Influence of Intraoperative Fluid Management on Postoperative Outcome and Mortality of Cytoreductive Surgery for Advanced Ovarian Cancer-A Retrospective Observational Study.

Background: The surgical treatment of advanced ovarian cancer is associated with extensive tissue trauma, prolonged operating times and a considerable volume shift. It, therefore, represents a challenge for anaesthesiological management. Aim: The aim of this single-centre, retrospective, observational study was to investigate whether intraoperative extensive volume supply influences postoperative outcomes and long-term survival. Methods: The study included 73 patients with a mean (SD) age of 63 (13) years who underwent extensive tumour-reducing surgery for ovarian cancer between 2012 and 2015. The effect of the intraoperative fluid balance on postoperative complications, such as anastomotic insufficiency or pleural effusions, was investigated using logistic regression. Further, the influence of fluid balance, lactate and creatinine levels on 5-year survival was analysed in a Cox regression model. Associations between anaesthesia time and the intraoperative fluid balance were examined using Spearman's rank correlation coefficients. Results: The mean (SD) postoperative fluid balance in the considered patient cohort was 9.1 (3.4) litres (l) at a mean (SD) anaesthesia time of 529 (106) minutes. Cox regression did not reveal a statistically significant effect of the fluid balance, but it did reveal a statistically significant association between the lactate level 24 h following surgery and the 5-year survival (HR [95%-CI] fluid balance: 0.97 [0.85, 1.11]; HR [95%-CI] lactate: 1.79 [1.24, 2.58]). According to logistic regression, the intraoperative fluid balance was associated with an increased chance of postoperative complications in the considered patient cohort (OR [95%-CI] 1.28 [1.1, 1.54]). Conclusions: We could not detect a negative impact of an increased fluid balance on 5-year survival, but a negative impact on postoperative complications was found in our patient cohort.

[Special features of the perioperative course in patients with frailty syndrome]. / Besonderheiten im perioperativen Verlauf bei Patienten mit dem Frailty-Syndrom.

The demographic change with an increase in the number of geriatric patients presents major challenges for perioperative medicine. Frailty is a multimorbidity complex that incorporates a combination of various factors, such as physical weakness, slower walking speed and unwanted weight loss. It is of great importance that these patients receive an individually adapted perioperative care. This includes, among others, a preoperative examination for frailty, a structured prehabilitation according to the concept of better in, better out, the compliance with the guidelines on prevention and timely treatment of postoperative delirium as well as the continuous maintenance of the body's homeostasis. By means of these measures the risk of complications in this patient group can be reduced and the best possible postoperative results can be achieved.

Pain levels and patient comfort after lower limb arthroplasty comparing i.v. patient-controlled analgesia, continuous peripheral nerve block and neuraxial analgesia: a retrospective cohort analysis of clinical routine data.

BACKGROUND: Insufficient pain control after lower limb arthroplasty results in delayed recovery and increased risk for pain chronicization. The ideal kind of analgesia is still discussed controversially. We conducted a retrospective analysis of single-center routine data from a German university hospital, including patients receiving either total hip (THA) or knee arthroplasty (TKA). METHODS: All patients received general anesthesia. Patients undergoing THA received either continuous epidural ropivacaine infusion (0.133%, Epi) or patient-controlled analgesia (PCA) with the Wurzburg Pain Drip (tramadol, metamizole and droperidol, WPD) or with piritramide (Pir). After TKA, patients received either continuous femoral nerve block (ropivacaine 0.2%, PNB) or Pir. RESULTS: The analyzed cohort comprised 769 cases. Use of WPD after THA (n = 333) resulted in significantly reduced Numeric Rating Scale (NRS) values at rest, compared to Epi (n = 48) and Pir (n = 72) (.75 [IQR 1.14] vs. 1.17 [1.5], p = .02 vs. 1.47 [1.33], p < .0001) as well as maximum NRS scores (2.4 [1.7] vs. 3.29 [1.94], p < .001 vs. 3.32 [1.76], p < .0001). Positive feedback during follow-up visits was significantly increased in patients with a WPD PCA (p < .0001), while negative feedback (senso-motoric weakness/technical problems/nausea/dizziness/constipation) was particularly increased in Epi patients and lowest in those with WPD (p < .0001). After TKA, Pir (n = 131) resulted in significantly reduced NRS values at rest, compared to PNB (n = 185) (1.4 [1.4] vs. 1.6 [1.68], p = .02). Positive feedback was increased in patients with a Pir PCA in comparison with PNB (p = .04), while negative feedback was increased in PNB patients (p = .04). Overall, WPD presented with the lowest rate of any complications (8.7%), followed by Pir (20.2%), PNB (27.6%) and Epi (31.3%) (p < .001). CONCLUSIONS: In the assessed population, the use of a WPD PCA after THA offered better pain control and patient comfort in comparison with continuous epidural or piritramide-based analgesia. After TKA, the use of a Pir PCA provided superior analgesia and a lower complication rate compared to continuous PNB.

Comparison of the Newborn Infant Parasympathetic Evaluation (NIPE™) index to changes in heart rate to detect intraoperative nociceptive stimuli in healthy and critically ill children below 2 years: An observational study.

BACKGROUND: The validity of current tools for intraoperative objective assessment of nociception/antinociception balance during anesthesia in young and very young surgery children is unknown. AIM: Primary aim of the study was to test the hypothesis that the Newborn Infant Parasympathetic Evaluation (NIPE) index performs better in indicating nociception in anesthetized children below 2 years than changes in heart rate. Secondary aims were to evaluate associations between intraoperative changes in NIPE index values and postoperative pain and emergence delirium. METHODS: Fifty-one children aged <2 years who underwent surgery were included in this prospective observational study. Patients were assigned to either group 1 (healthy children, n = 31) or group 2 (critically ill, ventilated premature infants and neonates, n = 20). The NIPE index and heart rate in response to three defined nociceptive stimuli were continuously recorded. Two different scales, Kindliche Unbehagens- und Schmerzskala (KUS) and Pediatric Anesthesia Emergence Delirium (PAED) as well as a Pain Questionnaire were used to assess postoperative pain levels and emergence delirium. RESULTS: In total, 110 nociceptive events were evaluated. The analysis revealed a statistically significant association between a decrease in the NIPE index and all nociceptive stimuli, with a sensitivity of 92% and a specificity of 96%. The mean percentage decrease ranged from approx. 15%-30% and was highly statistically significant in both groups and for each of the nociceptive events except for venous puncture (p = .004). In contrast, no consistent change in heart rate was demonstrated. The KUS and PAED scale scores were significantly associated with the duration of anesthesia (p = .04), but not with intraoperative NIPE depression. CONCLUSION: The NIPE index was reliable for assessing intraoperative nociception in children aged <2 years and was more reproducible for detecting specific nociceptive stimuli during general anesthesia than heart rate. An effect on postoperative outcome is still elusive.

From bench to bar side: Evaluating the red wine storage lesion.

Vitally essential red fluids like packed cells and red wine are seriously influenced in quality when stored over prolonged periods. In the case of red cell concentrates, the resulting storage lesion has particular significance in perioperative medicine. We hypothesized that, in contrast, aging rather improves the properties of red wine in several ways. A translational approach, including (I) in vitro experiments, (II) a randomized, blinded crossover trial of acute clinical effects, and (III) a standardized red wine blind tasting was used. Three monovarietal wines (Cabernet Sauvignon, Chianti, Shiraz) in three different vintages (range 2004-2016), each 5 years different, were assessed. Assessments were performed at a German university hospital (I, II) and on a garden terrace during a mild summer evening (III). Young wines induced cell stress and damage while significantly reducing cytoprotective proteins in HepG2 hepatoma cells. Sympathetic activity and multitasking skills were altered depending on wines' ages. Hangovers tended to be aggravated by young red wine. Aged variants performed better in terms of aroma and overall quality but worse in optical appearance. We found no evidence for a red wine storage lesion. However, we plead for consensus-based guidelines for proper storage, as it is common in clinical medicine.

Perioperative Vascular Biomarker Profiling in Elective Surgery Patients Developing Postoperative Delirium: A Prospective Cohort Study.

BACKGROUND: Postoperative delirium (POD) ranks among the most common complications in surgical patients. Blood-based biomarkers might help identify the patient at risk. This study aimed to assess how serum biomarkers with specificity for vascular and endothelial function and for inflammation are altered, prior to or following surgery in patients who subsequently develop POD. METHODS: This was a study on a subcohort of consecutively recruited elective non-cardiac as well as cardiac surgery patients (age > 60 years) of the single-center PROPDESC trial at a German tertiary care hospital. Serum was sampled prior to and following surgery, and the samples were subjected to bead-based multiplex analysis of 17 serum proteins (IL-3, IL-8, IL-10, Cripto, CCL2, RAGE, Resistin, ANGPT2, TIE2, Thrombomodulin, Syndecan-1, E-Selectin, VCAM-1, ICAM-1, CXCL5, NSE, and uPAR). Development of POD was assessed during the first five days after surgery, using the Confusion Assessment Method for ICU (CAM-ICU), the CAM, the 4-'A's test (4AT), and the Delirium Observation Scale (DOS). Patients were considered positive if POD was detected at least once during the visitation period by any of the applied methods. Non-parametric testing, as well as propensity score matching were used for statistical analysis. RESULTS: A total of 118 patients were included in the final analysis; 69% underwent non-cardiac surgery, median overall patient age was 71 years, and 59% of patients were male. In the whole cohort, incidence of POD was 28%. The male gender was significantly associated with the development of POD (p = 0.0004), as well as a higher ASA status III (p = 0.04). Incidence of POD was furthermore significantly increased in cardiac surgery patients (p = 0.002). Surgery induced highly significant changes in serum levels of almost all biomarkers except uPAR. In preoperative serum samples, none of the analyzed parameters was significantly altered in subsequent POD patients. In postoperative samples, CCL2 was significantly increased by a factor of 1.75 in POD patients (p = 0.03), as compared to the no-POD cohort. Following propensity score matching, CCL2 remained the only biomarker that showed significant differences in postoperative values (p = 0.01). In cardiac surgery patients, postoperative CCL2 serum levels were more than 3.5 times higher than those following non-cardiac surgery (p < 0.0001). Moreover, after cardiac surgery, Syndecan-1 serum levels were significantly increased in POD patients, as compared to no-POD cardiac surgery patients (p = 0.04). CONCLUSIONS: In a mixed cohort of elective non-cardiac as well as cardiac surgery patients, preoperative serum biomarker profiling with specificity for vascular dysfunction and for systemic inflammation was not indicative of subsequent POD development. Surgery-induced systemic inflammation-as evidenced by the significant increase in CCL2 release-was associated with POD, particularly following cardiac surgery. In those patients, postoperative glycocalyx injury might furthermore contribute to POD development.

Gene expression in the Angiopoietin/TIE axis is altered in peripheral tissue of ovarian cancer patients: A prospective observational study.

AIMS: Clinical studies suggest altered systemic vascular biology in cancer patients. We assessed expression patterns of endothelial activation- and vascular leakage-related genes in tumor as well as in tumor-free peripheral tissues from patients with and without ovarian cancer (OC). MAIN METHODS: Patients being scheduled for laparotomy for either gynecologic benign diagnosis (n = 10) or for advanced-stage OC (n = 22) were prospectively recruited to this observational study. Serum samples were taken preoperatively, and tissue samples were taken from peripheral abdominal wall musculature, tumor-free peritoneum and the tumor itself. KEY FINDINGS: Patients in OC group received significantly more fluid per time intraoperatively (p = 0.01). IL-8 and MCP-1/CCL2, VCAM-1 (CD 106) and ICAM-1 (CD 54) as well as Thrombomodulin were significantly increased in cancer patients' serum at baseline (p = 0.03). Expression of distinct vascular leakage-related genes (Angiopoietin-1 (ANG-1), ANG-2, TIE2, VEGFR1, VEGFR2) was significantly altered in tumor tissue of OC patients (p = 0.003), while in tumor-free peritoneal tissue, ANG-2/1 expression ratio was more than doubled in OC group (p = 0.03). In peripheral musculature, particularly genes from the ANG/TIE axis were significantly changed in OC patients (p = 0.005), suggesting a distinct vascular leakage-related genotype. Gene expression changes in OC patients were significantly associated with the postoperative fluid balance (p = 0.03). SIGNIFICANCE: Altered expression of barrier dysfunction- and angiogenesis-associated genes from the ANG/TIE axis was detected not only in tumor but also in peripheral tissues of cancer patients. This may contribute to a systemic vascular leakage-related genotype.

Risk Factors for Severe Complications in Ovarian Cancer Surgery.

Backround: Due to extensive surgical intervention for macroscopic complete cytoreduction in epithelial ovarian cancer (EOC) patients, severe complications in the postoperative course are possible. PATIENTS AND METHODS: A total of 345 EOC patients who underwent cytoreductive surgery were retrospectively evaluated regarding risk factors for an unfavorable postoperative course. Possible pre-, intra- and postoperative risk factors were statistically analyzed performing multivariate ordinal logistic regression. RESULTS: A total of 345 EOC patients underwent cytoreductive surgery. There were no complications in 114 patients, mild complications in 114 patients and severe complications in 117 patients. The risk factor evaluation identified age (p=0.049), smoking (p=0.032) and duration of surgery (p<0.0001) as significant factors for severe postoperative morbidity. CONCLUSION: In EOC patients age, smoking and the duration of surgery have significant impact on the postoperative course. Only the duration of surgery can be positively influenced by a well-trained EOC team.

5-HT3 blockade does not attenuate postspinal blood pressure change in cesarean section: A case-control study.

Spinal anesthesia (SpA) for elective caesarean section (CS) is often accompanied by clinically relevant arterial hypotension. The Bezold-Jarisch reflex, causing postspinal hypotension, has been shown to be antagonized by serotonin type 3 (5-HT3) blockade. Our aim was to assess if routine prophylactic administration of the 5-HT3 antagonist ondansetron (ODS) attenuates postspinal change in maternal blood pressure.Elective CS under SpA were retrospectively analyzed. Eighty parturients having routinely received 8 mg ODS prior to SpA were compared with 80 patients having not (control group).Mean arterial blood pressure significantly decreased from baseline to the postspinal period (P < .0001) without differences in blood pressure decreases between the 2 groups. This also applied to the heart rate. Overall use of cafedrine/theodrenaline was higher in the ODS group (0.8 (0.4-1.6) mL vs 0.8 (0-1.0) mL in the control group, P = .01). APGAR values showed a presumably clinically irrelevant decrease in control group compared with the ODS group.Our results suggest that routine administration of ODS in a dosage of 8 mg does not effectively attenuate postspinal change in maternal blood pressure during CS in our setting. Given the wide variability of anesthetic techniques, only large prospective and randomized multicenter trials will ultimately serve to elucidate this issue.

Differential modulation of endothelial cell function by fresh frozen plasma.

AIMS: In vivo studies suggest a positive influence of fresh frozen plasma (FFP) on endothelial properties and vascular barrier function, leading to improved outcomes in animal sepsis models as well as in major abdominal surgery. However, those effects are incompletely described. It was our aim to evaluate in vitro effects of FFP on endothelial key functions and to identify underlying mechanisms. MATERIALS AND METHODS: Human pulmonary microvascular endothelial cells (HPMECs) were prestimulated with LPS, followed by incubation with FFP. Permeability for FITC-dextran was assessed, and intercellular gap formation was visualized. NF-κB nuclear translocation and expression of pro-inflammatory, pro-adhesion, and leakage-related genes were evaluated, and monocyte adhesion to ECs was assessed. Intracellular cAMP levels as well as phosphorylation of functional proteins were analyzed. In patients undergoing major abdominal surgery, Syndecan-1 serum levels were assessed prior to and following FFP transfusion. KEY FINDINGS: Post-incubation of HPMVECs with FFP increased intracellular cAMP levels that had been decreased by preceding LPS stimulation. On one hand, this reduced endotoxin-mediated upregulation of IL-8, ICAM-1, VCAM-1, VEGF, and ANG-2. Impaired phosphorylation of functional proteins was restored, and intercellular cohesion and barrier function were rescued. On the other hand, NF-κB nuclear translocation as well as monocyte adhesion was markedly increased by the combination of LPS and FFP. Syndecan-1 serum levels were lower in surgery patients that were transfused with FFP compared to those that were not. SIGNIFICANCE: Our data provide evidence for a differential modulation of crucial endothelial properties by FFP, potentially mediated by elevation of intracellular cAMP levels.

Dynamic changes of angiopoietins and endothelial nitric oxide supply during fluid resuscitation for major gyn-oncological surgery: a prospective observation.

BACKGROUND: Despite goal-directed hemodynamic therapy, vascular function may deteriorate during surgery for advanced abdominal tumor masses. Fluid administration has been shown to be associated with distinct changes in serum levels of functional proteins. We sought to determine how serum total protein and angiopoietin (ANG) levels change during major abdominal tumor surgery. In addition, ex vivo endothelial nitric oxide synthase (eNOS) activation as well as NO bioavailability in vivo were assessed. METHODS: 30 patients scheduled for laparotomy for late-stage ovarian or uterine cancer were prospectively included. Advanced hemodynamic monitoring as well as protocol-driven goal-directed fluid optimization were performed. Total serum protein, ANG-1, -2, and soluble TIE2 were determined pre-, intra-, and postoperatively. Phosphorylation of eNOS was assessed in microvascular endothelial cells after incubation with patient serum, and microvascular reactivity was determined in vivo by near-infrared spectroscopy and arterial vascular occlusion. RESULTS: Cardiac output as well as preload gradually decreased during surgery and were associated with a median total fluid intake of 12.8 (9.7-15.4) mL/kg*h and a postoperative fluid balance of 6710 (4113-9271) mL. Total serum protein decreased significantly from baseline (66.5 (56.4-73.3) mg/mL) by almost half intraoperatively (42.7 (36.8-51.5) mg/mL, p < 0.0001) and remained at low level. While ANG-1 showed no significant dilutional change (baseline: 12.7 (11.9-13.9) ng/mL, postop.: 11.6 (10.8 -13.5) ng/mL, p = 0.06), serum levels of ANG-2 were even increased postoperatively (baseline: 2.2 (1.6-2.6) ng/mL vs. postop.: 3.4 (2.3-3.8) ng/mL, p < 0.0001), resulting in a significant shift in ANG-2 to ANG-1 ratio. Ex vivo phosphorylation of eNOS was decreased depending on increased ANG-2 levels and ANG-2/1 ratio (Spearman r = - 0.37, p = 0.007). In vivo, increased ANG-2 levels were associated with impaired capillary recruitment and NO bioavailability (Spearman r = - 0.83, p = 0.01). CONCLUSIONS: Fluid resuscitation-associated changes in serum vascular mediator profile during abdominal tumor surgery were accompanied by impaired eNOS activity ex vivo as well as reduced NO bioavailability in vivo. Our results may explain disturbed microvascular function in major surgery despite goal-directed hemodynamic optimization.

Supraglottic devices for airway management in awake craniotomy.

Awake craniotomy is a unique technique utilized for mapping neuro and motor function during neurosurgical procedures close to eloquent brain tissue. Since active communication is required only during surgical manipulation of eloquent brain tissue and the patient is "sedated" during other parts of the procedure, different methods for anesthesia management have been explored. Furthermore, airway management ranges from spontaneous breathing to oro or nasotracheal intubation. Case reports have described the use of laryngeal masks (LMs) previously; however, its safety compared to tracheal intubation has not been assessed.We conducted a retrospective analysis of 30 patients that underwent awake craniotomy for tumor surgery to compare the feasibility and safety of different airway management strategies. Nasal fiberoptic intubation (FOI) was performed in 21 patients while 9 patients received LM for airway management. Ventilation, critical events, and perioperative complications were evaluated.Cannot intubate situation occurred in 4 cases reinserting the tube after awake phase, while no difficulties were described reinserting the LM (P < .0001). Furthermore, duration of mechanical ventilation after tumor removal was significantly lower in the LM group compared to FOI group (62 ±â€Š24 vs. 339 ±â€Š82 [min] mean ±â€Šsem, P < .0001). Postoperatively, 2 patients in each group were diagnosed with and treated for respiratory complications including pneumonia, without statistical significance between groups.In summary, LM is a feasible airway management method for patients undergoing awake craniotomy, resulting in reduced ventilation duration compared to FOI procedure.

Network of Mediators for Vascular Inflammation and Leakage Is Dysbalanced during Cytoreductive Surgery for Late-Stage Ovarian Cancer.

BACKGROUND: Cytoreductive surgery (CS) in late-stage ovarian cancer patients is often challenging due to extensive volume shifts, and high fluid intake may provoke postoperative complications. Expression of vasoactive mediators is altered in cancer patients, which may affect systemic vascular function. We sought to assess how serum levels of vasoactive markers and mediators change during CS in ovarian cancer. METHODS: Following IRB approval and informed consent, pre- and postoperative serum samples were analyzed in 26 late-stage ovarian cancer patients using multiplex protein arrays and ELISA. RESULTS: The proinflammatory cytokines and chemokines IL-6, IL-8, and CCL2 were significantly elevated after 24 hrs compared to the baseline values, with IL-6 and IL-8 being most prominently increased. While ANGPT1 remained unchanged after surgery, its competitive antagonist ANGPT2 was significantly increased. In contrast, serum levels of the ANGPT receptor TIE2 were decreased to 0.6 of the baseline values. While VEGF-D, E-selectin, P-selectin, ICAM-1, and PECAM-1 remained unchanged, serum activity of both thrombomodulin and syndecan-1 was significantly increased following surgery. CONCLUSION: We identified a regulatory network of acute-phase reaction during CS in late-stage ovarian cancer. This suggests that IL-6 exerts positive regulation of other proinflammatory mediators and, by upregulating ANGPT2 and suppressing ANGPT1, induces a serum profile that promotes vascular leakage. This may contribute to the observed hemodynamic alterations during CS procedures.

Sub-cytotoxic doses of pharmaceutical silica nanoparticles show significant impact on the proteome of HepG2 cells.

The ever-growing application of nanoparticles (NPs) in medical and pharmaceutical domains has brought issues related to their toxicity into focus. However, a profound analysis of non-acute, sub-lethal effects of engineered pharmaceutical NPs is often disregarded during such toxicological investigations. Here, two selected NPs were investigated in cultured HepG2 cells in terms of their intracellular localization and the associated impact on pharmacokinetically relevant CYP3A4 isoform, as well as the induced changes observed in the proteome of such cells. Using SILAC (Stable Isotope Labeling by Amino acids in Cell culture)-based mass spectrometry facilitated quantitative proteomics, significant proteomic changes in NP-treated hepatocytes were detected, which were subsequently analyzed via bioinformatic tools. Both, silica NPs (SiO2 NP) and cargo-free PEGylated stealth liposomes resulted in the induction of CYP3A4-activity up to 150% in a dose-dependent manner, with different time-dependent response-patterns as a function of NP-type after a single treatment. Proteomic analysis revealed that the observed metabolic alterations are only one aspect of the cellular response to NP-exposure. SiO2NPs (free in cytoplasm) caused extensive changes in the proteome, whereas liposomes (compartmentalized) seemed unproblematic as they accounted for minimal changes in the protein profile. Based on the obtained results, proteomic analyses were revealed to be highly important for the toxicological assessment of NPs. Although sub-toxic concentrations of many NPs are considered as uncritical based on standard toxicological assays, proteomic analysis indicated that drug-free NPs could cause fundamental cellular modifications, which were attributed to different causal networks and regulatory pathways.

Synthetic CpG oligonucleotides induce a genetic profile ameliorating murine myocardial I/R injury.

We previously demonstrated that pre-conditioning with CpG oligonucleotide (ODN) 1668 induces quick up-regulation of gene expression 3 hours post-murine myocardial ischaemia/reperfusion (I/R) injury, terminating inflammatory processes that sustain I/R injury. Now, performing comprehensive microarray and biocomputational analyses, we sought to further enlighten the "black box" beyond these first 3 hours. C57BL/6 mice were pretreated with either CpG 1668 or with control ODN 1612, respectively. Sixteen hours later, myocardial ischaemia was induced for 1 hour in a closed-chest model, followed by reperfusion for 24 hours. RNA was extracted from hearts, and labelled cDNA was hybridized to gene microarrays. Data analysis was performed with BRB ArrayTools and Ingenuity Pathway Analysis. Functional groups mediating restoration of cellular integrity were among the top up-regulated categories. Genes known to influence cardiomyocyte survival were strongly induced 24 hours post-I/R. In contrast, proinflammatory pathways were down-regulated. Interleukin-10, an upstream regulator, suppressed specifically selected proinflammatory target genes at 24 hours compared to 3 hours post-I/R. The IL1 complex is supposed to be one regulator of a network increasing cardiovascular angiogenesis. The up-regulation of numerous protective pathways and the suppression of proinflammatory activity are supposed to be the genetic correlate of the cardioprotective effects of CpG 1668 pre-conditioning.

Vendor effects on murine gut microbiota influence experimental abdominal sepsis.

BACKGROUND: Experimental animal models are indispensable components of preclinical sepsis research. Reproducible results highly rely on defined and invariant baseline conditions. Our hypothesis was that the murine gut microbiota varies among different distributors of laboratory animals and that these variations influence the phenotype of abdominal sepsis derived from a bacterial inoculum model (intraperitoneal stool injection). MATERIALS AND METHODS: Male C57BL/6 mice (8-wk old) purchased from Charles River (CR), Janvier (J), and Harlan (H) were sacrificed, and the bacterial composition of feces was analyzed using CHROMagar orientation medium. Stool was injected intraperitoneally into CR mice, followed by clinical observation and gene expression analysis. Experiments were repeated 16 mo later under the same conditions. RESULTS: Stool analysis revealed profound intervendor differences in bacterial composition, mainly regarding Staphylococcus aureus and Bacillus licheniformis. Mice challenged with CR as well as H feces developed significantly higher severity of disease and died within the observation period, whereas stool from J mice did not induce any of these symptoms. Real-time polymerase chain reaction revealed corresponding results with significant upregulation of proinflammatory cytokines and vascular leakage-related mediators in CR and H injected animals. Sixteen months later, the bacterial fecal composition had significantly shifted. The differences in clinical phenotype of sepsis after intraperitoneal stool injection had vanished. CONCLUSIONS: We are the first to demonstrate vendor and time effects on the murine fecal microbiota influencing sepsis models of intraabdominal stool contamination. The intestinal microbiota must be defined and standardized when designing and interpreting past and future studies using murine abdominal sepsis models.

Pulmonary vascular inflammation: effect of TLR signalling on angiopoietin/TIE regulation.

Increased pulmonary vascular resistance is a critical complication in sepsis. Toll-like receptor (TLR) as well as angiopoietin (ANG) signalling both contribute to the emergence of pulmonary arterial hypertension. We hypothesized that TLR stimulation by bacterial ligands directly affects expression and secretion of ligands and receptors of the angiopoietin/TIE axis. Microvascular endothelial (HPMEC) and smooth muscle cells (SMC) of pulmonary origin were incubated with thrombin and with ligands for TLR2, -4, -5, and -9. Expression and secretion of ANG1, -2, TIE2 and IL-8 were determined using quantitative real-time PCR and ELISA. TLR stimulation had no impact either on the expression of ANG2 and TIE2 in HPMEC or on that of ANG1 in SMC. However, overall levels of both released ANG1 and -2 were halved upon stimulation with the TLR9 ligand CpG, and ANG2 release was significantly enhanced by TLR4 activation when initially provoked by sequentially performed stimulation. Furthermore, enhanced ANG2 activity increased endothelial permeability, as demonstrated in an in vitro transwell assay. We conclude that sole TLR stimulation by bacterial ligands plays no significant role for altered expression and secretion of ANG1, -2 and TIE2 in human pulmonary vascular cells. The interplay between various stimuli is required to induce imbalances between ANG1 and -2.

Common carotid artery diameter responds to intravenous volume expansion: an ultrasound observation.

BACKGROUND: In case of intravascular fluid depletion, large veins react to volume expansion with dilation. Little is known about the reaction of arterial vessels. We herein report on the effect of a standardized fluid bolus on the diameter of the common carotid artery (CCA) and its association with hemodynamic parameters, assessed in 20 mechanically ventilated patients after cardiac surgery. CCA was visualized using ultrasound, and the percentage increase in diastolic diameter was calculated by measuring before and after administration of crystalloid infusion solution. Invasive arterial blood pressure and pulse pressure variation (PPV) were assessed in parallel. RESULTS: Median diastolic CCA diameter was 6.2 (Q1-Q3: 5.4-7.1) mm, and it significantly increased to 6.7 (5.8-7.3) mm upon fluid administration [5.0 (1.9-10.5) % increase]. Mean arterial blood (MAP) pressure likewise increased from 68 (70-73) to 85 (71-100) mmHg, whereas PPV was significantly reduced from 17.6 (16.8-23.9) to 13.2 (6.7-18.1) %. There was a significant association between the change in CCA diameter and the hemodynamic response (delta-MAP: r = 0.53, delta-PPV: r = 0.56; p < 0.05). Furthermore, carotid diameter measured before volume expansion significantly correlated with the delta-PPV upon fluid administration (r = -0.5; p = 0.02). CONCLUSIONS: Diameter of the CCA increases in response to intravascular volume expansion. Additional studies on the interplay between carotid geometry and intravascular fluid status are necessary.

The Use of Internal Jugular Vein Ultrasonography to Anticipate Low or High Central Venous Pressure During Mechanical Ventilation.

BACKGROUND: Critically low or high central venous pressure (CVP) values, together with systemic hypotension, can indicate hypovolemia or acute heart failure. However, measuring CVP requires the insertion of a central venous catheter, a time-consuming procedure that can be associated with severe complications. OBJECTIVE: We sought to evaluate the use of ultrasonography of the internal jugular vein (IJV) to estimate low or high CVP values in patients who were on ventilation. METHODS: Ultrasonography of IJV dimensions and the collection of hemodynamic data was performed in 47 patients, and the ratio between IJV diameter in the 30° and 0° position was calculated (ratio(30/0)). The predictive value of ratio(30/0) for estimating low and high CVP levels was analyzed using receiver operating characteristic curves. RESULTS: The median IJV diameter ratio(30/0) was 0.49. CVP ranged from 1 to 13 mm Hg (median 7 mm Hg). Seventeen patients had a CVP ≤ 5 mm Hg or lower (defined as "low"), and in 11 patients, values of ≥ 10 mm Hg were measured (defined as "high"). The corresponding IJV diameter ratios increased significantly from 0.34 (in the low CVP group) to 0.9 (in the high CVP group). Receiver operating characteristic analysis revealed a good predictive value of the ratio(30/0) for the prediction of low or high CVP values, respectively. A ratio(30/0) of < 0.45 optimally indicated a low CVP, while > 0.65 was the cutoff value to detect a CVP ≥ 10 mm Hg. CONCLUSION: The estimation of low or high CVP values by IJV ultrasonography in different patient positions can be a helpful instrument for the rapid hemodynamic assessment of the critically ill patient.