Philippe Jouvet

Recognition and management of fatty acid oxidation defects: A series of 107 patients

In a personal series of 107 patients, we describe clinical presentations, methods of recognition and therapeutic management of inherited fatty acid oxidation (FAO) defects. As a whole, FAO disorders appear very severe: among the 107 patients, only 57 are still living. Including 47 siblings who died early in infancy, in total 97 patients died, of whom 30% died within the first week of life and 69% before 1 year. Twenty-eight patients presented in the neonatal period with sudden death, heart beat disorders, or neurological distress with various metabolic disturbances. Hepatic presentations were observed in 73% of patients (steatosis, hypoketotic hypoglycaemia, hepatomegaly, Reye syndrome). True hepatic failure was rare (10%); cholestasis was observed in one patient with LCHAD deficiency. Cardiac presentations were observed in 51% of patients: 67% patients presented with cardiomyopathy, mostly hypertrophic, and 47% of patients had heart beat disorders with various conduction abnormalities and arrhythmias responsible for collapse, near-miss and sudden unexpected death. All enzymatic blocks affecting FAO except CPT I and MCAD were found associated with cardiac signs. Muscular signs were observed in 51% of patients (of whom 64% had myalgias or paroxysmal myoglobinuria, and 29% had progressive proximal myopathy). Chronic neurologic presentation was rare, except in LCHAD deficiency (retinitis pigmentosa and peripheral neuropathy). Renal presentation (tubulopathy) and transient renal failure were observed in 27% of patients. The diagnosis of FAO disorders is generally based on the plasma acylcarnitine profile determined by FAB-MS/MS from simple blood spots collected on a Guthrie card. Urinary organic acid profile and total and free plasma carnitine can also be very helpful, mostly in acute attacks. If there is no significant disturbance between attacks, the diagnosis is based upon a long-chain fatty acid loading test, fasting test, and in vitro studies of fatty acid oxidation on fresh lymphocytes or cultured fibroblasts. Treatment includes avoiding fasting or catabolism, suppressing lipolysis, and carnitine supplementation. The long-term dietary therapy aims to prevent periods of fasting and restrict long-chain fatty acid intake with supplementation of medium-chain triglycerides. Despite these therapeutic measures, the long-term prognosis remains uncertain.

Arrhythmias and Conduction Defects as Presenting Symptoms of Fatty Acid Oxidation Disorders in Children

BACKGROUND The clinical manifestations of inherited disorders of fatty acid oxidation vary according to the enzymatic defect. They may present as isolated cardiomyopathy, sudden death, progressive skeletal myopathy, or hepatic failure. Arrhythmia is an unusual presenting symptom of fatty acid oxidation deficiencies. METHODS AND RESULTS Over a period of 25 years, 107 patients were diagnosed with an inherited fatty acid oxidation disorder. Arrhythmia was the predominant presenting symptom in 24 cases. These 24 cases included 15 ventricular tachycardias, 4 atrial tachycardias, 4 sinus node dysfunctions with episodes of atrial tachycardia, 6 atrioventricular blocks, and 4 left bundle-branch blocks in newborn infants. Conduction disorders and atrial tachycardias were observed in patients with defects of long-chain fatty acid transport across the inner mitochondrial membrane (carnitine palmitoyl transferase type II deficiency and carnitine acylcarnitine translocase deficiency) and in patients with trifunctional protein deficiency. Ventricular tachycardias were observed in patients with any type of fatty acid oxidation deficiency. Arrhythmias were absent in patients with primary carnitine carrier, carnitine palmitoyl transferase I, and medium chain acyl coenzyme A dehydrogenase deficiencies. CONCLUSIONS The accumulation of arrhythmogenic intermediary metabolites of fatty acids, such as long-chain acylcarnitines, may be responsible for arrhythmias. Inborn errors of fatty acid oxidation should be considered in unexplained sudden death or near-miss in infants and in infants with conduction defects or ventricular tachycardia. Diagnosis can be easily ascertained by an acylcarnitine profile from blood spots on filter paper.

Methylmalonic and propionic acidurias: management without or with a few supplements of specific amino acid mixture.

SummaryIn a series of 137 patients with methylmalonic acidaemia (MMA) and propionic acidaemia (PA) diagnosed since the early 1970s, we report in more detail 81 patients (51 MMA and 30 PA) diagnosed between 1988 and 2005. In this series, 14% of patients died at initial access revealing the disease before or despite treatment, 18% died later, and the remainder (68%) are still alive. All patients were treated with the same protocol of enteral feeds with a low-protein diet adjusted to individual tolerance, carnitine, antibiotics, and only occasional use of an amino acid (AA) mixture. There was intensive follow-up and monitoring using measurements of urinary urea. Thirty-nine patients with severe forms, followed for more than 3 years, are analysed in particular detail. Of the 17 PA patients, 6 had moderate disability (all neonatal-onset forms), whereas 11 were normal or slightly delayed in their mental development. Four presented with cardiomyopathy, of whom 2 died. Of the 22 MMA patients, 13 presented in the neonatal period, of whom 3 died later, 2 are in renal failure and only 5 are still alive and have a normal or slightly delayed mental development. In the 9 patients with late-onset forms, there were no deaths and all patients but one have normal mental development. Among the 39 patients, only 40% were given an AA supplement at 3 years, and 50% between 6 and 11 years. The actual intake of natural protein was 0.92, 0.78 and 0.77 g/kg per day at 3, 6 and 11 years, respectively, in patients without AA supplementation, whereas it was 0.75, 0.74 and 0.54 g/kg per day in the group who received small quantities of AA (0.4–0.6 g/kg per day). In both groups, feeding disorders were frequent: 55% at 3 years, 35% at 6 years and 12% at 11 years. Many patients were given a food supplement by tube overnight or were even exclusively tube fed: 60% at 3 years, 48% at 6 years and still 27% at 11 years. Growth velocity was near the normal values. Plasma valine and isoleucine were low to very low, as were leucine and phenylalanine but to a lesser extent. Albumin, vitamins, trace elements and markers of bone metabolism were within the normal values. IGF1, 24-hour urine calcium and body mass density were low. Body composition showed a normal to low lean mass and a normal to high fat mass.

Long term results of liver-kidney transplantation in children with primary hyperoxaluria.

Abstract. From 1990 to 2000, we performed eight liver-kidney transplants in eight children, aged 1–16 years, with end-stage renal failure (ESRF) due to primary hyperoxaluria (PH1). The duration of dialysis before transplantation ranged from 2 to 42 months (mean 14 months) and was <1 year in four patients. Only the first patient underwent postoperative hemodialysis; in the other five, we chose to induce maximal diuresis from the first hours with intravenous and intragastric hyperhydration (≥3 l/m2 per day). High water intake with nocturnal tube hydration was maintained for 6 months to 5 years, as long as oxaluria exceeded 0.5 mmol/day. A quadruple sequential immunosuppressive regimen was used. Two patients died during liver graft surgery. The other six patients are alive and well, with a mean follow-up of 7.4 years (range 5–11 years). Patient and graft survival is 75% at 5 years. At latest follow-up, liver tests were normal in all six patients; creatinine clearance ranged from 55 to 95 ml/min per 1.73 m2 (mean=74). Oxaluria was lower than 0.4 mmol/day in all patients (mean=0.22). The six patients underwent 15 renal biopsies, 1–11 years after transplantation. Chronic transplant nephropathy was present in four patients and mild cyclosporin nephrotoxicity in another. No oxalate crystals were seen and repeat ultrasonography has been consistently normal in all patients. The three patients with bone oxalosis showed progressive complete healing of bone lesions. All six children or adolescents now live a normal life. From this series, we conclude that early combined liver-kidney transplantation is the treatment of choice for children with ESRF due to primary hyperoxaluria.

Intravenous nicardipine in hypertensive children

Fourteen hypertensive patients hospitalized in a paediatric intensive care unit were studied to evaluate safety and hypotensive efficacy of intravenous nicardipine. Systolic and diastolic blood pressure significantly decreased 1 h after the beginning of the treatment (1 μg/kg per minute). Mean decrease in systolic blood pressure during the first 24 h was between 9.9% and 13.4% of the initial value. Mean lowering of diastolic blood pressure was between 16.7% and 25.6%. Nicardipine did not significantly affect heart rate with dose of 1 μg/kg per minute. No clinical side-effects were observed. Nicardipine could be a first line drug for the treatment of hypertension in paediatric intensive care units.

Liver transplantation in propionic acidaemia

Abstract Despite the improvement in dietary therapy during the past 20 years, the overall outcome of severe forms of propionic acidaemia (PA) remains often disappointing. Good results can be obtained at a very high price in terms of medical attention, family burden and high cost. In most early onset forms of PA, the intake of natural protein must be rigidly restricted to 8–12 g/day for the first 3 years of life, and then slowly increased to 15–20 g/day by the age of 6–8 years. Supplementation with a precursor-free aminoacid mixture to provide 1.5 g/kg protein per day is generally recommended, although remains controversial. From the age of 1 year onward, these children are often severely anorectic and most of the diet must be delivered by nocturnal gastric drip feeding or gastrostomy. Metronidazole is very effective in reducing the excretion of propionate metabolites derived from the gut. L-carnitine (50 to 100 mg/kg) is systematically given to promote propionylcarnitine synthesis and excretion. We report here a retrospective study of 33 patients with PA diagnosed during the last 20 years in our hospital. Of them, 2 have been liver transplanted. In these two patients who presented frequent severe and unexpected metabolic decompensations despite good compliance with the dietary therapy, orthotopic liver transplantation (OLT) was done at 7 and 9 years respectively. One child died 15 months after transplantation due to a severe lymphoproliferative disorder; the other child now aged 13.5 years is doing well. Despite a persistent methylcitrate excretion, she is under normal moderate daily protein intake (40–50 g/day) and still on carnitine supplementation. Interestingly, another patient who filled the criteria for OLT (very frequent and severe decompensations leading to frequent admissions to the intensive care unit despite excellent dietary management) was also placed on the list for OLT. From the time he was registered onward, he experienced no further episodes of metabolic decompensation, there was almost no interruption in his daily intake and he gained height and weight and developed well. He was finally removed from the list and is still doing very well 2 years thereafter. Correction of propionylCoA carboxylase deficiency restricted to hepatic tissues seems to induce a change towards clinical normalisation and a milder biochemical phenotype. Liver transplanted PA patients still require slight protein restriction and carnitine treatment. We consider that at the moment OLT should only be performed in severe forms of PA, mostly characterised by frequent and unexpected episodes of metabolic decompensation despite good dietary therapy. However, a strict appreciation of these criteria is difficult. A more generalised indication for OLT in PA will require more information about the long-term outcome of transplanted patients. We should also await other alternatives like auxiliary partial OLT from living donors or transplantation of isolated allogenic hepatocytes, genetically modified or not.

Assessment of high-frequency neonatal ventilator performances

AbstractObjective: To assess the efficacy and reliability of neonatal high-frequency ventilators. Design: Bench evaluation of neonatal high-frequency ventilators. Setting: Physiology department and university hospital neonatal intensive care unit. Interventions: HFV-Babylog 8000 (Dräger Medical), OHF 1 (Dufour), and SensorMedics 3100A (SensorMedics) ventilators were connected to a neonatal test-lung. Tidal volume, peak-to-peak pressure amplitude, and mean airway pressure were measured for several ventilator settings, endotracheal tube sizes, and lung compliances. Measurements and results: Increasing peak-to-peak pressure resulted in a linear increase in tidal volume delivery in the 0–30% range of maximum amplitude. No significant increase in tidal volume was observed with the HFV-Babylog8000 when pressure amplitude was above 50%. The maximum tidal volume delivered was substantially smaller with the HFV-Babylog8000 than with the OHF1 or SensorMedics3100A. Tidal volume increased with endotracheal tube size with all three ventilators. Increasing test-lung compliance resulted in lower tidal volumes only with OHF1. Decreasing mean airway pressure was responsible for a decrease in tidal volume delivery with HFV-Babylog8000. Conclusion: We found that under our test conditions two of the three ventilators delivered adequate tidal volumes at the usual frequency of 15Hz, regardless of the size of the endotracheal tube and of the mechanical properties of the respiratory system. When lung compliance increased or mean airway pressure decreased, both of which are common events during the recovery phase of hyaline membrane disease, we found that the intrinsic properties of two of the ventilators tested were responsible for a decrease in tidal volume. This decrease may account for some cases of heretofore unexplained hypercapnia.

Nitric oxide 2

Introduction: Permissive hypercapnia (PH) is a beneficial strategy for patients with acute respiratory distress syndrome (ARDS) to minimize barotrauma by decreasing the peak inspiratory pressure (PIP). Hypercapnia and hypoxia cause pulmonary vasoconstriction, pulmonary artery (PA) hypertension, and, thus, an increased afterload to the right ventricle. This increased afterload may result in increased right ventricular (RV) work load and subsequent RV dysfunction. One therapeutic approach is the use of inhaled nitric oxide (iNO), a selective PA vasodilator. The objectives of this study were to test the hypothesis that in a swine model of ARDS with PH, iNO would improve RV work load and not change intrinsic RV contractility. Methods: In 11 swine (25-35 kg), ARDS was induced by surfactant depletion. Hypercapnia was achieved by decreasing the PIP while increasing the PEEP to maintain a constant mean airway pressure. iNO was administered in concentrations of 2, 5, and 10 ppm in a random order, Pulmonary blood flow (Qpa) was determined by an ultrasonic flow probe. RV total power (TP) and stroke work (SW) were calculated by Fourier transformation of the PA pressure (Ppa) and Qpa data. Preload recruitable stroke work (PRSW), a preload and afterload independent measure of ventricular contractility, was determined by a shell-subtraction method and vena caval occlusion) Results: Data are represented as mean ± sent and compared by two-way analysis of variance with repeated measures. (* n < 0.05 vs. 0 nnm) 0 ppm 2 ppm 5 ppm 10 ppm er s*1000 /mL 24.6 ± 1.6 25.2 ± 2.4 23.3 ± 1.8 22.9 ± 2.5 mW 92±11 74±6* 66±6 75±8* [RSW

Fetal home monitoring for the prenatal management of gastroschisis

Background.  Fetal distress is a frequent complication of gastroschisis, and could be screened for by home monitoring, as many pregnant women expecting an affected child live far away from a specialized perinatal center. This study was undertaken to audit a policy of fetal home monitoring (FHM) to achieve early detection of fetal heart rate (FHR) abnormalities in gastroschisis.

Paludisme grave de l’enfant en réanimationEnquête nationale 1990-1995

BACKGROUND Severe malaria is a frequent complication of Plasmodium falciparum infections. More than one million children die of malaria each year. MATERIAL AND METHODS A French survey was carried out on 15 cases admitted to pediatric intensive care units between 1990 and 1995. The aim of this work was to evaluate the occurrence, mortality, morbidity and treatment of severe malaria in French intensive care units. RESULTS All cases were imported from Africa except one case of airport malaria. Diagnosis of many of these cases was delayed. All cases were treated with quinine, and five children received a loading dose. One child died and one has neurological sequelae. DISCUSSION Despite improvement in management, the prognosis of severe malaria remains poor. With reference to the literature, we propose management of severe malaria, emphasizing the necessity of a rapid effect with a loading dose of quinine.Resume Le paludisme grave est une complication des infections a Plasmodium falciparum chez l’enfant. Plus d’un million d’enfants decedent de paludisme chaque annee dans le monde. Les pays temperes sont egalement concernes. Materiel et methodes. – L’objectif du travail etait d’effectuer une enquete retrospective sur la periode 1990–1995 parmi les centres francais de reanimation pediatrique afin d’apprecier la frequence, la mortalite, la morbidite et la prise en charge du paludisme grave. Resultats. – Quinze observations ont ete recensees. Tous les cas etaient importes d’Afrique, sauf un cas de paludisme d’aeroport. Des prodromes et un retard diagnostique etaient frequents. La quinine a ete utilisee pour tous les enfants. Cinq enfants ont recu une dose de charge. Un enfant est decede et un a des sequelles neurologiques. Discussion. – Malgre une amelioration de la prise en charge, la mortalite et la morbidite restent lourdes. A partir de ces observations et des donnees de la litterature, nous proposons un schema therapeutique en insistant sur la necessite de traiter rapidement avec une dose de charge de quinine.