[Ultrasound-guided peripheral venous puncture in patients with a poor venous status]. / Die ultraschallgesteuerte periphere Venenpunktion bei schlechtem Venenstatus.

BACKGROUND: In the case of a poor peripheral venous status the use of conventional approaches is associated with several failed attempts, delay of treatment, increased pain and escalation to more invasive techniques. Ultrasound-guided venous access has become increasingly popular for difficult venous access; however, in German-speaking countries it has not yet become as popular as in English-speaking countries. First attempt success rates are high, but the factors contributing to the time needed for ultrasound-guided venous access are not well investigated. It is hypothesized that body mass index (BMI), vein diameter and depth contribute to the time needed for successfully establishing a peripheral vein access in patients with a difficult venous status. METHODS: This study included 68 patients with a poor venous status. After written consent was obtained patient characteristics were documented and upper extremity veins eligible for access were scanned with ultrasound with the aim of performing an ultrasound-guided venous access. The following time periods were documented: 1) first skin contact with the ultrasound probe, 2) time to identify an accessible vein, 3) time for venous access. RESULTS: Of the patients 67 were successfully punctured by ultrasound-guided venous access, 65 at the first attempt and 2 at the second attempt. In one patient conventional venous access was obtained at the same time. A higher BMI was associated with a significantly shorter total puncture time (+1 BMI point ≙ -2.25 s) and a shorter vein identification time (+1 BMI point ≙ -1.82 s). A greater vein diameter correlated with a shorter total time (-14.23 s/mm) and a greater depth correlated with an increased total time (+1.65 s/mm). CONCLUSION: A greater vein diameter and a higher BMI contribute to a shorter time period for ultrasound-guided venous access. Obese patients with difficult venous access may benefit from ultrasound-guided venous access, which could be explained by the imaging contrast with a higher proportion of subcutaneous fatty tissue.

Optimized Ki-67 staining in murine cells: a tool to determine cell proliferation.

The reliable analysis of the cell cycle status has become increasingly relevant for scientific and clinical work, especially for the determination of tumor cell growth. One established method to characterize the proliferation activity of cells is the analysis of the Ki-67 protein. Ki-67 is expressed in the nucleus during the whole cell cycle except for the G0 phase. Several different protocols exist for the examination of the Ki-67 protein in tissue and cell culture, but most of them are defined for human cells. For the analysis of the Ki-67 protein in murine tissue and cell culture there is a variety of protocols existing which recommend different fixation and permeabilization reagents or special kits. In this study, we established a reliable protocol for Ki-67 staining in murine cells and tissue based on PFA fixation, which can be used not only for flow cytometry but also for immunofluorescence microscopy analysis. We tested our protocol successfully with three different Ki-67 anti-mouse antibodies in cell culture, regenerating liver tissue and mouse melanoma tumor to demonstrate the general applicability.

Prospective observational cohort study of the association between antiplatelet therapy, bleeding and thrombosis in patients with coronary stents undergoing noncardiac surgery.

BACKGROUND: The perioperative management of antiplatelet therapy in noncardiac surgery patients who have undergone previous percutaneous coronary intervention (PCI) remains a dilemma. Continuing dual antiplatelet therapy (DAPT) may carry a risk of bleeding, while stopping antiplatelet therapy may increase the risk of perioperative major adverse cardiovascular events (MACE). METHODS: Occurrence of Bleeding and Thrombosis during Antiplatelet Therapy In Non-Cardiac Surgery (OBTAIN) was an international prospective multicentre cohort study of perioperative antiplatelet treatment, MACE, and serious bleeding in noncardiac surgery. The incidences of MACE and bleeding were compared in patients receiving DAPT, monotherapy, and no antiplatelet therapy before surgery. Unadjusted risk ratios were calculated taking monotherapy as the baseline. The adjusted risks of bleeding and MACE were compared in patients receiving monotherapy and DAPT using propensity score matching. RESULTS: A total of 917 patients were recruited and 847 were eligible for inclusion. Ninety-six patients received no antiplatelet therapy, 526 received monotherapy with aspirin, and 225 received DAPT. Thirty-two patients suffered MACE and 22 had bleeding. The unadjusted risk ratio for MACE in patients receiving DAPT compared with monotherapy was 1.9 (0.93-3.88), P=0.08. There was no difference in MACE between no antiplatelet treatment and monotherapy 1.03 (0.31-3.46), P=0.96. Bleeding was more frequent with DAPT 6.55 (2.3-17.96) P=0.0002. In a propensity matched analysis of 177 patients who received DAPT and 177 monotherapy patients, the risk ratio for MACE with DAPT was 1.83 (0.69-4.85), P=0.32. The risk of bleeding was significantly greater in the DAPT group 4.00 (1.15-13.93), P=0.031. CONCLUSIONS: OBTAIN showed an increased risk of bleeding with DAPT and found no evidence for protective effects of DAPT from perioperative MACE in patients who have undergone previous PCI.

Cardiovascular magnetic resonance assessment of acute cardiovascular effects of voluntary apnoea in elite divers.

BACKGROUND: Prolonged breath holding results in hypoxemia and hypercapnia. Compensatory mechanisms help maintain adequate oxygen supply to hypoxia sensitive organs, but burden the cardiovascular system. The aim was to investigate human compensatory mechanisms and their effects on the cardiovascular system with regard to cardiac function and morphology, blood flow redistribution, serum biomarkers of the adrenergic system and myocardial injury markers following prolonged apnoea. METHODS: Seventeen elite apnoea divers performed maximal breath-hold during cardiovascular magnetic resonance imaging (CMR). Two breath-hold sessions were performed to assess (1) cardiac function, myocardial tissue properties and (2) blood flow. In between CMR sessions, a head MRI was performed for the assessment of signs of silent brain ischemia. Urine and blood samples were analysed prior to and up to 4 h after the first breath-hold. RESULTS: Mean breath-hold time was 297 ± 52 s. Left ventricular (LV) end-systolic, end-diastolic, and stroke volume increased significantly (p < 0.05). Peripheral oxygen saturation, LV ejection fraction, LV fractional shortening, and heart rate decreased significantly (p < 0.05). Blood distribution was diverted to cerebral regions with no significant changes in the descending aorta. Catecholamine levels, high-sensitivity cardiac troponin, and NT-pro-BNP levels increased significantly, but did not reach pathological levels. CONCLUSION: Compensatory effects of prolonged apnoea substantially burden the cardiovascular system. CMR tissue characterisation did not reveal acute myocardial injury, indicating that the resulting cardiovascular stress does not exceed compensatory physiological limits in healthy subjects. However, these compensatory mechanisms could overly tax those limits in subjects with pre-existing cardiac disease. For divers interested in competetive apnoea diving, a comprehensive medical exam with a special focus on the cardiovascular system may be warranted. TRIAL REGISTRATION: This prospective single-centre study was approved by the institutional ethics committee review board. It was retrospectively registered under ClinicalTrials.gov (Trial registration: NCT02280226 . Registered 29 October 2014).

Use of failure-to-rescue to identify international variation in postoperative care in low-, middle- and high-income countries: a 7-day cohort study of elective surgery.

BACKGROUND: The incidence and impact of postoperative complications are poorly described. Failure-to-rescue, the rate of death following complications, is an important quality measure for perioperative care but has not been investigated across multiple health care systems. METHODS: We analysed data collected during the International Surgical Outcomes Study, an international 7-day cohort study of adults undergoing elective inpatient surgery. Hospitals were ranked by quintiles according to surgical procedural volume (Q1 lowest to Q5 highest). For each quintile we assessed in-hospital complications rates, mortality, and failure-to-rescue. We repeated this analysis ranking hospitals by risk-adjusted complication rates (Q1 lowest to Q5 highest). RESULTS: A total of 44 814 patients from 474 hospitals in 27 low-, middle-, and high-income countries were available for analysis. Of these, 7508 (17%) developed one or more postoperative complication, with 207 deaths in hospital (0.5%), giving an overall failure-to-rescue rate of 2.8%. When hospitals were ranked in quintiles by procedural volume, we identified a three-fold variation in mortality (Q1: 0.6% vs Q5: 0.2%) and a two-fold variation in failure-to-rescue (Q1: 3.6% vs Q5: 1.7%). Ranking hospitals in quintiles by risk-adjusted complication rate further confirmed the presence of important variations in failure-to-rescue, indicating differences between hospitals in the risk of death among patients after they develop complications. CONCLUSIONS: Comparison of failure-to-rescue rates across health care systems suggests the presence of preventable postoperative deaths. Using such metrics, developing nations could benefit from a data-driven approach to quality improvement, which has proved effective in high-income countries.

Preoperative patient assessment: Identifying patients at high risk.

Postoperative mortality remains alarmingly high with a mortality rate ranging between 0.4% and 4%. A small subgroup of multimorbid and/or elderly patients undergoing different surgical procedures naturally confers the highest risk of complications and perioperative death. Therefore, preoperative assessment should identify these high-risk patients and stratify them to individualized monitoring and treatment throughout all phases of perioperative care. A "tailored" perioperative approach might help further reduce perioperative morbidity and mortality. This article aims to elucidate individual morbidity-specific risks. It further suggests approaches to detect patients at the risk of perioperative complications.

Do intravascular hypo- and hypervolaemia result in changes in central blood volumes?

BACKGROUND: Hypovolaemia is generally believed to induce centralization of blood volume. Therefore, we evaluated whether induced hypo- and hypervolaemia result in changes in central blood volumes (pulmonary blood volume (PBV), intrathoracic blood volume (ITBV)) and we explored the effects on the distribution between these central blood volumes and circulating blood volume (Vd circ). METHODS: Six anaesthetized, spontaneously breathing Foxhound dogs underwent random blood volume alterations in steps of 150 ml (mild) to 450 ml (moderate), either by haemorrhage, retransfusion of blood, or colloid infusion. PBV, ITBV and Vd circ were measured using (transpulmonary) dye dilution. The PBV/Vd circ ratio and the ITBV/Vd circ ratio were used as an assessment of blood volume distribution. RESULTS: 68 blood volume alterations resulted in changes in Vdcirc ranging from -33 to +31%. PBV and ITBV decreased during mild and moderate haemorrhage, while during retransfusion, PBV and ITBV increased during moderate hypervolaemia only. The PBV/Vd circ ratio remained constant during all stages of hypo- and hypervolaemia (mean values between 0.20-0.22). This was also true for the ITBV/Vd circ ratio, which remained between 0.31 and 0.32, except for moderate hypervolaemia, where it increased slightly to 0.33 (0.02), P<0.05. CONCLUSIONS: Mild to moderate blood volume alterations result in changes of Vd circ, PBV and ITBV. The ratio between the central blood volumes and Vd circ generally remained unaltered. Therefore, it could be suggested that in anaesthetized spontaneously breathing dogs, the cardiovascular system maintains the distribution of blood between central and circulating blood volume.

Preoperative abnormalities in serum sodium concentrations are associated with higher in-hospital mortality in patients undergoing major surgery.

BACKGROUND: Abnormal serum sodium concentrations are common in patients presenting for surgery. It remains unclear whether these abnormalities are independent risk factors for postoperative mortality. METHODS: This is a secondary analysis of the European Surgical Outcome Study (EuSOS) that provided data describing 46 539 patients undergoing inpatient non-cardiac surgery. Patients were included in this study if they had a recorded value of preoperative serum sodium within the 28 days immediately before surgery. Data describing preoperative risk factors and serum sodium concentrations were analysed to investigate the relationship with in-hospital mortality using univariate and multivariate logistic regression techniques. RESULTS: Of 35 816 (77.0%) patients from the EuSOS database, 21 943 (61.3%) had normal values of serum sodium (138-142 mmol litre(-1)) before surgery, 8538 (23.8%) had hyponatraemia (serum sodium ≤137 mmol litre(-1)) and 5335 (14.9%) had hypernatraemia (serum sodium ≥143 mmol litre(-1)). After adjustment for potential confounding factors, moderate to severe hypernatraemia (serum sodium concentration ≥150 mmol litre(-1)) was independently associated with mortality [odds ratio 3.4 (95% confidence interval 2.0-6.0), P<0.0001]. Hyponatraemia was not associated with mortality. CONCLUSIONS: Preoperative abnormalities in serum sodium concentrations are common, and hypernatraemia is associated with increased mortality after surgery. Abnormalities of serum sodium concentration may be an important biomarker of perioperative risk resulting from co-morbid disease.

[Perioperative risk and mortality after major surgery]. / Perioperatives Risiko und Letalität nach großen chirurgischen Eingriffen.

Although anesthesia-associated mortality has been significantly reduced down to 0.00068-0.00082% over the last decades, recent studies have revealed a high perioperative mortality of 0.8- 4%. Apart from anesthesia and surgery-induced major complications, perioperative mortality is primarily negatively influenced by individual patient comorbidities. These risk factors predispose for acute critical incidents (e.g., myocardial infarction); however, the majority of fatal complications are a result of slowly progressing conditions, particularly infections or the sequelae of systemic inflammation. This implicates a broad window of opportunity for the detection and treatment of slow-onset complications to improve the perioperative outcome. The term "failure to rescue" (FTR), i.e., the proportion of patients who die from major complications compared to the number of all patients with complications, has been introduced as a valid indicator for the quality of perioperative care. Growing evidence has already shown that FTR is an underestimated factor in perioperative medicine accounting for or at least being involved in the development of postoperative mortality. While the incidence of severe postoperative complications amazingly does not show much variation between hospitals, FTR shows significant differences implying a major potential for improvement. With 14 million surgical procedures per year in Germany, a postoperative mortality of approximately 1% and an avoidable FTR rate of 40% mean that there are an estimated 60,000 preventable deaths per year. Hence, in the future it will be imperative to (1) identify patients at risk, (2) to prevent the development of postoperative complications with the use of adequate adjunctive therapeutic strategies, (3) to establish surveillance and monitoring systems for the early detection of postoperative complications and (4) to treat postoperative complications efficiently and in time when they arise.

Epidemiology of the high-risk population: perioperative risk and mortality after surgery.

PURPOSE OF REVIEW: This review will provide an overview of actual data concerning perioperative risk. Furthermore, strategies to prevent, detect and treat perioperative complications will be discussed. RECENT FINDINGS: Perioperative in-hospital mortality rate of 0.4-4% has not improved over the last years possibly resulting in one to several million deaths during or immediately after surgery each year worldwide. Perioperative complications and mortality are determined not only by the type of surgery but also by preexisting comorbidities of the patient. However, most potentially lethal complications have a slow onset like surgical site infections, pneumonia and sepsis. Therefore, a time window of opportunity might exist to detect and treat these complications as well as to improve outcome. In this context, failure to rescue (FTR) has been introduced as an indicator for the quality of perioperative care. There is growing evidence that FTR is a relevant phenomenon in perioperative medicine, possibly accounting for almost half of postoperative mortality. SUMMARY: It is imperative to reliably identify patients at risk for postoperative complications and to implement strategies into clinical practice allowing for prevention, early detection and effective treatment of complications. By bundling best practice concepts in all phases of perioperative care, patient outcome will be effectively improved.

[Anesthesia in children and adolescents with congenital heart defects]. / Anästhesie bei Kindern und Jugendlichen nach angeborenen Herzfehlern.

The incidence of congenital heart defects (CHD) has remained constant over many years; however, due to improved therapeutic options an increasing number of children and adolescents even with complex heart defects now reach adulthood. The increasing prevalence of adults with persisting or surgically corrected CHD as well as age-dependent non-cardiac comorbidities will increase the need for medical and non-cardiac surgical treatment in this population. Although elective medical care for these patients should be reserved for highly specialized centers, emergency treatment might become necessary in a non-specialized hospital setting as well. Due to the variety and complexity of CHD it is difficult to provide standardized guidelines for the anesthetic management. The treatment of patients with complex CHD requires a profound understanding of the underlying CHD and the current state of the hemodynamics by the anesthesiologist. Furthermore, typical comorbidities, such as chronic heart failure, altered coagulation and arrhythmia also have to be taken into account to ensure successful perioperative treatment. Especially in patients with shunt lesions or passive pulmonary blood flow the anesthetic management often substantially affects the hemodynamics and may be the starting point of severe decompensation. Awareness of anesthesia-induced changes of pulmonary and/or systemic vascular resistance as well as of preload alterations are the basis for successful anesthetic management. Finally, a multidisciplinary approach including cardiologists and radiologists in the planning is absolutely essential to achieve an optimal postoperative result for the patient.

Pre-conditioning with synthetic CpG-oligonucleotides attenuates myocardial ischemia/reperfusion injury via IL-10 up-regulation.

The aim of the study was to investigate whether pre-conditioning with CpG-oligodeoxynucleotides (CpG-ODN) may change cardiac ischemia/reperfusion (I/R)-dependent inflammation and modulates infarct size and cardiac performance. WT and TLR9-deficient mice were pre-treated with 1668-, 1612- and H154-thioate or D-Gal as control. Priming with 1668-thioate significantly induced inflammatory mediators in the serum and a concomitant increase of immune cells in the blood and spleen of WT mice. Furthermore, it induced myocardial pattern recognition receptors and pro-inflammatory cytokines peaking 2 h after priming and a continuous increase of IL-10. 16 h after pre-conditioning, myocardial ischemia was induced for 1 h. Infarct size determined after 24 h of I/R was reduced by 75 % due to pre-conditioning with 1668-thioate but not in the other groups. During reperfusion, cytokine expression in 1668-thioate primed mice increased further with IL-10 exceeding the other mediators by far. These changes were observed neither in animals pre-treated with 1612- or H154-thioate nor in TLR9-deficient mice. The 1668-thioate-dependent increase of IL-10 was further supported by results of a micro-array analysis 3 h after begin of reperfusion. Block of IL-10 signaling increased I/R size and prevented influence of priming. In the group pre-treated with 1668-thioate, cardiac function was preserved 24 h, 14 days and 28 days after I/R, whereas animals without pre-conditioning exhibited impaired heart function 24 h and 14 days after I/R. The excessive 1668-thioate-dependent IL-10 up-regulation during pre-conditioning and after I/R seems to be the key factor for reducing infarct size and improving cardiac function. This is in agreement with the finding that IL-10 block prevents cardioprotection by pre-conditioning.

In vivo TLR9 inhibition attenuates CpG-induced myocardial dysfunction.

The involvement of toll-like receptor 9 (TLR9), a receptor for bacterial DNA, in septic cardiac depression has not been clarified in vivo. Thus, the aim of the study was to test possible TLR9 inhibitors (H154-thioate, IRS954-thioate, and chloroquine) for their ability to protect the cardiovascular system in a murine model of CpG oligodeoxynucleotide- (ODN-) dependent systemic inflammation. Sepsis was induced by i.p. application of the TLR9 agonist 1668-thioate in C57BL/6 wild type (WT) and TLR9-deficient (TLR9-D) mice. Thirty minutes after stimulation TLR9 antagonists were applied i.v. Survival was monitored up to 18 h after stimulation. Cardiac mRNA expression of inflammatory mediators was analyzed 2 h and 6 h after stimulation with 1668-thioate and hemodynamic parameters were monitored at the later time point. Stimulation with 1668-thioate induced a severe sepsis-like state with significant drop of body temperature and significantly increased mortality in WT animals. Additionally, there was a time-dependent increase of inflammatory mediators in the heart accompanied by development of septic heart failure. These effects were not observed in TLR9-D mice. Inhibition of TLR9 by the suppressive ODN H154-thioate significantly ameliorated cardiac inflammation, preserved cardiac function, and improved survival. This suppressive ODN was the most efficient inhibitor of the tested substances.

Performance of a new pulse contour method for continuous cardiac output monitoring: validation in critically ill patients.

BACKGROUND: A new calibrated pulse wave analysis method (VolumeView™/EV1000™, Edwards Lifesciences, Irvine, CA, USA) has been developed to continuously monitor cardiac output (CO). The aim of this study was to compare the performance of the VolumeView method, and of the PiCCO2™ pulse contour method (Pulsion Medical Systems, Munich, Germany), with reference transpulmonary thermodilution (TPTD) CO measurements. METHODS: This was a prospective, multicentre observational study performed in the surgical and interdisciplinary intensive care units of four tertiary hospitals. Seventy-two critically ill patients were monitored with a central venous catheter, and a thermistor-tipped femoral arterial VolumeView™ catheter connected to the EV1000™ monitor. After initial calibration by TPTD CO was continuously assessed using the VolumeView-CCO software (CCO(VolumeView)) during a 72 h period. TPTD was performed in order to obtain reference CO values (COREF). TPTD and arterial wave signals were transmitted to a PiCCO2™ monitor in order to obtain CCO(PiCCO) values. CCO(VolumeView) and CCO(PiCCO) were recorded over a 5 min interval before assessment of CO(TPTD). Bland-Altman analysis, %(errors), and concordance (trend analysis) were calculated. RESULTS: A total of 338 matched sets of data were available for comparison. Bias for CCO(VolumeView)-CO(REF) was -0.07 litre min(-1) and for CCO(PiCCO)-CO(REF) +0.03 litre min(-1). Corresponding limits of agreement were 2.00 and 2.48 litre min(-1) (P<0.01), %(errors) 29 and 37%, respectively. Trending capabilities were comparable for both techniques. CONCLUSIONS: The performance of the new VolumeView™-CCO method is as reliable as the PiCCO2™-CCO pulse wave analysis in critically ill patients. However, an improved precision was observed with the VolumeView™ technique. CLINICALTRIALS.GOV IDENTIFIER: NCT01405040.

[Cardiopulmonary bypass in cardiac surgery]. / Kardiopulmonaler bypass in der herzchirurgie.

Cardiopulmonary bypass (CPB) is a standard procedure in cardiac surgery; however, apart from its therapeutic options a CPB might also initiate systemic and organ-specific complications, such as heart failure, renal and pulmonary dysfunction, impaired coagulation as well as neurological and cognitive dysfunction. The immunological response to the extracorporeal circulation generates systemic inflammation which often meets the definition of systemic inflammatory response syndrome (SIRS). The main inducers of SIRS are contact of blood with the artificial surfaces of the CPB, mechanical stress which affects the blood components and the extensive surgical trauma. Hence, a number of technical and surgical developments aim at reduction of the inflammatory response caused by the CPB. By reason of surgical demands, the majority of cardiothoracic procedures still depend on the use of CPB; however, there is an on-going development of new techniques trying to reduce the surgical trauma and the negative consequences of CPB. Here, minimized systems with biocompatible surfaces have been shown to be effective in attenuating the inflammatory response to CPB. Alternative procedures such as off-pump surgery may help to avoid CPB-associated complications but due to specific limitations will not replace conventional bypass surgery.

[Student evaluation of anesthesiological teaching: steering instrument of a continuous improvement process]. / Studentische Evaluation der anästhesiologischen Lehre : Steuerinstrument eines kontinuierlichen Verbesserungsprozesses.

BACKGROUND: The amendment to the higher education act ("Hochschulrahmengesetz") of 1998 postulates an evaluation of teaching for quality assurance. Hence, in the winter semester of 2004 the University Medical Center of Bonn introduced a semester questionnaire for students to evaluate the quality of teaching (EVALON). This evaluation is designed to be an objective benchmarking tool which is used for the distribution of university funds. It is also a steering instrument for direct improvement of teaching in clinical subjects. The aim of this study was to investigate, whether EVALON improved the quality of teaching between 2006 and 2010 and whether the department of anesthesiology improved its ranking in comparison with the other participating institutes. MATERIALS AND METHODS: Data from the EVALON questionnaire from the years 2006-2010 were analyzed for improvements in the quality of teaching in anesthesiology. This study focused on three essential contents of the EVALON questionnaire (structural content and organizational procedure of lectures and seminars, course presentation), which were used for the generation of a ranking list of all participating medical institutes and departments. On the basis of these results, 12.5% of the funding was assigned for educational purposes. RESULTS: There was an average return rate of the questionnaires of 74.5%. A significant increase in the overall assessment score of 43.4% could be observed from 5.3 in the summer semester of 2006 to 7.6 in the winter semester of 2009/10. The evaluation score for the department of anesthesiology concerning structural content of seminars and lectures increased by 79% from 4.8 in 2006 to 8.6 in 2010. The quality of organizational procedure was evaluated with a score of 4.9 in 2006 and improved by 74% to 8.5 in 2010. The course presentation skills of the teachers as evaluated by EVALON improved by 61% from a score of 5.2 in 2006 to 8.4 in 2010. In comparison with all other participating medical institutes the department of anesthesiology improved its ranking from position 36 in the winter semester 2006 to position 2 in the summer semester 2010. CONCLUSIONS: The reorganization of teaching anesthesiology, directly controlled by the results of EVALON improved the ranking of the department of anesthesiology. There was also a concomitant increase of the performance-oriented allocation of funds assigned to the department of anesthesiology based on the EVALON results.

Repinotan, a selective 5-HT1A-R-agonist, antagonizes morphine-induced ventilatory depression in anesthetized rats.

BACKGROUND: Spontaneous breathing during mechanical ventilation improves arterial oxygenation and cardiovascular function, but is depressed by opioids during critical care. Opioid-induced ventilatory depression was shown to be counteracted in anesthetized rats by serotonin(1A)-receptor (5-HT(1A)-R)-agonist 8-OH-DPAT, which cannot be applied to humans. Repinotan hydrochloride is a selective 5-HT(1A)-R-agonist already investigated in humans, but the effects on ventilation and nociception are unknown. In this study, we sought to establish (a) the effects of repinotan on spontaneous breathing and nociception, and (b) the interaction with the standard opiate morphine. METHODS: The dose-dependent effects of repinotan, given alone or in combination with morphine, on spontaneous minute ventilation (MV) and nociceptive tail-flick reflex latencies (TFLs) were measured simultaneously in spontaneously breathing anesthetized rats. An additional series with NaCl 0.9% and the 5-HT(1A)-R-antagonist WAY 100 135 served as controls. RESULTS: (a) Repinotan dose-dependently activated spontaneous breathing (MV, mean [95% confidence interval]; 53% [29%-77%]) of pretreatment level) and suppressed nociception (TLF, 91% maximum possible effect [68%-114%]) with higher doses of repinotan (2-200 µg/kg). On the contrary, nociception was enhanced with a small dose of repinotan (0.2 µg/kg; TFL, -47% maximum possible effect [-95% to 2%]). Effects were prevented by 5-HT(1A)-antagonist WAY 100 135. (B) Morphine-induced depression of ventilation (MV, -72% [-100% to -44%]) was reversed by repinotan (20 µg/kg), which returned spontaneous ventilation to pretreatment levels (MV, 18% [-40% to 77%]). The morphine-induced complete depression of nociception was sustained throughout repinotan and NaCl 0.9% administration. Despite a mild decrease in mean arterial blood pressure, there were no serious cardiovascular side effects from repinotan. CONCLUSIONS: The 5-HT(1A)-R-agonist repinotan activates spontaneous breathing in anesthetized rats even in morphine-induced ventilatory depression. The potency of 5-HT(1A)-R-agonists to stimulate spontaneous breathing and their antinociceptive effects should be researched further.

Patient state index vs bispectral index as measures of the electroencephalographic effects of propofol.

BACKGROUND: The patient state index (PSI) and the bispectral index (BIS) quantify anaesthetic depth based on the EEG using different algorithms. We compared both indices with regard to the prediction of the depth of propofol anaesthesia. METHODS: In 17 patients, propofol was infused until burst suppression occurred and stopped thereafter until BIS recovered to values above 60. This was repeated; afterwards, patients were intubated, for subsequent surgery. Without surgical stimulus, PSI and BIS were measured simultaneously and compared with the estimated effect-site concentrations of propofol. These were derived from simultaneous pharmacokinetic and -dynamic modelling in an individual two-stage and a population-based NONMEM approach. RESULTS: A close sigmoid relationship was observed between the propofol effect-site concentration and both PSI [coefficient of determination rho(2)=0.91 (sd 0.05)] and BIS [rho(2)=0.92 (0.03)], which was significantly steeper for PSI [gamma=2.2 (0.6)] than for BIS [gamma=1.8 (0.4)], and reached significantly lower values for PSI [E(max)=0.3 (1.1)] than for BIS [E(max)=5.3 (6.7)] at maximal propofol concentrations. A significantly smaller k(e0) was obtained for PSI [0.09 (0.03) min(-1)] compared with BIS [0.10 (0.02) min(-1)]. PSI and BIS correlated significantly with each other (rho(2)=0.866) and predicted propofol effect-site concentration with a comparable probability [P(K)=0.87 (0.05) and 0.86 (0.05), respectively]. NONMEM revealed E(0)=89.3 and 92.3, E(max)=1.9 and 8.6, C(e50)=1.38 and 1.92 microg ml(-1), gamma=1.6 and 1.48, and k(e0)=0.103 and 0.131 min(-1) as typical values for PSI and BIS, respectively. CONCLUSIONS: The PSI and the BIS monitors performed equally well in predicting depth of propofol anaesthesia. However, PSI was lower than BIS by approximately 10-15 points at high propofol concentrations.

The Entropy Module and Bispectral Index as guidance for propofol-remifentanil anaesthesia in combination with regional anaesthesia compared with a standard clinical practice group.

This study was designed to investigate the impact of the Entropy Module and Bispectral Index (BIS) monitoring on drug consumption and recovery times compared with standard anaesthetic practice in patients undergoing orthopaedic surgery using a combination of regional and general anaesthesia as performed by an experienced anaesthesiologist. We hypothesised that electroencephalogram monitoring would lead to a lower drug consumption as well as shorter recovery times. With institutional review board approval and written informed consent, 90 adult patients undergoing surgery to the upper or lower extremity received regional anaesthesia for post- and intraoperative pain control and were randomised to receive general anaesthesia by propofol/remifentanil infusion controlled either solely by clinical parameters or by targeting Entropy or BIS values of 50. Recovery times and drug consumption were recorded. Data from 79 patients were analysed. Compared with standard practice, patients with Entropy or BIS monitoring showed a similar propofol consumption (standard practice 101 +/- 22 microg/kg/minute, Entropy 106 +/- 24 microg/kg/minute, BIS 104 +/- 20 microg/kg/minute) and showed similar Aldrete scores (10/10) one minute after extubation: 9.1 +/- 0.3, 9.2 +/- 0.6 and 9.3 +/- 0.5, respectively. Time points of extubation were 7.3 +/- 2.9 minutes, 9.2 +/- 3.9 minutes and 6.8 +/- 2.9 minutes, respectively, demonstrating a significant difference between Entropy and BIS (P = 0.023). Compared with standard practice, targeting an Entropy or BIS value of 50 did not result in a reduction of propofol consumption during general anaesthesia combined with regional anaesthesia as performed by an experienced anaesthesiologist in orthopaedic patients.

A single exposure to hyperbaric oxygen increases levels of circulating nucleosomes but does not induce mononuclear cell apoptosis in divers.

Recent reports that hyperbaric oxygenation (HBO2) induced apoptosis in T-cell lines raised concern about a possible immunosuppressive effect of HBO2. Nucleosomes, DNA fragments wrapped around a histone core, have been observed in the circulation in diseases with increased cell death such as sepsis. Our aim was to investigate, whether HBO2 increases circulating nucleosomes as a marker of cell death and induces apoptosis of peripheral blood mononuclear cells in vivo. After informed consent 29 healthy volunteers were exposed to a 30 minute dive at 2.8 atmospheres absolute in a pressure chamber under resting conditions, while breathing 100% oxygen. Samples were obtained before and 24 hours after exposure. Circulating nucleosomes were measured in serum. Caspase-3 activation, Bcl-2 expression and mRNA of Bcl-2, Bcl-xl and Bax were analyzed in mononuclear cell extracts. Nucleosomes were elevated markedly 24h after exposure (p<0.01), while caspase-3 was not activated significantly. mRNA levels of Bcl-2, Bcl-xl and Bax were not altered. In conclusion, while evidence of elevated levels of circulating nucleosomes was found, mononuclear cell apoptosis was not affected by a single exposure to hyperbaric oxygen.