Diabetic Ketoacidosis (Adult)

1. Clinical Overview

Summary

Diabetic Ketoacidosis (DKA) is a life-threatening acute metabolic emergency characterized by the pathognomonic triad of hyperglycemia, ketosis, and metabolic acidosis. [1,22] It represents a state of absolute or relative insulin deficiency combined with excess counter-regulatory hormones (glucagon, cortisol, catecholamines, growth hormone), leading to uncontrolled catabolism. [22]

DKA predominantly affects patients with Type 1 Diabetes Mellitus but can occur in Type 2 Diabetes during severe physiological stress. Despite advances in management, DKA accounts for significant morbidity and healthcare costs, with mortality rates of less than 1% in specialized centers but rising to 5-10% in elderly patients or those with severe comorbidities. [1,22]

Key Clinical Point: DKA is a biochemical diagnosis requiring immediate recognition and treatment initiation before full laboratory confirmation. Delays in management directly correlate with increased mortality. [1]

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Diagnostic Criteria (JBDS-IP 2022)

The Joint British Diabetes Societies for Inpatient Care (JBDS-IP) defines DKA by the presence of all three of the following: [1]

Important Exception: Euglycemic DKA can occur with SGLT2 inhibitor use, pregnancy, or reduced carbohydrate intake, where glucose may be less than 11 mmol/L but ketosis and acidosis are present. [6,14,15]

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Severity Classification

DKA severity guides management intensity and monitoring location: [1,22]

Additional High-Risk Features: [1,22]

• Ketones > 6 mmol/L
• Blood glucose > 40 mmol/L
• Potassium less than 3.5 mmol/L on presentation
• GCS less than 12
• Oxygen saturation less than 92% on air
• Systolic BP less than 90 mmHg
• Pulse less than 60 or > 100 bpm
• Anion gap > 16

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2. Epidemiology

Incidence and Demographics

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Risk Factors for DKA

The "5 I's" Mnemonic: [1,22]

1. Infection (most common: 30-40%)
2. Insulin omission/error (20-40%)
3. Infarction (MI, stroke)
4. Intercurrent illness (pancreatitis, surgery)
5. Initial presentation of T1DM (10-25%)

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3. Pathophysiology - The Biochemical Storm

The Core Defect: Insulin Deficiency + Counter-Regulatory Hormone Excess

DKA results from absolute or relative insulin deficiency combined with an excess of counter-regulatory hormones (glucagon, cortisol, catecholamines, growth hormone). This hormonal imbalance triggers three parallel metabolic derangements: [22]

1. Hyperglycemia - from increased hepatic glucose production and decreased peripheral utilization
2. Ketogenesis - from unrestrained lipolysis and hepatic fatty acid oxidation
3. Metabolic Acidosis - from accumulation of ketoacid anions

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Molecular Mechanisms

1. Hyperglycemia: The Sugar Flood

Hepatic Glucose Overproduction: [22]

• Insulin deficiency removes the brake on hepatic glucose output
• Glucagon excess stimulates:
  • Glycogenolysis - breakdown of glycogen stores (depleted within 24 hours)
  • Gluconeogenesis - de novo glucose synthesis from amino acids (alanine, glutamine), lactate, and glycerol
• Key enzymes upregulated: Phosphoenolpyruvate carboxykinase (PEPCK), Glucose-6-phosphatase (G6Pase)

Peripheral Glucose Underutilization: [22]

• Insulin normally promotes GLUT4 transporter translocation to cell membranes in muscle and adipose tissue
• Without insulin, GLUT4 remains sequestered intracellularly
• Glucose cannot enter cells → intracellular starvation despite extracellular abundance

Result: Blood glucose typically 20-30 mmol/L (range: 11-50+ mmol/L)

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2. Osmotic Diuresis: The Fluid Hemorrhage

Mechanism: [22]

• When blood glucose exceeds renal threshold (~10 mmol/L), glucose spills into urine (glycosuria)
• Glucose acts as an osmotic agent, drawing water into the renal tubule
• Electrolytes (Na+, K+, Cl-, PO4³⁻, Mg²⁺, Ca²⁺) are dragged along with water

Consequences:

• Severe dehydration: Total body water deficit of 5-8 liters (average 100 mL/kg) [1]
• Electrolyte depletion: Despite normal/high serum levels initially, total body stores are depleted
• Hypotension: Reduced circulating volume → shock in severe cases
• Acute kidney injury: Pre-renal AKI from volume depletion

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3. Ketogenesis: The Acid Factory

Step 1 - Lipolysis: [22]

• Insulin normally inhibits hormone-sensitive lipase (HSL) in adipose tissue
• Without insulin, HSL is unopposed → massive triglyceride breakdown
• Free fatty acids (FFAs) are released into circulation at 10-20x normal rates

Step 2 - Hepatic Fatty Acid Uptake: [22]

• FFAs flood the liver via the portal circulation
• Carnitine palmitoyltransferase I (CPT-I) transports FFAs into mitochondria
• Glucagon activates CPT-I, promoting mitochondrial FFA entry

Step 3 - β-Oxidation: [22]

• FFAs undergo β-oxidation in hepatic mitochondria
• Each cycle cleaves 2-carbon units as acetyl-CoA
• Acetyl-CoA accumulates because:
  • The Krebs cycle is overwhelmed
  • Oxaloacetate is diverted to gluconeogenesis (can't condense with acetyl-CoA)

Step 4 - Ketone Body Synthesis: [22]

• Excess acetyl-CoA enters the ketogenic pathway:
  • 2 acetyl-CoA → Acetoacetyl-CoA (via thiolase)
  • Acetoacetyl-CoA + acetyl-CoA → HMG-CoA (via HMG-CoA synthase)
  • HMG-CoA → Acetoacetate (via HMG-CoA lyase)

The Three Ketone Bodies:

1. Acetoacetate - primary ketone formed
2. β-Hydroxybutyrate (β-OHB) - reduced form of acetoacetate (predominant ketone, measured in blood)
3. Acetone - spontaneous decarboxylation product (volatile, causes "fruity" breath odor)

Ratio: In DKA, β-OHB:Acetoacetate ratio is ~3:1 (normally 1:1) due to mitochondrial redox state [22]

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4. Metabolic Acidosis: The Buffer Collapse

Mechanism: [22]

• Ketone bodies are strong organic acids (pKa ~3.5-4.5)
• They dissociate in blood, releasing hydrogen ions (H⁺):
  • CH₃CH(OH)CH₂COO⁻ + H⁺ ⇌ β-Hydroxybutyrate + H⁺
  • CH₃COCH₂COO⁻ + H⁺ ⇌ Acetoacetate + H⁺

Buffering Cascade: [22]

1. Immediate buffering: Bicarbonate (HCO₃⁻) binds H⁺ → H₂CO₃ → H₂O + CO₂
2. Bicarbonate depletion: Serum HCO₃⁻ falls progressively (less than 15 → less than 10 → less than 5 mmol/L)
3. Respiratory compensation: Chemoreceptors detect acidosis → hyperventilation (Kussmaul breathing) to expel CO₂
4. Anion Gap widens: Unmeasured anions (ketones) replace HCO₃⁻

High Anion Gap Metabolic Acidosis (HAGMA): [22]

Anion Gap = [Na⁺] - ([Cl⁻] + [HCO₃⁻])

• Normal anion gap: 8-12 mmol/L
• DKA anion gap: typically > 16 mmol/L, often 20-30 mmol/L
• The "gap" represents unmeasured anions (ketones, lactate if hypoperfused)

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Image: Pathophysiology Cascade

Image

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The Vicious Cycle

DKA becomes self-perpetuating without intervention: [22]

1. Dehydration → ↓ renal perfusion → ↓ glucose/ketone excretion → worsening hyperglycemia/ketosis
2. Acidosis → ↓ cardiac contractility + peripheral vasodilation → ↓ tissue perfusion → lactic acidosis
3. Electrolyte shifts → Hypokalemia → arrhythmias → cardiac arrest
4. Counter-regulatory hormone surge → Further insulin resistance → Worsening hyperglycemia

Treatment breaks this cycle by:

• Restoring intravascular volume (fluids)
• Suppressing ketogenesis (insulin)
• Correcting electrolytes (potassium)

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4. Clinical Presentation

History: Timeline and Symptoms

Onset: [1,22]

• DKA typically develops over 12-24 hours (acute)
• Contrast with HHS, which evolves over days to weeks (subacute)

Prodromal Symptoms (hours to days before presentation):

• Polyuria - excessive urination from osmotic diuresis
• Polydipsia - intense thirst from dehydration
• Polyphagia - increased appetite (early, then anorexia)
• Weight loss - rapid loss (5-10 kg over days) from dehydration and catabolism
• Fatigue - from cellular energy deficit

Acute Symptoms (at presentation): [1,22]

Important: Abdominal pain in DKA is real (not "pseudoperitonitis") and resolves with treatment. Avoid unnecessary surgical exploration unless pain persists after DKA resolution. [22]

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Physical Examination

General Inspection

• Appearance: Unwell, distressed, lethargic or drowsy
• Kussmaul Respiration: Deep, rapid, sighing breaths (respiratory compensation for acidosis) [1]
• Acetone Breath: Fruity, "pear-drop" odor (acetone is volatile and exhaled) - present in ~50% [1]

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Assessment of Dehydration (5-8 Liter Deficit)

Key Point: Skin turgor is unreliable in elderly patients (reduced elasticity) and young adults (preserved elasticity). Use mucous membrane dryness and hemodynamic parameters instead. [1]

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Cardiovascular Examination

• Pulse: Tachycardia (compensatory, aiming for CO = HR × SV)
• Blood Pressure: Postural drop (early), frank hypotension (severe dehydration or septic shock)
• Capillary Refill Time: Prolonged (> 2 seconds) indicates poor perfusion

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Respiratory Examination

• Rate: Tachypnea (> 20 breaths/min)
• Pattern: Kussmaul Breathing - deep, labored, regular breaths without pause (blowing off CO₂ to compensate for metabolic acidosis) [1]
• Chest: Usually clear unless precipitant is pneumonia

Physiology: Peripheral chemoreceptors detect low pH → medullary respiratory center increases ventilation → ↓ PaCO₂ → partial compensation

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Neurological Examination

• Glasgow Coma Scale (GCS): Correlates inversely with severity of acidosis and osmolality [22]
  • pH less than 7.0 or osmolality > 320 mOsm/kg → high risk of reduced GCS
• Confusion/Drowsiness: Common (20-30%)
• Coma: Rare (less than 10%) but indicates severe DKA or alternative diagnosis (e.g., CVA, sepsis, hypoglycemia)

Red Flag: Progressive headache, bradycardia, or deteriorating GCS suggests cerebral edema (especially age less than 25 years) → give hypertonic saline immediately. [16,17]

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Abdominal Examination

• Tenderness: Generalized or localized (especially epigastrium) in 30-40% [22]
• Guarding/Rebound: May be present (DKA-related or precipitant like pancreatitis)
• Bowel Sounds: Often reduced (ileus from hypokalemia)

Pitfall: DKA can perfectly mimic an acute surgical abdomen. Re-assess after initial resuscitation before considering surgery. [1,22]

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Search for Precipitants

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Special Populations

Euglycemic DKA (EDKA)

Definition: DKA with blood glucose less than 14 mmol/L (sometimes less than 11 mmol/L) [6,14,15]

Causes: [6,14,15]

• SGLT2 Inhibitors (dapagliflozin, empagliflozin, canagliflozin) - most common modern cause
  • "Mechanism: Promote urinary glucose excretion → lower blood glucose but ketogenesis continues"
• Pregnancy - increased insulin sensitivity, fasting, nausea/vomiting
• Reduced Carbohydrate Intake - fasting, low-carb/ketogenic diets
• Alcohol Excess - impairs gluconeogenesis, promotes ketogenesis
• Chronic Liver Disease - reduced glycogen stores

Clinical Trap: Doctor sees glucose 8 mmol/L in unwell diabetic patient → assumes "not DKA" → delays treatment

Golden Rule: ALWAYS check ketones in any unwell diabetic patient, regardless of glucose level. [6,14,15]

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DKA in Pregnancy

Unique Features: [22]

• Lower threshold for diagnosis (glucose may be less than 11 mmol/L)
• Develops faster (accelerated starvation ketosis)
• Higher fetal mortality (up to 35% historically, now less than 5% with modern care)
• Severe DKA is an indication for ICU admission regardless of maternal pH

Management Principles: [22]

• More aggressive fluid resuscitation (avoid hypotension → fetal compromise)
• Earlier insulin initiation
• Continuous fetal heart rate monitoring
• Multidisciplinary care (endocrinology, obstetrics, ICU)

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5. Investigations

Immediate Bedside Tests (Before Full Labs)

Key Point: These three tests (glucose, ketones, pH) can diagnose DKA within 5 minutes at the bedside. Do not delay treatment waiting for full lab results. [1]

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Blood Tests

Venous Blood Gas (VBG) - The Gold Standard for Acidosis

Why VBG, not ABG? [1]

• VBG is less painful and faster
• Venous pH is only 0.03 units lower than arterial pH (negligible difference)
• Arterial puncture is unnecessary unless assessing oxygenation (e.g., ARDS suspected)

VBG Interpretation in DKA: [1,22]

Expected Compensation: [22]

• For every 1 mmol/L drop in HCO₃⁻, expect PaCO₂ to drop by ~1.2 mmHg
• Formula: Expected PaCO₂ = 1.5 × [HCO₃⁻] + 8 (±2)
• If measured PaCO₂ is higher than expected → respiratory component (e.g., exhaustion, respiratory failure)

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Anion Gap Calculation

Formula: Anion Gap = [Na⁺] - ([Cl⁻] + [HCO₃⁻]) [22]

• Normal: 8-12 mmol/L
• DKA: > 16 mmol/L (typically 20-30 mmol/L)

What the Anion Gap Represents: Unmeasured anions (ketones, lactate, albumin)

Differential Diagnosis of HAGMA (Mnemonic: GOLDMARK): [22]

• Glycerol (DKA, ethylene glycol)
• Oxoproline (chronic paracetamol use)
• Lactate (lactic acidosis - sepsis, metformin)
• D-lactate (short bowel syndrome)
• Methanol
• Aspirin (salicylate toxicity)
• Renal failure (uraemic acids)
• Ketones (DKA, alcoholic ketoacidosis, starvation)

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Biochemistry

The Potassium Paradox: [1,22]

• At presentation: Serum K⁺ may be 4.5-5.5 mmol/L ("normal")
• After 2 hours of insulin: Serum K⁺ may drop to 2.5 mmol/L (life-threatening)
• Rule: If K⁺ less than 3.5 mmol/L at ANY point → STOP INSULIN → GIVE POTASSIUM → Risk of fatal arrhythmia

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Hematology

Pitfall: Elevated WCC is expected in DKA even without infection. Use clinical context (fever, focal signs) and inflammatory markers (CRP, procalcitonin) to diagnose infection. [22]

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Osmolality

Calculation (simplified): [22] Serum Osmolality (mOsm/kg) = 2 × [Na⁺] + [Glucose] + [Urea]

• Normal: 275-295 mOsm/kg
• DKA: Usually less than 320 mOsm/kg
• HHS: > 320 mOsm/kg (key differentiator)

Significance:

• Osmolality > 320 mOsm/kg correlates with reduced GCS and risk of cerebral edema [22]
• Higher osmolality → slower correction required (to avoid osmotic demyelination)

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Urine Tests

Important: Urine ketone sticks detect acetoacetate but NOT β-hydroxybutyrate (the predominant ketone in DKA). Use blood ketone meters for accurate diagnosis and monitoring. [1]

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Microbiology (Search for Precipitants)

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Radiology

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Electrocardiogram (ECG)

Key Abnormalities to Monitor: [1,22]

Recommendation: Perform ECG on admission and repeat if K⁺ abnormalities develop. [1]

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Monitoring During Treatment

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6. Management - The JBDS-IP 2022 Protocol

Principles of DKA Management

The "3 Rs": [1]

1. Restore Volume - IV fluids to reverse dehydration and improve renal perfusion
2. Replace Electrolytes - Potassium replacement to prevent arrhythmias
3. Reverse Ketosis - Fixed-rate IV insulin to suppress ketogenesis

Key Concepts: [1]

• Fluids first, insulin second (volume expansion improves insulin sensitivity)
• Fixed-rate insulin (not variable-rate sliding scale) to suppress ketogenesis
• Potassium is the killer - K⁺ less than 3.5 mmol/L → HOLD INSULIN
• Never stop basal insulin (long-acting once-daily insulin) during DKA treatment

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Step 1: Fluid Resuscitation - The Priority

Rationale

Patients with DKA have a total body water deficit of 5-8 liters (average 100 mL/kg). [1,22] Fluid resuscitation:

• Improves tissue perfusion
• Enhances renal clearance of glucose and ketones
• Dilutes counter-regulatory hormones
• Improves insulin sensitivity

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Fluid Choice: 0.9% Saline vs Balanced Solutions

Standard Recommendation (JBDS-IP 2022): 0.9% Sodium Chloride (Normal Saline) [1]

Emerging Evidence: Balanced crystalloids (Hartmann's/Ringer's Lactate, Plasma-Lyte) may resolve DKA faster and reduce hyperchloremic metabolic acidosis. [3,5]

Meta-analysis (2024): Balanced solutions resolve DKA 2-3 hours faster than 0.9% saline and reduce time to pH normalization. [3]

Current Guidance: Either 0.9% saline OR balanced crystalloid is acceptable. [1,3,5] Avoid Hartmann's if severe lactic acidosis coexists (lactate confounds monitoring).

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Fluid Resuscitation Regimen (JBDS-IP 2022)

If Hypotensive (SBP less than 90 mmHg): [1]

• Give 500-1000 mL 0.9% saline IV bolus over 15 minutes
• Reassess hemodynamics
• Repeat bolus if still hypotensive
• Consider septic shock (start antibiotics, consider vasopressors/ICU)

Standard Fluid Protocol (normotensive or post-resuscitation): [1]

Total Over 12 Hours: ~4-6 liters (adjust for age, cardiac/renal function)

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Special Considerations

Elderly or Heart Failure: [1]

• Risk of fluid overload and pulmonary edema
• Reduce rates: 1L over 2 hours, then 1L over 4 hours, then 1L over 6 hours
• Monitor for raised JVP, bibasal crackles, hypoxia
• Consider central venous pressure (CVP) monitoring if severe cardiac disease

Pregnancy: [22]

• More aggressive fluid resuscitation (fetal perfusion depends on maternal BP)
• Continuous fetal heart rate monitoring

Renal Failure: [1]

• Reduce fluid volumes (risk of overload)
• May require renal replacement therapy (RRT)

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Step 2: Potassium Replacement - The Killer

The Potassium Paradox (Revisited)

At Presentation: [1,22]

• Acidosis shifts K⁺ out of cells into serum (K⁺/H⁺ exchange)
• Osmotic diuresis causes massive urinary K⁺ loss
• Result: Total body K⁺ is severely depleted (300-500 mmol deficit) BUT serum K⁺ may appear "normal" (4.5-5.5 mmol/L)

After Insulin Treatment: [1,22]

• Insulin shifts K⁺ into cells (activates Na⁺/K⁺-ATPase pump)
• Correction of acidosis also shifts K⁺ intracellularly
• Result: Serum K⁺ can drop from 5.0 to 2.5 mmol/L within 2-4 hours

Consequences of Hypokalemia: [1,22]

• Cardiac arrhythmias: Atrial fibrillation, ventricular ectopics, ventricular fibrillation
• Muscle weakness, respiratory failure (if severe)
• Ileus
• Hypokalemia is the leading iatrogenic cause of death in DKA management. [22]

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Potassium Replacement Protocol (JBDS-IP 2022)

Golden Rule: Check serum K⁺ before starting insulin. [1]

Delivery: Potassium chloride (KCl) is added to 0.9% saline bags as 40 mmol per liter (pre-made bags preferred). [1]

Monitoring: K⁺ levels can change rapidly. Hourly monitoring for the first 2-4 hours is mandatory. [1]

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Step 3: Fixed-Rate Intravenous Insulin Infusion (FRIII)

Why Fixed-Rate (Not Variable-Rate Sliding Scale)?

Fixed-Rate Insulin Infusion (FRIII): [1,22]

• Dose: 0.1 units/kg/hour (e.g., 70 kg patient = 7 units/hour)
• Goal: Suppress hepatic ketogenesis (not primarily to lower glucose)
• Provides a constant, predictable substrate to switch off lipolysis and ketone production

Variable-Rate Insulin Infusion (Sliding Scale):

• Dose varies based on blood glucose
• Goal: Control hyperglycemia
• Problem: Ineffective at suppressing ketogenesis (insulin levels fluctuate)

Key Concept: In DKA, we treat ketosis, not just hyperglycemia. Fixed-rate insulin ensures continuous suppression of ketone production. [1,12]

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FRIII Protocol (JBDS-IP 2022)

Preparation: [1]

• 50 units of Human Actrapid (short-acting insulin) in 50 mL 0.9% saline (= 1 unit/mL)
• Administer via dedicated IV pump (never share line with fluids - risk of dosing errors)

Dosing:

• 0.1 units/kg/hour (round to nearest 0.5 units for simplicity)
• Example: 70 kg patient → 7 units/hour

DO NOT STOP OR REDUCE INSULIN based on glucose alone. Continue until ketones clear. [1]

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Continuing Basal Insulin

CRITICAL RULE: If the patient is already on long-acting insulin (e.g., Lantus, Levemir, Tresiba), DO NOT STOP IT during DKA treatment. [1]

Rationale: [1]

• Long-acting insulin provides basal coverage
• When IV insulin is stopped (at DKA resolution), there is a lag before subcutaneous insulin takes effect
• Stopping basal insulin → rebound hyperglycemia and ketosis within 2-4 hours

Exception: If using twice-daily mixed insulin (e.g., NovoMix 30), continue the long-acting component but hold the short-acting component (to avoid hypoglycemia stacking with IV insulin). [1]

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Step 4: Adding Dextrose When Glucose Falls

The Dextrose Rule

When blood glucose drops below 14 mmol/L: [1]

• Start 10% Dextrose at 125 mL/hour (via separate IV line)
• Continue the fixed-rate insulin infusion (0.1 units/kg/hour)
• Continue 0.9% saline (reduce rate to 125-250 mL/hr to avoid fluid overload)

Rationale: [1,22]

• The goal is to clear ketones, not just normalize glucose
• Ketone clearance requires continuing insulin, even if glucose is normal
• Without dextrose, continuing insulin → hypoglycemia
• Dextrose allows safe continuation of insulin to suppress ketogenesis

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Running Three IV Lines Simultaneously

At glucose less than 14 mmol/L, patients typically have: [1]

1. 0.9% Saline (with 40 mmol KCl) at 125-250 mL/hr
2. 10% Dextrose at 125 mL/hr
3. Fixed-rate insulin at 0.1 units/kg/hr (via syringe pump)

Practical Tip: Use a three-way tap or multiple IV cannulas to run concurrent infusions safely.

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Step 5: Bicarbonate - DON'T (Usually)

JBDS-IP 2022 Recommendation: DO NOT give bicarbonate routinely. [1]

Rationale: [22]

• Bicarbonate does NOT improve outcomes in DKA
• May worsen intracellular acidosis (paradoxical CSF acidosis)
• Increases risk of cerebral edema in children
• Can cause hypokalemia, sodium overload, and alkalosis overshoot

Rare Indication: [1]

• Severe acidosis (pH less than 6.9) WITH life-threatening hyperkalemia or cardiac arrest
• Dose: 1.26% sodium bicarbonate (not 8.4% - too hypertonic) - seek senior/ICU input
• Monitor closely (risk of arrhythmias, paradoxical worsening)

Bottom Line: Focus on fluids and insulin. Acidosis corrects as ketones are metabolized. [1,22]

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Step 6: Search for and Treat Precipitants

Common Precipitants (see Epidemiology section): [1,22]

1. Infection (30-40%): Pneumonia, UTI, sepsis → empirical antibiotics if suspected
2. Insulin omission (20-40%): Diabetes education, psychological support, pump troubleshooting
3. MI/ACS: ECG, troponin, cardiology input
4. New diagnosis T1DM: Diabetes specialist team referral

Actions: [1]

• Blood cultures, urine culture, CXR
• ECG and troponin if chest pain or cardiac risk factors
• Consider pancreatitis (amylase/lipase)
• Review medication (e.g., steroids, antipsychotics)

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7. Resolution Criteria and Transition to Subcutaneous Insulin

When is DKA Resolved?

JBDS-IP 2022 Criteria - ALL of the following must be met: [1]

Important: Glucose normalizes before ketones clear. Do NOT stop DKA protocol based on glucose alone. [1]

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Transition to Subcutaneous Insulin

Once DKA Resolved: [1]

1. Calculate Total Daily Dose (TDD):

   • Weight-based: 0.5-0.8 units/kg/day
   • Example: 70 kg patient → 40-56 units/day total

2. Split into Basal and Bolus:

   • 50% as basal (long-acting once daily, e.g., Lantus 20 units)
   • 50% as bolus (short-acting before meals, e.g., Novorapid 6-8 units TDS)

3. Timing - CRITICAL:

   • Give subcutaneous insulin 30-60 minutes BEFORE stopping IV insulin
   • Rationale: Subcutaneous insulin takes 1-2 hours to reach therapeutic levels
   • Stopping IV insulin prematurely → rebound ketosis within hours [1]

4. Monitor:

   • Capillary glucose 4-hourly
   • Ketones daily until consistently less than 0.6 mmol/L
   • VBG if patient deteriorates

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Failed DKA Resolution

If ketones NOT falling by > 0.5 mmol/L per hour: [1]

Persistent DKA > 24 hours: Senior endocrinology review + consider HDU/ICU. [1]

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8. Complications

1. Hypokalemia and Arrhythmias

Incidence: Most common life-threatening complication (leading cause of iatrogenic death in DKA) [1,22]

Mechanism: Insulin-driven intracellular K⁺ shift + ongoing urinary losses [22]

Clinical Features:

• ECG changes: Flattened T waves, U waves, prolonged QT, ventricular ectopics
• Muscle weakness, paralysis (if severe)
• Cardiac arrest (VF, asystole)

Prevention: [1]

• Hourly K⁺ monitoring (first 4 hours)
• HOLD insulin if K⁺ less than 3.5 mmol/L
• Replace K⁺ aggressively (up to 40 mmol/hour via central line in ICU if severe)

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2. Cerebral Edema

Incidence: 0.5-1% of pediatric DKA cases; rare in adults (age > 25 years) [16,17,22]

Mortality: 20-25% [16,17]

Mechanism (incompletely understood): [16,17]

• Osmotic gradient shifts as glucose/osmolality falls
• Water moves into brain cells → cellular swelling
• Vasogenic edema from blood-brain barrier disruption
• Risk Factors: Age less than 5 years, new-onset T1DM, severe acidosis/dehydration, rapid correction of hyperglycemia, excessive IV fluids

Clinical Features (typically 4-12 hours after treatment initiation): [16,17]

• Headache (new or worsening)
• Altered mental status, irritability
• Vomiting
• Bradycardia (ominous sign - Cushing's triad)
• Rising BP with widening pulse pressure
• Reduced GCS, seizures, coma
• Neurological signs: Cranial nerve palsies, papilledema

Management: [1,16,17]

1. Immediate action (do NOT wait for CT):
   • Give 3% Hypertonic Saline 2-3 mL/kg IV over 10-15 minutes (first-line)
   • OR Mannitol 0.5-1 g/kg IV over 15-20 minutes (alternative)
2. Reduce IV fluid rate by one-third
3. Head elevation to 30 degrees
4. Urgent CT Head (once stabilized)
5. ICU transfer for intubation/ventilation if GCS less than 8
6. Neurosurgery consultation (if signs of herniation)

Prevention: [16,17]

• Avoid excessive fluid resuscitation (especially in children)
• Gradual correction of hyperglycemia (aim 3-5 mmol/L per hour)
• Avoid hypotonic fluids
• Close neurological monitoring (hourly GCS)

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3. Hypoglycemia

Incidence: 5-10% [22]

Causes:

• Continuing FRIII without adding dextrose when glucose less than 14 mmol/L
• Excessive insulin dose
• Inadequate carbohydrate intake after IV insulin stopped

Prevention: [1]

• Add 10% dextrose when glucose less than 14 mmol/L
• Do NOT reduce insulin rate (maintain 0.1 units/kg/hr to clear ketones)
• Monitor glucose hourly

Management:

• If conscious: 15-20 g oral glucose (Lucozade, GlucoGel)
• If unconscious/unable to swallow: 100 mL 10% Dextrose IV bolus
• Recheck glucose in 15 minutes

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4. Thromboembolism

Incidence: 1-2% [22]

Risk Factors:

• Severe dehydration (hyperviscosity)
• Prolonged immobility
• Central venous catheters
• HHS (higher risk than DKA due to extreme hyperosmolality)

Prevention: [1]

• Prophylactic LMWH (e.g., enoxaparin 40 mg SC daily) for ALL adults unless contraindicated
• Encourage early mobilization
• Adequate hydration

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5. Aspiration Pneumonia

Risk Factors:

• Reduced GCS
• Vomiting (common in DKA)

Prevention: [1]

• NBM (nil by mouth) until GCS > 12 and no vomiting
• Consider NG tube if persistent vomiting or reduced GCS
• Recovery position if drowsy

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6. Acute Respiratory Distress Syndrome (ARDS)

Incidence: Rare (less than 1%) [22]

Mechanism: Systemic inflammatory response, fluid overload, sepsis

Prevention:

• Avoid excessive fluid resuscitation (monitor lung sounds, SpO₂)
• Treat underlying sepsis

Management: ICU, mechanical ventilation, lung-protective strategies

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7. Hyperchloremic Metabolic Acidosis

Incidence: Very common with 0.9% saline resuscitation (30-50%) [3,5,22]

Mechanism: [3,5]

• 0.9% saline has Cl⁻ 154 mmol/L (supraphysiological)
• Large volumes → dilute HCO₃⁻ → non-anion gap metabolic acidosis
• Anion gap normalizes (ketones cleared) but pH remains less than 7.35, HCO₃⁻ less than 22

Clinical Significance:

• Confuses resolution assessment: pH low, but DKA is resolved (ketones less than 0.6)
• Generally benign and self-limiting (resolves over 24-48 hours)

How to Distinguish from Persistent DKA: [1]

• Check ketones: If less than 0.6 mmol/L → DKA resolved, hyperchloremic acidosis is the cause of low pH
• Check anion gap: Normal anion gap → hyperchloremic; high anion gap → persistent ketosis

Prevention: Use balanced crystalloids (Hartmann's/Plasma-Lyte) instead of 0.9% saline [3,5]

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8. Acute Kidney Injury (AKI)

Incidence: 30-50% (mostly pre-renal) [22]

Mechanism:

• Severe dehydration → renal hypoperfusion
• May progress to acute tubular necrosis (ATN) if prolonged

Management:

• Fluid resuscitation (resolves pre-renal AKI)
• Monitor urine output (catheterize if oliguric)
• Avoid nephrotoxins (NSAIDs, gentamicin)
• Renal replacement therapy (RRT) if severe/anuric

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9. DKA vs Hyperosmolar Hyperglycaemic State (HHS)

DKA and HHS are distinct hyperglycemic emergencies with overlapping features but critical differences: [1,19]

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Management Differences

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Mixed DKA-HHS

Some patients (especially Type 2 DM with severe stress) present with both ketosis and hyperosmolality: [1,22]

• Glucose > 30 mmol/L AND Ketones > 3.0 mmol/L AND Osmolality > 320 mOsm/kg

Management Approach: [1]

• Treat as DKA (start insulin with fluids)
• Use cautious fluid resuscitation (as in HHS) to avoid cerebral edema
• Treatment-dose LMWH (high thrombosis risk)
• Monitor osmolality closely (aim for slow correction)

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10. Special Scenario: Euglycemic DKA (EDKA)

Definition

DKA with blood glucose less than 14 mmol/L (sometimes less than 11 mmol/L), but with ketosis (β-OHB > 3.0 mmol/L) and acidosis (pH less than 7.3). [6,14,15]

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Causes

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SGLT2 Inhibitor-Associated EDKA

SGLT2 Inhibitors (e.g., dapagliflozin, empagliflozin, canagliflozin): [6,9,14]

• FDA-approved for T2DM, heart failure, chronic kidney disease
• Mechanism: Block renal SGLT2 transporter → glycosuria (urinary glucose excretion)
• Unintended Effect: Lower blood glucose BUT increase glucagon secretion and decrease insulin → promotes lipolysis → ketogenesis

Incidence: Rare but increasing (0.1-0.2% per year in SGLT2 users) [14]

Precipitants (Mnemonic: SIPS): [6,14]

• Surgery (especially bariatric surgery, fasting)
• Infection/Illness
• Pregnancy
• Starvation/low-carbohydrate diet

Clinical Trap: [6,14,15]

• Patient on SGLT2 inhibitor presents unwell, vomiting
• Doctor checks glucose: 8 mmol/L ("not diabetic emergency")
• Diagnosis delayed → worsening acidosis → ICU admission
• ALWAYS check ketones in unwell diabetic patients, regardless of glucose

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Diagnosis

EDKA Criteria (modified from standard DKA): [6,14,15]

1. Blood glucose less than 14 mmol/L (may be less than 11 mmol/L)
2. Blood ketones (β-OHB) > 3.0 mmol/L
3. pH less than 7.3 or Bicarbonate less than 15 mmol/L

Laboratory Findings: [6,14]

• Anion gap usually elevated (15-25 mmol/L)
• Lactate may be normal or mildly elevated
• Urine ketones strongly positive

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Management

Same as standard DKA with modifications: [1,6,14]

1. Stop SGLT2 Inhibitor immediately (do not restart during admission)
2. Fluid Resuscitation: 0.9% saline as per JBDS protocol
3. Insulin: Fixed-rate insulin 0.1 units/kg/hr
4. Dextrose: Start earlier (when glucose less than 12 mmol/L, rather than less than 14 mmol/L) to prevent hypoglycemia
5. Potassium: As per standard DKA protocol
6. Monitor: Glucose may drop rapidly → risk of hypoglycemia

Discharge Advice: [6,14]

• Do NOT restart SGLT2 inhibitor if EDKA occurred
• Educate on sick-day rules
• Increase ketone self-monitoring

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11. Paediatric Considerations

Key Message: Children are NOT small adults. DKA management differs significantly due to higher risk of cerebral edema (0.5-1% incidence, 20-25% mortality). [16,17]

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Differences in Paediatric DKA Management (BSPED Guidelines)

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Fluid Calculation in Children

Step 1: Calculate fluid deficit [16,17]

• Mild DKA (pH 7.2-7.3): 5% dehydration → 50 mL/kg
• Moderate DKA (pH 7.1-7.2): 7% dehydration → 70 mL/kg
• Severe DKA (pH less than 7.1): 10% dehydration → 100 mL/kg

Step 2: Calculate maintenance (Holliday-Segar formula) [16,17]

• First 10 kg: 100 mL/kg/day
• Next 10 kg: 50 mL/kg/day
• Remaining kg: 20 mL/kg/day

Step 3: Replace deficit + maintenance over 48 hours [16,17]

Example (20 kg child, 7% dehydration):

• Deficit = 70 mL/kg × 20 kg = 1400 mL
• Maintenance = (10 kg × 100) + (10 kg × 50) = 1500 mL/day = 3000 mL over 48 hrs
• Total = 1400 + 3000 = 4400 mL over 48 hours = ~90 mL/hr

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Cerebral Edema in Children

Pathophysiology (incompletely understood): [16,17]

• Rapid osmotic shifts as glucose falls → water moves into brain cells (cytotoxic edema)
• Blood-brain barrier disruption (vasogenic edema)
• Cerebral hypoperfusion during DKA → ischemia-reperfusion injury

Risk Factors: [16,17]

• Age less than 5 years (highest risk)
• New-onset Type 1 DM
• Severe acidosis (pH less than 7.1) or hyperglycemia (> 40 mmol/L) at presentation
• High urea (severe dehydration)
• Failure of sodium to rise as glucose falls (dilutional hyponatremia)
• Excessive IV fluids or rapid correction of hyperglycemia

Clinical Features (typically 4-12 hours after starting treatment): [16,17]

• Headache (new or worsening)
• Vomiting
• Irritability, confusion, altered behavior
• Cushing's Triad: Bradycardia, hypertension, irregular breathing (late sign - herniation imminent)
• Reduced GCS, seizures, coma
• Neurological signs: Unequal pupils, papilledema, cranial nerve palsies

Management (see Complications section): [16,17]

• 3% Hypertonic Saline 2-3 mL/kg IV (first-line)
• OR Mannitol 0.5-1 g/kg IV
• Reduce IV fluid rate by one-third
• Head elevation 30 degrees
• Urgent CT head (once stabilized)
• ICU transfer

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12. Prognosis

Mortality

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Predictors of Poor Outcome

High-Risk Features (associated with increased mortality): [22]

• Extremes of age (less than 5 years, > 65 years)
• Severe acidosis (pH less than 7.0)
• Hypotension/shock (SBP less than 90 mmHg)
• Severe hyperglycemia (> 50 mmol/L) or hyperosmolality (> 350 mOsm/kg)
• GCS less than 8
• Acute kidney injury (creatinine > 200 µmol/L)
• Hypokalemia (less than 3.0 mmol/L) or hyperkalemia (> 6.0 mmol/L) at presentation
• Precipitant: Sepsis, MI, stroke, pancreatitis

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Long-Term Outcomes

Recurrent DKA: [22]

• 15-20% of patients experience recurrent episodes
• Risk factors: Poor glycemic control (HbA1c > 9%), insulin omission, eating disorders, psychological issues, socioeconomic barriers

Cognitive Impact: [7]

• Recurrent severe hypoglycemia and DKA may impair cognitive function long-term (especially in children)
• Neurocognitive deficits: Memory, executive function, processing speed

Prevention of Recurrence: [1,22]

• Diabetes education (sick-day rules, insulin adjustment)
• Psychological support (address insulin omission, eating disorders)
• Continuous glucose monitoring (CGM) to detect early hyperglycemia
• Structured diabetes care (specialist nurse, MDT)

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13. Prevention

Sick-Day Rules (Patient Education)

The "Sick Day" Scenario: Illness, infection, surgery, vomiting → increased insulin requirements → risk of DKA [1]

Patient Advice (Mnemonic: SICK): [1,22]

• Sugar: Check blood glucose every 4 hours (more frequently if unwell)
• Insulin: NEVER stop insulin (even if not eating - continue basal insulin, adjust bolus)
• Carbs & fluids: Drink plenty (prevent dehydration), eat simple carbs if tolerated
• Ketones: Check blood ketones if glucose > 15 mmol/L or feeling unwell

When to Seek Help: [1]

• Blood ketones > 1.5 mmol/L AND blood glucose > 15 mmol/L
• Vomiting persistently (> 2 episodes)
• Unable to tolerate fluids
• Confusion, drowsiness
• Abdominal pain, shortness of breath

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Primary Prevention in Type 1 Diabetes

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14. Clinical Pitfalls and Troubleshooting

Pitfall 1: "Glucose is Normal, So It Can't Be DKA"

Scenario: Unwell diabetic patient on SGLT2 inhibitor, vomiting. Glucose = 9 mmol/L.

Error: Assume "not DKA" based on glucose alone.

Correct Approach: Check ketones - euglycemic DKA is possible. [6,14,15]

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Pitfall 2: "Insulin is Working, Glucose is 6 mmol/L, I'll Stop the IV Insulin"

Scenario: 6 hours into DKA treatment, glucose drops to 6 mmol/L. Doctor stops insulin to avoid hypoglycemia.

Error: Stopping insulin prematurely → ketones remain elevated → DKA not resolved → rebound hyperglycemia and ketosis within hours.

Correct Approach: Add 10% dextrose and continue insulin until ketones less than 0.6 mmol/L. [1]

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Pitfall 3: "K⁺ is 5.0 mmol/L, So They Don't Need Potassium"

Scenario: DKA patient, initial K⁺ = 5.0 mmol/L. No potassium added to fluids. After 2 hours of insulin, K⁺ = 2.8 mmol/L → cardiac arrest.

Error: Assuming normal serum K⁺ means adequate total body K⁺. Total body K⁺ is ALWAYS depleted in DKA. [1,22]

Correct Approach: Add 40 mmol KCl per liter of IV fluid if K⁺ 3.5-5.5 mmol/L. Monitor hourly. [1]

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Pitfall 4: "The Patient is Still Acidotic (pH 7.25), But Ketones Are 0.4 mmol/L"

Scenario: After 12 hours of treatment, pH 7.28, HCO₃⁻ 14 mmol/L, ketones 0.4 mmol/L, anion gap 10 mmol/L.

Error: Continue DKA protocol unnecessarily.

Correct Approach: DKA is resolved (ketones less than 0.6). The acidosis is hyperchloremic (non-anion gap) from 0.9% saline. Switch to subcutaneous insulin. [1,3,5]

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Pitfall 5: "Stopping Basal Insulin During DKA Treatment"

Scenario: Patient on Lantus 30 units OD. IV insulin started for DKA. Doctor holds Lantus "to avoid hypoglycemia."

Error: Stopping basal insulin → when IV insulin is stopped, there is no background insulin → rebound hyperglycemia/ketosis within 2-4 hours. [1]

Correct Approach: Continue basal insulin throughout DKA treatment. [1]

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Pitfall 6: "Abdominal Pain Must Be Surgical"

Scenario: Young T1DM patient with severe abdominal pain, guarding. Surgical team called for "acute abdomen."

Error: Laparotomy performed → no surgical pathology found → DKA-related abdominal pain.

Correct Approach: Treat DKA first, reassess abdomen after resuscitation. Abdominal pain resolves in most cases. Only pursue surgical causes if pain persists or worsens. [1,22]

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15. Examination Focus (MRCP, FRCA, ICU Vivas)

High-Yield Viva Questions

Question 1: "Why do we use fixed-rate insulin in DKA rather than a sliding scale?"

Model Answer: "The goal in DKA is to suppress ketogenesis, not just control glucose. Fixed-rate insulin (0.1 units/kg/hr) provides a constant, predictable substrate to switch off hepatic lipolysis and ketone production. Variable-rate sliding scales adjust insulin based on glucose levels, which fluctuate unpredictably, leading to inconsistent suppression of ketogenesis. Fixed-rate ensures continuous insulin delivery until ketones are cleared (less than 0.6 mmol/L)." [1,12]

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Question 2: "A patient's potassium is 5.2 mmol/L at presentation. Do they need potassium replacement?"

Model Answer: "Yes. Despite a 'normal' serum potassium, total body potassium is ALWAYS depleted in DKA (average 300-500 mmol deficit from osmotic diuresis). The serum K⁺ appears normal because acidosis shifts potassium out of cells. As soon as insulin therapy starts, potassium moves intracellularly, and serum K⁺ can drop precipitously to life-threatening levels. Therefore, if K⁺ is between 3.5-5.5 mmol/L, we add 40 mmol KCl per liter of IV fluid. We hold insulin if K⁺ less than 3.5 mmol/L to prevent fatal arrhythmias." [1,22]

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Question 3: "What is the leading cause of death in adults vs children with DKA?"

Model Answer:

• Adults: Hypokalemia (cardiac arrhythmias) and the underlying precipitant (sepsis, myocardial infarction, stroke). [1,22]
• Children: Cerebral edema, which accounts for 60-90% of pediatric DKA deaths. It occurs in 0.5-1% of cases with a mortality rate of 20-25%. [16,17]

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Question 4: "Why do we continue basal insulin during DKA treatment?"

Model Answer: "Basal insulin (long-acting, e.g., Lantus, Levemir) provides background coverage over 24 hours. If we stop it during DKA treatment, when we eventually stop the IV insulin infusion, there is a lag of 1-2 hours before subcutaneous insulin takes effect. During this gap, the patient has no insulin on board, leading to rebound hyperglycemia and ketosis within hours. Continuing basal insulin ensures seamless transition from IV to subcutaneous insulin." [1]

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Question 5: "A diabetic patient on dapagliflozin presents unwell with vomiting. Glucose is 8 mmol/L. What is your next step?"

Model Answer: "I would check blood ketones immediately. This patient is at risk of euglycemic DKA, a recognized complication of SGLT2 inhibitors (dapagliflozin). SGLT2 inhibitors cause glycosuria, lowering blood glucose, but ketogenesis continues. Euglycemic DKA is defined by glucose less than 14 mmol/L (sometimes less than 11 mmol/L) with ketones > 3.0 mmol/L and acidosis. The glucose level does NOT rule out DKA in this context. Always check ketones in any unwell diabetic patient, regardless of glucose." [6,14,15]

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Question 6: "Why don't we give bicarbonate in DKA?"

Model Answer: "Bicarbonate administration in DKA has no proven benefit and several potential harms. It does not improve outcomes and may cause:

• Paradoxical worsening of intracellular acidosis (CO₂ diffuses into cells faster than HCO₃⁻)
• Increased risk of cerebral edema (especially in children)
• Hypokalemia (K⁺ shifts intracellularly as pH rises)
• Sodium overload and alkalosis overshoot

The acidosis in DKA is self-correcting as ketones are metabolized to bicarbonate. Treatment focuses on fluids and insulin, not bicarbonate. The only exception is severe acidosis (pH less than 6.9) with life-threatening hyperkalemia or cardiac arrest, and this requires senior/ICU input." [1,22]

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Question 7: "How do you distinguish DKA from HHS?"

Model Answer:

The key differentiators are higher glucose and osmolality in HHS, and presence of ketones and acidosis in DKA. [1,19,22]

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Examination Pearls

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16. Patient/Layperson Explanation

"What is Diabetic Ketoacidosis?"

"Diabetic ketoacidosis, or DKA, is a serious complication of diabetes that happens when your body doesn't have enough insulin. Insulin is like a 'key' that unlocks your cells to let sugar (glucose) in for energy. Without insulin, your cells can't use the sugar in your blood, so they start burning fat for energy instead.

When fat is burned, it produces toxic waste products called ketones (like exhaust fumes from a car). These ketones build up in your blood and make it acidic (like battery acid). At the same time, because sugar can't get into your cells, it builds up in your blood to dangerously high levels.

Your body tries to get rid of the excess sugar by peeing it out, which makes you very thirsty and dehydrated. You might also feel sick, vomit, have tummy pain, and breathe very deeply. Some people notice their breath smells fruity (like pear drops).

DKA is a medical emergency. If not treated quickly, it can be life-threatening. Treatment involves:

1. Fluids through a drip to rehydrate you
2. Insulin through a drip to stop fat burning and clear the ketones
3. Potassium (a mineral) to replace what you've lost

Most people recover fully within 24-48 hours with treatment. To prevent DKA in the future, never stop your insulin, even if you're not eating. If you're unwell, check your blood sugar and ketones more often, and call your diabetes team if your ketones are high." [1,22]

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17. Key Guidelines and Evidence

Major Guidelines

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Landmark Evidence

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18. Summary - The DKA "Rule of Threes"

Diagnosis (3 Criteria)

1. Hyperglycemia (> 11 mmol/L)
2. Ketosis (> 3.0 mmol/L)
3. Acidosis (pH less than 7.3 or HCO₃⁻ less than 15)

Management (3 Pillars)

1. Fluids (0.9% saline: 1L/1hr, 1L/2hr, 1L/4hr)
2. Insulin (FRIII 0.1 units/kg/hr)
3. Potassium (40 mmol/L if K⁺ 3.5-5.5)

Resolution (3 Targets)

1. pH > 7.3
2. Ketones less than 0.6 mmol/L
3. Patient eating/drinking

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19. References

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2. Eledrisi MS, Alshanti MS, Shah MF, Brolosy B, Jaha N. Management of Diabetic Ketoacidosis in Adults: A Narrative Review. Saudi J Med Med Sci. 2020;8(3):165-173. DOI: 10.4103/sjmms.sjmms_478_19 PMID: 32952507

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9. Garg R, Bhutani R, Dixit S, Singh V, Verma R. Euglycemic Ketoacidosis Associated with SGLT-2 Inhibitors in Non-diabetic Patients-A Narrative Review. J Gen Intern Med. 2025;40(3):537-544. DOI: 10.1007/s11606-024-09073-2 PMID: 39354257

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19. Mustafa OG, Haq M, Dashora U, et al. Management of Hyperosmolar Hyperglycaemic State (HHS) in Adults: An updated guideline from the Joint British Diabetes Societies (JBDS) for Inpatient Care Group. Diabet Med. 2023;40(3):e15005. DOI: 10.1111/dme.15005 PMID: 36370077

20. Dunn BK, Hsu C, Miller G, Surani S. Treatment Challenges and Controversies in the Management of Critically Ill Diabetic Ketoacidosis (DKA) Patients in Intensive Care Units. Cureus. 2024;16(9):e68785. DOI: 10.7759/cureus.68785 PMID: 39360087

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24. Baldrighi M, Sainaghi PP, Bellan M, et al. Hyperglycemic Hyperosmolar State: A Pragmatic Approach to Properly Manage Sodium Derangements. Curr Diabetes Rev. 2018;14(6):534-541. DOI: 10.2174/1573399814666180320091451 PMID: 29557753

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Last Updated: 2026-01-06
Evidence Level: High (Level I-II evidence from systematic reviews, RCTs, international guidelines)
Citation Count: 20 PubMed-indexed citations