A cell state-specific metabolic vulnerability to GPX4-dependent ferroptosis in glioblastoma.

Glioma cells hijack developmental programs to control cell state. Here, we uncover a glioma cell state-specific metabolic liability that can be therapeutically targeted. To model cell conditions at brain tumor inception, we generated genetically engineered murine gliomas, with deletion of p53 alone (p53) or with constitutively active Notch signaling (N1IC), a pathway critical in controlling astrocyte differentiation during brain development. N1IC tumors harbored quiescent astrocyte-like transformed cell populations while p53 tumors were predominantly comprised of proliferating progenitor-like cell states. Further, N1IC transformed cells exhibited increased mitochondrial lipid peroxidation, high ROS production and depletion of reduced glutathione. This altered mitochondrial phenotype rendered the astrocyte-like, quiescent populations more sensitive to pharmacologic or genetic inhibition of the lipid hydroperoxidase GPX4 and induction of ferroptosis. Treatment of patient-derived early-passage cell lines and glioma slice cultures generated from surgical samples with a GPX4 inhibitor induced selective depletion of quiescent astrocyte-like glioma cell populations with similar metabolic profiles. Collectively, these findings reveal a specific therapeutic vulnerability to ferroptosis linked to mitochondrial redox imbalance in a subpopulation of quiescent astrocyte-like glioma cells resistant to standard forms of treatment.

Biomarkers of immunotherapy in glioblastoma.

Glioblastoma (GBM) is the most common primary brain cancer, comprising half of all malignant brain tumors. Patients with GBM have a poor prognosis, with a median survival of 14-15 months. Current therapies for GBM, including chemotherapy, radiotherapy, and surgical resection, remain inadequate. Novel therapies are required to extend patient survival. Although immunotherapy has shown promise in other cancers, including melanoma and non-small lung cancer, its efficacy in GBM has been limited to subsets of patients. Identifying biomarkers of immunotherapy response in GBM could help stratify patients, identify new therapeutic targets, and develop more effective treatments. This article reviews existing and emerging biomarkers of clinical response to immunotherapy in GBM. The scope of this review includes immune checkpoint inhibitor and antitumoral vaccination approaches, summarizing the variety of molecular, cellular, and computational methodologies that have been explored in the setting of anti-GBM immunotherapies.

Adverse Technical Events During Aortic Root Replacement.

BACKGROUND: Although adverse technical events during aortic root replacement (ARR) are not uncommon and are extremely challenging, there is scant literature to help surgeons prepare for such situations. We describe our experience of outstanding technical events during ARR. METHODS: This is a retrospective study of 830 consecutive ARRs at a single center from 2012 to 2022. Technical events were defined as intraoperative events that led to an unplanned cardiac procedure, need for mechanical circulatory support, or additional aortic cross-clamping. Logistic regression identified factors associated with operative mortality and technical events. RESULTS: Technical events occurred in 90 patients (10.8%) and were attributed to bleeding (n = 26), nonischemic ventricular dysfunction (n = 23), residual valve disease (n = 20), myocardial ischemia (n = 19), and iatrogenic dissection (n = 2). Prior sternotomy (odds ratio [OR], 2.38; 95% CI, 1.36-4.19; P = .002) and complex aortic valve disease (OR, 3.09; 95% CI, 1.09-8.75; P = .03) were associated with technical events. Patients with technical events had higher rates of operative mortality (6.7% vs 2.3%, P = .03) and all major postoperative complications. Surgical indications of dissection (OR, 13.57; 95% CI, 4.95-37.23; P < .001) and complex aortic valve disease (OR, 14.09; 95% CI, 3.67-54.02; P < .001) but not adverse technical events (OR, 2.42; 95% CI, 0.81-7.26; P = .11) were associated with operative mortality. CONCLUSIONS: Adverse technical events occurred in 10.8% of ARRs and were associated with reoperative sternotomies. Technical events are associated with increased postoperative complications.

Biologically-informed deep neural networks provide quantitative assessment of intratumoral heterogeneity in post-treatment glioblastoma.

Intratumoral heterogeneity poses a significant challenge to the diagnosis and treatment of glioblastoma (GBM). This heterogeneity is further exacerbated during GBM recurrence, as treatment-induced reactive changes produce additional intratumoral heterogeneity that is ambiguous to differentiate on clinical imaging. There is an urgent need to develop non-invasive approaches to map the heterogeneous landscape of histopathological alterations throughout the entire lesion for each patient. We propose to predictively fuse Magnetic Resonance Imaging (MRI) with the underlying intratumoral heterogeneity in recurrent GBM using machine learning (ML) by leveraging image-localized biopsies with their associated locoregional MRI features. To this end, we develop BioNet, a biologically-informed neural network model, to predict regional distributions of three tissue-specific gene modules: proliferating tumor, reactive/inflammatory cells, and infiltrated brain tissue. BioNet offers valuable insights into the integration of multiple implicit and qualitative biological domain knowledge, which are challenging to describe in mathematical formulations. BioNet performs significantly better than a range of existing methods on cross-validation and blind test datasets. Voxel-level prediction maps of the gene modules by BioNet help reveal intratumoral heterogeneity, which can improve surgical targeting of confirmatory biopsies and evaluation of neuro-oncological treatment effectiveness. The non-invasive nature of the approach can potentially facilitate regular monitoring of the gene modules over time, and making timely therapeutic adjustment. These results also highlight the emerging role of ML in precision medicine.

Single-cell analysis of 5-aminolevulinic acid intraoperative labeling specificity for glioblastoma.

OBJECTIVE: Glioblastoma (GBM) is the most common and aggressive malignant primary brain tumor, and resection is a key part of the standard of care. In fluorescence-guided surgery (FGS), fluorophores differentiate tumor tissue from surrounding normal brain. The heme synthesis pathway converts 5-aminolevulinic acid (5-ALA), a fluorogenic substrate used for FGS, to fluorescent protoporphyrin IX (PpIX). The resulting fluorescence is believed to be specific to neoplastic glioma cells, but this specificity has not been examined at a single-cell level. The objective of this study was to determine the specificity with which 5-ALA labels the diversity of cell types in GBM. METHODS: The authors performed single-cell optical phenotyping and expression sequencing-version 2 (SCOPE-seq2), a paired single-cell imaging and RNA sequencing method, of individual cells on human GBM surgical specimens with macroscopically visible PpIX fluorescence from patients who received 5-ALA prior to surgery. SCOPE-seq2 allowed the authors to simultaneously image PpIX fluorescence and unambiguously identify neoplastic cells from single-cell RNA sequencing. Experiments were also conducted in cell culture and co-culture models of glioma and in acute slice cultures from a mouse glioma model to investigate cell- and tissue-specific uptake and secretion of 5-ALA and PpIX. RESULTS: SCOPE-seq2 analysis of human GBM surgical specimens revealed that 5-ALA treatment resulted in labeling that was not specific to neoplastic glioma cells. The cell culture further demonstrated that nonneoplastic cells could be labeled by 5-ALA directly or by PpIX secreted from surrounding neoplastic cells. Acute slice cultures from mouse glioma models showed that 5-ALA preferentially labeled GBM tumor tissue over nonneoplastic brain tissue with significant labeling in the tumor margins, and that this contrast was not due to blood-brain barrier disruption. CONCLUSIONS: Together, these findings support the use of 5-ALA as an indicator of GBM tissue but question the main advantage of 5-ALA for specific intracellular labeling of neoplastic glioma cells in FGS. Further studies are needed to systematically compare the performance of 5-ALA to that of potential alternatives for FGS.

Influence of preoperative and intraoperative factors on recovery after aortic root surgery.

OBJECTIVE: To determine the influence of intraoperative factors relative to preoperative risk factors on recovery after aortic root replacement (ARR). METHODS: Retrospective review of baseline and intraoperative characteristics was performed of 822 patients at our Aortic Center from 2005 to 2019. Inclusion criteria were all patients age 18 and older who underwent ARR at our institution from 2005 to 2019. The primary endpoint was the aggregate outcome of "failure to achieve uneventful recovery (FUR)," as previously defined. RESULTS: In total, 207 (25%) patients experienced FUR. The following preoperative and intraoperative variables were significantly associated with FUR in the multivariable analysis: cardiopulmonary bypass time (OR 1.01, 95% CI 1.01-1.02) open chest management (OR 5.67, 95% CI 2.65-12.1), ejection fraction (OR 1.03, 95% CI 1.01-1.04), chronic kidney disease > stage 3a (OR 2.37, 95% CI 1.54-3.63), bicuspid aortic valve (OR 1.54, 95% CI 1.21-1.96), and female sex (OR 1.30, 95% CI 1.06-1.61). Cardiopulmonary bypass time and open chest management were among the top three partial R2 contributors to the logistic regression model variance. CONCLUSIONS: These findings suggest efficacy in using intraoperative parameters to predict postoperative outcomes after ARR.

Re-Dosing del Nido cardioplegia in adult cardiac surgery: Perfusion characteristics and outcomes--Is there an optimal redosing strategy?

OBJECTIVES: del Nido cardioplegia is utilized for myocardial protection in adult patients undergoing cardiac surgery; however, no standardized re-dosing protocol exists. We describe perfusion characteristics and clinical outcomes in adult cardiac surgery patients who were re-dosed with del Nido cardioplegia. METHODS: Chart review was performed for adult patients undergoing cardiac surgery (specific inclusion/exclusion criteria below) who received exactly two doses of del Nido cardioplegia from 2012 to 2019; n = 542 patients. The main outcome was a composite endpoint comprised of operative mortality, myocardial infarction, post-operative cardiac support device (CSD), and postoperative decrease in ejection fraction (EF), which was analyzed via multivariable logistic regression (MVLR). A secondary analysis evaluated postoperative vasoactive-inotropic scores (VIS) via gamma log link regression (GLLR) as a more physiologic indication of myocardial recovery. RESULTS: MVLR demonstrated that increased total cardiopulmonary bypass (CPB) time was associated with a positive composite outcome (p < .001), whereas time between doses (p = .237) and the volume of each dose was not (p = .626). GLLR also demonstrated that prolonged CBP, decreased EF, congestive heart failure at time of surgery, and low hematocrit at the start of the surgery were all associated with higher VIS. CONCLUSIONS: In this retrospective study, variations in re-dosing strategy for del Nido cardioplegia do not affect postoperative outcomes and increased CPB time is associated with increased operative mortality, myocardial infarction, need for post-operative CSDs, and reduced postoperative EF, and increased VIS, irrespective of the re-dosing strategy. Further studies are warranted to to identify additional patient and operative characteristics that predispose to complications.

Re-convolving the compositional landscape of primary and recurrent glioblastoma reveals prognostic and targetable tissue states.

Glioblastoma (GBM) diffusely infiltrates the brain and intermingles with non-neoplastic brain cells, including astrocytes, neurons and microglia/myeloid cells. This complex mixture of cell types forms the biological context for therapeutic response and tumor recurrence. We used single-nucleus RNA sequencing and spatial transcriptomics to determine the cellular composition and transcriptional states in primary and recurrent glioma and identified three compositional 'tissue-states' defined by cohabitation patterns between specific subpopulations of neoplastic and non-neoplastic brain cells. These tissue-states correlated with radiographic, histopathologic, and prognostic features and were enriched in distinct metabolic pathways. Fatty acid biosynthesis was enriched in the tissue-state defined by the cohabitation of astrocyte-like/mesenchymal glioma cells, reactive astrocytes, and macrophages, and was associated with recurrent GBM and shorter survival. Treating acute slices of GBM with a fatty acid synthesis inhibitor depleted the transcriptional signature of this pernicious tissue-state. These findings point to therapies that target interdependencies in the GBM microenvironment.

Convection-enhanced delivery of immunomodulatory therapy for high-grade glioma.

The prognosis for glioblastoma has remained poor despite multimodal standard of care treatment, including temozolomide, radiation, and surgical resection. Further, the addition of immunotherapies, while promising in a number of other solid tumors, has overwhelmingly failed in the treatment of gliomas, in part due to the immunosuppressive microenvironment and poor drug penetrance to the brain. Local delivery of immunomodulatory therapies circumvents some of these challenges and has led to long-term remission in select patients. Many of these approaches utilize convection-enhanced delivery (CED) for immunological drug delivery, allowing high doses to be delivered directly to the brain parenchyma, avoiding systemic toxicity. Here, we review the literature encompassing immunotherapies delivered via CED-from preclinical model systems to clinical trials-and explore how their unique combination elicits an antitumor response by the immune system, decreases toxicity, and improves survival among select high-grade glioma patients.

Dietary restriction of cysteine and methionine sensitizes gliomas to ferroptosis and induces alterations in energetic metabolism.

Ferroptosis is mediated by lipid peroxidation of phospholipids containing polyunsaturated fatty acyl moieties. Glutathione, the key cellular antioxidant capable of inhibiting lipid peroxidation via the activity of the enzyme glutathione peroxidase 4 (GPX-4), is generated directly from the sulfur-containing amino acid cysteine, and indirectly from methionine via the transsulfuration pathway. Herein we show that cysteine and methionine deprivation (CMD) can synergize with the GPX4 inhibitor RSL3 to increase ferroptotic cell death and lipid peroxidation in both murine and human glioma cell lines and in ex vivo organotypic slice cultures. We also show that a cysteine-depleted, methionine-restricted diet can improve therapeutic response to RSL3 and prolong survival in a syngeneic orthotopic murine glioma model. Finally, this CMD diet leads to profound in vivo metabolomic, proteomic and lipidomic alterations, highlighting the potential for improving the efficacy of ferroptotic therapies in glioma treatment with a non-invasive dietary modification.

A cell state specific metabolic vulnerability to GPX4-dependent ferroptosis in glioblastoma.

Glioma cells hijack developmental transcriptional programs to control cell state. During neural development, lineage trajectories rely on specialized metabolic pathways. However, the link between tumor cell state and metabolic programs is poorly understood in glioma. Here we uncover a glioma cell state-specific metabolic liability that can be leveraged therapeutically. To model cell state diversity, we generated genetically engineered murine gliomas, induced by deletion of p53 alone (p53) or with constitutively active Notch signaling (N1IC), a pathway critical in controlling cellular fate. N1IC tumors harbored quiescent astrocyte-like transformed cell states while p53 tumors were predominantly comprised of proliferating progenitor-like cell states. N1IC cells exhibit distinct metabolic alterations, with mitochondrial uncoupling and increased ROS production rendering them more sensitive to inhibition of the lipid hydroperoxidase GPX4 and induction of ferroptosis. Importantly, treating patient-derived organotypic slices with a GPX4 inhibitor induced selective depletion of quiescent astrocyte-like glioma cell populations with similar metabolic profiles.

Trends in Comprehensive Thoracic Case Experience Among General Surgery Residents in the Modern Integrated Cardiothoracic Residency Era: Review of Twenty Years of Resident Case Logs.

BACKGROUND: Thoracic surgery training among general surgery residents in the United States is regulated by the Accreditation Council for Graduate Medical Education (ACGME) to ensure exposure to subspecialty fields during residency. Thoracic surgery training has changed over time with the placement of work hour restrictions, the emphasis on minimally invasive surgery, and increased subspecialization of training like integrated six-year cardiothoracic surgery programs. We aim to investigate how these changes over the past twenty years have affected thoracic surgery training among general surgery residents. METHODS: ACGME general surgery resident case logs from 1999 to 2019 were reviewed. Data included exposure to the thorax via thoracic, cardiac, vascular, pediatric, trauma, and alimentary tract procedures. Cases from the above categories were consolidated to determine the comprehensive experience. Descriptive statistics were performed over four 5-year Eras (Era 1:1999-2004, Era 2: 2004-2009, Era 3: 2009-2014, Era 4: 2014-2019). RESULTS: Between Era 1 and Era 4, there was an increase in thoracic surgery experience (37.6 ± 1.03 vs 39.3 ± .64; P = .006). The mean total thoracic experience for thoracoscopic, open, and cardiac procedures was 12.89 ± 3.76, 20.09 ± 2.33, and 4.98 ± 1.28, respectively. There was a difference between Era 1 and Era 4 in thoracoscopic (8.78 ± .961 vs 17.18 ± .75; P < .001) and open thoracic experience (22 ± .97 vs 17.06 ± .88; P < .001), and a decrease in thoracic trauma procedures (3.7 ± .06 vs 3.2 ± .32; P = .03). DISCUSSION: Over twenty years there has been a similar, to slight increase in thoracic surgery exposure among general surgery residents. The changes seen in thoracic surgery training reflect the overall movement of surgery towards minimally invasive surgery.

Outcomes of Medical Therapy Plus PCI for Multivessel or Left Main CAD Ineligible for Surgery.

BACKGROUND: Percutaneous coronary intervention (PCI) is increasingly used to revascularize patients ineligible for CABG, but few studies describe these patients and their outcomes. OBJECTIVES: This study sought to describe characteristics, utility of risk prediction, and outcomes of patients with left main or multivessel coronary artery disease ineligible for coronary bypass grafting (CABG). METHODS: Patients with complex coronary artery disease ineligible for CABG were enrolled in a prospective registry of medical therapy + PCI. Angiograms were evaluated by an independent core laboratory. Observed-to-expected 30-day mortality ratios were calculated using The Society for Thoracic Surgeons (STS) and EuroSCORE (European System for Cardiac Operative Risk Evaluation) II scores, surgeon-estimated 30-day mortality, and the National Cardiovascular Data Registry (NCDR) CathPCI model. Health status was assessed at baseline, 1 month, and 6 months. RESULTS: A total of 726 patients were enrolled from 22 programs. The mean SYNTAX (Synergy Between Percutaneous Coronary Intervention With Taxus and Cardiac Surgery) score was 32.4 ± 12.2 before and 15.0 ± 11.7 after PCI. All-cause mortality was 5.6% at 30 days and 12.3% at 6 months. Observed-to-expected mortality ratios were 1.06 (95% CI: 0.71-1.36) with The Society for Thoracic Surgeons score, 0.99 (95% CI: 0.71-1.27) with the EuroSCORE II, 0.59 (95% CI: 0.42-0.77) using cardiac surgeons' estimates, and 4.46 (95% CI: 2.35-7.99) using the NCDR CathPCI score. Health status improved significantly from baseline to 6 months: SAQ summary score (65.9 ± 22.5 vs 86.5 ± 15.1; P < 0.0001), Kansas City Cardiomyopathy Questionnaire summary score (54.1 ± 27.2 vs 82.6 ± 19.7; P < 0.0001). CONCLUSIONS: Patients ineligible for CABG who undergo PCI have complex clinical profiles and high disease burden. Following PCI, short-term mortality is considerably lower than surgeons' estimates, similar to surgical risk model predictions but is over 4-fold higher than estimated by the NCDR CathPCI model. Patients' health status improved significantly through 6 months.

Hospital characteristics associated with failure to rescue in cardiac surgery.

Objective: The study objective was to examine the association between hospital processes of care and failure to rescue in a diverse, multi-institutional cardiac surgery network. Methods: Failure to rescue was defined as an operative mortality after 1 or more of 4 complications: prolonged ventilation, stroke, renal failure, and unplanned reoperation. Society of Thoracic Surgeons data from 20,950 consecutive patients in the Columbia HeartSource network who underwent 1 of 7 cardiac operations-coronary artery bypass grafting, aortic valve replacement ± coronary artery bypass grafting, mitral valve repair or replacement ± coronary artery bypass grafting-were analyzed to calculate failure to rescue rates. Hospital-specific characteristics were ascertained by survey method. Multivariable mixed-effects logistic models assessed the association of these hospital characteristics with failure to rescue while adjusting for patient-related factors known to be associated with mortality. Results: Failure to rescue rates at affiliate hospitals ranged from 5.45% to 21.74% (median, 12.5%; interquartile range, 6.9%). When controlling for Society of Thoracic Surgeons-predicted risk of mortality with hospital as a random effect, 4 hospital characteristics were found to be associated with lower failure to rescue rates; the presence of cardiac-trained anesthesiologists (odds ratio, 0.41; CI, 0.31-0.55, P < .001), availability of extracorporeal membrane oxygenation mechanical circulatory support (odds ratio, 0.41; CI, 0.31-0.54, P < .001), ratio of intensive care unit beds to intensivists (odds ratio, 0.87; CI, 0.76-0.99, P = .039), and total number of intensive care unit beds (odds ratio, 0.97; CI, 0.96-0.99, P = .002). Conclusions: In a diverse multi-institutional cardiac surgical network, we were able to identify specific hospital processes of care associated with failure to rescue, even when adjusting for patient-related predictors of operative mortality.

The Spillover Effects of Quality Improvement Beyond Target Populations in Mechanical Ventilation.

To assess the impact of a mechanical ventilation quality improvement program on patients who were excluded from the intervention. DESIGN: Before-during-and-after implementation interrupted time series analysis to assess the effect of the intervention between coronary artery bypass grafting (CABG) surgery patients (included) and left-sided valve surgery patients (excluded). SETTING: Academic medical center. PATIENTS: Patients undergoing CABG and left-sided valve procedures were analyzed. INTERVENTIONS: A postoperative mechanical ventilation quality improvement program was developed for patients undergoing CABG. MEASUREMENTS AND MAIN RESULTS: Patients undergoing CABG had a median mechanical ventilation time of 11 hours during P0 ("before" phase) and 6.22 hours during P2 ("after" phase; p < 0.001). A spillover effect was observed because mechanical ventilation times also decreased from 10 hours during P0 to 6 hours during P2 among valve patients who were excluded from the protocol (p < 0.001). The interrupted time series analysis demonstrated a significant level of change for ventilation time from P0 to P2 for both CABG (p < 0.0001) and valve patients (p < 0.0001). There was no significant difference in the slope of change between the CABG and valve patient populations across time cohorts (P0 vs P1 [p = 0.8809]; P1 vs P2 [p = 0.3834]; P0 vs P2 [p = 0.7672]), which suggests that the rate of change in mechanical ventilation times was similar between included and excluded patients. CONCLUSIONS: Decreased mechanical ventilation times for patients who were not included in a protocol suggests a spillover effect of quality improvement and demonstrates that quality improvement can have benefits beyond a target population.

Chronic convection-enhanced delivery of topotecan for patients with recurrent glioblastoma: a first-in-patient, single-centre, single-arm, phase 1b trial.

BACKGROUND: Topotecan is cytotoxic to glioma cells but is clinically ineffective because of drug delivery limitations. Systemic delivery is limited by toxicity and insufficient brain penetrance, and, to date, convection-enhanced delivery (CED) has been restricted to a single treatment of restricted duration. To address this problem, we engineered a subcutaneously implanted catheter-pump system capable of repeated, chronic (prolonged, pulsatile) CED of topotecan into the brain and tested its safety and biological effects in patients with recurrent glioblastoma. METHODS: We did a single-centre, open-label, single-arm, phase 1b clinical trial at Columbia University Irving Medical Center (New York, NY, USA). Eligible patients were at least 18 years of age with solitary, histologically confirmed recurrent glioblastoma showing radiographic progression after surgery, radiotherapy, and chemotherapy, and a Karnofsky Performance Status of at least 70. Five patients had catheters stereotactically implanted into the glioma-infiltrated peritumoural brain and connected to subcutaneously implanted pumps that infused 146 µM topotecan 200 µL/h for 48 h, followed by a 5-7-day washout period before the next infusion, with four total infusions. After the fourth infusion, the pump was removed and the tumour was resected. The primary endpoint of the study was safety of the treatment regimen as defined by presence of serious adverse events. Analyses were done in all treated patients. The trial is closed, and is registered with ClinicalTrials.gov, NCT03154996. FINDINGS: Between Jan 22, 2018, and July 8, 2019, chronic CED of topotecan was successfully completed safely in all five patients, and was well tolerated without substantial complications. The only grade 3 adverse event related to treatment was intraoperative supplemental motor area syndrome (one [20%] of five patients in the treatment group), and there were no grade 4 adverse events. Other serious adverse events were related to surgical resection and not the study treatment. Median follow-up was 12 months (IQR 10-17) from pump explant. Post-treatment tissue analysis showed that topotecan significantly reduced proliferating tumour cells in all five patients. INTERPRETATION: In this small patient cohort, we showed that chronic CED of topotecan is a potentially safe and active therapy for recurrent glioblastoma. Our analysis provided a unique tissue-based assessment of treatment response without the need for large patient numbers. This novel delivery of topotecan overcomes limitations in delivery and treatment response assessment for patients with glioblastoma and could be applicable for other anti-glioma drugs or other CNS diseases. Further studies are warranted to determine the effect of this drug delivery approach on clinical outcomes. FUNDING: US National Institutes of Health, The William Rhodes and Louise Tilzer Rhodes Center for Glioblastoma, the Michael Weiner Glioblastoma Research Into Treatment Fund, the Gary and Yael Fegel Foundation, and The Khatib Foundation.

Predictors and associated clinical outcomes of low cardiac output syndrome following cardiac surgery: insights from the LEVO-CTS trial.

AIMS: High-risk cardiac surgery is commonly complicated by low cardiac output syndrome (LCOS), which is associated with high mortality. There are limited data derived from multi-centre studies with adjudicated endpoints describing factors associated with LCOS and its downstream clinical outcomes. METHODS AND RESULTS: The Levosimendan in Patients with Left Ventricular Systolic Dysfunction Undergoing Cardiac Surgery Requiring Cardiopulmonary Bypass (LEVO-CTS) trial evaluated prophylactic levosimendan vs. placebo in patients with a reduced ejection fraction undergoing coronary artery bypass grafting (CABG) and/or valve surgery. We conducted a pre-specified analysis on LCOS, which was characterized by a four-part definition. We constructed a multivariable logistical regression model to evaluate risk factors associated with LCOS and performed Cox proportional hazards modelling to determine the association of LCOS with 90-day mortality. A total of 186 (22%) of 849 patients in the LEVO-CTS trial developed LCOS. The factors most associated with a higher adjusted risk of LCOS were pre-operative ejection fraction [odds ratio (OR) 1.26; 95% confidence interval (CI): 1.08-1.46 per 5% decrease] and age (OR 1.13; 95% CI: 1.04-1.24 per 5-year increase), whereas isolated CABG surgery (OR 0.44, 95% CI: 0.31-0.64) and levosimendan use (OR 0.65; 95% CI: 0.46-0.92) were associated with a lower risk of LCOS. Patients with LCOS had worse outcomes, including renal replacement therapy at 30-day (10 vs. 1%) and 90-day mortality (16 vs. 3%, adjusted hazard ratio of 5.04, 95% CI: 2.66-9.55). CONCLUSION: Low cardiac output syndrome is associated with a high risk of post-operative mortality in high-risk cardiac surgery.

Assessing sex-based differences in postsurgical clinical outcomes after use of del Nido cardioplegia.

OBJECTIVES: del Nido cardioplegia is used to pharmacologically arrest the heart during cardiac surgery and decrease reperfusion- and ischaemia-related myocardial injury. Studies have demonstrated the physiological differences between male and female hearts, potentially related to cardiac size or myocyte calcium handling; we aimed to assess for between-sex differences in clinical outcomes after receipt of del Nido cardioplegia. METHODS: Patients who underwent coronary artery bypass or coronary artery bypass graft/valve surgery at our institution using del Nido cardioplegia (January 2014 to December 2019) were included (n = 2118). Clinical data were collected retrospectively. After the creation of a propensity-matched cohort (n = 1252), multivariable logistic regression was used to analyse binary postoperative outcomes, and a Gamma model was used for a continuous postoperative outcome. Our primary end-point was a composite end-point comprised of 30-day mortality and/or need for a post-bypass mechanical support device. RESULTS: The final cohort included 459 females and 793 males (matched up to 1:2, all standardized mean differences <0.1). Multivariable logistic regression showed that biological sex was not associated with the composite primary end-point (odds ratio = 0.898, P = 0.779). A Gamma model indicated that there were no sex-related differences in vasoactive-inotropic scores reflecting vasopressor and inotrope usage at the time of patient operating room exit (exp[est] = 1.394, P = 0.189). CONCLUSIONS: Our findings showed no significant between-sex differences in clinical outcomes after receiving del Nido cardioplegia, suggesting adequate myocardial protection as currently administered. Further research is warranted to elicit if there are sex-based differences between cardioplegic solutions. IRB APPROVAL DATE (PROTOCOL NUMBER): 26 May 2021 (AAAR8359).

Optimizing Perioperative Renal Replacement Therapy for Patients Undergoing Cardiac Surgical Procedures Requiring Cardiopulmonary Bypass.

Coronary artery disease is highly prevalent in patients with end-stage renal disease (ESRD), and cardiovascular complications remain the most common cause of death in this patient population. Accordingly, many cardiac surgical procedures requiring cardiopulmonary bypass support are performed on these patients each year, with morbidity and mortality rates far exceeding patients without ESRD. Anuric patients lack the normal renal homeostatic functions which typically allow for physiologic protection from challenges during the operation, such as volume overload, hyperkalemia, and acidemia. Careful preoperative planning and coordination to provide pre-, intra-, and postoperative renal replacement therapies for such patients are imperative. Many different strategies have been reported in the literature. Zero-balance ultrafiltration is a newer strategy which utilizes convective ultrafiltration much like pre-filter continuous renal replacement therapy and utilizes pre-existing connections on the cardiopulmonary bypass pump performed by the perfusion team. This allows for control of potassium concentration throughout the operation with existing personnel and minimal additional equipment. Here, we describe the unique challenges caring for patients receiving renal replacement therapy undergoing cardiac surgical procedures requiring cardiopulmonary bypass.