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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., Competing Interests: The authors have declared that no competing interests exist.

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

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 (SpO 2 ) 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 StO 2,SenSmart X-100  = 0.34 × StO 2,INVOS 5100C  + 44.8% during apnea in infants and StO 2,SenSmart X-100  = 0.59 × StO 2,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 SpO 2 ., Conclusions: These findings confirm that different NIRS devices give very different estimates when the oxygenation is low. The large variation when compared to SpO 2 suggest that the sensor placement is very important in preterm infants.

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.

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.

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.

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 (S100β, 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 S100β, 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.

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.

Previously the NIRS oximeter OxyPrem was calibrated by comparison to the INVOS in a blood-lipid phantom. The aim of the present study was to test this calibration clinically. During vasculur occlusions in 10 adults and after birth in 25 term infants the relationship was OxyPrem = 1.24 x INVOS - 23.6% and OxyPrem = 1.15 x INVOS - 16.2% on the adult arm and infant head, respectively. The precsion during steady state was 4.0% (CI 3.4% to 4.6%) and 3.4% (CI 2.9% to 3.9%) on the arm, and 6.7% (CI 5.9% to 7.6%) and 4.7% (CI 3.5% to 5.9%) on the infant head for OxyPrem and INVOS, respectively. We conclude that the calibration on the blood-lipid phantom was unsuccessful in achieving agreement in clinical measurements.

Background: Since analysis of Sidestream Dark Field images still requires subjective interpretation, we wanted to determine intra-observer repeatability and to estimate the correlation between different evaluation methods., Methods: Fifty-four Sidestream Dark Field videos were analyzed twice by the same blinded observer using validated software. Vessels were detected, generating the parameter Total Vessel Density (TVD), and flow was determined by (i) classifying each vessel separately, generating the parameters Perfused Vessel Density (PVD) and Proportion of Perfused Vessels (PPV), and by (ii) the "Boerma" method, generating a Microvascular Flow Index (MFI) by quadrants., Results: Intraclass Correlation Coefficients (ICCs) were above 0.9 for TVD and above 0.8 for PDV and PPV. MFIby quadrants had the lowest reliability (ICC = 0.52 for capillaries and ICC = 0.59 for all vessels), significantly lower than for PVD (ICC = 0.89, p < 0.001 for capillaries and ICC = 0.90, p < 0.001 for all vessels) and PPV (ICC = 0.82, p = 0.003 for capillaries and ICC = 0.83, p = 0.01 for all vessels). Correlation coefficient (r) between PPV and MFIby quadrants corrected for measurement error was 0.39 (0.10 - 0.64) for capillaries and 1.01 (0.85 - 1.16) for all vessels., Conclusions: Intra-observer reliability for full evaluation of Sidestream Dark Field images was good for vessel detection and for flow classification but significantly poorer for the faster "Boerma" method. Furthermore, the Boerma method is likely to estimate different aspects of capillary flow than do the standard methods.

In a blood-lipid liquid phantom the prototype near-infrared spectroscopy oximeter OxyPrem was calibrated against the INVOS® 5100c adult sensor in respect to values of regional tissue oxygen haemoglobin saturation (rStO2) for possible inclusion in the randomised clinical trial - SafeBoosC. In addition different commercial NIRS oximeters were compared on changing haemoglobin oxygen saturation and compared against co-oximetry. The best calibration was achieved with a simple offset and a linear scaling of the OxyPrem rStO2 values. The INVOS adult and pediatric sensor gave systematically different values, while the difference between the NIRO® 300 and the two INVOS sensors were magnitude dependent. The co-oximetry proved unreliable on such low haemoglobin and high Intralipid levels.

Background: Despite widespread use in sick infants, it is still debated whether vasopressor-inotropes have direct cerebral effects that might affect neurological outcome. We aimed to test direct cerebrovascular effects of three commonly used vasopressor-inotropes (adrenaline, dopamine and noradrenaline) by comparing the responses to those of nonpharmacologically induced increases in blood pressure. We also searched for reasons for a mismatch between the response in perfusion and oxygenation., Methods: Twenty-four piglets had long and short infusions of the three vasopressor-inotropes titrated to raise mean arterial blood pressure (MAP) 10 mmHg in random order. Nonpharmacological increases in MAP were induced by inflation of a balloon in the descending aorta. We measured cerebral oxygenation (near-infrared spectroscopy), perfusion (laser-Doppler), oxygen consumption (co-oximetry of arterial and superior sagittal sinus blood), and microvascular heterogeneity (side stream dark field video microscopy)., Results: Vasopressor-inotropes increased cerebral oxygenation significantly less (p≤0.01) compared to non-pharmacological MAP increases, whereas perfusion was similar. Furthermore, cerebral total hemoglobin concentration increased significantly less during vasopressor-inotrope infusions (p = 0.001). These physiologic responses were identical between the three vasopressor-inotropes (p>0.05). Furthermore, they induced a mild, although insignificant increase in cerebral metabolism and microvascular heterogeneity (p>0.05). Removal of the scalp tissue did not influence the mismatch (p>0.05)., Conclusion: We demonstrated a moderate vasopressor-inotrope induced mismatch between cerebral perfusion and oxygenation. Scalp removal did not affect this mismatch, why vasopressor-inotropes appear to have direct cerebral actions. The statistically nonsignificant increases in cerebral metabolism and/or microvascular heterogeneity may explain the mismatch. Alternatively, it may simply reflect a vasopressor-inotrope-induced decrease in the arterial-to-venous volume ratio as detected by near-infrared spectroscopy.

Background: Every 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/design: SafeBoosC 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., Discussion: Cerebral 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 Registration: ClinicalTrial.gov, NCT01590316.

We compared absolute values of regional tissue hemoglobin saturation (StO(2)), reproducibility, and dynamic range of four different instruments on the forearm of adults. The sensors were repositioned 10 times on each subject. Dynamic range was estimated by exercise with subsequent arterial occlusion. Mean StO(2) was 70.1% ± 6.7 with INVOS 5100, 69.4% ± 5.0 with NIRO 200 NX, 63.4% ± 4.5 with NIRO 300, and 60.8% ± 3.6 with OxyPrem. The corresponding reproducibility S(w) was 5.4% (CI 4.4-6.9), 4.4% (CI 3.5-5.2), 4.1% (CI 3.3-4.9), and 2.7% (CI 2.2-3.2), respectively. The dynamic ranges ΔStO(2) were 45.0%, 46.8%, 44.8%, and 27.8%, respectively. In conclusion, the three commercial NIRS instruments showed different absolute values, whereas reproducibility and dynamic range were quite similar.