Cerebral Palsy - Early Diagnosis and Intervention Trial: protocol for the prospective multicentre CP-EDIT study with focus on diagnosis, prognostic factors, and intervention.

BACKGROUND: Early diagnosis of cerebral palsy (CP) is important to enable intervention at a time when neuroplasticity is at its highest. Current mean age at diagnosis is 13 months in Denmark. Recent research has documented that an early-diagnosis set-up can lower diagnostic age in high-risk infants. The aim of the current study is to lower diagnostic age of CP regardless of neonatal risk factors. Additionally, we want to investigate if an early intervention program added to standard care is superior to standard care alone. METHODS: The current multicentre study CP-EDIT (Early Diagnosis and Intervention Trial) with the GO-PLAY intervention included (Goal Oriented ParentaL supported home ActivitY program), aims at testing the feasibility of an early diagnosis set-up and the GO-PLAY early intervention. CP-EDIT is a prospective cohort study, consecutively assessing approximately 500 infants at risk of CP. We will systematically collect data at inclusion (age 3-11 months) and follow a subset of participants (n = 300) with CP or at high risk of CP until the age of two years. The GO-PLAY early intervention will be tested in 80 infants with CP or high risk of CP. Focus is on eight areas related to implementation and perspectives of the families: early cerebral magnetic resonance imaging (MRI), early genetic testing, implementation of the General Movements Assessment method, analysis of the GO-PLAY early intervention, parental perspective of early intervention and early diagnosis, early prediction of CP, and comparative analysis of the Hand Assessment for Infants, Hammersmith Infant Neurological Examination, MRI, and the General Movements method. DISCUSSION: Early screening for CP is increasingly possible and an interim diagnosis of "high risk of CP" is recommended but not currently used in clinical care in Denmark. Additionally, there is a need to accelerate identification in mild or ambiguous cases to facilitate appropriate therapy early. Most studies on early diagnosis focus on identifying CP in infants below five months corrected age. Little is known about early diagnosis in the 50% of all CP cases that are discernible later in infancy. The current study aims at improving care of patients with CP even before they have an established diagnosis. TRIAL REGISTRATION: ClinicalTrials.gov ID 22013292 (reg. date 31/MAR/2023) for the CP-EDIT cohort and ID 22041835 (reg. date 31/MAR/2023) for the GO-PLAY trial.

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).

Cerebral autoregulation in the first day after preterm birth: no evidence of association with systemic inflammation.

INTRODUCTION: Both systemic inflammation and impaired cerebral autoregulation (CA) have been associated with brain injury in preterm infants. We hypothesized that impaired CA represents a hemodynamic link between inflammation and brain injury. RESULTS: Neither fetal vasculitis nor interleukin-6 (IL-6) affected CA significantly. A high level of IL-6 was associated with hypotension (P = 0.03) irrespective of dopamine therapy. The magnitude of impairment in CA increased with decreasing mean arterial blood pressure (MAP) (P = 0.02). No significant associations were found between these parameters and either intraventricular hemorrhage (IVH) (n = 10) or neonatal mortality (n = 8). DISCUSSION: In conclusion, postnatal inflammation was weakly associated with arterial hypotension, and hypotension was weakly associated with impaired autoregulation. There was no direct association, however, between autoregulation and antenatal or postnatal signs of inflammation. METHODS: In our study, 60 infants (mean (±SD) of gestational age (GA) 27 (±1.3) wk) underwent continuous recording of MAP and cerebral oxygenation index (OI) by means of near-infrared spectroscopy (NIRS) for 2.3 ± 0.5 h, starting 18 ± 9 h after birth. Coherence and transfer function gain between MAP and OI represented the presence and degree of impairment of CA, respectively. We considered fetal vasculitis (placenta histology) to be an antenatal marker of inflammation, and used the level of IL-6 in blood, measured at 18 ± 10 h after birth, as a postnatal marker of inflammation. Definition of hypotension was MAP (mm Hg) ≤ GA (wk).

Cerebral Oximetry in Preterm Infants-To Use or Not to Use, That Is the Question.

The Safeguarding the Brains of our smallest Children (SafeBoosC) project was initially established to test the patient-relevant benefits and harms of cerebral oximetry in extremely preterm infants in the setting of a randomized clinical trial. Extremely preterm infants constitute a small group of patients with a high risk of death or survival with brain injury and subsequent neurodevelopmental disability. Several cerebral oximeters are approved for clinical use, but the use of additional equipment may disturb and thereby possibly harm these vulnerable, immature patients. Thus, the mission statement of the consortium is "do not disturb-unless necessary." There may also be more tangible risks such as skin breakdown, displacement of tubes and catheters due to more complicated nursing care, and mismanagement of cerebral oxygenation as a physiological variable. Other monitoring modalities have relevance for reducing the risk of hypoxic-ischemic brain injury occurring during acute illness and have found their place in routine clinical care without evidence from randomized clinical trials. In this manuscript, we discuss cerebral oximetry, pulse oximetry, non-invasive electric cardiometry, and invasive monitoring of blood pressure. We discuss the reliability of the measurements, the pathophysiological rationale behind the clinical use, the evidence of benefit and harms, and the costs. By examining similarities and differences, we aim to provide our perspective on the use or non-use of cerebral oximetry in newborn infants during intensive care.

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.

AIM: We hypothesized that compromised cardiac output in asphyxiated infants may influence on the rate of disappearance of lactate due to insufficient perfusion. METHODS: The 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. RESULTS: Cardiac 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. CONCLUSION: An 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.

BACKGROUND: 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". METHODS: 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. RESULTS: 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. CONCLUSION: 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.

[Flow cytometry: a fast method to detect foetomaternal haemorrhage]. / Neonatal anæmi på grund af føtomaternel blødning diagnosticeret ved flowcytometri.

The passage of foetal blood into maternal circulation is termed a foetomaternal haemorrhage (FMH). Most cases are clinically insignificant. However, in some cases a large FMH causes serious anaemia in the newborn child. Flow cytometry is a precise and fast method to analyse maternal blood for FMH and can be used both antenatally and postnatally. The clinician should consider using the analysis in cases of unexplained anaemia. We describe a case with severe FMH.

Testing impact of perinatal inflammation on cerebral autoregulation in preterm neonates: evaluation of a noninvasive method.

Increased preterm delivery rate and survival of preterm infants of whom a considerable proportion survive with neurodevelopmental impairment calls for better knowledge of mechanisms associated with brain injury. This thesis focuses on cerebral autoregulation and is based on clinical studies of very preterm infants and experimental studies in newborn piglets. Maintaining adequate cerebral perfusion is critical to avoid brain injury. In healthy neonates, cerebral autoregulation ensures an almost unchanged cerebral perfusion within a narrow range of arterial blood pressures. When autoregulation is impaired, cerebral blood flow follows changes in arterial blood pressure passively. Both impaired cerebral autoregulation and perinatal inflammation have been associated with perinatal brain injury in preterm neonates. We hypothesized that impaired cerebral autoregulation might represent a hemodynamic link between inflammation and brain injury. We used an apparently well established non-invasive method based on frequency analysis between spontaneous changes in arterial blood pressure and cerebral oxygenation as measured with near-infrared spectroscopy. It turned out that the methodology was weak. This led us to evaluate the precision and validity of this method. We monitored 22 preterm neonates and demonstrated that reliable detection of impaired cerebral autoregulation requires several hours of monitoring. However, weighting measurements with large variations in blood pressure in favour of those with small increases the precision. This reduces the required monitoring time in each infant (study I). Furthermore, we used a piglet model to validate the method against a conventional measure of cerebral autoregulation and demonstrated a significant correlation with degree of impaired autoregulation (study II). To study a possible link between cerebral autoregulation and perinatal inflammation, cerebral autoregulation was measured in 60 infants in their first postnatal day. Foetal vasculitis was used as a marker of antenatal (preceding) inflammation. Level of interleukin-6 in postnatal blood samples was used as a marker of postnatal (concurrent) inflammation. Neither ante- nor postnatal inflammation affected cerebral autoregulation significantly. There was, however, a trend towards a more severely impaired autoregulation in infants with signs of antenatal inflammation. Postnatal inflammation was significantly associated with hypotension, and blood pressure was inversely associated with degree of impaired cerebral autoregulation (study III). Also, we made use of our piglet model to study (i) if hypovolaemia affects cerebral autoregulation, and (ii) a possible direct cerebrovascular effect of dopamine therapy. Hypovolaemia without hypotension did not seem to affect autoregulation significantly. Dopamine, the most frequently used antihypotensive drug in neonates, elicited an unexplained mismatch between cerebral oxygenation and perfusion, as perfusion increased while oxygenation was unaffected (study IV). This mismatch has formed the basis for an ongoing explanatory study. Based on the findings in the present thesis we conclude the following: Our non-invasive method has potential use in clinical research. However, low precision hampers its clinical application. In preterm infants with perinatal inflammation, cerebral blood flow is at most moderately affected by variations in arterial blood pressure, provided inflammation induced hypotension is prevented. In newborn piglets, hypovolaemia alone did not affect cerebral autoregulation significantly, and dopamine therapy elicited an unexplained mismatch between cerebral perfusion and oxygenation.

Precision of coherence analysis to detect cerebral autoregulation by near-infrared spectroscopy in preterm infants.

Coherence between spontaneous fluctuations in arterial blood pressure (ABP) and the cerebral near-infrared spectroscopy signal can detect cerebral autoregulation. Because reliable measurement depends on signals with high signal-to-noise ratio, we hypothesized that coherence is more precisely determined when fluctuations in ABP are large rather than small. Therefore, we investigated whether adjusting for variability in ABP (variability(ABP)) improves precision. We examined the impact of variability(ABP) within the power spectrum in each measurement and between repeated measurements in preterm infants. We also examined total monitoring time required to discriminate among infants with a simulation study. We studied 22 preterm infants (GA<30) yielding 215 10-min measurements. Surprisingly, adjusting for variability(ABP) within the power spectrum did not improve the precision. However, adjusting for the variability(ABP) among repeated measurements (i.e., weighting measurements with high variability(ABP) in favor of those with low) improved the precision. The evidence of drift in individual infants was weak. Minimum monitoring time needed to discriminate among infants was 1.3-3.7 h. Coherence analysis in low frequencies (0.04-0.1 Hz) had higher precision and statistically more power than in very low frequencies (0.003-0.04 Hz). In conclusion, a reliable detection of cerebral autoregulation takes hours and the precision is improved by adjusting for variability(ABP) between repeated measurements.