LAUSR

Patients undergoing surgery suffer from “scheduled insult”. In general, surgical insult causes local inflammation via migrating inflammatory cells. Local inflammation is accompanied by systemic inflammatory responses characterized by fever and elevated levels of systemic inflammatory cytokines. In most cases, inflammation eventually subsides, which leads to wound healing. However, for those with severe inflammation it sometimes progresses to sepsis and multiple organ dysfunction syndrome (MODS). The mortality of sepsis and MODS, which includes acute respiratory distress syndrome (ARDS) and acute kidney injury (AKI), is high and is still regarded as a troublesome condition in critical care settings [1, 2]. Highly-invasive surgeries such as esophagectomy, pancreaticoduodenectomy, vascular surgery, cardiac surgery often associate with infectious complications, which resembles the clinical course of trauma, severe infection and sepsis. Therefore, managing patients’ postoperative immune status is based on findings reported from patients with trauma, severe infection and sepsis. The pathophysiologies of sepsis and ARDS are considered organ injuries associated with inflammatory cell infiltration mediated by systemic inflammatory responses and the subsequent release of tissue damaging mediators from inflammatory cells [3]. Systemic inflammatory response syndrome (SIRS) criteria allows the detection of early symptoms of sepsis. Patients who fulfill at least two of the following criteria are determined as SIRS: fever > 38.0 °C or < 36.0 °C, heart rate > 90 beats/min, respiratory rate > 20 breaths/min, white blood cell count > 12 × 109/L or < 4 × 109/L. SIRS scores are also used to evaluate postoperative inflammatory state. SIRS score on the second postoperative day was reported to be associated with APACHE III score at the time of evaluation, length of intensive care unit stay, multiple organ failure, and mortality [4]. Therefore, it is reasonable for researchers to consider strategies to reduce SIRS scores for better outcomes. Inhibiting inflammatory pathways including LPS binding protein, inhibiting NF-κB signaling, inhibiting adhesion molecules, and inhibiting leukocyte elastase have been investigated as therapeutic approaches for sepsis and ARDS. Although each treatment showed a promising effect in animal models, all failed to improve patient outcomes in clinical settings [5–7]. High dose steroid administration was associated with a worse outcome in a study using a large administrative database [8]. Similarly, Sivelestat sodium hydrate, a leukocyte elastase inhibitor, failed to improve the outcome for patients with pneumonia [9]. Animal studies and clinical trials reported that the mortality of sepsis increased by blocking of TNFα signaling [6]. Therefore, immune suppressive therapy might be a potential hazard that induces an immune compromised state and increases the risk of infection. Based on accumulating observations, our understanding of the pathophysiology of sepsis has evolved from simple hyper-immunity to the time-course transition of immune status— i.e., hyperto hypo-immunity, and therefore, it is acknowledged that the simple suppression/inhibition of hyper-immunity does not improve sepsis outcomes [10]. Previously, it was thought that compensatory anti-inflammatory response syndrome (CARS) comes after SIRS; however, this has changed to another scenario where the simultaneous expression of proand anti-inflammatory mediators occurs at the time of insult and the patient immune status is * Kanji Uchida [email protected]