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Diabetic Ketoacidosis (DKA)

Definition / Biochemical Triad

1. Hyperglycemia - glucose >250 mg/dL (though occasionally euglycemic DKA occurs, especially with SGLT-2 inhibitors)
2. Ketonemia/Ketonuria - urine ketones 2+ or more, OR serum ketones ≥3.0 mmol/L
3. Acidosis - arterial or venous pH <7.3, serum bicarbonate <18 mmol/L

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Pathophysiology

• Liver: Amino acids (from muscle proteolysis) and free fatty acids (FFAs) delivered to liver → converted to glucose (gluconeogenesis) and ketone bodies (β-hydroxybutyrate, acetoacetate, acetone)
• Adipose tissue: Insulin deficiency activates hormone-sensitive lipase → massive FFA release into circulation
• Kidneys: Hyperglycemia exceeds renal threshold → osmotic diuresis → profound loss of water, Na, K, Mg, Ca, phosphorus
• Net result: Hyperglycemia + hyperosmolality + ketoacidosis + severe dehydration and electrolyte depletion

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Precipitants

• Infections (UTI, pneumonia)
• Inadequate insulin / non-adherence
• New-onset Type 1 diabetes
• Acute coronary syndrome
• Unknown cause

• Stroke, PE, acute pancreatitis, alcohol intoxication
• Endocrinopathies (Cushing's, thyrotoxicosis, acromegaly)
• Drugs: corticosteroids, clozapine, olanzapine, cocaine, lithium, thiazides, SGLT-2 inhibitors (can cause euglycemic DKA)

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Clinical Features

• Prodrome (hours to days): polyuria, polydipsia, weakness, lethargy, nausea, anorexia
• Abdominal pain - can mimic an acute abdomen; paralytic ileus may occur
• Signs of dehydration: dry mucous membranes, reduced JVP, tachycardia, orthostatic hypotension
• Neurological: altered mental status, frank coma (correlates with hyperosmolality)
• Kussmaul breathing - deep, rapid respirations compensating for metabolic acidosis
• Fruity/acetone breath

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Diagnosis

Severity Classification

Key Labs

• Blood glucose: variable, 250 to >1000 mg/dL
• Serum ketones: Nitroprusside-based tests detect only acetoacetate, NOT β-hydroxybutyrate - can underestimate ketoacidosis severity. Use bedside capillary β-hydroxybutyrate monitors when available.
• Anion gap: elevated (proportional to drop in HCO₃); formula: Na - (Cl + HCO₃)
• Potassium: may be normal, high, or low initially - but total body K is ALWAYS depleted. K drops rapidly after insulin is started.
• Sodium: pseudohyponatremia (osmotic shift of water); corrected Na = measured Na + 1.6 × [(glucose - 100)/100]
• WBC: often elevated even without infection (due to acidosis itself)
• Amylase: often elevated but usually of non-pancreatic origin - do not diagnose pancreatitis solely on this

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Treatment

1. Fluids

• Fluid deficit typically 3-5 L in adults (up to 10 L in severe cases)
• Start with 0.9% NaCl (normal saline) even if serum osmolality is high - NS is still relatively hypotonic compared to the patient
• Rate: 2-4 L in first 2-4 hours in DKA
• If in hypovolemic shock: bolus IV NS as fast as possible; in children, 20 mL/kg boluses until SBP ≥80 mmHg
• Switch to D5W/0.45% NS when glucose drops to 250-300 mg/dL to prevent hypoglycemia and avoid rapid osmolality shifts

2. Insulin

• IV bolus is no longer recommended before infusion
• Regular insulin infusion at 0.1 units/kg/h (up to 5-10 units/h) - current ADA recommendation
• In mild DKA: subcutaneous or IM insulin (e.g., insulin lispro) has been shown safe and effective as an alternative
• Half-life of IV regular insulin is 3-10 minutes, so continuous infusion (not bolus dosing) is required in moderate-severe DKA
• Euglycemic DKA (e.g., from SGLT-2 inhibitors): add dextrose to IV fluids from the start of insulin therapy

3. Potassium

• Do NOT start insulin if K <3.5 mEq/L - correct potassium first
• Do not give K if K >5.5 mEq/L
• Target serum K: 3.5-5.0 mEq/L during treatment
• Even when initial K is high (due to acidosis driving K out of cells), K will fall sharply once insulin starts

4. Bicarbonate

• Not routinely recommended
• Consider only for severe acidosis (pH <6.9) or life-threatening hyperkalemia
• Risks: paradoxical CSF acidosis, hypokalemia, delayed ketone clearance

5. Phosphate

• Routine replacement not proven to improve outcomes
• Replace if symptomatic hypophosphatemia or levels <1 mg/dL

6. Magnesium

• Frequently depleted in DKA
• Replete with 1-3 g IV MgSO₄ if deficient; hypomagnesemia can cause refractory hypokalemia and fatal arrhythmias

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Resolution Criteria (to stop insulin infusion)

• Glucose <200-250 mg/dL
• HCO₃ ≥15 mmol/L
• pH ≥7.3
• Patient tolerating oral intake

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Complications

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DKA vs. HHS (Key Differences)

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Recent Evidence (2024-2026)

• A 2024 meta-analysis (PMID 39090718) found subcutaneous insulin is comparable to IV continuous infusion for adult DKA, supporting its use in mild-moderate cases.
• A 2026 meta-analysis of RCTs (PMID 41208563) in Diabetes, Obesity & Metabolism found that early subcutaneous basal insulin added to IV insulin infusion reduced rebound hyperglycemia and shortened transition time - this is now an emerging protocol.

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Hyperosmolar Hyperglycemic State (HHS)

Definition

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Epidemiology & Risk Factors

• Predominantly affects elderly patients with Type 2 DM
• ~20% have no known prior diagnosis of diabetes
• ~85% have underlying renal or cardiac impairment
• Mortality: historically 40-70%; current rates 8-25% with modern treatment (still substantially higher than DKA's <5%)
• Pediatric HHS has a much higher incidence of fatal cerebral edema than adult HHS

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Pathophysiology

1. Decreased insulin action → hepatic glycogenolysis + gluconeogenesis → hyperglycemia
2. Hyperglycemia → osmotic diuresis → severe dehydration
3. Patient (often elderly, demented, or debilitated) cannot drink enough water to compensate
4. Dehydration → reduced GFR → further glucose retention → worsening hyperglycemia
5. Hypotonic urine (Na ~50-70 mEq/L vs. ECF 140 mEq/L) = net free water loss → hypernatremia + hypertonicity

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Precipitants

• Infections - most common (gram-negative pneumonia, gram-negative sepsis, UTI)
• Acute MI or stroke (often the precipitating illness AND a complication)
• Severe dehydration (inadequate intake, vomiting, diarrhea)
• Drugs: diuretics, corticosteroids, antipsychotics, phenytoin (also contraindicated in treatment)
• Dialysis (peritoneal or hemodialysis)
• Total parenteral nutrition
• Burns
• Social isolation / inability to obtain water (dementia, prior stroke)

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Clinical Features

• Polyuria (early), then oliguria as volume depletes
• Polydipsia (often impaired by concurrent illness or dementia)
• Progressive weakness, lethargy
• Fever, thirst

• Profound dehydration - dry mucous membranes, poor skin turgor
• Orthostatic hypotension or frank hypotension
• Tachycardia
• Altered mental status - directly correlates with the degree and rate of osmolality rise; ranges from confusion to frank coma (up to 10% present in coma)
• Focal neurological deficits - hemiplegia, seizures (often focal/partial), aphasia
• No Kussmaul breathing (distinguishes from DKA)
• No fruity/acetone breath
• Arterial and venous thromboses are common

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Laboratory Findings

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Treatment

Priority Order: Fluids > Electrolytes > Insulin > Find Precipitant

1. Fluids (most important)

• Step 1 - Hemodynamic stabilization: 0.9% NaCl (normal saline), 1-3 L over first 2-3 hours
• Step 2 - Free water repletion:
  • If serum Na >150 mmol/L: switch to 0.45% NaCl (hypotonic saline)
  • If serum Na normal or low: continue 0.9% NaCl
• Rate of correction: Slower than DKA - too-rapid reversal of hyperosmolality worsens neurologic function (cerebral edema risk)
  • Target osmolality decrease: ~3-8 mOsm/kg/h
• Add dextrose to IV fluids when glucose drops to 250-300 mg/dL
• In elderly patients with CHF or renal failure: use hemodynamic monitoring to guide fluid administration - risk of pulmonary edema

2. Insulin

• Not as urgently required as in DKA - fluids alone lower glucose significantly
• Insulin is still needed to fully resolve hyperglycemia
• IV bolus: 0.1 unit/kg, then infusion at 0.1 units/kg/h
• If glucose not falling: double the infusion rate
• When glucose reaches 200-250 mg/dL: reduce infusion to 0.02-0.1 units/kg/h + add dextrose
• Continue infusion until patient eating and can transition to SC insulin
• SQ or IM insulin alone may be inadequate in severely hypoperfused patients due to erratic absorption
• Note: Continuous IV infusion is not always mandatory (unlike DKA) - fluids + treating the precipitant may control glucose adequately in mild cases

3. Potassium

• Replace guided by serum levels; K is more accurate in HHS than DKA (no acid-base distortion)
• Same principles as DKA: replace if K <5.5 mEq/L and urine output is adequate

4. Find and Treat the Precipitant

• Thorough workup for infection: blood cultures, urine culture, CXR
• ECG / troponins (ACS)
• CT head if focal neuro signs (stroke)
• Consider sepsis workup

5. Anticoagulation

• Give low-dose subcutaneous heparin prophylactically - HHS creates a highly prothrombotic state (hyperviscosity, volume depletion, immobility)

6. Seizures

• Phenytoin is contraindicated - ineffective for HHS seizures AND impairs endogenous insulin release
• Use benzodiazepines instead; seizures typically resolve with correction of osmolality

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Complications

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HHS vs. DKA - Quick Comparison

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