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Sepsis remains one of the leading causes of death worldwide. Oncostatin M (OSM), an interleukin (IL)-6 family cytokine, can be found at high levels in septic patients. However, little is known about its role in sepsis. This study aimed to determine if the genetic knockout of OSM receptor (OSMR) type II signaling would improve survival in a murine model of sepsis. Aged (>50 weeks) OSMR type II knockout (KO) mice and wild-type (WT) littermates received an intraperitoneal injection of fecal slurry (FS) or vehicle. The KO mice had better survival 48 h after the injection of FS than the WT mice ( p = 0.005). Eighteen hours post-FS injection, the KO mice had reduced peritoneal, serum, and tissue cytokine levels (including IL-1β, IL-6, TNFα, KG/GRO, and IL-10) compared to the WT mice ( p < 0.001 for all). Flow cytometry revealed decreased recruitment of CD11b + F4/80 + Ly6c high+ macrophages in the peritoneum of KO mice compared to WT mice (34 ± 6 vs. 4 ± 3%, P Int = 0.005). Isolated peritoneal macrophages from aged KO mice had better live E. coli killing capacity than those from WT mice ( p < 0.001). Peritoneal lavage revealed greater bacterial counts in KO mice than in WT mice (KO: 305 ± 22 vs. 116 ± 6 CFU (×10 9 )/mL; p < 0.001). In summary, deficiency in OSMR type II receptor signaling provided a survival benefit in the progression of sepsis. This coincided with reduced serum levels of pro-inflammatory (IL-1β, TNFα, and KC/GRO) and anti-inflammatory markers (IL-10), increased bacterial killing ability of macrophages, and reduced macrophage infiltration into to site of infection.

Background: Up to 40% of patients are receiving opioids at the time of total knee arthroplasty (TKA) in the United States despite evidence suggesting opioids are ineffective for pain associated with arthritis and have substantial risks. Our primary objective was to determine whether preoperative opioid users had worse knee pain and physical function outcomes 12 months after TKA than patients who were opioid-naive preoperatively; our secondary objective was to determine the prevalence of opioid use before and after TKA in Alberta, Canada., Methods: In this retrospective analysis of population-based data, we identified adult patients who underwent TKA between 2013 and 2015 in Alberta. We used multivariable linear regression to examine the association between preoperative opioid use and Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain and physical function scores 12 months after TKA, adjusting for potentially confounding variables., Results: Of the 1907 patients, 592 (31.0%) had at least 1 opioid dispensed before TKA, and 124 (6.5%) were classified as long-term opioid users. Long-term opioid users had worse adjusted WOMAC pain and physical function scores 12 months after TKA than patients who were opioid-naive preoperatively (pain score β = 7.7, 95% confidence interval [CI] 4.0 to 11.6; physical function score β = 7.8, 95% CI 4.0 to 11.6; p < 0.001 for both). The majority (89 ([71.8%]) of patients who were long-term opioid users preoperatively were dispensed opioids 180-360 days after TKA, compared to 158 (12.0%) patients who were opioid-naive preoperatively., Conclusion: A substantial number of patients were dispensed opioids before and after TKA, and patients who received opioids preoperatively had worse adjusted pain and functional outcome scores 12 months after TKA than patients who were opioidnaive preoperatively. These results suggest that patients prescribed opioids preoperatively should be counselled judiciously regarding expected outcomes after TKA., Competing Interests: None declared., (© 2021 Joule Inc. or its licensors.)

Background: Computed tomography (CT) scan quantifying skeletal muscle mass is the gold standard tool to identify sarcopenia. Unfortunately, high cost, limited availability, and radiation exposure limit its use. We suggest that ultrasound of the thigh muscle could be an objective, reproducible, portable, and risk-free tool, used as a surrogate to a CT scan, to help identify frail patients with sarcopenia., Materials and Methods: We included 49 patients over 64 y old, referred to the acute care surgery service. An ultrasound of thigh muscle thickness was standardized to patient thigh length (U/S whole/L ). CT skeletal muscle index (SMI) was calculated using skeletal muscle surface area of the L3 region divided by height 2 . Frailty status was assessed using the Canadian Study of Healthy Aging Clinical Frailty Scale., Results: The mean (SD) age was 76 (8) y, and 34% (n = 17) were men. CT-defined sarcopenia was identified in 65% (n = 11) of men and 75% (n = 24) of women. In general, women had longer stay in hospital than men (mean + SD 14 ± 9 versus 7 ± 3 d, P = 0.003). There was a significant positive correlation between thigh U/S whole/L and CT SMI. There was an inverse correlation between thigh U/S whole/L and frailty score; a similar relationship was observed between CT SMI and frailty. There was an association between U/S whole/L and postoperative major complications., Conclusions: This prospective observational study illustrates that the U/S whole/L index can be used as a surrogate to CT scan, whereby it can identify elderly frail patients with sarcopenia. Thigh ultrasound should be further tested as an objective tool to assess for stratifying frailty., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: Acute intestinal ischemia-reperfusion injury (AIIRI) is a devastating clinical condition relevant to multiple diseases processes, including sepsis, trauma, transplantation, and burns. An AIIRI is a contributor to the development of multiple organ dysfunction syndrome (MODS). Oncostatin M (OSM)/oncostatin M receptor (OSMR) signaling is an unrecognized and novel candidate pathway for the mediation of MODS. In this study, we hypothesized that OSM mediates the injury mechanism of AIIRI leading to MODS. Methods: Wild-type (WT) and OSMR-knockout (OSMR -/- ) C57BL/6 mice underwent AIIRI using a well-established model of selective occlusion of the superior mesenteric artery (SMA). Serum cytokine concentrations were measured using a multiplex detection system. Further tissue analysis was conducted with polymerase chain reaction, enzyme-linked immunosorbent assay, Western blots, and histologic review. Results: Survival was significantly higher in WT than in OSMR -/- groups at 30 minutes of ischemia with 2 hours of reperfusion (100% versus 42.9%; P = 0.015). No significant differences in the degree of local intestinal injury was seen in the two groups. In contrast, the degree of lung injury, as evidenced by myeloperixodase activity, was lower in OSMR -/- animals in the early AIIRI groups. There was a greater degree of renal dysfunction in OSMR -/- mice. Oncostatin M mediated interleukin (IL)-10 upregulation, with WT animals having significantly lower IL-10 concentrations (52.04 ± 23.06 pg/mL versus 324.37 ± 140.35 pg/mL; P = 0.046). Conclusion: Oncostatin M signalling is essential during acute intestinal ischemia-reperfusion injury. An OSMR deficiency results in decreased early lung injury but increased renal dysfunction. There was a significantly increased mortality rate after AIIRI in mice with OSMR deficiency. Augmentation of OSM may be a novel immunomodulatory strategy for AIIRI.

Background: A significant number of patients use opioids prior to total joint arthroplasty (TJA) in North America and there is growing concern that preoperative opioid use negatively impacts postoperative patient outcomes after surgery. This systematic review and meta-analysis evaluated the current evidence investigating the influence of preoperative opioid use on postoperative patient-reported outcomes (PRO) after total joint arthroplasty., Methods: A systematic search was performed using Ovid, Embase, Cochrane Library, Scopus, Web of Science Core Collection, CINAHL on February 15th, 2018. Studies reporting baseline and postoperative PRO among those prescribed preoperative opioids and those who were not prior to total knee and hip arthroplasty were included. Standardized mean differences (SMD) in absolute difference and relative change in PRO measures between the two groups was calculated using random effect models., Results: Six studies were included (n = 7356 patients); overall 24% of patients were prescribed preoperative opioids. Patients with preoperative opioid use had worse absolute postoperative PRO scores when compared to those with no preoperative opioid use (standardized mean difference (SMD) -0.53, 95% Confidence interval (CI) -0.75, - 0.32, p < 0.0001). When relative change in PRO score was analyzed, as measured by difference between postoperative and preoperative PRO scores, there was no group differences (SMD -0.26, 95% CI -0.56, 0.05, p = 0.10)., Conclusion: Patients prescribed preoperative opioids may attain worse overall pain and function benefits after TJA when compared to opioid-naïve patients, but do still benefit from undergoing TJA. These results suggest preoperative opioid users should be judiciously counselled regarding potential postoperative pain and function improvements after TJA.

Background: Among older inpatients, the highest incidence of delirium is within the surgical population. Limited data are available regarding postoperative delirium risk in the acute care surgical population. The purpose of our study was to establish the incidence of and risk factors for delirium in an older acute care surgery population., Methods: Patients aged 65 years or more who had undergone acute care surgery between April 2014 and September 2015 at 2 university-affiliated hospitals in Alberta were followed prospectively and screened for delirium by means of a validated chart review method. Delirium duration was recorded. We used separate multivariable logistic regression models to identify independent predictors for overall delirium and longer episodes of delirium (duration ≥ 48 h)., Results: Of the 322 patients included, 73 (22.7%) were identified as having experienced delirium, with 49 (15.2%) experiencing longer episodes of delirium. Postoperative delirium risk factors included Foley catheter use, intestinal surgery, gallbladder surgery, appendix surgery, intensive care unit (ICU) admission and mild to moderate frailty. Risk factors for prolonged postoperative delirium included Foley catheter use and mild to moderate frailty. Surgical approach (open v. laparoscopic) and overall operative time were not found to be significant., Conclusion: In keeping with the literature, our study identified Foley catheter use, frailty and ICU admission as risk factors for delirium in older acute care surgical patients. We also identified an association between delirium risk and the specific surgical procedure performed. Understanding these risk factors can assist in prevention and directed interventions for this high-risk population., Competing Interests: None declared., (© 2019 Joule Inc. or its licensors)

We have developed a novel, intraluminal preservation solution that is tailored to the metabolic requirements of the intestine. This organ-specific solution addresses many of the problems associated with low temperature organ storage including energy, oxidative and osmotic stresses. However, conservation of energy levels remains one of the most difficult obstacles to overcome due to the inherent sensitivity of the mucosa to ischemia. Creatine-loading has become a popular and scientifically proven method of augmenting energy reserves in athletes performing anaerobic burst work activities. We hypothesized that if we could develop a method that was able to augment cellular energy levels, the structure and function of the mucosa would be more effectively preserved. The purpose of this study was to determine if creatine-loading is a feasible and effective strategy for preserving the intestine. Our data indicate that creatine loading has significant impact on energy levels during storage with corresponding improvements in mucosal structure and function. Both of our rodent models, a) continuous perfusion for 4 h and b) a single flush with our intraluminal preservation solution supplemented with 50 mM creatine, demonstrated significant improvements in creatine phosphate, ATP, Energy Charge and ATP/AMP following cold storage (P < 0.05). Notably, after 10 h creatine phosphate was 324% greater in Creatine-treated tissues compared to Controls (P < 0.05). Preferential utilization of glutathione in the Creatine group was effective at controlling oxidative injury after 10 h storage (P < 0.05). Improvements in barrier function and electrophysiology with creatine-treatment reflected superior mucosal integrity after 10 h storage; Permeability and Transepithelial resistance measurements remained at fresh tissue values. This was in stark contrast to Control tissues in which permeability rose to >300% of fresh tissue values (P < 0.005) and transepithelial resistance dropped by 95% (P < 0.005). After 10 h storage, Park's grading of histologic injury reflected extensive villus denudation (grade 4) in control tissues compared to healthy tissue (grade 0) in the Creatine group. This study demonstrates that a strategy of creatine supplementation of our intraluminal preservation solution facilitates the preservation of the intestinal mucosa during storage., (Copyright © 2018. Published by Elsevier Inc.)

Background: Frailty is a state of vulnerability to diverse stressors. We assessed the impact of frailty on outcomes after discharge in older surgical patients., Methods: We prospectively followed patients 65 years of age or older who underwent emergency abdominal surgery at either of 2 tertiary care centres and who needed assistance with fewer than 3 activities of daily living. Preadmission frailty was defined according to the Canadian Study of Health and Aging Clinical Frailty Scale as "well" (score 1 or 2), "vulnerable" (score 3 or 4) or "frail" (score 5 or 6). We assessed composite end points of 30-day and 6-month all-cause readmission or death by multivariable logistic regression., Results: Of 308 patients (median age 75 [range 65-94] yr, median Clinical Frailty Score 3 [range 1-6]), 168 (54.5%) were classified as vulnerable and 68 (22.1%) as frail. Ten (4.2%) of those classified as vulnerable or frail received a geriatric consultation. At 30 days after discharge, the proportions of patients who were readmitted or had died were greater among vulnerable patients ( n = 27 [16.1%]; adjusted odds ratio [OR] 4.60, 95% confidence interval [CI] 1.29-16.45) and frail patients ( n = 12 [17.6%]; adjusted OR 4.51, 95% CI 1.13-17.94) than among patients who were well ( n = 3 [4.2%]). By 6 months, the degree of frailty independently and dose-dependently predicted readmission or death: 56 (33.3%) of the vulnerable patients (adjusted OR 2.15, 95% CI 1.01-4.55) and 37 (54.4%) of the frail patients (adjusted OR 3.27, 95% CI 1.32-8.12) were readmitted or had died, compared with 11 (15.3%) of the patients who were well., Interpretation: Vulnerability and frailty were prevalent in older patients undergoing surgery and unlikely to trigger specialized geriatric assessment, yet remained independently associated with greater risk of readmission for as long as 6 months after discharge. Therefore, the degree of frailty has important prognostic value for readmission., Trial Registration for Primary Study: ClinicalTrials.gov, no. NCT02233153., Competing Interests: Competing interests: None declared., (© 2018 Joule Inc. or its licensors.)

Background: As populations age, more elderly patients will undergo surgery. Frailty and complications are considered to increase in-hospital cost in older adults, but little is known on costs following discharge, particularly those borne by the patient. We examined risk factors for increased cost and the type of costs accrued following discharge in elderly surgical patients., Methods: Acute abdominal surgery patients aged 65 years and older were prospectively enrolled. We assessed baseline clinical characteristics, including Clinical Frailty Scale (CFS) scores. We calculated 6-month cost (in Canadian dollars) from patient-reported use following discharge according to the validated Health Resource Utilization Inventory. Primary outcomes were 6-month overall cost and cost for health care services, medical products and lost productive hours. Outcomes were log-transformed and assessed in multivariable generalized linear and zero-inflated negative binomial regressions and can be interpreted as adjusted ratios (AR). Complications were assessed according to Clavien-Dindo classification., Results: We included 150 patients (mean age 75.5 ± 7.6 yr; 54.1% men) in our analysis; 10.8% had major and 43.2% had minor complications postoperatively. The median 6-month overall cost was $496 (interquartile range $140-$1948). Disaggregated by cost type, frailty independently predicted increasing costs of health care services (AR 1.76, 95% confidence interval [CI] 1.43-2.18, p < 0.001) and medical products (AR 1.61, 95% CI 1.15-2.25, p = 0.005), but decreasing costs in lost productive hours (AR 0.39, p = 0.002). Complications did not predict increased cost., Conclusion: Frail patients accrued higher health care services and product costs, but lower costs from lost productive hours. Interventions in elderly surgical patients should consider patient-borne cost in older adults and lost productivity in less frail patients., Trial Registration: NCT02233153 (clinicaltrials.gov).

Sepsis and septic shock are the leading causes of death in critically ill patients. Acute intestinal ischemia/reperfusion (AII/R) is an adaptive response to shock. The high mortality rate from AII/R is due to the severity of the disease and, more importantly, the failure of timely diagnosis. The objective of this investigation is to use nuclear magnetic resonance (NMR) analysis to characterize urine metabolomic profile of AII/R injury in a mouse model. Animals were exposed to sham, early (30 min) or late (60 min) acute intestinal ischemia by complete occlusion of the superior mesenteric artery, followed by 2 hrs of reperfusion. Urine was collected and analyzed by NMR spectroscopy. Urinary metabolite concentrations demonstrated that different profiles could be delineated based on the duration of the intestinal ischemia. Metabolites such as allantoin, creatinine, proline, and methylamine could be predictive of AII/R injury. Lactate, currently used for clinical diagnosis, was found not to significantly contribute to the classification model for either early or late ischemia. This study demonstrates that patterns of changes in urinary metabolites are effective at distinguishing AII/R progression in an animal model. This is a proof-of-concept study to further support examination of metabolites in the clinical diagnosis of intestinal ischemia reperfusion injury in patients. The discovery of a fingerprint metabolite profile of AII/R will be a major advancement in the diagnosis, treatment, and prevention of systemic injury in critically ill patients.

Background: Acute mesenteric ischemia (AMI) has a high morbidity and mortality and often presents as a diagnostic challenge. Currently, there is no blood, urine, or radiologic tests that provide a definitive diagnosis of AMI. The aim of this study was to evaluate the clinical accuracy of urine intestinal fatty acid-binding protein (I-FABP) to diagnosis AMI., Materials and Methods: Twenty patients referred to the Acute Care Surgery service at University of Alberta Hospital with suspected AMI taken to the operating room for definitive diagnosis were recruited. Pathologic findings from surgical specimens confirmed a gold standard diagnosis for intestinal ischemia. The patients found to be nonischemic became the internal controls. Conventional clinical markers were examined in blood including white blood cell count, lactate, and creatinine. Blood was also examined by enzyme-linked immunosorbent assays (ELISAs) for I-FABP and interleukin-6. Urine was examined preoperatively and 6 and 24 h postoperatively for I-FABP., Results: Thirteen patients were pathologically diagnosed with AMI while five patients were nonischemic; two were excluded due to missing biologic specimens. There was no difference in age or gender between ischemic and nonischemic patients (56 ± 5 versus 66 ± 11 years old, respectively; six females with ischemic and three females in the nonischemic group). There was no difference in serum lactate and creatinine between the two groups. Serum interleukin-6 levels in patients with AMI were significantly higher than nonischemic controls (0.4 ± 0.2 ng/mL versus 0.2 ± 0.07 ng/mL, respectively, P = 0.03). There was a nonstatistically significant increase in serum I-FABP in AMI patients compared to internal controls (9 ± 3 ng/mL versus 2.4 ± 0.9 ng/mL, respectively, P = 0.2). Urine I-FABP was significantly higher in patients diagnosed with AMI than in controls (7 ± 1 ng/mL versus 2 ± 1 ng/mL, respectively, P = 0.007). The receiver operating characteristic curve illustrated that urine I-FABP discriminates significantly between patients with AMI and controls (area under receiver operating characteristic = 0.88, P = 0.03)., Conclusions: The traditional clinical markers lactate and white blood cell count were not able to differentiate AMI from nonischemic bowel. However, we found that urine I-FABP was a noninvasive biomarker with high specificity and sensitivity for accurately diagnosing AMI in patients. A noninvasive accurate tool for AMI would facilitate for a rapid treatment, while preventing unnecessary surgical interventions in high-risk patient populations., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Acute mesenteric ischemia (AMI) is a life-threatening condition that can result in multiple organ injury and death. A timely diagnosis and treatment would have a significant impact on the morbidity and mortality in high-risk patient population. The purpose of this study was to investigate if intestinal fatty acid binding protein (I-FABP) and α-defensins can be used as biomarkers for early AMI and resultant lung injury. C57BL/6 mice were subjected to intestinal ischemia by occlusion of the superior mesenteric artery. A time course of intestinal ischemia from 0.5 to 3 h was performed and followed by reperfusion for 2 h. Additional mice were treated with N-acetyl-cysteine (NAC) at 300 mg/kg given intraperitoneally prior to reperfusion. AMI resulted in severe intestinal injury characterized by neutrophil infiltrate, myeloperoxidase (MPO) levels, cytokine/chemokine levels, and tissue histopathology. Pathologic signs of ischemia were evident at 1 h, and by 3 h of ischemia, the full thickness of the intestine mucosa had areas of coagulative necrosis. It was noted that the levels of α-defensins in intestinal tissue peaked at 1 h and I-FABP in plasma peaked at 3 h after AMI. Intestinal ischemia also resulted in lung injury in a time-dependent manner. Pretreatment with NAC decreased the levels of intestinal α-defensins and plasma I-FABP, as well as lung MPO and cytokines. In summary, the concentrations of intestinal α-defensins and plasma I-FABP predicted intestinal ischemia prior to pathological evidence of ischemia and I-FABP directly correlated with resultant lung injury. The antioxidant NAC reduced intestinal and lung injury induced by AMI, suggesting a role for oxidants in the mechanism for distant organ injury. I-FABP and α-defensins are promising biomarkers, and may guide the treatment with antioxidant in early intestinal and distal organ injury.