Neonatal hyperammonemia is a critical illness with clinical manifestations of acute metabolic decompensated encephalopathy. A dramatic increase in blood ammonia levels can cross the brain barrier causing elevated extracellular potassium and increased glutamine synthesis in the brain. These changes together lead to increased intracellular osmotic pressure, brain edema, and release of inflammatory cytokines, resulting in irreversible damage to the brain, which can lead to intractable seizures, cognitive and motor deficits, cerebral palsy and even death in neonates. The duration of coma and the degree of hyperammonemia in hyperammonemic neonates are the most critical factors affecting their neurological prognosis. Therefore, it is crucial to recognize hyperammonemia in a timely manner and provide aggressive and effective treatment. Based on published case reports and retrospective studies of children aged 1 day to 7 years, the PCRRT Working Group issued a guideline for the treatment of neonatal and pediatric hyperammonemia by non-kidney replacement therapy (NKRT) and kidney replacement therapy (KRT), recommending CKRT specifically high-dose CVVHD as the first-line treatment for acute hyperammonemia. In this study, all 6 neonates had severe hyperammonemia and neurological manifestations such as impaired consciousness and convulsions during the course of their illness. We immediately started CRRT and adopted the CVVHDF mode to remove blood ammonia. A gradual return of consciousness was observed in all 6 neonates and the blood ammonia decreased to 137.33 ± 70.32µmol/L. In addition, by increasing the dialysis rate of CRRT, the rate of decline in blood ammonia was also increased. A pearson correlation analysis revealed a significant positive correlation between the dialysis rate and the rate of decrease in blood ammonia. Spinale corroborated this view, using a higher dialysis rate of CRRT (8000 ml/h/1.73m2, 4 times higher than the normal dialysate/replacement rate used for acute kidney injury) to efficiently and safely treat 2 neonates with OTCD. In a retrospective study by Markham, CRRT at the same dialysis rate was also successful in treating two neonates with hyperammonemia. Therefore, in neonates with severe hyperammonemia, high-clearance CRRT should be used to rapidly reduce blood ammonia levels in the early stages to reduce adverse neurological prognosis.