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IntroductionPostoperative pancreatic fistula (POPF) is still the most frequently occurring and clinically relevant complication after distal pancreatectomy (DP). Preoperative endoscopic injection of botulinum toxin (BTX) into the sphincter of Oddi represents an innovative approach to prevent POPF. The aim of this project (PREBOTPilot) is to generate the first randomised controlled trial data on the safety, feasibility and efficacy of preoperative endoscopic BTX injection into the sphincter of Oddi to prevent clinically relevant POPF following DP.Methods and analysisPREBOTPilot is an investigator-initiated, single-centre, randomised, controlled, open-label, phase II clinical trial with two parallel study groups and an exploratory study design. 60 patients scheduled for DP will be randomised to intervention and control group. In the intervention group, patients will undergo preoperative endoscopic injection of BTX into the sphincter of Oddi, whereas in the control group no preoperative endoscopy will be performed. The combined primary endpoint is the occurrence of clinically relevant POPF and/or death within 30 days after DP. The secondary endpoints comprise further postoperative outcome parameters and quality of life up to 3 months after DP as well as safety and feasibility of the procedure. Statistical analysis is based on the modified intention-to-treat population, excluding patients without status post DP. For safety analysis, rates of adverse events (AEs) and serious AEs will be calculated with 95% CIs for group comparisons.Ethics, funding and disseminationPREBOTPilot has been approved by the German Federal Institute for Drugs and Medical Devices (reference number 4043654) and the Ethics Committee of Heidelberg University (reference number AFmo-523/2019). This trial is supported by the German Federal Ministry of Education and Research (BMBF). The results of the trial will be presented at national and international conferences and published in a peer-reviewed journal.Trial registration numberDRKS00020401.

Background In the pathogenesis of sepsis, inflammation-induced changes in coagulation play a pivotal role. Methods In total, 90 patients (30 patients with septic shock, 30 surgical patients following major abdominal surgery and 30 healthy volunteers) were enrolled. Blood samples from patients with septic shock were collected at the time of sepsis diagnosis as well as 24 h, 4 days, 7 days, 14 days and 28 days later. Samples from surgical patients with a post-surgical inflammatory response were collected three times (before surgery, immediately after surgery and 24 h after surgery) and once from healthy volunteers. Thromboelastometry (ROTEM ®), as well as whole blood impedance aggregometry (Multiplate®) were performed. Additionally, plasma concentrations of interleukin-6 and tumour necrosis factor-alpha were measured using enzyme-linked immunosorbent assay kits. Results Thromboelastometry lysis index was shown to be a reliable biomarker for septic shock. Furthermore, in septic patients with overt disseminated intravascular coagulation, thromboelastometry revealed signs indicating a hypocoagulable status, whereas patients without overt disseminated intravascular coagulation were found to be hypercoagulable. Platelet aggregation capability, as assessed by whole blood impedance aggregometry, was significantly reduced in septic patients with overt disseminated intravascular coagulation, whereas it was comparable with healthy volunteers and in septic patients without overt disseminated intravascular coagulation. Conclusion Viscoelastic and aggregometric point-of-care testing was shown to be potentially useful for bedside diagnosis of sepsis. Moreover, viscoelastic and aggregometric point-of-care testing was able to determine the phase of septic coagulopathy (hypercoagulability vs. hypocoagulability) and therefore identified patients at high risk for overt disseminated intravascular coagulation.

Background: The safety and efficacy of subcutaneous immunotherapy (SCIT) with the high-dose hypoallergenic preparations Allergovit® have been well documented in several randomised clinical trials. The following study aimed to confirm these results in daily practice.

Background: Opinions about satisfaction with care are rarely obtained from disabled children and their carers, and few studies of this type exist in the area of pediatric anesthesia. We specifically aimed to assess groups of children with disabilities and Down syndrome and aimed to identify factors influencing satisfaction in these groups. Methods: We assessed two groups of children using the Paediatric Perianesthesia Questionnaire (PPQ). Families with Down syndrome children (Down syndrome group, DSG) were approached via a Down syndrome family support magazine, and families with disabled children were enrolled in hospitals. Two hundred and fifteen disabled children (125 from the journal, 90 from the hospitals) were compared to matching controls without disabilities. Controls were drawn randomly using computer-generated tables of random numbers using data from the PPQ validation, to match cases for confounding variables. Results: Satisfaction was lower in both groups with disabilities (P < 0.05) (lowest in the DSG), fewer would choose the hospital or anesthetic department again. In both of the disabled groups, negative comments were related to the anesthetists' behavior during the consultation, the content of the consultation, and how anxiety was dealt with. Ninety five percent in the DSG reported that the anesthetist had not mentioned or enquired about atlantoaxial instability. Satisfaction was lower than the rest of the respective group if memories of the disclosure of the disabling condition were negative (P = 0.006) or if potential offensive terms had been used during the consultation (P < 0.001). Conclusions: This is the first study to assess families with disabled children for satisfaction with anesthesia. Our findings suggest that parents of children with disabilities are less satisfied with their anesthetic care than parents of children without disabilities. Potential bias comes from the self-selection of the DSG and the recall period in this group.

Background Recent evidence suggests that the endothelial glycocalix plays an important role in lethal outcomes following sepsis. We therefore tested if the endothelial glycocalix is shed in patients with sepsis compared with patients after major abdominal surgery and healthy volunteers. Material and Methods A total of 150 individuals were tested for levels of inflammatory markers (intercellular adhesion molecule-1 [ICAM-1], vascular cell adhesion molecule-1 [VCAM-1], interleukin-6 [IL-6]) and glycocalix markers (syndecan-1, heparan sulfate). Three groups consisted of patients with severe sepsis or septic shock, patients after major abdominal surgery without systemic inflammatory response syndrome, and healthy volunteers. Blood was drawn, at the time of diagnosis or surgery, and 6, 24, and 48 h later. We correlated these markers to each other and to clinically used inflammation markers. Results Levels of inflammatory markers were markedly higher in patients with sepsis compared with patients after major abdominal surgery and healthy volunteers. After major abdominal surgery, glycocalix markers in human plasma were at levels comparable to patients with sepsis. In patients with sepsis, levels of IL-6 correlated with syndecan-1, ICAM-1, VCAM-1, and lactate, while ICAM-1 furthermore correlated with CRP and lactate levels. Conclusion High levels of glycocalix markers indicated that significant flaking of the endothelial glycocalix occurred in patients with sepsis, and to a lesser extent in patients after major abdominal surgery. This novel finding could explain the nonspecific capillary leaking syndrome of patients with sepsis and after major abdominal surgery, and may identify new targets for treating those patient populations.

Background Severe sepsis, septic shock, and resulting organ failure appear as the most common cause of death in intensive care medicine. Inflammatory mediators (interleukin-6/IL-6), cell adhesion molecules (intercellular adhesion molecule-1/ICAM-1, vascular cell adhesion molecule-1/VCAM-1), and redox active substances (manganese superoxide dismutase/MnSOD, macrophage migration inhibitory factor/MIF) must be considered to be central hubs in the inflammatory process. However, their exact pathophysiologic function and prognostic value are still poorly understood. Materials and Methods In total, 133 individuals (87 patients with severe sepsis or septic shock, 28 postoperative patients after major abdominal surgery, 18 healthy volunteers) were enrolled in the study. Blood samples from septic patients were collected within 24 h after the time of sepsis diagnosis, and 48 and 120 h later; samples from healthy volunteers were collected once, and samples from postoperative patients once immediately after surgery. In all patients we measured plasma levels of IL-6, sICAM-1, sVCAM-1, MnSOD, and MIF using enzyme linked immunosorbent assay (ELISA) kits. Results Healthy volunteers and postoperative patients showed comparable levels of cell adhesion molecules. Furthermore, their redox system was activated in a comparable manner, whereas in postoperative patients IL-6 was significantly elevated. Plasma levels of inflammatory mediators, cell adhesion molecules and redox active substances were significantly elevated in septic patients. In patients with sepsis who had died, plasma levels of MIF and MnSOD were significantly elevated in comparison with survivors. Conclusions Our results therefore demonstrate that redox active substances may play an important role in the septic inflammatory response. MIF and MnSOD appear to be early predictors for survival in septic patients.

Increased patients' serum anticholinergic activity (SAA) is described as a marker of cognitive dysfunction and can be influenced by different exogenous and endogenous factors. The role of cortisol in relation to SAA and cognition in perioperative conditions has not been investigated so far. In 30 men scheduled for urological surgery, the authors determined SAA and cortisol levels in blood and CSF and conducted neuropsychological testing in two subgroups with comparable pre- and intraoperative characteristics, one group with low SAA (mean=2.4 [SD=0.9], n=23) and the other with high SAA (mean=5.1 [SD=2.4], n=7) values. Increased SAA was associated with two times the number of anticholinergic medications but not with patients' age, medical history or impaired cognition. A significant linear correlation was detected between anticholinergic activities and cortisol levels. Thus, endogenous factors such as patients' stress levels should be taken into account for interpretation of the role of SAA.

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 (P0.05). 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.

Lethal sepsis occurs when an excessive inflammatory response evolves that cannot be controlled by physiologic anti-inflammatory mechanisms, such as the recently described cholinergic anti-inflammatory pathway. Here we studied whether the cholinergic anti-inflammatory pathway can be activated by pharmacologic cholinesterase inhibition in vivo.Prospective, randomized laboratory investigation that used an established murine sepsis model.Research laboratory in a university hospital.Female C57BL/6 mice.Sepsis in mice was induced by cecal ligation and puncture. Animals were treated immediately with intraperitoneal injections of nicotine (400 microg/kg), physostigmine (80 microg/kg), neostigmine (80 microg/kg), or solvent three times daily for 3 days.Treatment with physostigmine significantly reduced lethality (por = .01) as efficiently as direct stimulation of the cholinergic anti-inflammatory pathway with nicotine (por = .05). Administration of cholinesterase inhibitors significantly down-regulated the binding activity of nuclear factor-kappaB (por = .05) and significantly reduced the concentration of circulating proinflammatory cytokines tumor necrosis factor-alpha, interleukin-1beta, and interleukin-6 (por = .001), and pulmonary neutrophil invasion (por = .05). Animals treated with the peripheral cholinesterase inhibitor neostigmine showed no difference compared with physostigmine-treated animals.Our results demonstrate that cholinesterase inhibitors can be used successfully in the treatment of sepsis in a murine model and may be of interest for clinical use.

Alterations in microcirculatory permeability are a characteristic of early tissue injury. Moreover, tissue edema is an early indicator of tissue dysfunction, prior to organ failure, because tissue edema is associated with impaired gas exchange, arterial hypoxemia, and may also impair tissue oxygen distribution. As a result of increased microvascular permeability, plasma fluid is lost into the interstitial space, leading to hypovolemia. Currently, no effective pharmacological therapy is available to reduce increased permeability. High mortality rate in sepsis is still mainly associated with endothelial damage. In this regard platelets, besides leukocytes, play a major role for the development of microvascular hyperpermeability. This review considers endothelial cell dysfunction during endotoxemia including current insights into sepsis pathophysiology. New aspects of this complex pathogenesis are illustrated and their relevance for clinical sepsis therapy is emphasized.

Background Levels of pro- and anti-inflammatory cytokines have been determined in numerous investigations. However, measurements of isolated cytokines do not allow conclusions on the resulting immune state. The purpose of this study was to determine resulting immune functions in patients’ plasma. Additionally, similar measurements were performed with ultrafiltrate gained from continuous venovenous hemofiltration (CVVH). Materials and Methods Nine septic patients and six critically ill patients with renal dysfunction in a surgical intensive care unit were observed. Two immune functions were chosen for detailed investigation over a time period of 72 h. The ability of patients’ plasma to induce or suppress β 2 -integrin expression on neutrophils of healthy controls served as marker for leukocyte activation. Interleukin (IL)-6 production or inhibition in washed whole blood cells induced through patients’ plasma was used as a marker of cytokine secretion. Results Plasma from septic patients led to a constantly increased expression of β 2 -integrins on isolated, unstimulated neutrophils. At the same time, septic plasma permanently suppressed the production of IL-6 and IL-10 in stimulated whole blood. Ultrafiltrate from CVVH mirrors the equivalent immune response patterns found for plasma. We did not find significant differences pre- and postfilter or over the next 72 h in the potential to cause IL-6 and IL-10 production or β 2 -integrin expression. Conclusions Plasma from septic patients triggers an increased expression of adhesion molecules and inhibited secretion of IL-6 and IL-10 in stimulated whole blood cells compared with nonseptic critically ill patients. Moreover, CVVH withdraws triggering mediators from plasma in equally bioactive proportions.

Successful management of emergency patients with multiple trauma in the hospital resuscitation room depends on the immediate diagnosis and rapid treatment of the most life-threatening injuries. In order to reduce the time spent in the resuscitation room, an in-hospital algorithm was developed in an interdisciplinary team approach with respect to local structures. The aim of the study was to analyse whether this algorithm affects the interval between hospital admission and the completion of diagnostic procedures and the start of life-saving interventions. Moreover, in-hospital mortality was investigated before and after the algorithm was introduced.In this prospective study, all consecutive trauma patients in the resuscitation room were investigated before (group I, 01/04-10/04) and after (group II, 01/05-11/05) introduction of the algorithm. The times between hospital admission and the end of the diagnostic procedures (ultrasound [sono], chest X-ray [CF], and cranial computed tomography [CCT]), and between hospital admission and the start of life-saving interventions were registered and in-hospital mortality analysed.In the study period, 170 patients in group I and 199 patients in group II were investigated. Injury severity score (ISS) were comparable between the two groups. The intervals between admission and completion of diagnostic procedures were significantly lower after the algorithm was introduced (mean+/-S.D.): sono (11 +/- 10 min versus 7 +/- 6 min, p0.05), CF (21 +/- 12 min versus 12 +/- 9 min, p0.01), and CCT (55 +/- 27 min versus 32 +/- 14 min, p0.01). Moreover, the interval to the start of life-saving interventions was significantly shorter (126 +/- 90 min versus 51 +/- 20 min, p0.01). After introducing the algorithm, in-hospital mortality was reduced significantly from 33.3% to 16.7% (p0.05) in the most severely injured patients (ISSor=25).The introduction of an algorithm for early management of emergency patients significantly reduced the time spent in the resuscitation room. The periods to completion of sono, CF, and CCT, respectively, and the start of life-saving interventions were significantly shorter after introduction of the algorithm. Moreover, introduction of the algorithm reduced mortality in the most severely injured patients. Although further investigations are needed to evaluate the effects of the Heidelberg treatment algorithm in terms of outcome and mortality, the time reduction in the resuscitation room seems to be beneficial.

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; P0.05). 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.

Patients with malignant diseases are increasingly being treated with multimodal therapeutical concepts based on the three major modalities surgery, radiotherapy and chemotherapy. The perioperative period is crucial within this multimodal concept as the prognosis of patients may be directly influenced by perioperative measures. In addition, it is of major importance to avoid complications in the perioperative phase, as these might worsen the prognosis of the patient and in order to prevent a delay in the beginning of planned adjuvant therapies. These aspects demonstrate the important role of anesthesia in the treatment of patients with cancer. Further studies defining the relevance of anesthesiologic measures in oncologic patients are needed.

The role of reactive carbonyl species, such as methylglyoxal (MG), has been overlooked within the context of the sepsis syndrome. The aims of this study were to assess the impact of MG formation in different inflammatory settings and to evaluate its use for early diagnosis as well as prognosis of the sepsis syndrome. In total, 120 patients in three groups were enrolled in this observational clinical pilot study. The three groups included patients with septic shock (n = 60), postoperative controls (n = 30), and healthy volunteers (n = 30). Plasma samples from patients with septic shock were collected at sepsis onset and after 24 hours and 4, 7, 14, and 28 days. Plasma samples from postoperative controls were collected prior to surgery, immediately following the end of the surgical procedure as well as 24 hours later and from healthy volunteers once. Plasma levels of MG were determined by high-performance liquid chromatography. Additionally, plasma levels of procalcitonin, C-reactive protein, soluble CD14 subtype, and interleukin-6 were determined. Patients with septic shock showed significantly higher plasma levels of MG at all measured times, compared with postoperative controls. MG was found to identify patients with septic shock more effectively—area under the curve (AUC): 0.993—than procalcitonin (AUC: 0.844), C-reactive protein (AUC: 0.791), soluble CD14 subtype (AUC: 0.832), and interleukin-6 (AUC: 0.898) as assessed by receiver operating characteristic (ROC) analysis. Moreover, plasma levels of MG in non-survivors were significantly higher than in survivors (sepsis onset: *P = 0.018 for 90-day survival; **P = 0.008 for 28-day survival). Plasma levels of MG proved to be an early predictor for survival in patients with septic shock (sepsis onset: ROC-AUC 0.710 for 28-day survival; ROC-AUC 0.686 for 90-day survival). MG was identified as a marker for monitoring the onset, development, and remission of sepsis and was found to be more useful than routine diagnostic markers. Further studies are required to determine the extent of MG modification in sepsis and whether targeting this pathway could be therapeutically beneficial to the patient. German Clinical Trials Register DRKS00000505 . Registered 8 November 2010.

Summary We investigated the association of peri-operative myocardial ischaemia with activation of coagulation and endogenous fibrinolysis in patients undergoing vascular surgery. In 50 patients, continuous Holter monitoring was performed to assess peri-operative myocardial ischaemia and 12-lead electrocardiography was recorded preoperatively and 72 h postoperatively to assess myocardial infarction. Serial blood samples were drawn peri-operatively to determine the concentrations of fibrin monomers (for activation of coagulation), d-dimer (for endogenous fibrinolysis) and cardiac troponin T and I. Patients with myocardial ischaemia showed higher concentrations of fibrin monomers at 48 h, and higher concentrations of d-dimer preoperatively and at 24 and 48 h postoperatively. In patients with peri-operative myocardial ischaemia, strong positive correlations were observed between fibrin monomer and d-dimer concentrations at 15 min and 4 h postoperatively, and cardiac troponins at 15 min and at 4, 24, 48 and 72 h postoperatively. Early postoperative activation of coagulation and fibrinolysis is associated with peri-operative myocardial cell damage among patients who are at risk for, or have a history of, coronary artery disease plus peri-operative myocardial ischaemia.

Peri-operative myocardial ischaemia is the single most important risk factor for an adverse cardiac outcome after non-cardiac surgery. The present study examines whether intermittent 12-lead ECG recordings can be used as an early warning tool to identify patients suffering from peri-operative myocardial ischaemia and subsequent myocardial cell damage. Fifty-five vascular surgery patients at risk for or with a history of coronary artery disease were monitored for peri-operative myocardial ischaemia using intermittent 12-lead ECG recordings taken pre-operatively and at 15 min, 20 h, 48 h, 72 h and 84 h postoperatively. The effectiveness of the 12-lead ECG was gauged by examining concordance with continuous 3-channel Holter monitoring and capturing peri-operative myocardial ischaemia by serial analyses of creatine kinase myocardial band isoenzyme and cardiac troponin T and I. The incidence of peri-operative myocardial ischaemia detected by 12-lead ECG was 44% and was identifiable in most patients (88%) 15 min after surgery. The incidence of peri-operative myocardial ischaemia detected by continuous monitoring was 53%, with the most severe episodes occurring intra-operatively and during emergence from anaesthesia. The concordance of the 12-lead method with continuous monitoring was 72%. The concordance of creatine kinase myocardial band isoenzyme activity with the 12-lead method was 71% and with Holter monitoring 57%. The concordance of mass concentration of creatine kinase myocardial band with 12-lead ECG recordings was 75%, and the corresponding value for Holter monitoring was 68%. The concordance of cardiac troponin T and I levels with the 12-lead method was 85% and 87%, respectively, and concordance with Holter monitoring was 72% and 66%, respectively. The postoperative 12-lead ECG identified peri-operative myocardial ischaemia associated with subsequent myocardial cell damage in most patients undergoing vascular surgery.

INTRODUCTION In addition to its effects on platelet function, recent studies suggest that inhaled nitric oxide (NO) also influences the function of circulating leukocytes. Therefore, the aim of this work was to investigate the formation of platelet-leukocyte aggregates (PLAs) and platelet and leukocyte cell surface receptor expression during NO therapy in patients with acute respiratory distress syndrome. METHODS In 16 patients responding to NO therapy with an improvement in oxygenation (NO group) and in four nonresponders (control), platelet P-selectin expression, platelet fibrinogen binding, the expression CD11a on leukocytes, and the formation of PLAs were investigated at 0, 60, 120, and 180 mins of therapy or at corresponding time points by means of flow cytometry. In addition, PLA was investigated in 30 healthy volunteers during NO inhalation, in five mechanically ventilated patients without acute respiratory distress syndrome and without NO inhalation, and during NO incubation in platelet-rich plasma of ten healthy volunteers in vitro. RESULTS NO therapy inhibited PLA formation at 60 (13% +/- 4% in the NO group vs. 19% +/- 7% in the control group, p

Animal studies have demonstrated that reperfusion disorders occurring after cardiac arrest affect outcome. Reperfusion injury can be caused by activation of complement, polymorphonuclear leukocytes (PMN), and PMN-endothelial interaction. We studied different specific markers of these processes during and after cardiopulmonary resuscitation in humans.Prospective clinical trial.University hospital.A total of 55 patients who underwent out-of-hospital cardiopulmonary resuscitation for nontraumatic causes.Blood samples were drawn immediately, 15 mins, and 30 mins after initiation of cardiopulmonary resuscitation. In the case of restoration of spontaneous circulation, additional blood samples were taken at serial time points until 7 days after cardiac arrest.A marked activation of complement and PMN was found in all patients investigated. Serum concentrations of specific activation markers of the complement system, anaphylatoxin C3a and the soluble membrane attack complex SC5b-9, and PMN elastase were increased during cardiopulmonary resuscitation and for/=48 hrs after restoration of spontaneous circulation. Compared with controls at 30 mins after initiation of cardiac massage, concentrations of C3a, SC5b-9, and PMN elastase were increased in patients without and in those with restoration of spontaneous circulation. PMN elastase concentrations were significantly greater in patients without restoration of spontaneous circulation than in those who could be stabilized. In addition, the plasma concentrations of the soluble P-selectin were significantly increased between 15 mins and 24 hrs after the start of cardiopulmonary resuscitation. The concentrations of soluble intercellular adhesion molecule-1 were increased between 2 hrs and 72 hrs.Our data clearly demonstrate a marked activation of complement and PMN and an increased PMN-endothelial interaction during cardiopulmonary resuscitation and early reperfusion after cardiac arrest in humans. These changes are known to induce reperfusion disorders and tissue injury and point to new therapeutic options to improve outcome after cardiac arrest.

Background.Oxidative stress and leukocyte-endothelial interactions contribute significantly to the reperfusion injury of the transplanted liver. Therefore, we investigated the effect of N-acetylcysteine (NAC) on reperfusion injury and circulating adhesion molecules during human liver transplantation

1. The effects of propentofylline (PPF, 25 mg kg(-1) body weight per day) on rat cerebral energy state and cytokine expression as well as on behaviour and histopathology were studied after acute and long-term permanent bilateral common carotid artery occlusion (BCCAO). 2. In the absence of PPF, acute ischaemia led to a decrease in energy-rich phosphates in parietotemporal cortex and hippocampus which correlated with an increase in AMP and adenosine concentrations measured by high-performance liquid chromatography technique. The concentrations of cortical cytokines TNF alpha and IL1 beta were increased 12 and 19 fold, respectively. 3. PPF had a neuroprotective action after 20 min of BCCAO, reducing the deleterious effect of acute ischaemia on rat brain energy state and microglial reaction. Simultaneously, PPF treatment increased cyclic-AMP 3 fold. 4. Three weeks of permanent BCCAO did not significantly disturb brain energy metabolism, microglial reaction or histopathology. However, a significant reduction of 30 -- 50% in rat memory capacities and a locomotor hyperactivity were obtained. 5. Continuous PPF-application, however, led to a marked increase in rat working memory and to reduced locomotor activity, which were returned nearly to control levels by 1 week after permanent BCCAO. In summary, PPF showed a clear neuroprotective effect on cerebral energy state and pro-inflammatory cytokines under conditions of acute global ischaemia. Continuous administration of PPF led to memory improvement during permanent BCCAO. 6. These results underscore the benefit of treatment with PPF in clinical practice, particularly during stroke, but also in cerebrovascular and neurodegenerative disorders.

According to Traditional Chinese Medicine (TCM) acupuncture is a suitable treatment for complex chronic diseases such as bronchial asthma. In a randomized, controlled study we investigated immunologic effects of Chinese acupuncture on patients with allergic asthma.The effects of acupuncture treatment given according to the principles of TCM (TCM group, n = 20) were compared with those of acupuncture treatment using points not specific for asthma (control group, n = 18). All patients were treated 12 times for 30 minutes over a time period of 4 weeks. Patients' general well-being and several peripheral blood parameters (eosinophils, lymphocyte subpopulations, cytokines, in vitro lymphocyte proliferation) were determined before and after acupuncture treatment.In the TCM group, significantly more patients indicated an improvement in general well-being (79% in the TCM group versus 47% in the control group; p = 0.049) after acupuncture treatment. The following changes were found in the TCM group: within the lymphocyte subpopulations the CD3+ cells (p = 0.005) and CD4+ cells (p = 0.014) increased significantly. There were also significant changes in cytokine concentrations: interleukin (IL)-6 (p = 0.026) and IL-10 (p = 0.001) decreased whereas IL-8 (p = 0.050) rose significantly. Additionally, the in vitro lymphocyte proliferation rate increased significantly (p = 0.035) while the number of eosinophils decreased from 4.4% to 3.3% after acupuncture (p0.05). The control group, however, showed no significant changes apart from an increase in the CD4+ cells (p = 0.012).The results imply that asthma patients benefit from acupuncture treatment given in addition to conventional therapy. Furthermore, acupuncture performed in accordance with the principles of TCM showed significant immune-modulating effects.

BACKGROUND: Inhalation of nitric oxide (iNO) has been proposed for the treatment of acute pulmonary embolism. The present study evaluates the effects of oxygen (O2) and nitric oxide inhalation in a porcine model of sustained pulmonary hypertension induced by recurrent pulmonary microembolism. METHODS: Twelve pigs were embolized under general anesthesia with 300-microm microspheres intravenously three times over a period of seven weeks. Five pigs served as untreated controls. Hemodynamic and gas exchange responses to 100% oxygen and 40 ppm NO inhalation, and their combination (O2+iNO) were measured seven days after the last embolization. RESULTS: Recurrent microembolism caused sustained pulmonary hypertension (pulmonary vascular resistance index; PVRI 408 +/- 57 dyn x s x cm(-5) x m(-2)) as compared to the control group (PVRI 143 +/- 20 dyn x s x cm(-5) m(-2); P

Purpose: To determine whether the compromised intestinal villus blood flow in a rat model of endotoxemia could be improved by continuous infusion of the phosphodiesterase (PDE) inhibitor milrinone. Methods: Twenty-four anesthetized and ventilated rats were laparotomized and an ileal portion was exteriorized and opened by an antimesenteric incision. The ileal segment was fixed with the mucosal surface upward. Microcirculatory parameters were assessed by intravital videomicroscopy. The animals were randomly assigned to receive one of three treatments: infusion ofEscherchia coli lipopolysaccharides without phosphodiesterase inhibitor pretreatment (=LPS group); or infusion of LPS with milrinone pretreatment (=milrinone group), or without infusion of LPS or milrinone (=control group). Macrohemodynamic parameters (MAP, HR) and microhemodynamic parameters of ileal mucosa (mean diameter of central arterioles=DA and mean erythrocyte velocity within the arterioles=VE) were measured 30 min before and at 0, 60, and 120 min after induction of endotoxemia. Mucosal villus blood flow was calculated from DA and VE. Results: In the milrinone group MAP decreased 60 min after induction of endotoxemia whereas it remained stable in the control and the LPS group. In both groups given endotoxin VE decreased after start of LPS infusion. In contrast, DA decreased in the LPS group, but increased in the milrinone group after 120 min of endotoxemia. Thus, the endotoxin-induced decrease of intestinal villus blood flow was diminished but not fully restored by milrinone infusion. Conclusion: Our results indicate that milrinone has some beneficial microcirculatory effects during endotoxemia. Although it contributed to systemic hypotension, it attenuated intestinal mucosal hypoperfusion.

In the present study, the effect of poly(ADP-ribose) polymerase (PARP) inhibition on rat cortical energy state was investigated at 24 h after global cerebral ischemia induced by permanent bilateral common carotid artery ligation plus transient hypotension. The specific PARP inhibitor 3-aminobenzamide was injected 10 min before induction of ischemia at a dosage of 5, 10, and 20 mg/kg intracerebroventricularly. Twenty-four hours after ischemia cortical PARP enzyme activity increased from 0.425±0.144 to 0.794±0.193 units/mg protein. Cerebral ischemia was associated by a decrease in adenosine triphosphate (ATP) and phosphocreatine concentrations to 72.5 and 76.8% of controls, respectively. In addition, an 1.9- and 2.2-fold increase in adenosine monophosphate and adenosine was observed. Specific PARP inhibition with 10 mg/kg 3-aminobenzamide protected the rat energy state by preserving cortical phosphocreatine and NAD + . Cortical ATP was not changed significantly after PARP inhibition. In conclusion, activation of the nuclear enzyme PARP plays an important role in cerebral energy metabolism during rat global ischemia. Therefore, specific PARP inhibition may offer new strategies in the therapy of vascular diseases such as stroke.

Chronic cerebrovascular disorders are often complicated by additional temporary ischaemic insults, resulting in substantial deterioration of brain energy metabolism. In the present study, chronic limitations of oxygen supply were induced in Wistar rats by 2 weeks of permanent bilateral common carotid artery occlusion (2-vo) to initiate a 'preconditioning-like' effect that protects rat brain energy metabolism against further acute systemic hypotension (15 min). Haemodynamic parameters, arterial blood gases and body temperature were monitored. Energy metabolites were determined in rat parietotemporal cerebral cortex: adenosine 5'-triphosphate (ATP), adenosine 5'-diphosphate (ADP), adenosine 5'-monophosphate (AMP), phosphocreatine (PCr), and adenosine by the high-pressure liquid chromatography (HPLC) technique and lactate spectrophotometrically. After 2 weeks, permanent 2-vo led to a significant decrease in the concentrations of cortical tissue ATP and PCr, from 3.06+/-0.48 to 2. 09+/-0.28 and from 4.27+/-0.63 to 3.35+/-0.41 micromol/g, respectively. These changes were associated with a two-fold increase in AMP and adenosine. Acute systemic hypotension alone (non-preconditioning) reduced ATP and PCr drastically, to 0.97+/-0. 51 and 1.76+/-1.23 micromol/g. Tissue concentrations of lactate, AMP, and adenosine were markedly increased, three- to five-fold, in 'non-preconditioned' brain tissue. In contrast, after 2 weeks of 2-vo acute hypotension did not significantly alter the cortical energy state any further. The effects of preconditioning on tissue ATP and PCr were most pronounced at 5 min and 48 h after reperfusion. In conclusion, permanent 2-vo seems to activate compensatory mechanisms, which effectively protect the rat's cortical energy metabolism against an additional ischaemic attack ('preconditioning-like' effect).

A decrease in liver blood flow leads to dysfunction of hepatocytes and Kupffer cells, with subsequent local and systemic liberation of proinflammatory mediators that may maintain systemic inflammatory response syndrome (SIRS) and may lead to multiple organ dysfunction syndrome (MODS). There is only limited knowledge on the hepatic micro- and macrocirculation during sepsis or endotoxemia. Therefore, the aim of our study was to investigate alterations in hepatic portal blood flow (PBF) and sinusoidal blood flow (SBF) during endotoxemia. In male Wistar rats endotoxemia was induced by continuous infusion of 2 mg/kg/h lipopolysaccharides from Escherichia coli 026:B6 immediately after baseline measurements (n = 8). The control group (n = 8) received an equivalent volume of Ringer's solution. Mean arterial pressure (MAP), heart rate (HR), cardiac output (CO), PBF, and SBF were measured at baseline and 60 and 120 min after induction of endotoxemia. PBF was measured using an ultrasonic flow probe that was positioned around the portal vein. SBF was detected by in vivo videomicroscopy of the left liver lobe. In the LPS group MAP decreased, but CO remained at baseline values. During endotoxemia PBF decreased significantly from 23 ± 3 to 15 ± 4 mL/min (60 min) and 16 ± 3 mL/min (120 min). SBF also significantly decreased to 68.5% (60 min) and 57.1% (120 min) of baseline value. Our results demonstrate that during early endotoxemia hepatic macro- and microcirculatory perfusion is significantly decreased despite unchanged CO. This early reduction of hepatic perfusion might be caused by an increased hepatic vessel resistance as a consequence of liberation of vasoconstrictive mediators or/and by a decrease in intestinal perfusion.

UNLABELLED Cytokine production, neutrophil adhesion to endothelial cells, and release of reactive oxygen species are thought to be critical events in sepsis or ischemia/reperfusion. Modulation of leukocyte responses by anesthetics may have an important role in limiting tissue injury under these conditions. Therefore, we investigated the effect of ketamine on the expression of CD18, CD62L, and oxygen radical production of human neutrophils in vitro and on interleukin-6 production in endotoxin-stimulated human whole blood. Ketamine inhibited both the N-formyl-methionyl-leucyl-phenylalanine- and phorbol 12-myristate 13-acetate-induced up-regulation of CD18 and shedding of CD62L, determined by flow cytometry, in a concentration-dependent manner. Ketamine also caused a significant suppression of oxygen radical generation of isolated human neutrophils. In addition, there was a significant decrease in endotoxin-stimulated interleukin-6 production in human whole blood. The inhibitory effects were similar for racemic ketamine and its isomers S(+)-ketamine and R(-)-ketamine, suggesting that the inhibition of stimulated neutrophil function is most likely not mediated through specific receptor interactions. IMPLICATIONS Modulation of leukocyte responses by anesthetics may have an important role in limiting tissue injury in sepsis or ischemia/reperfusion. Therefore, we examined the effect of ketamine on stimulated neutrophil functions in vitro. These neutrophil functions were significantly inhibited by ketamine, independent of whether the racemic mixture or isomers were tested.

Objective To determine whether treatment with patient-controlled analgesia (PCA) alone or in combination with nonsteroidal anti-inflammatory drugs can prevent postoperative pulmonary complications after cardiac surgery, when compared with conventional nurse-controlled analgesia. Design Randomized controlled trial. Setting University Medical Center. Patients A total of 120 patients undergoing elective coronary artery bypass grafting. Interventions After extubation of the trachea, 120 patients were randomly allocated to three different methods of postoperative pain relief for 72 hrs. In group 1, patients received PCA with a bolus of 1.5 mg piritramide combined with a 10-min lockout interval. Group 2 patients were treated with a combination of PCA and administration of nonsteroidal anti-inflammatory drugs prescribed three times per day. Patients of group 3 received conventional nurse-controlled analgesia. Postoperative assessment included daily visual analog pain scoring (VAS) and chest radiographs. All chest radiographs were graded for the extent of atelectasis by a radiologist blinded as to treatment using a scale from 0 to 9 for each of the three lung fields of the right and left lungs. Measurements and main results Chest radiograph atelectasis scores and VAS values were similar among the three groups on the first and second days. On the third day, the chest radiograph atelectasis scores of the left lower and the right middle lung field were significantly better in the groups treated with PCA alone (4.7 +/- 3.0; 0.3 +/- 1.0) and in combination with nonsteroidal anti-inflammatory drugs (3.9 +/- 1.1; 0.4 +/- 1.2) than in the control group (5.5 +/- 3.1; 0.8 +/- 1.8). Furthermore, on the third day, the VAS values for maximum pain were higher in the control group (42.6 +/- 19.7) compared with the VAS values in the two groups with PCA (32.2 +/- 17.9 and 34.5 +/- 21.0). Conclusions PCA significantly decreases postoperative pulmonary atelectasis in patients after coronary artery bypass grafting when compared with nurse-controlled analgesia. In addition, patients treated with PCA experienced a higher quality of analgesia. We therefore conclude that treatment with PCA may reduce respiratory complications after coronary artery bypass grafting.

Intensive care patients with organ failure often suffer an acute catabolic state. Leptin is a 16-kDa hormone which is produced by mature adipocytes and correlates with human energy expenditure. We investigated whether continuous venovenous haemofiltration, which may eliminate molecules up to 20-30 kDa, is capable of removing human leptin. Leptin measurements were made in the plasma of 15 patients with sepsis before continuous venovenous haemofiltration (T0) and during the procedure at 24 h (T1), 48 h (T2), and 72 h (T3), using samples taken before and after haemofiltration. In addition, measurements were made in the ultrafiltrate at T1-T3. The plasma leptin level at T0 was 17.6 ng mL-1. The concentration at T1 was 17.5 ng mL-1 pre-filter and 26.5 ng mL-1 post-filter (T2: 14.2/23.2 ng mL-1; T3: 12.4/16.3 ng mL-1). This concentration effect after haemofiltration was also seen with albumin. The values measured at T3 tended to be lower than those recorded at T1. The mean leptin levels in the ultrafiltrate were 0.15-0.18 ng mL-1. The range of leptin levels in the ultrafiltrate was thus only 0.5-3% of that measured in plasma. We conclude that human leptin is only minimally elimininated into the ultrafiltrate by continuous venovenous haemofiltration and that plasma leptin levels may decrease during sepsis.

Background For the human brain, there are no data available concerning the significance of adenosine and its metabolites as biochemical indicators of cerebral ischemia. Since adenosine may counteract key pathogenetic mechanisms during cerebral ischemia, its sensitivity and specificity as a marker of cerebral ischemia was investigated in relation to hypoxanthine and lactate. Methods Arterial and jugular venous concentration changes of adenosine, hypoxanthine, and lactate were studied in 41 patients undergoing carotid endarterectomy. Cerebral tissue oxygenation was monitored continuously by somatosensory-evoked potentials. A carotid artery shunt (n = 6) was placed only after complete loss of somatosensory-evoked potentials. Results Before carotid artery clamping jugular venous concentrations of adenosine, hypoxanthine, and lactate in subsequently shunted patients were 229+/-88 nM, 1105+/-116 nM, and 0.85+/-0.52 mM, respectively (mean +/- SD). In patients who required shunting, carotid artery clamping induced a significant increase in jugular venous adenosine (389+/-114 nM) and jugular venous hypoxanthine (1444+/-168 nM). In contrast, the increase in jugular venous lactate (0.91+/-0.48 mM) did not reach statistical significance. Focal cerebral ischemia was indicated by jugular venous adenosine with a sensitivity and specificity of 0.83 and 0.71, respectively. Conclusions Carotid artery clamping induced significant increases in jugular venous adenosine and hypoxanthine in patients with inadequate collateral blood flow. In addition, focal cerebral ischemia was reflected by changes in adenosine concentrations.

Background Although malignant hyperthermia after application of sevoflurane has been reported, little is known about its action on intracellular calcium homeostasis of skeletal muscle. The authors compared the effect of sevoflurane with that of isoflurane and halothane on Ca2+ release of mammalian sarcoplasmic reticulum and applied a novel method to quantify Ca2+ turnover in permeabilized skeletal muscle fibers. Methods Liquid sevoflurane, isoflurane, and halothane at 0.6 mM, 3.5 mM, and 7.6 mm were diluted either in weakly calcium buffered solutions with no added Ca2+ (to monitor Ca2+ release) or in strongly Ca2+ buffered solutions with [Ca2+] values between 3 nM and 24.9 microm for [Ca+]-force relations. Measurements were taken on single saponin skinned muscle fiber preparations of BALB/c mice. Individual [Ca2+]force relations were characterized by the Ca2+ concentration at half-maximal force that indicates the sensitivity of the contractile proteins and by the steepness. Each force transient was transformed directly into a Ca2+ transient with respect to the individual [Ca2+]-force relation of the fiber. Results At 0.6 mM, single force transients induced by sevoflurane were lower compared with equimolar concentrations of isoflurane and halothane (P < 0.05). Similarly, calculated peak Ca2+ transients of sevoflurane were lower than those induced by equimolar halothane (P < 0.05). The Ca2+ concentrations at half maximal force were decreased after the addition of sevoflurane, isoflurane, and halothane in a concentration-dependent manner (P < 0.05). Conclusion Whereas sevoflurane, isoflurane, and halothane similarly increase the Ca2+ sensitivity of the contractile apparatus in skeletal muscle fibers, 0.6 mM sevoflurane induces smaller Ca2+ releases from the sarcoplasmic reticulum than does equimolar halothane.

The present study investigates the interrelation between cerebral energy metabolism and memory capacities after acute and permanent occlusions of carotid and vertebral arteries in adult Wistar rats (n=60). Tissue ATP, phosphocreatine, ADP, AMP and adenosine concentrations were determined in rat brain by high-pressure liquid chromatography (HPLC) analysis. Lactate and pyruvate were measured spectrophotometrically. Rats underwent psychometric testing by means of a holeboard test, closed field activity, and passive avoidance behaviour. Acute cerebral ischaemia was associated with a substantial deficit in energy load (−50%). Cortical adenosine and lactate exhibited a 7- and a 10-fold increase, respectively, in concentration. After 2 weeks of four-vessel occlusion, cortical ATP and phosphocreatine showed a partial enhancement in their concentrations if compared with acute ischaemia. Consequently, energy load (μmol/g) increased from 0.59 to 1.42 in cerebral cortex and from 0.58 to 1.14 in hippocampus under conditions of acute and permanent ischaemia, respectively. While lactate was normalized, adenosine showed a 2-fold increase in its cortical concentration. All animals improved their abilities in learning, memory and cognition after a 7-day training period. Acute vessel occlusion severely decreased working memory (WM), reference memory (RM) and locomotor activity. Simultaneously, the passive avoidance test showed a significant reduction in latency time from 247±85 s (sham) to 145±132 s. The partial improvement in brain energy state was accompanied by a relative improvement in WM and RM, although both memory capacities remained significantly lower than in controls. The data of the present study demonstrate a linear relationship between cerebral energy metabolism and brain memory capacities after acute and permanent vessel occlusions in rats.

To analyze the role of specific genes and proteins in neuronal signaling cascades following global cerebral ischemia, it would be useful to have a reproducible model of global cerebral ischemia in mice that potentially allows the investigation of mice with specific genomic mutations. We first report on the development of a model of reversible cardiocirculatory arrest in mice and the consequences of such an insult to neuronal degeneration and expression of immediate early genes (IEG) in the hippocampus. Cardiocirculatory arrest of 5 min duration was induced via ventricular fibrillation in mechanically ventilated NMRI mice. After successful cardiopulmonary resuscitation (CPR), animals were allowed to reperfuse spontaneously for 3 h (n=7) and 7 days (n=7). TUNEL staining revealed a selective degeneration of a subset of neurons in the hippocampal CA1 sector at 7 days. About 30% of all TUNEL-positive nuclei showed condensed chromatin and apoptotic bodies. Immunohistochemical studies of IEG expression performed at 3 h exhibited a marked induction of c-Fos, c-Jun, and Krox-24 protein in all sectors of the hippocampus, peaking in vulnerable CA1 pyramidal neurons and in dentate gyrus. In contrast, sham-operated animals (n=3) did not reveal neuronal degeneration or increased IEG expression in the hippocampus when compared with untreated control animals (n=3). In conclusion, we present a new model of global cerebral ischemia and reperfusion in mice with the use of complete cardiocirculatory arrest and subsequent CPR. Following 5 min of ischemia, a subset of CA1 pyramidal neurons was TUNEL-positive at 7 days. The expression of IEG was observed in all sectors of the hippocampus, including selectively vulnerable CA1 pyramidal neurons. This appears to be a good model which should be useful in evaluating the role of various genes in transgenic and knockout mice following global ischemia.

OBJECTIVE: To compare silver-coated and uncoated central venous catheters regarding bacterial colonization. To assess the relative contribution of catheter hub and skin colonization to catheter tip colonization. DESIGN: Prospective, randomized clinical trial. SETTING: Intensive care unit in a university hospital. PATIENTS: Patients after cardiac surgery who required a central venous double-lumen catheter (DLC). INTERVENTIONS: Sixty-seven adult patients were prospectively randomized to receive either a silver-coated (S group, n = 34) or an uncoated control (C group, n = 33) DLC. Blood cultures were drawn at catheter removal, and removed catheters were analyzed with quantitative cultures. Typing of microorganisms included DNA fingerprinting. MEASUREMENTS AND MAIN RESULTS: Catheters were removed if no longer necessary and aseptically divided into three segments: segment A, the catheter tip; segment B, an intermediate section; and segment C, the subcutaneous portion. Bacterial catheter colonization was quantitatively measured using sonication to detach adherent bacteria from the catheter segments in the broth and subsequent culture of an aliquot. Selected isolates of coagulase-negative staphylococci and other bacteria from catheter segments were examined by means of pulsed-field gel electrophoresis (PFGE) after macrorestriction digestion of bacterial DNA to study colonization pathogenesis. Quantitatively lower bacterial colonization could be demonstrated on the silver-coated catheters (200 +/- 550 colony forming units [CFUs]/cm catheter segment; mean +/- SD). The difference in the control catheters (1120 +/- 5350 CFUs/cm catheter segment; mean +/- SD) was not, however, significant (p = .25). The frequency of colonization of at least one catheter segment was 52.9% for the silver-coated catheters and 57.6% for the control catheters (p= .44), without any significant differences in the colonization of corresponding catheter segments. The rate of significant catheter colonization (i.e., > or = 10(3) CFUs/cm catheter by quantitative catheter culture or > or = 10(3) CFUs/mL by luminal flush) was nine in the silver group and seven in the control group, a difference that failed to reach significance (p = .41). Two patients in both groups developed catheter-related bacteremia. Pattern analysis after PFGE demonstrated that about 70% of the isolates found on the catheter tip were identical with those on the skin at the insertion site, whereas about 75% were identical with those recovered from the hub. In 29% of colonized catheters, identical bacteria were found on the hub and the skin at the insertion site. CONCLUSIONS: Silver-coating of DLCs did not significantly reduce bacterial catheter colonization compared with the control catheters. PFGE analysis of coagulase-negative staphylococci and other bacteria demonstrated various pathogenic routes of catheter-related colonization, whereby the microorganisms of the skin flora around the insertion site must be regarded as the main source of catheter-related infections.

Background: C1-esterase inhibitor (C1-INH) has been shown to have beneficial effects in patients with sepsis. However, the microcirculatory effects of C1-INH during sepsis are unknown. This study investigated the influence of C1-INH on leukocyte-endothelial cell adhesion, vascular leakage, and venular microhemodynamics in postcapillary venules of rat mesentery during endotoxemia. Methods: Thirty-two anesthetized Wistar rats randomly received 1 of 4 treatments: pretreatment with infusion of C1-INH in a concentration of 7.5 U · kg -1 body weight (C1-INH-7.5 group, n = 8) or in a concentration of 15 U · kg -1 body weight (C1-INH-15 group, n = 8) followed by continuous infusion of Escherichia coli lipopolysaccharide (LPS). The LPS group (n = 8) was pretreated with saline solution 30 minutes before LPS infusion. The control group (n = 8) received equivalent amounts of saline infusion. Leukocyte adherence, red blood cell velocity, and vessel diameters in postcapillary venules of rat mesentery were determined every 60 minutes during a period of 120 minutes using in vivo videomicroscopy. Vascular permeability was determined by measuring the extravasation of fluorescence-labeled albumin. Venular wall shear rate was calculated from mean red blood cell velocity and vessel diameter. Results: LPS infusion induced a decrease in venular wall shear rate and an increase in leukocyte adherence and vascular permeability in postcapillary venules of rat mesentery. All microcirculatory disturbances were attenuated by pretreatment with C1-INH, showing no significant difference between the 2 concentrations. Conclusions: Pretreatment with C1-INH attenuates endotoxin-induced leukocyte adherence and macromolecular leakage in postcapillary venules of rat mesentery, indicating that complement inhibition might be a therapeutic tool in the treatment of sepsis. (Surgery 1999;125:280-7.)

Background: A new commercially available rapid qualitative bedside immunoassay for cardiac troponin T has been developed. The aim of the study was to investigate whether this new rapid bedside cardiac troponin T assay facilitates diagnosing myocardial infarction in a pre-hospital setting. Methods: We evaluated the sensitivity and specificity of the new rapid bedside troponin T assay for myocardial infarction. In 68 patients with acute, central, crushing chest pain, who were strongly suspected of having myocardial infarction, the emergency doctor performed preclinically a bedside cardiac troponin T test. The results were compared with the diagnosis after admission to hospital, using the criteria of the World Health Organization. Results: The diagnosis of myocardial infarction was confirmed in 16/68 (24%) patients after admission to hospital, but only in 4/16 (25%) patients with myocardial infarction was a positive result observed preclinically with this test. The result was false positive in 1/5 patients (20%). Conclusions: In contrast to an excellent specificity (0.98), sensitivity (0.25) of the rapid troponin T assay was poor. Thus, we conclude that this test cannot improve the distinction between myocardial infarction and angina pectoris in a pre-hospital setting.

The objective of this study was to examine the intestinal metabolism of high-energy purine compounds as sensitive indicators of tissue ischemia during endotoxemia. Arterial (art) and portal venous (PV) concentrations as well as the intestinal net concentration changes of adenosine (ADO), hypoxanthine (Hypo), and uric acid (UA) were measured at baseline and after 60 and 120 min in rats that were subjected to a 1-hr continuous infusion of endotoxin (1.5 mg/kg; group E), and in control animals (group C). Furthermore, the arterial (SaO2) and portal venous oxygen saturation (S(PV)O2) was determined at the same time points. Animals in both groups remained normotensive throughout the study period and no differences in mean arterial blood pressure were observed. In both groups, adenosine concentrations remained constant throughout the study and no changes in the net concentration difference (NCD) of adenosine between arterial and portal venous blood were observed [ADO(NCD); baseline: group E, -23 +/- 46 nmole/L; group C, 17 +/- 84 nmole/L; 120 min: group E, 14 +/- 38 nmole/L; group C, 5 +/- 40 nmole/L]. In contrast to control animals, hypoxanthine and uric acid concentrations increased in arterial and portal venous blood in endotoxemic rats after 120 min. This was accompanied with an increase in the intestinal net concentration differences of both hypoxanthine and uric acid, indicating the gut as the predominant source of these two compounds during endotoxemia [Hypo(NCD); baseline: group E, -36 +/- 53 nmole/L; group C, -53 +/- 185 nmole/L; 120 min: group E, 538 +/- 211 nmole/L; group C, 99 +/- 100 nmole/L] [UA(NCD); baseline: group E, 2.04 +/- 1.62 micromole/L; group C, -0.04 +/- 1.11 micromole/L; 120 min: group E, 9.58 +/- 3.04 micromole/L; group C, 0.35 +/- 1.34 micromole/L]. Furthermore, in endotoxemic rats the portal venous oxygen saturation decreased despite unaltered arterial oxygen saturation [SaO2; baseline: group E, 95.2 +/- 0.9%; group C, 94.2 +/- 0.9%; 120 min: group E, 95.4 +/- 0.7%; group C, 96.4 +/- 0.9%] [S(PV)O2; baseline: group E, 86.2 +/- 3.1%; group C, 85.7 +/- 1.4%; 120 min: group E, 69.1 +/- 4.5%; group C, 82.3 +/- 1.9%]. These results indicate the presence of tissue ischemia in the intestinal tract during early, normotensive endotoxemia. Furthermore, because of the direct toxic damage mediated by oxygen radicals that are generated during the production of uric acid, intestinal mucosal injury observed during endotoxemia may be related to an enhancement of the ATP-degradation pathway.

Purpose: Although it is known that weaning from mechanical ventilation is associated with alterations in intrathoracic pressure, lung volume, and venous return, changes in intrathoracic fluid volumes during weaning are not reported. Especially in patients with impaired cardiac function, the development of pulmonary edema during weaning has been described. Thus, we investigated changes in intrathoracic fluid volumes in patients after coronary artery bypass grafting after changing the ventilatory pattern from mechanical to spontaneous ventilation. Materials and methods: Intrathoracic blood volume index (ITBVI), pulmonary blood volume index (PBVI), and extravascular lung water (EVLW) were calculated during mechanical ventilation (T1), Tpiece breathing (T2), and spontaneous breathing after extubation of the trachea (T3) in 72 consecutive patients after coronary artery bypass grafting using a combined dye-thermal dilution method. Results: Changing from mechanical ventilation to T-piece breathing resulted in an increase in ITBVI from 880 ± 22 mL/m2 to 970 ± 22 mL/m2 (P < .01), and in PBVI from 162 ± 6 mL/m2 to 173 ± 6 mL/m2 (P < .01). After extubation of the trachea, both parameters decreased again (ITBVI, 879 ± 20 mL/m2; PBVI, 160 ± 7 mL/m2). EVLW remained unchanged after transition to T-piece breathing (T1, 5.8 ± 0.3 mL/kg; T2, 6.0 ± 0.3 mL/kg), but increased to 6.6 ± 0.5 mL/kg (P < .01) after extubation of the trachea. However, pathological values of EVLW were not observed. Conclusions: In patients after coronary artery bypass grafting, changes in intrathoracic intravascular fluid volumes during weaning are restricted to the period of T-piece breathing and reflect an increased venous return. The maintenance of EVLW in the normal range during weaning indicates that cardiac function was matched to this elevated preload.

Background Inhaled nitric oxide (NO) is reported to prolong bleeding time in animals and humans and to inhibit platelet aggregation in persons with acute respiratory distress syndrome. In pulmonary embolism (PE), inhibition of platelet aggregation appears useful because further thrombus formation may lead to right ventricular dysfunction that results in circulatory failure. In the present study, the effect of inhaled NO on platelet aggregation after acute massive PE was investigated. Methods After acute massive PE was induced in 25 anesthetized pigs by injecting microspheres, 5, 20, 40, and 80 parts per million inhaled NO were administered stepwise for 10 min each in 11 animals (NO group). In the control group (n = 14). NO was not administered. Adenosine diphosphate-induced initial and maximal platelet aggregation were measured before PE (10), immediately after induction of PE (PE), at the end of each 10-min NO inhalation interval (t10-t40), and 15 min after cessation of NO inhalation (t55) in the NO group, and at corresponding times in the control group, respectively. Results Two animals in the control group and one in the NO group died within 10 min after PE induction and were excluded from analysis. Peaking at t40 and t55, respectively, initial (-13 +/- 6%; P < 0.05) and maximal (+44 +/- 17%; P < 0.05) platelet aggregation increased significantly after PE in the control group. In contrast, NO administration after PE led to a significant decrease in initial (maximum decrease, -9 +/- 3% at t40; P < 0.05) and maximal (maximum decrease, -15 +/- 7% at t30; P < 0.05) platelet aggregation. In the NO group, platelet aggregation had returned to baseline levels again at t55. In addition, NO administration significantly decreased mean pulmonary artery pressure and significantly increased end-tidal carbon dioxide concentration and mean systemic blood pressure. Conclusions Inhaled NO has a systemic and rapidly reversible inhibitory effect on platelet aggregation after acute massive PE in pigs. This may be beneficial in treating acute massive PE.

Objective: Experimental data indicate that early microcirculatory reperfusion is disturbed after cardiac arrest. We investigated the influence of prolonged cardiac arrest and basic life support (BLS) procedures on the quality of cerebral microcirculatory reperfusion. Materials and methods: In mechanically ventilated male Wistar rats anesthetized with N 2 O and halothane, cardiac arrest was induced by electrical fibrillation. Ten animals (group I) were subjected to 17 min of cardiac arrest (no-flow). Nine additional animals (group II) underwent only 12 min of cardiac arrest (no-flow), which was followed by a 5-min phase of BLS (i.e. mechanical ventilation and external cardiac compressions). In both groups, advanced resuscitation procedures including mechanical ventilation, external cardiac massage, 0.2 mg kg −1 epinephrine, 0.5 mmol kg −1 NaHCO 3 , and defibrillation were started 17 min after induction of cardiac arrest. The perfusion of the cerebral microcirculation was visualized by injection of 0.3 g kg −1 15% fluorescein isothiocyanate (FITC)–albumin 5 min after restoration of spontaneous circulation (ROSC), and the animals were decapitated 2 min later. The left hemispheres were fixed in 4% formalin, and coronal sections of 200 μ m thickness at three different standard levels of the rat brain were investigated using fluorescence microscopy. Areas without capillary filling (cerebral `no-reflow') were identified and calculated. Results: ROSC could be achieved in five of 10 animals (50%) of group I, and in six of nine animals (67%) of group II ( P =n.s.). The severity of cerebral `no-reflow' was higher in group II compared with group I (6.9±7.6 vs. 0.7±0.7% of total sectional areas; P ≤0.05). Two sham-operated animals showed homogeneous reperfusion. Conclusions: Wistar rats did not develop a marked cerebral `no-reflow' phenomenon after circulatory arrest. A relevant degree of cerebral `no-reflow' occurred, however, in animals subjected to a phase of BLS before circulatory stabilization. Therefore, low-flow states following prolonged cardiocirculatory arrest may aggravate early cerebral microcirculatory reperfusion disorders.

Christina Haarmann, DVM, Sabine Tacke, DVM, Pamela Doppler, MD, Werner Schmidt, PhD, Martha Maria Gebhard, PhD, Eike Martin, PhD Department of Veterinary Clinical Sciences, Clinic for Small Animals Surgery, Justus-Liebig-University of Giessen, Giessen, Germany Department of Anaesthesiology, University of Heidelberg, Heidelberg, Germany Department of Experimental Surgery, University of Heidelberg, Heidelberg, Germany

Acute massive pulmonary embolism increases pulmonary artery pressure (PAP) and pulmonary vascular resistance (PVR), which may lead to early right ventricular failure and subsequent cardiocirculatory deterioration. Inhaled nitric oxide (NO) selectively dilates pulmonary vessels in vivo. Thus, inhaled NO may be useful in preventing cardiocirculatory deterioration following pulmonary embolism. We investigated the effects of inhaled NO in the acute phase of massive pulmonary microembolism in 10 anesthetized and mechanically ventilated piglets (body weight, 18 +/- 2 kg). Microspheres of 300-microns diameter were injected i.v. in an amount sufficient to initially increase mean PAP to 45 mm Hg. Forty-five minutes after pulmonary embolization, the pretreatment control values were recorded. Thereafter, the piglets inhaled 40 ppm NO, and subsequently 80 ppm NO. When 40 ppm NO was inhaled, there was a significant decrease in systolic PAP (-10.3%; 44.5 +/- 2.2 to 39.9 +/- 2.4 mm Hg; p < 0.05) and mean PAP (-9.4%; 32.9 +/- 1.3 to 29.8 +/- 1.3 mm Hg; p < 0.05). PVR was changed by -13.6% (p = 0.07). Administration of 80 ppm NO resulted in a significant decrease in systolic PAP (-12.6%; to 38.9 +/- 1.9 mm Hg; p < 0.05), mean PAP (-11.9%; to 29.0 +/- 1.4 mm Hg; p < 0.05), and PVR (-19.4%; p < 0.05) compared with pretreatment values. Discontinuation of NO inhalation was associated with an immediate return to pretreatment values. Systemic hemodynamics and the arterial and mixed venous oxygen concentrations remained unchanged. We conclude that inhaled NO following acute massive pulmonary microembolism selectively decreases PAP and PVR without influencing systemic hemodynamics in piglets.

Dynamic cardiomyoplasty is a therapeutic possibility in irreversible cardiac insufficiency. With this operation, the latissimus dorsi muscle is mobilised and drawn into the thorax where it is placed around the heart. Lateral and supine positioning as well as thoracotomy and direct manipulation of the heart are associated with particular risks during surgery. Eight patients with the diagnosis of cardiomyopathy underwent cardiomyoplasty. The patients were classified as NYHA III-IV. Continuous dobutamine infusions were routinely started after induction of anaesthesia. All patients were intubated with single-lumen tubes. After sternotomy, lidocaine was administered. Monitoring included Swan-Ganz catheterisation and invasive blood pressure measurement. With early use of inotropic and vasodilatator agents the cardiac index and peripheral vascular resistance were adequately maintained. Double-lumen intubation seems to be unnecessary during cardiomyoplasty and only increases patient risk. Prophylactic lidocaine infusions are effective in preventing ventricular tachycardia and fibrillation. We conclude that adequate intraoperative management can improve the haemodynamic status of these patients so that cardiomyoplasty may be performed without significant morbidity.

Tonometric measurement of gastric intramural pH (pHi) is a noninvasive method to assess adequacy of splanchnic perfusion. Calculation of pHi may be influenced by various factors. This prospective study was designed to determine if stress ulcer prophylaxis with sucralfate interferes with pHi measurement. Twenty-five adult patients admitted to the intensive care unit (ICU) after open heart surgery were studied. Nasogastric tonometers were placed. Patients received sucralfate 1 g via the nasogastric tube 8 hours after termination of surgery, thereafter every 6 hrs. Gastric luminal pH and intramural pH were determined immediately prior and 1 hour after the first sucralfate administration. Gastric intramural pH was calculated from the arterial HCO3- concentration and the tonometrically determined intraluminal PCO2 value using the Henderson-Hasselbalch equation. Intraluminal PCO2(ss) was measured to 6.86 +/- 0.75 kPa prior to sucralfate administration as compared to 6.96 +/- 0.68 kPa 1 hour after 1 g sucralfate (P = 0.92). Intramural pH, as calculated by tonometry, was 7.31 +/- 0.05 vs 7.31 +/- 0.05, and was thus not influenced by sucralfate administration (P = 0.97). Mean gastric intraluminal juice pH was 4.2 +/- 1.3 compared to 4.2 +/- 1.2 (P = 0.59). These data suggest that sucralfate does not interfere with tonometrically determined intraluminal PCO2 measurement and calculation of gastric intramural pH.

Dysfunctions of the L-arginine (L-arg)/nitric-oxide (NO) pathway are suspected to be important for the pathogenesis of multiple organ dysfunction syndrome (MODS) in septic shock. Therefore plasma concentrations of L-arg and asymmetric dimethylarginine (ADMA) were measured in 60 patients with septic shock, 30 surgical patients and 30 healthy volunteers using enzyme linked immunosorbent assay (ELISA) kits. Plasma samples from patients with septic shock were collected at sepsis onset, and 24 h, 4 d, 7 d, 14 d and 28 d later. Samples from surgical patients were collected prior to surgery, immediately after the end of the surgical procedure as well as 24 h later and from healthy volunteers once. In comparison to healthy volunteers and surgical patients, individuals with septic shock showed significantly increased levels of ADMA, as well as a decrease in the ratio of L-arg and ADMA at all timepoints. In septic patients with an acute liver failure (ALF), plasma levels of ADMA and L-arg were significantly increased in comparison to septic patients with an intact hepatic function. In summary it can be stated, that bioavailability of NO is reduced in septic shock. Moreover, measurements of ADMA and L-arg appear to be early predictors for survival in patients with sepsis-associated ALF.

The use of inhaled nitric oxide (NO) in a five-year-old boy following cardiac surgery for a complex lesion is reported. Pulmonary hypertension causing right ventricular failure and severe hypoxaemia was dramatically reversed by 40 ppm NO added to the inhaled gases. The patient eventually died from the results of left ventricular failure.

Thrombolytic therapy has proved to be efficacious in the treatment of massive and fulminant pulmonary embolism (PE), but thrombolysis has been considered as contraindicated during cardiopulmonary resuscitation (CPR). This review on the administration of thrombolytic agents in patients who have suffered massive PE necessitating CPR summarises 14 anecdotal reports and three case series involving 34 patients. The case series revealed an overall initial survival rate of 55–100% following bolus administration of thrombolytic agents. In general, bleeding complications were managed conservatively. The establishment of the diagnosis may be feasible using echocardiography or bedside angiography during CPR. However, therapeutic measures should be taken without delay; the patient's history and the clinical picture may thus be the only diagnostic criteria. Even where myocardial infarction is misinterpreted as PE during CPR, bolus injection of a thrombolytic agent can be an appropriate therapeutic option. An alternative may be mechanical catheter fragmentation of the thrombus with subsequent local thrombolysis. Surgery may be restricted to hospitals with ready access to extracorporeal circulation. We conclude that early administration of thrombolytic agents during PE necessitating CPR may help to reduce mortality. We favour the administration of urokinase (2– to 3 000 000-U bolus) or rt-PA.

OBJECTIVE Nitric oxide (NO), an endogenous endothelium-derived relaxing factor, produces profound relaxation of vascular smooth muscle. Thus, inhaled NO is a potent and selective pulmonary vasodilator that may be useful for treatment of pulmonary hypertension of different aetiologies. However, the main danger of NO inhalation is spontaneous formation of toxic nitrogen dioxide (NO2) if NO is added to an oxygen-containing gas mixture. This chemical reaction depends on the time available for the oxidation and the concentration of NO and oxygen. The aim of this study was to assess in vitro the spontaneous formation of NO2 during administration of various NO concentrations with a ventilator. A modified ventilator system is described which can deliver NO within clinically relevant concentrations avoiding excessive formation of toxic NO2. METHODS The system was evaluated using an artificial lung. NO and NO2 concentrations were measured by chemiluminescence at the proximal and distal end of the inspiratory limb. In-vitro NO2 formation was assessed during administration of 10, 20, 40, 80 ppm NO while ventilating with an FiO2 of 0.25, 0.5 and 0.75, an inspiratory minute volume of 5, 7.5 and 10 l/min (IMV) and a respiratory rate of 12/min. RESULTS NO2 concentration correlated with increasing FiO2 and NO concentration and was inversely correlated to IMV. While ventilating with 5-40 ppm NO, an FiO2 of 0.25-0.75 and an IMV of 10 l per minute, the NO2 formation was measured to be less than 0.2 ppm and thus not clinically relevant. During administration of 80 ppm NO the NO2 formation increased to 0.3-0.6 ppm. CONCLUSION We conclude that for patients safety concentrations less than 80 ppm of inhaled NO should be used with this ventilator system. In addition, online monitoring of the NO2 concentration in the inspiratory limb should always be performed.