Cerebral oxygen saturation and autoregulation during hypotension in extremely preterm infants.

BACKGROUND: The impact of the permissive hypotension approach in clinically well infants on regional cerebral oxygen saturation (rScO2) and autoregulatory capacity (CAR) remains unknown. METHODS: Prospective cohort study of blinded rScO2 measurements within a randomized controlled trial of management of hypotension (HIP trial) in extremely preterm infants. rScO2, mean arterial blood pressure, duration of cerebral hypoxia, and transfer function (TF) gain inversely proportional to CAR, were compared between hypotensive infants randomized to receive dopamine or placebo and between hypotensive and non-hypotensive infants, and related to early intraventricular hemorrhage or death. RESULTS: In 89 potentially eligible HIP trial patients with rScO2 measurements, the duration of cerebral hypoxia was significantly higher in 36 hypotensive compared to 53 non-hypotensive infants. In 29/36 hypotensive infants (mean GA 25 weeks, 69% males) receiving the study drug, no significant difference in rScO2 was observed after dopamine (n = 13) compared to placebo (n = 16). Duration of cerebral hypoxia was associated with early intraventricular hemorrhage or death.  Calculated TF gain (n = 49/89) was significantly higher reflecting decreased CAR in 16 hypotensive compared to 33 non-hypotensive infants. CONCLUSIONS: Dopamine had no effect on rScO2 compared to placebo in hypotensive infants. Hypotension and cerebral hypoxia are associated with early intraventricular hemorrhage or death. IMPACT: Treatment of hypotension with dopamine in extremely preterm infants increases mean arterial blood pressure, but does not improve cerebral oxygenation. Hypotensive extremely preterm infants have increased duration of cerebral hypoxia and reduced cerebral autoregulatory capacity compared to non-hypotensive infants. Duration of cerebral hypoxia and hypotension are associated with early intraventricular hemorrhage or death in extremely preterm infants. Since systematic treatment of hypotension may not be associated with better outcomes, the diagnosis of cerebral hypoxia in hypotensive extremely preterm infants might guide treatment.

Nonlinear Transfer Entropy to Assess the Neurovascular Coupling in Premature Neonates.

In the adult brain, it is well known that increases in local neural activity trigger changes in regional blood flow and, thus, changes in cerebral energy metabolism. This regulation mechanism is called neurovascular coupling (NVC). It is not yet clear to what extent this mechanism is present in the premature brain. In this study, we explore the use of transfer entropy (TE) in order to compute the nonlinear coupling between changes in brain function, assessed by means of EEG, and changes in brain oxygenation, assessed by means of near-infrared spectroscopy (NIRS). In a previous study, we measured the coupling between both variables using a linear model to compute TE. The results indicated that changes in brain oxygenation were likely to precede changes in EEG activity. However, using a nonlinear and nonparametric approach to compute TE, the results indicate an opposite directionality of this coupling. The source of the different results provided by the linear and nonlinear TE is unclear and needs further research. In this study, we present the results from a cohort of 21 premature neonates. Results indicate that TE values computed using the nonlinear approach are able to discriminate between neonates with brain abnormalities and healthy neonates, indicating a less functional NVC in neonates with brain abnormalities.

Cerebral autoregulation and activity after propofol for endotracheal intubation in preterm neonates.

BACKGROUND: Despite increasing use of propofol in neonates, observations on cerebral effects are limited. AIM: To investigate cerebral autoregulation (CAR) and activity after propofol for endotracheal intubation in preterm neonates. METHODS: Twenty-two neonates received propofol before intubation as part of a published dose-finding study. Mean arterial blood pressure (MABP), near-infrared spectroscopy-derived cerebral oxygenation (rScO2), and amplitude-integrated electroencephalography (aEEG) were analyzed until 180 min after propofol. CAR was expressed as transfer function (TF) gain, indicating % change in rScO2 per 1 mmHg change in MABP. Values exceeding mean TF gain + 2 standard deviations (SD) defined impaired CAR. RESULTS: After intubation with a median propofol dose of 1 (0.5-4.5) mg/kg, rScO2 remained stable during decreasing MABP. Mean (±SD) TF gain was 0.8 (±0.3)%/mmHg. Impaired CAR was identified in 1 and 5 patient(s) during drug-related hypotension and normal to raised MABP, respectively. Suppressed aEEG was observed up to 60 min after propofol. CONCLUSIONS: Drug-related hypotension and decreased cerebral activity after intubation with low propofol doses in preterm neonates were observed, without evidence of cerebral ischemic hypoxia. CAR remained intact during drug-related hypotension in 95.5% of patients. Cerebral monitoring including CAR clarifies the cerebral impact of MABP fluctuations.

Impact of Changes in Systemic Physiology on fNIRS/NIRS Signals: Analysis Based on Oblique Subspace Projections Decomposition.

Measurements of cerebral and muscle oxygenation (StO2) and perfusion ([tHb]) with functional near-infrared spectroscopy (fNIRS) and near infrared spectroscopy (NIRS), respectively, can be influenced by changes in systemic physiology. The aim of our study was to apply the oblique subspace projections signal decomposition (OSPSD) to find the contribution from systemic physiology, i.e. heart rate (HR), electrocardiography (ECG)-derived respiration (EDR) and partial pressure of carbon dioxide (pCO2) to StO2 and [tHb] signals measured on the prefrontal cortex (PFC) and calf muscle. OSPSD was applied to two datasets (n1 = 42, n2 = 79 measurements) from two fNIRS/NIRS speech studies. We found that (i) all StO2 and [tHb] signals contained components related to changes in systemic physiology, (ii) the contribution from systemic physiology varied strongly between subjects, and (iii) changes in systemic physiology generally influenced fNIRS signals on the left and right PFC to a similar degree.

Relation Between EEG Activity and Brain Oxygenation in Preterm Neonates.

This study investigates the relationship between brain oxygenation, assessed by means of near infrared spectroscopy (NIRS), and brain function, assessed by means of electroencephalography (EEG). Using NIRS signals measuring the regional cerebral oxygen saturation (rScO2) and computing the fractional tissue oxygen extraction (FTOE), we compared how these variables relate to different features extracted from the EEG, such as the inter-burst interval (IBI) duration and amplitude, the amplitude of the EEG, and the amplitude of the burst. A cohort of 22 neonates undergoing sedation by propofol was studied and a regression of the NIRS-derived values to the different EEG features was made. We found that higher values of FTOE were related to higher values of EEG amplitude. These results might be of used in the monitoring of proper brain function in neonates.

Propofol Dose-Finding to Reach Optimal Effect for (Semi-)Elective Intubation in Neonates.

OBJECTIVE: To define the effective dose for 50% of patients (ED50) of propofol for successful intubation and to determine the rate of successful extubation in those patients with planned intubation, surfactant administration, and immediate extubation (INSURE procedure). In addition, pharmacodynamic effects were assessed. STUDY DESIGN: Neonates (n = 50) treated with propofol for (semi-)elective endotracheal intubation were stratified in 8 strata by postmenstrual and postnatal age. The first patient in each stratum received an intravenous bolus of 1 mg/kg propofol. Dosing for the next patient was determined using the up-and-down method. A propofol ED50 dose was calculated in each stratum with an effective sample size of at least 6, via the Dixon-Masey method, with simultaneous assessment of clinical scores and continuous vital sign monitoring. RESULTS: Propofol ED50 values for preterm neonates <10 days of age varied between 0.713 and 1.350 mg/kg. Clinical recovery was not attained at the end of the 21-minute scoring period. Mean arterial blood pressure showed a median decrease between 28.5% and 39.1% from baseline with a brief decrease in peripheral and regional cerebral oxygen saturation. Variability in mean arterial blood pressure area under the curve could not be explained by weight or age. CONCLUSIONS: Low propofol doses were sufficient to sedate neonates for intubation. Clinical recovery was accompanied by permissive hypotension (no clinical shock and no treatment). The propofol ED50 doses can be administered at induction, with subsequent up-titration if needed, while monitoring blood pressure. They can be used for further dosing optimalization and validation studies. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01621373; EudraCT: 2012-002648-26.

Reference values of regional cerebral oxygen saturation during the first 3 days of life in preterm neonates.

BACKGROUND: Currently, reliable reference values of regional cerebral oxygen saturation (rScO2) for different gestational age (GA) groups are lacking, which hampers the implementation of near-infrared spectroscopy (NIRS) alongside monitoring arterial oxygen saturation (SaO2) and blood pressure in neonatal intensive care. The aim of this study was to provide reference values for rScO2 and cerebral fractional tissue oxygen extraction (cFTOE; (SaO2 - rScO2)/SaO2) for small adult and neonatal NIRS sensors. METHODS: In this study, 999 infants born preterm (GA <32 wk) were monitored with NIRS during the first 72 h of life. Mixed modeling was used to generate reference curves grouped per 2 wk of GA. In addition, the influence of a hemodynamically significant patent ductus arteriosus, gender, and birth weight were explored. RESULTS: Average rScO2 was ~65% at admission, increased with GA (1% per week) and followed a parabolic curve in relation to postnatal age with a peak at ~36 h. The cFTOE showed similar but inverse effects. On average, the neonatal sensor measured 10% higher than the adult sensor. CONCLUSION: rScO2 and cFTOE reference curves are provided for the first 72 h of life in preterm infants, which might support the broader implementation of NIRS in neonatal intensive care.

Changes in Oxygenation Levels Precede Changes in Amplitude of the EEG in Premature Infants.

Brain function is supported by an appropriate balance between the metabolic demand and the supply of nutrients and oxygen. However, the physiological principles behind the regulation of brain metabolism and demand in premature infants are unknown. Some studies found that changes in hemodynamic variables in this population precede changes in EEG activity; however, these studies only used descriptive statistics. This paper describes the relationship between changes in cerebral oxygenation, assessed by means of near-infrared spectroscopy (NIRS), and changes in EEG, using mathematical methods taken from information dynamics. In a cohort of 35 neonates subjected to sedation by propofol, we quantified the direction of information transfer between brain oxygenation and EEG. The results obtained indicate that, as reported in other studies, changes in NIRS are likely to precede changes in EEG activity.

A New Framework for the Assessment of Cerebral Hemodynamics Regulation in Neonates Using NIRS.

We present a new framework for the assessment of cerebral hemodynamics regulation (CHR) in neonates using near-infrared spectroscopy (NIRS). In premature infants, NIRS measurements have been used as surrogate variables for cerebral blood flow (CBF) in the assessment of cerebral autoregulation (CA). However, NIRS measurements only reflect changes in CBF under constant changes in arterial oxygen saturation (SaO2). This condition is unlikely to be met at the bedside in the NICU. Additionally, CA is just one of the different highly coupled mechanisms that regulate brain hemodynamics. Traditional methods for the assessment of CA do not take into account the multivariate nature of CHR, producing inconclusive results. In this study we propose a newly developed multivariate methodology for the assessment of CHR. This method is able to effectively decouple the influences of SaO2 from the NIRS measurements, and at the same time, produces scores indicating the strength of the coupling between the systemic variables and NIRS recordings. We explore the use of this method, and its derived scores, for the monitoring of CHR using data from premature infants who developed a grade III-IV intra-ventricular hemorrhage during the first 3 days of life.

Differences in Contraction-Induced Hemodynamics and Surface EMG in Duchenne Muscular Dystrophy.

Duchenne muscular dystrophy (DMD) is the most common and devastating type of muscular dystrophy worldwide. In this study we have investigated the potential of the combined use of non-invasive near-infrared spectroscopy (NIRS) and surface electromyography (sEMG) to assess contraction-induced changes in oxygenation and myoelectrical activity, respectively in the biceps brachii of eight DMD patients aged 9-12 years and 11 age-matched healthy controls. Muscle tissue oxygenation index (TOI), oxyhemoglobin (HbO2), and sEMG signals were continuously measured during a sustained submaximal contraction of 60% maximal voluntary isometric contraction, and post-exercise recovery period. Compared to controls, DMD subjects showed significantly smaller changes in TOI during the contraction. In addition, during the reoxygenation phase some dynamic parameters extracted from the HbO2 measurements were significantly different between the two groups, some of which were correlated with functional performances on a 6-min walking test. In conclusion, non-invasive continuous monitoring of skeletal muscle oxygenation by NIRS is feasible in young children, and significant differences in contraction-induced deoxygenation and reoxygenation patterns were observed between healthy controls and DMD children.

Influence of the maternal use of labetalol on the neurogenic mechanism for cerebral autoregulation assessed by means of NIRS.

Labetalol is a drug used in the treatment of hypertensive disorders of pregnancy (HDP). In a previous study we investigated the influence of the maternal use of labetalol on the cerebral autoregulation (CA) mechanism of neonates. In that study, we found that labetalol induces impaired CA during the first day of life, with CA returning to a normal status by the third day after birth. This effect was hypothesized to be caused by labetalol-induced vasodilation. However, no strong evidence for this claim was found. In this study we aim to find stronger evidence for the vasodilation effect caused by labetalol, by investigating its effect on the neurogenic mechanism (NM) involved in CA. The status of the NM was assessed by means of transfer function analysis between the low frequency content of the autonomic control activity (LFA), obtained by processing of the heart rate (HR), and the regional cerebral oxygen saturation (rScO2). We found that neonates from mothers treated with labetalol presented a lower LFA and an impaired NM response during the first day of life, with values returning to normal by the end of the third day. These results reflect a vasodilation effect caused by labetalol, and indicate that the impaired CA observed in the previous study is caused by vasodilation.

Effect of maternal use of labetalol on the cerebral autoregulation in premature infants.

Hypertensive disorders of pregnancy (HDP) are normally treated to avoid maternal complications. In this study we aimed to investigate if there was an effect of maternal HDP treatment on the cerebral autoregulation of the neonates by analysing measurements of mean arterial blood pressure (MABP) and rScO2 by means of correlation, coherence, and transfer function analysis. We found that these infants presented higher values of transfer function gain, which indicates impaired cerebral autoregulation, with a decreasing trend towards normality. We hypothesised that this trend was due to a vasodilation effect of the maternal use of labetalol due to accumulation, which disappeared by the third day after birth. Therefore, we investigated the values of pulse pressure in order to find evidence for a vasodilatory effect. We found that lower values of pulse pressure were present in these infants when compared with a control population, which, together with increased transfer function gain values, suggests an effect of the drug on the cerebral autoregulation.

Canonical correlation analysis in the study of cerebral and peripheral haemodynamics interrelations with systemic variables in neonates supported on ECMO.

Neonates supported on extracorporeal membrane oxygenation (ECMO) are at high risk of brain injury due to haemodynamic instability. In order to monitor cerebral and peripheral (muscle) haemodynamic and oxygenation changes in this population we used a dual-channel near-infrared spectroscopy (NIRS) system. In addition, to assess interrelations between NIRS and systemic variables, collected simultaneously, canonical correlation analysis (CCA) was employed. CCA can quantify the relationship between a set of variables and assess levels of dependency. In four out of five patients, systemic variables were found to be less inter-related with cerebral rather than peripheral NIRS measurements. Moreover, during ECMO flow manipulations, we found that the interrelation between the systemic and the NIRS cerebral/peripheral variables changed. The CCA method presented here can be used to assess differences between NIRS cerebral and NIRS peripheral responses due to systemic variations which may be indicative of physiological differences in the mechanisms that regulate oxygenation and/or haemodynamics of the brain and the muscle.

Cerebral tissue oxygenation and regional oxygen saturation can be used to study cerebral autoregulation in prematurely born infants.

The coupling of cerebral intravascular oxygenation (dHbD) with mean arterial blood pressure (MABP) was taken as a reflection of autoregulation assuming constant arterial oxygen content. However, this method is sensitive to movement artifacts. We examined whether the cerebral tissue oxygenation index (cTOI) and regional oxygen saturation (rScO2) may replace dHbD and changes in total Hb (dHbT), respectively. Correlation (COR) and coherence (COH) were used to measure the agreement of MABP with rScO2/dHbT and cTOI/dHbD. dHbD/cTOI and dHbT/rScO2 recordings of, respectively, 34 and 20 preterm infants in need for intensive care were studied during the first days of life. dHbD and cTOI were obtained with the NIRO300 and rScO2 and dHbT with the INVOS4100. Invasive MABP was measured continuously. COR and COH scores of MABP versus dHbD/dHbT were compared with the corresponding ones by replacing dHbD/dHbT by cTOI/rScO2, respectively. Generally, no significant score differences were found for dHbD/cTOI. Differences for dHbT/rScO2 were slightly larger but still within the normal variation of the parameters. Differences become insignificant when restricting calculations to epochs of larger variation in MABP (>10 mm Hg). Hence, we suggest that cTOI and rScO2 can be used to study cerebral autoregulation in newborns.

Impaired cerebral autoregulation using near-infrared spectroscopy and its relation to clinical outcomes in premature infants.

The concordance between the change in the Mean Arterial Blood Pressure (MABP) and the Cerebral Blood Flow (CBF) is studied using the Correlation, Coherence and Partial Coherence methods in order to detect Impaired Cerebral Autoregulation in Neonates. The presence of impaired autoregulation is assessed by the use of the Critical Percentage of Recording Time (CPRT). The changes in CBF are reflected by the measurement of changes in cerebral intravascular oxygenation (HbD), regional cerebral oxygen saturation (rSO(2)), and cerebral tissue oxygenation (TOI), as measured by Near-Infrared Spectroscopy (NIRS) (INVOS4100 and NIRO300). The relation between impaired autoregulation and long term clinical outcomes in premature infants is studied.

The effect of early procedural pain in preterm infants on the maturation of electroencephalogram and heart rate variability.

ABSTRACT: Preterm infants show a higher incidence of cognitive, social, and behavioral problems, even in the absence of major medical complications during their stay in the neonatal intensive care unit (NICU). Several authors suggest that early-life experience of stress and procedural pain could impact cerebral development and maturation resulting in an altered development of cognition, behavior, or motor patterns in later life. However, it remains very difficult to assess this impact of procedural pain on physiological development. This study describes the maturation of electroencephalogram (EEG) signals and heart rate variability in a prospective cohort of 92 preterm infants (<34 weeks gestational age) during their NICU stay. We took into account the number of noxious, ie, skin-breaking, procedures they were subjected in the first 5 days of life, which corresponded to a median age of 31 weeks and 4 days. Using physiological signal modelling, this study shows that a high exposure to early procedural pain, measured as skin-breaking procedures, increased the level of discontinuity in both EEG and heart rate variability in preterm infants. These findings have also been confirmed in a subset of the most vulnerable preterm infants with a gestational age lower than 29 weeks. We conclude that a high level of early pain exposure in the NICU increases the level of functional dysmaturity, which can ultimately impact preterm infants' future developmental outcome.

Cerebral Oxygenation and Activity During Surgical Repair of Neonates With Congenital Diaphragmatic Hernia: A Center Comparison Analysis.

Background and aim: Neonatal brain monitoring is increasingly used due to reports of brain injury perioperatively. Little is known about the effect of sedatives (midazolam) and anesthetics (sevoflurane) on cerebral oxygenation (rScO2) and cerebral activity. This study aims to determine these effects in the perioperative period. Methods: This is an observational, prospective study in two tertiary pediatric surgical centers. All neonates with a congenital diaphragmatic hernia received perioperative cerebral oxygenation and activity measurements. Patients were stratified based on intraoperatively administrated medication: the sevoflurane group (continuous sevoflurane, bolus fentanyl, bolus rocuronium) and the midazolam group (continuous midazolam, continuous fentanyl, and continuous vecuronium). Results: Intraoperatively, rScO2 was higher in the sevoflurane compared to the midazolam group (84%, IQR 77-95 vs. 65%, IQR 59-76, p = < 0.001), fractional tissue oxygen extraction was lower (14%, IQR 5-21 vs. 31%, IQR 29-40, p = < 0.001), the duration of hypoxia was shorter (2%, IQR 0.4-9.6 vs. 38.6%, IQR 4.9-70, p = 0.023), and cerebral activity decreased more: slow delta: 2.16 vs. 4.35 µV 2 (p = 0.0049), fast delta: 0.73 vs. 1.37 µV 2 (p = < 0.001). In the first 30 min of the surgical procedure, a 3-fold increase in fast delta (10.48-31.22 µV 2) and a 5-fold increase in gamma (1.42-7.58 µV 2) were observed in the midazolam group. Conclusion: Sevoflurane-based anesthesia resulted in increased cerebral oxygenation and decreased cerebral activity, suggesting adequate anesthesia. Midazolam-based anesthesia in neonates with a more severe CDH led to alarmingly low rScO2 values, below hypoxia threshold, and increased values of EEG power during the first 30 min of surgery. This might indicate conscious experience of pain. Integrating population-pharmacokinetic models and multimodal neuromonitoring are needed for personalized pharmacotherapy in these vulnerable patients. Trial Registration: https://www.trialregister.nl/trial/6972, identifier: NL6972.

Maturation of the Autonomic Nervous System in Premature Infants: Estimating Development Based on Heart-Rate Variability Analysis.

This study aims at investigating the development of premature infants' autonomic nervous system (ANS) based on a quantitative analysis of the heart-rate variability (HRV) with a variety of novel features. Additionally, the role of heart-rate drops, known as bradycardias, has been studied in relation to both clinical and novel sympathovagal indices. ECG data were measured for at least 3 h in 25 preterm infants (gestational age ≤32 weeks) for a total number of 74 recordings. The post-menstrual age (PMA) of each patient was estimated from the RR interval time-series by means of multivariate linear-mixed effects regression. The tachograms were segmented based on bradycardias in periods after, between and during bradycardias. For each of those epochs, a set of temporal, spectral and fractal indices were included in the regression model. The best performing model has R 2 = 0.75 and mean absolute error MAE = 1.56 weeks. Three main novelties can be reported. First, the obtained maturation models based on HRV have comparable performance to other development models. Second, the selected features for age estimation show a predominance of power and fractal features in the very-low- and low-frequency bands in explaining the infants' sympathovagal development from 27 PMA weeks until 40 PMA weeks. Third, bradycardias might disrupt the relationship between common temporal indices of the tachogram and the age of the infant and the interpretation of sympathovagal indices. This approach might provide a novel overview of post-natal autonomic maturation and an alternative development index to other electrophysiological data analysis.

A Bradycardia-Based Stress Calculator for the Neonatal Intensive Care Unit: A Multisystem Approach.

Early life stress in the neonatal intensive care unit (NICU) can predispose premature infants to adverse health outcomes and neurodevelopment delays. Hands-on-care and procedural pain might induce apneas, hypoxic events, and sleep-wake disturbances, which can ultimately impact maturation, but a data-driven method based on physiological fingerprints to quantify early-life stress does not exist. This study aims to provide an automatic stress detector by investigating the relationship between bradycardias, hypoxic events and perinatal stress in NICU patients. EEG, ECG, and SpO 2 were recorded from 136 patients for at least 3 h in three different monitoring groups. In these subjects, the stress burden was assessed using the Leuven Pain Scale. Different subspace linear discriminant analysis models were designed to detect the presence or the absence of stress based on information in each bradycardic spell. The classification shows an area under the curve in the range [0.80-0.96] and a kappa score in the range [0.41-0.80]. The results suggest that stress seems to increase SpO 2 desaturations and EEG regularity as well as the interaction between the cardiovascular and neurological system. It might be possible that stress load enhances the reaction to respiratory abnormalities, which could ultimately impact the neurological and behavioral development.

Assessment of dynamic cerebral autoregulation in humans: Is reproducibility dependent on blood pressure variability?

We tested the influence of blood pressure variability on the reproducibility of dynamic cerebral autoregulation (DCA) estimates. Data were analyzed from the 2nd CARNet bootstrap initiative, where mean arterial blood pressure (MABP), cerebral blood flow velocity (CBFV) and end tidal CO2 were measured twice in 75 healthy subjects. DCA was analyzed by 14 different centers with a variety of different analysis methods. Intraclass Correlation (ICC) values increased significantly when subjects with low power spectral density MABP (PSD-MABP) values were removed from the analysis for all gain, phase and autoregulation index (ARI) parameters. Gain in the low frequency band (LF) had the highest ICC, followed by phase LF and gain in the very low frequency band. No significant differences were found between analysis methods for gain parameters, but for phase and ARI parameters, significant differences between the analysis methods were found. Alternatively, the Spearman-Brown prediction formula indicated that prolongation of the measurement duration up to 35 minutes may be needed to achieve good reproducibility for some DCA parameters. We conclude that poor DCA reproducibility (ICC<0.4) can improve to good (ICC > 0.6) values when cases with low PSD-MABP are removed, and probably also when measurement duration is increased.