Postnatal Brain Trajectories and Maternal Intelligence Predict Childhood Outcomes in Complex CHD.

Objective: To determine whether early structural brain trajectories predict early childhood neurodevelopmental deficits in complex CHD patients and to assess relative cumulative risk profiles of clinical, genetic, and demographic risk factors across early development. Study Design: Term neonates with complex CHDs were recruited at Texas Children's Hospital from 2005-2011. Ninety-five participants underwent three structural MRI scans and three neurodevelopmental assessments. Brain region volumes and white matter tract fractional anisotropy and radial diffusivity were used to calculate trajectories: perioperative, postsurgical, and overall. Gross cognitive, language, and visuo-motor outcomes were assessed with the Bayley Scales of Infant and Toddler Development and with the Wechsler Preschool and Primary Scale of Intelligence and Beery-Buktenica Developmental Test of Visual-Motor Integration. Multi-variable models incorporated risk factors. Results: Reduced overall period volumetric trajectories predicted poor language outcomes: brainstem ((ß, 95% CI) 0.0977, 0.0382-0.1571; p = 0.0022) and white matter (0.0023, 0.0001-0.0046; p = 0.0397) at 5 years; brainstem (0.0711, 0.0157-0.1265; p = 0.0134) and deep grey matter (0.0085, 0.0011-0.0160; p = 0.0258) at 3 years. Maternal IQ was the strongest contributor to language variance, increasing from 37% at 1 year, 62% at 3 years, and 81% at 5 years. Genetic abnormality's contribution to variance decreased from 41% at 1 year to 25% at 3 years and was insignificant at 5 years. Conclusion: Reduced postnatal subcortical-cerebral white matter trajectories predicted poor early childhood neurodevelopmental outcomes, despite high contribution of maternal IQ. Maternal IQ was cumulative over time, exceeding the influence of known cardiac and genetic factors in complex CHD, underscoring the importance of heritable and parent-based environmental factors.

Inducing oscillations in positive end-expiratory pressure improves assessment of cerebrovascular pressure reactivity in patients with traumatic brain injury.

The cerebral pressure reactivity index (PRx), through intracranial pressure (ICP) measurements, informs clinicians about the cerebral autoregulation (CA) status in adult-sedated patients with traumatic brain injury (TBI). Using PRx in clinical practice is currently limited by variability over shorter monitoring periods. We applied an innovative method to reduce the PRx variability by ventilator-induced slow (1/min) positive end-expiratory pressure (PEEP) oscillations. We hypothesized that, as seen in a previous animal model, the PRx variability would be reduced by inducing slow arterial blood pressure (ABP) and ICP oscillations without other clinically relevant physiological changes. Patients with TBI were ventilated with a static PEEP for 30 min (PRx period) followed by a 30-min period of slow [1/min (0.0167 Hz)] +5 cmH2O PEEP oscillations (induced (iPRx period). Ten patients with TBI were included. No clinical monitoring was discontinued and no additional interventions were required during the iPRx period. The PRx variability [measured as the standard deviation (SD) of PRx] decreased significantly during the iPRx period from 0.25 (0.22-0.30) to 0.14 (0.09-0.17) (P = 0.006). There was a power increase around the induced frequency (1/min) for both ABP and ICP (P = 0.002). In conclusion, 1/min PEEP-induced oscillations reduced the PRx variability in patients with TBI with ICP levels <22 mmHg. No other clinically relevant physiological changes were observed. Reduced PRx variability might improve CA-guided perfusion management by reducing the time to find "optimal" perfusion pressure targets. Larger studies with prolonged periods of PEEP-induced oscillations are required to take it to routine use.NEW & NOTEWORTHY Cerebral autoregulation assessment requires sufficient slow arterial blood pressure (ABP) waves. However, spontaneous ABP waves may be insufficient for reliable cerebral autoregulation estimations. Therefore, we applied a ventilator "sigh-function" to generate positive end-expiratory pressure oscillations that induce slow ABP waves. This method demonstrated a reduced variability of the pressure reactivity index, commonly used as continuous cerebral autoregulation measure in a traumatic brain injury population.

Comparison of different metrics of cerebral autoregulation in association with major morbidity and mortality after cardiac surgery.

BACKGROUND: Cardiac surgery studies have established the clinical relevance of personalised arterial blood pressure management based on cerebral autoregulation. However, variabilities exist in autoregulation evaluation. We compared the association of several cerebral autoregulation metrics, calculated using different methods, with outcomes after cardiac surgery. METHODS: Autoregulation was measured during cardiac surgery in 240 patients. Mean flow index and cerebral oximetry index were calculated as Pearson's correlations between mean arterial pressure (MAP) and transcranial Doppler blood flow velocity or near-infrared spectroscopy signals. The lower limit of autoregulation and optimal mean arterial pressure were identified using mean flow index and cerebral oximetry index. Regression models were used to examine associations of area under curve and duration of mean arterial pressure below thresholds with stroke, acute kidney injury (AKI), and major morbidity and mortality. RESULTS: Both mean flow index and cerebral oximetry index identified the cerebral lower limit of autoregulation below which MAP was associated with a higher incidence of AKI and major morbidity and mortality. Based on magnitude and significance of the estimates in adjusted models, the area under curve of MAP < lower limit of autoregulation had the strongest association with AKI and major morbidity and mortality. The odds ratio for area under the curve of MAP < lower limit of autoregulation was 1.05 (95% confidence interval, 1.01-1.09), meaning every 1 mm Hg h increase of area under the curve was associated with an average increase in the odds of AKI by 5%. CONCLUSIONS: For cardiac surgery patients, area under curve of MAP < lower limit of autoregulation using mean flow index or cerebral oximetry index had the strongest association with AKI and major morbidity and mortality. Trials are necessary to evaluate this target for MAP management.

Association of Cerebrovascular Stability Index and Head Circumference Between Infants With and Without Congenital Heart Disease.

Congenital heart disease (CHD) is a common birth defect in the United States. CHD infants are more likely to have smaller head circumference and neurodevelopmental delays; however, the cause is unknown. Altered cerebrovascular hemodynamics may contribute to neurologic abnormalities, such as smaller head circumference, thus we created a novel Cerebrovascular Stability Index (CSI), as a surrogate for cerebral autoregulation. We hypothesized that CHD infants would have an association between CSI and head circumference. We performed a prospective, longitudinal study in CHD infants and healthy controls. We measured CSI and head circumference at 4 time points (newborn, 3, 6, 9 months). We calculated CSI by subtracting the average 2-min sitting from supine cerebral oxygenation (rcSO2) over three consecutive tilts (0-90°), then averaged the change score for each age. Linear regressions quantified the relationship between CSI and head circumference. We performed 177 assessments in total (80 healthy controls, 97 CHD infants). The average head circumference was smaller in CHD infants (39.2 cm) compared to healthy controls (41.6 cm) (p < 0.001) and head circumference increased by 0.27 cm as CSI improved in the sample (p = 0.04) overall when combining all time points. Similarly, head circumference increased by 0.32 cm as CSI improved among CHD infants (p = 0.04). We found CSI significantly associated with head circumference in our sample overall and CHD infants alone, which suggests that impaired CSI may affect brain size in CHD infants. Future studies are needed to better understand the mechanism of interaction between CSI and brain growth.

The Utility of Cerebral Autoregulation Indices in Detecting Severe Brain Injury Varies by Cooling Treatment Phase in Neonates with Hypoxic-Ischemic Encephalopathy.

Identifying the hemodynamic range that best supports cerebral perfusion using near infrared spectroscopy (NIRS) autoregulation monitoring is a potential physiologic marker for neonatal hypoxic-ischemic encephalopathy (HIE) during therapeutic hypothermia. However, an optimal autoregulation monitoring algorithm has not been identified for neonatal clinical medicine. We tested whether the hemoglobin volume phase (HVP), hemoglobin volume (HVx), and pressure passivity index (PPI) identify changes in autoregulation that are associated with brain injury on MRI or death. The HVP measures the phase difference between a NIRS metric of cerebral blood volume, the total hemoglobin (THb), and mean arterial blood pressure (MAP) at the frequency of maximum coherence. The HVx is the correlation coefficient between MAP and THb. The PPI is the percentage of coherent MAP-DHb (difference between oxygenated and deoxygenated hemoglobin, a marker of cerebral blood flow) epochs in a chosen time period. Neonates cooled for HIE were prospectively enrolled in an observational study in two neonatal intensive care units. In analyses adjusted for study site and encephalopathy level, all indices detected relationships between poor autoregulation in the first 6 h after rewarming with a higher injury score on MRI. Only HVx and PPI during hypothermia and the PPI during rewarming identified autoregulatory dysfunction associated with a poor outcome independent of study site and encephalopathy level. Our findings suggest that the accuracy of mathematical autoregulation algorithms in detecting the risk of brain injury or death may depend on temperature and postnatal age. Extending autoregulation monitoring beyond the standard 72 h of therapeutic hypothermia may serve as a method to provide personalized care by assessing the need for and efficacy of future therapies after the hypothermia treatment phase.

Wavelet Autoregulation Monitoring Identifies Blood Pressures Associated With Brain Injury in Neonatal Hypoxic-Ischemic Encephalopathy.

Dysfunctional cerebrovascular autoregulation may contribute to neurologic injury in neonatal hypoxic-ischemic encephalopathy (HIE). Identifying the optimal mean arterial blood pressure (MAPopt) that best supports autoregulation could help identify hemodynamic goals that support neurologic recovery. In neonates who received therapeutic hypothermia for HIE, we hypothesized that the wavelet hemoglobin volume index (wHVx) would identify MAPopt and that blood pressures closer to MAPopt would be associated with less brain injury on MRI. We also tested a correlation-derived hemoglobin volume index (HVx) and single- and multi-window data processing methodology. Autoregulation was monitored in consecutive 3-h periods using near infrared spectroscopy in an observational study. The neonates had a mean MAP of 54 mmHg (standard deviation: 9) during hypothermia. Greater blood pressure above the MAPopt from single-window wHVx was associated with less injury in the paracentral gyri (p = 0.044; n = 63), basal ganglia (p = 0.015), thalamus (p = 0.013), and brainstem (p = 0.041) after adjustments for sex, vasopressor use, seizures, arterial carbon dioxide level, and a perinatal insult score. Blood pressure exceeding MAPopt from the multi-window, correlation HVx was associated with less injury in the brainstem (p = 0.021) but not in other brain regions. We conclude that applying wavelet methodology to short autoregulation monitoring periods may improve the identification of MAPopt values that are associated with brain injury. Having blood pressure above MAPopt with an upper MAP of ~50-60 mmHg may reduce the risk of brain injury during therapeutic hypothermia. Though a cause-and-effect relationship cannot be inferred, the data support the need for randomized studies of autoregulation and brain injury in neonates with HIE.

Lower Limit of Reactivity Assessed with PRx in an Experimental Setting.

In traumatic brain injury, longer time spent with a cerebral perfusion pressure (CPP) below the pressure reactivity index (PRx)-derived lower limit of reactivity (LLR) has been shown to be statistically associated with higher mortality. We set out to scrutinise the behaviour of LLR and the methods of its estimation in individual cases by performing retrospective analysis of intracranial pressure (ICP), arterial blood pressure (ABP) and laser Doppler flow (LDF) signals recorded in nine piglets undergoing controlled, terminal hypotension. We focused on the sections of the recordings with stable experimental conditions where a clear breakpoint of LDF/CPP characteristic (LLA) could be identified.In eight of the nine experiments, when CPP underwent a monotonous decrease, the relationship PRx/CPP showed two breakpoints (1 - when PRx starts to rise; 2 - when PRx saturates at PRx > 0.3), with LDF-based LLA sitting between them. LLR (CPP at PRx reaching 0.3 in the error bar chart) was close to the lower LLR breakpoint.In conclusion, when CPP has a monotonous decrease, PRx starts worsening before CPP crosses the LLA. A further decrease in CPP below LLA would cause a decrease in CBF, even if the pressure reactivity is not completely lost. This pattern should be taken into account when PRx is used to detect LLA continuously.

Near-Infrared Spectroscopy: Clinical Use in High-Risk Neonates.

In this review, we describe the near-infrared spectroscopy (NIRS) technology and its clinical use in high-risk neonates in critical care settings. We searched databases (e.g., PubMed, Google Scholar, EBSCOhost) to find studies describing the use of NIRS on critically ill and high-risk neonates. Near-infrared spectroscopy provides continuous noninvasive monitoring of venous oxygen saturation. It uses technology similar to pulse oximetry to measure the oxygen saturation of hemoglobin in a tissue bed to describe the relative delivery and extraction of oxygen. Near-infrared spectroscopy can be a valuable bedside tool to provide clinicians indirect evidence of perfusion. It may prompt early interventions that promote oxygen delivery, which can improve high-risk neonatal outcomes.

A robust Fourier-based method to measure pulse pressure variability.

OBJECTIVE: To propose a new method to estimate pulse pressure variability (PPV) in the arterial blood pressure waveform. METHODS: Traditional techniques of calculating PPV using peak finding have a fundamental flaw that prevents them from accurately resolving PPV for small tidal volumes, limiting the use of PPV to only mechanical ventilated patients. The improved method described here addresses this limitation using Fourier analysis of an oscillatory signal that exhibits a time-varying modulation of its amplitude. The analysis reveals a constraint on the spectral representation that must be satisfied for any oscillatory signal that exhibits a time-varying modulation of its amplitude. This intrinsic mathematical structure is taken advantage of in order to improve the robustness of the algorithm. RESULTS: The applicability of the method is tested using synthetic data and 100 h of physiologic data collected from patients admitted to Texas Children's Hospital. SIGNIFICANCE AND CONCLUSION: The proposed method accurately recovers values of PPV at signal-to-noise ratios six times smaller than the traditional method. This is a significant advance for the potential use of PPV to recognize fluid responsiveness during low tidal volume ventilation or spontaneous breathing for which the signal-to-noise ratio is expected to be small.

Comparison of wavelet and correlation indices of cerebral autoregulation in a pediatric swine model of cardiac arrest.

Existing cerebrovascular blood pressure autoregulation metrics have not been translated to clinical care for pediatric cardiac arrest, in part because signal noise causes high index time-variability. We tested whether a wavelet method that uses near-infrared spectroscopy (NIRS) or intracranial pressure (ICP) decreases index variability compared to that of commonly used correlation indices. We also compared whether the methods identify the optimal arterial blood pressure (ABPopt) and lower limit of autoregulation (LLA). 68 piglets were randomized to cardiac arrest or sham procedure with continuous monitoring of cerebral blood flow using laser Doppler, NIRS and ICP. The arterial blood pressure (ABP) was gradually reduced until it dropped to below the LLA. Several autoregulation indices were calculated using correlation and wavelet methods, including the pressure reactivity index (PRx and wPRx), cerebral oximetry index (COx and wCOx), and hemoglobin volume index (HVx and wHVx). Wavelet methodology had less index variability with smaller standard deviations. Both wavelet and correlation methods distinguished functional autoregulation (ABP above LLA) from dysfunctional autoregulation (ABP below the LLA). Both wavelet and correlation methods also identified ABPopt with high agreement. Thus, wavelet methodology using NIRS may offer an accurate vasoreactivity monitoring method with reduced signal noise after pediatric cardiac arrest.

Comparison of Frequency- and Time-Domain Autoregulation and Vasoreactivity Indices in a Piglet Model of Hypoxia-Ischemia and Hypothermia.

INTRODUCTION: The optimal method to detect impairments in cerebrovascular pressure autoregulation in neonates with hypoxic-ischemic encephalopathy (HIE) is unclear. Improving autoregulation monitoring methods would significantly advance neonatal neurocritical care. METHODS: We tested several mathematical algorithms from the frequency and time domains in a piglet model of HIE, hypothermia, and hypotension. We used laser Doppler flowmetry and induced hypotension to delineate the gold standard lower limit of autoregulation (LLA). Receiver operating characteristics curve analyses were used to determine which indices could distinguish blood pressure above the LLA from that below the LLA in each piglet. RESULTS: Phase calculation in the frequency band with maximum coherence, as well as the correlation between mean arterial pressure (MAP) and near-infrared spectroscopy relative total tissue hemoglobin (HbT) or regional oxygen saturation (rSO2), accurately discriminated functional from dysfunctional autoregulation. Neither hypoxia-ischemia nor hypothermia affected the accuracy of these indices. Coherence alone and gain had low diagnostic value relative to phase and correlation. CONCLUSION: Our findings indicate that phase shift is the most accurate component of autoregulation monitoring in the developing brain, and it can be measured using correlation or by calculating phase when coherence is maximal. Phase and correlation autoregulation indices from MAP and rSO2 and vasoreactivity indices from MAP and HbT are accurate metrics that are suitable for clinical HIE studies.

Observed and calculated cerebral critical closing pressure are highly correlated in preterm infants.

BACKGROUND: Cerebrovascular critical closing pressure (CrCP) is the arterial blood pressure (ABP) at which cerebral blood flow ceases. Preterm ABP is low and close to CrCP. The diastolic closing margin (diastolic ABP minus CrCP) has been associated with intraventricular hemorrhage in preterm infants. CrCP is estimated from middle cerebral artery cerebral blood flow velocity (CBFV) and ABP waveforms. However, these estimations have not been validated due to a lack of gold standard. Direct observation of the CrCP in preterm infants with hypotension is an opportunity to validate synchronously estimated CrCP. METHODS: ABP and CBFV tracings were obtained from 24 extremely low birth weight infants. Recordings where diastolic CBFV was zero were identified. The gold standard CrCP was delineated using piecewise regression of ABP and CBFV values paired by rank ordering and then estimated using a published formula. The measured and estimated values were compared using linear regression and Bland-Altman analysis. RESULTS: Linear regression showed a high degree of correlation between measured and calculated CrCP (r2 = 0.93). CONCLUSIONS: This is the first study to validate a calculated CrCP by comparing it to direct measurements of CrCP from preterm infants when ABP is lower than CrCP.

Neonatal cerebrovascular autoregulation.

Cerebrovascular pressure autoregulation is the physiologic mechanism that holds cerebral blood flow (CBF) relatively constant across changes in cerebral perfusion pressure (CPP). Cerebral vasoreactivity refers to the vasoconstriction and vasodilation that occur during fluctuations in arterial blood pressure (ABP) to maintain autoregulation. These are vital protective mechanisms of the brain. Impairments in pressure autoregulation increase the risk of brain injury and persistent neurologic disability. Autoregulation may be impaired during various neonatal disease states including prematurity, hypoxic-ischemic encephalopathy (HIE), intraventricular hemorrhage, congenital cardiac disease, and infants requiring extracorporeal membrane oxygenation (ECMO). Because infants are exquisitely sensitive to changes in cerebral blood flow (CBF), both hypoperfusion and hyperperfusion can cause significant neurologic injury. We will review neonatal pressure autoregulation and autoregulation monitoring techniques with a focus on brain protection. Current clinical therapies have failed to fully prevent permanent brain injuries in neonates. Adjuvant treatments that support and optimize autoregulation may improve neurologic outcomes.

Elevated arterial blood pressure after superior cavo-pulmonary anastomosis is associated with elevated pulmonary artery pressure and cerebrovascular dysautoregulation.

BACKGROUND: Elevated arterial blood pressure (ABP) is common after superior bidirectional cavopulmonary anastomosis (BCPA). The effects of elevated ABP after BCPA on cerebrovascular hemodynamics are unknown. We sought to determine the relationship between elevated ABP and cerebrovascular autoregulation after BCPA. METHODS: Prospective, observational study on infants with single-ventricle physiology after BCPA surgery. Continuous recordings of mean ABP, mean cavopulmonary artery pressure (PAP), near-infrared spectroscopy measures of cerebral oximetry (regional cerebral oxygen saturation (rSO2)), and relative cerebral blood volume index were obtained from admission to extubation. Autoregulation was measured as hemoglobin volume index (HVx). Physiologic variables, including the HVx, were tested for variance across ABP. RESULTS: Sixteen subjects were included in the study. Elevated ABP post-BCPA was associated with both, elevated PAP (P<0.0001) and positive HVx (dysautoregulation; P<0.0001). No association was observed between ABP and alterations in rSO2. Using piecewise regression, the relationship of PAP to ABP demonstrated a breakpoint at 68 mm Hg (interquartile range (IQR) 62-70 mm Hg). Curve fit of HVx as a function of ABP identified optimal ABP supporting robust autoregulation at a median ABP of 55 mm Hg (IQR 51-64 mm Hg). CONCLUSIONS: Elevated ABP post-BCPA is associated with cerebrovascular dysautoregulation, and elevated PAP. The effects, of prolonged dysautoregulation within this population, require further study.

An effective model of cerebrovascular pressure reactivity and blood flow autoregulation.

Understanding cerebral blood flow dynamics is crucial for the care of patients at risk of poor cerebral perfusion. We describe an effective model of cerebral hemodynamics designed to reveal important macroscopic features of cerebral blood flow without having to resolve the detailed microvasculature of the brain. Based on principles of fluid and elastic dynamics and vascular pressure-reactivity, the model quantifies the physical means by which the vasculature executes autoregulatory reflexes. We demonstrate that the frequency response of the proposed model matches experimental measurements and explains the influence of mechanical factors on the autoregulatory performance. Analysis of the model indicates the existence of an optimal mean arterial pressure which minimizes the sensitivity of the flow to changes in perfusion pressure across the frequency spectrum of physiological oscillations. We highlight the simplicity of the model and its potential to improve monitoring of brain perfusion via real-time computational simulations of cerebro- and cardio-vascular interventions.

Impaired cerebral autoregulation and elevation in plasma glial fibrillary acidic protein level during cardiopulmonary bypass surgery for CHD.

BACKGROUND: Cerebrovascular reactivity monitoring has been used to identify the lower limit of pressure autoregulation in adult patients with brain injury. We hypothesise that impaired cerebrovascular reactivity and time spent below the lower limit of autoregulation during cardiopulmonary bypass will result in hypoperfusion injuries to the brain detectable by elevation in serum glial fibrillary acidic protein level. METHODS: We designed a multicentre observational pilot study combining concurrent cerebrovascular reactivity and biomarker monitoring during cardiopulmonary bypass. All children undergoing bypass for CHD were eligible. Autoregulation was monitored with the haemoglobin volume index, a moving correlation coefficient between the mean arterial blood pressure and the near-infrared spectroscopy-based trend of cerebral blood volume. Both haemoglobin volume index and glial fibrillary acidic protein data were analysed by phases of bypass. Each patient's autoregulation curve was analysed to identify the lower limit of autoregulation and optimal arterial blood pressure. RESULTS: A total of 57 children had autoregulation and biomarker data for all phases of bypass. The mean baseline haemoglobin volume index was 0.084. Haemoglobin volume index increased with lowering of pressure with 82% demonstrating a lower limit of autoregulation (41±9 mmHg), whereas 100% demonstrated optimal blood pressure (48±11 mmHg). There was a significant association between an individual's peak autoregulation and biomarker values (p=0.01). CONCLUSIONS: Individual, dynamic non-invasive cerebrovascular reactivity monitoring demonstrated transient periods of impairment related to possible silent brain injury. The association between an impaired autoregulation burden and elevation in the serum brain biomarker may identify brain perfusion risk that could result in injury.