[Show abstract][Hide abstract] ABSTRACT: Sedation prior to performance of diagnostic esophagogastroduodenoscopy (EGDE) is widespread and increases patient comfort. But 98% of all serious adverse events during EGDEs are ascribed to sedation. The S3 guideline for sedation procedures in gastrointestinal endoscopy published in 2008 in Germany increases patient safety by standardization. These new regulations increase costs because of the need for more personnel and a prolonged discharge procedure after examinations with sedation. Many patients have difficulties to meet the discharge criteria regulated by the S3 guideline, e.g. the call for a second person to escort them home, to resign from driving and working for the rest of the day, resulting in a refusal of sedation. Therefore, we would like to examine if an acupuncture during elective, diagnostic EGDEs could increase the comfort of patients refusing systemic sedation.
A single-center, double blinded, placebo controlled superiority trial to compare the success rates of elective, diagnostic EGDEs with real and placebo acupuncture. All patients aged 18 years or older scheduled for elective, diagnostic EGDE who refuse a systemic sedation are eligible. 354 patients will be randomized. The primary endpoint is the rate of successful EGDEs with the randomized technique. Intervention: Real or placebo acupuncture before and during EGDE. Duration of study: Approximately 24 months.
Organisation/Responsibility The ACUPEND--Trial will be conducted in accordance with the protocol and in compliance with the moral, ethical, and scientific principles governing clinical research as set out in the Declaration of Helsinki (1989) and Good Clinical Practice (GCP). The Interdisciplinary Endoscopy Center (IEZ) of the University Hospital Heidelberg is responsible for design and conduct of the trial, including randomization and documentation of patients' data. Data management and statistical analysis will be performed by the independent Institute for Medical Biometry and Informatics (IMBI) and the Center of Clinical Trials (KSC) at the Department of General, Visceral and Transplantation Surgery, University of Heidelberg.
The trial is registered at Germanctr.de (DRKS00000164) on December 10th 2009. The first patient was randomized on February 2nd 2010.
[Show abstract][Hide abstract] ABSTRACT: Thioredoxin (TRX) is assumed to be beneficial in acute inflammatory diseases because of its potent antioxidant properties and an inhibitory effect on neutrophil evasion into sites of inflammation.
To compare plasma levels of thioredoxin in septic patients and to investigate the role of thioredoxin in a polymicrobial septic mouse model.
A combined single-center noninterventional clinical observation study and randomized controlled experimental investigation.
Intensive care unit of a university hospital and laboratories of four university hospitals.
To evaluate the role of TRX in sepsis, we measured TRX in plasma of septic patients and compared its levels in survivors and patients who did not survive sepsis. In addition, we examined the effect of neutralization of endogenous TRX as well as of treatment with recombinant TRX in a mouse peritonitis model of cecal ligation and puncture (CLP). We found that the serum plasma levels of TRX were significantly higher in patients with sepsis compared with healthy individuals. Furthermore, nonsurvivors showed even higher TRX levels than survivors of sepsis. The CLP septic mouse model revealed that neutralization of endogenous TRX impaired survival of septic mice, whereas treatment with recombinant TRX after CLP strongly enhanced the survival of mice.
Our results therefore demonstrate a critical role for TRX in the septic inflammatory response and suggest TRX as a potential therapeutic target for septic shock.
Critical care medicine 08/2009; 37(7):2155-9. · 6.37 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Severe sepsis, septic shock, and resulting organ failure represent the most common cause of death in intensive care medicine, with mortality ranging from 40% to 70%. It is still unclear whether necrosis or apoptosis plays the predominant role in severe sepsis. Determining the prevalent mode of cell death would be valuable, as new therapeutic agents (eg, antiapoptotic drugs such as caspase inhibitors) may improve unsatisfactory outcomes in patients with severe sepsis. Furthermore, the prognostic value of newly developed cell death serum biomarkers is of great interest.
In total, 147 patients (101 patients with severe sepsis, 28 postoperative patients after major abdominal surgery, 18 healthy volunteers) were enrolled. Baseline and clinical data were evaluated. Blood samples from patients with severe sepsis were collected at the time of sepsis diagnosis, and 48 and 120 hours later; samples from healthy volunteers were collected once, and from postoperative patients, once immediately after surgery. We measured caspase-cleaved and uncleaved cytokeratin-18 (CK-18, intermediate filament protein) as a marker of cell death, isolated CK-18 fragments as a marker of apoptosis, as well as IL-6, soluble vascular cell adhesion molecule, and soluble intercellular adhesion molecule.
Age and sex of patients with severe sepsis and postoperative patients were comparable, whereas healthy volunteers were significantly younger. In healthy volunteers, the mode of cellular turnover was primarily apoptotic cell death. Postoperative patients showed comparable levels of apoptotic activity, but necrotic cell death was markedly increased, probably due to surgical tissue injury. In contrast, patients with severe sepsis, and especially non-survivors of the septic group showed increased levels of markers for both apoptotic and necrotic cell death. In severe septic patients with liver dysfunction, necrosis is increased relative to severe septic patients with intact hepatic function. For severe septic patients with liver dysfunction, a cut-off value for caspase-cleaved and uncleaved cytokeratin-18 could be calculated, in order to identify patients at high risk for death due to severe sepsis.
The measurement of caspase-cleaved and uncleaved cytokeratin-18 appears to be an early predictor for survival in severe septic patients with hepatic dysfunction. Furthermore, the loss of parenchymal cells due to necrosis may be the primary mode of cell death in these patients. This may limit possible therapeutic options.
Critical care (London, England) 07/2009; 13(3):R93. · 4.72 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Central venous pressure, intrathoracic blood volume, and left ventricular end-diastolic area are reliable measures of cardiac preload under stable clinical conditions. The purpose of this study was to compare different preload parameters over 24 h under conditions of multiple, frequently changing treatments in early septic shock.
In 28 mechanically ventilated patients within 6 h of the onset of septic shock, left ventricular end-diastolic area was measured using transoesophageal echocardiography. Intrathoracic blood volume, stroke volume variation, and central venous pressure were analysed as preload parameters. The relation between parameter changes and changes in therapy was examined with respect to cardiac index and stroke volume index.
Regarding preload variables, linear regression analyses revealed a significant correlation between left ventricular end-diastolic area and stroke volume index (r=0.59, P<0.001) and cardiac index (r=0.41, P<0.001), respectively. Changes in left ventricular end-diastolic index and intrathoracic blood volume index reflected changes in the stroke volume index, whereas central venous pressure did not. Myocardial responsiveness also failed to predict changes in the stroke volume index.
Only the left ventricular end-diastolic area index may help predict preload in ventilated patients with early septic shock.
European Journal of Anaesthesiology 05/2009; 26(9):759-65. · 2.79 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: To evaluate plasma levels of soluble TREM-1 (sTREM-1) in patients with systemic inflammatory response syndrome (SIRS), severe sepsis, and septic shock and to determine whether plasma sTREM-1 could be used as a diagnostic and prognostic marker in sepsis in the surgical ICU.
The study was designed as an observational noninterventional clinical study in a surgical ICU of a university hospital. For this, 65 intensive care patients were enrolled within the first 24 h after onset of SIRS (n = 11), severe sepsis (n = 39) or septic shock (n = 15). In addition, 21 healthy volunteers served as controls. At days 0, 1, and 3 after diagnosis, plasma sTREM-1 was measured by ELISA.
Plasma sTREM-1 concentrations in healthy controls did not significantly differ from those in patients with SIRS, severe sepsis, or septic shock at days 0, 1, and 3. Survivors were defined as septic patients surviving for at least 28 days. There were no differences in plasma sTREM-1 levels between survivors (n = 22) and nonsurvivors (n = 27) on any day.
In this study in patients with SIRS, severe sepsis, or septic shock, plasma sTREM-1 levels were not elevated as compared with healthy controls. Measurement of plasma sTREM-1 did not distinguish between patients with SIRS, severe sepsis, or septic shock or between survivors and nonsurvivors. The suggested role of sTREM-1 as a diagnostic and prognostic marker in sepsis should be carefully verified.
European Journal of Anaesthesiology 04/2009; 26(6):504-7. · 2.79 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: We report the case of a 72-year-old man who died in septic shock following pancreatectomy. At autopsy, organs were discoloured with a rapid colour change from turquoise to dark green, especially of the myocardium. The patient had received 200 mg methylene blue (MB), i.v., for treatment of septic shock 90 min prior to death. Analysis of tissue samples by liquid extraction and liquid chromatography coupled to tandem mass spectrometry demonstrated different concentrations of MB and its metabolites azure A and B in the heart, lungs, kidneys, and liver. Our findings clearly demonstrate the relation of MB administration and organ discolouration at autopsy and shed a new light on MB distribution and accumulation in septic shock.
Archiv für Pathologische Anatomie und Physiologie und für Klinische Medicin 03/2009; 454(3):341-4. · 2.68 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The aim of this study was to evaluate whether a single preoperative limited oral intake of a carbohydrate drink could improve perioperative patient comfort and satisfaction with anesthesia care in elective day-stay ophthalmologic surgery.
A single-center, prospective, randomized clinical trial was conducted in a university hospital. The study included ASA I-III patients undergoing ophthalmologic surgery. Patients undergoing both general anesthesia and local anesthesia were included in the study. The control group fasted in accordance to nil per os after midnight, while patients in the experimental group received 200 mL of a carbohydrate drink 2 h before the operation. Both groups were allowed to drink and eat until midnight ad libitum. Patient characteristics, subjective perceptions, taste of the drink, and satisfaction with anesthesia care were ascertained using a questionnaire administered three times: after the anesthesiologist's visit, before surgery and before discharge from the ward to assess patient comfort. An analysis of variance and the Mann-Whitney U-test were used for statistical analysis.
A total of 123 patients were included and 109 patients were randomly assigned to one of two preoperative fasting regimens. Patients drinking 200 mL 2 h before surgery were not as hungry (P<0.05), not as thirsty preoperatively (P<0.001) and not as thirsty after surgery (P<0.05), resulting in increased postoperative satisfaction with anesthesia care (P<0.05).
Standardized limited oral preoperative fluid intake increases patient comfort and satisfaction with anesthesia care and should be a part of modern day-stay ophthalmologic surgery.
[Show abstract][Hide abstract] ABSTRACT: (1) To evaluate in septic patients the plasma levels of soluble receptor for advanced glycation end products (sRAGE), a soluble splice variant of the full length receptor RAGE, which is involved in acute inflammation (2) to determine whether sRAGE could be used as a potential diagnostic and prognostic marker in sepsis in the surgical intensive care unit.
An observational clinical noninterventional pilot study in a surgical intensive care unit with patients admitted to the intensive care unit over a 6-mo period with clinical evidence of severe sepsis or septic shock.
Twenty-nine intensive care patients were enrolled in the study within the first 24 h after onset of severe sepsis or septic shock. Eight healthy volunteers served as controls. Plasma sRAGE concentrations were elevated in septic patients compared with healthy volunteers (1764 +/- 138 versus 1026 +/- 177 pg/mL, P < 0.05). Additionally, nonsurvivors after 28 days have had higher plasma sRAGE concentrations than survivors (2302 +/- 189 versus 1326 +/- 112 pg/mL, P < 0.001). Receiver operating characteristic curve analysis of plasma sRAGE concentrations of septic patients showed a specificity of 75% and a sensitivity of 84.6% with 1596 pg/mL as cutoff.
This is the first study showing elevated plasma sRAGE concentrations in septic patients. It is noteworthy that nonsurvivors had higher plasma sRAGE concentrations than survivors, suggesting that sRAGE is related to severity and outcome of septic patients. Further clinical studies are required to investigate the usefulness of sRAGE as a new sepsis marker.
Journal of Surgical Research 06/2008; 147(1):79-83. · 2.02 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The pathogenesis and mechanisms of septic encephalopathy are not completely understood. We compared two different models of sepsis: lipopolysaccharide-induced endotoxemia and cecal ligation and puncture (CLP) bacteremia in rats with respect to changes in endothelial expression of the adhesion molecules intercellular adhesion molecule-1 (ICAM-1), platelet-endothelial cell adhesion molecule-1 (PECAM-1), and of cerebral albumin extravasation as a marker for capillary breakdown of the blood brain barrier.
Male Wistar rats were divided into control, endotoxemia, or CLP-group. Mean arterial blood pressure was measured via femoral artery catheterization. Brain tissue for immunohistochemistry was harvested at 1 h, 6 h, and 24 h after induction of sepsis.
The CLP-group showed a decrease in mean arterial pressure after 24 h in comparison with the sham-group (P < 0.05). Cerebral ICAM-1 expression was at its maximum 24 h after induction of sepsis, with the highest expression in the CLP-group. There was no difference in PECAM-1 expression between the groups. Cerebral albumin extravasation increased early after 6 h in both septic groups with a maximum at 24 h after induction of sepsis.
These results suggest that there are early changes in the integrity of the blood-brain barrier in the central nervous system in an ongoing septic progress. This provides evidence that these changes are due to inflammatory mediators, and not to the presence of live bacteria. Increased ICAM-1 expression might be an early factor involved in these pathogenic events. Although the role of PECAM-1 cannot conclusively be determined, we were able to show its expression on cerebral endothelium in all groups.
Journal of Surgical Research 05/2008; 146(2):276-81. · 2.02 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: In acute lung injury (ALI) pulmonary hyporesponsiveness to inhaled nitric oxide (iNO) still represents an unresolved clinical challenge. In septic ALI-patients the incidence of hyporesponsiveness to iNO is increased; therefore, endotoxemia appears to play a major role. Experimental data suggest that endotoxemia, e.g., induced by lipopolysaccharides (LPS), contribute to the hyporesponsiveness to iNO. Guanosine 3',5'-cyclic monophosphate (cGMP) is metabolized by phosphodiesterases (PDE). The role of PDE in reduced pulmonary vascular response in experimental endotoxemia is still not known. Here, we hypothesized that PDE activity modulates initial pulmonary responsiveness to iNO in ALI following systemic endotoxin exposure. Rats were treated with LPS or used as controls. Lungs were isolated-perfused 0-36 h after LPS injection and the synthetic thromboxane analogue U46619 was added to increase pulmonary artery pressure by 6-8 mmHg (n = 47). Then, the pulmonary vasodilatory response to 3 doses of iNO (0.4, 4 and 40 ppm) was measured. Furthermore, lungs were prepared as described previously, and 2, 10, and 18 h after LPS the change in pulmonary artery pressure in response to two different inhibitors of PDE, one of which is PDE sensitive (8-Br-cGMP) and one is PDE stable (8-pCPT-cGMP), was determined (n = 43). Serum nitrite/nitrate levels started to increase 4 h after LPS, with a maximum at 18 h. In contrast, decreased pulmonary vasoreactivity in response to iNO developed as early as 2 h later and remained depressed up to 18 h. The pulmonary vasoreactivity to the PDE-sensitive 8-Br-cGMP after LPS-stimulation was lower than that in lungs treated with the PDE-stable 8-pCPT-cGMP. In rats pretreated with LPS, hyporesponsiveness of pulmonary vessels to iNO is time-limited and associated with increased serum nitrite/nitrate levels, and appears to be attributed in part to increased pulmonary PDE activity.
Journal of Surgical Research 03/2008; 150(1):66-73. · 2.02 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Sepsis still represents an important clinical and economic challenge for intensive care units. Severe complications like multi-organ failure with high mortality and the lack of specific diagnostic tools continue to hamper the development of improved therapies for sepsis. Fundamental questions regarding the cellular pathogenesis of experimental and clinical sepsis remain unresolved. According to experimental data, inhibiting macrophage migration inhibitory factor, high-mobility group box protein 1 (HMGB1), and complement factor C5a and inhibiting the TREM-1 (triggering receptor expressed on myeloid cells 1) signaling pathway and apoptosis represent promising new therapeutic options. In addition, we have demonstrated that blocking the signal transduction pathway of receptor of advanced glycation endproducts (RAGE), a new inflammation-perpetuating receptor and a member of the immunoglobulin superfamily, increases survival in experimental sepsis. The activation of RAGE by advanced glycation end-products, S100, and HMGB1 initiates nuclear factor kappa B and mitogen-activated protein kinase pathways. Importantly, the survival rate of RAGE knockout mice was more than fourfold that of wild-type mice in a septic shock model of cecal ligation and puncture (CLP). Additionally, the application of soluble RAGE, an extracellular decoy for RAGE ligands, improves survival in mice after CLP, suggesting that RAGE is a central player in perpetuating the innate immune response. Understanding the basic signal transduction events triggered by this multi-ligand receptor may offer new diagnostic and therapeutic options in patients with sepsis.
Critical care (London, England) 02/2008; 12(1):201. · 4.72 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Inhalation of nitric oxide (NO) and inhibition of phosphodiesterase type 5 (PDE5) selectively dilate the pulmonary circulation in patients with acute lung injury (ALI) associated with pulmonary hypertension. PDE5 inhibitors administered at doses that decrease pulmonary artery pressures have been shown to worsen arterial oxygenation. We investigated the efficacy of doses of PDE5 inhibitors that do not reduce pulmonary artery pressure alone (subthreshold doses) to improve the response to inhaled NO in an animal model of ALI.
Adult Sprague-Dawley rats were pre-treated with 0.5 mg/kg Escherichia coli 0111:B4 endotoxin and 16 to 18 h later, their lungs were isolated perfused and ventilated. The thromboxane mimetic U46619 was used to induce pulmonary hypertension. After the determination of subthreshold doses of two different PDE5 inhibitors, either 50 microg zaprinast or 10 ng sildenafil was added to the perfusate and the decrease of pulmonary artery pressure measured in the presence and absence of inhaled NO.
In the presence of 4 or 10 ppm NO, zaprinast (-1.6 +/- 0.4 and -2.9 +/- 0.6 mmHg, respectively) and sildenafil (-1.9 +/- 0.4 and -2.4 + 0.3 mmHg, respectively) improved responsiveness to inhaled NO compared to lungs from rats treated with LPS only (0.7 +/- 0.1 and -1.0 +/- 0.1 mmHg, respectively; P<0.05). Neither zaprinast nor sildenafil prolonged the pulmonary vasodilatory response to inhaled NO.
Subthreshold doses of PDE5 inhibitors improved responsiveness to inhaled NO. Combining inhaled NO with subthreshold doses of PDE5 inhibitors may offer a therapeutic strategy with minimal side-effects in ALI associated with pulmonary hypertension.
Journal of Surgical Research 04/2007; 138(2):224-30. · 2.02 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: In conclusion, sepsis is still an important clinical challenge for ICUs with few therapeutic options. This chapter has summarized
the current knowledge on RAGE, an inflammation perpetuating receptor, which plays a pivotal role in sepsis. RAGE is involved
in signal transduction from pathogen substrates to cell activation during the onset of inflammation and perpetuates the immune
response. Targeting this receptor might attenuate hyperinflammation. Essentially, understanding of the basic signal transduction
of these receptors may offer new diagnostic and therapeutic options in septic patients.