Correlation of Cerebral Microdialysis with Non-Invasive Diffuse Optical Cerebral Hemodynamic Monitoring during Deep Hypothermic Cardiopulmonary Bypass.

Neonates undergoing cardiac surgery involving aortic arch reconstruction are at an increased risk for hypoxic-ischemic brain injury. Deep hypothermia is utilized to help mitigate this risk when periods of circulatory arrest are needed for surgical repair. Here, we investigate correlations between non-invasive optical neuromonitoring of cerebral hemodynamics, which has recently shown promise for the prediction of postoperative white matter injury in this patient population, and invasive cerebral microdialysis biomarkers. We compared cerebral tissue oxygen saturation (StO2), relative total hemoglobin concentration (rTHC), and relative cerebral blood flow (rCBF) measured by optics against the microdialysis biomarkers of metabolic stress and injury (lactate-pyruvate ratio (LPR) and glycerol) in neonatal swine models of deep hypothermic cardiopulmonary bypass (DHCPB), selective antegrade cerebral perfusion (SACP), and deep hypothermic circulatory arrest (DHCA). All three optical parameters were negatively correlated with LPR and glycerol in DHCA animals. Elevation of LPR was found to precede the elevation of glycerol by 30-60 min. From these data, thresholds for the detection of hypoxic-ischemia-associated cerebral metabolic distress and neurological injury are suggested. In total, this work provides insight into the timing and mechanisms of neurological injury following hypoxic-ischemia and reports a quantitative relationship between hypoxic-ischemia severity and neurological injury that may inform DHCA management.

Does supply meet demand? A comparison of perfusion strategies on cerebral metabolism in a neonatal swine model.

OBJECTIVE: We aimed to determine the effects of selective antegrade cerebral perfusion compared with other perfusion strategies on indices of cerebral blood flow, oxygenation, cellular stress, and mitochondrial function. METHODS: One-week-old piglets (n = 41) were assigned to 5 treatment groups. Thirty-eight were placed on cardiopulmonary bypass. Of these, 30 were cooled to 18°C and underwent deep hypothermic circulatory arrest (n = 10), underwent selective antegrade cerebral perfusion at 10 mL/kg/min (n = 10), or remained on continuous cardiopulmonary bypass (deep hypothermic cardiopulmonary bypass, n = 10) for 40 minutes. Other subjects remained on normothermic cardiopulmonary bypass (n = 8) or underwent sham surgery (n = 3). Novel, noninvasive optical measurements recorded cerebral blood flow, cerebral tissue oxyhemoglobin concentration, oxygen extraction fraction, total hemoglobin concentration, and cerebral metabolic rate of oxygen. Invasive measurements of cerebral microdialysis and cerebral blood flow were recorded. Cerebral mitochondrial respiration and reactive oxygen species generation were assessed after the piglets were killed. RESULTS: During hypothermia, deep hypothermic circulatory arrest piglets experienced increases in oxygen extraction fraction (P < .001), indicating inadequate matching of oxygen supply and demand. Deep hypothermic cardiopulmonary bypass had higher cerebral blood flow (P = .046), oxyhemoglobin concentration (P = .019), and total hemoglobin concentration (P = .070) than selective antegrade cerebral perfusion, indicating greater oxygen delivery. Deep hypothermic circulatory arrest demonstrated worse mitochondrial function (P < .05), increased reactive oxygen species generation (P < .01), and increased markers of cellular stress (P < .01). Reactive oxygen species generation was increased in deep hypothermic cardiopulmonary bypass compared with selective antegrade cerebral perfusion (P < .05), but without significant microdialysis evidence of cerebral cellular stress. CONCLUSIONS: Selective antegrade cerebral perfusion meets cerebral metabolic demand and mitigates cerebral mitochondrial reactive oxygen species generation. Excess oxygen delivery during deep hypothermia may have deleterious effects on cerebral mitochondria that may contribute to adverse neurologic outcomes. We describe noninvasive measurements that may help guide perfusion strategies.

Effects of circulatory arrest and cardiopulmonary bypass on cerebral autoregulation in neonatal swine.

BACKGROUND: Cerebral autoregulation mechanisms help maintain adequate cerebral blood flow (CBF) despite changes in cerebral perfusion pressure. Impairment of cerebral autoregulation, during and after cardiopulmonary bypass (CPB), may increase risk of neurologic injury in neonates undergoing surgery. In this study, alterations of cerebral autoregulation were assessed in a neonatal swine model probing four perfusion strategies. METHODS: Neonatal swine (n = 25) were randomized to continuous deep hypothermic cardiopulmonary bypass (DH-CPB, n = 7), deep hypothermic circulatory arrest (DHCA, n = 7), selective cerebral perfusion (SCP, n = 7) at deep hypothermia, or normothermic cardiopulmonary bypass (control, n = 4). The correlation coefficient (LDx) between laser Doppler measurements of CBF and mean arterial blood pressure was computed at initiation and conclusion of CPB. Alterations in cerebral autoregulation were assessed by the change between initial and final LDx measurements. RESULTS: Cerebral autoregulation became more impaired (LDx increased) in piglets that underwent DH-CPB (initial LDx: median 0.15, IQR [0.03, 0.26]; final: 0.45, [0.27, 0.74]; p = 0.02). LDx was not altered in those undergoing DHCA (p > 0.99) or SCP (p = 0.13). These differences were not explained by other risk factors. CONCLUSIONS: In a validated swine model of cardiac surgery, DH-CPB had a significant effect on cerebral autoregulation, whereas DHCA and SCP did not. IMPACT: Approximately half of the patients who survive neonatal heart surgery with cardiopulmonary bypass (CPB) experience neurodevelopmental delays. This preclinical investigation takes steps to elucidate and isolate potential perioperative risk factors of neurologic injury, such as impairment of cerebral autoregulation, associated with cardiac surgical procedures involving CPB. We demonstrate a method to characterize cerebral autoregulation during CPB pump flow changes in a neonatal swine model of cardiac surgery. Cerebral autoregulation was not altered in piglets that underwent deep hypothermic circulatory arrest (DHCA) or selective cerebral perfusion (SCP), but it was altered in piglets that underwent deep hypothermic CBP.

Non-invasive diffuse optical neuromonitoring during cardiopulmonary resuscitation predicts return of spontaneous circulation.

Neurologic injury is a leading cause of morbidity and mortality following pediatric cardiac arrest. In this study, we assess the feasibility of quantitative, non-invasive, frequency-domain diffuse optical spectroscopy (FD-DOS) neuromonitoring during cardiopulmonary resuscitation (CPR), and its predictive utility for return of spontaneous circulation (ROSC) in an established pediatric swine model of cardiac arrest. Cerebral tissue optical properties, oxy- and deoxy-hemoglobin concentration ([HbO2], [Hb]), oxygen saturation (StO2) and total hemoglobin concentration (THC) were measured by a FD-DOS probe placed on the forehead in 1-month-old swine (8-11 kg; n = 52) during seven minutes of asphyxiation followed by twenty minutes of CPR. ROSC prediction and time-dependent performance of prediction throughout early CPR (< 10 min), were assessed by the weighted Youden index (Jw, w = 0.1) with tenfold cross-validation. FD-DOS CPR data was successfully acquired in 48/52 animals; 37/48 achieved ROSC. Changes in scattering coefficient (785 nm), [HbO2], StO2 and THC from baseline were significantly different in ROSC versus No-ROSC subjects (p < 0.01) after 10 min of CPR. Change in [HbO2] of + 1.3 µmol/L from 1-min of CPR achieved the highest weighted Youden index (0.96) for ROSC prediction. We demonstrate feasibility of quantitative, non-invasive FD-DOS neuromonitoring, and stable, specific, early ROSC prediction from the third minute of CPR.

Epinephrine's effects on cerebrovascular and systemic hemodynamics during cardiopulmonary resuscitation.

BACKGROUND: Despite controversies, epinephrine remains a mainstay of cardiopulmonary resuscitation (CPR). Recent animal studies have suggested that epinephrine may decrease cerebral blood flow (CBF) and cerebral oxygenation, possibly potentiating neurological injury during CPR. We investigated the cerebrovascular effects of intravenous epinephrine in a swine model of pediatric in-hospital cardiac arrest. The primary objectives of this study were to determine if (1) epinephrine doses have a significant acute effect on CBF and cerebral tissue oxygenation during CPR and (2) if the effect of each subsequent dose of epinephrine differs significantly from that of the first. METHODS: One-month-old piglets (n = 20) underwent asphyxia for 7 min, ventricular fibrillation, and CPR for 10-20 min. Epinephrine (20 mcg/kg) was administered at 2, 6, 10, 14, and 18 min of CPR. Invasive (laser Doppler, brain tissue oxygen tension [PbtO2]) and noninvasive (diffuse correlation spectroscopy and diffuse optical spectroscopy) measurements of CBF and cerebral tissue oxygenation were simultaneously recorded. Effects of subsequent epinephrine doses were compared to the first. RESULTS: With the first epinephrine dose during CPR, CBF and cerebral tissue oxygenation increased by > 10%, as measured by each of the invasive and noninvasive measures (p < 0.001). The effects of epinephrine on CBF and cerebral tissue oxygenation decreased with subsequent doses. By the fifth dose of epinephrine, there were no demonstrable increases in CBF of cerebral tissue oxygenation. Invasive and noninvasive CBF measurements were highly correlated during asphyxia (slope effect 1.3, p < 0.001) and CPR (slope effect 0.20, p < 0.001). CONCLUSIONS: This model suggests that epinephrine increases CBF and cerebral tissue oxygenation, but that effects wane following the third dose. Noninvasive measurements of neurological health parameters hold promise for developing and directing resuscitation strategies.

Noninvasive optical measurement of microvascular cerebral hemodynamics and autoregulation in the neonatal ECMO patient.

BACKGROUND: Extra-corporeal membrane oxygenation (ECMO) is a life-saving intervention for severe respiratory and cardiac diseases. However, 50% of survivors have abnormal neurologic exams. Current ECMO management is guided by systemic metrics, which may poorly predict cerebral perfusion. Continuous optical monitoring of cerebral hemodynamics during ECMO holds potential to detect risk factors of brain injury such as impaired cerebrovascular autoregulation (CA). METHODS: We conducted daily measurements of microvascular cerebral blood flow (CBF), oxygen saturation, and total hemoglobin concentration using diffuse correlation spectroscopy (DCS) and frequency-domain diffuse optical spectroscopy in nine neonates. We characterize CA utilizing the correlation coefficient (DCSx) between CBF and mean arterial blood pressure (MAP) during ECMO pump flow changes. RESULTS: Average MAP and pump flow levels were weakly correlated with CBF and were not correlated with cerebral oxygen saturation. CA integrity varied between individuals and with time. Systemic measurements of MAP, pulse pressure, and left cardiac dysfunction were not predictive of impaired CA. CONCLUSIONS: Our pilot results suggest that systemic measures alone cannot distinguish impaired CA from intact CA during ECMO. Furthermore, optical neuromonitoring could help determine patient-specific ECMO pump flows for optimal CA integrity, thereby reducing risk of secondary brain injury. IMPACT: Cerebral blood flow and oxygenation are not well predicted by systemic proxies such as ECMO pump flow or blood pressure. Continuous, quantitative, bedside monitoring of cerebral blood flow and oxygenation with optical tools enables new insight into the adequacy of cerebral perfusion during ECMO. A demonstration of hybrid diffuse optical and correlation spectroscopies to continuously measure cerebral blood oxygen saturation and flow in patients on ECMO, enabling assessment of cerebral autoregulation. An observation of poor correlation of cerebral blood flow and oxygenation with systemic mean arterial pressure and ECMO pump flow, suggesting that clinical decision making guided by target values for these surrogates may not be neuroprotective. ~50% of ECMO survivors have long-term neurological deficiencies; continuous monitoring of brain health throughout therapy may reduce these tragically common sequelae through brain-focused adjustment of ECMO parameters.

Non-invasive optical neuromonitoring of the temperature-dependence of cerebral oxygen metabolism during deep hypothermic cardiopulmonary bypass in neonatal swine.

Management of deep hypothermic (DH) cardiopulmonary bypass (CPB), a critical neuroprotective strategy, currently relies on non-invasive temperature to guide cerebral metabolic suppression during complex cardiac surgery in neonates. Considerable inter-subject variability in temperature response and residual metabolism may contribute to the persisting risk for postoperative neurological injury. To characterize and mitigate this variability, we assess the sufficiency of conventional nasopharyngeal temperature (NPT) guidance, and in the process, validate combined non-invasive frequency-domain diffuse optical spectroscopy (FD-DOS) and diffuse correlation spectroscopy (DCS) for direct measurement of cerebral metabolic rate of oxygen (CMRO2). During CPB, n = 8 neonatal swine underwent cooling from normothermia to 18℃, sustained DH perfusion for 40 min, and then rewarming to simulate cardiac surgery. Continuous non-invasive and invasive measurements of intracranial temperature (ICT) and CMRO2 were acquired. Significant hysteresis (p < 0.001) between cooling and rewarming periods in the NPT versus ICT and NPT versus CMRO2 relationships were found. Resolution of this hysteresis in the ICT versus CMRO2 relationship identified a crucial insufficiency of conventional NPT guidance. Non-invasive CMRO2 temperature coefficients with respect to NPT (Q10 = 2.0) and ICT (Q10 = 2.5) are consistent with previous reports and provide further validation of FD-DOS/DCS CMRO2 monitoring during DH CPB to optimize management.

Electroencephalographic Response to Deep Hypothermic Circulatory Arrest in Neonatal Swine and Humans.

BACKGROUND: Piglets are used to study neurologic effects of deep hypothermic circulatory arrest (DHCA), but no studies have compared human and swine electroencephalogram (EEG) responses to DHCA. The importance of isoelectricity before circulatory arrest is not fully known in neonates. We compared the EEG response to DHCA in human neonates and piglets. METHODS: We recorded 2 channel, left and right centroparietal, subdermal EEG in 10 neonatal patients undergoing operations involving DHCA and 10 neonatal piglets that were placed on cardiopulmonary bypass and underwent a simulated procedure using DHCA. EEG waveforms were analyzed for the presence and extent of burst suppression and isoelectricity by automated moving window analysis. The patients were monitored with 16-channel array EEG for 48 hours postoperatively and underwent postoperative brain magnetic resonance imaging. RESULTS: After induction of anesthesia, humans and piglets both displayed slowing or brief suppression, then mild burst suppression, and then severe burst suppression during cooling. All piglets subsequently achieved isoelectricity at 22.4° ± 6.9°C, whereas only 1 human did at 20.2°C. Piglets and humans emerged from severe, mild, and then brief suppression patterns during rewarming. Among the patients, there were no seizures during postoperative monitoring and 1 instance of increased white matter injury on postoperative magnetic resonance imaging. CONCLUSIONS: Our data suggest that current cooling strategies may not be sufficient to eliminate all EEG activity before circulatory arrest in humans but are sufficient in swine. This important difference between the swine and human response to DHCA should be considered when using this model.

Preoperative cerebral hemodynamics from birth to surgery in neonates with critical congenital heart disease.

BACKGROUND: Hypoxic-ischemic white matter brain injury commonly occurs in neonates with critical congenital heart disease. Recent work has shown that longer time to surgery is associated with increased risk for this injury. In this study we investigated changes in perinatal cerebral hemodynamics during the transition from fetal to neonatal circulation to ascertain mechanisms that might underlie this risk. METHODS: Neonates with either transposition of the great arteries (TGA) or hypoplastic left heart syndrome (HLHS) were recruited for preoperative noninvasive optical monitoring of cerebral oxygen saturation, cerebral oxygen extraction fraction, and cerebral blood flow using diffuse optical spectroscopy and diffuse correlation spectroscopy, 2 noninvasive optical techniques. Measurements were acquired daily from day of consent until the morning of surgery. Temporal trends in these measured parameters during the preoperative period were assessed with a mixed effects model. RESULTS: Forty-eight neonates with TGA or HLHS were studied. Cerebral oxygen saturation was significantly and negatively correlated with time, and oxygen extraction fraction was significantly and positively correlated with time. Cerebral blood flow did not significantly change with time during the preoperative period. CONCLUSIONS: In neonates with TGA or HLHS, increasing cerebral oxygen extraction combined with an abnormal cerebral blood flow response during the time between birth and heart surgery leads to a progressive decrease in cerebral tissue oxygenation The results support and help explain the physiological basis for recent studies that show longer time to surgery increases the risk of acquiring white matter injury.

Cerebral mitochondrial dysfunction associated with deep hypothermic circulatory arrest in neonatal swine.

OBJECTIVES: Controversy remains regarding the use of deep hypothermic circulatory arrest (DHCA) in neonatal cardiac surgery. Alterations in cerebral mitochondrial bioenergetics are thought to contribute to ischaemia-reperfusion injury in DHCA. The purpose of this study was to compare cerebral mitochondrial bioenergetics for DHCA with deep hypothermic continuous perfusion using a neonatal swine model. METHODS: Twenty-four piglets (mean weight 3.8 kg) were placed on cardiopulmonary bypass (CPB): 10 underwent 40-min DHCA, following cooling to 18°C, 10 underwent 40 min DHCA and 10 remained at deep hypothermia for 40 min; animals were subsequently rewarmed to normothermia. 4 remained on normothermic CPB throughout. Fresh brain tissue was harvested while on CPB and assessed for mitochondrial respiration and reactive oxygen species generation. Cerebral microdialysis samples were collected throughout the analysis. RESULTS: DHCA animals had significantly decreased mitochondrial complex I respiration, maximal oxidative phosphorylation, respiratory control ratio and significantly increased mitochondrial reactive oxygen species (P < 0.05 for all). DHCA animals also had significantly increased cerebral microdialysis indicators of cerebral ischaemia (lactate/pyruvate ratio) and neuronal death (glycerol) during and after rewarming. CONCLUSIONS: DHCA is associated with disruption of mitochondrial bioenergetics compared with deep hypothermic continuous perfusion. Preserving mitochondrial health may mitigate brain injury in cardiac surgical patients. Further studies are needed to better understand the mechanisms of neurological injury in neonatal cardiac surgery and correlate mitochondrial dysfunction with neurological outcomes.