Continuous Renal Replacement Therapy in the Initial Management of Neonatal Hyperammonemia Due to Urea Cycle Defects

Abstract

After completing this article, readers should be able to:MP was born at 39 weeks' estimated gestational age by vaginal delivery to a 35-year-old gravida 3 para 2 woman who had an uncomplicated pregnancy. The 3- and 6-year-old female siblings of the patient were healthy. Apgar scores were 8 at 1 minute and 9 at 5 minutes. The newborn was discharged to home after a 2-day stay in the well baby nursery during which time she appeared to be alert and was breastfeeding appropriately. She presented to the emergency department less than 1 day later after her parents noted increasing lethargy and very poor feeding at home. She was admitted to the neonatal intensive care unit (NICU). Results of a complete blood count with differential count and C-reactive protein evaluation were unremarkable, but the patient progressed to worsening lethargy, respiratory failure, and abdominal distension requiring intubation within hours of admission. The anterior fontanelle was soft on admission physical examination. Further testing revealed a base deficit of 6.1 on arterial blood gas, serum ammonia level of 810 mcmol/L (1,134 mcg/dL), serum lactate level of 5.6 mmol/L (5.6 mEq/L), and serum pyruvate level of 0.06 mmol/L. Results of liver function tests were abnormal, and the infant had a prothrombin time of 35.9 seconds, a partial thromboplastin time of 54.3 seconds, and a fibrinogen concentration of 1.75 g/L (175 mg/dL). Genetic and nephrology consultations were requested immediately. Additional metabolic studies were obtained, including measurement of plasma amino acids; acylcarnitine profile; total, free, and esterified carnitine levels; plasma free fatty acid levels; and urine organic and orotic acid levels.Hemodialysis was initiated after placement of an 8F Medcomp dialysis catheter in the right internal jugular vein. The patient suffered a cardiac arrest immediately after initiating the first session of hemodialysis, probably due to hypocalcemia induced by the priming blood. A subsequent hemodialysis session that day was successful using an HG100 filter and a blood flow rate (BFR) of 50 to 75 mL/min. After a second uneventful hemodialysis session on the second hospital day, continuous venovenous hemodiafiltration (CVVHD) was started using a HF400 filter. Filter replacement fluid was infused to allow a filtration rate of 150 mL/h without net fluid removal, and the initial dialysate flow rate was 200 mL/h. Hemodialysis and CVVHD were interrrupted almost daily because of clotting of the circuit, despite activated clotting times (ACTs) within the target range and the coagulopathic state of the patient. The patient's coagulopathy necessitated multiple infusions of cryoprecipitate and fresh frozen plasma over the first few hospital days. The dialysate flow rate was increased over the following 4 days to a maximum of 700 mL/h. CVVHD was discontinued on the seventh hospital day. Hemodialysis rapidly, but transiently decreased the blood ammonia level to less than 200 mcmol/L (280 mcg/dL). With the initiation of CVVHD, the blood ammonia levels stabilized in the range of 150 to 200 mcmol/L (210 to 280 mcg/dL) (Fig. 1 ). When the blood ammonia level fell to less than 200 mcmol/L (280 mcg/dL), the patient began to show increased activity and responsiveness. On the sixth hospital day, her blood ammonia levels fell abruptly and dramatically and remained within the normal range of 9 to 33 mcmol/L (12.6 to 46.2 mcg/dL), even after CVVHD was discontinued.The patient's presentation and initial laboratory results suggested a urea cycle defect. Therefore, continuous intravenous infusions of sodium benzoate, sodium phenylacetate, and arginine hydrochloride were initiated on the day of admission after correction of the acidosis. The rate of the arginine infusion was increased on the fourth hospital day. Intravenous carnitine therapy also was started. Evaluation of urine organic acids revealed elevated orotic acid and hydroxy-fatty acid levels. The acylcarnitine profile documented markedly elevated long-chain species, including 3-hydroxy species, which were considered to be due to liver dysfunction. Examination of plasma amino acids showed elevated citrulline concentrations, suggestive of citrullinemia. The diagnosis of citrullinemia was confirmed later by skin fibroblast assay of argininosuccinic acid synthase activity.The patient received hyperalimentation, including 0.5 g/kg per day of amino acids, starting on the third hospital day and increasing to 1.0 g/kg per day by the next day. She was extubated to room air 9 days after admission. There was initial concern about possible gastroesophageal reflux, but a pH probe study was negative. Oral feedings were not started until hospital day 8 due to the question of reflux and the critical condition of the patient. A low-protein formula and human milk mixture was advanced slowly to supply 2 g/kg protein per day, and serial plasma ammonia and amino acid levels were followed closely. The patient was changed to oral medications of arginine hydrochloride and phenylbutyrate after her feedings were advanced successfully. She had no seizure activity during her hospitalization, although electroencephalography performed early in her course was abnormal for bursts of sharp wave activity consistent with the hyperammonemia at the time of the study. The hepatology/gastroenterology service was consulted because of mildly but consistently abnormal liver function tests and the possible need for liver transplantation in the future. She was discharged to home after 37 days in the NICU with normal findings on neurologic examination and close follow-up with multiple medical services.Hyperammonemia is caused by specific defects in the urea cycle or related pathways that result in impaired disposal of excess amino nitrogen produced by metabolism (Fig. 2 ). The condition is an unusual but important disorder in the neonate, with a frequency of about 1 in 30,000 live births. Most of the 30% to 50% of infants who present with hyperammonemic coma due to an inborn error of metabolism and who survive the neonatal period will develop significant neurologic deficits (seizures, cortical atrophy, spastic quadriparesis). Because the inheritance of most inborn disorders of metabolism leading to hyperammonemia is autosomal recessive, a prior history of unexplained perinatal death in siblings may be significant. Important exceptions include ornithine transcarbamylase (OTC) deficiency, which is inherited as an X-linked trait (with about 20% of female heterozygotes being symptomatic), and the hyperinsulinism-hyperammonemia syndrome, an autosomal dominant condition caused by glutamate dehydrogenase gene mutations.The presenting symptoms of hyperammonemia due to urea cycle defects such as OTC deficiency are stereotypical but nonspecific. Lethargy, vomiting, grunting, tachypnea, and hypothermia often are interpreted initially as representing sepsis. A bulging fontanelle reflects cerebral edema. Untreated, the condition progresses to seizures, coma, and eventually death. Although most cases of neonatal hyperammonemia are due to defects in enzymes of the urea cycle, a wide variety of other metabolic defects can lead to secondary hyperammonemia (eg, organic acidurias, fatty acid oxidation defects, dibasic amino acid transport defects, primary lactic acidosis, fulminant liver failure). Urea cycle defects are suggested by a presentation at more than 24 hours of age in the absence of acidosis or ketosis. If acidosis is present in a urea cycle defect, it usually represents lactic acidosis due to poor peripheral perfusion in a critically ill infant.Transient hyperammonemia of the newborn is a condition of undetermined etiology that typically occurs earlier than the “genetic” syndromes (usually within the first 48 h) in preterm neonates of low birthweight. Although it can lead to plasma ammonia concentrations greater than 2,000 mcmol/L (2,801 mcg/dL) and significant morbidity or death, some studies have suggested a good neurologic outcome in patients who survive the neonatal period, with little risk of recurrent hyperammonemia.Normal values of blood ammonia nitrogen in neonates in our institution range from 7 to 33 mcmol/L (9.7 to 46.2 mcg/dL), although levels between 50 and 90 mcmol/L (70 and 126 mcg/dL) appear to be relatively common in the first 2 weeks of life in otherwise normal neonates.The initial management of neonatal hyperammonemia consists of measures to decrease protein catabolism (provision of adequate calories and elimination of exogenous protein intake), continuous intravenous infusion of the nitrogen “scavengers” sodium benzoate and sodium phenylacetate, and administration of arginine hydrochloride to “prime” the urea cycle. In very sick neonates who have anuria or severely reduced renal function, the utility of scavengers such as sodium benzoate, which depend on renal elimination, is limited.If plasma ammonia concentrations are dangerously elevated (eg, >400 to 500 mcmol/L [560 to 700 mcg/dL]) or accompanied by coma, they must be reduced immediately to prevent permanent neurologic damage. This usually is accomplished by dialysis, although exchange transfusion (ET) also has been used when immediate access to dialysis was not possible. Blood ammonia concentrations greater than approximately three times the upper limit of normal are cytotoxic. It is the duration of hyperammonemic coma, however, rather than the peak blood ammonia level that determines neurologic outcome. Enhanced removal of ammonia by dialysis often is a temporizing measure that is pursued until a definite diagnosis can be made or until metabolic interventions can take effect.Peritoneal dialysis (PD) also can enhance ammonia clearance. Very rapid equilibration of blood ammonia with the dialysate has led to the use of very short exchange cycles of approximately every 30 to 60 minutes. Although each ET removes more ammonia than the single cycle of PD, only a limited number of ETs can be undertaken in the course of a day. Accordingly, PD can remove more total ammonia than ET (15 to 20 mg/d for PD compared with 1.2 to 3.6 mg per double-volume ET). Hemodialysis (HD) is very effective for rapid lowering of blood ammonia levels, although the risks of morbidity and mortality in sick neonates are significant, as illustrated by the patient in the case study.A number of studies have compared the relative efficiencies of ammonia removal by ET, PD, HD and continuous arteriovenous hemo(dia)filtration (CAVH, CAVHD). In a male neonate who had OTC deficiency, Donn and colleagues documented an ammonia removal rate of 12.6 mg/h with HD, 3.4 mg/h with ET, and 1.4 mg/h with PD. Siegel and Brown reported a rate of approximately 2 mg/h by rapid-cycle PD in a small neonate who had OTC deficiency. Blood ammonia levels were not lowered substantially, however, probably because of a very high rate of ammonia production. Pérez Rodríguez and coworkers found that double-volume ET could lower blood ammonia levels by approximately 214 mcmol/L (300 mcg/dL) per hour compared with approximately 21 mcmol/L (30 mcg/dL) per hour with PD and about 93 mcmol/L (130 mcg/dL) per hour with HD. The rates of reduction varied and were proportional to the initial blood ammonia concentration. Recently, Wong and colleagues showed that CAVH/D cleared ammonia at about five times the rate of PD, similar to the relative rates of HD and PD.The apparent effectiveness of any form of adjunctive ammonia removal is a function of both its characteristic clearance and the rate of ammonia production. Thus, it may be difficult to ascribe a specific quantitative efficacy to any single component (eg, dialysis, medications) of the overall management strategy. For example, in a report of Rutledge and colleagues, a neonate who had argininosuccinate synthetase deficiency had a blood ammonia concentration of 931 mcmol/L (1,304 mcg/dL) several hours after the initiation of infusions of sodium benzoate, phenylacetate, and arginine. The level subsequently fell to 280 mcmol/L (392 mcg/dL) after 1.5 hours of HD, but rose to 411 mcmol/L (576 mcg/dL) about 6 hours later. Even though a second HD treatment could not be administered, ammonia levels fell to 331 mcmol/L (464 mcg/dL) and after 11 hours of PD, to 50 mcmol/L (70 mcg/dL). This lower level more likely was due principally to decreased ammonia production (due to metabolic stabilization) and benzoate/phenylacetate/arginine infusions than to removal of ammonia by PD.The current immediate management of hyperammonemic coma in neonates at the Lucile S. Packard Children's Hospital at Stanford involves several steps (TableT1 ). The first step is to obtain appropriate diagnostic studies that include measurement of the blood ammonia level and comprehensive chemistries. Central vascular access is established both for infusion of high-concentration dextrose solutions and medications and for continuous renal replacement therapy (CRRT). Intravenous infusion of glucose to a goal of 12 mg/kg per minute is designed to prevent tissue catabolism. If such high-dose glucose infusion leads to hyperglycemia (greater than the target blood glucose range of 8.33 to 11.1 mmol/L [150 to 200 mg/dL]), an insulin drip (eg, 0.1 U/kg per hour) may be started. We discontinue exogenous protein intake for 24 to 48 hours and correct hypovolemia, anemia, and acidosis, especially prior to initiation of arginine hydrochloride therapy. A urinary catheter is placed to monitor urine output.The goal of mechanical ventilation is to produce a mild respiratory alkalosis (Paco2 of 30 to 35 mm Hg), and paralysis may be induced as needed.Specific medications are started immediately only if the hyperammonemia is considered likely to be due to urea cycle defect. These agents include sodium benzoate and sodium phenylacetate (each as 250 mg/kg loading doses over 1.5 h followed by continuous infusions in 25 mL/kg D10W at 250 mg/kg per day) and arginine hydrochloride 10% (load with 2 mL/kg=0.2 g/kg in D10W over 1.5 h, followed by 2 mL/kg per day by continuous infusion). The arterial blood gas should be examined after administration of the loading doses because acidosis may occur and should be corrected. Neomycin 50 mg/kg per day PR every 6 hours (only in neonates >2 d of age for 48 h) or lactulose (2.5 mL NG/PO tid prn) also may be used for a few days to decrease intestinal production of ammonia.“Nitrogen scavengers” enhance nonurea excretion of waste nitrogen from the body. Sodium benzoate combines with the amino acid glycine (which contains a single nitrogen) to produce hippurate, which is cleared almost completely from the blood in a single passage through the kidney (ie, approximately four times faster than the glomerular filtration rate). Sodium phenylacetate conjugates to glutamine (with two nitrogens) and also is cleared efficiently by the kidney.In addition to the previously described maneuvers, the initial management in severe cases of hyperammonemia includes the use of CRRTs such as continuous venovenous hemofiltration (CVVH) or CVVHD to enhance the removal of ammonia. For more details about CRRT, see the accompanying article in this issue by Yorgin and colleagues.CAVH, CVVH, and CVVHD have several similarities to HD. In CAVH, the force moving blood through the extracorporeal circuit is the patient's arteriovenous pressure gradient; in CVVH and CVVHD, blood is pumped through the circuit by a peristaltic pump. In all of these forms of CRRT, fluid crosses the artificial kidney membrane (hemofilter) under the influence of a hydrostatic pressure gradient. Solutes are removed from the blood at a rate equal to their blood concentration times the fluid filtration rate. The filtration rate is regulated by adjusting the outflow rate from the filter by an infusion pump through which the effluent flows. The addition of counterflowing dialysate fluid (in the filter housing holding the bundle of filter fibers) allows for additional solute removal by diffusion down a chemical concentration gradient (dialysis). Dialysis is much more efficient at removing small solutes such as ammonia than filtration alone.PD generally is considered inadequate to remove ammonia in severe cases of hyperammonemia. Intermittent HD removes ammonia about 5 to 10 times as fast as PD, but it typically is used only for a few hours per day, which can lead to a lower net daily removal rate than PD (as well as to intermittently high blood ammonia levels). CVVH/CAVH provide relatively rapid rates of removal coupled with the advantage of continuous operation. CAVH has been used less often than CVVH in recent years. In our opinion, the optimal form of therapy for severe neonatal hyperammonemia is the initial use of HD to lower blood ammonia levels rapidly, followed by CVVH or CVVHD. If we start with CVVH, counterflow dialysis (CVVHD) may be added if ammonia clearance is inadequate. Blood ammonia equilibrates relatively rapidly, so the adequacy of ammonia removal by CVVH/D can be assessed within a reasonable period of time.Probably the most difficult issue in neonatal CRRT is vascular access. Because the required vascular catheters are large, access usually is obtained via the external or internal jugular vein, femoral artery/vein, or umbilical artery/vein. Either one double-lumen (DL) catheter or two single-lumen (SL) catheters may be used. For CVVH, both the “arterial” catheter (taking blood to the extracorporeal circuit) and the “venous” catheter (returning blood to the body) are placed in veins. Use of the relatively large catheters is necessary to permit a sufficiently high BFR to prevent clotting, but if a catheter is too large for the vein, it may cause vascular damage, increasing the risk of later thrombosis, or it can collapse the vein, halting blood flow. Medcomp or Cook 7 Fr DL hemodialysis catheters have been used in children weighing as little as 2.3 kg. Other possible catheters include Vas-Cath 6.5 Fr DL, 16 G Medcomp SL in the femoral or umbilical vein, and 5 Fr Cook/Medcomp in the umbilical artery with a 5 or 8.5 Fr catheter in the umbilical vein. Small catheters, such as umbilical artery catheters, are less likely to support the BFR necessary for adequate clearance of blood ammonia.In neonates and small infants, recirculation (drawing already processed effluent blood back into the circuit via the adjacent arterial catheter opening) is a particular problem. Apparent recirculation rates as high as 40% to 80% have been found, even when separate venous catheters with tips in different parts of the inferior vena cava and iliac vein have been used. Excessive recirculation can be reduced by transdiaphragmatic placement of venous catheters (eg, one in the internal jugular vein and one in the femoral vein). Soft catheters are subject to external segment kinking and require good stabilization. Regular (nonHD) soft silastic catheters (eg, Hickman) tend to collapse with negative pressures and are not suitable for CVVH.To avoid hemodynamic instability, it is necessary to use a blood prime if the extracorporeal circuit volume is more than 7% to 10% of estimated blood volume (80 to 85 mL/kg in neonates). For example, because neonatal HD blood lines (used for CVVH) have a volume of 32 mL and a Minifilter Plus® hemofilter has a volume of 15 mL, any infant weighing less than 5 kg is likely to need a blood prime for this system. It is advisable use fresh or washed blood for large blood primes, especially in patients who have compromised renal function, to avoid a large potassium load. In addition, large blood primes may induce significant hypocalcemia, so serum ionized calcium should be measured before setting up the circuit and monitored closely afterward.Clearance of small solutes such as ammonia is proportional to the filter surface area (in the setting of adequate BFR). Two filters often used in neonates are the Amicon Minifilter Plus® (membrane area, 0.08 m2; filter volume, 15 mL) in small neonates (2.5 kg) and the Menntech HF400 (membrane area, 0.30 m2; filter volume, 28 mL). The Minifilter Plus® may need special adapters to connect to a standard HD tubing set. Although smaller filters may suffice for treatment of fluid overload in neonates, they may be inadequate for solute clearance.A principle concern in CVVH is assuring an adequate BFR to avoid relative stasis and clotting of the filter. Clearance of ammonia based on ultrafiltration alone (CVVH) is independent of BFR in contrast to clearance in CVVH/D or HD, which increases with BFR up to a BFR about two thirds of the dialysate flow rate. Initial BFRs usually are in the range of 3 to 5 mL/kg per minute and increase to 6 to 10 mL/kg per minute as necessary to maximize ammonia clearance.There is a high risk of intracranial hemorrhage in preterm (<35 wk estimated gestational age) neonates, which could be a contraindication to anticoagulation. Routine anticoagulation also is not necessary among patients who have a significant coagulopathy. Some studies have suggested that regional anticoagulation does not increase circuit lifetimes under any circumstances. Regional anticoagulation (anticoagulation of the circuit only) may be used in patients at particular risk of bleeding. We have used citrate-based regional anticoagulation successfully in neonates. Heparin-based anticoagulation is used most commonly in patients who can tolerate some systemic anticoagulation. No heparin loading dose is given to neonates. The rate of infusion of heparin (10 U/mL) into the post-pump, prefilter port is adjusted to give a postfilter circuit ACT of 150 to 200 seconds (usually requiring doses of 5 to 20 U/kg per hour). The coagulation status of the patient (ie, the systemic blood) should be monitored regularly via ACT and partial thromboplastin time.In CVVH, clearance of ammonia is proportional to the ultrafiltration (UF) rate. A reasonable initial UF rate for “pure” hemofiltration used for fluid removal is 1 to 2 mL/kg per hour. The ammonia clearance with this low rate of UF is less than 1% of that which can be attained even with PD and is likely to be inadequate for removing ammonia in more severe cases. The ammonia clearance rate with CVVH may be considerably enhanced simply by increasing the rate of UF by a set amount and compensating for the increased fluid removal by infusing the same amount of a physiologic filter replacement fluid (FRF) into the circuit “prepump” (so-called predilution replacement). If 500 mL/h of predilution FRF is infused and the total UF rate is correspondingly increased to 500 mL/h, the rate of ammonia removal would be about twice that which is achieved with PD and about one third the rate of removal with HD without any net fluid removal. At such high rates of UF in neonates, the actual UF rate must be verified periodically by volumetric or weight assessment of the CVVH effluent. It may exceed by up to 10% the nominal pump setting, potentially leading to unaccounted fluid losses (or gains) of up to 50 mL/h! In CVVHD, the small solute clearance increases with greater dialysate flow rates as long as BFR is adequate. Initial countercurrent flow rates are usually in the range 300 to 500 mL/h.Dialysis fluid may be custom-made by the hospital pharmacy or commercial peritoneal dialysate (eg, Baxter 1.5% dextrose Dianeal®) may be used. When dialysate is made in the hospital pharmacy, it is probably advisable to check the sodium and potassium concentrations before use. FRF and dialysate must not contain calcium in patients receiving citrate-based anticoagulation. Instead, a separate infusion of calcium directly into the systemic circulation makes up for CVVH-related losses. Both bicarbonate-based and lactate-based solutions have been used as dialysate and FRF. Use of the latter depends on the ability of the liver to metabolize lactate to bicarbonate. Some centers add calcium to the bicarbonate-based FRF; others use a separate 10% calcium gluconate infusion adjusted to maintain blood ionized calcium concentrations greater than 0.5 mmol/L (1.0 mEq/L) and a calcium-free FRF.Frequent laboratory monitoring is necessary to assess the efficacy of ammonia removal and to monitor for effects of CRRT on electrolytes and acid-base status. Initially, blood gases are obtained hourly, blood ammonia is evaluated every 2 hours, and other chemistries are checked every 4 hours. The frequency of monitoring decreases as stable blood values are acheived.The use of CRRT for treatment of neonatal hyperammonemia is very effective, but very labor-intensive and requires extensive involvement of highly trained personnel. It also is associated with substantial risks for morbidity. Significant bleeding may result from systemic anticoagulation or from the presence of large vascular catheters. Daily head ultrasonography during CRRT is indicated in many patients to monitor for intraventricular hemorrhage. Clotting of the filter or vascular catheter may lead to loss of the circuit. Several studies have shown an average loss rate of vascular access or CVVH/D filter of about one per day.Electrolyte imbalance is an ever-present potential complication of CVVH, including potentially life-threatening hypocalcemia when initiating CVVH in small infants. Other electrolyte and acid-base disturbances may be due to the specific medical therapies used (high sodium load from sodium benzoate and sodium phenylacetate, acid load from arginine hydrochloride) or from errors in the composition of FRF or dialysate solutions when made in the hospital pharmacy without adequate testing.Excessive cooling of neonates and small infants is prevented by close attention to patient temperature and the use of blood warmers in the postfilter (venous) circuit.Hemodynamic instability is probably the single most common complication. It may be due to excessive rates of fluid removal or other mechanisms (metabolic disturbances) and may restrict the upper limit of achievable BFR.High-flux, aggressive CVVH and CVVH/D are used in hyperammonemia because they efficiently remove small molecules such as ammonia from the blood. Other small molecules removed by the processes include amino acids, water-soluble vitamins, and carnitine. Removal of nutrients such as phosphate (the blood concentrations of which are measured easily) by CVVH can be compensated for by providing additional amounts in hyperalimentation or supplemental infusions. This is more difficult to accomplish with nutrients such as amino acids, carnitine, and vitamins, the blood levels of which typically are not measured by the routine clinical laboratory. A recent study in critically ill children documented amino acid losses of about 12 g/d per 1.73 m2 in both high-flux CVVH and CVVH/D. In addition to leading to net negative nitrogen balance, the removal of significant amounts of amino acids by CVVH makes it difficult to determine net protein intake. It is important to correct all known nutrient deficiencies in these patients. Phosphate depletion, for example, may limit the activity of the urea cycle enzyme carbamyl phosphate synthetase. Some centers have found it necessary to provide supplemental intravenous infusions of amino acids to neonates who have hyperammonemia and are undergoing CRRT.Adjusting drug doses appropriately for neonates treated with CRRT can be complicated by the difficulty in calculating the rate of removal of any given medication by CVVH. Most drugs are small molecules that pass through the hemofilter with little or no restriction unless they are significantly protein-bound. Although it is possible to estimate drug clearances as the sum of UF rate and some fraction (probably <80%) of dialysate flow rate plus endogenous clearance, dosing should be based on blood levels wherever feasible.After initial stabilization, hyperalimentation that includes intralipid should be started to provide 100 to 120 kcal/kg per day. To aid in preventing catabolism, amino acids at 0.25 to 0.50 g/kg per day should be started within 48 hours of admission and increased as tolerated to approximately 1.0 g/kg per day. Greater amounts of amino acids may be necessary in the setting of high-flux CVVH/D. When the patient's condition allows it, oral or nasogastric nutrition should be initiated and intravenous hyperalimentation weaned. The level of protein intake that eventually is tolerated (usually 0.7 to 1.6 g/kg per day) and the rapidity of the increase in dietary protein intake must be established for each individual. It may be beneficial to supply a portion of the daily protein as essential amino acids or cognate keto acids to decrease the amino nitrogen load. Intravenous sodium benzoate and phenylacetate are switched to oral phenylbutyrate as soon as possible.The decision of when to remove vascular access for CVVH is difficult. It may require a week or more to arrive at a definitive diagnosis. A patient who has been stabilized adequately on a medical regimen may experience a subsequent hyperammonemic crisis if sepsis or another condition compromises nutrition. The decision to remove vascular access should be made jointly (and cautiously!) by representatives of the neonatal, nephrology, genetics, and pediatric surgery teams. It is important to remember that discontinuation of CVVH will lead to a net gain in protein/amino acids available for catabolism.Neonatal hyperammonemia is a rare occurrence, even in large tertiary care neonatal units. This fact combined with the substantial heterogeneity of disease severity makes it very difficult to judge the relative merits of competing treatment options.