continuous renal replacement therapy intensity in hyperammonemia

Conditions: Acute Liver Failure; Acute on Chronic Liver Failure (ACLF); Acute Kidney Injury; Ammonia Metabolism

Summary: acute liver failure (alf) and acute-on-chronic liver failure (aclf) are life-threatening conditions often associated with hyperammonemia, hepatic encephalopathy, and multi-organ dysfunction. ammonia plays a central role in the pathogenesis of cerebral edema and neurotoxicity. continuous renal replacement therapy (crrt) has been shown to effectively reduce serum ammonia levels and may improve transplant-free survival in alf. however, the optimal dialysis dose for ammonia clearance and neurological recovery remains uncertain. this randomized, multicenter clinical trial aims to compare conventional-dose (25-35 ml/kg/h) versus high-dose (45-55 ml/kg/h) crrt in patients with alf or aclf and arterial ammonia \>72 μmol/l. the primary outcome is the number of coma- and delirium-free days. secondary outcomes include ammonia clearance and additional parameters of cerebral function monitoring.

acute liver failure (alf) and acute-on-chronic liver failure (aclf) are critical conditions characterized by rapid deterioration in hepatic function, coagulopathy, hepatic encephalopathy, and multi-organ failure. elevated serum ammonia levels are frequently observed in these patients and are strongly associated with cerebral dysfunction, including coma and delirium. ammonia contributes to the development of brain edema through mechanisms involving astrocyte swelling, oxidative stress, and altered neurotransmission. rapid and effective reduction of ammonia is a key therapeutic target in the management of these patients. continuous renal replacement therapy (crrt) is commonly used in critically ill patients with alf or aclf, particularly in those with hyperammonemia. while crrt is effective in lowering ammonia levels, there is currently no consensus regarding the optimal dialysis dose to maximize ammonia clearance and improve neurological outcomes. observational data and small interventional studies suggest a potential benefit of higher crrt doses in terms of ammonia removal and clinical improvement, but robust evidence from randomized trials is lacking. this study is a randomized, controlled, multicenter clinical trial designed to compare the effects of two different crrt dosing strategies on cerebral function in patients with alf or aclf and arterial ammonia levels \>72 μmol/l. eligible patients will be randomized to receive either conventional-dose crrt (25-35 ml/kg/h) or high-dose crrt (45-55 ml/kg/h). all other aspects of clinical management will follow current standard-of-care protocols. the primary endpoint is the number of coma- and delirium-free days during the intervention period. secondary outcomes include the degree of ammonia clearance, time to normalization of ammonia levels, filter lifespan, need for rescue therapies (e.g., liver transplantation), mortality, and neurological function monitoring using noninvasive technologies. the study seeks to generate high-quality evidence to guide crrt dosing decisions in the context of hyperammonemia due to liver failure.

Eligibility criteria:
inclusion criteria: * age ≥ 18 years * diagnosis of acute liver failure (alf) or acute-on-chronic liver failure (aclf) presence of hyperammonemia, defined as: arterial ammonia \>72 μmol/l and hepatic encephalopathy grade ≥2 or arterial ammonia \>100 μmol/l regardless of encephalopathy grade * indication for continuous renal replacement therapy (crrt), as determined by the attending medical team * informed consent provided by the patient or legal representative exclusion criteria: * age \< 18 years * pregnancy * diagnosis of acute liver failure (alf) in the context of severe hemodynamic instability * alf secondary to ischemic hepatic injury

Keywords: ammonia continuous renal replacement therapy acute liver failure acute on chronic liver failure acute kidney injury