Management of peri-surgical anemia in elective surgery. Conclusions and recommendations according to Delphi-UCLA methodology.

INTRODUCTION: Preoperative anemia affects approximately one third of surgical patients. It increases the risk of blood transfusion and influences short- and medium-term functional outcomes, increases comorbidities, complications and costs. The "Patient Blood Management" (PBM) programs, for integrated and multidisciplinary management of patients, are considered as paradigms of quality care and have as one of the fundamental objectives to correct perioperative anemia. PBM has been incorporated into the schemes for intensified recovery of surgical patients: the recent Enhanced Recovery After Surgery 2021 pathway (in Spanish RICA 2021) includes almost 30 indirect recommendations for PBM. OBJECTIVE: To make a consensus document with RAND/UCLA Delphi methodology to increase the penetration and priority of the RICA 2021 recommendations on PBM in daily clinical practice. MATERIAL AND METHODS: A coordinating group composed of 6 specialists from Hematology-Hemotherapy, Anesthesiology and Internal Medicine with expertise in anemia and PBM was formed. A survey was elaborated using Delphi RAND/UCLA methodology to reach a consensus on the key areas and priority professional actions to be developed at the present time to improve the management of perioperative anemia. The survey questions were extracted from the PBM recommendations contained in the RICA 2021 pathway. The development of the electronic survey (Google Platform) and the management of the responses was the responsibility of an expert in quality of care and clinical safety. Participants were selected by invitation from speakers at AWGE-GIEMSA scientific meetings and national representatives of PBM-related working groups (Seville Document, SEDAR HTF section and RICA 2021 pathway participants). In the first round of the survey, the anonymized online questionnaire had 28 questions: 20 of them were about PBM concepts included in ERAS guidelines (2 about general PBM organization, 10 on diagnosis and treatment of preoperative anemia, 3 on management of postoperative anemia, 5 on transfusion criteria) and 8 on pending aspects of research. Responses were organized according to a 10-point Likter scale (0: strongly disagree to 10: strongly agree). Any additional contributions that the participants considered appropriate were allowed. They were considered consensual because all the questions obtained an average score of more than 9 points, except one (question 14). The second round of the survey consisted of 37 questions, resulting from the reformulation of the questions of the first round and the incorporation of the participants' comments. It consisted of 2 questions about general organization of PBM programme, 15 questions on the diagnosis and treatment of preoperative anemia; 3 on the management of postoperative anemia, 6 on transfusional criteria and finally 11 questions on aspects pending od future investigations. Statistical treatment: tabulation of mean, median and interquartiles 25-75 of the value of each survey question (Tables 1, 2 and 3). RESULTS: Except for one, all the recommendations were accepted. Except for three, all above 8, and most with an average score of 9 or higher. They are grouped into: 1.- "It is important and necessary to detect and etiologically diagnose any preoperative anemia state in ALL patients who are candidates for surgical procedures with potential bleeding risk, including pregnant patients". 2.- "The preoperative treatment of anemia should be initiated sufficiently in advance and with all the necessary hematinic contributions to correct this condition". 3.- "There is NO justification for transfusing any unit of packed red blood cells preoperatively in stable patients with moderate anemia Hb 8-10g/dL who are candidates for potentially bleeding surgery that cannot be delayed." 4.- "It is recommended to universalize restrictive criteria for red blood cell transfusion in surgical and obstetric patients." 5.- "Postoperative anemia should be treated to improve postoperative results and accelerate postoperative recovery in the short and medium term". CONCLUSIONS: There was a large consensus, with maximum acceptance,strong level of evidence and high recommendation in most of the questions asked. Our work helps to identify initiatives and performances who can be suitables for the implementation of PBM programs at each hospital and for all patients.

A critical review of the perioperative fluid therapy and hemodynamic monitoring recommendations of the Enhanced Recovery of the Adult Pathway (RICA): A position statement of the fluid therapy and hemodynamic monitoring Subcommittee of the Hemostasis, Transfusion Medicine and Fluid Therapy Section (SHTF) of the Spanish Society of Anesthesiology and Critical Care (SEDAR).

In an effort to standardize perioperative management and improve postoperative outcomes of adult patients undergoing surgery, the Ministry of Health, through the Spanish Multimodal Rehabilitation Group (GERM), and the Aragonese Institute of Health Sciences, in collaboration with multiple Spanish scientific societies and based on the available evidence, published in 2021 the Spanish Intensified Adult Recovery (RICA) guideline. This document includes 12 perioperative measures related to fluid therapy and hemodynamic monitoring. Fluid administration and hemodynamic monitoring are not straightforward but are directly related to postoperative patient outcomes. The Fluid Therapy and Hemodynamic Monitoring Subcommittee of the Hemostasis, Transfusion Medicine and Fluid Therapy Section (SHTF) of the Spanish Society of Anesthesiology and Critical Care (SEDAR) has reviewed these recommendations and concluded that they should be revised as they do not follow an adequate methodology.

Postoperative arterial hypotension: the unnoticed enemy.

Postoperative hypotension is a frequently underestimated health problem associated with high morbidity and mortality and increased use of health care resources. It also poses significant clinical, technological, and human challenges for healthcare. As it is a modifiable and avoidable risk factor, this document aims to increase its visibility, defining its clinical impact and the technological challenges involved in optimizing its management, taking clinical-technological, humanistic, and economic aspects into account.

Fluid challenges in operating room: A planned sub study of the Fluid Day observational study.

BACKGROUND: Intraoperative fluid administration is a ubiquitous intervention in surgical patients. But inadequate fluid administration may lead to poor postoperative outcomes. Fluid challenges (FCs), in or outside the so-called goal-directed fluid therapy, allows testing the cardiovascular system and the need for further fluid administration. Our primary aim was to evaluate how anesthesiologists conduct FCs in the operating room in terms of type, volume, variables used to trigger a FC and to compare the proportion of patients receiving further fluid administration based on the response to the FC. METHODS: This was a planned substudy of an observational study conducted in 131 centres in Spain in patients undergoing surgery. RESULTS: A total of 396 patients were enrolled and analysed in the study. The median [interquartile range] amount of fluid given during a FC was 250ml (200-400). The main indication for FC was a decrease in systolic arterial pressure in 246 cases (62.2%). The second was a decrease in mean arterial pressure (54.4%). Cardiac output was used in 30 patients (7.58%), while stroke volume variation in 29 of 385 cases (7.32%). The response to the initial FC did not have an impact when prescribing further fluid administration. CONCLUSIONS: The current indication and evaluation of FC in surgical patients is highly variable. Prediction of fluid responsiveness is not routinely used, and inappropriate variables are frequently evaluated for assessing the hemodynamic response to FC, which may result in deleterious effects.

Research priorities in perioperative fluid therapy and hemodynamic monitoring: A Delphi Consensus Survey from the Fluid Therapy and Hemodynamic Monitoring Subcommittee of the Hemostasis, Transfusion Medicine and Fluid Therapy Section (SHTF) of the Spanish Society of Anesthesiology and Critical Care (SEDAR).

BACKGROUND: Research in fluid therapy and perioperative hemodynamic monitoring is difficult and expensive. The objectives of this study were to summarize these topics and to prioritize these topics in order of research importance. METHODS: Electronic structured Delphi questionnaire over three rounds among 30 experts in fluid therapy and hemodynamic monitoring identified through the Fluid Therapy and Hemodynamic Monitoring Subcommittee of the Hemostasis, Transfusion Medicine and Fluid Therapy Section of the Spanish Society of Anesthesiology and Critical Care. RESULTS: 77 topics were identified and ranked in order of prioritization. Topics were categorized into themes of crystalloids, colloids, hemodynamic monitoring and others. 31 topics were ranked as essential research priority. To determine whether intraoperative hemodynamic optimization algorithms based on the invasive or noninvasive Hypotension Prediction Index versus other management strategies could decrease the incidence of postoperative complications. As well as whether the use of renal stress biomarkers together with a goal-directed fluid therapy protocol could reduce hospital stay and the incidence of acute kidney injury in adult patients undergoing non-cardiac surgery, reached the highest consensus. CONCLUSIONS: The Fluid Therapy and Hemodynamic Monitoring Subcommittee of the Hemostasis, Transfusion Medicine and Fluid Therapy Section of the Spanish Society of Anesthesiology and Critical Care will use these results to carry out the research.

Perioperative colloids: From theory to practice.

INTRODUCTION: Fluid administration is the cornerstone in hypovolemic patient's reanimation. Clinical guidelines restrict colloid administration favouring crystalloids. Currently, we don't know exactly which is the daily clinical practice during the perioperative period. The objective of this study is to describe perioperative use of colloids analysing possible reasons aiming to use them. MATERIAL AND METHODS: Prospective, cross-section, national, multicentre observational study. Fluid Day sub-study. We enrolled all patient's older than 18 years old who underwent surgery during the 24 h of the 2-days study (February, 2019, 18th and 20th). We registered demographic data, comorbidities, anaesthetic and surgical procedure data, fluids administered, perioperative bleeding and monitoring type used during the perioperative period. RESULTS: A total of 5928 cases were analysed and 542 patients (9.1%) received any type of colloids, being hydroxiethyl-starch the most frequently used (5.1%). Patients receiving colloids suffered more longing surgery (150 [90-255] vs. 75 [45-120] min), were urgently operated (13.7 vs. 7.5%) and were more frequent classified as high risk (22 vs. 4.8%). Their recovery was mostly in critical care units (45.1 vs.15.8%). Patients with bleeding less than 500 ml received colloids in a percentage of 5.9 versus 45.9% when this figure was overcome. Patients who received colloids were anaemic more frequently: 29.4 vs. 16.3%. Colloids administration had a higher risk for transfusion (OR 15.7). Advanced monitoring also increased the risk for receiving colloids (OR 9.43). CONCLUSIONS: In our environment with routine clinical practice, colloids administration is limited and close linked to perioperative bleeding.

Mechanotransduction in tumor dynamics modeling.

Mechanotherapy is a groundbreaking approach to impact carcinogenesis. Cells sense and respond to mechanical stimuli, translating them into biochemical signals in a process known as mechanotransduction. The impact of stress on tumor growth has been studied in the last three decades, and many papers highlight the role of mechanics as a critical self-inducer of tumor fate at the in vitro and in vivo biological levels. Meanwhile, mathematical models attempt to determine laws to reproduce tumor dynamics. This review discusses biological mechanotransduction mechanisms and mathematical-biomechanical models together. The aim is to provide a common framework for the different approaches that have emerged in the literature from the perspective of tumor avascularity and to provide insight into emerging mechanotherapies that have attracted interest in recent years.

Expected-value bias in mid-trimester preterm birth screening.

OBJECTIVES: Cervical length (CL) measurement ≤ 25 mm on mid-trimester ultrasound scan is a known risk factor for preterm birth, for which vaginal progesterone is recommended. The aims of this study were to evaluate whether CL measurement is affected by observer bias and to assess the impact on short cervix prevalence of masking CL measurement during routine mid-trimester ultrasound scan. METHODS: This was a flash study designed for a 2-month period (October and November 2018) at Cruces University Hospital (Bizkaia, Spain), in which all CL measurements from routine mid-trimester scans were masked. During the study period, there was no modification of the routine screening method, and women with a short cervix were prescribed 200 mg vaginal progesterone daily as per usual. The control group included women examined in a 2-month period (April and May 2018) prior to the study, in which CL measurements were taken as usual by a non-blinded operator. The primary outcome was the prevalence of short cervix in each group. RESULTS: A total of 983 CL measurements were analyzed, including 457 in the blinded group and 526 in the control group. The prevalence of short cervix was 2.7% in the non-blinded group and 5.5% in the blinded group (P = 0.024). We identified a statistically significant difference in the incidence of CL of 24-25 mm between the two groups, with a lower prevalence in the non-blinded vs blinded group (0.6% vs 2.4%; P < 0.005). Moreover, the distribution of CL values was normal in the blinded group, in contrast to the non-blinded group, which was characterized by skewed distribution of CL values. CONCLUSIONS: Expected-value bias exists and should be taken into account when measuring CL in mid-trimester preterm birth screening. Blinding has demonstrated to be an effective strategy to improve the performance of CL screening in clinical practice. © 2021 International Society of Ultrasound in Obstetrics and Gynecology.

Association between preoperative baseline pulse pressure and estimated pulse wave velocity and acute renal failure and mortality following colorectal surgery. A single-centre observational study.

BACKGROUND: Elevated pulse wave velocity is a haemodynamic parameter considered to be a risk factor for the development of cardiovascular alterations, while pulse pressure is a predictor of cardiovascular complications and development of acute renal failure after both cardiac and non-cardiac surgery. Our objective was to determine whether baseline pulse pressure and estimated pulse wave velocity are associated with renal failure and 30-day mortality following colorectal surgery. METHODS: Retrospective observational study. A total of 816 adult patients undergoing elective colorectal surgery were evaluated by performing multivariable logistic regression analysis to determine whether baseline pulse pressure and estimated pulse wave velocity were independently associated with complications, specifically renal failure and 30-day postoperative mortality, and whether pulse pressure and estimated pulse wave velocity thresholds correlated with outcomes. RESULTS: Baseline pulse pressure was 56.00 mmHg (45.00;68.00) and estimated pulse wave velocity was 13.16 m/s (10.76;14.85). Baseline pulse pressure was not associated with acute renal failure or mortality in the univariate model. Baseline estimated pulse wave velocity was not associated with complications, acute renal failure, or mortality. An estimated pulse wave velocity of 13.78 m/s significantly predicted acute renal failure (AUC 0.654 [0.588-0.720]) and mortality (AUC 0.698 [0.600-0.796]). CONCLUSIONS: Neither pulse pressure nor preoperative baseline estimated pulse wave velocity were associated with acute renal failure or postoperative mortality. The preoperative estimated pulse wave velocity threshold of 13.78 m/s predicted an increased risk of acute renal failure and postoperative mortality.

Intraoperative crystalloid utilization variability and association with postoperative outcomes: A post hoc analysis of two multicenter prospective cohort studies.

BACKGROUND: The optimal regimen for intravenous administration of intraoperative fluids remains unclear. Our goal was to analyze intraoperative crystalloid volume administration practices and their association with postoperative outcomes. METHODS: We extracted clinical data from two multicenter observational studies including adult patients undergoing colorectal surgery and total hip (THA) and knee arthroplasty (TKA). We analyzed the distribution of intraoperative fluid administration. Regression was performed using a general linear model to determine factors predictive of fluid administration. Patient outcomes and intraoperative crystalloid utilization were summarized for each surgical cohort. Regression models were developed to evaluate associations of high or low intraoperative crystalloid with the likelihood of increased postoperative complications, mainly acute kidney injury (AKI) and hospital length of stay (LOS). RESULTS: 7580 patients were included. The average adjusted intraoperative crystalloid infusion rate across all surgeries was to 7.9 (SD 4) mL/kg/h. The regression model strongly favored the type of surgery over other patient predictors. We found that high fluid volume was associated with 40% greater odds ratio (OR 1.40; 95% confidence interval 1.01-1.95, p = 0.044) of postoperative complications in patients undergoing THA, while we found no associations for the other types of surgeries, AKI and LOS CONCLUSIONS: A wide variability was observed in intraoperative crystalloid volume administration; however, this did not affect postoperative outcomes.

Association between preoperative baseline pulse pressure and estimated pulse wave velocity and acute renal failure and mortality following colorectal surgery. A single-centre observational study. / Asociación entre la presión de pulso y la velocidad onda pulso estimada basal preoperatoria con las complicaciones postoperatorias, insuficiencia renal aguda y mortalidad tras cirugía colorrectal. Estudio unicéntrico observacional.

BACKGROUND: Elevated pulse wave velocity is a haemodynamic parameter considered to be a risk factor for the development of cardiovascular alterations, while pulse pressure is a predictor of cardiovascular complications and development of acute renal failure after both cardiac and non-cardiac surgery. Our objective was to determine whether baseline pulse pressure and estimated pulse wave velocity are associated with renal failure and 30-day mortality following colorectal surgery. METHODS: Retrospective observational study. A total of 816 adult patients undergoing elective colorectal surgery were evaluated by performing multivariable logistic regression analysis to determine whether baseline pulse pressure and estimated pulse wave velocity were independently associated with complications, specifically renal failure and 30-day postoperative mortality, and whether pulse pressure and estimated pulse wave velocity thresholds correlated with outcomes. RESULTS: Baseline pulse pressure was 56.00mmHg (45.00;68.00) and estimated pulse wave velocity was 13.16m/s (10.76;14.85). Baseline pulse pressure was not associated with acute renal failure or mortality in the univariate model. Baseline estimated pulse wave velocity was not associated with complications, acute renal failure, or mortality. An estimated pulse wave velocity of 13.78m/s significantly predicted acute renal failure (AUC 0.654 [0.588-0.720]) and mortality (AUC 0.698 [0.600-0.796]). CONCLUSIONS: Neither pulse pressure nor preoperative baseline estimated pulse wave velocity were associated with acute renal failure or postoperative mortality. The preoperative estimated pulse wave velocity threshold of 13.78m/s predicted an increased risk of acute renal failure and postoperative mortality.

Pancreatic cancer prognosis is predicted by an ATAC-array technology for assessing chromatin accessibility.

Unlike other malignancies, therapeutic options in pancreatic ductal adenocarcinoma (PDAC) are largely limited to cytotoxic chemotherapy without the benefit of molecular markers predicting response. Here we report tumor-cell-intrinsic chromatin accessibility patterns of treatment-naïve surgically resected PDAC tumors that were subsequently treated with (Gem)/Abraxane adjuvant chemotherapy. By ATAC-seq analyses of EpCAM+ PDAC malignant epithelial cells sorted from 54 freshly resected human tumors, we show here the discovery of a signature of 1092 chromatin loci displaying differential accessibility between patients with disease free survival (DFS) < 1 year and patients with DFS > 1 year. Analyzing transcription factor (TF) binding motifs within these loci, we identify two TFs (ZKSCAN1 and HNF1b) displaying differential nuclear localization between patients with short vs. long DFS. We further develop a chromatin accessibility microarray methodology termed "ATAC-array", an easy-to-use platform obviating the time and cost of next generation sequencing. Applying this methodology to the original ATAC-seq libraries as well as independent libraries generated from patient-derived organoids, we validate ATAC-array technology in both the original ATAC-seq cohort as well as in an independent validation cohort. We conclude that PDAC prognosis can be predicted by ATAC-array, which represents a low-cost, clinically feasible technology for assessing chromatin accessibility profiles.

Viscoelastic model characterization of human cervical tissue by torsional waves.

The understanding of changes in the viscoelastic properties of cervical tissue during the gestation process is a challenging problem. In this work, we explore the importance of considering the multilayer nature (epithelial and connective layers) of human cervical tissue for characterizing the viscoelastic parameters from torsional waves. For this purpose, torsional wave propagations are simulated in three multilayer cervical tissue models (pure elastic, Kelvin-Voigt (KV) and Maxwell) using the finite difference time domain method. High-speed camera measurements have been carried out in tissue-mimicking phantoms in order to obtain the boundary conditions of the numerical simulations. Finally, a parametric modeling study through a probabilistic inverse procedure was performed to rank the most plausible rheological model and to reconstruct the viscoelastic parameters. The procedure consist in comparing the experimental signals obtained in human cervical tissues using the Torsional Wave Elastography (TWE) technique with the synthetic signals from the numerical models. It is shown that the rheological model that best describes the nature of cervical tissue is the Kelvin-Voigt model. Once the most plausible model has been selected, the stiffness and viscosity parameters have been reconstructed of the epithelial and connective layers for the measurements of the 18 pregnant women, along with the thickness of the epithelial layer.

Characterization of non-linear mechanical behavior of the cornea.

The objective of this study was to evaluate which hyperelastic model could best describe the non-linear mechanical behavior of the cornea, in order to characterize the capability of the non-linear model parameters to discriminate structural changes in a damaged cornea. Porcine corneas were used, establishing two different groups: control (non-treated) and NaOH-treated (damaged) corneas (n = 8). NaOH causes a chemical burn to the corneal tissue, simulating a disease associated to structural damage of the stromal layer. Quasi-static uniaxial tensile tests were performed in nasal-temporal direction immediately after preparing corneal strips from the two groups. Three non-linear hyperelastic models (i.e. Hamilton-Zabolotskaya model, Ogden model and Mooney-Rivlin model) were fitted to the stress-strain curves obtained in the tensile tests and statistically compared. The corneas from the two groups showed a non-linear mechanical behavior that was best described by the Hamilton-Zabolotskaya model, obtaining the highest coefficient of determination (R2 > 0.95). Moreover, Hamilton-Zabolotskaya model showed the highest discriminative capability of the non-linear model parameter (Parameter A) for the tissue structural changes between the two sample groups (p = 0.0005). The present work determines the best hyperelastic model with the highest discriminative capability in description of the non-linear mechanical behavior of the cornea.

Temperature-dependent infrared ellipsometry of Mo-doped VO2 thin films across the insulator to metal transition.

We present a spectroscopic ellipsometry study of Mo-doped VO2 thin films deposited on silicon substrates for the mid-infrared range. The dielectric functions and conductivity were extracted from analytical fittings of Ψ and Δ ellipsometric angles showing a strong dependence on the dopant concentration and the temperature. Insulator-to-metal transition (IMT) temperature is found to decrease linearly with increasing doping level. A correction to the classical Drude model (termed Drude-Smith) has been shown to provide excellent fits to the experimental measurements of dielectric constants of doped/undoped films and the extracted parameters offer an adequate explanation for the IMT based on the carriers backscattering across the percolation transition. The smoother IMT observed in the hysteresis loops as the doping concentration is increased, is explained by charge density accumulation, which we quantify through the integral of optical conductivity. In addition, we describe the physics behind a localized Fano resonance that has not yet been demonstrated and explained in the literature for doped/undoped VO2 films.

Patient Blood Management for primary hip and knee replacement. A survey among POWER.2 study researchers. / Patient Blood Management en artroplastia primaria de cadera y rodilla. Encuesta entre los investigadores del estudio POWER.2.

BACKGROUND: Implementation of Patient Blood Management programs remain variable in Europe, and even in centres with well-established PBM programs variability exists in transfusion practices. OBJECTIVES AND METHODS: We conducted a survey in order to assess current practice in perioperative Patient Blood Management in patients undergoing total hip and knee replacement among researchers involved in POWER.2 Study in Spain (an observational prospective study evaluating enhanced recovery pathways in orthopaedic surgery). RESULTS: A total of 322 responses were obtained (37.8%). Half of responders check Haemoglobin levels in patients at least 4 weeks before surgery; 35% treat all anaemic patients, although 99.7% consider detection and treatment of preoperative anaemia could influence the postoperative outcomes. Lack of infrastructure (76%) and lack of time (51%) are the main stated reasons not to treat anaemic patients. Iron status is routinely checked by 19% before surgery, and 36% evaluate it solely in the anaemic patient. Hb<9.9 g/dl is the threshold to delay surgery for 61% of clinicians, and 22% would consider transfusing preoperatively clinically stable patients without active bleeding. The threshold to transfuse patients without cardiovascular disease is 8 g/dl for 43%, and 7 g/dl for 34% of the responders; 75% of clinicians consider they use "restrictive thresholds", and 90% follow the single unit transfusion policy. CONCLUSIONS: The results of our survey show variability in clinical practice in Patient Blood Management in major orthopaedic surgery, despite being the surgery with the greatest tradition in these programs.