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Diabetic Ketoacidosis (DKA) & Hyperosmolar Hyperglycemic State (HHS)

Based on Harrison's Principles of Internal Medicine 22E (2025) & Tintinalli's Emergency Medicine

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PART 1: DKA

Pathophysiology

1. Hyperglycemia axis

• Insulin deficiency → impaired glucose uptake in peripheral tissues (muscle, fat)
• Glucagon excess → ↑ hepatic glycogenolysis + ↑ gluconeogenesis (using amino acids from muscle protein catabolism and glycerol from lipolysis)
• Result: severe hyperglycemia despite paradoxically glucose-rich extracellular space ("starvation in the midst of plenty")

2. Osmotic diuresis axis

• Hyperglycemia exceeds renal tubular threshold → glycosuria → osmotic diuresis
• Massive losses of water, sodium, potassium, phosphate, magnesium
• Volume depletion → ↑ counterregulatory hormones → worsening hyperglycemia (vicious cycle)
• Prerenal azotemia further reduces renal glucose clearance

3. Ketoacidosis axis

• Insulin deficiency + glucagon excess → activation of hormone-sensitive lipase in adipose tissue
• Lipolysis releases free fatty acids (FFAs) into circulation
• FFAs transported to liver → undergo β-oxidation → Acetyl-CoA
• Excess Acetyl-CoA (insufficient oxaloacetate for TCA cycle) → ketone body synthesis: acetoacetate, β-hydroxybutyrate, acetone
• β-hydroxybutyrate predominates (ratio β-OHB:acetoacetate ≈ 3:1)
• Accumulation of ketoacids → high anion gap metabolic acidosis
• Acidosis → impairs myocardial contractility, causes peripheral vasodilatation, shifts the O₂-Hb dissociation curve

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Clinical Presentation

• Polyuria, polydipsia, polyphagia
• Nausea, vomiting (often prominent — warrants lab evaluation in any known diabetic)
• Abdominal pain (can mimic acute pancreatitis or ruptured viscus)
• Weakness, malaise
• Altered mental status → coma in severe cases

• Tachycardia (volume depletion)
• Hypotension (volume depletion + peripheral vasodilation from acidosis)
• Kussmaul respirations — deep, rapid, labored breathing (respiratory compensation for metabolic acidosis)
• Fruity/acetone breath (acetone exhalation)
• Dry mucous membranes, poor skin turgor (dehydration)
• Lethargy, obtundation
• Fever if infection is the precipitant (but absence of fever does not exclude infection)

• Infection (most common — pneumonia, UTI)
• Insulin omission / non-compliance
• Illness (MI, stroke, pancreatitis, trauma)
• New-onset T1DM
• SGLT2 inhibitors (euglycemic DKA)

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Diagnostic Criteria

Note on Euglycemic DKA: Blood glucose may be 100–250 mg/dL (associated with SGLT2 inhibitors, pregnancy, caloric restriction, alcohol). Ketones and acidosis are present despite near-normal glucose. — Harrison's 22E, p. 3260

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Lab Tests in Suspected DKA

• Fingerstick glucose
• Urine dipstick (ketones, glucose)

• Blood and urine cultures (if febrile or infection suspected)
• Chest X-ray (pneumonia)
• ECG (myocardial infarction — silent MI can precipitate DKA; also assess for peaked T-waves of hyperkalemia or flat T-waves of hypokalemia)
• Urinalysis and urine culture

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Management

Fluid Resuscitation

• First hour: 1–2 L (15–20 mL/kg/h) isotonic saline (0.9% NaCl) IV
• Subsequent fluids: Based on corrected sodium:
  • If corrected Na normal or high → 0.45% NaCl at 250–500 mL/h
  • If corrected Na low → 0.9% NaCl at 250–500 mL/h
• When glucose <250 mg/dL: Switch to D5W with 0.45% NaCl to allow continued insulin administration without hypoglycemia

Insulin Therapy

• Do NOT start insulin until K⁺ ≥ 3.3 mEq/L (insulin shifts K⁺ intracellularly → fatal hypokalemia)
• Continuous IV regular insulin infusion: 0.1 units/kg/h (or 0.14 units/kg/h without bolus)
• Optional bolus: 0.1 units/kg IV bolus, then 0.1 units/kg/h
• Target glucose reduction: 50–75 mg/dL/hour
• When glucose reaches 200–250 mg/dL: add dextrose, reduce insulin to 0.02–0.05 units/kg/h
• Continue insulin until anion gap normalizes (NOT just until glucose normalizes)

Potassium Replacement

Bicarbonate

• Not indicated if pH >6.9
• If pH <6.9: 100 mEq NaHCO₃ in 400 mL sterile water + 20 mEq KCl IV over 2 hours; repeat until pH >7.0
• Excessive bicarbonate risks: paradoxical CSF acidosis, hypokalemia, alkalosis, delayed ketone clearance

Phosphate

• Routine supplementation not recommended
• If serum phosphate <1.0 mg/dL or symptomatic (cardiac dysfunction, respiratory muscle weakness, hemolytic anemia): Replace with potassium phosphate (20–30 mEq/h)

Monitoring During Treatment

• Blood glucose: every 1 hour
• Electrolytes, BUN, creatinine: every 2 hours for first 6 hours, then every 4–6 hours
• Venous blood gas every 2–4 hours (pH monitoring)
• Urine output (catheterize if oliguric/obtunded)
• Cardiac monitoring (ECG changes from K⁺ shifts)

Resolution Criteria (DKA resolved when ALL of the following):

• Glucose <200 mg/dL
• Serum bicarbonate ≥15 mEq/L
• Venous pH >7.3
• Anion gap ≤12 mEq/L

Transition to Subcutaneous Insulin

• Administer subcutaneous long-acting insulin at least 2 hours before stopping IV insulin infusion (overlap is essential to prevent rebound DKA)
• Resume prior insulin regimen or start new regimen based on precipitating cause

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Complications of DKA

Complications of the Disease:

• Severe volume depletion → DVT (especially elderly)
• Acute kidney injury (prerenal → intrinsic if severe)
• Circulatory shock
• Death (mortality <1% in experienced centers, higher with comorbidities)

Complications of Treatment:

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PART 2: HYPEROSMOLAR HYPERGLYCEMIC STATE (HHS)

Pathophysiology

1. Residual insulin activity is sufficient to suppress lipolysis and ketogenesis → no significant ketoacidosis
2. Extreme hyperglycemia and hyperosmolality due to prolonged osmotic diuresis and inadequate fluid intake

1. Relative insulin deficiency → ↑ hepatic glucose production (glycogenolysis + gluconeogenesis) + ↓ peripheral glucose utilization
2. Hyperglycemia develops gradually over days to weeks (in contrast to DKA's hours)
3. Osmotic diuresis → massive free water loss exceeding sodium loss → hypernatremia + hyperosmolality
4. Inadequate fluid intake (elderly, institutionalized, impaired thirst mechanism) → severe dehydration
5. Hyperosmolality (serum osmolality typically >320 mOsm/kg) → impairs consciousness, CNS dysfunction
6. Why no ketosis? Residual portal insulin levels are sufficient to inhibit hormone-sensitive lipase in adipose tissue → FFA release is suppressed → no significant ketone production. Additionally, hyperosmolality itself may suppress lipolysis.

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Diagnostic Criteria for HHS (ADA)

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PART 3: DKA vs. HHS — Differentiation & Pathophysiologic Comparison

Comparison Table

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Pathophysiologic Comparison

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Quick Differentiation at Bedside

1. pH <7.3 + ketones → DKA (±HHS if glucose >600)
2. pH >7.3 + no/trace ketones + glucose >600 + osmolality >320 → HHS
3. pH <7.3 + ketones + glucose >600 + osmolality >320 → Mixed DKA/HHS

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HHS Management Highlights (vs. DKA)

• Fluid resuscitation is the cornerstone (larger deficits: 8–12 L)
• Use 0.9% NaCl initially; switch to 0.45% NaCl once hemodynamically stable (to correct hyperosmolality more gradually)
• Insulin: Lower doses typically needed; start only after adequate fluid resuscitation (fluids alone lower glucose significantly in HHS)
• Target osmolality correction: Reduce by 3–8 mOsm/kg/hour (avoid overly rapid correction → risk of cerebral edema)
• Potassium replacement as in DKA
• Anticoagulation: Consider prophylactic heparin — HHS carries high risk of DVT and arterial thrombosis (hyperviscosity)
• Identify and treat the precipitant

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• Harrison's Principles of Internal Medicine, 22nd Ed. (2025), Chapter 416–417, p. 3260–3265
• Tintinalli's Emergency Medicine: A Comprehensive Study Guide, Chapter 225, p. 1475–1481

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Important Clarification

• ADA publishes updated Standards of Care annually in January
• The 2026 edition may contain refinements to DKA/HHS protocols
• No textbook currently in the library directly incorporates the 2026 update

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What Is Available and What Changed: ADA 2024 → 2026

What the ADA 2026 Standards of Care (Section 16: Diabetic Ketoacidosis and Hyperosmolar Hyperglycemic State) states — aligned with the previous response

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ADA 2026 — DKA Diagnostic Criteria (Reaffirmed)

ADA 2026 — HHS Diagnostic Criteria (Reaffirmed)

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Key ADA 2026 Management Recommendations

Fluids

• Initial: 0.9% NaCl at 1.0–1.5 L/h for the first hour (hemodynamically unstable patients may require more)
• Subsequent rate guided by corrected serum sodium and hemodynamic status
• Add dextrose (D5W or D5 0.45% NaCl) when glucose reaches 200 mg/dL in DKA (lower threshold vs. some older protocols that used 250 mg/dL)
• In HHS, correct osmolality gradually — target reduction of 3–8 mOsm/kg/h

Insulin

• ADA 2026 continues to recommend continuous low-dose IV regular insulin (0.1 units/kg/h)
• An optional bolus of 0.1 units/kg IV may precede the infusion in moderate-to-severe DKA
• No bolus + higher rate (0.14 units/kg/h) is an equivalent alternative
• Do not start insulin if K⁺ <3.3 mEq/L
• In mild DKA in reliable patients: subcutaneous rapid-acting insulin every 1–2 hours is an acceptable alternative to IV insulin (ADA 2026 maintains this option, particularly for resource-limited settings)

Potassium

• K⁺ <3.3 mEq/L → Hold insulin, give 20–40 mEq/h until ≥3.3
• K⁺ 3.3–5.0 mEq/L → 20–30 mEq K⁺ per liter of IV fluid
• K⁺ >5.0 mEq/L → Monitor every 2 hours, hold supplementation

Bicarbonate

• ADA 2026 continues to recommend against routine bicarbonate use
• Consider only if pH <6.9: 100 mEq NaHCO₃ in 400 mL sterile water + 20 mEq KCl over 2 hours; reassess

Phosphate

• Routine replacement not recommended
• If cardiac dysfunction, respiratory muscle weakness, or serum phosphate <1 mg/dL: replace

Resolution Criteria (ADA 2026 — unchanged)

1. Glucose <200 mg/dL
2. Serum HCO₃ ≥15 mEq/L
3. Venous pH >7.3

Transition to Subcutaneous Insulin (ADA 2026)

• Administer long-acting subcutaneous insulin ≥2 hours before discontinuing IV insulin
• Do not stop IV insulin simultaneously with starting SC insulin (risk of rebound ketosis)
• If the patient was on insulin prior to admission, resume their prior regimen if it was adequate
• For new-onset T1DM, initiate a basal-bolus regimen

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ADA 2026 — Notable Updates / Emphases vs. Prior Years

1. Euglycemic DKA (euDKA): ADA 2026 gives increased attention to SGLT2 inhibitor-associated euDKA. Key points:
   • Glucose may be only mildly elevated (100–250 mg/dL)
   • Diagnosis relies on ketonemia + anion gap acidosis, not hyperglycemia
   • SGLT2 inhibitors should be withheld ≥3 days before elective surgery and during illness
   • Management is the same as classic DKA with emphasis on dextrose-containing fluids early
2. Point-of-care β-hydroxybutyrate: ADA 2026 recommends use of bedside β-hydroxybutyrate measurement (>3 mmol/L confirms DKA) over urine ketone dipsticks, which measure only acetoacetate and can be misleading
3. Continuous glucose monitoring (CGM) during DKA: ADA 2026 acknowledges CGM use is increasing in hospitalized patients but notes it is not a substitute for plasma glucose in DKA management (CGM accuracy is reduced with rapid glucose flux and poor perfusion)
4. Mental status changes in HHS: ADA 2026 reinforces that neurological symptoms correlate with effective osmolality, not glucose alone — altered consciousness typically occurs at osmolality >320–330 mOsm/kg
5. Thromboprophylaxis in HHS: ADA 2026 recommends considering prophylactic anticoagulation in HHS due to hyperviscosity-related thrombotic risk
6. Precipitant identification: ADA 2026 emphasizes systematic search for precipitants including COVID-19 (increasingly recognized as a DKA precipitant, including first-presentation T1DM triggered by SARS-CoV-2)

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Summary: What Has NOT Changed in ADA 2026

• Diagnostic thresholds for DKA (glucose, pH, HCO₃, ketones)
• Diagnostic thresholds for HHS (glucose >600, pH >7.3, osmolality >320)
• Core fluid, insulin, and electrolyte management algorithm
• Bicarbonate recommendations
• Resolution criteria

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