Diabetic Ketoacidosis (DKA)

Definition / Biochemical Triad

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

Pathophysiology

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

Precipitants

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

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

Clinical Features

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

Diagnosis

Severity Classification

Key Labs

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

Treatment

1. Fluids

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

2. Insulin

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

3. Potassium

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

4. Bicarbonate

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

5. Phosphate

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

6. Magnesium

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

Resolution Criteria (to stop insulin infusion)

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

Complications

DKA vs. HHS (Key Differences)

Recent Evidence (2024-2026)

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

Hyperosmolar Hyperglycemic State (HHS)

Definition

Epidemiology & Risk Factors

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

Pathophysiology

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

Precipitants

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

Clinical Features

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

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

Laboratory Findings

Treatment

Priority Order: Fluids > Electrolytes > Insulin > Find Precipitant

1. Fluids (most important)

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

2. Insulin

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

3. Potassium

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

4. Find and Treat the Precipitant

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

5. Anticoagulation

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

6. Seizures

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

Complications

HHS vs. DKA - Quick Comparison

Organophosphate (OP) Poisoning

Sources & Exposure Routes

• Agricultural insecticides (most common worldwide) - malathion, parathion, chlorpyrifos, fenthion, dichlorvos
• Chemical warfare nerve agents - sarin, soman, tabun, VX (extremely potent; death within minutes)
• Industrial/household pesticides
• Ophthalmologic preparations (echothiophate)

• Ingestion (fastest absorption)
• Inhalation (vapor, aerosol)
• Dermal/transdermal (slowest but clinically important - can cause secondary poisoning of healthcare workers)
• Conjunctival

Mechanism of Toxicity

1. Muscarinic receptors - parasympathetic postganglionic synapses (glands, smooth muscle, heart)
2. Nicotinic receptors - neuromuscular junctions + sympathetic/parasympathetic ganglia + adrenal medulla
3. CNS - central cholinergic pathways

• Soman: ages within minutes
• Sarin: hours
• Most agricultural OPs: hours to days

Clinical Features

SLUDGE / DUMBELS - Muscarinic Effects

Nicotinic Effects (NMJ + Ganglionic)

• Neuromuscular: muscle fasciculations, cramps, weakness → paralysis (including respiratory muscles)
• Ganglionic (sympathetic): pallor, tachycardia, hypertension, mydriasis (can mask miosis)
• Mixed autonomic features are common - parasympathetic usually predominates

CNS Effects

• Anxiety, restlessness, tremor, headache, dizziness
• Confusion, delirium, hallucinations
• Seizures (often refractory)
• Coma

Death is due to: bronchorrhea + respiratory muscle paralysis + CNS depression

Three Temporal Syndromes

Diagnosis

• Clinical - history + cholinergic toxidrome; do NOT wait for labs to start treatment
• Plasma butyrylcholinesterase - easier to measure, more available; depressed up to 50% in asymptomatic exposure; normalizes in 28-42 days (if untreated)
• RBC acetylcholinesterase - more accurate indicator of synaptic inhibition; reduced to 10-20% of normal in moderate poisoning, <10% in severe; recovers over up to 120 days
• Note: cholinesterase levels vary widely between individuals; no single threshold is diagnostic
• ECG: QT prolongation, ST changes, peaked T waves, AV block, torsades de pointes, VF
• Routine labs: may show pancreatitis, hypo/hyperglycemia, leukocytosis, elevated liver enzymes
• CXR: pulmonary edema in severe cases

Treatment

Step 1 - Decontamination (FIRST - protect staff)

• Wear PPE: neoprene or nitrile gloves (NOT latex), gown, eye protection
• Remove ALL clothing (place in sealed plastic bags as hazardous waste)
• Wash skin with copious soap and water including scalp, hair, fingernails, skin folds, conjunctivae
• Decontaminate instruments with chlorine bleach
• Contaminated runoff water = hazardous waste
• Do NOT transport by helicopter (risk of secondary poisoning)

Step 2 - Supportive Care

• 100% oxygen via non-rebreather mask
• Cardiac monitor + pulse oximetry
• IV access with baseline blood sampling
• Gentle suctioning of airway secretions
• Endotracheal intubation if: coma, seizures, respiratory failure, severe bronchospasm, excessive secretions
• Use non-depolarizing NMJ blockers (e.g., rocuronium) for intubation - avoid succinylcholine (metabolized by plasma cholinesterase → prolonged paralysis)
• Hypotension: isotonic crystalloid boluses

Step 3 - ATROPINE (primary antidote)

• Adults: 1.2-3 mg IV initial bolus (based on severity)
• Children: 0.05 mg/kg IV initial bolus
• Double the dose every 5 minutes until atropinization achieved
• Very large ingestions may require 200-500 mg in the first hour - arrange pharmacy backup early
• Maintenance infusion: 10-20% of total loading dose per hour

• ✅ Chest clear on auscultation (dry lungs - bronchorrhea resolved)
• ✅ Heart rate >80 bpm
• ✅ Systolic BP >80 mmHg
• ✅ Reduced secretions, eased respiratory effort

Tachycardia and mydriasis at therapeutic doses are acceptable - NOT a reason to stop atropine. Excessive atropine causes anticholinergic toxidrome (flushing, dry skin, delirium, hyperthermia).

Step 4 - PRALIDOXIME (2-PAM) - Oxime

• Respiratory depression or failure
• Muscle fasciculations
• Seizures
• Dysrhythmias
• Hemodynamic instability
• Requiring large/repeated doses of atropine

• Adults: 1-2 g IV bolus over 30 minutes (can repeat hourly based on response)
• Children: 25-50 mg/kg IV over 30 minutes
• Alternative: 2 g bolus over 20 min → infusion 500 mg/h for up to 7 days
• Can also be given IM (military autoinjectors)

Controversy: Recent evidence has questioned the benefit of pralidoxime in agricultural OP poisoning. The 2026 umbrella review (PMID 42258859) noted ongoing debate about oxime efficacy. Most guidelines still recommend it for moderate-severe cases.

Step 5 - Benzodiazepines (for seizures)

• Diazepam or lorazepam IV for seizure control
• Seizures in OP poisoning are often refractory to phenytoin

Step 6 - Decontamination of GI tract

• Gastric lavage: no proven benefit; if done, must be within 1 hour of large ingestion with airway protected first
• Activated charcoal: no proven clinical benefit
• Hemodialysis/hemoperfusion: no proven value

Glycopyrrolate - Alternative Anticholinergic

Key Drug Cautions in OP Poisoning

OP vs. Carbamate Poisoning - Key Differences

Prognosis

• Severity depends on: specific compound, amount, route, time to treatment
• Fenthion is particularly dangerous - initial symptoms may be mild but progress to life-threatening toxicity as it is released from lipid stores
• Patients stabilized after acute phase still need neurological follow-up for IMS (24-96 h) and delayed neuropathy (7-21 days)
• Suicidal ingestions require psychiatric consultation after medical stabilization