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Diabetic Ketoacidosis (DKA) - Clinical Notes

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Definition

• D - Hyperglycemia (blood glucose >250 mg/dL, though euglycemic DKA can occur) OR a known history of diabetes
• K - Ketonemia (urine ketones 2+ or serum β-hydroxybutyrate ≥3.0 mmol/L in adults; ≥3.8 mmol/L in children)
• A - Acidosis (arterial or venous pH <7.3, serum HCO₃⁻ <18 mmol/L)

• Goldman-Cecil Medicine, p. 2483-2484

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Pathophysiology

Insulin deficiency
       ↓
┌──────────────────────────────────┐
│ LIVER                            │
│  ↑ Gluconeogenesis               │
│  ↑ Glycogenolysis                │
│  ↑ Ketogenesis (β-OHB, AcAc)    │
└──────────────────────────────────┘
       ↓
┌──────────────────────────────────┐
│ ADIPOSE TISSUE                   │
│  ↑ Hormone-sensitive lipase      │
│  ↑ Free fatty acids → liver      │
└──────────────────────────────────┘
       ↓
┌──────────────────────────────────┐
│ MUSCLE                           │
│  ↑ Proteolysis                   │
│  ↑ Amino acids → liver           │
└──────────────────────────────────┘

1. Hyperglycemia → osmotic diuresis → dehydration, electrolyte loss (Na⁺, K⁺, Mg²⁺, PO₄³⁻, Ca²⁺, Cl⁻)
2. Ketone production (β-hydroxybutyrate > acetoacetate > acetone) → anion gap metabolic acidosis
3. Hemoconcentration → further worsens hyperglycemia and hyperosmolality

• Early DKA: ECF volume near-normal → ketoacid anions rapidly excreted as Na⁺/K⁺ salts in urine, with NaCl retention → normal gap (hyperchloremic) metabolic acidosis
• Established DKA: Volume depletion reduces renal excretion → ketoacid anions retained → elevated anion gap metabolic acidosis
• During treatment: ECF restored, Na⁺ salts of ketoacids excreted again, NaCl administered → anion gap acidosis transitions back to hyperchloremic normal gap acidosis (may take days to fully resolve)
• Comprehensive Clinical Nephrology, 7th Ed; Rosen's Emergency Medicine

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Precipitating Factors

• Infections (most frequent trigger)
• Inadequate insulin / non-adherence
• New-onset diabetes
• Acute coronary syndrome
• Unknown

• Intercurrent illness: stroke, pulmonary embolism, acute pancreatitis, mesenteric thrombosis
• Alcohol intoxication
• Endocrinopathies: Cushing's syndrome, thyrotoxicosis, acromegaly
• Drugs: corticosteroids, clozapine, olanzapine, cocaine, lithium, sympathomimetics, thiazide diuretics, SGLT2 inhibitors (can cause euglycemic DKA)
• Severe burns, hyperthermia/hypothermia
• Goldman-Cecil Medicine

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Clinical Features

• Polyuria, polydipsia, polyphagia
• Weakness, lethargy, weight loss
• Nausea, vomiting
• Abdominal pain (~50% of cases, especially in children; in adults, may represent true abdominal disease triggering DKA)
• Visual blurring, anorexia

• Kussmaul breathing - deep, rapid respirations (compensatory respiratory alkalosis for metabolic acidosis)
• Fruity/acetone breath
• Tachycardia, orthostatic hypotension or frank hypotension
• Dry skin and mucous membranes (dehydration)
• Depressed sensorium/coma (reflects hyperosmolality - this, NOT acidosis alone, is the prime determinant of mental status depression)
• Elevated temperature suggests precipitating infection (DKA itself rarely causes fever)
• Rosen's Emergency Medicine; Goldman-Cecil Medicine

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Diagnosis

Diagnostic Criteria (Severity Classification)

DKA vs. HHS (Comparison)

• Rosen's Emergency Medicine

Lab Workup

• Serum glucose, BMP (electrolytes, BUN/Cr, anion gap)
• Venous or arterial blood gas (venous pH correlates well with arterial; use arterial if respiratory compensation concerns exist)
• Serum/urine ketones - note: nitroprusside tests detect only acetoacetate and acetone, NOT β-hydroxybutyrate (the predominant ketone). This can give falsely low results. Direct β-OHB measurement is preferred.
• Serum magnesium (deficits common)
• ECG - if immediate K⁺ not available; can detect hyperkalemia/hypokalemia
• Urinalysis (confirm ketones, rule out UTI as precipitant)
• Blood/urine cultures as clinically indicated
• Serum amylase may be elevated (usually non-pancreatic in origin - avoid erroneous pancreatitis diagnosis)

• Sodium: Often pseudohyponatremia due to hyperglycemia (osmotic shift of water into vasculature). Corrected Na = Measured Na + 1.6 × [(glucose - 100)/100]
• Potassium: Initial level may be normal or HIGH (acidosis shifts K⁺ out of cells) despite profound total-body K⁺ depletion. As insulin is given and acidosis corrects, K⁺ shifts back intracellularly → life-threatening hypokalemia can develop.
• WBC: Often elevated even without infection (metabolic acidosis itself can cause leukocytosis)

• Water: 70-120 mL/kg
• Sodium: 8-10 mEq/L
• Potassium: 5-7 mEq/L
• Chloride: 6-8 mEq/L
• Phosphorus: 3 mEq/L
• Rosen's Emergency Medicine; Goldman-Cecil Medicine

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Treatment

1. Fluid Resuscitation

• Immediate IV fluid replacement to correct profound dehydration and restore renal perfusion
• Start with 0.9% Normal Saline (NS)
• Typical initial rate: 15-20 mL/kg/h in first 1-2 hours, then adjusted based on hemodynamics and urinary output
• When blood glucose drops to 250-300 mg/dL, switch to dextrose-containing fluids (e.g., D5 0.45% NS) to prevent hypoglycemia and rapid osmolarity shifts
• Euglycemic DKA (common with SGLT2 inhibitors): add dextrose to fluids from the START of insulin therapy

2. Insulin

• IV regular insulin is the route of choice in moderate-to-severe DKA
• Start at 0.1 units/kg/h (up to 5-10 units/h)
• No IV bolus before infusion - no longer recommended
• IV insulin has a half-life of 3-10 minutes; infusion maintains steady levels better than bolus
• In selected mild DKA patients who are well-hydrated: subcutaneous or IM insulin (lispro or regular) is proven safe and effective - outpatient management may be feasible with good follow-up
• Goal: Reduce blood glucose by ~50-75 mg/dL/h; close the anion gap; clear ketones

3. Potassium Replacement (Critical)

• Do NOT start insulin if K⁺ <3.5 mEq/L - insulin will worsen hypokalemia dangerously
• If K⁺ <3.5: replace K⁺ first, then start insulin
• If K⁺ 3.5-5.0: add 20-40 mEq KCl per liter of IV fluid
• If K⁺ >5.0: hold K⁺, monitor every 2 hours
• Ongoing potassium losses continue during therapy; anticipate significant supplementation

4. Phosphate

• Deficits are common; typically repleted when significant hypophosphatemia develops during treatment
• Routine aggressive phosphate replacement not shown to improve outcomes

5. Magnesium

• Deficiency common in DKA (both from initial pathophysiology and therapy-induced diuresis)
• Hypomagnesemia can cause vomiting, mental changes, recalcitrant hypokalemia/hypocalcemia, and fatal cardiac arrhythmias
• Typical adult repletion: 1-3 g MgSO₄ IV

6. Bicarbonate

• Controversial - generally NOT recommended except in severe cases (pH <6.9 or life-threatening hyperkalemia)
• Bicarbonate can paradoxically worsen intracellular/CSF acidosis, worsen hypokalemia, and delay ketone clearance
• Insulin and fluids alone are sufficient to correct acidosis in most cases

7. Monitor and Switch to Subcutaneous Insulin

• Resolution criteria: glucose <200-250 mg/dL, anion gap closed, pH >7.3, HCO₃⁻ >15 mmol/L, patient tolerating oral intake
• Overlap subcutaneous basal insulin with IV insulin for 1-2 hours before stopping infusion to prevent rebound ketosis

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Special Populations

Pediatric DKA

• Cerebral edema is the most feared complication (~1% incidence overall, but significant mortality)
• Degree of acidosis/uremia predicts cerebral edema better than specific fluid or insulin regimens
• Recent large prospective study (n=1255) showed similar cerebral edema risk with restrictive vs. permissive fluid resuscitation
• Treat suspected cerebral edema immediately with mannitol

SGLT2 Inhibitor-Associated DKA (Euglycemic DKA)

• Blood glucose may be ≤300 mg/dL in up to 18% of DKA patients; more common with SGLT2 inhibitors
• High index of suspicion needed; do not be falsely reassured by near-normal glucose

Pregnancy

• DKA can occur at lower glucose thresholds in pregnancy
• Associated with significant fetal risk; systematic review data (PMID 40447103) shows adverse pregnancy outcomes following DKA

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Differential Diagnosis

• Alcoholic ketoacidosis - euglycemic/hypoglycemic; alkalemia common; β-OHB predominates
• Starvation ketosis - mild; common in 3rd trimester and nursing mothers
• Lactic acidosis
• Toxic ingestions (methanol, ethylene glycol, salicylates)
• Uremia
• Sepsis

• Rosen's Emergency Medicine

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Complications

• Hypokalemia (most dangerous during treatment)
• Hypoglycemia (iatrogenic, from insulin)
• Cerebral edema (especially in pediatric patients)
• Aspiration (ileus/vomiting + altered mental status)
• Thrombosis (hypercoagulable state from dehydration)
• Acute kidney injury (prerenal from dehydration)
• Hyperchloremic non-anion gap acidosis (expected, post-treatment, from large NS administration)

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Prevention

• Sick-day rules education: continue insulin even when not eating; frequent glucose monitoring; check urine/serum ketones when ill; small frequent carbohydrate-containing fluids; increase insulin as needed
• Follow-up with diabetes educator or specialist after any DKA episode

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Prognosis

• DKA mortality: ~4%
• HHS mortality: up to 20% (comparatively worse due to older patient population and severity of precipitating illness)
• Risk factors for death: extremes of age, comorbidities, severity of precipitating illness
• Goldman-Cecil Medicine, p. 2485

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Recent Evidence (2024-2026)

• Subcutaneous vs. IV insulin meta-analysis (PMID 39090718) - systematic review comparing subcutaneous insulin vs continuous insulin infusion in adult DKA; supports use of SQ insulin in selected patients
• Early SQ basal insulin with IV infusion (PMID 41208563) - 2026 meta-analysis of RCTs on early basal insulin overlap strategy to reduce rebound ketosis on transition from IV insulin

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Hyperosmolar Hyperglycemic State (HHS) - Clinical Notes

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Definition & Overview

• Marked hyperglycemia (glucose typically >600 mg/dL, can exceed 1000 mg/dL)
• Severe hyperosmolality (>320 mOsm/kg)
• Profound dehydration
• Altered mental status - ranging from confusion to frank coma
• Absence or only mild ketonemia/acidosis (pH >7.3, HCO₃⁻ >18-20 mmol/L)

• Rosen's Emergency Medicine; Washington Manual of Medical Therapeutics

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Epidemiology

• Incidence: <1 case per 1000 person-years (significantly less common than DKA)
• 30-40% of cases represent first presentation of T2DM
• ~85% of patients have underlying renal or cardiac impairment as a predisposing factor
• ~20% have no known history of diabetes at presentation
• Most common associated comorbidities: chronic renal insufficiency, GI bleeding, gram-negative pneumonia, gram-negative sepsis
• Washington Manual; Rosen's EM

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Pathophysiology

Relative insulin deficiency
         ↓
↑ Hepatic glucose production (glycogenolysis + gluconeogenesis)
↓ Peripheral glucose uptake (skeletal muscle)
         ↓
     Hyperglycemia
         ↓
  Osmotic diuresis → hypotonic urine (Na 50-70 mEq/L vs. ECF 140 mEq/L)
         ↓
Profound intravascular volume depletion
+ Patient cannot compensate (old age, dementia, stroke, physical infirmity)
         ↓
↓ GFR → ↓ renal glucose excretion → worsening hyperglycemia
↑ Hemoconcentration → ↑ osmolality → ↑ Na⁺

• Suppress lipolysis (free fatty acid levels lower than in DKA)
• Suppress hepatic ketogenesis (portal vein insulin concentrations are higher than in DKA)
• The insulin/glucagon ratio does not favor ketone body synthesis

• Goldman-Cecil Medicine; Harrison's 22e; Rosen's EM

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Precipitating Factors

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Clinical Features

• Polyuria, polydipsia, thirst
• Progressive lethargy and confusion
• Weakness, weight loss
• Oliguria (late - as volume depletion reduces urine output)
• Fever (from precipitating infection, not HHS itself)

• Nausea and vomiting (less prominent)
• Abdominal pain
• Kussmaul breathing (no acidosis to compensate for)
• Fruity/acetone breath

• Orthostatic hypotension or frank hypotension
• Tachycardia
• Marked dehydration (dry mucous membranes, poor skin turgor)
• Altered mental status - severity correlates directly with degree and rate of osmolality rise
  • 10% present with frank coma
  • 10% have no mental status changes at all
• Focal neurologic findings - common and can mimic stroke: hemisensory/motor deficits, aphasia, extensor plantar reflexes
• Seizures (focal or generalized)
• Arterial and venous thromboses are common
• Harrison's 22e; Goldman-Cecil Medicine; Rosen's EM

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Diagnosis

Diagnostic Criteria

HHS vs. DKA (Side-by-Side)

Lab Workup

• Serum glucose, BMP (electrolytes, BUN/Cr)
• Serum osmolality (measured: 2×Na + glucose/18 + BUN/2.8)
• Blood gas (venous acceptable) - to confirm no significant acidosis
• Corrected serum sodium: Add 1.6 mEq to measured Na for each 100 mg/dL rise in glucose above 100 mg/dL (or per some sources: add 1.6 for each 5.6 mmol/L rise)
• Urine ketones (typically absent or minimal)
• ECG (to exclude ACS as precipitant; assess K⁺ status)
• Blood cultures, CXR, urinalysis (to identify precipitating infection)
• Consider troponin, lipase as clinically indicated
• Lactate (if hemodynamically compromised)

• Measured sodium often LOW or normal despite extreme hyperglycemia (pseudohyponatremia) - corrected Na is usually ELEVATED
• Potassium: initial level may appear normal or high, but total body stores are depleted. Because acidosis is less severe than in DKA, the gap between serum K⁺ and actual stores is smaller than in DKA - levels more accurately reflect total body K⁺ than in DKA.

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Treatment

1. Fluids (Most Important Intervention)

• 0.9% Normal Saline: 1-3 L over the first 2-3 hours
• Goal: restore hemodynamic stability and intravascular volume

• If Na >150 mEq/L: switch to 0.45% saline (hypotonic)
• Then transition to D5W to replace free water deficit
• Free water deficit can be 9-12 L - reverse over 24-72 hours
• Typical infusion rate: 200-300 mL/h of hypotonic solution
• Key principle: Do NOT correct osmolality too rapidly - overly rapid reversal of hyperosmolality risks worsening neurologic function (osmotic encephalopathy / cerebral edema)
• Rate of glucose reduction: avoid correcting >100 mg/dL/hour

2. Insulin (Secondary Role)

• Do NOT start insulin if K⁺ <3.5 mEq/L (same rule as DKA)
• Washington Manual: Bolus 5-10 units IV (if glucose >600 mg/dL; smaller bolus if glucose <600), then infusion at 0.10-0.15 units/kg/h
• Harrison's: Bolus 0.1 units/kg then infusion at 0.1 units/kg/h
• Avoid IV insulin infusion at high rates if not needed - fluid rehydration alone often brings glucose down significantly
• When glucose drops to 250-300 mg/dL: add D5 to IV fluids and reduce insulin to 1-2 units/h
• When patient is eating and hemodynamically stable: transition to subcutaneous insulin; administer SC basal insulin 2 hours before stopping the infusion
• Some patients can later transition to oral agents

3. Potassium

• Add KCl 10-20 mEq/h to fluids as soon as urine output is confirmed and K⁺ <5 mEq/L
• Goal: maintain K⁺ 4-5 mEq/L during treatment
• In patients on diuretics: K⁺ deficit may be large and accompanied by magnesium deficiency

4. Phosphate and Magnesium

• Hypophosphatemia can develop during therapy; use KPO₄ when replacing K⁺ and begin nutrition
• Magnesium repletion as needed, especially if patient was on diuretics

5. Bicarbonate

• Not routinely recommended
• May be required only if concurrent significant lactic acidosis is present

6. Treat the Precipitant (Critical)

• Broad-spectrum antibiotics early if infection is known or suspected
• Maintain high suspicion for: pancreatitis, GI bleeding, renal failure, acute MI, thromboembolic events (mesenteric thrombosis, DVT/PE)

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Complications

• Thromboembolic events - very common due to hemoconcentration and hyperviscosity:
  • Cerebral venous thrombosis
  • Mesenteric thrombosis
  • Acute MI
  • DVT/PE
• Hypokalemia (from insulin and fluid therapy)
• Hypoglycemia (iatrogenic)
• Cerebral edema - rare in adults (mainly reported with glucose >700 mg/dL); more likely reflects severity of illness rather than fluid regimen
• Osmotic encephalopathy - from too-rapid correction of hyperosmolality
• Acute kidney injury (prerenal → intrinsic if severe)
• Aspiration pneumonia (from altered mental status)
• Rhabdomyolysis (from severe dehydration)

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Differential Diagnosis

• Ischemic or hemorrhagic stroke
• Hypoglycemia
• Hyponatremia
• Uremia / hyperammonemia
• Drug overdose / intoxication
• Septic encephalopathy
• Meningitis/encephalitis

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Prognosis

• Mortality: up to 15-20% (some series) - substantially higher than DKA (~4%)
• Higher mortality reflects: older patient population, severity of precipitating illness, multiple comorbidities
• Outcome correlates with degree and duration of hyperosmolarity and with the nature of the precipitating condition

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Key Differences from DKA - Summary

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