BackgroundIsovaleric aciduria (IVA), propionic aciduria (PA) and methylmalonic aciduria (MMA) are inherited organic acidurias (OAs) in which impaired organic acid metabolism induces hyperammonaemia arising partly from secondary deficiency of N-acetylglutamate (NAG) synthase. Rapid reduction in plasma ammonia is required to prevent neurological complications. This retrospective, multicentre, open-label, uncontrolled, phase IIIb study evaluated the efficacy and safety of carglumic acid, a synthetic structural analogue of NAG, for treating hyperammonaemia during OA decompensation.MethodsEligible patients had confirmed OA and hyperammonaemia (plasma NH3 > 60 μmol/L) in ≥1 decompensation episode treated with carglumic acid (dose discretionary, mean (SD) first dose 96.3 (73.8) mg/kg). The primary outcome was change in plasma ammonia from baseline to endpoint (last available ammonia measurement at ≤18 hours after the last carglumic acid administration, or on Day 15) for each episode. Secondary outcomes included clinical response and safety.ResultsThe efficacy population (received ≥1 dose of study drug and had post-baseline measurements) comprised 41 patients (MMA: 21, PA: 16, IVA: 4) with 48 decompensation episodes (MMA: 25, PA: 19, IVA: 4). Mean baseline plasma ammonia concentration was 468.3 (±365.3) μmol/L in neonates (29 episodes) and 171.3 (±75.7) μmol/L in non-neonates (19 episodes). At endpoint the mean plasma NH3 concentration was 60.7 (±36.5) μmol/L in neonates and 55.2 (±21.8) μmol/L in non-neonates. Median time to normalise ammonaemia was 38.4 hours in neonates vs 28.3 hours in non-neonates and was similar between OA subgroups (MMA: 37.5 hours, PA: 36.0 hours, IVA: 40.5 hours). Median time to ammonia normalisation was 1.5 and 1.6 days in patients receiving and not receiving concomitant scavenger therapy, respectively. Although patients receiving carglumic acid with scavengers had a greater reduction in plasma ammonia, the endpoint ammonia levels were similar with or without scavenger therapy. Clinical symptoms improved with therapy. Twenty-five of 57 patients in the safety population (67 episodes) experienced AEs, most of which were not drug-related. Overall, carglumic acid seems to have a good safety profile for treating hyperammonaemia during OA decompensation.ConclusionCarglumic acid when used with or without ammonia scavengers, is an effective treatment for restoration of normal plasma ammonia concentrations in hyperammonaemic episodes in OA patients.

NIV can be successfully applied to infants and children with ARF using this volumetric ventilator with specific NIV mode. It should be considered particularly in children whose underlying condition warrants avoidance of intubation.

ᰔPositive galactomannan antigen (GM) test results with serum by the Platelia Aspergillus assay (Bio-Rad, Marnes-LaCoquette, France) have been reported to occur during invasive fungal infections caused by Penicillium marneffei (8), Cryptococcus neoformans (2), Geotrichum capitatum (3), or Histoplasma capsulatum (1,6, 11). We report on a case of a positive GM result in bronchoalveolar lavage fluid (BAL fluid) in the clinical setting of a possibly invasive infection caused by Lichtheimia ramosa. The patient was a 10-year-old girl with acute myeloblastic leukemia in second relapse who presented with fever (101°F), cough, and dyspnea. A chest X ray showed diffuse reticular changes, and a blood count revealed severe neutropenia (200 leukocytes/l). The patient began empirical treatment with ceftazidime and amikacin. Vancomycin was later added on the basis of Gram stain results from a positive blood culture. A computed tomography (CT) scan was performed 48 h after admission. A nodular lesion in the right upper lobe compatible with invasive aspergillosis was observed. Voriconazole therapy was then initiated. Worsening of the patient's clinical condition prompted the addition of meropenem and caspofungin to the antibiotic regimen. Fiberoptic bronchoscopy was performed (14 days after admission), and BAL fluid in saline solution was submitted to the Microbiology Service for microscopic examination, culture, and GM testing. Nonseptate hyphae with irregular branching were seen by calcofluor white staining of a direct smear. Lichtheimia ramosa (deposited in the Spanish Type Culture Collection) was isolated on Sabouraud glucose medium within 48 h of plating. Microbial identification was confirmed by direct sequencing of the internal transcribed spacer 2 (ITS2) region of the ribosomal DNA gene (9). The antifungal susceptibility profile as determined by a conventional microdilution method was as follows: the isolate was susceptible to amphotericin B (0.25 g/ml) and posaconazole (0.5 g/ml) and resistant to the echinocandins (Ͼ8 g/ml). The BAL fluid (two different aliquots) tested positive by the GM assay (index value, 2.9). The positive results were reproduced in a second analysis of samples. Aspergillus species DNA was not detected in BAL fluid by realtime PCR (FXG:RESP Asp ϩ test kit and Cepheid SmartCycler; Myconostica Ltd., Manchester, United Kingdom). The patient was admitted to the intensive care unit and died shortly thereafter. Serial serum samples obtained at hospital admission until 16 h prior to death (n ϭ 3) tested negative by the GM assay (index values of 0.103, 0.104, and 0.107).A mycelial extract antigen from the isolated organism was prepared (4) and tested at a 1:100 dilution in phosphate-buffered saline by the GM assay, yielding a positive result (index value, 1.23). Extracellular polysaccharide antigens produced by Zygomycetes, such as Rhizopus oryzae, Lichtheimia corymbifera, and Cunninghamella bertholletiae (but not by Lichtheimia ramosa), have been shown previously to test negative (index values Յ 0.5) in the...

This study provides "normal" values for global end-diastolic volume index and limits of cardiac preload responsiveness in pediatric patients with cardiovascular dysfunction and dilated cardiomyopathy: 1.33 times normal global end-diastolic volume index represents the upper limit of patent cardiac preload responsiveness, with the highest expected responsiveness being below 0.67 times normal global end-diastolic volume index. The maximum response of the Frank-Starling relationship and therefore the level of no additional preload reserve is 1.33 to 1.51 times normal global end-diastolic volume index. Above 1.51 times normal global end-diastolic volume index preload responsiveness is unlikely, and the risk of pulmonary edema is maximal.

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