Intermittent dialysis and continuous modalities for patients with hyperammonemia

INTRODUCTION — 

Hyperammonemia (HA) is a toxic accumulation of ammonia in blood that can cause cerebral edema and brain herniation leading to coma or death in patients with acute liver failure, inborn errors of metabolism, and other conditions of nonhepatic HA [1,2]. Clinically, HA presents with mental status changes ranging from subtle impairments in attention, reaction time, and working memory to disorientation, somnolence, confusion, and unconsciousness.

This topic will discuss the practical aspects of hemodialysis (HD), continuous venovenous hemofiltration (CVVH), and continuous venovenous hemodialysis (CVVHD) for HA. Pathophysiology, clinical presentation, thresholds for treatment, and detailed nondialysis and nonhemofiltration management of HA occurring as part of various medical conditions are covered elsewhere:

●Inborn errors of metabolism (see "Metabolic emergencies in suspected inborn errors of metabolism: Presentation, evaluation, and management", section on 'Hyperammonemia')

●Urea cycle disorders (see "Urea cycle disorders: Clinical features and diagnosis" and "Urea cycle disorders: Management", section on 'Ammonia removal')

●Hepatic encephalopathy among patients with acute liver failure (see "Acute liver failure in adults: Management and prognosis", section on 'Hepatic encephalopathy')

●As a complication of lung transplant (see "Noninfectious complications following lung transplantation", section on 'Hyperammonemia')

●As a manifestation of valproic acid poisoning (see "Valproic acid poisoning", section on 'Hyperammonemia' and "Valproic acid poisoning", section on 'Valproate-related hyperammonemic encephalopathy' and "Valproic acid poisoning", section on 'Hemodialysis and hemoperfusion')

GENERAL PRINCIPLES

Patients with kidney disease — Patients with hyperammonemia (HA) may have concomitant advanced kidney disease (acute kidney injury or end-stage kidney disease) requiring dialysis. When the need for kidney replacement therapy (KRT) is primarily driven by advanced kidney disease, the indications and management of KRT are no different for patients with HA. This is discussed in detail elsewhere. (See "Kidney replacement therapy (dialysis) in acute kidney injury in adults: Indications, timing, and dialysis dose" and "Indications for initiation of dialysis in chronic kidney disease".)

Dialysis and continuous modalities for HA in patients with no kidney disease or kidney disease not requiring dialysis, such as with HA due to an inborn error of metabolism, are presented below. (See 'Choice of modality' below and 'Initial dialysis prescription' below.)

Dialysis as adjunctive therapy — When performed for HA, dialysis should be considered as an adjunctive therapy; it is a temporary measure used to prevent neurotoxicity while the underlying cause of HA can be identified and treated. The treatment of, and the role of dialysis in, the underlying conditions causing HA are detailed elsewhere:

●Genetic disorders of the urea cycle (see "Urea cycle disorders: Management")

●Inborn errors of metabolism (see "Metabolic emergencies in suspected inborn errors of metabolism: Presentation, evaluation, and management", section on 'Immediate management')

●Acute liver failure (ie, severe acute liver injury in a patient without cirrhosis or preexisting liver disease) (see "Acute liver failure in adults: Management and prognosis")

●Valproate toxicity (see "Valproic acid poisoning")

●Posttransplant HA (see "Noninfectious complications following lung transplantation", section on 'Hyperammonemia')

Extracorporeal ammonia clearance and rebound — Because ammonia is a small molecule (molecular mass 17 mg/mmol) that is water soluble and not significantly protein bound, it is well cleared by dialysis. Indeed, one study concluded that in vitro clearance of ammonia is as high as 225 mL/min by hemodialysis (HD) [3].

However, there is often a major rebound effect of ammonia after discontinuation of HD due to its large volume of distribution. Thus, shortly after its removal from the intravascular space, ammonia re-enters the circulation from the extravascular space down a concentration gradient. We manage this rebound by following HD with continuous KRT. (See 'Choice of modality' below and 'Initial dialysis prescription' below.)

CHOICE OF MODALITY — 

Choice of dialysis modality is affected by local resources. Local means and expertise to perform hemodialysis (HD) and continuous venovenous hemodialysis (CVVHD) in children, and particularly in neonates, may not be available in the emergency setting.

●Adults – Among adult patients selected for extracorporeal therapy, we use intermittent HD followed by continuous venovenous hemofiltration (CVVH), since these modalities can rapidly remove ammonia. We prescribe HD first, given its superior clearance profile for ammonia, to lower blood ammonia levels acutely. CVVH is used subsequently to prevent ammonia rebound. We place a temporary nontunneled or tunneled HD catheter for initiation of therapy.

Some centers may use CVVHD instead of CVVH as an equivalent alternative. In centers where continuous modalities are unavailable, sustained low-efficiency dialysis (SLED) may be used as an alternative until the patient is transferred to a facility where continuous modalities are available. SLED can be performed with a blood flow (Qb) as low as 60 mL/min, which is tolerated well in patients who are hemodynamically unstable.

Because peritoneal dialysis (PD) is less efficient at removing ammonia, we do not use PD to treat hyperammonemia (HA) unless there is no other available modality.

●Children – An initial HD session followed by CVVHD is effective for children as well as adults: very rapid ammonia clearance can be achieved by one or more sessions of HD followed by CVVHD to provide continuous removal of ammonia without rebound [3-5]. However, the availability of HD is limited in many pediatric centers, and in small children (eg, <5 kg) high-dose CVVHD (ie, Qb 8 to 10 mL/kg/min) can approximate the ammonia clearance of HD. As such, CVVHD is a reasonable initial modality for children with HA and is recommended by consensus guidelines [5].

If unable to obtain vascular access for HD or CVVHD in particularly small children, some centers may use extracorporeal membrane oxygenation (ECMO) with HD. Accessing the ECMO circuit for HD or CVVHD can rapidly reduce ammonia levels [6] but with greater morbidity than dialysis performed via conventional vascular access.

Other modalities, such as CVVH, continuous venovenous hemodiafiltration (CVVHDF), or PD, may be prescribed depending upon local availability. PD is the least preferred modality and should be performed only until infants and children are transferred expeditiously to a tertiary care center capable of providing HD and CVVHD. The clearance of ammonia across the peritoneal membrane is markedly slower than HD or continuous modalities, with levels of <200 micromol/L achieved in 36 hours by PD as compared with 24 hours by CVVHD [4,7].

Continuous kidney replacement therapy (CKRT) and HD both reduce ammonia levels expeditiously. For example, CVVHD can reduce ammonia by 50 percent in just under five hours, achieving levels <200 micromol/L by approximately 24 hours [7]. High dialysate flow (Qd) or replacement fluid (RF) flow increases clearance. Thus, Qd or RF rates can be tailored to ammonia levels and can be reduced as the ammonia levels improve [7,8]. In children with very high ammonia levels (>1500 micromol/L), Qb of 30 to 50 mL/min and Qd >1000 mL/hour (Qd/Qb >1.5) offer the maximum potential of CKRT in neonates [5]. However, such high blood flows may be difficult to achieve, and not all machines can achieve these Qd levels.

Despite its efficiency, providing HD or CVVHD among infants and small children requires highly specialized skills and resources [7-9]. Conventional pediatric CVVHD machines are designed for children over 25 kg. Thus, the volume of the extracorporeal circuit may exceed an infant's or a small child's entire blood volume, necessitating priming of the extracorporeal circuit with blood, technical adaptations, or the use of machines designed for such children [10]. In addition, single-lumen catheters are usually needed to achieve adequate Qbs, and their small vessel size can result in the need for frequent catheter adjustments to keep them working adequately. These issues are discussed at length elsewhere. (See "Hemodialysis for children with chronic kidney disease", section on 'Central venous catheters'.)

INITIAL DIALYSIS PRESCRIPTION

Adults — Among adult patients selected for extracorporeal therapy, our goal is to provide continuous removal of ammonia by performing daily hemodialysis (HD) and treating with continuous venovenous hemofiltration (CVVH) in between sessions of HD to prevent ammonia rebound. The optimal extracorporeal prescription is unknown, but our approach is as follows:

●For most patients, we initiate HD using a blood flow (Qb) of 400 to 450 mL/min and dialysate flow (Qd) of 800 mL/min. We use an HD session length of four to six hours, depending upon the severity of the hyperammonemia (HA). However, for patients with clinical evidence of severe neurologic compromise, we initiate HD with a lower Qb of 250 mL/min and a Qd of 500 mL/min, and we use a shorter initial HD session length of approximately three to four hours. In such patients, a lower initial dose of dialysis theoretically may prevent a worsening of cerebral edema caused by rapid, large reductions in plasma ammonia.

●Once the initial HD session is complete, we immediately transition the patient to CVVH. CVVH is initiated with a Qb of 250 mL/min and bicarbonate-based replacement fluid (RF) at a rate of 50 mL/kg/hr. Qb on CVVH may be increased to a maximum of 300 mL/min and RF to a maximum of 80 mL/kg/hr if ammonia levels continue to rise. If CVVH fails to clear ammonia as rapidly as it is produced, as suggested by rising ammonia levels on serial checks, we perform another four-to-six-hour session of HD as above, followed immediately by resumption of CVVH.

Citrate may be used as an RF in patients with recurrent clotting of the CVVH filters. For patients on citrate RF, we monitor ionized calcium levels at least every 12 hours. However, patients with severe acute liver failure may not be able to tolerate citrate RF or regional citrate anticoagulation (see "Anticoagulation for continuous kidney replacement therapy"). We monitor ammonia levels every 12 to 24 hours while on CVVH. (See 'Monitoring during treatment' below.)

High-quality evidence to support a specific regimen for the extracorporeal removal of ammonia is lacking. Our approach with regard to the dialytic modality and prescription is based upon our knowledge of the dialytic properties of ammonia.

Children — We generally initiate extracorporeal therapy with HD, although high-dose continuous venovenous hemodialysis (CVVHD) is a reasonable alternative. (See 'Choice of modality' above.)

●If HD is initial therapy, the initial prescription is identical to HD for other indications (see "Hemodialysis for children with chronic kidney disease", section on 'Hemodialysis equipment' and "Hemodialysis for children with chronic kidney disease", section on 'Dialysis prescription'). HD is maintained with hourly assessment of ammonia levels until two sequential levels <200 micromol/L are obtained, at which point children can be converted to conventionally dosed CVVHD (Qb 3 to 5 mL/kg/min) if ongoing ammonia removal is desired. (See 'Subsequent dialytic approach' below.)

●If high-dose CVVHD is initial therapy, we set Qb to 8 to 10 mL/kg/min with Qd/Qb >1.5. If after two sequential hourly ammonia levels are <200 micromol/L, the CVVHD prescription is changed to conventional dosing (ie, Qb 3 to 5 mL/kg/min) [3,5]. The Qd typically varies by age:

•Among neonates, who are likely to have severe HA, a high initial Qd (40,000 mL/hr/1.73 m²) is often used to optimize ammonia clearance; after a period of two to four hours, the Qd is reduced to 4000 mL/hr/1.73 m² to provide ongoing clearance and prevent rebound [11].

•Among older children, who generally have less severe HA, a Qd up to 8000 mL/hr/1.73 m² is typically used.

Some centers lack the infrastructure and capability to perform HD, CVVH, or CVVHD in small children, but they are able to provide peritoneal dialysis (PD). However, PD should be performed only until infants and children are transferred expeditiously to a tertiary care center capable of providing HD and CVVHD. (See 'Choice of modality' above.)

MONITORING DURING TREATMENT — 

Among patients who are treated with hemodialysis (HD) or continuous modalities (continuous venovenous hemofiltration [CVVH] or continuous venovenous hemodialysis [CVVHD]) for hyperammonemia (HA), we monitor the following:

Ammonia levels and neurologic status — Monitoring of ammonia levels and neurologic status is critical to help tailor dialysis and hemofiltration for a given patient. The frequency of serum ammonia monitoring is different between adults and children:

●Among adults, we measure ammonia levels every 8 to 12 hours until the patient's neurologic status improves steadily or until the ammonia levels are consistently less than 100 micromol/L [12]. We also perform neurologic assessments every 12 hours to determine if the dialysis prescription needs to be adjusted (see 'Subsequent dialytic approach' below). Initially, our neurologic assessment focuses upon the level of consciousness. Once a patient is conscious, then we closely assess more subtle aspects of neurologic status, such as orientation.

●Among children, we monitor ammonia levels hourly during initial HD or high-dose continuous kidney replacement therapy (CKRT) until two sequential levels are <200 micromol/L. Then, HD or high-dose CKRT may be converted to less intense CKRT, where ammonia levels may initially be done every two to four hours and then spaced to every four to six hours. Once the levels are below the range where dialysis may be indicated and there has been satisfactory treatment of the underlying cause of pathologic ammonia generation, we monitor the levels daily until they fall below the upper limit of normal. (See 'Subsequent dialytic approach' below.)

Blood pH — We monitor the arterial or venous pH at least daily, unless more frequent monitoring is clinically indicated to look for alkalemia. If the patient develops alkalemia, then we lower the replacement fluid (RF) rate (for patients on CVVH) or lower the bicarbonate content in the dialysate (for patients on HD). We aim for a normal physiologic pH (7.36 to 7.44).

Avoiding alkalemia is important because, at higher blood pH, ammonium ions (NH4) are converted to ammonia (NH3), thereby increasing the ammonia concentration substantially [13]. In brain astrocytes, ammonia is metabolized to glutamate; therefore, higher ammonia concentrations lead, sequentially, to higher glutamate concentrations, an increase in intracellular osmolality, astrocyte swelling, and disruption of the blood-brain barrier. This disruption of the blood-brain barrier leads to cerebral edema, which may be irreversible. Thus, prevention of alkalemia, as may be caused by use of a bicarbonate-based RF, is crucial in the management of HA.

Electrolytes — Monitoring for and treatment of CKRT/HD-related electrolyte and mineral imbalances are the same as in patients without HA. (See "Prescription of continuous kidney replacement therapy in acute kidney injury in adults" and "Hypophosphatemia: Evaluation and treatment", section on 'Patients on kidney replacement therapy'.)

Hypokalemia should be treated since it increases ammonia production by the kidney.

Hemodynamic parameters — Evaluation and management of hemodynamic parameters in patients with HA receiving HD or on continuous modalities are the same as in patients without HA. These are discussed at length elsewhere. (See "Intradialytic hypotension in an otherwise stable patient", section on 'Acute management' and "Intradialytic hypotension in an otherwise stable patient", section on 'Prevention of recurrent episodes' and "Prescription of continuous kidney replacement therapy in acute kidney injury in adults", section on 'Hypotension'.)

SUBSEQUENT DIALYTIC APPROACH — 

After the initial treatment (see 'Initial dialysis prescription' above), our subsequent approach to dialysis depends on whether the patient is an adult or a child, the clinical status of the patient, and the serum ammonia level.

●Dialytic approach – Our approach in adults and children is as follows:

•Among adults, restoration of mental status is the primary determinant of decisions regarding modifying the dialysis prescription.

-If the neurologic status is not improving and ammonia levels are rising, we intensify dialysis (as presented below) until ammonia levels stabilize.

-If the neurologic status is not improving and ammonia levels have plateaued, it is reasonable to intensify dialysis (as presented below) for an additional time-limited period to see if further reductions in ammonia result in clinical improvement. (See 'When to discontinue dialysis' below.)

-If the neurologic status is not improving despite declining ammonia levels, then we obtain brain imaging (computed tomography [CT] or magnetic resonance imaging [MRI]) to assess for complications of hyperammonemia (HA), such as cerebral edema or brain herniation, and look for other structural abnormalities.

-If the neurologic status is improving, we continue dialysis until mental status is at baseline and ammonia levels have stabilized. (See 'When to discontinue dialysis' below.)

•Among children, the dialysis prescription is tailored to lower serum ammonia to levels consistently below 200 micromol/L (see 'When to discontinue dialysis' below). If ammonia levels are not decreasing, we intensify dialysis (as presented below).

●Intensified dialysis prescription – The prescription for intensified dialysis is different for adults and children.

•For adults, we intensify dialysis for patients on intermittent hemodialysis (HD) by increasing the dialysate rate (Qd) to a maximum of 800 mL/min, followed by the blood flow rate (Qb) to a maximum of 450 mL/min. For adults on continuous venovenous hemofiltration (CVVH) who require intensification, we increase the replacement fluid (RF) to a maximum of 80 mL/kg/hr, followed by an increase in Qb to a maximum of 300 mL/min, or switch them to HD. We preferentially increase the RF or Qd rate before altering the Qb.

•Among children, intensification of HD or continuous venovenous hemodialysis (CVVHD) is limited by the blood volume of the child; the maximum Qb is 8 to 10 mL/min/kg but extracorporeal blood volumes exceeding 10 percent of total blood volume may cause significant hemodynamic instability unless the circuit is primed with blood. Maximum Qd is generally prescribed as two times the Qb.

WHEN TO DISCONTINUE DIALYSIS — 

Our approach to dialysis discontinuation is different between adults and children and depends on clinical improvement as follows:

Patients with clinical improvement

●Among adults, we discontinue dialysis and hemofiltration in patients with hyperammonemia (HA) when the mental status is restored to the baseline and ammonia levels are declining or have stabilized. We are further reassured by ammonia levels consistently below 150 micromol/L. However, the duration and intensity of dialysis for HA in adults are generally dictated by the clinical status of the patient, rather than a specific blood ammonia level. In our experience, mental status improves well before blood ammonia levels normalize. Depending upon the etiology of the HA, ammonia levels may remain elevated two- to threefold when the mental status has returned to baseline.

●Among children, we stop dialysis when ammonia levels are below 200 micromol/L (without evidence of rebound) and the neurologic status has returned to baseline.

Patients without clinical improvement — Among adults and children whose mental status continues to worsen or fails to improve despite 48 to 72 hours of effective therapy (ie, improvement of ammonia levels), we typically discontinue dialysis due to its likely futility. For patients with refractory encephalopathy, a multidisciplinary discussion among nephrologists, neurologists, hepatologists, and intensivists is often needed to determine need for discontinuation of dialysis.

PROGNOSIS — 

The prognosis of patients with hyperammonemia (HA) who require dialysis depends primarily upon the course and definitive management of the underlying cause of the HA. (See "Noninfectious complications following lung transplantation", section on 'Hyperammonemia' and "Acute liver failure in adults: Management and prognosis", section on 'Prognostic models' and "Acute liver failure in adults: Management and prognosis", section on 'Prognosis'.)

Reports of outcomes for infants with HA suggest that its duration, rather than the peak level, is the important determinant of the outcome. Studies suggest that presence of coma for longer than three days predicts a higher mortality and a worse neurologic outcome [4]. A plasma ammonia >1000 micromol/L also generally correlates with a less favorable prognosis [4].

SOCIETY GUIDELINE LINKS — 

Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Dialysis" and "Society guideline links: Urea cycle disorders".)

SUMMARY AND RECOMMENDATIONS

●Overview – Hyperammonemia (HA) is a toxic accumulation of ammonia in blood that can cause cerebral edema and brain herniation leading to coma or death in patients with acute liver failure, inborn errors of metabolism, and other conditions of nonhepatic HA states. When performed for HA, dialysis should be considered as an adjunctive therapy; it is a temporary measure used to prevent neurotoxicity while the underlying cause of HA can be identified and treated. (See 'Introduction' above and 'Dialysis as adjunctive therapy' above.)

●Extracorporeal ammonia clearance – Because ammonia is a small molecule that is water soluble and not significantly protein bound, it is well cleared by dialysis. However, there is often a major rebound effect of ammonia after discontinuation of hemodialysis (HD) due to its large volume of distribution. Thus, shortly after its removal from the intravascular space, ammonia re-enters the circulation from the extravascular space down a concentration gradient. (See 'Extracorporeal ammonia clearance and rebound' above.)

●Choice of modality – Among patients selected for extracorporeal removal of ammonia, we suggest intermittent HD followed by continuous kidney replacement therapy (CKRT), rather than HD or CKRT alone (Grade 2C). We prescribe HD first to lower blood ammonia levels rapidly and then use CKRT to prevent ammonia rebound. However, the availability of HD is limited in many pediatric centers, and in children high-dose continuous venovenous hemodialysis (CVVHD) is a reasonable alternative to initial treatment with HD. (See 'Choice of modality' above.)

●Dialysis prescription – Our initial prescriptions for HD and CKRT in adults and children are presented above (see 'Initial dialysis prescription' above). After the initial treatment, our subsequent approach to dialysis depends on whether the patient is an adult or a child, the clinical status of the patient, and the serum ammonia level. (See 'Subsequent dialytic approach' above.)

●Monitoring – Among patients who are treated with HD or continuous modalities for HA, we monitor ammonia levels, neurologic status, arterial or venous pH, electrolytes, and hemodynamic parameters. Among adults, we discontinue dialysis in patients with HA when the mental status is restored to the baseline and ammonia levels are declining or have stabilized. Among children, we wean dialysis and continuous modalities when ammonia levels are consistently below 200 micromol/L. (See 'Monitoring during treatment' above and 'When to discontinue dialysis' above.)

●Prognosis – The prognosis of patients with HA who require dialysis depends primarily upon the course and definitive management of the underlying cause of the HA. Reports of outcomes for infants with HA suggest that its duration, rather than the peak level, is the important determinant of the outcome. (See 'Prognosis' above.)

ACKNOWLEDGMENT — 

The UpToDate editorial staff acknowledges Lesley Rees, MD, FRCPCH, who contributed to earlier versions of this topic review.