Novel inflammatory mediator profile observed during pediatric heart surgery with cardiopulmonary bypass and continuous ultrafiltration.

BACKGROUND: Cardiopulmonary bypass (CPB) is associated with systemic inflammation, featuring increased levels of circulating pro-inflammatory cytokines. Intra-operative ultrafiltration extracts fluid and inflammatory factors potentially dampening inflammation-related organ dysfunction and enhancing post-operative recovery. This study aimed to define the impact of continuous subzero-balance ultrafiltration (SBUF) on circulating levels of major inflammatory mediators. METHODS: Twenty pediatric patients undergoing cardiac surgery, CPB and SBUF were prospectively enrolled. Blood samples were collected prior to CPB initiation (Pre-CPB Plasma) and immediately before weaning off CPB (End-CPB Plasma). Ultrafiltrate effluent samples were also collected at the End-CPB time-point (End-CPB Effluent). The concentrations of thirty-nine inflammatory factors were assessed and sieving coefficients were calculated. RESULTS: A profound increase in inflammatory cytokines and activated complement products were noted in plasma following CBP. Twenty-two inflammatory mediators were detected in the ultrafiltrate effluent. Novel mediators removed by ultrafiltration included cytokines IL1-Ra, IL-2, IL-12, IL-17A, IL-33, TRAIL, GM-CSF, ET-1, and the chemokines CCL2, CCL3, CCL4, CXCL1, CXCL2 and CXCL10. Mediator extraction by SBUF was significantly associated with molecular mass < 66 kDa (Chi2 statistic = 18.8, Chi2 with Yates' correction = 16.0, p < 0.0001). There was a moderate negative linear correlation between molecular mass and sieving coefficient (Spearman R = - 0.45 and p = 0.02). Notably, the anti-inflammatory cytokine IL-10 was not efficiently extracted by SBUF. CONCLUSIONS: CPB is associated with a burden of circulating inflammatory mediators, and SBUF selectively extracts twenty of these pro-inflammatory factors while preserving the key anti-inflammatory regulator IL-10. Ultrafiltration could potentially function as an immunomodulatory therapy during pediatric cardiac surgery. Trial registration ClinicalTrials.gov, NCT05154864. Registered retrospectively on December 13, 2021. https://clinicaltrials.gov/ct2/show/record/NCT05154864 .

Circulating tumor cells detected in follow-up predict survival outcomes in tri-modality management of advanced non-metastatic esophageal cancer: a secondary analysis of the QUINTETT randomized trial.

BACKGROUND: Our aim was to establish if presence of circulating tumor cells (CTCs) predicted worse outcome in patients with non-metastatic esophageal cancer undergoing tri-modality therapy. METHODS: We prospectively collected CTC data from patients with operable non-metastatic esophageal cancer from April 2009 to November 2016 enrolled in our QUINTETT esophageal cancer randomized trial (NCT00907543). Patients were randomized to receive either neoadjuvant cisplatin and 5-fluorouracil (5-FU) plus radiotherapy followed by surgical resection (Neoadjuvant) or adjuvant cisplatin, 5-FU, and epirubicin chemotherapy with concurrent extended volume radiotherapy following surgical resection (Adjuvant). CTCs were identified with the CellSearch® system before the initiation of any treatment (surgery or chemoradiotherapy) as well as at 6-, 12-, and 24-months post-treatment. The threshold for CTC positivity was one and the findings were correlated with patient prognosis. RESULTS: CTC data were available for 74 of 96 patients and identified in 27 patients (36.5%) at a median follow-up of 13.1months (interquartile range:6.8-24.1 months). Detection of CTCs at any follow-up visit was significantly predictive of worse disease-free survival (DFS;hazard ratio [HR]: 2.44; 95% confidence interval [CI]: 1.41-4.24; p=0.002), regional control (HR: 6.18; 95% CI: 1.18-32.35; p=0.031), distant control (HR: 2.93; 95% CI: 1.52-5.65;p=0.001) and overall survival (OS;HR: 2.02; 95% CI: 1.16-3.51; p=0.013). After adjusting for receiving neoadjuvant vs. adjuvant chemoradiotherapy, the presence of CTCs at any follow-up visit remained significantly predictive of worse OS ([HR]:2.02;95% [Cl]:1.16-3.51; p=0.013) and DFS (HR: 2.49;95% Cl: 1.43-4.33; p=0.001). Similarly, any observed increase in CTCs was significantly predictive of worse OS (HR: 3.14; 95% CI: 1.56-6.34; p=0.001) and DFS (HR: 3.34; 95% CI: 1.67-6.69; p<0.001). CONCLUSION: The presence of CTCs in patients during follow-up after tri-modality therapy was associated with significantly poorer DFS and OS regardless of timing of chemoradiotherapy.

Subzero balance - simple modified ultrafiltration (SBUF-SMUF) technique for pediatric cardiopulmonary bypass.

The use of cardiopulmonary bypass (CPB) can be associated with significant hemodilution, coagulopathy and a systemic inflammatory response for infants and children undergoing cardiac surgery. Intra-operative ultrafiltration has been used for decades to ameliorate these harmful effects. The novel combination of a continuous and non-continuous form of ultrafiltration, Subzero Balance Simple Modified Ultrafiltration (SBUF-SMUF) here described, seeks to enhance recovery from pediatric cardiac surgery and CPB.

Ticagrelor use and practice patterns among Canadian cardiac surgeons.

BACKGROUND AND AIM: The P2Y12 platelet receptor inhibitor ticagrelor is widely used in patients following acute coronary syndromes or in those who have received coronary stents. Bentracimab is a monoclonal antibody-based reversal agent that is being formally evaluated in a Phase 3 clinical trial. Here, we probe the knowledge, attitudes, and practice patterns of cardiac surgeons regarding their perioperative management of ticagrelor and potential application of a ticagrelor reversal agent. METHODS: A questionnaire was developed by a working group of cardiac surgeons to inquire into participants' practices and beliefs regarding ticagrelor and disseminated to practicing, Canadian-trained cardiac surgeons. RESULTS: A total of 70 Canadian-trained cardiac surgeons participated. Bleeding risk was identified as the most significant consideration when surgically revascularizing ticagrelor-treated patients (90%). There is variability in the duration of withholding ticagrelor before coronary artery bypass graft procedure in a stable patient; 44.3% wait 3 days and 32.9% wait 4 days or longer. Currently, 15.7% of cardiac surgeons prophylactically give platelet transfusions and fresh frozen plasma intraoperatively following protamine infusion in patients who have recently received ticagrelor. Interestingly, 47.1% of surveyed surgeons were aware of a reversal agent for ticagrelor, 91.4% of cardiac surgeons would consider utilizing a ticagrelor reversal agent if available, and 51.4% acknowledged that the introduction of such an agent would be a major advance in clinical practice. CONCLUSIONS: The present survey identified ticagrelor-related bleeding as a major concern for cardiac surgeons. Surgeons recognized the significant unmet need that a ticagrelor reversal agent would address.

Continuous Ultrafiltration Enhances Recovery After Adult Cardiac Surgery With Cardiopulmonary Bypass: A Systematic Review and Meta-analysis.

Background: Cardiac surgery with cardiopulmonary bypass is associated with systemic inflammation. Ultrafiltration used throughout the cardiopulmonary bypass time, continuously, is hypothesized to be an immunomodulatory therapy. Methods: A systematic review and meta-analysis of randomized trials investigating continuous forms of ultrafiltration during adult cardiac surgery (CRD42020219309) was conducted and is reported following PRISMA guidelines. MEDLINE, Embase, CENTRAL, and Scopus were searched on November 3, 2021. The primary endpoint was operative mortality, and secondary outcomes included intensive care unit length of stay (ICU LOS), ventilation time, acute kidney injury or renal failure, and pneumonia. Each study was assessed for risk of bias using the Cochrane Risk-of Bias-Tool for Randomized Trials (RoB2) instrument. Outcomes were analyzed with inverse variance random-effects models and assessed for GRADE quality of evidence. Results: Twelve randomized trials consisting of 989 adult patients undergoing coronary, valvular, or concomitant cardiac procedures were included. Compared to controls, patients receiving continuous ultrafiltration had no statistical difference in operative mortality; risk ratio of 0.32 (95% confidence interval [CI]: 0.10-1.03; P = 0.06). Reductions occurred in ICU LOS, by 7.01 hours (95% CI: 1.86-12.15; P = 0.008); ventilation time, by 2.11 hours (95% CI: 0.71-3.51; P = 0.003); and incidence of pneumonia, with a risk ratio of 0.33 (95% CI: 0.15-0.75; P = 0.008). There wasno difference in renal injury. The GRADE quality of evidence for these outcomes ranged from very low to low. Conclusions: Continuous forms of ultrafiltration enhance recovery after adult cardiac surgery by reducing ICU LOS, ventilation time, and incidence of pneumonia. A multicentre randomized trial could confirm and generalize these findings.

Contexte: La chirurgie cardiaque avec pontage cardiopulmonaire est associée à une inflammation généralisée. On croit que l'ultrafiltration utilisée en continu tout au long du pontage cardiopulmonaire pourrait se révéler un traitement immunomodulateur. Méthodologie: Une revue systématique et une métanalyse d'essais avec répartition aléatoire portant sur les formes d'ultrafiltration continue utilisées pendant une chirurgie cardiaque chez l'adulte (CRD42020219309) ont été réalisées, et les résultats sont présentés selon les lignes directrices PRISMA. Les bases de données MEDLINE, Embase, CENTRAL et Scopus ont été interrogées le 3 novembre 2021. L'étude avait pour critère d'évaluation principal la mortalité pendant la chirurgie, et pour critères secondaires, la durée du séjour aux soins intensifs, la durée de ventilation, la survenue de lésions rénales aiguës ou d'insuffisance rénale et la pneumonie. Pour chaque étude, le risque de biais a été évalué à l'aide de l'instrument Risk-of Bias-Tool for Randomized Trials (RoB2) du réseau Cochrane. Les résultats ont été analysés à l'aide de modèles à effets aléatoires selon l'inverse de la variance, et la qualité des données a été évaluée selon l'échelle GRADE. Résultats: Ont été incluses les données de douze essais avec répartition aléatoire auxquels ont pris part 989 patients adultes ayant subi une intervention chirurgicale coronarienne ou valvulaire, ou une chirurgie cardiaque concomitante. Le taux de mortalité enregistré pendant la chirurgie chez les patients qui avaient reçu une ultrafiltration continue ne s'est pas avéré statistiquement différent de celui relevé chez les témoins; rapport de risque = 0,32 (intervalle de confiance [IC] à 95 % : 0,10 à 1,03; p = 0,06). La durée du séjour aux soins intensifs a diminué de 7,01 heures (IC à 95 % : 1,86 à 12,15; p = 0,008), et le temps de ventilation, de 2,11 heures (IC à 95 % : 0,71 à 3,51; p = 0,003); l'incidence de pneumonie a également baissé (rapport de risques = 0,33 [IC à 95 % : 0,15 à 0,75; p = 0,008]). Aucune différence n'a été observée sur le plan des lésions rénales. La qualité des données selon l'échelle GRADE pour ces résultats allait de faible à très faible. Conclusions: L'ultrafiltration continue améliore le rétablissement après une chirurgie cardiaque chez l'adulte en réduisant la durée du séjour aux soins intensifs, le temps de ventilation et l'incidence de pneumonie. Un essai multicentrique à répartition aléatoire pourrait confirmer et généraliser ces conclusions.

The quality of life in neoadjuvant versus adjuvant therapy of esophageal cancer treatment trial (QUINTETT): Randomized parallel clinical superiority trial.

BACKGROUND: We compared the health-related quality of life (HRQOL) in patients undergoing trimodality therapy for resectable stage I-III esophageal cancer. METHODS: A total of 96 patients were randomized to standard neoadjuvant cisplatin and 5-fluorouracil chemotherapy plus radiotherapy (neoadjuvant) followed by surgical resection or adjuvant cisplatin, 5-fluorouracil, and epirubicin chemotherapy with concurrent extended volume radiotherapy (adjuvant) following surgical resection. RESULTS: There was no significant difference in the functional assessment of cancer therapy-esophageal (FACT-E) total scores between arms at 1 year (p = 0.759) with 36% versus 41% (neoadjuvant vs. adjuvant), respectively, showing an increase of ≥15 points compared to pre-treatment (p = 0.638). The HRQOL was significantly inferior at 2 months in the neoadjuvant arm for FACT-E, European Organization for Research and Treatment of Cancer quality of life questionnaire (EORTC QLQ-OG25), and EuroQol 5-D-3 L in the dysphagia, reflux, pain, taste, and coughing domains (p < 0.05). Half of patients were able to complete the prescribed neoadjuvant arm chemotherapy without modification compared to only 14% in the adjuvant arm (p < 0.001). Chemotherapy related adverse events of grade ≥2 occurred significantly more frequently in the neoadjuvant arm (100% vs. 69%, p < 0.001). Surgery related adverse events of grade ≥2 were similar in both arms (72% vs. 86%, p = 0.107). There were no 30-day mortalities and 2% vs. 10% 90-day mortalities (p = 0.204). There were no significant differences in either overall survival (OS) (5-year: 35% vs. 32%, p = 0.409) or disease-free survival (DFS) (5-year: 31% vs. 30%, p = 0.710). CONCLUSION: Trimodality therapy is challenging for patients with resectable esophageal cancer regardless of whether it is given before or after surgery. Newer and less toxic protocols are needed.

Do continuous forms of intra-operative ultrafiltration enhance recovery after adult cardiac surgery with cardiopulmonary bypass? A protocol for systematic review and meta-analysis of randomized controlled trials.

BACKGROUND: Cardiac surgery with cardiopulmonary bypass (CPB) is associated with a systemic inflammatory syndrome that adversely impacts cardiopulmonary function and can contribute to prolonged postoperative recovery. Intra-operative ultrafiltration during CPB is a strategy developed by pediatric cardiac specialists, aiming to dampen the inflammatory syndrome by removing circulating cytokines and improving coagulation profiles during the cardiac operation. Although ultrafiltration is commonly used in the pediatric population, it is not routinely used in the adult population. This study aims to evaluate if randomized evidence supports the use of continuous intra-operative ultrafiltration to enhance recovery for adults undergoing cardiac surgery with CPB. METHODS: This systematic review and meta-analysis will include randomized controlled trials (RCT) that feature continuous forms of ultrafiltration during adult cardiac surgery with CPB, specifically assessing for benefit in mortality rates, invasive ventilation time and intensive care unit length of stay (ICU LOS). Relevant RCTs will be retrieved from databases, including MEDLINE, Embase, CENTRAL and Scopus, by a pre-defined search strategy. Search results will be screened for inclusion and exclusion criteria by two independent persons with consensus. Selected RCTs will have study demographics and outcome data extracted by two independent persons and transferred into RevMan. Risk of bias will be independently assessed by the Revised Cochrane Risk-of-Bias (RoB2) tool and studies rated as low-, some-, or high- risk of bias. Meta-analyses will compare the intervention of continuous ultrafiltration against comparators in terms of mortality, ventilation time, ICU LOS, and renal failure. Heterogeneity will be measured by the χ2 test and described by the I2 statistic. A sensitivity analysis will be completed by excluding included studies judged to have a high risk of bias. Summary of findings and certainty of the evidence, determined by the GRADE approach, will display the analysis findings. DISCUSSION: The findings of this systematic review and meta-analysis will summarize the evidence to date of continuous forms of ultrafiltration in adult cardiac surgery with CPB, to both inform adult cardiac specialists about this technique and identify critical questions for future research in this subject area. SYSTEMATIC REVIEW REGISTRATION: This systematic review and meta-analysis is registered in PROSPERO CRD42020219309  ( https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42020219309 ).

Interprofessional Patient-Specific Simulation Preparation to Improve Management of Neonatal High-Acuity Low-Occurrence (HALO) Scenarios.

Fetal compressive intrapericardial teratoma is a rare and life-threatening condition, qualifying as a high-acuity low-occurrence (HALO) event. To prepare for delivery and immediate neonatal management, specialists from pediatric cardiology, cardiac surgery, maternal-fetal-medicine, neonatology, cardiac anesthesia, critical care, clinical perfusion, obstetrical nursing, and operating room nursing convened. An in situ operating room simulation was used to identify and introduce key team members, derive and practice the anticipated clinical management algorithm, position human and equipment resources strategically, and ensure that each specialist team was familiar with the environment and available equipment. As rehearsed in the simulation, the cesarean delivery of the patient and neonatal cardiac surgery was uncomplicated and yielded a favourable clinical outcome. A patient-specific HALO simulation preparation (PSHSP) can facilitate positive clinical outcomes and improve health care team confidence in HALO scenarios such as the birth of newborns anticipated to have cardiorespiratory instabilty.

Infective Endocarditis Secondary to Injection Drug Use: A Survey of Canadian Cardiac Surgeons.

BACKGROUND: Injection drug use-associated infective endocarditis (IDU-IE) is a growing epidemic. The objective of this survey was to identify the beliefs and practice patterns of Canadian cardiac surgeons regarding surgical management of IDU-IE. METHODS: A 30-question survey was developed by a working group and distributed to all practicing adult cardiac surgeons in Canada. Data were analyzed using descriptive statistics. RESULTS: Of 146 surgeons, 94 completed the survey (64%). Half of surgeons (49%) would be less likely to operate on patients with IE if associated with IDU. In the case of prosthetic valve IE owing to continued IDU, 36% were willing to reoperate once and 14% were willing to reoperate twice or more. Most surgeons required commitments from patients before surgery (73%), and most referred patients to addiction services (81%). Some surgeons would offer a Ross procedure (10%) or homograft (8%) for aortic valve IE, and 47% would consider temporary mechanical circulatory support. Whereas only 17% of surgeons worked at an institution with an endocarditis team, 71% agreed that there was a need for one at each institution. Most surgeons supported the development of IDU-IE-specific guidelines (80%). CONCLUSIONS: Practice patterns and surgical management of IDU-IE vary considerably across Canada. Areas of clinical unmet needs include the development of a formal addiction services referral protocol for patients, the development of an interdisciplinary endocarditis team, as well as the creation of IDU-IE clinical practice guidelines.

Ultrafiltration in Pediatric Cardiac Surgery Review.

INTRODUCTION: The use of cardiopulmonary bypass in pediatric cardiac surgery is associated with significant inflammation, fluid overload, and end-organ dysfunction yielding morbidity and mortality. For decades, various intraoperative ultrafiltration techniques such as conventional ultrafiltration, modified ultrafiltration (MUF), zero-balance ultrafiltration (ZBUF), and combination techniques (ZBUF-MUF) have been used to mitigate these toxicities and promote improved postoperative outcomes. However, there is currently no consensus on the ultrafiltration technique or strategy that yields the most benefit for infants and children undergoing open heart surgery. METHODS: A librarian-conducted PubMed literature search from 1990 to 2018 yielded 90 clinical studies or publications on the various forms of ultrafiltration and the impact on physiologic markers and clinical outcomes. All publications were reviewed, summarized, and conclusions synthesized. The data sets were not combined for systematic or meta-analysis due to significant heterogeneity in study protocols and patient populations. RESULTS: Modified ultrafiltration significantly promotes improved myocardial function, reduction in fluid overload, and reduced bleeding and transfusion complications. Furthermore, ZBUF has shown a consistent reduction in inflammatory cytokines and improved pulmonary function and compliance. There is conflicting evidence that MUF, ZBUF, and ZBUF-MUF culminate in reduced ventilation time and intensive care unit stay. CONCLUSION: Various modes of ultrafiltration have been shown to be associated with improved physiologic function or clinical outcomes in pediatric cardiac surgery. There are some inconsistent trial results that can be explained by heterogeneity in ultrafiltration, clinical staff preferences, and institution protocols. Ultrafiltration has some essential benefit as it is ubiquitously used at pediatric heart centers; however, the optimal protocol could be yet identified.

Development of an In Situ Thoracic Surgery Crisis Simulation Focused on Nontechnical Skill Training.

BACKGROUND: Our vision was to develop an inexpensive training simulation in a functional operating room (in situ) that included surgical trainees and nursing and anesthesia staff to focus on effective interprofessional communication and teamwork skills. METHODS: The simulation scenario revolved around an airway obstruction by residual tumor after pneumonectomy. This model included our thoracic operating room with patient status displayed by an open access vital sign simulator and a reversibly modified Laerdal airway mannequin (Shavanger, Norway). The simulation scenario was run seven times. Simulations were video recorded and scored with the use of Non-Technical Skills for Surgeons (NOTSS) and TeamSTEPPS2. Latent safety threats (LSTs) and feedback were obtained during the debriefing after the simulation. Feedback was captured with the Method Material Member Overall (MMMO) questionnaire. RESULTS: Several LSTs were identified, which included missing and redundant equipment and knowledge gaps in participants' roles. Consultant surgeons received a higher overall score than thoracic surgery fellows on both NOTSS (3.8 versus 3.3) and TeamSTEPPS2 (4.1 versus 3.2) evaluations, suggesting that the scenario effectively differentiated learners from experts with regards to nontechnical skills. The MMMO overall simulation experience score was 4.7 of 5, confirming a high-fidelity model and useful experiential learning model. At the Canadian Thoracic Bootcamp, the MMMO overall experience score was 4.8 of 5, further supporting this simulation as a robust model. CONCLUSIONS: An inexpensive in situ intraoperative crisis simulation model for thoracic surgical emergencies was created, implemented, and demonstrated to be effective as a proof of concept at identifying latent threats to patient safety and differentiating the nontechnical skills of trainees and consultant surgeons.

Bilateral caudate nucleus infarcts: A case report of a rare complication following endoscopic resection of a tuberculum sellae meningioma.

BACKGROUND: We present a rare complication of bilateral caudate infarcts and necrosed nasoseptal flaps after endoscopic transsphenoidal resection of tuberculum sellae meningioma. This case highlights the importance of early and accurate diagnosis and treatment of a postoperative cerebrospinal fluid (CSF) leak and associated bacterial meningitis, and reviews any existing guidelines regarding its management. CASE DESCRIPTION: A 54-year-old otherwise healthy man presented with progressive bitemporal hemianopsia. Magnetic resonance imaging of the head revealed a large, homogeneously enhancing sellar and suprasellar mass consistent with a meningioma. An endoscopic endonasal transsphenoidal approach was performed to resect the tuberculum sellae meningioma. The patient developed basal bacterial meningitis secondary to a CSF leak, requiring repair on two separate occasions. At the time of both repairs, there was evidence of necrosis of the nasoseptal flaps used for the repairs. Soon after the diagnosis of meningitis, the patient developed bilateral caudate infarcts. CONCLUSION: This report discusses the possible underlying etiologies for the bilateral caudate infarcts and necrosed flaps including bacterial meningitis with associated local vasospasm of nearby vessels resulting in infarction. This case emphasizes the importance of concise management of postendoscopic CSF leak and discusses the guidelines regarding antimicrobial therapy and the management of lumbar drains.

Quantitative evaluation of vision-related and health-related quality of life after endoscopic transsphenoidal surgery for pituitary adenoma.

OBJECTIVE Endoscopic resection of pituitary adenomas has been reported to improve vision function in up to 80%-90% of patients with visual impairment due to these adenomas. It is unclear how these reported rates translate into improvement in visual outcomes and general health as perceived by the patients. The authors evaluated self-assessed health-related quality of life (HR-QOL) and vision-related QOL (VR-QOL) in patients before and after endoscopic resection of pituitary adenomas. METHODS The authors prospectively collected data from 50 patients who underwent endoscopic resection of pituitary adenomas. This cohort included 32 patients (64%) with visual impairment preoperatively. Twenty-seven patients (54%) had pituitary dysfunction, including 17 (34%) with hormone-producing tumors. Patients completed the National Eye Institute Visual Functioning Questionnaire and the 36-Item Short Form Health Survey preoperatively and 6 weeks and 6 months after surgery. RESULTS Patients with preoperative visual impairment reported a significant impact of this condition on VR-QOL preoperatively, including general vision, near activities, and peripheral vision; they also noted vision-specific impacts on mental health, role difficulties, dependency, and driving. After endoscopic resection of adenomas, patients reported improvement across all these categories 6 weeks postoperatively, and this improvement was maintained by 6 months postoperatively. Patients with preoperative pituitary dysfunction, including hormone-producing tumors, perceived their general health and physical function as poorer, with some of these patients reporting improvement in perceived general health after the endoscopic surgery. All patients noted that their ability to work or perform activities of daily living was transiently reduced 6 weeks postoperatively, followed by significant improvement by 6 months after the surgery. CONCLUSIONS Both VR-QOL and patient's perceptions of their ability to do work and perform other daily activities as a result of their physical health significantly improved by 6 months after endoscopic resection of pituitary adenoma. The use of multidimensional QOL questionnaires provides a precise assessment of perceived outcomes after endoscopic surgery.