A Potential Association between Ribonuclease 1 Dynamics in the Blood and the Outcome in COVID-19 Patients.

The COVID-19 pandemic caused by the new SARS-CoV-2 coronavirus is the most recent and well-known outbreak of a coronavirus. RNase 1 is a small endogenous antimicrobial polypeptide that possesses antiviral activity against viral diseases. In this study, we investigated a potential association between ribonuclease 1 and the outcome in COVID-19 patients and the impact of increased and decreased RNase 1 levels serum during the course of the disease. Therefore, two patient populations, Cohort A (n = 35) and B (n = 80), were subclassified into two groups, in which the RNase 1 concentration increased or decreased from time point one to time point two. We show that the RNase 1 serum levels significantly increased in the increasing group of both cohorts (p = 0.0171; p < 0.0001). We detect that patients in the increasing group who died had significantly higher RNase 1 serum levels at both time points in Cohort A (p = 0.0170; p = 0.0393) and Cohort B (p = 0.0253; p = 0.0034) than patients who survived. Additionally, we measured a significant correlation of RNase 1 serum levels with serum creatinine as well as creatinine clearance in the increasing and decreasing group at both time points of Cohort A. Based on these results, there is now good evidence that RNase 1 may play a role in renal dysfunction associated with ICU COVID-19 patients and that increasing RNase 1 serum level may be a potential biomarker to predict outcome in COVID-19 patients.

[Weaning from prolonged mechanical ventilation on a specialised weaning unit: a retrospective comparison of patients with and without SARS-CoV-2 infection]. / Entwöhnung von der Langzeitbeatmung nach ARDS auf einer spezialisierten Weaning-Einheit ­ ein retrospektiver Vergleich von Patienten mit und ohne SARS-CoV-2 Infektion.

BACKGROUND: Available data on patients requiring prolonged mechanical ventilation due to severe COVID-19 are sparse. Here we compare patients with ARDS related or not related to SARS-CoV-2 infection treated in a specialised weaning unit. METHODS: A retrospective analysis of all patients with prolonged mechanical ventilation associated with an ARDS admitted from the 21st November 2013 to the 23rd July 2021 to the weaning unit of the University Hospital RWTH Aachen was performed. ARDS patients with COVID-19 (cARDS) were compared to patients with ARDS not related to COVID-19 (ncARDS). RESULTS: In total, n=129 patients in prolonged need for mechanical ventilation after ARDS were treated in the weaning unit, of whom n=38 had been suffering from ARDS related to COVID-19. Both patients groups were similar in terms of demographic parameters, underlying chronic illnesses, severity of ARDS and the duration of mechanical ventilation before being admitted to the weaning unit. During ICU stay, prone positioning and therapy with systemic corticosteroids was used more frequently in cARDS patients. Furthermore, therapy with vasoconstrictors was needed more often (cARDS: 42.1% vs. ncARDS 12.1%; p=0.0003) and urinary output was lower (cARDS: 1980 ml vs. ncARDS: 2600 ml; p=0.0037) in this patient group. The clinical course of the weaning process was similar in patients with cARDS and ncARDS, there were no significant differences in the occurrence of complications and the duration of mechanical ventilation. There were n=5 deaths (13.2%) in the cARDS and n=15 deaths (16.5%) in the ncARDS group. After hospital discharge, n=4 patients required non-invasive ventilation whereas out-of-hospital invasive ventilation was only necessary in one patient (all in the ncARDS group). CONCLUSION: After having survived the acute phase, the disease prognosis of patients with severe COVID-19 is favourable and most patients can be successfully weaned from mechanical ventilation. In addition, there were only minor differences compared to patients with ARDS unrelated to COVID-19.

Investigating the influence of neuter status on paw preference in dogs and cats.

Motor lateralization is commonly observed through preferential paw use in dogs and cats. Previous studies have uncovered sex-related differences in paw preference, hypothesizing that these differences may be related to sex hormones. The current study aimed to compare neutered and entire individuals to further investigate whether paw preference is influenced by sex hormones. Dog and cat owners were required to fill in a questionnaire with demographic information such as sex and neuter status of their pets. They then carried out two simple paw preference tasks within their homes: a "reaching for food" task and a "reaching for a toy" task. This study revealed an overall preference among the 272 dogs and 137 cats tested to use their right paw in both tasks. In cats, the degree of paw preference (i.e., regardless of the direction) was significantly influenced by an interaction between neuter status and life stage. Also in dogs, both life stage and an interaction between neuter status and life stage tended to influence the degree of paw preference. Post-hoc power analysis revealed a lack of statistical power, suggesting that future studies using a larger sample size are needed to further investigate potential effects of neuter status on paw preference.

Body mass index and leptin levels in serum and cerebrospinal fluid in relation to delayed cerebral ischemia and outcome after aneurysmal subarachnoid hemorrhage.

Aneurysmal subarachnoid hemorrhage (SAH) is associated with a high mortality rate and may leave surviving patients severely disabled. After the initial hemorrhage, clinical outcome is further compromised by the occurrence of delayed cerebral ischemia (DCI). Overweight and obesity have previously been associated with protective effects in the post-bleeding phase. The aim of this study was to assess the effects of a patient's body mass index (BMI) and leptin levels on the occurrence of DCI, DCI-related cerebral infarction, and clinical outcome. In total, 263 SAH patients were included of which leptin levels were assessed in 24 cases. BMI was recorded along disease severity documented by the Hunt and Hess and modified Fisher scales. The occurrence of clinical or functional DCI (neuromonitoring, CT Perfusion) was assessed. Long-term clinical outcome was documented after 12 months (extended Glasgow outcome scale). A total of 136 (51.7%) patients developed DCI of which 72 (27.4%) developed DCI-related cerebral infarctions. No association between BMI and DCI occurrence (P = .410) or better clinical outcome (P = .643) was identified. Early leptin concentration in serum (P = .258) and CSF (P = .159) showed no predictive value in identifying patients at risk of unfavorable outcomes. However, a significant increase of leptin levels in CSF occurred from 326.0 pg/ml IQR 171.9 prior to DCI development to 579.2 pg/ml IQR 211.9 during ongoing DCI (P = .049). In our data, no association between obesity and clinical outcome was detected. After DCI development, leptin levels in CSF increased either by an upsurge of active transport or disruption of the blood-CSF barrier. This trial has been registered at ClinicalTrials.gov (NCT02142166) as part of a larger-scale prospective data collection. BioSAB: https://clinicaltrials.gov/ct2/show/NCT02142166.

Hematological and Chemical Profiles in a Porcine Model of Severe Multiple Trauma.

BACKGROUND: Clinical chemistry and hematological tests are widely used to monitor the clinical course of several diseases. However, these parameters are sparse in large-animal models of multiple trauma (MT). Thus, we aimed to provide these missing data to improve future experimental setups in trauma research. METHODS: Male pigs (German Landrace pigs) were randomized into either an MT group (n = 8) including blunt thoracic trauma, tibial fracture, and controlled hemorrhage or a sham group (n = 8) without any trauma. After trauma induction, all animals received intensive care treatment for 72 h under anesthesia, including mechanical ventilation and volume resuscitation. Blood and urine samples were obtained to measure common hematological and chemical parameters before trauma (0 h), after trauma (1.5 h), during resuscitation (2.5 h), after fracture stabilization (3.5 h), and at 12, 24, 48, and 72 h. Statistical analyses were performed using a linear mixed model (group × time) and Welch's ANOVA. RESULTS: MT led to a perceptible immunological reaction. Between groups, significantly different time courses of leukocyte counts (p = 0.034) and lymphocyte proportions (p = 0.001) were observed. Moreover, MT changed the time course of total protein (p = 0.006). Significantly lower concentrations compared to sham were found in MT at each single time point starting at 1.5 h to the end of the observation period (all p < 0.05). CONCLUSIONS: Our results indicate that a traumatic insult leads to significant alterations in the immune system already shortly after trauma. Together with the additional catabolic reactions observed, these alterations might contribute to the occurrence of later complications. The presented data provide valid references for further experimental setups with prolonged observation times, especially in similar porcine models of MT.

Postoperatively increased bioactive adrenomedullin is related to adverse outcome after complex aortic surgery.

Background: Open and endovascular thoracoabdominal aortic aneurysm repair is related to major complications and increased mortality rates. Up to now, specific biomarkers for adverse outcome are scarce, although routine usage of such biomarkers could enable an earlier and more appropriate treatment of complications during the postoperative course after complex aortic aneurysm repair. Patients and methods: In a prospective single-center study including 33 patients (48.5 % women, mean age 63.0 ± 16.2 years) undergoing elective complex open and endovascular aortic aneurysm repair, bioactive adrenomedullin (bio-ADM) was measured for 72 h perioperatively and an association with clinical endpoints, namely cardiogenic shock, death and the combined endpoint of the two aforementioned parameters was assessed. Furthermore, the association between bio-ADM and baseline characteristics and perioperative details including sepsis biomarkers score were assessed. Results: 51.5 % (n = 17) of patients developed postoperative acute kidney injury, 21.2 % (n = 7) pneumonia and 18.2 % (n = 6) sepsis. Cardiogenic shock was observed in 12.1 % (n = 4) patients. The in-hospital mortality rate was 18.2 % (n = 6), and 24.2 % (n = 8) of patients developed cardiogenic shock and/or died in hospital. A significant correlation of bio-ADM concentrations from all available time points was observed with leukocytes (r = 0.37, P < 0.0001), C-reactive protein (r = 0.56, P < 0.001) and serum creatinine levels (r = 0.52, P < 0.001). Increased bio-ADM at 12 h, 24 h, 48 h and 72 h after admission to ICU was associated with both, in-hospital death and cardiogenic shock, with an area under the curve for the combined endpoint of 0.598, 0.720, 0.880 and 0.967. Bio-ADM concentrations at 48 h and 72 h after admission to ICU were predictive for in-hospital death and cardiogenic shock (both P < 0.01). Conclusions: Bio-ADM may serve as postoperative biomarker for cardiogenic shock and death after complex open and endovascular aortic aneurysm repair, potentially enabling an earlier and by that more adequate treatment of adverse outcome after major surgery.

Effect of Regional Citrate Anticoagulation vs Systemic Heparin Anticoagulation During Continuous Kidney Replacement Therapy on Dialysis Filter Life Span and Mortality Among Critically Ill Patients With Acute Kidney Injury: A Randomized Clinical Trial.

Importance: Although current guidelines suggest the use of regional citrate anticoagulation (which involves the addition of a citrate solution to the blood before the filter of the extracorporeal dialysis circuit) as first-line treatment for continuous kidney replacement therapy in critically ill patients, the evidence for this recommendation is based on few clinical trials and meta-analyses. Objective: To determine the effect of regional citrate anticoagulation, compared with systemic heparin anticoagulation, on filter life span and mortality. Design, Setting, and Participants: A parallel-group, randomized multicenter clinical trial in 26 centers across Germany was conducted between March 2016 and December 2018 (final date of follow-up, January 21, 2020). The trial was terminated early after 596 critically ill patients with severe acute kidney injury or clinical indications for initiation of kidney replacement therapy had been enrolled. Interventions: Patients were randomized to receive either regional citrate anticoagulation (n = 300), which consisted of a target ionized calcium level of 1.0 to 1.40 mg/dL, or systemic heparin anticoagulation (n = 296), which consisted of a target activated partial thromboplastin time of 45 to 60 seconds, for continuous kidney replacement therapy. Main Outcomes and Measures: Coprimary outcomes were filter life span and 90-day mortality. Secondary end points included bleeding complications and new infections. Results: Among 638 patients randomized, 596 (93.4%) (mean age, 67.5 years; 183 [30.7%] women) completed the trial. In the regional citrate group vs systemic heparin group, median filter life span was 47 hours (interquartile range [IQR], 19-70 hours) vs 26 hours (IQR, 12-51 hours) (difference, 15 hours [95% CI, 11 to 20 hours]; P < .001). Ninety-day all-cause mortality occurred in 150 of 300 patients vs 156 of 296 patients (Kaplan-Meier estimator percentages, 51.2% vs 53.6%; unadjusted difference, -2.4% [95% CI, -10.5% to 5.8%]; unadjusted hazard ratio, 0.91 [95% CI, 0.72 to 1.13]; unadjusted P = .38; adjusted difference, -6.1% [95% CI, -12.6% to 0.4%]; primary adjusted hazard ratio, 0.79 [95% CI, 0.63 to 1.004]; primary adjusted P = .054). Of 38 prespecified secondary end points, 34 showed no significant difference. Compared with the systemic heparin group, the regional citrate group had significantly fewer bleeding complications (15/300 [5.1%] vs 49/296 [16.9%]; difference, -11.8% [95% CI, -16.8% to -6.8%]; P < .001) and significantly more new infections (204/300 [68.0%] vs 164/296 [55.4%]; difference, 12.6% [95% CI, 4.9% to 20.3%]; P = .002). Conclusions and Relevance: Among critically ill patients with acute kidney injury receiving continuous kidney replacement therapy, anticoagulation with regional citrate, compared with systemic heparin anticoagulation, resulted in significantly longer filter life span. The trial was terminated early and was therefore underpowered to reach conclusions about the effect of anticoagulation strategy on mortality. Trial Registration: ClinicalTrials.gov Identifier: NCT02669589.

Geriatric Polytrauma-Cardiovascular and Immunologic Response in a Murine Two-Hit Model of Trauma.

BACKGROUND: The aims of the present study were to establish a clinically relevant two-hit model with trauma/hemorrhage followed by sepsis in older mice and investigate age-dependent cardiovascular and immunologic specificities under these conditions. MATERIALS AND METHODS: In aged mice (12, 18, and 24 mo old), a femur fracture followed by hemorrhage was induced. After resuscitation, animals were monitored for 72 h before sepsis was induced. Vital signs were monitored during shock. Systemic interleukin (IL)-6 levels were measured daily. Expression of sarcoplasmic or endoplasmic reticulum calcium ATPase (SERCA) and IL-6 receptor were analyzed in heart, lung, and liver tissues. RESULTS: After induction of shock, mean arterial pressure decreased significantly in all groups (12 mo, P < 0.001; 18 mo, P < 0.001; 24 mo, P = 0.013). Compared with younger animals, 24-mo old mice were not able to adequately compensate for hypovolemia by an increase of heart rate (P = 0.711). Expression of SERCA2 (P = 0.002) and IL-6 receptor on myocytes (P = 0.037), lung (P = 0.005), and liver (P = 0.009) tissues were also lowest in this group. Systemic IL-6 values showed the most distinct posttraumatic response in 24-mo-old mice (P = 0.016). Survival rate decreased significantly with increased age (P = 0.005). CONCLUSIONS: The increased mortality rate in older animals was associated with a limited compensatory physiological response and a more distinct immunologic reaction after trauma and sepsis. A decreased SERCA2 expression and missing feedback loops due to a reduced density of organ bound immune receptors might represent possible explanations for the observed age-dependent differences.

[Not Available]. / Kasuistik - 44-jähriger Patient mit Fieber und Hautrötung in der Notaufnahme.

Skin and soft tissue infections may progress rapidly and take a fatal ending unless not treated in time. A 44-year old male patient without any pre-existing conditions got hospitalized with a bursitis ofthe right olecranon and unspecific general symptoms. Within a short period of time he became critically ill due this seemingly harmless infection. We describe our approach leading to the right diagnoses and the treatment of this unexpected progress.

Alterations in zinc binding capacity, free zinc levels and total serum zinc in a porcine model of sepsis.

Zinc is crucial for immune function. In addition, the redistribution of zinc and other nutrients due to infection is an integral part of the host immune response to limit availability to pathogens. However, the major zinc binding protein albumin is down regulated during the acute phase response, implicating a decrease in zinc binding capacity. A prospective animal study with eight female German landrace pigs was conducted to investigate alterations in zinc binding capacity, total serum zinc and free zinc levels in the initial phase of sepsis. Sepsis was induced by instillation of autologous feces via midline laparotomy. Total serum zinc declined significantly after 1 h (10.89 ± 0.42 µM vs. 7.67 ± 0.41 µM, p < 0.001), total serum copper and iron reached a significant reduction at 4 h. Urinary excretion of zinc declined in line with total serum zinc. In comparison to total serum zinc, free zinc levels declined to a lesser, though significant, extent. Zinc binding capacity of serum decreased over time, whereby free zinc levels after addition of zinc correlated negatively with total serum protein and albumin levels. In addition IL-6 and TNF-α concentrations were measured and increased significantly 2 h after induction of sepsis. Hence, total serum zinc was the first marker of inflammation in our experiment, and might therefore be a promising biomarker for the early diagnosis of sepsis. Furthermore the observation of a substantially different serum free zinc homeostasis during sepsis provides valuable information for a potential therapeutic zinc supplementation, which has to take buffering capacity by serum proteins into account.

Accuracy and precision of calibrated arterial pulse contour analysis in patients with subarachnoid hemorrhage requiring high-dose vasopressor therapy: a prospective observational clinical trial.

INTRODUCTION: Calibrated arterial pulse contour analysis has become an established method for the continuous monitoring of cardiac output (PCCO). However, data on its validity in hemodynamically instable patients beyond the setting of cardiac surgery are scarce. We performed the present study to assess the validity and precision of PCCO-measurements using the PiCCO™-device compared to transpulmonary thermodilution derived cardiac output (TPCO) as the reference technique in neurosurgical patients requiring high-dose vasopressor-therapy. METHODS: A total of 20 patients (16 females and 4 males) were included in this prospective observational clinical trial. All of them suffered from subarachnoid hemorrhage (Hunt&Hess grade I-V) due to rupture of a cerebral arterial aneurysm and underwent high-dose vasopressor therapy for the prevention/treatment of delayed cerebral ischemia (DCI). Simultaneous CO measurements by bolus TPCO and PCCO were obtained at baseline as well as 2 h, 6 h, 12 h, 24 h, 48 h and 72 h after inclusion. RESULTS: PCCO- and TPCO-measurements were obtained at baseline as well as 2 h, 6 h, 12 h, 24 h, 48 h and 72 h after inclusion. Patients received vasoactive support with (mean ± standard deviation, SD) 0.57 ± 0.49 µg · kg-1 · min-1 norepinephrine resulting in a mean arterial pressure of 103 ± 13 mmHg and a systemic vascular resistance of 943 ± 248 dyn · s · cm-5. 136 CO-data pairs were analyzed. TPCO ranged from 5.2 to 14.3 l · min-1 (mean ± SD 8.5 ± 2.0 l · min-1) and PCCO ranged from 5.0 to 14.4 l · min-1 (mean ± SD 8.6 ± 2.0 l · min-1). Bias and limits of agreement (1.96 SD of the bias) were -0.03 ± 0.82 l · min-1 and 1.62 l · min-1, resulting in an overall percentage error of 18.8%. The precision of PCCO-measurements was 17.8%. Insufficient trending ability was indicated by concordance rates of 74% (exclusion zone of 15% (1.29 l · min-1)) and 67% (without exclusion zone), as well as by polar plot analysis. CONCLUSIONS: In neurosurgical patients requiring extensive vasoactive support, CO values obtained by calibrated PCCO showed clinically and statistically acceptable agreement with TPCO-measurements, but the results from concordance and polar plot analysis indicate an unreliable trending ability.

Diaphragm ultrasound in patients with prolonged weaning from mechanical ventilation.

Background: Several publications have examined diaphragmatic ultrasound using two-dimensional (2D) parameters in the context of weaning from mechanical ventilation (MV) and extubation. However, the studied cohorts had rather short duration of ventilation. Examinations on patients with prolonged weaning after long-term ventilation were missing. It was the aim of this study to assess of the diaphragm and peripheral musculature of patients undergoing prolonged weaning creating a chronological sequence of ultrasonic parameters during the course of weaning. Methods: This study was carried out as a monocentric, prospective observational cross-sectional study. Patients in prolonged weaning who were transferred to a specialized weaning unit were eligible for inclusion if they were ventilated invasively by means of an endotracheal tube or tracheal cannula and if their expected treatment period was at least 5 days. Diaphragmatic function and one representative peripheral muscle were examined in 50 patients between March 2020 and April 2021. The 2D sonographic parameters of diaphragm and diaphragmatic function consisted of diaphragmatic thickness (Tdi) at the end of inspiration and expiration, the fractional thickening (FT) and the diaphragmatic excursion. Additionally, the M. quadriceps femoris was sonographically assessed at two locations. The difference of measurements between the first and the last measuring timepoint were examined using the Wilcoxon signed-rank test. For a longer chronological sequence, the Friedman's rank sum test with subsequent Wilcoxon-Nemenyi-McDonald-Thompson test for multiple comparisons was carried out. Results: Fifty patients with prolonged weaning were included. The median duration of MV before transfer to the weaning unit was 11.5 [interquartile range (IQR) 10] days. Forty-one patients could be assessed over the full course of weaning, with 38 successfully weaned. Within these 41 patients, the sonographic parameters of the diaphragm slightly increased over the course of weaning indicating an increase in thickness and mobility. Especially parameters which represented an active movement reached statistical significance, i.e., inspiratory Tdi when assessed under spontaneous breathing [begin 3.41 (0.99) vs. end 3.43 (1.31) mm; P=0.01] and diaphragmatic excursion [begin 0.7 (0.8) vs. end 0.9 (0.6) cm; P=0.01]. The presence of positive end-expiratory pressure (PEEP) and pressure support did not influence the sonographic parameters significantly. The M. quadriceps femoris, in contrast, decreased slightly but constantly over the time [lower third: begin 1.36 (0.48) vs. end 1.28 (0.36) cm; P=0.054]. Conclusions: The present study is the first one to longitudinally analyse diaphragmatic ultrasound in patients with prolonged weaning. Sonographic assessment showed that Tdi and excursion increased over the course of prolonged weaning, while the diameter of a representative peripheral muscle decreased. However, the changes are rather small, and data show a wide dispersion. To allow a potential, standardized use of diaphragm ultrasound for diagnostic decision support in prolonged weaning, further studies in this specific patient group are required.

Effects of structured protocolized physical therapy on the duration of mechanical ventilation in patients with prolonged weaning.

PURPOSE: 20% of patients with mechanical ventilation (MV) have a prolonged, complex weaning process, often experiencing a condition of ICU-acquired weakness (ICUAW), with a severe decrease in muscle function and restricted long-term prognosis. We aimed to analyze a protocolized, systematic approach of physiotherapy in prolonged weaning patients and hypothesized that the duration of weaning from MV would be shortened. METHODS: ICU patients with prolonged weaning were included before (group 1) and after (group 2) introduction of a quality control measure of a structured and protocolized physiotherapy program. Primary endpoint was the tested dynamometric handgrip strength and the Surgical Intensive Care Unit Optimal Mobilization Score (SOMS). Secondary endpoints were weaning success rate, ventilator-free days, hospital mortality, the prevalence of ICUAW, infections and delirium. RESULTS: 106 patients were included. Both the SOMS and the handgrip test were significantly improved after introducing the program. Despite no differences in weaning success rates at discharge, the total length of MV was significantly shorter in group 2, which also had lower prevalence of infection and higher probability of survival. CONCLUSIONS: Protocolized, systematic physiotherapy resulted in an improvement of the clinical outcome in patients with prolonged weaning. Results were objectifiable with the SOMS and the handgrip test.

Ribonuclease inhibitor 1 emerges as a potential biomarker and modulates inflammation and iron homeostasis in sepsis.

Sepsis, marked by organ dysfunction, necessitates reliable biomarkers. Ribonuclease inhibitor 1 (RNH1), a ribonuclease (RNase) inhibitor, emerged as a potential biomarker for acute kidney injury and mortality in thoracoabdominal aortic aneurysm patients. Our study investigates RNH1 dynamics in sepsis, its links to mortality and organ dysfunction, and the interplay with RNase 1 and RNase 5. Furthermore, we explore RNH1 as a therapeutic target in sepsis-related processes like inflammation, non-canonical inflammasome activation, and iron homeostasis. We showed that RNH1 levels are significantly higher in deceased patients compared to sepsis survivors and correlate with creatine kinase, aspartate and alanine transaminase, bilirubin, serum creatinine and RNase 5, but not RNase 1. RNH1 mitigated LPS-induced TNFα and RNase 5 secretion, and relative mRNA expression of ferroptosis-associated genes HMOX1, FTH1 and HAMP in PBMCs. Monocytes were identified as the predominant type of LPS-positive PBMCs. Exogenous RNH1 attenuated LPS-induced CASP5 expression, while increasing IL-1ß secretion in PBMCs and THP-1 macrophages. As RNH1 has contradictory effects on inflammation and non-canonical inflammasome activation, its use as a therapeutic agent is limited. However, RNH1 levels may play a central role in iron homeostasis during sepsis, supporting our clinical observations. Hence, RNH1 shows promise as biomarkers for renal and hepatic dysfunction and hepatocyte injury, and may be useful in predicting the outcome of septic patients.

The anti-inflammatory effect of the synthetic antimicrobial peptide 19-2.5 in a murine sepsis model: a prospective randomized study.

INTRODUCTION: Increasing rates of multi-resistant bacteria are a major problem in the treatment of critically ill patients. Furthermore, conventional antibiotics lead to the release of bacterial derived membrane parts initiating pro-inflammatory cascades with potential harm to the patient. Antimicrobial peptides (AMP) may kill bacteria without releasing pro-inflammatory factors. Thus, we compared three newly developed synthetic anti-lipopolysaccharide peptides (SALPs) with a broader range of efficacy to suppress cytokine release in plasma and CD14 mRNA expression in organ tissue in a murine, polymicrobial sepsis model. METHODS: A randomized, experimental trial was conducted in an animal research facility. Male NMRI mice (n = 90; 8- to 12-weeks old) were randomized to the following six groups: (i) sham operation and parenteral vehicle (NaCl 0.9%) administration (sham); (ii) cecal ligation and puncture (CLP) and vehicle infusion (sepsis-control), (iii) CLP and polymyxin B infusion (polyB), or (iv to vi) CLP and infusion of three different synthetic antimicrobial peptides Peptide 19-2.5 (Pep2.5), Peptide 19-4 (Pep4) or Peptide 19-8 (Pep8). All animals underwent arterial and venous catheterization for hemodynamic monitoring 48 hours prior to CLP or sham-operation. Physical appearance and behavior (activity), plasma cytokine levels, and CD14 mRNA expression in heart, lung, liver, spleen and kidney tissue were determined 24 hours after CLP or sham operation. RESULTS: Only Pep2.5 significantly enhanced the activity after CLP, whereas none of the therapeutic regimens elevated the mean arterial pressure or heart rate. The strongly elevated IL-6, IL-10 and monocyte chemoattractant protein serum levels in septic animals were significantly reduced after Pep2.5 administration (P < 0.001, P < 0.001, and P < 0.001, respectively). Similarly, Pep2.5 significantly reduced the sepsis-induced CD14 mRNA expression in heart (P = 0.003), lung (P = 0.008), and spleen tissue (P = 0.009) but not in kidney and liver. CONCLUSIONS: Structurally variable SALPs exhibit major differences in their anti-inflammatory effect in vivo. Continuous parenteral administration of Pep2.5 is able to reduce sepsis-induced cytokine release and tissue inflammation.

Local YB-1, Epo, and EpoR concentrations in fractured bones: results from a porcine model of multiple trauma.

Little is known about the impact of multiple trauma (MT)-related systemic hypoxia on osseous protein concentration of the hypoxia transcriptome. To shed light on this issue, we investigated erythropoietin (Epo), erythropoietin receptor (EpoR), and Y-box binding protein 1 (YB-1) concentrations in the fracture zone in a porcine MT + traumatic hemorrhage (TH) model. Sixteen male domestic pigs were randomized into two groups: an MT + TH group and a sham group. A tibia fracture, lung contusion, and TH were induced in the MT + TH group. The total observation period was 72 h. YB-1 concentrations in bone marrow (BM) were significantly lower in the fracture zone of the MT + TH animals than in the sham animals. Significant downregulation of BM-localized EpoR concentration in both unfractured and fractured bones was observed in the MT + TH animals relative to the sham animals. In BM, Epo concentrations were higher in the fracture zone of the MT + TH animals compared with that in the sham animals. Significantly higher Epo concentrations were detected in the BM of fractured bone compared to that in cortical bone. Our results provide the first evidence that MT + TH alters hypoxia-related protein concentrations. The impacts of both the fracture and concomitant injuries on protein concentrations need to be studied in more detail to shed light on the hypoxia transcriptome in fractured and healthy bones after MT + TH.

Standardized pharmacological management of delirium after on-pump cardiac surgery reduces ICU stay and ventilation in a retrospective pre-post study.

Cardiac surgery patients not only undergo a highly invasive procedure but are at risk for a diversity of postoperative complications. Up to 53% of these patients suffer from postoperative delirium (POD). This severe and common adverse event increases mortality and prolonged mechanical ventilation and extends the intensive care unit stay. The objective of this study was to test the hypothesis that standardized pharmacological management of delirium (SPMD) may reduce the length of stay in the intensive care unit (ICU), duration of postoperative mechanical ventilation, and the incidence of postoperative complications such as pneumonia or bloodstream infections in on-pump cardiac surgery ICU patients. In this retrospective, single-center observational cohort study, 247 patients were examined between May 2018 to June 2020, who underwent on-pump cardiac surgery, suffered from POD, and received pharmacological POD treatment. 125 were treated before and 122 after SPMD implementation in the ICU. The primary endpoint was a composite outcome, including the length of ICU stay, postoperative mechanical ventilation time, and ICU survival rate. The secondary endpoints were complications including postoperative pneumonia and bloodstream infections. Although the ICU survival rate was not significantly different between both groups, the length of ICU stay (control group: 23 ± 27 days; SPMD group: 16 ± 16 days; p = 0.024) and the duration of mechanical ventilation were significantly reduced in the SPMD-cohort (control group: 230 ± 395 h; SPMD group: 128 ± 268 h; p = 0.022). Concordantly, the pneumonic risk was reduced after SPMD introduction (control group: 44.0%; SPMD group: 27.9%; p = 0.012) as well as the incidence for bloodstream infections (control group: 19.2%; SPMD group: 6.6%; p = 0.004). Standardized pharmacological management of postoperative delirium in on-pump cardiac surgery ICU patients reduced the length of ICU stay and duration of mechanical ventilation significantly, leading to a decrease in pneumonic complications and bloodstream infections.

Impairment of renal function using hyperoncotic colloids in a two hit model of shock: a prospective randomized study.

INTRODUCTION: One of the therapeutic essentials in severe sepsis and septic shock is an adequate fluid replacement to restore and maintain circulating plasma volume, improve organ perfusion and nutritive microcirculatory flow. The type of solution to be used as a fluid replacement remains under discussion. The aim of the study was to evaluate the effects of clinically used fluid replacement solutions on renal function and inflammatory response. METHODS: A total of 23 anesthetized and ventilated female German Landrace pigs were investigated over 19 hours using a two-hit model that combined hemorrhagic and septic shock. The septic shock was induced using an Escherichia coli laden clot placed into the abdominal cavity. Infusions of 6% hydroxyethylstarch 130/0.42 in acetate (6% HES 130), 4% gelatin in acetate (4% gelatin) and 10% hydroxyethylstarch 200/0.5 in saline (10% HES200) compared to Ringer's acetate (RAc) were used for fluid replacement to maintain a central venous pressure of 12 mmHg. Ringer's acetate was also used in the sham-treated group (SHAM). RESULTS: At study end the cardiac output (10% HES200 143±48 ml/kgBW; 6% HES130 171±47 ml/kgBW; RAc 137±32 ml/kgBW; 4% gelatin 160±42 ml/kgBW), as well as mean arterial pressure did not differ between groups. N-acetyl-beta-D-glucosamidase was significantly higher in the hydroxyethylstarch 200 (157±115 U/g creatinine; P<0.05) group compared to hydroxyethylstarch 130 (24±9 U/g creatinine), Ringer's acetate (2±3 U/g creatinine) and SHAM (21±15 U/g creatinine) at the study's end. Creatinine significantly increased by 87±84 percent of baseline in the 10% HES200 group compared to RAc and 6% HES130. We demonstrated in the histology of the kidneys a significant increase in osmotic-nephrosis like lesions for 4% gelatin compared to RAc, 6% HES130 and SHAM. Urine output was lowest in the 10% HES200 and 4% gelatin group, however not significantly.Interleukin(IL)-6 levels were significantly elevated in the 10% HES200 group (3,845±1,472 pg/ml) two hours after sepsis induction compared to all other groups (6% HES130 1,492±604 pg/ml; RAc 874±363 pg/ml; 4% gelatin 1,623±1,242 pg/ml). CONCLUSIONS: Despite similar maintenance of macrocirculation 6% hydroxyethylstarch 130/0.42 and Ringer's acetate significantly preserve renal function and attenuate tubular damage better than 10% hydroxyethylstarch 200/0.5 in saline.

Testing of behavioural asymmetries as markers for brain lateralization of emotional states in pet dogs: A critical review.

Domestic dogs (Canis familiaris) hold a unique position in human society, particularly in their role as social companions; as such, it is important to understand their emotional lives. There has been growing interest in studying behavioural biases in dogs as indirect markers (reflecting lateralized brain activity) of their emotional states. In this paper, we not only review the previous literature on emotion-related behavioural lateralization in dogs, but also propose and apply the concept of evidential weight to previous research. This allows us to examine different hypotheses about emotion-related brain asymmetries (i.e., Right-Hemisphere-, Valence-, Approach-Withdrawal-Hypothesis) on the basis of a "likelihood-ist" concept of evidence. We argue that previous studies have not been able to discriminate well between competing hypotheses and tended to focus on confirmation bias than critically assess different hypotheses; as such there is a strong case for more systematic investigation to pull these theories apart. We present the areas for future research and explain their importance for understanding the emotional lives of dogs.