Diabetic Ketoacidosis and HHS

Precipitants grouped by mechanism (the classic "I"s)

• Infection: the single most common precipitant of both DKA and HHS, especially pneumonia and urinary tract infection; sepsis raises cortisol and catecholamines, amplifying counter-regulatory drive against insulin
• Insulin deficiency or omission: missed doses, insulin pump/infusion-set failure (no subcutaneous depot, so ketosis develops within hours), new-onset type 1 diabetes presenting de novo as DKA, or cost-related rationing
• Ischemia/infarction: myocardial infarction, stroke, mesenteric ischemia, and pancreatitis — stress hormone surges; an MI may be silent in autonomic neuropathy, so the ADA advises a low threshold for ECG and troponin in older patients
• Iatrogenic and drug-related: glucocorticoids, thiazides, atypical antipsychotics, sympathomimetics, and immune checkpoint inhibitors (which can cause fulminant autoimmune diabetes); SGLT2 inhibitors cause euglycemic DKA by promoting glucosuria and glucagon secretion while masking hyperglycemia — the ADA Standards of Care recommend holding them several days before elective surgery and during acute illness
• Intoxication and physiologic stress: alcohol, cocaine, pregnancy (accelerated starvation plus placental insulin resistance makes DKA occur at lower glucose levels), trauma, and burns

Non-modifiable risk factors

• Type 1 diabetes and prior DKA: a previous episode is the strongest single predictor of recurrence
• Age extremes: children/adolescents skew toward DKA; elderly patients with limited thirst access and impaired renal concentrating ability skew toward HHS
• Ketosis-prone type 2 diabetes: disproportionately affects Black and Hispanic patients, who may present in DKA yet later be managed without insulin

Modifiable risk factors

• Adherence and access barriers: insulin cost, insurance lapse, health illiteracy, and lack of sick-day rules
• Disordered eating: deliberate insulin omission for weight control, most often in young women with type 1 diabetes
• Substance use, untreated depression, and missed vaccinations (influenza/pneumococcal per ACIP), each of which raises infection or nonadherence risk

• Insulin deficiency or resistance with relative excess of counter-regulatory hormones (glucagon, catecholamines, cortisol, growth hormone) leads to uncontrolled hepatic glucose production and impaired peripheral glucose utilization; in DKA, absolute insulin deficiency predominates, while in HHS, enough insulin remains to suppress lipolysis but insufficient to suppress hyperglycemia

• Hyperglycemia-induced osmotic diuresis causes profound intracellular and extracellular dehydration; the filtered load of glucose exceeds renal reabsorptive capacity (~180 mg/dL threshold), leading to glucosuria and obligate water loss that can total 8-10 liters in DKA and >10 liters in HHS

• Free fatty acid (FFA) mobilization and ketone body production occur in DKA due to unopposed lipolysis; FFAs undergo β-oxidation in hepatic mitochondria to produce acetyl-CoA, which is converted to ketone bodies (acetoacetate, β-hydroxybutyrate, acetone); in HHS, residual insulin is sufficient to partially suppress lipolysis, so ketone production is minimal despite severe hyperglycemia

• Metabolic acidosis develops in DKA as ketone bodies (strong acids) accumulate faster than they can be utilized or excreted, consuming bicarbonate buffer and lowering blood pH; this triggers respiratory compensation via increased minute ventilation (producing Kussmaul respirations)

• Electrolyte abnormalities reflect total body depletion despite variable serum levels: total body potassium deficit averages 3-10 mEq/kg (serum K+ may be normal or high initially due to acidosis-induced shift from intracellular space); sodium and chloride depletion are massive; phosphate and magnesium are severely depleted

• Cerebral edema risk, particularly in pediatric DKA, results from osmotic shifts and inflammatory cytokine release; rapid correction of hyperglycemia lowers serum osmolality faster than brain osmolytes equilibrate, causing water influx into the intracellular space

• Classic DKA triad: polyuria and polydipsia (hours to days), rapid deep respirations (Kussmaul breathing—often described as "fruity" smell from acetone), and altered mental status ranging from lethargy to coma; patients often present with nausea, vomiting, and abdominal pain

• HHS presentation: insidious onset over days to weeks with progressive dehydration, confusion, weakness, and altered mental status; notably absence of Kussmaul respirations and normal or mildly acidotic pH; more common in elderly patients with undiagnosed or poorly controlled type 2 diabetes often precipitated by infection or medication non-compliance

• Physical examination findings: signs of marked dehydration (dry mucous membranes, poor skin turgor, hypotension, tachycardia), hypothermia (despite absence of sepsis suggesting impaired thermoregulation), fruity breath odor in DKA, and potential focal neurological deficits or seizures from hyperosmolarity in HHS

• Important clinical pearls: DKA can present with relatively mild hyperglycemia (sometimes <300 mg/dL in euglycemic DKA associated with SGLT2 inhibitors); HHS often presents with glucose >600 mg/dL and profound osmolality (>320 mOsm/kg); both can coexist ("double diabetes")

• DKA diagnostic criteria: (1) arterial or venous pH <7.30 (or serum bicarbonate <18 mEq/L), (2) elevated anion gap metabolic acidosis, (3) elevated serum or urine ketones, (4) hyperglycemia (usually >250 mg/dL, though may be <200 mg/dL in euglycemic DKA), and (5) clinical context of diabetes or newly presenting diabetes; severity classified as mild (pH 7.25-7.30), moderate (pH 7.15-7.24), or severe (pH <7.15)

• HHS diagnostic criteria: (1) serum glucose >600 mg/dL (often >1000 mg/dL), (2) serum osmolality >320 mOsm/kg, (3) pH >7.30 with serum bicarbonate >15 mEq/L (minimal or no acidosis), (4) absent or small serum/urine ketones, and (5) altered mental status

• Laboratory workup essential for both: basic metabolic panel (BMP) for glucose, electrolytes (particularly K+, Na+, Cl−), renal function; venous or arterial blood gas for pH and bicarbonate; serum or urine ketones; serum osmolality (calculated osmolality = 2[Na+] + glucose/18 + BUN/2.8); anion gap = [Na+] − ([Cl−] + [HCO3−]); elevated anion gap confirms metabolic acidosis; beta-hydroxybutyrate preferred over acetoacetate for detecting ketosis as it's the predominant ketone

• ECG monitoring essential: hyperkalemia may show peaked T waves, prolonged PR interval, or widened QRS; hypokalemia shows U waves and ST depression; critical for detecting cardiac arrhythmias

• Aggressive fluid resuscitation—first priority: Initial bolus of 0.9% normal saline at 15-20 mL/kg IV (or ~1-1.5 L over first hour) to restore intravascular volume and improve renal perfusion; follow with hypotonic fluid (0.45% saline) once serum sodium normalized or rising; fluid deficit often 6-10 L, requiring 24-48 hours total replacement; goal is to lower serum osmolality gradually (no faster than 3-4 mOsm/kg/hour to avoid cerebral edema)

• Insulin therapy (after K+ >3.3 mEq/L): IV regular insulin 0.1 units/kg bolus followed by 0.1 units/kg/hour continuous infusion; increase by 2-3 units/hour every 1-2 hours if glucose not falling by 50-75 mg/dL/hour; once glucose reaches 200-250 mg/dL, decrease insulin infusion to 0.02-0.05 units/kg/hour and switch IV fluids to dextrose-containing solution (D5 in 0.45% saline) to prevent hypoglycemia while continuing to lower ketones and correct acidosis

• Potassium replacement critical: Do NOT give insulin until K+ is >3.3 mEq/L due to risk of severe hypokalemia and cardiac arrhythmias from transcellular shift; add 20-40 mEq K+ to each liter of IV fluid once K+ <5.5 mEq/L and patient is urinating; target serum K+ 4-5 mEq/L; monitor closely every 2-4 hours initially

• Sodium bicarbonate for pH <6.9 (severe acidemia): administer 100 mEq NaHCO3 in 400 mL of sterile water with 20 mEq KCl IV over 2 hours; recheck pH and repeat if needed; controversial below pH 6.9 due to risk of hypokalemia, but prevents cardiovascular complications of severe acidosis; NOT recommended for pH >7.15

• Phosphate and magnesium replacement: add 20-30 mEq phosphate (as potassium phosphate) to fluids; generally replace magnesium if severe depletion; careful with phosphate administration as hyperphosphatemia can develop

Complications of the disease itself

• Cerebral edema (emergency): predominantly pediatric DKA; osmotic disequilibrium plus cytokine-mediated blood–brain barrier injury drives water into brain cells. Signals are headache, recurrent vomiting, incontinence, and the Cushing response (bradycardia with hypertension) with declining mental status hours into therapy. ISPAD guidance is to treat immediately with hyperosmolar therapy (mannitol or hypertonic saline) — imaging must not delay treatment
• Thrombosis (emergency): hyperviscosity and dehydration, most pronounced in HHS, predispose to stroke, MI, and venous thromboembolism; new focal deficits or unilateral leg swelling are the tells
• Rhabdomyolysis and acute kidney injury: extreme hyperosmolality plus hypoperfusion; suspect with markedly elevated CK or disproportionate hyperkalemia and dark urine
• Aspiration pneumonitis: gastroparesis and depressed sensorium; obtunded patients warrant airway protection
• Rhino-orbital-cerebral mucormycosis (emergency): acidosis frees iron from transferrin, feeding Rhizopus; look for black necrotic turbinate eschar, facial pain, and ophthalmoplegia — surgical debridement plus amphotericin B

Complications of treatment

• Hypokalemia (emergency): insulin and bicarbonate drive K⁺ intracellularly on top of a large total-body deficit; manifests as flattened T waves, U waves, and ventricular arrhythmia. This is why potassium precedes insulin
• Hypoglycemia: from failure to add dextrose once glucose approaches 200–250 mg/dL while the insulin infusion continues to clear ketones
• Hyperchloremic non-anion-gap acidosis: expected after large-volume normal saline and ketoanion loss in urine; bicarbonate stays low while the gap closes — recognize it rather than escalating therapy
• Recurrent ketoacidosis: stopping the insulin infusion before the anion gap closes, or without overlapping subcutaneous insulin
• Volume overload/pulmonary edema and ARDS: aggressive fluids in cardiac or renal impairment; rising oxygen requirement is the clue

• Potassium before insulin: if K⁺ is <3.3 mEq/L, the single best next step is potassium repletion and fluids — not the insulin drip. Insulin drives K⁺ intracellularly and can precipitate fatal arrhythmia in a patient whose "normal" serum K⁺ hides a several-hundred-mEq total-body deficit
• Correct the sodium: hyperglycemia pulls water into the vascular space, producing dilutional pseudohyponatremia. Add roughly 1.6–2.4 mEq/L to measured Na⁺ for every 100 mg/dL of glucose above 100; a rising corrected sodium during therapy is reassuring, not alarming
• β-hydroxybutyrate is the ketone to measure: the urine nitroprusside test detects acetoacetate and acetone but not β-hydroxybutyrate, so it under-reads early severe DKA and paradoxically appears to worsen during treatment as β-hydroxybutyrate is oxidized back to acetoacetate. The ADA/EASD consensus favors direct serum β-hydroxybutyrate for diagnosis and monitoring
• Euglycemic DKA is the association examiners love: an SGLT2 inhibitor user with anion-gap acidosis, ketonemia, and glucose under 250 mg/dL. Treat with insulin and dextrose simultaneously — withholding insulin because the glucose looks acceptable is the trap
• The gap closes before the sugar does: the endpoint of the infusion is resolution of acidosis (closed anion gap, bicarbonate recovered), not a normal glucose. Overlap subcutaneous basal insulin 1–2 hours before stopping IV insulin, or ketosis rebounds
• Common distractors that need no specific therapy: leukocytosis from catecholamine demargination (though a marked left shift or very high count still argues for infection), elevated amylase/lipase without pancreatitis, and diffuse abdominal pain that resolves with correction of acidosis. Conversely, normothermia or hypothermia does not exclude sepsis — fever is often absent from peripheral vasodilation
• Bicarbonate is not routine: reserved for extreme acidemia; indiscriminate use worsens hypokalemia, shifts the oxyhemoglobin curve, and may cause paradoxical CSF acidosis