Gene Expression-Based Diagnosis of Infections in Critically Ill Patients-Prospective Validation of the SepsisMetaScore in a Longitudinal Severe Trauma Cohort.

OBJECTIVES: Early diagnosis of infections is pivotal in critically ill patients. Innovative gene expression-based approaches promise to deliver precise, fast, and clinically practicable diagnostic tools to bedside. This study aimed to validate the SepsisMetaScore, an 11-gene signature previously reported by our study group, in a representative longitudinal cohort of trauma patients. DESIGN: Prospective observational cohort study. SETTING: Surgical ICUs of the University Medical Center Goettingen, Germany. PATIENTS: Critically ill patients with severe traumatic injuries. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Paired box gene (PAXgene) RNA blood tubes were drawn at predefined time points over the course of disease. The performance of the SepsisMetaScore was tested using targeted polymerase chain reaction and compared with Procalcitonin using area under the receiver operating characteristics analyses. The SepsisMetaScore showed significant differences between infected and noninfected patients (n = 52). It was able to accurately discriminate infectious from noninfectious acute inflammation with an area under the receiver operating characteristics of 0.92 (95% CI, 0.85-0.99) and significantly outperformed Procalcitonin (area under the receiver operating characteristics curve = 0.53; 95% CI, 0.42-0.64) early in the course of infection (p = 0.014). CONCLUSIONS: We demonstrated the clinical utility for diagnosis of infections with higher accuracy using the SepsisMetaScore compared with Procalcitonin in a prospective cohort of severe trauma patients. Future studies should assess whether the SepsisMetaScore may substantially improve clinical practice by accurate differentiation of infections from sterile inflammation and identification of patients at risk for sepsis. Our results support further investigation of the SepsisMetaScore for the development of tailored precision treatment of critically ill patients.

TIM-3 Genetic Variants Are Associated with Altered Clinical Outcome and Susceptibility to Gram-Positive Infections in Patients with Sepsis.

Background: Previous studies have reported the fundamental role of immunoregulatory proteins in the clinical phenotype and outcome of sepsis. This study investigated two functional single nucleotide polymorphisms (SNPs) of T cell immunoglobulin and mucin domain-containing protein 3 (TIM-3), which has a negative stimulatory function in the T cell immune response. Methods: Patients with sepsis (n = 712) were prospectively enrolled from three intensive care units (ICUs) at the University Medical Center Goettingen since 2012. All patients were genotyped for the TIM-3 SNPs rs1036199 and rs10515746. The primary outcome was 28-day mortality. Disease severity and microbiological findings were secondary endpoints. Results: Kaplan-Meier survival analysis demonstrated a significantly lower 28-day mortality for TIM-3 rs1036199 AA homozygous patients compared to C-allele carriers (18% vs. 27%, p = 0.0099) and TIM-3 rs10515746 CC homozygous patients compared to A-allele carriers (18% vs. 26%, p = 0.0202). The TIM-3 rs1036199 AA genotype and rs10515746 CC genotype remained significant predictors for 28-day mortality in the multivariate Cox regression analysis after adjustment for relevant confounders (adjusted hazard ratios: 0.67 and 0.70). Additionally, patients carrying the rs1036199 AA genotype presented more Gram-positive and Staphylococcus epidermidis infections, and rs10515746 CC homozygotes presented more Staphylococcus epidermidis infections. Conclusion: The studied TIM-3 genetic variants are associated with altered 28-day mortality and susceptibility to Gram-positive infections in sepsis.

Pre-hospital transthoracic echocardiography for early identification of non-ST-elevation myocardial infarction in patients with acute coronary syndrome.

BACKGROUND: Non-ST elevation myocardial infarction (NSTEMI) is a common manifestation of acute coronary syndrome (ACS), but delayed diagnosis can increase mortality. In this proof of principle study, the emergency physician performed transthoracic echocardiography (TTE) on scene to determine whether NSTEMI could be correctly diagnosed pre-hospitalization. This could expedite admission to the appropriate facility and reduce the delay until initiation of correct therapy. METHODS: Pre-hospital TTE was performed on scene by the emergency physician in patients presenting with ACS but without ST-elevation in the initial 12-lead electrocardiography (ECG) (NSTE-ACS). A presumptive NSTEMI diagnosis was made if regional wall motion abnormalities (RWMA) were detected. These patients were admitted directly to a specialist cardiac facility. Patient characteristics and pre-admission and post-admission clinical, pre-hospital TTE data, and therapeutic measures were recorded. RESULTS: Patients with NSTE-ACS (n = 53; 72.5 ± 13.4 years of age; 23 female) were studied. The 20 patients with pre-hospital RWMA and presumptive NSTEMI, and two without RWMA were conclusively diagnosed with NSTEMI in hospital. Percutaneous coronary intervention was performed in 50% of the patients presumed to have NSTEMI immediately after admission. The RWMA seen before hospital TTE corresponded with the in-hospital ECG findings and/or the supply regions of the occluded coronary vessels seen during PCI in 85% of the cases. The diagnostic sensitivity of pre-hospital TTE for NSTEMI was 90.9% with 100% specificity. CONCLUSIONS: Pre-hospital transthoracic echocardiography by the emergency physician can correctly diagnose NSTEMI in more than 90% of cases. This can expedite the initiation of appropriate therapy and could thereby conceivably reduce morbidity and mortality. TRIAL REGISTRATION: Deutsche Register klinischer Studien, DRKS00004919 . Registered on 29 April 2013.

Impact of statin therapy on mortality in patients with sepsis-associated acute respiratory distress syndrome (ARDS) depends on ARDS severity: a prospective observational cohort study.

BACKGROUND: Previous investigations have presumed a potential therapeutic effect of statin therapy in patients with acute respiratory distress syndrome (ARDS). Statins are expected to attenuate inflammation in the lungs of patients with ARDS due to their anti-inflammatory effects. Clinical investigations of the role of statin therapy have revealed contradictory results. This study aimed to investigate whether pretreatment and continuous therapy with statins in patients with sepsis-associated ARDS are associated with 28-day survival according to disease severity (mild, moderate, or severe). METHODS: Patients with sepsis-associated ARDS from the surgical intensive care were enrolled in this prospective observational investigation. ARDS was classified into three groups (mild, moderate, and severe); 28-day mortality was recorded as the primary outcome variable and organ failure was recorded as secondary outcome variable. Sequential Organ Failure Assessment scores and the requirements for organ support were evaluated throughout the observational period to assess organ failure. RESULTS: 404 patients with sepsis-associated ARDS were enrolled in this investigation. The distribution of the ARDS subgroups was 13 %, 59 %, and 28 % for mild, moderate, and severe disease, respectively. Statin therapy improved 28-day survival exclusively in the patients with severe ARDS compared with patients without statin therapy (88.5 % and 62.5 %, respectively; P = 0.0193). To exclude the effects of several confounders, we performed multivariate Cox regression analysis, which showed that statin therapy remained a significant covariate for mortality (hazard ratio, 5.46; 95 % CI, 1.38-21.70; P = 0.0156). Moreover, after carrying a propensity score-matching in the severe ARDS cohort, Kaplan-Meier survival analysis confirmed the improved 28-day survival among patients with statin therapy (P = 0.0205). Patients with severe ARDS who received statin therapy had significantly more vasopressor-free days compared with those without statin therapy (13 ± 7 and 9 ± 7, respectively; P = 0.0034), and they also required less extracorporeal membrane oxygenation (ECMO) therapy and had more ECMO-free days (18 ± 9 and 15 ± 9, respectively; P = 0.0873). CONCLUSIONS: This investigation suggests a beneficial effect of continuous statin therapy in patients with severe sepsis-associated ARDS and a history of prior statin therapy. Further study is warranted to elucidate this potential effect.

Remifentanil added to sufentanil-sevoflurane anesthesia suppresses hemodynamic and metabolic stress responses to intense surgical stimuli more effectively than high-dose sufentanil-sevoflurane alone.

BACKGROUND: Even extremely high-doses of the potent opioid, sufentanil, cannot reliably suppress stress responses to intense surgical stimuli such as sternotomy. The chemically related opioid remifentanil with its different pharmacokinetics and binding affinities for delta- and kappa-opioid receptors might be more effective in attenuating these responses. METHODS: ASA I-III patients scheduled for a surgical procedure with sternotomy under balanced anesthesia (sevoflurane and sufentanil 3 µg.kg(-1) bolus, 0.017 µg.kg(-1).min(-1) infusion) were randomized into two groups. Patients in the study group were supplemented with remifentanil (2 µg.kg(-1) bolus, 2-7 µg.kg(-1).min(-1) infusion) starting ten minutes before sternotomy. Heart rate, arterial blood pressures, cardiac index, ejection fraction, systemic vascular resistance index (SVRI), total body oxygen uptake (VO2) and electric dermal response were measured and compared between the groups. RESULTS: 62 patients were studied (study group 32, control group 30). Systolic and mean arterial blood pressures, SVRI, VO2 and skin conductance increased during sternotomy and sternal spread in the control group but not in the study group. Systolic blood pressure increase: 7.5 ± 19 mmHg vs. -3.4 ± 8.9 (p = 0.005); VO2 increase: 31 ± 46% vs. -0.4 ± 32%; incidence of systolic blood pressure increase greater than 15 percent: 20% vs. 3% (p = 0.035) (control vs. study group). CONCLUSION: High-dose remifentanil added to sevoflurane-sufentanil anesthesia suppresses the sympathoadrenergic response to sternotomy and sternal spread better than high-dose sufentanil alone. CLINICAL TRIAL NUMBER: DRKS00004327, August 31, 2012.

The regulatory toll-like receptor 4 genetic polymorphism rs11536889 is associated with renal, coagulation and hepatic organ failure in sepsis patients.

BACKGROUND: Toll-like receptor 4 (TLR4), a lipopolysaccharide (LPS) receptor complex signal-transducing molecule, plays a crucial role in sensing LPS from gram-negative bacteria. TLR4 signaling pathway activation by LPS plays a major role in sepsis pathogenesis. A single nucleotide polymorphism, rs11536889, in the 3'-untranslated region of the TLR4 gene is thought to affect TLR4 translation. This study aimed to investigate whether organ failure in sepsis patients is related to the TLR4 rs11536889 genotype. METHODS: Adult Caucasian patients with sepsis from the intensive care unit of a university medical center were followed up for 90 days, and organ failure was recorded as the primary outcome variable. Blood samples were collected at enrollment for TLR4 rs11536889 genotyping. Sepsis-related organ failure assessment (SOFA) scores were quantified at sepsis onset and throughout the observational period to monitor organ failure. RESULTS: A total of 210 critically ill patients with sepsis were enrolled into this study. Wild-type GG was compared to GC/CC. During their stay in the intensive care unit, GG patients presented significantly higher SOFA scores than did C allele carriers (7.9 ± 4.5 and 6.8 ± 4.2, respectively; p = 0.0005). Analysis of organ-specific SOFA sub-scores revealed significant differences in three organ systems: renal, coagulation and hepatic (p = 0.0005, p = 0.0245 and p < 0.0001, respectively). Additionally, the rs11536889 polymorphism was associated with a higher incidence of gram-negative infections. CONCLUSIONS: These results offer the first evidence that TLR4 rs11536889 is a useful marker of organ failure in patients with sepsis.

Blood pressure response to combined general anaesthesia/interscalene brachial plexus block for outpatient shoulder arthroscopy.

BACKGROUND: Shoulder surgery is often performed in the beach-chair position, a position associated with arterial hypotension and subsequent risk of cerebral ischaemia. It can be performed under general anaesthesia or with an interscalene brachial plexus block, each of which has specific advantages but also specific negative effects on blood pressure control. It would be worthwhile to combine the advantages of the two, but the effects of the combination on the circulation are not well investigated. We studied blood pressure, heart rate, and incidence of adverse circulatory events in patients undergoing shoulder surgery in general anaesthesia with or without an interscalene block. METHODS: Prospective, randomised, blinded study in outpatients (age 18 to 80 years) undergoing shoulder arthroscopy. General anaesthesia was with propofol/opioid, interscalene block with 40 ml 1% mepivacaine. Hypotension requiring treatment was defined as a mean arterial pressure <60 mmHg or a systolic pressure <80% of baseline; relevant bradycardia was a heart rate <50 bpm with a decrease in blood pressure. RESULTS: Forty-two patients had general anaesthesia alone, 41 had general anaesthesia plus interscalene block. The average systolic blood pressure under anaesthesia in the beach-chair position was 114 ± 7.3 vs. 116 ± 8.3 mmHg (p = 0.09; all comparisons General vs. General-Regional). The incidence of a mean arterial pressure under 60 mmHg or a decrease in systolic pressure of more than 20% from baseline was 64% vs. 76% (p = 0.45). The number of patients with a heart rate lower than 50 and a concomitant blood pressure decrease was 8 vs. 5 (p = 0.30). CONCLUSION: One can safely combine interscalene block with general anaesthesia for surgery in the beach-chair position in ASA I and II patients. CLINICAL TRIAL NUMBER: DRKS00005295.

The effect of changing the sequence of cuff inflation and device fixation with the LMA-Supreme® on device position, ventilatory complications, and airway morbidity: a clinical and fiberscopic study.

BACKGROUND: The conventional sequence when using supraglottic airway devices is insertion, cuff inflation and fixation. Our hypothesis was that a tighter fit of the cuff and tip could be achieved with a consequently lower incidence of air leak, better separation of gastrointestinal and respiratory tracts and less airway morbidity if the device were first affixed and the cuff then inflated. METHODS: Our clinical review board approved the study (public registry number DRKS00003174). An LMA Supreme® was inserted into 184 patients undergoing lower limb arthroscopy in propofol-remifentanil anaesthesia who were randomly assigned to either the control (inflation then fixation; n = 92) or study group (fixation then inflation; n = 92). The cuff was inflated to 60 cmH2O. The patients' lungs were ventilated in pressure-controlled mode with 5 cmH2O PEEP, Pmax to give 6 ml kg-1 tidal volume, and respiratory rate adjusted to end-tidal CO2 of 4.8 and 5.6 kPa. Correct cuff and tip position were determined by leak detection, capnometry trace, oropharyngeal leak pressure, suprasternal notch test, and lube-tube test. Bowl and cuff position and the presence of glottic narrowing were assessed by fiberscopic examination. Postoperative dysphagia, hoarseness and sore throat were assessed with a questionnaire. Ventilatory impairment was defined as a tidal volume < 6 ml kg-1 with Pmax at oropharyngeal leak pressure, glottic narrowing was defined as an angle between the vocal cords under 16 degrees. RESULTS: The incidence of incorrect device position (18% vs. 21%), failed ventilation (10% vs. 9%), leak pressure (24.8 vs. 25.2 cmH2O, p = 0.63), failed lube-tube test (16.3% vs. 17.6%) and glottic narrowing (19.3% vs. 14.1%, p = 0.35) was similar in both groups (control vs. study, resp.). When glottic narrowing occurred, it was more frequently associated with ventilatory impairment in the control group (77% vs. 39%; p = 0.04). Airway morbidity was more common in the control group (33% vs. 19%; p < 0.05). CONCLUSIONS: Altering the sequence of cuff inflation and device fixation does not affect device position, oropharyngeal leak pressures or separation of gastrointestinal and respiratory tracts. It reduces the incidence of glottic narrowing with impaired ventilation and also perioperative airway morbidity.

Differences in Mortality and Sepsis-Associated Organ Dysfunction between Surgical and Non-Surgical Sepsis Patients.

(1) Background: Patients with sepsis following surgical intervention may exhibit fundamental distinctions from those experiencing sepsis without prior surgery. Despite the potential clinical importance of distinguishing these two sepsis subpopulations, dissimilarities, particularly in outcome, between surgical and non-surgical patients have been subject to limited scientific investigations in the existing literature. This study aimed to investigate the differences in mortality and sepsis-associated organ dysfunction between these two groups. (2) Methods: A retrospective analysis was conducted using data from a large cohort of prospectively enrolled patients with sepsis (n = 737) admitted to three intensive care units at University Medical Center Goettingen; patients were categorized into surgical (n = 582) and non-surgical sepsis groups (n = 155). The primary outcomes assessed were 28- and 90-day mortality rates, and secondary endpoints were multiple clinical parameters and measures of sepsis-associated organ dysfunction. (3) Results: Non-surgical patients presented a significantly higher 90-day mortality (37%) compared to surgical sepsis patients (30%, p = 0.0457). Moreover, the non-surgical sepsis group exhibited increased sepsis-associated organ dysfunction, as evidenced by higher average SOFA scores (p < 0.001), elevated levels of serum Procalcitonin (p = 0.0102), and a higher utilization of organ replacement therapies such as ventilation (p < 0.001), vasopressor treatment (p < 0.001), and renal replacement therapy (p = 0.0364). Additionally, non-surgical sepsis patients had higher organ-specific SOFA respiratory (p < 0.001), cardiovascular (p < 0.001), renal (p < 0.001), coagulation (0.0335), and central nervous system (p = 0.0206) subscores. (4) Conclusions: These results suggested that patients with non-surgical sepsis may face distinct challenges and a higher risk of adverse outcomes compared to patients with sepsis following surgical intervention. These findings have important implications for clinical decision-making, patient management, and resource allocation in sepsis care.

Association of Sex Differences with Mortality and Organ Dysfunction in Patients with Sepsis and Septic Shock.

BACKGROUND: Despite recent advances in the clinical management and understanding of sepsis and septic shock, these complex clinical syndromes continue to have high mortality rates. The effect of sex on these diseases' mortality, clinical presentation and morbidity remains controversial. This study aimed to investigate the association of sex with mortality and organ dysfunction in patients with sepsis and septic shock. METHODS: Prospectively enrolled patients with clinically defined sepsis and septic shock in three intensive care units at University Medical Center Göttingen, Germany, were investigated. The primary outcomes were 28- and 90-day mortality, while the secondary endpoints included the evaluation of organ dysfunction as measured by clinical scores and laboratory parameters. RESULTS: A total of 737 septic patients were enrolled, including 373 in septic shock, 484 males, and 253 females. No significant differences in 28- and 90-day mortality were observed in the cohort. However, men with sepsis had significantly higher SOFA scores, SOFA respiratory and renal subscores, bilirubin and creatinine values, and lower weight-adapted urine outputs, indicating higher organ dysfunction compared to women. CONCLUSIONS: Our findings revealed notable differences in organ dysfunction between male and female patients, with males exhibiting more pronounced dysfunction across multiple clinical indicators. These results highlight the potential influence of sex on sepsis disease severity and suggest the need for tailored approaches in sepsis management according to patient sex.

Effect of the Lymphocyte Activation Gene 3 Polymorphism rs951818 on Mortality and Disease Progression in Patients with Sepsis-A Prospective Genetic Association Study.

(1) Background: Sepsis is a leading cause of death and a global public health problem. Accordingly, deciphering the underlying molecular mechanisms of this disease and the determinants of its morbidity and mortality is pivotal. This study examined the effect of the rs951818 SNP of the negative costimulatory lymphocyte-activation gene 3 (LAG-3) on sepsis mortality and disease severity. (2) Methods: 707 consecutive patients with sepsis were prospectively enrolled into the present study from three surgical ICUs at University Medical Center Goettingen. Both 28- and 90-day mortality were analyzed as the primary outcome, while parameters of disease severity served as secondary endpoints. (3) Results: In the Kaplan-Meier analysis LAG-3 rs951818 AA-homozygote patients showed a significantly lower 28-day mortality (17.3%) compared to carriers of the C-allele (23.7%, p = 0.0476). In addition, these patients more often received invasive mechanical ventilation (96%) during the course of disease than C-allele carriers (92%, p = 0.0466). (4) Conclusions: Genetic profiling of LAG-3 genetic variants alone or in combination with other genetic biomarkers may represent a promising approach for risk stratification of patients with sepsis. Patient-individual therapeutic targeting of immune checkpoints, such as LAG-3, may be a future component of sepsis therapy. Further detailed investigations in clinically relevant sepsis models are necessary.

Extracorporeal circulation for rewarming in drowning and near-drowning pediatric patients.

Drowning and near-drowning is often associated with severe hypothermia requiring active core rewarming.We performed rewarming by cardiopulmonary bypass(CPB). Between 1987 and 2007, 13 children (9 boys and 4 girls) with accidental hypothermia were rewarmed by extracorporeal circulation (ECC) in our institution. The average age of the patients was 3.2 years. Resuscitation was started immediately upon the arrival of the rescue team and was continuously performed during the transportation.All patients were intubated and ventilated. Core temperature at admission ranged from 20 to 29°C (mean 25.3°C). Connection to the CPB was performed by thoracic (9 patients) or femoral/iliac means (4 patients). Restoration of circulation was achieved in 11 patients (84.6%). After CPB termination two patients needed an extracorporeal membrane oxygenation system due to severe pulmonary edema.Five patients were discharged from hospital after prolonged hospital stay. During follow-up, two patients died(10 and 15 months, respectively) of pulmonary complications and one patient was lost to follow-up. The two remaining survivors were without neurological deficit.Modes of rewarming, age, sex, rectal temperature, and serum electrolytes did not influence mortality. In conclusion,drowning and near-drowning with severe hypothermia remains a challenging emergency. Rewarming by ECC provides efficient rewarming and full circulatory support.Although nearly half of the children may survive after rewarming by ECC, long-term outcome is limited by pulmonary and neurological complications.

Aortic valve surgery in congenital heart disease: a single-center experience.

The optimal treatment of congenital aortic valve lesions is a controversial issue. This study was performed to evaluate the outcome after surgical treatment of aortic valve lesions in congenital aortic valve disease. Between the years of 2000 and 2008, 61 patients (mean age: 12.6 +/- 9.6 years, range: 1 day to 40 years) underwent aortic valve surgery for congenital aortic valve disease. Twenty-four patients had undergone previous cardiovascular operations. Indications for surgery were aortic regurgitation in 14.7% (n = 9), aortic stenoses in 26.2% (n = 16), and mixed disease in 59.1% (n = 36). The Ross procedure was performed in 37.7% (n = 23), aortic valve replacement with biological or mechanical prostheses in 29.5% (n = 18). Concomitant procedures were performed in 91.8% (n = 56) due to associated congenital cardiac defects. The overall mortality rate was 5%. Six patients needed reoperation. Implantation of permanent pacemakers occurred in six patients for permanent atrioventricular block. At the latest clinical evaluation, all survivors are in New York Heart Association class I-II and are living normal lives. Aortic valve surgeries in patients with congenital heart disease have had low mortality and morbidity rates in our series. Surgical technique as well as timing should be tailored for each patient. Aortic valve replacement should be delayed until the implantation of an adult-sized prosthesis is possible.

Relation between renal dysfunction requiring renal replacement therapy and promoter polymorphism of the erythropoietin gene in cardiac surgery.

Several genetic polymorphisms have been identified to play a role in the occurrence and progression of renal dysfunction after cardiac surgery with cardiopulmonary bypass (CPB). Recently, it was demonstrated that the T allele of SNP rs1617640 in the promoter of the erythropoetin (EPO) gene is significantly associated with proliferative diabetic retinopathy (PDR) and end-stage renal disease (ESRD) due to increased EPO expression. This disease risk-associated gene and its potential pathway mediating severe microvascular complications in T-allele carriers could also play a role on renal dysfunction in patients who underwent cardiac surgery with CPB. We hypothesized that the patients' ability to produce increased EPO concentrations will affect morbidity and mortality after CPB. We conducted a prospective single center study between April 2006 and May 2007. In 481 patients who underwent cardiac surgery with CPB we prospectively examined the SNP rs1617640 in the promoter of the EPO gene by DNA sequencing. The patients were grouped according to their genotype (GG, GT, and TT). The genotype distribution of SNP rs1617640 in the promoter of the EPO gene was 36% (TT), 49% (TG), and 15% (GG). There was no difference in age, body mass index, gender, CPB time, or length of stay in intensive care unit. The hospitalization was irrespective of the patients' genotypes. The baseline creatinine in the TT group was 0.2 points higher than in the other groups; however this was without statistical significance in the multivariate analysis. No significant difference was shown in Euroscore, the Simplified Acute Physiology Score II, the Acute Physiology and Chronic Health Evaluation Score II, Acute Renal Failure Score, or the Risk, Injury, Failure, Loss of Kidney Function Score. The mortality was equal across the genotypes. However, an association between the TT genotype and acute renal replacement therapy (P=0.03), intra-aortic balloon pump usage (P=0.02), and serum creatine phosphokinase-MB increase (P=0.03) were observed after cardiac surgery. Our analysis suggests that the risk allele (T) of rs1617640 plays a role in the development of renal dysfunction after cardiac surgery with CPB. Patients with the TT risk allele required more frequent acute renal replacement therapy. Since our result is close to the border of significance, this hypothesis should be investigated in larger prospective studies with long-term follow-up to emphasize this polymorphism as a potential risk factor.

The role of phospho-adenosine monophosphate-activated protein kinase and vascular endothelial growth factor in a model of chronic heart failure.

We established a stable and reproducible animal model of chronic heart failure (CHF) in sheep to investigate biomolecular changes. Therefore, two biomarkers, adenosine monophosphate-activated protein kinase (AMPK) and vascular endothelial growth factor-A (VEGF-A) were examined to reveal their role during chronic ischemic conditions of the heart. AMPK was studied because it plays an important role in cellular energy homeostasis and its upregulation is associated with myocardial ischemia, whereas VEGF-A was studied because it acts as an important signaling protein for neoangiogenesis. We examined 15 juvenile sheep (mean weight, 78±4kg; control, n=3; ShamOP, n=2; coronary microembolization [CME], n=10). CHF was induced under fluoroscopic guidance by multiple sequential microembolizations (MEs) through bolus injection of polysterol microspheres (90µm, n=25.000) into the left main coronary artery. CME was repeated up to three times at 2- to 3-week intervals until animals started to develop stable signs of CHF. All animals were followed for 3 months. Phosphorylation of AMPK, marking the activated protein form, was detected by Western blotting. VEGF-A and vascular endothelial growth factor-receptor 2 (VEGF-R2) mRNA were detected by real-time polymerase chain reaction. Glyceraldehyde-3-phosphate-dehydrogenase (GAPDH) was used as a reference housekeeping gene. All 10 CHF animals developed clinical signs of CHF as indicated by a significant decrease of cardiac output, decreased ejection fraction, as well as occurrence of tachycardia and tachypnoea. Western blots showed significant phosphorylation of AMPK in CME animals compared to the control group (phospho-adenosine monophosphate-activated protein kinase α) (GAPDH control: 0.0, CME left ventricle [LV]: 0.39±0.20, CME right ventricle [RV]: 0.53±0.30; P<0.05). VEGF-A and VEGF-R2 expression in CME animal myocardium was within the range of the control group, but this data did not reach statistical significance due to the small size of this group. While microinjection was performed into the left main coronary artery, phosphorylation of AMPK and expression of VEGF-A and VEGF-R2 were significantly higher in the RV than in the LV. Multiple sequential intracoronary MEs can effectively induce myocardial dysfunction with clinical and biomolecular signs of chronic ischemic cardiomyopathy. Quantitative analysis of biomolecular markers showed a significantly higher phosphorylation of AMPK in CHF animals compared with control myocardium.

High flow biphasic positive airway pressure by helmet--effects on pressurization, tidal volume, carbon dioxide accumulation and noise exposure.

INTRODUCTION: Non-invasive ventilation (NIV) with a helmet device is often associated with poor patient-ventilator synchrony and impaired carbon dioxide (CO2) removal, which might lead to failure. A possible solution is to use a high free flow system in combination with a time-cycled pressure valve placed into the expiratory circuit (HF-BiPAP). This system would be independent from triggering while providing a high flow to eliminate CO2. METHODS: Conventional pressure support ventilation (PSV) and time-cycled biphasic pressure controlled ventilation (BiVent) delivered by an Intensive Care Unit ventilator were compared to HF-BiPAP in an in vitro lung model study. Variables included delta pressures of 5 and 15 cmH2O, respiratory rates of 15 and 30 breaths/min, inspiratory efforts (respiratory drive) of 2.5 and 10 cmH2O) and different lung characteristics. Additionally, CO2 removal and noise exposure were measured. RESULTS: Pressurization during inspiration was more effective with pressure controlled modes compared to PSV (P < 0.001) at similar tidal volumes. During the expiratory phase, BiVent and HF-BiPAP led to an increase in pressure burden compared to PSV. This was especially true at higher upper pressures (P < 0.001). At high level of asynchrony both HF-BiPAP and BiVent were less effective. Only HF-BiPAP ventilation effectively removed CO2 (P < 0.001) during all settings. Noise exposure was higher during HF-BiPAP (P < 0.001). CONCLUSIONS: This study demonstrates that in a lung model, the efficiency of NIV by helmet can be improved by using HF-BiPAP. However, it imposes a higher pressure during the expiratory phase. CO2 was almost completely removed with HF-BiPAP during all settings.

Mechanical aortic valve replacement in children and adolescents after previous repair of congenital heart disease.

Due to improved outcome after surgery for congenital heart defects, children, adolescents, and grown-ups with congenital heart defects become an increasing population. In order to evaluate operative risk and early outcome after mechanical aortic valve replacement (AVR) in this population, we reviewed patients who underwent previous repair of congenital heart defects. Between July 2002 and November 2008, 15 (10 male and 5 female) consecutive patients (mean age 14.5 +/- 10.5 years) underwent mechanical AVR. Hemodynamic indications for AVR were aortic stenosis in four (27%), aortic insufficiency in eight (53%), and mixed disease in three (20%) after previous repair of congenital heart defects. All patients had undergone one or more previous cardiovascular operations due to any congenital heart disease. Concomitant cardiac procedures were performed in all of them. In addition to AVR, in two patients, a mitral valve exchange was performed. One patient received a right ventricle-pulmonary artery conduit replacement as concomitant procedure. The mean size of implanted valves was 23 mm (range 17-29 mm). There were neither early deaths nor late mortality until December 2008. Reoperations were necessary in five (33%) and included implantation of a permanent pacemaker due to complete atrioventricular block in two (15%), mitral valve replacement with a mechanical prosthesis due to moderate to severe mitral regurgitation in one (7%), aortocoronary bypass grafting due to stenosis of a coronary artery in one (7%), and in one (7%), a redo subaortic stenosis resection was performed because of a secondary subaortic stenosis. At the latest clinical evaluation, all patients were in good clinical condition without a pathological increased gradient across the aortic valve prosthesis or paravalvular leakage in echocardiography. Mechanical AVR has excellent results in patients after previous repair of congenital heart defects in childhood, even in combination with complex concomitant procedures. Previous operations do not significantly affect postoperative outcome.

Hemodynamic changes in a model of chronic heart failure induced by multiple sequential coronary microembolization in sheep.

Although a large variety of animal models for acute ischemia and acute heart failure exist, valuable models for studies on the effect of ventricular assist devices in chronic heart failure are scarce. We established a stable and reproducible animal model of chronic heart failure in sheep and aimed to investigate the hemodynamic changes of this animal model of chronic heart failure in sheep. In five sheep (n = 5, 77 +/- 2 kg), chronic heart failure was induced under fluoroscopic guidance by multiple sequential microembolization through bolus injection of polysterol microspheres (90 microm, n = 25.000) into the left main coronary artery. Coronary microembolization (CME) was repeated up to three times in 2 to 3-week intervals until animals started to develop stable signs of heart failure. During each operation, hemodynamic monitoring was performed through implantation of central venous catheter (central venous pressure [CVP]), arterial pressure line (mean arterial pressure [MAP]), implantation of a right heart catheter {Swan-Ganz catheter (mean pulmonary arterial pressure [PAP mean])}, pulmonary capillary wedge pressure (PCWP), and cardiac output [CO]) as well as pre- and postoperative clinical investigations. All animals were followed for 3 months after first microembolization and then sacrificed for histological examination. All animals developed clinical signs of heart failure as indicated by increased heart rate (HR) at rest (68 +/- 4 bpm [base] to 93 +/- 5 bpm [3 mo][P < 0.05]), increased respiratory rate (RR) at rest (28 +/- 5 [base] to 38 +/- 7 [3 mo][P < 0.05]), and increased body weight 77 +/- 2 kg to 81 +/- 2 kg (P < 0.05) due to pleural effusion, peripheral edema, and ascites. Hemodynamic signs of heart failure were revealed as indicated by increase of HR, RR, CVP, PAP, and PCWP as well as a decrease of CO, stroke volume, and MAP 3 months after the first CME. Multiple sequential intracoronary microembolization can effectively induce myocardial dysfunction with clinical and hemodynamic signs of chronic ischemic cardiomyopathy. The present model may be suitable in experimental work on heart failure and left ventricular assist devices, for example, for studying the impact of mechanical unloading, mechanisms of recovery, and reverse remodeling.

Subparaneural Injection in Popliteal Sciatic Nerve Blocks Evaluated by MRI.

Intraneural injection of a local anesthetic can damage the nerve, yet it occurs frequently during distal sciatic block with no neurological sequelae. This has led to a controversy about the optimal needle tip placement that results from the particular anatomy of the sciatic nerve with its paraneural sheath. The study population included patients undergoing lower extremity surgery under popliteal sciatic nerve block. Ultrasound-guidance was used to position the needle tip subparaneurally and to monitor the injection of the local anesthetic. Sonography and magnetic resonance imaging were used to assess the extent of the subparaneural injection. Twenty-two patients participated. The median sciatic cross-sectional area increased from 57.8 mm2 pre-block to 110.8 mm2 immediately post-block. An intraneural injection according to the current definition was seen in 21 patients. Two patients had sonographic evidence of an intrafascicular injection, which was confirmed by MRI in one patient (the other patient refused further examinations). No patient reported any neurological symptoms. A subparaneural injection in the popliteal segment of the distal sciatic nerve is actually rarely intraneural, i.e. intrafascicular. This may explain the discrepancy between the conventional sonographic evidence of an intraneural injection and the lack of neurological sequelae.

Favorable 90-Day Mortality in Obese Caucasian Patients with Septic Shock According to the Sepsis-3 Definition.

Septic shock is a frequent life-threatening condition and a leading cause of mortality in intensive care units (ICUs). Previous investigations have reported a potentially protective effect of obesity in septic shock patients. However, prior results have been inconsistent, focused on short-term in-hospital mortality and inadequately adjusted for confounders, and they have rarely applied the currently valid Sepsis-3 definition criteria for septic shock. This investigation examined the effect of obesity on 90-day mortality in patients with septic shock selected from a prospectively enrolled cohort of septic patients. A total of 352 patients who met the Sepsis-3 criteria for septic shock were enrolled in this study. Body-mass index (BMI) was used to divide the cohort into 24% obese (BMI ≥ 30 kg/m2) and 76% non-obese (BMI < 30 kg/m2) patients. Kaplan-Meier survival analysis revealed a significantly lower 90-day mortality (31% vs. 43%; p = 0.0436) in obese patients compared to non-obese patients. Additional analyses of baseline characteristics, disease severity, and microbiological findings outlined further statistically significant differences among the groups. Multivariate Cox regression analysis estimated a significant protective effect of obesity on 90-day mortality after adjustment for confounders. An understanding of the underlying physiologic mechanisms may improve therapeutic strategies and patient prognosis.