Adjusting Acute Kidney Injury Kidney Disease: Improving Global Outcomes Urine Output Criterion for Predicted Body Weight Improves Prediction of Hospital Mortality.

BACKGROUND: Based on the Kidney Disease: Improving Global Outcomes (KDIGO) definitions, urine output, serum creatinine, and need for kidney replacement therapy are used for staging acute kidney injury (AKI). Currently, AKI staging correlates strongly with mortality and can be used as a predictive tool. However, factors associated with the development of AKI may affect its predictive ability. We tested whether adjustment for predicted (versus actual) body weight improved the ability of AKI staging to predict hospital mortality. METHODS: A total of 3279 patients who had undergone cardiac surgery in a university hospital were retrospectively analyzed. AKI was staged according to KDIGO criteria (standard staging) and after adjustment for hourly urine output adjusted by predicted body weight for each patient and each day of their hospital stay. RESULTS: The incidence of AKI (all stages) was 43% (predicted body weight adjusted) and 50% (standard staging), respectively ( P < .001). In sensitivity-specificity analyses for predicting hospital mortality, the area under the curve was significantly higher after adjustment for predicted body weight than with standard staging ( P = .002). CONCLUSIONS: Compared to standard staging, adjustment of urine output for predicted body weight increases the specificity and improves prediction of hospital mortality in patients undergoing cardiac surgery.

Serum Biomarkers of a Pro-Neuroinflammatory State May Define the Pre-Operative Risk for Postoperative Delirium in Spine Surgery.

Advances in spine surgery enable technically safe interventions in older patients with disabling spine disease, yet postoperative delirium (POD) poses a serious risk for postoperative recovery. This study investigates biomarkers of pro-neuroinflammatory states that may help objectively define the pre-operative risk for POD. This study enrolled patients aged ≥60 scheduled for elective spine surgery under general anesthesia. Biomarkers for a pro-neuroinflammatory state included S100 calcium-binding protein ß (S100ß), brain-derived neurotrophic factor (BDNF), Gasdermin D, and the soluble ectodomain of the triggering receptor expressed on myeloid cells 2 (sTREM2). Postoperative changes of Interleukin-6 (IL-6), Interleukin-1ß (IL-1ß), and C-reactive protein (CRP) were assessed as markers of systemic inflammation preoperatively, intraoperatively, and early postoperatively (up to 48 h). Patients with POD (n = 19, 75.7 ± 5.8 years) had higher pre-operative levels of sTREM2 (128.2 ± 69.4 pg/mL vs. 97.2 ± 52.0 pg/mL, p = 0.049) and Gasdermin D (2.9 ± 1.6 pg/mL vs. 2.1 ± 1.4 pg/mL, p = 0.29) than those without POD (n = 25, 75.6 ± 5.1 years). STREM2 was additionally a predictor for POD (OR = 1.01/(pg/mL) [1.00-1.03], p = 0.05), moderated by IL-6 (Wald-χ2 = 4.06, p = 0.04). Patients with POD additionally showed a significant increase in IL-6, IL-1ß, and S100ß levels on the first postoperative day. This study identified higher levels of sTREM2 and Gasdermin D as potential markers of a pro-neuroinflammatory state that predisposes to the development of POD. Future studies should confirm these results in a larger cohort and determine their potential as an objective biomarker to inform delirium prevention strategies.

Duration of Surgery and Intraoperative Blood Pressure Management Are Modifiable Risk Factors for Postoperative Neurocognitive Disorders After Spine Surgery: Results of the Prospective CONFESS Study.

STUDY DESIGN: Prospective quasi-experimental observational study. OBJECTIVE: The objective of this study was to evaluate whether duration of surgery is a modifiable risk factor for postoperative delirium (POD) after spine surgery and explore further modifiable risk factors. In addition, we sought to investigate the association between POD and postoperative cognitive dysfunction and persistent neurocognitive disorders. SUMMARY OF BACKGROUND DATA: Advances in spine surgery enable technically safe interventions in elderly patients with disabling spine disease. The occurrence of POD and delayed neurocognitive complications ( e.g. postoperative cognitive dysfunction/persistent neurocognitive disorder) remain a concern since these contribute to inferior functional outcomes and long-term care dependency after spine surgery. MATERIALS AND METHODS: This prospective single-center study recruited patients aged 60 years or above and scheduled for elective spine surgery between February 2018 and March 2020. Functional (Barthel Index, BI) and cognitive outcomes [Consortium to Establish a Registry for Alzheimer's Disease (CERAD) test battery; telephone Montréal Cognitive Assessment] were assessed at baseline, three (V3), and 12 months postoperatively. The primary hypothesis was that the duration of surgery predicts POD. Multivariable predictive models of POD included surgical and anesthesiological parameters. RESULTS: Twenty-two percent of patients developed POD (n=22/99). In a multivariable model, duration of surgery [OR adj =1.61/h (95% CI, 1.20-2.30)], age [OR adj =1.22/yr (95% CI, 1.10-1.36)], and baseline deviations of intraoperative systolic blood pressure [25th percentile: OR adj =0.94/mm Hg (95% CI, 0.89-0.99); 90th percentile: OR adj =1.07/mm Hg (95% CI, 1.01-1.14)] were significantly associated with POD. Postoperative cognitive scores generally improved (V3, ΔCERAD total z -score: 0.22±0.63). However, this positive group effect was counteracted by POD [beta: -0.87 (95% CI, -1.31 to 0.42)], older age [beta: -0.03/yr (95% CI, -0.05 to 0.01)], and lack of functional improvement [ΔBI; beta: -0.04/point (95% CI, -0.06 to 0.02)]. Cognitive scores at twelve months remained inferior in the POD group, adjusted for baseline cognition/age. CONCLUSIONS: This study identified distinct neurocognitive effects after spine surgery, which are influenced by perioperative risk factors. Potential cognitive benefits are counteracted by POD, rendering its prevention critical in an aging population.

Cost-Effectiveness of Propofol (Diprivan) Versus Inhalational Anesthetics to Maintain General Anesthesia in Noncardiac Surgery in the United States.

OBJECTIVES: It is not known whether using propofol total intravenous anaesthesia (TIVA) to reduce incidence of postoperative nausea and vomiting (PONV) is cost-effective. We assessed the economic impact of propofol TIVA versus inhalational anesthesia in adult patients for ambulatory and inpatient procedures relevant to the US healthcare system. METHODS: Two models simulate individual patient pathways through inpatient and ambulatory surgery with propofol TIVA or inhalational anesthesia with economic inputs from studies on adult surgical US patients. Efficacy inputs were obtained from a meta-analysis of randomized controlled trials. Probabilistic and deterministic sensitivity analyses assessed the robustness of the model estimates. RESULTS: Lower PONV rate, shorter stay in the post-anesthesia care unit, and reduced need for rescue antiemetics offset the higher costs for anesthetics, analgesics, and muscle relaxants with propofol TIVA and reduced cost by 11.41 ± 10.73 USD per patient in the inpatient model and 11.25 ± 9.81 USD in the ambulatory patient model. Sensitivity analyses demonstrated strong robustness of the results. CONCLUSIONS: Maintenance of general anesthesia with propofol was cost-saving compared to inhalational anesthesia in both inpatient and ambulatory surgical settings in the United States. These economic results support current guideline recommendations, which endorse propofol TIVA to reduce PONV risk and enhance postoperative recovery.

Incidence, characteristics and risk factors for perioperative cardiac arrest and 30-day-mortality in preterm infants requiring non-cardiac surgery.

STUDY OBJECTIVE: To determine 30-day-mortality, incidence and characteristics of perioperative cardiac arrest as well as the respective independent risk factors in preterm infants undergoing non-cardiac surgery. DESIGN: Retrospective observational Follow-up-study. SETTING: Bielefeld University Hospital, a German tertiary care hospital. PATIENTS: Population of 229 preterm infants (age < 37th gestational week at the time of surgery) who underwent non-cardiac surgery between 01/2008-12/2018. MEASUREMENTS: Primary endpoint was overall 30-day-mortality. Secondary endpoints were the incidence of perioperative cardiac arrest and identification of independent risk factors. We performed univariate and multivariate analyses and calculated odds ratios (OR) for risk factors associated with these endpoints. MAIN RESULTS: 30-day-mortality was 10.9% and perioperative mortality 0.9%. Univariate risk factors for 30-day-mortality were perioperative cardiac arrest (OR,12.5;95%CI,3.1 to 50.3), comorbidities of lungs (OR,3.7;95%CI,1.2 to 11.3) and gastrointestinal tract (OR,3.5;95%CI,1.3 to 9.6); sepsis (OR,3.6;95%CI,1.4 to 9.5); surgery between 22:01-7:00 (OR,7.3;95%CI,2.4 to 21.7); emergency (OR,4.5;95%CI,1.6 to 12.4); pre-existing catecholamine therapy (OR,5.0;95%CI,2.1 to 11.9). Multivariate logistic regression indicated that perioperative cardiac arrest (OR,13.9;95%CI,2.7 to 71.3), low body weight (weight < 1000 g: OR,26.0;95%CI,3.2 to 212; 1000-1499 g: OR,10.3; 95%CI,1.1 to 94.9 compared to weight > 2000 g), and time of surgery (OR,5.9;95%CI,1.6 to 21.3) for 22:01-7:00 compared to 7:01-15:00) were the major independent risk factors of mortality. Incidence of perioperative cardiac arrests was 3.9% (9 of 229;95%CI,1.8 to 7.3). Univariate risk factors were congenital anomalies of the airways (OR,4.7;95%CI,1.2 to 20.3), lungs (OR,4.7;95%CI,1.2 to 20.3) and heart (OR,8.0;95%CI,2 to 32.2), pre-existing catecholamine therapy (OR,59.5;95%CI,3.4 to 1039), specifically, continuous infusions of epinephrine (OR,432;95%CI,43.2 to 4318). CONCLUSIONS: 30-day-mortality and the incidence of perioperative cardiac arrest of preterms undergoing non-cardiac surgery were higher than previously reported. The identified independent risk factors may improve interdisciplinary perioperative risk assessment, optimal preoperative stabilization and scheduling of optimal surgical timing.

[Aortoesophageal fistula-A rare differential diagnosis of upper gastrointestinal bleeding]. / Die aortoösophageale Fistel ­ Eine seltene Differenzialdiagnose der oberen Gastrointestinalblutung.

Approximately 1% of all patients are admitted to an emergency room for upper gastrointestinal hemorrhage. Differential diagnostics reveal an aortoesophageal fistula (AEF) as the cause of the bleeding in very few cases. Despite increasing means of diagnostics and treatment, mortality is high in patients with AEF even under maximum medical care. These are often fulminant situations with fatal outcome for the patient. We report a case that supports this observation described from previous cases and give a closer look at this rare emergency situation. A 54-year-old patient was taken to a maximum care hospital with the clinical diagnosis of upper gastrointestinal bleeding after receiving emergency medical treatment. The source of bleeding was quickly identified as an AEF following lobectomy for bronchial cancer. Despite maximum interventional intensive treatment, the patient died a few hours after hospital admission in hemorrhagic shock due to fulminant hemorrhage from the fistula.

Impact of ASA-score, age and learning curve on early outcome in the initiation phase of an oncological robotic colorectal program.

The ASA score is known to be an independent predictor of complications and mortality following colorectal surgery. We evaluated early outcome in the initiation phase of a robotic oncological colorectal resection program in dependence of comorbidity and learning curve. 43 consecutive colorectal cancer patients (median age: 74 years) who underwent robotic surgery were firstly analysed defined by physical status (group A = ASA1 + 2; group B = ASA3). Secondly, outcome was evaluated relating to surgery date (group E: early phase; group L: late phase). There were no differences among groups A and B with regard to gender, BMI, skin-to-skin operative times (STS), N- and M-status, hospital-stay as well as overall rate of complications according to Dindo-Clavien and no one-year mortality. GroupA when compared to group B demonstrated significantly lower mean age (65.5 years ± 11.4 years vs 75.8 years ± 8.9 years), T-stage and ICU-stay. When separately analyzed for patients age ICU-stay was comparable (> 75 years vs. < 75 years). Group E and L demonstrated comparable characteristics and early outcome except more frequent lymphatic fistulas in group E. STS was reduced in group L compared to group E. Beyond learning curve aspects in our series, we could demonstrate that patient's physical condition according to ASA rather than age may have an impact on early outcome in the initial phase of a robotic oncological colorectal program.

Correction: Evaluating Mechanisms of Postoperative Delirium and Cognitive Dysfunction Following Elective Spine Surgery in Elderly Patients (CONFESS): Protocol for a Prospective Observational Trial.

[This corrects the article DOI: 10.2196/15488.].

Evaluating Mechanisms of Postoperative Delirium and Cognitive Dysfunction Following Elective Spine Surgery in Elderly Patients (CONFESS): Protocol for a Prospective Observational Trial.

BACKGROUND: Elderly people are at particular high risk for postoperative delirium (POD) following spine surgery, which is associated with longer hospital stays, higher costs, risk for delayed complications, long-term care dependency, and cognitive dysfunction (POCD). It is insufficiently understood which mechanisms and risk factors contribute to the development of POD and POCD following these major but plannable surgeries. OBJECTIVE: This study aims to identify modifiable risk factors in spine surgery. A better understanding thereof would help adapt medical management and surgical strategies to individual risk profiles. METHODS: This is a single-center observational study jointly conducted by the departments of neurosurgery, neurology, and anesthesiology at a tertiary care hospital in Germany. All patients aged 60 years and older presenting to the neurosurgery outpatient clinic or ward for elective spine surgery are screened for eligibility. Exclusion criteria include presence of neurodegenerative or history of psychiatric disease and medication with significant central nervous system activity (eg, antidepressants, antipsychotics, sedatives). Surgical and anesthetic procedures including duration of surgery as primary end point of this study are thoroughly documented. All patients are furthermore evaluated for their preoperative cognitive abilities by a number of tests, including the Consortium to Establish a Registry for Alzheimer's Disease Plus test battery. Physical, mental, and social health and well-being are assessed using the Patient-Reported Outcome Measurement Information System Profile 29 and Hospital Anxiety and Depression Scale. Patients additionally receive preoperative cerebrovascular ultrasound and structural and functional brain imaging. The immediate postoperative period includes screening for POD using the Nursing Delirium Screening Scale and validation through Diagnostic and Statistical Manual of Mental Disorders, 5th Edition, criteria. We furthermore investigate markers of (neuro)inflammation (eg, interleukins, C-reactive protein, tumor necrosis factor alpha). Preoperative examinations are repeated 3 months postoperatively to investigate the presence of POCD and its mechanisms. Statistical analyses will compare delirious and nondelirious patients for predictors of immediate (POD) and delayed (POCD) cognitive dysfunction. RESULTS: This is the first study to prospectively evaluate risk factors for POD and POCD in spine surgery. Recruitment is ongoing, and data collection is estimated to be finished with the inclusion of 200 patients by mid-2020. CONCLUSIONS: The identification of mechanisms, possibly common, underlying POD and POCD would be a major step toward defining effective interventional strategies early in or even before the postoperative period, including the adaptation of surgical strategies to individual risk profiles. TRIAL REGISTRATION: ClinicalTrials.gov NCT03486288; https://clinicaltrials.gov/ct2/show/NCT03486288. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/15488.

Differential Effects of Selective and Nonselective Potassium Channel Inhibitors in Ovine Endotoxemic Shock (Macrocirculation) and in a Rat Model of Septic Shock (Microcirculation).

BACKGROUND: Potassium-(K)-channel inhibitors may increase systemic vascular resistance in vasodilatory shock states. OBJECTIVE: The purpose of the present study was to compare the macro- and microvascular effects of the adenosine triphosphate-sensitive K-channel-(KATP)-inhibitor glipizide and the nonselective K-channel inhibitor tetraethylammonium (TEA) in ovine endotoxemic shock and septic shock in rats. DESIGN: Two randomized, controlled laboratory studies. ANIMALS: Thirty female sheep and 40 male Sprague Dawley rats. SETTING: Animal research facility INTERVENTION:: Systemic hemodynamics were analyzed in ovine endotoxemic shock with guideline-oriented supportive therapy. Sheep were allocated to three treatment groups for 12 h: glipizide 10 mg kg·h, TEA 8 mg kg·h, or 0.9% saline. The microvascular effects of each drug were evaluated in septic rats (cecal ligation and puncture model) receiving a 2-h infusion of each study drug: glipizide 20 mg kg·h; TEA 50 mg kg·h, or 0.9% saline, respectively, followed by intravital microscopy of villi microcirculation. RESULTS: Compared with the control group, glipizide infusion increased systemic vascular resistance index and decreased cardiac index and heart rate (HR) in sheep (P < 0.05), whereas TEA infusion decreased HR and resulted in a decreased survival time (P = 0.001). In rats, glipizide infusion resulted in an increase in mean arterial pressure and a decrease in HR compared with baseline measurement (P < 0.05) without relevant effects on the villi microcirculation. TEA decreased HR and decreased capillary perfusion of the villi microcirculation compared with the sham group (P = 0.002). CONCLUSIONS: Selective inhibition of KATP-channels in ovine endotoxemic shock with glipizide partially restored vasomotor tone without exerting harmful effects on intestinal microcirculation in septic shock in rats. On the contrary, nonselective K-channel inhibition with TEA showed deleterious effects in both models, including impaired microcirculation and decreased survival time. Future research on glipizide in vasodilatory shock may be warranted.

Propofol vs. inhalational agents to maintain general anaesthesia in ambulatory and in-patient surgery: a systematic review and meta-analysis.

BACKGROUND: It is unclear if anaesthesia maintenance with propofol is advantageous or beneficial over inhalational agents. This study is intended to compare the effects of propofol vs. inhalational agents in maintaining general anaesthesia on patient-relevant outcomes and patient satisfaction. METHODS: Studies were identified by electronic database searches in PubMed™, EMBASE™ and the Cochrane™ library between 01/01/1985 and 01/08/2016. Randomized controlled trials (RCTs) of peer-reviewed journals were studied. Of 6688 studies identified, 229 RCTs were included with a total of 20,991 patients. Quality control, assessment of risk of bias, meta-bias, meta-regression and certainty in evidence were performed according to Cochrane. Common estimates were derived from fixed or random-effects models depending on the presence of heterogeneity. Post-operative nausea and vomiting (PONV) was the primary outcome. Post-operative pain, emergence agitation, time to recovery, hospital length of stay, post-anaesthetic shivering and haemodynamic instability were considered key secondary outcomes. RESULTS: The risk for PONV was lower with propofol than with inhalational agents (relative risk (RR) 0.61 [0.53, 0.69], p < 0.00001). Additionally, pain score after extubation and time in the post-operative anaesthesia care unit (PACU) were reduced with propofol (mean difference (MD) - 0.51 [- 0.81, - 0.20], p = 0.001; MD - 2.91 min [- 5.47, - 0.35], p = 0.03). In turn, time to respiratory recovery and tracheal extubation were longer with propofol than with inhalational agents (MD 0.82 min [0.20, 1.45], p = 0.01; MD 0.70 min [0.03, 1.38], p = 0.04, respectively). Notably, patient satisfaction, as reported by the number of satisfied patients and scores, was higher with propofol (RR 1.06 [1.01, 1.10], p = 0.02; MD 0.13 [0.00, 0.26], p = 0.05). Secondary analyses supported the primary results. CONCLUSIONS: Based on the present meta-analysis there are several advantages of anaesthesia maintenance with propofol over inhalational agents. While these benefits result in an increased patient satisfaction, the clinical and economic relevance of these findings still need to be addressed in adequately powered prospective clinical trials.

Electric Nerve Stimulation Does Not Correctly Predict Needle-Nerve Distance and Potential Local Anesthetic Spread for Interscalene Brachial Plexus Blockade.

This study evaluated electric nerve stimulation as a nerve location tool. After eliciting motor response in 43 patients undergoing shoulder surgery, the needle tip's position, distance from the closest nerve, and spread of saline were evaluated using ultrasound imaging. The needle's tip resided 1 to 4 mm from the closest nerve in 21, in direct contact with it in 7, and 6 to 18 mm away in 15 patients. In 21 patients, subsequent saline dissection did not reach the brachial plexus. Thus, the success rate of electric nerve stimulation for correct needle-nerve distance identification was 48.8%, with correct fluid spread reached in only 51.2% of patients.

Comparison of an automatic analysis and a manual analysis of conjunctival microcirculation in a sheep model of haemorrhagic shock.

BACKGROUND: Life-threatening diseases of critically ill patients are known to derange microcirculation. Automatic analysis of microcirculation would provide a bedside diagnostic tool for microcirculatory disorders and allow immediate therapeutic decisions based upon microcirculation analysis. METHODS: After induction of general anaesthesia and instrumentation for haemodynamic monitoring, haemorrhagic shock was induced in ten female sheep by stepwise blood withdrawal of 3 × 10 mL per kilogram body weight. Before and after the induction of haemorrhagic shock, haemodynamic variables, samples for blood gas analysis, and videos of conjunctival microcirculation were obtained by incident dark field illumination microscopy. Microcirculatory videos were analysed (1) manually with AVA software version 3.2 by an experienced user and (2) automatically by AVA software version 4.2 for total vessel density (TVD), perfused vessel density (PVD) and proportion of perfused vessels (PPV). Correlation between the two analysis methods was examined by intraclass correlation coefficient and Bland-Altman analysis. RESULTS: The induction of haemorrhagic shock decreased the mean arterial pressure (from 87 ± 11 to 40 ± 7 mmHg; p < 0.001); stroke volume index (from 38 ± 14 to 20 ± 5 ml·m-2; p = 0.001) and cardiac index (from 2.9 ± 0.9 to 1.8 ± 0.5 L·min-1·m-2; p < 0.001) and increased the heart rate (from 72 ± 9 to 87 ± 11 bpm; p < 0.001) and lactate concentration (from 0.9 ± 0.3 to 2.0 ± 0.6 mmol·L-1; p = 0.001). Manual analysis showed no change in TVD (17.8 ± 4.2 to 17.8 ± 3.8 mm*mm-2; p = 0.993), whereas PVD (from 15.6 ± 4.6 to 11.5 ± 6.5 mm*mm-2; p = 0.041) and PPV (from 85.9 ± 11.8 to 62.7 ± 29.6%; p = 0.017) decreased significantly. Automatic analysis was not able to identify these changes. Correlation analysis showed a poor correlation between the analysis methods and a wide spread of values in Bland-Altman analysis. CONCLUSIONS: As characteristic changes in microcirculation during ovine haemorrhagic shock were not detected by automatic analysis and correlation between automatic and manual analyses (current gold standard) was poor, the use of the investigated software for automatic analysis of microcirculation cannot be recommended in its current version at least in the investigated model. Further improvements in automatic vessel detection are needed before its routine use.

Increased bone remodelling around titanium implants coated with chondroitin sulfate in ovariectomized rats.

Coating titanium implants with artificial extracellular matrices based on collagen and chondroitin sulfate (CS) has been shown to enhance bone remodelling and de novo bone formation in vivo. The aim of this study was to evaluate the effect of estrogen deficiency and hormone replacement therapy (HRT) on the osseointegration of CS-modified Ti implants. 30 adult female, ovariectomized Wistar rats were fed either with an ethinyl-estradiol-rich diet (E) to simulate a clinical relevant HRT or with a genistein-rich diet (G) to test an alternative therapy based on nutritionally relevant phytoestrogens. Controls (C) received an estrogen-free diet. Uncoated titanium pins (Ti) or pins coated with type-I collagen and CS (Ti/CS) were inserted 8weeks after ovarectomy into the tibia. Specimens were retrieved 28days after implantation. Both the amount of newly formed bone and the affinity index (P<0.05) were moderately higher around Ti/CS implants as compared to uncoated Ti. The highest values were measured in the G-Ti/CS and E-Ti/CS groups, the lowest values for the E-Ti and G-Ti controls. Quantitative synchrotron radiation micro-computed tomography (SRµCT) revealed the highest increase in total bone formation around G-Ti/CS as compared to C-Ti (P<0.01). The effects with respect to direct bone apposition were less pronounced with SRµCT. Using scanning nanoindentation, both the indentation modulus and the hardness of the newly formed bone were highest in the E-Ti/CS, G-Ti/CS and G-Ti groups as compared to C-Ti (P<0.05). Coatings with collagen and CS appear to improve both the quantity and quality of bone formed around Ti implants in ovarectomized rats. A simultaneous ethinyl estradiol- and genistein-rich diet seems to enhance these effects.

Advantages and pitfalls of combining intravenous antithrombin with nebulized heparin and tissue plasminogen activator in acute respiratory distress syndrome.

BACKGROUND: Pulmonary coagulopathy has become an important therapeutic target in adult respiratory distress syndrome (ARDS). We hypothesized that combining intravenous recombinant human antithrombin (rhAT), nebulized heparin, and nebulized tissue plasminogen activator (TPA) more effectively improves pulmonary gas exchange compared with a single rhAT infusion, while maintaining the anti-inflammatory properties of rhAT in ARDS. Therefore, the present prospective, randomized experiment was conducted using an established ovine model. METHODS: Following burn and smoke inhalation injury (40% of total body surface area, third-degree flame burn, and 4 × 12 breaths of cold cotton smoke), 18 chronically instrumented sheep were randomly assigned to receive intravenous saline plus saline nebulization (control), intravenous rhAT (6 IU/kg/h) started 1 hour after injury plus saline nebulization (AT i.v.) or intravenous rhAT combined with nebulized heparin (10,000 IU every 4 hours, started 2 hours after injury), and nebulized TPA (2 mg every 4 hours, started 4 hours after injury) (triple therapy, n = 6 each). All animals were mechanically ventilated and fluid resuscitated according to standard protocols during the 48-hour study period. RESULTS: Both treatment approaches attenuated ARDS compared with control animals. Notably, triple therapy was associated with an improved PaO2/FiO2 ratio (p = 0.007), attenuated pulmonary obstruction (p = 0.02) and shunting (p = 0.025), as well as reduced ventilatory pressures (p < 0.05 each) versus AT i.v. at 48 hours. However, the anti-inflammatory effects of sole AT i.v., namely, the inhibition of neutrophil activation (neutrophil count in the lymph and pulmonary polymorphonuclear cells, p < 0.05 vs. control each), pulmonary transvascular fluid flux (lymph flow, p = 0.004 vs. control), and systemic vascular leakage (cumulative net fluid balance, p < 0.001 vs. control), were abolished in the triple therapy group. CONCLUSION: Combining intravenous rhAT with nebulized heparin and nebulized TPA more effectively restores pulmonary gas exchange, but the anti-inflammatory effects of sole rhAT are abolished with the triple therapy. Interferences between the different anticoagulants may represent a potential explanation for these findings.

Renal effects of levosimendan: a consensus report.

Renal dysfunction is common in clinical settings in which cardiac function is compromised such as heart failure, cardiac surgery or sepsis, and is associated with high morbidity and mortality. Levosimendan is a calcium sensitizer and potassium channel opener used in the treatment of acute heart failure. This review describes the effects of the inodilator levosimendan on renal function. A panel of 25 scientists and clinicians from 15 European countries (Austria, Finland, France, Hungary, Germany, Greece, Italy, Portugal, the Netherlands, Slovenia, Spain, Sweden, Turkey, the United Kingdom, and Ukraine) convened and reached a consensus on the current interpretation of the renal effects of levosimendan described both in non-clinical research and in clinical study reports. Most reports on the effect of levosimendan indicate an improvement of renal function in heart failure, sepsis and cardiac surgery settings. However, caution should be applied as study designs differed from randomized, controlled studies to uncontrolled ones. Importantly, in the largest HF study (REVIVE I and II) no significant changes in the renal function were detected. As it regards the mechanism of action, the opening of mitochondrial KATP channels by levosimendan is involved through a preconditioning effect. There is a strong rationale for randomized controlled trials seeking beneficial renal effects of levosimendan. As an example, a study is shortly to commence to assess the role of levosimendan for the prevention of acute organ dysfunction in sepsis (LeoPARDS).

Antithrombin attenuates myocardial dysfunction and reverses systemic fluid accumulation following burn and smoke inhalation injury: a randomized, controlled, experimental study.

INTRODUCTION: We hypothesized that maintaining physiological plasma levels of antithrombin attenuates myocardial dysfunction and inflammation as well as vascular leakage associated with burn and smoke inhalation injury. Therefore, the present prospective, randomized experiment was conducted using an established ovine model. METHODS: Following 40% of total body surface area, third degree flame burn and 4 × 12 breaths of cold cotton smoke, chronically instrumented sheep were randomly assigned to receive an intravenous infusion of 6 IU/kg/h recombinant human antithrombin (rhAT) or normal saline (control group; n = 6 each). In addition, six sheep were designated as sham animals (not injured, continuous infusion of vehicle). During the 48 h study period the animals were awake, mechanically ventilated and fluid resuscitated according to standard formulas. RESULTS: Compared to the sham group, myocardial contractility was severely impaired in control animals, as suggested by lower stroke volume and left ventricular stroke work indexes. As a compensatory mechanism, heart rate increased, thereby increasing myocardial oxygen consumption. In parallel, myocardial inflammation was induced via nitric oxide production, neutrophil accumulation (myeloperoxidase activity) and activation of the p38-mitogen-activated protein kinase pathway resulting in cytokine release (tumor necrosis factor-alpha, interleukin-6) in control vs. sham animals. rhAT-treatment significantly attenuated these inflammatory changes leading to a myocardial contractility and myocardial oxygen consumption comparable to sham animals. In control animals, systemic fluid accumulation progressively increased over time resulting in a cumulative positive fluid balance of about 4,000 ml at the end of the study period. Contrarily, in rhAT-treated animals there was only an initial fluid accumulation until 24 h that was reversed back to the level of sham animals during the second day. CONCLUSIONS: Based on these findings, the supplementation of rhAT may represent a valuable therapeutic approach for cardiovascular dysfunction and inflammation after burn and smoke inhalation injury.

Selective V(1a) agonism attenuates vascular dysfunction and fluid accumulation in ovine severe sepsis.

Vasopressin analogs are used as a supplement to norepinephrine in septic shock. The isolated effects of vasopressin agonists on sepsis-induced vascular dysfunction, however, remain controversial. Because V(2)-receptor stimulation induces vasodilation and procoagulant effects, a higher V(1a)- versus V(2)-receptor selectivity might be advantageous. We therefore hypothesized that a sole, titrated infusion of the selective V(1a)-agonist Phe(2)-Orn(8)-Vasotocin (POV) is more effective than the mixed V(1a)-/V(2)-agonist AVP for the treatment of vascular and cardiopulmonary dysfunction in methicillin resistant staphylococcus aureus pneumonia-induced, ovine sepsis. After the onset of hemodynamic instability, awake, chronically instrumented, mechanically ventilated, and fluid resuscitated sheep were randomly assigned to receive continuous infusions of either POV, AVP, or saline solution (control; each n = 6). AVP and POV were titrated to maintain mean arterial pressure above baseline - 10 mmHg. When compared with that of control animals, AVP and POV reduced neutrophil migration (myeloperoxidase activity, alveolar neutrophils) and plasma levels of nitric oxide, resulting in higher mean arterial pressures and a reduced vascular leakage (net fluid balance, chest and abdominal fluid, pulmonary bloodless wet-to-dry-weight ratio, alveolar and septal edema). Notably, POV stabilized hemodynamics at lower doses than AVP. In addition, POV, but not AVP, reduced myocardial and pulmonary tissue concentrations of 3-nitrotyrosine, VEGF, and angiopoietin-2, thereby leading to an abolishment of cumulative fluid accumulation (POV, 9 ± 15 ml/kg vs. AVP, 110 ± 13 ml/kg vs. control, 213 ± 16 ml/kg; P < 0.001 each) and an attenuated cardiopulmonary dysfunction (left ventricular stroke work index, PaO(2)-to-FiO(2) ratio) versus control animals. Highly selective V(1a)-agonism appears to be superior to unselective vasopressin analogs for the treatment of sepsis-induced vascular dysfunction.