Dose rationale and pharmacokinetics of dexmedetomidine in mechanically ventilated new-borns : impact of design optimisation

Purpose: There is a need for alternative analgosedatives such as dexmedetomidine in neonates. Given the ethical and practical difficulties, protocol design for clinical trials in neonates should be carefully considered before implementation. Our objective was to identify a protocol design suitable for subsequent evaluation of the dosing requirements for dexmedetomidine in mechanically ventilated neonates. Methods: A published paediatric pharmacokinetic model was used to derive the dosing regimen for dexmedetomidine in a first-in-neonate study. Optimality criteria were applied to optimise the blood sampling schedule. The impact of sampling schedule optimisation on model parameter estimation was assessed by simulation and re-estimation procedures for different simulation scenarios. The optimised schedule was then implemented in a neonatal pilot study. Results: Parameter estimates were more precise and similarly accurate in the optimised scenarios, as compared to empirical sampling (normalised root mean square error: 1673.1% vs. 13,229.4% and relative error: 46.4% vs. 9.1%). Most importantly, protocol deviations from the optimal design still allowed reasonable parameter estimation. Data analysis from the pilot group (n = 6) confirmed the adequacy of the optimised trial protocol. Dexmedetomidine pharmacokinetics in term neonates was scaled using allometry and maturation, but results showed a 20% higher clearance in this population compared to initial estimates obtained by extrapolation from a slightly older paediatric population. Clearance for a typical neonate, with a post-menstrual age (PMA) of 40 weeks and weight 3.4 kg, was 2.92 L/h. Extension of the study with 11 additional subjects showed a further increased clearance in pre-term subjects with lower PMA. Conclusions: The use of optimal design in conjunction with simulation scenarios improved the accuracy and precision of the estimates of the parameters of interest, taking into account protocol deviations, which are often unavoidable in this event-prone population

Neurofibromatosis type 1 vasculopathy: when to screen?

INTRODUCTION: Case Description. A male infant born after an uneventful pregnancy and delivery was admitted to the neonatology ward on the first day of life because of feeding difficulties. Parenteral nutrition was initiated and continued for two days. Abdominal ultrasound screening showed a vascular malformation in the liver, which was further investigated by magnetic resonance imaging, describing the lesion as an arteriovenous malformation. No other abdominal vascular lesions were found. Favorable progression of drinking behaviour allowed the child to be discharged home on day 8. The appearance of multiple brownish maculae on the back and trunk of the infant by the age of 3 months initiated diagnostic evaluation for neurofibromatosis 1 (NF1). Dermatologic evalution classified the lesions as typical café-au-lait maculae. No axillary or inguinal freckling was found. Ophthalmologic examination showed no abnormalities. Gene analysis revealed a mutation in the NF1 gene; which confirmed the clinical diagnosis of NF1. CONCLUSION Discussion. NF1 is an autosomal dominant disorder with a prevalence of one in 3000 individuals. NF1 diagnosis in patients with negative familial history can have significant delay due to the initial absence of at least two of the seven diagnostic criteria, as defined by the National Institutes of Health consensus statement. Significant vascular lesions are a rare but well-known feature of the disease and routine vascular screening is not recommended. NF1 vasculopathy includes a wide spectrum of vascular abnormalities. The most common lesions are aneurysms or stenoses of the aortic, renal and mesenteric arteries. Arteriovenous malformations are also part of the spectrum. Once a vascular abnormality has been identified screening for other lesions by non-invasive imaging of head, chest and abdomen is justified. Patients with NF1 vasculopathy have a reduced life expectancy when compared with NF1 patients without vasculopathy, especially when arteries of the heart or brain are involved

Therapeutic Drug Monitoring of Meropenem in Neonate with Necrotizing Enterocolitis: A Challenge

Necrotizing enterocolitis (NEC) continues to be a major cause of neonatal morbidity and mortality. We describe the added value of therapeutic drug monitoring by presenting the case of a preterm infant with severe NEC treated with meropenem. Dosing strategy will achieve adequate patient outcome when treating pathogens with elevated MIC. As safe as meropenem is, there are not enough data for 40 mg/kg, every 8 h infused over 4 h; accordingly, strict monitoring of blood levels is mandatory. Based on our findings, a 4 h prolonged infusion of 40 mg/kg meropenem, every 8 h, will achieve an adequate patient outcome

Ping­pong skull fracture in the newborn: to treat or not to treat ?

Case Description: A 2.870g female infant was born at 38 weeks via vaginal delivery in occipito-posterior position. Because of a prolonged second stage of labour and recurrent late decelerations indicating foetal distress, the delivery was vacuum-assisted with a cup placed on the right side of the forehead. At birth, a depression of the left parietal skull was noted, measuring approximately 5 mm in depth and 40 mm in diameter. The depression had a bony base and no accompanying oedema or hematoma. Neurologic and physical examination revealed no other abnormalities. A thorough review of the perinatal history could not identify a causal trauma. Radiography of the maternal pelvis showed no abnormalities. An X-ray of the skull was performed to evaluate the depression, indicating a ping-pong fracture. Computed tomography (CT) scan additionally demonstrated a small zone of contusion below the depression. Surgical elevation was opted because of this underlying contusion. A follow-up CT-scan was performed the day after surgery, which showed complete resolution of the depression and a small subarachnoid haemorrhage. The child was discharged home on day 7 with a normal neurological examination. Discussion: A ping-pong fracture is a type of fracture seen only in neonates and young infants. It consists of a depression of the skull without cortical break. These depressed skull fractures can either be congenital or acquired. Congenital depressions of the neonatal skull unrelated to trauma are rare and often puzzling in origin. They are referred to as “faulty fetal packing”, since they are caused by external pressure in utero, e.g. by a bony prominence of the maternal pelvis or spine. Non-traumatic, congenital depression fractures are the result of moulding of the soft foetal skull during its intra-uterine stay. Intra-cranial abnormalities are therefore rare. Acquired depressed skull fractures are more common and are usually caused by birth trauma due to obstetric manoeuvres or instrumental delivery. The acquired type of depressed fracture carries a higher risk of intra-cranial lesions, because of the sudden and important force applied to the skull. Management of ping-pong fractures in newborns is based on careful history taking and thorough clinical examination. A difficult delivery, e.g. with need for instrumentation, is more likely to cause traumatic ping-pong fractures and must always alert the clinician with respect to possible intra-cranial damage. Surgical lifting of the bone must be considered and was therefore applied in this case. A trouble-free birth without perinatal history for trauma and a newborn without neurological symptoms, is more likely a case of “faulty fetal packing”. This can be treated conservatively, as full and spontaneous resolution within the first few months of life has been described. Surgical correction is necessary when spontaneous resolution has not occurred by 6 months of age or when neurological symptoms appear

Clipping of an aortopulmonary window in a small neonate with bronchial bleeding : a simple solution for a complex condition

Although the conventional treatment of aortopulmonary (AP) window consists of reconstructive surgery with the use of cardiopulmonary bypass (CPB), some conditions like low birth weight or active respiratory tract bleeding may lead to diverting therapeutic options. We present a case of a premature 1.9 kg neonate with severe pulmonary arterial hypertension based on the association of an AP window and large patent ductus arteriosus. Because of intrabronchial hemorrhage, a conservative strategy was chosen excluding the need for heparinization and CPB. Through median sternotomy, the ductus arteriosus and AP window were clipped, effectively occluding both shunts. The postoperative course was uneventful with a rapid decrease of pulmonary artery pressure. Although classical surgical reconstruction is still advocated as primary therapy, this case illustrates the suitability of an alternative approach without the need for CPB and full heparinization in a patient with an increased risk of bleeding complications

An immature teratoma of the umbilical cord: a case report and review of the literature

status: accepte