Abstract: PURPOSE: Therapeutic hypothermia reduces mortality and neurologic impairment in neonates with hypoxic-ischemic encephalopathy. Topiramate exerts a neuroprotective effect in asphyxiated neonatal animal models. However, no studies have investigated the association of hypothermia and topiramate, because topiramate pharmacokinetics during hypothermia and the optimal administration schedule are unknown. The influence of hypothermia on topiramate pharmacokinetics was evaluated in asphyxiated neonates treated with prolonged whole-body hypothermia and topiramate. METHODS: Thirteen term newborns were treated with mild or deep whole body hypothermia for 72 h; all received oral topiramate, 5 mg/kg once a day for the first 3 days of life, and seven had concomitant phenobarbital treatment. Topiramate concentrations were measured on serial dried blood spots. RESULTS: Topiramate concentrations were within the reference range in 11 of 13 newborns, whereas concentrations exceeded the upper limit in 2 of 13, both newborns on deep hypothermia. Topiramate concentrations reached a virtual steady state in nine newborns, for whom pharmacokinetic parameters were calculated. Values of topiramate maximal and minimal concentration, half-life, average concentration, and area under the time-concentration curve resulted in considerably higher values than those reported in normothermic infants. With respect to normothermic infants, time of maximal concentration was mildly delayed and apparent total body clearance was lower, suggesting slower absorption and elimination. Pharmacokinetic parameters did not differ significantly between infants on deep versus mild hypothermia and in those on topiramate monotherapy versus add-on phenobarbital. CONCLUSION: Most neonates on prolonged hypothermia treated with topiramate 5 mg/kg once a day exhibited drug concentrations within the reference range for the entire treatment duration.
Abstract: BACKGROUND: Several studies have demonstrated the efficiency and safety of mild hypothermia (33 degrees C) used for treating moderate encephalopathy. In animal models, deep hypothermia proved to be neuroprotective. OBJECTIVES: To determine the safety of whole-body deep hypothermia between 30 and 33 degrees C in moderate-severe hypoxic-ischemic encephalopathy in newborn term infants. METHODS: Mortality rates, incidence of brain damage detected by magnetic resonance imaging (MRI) and neurological outcomes of 39 term asphyxiated infants were retrospectively compared. A first group of patients (control group C) was treated with routine standard methods, a second group (MH) was treated with mild whole-body hypothermia (32-34 degrees C) and a third group (DH) was treated with deep whole-body hypothermia (30-33 degrees C), for 72 h. Mean arterial pH, basic excess (BE) and lactic acid in the blood were measured. Laboratory and clinical side effects of hypothermia were investigated. A conventional brain MRI was performed after the second week of life. Results: 39 term asphyxiated newborns were enrolled in the study: 11 in group C, 10 in group MH, and 18 in group DH. During the first 72 h, disseminated intravascular coagulation was recorded in 2 cases (18%) in group C, pulmonary hypertension in 2 patients (20%) in group MH, and pneumonia in 3 cases (16%) in group DH. Severe cerebral lesions and poor neurological outcome were observed in 4 cases (36%) in group C, 1 case (10%) in group MH, and 1 case (5%) in group DH. A statistically significant difference in brain damage and major clinical neurological abnormalities was observed between group C and groups MH and DH, whereas no differences were demonstrated between asphyxiated infants treated with mild or deep hypothermia. CONCLUSIONS: The results support the safety of deep hypothermia. Further studies are needed to confirm these results and the neuroprotective effect of this approach.
Abstract: INTRODUCTION: Neonatal persistent pulmonary hypertension (NPPH) is characterised by persistently high pulmonary vascular resistance (PVR). Sildenafil has recently been suggested as an alternative to or an associative therapy with inhaled nitric oxide (iNO) to reduce mortality (10-40%) and morbidity (major neurologic disabilities among surviving newborns remains approximately 15-60%). The objective is to report three cases of NPPH treated with sildenafil in association of iNO. CASE REPORTS. Echocardiography examination of three newborn babies with respiratory distress syndrome and a gestational age between 33 and 39 weeks revealed pulmonary hypertension following early onset sepsis. Synchronized intermittent mandatory ventilation (SIMV) and surfactant therapy had no effect on oxygen saturation (SatO2) and oxygen alveolar-arterial difference (AaDO2). High frequency oscillatory ventilation (HFOV) and iNO therapy proved to be equally ineffective. Oral sildenafil was administered at 2 mg/Kg/6 hs. A gradual but significant improvement in oxygenation was achieved and a reduction in AaDO2 along with oxygenation index (OI) and pulmonary arterial pressure (PAP) was observed in the first 6-10 hrs after administration of sildenafil. The therapy was maintained for 36-48 hrs with total success. CONCLUSIONS: A beneficial pulmonary vasodilator effect was obtained in treating NPPH with sildenafil where conventional methods had failed. Sildenafil used in association with iNO reduces the duration of treatment, the quantity of iNO normally required and the associated toxic effects. A multicentric, randomized trial could be useful in demonstrating the safety, efficacy, doses and forms of administration of sildenafil.
