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BACKGROUND: Transfusion-associated circulatory overload (TACO) is a leading cause of transfusion-related morbidity and mortality. TACO follows a two-hit pathophysiology, where comorbidities like cardiac or renal failure act as the first hit followed by blood transfusion as a second hit. Observational studies suggest that plasma transfusion is more likely to cause TACO than other blood products. We conducted a randomized animal study to gather evidence that plasma transfusion can induce TACO. MATERIAL AND METHODS: As a first hit a large myocardial infarction was created in male Wistar rats. Then animals were randomized to receive 4 units of solvent/ detergent-treated pooled plasma (SDP), fresh frozen plasma (FFP), a colloid control (albumin 5%) or a crystalloid fluid control (Ringer’s lactate) (n=10 per group). The primary outcome was the difference between pre- and post-transfusion left-ventricular end diastolic pressure (ΔLVEDP). Secondary outcomes were markers for acute lung injury; lung wet/dry weight ratio, PaO(2)/FiO(2) ratio and pulmonary histological assessment. RESULTS: Pre-transfusion characteristics were similar between groups. ΔLVEDP increased significantly after transfusion with SDP (7.7 mmHg; 4.5–10.5) and albumin (13.0 mmHg; 6.5–15.2), but not after FFP (7.9 mmHg, 1.1; 11.3) compared to infusion with Ringer’s lactate (0.6 mmHg; 0.4–2.2), p=0.007, p=0.0005 and p=0.14 respectively. There were no significant differences in ΔLVEDP between groups receiving SDP, FFP or albumin. There was no increase in acute lung injury in any group compared to other groups. DISCUSSION: Circulatory overload, measured as ΔLVEDP, was induced after transfusion of SDP or albumin, but not after infusion of Ringer’s lactate. These results show that the effect of plasma transfusion on ΔLVEDP differs from fluid overload induced by crystalloid infusion. Colloid osmotic pressure may be an important component in the development of TACO and should be a target for future research.

Background and Objectives: Transfusion-associated circulatory overload (TACO) is a pulmonary transfusion complication and a leading cause of transfusion-related morbidity and mortality. Volume overload and rising hydrostatic pressure as a consequence of transfusion are seen as the central pathway leading to TACO. A possible preventative measure for TACO could be the use of low-volume blood products like volume-reduced lyophilized plasma. We hypothesize that volume-reduced lyophilized plasma decreases circulatory overload leading to a reduced pulmonary capillary pressure and can therefore be an effective strategy to prevent TACO. Materials and Methods: A validated two-hit animal model in rats with heart failure was used. Animals were randomized to receive 4 units of either solvent-detergent pooled plasma (SDP) as control, standard volume lyophilized plasma (LP-S) or hyperoncotic volume-reduced lyophilized plasma (LP-VR). The primary outcome was the difference between pre-transfusion and post-transfusion left ventricular end-diastolic pressure (ΔLVEDP). Secondary outcomes included markers for acute lung injury. Results: LVEDP increased in all randomization groups following transfusion. The greatest elevation was seen in the group receiving LP-VR (+11.9 mmHg [5.9–15.6]), but there were no significant differences when compared to groups receiving either LP-S (+6.3 mmHg [2.9–13.4], p = 0.29) or SDP (+7.7 mmHg [4.5–10.5], p = 0.55). There were no significant differences in markers for acute lung injury, such as pulmonary wet/dry weight ratios, lung histopathology scores or PaO2/FiO2 ratio between the three groups. Conclusion: Transfusion with hyperoncotic volume-reduced plasma did not attenuate circulatory overload compared to standard volume plasma and was therefore not an effective preventative strategy for TACO in this rat model.

Cystic fibrosis transmembrane conductance regulator (CFTR) modulators reduce agonist-induced platelet activation and function. CFTR modulators, such as ivacaftor, present a promising therapeutic strategy in thrombocytopathies, including severe COVID-19. https://bit.ly/3HJykdt

OBJECTIVE Awake craniotomies are often characterized by alternating asleep-awake-asleep periods. Preceding the awake phase, patients are weaned from anesthesia and mechanical ventilation. Although clinicians aim to minimize the time to awake for patient safety and operating room efficiency, in some patients, the time to awake exceeds 20 minutes. The goal of this study was to determine the average time to awake and the factors associated with prolonged time to awake (> 20 minutes) in patients undergoing awake craniotomy. METHODS Records of patients who underwent awake craniotomy between 2003 and 2020 were evaluated. Time to awake was defined as the time between discontinuation of propofol and remifentanil infusion and the time of extubation. Patient and perioperative characteristics were explored as predictors for time to awake using logistic regression analyses. RESULTS Data of 307 patients were analyzed. The median (IQR) time to awake was 13 (10–20) minutes and exceeded 20 minutes in 17% (95% CI 13%–21%) of the patients. In both univariate and multivariable analyses, increased age, nonsmoker status, and American Society of Anesthesiologists (ASA) class III versus II were associated with a time to awake exceeding 20 minutes. BMI, as well as the use of alcohol, drugs, dexamethasone, or antiepileptic agents, was not significantly associated with the time to awake. CONCLUSIONS While most patients undergoing awake craniotomy are awake within a reasonable time frame after discontinuation of propofol and remifentanil infusion, time to awake exceeded 20 minutes in 17% of the patients. Increasing age, nonsmoker status, and higher ASA classification were found to be associated with a prolonged time to awake.

During hyperinflammatory conditions that can occur in acute critical illness, such as shock or hypoperfusion, inflammatory mediators activate the endothelium, fueling a proinflammatory host-response as well as procoagulant processes. These changes result in shedding of the glycocalyx, endothelial hyperpermeability, edema formation, and lead to disturbed microcirculatory perfusion and organ failure. Different fluid strategies that are used in shock may have differential effects on endothelial integrity. Collectively, low protein content fluids seem to have negative effects on the endothelial glycocalyx, aggravating endothelial hyperpermeability, whereas fluids containing albumin or plasma proteins may be superior to normal saline in protecting the glycocalyx and endothelial barrier function. Targeting the endothelium may be a therapeutic strategy to limit organ failure, which hitherto has not received much attention. Treatment targets aimed at restoring the endothelium should focus on maintaining glycocalyx function and/or targeting coagulation pathways or specific endothelial receptors. Potential treatments could be supplementing glycocalyx constituents or inhibiting glycocalyx breakdown. In this review, we summarize mechanisms of endothelial dysfunction during acute critical illness, such as the systemic inflammatory response, shedding of the glycocalyx, endothelial activation, and activation of coagulation. In addition, this review focuses on the effects of different fluid strategies on endothelial permeability. Also, potential mechanisms for treatment options to reduce endothelial hyperpermeability with ensuing organ failure are evaluated. Future research is needed to elucidate these pathways and to translate these data to the first human safety and feasibility trials.

PURPOSE: To compare the effectiveness of different types of pharmacological agents to reduce organ specific edema following cardiopulmonary bypass (CPB).METHODS: Pubmed, Embase.com and Cochrane were searched for studies administrating a pharmacological agent before CPB. Primary outcome was postoperative edema.RESULTS: Forty-four studies (clinical n = 6, preclinical n = 38) fulfilled eligibility criteria. Steroids were used in most clinical studies (n = 5, 83%) and reduced postoperative edema in 4 studies, however heterogeneity precluded meta-analysis. In preclinical studies, a total of 31 different drugs were tested of which 20 (65%) reduced edema in at least one organ. Particularly neutrophil inhibitors, and modulators of coagulation or endothelial barrier reduced pulmonary edema (SMD -2.77 [-3.93, -1.61]; -1.29 [-2.12, -0.46], -2.33 [-4.69, 0.03], respectively) compared to no treatment. Reducing renal (SMD -0.91 [CI -1.65 to -0.18]), intestinal (SMD -1.98 [CI -3.92 to -0.04]) or myocardial (SMD -1.95 [CI -3.91 to -0.01]) edema following CPB required specific modulators of endothelial barrier.CONCLUSION: Overall, neutrophil inhibitors and direct modulators of endothelial barrier (PAR1, Tie2 signaling) most effectively reduced edema following CPB, in particular pulmonary edema. Future research should focus on a combination of these strategies to reduce edema and assess the effect on organ function and outcome following CPB.

Pharmacological conditioning aims to protect the heart from myocardial ischemia-reperfusion injury (IRI). Despite extensive research in this area, today, a significant gap remains between experimental findings and clinical practice. This review provides an update on recent developments in pharmacological conditioning in the experimental setting and summarizes the clinical evidence of these cardioprotective strategies in the perioperative setting. We start describing the crucial cellular processes during ischemia and reperfusion that drive acute IRI through changes in critical compounds (∆GATP, Na+, Ca2+, pH, glycogen, succinate, glucose-6-phosphate, mitoHKII, acylcarnitines, BH4, and NAD+). These compounds all precipitate common end-effector mechanisms of IRI, such as reactive oxygen species (ROS) generation, Ca2+ overload, and mitochondrial permeability transition pore opening (mPTP). We further discuss novel promising interventions targeting these processes, with emphasis on cardiomyocytes and the endothelium. The limited translatability from basic research to clinical practice is likely due to the lack of comorbidities, comedications, and peri-operative treatments in preclinical animal models, employing only monotherapy/monointervention, and the use of no-flow (always in preclinical models) versus low-flow ischemia (often in humans). Future research should focus on improved matching between preclinical models and clinical reality, and on aligning multitarget therapy with optimized dosing and timing towards the human condition.

BACKGROUND: Microvascular leakage is proposed as main contributor to disturbed microcirculatory perfusion following hemorrhagic shock and fluid resuscitation, leading to organ dysfunction and unfavorable outcome. Currently, no drugs are available to reduce or prevent microvascular leakage in clinical practice. We therefore aimed to provide an overview of therapeutic agents targeting microvascular leakage following experimental hemorrhagic shock and fluid resuscitation.METHODS: PubMed, EMBASE.com and Cochrane Library were searched in January 2021 for preclinical studies of hemorrhagic shock using any therapeutic agent on top of standard fluid resuscitation. Primary outcome was vascular leakage, defined as edema, macromolecule extravasation or glycocalyx degradation. Drugs were classified by targeting pathways and subgroup analyses were performed per organ.RESULTS: Forty-five studies, published between 1973 and 2020, fulfilled eligibility criteria. The included studies tested 54 different therapeutics mainly in pulmonary and intestinal vascular beds. Most studies induced trauma besides hemorrhagic shock. Forty-four therapeutics (81%) were found effective to reduce microvascular leakage, edema formation or glycocalyx degradation in at least one organ. Targeting oxidative stress and apoptosis was the predominantly effective strategy (SMD: -2.18, CI [-3.21,-1.16], P CONCLUSION: Pharmacological modulation of pathways involved in cell metabolism, inflammation, endothelial barrier regulation, sex hormones and especially oxidative stress and apoptosis were effective in reducing microvascular leakage in experimental hemorrhagic shock with fluid resuscitation. Future studies should investigate whether targeting these pathways can restore microcirculatory perfusion and reduce organ injury following hemorrhagic shock.SYSTEMATIC REVIEW REGISTRATION NUMBER: CRD42018095432.

Background Hemorrhagic shock is associated with acute kidney injury and increased mortality. Targeting the endothelial angiopoietin/Tie2 system, which regulates endothelial permeability, previously reduced hemorrhagic shock-induced vascular leakage. We hypothesized that as a consequence of vascular leakage, renal perfusion and function is impaired and that activating Tie2 restores renal perfusion and function. Methods Rats underwent 1 h of hemorrhagic shock and were treated with either vasculotide or PBS as control, followed by fluid resuscitation for 4 h. Microcirculatory perfusion was measured in the renal cortex and cremaster muscle using contrast echography and intravital microscopy, respectively. Changes in the angiopoietin/Tie2 system and renal injury markers were measured in plasma and on protein and mRNA level in renal tissue. Renal edema formation was determined by wet/dry weight ratios and renal structure by histological analysis. Results Hemorrhagic shock significantly decreased renal perfusion (240 ± 138 to 51 ± 40, p p p = 0.08, cremaster perfusion 7 ± 2 perfused vessels, p p p p = 0.05), of which angiopoietin-2 elevation was associated with renal edema formation (r = 0.81, p p p p p > 0.9 at all time points) or reduce renal injury (NGAL p = 0.26, KIM-1 p = 0.78, creatinine p > 0.9, renal edema p = 0.08), but temporarily improved cremaster perfusion at 3 h following start of fluid resuscitation compared to untreated rats (resuscitation + 3 h: 11 ± 3 vs 8 ± 3 perfused vessels, p Conclusion Hemorrhagic shock-induced renal impairment cannot be restored by standard fluid resuscitation, nor by activation of Tie2. Future treatment strategies should focus on reducing angiopoietin-2 levels or on activating Tie2 via an alternative strategy.

OBJECTIVE: Microcirculatory perfusion disturbances following hemorrhagic shock and fluid resuscitation contribute to multiple organ dysfunction and mortality. Standard fluid resuscitation is insufficient to restore microcirculatory perfusion, however, additional therapies are lacking. We conducted a systematic search to provide an overview of potential non-fluid based therapeutic interventions to restore microcirculatory perfusion following hemorrhagic shock.METHODS: A structured search of PubMed, EMBASE and Cochrane Library was performed in March 2020. Animal studies needed to report at least one parameter of microcirculatory flow (perfusion, red blood cell velocity, functional capillary density).RESULTS: The search identified 1269 records of which 48 fulfilled all eligibility criteria. In total, 62 drugs were tested of which 29 were able to restore microcirculatory perfusion. Particularly complement inhibitors (75% of drugs tested successfully restored blood flow), endothelial barrier modulators (100% successful), antioxidants (66% successful), drugs targeting cell metabolism (83% successful) and sex hormones (75% successful) restored microcirculatory perfusion. Other drugs consisted of attenuation of inflammation (100% not successful), vasoactive agents (68% not successful) and steroid hormones (75% not successful).CONCLUSION: Improving mitochondrial function, inhibition of complement inhibition and reducing microvascular leakage via restoration of endothelial barrier function seems beneficial to restore microcirculatory perfusion following hemorrhagic shock and fluid resuscitation.

Background Microcirculatory perfusion disturbances are associated with increased morbidity and mortality in patients undergoing cardiac surgery with cardiopulmonary bypass (CPB). Technological advancements made it possible to monitor sublingual microcirculatory perfusion over time. The goal of this review is to provide an overview of the course of alterations in sublingual microcirculatory perfusion following CPB. The secondary goal is to identify which parameter of sublingual microcirculatory perfusion is most profoundly affected by CPB. Methods PubMed and Embase databases were systematically searched according to PRISMA guidelines and as registered in PROSPERO. Studies that reported sublingual microcirculatory perfusion measurements before and after onset of CPB in adult patients undergoing cardiac surgery were included. The primary outcome was sublingual microcirculatory perfusion, represented by functional capillary density (FCD), perfused vessel density (PVD), total vessel density (TVD), proportion of perfused vessels (PPV), and microvascular flow index (MFI). Results The search identified 277 studies, of which 19 fulfilled all eligibility criteria. Initiation of CPB had a profound effect on FCD, PVD, or PPV. Seventeen studies (89%) reported one or more of these parameters, and in 11 of those studies (65%), there was a significant decrease in these parameters during cardiac surgery; the other 6 studies (35%) reported no effect. In 29% of the studies, FCD, PVD, or PPV normalized by the end of cardiac surgery, and in 24% percent of the studies, this effect lasted at least 24 h. There was no clear effect of CPB on TVD and a mixed effect on MFI. Conclusion CPB during cardiac surgery impaired sublingual microcirculatory perfusion as reflected by reduced FCD, PVD, and PPV. Four studies reported this effect at least 24 h after surgery. Further research is warranted to conclude on the duration of CPB-induced microcirculatory perfusion disturbances and the relationship with clinical outcome. Trial registration PROSPERO, CRD42019127798

Background Microcirculatory dysfunction is associated with multiple organ failure and unfavorable patient outcome. We investigated whether therapeutically targeting the endothelial angiopoietin/Tie2 system preserves microvascular integrity during hemorrhagic shock. Methods Rats were treated with the angiopoietin-1 mimetic vasculotide and subjected to hemorrhagic shock and fluid resuscitation. Microcirculatory perfusion and leakage were assessed with intravital microscopy (n = 7 per group) and Evans blue dye extravasation (n = 8 per group), respectively. The angiopoietin/Tie2 system was studied at protein and RNA level in plasma, kidneys, and lungs. Results Hemorrhagic shock significantly reduced continuously perfused capillaries (7 ± 2 vs. 11 ± 2) and increased nonperfused vessels (9 ± 3 vs. 5 ± 2) during hemorrhagic shock, which could not be restored by fluid resuscitation. Hemorrhagic shock increased circulating angiopoietin-2 and soluble Tie2 significantly, which associated with microcirculatory perfusion disturbances. Hemorrhagic shock significantly decreased Tie2 gene expression in kidneys and lungs and induced microvascular leakage in kidneys (19.7 ± 11.3 vs. 5.2 ± 3.0 µg/g) and lungs (16.1 ± 7.0 vs. 8.6 ± 2.7 µg/g). Vasculotide had no effect on hemodynamics and microcirculatory perfusion during hemorrhagic shock but restored microcirculatory perfusion during fluid resuscitation. Interestingly, vasculotide attenuated microvascular leakage in lungs (10.1 ± 3.3 µg/g) and significantly reduced the required amount of volume supplementation (1.3 ± 1.4 vs. 2.8 ± 1.5 ml). Furthermore, vasculotide posttreatment was also able to restore microcirculatory perfusion during fluid resuscitation. Conclusions Targeting Tie2 restored microvascular leakage and microcirculatory perfusion and reduced fluid resuscitation requirements in an experimental model of hemorrhagic shock. Therefore, the angiopoietin/Tie2 system seems to be a promising target in restoring microvascular integrity and may reduce organ failure during hemorrhagic shock.

BACKGROUND: Endothelial hyperpermeability is suggested to play a role in the development of microcirculatory perfusion disturbances and organ failure following hemorrhagic shock, but evidence is limited.OBJECTIVE: To study the effect of plasma from traumatic hemorrhagic shock patients on in vitro endothelial barrier function.METHODS: Plasma from traumatic hemorrhagic shock patients was obtained at the emergency department (ED), the intensive care unit (ICU), 24 h after ICU admission and from controls (n = 8). Sublingual microcirculatory perfusion was measured using incident dark field videomicroscopy at matching time points. Using electric cell-substrate impedance sensing, the effects of plasma exposure on in vitro endothelial barrier function of human endothelial cells were assessed.RESULTS: Plasma from traumatic hemorrhagic shock patients collected at ED admission induced a 19% loss of in vitro endothelial resistance compared to plasma from controls (p 0.99). Interestingly, in vitro endothelial resistance showed a positive association with in vivo microcirculatory perfusion (r = 0.56, p CONCLUSIONS: Plasma from traumatic hemorrhagic shock patients obtained following ED admission, but not at later stages, induced in vitro endothelial hyperpermeability. This coincided with in vivo microcirculatory perfusion disturbances.

Objective Heparin biocompatible coating is frequently used to reduce inflammation and blood coagulation during cardiopulmonary bypass (CPB) in cardiac surgery. Whether heparin coating is protective or damaging to the vascular endothelium is however unclear. We investigated whether heparin-coated circuits are associated with better preservation of microcirculatory perfusion and glycocalyx dimensions compared to non-heparin phosphorylcholine-coated circuits. Design Prospective, randomized blinded study. Setting Tertiary university hospital. Participants A total of 26 adults undergoing elective coronary artery bypass graft surgery with CPB. Interventions Phosphorylcholine (PC, n=13) versus heparin-coated circuits (HC, n=13). Measurements and Main Results Sublingual microcirculatory perfusion was measured before, during and after CPB using side stream dark field imaging and analyzed for perfused vessel density and perfused boundary region, an inverse parameter for glycocalyx dimensions. Onset of CPB was associated with an increase in perfused boundary region in the PC group that continued until the 3rd postoperative day (2.0±0.2 to 2.5±0.2 µm; p=0.018). This was paralleled by increased plasma syndecan-1 levels in the PC group. Contrastingly, both parameters remained unaltered in the HC group compared to baseline levels. CPB decreased perfused vessel density in both groups (CPB vs pre-CPB: PC: 17±2 to 13±2 mm/mm2, p=0.006; HC: 16±2 to 11±2 mm/mm2, p=0.003) and remained equally altered in the first three postoperative days. Conclusion The use of a heparin-coated circuit is associated with better preservation of the endothelial glycocalyx compared to phosphorylcholine-coated circuits, whereas microcirculatory perfusion was equally disturbed in both groups. Hence, CPB-induced microcirculatory perfusion disturbances seem to be coating independent.

Background. Type 2 diabetes mellitus (T2DM) increases the risk of myocardial ischemia, followed by increased perioperative risk of cardiovascular morbidity. We investigated whether reducing caloric intake reduces ischemic injury and myocardial dysfunction and affects the protective effects of the volatile anesthetic sevoflurane in diet-induced T2DM rats.Methods. Rats received a western (WD) or control diet (CD). Caloric intake was reduced by reversing WD-fed rats to CD. Myocardial function was determined with echocardiography. After 8 weeks of diet feeding, myocardial infarction was induced and the effect of sevoflurane was studied on myocardial function and ischemia/reperfusion injury.Results. WD-feeding resulted in a mild T2DM phenotype and myocardial dysfunction. Sevoflurane further impaired systolic function in WD-fed rats. Unexpectedly, WD-feeding reduced infarct size compared to CD-feeding. Sevoflurane reduced infarct size in CD-fed rats; however it enlarged infarct size in WD-fed rats. Caloric reduction restored myocardial dysfunction and the protective effect of sevoflurane against ischemia compared to WD-fed rats, whereas the protective effects of WD-feeding persisted.Conclusion. Caloric reduction restored the T2DM phenotype and myocardial function, while the cardioprotective properties of WD-feeding or sevoflurane persisted. Our data suggest that reducing caloric intake in T2DM might be a possible intervention to reduce perioperative risk of cardiovascular morbidity.

Obesity is a frequent comorbidity among patients undergoing cardiac surgery with cardiopulmonary bypass (CPB). Cardiac surgery with CPB impairs microcirculatory perfusion, which is associated with multiple organ failure. As microvascular function is frequently compromised in obese patients, we studied whether cardiac surgery with CPB has a more detrimental effect on microcirculatory perfusion in obese patients. Sublingual microcirculatory perfusion was measured with sidestream dark field (SDF) imaging in obese patients (body mass index &ge, 32 kg/m2, n = 14) without type II diabetes mellitus and in lean patients (BMI 20&ndash, 25 kg/m2, n = 22) undergoing cardiac surgery with CPB. CPB reduced systolic blood pressure and mean arterial pressure more profoundly in lean compared with obese patients (SBP: 38% vs. 18%, MAP: 11% vs. 8%, p &lt, 0.05), and both restored after weaning from CPB. No differences were present in intraoperative glucose, hematocrit, hemoglobin, lactate, and blood gas values between obese and lean patients. Microcirculatory perfusion did not differ between obese and lean patients the day before surgery. CPB decreased microcirculatory perfusion with 9% in both groups, but this was only significant in lean patients (p &lt, 0.05). Three days following surgery, microcirculatory perfusion was restored in both groups. In conclusion, microcirculatory perfusion was equally disturbed during cardiac surgery with CPB in metabolically healthy obese patients compared to lean patients.

Myocardial contrast echocardiography (MCE) offers the opportunity to study myocardial perfusion defects in mice in detail. The value of MCE compared with single-photon emission computed tomography, positron emission tomography, and computed tomography consists of high spatial resolution, the possibility of quantification of blood volume, and relatively low costs. Nevertheless, a number of technical and physiological aspects should be considered to ensure reproducibility among research groups. The aim of this overview is to describe technical aspects of MCE and the physiological parameters that influence myocardial perfusion data obtained with this technique. First, technical aspects of MCE discussed in this technical review are logarithmic compression of ultrasound data by ultrasound systems, saturation of the contrast signal, and acquisition of images during different phases of the cardiac cycle. Second, physiological aspects of myocardial perfusion that are affected by the experimental design are discussed, including the anesthesia regimen, systemic cardiovascular effects of vasoactive agents used, and fluctuations in body temperature that alter myocardial perfusion. When these technical and physiological aspects of MCE are taken into account and adequately standardized, MCE is an easily accessible technique for mice that can be used to study the control of myocardial perfusion by a wide range of factors.

RATIONALE: Diaphragm weakness in critically ill patients prolongs ventilator dependency and duration of hospital stay, and increases mortality and health care costs. The mechanisms underlying diaphragm weakness include cross-sectional fiber atrophy and contractile protein dysfunction, but whether additional mechanisms are at play is unknown.OBJECTIVES: To test the hypothesis that mechanical ventilation with positive end-expiratory pressure (PEEP) induces longitudinal atrophy by displacing the diaphragm in caudal direction and reducing the length of fibers.METHODS: We studied structure and function of diaphragm fibers of mechanically ventilated critically ill patients, and mechanically ventilated rats with normal and increased titin compliance.MEASUREMENTS AND MAIN RESULTS: (1) PEEP causes a caudal movement of the diaphragm, both in critically ill patients and in rats, and this caudal movement reduces fiber length; (2) diaphragm fibers of 18h mechanically ventilated rats (PEEP: 2.5 cmH2O) adapt to the reduced length by absorbing serially-linked sarcomeres, the smallest contractile units in muscle (i.e. longitudinal atrophy); (3) increasing the compliance of titin molecules reduces longitudinal atrophy.CONCLUSION: Mechanical ventilation with PEEP results in longitudinal atrophy of diaphragm fibers, a response which is modulated by the elasticity of the giant sarcomeric protein titin. We postulate that longitudinal atrophy, in concert with the aforementioned cross-sectional atrophy, hampers spontaneous breathing trials in critically ill patients: during these efforts end-expiratory lung volume is reduced, and the shortened diaphragm fibers are stretched to excessive sarcomere lengths. At these lengths, muscle fibers generate less force and diaphragm weakness ensues.

Background: Rotational thromboelastometry is increasingly used to detect hyperfibrinolysis, which is a predictor of unfavorable outcome in patients with coagulation disturbances. In an in vitro study, the authors investigated which thromboelastometric hemostatic parameters could be valuable for fast diagnosis of the severity of hyperfibrinolysis and confirmed their findings in a patient population with hyperfibrinolysis. Methods: Thromboelastometry was performed after adding increasing concentrations of tissue plasminogen activator (0 to 400 ng/ml) to citrated blood samples of 15 healthy volunteers. Lysis parameters included the clotting time, maximum clot firmness, maximum lysis, and lysis onset time (LOT). The relation of tissue plasminogen activator with the LOT was further investigated in a patient population with out-of-hospital cardiac arrest and hyperfibrinolysis. Results: The LOT showed a dose-dependent association with increasing tissue plasminogen activator concentrations. Late, intermediate, or fulminant hyperfibrinolysis was associated with an average LOT (mean ± SD) of 42.7 ± 13.8, 23.2 ± 8.2, and 17.5 ± 4.6 min in the in vitro study and estimated 42.2 ± 8.3, 29.1 ± 1.2, and 14.6 ± 7.7 min in patients, respectively. The authors found a moderately negative correlation between patient plasma tissue plasminogen activator levels and the LOT (r = −0.67; P = 0.01). Conclusion: This study shows that the LOT may be used for fast detection of severe hyperfibrinolysis, with a better resolution than the maximum lysis, and should be further evaluated for optimization of therapeutic strategies in patients with severe clot breakdown.

Background While most studies focus on cardiovascular morbidity following anesthesia and surgery in excessive obesity, it is unknown whether these intraoperative cardiovascular alterations also occur in milder forms of adiposity without type 2 diabetes and if insulin is a possible treatment to improve intraoperative myocardial performance. In this experimental study we investigated whether mild adiposity without metabolic alterations is already associated with cardiometabolic dysfunction during anesthesia, mechanical ventilation and surgery and whether these myocardial alterations can be neutralized by intraoperative insulin treatment. Methods Mice were fed a western (WD) or control diet (CD) for 4 weeks. After metabolic profiling, mice underwent general anesthesia, mechanical ventilation and surgery. Cardiac function was determined with echocardiography and left-ventricular pressure–volume analysis. Myocardial perfusion was determined with contrast-enhanced echocardiography. WD-fed mice were subsequently treated with insulin by hyperinsulinemic euglycemic clamping followed by the same measurements of cardiac function and perfusion. Results Western-type diet feeding led to a 13 % increase in bodyweight, (p

Although hemodilution is attributed as the main cause of microcirculatory impairment during cardiopulmonary bypass (CPB), this relationship has never been investigated. We investigated the distinct effects of hemodilution with or without CPB on microvascular perfusion and subsequent renal tissue injury in a rat model. Male Wistar rats (375–425 g) were anesthetized, prepared for cremaster muscle intravital microscopy, and subjected to CPB ( n = 9), hemodilution alone ( n = 9), or a sham procedure ( n = 6). Microcirculatory recordings were performed at multiple time points and analyzed for perfusion characteristics. Kidney and lung tissue were investigated for mRNA expression for genes regulating inflammation and endothelial adhesion molecule expression. Renal injury was assessed with immunohistochemistry. Hematocrit levels dropped to 0.24 ± 0.03 l/l and 0.22 ± 0.02 l/l after onset of hemodilution with or without CPB. Microcirculatory perfusion remained unaltered in sham rats. Hemodilution alone induced a 13% decrease in perfused capillaries, after which recovery was observed. Onset of CPB reduced the perfused capillaries by 40% (9.2 ± 0.9 to 5.5 ± 1.5 perfused capillaries per microscope field; P < 0.001), and this reduction persisted throughout the experiment. Endothelial and inflammatory activation and renal histological injury were increased after CPB compared with hemodilution or sham procedure. Hemodilution leads to minor and transient disturbances in microcirculatory perfusion, which cannot fully explain impaired microcirculation following cardiopulmonary bypass. CPB led to increased renal injury and endothelial adhesion molecule expression in the kidney and lung compared with hemodilution. Our findings suggest that microcirculatory impairment during CPB may play a role in the development of kidney injury.

Preservation of myocardial perfusion during surgery is particularly important in patients with increased risk for perioperative complications, such as diabetes. Volatile anesthetics, like sevoflurane, have cardiodepressive effects and may aggravate cardiovascular complications. We investigated the effect of sevoflurane on myocardial perfusion and function in prediabetic rats. Rats were fed a western diet (WD;n=18) or control diet (CD;n=18) for 8 weeks and underwent (contrast) echocardiography to determine perfusion and function during baseline and sevoflurane exposure. Myocardial perfusion was estimated based on the product of microvascular filling velocity and blood volume. WD-feeding resulted in a prediabetic phenotype characterized by obesity, hyperinsulinemia, hyperlipidemia, glucose intolerance, and hyperglycemia. At baseline, WD-feeding impaired myocardial perfusion and systolic function compared to CD-feeding. Exposure of healthy rats to sevoflurane increased the microvascular filling velocity without altering myocardial perfusion but impaired systolic function. In prediabetic rats, sevoflurane did also not affect myocardial perfusion; however, it further impaired systolic function. Diet-induced prediabetes is associated with impaired myocardial perfusion and function in rats. While sevoflurane further impaired systolic function, it did not affect myocardial perfusion in prediabetic rats. Our findings suggest that sevoflurane anesthesia leads to uncoupling of myocardial perfusion and function, irrespective of the metabolic state.

Contains fulltext : 155008.pdf (Publisher’s version ) (Closed access) RATIONALE: The clinical significance of diaphragm weakness in critically ill patients is evident: it prolongs ventilator dependency, and increases morbidity and duration of hospital stay. To date, the nature of diaphragm weakness and its underlying pathophysiologic mechanisms are poorly understood. OBJECTIVES: We hypothesized that diaphragm muscle fibers of mechanically ventilated critically ill patients display atrophy and contractile weakness, and that the ubiquitin-proteasome pathway is activated in the diaphragm. METHODS: We obtained diaphragm muscle biopsies from 22 critically ill patients who received mechanical ventilation before surgery and compared these with biopsies obtained from patients during thoracic surgery for resection of a suspected early lung malignancy (control subjects). In a proof-of-concept study in a muscle-specific ring finger protein-1 (MuRF-1) knockout mouse model, we evaluated the role of the ubiquitin-proteasome pathway in the development of contractile weakness during mechanical ventilation. MEASUREMENTS AND MAIN RESULTS: Both slow- and fast-twitch diaphragm muscle fibers of critically ill patients had approximately 25% smaller cross-sectional area, and had contractile force reduced by half or more. Markers of the ubiquitin-proteasome pathway were significantly up-regulated in the diaphragm of critically ill patients. Finally, MuRF-1 knockout mice were protected against the development of diaphragm contractile weakness during mechanical ventilation. CONCLUSIONS: These findings show that diaphragm muscle fibers of critically ill patients display atrophy and severe contractile weakness, and in the diaphragm of critically ill patients the ubiquitin-proteasome pathway is activated. This study provides rationale for the development of treatment strategies that target the contractility of diaphragm fibers to facilitate weaning.

Overweight and obesity lead to higher morbidity risks, which are alleviated even by mild weight loss. To gain insight in the molecular effects of weight loss in adipose tissue, we analyzed the effects of short-term dietary restriction (DR) on mice fed a low-fat diet (lean mice) or a high-fat diet (obese mice). Female C57B16/J mice on both diets were on DR until an average body weight loss of 20%, which was achieved in 8 to 12 days depending on body weight at the start of DR. Plasma free fatty acids and blood glucose levels decreased significantly on DR. In the (restricted) low-fat diet groups, gene expression analysis using adipose-enriched cDNA microarrays revealed only two transcripts to be significant differentially expressed by DR: up-regulation of malic enzyme (Modi) and down-regulation of major urinary protein 1 (Mup1). Real-time polymerase chain reaction analysis confirmed these findings and showed, for the high-fat diet groups, an identical expression pattern for Mup1, whereas Mod1 showed an opposed gene expression pattern for the high-fat diet groups. In conclusion, initial weight loss induces transcriptional changes only in a very small number of adipose genes, which also depends on the (restricted) diet used.

Background: The authors investigated whether patients with out-of-hospital cardiac arrest with an initial low cerebral oxygen level during cardiopulmonary resuscitation are more prone to develop hyperfibrinolysis than patients with normal cerebral oxygenation levels and which part of the fibrinolytic system is involved in this response. Methods: In 46 patients, hyperfibrinolysis was diagnosed immediately upon emergency department admission using rotational thromboelastometry and defined as a lysis more than 15%. Simultaneously, initial cerebral tissue oxygenation was measured using near-infrared spectroscopy, and oxygen desaturation was defined as a tissue oxygenation index (TOI) of 50% or less. Blood sample analysis included markers for hypoperfusion and fibrinolysis. Results: There was no difference in prehospital cardiopulmonary resuscitation duration between patients with or without hyperfibrinolysis. An initial TOI of 50% or less was associated with more clot lysis (91% [17 to 100%; n = 16]) compared with patients with a normal TOI (6% [4 to 11%]; n = 30; P < 0.001), with lower levels of plasminogen (151.6 ± 61.0 vs. 225.3 ± 47.0 μg/ml; P < 0.001) and higher levels of tissue plasminogen activator (t-PA; 18.3 ± 7.4 vs. 7.9 ± 4.7 ng/ml; P < 0.001) and plasminogen activator inhibitor-1 (19.3 ± 8.9 vs. 12.1 ± 6.1 ng/ml; P = 0.013). There were no differences in (activated) protein C levels among groups. The initial TOI was negatively correlated with t-PA (r = −0.69; P < 0001). Mortality rates were highest in patients with hyperfibrinolysis. Conclusion: Activation of the fibrinolytic system is more common in out-of-hospital cardiac arrest patients with an initial cerebral tissue oxygenation value of 50% or less during resuscitation and is linked to increased levels of t-PA rather than involvement of protein C.

In type 2 diabetic patients, cardiac events in the perioperative period may be associated with diminished myocardial vasomotor function and endothelial dysfunction. The influence of sevoflurane anaesthesia on myocardial endothelial dysfunction in type 2 diabetic mellitus is investigated in this pilot study. Six males with type 2 diabetes mellitus and eight healthy controls were included. Using myocardial contrast echocardiography, myocardial blood flow (MBF) was measured at rest, during adenosine-induced hyperaemia (endothelium-independent vasodilation) and after sympathetic stimulation by the cold pressor test (endothelium-dependent vasodilation). Measurements were performed before and after induction of sevoflurane anaesthesia. Sevoflurane anaesthesia decreased resting MBF in diabetics but not in controls (P = 0.03), while baseline MBF did not differ between diabetics and controls. Without anaesthesia, adenosine-induced hyperaemia increased MBF in both groups compared to resting values. Adenosine combined with sevoflurane resulted in a lower hyperaemic MBF in both groups compared to no anaesthesia. Differences in MBF in response to adenosine before and after sevoflurane administration were larger in diabetic patients, however not statistically significant in this pilot group (P = 0.08). Myocardial blood flow parameters after the cold pressor test were not different between groups. These pilot data in type 2 diabetic patients show that sevoflurane anaesthesia decreases resting myocardial blood flow compared to healthy controls. Further, we observed a trend towards a lower endothelium-independent vasodilation capacity in diabetic patients under sevoflurane anaesthesia. Endothelium-dependent vasodilation was not affected by sevoflurane in diabetic patients. These data provide preliminary insight into myocardial responses in type 2 diabetic patients under general anaesthesia. http://www.clinicialtrials.gov , NCT00866801

Objectives This study investigated whether a tailored approach to heparin and protamine management improved thromboelastometric parameters after cardiopulmonary bypass and reduced postoperative blood loss compared with activated coagulation time (ACT)-based fixed target heparin and protamine management. Design Randomized controlled study. Setting Tertiary university hospital. Participants Patients undergoing elective valve surgery (n = 38). Interventions Heparin and protamine management were based either on the ACT (n = 19) or hemostasis management system (HMS) measurements (n = 19; HMS Plus; Medtronic, Minneapolis, MN). Measurements and Main Results The target ACT for initiation of cardiopulmonary bypass was 480 seconds. Study variables included rotational thromboelastometry EXTEM (extrinsic coagulation), HEPTEM (intrinsic coagulation with heparinase), and FIBTEM (fibrin part of clot formation) tests and 24-hour blood loss. The use of HMS reduced the median protamine-to-heparin ratio from 1.00 (1.00-1.00) to 0.62 (0.56-0.66; p

Volatile anaesthetics exert protective effects on the heart against perioperative ischaemic injury. However, there is growing evidence that these cardioprotective properties are reduced in case of type 2 diabetes mellitus. A strong predictor of postoperative cardiac function is myocardial substrate metabolism. In the type 2 diabetic heart, substrate metabolism is shifted from glucose utilisation to fatty acid oxidation, resulting in metabolic inflexibility and cardiac dysfunction. The ischaemic heart also loses its metabolic flexibility and can switch to glucose or fatty acid oxidation as its preferential state, which may deteriorate cardiac function even further in case of type 2 diabetes mellitus. Recent experimental studies suggest that the cardioprotective properties of volatile anaesthetics partly rely on changing myocardial substrate metabolism. Interventions that target at restoration of metabolic derangements, like lifestyle and pharmacological interventions, may therefore be an interesting candidate to reduce perioperative complications. This review will focus on the current knowledge regarding myocardial substrate metabolism during volatile anaesthesia in the obese and type 2 diabetic heart during perioperative ischaemia.

Background Glucose intolerance is a major health problem and is associated with increased risk of progression to type 2 diabetes mellitus and cardiovascular disease. However, whether glucose intolerance is related to impaired myocardial perfusion is not known. The purpose of the present study was to study the effect of diet-induced glucose intolerance on myocardial function and perfusion during baseline and pharmacological induced hyperaemia. Methods Male Wistar rats were randomly exposed to a high fat diet (HFD) or control diet (CD) (n = 8 per group). After 4 weeks, rats underwent an oral glucose tolerance test. Subsequently, rats underwent (contrast) echocardiography to determine myocardial function and perfusion during baseline and dipyridamole-induced hyperaemia (20 mg/kg for 10 min). Results Four weeks of HFD feeding resulted in glucose intolerance compared to CD-feeding. Contractile function as represented by fractional shortening was not altered in HFD-fed rats compared to CD-fed rats under baseline conditions. However, dipyridamole increased fractional shortening in CD-fed rats, but not in HFD-fed rats. Basal myocardial perfusion, as measured by estimate of perfusion, was similar in CD- and HFD-fed rats, whereas dipyridamole increased estimate of perfusion in CD-fed rats, but not in HFD-fed rats. However, flow reserve was not different between CD- and HFD-fed rats. Conclusions Diet-induced glucose intolerance is associated with impaired myocardial function during conditions of hyperaemia, but myocardial perfusion is maintained. These findings may result in new insights into the effect of glucose intolerance on myocardial function and perfusion during hyperaemia.

Background In patients with myocardial infarction or heart failure, right ventricular (RV) dysfunction is associated with death, shock and arrhythmias. In patients with type 2 diabetes mellitus, structural and functional alterations of the left ventricle (LV) are highly prevalent, however, little is known about the impact of diabetes on RV characteristics. The purpose of the present study was to investigate whether LV changes are paralleled by RV alterations in a rat model of diabetes. Methods Zucker diabetic fatty (ZDF) and control (ZL) rats underwent echocardiography and positron emission tomography (PET) scanning using [18F]-2-fluoro-2-deoxy-D-glucose under hyperinsulinaemic euglycaemic clamp conditions. Glucose, insulin, triglycerides and fatty acids were assessed from trunk blood. Another group of rats received an insulin or saline injection to study RV insulin signaling. Results ZDF rats developed hyperglycaemia, hyperinsulinaemia and dyslipidaemia (all p < 0.05). Echocardiography revealed depressed LV fractional shortening and tricuspid annular plane systolic excursion (TAPSE) in ZDF vs. ZL rats (both p < 0.05). A decrease in LV and RV insulin-mediated glucose utilisation was found in ZDF vs. ZL rats (both p < 0.05). LV associated with RV with respect to systolic function (r = 0.86, p < 0.05) and glucose utilisation (r = 0.74, p < 0.05). TAPSE associated with RV MRglu (r = 0.92, p < 0.05) and M-value (r = 0.91, p < 0.0001) and RV MRglu associated with M-value (r = 0.77, p < 0.05). Finally, reduced RV insulin-stimulated phosphorylation of Akt was found in ZDF vs. ZL (p < 0.05). Conclusions LV changes were paralleled by RV alterations in insulin-stimulated glucose utilisation and RV systolic function in a rat model of diabetes, which may be attributed to ventricular interdependence as well as to the uniform effect of diabetes. Since diabetic patients are prone to develop diabetic cardiomyopathy and myocardial ischaemia, it might be suggested that RV dysfunction plays a central role in cardiac abnormalities in this population.

Background In vitro data suggest that changes in myocardial substrate metabolism may contribute to impaired myocardial function in diabetic cardiomyopathy (DCM). The purpose of the present study was to study in a rat model of early DCM, in vivo changes in myocardial substrate metabolism and their association with myocardial function. Methods Zucker diabetic fatty (ZDF) and Zucker lean (ZL) rats underwent echocardiography followed by [11C]palmitate positron emission tomography (PET) under fasting, and [18F]-2-fluoro-2-deoxy-D-glucose PET under hyperinsulinaemic euglycaemic clamp conditions. Isolated cardiomyocytes were used to determine isometric force development. Results PET data showed a 66% decrease in insulin-mediated myocardial glucose utilisation and a 41% increase in fatty acid (FA) oxidation in ZDF vs. ZL rats (both p < 0.05). Echocardiography showed diastolic and systolic dysfunction in ZDF vs. ZL rats, which was paralleled by a significantly decreased maximal force (68%) and maximal rate of force redevelopment (69%) of single cardiomyocytes. Myocardial functional changes were significantly associated with whole-body insulin sensitivity and decreased myocardial glucose utilisation. ZDF hearts showed a 68% decrease in glucose transporter-4 mRNA expression (p < 0.05), a 22% decrease in glucose transporter-4 protein expression (p = 0.10), unchanged levels of pyruvate dehydrogenase kinase-4 protein expression, a 57% decreased phosphorylation of AMP activated protein kinase α1/2 (p < 0.05) and a 2.4-fold increased abundance of the FA transporter CD36 to the sarcolemma (p < 0.01) vs. ZL hearts, which are compatible with changes in substrate metabolism. In ZDF vs. ZL hearts a 2.4-fold reduced insulin-mediated phosphorylation of Akt was found (p < 0.05). Conclusion Using PET and echocardiography, we found increases in myocardial FA oxidation with a concomitant decrease of insulin-mediated myocardial glucose utilisation in early DCM. In addition, the latter was associated with impaired myocardial function. These in vivo data expand previous in vitro findings showing that early alterations in myocardial substrate metabolism contribute to myocardial dysfunction.

The HRRT scanner accepts, with a minor adjustment of the connectors, positive TTL signals. The connectors are sampled reliably with a frequency of 1000 Hz. The presence as well as the duration of TTL signals can be derived from the gating tag words inserted in the listmode file. Emission data can be sorted into bins with less than 1% data loss due to rounding errors resulting from the bin definitions. A first example of cardiac gating is presented for the HRRT scanner. At present, use of TTL signals during transmission scans is limited due to the fixed trajectory of the transmission source. Future work will therefore focus on assessment of optimal attenuation and scatter correction methods for gated emission measurements. Yet, a substantial improvement of image quality was seen and the usefullness of physiological gating for HRRT small animal studies has been demonstrated. The gain in image quality observed by physical gating in combination with PSF reconstructions [2] may enable use of image derived input functions [9], which will be explored in the near future.