone (with no insulin) significantly decreases blood glucose concentration in dogs with DKA.16 Although the mechanism by which fluid therapy alone decreases blood glucose concentration is incompletely understood, one possible explanation is that improving renal perfusion decreases the concentration of counter regulatory hormones, most importantly glucagon.17 Correction and monitoring of electrolyte abnormalities is the second most important component of therapy. Electrolyte supplementation must be monitored frequently because frequent adjustments may be required. An animal that appears hyperkalemic at the time of initial examination may become hypokalemic shortly after fluid therapy has begun. Hypokalemia should be treated by administering potassium as an IV constant rate infusion (CRI) at a rate that should generally not exceed 0.5 mEq/kg/hr (Table 64-1). The potassium supplementation protocol described in Table 64-1 is based on the clinical experience and has not been scientifically validated. If higher dosages are required, continuous electrocardiographic monitoring should be performed simultaneously. Hypophosphatemia is corrected with an IV CRI of potassium phosphate (solution contains 4.4 mEq/ml of potassium and 3 mM/ ml of phosphate) at a rate of 0.03 to 0.12 mM/kg/hr. Serum potassium concentration must be taken into account when giving potassium phosphate for correction of hypophosphatemia. A magnesium sulfate solution (containing 4 mEq/ml of magnesium) given intravenously as a CRI of 0.5 to 1 mEq/kg q24h has been used successfully for correction of hypomagnesemia. Toxicity from erroneously administered intravenous magnesium has been reported in one diabetic cat and one dog with acute renal disease.18 Signs of magnesium toxicity in these animals included vomiting, weakness, generalized flaccid muscle tone, mental dullness, bradycardia, respiratory depression, and hypotension.18 Care must be taken to administer intravenous magnesium only to patients that have documented decreased Copyright © 2014. Elsevier. All rights reserved. Table 64-1 Potassium Supplementation for Hypokalemic Animals with Diabetic Ketoacidosis K Concentration (mmol/L) Rate of Potassium Supplementation (mEq/kg/hr)* 250 0.9% NaCl 10 200 to 250 0.9% NaCl + 2.5% dextrose 7 150 to 200 0.9% NaCl + 2.5% dextrose 5 100 to 150 0.9% NaCl + 5% dextrose 5 600 mg/dl) and hyperosmolality with no or minimal urine ketones. Absence or resistance to insulin and increases in diabetogenic hormone levels stimulate glycogenolysis, and gluconeogenesis, hyperglycemia, osmotic diuresis, and dehydration result. Reduction of glomerular filtration rate (GFR) is essential to attain the severe, progressive hyperglycemia associated with HHS. Renal failure and congestive heart failure are common concurrent diseases that likely contribute to HHS via reduction of GFR. The most important goals of therapy are to replace fluid deficits and then slowly decrease the glucose concentration, thereby avoiding rapid intracranial shifts in osmolality and preventing cerebral edema. Fluid therapy will start to reduce blood glucose levels via dilution and by increasing GFR and subsequent urinary glucose excretion. Prognosis for feline HHS patients is poor (12% long-term survival), primarily as a result of concurrent disease. Dogs have a better prognosis (62% discharged from hospital). Nonketotic hyperglycemic hyperosmolar syndrome (HHS) is an uncommon form of diabetic crisis marked by severe hyperglycemia (>600 mg/dl), minimal or absent urine ketones, and serum osmolality more than 350 mOsm/kg.1 Other names for this syndrome include hyperosmolar hyperglycemic nonketotic state and hyperosmolar nonketotic coma. These terms have been replaced by hyperglycemic hyperosmolar syndrome in human medicine to better reflect the variable degrees of ketosis and inconsistent incidence of coma that occur with this syndrome.2,3 Coma appears to be an uncommon form of this syndrome in animals. HHS is an infrequent, albeit well-documented, complication of diabetes mellitus.4-8 The incidence in humans with diabetes has been estimated to represent less than 1% of all adult human diabetic hospital admissions,3,9,10 but incidence has been on the rise among diabetic children over the last decade 11,12 and has also been documented as a consequence of methadone toxicity in toddlers.13 In comparison, HHS accounted for 6.4% of total emergency room visits by diabetic cats 4 and HHS, with or without ketosis, was identified in 5% of dogs with diabetes mellitus.5 This chapter reviews the pathogenesis, clinical findings, diagnostic evaluation, and treatment of HHS. PATHOGENESIS Pathogenesis of HHS involves hormonal alterations, reduction of glomerular filtration rate (GFR), and contributions from concurrent disease. Hormonal Alterations HHS begins with a relative or absolute lack of insulin coupled with increases in circulating levels of counterregulatory hormones includ- ing glucagon, epinephrine, cortisol, and growth hormone. These counterregulatory hormones are elevated in response to an additional stressor, such as concurrent disease. Epinephrine and glucagon inhibit insulin-mediated glucose uptake in muscle and stimulate hepatic glycogenolysis and gluconeogenesis, increasing circulating glucose concentration. Cortisol and growth hormone inhibit insulin activity and potentiate the effects of glucagon and epinephrine on hepatic glycogenolysis and gluconeogenesis. In conjunction with insulin deficiency, increases in the diabetogenic hormones increase protein catabolism, which in turn impairs insulin activity in muscle and provides amino acids for hepatic gluconeogenesis.13 Pathogenesis of HHS is very similar to that of diabetic ketoacidosis, except that in HHS it is believed that small amounts of insulin and hepatic glucagon resistance inhibit lipolysis, thereby preventing ketosis3,15,16 and instead promoting HHS. Lower levels of growth hormone have also been documented in patients with HHS.16,17 Hyperglycemia is the primary result of these hormonal alterations. It promotes osmotic diuresis, and osmotic diuresis increases the magnitude of the hyperglycemia, thus leading to a vicious circle of progressive diuresis, dehydration, and hyperosmolality. Neurologic signs are thought to develop secondary to cerebral dehydration induced by the severe hyperosmolality. In humans, elevated blood urea nitrogen (BUN) levels, acidemia, elevated sodium concentration, and osmolality, but not glucose concentration, are correlated with the severity of neurologic signs.18 Reduction of Glomerular Filtration Rate Osmotic diuresis, additional losses such as via vomiting, and decreased water intake contribute to progressive dehydration, hypovolemia, and ultimately a reduction in the GFR as the syndrome progresses. Severe hyperglycemia can occur only in the presence of reduced GFR, because there is no maximum rate of glucose loss via the kidney.19,20 That is, all glucose that enters the kidney in excess of the renal threshold will be excreted in the urine. An inverse correlation exists between GFR and serum glucose in diabetic humans.19 Reductions in GFR increase the magnitude of hyperglycemia, which exacerbates glucosuria and osmotic diuresis. Human HHS survivors have also shown a reduced thirst response to rising vasopressin levels, which may also contribute to dehydration21 and decreased GFR. Influence of Concurrent Disease Concurrent disease is important for initiating the hormonal changes associated with HHS and can also be important for exacerbating hyperglycemia. Diseases that are thought to predispose previously stable diabetics to a diabetic crisis include renal failure, congestive heart failure (CHF), infection, neoplasia, and other endocrinopathies,1,22 although any disease can occur. Pancreatitis and hepatic disease appear to be uncommon concurrent diseases in cats with HHS,4 while pancreatitis was more common in dogs, identified in approximately one third of all canine HHS patients.5 Renal failure and CHF also exacerbate the hyperglycemia associated with HHS because of their effects on GFR. Decreased GFR is 347 Silverstein, D., & Hopper, K. (2014). Small animal critical care medicine. Elsevier. Created from purdue on 2024-02-13 21:44:55. 348 PART VII ENDOCRINE DISORDERS inherent to renal failure. Inability to concentrate urine provides another source for obligatory diuresis. Myocardial failure, diuretic use, and third spacing of fluids associated with CHF may decrease GFR. Cardiac medications such as β-blockers and diuretics are also known to alter carbohydrate metabolism, thus predisposing to diabetic crisis.3 HISTORY AND CLINICAL SIGNS Animals diagnosed with HHS may be previously diagnosed diabetics receiving insulin or may be newly diagnosed at the time HHS is recognized. The most common client complaints are fairly nonspecific and include decreased appetite, lethargy, vomiting, behavior changes, and weakness. Owners may report polyuria, polydipsia, and polyphagia consistent with diabetes, although these clinical signs may have gone unrecognized. History may also reveal recent onset of neurologic signs including circling, pacing, mentation changes, or seizure. Weight loss is an inconsistent finding. Recent steroid administration was seen in approximately 18% of dogs with HHS.5 PHYSICAL EXAMINATION Vital parameters (temperature, pulse, and respiration) and body weight vary considerably with severity of the syndrome and presence and chronicity of comorbid diseases. Hypothermia is not uncommon as the syndrome progresses. Dehydration, marked by decreased skin turgor, dry or tacky mucous membranes, sunken eyes, and possibly prolonged capillary refill time, are common findings on physical examination in both dogs and cats. Mentation changes are also common. Most animals are reported as being depressed, but severely affected patients may be obtunded, stuporous, or comatose. Additional neurologic abnormalities including weakness or ataxia, abnormal pupillary light reflexes or other cranial nerve abnormalities, twitching, or seizure activity may be noted. Plantigrade stance, especially in cats, may be present subsequent to unregulated diabetes mellitus. Other findings in patients with HHS are dependent on coexisting diseases. Animals should be examined closely for signs of heart disease, which may include any of the following: heart murmur, gallop, bradycardia, tachycardia or other arrhythmias, dull lung sounds, crackles, increased respiratory rate and effort, pallor, prolonged capillary refill time, and decreased blood pressure. Increased respiratory rate and effort may suggest cardiac failure but could also be secondary to infection, hyperosmolality, acidosis, asthma, or neoplasia. Animals with renal failure may have kidneys of abnormal size, oral ulceration, and pallor from anemia and may smell of uremia. Dogs with pancreatitis may have abdominal pain and vomiting. Copyright © 2014. Elsevier. All rights reserved. DIAGNOSTIC CRITERIA The criteria for diagnosis of HHS in veterinary medicine are a serum glucose concentration greater than 600 mg/dl, absence of urine ketones, and serum osmolality greater than 350 mOsm/kg.1 In humans the criteria for diagnosis of HHS require a serum glucose greater than 600 mg/dl, arterial pH greater than 7.3, serum bicarbonate greater than 15 mmol/L, effective serum osmolality greater than 320 mOsm/kg, and anion gap less than 12 mmol/L. In addition, humans with HHS may have small quantities of urine and serum ketones, measured by the nitroprusside method.2,3 Dogs with HHS have been classified as being ketotic or nonketotic at the time of the hyperosmolar event.5 Glucose concentrations can reach 1600 mg/dl in severely affected animals.1 Blood glucose concentration may exceed the readable range on patient-side analyzers. Clinical suspicion for HHS should remain Silverstein, D., & Hopper, K. (2014). Small animal critical care medicine. Elsevier. Created from purdue on 2024-02-13 21:44:55. BOX 65-1 Important Calculations Dehydration deficit: Fluid deficit (ml) = body wt (kg) × % dehydration (as decimal) × 1000 (ml/L) Osmolality: Serum osm(calc) = 2(Na+) + (BUN ÷ 2.8) + (glucose ÷ 18) Effective osmolality: Effective osm = 2(Na+) + (glucose ÷ 18) Corrected sodium: Na+(corr) = Na+(meas) + 1.6([measured glucose – normal glucose] ÷ 100) BUN, Blood urea nitrogen; K+, potassium; Na+, sodium; osm, osmolality; Na+(meas), measured sodium concentration. Note: BUN and glucose measured in mg/dl, electrolytes in mEq/L. high in this situation, and additional diagnostic methods should be instituted to better define the severity of hyperglycemia, state of diabetes, and presence of coexisting diseases. Measuring glucose is also vital to rule out hypoglycemia as a cause of neurologic signs. Osmolality measured by freezing point depression is not a commonly available patient-side test. Estimated serum osmolality can be calculated for dogs and cats using the following formula23,24: Serum osm(calc ) = 2(Na + ) + (BUN ÷ 2.8) + (glucose ÷ 18) BUN and glucose are measured in mg/dl and Na+ is measured in mEq/L. Because BUN equilibrates readily across cell membranes and effects of potassium on osmolality are small, calculating effective osmolality may be a better estimate20: Effective osm = 2(Na + ) + (glucose ÷ 18) Glucose is measured in mg/dl and Na+ is measured in mEq/L. Normal serum osmolality is 290 to 310 mOsm/kg. Neurologic signs have been documented in animals when osmolality exceeds 340 mOsm/kg (Box 65-1).25 Urine ketones can be assessed quickly using urine dipsticks. If urine is not available, serum ketones may be assessed by placing a few drops of serum on urine dipsticks26 or using a blood ketone meter.27-28 Additional Diagnostic Evaluation Additional diagnostic parameters, including serum chemistry analysis (with precise glucose measurement), complete blood cell count, urinalysis, urine culture, and (venous) blood gas, should be pursued in patients with confirmed or suspected HHS. Blood cell count abnormalities are varied and nonspecific. The packed cell volume and total solids level may be high secondary to dehydration. Chemistry abnormalities are dependent on degree of dehydration and presence of underlying disease. The most common biochemical abnormalities in cats with HHS include azotemia, hyperphosphatemia, elevated aspartate transaminase, acidosis, elevated lactate concentration, and hypochloremia.4 Azotemia may be prerenal or renal in origin. Dogs with HHS and ketosis were less likely to be azotemic than their nonketotic counterparts.5 Venous blood gas analysis should be used to assess the degree of acidemia. It is not possible to differentiate HHS from DKA in cats based on the degree of metabolic acidosis.4 In dogs, low pH has been associated with poorer outcome.5 In HHS, metabolic acidosis is caused by accumulation of uremic acids and lactic acid, rather than ketones. Lactic acidosis is an indicator of poor tissue perfusion secondary to dehydration and hypovolemia. CHAPTER 65 Serum electrolytes should be monitored to help in choosing fluid therapy and to calculate the osmolality. Sodium concentration is the prime determinate of serum osmolality. In HHS the true magnitude of sodium concentration will be masked by the hyperglycemia. Measured serum sodium is reduced by hyperglycemia-induced osmotic pull of water into the vasculature.29 Sodium level should be expected to rise as glucose levels return to normal. Calculating the corrected serum sodium value can give a better indication of severity of free water loss (see Box 65-1). For every 100 mg/dl increase in glucose above normal, the measured serum sodium decreases by 1.6 mEq/dl.29 A corrected serum sodium level can be calculated using the following formula: Na + (corr ) = Na + (measured ) + 1.6 ([measured glucose − normal glucose]/100) Sodium is measured in mEq/L and glucose is measured in mg/dl. This effect is nonlinear, however; mild hyperglycemia leads to smaller changes in plasma sodium concentration than more severe hyperglycemia Animals in diabetic crisis are classically expected to have low total body potassium concentrations,1 although cats with HHS tend to have a normal serum potassium concentration.4 Dogs with nonketotic HHS had average potassium concentrations that were higher than dogs with HHS and ketotis.5 Potassium losses are expected via diuresis, vomiting, and decreased intake; increases in potassium may occur secondary to acidosis, severe hyperosmolality,30 insulin deficiency, and poor renal perfusion. Potassium levels are expected to decrease as acidosis improves and with insulin-induced cotransport of glucose and potassium into cells. A thorough search for underlying disease should be undertaken in all patients with HHS. Additional diagnostic techniques, including thoracic and abdominal radiographs, abdominal ultrasonography, echocardiogram, retroviral testing (cats), and endocrine testing (thyroid hormone in cats and adrenal axis testing for dogs), may be indicated based on historical or physical findings or results of preliminary diagnostic results. TREATMENT Goals of therapy for patients with HHS include replacing the fluid deficit, slowly reducing serum glucose levels, addressing electrolyte abnormalities, and treating concurrent disease.2 Copyright © 2014. Elsevier. All rights reserved. Fluids The fluid therapy plan should include resuscitation, dehydration deficit, ongoing losses and maintenance fluid needs (see Box 65-1). To prevent exacerbation of neurologic signs, it is important not to lower the serum glucose or sodium too rapidly. Hyperosmolality induces formation of osmotically active idiogenic osmoles in the brain. These idiogenic osmoles protect against cerebral dehydration by preventing movement of water from the brain into the hyperosmolar blood. Because idiogenic osmoles are eliminated slowly, rapid reduction of serum osmolality establishes an osmotic gradient across the blood-brain barrier, leading to cerebral edema and neurologic signs.31 In humans, fluid losses in HHS are estimated to be double that of a DKA patient and vascular volume is anticipated to decrease when water moves to the interstitium and intracellular space as intravascular glucose and osmolality decline. Insufficient fluid resuscitation can contribute to cardiovascular collapse and death.3,32-36 The first goal of therapy is to replace vascular volume in those patients with signs of hypovolemia or hypovolemic shock. An initial 20 ml/kg (cat) to 30 ml/kg (dog) bolus of an isotonic replacement crystalloid is recommended, after which the patient is reevaluated Silverstein, D., & Hopper, K. (2014). Small animal critical care medicine. Elsevier. Created from purdue on 2024-02-13 21:44:55. Hyperglycemic Hyperosmolar Syndrome and the need for more boluses assessed. Isotonic saline (0.9% saline) is typically the initial fluid of choice because it both addresses the fluid deficits and replaces glucose with sodium in the extracellular space, thus preventing a rapid shift in osmolality. On its own, fluid therapy will start to reduce blood glucose levels via dilution and by increasing GFR and subsequent urinary glucose excretion.37 After vascular volume has been restored, dehydration deficits should be replaced more slowly using crystalloid solutions of varying sodium concentrations as needed to correct hypernatremia. Hypernatremia should be corrected slowly with a decrease of no more than 1 mEq/L/hr.38 While lower sodium-containing fluids, such as 0.75% or 0.5% NaCl, may be needed to reduce the serum sodium, it may be necessary to switch back to isotonic saline if the sodium is dropping to quickly or if there are problems maintaining vascular volume as the hyperglycemia is corrected and water moves out of the vascular space.39 Chapter 50 provides further discussion of the treatment of hypernatremia. Dehydration deficit (in milliters) should be calculated with the following formula: Body wt (kg) × % Dehydration (expressed as decimal) × 1000 (ml/L) In humans the fluid deficit is assumed to be 12% to 15% of body weight,3,33-35 and this massive dehydration deficit is often best replaced over 24 to 48 hours. Treating a patient with HHS and concurrent CHF presents a dilemma. Even maintenance amounts of parenteral fluids could be detrimental, so rehydration must be done more slowly and with care. Forced enteral fluid supplementation, as via a nasoesophageal tube, may be a viable option to aid in rehydration of some patients with CHF that are not vomiting. Insulin Unlike in DKA where insulin therapy is vital because of its role in reducing ketogenesis, insulin therapy is not as critical for reversal of HHS because much of the syndrome can be improved just by correcting fluid deficit. In the nonketotic HHS patient, insulin should not be given until the hypovolemia has resolved, the dehydration has improved, and the glucose concentrations are no longer adequately declining (50% OR Cortisol increment < 3 mcg/dl NO Stop corticosteroids YES Continue hydrocortisone for 5 days, then taper over 2-3 days OR Continue hydrocortisone for 7 days at full dose and stop FIGURE 72-1 Decision tree for practical use of corticosteroids in dogs and cats with septic shock. (Adapted from Annane D: Corticosteroids for severe sepsis: an evidence-based guide for physicians, Ann Intensive Care 1:7, 2011). Silverstein, D., & Hopper, K. (2014). Small animal critical care medicine. Elsevier. Created from purdue on 2024-02-13 21:44:55. CHAPTER 72 Copyright © 2014. Elsevier. All rights reserved. REFERENCES 1. Annane D, Sebille V, Charpentier C, et al: Effect of treatment with low doses of hydrocortisone and fludrocortisone on mortality in patients with septic shock, JAMA 288:862, 2002. 2. Marik PE, Zaloga GP: Adrenal insufficiency during septic shock, Crit Care Med 31:141, 2003. 3. Manglik S, Flores E, Lubarsky L, et al: Glucocorticoid insufficiency in patients who present to the hospital with severe sepsis: a prospective clinical trial, Crit Care Med 31:1668, 2003. 4. Soni A, Pepper GM, Wyrwinski PM, et al: Adrenal insufficiency occurring during septic shock: incidence, outcome, and relationship to peripheral cytokine levels, Am J Med 98:266, 1995. 5. Sprung CL, Annane D, Keh D, et al: Hydrocortisone therapy for patients with septic shock, N Engl J Med 358:111, 2008. 6. Bone RC, Balk RA, Cerra FB, et al: American College of Chest Physicians/ Society of Critical Care Medicine Consensus Conference: definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis, Crit Care Med 20:864, 1992. 7. Chang SS, Liaw SJ, Bullard MJ, et al: Adrenal insufficiency in critically ill emergency department patients: a Taiwan preliminary study, Acad Emerg Med 8:761, 2001. 8. Marik PE, Gayowski T, Starzl TE: The hepatoadrenal syndrome: a common yet unrecognized clinical condition, Crit Care Med 33:1254, 2005. 9. De Waele JJ, Hoste E, Decruyenaere J, et al: Adrenal insufficiency in severe acute pancreatitis, Pancreas 27:244, 2003. 10. De Waele JJ, Hoste EA, Baert D, et al: Relative adrenal insufficiency in patients with severe acute pancreatitis, Intensive Care Med 33:1754, 2007. 11. Graves KK, Faraklas I, Cochran A: Identification of risk factors associated with critical illness related corticosteroid insufficiency in burn patients, J Burn Care Res 33:330, 2012. 12. Bruno JJ, Hernandez M, Ghosh S, et al: Critical illness-related corticosteroid insufficiency in cancer patients, Support Care Cancer 20:1159, 2012. 13. Ho HC, Chapital AD, Yu M: Hypothyroidism and adrenal insufficiency in sepsis and hemorrhagic shock, Arch Surg 139:1199, 2004. 14. Marik PE: Glucocorticoids in sepsis: dissecting facts from fiction, Crit Care 15:158, 2011. 15. Venkatesh B, Cohen J: Adrenocortical (dys)function in septic shock—a sick euadrenal state, Best Pract Res Clin Endocrinol Metab 25:719, 2011. 16. Hsu JL, Liu V, Patterson AJ, et al: Potential for overuse of corticosteroids and vasopressin in septic shock, Crit Care 16:447, 2012. 17. Dellinger RP, Levy MM, Rhodes A, et al: Surviving Sepsis Campaign: international guidelines for management of severe sepsis and septic shock, 2012, Intensive Care Med 39:165, 2013. 18. Rothwell PM, Udwadia ZF, Lawler PG: Cortisol response to corticotropin and survival in septic shock, Lancet 337:582, 1991. 19. Span LF, Hermus AR, Bartelink AK, et al: Adrenocortical function: an indicator of severity of disease and survival in chronic critically ill patients, Intensive Care Med 18:93, 1992. 20. Annane D, Sebille V, Troche G, et al: A 3-level prognostic classification in septic shock based on cortisol levels and cortisol response to corticotrophin, JAMA 283:1038, 2000. 21. Bollaert PE, Charpentier C, Levy B, et al: Reversal of late septic shock with supraphysiologic doses of hydrocortisone, Crit Care Med 26:645, 1998. 22. Briegel J, Forst H, Haller M, et al: Stress doses of hydrocortisone reverse hyperdynamic septic shock: a prospective, randomized, double-blind, single-center study, Crit Care Med 27:723, 1999. 23. Annane D, Bellissant E, Sebille V, et al: Impaired pressor sensitivity to noradrenaline in septic shock patients with and without impaired adrenal function reserve, Br J Clin Pharmacol 46:589, 1998. 24. Oppert M, Reinicke A, Graf KJ, et al: Plasma cortisol levels before and during “low-dose” hydrocortisone therapy and their relationship to hemodynamic improvement in patients with septic shock, Intensive Care Med 26:1747, 2000. 25. Rivers EP, Gaspari M, Saad GA, et al: Adrenal insufficiency in high-risk surgical ICU patients, Chest 119:889, 2001. 26. Daley MR: Corticosteroids for septic shock, N Engl J Med 358:2068; author reply 2070, 2008. Silverstein, D., & Hopper, K. (2014). Small animal critical care medicine. Elsevier. Created from purdue on 2024-02-13 21:44:55. Critical Illness–Related Corticosteroid Insufficiency 27. Seam N: Corticosteroids for septic shock, N Engl J Med 358:2068; author reply 2070, 2008. 28. Luboshitzky R, Qupti G: Corticosteroids for septic shock, N Engl J Med 358:2069; author reply 2070, 2008. 29. Bollaert PE: Corticosteroids for septic shock, N Engl J Med 358:2069; author reply 2070, 2008. 30. Marik PE, Pastores SM, Kavanagh BP: Corticosteroids for septic shock, N Engl J Med 358:2069; author reply 2070, 2008. 31. Manoach S: Corticosteroids for septic shock, N Engl J Med 358:2070; author reply 2070, 2008. 32. Dellinger RP: Steroid therapy of septic shock: the decision is in the eye of the beholder, Crit Care Med 36:1987, 2008. 33. Chaudhury P, Marshall JC, Solomkin JS: CAGS and ACS evidence based reviews in surgery. 35: Efficacy and safety of low-dose hydrocortisone therapy in the treatment of septic shock, Can J Surg 53:415, 2010. 34. Lamontagne F, Meade MO: Low-dose hydrocortisone did not improve survival in patients with septic shock but reversed shock earlier, ACP J Club 148:6, 2008. 35. Moreno R, Sprung CL, Annane D, et al: Time course of organ failure in patients with septic shock treated with hydrocortisone: results of the Corticus study, Intensive Care Med 37:1765, 2011. 36. Sprung CL, Annane D, Singer M, et al: Glucocorticoids in sepsis: dissecting facts from fiction, Crit Care 15:446, 2011. 37. Cooper MS, Stewart PM: Corticosteroid insufficiency in acutely ill patients, N Engl J Med 348:727, 2003. 38. Burkitt JM, Haskins SC, Nelson RW, et al: Relative adrenal insufficiency in dogs with sepsis, J Vet Intern Med 21:226, 2007. 39. Martin LG, Groman RP, Fletcher DJ, et al: Pituitary-adrenal function in dogs with acute critical illness, J Am Vet Med Assoc 233:87, 2008. 40. Peyton JL, Burkitt JM: Critical illness-related corticosteroid insufficiency in a dog with septic shock, J Vet Emerg Crit Care (San Antonio) 19:262, 2009. 41. Durkan S, de Laforcade A, Rozanski E, et al: Suspected relative adrenal insufficiency in a critically ill cat, J Vet Emerg Crit Care 17:197, 2007. 42. Sakaue M, Hoffman BB: Glucocorticoids induce transcription and expression of the alpha 1B adrenergic receptor gene in DTT1 MF-2 smooth muscle cells, J Clin Invest 88:385, 1991. 43. Collins S, Caron MG, Lefkowitz RJ: Beta-adrenergic receptors in hamster smooth muscle cells are transcriptionally regulated by glucocorticoids, J Biol Chem 263:9067, 1988. 44. Saito T, Takanashi M, Gallagher E, et al: Corticosteroid effect on early beta-adrenergic down-regulation during circulatory shock: hemodynamic study and beta-adrenergic receptor assay, Intensive Care Med 21:204, 1995. 45. Bellissant E, Annane D: Effect of hydrocortisone on phenylephrine— mean arterial pressure dose-response relationship in septic shock, Clin Pharmacol Ther 68:293, 2000. 46. Schroeder S, Wichers M, Klingmuller D, et al: The hypothalamic-pituitaryadrenal axis of patients with severe sepsis: altered response to corticotropinreleasing hormone, Crit Care Med 29:310, 2001. 47. Marik PE, Pastores SM, Annane D, et al: Recommendations for the diagnosis and management of corticosteroid insufficiency in critically ill adult patients: consensus statements from an international task force by the American College of Critical Care Medicine, Crit Care Med 36:1937, 2008. 48. Annane D: Corticosteroids for severe sepsis: an evidence-based guide for physicians, Ann Intensive Care 1:7, 2011. 49. Prittie JE, Barton LJ, Peterson ME, et al: Hypothalamo-pituitary-adrenal (HPA) axis function in critically ill cats, J Vet Emerg Crit Care 13:165, 2003. 50. Costello MF, Fletcher DJ, Silverstein DC, et al: Adrenal insufficiency in feline sepsis. In: ACVECC postgraduate course 2006: sepsis in veterinary medicine, 2006, p 41. 51. Burkitt Creedon JM, Hopper K: Low-dose hydrocortisone in dogs with septic shock In 17th International Veterinary Emergency and Critical Care Symposium 2011, p 736. 52. Briegel J, Schelling G, Haller M, et al: A comparison of the adrenocortical response during septic shock and after complete recovery, Intensive Care Med 22:894, 1996. 379 CHAPTER 73 HYPOADRENOCORTICISM Jamie M. Burkitt Creedon, DVM, DACVECC KEY POINTS Hypoadrenocorticism (Addison’s disease) is uncommon in dogs and rare in cats. Primary hypoadrenocorticism is due to failure of the adrenal glands, whereas secondary hypoadrenocorticism is due to pituitary or hypothalamic malfunction. Young to middle-aged female dogs are predisposed. Certain breeds are overrepresented, but most dogs with Addison’s disease are of mixed breeding. Diagnosis is challenging because signs and clinicopathologic findings of hypoadrenocorticism mimic many other disease processes. Definitive diagnosis is by adrenocorticotropic hormone (ACTH) stimulation test, ideally coupled with an endogenous ACTH concentration. Treatment of the animal in crisis consists of aggressive, appropriate fluid resuscitation followed by hormone replacement. Hyperkalemia leading to electrocardiographic (ECG) changes can be life threatening and must be treated promptly and appropriately. Cats may require 3 to 5 days for a good clinical response to therapy. Long-term prognosis is very good with lifelong hormone supplementation. Copyright © 2014. Elsevier. All rights reserved. The adrenal cortex is responsible for secreting many important hormones, including cortisol and aldosterone. Cortisol is a glucocorticoid released in small amounts in a circadian rhythm and in larger amounts during times of physiologic stress. It has many important homeostatic functions, including regulation of carbohydrate, lipid, and protein metabolism; modulation of immune system function; and ensuring proper production of catecholamines and function of adrenergic receptors. Serum cortisol concentration is determined by the hormonal cascade and negative feedback mechanisms of the hypothalamic-pituitary-adrenal axis. The hypothalamus produces corticotropin-releasing hormone (CRH), which stimulates the anterior pituitary to release adrenocorticotropic hormone (ACTH). ACTH in circulation stimulates the zona fasciculata and zona reticularis of the adrenal cortex to produce and release cortisol. Cortisol has negative feedback action on both the hypothalamic release of CRH and the pituitary release of ACTH. Thus, when circulating cortisol concentration is low, CRH and ACTH will increase, stimulating the adrenal glands to produce more cortisol. The increased serum cortisol concentration inhibits the release of more CRH and ACTH. Aldosterone is a mineralocorticoid released from the zona glomerulosa of the adrenal cortex under the influence of a complex hormonal cascade that starts in the kidney. Its main purposes are to maintain normovolemia and enhance potassium excretion. When effective circulating volume is depleted, glomerular filtration decreases. The macula densa, a group of specialized cells in the distal portion of the thick ascending loop of Henle, senses decreased filtrate (specifically chloride) delivery. The macula densa then induces renin 380 Silverstein, D., & Hopper, K. (2014). Small animal critical care medicine. Elsevier. Created from purdue on 2024-02-13 21:44:55. release from the nearby juxtaglomerular cells of the afferent arteriole serving that nephron. Renin cleaves the circulating hormone angiotensinogen into angiotensin I. Angiotensin I is then converted to angiotensin II by angiotensin-converting enzyme located in the lung, on endothelial cells throughout the body, and in many other organs. Angiotensin II stimulates the zona glomerulosa to release aldosterone, which stimulates cells of the renal collecting duct to reabsorb sodium and excrete potassium. Sodium reabsorption leads to water retention and thus augmentation of effective circulating volume. The adrenal cortex also releases a significant amount of aldosterone in response to hyperkalemia and a minimal amount in response to ACTH. Hypoadrenocorticism, also called Addison’s disease, is an uncommon disease in dogs and is rare in cats. Primary hypoadrenocorticism is caused by adrenal gland dysfunction, whereas secondary hypoadrenocorticism occurs when hypothalamic or pituitary malfunction prevents the release of CRH or ACTH, respectively. In most cases, patients with primary hypoadrenocorticism have both glucocorticoid and mineralocorticoid insufficiency. However, there are many reports of dogs with atypical primary hypoadrenocorticism who have only glucocorticoid insufficiency.1-5 Dogs with atypical primary hypoadrenocorticism may develop mineralocorticoid deficiency within months of initial diagnosis.1,2,4 Very rarely, mineralocorticoid deficiency may occur before glucocorticoid deficiency.6 Because aldosterone release is mediated primarily by the renin-angiotensin cascade and serum potassium concentration, patients with secondary hypoadrenocorticism do not usually have the classic electrolyte abnormalities seen in patients with typical primary hypoadrenocorticism (see Clinicopathologic Findings). WHO IS AFFECTED? Hypoadrenocorticism usually occurs in young to middle-aged dogs, and females are reported to be more commonly affected than males.2,4,7-11 Although the average age of onset is approximately 4 years,4,5,7-11 naturally occurring hypoadrenocorticism has been documented in dogs as young as 2 months,10 as well as in geriatric dogs. Dogs with only glucocorticoid deficiency may be older at time of onset than those with classic hypoadrenocorticism.5 The most commonly affected pure breeds vary somewhat by report and include the Portuguese Water Dog, Great Dane, West Highland White Terrier, Standard Poodle, Wheaton Terrier, and Rottweiler.7 It is important to note that mixed breed dogs are more commonly affected than any individual breed.4,12 Primary hypoadrenocorticism is rare in cats. There appears to be no sex predilection in this species, and most are domestic shorthaired or longhaired cats.4,13-19 Most cats are young to middle aged, with ages ranging from 1 to 14 years.16,18 There is a single report of glucocorticoid-only hypoadrenocorticism in a cat.18 ETIOLOGY The cause of naturally occurring primary hypoadrenocorticism in dogs and cats is unknown, but the most widely accepted theory is CHAPTER 73 4,8 one of immune-mediated destruction of the adrenal cortices. In support of this theory, young to middle-aged female dogs are most commonly affected by both Addison’s disease and established immune-mediated diseases, and naturally occurring primary hypoadrenocorticism in humans is caused by immune-mediated destruction of the adrenal cortices. On necropsy, adrenal glands of affected animals are atrophied and fibrosed, consistent with prior immunemediated destruction.4,8,14,16 Other documented causes of primary hypoadrenocorticism in dogs and cats include adrenal neoplastic infiltration,20,21 trauma,22 suspected hemorrhage or hypoperfusion,23 and iatrogenic destruction caused by mitotane24 or trilostane25-28 therapy for hyperadrenocorticism. Adrenal infiltration with infectious organisms has also been implicated.4 Secondary hypoadrenocorticism is due to hypothalamic or pituitary malfunction; decreased CRH or ACTH secretion causes decreased adrenal cortisol production. The most common cause of secondary hypoadrenocorticism is steroid withdrawal after longterm glucocorticoid therapy.4,29 Long-term steroid administration causes negative feedback on the hypothalamus and pituitary, significantly decreasing ACTH production, which leads to adrenal cortical atrophy. Other documented causes of secondary hypoadrenocorticism in dogs and cats include hypothalamic or pituitary neoplasia,30 trauma,31,32 and iatrogenesis (surgical). CLINICAL PRESENTATION The clinical picture of hypoadrenocorticism is often vague and mimics other disease processes, most of which are significantly more common than Addison’s disease. The classic signs and basic diagnostic test results in the hypoadrenal patient are generally nonspecific, and the vast majority of Addisonian patients will not have all the classic signs. Therefore the clinician must remember to place hypoadrenocorticism on the rule-out list for the patient that has any of these clinical signs. History The history for patients with Addison’s disease is often vague and nonspecific and usually includes decreased appetite, lethargy, gastrointestinal (GI) disturbance, and weight loss. GI bleeding manifested by hematemesis, hematochezia, or melena may be present.1,3,4,9,33 Other historical findings may include polyuria, polydipsia, weakness, shaking, pain, muscle cramps, and other nonspecific problems.1,4,7,8,34 Because the clinical signs are often vague, patients may be brought for treatment in acute crisis without specific prior clinical signs. Thus the absence of such signs does not exclude hypoadrenocorticism as a diagnosis. Copyright © 2014. Elsevier. All rights reserved. Physical Examination Physical examination findings can vary significantly, depending on whether the hypoadrenocorticism involves hypoaldosteronism and on the severity and duration of illness. The most common physical examination findings include lethargy, weakness, poor body or coat condition, and dehydration. Collapse, hypovolemic shock, GI bleeding, abdominal pain, bradycardia, and hypothermia are common (particularly in emergency and critical care practice), although not all these abnormalities should be expected concurrently in any individual.1,4,7-9,16 Patients with secondary hypoadrenocorticism or atypical primary hypoadrenocorticism may be less likely to arrive in crisis because these patients have adequate aldosterone to maintain intravascular volume and normal electrolyte concentrations.1,3-5 Clinicopathologic Findings The most common clinicopathologic findings are a decrease in the sodium/potassium ratio, azotemia with an inappropriately low urine Silverstein, D., & Hopper, K. (2014). Small animal critical care medicine. Elsevier. Created from purdue on 2024-02-13 21:44:55. Hypoadrenocorticism specific gravity, anemia, and a leukogram inconsistent with the patient’s degree of illness. The normal sodium/potassium ratio is 27 : 1 to 40 : 1. Patients with typical primary hypoadrenocorticism (i.e., with aldosterone insufficiency) usually have a pretreatment sodium/potassium ratio (Na : K) of less than 28 : 1.10 Note that these patients need not have both hyponatremia and hyperkalemia; rather, some have only one of these abnormalities, and the ratio of these cations can still be less than 28 : 1. Patients with only glucocorticoid insufficiency are unlikely to have these electrolyte changes.1-5 Though hypoadrenocorticism appears to be the disease most commonly associated with low Na : K,28 many other diseases and conditions occasionally are associated with low sodium/potassium ratios. Such diseases include renal failure or postrenal obstruction,28,35,36 severe GI disease,4,28,36,37 parasitic infestation,35,37,38 pregnancy,39 body cavity effusions,36 and others.4,36,40 Moreover, although a low sodium/ potassium ratio is the classic electrolyte abnormality of Addison’s disease, not all patients with hypoadrenocorticism have this change, which may be present with other conditions. Most Addisonian patients are azotemic and hyperphosphatemic on arrival.4,7-9,16 These changes are generally attributed to hypovolemia and are therefore prerenal in origin. However, most dogs and cats with hypoadrenocorticism have inappropriately low urine specific gravity (i.e.,