Diabetic Ketoacidosis and Hyperosmolar Hyperglycemic State - EMBR 2nd Edition

Educational Objectives

The Audio-Digest Emergency Medicine Board Review — Second Edition

The lecture you’ve selected is part of the Audio Digest Emergency Board Review Course. Our overall Board Review Course is designed to match the defined learning objectives of the American Board of Emergency Medicine, and it is intended to provide a source of review material for those who are preparing for the ABEM's Continuous Certification Examination and for those preparing for the ABEM’s Initial Certification Examination. The goal is to provide a comprehensive update in many aspects of emergency medicine practice that will enhance the lifelong learning experience.

Course Objectives

Upon completing this educational activity, participants will be able to:

1. Rapidly diagnose and medically respond to a wide variety of critical issues presenting in the emergency department.
2. Triage the need for medical care (as appropriate) and initiate therapeutic procedures where needed.
3. Manage patients who require continuing respiratory and cardiovascular support until stable or transitioned to other hospital care centers.
4. Determine circumstances in which hospital care beyond the emergency department is required, and initiate procedures to obtain such care.
5. Prescribe drugs as appropriate for the short term management of presenting medical problems.

After listening to this lecture and reading the accompanying summary, the clinician will be better able to:

1. Discuss the differential diagnosis and management of diabetic ketoacidosis and hyperosmolar hyperglycemic state.

Summary

Diabetic ketoacidosis (DKA): syndrome defined by the biochemical presence of hyperglycemia, ketonemia, and acidemia

Hyperosmolar hyperglycemic state (HHS): hyperglycemia in the absence of significant ketonemia and acidemia

Hyperglycemic crises: HHS and DKA are collectively referred to as the hyperglycemia crises; hyperglycemic crises matter in part because of the incidence and economic impact; DKA affects 0.5% to 1% of patients with diabetes annually resulting in approximately 140,000 hospitalizations per year in the United Sates or approximately 5% of diabetes admissions; hospitalizations for DKA are increasing with the estimated annual cost rising to approximately $2.5 billion; underlying cause of both conditions is insulin deficiency and concomitant elevation of counterregulatory hormones; the 2 syndromes represent different points along a single biochemical and clinical spectrum; individuals may present with DKA and HHS at different times; a single episode may also have features of both syndromes; distinguishing between the two is important, because there are important differences in management

American Diabetes Association diagnostic criteria: a key difference between DKA and HHS is the serum glucose (>250 mg/dL in DKA and >600 mg/dL in HHS); HHS has acidosis; pH is by definition <7.30 and in HHS it is >7.30; bicarbonate concentration may be minimally depressed in HHS but is always <18 mEq/L and typically is <15 mEq/L or under in DKA; serum concentration of ketones, which may be minimally present in HHS, are almost invariably 3 to 4+ mEq/L in DKA; serum osmolality is variable in DKA but is >120 mOsm/kg; mental status may include lethargy, stupor, or coma in DKA but trends toward the patient being alert whereas in HHS the majority of patients have a greater degree of alteration and trend toward stupor and coma

DKA: encompasses a spectrum of severity from minimally symptomatic to critically ill and can be graded as mild, moderate, or severe; grading facilitates the tailoring of evaluation and management to the needs of the individual patient; majority of DKA cases occur in patients with Type 1 diabetes but it is increasingly recognized as a complication of Type 2 diabetes, particularly in the setting of new onset diabetes among obese African American and Hispanic young adults, teens, and children; adults account for approximately 80% of DKA cases, and 37% of patients are older than age 50; the per-episode mortality of DKA has remained in recent years and is significant at approximately 1%; mortality is higher in patients >65 years of age and in the presence of major comorbidities such as end-stage kidney disease or acute comorbidities (eg, myocardial infarction [MI], sepsis)

HHS: has been known by several other names in the past including hyperosmolar nonketotic state and hyperosmolar coma; hyperosmolar hyperglycemic state is the current term endorsed by the ADA, as it more accurately reflects the biochemical and clinical features of the illness, specifically mild ketosis, which is common in HHS, and coma is present in <30% of cases; primarily a complication of Type 2 diabetes but may occur in Type 1; approximately one-third of episodes occur in the absence of a prior history of diabetes although most previously undiagnosed patients prove to subsequently have mild Type 2 diabetes; less common than DKA and accounts for <1% of diabetes admissions; mean age has been approximately 65 but incidence is increasing in young adults, adolescents, and children, as the prevalence of Type 2 diabetes increases; mortality of HHS is higher than DKA at 5% to 20%; patients with major acute or chronic comorbidity and more severe illness on presentation, as indicated by coma, hypothermia, or hypotension, have higher mortality rates; clinical presentation, diagnostic evaluation, and management of the hyperglycemic crises can best be understood through the pathophysiology

Pathophysiology: DKA and HHS occur as a result of insufficient effective circulating insulin; in health glucose homeostasis is maintained by a balance between circulating insulin levels and the counterregulatory hormones, glucagon, catecholamines, cortisol, and growth hormone; insulin acts to increase glucose use and to suppress gluconeogenesis, glycogenolysis, and ketogenesis; without adequate insulin, glucose cannot be used as an energy substrate; counterregulatory hormones have the opposite effect, decreasing glucose uptake and use and promoting gluconeogenesis, lipolysis, and ketogenesis; ketones, acetoacetate, and beta hydroxybutyrate can be used as substrate by the brain and other tissues but in excess cause ketonemia and metabolic acidosis; insufficient insulin effect results in elevated blood glucose, ketonemia, and ketoacidemia; functional insulin deficiency may result from the absence of insulin or elevated counterregulatory hormones that overwhelm insulin’s effects in the presence of normal or even high circulating insulin levels (eg, relative insufficiency); episodes of DKA and HHS are typically the result of the simultaneous occurrence of both insufficient insulin, absolute or relative, and counterregulatory hormones; hyperglycemic crises are associated with high levels of circulating pro-inflammatory cytokines, oxidative stress, and circulating adhesion molecules promoting platelet aggregation; abnormalities may play a role in the cerebral edema sometimes seen in DKA, particularly in children; also play a role in the high rate of MI and stroke seen in association with hyperglycemic crises in older patients; DKA and HHS are hypercoagulable states; treatment of hyperglycemic crises with insulin and normalization of the serum glucose corrects the abnormalities; clinical features of the hyperglycemic crises are the direct product of insulin deficiency; insulin deficiency results in gluconeogenesis, glycogenolysis, and decreased glucose use with resultant hyperglycemia; hyperglycemia in turn produces osmotic diuresis, which accounts for the polyuria and polydipsia seen early in the course of hyperglycemic crises and the dehydration with tachycardia and hypotension that occurs later; water and electrolyte deficits are variable but typically quite large; if insulin deficiency is more severe, ketogenesis accelerates and ketoacids are generated, resulting in DKA; ketonemia gives rise to nausea, vomiting, and abdominal pain; if symptoms inhibit fluid intake, dehydration worsens, urine output drops, and in the absence of a brisk osmotic diuresis keotacid and glucose levels climb, resulting in acidemia and hyperosmolarity, which in turn engender altered mentation; respiratory alkalosis with tachypnea is a compensatory response to the ketoacidemia; inadequate insulin therapy, nonadherence, or an insufficient regimen resulting in absolute insulin deficiency is a common precipitant of DKA, especially in populations with low income, no health insurance, and low educational attainment; psychological disorders, including eating disorders, are a common factor in precipitating DKA in younger patients; insulin pumps have been associated with a higher incidence of DKA but with technological improvements seem to be less and less the case; major illness, most commonly infections, but also MI, stroke, pancreatitis, and other illnesses, provokes high levels of counterregulatory hormones and insulin resistance are also common precipitants of DKA; new-onset diabetes is identified in approximately 20% of cases; medications, including corticosteroids and second-generation antipsychotics, can precipitate DKA even in patients without a history of diabetes; DKA develops in hours or more commonly days with the onset more rapid in the presence of low circulating insulin levels and more severely elevated counterregulatory hormones, as occurs in the presence of major illness; ability to consume fluids and maintain high urine output and thereby an osmotic diuresis of glucose and ketoacids is an important compensatory mechanism as DKA develops; conversely the inability to consume fluids and the presence of impaired renal function, particularly anuric renal failure, accelerate the development and exacerbate the severity of DKA; polyuria, an early symptom, diminishes as the patient becomes dehydrated; signs of dehydration such as dry mucous membranes, more skin turgor, tachycardia, positional dizziness, and hypotension and the catecholamine response, tachycardia, may all be prominent; patients typically progress from polydipsia to anorexia, nausea, and vomiting; abdominal distention, diminished bowel sounds, and abdominal tenderness are present in one-half to three-quarters of cases of DKA; gastric distention and evidence of ileus may be seen on abdominal radiography; abdominal abnormalities may be ascribed to ketosis but if abdominal pain and tenderness are prominent or fail to improve as metabolic abnormalities resolve, other intra-abdominal pathology should be considered

Ketoacidosis: presents as hyperpnea, an increase in both the rate and depth of breathing, and with the odor of acetone on the breath; in the absence of severe hypotension, altered mentation, lethargy, confusion, or even coma correlates with and has been attributed to the severity of hyperglycemia and hyperosmolarity and to the acidosis; symptoms of a precipitating illness may dominate the clinical presentation or may be obscured by the symptoms of the metabolic derangements of DKA; signs and symptoms of infection should be sought (fever is an unreliable sign of infection in patients with DKA and HHS); DKA and HHS patients presenting with hypothermia often have a serious underlying infection, and hypothermia is associated with a higher mortality rate; essential pathophysiologic difference between DKA and HHS is the severity of insulin deficiency; higher levels of effective circulating insulin are required to maintain glucose homeostasis than to suppress ketogenesis; HHS develops when levels of circulating insulin are adequate to suppress ketogenesis but inadequate to promote glucose use or to suppress gluconeogenesis; HHS is primarily found in patients who secrete some insulin but have insulin resistance at baseline (may have a diagnosis of Type 2 diabetes and are experiencing a concurrent illness that elevates counterregulatory hormones exacerbating insulin resistance and resulting in hyperglycemia); even more than with DKA, the clinical features of HHS are the result of hyperglycemia; hyperglycemia produces an osmotic diuresis of glucose, which accounts for the polyuria and polydipsia seen early on and dehydration that develops later; HHS develops slowly over several days to even weeks in contrast to DKA, which rarely develops over more than a couple of days; loss of water and electrolytes are large and typically exceed those found in DKA presumably because of prolonged diuresis resulting in gradual decline and frequently a delayed diagnosis; ingestion of fluids to replace fluids lost is an important compensatory mechanism; impaired thirst, and the inability to drink fluids or lack of access to fluids accelerates the development of HHS; as water loss worsens, hyperosmolarity in the extracellular space promotes the movement of water out of the intracellular space, resulting in intracellular hyperosmolarity and cellular dysfunction; although this process occurs in all tissues, alteration in brain function dominates the clinical presentation and correlates with the rising osmolarity; most common reason patients with HHS are brought to medical attention is decreased level of consciousness; confusion and lethargy are increasingly common, although there is substantial individual variation as the effective osmolarity exceeds 320 mOsm/L; obtundation with an osmolarity of >340 mOsm/L and coma with an osmolarity of >350 mOsm/L; hyperosmolarity may also cause a variety of other neurologic signs and symptoms; seizures both focal and generalized have been reported in approximately 15% of cases of HHS; focal weakness, aphasia, myoclonic jerks, and other neurologic abnormalities may also occur; neurologic findings may mimic an acute stroke yet resolve with the treatment of HHS; conversely recrudescence of the signs of a prior stroke may occur during an episode of HHS, and an acute stroke may coexist with or precipitate HHS (HHS is a hypercoagulable state); nausea is common with HHS but repeated vomiting and abdominal pain are less common with HHS than DKA presumably because ketosis is less severe; prominent abdominal symptoms should prompt consideration of possible coexisting intra-abdominal pathology; major illness, most commonly infection but also MI, stroke, pancreatitis, and other illnesses that provoke high levels of counterregulatory hormones and insulin resistance, are common precipitants of HHS; pneumonia, urinary tract infection (UTI) and sepsis are the most common infections; symptoms of a precipitating illness may dominate the clinical presentation or may be difficult to discern because of altered mental status; medications such as corticosteroids, thiazide and other diuretics, and second-generation antipsychotic medications, particularly clozapine and olanzapine, can precipitate HHS; reduced thirst and decreased water intake commonly contributes; tube feedings and parenteral nutrition have also been implicated; among patients with known diabetes, noncompliance with medication, failure to monitor blood glucose, and poor diabetes education can also contribute to the development of HHS; significant overlap in the clinical and biochemical features of DKA and HHS; depending on the criteria used and the population studied, one-third to one-half of patients have a mixed disorder with features of both conditions; either hyperosmolarity in patients who meet the diagnostic criteria or mild ketoacidosis in patients whose presentations are otherwise consistent with HHS; essential action is to exclude moderate to severe ketoacidosis in the setting of hyperglycemia; patients with DKA tend to be younger, to have become ill more rapidly, and to demonstrate the signs and symptoms of ketoacidosis, ie, nausea, vomiting, abdominal pain, rapid deep breathing, and the nail polish odor of acetone on the breath; urine value of 3 to 4+ designates ketonuria on urinalysis and supports the diagnosis of DKA, so urinalysis should be performed early in the assessment; by definition, patients with HHS have a serum pH level >7.3, serum bicarbonate >18 mEq/L, and low levels of ketonemia and ketonuria; mild anion gap metabolic acidosis is common in HHS, probably attributable to contributions of ketoacids, lactic acid, and renal insufficiency with accumulation of fixed acid metabolites; venous or arterial blood gas can exclude severe acidosis in the critically ill; measurement of serum electrolytes and calculation of the anion gap is sufficient in less severely ill patients; in addition to distinguishing DKA from HHS, it is important to distinguish both hyperglycemic crises from other serious metabolic illness

Ketosis: may result from any physiologic starvation state including fasting, hyperemesis of pregnancy, and ketotic hypoglycemia; causes of metabolic acidosis are numerous and include lactic acidosis and uremic acidosis; it is the simultaneous convergence of hyperglycemia, ketosis, and metabolic acidosis that establishes the diagnosis of DKA; in patients known to have diabetes who present with the typical signs and symptoms of metabolic derangements of DKA it is enough to establish the presence of hyperglycemia, ketosis, and acidosis to be confident of the diagnosis; when history is less definitive, particularly when there is severe metabolic acidosis, it is important to consider alternative causes

Alcoholic ketoacidosis (AKA): most closely resembles DKA but can usually be distinguished by the history and the absence of hyperglycemia; lactic acidosis arising from intra-abdominal pathology and metabolic acidosis resulting from toxic ingestions, including salicylates, methanol, and ethylene glycol, are particularly important diagnoses to consider

Concomitant illness: because DKA and HHS are often precipitated by illness that results in high levels of stress hormones, an important consideration is whether the hyperglycemic crises account for the entirety of the patient’s condition or whether a concomitant acute condition is present; consider coexistence of infection in all hyperglycemic crises patients; MI should be considered in adults; intra-abdominal pathology should be considered in all patients for whom abdominal complaints are prominent

Differential diagnosis of altered mental status: falls within the broader differential diagnosis of altered mental status and decreased level of consciousness; prompt measurement of blood glucose is appropriate for all patients with altered mental status; initial evaluation and management should begin simultaneously; if patient appears critically ill, assess and stabilize the ABCs even as ECG is being performed and pulse oximetry monitoring has begun; oxygen administration can be guided by the physical assessment and pulse oximetry; blood pressure should be measured, IV access established, and bloods drawn for laboratory; IV normal saline therapy should be started if indicated by blood pressure, heart rate, and the brief physical assessment if not contraindicated by history of anuric renal failure or severe heart failure; bedside blood glucose should be measured for any patient with altered mental status or if either hyper- or hypoglycemia is suspected; only after these actions (which are appropriate for any seriously ill patient) are rapidly initiated should diagnosis-specific evaluation and treatment begin; in many cases a tentative diagnosis of a hyperglycemic crisis can be made within minutes of the patient’s arrival; history of diabetes, bedside glucose >250 mg/dL, or both, generally triggers the workup; question any patient with a history of diabetes regarding medications, current adherence, results of recent home glucose monitoring, and urine ketone monitoring; ask about prior episodes of DKA or HHS, symptoms of those conditions, self-treatment with oral fluids or additional insulin, and an estimate of oral fluid intake and urine output; in the setting of altered mental status, a baseline mental status and level of function should be determined; eliciting the history of kidney or heart disease is also important to the subsequent fluid management; approximately 10% to 20% of cases of DKA and 30% to 40% of cases of HHS occur in patients without a history of diabetes, and symptoms of a hyperglycemic crisis should be elicited from patients whose presentation suggests those diagnoses; it is particularly important to try to identify the underlying precipitant so that it can be addressed specifically, whether an infection, MI, a financial problem, behavioral issue, or the failure of the caregiver to provide sufficient fluids to an immobile patient dependent on others for care; if patient is unable to give necessary history, question other available resources, including family caregivers and paramedics; bedside glucose level >250 mg/dL is highly sensitive but poorly specific for DKA; euglycemic DKA has been described but an initial glucose level of <180 was found in only 1% of DKA cases in a series of 722 consecutive episodes; bedside glucose level of >500 mg/dL, particularly in the context of a history of diabetes, altered mental status, or both, generally suggests HHS; most patients with elevated glucose level have uncontrolled diabetes and no hyperglycemic crisis so additional evidence is necessary; hyperpnea in the presence of clear lungs and normal oxygen saturation support the diagnosis of DKA; presence of 3 to 4+ ketonuria on urinalysis improves the specificity of the diagnosis; urinalysis should be performed early in the assessment; in most cases the history, physical examination, bedside glucose level and urine ketones are sufficient to guide therapy until laboratory results provide further confirmation; newer alternative diagnostic strategies include use of venous blood gas with electrolytes and bedside measurement of capillary blood ketones using a ketone meter; both have acceptable sensitivity and specificity for initial screening and available resources dictate which is preferable at a given institution; for many years an arterial blood gas was used to quickly establish the presence of acidosis; in DKA the pH on a venous blood gas (VBG) and an arterial blood gas (ABG) correspond closely, so VBG may be substituted; ABG is preferable only if there is concern for other conditions (eg, ventilatory failure or salicylate intoxication), in which case an arterial partial pressure of carbon dioxide is useful; in less severely ill patients, the presence of the expected anion gap metabolic acidosis of DKA can be determined using serum bicarbonate and the calculated anion gap, in which case a blood gas is unnecessary; tentative diagnosis of HHS can often be inferred at the bedside but can be confirmed on the basis of biochemical data only; in addition to hyperglycemia with a glucose level >600 mg/dL, the definition of HHS requires an effective serum osmolality >320 mOsm/kg; osmolarity in mmol/L is the commonly used surrogate (calculated using 2x the serum sodium concentration, plus glucose concentration [measured in mg/dL] divided by 18, plus blood urea nitrogen [BUN] concentration divided by 2.8); normal value is 290±5 mmol/L; calculation includes urea, which diffuses freely across cell membranes and therefore does not create an osmotic gradient within the intracellular and extracellular spaces, nor does it contribute to the pathogenesis of HHS; calculated effective osmolarity (normal of 285±5 mmol/L) excludes urea from the calculation; with normal renal function the contribution of the BUN to osmolarity is small and the difference between osmolarity and effective osmolarity is insignificant; initial laboratory evaluation should include measurement of electrolytes, urea nitrogen, creatinine, glucose, serum osmolarity, serum ketones, and a urinalysis; mean glucose concentrations of patients with HHS has been reported to be 930 mg/dL (much greater than maximum measurable by a bedside glucose meter, which is now ~600 mg/dL) so must be confirmed by laboratory management; anion gap should be calculated (sodium concentration minus chloride plus bicarbonate concentration with a normal of 7-9 mmEq/L); serum magnesium, calcium, and phosphate are often measured but are less immediately essential; because of simultaneous loss of water and electrolytes laboratory results may not fully reflect the deficit; osmotic diuresis and dehydration of DKA and particularly HHS may cause hypernatremia, which may not be apparent from the measured serum sodium concentration; hyperglycemia causes water to move from the intracellular to the extracellular space, thereby reducing the measured serum sodium concentration by dilution; the effect resolves as hyperglycemia is corrected; common practice is to correct for the dilutional effect by adding a factor of 1.6 to 2.4 mmEq (not actually a linear relationship and number to pick is controversial) to the reported sodium concentration for every 100 mg of glucose >100 mg/dL; corrected serum sodium is commonly used to guide fluid therapy

Poor renal perfusion: dehydration results in poor renal perfusion, which is reflected in elevated BUN and creatinine; underlying chronic renal insufficiency is common in older adult patients with DKA and HHS; urine and serum ketones aid in distinguishing HHS from DKA; direct measurement of the serum beta-hydroxybutyrate, the predominant ketone in DKA, is preferred over the older nitroprusside test; the nitroprusside test provides a semiquantitative estimate of acetylacetone and acetone but does not measure beta–hydroxybutyrate, resulting in an underestimation of the severity of ketoacidosis

Laboratory studies: complete blood count (CBC) is routinely ordered often with the intent of using the white blood cell (WBC) count to determine if infection is present; unfortunately an elevated WBC is typical in hyperglycemic crises with or without infection; in DKA only a WBC of >25,000 or an elevated band neutrophil count has been shown to support a diagnosis of infection; chest radiography, urinalysis, blood and urine cultures, and sometimes a lumbar puncture are appropriate to evaluate for infection in HHS and in cases of DKA in which infection is suspected as a precipitant or a comorbidity; hemoconcentration can be expected to elevate the hemoglobin and hematocrit; additional testing should be individualized; ECG is generally indicated but serum troponin is only necessary for select patients; ordering of urine and blood culture should be based on a reasonable suspicion of infection in cases of DKA but is routine when evaluating the typically elderly patient presenting with HHS; chest x-ray is only indicated if pulmonary or cardiac disease is suspected in DKA but is usually indicated in HHS; serum amylase and lipase are frequently elevated in DKA even in the absence of clinical pancreatitis; abdominal computed tomography (CT) findings correlate much better with clinical outcomes, making CT the test of choice for patients with severe and persistent abdominal pain; intravenous contrast should generally be avoided; CT of the brain is indicated when altered mental status or focal neurologic abnormalities are present

Management of hyperglycemic crises: directed at correction of the metabolic derangements and treatment of comorbidities; while specifics of the individual patient’s presentation should guide fluid, electrolyte, and insulin therapy, adherence to written protocols decreases variability of care and improves outcomes; published protocols are broadly available and have been adopted by many hospitals and health-care organizations

Management of DKA: components of therapy remain the same across the spectrum of DKA but aggressiveness of treatment depends on severity; rapid infusions of large volumes of fluid and IV insulin are typically required for patients suffering from severe DKA; patients with mild DKA may do well with only oral rehydration and subcutaneous insulin; fluid deficit with DKA averages approximately 6 L, making hydration an essential first step; for most adults a liter of normal saline should be infused in 30 to 60 minutes; common exception is patient with diabetes and anuric hemodialysis-requiring chronic kidney disease; for most patients the first liter should be followed by an additional 1 to 2 L of normal saline during the next 2 to 4 hours with infusion rate dictated by the patient’s hemodynamic stability and response to therapy as reflected by vital signs and urine output; fluid restores circulating volume and tissue perfusion while decreasing circulatory counterregulatory catecholamines and begins to reduce serum glucose and osmolality by restoring osmotic diuresis; water deficits are typically greater than corresponding sodium and chloride deficits, making it appropriate to change to half-normal saline at 250 mL/hr after initial 2 to 3 L saline infusion, at which point blood pressure, pulse, and signs of tissue perfusion should be normalizing; patients found to have hypernatremia should be changed to half-normal saline (0.45% sodium chloride) when serum sodium results are obtained, which typically occurs after the first liter of normal saline has already been infused; when glucose is decreased to <250 mg/dL, IV fluids should be changed to D5 0.45% (ie, 5% dextrose and half-normal saline) to prevent hypoglycemia; infusion rate can further be reduced once the patient begins to drink, provided there is good urine output and the metabolic derangements are resolving; remaining fluid deficits are corrected over the following 1 to 2 days; patients should be reassessed frequently during treatment; need for adequate fluid replacement must be balanced against the risk of volume overload; particular attention is warranted in elderly patients and those with cardiac or kidney compromise; fluid management in pediatric DKA is controversial and is typically less aggressive than in adults; exercise caution because clinically significant cerebral edema occurs in approximately 0.7% to 1% of pediatric DKA episodes but is rare in adults; insulin inhibits ketogenesis independent of its effects on glucose production and use and is essential for the correction of ketoacidosis and hyperglycemia

Treatment goals: inhibition of ketone production and correction of hyperglycemia at a rate of 50 to 75 mg/hr; there are reports of successful use of subcutaneous rapid-acting insulin, and intramuscular insulin was used in the past; intravenous insulin is preferred for the treatment of moderate to severe DKA; it is debatable that only with mild DKA is subcutaneous insulin appropriate; IV insulin provides predictable and titratable insulin levels; subcutaneous insulin, which is adequate for mild DKA may be poorly absorbed in the setting of severe dehydration and hypotension; patients using an insulin pump should remove the device when being treated with IV insulin; once hydration has begun, physiologic doses of insulin, such as regular insulin 1 to 5 units/hr IV are generally all that is required; doses of 10 to 15 units/hr or more may be necessary in the setting of infection or other states in which there are high levels of counterregulatory hormones; because of the variability, the recommended initial saline infusion is 0.1 units/kg/hr; if decline in serum glucose is <50 mg/dL/hr, insulin infusion rate may be doubled; guidelines for care of adult patients with DKA recommend an initial bolus of regular insulin of 0.1 units/kg IV; pediatric guidelines no longer recommend an initial bolus because of concerns about excessively rapid correction of serum glucose at rates >100 mg/dL/hr and a decline in osmolarity of >3 mOsm/kg/hr and potential increased risk of cerebral edema; if no insulin bolus is given to an adult patient, data suggest a slightly higher insulin infusion rate of 0.14 units/kg/hr may reduce the number of patients who require supplemental insulin to achieve the target rate of decrease in glucose levels; whether there are sufficient grounds to justify either an initial bolus or higher infusion rate is controversial; insulin should be withheld until hypokalemia has been excluded; if hypokalemia is noted, an initial bolus of insulin should not be given and the insulin infusion should be delayed until after correction of serum potassium is under way;

Ketonemia: typically takes longer to resolve than hyperglycemia; to correct ketosis and avoid hypoglycemia, it is typically necessary to infuse insulin and glucose simultaneously as treatment goes on; protocols vary as to how it should be done specifically, but commonly IV fluids are changed to D5 half-normal saline at 150 to 200 mL/hr when blood glucose decreases to <250 mg/dL with insulin infusion continued at the same or at a reduced rate of 0.5 units/kg/hr; may be necessary to temporarily suspend insulin infusion to avoid impending or actual hypoglycemia; prolonged withdrawal of insulin should be avoided, because it almost always results in relapse of DKA

DKA: standard criteria for resolution of DKA are a glucose level <200 and 2 of the following: 1) serum bicarbonate level >15 mmEq/L, 2) venous pH of >7.3, or 3) an anion gap of <12 mmEq/L; once DKA has resolved and the patient is able to eat, begin subcutaneous insulin; patients should receive both long-acting (ie, basal insulin) and a rapid or short-acting insurance given before meals, or restart patient’s insulin pump; the prior insulin dose, if known, provides a basis for restarting subcutaneous insulin with the dose, time of administration, and caloric intake matching the patient’s usual pattern; if prior dose is unknown or patient was not previously on insulin, consultation with the physician who will be providing ongoing care is indicated

Insulin regimen: multiple daily insulin regimen using a basal/bolus approach of a rapid-acting premeal insulin plus a basal insulin or the use of an insulin pump with rapid-acting insulin is now common; regular insulin plus NPH insulin is less expensive but may cause more hypoglycemia; to insure adequate insulin levels and avoid relapse, subcutaneous insulin should be administered before stopping IV insulin; a delay of 30 to 60 minutes is recommended when using rapid-acting insulin and 1 to 2 hours when administering regular insulin

Potassium: almost all patients with DKA are potassium depleted, and deficits of 2 to 5 mmEq/kg of body weight are common; initial serum potassium is usually elevated, caused by acidosis and insufficient insulin effect, both of which resolve in an intracellular to extracellular potassium shift; administration of IV fluids and insulin causes a decline in the serum potassium through dilution, diuresis, and cellular uptake; to avoid serious symptomatic hypokalemia with the potential for dysrhythmias and respiratory muscle weakness, insulin should not be administered until the potassium is known to be >3.5 mmEq/L (a higher level may be advisable); IV potassium replacement is indicated for all DKA patients whose potassium is <5.3 mmEq/L and who are urinating >50 mL/hr; replacement rate of 10 mmEq/hr is often sufficient to maintain serum potassium of 4 to 5 mmEq/L; higher rates are indicated for potassium levels <3.5 or when treating symptomatic hypokalemia; patients who have consumed large amounts of potassium or who are in renal failure may not be potassium depleted and may present with severe hyperkalemia, so potassium should generally not be administered until serum potassium is known and patient is urinating

Resolution of acidosis in DKA: 3 mechanisms contribute to resolution, including suppression of ketogenesis by insulin, diuresis of ketoacids by hydration, and oxidation of ketoacids by skeletal muscle, brain, and kidneys; hyperventilation-induced respiratory alkalosis is an important compensatory mechanism; there is no clear evidence that administration of sodium bicarbonate improves outcome even in severe DKA in children or adults; bicarbonate corrects the arterial acidosis but not the intracellular or central nervous system acidosis and also decreases tissue oxygen uptake, exacerbates hypokalemia, and is an osmolar load, thereby potentially contributing to the development of cerebral edema; broadly agreed that bicarbonate has no role in the management of mild to moderate DKA and its use in severe DKA is controversial; if administered, it should be diluted and administered as an infusion, not as a bolus injection

Phosphate: lost with osmotic diuresis so that patients in DKA have a phosphate deficit despite normal or increased initial serum levels; deficit only becomes apparent if phosphate is rechecked during the course of therapy; eating replenishes phosphate and randomized trials of IV phosphate replacement have not demonstrated benefit; furthermore, rapid administration of phosphate can cause hypocalcemia; phosphate replacement is widely recommended in severe or symptomatic hypophosphatemia with levels <1 mg/dL; if given, potassium phosphate 20 to 30 mmEq should be administered slowly in a dilute solution and calcium level should be rechecked after treatment

Complications: infections, principally pneumonia, UTIs, and sepsis, complicate approximately one-third of episodes of DKA; other serious medical illnesses including MI and stroke, and complicate an additional 15% of episodes; comorbidities may precipitate DKA or be a consequence of its metabolic derangements; in either case the conditions increase morbidity and mortality and effective management is essential

Renal failure: management of DKA in patients with renal failure is particularly difficult; hyperglycemia and ketoacidosis may be severe even though fluids and electrolyte deficits are minimal or absent; hemodialysis is often the only way to correct the abnormalities; consult nephrologist and make arrangements for hemodialysis in an ICU setting as soon as the patient is recognized to have simultaneous renal failure and DKA

Monitoring: an important component of the management of DKA, facilitated by using standardized protocols and flow sheets; vital signs, fluid balance (ie, IV fluid administration and urine output), insulin and other therapeutic interventions, and serial laboratory studies should all be recorded; glucose and potassium should be measured every 1 to 2 hours, and sodium and bicarbonate should be measured every 2 to 4 hours; generally no need to repeat serum ketones or blood gases after the initial assessment as long as patient is improving; magnesium and phosphate should be reassessed 4 to 8 hours after therapy is initiated if patient is still in ED

Complications: most complications of the treatment of DKA are predictable and largely preventable; hyperchloremic metabolic acidosis is frequently noted during treatment but is generally clinically insignificant and can be minimized by switching IV fluids to half-normal saline after replenishing the intravascular space with normal saline; hypokalemia can be minimized by replacing potassium aggressively, omitting insulin bolus if potassium is low, and avoiding administration of bicarbonate; hypoglycemia can be avoided by changing to D5 half-normal saline when glucose declines to <250 mg/dL; fluid overload can be prevented by monitoring fluid balance and frequently reassessing the patient; neurologic deterioration during treatment of DKA, particularly in children, should prompt consideration of cerebral edema; diminishing the risk of DKA-associated cerebral edema is problematic because the mechanism is complex and prevention strategies have not been prospectively validated; incidence of cerebral edema can probably be reduced and outcomes improved when it does occur by correcting hyperosmolarity slowly, monitoring mental status, and treating the cerebral edema aggressively when it is recognized; confirmatory brain CT should not delay therapy

Management of HHS: directed at the replacement of fluid and electrolytes with the goal rate of the correction of hyperglycemia of 50 to 75 mg/hr; correction should not exceed 3 mOsm/kg/hr; treatment of comorbidities is essential; as with DKA, treatment begins with ABCs, monitoring, vital signs, IV access, and blood draw for laboratory studies, including a bedside measurement of the glucose; fluid deficits average 9 L in HHS, making rehydration an essential first step; a liter of normal saline should be infused over an hour unless known congestive heart failure or severe renal insufficiency dictate more cautious administration; expansion of the intravascular volume with saline diminishes the serum glucose and osmolarity by dilution and re-initiates the osmotic diuresis curtailed by severe dehydration and poor renal perfusion; patients who remain hypotensive after the first liter of fluid should continue to receive normal saline with the infusion rate dictated by the patient’s response to therapy as reflected by vital signs and urine output; fluid administration after stabilizing resuscitation should be guided by corrected serum sodium; intravenous fluids should be changed to half-normal saline for patients whose corrected serum sodium is normal or elevated; patients who are hyponatremic should continue to receive 0.9% normal saline; when glucose decreases to <300 mg/dL, intravenous fluids should be changed to D5 half-normal saline to prevent hypoglycemia and a too-rapid decline of osmolarity

Goal of fluid therapy: replace half of the fluid deficit over approximately 12 to 24 hours and the remainder over the next 24 hours; even after the initial infusion of 1 to 2 L, subsequent infusion rates of 250 to 500 mL/hr are often necessary; infusion rate can be reduced once patient begins to drink if there is sufficient urine output and metabolic derangements are improving; fluid management in pediatric HHS is less aggressive than in adults because of the same concerns for cerebral edema; in most cases, patients with HHS are significantly potassium-depleted with deficits commonly in the range of 4 to 6 mmEq/kg; initial potassium level is usually normal or elevated because of relative insulin deficiency and mild metabolic acidosis often present in HHS, both of which result in intracellular to extracellular potassium shift; administration of intravenous fluids and insulin cause a decline in the serum potassium; ADA recommends managing potassium and also phosphate in HHS according to the same guidelines as in DKA

Insulin therapy: should not be initiated until fluid resuscitation is well under way and the serum potassium known; hyperglycemia and hyperosmolarity result in the net movement of water into the extracellular space maintaining intravascular volume despite severe dehydration; insulin administration results in the intracellular shift of both glucose and (with the resulting decline in extracellular osmolarity) water as well; fluid therapy alone results in a decline of glucose ranging from 25 to 50 mg/dL/hr and occasionally up to 250 mg/dL/hr, often achieving and occasionally exceeding the target goals for the resolution of hyperglycemia and hyperosmolarity; optimum insulin regimen has not been definitively determined; in the absence of better data the ADA recommends the same insulin regimen for HHS as they recommend for DKA

Complications: infections, particularly pneumonia, UTI, and sepsis complicate approximately half of HHS episodes; appropriate to have a low threshold for initiating broad-spectrum antibiotics in ED

Comorbidities: serious comorbidities to consider include MI and stroke

Monitoring: an important component of the management of HHS and the same standardized protocols and flow sheets that improve outcomes in DKA are expected to have similar benefit with HHS

Complications of treatment: predictable and largely preventable; fluid overload is a potential complication of fluid replacement particularly in patients with pre-existing heart failure or kidney disease; patients should be reassessed frequently and the need for adequate fluid replacement balanced against the risk of fluid overload; caution is warranted in the elderly and in patients with cardiac or renal compromise; careful monitoring of the fluids given, urine output, vital signs, and laboratory parameters is essential; hypokalemia can be minimized by replacing potassium aggressively and electing not to give an insulin bolus if the potassium is low; hypoglycemia can be avoided by changing to D5 half-normal saline when the glucose declines to <300 mg/dL; HHS-associated cerebral edema is managed in the same manner as DKA-associated cerebral edema

Summary of critical interventions in management of DKA and HHS: assess and stabilize the ABCs; check bedside glucose in all patients with altered mental status; promptly begin aggressive fluid replacement, typically 2 L in the first 4 hours for DKA; fluid replacement can be more moderate in HHS, particularly in the presence of heart failure or moderate to severe kidney disease; provide sufficient potassium replacement beginning when the patient is making urine and the potassium is <5.3 mmEq/L for DKA; avoid hypoglycemia and an excessive decline in osmolarity by changing intravenous fluids to D5 half-normal saline when serum glucose declines to 250 in DKA or 300 in HHS; maintain continuous insulin infusion until the anion gap is normal for DKA patients; identify and treat comorbidities and precipitants; monitor frequently until hyperglycemic crises resolve, patients resumes routine medications, and is eating and drinking normally; patients with severe DKA, as indicated by a pH <7.2, hypotension, anuria, coma, or need for intubation should be admitted to intensive care unit; serious comorbidities and age >65 increase mortality and should lower the threshold for ICU admission; location in the hospital for a patient with DKA that is less severely ill often depends on where an insulin drip can be administered and whether or not the frequent monitoring of blood glucose levels is possible outside of an ICU setting; a monitored bed is appropriate for patients with moderate DKA and patients whose DKA was initially severe but has improved with therapy in ED; a floor bed is appropriate only for patients whose episode is minor or an episode that is almost fully resolved; patients whose DKA was initially only mild or moderate and was resolved in ED may be considered for discharge home if there were no important comorbidities; safe discharge depends not only on the resolution of metabolic derangement and the absence of ongoing precipitants, but also on the patient’s capacity for self-care, available social support, and availability of close follow-up; patients with severe HHS, as indicated by decreased level of consciousness, seizures, hypotension, or hypothermia should be admitted to an ICU; monitored bed is appropriate for awake patients with moderate HHS and for those in whom HHS has substantially improved with ED therapy; a floor bed is only appropriate for patients whose episode has almost fully resolved; comorbidities should also be considered when selecting a level of care; patients with serious infections or cardiac or renal disease generally require an ICU admission; because of the need for immediate and closely monitored treatment for at least 24 hours, it is usually preferable to avoid transfer of patients with DKA or HHS to another facility until after the metabolic derangements have substantially corrected and any serious underlying illness has been fully stabilized

Common pitfalls in care: failure to check a bedside glucose in all patients with altered mental status; failure to give adequate volumes of appropriate fluid starting with 1 L of normal saline in the first hour for adult patients; failure to give adequate IV insulin in severe DKA; failure to manage potassium appropriately either by administering insulin in the setting of hypokalemia, failing to adequately replace potassium as hypokalemia develops, or administering excessive potassium to patients who are anuric; failure to monitor blood glucose frequently and to switch to glucose-containing IV fluids when blood glucose levels decline to <250 mg/dL; reliance on sodium bicarbonate to correct the acidosis of DKA; failure to search for and treat precipitating causes and other comorbidities

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Acknowledgements

CME/CE INFO

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The Audio- Digest Foundation designates this enduring material for a maximum of 0 AMA PRA Category 1 Credits™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

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Lecture ID:

EMBR170113

Expiration:

This CME course qualifies for AMA PRA Category 1 Credits™ for 3 years from the date of publication.

Instructions:

To earn CME/CE credit for this course, you must complete all the following components in the order recommended: (1) Review introductory course content, including Educational Objectives and Faculty/Planner Disclosures; (2) Listen to the audio program and review accompanying learning materials; (3) Complete posttest (only after completing Step 2) and earn a passing score of at least 80%. Taking the course Pretest and completing the Evaluation Survey are strongly recommended (but not mandatory) components of completing this CME/CE course.

Estimated time to complete this CME/CE course:

Approximately 2x the length of the recorded lecture to account for time spent studying accompanying learning materials and completing tests.