Biallelic Mutations in PDE10A Lead to Loss of Striatal PDE10A and a Hyperkinetic Movement Disorder with Onset in Infancy.

Deficits in the basal ganglia pathways modulating cortical motor activity underlie both Parkinson disease (PD) and Huntington disease (HD). Phosphodiesterase 10A (PDE10A) is enriched in the striatum, and animal data suggest that it is a key regulator of this circuitry. Here, we report on germline PDE10A mutations in eight individuals from two families affected by a hyperkinetic movement disorder due to homozygous mutations c.320A>G (p.Tyr107Cys) and c.346G>C (p.Ala116Pro). Both mutations lead to a reduction in PDE10A levels in recombinant cellular systems, and critically, positron-emission-tomography (PET) studies with a specific PDE10A ligand confirmed that the p.Tyr107Cys variant also reduced striatal PDE10A levels in one of the affected individuals. A knock-in mouse model carrying the homologous p.Tyr97Cys variant had decreased striatal PDE10A and also displayed motor abnormalities. Striatal preparations from this animal had an impaired capacity to degrade cyclic adenosine monophosphate (cAMP) and a blunted pharmacological response to PDE10A inhibitors. These observations highlight the critical role of PDE10A in motor control across species.

Electrical activity of the diaphragm during neurally adjusted ventilatory assist in pediatric patients.

BACKGROUND: Neurally adjusted ventilatory assist (NAVA) is a ventilation mode which provides respiratory support proportional to the electrical activity of the diaphragm (Edi). The aims of this trial were to assess the feasibility of aiming at peak Edi between 5 and 15 µV during NAVA in clinical practice, to study the effect of age, sedation level and ventilatory settings on the Edi signal and to give some reference values for Edi in a pediatric population. METHODS: As a part of a larger randomized controlled trial, 81 patients received Edi catheter for monitoring Edi and guiding NAVA ventilation. The goal for peak Edi during invasive ventilation was 5-15 µV. Edi activity and NAVA levels were observed during invasive ventilation and an hour after extubation. RESULTS: Sixty-six patients with healthy lungs (81.5%) were ventilated, mostly as part of postoperative care, while respiratory distress was the indication for invasive ventilation in the remaining 15 patients (18.5%). NAVA levels varied from 0.2 to 2.0 cmH2O/µV in the patients with healthy lungs, but were higher, from 0.7 to 4.0 cmH2O/µV, in the respiratory distress patients (P < 0.001). The latter had higher peak Edi values in all phases of treatment. The effect of age and level of sedation on Edi was statistically significant, but carried only limited clinical relevance. The peak post-extubation Edi levels of the patients with healthy lungs and respiratory distress, respectively, were 9 ± 7 and 20 ± 14 µV. Two out of the three patients for whom extubation failed had an atypical Edi pattern prior to extubation. CONCLUSIONS: Optimizing the level of support during NAVA by aiming at a peak Edi between 5 and 15 µV was an applicable strategy in our pediatric population. Relatively high post-extubation Edi signal levels were seen in patients recovering from respiratory distress. Information revealed by the Edi signal could be used to find patients with a potential risk of extubation failure.

Neurally adjusted ventilatory assist (NAVA) in pediatric intensive care--a randomized controlled trial.

BACKGROUND: Neurally adjusted ventilatory assist (NAVA) has been shown to improve patient-ventilator synchrony during invasive ventilation. The aim of this trial was to study NAVA as a primary ventilation mode in pediatric intensive care and to compare it with current standard ventilation modes. METHODS: One hundred seventy pediatric intensive care patients were randomized to conventional ventilation or NAVA. The primary endpoints were time on the ventilator and the amount of sedation needed. To enable comparison between sedative agents, a "sedative unit" was defined for each drug. RESULTS: The median time on the ventilator was 3.3 hr in the NAVA group and 6.6 hr in the control group (P = 0.17), and the length of stay in the PICU 49.5 hr in the NAVA group and 72.8 hr in the control group (P = 0.10, per protocol P = 0.03). The amount of sedation needed in the total patient population did not differ between the groups (P = 0.20), but when postoperative patients were excluded (19 vs. 20 patients), the amount was significantly lower in the NAVA group (0.80 vs. 2.23 units/hr, P = 0.03). Lower peak inspiratory pressure and a lower inspired oxygen fraction were found in the NAVA group (P = 0.001 for both). Arterial blood CO2 tensions were slightly higher in the NAVA group up to 32 hr of treatment (P = 0.008). There were no significant differences in the other ventilatory or vital parameters, arterial blood gas values or complications. CONCLUSIONS: We found NAVA to be a safe and feasible primary ventilation mode for use with children. It outscored standard ventilation in some aspects, as it was able to enhance oxygenation even at lower airway pressures and led to reduced use of sedatives during longer periods of treatment.

Current trends in paediatric and neonatal ventilatory care -- a nationwide survey.

AIM: To assess daily practices in paediatric and neonatal ventilatory care in Finland. METHODS: All neonatal and paediatric intensive care units in Finland were sent a questionnaire on ventilatory strategies and were offered a 3-month prospective survey. RESULTS: A total of 96% of units returned the questionnaire, and clinicians agreed on most of the principles of lung-protective ventilation. Seventeen hospitals (94%) joined the prospective survey. On average, 2.3 new ventilation episodes were started daily, and totally 211 episodes were monitored. Pulmonary problems (64%) were the main cause of treatment in neonates and postoperative care (68%) in older children. Synchronized intermittent mandatory ventilation with pressure support was the primary mode in 42% of episodes. Hypocapnia was observed repeatedly in all units. In adult intensive care units, children often received high oxygen fraction, leading to hyperoxia, and they were frequently sedated with propofol, which is not licensed for that purpose. A large proportion of children had only light sedation or no sedation at all. Despite the different strategies and practices, most episodes resulted in a favourable outcome. CONCLUSION: Most of the principles of lung-protective ventilation have been well accepted by clinicians. More attention should be paid to achieving normocapnia and normoxia and to the correct use of sedatives, especially in units that only occasionally provide paediatric ventilation.

Early corticosteroid treatment does not affect severity of unconjugated hyperbilirubinemia in extreme low birth weight preterm infants.

AIM: To determine the relationship between early postnatal dexamethasone (DXM) treatment and the severity of hyperbilirubinemia in extreme low birth weight (ELBW) preterm infants. METHODS: In 54 ELBW preterm infants, total serum bilirubin concentrations (TSB) and phototherapy (PT) data during the first 10 days were evaluated retrospectively. ELBW infants had participated in a randomized controlled trial of early DXM treatment which aimed to assess effects on chronic lung disease. Infants had been treated with DXM (0.25 mg/kg twice daily at postnatal day 1 and 2) or with placebo (normal saline). Analysis was performed on an intention to treat basis. RESULTS: Twenty-five Infants had been randomized into the DXM group; 29 into the placebo group. Mean (±SD) TSB [120 (±19) µmol/L vs. 123 (±28) µmol/L, DXM versus placebo, respectively] and maximum TSB [178 (±23) µmol/L vs. 176 (±48), DXM versus placebo, respectively] concentrations were similar. TSB concentrations peaked 30 h earlier in the DXM group (p ≤ 0.05). The need for PT as well as the duration of PT was similar in both groups. CONCLUSIONS: Early DXM treatment does not affect the severity of neonatal hyperbilirubinemia in ELBW preterm infants. Our results seem compatible with the concept that factors other than bilirubin conjugation capacity are important for the pathophysiology of neonatal jaundice in ELBW preterm infants.

Early hypoadrenalism in premature infants at risk for bronchopulmonary dysplasia or death.

AIM: To study the relationship between serum cortisol and dehydroepiandrosterone sulphate (DHEAS) concentrations and death or bronchopulmonary dysplasia at 36 weeks of postmenstrual age in preterm infants. METHODS: Prospective measurement of cord, day of birth (D0) and day 4 (D4) serum cortisol and DHEAS concentrations and performance of low-dose (LD) ACTH tests in 89 preterm infants with gestational age <34 weeks at birth and in need of mechanical ventilation. RESULTS: Serum DHEAS levels correlated negatively with gestational age. At all sampling times, basal serum cortisol levels correlated positively with gestation-adjusted DHEAS levels (r = 0.39-0.46, p = 0.0032-<0.0001). The mean cord, D0 basal and stimulated cortisol, and cord and D0 DHEAS adjusted for gestational age were lower in the poor than good outcome infants (p < 0.02 for all). In the multiple logistic regression analyses, gestational age was the most significant factor affecting outcome, but low cord and D0 basal and stimulated cortisol and gestation-adjusted DHEAS levels also predicted poor outcome (OR 5.7-22; p = 0.049-0.014). CONCLUSIONS: Low cord and first day serum cortisol and DHEAS levels associated with poor outcome in preterm infants, which suggests general relative adrenocortical insufficiency in some premature newborns.

Marked variation in oxycodone pharmacokinetics in infants.

BACKGROUND: The pharmacokinetics of oxycodone (13-hydroxy-7,8-dihydrocodeinone) has been studied in adults and in children who are older than 6 months but there is no information on the disposition of oxycodone in neonates and young infants. The aim of this study was to study the pharmacokinetics of oxycodone in infants varying in age from 0 to 6 months. METHODS: Twenty-two infants undergoing surgery were given postoperatively an intravenous bolus of 0.1 mg.kg(-1) of oxycodone hydrochloride. Ten of the patients were younger than 1 week (group 1), six from 1 week to 2 months (group 2) and six from 2 to 6 months (group 3). Plasma samples were collected for the analysis of oxycodone concentrations up to 24 h. Pharmacokinetics were characterized by noncompartmental methods. RESULTS: The median (range) values for the clearance (Cl) were 9.9 (2.3-17.2), 20.1 (3.7-40.4) and 15.4 (14.8-80.2) ml.min(-1).kg(-1) in the above three groups. The values for volume of distribution at steady-state were 3.3 (1.9-4.7), 5.6 (1.3-8.5) and 3.2 (1.8-6.0) l.kg(-1) and for elimination half-life (t(1/2)) 4.4 (2.4-14.1), 3.6 (1.6-11.6) and 2.0 (0.8-3.9) h, respectively. Both Cl (r = 0.46) and half-life (r = -0.46) were correlated to the age of the patient (P < 0.05). There were 13 patients who were on mechanical ventilation at the time of oxycodone administration. None of the spontaneously breathing infants had hypoventilation which required assistance during the study. CONCLUSIONS: The values for Cl and t(1/2) varied greatly between the subjects. This variability was most pronounced in the two youngest groups. Routine dosing of oxycodone in young infants may be dangerous. The dose of oxycodone must be titrated individually.

Early neonatal dexamethasone treatment for prevention of bronchopulmonary dysplasia. Randomised trial and meta-analysis evaluating the duration of dexamethasone therapy.

UNLABELLED: The aim of the aborted trial was to determine whether the short early dexamethasone (DX) given after the birth improves the early outcome. We also reviewed the evidence (meta-analysis) to determine whether the duration of early DX treatment influences the early outcome, particularly in terms of bronchopulmonary dysplasia (BPD). The participants of the randomised multicentre, double-blinded placebo-controlled trial had a birth weight 500-999 g, gestation < or = 31.0 weeks, and respiratory failure by the age of 4 h. The infants received either four doses of DX (0.25 mg/kg at 12 h intervals) or placebo. The meta-analysis was performed to determine the beneficial and adverse effects of early short (<96 h duration) versus early prolonged (>96 h) DX treatment. The trial was discontinued after 109 infants had been enrolled. There was a non-significant improvement in the outcome (survival without BPD, severe intracranial haemorrhage or periventricular leukomalacia; RR 1.27; 95% CI 0.87-1.85). The risks for gastrointestinal perforation and hyperglycaemia tended to increase. A total of 15 trials were included in the meta-analysis: 10 involved prolonged (i.e. >96 h; 1594 infants) and five short interventions (1069 infants). Early prolonged DX decreased the RR for BPD to 0.72 (95% CI 0.61-0.87), whereas early short DX course did not significantly decrease the risk (RR 0.82; 95% CI 0.64-1.05). Gastrointestinal haemorrhages and perforations were significantly increased only in the early prolonged DX group. CONCLUSION: The dosage and duration of early corticosteroid given to small premature infants influences the risk of the side-effects and the early outcome.