Study guide
10.2 Non-Hepatic Hyperammonemia & Metabolic Encephalopathy
ABIM Critical Care Medicine Study Guide Exam
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1 Chapter 1: Exam Orientation: Format, Blueprint & Study Strategy
1.1 ABIM Critical Care Medicine Exam: Format, Blueprint & Study Strategy
2 Chapter 2: Acute Respiratory Failure & ARDS
2.1 ARDS Definition, Pathophysiology & Phenotypes 2.2 Lung-Protective Mechanical Ventilation 2.3 Refractory ARDS: Prone Positioning, Neuromuscular Blockade & VV-ECMO
3 Chapter 3: Obstructive Airways, Pulmonary Vascular & Pleural Emergencies
3.1 Severe Asthma & COPD Exacerbations in the ICU 3.2 Massive & Submassive Pulmonary Embolism 3.3 Pulmonary Hypertension & Right Ventricular Failure in the ICU 3.4 Massive Hemoptysis, Complex Pleural Effusions & Thoracic Drainage
4 Chapter 4: Airway, Parenchymal & Nonthrombotic Pulmonary Emergencies
4.1 Airway Management, Upper-Airway Obstruction & Artificial-Airway Complications 4.2 Diffuse Alveolar Hemorrhage, Interstitial Lung Disease, Pulmonary Vasculitis & Noncardiogenic Edema 4.3 Severe Community-Acquired & Viral Pneumonia 4.4 Nonthrombotic Embolism (Air, Fat, Amniotic Fluid, Tumor, Septic) & Acute Chest Syndrome
5 Chapter 5: Mechanical Ventilation Modes, Dyssynchrony & Liberation
5.1 Mechanical Ventilator Modes & Advanced Breath Delivery 5.2 Patient-Ventilator Dyssynchrony & Waveform Analysis 5.3 Ventilator Liberation, Spontaneous Breathing Trials & Post-Extubation Support
6 Chapter 6: Shock Syndromes & Hemodynamic Principles
6.1 Shock Classification, Cellular Pathophysiology & Biomarkers 6.2 Hemodynamic Monitoring: Arterial Lines, CVP & Pulmonary Artery Catheter 6.3 Dynamic Assessment of Fluid Responsiveness & Resuscitation Targets
7 Chapter 7: Vasoactive Therapies & Mechanical Circulatory Support
7.1 Vasopressors & Inotropes: Pharmacology & Clinical Titration 7.2 Temporary Mechanical Circulatory Support: IABP, Impella & TandemHeart 7.3 Venoarterial ECMO (VA-ECMO) & Differential Hypoxemia 7.4 Post-Cardiac Arrest Care, Targeted Temperature Management & Neuroprognostication
8 Chapter 8: Acute Kidney Injury & Renal Replacement Therapy
8.1 KDIGO AKI Classification, Etiologies & Diagnostic Evaluation 8.2 Continuous Renal Replacement Therapy (CRRT) vs Intermittent Hemodialysis 8.3 Indications & Timing for RRT in Critical Illness: AKIKI & STARRT-AKI
9 Chapter 9: Electrolyte, Acid-Base & Endocrine Emergencies
9.1 Severe Dysnatremias: Hyponatremia, Hypernatremia & Osmotic Demyelination 9.2 Potassium, Calcium, Magnesium & Phosphate Disorders 9.3 Complex & Mixed Acid-Base Disorders: Boston vs Copenhagen vs Stewart 9.4 Endocrine Crises: DKA, HHS, Thyroid Storm, Myxedema Coma & Adrenal Crisis
10 Chapter 10: Glycemic Control, Hyperammonemia, Pituitary & Adrenal Disorders
10.1 ICU Glycemic Control & Severe Hypoglycemia 10.2 Non-Hepatic Hyperammonemia & Metabolic Encephalopathy 10.3 Pituitary Emergencies, Adrenal Excess & Critical Illness-Related Corticosteroid Insufficiency
11 Chapter 11: Acute Coronary Syndromes & Cardiac Arrhythmias
11.1 Acute Coronary Syndromes & Mechanical Complications of Myocardial Infarction 11.2 Critical Tachyarrhythmias: Atrial Fibrillation with RVR, VT & VF 11.3 Critical Bradyarrhythmias, Conduction Blocks & Temporary Cardiac Pacing
12 Chapter 12: Acute Heart Failure, Valvular & Pericardial Emergencies
12.1 Acute Decompensated Heart Failure & Cardiogenic Pulmonary Edema 12.2 Acute Valvular Regurgitation & Prosthetic Valve Emergencies 12.3 Pericardial Tamponade & Acute Aortic Syndromes
13 Chapter 13: Myocardial Disease, Hypertensive & Cardiac Device Emergencies
13.1 Fulminant Myocarditis, Stress & Peripartum Cardiomyopathy, and Hypertrophic Cardiomyopathy 13.2 Hypertensive Emergencies & Ruptured Abdominal Aortic Aneurysm 13.3 Implanted Cardiac Devices, LVAD Emergencies & Electrical Storm
14 Chapter 14: Sepsis & Systemic Infectious Diseases
14.1 Sepsis-3 Definitions & Surviving Sepsis Campaign 2026 Guidelines 14.2 Refractory Septic Shock & Adjunctive Therapies 14.3 Multidrug-Resistant Pathogens & Antimicrobial Stewardship in the ICU
15 Chapter 15: ICU-Acquired & Severe Focal Infections
15.1 Hospital-Acquired & Ventilator-Associated Pneumonia 15.2 Central Line-Associated Bloodstream Infections & Catheter-Associated UTIs 15.3 Intra-Abdominal Sepsis, Necrotizing Soft Tissue Infections & CNS Infections
16 Chapter 16: Focal, Special-Host & Systemic Infections
16.1 CNS Infections Beyond Bacterial Meningitis: Encephalitis, Brain Abscess & Epidural Abscess 16.2 Infections in the Immunocompromised Host, Tropical & Bioterror Infections 16.3 Infective Endocarditis, Device Infections & Other Focal Cardiovascular Infections 16.4 Antimicrobial Pharmacokinetics, Allergy, Toxicity & Infection Prevention 16.5 Gastrointestinal & Hepatobiliary Infections: Fulminant C. difficile, Typhlitis, CMV Colitis & Abscesses
17 Chapter 17: Neurocritical Care & Coma
17.1 Coma, Altered Mental Status & Acute Delirium in the ICU 17.2 Status Epilepticus & Non-Convulsive Status Epilepticus 17.3 Acute Ischemic Stroke & Intracranial Hemorrhage
18 Chapter 18: Cerebrovascular Syndromes, Encephalopathy & Withdrawal States
18.1 Cerebral Venous Sinus Thrombosis, PRES & Reversible Cerebral Vasoconstriction Syndrome 18.2 Alcohol & Sedative Withdrawal, Wernicke Encephalopathy & Drug-Induced Encephalopathy
19 Chapter 19: Intracranial Hypertension & Neuromuscular Weakness
19.1 Intracranial Pressure Monitoring, Cerebral Perfusion & Tiered ICP Management 19.2 Acute Neuromuscular Respiratory Failure, ICU-Acquired Weakness & Brain Death Determination
20 Chapter 20: Traumatic Brain Injury, Spinal Cord Injury & Toxin-Mediated Paralysis
20.1 Traumatic Brain Injury Management & Paroxysmal Sympathetic Hyperactivity 20.2 Acute Spinal Cord Injury, Neurogenic Shock & Autonomic Dysreflexia 20.3 Toxin-Mediated Paralysis & Neuromuscular Crises: Botulism, Tetanus, Tick Paralysis & Myasthenic Crisis
21 Chapter 21: Gastrointestinal, Hepatic & Abdominal Emergencies
21.1 Acute Upper & Lower Gastrointestinal Bleeding in the ICU 21.2 Acute Liver Failure & Severe Acute Pancreatitis 21.3 Abdominal Compartment Syndrome & Acute Mesenteric Ischemia
22 Chapter 22: Luminal GI Emergencies & Complications of Cirrhosis
22.1 Esophageal, Gastric & Bowel Emergencies: Perforation, Obstruction, Ogilvie Syndrome & Colonic Ischemia 22.2 Complications of Cirrhosis: Alcohol-Associated Hepatitis, Hepatorenal Syndrome & Pulmonary Vascular Syndromes
23 Chapter 23: Trauma, Burns & Perioperative Critical Care
23.1 Polytrauma Resuscitation, Damage Control & Massive Transfusion 23.2 Severe Burn Injury, Inhalation Injury & Environmental Emergencies 23.3 Perioperative Critical Care for High-Risk Surgical Patients
24 Chapter 24: Thoracic Trauma, Environmental Injury & Obstetric Critical Care
24.1 Thoracic Trauma: Flail Chest, Pulmonary Contusion, Great Vessel & Tracheobronchial Injury 24.2 Environmental Injury: Drowning, Diving, Altitude, Heat, Cold, Electrical & Radiation 24.3 Obstetric & Genitourinary Emergencies and the Physiology of Pregnancy
25 Chapter 25: Transplantation, Donor Management & Post-Cardiac Surgery Care
25.1 Solid Organ Transplant Recipients & Deceased Donor Management 25.2 Post-Cardiac Surgery Critical Care: Bleeding, Tamponade, Low Output & Vasoplegia
26 Chapter 26: Hematologic Emergencies, Toxicology, Critical Ultrasound & ICU Liberation
26.1 Hematologic Emergencies in the ICU: HIT, DIC, TMA & Anticoagulant Reversal 26.2 Critical Care Toxicology, Toxidromes & Specific Antidotes 26.3 Critical Care Point-of-Care Ultrasound (POCUS) 26.4 ICU Liberation, Analgosedation, Goals of Care & Critical Care Ethics
27 Chapter 27: Transfusion Medicine, Hematologic & Oncologic Disorders
27.1 Transfusion Medicine: Products, Thresholds, Reactions & Apheresis 27.2 Red and White Cell Disorders, Hemoglobinopathies, Factor Deficiencies & Hypercoagulable States 27.3 Oncologic Emergencies, Hematopoietic Cell Transplant Complications & Cellular Therapy Toxicity
28 Chapter 28: Clinical Pharmacology, Adverse Drug Reactions & Specific Poisonings
28.1 Pharmacokinetic Principles, Dose Adjustment & Drug Interactions in Critical Illness 28.2 Adverse Drug Reactions: Anaphylaxis, Severe Cutaneous Reactions & Hyperthermic Syndromes 28.3 Specific Poisonings: Sodium-Channel Blockers, Lithium, Valproate, Theophylline, Iron, Sulfonylureas & Methemoglobinemia
29 Chapter 29: Ethics, Research Methods, Administration & Abdominal Ultrasound
29.1 Advance Care Planning, Nonbeneficial Treatment, Informed Consent & Confidentiality 29.2 Critical Care Research Methods, Statistics, IRB Oversight & Quality Improvement 29.3 Abdominal, Vascular & Procedural Point-of-Care Ultrasound
10.2 Non-Hepatic Hyperammonemia & Metabolic Encephalopathy
Key Takeaways Explain This Topic AI
Valproate-induced hyperammonemic encephalopathy can occur with normal liver enzymes and a therapeutic valproate level; treatment is drug withdrawal plus L-carnitine 100 mg/kg IV.
An ammonia level above roughly 150 to 200 micromoles per liter with encephalopathy is treated as a neurologic emergency, because sustained elevation causes cerebral edema.
High-flux intermittent hemodialysis clears ammonia faster than continuous kidney replacement therapy and is preferred for life-threatening levels when hemodynamics allow.
Nitrogen scavenger therapy uses sodium phenylacetate with sodium benzoate; carglumic acid is specific for N-acetylglutamate synthase deficiency and valproate toxicity.
Ammonia samples must be drawn without a tourniquet or fist clenching, placed on ice, and run promptly, because delays and hemolysis falsely elevate the result.
Last updated: October 2026
When Ammonia Is High and the Liver Looks Normal
Ammonia is produced by gut bacteria and by glutamine metabolism in enterocytes and kidney, and it is cleared by the hepatic urea cycle. Encephalopathy follows when astrocytes convert ammonia and glutamate into glutamine, which acts as an osmolyte and causes astrocyte swelling, raised intracranial pressure, and impaired neurotransmission.
Non-hepatic causes to recognize :
Category Mechanism and clues
Valproate Inhibits carbamoyl phosphate synthetase I and depletes carnitine. Encephalopathy occurs with normal transaminases and a therapeutic level; risk rises with topiramate, phenobarbital, and carnitine deficiency
Urea cycle disorders Partial ornithine transcarbamylase deficiency is the commonest in adults, often unmasked by postpartum state, surgery, steroids, high protein load, or starvation. Look for a respiratory alkalosis with a normal anion gap and low BUN, with a family history of unexplained encephalopathy
Urinary diversion Ureterosigmoidostomy or an obstructed ileal conduit lets urease-splitting bacteria return ammonia to the circulation
Urease-producing infection Proteus , Klebsiella , Corynebacterium urealyticum , and Ureaplasma (hyperammonemia syndrome after lung transplantation)
Post-bariatric and nutritional Gastric bypass with protein malnutrition, zinc deficiency, and small-bowel bacterial overgrowth
High nitrogen load Massive transfusion, total parenteral nutrition, gastrointestinal bleeding, severe catabolism, seizures, and rhabdomyolysis
Drugs and toxins Glycine from transurethral irrigation, asparaginase, salicylates, carbonic anhydrase inhibitors, 5-fluorouracil, glufosinate
Organ failure Portosystemic shunt with preserved synthetic function (including congenital shunts and post-TIPS), severe heart failure
Measuring Ammonia Correctly
Pre-analytic error is common and causes needless treatment:
Draw without a tourniquet and without fist clenching, because muscle releases ammonia.
Avoid hemolysis; erythrocytes contain far more ammonia than plasma.
Place the sample on ice and run it within about 15 to 20 minutes.
Note that the degree of elevation correlates poorly with encephalopathy in chronic liver disease but correlates strongly in acute, non-hepatic hyperammonemia.
Emergency Management
Treat an ammonia level above about 150 to 200 micromoles per liter with encephalopathy, or any rapidly rising level, as an emergency.
Stop all nitrogen intake : hold protein and amino acid infusions for 24 to 48 hours, then reintroduce protein at a low dose to avoid driving catabolism.
Stop the offending drug : valproate, topiramate, and asparaginase.
Reverse catabolism : give dextrose 10% with insulin as needed (aim for roughly 1.5 times basal calories) and intralipid, because starvation breaks down muscle and generates nitrogen.
Nitrogen scavengers :
Sodium phenylacetate and sodium benzoate (for example, Ammonul) conjugate glycine and glutamine for renal excretion. Watch for hypokalemia and volume overload.
L-arginine or citrulline supports urea cycle flux in specific enzyme defects.
Carglumic acid replaces N-acetylglutamate, the activator of carbamoyl phosphate synthetase I. It is specific for N-acetylglutamate synthase deficiency and is used in valproate-induced hyperammonemia.
L-carnitine 100 mg/kg IV (then 15 mg/kg every 4 to 6 hours) for valproate toxicity.
Extracorporeal clearance : ammonia is a small, water-soluble molecule that dialyzes efficiently.
High-flux intermittent hemodialysis has the highest clearance and is preferred for life-threatening levels when hemodynamics allow.
CRRT follows for ongoing control and in unstable patients.
Lactulose and rifaximin act slowly on gut production and are not adequate alone for severe non-hepatic hyperammonemia.
Neuroprotection : treat raised intracranial pressure, avoid hyponatremia and hyperthermia, control seizures, and keep the head elevated.
Find the cause : plasma amino acids, urine orotic acid and organic acids, acylcarnitine profile, valproate and carnitine levels, urine culture for urease producers, and imaging for portosystemic shunts.
Orotic acid helps separate urea cycle defects: it is high in ornithine transcarbamylase deficiency and low in carbamoyl phosphate synthetase I and N-acetylglutamate synthase deficiency .
Other Metabolic Encephalopathies in the ICU
Cause Discriminating features Treatment
Uremic encephalopathy Asterixis, myoclonus, seizures with severe azotemia Kidney replacement therapy; avoid rapid correction in severe azotemia (dialysis disequilibrium)
Hypoglycemia Rapid onset, focal deficits possible Dextrose; thiamine first if malnourished
Hyponatremia or hypernatremia Rate of change matters more than the number Controlled correction (see the dysnatremia section)
Hypercapnia Headache, somnolence, papilledema Improve ventilation; avoid oxygen-induced hypoventilation in chronic hypercapnia
- Thiamine deficiency (Wernicke) Confusion, ophthalmoparesis, ataxia High-dose IV thiamine before glucose
- Hypothyroid or adrenal crisis Hypothermia, hypoglycemia, hyponatremia Hormone replacement
- Hypercalcemia Confusion, constipation, polyuria Saline, calcitonin, bisphosphonate
Cefepime neurotoxicity Myoclonus, nonconvulsive status, kidney impairment with unadjusted dosing Stop the drug; dialysis in severe cases
Serotonin syndrome or neuroleptic malignant syndrome Hyperthermia with specific motor signs See the toxicology sections
The practical rule in the ICU is to measure what is correctable (glucose, sodium, calcium, ammonia, CO2, thyroid and cortisol when suspected), screen for drugs, and get an EEG early, because nonconvulsive status epilepticus mimics metabolic encephalopathy.