Immediate Treatment for Hyperammonemia with Lactic Acidosis
For a patient presenting with both hyperammonemia and lactic acidosis, immediately discontinue all oral feeds, stop any metformin or other causative medications, initiate aggressive caloric support with intravenous glucose and lipids, administer nitrogen-scavenging agents, and prepare for urgent kidney replacement therapy while addressing the underlying cause of lactic acidosis. 1, 2
Critical First Steps (Within Minutes)
Discontinue Causative Agents
- Stop metformin immediately if the patient is taking it, as metformin-associated lactic acidosis is characterized by elevated blood lactate (>5 mmol/L) and metformin plasma levels >5 mcg/mL 2
- Discontinue all oral protein intake to reduce nitrogen load and prevent further ammonia production 1, 3
- Review all medications for other potential causes of lactic acidosis, including epinephrine, albuterol, and nucleoside reverse transcriptase inhibitors 4
Immediate Metabolic Support
- Start intravenous glucose at 8-10 mg/kg/min to prevent protein catabolism, which would worsen ammonia production 1, 3
- Provide intravenous lipids starting at 0.5 g/kg daily (up to 3 g/kg daily) for adequate caloric support 1, 5
- Target total caloric intake of ≥100 kcal/kg daily to prevent endogenous protein breakdown 1, 3
Pharmacological Interventions
Nitrogen-Scavenging Agents (Administer Immediately)
- Intravenous sodium benzoate: 250 mg/kg for body weight <20 kg; 5.5 g/m² for body weight >20 kg 1, 3
- Intravenous sodium phenylacetate: 250 mg/kg for body weight <20 kg; 5.5 g/m² for body weight >20 kg 1, 3
- Administer as bolus over 90-120 minutes followed by continuous infusion over 24 hours 3
Urea Cycle Support
- Intravenous L-arginine hydrochloride dosing depends on the specific urea cycle disorder 1, 5:
- For OTC and CPS deficiencies: 200 mg/kg (body weight <20 kg) or 4 g/m² (body weight >20 kg)
- For ASS and ASL deficiencies: 600 mg/kg (body weight <20 kg) or 12 g/m² (body weight >20 kg)
Additional Therapy for Organic Acidemias
- L-carnitine: 50 mg/kg loading dose over 90 minutes, then 100-300 mg/kg daily if organic acidemia is suspected 3, 5
- Note: L-carnitine is NOT indicated for urea cycle disorders 5
Kidney Replacement Therapy (Prepare Immediately)
Indications for Urgent Dialysis
Initiate kidney replacement therapy immediately if any of the following are present 1, 3:
- Ammonia levels >300-400 μmol/L despite medical therapy
- Ammonia levels >150 μmol/L with rapidly deteriorating neurological status, coma, or cerebral edema
- Moderate to severe encephalopathy at any ammonia level
- Persistent ammonia levels >400 μmol/L refractory to medical measures
Preferred Dialysis Modality
High-dose continuous venovenous hemodialysis (CVVHD) is first-line for hemodynamically unstable patients 1, 3:
- Blood flow rate (Qb): 30-50 mL/min
- Dialysate flow rate to blood flow rate ratio (Qd/Qb): >1.5
- Use warmed dialysate to maintain hemodynamic stability
- Continue until ammonia <200 μmol/L on two consecutive hourly measurements
Intermittent hemodialysis is preferred for rapid ammonia clearance in hemodynamically stable patients 1, 3:
- Achieves 50% reduction in ammonia within 1-3 hours
- More effective than CVVHD for rapid clearance (75% reduction within 3-4 hours) 3
- Risk of post-dialytic ammonia rebound; consider transitioning to CVVHD afterward
Special Consideration for Metformin-Associated Lactic Acidosis
- Prompt hemodialysis is specifically recommended for metformin-associated lactic acidosis, as metformin is dialyzable with clearance up to 170 mL/min under good hemodynamic conditions 2
- Hemodialysis corrects the acidosis, removes accumulated metformin, and has resulted in reversal of symptoms and recovery 2
Management of Lactic Acidosis Component
Address Underlying Cause
- Treating the underlying cause is the only warranted intervention for lactic acidosis 6, 7
- Identify and correct tissue hypoxia (Type A lactic acidosis): circulatory, pulmonary, or hemoglobin transfer disorders 8
- Rule out liver disease, thiamine deficiency, or drugs inhibiting gluconeogenesis 8
Bicarbonate Therapy (Use with Extreme Caution)
- Sodium bicarbonate administration does NOT improve cardiovascular function or reduce mortality in lactic acidosis 7
- Bicarbonate can worsen outcomes by: 8, 7
- Increasing lactate production
- Generating excess CO₂ with intracellular acidification
- Reducing serum calcium concentration
- If bicarbonate is used despite these concerns, consider hyperventilation and calcium supplementation to mitigate adverse effects 7
Monitoring Protocol
Frequent Laboratory Assessment
- Check plasma ammonia levels every 3-4 hours until normalized 1, 3
- Ensure proper ammonia sample collection: free-flowing venous or arterial blood, transported on ice, processed within 15 minutes 1, 3
- Monitor lactate levels, arterial blood gases, and anion gap serially 2
- Monitor electrolytes closely, especially during CKRT 1, 5
Neurological Monitoring
- Assess Glasgow Coma Scale and neurological status regularly for signs of encephalopathy 3
- Monitor for cerebral edema: pupillary changes, posturing, bradycardia 1
Critical Pitfalls to Avoid
Time-Dependent Neurological Damage
- The duration of hyperammonemic coma prior to dialysis is the most important prognostic factor, NOT the rate of ammonia clearance 1
- Delayed recognition and treatment leads to irreversible neurological damage 1, 3
- Treat aggressively and immediately; do not wait for confirmatory testing
Protein Reintroduction
- Do NOT prolong protein restriction beyond 48 hours, as this causes catabolism and paradoxically worsens ammonia levels 1, 3
- Begin reintroducing protein at 0.25 g/kg daily increments when ammonia trends toward 80-100 μmol/L 1
- Target 1.5 g/kg daily as tolerated 1, 5
Concurrent Therapy During Dialysis
- Nitrogen scavengers will be partially removed during CKRT but remain effective when used concurrently 3, 5
- Continue pharmacological therapy throughout dialysis 3