R Vargha, D Möslinger, *O Wagner and J Golej
From the General Hospital of Vienna, Department of Pediatrics and Adolescent Medicine, Division of General Pediatrics and Neonatology; and *Department of Neonatology, Landesfrauen- und Kinderklinik Linz, Austria.
Correspondence to:
Dr Regina Vargha, General Hospital of Vienna, Department of Pediatrics and Adolescent Medicine, Währinger Gürtel 18-20, Austria – 1090 Vienna.
Email: [email protected]
Received: April 19, 2010;
Initial review: May 18, 2010;
Accepted: September 24, 2010.
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The accumulation of toxic metabolites leads to the
neurological deterioration of newborns with
inborn urea cycle disorder and is associated with
high morbidity and mortality, when cerebral edema appears. We herein report a neonate where attempts of pharmacological lowering and the extracorporeal removal of plasma ammonia levels [1] were expanded to include therapeutic hypothermia.
Case Report
A 50-hour-old, term, newborn boy (gestation 39 weeks, birthweight 3.2kg) was admitted to a neonatal intensive care unit in an external hospital because of respiratory failure and convulsions. Infection parameters were negative, but arterial lactate was increased (6.3 mmol/L). Initial metabolic workup showed an ammonia concentration of 2320 µmol/L. Because of a suspected urea cycle disorder, protein intake was stopped and intravenous sodium benzoate, arginine-hydrochloride and high glucose were started. The boy was transferred to our institution by helicopter. The newborn had hepatomegaly, and adequate oxygenation and perfusion under moderate catecholamine and ventilator support.
Cardiac ultrasound revealed a small muscular ventricle septal defect without hemodynamic relevance, and the ductus arteriosus had already closed. Transfontanella doppler sonography showed systolic peaks and a markedly elevated pulsatility index of 3.0 (normal values 0.65-0.85) in the anterior cerebral artery [2]. Assuming the presence of cerebral edema, therapeutic hypothermia was started immediately and carried out according to our institutional protocol of neuroprotection, by cooling the boy instantly to a rectal temperature of 33.0°C for 48 hours using CritiCool™ cooling therapy system (MTRE Advanced Technologies, Israel), after obtaining parental informed consent.
The child was loaded with a combination of arginine–HCL 4 mmol/kg/h and sodium benzoate 250 mg/kg/h, simultaneously. L-carnitine was added with 75 mg/kg/d. Parenteral nutrition was continued with glucose 8.5 mg/kg/min and fat (Intralipid) with 0.1 g/kg/d. Insulin was necessary to keep blood glucose under 180 mg/dL. A reassessment of ammonia after one hour showed an increase to 2391 µmol/L and venovenous hemodia-filtration (VVHDF) was started urgently. The loading of arginine-HCl and sodium benzoate was continued during the first hour of VVHDF, before the dosages were reduced to 0.25 mmol/kg/h and 8 mg/kg/h, respectively. Hemosol B0 bicarbonate solution (Gambro, Sondalo, Italy) served as a replacement and dialysis fluid. Serum ammonia concentrations decreased continuously under this treatment and showed a concentration of 830.4 µmol/L after three hours of dialysis. At this point, transfontanella doppler showed improved cerebral perfusion with a PI of 0.9. VVHDF was stopped after six hours at a serum ammonia concentration of 224.3 µmol/L. There was no rebound of ammonia or nor a recurrence of cerebral edema. The metabolic investigation revealed an argininosuccinate lyase deficiency, confirmed by enzymatic analysis in erythrocytes. Extubation was possible on day 10, and the boy was then transferred to an intermediate care unit. MRI showed cystic and ischemic lesions in the parieto–occipital white matter and wide ventricles, characteristic of metabolic stroke. During an eight months follow-up, the boy showed an improved cerebral MRI and promising neuromotor development.
Discussion
This report concerns a term newborn who suffered from severe cerebral edema caused by an inborn urea cycle disorder. Similar to acute liver failure in adults, toxic metabolites such as ammonia, glutamate and glutamine are significantly increased in such cases [3]. Although the pathogenesis of cerebral edema is still not completely understood, accumulation of these metabolites has been shown to cause astrocyte swelling [4] and, in addition, cellular mitochondrial dysfunction. This, in turn, can induce cerebral oxidative stress, leading to cerebro-vascular dilation and hyperemia. However, there is evidence that induction of hypothermia can reverse many pathophysiologic abnormalities leading to cerebral edema [5].
Jalan, et al. [6, 7] reported about a decline of the markers of oxidative stress and the restoring of cerebrovascular autoregulation, when moderate hypothermia was used for uncontrolled intracranial hypertension in instances of acute liver failure in adults. Whitelaw, et al. [8] hypothesized that mild systemic cooling through the removal of an overhead heat source could have reduced the enzymatic production of ammonia in a comatose newborn with hyperammonia, who had not responded to hemofiltration. We used therapeutic hypo-thermia on the basis of these reports. However, it was carried out actively by a cooling-system and already initiated before the start of hemodiafiltration, one hour after admission. A considerable reduction of cerebral edema was already experienced just four hours after admission, because PI decreased and remained at normal ranges.
The monitoring of cerebral edema by the PI remains debatable. On the one hand, PI has been shown to correlate strongly to intracranial pressure [9], but conversely, absolute values of PI were not reliable to guide clinical decisions in a group of traumatic brain injury patients, according to a recent study [10]. However, PI has been frequently used as a non-invasive estimate of ICP and CPP and has enabled continuous assessment of the cerebral dynamics of the anti-coagulated newborn during CVVHDF.
Contributors: All authors contributed to management, review of the case and drafting of the manuscript.
Funding: None; Competing interests: None stated.
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