ClinicalKey’ CLINICAL OVERVIEW Diabetic ketoacidosis Elsevier Point of Care (see details) Updated March 13, 2017. Copyright Elsevier BV. All rights reserved. Synopsis Urgent Action Key Points + Initial urgent actions for DKA. + DKAis the condition of hyperglycemia, anion gap metabolic acidosis, and ketonemia associated with insulin deficiency in patients with type 1 diabetes mellitus. DKA also sometimes occurs in patients with type 2 diabetes mellitus + Rapidly assess patients in whom DKA is suspected with bedside finger-stick glucose test and urine dipstick test for + Lack of compliance with insulin administration (missing ketones doses) and/or a precipitating physiologie stressor, such as an infection or myocardial infarction, are the most common causes of DKA » For the rare patient with DKA in shock, rapidly restore circulatory volume with + Diagnostic criteria for DKA include a pH of 7.3 or lower, with a isotonic saline (20 mL/kg serum bicarbonate level less than 18 mEq/L, and ketonemia boluses for pediatric patients) infused as quickly as possible ‘through a large-bore cannula with hyperglycemia + + Treat intravascular volume depletion rapidly with 0.9% normal saline. Potassium supplementation is needed in most patients, * Starttreatment of DKA with volume expansion, establishing at least 1 large- bore IV line to deliver 0.9% normal saline Insulin is administered by IV infusion 2 + Frequent laboratory monitoring (or bedside point-of-care testing) of glucose, electrolytes, and calculation of anion gap are necessary to adjust insulin dosage, IV fluid composition, + Begin an TV infusion of regular and IV fluid infusion rate insulin only after rehydration Pitfalls has begun and a potassium level is documented to be + Do not rely on urine ketone analysis to document the presence within reference range or high. of ketosis, as it will only detect acetoacetate level, and therefore If potassium is low, add may show falsely low levels. Serum B-hydroxybutyrate is the potassium to infusing IV fluids preferred test for ketonemia before administering insulin + Initiate potassium replacement before beginning insulin + Perform ECG in all adult therapy if the patient is hypokalemic, and proactively if/when patients to assess for myocardial ischemia orpotassium levels fall into the reference range due to total body infaretion as a precipitating deficiency of intracellular potassium stores stressor causing DKA + Administration of insulin before correcting potassium + Suspect infection as the deficiencies can lead to hypokalemia and cardiac arrhythmias precipitating stressor in febrile patients. Obtain cultures and begin appropriate empiric antibiotics quickly in this group + Acute coronary syndrome with silent myocardial ischemia can precipitate DKA + Initial insulin therapy for children with DKA does not include a bolus of insulin + Initial urgent actions for cerebral + Because hyperglycemia resolves faster than the ketoacidosis, edema (children) 4 ongoing insulin therapy is required even after glucose levels . “aos + Reduce the rate of fluid have fallen until ketoacidosis resolves wee eee administration by one-third + Relapse of ketoacidosis can occur if an IV insulin infusion is nen i oe + Give hypertonic saline (3%); discontinued without overlap with subcutaneous insulin (2 ive hypertonic saline (3%) suggested dose 2.5 to 5 mL/kg hours) : over 10 to 15 minutes Terminology + Ifno response, give mannitol, Clinical Clarification 0.5 to 1 g/kg IV over 10 to 15 minutes + Diabetic ketoacidosis is a hyperglycemic crisis that occurs as an ms acute metabolic complication of diabetes mellitus, defined by Elevate head of the bed to 30° hyperglycemia, ketonemia, and anion gap metabolie acidosis + Be prepared to intubate if + Caused by absolute or relative insulin deficiency and an there are any signs of increase in counterregulatory hormones (eg, glucagon, impending respiratory failure catecholamines, cortisol) 4 Classification + Adults + Mild DKA*+ ~ Plasma glucose greater than 250 mg/dL. - Ketones present in serum or urine - Blood gas pH 7.25 to 7.3 ~ Serum bicarbonate level of 15 to 18 mEq/L - Anion gap level higher than 10 mEq/L - Alert mental status+ Moderate DKA4 ~ Plasma glucose greater than 250 mg/dL. ~ Alert to drowsy mental status ~ Ketones present in serum or urine - Blood gas pH 7 to 7.24 ~ Serum bicarbonate level of 10 to less than 15 mEq/L. - Anion gap level higher than 12 mEq/L ~ Alert or drowsy mental status ere DKA* ~ Plasma glucose greater than 250 mg/dL. - Ketones present in serum or urine ~ Blood gas pH less than 7 - Serum bicarbonate level lower than 10 mEq/L - Anion gap level higher than 12 mEq/L - Stuporous or comatose mental status + Children + Mild DKA ~ Venous pH 7.2 to 7.3 or bicarbonate less than 15 mEq/L + Moderate DKA ~ Venous pH 7.1 to 7.2 or bicarbonate less than 10 mEq/L3 + Severe DKA ~ Venous pH less than 7.1 or bicarbonate less than 5 mEq/L3 + Euglycemie DKA + Ketonemia and anion gap metabolic acidosis are present, but glucose is lower than 200 mg/dL.& + Uncommon; observed in pregnancy, in patients who are vomiting, or in patients using sodium- glucose cotransporter 2 (SGLT2) inhibitors ®Diagnosis Clinical Presentation + History + Adult patients most often have a history of type 1 diabetes mellitus, although it can rarely develop in patients with ketosis-prone type 2 diabetes 4 + Children and young adults (younger than 20 years) present with DKA as the initial mani z diabetes in 30% of cas + Most common symptoms, which usually develop over a period of hours to days: ~ Polydipsia ~ Polyuria «Fatigue ~ Blurry vision ~ Weight loss + Other symptoms that are found variably include: - Nausea, vomiting, and abdominal pain (40%-75% of cases) ® - Abdominal pain attributable solely to DKA is typically diffuse, and follows periods of protracted vomiting and worsening acidemia 2 = Dyspnea, due to tachypnea - Headache, due to cerebral edema (children) #2 - New-onset enuresis (children) 12 - Confusion or drowsiness + Other symptoms that can suggest a precipitating event: ~ Chest pain (acute coronary syndrome) - Fever (many infections), though hypothermia can also occur from peripheral vasodilation ~ Cough and dyspnea (pneumonia or heart failure) » Medication and substance history may identify a precipitant or alternative diagnosis - Ingestion of agents that may cause or exacerbate hyperglycemia: 2~ Sympathomimetic amines ~ Corticosteroids = Atypical antipsychotics ~ Ingestion of agents that may cause a metabolic acidosis unrelated to DKA: Alcohol Methanol Ethylene glycol Isoniazid + Phys examination + Physical examination findings vary, depending upon the degree of dehydration and any other accompanying conditions + Tachycardia and hypotension, due to volume depletion + Dry mucous membranes, poor skin turgor, sunken eyes Kussmaul respiration (tachypnea with deep inspirations) + Fruity breath odor + Altered mental status, ranging from drowsiness to coma with increasing severity of DKA + Fever, in the setting of infection Causes and Risk Factors + Causes + Type 1 diabetes mellitus plus precipitating factors - Medical or surgical illness (altogether accounts for 60% of cases) ~ Infection (eg, sepsis, pneumonia, urinary tract infection, meningitis) ~ Myocardial ischemia ~ Cerebrovascular accident - Gastrointestinal bleeding - Pancreatitis (common in adults, 2 but rare in children ~ Less common: ©~ Gastrointestinal diseases causing nausea and vomiting ~ Trauma = Surgery ~ Alcohol use ~ Iegal substance abuse (eg, cocaine) ~ Pregnaney ~ Eating disorders ~ Ingestion of drugs that decrease carbohydrate metabolism ~ Sympathomimeties ~ Corticosteroids - Atypical antipsychotics = Thiazide diuretics ~ Off-label use of sodium-glucose cotransporter 2 (SGLT2) inhibitors in patients with type 1 diabetes ~ Inadequate exogenous insulin (accounts for 40% of cases) 12 ~ Omission of insulin from noncompliance ~ Insulin pump malfunction ~ Type 2 diabetes mellitus plus precipitating factors, ~ Acute decrease in insulin production owing to pancreatic f-cell dysfunction and temporary insulin resistance #2 ~ Use of sodium-glucose cotransporter 2 (SGLT2) inhibitors 2 4 + Risk factors and/or associations + Age ~ Incidence and mortality higher in children than in adults - 30% of children/young adults under age 20 years are first diagnosed with diabetes when they present with DKAZ Other risk factors/associations- Higher frequency of DKA is observed in patients of lower socioeconomic status 15 - Recurrent DKA is associated with greater fragmentation of health care 18 Diagnostic Procedures Primary diagnostic tools + History and physical examination suggest the disorder but biochemical criteria define the condition + Obtain initial laboratory evaluation in all patients, including determination of plasma glucose, BUN/creatinine levels, serum or urine ketones, electrolytes (with calculated anion gap), osmolality, urinalysis, venous or arterial pH, and CBC with differential # + A tentative diagnosis can be made with bedside tests of capillary blood glucose and urina dipstick ketones + Biochemical diagnostic criteria for DKA in adults are: 4 + Hyperglycemia (blood glucose greater than 250 mg/dL) + Arterial or venous pH less than 7.3 or bicarbonate less than 18 mEq/L + Ketonemia (positive acetoacetate 7 or B-hydroxybutyrate greater than 31 mg/dl. [3 mmol/L] in DKA in adults, or greater than 40 mg/dL [3.8 mmol/L] in children) *8 » Ketonuria + Anion gap greater than 10 mmol/L + Biochemical diagnostic criteria for DKA in children ar + Hyperglycemia (blood glucose greater than 200 mg/dL) + Arterial or venous pH less than 7.3 or bicarbonate less than 15 mmol/L + Ketonemia (positive acetoacetate or f-hydroxybutyrate greater than 3 mmol/L) 42 » Ketonuria + Diagnostic caveats yut other crit » Ineuglycemic DKA, the glucose level is below 200 mg/dL, eria apply © + The majority of patients have a low serum bicarbonate level, low pH, and elevated anion gap, but approximately 10% will have at least 1 of these reported as within reference range 12 + Acetoacetate may be negative early in ketoacidosisLaboratory + Initial diagnostic testing + Capillary blood glucose (while chemistry panel results are pending) + + Chemistry panel, including glucose, sodium, potassium, phosphate, magnesium, bicarbonate, BUN, and creatinine 4 ~ Sodium must be corrected for hyperglycemia. ~ Measured sodium (mEq/L) + 0.016 x [glucose (mg/dL) - 100] for glucose level lower than 400 mg/dL. - Measured sodium (mEq/L) + 0.024 x [glucose (mg/dL) - 100] for glucose level higher than 400 mg/dL. ~ Corrected potassium (for acidemia) may be estimated, as acidosis drives potassium from intracellular to extracellular compartments 1 ~ Subtract 0.6 mEq/L from measured laboratory test value for each decrease of 0.1 in blood gas pH 22 + Calculated anion gap level 2 ~ Sodium (mEq/L) - [chloride (mEq/L) + bicarbonate (mEq/L)] ~ Reference range is 6 to 10 mEq/L; above 10 mEq/L is consistent with DKA Serum osmolality ~ Differentiates DKA from hyperglycemic hyperosmolar state in patients with type 2 diabetes 2 ~ Reference range is 285 to 295 mOsm/kg; greater than 320 mOsm/kg is found in hyperglycemic hyperosmolar state 2 + Blood gas analysis - Venous blood gas is comparable to arterial blood gas for measuring pH in DKA 22 = Arterial blood gas adds information if there is suspected mixed acid-base disorder (ie, vomiting that is confusing the acid-base picture) and helps to clarify the degree of respiratory compensation + In the absence of a mixed acid-base disorder, pH is used to differentiate from hyperglycemic hyperosmolar state, and degree of acidosis is 1 parameter used to classify DKA as mild,moderate, or severe 4 pH greater than 7.3: consistent with hyperglycemic hyperosmolar state consistent with mild DKA. pH7.25 to 7. pH 7 to 7.24: consistent with moderate DKA pH less than 7: consistent with severe DKA + Serum ketone level 2 = Direct measurement of B-hydroxybutyrate is preferred diagnostic test of ketonemia because itis an carly and most abundant ketoacid that may first signal development of DKA 22 ~ May be measured either via a laboratory service or by a point-of-care meter ~ Serum B-hydroxybutyrate will be greater than 31 mg/dL or (3 mmol/L) in DKA in adults or greater than 40 mg/dL (3.8 mmol/L) in children 2 ~ Serum acetoacetate (via nitroprusside reaction) is an acceptable alternative test if testing for B-hydroxybutyrate is not available Urine ketone bodies ~ Urine ketone tests measure acetoacetate, which may be present in low concentrations initially, even when there is a high level of serum B-hydroxybutyrate ~ Urine ketone bodies as detected by dipstick testing are rapid, convenient, and sensitive (98%) but have poor specificity for DKA (approximately 35%) 24 + Hemoglobin A1C ~ Not essential for diagnosis or management of DKA, but may be useful in the evaluation as it provides information about the duration of hyperglycemia + Other laboratory testing to aid differential diagnosis or to identify precipitating event, as driven by the clinical presentation: 2 + CBC (to evaluate for hemorthage or infection as precipitating causes) + Blood and urine cultures if there is fever + Serum lactate, if sepsis is suspected + Cardiac biomarkers, such as troponin, if there is chest pain or abnormal ECG result Specific toxin level (eg, salicylate, acetaminophen, alcohols) if suspected + Amylase and lipase (if abdominal pain or pancreatitis suspected)- Not specific for pancreatitis in DKA as elevated levels are found in almost one-third of patients with DKA overall 2 ~ Iflevels are elevated, follow with abdominal CT scan 4 Imaging + Imaging is not a required component to make a diagnosis of DKA, but may be necessary to evaluate for precipitating causes + Ifobtained, direct imaging at specific anatomic areas as deemed appropriate according to presenting signs, symptoms, and examination; these can include a chest radiograph, or computed tomograph of the brain, abdomen and pelvis, or chest 2 Functional testing + Perform ECG on all adults, as acute coronary syndrome/acute myocardial infaretion are common precipitants of DKA2 Other diagnostic tools + Calculation of water deficit » For hypernatremic patients with severe dehydration, an estimate of the water deficit is useful to gauge the amount of fluid necessary to restore a euvolemic state + Water deficit: 0.6 x (body weight in kg) x (1 — [corrected sodium / 140] #8 + Although the measured serum osmolality is sufficient in most cases, a calculated osmolality is needed to determine the osmolar gap, which is useful to assess for other causes of high anion gap metabolic acidosis + Calculated formula: [2 x measured sodium (mEq/)] + [glucose (mg/dL) / 18] + [BUN (mg/dL) / 2.8) 24 + Osmolal gap - Difference between measured osmolality and calculated osmolality ~ Can be used as a rapid sereen for ethanol, methanol, or ethylene glycol intoxication when there is a high anion gap acidosis - High osmolal gap indicates presence of an abnormal solute present in significant amount ~ Osmolal gap greater than 10 can be caused by most toxic aleohols (ethanol, methanol, ethylene glycol) 2+ Although the standard anion gap is sufficient in most cases, adjustment for the albumin concentration is recommended in cases of hypoalbuminemia + Albumin-corrected anion gap: anion gap ~ 2.5 x [4 - serum albumin (g/d1)] 24 Differential Diagnosis Most common, Hyperglycemic hyperosmolar state + An acute metabolic complication of diabetes that most often occurs in patients with type 2 diabetes 11 + Defined by hyperglycemia (usually greater than 600 mg/dL), serum osmolality greater than 320 mOsm/kg, absence of appreciable metabolic acidosis or ketonemia + Major overlapping clinical features include hyperglycemia, altered mental status, and dehydration + Differentiating factors include the following: + Ketonemia and ketonuria, if present, are much less severe in hyperglycemic hyperosmolar state Hyperglycemia is elevated in both conditions but more pronounced in hyperglycemic hyperosmolar state, where glucose concentrations are frequently greater than 600 mg/dL. a + Osmolality is usually within reference range or mildly elevated in DKA, but is elevated in hyperglycemic hyperosmolar state to more than 320 mOsm/kg “+ + Typically, there is no metabolic acidosis in hyperglycemic hyperosmolar state (the latter shows bicarbonate greater than 18 and pH greater than 7.3) + + Severity of dehydration is typically more severe in hyperglycemic hyperosmolar state 12 + Onset of hyperglycemic hyperosmolar state occurs over several days, whereas DKA can occur within several hours to up to 2 days Other causes of anion gap metabolic acidosisAlcoholic ketoacidosis Starvation ketosis Lactic acidosis 22 Occurs most frequently in people who abuse alcohol and stop drinking abruptly Similar to DKA, high anion gap acidosis and serum ketonemia (primarily B-hydroxybutyrate) are present Differentiating factors include the following: + Glucose level will usually be within reference range or low in. alcoholic ketoacidosis; severe hyperglycemia is uncommon £ + Ketonemia is more severe in alcoholic ketoacidosis with a B- hydroxybutyrate to acetoacetate ratio of 7:1 oF higher, versus a ratio of 3:1 in DKA + Blood ethanol screen is positive in aleoholic ketoacidosis + Osmolal gap greater than 10 mOsm/kg is consistent with aleoholic ketoacidosis Oceurs in the setting of prolonged fasting, very low carbohydrate diets, or vomiting during pregnancy 22 Similar to DKA, laboratory abnormalities show a high anion gap metabolic acidosis; however, the degree of acidosis is typically not as severe Differentiated from DKA by serum bicarbonate, which is usually greater than or equal to 18 mEq/L, and the absence of hyperglycemia 4 Rapid resolution oceurs following treatment with IV dextrose Similar to DKA, laboratory abnormalities show a high ani metabolic acidosis n gap Major causes include sepsis, systemic inflammatory response syndrome, cardiogenic or hypovolemic shock, hypoxemia, and severe trauma Metformin, an oral hypoglycemic medication that is sometimes used off-label in insulin resistant patients with type 1 diabetes, can cause lactic acidosis in the setting of renal failure, so maintain high degree of suspicion if patient is on metforminUremia Toxic ingestion of methanol, ethylene glycol, salicylates, or isoniazid Treatment Goals + Factors that favor a diagnosis of lactic acidosis include the following: + Elevated blood lactate level (confirm clevated venous lactate level by arterial sampling) confirms a diagnosis of hyperlactatemia + Glucose level within reference range Increase in the anion gap closely mirrors the rise in blood lactate level + Shared clinical features include symptoms of nausea, vomiting, fatigue, and altered mental status + Similar to DKA, laboratory abnormalities show a high anion gap metabolic acidosis, which develops when the GER falls below 10 mL/minute/1.73 m? 2 + Differentiated by renal function tests and absence of ketonemia and hyperglycemia 4 + Shared clinical features include symptoms of altered mental status + Similar to DKA, toxic alcohols cause an inerease in anion gap levels, but patient is not usually hyperglycemic + Osmolal gap greater than 10 mOsm/kg is indicative of ingestion of a toxic alcohol, and gap greater than 25 mOsm/kg is typical of methanol or ethylene glycol toxicity #2 + Measurement of serum salicylate, ethanol, and methanol levels are diagnostic + Ethylene glycol (antifreeze) is suggested by the presence of calcium oxalate and hippurate crystals in the urine 1 + Methanol toxicity is suggested by visual symptoms + Isoniazid toxicity usually produces seizures + Restore circulatory volume and tissue perfusion+ Correct hyperglycemia, acidosis, and electrolyte abnormalities a + Monitor for and manage any complications of DKA or its 7 treatment + Identify and treat the precipitating event Disposition + Admission criteria ‘Most patients with DKA require admission owing to the need Protocol for management of adult for prolonged clinical and laboratory assessment and Patients with diabetic ketoacidosis. correction/treatment of the precipitating event, even if fluid resuscitation and correction of acidosis has been accomplished in the emergency department 2 Discharge home from the emergency department or observation unit may be considered for adults if all of the following are present: DKA is mild ‘The precipitating event is easily remedied (missed doses of insulin) and all metabolic abnormalities, ineluding hyperglycemia, acidosis, and electrolyte deficiencies, are corrected and remain stable Patient easily tolerates oral fluids Patient has insulin and glucometer at home and is reliable enough to use them correctly Admit most children with DKA Criteria for ICU admission Underlying critical illness (eg, myocardial ischemia, sepsis, or gastrointestinal hemorrhage) Continued severe acidosis, hypoxia, hypotensio risk for pulmonary or cerebral edema suspected sepsis, altered mental status, or high Conditions that increase risk of cerebral edema in children include the followin; Age younger than 5 years Low PCO2 High BUN level Severe acidosis Generally, admit all children younger than 5 years to the ICU because of the high risk for cerebral edema 2+ Recommendations for specialist referral Refer to an intensivist when admission to the ICU is warranted + Refer to an endocrinologist/diabetologist or internal medicine specialist for inpatient management + For children with DKA, refer to pediatric endocrinologist and/or pediatric intensivist (when possible) for care management Treatment Options + Initial treatment often occurs in the emergency department and is continued in the inpatient setting + Major components of treatment include administration of fluids, insulin, and electrolytes + Initial treatment steps: + The critical first step is to replenish lost fluids - Begin aggressive fluid therapy using isotonic saline at a rate of 500 to 1000 mL/hour to increase blood pressure and restore renal perfusion 2 = Goal is to replace total volume loss within 24 to 36 hours, with 50% of resuscitation fluid being administered during the first 12 hours 2 = Net fluid losses in DKA average 10% to 15% of body weight in adults 42 and 5% to 10% in children a Begin insulin therapy after fluids have been started 2 - An insulin bolus is often given in adults, but is not standard practice for children ~ Insulin is typical administered via IV infusion in DKA ~ In critically ill and mentally obtunded patients with DKA, continuous IV insulin is the standard of care 22 - For uncomplicated mild cases only, subcutaneous injections of rapid-acting insulin analogs are an acceptable alternative provided that fluids are replaced adequately and glucose is monitored frequently 2 * Start electrolyte infusions in the IV fluids to correct imbalances, in accordance with results from laboratory testing + = Initiate IV potassium when serum concentration is below the upper limit of reference range for the particular laboratory (usually 5-5.2 mEq/L) - Bicarbonate and phosphate replacement is usually unnecessary, but should be monitored closely~ Drug therapy Insulin ~ Adult insulin therapy? ~ Delay insulin administration until IV fluid is infusing and potassium level is higher than 3 mEq/L2 = Continuous IV infusion of regular insulin is indicated for patients with moderate to severe DKA, or for patients with coexisting critical illness (ie, hypotension, anasarca) ~ Either continuous IV regular insulin infusion or subcutaneous injections of rapid-acting insulin analogs are acceptable in uncomplicated, mild DKA (non-ICU settings) 22 ~ Continuous IV insulin infusion has the advantage of rapid half-life and easy titration, but usually requires greater hospital resources (nursing personnel) ~ Use of subcutaneous injections of rapid-acting insulin analogs lispro or aspart © leads to resolution of DKA equally rapidly as IV infusion of regular insulin, but only has been studied in mild DKA cases ~ Clinical outcomes are similar for treating mild DKA when using IV regular insulin versus subcutaneous rapid-acting analogs, provided that aggressive fluid replacement and blood glucose monitoring are frequent ~ IVroute ~ Administer regular insulin bolus of 0.1 units/kg? ~ Continue regular insulin infusion of 0.1 units/kg/hour 2 ~ Glucose typically falls at a rate of approximately 60 to 120 mg/dL/hour with insulin and hydration? ~ Reduce regular insulin rate to 0.05 units/kg/hour (or half of initial rate) onee blood glucose concentration reaches 250 mg/dL.2 = Thereafter, adjust regular insulin infusion rate (range of 0.02-0.05 units/kg/hour) to maintain glucose level between 150 to 200 mg/dL. until resolution of ketoacidosis 4 - Subcutaneous route = Administer rapid-acting insulin analog bolus of 0.2 units/kg 2 - Continue rapid-acting insulin analog with doses of 0.2 units/kg every 2 hours 2~ Reduce insulin rate to 0.1 units/kg (or half of initial rate) every 2 hours once blood glucose concentration reaches 250 mg/dL? - Thereafter, adjust insulin dose and frequency to maintain glucose level between 150 to 200 mg/dL until resolution of ketoacidosis + ~ Pediatric insulin therapy - Do not administer insulin until after volume expansion and potassium (if low initially) replacement have begun ~ IV route is usually preferred for patients with uncomplicated DKA; however, subcutaneous insulin is acceptable in circumstances where continuous IV administration is not possible? - IVroute ~ Give regular insulin via IV infusion without an initial bolus ~ IV bolus of insulin is not advisable in children with DKA because it may increase risk of cerebral edema and exacerbate hypokalemia ~ Start infusion at 0.1 units/kg/hour intravenously, and progressively reduce rate (ie, to 0.05 units/kg/hour, then 0.03 units/kg/hour) as blood glucose falls = Continue insulin infusion until DKA resolves (as measured by pH higher than 7.3, bicarbonate level higher than 15 mEq/L, or closure of the anion gap); glucose will normalize earlier than DKA will resolve ~ Subcutaneous route * = Administer rapid-acting insulin analog bolus of 0.3 units/kg ~ After 1 hour, administer subcutaneous lispro or aspart at 0.15 to 0.2 units/kg every 2 hours Once blood glucose level falls to 250 mg/day, reduce subcutaneous insulin lispro or aspart to 0.05 unit/kg/hour Subcutaneous route should not be used in patients whose peripheral circulation is impaired ~ Regular insulin (preferred) ~ Regular insulin is preferred over the rapid-acting insulin analogs for the IV route ~ Insulin Regular (Recombinant) Solution for injection; Infants, Children, and Adolescents: 0.05 to 0.1 unit/kg/hour IV beginning 1 to 2 hours after starting fluid replacement; continue until DKA resolves. If patient is very sensitive to insulin, the infusion rate may be reduced if acidosis continues to resolve. Add 5% dextrose to IV fluid when blood glucose reaches 250 to 300 mg/dL or sooner if blood glucose decline is precipitous. Once DKA has resolved and the patient is tolerating oral intake, transition to subcutaneous insulin. Give first dose of rapid-actinginsulin 15 to 30 minutes or regular insulin 1 to 2 hours prior to stopping insulin infusion and providing a meal. ~ Insulin Regular (Recombinant) Solution for injection; Adults: Initially, 0.14 units/kg/hour IV continuous infusion. Alternatively, 0.1 units/kg IV bolus, followed by 0.1 units/kg/hour via continuous IV infusion. If serum glucose does not decrease by at least 10% in the first hour, give 0.14 units/kg as an IV bolus, then continue the previous treatment. Adequate fluid therapy must also be initiated (usually 0.9% NaCl Injection for the first hour, then 0.45% NaCl Injection if indicated); adjust fluid type and requirements as needed. Adjust insulin infusion to achieve a blood glucose reduction rate of about 50 to 75 mg/dL/hour. When the blood glucose reaches 250 mg/dL, reduce the insulin infusion rate to 0.02 to 0.05 units/kg/hour or give rapid-acting insulin at 0.1 units/kg subcutaneously every 2 hours. Once blood glucose is approximately 200 to 250 mg/dL, add 5% dextrose to IV fluid. Adjust insulin and IV fluids to maintain a blood glucose of roughly 150 to 200 mg/dl. until the acidosis is resolved. ~ Insulin lispro ~ Subcutaneous route ~ Insulin Lispro Solution for injection; Children and Adolescents: 0.3 unit/kg subcutaneously, followed 1 hour later by 0.1 unit/kg/dose subcutaneously every 1 hour or 0.15—0.2 units/kg/dose subcutaneously every 2 hours. If BG falls to < 250 mg/dL before DKA resolves, reduce to 0.05 unit/kg/dose every 1 hour to keep BG approximately 200 mg/dL. until DKA resolves. Consider adding glucose to IV fluids if concern of hypoglycemia or precipitous fall in BG. ~ Insulin Lispro Solution for injection; Adults: ADA recommends regular insulin continuous IV, unless DKA is mild. Initially, 0.2 units/kg subcutaneously, then 0.2 unit/kg. subcutaneously every 2 hours until blood glucose level is 250 mg/dL or lower, then 0.1 units/kg subcutaneously every 2 hours. Check blood glucose every 1 to 2 hours; concentrations should decrease 80 to 100 mg/dL/hour. Rapid blood glucose decrease is associated with adverse effects. Initiate IV fluids. Monitor serum potassium and replace as, indicated - IVroute = Insulin Lispro Solution for injection; Children and Adolescents: 0.05—0.1 unit/kg/hour IV beginning 1-2 hours AFTER starting fluid replacement therapy. Do NOT administer an IV bolus at the start of therapy. Generally, maintain the infusion rate between 0.05—0.1 unit/kg/hour until resolution of DKA. If the patient is sensitive to insulin, the dosage may be reduced to prevent hypoglycemia if the metabolic acidosis continues to resolve. Add dextrose to IV fluids when plasma glucose falls to approximately 250—300 mg/dl. or sooner if the rate of glucose decline is precipitous. Monitor vital signs, fluid status, acid-base status, blood glucose, blood beta-hydroxybutyrate [if test is available], serum electrolytes, and neurological status until DKA is fully resolved. Once ketoacidosis has resolved and patient is tolerating oral intake, transition to subcutaneous insulin. Administer rapid-acting insulin 15—30 minutes or regular insulin 1—2 hours prior to stopping insulin infusion and providing a ‘meal; continue subcutancous insulin at a dose individualized to patient's response. ~ Insulin Lispro Solution for injection; Adults: Insulin lispro may be used as an intravenous infusion at concentrations from 0.1 unit/ml—1 unit/mL in infusion systems containing 0.9% NaCl. Usual dosing of insulin IV for diabetic ketoacidosis: 0.1 to 0.15 units/kg IV bolus followed by 0.1 units/kg/hour via continuous TV infusion. Use adequate fluid therapy as well. Check blood glucose levels hourly and adjust the insulin infusion rate as needed. When the blood glucose falls to <= 250 mg/dL, usually decrease insulin to 0.05—0.1 unit/kg/hour IV and change fluid therapy to a 5% dextrose-containing fluid infusion; adjust to maintain a blood glucose 150—250 mg/dL. until the acidosis is corrected. ~ Insulin aspart - Subcutaneous route - Insulin Aspart (Recombinant) Solution for injection; Children and Adolescents: 0.3 unit/kg subcutaneously, followed 1 hour later by 0.1 unit/kg/dose subcutaneously every 1 hour or 0.15 to 0.2 unit/kg/dose subcutaneously every 2 hours. If blood glucose declines to less than 250 mg/dL before DKA resolves, reduce to 0.05 unit/kg/dose every 1 hour to keep blood glucose approximately 200 mg/dL until DKA resolves. Consider adding glucose to IV fluids if concern of hypoglycemia or precipitous fall in blood glucose. ~ Insulin Aspart (Recombinant) Solution for injection; Adults: Initially, 0.2 units/kg subcutaneously, then 0.2 unit/kg every 2 hours until blood glucose level is 250 mg/dL or lower, then reduce dose to 0.1 units/kg subcutaneously every 2 hours. Check blood glucose every 1 to 2 hours; concentrations should decrease 80 to 100 mg/dL /hour. Rapid blood glucose decrease is associated with adverse effects. Initiate IV fluids. Monitor serum potassium and replace as indicated. - IVroute = Insulin Aspart (Recombinant) Solution for injection; Children and Adolescents: 0.05 to 0.1 unit/kg/hour IV infusion beginning 1 to 2 hours after starting fluid reple until DKA resolves. If patient is particularly sensitive to insulin, may reduce dosage if, acidosis continues to resolve. Add glucose to IV fluid when blood glucose is redueed to approximately 250 to 300 mg/dL or sooner if rate of blood glucose decline is precipitous. ment; continue ~ Insulin Aspart (Recombinant) Solution for injection; Adults: Can be used with close medical supervision; specific IV dose recommendations are not available. + Nondrug and supportive care + IV fluids 2 = Immediately begin therapy to replace fluids, preceding insulin therapy - Adult fluids. Administer 0.9% normal saline at 0.5 to 1 L/hour for the first 1 to 2 hours 2 ~ Subsequent choice of fluid depends on serum sodium, state of hydration, and glucose levels ~ After 1 to 2 hours, evaluate corrected serum sodium, ~ Ifsodium is low, reduce IV fluid rate to 250 to 500 mL/hour, depending upon state of, hydration; change to 0.45% normal saline once sodium is within reference range 2 = Ifsodium is within reference range or high, switch to 0.45% normal saline at 250 to 500 mL/hour, with rate reduetion depending upon state of hydration 2 - Measure and a: level every hour? gluco: «Add 5% dextrose to IV fluids when the glucose level is approximately 200 to 250 mg/dL ~ Continue 5% dextrose in IV fluids (typically with 0.45% normal saline by this point) until resolution of ketoacidosis 2 ~ Aim to replace the total volume loss within 24 to 36 hours, with 50% of resuscitation fluid being administered during the first 12 hours 22 «Pediatric fluids - Administer 0.9% normal saline at 10 to 20 mL/kg over the first 1 to 2 hours 2 = Higher-volume fluid infusion rates (20 mL/kg bolus + 1.5 x maintenance rate) for pediatric DKA patients shortens metabolic normalization time, compared with lower volume rates (10 mL/kg bolus + 1.25 x maintenance rate) 2° ~ Subsequent choice of fluid depends on serum sodium, state of hydration, and glucose levels = After 1 to 2 hours, replace fluid deficit with an isotonic solution (0.9% saline or lactated Ringer solution) for at least 4 to 6 hours 2 ~ Thereafter, replace fluid deficit with an isotonic solution or 0.45% saline solution, with added potassium 2 ~ Aim to replace the estimated fluid deficit evenly over 48 hours 2 ~ Measure and assess glucose level every hour ~ Add 5% dextrose to IV fluids when the glucose level falls to approximately 250 mg/dL? ~ Ifblood glucose level falls very rapidly after fluid expansion, consider adding glucose before glucose decreases to 300 mg/dL3~ If metabolic acidosis persists, change to 10% or 12.5% dextrose, while continuing insulin infusion, to prevent hypoglycemia 2 Electrolytes = Potassium ~ Potassium deficit in both children and adults is approximately 3 to 5 mEq/kg (although initial serum potassium level may be measured as within reference range or frankly elevated, owing to hypertonicity, insulin deficiency, and acidosis) 2 ~ Ensure that there is adequate urine output and kidney function before replacing potassium ~ Adults ~ Potassium repletion in IV fluids is required unless initial potassium is higher than the upper limit of reference range for the particular laboratory (usually §-5.2 mEq/L) or there isno urine output+ ~ Add 20 to 30 mEq/hour of potassium chloride to 0.45% normal saline and infuse until the serum potassium is greater than 3.3 mEq/L; continue to add potassium chloride to each liter of IV fluid to maintain potassium within reference range 1 ~ If the initial potassium level is low, assume there is a large potassium deficit, and that repletion may require more potassium chloride ~ Children ~ Ifhypokalemie at presentation, start potassium replacement (20 mEq/L) when initiating volume expansion (before starting an insulin infusion) 2 ~ Ifnormokalemie, start potassium replacement after volume expansion (when beginning insulin) ~ If hyperkalemie, defer potassium replacement until urine output is well maintained and potassium level is falling ~ Begin with 40 mEq/L potassium in the infusate, or 20 mEq/L potassium in the patient receiving fluid at a rate greater than 10 mL/kg/hour# - May use potassium chloride, potassium phosphate, or potassium acetate individually or in combination - Administration of potassium entirely as potassium chloride increases the risk of hyperchloremie metabolic acidosis, whereas administration entirely as potassium phosphate can result in hypocalcemia - Bicarbonate- Adults ~ Bicarbonate is rarely required in the management of DKA in adults, as it has not been shown hasten rate of recovery from ketoacidosis or hyperglycemia and may contribute to hypokalemia and cerebral edema 22 ~ Correction of acidosis with bicarbonate is only recommended if venous pI is less than 6.9 1 ~ For adults with pH less than 6.9, give 100 mEq sodium bicarbonate in 400 mL of sterile water with 20 mEq potassium chloride administered at a rate of 200 mL/hour for 2 hours ‘until the venous pH is greater than 74 ~ IfpHTis less than 7 after first infusion, repeat every 2 hours until pH reaches greater than 7 1 ~ Children ~ Bicarbonate is not recommended in children, even in more extreme acidemia of pH less than 6.9% - Bicarbonate replacement is associated with elevated risks of cerebral edema and prolonged hospitalization in pediatric patients ~ Phosphate ~ Adults - Phosphate is rarely required in management of DKA, as replacement has not been shown to affect clinical outcomes, and aggressive repletion can precipitate hypocalcemia 28 ~ Correction of hypophosphatemia is only recommended under very limited circumstances (ie, cardiogenic shock, respiratory failure, or serum phosphorus less than 1 mg/dL) 22 ~ If phosphate level is lower than 1 mg/dL or if phosphate is low and patient is in cardiac or jum phosphate to each liter of fluid, with fluid running respiratory failure, add 1 ml. pota: at 500 mL/hour 32 - 1mL of potassium phosphate = 4.4 mEq potassium + 3 mmol (93 mg) phosphate 22 ~ The maximal rate of phosphate replacement considered safe is 4.5 mmol/hour (1.5 mL/hour of K2POs), or a total of 90 mmol/day © ~ Monitor serum phosphate, magnesium, and calcium levels in patients receiving phosphate infusion? - Children~ Phosphate is rarely required in management of DKA in children, as replacement has not shown clinical benefit #2 - Correction of hypophosphatemia is only recommended when serum phosphate is lower than 1 mg/dL and the patient is symptomatic (ie, encephalopathy, respiratory failure, myopathy) 2 ~ Potassium phosphate may be added to replacement IV fluids alone or in combination with potassium chloride or potassium acetate 2 - Monitor serum calcium level in patients receiving phosphate infusion 3 + Comorbidities + Special populations + Adolescents with recurrent DKA - Psychologic evaluation for concurrent psychiatric disease is recommended 4+ ~ Incidence of depression in this population, leading to more missed insulin doses - Childhood Depression Inventory is a validated tool to screen for depression 42 - Higher incidence of recurrent DKA also seen in adolescents with eating disorders + DKA in patients with chronic kidney disease 2 ~ Clinical presentation and laboratory values in patients with DKA on dialysis may differ from those not on dialysis, ~ Patients on dialysis usually have minimal or no signs of volume depletion - Hyperkalemia is typically more severe in patients on dialysis compared with those not on dialysis for the same levels of hyperglycemia - Metabolic acidosis is usually present in DKA, but a mixed acid-base disorder can occur owing to concomitant metabolic alkalosis from exposure to high bicarbonate dialysate ~ High anion gap will always be present and serves as a valuable clue, particularly when the anion gap is very high (ie, more than 20 mEq/L?*) ~ Optimal treatment strategies for DKA in patients on dialysis have not been determined by prospective studies ~ IV fluids are usually not required, unless there is evidence or history of extracellular fluid loss such as vorniting, diarrhea, or excessive insensible losses - If fluids are needed, give small boluses of normal saline (250 mL) 22 while monitoring respiratory and hemodynamic parameters closely~ Suggested initial rate of IV insulin administration for patients on dialysis is similar to that of patients not on dialysis, with initial insulin bolus to 0.1 units/kg followed by continuous insulin infusion at 0.05 units/kg/hour 22 ~ Insulin is typically the only treatment necessary for hyperkalemia due to DKA in patients on dialysis; give potassium only if the level falls below 3.3 mEq/L - Emergent hemodialysis for patients in DKA is controversial; the main indications are pulmonary edema and severe hyperkalemia + DKA in patients with cardiac disease - Administer IV fluids cautiously to avoid volume overload and pulmonary edema 1 + DKA in pregnant women - Pregnant women develop DKA at significantly lower blood glucose values, and DKA progresses more rapidly in this population than in women who are not pregnant 42 - After 24 weeks of gestation, continuously monitor fetal status owing to fetal hypoxemia and acidosis #4 ~ If Cesarean delivery of a term infant is deemed necessary because of nonreassuring fetal heart rate tracings or fetal distress, delay until maternal metabolic status is stabilized (correction of acidosis, electrolyte replacement, and intravascular volume repletion) 42 ~ Preterm labor management must take into account maternal condition, viability of the fetus (gestational age), and fetal heart rate tracings #2 - Magnesium sulfate is the tocolytic of choice - Avoid B-adrenergic tocolytics, which can exacerbate hyperglycemia and nifedi dehydrated and hypotensive ine if patient is DKA associated with sodium-glucose cotransporter 2 (SGLT2) inhibitor therapy 18 ~ Be aware that low serum bicarbonate and/or the presence of positive urinary ketones may not correctly identify DKA; direct measurement of serum ketones ((¢-hydroxybutyrate) is more accurate ~ For management, stop the drug immediately and proceed with the traditional DKA treatment protocol Monitoring + Clinical monitoring during treatment + Hourly vital signs and fluid input/output measurementsHourly assessment by examination for complications related to fluid replacement ~ Signs of pulmonary edema, through auscultation of the lungs ~ Signs indicative of cerebral edema, particularly in children 2 Headache Change in mental status (eg, restlessness, irritability, increased drowsiness, incontinence) Decreasing heart rate, rising blood pressure, decreasing oxygen saturation Change in neurologic examination Use cardiac monitoring to detect worsening hypokalemia + Serial monitoring of metabolic parameters during treatment (at intervals noted, until there is resolution of DKA)# 12 + Glucose: measure hourly by finger stick, until DKA has resolved and transition to subcutaneous insulin has occurred Electrolytes: measure every 2 to 4 hours ~ Calejum level should be monitored carefully, if phosphate is given 3 + Anion gap: calculate every 1 to 2 hours + Venous pH: measure every 2 to 4 hours (usually corrects slowly over a period of hours to days) Unnecessary (optional) parameters to monitor ~ Ketonemia and ketonuria will persist 1 or 2 days beyond resolution of hyperglycemia and acidosis; repeat measurement is usually not helpful + Transition from IV to subcutaneous insulin For patients treated with IV infusion of insulin, transition to subcutaneous route is appropriate once ketoacidosis has resolved, the patient is alert, and oral intake is tolerated + Inject subcutaneous insulin 2 hours before stopping the insulin infusion ~ Patients previously treated with insulin can resume their usual home insulin schedule and dose if outpatient glycemic control was acceptable ~ Initiate a multidose insulin regimen in patients who are insulin-naive, preferably consisting of a basal-bolus protocol using insulin analogs, beginning at a total daily dose of 0.5 to 0.7 units/kg/day 2~ Continue subcutaneous insulin with individualized dose based on the patient’s response; continue finger-stick glucose monitoring at hourly intervals during this process ~ Continue finger-stick glucose monitoring at hourly intervals during the transition process, but may decrease frequency incrementally thereafter (ie, to every 4 hours) 2? + Criteria for resolution of DKA. + Blood glucose less than 200 mg/dL. plus any 2 of the following: ~ Serum bicarbonate 15 mEq/L or higher + - Venous blood pH greater than 7.34 ~ Anion gap 12 mEq/L or less+ Complications and Prognosis Complications + Treatment-related complications: + Hypokalemia will usually occur if not replaced, especially if bicarbonate is administered # + Hypoglycemia can develop with overzealous treatment with insulin + Pulmonary edema ~ Occurs most commonly in patients with known cardiac disease ~ In these patients, administer fluids cautiously with frequent pulmonary auscultation and monitor oxygen saturation with pulse oximetry Adult respiratory distress syndrome 45 = Perform frequent pulmonary auscultation and monitor oxygen saturation with pulse oximetry - Administer fluids cautiously if there are any signs of pulmonary edema ~ Usually requires mechanical ventilation + Non-treatment-related complications + Cerebral edema ~ May or may not be a treatment-related complication, as most evidence associates it with disease severity ~ Occurs most commonly in children with DKA who are younger than 15 years #*~ Risk factors include pH lower than 7, PCO: lower than 20 mm Hg, and more than 50 mL/kg fluids administered in first 4 hours 13 - Immediate treatment measures? 43 ~ Head-up positioning Halt current IV fluids - Administer mannitol at 0.5 to 1 g/kg over 20 minutes (repeat if needed in 30-120 minutes) Infuse hypertonic saline (5-10 mL/kg over 30 minutes) + Disseminated intravascular coagulation (rare) Prognosis + The majority of patients who are treated rapidly and appropriately recover within 48 hours without sequelae 22 48 + Overall mortality in the United States is less than 1%, but is much higher in developing countries (approximately 11%-30%) 4 + Higher rates are reported in patients older than 60 years 4” and in individuals with severe concomitant illnesses 2 + The mortality rate in children is 0.15% to 0.30%; cerebral edema is responsible for 60% to 90% of these deaths 2 + Mortality in adults is usually related to the underlying, precipitating event 2 Screening and Prevention SCREENING Prevention + Strategies that effectively prevent DKA in new-onset type 1 diabetes have not been conclusively identified Studies are underway to determine if expanding physician and publie awareness of the condition may reduce DKA at first diagnosis #® + Prevention of recurrent DKA in established type 1 diabetes involves 2 main issues: #2 Better access to medical care + Improved management of individual patients, including edueation about sick day management 2+ Use sick day measures for acute illnesses 52 + Encourage increase in fluid intake + Administer additional immediate-acting insulin boluses to correct for hyperglycemia and ketonemia, even if oral intake is decreased + Instruct patient to monitor blood glucose every 2 to 3 hours + Check ketones if the patient is hyperglycemic or experiencing abdominal pain, nausea, or vomiting + Participation in initiatives to educate patients in self-management can be effective for preventing DKA 49 St + Compliance with prescribed insulin regimen + Compliance with self-monitoring of blood glucose Providing education regarding sick-day management &2 ~ Contact physician early in the process - 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