INTRODUCTION

Ammonia is a resultant molecule from the normal protein metabolism, but in high concentrations can be toxic and lead to severe neurological dysfunction, with irreversible cerebral damage¹. Ammonia intoxication can occur in patients with urea cycle defects, organic acidemias, fatty acid oxidation defects, liver failure, Reye syndrome, post‑chemotherapy or due to exposure to various toxins or drugs¹.

The metabolism of ammonia depends on the enzymatic activity of multiple organs, including kidneys, liver, muscle, intestine and brain.

The intestine is the largest producer of ammonia. It is generated by the intestinal mucosa, from the intraluminal metabolism of amino acids, and through the bacterial degradation of urea and other nitrogenous products. It then enters the portal circulation to the liver for detoxification. Finally, its elimination occurs through the conversion to urea in the liver and to glutamine in the brain and muscle. Urea synthesized in the liver undergoes hydrolysis at the level of the intestine, generating ammonia, which in turn returns to the liver to be converted back into urea. In addition to the urea cycle, the liver also processes ammonia through its use for glutamine synthesis^1-3.

Several theories try to explain the occurrence of encephalopathy secondary to high levels of ammonia^1,2,4,5. The cerebral cells most affected by hyperammonaemia are the astrocytes⁶. They are the main carriers of glutamine synthetase in the brain, which is responsible for the conversion of ammonia and glutamate into glutamine^4,6. In turn, glutamine appears to play a key role in ammonia neurotoxicity in hepatic encephalopathy. Its action occurs either, indirectly, by the formation of reactive oxygen species, or directly, since it causes edema of astrocytes, contributing to cerebral dysfunction associated with hyperammonemia^7-9. In addition to the damage to astrocytes via the glutamine pathway, ammonia itself is also neurotoxic^1,7,8.

The presence of acute kidney injury (AKI) can be both the cause and effect of the pathological process that increases blood ammonia levels². In the presence of renal dysfunction, up to 20% of the daily ammonia excreted at the renal level may be compromised¹⁰.

Although there is no clear cut‑off of the ammonia blood level that correlates with the presence of neurological signs and symptoms, concentrations above 150‑200umol/L appear to be associated with increased intracranial pressure, cerebral herniation and death¹¹, especially in the presence of liver failure¹². Neurological manifestations require prompt intervention.

The role of extracorporeal dialysis in reducing blood ammonia levels and improving cerebral edema is still uncertain. While in children there are some studies that show the effectiveness of various dialysis techniques (peritoneal dialysis, intermittent hemodialysis and continuous techniques), in adults the literature is scarce. There are no established guidelines on which ammonia value justifies initiating extracorporeal dialysis technique (ECDT) or which techniques are more appropriate in the case of hyperammonemic encephalopathy^3,10,13.

Our case aroused the interest of a multidisciplinary team to the creation of a protocol for patients with encephalopathy due to hyperammonemia, since a good neurological outcome requires a prompt intervention.

CASE REPORT

Our case describes a 22‑year‑old, previously healthy, woman, with no known allergies and no drugs or herbal medicines consumption.

Besides her 54‑year‑old father who had type 2 diabetes, she had no other relevant family history.

She presented with polyuria, polydipsia, anorexia, vomiting and significant (>10%) weight loss over a month. At admission, the patient was hemodynamically stable and presented Kussmaul breathing, slurred speech, but showing orientation to time, place and person.

Cold extremities were detected. Laboratory data revealed hypoglycemia (57 mg/dL), high anion gap metabolic acidosis with severe acidemia, normal lactate, sérum creatinine of 1.12 mg/dl and 261 (N 26‑74) umol/l of ammonia. Urine analysis showed ketone bodies,

She evolved with progressive encephalopathy and neurological deterioration. In the presence of hypoglycemic with ketonuria and hyperammonemic encephalopathy, a hereditary metabolic disease was suspected. Lipids and protein ingestion were stopped, and glucose solution, carnitine and benzoate were started. It was decided to start a blood purification technique for ammonia removal and acid‑base correction.

Continuous venovenous hemodiafiltration (CVVHDF) was performed for 3 days with a drastic neurologic improvement. Table 1 demonstrates the concomitant evolution of her analytical parameters.

Further investigation was done to find the etiology of the metabolic disorder. Plasma amino acids quantification revealed low counts of valine, leucine, tyrosine and arginine and acylcarnitines dosing showed low free carnitine level and high tetradecanoyl-, tetradecenoyl‑and hexadecenoylcarnitine, suggesting a fatty acid beta‑oxidation deficit.

She had a full recovery, and at the time of discharge had no neurological changes, with a strict diet free of fat, animal protein and high‑protein vegetables, plus supplementation with benzoate, carnitine, riboflavin, maltodextrin and essential amino acids.

Etiologic study was conducted, and a genetic test was performed with a result compatible with type 2 glutaric aciduria. After supplementation, the levels of free carnitine were within the normal range of values 32.83 uM (reference value 19.24‑48.48 uM) and the specific plasma acylcarnitines were above the normal range.

DISCUSSION

Type 2 glutaric aciduria or multiple acyl‑CoA dehydrogenase deficiency can present as a hypoketotic hypoglycemia. However, hypoketotic is different from nonketotic and the presence of minimal ketone bodies, as we have seen in this patient in the beginning of the case report, doesn’t exclude our diagnosis¹⁴.

The treatment for acute hyperammonemia should be instituted as soon as possible with the aim of rapidly reducing both the production of nitrogen degradation products and blood ammonia levels.

Rapid rehydration, discontinuation of protein intake and electrolyte and mineral imbalances correction should be performed^1,15. The best timing for EBPT initiation in these patients is yet to be defined.

However, it has been proposed to start when blood ammonia levels are three times higher than the upper limit of normal or in the presence of severe encephalopathy¹⁶. Warrilow and Bellomo¹⁷ suggest that the onset of EBPT should occur in the early stages of hyperammonemia, before the development of AKI. A study carried out in patients with valproic acid intoxication reported clinical improvement when extracorporeal techniques were started within the first 24 hours after admission¹⁸.

There are important factors that determine whether a toxin or medication can be successfully removed by a dialysis technique, mainly the molecular weight and toxin ability to bind to plasma proteins, particularly albumin². Another factor to be considered is the rebound effect, which consists of the moving of the drug from the extravascular to the intravascular compartment. Ammonia has a low molecular weight (17g/mol) and does not bind significantly to plasma proteins, making it easily dialyzable. However, it has an important rebound effect, that is why, in children, continuous and intermittent techniques have been shown to mitigate this effect and consequently reduce significantly blood ammonia concentrations¹⁹.

Both continuous and intermittent techniques are effective in removing ammonia, differing only in the removal rate. Intermittent techniques are very effective in rapid ammonia clearance, which is the main reason for their choice^17,20. They allow a 50% reduction in blood ammonia concentrations in just 1 to 2 hours, compared to the 2 to 14.5 hours of continuous techniques²⁰. Still, other studies favor continuous techniques since they allow a constant removal of ammonia as it is being produced, plus they are associated with greater hemodynamic stability and slower reductions of cerebral ammonia levels^2,21.

High filtration rates lead to a greater reduction in ammonia concentrations, presumably related to the greater dilution due to the volume of substitution (> 35mL/Kg/hour)¹⁰.

Some authors suggest that intermittent techniques reduces more effectively ammonia blood levels leading to a more rapid resolution of the encephalopathy, which appears to be a major determinant of short‑term outcomes^22,23. Since ammonia has a high diffusive clearance and because its diffusion rate is largely determined by blood flow (Qb), the use of intermittent techniques allows a higher rate of blood ammonia removal. However, the choice of the technique depends on the availability and experience of each center and on which is possible to start earlier. Continuous techniques should be used in order to prevent rebound and ideally after intermittent technique is discontinued¹⁹.

It is also important to point out that caution should be taken to avoid alkalosis and hypokalemia since it can lead to increase of NH3 production, which can cross the hematoencephalic barrier, contrarily to NH4+, and exacerbate the encephalopathy².

It is difficult to understand the real impact of a specific intervention in the setting of measures adopted to treat these pathologies, namely metabolic corrections and diets low in protein.

Although the data is inconsistent, the standard of care in hyperammonemia consists of rapid hydration, use of nitrogen chelators and continuous high‑dose techniques^24,25.

At our center, in the presence of patients with hyperammonaemia (blood levels superior to 200umol/L) and severe encephalopathy, with suspicion of an associated enzyme deficit, an EBPT is began as soon as possible. If the patient is hemodynamically stable, we prefer to initiate a prolonged intermittent technique (SLED - sustained low efficiency dialysis), given the greater capacity of ammonia purification rate. But if hemodynamic instability is present, we would elect a continuous technique (CRRT - continuous renal replacement therapy) and although it has a lower ammonia removal rate, it would avoid the rebound effect. Moreover, although not performed at our center, in case of hemodynamic stability, one could consider a hybrid protocol with intermitente hemodialysis followed by a continuous technique in order to maximize ammonia removal plus avoid the rebound effect²⁶.

According to the experience of the staff of the intensive care unit on the day of the admission, CRRT was the modality selected, even though our patient was hemodynamically stable.

Serum dosage of ammonia should be performed before and after the technique. The ECDT is suspended when the maintenance of the plasma ammonia concentration is below 100 umol/L after, at least, 12 hours of technique suspension, and if there is concomitant neurological improvement.

Our SLED scheme consists of the use of Qb from 100 to 200mL/min with a dialysate flow (Qd) of 300ml/min for a 10‑hour period. When we use CRRT, and considering ammonia’s low molecular weight, we give primacy to a technique with a diffusion mechanism, as CVVHD and CVVHDF²⁶. If we consider CVVHDF, we aim to reach a replacement volume superior to 35ml/Kg/h in post dilution. For both techniques we use bicarbonate‑based solutions with a high level of potassium, in order to reach values between 4 and 4,5 mmol/L. The choice of hypocoagulation is made individually according to each patient characteristics.

Table 2 summarizes the studies published to date in the field of the use of EBPT for the management of acute hyperammonemic encephalopathy.

CONCLUSION

Hyperammonemia in adults is usually associated with liver failure rather than with metabolic disorders, as in our patient.

In the presence of encephalopathy, EBPT should be considered. Ammonia, as urea, is a small molecule and does not bind significantly to proteins, and is easily dialysable either by intermittent or continuous techniques.

Although greater Qb can be achieved by intermittent hemodialysis, CVVHDF offers a more continuous clearance, with less rebound effect.