Role of RRT in Adult Patients with Hyperammonemia

Abstract

Hyperammonemia is not uncommonly encountered in adult critically ill patients in the intensive care unit (ICU). Although it often occurs in patients with underlying liver disease, it may also occur in patients with no evidence of acute or chronic liver disease. Hyperammonemia can cause serious complications, including acute brain injury (sometimes called hyperammonemia-induced encephalopathy). Hyperammonemia-induced encephalopathy often carries a poor prognosis and may even lead to death. Nephrologists may get involved in the management of hyperammonemic patients (with or without acute kidney injury) for consideration of renal replacement therapy (RRT) as an intervention to lower the ammonia level. This chapter will discuss the role of RRT in adult patients with hyperammonemia.

1. Introduction

The term hyperammonemia denotes an elevated ammonia level in the blood, however, it is often used in clinical practice to refer to a toxic accumulation of ammonia in the blood with its associated serious complications. The normal reference range of ammonia level in adults is 10 to 80 mcg/dL or 6 to 47 μmol/L (SI units) [1], but this range may vary slightly among different laboratories. Ammonia is most damaging to the brain, and this applies to both acute and chronic hyperammonemia [2, 3]. Cerebral edema and brain herniation are more common in patients with acute hyperammonemia, but patients with chronic hypernatremia (e.g., chronic liver disease patients) may develop encephalopathy and have a different mechanism of neurotoxicity caused by hyperammonemia [2, 3]. This serious and potentially fatal condition must be promptly recognized, evaluated, and treated. Although the role of RRT in the management of patients with hyperammonemia is more evident in the pediatric population [4], it is less clear in the adult population. This chapter will give a brief overview of hyperammonemia pathophysiology, causes, manifestations, and general management, but will discuss in detail the available data about the role of RRT in adult patients with hyperammonemia.

2. Pathophysiology of hyperammonemia

Ammonia is normally produced via the metabolism of nitrogen-containing compounds [2]. The main sites of ammonia production in the body are the intestine, and to a lesser extent, the kidneys and the muscles [2]. In the intestine, the ammonia is produced via the digestion and metabolism of dietary proteins by the mucosal bacteria, via urease-producing bacteria and microbial proteolysis, as well as via the uptake of glutamine from the systemic circulation with subsequent deamination to glutamate and ammonia [2]. In the kidneys, ammonia is produced by the catabolism of glutamine in the proximal convoluted tubules (ammoniagenesis) [2]. In the muscles, ammonia is the product of muscle metabolism, and this production is increased in certain situations such as seizures, intense exercise, or in catabolic states [2].

The liver is responsible for clearing 90% of the ammonia in the body, and it converts ammonia to urea via the urea cycle [2]. If the liver fails or becomes overwhelmed by the excess production of ammonia, the kidneys will decrease the ammonia production in the proximal tubules, and will also increase the urinary excretion of ammonia. Additionally, the brain and the muscles will try to help by metabolizing ammonia to glutamine [2].

Ammonia metabolism is regulated by the extracellular pH, potassium level, and mineralocorticoids and glucocorticoid secretion in the body [2].

With severe hyperammonemia, the osmotic stress is increased in the astrocytes of the brain, which may lead to astrocyte swelling with subsequent cerebral edema and brain herniation. Additionally, the accumulation of glutamine in the astrocytes will affect the energy delivery to neurons, increase oxidative stress, and increase the production of inflammatory cytokines. Together will lead to cellular apoptosis, dysfunction of neurotransmitters, mitochondrial dysfunction, neuronal irritability, and alteration of blood-brain barrier [2]. All cell types of the brain are affected by these changes [2].

3. Causes of hyperammonemia in adults

Hyperammonemia occurs when there is increased production or decreased clearance of ammonia. In the adult population, liver failure is responsible for the majority of cases of hyperammonemia, while non-hepatic causes are rare and account for the minority of cases [2, 5, 6, 7, 8]. With non-hepatic causes of hyperammonemia, there is excessive production of ammonia which may exceed the handling capacity of the liver or may bypass the liver to enter directly into the systemic circulation [5, 6, 7, 8].

The causes of hyperammonemia in adults are summarized in Table 1.

Hepatic:
Most common cause in adults.
In chronic liver disease; it is precipitated by gastrointestinal bleeding, infection, electrolytes disturbance, or/and constipation.
Also, in patients with acute hepatic failure.
Non-Hepatic:
Increased production	Decreased clearance
Catabolic states: e.g., burn, trauma, starvation	Late-onset urea-cycle disorders: precipitated by a stressful condition
Nutritional: e.g., total parenteral nutrition	Bariatric surgery: e.g., gastric bypass
Infection: e.g., by urease-producing organisms	Anatomic: e.g., porto-systemic shunts, urinary diversion
Muscular: e.g., seizure, intense exercise	Anti-epileptics: e.g., valproate, topiramate, carbamazepine
Malignancy: e.g., multiple myeloma	Analgesics: e.g., gabapentin, salicylates
Drugs: e.g., steroids, 5-Fluorouracil, Cytarabine	Other drugs: tacrolimus, cyclosporine, acetazolamide, haloperidol
Others: gastrointestinal bleeding, hemolysis, organ transplantation	Others: organ transplantation

Table 1.

Causes of hyperammonemia in adults.

4. Clinical manifestations

In mild cases, symptoms may include headache, vomiting, irritability, behavioral changes, ataxia, and gait abnormalities [2, 7, 8]. Severe hyperammonemia may present with seizures, encephalopathy, coma, and even death [2, 7, 8].

In addition to the severity of hyperammonemia, the clinical manifestations depend on the onset (acute versus chronic). Patients with chronic hyperammonemia (e.g., chronic liver disease patients) have a gradual accumulation of ammonia, allowing for compensatory mechanisms to decrease osmolarity. Additionally, patients with chronic hyperammonemia may have compensatory increase in the ammonia metabolism by other organs (e.g., muscles), which may blunt some of the symptoms. Therefore, they are less like to present with cerebral edema and herniation than patients with acute conditions [5, 8].

5. General management

When managing a patient with hyperammonemia, several factors should be taken into consideration, including the onset (acute vs. chronic), presence or absence of symptoms, degree or severity of the hyperammonemia, and the underlying cause. Acute severe hyperammonemia carries the highest risk of adverse outcomes and is potentially fatal. Thus, all measures must be taken to lower the ammonia level rapidly [9]. The following are essential lines of general management [2, 8, 9, 10]:

• Ensure that the result is not falsely positive. If the blood sample was kept at room temperature for a long time, it will lead to in vitro deamination and falsely elevated ammonia levels. Therefore, in cases of hyperammonemia, the first step is to repeat the test with a sample taken without a tourniquet and placed on ice immediately at the bedside, and then processed within 30 to 60 minutes maximum [5, 9].

• In addition to monitoring ammonia levels, blood gases, and requesting appropriate neurological images, investigating for the underlying cause is important. For example, investigating for underlying liver disease by sending liver function tests, coagulation profile, alcohol and acetaminophen levels, viral serology, and liver ultrasound with the duplex study. Additionally, looking for a source of infection, especially infection with urease-producing organisms, is very crucial. If hyperammonemia is still not explained, one needs to consider investigating for underlying urea cycle disorders as soon as possible. As mentioned above, some of the cases of non-hepatic hyperammonemia in adults could be related to undiagnosed urea cycle disorder, which becomes unmasked under stressful conditions. Therefore, it might be prudent to involve a biochemical geneticist (metabolic) physician early on to provide some guidance on further investigations and management.

• Treating the underlying cause of hyperammonemia is also the best strategy to prevent the recurrence. But other strategies to lower the ammonia level should not be delayed if immediate management of the underlying cause is not feasible.

• Aim for a physiological pH between 7.35 and 7.44 and avoid alkalemia. Alkalemia will further increase the ammonia level by converting ammonium ion to ammonia. Hypokalemia must also be corrected as it may increase renal ammonia production.

• Ammonia level varies based on the patient’s age and there is no consensus about which level needs immediate action. However, a level above 100 μmol/L in adult patients is considered serious and requires immediate attention.

• Table 2 summarizes the non-dialysis lines of management, which are used to lower the ammonia level.

Nutritional	Stop all sources of protein (enteral and parenteral) for 48 hours only.
	Start high-rate IVF as D10%, 0.45 NS. Do not stop for any reason.
	For hyperglycemia, start insulin infusion.
	Contact the pharmacy to prepare lipid emulsion IV 2–3 g/kg.
Antibiotics	To treat any underlying infection and prevent superinfection.
	It may also alter gut flora and reduce the metabolizing intestinal bacteria.
	It is particularly important for immunocompromised patients.
	Consider both parenteral and enteral antibiotics
Laxatives	Use lactulose and other laxatives to decontaminate the gut.
	They reduce the production of ammonia by intestinal bacteria.
	Also, they promote the growth of non-urease-producing lactobacilli.
	Particularly important for patients with liver diseases.
Zinc	Check zinc level and give daily zinc supplementation.
	Zinc deficiency is common in alcoholics, malabsorption, or urinary loss.
	Zinc is a cofactor for urea cycle enzymes.
	So, it speeds up the urea formation from amino acids and ammonia.
Avoid	Valproic acid as it decreases urea cycle function.
	Steroids as they increase the protein turnover.
	Mannitol (ineffective in managing cerebral edema caused by hyperammonemia).
Empirical treatment for undiagnosed cases (functional deficiency or late-onset urea cycle disorder)
L-carnitine	It stimulates the synthesis of urea as it favors mitochondrial respiration.
	Start levocarnitine IV/PO 100 mg/kg/day divided q 6–8 h,
	Also give hydroxycobalamin 1 mg IM/IV/PO, and biotin 10 mg IV/PO
L-Arginine	It is a urea cycle enhancer and should be given in all cases of unknown etiology.
	Available as oral and intravenous.
Sodium phenylacetate + sodium benzoate	It promotes ammonia degradation through “alternate” metabolic pathways.
	Give IV KCL as it may cause hyperchloremic hypokalemic metabolic acidosis.
	To be considered when the ammonia level is >150 μmol/L
	Use with caution in hepatic and renal insufficiency, and watch for toxicity
N-carbamylglutamate	Give 100 mg/kg through NG once followed by 50 mg/kg q 6 h.
	Once appropriate enzymatic deficiency is excluded, it should be stopped.

Table 2.

General and initial lines of management for hyperammonemia.

6. Role of renal replacement therapy

6.1 Ammonia clearance by dialysis

In general, solute-related factors that may affect the extent of its removal by dialysis include its molecular size, its water solubility, its volume of distribution, and its protein binding. Ammonia is a small molecule with a molecular mass of 17 mg/mmol, it is water soluble, has a volume of distribution that is considered to be equal to the total body water, and is not significantly protein-bound [11]. Therefore, it is highly dialyzable.

Hemodialysis prescription-related factors affecting the clearance of ammonia include the blood flow rate (Qb), the dialysate flow rate (Qd), and the dialyzer surface area [12]. This is supported by an in vitro study of the clearance of ammonia with single-pass dialyzers, which showed that ammonia clearance by dialysis is between 62% and 99% and could approach that of the liver [12]. In this study, ammonia clearance was directly dependent on the blood flow rate, which was modulated by the dialysate flow rate. For example, when the dialysate flow rate is 300 ml/min, an increase in ammonia clearance was observed with an increase in blood flow until a plateau was reached at 200 ml/min. When the dialysate flow is 500 ml/min, the same was observed but it plateaued at a blood flow rate of 300 ml/min [12]. At a dialysate flow rate of 800 ml/min, a further degree of ammonia clearance was observed with increasing blood flow rate but no plateau was observed within the range of the blood flow rate used. In other words, with a blood flow rate of 200 to 300 ml/min and a dialysate flow rate of 800 ml/min, a rate of ammonia extraction of up to 99% can be seen if there is no ongoing generation of ammonia [12, 13]. The influence of the dialyzer surface area on ammonia clearance depends on the blood flow rate. With a blood flow rate of 500 ml/min and a large surface area dialyzer (2.1 m²), ammonia clearance may approach 450 ml/min. However, the ammonia clearance was not affected when using large surface area dialyzers at a blood flow rate of 100–200 ml/min. Of note, hemodialysis removes urea and glutamine, which may magnify the ammonia-lowering effects and benefits of hemodialysis [12].

6.2 Is dialysis indicated?

When coming to the role of RRT in the management of adult patients with hyperammonemia, it is important to remember that data reporting the clinical outcomes of this intervention and supporting its usefulness are limited. One retrospective review of adult patients in the intensive care unit (ICU) with hyperammonemia not due to liver failure showed that the requirement of dialysis was not a predictor of mortality [5]. However, this retrospective study of a small sample size does not inform us when to start RRT for such patients. It is difficult to have well-established evidence-based guidelines for managing adult patients with this condition with the rarity and heterogeneous nature of available data. One guideline discussing the acute management of hyperammonemia patients suggested starting RRT for adult patients when the ammonia level exceeds 200 μmol/L [9]. Nevertheless, the level of evidence to support this recommendation was low, and most of the recommendations in this guideline were based on extrapolated data from pediatric patients [9]. However, this extrapolation is of limited value because of different patients’ demographics, and different distribution of underlying causes of hyperammonemia. The following are the summaries of recommendations from different reports based on the authors’ opinions:

• Long et al. supported a more conservative initiation of RRT for ammonia levels >150 μmol/L (or > 200–250 μmol/L for adult cases of urea cycle disorder), for hyperammonemic encephalopathy, coma, or seizures, or for rising ammonia in the face of other therapy. If early and rapid clearance is necessary (e.g., impending brain herniation), plasmapheresis could be considered followed by CRRT [2]. This opinion was based mainly on case reports of patients with late-onset urea cycle disorders.

• Boer et al. suggested that dialysis should be considered in all patients with acute kidney injury and severe hyperammonemia when other treatment modalities fail to lower ammonia levels within hours [14]. This was the author’s opinion, and the definition of severe hyperammonemia was not clarified in his report.

• Alfadhel and Häberle J et al. published guidelines and suggested that RRT to be the first-line therapy in the case of adult patients with acute hyperammonemia when the ammonia level exceeds 200 μmol/L [9, 15]. However, this suggestion was based on the low level of evidence (case reports, case series, and expert opinion) from patients with urea cycle disorders.

• Stergachis et al. presented a retrospective study of adult patients with noncirrhotic hyperammonemia and reported that RRT was utilized with an ammonia level above 250 μmol/L (range 322 to 4530 μmol/L) [16]. No clear-cut recommendations or outcomes were reported.

• Gupta et al. reviewed the available literature on the role of RRT for patients with hyperammonemia, and the limited data in adult patients was acknowledged [10]. The conclusion was that the clinical judgment of the treating physician as to when to initiate RRT is important [10].

• Bélanger-Quintana et al. provided recommendations for the management of hyperammonemia in the adults and pediatric patients, and the initiation of RRT was recommended when the ammonia level is >150–200 μmol/L [17].

With the lack of strong evidence, and thus the lack of consensus recommendations, the decision about initiating RRT for adult patients with hyperammonemia needs to be individualized. This must take into consideration if other treatment modalities failed to lower ammonia levels or not, the presence of neurological consequences of hyperammonemia, and the ammonia level (more than 150 μmol/L). The role of RRT in some of the identifiable causes of hyperammonemia is discussed below.

6.3 Continuous renal replacement therapy (CRRT) vs. intermittent hemodialysis

If the decision was made to start renal replacement therapy for the management of hyperammonemia, the next decision to make is whether to start intermittent hemodialysis or CRRT. To decide about this, a few points must be remembered:

• At the beginning of dialysis, the production of ammonia is likely more than the elimination, until the levels reach a steady state [11].

• Intermittent hemodialysis can lower blood ammonia levels rapidly and efficiently [6, 11, 12]. In fact, in vitro data of a single-compartment dialysis model showed that ammonia was decreased by 80% during the first half an hour of hemodialysis [12]. This rapid onset of action is very important to prevent brain injury. However, ammonia has a high volume of distribution, and once conventional hemodialysis is stopped, it diffuses back from the extravascular space. This rebound effect is considered a major disadvantage of intermittent hemodialysis, especially if ammonia generation is continued [11].

• On the other hand, CRRT will provide a steady removal of ammonia, and its continuous nature will address the issue of rebound increase in ammonia level seen with intermittent HD. However, it provides a slow rate of ammonia clearance compared to intermittent hemodialysis., and it will take a longer time to reach a steady state [11].

A scoping review of 28 studies looking at ammonia clearance by RRT in adult and pediatric patients concluded that intermittent hemodialysis provides the highest ammonia clearance followed by CRRT and, at very low levels, peritoneal dialysis [6]. In this review, clearance correlated with Qb and Qd in the case of intermittent hemodialysis, and with the effluent flow rate in CRRT [6].

Therefore, it might be prudent to start with conventional hemodialysis to ensure rapid reduction in ammonia level, followed by CRRT to prevent the rebound increase in ammonia level. However, this decision needs to be individualized and must take into consideration the advantage and disadvantages of each modality of RRT, the available resources, patient’s condition, ammonia generation and metabolism in each specific case, and various organ functions (e.g., kidneys, liver, muscles, intestine, and brain) [11].

Of note: ammonia is osmotically active, yet, its rapid removal by dialysis is not associated with dialysis disequilibrium syndrome [18]. This is because the contribution of ammonia (even in the case of severe hyperammonemia) to plasma osmolality is negligible [17]. Additionally, the rapid equilibration of ammonia across the cell membrane will minimize any risk of dialysis disequilibrium syndrome.

6.4 Dialysis prescription

Dialysis prescription need to be tailored according to the patient’s condition and diagnosis. The main aim is to provide a rapid reduction of ammonia levels, and then attempt to prevent ammonia rebound to prevent irreversible neurological damage.

Considering all the above-discussed points, below is a suggested prescription of RRT for adult patients with acute hyperammonemia [11, 14].

Initially, consider starting with a session of intermittent hemodialysis with the following details:

• Blood flow (Qb) of 400 to 450 mL/min.

• Dialysate flow (Qd) of 800 mL/min.

• If the patient is hemodynamically unstable or then developed new onset symptoms suggestive of cerebral edema, Qb could be decreased to 250 mL/min and Qd to 500 or 600 mL/min.

• Session length of 4 to 6 hours.

After the completion of the first session of intermittent hemodialysis, CRRT should be immediately started:

• Mode: continuous venovenous hemofiltration (CVVH). It is acceptable to use continuous venovenous hemodialysis (CVVHD) instead and adjust the dialysate flow rate accordingly.

• Blood flow (Qb) of 250 mL/minute.

• Replacement: replacement fluid (RF) at a rate of 50 ml/kg/hour.

• If circuit anticoagulation is used, citrate should be avoided in patients with liver disease.

• Monitor ammonia level Q 12 to 24 hours.

• If the ammonia level continues to rise, increase the Qb to a maximum of 300 mL/min and the replacement fluid to a maximum of 80 mL/kg/hour. If the patient developed alkalemia, the rate of the replacement fluid could be lowered again.

Continue monitoring the patient’s ammonia level and arterial blood gases, and perform frequent neurological assessments. If the ammonia level does not improve or it continues to rise, the following options could be considered:

• Repeat the cycle of intermittent hemodialysis followed by CRRT.

• Consider using an ultra-high dose of continuous venovenous hemodiafiltration (CVVHDF) after a session of intermittent hemodialysis. This method was successful in one case report of a woman with refractory hyperammonemia (caused by acute liver failure, AKI, pelvic hematoma, and uterine necrosis) and cerebral edema complicating an emergency cesarean section [14]. In this case, they used intermittent hemodialysis with Qb of 400 ml/min, and Qd of 500 ml/min, for a duration of 4 hours, followed by immediate start of CVVHDF with 2 CRRT machines, resulting in an ultra-high effluent rate (100 mL/kg/hour). For each of the CRRT machines, the Qb was 160 mL/min; RF rate was 1400 mL/h; and Qd was 2800 mL/h. This strategy was successful to restore the patient’s baseline neurological condition [14].

Dialysis could be discontinued if the patient is back to the baseline neurological status, the ammonia level has decreased or stabilized, and if no improvement in the neurological status despite 48 hours of maximum therapy and decreasing ammonia level. In the latter situation, a new CT or MRI of the brain should be considered.

6.5 Dialysis and cause-specific situations

6.5.1 Liver disease

In patients with chronic liver disease; the rise in serum ammonia is slow and gradual [19]. As mentioned before, this slow rise will allow for compensatory mechanisms to decrease the osmolarity, and also for compensatory increase in the ammonia metabolism by other organs [5, 8, 19]. Therefore, hemodialysis in chronic liver disease patients (who may already have chronic hyponatremia) may worsen cerebral edema due to the rapid reduction of osmolality, rapid change in the blood pH, and the effect of the bicarbonate-based solution on increasing CO2 production and cerebral vasodilatation [19]. Therefore, RRT for the sole purpose of hyperammonemia in chronic liver disease patients is not indicated, and there is insufficient data to support its use in such a setting [19]. If RRT is used for the conventional indications in the setting of AKI, CRRT with its slow nature of clearance is less likely to worsen cerebral edema, especially with lower Qb rates [11, 19].

In adult patients with acute liver failure and hyperammonemia, CRRT provides significant ammonia clearance and this clearance was shown to be correlated with the ultrafiltration rate [20]. In one retrospective analysis of adult patients with hyperammonemia and acute liver failure, early start of CRRT (likely for hyperammonemia rather than for conventional indication of AKI) was associated with prevention of worsening hyperammonemia, which in turn, was associated with increased transplant-free survival [21]. However, ICU mortality was nearly four times higher in this group of patients [21]. Another retrospective review showed that the early start of CRRT in patients with acute liver failure and hyperammonemia resulted in reduced ammonia concentration, and this effect was related to the cumulative dose of dialysis [22]. However, most patients in this study did not demonstrate obvious neurologic recovery during the initial 5 days of ICU management despite the reduction in ammonia level [22]. There is also some evidence to support the use of high-volume plasma exchange in this group of patients [23, 24].

To summarize, the early start of RRT for hyperammonemia (level > 100 μmol/L) may have a beneficial role in patients with acute liver failure. CRRT is preferred over intermittent hemodialysis in patients with liver diseases.

6.5.2 Multiple myeloma

Patients with multiple myeloma may develop hyperammonemia, which may lead to encephalopathy or even death. The mechanism of hyperammonemia in multiple myeloma is unknown, but possible mechanisms are: the production of ammonia by myeloma cells as a result of amino acid metabolism, the Infiltration of the liver by plasma cells or amyloid leading to systemic-portal shunt, and the interference with urea metabolism, and some subtypes of multiple myeloma might undergo leukemic changes which would predispose these patients to hyperammonemia [25].

Treatment of hyperammonemia in such patients is by treating the underlying multiple myeloma, which will lead to a sustained and rapid reduction in the ammonia level as well as an improvement in the mental status [8, 13, 26]. Data about the role of RRT suggests that dialysis plays only a minor role in lowering ammonia in this patient population [26]. Some data showed that patients who received hemodialysis without concurrent therapy of the underlying myeloma had no response [25]. However, if definitive treatment cannot be immediately instituted for any reason, RRT could be considered depending on the severity and clinical status. In one report of severe cases of hyperammonemia in the setting of multiple myeloma, simultaneous hemodialysis and CVVHD were successfully used to augment ammonia clearance, allowing for definitive treatment to be administered [13].

6.5.3 Valproic acid-induced hyperammonemia

Therapeutic concentration of valproic acid is between 50 and 100 mg/L (350–700 μmol/L). Valproic acid-associated hyperammonemia may occur after acute overdose or chronic use and does not necessarily result in clinical encephalopathy [27]. Hyperammonemia in this setting is because valproic acid and its metabolites inhibit enzymes and cofactors necessary for normal functions of urea cycle. Valproic acid is primarily metabolized in the liver. In case of toxicity, management is usually supportive (e.g., protection of airway, cardiovascular stabilization, and supplementation with L- carnitine). Valproic acid has a small molecular mass of 144 Dalton, a small volume of distribution, and is highly protein bound [27]. At therapeutic levels, RRT has little impact on the elimination of valproic acid because of its high degree of protein binding, which limits the amount of free drug available for diffusion. In case of overdose, protein-binding sites become saturated and more free drug is available for elimination by RRT. Therefore, in the case of valproic acid intoxications associated with hyperammonemic encephalopathy, dialysis serves a definitive role in correcting hyperammonemia. This is regardless of the underlying renal function.

RRT is recommended in the following situations [27]:

• Serum valproic acid concentration is more than 1300 mg/L (9000 μmol/L),

• Cerebral edema, or

• Shock attributed to valproic acid toxicity.

RRT is suggested if any of the following is present [27]:

• Serum valproic acid concentration > 900 mg/L (6250 μ mol/L).

• Coma or respiratory depression requiring mechanical ventilation.

• Acute hyperammonemia.

• pH is less than 7.10.

Intermittent hemodialysis is the preferred method of RRT in such cases, followed by CRRT if intermittent hemodialysis is not feasible. RRT can be discontinued when [27]:

• The valproic acid is between 50 and 100 g/L (350 to 700 micromol/L).

• There is clinical improvement like improvement in hemodynamics, or improvement in mental status.

• Improvement in electrolytes and acid-base abnormalities.

6.5.4 Organ transplantation and hyperammonemia

Hyperammonemia is a rare but serious complication following solid-organ transplantation. The most common occurrence is after lung transplantation, and to a lesser extent after other solid-organ transplant transplantations [28]. The mechanisms of hyperammonemia in transplant recipients are not well understood. The mortality is usually high in such patients; therefore, prompt recognition and treatment are necessary [28]. Conservative therapy is usually ineffective, and RRT is often required in most patients [28]. The RRT modality depends on the patient’s condition and hemodynamic status.

6.5.5 Seizure

It is difficult to differentiate if hyperammonemia is caused by seizure or vice versa [2]. If seizure is unlikely to be caused by hyperammonemia, then traditional investigations and management of seizure need to be instituted. Hyperammonemia caused by seizure is more common in patients with generalized tonic-clonic seizures [29]. It is usually self-limiting and rarely requires RRT. In such cases, ammonia clearance is usually rapid over 3–8 hours [29]. In all cases, it is important to closely monitor the ammonia level and decide accordingly.

6.5.6 Urea cycle disorders

Adult patients with urea cycle disorders may present as already-diagnosed cases, with hyperammonemia being part of the acute relapse presentation. Less commonly, they may manifest for the first time in adulthood when they are exposed to stressful conditions [2]. It is important in known cases, or in undiagnosed non-hepatic cases of hyperammonemia, to immediately start all previously mentioned lines of management (see Table 2). These are specifically important as empiric therapies when the ammonia is more than 100 μmol/L. Consultation with a genetic specialist is important to guide further investigation and therapies [2]. The level at which RRT is initiated varies between guidelines and recommendations [2, 17]. In adult patients, ammonia level > 150–200 μmol/L or > 200–250 μmol/L have been suggested [2, 17]. However, other previously mentioned indications (e.g., hyperammonemic encephalopathy, coma, seizures, or rising ammonia despite conservative therapy) should also be considered when deciding about RRT. Intermitted hemodialysis is the preferred modality in such cases, and sometimes can be followed by CRRT.

7. Peritoneal dialysis and hyperammonemia

Data suggest that peritoneal dialysis (PD) is insufficient to achieve adequate ammonia clearance compared to other modalities of RRT [6]. A scoping review of data addressing the ammonia clearance by PD indicated a low rate of clearance (less than 40 mL/min). Unfortunately, studies about the effectiveness of PD in the management of adult patients with hyperammonemia are limited. PD might be considered when other effective forms of RRT are not readily available.

8. Conclusions

Hyperammonemia is a serious condition and must be considered in all patients with unexplained alterations in neurological status. Hyperammonemia in adult patients is usually caused by liver diseases, and non-hepatic causes are uncommon. Treatment of non-hepatic causes of hyperammonemia includes general supportive measures, as well as investigating and treating the underlying cause. Data about the role of RRT in the management of adult patients with hyperammonemia are limited. In such cases, many factors must be taken into consideration, including the clinical condition of the patient, severity of hyperammonemia, underlying cause, and response to supportive therapy. If RRT is considered, the choice of modality and the dialysis prescription depend on the patient’s condition and available resources. Intermittent hemodialysis provides the highest and the most rapid degree of ammonia clearance, followed by CRRT, then PD.

Conflict of interest

The authors declare no conflict of interest.