What urea cycle disorders cause shock?

From the Guidelines

Urea cycle disorders that can cause shock include carbamoyl phosphate synthetase I deficiency, ornithine transcarbamylase deficiency, argininosuccinate synthetase deficiency (citrullinemia), argininosuccinate lyase deficiency, and arginase deficiency, and management requires immediate reduction of ammonia levels through hemodialysis or continuous renal replacement therapy, along with nitrogen scavenger medications and arginine supplementation.

Pathophysiology of Urea Cycle Disorders

Urea cycle disorders lead to hyperammonemia, which can progress to shock through cerebral edema, systemic inflammatory response, and cardiovascular collapse 1. The pathophysiology involves ammonia's toxic effects on the brain, disruption of neurotransmitter systems, and mitochondrial dysfunction, leading to cerebral edema, increased intracranial pressure, and ultimately cardiovascular collapse.

Management of UCD-Induced Shock

Management of UCD-induced shock requires:

• Immediate reduction of ammonia levels through hemodialysis or continuous renal replacement therapy
• Nitrogen scavenger medications like sodium phenylacetate/sodium benzoate (Ammonul) at loading doses of 250 mg/kg followed by maintenance infusions, or oral sodium phenylbutyrate at 450-600 mg/kg/day
• Arginine supplementation (200-600 mg/kg/day IV) to support the urea cycle
• Protein restriction, high-calorie non-protein nutrition, and prevention of catabolism with IV glucose and lipids
• Intensive care monitoring with mechanical ventilation and vasopressor support as needed

Key Considerations

• Early recognition is vital as mortality increases with ammonia levels above 1000 μmol/L and prolonged hyperammonemic coma
• The choice of dialysis modality depends on institutional preference, local facilities, and the patient's condition 1
• Nitrogen scavengers can be administered in conjunction with dialysis, but will be dialysed along with other small molecules 1

Recommendations

• Stop protein intake immediately to prevent further ammonia production
• Initiate IV glucose and lipids to prevent catabolism and support energy production
• Administer nitrogen scavenger medications as soon as possible to reduce ammonia levels
• Consider dialysis if ammonia levels are severely elevated or if the patient is not responding to medical management.

From the FDA Drug Label

1. 1 Mechanism of Action Urea cycle disorders can result from decreased activity of any of the following enzymes: N-acetylglutamate synthetase (NAGS), carbamyl phosphate synthetase (CPS), argininosuccinate synthetase (ASS), ornithine transcarbamylase (OTC), argininosuccinate lyase (ASL), or arginase (ARG) In 16 of the 64 deaths, the patient received a known overdose of Sodium Phenylacetate and Sodium Benzoate Injection Causes of death in these patients included cardiorespiratory failure/arrest (6 patients), hyperammonemia (3 patients), increased intracranial pressure (2 patients), pneumonitis with septic shock and coagulopathy (1 patient)

The urea cycle disorders that can cause shock include:

• OTC (ornithine transcarbamylase) deficiency: can lead to hyperammonemia, which can cause cardiorespiratory failure/arrest, increased intracranial pressure, and other complications that may result in shock.
• CPS (carbamyl phosphate synthetase) deficiency: can also lead to hyperammonemia, which can cause similar complications.
• ASS (argininosuccinate synthetase) deficiency: can lead to hyperammonemia and other metabolic disturbances that may increase the risk of shock.
• ASL (argininosuccinate lyase) deficiency: can lead to hyperammonemia and other metabolic disturbances that may increase the risk of shock.
• ARG (arginase) deficiency: can lead to hyperammonemia and other metabolic disturbances that may increase the risk of shock.
• NAGS (N-acetylglutamate synthetase) deficiency: can lead to hyperammonemia and other metabolic disturbances that may increase the risk of shock. One specific cause of shock mentioned is pneumonitis with septic shock and coagulopathy 2.

From the Research

Urea Cycle Disorders that Cause Shock

• Urea cycle disorders (UCDs) can cause hyperammonemia, which can lead to shock and even death if left untreated 3, 4, 5, 6, 7
• The most common UCDs that can cause shock in adults are ornithine transcarbamylase deficiency (OTCD) and type II citrullinemia 6
• Hyperammonemia can cause irreversible neurologic injury, and it is crucial to screen for UCDs in adults with unexplained neurologic symptoms 7
• Treatment for UCDs includes adapted nutrition, scavenging agents, and dialysis, with liver transplantation being the definitive therapy 4, 6

Causes of Shock in UCDs

• Hyperammonemia is the primary cause of shock in UCDs, and it can be triggered by various factors such as infection, surgery, or high protein intake 3, 5, 6
• Brain edema and cerebral herniation are potential complications of hyperammonemia, and emergent hemodialysis is mandatory if ammonia levels are above 200 µmol/l 6

Management of UCDs

• A comprehensive, multitiered approach to management is needed to prevent progression and irreversible injury in UCDs 7
• Decreasing ongoing ammonia production, avoiding catabolism, and supporting endogenous and exogenous ammonia clearance are key components of UCD management 7
• Core neuroprotective and supportive critical care supplements this focused therapy 7