Novel roles of cardiac-derived erythropoietin in cardiac development and function.

The role of erythropoietin (EPO) has extended beyond hematopoiesis to include cytoprotection, inotropy, and neurogenesis. Extra-renal EPO has been reported for multiple tissue/cell types, but the physiological relevance remains unknown. Although the EPO receptor is expressed by multiple cardiac cell types and human recombinant EPO increases contractility and confers cytoprotection against injury, whether the heart produces physiologically meaningful amounts of EPO in vivo is unclear. We show a distinct circadian rhythm of cardiac EPO mRNA expression in adult mice and increased mRNA expression during embryogenesis, suggesting physiological relevance to cardiac EPO production throughout life. We then generated constitutive, cardiomyocyte-specific EPO knockout mice driven by the Mlc2v promoter (EPOfl/fl:Mlc2v-cre+/-; EPOΔ/Δ-CM). During cardiogenesis, cardiac EPO mRNA expression and cellular proliferation were reduced in EPOΔ/Δ-CM hearts. However, in adult EPOΔ/Δ- CM mice, total heart weight was preserved through increased cardiomyocyte cross-sectional area, indicating the reduced cellular proliferation was compensated for by cellular hypertrophy. Echocardiography revealed no changes in cardiac dimensions, with modest reductions in ejection fraction, stroke volume, and tachycardia, whereas invasive hemodynamics showed increased cardiac contractility and lusitropy. Paradoxically, EPO mRNA expression in the heart was elevated in adult EPOΔ/Δ-CM, along with increased serum EPO protein content and hematocrit. Using RNA fluorescent in situ hybridization, we found that Epo RNA colocalized with endothelial cells in the hearts of adult EPOΔ/Δ-CM mice, identifying the endothelial cells as a cell responsible for the EPO hyper-expression. Collectively, these data identify the first physiological roles for cardiomyocyte-derived EPO. We have established cardiac EPO mRNA expression is a complex interplay of multiple cell types, where loss of embryonic cardiomyocyte EPO production results in hyper-expression from other cells within the adult heart.

Transfusion thresholds in acute coronary syndromes.

PURPOSE OF REVIEW: Anemia is prevalent in patients with acute coronary syndromes. In this setting, there is uncertainty and controversy surrounding the optimal transfusion strategy for managing anemia. The goal of this review is to summarize the current clinical evidence, guidelines, and future directions for managing transfusion in acute coronary syndromes. RECENT FINDINGS: There is limited evidence from randomized trials evaluating restrictive versus liberal transfusion in patients hospitalized with and/or for acute coronary syndromes. The results from these studies suggest clinical equipoise between transfusion strategies for short term outcomes, and a trend toward favoring a liberal strategy for long term major adverse cardiac events. There is inconsistency across clinical practice guidelines with respect to the optimal strategy for managing anemia and transfusion in acute coronary syndromes due to insufficient evidence. SUMMARY: More evidence is urgently needed to conclusively establish the optimal strategy for transfusion management in the setting of acute coronary syndromes. These data will directly inform harmonization of clinical practice guidelines. Future investigations should explore alternative strategies to hemoglobin for quantifying the degree of anemic stress for personalizing transfusion therapy, the effects on functional outcomes, and managing anemia following hospital discharge.

Restrictive versus liberal transfusion in patients with diabetes undergoing cardiac surgery: An open-label, randomized, blinded outcome evaluation trial.

AIM: To characterize the association between diabetes and transfusion and clinical outcomes in cardiac surgery, and to evaluate whether restrictive transfusion thresholds are harmful in these patients. MATERIALS AND METHODS: The multinational, open-label, randomized controlled TRICS-III trial assessed a restrictive transfusion strategy (haemoglobin [Hb] transfusion threshold <75 g/L) compared with a liberal strategy (Hb <95 g/L for operating room or intensive care unit; or <85 g/L for ward) in patients undergoing cardiac surgery on cardiopulmonary bypass with a moderate-to-high risk of death (EuroSCORE ≥6). Diabetes status was collected preoperatively. The primary composite outcome was all-cause death, stroke, myocardial infarction, and new-onset renal failure requiring dialysis at 6 months. Secondary outcomes included components of the composite outcome at 6 months, and transfusion and clinical outcomes at 28 days. RESULTS: Of the 5092 patients analysed, 1396 (27.4%) had diabetes (restrictive, n = 679; liberal, n = 717). Patients with diabetes had more cardiovascular disease than patients without diabetes. Neither the presence of diabetes (OR [95% CI] 1.10 [0.93-1.31]) nor the restrictive strategy increased the risk for the primary composite outcome (diabetes OR [95% CI] 1.04 [0.68-1.59] vs. no diabetes OR 1.02 [0.85-1.22]; Pinteraction  = .92). In patients with versus without diabetes, a restrictive transfusion strategy was more effective at reducing red blood cell transfusion (diabetes OR [95% CI] 0.28 [0.21-0.36]; no diabetes OR [95% CI] 0.40 [0.35-0.47]; Pinteraction  = .04). CONCLUSIONS: The presence of diabetes did not modify the effect of a restrictive transfusion strategy on the primary composite outcome, but improved its efficacy on red cell transfusion. Restrictive transfusion triggers are safe and effective in patients with diabetes undergoing cardiac surgery.

ONTraC: A 20-Year History of a Successfully Coordinated Provincewide Patient Blood Management Program: Lessons Learned and Goals Achieved.

Our understanding of the risks associated with perioperative anemia and transfusion, in terms of increased morbidity and mortality, has evolved over the past 2 decades. By contrast, our understanding of the potential mechanisms of injury and optimal treatment strategies remains incomplete. As such, the important role of effective patient blood management (PBM) programs, which address both the effective treatment of anemia and minimizes the need for red blood cell (RBC) transfusion, is of central importance to optimizing patient care and improving patient outcomes. We report on important clinical outcomes of the Ontario Transfusion Coordinator (ONTraC Program), a network of 25 hospital sites, working in coordination over the past 20 years. Transfusion nurse coordinators were assigned to apply multimodal best practice in PBM (including recommended changes in surgical approach; diagnosis, assessment, and treatment of anemia; and adherence to more restrictive RBC transfusion thresholds). Data were collected on various clinical parameters. We further described lessons learned and difficulties encountered in this multisite PBM initiative. A significant reduction in RBC transfusions was observed for numerous indexed surgeries. For example, RBC transfusion rates for knee arthroplasty decreased from 25% in 2002 to 0.4% in 2020. For coronary artery bypass graft (CABG) surgery, transfusion rates decreased from 60% in 2002 to 27% in 2020. We also observed a decrease in RBC units utilized per transfused patient for knee (2.1 ± 0.5 [2002] vs 1.0 ± 0.6 [2020] units per patient) and CABG surgery (3.3 ± 0.6 [2002] vs 2.3 ± 1.9 [2020] units per patient). These reductions were associated with favorable clinical outcomes, including reduced length of hospital stay (P = .00003) and a reduced rate of perioperative infections (P < .001) for nontransfused versus transfused patients. These advances have been achieved with estimated savings in the tens of millions of dollars annually. Our experience and data support the hypothesis that instituting an integrated network of transfusion nurse coordinators can provide an effective provincewide PBM program, reduce RBC transfusions, improve some patient outcomes, and reduce health care costs, as an example of a "win-win-win" medical program.

Update on Applications and Limitations of Perioperative Tranexamic Acid.

Tranexamic acid (TXA) is a potent antifibrinolytic with documented efficacy in reducing blood loss and allogeneic red blood cell transfusion in several clinical settings. With a growing emphasis on patient blood management, TXA has become an integral aspect of perioperative blood conservation strategies. While clinical applications of TXA in the perioperative period are expanding, routine use in select clinical scenarios should be supported by evidence for efficacy. Furthermore, questions regarding optimal dosing without increased risk of adverse events such as thrombosis or seizures should be answered. Therefore, ongoing investigations into TXA utilization in cardiac surgery, obstetrics, acute trauma, orthopedic surgery, neurosurgery, pediatric surgery, and other perioperative settings continue. The aim of this review is to provide an update on the current applications and limitations of TXA use in the perioperative period.

Opioid prescribing and utilization patterns in patients having elective hip and knee arthroplasty: association between prescription patterns and opioid consumption.

PURPOSE: Although guidelines can reduce postoperative opioid prescription, the problem of unused opioids persists. We assessed the pattern of opioid prescription and utilization after total hip arthroplasty (THA) and total knee arthroplasty (TKA). We hypothesized that opioid prescription patterns can influence opioid utilization. METHODS: With institutional ethics approval, patients undergoing THA and TKA were enrolled prospectively. Surveys on opioid use were completed at two, six, and 12 weeks after surgery. Patients' age, sex, American Society of Anesthesiologists' Physical Status score, first 24-hr opioid consumption, quantity of opioid prescribed, and quantity of opioid utilized were analyzed to evaluate their effect on opioid consumption, unused opioid, and patient satisfaction. RESULTS: Patients received prescriptions ranging from 200 morphine milligram equivalents (MME) to 800 MME. Three hundred and thirty THA and 230 TKA patients completed the surveys. Opioid utilization was influenced by the amount of prescribed opioids for both THA and TKA. The percentage of prescribed opioids used (~55% in THA and ~75% in TKA) and the proportion of patients using all prescribed opioids (~22% in THA and ~50% in TKA) were higher after TKA vs THA (P < 0.001 for both). Patients who used opioids for two days or less accounted for most (~50%) of the unused opioid. Patient satisfaction remained high and was not influenced by the amount of prescribed opioid. CONCLUSION: This study showed that larger prescriptions are associated with higher opioid consumption. A wide variation in opioid consumption requires approaches to minimize the initial opioid prescription and to provide additional prescriptions for patients that require higher levels of analgesia.

RéSUMé: OBJECTIF: Bien que les lignes directrices puissent réduire la prescription d'opioïdes postopératoires, le problème des opioïdes inutilisés persiste. Nous avons évalué les schémas de prescription et d'utilisation d'opioïdes après une arthroplastie totale de la hanche (ATH) et une arthroplastie totale du genou (ATG). Nous avons émis l'hypothèse que les schémas de prescription d'opioïdes pouvaient influencer l'utilisation des opioïdes. MéTHODE: Avec l'approbation du comité d'éthique de notre établissement, les patients bénéficiant d'une ATH et une ATG ont été recrutés de manière prospective. Les questionnaires sur la consommation d'opioïdes ont été complétés deux, six et 12 semaines après la chirurgie. L'âge, le sexe et le score de statut physique selon l'American Society of Anesthesiologists des patients, ainsi que la consommation d'opioïdes au cours des premières 24 heures postopératoires, la quantité d'opioïdes prescrits et la quantité d'opioïdes utilisés ont été analysés pour évaluer leur effet sur la consommation d'opioïdes, les opioïdes inutilisés et la satisfaction des patients. RéSULTATS: Les patients ont reçu des ordonnances allant de 200 équivalents de morphine en milligrammes (EMM) à 800 EMM. Trois cent trente patients bénéficiant d'une ATH et 230 patients d'une ATG ont répondu aux questionnaires. L'utilisation des opioïdes a été influencée par la quantité d'opioïdes prescrits pour l'ATH et l'ATG. Le pourcentage d'opioïdes prescrits utilisés (~55 % dans l'ATH et ~75 % dans l'ATG) et la proportion de patients utilisant tous les opioïdes prescrits (~22 % dans l'ATH et ~50 % dans l'ATG) étaient plus élevés après l'ATG vs l'ATH (P < 0,001 pour les deux). Les patients qui ont utilisé des opioïdes pendant deux jours ou moins étaient à l'origine de la plupart (~ 50%) des opioïdes inutilisés. La satisfaction des patients est demeurée élevée et n'a pas été influencée par la quantité d'opioïdes prescrits. CONCLUSION: Cette étude a démontré que les ordonnances plus élevées sont associées à une consommation plus élevée d'opioïdes. Une grande variation dans la consommation d'opioïdes nécessite des approches visant à minimiser la prescription initiale d'opioïdes et à fournir des ordonnances supplémentaires aux patients qui nécessitent des niveaux plus élevés d'analgésie.

Six-Month Outcomes after Restrictive or Liberal Transfusion for Cardiac Surgery.

BACKGROUND: We reported previously that, in patients undergoing cardiac surgery who were at moderate-to-high risk for death, a restrictive transfusion strategy was noninferior to a liberal strategy with respect to the composite outcome of death from any cause, myocardial infarction, stroke, or new-onset renal failure with dialysis by hospital discharge or 28 days after surgery, whichever came first. We now report the clinical outcomes at 6 months after surgery. METHODS: We randomly assigned 5243 adults undergoing cardiac surgery to a restrictive red-cell transfusion strategy (transfusion if the hemoglobin concentration was <7.5 g per deciliter intraoperatively or postoperatively) or a liberal red-cell transfusion strategy (transfusion if the hemoglobin concentration was <9.5 g per deciliter intraoperatively or postoperatively when the patient was in the intensive care unit [ICU] or was <8.5 g per deciliter when the patient was in the non-ICU ward). The primary composite outcome was death from any cause, myocardial infarction, stroke, or new-onset renal failure with dialysis occurring within 6 months after the initial surgery. An expanded secondary composite outcome included all the components of the primary outcome as well as emergency department visit, hospital readmission, or coronary revascularization occurring within 6 months after the index surgery. The secondary outcomes included the individual components of the two composite outcomes. RESULTS: At 6 months after surgery, the primary composite outcome had occurred in 402 of 2317 patients (17.4%) in the restrictive-threshold group and in 402 of 2347 patients (17.1%) in the liberal-threshold group (absolute risk difference before rounding, 0.22 percentage points; 95% confidence interval [CI], -1.95 to 2.39; odds ratio, 1.02; 95% CI, 0.87 to 1.18; P=0.006 for noninferiority). Mortality was 6.2% in the restrictive-threshold group and 6.4% in the liberal-threshold group (odds ratio, 0.95; 95% CI, 0.75 to 1.21). There were no significant between-group differences in the secondary outcomes. CONCLUSIONS: In patients undergoing cardiac surgery who were at moderate-to-high risk for death, a restrictive strategy for red-cell transfusion was noninferior to a liberal strategy with respect to the composite outcome of death from any cause, myocardial infarction, stroke, or new-onset renal failure with dialysis at 6 months after surgery. (Funded by the Canadian Institutes of Health Research and others; TRICS III ClinicalTrials.gov number, NCT02042898 .).

Recent cannabis use and myocardial infarction in young adults: a cross-sectional study.

BACKGROUND: Cannabis use is increasing among young adults, but its effects on cardiovascular health are poorly understood. We aimed to assess the association between recent cannabis use and history of myocardial infarction (MI) in young adults (aged 18-44 yr). METHODS: We performed a cross-sectional study using pooled data from the 2017 and 2018 cohorts of the American Behavioral Risk Factor Surveillance System survey of US adults. We analyzed the association between any recent cannabis use and history of MI using a weighted logistic regression model that adjusted for demographic factors, socioeconomic factors, health-related behaviours, concomitant substance use and other comorbidities. We also assessed this association after stratifying by frequency of use and by primary method of consumption. RESULTS: Among 33 173 young adults (18.5 million weighted), 4610 respondents (3.2 million weighted) reported recent cannabis use (17.5%, 95% confidence interval [CI] 16.8%-18.2%). A history of MI was more frequent among recent cannabis users (n = 61 of 4610, 1.3%) relative to nonusers (n = 240 of 28 563 [0.8%], adjusted odds ratio [OR] 2.07, 95% CI 1.12-3.82). A history of MI was associated with cannabis use of more than 4 times per month (adjusted OR 2.31, 95% CI 1.18-4.50), and with smoking as a primary method of consumption (adjusted OR 2.01, 95% CI 1.02-3.98). INTERPRETATION: Our study provides evidence supporting an association between recent cannabis use and history of MI in young adults. Increasing cannabis use in an at-risk population could have negative implications for cardiovascular health.

Renal microvascular oxygen tension during hyperoxia and acute hemodilution assessed by phosphorescence quenching and excitation with blue and red light.

PURPOSE: The kidney plays a central physiologic role as an oxygen sensor. Nevertheless, the direct mechanism by which this occurs is incompletely understood. We measured renal microvascular partial pressure of oxygen (PkO2) to determine the impact of clinically relevant conditions that acutely change PkO2 including hyperoxia and hemodilution. METHODS: We utilized two-wavelength excitation (red and blue spectrum) of the intravascular phosphorescent oxygen sensitive probe Oxyphor PdG4 to measure renal tissue PO2 in anesthetized rats (2% isoflurane, n = 6) under two conditions of altered arterial blood oxygen content (CaO2): 1) hyperoxia (fractional inspired oxygen 21%, 30%, and 50%) and 2) acute hemodilutional anemia (baseline, 25% and 50% acute hemodilution). The mean arterial blood pressure (MAP), rectal temperature, arterial blood gases (ABGs), and chemistry (radiometer) were measured under each condition. Blue and red light enabled measurement of PkO2 in the superficial renal cortex and deeper cortical and medullary tissue, respectively. RESULTS: PkO2 was higher in the superficial renal cortex (~ 60 mmHg, blue light) relative to the deeper renal cortex and outer medulla (~ 45 mmHg, red light). Hyperoxia resulted in a proportional increase in PkO2 values while hemodilution decreased microvascular PkO2 in a linear manner in both superficial and deeper regions of the kidney. In both cases (blue and red light), PkO2 correlated with CaO2 but not with MAP. CONCLUSION: The observed linear relationship between CaO2 and PkO2 shows the biological function of the kidney as a quantitative sensor of anemic hypoxia and hyperoxia. A better understanding of the impact of changes in PkO2 may inform clinical practices to improve renal oxygen delivery and prevent acute kidney injury.

RéSUMé: OBJECTIF: Les reins jouent un rôle physiologique central en tant que détecteurs d'oxygène. Cependant, le mécanisme direct de ce rôle n'est pas complètement compris. Nous avons mesuré la pression partielle d'oxygène microvasculaire rénal (PkO2) afin de déterminer l'impact de conditions pertinentes d'un point de vue clinique qui modifient de façon aiguë la PkO2, y compris l'hyperoxie et l'hémodilution. MéTHODE: Nous avons utilisé l'excitation à deux longueurs d'onde (spectres rouge et bleu) de la sonde phosphorescente, sensible à l'oxygène, intravasculaire Oxyphor PdG4 afin de mesurer la PO2 dans le tissu rénal de rats sous anesthésie (isoflurane 2 %, n = 6) dans deux conditions de contenu en oxygène du sang artériel (CaO2) altéré : 1) hyperoxie (fraction d'oxygène inspiré 21 %, 30 % et 50 %) et 2) anémie par hémodilution aiguë (valeurs de base, hémodilution aiguë 25 % et 50 %). La tension artérielle moyenne (TAM), la température rectale, les gaz sanguins artériels et la chimie (radiomètre) ont été mesurés dans chacune des conditions. Les lumières bleue et rouge ont permis de mesurer la PkO2 dans le cortex rénal superficiel et les tissus cortical et médullaire plus profonds, respectivement. RéSULTATS: La PkO2 était plus élevée dans le cortex rénal superficiel (~ 60 mmHg, lumière bleue) comparativement au cortex rénal plus profond et à la zone médullaire extérieure (~ 45 mmHg, lumière rouge). L'hyperoxie a entraîné une augmentation proportionnelle des valeurs de PkO2, alors que l'hémodilution a diminué la PkO2 microvasculaire de façon linéaire tant dans les régions rénales superficielles que plus profondes. Dans les deux cas (lumières bleue et rouge), la PkO2 était corrélée au CaO2 mais pas à la TAM. CONCLUSION: La relation linéaire observée entre le CaO2 et la PkO2 montre la fonction biologique du rein en tant que détecteur quantitatif de l'hypoxie anémique et de l'hyperoxie. Une meilleure compréhension de l'impact des changements de la PkO2 pourrait guider les pratiques cliniques afin d'améliorer la distribution d'oxygène aux reins et prévenir l'insuffisance rénale aiguë.

A mathematical model of cerebral blood flow control in anaemia and hypoxia.

KEY POINTS: The control of cerebral blood flow in hypoxia, anaemia and hypocapnia is reviewed with an emphasis on the links between cerebral blood flow and possible stimuli. A mathematical model is developed to examine the changes in the partial pressure of oxygen in brain tissue associated with changes in cerebral blood flow regulation produced by carbon dioxide, anaemia and hypoxia. The model demonstrates that hypoxia, anaemia and hypocapnia, alone or in combination, produce varying degrees of cerebral hypoxia, an effect exacerbated when blood flow regulation is impaired. The suitability of brain hypoxia as a common regulator of cerebral blood flow in hypoxia and anaemia was explored, although we failed to find support for this hypothesis. Rather, cerebral blood flow appears to be related to arterial oxygen concentration in both anaemia and hypoxia. ABSTRACT: A mathematical model is developed to examine the changes in the partial pressure of oxygen in brain tissue associated with changes in cerebral blood flow regulation produced by carbon dioxide, anaemia and hypoxia. The model simulation assesses the physiological plausibility of some currently hypothesized cerebral blood flow control mechanisms in hypoxia and anaemia, and also examines the impact of anaemia and hypoxia on brain hypoxia. In addition, carbon dioxide is examined for its impact on brain hypoxia in the context of concomitant changes associated with anaemia and hypoxia. The model calculations are based on a single compartment of brain tissue with constant metabolism and perfusion pressure, as well as previously developed equations describing oxygen and carbon dioxide carriage in blood. Experimental data are used to develop the control equations for cerebral blood flow regulation. The interactive model illustrates that there are clear interactions of anaemia, hypoxia and carbon dioxide in the determination of cerebral blood flow and brain tissue oxygen tension. In both anaemia and hypoxia, cerebral blood flow increases to maintain oxygen delivery, with brain hypoxia increasing when cerebral blood flow control mechanisms are impaired. Hypocapnia superimposes its effects, increasing brain hypoxia. Hypoxia, anaemia and hypocapnia, alone or in combination, produce varying degrees of cerebral hypoxia, and this effect is exacerbated when blood flow regulation is degraded by conditions that negatively impact cerebrovascular control. Differences in brain hypoxia in anaemia and hypoxia suggest that brain oxygen tension is not a plausible sensor for cerebral blood flow control.

Restrictive or Liberal Red-Cell Transfusion for Cardiac Surgery.

BACKGROUND: The effect of a restrictive versus liberal red-cell transfusion strategy on clinical outcomes in patients undergoing cardiac surgery remains unclear. METHODS: In this multicenter, open-label, noninferiority trial, we randomly assigned 5243 adults undergoing cardiac surgery who had a European System for Cardiac Operative Risk Evaluation (EuroSCORE) I of 6 or more (on a scale from 0 to 47, with higher scores indicating a higher risk of death after cardiac surgery) to a restrictive red-cell transfusion threshold (transfuse if hemoglobin level was <7.5 g per deciliter, starting from induction of anesthesia) or a liberal red-cell transfusion threshold (transfuse if hemoglobin level was <9.5 g per deciliter in the operating room or intensive care unit [ICU] or was <8.5 g per deciliter in the non-ICU ward). The primary composite outcome was death from any cause, myocardial infarction, stroke, or new-onset renal failure with dialysis by hospital discharge or by day 28, whichever came first. Secondary outcomes included red-cell transfusion and other clinical outcomes. RESULTS: The primary outcome occurred in 11.4% of the patients in the restrictive-threshold group, as compared with 12.5% of those in the liberal-threshold group (absolute risk difference, -1.11 percentage points; 95% confidence interval [CI], -2.93 to 0.72; odds ratio, 0.90; 95% CI, 0.76 to 1.07; P<0.001 for noninferiority). Mortality was 3.0% in the restrictive-threshold group and 3.6% in the liberal-threshold group (odds ratio, 0.85; 95% CI, 0.62 to 1.16). Red-cell transfusion occurred in 52.3% of the patients in the restrictive-threshold group, as compared with 72.6% of those in the liberal-threshold group (odds ratio, 0.41; 95% CI, 0.37 to 0.47). There were no significant between-group differences with regard to the other secondary outcomes. CONCLUSIONS: In patients undergoing cardiac surgery who were at moderate-to-high risk for death, a restrictive strategy regarding red-cell transfusion was noninferior to a liberal strategy with respect to the composite outcome of death from any cause, myocardial infarction, stroke, or new-onset renal failure with dialysis, with less blood transfused. (Funded by the Canadian Institutes of Health Research and others; TRICS III ClinicalTrials.gov number, NCT02042898 .).

Renal tissue Po2 sensing during acute hemodilution is dependent on the diluent.

Sensing changes in blood oxygen content ([Formula: see text]) is an important physiological role of the kidney; however, the mechanism(s) by which the kidneys sense and respond to changes in [Formula: see text] are incompletely understood. Accurate measurements of kidney tissue oxygen tension ([Formula: see text]) may increase our understanding of renal oxygen-sensing mechanisms and could inform decisions regarding the optimal fluid for intravascular volume resuscitation to maintain renal perfusion. In some clinical settings, starch solution may be nephrotoxic, possibly due to inadequacy of tissue oxygen delivery. We hypothesized that hemodilution with starch colloid solutions would reduce [Formula: see text] to a more severe degree than other diluents. Anesthetized Sprague-Dawley rats (n = 77) were randomized to undergo hemodilution with either colloid (6% hydroxyethyl starch or 5% albumin), crystalloid (0.9% saline), or a sham procedure (control) (n = 13-18 rats/group). Data were analyzed by ANOVA with significance assigned at P < 0.05. After hemodilution, mean arterial pressure (MAP) decreased marginally in all groups, while hemoglobin (Hb) and [Formula: see text] decreased in proportion to the degree of hemodilution. Cardiac output was maintained in all groups after hemodilution. [Formula: see text] decreased in proportion to the reduction in Hb in all treatment groups. At comparably reduced Hb, and maintained arterial oxygen values, hemodilution with starch resulted in larger decreases in [Formula: see text] relative to animals hemodiluted with albumin or saline (P < 0.008). Renal medullary erythropoietin (EPO) mRNA levels increased more prominently, relative to other hypoxia-regulated molecules (GLUT-1, GAPDH, and VEGF). Our data demonstrate that the kidney acts as a biosensor of reduced [Formula: see text] following hemodilution and that [Formula: see text] may provide a quantitative signal for renal cellular responsiveness to acute anemia. Evidence of a more severe reduction in [Formula: see text] following hemodilution with starch colloid solution suggests that tissue hypoxia may contribute to starch induced renal toxicity.

Effect of bilateral scalp nerve blocks on postoperative pain and discharge times in patients undergoing supratentorial craniotomy and general anesthesia: a randomized-controlled trial.

PURPOSE: Post-craniotomy pain is a common clinical issue and its optimal management remains incompletely studied. Utilization of a regional scalp block has the potential advantage of reducing perioperative pain and opioid consumption, thereby facilitating optimal postoperative neurologic assessment. The purpose of this study was to assess the efficacy of regional scalp block on post-craniotomy pain and opioid consumption. METHODS: We performed a prospective randomized-controlled trial in adults scheduled to undergo elective supratentorial craniotomy under general anesthesia to assess the efficacy of postoperative bilateral scalp block with 0.5% bupivacaine with 1:200,000 epinephrine compared with placebo on postoperative pain and opioid consumption. The primary outcome was the visual analogue scale (VAS) for pain at 24 hr postoperatively. RESULTS: Eighty-nine patients were enrolled (n = 44 in block group; n = 45 in control group). There was no difference in the mean (standard deviation) VAS score at 24 hr postoperatively between the treatment group and the control group [31.2 (21.4) mm vs 23.0 (19.2) mm, respectively; mean difference, 6.6; 95% confidence interval, -2.3, 15.5; P = 0.15]. There was also no significant difference in postoperative opioid consumption. Distribution of individual VAS score and opioid consumption revealed that postoperative pain was highly variable following craniotomy. Time to hospital discharge was not different between treatment and placebo groups. No adverse events associated with scalp block were identified. CONCLUSION: These data show that bilateral scalp blocks using bupivacaine with epinephrine did not reduce mean postoperative VAS score or overall opioid consumption at 24 hr nor the time-to-discharge from the postanesthesia care unit or from hospital. TRIAL REGISTRATION: www.ClinicalTrials.gov, NCT00972790; registered 9 September, 2009.

When to transfuse your acute care patient? A narrative review of the risk of anemia and red blood cell transfusion based on clinical trial outcomes.

This narrative review critically evaluates the evidence for risk of anemia and red blood cell (RBC) transfusion. For this purpose, it assesses large prospective randomized-controlled trials (RCTs) in medical, surgical, and critical care patient populations in which the impact of specific hemoglobin transfusion thresholds are compared. In these trials, the risks of anemia relative to those of RBC transfusion are assessed. The results of published systematic reviews and meta-analyses are also discussed. Lastly, recommendations for patient blood management and treatment of anemia are explored. The main conclusion of this review emphasizes that the decision to transfuse RBCs is complex and depends on the interaction between multiple factors including the balance between the risk of anemia and the risk of RBC transfusion, existing patient comorbidities, and medical and surgical exposures. The transfusion thresholds recommended by current guidelines vary for medical and surgical patient populations. Guidelines suggesting specific transfusion thresholds for different patient populations should be viewed as a starting point for making an informed decision about RBC transfusion. Alternatives to transfusion (i.e., patient blood management), biomarkers of anemia-induced tissue hypoxia, and transfusion alternatives should continue to be evaluated in large RCTs, with the goal of improving event-free survival in critically ill and perioperative patients.

RéSUMé: Ce compte rendu narratif évalue de façon critique les données probantes concernant le risque de l'anémie et de la transfusion d'érythrocytes. Pour ce faire, nous avons évalué des études randomisées contrôlées (ERC) prospectives de grande envergure réalisées auprès de populations de patients médicaux, chirurgicaux et de soins intensifs dans lesquelles l'impact de seuils spécifiques de transfusion d'hémoglobine est comparé. Dans ces études, les risques de l'anémie sont comparés aux risques de la transfusion d'érythrocytes. Les résultats des comptes rendus systématiques et méta-analyses publiés sont également présentés. Enfin, les recommandations concernant la gestion du sang des patients et le traitement de l'anémie sont explorées. La conclusion principale de ce compte rendu souligne que la décision de transfuser des érythrocytes est complexe et dépend de l'interaction de plusieurs facteurs, notamment de l'équilibre entre le risque de l'anémie et le risque de la transfusion d'érythrocytes, les comorbidités existantes du patient, et les risques médicaux et chirurgicaux. Les seuils de transfusion recommandés par les directives actuelles sont différents pour les populations de patients médicaux et chirurgicaux. Les directives proposant des seuils de transfusion spécifiques en fonction des différentes populations de patients devraient être considérées comme point de départ pour prendre une décision informée concernant la transfusion d'érythrocytes. Les alternatives à la transfusion (c.-à-d. la gestion du sang des patients), les biomarqueurs d'une hypoxie tissulaire induite par l'anémie et les alternatives à la transfusion devraient continuer à être évalués dans des ERC d'envergure, avec pour but l'amélioration de la survie sans complication des patients en état critique et périopératoires.

Delphi Approach for the Design of an Intraoperative Blood Conservation Pathway for Open Myomectomy.

OBJECTIVE: Myomectomy is offered for treatment of symptomatic uterine fibroids in women who desire to maintain fertility. An open approach, sometimes necessitated by the size or number of fibroids, is associated with a high rate of perioperative blood transfusion. Our goal was to obtain expert consensus on interventions aimed at reducing blood loss and subsequent transfusion in open myomectomy for inclusion in an intraoperative care pathway. METHODS: A two-round modified Delphi approach was used to generate consensus on a pathway of interventions to reduce blood loss in open myomectomy. A multidisciplinary expert panel consisting of anaesthesiologists, hematologists, and gynaecologic surgeons rated interventions for inclusion in or exclusion from the pathway (Canadian Task Force Classification III). RESULTS: Twenty-three expert panel members participated in the Delphi. Consensus was achieved in both the Delphi's first (Cronbach α = 0.92) and second (Cronbach α = 0.94) rounds. Of 11 proposed interventions, five (dilute vasopressin, tranexamic acid, pericervical tourniquet, cell saver, and restrictive transfusion practice) reached consensus for inclusion in the pathway. CONCLUSION: A modified Delphi consensus approach was used to inform the development of an intraoperative pathway to reduce blood loss and subsequent transfusion in women undergoing open myomectomy. Future studies will investigate the effect of this intraoperative blood conservation pathway on reducing intraoperative blood loss and blood transfusion rates among women undergoing open myomectomy.

Safety of a Restrictive versus Liberal Approach to Red Blood Cell Transfusion on the Outcome of AKI in Patients Undergoing Cardiac Surgery: A Randomized Clinical Trial.

BACKGROUND: Safely reducing red blood cell transfusions can prevent transfusion-related adverse effects, conserve the blood supply, and reduce health care costs. Both anemia and red blood cell transfusion are independently associated with AKI, but observational data are insufficient to determine whether a restrictive approach to transfusion can be used without increasing AKI risk. METHODS: In a prespecified kidney substudy of a randomized noninferiority trial, we compared a restrictive threshold for red blood cell transfusion (transfuse if hemoglobin<7.5 g/dl, intraoperatively and postoperatively) with a liberal threshold (transfuse if hemoglobin<9.5 g/dl in the operating room or intensive care unit, or if hemoglobin<8.5 g/dl on the nonintensive care ward). We studied 4531 patients undergoing cardiac surgery with cardiopulmonary bypass who had a moderate-to-high risk of perioperative death. The substudy's primary outcome was AKI, defined as a postoperative increase in serum creatinine of ≥0.3 mg/dl within 48 hours of surgery, or ≥50% within 7 days of surgery. RESULTS: Patients in the restrictive-threshold group received significantly fewer transfusions than patients in the liberal-threshold group (1.8 versus 2.9 on average, or 38% fewer transfusions in the restricted-threshold group compared with the liberal-threshold group; P<0.001). AKI occurred in 27.7% of patients in the restrictive-threshold group (624 of 2251) and in 27.9% of patients in the liberal-threshold group (636 of 2280). Similarly, among patients with preoperative CKD, AKI occurred in 33.6% of patients in the restrictive-threshold group (258 of 767) and in 32.5% of patients in the liberal-threshold group (252 of 775). CONCLUSIONS: Among patients undergoing cardiac surgery, a restrictive transfusion approach resulted in fewer red blood cell transfusions without increasing the risk of AKI.

Restrictive compared with liberal red cell transfusion strategies in cardiac surgery: a meta-analysis.

AIMS: To determine whether a restrictive strategy of red blood cell (RBC) transfusion at lower haemoglobin concentrations is inferior to a liberal strategy of RBC transfusion at higher haemoglobin concentrations in patients undergoing cardiac surgery. METHODS AND RESULTS: We conducted a systematic review, meta-analysis, and trial sequential analysis of randomized controlled trials of the effect of restrictive and liberal RBC transfusion strategies on mortality within 30 days of surgery as the primary outcome. Secondary outcomes were those potentially resulting from anaemia-induced tissue hypoxia and transfusion outcomes. We searched the electronic databases MEDLINE, EMBASE, and the Cochrane Library until 17 November 2017. Thirteen trials were included. The risk ratio (RR) of mortality derived from 4545 patients assigned to a restrictive strategy when compared with 4547 transfused according to a liberal strategy was 0.96 [95% confidence interval (CI) 0.76-1.21, I2 = 0]. A restrictive strategy did not have a statistically significant effect on the risk of myocardial infarction (RR 1.01, 95% CI 0.81-1.26; I2=0), stroke (RR 0.93, 95% CI 0.68-1.27, I2 = 0), renal failure (RR 0.96, 95% CI 0.76-1.20, I2 = 0), or infection (RR 1.12, 95% CI 0.98-1.29, I2 = 0). Subgroup analysis of adult and paediatric trials did not show a significant interaction. At approximately 70% of the critical information size, the meta-analysis of mortality crossed the futility boundary for inferiority of the restrictive strategy. CONCLUSION: The current evidence does not support the notion that restrictive RBC transfusion strategies are inferior to liberal RBC strategies in patients undergoing cardiac surgery.

A rationale for universal tranexamic acid in major joint arthroplasty: overall efficacy and impact of risk factors for transfusion.

BACKGROUND: Tranexamic acid (TXA) therapy is effective in reducing postoperative red blood cell (RBC) transfusion in total joint arthroplasty (TJA), yet uncertainty persists regarding comparative efficacy and safety among specific patient subgroups. We assessed the impact of a universal TXA protocol on RBC transfusion, postoperative hemoglobin (Hb), and adverse outcomes to determine whether TXA is safe and effective in TJA, both overall and in clinically relevant subgroups. STUDY DESIGN AND METHODS: A retrospective observational study was performed on patients undergoing TJA at our institution spanning 1 year before and after the implementation of a universal protocol to administer intravenous (IV) TXA. The primary outcome was percentage of patients transfused, and secondary outcomes were perioperative Hb and occurrence of adverse events (death, myocardial infarction, stroke, seizure, pulmonary embolism, deep vein thrombosis, and acute kidney injury ). Outcomes were compared in pre- and post-protocol groups with χ2 analysis. Logistic regression compared risk of transfusion in pre- and post-protocol subgroups of patients with differing risk for transfusion (anemia, body mass index [BMI], and sex). RESULTS: No differences were found in baseline patient characteristics across pre- and post-protocol groups (n = 1084 and 912, respectively). TXA use increased from 32.3% to 92.2% while transfusion rates decreased from 10.3% to 4.8% (p < 0.001). Postoperative Day 3 Hb increased from 95.8 to 101.4 g/L (p < 0.001). Logistic regression demonstrated reduced transfusion in post-protocol subgroups regardless of sex, anemia, or BMI (p < 0.001). No increase in adverse events was observed (p = 0.8451). CONCLUSIONS: Universal TXA was associated with a reduction of RBC transfusion, overall and in clinically relevant subgroups, strengthening the rationale for universal therapy.

Severe and near-fatal anaphylactic reactions triggered by chlorhexidine-coated catheters in patients undergoing renal allograft surgery: a case series.

PURPOSE: Although intraoperative anaphylaxis during surgery is a rare event, we describe five patients who experienced perioperative anaphylactic reactions during renal transplantation and were referred for investigation. CLINICAL FEATURES: Skin-prick and intradermal skin tests were done to investigate potential allergies to drugs given perioperatively prior to the development of anaphylaxis, including basiliximab, propofol, cefazolin, cis-atracurium, fentanyl, latex, remifentanil, and chlorhexidine. In addition, in vitro serologic testing for specific IgE was done in patients suspected to have had chlorhexidine anaphylaxis. All five patients were male, with a mean age of 48 yr (range 30-69). Skin testing for all drugs was non-reactive except for chlorhexidine, which was positive in four of five patients (one patient refused intradermal testing). In vitro test results for chlorhexidine-specific IgE were positive in all of the patients. Anesthetic records showed that intraoperative anaphylaxis had occurred immediately after insertion of a chlorhexidine-coated central venous catheter. CONCLUSIONS: Intraoperative insertion of chlorhexidine-coated central venous catheters can trigger life-threatening anaphylaxis in susceptible patients undergoing renal transplantation.

Efficacy and safety of erythropoietin and iron therapy to reduce red blood cell transfusion in surgical patients: a systematic review and meta-analysis.

PURPOSE: Iron restricted anemia is prevalent in surgical patients and is associated with an increased risk of allogeneic red blood cell (RBC) transfusion and adverse events. Treatment of anemia includes oral and intravenous iron and erythropoiesis stimulating agents (ESAs). More recent studies have focused on the use of intravenous iron as the primary approach to treating anemia. Nevertheless, the optimal treatment strategy for anemia remains to be established. Our primary objective was to evaluate the efficacy and safety of ESA and iron therapy relative to iron therapy alone in reducing RBC transfusion in surgical patients. SOURCE: We searched the Cochrane Library, MEDLINE, EMBASE, and ClinicalTrials.gov from inception to May 2018. We included randomized-controlled trials in which adult surgical patients received an ESA and iron, vs iron alone, prior to cardiac and non-cardiac surgery. Our primary outcome was RBC transfusion rate. Secondary outcomes included hemoglobin concentration (post-treatment and postoperatively), number of RBC units transfused, mortality, stroke, myocardial infarction (MI), renal dysfunction, pulmonary embolism (PE), and deep vein thrombosis (DVT). PRINCIPAL FINDINGS: In total, 25 studies (4,719 participants) were included. Erythropoiesis stimulating agents and iron therapy reduced RBC transfusion relative to iron therapy (relative risk [RR] 0.57; 95% confidence interval [CI], 0.46 to 0.71) without any change in mortality (RR 1.31; 95% CI, 0.80 to 2.16), stroke (RR 1.91; 95% CI, 0.63 to 5.76), MI (RR 1.12; 95% CI, 0.50 to 2.50), renal dysfunction (RR 0.96; 95% CI, 0.72 to 1.26), PE (RR 0.92; 95% CI, 0.15 to 5.83), or DVT (RR 1.48; 95% CI, 0.95 to 2.31). CONCLUSION: Administration of ESA and iron therapy reduced the risk for RBC transfusion compared with iron therapy alone in patients undergoing cardiac and non-cardiac surgery. Nevertheless, publication bias and heterogeneity reduces the confidence of the finding. Although the analysis was probably under-powered for some outcomes, no difference in the incidence of serious adverse events was observed with ESA and iron compared with iron alone. Further large prospective trials are required to confirm these findings.