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DEFINITION

• A metabolic acidosis characterized by the triad of hyperglycemia (glucose >250 mg/dL), metabolic acidosis (arterial pH < 7.3, serum bicarbonate < 18 meq/L) and moderate ketonuria or ketonemia
• Most, but not all, patients have type 1 diabetes
• Patients with type 2 diabetes also susceptible during acute illness (especially of African American or Hispanic descent) referred to as "ketosis-prone type 2 diabetes", likely due to greater relative insulinopenia (Linfoot)

EPIDEMIOLOGY

• Most patients 18 - 44 years (56%); two-thirds have type 1 diabetes and one-third have type 2 diabetes (Kitabchi, Wang)
• Mortality rates < 1% in adults, >5% in elderly, but most common cause of death in children and adolescents with type 1 diabetes (CDC)
• Infection most common precipitant
• Other common causes: myocardial infarction, pancreatitis, failure of insulin delivery from pump, non-adherence, psychological factors, drugs (e.g. steroids, thiazides ).
• Often the presenting manifestation in new-onset type 1 diabetes
• 35% increase in number of hospitalizations over a decade with DKA as discharge diagnosis, rising from 93,000 (1995) to 120,000 (2005) discharges in the U.S. (CDC)
• More than one third of hospitalizations are repeat DKA admissions (CDC-MMWR)
• Average length of stay declined from 7.9 days in 1980 to 3.6 days in 2005 (CDC)
• No significant differences by age, sex, ethnicity in emergency room visits for DKA, although trend towards increased DKA visits among blacks, perhaps due to ketosis-prone diabetes (see diagnosis and classification of diabetes) (Ginde).
• DKA episodes represent 1 out of every 4 dollars spent on medical care for patients with type I diabetes (Javor). Cost of avoidable hospitalizations due to short-term uncontrolled diabetes including DKA is 2.8 billion USD (Kim).

DIAGNOSIS

• Can develop rapidly, in less than 24 hours, especially if an insulin pump stops delivery for any reason.
• Perform a thorough physical examination looking for evidence of deep, rapid breathing (Kussmaul respiration), dehydration, volume depletion, and an underlying precipitant.
• Arterial blood gas to assess acidosis and respiratory compensation; venous pH can be used after initial draw by adding 0.03 to venous pH value.
• Serum and urine ketones to identify ketosis as cause of acidosis; caveat: positive ketones can occur with fasting (bicarbonate usually not <18 mEq/L) or alcohol (glucose rarely >200 mg/dl); false positive ketones with captopril, sulfhydryl drugs.
• Further laboratory tests including complete blood cell count (WBC frequently >10,000 mm³), electrolytes, blood urea nitrogen, creatinine, transaminases, amylase, lipase, cardiac enzymes, lactate, plasma osmolality, toxicology screen, urinalysis.
• Correct serum sodium by adding 1.6 mEq/L to the measured Na⁺ for each 100 mg/dl glucose above 100 mg/dl; elevated corrected Na⁺ reflects dehydration.
• Hyperkalemia and hyperphosphatemia may exist despite actual total body depletion due to extracellular shifts associated with insulin deficiency.
• High anion gap reflects degree of acidosis and hydration, calculated as: Na⁺ - (Cl^- + HCO3^-) (meq/L). Use uncorrected Na⁺. Normal anion gap (AG) = serum albumin x 3. High AG >10-12. mEq/L.
• Calculated osmolality should be compared with measured osmolality to exclude unmeasured osmoles (ethanol, methanol) if toxic ingestion suspected; serum osmolality (mOsm/L) = 2(Na⁺+K⁺) (mEq/L) + Glucose (mg/dL) /18 + BUN (mg/dL)/2.8
• Electrocardiogram, chest X-ray, and urine, sputum, or blood cultures should also be considered.

SIGNS AND SYMPTOMS

• Signs: poor skin turgor, dry mucous membranes, absence of axillary sweat, tachycardia, orthostatic hypotension, Kussmaul respirations (rapid and deep breathing as respiratory compensation for metabolic acidosis), fruity breath odor from ketonemia, emesis and abdominal guarding, guaiac-positive stools resulting from hemorrhagic gastritis
• Symptoms: polyuria, polydipsia, weight loss, dehydration, weakness, fatigue, nausea, vomiting, "air hunger", abdominal pain, fatigue, stupor, coma, seizures
• Altered mental status (usually when serum osmolality >360 mOsm/L), hypotension, and severe comorbidities identifies those at highest risk for a bad outcome

Tables/Images

CLINICAL TREATMENT

• Goal is to expand intravascular, interstitial, and intracellular volume and restore renal perfusion.
• Fluid replacement should correct estimated deficits in 24 hours. Average fluid deficit 6 L.
• Potassium replacement must be initiated concurrently with fluid therapy if K+ <5.2 meq/L; see section on correction of electrolyte imbalances below.
• In absence of cardiac compromise, isotonic saline (0.9% NaCl) infused at 15-20 mL*kg body weight^-1*h^-1 or 1-1.5 L during first hour and then continued at this rate for severe dehydration.
• Normal or elevated corrected sodium: 0.45% NaCl infused at 250 - 500 mL/h after first hour depending on hydration status for mild dehydration.
• Low corrected serum sodium: 0.9% NaCl at 250 - 500 mL/h after first hour depending on hydration status for mild dehydration.
• Measure improvement by monitoring blood pressure, fluid input/output, laboratory values, physical examination.
• In patients with cardiac or renal compromise, monitor more carefully to avoid iatrogenic volume overload.
• Hyperglycemia (glucose <250 mg/dL) corrected faster than ketoacidosis (pH >7.30, bicarbonate>18 mEq/L); mean duration 6 hours versus 12 hours.
• Once plasma glucose <200 mg/dL, change to 5% dextrose with 0.45% NaCl at 125 - 250 mL/hr to allow continued insulin therapy until ketonemia is resolved.

• Insulin therapy effective in DKA regardless of route (intravenous, subcutaneous, or intramuscular)
• Continuous intravenous infusion of regular insulin preferred due to short half-life and easy titration; glucose should be checked every hour while on IV insulin infusion using glucometer and at least every 2 - 4 hours by laboratory testing. Rapid-acting analogs such as lispro, aspart, and glulisine insulin may be as effective during the acute treatment of DKA but still require further investigation (Kitabchi, Umpierrez)
• Either 0.1 U/kg body weight as IV bolus followed by 0.1 U/kg/hr IV continuous insulin infusion or 0.14 U/kg body weight/hr without bolus
• If glucose does not fall by 50-75 mg/dl in first hour, increase insulin infusion until steady glucose decline achieved. Alternatively, if glucose does not fall by 10% in first hour, give IV bolus of 0.14 U/kg and resume previous treatment.
• When glucose falls below 200 mg/dL, reduce regular insulin infusion to 0.02 - 0.05 U/kg/hr IV, or give rapid-acting insulin 0.1 U/kg subcutaneously to maintain glucose between 125 - 200 mg/dl until ketosis resolved.
• In patients with mild DKA, subcutaneous rapid-acting insulin every 1 - 2 hours in non-intensive care settings may be as safe and effective as intravenous insulin therapy.
• Resolution of ketoacidosis includes blood glucose < 200 mg/dL, and two of the following: serum bicarbonate > 15 mEq/L, pH > 7.3, calculated anion gap < 12 mEq/L.
• To transition to subcutaneous insulin after resolution, give overlap of at least 1 - 2 hours between discontinuation of IV insulin and administration of subcutaneous insulin. Human insulin (NPH and regular) regimens are usually given in two or three doses per day. Basal-bolus regimens with basal (glargine and detemir) and rapid-acting insulin analogs (lispro, aspart, or glulisine) may be more physiologic in patients with type 1 diabetes.
• In patients who were previously well-controlled on insulin, resume previous regimen; in insulin-naive patients, total insulin dosage should be 0.5 - 0.8 U/kg/day divided in multiple doses with dose modifications based on insulin needs during hospitalization (See initiation of insulin in type 1 diabetes module).
• If patient NPO, intravenous insulin preferred in hospital with replacement fluids

• Potassium: First establish adequate renal function (urine output > 50 mL/hr). If K⁺<3.3 mEq/L, hold insulin and give 20 - 30 mEq/hr until K⁺ > 3.3 mEq/L. If K⁺>5.2 mEq/L, do not give K⁺ but check serum K⁺ every 2 hours. If K⁺ between 3.3 - 5.2 mEq/lL, give 20-30 mEq K⁺ in each liter of IV fluid to keep K⁺ between 4 - 5 mEq/lL.
• Bicarbonate: If pH >6.9, do not supplement with bicarbonate. If pH <6.9, give 100 mmol bicarbonate in 400 mmol water + 20 mEq KCl and infuse for 2 hours; repeat every 2 hours until pH>7.
• Phosphate: In patients with cardiac dysfunction, anemia, respiratory compromise or serum phosphate < 1.0 mg/dl, 20-30 mEq potassium phosphate in replacement fluids may be considered (maximum tolerated rate 4.5 mmol/hr or 1.5 ml/h)
• Magnesium: Often depleted, replace to maintain goal of > 2 mg/dL and help with resolution of hypokalemia.
• Serum electrolyte panel including BUN and creatinine should be checked every 2 - 4 hours to monitor electrolyte imbalances and resolution of anion gap.

• Common: hypoglycemia, hypokalemia due to overtreatment with insulin and bicarbonate
• Hyperchloremic non-anion gap acidosis can be seen in recovery phase and is self-limited
• Cerebral edema occurs in 0.3 - 1.0% of DKA episodes in children, rare in adults, and associated with high mortality rate. Symptoms include headache, seizures, sphincter incontinence, pupillary changes, high blood pressure, low heart rate, respiratory depression, and deterioration in consciousness. Preventive measures include gradual reduction of plasma osmolarity and glucose, and avoiding aggressive hydration. Treatment includes mannitol and mechanical ventilation.

FOLLOW UP

• In patients with ketosis-prone type 2 diabetes, 40% still non-insulin dependent at 10 years. (Mauvais-Jarvis)

EXPERT COMMENTS

• Hypokalemia is the most frequent cause of death during treatment of DKA; pay close attention to potassium replacement.
• Fluid therapy will also decrease blood glucose, but insulin therapy is necessary for resolution of ketonemia. Correction of electrolyte imbalances is especially important to preserve cardiac, neurologic, and respiratory function.
• Patients often need to be monitored on general medicine floor or intensive care unit until DKA is resolved.
• Euglycemic DKA (glucose < 250 mg/dL) could be due to many factors, including insulin injection en route to hospital or antecedent food restriction.
• DKA and hyperosmotic states often overlap, with some degree of both hyperosmolarity and ketoacidosis.
• Nausea, vomiting, diffuse abdominal pain, often with elevated WBC and liver enzymes, are more frequent in patients with DKA (> 50%) than in hyperosmolar hyperglycemic state
• Since IV insulin disappears from blood with a half-life of <6 minutes, subcutaneously delivered insulin must be given before stopping IV insulin, to avoid relapse into DKA.
• Most cases of DKA can be prevented with better health care access, patient education (especially sick day management), and early contact with a health care provider.
• Home glucose ketone monitoring may guide insulin therapy at home and possibly prevent hospitalization.
• Explore possible economic reasons for self-discontinuation of insulin therapy, especially among minority populations, and help provide resources to overcome barriers.

Basis for Recommendations

• Kitabchi AE, Umpierrez GE, Miles JM, et al.; Hyperglycemic crises in adult patients with diabetes.; Diabetes Care; 2009; Vol. 32; pp. 1335-43;
  ISSN: 1935-5548;
  PUBMED: 19564476
  Rating: Basis for recommendation
  Comments:ADA consensus statement for management of DKA and HHS.
  
  

REFERENCES

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