Doxapram versus placebo in preterm newborns: a study protocol for an international double blinded multicentre randomized controlled trial (DOXA-trial).

BACKGROUND: Apnoea of prematurity (AOP) is one of the most common diagnoses among preterm infants. AOP often leads to hypoxemia and bradycardia which are associated with an increased risk of death or disability. In addition to caffeine therapy and non-invasive respiratory support, doxapram might be used to reduce hypoxemic episodes and the need for invasive mechanical ventilation in preterm infants, thereby possibly improving their long-term outcome. However, high-quality trials on doxapram are lacking. The DOXA-trial therefore aims to investigate the safety and efficacy of doxapram compared to placebo in reducing the composite outcome of death or severe disability at 18 to 24 months corrected age. METHODS: The DOXA-trial is a double blinded, multicentre, randomized, placebo-controlled trial conducted in the Netherlands, Belgium and Canada. A total of 396 preterm infants with a gestational age below 29 weeks, suffering from AOP unresponsive to non-invasive respiratory support and caffeine will be randomized to receive doxapram therapy or placebo. The primary outcome is death or severe disability, defined as cognitive delay, cerebral palsy, severe hearing loss, or bilateral blindness, at 18-24 months corrected age. Secondary outcomes are short-term neonatal morbidity, including duration of mechanical ventilation, bronchopulmonary dysplasia and necrotising enterocolitis, hospital mortality, adverse effects, pharmacokinetics and cost-effectiveness. Analysis will be on an intention-to-treat principle. DISCUSSION: Doxapram has the potential to improve neonatal outcomes by improving respiration, but the safety concerns need to be weighed against the potential risks of invasive mechanical ventilation. It is unknown if the use of doxapram improves the long-term outcome. This forms the clinical equipoise of the current trial. This international, multicentre trial will provide the needed high-quality evidence on the efficacy and safety of doxapram in the treatment of AOP in preterm infants. TRIAL REGISTRATION: ClinicalTrials.gov NCT04430790 and EUDRACT 2019-003666-41. Prospectively registered on respectively June and January 2020.

Monitoring Circulation During Transition in Extreme Low Gestational Age Newborns: What's on the Horizon?

Echocardiography and near-infrared spectroscopy have significantly changed our view on hemodynamic transition of the extreme preterm infant. Instead of focusing on maintaining an arbitrary target value of blood pressure, we aim for circulatory well-being by a comprehensive holistic assessment of markers of cardiovascular instability. Most of these clinical and biochemical indices are influenced by transition itself and remain poor discriminators to identify patients with a potential need for therapeutic intervention. At the same time, the evolution in data capturing and storage has led to a change in our approach to monitor vital parameters. Continuous trend monitoring has become more and more relevant. By using signal extraction methods, changes in trends over time can be quantified. In this review, we will discuss the impact of these innovations on the current monitoring practices and explore some of the potential benefits these techniques may have in improving real-time detection of extreme low birth weight infants at risk for morbidity related to impaired hemodynamic transition.

Decreased Variability and Low Values of Perfusion Index on Day One Are Associated with Adverse Outcome in Extremely Preterm Infants.

OBJECTIVE: To develop new quantitative features for the Perfusion Index signal recorded continuously over the first 24 hours of life in a cohort of extremely low gestational age newborns and to assess the association of these features with normal and adverse short-term outcome. STUDY DESIGN: A cohort study of extremely low gestational age newborns. Adverse outcome was defined as early mortality before 72 hours of life, acquired severe periventricular-intraventricular hemorrhage, or severe cystic leukomalacia. Perfusion Index values were obtained from the plethysmographic signal of a pulse oximeter. Perfusion Index signals were separated into low-frequency (trend) and high-frequency (detrend) components. Three features were extracted during four 6-hour epochs: mean of the trend component (mean-trend), SD of the trend component (SD-trend), and SD of the detrend component (SD-detrend). The SD features represent long-term variability (SD-trend) and short-term variability (SD-detrend) of the Perfusion Index. A mixed-effects model was fitted to each feature. RESULTS: Ninety-nine infants were included in the analysis. Quadratic-time mixed-effects models provided the best fit for all 3 features. The mean-trend component was lower for the adverse outcome compared with the normal outcome group with a difference of 0.142 Perfusion Index (P = .001). SD-detrend component was also lower for the adverse compared with the normal outcome group, although this difference of 0.031 Perfusion Index/days2 was dependent on time (P < .001). CONCLUSION: Low values and reduced short-term variability of Perfusion Index on day 1 are associated with adverse outcome.

A rare infectious cause of severe neonatal skin lesions.

We present a case of a preterm infant of 28 weeks' gestation with unique cutaneous lesions characteristic of a congenital herpes simplex virus (HSV) type 1 infection. The infant was prematurely delivered due to intractable labour. The mother had no history or clinical signs of genital infection before or during pregnancy. The infant's skin lesions were described as rough white-yellow plaques; a skin biopsy demonstrated calcified plaques and absent epidermis. HSV type 1 was later determined using PCR on the infant's skin biopsy and cerebral spinal fluid as well as the mother's vaginal swab and the placenta. Calcifications have already been described by Allee et al, alongside a diagnosis of HSV type 2. As is well known, the morbidity and mortality of congenital herpes infections are very high.

Extremely elevated cerebrospinal fluid protein levels in a child with neurologic symptoms: beware of haemophagocytic lymphohistiocytosis.

Neurologic symptoms can be the initial manifestation of haemophagocytic lymphohistiocytosis (HLH). In this case study, we present a 3-year old boy with a clinical picture of encephalitis, a cerebrospinal fluid (CSF) protein level up to 1165 mg/dl and diffuse cerebral MRI abnormalities. The diagnosis of HLH was established only 6 weeks after initial presentation. The boy recovered after HLH therapy with persisting mild cognitive defects. Genetic investigation demonstrated X-linked lymphoproliferative disease (XLP) as the underlying cause of HLH. The extremely elevated protein level in CSF in this case has not yet been reported in patients with HLH.