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Diabetic ketoacidosis

Straight to the point of care

Last updated: Feb 07, 2020

Table of ContentsSummary 3

Basics 4

Definition 4

Epidemiology 4

Etiology 4

Pathophysiology 5

Classification 6

Prevention 8

Primary prevention 8

Screening 8

Diagnosis 9

Case history 9

Step-by-step diagnostic approach 9

Risk factors 13

History & examination factors 14

Diagnostic tests 16

Differential diagnosis 19

Diagnostic criteria 20

Treatment 22

Step-by-step treatment approach 22

Treatment details overview 27

Treatment options 31

Follow up 70

Recommendations 70

Complications 71

Prognosis 71

Guidelines 72

Diagnostic guidelines 72

Treatment guidelines 72

References 73

Images 81

Disclaimer 85

Summary

◊ Diabetic ketoacidosis is characterized by a biochemical triad of hyperglycemia, ketonemia, andacidemia, with rapid symptom onset.

◊ Common symptoms and signs include polyuria, polydipsia, polyphagia, weakness, weight loss,tachycardia, dry mucous membranes, poor skin turgor, hypotension, and, in severe cases, shock.

◊ Successful treatment includes correction of volume depletion, hyperglycemia, electrolyte imbalances,and comorbid precipitating events, with frequent monitoring.

◊ Complications of treatment include hypoglycemia, hypokalemia, hypoxemia, and rarely pulmonaryedema.

◊ Cerebral edema, a rare but potentially rapidly fatal complication, occurs mainly in children. It may beprevented by avoiding overly rapid fluid and electrolyte replacement.

Diabetic ketoacidosis BasicsBA

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DefinitionDiabetic ketoacidosis (DKA) is an acute metabolic complication of diabetes that is potentially fatal andrequires prompt medical attention for successful treatment. It is characterized by absolute insulin deficiencyand is the most common acute hyperglycemic complication of type 1 diabetes mellitus.[1]

Triad of DKAAdapted with permission from: Kitabchi AE, Wall BM. Diabetic ketoacidosis. Med Clin North Am. 1995;79:9-37

EpidemiologyIn the US from 2000-2009, the rate of hospitalizations for DKA decreased overall, from 21.9 to 19.5 in 1000persons with diabetes, but then increased from 2009-2014 to 30.2 in 1000 persons with diabetes.[7] In 2014,rates of hospitalization for DKA were highest among people aged <45 years (44.3 in 1000 persons withdiabetes) and decreased with age (5.2 in 1000 persons with diabetes aged 45-64 years; 1.6 in 1000 65-74years; and 1.4 in 1000 ≥75 years).[7]From 2000-2014, in-hospital mortality rates among people with DKAconsistently decreased, from 1.1% to 0.4%.[7] In 2014 in the US, about 207,000 emergency departmentvisits for people aged ≥18 years were for hyperglycemic crises (e.g., DKA, hyperglycemic hyperosmolarstate).[8]

EtiologyIn DKA, there is a reduction in the net effective concentration of circulating insulin along with an elevation ofcounter-regulatory hormones (glucagon, catecholamines, cortisol, and growth hormone). These alterationslead to extreme manifestations of metabolic derangements that can occur in diabetes. The two most common

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Diabetic ketoacidosis Basics

precipitating events are inadequate insulin therapy or infection. Underlying medical conditions such asmyocardial infarction or stroke that provoke the release of counter-regulatory hormones are also likely toresult in DKA in patients with diabetes. Drugs that affect carbohydrate metabolism, such as corticosteroids,thiazides, pentamidine, sympathomimetic agents (e.g., dobutamine and terbutaline), second-generationantipsychotic agents, and immune checkpoint inhibitors may contribute to the development of DKA.[1] [9] [10]The use of sodium-glucose cotransporter 2 (SGLT-2) inhibitors has also been implicated in the developmentof euglycemic DKA in patients with both type 1 and type 2 diabetes.[11] [12] [13] [14]

PathophysiologyReduced insulin concentration or action, along with increased insulin counter-regulatory hormones, leads tothe hyperglycemia, volume depletion, and electrolyte imbalance that underlie the pathophysiology of DKA.Hormonal alterations in DKA lead to increased gluconeogenesis, hepatic and renal glucose production, andimpaired glucose utilization in peripheral tissues, which result in hyperglycemia and hyperosmolarity. Insulindeficiency leads to release of free fatty acids from adipose tissue (lipolysis), hepatic fatty acid oxidation, andformation of ketone bodies (beta-hydroxybutyrate and acetoacetate), which result in ketonemia and acidosis.Studies have demonstrated the elevation of proinflammatory cytokines and inflammatory biomarkers (e.g.,CRP), markers of oxidative stress, lipid peroxidation, and cardiovascular risk factors with hyperglycemiccrises. All of these parameters return to normal following insulin and hydration therapies within 24 hours ofhyperglycemic crises. Elevation of proinflammatory cytokines, and markers of lipid peroxidation and oxidativestress, have also been demonstrated in non-diabetic patients with insulin-induced hypoglycemia.[15] Theobserved proinflammatory and procoagulant states in hyperglycemic crises and hypoglycemia may be theresult of adaptive responses to acute stress and not hyperglycemia or hypoglycemia per se.[1] [15] [16] Ithas also been postulated that ketosis-prone diabetes comprises different syndromes based on autoantibodystatus, human leukocyte antigen (HLA) genotype, and beta-cell functional reserve.[17]

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This PDF of the BMJ Best Practice topic is based on the web version that was last updated: Feb 07, 2020.BMJ Best Practice topics are regularly updated and the most recent version of the topicscan be found on bestpractice.bmj.com . Use of this content is subject to our disclaimer (.


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Diabetic ketoacidosis BasicsBA

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Pathogenesis of DKA and HHS; triggers include stress, infection, andinsufficient insulin. FFA: free fatty acid; HHS: hyperosmolar hyperglycemic state

From: Kitabchi AE, Umpierrez GE, Miles JM, et al. Diabetes Care. 2009,32:1335-43; used with permission

ClassificationClinical DKA classification[1]Diagnostic criteria and classification:

Mild DKA

• Plasma glucose: >250 mg/dL• Arterial pH: 7.25 to 7.30• Serum bicarbonate: 15-18 mEq/L• Urine ketone: positive• Serum ketone: positive• Effective serum osmolality: variable• Anion gap: >10• Mental status: alert.

Moderate DKA

• Plasma glucose: >250 mg/dL• Arterial pH: 7.00 to <7.24




Diabetic ketoacidosis Basics

• Serum bicarbonate: 10 to <15 mEq/L• Urine ketone: positive• Serum ketone: positive• Effective serum osmolality: variable• Anion gap: >12• Mental status: alert and/or drowsy.

Severe DKA

• Plasma glucose: >250 mg/dL• Arterial pH: <7.00• Serum bicarbonate: <10 mEq/L• Urine ketone: positive• Serum ketone: positive• Effective serum osmolality: variable• Anion gap: >12• Mental status: stupor and/or coma.

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Diabetic ketoacidosis PreventionPR

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Primary preventionPatient education about management of their diabetes during periods of mild illness (sick-day management)is vital for preventing DKA. This should include information on when to contact a healthcare professional,blood glucose monitoring, use of insulin, and initiation of appropriate nutrition during illness. This informationshould be reinforced with patients periodically. Patients should be advised to continue insulin and to seekprofessional advice early in the course of the illness. Close follow-up is very important, as it has been shownthat 3-month visits to the endocrine clinic will reduce the number of emergency department admissions forDKA.[1] [33] [34] Self-monitoring of ketones is also emerging as a potential strategy.[35]

SGLT-2 inhibitor-associated DKA in patients with type 2 diabetes is typically precipitated by insulin omissionor significant dose reduction, severe acute illness, dehydration, extensive exercise, surgery, low-carbohydratediets, or excessive alcohol intake. DKA prevention strategies should include withholding SGLT-2 inhibitorswhen precipitants are present, and avoiding insulin omission or large insulin dose reduction.[36] [37]

Many cases can be prevented by better access to medical care, proper education, and effectivecommunication with a healthcare provider during an intercurrent illness. Adequate supervision byfamily and healthcare provider may decrease the rates of hospitalization and mortality.[1] [38] Hospitaladmission with DKA, and recurrent admissions in particular, may be considered a "red flag" for triggeringpsychiatric assessment so that mental health problems can be addressed and further admissions with DKAprevented.[19]

ScreeningIf a patient is brought to the emergency department with signs and symptoms of hyperglycemia (polyuria,polydipsia, and abdominal pain), volume depletion, acetone breath, and changes in mental status (evenwithout a history of diabetes), then plasma glucose and urine ketones should be checked. In the presenceof high plasma glucose and/or positive urine ketones, full diagnostic laboratory evaluations for DKA andhyperosmolar hyperglycemic state should be performed.[1]




Diabetic ketoacidosis Diagnosis

Case historyCase history #1A 20-year-old man is brought to the emergency department with abdominal pain, nausea, and vomitingwith increasing polyuria, polydipsia, and drowsiness since the day before. He was diagnosed withtype 1 diabetes 2 years previously. He mentions that he ran out of insulin 2 days ago. Vital signs atadmission are: BP 106/67 mmHg, heart rate 123 beats per minute, respiratory rate 32 breaths perminute, temperature 98.8°F (37.1°C). On mental status examination, he is drowsy. Physical examinationreveals Kussmaul breathing (deep and rapid respiration due to ketoacidosis) with acetone odor and mildgeneralized abdominal tenderness without guarding and rebound tenderness. Initial laboratory data are:blood glucose 450 mg/dL, arterial pH 7.24, pCO₂ 25 mmHg, bicarbonate 12 mEq/L, WBC count 18,500/microliter, sodium 128 mEq/L, potassium 5.2 mEq/L, chloride 97 mEq/L, BUN 32 mg/dL, creatinine 1.7mg/dL, serum ketones strongly positive.

Other presentationsIt is now well recognized that new-onset type 2 diabetes can manifest with DKA. These patients areobese and have undiagnosed hyperglycemia, impaired insulin secretion, and insulin resistance. However,after treatment of the acute hyperglycemic episode with insulin, beta-cell function and insulin effectsimprove so these patients are able to discontinue insulin therapy and may be treated orally or by dietalone, with 40% remaining insulin-independent 10 years following the initial episodes of DKA. Thesepatients do not have the typical autoimmune laboratory findings of type 1 diabetes.[2] This type ofdiabetes has been labeled as "type 1 and ½" or "type 1 and a half" diabetes, "Flatbush" diabetes,or "ketosis-prone" diabetes. Conversely, an extreme hyperosmolar state similar to hyperosmolarhyperglycemic state (HHS) has been reported in combination with DKA in type 1 diabetes.[3] [4] [5] [6]

Step-by-step diagnostic approachThe symptoms of DKA usually develop rapidly over 1 day or less. DKA may be the initial presentation inup to 25% of people with newly diagnosed diabetes. Hyperglycemia is a key diagnostic criterion for DKA;however, a wide range of plasma glucose levels can be present on admission, and approximately 10% ofDKA patients present with glucose <250 mg/dL (“euglycemic DKA”).[1] Hyperosmolar hyperglycemic state(HHS) is often discussed as a separate condition. However, DKA and HHS represent two points on thespectrum of metabolic derangements in diabetes. In contrast to DKA, HHS may evolve insidiously over daysto weeks. Symptoms of hyperglycemia in both DKA and HHS include polyuria, polydipsia, weakness, andweight loss.

Important factors to consider in the patient's past or current medical history include infection, myocardialinfarction, pancreatitis, stroke, acromegaly, hyperthyroidism, and Cushing syndrome, as these may beprecipitants or risk factors for DKA. In euglycemic DKA, pregnancy, starvation, concomitant alcohol use, andsodium-glucose cotransporter 2 (SGLT-2) inhibitors have all been implicated in its etiology.[12] [39]

It is essential to take a full medication history, in particular looking for corticosteroids, thiazides, pentamidine,sympathomimetics, second-generation antipsychotic agents, and immune checkpoint inhibitors, as theseaffect carbohydrate metabolism and may participate in the development of hyperglycemic crises.[1] [25] [11]

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Diabetic ketoacidosis DiagnosisD

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[27] [40] Cocaine abuse may be an independent risk factor associated with recurrent DKA.[28] [10] SGLT-2inhibitors (e.g., canagliflozin, dapagliflozin, empagliflozin), used for glycaemic control of type 2 diabetes, havebeen the subject of an FDA warning about a risk for DKA.[29]

Physical examPhysical signs of volume depletion include dry mucous membranes, poor skin turgor, tachycardia,hypotension, and, in severe cases, shock. DKA patients may exhibit nausea, vomiting, Kussmaulrespiration, acetone breath, and, occasionally, abdominal pain. Abdominal pain may correlate with thedegree of acidosis in patients with DKA, and it may be confused with an acute abdominal crisis. Mildhypothermia may be observed in some patients, due to peripheral vasodilation. Hyperthermia is not usual,even in the presence of infection.[1] Mental status may be altered in DKA, varying from alert in mild DKAto stupor and/or coma in severe DKA. In HHS, mental obtundation and coma are more frequent. Focalneurologic signs (hemianopia and hemiparesis) and seizures may also be features in HHS.[1]

Initial laboratory evaluationPlasma glucose

• Plasma glucose is typically >250 mg/dL with presence of acidosis and ketonemia. However, awide range of plasma glucose levels can be present on admission, and approximately 10% of DKApatients present with glucose <250 mg/dL (euglycemic DKA).[1]

Urinalysis

• Positive for glucose and ketones. Other potential findings include leukocytes and nitrites in thepresence of infection, and myoglobinuria and/or hemoglobinuria in rhabdomyolysis.

Arterial and venous blood gases

• Arterial blood gas (ABG) shows a metabolic acidosis, which is essential for the diagnosis of DKA.Arterial pH measurement is necessary for diagnosis of DKA, but venous pH is recommended formonitoring treatment, due to the pain and risk of infection in obtaining frequent arterial samples.A venous pH sample is usually 0.03 units lower than arterial pH, and this difference should beconsidered.

• The pH varies from 7.00 to 7.30, and the arterial bicarbonate ranges from <10 mEq/L in severeDKA to >15 mEq/L in mild DKA.

Capillary or serum ketones (beta-hydroxybutyrate)

• There are three main ketones that are produced in DKA that can be measured: acetone,acetoacetate, and beta-hydroxybutyrate (BOHB).

• In early DKA, the acetoacetate concentration is low, but it is a major substrate for ketonemeasurement by many laboratories (nitroprusside reaction method). Therefore, serum ketonemeasurement by usual laboratory techniques has a high specificity, but low sensitivity for thediagnosis of DKA; hence a negative test for serum ketones does not exclude DKA. Acetone israrely measured due to its volatile nature.[41] Conversely, BOHB is an early and abundant ketoacidthat can be the first signal of the development of DKA. Point-of-care BOHB testing is widelyavailable and is highly sensitive and specific for the diagnosis of DKA.[42]





• During the treatment of DKA, BOHB is converted to acetoacetate, which is detected by thenitroprusside method. Therefore, the increase in acetoacetate during the treatment of DKA maymistakenly indicate a worsening of ketonemia.

• Another potential source of error in detecting ketone bodies is the patient's medications. Somedrugs, such as the ACE inhibitor captopril, contain sulfhydryl groups that can react with the reagentin the nitroprusside test and give a false-positive result. Therefore, clinical judgement and otherbiochemical tests will be required in patients who are receiving such medications.[1]

BUN

• Typically increased due to volume depletion.

Serum electrolytes[1] [18]

• Sodium: serum sodium is usually low due to osmotic reflux of water from the intracellular toextracellular space in the presence of hyperglycemia. Total sodium deficit is 7 to 10 mEq/kg. Hypernatremia in the presence of hyperglycemia indicates profound volume depletion.Alternately, in the presence of high serum chylomicron concentration, pseudonormoglycemia andpseudohyponatremia may occur.

• Calculation of the corrected sodium: the corrected serum sodium level should be evaluated as thisis used to guide appropriate fluid replacement. The equation for conventional units is: correctedsodium (mEq/L) = measured sodium (mEq/L) + 0.016 (glucose [mg/dL] - 100).

• Potassium: total potassium deficit is 3 to 5 mEq/kg. Serum potassium is usually elevated due toextracellular shift of potassium caused by insulin insufficiency, hypertonicity, and acidemia, but thetotal body potassium concentration is low due to increased diuresis. Therefore, low potassium levelon admission indicates severe total-body potassium deficit.

• Chloride: usually low. The total chloride deficit is 3 to 5 mEq/kg.• Magnesium: usually low. The total body deficit of magnesium is usually 1 to 2 mEq/kg.• Calcium: usually low. Total body calcium deficit is usually about 1 to 2 mEq/kg.• Phosphate: despite the total body phosphate deficit averaging 1.0 mmol/kg, serum phosphate is

often normal or increased at presentation, but decreases with insulin therapy.

Anion gap

• The calculated serum anion gap in mEq/L (serum sodium - [serum chloride + bicarbonate]) givesan estimate of the unmeasured anions in plasma, which in DKA are ketoacids. The anion gap istypically more than 10 to 12 mEq/L in DKA.

• Normalization of the anion gap reflects correction of the ketoacidosis as these anions are removedfrom the blood.

Creatine phosphokinase

• Rhabdomyolysis is common in cocaine users with concurrent DKA, and creatine phosphokinaselevels should be assessed in known or suspected cocaine users who present with DKA.[28]

• In rhabdomyolysis, pH and serum osmolality are usually mildly elevated and plasma glucose andketones are normal. Myoglobinuria and/or hemoglobinuria are detected on urinalysis.

Serum lactate

• Measured to exclude lactic acidosis. Lactate levels are normal in DKA but elevated in lacticacidosis.

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Liver function tests (LFTs)

• Usually normal, and are used to screen for an underlying hepatic precipitant. Abnormal LFTsindicate underlying liver disease such as fatty liver, or other conditions such as congestive heartfailure.

Serum amylase and lipase

• Amylase is elevated in the majority of patients with DKA, but this may be due to nonpancreaticsources such as parotid glands.

• Serum lipase is usually normal and may be beneficial in differentiating pancreatitis in patients withelevated amylase level. However, mildly elevated serum lipase level in the absence of pancreatitishas also been reported in patients with DKA.[1]

Plasma osmolality

• This is variable in DKA.

CBC with differential

• Leukocytosis is present in hyperglycemic crises and correlates with blood ketone levels. However,leukocytosis >25,000/microliter may indicate infection and requires further evaluations.[1]

Additional testsECG

• Used to exclude myocardial infarction (MI) as a precipitant or to look for cardiac effects ofelectrolyte disturbances (usually of potassium). Evidence of MI includes Q waves or ST segmentchanges. Evidence of hypokalemia (U waves) or hyperkalemia (tall T waves) may be present.

• A high index of suspicion for MI should be maintained as diabetic patients often present withatypical symptoms.

Chest x-ray

• Indicated to exclude pneumonia. In pneumonia, may show typical changes of pneumonia includinginfiltration, consolidation, effusions, and cavitation.

Blood, urine, or sputum cultures

• Should be obtained if there are signs of infection such as chills, constitutional upset (e.g., fatigue,confusion, anxiety), or symptoms and signs of specific infections. The most common precipitatinginfections are pneumonia and urinary tract infections. Patients are usually normothermic orhypothermic due to peripheral vasodilation so fever may not be seen.

Cardiac biomarkers

• Usually normal, but are elevated if MI is the precipitant. A high index of suspicion should bemaintained as diabetic patients often present with atypical symptoms.

Typical deficits in mild DKATypical deficits[18]





Mild DKA:

• Total water (L): 6• Water (mL/kg): 100• Na+ (mEq/kg): 7 to 10• Cl- (mEq/kg): 3 to 5• K+ (mEq/kg): 3 to 5• PO4 (mmol/kg): 5 to 7• Mg++ (mEq/kg): 1 to 2• Ca++ (mEq/kg): 1 to 2.

Notes: Deficits based on per kg of body weight.

Risk factorsStronginadequate or inappropriate insulin therapy• Reduction in the net effective concentration of insulin leads to impaired carbohydrate, lipid, and

ketone metabolism in DKA. Decreased insulin results in increased gluconeogenesis, acceleratedglycogenolysis, and impaired glucose utilization by peripheral tissues.[1]

• Non-compliance with insulin therapy has been found to be the leading precipitating factor in blackpeople and is present in over 30% of patients with DKA.[18] [9] Psychological and social factors mayimpact on glycemic control, and low socio-economic status is correlated with a higher risk for DKA.[19][20]

infection• The most common precipitating factor in DKA is infection. Increased counter-regulatory hormones,

particularly epinephrine, as a systemic response to infection lead to insulin resistance, increasedlipolysis, ketogenesis, and volume depletion, which may contribute to the development ofhyperglycemic crises in patients with diabetes.[1]

myocardial infarction#• Underlying cardiovascular events, particularly myocardial infarction, provoke the release of counter-

regulatory hormones that are likely to result in DKA in patients with diabetes.[1] [21]

Weakpancreatitis• Medical conditions such as pancreatitis, characterized by increased levels of counter-regulatory

hormones and compromised access to water and insulin, may contribute in the development ofhyperglycemic crises.[1] [22]

stroke• Acute medical events such as stroke, with increased levels of counter-regulatory hormones and

compromised access to water and insulin, may contribute to the development of hyperglycemiccrises.[1]

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acromegaly• Hormonal derangements in some endocrine glands lead to increased counter-regulatory hormones

and development of DKA in patients with concomitant diabetes.[23]

hyperthyroidism• Hormonal derangements in some endocrine glands lead to increased counter-regulatory hormones

and development of DKA in patients with concomitant diabetes.[24]

drugs (e.g., corticosteroids, thiazides, pentamidine, sympathomimetics,second-generation antipsychotics, cocaine, immune checkpoint inhibitors,or SGLT-2 inhibitors)• Drugs that affect carbohydrate metabolism may precipitate hyperglycemic crises.[25] [11] [26]

[27] Cocaine abuse may be an independent risk factor associated with recurrent DKA.[28] [10]• Sodium-glucose cotransporter-2 (SGLT-2) inhibitors (e.g., canagliflozin, dapagliflozin, empagliflozin),

used for glycemic control of type 2 diabetes, have been the subject of an FDA warning about a risk forDKA.[29]

• Immune checkpoint inhibitor therapy for cancer (PD-1 and PD-L1 blocking antibodies such asnivolumab, pembrolizumab, and avelumab) appears to be associated with a risk for DKA and type 1diabetes mellitus.[30] [31]

Cushing syndrome• Hypercortisolism leads to insulin resistance and may occasionally precipitate DKA in patients with

concomitant diabetes; it more commonly precipitates hyperosmolar hyperglycemic state.

Hispanic or black ancestry• Ancestry plays a role in ketosis-prone diabetes, with DKA a presenting manifestation of undiagnosed

type 2 diabetes in young adults. Approximately 80% of obese black patients with DKA have type2 diabetes, characterized by higher insulin secretion, the absence of autoimmune markers, and alack of human leukocyte antigen (HLA) genetic association compared with lean patients with type 1diabetes.[3]

bariatric surgery• DKA has been reported in patients with type 1 diabetes who have had bariatric surgery.[32]

History & examination factorsOther diagnostic factorspolyuria (common)• Symptom of hyperglycemia.

polyphagia (common)• Symptom of hyperglycemia.

polydipsia (common)• Symptom of hyperglycemia.





weight loss (common)• Symptom of hyperglycemia.

weakness (common)• Symptom of hyperglycemia.

nausea or vomiting (common)• Abdominal pain, nausea, and vomiting in DKA correlate with the degree of acidosis and may be

confused with acute abdominal crisis.[1]

abdominal pain (common)• Abdominal pain, nausea, and vomiting in DKA correlate with the degree of acidosis and may be

confused with acute abdominal crisis.[1]

dry mucous membranes (common)• Sign of volume depletion.

poor skin turgor (common)• Sign of volume depletion.

sunken eyes (common)• Sign of volume depletion.

tachycardia (common)• Sign of volume depletion.

hypotension (common)• Sign of volume depletion.

Kussmaul respiration (common)• Rapid and deep respiration due to acidosis. Common in DKA.

acetone breath (common)• Sign of ketosis. Common in DKA.

altered mental status (common)• Mental status may be altered, and varies from alert in mild DKA to stupor/coma in severe DKA. Studies

have shown that acidosis is independently associated with altered sensorium in DKA patients, buthyperosmolarity and serum ketone levels are not. Combination of hyperosmolarity and acidosispredicts altered sensorium with good sensitivity (61%) and specificity (87%) in DKA patients.[43]

hypothermia (uncommon)• Although concomitant infection is common, patients usually are normothermic or hypothermic due to

peripheral vasodilation. Severe hypothermia is a poor prognostic sign.[44]

DIAG

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Diagnostic tests1st test to order

Test Resultplasma glucose

• A plasma glucose test should be performed as an initial laboratoryevaluation. In DKA, it is usually >250 mg/dL with acidosis andketonemia.

• However, 10% of DKA patients present with blood glucose <250 mg/dL, which is termed euglycemic DKA.[1]

elevated

ABG• Acidosis is essential for the diagnosis of DKA. Arterial pH

measurement is necessary for diagnosis of DKA, but venous pH isrecommended for monitoring treatment, due to the pain and risk ofinfection in obtaining frequent arterial samples. A venous pH sampleis usually 0.03 units lower than arterial pH, and this difference shouldbe considered.

• In hyperosmolar hyperglycemic state, the arterial pH is usually >7.30and the arterial bicarbonate is >15 mEq/L.[1]

pH varies from 7.00 to7.30 in DKA; arterialbicarbonate ranges from<10 mEq/L in severe DKAto >15 mEq/L in mild DKA

capillary or serum ketones• There are three main ketones that are produced in DKA that can be

measured: acetone, acetoacetate, and beta-hydroxybutyrate (BOHB).• In early DKA, acetoacetate concentration is low, but it is a

major substrate for ketone measurement by many laboratories(nitroprusside reaction method). Therefore, serum ketonemeasurement by usual laboratory techniques has a high specificity,but low sensitivity for the diagnosis of DKA; hence a negative test forserum ketones does not exclude DKA. Acetone is rarely measureddue to its volatile nature.[41] Conversely, BOHB is an early andabundant ketoacid that can be the first signal of the development ofDKA. Point-of-care BOHB testing is widely available and is highlysensitive and specific for the diagnosis of DKA.[42]

• During the treatment of DKA, BOHB is converted to acetoacetate,which is detected by the nitroprusside method. Therefore, theincrease in acetoacetate during the treatment of DKA may mistakenlyindicate a worsening of ketonemia.

• Another potential source of error in detecting ketone bodies isthe patient's medications. Some drugs, such as the ACE inhibitorcaptopril, contain sulfhydryl groups that can react with the reagentin the nitroprusside test and give a false-positive result. Therefore,clinical judgement and other biochemical tests will be required inpatients who are receiving such medications.[1]

beta-hydroxybutyrateelevated ≥3.8 mmol/L inadults or ≥3.0 mmol/L inchildren

urinalysis• Glucose and ketones are typical findings in DKA.[1]

positive for glucose andketones; positive forleukocytes and nitrites inthe presence of infection

serum BUN• Increased due to volume depletion.[1]

elevated

serum creatinine• Increased due to volume depletion.[1]

elevated





Test Resultserum sodium

• Serum sodium is usually low due to osmotic reflux of water from theintracellular to extracellular space in the presence of hyperglycemia.Total sodium deficit is 7 to 10 mEq/kg. Hypernatremia in the presenceof hyperglycemia in DKA indicates profound volume depletion.Alternately, in the presence of high serum chylomicron concentration,pseudonormoglycemia and pseudohyponatremia may occur in DKA.

• The corrected serum sodium level should be evaluated as this is usedto guide appropriate fluid replacement. The equation for conventionalunits is: corrected sodium (mEq/L) = measured sodium (mEq/L) +0.016 (glucose [mg/dL] - 100).[1] [18]

usually low

serum potassium• Total potassium deficit is 3 to 5 mEq/kg. Serum potassium is

usually elevated due to extracellular shift of potassium causedby insulin insufficiency, hypertonicity, and acidemia, but the totalbody potassium concentration is low due to increased diuresis.Therefore, low potassium level on admission indicates severe total-body potassium deficit.[1] [18]

usually elevated

serum chloride• Total chloride deficit is 3 to 5 mEq/kg.[1] [18]

usually low

serum magnesium• Total body deficit of magnesium is usually 1 to 2 mEq/kg.[1] [18]

usually low

serum calcium• Total body calcium deficit is usually about 1 to 2 mEq/kg.[1] [18]

usually low

serum phosphate• Despite the total body phosphate deficit averaging 1.0 mmol/kg,

serum phosphate is often normal or increased at presentation, butdecreases with insulin therapy.[1] [18]

normal or elevated

anion gap calculation• Anion gap is calculated by subtracting the sum of serum chloride and

bicarbonate from measured sodium concentration. [1]

elevated anion gap (>10-12mEq/L)

serum creatine phosphokinase• In patients with history of cocaine abuse and DKA, rhabdomyolysis

is common; therefore, checking creatine phosphokinase level can beinitially assessed in patients with DKA if clinically indicated.

• In rhabdomyolysis, pH and serum osmolality are usually mildlyelevated and plasma glucose and ketones are normal. Myoglobinuriaand/or hemoglobinuria are detected in urinalysis.[1] [18]

elevated inrhabdomyolysis

serum lactate• Plasma glucose and serum ketones are normal in lactic acidosis.

Serum lactate is >5 mmol/L in lactic acidosis.[1]

elevated in lactic acidosis

LFT• Used to identify underlying diseases such as fatty liver or congestive

heart failure.[1]

usually normal

serum amylase• Amylase is elevated in majority of patients with DKA, but this may be

due to nonpancreatic sources such as parotid glands.[1]

usually elevated due toextrapancreatic sources

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Test Resultserum lipase

• Serum lipase may be beneficial in differentiating pancreatitis inpatients with elevated amylase level. However, mildly elevated serumlipase level in the absence of pancreatitis has also been reported inpatients with DKA.[1]

usually normal

serum osmolality• The serum osmolality is variable in DKA but is >320 mOsm/kg in

hyperosmolar hyperglycemic state.[1]

variable

CBC• Leukocytosis is present in hyperglycemic crises and correlates with

blood ketone levels. However, leukocytosis >25,000/microliter mayindicate infection and requires further evaluations.[1]

elevated white cell count

Other tests to consider

Test Resultchest x-ray

• The most common infections are pneumonia and urinary tractinfections.[1]

may be compatible withpneumonia

ECG• If clinically indicated, should be performed for identification of the

precipitating cardiovascular diseases, such as myocardial infarction(MI) or severe electrolyte abnormalities.[1]

• Evidence of MI includes Q waves or ST segment changes.• Evidence of hypokalemia (U waves) or hyperkalemia (tall T waves)

may be present.[1]

may show evidence of MIor hyper- or hypokalemia

cardiac biomarkers• MI is a common precipitant of DKA in diabetic patients.[1]

may be elevated in thepresence of MI

blood, urine, or sputum cultures• If indicated clinically, further sepsis workup should be performed.[1]

positive in the presence ofinfection





Differential diagnosis

Condition Differentiating signs /symptoms

Differentiating tests

Hyperosmolarhyperglycemic state (HHS)

• Patients are typically olderthan patients with DKA andare usually patients with type2 diabetes. Older nursinghome residents with poorfluid intake are at high risk.

• Symptoms evolve insidiouslyover days to weeks.

• Mental obtundationand coma are morefrequent. Focal neurologicsigns (hemianopia andhemiparesis) and seizuresare also seen. Seizures maybe the dominant clinicalfeatures.[1]

• Serum glucose is >600 mg/dL. Serum osmolality isusually >320 mOsm/kg.

• Urine ketones are normal oronly mildly positive. Serumketones are negative.

• Anion gap is variable buttypically <12 mEq/L.

• Total chloride deficit is 5 to15 mEq/kg.

• ABG: arterial pH is typically>7.30, whereas in DKA itranges from 7.00 to 7.30.Arterial bicarbonate is >15mEq/L.

Lactic acidosis • The presentation is identicalto that of DKA. In purelactic acidosis, the serumglucose and ketones shouldbe normal and the serumlactate concentration shouldbe elevated.

• Serum lactate >5 mmol/L.[1]

Starvation ketosis • Starvation ketosisresults from inadequatecarbohydrate availabilityresulting in physiologicallyappropriate lipolysis andketone production to providefuel substrates for muscle.

• The blood glucose is usuallynormal. Although the urinecan have large amounts ofketones, the blood rarelydoes. Arterial pH is normaland the anion gap is at mostmildly elevated.[1]

Alcoholic ketoacidosis • Classically, these are peoplewith long-standing alcoholuse disorder for whomethanol has been the maincaloric source for days toweeks. The ketoacidosisoccurs when for somereason alcohol and caloricintake decreases.

• In isolated alcoholicketoacidosis, the metabolicacidosis is usually mildto moderate in severity.The anion gap is elevated.Serum and urine ketonesare always present. Bloodalcohol may be undetectableand the patient may behypoglycemic.[1]

Salicylate poisoning • Can be differentiated byhistory and laboratoryinvestigation. Salicylateintoxication produces ananion gap metabolic acidosisusually with a respiratoryalkalosis.

• The plasma glucose isnormal or low, ketonesare negative, osmolalityis normal, and salicylatesare positive in blood and/or urine. It should be notedthat salicylates may causefalse-positive or false-

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Condition Differentiating signs /symptoms

Differentiating tests

negative urinary glucosedetermination.[1]

Ethylene glycol/methanolintoxication

• Methanol and ethylene glycolalso produce an anion gapmetabolic acidosis withouthyperglycemia or ketones.

• Methanol/ethylene glycolserum levels are elevated.They can produce anincrease in the measuredserum osmolality.[1]

Uremic acidosis • This is characterized bymarkedly elevated BUNand creatinine with normalplasma glucose. The pH andanion gap are usually mildlyabnormal.

• Elevated BUN usually>200 mg/dL and elevatedcreatinine usually >10 mg/dL.[1]

Diagnostic criteriaHyperglycemic crises in adult patients with diabetes: a consensusstatement from the American Diabetes Association[1]Plasma glucose (mg/dL)

• >250 in DKA.

Arterial pH

• 7.25 to 7.3 in mild DKA• 7.00 to <7.24 in moderate DKA• <7.00 in severe DKA.

Serum bicarbonate (mEq/L)

• 15-18 in mild DKA• 10-15 in moderate DKA• <10 in severe DKA.

Urine and serum ketones (nitroprusside reaction method)

• + in DKA.

Effective serum osmolality (mOsm/kg)

• variable in DKA.

Anion gap (mEq/L)

• >10 in mild DKA• >12 in moderate and severe DKA.

Mental status





• alert in mild DKA• alert/drowsy in moderate DKA• stupor/coma in severe DKA.[1]

The most widely used diagnostic criteria for DKA are plasma glucose >250 mg/dL, arterial pH <7.3, andpresence of ketonemia and/or ketonuria. However, severity of DKA or the required number of criteria fordiagnosis have not been officially stated, and the above-mentioned classification has been based heavily onprospective studies of DKA.[1]

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Step-by-step treatment approachThe main goals of treatment are:

• Restoration of volume deficits• Resolution of hyperglycemia and ketosis/acidosis• Correction of electrolyte abnormalities (potassium level should be >3.3 mEq/L before initiation of

insulin therapy; use of insulin in a patient with hypokalemia may lead to respiratory paralysis, cardiacarrhythmias, and death)

• Treatment of the precipitating events and prevention of complications.

It must be emphasized that successful treatment requires frequent monitoring of clinical and laboratoryparameters to achieve resolution criteria. A treatment protocol and a flow sheet for recording the treatmentstages and laboratory data should be maintained.[1] [46] [47] [48]

Initial and supportive treatmentThe majority of patients present to the emergency department, where treatment should be initiated. Thereare several important steps that should be followed in early management:

• Fluid therapy should be started immediately after initial laboratory evaluations.• Infusion of isotonic solution of 0.9% sodium chloride at a rate of 1.0 to 1.5 L/hour should be used

for the first hour of fluid therapy.

Indications for admission to the intensive care unit (ICU) are hemodynamic instability or cardiogenicshock, altered mental status, respiratory insufficiency, severe acidosis, and hyperosmolar state withcoma.

The diagnosis of hemodynamic instability should made by observing for hypotension and clinical signsof poor tissue perfusion, including oliguria, cyanosis, cool extremities, and altered mental state. Afteradmission to ICU, central venous and arterial lines are required, with continuous percutaneous oximetry.Oxygenation and airway protection are critical. Intubation and mechanical ventilation are commonlyrequired, with constant monitoring of respiratory parameters. Nasogastric suctioning is always performedbecause of frequent ileus and danger of aspiration.

Initial management in hemodynamically unstable patients includes fluid resuscitation to correcthypovolemia and hypotension, close monitoring, and vasopressor therapy. Dopamine is the vasopressorof choice, given in an intravenous infusion whose rate is adjusted according to blood pressure and otherhemodynamic parameters. If the patient remains hypotensive despite moderate doses of dopamine, adirect vasoconstrictor (e.g., norepinephrine) should be started and titrated to maintain a mean arterialpressure of 60 mmHg.[1] [52]

Fluid therapyFluid deficit averages 6 liters.[53] After the initial management, continuous fluid therapy should be started.The goal is the restoration of fluid loss. Correction of fluid deficits should be undertaken gradually over12-24 hours, as overly rapid correction can result in the patient developing cerebral edema.[54] [55]After initial therapy with 1.0 to 1.5 L of isotonic solution (0.9% NaCl) for the first hour of admission inall patients, hydration status should be evaluated clinically. The presence of orthostatic hypotension orsupine hypotension with dry mucous membranes and poor skin turgor indicates severe volume depletion,which should be treated by infusion of 0.9% NaCl at the rate of 1.0 L/hour until signs of severe volume




Diabetic ketoacidosis Treatment

depletion are resolved. These patients then continue to receive fluid therapy as for mild volume depletion,based on the corrected serum sodium level.

In patients with mild volume depletion (characterized by an absence of hypotension), corrected serumsodium level should be evaluated (corrected sodium [mEq/L] = measured sodium [mEq/L] + 0.016[glucose (mg/dL) - 100]).

• In hyponatremic patients: 0.9% NaCl should be started at 250-500 mL/hour and when the plasmaglucose reaches 200 mg/dL, fluid therapy should be changed to 5% dextrose with 0.45% NaCl at150-250 mL/hour.[1] [52]

• In hypernatremic or eunatremic patients, 0.45% NaCl at 250-500 mL/hour is recommended andwhen plasma glucose reaches 200 mg/dL, it should be changed to 5% dextrose with 0.45% NaCl at150-250 mL/hour.[1] [40] [52] [56]

Insulin therapyThe goal is the steady but gradual reduction of serum glucose and plasma osmolality by low-dose insulintherapy, in order to reduce the risk of treatment complications including hypoglycemia and hypokalemia.

Patients should receive a continuous intravenous infusion of regular insulin after exclusion of hypokalemia(i.e., potassium level should be >3.3 mEq/L before initiation of insulin therapy). Two alternative low-doseregimens are recommended by current guidelines.[1] [45] The first option is a continuous intravenousinfusion of regular insulin at a dose of 0.14 units/kg/hour (approximately 10 units/hour in a 70 kg patient)with no initial bolus.[1] This is based on studies that show the use of low-dose regular insulin administeredby intravenous infusion is sufficient for the treatment of DKA, provided the dose is above 0.1 units/kg/hour.The alternative regimen involves an initial intravenous bolus dose of 0.1 units/kg followed by a continuousinfusion at a dose of 0.1 units/kg/hour.[53] These low-dose insulin therapy protocols decrease plasmaglucose concentration at a rate of 50 to 75 mg/dL/hour.[1]

If plasma glucose does not fall by at least 10% or 50 mg/dL in the first hour of insulin infusion, then a doseof 0.14 units/kg of regular insulin should be administered as an intravenous bolus and the continuousinsulin infusion rate should be continued (either 0.1 units/kg/hour or 0.14 units/kg/hour depending on theregimen selected).[1] [53] Insulin injection by a sliding scale is no longer recommended. When serumglucose is <200 mg/dL, the infusion can be reduced to 0.02 to 0.05 units/kg/hour, at which time dextrosemay be added to the intravenous fluids.[1] [53] The rate of insulin infusion (or the dextrose concentration)should then be adjusted to maintain a plasma glucose level of between 150-200 mg/dL.[1]

Patients with severe DKA (plasma glucose >250 mg/dL, arterial pH <7.00, serum bicarbonate <10 mEq/L), hypotension, anasarca (severe generalized edema), or associated severe critical illness should bemanaged with intravenous regular insulin in the ICU using the regimen described above.[1] [57] [58][59] Patients with mild to moderate DKA (plasma glucose >250 mg/dL, arterial pH 7.00 to 7.30, serumbicarbonate 10-18 mEq/L) that is not complicated by acute myocardial infarction, congestive heartfailure, end-stage renal or hepatic failure, steroid use, or pregnancy, may be given rapid-acting insulinsubcutaneously as an alternative to intravenous regular insulin.[60] [61] [62] This has been demonstratedto be safe and effective from studies in adults in one center.[1] A suggested protocol would be an initialsubcutaneous injection of rapid-acting insulin at a dose of 0.3 units/kg, followed 1 hour later by anothersubcutaneous injection of 0.2 units/kg. Thereafter, they should receive 0.2 units/kg every 2 hours untilblood glucose becomes <250 mg/dL. At this point, the insulin dose should be decreased by half to 0.1units/kg every 2 hours until the resolution of DKA.[58] Until the results of these studies are replicated in

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multicenter trials, the administration of continuous intravenous infusion of regular insulin should remainthe preferred route because of its short half-life and easy titration (compared with the delayed onset ofaction and prolonged half-life of subcutaneously administered insulin). However, in places where there areincreased waiting times for ICU admission or with limited medical resources, the use of insulin analogsfor the treatment of mild uncomplicated DKA episodes can be considered in outpatient, general wards, oremergency departments.

Management of adult DKA. Abbreviations: blood glucose (BG); diabeticketoacidosis (DKA); hour (h); intravenous (IV); subcutaneous (SC)

Image created BMJ Knowledge Centre based on Gosmanov AR, GosmanovaEO, Dillard-Cannon E. Management of adult diabetic ketoacidosis. Diabetes,

Metabolic Syndrome and Obesity: Targets and Therapy. 2014;7:255-64.

Potassium therapyInsulin therapy and correction of acidemia and hyperosmolality will drive potassium into cells, which maycause serious hypokalemia. The goal, therefore, is to correct the actual potassium deficits and therebyprevent fatal complications of hypokalemia, including respiratory paralysis and cardiac dysrhythmia.

Insulin therapy should be withheld until the serum potassium level reaches 3.3 mEq/L. Likewise, if plasmapotassium falls below 3.3 mEq/L at any point during therapy, insulin should be stopped and potassiumreplaced intravenously. In all patients with a serum potassium level <5.3 mEq/L and an adequate urineoutput of >50 mL/hour, 20-30 units (mEq) of potassium should be added to each liter of infusion fluidto prevent hypokalemia caused by insulin therapy. If potassium level is >5.3 mEq/L, replacement is notneeded but potassium level should be checked every 2 hours.[1]





Bicarbonate therapyBicarbonate use in DKA remains controversial. At arterial blood pH >7.0, administration of insulin blockslipolysis and resolves ketoacidosis without the need to add bicarbonate. Administering bicarbonatetherapy in these patients may result in increased risk of hypokalemia, decreased tissue oxygen uptake,and cerebral edema.

Bicarbonate therapy may be used in adult patients with an arterial blood pH <7 in DKA, although dataare limited.[63] Based on studies in adult patients with an arterial blood pH of 6.9 to 7.0, 50 mmol sodiumbicarbonate in 200 mL sterile water with 10 mEq potassium chloride (KCl) may be administered over 1hour until pH is >7.0.

In adult patients with pH <6.9, it is recommended that 100 mmol sodium bicarbonate in 400 mL sterilewater (an isotonic solution) with 20 mEq KCl be administered at a rate of 200 mL/hour for 2 hours until pH>7.0. For monitoring of treatment, venous pH is sufficient and should be checked at least each hour in thissetting. Treatment should be repeated every 2 hours until pH >7.0.

Bicarbonate therapy as well as insulin therapy lowers serum potassium; therefore, KCl is added to isotonicbicarbonate infusion.[1] [64]

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Algorithm for the management of potassium and bicarbonateModified from: Kitabchi AE, Umpierrez GE, Miles JM, et al. Diabetes Care. 2009,32:1335-43

Phosphate therapyDespite total body phosphate deficits in DKA that average 1.0 mmol/kg of body weight, serum phosphateis often normal or increased at presentation, but decreases with insulin therapy. Previous studies havefailed to show any beneficial effects of phosphate replacement in DKA patients. Therefore, routinereplacement of phosphate is not recommended.

However, to avoid cardiac, respiratory, and skeletal muscle dysfunction, careful phosphate therapy may beindicated in patients with cardiac dysfunction (e.g., with signs of left ventricular dysfunction), symptomaticanemia, or respiratory depression (e.g., decreased oxygen saturation), and in those with confirmedhypophosphatemia (serum phosphate concentration <1.0 mg/dL).[1]





Monitoring of therapyMonitoring of respiratory parameters and hemodynamic status are essential in hemodynamically unstablepatients.

Subsequent to initial laboratory evaluation, serum glucose and electrolytes are measured at least hourly;calcium, magnesium, and phosphate are checked every 2 hours, and BUN, creatinine, and ketones every2-6 hours, depending on the patient's clinical condition and response to therapy.

Serial beta hydroxybutyrate (BOHB) measurements may aid monitoring of the response to treatmentin DKA. However, measurement of ketone bodies, in the absence of a meter with capacity to measureBOHB, is not recommended. BOHB is converted to acetoacetate, which is detected by the nitroprussidemethod, during the treatment of DKA. Therefore, the increase in acetoacetate during DKA treatment maymistakenly indicate a worsening of ketonemia.

Present evidence suggests monitoring bicarbonate, anion gap, and pH to reflect the response to therapy.A flow sheet classifying these findings as well as mental status, vital signs, insulin dose, fluid andelectrolytes therapies, and urine output allows easy analysis of response to therapy and resolution ofcrises. Metabolic panel measurement during DKA therapy provides dynamic information on the changesin renal function and sodium level.

Management and monitoring should continue until resolution of DKA. The criteria for resolution are:[1]

• plasma glucose is <200 mg/dL (at this point, insulin can be decreased by 50%)• serum bicarbonate is >18 mEq/L• venous pH is >7.3• anion gap is <10.

Treatment details overviewPlease note that formulations/routes and doses may differ between drug names and brands, drugformularies, or locations. Treatment recommendations are specific to patient groups: see disclaimer

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Acute ( summary )severe volume depletion

serum potassium <3.3mEq/L

1st intravenous fluids

plus supportive care + ICU admission

plus potassium therapy

plus intravenous insulin once serumpotassium reaches 3.3 mEq/L

adjunct vasopressors

adjunct bicarbonate therapy

adjunct phosphate therapy

serum potassium 3.3 to5.3 mEq/L



plus intravenous insulin





serum potassium >5.3mEq/L







mild to moderate volume depletion:hyponatremic



plus supportive care ± ICU admission


plus insulin once serum potassium reaches 3.3mEq/L






Acute ( summary )adjunct phosphate therapy




plus insulin







plus insulin



mild to moderate volume depletion:eunatremic or hypernatremic











plus insulin







plus insulin

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Acute ( summary )adjunct bicarbonate therapy


Ongoing ( summary )DKA resolved and patient able totolerate oral intake

1st establish regular subcutaneous insulinregime





Treatment optionsPlease note that formulations/routes and doses may differ between drug names and brands, drugformularies, or locations. Treatment recommendations are specific to patient groups: see disclaimer

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Acutesevere volume depletion



» Severe volume depletion is indicated bythe presence of orthostatic hypotension orsupine hypotension, dry mucous membranes,and poor skin turgor. Extreme cases may behemodynamically unstable.

» The goal of initial fluid therapy is to restoretissue perfusion. The initial choice of fluid isisotonic saline infused at a rate of 1.0 to 1.5 L(or 15-20 mL/kg body weight) for the first hour.In patients with severe volume depletion orcardiogenic shock, isotonic fluid therapy andhemodynamic monitoring should continue inthe intensive care unit until the patient becomesstable.

» Electrolytes should be checked at least hourly(to monitor potassium levels) and BUN, venouspH, creatinine, and glucose should be checkedevery 2-4 hours until the resolution of DKA.

» When plasma glucose reaches 200 mg/dL,fluid therapy should be changed to 5% dextrosewith 0.45% NaCl at 150-250 mL/hour in order toavoid hypoglycemia.[1]


Treatment recommended for ALL patients inselected patient group

» Indications for intensive care unit (ICU)admission include hemodynamic instabilityor cardiogenic shock, altered mental status,respiratory insufficiency, and severe acidosis.

» After admission to ICU, central venous andarterial lines are required as well as Swan-Ganzcatheterization and continuous percutaneousoximetry.

» Intubation and mechanical ventilation arecommonly required, with constant monitoring ofrespiratory parameters.

» Nasogastric suctioning is always performedbecause of frequent ileus and danger ofaspiration.[1]



Primary options





Acute» potassium phosphate: 20-30 mEq added toeach liter of infusion fluid initially, adjust doseaccording to serum potassium levelIf potassium is <3.3 mEq/L at any point oftherapy, insulin should be discontinued.

OR

» potassium chloride: 20-30 mEq added toeach liter of infusion fluid initially, adjust doseaccording to serum potassium levelIf potassium is <3.3 mEq/L at any point oftherapy, insulin should be discontinued.

» Insulin therapy and correction ofhyperosmolarity and acidemia decrease plasmaconcentration of potassium. For this reason,insulin therapy should be withheld until theserum potassium level reaches 3.3 mEq/L.

» Likewise, if plasma potassium falls <3.3 mEq/L at any point of therapy, insulin should bediscontinued.

» The dose of potassium replacement is 20-30mEq added to each liter of infusion fluid.[1]

» Choices are potassium phosphate orpotassium chloride. One third of the potassiumreplacement should be administered aspotassium phosphate to avoid excessive chlorideadministration.

» The serum potassium level should bemonitored at least hourly and replacementadjusted accordingly.

plus intravenous insulin once serum potassiumreaches 3.3 mEq/L


Primary options

» insulin regular: consult local protocols fordosing guidelines

» Insulin therapy should not be commenced untilserum potassium reaches 3.3 mEq/L.

» Patients should receive a continuousintravenous infusion of regular insulin afterexclusion of hypokalemia (i.e., potassium levelshould be >3.3 mEq/L before initiation of insulintherapy). Two alternative low-dose regimens arerecommended by current guidelines.[1] [45] Thefirst option is a continuous intravenous infusionof regular insulin at a dose of 0.14 units/kg/hour

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Acute(approximately 10 units/hour in a 70 kg patient)with no initial bolus.[1] This is based on studiesthat show the use of low-dose regular insulinadministered by intravenous infusion is sufficientfor the treatment of DKA, provided the doseis >0.1 units/kg/hour. The alternative regimeninvolves an initial intravenous bolus dose of0.1 units/kg followed by a continuous infusionat a dose of 0.1 units/kg/hour.[53] These low-dose insulin therapy protocols decrease plasmaglucose concentration at a rate of 50-75 mg/dL/hour.[1]

» If plasma glucose does not fall by at least10% or 50 mg/dL in the first hour of insulininfusion, then a dose of 0.14 units/kg of regularinsulin should be administered as an intravenousbolus and the continuous insulin infusion rateshould be continued (either 0.1 units/kg/hour or0.14 units/kg/hour depending on the regimenselected).[1] [53] Insulin injection by a slidingscale is no longer recommended. When serumglucose reaches 200 mg/dL, the infusion can bereduced to 0.02 to 0.05 units/kg/hour, at whichtime dextrose may be added to the intravenousfluids.[1] [53] The rate of insulin infusion (or thedextrose concentration) should then be adjustedto maintain a plasma glucose level of between150-200 mg/dL.[1]

» This regimen should be followed until allremaining criteria for resolution are met: serumbicarbonate >18 mEq/L, venous pH >7.3, andanion gap <10.[1]


Treatment recommended for SOME patients inselected patient group

Primary options

» dopamine: 5-10 micrograms/kg/minintravenously initially, adjust rate accordingto blood pressure and other hemodynamicparameters

Secondary options

» norepinephrine: 0.5 micrograms/kg/minintravenously initially, titrate to maintain amean arterial pressure of 60 mmHg

» In hemodynamically unstable patients,vasopressor therapy (dopamine therapy)may also be required. Often these patientsrequire high doses of dopamine, in the orderof 20 micrograms/kg/minute. If the patientremains hypotensive despite moderate doses





Acuteof dopamine, a direct vasoconstrictor (e.g.,norepinephrine) should be started.[1] [52]



Primary options

» sodium bicarbonate: serum pH 6.9 to 7.0:50 mmol intravenous infusion over 1 houruntil pH >7.0; serum pH <6.9: 100 mmolintravenous infusion at a rate of 200 mL/hourfor 2 hours or until pH >7.0

» Bicarbonate therapy may be used in adultpatients with pH <7 or a bicarbonate level <5mEq/L, although data are limited.[1] [63]

» In adults with pH 6.9 to 7.0, 50 mmol sodiumbicarbonate (1 ampule) in 200 mL sterile waterwith 10 mEq KCl may be administered over 1hour until pH is >7.0.

» In adults with pH <6.9, we recommend that100 mmol sodium bicarbonate in 400 mL sterilewater with 20 mEq KCl be administered at arate of 200 mL/hour for 2 hours or until pH >7.0.Treatment should be repeated every 2 hoursuntil pH >7.0. Bicarbonate therapy, like insulintherapy, lowers serum potassium; therefore, KClis added to isotonic bicarbonate.[1] [64]



Primary options

» potassium phosphate: 20-30 mEq added toeach liter of infusion fluid

» Routine replacement of phosphate is notrecommended.

» However, to avoid cardiac, respiratory, andskeletal muscle dysfunction, careful phosphatetherapy may be indicated in patients with cardiacdysfunction (e.g., with signs of left ventriculardysfunction), symptomatic anemia, or respiratorydepression (e.g., decreased oxygen saturation),and in those with confirmed hypophosphatemia(serum phosphate concentration <1.0 mg/dL).[1]

» The dose is 20-30 mEq/L potassiumphosphate added to replacement fluids.

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Acute» Phosphate therapy above the recommendeddose may result in severe hypocalcemia.[1] [75][76]

serum potassium 3.3 to 5.3mEq/L



» The goal of initial fluid therapy is to restoretissue perfusion. The initial choice of fluid isisotonic saline infused at a rate of 1.0 to 1.5 L(or 15-20 mL/kg body weight) for the first hour.In patients with severe volume depletion (i.e.,orthostatic or supine hypotension, dry mucousmembranes, and poor skin turgor) or cardiogenicshock, isotonic fluid therapy and hemodynamicmonitoring should continue in the intensive careunit until the patient becomes stable.

» Electrolytes should be checked at least hourly(to monitor potassium levels) and BUN, venouspH, creatinine, and glucose should be checkedevery 2-4 hours until the resolution of DKA.







» Nasogastric suctioning is always performedbecause of frequent ileus and danger ofaspiration.







AcutePrimary options


» Patients should receive a continuousintravenous infusion of regular insulin afterexclusion of hypokalemia (i.e., potassium levelshould be >3.3 mEq/L before initiation of insulintherapy). Two alternative low-dose regimens arerecommended by current guidelines.[1] [45] Thefirst option is a continuous intravenous infusionof regular insulin at a dose of 0.14 units/kg/hour(approximately 10 units/hour in a 70 kg patient)with no initial bolus.[1] This is based on studiesthat show the use of low-dose regular insulinadministered by intravenous infusion is sufficientfor the treatment of DKA, provided the dose isabove 0.1 units/kg/hour. The alternative regimeninvolves an initial intravenous bolus dose of0.1 units/kg followed by a continuous infusionat a dose of 0.1 units/kg/hour.[53] These low-dose insulin therapy protocols decrease plasmaglucose concentration at a rate of 50 to 75 mg/dL/hour.[1]

» If plasma glucose does not fall by at least10% or 50 mg/dL in the first hour of insulininfusion, then a dose of 0.14 units/kg of regularinsulin should be administered as an intravenousbolus and the continuous insulin infusion rateshould be continued (either 0.1 units/kg/hour or0.14 units/kg/hour depending on the regimenselected).[1] [53] Insulin injection by a slidingscale is no longer recommended. When serumglucose reaches 200 mg/dL, the infusion canbe reduced to 0.05 units/kg/hour, at which timedextrose may be added to the intravenousfluids.[1] [53] The rate of insulin infusion (or thedextrose concentration) should then be adjustedto maintain a plasma glucose level of between150-200 mg/dL.[1]


» If plasma potassium falls below 3.3 mEq/Lat any point, insulin should be discontinuedand potassium replaced intravenously. Insulintherapy can be restarted when the potassiumlevel returns to 3.3 mEq/L.



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» potassium phosphate: 20-30 mEq added toeach liter of infusion fluid initially, adjust doseaccording to serum potassium levelIf potassium is <3.3 mEq/L at any point oftherapy, insulin should be discontinued andpotassium replaced intravenously.

OR

» potassium chloride: 20-30 mEq added toeach liter of infusion fluid initially, adjust doseaccording to serum potassium levelIf potassium is <3.3 mEq/L at any point oftherapy, insulin should be discontinued andpotassium replaced intravenously.

» Insulin therapy and correction ofhyperosmolarity and acidemia decrease theplasma concentration of potassium. Concurrentpotassium replacement is recommended ifthe serum potassium is in the range 3.3 to 5.3mEq/L, to prevent cardiac arrhythmias due tohypokalemia. The dose is 20-30 mEq addedto each liter of infusion fluid. If potassium is<3.3 mEq/L at any point of therapy, insulinshould be discontinued and potassium replacedintravenously.[1]





Primary options


Secondary options






Acute» In hemodynamically unstable patients,vasopressor therapy (dopamine therapy)may also be required. Often these patientsrequire high doses of dopamine, in the orderof 20 micrograms/kg/minute. If the patientremains hypotensive despite moderate dosesof dopamine, a direct vasoconstrictor (e.g.,norepinephrine) should be started.[1] [52]



Primary options




» In adults with pH <6.9, we recommend that100 mmol sodium bicarbonate in 400 mL sterilewater with 20 mEq KCl be administered at arate of 200 mL/hour for 2 hours or until pH >7.0.Treatment should be repeated every 2 hoursuntil pH >7.0. Bicarbonate therapy, like insulintherapy, lowers serum potassium; therefore, KClis added to isotonic bicarbonate.[64]



Primary options




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Acute» The dose is 20-30 mEq/L potassiumphosphate added to replacement fluids.

» Phosphate therapy above the recommendeddose may result in severe hypocalcemia.[1] [75][76]




» The goal of initial fluid therapy is to restoretissue perfusion. The initial choice of fluid isisotonic saline infused at a rate of 1.0 to 1.5 L(or 15-20 mL/kg body weight) for the first hour.In patients with severe volume depletion (i.e.,orthostatic or supine hypotension, dry mucousmembranes, and poor skin turgor) or cardiogenicshock, isotonic fluid therapy and hemodynamicmonitoring should continue in the intensive careunit until the patient becomes stable.

» Electrolytes should be checked at least hourly(to monitor potassium levels), and BUN, venouspH, creatinine, and glucose should be checkedevery 2-4 hours until the resolution of DKA.







» Nasogastric suctioning is always performedbecause of frequent ileus and danger ofaspiration.






AcuteTreatment recommended for ALL patients inselected patient group

Primary options


» Patients should receive a continuousintravenous infusion of regular insulin afterexclusion of hypokalemia (i.e., potassium levelshould be >3.3 mEq/L before initiation of insulintherapy). Two alternative low-dose regimens arerecommended by current guidelines.[1] [45] Thefirst option is a continuous intravenous infusionof regular insulin at a dose of 0.14 units/kg/hour(approximately 10 units/hour in a 70 kg patient)with no initial bolus.[1] This is based on studiesthat show the use of low-dose regular insulinadministered by intravenous infusion is sufficientfor the treatment of DKA, provided the dose isabove 0.1 units/kg/hour. The alternative regimeninvolves an initial intravenous bolus dose of0.1 units/kg followed by a continuous infusionat a dose of 0.1 units/kg/hour.[53] These low-dose insulin therapy protocols decrease plasmaglucose concentration at a rate of 50-75 mg/dL/hour.[1]



» Potassium replacement is not required, butpotassium levels should be checked every 2hours.



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Secondary options


» In hemodynamically unstable patients,vasopressor therapy (dopamine therapy)may also be required. Often these patientsrequire high doses of dopamine, in the orderof 20 micrograms/kg/minute. If the patientremains hypotensive despite moderate dosesof dopamine, a direct vasoconstrictor (e.g.,norepinephrine) should be started.[1] [52]



Primary options

» sodium bicarbonate: serum pH 6.9 to 7.0:50 mmol intravenous infusion over 1 houruntil pH >7.0; serum pH <6.9: 100 mmolintravenous infusion over 2 hours or until pH>7.0






Primary options





Acute» potassium phosphate: 20-30 mEq added toeach liter of infusion fluid





mild to moderate volume depletion:hyponatremic



» Mild to moderate volume depletion is indicatedby the absence of orthostatic hypotension orsupine hypotension, dry mucous membranes,and poor skin turgor. The goal is to graduallyreplace half of the fluid deficit over 12-24 hours,to prevent complications such as cerebraledema.

» The initial choice of fluid is isotonic salineinfused at a rate of 1.0 to 1.5 L (or 15-20 mL/kgbody weight) for the first hour.

» Following the initial fluid replacement,corrected serum sodium level shouldbe evaluated (corrected sodium [mEq/L] = measured sodium [mEq/L] + 0.016[glucose (mg/dL) - 100]). In patients found to behyponatremic, 0.9% NaCl should be started at250-500 mL/hour.




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» Indications for intensive care unit (ICU)admission include altered mental status,respiratory insufficiency, and severe acidosis.

» After admission to ICU, central venous andarterial lines are required as well as Swan-Ganzcatheterization and continuous percutaneousoximetry. Intubation and mechanical ventilationare commonly required, with constant monitoringof respiratory parameters. Nasogastricsuctioning is always performed because offrequent ileus and danger of aspiration.

» Mild cases of DKA may be managed withoutICU admission.[1]



Primary options


OR




» The dose is 20-30 mEq added to each liter ofinfusion fluid.[1]

» Choices for potassium therapy are potassiumphosphate or potassium chloride. One thirdof the potassium replacement should be





Acuteadministered as potassium phosphate to avoidexcessive chloride administration.



Primary options


Secondary options

» insulin aspart: consult local protocols fordosing guidelines

OR

» insulin lispro: consult local protocols fordosing guidelines

» Insulin therapy should not be commenced untilserum potassium reaches 3.3 mEq/L.


» If plasma glucose does not fall by at least10% or 50 mg/dL in the first hour of insulininfusion, then a dose of 0.14 units/kg of regularinsulin should be administered as an intravenousbolus and the continuous insulin infusion rateshould be continued (either 0.1 units/kg/hour or0.14 units/kg/hour depending on the regimenselected).[1] [53] Insulin injection by a slidingscale is no longer recommended. When serumglucose reaches 200 mg/dL, the infusion can bereduced to 0.02 to 0.05 units/kg/hour, at which

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Acutetime dextrose may be added to the intravenousfluids.[1] [53] The rate of insulin infusion (or thedextrose concentration) should then be adjustedto maintain a plasma glucose level of 150-200mg/dL.[1]

» Patients with mild to moderate DKA (plasmaglucose >250 mg/dL, arterial pH 7.00-7.30,serum bicarbonate 10-18 mEq/L) that is notcomplicated by acute MI, congestive heartfailure, end-stage renal or hepatic failure,steroid use, or pregnancy, may be givenrapid-acting insulin subcutaneously as analternative to intravenous regular insulin.[60][61] [62] This has been demonstrated to besafe and effective from studies in adults in onecenter.[1] A suggested protocol would be aninitial subcutaneous injection of rapid-actinginsulin at a dose of 0.3 units/kg, followed 1hour later by another subcutaneous injectionof 0.2 units/kg. Thereafter, they should receive0.2 units/kg every 2 hours until blood glucosebecomes <250 mg/dL. At this point, the insulindose should be decreased by half to 0.1 units/kg every 2 hours until the resolution of DKA.[58]Until the results of these studies are replicatedin multicenter trials, the administration ofcontinuous intravenous infusion of regular insulinshould remain the preferred route becauseof its short half-life and easy titration. This iscompared with the delayed onset of actionand prolonged half-life of subcutaneouslyadministered insulin. However, in places wherethere are increased waiting times for intensivecare unit (ICU) admission or with limited medicalresources, the use of insulin analogs for thetreatment of mild uncomplicated DKA episodescan be considered in outpatient, general wards,or emergency departments. Patients with severeDKA (plasma glucose >250 mg/dL, arterialpH <7.00, serum bicarbonate <10 mEq/L),hypotension, anasarca (severe generalizededema), or associated severe critical illnessshould be managed with intravenous regularinsulin in the ICU using the regimen describedabove.[1] [58] [57] [59]




Primary options





Acute» sodium bicarbonate: serum pH 6.9 to 7.0:50 mmol intravenous infusion over 1 houruntil pH >7.0; serum pH <6.9: 100 mmolintravenous infusion at a rate of 200 mL/hourfor 2 hours or until pH >7.0






Primary options








» Mild to moderate volume depletion is indicatedby the absence of orthostatic hypotension orsupine hypotension, dry mucous membranes,and poor skin turgor. The goal is to graduallyreplace half of the fluid deficit over 12-24 hours,

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Acuteto prevent complications such as cerebraledema.










plus insulin


Primary options


Secondary options






AcuteOR



» If plasma glucose does not fall by at least10% or 50 mg/dL in the first hour of insulininfusion, then a dose of 0.14 units/kg of regularinsulin should be administered as an intravenousbolus and the continuous insulin infusion rateshould be continued (either 0.1 units/kg/hour or0.14 units/kg/hour depending on the regimenselected).[1] [53] Insulin injection by a slidingscale is no longer recommended. When serumglucose reaches 200 mg/dL, the infusion can bereduced to 0.02 to 0.05 units/kg/hour, at whichtime dextrose may be added to the intravenousfluids.[1] [53] The rate of insulin infusion (or thedextrose concentration) should then be adjustedto maintain a plasma glucose level of 150-200mg/dL.[1]

» Patients with mild to moderate DKA (plasmaglucose >250 mg/dL, arterial pH 7.00 to 7.30,serum bicarbonate 10-18 mEq/L) that is notcomplicated by acute MI, congestive heartfailure, end-stage renal or hepatic failure,steroid use, or pregnancy, may be givenrapid-acting insulin subcutaneously as analternative to intravenous regular insulin.[60][61] [62] This has been demonstrated to besafe and effective from studies in adults in onecenter.[1] A suggested protocol would be aninitial subcutaneous injection of rapid-actinginsulin at a dose of 0.3 units/kg, followed 1hour later by another subcutaneous injection

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Acuteof 0.2 units/kg. Thereafter, they should receive0.2 units/kg every 2 hours until blood glucosebecomes <250 mg/dL. At this point, the insulindose should be decreased by half to 0.1 units/kg every 2 hours until the resolution of DKA.[58]Until the results of these studies are replicatedin multicenter trials, the administration ofcontinuous intravenous infusion of regular insulinshould remain the preferred route becauseof its short half-life and easy titration. This iscompared with the delayed onset of actionand prolonged half-life of subcutaneouslyadministered insulin. However, in places wherethere are increased waiting times for intensivecare unit (ICU) admission or with limited medicalresources, the use of insulin analogs for thetreatment of mild uncomplicated DKA episodescan be considered in outpatient, general wards,or emergency departments. Patients with severeDKA (plasma glucose >250 mg/dL, arterialpH <7.00, serum bicarbonate <10 mEq/L),hypotension, anasarca (severe generalizededema), or associated severe critical illnessshould be managed with intravenous regularinsulin in the ICU using the regimen describedabove.[1] [58] [57] [59]

» The intravenous or subcutaneous regimensshould be followed until all remaining criteria forresolution are met: serum bicarbonate >18 mEq/L, venous pH >7.3, and anion gap <10.[1]



Primary options


OR


» Insulin therapy and correction ofhyperosmolarity and acidemia decrease theplasma concentration of potassium. Concurrent





Acutepotassium replacement is recommended ifthe serum potassium is in the range 3.3 to 5.3mEq/L, to prevent cardiac arrhythmias due tohypokalemia. The dose is 20-30 mEq added toeach liter of infusion fluid. If potassium is <3.3mEq/L at any point of therapy, insulin should bediscontinued.[1]





Primary options







Primary options



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Acute» However, to avoid cardiac, respiratory, andskeletal muscle dysfunction, careful phosphatetherapy may be indicated in patients with cardiacdysfunction (e.g., with signs of left ventriculardysfunction), symptomatic anemia, or respiratorydepression (e.g., decreased oxygen saturation),and in those with confirmed hypophosphatemia(serum phosphate concentration <1.0 mg/dL).[1]









» Electrolytes, BUN, venous pH, creatinine, andglucose should be checked every 2-4 hours untilthe resolution of DKA.









Acute» After admission to ICU, central venous andarterial lines are required as well as Swan-Ganzcatheterization and continuous percutaneousoximetry. Intubation and mechanical ventilationare commonly required, with constant monitoringof respiratory parameters. Nasogastricsuctioning is always performed because offrequent ileus and danger of aspiration.

» Mild cases of diabetic ketoacidosis may bemanaged without ICU admission.[1]

plus insulin


Primary options


Secondary options


OR



» If plasma glucose does not fall by at least10% or 50 mg/dL in the first hour of insulininfusion, then a dose of 0.14 units/kg of regularinsulin should be administered as an intravenousbolus and the continuous insulin infusion rateshould be continued (either 0.1 units/kg/hour or

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Acute0.14 units/kg/hour depending on the regimenselected).[1] [53] Insulin injection by a slidingscale is no longer recommended. When serumglucose reaches 200 mg/dL, the infusion can bereduced to 0.02 to 0.05 units/kg/hour, at whichtime dextrose may be added to the intravenousfluids.[1] [53] The rate of insulin infusion (or thedextrose concentration) should then be adjustedto maintain a plasma glucose level of between150 and 200 mg/dL.[1]

» Patients with mild to moderate DKA (plasmaglucose >250 mg/dL, arterial pH 7.00 to 7.30,serum bicarbonate 10-18 mEq/L) that is notcomplicated by acute MI, congestive heartfailure, end-stage renal or hepatic failure,steroid use, or pregnancy, may be givenrapid-acting insulin subcutaneously as analternative to intravenous regular insulin.[60][61] [62] This has been demonstrated to besafe and effective from studies in adults in onecenter.[1] A suggested protocol would be aninitial subcutaneous injection of rapid-actinginsulin at a dose of 0.3 units/kg, followed 1hour later by another subcutaneous injectionof 0.2 units/kg. Thereafter, they should receive0.2 units/kg every 2 hours until blood glucosebecomes <250 mg/dL. At this point, the insulindose should be decreased by half to 0.1 units/kg every 2 hours until the resolution of DKA.[58]Until the results of these studies are replicatedin multicenter trials, the administration ofcontinuous intravenous infusion of regular insulinshould remain the preferred route becauseof its short half-life and easy titration. This iscompared with the delayed onset of actionand prolonged half-life of subcutaneouslyadministered insulin. However, in places wherethere are increased waiting times for intensivecare unit (ICU) admission or with limited medicalresources, the use of insulin analogs for thetreatment of mild uncomplicated DKA episodescan be considered in outpatient, general wards,or emergency departments. Patients with severeDKA (plasma glucose >250 mg/dL, arterialpH <7.00, serum bicarbonate <10 mEq/L),hypotension, anasarca (severe generalizededema), or associated severe critical illnessshould be managed with intravenous regularinsulin in the ICU using the regimen describedabove.[1] [58] [57] [59]






Acuteadjunct bicarbonate therapy


Primary options







Primary options






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Acutemild to moderate volume depletion:eunatremic or hypernatremic





» Following the initial fluid replacement,corrected serum sodium level shouldbe evaluated (corrected sodium [mEq/L] = measured sodium [mEq/L] + 0.016[glucose (mg/dL) - 100]). In patients found to behypernatremic or eunatremic, 0.45% NaCl at 250to 500 mL/hour is recommended.









Primary options





Acute» potassium phosphate: 20-30 mEq added toeach liter of infusion fluid initially, adjust doseaccording to serum potassium levelIf potassium is <3.3 mEq/L at any point oftherapy, insulin should be discontinued andpotassium replaced intravenously.

OR




» The dose is 20-30 mEq added to each liter ofinfusion fluid.[1]

» Choices for potassium therapy are potassiumphosphate or potassium chloride. One thirdof the potassium replacement should beadministered as potassium phosphate to avoidexcessive chloride administration.




Primary options


Secondary options


OR


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Acute» Insulin therapy should not be commenced untilserum potassium reaches 3.3 mEq/L.

» Patients should receive a continuousintravenous infusion of regular insulin afterexclusion of hypokalemia (i.e., potassium levelshould be >3.3 mEq/L before initiation of insulintherapy). Two alternative low-dose regimens arerecommended by current guidelines.[1] [45] Thefirst option is a continuous intravenous infusionof regular insulin at a dose of 0.14 units/kg/hour(approximately 10 units/hour in a 70 kg patient)with no initial bolus.[1] This is based on studiesthat show the use of low-dose regular insulinadministered by intravenous infusion is sufficientfor the treatment of DKA, provided the doseis >0.1 units/kg/hour. The alternative regimeninvolves an initial intravenous bolus dose of0.1 units/kg followed by a continuous infusionat a dose of 0.1 units/kg/hour.[53] These low-dose insulin therapy protocols decrease plasmaglucose concentration at a rate of 50 to 75 mg/dL/hour.[1]


» Patients with mild to moderate DKA (plasmaglucose >250 mg/dL, arterial pH 7.00 to 7.30,serum bicarbonate 10-18 mEq/L) that is notcomplicated by acute MI, congestive heartfailure, end-stage renal or hepatic failure,steroid use, or pregnancy, may be givenrapid-acting insulin subcutaneously as analternative to intravenous regular insulin.[60][61] [62] This has been demonstrated to besafe and effective from studies in adults in onecenter.[1] A suggested protocol would be aninitial subcutaneous injection of rapid-actinginsulin at a dose of 0.3 units/kg, followed 1hour later by another subcutaneous injectionof 0.2 units/kg. Thereafter, they should receive0.2 units/kg every 2 hours until blood glucose





Acutebecomes <250 mg/dL. At this point, the insulindose should be decreased by half to 0.1 units/kg every 2 hours until the resolution of DKA.[58]Until the results of these studies are replicatedin multicenter trials, the administration ofcontinuous intravenous infusion of regular insulinshould remain the preferred route becauseof its short half-life and easy titration. This iscompared with the delayed onset of actionand prolonged half-life of subcutaneouslyadministered insulin. However, in places wherethere are increased waiting times for intensivecare unit (ICU) admission or with limited medicalresources, the use of insulin analogs for thetreatment of mild uncomplicated DKA episodescan be considered in outpatient, general wards,or emergency departments. Patients with severeDKA (plasma glucose >250 mg/dL, arterialpH <7.00, serum bicarbonate <10 mEq/L),hypotension, anasarca (severe generalizededema), or associated severe critical illnessshould be managed with intravenous regularinsulin in the ICU using the regimen describedabove.[1] [58] [57] [59]




Primary options




» In adults with pH <6.9, we recommend that100 mmol sodium bicarbonate in 400 mL sterilewater with 20 mEq KCl be administered at arate of 200 mL/hour for 2 hours or until pH >7.0.Treatment should be repeated every 2 hoursuntil pH >7.0. Bicarbonate therapy, like insulin

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Acutetherapy, lowers serum potassium; therefore, KClis added to isotonic bicarbonate.[1] [64]



Primary options








» Mild to moderate volume depletion is indicatedby the absence of orthostatic hypotension orsupine hypotension, dry mucous membranes,and poor skin turgor. The goal is to graduallyreplace half of the fluid deficit over 12 to 24hours, to prevent complications such as cerebraledema.


» Following the initial fluid replacement,corrected serum sodium level shouldbe evaluated (corrected sodium [mEq/L] = measured sodium [mEq/L] + 0.016[glucose (mg/dL) - 100]). In patients found to behypernatremic or eunatremic, 0.45% NaCl at250-500 mL/hour is recommended.











plus insulin


Primary options


Secondary options


OR



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Acute» If plasma glucose does not fall by at least10% or 50 mg/dL in the first hour of insulininfusion, then a dose of 0.14 units/kg of regularinsulin should be administered as an intravenousbolus and the continuous insulin infusion rateshould be continued (either 0.1 units/kg/hour or0.14 units/kg/hour depending on the regimenselected).[1] [53] Insulin injection by a slidingscale is no longer recommended. When serumglucose reaches 200 mg/dL, the infusion can bereduced to 0.02 to 0.05 units/kg/hour, at whichtime dextrose may be added to the intravenousfluids.[1] [53] The rate of insulin infusion (or thedextrose concentration) should then be adjustedto maintain a plasma glucose level of between150-200 mg/dL.[1]

» Patients with mild to moderate DKA (plasmaglucose >250 mg/dL, arterial pH 7.00 to 7.30,serum bicarbonate 10-18 mEq/L) that is notcomplicated by acute MI, congestive heartfailure, end-stage renal or hepatic failure,steroid use, or pregnancy, may be givenrapid-acting insulin subcutaneously as analternative to intravenous regular insulin.[60][61] [62] This has been demonstrated to besafe and effective from studies in adults in onecenter.[1] A suggested protocol would be aninitial subcutaneous injection of rapid-actinginsulin at a dose of 0.3 units/kg, followed 1hour later by another subcutaneous injectionof 0.2 units/kg. Thereafter, they should receive0.2 units/kg every 2 hours until blood glucosebecomes <250 mg/dL. At this point, the insulindose should be decreased by half to 0.1 units/kg every 2 hours until the resolution of DKA.[58]Until the results of these studies are replicatedin multicenter trials, the administration ofcontinuous intravenous infusion of regular insulinshould remain the preferred route becauseof its short half-life and easy titration. This iscompared with the delayed onset of actionand prolonged half-life of subcutaneouslyadministered insulin. However, in places wherethere are increased waiting times for intensivecare unit (ICU) admission or with limited medicalresources, the use of insulin analogs for thetreatment of mild uncomplicated DKA episodescan be considered in outpatient, general wards,or emergency departments. Patients with severeDKA (plasma glucose >250 mg/dL, arterialpH <7.00, serum bicarbonate <10 mEq/L),hypotension, anasarca (severe generalizededema), or associated severe critical illnessshould be managed with intravenous regularinsulin in the ICU using the regimen describedabove.[1] [58] [57] [59]





Acute» The intravenous or subcutaneous regimensshould be followed until all remaining criteria forresolution are met: serum bicarbonate >18 mEq/L, venous pH >7.3, and anion gap <10.[1]



Primary options


OR


» Insulin therapy and correction ofhyperosmolarity and acidemia decrease theplasma concentration of potassium. Concurrentpotassium replacement is recommended ifthe serum potassium is in the range 3.3 to 5.3mEq/L, to prevent cardiac arrhythmias due tohypokalemia. The dose is 20-30 mEq added toeach liter of infusion fluid. If potassium is <3.3mEq/L at any point of therapy, insulin should bediscontinued.[1]





Primary options

» sodium bicarbonate: serum pH 6.9 to 7.0:50 mmol intravenous infusion over 1 houruntil pH >7.0; serum pH <6.9: 100 mmol

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Acuteintravenous infusion at a rate of 200 mL/hourfor 2 hours or until pH >7.0



» In adults with pH <6.9, we recommend that100 mmol sodium bicarbonate in 400 mL sterilewater with 20 mEq KCl be administered at arate of 200 mL/hour for 2 hours or until pH >7.0.Treatment should be repeated every 2 hoursuntil pH >7.0. Bicarbonate therapy, like insulintherapy, lowers serum potassium; therefore, KClis added to isotonic bicarbonate.[64]



Primary options













Acute» The initial choice of fluid is isotonic salineinfused at a rate of 1.0 to 1.5 L (or 15-20 mL/kgbody weight) for the first hour.

» Following the initial fluid replacement,corrected serum sodium level shouldbe evaluated (corrected sodium [mEq/L] = measured sodium [mEq/L] + 0.016[glucose (mg/dL) - 100]). In patients found to behypernatremic or eunatremic, 0.45% NaCl at 250to 500 mL/hour is recommended.


» Electrolytes, BUN, venous pH, creatinine, andglucose should be checked every 2-4 hours untilthe resolution of DKA.






plus insulin


Primary options


Secondary options


OR


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Acute» Patients should receive a continuousintravenous infusion of regular insulin afterexclusion of hypokalemia (i.e., potassium levelshould be >3.3 mEq/L before initiation of insulintherapy). Two alternative low-dose regimens arerecommended by current guidelines.[1] [45] Thefirst option is a continuous intravenous infusionof regular insulin at a dose of 0.14 units/kg/hour(approximately 10 units/hour in a 70 kg patient)with no initial bolus.[1] This is based on studiesthat show the use of low-dose regular insulinadministered by intravenous infusion is sufficientfor the treatment of DKA, provided the dose isabove 0.1 units/kg/hour. The alternative regimeninvolves an initial intravenous bolus dose of0.1 units/kg followed by a continuous infusionat a dose of 0.1 units/kg/hour.[53] These low-dose insulin therapy protocols decrease plasmaglucose concentration at a rate of 50-75 mg/dL/hour.[1]

» If plasma glucose does not fall by at least10% or 50 mg/dL in the first hour of insulininfusion, then a dose of 0.14 units/kg of regularinsulin should be administered as an intravenousbolus and the continuous insulin infusion rateshould be continued (either 0.1 units/kg/hour or0.14 units/kg/hour depending on the regimenselected).[1] [53] Insulin injection by a slidingscale is no longer recommended. When serumglucose reaches 200 mg/dL, the infusion can bereduced to 0.02 to 0.05 units/kg/hour, at whichtime dextrose may be added to the intravenousfluids.[1] [53] The rate of insulin infusion (or thedextrose concentration) should then be adjustedto maintain a plasma glucose level of 150-200mg/dL.[1]

» Patients with mild to moderate DKA (plasmaglucose >250 mg/dL, arterial pH 7.00 to 7.30,serum bicarbonate 10-18 mEq/L) that is notcomplicated by acute MI, congestive heartfailure, end-stage renal or hepatic failure,steroid use, or pregnancy, may be givenrapid-acting insulin subcutaneously as analternative to intravenous regular insulin.[60][61] [62] This has been demonstrated to besafe and effective from studies in adults in onecenter.[1] A suggested protocol would be aninitial subcutaneous injection of rapid-actinginsulin at a dose of 0.3 units/kg, followed 1hour later by another subcutaneous injectionof 0.2 units/kg. Thereafter, they should receive0.2 units/kg every 2 hours until blood glucosebecomes <250 mg/dL. At this point, the insulindose should be decreased by half to 0.1 units/kg every 2 hours until the resolution of DKA.[58]





AcuteUntil the results of these studies are replicatedin multicenter trials, the administration ofcontinuous intravenous infusion of regular insulinshould remain the preferred route becauseof its short half-life and easy titration. This iscompared with the delayed onset of actionand prolonged half-life of subcutaneouslyadministered insulin. However, in places wherethere are increased waiting times for intensivecare unit (ICU) admission or with limited medicalresources, the use of insulin analogs for thetreatment of mild uncomplicated DKA episodescan be considered in outpatient, general wards,or emergency departments. Patients with severeDKA (plasma glucose >250 mg/dL, arterialpH <7.00, serum bicarbonate <10 mEq/L),hypotension, anasarca (severe generalizededema), or associated severe critical illnessshould be managed with intravenous regularinsulin in the ICU using the regimen describedabove.[1] [58] [57] [59]





Primary options




» In adults with pH <6.9, we recommend that100 mmol sodium bicarbonate in 400 mL sterilewater with 20 mEq KCl be administered at arate of 200 mL/hour for 2 hours or until pH >7.0.Treatment should be repeated every 2 hoursuntil pH >7.0. Bicarbonate therapy, like insulin

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Acutetherapy, lowers serum potassium; therefore, KClis added to isotonic bicarbonate.[1] [64] [75]



Primary options





» Phosphate therapy above the recommendeddose may result in severe hypocalcemia.[1] [76]





OngoingDKA resolved and patient able totolerate oral intake

1st establish regular subcutaneous insulinregime

» When DKA has resolved and the patientis able to tolerate oral intake, transition tosubcutaneous insulin needs to be initiated.Patient should be given subcutaneous insulin1-2 hours before the termination of insulininfusion to allow sufficient time for subcutaneousinsulin to start work at this time. Intermediate orlong-acting insulin is recommended for basalrequirements and short-acting insulin for prandialglycemic control.

» If a patient used insulin as their diabetestreatment prior to DKA, the same dose canbe started; otherwise, the following regimenis recommended: total daily insulin dose of0.5 to 0.8 units/kg/day, with 30% to 50% ofthe total daily dose given as basal long-actinginsulin, usually at night as a single dose, and theremainder of the total daily dose given as divideddoses of fast-acting insulin before each meal.[1][58] [59]

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Diabetic ketoacidosis Follow upFO

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RecommendationsMonitoringIt is possible to manage mild DKA without admission to the intensive care unit (ICU); however, manycases will require ICU care.

After admission to ICU, central venous and arterial lines are usually required. Swan-Ganz catheterizationand continuous percutaneous oximetry are needed in patients with hemodynamic instability. Monitoring ofrespiratory parameters is also required to ensure adequate oxygenation and airway protection.

Initially, serum glucose, electrolytes, BUN, creatinine, calcium, magnesium, phosphate, ketones,lactate, creatine phosphokinase, LFTs, urinalysis, ECG, upright chest radiograph, CBC, and ABGs areobtained. Subsequently, glucose and electrolytes are measured at least hourly; calcium, magnesium, andphosphate are checked every 2 hours and BUN, creatinine, and ketones every 2 to 6 hours, depending onthe patient's clinical condition and response to therapy.

Serial beta hydroxybutyrate (BOHB) measurements may aid monitoring of the response to treatmentin DKA. However, measurement of ketone bodies, in the absence of a meter with capacity to measureBOHB, is not recommended. BOHB is converted to acetoacetate, which is detected by the nitroprussidemethod, during the treatment of DKA. Therefore, the increase in acetoacetate during DKA treatment maymistakenly indicate a worsening of ketonemia.

Monitoring bicarbonate, anion gap, and pH has also been shown to reflect the response to therapy. A flowsheet classifying these findings as well as mental status, vital signs, insulin dose, fluid and electrolytestherapies, and urine output allows easy analysis of response to therapy and resolution of crises.[1] [38][83] [84]

Patient instructionsManagement should be reviewed periodically with all patients. This should include:

• When to contact the healthcare provider• Blood glucose goals and the use of supplemental short- or rapid-acting insulin during illness• Means to suppress fever and treat infection• Initiation of an easily digestible fluid diet containing electrolytes and glucose during illness.

Patients should be advised to always continue insulin during illness and to seek professional advice early.

Sodium-glucose cotransporter 2 (SGLT-2) inhibitor-associated DKA in patients with type 2 diabetes istypically precipitated by insulin omission or significant dose reduction, severe acute illness, dehydration,extensive exercise, surgery, low-carbohydrate diets, or excessive alcohol intake. DKA preventionstrategies should include withholding SGLT-2 inhibitors when precipitants are present, and avoidinginsulin omission or large insulin dose reduction.[36] [37]

The patient (or family member or carer) must be able to accurately measure and record blood glucose,insulin administration, temperature, respiratory rate, and pulse. Blood ketone (BOHB) should be checkedwhen blood glucose is >300 mg/dL and, if it is high, the patient should present to the hospital for furtherevaluation. The frequency of blood glucose monitoring depends on the patient's clinical condition: inuncontrolled diabetes (HbA1c >7.0%), it is recommended to check blood glucose before each meal, plusat bedtime.[1] [85]




Diabetic ketoacidosis Follow up

Complications

Complications Timeframe Likelihoodhypoglycemia short term high

This iatrogenic complication can occur with excessive high-dose insulin therapy. It can be prevented byfollowing current treatment protocols with frequent monitoring of plasma glucose and use of glucose-containing intravenous fluids.[1]

hypokalemia short term high

This iatrogenic complication can occur with excessive high-dose insulin therapy and bicarbonate therapy. Itcan be prevented by following current treatment protocols with frequent monitoring of potassium levels andappropriate replacement.[1] [52] [64]

arterial or venous thromboembolic events short term medium

Standard prophylactic low-dose heparin is certainly reasonable in these patients.[1] [38] [82] Applyingprophylactic treatment is based on clinical evaluation by the physician of risk factors for thromboembolicevents. Currently no evidence exists for full anticoagulation.

nonanion gap hyperchloremic acidosis short term low

This occurs due to urinary loss of ketoanions that are needed for bicarbonate regeneration, and alsoincreased reabsorption of chloride secondary to intensive administration of chloride-containing fluids. Thisacidosis usually resolves and should not affect the treatment. It is more likely in pregnant women.[1] [64]

cerebral edema/brain injury short term low

This occurs in 0.7% to 10% of children with DKA and is rare in adults with DKA. Children at ages under5 years are at increased risk.[77] It is manifested by headache, lethargy, papillary changes, and seizure.Mortality is high. Mannitol infusion and mechanical ventilation should be used to treat this condition.Prevention may be achieved by avoidance of overzealous hydration and by maintaining the glucoselevel at 150-200 mg/dL in DKA..[1] [18] [78] [79] Results of the first prospective randomised study toevaluate fluid regimens in children with DKA found that neither the sodium chloride content nor the speedof delivery of intravenous fluids affected the short- and long-term neurologic outcomes.[80]

acute respiratory distress syndrome (ARDS) short term low

Treatment-related reduction in colloid osmotic pressure may lead to accumulation of water in the lungs,decreased lung compliance and possibly hypoxemia in DKA. Management includes the monitoringof blood oxygen levels with pulse oximetry and lowering the fluid intake with addition of colloidreplacement.[18] [81]

Prognosis

The mortality rate is 5% in experienced centers. Death is rarely caused by the metabolic complications ofhyperglycemia or ketoacidosis but rather relates to the underlying illness. The prognosis is substantiallyworsened at the extremes of age and in the presence of coma and hypotension.[1]

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Diabetic ketoacidosis GuidelinesG

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Diagnostic guidelines

International

Standards of medical care in diabetes - 2020 (https://professional.diabetes.org/content-page/standards-medical-care-diabetes) [45]Published by: American Diabetes Association Last published: 2020

Hyperglycemic crises in adult patients with diabetes (https://care.diabetesjournals.org/content/32/7.toc) [1]Published by: American Diabetes Association Last published: 2009

Treatment guidelines

International

Standards of medical care in diabetes - 2020 (https://professional.diabetes.org/content-page/standards-medical-care-diabetes) [45]Published by: American Diabetes Association Last published: 2020

Hyperglycemic crises in adult patients with diabetes: a consensus statementfrom the American Diabetes Association (https://care.diabetesjournals.org/content/32/7.toc) [1]Published by: American Diabetes Association Last published: 2009



https://professional.diabetes.org/content-page/standards-medical-care-diabetes


https://care.diabetesjournals.org/content/32/7.toc








Diabetic ketoacidosis References

Key articles

• Kitabchi AE, Umpierrez GE, Miles JM, et al. Hyperglycemic crises in adult patients withdiabetes: a consensus statement from the American Diabetes Association. Diabetes Care. 2009Jul;32(7):1335-43. Full text (https://care.diabetesjournals.org/content/32/7/1335.full) Abstract (http://www.ncbi.nlm.nih.gov/pubmed/19564476?tool=bestpractice.bmj.com)

• Joint British Diabetes Societies Inpatient Care Group. The management of diabetic ketoacidosis inadults. September 2013 [internet publication]. Full text (https://www.diabetes.org.uk/professionals/position-statements-reports/specialist-care-for-children-and-adults-and-complications/the-management-of-diabetic-ketoacidosis-in-adults)

• American Diabetes Association. Standards of medical care in diabetes - 2019. Diabetes Care. 2019Jan;42(suppl 1):S1-S193. Full text (https://care.diabetesjournals.org/content/42/Supplement_1)

References

1. Kitabchi AE, Umpierrez GE, Miles JM, et al. Hyperglycemic crises in adult patients withdiabetes: a consensus statement from the American Diabetes Association. Diabetes Care. 2009Jul;32(7):1335-43. Full text (https://care.diabetesjournals.org/content/32/7/1335.full) Abstract (http://www.ncbi.nlm.nih.gov/pubmed/19564476?tool=bestpractice.bmj.com)

2. Balasubramanyam A, Nalini R, Hampe CS, et al. Syndromes of ketosis-prone diabetes mellitus.Endocr Rev. 2008 May;29(3):292-302. Full text (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2528854/) Abstract (http://www.ncbi.nlm.nih.gov/pubmed/18292467?tool=bestpractice.bmj.com)

3. Umpierrez GE, Woo W, Hagopian WA, et al. Immunogenetic analysis suggests differentpathogenesis for obese and lean African-Americans with diabetic ketoacidosis. DiabetesCare. 1999 Sep;22(9):1517-23. Abstract (http://www.ncbi.nlm.nih.gov/pubmed/10480519?tool=bestpractice.bmj.com)

4. Mauvais-Jarvis F, Sobngwi E, Porcher R, et al. Ketosis-prone type 2 diabetes in patientsof sub-Saharan African origin: clinical pathophysiology and natural history of beta-celldysfunction and insulin resistance. Diabetes. 2004 Mar;53(3):645-53. Full text (https://diabetes.diabetesjournals.org/content/53/3/645.full) Abstract (http://www.ncbi.nlm.nih.gov/pubmed/14988248?tool=bestpractice.bmj.com)

5. Umpierrez GE, Smiley D, Kitabchi AE. Narrative review: ketosis-prone type 2 diabetes mellitus. AnnIntern Med. 2006 Mar 7;144(5):350-7. Abstract (http://www.ncbi.nlm.nih.gov/pubmed/16520476?tool=bestpractice.bmj.com)

6. Kitabchi AE, Umpierrez GE, Fisher JN, et al. Thirty years of personal experience in hyperglycemiccrises: diabetic ketoacidosis and hyperglycemic hyperosmolar state. J Clin EndocrinolMetab. 2008 May;93(5):1541-52. Abstract (http://www.ncbi.nlm.nih.gov/pubmed/18270259?tool=bestpractice.bmj.com)

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https://www.diabetes.org.uk/professionals/position-statements-reports/specialist-care-for-children-and-adults-and-complications/the-management-of-diabetic-ketoacidosis-in-adults



https://care.diabetesjournals.org/content/42/Supplement_1




https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2528854/





https://diabetes.diabetesjournals.org/content/53/3/645.full









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75. Fisher JN, Kitabchi AE. A randomized study of phosphate therapy in the treatment of diabeticketoacidosis. J Clin Endocrinol Metab. 1983 Jul;57(1):177-80. Abstract (http://www.ncbi.nlm.nih.gov/pubmed/6406531?tool=bestpractice.bmj.com)

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Diabetic ketoacidosis Images

Images

Figure 1: Triad of DKA

Adapted with permission from: Kitabchi AE, Wall BM. Diabetic ketoacidosis. Med Clin North Am.1995;79:9-37

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Figure 2: Pathogenesis of DKA and HHS; triggers include stress, infection, and insufficient insulin. FFA: freefatty acid; HHS: hyperosmolar hyperglycemic state

From: Kitabchi AE, Umpierrez GE, Miles JM, et al. Diabetes Care. 2009,32:1335-43; used with permission




Diabetic ketoacidosis Images

Figure 3: Management of adult DKA. Abbreviations: blood glucose (BG); diabetic ketoacidosis (DKA); hour(h); intravenous (IV); subcutaneous (SC)

Image created BMJ Knowledge Centre based on Gosmanov AR, Gosmanova EO, Dillard-Cannon E.Management of adult diabetic ketoacidosis. Diabetes, Metabolic Syndrome and Obesity: Targets andTherapy. 2014;7:255-64.

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Figure 4: Algorithm for the management of potassium and bicarbonate

Modified from: Kitabchi AE, Umpierrez GE, Miles JM, et al. Diabetes Care. 2009,32:1335-43




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Contributors:

// Authors:

Aidar R. Gosmanov, MD, PhD, FACEAssociate Professor of MedicineDivision of Endocrinology, Albany Medical College , Chief, Endocrinology Section, Albany VAMC, Albany,NYDISCLOSURES: ARG declares that he has no competing interests.

Laleh Razavi Nematollahi, MDAssistant Professor of MedicineCase Western Reserve University, Cleveland, OH DISCLOSURES: LRN declares that she has no competing interests.

// Acknowledgements:Dr Aidar Gosmanov and Dr Laleh Razavi Nematollahi would like to gratefully acknowledge Professor AbbasE. Kitabchi, the previous contributor to this topic.DISCLOSURES: AEK is an author of a number of references in this topic.

// Peer Reviewers:

David Jenkins, DM, FRCPConsultant PhysicianWorcestershire Royal Hospital, Worcester, UKDISCLOSURES: DJ declares that he has no competing interests.

Udaya M. Kabadi, MD, FRCP(C), FACP, FACEProfessor of MedicineUniversity of Iowa, Iowa City, IADISCLOSURES: UMK declares that she has no competing interests.

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