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Outcomes in patients requiring prolonged inotropes (PI) following surgery for congenital heart disease (CHD) have not been well studied. We aimed to describe the burden of PI use in the immediate postoperative period after CHD surgery and identify risk factors for in-hospital mortality. We conducted a retrospective cohort study using the Pediatric Health Information System® (PHIS) database. Patients 0-18 years with CHD who underwent cardiovascular surgery from 2010 to 2020 were included. Patients who received inotropic medications for > 7 consecutive days after surgery were in the PI group and all others in the control group. Patients who died before 7 days were excluded. Multivariable mixed-effect logistic regression was used to examine risk factors for in-hospital mortality. There were 110,271 patients from 48 centers included, 10,292 in the PI group and 99,979 in the control group. In-hospital mortality was significantly higher in the PI group (24.9% vs. 4.6%, p < 0.001). Ventricular assist device use was rare (1.6%). After adjustment, odds of in-hospital mortality in the PI group was 3.5 (95% CI 3.3-3.8) times higher than in controls. Independent risk factors for in-hospital mortality were age, non-White race, class of CHD, number of complex chronic conditions, preoperative inotrope, preoperative extracorporeal membrane oxygenation, sepsis, stroke, renal failure, number of inotropes at 7 days, and discharge year (p < 0.01 for all). Postoperative PI use in CHD is common and carries a considerable burden of mortality. Additional work is needed to understand which risk factors are modifiable and which patients may benefit from reintervention or advanced heart failure therapies., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Objectives: For neonates and infants with aortic valve pathology, the Ross procedure historically has been associated with high rates of morbidity and mortality. Data regarding long-term durability are lacking., Methods: The international, multi-institutional Ross Collaborative included 6 tertiary care centers. Infants who underwent a Ross operation between 1996 and 2016 (allowing a minimum 5 years of follow-up) were retrospectively identified. Serial echocardiograms were examined to study evolution in neoaortic size and function., Results: Primary diagnoses for the 133 patients (n = 30 neonates) included isolated aortic stenosis (14%, n = 19), Shone complex (14%, n = 19), and aortic stenosis plus other (excluding Shone complex; n = 95, 71%), including arch obstruction (n = 55), left ventricular hypoplasia (n = 9), and mitral disease (moderate or greater stenosis or regurgitation, n = 31). At the time of the Ross procedure, median age was 96 days (interquartile range, 36-186), and median weight was 4.4 kg (3.6-6.5). In-hospital mortality occurred in 13 of 133 patients (10%) (4/30 [13%] neonates). Postdischarge mortality occurred in 10 of 120 patients (8%) at a median of 298 days post-Ross. Post-Ross neoaortic dilatation occurred, peaking at 4 to 5 SDs above normal at 2 to 3 years before returning to near-baseline z-score at a median follow-up of 11.5 [6.4-17.4] years. Autograft/left ventricular outflow tract reintervention was required in 5 of 120 patients (4%) at a median of 10.3 [4.1-12.8] years. Freedom from moderate or greater neoaortic regurgitation was 86% at 15 years., Conclusions: Neonates and infants experience excellent postdischarge survival and long-term freedom from autograft reintervention and aortic regurgitation after the Ross. Neoaortic dilatation normalizes in this population in the long-term. Increased consideration should be given to Ross in neonates and infants with aortic valve disease., Competing Interests: Conflict of Interest Statement The authors reported no conflicts of interest. The Journal policy requires editors and reviewers to disclose conflicts of interest and to decline handling or reviewing manuscripts for which they may have a conflict of interest. The editors and reviewers of this article have no conflicts of interest., (Copyright © 2024 The American Association for Thoracic Surgery. Published by Elsevier Inc. All rights reserved.)

Congenital coronary artery stenosis coexisting with aortic coarctation in nonsyndromic patients has not previously been reported. This report describes a nonsyndromic aortic coarctation patient who experienced intraoperative cardiac arrest due to a previously undiagnosed critical left main coronary artery stenosis. The patient was successfully resuscitated, underwent patch coronary ostioplasty, and was discharged home. He remains well for four months following repair.

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, R 2  = 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., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Objective: The thoracic duct is the largest lymphatic vessel in the body, and carries fluid and nutrients absorbed in abdominal organs to the central venous circulation. Thoracic duct obstruction can cause significant failure of the lymphatic circulation (i.e., protein-losing enteropathy, plastic bronchitis, etc.). Surgical anastomosis between the thoracic duct and central venous circulation has been used to treat thoracic duct obstruction but cannot provide lymphatic decompression in patients with superior vena cava obstruction or chronically elevated central venous pressures (e.g., right heart failure, single ventricle physiology, etc.). Therefore, this preclinical feasibility study sought to develop a novel and optimal surgical technique for creating a thoracic duct-to-pulmonary vein lymphovenous anastomosis (LVA) in swine that could remain patent and preserve unidirectional lymphatic fluid flow into the systemic venous circulation to provide therapeutic decompression of the lymphatic circulation even at high central venous pressures., Methods: A thoracic duct-to-pulmonary vein LVA was attempted in 10 piglets (median age 80 [IQR 80-83] days; weight 22.5 [IQR 21.4-26.8] kg). After a right thoracotomy, the thoracic duct was mobilized, transected, and anastomosed to the right inferior pulmonary vein. Animals were systemically anticoagulated on post-operative day 1. Lymphangiography was used to evaluate LVA patency up to post-operative day 7., Results: A thoracic duct-to-pulmonary vein LVA was successfully completed in 8/10 (80.0%) piglets, of which 6/8 (75.0%) survived to the intended study endpoint without any complication (median 6 [IQR 4-7] days). Initially, 2/10 (20.0%) LVAs were aborted intraoperatively, and 2/10 (20.0%) animals were euthanized early due to post-operative complications. However, using an optimized surgical technique, the success rate for creating a thoracic duct-to-pulmonary vein LVA in six animals was 100%, all of which survived to their intended study endpoint without any complications (median 6 [IQR 4-7] days). LVAs remained patent for up to seven days., Conclusion: A thoracic duct-to-pulmonary vein LVA can be completed safely and remain patent for at least one week with systemic anticoagulation, which provides an important proof-of-concept that this novel intervention could effectively offload the lymphatic circulation in patients with lymphatic failure and elevated central venous pressures., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Lymphatic failure is a broad term that describes the lymphatic circulation's inability to adequately transport fluid and solutes out of the interstitium and into the systemic venous circulation, which can result in dysfunction and dysregulation of immune responses, dietary fat absorption, and fluid balance maintenance. Several investigations have recently elucidated the nexus between lymphatic failure and congenital heart disease, and the associated morbidity and mortality is now well-recognized. However, the precise pathophysiology and pathogenesis of lymphatic failure remains poorly understood and relatively understudied, and there are no targeted therapeutics or interventions to reliably prevent its development and progression. Thus, there is growing enthusiasm towards the development and application of novel percutaneous and surgical lymphatic interventions. Moreover, there is consensus that further investigations are needed to delineate the underlying mechanisms of lymphatic failure, which could help identify novel therapeutic targets and develop innovative procedures to improve the overall quality of life and survival of these patients. With these considerations, this review aims to provide an overview of the lymphatic circulation and its vasculature as it relates to current understandings into the pathophysiology and pathogenesis of lymphatic failure in patients with congenital heart disease, while also summarizing strategies for evaluating and managing lymphatic complications, as well as specific areas of interest for future translational and clinical research efforts., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Despite improvements in survival after illnesses requiring extracorporeal life support, cerebral injury continues to hinder successful outcomes. Cerebral autoregulation (CA) is an innate protective mechanism that maintains constant cerebral blood flow in the face of varying systemic blood pressure. However, it is impaired in certain disease states and, potentially, following initiation of extracorporeal circulatory support. In this review, we first discuss patient-related factors pertaining to venovenous and venoarterial extracorporeal membrane oxygenation (ECMO) and their potential role in CA impairment. Next, we examine factors intrinsic to ECMO that may affect CA, such as cannulation, changes in pulsatility, the inflammatory and adaptive immune response, intracranial hemorrhage, and ischemic stroke, in addition to ECMO management factors, such as oxygenation, ventilation, flow rates, and blood pressure management. We highlight potential mechanisms that lead to disruption of CA in both pediatric and adult populations, the challenges of measuring CA in these patients, and potential associations with neurological outcome. Altogether, we discuss individualized CA monitoring as a potential target for improving neurological outcomes in extracorporeal life support., (© 2024. The Author(s).)

Optimal oxygen management during pediatric cardiopulmonary bypass (CPB) is unknown. We previously demonstrated an increase in cortical mitochondrial reactive oxygen species and decreased mitochondrial function after CPB using hyperoxic oxygen management. This study investigates whether controlled oxygenation (normoxia) during CPB reduces cortical mitochondrial dysfunction and oxidative injury. Ten neonatal swine underwent three hours of continuous CPB at 34 °C (flow > 100 mL/kg/min) via cervical cannulation targeting a partial pressure of arterial oxygen (PaO 2 ) goal < 150 mmHg (normoxia, n = 5) or >300 mmHg (hyperoxia, n = 5). The animals underwent continuous hemodynamic monitoring and serial arterial blood sampling. Cortical microdialysate was serially sampled to quantify the glycerol concentration (represents neuronal injury) and lactate-to-pyruvate ratio (represents bioenergetic dysfunction). The cortical tissue was analyzed via high-resolution respirometry to quantify mitochondrial oxygen consumption and reactive oxygen species generation, and cortical oxidized protein carbonyl concentrations were quantified to assess for oxidative damage. Serum PaO 2 was higher in hyperoxia animals throughout CPB ( p < 0.001). There were no differences in cortical glycerol concentration between groups ( p > 0.2). The cortical lactate-to-pyruvate ratio was modestly elevated in hyperoxia animals ( p < 0.03) but the values were not clinically significant (<30). There were no differences in cortical mitochondrial respiration ( p = 0.48), protein carbonyls ( p = 0.74), or reactive oxygen species generation ( p = 0.93) between groups. Controlled oxygenation during CPB does not significantly affect cortical mitochondrial function or oxidative injury in the acute setting. Further evaluation of the short and long-term effects of oxygen level titration during pediatric CPB on cortical tissue and other at-risk brain regions are needed, especially in the presence of cyanosis.

Introduction: As the adult Fontan population with Fontan associated liver disease continues to increase, more patients are being referred for transplantation, including combined heart and liver transplantation., Methods: We report updated mortality and morbidity outcomes after combined heart and liver transplant in a retrospective cohort series of 40 patients (age 14 to 49 years) with Fontan circulation across two centers from 2006-2022., Results: The 30-day, 1-year, 5-year and 10-year survival rate was 90%, 80%, 73% and 73% respectively. Sixty percent of patients met a composite comorbidity of needing either post-transplant mechanical circulatory support, renal replacement therapy or tracheostomy. Cardiopulmonary bypass time > 283 min (4.7 h) and meeting the composite comorbidity were associated with mortality by Kaplan Meier analysis., Conclusion: Further study to mitigate early mortality and the above comorbidities as well as the high risk of bleeding and vasoplegia in this patient population is warranted., (© 2024 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Objectives: The primary objectives were to examine utilization of the Hybrid versus the Norwood procedure for patients with hypoplastic left heart syndrome or variants and the impact on hospital mortality. The Hybrid procedure was 1st used at our institution in 2004., Methods: Review of all subjects undergoing the Norwood or Hybrid procedure between 1 January 1984 and 31 December 2022. The study period was divided into 8 eras: era 1, 1984-1988; era 2, 1989-1993; era 3, 1994-1998; era 4, 1999-2003; era 5, 2004-2008; era 6, 2009-2014; era 7, 2015-2018 and era 8, 2019-2022. The primary outcome was in-hospital mortality. Mortality rates were computed using standard binomial proportions with 95% confidence intervals. Rates across eras were compared using an ordered logistic regression model with and adjusted using the Tukey-Kramer post-hoc procedure for multiple comparisons. In the risk-modelling phase, logistic regression models were specified and tested., Results: The Norwood procedure was performed in 1899 subjects, and the Hybrid procedure in 82 subjects. Use of the Hybrid procedure increased in each subsequent era, reaching 30% of subjects in era 8. After adjustment for multiple risk factors, use of the Hybrid procedure was significantly and positively associated with hospital mortality., Conclusions: Despite the increasing use of the Hybrid procedure, overall mortality for the entire cohort has plateaued. After adjustment for risk factors, use of the Hybrid procedure was significantly and positively associated with mortality compared to the Norwood procedure., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.)

Background: Pediatric pulmonary embolism (PE) is rare and potentially life-threatening. Though thrombolysis and thrombectomy are increasingly used in adult PE, trends in pediatric treatment and outcomes remain incompletely described., Objectives: The purpose of this study was to describe the incidence of PE, proportion of cases treated with anticoagulation alone, systemic thrombolysis, and directed therapy (local thrombolysis and thrombectomy), clinical outcomes, and total costs., Methods: A multicenter observational study was performed using administrative data from the Pediatric Health Information System database to study PE treated at U.S. pediatric hospitals from 2015 to 2021. Outcomes by treatment were evaluated using multivariable generalized linear mixed effects models., Results: Of 3,136 subjects, 70% were at least 12 years of age, and 46% were male. Sixty-two percent had at least 1 comorbidity, and congenital heart disease of any kind was the most prevalent (20%). Eighty-eight percent of subjects received anticoagulation alone, 7% received systemic thrombolysis, and 5% received directed therapy. Overall in-hospital mortality was 7.5%. Treatment approach did not change over time ( P  = 0.98). After adjusting for patient characteristics, directed therapy was associated with a lower risk of mortality (adjusted percentage -3%, [95% CI: -5% to 0%]) than anticoagulation alone. Systemic thrombolysis was associated with a greater total cost of hospitalization ($113,043 greater [95% CI: $62,866, $163,219]). Length of hospital stay did not differ by treatment., Conclusions: Pediatric patients with PE have a high incidence of underlying chronic disease. Anticoagulation alone remains the mainstay of treatment, with thrombolysis and thrombectomy rarely being used. Given the relative rarity of pediatric PE, additional research requiring innovative study designs is paramount., Competing Interests: The current study used resources from the Children's Hospital of Philadelphia Cardiac Center Clinical Research Core. Dr Raffini has received consulting fees from Boehringer Ingelheim, Genentech, and CSL Behring. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.PERSPECTIVESCOMPETENCY IN MEDICAL KNOWLEDGE 1: Most pediatric patients with PE have at least 1 chronic disease, of which cardiac disease is the most common. COMPETENCY IN MEDICAL KNOWLEDGE 2: Most pediatric patients with PE are treated with anticoagulation, though the choice of anticoagulation has shifted over time. COMPETENCY IN PATIENT CARE: Though most pediatric patients with PE are treated with anticoagulation, thrombolysis and thrombectomy must also be considered as treatment modalities. TRANSLATIONAL OUTLOOK: Though anticoagulation is the mainstay of pediatric PE treatment, better delineation of which patients may benefit from thrombolysis or thrombectomy is necessary., (© 2024 The Authors.)

Competing Interests: The authors reported no conflicts of interest. The Journal policy requires editors and reviewers to disclose conflicts of interest and to decline handling manuscripts for which they may have a conflict of interest. The editors and reviewers of this article have no conflicts of interest.

Introduction: Carbon monoxide (CO) is a colorless and odorless gas that is a leading cause of environmental poisoning in the USA with substantial mortality and morbidity. The mechanism of CO poisoning is complex and includes hypoxia, inflammation, and leukocyte sequestration in brain microvessel segments leading to increased reactive oxygen species. Another important pathway is the effects of CO on the mitochondria, specifically at cytochrome c oxidase, also known as Complex IV (CIV). One of the glaring gaps is the lack of rigorous experimental models that may recapitulate survivors of acute CO poisoning in the early phase. The primary objective of this preliminary study is to use our advanced swine platform of acute CO poisoning to develop a clinically relevant survivor model to perform behavioral assessment and MRI imaging that will allow future development of biomarkers and therapeutics., Methods: Four swine (10 kg) were divided into two groups: control (n = 2) and CO (n = 2). The CO group received CO at 2000 ppm for over 120 min followed by 30 min of re-oxygenation at room air for one swine and 150 min followed by 30 min of re-oxygenation for another swine. The two swine in the sham group received room air for 150 min. Cerebral microdialysis was performed to obtain semi real-time measurements of cerebral metabolic status. Following exposures, all surviving animals were observed for a 24-h period with neurobehavioral assessment and imaging. At the end of the 24-h period, fresh brain tissue (cortical and hippocampal) was immediately harvested to measure mitochondrial respiration., Results: While a preliminary ongoing study, animals in the CO group showed alterations in cerebral metabolism and cellular function in the acute exposure phase with possible sustained mitochondrial changes 24 h after the CO exposure ended., Conclusions: This preliminary research further establishes a large animal swine model investigating survivors of CO poisoning to measure translational metrics relevant to clinical medicine that includes a basic neurobehavioral assessment and post exposure cellular measures., (© 2023. American College of Medical Toxicology.)

Background: Children undergoing orthotopic heart transplant (OHT) may require complex reconstruction of superior vena cava (SVC) anomalies. SVC anatomy and mode of reconstruction are potential risk factors for SVC obstruction., Methods: A retrospective single-center review was conducted of patients undergoing initial OHT between January 1, 1990, and July 1, 2021. Simple SVC anatomy included a single right SVC to the right atrium or bilateral SVCs with a left SVC to an intact coronary sinus, without prior superior cavopulmonary connection. Presence of anomalous SVC anatomy, superior cavopulmonary connection, or previous atrial switch operation defined complex anatomy. Reconstructive strategies included atrial anastomosis; direct SVC-to-SVC anastomosis; and augmented SVC anastomosis using innominate vein, patch, cavopulmonary connection, or interposition graft. The primary outcome was reintervention for SVC obstruction., Results: Of 288 patients, pretransplant diagnoses included congenital heart disease (n = 155 [54%]), cardiomyopathy (n = 125 [43%]), and other (n = 8 [3%]). Most (n = 208 [72%]) had simple SVC anatomy compared with complex SVC anatomy (80 [28%]). Reintervention for SVC obstruction occurred in 15 of 80 (19%) with complex anatomy and 1 of 208 (0.5%) with simple anatomy (P = .0001). Reintervention was more common when innominate vein or a patch was used (9/25 [36%]) compared with an interposition graft (1/7 [14%]) or direct anastomosis (6/82 [7%]; χ 2  = 13.1; P = .001). Most reinterventions occurred within 30 days of OHT (14/16 [88%])., Conclusions: Patients with complex SVC anatomy have a higher rate of reintervention for SVC obstruction after OHT compared with those with simple SVC anatomy. In cases of complex SVC anatomy, interposition grafts may be associated with less reintervention compared with complex reconstructions using donor tissue., (Copyright © 2024 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

We report a case of hypoplastic left heart syndrome and with subsequent aortopathy and then found to have hereditary haemorrhagic telangiectasia/juvenile polyposis syndrome due to a germline SMAD4 pathologic variant. The patient's staged palliation was complicated by the development of neoaortic aneurysms, arteriovenous malformations, and gastrointestinal bleeding thought to be secondary to Fontan circulation, but workup revealed a SMAD4 variant consistent with hereditary haemorrhagic telangiectasia/juvenile polyposis syndrome. This case underscores the importance of genetic modifiers in CHD, especially those with Fontan physiology.

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 (CMRO 2 ) 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 CMRO 2 relative to baseline at CPB initiation; following correction, CMRO 2 did not differ from baseline at this timepoint. After CPB initiation, OEF increased but CBF and CMRO 2 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.

Background: Infants with single ventricle heart disease and severe atrioventricular valve regurgitation have poor outcomes following conventional staged palliation. As such, ventricular assist device (VAD) placement along with hybrid stage 1 palliation has been proposed as a bridge to heart transplant. We present a novel surgical technique for VAD implantation concurrent with hybrid stage 1 that avoids cardiopulmonary bypass., Methods: We performed a retrospective review of our institutional experience with this novel surgical technique., Results: Three patients (weight, 2.7-3.5 kg; age, 3 to 5 days) underwent hybrid stage 1 with VAD placement, consisting of bilateral 3.5-mm expandable polytetrafluoroethylene (PTFE) pulmonary artery bands, a ductal stent, a 6-mm Berlin Heart outflow cannula onto the main pulmonary trunk with a 10-mm graft, a 6-mm Berlin Heart outflow cannula onto the right atrium, and a 10-mL Berlin Heart pump. In patients with severe aortic arch hypoplasia or coarctation, a 4-mm PTFE graft was sewn from the VAD outflow graft to the innominate artery to protect coronary and cerebral perfusion. Procedures were performed off bypass with minimal blood product use. Patients were extubated on postoperative days 2, 2, and 5. There were no procedural complications. All patients were transferred out of the intensive care unit and demonstrated appropriate weight gain. Anticoagulation strategy was bivalirudin and antiplatelet therapy. The patients underwent transplantation after 149 days, 157 days, and 288 days of support., Conclusions: Off-pump single ventricle VAD placement is technically feasible and can be done at the time of hybrid stage 1 palliation with minimal operative morbidity as a bridge to transplant., Competing Interests: Dr Rossano has served as a consultant for Bayer, Merck, Bristol Myers Squibb, and AskBio. Dr Maeda reported serving as a surgical consultant for Berlin Heart, Abbott Laboratories, and PECA Labs. All other authors reported no conflicts of interest. The Journal policy requires editors and reviewers to disclose conflicts of interest and to decline handling or reviewing manuscripts for which they may have a conflict of interest. The editors and reviewers of this article have no conflicts of interest., (© 2023 The Author(s).)

Objectives: Historically, our center has primarily used deep hypothermic circulatory arrest, but in recent years some surgeons have selectively used regional cerebral perfusion as an alternative. We aimed to compare the incidence of postoperative electroencephalographic seizure incidence in neonates undergoing surgery with regional cerebral perfusion and deep hypothermic circulatory arrest., Methods: A retrospective analysis was performed in neonates who underwent surgery between 2012 and 2022 with either deep hypothermic circulatory arrest or regional cerebral perfusion with routine postoperative continuous electroencephalography monitoring for 48 hours. Propensity matching was performed to compare postoperative seizure risk between the 2 groups., Results: Among 1136 neonates undergoing cardiac surgery with cardiopulmonary bypass, regional cerebral perfusion was performed in 99 (8.7%) and deep hypothermic circulatory arrest in 604 (53%). The median duration of regional cerebral perfusion was 49 minutes (interquartile range, 38-68) and deep hypothermic circulatory arrest was 41 minutes (interquartile range, 31-49). The regional cerebral perfusion group had significantly longer total support, cardiopulmonary bypass, and aortic crossclamp times. Overall seizure incidence was 11% (N = 76) and 13% (N = 35) in the most recent era (2019-2022). The unadjusted seizure incidence was similar in neonates undergoing regional cerebral perfusion (N = 12, 12%) and deep hypothermic circulatory arrest (N = 64, 11%). After propensity matching, the seizure incidence was similar in neonates undergoing regional cerebral perfusion (N = 12, 12%) and deep hypothermic circulatory arrest (N = 37, 12%) (odds ratio, 0.97; 95% CI, 0.55-1.71; P = . 92)., Conclusions: In this contemporary single-center experience, the incorporation of regional cerebral perfusion did not result in a change in seizure incidence in comparison with deep hypothermic circulatory arrest. However, unmeasured confounders may have impacted these findings. Further studies are needed to determine the impact, if any, of regional cerebral perfusion on postoperative seizure incidence., Competing Interests: The authors reported no conflicts of interest. The Journal policy requires editors and reviewers to disclose conflicts of interest and to decline handling or reviewing manuscripts for which they may have a conflict of interest. The editors and reviewers of this article have no conflicts of interest., (© 2023 The Author(s).)

Objectives: Recent research suggests that increased cerebral oxygen use during surgical intervention for neonates with congenital heart disease may play a role in the development of postoperative white matter injury. The objective of this study is to determine whether increased cerebral electrical activity correlates with greater decrease of cerebral oxygen saturation during deep hypothermic circulatory arrest., Methods: Neonates with critical congenital heart disease requiring surgical intervention during the first week of life were studied. All subjects had continuous neuromonitoring with electroencephalography and an optical probe (to quantify cerebral oxygen saturation) during cardiac surgical repair that involved the use of cardiopulmonary bypass and deep hypothermic circulatory arrest. A simple linear regression was used to investigate the association between electroencephalography metrics before the deep hypothermic circulatory arrest period and the change in cerebral oxygen saturation during the deep hypothermic circulatory arrest period., Results: Sixteen neonates had both neuromonitoring modalities attached during surgical repair. Cerebral oxygen saturation data from 5 subjects were excluded due to poor data quality, yielding a total sample of 11 neonates. A simple linear regression model found that the presence of electroencephalography activity at the end of cooling is positively associated with the decrease in cerebral oxygen saturation that occurs during deep hypothermic circulatory arrest ( P  < .05)., Conclusions: Electroencephalography characteristics within 5 minutes before the initiation of deep hypothermic circulatory arrest may be useful in predicting the decrease in cerebral oxygen saturation that occurs during deep hypothermic circulatory arrest. Electroencephalography may be an important tool for guiding cooling and the initiation of circulatory arrest to potentially decrease the prevalence of new white matter injury in neonates with critical congenital heart disease., (© 2023 The Author(s).)

Background: Surgical procedures involving the aortic arch present unique challenges to maintaining cerebral perfusion, and optimal neuroprotective strategies to prevent neurological injury during such high-risk procedures are not completely understood. The use of antegrade cerebral perfusion (ACP) has gained favor as a neuroprotective strategy over deep hypothermic circulatory arrest (DHCA) due to the ability to selectively perfuse the brain. Despite this theoretical advantage over DHCA, there has not been conclusive evidence that ACP is superior to DHCA. One potential reason for this is the incomplete understanding of ideal ACP flow rates to prevent both ischemia from underflowing and hyperemia and cerebral edema from overflowing. Critically, there are no continuous, noninvasive measurements of cerebral blood flow (CBF) and cerebral oxygenation (StO 2 ) to guide ACP flow rates and help develop standard clinical practices. The purpose of this study is to demonstrate the feasibility of using noninvasive, diffuse optical spectroscopy measurements of CBF and cerebral oxygenation during the conduct of ACP in human neonates undergoing the Norwood procedure., Methods: Four neonates prenatally diagnosed with hypoplastic left heart syndrome (HLHS) or a similar variant underwent the Norwood procedure with continuous intraoperative monitoring of CBF and cerebral oxygen saturation (StO 2 ) using two non-invasive optical techniques, namely diffuse correlation spectroscopy (DCS) and frequency-domain diffuse optical spectroscopy (FD-DOS). Changes in CBF and StO 2 due to ACP were calculated by comparing these parameters during a stable 5 min period of ACP to the last 5 min of full-body CPB immediately prior to ACP initiation. Flow rates for ACP were left to the discretion of the surgeon and ranged from 30 to 50 ml/kg/min, and all subjects were cooled to 18°C prior to initiation of ACP., Results: During ACP, the continuous optical monitoring demonstrated a median (IQR) percent change in CBF of -43.4% (38.6) and a median (IQR) absolute change in StO 2 of -3.6% (12.3) compared to a baseline period during full-body cardiopulmonary bypass (CPB). The four subjects demonstrated varying responses in StO 2 due to ACP. ACP flow rates of 30 and 40 ml/kg/min ( n  = 3) were associated with decreased CBF during ACP compared to full-body CPB. Conversely, one subject with a higher flow6Di rate of 50 ml/kg/min demonstrated increased CBF and StO 2 during ACP., Conclusions: This feasibility study demonstrates that novel diffuse optical technologies can be utilized for improved neuromonitoring in neonates undergoing cardiac surgery where ACP is utilized. Future studies are needed to correlate these findings with neurological outcomes to inform best practices during ACP in these high-risk neonates., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2023 Shaw, Mavroudis, Ko, Jahnavi, Jacobwitz, Ranieri, Forti, Melchior, Baker, Yodh, Licht, Nicolson and Lynch.)

Cardiac surgery utilizing circulatory arrest is most commonly performed under deep hypothermia (∼18°C) to suppress tissue oxygen demand and provide neuroprotection during operative circulatory arrest. Studies investigating the effects of deep hypothermic circulatory arrest (DHCA) on neurodevelopmental outcomes of patients with congenital heart disease give conflicting results. Here, we address these issues by quantifying changes in cerebral oxygen saturation, blood flow, and oxygen metabolism in neonates during DHCA and investigating the association of these changes with postoperative brain injury. Neonates with critical congenital heart disease undergoing DHCA were recruited for continuous intraoperative monitoring of cerebral oxygen saturation (ScO 2 ) and an index of cerebral blood flow (CBF i ) using 2 noninvasive optical techniques, diffuse optical spectroscopy (DOS) and diffuse correlation spectroscopy (DCS). Pre- and postoperative brain magnetic resonance imaging (MRI) was performed to detect white matter injury (WMI). Fifteen neonates were studied, and 11/15 underwent brain MRI. During DHCA, ScO 2 decreased exponentially in time with a median decay rate of -0.04 min -1 . This decay rate was highly variable between subjects. Subjects who had larger decreases in ScO 2 during DHCA were more likely to have postoperative WMI (P = 0.02). Cerebral oxygen extraction persists during DHCA and varies widely from patient-to-patient. Patients with a higher degree of oxygen extraction during DHCA were more likely to show new WMI in postoperative MRI. These findings suggest cerebral oxygen extraction should be monitored during DHCA to identify patients at risk for hypoxic-ischemic injury, and that current commercial cerebral oximeters may underestimate cerebral oxygen extraction., (Copyright © 2021 Elsevier Inc. All rights reserved.)

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 (StO 2 ), 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.

Introduction: Carbon monoxide (CO) is a colorless and odorless gas that is a leading cause of environmental poisoning in the USA with substantial mortality and morbidity. The mechanism of CO poisoning is complex and includes hypoxia, inflammation, and leukocyte sequestration in brain microvessel segments leading to increased reactive oxygen species. Another important pathway is the effects of CO on the mitochondria, specifically at cytochrome c oxidase, also known as Complex IV (CIV). The purpose of this ongoing study is the preliminary development of a porcine model of CO poisoning for investigation of alterations in brain mitochondrial physiology., Methods: Four pigs (10 kg) were divided into two groups: Sham (n = 2) and CO (n = 2). Administration of a dose of CO at 2000 ppm to the CO group over 120 minutes followed by 30 minutes of re-oxygenation at room air. The control group received room air for 150 minutes. Non-invasive optical monitoring was used to measure CIV redox states. Cerebral microdialysis was performed to obtain semi real-time measurements of cerebral metabolic status. At the end of the exposure, fresh brain tissue (cortical and hippocampal) was immediately harvested to measure mitochondrial respiration. Snap frozen cortical tissue was also used for ATP concentrations and western blotting., Results: While a preliminary ongoing study, animals in the CO group showed possible early decreases in brain mitochondrial respiration, citrate synthase density, CIV redox changes measured with optics, and an increase in the lactate-to-pyruvate ratio., Conclusions: There is a possible observable phenotype highlighting the important role of mitochondrial function in the injury of CO poisoning., (© 2022. American College of Medical Toxicology.)

Objective: The effect of cardiac arrest (CA) on cerebral transcriptomics and metabolomics is unknown. We previously demonstrated hemodynamic-directed CPR (HD-CPR) improves survival with favorable neurologic outcomes versus standard CPR (Std-CPR). We hypothesized HD-CPR would preserve the cerebral transcriptome and metabolome compared to Std-CPR., Design: Randomized pre-clinical animal trial., Setting: Large animal resuscitation laboratory at an academic children's hospital., Subjects: Four-week-old female piglets (8-11 kg)., Interventions: Pigs (1-month-old), three groups: 1) HD-CPR (compression depth to systolic BP 90 mmHg, vasopressors to coronary perfusion pressure 20 mmHg); 2) Std-CPR and 3) shams (no CPR). HD-CPR and Std-CPR underwent asphyxia, induced ventricular fibrillation, 10-20 min of CPR and post-resuscitation care. Primary outcomes at 24 h in cerebral cortex: 1) transcriptomic analysis (n = 4 per treatment arm, n = 8 sham) of 1727 genes using differential gene expression and 2) metabolomic analysis (n = 5 per group) of 27 metabolites using one-way ANOVA, post-hoc Tukey HSD., Measurements and Main Results: 65 genes were differentially expressed between HD-CPR and Std-CPR and 72 genes between Std-CPR and sham, but only five differed between HD-CPR and sham. Std-CPR increased the concentration of five AA compared to HD-CPR and sham, including the branched chain amino acids (BCAA), but zero metabolites differed between HD-CPR and sham., Conclusions: In cerebral cortex 24 h post CA, Std-CPR resulted in a different transcriptome and metabolome compared with either HD-CPR or sham. HD-CPR preserves the transcriptome and metabolome, and is neuroprotective. Global molecular analyses may be a novel method to assess efficacy of clinical interventions and identify therapeutic targets., Institutional Protocol Number: IAC 16-001023., (© 2022 The Author(s).)

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., (© 2021. The Author(s).)

The risk of redo sternotomy is greatly elevated in the setting of aortic proximity to the sternum. Current strategies to avoid catastrophic neurologic injury upon sternal reentry include establishment of peripheral bypass with the use of deep hypothermia and low-flow bypass, both of which may increase risk of neurologic complications. Here, we describe a technique for safe sternal reentry and illustrate its successful use in a patient with close proximity of the aorta to the sternum. With this technique, peripheral cardiopulmonary bypass is established prior to sternal reentry via cannulation of the right axillary artery and femoral vein, and the patient is cooled as the innominate artery is dissected, mobilized, and controlled. This permits the rapid institution of selective antegrade cerebral perfusion (SACP) in the event of aortic injury during sternal reentry. Once the innominate artery is isolated and SACP is initiated, one can safely complete the redo sternotomy, dissection, and distal ascending aortic cross-clamping to continue the operation without interruption in cerebral blood flow. This technique offers a safe approach in select patients and should be utilized in similar high-risk cases.

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., (Copyright © 2020 The American Association for Thoracic Surgery. Published by Elsevier Inc. All rights reserved.)

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., (© The Author(s) 2020. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.)

Aim: Inhaled nitric oxide (iNO) during cardiopulmonary resuscitation (CPR) improved systemic hemodynamics and outcomes in a preclinical model of adult in-hospital cardiac arrest (IHCA) and may also have a neuroprotective role following cardiac arrest. The primary objectives of this study were to determine if iNO during CPR would improve cerebral hemodynamics and mitochondrial function in a pediatric model of lipopolysaccharide-induced shock-associated IHCA., Methods: After lipopolysaccharide infusion and ventricular fibrillation induction, 20 1-month-old piglets received hemodynamic-directed CPR and were randomized to blinded treatment with or without iNO (80 ppm) during and after CPR. Defibrillation attempts began at 10 min with a 20-min maximum CPR duration. Cerebral tissue from animals surviving 1-h post-arrest underwent high-resolution respirometry to evaluate the mitochondrial electron transport system and immunohistochemical analyses to assess neuropathology., Results: During CPR, the iNO group had higher mean aortic pressure (41.6 ± 2.0 vs. 36.0 ± 1.4 mmHg; p = 0.005); diastolic BP (32.4 ± 2.4 vs. 27.1 ± 1.7 mmHg; p = 0.03); cerebral perfusion pressure (25.0 ± 2.6 vs. 19.1 ± 1.8 mmHg; p = 0.02); and cerebral blood flow relative to baseline (rCBF: 243.2 ± 54.1 vs. 115.5 ± 37.2%; p = 0.02). Among the 8/10 survivors in each group, the iNO group had higher mitochondrial Complex I oxidative phosphorylation in the cerebral cortex (3.60 [3.56, 3.99] vs. 3.23 [2.44, 3.46] pmol O 2 /s mg; p = 0.01) and hippocampus (4.79 [4.35, 5.18] vs. 3.17 [2.75, 4.58] pmol O 2 /s mg; p = 0.02). There were no other differences in mitochondrial respiration or brain injury between groups., Conclusions: Treatment with iNO during CPR resulted in superior systemic hemodynamics, rCBF, and cerebral mitochondrial Complex I respiration in this pediatric cardiac arrest model., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Objective: Cerebral mitochondrial dysfunction is a key mediator of neurologic injury following cardiac arrest (CA) and is regulated by the balance of fusion and fission (mitochondrial dynamics). Under stress, fission can decrease mitochondrial mass and signal apoptosis, while fusion promotes oxidative phosphorylation efficiency. This study evaluates mitochondrial dynamics and content in brain tissue 24 h after CA between two cardiopulmonary resuscitation (CPR) strategies., Interventions: Piglets (1 month), previously randomized to three groups: (1) Std-CPR (n = 5); (2) HD-CPR (n = 5; goal systolic blood pressure 90 mmHg, goal coronary perfusion pressure 20 mmHg); (3) Shams (n = 7). Std-CPR and HD-CPR groups underwent 7 min of asphyxia, 10 min of CPR, and standardized post-resuscitation care. Primary outcomes: (1) cerebral cortical mitochondrial protein expression for fusion (OPA1, OPA1 long to short chain ratio, MFN2) and fission (DRP1, FIS1), and (2) mitochondrial mass by citrate synthase activity. Secondary outcomes: (1) intra-arrest haemodynamics and (2) cerebral performance category (CPC) at 24 h., Results: HD-CPR subjects had higher total OPA1 expression compared to Std-CPR (1.52; IQR 1.02-1.69 vs 0.67; IQR 0.54-0.88, p = 0.001) and higher OPA1 long to short chain ratio than both Std-CPR (0.63; IQR 0.46-0.92 vs 0.26; IQR 0.26-0.31, p = 0.016) and shams. Citrate synthase activity was lower in Std-CPR than sham (11.0; IQR 10.15-12.29 vs 13.4; IQR 12.28-15.66, p = 0.047), but preserved in HD-CPR. HD-CPR subjects had improved intra-arrest haemodynamics and CPC scores at 24 h compared to Std-CPR., Conclusions: Following asphyxia-associated CA, HD-CPR exhibits increased pro-mitochondrial fusion protein expression, preservation of mitochondrial mass, improved haemodynamics and superior neurologic scoring compared to Std-CPR., Institutional Protocol Number: IAC 16-001023., (© 2021 The Authors.)

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 ([HbO 2 ], [Hb]), oxygen saturation (StO 2 ) 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 (J w , 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), [HbO 2 ], StO 2 and THC from baseline were significantly different in ROSC versus No-ROSC subjects (p < 0.01) after 10 min of CPR. Change in [HbO 2 ] 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.

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.

Aim: Compare vasopressin to a second dose of epinephrine as rescue therapy after ineffective initial doses of epinephrine in diverse models of pediatric in-hospital cardiac arrest., Methods: 67 one- to three-month old female swine (10-30 kg) in six experimental cohorts from one laboratory received hemodynamic-directed CPR, a resuscitation method where high quality chest compressions are provided and vasopressor administration is titrated to coronary perfusion pressure (CoPP) ≥20 mmHg. Vasopressors are given when CoPP is <20 mmHg, in sequences of two doses of 0.02 mg/kg epinephrine separated by minimum one-minute, then a rescue dose of 0.4 U/kg vasopressin followed by minimum two-minutes. Invasive measurements were used to evaluate and compare the hemodynamic and neurologic effects of each vasopressor dose., Results: Increases in CoPP and cerebral blood flow (CBF) were greater with vasopressin rescue than epinephrine rescue (CoPP: +8.16 [4.35, 12.06] mmHg vs. + 5.43 [1.56, 9.82] mmHg, p = 0.02; CBF: +14.58 [-0.05, 38.12] vs. + 0.00 [-0.77, 18.24] perfusion units (PFU), p = 0.005). Twenty animals (30%) failed to achieve CoPP ≥20 mmHg after two doses of epinephrine; 9/20 (45%) non-responders achieved CoPP ≥20 mmHg after vasopressin. Among all animals, the increase in CBF was greater with vasopressin (+14.58 [-0.58, 38.12] vs. 0.00 [-0.77, 18.24] PFU, p = 0.005)., Conclusions: CoPP and CBF rose significantly more after rescue vasopressin than after rescue epinephrine. Importantly, CBF increased after vasopressin rescue, but not after epinephrine rescue. In the 30% that failed to meet CoPP of 20 mmHg after two doses of epinephrine, 45% achieved target CoPP with a single rescue vasopressin dose., (© 2020 The Authors.)

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 [PbtO 2 ]) 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.

Background Hyperoxia during cardiopulmonary resuscitation (CPR) may lead to oxidative injury from mitochondrial-derived reactive oxygen species, despite guidelines recommending 1.0 inspired oxygen during CPR. We hypothesized exposure to 1.0 inspired oxygen during CPR would result in cerebral hyperoxia, higher mitochondrial-derived reactive oxygen species, increased oxidative injury, and similar survival compared with those exposed to 21% oxygen. Methods and Results Four-week-old piglets (n=25) underwent asphyxial cardiac arrest followed by randomization and blinding to CPR with 0.21 (n=10) or 1.0 inspired oxygen (n=10) through 10 minutes post return of spontaneous circulation. Sham was n=5. Survivors received 4 hours of protocolized postarrest care, whereupon brain was obtained for mitochondrial analysis and neuropathology. Groups were compared using Kruskal-Wallis test, Wilcoxon rank-sum test, and generalized estimating equations regression models. Both 1.0 and 0.21 groups were similar in systemic hemodynamics and cerebral blood flow, as well as survival (8/10). The 1.0 animals had relative cerebral hyperoxia during CPR and immediately following return of spontaneous circulation (brain tissue oxygen tension, 85% [interquartile range, 72%-120%] baseline in 0.21 animals versus 697% [interquartile range, 515%-721%] baseline in 1.0 animals; P =0.001 at 10 minutes postarrest). Cerebral mitochondrial reactive oxygen species production was higher in animals treated with 1.0 compared with 0.21 ( P <0.03). Exposure to 1.0 oxygen led to increased cerebral oxidative injury to proteins and lipids, as evidenced by significantly higher protein carbonyls and 4-hydroxynoneals compared with 0.21 ( P <0.05) and sham ( P <0.001). Conclusions Exposure to 1.0 inspired oxygen during CPR caused cerebral hyperoxia during resuscitation, and resultant increased mitochondrial-derived reactive oxygen species and oxidative injury following cardiac arrest.

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 ( CMRO 2 ). 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 CMRO 2 were acquired. Significant hysteresis ( p  < 0.001) between cooling and rewarming periods in the NPT versus ICT and NPT versus CMRO 2 relationships were found. Resolution of this hysteresis in the ICT versus CMRO 2 relationship identified a crucial insufficiency of conventional NPT guidance. Non-invasive CMRO 2 temperature coefficients with respect to NPT ( Q 10  = 2.0) and ICT ( Q 10  = 2.5) are consistent with previous reports and provide further validation of FD-DOS/DCS CMRO 2 monitoring during DH CPB to optimize management.

Objectives: Less than half of the thousands of children who suffer in-hospital cardiac arrests annually survive, and neurologic injury is common among survivors. Hemodynamic-directed cardiopulmonary resuscitation improves short-term survival, but its impact on longer term survival and mitochondrial respiration-a potential neurotherapeutic target-remains unknown. The primary objectives of this study were to compare rates of 24-hour survival with favorable neurologic outcome after cardiac arrest treated with hemodynamic-directed cardiopulmonary resuscitation versus standard depth-guided cardiopulmonary resuscitation and to compare brain and heart mitochondrial respiration between groups 24 hours after resuscitation., Design: Randomized preclinical large animal trial., Setting: A large animal resuscitation laboratory at a large academic children's hospital., Subjects: Twenty-eight 4-week-old female piglets (8-11 kg)., Interventions: Twenty-two swine underwent 7 minutes of asphyxia followed by ventricular fibrillation and randomized treatment with either hemodynamic-directed cardiopulmonary resuscitation (n = 10; compression depth titrated to aortic systolic pressure of 90 mm Hg, vasopressors titrated to coronary perfusion pressure ≥ 20 mm Hg) or depth-guided cardiopulmonary resuscitation (n = 12; depth 1/3 chest diameter, epinephrine every 4 min). Six animals (sham group) underwent anesthesia and instrumentation without cardiac arrest. The primary outcomes were favorable neurologic outcome (swine Cerebral Performance Category ≤ 2) and mitochondrial maximal oxidative phosphorylation utilizing substrate for complex I and complex II (OXPHOSCI+CII) in the cerebral cortex and hippocampus., Measurements and Main Results: Favorable neurologic outcome was more likely with hemodynamic-directed cardiopulmonary resuscitation (7/10) than depth-guided cardiopulmonary resuscitation (1/12; p = 0.006). Hemodynamic-directed cardiopulmonary resuscitation resulted in higher intra-arrest coronary perfusion pressure, aortic pressures, and brain tissue oxygenation. Hemodynamic-directed cardiopulmonary resuscitation resulted in higher OXPHOSCI+CII (pmol oxygen/s × mg/citrate synthase) in the cortex (6.00 ± 0.28 vs 3.88 ± 0.43; p < 0.05) and hippocampus (6.26 ± 0.67 vs 3.55 ± 0.65; p < 0.05) and higher complex I respiration (pmol oxygen/s × mg) in the right (20.62 ± 1.06 vs 15.88 ± 0.81; p < 0.05) and left ventricles (20.14 ± 1.40 vs 14.17 ± 1.53; p < 0.05)., Conclusions: In a model of asphyxia-associated pediatric cardiac arrest, hemodynamic-directed cardiopulmonary resuscitation increases rates of 24-hour survival with favorable neurologic outcome, intra-arrest hemodynamics, and cerebral and myocardial mitochondrial respiration.

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., (Copyright © 2018 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

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.

Rationale: Many in-hospital cardiac arrests are precipitated by hypotension, often associated with systemic inflammation. These patients are less likely to be successfully resuscitated, and novel approaches to their treatment are needed., Objectives: To determine if the addition of inhaled nitric oxide (iNO) to hemodynamic-directed cardiopulmonary resuscitation (HD-CPR) would improve short-term survival from cardiac arrest associated with shock and systemic inflammation., Methods: In 3-month-old swine (n = 21), LPS was intravenously infused, inducing systemic hypotension. Ventricular fibrillation was induced, and animals were randomized to blinded treatment with either: 1) HD-CPR with iNO, or 2) HD-CPR without iNO. During HD-CPR, chest compression depth was titrated to peak aortic compression pressure of 100 mm Hg, and vasopressor administration was titrated to coronary perfusion pressure greater than or equal to 20 mm Hg. Defibrillation attempts began after 10 minutes of resuscitation. The primary outcome was 45-minute survival., Measurements and Main Results: The iNO group had higher rates of 45-minute survival (10 of 10 vs. 3 of 11; P = 0.001). During cardiopulmonary resuscitation, the iNO group had lower pulmonary artery relaxation pressure (mean ± SEM, 10.9 ± 2.4 vs. 18.4 ± 2.4 mm Hg; P = 0.03), higher coronary perfusion pressure (21.1 ± 1.5 vs. 16.9 ± 1.0 mm Hg; P = 0.005), and higher aortic relaxation pressure (36.6 ± 1.6 vs. 30.4 ± 1.1 mm Hg; P < 0.001) despite shallower chest compressions (5.88 ± 0.25 vs. 6.46 ± 0.40 cm; P = 0.02) and fewer vasopressor doses in the first 10 minutes (median, 4 [interquartile range, 3-4] vs. 5 [interquartile range, 5-6], P = 0.03)., Conclusions: The addition of iNO to HD-CPR in LPS-induced shock-associated cardiac arrest improved short-term survival and intraarrest hemodynamics.

Background: Surgeons in training for congenital cardiac surgery face considerable challenges owing to procedure complexity, closely scrutinized outcomes, and a steep learning curve. Simulation methods have been initiated in other surgical specialties, but have yet to be established for congenital cardiac surgery trainees. The purpose of this study was to assess high-fidelity simulation as a method to train and improve skills of resident trainees learning critical components of index congenital cardiac surgical procedures., Methods: Using 5 neonatal piglets over a period of 2.5 days, the following procedures were simulated: Norwood procedure, arterial switch operation, neonatal Ross procedure, tetralogy of Fallot repair, systemic to pulmonary artery shunt procedures, transmediastinal coarctation repair, atrial septal defect repair, ventricular septal defect repair, and right ventricular to pulmonary artery conduit. Anastomoses were tested with saline, all procedures were timed and video recorded, and resident trainee techniques and skills were critiqued by the instructor., Results: All aspects of the procedures were simulated with minimal modifications. Anastomoses were tested, and the procedure successfully replicated without the pressures of operative time. Operative techniques involving suture placement in neonatal tissue, depth perception, and patch size estimation were corrected in real time, resulting in observed improvement of surgical skills. Video review allowed for further pedagogic value through examination and documentation of competency., Conclusions: This neonatal porcine simulation model allows surgical trainees in congenital heart surgery to make and correct mistakes in a safe and controlled learning environment without compromising patient safety, thereby fostering surgeon competence and confidence., (Copyright © 2018 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Background: We have previously shown that the minor alleles of vascular endothelial growth factor A (VEGFA) single-nucleotide polymorphism rs833069 and superoxide dismutase 2 (SOD2) single-nucleotide polymorphism rs2758331 are both associated with improved transplant-free survival after surgery for CHD in infants, but the underlying mechanisms are unknown. We hypothesised that one or both of these minor alleles are associated with better systemic ventricular function, resulting in improved survival., Methods: This study is a follow-up analysis of 422 non-syndromic CHD patients who underwent neonatal cardiac surgery with cardiopulmonary bypass. Echocardiographic reports were reviewed. Systemic ventricular function was subjectively categorised as normal, or as mildly, moderately, or severely depressed. The change in function was calculated as the change from the preoperative study to the last available study. Stepwise linear regression, adjusting for covariates, was performed for the outcome of change in ventricular function. Model comparison was performed using Akaike's information criterion. Only variables that improved the model prediction of change in systemic ventricular function were retained in the final model., Results: Genetic and echocardiographic data were available for 335/422 subjects (79%). Of them, 33 (9.9%) developed worse systemic ventricular function during a mean follow-up period of 13.5 years. After covariate adjustment, the presence of the VEGFA minor allele was associated with preserved ventricular function (p=0.011)., Conclusions: These data support the hypothesis that the mechanism by which the VEGFA single-nucleotide polymorphism rs833069 minor allele improves survival may be the preservation of ventricular function. Further studies are needed to validate this genotype-phenotype association and to determine whether this mechanism is related to increased vascular endothelial growth factor production.