Andrew D. Shaw

KIR enrichment at the effector-target cell interface is more sensitive than signaling to the strength of ligand binding

Target cell lysis by natural killer cells is inhibited by killer cell immunoglobulin‐like receptors (KIR) that bind major histocompatibility complex classu2004I molecules. Many lymphocyte receptors, including KIR, become enriched at the interface with ligand‐bearing cells. The contribution of the enrichment to inhibitory signaling has not been determined. We now describe a KIR variant with enhanced green fluorescent protein (EGFP) at the Nu2004terminus that can mediate inhibitory signaling, but its enrichment is markedly reduced. This receptor is only slightly weaker at inhibiting lysis than the same KIR tagged with EGFP in the cytoplasmic tail, even though the latter enriched as extensively as wild‐type KIR. A slight defect was also detected in the ability of the receptor to reduce adhesion to target cells and for binding of a soluble counterpart to cell surface HLA‐C. Our findings suggest that the strength of the interaction required to readily detect receptor enrichment exceeds that required for signaling.

American Society for Enhanced Recovery (ASER) and Perioperative Quality Initiative (POQI) joint consensus statement on perioperative fluid management within an enhanced recovery pathway for colorectal surgery

BackgroundEnhanced recovery may be viewed as a comprehensive approach to improving meaningful outcomes in patients undergoing major surgery. Evidence to support enhanced recovery pathways (ERPs) is strong in patients undergoing colorectal surgery. There is some controversy about the adoption of specific elements in enhanced recovery “bundles” because the relative importance of different components of ERPs is hard to discern (a consequence of multiple simultaneous changes in clinical practice when ERPs are initiated). There is evidence that specific approaches to fluid management are better than alternatives in patients undergoing colorectal surgery; however, several specific questions remain.MethodsIn the “Perioperative Quality Initiative (POQI) Fluids” workgroup, we developed a framework broadly applicable to the perioperative management of intravenous fluid therapy in patients undergoing elective colorectal surgery within an ERP.DiscussionWe discussed aspects of ERPs that impact fluid management and made recommendations or suggestions on topics such as bowel preparation; preoperative oral hydration; intraoperative fluid therapy with and without devices for goal-directed fluid therapy; and type of fluid.

American Society for Enhanced Recovery (ASER) and Perioperative Quality Initiative (POQI) joint consensus statement on optimal analgesia within an enhanced recovery pathway for colorectal surgery: part 1—from the preoperative period to PACU

BackgroundWithin an enhanced recovery pathway (ERP), the approach to treating pain should be multifaceted and the goal should be to deliver “optimal analgesia,” which we define in this paper as a technique that optimizes patient comfort and facilitates functional recovery with the fewest medication side effects.MethodsWith input from a multi-disciplinary, international group of clinicians, and through a structured review of the literature and use of a modified Delphi method, we achieved consensus surrounding the topic of optimal analgesia in the perioperative period for colorectal surgery patients.DiscussionAs a part of the first Perioperative Quality Improvement (POQI) workgroup meeting, we sought to develop a consensus document describing a comprehensive, yet rational and practical, approach for developing an evidence-based plan for achieving optimal analgesia, specifically for a colorectal surgery ERP. The goal was two-fold: (a) that application of this process would lead to improved patient outcomes and (b) that investigation of the questions raised would identify knowledge gaps to aid the direction for research into analgesia within ERPs in the years to come. This document details the evidence for a wide range of analgesic components, with particular focus from the preoperative period to the post-anesthesia care unit. The overall conclusion is that the combination of analgesic techniques employed in the perioperative period is not important as long as it is effective in delivering the goal of optimal analgesia as set forth in this document.

American Society for Enhanced Recovery (ASER) and Perioperative Quality Initiative (POQI) joint consensus statement on prevention of postoperative infection within an enhanced recovery pathway for elective colorectal surgery

BackgroundColorectal surgery (CRS) patients are an at-risk population who are particularly vulnerable to postoperative infectious complications. Infectious complications range from minor infections including simple cystitis and superficial wound infections to life-threatening situations such as lobar pneumonia or anastomotic leak with fecal peritonitis. Within an enhanced recovery pathway (ERP), there are multiple approaches that can be used to reduce the risk of postoperative infections.MethodsWith input from a multidisciplinary, international group of experts and through a focused (non-systematic) review of the literature, and use of a modified Delphi method, we achieved consensus surrounding the topic of prevention of postoperative infection in the perioperative period for CRS patients.DiscussionAs a part of the first Perioperative Quality Initiative (POQI-1) workgroup meeting, we sought to develop a consensus statement describing a comprehensive, yet practical, approach for reducing postoperative infections, specifically for CRS within an ERP. Surgical site infection (SSI) is the most common postoperative infection. To reduce SSI, we recommend routine use of a combined isosmotic mechanical bowel preparation with oral antibiotics before elective CRS and that infection prevention strategies (also called bundles) be routinely implemented as part of colorectal ERPs. We recommend against routine use of abdominal drains. We also give consensus guidelines for reducing pneumonia, urinary tract infection, and central line-associated bloodstream infection (CLABSI).

American Society for Enhanced Recovery (ASER) and Perioperative Quality Initiative (POQI) joint consensus statement on measurement to maintain and improve quality of enhanced recovery pathways for elective colorectal surgery

BackgroundThis article sets out a framework for measurement of quality of care relevant to enhanced recovery pathways (ERPs) in elective colorectal surgery. The proposed framework is based on established measurement systems and/or theories, and provides an overview of the different approaches for improving clinical monitoring, and enhancing quality improvement or research in varied settings with different levels of available resources.MethodsUsing a structure-process-outcome framework, we make recommendations for three hierarchical tiers of data collection.DiscussionCore, Quality Improvement, and Best Practice datasets are proposed. The suggested datasets incorporate patient data to describe case-mix, process measures to describe delivery of enhanced recovery and clinical outcomes. The fundamental importance of routine collection of data for the initiation, maintenance, and enhancement of enhanced recovery pathways is emphasized.

American Society for Enhanced Recovery (ASER) and Perioperative Quality Initiative (POQI) Joint Consensus Statement on Optimal Analgesia within an Enhanced Recovery Pathway for Colorectal Surgery: Part 2—From PACU to the Transition Home

BackgroundWithin an enhanced recovery pathway (ERP), the approach to treating pain should be multifaceted and the goal should be to deliver “optimal analgesia”, which we define in this paper as a technique that optimizes patient comfort and facilitates functional recovery with the fewest medication side effects.MethodsWith input from a multidisciplinary, international group of experts and through a structured review of the literature and use of a modified Delphi method, we achieved consensus surrounding the topic of optimal analgesia in the perioperative period for colorectal surgery patients.DiscussionAs a part of the first Perioperative Quality Improvement (POQI) workgroup meeting, we sought to develop a consensus document describing a comprehensive, yet rational and practical, approach for developing an evidence-based plan for achieving optimal analgesia, specifically for a colorectal surgery within an ERP. The goal was twofold: (a) that application of this process would lead to improved patient outcomes and (b) that investigation of the questions raised would identify knowledge gaps to aid the direction for research into analgesia within ERPs in the years to come. This document details the evidence for a wide range of analgesic components, with particular focus on care in the post-anesthesia care unit, general care ward, and transition to home after discharge. The preoperative and operative consensus statement for analgesia was covered in Part 1 of this paper. The overall conclusion is that the combination of analgesic techniques employed in the perioperative period is not important as long as it is effective in delivering the goal of “optimal analgesia” as set forth in this document.

2-Aminopurine Enhances the Oncolytic Activity of an E1b-Deleted Adenovirus in Hepatocellular Carcinoma Cells

Adenoviruses with deletions of viral genes have been extensively studied as potential cancer therapeutics. Although a high degree of cancer selectivity has been demonstrated with these conditionally replicating adenoviruses, low levels of virus replication can be detected in normal cells. Furthermore, these mutations were also found to reduce the activity of the replicating viruses in certain cancer cells. Recent studies have shown that co-administration of chemotherapeutic drugs may increase the activity of these viruses without affecting their specificity. We constructed an adenovirus with deletions of both the E1b and the VA-RNA genes and found that replication of this virus was selective for human hepatocellular carcinoma (HCC) cell lines when compared to normal cell lines. Furthermore, we show that 2-aminopurine (2′AP) treatment selectively enhanced virus replication and virus-mediated death of HCC cells. 2′AP did not compensate for the loss of VA-RNA activities, but rather the loss of an E1b-55K activity, such as the DNA damage response, suggesting that co-administration of 2′AP derivatives that block host DNA damage response, may increase the oncolytic activity of AdΔE1bΔVA without reducing its selectivity for HCC cells.

Pulmonary artery catheter use in adult patients undergoing cardiac surgery: a retrospective, cohort study

BackgroundThe utility of pulmonary artery catheters (PACs) and their measurements depend on a variety of factors including data interpretation and personnel training. This US multi-center, retrospective electronic health record (EHR) database analysis was performed to identify associations between PAC use in adult cardiac surgeries and effects on subsequent clinical outcomes.MethodsThis cohort analysis utilized the Cerner Health Facts database to examine patients undergoing isolated coronary artery bypass graft (CABG), isolated valve surgery, aortic surgery, other complex non-valvular and multi-cardiac procedures, and/or heart transplant from January 1, 2011, to June 30, 2015. A total of 6844 adults in two cohorts, each with 3422 patients who underwent a qualifying cardiac procedure with or without the use of a PAC for monitoring purposes, were included. Patients were matched 1:1 using a propensity score based upon the date and type of surgery, hospital demographics, modified European System for Cardiac Operative Risk Evaluation (EuroSCORE II), and patient characteristics. Primary outcomes of 30-day in-hospital mortality, length of stay, cardiopulmonary morbidity, and infectious morbidity were analyzed after risk adjustment for acute physiology score.ResultsThere was no difference in the 30-day in-hospital mortality rate between treatment groups (OR, 1.17; 95% CI, 0.65–2.10; pu2009=u20090.516). PAC use was associated with a decreased length of stay (9.39xa0days without a PAC vs. 8.56xa0days with PAC; pu2009<u20090.001), a decreased cardiopulmonary morbidity (OR, 0.87; 95% CI, 0.79–0.96; pu2009<u20090.001), and an increased infectious morbidity (OR, 1.28; 95% CI, 1.10–1.49; pu2009<u20090.001).ConclusionsUse of a PAC during adult cardiac surgery is associated with decreased length of stay, reduced cardiopulmonary morbidity, and increased infectious morbidity but no increase in the 30-day in-hospital mortality. This suggests an overall potential benefit associated with PAC-based monitoring in this population.Trial registrationThe study was registered at clinicaltrials.gov (NCT02964026) on November 15, 2016.

Core Concepts: Post-cardiac Surgery Acute Kidney Injury

Acute kidney injury (AKI) complicates the postoperative course in 30% of adult cardiac surgery patients. Similar rates are observed in pediatric cardiac surgery patients. In both children and adults, a diagnosis of AKI carries a marked increase of extrarenal organ morbidity and a fivefold increase in the risk of death during hospitalization. Renal ischemia, inflammation, hemolysis, and oxidative stress contribute to the development of AKI after cardiac surgery. Preventive strategies for AKI following cardiac surgery remain limited, including maintenance of renal perfusion and intravascular volume while avoiding volume overload, administration of balanced salt crystalloid intravenous fluids, and limiting the duration of cardiopulmonary bypass. Although severe AKI requiring dialysis is rare after cardiac surgery, mild AKI is common. This is significant, as it increases the incidence of new and progressive chronic kidney disease. In turn, this complication leads to adverse medium- and long-term outcomes in cardiac surgical patients. Several early-phase clinical trials are underway in cardiac surgery patients, both for the prevention and treatment of AKI. The findings of these studies may lead to the approval of new therapeutic options for this important complication of heart surgery. In conjunction with this, the development and validation of biomarkers indicative of tubular damage to predict AKI onset and prognosis may supplant creatinine-based criteria for AKI endpoints in clinical trials and become incorporated in future consensus guidelines for clinical diagnosis.

Fluids and Organ Dysfunction: A Narrative Review of the Literature and Discussion of 5 Controversial Topics

Evidence-based clinical decision making is at the forefront of modern cardiothoracic anesthesia practice. Therefore, as a field, cardiac anesthesiologist should strive to ensure that the available evidence is of the highest possible quality. In this narrative review, 5 important topics that the authors believe require additional investigation in cardiothoracic anesthesia and critical care related to fluid therapy and organ dysfunction are outlined briefly. In particular, the authors believe that the areas of pulmonary artery catheter use, restrictive versus liberal transfusion strategies, cardiopulmonary bypass prime composition, colloid use in resuscitation and its effects on acute kidney injury, and management of acute kidney injury after cardiac surgery hold many unanswered questions and opportunities for continued improvement in the specialty of cardiac anesthesia. This article accompanies a presentation at the 46th Association of Cardiac Anesthesiologists Annual Meeting on October 22, 2017.