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Hypoxia and immunity are highly intertwined at clinical, cellular, and molecular levels. The prevention of tissue hypoxia and modulation of systemic inflammation are cornerstones of daily practice in the intensive care unit. Potentially, immunologic effects of hypoxia may contribute to outcome and represent possible therapeutic targets. Hypoxia and activation of downstream signaling pathways result in enhanced innate immune responses, aimed to augment pathogen clearance. On the other hand, hypoxia also exerts antiinflammatory and tissue-protective effects in lymphocytes and other tissues. Although human data on the net immunologic effects of hypoxia and pharmacologic modulation of downstream pathways are limited, preclinical data support the concept of tailoring the immune response through modulation of the oxygen status or pharmacologic modulation of hypoxia-signaling pathways in critically ill patients. [ABSTRACT FROM AUTHOR]

Background: Immunotherapy is now considered as the new pillar in treatment of cancer patients. Dendritic cells (DCs) play an essential role in stimulating anti-tumor immune responses, as they are capable of cross-presenting exogenous tumor antigens in MHCI complexes to activate naïve CD8+ T cells. Analgesics, like non-steroid anti-inflammatory drugs (NSAIDs), are frequently given to cancer patients to help relieve pain, however little is known about their impact on DC function. Methods: Here, we investigated the effect of the NSAIDs diclofenac, ibuprofen and celecoxib on the three key processes of DCs required for proper CD8+ cytotoxic T cell induction: antigen cross-presentation, co-stimulatory marker expression, and cytokine production. Results: Our results show that TLR-induced pro- and anti-inflammatory cytokine excretion by human monocyte derived and murine bone-marrow derived DCs is diminished after NSAID exposure. Conclusions: These results indicate that various NSAIDs can affect DC function and warrant further investigation into the impact of NSAIDs on DC priming of T cells and cancer immunotherapy efficacy. [ABSTRACT FROM AUTHOR]

Objective Patients and Methods Results Conclusion To compare the effectiveness of low intra‐abdominal pressure (IAP) facilitated by deep neuromuscular block (NMB) to standard practice in improving the quality of recovery, preserving immune function, and enhancing parietal perfusion during robot‐assisted radical prostatectomy (RARP).In this blinded, randomised controlled trial, 96 patients were randomised to the experimental group with low IAP (8 mmHg) facilitated by deep NMB (post‐tetanic count 1–2) or the control group with standard IAP (14 mmHg) and moderate NMB (train‐of‐four 1–2). Recovery was measured using the 40‐item Quality of Recovery questionnaire and 36‐item Short‐Form Health survey. Immune function was evaluated by plasma damage‐associated molecular patterns, cytokines, and ex vivo lipopolysaccharide‐stimulated cytokine production. Parietal peritoneum perfusion was measured by analysing the recordings of indocyanine‐green injection.Quality of recovery was not superior in the experimental group (n = 46) compared to the control group (n = 50). All clinical outcomes, including pain scores, postoperative nausea and vomiting, and hospital stay were similar. There were no significant differences in postoperative plasma concentrations of damage‐associated molecular patterns, cytokines, and ex vivo cytokine production capacity. The use of low IAP resulted in better parietal peritoneum perfusion.Despite better perfusion of the parietal peritoneum, low IAP facilitated by deep NMB did not improve the quality of recovery or preserve immune function compared to standard practice in patients undergoing RARP. [ABSTRACT FROM AUTHOR]

Background: Residual neuromuscular blockade (rNMB) remains a persistent and preventable problem, with serious risks. Methods: Our objective was to describe and assess patterns in the use of neuromuscular blocking agents (NMBAs), neuromuscular transmission (NMT) monitoring, and factors associated with the use of sugammadex. We performed a retrospective, observational cohort study based on electronic medical records in a large teaching hospital in the Netherlands that introduced an integrated NMT monitoring module with automatic recording in 2017. A total of 22,000 cases were randomly selected from all surgeries between January 2015 and December 2019 that required endotracheal intubation with the use of an NMBA. A total of 14,592 cases fulfilled all the inclusion criteria for complete analyses. Results: Relative NMBA usage remained the same over time. For rocuronium, spontaneous reversal decreased from 86 to 81%, sugammadex reversal increased from 12 to 18%. There was a decline in patients extubated in the operating room (OR) with neither documented NMT monitoring nor sugammadex-mediated reversal from 46 to 31%. The percentage of patients extubated in the OR without a documented train-of-four ratio ≥ 0.9, decreased from 77 to 56%. Several factors were independently associated with the use of sugammadex, including BMI > 30 kg/m2 (odds ratio: 1.41; 95% CI: 1.24–1.60), ASA class 3 or 4 (1.20; 1.07–1.34), age > 60 years (1.37; 1.23–1.53), duration of surgery < 120 min (3.01; 2.68–3.38), emergency surgery (1.83; 1.60–2.09), laparoscopic surgery (2.01; 1.71–2.36), open abdominal/thoracic surgery (1.56; 1.38–1.78), NMT monitoring used (5.31; 4.63–6.08), total dose of rocuronium (1.99; 1.76–2.25), and (inversely) use of inhalational anaesthetics (0.88; 0.79–0.99). Conclusion: Our data demonstrate that the implementation of NMT monitoring with automatic recording coincides with a gradual increase in the (documented) use of NMT monitoring and an increased use of sugammadex with a more precise dose. Factors associated with sugammadex use include higher age, ASA score, BMI, abdominal and thoracic surgery, higher rocuronium doses, emergency surgery and the use of NMT monitoring. Trial registration N/A. Key points: • Introduction of NMT monitoring with automatic recording coincides with an increase in (documented) use of NMT monitoring. • Sugammadex is more frequently used in patients with a presumed higher a priori risk of pulmonary complications. • Despite increased NMT monitoring and use of sugammadex a significant percentage of patients remain at potential risk of rNMB. [ABSTRACT FROM AUTHOR]

Investigates whether stimulation of &alpha[sub1]-adrenoceptors induces nitric oxide (NO) release in rat pulmonary arteries. Method used in isolating second-order pulmonary arteries; Materials used in NO measurement; Effect of NO synthase on phenylphrine-induced vasoconstriction in cannulated arteries; Mechanisms for α[sub1]-adrenoceptor-induced NO release.

Background: Isoflurane is used as an inhalation anesthetic in medical, paramedical, and veterinary practice. Epidemiological studies suggest an increased risk of miscarriages and malformations at birth related to maternal exposure to isoflurane and other inhalation anesthetics. However, these studies cannot be used to derive an occupational exposure level (OEL), because exposure was not determined quantitatively and other risk factors such as co-exposures to other inhalation anesthetics and other work-related factors may also have contributed to the observed adverse outcomes. The aim of this systematic review project is to assess all available evidence on the effects of isoflurane in studies of controlled exposures in laboratory animals to derive a health-based recommended OEL. Methods: A comprehensive search strategy was developed to retrieve all animal studies addressing isoflurane exposure from PubMed, EMBASE, and Web of Science. Title-abstract screening will be performed by machine learning, and full-text screening by one reviewer. Discrepancies will be resolved by discussion. We will include primary research in healthy, sexually mature (non human) vertebrates of single exposure to isoflurane. Studies describing combined exposure and treatments with > = 1 vol% isoflurane will be excluded. Subsequently, details regarding study identification, study design, animal model, and intervention will be summarized. All relevant exposure characteristics and outcomes will be extracted. The risk of bias will be assessed by two independent reviewers using an adapted version of the SYRCLE’s risk of bias tool and an addition of the OHAT tool. For all outcomes for which dose–response curves can be derived, the benchmark dose (BMD) approach will be used to establish a point of departure for deriving a recommended health-based recommended OEL for 8 h (workshift exposure) and for 15 min (short-term exposure). Discussion: Included studies should be sufficiently sensitive to detect the adverse health outcomes of interest. Uncertainties in the extrapolation from animals to humans will be addressed using assessment factor. These factors are justified in accordance with current practice in chemical risk assessment. A panel of experts will be involved to reach consensus decisions regarding significant steps in this project, such as determination of the critical effects and how to extrapolate from animals to humans. Systematic review registration: PROSPERO CRD42022308978 [ABSTRACT FROM AUTHOR]

Objectives: ENT surgeons and anesthesiologists work closely together in managing challenging airway cases. Sharing knowledge, experiences, and expectations interdisciplinary is essential in order to facilitate decision‐making and adequate management in emergency front‐of‐neck airway cases. Methods: A survey was performed, to analyze level of experience, technique of preference, training, knowledge of material and protocols, and self‐efficacy scores of Dutch ENT surgeons and residents in performing an urgent or emergency front‐of‐neck airway. Results: Within one year (January 2014–2015), 25.7% of the 257 respondents had performed an urgent or emergency front‐of‐neck airway. Of all reported emergency front‐of‐neck airways (N = 30), 80% were managed by tracheotomy. In future emergency front‐of‐neck airway cases, 74% stated cricothyrotomy would be their technique of preference. The majority would choose an uncuffed large‐bore cannula technique. Post‐academic hands‐on training was attended by 42% of respondents. Self‐efficacy scores were highest for surgical tracheotomy, and higher when trained or experienced. In case of an emergency scenario, 8.6% would not perform a front‐of‐neck airway themselves. The main reasons for reluctance to start in general were lack of experience and lack of training. Reported items for improvement were mainly the development of a protocol and training. Conclusion: The chance of encountering an airway emergency scenario requiring front‐of‐neck airway is realistic. There is inconsistency between advised technique, technique of preference and technique actually performed by ENT surgeons. This study shows that there is both a need and desire for improvement in training and organization of care. Interdisciplinary guidelines and education is needed and could eventually safe lives. Level of evidence: 5 [ABSTRACT FROM AUTHOR]

Background: Conflicting data exist regarding the effects of deep neuromuscular blockade (NMB) on abdominal dimensions during laparoscopic procedures. We performed a clinical study to establish the influence of moderate and deep neuromuscular blockade (NMB) on the abdominal working space, measured by Magnetic Resonance Imaging (MRI), during laparoscopic donor nephrectomy with standard pressure (12 mmHg) pneumoperitoneum under sevoflurane anaesthesia. Methods: Ten patients were intraoperatively scanned three times in the lateral decubitus position, with pneumoperitoneum maintained by a mobile insufflator. The first scan without NMB (T1) was followed by scans with moderate (T2) and deep NMB (T3). The skin-sacral promontory (S-SP) distance was measured, and 3D pneumoperitoneum volumes were reconstructed. Results: The mean difference in the S-SP distance was -0.32 cm between T2 and T3 (95% CI -1.06 - 0.42 cm; p = 0.344) and + 2.1 cm between T1 and T2 (95% CI 0.81 - 3.39 cm; p = 0.006). The mean differences in pneumoperitoneum volume were 166 mL between T2 and T3 (95% CI, 5 - 327 mL; p = 0.044) and 108 mL between T1 and T2 (95% CI, -273 - 488 mL; p = 0.525). The pneumoperitoneum volume showed high inter-individual variability and no increase in three patients with a high volume at T1. Conclusions: During laparoscopic surgery in the lateral decubitus position with standard pressure under sevoflurane anaesthesia, deep NMB did not increase the S-SP distance compared to moderate NMB. Moderate NMB increased the S-SP distance by a mean of 2.1 cm (15.2%) compared with no NMB. The mean pneumoperitoneum volume increased slightly from moderate to deep NMB, with high inter-individual variability. Trial registration: Clinicaltrials.gov ID: NCT03287388. [ABSTRACT FROM AUTHOR]

The FDA issued a warning that repeated and prolonged use of inhalational anaesthetics in children younger than 3 years may increase the risk of neurological damage. Robust clinical evidence supporting this warning is however lacking. A systematic review of all preclinical evidence concerning isoflurane, sevoflurane, desflurane and enflurane exposure in young experimental animals on neurodegeneration and behaviour may elucidate how severe this risk actually is PubMed and Embase were comprehensively searched on November 23, 2022. Based on predefined selection criteria the obtained references were screened by two independent reviewers. Data regarding study design and outcome data (Caspase-3 and TUNEL for neurodegeneration, Morris water maze (MWM), Elevated plus maze (EPM), Open field (OF) and Fear conditioning (FC)) were extracted, and individual effect sizes were calculated and subsequently pooled using the random effects model. Subgroup analyses were predefined and conducted for species, sex, age at anesthesia, repeated or single exposure and on time of outcome measurement. Out of the 19.796 references screened 324 could be included in the review. For enflurane there were too few studies to conduct meta-analysis (n = 1). Exposure to sevoflurane, isoflurane and desflurane significantly increases Caspase-3 levels and TUNEL levels. Further, sevoflurane and isoflurane also cause learning and memory impairment, and increase anxiety. Desflurane showed little effect on learning and memory, and no effect on anxiety. Long term effects of sevoflurane and isoflurane on neurodegeneration could not be analysed due to too few studies. For behavioural outcomes, however, this was possible and revealed that sevoflurane caused impaired learning and memory in all three related outcomes and increased anxiety in the elevated plus maze. For isoflurane, impaired learning and memory was observed as well, but only sufficient data was available for two of the learning and memory related outcomes. Further, single exposure to either sevoflurane or isoflurane increased neurodegeneration and impaired learning and memory. In summary, we show evidence that exposure to halogenated ethers causes neurodegeneration and behavioural changes. These effects are most pronounced for sevoflurane and isoflurane and already present after single exposure. To date there are not sufficient studies to estimate the presence of long term neurodegenerative effects. Nevertheless, we provide evidence in this review of behavioral changes later in life, suggesting some permanent neurodegenerative changes. Altogether, In contrast to the warning issued by the FDA we show that already single exposure to isoflurane and sevoflurane negatively affects brain development. Based on the results of this review use of sevoflurane and isoflurane should be restrained as much as possible in this young vulnerable group, until more research on the long term permanent effects have been conducted. [ABSTRACT FROM AUTHOR]

Background: Laparoscopic surgery has several advantages when compared to open surgery, including faster postoperative recovery and lower pain scores. However, for laparoscopy, a pneumoperitoneum is required to create workspace between the abdominal wall and intraabdominal organs. Increased intraabdominal pressure may also have negative implications on cardiovascular, pulmonary, and intraabdominal organ functionings. To overcome these negative consequences, several trials have been performed comparing low- versus standard-pressure pneumoperitoneum.Methods: A systematic review of all randomized controlled clinical trials and observational studies comparing low- versus standard-pressure pneumoperitoneum.Results and Conclusions: Quality assessment showed that the overall quality of evidence was moderate to low. Postoperative pain scores were reduced by the use of low-pressure pneumoperitoneum. With appropriate perioperative measures, the use of low-pressure pneumoperitoneum does not seem to have clinical advantages as compared to standard pressure on cardiac and pulmonary function. Although there are indications that low-pressure pneumoperitoneum is associated with less liver and kidney injury when compared to standard-pressure pneumoperitoneum, this does not seem to have clinical implications for healthy individuals. The influence of low-pressure pneumoperitoneum on adhesion formation, anastomosis healing, tumor metastasis, intraocular and intracerebral pressure, and thromboembolic complications remains uncertain, as no human clinical trials have been performed. The influence of pressure on surgical conditions and safety has not been established to date. In conclusion, the most important benefit of low-pressure pneumoperitoneum is lower postoperative pain scores, supported by a moderate quality of evidence. However, the quality of surgical conditions and safety of the use of low-pressure pneumoperitoneum need to be established, as are the values and preferences of physicians and patients regarding the potential benefits and risks. Therefore, the recommendation to use low-pressure pneumoperitoneum during laparoscopy is weak, and more studies are required. [ABSTRACT FROM AUTHOR]

Background: Minimally invasive adrenalectomy is the standard of care for small adrenal tumours. Both the transperitoneal lateral approach and posterior retroperitoneal approach are widely used and have been proven to be safe and effective. However, the prevalence of chronic postsurgical pain has not been specifically investigated in previous studies. The primary goal of this study was to identify the prevalence of chronic postsurgical pain after minimally invasive adrenalectomy. Methods: A cross-sectional study was performed among all consecutive patients who had undergone minimally invasive adrenalectomy in a single university medical centre. The primary outcome was the prevalence of chronic postsurgical pain. Secondary outcomes were the prevalence of localized hypoesthesia, risk factors for the development of chronic postsurgical pain, and the Health-Related Quality of Life. Three questionnaires were used to measure the prevalence and severity of chronic postsurgical pain, hypoesthesia, and Health-Related Quality of Life. Logistic regression analysis was performed to determine risk factors for development of chronic postsurgical pain. Results: Six hundred two patients underwent minimally invasive adrenalectomy between January 2007 and September 2019, of whom 328 signed informed consent. The prevalence of chronic postsurgical pain was 14.9%. In the group of patients with chronic postsurgical pain, 33% reported hypoesthesia as well. Young age was a significant predictor for developing chronic postsurgical pain. The prevalence of localized hypoesthesia was 15.2%. In patients with chronic postsurgical pain, Health-Related Quality of Life was significantly lower, compared to patients without pain. Conclusions: The prevalence of chronic postsurgical pain following minimally invasive adrenalectomy is considerable. Furthermore, the presence of chronic postsurgical pain was correlated with a significant and clinically relevant lower Health-Related Quality of Life. These findings should be included in the preoperative counselling of the patient. In the absence of evidence for effective treatment in established chronic pain, prevention should be the key strategy and topic of future research. [ABSTRACT FROM AUTHOR]

Background: Standardized risk assessment tools can be used to identify patients at higher risk for postoperative complications and death. In this study, we validate the PreOperative Score to predict Post-Operative Mortality (POSPOM) for in-hospital mortality in a large cohort of non-cardiac surgery patients. In addition, the performance of POSPOM to predict postoperative complications was studied. Methods: Data from the control cohort of the TRACE (routine posTsuRgical Anesthesia visit to improve patient outComE) study was analysed. POSPOM scores for each patient were calculated post-hoc. Observed in-hospital mortality was compared with predicted mortality according to POSPOM. Discrimination was assessed by receiver operating characteristic curves with C-statistics for in-hospital mortality and postoperative complications. To describe the performance of POSPOM sensitivity, specificity, negative predictive values, and positive predictive values were calculated. For in-hospital mortality, calibration was assessed by a calibration plot. Results: In 2490 patients, the observed in-hospital mortality was 0.5%, compared to 1.3% as predicted by POSPOM. 27.1% of patients had at least one postoperative complication of which 22.4% had a major complication. For in-hospital mortality, POSPOM showed strong discrimination with a C-statistic of 0.86 (95% CI, 0.78–0.93). For the prediction of complications, the discrimination was poor to fair depending on the severity of the complication. The calibration plot showed poor calibration of POSPOM with an overestimation of in-hospital mortality. Conclusion: Despite the strong discriminatory performance, POSPOM showed poor calibration with an overestimation of in-hospital mortality. Performance of POSPOM for the prediction of any postoperative complication was poor but improved according to severity. [ABSTRACT FROM AUTHOR]

Study objective: To assess whether different intensities of intra-abdominal pressure and deep neuromuscular blockade influence the risk of intra-operative surgical complications during laparoscopic donor nephrectomy. Design: A pooled analysis of ten previously performed prospective randomized controlled trials. Setting: Laparoscopic donor nephrectomy performed in four academic hospitals in the Netherlands: Radboudumc, Leiden UMC, Erasmus MC Rotterdam, and Amsterdam UMC. Patients: Five hundred fifty-six patients undergoing a transperitoneal, fully laparoscopic donor nephrectomy enrolled in ten prospective, randomized controlled trials conducted in the Netherlands from 2001 to 2017. Interventions: Moderate (tetanic count of four > 1) versus deep (post-tetanic count 1–5) neuromuscular blockade and standard (≥10 mmHg) versus low (<10 mmHg) intra-abdominal pressure. Measurements: The primary endpoint is the number of intra-operative surgical complications defined as any deviation from the ideal intra-operative course occurring between skin incision and closure with five severity grades, according to ClassIntra. Multiple logistic regression analyses were used to identify predictors of intra- and postoperative complications. Main results: In 53/556 (9.5%) patients, an intra-operative complication with ClassIntra grade ≥ 2 occurred. Multiple logistic regression analyses showed standard intra-abdominal pressure (OR 0.318, 95% CI 0.118–0.862; p = 0.024) as a predictor of less intra-operative complications and moderate neuromuscular blockade (OR 3.518, 95% CI 1.244–9.948; p = 0.018) as a predictor of more intra-operative complications. Postoperative complications occurred in 31/556 (6.8%), without significant predictors in multiple logistic regression analyses. Conclusions: Our data indicate that the use of deep neuromuscular blockade could increase safety during laparoscopic donor nephrectomy. Future randomized clinical trials should be performed to confirm this and to pursue whether it also applies to other types of laparoscopic surgery. Trial registration: Clinicaltrials.gov LEOPARD-2 (NCT02146417), LEOPARD-3 trial (NCT02602964), and RELAX-1 study (NCT02838134), Klop et al. (NTR 3096), Dols et al. 2014 (NTR1433). [ABSTRACT FROM AUTHOR]

Abstract: Background: Due to advancements in technology, the use of a portable ultrasound (US) machine in the out-of-hospital setting is increasingly feasible. It has diagnostic and therapeutic advantages and may improve the management and treatment of patients. It can be used in-flight and can be easily taught to flight clinicians who have little previous experience with this modality. Study Objectives: The goal of this study was to evaluate the impact of ultrasound chest examinations on the care of patients treated by a Helicopter Emergency Medical Service (HEMS). Methods: Since 2007, portable US has been used by the HEMS of Nijmegen, The Netherlands. Data on every air medical flight are routinely collected in a database. Every portable US examination of the chest performed between 2007 and 2010 was reviewed for this study. Data on patient characteristics, properties of US examinations, US diagnoses, and impact on medical treatment were collected and analyzed. Results: Of a total of 2572 patients, 326 portable US examinations of the chest were performed on 281 (11%) patients. The mean duration of a portable US examination was 2.77 (SD 1.30) min, and the duration decreased over time. After the US examination, the plan for treatment changed in 60 (21%) patients. In 10 patients (4%) the plan to place a chest tube was abandoned. In 10 patients (4%) the initially selected destination for definitive care changed, and it changed to a lower-level hospital more often than to a higher-level one. In 9 patients (3%), cardiopulmonary resuscitation was stopped and in 31 patients there were other changes. Conclusion: Out-of-hospital US examinations can alter and improve treatment decisions and destinations for definitive care. [Copyright &y& Elsevier]

Chronic pain is common and undesirable after surgery. Progression from acute to chronic pain involves altered pain processing. The authors studied relationships between presence of chronic pain versus preoperative descending pain control (diffuse noxious inhibitory controls; DNICs) and postoperative persistence and spread of skin and deep tissue hyperalgesia (change in electric/pressure pain tolerance thresholds; ePTT/pPTT) up to 6 months postoperatively. In 20 patients undergoing elective major abdominal surgery under standardized anesthesia, we determined ePTT/pPTT (close to [abdomen] and distant from [leg] incision), eDNIC/pDNIC (change in ePTT/pPTT with cold pressor pain task; only preoperatively), and a 100 mm long pain visual analogue scale (VAS) (0 mm = no pain, 100 mm = worst pain imaginable), both at rest and on movement preoperatively, and 1 day and 1, 3, and 6 months postoperatively. Patients reporting chronic pain 6 months postoperatively had more abdominal and leg skin hyperalgesia over the postoperative period. More inhibitory preoperative eDNIC was associated with less late postoperative pain, without affecting skin hyperalgesia. More inhibitory pDNIC was linked to less postoperative leg deep tissue hyperalgesia, without affecting pain VAS. This pilot study for the first time links chronic pain after surgery, poorer preoperative inhibitory pain modulation (DNIC), and greater postoperative degree, persistence, and spread of hyperalgesia. If confirmed, these results support the potential clinical utility of perioperative pain processing testing. [ABSTRACT FROM AUTHOR]

Summary: Aim: Feedback during CPR may facilitate quality in chest compressions, but has also been associated with caregiver complaints such as stiff wrists, the need for more force and increased fatigue. This concern about extra work is, when using the CPREzy™ with its own spring-loaded surface, particularly relevant in the face of an increased number of successive compressions. This manuscript evaluates the objective workloads for caregivers with and without the CPREzy™. Materials and methods: An air pressure driven, piston device was used to generate controlled compressions in a manikin model. The pressure was applied for chest compressions with each of the following: the cylindrical end of the piston, a wooden block as dummy for the CPREzy™, and the CPREzy™ itself. Three manikins with subjectively different spring compliances were selected for the tests. Series of 20 compressions were performed over a wide range of pressures. Results: No additional force is required to achieve a given depth of compression with or without the CPREzy™. However, some additional work is required, ranging from 21 to 26.5%. This work is caused by the longer compression distance associated with the need to compress two springs (e.g. the CPREzy™ and the chest wall) instead of one (e.g. the chest wall). Conclusion: The subjective feeling of increased rescuer fatigue with the CPREzy™ can, at least in part, be attributed to the extra work required for compressing the spring of the CPREzy™. Improved accuracy in chest compression depth is likely to be another, more significant, factor in rescuer fatigue. [Copyright &y& Elsevier]

Background: Many patients with severe acute lung injury do not respond to nitric oxide (NO) inhalational therapy with alleviation of pulmonary arterial hypertension and hypoxemia, so this treatment remains controversial. Materials and methods.: We investigated in endotoxin-exposed Wistar rat pulmonary arteries whether endogenous NO alters contractile and relaxing responses, by electrochemical NO and isometric force measurements. Results: Receptor-independent contraction was similar in control and endotoxin-exposed arteries, while thromboxane analogue (TxA)-dependent contraction was less in the latter. Neither non-selective NO synthase (NOS) inhibition by NG-nitro-l-arginine (l-NA) or selective inducible-NOS2 inhibition by aminoguanidine (AG) improved TxA-induced contraction in endotoxin-exposed arteries. Acetylcholine-induced relaxation was impaired in endotoxin-exposed pulmonary arteries, despite a comparable acetylcholine-induced NO release in control arteries. Additionally, NO solution-induced relaxation of endotoxin-exposed arteries was impaired, but could be improved by l-NA or AG. Application of a phosphodiesterase-insensitive cyclic guanosine monophosphate analogue induced similar relaxation in both control and endotoxin-exposed arteries. Conclusions: Endotoxin-associated NOS2-derived NO is thus associated with impaired NO-mediated relaxation, but does not underlie reduced receptor-mediated pulmonary contractile responses. An increased phosphodiesterase activity may underlie the former, so this route can be explored to replace or improve the effect of inhalational NO therapy in severe sepsis-induced acute lung injury in patients. [Copyright &y& Elsevier]

Background. Recently, it has been suggested that Chlamydia pneumoniae possibly plays a possible role in the pathogenesis of atherosclerosis. We investigated whether treatment with clarithromycin prior to coronary artery bypass graft (CABG) surgery would prevent subsequent cardiovascular events and mortality. Methods. Patients who were scheduled for CABG surgery were randomly assigned to receive either clarithromycin or placebo until the day of surgery in a double-blind trial. During the 2 years of follow-up, mortality and cardiovascular events were assessed. Results. Follow-up at 2 years was achieved for 473 patients. The mean duration of treatment was 16 days. Patient characteristics at baseline were well balanced between the 2 treatment groups. Mortality was equal in the 2 groups: 10 (4.2%) of 238 patients in the clarithromycin group and 9 (3.8%) of 235 patients in the placebo group (relative risk, 1.10; 95% CI, 0.42-2.89; P = 1.0). Also, there were no significant differences in the proportion of patients who experienced cardiovascular events during the follow-up period: 20 (8.4%) of 238 patients in the clarithromycin group and 19 (8.1%) of 235 patients in the placebo group (relative risk, 1.04; 95% CI, 0.55-1.98; P = 1.0). The overall rate of such events was 58 (12.3%) of 473 patients. Conclusions. Treatment with clarithromycin in patients scheduled for CABG surgery did not reduce the subsequent occurrence of cardiovascular events or mortality during a 2-year follow-up period. [ABSTRACT FROM AUTHOR]

Presents a study that postulated a role for RhoA/Rho kinase and nitric oxide (NO) in the modulation of pulmonary vascular reactivity. Role of myosin light chain phosphatase in the regulation of smooth muscle cell contraction; Vascular reactivity characteristics in endothelium-denuded arteries; Effects of endothelium removal and NO synthase inhibition on pulmonary vascular reactivity.

Background: Cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) are high-risk extensive abdominal surgery. During high-risk surgery, less invasive methods for cardiac index (CI) measurement have been widely used in operating theater. We investigated the accuracy of CI derived from different methods (FroTrac, ProAQT, ClearSight, and arterial pressure waveform analysis [APWA], from PICCO) and compared them to transpulmonary thermodilution (TPTD) during CRS and HIPEC in the operative room and intensive care unit (ICU). Methods: Twenty-five patients scheduled for CRS-HIPEC were enrolled. During nine predefined time-points, simultaneous hemodynamic measurements were performed in the operating room and ICU. Absolute and relative changes of CI were analyzed using a Bland-Altman plot, four-quadrant plot, and interchangeability. Results: The mean bias was -0.1 L/min/m2 for ClearSight, ProAQT, and APWA and was -0.2 L/min/m2 for FloTrac compared with TPTD. All devices had large limits of agreement (LoA). The percentage of errors and interchangeabilities for ClearSight, FloTrac, ProAQT, and APWA were 50%, 50%, 54%, 36% and 36%, 47%, 40%, 72%, respectively. Trending capabilities expressed as concordance using clinically significant CI changes were -7° ± 39°, -19° ± 38°, -13° ± 41°, and -15° ± 39°. Interchangeability in trending showed low percentages of interchangeable and gray zone data pairs for all devices. Conclusions: During CRS-HIPEC, ClearSight, FloTrac and ProAQT systems were not able to reliably measure CI compared to TPTD. Reproducibility of changes over time using concordance, angular bias, radial LoA, and interchangeability in trending of all devices was unsatisfactory. [ABSTRACT FROM AUTHOR]

Our research group recently published a positive association between early postoperative pain and 30-day postoperative complications in a broad surgical population. To investigate whether heterogeneity of the population and surgical procedures influenced these results, we explored this association in a homogenous surgical population. A secondary analysis of the LEOPARD-2 (clinicaltrials.gov NCT02146417) and RELAX-1 study (NCT02838134) in laparoscopic donor nephrectomy patients (n = 160) was performed. Pain scores on the postanesthesia care unit and postoperative day (POD) 1 and 2 were compared between patients with infectious, noninfectious, and no complications 30 days after surgery. Patients who developed infectious complications had significantly higher pain scores on POD1 and 2 (6.7 ± 2.1 and 6.4 ± 2.8) than patients without complications (4.9 ± 2.2 and 4.1 ± 1.9), respectively (P = 0.006 and P = 0.000). Unacceptable pain (numeric rating scale [NRS] ≥ 6) on POD1 was reported by 72% of patients who developed infectious complications, compared to 38% with noninfectious complications and 30% without complications (P = 0.018). This difference was still present on POD2 at 67% with infectious complications, 21% with noninfectious, and 40% without complications (P = 0.000). Multiple regression analysis identified unacceptable pain (numeric rating scale ≥6) on POD2 as a significant predictor for 30-day infectious complications (odds ratio 6.09, P = 0.001). Results confirm the association between early postoperative pain and 30-day infectious complications in a separate, homogenous surgical population. Further clinical trials should focus on finetuning of postoperative analgesia to elucidate the effects on the endocrine and immune response, preserve immune homeostasis, and prevent postoperative infectious complications. [ABSTRACT FROM AUTHOR]

Background: There is increasing evidence for the use of lower insufflation pressures during laparoscopic surgery. Deep neuromuscular blockade allows for a safe reduction in intra-abdominal pressure without compromising the quality of the surgical field. While there is considerable evidence to support superior surgical conditions during deep neuromuscular blockade, there is only a limited amount of studies investigating patient outcomes. Moreover, results are not always consistent between studies and vary between different types of laparoscopic surgery. This study will investigate the effect of low-pressure pneumoperitoneum facilitated by deep NMB on quality of recovery after laparoscopic colorectal surgery.Methods: The RECOVER study is a multicenter double-blinded randomized controlled trial consisting of 204 patients who will be randomized in a 1:1 fashion to group A, low-pressure pneumoperitoneum (8 mmHg) facilitated by deep neuromuscular blockade (post tetanic count of 1-2), or group B, normal-pressure pneumoperitoneum (12 mmHg) with moderate neuromuscular blockade (train-of-four response of 1-2). The primary outcome is quality of recovery on postoperative day 1, quantified by the Quality of Recovery-40 questionnaire.Discussion: Few studies have investigated the effect of lower insufflation pressures facilitated by deep neuromuscular blockade on patient outcomes after laparoscopic colorectal procedures. This study will identify whether low pressure pneumoperitoneum and deep neuromuscular blockade will enhance recovery after colorectal laparoscopic surgery and, moreover, if this could be a valuable addition to the Enhanced Recovery After Surgery guidelines.Trial Registration: EudraCT 2018-001485-42. Registered on April 9, 2018. Clinicaltrials.govNCT03608436. Registered on July 30, 2018. [ABSTRACT FROM AUTHOR]

Background: In-hospital cardiac arrest is a major cause of death in European countries, and survival of patients remains low ranging from 20% to 25%. Aims: The purpose of this study was to assess healthcare professionals' knowledge on cardiopulmonary resuscitation among university hospitals in 12 European countries and correlate it with the return of spontaneous circulation rates of their patients after in-hospital cardiac arrest. Methods and results: A total of 570 healthcare professionals from cardiology, anaesthesiology and intensive care medicine departments of European university hospitals in Italy, Poland, Hungary, Belgium, Spain, Slovakia, Germany, Finland, The Netherlands, Switzerland, France and Greece completed a questionnaire. The questionnaire consisted of 12 questions based on epidemiology data and cardiopulmonary resuscitation training and 26 multiple choice questions on cardiopulmonary resuscitation knowledge. Hospitals in Switzerland scored highest on basic life support (P =0.005) while Belgium hospitals scored highest on advanced life support (P <0.001) and total score in cardiopulmonary resuscitation knowledge (P =0.01). The Swiss hospitals scored highest in cardiopulmonary resuscitation training (P <0.001). Correlation between cardiopulmonary resuscitation knowledge and return of spontaneous circulation rates of patients with in-hospital cardiac arrest demonstrated that each additional correct answer on the advanced life support score results in a further increase in return of spontaneous circulation rates (odds ratio 3.94; 95% confidence interval 2.78 to 5.57; P <0.001). Conclusion: Differences in knowledge about resuscitation and course attendance were found between university hospitals in 12 European countries. Education in cardiopulmonary resuscitation is considered to be vital for patients' return of spontaneous circulation rates after in-hospital cardiac arrest. A higher level of knowledge in advanced life support results in higher return of spontaneous circulation rates. [ABSTRACT FROM AUTHOR]

Background: Extracorporeally induced whole‐body hyperthermia (eWBH) might be a beneficial treatment in cancer patients. Objectives of this pig study were to assess thermal distribution, (patho‐)physiological effects, and safety of eWBH with a new WBH device. Methods: Fourteen healthy adult pigs were anesthetized, mechanically ventilated, and cannulated; 12 were included in the analysis. Blood was heated in 11 pigs (one pig served as control) using a WBH device (Vithèr Hyperthermia B.V.) containing two separate fluidic circuits and a heat exchanger. Temperature was monitored on nine different sites, including the brain. Core temperature (average of 4 deep probes) was elevated to 42°C for 2 hr. Results: Elevation of core body temperature to 42°C took on average (± standard deviation) 38 ± 8 min. Initially observed temperature spikes diminished after lowering maximal blood temperature to 45°C. Hereafter, brain temperature spikes never exceeded 42.5°C, mean brain temperature was at highest 41.9°C during maintenance. WBH resulted in increased heart rates and decreased mean arterial pressures. The vast amounts of fluids required to counter hypotension tended to be smaller after corticosteroid administration. Hemodialysis was started in three animals (potassium increase prevention in two and hyperkalemia treatment in one). Severe rhabdomyolysis was observed in all pigs (including the control). All animals survived the procedure until planned euthanasia 1, 6, or 24 hr post procedure. Conclusion: Fast induction of eWBH with homogenous thermal distribution is feasible in pigs using the Vithèr WBH device. Severe hemodynamic disturbances, rhabdomyolysis, and hyperkalemia were observed. [ABSTRACT FROM AUTHOR]

Systemic inflammation and hypoxia frequently occur simultaneously in critically ill patients, and are both associated with platelet activation and coagulopathy. However, human in vivo data on the effects of hypoxia on platelet function and plasmatic coagulation under systemic inflammatory conditions are lacking. In the present study, 20 healthy male volunteers were randomized to either 3.5 h of hypoxia (peripheral saturation 80–85%) or normoxia (room air), and systemic inflammation was elicited by intravenous administration of 2 ng/kg endotoxin. Various parameters of platelet function and plasmatic coagulation were determined serially. Endotoxemia resulted in increased circulating platelet–monocyte complexes and enhanced platelet reactivity, effects which were attenuated by hypoxia. Furthermore, endotoxin administration resulted in decreased plasma levels of platelet factor-4 levels and increased concentrations of von Willebrand factor. These endotoxemia-induced effects were not influenced by hypoxia. Neither endotoxemia nor hypoxia affected thrombin generation. In conclusion, our data reveal that hypoxia attenuates the endotoxemia-induced increases in platelet–monocyte formation and platelet reactivity, while leaving parameters of plasmatic coagulation unaffected. [ABSTRACT FROM AUTHOR]

Despite the large amount of human and experimental studies no effective (prophylactic) treatment exists for chemotherapy induced peripheral neuropathy (CIPN), a disabling side effect of many cancer treatments. One of the underlying reasons for this could be that often the preclinical animal models used are not the best representation of the clinical situation. We therefore present a systematic summary and comparison of all animal models currently described in literature for CIPN focusing on stimulus evoked pain-like behaviour and neurophysiological alterations in nerve function (650 included papers, and a comparison of 183 models), that resulted in a clear overview of the most effective and robust CIPN models using an administration route used in clinical practice. Using our three-step approach (step 1: efficacy; step; 2 robustness and step 3: mimicking the clinical situation) we show that all mice CIPN models treated with either paclitaxel or cisplatin using an administration route used in clinical practice seem suitable models. Three specific models using paclitaxel or cisplatin that stand out are 1) C57BL/6 female mice receiving paclitaxel and 2) CD1 male mice receiving paclitaxel and 3) C57BL/6 male mice receiving cisplatin. This overview may help scientists selecting suitable CIPN models for their research. We hypothesize that by using effective and robust animal models that mimic the clinical situation as much as possible, the translational value of preclinical study results with respect to the potential of identifying promising treatments for CIPN in the future, will prove. The methodology described in this paper, aimed at comparing animal models, is novel and can be used by scientist in other research fields as well. [ABSTRACT FROM AUTHOR]

Objective: Local infiltration analgesia (LIA) with ropivacaine is increasingly used to provide postoperative analgesia after total knee arthroplasty (TKA). TKA may be performed with or without the use of a tourniquet. The absence of local blood flow when infiltrating local anaesthesia below an inflated tourniquet may affect the rate of systemic absorption, and this may have an effect on the duration and intensity of analgesia as compared with LIA without the use of a tourniquet. The aim of the present study was to investigate the influence of tourniquet use during surgery on the time to first request (TTFR) of opioids and opioid consumption. Methods: Two historical time-based cohorts (one with and one without tourniquet during surgery) of 300 patients underwent primary TKA under spinal anaesthesia and received LIA to provide postoperative analgesia. The cohorts were compared for TTFR of opioids and opioid consumption. Results: TTFR did not significantly differ between the tourniquet and non-tourniquet groups with a median (25th-75th percentile) of 240 (102-651) and 282 (100-720) min, respectively. The median (25th-75th percentile) oxycodone use was higher in the tourniquet group with 50 (20-90) versus 40 (10-77.5) mg (p=0.01). Conclusion: There was no difference in the time to first opioid consumption, suggesting that the presence of an inflated tourniquet during local anaesthetic injection does not alter systemic absorption sufficiently to affect the duration of analgesia. However, the use of a tourniquet was associated with a higher opioid consumption, which is most likely caused by pain resulting from the tourniquet itself. [ABSTRACT FROM AUTHOR]

Background: Diagnostic ultrasound is increasingly used by nonradiologists in trauma victims and critically ill patients. In the emergency department, the extended focused assessment with sonography for trauma and Polytrauma Rapid Echo-evaluation Program protocol are often used to assess these patients. Dutch Polytrauma Rapid Echo-evaluation Program-trained Emergency physicians are implementing the use of ultrasound in the emergency department but might encounter barriers to overcome. Objectives: This study aims to explore individual experiences of Dutch emergency physicians. Methods: We performed a qualitative study by conducting semi-structured interviews in Dutch emergency physicians working in a Level 2 emergency department that completed the 2-day Polytrauma Rapid Echo-evaluation Program course at least 1 year before the interviews. Data were analyzed using directed content analysis. Results: Eight emergency physicians employed by eight different hospitals were interviewed. Thirteen categories were identified in the transcribed interviews and these were combined into four general themes: (1) the desire to develop the Emergency Medicine specialty, both nationally and local; (2) incentives to start using ultrasound; (3) exploring practical applications of ultrasound; and (4) barriers faced while implementing emergency physician-performed ultrasound on the emergency department. The interviewees regard the course to be a solid base and are eager to independently perform ultrasound examinations, although challenges are faced. Conclusion: This exploratory study provides essential insight in Dutch emergency physicians implementing ultrasound in their emergency department. It shows that there is a need to develop a quality assurance system and it identified barriers that have to be dealt with. [ABSTRACT FROM AUTHOR]

Chemotherapy may result in the release of danger-associated molecular patterns (DAMPs), which can cause immunoparalysis (deactivation of the immune system). We investigated DAMPs following chemotherapy and their relationship with markers of immunoparalysis in leukemia patients. In 6 patients with acute myeloid leukemia or myelodysplastic syndrome and 12 healthy subjects, DAMPs, cytokines, and markers of immunoparalysis were determined before and during the first week after chemotherapy initiation. In the patients, plasma levels of nuclear DNA (a marker of general DAMP release) were profoundly increased before chemotherapy and further increased 4-6 h afterwards, while the specific DAMP mitochondrial DNA showed only a trend towards increase. Circulating cytokine levels did not change following chemotherapy. Leukocyte cytokine production capacity and HLA-DR expression were similar in patients and healthy controls until day 4 when leukocytes were found to be virtually absent. In conclusion, in the early phase following chemotherapy in leukemia patients, increased DAMP release does not induce immunoparalysis. [ABSTRACT FROM AUTHOR]

Background: Postoperative recovery after live donor nephrectomy is largely determined by the consequences of postoperative pain and analgesia consumptions. The use of deep neuromuscular blockade has been shown to reduce postoperative pain scores after laparoscopic surgery. In this study, we will investigate whether deep neuromuscular blockade also improves the early quality of recovery after live donor nephrectomy.Methods: The RELAX-study is a phase IV, multicenter, double-blinded, randomized controlled trial, in which 96 patients, scheduled for living donor nephrectomy, will be randomized into two groups: one with deep and one with moderate neuromuscular blockade. Deep neuromuscular blockade is defined as a post-tetanic count of 1-2. Our primary outcome measurement will be the Quality of Recovery-40 questionnaire (overall score) at 24 h after extubation.Discussion: This study is, to our knowledge, the first randomized study to assess the effectiveness of deep neuromuscular blockade during laparoscopic donor nephrectomy in enhancing postoperative recovery. The study findings may also be applicable for other laparoscopic procedures.Trial Registration: clinicaltrials.gov, NCT02838134 . Registered on 29 June 2016. [ABSTRACT FROM AUTHOR]

Background: Distant metastasis or local recurrence after primary tumour resection remain a major clinical problem. The anaesthetic technique used during oncologic surgery is suggested to influence the metastatic process. While awaiting the results of ongoing randomised controlled trials (RCTs), we have analyzed the evidence regarding the influence of anaesthetic drugs on experimental tumour metastasis in animal studies. Methods: PubMed and Embase were searched until April 21st, 2015. Studies were included in the systematic review when they 1) assessed the effect of an anaesthetic drug used in clinical practice on the number or incidence of metastasis in animal models with experimental cancer, 2) included an appropriate control group, and 3) presented unique data. Results: 20 studies met the inclusion criteria (published between 1958–2010). Data on number of metastases could be retrieved from 17 studies. These studies described 41 independent comparisons, 33 of which could be included in the meta-analysis (MA). The incidence of metastases was studied in 3 unique papers. From these 3 papers, data on 7 independent comparisons could be extracted and included in the MA. Locally administered local anaesthetics appear to decrease the number of metastases (SMD -6.15 [-8.42; -3.88]), whereas general anaesthetics (RD: 0.136 [0.045, 0.226]), and more specifically volatile anaesthetics (SMD 0.54 [0.24; 0.84]), appear to increase the number and risk of metastases in animal models for cancer. Conclusions: Anaesthetics influence the number and incidence of metastases in experimental cancer models. Although more high quality experimental research is necessary, based on the currently available evidence from animal studies, there is no indication to suggest that locally administered local anaesthetics are harmful during surgery in cancer patients. Volatile anaesthetics, however, might increase metastasis in animal models and clinical trials investigating this possibly harmful effect should receive priority. The results of our systematic review in animal studies are broadly consistent with clinical reports that anaesthetic technique does seem to affect the tumour metastasis process. [ABSTRACT FROM AUTHOR]

Purpose: Danger-associated molecular patterns (DAMPs) released of trauma could contribute to an immune suppressed state that renders patients vulnerable towards nosocomial infections. We investigated DAMP release in trauma patients, starting in the prehospital phase, and assessed its relationship with immune suppression and nosocomial infections.Methods: Blood was obtained from 166 adult trauma patients at the trauma scene, emergency room (ER), and serially afterwards. Circulating levels of DAMPs and cytokines were determined. Immune suppression was investigated by determination of HLA-DRA gene expression and ex vivo lipopolysaccharide-stimulated cytokine production.Results: Compared with healthy controls, plasma levels of nuclear DNA (nDNA) and heat shock protein-70 (HSP70) but not mitochondrial DNA were profoundly increased immediately following trauma and remained elevated for 10 days. Plasma cytokines were increased at the ER, and levels of anti-inflammatory IL-10 but not of pro-inflammatory cytokines peaked at this early time-point. HLA-DRA expression was attenuated directly after trauma and did not recover during the follow-up period. Plasma nDNA (r = -0.24, p = 0.006) and HSP70 (r = -0.38, p < 0.0001) levels correlated negatively with HLA-DRA expression. Ex vivo cytokine production revealed an anti-inflammatory phenotype already at the trauma scene which persisted in the following days, characterized by attenuated TNF-α and IL-6, and increased IL-10 production. Finally, higher concentrations of nDNA and a further decrease of HLA-DRA expression were associated with infections.Conclusions: Plasma levels of DAMPs are associated with immune suppression, which is apparent within minutes/hours following trauma. Furthermore, aggravated immune suppression during the initial phase following trauma is associated with increased susceptibility towards infections. [ABSTRACT FROM AUTHOR]

Aim: Pulmonary ventilation remains an important part of cardiopulmonary resuscitation, affecting gas exchange and haemodynamics. We designed and studied an improved method of ventilation for CPR, constructed specifically to support both gas exchange and haemodynamics. This method uses continuous insufflation of oxygen at three levels of pressure, resulting in tri-level pressure ventilation (TLPV). We hypothesized that TLPV improves gas exchange and haemodynamics compared to manual gold standard ventilation (GSV).Methods: In 14 pigs, ventricular fibrillation was induced and automated CPR performed for 10 min with either TLPV or GSV. After defibrillation, CPR was repeated with the other ventilation method. Gas exchange and haemodynamics were monitored. Data are presented as mean±standard error of the mean.Results: TLPV was superior to GSV for PaO2 (163±36 mmHg difference; P=0.001), and peak AWP (-20±2 cmH2O difference; P=0.000) and higher for mean AWP (8±0.2 cmH2O difference; P=0.000). TLPV was comparable to GSV for CPP (5±3 mmHg difference; P=0.012), VCO2 (0.07±0.3 mL/min/kg difference; P=0.001), SvO2 (4±3%-point; P=0.001), mean carotid flow (-0.5±4 mL/min difference; P=0.016), and pHa (0.00±0.03 difference; P=0.002). The PaCO2 data do not provide a conclusive result (4±4 mmHg difference).Conclusion: We conclude that the ventilation strategy with a tri-level pressure cycle performs comparable to an expert, manual ventilator in an automated-CPR swine model. [ABSTRACT FROM AUTHOR]

Objectives: After cardiac arrest, patients are highly vulnerable toward infections, possibly due to a suppressed state of the immune system called "immunoparalysis." We investigated if immunoparalysis develops following cardiac arrest and whether the release of danger-associated molecular patterns could be involved. Design: Observational study. Setting: ICU of a university medical center. Patients: Fourteen post-cardiac arrest patients treated with mild therapeutic hypothermia for 24 hours and 11 control subjects. Measurements and Main Results: Plasma cytokines showed highest levels within 24 hours after cardiac arrest and decreased during the next 2 days. By contrast, ex vivo production of cytokines interleukin-6, tumor necrosis factor-α, and interleukin-10 by lipopolysaccharide-stimulated leukocytes was severely impaired compared with control subjects, with most profound effects observed at day 0, and only partially recovering afterward. Compared with incubation at 37°C, incubation at 32°C resulted in higher interleukin-6 and lower interleukin-10 production by lipopolysaccharide-stimulated leukocytes of control subjects, but not of patients. Plasma nuclear DNA, used as a marker for general danger-associated molecular pattern release, and the specific danger-associated molecular patterns (EN-RAGE and heat shock protein 70) were substantially higher in patients at days 0 and 1 compared with control subjects. Furthermore, plasma heat shock protein 70 levels were negatively correlated with ex vivo production of inflammatory mediators interleukin-6, tumor necrosis factor-α, and interleukin-10. Extracellular newly identified receptor for advanced glycation end products-binding protein levels only showed a significant negative correlation with ex vivo production of interleukin-6 and tumor necrosis factor-α and a borderline significant inverse correlation with interleukin-10. No significant correlations were observed between plasma nuclear DNA levels and ex vivo cytokine production. Interventions: None. Conclusions: Release of danger-associated molecular patterns during the first days after cardiac arrest is associated with the development of immunoparalysis. This could explain the increased susceptibility toward infections in cardiac arrest patients. [ABSTRACT FROM AUTHOR]

Analgesics are commonly used to manage pain in cancer patients. It has been suggested that there might be a relation between analgesics and the outgrowth of metastases. Opioids might increase and non-steroidal anti-inflammatory drugs decrease the risk of metastasis. Robust analysis of all preclinical evidence, however, has so far been lacking. Therefore, we conducted a systematic review and meta-analysis on the effect of treatment with analgesics on metastasis in experimental animal models. One hundred forty-seven studies met the inclusion criteria. Study characteristics, outcome data on the number, and incidence of metastases were extracted, and methodological quality was assessed. In the meta-analysis, we included 215 (± 4000 animals) and 137 (± 3000 animals) comparisons between analgesic vs control treatment, respectively, on the number and incidence of metastases. Overall, treatment with analgesics significantly decreases the number and risk of metastasis. This effect appears mainly to be the consequence of the efficacy of NSAIDs. Other factors that modify the efficacy are species, type of NSAIDs administered, timing, and duration of treatment. There is no evidence indicating that treatment with any analgesics increases the occurrence of metastases. Our findings appear robust for the various animal models and designs included in this review, which increases our confidence in the result and translatability to the clinical situation. [ABSTRACT FROM AUTHOR]

Background: In what way volume, concentration and dose affect block duration is controversial. The purpose of the present study is to investigate the effect of dose, volume and concentration of mepivacaine on the duration of sensory and motor blockade in ultrasound-guided single shot axillary brachial plexus blockade. Methods: In this parallel group randomized trial conducted in the Sint Maartenskliniek Nijmegen, 45 adult patients undergoing minor orthopaedic forearm, wrist or hand surgery were randomized to 3 groups. Group A: 20 mL mepivacaine 1.5 %, Group B: 30 mL mepivacaine 1 % and Group C: 30 mL mepivacaine 1.5 %. Randomization was computer-generated, with allocation concealment by opaque sequentially numbered sealed envelopes. Patients and observers were blinded to group allocation. Primary outcome measure: duration of sensory block. Results: Forty-five patients were randomized, four patients were excluded and replaced, and 15 patients in each group were included in the analysis. Mean (95 % CI) sensory and motor block duration was 256 (230-282) and 254 (226-282) minutes in Group A, 226 (209-243) and 220 (200-240) minutes in Group B and 270 (249-291) and 264 (244-284) minutes in Group C. Duration of sensory and motor block duration differed significantly between groups (p = 0.012 and p = 0.016 respectively). Post-hoc analysis showed a significantly reduced sensory and motor block duration in Group B when compared to Group C of 44 min. No local anesthetic systemic toxicity was reported. Conclusions: When using mepivacaine for axillary brachial plexus block, a higher dose and concentration was associated with a longer duration of sensory and motor blockade, but not a higher volume. Trial Registration: The Netherlands National Trial Register NTR3648. Registered October 3, 2012. [ABSTRACT FROM AUTHOR]

Background: Duration of peripheral nerve blocks depends on multiple factors. Both technique and type of local anesthetic used, either with or without adjuncts, may result in different duration times of the block. The purpose of the present study was to compare the duration of postoperative analgesia of 30 mL ropivacaine 0.75 % with or without epinephrine for popliteal sciatic nerve block. Methods: Thirty-eight patients were included to receive ultrasound guided continuous popliteal nerve block with ropivacaine 0.75 % either without (ROPI) or with epinephrine 5 μg/mL (ROPI-EPI) for ankle fusion, subtalar fusion, or a combination of both. The primary outcome parameter was the duration of postoperative analgesia as reflected by the time to first request for postoperative analgesia (TTFR) through the popliteal nerve catheter. Secondary outcome measures included the onset of sensory and motor block and NRS score for pain at rest and during movement. Results: Thirty patients, 15 in each group, were studied. Eight patients were withdrawn because of specific withdrawal criteria described in the protocol and replaced according to their group allocation. Median [interquartile range] TTFR was 463 [300-1197] min and 830 [397-1128] min for the ROPI vs ROPI-EPI group respectively. Hodges Lehman median difference between groups was 71 min (95 % CI −415 - 473 min). There was no difference in any clinical outcome measure between the groups. Conclusion: The results of this study did not show any significant increase in the duration of postoperative analgesia by adding epinephrine to ropivacaine for popliteal nerve block. This may be due to the intrinsic vasoconstrictive properties of ropivacaine. The absence of a significant difference can also be the result of a type II error caused by a large variation in the individual TTFR. Trial registration: Trial register.nl identifier: NTR3330, keyword TTFR [ABSTRACT FROM AUTHOR]

Study objective: The study objective is to investigate the effects of a simple price list sticker placed on vaporizers on anesthetic use and costs. The price list only showed the cost per hour of the annually most expensive drugs, which had a low-cost alternative. Design: The design is a prospective database study with historical controls. Setting: The setting is at operating rooms. Patients: All patients are undergoing a surgical procedure under anesthesia in both study periods, except cardiothoracic and day care patients. Interventions: The intervention is application of a price list sticker on the vaporizers. Measurements: Monthly cost and amount of anesthetic agents used during the 9 months before and after the intervention. Main results: After application of the price stickers, the use of both the annuallymost expensive agents and the anesthetic budget decreased substantially. Most notable was a decrease of 28% in the use of sevoflurane. Conclusions: Price sticker on vaporizersmay be an effective, simple, and cheapmethod to reduce anesthetic costs. [ABSTRACT FROM AUTHOR]

Abstract: Introduction: Reliable, non-invasive detection of return of spontaneous circulation (ROSC) with minimal interruptions to chest compressions would be valuable for high-quality cardiopulmonary resuscitation (CPR). We investigated the potential of photoplethysmography (PPG) to detect the presence of a spontaneous pulse during automated CPR in an animal study. Methods: Twelve anesthetized pigs were instrumented to monitor circulatory and respiratory parameters. Here we present the simultaneously recorded PPG and arterial blood pressure (ABP) signals. Ventricular fibrillation was induced, followed by 20min of automated CPR and subsequent defibrillation. After defibrillation, pediatric-guidelines-style life support was given in cycles of 2min. PPG and ABP waveforms were recorded during all stages of the protocol. Raw PPG waveforms were acquired with a custom-built photoplethysmograph controlling a commercial reflectance pulse oximetry probe attached to the nose. ABP was measured in the aorta. Results: In nine animals ROSC was achieved. Throughout the protocol, PPG and ABP frequency content showed strong resemblance. We demonstrate that (1) the PPG waveform allows for the detection of a spontaneous pulse during ventilation pauses, and that (2) frequency analysis of the PPG waveform allows for the detection of a spontaneous pulse and the determination of the pulse rate, even during ongoing chest compressions, if the pulse and compression rates are sufficiently distinct. Conclusions: These results demonstrate the potential of PPG as a non-invasive means to detect pulse presence or absence, as well as pulse rate during CPR. [Copyright &y& Elsevier]

Introduction The Episure Autodetect syringe, a spring-loaded syringe, is a loss-of-resistance syringe with an internal compression that applies constant pressure on the plunger. As the principle of loss-of-resistance is the same for adult and for pediatric patients, the Episure Autodetect syringe should be able to identify correctly the epidural space also in pediatric patients. Methods A retrospective review was carried out for all pediatric patients, in which the Episure Autodetect syringe was used for locating the epidural space between 2007 and 2011 in our department. Results In 17 pediatric patients (9 months-14 years, 7.5-43 kg weight), the Episure syringe was used. In all 17 patients, the epidural space was correctly identified using the spring-loaded syringe as evidenced by satisfactory analgesia. No accidental dural punctures or false loss-of-resistances were observed. Conclusion The spring-loaded Episure Autodetect syringe might be a potentially useful loss-of-resistance syringe for identification of the epidural space in pediatric patients. [ABSTRACT FROM AUTHOR]

Purpose: Diaphragm weakness induced by mechanical ventilation may contribute to difficult weaning from the ventilator. For optimal force generation the muscle proteins myosin and titin are indispensable. The present study investigated if myosin and titin loss or dysfunction are involved in mechanical ventilation-induced diaphragm weakness. Methods: Male Wistar rats were either assigned to a control group ( n = 10) or submitted to 18 h of mechanical ventilation (MV, n = 10). At the end of the experiment, diaphragm and soleus muscle were excised for functional and biochemical analysis. Results: Maximal specific active force generation of muscle fibers isolated from the diaphragm of MV rats was lower than controls (128 ± 9 vs. 165 ± 13 mN/mm, p = 0.02) and was accompanied by a proportional reduction of myosin heavy chain concentration in these fibers. Passive force generation upon stretch was significantly reduced in diaphragm fibers from MV rats by ca. 35%. Yet, titin content was not significantly different between control and MV diaphragm. In vitro pre-incubation with phosphatase-1 decreased passive force generation upon stretch in diaphragm fibers from control, but not from MV rats. Mechanical ventilation did not affect active or passive force generation in the soleus muscle. Conclusions: Mechanical ventilation leads to impaired diaphragm fiber active force-generating capacity and passive force generation upon stretch. Loss of myosin contributes to reduced active force generation, whereas reduced passive force generation is likely to result from a decreased phosphorylation status of titin. These impairments were not discernable in the soleus muscle of 18 h mechanically ventilated rats. [ABSTRACT FROM AUTHOR]

Pulmonary inflammation contributes to ventilator-induced lung injury. Sepsis-induced pulmonary inflammation (first hit) may be potentiated by mechanical ventilation (MV, second hit). Electrical stimulation of the vagus nerve has been shown to attenuate inflammation in various animal models through the cholinergic anti-inflammatory pathway. We determined the effects of vagotomy (VGX) and vagus nerve stimulation (VNS) on systemic and pulmonary inflammation in a two-hit model. Male Sprague-Dawley rats were i.v. administered lipopolysaccharide (LPS) and subsequently underwent VGX, VNS or a sham operation. 1 hour following LPS, MV with low (8 mL/kg) or moderate (15 mL/kg) tidal volumes was initiated, or animals were left breathing spontaneously (SP). After 4 hours of MV or SP, rats were sacrificed. Cytokine and blood gas analysis was performed. MV with 15, but not 8 mL/kg, potentiated the LPS-induced pulmonary pro-inflammatory cytokine response (TNF-α, IL-6, KC: p<0.05 compared to LPS-SP), but did not affect systemic inflammation or impair oxygenation. VGX enhanced the LPS-induced pulmonary, but not systemic pro-inflammatory cytokine response in spontaneously breathing, but not in MV animals (TNF-α, IL-6, KC: p<0.05 compared to SHAM), and resulted in decreased pO2 (p<0.05 compared to sham-operated animals). VNS did not affect any of the studied parameters in both SP and MV animals. In conclusion, MV with moderate tidal volumes potentiates the pulmonary inflammatory response elicited by systemic LPS administration. No beneficial effects of vagus nerve stimulation performed following LPS administration were found. These results questions the clinical applicability of stimulation of the cholinergic anti-inflammatory pathway in systemically inflamed patients admitted to the ICU where MV is initiated. [ABSTRACT FROM AUTHOR]

Abstract: A rat model of osteoarthritis was used to investigate the effect of pre-treatment with capsaicin on the symptoms of osteoarthritis induced by the injection of monosodium iodoacetate. This model mimics both histopathology and symptoms associated of human osteoarthritis. Injection of monosodium iodoacetate, an inhibitor of glycolysis, into the femorotibial joints of rodents promotes loss of articular trabecular bone and invokes pain symptoms similar to those noted in human osteoarthritis. Twenty rats were divided in two groups either receiving placebo or monosodium iodoacetate. Each group was subdivided in two groups either receiving pre-treatment with capsaicin two weeks before monosodium iodoacetate injection or not, resulting in four groups of five rats each. The impact of a single intra-articular administration of capsaicin (0.5%) on the generation of evoked mechanical pain (hind limb weight bearing, automated von Frey monofilament and RotaRod tests) and bone lesions (micro-CT scan radiographic analyses of bone structure) following monosodium iodoacetate-induced osteoarthritis in rats was determined. Evoked mechanical pain as monitored over a period of 4weeks after monosodium iodoacetate injection was abolished in capsaicin pre-treated animals and pain values are comparable to those of capsaicin controls. Chronic joint pathological changes such as bone erosion and trabecular damage were significantly reduced by pre-treatment with a single administration of capsaicin. Decrease of bone volume was considerably ameliorated and trabecular connectivity was substantially better in capsaicin pre-treated animals. Capsaicin, an agonist activator of the vanilloid nociceptors (TRPV1), appears to be effective in protecting bone from arthritic damage. The present results support the hypothesis that capsaicin-sensitive sensory neurons contribute to bone lesions in the monosodium iodoacetate-induced osteoarthritis rat model. [Copyright &y& Elsevier]

Summary: Objective: To determine the incidence and success rate of out-of-hospital tracheal intubation (TI) and ventilation of children, taking account of the type of healthcare provider involved. Methods: A prospective observational study to analyse a consecutive group of children for which a helicopter-transported medical team (HMT) was called. In all cases, the emergency medical service (EMS)-paramedics arrived at the scene first. Data regarding type of incident, physiological parameters, treatment, and survival until hospital discharge were collected and subsequently analysed. Results: Of the 300 children examined and treated by the HMT on scene, 155 (52%) children required out-of-hospital tracheal intubation. Ninety-five children had an initial Glasgow Coma Scale (GCS) rating of 3–4: the EMS-paramedics performed bag-valve-mask-ventilation (BVMV) until arrival with subsequent TI carried out by the HMT (54 children, survival 63%) or the EMS-paramedics performed TI themselves (41 children, subsequent correction of tube/ventilation by HMT in 37% and survival rate 5%). Two hundred and five children had an initial GCS of 5–15, from which 60 children required TI (survival rate 67%) and 145 children required no TI (survival rate 100%). Conclusion: We do not recommend early TI by EMS-paramedics in children with a GCS of 3–4. The rate of complications of this procedure is unacceptably high. BVMV is the preferred choice for ventilation by paramedics, whenever possible. Out-of-hospital TI performed by HMT is safe and effective. The HMT has skills in advanced airway management not provided by the EMS. [Copyright &y& Elsevier]

Abstract: Randomized clinical trials (RCTs) are prospective empirical studies used to investigate the effect of a particular medical intervention. The design of a clinical trial is a delicate decision process, as each of the decisions that are taken in this process influences the eventual result of the clinical trial. Despite the efforts that are put into trial design, many trials fail to show an effect of the intervention. In some of these situations the intervention may be truly ineffective, however, more often this is caused by problems with the inclusion of patients and a resulting lack of statistical power to show the effect. To avoid this problem, in the design of a trial, the statistical power that can be achieved with the current design choices is calculated and balanced with economic considerations. In the choice of the entry criteria however, an important step in the design process, the influence of the chosen criteria on statistical power and number of eligible patients is not quantified. As these criteria influence the characteristics of the study population and the number of patients that will be eligible for the trial, and thereby the chances of finding an effect of the intervention, we believe that also in the choice of entry criteria explicit estimates of the number of eligible patients should be made. This paper presents a method to arrive at precise, objective estimates of statistical power and the number of eligible patients, using a registry database. Furthermore, we describe how this method is incorporated in the process of choosing entry criteria for a clinical trial. We illustrate the method with an example in the area of severe sepsis. [Copyright &y& Elsevier]

Objective: To understand the impact of patient selection criteria used in recent sepsis trials on baseline mortality risk and number of eligible patients.Design: Observational cohort study, with retrospective analysis of prospectively collected data.Methods and Main Results: Using a MEDLINE search, we selected recent randomized controlled trials in patients with severe sepsis and studied the mortality rate in the control groups of these trials. Nine articles fulfilled the search criteria and were used in our analyses. The 28-day mortality rate in the control groups of these trials varied between 28.0% and 89.0%. Differences in this mortality rate might be due to the use of different entry criteria but also to other factors that vary between the trials. To eliminate the influence of these confounding factors when studying the effect of the use of entry criteria on baseline mortality risk and number of eligible patients, we projected the entry criteria of these nine trials on a large independent database of >70,000 Dutch intensive care patients admitted between 1996 and 2003. This yielded nine groups of patients who would have been eligible for the respective trials. The percentage of patients who would have been eligible for these trials varied between 1.5% and 6.0%. Six of these groups had a similar intensive care mortality rate (between 25.0% and 28.9%). The projection of the entry criteria of the three other trials onto the database resulted in groups of patients with considerably higher intensive care mortality. For in-hospital mortality rate in these groups, similar results were found.Conclusions: The majority of the trials we studied used entry criteria that select patients with a similar mortality risk. This suggests that differences in baseline mortality risk reported in recent sepsis trials are to be attributed to other factors that vary between trials rather than to differences in entry criteria. However, entry criteria do have an important influence on the number of eligible patients for sepsis trials without influencing baseline mortality rate. [ABSTRACT FROM AUTHOR]

Endotoxemia is associated with changed pulmonary vascular function with respect to vasoreactivity, endothelial permeability, and activation of inducible nitric oxide synthase II (NOSII). However, whether altered passive arterial wall mechanics contribute to this endotoxin-induced pulmonary vascular dysfunction is still unknown. Therefore, we investigated whether endotoxin affects the passive arterial mechanics and compliance of isolated rat pulmonary arteries. Pulmonary arteries of pentobarbital-anesthetized Wistar rats (n = 55) were isolated and exposed to Escherichia coli endotoxin (50 μg/ml) for 20 h. Endotoxin increased pulmonary artery diameter and compliance (transmural pressure = 13 mmHg) in an endothelium-, Ca2+-, or NOSII-induced NO release-independent manner. Interestingly, the endotoxin-induced alterations in the passive arterial mechanics were accompanied by disassembly of the smooth muscle cell (SMC) F-actin cytoskeleton. Disassembly of F-actin by incubation of control arteries with the cytoskeleton-disrupting agent cytochalasin B or the Rho-kinase inhibitor Y-27632 induced a similar increase in passive arterial diameter and compliance. In contrast, RhoA activation by lysophosphatidic acid prevented the endotoxin-induced alterations in the pulmonary SMC F-actin cytoskeleton and passive mechanics. In conclusion, these findings indicate that disassembly of the SMC F-actin cytoskeleton and RhoA/Rho-kinase signaling act as mediators of endotoxin-induced changes in the pulmonary arterial mechanics. They imply the involvement of F-actin rearrangement and RhoA/Rho-kinase signaling in endotoxemia-induced vascular lung injury. [ABSTRACT FROM AUTHOR]