A phase II randomized clinical trial on cerebral near-infrared spectroscopy plus a treatment guideline versus treatment as usual for extremely preterm infants during the first three days of life (SafeBoosC): study protocol for a randomized controlled trial

Abstract

BackgroundEvery year in Europe about 25,000 infants are born extremely preterm. These infants have a 20% mortality rate, and 25% of survivors have severe long-term cerebral impairment. Preventative measures are key to reduce mortality and morbidity in an extremely preterm population. The primary objective of the SafeBoosC phase II trial is to examine if it is possible to stabilize the cerebral oxygenation of extremely preterm infants during the first 72 hours of life through the application of cerebral near-infrared spectroscopy (NIRS) oximetry and implementation of an clinical treatment guideline based on intervention thresholds of cerebral regional tissue saturation rStO2.Methods/DesignSafeBoosC is a randomized, blinded, multinational, phase II clinical trial. The inclusion criteria are: neonates born more than 12 weeks preterm; decision to conduct full life support; parental informed consent; and possibility to place the cerebral NIRS oximeter within 3 hours after birth. The infants will be randomized into one of two groups. Both groups will have a cerebral oximeter monitoring device placed within three hours of birth. In the experimental group, the cerebral oxygenation reading will supplement the standard treatment using a predefined treatment guideline. In the control group, the cerebral oxygenation reading will not be visible and the infant will be treated according to the local standards. The primary outcome is the multiplication of the duration and magnitude of rStO2 values outside the target ranges of 55% to 85%, that is, the ‘burden of hypoxia and hyperoxia’ expressed in ‘%hours’. To detect a 50% difference between the experimental and control group in %hours, 166 infants in total must be randomized. Secondary outcomes are mortality at term date, cerebral ultrasound score, and interburst intervals on an amplitude-integrated electroencephalogram at 64 hours of life and explorative outcomes include neurodevelopmental outcome at 2 years corrected age, magnetic resonance imaging at term, blood biomarkers at 6 and 64 hours after birth, and adverse events.DiscussionCerebral oximetry guided interventions have the potential to improve neurodevelopmental outcome in extremely preterm infants. It is a logical first step to test if it is possible to reduce the burden of hypoxia and hyperoxia.Trial registrationClinicalTrial.gov, NCT01590316

The SafeBoosC Phase II Randomised Clinical Trial: A Treatment Guideline for Targeted Near-Infrared-Derived Cerebral Tissue Oxygenation versus Standard Treatment in Extremely Preterm Infants

“…We stress that this guideline is not approved for general use outside randomised clinical trials. We look forward to be able to report the results of the present SafeBoosC phase II randomised clinical trial and the planned SafeBoosC phase III randomised clinical trial that will evaluate the combined effect of NIRS and this treatment guideline [8,9]. …”

“…We assume a rather steady cerebral metabolic rate of oxygen. Given that the SafeBoosC intervention period focuses on the first 3 days after an extremely low gestational age neonate is born [8,9], disease states and related factors most commonly present during that period were of particular interest. The definition of normal range for cerebral rSt O 2 in this trial (55-85%) was derived from Lemmers and van Bel [unpubl.…”

“…The SafeBoosC phase II randomised clinical trial hypothesises that the burden of hypo- and hyperoxia can be reduced, and consequently the risk of brain injury, by the combined use of close monitoring of the cerebral rSt O 2 and an evidence-based treatment guideline to correct deviations in rSt O 2 outside a predefined target range [7,8,9]. Accordingly, a treatment guideline has been developed focusing on interventions that could have an impact on arterial oxygen saturation (Sa O 2 ), haemoglobin concentration, and cerebral blood flow (CBF), which are the main determinants of oxygen delivery to the brain.…”

Hyperoxia and the Immature Brain

“…However, excessive O 2 tensions occur in the brain when care providers increase the FiO 2 more than is necessary to compensate for pulmonary deficits during certain time periods. Before discussing therapeutic approaches, we aim to emphasise the need for the real-time monitoring of brain oxygen levels in routine NICU settings to prevent hyperoxia [129][130][131] . Technical advances in this field should receive higher priority than solely focussing on the discovery of therapies treating hyperoxia-induced injury.…”

Intermittent Hypoxemia/Bradycardia and the Developing Brain: How Much Is Too Much?

“…whether it truly helps with clinical decision making, ultimately leading to better patient outcomes [3]. The clinical application for NIRS used in the study by Schmid et al [2] may represent an example for a move in that direction.…”