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Purpose: Introducing advanced hemodynamic monitoring might be beneficial during Helicopter Emergency Medical Service (HEMS) care. However, it should not increase the on-scene-time, it should be easy to use and should be non-invasive. The goal of this study was to investigate the feasibility of non-invasive cardiac output measurements by electrical cardiometry (EC) and the quality of the EC signal during pre-hospital care provided by our HEMS., Methods: A convenience sample of fifty patients who required HEMS assistance were included in this study. Problems with respect to connecting the patient, entering patient characteristics and measuring were inventoried. Quality of EC signal of the measurements was assessed during prehospital helicopter care. We recorded the number of measurements with a signal quality indicator (SQI) ≥ 80 and the number of patients having at least 1 measurement with a SQI ≥ 80. Furthermore, the SQI value distribution of the measurements within each patient was analysed., Results: In the experience of the attending HEMS caregivers application of the device was easy and did not result in increased duration of on-scene time. Patch adhesion was reported as a concern due to clammy skin in 22% of all cases. 684 measurements were recorded during HEMS care. In 47 (94%) patients at least 1 measurement with an SQI ≥ 80 was registered. Of all recorded measurements 5.8% had an SQI < 40, 11.4% had an SQI 40-59, 14.9% had a SQI between 60 and 79 and 67.8% had SQI ≥ 80., Conclusion: Cardiac output measurements are feasible during prehospital HEMS care with good quality of the EC signal. Monitoring was easy to use and quick to install. In our view it is an promising candidate for the prehospital setting. Further research is needed to determine its clinical value during clinical decision making., (© 2021. The Author(s).)

Positive end-expiratory pressure (PEEP) is routinely applied in mechanically ventilated patients to improve gas exchange and respiratory mechanics by increasing end-expiratory lung volume (EELV). In a recent experimental study in rats, we demonstrated that prolonged application of PEEP causes diaphragm remodeling, especially longitudinal muscle fiber atrophy. This is of potential clinical importance, as the acute withdrawal of PEEP during ventilator weaning decreases EELV and thereby stretches the adapted, longitudinally atrophied diaphragm fibers to excessive sarcomere lengths, having a detrimental effect on force generation. Whether this series of events occurs in the human diaphragm is unknown. In the current study, we investigated if short-term application of PEEP affects diaphragm geometry and function, which are prerequisites for the development of longitudinal atrophy with prolonged PEEP application. Nineteen healthy volunteers were noninvasively ventilated with PEEP levels of 2, 5, 10, and 15 cmH 2 O. Magnetic resonance imaging was performed to investigate PEEP-induced changes in diaphragm geometry. Subjects were instrumented with nasogastric catheters to measure diaphragm neuromechanical efficiency (i.e., diaphragm pressure normalized to its electrical activity) during tidal breathing with different PEEP levels. We found that increasing PEEP from 2 to 15 cmH 2 O resulted in a caudal diaphragm displacement (19 [14-26] mm, P < 0.001), muscle shortening in the zones of apposition (20.6% anterior and 32.7% posterior, P < 0.001), increase in diaphragm thickness (36.4% [0.9%-44.1%], P < 0.001) and reduction in neuromechanical efficiency (48% [37.6%-56.6%], P < 0.001). These findings demonstrate that conditions required to develop longitudinal atrophy in the human diaphragm are present with the application of PEEP. NEW & NOTEWORTHY We demonstrate that PEEP causes changes in diaphragm geometry, especially muscle shortening, and decreases in vivo diaphragm contractile function. Thus, prerequisites for the development of diaphragm longitudinal muscle atrophy are present with the acute application of PEEP. Once confirmed in ventilated critically ill patients, this could provide a new mechanism for ventilator-induced diaphragm dysfunction and ventilator weaning failure in the intensive care unit (ICU).

Introduction: Malignant hyperthermia (MH) and exertional rhabdomyolysis (ERM) have long been considered episodic phenotypes occurring in response to external triggers in otherwise healthy individuals with variants in RYR1. However, recent studies have demonstrated a clinical and histopathological continuum between patients with RYR1-related congenital myopathies and those with ERM or MH susceptibility. Furthermore, animal studies have shown non-neuromuscular features such as a mild bleeding disorder and an immunological gain-of-function associated with MH/ERM related RYR1 variants raising important questions for further research. Awareness of the neuromuscular disease spectrum and potential multisystem involvement in RYR1-related MH and ERM is essential to optimize the diagnostic work-up, improve counselling and and future treatment strategies for patients affected by these conditions. This study will examine in detail the nature and severity of continuous disease manifestations and their effect on daily life in patients with RYR1-related MH and ERM., Methods: The study protocol consists of four parts; an online questionnaire study, a clinical observational study, muscle imaging, and specific immunological studies. Patients with RYR1-related MH susceptibility and ERM will be included. The imaging, immunological and clinical studies will have a cross-sectional design, while the questionnaire study will be performed three times during a year to assess disease impact, daily living activities, fatigue and pain. The imaging study consists of muscle ultrasound and whole-body magnetic resonance imaging studies. For the immunological studies, peripheral mononuclear blood cells will be isolated for in vitro stimulation with toll-like receptor ligands, to examine the role of the immune system in the pathophysiology of RYR1-related MH and ERM., Discussion: This study will increase knowledge of the full spectrum of neuromuscular and multisystem features of RYR1-related MH and ERM and will establish a well-characterized baseline cohort for future studies on RYR1-related disorders. The results of this study are expected to improve recognition of RYR1-related symptoms, counselling and a more personalized approach to patients affected by these conditions. Furthermore, results will create new insights in the role of the immune system in the pathophysiology of MH and ERM., Trial Registration: This study was pre-registered at ClinicalTrials.gov (ID: NCT04610619)., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2021 the Author(s). Published by Wolters Kluwer Health, Inc.)

Background: Obtaining complete topical anaesthesia of the airway remains a clinical challenge. Particle size is one of the most important variables for the dose deposited and the distribution of aerosols in the airways. The mass median aerodynamic diameter of the particles should be in the range of 5-20 µm. We developed the "Trachospray" as a soft mist spray device for local anaesthetics. This in-vitro comparative test was designed to compare the performance of the new Trachospray device with two existing medical devices. The performance was determined by comparing the spray deposition patterns in the mouth, throat, trachea and lungs., Methods: The human airway was simulated with an artificial idealized mouth and throat model, connected to a Next Generation Impactor. Four measurements were taken for each device (Trachospray, jet nebulizer and a spray pump) with 5.85% NaCl. A fifth measurement was carried out with 0.5% fluorescein solution for a visual inspection of the deposition patterns. The mass median aerodynamic diameter and geometric standard deviation of the droplets were measured., Results: The Trachospray produced an even coverage in the mouth, hypopharynx and vocal cords, with only a small lung fraction. The jet nebulizer produced a much thinner layer coverage of the tongue and surface around the vocal chords with a high lung deposition. The spray pump produced big droplets which deposited mainly at the hypopharynx., Conclusion: The Trachospray device deposits local anaesthetics in the targeted areas for topical anaesthesia of the airway and has promising characteristics for providing effective airway anaesthesia., Competing Interests: G.J. van Geffen, M. van Barneveld and J. Bruhn have a patent pending for the Trachospray device. G.J. van Geffen, H. Markerink and J. Bruhn report non-financial support from Medspray Anesthesia, during the conduct of the study. The authors report no other conflicts of interest in this work., (© 2021 van Geffen et al.)

Background: Laparoscopy is the gold standard for many surgical procedures and is embraced as minimally invasive surgery in the enhanced recovery after surgery programme. Lowering intra-abdominal pressure during laparoscopy may decrease the degree of surgical injury and further enhance patient outcomes. This study aims to assess the effect of low pressure pneumoperitoneum on peritoneal perfusion during laparoscopic surgery., Materials and Methods: We performed a prospective randomized intervention study in 30 adults undergoing colorectal robot assisted laparoscopic surgery at a secondary care medical center in the Netherlands between June and December 2018. A 3 min video recording of the parietal peritoneum was made with the Da Vinci® Firefly mode following intravenous injection of 0.2 mg/kg indocyanine green at a pneumoperitoneum pressure of 8, 12 or 16 mmHg. Observers were blinded for the level of intra-abdominal pressure that was used. Fluorescent intensity in [-] over time was extracted from each video in MATLAB. Time to reach maximal fluorescent intensity (TMFI) and maximum fluorescent intensity (MFI) were compared among groups. The study was registered at clinicaltrials.gov (NCT03928171)., Results: Mean TMFI was shorter at low pressure (8 mmHg) than standard pressure (12 and 16 mmHg): 44 ± 12 versus 58 ± 18 s (p = 0.032), respectively. Mean MFI was higher at 8 mmHg than 12 and 16 mmHg (222 ± 25 versus 188 ± 54, p = 0.033). Regression analysis identified intra-abdominal pressure, mean arterial pressure and female gender as significant predictors of peritoneal perfusion., Conclusion: Low pressure pneumoperitoneum was associated with improved perfusion of the parietal peritoneum. Current available evidence supported feasibility and enhanced postoperative recovery. Future investigations should focus on optimizing factors that facilitate lower intra-abdominal pressure and explore effects on other clinically relevant patient outcomes such as anastomotic leakage and immune homeostasis., Competing Interests: Declaration of competing interest MW received grants from Merck Sharp & Dohme outside the submitted work. JM: Merck MSD, GE Healthcare, Johnson & Johnson and Conmed pain paid to institution, society and personal for lectures given., (Copyright © 2020 IJS Publishing Group Ltd. Published by Elsevier Ltd. All rights reserved.)

Chemotherapy induced painful peripheral neuropathy (CIPN) is a common dose-limiting side effect of several chemotherapeutic agents. Despite large amounts of human and animal studies, there is no sufficiently effective pharmacological treatment for CIPN. Although reducing pain is often a focus of CIPN treatment, remarkably few analgesics have been tested for this indication in clinical trials. We conducted a systematic review and meta-analyses regarding the effects of analgesics on stimulus evoked pain-like behaviour during CIPN in animal models. This will form a scientific basis for the development of prospective human clinical trials. A comprehensive search identified forty-six studies. Risk of bias (RoB) analyses revealed that the design and conduct of the included experiments were poorly reported, and therefore RoB was unclear in most studies. Meta-analyses showed that administration of analgesics significantly increases pain threshold for mechanical (SMD: 1.68 [1.41; 1.82]) and cold (SMD: 1. 41 [0.99; 1.83]) evoked pain. Subgroup analyses revealed that dexmedetomidine, celecoxib, fentanyl, morphine, oxycodone and tramadol increased the pain threshold for mechanically evoked pain, and lidocaine and morphine for cold evoked pain. Altogether, this meta-analysis shows that there is ground to investigate the use of morphine in clinical trials. Lidocaine, dexmedetomidine, celecoxib, fentanyl, oxycodone and tramadol might be good alternatives, but more animal-based research is necessary.

Background: Shared decision-making (SDM) and decision-support tools have attracted broad support in healthcare as they improve medical decision-making. Experts disagree on how these can help patients evaluate their present situation and possible outcomes of therapy, and how they might reduce decisional conflict. Little is known about their implementation, especially in anaesthesiology., Objective: To obtain a more fundamental understanding of pre-operative SDM and evaluate the use of a decision-support tool for postoperative analgesia after major thoracic and abdominal surgery., Design: A qualitative study with semistructured, in-depth interviews of patients and professionals., Setting: Patient recruitment took place at the Radboud University Medical Centre in Nijmegen and the Canisius Wilhelmina Hospital in Nijmegen, a nonacademic teaching centre. Professionals of the Radboud University Medical Centre were invited to participate in the interviews., Participants: Interviews were performed with 10 individual patients and two focus groups both consisting of eight different professionals., Main Outcome Measures: To gain insight into the provision of pre-operative information, decision-making processes and the clarity and usability of a prototype decision-support tool., Results: Professionals seemed to provide their patients with information directed towards the application of epidural analgesia, providing little attention to its negative effects. For many patients, the information was not tailored to their needs. Patients' involvement in decision-making was minimal, but they did not feel a need for more involvement. They were positive about the decision-support tool, although they indicated that it would not have influenced their treatment decision. Professionals expressed their doubt about the capacity of their patients to fully understand the decisions involved and about the clinical usability of the decision-support tool, because patients might misinterpret the information provided., Conclusion: The results of this study suggest that both patients and professionals did not adhere to some 'self-evident' principles of SDM when postoperative analgesia after major thoracic and abdominal surgery was discussed.

Background and Objectives: Local infiltration analgesia (LIA) with ropivacaine for total knee arthroplasty (TKA) is increasingly used. Despite the high doses of ropivacaine, LIA is considered safe, and this perception is sustained by pharmacokinetic data demonstrating that maximum concentrations of ropivacaine stay well below the toxic threshold in plasma. These pharmacokinetic studies all involve TKA procedures with the use of a tourniquet. Recently, performing TKA without the use of a tourniquet is gaining popularity, but no pharmacokinetic data exist when LIA is administered for TKA without the use of a tourniquet. The purpose of this study was to describe the pharmacokinetic profile of a single-shot ropivacaine (200 mL 0.2%) and 0.75 mg epinephrine (1000 μg/mL) when used for LIA in patients for TKA without a tourniquet., Methods: In this prospective cohort study, 20 patients treated with LIA for TKA without a tourniquet were studied. Plasma samples were taken at 20, 40, 60, 90, 120, 240, 360, 480, 600, 720, and 1440 minutes after local anesthetic infiltration, in which total and unbound ropivacaine concentrations were determined., Results: Results are given as median (interquartile range [IQR]). Median peak ropivacaine concentration was 1.16 μg/mL (IQR, 0.46); median peak unbound ropivacaine concentration was 0.05 μg/mL (IQR, 0.02). The corresponding times to reach the maximum concentration for total and unbound ropivacaine were 360 (IQR, 240) and 360 (IQR, 360) minutes, respectively., Conclusions: Although great interindividual variability in ropivacaine concentration was found, both total and unbound maximum serum concentrations remained below the assumed systemic toxic thresholds in all samples., Clinical Trial Registration: This study was registered at Netherlands Trial Registry (http://www.trialregister.nl), trial ID NTR6306.

Background: Diaphragm dysfunction develops frequently in ventilated intensive care unit (ICU) patients. Both disuse atrophy (ventilator over-assist) and high respiratory muscle effort (ventilator under-assist) seem to be involved. A strong rationale exists to monitor diaphragm effort and titrate support to maintain respiratory muscle activity within physiological limits. Diaphragm electromyography is used to quantify breathing effort and has been correlated with transdiaphragmatic pressure and esophageal pressure. The neuromuscular efficiency index (NME) can be used to estimate inspiratory effort, however its repeatability has not been investigated yet. Our goal is to evaluate NME repeatability during an end-expiratory occlusion (NMEoccl) and its use to estimate the pressure generated by the inspiratory muscles (Pmus)., Methods: This is a prospective cohort study, performed in a medical-surgical ICU. A total of 31 adult patients were included, all ventilated in neurally adjusted ventilator assist (NAVA) mode with an electrical activity of the diaphragm (EAdi) catheter in situ. At four time points within 72 h five repeated end-expiratory occlusion maneuvers were performed. NMEoccl was calculated by delta airway pressure (ΔPaw)/ΔEAdi and was used to estimate Pmus. The repeatability coefficient (RC) was calculated to investigate the NMEoccl variability., Results: A total number of 459 maneuvers were obtained. At time T = 0 mean NMEoccl was 1.22 ± 0.86 cmH 2 O/μV with a RC of 82.6%. This implies that when NMEoccl is 1.22 cmH 2 O/μV, it is expected with a probability of 95% that the subsequent measured NMEoccl will be between 2.22 and 0.22 cmH2O/μV. Additional EAdi waveform analysis to correct for non-physiological appearing waveforms, did not improve NMEoccl variability. Selecting three out of five occlusions with the lowest variability reduced the RC to 29.8%., Conclusions: Repeated measurements of NMEoccl exhibit high variability, limiting the ability of a single NMEoccl maneuver to estimate neuromuscular efficiency and therefore the pressure generated by the inspiratory muscles based on EAdi.

Hypoxia and inflammation are closely intertwined phenomena. Critically ill patients often suffer from systemic inflammatory conditions and concurrently experience short-lived hypoxia. We evaluated the effects of short-term hypoxia on systemic inflammation, and show that it potently attenuates pro-inflammatory cytokine responses during murine endotoxemia. These effects are independent of hypoxia-inducible factors (HIFs), but involve augmented adenosine levels, in turn resulting in an adenosine 2B receptor-mediated post-transcriptional increase of interleukin (IL)-10 production. We translated our findings to humans using the experimental endotoxemia model, where short-term hypoxia resulted in enhanced plasma concentrations of adenosine, augmentation of endotoxin-induced circulating IL-10 levels, and concurrent attenuation of the pro-inflammatory cytokine response. Again, HIFs were shown not to be involved. Taken together, we demonstrate that short-term hypoxia dampens the systemic pro-inflammatory cytokine response through enhanced purinergic signaling in mice and men. These effects may contribute to outcome and provide leads for immunomodulatory treatment strategies for critically ill patients., (Copyright © 2018 The Authors. Published by Elsevier B.V. All rights reserved.)

Exogenous administration of mitochondrial DNA (mtDNA) causes inflammatory lung injury in a toll-like receptor (TLR) 9-dependent manner. We investigated whether mechanical ventilation results in endogenous release of mtDNA and whether TLR9 plays a role in the pulmonary inflammatory response induced by mechanical ventilation.Wild-type and TLR9/ C57bl/6 mice were ventilated with low (8 mL/kg) and high (32 mL/kg) tidal volumes for 4 hours. Levels of nuclear DNA and mtDNA in bronchoalveolar lavage fluid, as well as pulmonary concentrations of keratinocyte-derived chemokine, interleukin-1β, and interleukin-6, were determined.Cytokine and nuclear DNA, but not mtDNA, levels were increased after mechanical ventilation with both tidal volumes. Cytokine concentrations were similar between wild-type and TLR9/ mice. Mechanical ventilation does not result in the release of mtDNA, and TLR9 is not involved in mechanical ventilation-induced inflammation.

Introduction: Soluble urokinase-type plasminogen activator (suPAR) represents a marker for immune activation and has predictive value in critically ill patients. The kinetics of suPAR and its correlation with the immune response and outcome in trauma patients are unknown., Methods: Plasma concentrations of inflammatory cytokines and suPAR were determined in adult trauma patient (n = 69) samples obtained by the Helicopter Emergency Medical Services at arrival at the emergency department (ED) and at days 1, 3, 5, 7, 10, and 14., Results: Initial suPAR levels were unrelated to injury severity score and higher in nonsurvivors compared with survivors, although no difference was observed between early and late mortality. The area under the receiver operating characteristic curve to predict mortality was 0.6 (95% confidence interval, 0.48-0.72). Soluble urokinase-type plasminogen activator levels increased over time in 94% of patients, although suPAR increase did not precede death. Tumor necrosis factor α at the ED correlated with suPAR at that time point, whereas concentrations of other proinflammatory cytokines at the ED correlated with suPAR levels at days 1 and 5., Conclusions: After trauma, initial suPAR plasma concentrations are higher in nonsurvivors compared with survivors, but its predictive value is low. Soluble urokinase-type plasminogen activator levels increase over time after trauma, and concentrations at later time points are related to cytokine levels at the ED., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Introduction: Controlled mechanical ventilation and endotoxemia are associated with diaphragm muscle atrophy and dysfunction. Oxidative stress and activation of inflammatory pathways are involved in the pathogenesis of diaphragmatic dysfunction. Levosimendan, a cardiac inotrope, has been reported to possess anti-oxidative and anti-inflammatory properties. The aim of the present study was to investigate the effects of levosimendan on markers for diaphragm nitrosative and oxidative stress, inflammation and proteolysis in a mouse model of endotoxemia and mechanical ventilation., Methods: Three groups were studied: (1) unventilated mice (CON, n =8), (2) mechanically ventilated endotoxemic mice (MV LPS, n =17) and (3) mechanically ventilated endotoxemic mice treated with levosimendan (MV LPS + L, n =17). Immediately after anesthesia (CON) or after 8 hours of mechanical ventilation, blood and diaphragm muscle were harvested for biochemical analysis., Results: Mechanical ventilation and endotoxemia increased expression of inducible nitric oxide synthase (iNOS) mRNA and cytokine levels of interleukin (IL)-1β, IL-6 and keratinocyte-derived chemokine, and decreased IL-10, in the diaphragm; however, they had no effect on protein nitrosylation and 4-hydroxy-2-nonenal protein concentrations. Levosimendan decreased nitrosylated proteins by 10% (P <0.05) and 4-hydroxy-2-nonenal protein concentrations by 13% (P <0.05), but it augmented the rise of iNOS mRNA by 47% (P <0.05). Levosimendan did not affect the inflammatory response in the diaphragm induced by mechanical ventilation and endotoxemia., Conclusions: Mechanical ventilation in combination with endotoxemia results in systemic and diaphragmatic inflammation. Levosimendan partly decreased markers of nitrosative and oxidative stress, but did not affect the inflammatory response.

A 71-year-old man underwent facial reconstructive surgery and a tracheotomy after nasal carcinoma. Several hours after surgery, accidental decannulation occurred and the patient died because the airway could not be resecured in time. This incident led to the implementation of an algorithm for emergency airway management in patients with a surgical airway after tracheotomy or laryngectomy. All such patients have an information sheet attached to their bed, together with the appropriate algorithm. This helps staff to provide care in a standardised manner in cases of airway emergency and prevents fixation errors or omission of treatment options.

Background: Children with mitochondrial disorders are frequently anesthetized for a wide range of operations. These disorders may interfere with the response to surgery and anesthesia. We examined anesthetic sensitivity to and respiratory effects of isoflurane in the Ndufs4 knockout (KO) mouse model. These mice exhibit an isolated mitochondrial complex I (CI) deficiency of the respiratory chain, and they also display clinical signs and symptoms resembling those of patients with mitochondrial CI disease., Methods: We investigated seven Ndufs4(-/-) knockout (KO), five Ndufs4(+/-) heterozygous (HZ) and five Ndufs4(+/+) wild type (WT) mice between 22 and 25 days and again between 31 and 34 days post-natal. Animals were placed inside an airtight box, breathing spontaneously while isoflurane was administered in increasing concentrations. Minimum alveolar concentration (MAC) was determined with the bracketing study design, using the response to electrical stimulation to the hind paw., Results: MAC for isoflurane was significantly lower in KO mice than in HZ and WT mice: 0.81% ± 0.01 vs 1.55 ± 0.05% and 1.55 ± 0.13%, respectively, at 22-25 days, and 0.65 ± 0.05%, 1.65 ± 0.08% and 1.68 ± 0.08% at 31-34 days. The KO mice showed severe respiratory depression at lower isoflurane concentrations than the WT and HZ mice., Conclusion: We observed an increased isoflurane anesthetic sensitivity and severe respiratory depression in the KO mice. The respiratory depression during anesthesia was strongly progressive with age. Since the pathophysiological consequences from complex I deficiency are mainly reflected in the central nervous system and our mouse model involves progressive encephalopathy, further investigation of isoflurane effects on brain mitochondrial function is warranted.

Introduction: Nexfin (Edwards Lifesciences, Irvine, CA) allows for noninvasive continuous monitoring of blood pressure (ABPNI) and cardiac output (CONI) by measuring finger arterial pressure (FAP). To evaluate the accuracy of FAP in measuring ABPNI and CONI as well as the adequacy of detecting changes in ABP and CO, we compared FAP to intra-arterially measured blood pressure (ABPIA) and transpulmonary thermodilution(COTD) in post cardiac surgery patients during a fluid challenge (FC)., Methods: Twenty sedated patients post cardiac surgery were included, and 28 FCs were performed. Measurements of ABP and CO were simultaneously collected before and after an FC, and we compared CO and blood pressure., Results: Finger arterial pressure was obtainable in all patients.When comparing ABPNI with ABPIA, bias was2.7 mm Hg (limits of agreement [LOA], ± 22.2), 4.9 mm Hg (LOA, ± 13.6), and 4.2 mm Hg (LOA, ±13.7) for systolic,diastolic, and mean arterial pressure, respectively. Concordance between changes in ABPNI and ABPIA was 100%.Mean bias between CONI and COTD was -0.26 (LOA, ± 2.2), with a percentage error of 38.9%. Concordance between changes in CONI vs COTD and was 100%., Conclusion: Finger arterial pressure reliably measures ABP and adequately tracks changes in ABP. Although CONI is not interchangeable with COTD, it follows changes in CO closely.

Purpose: Mechanical ventilation can cause ventilator-induced lung injury, characterized by a sterile inflammatory response in the lungs resulting in tissue damage and respiratory failure. The cytokine interleukin-1β (IL-1β) is thought to play an important role in the pathogenesis of ventilator-induced lung injury. Cleavage of the inactive precursor pro-IL-1β to form bioactive IL-1β is mediated by several types of proteases, of which caspase-1, activated within the inflammasome, is the most important. Herein, we studied the roles of IL-1β, caspase-1 and neutrophil factors in the mechanical ventilation-induced inflammatory response in mice., Methods: Untreated wild-type mice, IL-1αβ knockout and caspase-1 knockout mice, pralnacasan (a selective caspase-1 inhibitor)-treated mice, anti-keratinocyte-derived chemokine (KC)-treated mice and cyclophosphamide-treated neutrophil-depleted wild-type mice were ventilated using clinically relevant ventilator settings (tidal volume 8 ml/kg). The lungs and plasma were collected to determine blood gas values, cytokine profiles and neutrophil influx., Results: Mechanical ventilation resulted in increased pulmonary concentrations of IL-1β and KC and increased pulmonary neutrophil influx compared with non-ventilated mice. Ventilated IL-1αβ knockout mice did not demonstrate this increase in cytokines. No significant differences were observed between wild-type and caspase-1-deficient or pralnacasan-treated mice. In contrast, in anti-KC antibody-treated mice and neutropenic mice, inflammatory parameters decreased in comparison with ventilated non-treated mice., Conclusions: Our results illustrate that IL-1 is indeed an important cytokine in the inflammatory cascade induced by mechanical ventilation. However, the inflammasome/caspase-1 appears not to be involved in IL-1β processing in this type of inflammatory response. The attenuated inflammatory response observed in ventilated anti-KC-treated and neutropenic mice suggests that IL-1β processing in mechanical ventilation-induced inflammation is mainly mediated by neutrophil factors.

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(2), 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.

In the Netherlands, the majority of elective-surgery patients are evaluated by the anaesthesiologist at the preoperative assessment clinic. We believe that this visit can be omitted in selected patients as it has only minimal benefit, whereas its disadvantages can be substantial. Alternatively, the initial screening could be performed by the completion of a questionnaire via the telephone, via internet, by a nurse or by the surgeon. These data can then be evaluated by the anaesthesiologist; this is called the 'paper-based' preoperative evaluation. This method does require the conscientious cooperation between anaesthesiologists and surgeons; it should be clear which patients are eligible, what type of anaesthetic technique should be used, how the patient should be informed and how the informed consent is obtained. In our opinion, this paper-based evaluation combines safety and efficiency with patient-friendliness. It should be anchored in current guidelines to ensure quality.

Unlabelled: The doublecortin-like kinase (DCLK) gene is crucially involved in neuronal plasticity and microtubule-guided retrograde transport of signaling molecules. We have explored the possibility that DCLK is involved in pain-induced signaling events in adult male Wistar rats. Our results show that both DCLK-short and DCLK-long splice variants are present in the cell body and proximal dendrites of neurons in stress-related nuclei, ie, the paraventricular nucleus of the hypothalamus (PVN) and the non-preganglionic Edinger-Westphal nucleus (npEW) in the rostroventral periaqueductal grey. We found that DCLK-long but not DCLK-short is phosphorylated in its serine/proline-rich domain. Furthermore, we demonstrate that phosphorylation of DCLK-long in the npEW is increased by acute pain, whereas DCLK-long phosphorylation in the PVN remains unaffected. This is the first report revealing that DCLK isoforms in the PVN and npEW occur in the adult mammalian brain and that pain differentially affects DCLK-long-mediated neuronal plasticity in these 2 stress-sensitive brain centers., Perspective: Pain is a burden for society and the individual, and although the mechanisms underlying pain are relatively well known, its treatment remains difficult and incomplete. Pain stress can lead to diseases like chronic pain and depression. The differential DCLK-phosphorylation in stress-sensitive brain areas is a potential novel therapeutic target in pain research., (Copyright © 2010 American Pain Society. Published by Elsevier Inc. All rights reserved.)

Objective: To study whether there are differences between day and night in the dispatch of helicopter emergency medical services (HEMS) and in their response and travelling times, medical treatment and transport of patients., Design: Retrospective, descriptive study., Method: All data on helicopter emergency medical service (HEMS) missions available 24/7 from Nijmegen, the Netherlands, during 2007 and 2008 were collected. All missions in this period were divided into daytime and night-time missions. Next, the reason for dispatch, the duration of distinct times during the mission, the method of transport of the HEMS team, medical treatments and patient transport were compared., Results: In 2007 and 2008 the HEMS team was dispatched 2891 times. 1107 patients were treated during daytime and 479 during the night. The mean distance to the incident scene was longer for night missions. During night-time the HEMS team was dispatched more often for road traffic accidents and violence-related accidents but less often for falls, drowning, horse riding accidents and people becoming trapped (non-traffic-related). There were no differences in medical treatment given by the HEMS physician between day and night, but fewer patients were transported by helicopter at night. Travelling times and on-scene times were only slightly different., Conclusion: The number of dispatches of the HEMS team at night was higher than expected, but night missions were cancelled more often due to weather conditions than missions by day. Prehospital times and operations of the Netherlands HEMS differed slightly between day and night.

The use of medicinal oxygen can be dangerous. The spontaneous combustion of an oxygen cylinder was the cause of a fire in an operating theatre and an emergency medical service. The fire developed after turning on the gas main while the flow supply valve was already open. Not opening the pressure reduction valve while the oxygen flow supply valve is open can prevent this type of fire. Information from the contractor shows that the probability of such an incident is 1 in a million.

Background: Mechanical ventilation (MV) can induce lung injury. Proinflammatory cytokines have been shown to play an important role in the development of ventilator-induced lung injury. Previously, the authors have shown a role for Toll-like receptor 4 signaling. The current study aims to investigate the role of Toll/interleukin-1 receptor domain-containing adapter-inducing interferon-beta (TRIF), a protein downstream of Toll-like receptors, in the development of the inflammatory response after MV in healthy mice., Methods: Wild-type C57BL6 and TRIF mutant mice were mechanically ventilated for 4 h. Lung tissue and plasma was used to investigate changes in cytokine profile, leukocyte influx, and nuclear factor-kappaB activity. In addition, experiments were performed to assess the role of TRIF in changes in cardiopulmonary physiology after MV., Results: MV significantly increased messenger RNA expression of interleukin (IL)-1beta in wild-type mice, but not in TRIF mutant mice. In lung homogenates, MV increased levels of IL-1alpha, IL-1beta, and keratinocyte-derived chemokine in wild-type mice. In contrast, in TRIF mutant mice, only a minor increase in IL-1beta and keratinocyte-derived chemokine was found after MV. Nuclear factor-kappaB activity after MV was significantly lower in TRIF mutant mice compared with wild-type mice. In plasma, MV increased levels of IL-6 and keratinocyte-derived chemokine. In TRIF mutant mice, no increase of IL-6 was found after MV, and the increase in keratinocyte-derived chemokine appeared less pronounced. TRIF deletion did not affect cardiopulmonary physiology after MV., Conclusions: The current study supports a prominent role for TRIF in the development of the pulmonary and systemic inflammatory response after MV.

Unlabelled: Visceral nociception readily sensitizes the central nervous system, causing referred somatic pain and hyperalgesia via somato-visceral convergence. Hyperalgesia in the perioperative period may increase vulnerability to subsequent development of chronic pain. The study aim is to investigate the role of angina pectoris, an ischemic visceral pain, in long-term pain after coronary artery bypass surgery (CABG). We sent questionnaires to 369 patients who underwent CABG surgery in 2003. Questions were asked about angina pectoris and other pain in the period before surgery, the first week postoperatively (= acute pain), and the period after 3 months after surgery (= chronic pain). We obtained results from 256 patients (response rate = 69%). The point prevalence of chronic pain after CABG was 27% after a mean follow-up of 16 months (SD +/- 3 months). Patients with chronic pain after CABG had more angina pectoris than those without chronic pain: Before surgery (P = .07), early on postoperatively (P = .004), and more than 3 months after surgery (P = .000004). We found cumulative prevalences of chronic pain after CABG at 3 months of 39%, and of 32% after 6 months. Other predictive factors for chronic pain after CABG were acute postoperative pain (P = .00002) and younger age (P = .002). Angina pectoris is associated with chronic pain after CABG surgery. Other predictive factors include acute postoperative pain and younger age., Perspective: The influence of postoperative angina pectoris for chronic pain after CABG surgery has not been described in the literature to date. Visceral nociception may play an important role in the development of chronic pain after surgery and should be taken into account in future studies.

Introduction: The aim of the study was to assess the influence of annual volume and factors related to intensive care unit (ICU) organization on in-hospital mortality among patients admitted to the ICU with severe sepsis., Methods: A retrospective cohort study was conducted using the database of the Dutch National Intensive Care Evaluation (NICE) registry. Analyses were based on consecutive patients admitted between 1 January 2003 and 30 June 2005 who fulfilled criteria for severe sepsis within the first 24 hours of admission. A 13-item questionnaire was sent to all 32 ICUs across The Netherlands that participated in the NICE registry within this period in order to obtain information on ICU organization and staffing. The association between in-hospital mortality and factors related to ICU organization was investigated using logistic regression analysis, combined with generalized estimation equations to account for potential correlations of outcomes within ICUs. Correction for patient-related factors took place by including Simplified Acute Physiology Score II, age, sex and number of dysfunctioning organ systems in the analyses., Results: Analyses based on 4,605 patients from 28 ICUs (questionnaire response rate 90.6%) revealed that a higher annual volume of severe sepsis patients is associated with a lower in-hospital mortality (P = 0.029). The presence of a medium care unit (MCU) as a step-down facility with intermediate care is associated with a higher in-hospital mortality (P = 0.013). For other items regarding ICU organization, no independent significant relationships with in-hospital mortality were found., Conclusion: A larger annual volume of patients with severe sepsis admitted to Dutch ICUs is associated with lower in-hospital mortality in this patient group. The presence of a MCU as a step-down facility is associated with greater in-hospital mortality. No other significant associations between in-hospital mortality and factors related to ICU organization were found.

Atherosclerosis can to a certain extent be regarded as an inflammatory disease. Also, inflammatory markers may provide information about cardiovascular risk. Whether macrolide antibiotics, especially clarithromycin, have an anti-inflammatory effect in patients with atherosclerosis is not exactly known. To study this phenomenon, a placebo-controlled, randomized, double-blind study was performed. A total of 231 patients with documented coronary artery disease received a daily dose of either 500 mg of slow-release clarithromycin or placebo until the day of surgery. Levels of inflammatory markers (C-reactive protein, interleukin-2 receptor [IL-2R], IL-6, IL-8, and tumor necrosis factor alpha) were assessed during the preoperative outpatient visit, on the day of surgery, and 8 weeks after surgery. Also, changes in the levels of inflammatory markers between visits were determined by delta calculations. Baseline patient characteristics were balanced between the two treatment groups: the average age was 66 years (standard deviation [SD] = 9.0), 79% of the patients were male, and the average number of tablets used was 16 (SD = 9.3). The inflammatory markers of the groups as well as the delta calculations were not significantly changed. Treatment with clarithromycin did not influence the inflammatory markers in patients with atherosclerosis.