Anaerobic Lactate Production Is Associated With Decreased Microcirculatory Blood Flow and Decreased Mitochondrial Respiration Following Cardiovascular Surgery With Cardiopulmonary Bypass.

OBJECTIVES: Quantify the relationship between perioperative anaerobic lactate production, microcirculatory blood flow, and mitochondrial respiration in patients after cardiovascular surgery with cardiopulmonary bypass. DESIGN: Serial measurements of lactate-pyruvate ratio (LPR), microcirculatory blood flow, plasma tricarboxylic acid cycle cycle intermediates, and mitochondrial respiration were compared between patients with a normal peak lactate (≤ 2 mmol/L) and a high peak lactate (≥ 4 mmol/L) in the first 6 hours after surgery. Regression analysis was performed to quantify the relationship between clinically relevant hemodynamic variables, lactate, LPR, and microcirculatory blood flow. SETTING: This was a single-center, prospective observational study conducted in an academic cardiovascular ICU. PATIENTS: One hundred thirty-two patients undergoing elective cardiovascular surgery with cardiopulmonary bypass. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Patients with a high postoperative lactate were found to have a higher LPR compared with patients with a normal postoperative lactate (14.4 ± 2.5 vs. 11.7 ± 3.4; p = 0.005). Linear regression analysis found a significant, negative relationship between LPR and microcirculatory flow index (r = -0.225; ß = -0.037; p = 0.001 and proportion of perfused vessels: r = -0.17; ß = -0.468; p = 0.009). There was not a significant relationship between absolute plasma lactate and microcirculation variables. Last, mitochondrial complex I and complex II oxidative phosphorylation were reduced in patients with high postoperative lactate levels compared with patients with normal lactate (22.6 ± 6.2 vs. 14.5 ± 7.4 pmol O2/s/106 cells; p = 0.002). CONCLUSIONS: Increased anaerobic lactate production, estimated by LPR, has a negative relationship with microcirculatory blood flow after cardiovascular surgery. This relationship does not persist when measuring lactate alone. In addition, decreased mitochondrial respiration is associated with increased lactate after cardiovascular surgery. These findings suggest that high lactate levels after cardiovascular surgery, even in the setting of normal hemodynamics, are not simply a type B phenomenon as previously suggested.

Early Impairment of Cerebral Bioenergetics After Cardiopulmonary Bypass in Neonatal Swine.

Objectives: We previously demonstrated cerebral mitochondrial dysfunction in neonatal swine immediately following a period of full-flow cardiopulmonary bypass (CPB). The extent to which this dysfunction persists in the postoperative period and its correlation with other markers of cerebral bioenergetic failure and injury is unknown. We utilized a neonatal swine model to investigate the early evolution of mitochondrial function and cerebral bioenergetic failure after CPB. Methods: Twenty piglets (mean weight 4.4 ± 0.5 kg) underwent 3 h of CPB at 34 °C via cervical cannulation and were followed for 8, 12, 18, or 24 h (n = 5 per group). Markers of brain tissue damage (glycerol) and bioenergetic dysfunction (lactate to pyruvate ratio) were continuously measured in cerebral microdialysate samples. Control animals (n = 3, mean weight 4.1 ± 1.2 kg) did not undergo cannulation or CPB. Brain tissue was extracted immediately after euthanasia to obtain ex-vivo cortical mitochondrial respiration and frequency of cortical microglial nodules (indicative of cerebral microinfarctions) via neuropathology. Results: Both the lactate to pyruvate ratio (P < .0001) and glycerol levels (P = .01) increased in cerebral microdialysate within 8 h after CPB. At 24 h post-CPB, cortical mitochondrial respiration was significantly decreased compared with controls (P = .046). The presence of microglial nodules increased throughout the study period (24 h) (P = .01, R2 = 0.9). Conclusion: CPB results in impaired cerebral bioenergetics that persist for at least 24 h. During this period of bioenergetic impairment, there may be increased susceptibility to secondary injury related to alterations in metabolic delivery or demand, such as hypoglycemia, seizures, and decreased cerebral blood flow.

Diffuse Optical Monitoring of Cerebral Hemodynamics and Oxygen Metabolism during and after Cardiopulmonary Bypass: Hematocrit Correction and Neurological Vulnerability.

Cardiopulmonary bypass (CPB) provides cerebral oxygenation and blood flow (CBF) during neonatal congenital heart surgery, but the impacts of CPB on brain oxygen supply and metabolic demands are generally unknown. To elucidate this physiology, we used diffuse correlation spectroscopy and frequency-domain diffuse optical spectroscopy to continuously measure CBF, oxygen extraction fraction (OEF), and oxygen metabolism (CMRO2) in 27 neonatal swine before, during, and up to 24 h after CPB. Concurrently, we sampled cerebral microdialysis biomarkers of metabolic distress (lactate-pyruvate ratio) and injury (glycerol). We applied a novel theoretical approach to correct for hematocrit variation during optical quantification of CBF in vivo. Without correction, a mean (95% CI) +53% (42, 63) increase in hematocrit resulted in a physiologically improbable +58% (27, 90) increase in CMRO2 relative to baseline at CPB initiation; following correction, CMRO2 did not differ from baseline at this timepoint. After CPB initiation, OEF increased but CBF and CMRO2 decreased with CPB time; these temporal trends persisted for 0-8 h following CPB and coincided with a 48% (7, 90) elevation of glycerol. The temporal trends and glycerol elevation resolved by 8-24 h. The hematocrit correction improved quantification of cerebral physiologic trends that precede and coincide with neurological injury following CPB.

Low postoperative perfused vessel density is associated with increased soluble endothelial cell adhesion molecules during circulatory shock after cardiac surgery.

INTRODUCTION: Microcirculatory dysfunction after cardiovascular surgery is associated with significant morbidity and worse clinical outcomes. Abnormal capillary blood flow can occur from multiple causes, including cytokine-mediated vascular endothelial injury, microthrombosis, and an inadequate balance between vasoconstriction and vasodilation. In response to proinflammatory cytokines, endothelial cells produce cellular adhesion molecules (CAMs) which regulate leukocyte adhesion, vascular permeability, and thus can mediate tissue injury. The relationship between changes in microcirculatory flow during circulatory shock and circulating adhesion molecules is unclear. The objective of this study was to compare changes in plasma soluble endothelial cell adhesion molecules (VCAM-1, ICAM-1, and E-Selectin) in patients with functional derangements in microcirculatory blood flow after cardiovascular surgery. METHODS: Adult patients undergoing elective cardiac surgery requiring cardiopulmonary bypass who exhibited postoperative shock were enrolled in the study. Sublingual microcirculation imaging was performed prior to surgery and within 2 h of ICU admission. Blood samples were taken at the time of microcirculation imaging for biomarker analysis. Plasma soluble VCAM-1, ICAM-1, and E-selectin in addition to plasma cytokines (IL-6, IL-8, and IL-10) were measured by commercially available enzyme-linked immunoassay. RESULTS: Of 83 patients with postoperative shock who were evaluated, 40 patients with clinical shock had a postoperative perfused vessel density (PVD) >1 SD above (High PVD group = 28.5 ± 2.3 mm/mm2, n = 20) or below (Low PVD = 15.5 ± 2.0 mm/mm2, n = 20) the mean postoperative PVD and were included in the final analysis. Patient groups were well matched for comorbidities, surgical, and postoperative details. Overall, there was an increase in postoperative plasma VCAM-1 and E-Selectin compared to preoperative levels, but there was no difference between circulating ICAM-1. When grouped by postoperative microcirculation, patients with poor microcirculation were found to have increased circulating VCAM-1 (2413 ± 1144 vs. 844 ± 786 ng/mL; p < 0.0001) and E-Selectin (242 ± 119 vs. 87 ± 86 ng/mL; p < 0.0001) compared to patients with increased microcirculatory blood flow. Microcirculatory flow was not associated with a difference in plasma soluble ICAM-1 (394 ± 190 vs. 441 ± 256; p = 0.52). CONCLUSIONS: Poor postoperative microcirculatory blood flow in patients with circulatory shock after cardiac surgery is associated with increased plasma soluble VCAM-1 and E-Selectin, indicating increased endothelial injury and activation compared to patients with a high postoperative microcirculatory blood flow. Circulating endothelial cell adhesion molecules may be a useful plasma biomarker to identify abnormal microcirculatory blood flow in patients with shock.

Alteration in Cerebral Metabolism in a Rodent Model of Acute Sub-lethal Cyanide Poisoning.

INTRODUCTION: Cyanide exposure can occur in various settings such as industry and metallurgy. The primary mechanism of injury is cellular hypoxia from Complex IV (CIV) inhibition. This leads to decreased ATP production and increased reactive oxygen species production. The brain and the heart are the organs most affected due to their high metabolic demand. While the cardiac effects of cyanide are well known, the cerebral effects on cellular function are less well described. We investigated cerebral metabolism with a combination of brain respirometry, microdialysis, and western blotting using a rodent model of sub-lethal cyanide poisoning. METHODS: Twenty rodents were divided into two groups: control (n = 10) and sub-lethal cyanide (n = 10). Cerebral microdialysis was performed during a 2 mg/kg/h cyanide exposure to obtain real-time measurements of cerebral metabolic status. At the end of the exposure (90 min), brain-isolated mitochondria were measured for mitochondrial respiration. Brain tissue ATP concentrations, acyl-Coenzyme A thioesters, and mitochondrial content were also measured. RESULTS: The cyanide group showed significantly increased lactate and decreased hypotension with decreased cerebral CIV-linked mitochondrial respiration. There was also a significant decrease in cerebral ATP concentration in the cyanide group and a significantly higher cerebral lactate-to-pyruvate ratio (LPR). In addition, we also found decreased expression of Complex III and IV protein expression in brain tissue from the cyanide group. Finally, there was no change in acyl-coenzyme A thioesters between the two groups. CONCLUSIONS: The key finding demonstrates mitochondrial dysfunction in brain tissue that corresponds with a decrease in mitochondrial function, ATP concentrations, and an elevated LPR indicating brain dysfunction at a sub-lethal dose of cyanide.

Co-administration of Ketamine in Pediatric Patients with Neurologic Conditions at Risk for Intracranial Hypertension.

BACKGROUND: Ketamine has traditionally been avoided as an induction agent for tracheal intubation in patients with neurologic conditions at risk for intracranial hypertension due to conflicting data in the literature. The objective of this study was to evaluate and compare the effects of ketamine versus other medications as the primary induction agent on peri-intubation neurologic, hemodynamic and respiratory associated events in pediatric patients with neurologic conditions at risk for intracranial hypertension. METHODS: This retrospective observational study enrolled patients < 18 years of age at risk for intracranial hypertension who were admitted to a quaternary children's hospital between 2015 and 2020. Associated events included neurologic, hemodynamic and respiratory outcomes comparing primary induction agents of ketamine versus non-ketamine for tracheal intubation. RESULTS: Of 143 children, 70 received ketamine as the primary induction agent prior to tracheal intubation. Subsequently after tracheal intubation, all the patients received adjunct analgesic and sedative medications (fentanyl, midazolam, and/or propofol) at doses that were inadequate to induce general anesthesia but would keep them comfortable for further diagnostic workup. There were no significant differences between associated neurologic events in the ketamine versus non-ketamine groups (p = 0.42). This included obtaining an emergent computed tomography scan (p = 0.28), an emergent trip to the operating room within 5 h of tracheal intubation (p = 0.6), and the need for hypertonic saline administration within 15 min of induction drug administration for tracheal intubation (p = 0.51). There were two patients who had clinical and imaging evidence of herniation, which was not more adversely affected by ketamine compared with other medications (p = 0.49). Of the 143 patients, 23 had pre-intubation and post-intubation intracranial pressure values recorded; 11 received ketamine, and 3 of these patients had intracranial hypertension that resolved or improved, whereas the remaining 8 children had intracranial pressure within the normal range that was not exacerbated by ketamine. There were no significant differences in overall associated hemodynamic or respiratory events during tracheal intubation and no 24-h mortality in either group. CONCLUSIONS: The administration of ketamine as the primary induction agent prior to tracheal intubation in combination with other agents after tracheal intubation in children at risk for intracranial hypertension was not associated with an increased risk of peri-intubation associated neurologic, hemodynamic or respiratory events compared with those who received other induction agents.

Topical nitroglycerin to detect reversible microcirculatory dysfunction in patients with circulatory shock after cardiovascular surgery: an observational study.

Persistent abnormalities in microcirculatory function are associated with poor clinical outcomes in patients with circulatory shock. We sought to identify patients with acutely reversible microcirculatory dysfunction using a low-dose topical nitroglycerin solution and handheld videomicroscopy during circulatory shock after cardiac surgery. Forty subjects were enrolled for the study, including 20 preoperative control and 20 post-operative patients with shock. To test whether microcirculatory dysfunction is acutely reversible during shock, the sublingual microcirculation was imaged with incident dark field microscopy before and after the application of 0.1 mL of a 1% nitroglycerin solution (1 mg/mL). Compared to the control group, patients with shock had a higher microcirculation heterogeneity index (MHI 0.33 vs. 0.12, p < 0.001) and a lower microvascular flow index (MFI 2.57 vs. 2.91, p < 0.001), total vessel density (TVD 22.47 vs. 25.90 mm/mm2, p = 0.005), proportion of perfused vessels (PPV 90.76 vs. 95.89%, p < 0.001) and perfused vessel density (PVD 20.44 vs. 24.81 mm/mm2, p < 0.001). After the nitroglycerin challenge, patients with shock had an increase in MFI (2.57 vs. 2.97, p < 0.001), TVD (22.47 vs. 27.51 mm/mm2, p < 0.009), PPV (90.76 vs. 95.91%, p < 0.001), PVD (20.44 vs. 26.41 mm/mm2, p < 0.001), venular RBC velocity (402.2 vs. 693.9 µm/s, p < 0.0004), and a decrease in MHI (0.33 vs. 0.04, p < 0.001. Thirteen of 20 patients showed a pharmacodynamic response, defined as an increase in PVD > 1.8 SD from shock baseline. Hemodynamics and vasoactive doses did not change during the 30-min study period. Our findings suggest a topical nitroglycerin challenge with handheld videomicroscopy can safely assess for localized recruitment of the microcirculatory blood flow in patients with circulatory shock and may be a useful test to identify nitroglycerin responsiveness.

Protocol for the MicroRESUS study: The impact of circulatory shock and resuscitation on microcirculatory function and mitochondrial respiration after cardiovascular surgery.

BACKGROUND: Despite current resuscitation strategies, circulatory shock and organ injury after cardiac surgery occur in 25-40% of patients. Goal-directed resuscitation after cardiac surgery has generated significant interest, but clinical practice to normalize hemodynamic variables including mean arterial pressure, cardiac filling pressures, and cardiac output may not reverse microcirculation abnormalities and do not address cellular dysoxia. Recent advances in technology have made it possible to measure critical components of oxygen delivery and oxygen utilization systems in live human tissues and blood cells. The MicroRESUS study will be the first study to measure microcirculatory and mitochondrial function in patients with circulatory shock and link these findings with clinical outcomes. METHODS AND ANALYSIS: This will be a prospective, observational study that includes patients undergoing elective cardiovascular surgery with cardiopulmonary bypass (CPB). Microcirculation will be quantified with sublingual incident dark field videomicroscopy. Mitochondrial respiration will be measured by performing a substrate-uncoupler-inhibitor titration protocol with high resolution respirometry on peripheral blood mononuclear cells at baseline and serial timepoints during resuscitation and at recovery as a possible liquid biomarker. Plasma samples will be preserved for future analysis to examine endothelial injury and other mechanisms of microcirculatory dysfunction. Thirty-day ventilator and vasopressor-free days (VVFDs) will be measured as a primary outcome, along with sequential organ failure assessment scores, and other clinical parameters to determine if changes in microcirculation and mitochondrial respiration are more strongly associated with clinical outcomes compared to traditional resuscitation targets. DISCUSSION: This will be the first prospective study to examine both microcirculatory and mitochondrial function in human patients with circulatory shock undergoing cardiac bypass and address a key mechanistic knowledge gap in the cardiovascular literature. The results of this study will direct future research efforts and therapeutic development for patients with shock.

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.

Chronic hypoxemia induces mitochondrial respiratory complex gene expression in the fetal sheep brain.

Objective: The molecular pathways underlying hypoxemia-induced alterations in neurodevelopment of infants with congenital heart disease have not been delineated. We used transcriptome analysis to investigate differential gene expression induced by hypoxemia in an ovine artificial-womb model. Methods: Mid-gestation fetal sheep (median [interquartile range] 109 [107-112] days' gestation) were cannulated via the umbilical vessels, attached to a pumpless, low-resistance oxygenator circuit, and incubated in a sterile, fluid environment for 22 [21-23] days. Fetuses were maintained with an oxygen delivery of 20-25 mL/kg/min (normoxemia, n = 3) or 14-16 mL/kg/min (hypoxemia, n = 4). Transcriptional profiling by RNA sequencing was carried out on left frontal brains and hypoxemia-regulated genes were identified by differential gene expression analysis. Results: A total of 228 genes whose expression was up or down regulated by ≥1.5-fold (false discovery rate ≤0.05) were identified. The majority of these genes were induced in hypoxemic animals compared to normoxemic controls, and functional enrichment analysis identified respiratory electron transport as a pathway strongly upregulated in the brain during chronic hypoxemia. Further examination of hypoxemia-induced genes showed robust induction of all 7 subunits of the mitochondrial NADH:ubiquinone oxidoreductase (complex I). Other hypoxemia-induced genes included cytochrome B, a component of complex III, and ATP6, ATP8, both of which are components of complex V. Conclusions: Chronic fetal hypoxemia leads to upregulation of multiple mitochondrial respiratory complex genes critical for energy production and reactive oxygen species generation, including complex I. These data provide valuable insight into potential pathways involved in chronic hypoxemia-induced neuropathology and offers potential therapeutic targets for fetal neuroprotection in fetuses with congenital heart defects.

Flexible Bronchoscopy in Pediatric Venovenous Extracorporeal Membrane Oxygenation.

BACKGROUND: Pediatric patients with ARDS will on occasion need venovenous extracorporeal membrane oxygenation (VV-ECMO) for organ support. As these patients recover, they may benefit from lung recruitment maneuvers including flexible bronchoscopy (FB). The objective of this study was to assess the clinical course of patients who underwent FB while on VV-ECMO for ARDS. METHODS: This was a secondary analysis of a retrospective multi-center cohort at 10 United States pediatric academic quaternary care centers. Data were collected on 204 subjects age 14 d-18 y on VV-ECMO. RESULTS: 271 FBs were performed on 129 (63%) subjects. Pre-FB tidal volume was 1.8 mL/kg compared to 2.22 mL/kg following FB (P = .007). Dynamic compliance also improved from pre-FB to post-FB (2.23 vs 3.04 mL/cm H2O, P = .005). There was a low incidence of complications following FB (3.1%). Subjects in the FB group had fewer ECMO-free days (EFDs) (17.9 vs 22.1 d, P < .001), fewer ventilator-free days (VFDs) (40.0 vs 46.5 d, P = .001), and longer ICU length of stay (LOS) (18 vs 32 d, P < .001). Subjects in the early versus late FB group had more EFDs (19.4 vs 15.2 d, P = .003), more VFDs (43.0 vs 34.0 d, P = .004), and shorter ICU LOS (27.5 vs 35.5 d, P = .045). Mortality in the subjects who had at least one FB was 27.1% compared to 40% in the subjects who did not have a FB while on VV-ECMO (P = .057). CONCLUSIONS: FB can be performed on patients while anticoagulated on VV-ECMO with a low incidence of complications. FB may be beneficial especially when performed early in the course of VV-ECMO.

Cerebral microcirculation mapped by echo particle tracking velocimetry quantifies the intracranial pressure and detects ischemia.

Affecting 1.1‰ of infants, hydrocephalus involves abnormal accumulation of cerebrospinal fluid, resulting in elevated intracranial pressure (ICP). It is the leading cause for brain surgery in newborns, often causing long-term neurologic disabilities or even death. Since conventional invasive ICP monitoring is risky, early neurosurgical interventions could benefit from noninvasive techniques. Here we use clinical contrast-enhanced ultrasound (CEUS) imaging and intravascular microbubble tracking algorithms to map the cerebral blood flow in hydrocephalic pediatric porcine models. Regional microvascular perfusions are quantified by the cerebral microcirculation (CMC) parameter, which accounts for the concentration of micro-vessels and flow velocity in them. Combining CMC with hemodynamic parameters yields functional relationships between cortical micro-perfusion and ICP, with correlation coefficients exceeding 0.85. For cerebral ischemia cases, the nondimensionalized cortical micro-perfusion decreases by an order of magnitude when ICP exceeds 50% of the MAP. These findings suggest that CEUS-based CMC measurement is a plausible noninvasive method for assessing the ICP and detecting ischemia.

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.

Arterial spin labeling as an ancillary assessment to postoperative conventional angiogram in pediatric moyamoya disease.

OBJECTIVE: Digital subtraction angiography (DSA) is commonly performed after pial synangiosis surgery for pediatric moyamoya disease to assess the degree of neovascularization. However, angiography is invasive, and the risk of ionizing radiation is a concern in children. In this study, the authors aimed to identify whether arterial spin labeling (ASL) can predict postoperative angiogram grading. In addition, they sought to determine whether patients who underwent ASL imaging without DSA had similar postoperative outcomes when compared with patients who received ASL imaging and postoperative DSA. METHODS: The medical records of pediatric patients who underwent pial synangiosis for moyamoya disease at a quaternary children's hospital were reviewed during a 10-year period. ASL-only and ASL+DSA cohorts were analyzed. The frequency of preoperative and postoperative symptoms was analyzed within each cohort. Three neuroradiologists assigned a visual ASL grade for each patient indicating the change from the preoperative to postoperative ASL perfusion sequences. A postoperative neovascularization grade was also assigned for patients who underwent DSA. RESULTS: Overall, 21 hemispheres of 14 patients with ASL only and 14 hemispheres of 8 patients with ASL+DSA were analyzed. The groups had similar rates of MRI evidence of acute or chronic stroke preoperatively (61.9% in the ASL-only group and 64.3% in the ASL+DSA group). In the entire cohort, transient ischemic attack (TIA) (p = 0.027), TIA composite (TIA or unexplained neurological symptoms; p = 0.0006), chronic headaches (p = 0.035), aphasia (p = 0.019), and weakness (p = 0.001) all had decreased frequency after intervention. The authors found a positive association between revascularization observed on DSA and the visual ASL grading (p = 0.048). The visual ASL grades in patients with an angiogram indicating robust neovascularization demonstrated improved perfusion when compared with the ASL grades of patients with a poor neovascularization. CONCLUSIONS: Noninvasive ASL perfusion imaging had an association with postoperative DSA neoangiogenesis following pial synangiosis surgery in children. There were no significant postoperative stroke differences between the ASL-only and ASL+DSA cohorts. Both cohorts demonstrated significant improvement in preoperative symptoms after surgery. Further study in larger cohorts is necessary to determine whether the results of this study are validated in order to circumvent the invasive catheter angiogram.

Urgent Neurosurgical Interventions in the COVID-19-Positive Pediatric Population.

BACKGROUND: Urgent neurosurgical interventions for pediatric patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are rare. These cases pose additional stress on a potentially vulnerable dysregulated inflammatory response that can place the child at risk of further clinical deterioration. Our aim was to describe the perioperative course of SARS-CoV-2-positive pediatric patients who had required an urgent neurosurgical intervention. METHODS: We retrospectively analyzed pediatric patients aged ≤18 years who had been admitted to a quaternary children's hospital with a positive polymerase chain reaction test result for SARS-CoV-2 virus from March 2020 to October 2021. The clinical characteristics, anesthetic and neurosurgical operative details, surgical outcomes, and non-neurological symptoms were collected and analyzed. RESULTS: We identified 8 SARS-CoV-2-positive patients with a mean age of 8.83 years (median, 8.5 years; range, 0.58-18 years). Of the 8 patients, 6 were male. All children had had mild or asymptomatic coronavirus disease 2109. The anesthetic and surgical courses for these patients were, overall, uncomplicated. All the patients had been admitted to a specialized isolation unit in the pediatric intensive care unit for cardiopulmonary and neurological monitoring. The use of increased protective personal equipment during anesthesia and surgery did not impede a successful neurosurgical operation. CONCLUSIONS: SARS-CoV-2-positive pediatric patients with minimal coronavirus disease 2019-related symptoms who require urgent neurosurgical interventions face unique challenges regarding their anesthetic status, operative delays due to SARS-CoV-2 polymerase chain reaction testing, and requirements for additional protective personal equipment. Despite these clinical challenges, the patients in our study had not experienced adverse postoperative consequences, and no healthcare professional involved in their care had contracted the virus.

Veno-Venous Extracorporeal Membrane Oxygenation for Children With Cancer or Hematopoietic Cell Transplant: A Ten Center Cohort.

We performed a multicenter retrospective cohort study of children with 14 days to 18 years of age in the United States from 2011 to 2016 with cancer or hematopoietic cell transplant (HCT) who were supported with veno-venous extracorporeal membrane oxygenation (V-V ECMO). We compared the outcomes of children with oncological diagnoses or HCT supported with V-V ECMO to other children who have received V-V ECMO support. In this cohort of 204 patients supported with V-V ECMO, 30 (15%) had a diagnosis of cancer or a history of HCT. There were 21 patients who had oncological diagnoses without HCT and 9 children were post-HCT. The oncology/HCT group had a higher overall ICU mortality (67% vs. 28%, P < 0.001), mortality on ECMO (43% vs. 21%, P < 0.01), and ICU mortality among ECMO survivors (35% vs. 8%, P < 0.01). The oncology/HCT group had a higher rate of conversion to veno-arterial (V-A) ECMO (23% vs. 9%, P = 0.02) (RR, 2.5; 95% CI, 1.1-5.6). Children with cancer or HCT were older (6.6 vs. 2.9 years, P = 0.02) and had higher creatinine levels (0.65 vs. 0.4 mg/dL, P = 0.04) but were similar to the rest of the cohort for other pre-ECMO variables. For post-HCT patients, survival was significantly worse for those whose indication for HCT was cancer or immunodeficiency (0/6) as compared to other nonmalignant indications (3/3) (P = 0.01).

Low Microcirculatory Perfused Vessel Density and High Heterogeneity are Associated With Increased Intensity and Duration of Lactic Acidosis After Cardiac Surgery with Cardiopulmonary Bypass.

INTRODUCTION: Lactic acidosis after cardiac surgery with cardiopulmonary bypass is common and associated with an increase in postoperative morbidity and mortality. A number of potential causes for an elevated lactate after cardiopulmonary bypass include cellular hypoxia, impaired tissue perfusion, ischemic-reperfusion injury, aerobic glycolysis, catecholamine infusions, and systemic inflammatory response after exposure to the artificial cardiopulmonary bypass circuit. Our goal was to examine the relationship between early abnormalities in microcirculatory convective blood flow and diffusive capacity and lactate kinetics during early resuscitation in the intensive care unit. We hypothesized that patients with impaired microcirculation after cardiac surgery would have a more severe postoperative hyperlactatemia, represented by the lactate time-integral of an arterial blood lactate concentration greater than 2.0 mmol/L. METHODS: We measured sublingual microcirculation using incident darkfield video microscopy in 50 subjects on intensive care unit admission after cardiac surgery. Serial measurements of systemic hemodynamics, blood gas, lactate, and catecholamine infusions were recorded each hour for the first 6 h after surgery. Lactate area under the curve (AUC) was calculated over the first 6 h. The lactate AUC was compared between subjects with normal and low perfused vessel density (PVD < 18 mm/mm2), high microcirculatory heterogeneity index (MHI > 0.4), and low vessel-by-vessel microvascular flow index (MFIv < 2.6). RESULTS: Thirteen (26%) patients had a low postoperative PVD, 20 patients (40%) had a high MHI, and 26 (52%) patients had a low MFIv. Patients with low perfused vessel density had higher lactate AUC compared with subjects with a normal PVD (22.3 [9.4-31.0] vs. 2.6 [0-8.8]; P < 0.0001). Patients with high microcirculatory heterogeneity had a higher lactate AUC compared with those with a normal MHI (2.5 [0.1-8.2] vs. 13.1 [3.7-31.1]; P < 0.001). We did not find a difference in lactate AUC when comparing high and low MFIv. CONCLUSION: Low perfused vessel density and high microcirculatory heterogeneity are associated with an increased intensity and duration of lactic acidosis after cardiac surgery with cardiopulmonary bypass.

Increased cerebral mitochondrial dysfunction and reactive oxygen species with cardiopulmonary bypass.

OBJECTIVES: Neurodevelopmental injury after cardiac surgery using cardiopulmonary bypass (CPB) for congenital heart defects is common, but the mechanism behind this injury is unclear. This study examines the impact of CPB on cerebral mitochondrial reactive oxygen species (ROS) generation and mitochondrial bioenergetics. METHODS: Twenty-three piglets (mean weight 4.2 ± 0.5 kg) were placed on CPB for either 1, 2, 3 or 4 h (n = 5 per group) or underwent anaesthesia without CPB (sham, n = 3). Microdialysis was used to measure metabolic markers of ischaemia. At the conclusion of CPB or 4 h of sham, brain tissue was harvested. Utilizing high-resolution respirometry, with simultaneous fluorometric analysis, mitochondrial respiration and ROS were measured. RESULTS: There were no significant differences in markers of ischaemia between sham and experimental groups. Sham animals had significantly higher mitochondrial respiration than experimental animals, including maximal oxidative phosphorylation capacity of complex I (OXPHOSCI) (3.25 ± 0.18 vs 4-h CPB: 1.68 ± 0.10, P < 0.001) and maximal phosphorylating respiration capacity via convergent input through complexes I and II (OXPHOSCI+CII) (7.40 ± 0.24 vs 4-h CPB: 3.91 ± 0.20, P < 0.0001). At 4-h, experimental animals had significantly higher ROS related to non-phosphorylating respiration through complexes I and II (ETSCI+CII) than shams (1.08 ± 0.13 vs 0.64 ± 0.04, P = 0.026). CONCLUSIONS: Even in the absence of local markers of ischaemia, CPB is associated with decreased mitochondrial respiration relative to shams irrespective of duration. Exposure to 4 h of CPB resulted in a significant increase in cerebral mitochondrial ROS formation compared to shorter durations. Further study is needed to improve the understanding of cerebral mitochondrial health and its effects on the pathophysiology of neurological injury following exposure to CPB.

Severe Impairment of Microcirculatory Perfused Vessel Density Is Associated With Postoperative Lactate and Acute Organ Injury After Cardiac Surgery.

OBJECTIVE: Resuscitation after cardiac surgery needs to address multiple pathophysiological processes that are associated with significant morbidity and mortality. Functional microcirculatory derangements despite normal systemic hemodynamics have been previously described but must be tied to clinical outcomes. The authors hypothesized that microcirculatory dysfunction after cardiac surgery would include impaired capillary blood flow and impaired diffusive capacity and that subjects with the lowest quartile of perfused vessel density would have an increased postoperative lactate level and acute organ injury scores. DESIGN: Prospective, observational study. SETTING: A single, tertiary university cardiovascular surgical intensive care unit. PARTICIPANTS: 25 adults undergoing elective cardiac surgery requiring cardiopulmonary bypass. INTERVENTION: Sublingual microcirculation was imaged using incident dark field microscopy before and 2 to 4 hours after surgery in the intensive care unit. MEASUREMENTS AND MAIN RESULTS: Compared with baseline measurements, postoperative vessel-by-vessel microvascular flow index (2.9 [2.8-2.9] v 2.5 [2.4-2.7], p < 0.0001) and perfused vessel density were significantly impaired (20.7 [19.3-22.9] v 16.3 [12.8-17.9], p < 0.0001). The lowest quartile of perfused vessel density (<12.8 mm/mm2) was associated with a significantly increased postoperative lactate level (6.0 ± 2.9 v 1.8 ± 1.2, p < 0.05), peak lactate level (7.6 ± 2.8 v 2.8 ± 1.5, p = 0.03), and sequential organ failure assessment (SOFA) score at 24 and 48 hours. CONCLUSION: In patients undergoing cardiac surgery, there was a significant decrease in postoperative microcirculatory convective blood flow and diffusive capacity during early postoperative resuscitation. Severely impaired perfused vessel density, represented by the lowest quartile of distribution, is significantly related to hyperlactatemia and early organ injury.