Elevated Plasma Soluble PD-L1 Levels in Out-of-Hospital Cardiac Arrest Patients.

Background: A deregulated immune system has been implicated in the pathogenesis of post-cardiac arrest syndrome (PCAS). A soluble form of programmed cell death-1 (PD-1) ligand (sPD-L1) has been found at increased levels in cancer and sustained inflammation, thereby deregulating immune functions. Here, we aim to study the possible involvement of sPD-L1 in PCAS. Methods: Thirty out-of-hospital cardiac arrest (OHCA) patients consecutively admitted to the ER of Mie University Hospital were prospectively enrolled. Plasma concentrations of sPD-L1 were measured by an enzyme-linked immunosorbent assay in blood samples of all 30 OHCA patients obtained during cardiopulmonary resuscitation (CPR). In 13 patients who achieved return-of-spontaneous-circulation (ROSC), sPD-L1 levels were also measured daily in the ICU. Results: The plasma concentrations of sPD-L1 in OHCA were significantly increased; in fact, to levels as high as those observed in sepsis. sPD-L1 levels during CPR correlated with reduced peripheral lymphocyte counts and increased C-reactive protein levels. Of 13 ROSC patients, 7 cases survived in the ICU for more than 4 days. A longitudinal analysis of sPD-L1 levels in the 7 ROSC cases revealed that sPD-L1 levels occurred in parallel with organ failure. Conclusions: This study suggests that ischemia- reperfusion during CPR may aberrantly activate immune and endothelial cells to release sPD-L1 into circulation, which may play a role in the pathogenesis of immune exhaustion and organ failures associated with PCAS.

Cellular and Exosomal Regulations of Sepsis-Induced Metabolic Alterations.

Sepsis is a sustained systemic inflammatory condition involving multiple organ failures caused by dysregulated immune response to infections. Sepsis induces substantial changes in energy demands at the cellular level leading to metabolic reprogramming in immune cells and stromal cells. Although sepsis-associated organ dysfunction and mortality have been partly attributed to the initial acute hyperinflammation and immunosuppression precipitated by a dysfunction in innate and adaptive immune responses, the late mortality due to metabolic dysfunction and immune paralysis currently represent the major problem in clinics. It is becoming increasingly recognized that intertissue and/or intercellular metabolic crosstalk via endocrine factors modulates maintenance of homeostasis, and pathological events in sepsis and other inflammatory diseases. Exosomes have emerged as a novel means of intercellular communication in the regulation of cellular metabolism, owing to their capacity to transfer bioactive payloads such as proteins, lipids, and nucleic acids to their target cells. Recent evidence demonstrates transfer of intact metabolic intermediates from cancer-associated fibroblasts via exosomes to modify metabolic signaling in recipient cells and promote cancer progression. Here, we review the metabolic regulation of endothelial cells and immune cells in sepsis and highlight the role of exosomes as mediators of cellular metabolic signaling in sepsis.

Longer term hemodialysis-dependent chronic renal failure increases the risk of post-cardiac surgery vasoplegic syndrome.

PURPOSE: We evaluated whether longer term hemodialysis (HD) is associated with a higher incidence of vasoplegic syndrome (VS) after cardiac surgery. METHODS: This retrospective, single-center cohort study included 562 consecutive patients who underwent cardiac surgery in a tertiary hospital from January 2015 to December 2016. We assessed VS occurrence and its relationship with HD duration and other risk factors. To assess the effect of the HD duration on VS occurrence, we constructed ordinal variables: HD = 0 (non-HD), 0 < HD ≤ 5 (HD ≤ 5 years), 5 < HD ≤ 10, and 10 < HD. RESULTS: The overall mean (± standard deviation) age of patients was (73 ± 11) years, and there were 60.9% men. Forty-one patients (7.3%) were HD dependent. Cardiac surgeries included all coronary artery bypass graft procedures, all valvular procedures, and aortic surgery involving cardiopulmonary bypass (CPB). Sixty-six patients (10%) developed VS. Most preoperative patient characteristics were comparable between the VS and no-VS groups; a chronic HD status and a total CPB time of > 180 min were significantly more common in the VS group (P < 0.0001 and P = 0.02, respectively). Longer term HD significantly correlated with VS incidence (P < 0.0001). Ordinal variables for the HD duration and age and known risk factors for VS (preoperative use of angiotensin-converting enzyme inhibitors and beta-blockers, low left-ventricular ejection fraction, and CPB time > 180 min) were subjected to multivariate regression analysis. Long-term HD was identified as an independent predictor of VS (odds ratio, 2.29, 95% confidence interval, 1.66-3.18). CONCLUSIONS: Longer term HD may be associated with a higher VS incidence after cardiac surgery. VS should be given attention after cardiac surgery in chronic HD-dependent patients.

Immune Deregulation in Sepsis and Septic Shock: Reversing Immune Paralysis by Targeting PD-1/PD-L1 Pathway.

Sepsis remains a major problem for human health worldwide, thereby manifesting high rates of morbidity and mortality. Sepsis, once understood as a monophasic sustained hyperinflammation, is currently recognized as a dysregulated host response to infection, with both hyperinflammation and immunoparalysis occurring simultaneously from the earliest stages of sepsis, involving multiple organ dysfunctions. Despite the recent progress in the understanding of the pathophysiology underlying sepsis, no specific treatment to restore immune dysregulation in sepsis has been validated in clinical trials. In recent years, treatment for immune checkpoints such as the programmed cell death protein 1/programmed death ligand (PD-1/PD-L) pathway in tumor-infiltrating T-lymphocytes has been successful in the field of cancer immune therapy. As immune-paralysis in sepsis involves exhausted T-lymphocytes, future clinical applications of checkpoint inhibitors for sepsis are expected. In addition, the functions of PD-1/PD-L on innate lymphoid cells and the role of exosomal forms of PD-L1 warrant further research. Looking back on the history of repeatedly failed clinical trials of immune modulatory therapies for sepsis, sepsis must be recognized as a difficult disease entity for performing clinical trials. A major obstacle that could prevent effective clinical trials of drug candidates is the disease complexity and heterogeneities; clinically diagnosed sepsis could contain multiple sepsis subgroups that suffer different levels of hyper-inflammation and immune-suppression in distinct organs. Thus, the selection of appropriate more homogenous sepsis subgroup is the key for testing the clinical efficacy of experimental therapies targeting specific pathways in either hyperinflammation and/or immunoparalysis. An emerging technology such as artificial intelligence (AI) may help to identify an immune paralysis subgroup who would best be treated by PD-1/PD-L1 pathway inhibitors.

Transient Neurological Events After Surgery for Pediatric Moyamoya Disease: A Retrospective Study of Postoperative Sedation Practices.

BACKGROUND: Moyamoya disease is a cerebrovascular disease characterized by bilateral stenosis of the intracranial internal carotid arteries and an abnormal collateral vascular network at the base of the brain. Transient neurological events (TNEs), which are episodes of neurological dysfunction lasting <24 hours, are associated with stroke in pediatric patients with Moyamoya disease. Perioperative agitation often occurs in pediatric patients. We hypothesized that anesthetic technique and postoperative sedation would modify the association between TNE and superficial temporal artery-middle cerebral artery (STA-MCA) bypass in pediatric patients with Moyamoya disease. METHODS: We retrospectively reviewed the medical records of patients with Moyamoya disease aged 15 years and below who underwent STA-MCA bypass under general anesthesia at a single cerebrovascular center in Japan between January 1999 and March 2016. The primary outcome was TNE. Mixed-effects logistic regression was used to evaluate whether postoperative sedation and anesthetic agents were associated with TNE. RESULTS: Among 277 hemispheres in 154 pediatric patients who underwent STA-MCA bypass, 107 patients (39%) experienced TNE within 1 week after surgery. Crying (adjusted odds ratio, 3.11; 95% confidence interval, 1.01-9.59; P=0.048) was an independent risk factor for TNE. Postoperative sedation was associated with a lower incidence of TNE (adjusted odds ratio, 0.514; 95% confidence interval, 0.264-0.997; P=0.049), but premedication and anesthetic agents were not associated with TNE. CONCLUSION: In pediatric patients with Moyamoya disease, crying was associated with increased TNE and postoperative sedation is associated with decreased TNE.

Use of preoperative haemostasis and ABO blood typing tests in children: a retrospective observational study using a nationwide claims database in Japan.

OBJECTIVES: To describe the prevalence and factors associated with preoperative haemostasis and ABO blood typing tests for children because these tests might represent low-value care. DESIGN: A retrospective observational study. SETTING: Nationwide insurance claims database in Japan. PARTICIPANTS: Patients aged 1-17 years who underwent common non-cardiac surgeries between April 2012 and March 2018 were included. Patients with high-risk comorbidities for bleeding (n=175) and those with multiple eligible surgeries were excluded (n=2121). MAIN OUTCOME MEASURES: We described the proportions of each preoperative test performed within 60 days before an index surgery, including platelet count, prothrombin time (PT), activated partial thromboplastin time (aPTT) and ABO blood typing tests. We also explored the associations between patient-level and institutional-level factors and any preoperative tests, using multilevel logistic regression analysis. RESULTS: We included 13 018 patients (median (IQR) age, 5.2 (2.9-7.7) years; 8276 (63.6%) boys) from 1499 institutions. The overall proportion of each test was as follows: platelet count, 78.6%; PT, 54.4%; aPTT, 56.4% and ABO blood typing tests, 50.4%. The proportion of patients undergoing any preoperative tests in the overall sample was 79.3%. Multilevel logistic regression analysis indicated that preoperative tests were associated with type of anaesthesia (general anaesthesia: adjusted OR 7.06; 95% CI 4.94 to 10.11), type of surgery (tonsillectomy: adjusted OR 3.45; 95% CI 2.75 to 4.33) and surgical setting (inpatient procedure: adjusted OR 5.41; 95% CI 3.83 to 7.66). There was one postoperative transfusion event (0.008%) in the entire cohort and 37 postoperative reoperation events for surgical bleeding after tonsillectomy (0.90%). CONCLUSIONS: In the largest Japanese cohort reported to date, preoperative haemostasis and ABO blood typing tests were performed in a majority of children prior to common paediatric surgeries. Preoperative tests were associated with anaesthesia, surgical type and surgical setting.

Reiterative ventricular fibrillation caused by R-on-T during temporary epicardial pacing: a case report.

Epicardial pacemaker wire insertion is standard following cardiothoracic surgery. However, undersensing of pacing wires may cause the R-on-T phenomenon, which induces ventricular fibrillation. We report a case of a male patient with severe mitral regurgitation scheduled for mitral valve replacement who experienced two ventricular fibrillation episodes related to the R-on-T phenomenon caused by undersensing of the epicardial pacing wire. Both undersensing events happened despite an appropriately low sensing threshold. Notably, the stimulated T wave followed the QRS of the premature ventricular contraction (PVC). This case suggests that a PVC's R wave may be undersensed despite a low sensing threshold. This critical complication may have occurred because pacemakers sense R waves using a slew rate, which is the quotient of voltage over time. As a result, pacemakers may undersense wide QRS waves such as PVCs. Avoiding this dangerous phenomenon completely is not possible using epicardial pacemakers; therefore we recommend carefully adapting epicardial pacing especially when PVC waves occur frequently.