Storage injury and blood transfusions in trauma patients.

PURPOSE OF REVIEW: The aim of the present review was to concisely summarize recent studies and current knowledge about effects of red blood cell storage injury in trauma patients. RECENT FINDINGS: Despite a pathophysiological rationale for older packed red blood cells (PRBCs) being associated with adverse events in the host organism, recent large clinical trials failed to show negative effects of transfusion with older PRBCs on clinically relevant outcomes in mixed patient population. However, there is a lack of well-designed randomized controlled trials focusing on the effects of storage lesion of PRBCs in trauma patients. SUMMARY: In the absence of specific evidence for trauma patients, we recommend to continue with a conservative transfusion regime and standard of care blood banking practice of using older PRBCs first.

Mechanical Stress and the Induction of Lung Fibrosis via the Midkine Signaling Pathway.

RATIONALE: Lung-protective ventilatory strategies have been widely used in patients with acute respiratory distress syndrome (ARDS), but the ARDS mortality rate remains unacceptably high and there is no proven pharmacologic therapy. OBJECTIVES: Mechanical ventilation can induce oxidative stress and lung fibrosis, which may contribute to high dependency on ventilator support and increased ARDS mortality. We hypothesized that the novel cytokine, midkine (MK), which can be up-regulated in oxidative stress, plays a key role in the pathogenesis of ARDS-associated lung fibrosis. METHODS: Blood samples were collected from 17 patients with ARDS and 10 healthy donors. Human lung epithelial cells were challenged with hydrogen chloride followed by mechanical stretch for 72 hours. Wild-type and MK gene-deficient (MK(-/-)) mice received two-hit injury of acid aspiration and mechanical ventilation, and were monitored for 14 days. MEASUREMENTS AND MAIN RESULTS: Plasma concentrations of MK were higher in patients with ARDS than in healthy volunteers. Exposure to mechanical stretch of lung epithelial cells led to an epithelial-mesenchymal transition profile associated with increased expression of angiotensin-converting enzyme, which was attenuated by silencing MK, its receptor Notch2, or NADP reduced oxidase 1. An increase in collagen deposition and hydroxyproline level and a decrease in lung tissue compliance seen in wild-type mice were largely attenuated in MK(-/-) mice. CONCLUSIONS: Mechanical stretch can induce an epithelial-mesenchymal transition phenotype mediated by the MK-Notch2-angiotensin-converting enzyme signaling pathway, contributing to lung remodeling. The MK pathway is a potential therapeutic target in the context of ARDS-associated lung fibrosis.

Experimental blunt chest trauma--cardiorespiratory effects of different mechanical ventilation strategies with high positive end-expiratory pressure: a randomized controlled study.

BACKGROUND: Uncertainty persists regarding the optimal ventilatory strategy in trauma patients developing acute respiratory distress syndrome (ARDS). This work aims to assess the effects of two mechanical ventilation strategies with high positive end-expiratory pressure (PEEP) in experimental ARDS following blunt chest trauma. METHODS: Twenty-six juvenile pigs were anesthetized, tracheotomized and mechanically ventilated. A contusion was applied to the right chest using a bolt-shot device. Ninety minutes after contusion, animals were randomized to two different ventilation modes, applied for 24 h: Twelve pigs received conventional pressure-controlled ventilation with moderately low tidal volumes (VT, 8 ml/kg) and empirically chosen high external PEEP (16 cmH2O) and are referred to as the HP-CMV-group. The other group (n = 14) underwent high-frequency inverse-ratio pressure-controlled ventilation (HFPPV) involving respiratory rate of 65 breaths · min(-1), inspiratory-to-expiratory-ratio 2:1, development of intrinsic PEEP and recruitment maneuvers, compatible with the rationale of the Open Lung Concept. Hemodynamics, gas exchange and respiratory mechanics were monitored during 24 h. Computed tomography and histology were analyzed in subgroups. RESULTS: Comparing changes which occurred from randomization (90 min after chest trauma) over the 24-h treatment period, groups differed statistically significantly (all P values for group effect <0.001, General Linear Model analysis) for the following parameters (values are mean ± SD for randomization vs. 24-h): PaO2 (100% O2) (HFPPV 186 ± 82 vs. 450 ± 59 mmHg; HP-CMV 249 ± 73 vs. 243 ± 81 mmHg), venous admixture (HFPPV 34 ± 9.8 vs. 11.2 ± 3.7%; HP-CMV 33.9 ± 10.5 vs. 21.8 ± 7.2%), PaCO2 (HFPPV 46.9 ± 6.8 vs. 33.1 ± 2.4 mmHg; HP-CMV 46.3 ± 11.9 vs. 59.7 ± 18.3 mmHg) and normally aerated lung mass (HFPPV 42.8 ± 11.8 vs. 74.6 ± 10.0 %; HP-CMV 40.7 ± 8.6 vs. 53.4 ± 11.6%). Improvements occurring after recruitment in the HFPPV-group persisted throughout the study. Peak airway pressure and VT did not differ significantly. HFPPV animals had lower atelectasis and inflammation scores in gravity-dependent lung areas. CONCLUSIONS: In this model of ARDS following unilateral blunt chest trauma, HFPPV ventilation improved respiratory function and fulfilled relevant ventilation endpoints for trauma patients, i.e. restoration of oxygenation and lung aeration while avoiding hypercapnia and respiratory acidosis.

Intraoperative protective mechanical ventilation for prevention of postoperative pulmonary complications: a comprehensive review of the role of tidal volume, positive end-expiratory pressure, and lung recruitment maneuvers.

Postoperative pulmonary complications are associated with increased morbidity, length of hospital stay, and mortality after major surgery. Intraoperative lung-protective mechanical ventilation has the potential to reduce the incidence of postoperative pulmonary complications. This review discusses the relevant literature on definition and methods to predict the occurrence of postoperative pulmonary complication, the pathophysiology of ventilator-induced lung injury with emphasis on the noninjured lung, and protective ventilation strategies, including the respective roles of tidal volumes, positive end-expiratory pressure, and recruitment maneuvers. The authors propose an algorithm for protective intraoperative mechanical ventilation based on evidence from recent randomized controlled trials.

Modulation of stress versus time product during mechanical ventilation influences inflammation as well as alveolar epithelial and endothelial response in rats.

BACKGROUND: Mechanical ventilation can lead to lung biotrauma when mechanical stress exceeds safety thresholds. The authors investigated whether the duration of mechanical stress, that is, the impact of a stress versus time product (STP), influences biotrauma. The authors hypothesized that higher STP levels are associated with increased inflammation and with alveolar epithelial and endothelial cell injury. METHODS: In 46 rats, Escherichia coli lipopolysaccharide (acute lung inflammation) or saline (control) was administered intratracheally. Both groups were protectively ventilated with inspiratory-to-expiratory ratios 1:2, 1:1, or 2:1 (n = 12 each), corresponding to low, middle, and high STP levels (STPlow, STPmid, and STPhigh, respectively). The remaining 10 animals were not mechanically ventilated. RESULTS: In animals with mild acute lung inflammation, but not in controls: (1) messenger RNA expression of interleukin-6 was higher in STPhigh (28.1 ± 13.6; mean ± SD) and STPlow (28.9 ± 16.0) versus STPmid (7.4 ± 7.5) (P < 0.05); (2) expression of the receptor for advanced glycation end-products was increased in STPhigh (3.6 ± 1.6) versus STPlow (2.3 ± 1.1) (P < 0.05); (3) alveolar edema was decreased in STPmid (0 [0 to 0]; median, Q1 to Q3) compared with STPhigh (0.8 [0.6 to 1]) (P < 0.05); and (4) expressions of vascular cell adhesion molecule-1 and intercellular adhesion molecule-1 were higher in STPlow (3.0 ± 1.8) versus STPhigh (1.2 ± 0.5) and STPmid (1.4 ± 0.7) (P < 0.05), respectively. CONCLUSIONS: In the mild acute lung inflammation model used herein, mechanical ventilation with inspiratory-to-expiratory of 1:1 (STPmid) minimized lung damage, whereas STPhigh increased the gene expression of biological markers associated with inflammation and alveolar epithelial cell injury and STPlow increased markers of endothelial cell damage.

Higher levels of spontaneous breathing reduce lung injury in experimental moderate acute respiratory distress syndrome.

OBJECTIVES: To assess the effects of different levels of spontaneous breathing during biphasic positive airway pressure/airway pressure release ventilation on lung function and injury in an experimental model of moderate acute respiratory distress syndrome. DESIGN: Multiple-arm randomized experimental study. SETTING: University hospital research facility. SUBJECTS: Thirty-six juvenile pigs. INTERVENTIONS: Pigs were anesthetized, intubated, and mechanically ventilated. Moderate acute respiratory distress syndrome was induced by repetitive saline lung lavage. Biphasic positive airway pressure/airway pressure release ventilation was conducted using the airway pressure release ventilation mode with an inspiratory/expiratory ratio of 1:1. Animals were randomly assigned to one of four levels of spontaneous breath in total minute ventilation (n = 9 per group, 6 hr each): 1) biphasic positive airway pressure/airway pressure release ventilation, 0%; 2) biphasic positive airway pressure/airway pressure release ventilation, > 0-30%; 3) biphasic positive airway pressure/airway pressure release ventilation, > 30-60%, and 4) biphasic positive airway pressure/airway pressure release ventilation, > 60%. MEASUREMENTS AND MAIN RESULTS: The inspiratory effort measured by the esophageal pressure time product increased proportionally to the amount of spontaneous breath and was accompanied by improvements in oxygenation and respiratory system elastance. Compared with biphasic positive airway pressure/airway pressure release ventilation of 0%, biphasic positive airway pressure/airway pressure release ventilation more than 60% resulted in lowest venous admixture, as well as peak and mean airway and transpulmonary pressures, redistributed ventilation to dependent lung regions, reduced the cumulative diffuse alveolar damage score across lungs (median [interquartile range], 11 [3-40] vs 18 [2-69]; p < 0.05), and decreased the level of tumor necrosis factor-α in ventral lung tissue (median [interquartile range], 17.7 pg/mg [8.4-19.8] vs 34.5 pg/mg [29.9-42.7]; p < 0.05). Biphasic positive airway pressure/airway pressure release ventilation more than 0-30% and more than 30-60% showed a less consistent pattern of improvement in lung function, inflammation, and damage compared with biphasic positive airway pressure/airway pressure release ventilation more than 60%. CONCLUSIONS: In this model of moderate acute respiratory distress syndrome in pigs, biphasic positive airway pressure/airway pressure release ventilation with levels of spontaneous breath higher than usually seen in clinical practice, that is, more than 30% of total minute ventilation, reduced lung injury with improved respiratory function, as compared with protective controlled mechanical ventilation.

The effects of salbutamol on epithelial ion channels depend on the etiology of acute respiratory distress syndrome but not the route of administration.

INTRODUCTION: We investigated the effects of intravenous and intratracheal administration of salbutamol on lung morphology and function, expression of ion channels, aquaporin, and markers of inflammation, apoptosis, and alveolar epithelial/endothelial cell damage in experimental pulmonary (p) and extrapulmonary (exp) mild acute respiratory distress syndrome (ARDS). METHODS: In this prospective randomized controlled experimental study, 56 male Wistar rats were randomly assigned to mild ARDS induced by either intratracheal (n = 28, ARDSp) or intraperitoneal (n = 28, ARDSexp) administration of E. coli lipopolysaccharide. Four animals with no lung injury served as controls (NI). After 24 hours, animals were anesthetized, mechanically ventilated in pressure-controlled mode with low tidal volume (6 mL/kg), and randomly assigned to receive salbutamol (SALB) or saline 0.9% (CTRL), intravenously (i.v., 10 µg/kg/h) or intratracheally (bolus, 25 µg). Salbutamol doses were targeted at an increase of ≈ 20% in heart rate. Hemodynamics, lung mechanics, and arterial blood gases were measured before and after (at 30 and 60 min) salbutamol administration. At the end of the experiment, lungs were extracted for analysis of lung histology and molecular biology analysis. Values are expressed as mean ± standard deviation, and fold changes relative to NI, CTRL vs. SALB RESULTS: The gene expression of ion channels and aquaporin was increased in mild ARDSp, but not ARDSexp. In ARDSp, intravenous salbutamol resulted in higher gene expression of alveolar epithelial sodium channel (0.20 ± 0.07 vs. 0.68 ± 0.24, p < 0.001), aquaporin-1 (0.44 ± 0.09 vs. 0.96 ± 0.12, p < 0.001) aquaporin-3 (0.31 ± 0.12 vs. 0.93 ± 0.20, p < 0.001), and Na-K-ATPase-α (0.39 ± 0.08 vs. 0.92 ± 0.12, p < 0.001), whereas intratracheal salbutamol increased the gene expression of aquaporin-1 (0.46 ± 0.11 vs. 0.92 ± 0.06, p < 0.001) and Na-K-ATPase-α (0.32 ± 0.07 vs. 0.58 ± 0.15, p < 0.001). In ARDSexp, the gene expression of ion channels and aquaporin was not influenced by salbutamol. Morphological and functional variables and edema formation were not affected by salbutamol in any of the ARDS groups, regardless of the route of administration. CONCLUSION: Salbutamol administration increased the expression of alveolar epithelial ion channels and aquaporin in mild ARDSp, but not ARDSexp, with no effects on lung morphology and function or edema formation. These results may contribute to explain the negative effects of ß2-agonists on clinical outcome in ARDS.

Mechanical ventilation-associated lung fibrosis in acute respiratory distress syndrome: a significant contributor to poor outcome.

One of the most challenging problems in critical care medicine is the management of patients with the acute respiratory distress syndrome. Increasing evidence from experimental and clinical studies suggests that mechanical ventilation, which is necessary for life support in patients with acute respiratory distress syndrome, can cause lung fibrosis, which may significantly contribute to morbidity and mortality. The role of mechanical stress as an inciting factor for lung fibrosis versus its role in lung homeostasis and the restoration of normal pulmonary parenchymal architecture is poorly understood. In this review, the authors explore recent advances in the field of pulmonary fibrosis in the context of acute respiratory distress syndrome, concentrating on its relevance to the practice of mechanical ventilation, as commonly applied by anesthetists and intensivists. The authors focus the discussion on the thesis that mechanical ventilation-or more specifically, that ventilator-induced lung injury-may be a major contributor to lung fibrosis. The authors critically appraise possible mechanisms underlying the mechanical stress-induced lung fibrosis and highlight potential therapeutic strategies to mitigate this fibrosis.

Higher levels of spontaneous breathing induce lung recruitment and reduce global stress/strain in experimental lung injury.

BACKGROUND: Spontaneous breathing (SB) in the early phase of the acute respiratory distress syndrome is controversial. Biphasic positive airway pressure/airway pressure release ventilation (BIPAP/APRV) is commonly used, but the level of SB necessary to maximize potential beneficial effects is unknown. METHODS: Experimental acute respiratory distress syndrome was induced by saline lung lavage in anesthetized and mechanically ventilated pigs (n = 12). By using a Latin square and crossover design, animals were ventilated with BIPAP/APRV at four different levels of SB in total minute ventilation (60 min each): (1) 0% (BIPAP/APRV0%); (2) greater than 0 to 30% (BIPAP/APRV>0-30%); (3) greater than 30 to 60% (BIPAP/APRV>30-60%); and (4) greater than 60% (BIPAP/APRV>60%). Gas exchange, hemodynamics, and respiratory variables were measured. Lung aeration was assessed by high-resolution computed tomography. The distribution of perfusion was marked with Ga-labeled microspheres and evaluated by positron emission tomography. RESULTS: The authors found that higher levels of SB during BIPAP/APRV (1) improved oxygenation; (2) decreased mean transpulmonary pressure (stress) despite increased inspiratory effort; (3) reduced nonaerated lung tissue, with minimal changes in the distribution of perfusion, resulting in decreased low aeration/perfusion zones; and (4) decreased global strain (mean ± SD) (BIPAP/APRV0%: 1.39 ± 0.08; BIPAP/APRV0-30%: 1.33 ± 0.03; BIPAP/APRV30-60%: 1.27 ± 0.06; BIPAP/APRV>60%: 1.25 ± 0.04, P < 0.05 all vs. BIPAP/APRV0%, and BIPAP/APRV>60% vs. BIPAP/APRV0-30%). CONCLUSIONS: In a saline lung lavage model of experimental acute respiratory distress syndrome in pigs, levels of SB during BIPAP/APRV higher than currently recommended for clinical practice, that is, 10 to 30%, improve oxygenation by increasing aeration in dependent lung zones without relevant redistribution of perfusion. In presence of lung recruitment, higher levels of SB reduce global stress and strain despite an increase in inspiratory effort.

A new adaptive controller for volume-controlled mechanical ventilation in small animals.

BACKGROUND: This study aimed to develop and evaluate an adaptive control system for volume-controlled ventilation (VCV) in small animals to guarantee accurate delivery of tidal volume (VT) in the presence of changes in lung mechanics. METHODS: The adaptive control system to control the Harvard Inspira ventilator was designed and evaluated on a custom-made physical model during step changes of resistance and elastance of the respiratory system assessing difference in minute ventilation (ΔMVc) during convergence cycles (NC). The controller was then evaluated during conventional and variable volume VCV in rats with acute respiratory distress syndrome (ARDS) induced by intratracheal HCl (six animals/group), where the difference between desired and applied VT (dVT,d), its root-mean square error (RMSE) and relative deviation from target minute ventilation (ΔMV) were determined. RESULTS: The controller showed fast convergence NC < 20 cycles with an acceptable ΔMVC < 10% in simulations and nearly abolished dVT,d (VCV: 0.23 ± 0.1 mL to 0.0 ± 0.0 mL, P < .001 and vVCV: 0.05 ± 0.8 mL to 0.0 ± 0.0 mL, P < .001), significantly reduced RMSE (VCV: 0.23 ± 0.1 to 0.04 ± 0.01 mL, P < .001 and vVCV: 0.13 ± 0.04 to 0.08 ± 0.02 mL, P < .001) and ΔMV (VCV: 11.6 ± 4.2 to 0.04 ± 0.15%, P < .001 and vVCV: -3 ± 3.8 to -0.35 ± 1.3 %, P < .001) in animal experiments. In VCV the improvement was more pronounced, due to reduced respiratory system elastance in this group (VCV: 5.6 cmH2O mL(-1) versus vVCV: 3.8 cmH2O mL(-1), P < .001). CONCLUSIONS: The new adaptive controller ensured accurate delivery of VT in VCV and proved valuable for mechanical ventilation of small animals especially in ARDS research.

[Extracorporeal cardiopulmonary resuscitation-An orientation]. / Extrakorporale kardiopulmonale Reanimation ­ eine Standortbestimmung.

Both in-hospital and out-of-hospital cardiac arrests are associated with a high mortality. In the past survival advantages for patients could be achieved by optimizing the chain of rescue and postresuscitation treatment; however, for patients with refractory cardiac arrest, there have so far been few promising treatment options. For selected patients with refractory cardiac arrest who do not achieve return of spontaneous circulation with conventional cardiopulmonary resuscitation (CPR), extracorporeal (e)CPR using venoarterial extracorporeal membrane oxygenation is an option to improve the probability of survival. This article describes the technical features, important aspects of treatment, and the current data situation on eCPR in patients with in-hospital or out-of-hospital cardiac arrest.

[Ventilation concepts under extracorporeal membrane oxygenation (ECMO) in acute respiratory distress syndrome (ARDS)]. / Beatmungskonzepte unter extrakorporaler Membranoxygenierung bei akutem Lungenversagen.

Extracorporeal membrane oxygenation (ECMO) is often the last resort for escalation of treatment in patients with severe acute respiratory distress syndrome (ARDS). The success of treatment is mainly determined by patient-specific factors, such as age, comorbidities, duration and invasiveness of the pre-existing ventilation treatment as well as the expertise of the treating ECMO center. In particular, the adjustment of mechanical ventilation during ongoing ECMO treatment remains controversial. Although a reduction of invasiveness of mechanical ventilation seems to be reasonable due to physiological considerations, no improvement in outcome has been demonstrated so far for the use of ultraprotective ventilation regimens.

A contemporary training concept in critical care cardiology.

Critical care cardiology (CCC) in the modern era is shaped by a multitude of innovative treatment options and an increasingly complex, ageing patient population. Generating high-quality evidence for novel interventions and devices in an intensive care setting is exceptionally challenging. As a result, formulating the best possible therapeutic approach continues to rely predominantly on expert opinion and local standard operating procedures. Fostering the full potential of CCC and the maturation of the next generation of decision-makers in this field calls for an updated training concept, that encompasses the extensive knowledge and skills required to care for critically ill cardiac patients while remaining adaptable to the trainee's individual career planning and existing educational programs. In the present manuscript, we suggest a standardized training phase in preparation of the first ICU rotation, propose a modular CCC core curriculum, and outline how training components could be conceptualized within three sub-specialization tracks for aspiring cardiac intensivists.

Effects of intravascular volume replacement on lung and kidney function and damage in nonseptic experimental lung injury.

BACKGROUND: Intravascular volume replacement is often required in the presence of increased pulmonary capillary leakage, for example in patients with volutrauma with major hemorrhage. In the present study, the effects of Ringer's acetate (RA), gelatin-polysuccinate (GEL), and a modern hydroxyethyl starch (HES, 6% 130/0.42) on lung and kidney function and damage were compared in a two-hit model of acute lung injury. The authors hypothesized that GEL and HES, compared to RA: (1) reduced lung histological damage, (2) impaired kidney morphology and function. METHODS: Acute lung injury was induced in 30 anesthetized pigs by tidal volumes approximately 40 ml/kg, after saline lung lavage. Protective ventilation was initiated and approximately≈25% of estimated blood volume was drawn. Animals were randomly assigned to receive RA, GEL, or HES (n = 10/group) aimed at approximately 90% of intrathoracic blood volume before blood drainage. RESULTS: Fluid volumes were higher with RA (2,250 ± 764 ml) than GEL (704 ± 159 ml) and HES (837 ± 82 ml) (P < 0.05). Compared to RA, HES reduced diffuse alveolar damage overall, and GEL in nondependent zones only. GEL and HES yielded lower wet-to-dry ratios compared to RA (6.5 ± 0.5 and 6.5 ± 0.6 vs. 7.9 ± 0.9, respectively, P < 0.05). HES and RA resulted in less kidney damage than GEL, but kidney function did not differ significantly among groups. Compared to GEL, HES yielded lower lung elastance (55 ± 12 vs. 45 ± 13 cm H2O/l, P < 0.05) and intra-abdominal pressure (15 ± 5 vs. 11 ± 4 cm 14;H2O, P < 0.05). CONCLUSIONS: In this model of acute lung injury, intravascular volume expansion after major hemorrhage with HES yielded less lung damage than RA and less kidney damage than GEL.

Short-term effects of noisy pressure support ventilation in patients with acute hypoxemic respiratory failure.

INTRODUCTION: This study aims at comparing the very short-term effects of conventional and noisy (variable) pressure support ventilation (PSV) in mechanically ventilated patients with acute hypoxemic respiratory failure. METHODS: Thirteen mechanically ventilated patients with acute hypoxemic respiratory failure were enrolled in this monocentric, randomized crossover study. Patients were mechanically ventilated with conventional and noisy PSV, for one hour each, in random sequence. Pressure support was titrated to reach tidal volumes approximately 8 mL/kg in both modes. The level of positive end-expiratory pressure and fraction of inspired oxygen were kept unchanged in both modes. The coefficient of variation of pressure support during noisy PSV was set at 30%. Gas exchange, hemodynamics, lung functional parameters, distribution of ventilation by electrical impedance tomography, breathing patterns and patient-ventilator synchrony were analyzed. RESULTS: Noisy PSV was not associated with any adverse event, and was well tolerated by all patients. Gas exchange, hemodynamics, respiratory mechanics and spatial distribution of ventilation did not differ significantly between conventional and noisy PSV. Noisy PSV increased the variability of tidal volume (24.4 ± 7.8% vs. 13.7 ± 9.1%, P <0.05) and was associated with a reduced number of asynchrony events compared to conventional PSV (5 (0 to 15)/30 min vs. 10 (1 to 37)/30 min, P <0.05). CONCLUSIONS: In the very short term, noisy PSV proved safe and feasible in patients with acute hypoxemic respiratory failure. Compared to conventional PSV, noisy PSV increased the variability of tidal volumes, and was associated with improved patient-ventilator synchrony, at comparable levels of gas exchange. TRIAL REGISTRATION: ClinicialTrials.gov, NCT00786292.

[Extracorporeal cardiopulmonary resuscitation-An orientation]. / Extrakorporale kardiopulmonale Reanimation ­ eine Standortbestimmung.

Both in-hospital and out-of-hospital cardiac arrests are associated with a high mortality. In the past survival advantages for patients could be achieved by optimizing the chain of rescue and postresuscitation treatment; however, for patients with refractory cardiac arrest, there have so far been few promising treatment options. For selected patients with refractory cardiac arrest who do not achieve return of spontaneous circulation with conventional cardiopulmonary resuscitation (CPR), extracorporeal (e)CPR using venoarterial extracorporeal membrane oxygenation is an option to improve the probability of survival. This article describes the technical features, important aspects of treatment, and the current data situation on eCPR in patients with in-hospital or out-of-hospital cardiac arrest.

Hemostatic disorders associated with extracorporeal membrane oxygenation.

Hemostatic disorders are common during extracorporeal membrane oxygenation (ECMO)-therapy. This includes both bleeding and thrombotic complications. Particularly bleeding is often associated with fatal outcome. The early identification of hemorrhagic diathesis and the diagnosis of the underlying pathology are essential. A distinction into device-, disease-, and drug-related disorders appears reasonable. However, both correct diagnosis and therapy can be challenging and sometimes counterintuitive. Since bleeding seems to be more frequent and dangerous compared to thrombosis, the understanding of coagulation disorders and minimizing anticoagulation has been focused in recent years. Due to progress in membrane coating and configuration of modern ECMO circuits it is even possible to perform ECMO without any anticoagulation in well selected cases. It became apparent that routine laboratory tests are likely to miss severe coagulation disorders during ECMO-therapy. Better understanding can also help to individualize anticoagulation in patients and hence preventing complications. Acquired von Willebrand syndrome, platelet dysfunction, waste coagulopathy as well as silent hemolysis should be taken into account when bleeding or thromboembolic complications appear. Recognizing impaired intrinsic fibrinolysis may favour intensified anticoagulation even in patients exhibiting signs of bleeding. Drug monitoring with standard coagulation tests, viscoelastic tests and anti-Xa-levels as wells as screening for disorders of primary hemostasis should be implemented in clinical routine to guide physicians through complex anticoagulative therapy. The patient's coagulative status should be interpreted taking the underlying disease and current therapy into account in order to enable a personalized approach to hemostasis in patients treated with ECMO.

Bleeding management in patients with direct oral anticoagulants.

Bleeding events in patients under direct oral anticoagulation (DOAC) can be life-threating but are commonly not related to drug overdose. However, a relevant DOAC plasma concentration impairs the hemostasis and should therefore be ruled out immediately after hospital admission. The effect of DOAC is typically not visible in standard coagulation tests such as activated partial thrombin time or thromboplastin time. Specific anti-Xa or anti-IIa assays allow a specific drug monitoring, but they are too time-consuming in critical bleeding events and typically not available 24 h/7 d in routine care. Recent advantages in point-of-care (POC) testing might improve patient care by early exclusion of relevant DOAC levels, but sufficient validation is still lacking. POC urine analysis help to exclude DOAC in emergency patients, but does not provide a quantitative information about plasma concentration. POC viscoelastic testing (VET) can determine the DOAC effect on clotting time and helps further to reveal other concomitant bleeding disorders in emergency, e.g., factor deficiency or hyperfibrinolysis. If a relevant plasma concentration of the DOAC is assumed or was proven by either laboratory assays or POC testing, restoration of factor IIa or factor IIa activity is key for effective hemostasis. Limited evidence suggests that specific reversals for DOAC, e.g., idarucizumab for dabigatran and andexanet alfa for apixaban or rivaroxaban, might be superior to increasing thrombin generation by administration of prothrombin complex concentrates. To determinate, if DOAC reversal is indicated or not, time from last intake, anti-Xa/dTT values or results from POC tests can be considered. This experts' opinion provides a feasible decision algorithm for clinical practice.

A multicentric consortium study demonstrates that dimethylarginine dimethylaminohydrolase 2 is not a dimethylarginine dimethylaminohydrolase.

Dimethylarginine dimethylaminohydrolase 1 (DDAH1) protects against cardiovascular disease by metabolising the risk factor asymmetric dimethylarginine (ADMA). However, the question whether the second DDAH isoform, DDAH2, directly metabolises ADMA has remained unanswered. Consequently, it is still unclear if DDAH2 may be a potential target for ADMA-lowering therapies or if drug development efforts should focus on DDAH2's known physiological functions in mitochondrial fission, angiogenesis, vascular remodelling, insulin secretion, and immune responses. Here, an international consortium of research groups set out to address this question using in silico, in vitro, cell culture, and murine models. The findings uniformly demonstrate that DDAH2 is incapable of metabolising ADMA, thus resolving a 20-year controversy and providing a starting point for the investigation of alternative, ADMA-independent functions of DDAH2.

Circadian rhythms: from basic mechanisms to the intensive care unit.

OBJECTIVE: : Circadian rhythms are intrinsic timekeeping mechanisms that allow for adaptation to cyclic environmental changes. Increasing evidence suggests that circadian rhythms may influence progression of a variety of diseases as well as effectiveness and toxicity of drugs commonly used in the intensive care unit. In this perspective, we provide a brief review of the molecular mechanisms of circadian rhythms and its relevance to critical care. DATA SOURCES, STUDY SELECTION, DATA EXTRACTION, AND DATA SYNTHESIS:: Articles related to circadian rhythms and organ systems in normal and disease conditions were searched through the PubMed library with the goal of providing a concise review. CONCLUSIONS: : Critically ill patients may be highly vulnerable to disruption of circadian rhythms as a result of the severity of their underlying diseases as well as the intensive care unit environment where noise and frequent therapeutic/diagnostic interventions take place. Further basic and clinical research addressing the importance of circadian rhythms in the context of critical care is warranted to develop a better understanding of the complex pathophysiology of critically ill patients as well as to identify novel therapeutic approaches for these patients.