Nephrology Dialysis Transplantation 2005 20(2):453-455; doi:10.1093/ndt/gfh495
Nephrol Dial Transplant Vol. 20 No. 2 © ERA–EDTA 2005; all rights reserved
Teaching Point
(Section Editor: K. Kühn)
Supported by an educational grant from 
Successful extracorporeal treatment of a male with hyperammonaemic coma
Maria Haller1,
Angelika Henzler-Le Boulanger2,
Jörn Oliver Sass1,
Matthias Brandis1 and
Lothar Bernd Zimmerhackl1
1 Zentrum für Kinderheilkunde und Jugendmedizin, Albert-Ludwigs-Universität, Freiburg und 2 Kinderklinik, Kliniken des Landkreises Lörrach, Lörrach, 3 Klinik für Kinder- und Jugendheilkunde, Med. Univ. Innsbruck, Germany
Correspondence and offprint requests to: Professor Dr Lothar-Bernd Zimmerhackl, Universitätsklinik für Kinder- und Jugendheilkunde, Anichstraße 35, A-6020 Innsbruck, Austria. Email: othar-bernd.zimmerhackl{at}uklibk.ac.at
Keywords: citrullinaemia; haemodiafiltration; inborn errors of metabolism; intensive care; nutrition; peritoneal dialysis
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Introduction
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Children with urea cycle disorders present with hyperammonaemia
and its non-specific symptoms. Acute hyperammonaemia is a medical
emergency as the developmental and neurological outcome depends
on the duration of hyperammonaemic coma [
1]. The longer endogenous
protein catabolism continues, the more ammonia will be produced
and accumulate and the greater is the risk of coma. To minimize
permanent brain damage, early diagnosis and appropriate therapy
is mandatory. With diagnosis of hyperammonaemia, it is essential
to differentiate between urea cycle defects and other causes
of encephalopathy. In
Figure 1 a practicable flowchart for establishing
the correct diagnosis is depicted [
2]. The emergency therapy
in children with inborn metabolic disorders presenting with
acute hyperammonaemia includes protein restriction, high caloric
nutrition using carbohydrates and (later on) lipids, and activation
of alternative nitrogen pathways by administration of sodium
benzoate and/or phenylbutyrate/phenylacetate. Arginine supplementation
can replenish urea cycle substrates. Additionally, essential
amino acids should be given. Renal replacement therapy is indicated
in cases of rising ammonia levels despite intensive therapy
and has been proposed (without established evidence for this
value) as an indication if ammonia levels are >400 µmol/l.
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Fig. 1. Flowchart for the differential diagnosis of hyperammonaemia (CPS = carbamyl phosphate synthetase deficiency; NAGS = N-acetylglutamate synthetase deficiency; OTC = ornithine transcarbamylase deficiency; AG = arginase deficiency; ASS = argininosuccinate synthetase deficiency; ASL = argininosuccinate lyase deficiency. The diagnostic path in our patient is marked in red (figure adapted from [2]).
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Case
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A male newborn (37 weeks of gestation, birth weight 2860 g,
length 50 cm) was admitted to hospital due to symptoms of vomiting,
temperature instability, arterial hypertension and hyperexcitation
on the second day of life. The next morning, he developed impaired
consciousness and muscular hypotonia; extensive diagnostic procedures
were conducted and revealed an ammonia level of 406 µmol/l
and a lactate level of 2.5 mmol/l. The patient showed a mild
respiratory alkalosis with normal electrolytes. Prothrombin
time (PTT) and international normalized ratio (INR) were elevated
(PTT 41 s, INR 1.8). Restriction of natural protein was initiated.
Emergency measures were taken by administration of sodium benzoate
to activate alternative nitrogen waste pathways, and administration
of arginine and high dosage intravenous glucose to stop catabolism
and to keep the urea cycle at high throughput. The diagnosis
of citrullinaemia with a plasma citrulline of 2827 µmol/l
and plasma glutamine of 3777 µmol/l was established. Despite
this therapy, the serum ammonia level rose during the following
hours to 609 µmol/l and the lactate to 4 mmol/l. The same
day, the infant was transferred to our university hospital which
has specialized units for dialysis and inborn errors of metabolism
for further treatment. On admission, the baby was stuporeous
with muscular hypertension. Laboratory tests showed a venous
pH of 7.36, normal values for electrolytes, albumin, alanine
aminotransferase and blood cell count. The creatinine concentration
was 106.96 µmol/l on day 3, and the total bilirubin was
152.19 µmol/l (age-adapted normal value: up to 205 µmol/l).
The serum ammonia showed a level of 874 µmol/l (normal
value: up to 40 µmol/l). After appropriate vascular access,
haemodiafiltration (HDF) was started [blood flow rate 45–65
ml/min, dialysate flow rate 1000 ml/h (dialysator: Baxter BM
11, filter: Cobe 100), dialysate bath: HF-BIC 35-010, bicarbonate
haemofiltration solution, Fresenius Medical Care)]. At that
point, the serum ammonia level was 1223 µmol/l. After
4.5 h of HDF, the serum ammonia level had decreased to 588 µmol/l
(see
Figure 2). A new prescription of HDF was chosen because
of an immediate rebound of the serum ammonia level to 688 µmol/l
1–2 h after stopping HDF. After the following 2 h of HDF,
the serum ammonia level decreased to 89 µmol/l. In combination
with the above-mentioned nutritional management and the supplement
of medication, the serum ammonia concentration did not rise
above 30–50 µmol/l during the next 7 days (
Figure 3).
Dialysis was no longer necessary. With the clearance of
ammonia by dialysis, the patient clinically improved immediately:
he regained consciousness at the end of dialysis and had a normal
muscular tonus. The electroencephalograph (EEG) showing initially
general suppression also improved within several days. The patient
is now 22 months old and appears to have a normal neurological
development under continuous management. Feeding is performed
via a percutaneous gastrostomy fistula.
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Fig. 2. Course of the serum ammonia level in our patient during haemodiafiltration (HDF) combined with protein restriction, high caloric nutrition and administration of sodium benzoate, phenylacetate and arginine.
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Fig. 3. Mathematical exponential one-compartment-model for the elimination of ammonia during peritoneal dialysis and haemodialysis [C(t) = C0(CAT) x e–(CL x t/V); 1 g protein = 33 mM NH3; CAT = catabolism (% of energy demand provided by protein); V = 0.58; onset concentration 500 µM/l NH3]. All underlying dialysances correspond to literature data. There is an assumption of 0% endogenous protein catabolism.
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Comments
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The inital therapeutic modality for rapid correction of acute
hyperammonaemia in children with inborn metabolic disorders
is protein restriction combined with high caloric nutrition
(glucose up to 30–35 g/kg/day) via a central venous line
to stop endogenous protein catabolism. In combination with the
halting of catabolism and activation of alternative nitrogen
waste pathways, renal replacement therapy is mandatory for treatment
of acute hyperammonaemia [
3]. Peritoneal dialysis (PD) provides
insufficient clearance of ammonia, while haemodialysis (HD)
leads to a significantly higher and more rapid reduction of
ammonia as a result of higher dialysance. In
Figure 3, a mathematical
exponential one-compartment model, as used in pharmacodynamic
studies and the description of dialysance characteristics, was
used to describe the behaviour of serum ammonia with regard
to the different dialysances of PD, HD and HDF. During HD and
HDF, the serum ammonia level dropped much faster than during
PD. Furthermore, assuming that a catabolic state is present
and 0.5% of the energy demand is provided by protein catabolism,
the situation would be even more aggravated in favour of HD
(not shown as the figure). Due to the high volume filtered during
HDF, this form of dialysis allows a higher infusion rate enabling
administration of large amounts of calories as an intravenous
infusion to prevent or to interrupt catabolism.
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Teaching points
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- For a good neurological outcome of patients with a hyperammonaemic coma, early diagnosis and rapid initiation of therapy including dialysis is mandatory.
- Due to a better ammonia clearance (dialysance) and the additional possibility to administer high levels of intravenous fluid replacement, which allows high caloric nutrition, HDF should be used. PD is insufficient because of significantly lower clearance characteristics.
- Special care should be taken to use appropriate equipment for the size of the patient (low extracorporeal blood volume, small filter with low filter volume, etc.). Therefore, it is important to transfer patients with severe hyperammonaemia as soon as possible to a specialized centre, where HDF and monitoring of ammonia and amino acids can be performed.
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Acknowledgments
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We thank Dr M. Baumgartner, UKBB Basel, Switzerland, for establishing
the diagnosis of the patient and for his information regarding
the neurological development of the patient, and Dr Beate Ermisch-Omran,
Freiburg, for fruitful discussion. Parts of this publication
have been presented at the annual meeting of the Deutsche Gesellschaft
für Kinderheilkunde und Jugendmedizin in Freiburg 2001
and appeared as an abstract (
Monatsschr Kinderheilkd 2001; 149
[Suppl 2]: 184).
Conflict of interest statement. None declared.
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References
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- Msall M, Batshaw ML, Suss R, Brusilow SW, Mellits ED. Neurologic outcome in children with inborn errors of urea synthesis. Outcome of urea-cycle enzymopathies. N Engl J Med 1984; 310: 1500–1505[Abstract]
- Mathias RS, Kostiner D, Packman S. Hyperammonemia in urea cycle disorders: role of the nephrologist. Am J Kidney Dis 2001; 37: 1069–1080[Medline]
- Ermisch B, Hildebrandt F, Zimmerhackl LB et al. Behandlung des hyperammonämischen Komas bei Neugeborenen und Säuglingen durch Hämodialyse oder Hämodiafiltration. Monatssch Kinderheilkd 1997; 145: 714–718[CrossRef]
Received for publication: 2. 7.03
Accepted in revised form: 12. 8.04
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