**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:


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


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:


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 bicarbonatebased 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]:


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


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]:


#### *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.
