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Intermittent dialysis and continuous modalities for patients with hyperammonemia

Intermittent dialysis and continuous modalities for patients with hyperammonemia
Literature review current through: Jan 2024.
This topic last updated: May 12, 2023.

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. The laboratory definition of clinically significant HA is usually described as a twofold increase above the upper limit of normal in arterial blood. However, there is relatively poor correlation with symptoms at this level, and severe symptoms generally occur with higher levels of ammonia. An absolute ammonia level above which dialysis is needed among adults is not well defined and relies heavily on clinical evaluation.

In children, the commonest causes of HA are the inborn errors of metabolism, including urea cycle disorders and organic acidemias, while mitochondrial disorders and hepatic dysfunction are less common. As in adults, HA in children presents with an evolving encephalopathy. Neonates with a urea cycle defect or organic acidemia may present as an emergency, usually 48 hours after starting protein-containing feeds. Ammonia levels can rapidly rise to a level (arbitrarily defined as 250 micromol/L in a child who is not responding to medical management) at which removal by hemodialysis (HD) or continuous venovenous hemodialysis (CVVHD) may be needed to prevent long-term brain injury. Not all children present in infancy, and they can continue to present throughout childhood. They may have episodes of metabolic decompensation, particularly in association with infections, leading to symptomatic HA [1,3].

This topic will discuss the practical aspects of HD, continuous venovenous hemofiltration (CVVH), and CVVHD for HA. Pathophysiology, thresholds for treatment, and detailed nondialysis and non-hemofiltration 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')

Hepatic encephalopathy (see "Acute liver failure in adults: Management and prognosis", section on 'Hepatic encephalopathy')

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

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')

Artificial hepatic assist devices used for treatment of HA and encephalopathy resulting from liver failure are discussed at length elsewhere. (See "Acute liver failure in adults: Management and prognosis", section on 'Artificial hepatic assist devices'.)

INTERMITTENT HEMODIALYSIS AND CONTINUOUS MODALITIES FOR HYPERAMMONEMIA — Intermittent dialysis and continuous modalities (continuous venovenous hemofiltration [CVVH] or continuous venovenous hemodialysis [CVVHD]) may be indicated for hyperammonemia (HA) that is insufficiently responsive to medical management alone.

Patients with 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 and dialysis prescription' below.)

Medical management of HA and the underlying conditions causing HA are discussed separately:

HA in patients with genetic disorders of the urea cycle (see "Urea cycle disorders: Management", section on 'Hemodialysis')

Valproate toxicity (see "Valproic acid poisoning", section on 'Hemodialysis and hemoperfusion')

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

CHOICE OF MODALITY AND DIALYSIS PRESCRIPTION — Among adult patients, we use intermittent hemodialysis (HD) followed by continuous venovenous hemofiltration (CVVH), since these extracorporeal modalities can rapidly remove ammonia. We do not use peritoneal dialysis (PD) to treat hyperammonemia (HA) unless there is no other available modality. We place a temporary nontunneled or tunneled HD catheter for initiation of therapy.

Consensus guidelines on the management of children with HA using continuous kidney replacement therapy (CKRT) have been published [4]. Choice of dialysis modality is affected by local resources. An initial HD session followed by continuous venovenous hemodialysis (CVVHD) is also appropriate for children as well as adults. However, local means and expertise to perform HD and CVVHD in children, and particularly in neonates, are not widely available in the emergency setting. Although PD is a less efficient method for ammonia removal, placement of a peritoneal catheter is an easy and more widely available procedure. Thus, if HD is not available as the initial modality, PD is performed, to avoid any delay in ammonia clearance, while arrangements are made to transport the child to a center that can perform HD and CVVHD.

Adults with hyperammonemia — Among adult patients, our goal is to provide continuous removal of ammonia by performing daily HD and treating with 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 HA. For patients with cerebral edema, 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.

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, then we switch back to HD.

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 hepatic dysfunction should not be receiving citrate RF.

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 Qb as low as 60 mL/min, which is tolerated well in patients who are hemodynamically unstable.

If symptoms persist and levels of ammonia remain elevated, we repeat the cycle of an intermittent HD session followed immediately by CVVH.

We monitor ammonia levels every 12 to 24 hours while on CVVH. (See 'Monitoring' 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.

Factors that affect the clearance of ammonia by dialysis include its molecular size, water solubility, volume of distribution, and protein binding. Ammonia is a small molecule (molecular mass 17 mg/mmol) that is water soluble and not significantly protein bound. Its diffusive clearance is similar to urea, and it should, therefore, be well cleared by dialysis. Indeed, one study concluded that in vitro clearance of ammonia is as high as 225 mL/min by HD [5]. The clearance of ammonia was dependent upon Qb, Qd rate, and the dialyzer membrane surface area. Thus, we aim to achieve maximal Qb and Qd rates while using a large surface area dialyzer. These dialysis goals may have to be modified in patients with severe liver disease who have subsequent hemodynamic changes, which may necessitate lower Qb rates. (See 'Monitoring' below.)

The prescription and duration of dialysis or hemofiltration delivered also depend upon ammonia metabolism in a given patient. The ammonia level depends upon the enzymatic activity of multiple different organs, including the kidney, liver, muscle, intestine, and brain. The intestine and the kidney are both potentially major sites of ammonia production. At the beginning of dialysis, the appearance of ammonia may be greater than the elimination until the levels reach steady state. Thus, we prescribe HD first, given its superior clearance profile for ammonia, to lower blood ammonia levels acutely.

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 CVVH. Monitoring of ammonia levels is critical to help tailor dialysis and hemofiltration for a given patient. (See 'Monitoring' below.)

Children with hyperammonemia — Among infants and children with HA, CVVHD is recommended as the treatment of choice by the consensus guidelines in order to provide continuous removal of ammonia without rebound [4]. Very rapid ammonia clearance can be achieved by one or more sessions of HD followed by CVVHD to prevent ammonia returning to predialysis levels [3-5]. 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.

CVVHD has been shown to reduce ammonia by 50 percent in just under five hours, achieving levels <200 micromol/L by approximately 24 hours [6]. High Qd or RF flow increases clearance. Thus, Qd or RF rates can be tailored to ammonia levels and can be reduced as the ammonia levels improve [6,7]. In children with very high ammonia levels (>1500 mcmol/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 [4]. 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 [6-8]. 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 [9]. 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'.)

Indications for initiation of dialysis for HA in children with urea cycle disorders are presented elsewhere. (See "Urea cycle disorders: Management", section on 'Hemodialysis'.)

Our approach to dialysis among children is aimed at maximizing clearance of ammonia by maximizing Qb and Qd:

We initially start with HD and continue for four hours, if tolerated. Our initial HD 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'.)

After completion of HD, or if HD is poorly tolerated, we begin CVVHD as follows [5]:

We initiate CVVHD with a Qb of 3 to 5 mL/min/kg and increase to 8 to 10 mL/min/kg as tolerated.

Qd depends upon the initial ammonia level and the age of the child. Among neonates, who are likely to have severe HA, we use a biphasic approach with a high initial Qd (40,000 mL/hr/1.73 m2) for optimum ammonia clearance; after a period of two to four hours, we reduce the Qd to 4000 mL/hr/1.73 m2 to prevent rebound [10]. Among older children, who generally have less severe HA, we use a Qd of up to 8000 mL/hr/1.73 m2.

Some centers lack the infrastructure and capability to perform HD, CVVH, or CVVHD in small children, but they are able to provide PD. The clearance of ammonia across the peritoneal membrane is 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 [3,6].

MONITORING DURING TREATMENT

Monitoring — 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 – 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 [11]. We also perform neurologic assessments every 12 hours to determine if the dialysis prescription needs to be adjusted. 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. As long as there is steady improvement, we do not alter the dialysis prescription.

Among infants and children, we monitor ammonia levels every four to six hours until levels are consistently <200 micromol/L. Once the levels are below the range where dialysis may be indicated, we monitor the levels daily until they fall below the upper limit of normal.

Our approach is as follows:

Among infants and children, when the neurologic status has returned to baseline and ammonia levels are below 200 micromol/L, we stop dialysis and monitor ammonia levels daily. Among adults, restoration of mental status is the primary determinant of decisions regarding modifying the prescription and discontinuing dialysis. (See 'When to discontinue dialysis' below.)

If the neurologic status has returned to baseline but the ammonia levels are rising, we continue dialysis and monitor ammonia levels until they stabilize. Once stabilized, we discontinue dialysis. (See 'When to discontinue dialysis' below.)

If the neurologic status is stable (but not yet at baseline) and ammonia levels are rising, we intensify dialysis until ammonia levels stabilize.

If the neurologic status is worsening with rising ammonia levels, we intensify dialysis until ammonia levels stabilize.

If the neurologic status is worsening despite declining ammonia levels, then we obtain brain imaging (computed tomography [CT] or magnetic resonance imaging [MRI]) to assess for complications of HA, such as cerebral edema or brain herniation, and look for other structural abnormalities.

For adults, we intensify dialysis for patients on intermittent 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 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. For adults and children, we preferentially increase the RF or Qd rate before altering the Qb.

Among children, intensification of intermittent HD is limited by the blood volume of the child; the maximum Qb is 8 to 10 mL/min/kg, and the maximum Qd is two times the Qb.

Arterial or venous 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 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 [12]. 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.

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'.)

When to discontinue dialysis — Among adults, we discontinue dialysis and hemofiltration in patients with 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 wean dialysis and continuous modalities when ammonia levels are consistently below 200 micromol/L [6].

Among adults, we also discontinue dialysis if the mental status continues to worsen or fails to improve despite 48 hours of effective therapy (ie, improvement of ammonia levels) due to its likely futility. For both adults and pediatric patients, a multidisciplinary discussion among nephrologists, neurologists, hepatologists, and intensivists is often needed to determine need for alteration of prescription or 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 [3]. A plasma ammonia >1000 micromol/L also generally correlates with a less favorable prognosis [3].

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

General principles – 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. Clinically, HA presents with mental status changes ranging from subtle impairments in attention to somnolence, confusion, and coma. Among adults, an absolute ammonia level above which dialysis is needed is not well defined and relies heavily upon clinical evaluation. Among children, dialysis is needed if the ammonia level is above 250 micromol/L to prevent long-term brain injury. (See 'Introduction' above.)

Intermittent hemodialysis and continuous modalities – Intermittent hemodialysis (HD) followed by continuous modalities (continuous venovenous hemofiltration [CVVH] or continuous venovenous hemodialysis [CVVHD]) may be indicated for HA that is insufficiently responsive to medical management alone. 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. (See 'Intermittent hemodialysis and continuous modalities for hyperammonemia' above.)

Choice of modality and dialysis prescription – Among patients with HA, we use intermittent HD in combination with CVVH or CVVHD, since these extracorporeal modalities can rapidly remove ammonia. We do not use peritoneal dialysis (PD) to treat HA unless there is no other available modality (some centers lack the ability to perform HD, CVVH, and CVVHD in infants and children). In such cases, PD should be performed only until the patient is transferred expeditiously to a tertiary care center that can perform HD, CVVH, or CVVHD in these patients.

In patients who have completed an HD session, we suggest CVVH or CVVHD rather than simply waiting until the next routine HD session (Grade 2C). Our goal is to provide continuous removal of ammonia by performing daily HD and treating with a continuous modality in between sessions of HD to prevent ammonia rebound. In infants with inborn errors of metabolism, an initial HD session (followed by CVVHD) is usually enough. (See 'Choice of modality and dialysis prescription' above.)

Our prescriptions for HD, CVVH, and CVVHD in adults and children are presented above. (See 'Adults with hyperammonemia' above and 'Children with hyperammonemia' above.)

Monitoring – Among patients who are treated with HD or continuous modalities for HA, we monitor ammonia levels, neurologic status, arterial or venous pH, 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.)

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 (deceased), who contributed to earlier versions of this topic review.

  1. Clemmesen JO, Larsen FS, Kondrup J, et al. Cerebral herniation in patients with acute liver failure is correlated with arterial ammonia concentration. Hepatology 1999; 29:648.
  2. Butterworth RF. Pathogenesis of hepatic encephalopathy and brain edema in acute liver failure. J Clin Exp Hepatol 2015; 5:S96.
  3. Häberle J, Burlina A, Chakrapani A, et al. Suggested guidelines for the diagnosis and management of urea cycle disorders: First revision. J Inherit Metab Dis 2019; 42:1192.
  4. Raina R, Bedoyan JK, Lichter-Konecki U, et al. Consensus guidelines for management of hyperammonaemia in paediatric patients receiving continuous kidney replacement therapy. Nat Rev Nephrol 2020; 16:471.
  5. Cordoba J, Blei AT, Mujais S. Determinants of ammonia clearance by hemodialysis. Artif Organs 1996; 20:800.
  6. Cho H. Renal replacement therapy in neonates with an inborn error of metabolism. Korean J Pediatr 2019; 62:43.
  7. Aygun F, Aygun D, Erbek Alp F, et al. The impact of continuous renal replacement therapy for metabolic disorders in infants. Pediatr Neonatol 2018; 59:85.
  8. Tal L, Angelo JR, Akcan-Arikan A. Neonatal extracorporeal renal replacement therapy-a routine renal support modality? Pediatr Nephrol 2016; 31:2013.
  9. Hothi DK. Designing technology to meet the therapeutic demands of acute renal injury in neonates and small infants. Pediatr Nephrol 2014; 29:1869.
  10. Hanudel M, Avasare S, Tsai E, et al. A biphasic dialytic strategy for the treatment of neonatal hyperammonemia. Pediatr Nephrol 2014; 29:315.
  11. Ge PS, Runyon BA. Serum ammonia level for the evaluation of hepatic encephalopathy. JAMA 2014; 312:643.
  12. Gupta S, Fenves AZ, Hootkins R. The Role of RRT in Hyperammonemic Patients. Clin J Am Soc Nephrol 2016; 11:1872.
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