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Diabetic Ketoacidosis (DKA) - Harrison's Principles of Internal Medicine, 22nd Edition (2025)

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1. Definition and Overview

• Hyperglycemia (serum glucose >13.9 mmol/L [>250 mg/dL])
• Ketosis (elevated serum/urine ketones, β-hydroxybutyrate >3.0 mmol/L)
• Metabolic acidosis (serum bicarbonate <15-18 mEq/L with increased anion gap, arterial pH 6.8-7.3)

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2. Pathophysiology

• The decreased insulin-to-glucagon ratio drives:
  • Gluconeogenesis and glycogenolysis in the liver - causing hyperglycemia
  • Increased substrate delivery from fat and muscle (free fatty acids, amino acids) to the liver
• Reduced insulin + elevated catecholamines and growth hormone increase lipolysis and free fatty acid (FFA) release from adipocytes
• The surge in FFAs causes a massive shift toward ketone body synthesis in the liver (ketonosis)
• β-hydroxybutyrate is synthesized at a threefold greater rate than acetoacetate in DKA (important diagnostic point - see below)
• Hyperglycemia leads to osmotic diuresis, causing volume depletion, and tachycardia
• Markers of inflammation (cytokines, C-reactive protein) are elevated

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3. Precipitating Factors

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4. Clinical Features

• Hypotension: volume depletion + peripheral vasodilation
• Cerebral edema: an extremely serious complication, most frequent in children
• Nausea and vomiting in a diabetic patient always warrant lab evaluation for DKA

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5. Laboratory Abnormalities and Diagnosis

Key Diagnostic Nuances

1. Corrected sodium: For every 5.6 mmol/L (100 mg/dL) rise in glucose, true sodium is 1.6 mEq/L lower than measured. A normal serum Na in DKA actually indicates a more profound water deficit.
2. β-hydroxybutyrate vs. acetoacetate: β-hydroxybutyrate is produced at 3x the rate but the classic nitroprusside reagent detects acetoacetate preferentially, not β-hydroxybutyrate. Therefore, serum β-hydroxybutyrate assays are preferred for accuracy. Certain drugs (captopril, penicillin, valproic acid) can cause false-positive nitroprusside reactions.
3. Euglycemic DKA: Glucose may be only minimally elevated or even normal - seen especially in patients treated with SGLT-2 inhibitors.
4. Amylase: Often elevated in DKA but is usually of salivary origin - not diagnostic of pancreatitis. If pancreatitis is suspected, serum lipase should be obtained (often not elevated in DKA).
5. Leukocytosis, hypertriglyceridemia, and hyperlipoproteinemia are commonly found.
6. Elevated BUN and creatinine reflect intravascular volume depletion.
7. Degree of acidosis and hyperglycemia do not necessarily correlate - ketonemia is the consistent and distinguishing finding vs. simple hyperglycemia.

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6. DKA Severity Classification

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7. Management (Harrison's Table 416-9)

Step-by-step Management Protocol

• Elevated serum glucose + elevated serum β-hydroxybutyrate + metabolic acidosis

• Severe DKA: ICU level care
• Mild to moderate: step-down unit with close nursing and laboratory monitoring

• Serum electrolytes: K⁺, Na⁺, Mg²⁺, Cl⁻, bicarbonate, phosphate
• Acid-base status: ABG / venous pH, pCO₂, HCO₃⁻
• CBC, blood glucose, BUN, creatinine
• Urinalysis
• Urine/blood cultures, CXR (if infection suspected)
• ECG

A. Fluid Resuscitation

• Initial bolus: Normal saline (0.9%) or Lactated Ringer's (LR) - large volume
• Fluid deficit is often 3-5 liters - replace sodium and free water over next 24 hours
• Once hemodynamic stability and adequate urine output are achieved, switch to 0.45% saline or Lactated Ringer's (depending on calculated volume deficit)
• LR is associated with more rapid DKA resolution and a reduced trend toward hyperchloremia compared to normal saline - this is consistent with recent meta-analysis evidence (see below)
• If vomiting or altered mental status: insert nasogastric tube to prevent aspiration

B. Insulin Therapy

• Initial bolus: IV short-acting regular insulin 0.1 units/kg
• Follow with continuous IV insulin infusion to maintain adequate circulating insulin levels
• Goal: lower serum glucose by ~50-75 mg/dL/hour
• Do NOT stop insulin until ketoacidosis is resolved (not just when glucose normalizes)
• When glucose approaches ~250 mg/dL, add dextrose to IV fluids to allow continued insulin administration until ketosis clears

C. Potassium Replacement

• Despite apparent normal or elevated K⁺ at presentation, total body K⁺ is depleted
• Insulin therapy drives K⁺ intracellularly - hypokalemia will develop with treatment
• Begin K⁺ replacement when serum K⁺ <5.5 mEq/L and urine output is confirmed
• If K⁺ <3.5 mEq/L, hold insulin and replace K⁺ first before starting insulin

D. Phosphate and Magnesium

• Total-body stores of phosphate and magnesium are reduced
• Insulin therapy for DKA is a paradigm for hypophosphatemia during refeeding - severity relates to extent of antecedent depletion
• Replace as needed based on labs

E. Bicarbonate

• Not routinely recommended
• Consider only in very severe acidosis (pH <6.9) - insufficient evidence of benefit in most cases

F. Monitor and Reassess Frequently

• Maintain a comprehensive flow sheet: vital signs, fluid I&O, labs, insulin administered
• Seek and aggressively treat the precipitating event

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8. Complications

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9. Prognosis and Prevention

• Mortality rate is low (<1%) with appropriate therapy
• Mortality is related more to the underlying precipitating event (infection, COVID-19, pregnancy, ESRD, myocardial infarction) than to DKA itself
• Even a single episode of DKA is associated with a greatly increased 1-year mortality rate
• Recurrent DKA may indicate underlying mental health issues
• Structural barriers to care, insulin cost, and social determinants of health often play a role

Patient Education After DKA

• Symptoms of DKA and precipitating factors
• Management of diabetes during concurrent illness ("sick day rules")
• The sequence of events that led to the episode

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10. Euglycemic DKA - Special Note

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11. DKA vs. HHS - Key Differences

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Recent Evidence Update (2024-2026)

1. Balanced electrolyte solutions vs. 0.9% saline (PMID 38925619): A 2024 meta-analysis confirms that balanced solutions (e.g., LR, Plasma-Lyte) result in faster DKA resolution than normal saline - consistent with Harrison's 22e recommendation to consider Ringer's lactate.
2. Subcutaneous vs. IV insulin infusion (PMID 39090718): A 2024 systematic review comparing subcutaneous insulin protocols vs. continuous IV insulin infusion in adult DKA. This is an area where practice may evolve, as SQ protocols have shown comparable outcomes in mild-moderate DKA.
3. Early subcutaneous basal insulin alongside IV infusion (PMID 41208563): A 2026 meta-analysis of RCTs found that adding early basal subcutaneous insulin to IV insulin infusion during DKA management may reduce DKA recurrence and facilitate transition off IV insulin.

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