When should dialysis be started for hyperammonemia, including specific plasma ammonia thresholds and clinical signs, and which dialysis modality is preferred?

Dialysis Recommendations for Hyperammonemia

When to Initiate Dialysis

Kidney replacement therapy (KRT) should be initiated urgently when ammonia levels exceed 150 μmol/L (255 μg/dL) in the presence of rapidly deteriorating neurological status, coma, or cerebral edema. 1, 2

Specific Ammonia Thresholds for Dialysis Initiation

• Ammonia >150 μmol/L with neurological deterioration: Immediate CKRT is indicated when patients develop moderate to severe encephalopathy (lethargy, distal flexion, reduced activity, hypotonia, weak suck, constricted pupils, bradycardia) or severe encephalopathy (stupor, coma, absent activity, decerebrate posture, flaccid tone, absent reflexes, non-reactive pupils). 2

• Ammonia 301-499 μmol/L (513-850 μg/dL): Initiate nitrogen-scavenging agents immediately while preparing for dialysis if moderate to severe encephalopathy or seizures are present. 1

• Ammonia >300-400 μmol/L despite medical management: Consider CKRT when levels remain persistently elevated despite nitrogen-scavenging therapy. 1, 2, 3

• Ammonia >400 μmol/L: Do not delay dialysis while waiting for medical management alone, especially with neurological symptoms. 4

• Ammonia ≥600 μg/dL (360 μmol/L): Hemodialysis is indicated to rapidly remove ammonia and mitigate brain damage at this threshold. 5

Clinical Decision Algorithm

The decision to initiate KRT should be based primarily on clinical status rather than rigid ammonia thresholds alone. 2 Key clinical indicators include:

• Presence of encephalopathy (any grade)
• Seizure activity with consistent EEG findings
• Rapid rise in ammonia levels within hours
• Failure to respond to nitrogen-scavenging agents after 2 hours 1

Important caveat: If ammonia levels fail to fall below 150 μmol/L or by more than 40% within 4-8 hours after receiving nitrogen-scavenging therapy, hemodialysis is recommended. 6

Preferred Dialysis Modality

High-dose continuous venovenous hemodialysis (CVVHD) is the first-line preferred modality for severe hyperammonemia when available. 2, 3

CVVHD Technical Parameters

• Blood flow rate (Qb): 30-50 mL/min 2, 3
• Dialysate flow rate (Qd): Aim for Qd/Qb ratio >1.5 2, 3
• Dialysate temperature: Use warmed dialysate to maintain hemodynamic stability 2, 3
• Duration: Continue until ammonia <200 μmol/L on two consecutive hourly measurements 2, 3

Comparative Efficacy of Dialysis Modalities

CVVHD provides superior ammonia clearance compared to other modalities while preserving hemodynamic stability and minimizing rebound hyperammonemia. 2 The clearance rates differ significantly:

• Intermittent hemodialysis (HD): Achieves 50% reduction in ammonia within 1-2 hours, with clearance of 3.95-5.37 mL/min/kg and filtration fraction of 95-96%. 1, 2

• CVVHD: Achieves 50% reduction within 2-14 hours, with clearance of 2.65-6.80 mL/min/kg and filtration fraction of 53-58%. 1

• Continuous arteriovenous hemodialysis (CAVHD): Lower clearance of 0.87-0.97 mL/min/kg with filtration fraction of 12.5-14.3%. 1

Alternative and Hybrid Approaches

Intermittent hemodialysis followed by CKRT (hybrid/sequential therapy) is recommended when rapid ammonia clearance is needed, particularly in hemodynamically unstable neonates. 2, 3 This approach:

• Achieves rapid initial reduction (75% decrease within 3-4 hours) 3
• Prevents rebound hyperammonemia through subsequent CKRT 2
• Maintains hemodynamic stability in critically ill patients 2

Peritoneal dialysis is not recommended as first-line therapy due to inferior ammonia clearance compared to CVVHD and HD. 1

Treatment Goals

• Target ammonia post-KRT: <200 μmol/L (280.1 μg/dL) 1
• Monitoring frequency: Check plasma ammonia every 3-4 hours until normalized 2, 3
• Neurological assessment: Regular evaluation for signs of encephalopathy, cerebral edema (pupillary changes, posturing, bradycardia) 2

Critical Prognostic Factor

The duration of hyperammonemic coma prior to dialysis initiation is the most important prognostic factor for neurological outcome, not the rate of ammonia clearance. 2 This underscores the importance of early recognition and immediate treatment initiation. Despite effective ammonia clearance with dialysis, mortality remains high (25%) in neonatal-onset cases, with only 20% achieving normal outcomes. 7

Common Pitfalls and Caveats

• Sample collection errors: Ammonia samples must be collected from free-flowing venous or arterial blood, transported on ice, and processed within 15 minutes to avoid false elevations. 2, 3, 4

• Delayed dialysis initiation: Waiting for medical management alone at levels >400 μmol/L with neurological symptoms increases risk of irreversible brain damage. 4

• Nitrogen scavenger clearance: Nitrogen-scavenging agents will be dialyzed during CKRT but remain effective when used concurrently. 3

• Prolonged protein restriction: Do not extend protein restriction beyond 48 hours, as this causes catabolism and worsens ammonia levels; reintroduce protein gradually (0.25 g/kg daily increments) when ammonia trends toward 80-100 μmol/L. 2, 4

• Inappropriate use of lactulose: Do not use lactulose for urea cycle disorders or non-hepatic hyperammonemia, as it is ineffective and delays definitive treatment. 4