24.1 Diabetic Ketoacidosis & Hyperosmolar Hyperglycemic State

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24 Chapter 24: Metabolic, Endocrine & Electrolyte Emergencies

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59 Chapter 59: Chronic Musculoskeletal & Rheumatologic Disorders

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67 Chapter 67: Continuity Care: Sleep, Fatigue, Cancer, Pregnancy & the Adult Preventive Visit

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24.1 Diabetic Ketoacidosis & Hyperosmolar Hyperglycemic State

Key Takeaways Explain This Topic AI

DKA is driven by absolute or profound relative insulin deficiency with counterregulatory hormone excess driving unchecked lipolysis, free fatty acid oxidation, and ketogenesis (beta-hydroxybutyrate >3.0 mmol/L, anion gap >10-12 mEq/L, arterial pH <=7.30); HHS is characterized by relative insulin deficiency sufficient to suppress ketogenesis but leading to extreme hyperglycemia (>600 mg/dL), severe hyperosmolality (>320 mOsm/kg), and massive fluid deficits (8-10 L).

The mandatory potassium rule in adult hyperglycemic emergencies (2024 consensus): if serum potassium is <3.5 mEq/L, start IV potassium (about 10 mEq/h) and delay insulin until K+ is >3.5 mEq/L to prevent fatal dysrhythmias and respiratory muscle weakness; at 3.5-5.0 give insulin with 20-30 mEq K+ per liter; above 5.0 give insulin and start K+ once it falls below 5.0.

When blood glucose falls below 250 mg/dL in DKA (or 300 mg/dL in HHS), add 5-10% dextrose to the IV fluids while continuing IV insulin infusion at about 0.05 units/kg/h to prevent hypoglycemia and rapid osmolar collapse while clearing ketoacidosis and closing the anion gap.

DKA resolution requires plasma ketone (beta-hydroxybutyrate) <0.6 mmol/L and venous pH >=7.3 or bicarbonate >=18 mEq/L, ideally with glucose <200 mg/dL, not the anion gap or urine ketones (2024 adult consensus); subcutaneous basal insulin must be administered 1-2 hours prior to stopping the IV insulin infusion to prevent rapid rebound ketoacidosis.

Euglycemic DKA (blood glucose <200 mg/dL) is frequently precipitated by SGLT2 inhibitors (-gliflozins), pregnancy, or prolonged fasting; clinicians must calculate the serum anion gap and check serum beta-hydroxybutyrate in any unwell patient taking an SGLT2 inhibitor regardless of normal blood glucose.

Last updated: October 2026

Pathophysiologic Hallmarks: DKA versus HHS

Diabetic ketoacidosis (DKA) and hyperosmolar hyperglycemic state (HHS) represent two distinct clinical endpoints along the spectrum of decompensated hyperglycemic emergencies. While both disorders are characterized by impaired glucose utilization and hyperosmolality, fundamental differences in residual beta-cell secretory capacity, counterregulatory hormone surges, and degree of dehydration dictate their clinical presentations, diagnostic criteria, and treatment nuances. PATHOPHYSIOLOGIC DIVERGENCE: DKA VS. HHS

• ABSOLUTE INSULIN DEFICIENCY RELATIVE INSULIN DEFICIENCY
• (DKA) (HHS)
• │ │
• ┌─────────────────┴─────────────────┐ ┌─────────┴─────────┐
• ▼ ▼ ▼ │
• Surge in Counter- Unchecked Adipose Extreme Hepatic │
• regulatory Hormones Lipolysis (HSL) Gluconeogenesis & │
• (Glucagon, Cortisol, Epinephrine) │ Glycogenolysis │
• │ ▼ │ │
• │ Free Fatty Acids ▼ │
• ▼ │ Extreme Hyper- │
• Mitochondrial CPT-1 ▼ glycemia >600 │
• Overactivation in Liver ────────► Hepatic Ketogenesis │ │
• (Beta-hydroxybutyrate ▼ │
• & Acetoacetate) Severe Osmotic │
• │ Diuresis │
• ▼ │ ▼
• Anion Gap Acidosis Profound Fluid Residual Insulin
• (pH <=7.30, HCO3 <=18) Deficit (8-10 L) Blocks Lipolysis
• 1. Diabetic Ketoacidosis (DKA)

Hormonal Milieu : Driven by absolute or severe relative insulin deficiency combined with a marked hypersecretion of counterregulatory hormones: glucagon, epinephrine, cortisol, and growth hormone.

Lipolysis and Ketogenesis :

In adipose tissue, the absence of insulin releases the tonic inhibition of hormone-sensitive lipase (HSL) . This leads to unrestrained lipolysis and the massive release of free fatty acids (FFAs) into the systemic circulation.

In hepatocytes, high glucagon-to-insulin ratios activate carnitine palmitoyltransferase-1 (CPT-1) , the rate-limiting enzyme that shunts FFAs across the mitochondrial membrane for accelerated beta-oxidation.

Excessive acetyl-CoA generated from beta-oxidation overwhelms the Krebs cycle and is channeled into ketogenesis, producing acetoacetate and beta-hydroxybutyrate .

Biochemical Pearl : Under physiologic conditions, the ratio of beta-hydroxybutyrate to acetoacetate is approximately 1:1. In DKA, altered mitochondrial redox state (high NADH/NAD+ ratio) drives the equilibrium heavily toward beta-hydroxybutyrate (ratios of 3:1 to 10:1) . Standard nitroprusside urine and serum dipstick tests react exclusively with acetoacetate, frequently underestimating the severity of ketoacidosis at presentation. Point-of-care or laboratory serum beta-hydroxybutyrate (>3.0 mmol/L) is the gold-standard diagnostic and monitoring test.

2. Hyperosmolar Hyperglycemic State (HHS)

Hormonal Milieu : Driven by relative insulin deficiency and inadequate fluid intake, characteristically in older individuals with type 2 diabetes undergoing acute physiological stress (e.g., pneumonia, sepsis, myocardial infarction, stroke).

Suppression of Ketogenesis :

Endogenous portal insulin concentrations in HHS are approximately 1/10th of the level required for peripheral tissue glucose uptake, but sufficient to inhibit hormone-sensitive lipase in visceral adipose tissue.

Consequently, lipolysis is suppressed, circulating FFA levels remain low, and hepatic ketogenesis is prevented or minimal.

Extreme Hyperglycemia & Dehydration :

Relative insulin deficiency and elevated glucagon drive unbridled hepatic gluconeogenesis and glycogenolysis.

Glomerular filtration of extreme glucose loads exceeds the renal tubular absorptive threshold (~180-200 mg/dL), triggering massive osmotic diuresis .

Persistent glucosuria leads to substantial free water loss, hypovolemia, decreased GFR, and progressive failure of renal glucose excretion. This vicious cycle drives plasma glucose to extreme levels (frequently >600 to 1200 mg/dL ), marked hyperosmolality (effective serum osmolality >320 mOsm/kg ), and staggering total body water deficits of 8 to 10 liters (100 to 200 mL/kg) , representing 10% to 15% of total body weight.

Diagnostic Criteria: DKA versus HHS Master Comparison Matrix

Diagnostic Parameter Mild DKA Moderate DKA Severe DKA Hyperosmolar Hyperglycemic State (HHS)

Plasma Glucose (mg/dL) ≥200 or known diabetes (euDKA <200) ≥200 or known diabetes ≥200 or known diabetes >600 (often >1000)

• Arterial pH 7.25 to 7.30 7.00 to 7.24 <7.00 >7.30
• Serum Bicarbonate (mEq/L) 15 to 18 10 to <15 <10 >18
• Urine Ketones Positive Positive Positive Absent or small trace

Serum Ketones (Beta-hydroxybutyrate) Positive (>3.0 mmol/L) Positive (>3.0 mmol/L) Strongly Positive (>3.0 mmol/L) Absent, trace, or mildly elevated

• Effective Serum Osmolality (mOsm/kg) Variable Variable Variable >320 mOsm/kg
• Serum Anion Gap (mEq/L) >10 to 12 >12 >12 Variable (typically normal <=12 )
• Mental Status Alert Alert or mildly drowsy Stupor or Coma Stupor, lethargy, or Coma
• Typical Fluid Deficit 3 to 5 Liters 4 to 6 Liters 5 to 7 Liters 8 to 10+ Liters (100-200 mL/kg)
• Essential Calculations for Hyperglycemic Emergencies

Serum Anion Gap :

Anion Gap = [Na+] - ([Cl-] + [HCO3-])

Normal reference range: 8 to 12 mEq/L. DKA presents with a high anion gap metabolic acidosis driven by unmeasured ketoacid anions.

Effective Serum Osmolality (excludes urea because BUN freely crosses cell membranes and does not exert an effective osmotic driving force):

Effective Osmolality (mOsm/kg) = 2 x [Measured Na+ (mEq/L)] + [Glucose (mg/dL) / 18]

Normal reference range: 275 to 295 mOsm/kg. HHS diagnostic threshold is >320 mOsm/kg .

Corrected Sodium (accounts for hyperglycemia-induced osmotic fluid shifts from intracellular to extracellular space, diluting serum sodium):

Corrected Na+ = Measured Na+ + 1.6 x [(Glucose - 100) / 100]

Clinical Tip : When plasma glucose exceeds 400 mg/dL, many authorities utilize a correction factor of 2.0 or 2.4 instead of 1.6.

Euglycemic Diabetic Ketoacidosis (euDKA)

Euglycemic DKA is defined as the presence of ketoacidosis (arterial pH <=7.30, serum bicarbonate <=18 mEq/L, elevated anion gap >10-12 mEq/L, positive serum beta-hydroxybutyrate >3.0 mmol/L) occurring in the setting of normal or near-normal blood glucose (<200 mg/dL) ; about 10% of adults with DKA present this way (2024 adult consensus).

Major Etiologies and Triggers

Sodium-Glucose Cotransporter-2 (SGLT2) Inhibitors (e.g., Empagliflozin, Dapagliflozin, Canagliflozin):

SGLT2 inhibitors block glucose reabsorption in the renal proximal convoluted tubule, inducing glycosuria and lowering plasma glucose.

Euvolemic glycosuria lowers circulating glucose concentrations, blunting endogenous pancreatic beta-cell insulin secretion.

Simultaneously, decreased insulin and direct effects on pancreatic alpha cells trigger hypersecretion of glucagon.

The resulting high glucagon-to-insulin ratio stimulates hepatic CPT-1 and uninhibited ketogenesis. Because the kidneys continue to excrete glucose into the urine, plasma glucose remains deceptively normal or mildly elevated despite life-threatening metabolic ketoacidosis.

Other Triggers of euDKA :

Pregnancy : High fetal/placental glucose consumption, elevated GFR, and placental lactogen activity promote rapid ketogenesis during maternal fasting.

Severe Prolonged Fasting / Ketogenic Diets : Depleted hepatic glycogen stores limit glucose generation despite severe insulin deficiency.

Heavy Alcohol Abuse : Impaired gluconeogenesis alongside high counterregulatory hormone production.

Perioperative Stress / Sepsis : Decreased oral intake combined with acute stress in patients continuing SGLT2 inhibitors.

Warning

Critical Board Rule on euDKA : In any patient prescribed an SGLT2 inhibitor who presents with malaise, nausea, vomiting, abdominal pain, or tachypnea, never rely on a normal fingerstick blood glucose to exclude DKA. Clinicians must immediately check a comprehensive metabolic panel, calculate the anion gap, and measure serum beta-hydroxybutyrate.

Emergency Resuscitation and Management Protocol HYPERGLYCEMIC EMERGENCY RESUSCITATION SEQUENCE

• STEP 1: FLUIDS STEP 2: POTASSIUM STEP 3: INSULIN
• ┌─────────────────────┐ ┌─────────────────────┐ ┌─────────────────────┐
• │ 0.9% NaCl 0.5-1 L/h │ │ Check Serum K+ │ │ Regular Insulin IV │
• │ for the first 2-4 h.│ │ BEFORE Insulin! │ │ 0.1 units/kg/h │
• │ Reassess corrected │ │ • <3.5: HOLD INSULIN│ │ Target reduction: │
• │ sodium: │ │ Give KCl ~10 mEq/h│ │ 50-75 mg/dL per h │
• │ • High/Normal: │ │ • 3.5-5.0: Add KCl │ │ Add 5-10% dextrose │
• │ 0.45% NaCl │ │ 20-30 mEq/L fluid │ │ at <250 (DKA) │
• │ • Low: 0.9% NaCl │ │ • >5.0: No K+ until │ │ or 300 (HHS) │
• │ │ │ K+ falls below 5.0│ │ │
• └─────────────────────┘ └─────────────────────┘ └─────────────────────┘
• Step 1: Intravenous Fluid Resuscitation

Hour 1 (Initial Volume Expansion) :

Administer isotonic saline or a balanced crystalloid at 500 to 1,000 mL/h for the first 2 to 4 hours (adults without renal or cardiac compromise) to restore intravascular volume and re-establish renal perfusion; use smaller boluses (for example, 250 mL) with frequent reassessment in older adults, heart failure, or dialysis-dependent kidney disease (2024 adult consensus).

Subsequent Hours (Maintenance and Deficit Replacement) :

Assess hemodynamic status and calculate corrected serum sodium :

If Corrected Sodium is Normal (135-145 mEq/L) or Elevated (>145 mEq/L) : Switch fluids to 0.45% NaCl (half-normal saline) at 250 to 500 mL/h to replace ongoing free water deficits.

If Corrected Sodium is Low (<135 mEq/L) : Continue 0.9% NaCl at 250 to 500 mL/h .

Rate Limit : Replace the calculated fluid deficit over 24 to 48 hours. Do not decrease effective serum osmolality faster than 3 mOsm/kg/h to avoid precipitating iatrogenic cerebral edema.

Step 2: Potassium Management (The Cardinal Safety Rule)

Total body potassium depletion is universal in DKA (typically 3 to 5 mEq/kg deficit, representing 300-500 mEq) due to osmotic kaliuresis, urinary ketoacid excretion, and secondary hyperaldosteronism. However, initial serum potassium levels are frequently normal or falsely elevated because acidosis, hyperosmolality, and insulinopenia drive potassium out of intracellular compartments.

Threshold 1: Serum Potassium <3.5 mEq/L (EMERGENCY HOLD; 2024 adult consensus) :

DO NOT START INSULIN!

Initiating insulin drives remaining intravascular potassium into cells via activation of Na+/K+-ATPase, triggering catastrophic hypokalemia, lethal ventricular arrhythmias, and diaphragmatic paralysis.

Start IV potassium chloride at about 10 mEq/h and delay insulin until serum potassium rises above 3.5 mEq/L .

Threshold 2: Serum Potassium 3.5 to 5.0 mEq/L :

Add 20 to 30 mEq KCl per liter of IV maintenance fluid (mix 2/3 as KCl and 1/3 as potassium phosphate to avoid hyperchloremic acidosis and address phosphate loss).

Target serum potassium between 4.0 and 5.0 mEq/L .

Initiate insulin infusion safely.

Threshold 3: Serum Potassium >5.0 mEq/L :

Do not add potassium to IV fluids.

Initiate insulin infusion.

Recheck serum potassium 2 hours after insulin starts, then every 4 hours ; as soon as potassium falls below 5.0 mEq/L, add 20-30 mEq KCl per liter of IV fluid.

Step 3: Intravenous Insulin Administration

Infusion Dosing :

Continuous IV infusion of Regular Insulin at 0.1 units/kg/h (with or without an initial IV bolus of 0.1 units/kg), OR a continuous infusion of 0.14 units/kg/h without a bolus .

Target Glycemic Rate of Fall :

Target plasma glucose reduction of 50 to 75 mg/dL per hour .

If glucose does not drop by at least 50 mg/dL in the first hour, verify IV line patency and double the insulin infusion rate every hour until a steady decline of 50-75 mg/dL/h is attained.

The Critical Dextrose Addition Rule :

In DKA : When plasma glucose falls below 250 mg/dL , add 5-10% dextrose to the IV fluids and decrease the insulin infusion rate to about 0.05 units/kg/h , titrating to keep blood glucose near 200 mg/dL until the ketoacidosis resolves (2024 adult consensus).

In HHS : When plasma glucose reaches 300 mg/dL , add 5% Dextrose to IV fluids (D5 0.45% NaCl) and titrate insulin to maintain blood glucose at 200-300 mg/dL until plasma osmolality normalizes and the patient is mentally alert.

Pathophysiologic Rationale : Never stop insulin infusion merely because glucose falls below 250 mg/dL! Hyperglycemia corrects much faster than ketoacidosis. Ongoing insulin is strictly required to suppress lipolysis, shut down hepatic ketogenesis, and close the anion gap. Adding dextrose prevents hypoglycemia and rapid osmolar collapse while allowing continued insulin-mediated ketoacid clearance.

Step 4: Bicarbonate and Phosphate Administration

Sodium Bicarbonate :

Indication : Routine bicarbonate is not recommended; consider it only if pH is <7.0 (2024 adult consensus).

Dosing : 100 mmol sodium bicarbonate in 400 mL sterile water with 20 mEq KCl infused over 2 hours. Repeat every 2 hours until venous pH >7.00.

Risks of Routine Bicarbonate (pH >=7.0) : Routine use provides no clinical benefit and produces severe adverse effects:

Paradoxical Central Nervous System Acidosis : Exogenous HCO3- combines with H+ to form CO2; lipophilic CO2 freely diffuses across the blood-brain barrier faster than hydrophilic HCO3-, paradoxically worsening CSF acidosis;

• Severe hypokalemia;
• Impaired tissue oxygen delivery (leftward shift of the oxyhemoglobin dissociation curve);

Delayed clearance of blood ketoacids and lactate.

Phosphate Repletion :

Severe hypophosphatemia (<1.0 mg/dL) can precipitate diaphragmatic weakness, respiratory failure, skeletal muscle dysfunction, and rhabdomyolysis.

Replete with 20 to 30 mmol potassium phosphate added to replacement fluids if serum phosphate drops <1.0 mg/dL or if symptomatic weakness develops.

• DKA Resolution Criteria & Subcutaneous Transition Protocol
• Criteria for Resolution of DKA

DKA is resolved when plasma ketone (beta-hydroxybutyrate) is <0.6 mmol/L AND venous pH is >=7.3 or serum bicarbonate is >=18 mEq/L (2024 adult consensus). Ideally, blood glucose is also <200 mg/dL .

Do not use the anion gap as a resolution criterion: large volumes of 0.9% saline cause hyperchloremic acidosis that can make it misleading.

Do not use urine ketones: beta-hydroxybutyrate converts to acetoacetate as the acidosis improves, so the dipstick can stay positive.

HHS Resolution (2024 adult consensus): measured or calculated serum osmolality <300 mOsm/kg, hyperglycemia corrected with blood glucose <250 mg/dL, urine output >0.5 mL/kg/h, and improved cognitive status.

Transition to Subcutaneous Insulin: The 1-2 Hour Overlap Rule

The patient must be awake, alert, clinically stable, and able to tolerate oral nutrition.

Mandatory Timing Rule : Administer subcutaneous basal insulin (e.g., Insulin Glargine, Detemir, or Degludec) 1 to 2 hours PRIOR to discontinuing the intravenous insulin infusion .

Why is Overlap Critical? Intravenous regular insulin has an elimination half-life of only 4 to 5 minutes , with biologic effects vanishing within 30 to 60 minutes of stopping the drip. Subcutaneous basal insulin requires 1 to 2 hours for systemic absorption and onset. Abruptly stopping the IV infusion without prior subcutaneous basal coverage produces an immediate absolute insulin deficiency, precipitating rapid rebound ketoacidosis within hours .

Loading diagram... Clinical Resuscitation and Titration Algorithm for DKA and HHS