DKA

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Diabetic Ketoacidosis (DKA)

Definition

DKA is defined by three core biochemical features (the "DKA triad"):

Hyperglycemia - blood glucose typically >250 mg/dL (though euglycemic DKA at ≤300 mg/dL occurs in up to 18%, especially with SGLT2 inhibitor use)
Ketonemia/Ketonuria - urine ketones ≥2+ or serum ketones ≥3.0 mmol/L
Metabolic acidosis - arterial/venous pH <7.3, serum bicarbonate <18 mmol/L

Mild DKA: pH 7.20-7.30; Severe DKA: pH <7.00.

Goldman-Cecil Medicine, p. 2483

Pathophysiology

The central defect is insulin deficiency + glucagon excess, creating a state that mimics starvation at the cellular level.

Metabolic consequences:

Pathway	Effect
Lipolysis (hormone-sensitive lipase activated)	Free fatty acids (FFAs) released from adipose tissue
Hepatic beta-oxidation of FFAs	Ketone body production: β-hydroxybutyrate, acetoacetate, acetone
Proteolysis	Amino acids → liver → gluconeogenesis
Glucogenolysis	Further raises blood glucose
Osmotic diuresis	Profound dehydration + electrolyte loss

Glucose in the renal tubules draws water, Na+, K+, Mg2+, Ca2+, phosphorus into urine. Combined with vomiting and poor intake, this produces the profound dehydration and electrolyte imbalances of DKA. - Rosen's Emergency Medicine, p. 2542

Why ketones accumulate:

Despite increased ketone production, peripheral tissues reduce their use of ketones (mimicking starvation physiology). The body's own protective mechanism thus backfires, amplifying ketoacidosis.

Average fluid/electrolyte deficits in severe DKA:

Water: 70-120 mL/kg
Sodium: 8-10 mEq/kg
Potassium: 5-7 mEq/kg
Phosphorus: ~3 mEq/kg
Rosen's Emergency Medicine, Table 115.3

Precipitants

Most Common	Other
Infections	Cerebrovascular accident
Inadequate insulin / non-adherence	Acute pulmonary embolism
New-onset diabetes	Pancreatitis
Acute coronary syndrome	Cushing syndrome, thyrotoxicosis
Unknown	Drugs: corticosteroids, clozapine, olanzapine, cocaine, SGLT2 inhibitors, thiazides

Goldman-Cecil Medicine, Table 210-11

Clinical Features

Prodrome (hours to days): polyuria, polydipsia, weakness, lethargy, nausea, anorexia
Pain: nonspecific upper abdominal pain that can mimic acute abdomen; paralytic ileus in severe cases
Dehydration signs: dry skin and mucous membranes, decreased JVP, tachycardia, orthostatic hypotension
Neurological: depressed mental status, frank coma in severe cases
Respiratory: Kussmaul breathing - deep, rapid respirations as respiratory compensation for metabolic acidosis; fruity breath (acetone)
Goldman-Cecil Medicine, p. 2484

Diagnosis & Lab Findings

Test	Findings in DKA
Glucose	Usually >350 mg/dL; euglycemic DKA possible
pH (venous preferred)	<7.3 (venous correlates well with arterial, less invasive)
Bicarbonate	<18 mEq/L
Anion gap	Elevated (from acetoacetate + β-hydroxybutyrate + lactate)
Potassium	Initially normal or HIGH (K+ shifts out of cells in exchange for H+), but total body K+ is DEPLETED
Sodium	Often low (dilutional from osmotic water shift); correct for hyperglycemia
Ketones	Urine ≥2+ or serum β-hydroxybutyrate ≥3 mmol/L
WBC	Elevated even without infection (due to acidosis itself)
Amylase	Often elevated - usually non-pancreatic origin

Key pitfall on ketone testing: Nitroprusside-based strips only detect acetoacetate. β-hydroxybutyrate (the predominant ketone in DKA) does NOT react - so dipstick ketones can be falsely low. Use serum β-hydroxybutyrate when available.

Corrected sodium: For every 100 mg/dL glucose above 100, add 1.6-2.4 mEq/L to measured Na+.

Winter's formula to check respiratory compensation: Expected PaCO₂ = (1.5 × HCO₃⁻) + 8 ± 2

Delta gap (Delta AG - Delta HCO₃):

+6: coexisting metabolic alkalosis
<-6: coexisting hyperchloremic acidosis
Rosen's Emergency Medicine, pp. 2543-2544

Treatment

Treatment has four pillars: fluids, insulin, electrolytes, treat the precipitant.

1. Fluids

Start 0.9% normal saline (even if osmolality is high - NS is still relatively hypotonic)
Rate: 2-4 L in the first 2-4 hours in DKA
Switch to 0.45% NaCl once corrected sodium is normal
Add dextrose (D5 or D10) once glucose falls to 250 mg/dL to allow continued insulin infusion without causing hypoglycemia

2. Potassium (CRITICAL - must be addressed BEFORE insulin)

Serum K+	Action
<3.5 mEq/L	Hold insulin, replace K+ aggressively (20-40 mEq/hr IV)
3.5-5.5 mEq/L	Give 20-40 mEq K+ per liter of IV fluid, start insulin
>5.5 mEq/L	Hold K+ replacement, start insulin, recheck frequently

ECG can help if immediate potassium level unavailable (look for hyperkalemia or hypokalemia signs).

3. Insulin

Fixed-rate IV insulin infusion: 0.1 units/kg/hour
Do NOT give insulin bolus unless glucose >500 mg/dL and no IV access available
If the patient was already on a background long-acting subcutaneous insulin, continue it alongside IV insulin
Once glucose falls to 250 mg/dL AND ketones <1.0 mmol/L: reduce infusion to 0.05 units/kg/hour
Continue IV insulin until the patient can eat AND ketoacidosis is resolved, then overlap with subcutaneous insulin (give subcut dose 1-2 hours before stopping IV)

4. Bicarbonate

Generally NOT recommended unless severe acidosis (pH <6.9) because:
- Paradoxical CNS acidosis
- Worsens hypokalemia
- Delays ketone clearance
If used: 100 mEq NaHCO₃ over 2 hours with 20 mEq KCl

5. Phosphate

Routine replacement not generally recommended
Consider if symptomatic (respiratory weakness, cardiac dysfunction) or phosphate <1.0 mg/dL
Goldman-Cecil Medicine, pp. 2484-2485; Rosen's Emergency Medicine

DKA vs HHS - Key Differences

Feature	DKA	HHS
Glucose	250-800 mg/dL	Often >600 mg/dL (can exceed 1000)
pH	<7.3	>7.3
Bicarb	<18 mEq/L	>18 mEq/L
Ketones	Significant	Absent or trace
Osmolality	Mildly elevated	>320 mOsmol/L
Age/Type	Usually T1DM, younger	Usually T2DM, elderly
Onset	Hours-days	Days-weeks
Treatment	Fluids + insulin from start	Fluids first; insulin when glucose stops falling

Complications to Monitor

Cerebral edema - most feared complication, especially in children; risk increased by rapid correction of osmolality
Hypokalemia - life-threatening, especially after insulin starts
Hypoglycemia - from aggressive insulin without dextrose
ARDS - especially in older adults
Thromboembolic events - from hemoconcentration

Recent Evidence Note

Two recent meta-analyses (2024-2026) are relevant to insulin delivery strategy in DKA:

A 2024 systematic review (PMID: 39090718) compared subcutaneous insulin vs. continuous insulin infusion - subcutaneous regimens showed non-inferior outcomes in selected patients.
A 2026 meta-analysis of RCTs (PMID: 41208563) examined early subcutaneous basal insulin added to IV insulin infusion - supports the practice of overlapping subcutaneous basal insulin early to reduce rebound DKA after infusion discontinuation.

These may update classic IV-only protocols, particularly in stable, mild-moderate DKA in adults.

Chart formate

Here is the DKA content in chart/table format:

DKA - Quick Reference Charts

1. DEFINITION & SEVERITY

Parameter	Mild	Moderate	Severe
Glucose	>250 mg/dL	>250 mg/dL	>250 mg/dL
pH	7.25 - 7.30	7.00 - 7.24	<7.00
Bicarbonate	15-18 mEq/L	10-14 mEq/L	<10 mEq/L
Ketones (urine)	2+	2-3+	3+
Anion gap	>10	>12	>12
Mental status	Alert	Alert/drowsy	Stupor/coma

2. PATHOPHYSIOLOGY AT A GLANCE

Defect	Consequence	End Result
Insulin deficiency + glucagon excess	Lipolysis activated	FFAs → ketones
Hormone-sensitive lipase activated	β-hydroxybutyrate + acetoacetate produced	Anion gap metabolic acidosis
Proteolysis + gluconeogenesis	Hepatic glucose output ↑	Hyperglycemia
Hyperglycemia exceeds renal threshold	Osmotic diuresis	Dehydration + electrolyte loss
Intracellular acidosis	K+ shifts out of cells	Pseudohyperkalemia; total body K+ depleted

3. PRECIPITANTS

Category	Examples
Infection	UTI, pneumonia, sepsis
Insulin issues	Non-adherence, missed doses, pump failure
New diagnosis	First presentation of T1DM
Cardiac	Acute MI, ACS
Drugs	Corticosteroids, SGLT2 inhibitors, clozapine, olanzapine, cocaine, thiazides
Endocrine	Cushing syndrome, thyrotoxicosis, acromegaly
Other	CVA, PE, pancreatitis, burns, alcohol

4. CLINICAL FEATURES

System	Symptoms/Signs
General	Weakness, lethargy, malaise
Metabolic	Polyuria, polydipsia, weight loss
GI	Nausea, vomiting, abdominal pain, ileus
Respiratory	Kussmaul breathing (deep, rapid), fruity breath
Cardiovascular	Tachycardia, orthostatic hypotension
Skin/Mucosa	Dry skin, dry mucous membranes
CNS	Depressed consciousness → coma
Eyes	Reduced JVP, sunken eyes

5. LAB FINDINGS

Test	Expected Finding	Key Pitfall
Glucose	>250 mg/dL (euglycemic DKA possible with SGLT2i)	Can be normal in euglycemic DKA
pH (venous)	<7.30	Venous preferred - less invasive, correlates well
Bicarbonate	<18 mEq/L	Vomiting can mask severity (pseudo-normal)
Anion gap	Elevated (>12)	May be normal if aggressive NS given
Potassium	Normal or HIGH initially	Total body K+ is depleted - will crash with insulin
Sodium	Low (dilutional)	Correct for glucose: +1.6 mEq/L per 100 mg/dL ↑ glucose
Ketones (dipstick)	Positive	Misses β-hydroxybutyrate - use serum BHB
WBC	Elevated	Not always infection - acidosis itself raises WBC
Amylase	Elevated	Usually non-pancreatic - does NOT mean pancreatitis

6. TREATMENT PROTOCOL

Step	Action	Details
1. Fluids	0.9% Normal Saline	2-4 L in first 2-4 hours
	Switch fluid	0.45% NaCl once corrected Na+ is normal
	Add dextrose	D5 or D10 when glucose reaches 250 mg/dL
2. Potassium (check BEFORE insulin)	K+ <3.5 mEq/L	Hold insulin - replace K+ 20-40 mEq/hr first
	K+ 3.5-5.5 mEq/L	Add 20-40 mEq K+ per liter IV fluid, start insulin
	K+ >5.5 mEq/L	Hold K+ replacement, start insulin, recheck q2h
3. Insulin	IV infusion	0.1 units/kg/hour fixed rate
	Reduce rate	When glucose ≤250 AND ketones <1.0 mmol/L → 0.05 units/kg/hr
	Transition	Give subcutaneous dose 1-2 hrs before stopping IV
4. Bicarbonate	Generally avoid	Only if pH <6.9 - risk: CNS acidosis, hypokalemia
5. Phosphate	Usually not needed	Replace only if PO₄ <1.0 mg/dL or symptomatic
6. Precipitant	Identify and treat	Cultures, ECG, imaging as needed

7. POTASSIUM MANAGEMENT FLOWCHART

Check serum K+ FIRST
        |
   ─────┼─────────────────
   |                     |
K+ <3.5               K+ ≥3.5
   |                     |
Hold insulin         Start insulin 0.1 u/kg/hr
Replace K+ aggressively    |
Recheck K+           ─────┼─────────────────
Then start insulin    |                    |
                   K+ 3.5-5.5          K+ >5.5
                   Add 40 mEq/L       Hold K+ in fluids
                   to IV fluids       Recheck q2h

8. DKA vs HHS

Feature	DKA	HHS
Glucose	250-800 mg/dL	>600 mg/dL (often >1000)
pH	<7.30	>7.30
Bicarbonate	<18 mEq/L	>18 mEq/L
Ketones	Significant	Absent/trace
Serum osmolality	Mildly elevated	>320 mOsmol/L
Onset	Hours-days	Days-weeks
Typical patient	T1DM, younger	T2DM, elderly
Initial insulin	Yes, from start	Fluids first; insulin when glucose stops falling
Mortality	~1-5%	~10-20%

9. COMPLICATIONS

Complication	Timing	Notes
Hypokalemia	During treatment	Most common; life-threatening arrhythmias
Hypoglycemia	During treatment	If glucose not monitored hourly
Cerebral edema	During treatment	Most feared in children; from rapid osmolality correction
ARDS	During/after treatment	Especially in elderly
Thromboembolism	During illness	Hemoconcentration promotes clotting
Rebound DKA	After stopping IV insulin	Prevent by overlapping subcutaneous insulin

10. MONITORING FREQUENCY

Parameter	Frequency
Blood glucose	Every 1 hour
Serum K+	Every 2 hours (more frequent if <3.5)
Venous pH / HCO₃	Every 2-4 hours
Serum ketones / BHB	Every 2-4 hours
Fluid balance	Every 1 hour
ECG	Continuous cardiac monitoring

Pathophysiology of dka

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Here is a complete, detailed breakdown of DKA pathophysiology with the official textbook diagram:

Pathophysiology of DKA

Master Diagram (Tintinalli's Emergency Medicine)

The Central Defect

Everything in DKA flows from one root cause:

Insulin deficiency + Counter-regulatory hormone excess (glucagon > catecholamines > cortisol > GH)

Insulin is the body's only anabolic hormone from the pancreas. Without it, the liver, adipose tissue, and skeletal muscle switch from storage mode to breakdown mode. The result is four simultaneous catastrophes: hyperglycemia, ketogenesis, dehydration, and acidosis.

Pathway 1 - HYPERGLYCEMIA

Step	Mechanism
Insulin absent	Cells cannot take up glucose (GLUT-4 not activated in muscle/fat)
Glucagon excess	Activates glycogenolysis (breaks down liver glycogen)
Cortisol + catecholamines	Drive gluconeogenesis (amino acids + glycerol → glucose)
Proteolysis	Releases amino acids → liver → gluconeogenic precursors
Net result	Blood glucose rises far beyond renal T-max (~180 mg/dL)

Key point: Even though glucose floods the bloodstream, cells are starving - "starvation in the midst of plenty." This drives further counter-regulatory hormone release, worsening the cycle.

Pathway 2 - KETOGENESIS

This is the most dangerous pathway and the one that distinguishes DKA from simple hyperglycemia.

Step-by-step:

1. Lipolysis activated

Normally, insulin suppresses hormone-sensitive lipase (HSL) in adipose tissue
With insulin absent, HSL is unrestrained
Triglycerides are cleaved → free fatty acids (FFAs) + glycerol
Glycerol → liver → gluconeogenesis (worsens hyperglycemia)
FFAs → bound to albumin → transported to liver

2. FFAs enter hepatic mitochondria via carnitine shuttle

Malonyl-CoA (which normally blocks the carnitine transferase-1 gate) is LOW in insulin deficiency
FFAs freely enter mitochondria via carnitine acyltransferase-1 (CAT-1)

3. Beta-oxidation produces excess Acetyl-CoA

FFAs are broken down to Acetyl-CoA
Normally Acetyl-CoA enters the TCA cycle
In insulin deficiency, TCA cycle is overwhelmed and oxaloacetate is depleted (diverted to gluconeogenesis)
Excess Acetyl-CoA is shunted to ketogenesis

4. Three ketone bodies produced:

Ketone	Notes
Acetoacetate	Detected by nitroprusside dipstick
β-hydroxybutyrate (BHB)	Predominant ketone in DKA; NOT detected by dipstick
Acetone	Volatile; causes fruity breath; weak dipstick reaction

Ratio of BHB:acetoacetate is normally 1:1; in DKA rises to 3:1 or higher due to excess NADH from beta-oxidation shifting the equilibrium toward BHB.

5. Peripheral ketone utilization also falls

Insulin normally promotes peripheral use of ketones as fuel
Without insulin, brain, cardiac, and skeletal muscle reduce ketone uptake
Combined with increased production → ketonemia accumulates rapidly

Pathway 3 - METABOLIC ACIDOSIS

Source	Contribution to Acidosis
β-hydroxybutyrate	Major contributor to anion gap
Acetoacetate	Second major contributor
Lactate	Minor contributor (from hypoperfusion)
FFAs, phosphates	Minor contributors

Anion gap = Na⁺ - (Cl⁻ + HCO₃⁻) - elevated because unmeasured anions (ketoacids) replace HCO₃⁻

Respiratory compensation: Acidemia stimulates the medullary respiratory center → Kussmaul breathing (deep, rapid) → CO₂ blown off → partially compensates pH

Additional complexity:

Vomiting + loss of HCl → concurrent metabolic alkalosis can mask severity
Aggressive NS resuscitation → hyperchloremic (non-AG) acidosis superimposed
Ketonuria = loss of HCO₃⁻ equivalents (ketoanions excreted = potential bicarb lost); chloride retained in exchange

Pathway 4 - DEHYDRATION & ELECTROLYTE CHAOS

Osmotic Diuresis Cascade:

Hyperglycemia
    ↓
Glucose exceeds renal T-max → Glycosuria
    ↓
Osmotic diuresis (glucose in tubules drags water + electrolytes)
    ↓
Loss of: Na+, K+, Mg2+, PO4³⁻, Ca2+, Cl⁻ (5-10 L fluid lost)
    ↓
Volume depletion → ↓GFR → Less glucose excreted → Worse hyperglycemia
    ↓
Hemoconcentration → Further osmolality ↑

RAAS Activation:

Volume depletion activates renin-angiotensin-aldosterone system
Aldosterone causes further renal K+ wasting (on top of osmotic diuresis losses)
This is why total body K+ is massively depleted even when serum K+ appears normal or high

Potassium Paradox (the most clinically dangerous electrolyte):

Phase	Serum K+	Total Body K+	Why
Presentation	Normal or HIGH	DEPLETED	Acidosis drives K+ out of cells (H+/K+ exchange); insulin lack impairs cellular uptake
After insulin given	DROPS RAPIDLY	Already depleted	Insulin drives K+ back into cells; ongoing urinary losses
Risk	False reassurance → life-threatening hypokalemia

Sodium Paradox:

Measured Na+ is often LOW (dilutional - hyperglycemia draws water from cells into plasma)
Correct: add 1.6 mEq/L to measured Na+ for every 100 mg/dL glucose >100
True Na+ is actually higher than measured

Pathway 5 - VASCULAR & PROSTAGLANDIN EFFECTS

A less-known but important mechanism:

As adipose tissue breaks down, prostaglandins I₂ and E₂ are released
Both cause paradoxical vasodilation despite profound volume depletion
This explains why peripheral vasodilation and flushing can occur even in shock states
Also contributes to nausea, vomiting, and abdominal pain

Why Abdominal Pain Occurs in DKA

Cause	Mechanism
Gastric dysmotility / ileus	Electrolyte imbalance (hypokalemia) + acidosis
Prostaglandin release	From lipolysis
Mesenteric vasodilation	Prostaglandins I₂ and E₂
True pancreatitis	Can be precipitant OR consequence

Important: Amylase is elevated in ~75% of DKA but is usually salivary origin, not pancreatic. Lipase is more specific.

Why Consciousness is Impaired

Factor	Effect on CNS
Hyperosmolarity (from hyperglycemia + dehydration)	Most important determinant of mental status
Intracellular dehydration of neurons	Cellular shrinkage
Acidosis	Impairs neuronal function
Reduced cerebral perfusion	From hypovolemia/shock

Complete Pathophysiology Summary Table

Hormone/Defect	Target Organ	Effect	Clinical Result
↓ Insulin	Liver	↑ Glycogenolysis, ↑ gluconeogenesis	Hyperglycemia
↓ Insulin	Adipose	HSL activation → lipolysis	FFAs → ketones
↓ Insulin	Muscle	↓ Glucose uptake, proteolysis	Amino acids → gluconeogenesis
↑ Glucagon	Liver	↑ Gluconeogenesis, ↑ ketogenesis, ↓ malonyl-CoA	Hyperglycemia + ketosis
↑ Cortisol	Liver/muscle	↑ Proteolysis, ↑ gluconeogenesis	Hyperglycemia
↑ Catecholamines	Adipose	↑ Lipolysis	More FFAs
↑ Growth hormone	Muscle/adipose	Anti-insulin effects	Insulin resistance
Hyperglycemia	Kidney	Osmotic diuresis	Dehydration + electrolyte loss
↓ Volume	RAAS	Aldosterone ↑	Further K+ wasting
Acidosis	All cells	H+/K+ exchange	Pseudohyperkalemia
↓ Insulin + ↓ K+	Muscle/heart	Reduced K+ uptake	Hypokalemia after treatment
Ketoacids	Buffering system	HCO₃⁻ consumed	Anion gap metabolic acidosis
Low pH	Medulla	Respiratory drive ↑	Kussmaul breathing

Tintinalli's Emergency Medicine, p. 1475-1476; Rosen's Emergency Medicine, p. 2542

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