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Background: Delirium occurs frequently following cardiothoracic surgery, and infectious disease is an important risk factor for delirium. Surgery and cardiopulmonary bypass induce suppression of the immune response known as immunoparalysis. We aimed to investigate whether delirious patients had more pronounced immunoparalysis following cardiothoracic surgery than patients without delirium, to explain this delirium-infection association., Methods: A prospective matched case-control study was performed in two university hospitals. Cytokine production (tumor necrosis factor (TNF)-α, interleukin (IL)-6, IL-8 and IL-10) of ex vivo lipopolysaccharide (LPS)-stimulated whole blood was analyzed in on-pump cardiothoracic surgery patients preoperatively, and at 5 timepoints up to 3 days after cardiothoracic surgery. Delirium was assessed by trained staff using two validated delirium scales and chart review., Results: A total of 89 patients were screened of whom 14 delirious and 52 non-delirious patients were included. Ex vivo-stimulated production of TNF-α, IL-6, IL-8, and IL-10 was severely suppressed following cardiothoracic surgery compared to pre-surgery. Postoperative release of cytokines in non-delirious patients was attenuated by 84% [IQR: 13-93] for TNF-α, 95% [IQR: 78-98] for IL-6, and 69% [IQR: 55-81] for IL-10. The attenuation in ex vivo-stimulated production of these cytokines was not significantly different in patients with delirium compared to non-delirious patients (p > 0.10 for all cytokines)., Conclusions: The post-operative attenuation of ex vivo-stimulated production of pro- and anti-inflammatory cytokines was comparable between patients that developed delirium and those who remained delirium-free after on-pump cardiothoracic surgery. This finding suggests that immunoparalysis is not more common in cardiothoracic surgery patients with delirium compared to those without., (© 2021. The Author(s).)

Introduction: Postoperative cognitive dysfunction occurs frequently after coronary artery bypass grafting (CABG). The underlying mechanisms remain poorly understood, but neuroinflammation might play a pivotal role. We hypothesise that systemic inflammation induced by the surgical trauma could activate the innate immune (glial) cells of the brain. This could lead to an exaggerated neuroinflammatory cascade, resulting in neuronal dysfunction and loss of neuronal cells. Therefore, the aims of this study are to assess neuroinflammation in vivo presurgery and postsurgery in patients undergoing major cardiac surgery and investigate whether there is a relationship of neuroinflammation to cognitive outcomes, changes to brain structure and function, and systemic inflammation., Methods and Analysis: The FOCUS study is a prospective, single-centre observational study, including 30 patients undergoing elective on-pump CABG. Translocator protein (TSPO) positron emission tomography neuroimaging will be performed preoperatively and postoperatively using the second generation tracer 18 F-DPA-714 to assess the neuroinflammatory response. In addition, a comprehensive cerebral MRI will be performed presurgery and postsurgery, in order to discover newly developed brain and vascular wall lesions. Up to 6 months postoperatively, serial extensive neurocognitive assessments will be performed and blood will be obtained to quantify systemic inflammatory responses and peripheral immune cell activation., Ethics and Dissemination: Patients do not benefit directly from engaging in the study, but imaging neuroinflammation is considered safe and no side effects are expected. The study protocol obtained ethical approval by the Medical Research Ethics Committee region Arnhem-Nijmegen. This work will be published in peer-reviewed international medical journals and presented at medical conferences., Trial Registration Number: NCT04520802., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Decades of sepsis research into a specific immune system-targeting adjunctive therapy have not resulted in the discovery of an effective compound. Apart from antibiotics, source control, resuscitation and organ support, not a single adjunctive treatment is used in current clinical practice. The inability to determine the prevailing immunological phenotype of patients and the related large heterogeneity of study populations are regarded by many as the most important factors behind the disappointing results of past clinical trials. While the therapeutic focus has long been on immunosuppressive strategies, increased appreciation of the importance of sepsis-induced immunoparalysis in causing morbidity and mortality in sepsis patients has resulted in a paradigm shift in the sepsis research field towards strategies aimed at enhancing the immune response. However, similar to immunosuppressive therapies, precision medicine is imperative for future trials with immunostimulatory compounds to succeed. As such, identifying those patients with a severely suppressed or hyperactive immune system who will most likely benefit from either immunostimulatory or immunosuppressive therapy, and accurate monitoring of both the immune and treatment response is crucial. This review provides an overview of the challenges lying ahead on the path towards precision immunotherapy for patients suffering from sepsis.