The effects of cerebral oximetry in mechanically ventilated newborns: a protocol for the SafeBoosC-IIIv randomised clinical trial

Background The SafeBoosC project aims to test the clinical value of non-invasive cerebral oximetry by near-infrared spectroscopy in newborn infants. The purpose is to establish whether cerebral oximetry can be used to save newborn infants’ lives and brains or not. Newborns contribute heavily to total childhood mortality and neonatal brain damage is the cause of a large part of handicaps such as cerebral palsy. The objective of the SafeBoosC-IIIv trial is to evaluate the benefits and harms of cerebral oximetry added to usual care versus usual care in mechanically ventilated newborns. Methods/design SafeBoosC-IIIv is an investigator-initiated, multinational, randomised, pragmatic phase-III clinical trial. The inclusion criteria will be newborns with a gestational age more than 28 + 0 weeks, postnatal age less than 28 days, predicted to require mechanical ventilation for at least 24 h, and prior informed consent from the parents or deferred consent or absence of opt-out. The exclusion criteria will be no available cerebral oximeter, suspicion of or confirmed brain injury or disorder, or congenital heart disease likely to require surgery. A total of 3000 participants will be randomised in 60 neonatal intensive care units from 16 countries, in a 1:1 allocation ratio to cerebral oximetry versus usual care. Participants in the cerebral oximetry group will undergo cerebral oximetry monitoring during mechanical ventilation in the neonatal intensive care unit for as long as deemed useful by the treating physician or until 28 days of life. The participants in the cerebral oximetry group will be treated according to the SafeBoosC treatment guideline. Participants in the usual care group will not receive cerebral oximetry and will receive usual care. We use two co-primary outcomes: (1) a composite of death from any cause or moderate to severe neurodevelopmental disability at 2 years of corrected age and (2) the non-verbal cognitive score of the Parent Report of Children’s Abilities-Revised (PARCA-R) at 2 years of corrected age. Discussion There is need for a randomised clinical trial to evaluate cerebral oximetry added to usual care versus usual care in mechanically ventilated newborns. Trial registration The protocol is registered at www.clinicaltrials.gov (NCT05907317; registered 18 June 2023)

Extremely Preterm Infant Admissions Within the SafeBoosC-III Consortium During the COVID-19 Lockdown

Objective: To evaluate if the number of admitted extremely preterm (EP) infants (born before 28 weeks of gestational age) differed in the neonatal intensive care units (NICUs) of the SafeBoosC-III consortium during the global lockdown when compared to the corresponding time period in 2019. Design: This is a retrospective, observational study. Forty-six out of 79 NICUs (58%) from 17 countries participated. Principal investigators were asked to report the following information: (1) Total number of EP infant admissions to their NICU in the 3 months where the lockdown restrictions were most rigorous during the first phase of the COVID-19 pandemic, (2) Similar EP infant admissions in the corresponding 3 months of 2019, (3) the level of local restrictions during the lockdown period, and (4) the local impact of the COVID-19 lockdown on the everyday life of a pregnant woman. Results: The number of EP infant admissions during the first wave of the COVID-19 pandemic was 428 compared to 457 in the corresponding 3 months in 2019 (−6.6%, 95% CI −18.2 to +7.1%, p = 0.33). There were no statistically significant differences within individual geographic regions and no significant association between the level of lockdown restrictions and difference in the number of EP infant admissions. A post-hoc analysis based on data from the 46 NICUs found a decrease of 10.3%in the total number of NICU admissions (n = 7,499 in 2020 vs. n = 8,362 in 2019). Conclusion: This ad hoc study did not confirm previous reports of a major reduction in the number of extremely pretermbirths during the first phase of the COVID-19 pandemic. Clinical Trial Registration: ClinicalTrial.gov, identifier: NCT04527601 (registered August 26, 2020), https://clinicaltrials.gov/ct2/show/NCT04527601

Lactate acidosis and cardiac output during initial therapeutic cooling in asphyxiated newborn infants

AimWe hypothesized that compromised cardiac output in asphyxiated infants may influence on the rate of disappearance of lactate due to insufficient perfusion.MethodsThe study was a prospective, observational study, where infants with perinatal asphyxia who met the criteria for therapeutic hypothermia were included. Cardiac output, stroke volume and heart rate were measured by electrical velocimetry in 15 newborn infants with perinatal asphyxia during the first six hours of active therapeutic hypothermia. Results from routine blood samples were collected retrospectively. Cardiac parameters were also measured in 10 healthy, term infants after caesarian section. Cardiac parameters were compared between the asphyxiated group and the control group prior to and during hypothermia. Rate of disappearance of lactate was correlated to cardiac output in the asphyxiated infants.ResultsCardiac output was stable in the healthy infants from 0.5 to 6 hours postnatally. The infants with perinatal asphyxia had lower cardiac output prior to and during therapeutic hypothermia compared to the control group. Rate of disappearance of lactate was not related to cardiac output.ConclusionAn association between disappearance of lactate acidosis and low cardiac output was not confirmed. A low rate of disappearance of lactate may rather be an indicator of organ injury due to asphyxia

Dopamine therapy does not affect cerebral autoregulation during hypotension in newborn piglets

<div><p>Background</p><p>Hypotensive neonates who have been treated with dopamine have poorer neurodevelopmental outcome than those who have not been treated with dopamine. We speculate that dopamine stimulates adrenoceptors on cerebral arteries causing cerebral vasoconstriction. This vasoconstriction might lead to a rightward shift of the cerebral autoregulatory curve; consequently, infants treated with dopamine would have a higher risk of low cerebral blood flow at a blood pressure that is otherwise considered “safe”.</p><p>Methods</p><p>In anaesthetized piglets, perfusion of the brain, monitored with laser-doppler flowmetry, and cerebral venous saturation was measured at different levels of hypotension. Each piglet was studied in two phases: a phase with stepwise decreases in MAP and a phase with stepwise increases in MAP. We randomized the order of the two phases, whether dopamine was given in the first or second phase, and the infusion rate of dopamine (10, 25, or 40 μg/kg/min). In/deflation of a balloon catheter, placed in vena cava, induced different levels of hypotension. At each level of hypotension, fluctuations in MAP were induced by in/deflations of a balloon catheter in descending aorta.</p><p>Results</p><p>During measurements, PaCO₂ and arterial saturation were stable. MAP levels ranged between 14 and 82 mmHg. Cerebral autoregulation (CA) capacity was calculated as the ratio between %-change in cerebrovascular resistance and %-change in MAP induced by the in/deflation of the arterial balloon. A breakpoint in CA capacity was identified at a MAP of 38±18 mmHg without dopamine and at 44±18, 31±14, and 24±14 mmHg with dopamine infusion rates of 10, 25, and 40 μg/kg/min (p = 0.057). Neither the index of steady-state cerebral perfusion nor cerebral venous saturation were affected by dopamine infusion.</p><p>Conclusion</p><p>Dopamine infusion tended to improve CA capacity at low blood pressures while an index of steady-state cerebral blood flow and cerebral venous saturation were unaffected by dopamine infusion. Thus, dopamine does not appear to impair CA in newborn piglets.</p></div

Experimental protocol.

<p>The protocol consisted of two phases: a phase where mean arterial blood pressure (MAP) was decreased and a phase where MAP was increased. At each MAP level, five small fluctuations in MAP was induced by the balloon catheter placed in aorta. We randomized the order of the two phases, whether dopamine was given in first or second phase, and the infusion rate of dopamine. In this illustration the piglet was randomized to have a decreasing MAP in the first phase and an increasing MAP in the second phase, also dopamine was randomized to be given during the second phase (arrow points to initiation of dopamine). *Indicates inflation of the venous balloon causing reduced MAP, whereas ** indicates increased MAP caused by deflation of the venous balloon. Before and between the two phases the piglet recovered for 0.5–1 hour.</p

Relation between mean arterial blood pressure and cerebral autoregulation capacity.

<p>This relationship is best described by a regression line with a breakpoint and are illustrated as the non-linear regression lines in the figure. Below the breakpoint, the line had a positive slope (1.7%/mmHg); and the line is horizontal above the breakpoint. These parameters were kept fixed in the individual calculations of breakpoints. Based on individual calculations of breakpoints, the mean breakpoint without dopamine was at 38mmHg. With 10 μg/kg/min, 25 μg/kg/min and 40 μg/kg/min the mean breakpoints were at 44mmHg, 31mmHg and 24mmHg, respectively.</p

Relation between individual breakpoints of ‘outcome variables’ and dopamine infusion in 18 piglets.

<p>Each piglet was studied twice—without and with one of the three infusion rates of dopamine. (a) Cerebral venous saturation (regression coefficient = 0.09 mmHg/μg*kg^-1*min^-1, p = 0.558). (b) The index of steady-state cerebral blood flow (regression coefficient = -0.02 mmHg/μg*kg^-1*min^-1, p = 0.863). (c) CA capacity (regression coefficient = -0.36 mmHg/μg*kg^-1*min^-1, p = 0.057).</p