End organ perfusion and pediatric microcirculation assessment

Cardiovascular instability and reduced oxygenation are regular perioperative critical events associated with anesthesia requiring intervention in neonates and young infants. This review article addresses the current modalities of assessing this population's adequate end-organ perfusion in the perioperative period. Assuring adequate tissue oxygenation in critically ill infants is based on parameters that measure acceptable macrocirculatory hemodynamic parameters such as vital signs (mean arterial blood pressure, heart rate, urinary output) and chemical parameters (lactic acidosis, mixed venous oxygen saturation, base deficit). Microcirculation assessment represents a promising candidate for assessing and improving hemodynamic management strategies in perioperative and critically ill populations. Evaluation of the functional state of the microcirculation can parallel improvement in tissue perfusion, a term coined as “hemodynamic coherence”. Less information is available to assess microcirculatory disturbances related to higher mortality risk in critically ill adults and pediatric patients with septic shock. Techniques for measuring microcirculation have substantially improved in the past decade and have evolved from methods that are limited in scope, such as velocity-based laser Doppler and near-infrared spectroscopy, to handheld vital microscopy (HVM), also referred to as videomicroscopy. Available technologies to assess microcirculation include sublingual incident dark field (IDF) and sublingual sidestream dark field (SDF) devices. This chapter addresses (1) the physiological basis of microcirculation and its relevance to the neonatal and pediatric populations, (2) the pathophysiology associated with altered microcirculation and endothelium, and (3) the current literature reviewing modalities to detect and quantify the presence of microcirculatory alterations

Patient Safety in the Critical Care Setting: Common Risks and Review of Evidence-Based Mitigation Strategies

The Intensive Care Unit (ICU) has evolved in the last 50 years. This evolution’s main drivers include equipment and software improvements, the patient safety movement, and a better pathophysiological understanding of critical illness. There is mounting pressure from accreditation agencies, governmental regulation, financial challenges, operational dynamics, staffing changes, and increased acuity affecting-ICU care delivery and impacting patient safety. There are higher than ever expectations to improve clinical outcomes after an intensive care stay, to enhance patient safety, to increase family involvement in decision making, and merge the multidisciplinary medical experience into an effective teamwork. Leadership focus is directed towards increasing diversity and inclusion in the workforce while enhancing psychological safety. This review addresses the common risks for patient safety in the intensive care setting and describes the changes in mindset and application of evidence-based mitigation strategies

Activating PIK3CA Mutations Induce an Epidermal Growth Factor Receptor (EGFR)/Extracellular Signal-regulated Kinase (ERK) Paracrine Signaling Axis in Basal-like Breast Cancer

Mutations in PIK3CA, the gene encoding the p110α catalytic subunit of phosphoinositide 3-kinase (PI3K) have been shown to transform human mammary epithelial cells (MECs). These mutations are present in all breast cancer subtypes, including basal-like breast cancer (BLBC). Using liquid chromatography-tandem mass spectrometry (LC-MS/MS), we identified 72 protein expression changes in human basal-like MECs with knock-in E545K or H1047R PIK3CA mutations versus isogenic MECs with wild-type PIK3CA. Several of these were secreted proteins, cell surface receptors or ECM interacting molecules and were required for growth of PIK3CA mutant cells as well as adjacent cells with wild-type PIK3CA. The proteins identified by MS were enriched among human BLBC cell lines and pointed to a PI3K-dependent amphiregulin/EGFR/ERK signaling axis that is activated in BLBC. Proteins induced by PIK3CA mutations correlated with EGFR signaling and reduced relapse-free survival in BLBC. Treatment with EGFR inhibitors reduced growth of PIK3CA mutant BLBC cell lines and murine mammary tumors driven by a PIK3CA mutant transgene, all together suggesting that PIK3CA mutations promote tumor growth in part by inducing protein changes that activate EGFR

Impact of primary kidney disease on the effects of empagliflozin in patients with chronic kidney disease: secondary analyses of the EMPA-KIDNEY trial

Background: The EMPA KIDNEY trial showed that empagliflozin reduced the risk of the primary composite outcome of kidney disease progression or cardiovascular death in patients with chronic kidney disease mainly through slowing progression. We aimed to assess how effects of empagliflozin might differ by primary kidney disease across its broad population. Methods: EMPA-KIDNEY, a randomised, controlled, phase 3 trial, was conducted at 241 centres in eight countries (Canada, China, Germany, Italy, Japan, Malaysia, the UK, and the USA). Patients were eligible if their estimated glomerular filtration rate (eGFR) was 20 to less than 45 mL/min per 1·73 m2, or 45 to less than 90 mL/min per 1·73 m2 with a urinary albumin-to-creatinine ratio (uACR) of 200 mg/g or higher at screening. They were randomly assigned (1:1) to 10 mg oral empagliflozin once daily or matching placebo. Effects on kidney disease progression (defined as a sustained ≥40% eGFR decline from randomisation, end-stage kidney disease, a sustained eGFR below 10 mL/min per 1·73 m2, or death from kidney failure) were assessed using prespecified Cox models, and eGFR slope analyses used shared parameter models. Subgroup comparisons were performed by including relevant interaction terms in models. EMPA-KIDNEY is registered with ClinicalTrials.gov, NCT03594110. Findings: Between May 15, 2019, and April 16, 2021, 6609 participants were randomly assigned and followed up for a median of 2·0 years (IQR 1·5–2·4). Prespecified subgroupings by primary kidney disease included 2057 (31·1%) participants with diabetic kidney disease, 1669 (25·3%) with glomerular disease, 1445 (21·9%) with hypertensive or renovascular disease, and 1438 (21·8%) with other or unknown causes. Kidney disease progression occurred in 384 (11·6%) of 3304 patients in the empagliflozin group and 504 (15·2%) of 3305 patients in the placebo group (hazard ratio 0·71 [95% CI 0·62–0·81]), with no evidence that the relative effect size varied significantly by primary kidney disease (pheterogeneity=0·62). The between-group difference in chronic eGFR slopes (ie, from 2 months to final follow-up) was 1·37 mL/min per 1·73 m2 per year (95% CI 1·16–1·59), representing a 50% (42–58) reduction in the rate of chronic eGFR decline. This relative effect of empagliflozin on chronic eGFR slope was similar in analyses by different primary kidney diseases, including in explorations by type of glomerular disease and diabetes (p values for heterogeneity all >0·1). Interpretation: In a broad range of patients with chronic kidney disease at risk of progression, including a wide range of non-diabetic causes of chronic kidney disease, empagliflozin reduced risk of kidney disease progression. Relative effect sizes were broadly similar irrespective of the cause of primary kidney disease, suggesting that SGLT2 inhibitors should be part of a standard of care to minimise risk of kidney failure in chronic kidney disease. Funding: Boehringer Ingelheim, Eli Lilly, and UK Medical Research Council

Mortality and pulmonary complications in patients undergoing surgery with perioperative SARS-CoV-2 infection: an international cohort study

Background: The impact of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) on postoperative recovery needs to be understood to inform clinical decision making during and after the COVID-19 pandemic. This study reports 30-day mortality and pulmonary complication rates in patients with perioperative SARS-CoV-2 infection. Methods: This international, multicentre, cohort study at 235 hospitals in 24 countries included all patients undergoing surgery who had SARS-CoV-2 infection confirmed within 7 days before or 30 days after surgery. The primary outcome measure was 30-day postoperative mortality and was assessed in all enrolled patients. The main secondary outcome measure was pulmonary complications, defined as pneumonia, acute respiratory distress syndrome, or unexpected postoperative ventilation. Findings: This analysis includes 1128 patients who had surgery between Jan 1 and March 31, 2020, of whom 835 (74·0%) had emergency surgery and 280 (24·8%) had elective surgery. SARS-CoV-2 infection was confirmed preoperatively in 294 (26·1%) patients. 30-day mortality was 23·8% (268 of 1128). Pulmonary complications occurred in 577 (51·2%) of 1128 patients; 30-day mortality in these patients was 38·0% (219 of 577), accounting for 81·7% (219 of 268) of all deaths. In adjusted analyses, 30-day mortality was associated with male sex (odds ratio 1·75 [95% CI 1·28–2·40], p\textless0·0001), age 70 years or older versus younger than 70 years (2·30 [1·65–3·22], p\textless0·0001), American Society of Anesthesiologists grades 3–5 versus grades 1–2 (2·35 [1·57–3·53], p\textless0·0001), malignant versus benign or obstetric diagnosis (1·55 [1·01–2·39], p=0·046), emergency versus elective surgery (1·67 [1·06–2·63], p=0·026), and major versus minor surgery (1·52 [1·01–2·31], p=0·047). Interpretation: Postoperative pulmonary complications occur in half of patients with perioperative SARS-CoV-2 infection and are associated with high mortality. Thresholds for surgery during the COVID-19 pandemic should be higher than during normal practice, particularly in men aged 70 years and older. Consideration should be given for postponing non-urgent procedures and promoting non-operative treatment to delay or avoid the need for surgery. Funding: National Institute for Health Research (NIHR), Association of Coloproctology of Great Britain and Ireland, Bowel and Cancer Research, Bowel Disease Research Foundation, Association of Upper Gastrointestinal Surgeons, British Association of Surgical Oncology, British Gynaecological Cancer Society, European Society of Coloproctology, NIHR Academy, Sarcoma UK, Vascular Society for Great Britain and Ireland, and Yorkshire Cancer Research

A “Fundamentals” Train-the-Trainer Approach to Building Pediatric Critical Care Expertise in the Developing World

Pediatric Fundamental Critical Care Support (PFCCS) is an educational tool for training non-intensivists, nurses, and critical care practitioners in diverse health-care settings to deal with the acute deterioration of pediatric patients. Our objective was to evaluate the PFCCS course as a tool for developing a uniform, reproducible, and sustainable model for educating local health-care workers in the optimal management of critically ill children in the Republic of Georgia. Over a period of 18 months and four visits to the country, we worked with Georgian pediatric critical care leadership to complete the following tasks: (1) survey health-care needs within the Republic of Georgia, (2) present representative PFCCS lectures and simulation scenarios to evaluate interest and obtain “buy-in” from key stakeholders throughout the Georgian educational infrastructure, and (3) identify PFCCS instructor candidates. Georgian PFCCS instructor training included the following steps: (1) US PFCCS consultant and content experts presented PFCCS course to Georgian instructor candidates. (2) Simulation learning principles were taught and basic equipment was acquired. (3) Instructor candidates presented PFCCS to Georgian learners, mentored by PFCCS course consultants. Objective evaluation and debriefing with instructor candidates concluded each visit. Between training visits Georgian instructors translated PFCCS slides to the Georgian language. Six candidates were identified and completed PFCCS instructor training. These Georgian instructors independently presented the PFCCS course to 15 Georgian medical students. Student test scores improved significantly from pretest results (n = 14) (pretest: 38.7 ± 7 vs. posttest 62.7 ± 6, p < 0.05). A Likert-type scale of 1 to 5 (1 = not useful or effective, 5 = extremely useful or effective) was used to evaluate each student’s perception regarding (1) relevance of course content to clinical work students rated as median (IQR): (a) relevance of PFCCS content to clinical work, 5 (4–5); (b) effectiveness of lecture delivery, 4 (3–4); and (c) value of skill stations for clinical practice, 5 (4–5). Additionally, the mean (±SD) responses were 4.6 (±0.5), 3.7 (±0.6), and 4.5 (±0.6), respectively. Training local PFCCS instructors within an international environment is an effective method for establishing a uniform, reproducible, and sustainable approach to educating health-care providers in the fundamentals of pediatric critical care. Future collaborations will evaluate the clinical impact of PFCCS throughout the Georgian health-care system