What is the most likely cause of headache, nausea, irritability, confusion, and combativeness in a patient with chronic kidney disease (CKD) on hemodialysis (HD) who recently resumed treatment after a 2-week hiatus?

Dialysis Disequilibrium Syndrome

The most likely diagnosis is Dialysis Disequilibrium Syndrome (DDS), given the temporal relationship of neurological symptoms (headache, nausea, irritability, confusion, combativeness) occurring on the third hospital day after aggressive hemodialysis in a severely uremic patient who missed dialysis for 2 weeks. 1, 2

Clinical Context Supporting DDS

This patient presents with classic risk factors for DDS:

• Severe baseline uremia with BUN 127 mg/dL and creatinine 11 mg/dL after missing 2 weeks of dialysis 2, 3
• Aggressive initial dialysis with 4-hour session achieving significant solute removal (evidenced by symptom improvement post-HD) 4
• Severe metabolic acidosis (pH 7.03, HCO3 9) at presentation, which predisposes to DDS through cerebrospinal fluid acidosis mechanisms 3
• Timing of symptoms appearing on day 3 during the pre-HD period, consistent with cumulative cerebral edema from repeated dialysis sessions 1, 2

Pathophysiology

DDS results from cerebral edema caused by:

• Reverse urea effect: Dialysis removes urea faster from blood than from brain tissue, creating an osmotic gradient that draws water into the brain 2, 5
• Cerebrospinal fluid acidosis: Rapid correction of systemic acidosis (from pH 7.03 to 7.36 post-HD) causes paradoxical brain pH lowering, displacing Na+ and K+ from organic anions and making them osmotically active 2, 5
• Idiogenic osmoles: The brain produces osmoles in response to chronic hyperosmolar states; rapid dialysis-induced osmolality reduction causes water shift into brain tissue 2

Why Not the Other Options

Uremic encephalopathy (Option A) is unlikely because:

• Symptoms improved immediately post-HD on day 1, indicating uremia was adequately treated 1
• Uremic encephalopathy would worsen with missed dialysis but improve with treatment, not develop after treatment 6

Hyponatremia (Option B) is unlikely because:

• Baseline sodium was 134 mmol/L (only mildly low) 3
• No evidence of severe hyponatremia that would cause acute neurological deterioration 3
• DDS can occur even with normal sodium levels due to urea disequilibrium 1

Depression (Option C) is implausible because:

• Acute onset of confusion and combativeness represents delirium, not depression 6
• Depression does not cause acute altered mental status or combativeness 6
• The temporal relationship to dialysis points to a dialysis-related complication 1, 2

Critical Management Points

Immediate actions required:

• Reduce dialysis intensity: Shorten subsequent HD sessions to 25-30% of normal duration, lower blood flow rates, or use less efficient dialyzers 2, 4
• Increase dialysis frequency: Provide more frequent but gentler treatments rather than aggressive sessions 2, 4
• Raise blood osmolality: Consider mannitol or hypertonic saline to counteract cerebral edema if symptoms are severe 2
• Anticonvulsant prophylaxis: Administer if patient is at high risk for seizures given the severity of presentation 2
• Consider alternative modalities: Switch to continuous renal replacement therapy (CVVH/CVVHDF) or peritoneal dialysis, which have lower risk of DDS 4, 5

Critical Pitfalls to Avoid

• Do not continue aggressive dialysis in severely uremic patients—this is the primary cause of DDS 2, 3
• Do not assume symptoms are psychiatric or behavioral—combativeness and confusion in this context represent cerebral edema and can progress to seizures, coma, and death 1, 3
• Do not delay intervention—severe DDS can cause irreversible brain injury and death within hours 3
• Do not overlook severe metabolic acidosis (pH 6.95-7.03) as a major risk factor requiring especially gentle initial dialysis 3

Prognosis

Death from DDS is rare in adults but has been documented, particularly when severe uremia is combined with aggressive dialysis and severe acidosis 3. The urea reduction ratio of 71% in this patient's first session was excessive for someone with BUN >125 mg/dL 3. Early recognition and immediate reduction of dialysis intensity are essential to prevent progression to seizures, coma, or death 1, 2, 4.