Cerebral oximetry monitoring versus usual care for extremely preterm infants: a study protocol for the 2-year follow-up of the SafeBoosC-III randomised clinical trial.

BACKGROUND: In the SafeBoosC-III trial, treatment guided by cerebral oximetry monitoring for the first 72 hours after birth did not reduce the incidence of death or severe brain injury in extremely preterm infants at 36 weeks' postmenstrual age, as compared with usual care. Despite an association between severe brain injury diagnosed in the neonatal period and later neurodevelopmental disability, this relationship is not always strong. The objective of the SafeBoosC-III follow-up study is to assess mortality, neurodevelopmental disability, or any harm in trial participants at 2 years of corrected age. One important challenge is the lack of funding for local costs for a trial-specific assessment. METHODS: Of the 1601 infants randomised in the SafeBoosC-III trial, 1276 infants were alive at 36 weeks' postmenstrual age and will potentially be available for the 2-year follow-up. Inclusion criteria will be enrollment in a neonatal intensive care unit taking part in the follow-up study and parental consent if required by local regulations. We aim to collect data from routine follow-up programmes between the ages of 18 and 30 months of corrected age. If no routine follow-up has been conducted, we will collect informal assessments from other health care records from the age of at least 12 months. A local co-investigator blinded to group allocation will classify outcomes based on these records. We will supplement this with parental questionnaires including the Parent Report of Children's Abilities-Revised. There will be two co-primary outcomes: the composite of death or moderate or severe neurodevelopmental disability and mean Bayley-III/IV cognitive score. We will use a 3-tier model for prioritisation, based on the quality of data. This approach has been chosen to minimise loss to follow-up assuming that little data is better than no data at all. DISCUSSION: Follow-up at the age of 2 years is important for intervention trials in the newborn period as only time can show real benefits and harms later in childhood. To decrease the risk of generalisation and data-driven biased conclusions, we present a detailed description of the methodology for the SafeBoosC-III follow-up study. As funding is limited, a pragmatic approach is necessary. TRIAL REGISTRATION: ClinicalTrials.gov NCT05134116 . Registered on 24 November 2021.

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 Oximetry Monitoring in Extremely Preterm Infants.

BACKGROUND: The use of cerebral oximetry monitoring in the care of extremely preterm infants is increasing. However, evidence that its use improves clinical outcomes is lacking. METHODS: In this randomized, phase 3 trial conducted at 70 sites in 17 countries, we assigned extremely preterm infants (gestational age, <28 weeks), within 6 hours after birth, to receive treatment guided by cerebral oximetry monitoring for the first 72 hours after birth or to receive usual care. The primary outcome was a composite of death or severe brain injury on cerebral ultrasonography at 36 weeks' postmenstrual age. Serious adverse events that were assessed were death, severe brain injury, bronchopulmonary dysplasia, retinopathy of prematurity, necrotizing enterocolitis, and late-onset sepsis. RESULTS: A total of 1601 infants underwent randomization and 1579 (98.6%) were evaluated for the primary outcome. At 36 weeks' postmenstrual age, death or severe brain injury had occurred in 272 of 772 infants (35.2%) in the cerebral oximetry group, as compared with 274 of 807 infants (34.0%) in the usual-care group (relative risk with cerebral oximetry, 1.03; 95% confidence interval, 0.90 to 1.18; P = 0.64). The incidence of serious adverse events did not differ between the two groups. CONCLUSIONS: In extremely preterm infants, treatment guided by cerebral oximetry monitoring for the first 72 hours after birth was not associated with a lower incidence of death or severe brain injury at 36 weeks' postmenstrual age than usual care. (Funded by the Elsass Foundation and others; SafeBoosC-III ClinicalTrials.gov number, NCT03770741.).

Haloperidol for the Treatment of Delirium in ICU Patients.

BACKGROUND: Haloperidol is frequently used to treat delirium in patients in the intensive care unit (ICU), but evidence of its effect is limited. METHODS: In this multicenter, blinded, placebo-controlled trial, we randomly assigned adult patients with delirium who had been admitted to the ICU for an acute condition to receive intravenous haloperidol (2.5 mg 3 times daily plus 2.5 mg as needed up to a total maximum daily dose of 20 mg) or placebo. Haloperidol or placebo was administered in the ICU for as long as delirium continued and as needed for recurrences. The primary outcome was the number of days alive and out of the hospital at 90 days after randomization. RESULTS: A total of 1000 patients underwent randomization; 510 were assigned to the haloperidol group and 490 to the placebo group. Among these patients, 987 (98.7%) were included in the final analyses (501 in the haloperidol group and 486 in the placebo group). Primary outcome data were available for 963 patients (97.6%). At 90 days, the mean number of days alive and out of the hospital was 35.8 (95% confidence interval [CI], 32.9 to 38.6) in the haloperidol group and 32.9 (95% CI, 29.9 to 35.8) in the placebo group, with an adjusted mean difference of 2.9 days (95% CI, -1.2 to 7.0) (P = 0.22). Mortality at 90 days was 36.3% in the haloperidol group and 43.3% in the placebo group (adjusted absolute difference, -6.9 percentage points [95% CI, -13.0 to -0.6]). Serious adverse reactions occurred in 11 patients in the haloperidol group and in 9 patients in the placebo group. CONCLUSIONS: Among patients in the ICU with delirium, treatment with haloperidol did not lead to a significantly greater number of days alive and out of the hospital at 90 days than placebo. (Funded by Innovation Fund Denmark and others; AID-ICU ClinicalTrials.gov number, NCT03392376; EudraCT number, 2017-003829-15.).

Cerebral near-infrared spectroscopy monitoring (NIRS) in children and adults: a systematic review with meta-analysis.

BACKGROUND: Cerebral oxygenation monitoring utilising near-infrared spectroscopy (NIRS) is increasingly used to guide interventions in clinical care. The objective of this systematic review with meta-analysis and Trial Sequential Analysis is to evaluate the effects of clinical care with access to cerebral NIRS monitoring in children and adults versus care without. METHODS: This review conforms to PRISMA guidelines and was registered in PROSPERO (CRD42020202986). Methods are outlined in our protocol (doi: 10.1186/s13643-021-01660-2). RESULTS: Twenty-five randomised clinical trials were included (2606 participants). All trials were at a high risk of bias. Two trials assessed the effects of NIRS during neonatal intensive care, 13 during cardiac surgery, 9 during non-cardiac surgery and 1 during neurocritical care. Meta-analyses showed no significant difference for all-cause mortality (RR 0.75, 95% CI 0.51-1.10; 1489 participants; I2 = 0; 11 trials; very low certainty of evidence); moderate or severe, persistent cognitive or neurological deficit (RR 0.74, 95% CI 0.42-1.32; 1135 participants; I2 = 39.6; 9 trials; very low certainty of evidence); and serious adverse events (RR 0.82; 95% CI 0.67-1.01; 2132 participants; I2 = 68.4; 17 trials; very low certainty of evidence). CONCLUSION: The evidence on the effects of clinical care with access to cerebral NIRS monitoring is very uncertain. IMPACT: The evidence of the effects of cerebral NIRS versus no NIRS monitoring are very uncertain for mortality, neuroprotection, and serious adverse events. Additional trials to obtain sufficient information size, focusing on lowering bias risk, are required. The first attempt to systematically review randomised clinical trials with meta-analysis to evaluate the effects of cerebral NIRS monitoring by pooling data across various clinical settings. Despite pooling data across clinical settings, study interpretation was not substantially impacted by heterogeneity. We have insufficient evidence to support or reject the clinical use of cerebral NIRS monitoring.

Early cerebral hypoxia in extremely preterm infants and neurodevelopmental impairment at 2 year of age: A post hoc analysis of the SafeBoosC II trial.

BACKGROUND: The SafeBoosC II, randomised clinical trial, showed that the burden of cerebral hypoxia was reduced with the combination of near infrared spectroscopy and a treatment guideline in extremely preterm infants during the first 72 hours after birth. We have previously reported that a high burden of cerebral hypoxia was associated with cerebral haemorrhage and EEG suppression towards the end of the 72-hour intervention period, regardless of allocation. In this study we describe the associations between the burden of cerebral hypoxia and the 2-year outcome. METHODS: Cerebral oxygenation was continuously monitored from 3 to 72 hours after birth in 166 extremely preterm infants. At 2 years of age 114 of 133 surviving children participated in the follow-up program: medical examination, Bayley II or III test and the parental Ages and Stages Questionnaire. The infants were classified according to the burden of hypoxia: within the first three quartiles (n = 86, low burden) or within in the 4th quartile (n = 28, high burden). All analyses were conducted post hoc. RESULTS: There were no statistically significant differences between the quantitative assessments of neurodevelopment in the groups of infants with the low burden of cerebral hypoxia versus the group of infants with the high burden of cerebral hypoxia. The infants in the high hypoxia burden group had a higher-though again not statistically significant-rate of cerebral palsy (OR 2.14 (0.33-13.78)) and severe developmental impairment (OR 4.74 (0.74-30.49). CONCLUSIONS: The burden of cerebral hypoxia was not significantly associated with impaired 2-year neurodevelopmental outcome in this post-hoc analysis of a feasibility trial.

The clinical effects of cerebral near-infrared spectroscopy monitoring (NIRS) versus no monitoring: a protocol for a systematic review with meta-analysis and trial sequential analysis.

BACKGROUND: Multiple clinical conditions are associated with cerebral hypoxia/ischaemia and thereby an increased risk of hypoxic-ischaemic brain injury. Cerebral near-infrared spectroscopy monitoring (NIRS) is a tool to monitor brain oxygenation and perfusion, and the clinical uptake of NIRS has expanded over recent years. Specifically, NIRS is used in the neonatal, paediatric, and adult perioperative and intensive care settings. However, the available literature suggests that clinical benefits and harms of cerebral NIRS monitoring are uncertain. As rates of clinically significant hypoxic-ischaemic brain injuries are typically low, it is difficult for randomised clinical trials to capture a sufficiently large number of events to evaluate the clinical effect of cerebral NIRS monitoring, when focusing on specific clinical settings. The aim of this systematic review will be to evaluate the benefits and harms of clinical care with access to cerebral NIRS monitoring versus clinical care without cerebral NIRS monitoring in children and adults across all clinical settings. METHODS: We will conduct a systematic review with meta-analysis and trial sequential analysis. We will only include randomised clinical trials. The primary outcomes are all-cause mortality, moderate or severe persistent cognitive or neurological deficit, and proportion of participants with one or more serious adverse events. We will search CENTRAL, EMBASE, MEDLINE, and the Science Citation Index Expanded from their inception and onwards. Two reviewers will independently screen all citations, full-text articles, and extract data. The risk of bias will be appraised using the Cochrane risk of bias tool version 2.0. If feasible, we will conduct both random-effects meta-analysis and fixed-effect meta-analysis of outcome data. Additional analysis will be conducted to explore the potential sources of heterogeneity (e.g. risk of bias, clinical setting). DISCUSSION: As we include trials across multiple clinical settings, there is an increased probability of reaching a sufficient information size. However, heterogeneity between the included trials may impair our ability to interpret results to specific clinical settings. In this situation, we may have to depend on subgroup analyses with inherent increased risks of type I and II errors. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42020202986 . This systematic review protocol has been submitted for registration in the International Prospective Register of Systematic Reviews (PROSPERO) (http://www.crd.york.ac.uk/prospero) on the 12th of October 2020 and published on the 12th of November 2020 (registration ID CRD42020202986 ).

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.

Correction: Comparison of INVOS 5100C and Nonin SenSmart X-100 oximeter performance in preterm infants with spontaneous apnea.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Comparison of INVOS 5100C and Nonin SenSmart X-100 oximeter performance in preterm infants with spontaneous apnea.

BACKGROUND: Tissue oximeters are not interchangeable. Two instruments with sensors dedicated to preterm infants-INVOS 5100C and Nonin SenSmart X-100-have not yet been compared. METHODS: By measuring cerebral oxygenation in ten preterm infants with spontaneous apneic episodes defined by pulse oximeter readings (SpO2) below 80%, as well as tissue oxygenation during vascular occlusion on the forearm of ten adults, simultaneously we compared performance in the hypoxic range. RESULTS: We found the mean conversion equations to be StO2,SenSmart X-100 = 0.34 × StO2,INVOS 5100C + 44.8% during apnea in infants and StO2,SenSmart X-100 = 0.59 × StO2,INVOS 5100C + 34.4% during vascular occlusion. The individual regressions displayed large and statistically significant variations in both infants and adults. In three infants the INVOS sensor showed very little reaction to decreases in SpO2. CONCLUSIONS: These findings confirm that different NIRS devices give very different estimates when the oxygenation is low. The large variation when compared to SpO2 suggest that the sensor placement is very important in preterm infants.

Detailed statistical analysis plan for the SafeBoosC III trial: a multinational randomised clinical trial assessing treatment guided by cerebral oxygenation monitoring versus treatment as usual in extremely preterm infants.

BACKGROUND: Infants born extremely preterm are at high risk of dying or suffering from severe brain injuries. Treatment guided by monitoring of cerebral oxygenation may reduce the risk of death and neurologic complications. The SafeBoosC III trial evaluates the effects of treatment guided by cerebral oxygenation monitoring versus treatment as usual. This article describes the detailed statistical analysis plan for the main publication, with the aim to prevent outcome reporting bias and data-driven analyses. METHODS/DESIGN: The SafeBoosC III trial is an investigator-initiated, randomised, multinational, pragmatic phase III trial with a parallel group structure, designed to investigate the benefits and harms of treatment based on cerebral near-infrared spectroscopy monitoring compared with treatment as usual. Randomisation will be 1:1 stratified for neonatal intensive care unit and gestational age (lower gestational age (< 26 weeks) compared to higher gestational age (≥ 26 weeks)). The primary outcome is a composite of death or severe brain injury at 36 weeks postmenstrual age. Primary analysis will be made on the intention-to-treat population for all outcomes, using mixed-model logistic regression adjusting for stratification variables. In the primary analysis, the twin intra-class correlation coefficient will not be considered. However, we will perform sensitivity analyses to address this. Our simulation study suggests that the inclusion of multiple births is unlikely to significantly affect our assessment of intervention effects, and therefore we have chosen the analysis where the twin intra-class correlation coefficient will not be considered as the primary analysis. DISCUSSION: In line with the Declaration of Helsinki and the International Conference on Harmonization Good Clinical Practice guidelines, we have developed and published this statistical analysis plan for the SafeBoosC III trial, prior to any data analysis. TRIAL REGISTRATION: ClinicalTrials.org, NCT03770741. Registered on 10 December 2018.

No neurodevelopmental benefit of cerebral oximetry in the first randomised trial (SafeBoosC II) in preterm infants during the first days of life.

AIM: Cerebral hypoxia has been associated with neurodevelopmental impairment. We studied whether reducing cerebral hypoxia in extremely preterm infants during the first 72 hours of life affected neurological outcomes at two years of corrected age. METHODS: In 2012-2013, the phase II randomised Safeguarding the Brains of our smallest Children trial compared visible cerebral near-infrared spectroscopy (NIRS) monitoring in an intervention group and blinded NIRS monitoring in a control group. Cerebral hypoxia was significantly reduced in the intervention group. We followed up 115 survivors from eight European centres at two years of corrected age, by conducting a medical examination and assessing their neurodevelopment with the Bayley Scales of Infant and Toddler Development, Second or Third Edition, and the parental Ages and Stages Questionnaire (ASQ). RESULTS: There were no differences between the intervention (n = 65) and control (n = 50) groups with regard to the mean mental developmental index (89.6 ± 19.5 versus 88.4 ± 14.7, p = 0.77), ASQ score (215 ± 58 versus 213 ± 58, p = 0.88) and the number of children with moderate-to-severe neurodevelopmental impairment (10 versus six, p = 0.58). CONCLUSION: Cerebral NIRS monitoring was not associated with long-term benefits or harm with regard to neurodevelopmental outcome at two years of corrected age.

Cerebral near-infrared spectroscopy monitoring versus treatment as usual for extremely preterm infants: a protocol for the SafeBoosC randomised clinical phase III trial.

BACKGROUND: Cerebral oxygenation monitoring may reduce the risk of death and neurologic complications in extremely preterm infants, but no such effects have yet been demonstrated in preterm infants in sufficiently powered randomised clinical trials. The objective of the SafeBoosC III trial is to investigate the benefits and harms of treatment based on near-infrared spectroscopy (NIRS) monitoring compared with treatment as usual for extremely preterm infants. METHODS/DESIGN: SafeBoosC III is an investigator-initiated, multinational, randomised, pragmatic phase III clinical trial. Inclusion criteria will be infants born below 28 weeks postmenstrual age and parental informed consent (unless the site is using 'opt-out' or deferred consent). Exclusion criteria will be no parental informed consent (or if 'opt-out' is used, lack of a record that clinical staff have explained the trial and the 'opt-out' consent process to parents and/or a record of the parents' decision to opt-out in the infant's clinical file); decision not to provide full life support; and no possibility to initiate cerebral NIRS oximetry within 6 h after birth. Participants will be randomised 1:1 into either the experimental or control group. Participants in the experimental group will be monitored during the first 72 h of life with a cerebral NIRS oximeter. Cerebral hypoxia will be treated according to an evidence-based treatment guideline. Participants in the control group will not undergo cerebral oxygenation monitoring and will receive treatment as usual. Each participant will be followed up at 36 weeks postmenstrual age. The primary outcome will be a composite of either death or severe brain injury detected on any of the serial cranial ultrasound scans that are routinely performed in these infants up to 36 weeks postmenstrual age. Severe brain injury will be assessed by a person blinded to group allocation. To detect a 22% relative risk difference between the experimental and control group, we intend to randomise a cohort of 1600 infants. DISCUSSION: Treatment guided by cerebral NIRS oximetry has the potential to decrease the risk of death or survival with severe brain injury in preterm infants. There is an urgent need to assess the clinical effects of NIRS monitoring among preterm neonates. TRIAL REGISTRATION: ClinicalTrial.gov, NCT03770741. Registered 10 December 2018.

In vivo validation of cerebral near-infrared spectroscopy: a review.

We summarize the available in vivo validation of cerebral near-infrared spectroscopy (NIRS) oximetry to inform future in vivo validation strategies. In particular, to establish a way forward in the assessment of NIRS instrumentation for future randomized trials, a systematic literature search is performed. The records are screened and abstracts are assessed to select studies fulfilling our inclusion criteria. Twenty-two pediatric and 28 adult studies are analyzed after exclusion of three articles in each group. All studies compare regional cerebral tissue oxygenation measured by cerebral NIRS to invasive measurement of central or jugular venous oxygen saturation. In studies without Bland-Altman plots, we extracted data from scatter plots enabling estimation of mean difference (MD), standard deviation (SD), and limits of agreement (LOA). To assess the agreement between rStO 2 (regional cerebral tissue oxygenation) estimated by NIRS and by blood samples, weighted averages of the MDs and SDs from each study are calculated. We found a fair agreement between the overall mean of cerebral tissue oxygenation and the mean of a reference value measured by co-oximetry whatever NIRS instrument or site of blood sampling used. Cerebral oxygenation overestimates the reference at low values, some instruments apparently more than others. Thus, a high degree of scatter and a lack of a good reference method complicate in vivo validation of NIRS. It is difficult to draw any firm conclusions despite the large number of studies, and the result of this review leaves us questioning if more of such validation studies of cerebral NIRS oximetry are really needed. Furthermore, the combination of lack of validation and poor repeatability is an important issue when designing a randomized clinical trial of implementing cerebral NIRS oximetry into clinical care.

Cerebral near-infrared spectroscopy monitoring for prevention of brain injury in very preterm infants.

BACKGROUND: Cerebral injury and long-term neurodevelopmental impairment is common in extremely preterm infants. Cerebral near-infrared spectroscopy (NIRS) enables continuous estimation of cerebral oxygenation. This diagnostic method coupled with appropriate interventions if NIRS is out of normal range (that is cerebral oxygenation within the 55% to 85% range) may offer benefits without causing more harms. Therefore, NIRS coupled with appropriate responses to abnormal findings on NIRS needs assessment in a systematic review of randomised clinical trials and quasi-randomised studies. OBJECTIVES: To evaluate the benefits and harms of interventions that attempt to alter cerebral oxygenation guided by cerebral NIRS monitoring in order to prevent cerebral injury, improve neurological outcome, and increase survival in preterm infants born more than 8 weeks preterm. SEARCH METHODS: We used the standard search strategy of the Cochrane Neonatal Review Group to search the Cochrane Central Register of Controlled Trials (CENTRAL 2016, Issue 8), MEDLINE via PubMed (1966 to 10 September 2016), Embase (1980 to 10 September 2016), and CINAHL (1982 to 10 September 2016). We also searched clinical trial databases, conference proceedings, and the reference lists of retrieved articles for randomised clinical trials and quasi-randomised studies. SELECTION CRITERIA: Randomised clinical trials and quasi-randomised clinical studies comparing continuous cerebral NIRS monitoring for at least 24 hours versus blinded NIRS or versus no NIRS monitoring. DATA COLLECTION AND ANALYSIS: Two review authors independently selected, assessed the quality of, and extracted data from the included trials and studies. If necessary, we contacted authors for further information. We conducted assessments of risks of bias; risks of design errors; and controlled the risks of random errors with Trial Sequential Analysis. We assessed the quality of the evidence with GRADE. MAIN RESULTS: One randomised clinical trial met inclusion criteria, including infants born more than 12 weeks preterm. The trial employed adequate methodologies and was assessed at low risk of bias. One hundred and sixty-six infants were randomised to start continuous cerebral NIRS monitoring less than 3 hours after birth until 72 hours after birth plus appropriate interventions if NIRS was out of normal range according to a guideline versus conventional monitoring with blinded NIRS. There was no effect of NIRS plus guideline of mortality until term-equivalent age (RR 0.50, 95% CI 0.29 to 1.00; one trial; 166 participants). There were no effects of NIRS plus guideline on intraventricular haemorrhages: all grades (RR 0.93, 95% CI 0.65 to 1.34; one trial; 166 participants); grade III/IV (RR 0.57, 95% CI 0.25 to 1.31; one trial; 166 participants); and cystic periventricular leukomalacia (which did not occur in either group). Likewise, there was no effect of NIRS plus guideline on the occurrence of a patent ductus arteriosus (RR 1.96, 95% CI 0.94 to 4.08; one trial; 166 participants); chronic lung disease (RR 1.27, 95% CI 0.94 to 1.50; one trial; 166 participants); necrotising enterocolitis (RR 0.83, 95% CI 0.33 to 1.94; one trial; 166 participants); and retinopathy of prematurity (RR 1.64, 95% CI 0.75 to 3.00; one trial; 166 participants). There were no serious adverse events in any of the intervention groups. NIRS plus guideline caused more skin marks from the NIRS sensor in the control group than in the experimental group (unadjusted RR 0.31, 95% CI 0.10 to 0.92; one trial; 166 participants). There are no data regarding neurodevelopmental outcome, renal impairment or air leaks.The quality of evidence for all comparisons discussed above was assessed as very low apart from all-cause mortality and adverse events: these were assessed as low and moderate, respectively. The validity of all comparisons is hampered by a small sample of randomised infants, risk of bias due to lack of blinding, and indirectness of outcomes. AUTHORS' CONCLUSIONS: The only eligible randomised clinical trial did not demonstrate any consistent effects of NIRS plus a guideline on the assessed clinical outcomes. The trial was, however, only powered to detect difference in cerebral oxygenation, not morbidities or mortality. Our systematic review did not reach sufficient power to prove or disprove effects on clinical outcomes. Further randomised clinical trials with low risks of bias and low risks of random errors are needed.

Early biomarkers of brain injury and cerebral hypo- and hyperoxia in the SafeBoosC II trial.

BACKGROUND: The randomized clinical trial, SafeBoosC II, examined the effect of monitoring of cerebral oxygenation by near-infrared spectroscopy combined with a guideline on treatment when cerebral oxygenation was out of the target range. Data on cerebral oxygenation was collected in both the intervention and the control group. The primary outcome was the reduction in the burden of cerebral hypo- and hyperoxia between the two groups. In this study we describe the associations between the burden of cerebral hypo- and hyperoxia, regardless of allocation to intervention or control group, and the biomarkers of brain injury from birth till term equivalent age that was collected as secondary and explorative outcomes in the SafeBoosC II trial. METHODS: Cerebral oxygenation was continuously monitored during the first 72h of life in 166 extremely preterm infants. Cranial ultrasound was performed at day 1,4,7,14, and 35 and at term. Electroencephalogram (EEG) was recorded at 64h. Blood-samples taken at 6 and 64 hours were analysed for the brain injury biomarkers; S100beta, brain-fatty-acid-binding-protein, and neuroketal. All analyses were conducted post hoc. RESULTS: Significantly more infants with a cerebral burden of hypoxia within the 4th quartile versus infants within quartile 1-3 were diagnosed with severe intracranial haemorrhage (11/39 versus 11/117, p = 0.003), had low burst rate on EEG (12/28 versus 21/103, p = 0.015), or died (14/41 versus 18/123, p = 0.006), whereas none of these events were significantly associated with cerebral hyperoxia. The blood biomarkers were not significantly associated with the burden of cerebral hypo- or hyperoxia. CONCLUSIONS: The explorative analysis showed that early burden of cerebral hypoxia, but not hyperoxia was significantly associated with low brain electrical activity and severe intracranial haemorrhage while none of the three blood biomarkers were associated with the burden of either cerebral hypo- or hyperoxia.

Quantifying cerebral hypoxia by near-infrared spectroscopy tissue oximetry: the role of arterial-to-venous blood volume ratio.

Tissue oxygenation estimated by near-infrared spectroscopy (NIRS) is a volume-weighted mean of the arterial and venous hemoglobin oxygenation. In vivo validation assumes a fixed arterial-to-venous volume-ratio (AV-ratio). Regulatory cerebro-vascular mechanisms may change the AV-ratio. We used hypotension to investigate the influence of blood volume distribution on cerebral NIRS in a newborn piglet model. Hypotension was induced gradually by inflating a balloon-catheter in the inferior vena cava and the regional tissue oxygenation from NIRS ( rStO 2 , NIRS ) was then compared to a reference ( rStO 2 , COX ) calculated from superior sagittal sinus and aortic blood sample co-oximetry with a fixed AV-ratio. Apparent changes in the AV-ratio and cerebral blood volume (CBV) were also calculated. The mean arterial blood pressure (MABP) range was 14 to 82 mmHg. PaCO 2 and SaO 2 were stable during measurements. rStO 2 , NIRS mirrored only 25% (95% Cl: 21% to 28%, p < 0.001 ) of changes in rStO 2 , COX . Calculated AV-ratio increased with decreasing MABP (slope: ? 0.007 · mmHg ? 1

Cerebral oximetry in preterm infants: an agenda for research with a clear clinical goal.

Preterm birth constitutes a major cause of death before 5 years of age and it is a major cause of neurodevelopmental impairment across the world. Preterm infants are most unstable during the transition between fetal and newborn life during the first days of life and most brain damage occurs in this period. The brain of the preterm infant is accessible for tissue oximetry by near-infrared spectroscopy. Cerebral oximetry has the potential to improve the long-term outcome by helping to tailor the support of respiration and circulation to the individual infant's needs, but the evidence is still lacking. The goals for research include testing the benefit and harms of cerebral oximetry in large-scale randomized trials, improved definition of the hypoxic threshold, better understanding the effects of intensive care on cerebral oxygenation, as well as improved precision of oximeters and calibration among devices or standardization of values in the hypoxic range. These goals can be pursued in parallel.

Brain injury in the international multicenter randomized SafeBoosC phase II feasibility trial: cranial ultrasound and magnetic resonance imaging assessments.

BACKGROUND: Abnormal cerebral perfusion during the first days of life in preterm infants is associated with higher grades of intraventricular hemorrhages and lower developmental score. In SafeBoosC II, we obtained a significant reduction of cerebral hypoxia by monitoring cerebral oxygenation in combination with a treatment guideline. Here, we describe (i) difference in brain injury between groups, (ii) feasibility of serial cranial ultrasound (cUS) and magnetic resonance imaging (MRI), (iii) local and central cUS assessment. METHODS: Hundred and sixty-six extremely preterm infants were included. cUS was scheduled for day 1, 4, 7, 14, and 35 and at term-equivalent age (TEA). cUS was assessed locally (unblinded) and centrally (blinded). MRI at TEA was assessed centrally (blinded). Brain injury classification: no, mild/moderate, or severe. RESULTS: Severe brain injury did not differ significantly between groups: cUS (experimental 10/80, control 18/77, P = 0.32) and MRI (5/46 vs. 3/38, P = 0.72). Kappa values for local and central readers were moderate-to-good for severe and poor-to-moderate for mild/moderate injuries. At TEA, cUS and MRI were assessed in 72 and 64%, respectively. CONCLUSION: There was no difference in severe brain injury between groups. Acquiring cUS and MRI according the standard operating procedures must be improved for future trials. Whether monitoring cerebral oxygenation during the first 72 h of life prevents brain injury should be evaluated in larger multicenter trials.

The SafeBoosC II randomized trial: treatment guided by near-infrared spectroscopy reduces cerebral hypoxia without changing early biomarkers of brain injury.

BACKGROUND: The SafeBoosC phase II multicentre randomized clinical trial investigated the benefits and harms of monitoring cerebral oxygenation by near-infrared spectroscopy (NIRS) combined with an evidence-based treatment guideline vs. no NIRS data and treatment as usual in the control group during the first 72 h of life. The trial demonstrated a significant reduction in the burden of cerebral hypoxia in the experimental group. We now report the blindly assessed and analyzed treatment effects on electroencephalographic (EEG) outcomes (burst rate and spectral edge frequency 95% (SEF95)) and blood biomarkers of brain injury (S100ß, brain fatty acid-binding protein, and neuroketal). METHODS: One hundred and sixty-six extremely preterm infants were randomized to either experimental or control group. EEG was recorded at 64 h of age and blood samples were collected at 6 and 64 h of age. RESULTS: One hundred and thirty-three EEGs were evaluated. The two groups did not differ regarding burst rates (experimental 7.2 vs. control 7.7 burst/min) or SEF95 (experimental 18.1 vs. control 18.0 Hz). The two groups did not differ regarding blood S100ß, brain fatty acid-binding protein, and neuroketal concentrations at 6 and 64 h (n = 123 participants). CONCLUSION: Treatment guided by NIRS reduced the cerebral burden of hypoxia without affecting EEG or the selected blood biomarkers.