[Effect of anesthesia on tumor recurrence.] / A mutéti érzéstelenítés hatása a daganatkiújulásra.

Cancers cause nearly a quarter of all deaths in Hungary. The long-term success of tumor resection operations, i.e., the absence of recurrence and metastasis as well as survival, are also influenced by anesthetic methods. This was confirmed by experiments on cell cultures and animal models. Propofol and local anesthetics have been shown to reduce tumor cell viability and metastatic potential compared to inhalation anesthetics and opioids. However, studies conducted on patient groups only confirmed the advantage of propofol compared to inhalation anesthetics. Unfortunately, the epidural, additional use of local anesthetics for general anesthesia did not reduce the recurrence-free and survival time of the patients. Further clinical studies are necessary to reveal the actual effect of surgical anesthesia in each type of cancer in the future. Orv Hetil. 2023; 164(22): 843-846.

Can we predict critical care mortality with non-conventional inflammatory markers in SARS-CoV-2 infected patients?

BACKGROUND: Severe COVID-19 disease is associated with multiple organ involvement,then failure and often fatal outcomes.In addition,inflammatory mechanisms and cytokine storms,documented in many COVID-19 patients,are responsible for the progression of the disease and high mortality rates.Inflammatory parameters,such as procalcitonin(PCT) and C-reactive protein(CRP), are widely used in clinical practice. OBJECTIVE: To evaluate the predictive power of non-conventional inflammatory markers regarding mortality risk. METHODS: In our prospective study 52 patients were followed for 5 days after admission to an intensive care unit immediately with severe SARS-CoV-2 infection.We compared leukocyte-,platelet antisedimentation rate (LAR, PAR),neutrophil lymphocyte ratio(NLR), CRP, PCT levels. RESULTS: In non-surviving(NSU) patients LAR remained largely constant from D1 to D4 with a statistically significant drop(p < 0.05) only seen on D5.The NSU group showed statistically significant(p < 0.05) elevated LAR medians on D4 and D5, compared to the SU group.NLR values were continually higher in the non-survivor group.The difference between the SU and NSU groups were statistically significant on every examined day.PAR, CRP and PCT levels didn't show any significant differences between the SU and NSU groups. CONCLUSIONS: In conclusion, this study suggests that LAR and NLR are especially worthy of further investigation as prognostic markers.LAR might be of particular relevance as it is not routinely obtained in current clinical practice.It would seem beneficial to include LAR in data sets to train prognostic artificial intelligence.

"Growth-Promoting Effect" of Antibiotic Use Could Explain the Global Obesity Pandemic: A European Survey.

Clinical observations indicated a higher rate of obesity among children who received antibiotics at early ages. Experimental studies supported the role of the modified gut microbiome in the development of obesity as well. For identifying antibiotic classes that might promote or inhibit obesity-related dysbiosis, a database of the average yearly antibiotic consumption (2008-2018) has been developed using the European Center for Disease Prevention and Control (ECDC) yearly reports of antibiotic consumption in the community for the major antibiotic classes in 30 European countries, which were compared to the childhood and adult obesity prevalence featured in the Obesity Atlas. Pearson's chi-square test was applied to estimate positive/negative correlations between antibiotic consumption and obesity. One-way ANOVA has been applied to test the differences in antibiotic consumption between groups, and logistic regression analysis was performed to determine the odds ratios (OR) of antibiotic consumption for obesity. Strong, positive associations were estimated between childhood obesity and the total consumption of systemic antibiotics, broad-spectrum, beta-lactamase-resistant penicillin, cephalosporin, and quinolone, and a negative correlation was found with the consumption of tetracycline, broad-spectrum, beta-lactamase-sensitive penicillin, and narrow-spectrum, beta-lactamase-sensitive penicillin. Our observation indicated that the "growth-promoting effect" of the consumption of certain antibiotic classes might be identified as a possible etiology in the development of obesity and might be the explanation for the obesity "pandemic".

Antibiotic Consumption Patterns in European Countries Are Associated with the Prevalence of Parkinson's Disease; the Possible Augmenting Role of the Narrow-Spectrum Penicillin.

Parkinson's disease: Parkinson's disease (PD) is the second-most common neurodegenerative disease, affecting at least 0.3% of the worldwide population and over 3% of those over 80 years old. According to recent research (2018), in 2016, 6.1 million (95% uncertainty interval (UI) 5.0-7.3) individuals had Parkinson's disease globally, compared with 2.5 million (2.0-3.0) in 1990. The pandemic-like spreading of PD is considered a slow-moving disaster. Most recent studies indicated the possible role of an altered microbiome, dysbiosis, in the development of PD, which occurs long before the clinical diagnosis of PD. Antibiotics are considered as major disruptors of the intestinal flora and we have hypothesized that, as different classes of antibiotics might induce different dysbiosis, certain classes of antibiotics could trigger the PD-related dysbiosis as well. Comparative analyses were performed between the average yearly antibiotic consumption of 30 European countries (1997-2016) and the PD prevalence database (estimated for 2016). We divided the time frame of antibiotic consumption of 1997-2016 into four subsections to estimate the possible time lapse between antibiotic exposure and the prevalence, prevalence change, and PD-related death rates estimated for 2016. Our results indicated that countries with high consumption of narrow-spectrum penicillin experienced a higher increase in PD prevalence than the others. Countries reporting a decline in PD from 1990 to 2016 demonstrated a reduction in the consumption of narrow-spectrum penicillin in this period.

Antibiotic Consumption Patterns in European Countries Might Be Associated with the Prevalence of Type 1 and 2 Diabetes.

Several publications have raised the issue that the development of diabetes precedes the alteration of the microbiome (dysbiosis) and the role of environmental factors. Antibiotic use induces dysbiosis, and we wanted to estimate the associations between the consumption of antibiotics and the prevalence of diabetes (both types 1 and 2; T1D and T2D, respectively) in European countries. If such an association exists, the dominant use antibiotic classes might be reflected in the prevalence rates of T1D and T2D in different countries. Comparisons were performed between the prevalence of diabetes estimated for 2019 and featured in the Diabetes Atlas and the average yearly consumption of antibiotic classes between 2010 and 2109, calculated from the European Centre for Disease Prevention and Control (ECDC) yearly reports on antibiotic consumption in Europe. Pearson's correlation and variance analyses were used to estimate the possible relationship. Strong positive (enhancer) associations were found between the prevalence of T1D and the consumption of tetracycline (J01A: p = 0.001) and the narrow-spectrum penicillin (J01CE: p = 0.006; CF: p = 0.018). A strong negative (inhibitor) association was observed with broad-spectrum, beta-lactamase-resistant penicillin (J01CR: p = 0.003), macrolide (J01F: p = 0.008), and quinolone (J01M: p = 0.001). T2D showed significant positive associations with cephalosporin (J01D: p = 0.048) and quinolone (J01M: p = 0.025), and a non-significant negative association was detected with broad-spectrum, beta-lactamase-sensitive penicillin (J01CA: p = 0.067). Countries showing the highest prevalence rates of diabetes (top 10) showed concordance with the higher consumption of "enhancer" and the lower consumption of "inhibitor" antibiotics (top 10), as indicated by variance analysis. Countries with high prevalence rates of T1D showed high consumption of tetracycline (p = 0.015) and narrow-spectrum, beta-lactamase sensitive penicillin (p = 0.008) and low consumption of "inhibitor" antibiotics [broad-spectrum, beta-lactamase-resistant, combination penicillin (p = 0.005); cephalosporin (p = 0.036); and quinolone (p = 0.003)]. Countries with high prevalence rates of T2D consumed more cephalosporin (p = 0.084) and quinolone (p = 0.054) and less broad-spectrum, beta-lactamase-sensitive penicillin (p = 0.012) than did other countries. The development of diabetes-related dysbiosis might be related to the higher consumption of specific classes of antibiotics, showing positive (enhancer) associations with the prevalence of diabetes, and the low consumption of other classes of antibiotics, those showing negative (inhibitory) associations. These groups of antibiotics are different in T1D and T2D.

Alzheimer's Disease-Related Dysbiosis Might Be Triggered by Certain Classes of Antibiotics with Time-Lapse: New Insights into the Pathogenesis?

BACKGROUND: Several putative factors are identified in the literature as causative agents or risk factors for the development of Alzheimer's disease (AD). The amyloid cascade hypothesis has been the main hypothesis about the pathophysiology of AD for decades, but recent studies raised the possible role of dysbiosis in the development of AD, which prevents memory loss. OBJECTIVE: Finding possible associations between antibiotic consumption patterns and the prevalence of AD in European countries. METHODS: Antibiotic consumption (European Centre for Disease Prevention and Control, ECDC) for 1997-2007, 2008-2018, and as the whole 1997-2018 period, has been compared to the AD prevalence for 2018 expressed in percentage of the population and statistically analyzed by Pearson calculation. RESULTS: A significant positive correlation has been found between the AD prevalence (2018) and the average quinolone consumption for the years 1997-2007 (r: 0.37, p: 0.044). A similar association was not observed for the entire 22 years (1997-2018) of the average quinolone consumption, and the years 2008-2018, indicating 10-20 years of time-lapse between the antibiotic exposure and the development of AD. The ratio of broad-spectrum and narrow-spectrum antibiotics (B/N) estimated in the ECDC database for the years of 2008-2018 showed a strong positive association with AD prevalence (2018) (r: 0.406, p: 0.026) and a positive correlation tendency for the entire 22 years 1997-2018 (r: 0.344, p: 0.063), but none for the years 1997-2007 (r: 0.256, p: 0.241). CONCLUSION: Our study indicated the possible sequential role of certain classes of antibiotics in the development of dysbiosis leading to amyloid deposits of AD, which strengthen the possible role of different mediator molecules (short-chain fatty acids, lipopolysaccharides, etc.) produced by the altered microbiome in the development of AD.

Changes of pituitary adenylate cyclase activating polypeptide (PACAP) level in polytrauma patients in the early post-traumatic period.

In polytrauma patients who survive the primary insult, the imbalance between the pro- and anti-inflammatory processes seems to be responsible for life-threatening complications such as sepsis or multiple organ dysfunction syndrome. Measurement of C-reactive protein (CRP) and procalcitonin (PCT) is a standard way for differentiating between infectious (bacterial) and non-infectious inflammation. Monitoring of immune cell functions, like leukocyte anti-sedimentation rate (LAR) can also be useful to diagnose infectious complications. Pituitary adenylate cyclase activating polypeptide (PACAP) is a neuropeptide with well-known immunomodulatory and anti-inflammatory effects. The aim of our study was to determine the changes of PACAP38 levels in polytrauma patients in the early post-traumatic period in intensive care unit and analyse possible correlation of its level with conventional (CRP, PCT) and unconventional (LAR) laboratory parameters. Twenty polytrauma patients were enrolled. Blood samples were taken daily for five days. We observed significant correlation between PACAP38 and CRP levels on day 4 and 5 as well as between PACAP38 and LAR levels all of the days. This could be due to the anti-inflammatory and cytoprotective functions of PACAP38 as part of an endogenous response to the trauma induced systemic inflammatory response syndrome. These significant correlations could have clinical importance in monitoring the dynamic balance of pro- and anti-inflammatory processes in case of polytraumatic patients.

Lack of early platelet and leukocyte activation can indicate complications after major burn injury.

BACKGROUND: Major burn injury causes massive tissue destruction consequently enhanced platelet function and leukocyte-mediated inflammatory response. METHODS: In a prospective, observational study 23 consecutive patients with more than 20% body surface burn injury were followed for five days (T1-T5) after admission to a university intensive care (ICU). Platelet and leukocyte antisedimentation rate (PAR and LAR) was measured by one-hour gravity sedimentation. It detects the percentage of total platelet and leukocyte number crossed the half line of blood sample column, therefore, they can be regarded as cells of decreased specific gravity. We aimed to investigate the time course of PAR and LAR after burn injury, as the trend of platelet and the leukocyte activation in the early post-burn period. RESULTS: Daily mean PAR and LAR values continuously increased in the observation period (T1 to T5). Daily mean PAR and LAR were lower in ICU non-survivors (n = 7) compared to survivors (n = 16) between T2 and T4 (p < 0.05 and p < 0.01). PAR values of septic patients (n = 10) were lower than that of non-septic ones (n = 13, p < 0.01 at T5). CONCLUSIONS: Both PAR and LAR, as novel bedside test can predict septic complications and unfavorable outcome after major burn injury. Further studies with higher sample size are warranted.

New composite scale for evaluating peripheral nerve block quality in upper limb orthopaedics surgery.

INTRODUCTION: Developments in ultrasound guided (UG) peripheral nerve block (PNB) techniques have significant advantages for patients undergoing trauma surgery. Brachial plexus blockade (BPB) for upper extremity surgery provide superior analgesia, improve recovery and patient satisfaction. To the best of our knowledge there is no tool for evaluation of the quality of UG PNB which concerns the quality of PNB, the tolerance of the patient towards the anaesthetic approach, and postoperative analgesia as well. PATIENTS AND METHODS: Standardized UG BPB anaesthesia - was performed; interscalene-supraclavicular (ISC-SC) and axillary-supraclavicular (AX-SC) approach for upper limb surgery. A GCS like tool was developed with which the Sensory, Motor, Coping of patient and Postoperative (SMCP) pain qualities were measured. The quality of PNBs were evaluated by a quality of anaesthesia graded by anaesthesiologist (QAGA) and the SMCP scale as well, the means of midazolam and opioid consumption during surgery, vital parameters, postoperative pain intensity (VNRS) were compared between the two groups. RESULTS: Ninety three unpremedicated adult patients with ASA I-III were scheduled for unilateral upper limb surgery. Nearly the same mean volumes of local anaesthetic solution were used in the AX-SC and ISC-SC groups (28.3-31.0 ml). There were no significant difference in the quality of PNB measured by QAGA or SMCP scale between the AX-SC and the ISC-SC groups, however 75 patients were assessed as Excellent with the SMCP scale vs. 39 with the QAGA. 97.8% of the patients were in the Excellent and Good category evaluated with SMPC vs. 86% with QAGA (p < 0.001). There was no surgery abandoned due to failed PNB and no tourniquet pain was detected. There was no evidence of side effects or complications of PNB during the follow-up period. DISCUSSION: This composite tool is designed for evaluating the loss of sensory and motor function; the coping of the patient and the postoperative pain as well. Our novel SMCP evaluation tool focuses on the overall condition of the patient during surgery and in the postoperative period. This more precise outcome evaluating scale is significantly superior to the formerly used QAGA in representing the high success rate of UG PNB.

Onset times and duration of analgesic effect of various concentrations of local anesthetic solutions in standardized volume used for brachial plexus blocks.

Visualization of the nerve structures of brachial plexus allows anesthesiologists to use a lower dose of local anesthetics. The content of this low dose is not unequivocal, consequently, the pharmacokinetics of local anesthetics used by various authors are difficult to compare. In this study, the onset times and duration of the analgesic effect of local anesthetic mixture solutions used for brachial plexus blocks are investigated and the quality of anesthesia is compared. 85 unpremedicated American Society of Anesthesiologist physical status I-III, 19-83-year-old patients scheduled for upper limb trauma surgery are assigned to four groups for the axillary-supraclavicular block with lidocaine 1% and bupivacaine 0,5% 1:1 mixture (Group LB) or bupivacaine 0.33% (Group BS) or lidocaine 0,66% (Group LS) or bupivacaine 0.5% and lidocaine 1% 2:1 mixture (Group BL). 0.4 ml/kg was administered to the four groups. The onset time was significantly shorter in the lidocaine group (LS 13.0 ± 1.02) than in the other study groups (LB 16.64 ± 0.89; BS 17.21 ± 0.74; BL 16.92 ± 0.51 min ±SEM, p = 0.002). No differences were observed in the onset times between LB, BS, and BL groups (p > 0.05). Statistical differences were found in the duration of local anesthetics between LB (392.9 ± 20.4), BS (546.4 ± 14.9), LS (172.85 ± 7.8), and BL (458.7 ± 11.9 min ±SEM, p = 0.001). Lidocaine does not shorten the onset times, but significantly decreases the duration of action of bupivacaine when used in mixture solutions. Lidocaine exhibits a good quality of block in the applied dose, while other solutions have excellent quality. Bupivacaine without lidocaine has the longest duration of action to achieve the longest postoperative analgesia.

Changes of para-, meta- and ortho-tyrosine over time in burned patients.

PURPOSE: Serious burn injury leads to oxidative stress resulting in production of meta- and ortho-tyrosine, while para-tyrosine is the physiological isoform. Our aim was to investigate the metabolism of these tyrosine isoforms following major burn injury. METHODS: Fifteen patients requiring intensive care were followed for 5 consecutive days after major burn injury. Serum and urine concentrations of para-, meta-, and ortho-tyrosine were measured with high performance liquid chromatography. Fifteen healthy matching individuals were invited as control group. RESULTS: Median serum concentration of normal isoform para-tyrosine decreased in burned patients between days 2 and 5 (p < 0.01). Mean meta-, and ortho-tyrosine levels were significantly higher in patients compared to controls in the same time period (p < 0.05). Renal excretion of para-tyrosine increased significantly in our observation period (p < 0.01). CONCLUSIONS: Pathologic isoforms of tyrosine accumulate in serum meanwhile the level of normal isoform decreases possibly due to belated enhanced renal excretion or, to decreased synthesis after major burn injury.

Endoscopic sphincterotoMy for delayIng choLecystectomy in mild acute biliarY pancreatitis (EMILY study): protocol of a multicentre randomised clinical trial.

INTRODUCTION: According to the literature, early cholecystectomy is necessary to avoid complications related to gallstones after an initial episode of acute biliary pancreatitis (ABP). A randomised, controlled multicentre trial (the PONCHO trial) revealed that in the case of gallstone-induced pancreatitis, early cholecystectomy was safe in patients with mild gallstone pancreatitis and reduced the risk of recurrent gallstone-related complications, as compared with interval cholecystectomy. We hypothesise that carrying out a sphincterotomy (ES) allows us to delay cholecystectomy, thus making it logistically easier to perform and potentially increasing the efficacy and safety of the procedure. METHODS/DESIGN: EMILY is a prospective, randomised, controlled multicentre trial. All patients with mild ABP, who underwent ES during the index admission or in the medical history will be informed to take part in EMILY study. The patients will be randomised into two groups: (1) early cholecystectomy (within 6 days after discharge) and (2) patients with delayed (interval) cholecystectomy (between 45 and 60 days after discharge). During a 12-month period, 93 patients will be enrolled from participating clinics. The primary endpoint is a composite endpoint of mortality and recurrent acute biliary events (that is, recurrent ABP, acute cholecystitis, uncomplicated biliary colic and cholangitis). The secondary endpoints are organ failure, biliary leakage, technical difficulty of the cholecystectomy, surgical and other complications. ETHICS AND DISSEMINATION: The trial has been registered internationally ISRCTN 10667869, and approved by the relevant organisation, the Scientific and Research Ethics Committee of the Hungarian Medical Research Council (EKU/2018/12176-5). TRIAL REGISTRATION NUMBER: ISCRTN 10667869; Pre-results.

A novel approach of platelet function test for prediction of attenuated response to clopidogrel.

BACKGROUND: Elevated mean platelet volume (MPV) and immature platelet fraction (IPF) are predictive for vascular risk. Both can be associated with residual platelet reactivity. We aimed to explore associations among platelet characteristics and responder status in stroke patients on clopidogrel. METHODS: Blood samples from 46 patients and 15 healthy subjects were analyzed for platelet count, MPV, IPF, large cell ratio (LCR) and high-fluorsecent immature platelet fraction (H-IPF). As a novelty, not only whole blood, but upper and lower half blood samples after 1-hour gravity sedimentation were analyzed. Platelet aggregometry was used for the whole blood and separated samples to explore area under the curve (AUC) in patients and controls. RESULTS: The AUC of the whole blood showed significant differences compared to the upper and lower samples separated after 1-hour sedimentation in patients and controls (p < 0.001 and p = 0.005 respectively). Remarkably, AUC measured in the upper samples in 59% of patients on clopidogrel were exceeding the therapeutic range suggesting that ascending platelets exert aggregation in the presence of ADP. This observation was associated with increased MPV and LCR in the upper samples (both p = 0.04). Patients on clopidogrel were characterized as responders and non-responders and the percentage of H-IPF was significantly higher among non-responders compared to controls in the upper samples (p = 0.04). CONCLUSIONS: The modified platelet function test may help to stratify patients with high residual platelet reactivity.

Comparison of the perioperative time courses of matrix metalloproteinase-9 (MMP-9) and its inhibitor (TIMP-1) during carotid artery stenting (CAS) and carotid endarterectomy (CEA).

BACKGROUND: Our aim was to compare the perioperative time courses of matrix metalloproteinase-9 (MMP-9) and its inhibitor (TIMP-1) in during carotid endarterectomy (CEA) and carotid artery stenting (CAS). METHODS: In our prospective study, twenty-five patients who were scheduled to undergo CAS were enrolled. We used a matched, historical CEA group as controls. Blood samples were collected at four time points: T1: preoperative; T2: 60 min after stent insertion; T3: first postoperative morning; and T4: third postoperative morning. Plasma MMP-9 and TIMP-1 levels were measured by ELISA. RESULTS: In the CEA group, the plasma levels of MMP-9 were significantly elevated at T3 compared to T1. In the CAS group, there was no significant difference in MMP-9 levels in the perioperative period. MMP-9 levels were significantly higher in the T3 samples of the CEA group compared to the CAS group. Significantly lower TIMP-1 levels were measured in both groups at T2 than at T1 in both groups. MMP-9/TIMP-1 at T3 was significantly higher than that at T1 in the CEA group compared to both T1 and the CAS group. CONCLUSIONS: CAS triggers smaller changes in the MMP-9-TIMP-1 system during the perioperative period, which may correlate with a lower incidence of central nervous system complications. Additional studies as well as cognitive and functional surveys are warranted to determine the clinical relevance of our findings. TRIAL REGISTRATION: NIH U.S. National Library of Medicine, Clinicaltrials.gov,NCT03410576, 24.01.2018, Retrospectively registered.

Cost-effectiveness of anesthesia maintained with sevoflurane or propofol with and without additional monitoring: a prospective, randomized controlled trial.

BACKGROUND: We compared cost-effectiveness of anesthesia maintained with sevoflurane or propofol with and without additional monitoring, in the clinical setting of ear-nose-throat surgery. METHODS: One hundred twenty adult patients were randomized to four groups. In groups SEVO and SEVO+ anesthesia was maintained with sevoflurane, in group SEVO+ with additional bispectral index (BIS) and train-of-four (TOF) monitoring. In groups PROP and PROP+ anesthesia was maintained with propofol, in group PROP+ with additional BIS and TOF monitoring. RESULTS: Total cost of anesthesia per hour was greater in group SEVO+ compared to SEVO [€ 19.95(8.53) vs. 12.15(5.32), p <  0.001], and in group PROP+ compared to PROP (€ 22.11(8.08) vs. 13.23(4.23), p <  0.001]. Time to extubation was shorter in group SEVO+ compared to SEVO [11.1(4.7) vs. 14.5(3.9) min, p = 0.002], and in PROP+ compared to PROP [12.6(5.4) vs. 15.2(4.7) min, p <  0.001]. Postoperatively, arterial blood pressure returned to its initial values sooner in groups SEVO+ and PROP+. CONCLUSIONS: Our study demonstrated that the use of BIS and TOF monitoring decreased the total cost of anesthesia drugs and hastened postoperative recovery. However, in our circumstances, these were associated with higher disposables costs. Detailed cost analysis and further investigations are needed to identify patient populations who would benefit most from additional monitoring. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02920749 . Retrospectively registered (date of registration September 2016).

A randomized placebo-controlled phase II study of a Pseudomonas vaccine in ventilated ICU patients.

BACKGROUND: Currently, no vaccine against Pseudomonas is available. IC43 is a new, recombinant, protein (OprF/I)-based vaccine against the opportunistic pathogen, Pseudomonas aeruginosa, a major cause of serious hospital-acquired infections. IC43 has proven immunogenicity and tolerability in healthy volunteers, patients with burns, and patients with chronic lung diseases. In order to assess the immunogenicity and safety of IC43 in patients who are most at risk of acquiring Pseudomonas infections, it was evaluated in mechanically ventilated ICU patients. METHODS: We conducted a randomized, placebo-controlled, partially blinded study in mechanically ventilated ICU patients. The immunogenicity of IC43 at day 14 was determined as the primary endpoint, and safety, efficacy against P. aeruginosa infections, and all-cause mortality were evaluated as secondary endpoints. Vaccinations (100 µg or 200 µg IC43 with adjuvant, or 100 µg IC43 without adjuvant, or placebo) were given twice in a 7-day interval and patients were followed up for 90 days. RESULTS: Higher OprF/I IgG antibody titers were seen at day 14 for all IC43 groups versus placebo (P < 0.0001). Seroconversion (≥4-fold increase in OprF/I IgG titer from days 0 to 14) was highest with 100 µg IC43 without adjuvant (80.6%). There were no significant differences in P. aeruginosa infection rates, with a low rate of invasive infections (pneumonia or bacteremia) in the IC43 groups (11.2-14.0%). Serious adverse events (SAEs) considered possibly related to therapy were reported by 2 patients (1.9%) in the group of 100 µg IC43 with adjuvant. Both SAEs resolved and no deaths were related to study treatment. Local tolerability symptoms were mild and rare (<5% of patients), a low rate of treatment-related treatment-emergent adverse events (3.1-10.6%) was observed in the IC43 groups. CONCLUSION: This phase II study has shown that IC43 vaccination of ventilated ICU patients produced a significant immunogenic effect. P. aeruginosa infection rates did not differ significantly between groups. In the absence of any difference in immune response following administration of 100 µg IC43 without adjuvant compared with 200 µg IC43 with adjuvant, the 100 µg dose without adjuvant was considered for further testing of its possible benefit of improved outcomes. There were no safety or mortality concerns. TRIAL REGISTRATION: ClinicalTrials.gov, NCT00876252 . Registered on 3 April 2009.

Can leukocyte antisedimentation rate (LAR) predict septic complications and critical care survival early in polytrauma and burn victims?

BACKGROUND: In polytrauma and burn injury Systemic Inflammatory Response Syndrome (SIRS) develops. SIRS is presented in many hospitalized patients, including those who never develop infection or sepsis. Both in SIRS and sepsis the leukocyte activation occurs. In acute phase reaction leukocytes' upward flotation i.e. leukocyte antisedimentation rate (LAR) can indicate infectious origin. OBJECTIVE: To evaluate the predictive power of LAR, serum C-reactive protein (CRP) and procalcitonin (PCT) levels regarding mortality risk and development of septic complications. METHODS: In a prospective, observational study, 36 patients were followed for 5 days (T1-T5) after admission to a critical care unit immediately with severe polytrauma or burn injury. Eleven patients developed septic complications, their LAR, CRP and PCT levels were analyzed before and after 3 days of sepsis was declared. RESULTS: Ten patients died due to septic complications. In survivors LAR at T1 (p < 0.001) and T2 (p < 0.001) as well as CRP at T1 (p < 0.05) were significantly higher compared to controls and non survivors. In septic patients LAR (p < 0.05) and CRP (p < 0.05) showed a significant drop one day before sepsis was declared. PCT levels failed to predict this. CONCLUSIONS: Drop in LAR and CRP levels may be warning signs regarding the onset of septic complications after severe polytrauma and burn injury.

Perioperative time course of matrix metalloproteinase-9 (MMP-9), its tissue inhibitor TIMP-1 & S100B protein in carotid surgery.

BACKGROUND & OBJECTIVES: Ischaemic stroke is a life burdening disease for which carotid endarterectomy (CEA) is considered a gold standard intervention. Pro-inflammatory markers like matrix metalloproteinases (MMPs) and their inhibitors (TIMPs) and S-100 Beta (S100B) may have a role in the early inflammation and cognitive decline following CEA. This study was aimed to describe the perioperative time courses and correlations between of MMP-9, TIMP-1 and S100B following CEA. METHODS: Fifty four patients scheduled for CEA were enrolled. Blood samples were collected at four time points, T 1 : preoperative, T 2 : 60 min after cross-clamp release, T 3 : first postoperative morning, T 4 : third postoperative morning. Twenty atherosclerotic patients were included as controls. Plasma MMP-9, TIMP-1 and S100B levels were estimated by ELISA. RESULTS: TIMP-1 was decreased significantly in the CEA group (P<0.01). Plasma MMP-9 was elevated and remained elevated from T 1-4 in the CEA group (P<0.05) with a marked elevation in T 3 compared to T 1 (P<0.05). MMP-9/TIMP-1 was elevated in the CEA group and increased further by T 2 and T 3 (P<0.05). S100B was elevated on T 2 and decreased on T 3-4 compared to T 1 . INTERPRETATION & CONCLUSIONS: Our study provides information on the dynamic changes of MMP-9-TIMP-1 system and S100B in the perioperative period. Preoperative reduction of TIMP-1 might be predictive for shunt requirement but future studies are required for verification.

Role of Tyrosine Isomers in Acute and Chronic Diseases Leading to Oxidative Stress - A Review.

Oxidative stress plays a major role in the pathogenesis of a variety of acute and chronic diseases. Measurement of the oxidative stress-related end products may be performed, e.g. that of structural isomers of the physiological para-tyrosine, namely meta- and ortho-tyrosine, that are oxidized derivatives of phenylalanine. Recent data suggest that in sepsis, serum level of meta-tyrosine increases, which peaks on the 2(nd) and 3(rd) days (p<0.05 vs. controls), and the kinetics follows the intensity of the systemic inflammation correlating with serum procalcitonin levels. In a similar study subset, urinary meta-tyrosine excretion correlated with both need of daily insulin dose and the insulin-glucose product in non-diabetic septic cases (p<0.01 for both). Using linear regression model, meta-tyrosine excretion, urinary meta-tyrosine/para-tyrosine, urinary ortho-tyrosine/para-tyrosine and urinary (meta- + orthotyrosine)/ para-tyrosine proved to be markers of carbohydrate homeostasis. In a chronic rodent model, we tried to compensate the abnormal tyrosine isomers using para-tyrosine, the physiological amino acid. Rats were fed a standard high cholesterol-diet, and were given para-tyrosine or vehicle orally. High-cholesterol feeding lead to a significant increase in aortic wall meta-tyrosine content and a decreased vasorelaxation of the aorta to insulin and the glucagon-like peptide-1 analogue, liraglutide, that both could be prevented by administration of para-tyrosine. Concluding, these data suggest that meta- and ortho-tyrosine are potential markers of oxidative stress in acute diseases related to oxidative stress, and may also interfere with insulin action in septic humans. Competition of meta- and ortho-tyrosine by supplementation of para-tyrosine may exert a protective role in oxidative stress-related diseases.

L-Arginine Pathway in COPD Patients with Acute Exacerbation: A New Potential Biomarker.

BACKGROUND: Acute exacerbation of chronic obstructive pulmonary disease (AECOPD) remains a major cause of mortality. Clinical criteria of AECOPD are subjective. Biomarkers for AECOPD may aid in the initiation of early treatment. Increased production of asymmetric and symmetric dimethylarginine (ADMA, SDMA) is related to hypoxia. In COPD, a rise in ADMA results in a shift of L-arginine breakdown, contributing to airway obstruction. We aimed to compare serum levels of ADMA, SDMA and L-arginine in patients with and without AECOPD. METHODS: L-arginine metabolites quantified by high-performance liquid chromatography in venous blood samples and partial capillary oxygen pressure were prospectively investigated in 32 patients with COPD, 12 with AECOPD and 30 healthy subjects. RESULTS: Both ADMA and SDMA were significantly higher in AECOPD compared to stable COPD (p = 0.004 and p < 0.001, respectively). Oxygen content in capillaries correlated with serum ADMA concentration. However, the concentration of L-arginine was not different between AECOPD and stable COPD. Both ADMA and SDMA separated AECOPD with high sensitivity and specificity (AUC: 0.81, p = 0.001; AUC: 0.91, p < 0.001, respectively). A cut-off value ≥0.57 for SDMA was an independent variable to confirm AECOPD in a regression model (OR: 1.632, p = 0.001). All markers were significantly higher in the sera of both patient groups compared to the controls (p < 0.05, respectively). CONCLUSIONS: COPD is associated with elevated L-arginine, ADMA and SDMA serum levels. In patients with AECOPD, production of ADMA and SDMA are more pronounced presumably due to more severe hypoxic insult. Methylated arginine derivatives in the sera may help early recognition of AECOPD.