Pharmacosimulation of delays and interruptions during administration of tirofiban: a systematic comparison between EU and US dosage regimens.

Tirofiban is a glycoproteine (GP) IIb/IIIa receptor antagonist, which inhibits platelet-platelet aggregation and is a potential adjunctive antithrombotic treatment in patients with acute coronary syndromes (ACS) or high-risk percutaneous coronary interventions (PCI). It is administered intravenously as a bolus followed by continuous infusion. However, the dosage recommendations in the United States (US) and European Union (EU) differ considerably. Furthermore, in routine clinical practice, deviations from the recommendations may occur. The objective of the present study was to investigate the impact of different alterations on tirofiban plasma concentrations in US and EU administration regimens and to give suggestions for delay management in clinical practice. We therefore mathematically simulated the effects of different bolus-infusion delays and infusion interruptions in different scenarios according to the renal function. Here, we provide a systematic assessment of concentration patterns of tirofiban in the US versus EU dosage regimens. We show that differences between the two regimens have important effects on plasma drug levels. Furthermore, we demonstrate that deviations from the proper administration mode affect the concentration of tirofiban. Additionally, we calculated the optimal dosage of a second bolus to rapidly restore the initial concentration without causing overdosage. In conclusion, differences in tirofiban dosing regimens between the U.S and EU and potential infusion interruptions have important effects on drug levels that may impact on degrees of platelet inhibition and thus antithrombotic effects. Thus, the findings of our modelling studies may help to explain differences in clinical outcomes observed in previous clinical trials on tirofiban.

No impact of weather conditions on the outcome of intensive care unit patients.

Global warming leads to increased exposure of humankind to meteorological variation, including short-term weather changes. Weather conditions involve changes in temperature, heat and cold, in air pressure and in air humidity. Every single condition influences the incidence and mortality of different diseases such as myocardial infarction and stroke. This study investigated the impact of weather conditions on short- and long-term mortality of 4321 critically ill patients (66 ± 14 years, 2638 men) admitted to an intensive care unit (ICU) over a period of 5 years. Meteorological information (air temperature, air pressure and humidity) for the same period was retrieved. The influence of absolute weather parameters, different seasons, sudden weather changes including "warm" and "cold" spells on ICU and long-term mortality was analyzed. After correction for Simplified Acute Physiology Score (SAPS-2), no impact of meteorological conditions on mortality was found. Different seasons, sudden weather changes, "warm spells" or "cold spells" did not affect the outcome of critically ill patients.

Management and outcomes in critically ill nonagenarian versus octogenarian patients.

BACKGROUND: Intensive care unit (ICU) patients age 90 years or older represent a growing subgroup and place a huge financial burden on health care resources despite the benefit being unclear. This leads to ethical problems. The present investigation assessed the differences in outcome between nonagenarian and octogenarian ICU patients. METHODS: We included 7900 acutely admitted older critically ill patients from two large, multinational studies. The primary outcome was 30-day-mortality, and the secondary outcome was ICU-mortality. Baseline characteristics consisted of frailty assessed by the Clinical Frailty Scale (CFS), ICU-management, and outcomes were compared between octogenarian (80-89.9 years) and nonagenarian (> 90 years) patients. We used multilevel logistic regression to evaluate differences between octogenarians and nonagenarians. RESULTS: The nonagenarians were 10% of the entire cohort. They experienced a higher percentage of frailty (58% vs 42%; p < 0.001), but lower SOFA scores at admission (6 + 5 vs. 7 + 6; p < 0.001). ICU-management strategies were different. Octogenarians required higher rates of organ support and nonagenarians received higher rates of life-sustaining treatment limitations (40% vs. 33%; p < 0.001). ICU mortality was comparable (27% vs. 27%; p = 0.973) but a higher 30-day-mortality (45% vs. 40%; p = 0.029) was seen in the nonagenarians. After multivariable adjustment nonagenarians had no significantly increased risk for 30-day-mortality (aOR 1.25 (95% CI 0.90-1.74; p = 0.19)). CONCLUSION: After adjustment for confounders, nonagenarians demonstrated no higher 30-day mortality than octogenarian patients. In this study, being age 90 years or more is no particular risk factor for an adverse outcome. This should be considered- together with illness severity and pre-existing functional capacity - to effectively guide triage decisions. TRIAL REGISTRATION: NCT03134807 and NCT03370692 .

Sublingual microcirculation in prehospital critical care medicine: A proof-of-concept study.

OBJECTIVE: Diagnostic and risk stratification are limited in emergencies. The measurement of microcirculation might identify patients with poor perfusion but compensated macrocirculation such as in beginning shock. This proof-of-concept study examines whether sublingual prehospital sidestream dark-field microscopy is feasible. METHODS: This prospective observational study included patients receiving medical aid by an emergency ambulance who had a spontaneous circulation and offered access to the sublingual mucosa. Sublingual measurement of microcirculation was performed using a sidestream dark field camera. Video quality was evaluated with microcirculation image quality score (microcirculation image quality score). AVA 4.3C software calculated microcirculatory parameters. RESULTS: Thirty patients (47% male) were included. The average age was 63 years (±20 years SD), the severity of the disease (quantified by National Advisory Committee on Aeronautics) was 3.4 (±0.7 SD). Macrocirculation presented within the normal range. The most frequent cause preventing the measurement was a time-critical disease (64%). In 17 patients (57%), the videos could be analyzed immediately. The average quality of the video was 2.2 ± 0.45 points ('acceptable'). There were minor restrictions of microcirculation. Microcirculation correlated with National Advisory Committee on Aeronautics, but not with the macrocirculation. No complications occurred. CONCLUSION: The prehospital sublingual measurement is safe and valid. Despite normal macrocirculation, microcirculation was impaired and correlated with National Advisory Committee on Aeronautics.

Anaemia is associated with severe RBC dysfunction and a reduced circulating NO pool: vascular and cardiac eNOS are crucial for the adaptation to anaemia.

Anaemia is frequently present in patients with acute myocardial infarction (AMI) and contributes to an adverse prognosis. We hypothesised that, besides reduced oxygen carrying capacity, anaemia is associated with (1) red blood cell (RBC) dysfunction and a reduced circulating nitric oxide (NO) pool, (2) compensatory enhancement of vascular and cardiac endothelial nitric oxide synthase (eNOS) activity, and (3) contribution of both, RBC dysfunction and reduced circulatory NO pool to left ventricular (LV) dysfunction and fatal outcome in AMI. In mouse models of subacute and chronic anaemia from repeated mild blood loss the circulating NO pool, RBC, cardiac and vascular function were analysed at baseline and in reperfused AMI. In anaemia, RBC function resulted in profound changes in membrane properties, enhanced turnover, haemolysis, dysregulation of intra-erythrocytotic redox state, and RBC-eNOS. RBC from anaemic mice and from anaemic patients with acute coronary syndrome impaired the recovery of contractile function of isolated mouse hearts following ischaemia/reperfusion. In anaemia, the circulating NO pool was reduced. The cardiac and vascular adaptation to anaemia was characterised by increased arterial eNOS expression and activity and an eNOS-dependent increase of end-diastolic left ventricular volume. Endothelial dysfunction induced through genetic or pharmacologic reduction of eNOS-activity abrogated the anaemia-induced cardio-circulatory compensation. Superimposed AMI was associated with decreased survival. In summary, moderate blood loss anaemia is associated with severe RBC dysfunction and reduced circulating NO pool. Vascular and cardiac eNOS are crucial for the cardio-circulatory adaptation to anaemia. RBC dysfunction together with eNOS dysfunction may contribute to adverse outcomes in AMI.

Poor glycemic control impairs the cardioprotective effects of red blood cells on myocardial ischemia/reperfusion injury.

Red blood cells (RBCs) play an important role in the cardiac ischemia/reperfusion (I/R) injury. Cardiovascular risk factors impair the RBC function in an endothelial nitric oxide synthase (eNOS) dependent manner. However, it is unclear whether the protective role of RBCs can be rescued by modifying cardiovascular risk factors or by pharmacologic intervention. RBCs obtained from elderly patients with or without diabetes as well as from young volunteers were treated with vehicle, eNOS inhibitor l-NAME and/or arginase inhibitor nor-NOHA before loading to the coronary system of isolated murine hearts in a Langendorff system before 40 min of global ischemia. RBCs from young and healthy volunteers as well as from aged persons and elderly diabetes patients with satisfying blood glucose control improved left ventricular function upon 60 min of reperfusion with Krebs-Henseleit buffer and reduced the infarct size compared to buffer treated controls. This cardioprotective effect was abolished in RBCs from aged diabetes patients with poor blood glucose control. Treatment of RBCs from elderly diabetes patients with nor-NOHA partly rescued the cardioprotective function. Thus, effective glucose control in aged diabetes patients rescues RBC-dependent cardioprotection in an ex-vivo model of myocardial I/R injury.

Dynamic Changes of Heart Failure Biomarkers in Response to Parabolic Flight.

BACKGROUND: we aimed at investigating the influence of weightlessness and hypergravity by means of parabolic flight on the levels of the heart failure biomarkers H-FABP, sST2, IL-33, GDF-15, suPAR and Fetuin-A. METHODS: 14 healthy volunteers (males: eight; mean age: 28.9) undergoing 31 short-term phases of weightlessness and hypergravity were included. At different time points (baseline, 1 h/24 h after parabolic flight), venous blood was drawn and analyzed by the use of ELISA. RESULTS: sST2 evidenced a significant decrease 24 h after parabolic flight (baseline vs. 24, p = 0.009; 1 h vs. 24 h, p = 0.004). A similar finding was observed for GDF-15 (baseline vs. 24 h, p = 0.002; 1 h vs. 24 h, p = 0.025). The suPAR showed a significant decrease 24 h after parabolic flight (baseline vs. 24 h, p = 0.1726; 1 h vs. 24 h, p = 0.009). Fetuin-A showed a significant increase at 1 h and 24 h after parabolic flight (baseline vs. 24 h, p = 0.007; 1 h vs. 24 h, p = 0.04). H-FABP and IL-33 showed no significant differences at all time points. CONCLUSION: Our results suggest a reduction in cardiac stress induced by exposure to gravitational changes. Moreover, our findings indicate an influence of gravitational changes on proliferative processes and calcium homeostasis.

Admission Body Temperature in Critically Ill Patients as an Independent Risk Predictor for Overall Outcome.

INTRODUCTION: Body temperature (BT) abnormalities are frequently observed in critically ill patients. We aimed to assess admission BT in a heterogeneous critically ill patient population admitted to an intensive care unit (ICU) as a prognostic parameter for intra-ICU and long-term mortality. METHODS: A total of 6,514 medical patients (64 ± 15 years) admitted to a German ICU between 2004 and 2009 were included. A follow-up of patients was performed retrospectively. The association of admission BT with both intra-ICU and long-term mortality was investigated by logistic regression. RESULTS: Patients with hypothermia (<36°C BT) were clinically worse and had more pronounced signs of multi-organ failure. Admission BT was associated with adverse overall outcome, with a 2-fold increase for hyperthermia (mortality 12%; odds ratio [OR] 1.80, 95% confidence interval [CI] 1.43-2.26; p < 0.001), and a 4-fold increase for the risk of hypothermia (mortality 24%; OR 4.05, 95% CI 3.38-4.85; p < 0.001) with respect to intra-ICU and long-term mortality. Moreover, hypothermia was even more harmful than hyperthermia, and both were strongly associated with intra-ICU mortality, especially in patients admitted with acute coronary syndrome (hypothermia: hazard ratio 6.12, 95% CI 4.12-9.11; p < 0.001; hyperthermia: OR 2.70, 95% CI 1.52-4.79; p< 0.001). CONCLUSION: Admission BT is an independent risk predictor for both overall intra-ICU and long-term mortality in critically ill patients admitted to an ICU. Therefore, BT at admission might not only serve as a parameter for individual risk stratification but can also influence individual therapeutic decision-making.

Hypoglycemia but Not Hyperglycemia Is Associated with Mortality in Critically Ill Patients with Diabetes.

BACKGROUND: Both severe hyperglycemia (> 200 mg/dL) and hypoglycemia (≤70 mg/dL) are known to be associated with increased mortality in critically ill patients. Therefore, we investigated associations of a single episode of blood glucose deviation (concentration either ≤70 mg/dL and/or > 200 mg/dL) during an intensive care unit (ICU) stay with mortality in these patients. METHODS: A total of 4,986 patients (age 65 ± 15 years; 39% female; 14% type 2 diabetes [T2DM] based on medical records) admitted to a German ICU in a tertiary care hospital were investigated retrospectively. The intra-ICU and long-term mortality of patients between 4 and 7 years after their ICU submission were assessed. RESULTS: A total 62,659 glucose measurements were analyzed. A single glucose deviation was associated with adverse outcomes compared to patients without a glucose deviation, represented by both intra-ICU mortality (22 vs. 10%; OR 2.62; 95% CI 2.23-3.09; p < 0.001) and long-term mortality (HR 2.01; 95% CI 1.81-2.24; p < 0.001). In patients suffering from T2DM hypoglycemia (30 vs. 13%; OR 2.94; 95% CI 2.28-3.80; p < 0.001) but not hyperglycemia (16 vs. 14%; OR 1.05; 95% CI 0.68-1.62; p = 0.84) was associated with mortality. CONCLUSION: In patients with dia-betes, hypo- but not hyperglycemia was associated with increased mortality, whereas in patients without diabetes, both hyper- and hypoglycemia were associated with adverse outcome. Blood glucose concentration might need differential approaches depending on concomitant diseases.

Clinical Frailty Scale (CFS) reliably stratifies octogenarians in German ICUs: a multicentre prospective cohort study.

BACKGROUND: In intensive care units (ICU) octogenarians become a routine patients group with aggravated therapeutic and diagnostic decision-making. Due to increased mortality and a reduced quality of life in this high-risk population, medical decision-making a fortiori requires an optimum of risk stratification. Recently, the VIP-1 trial prospectively observed that the clinical frailty scale (CFS) performed well in ICU patients in overall-survival and short-term outcome prediction. However, it is known that healthcare systems differ in the 21 countries contributing to the VIP-1 trial. Hence, our main focus was to investigate whether the CFS is usable for risk stratification in octogenarians admitted to diversified and high tech German ICUs. METHODS: This multicentre prospective cohort study analyses very old patients admitted to 20 German ICUs as a sub-analysis of the VIP-1 trial. Three hundred and eight patients of 80 years of age or older admitted consecutively to participating ICUs. CFS, cause of admission, APACHE II, SAPS II and SOFA scores, use of ICU resources and ICU- and 30-day mortality were recorded. Multivariate logistic regression analysis was used to identify factors associated with 30-day mortality. RESULTS: Patients had a median age of 84 [IQR 82-87] years and a mean CFS of 4.75 (± 1.6 standard-deviation) points. More than half of the patients (53.6%) were classified as frail (CFS ≥ 5). ICU-mortality was 17.3% and 30-day mortality was 31.2%. The cause of admission (planned vs. unplanned), (OR 5.74) and the CFS (OR 1.44 per point increase) were independent predictors of 30-day survival. CONCLUSIONS: The CFS is an easy determinable valuable tool for prediction of 30-day ICU survival in octogenarians, thus, it may facilitate decision-making for intensive care givers in Germany. TRIAL REGISTRATION: The VIP-1 study was retrospectively registered on ClinicalTrials.gov (ID: NCT03134807 ) on May 1, 2017.

The Lactate/Albumin Ratio: A Valuable Tool for Risk Stratification in Septic Patients Admitted to ICU.

The lactate/albumin ratio has been reported to be associated with mortality in pediatric patients with sepsis. We aimed to evaluate the lactate/albumin ratio for its prognostic relevance in a larger collective of critically ill (adult) patients admitted to an intensive care unit (ICU). A total of 348 medical patients admitted to a German ICU for sepsis between 2004 and 2009 were included. Follow-up of patients was performed retrospectively between May 2013 and November 2013. The association of the lactate/albumin ratio (cut-off 0.15) and both in-hospital and post-discharge mortality was investigated. An optimal cut-off was calculated by means of Youden's index. The lactate/albumin ratio was elevated in non-survivors (p < 0.001). Patients with an increased lactate/albumin ratio were of similar age, but clinically in a poorer condition and had more pronounced laboratory signs of multi-organ failure. An increased lactate/albumin ratio was associated with adverse in-hospital mortality. An optimal cut-off of 0.15 was calculated and was associated with adverse long-term outcome even after correction for APACHE2 and SAPS2. We matched 99 patients with a lactate/albumin ratio >0.15 to case-controls with a lactate/albumin ratio <0.15 corrected for APACHE2 scores: The group with a lactate/albumin ratio >0.15 evidenced adverse in-hospital outcome in a paired analysis with a difference of 27% (95%CI 10-43%; p < 0.01). Regarding long-term mortality, again, patients in the group with a lactate/albumin ratio >0.15 showed adverse outcomes (p < 0.001). An increased lactate/albumin ratio was significantly associated with an adverse outcome in critically ill patients admitted to an ICU, even after correction for confounders. The lactate/albumin ratio might constitute an independent, readily available, and important parameter for risk stratification in the critically ill.

Arginase Inhibition Reverses Monocrotaline-Induced Pulmonary Hypertension.

Pulmonary hypertension (PH) is a heterogeneous disorder associated with a poor prognosis. Thus, the development of novel treatment strategies is of great interest. The enzyme arginase (Arg) is emerging as important player in PH development. The aim of the current study was to determine the expression of ArgI and ArgII as well as the effects of Arg inhibition in a rat model of PH. PH was induced in 35 Sprague-Dawley rats by monocrotaline (MCT, 60 mg/kg as single-dose). There were three experimental groups: sham-treated controls (control group, n = 11), MCT-induced PH (MCT group, n = 11) and MCT-induced PH treated with the Arg inhibitor Nω-hydroxy-nor-l-arginine (nor-NOHA; MCT/NorNoha group, n = 13). ArgI and ArgII expression was determined by immunohistochemistry and Western blot. Right ventricular systolic pressure (RVPsys) was measured and lung tissue remodeling was determined. Induction of PH resulted in an increase in RVPsys (81 ± 16 mmHg) compared to the control group (41 ± 15 mmHg, p = 0.002) accompanied by a significant elevation of histological sum-score (8.2 ± 2.4 in the MCT compared to 1.6 ± 1.6 in the control group, p < 0.001). Both, ArgI and ArgII were relevantly expressed in lung tissue and there was a significant increase in the MCT compared to the control group (p < 0.01). Arg inhibition resulted in a significant reduction of RVPsys to 52 ± 19 mmHg (p = 0.006) and histological sum-score to 5.8 ± 1.4 compared to the MCT group (p = 0.022). PH leads to increased expression of Arg. Arg inhibition leads to reduction of RVPsys and diminished lung tissue remodeling and therefore represents a potential treatment strategy in PH.

Differential Impact of Hyperglycemia in Critically Ill Patients: Significance in Acute Myocardial Infarction but Not in Sepsis?

Hyperglycemia is a common condition in critically ill patients admitted to an intensive care unit (ICU). These patients represent an inhomogeneous collective and hyperglycemia might need different evaluation depending on the underlying disorder. To elucidate this, we investigated and compared associations of severe hyperglycemia (>200 mg/dL) and mortality in patients admitted to an ICU for acute myocardial infarction (AMI) or sepsis as the two most frequent admission diagnoses. From 2006 to 2009, 2551 patients 69 (58-77) years; 1544 male; 337 patients suffering from type 2 diabetes (T2DM)) who were admitted because of either AMI or sepsis to an ICU in a tertiary care hospital were investigated retrospectively. Follow-up of patients was performed between May 2013 and November 2013. In a Cox regression analysis, maximum glucose concentration at the day of admission was associated with mortality in the overall cohort (HR = 1.006, 95% CI: 1.004-1.009; p < 0.001) and in patients suffering from myocardial infarction (HR = 1.101, 95% CI: 1.075-1.127; p < 0.001) but only in trend in patients admitted to an ICU for sepsis (HR = 1.030, 95% CI: 0.998-1.062; p = 0.07). Severe hyperglycemia was associated with adverse intra-ICU mortality in the overall cohort (23% vs. 13%; p < 0.001) and patients admitted for AMI (15% vs. 5%; p < 0.001) but not for septic patients (39% vs. 40%; p = 0.48). A medical history of type 2 diabetes (n = 337; 13%) was not associated with increased intra-ICU mortality (15% vs. 15%; p = 0.93) but in patients with severe hyperglycemia and/or a known medical history of type 2 diabetes considered in combination, an increased mortality in AMI patients (intra-ICU 5% vs. 13%; p < 0.001) but not in septic patients (intra-ICU 38% vs. 41%; p = 0.53) could be evidenced. The presence of hyperglycemia in critically ill patients has differential impact within the different etiological groups. Hyperglycemia in AMI patients might identify a sicker patient collective suffering from pre-diabetes or undiagnosed diabetes with its' known adverse consequences, especially in the long-term. Hyperglycemia in sepsis might be considered as adaptive survival mechanism to hypo-perfusion and consecutive lack of glucose in peripheral cells. AMI patients with hyperglycemic derailment during an ICU-stay should be closely followed-up and extensively screened for diabetes to improve patients' outcome.

The clinical frailty scale - does it predict outcome of the very-old in UK ICUs?

Introduction: The age of patients admitted into critical care in the UK is increasing. Clinical decisions for very-old patients, usually defined as over 80, can be challenging. Clinicians are frequently asked to predict outcomes as part of discussions around the pros and cons of an intensive care unit (ICU) admission. Measures of overall health in old age, such as the clinical frailty scale (CFS), are increasingly used to help guide these discussions. We aimed to understand the characteristics of the very-old critically unwell population in the UK and the associations between frailty and outcome of an ICU admission in our healthcare system (National Health Service, NHS). Methods: Baseline characteristics, ICU interventions and outcomes (ICU- and 30-day mortality) were recorded for sequential admissions of very old patients to UK ICUs as part of the European VIP 1 and 2 studies. Patient characteristics, interventions and outcome measures were compared by frailty group using standard statistical tests. Multivariable logistic regression modelling was undertaken to test association between baseline characteristics, admission type and outcome. Results: 1858 participants were enrolled from 95 ICUs in the UK. The median age was 83. The median CFS was 4 (IQR 3-5). 30-day survival was significantly lower in the frail group (CFS > 4, 58%) compared to vulnerable (CFS = 4, 65%) and fit (CFS < 4 68%, p = .004). Sequential organ failure assessment (SOFA) score, reason for admission and CFS were all independently associated with increased 30-day mortality (p < .01). Conclusion: In the UK, frailty is associated with an increase in mortality at 30-days following an ICU admission. At moderate frailty (CFS 5-6), three out of every five patients admitted survived to 30-days. This is a similar mortality to septic shock.

Comprehensive Analysis of Macrocirculation and Microcirculation in Microgravity During Parabolic Flights.

BACKGROUND: Profound knowledge about cardiovascular physiology in the setting of microgravity can help in the course of preparations for human space missions. So far, influences of microgravity on the cardiovascular system have been demonstrated, particularly pertaining to venous fluid shifts. Yet, little is known about the mechanisms of these adaptations on continuous macrocirculatory level and regarding the microcirculation. METHODS: Twelve healthy volunteers were subjected to alternating microgravity and hypergravity in the course of parabolic flight maneuvers. Under these conditions, as well as in normal gravity, the sublingual microcirculation was assessed by intravital sidestream dark field microscopy. Furthermore, hemodynamic parameters such as heart rate, blood pressure, and cardiac output were recorded by beat-to-beat analysis. In these settings, data acquisition was performed in seated and in supine postures. RESULTS: Systolic [median 116 mmHg (102; 129) interquartile range (IQR) vs. 125 mmHg (109; 136) IQR, p = 0.01] as well as diastolic [median 72 mmHg (61; 79) IQR vs. 80 mmHg (69; 89) IQR, p = 0.003] blood pressure was reduced, and cardiac output [median 6.9 l/min (6.5; 8.8) IQR vs. 6.8 l/min (6.2; 8.5) IQR, p = 0.0002] increased in weightlessness compared to normal gravitation phases in the seated but not in the supine posture. However, microcirculation represented by perfused proportion of vessels and by total vessel density was unaffected in acute weightlessness. CONCLUSION: Profound changes of the macrocirculation were found in seated postures, but not in supine postures. However, microcirculation remained stable in all postures.

Sublingual microcirculation detects impaired perfusion in dehydrated older patients.

BACKGROUND: Dehydration occurs frequently in older patients and constitutes a significant clinical problem. OBJECTIVE: This proof-of-concept study examines whether 1) sublingual measurement in dehydrated old patients is feasible, 2) frailty and incompliance in old, awake patients affects video-quality, 3) dehydration impacts microcirculationMETHODS:This prospective observational study included clinically dehydrated patients aged ≥65 years immediately after admission. Dehydration was assessed clinically. A sidestream dark field camera (SDF) was used for measurement. Video-quality was evaluated with MIQS (microcirculation image quality score). Both AVA 4.3C- and AVA POEM-software analyzed the videos. Seventeen patients ≥65 years not showing dehydration served as control. RESULTS: Thirteen patients (8 female) were included. The average age was 83±8 years. The mini-mental test was 17±15 points, the Clinical Frailty Scale 4±3, the Barthel-Index 59±39. None of these parameters correlated with MIQS (3.4±4.2 SD ("acceptable")). Dehydrated patients had a slightly impaired microcirculation, with a significantly lower percentage of perfused small vessels compared to control (83.1±7.7% versus 88.0±6.0%, P < 0.05). After rehydration, there was acute improvement in the microcirculation. CONCLUSIONS: Sublingual microcirculatory SDF-measurement is both, safe and valid for dehydrated old patients - regardless of frailty, age or cognitive performance. Dehydration leads to an impaired microcirculation.

A Model of Blood Component-Heart Interaction in Cardiac Ischemia-Reperfusion Injury using a Langendorff-Based Ex Vivo Assay.

INTRODUCTION: Myocardial infarction is one of the leading causes of morbidity and mortality worldwide. Cellular interactions of red blood cells (RBCs) and platelets with endothelial cells and cardiomyocytes play a crucial role in cardiac ischemia/reperfusion (I/R) injury. However, addressing the specific impact of such cell-to-cell interactions in commonly employed in vivo models of cardiac I/R injury is challenging due to overlap of neuronal, hormonal, and immunological pathways. This study aimed to refine a Langendorff-based ex vivo transfer model to evaluate the impact of specific blood components on cardiac I/R injury. MATERIAL AND METHODS: Murine whole blood, defined murine blood components (RBCs, platelet-rich plasma [PRP], and platelet-poor plasma [PPP], respectively) as well as human RBCs were loaded to the coronary system of isolated murine hearts in a Langendorff system before initiating global ischemia for 40 minutes. Following 60 minutes of reperfusion with Krebs Henseleit Buffer, left ventricular function and coronary flow were assessed. Infarct size was determined by specific histological staining following 120 minutes of reperfusion. RESULTS: Loading of murine whole blood to the coronary system of isolated murine hearts at the beginning of 40 minutes of global ischemia improved left ventricular function after 60 minutes of reperfusion and reduced the infarct size in comparison to buffer-treated controls. Similarly, isolated murine RBCs, PRP, and PPP mediated a protective effect in the cardiac I/R model. Furthermore, human RBCs showed a comparable protective capacity as murine RBCs. CONCLUSION: This Langendorff-based transfer model of cardiac I/R injury is a feasible, time-, and cost-effective model to evaluate the impact of blood components on myocardial infarction. The presented method facilitates loading of blood components of genetically modified mice to murine hearts of a different mouse strain, thus complementing time- and cost-intensive chimeric models and contributing to the development of novel targeted therapies.

Exposure to acute normobaric hypoxia results in adaptions of both the macro- and microcirculatory system.

Although acute hypoxia is of utmost pathophysiologic relevance in health and disease, studies on its effects on both the macro- and microcirculation are scarce. Herein, we provide a comprehensive analysis of the effects of acute normobaric hypoxia on human macro- and microcirculation. 20 healthy participants were enrolled in this study. Hypoxia was induced in a normobaric hypoxia chamber by decreasing the partial pressure of oxygen in inhaled air stepwisely (pO2; 21.25 kPa (0 k), 16.42 kPa (2 k), 12.63 kPa (4 k) and 9.64 kPa (6 k)). Macrocirculatory effects were assessed by cardiac output measurements, microcirculatory changes were investigated by sidestream dark-field imaging in the sublingual capillary bed and videocapillaroscopy at the nailfold. Exposure to hypoxia resulted in a decrease of systemic vascular resistance (p < 0.0001) and diastolic blood pressure (p = 0.014). Concomitantly, we observed an increase in heart rate (p < 0.0001) and an increase of cardiac output (p < 0.0001). In the sublingual microcirculation, exposure to hypoxia resulted in an increase of total vessel density, proportion of perfused vessels and perfused vessel density. Furthermore, we observed an increase in peripheral capillary density. Exposure to acute hypoxia results in vasodilatation of resistance arteries, as well as recruitment of microvessels of the central and peripheral microcirculation. The observed macro- and microcirculatory effects are most likely a result from compensatory mechanisms to ensure adequate tissue oxygenation.

Therapy limitation in octogenarians in German intensive care units is associated with a longer length of stay and increased 30 days mortality: A prospective multicenter study.

PURPOSE: The approach to limit therapy in very old intensive care unit patients (VIPs) significantly differs between regions. The focus of this multicenter analysis is to illuminate, whether the Clinical Frailty Scale (CFS) is a suitable tool for risk stratification in VIPs admitted to intensive care units (ICUs) in Germany. Furthermore, this investigation elucidates the impact of therapeutic limitation on the length of stay and mortality in this setting. METHODS: German cohorts' data from two multinational studies (VIP-1, VIP-2) were combined. Univariate and multivariate logistic regression were used to evaluate associations with mortality. RESULTS: 415 acute VIPs were included. Frail VIPs (CFS > 4) were older (85 [IQR 82-88] vs. 83 [IQR 81-86] years p < .001) and suffered from an increased 30-day-mortality (43.4% versus 23.9%, p < .0001). CFS was an independent predictor of 30-day-mortality in a multivariate logistic regression model (aOR 1.23 95%CI 1.04-1.46 p = .02). Patients with any limitation of life-sustaining therapy had a significantly increased 30-day mortality (86% versus 16%, p < .001) and length of stay (144 [IQR 72-293] versus 96 [IQR 47.25-231.5] hours, p = .026). CONCLUSION: In German ICUs, any limitation of life-sustaining therapy in VIPs is associated with a significantly increased ICU length of stay and mortality. CFS reliably predicts the outcome.

Sex-specific outcome disparities in very old patients admitted to intensive care medicine: a propensity matched analysis.

Female and male very elderly intensive patients (VIPs) might differ in characteristics and outcomes. We aimed to compare female versus male VIPs in a large, multinational collective of VIPs with regards to outcome and predictors of mortality. In total, 7555 patients were included in this analysis, 3973 (53%) male and 3582 (47%) female patients. The primary endpoint was 30-day-mortality. Baseline characteristics, data on management and geriatric scores including frailty assessed by Clinical Frailty Scale (CFS) were documented. Two propensity scores (for being male) were obtained for consecutive matching, score 1 for baseline characteristics and score 2 for baseline characteristics and ICU management. Male VIPs were younger (83 ± 5 vs. 84 ± 5; p < 0.001), less often frail (CFS > 4; 38% versus 49%; p < 0.001) but evidenced higher SOFA (7 ± 6 versus 6 ± 6 points; p < 0.001) scores. After propensity score matching, no differences in baseline characteristics could be observed. In the paired analysis, the mortality in male VIPs was higher (mean difference 3.34% 95%CI 0.92-5.76%; p = 0.007) compared to females. In both multivariable logistic regression models correcting for propensity score 1 (aOR 1.15 95%CI 1.03-1.27; p = 0.007) and propensity score 2 (aOR 1.15 95%CI 1.04-1.27; p = 0.007) male sex was independently associated with higher odds for 30-day-mortality. Of note, male gender was not associated with ICU mortality (OR 1.08 95%CI 0.98-1.19; p = 0.14). Outcomes of elderly intensive care patients evidenced independent sex differences. Male sex was associated with adverse 30-day-mortality but not ICU-mortality. Further research to identify potential sex-specific risk factors after ICU discharge is warranted.Trial registration: NCT03134807 and NCT03370692; Registered on May 1, 2017 https://clinicaltrials.gov/ct2/show/NCT03370692 .