Quality of Recovery and Innate Immune Homeostasis in Patients Undergoing Low-pressure Versus Standard-pressure Pneumoperitoneum During Laparoscopic Colorectal Surgery (RECOVER): A Randomized Controlled Trial.

OBJECTIVE: To study the effects of intra-abdominal pressure on the quality of recovery and innate cytokine production capacity after laparoscopic colorectal surgery within the enhanced recovery after surgery program. BACKGROUND: There is increasing evidence for the safety and advantages of low-pressure pneumoperitoneum facilitated by deep neuromuscular blockade (NMB). Nonetheless, there is a weak understanding of the relationship between clinical outcomes, surgical injury, postoperative immune dysfunction, and infectious complications. METHODS: Randomized controlled trial of 178 patients treated at standard-pressure pneumoperitoneum (12 mm Hg) with moderate NMB (train-of-four 1-2) or low pressure (8 mm Hg) facilitated by deep NMB (posttetanic count 1-2). The primary outcome was the quality of recovery (Quality of Recovery 40 questionnaire) on a postoperative day 1 (POD1). The primary outcome of the immune substudy (n=100) was ex vivo tumor necrosis factor α production capacity upon endotoxin stimulation on POD1. RESULTS: Quality of Recovery 40 score on POD1 was significantly higher at 167 versus 159 [mean difference (MD): 8.3 points; 95% confidence interval (CI): 2.5, 14.1; P =0.005] and the decline in cytokine production capacity was significantly less for tumor necrosis factor α and interleukin-6 (MD: -172 pg/mL; 95% CI: -316, -27; P =0.021 and MD: -1282 pg/mL; 95% CI: -2505, -59; P =0.040, respectively) for patients operated at low pressure. Low pressure was associated with reduced surgical site hypoxia and inflammation markers and circulating damage-associated molecular patterns, with a less impaired early postoperative ex vivo cytokine production capacity. At low pressure, patients reported lower acute pain scores and developed significantly less 30-day infectious complications. CONCLUSIONS: Low intra-abdominal pressure during laparoscopic colorectal surgery is safe, improves the postoperative quality of recovery and preserves innate immune homeostasis, and forms a valuable addition to future enhanced recovery after surgery programs.

Personality in anaesthesiologists, a systematic review of the literature.

BACKGROUND: As a central part of their job, anaesthesiologists often have to perform demanding tasks under high-stakes conditions. Yet, some anaesthesiologists seem better able to deal with the demands of the profession than others. OBJECTIVES: This review aims to answer the following questions. What are the necessary or desirable qualities of an anaesthesiologist? Which personality traits or characteristics have been found in anaesthesiologists? How does personality relate to job performance and work stress among anaesthesiologists? DESIGN: Systematic review of studies that examined anaesthesiologists' personality or personality characteristics. We performed our synthesis in terms of the five-factor model of personality. DATA SOURCES: The search was conducted in the PubMed, EMBASE and Web of Science databases. Literature was included until December 2020. ELIGIBILITY CRITERIA: We included qualitative and quantitative studies that examined anaesthesiologists' personality; also, we included studies that focused on anaesthesiologists' stress, performance or mental health but only if these topics were examined from the perspective of personality. RESULTS: We included 6 qualitative and 25 quantitative articles. Synthesis of the qualitative articles revealed two classes of desirable technical and nontechnical personality characteristics. Synthesis of the quantitative articles suggested that anaesthesiologists do not essentially differ from other medical specialists. Moreover, our synthesis revealed several personality traits that predict good performance, low stress and good mental health among anaesthesiologists: lower Neuroticism, higher Extraversion, higher Openness and higher Conscientiousness. CONCLUSION: Those personality traits that predict performance, stress or mental health in anaesthesiologists, also predict performance, stress or mental health in other high demand/high stakes environments (both medical and nonmedical). The ideal anaesthesiologist would be lower on Neuroticism, higher on Extraversion and higher on Conscientiousness.

Chronic stress indicated by hair cortisol concentration in anaesthesiologists and its relationship to work experience and emotional intelligence: A cross-sectional biomarker and survey study.

BACKGROUND: Anaesthesia is a stressful medical specialty. The reaction to stress is constituted by behavioural, psychological and physiological components. Chronic physiological stress can have negative consequences for health. OBJECTIVES: First, we hypothesised that chronic physiological stress is higher for both beginning and late-career consultant anaesthesiologists. Second, we hypothesised that individuals high in emotional intelligence endure lower physiological stress. DESIGN: Cross-sectional biomarker and survey study. SETTING: Participants were recruited during the May 2019 annual meeting of the Dutch Anaesthesia Society. PARTICIPANTS: Of the 1348 colleagues who attended the meeting, 184 (70 male/114 female) participated in the study. Of the study participants, 123 (67%) were consultant anaesthesiologists (52 male/71 female) and 61 (33%) were resident anaesthesiologists (18 male/43 female). Exclusion criteria were endocrine disorders and not having enough hair. Also, experience of a recent major life event led to exclusion from analysis of our hypotheses. MAIN OUTCOME MEASURES: Chronic physiological stress was measured by hair cortisol concentration. Emotional intelligence was assessed using a validated Dutch version of the Trait Emotional Intelligence Questionnaire. As secondary measures, psychological sources of stress were assessed using validated Dutch versions of the home-work interference (SWING) and the effort-reward imbalance questionnaires. RESULTS: In support of Hypothesis 1, hair cortisol concentration was highest among early and late-career consultant anaesthesiologists (quadratic effect: b = 45.5, SE = 16.1, t = 2.8, P = 0.006, R2 = 0.14). This nonlinear pattern was not mirrored by self-reported sources of psychological stress. Our results did not support Hypothesis 2; we found no evidence for a relationship between emotional intelligence and physiological stress. CONCLUSION: In the early and later phases of an anaesthesiologist's career, physiological chronic stress is higher than in the middle of the career. However, this physiological response could not be explained from known sources of psychological stress. We discuss these findings against the background of key differences between physiological and psychological stress.

The influence of hypoxia on platelet function and plasmatic coagulation during systemic inflammation in humans in vivo.

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.

Estimation of the diaphragm neuromuscular efficiency index in mechanically ventilated critically ill patients.

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 cmH2O/µV with a RC of 82.6%. This implies that when NMEoccl is 1.22 cmH2O/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.

Immunologic Consequences of Hypoxia during Critical Illness.

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.

What is the evidence for the use of low-pressure pneumoperitoneum? A systematic review.

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.

Work stress and satisfaction in relation to personality profiles in a sample of Dutch anaesthesiologists: A questionnaire survey.

BACKGROUND: Working in anaesthesia is stressful, but also satisfying. Work-related stress can have a negative impact on mental health, whereas work-related satisfaction protects against these harmful effects. OBJECTIVE(S): How work stress and satisfaction are experienced may be related to personality. Our aim was to study the relationship between personality and perception of work in a sample of Dutch anaesthesiologists. DESIGN: Questionnaire survey. SETTING: Data were collected in the Netherlands from July 2012 until December 2012. PARTICIPANTS: We sent electronic questionnaires to all 1955 practising resident and consultant members of the Dutch Anaesthesia Society. Of those, 655 (33.5%) were returned and could be used for analysis. MAIN OUTCOME MEASURES: The questionnaires assessed general work-related stress and satisfaction and anaesthesia-specific stress. A factor analysis was performed on the stress and satisfaction questionnaires. Personality traits were assessed using the Big Five Inventory. To identify personality profiles, a cluster analysis was performed on the Big Five Inventory. Scores of the extracted factors contributing to job stress and satisfaction were compared between the profiles we identified. RESULTS: Our analysis extracted six factors concerning general job stress. Of those, the emotionally difficult caseload contributed the most to job stress. The analysis also extracted four factors concerning general job satisfaction. Good relationships with patients and their families and being appreciated by colleagues contributed the most to satisfaction. The cluster analysis resulted in two distinct personality profiles: a distressed profile (n = 215) and a resilient profile (n = 440). General and anaesthesia-specific job stress was significantly higher and job satisfaction was significantly lower in the distressed profile, compared with the resilient profile. Experience of the emotionally difficult caseload did not differ between the two profiles CONCLUSION: Personality profiles were found to be related to anaesthesiologists' experience of work-related stress and satisfaction. One-third of the anaesthesiologists in our sample were categorised as distressed and are at risk of developing work-related mental health problems.

Psychological distress, burnout and personality traits in Dutch anaesthesiologists: A survey.

BACKGROUND: The practice of anaesthesia comes with stress. If the demands of a stressful job exceed the resources of an individual, that person may develop burnout. Burnout poses a threat to the mental and physical health of the anaesthesiologist and therefore also to patient safety. OBJECTIVES: Individual differences in stress appraisal (perceived demands) are an important factor in the risk of developing burnout. To explore this possible relationship, we assessed the prevalence of psychological distress and burnout in the Dutch anaesthesiologist population and investigated the influence of personality traits. DESIGN: Survey study. SETTING: Data were collected in the Netherlands from July 2012 until December 2012. PARTICIPANTS: We sent electronic surveys to all 1955 practising resident and consultant members of the Dutch Anaesthesia Society. Of these, 655 (33.5%) were returned and could be used for analysis. MAIN OUTCOME MEASURES: Psychological distress, burnout and general personality traits were assessed using validated Dutch versions of the General Health Questionnaire (cut-off point ≥2), the Maslach Burnout Inventory and the Big Five Inventory. Sociodemographic variables and personality traits were entered into regression models as predictors for burnout and psychological distress. RESULTS: Respectively, psychological distress and burnout were prevalent in 39.4 and 18% of all respondents. The prevalence of burnout was significantly different in resident and consultant anaesthesiologists: 11.3% vs. 19.8% (χ 5.4; P < 0.02). The most important personality trait influencing psychological distress and burnout was neuroticism: adjusted odds ratio 6.22 (95% confidence interval 4.35 to 8.90) and 6.40 (95% confidence interval 3.98 to 10.3), respectively. CONCLUSION: The results of this study show that psychological distress and burnout have a high prevalence in residents and consultant anaesthesiologists and that both are strongly related to personality traits, especially the trait of neuroticism. This suggests that strategies to address the problem of burnout would do well to focus on competence in coping skills and staying resilient. Personality traits could be taken into consideration during the selection of residents. In future longitudinal studies the question of how personal and situational factors interact in the development of burnout should be addressed.

Exposure to halogenated ethers causes neurodegeneration and behavioural changes in young healthy experimental animals: a systematic review and meta analyses.

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.

Low intra-abdominal pressure in laparoscopic surgery: a systematic review and meta-analysis.

BACKGROUND: Guidelines do not provide clear recommendations with regard to the use of low intra-abdominal pressure (IAP) during laparoscopic surgery. The aim of this meta-analysis is to assess the influence of low versus standard IAP during laparoscopic surgery on the key-outcomes in perioperative medicine as defined by the StEP-COMPAC consensus group. MATERIALS AND METHODS: We searched the Cochrane Library, PubMed, and EMBASE for randomized controlled trials comparing low IAP (<10 mmHg) with standard IAP (10 mmHg or higher) during laparoscopic surgery without time, language, or blinding restrictions. According to the PRISMA guidelines, two review authors independently identified trials and extracted data. Risk ratio (RR), and mean difference (MD), with 95% CIs were calculated using random-effects models with RevMan5. Main outcomes were based on StEP-COMPAC recommendations, and included postoperative complications, postoperative pain, postoperative nausea and vomiting (PONV) scores, and length of hospital stay. RESULTS: Eighty-five studies in a wide range of laparoscopic procedures (7349 patients) were included in this meta-analysis. The available evidence indicates that the use of low IAP (<10 mmHg) leads to a lower incidence of mild (Clavien-Dindo grade 1-2) postoperative complications (RR=0.68, 95% CI: 0.53-0.86), lower pain scores (MD=-0.68, 95% CI: -0.82 to 0.54) and PONV incidence (RR=0.67, 95% CI: 0.51-0.88), and a reduced length of hospital stay (MD=-0.29, 95% CI: -0.46 to 0.11). Low IAP did not increase the risk of intraoperative complications (RR=1.15, 95% CI: 0.77-1.73). CONCLUSIONS: Given the established safety and the reduced incidence of mild postoperative complications, lower pain scores, reduced incidence of PONV, and shorter length of stay, the available evidence supports a moderate to strong recommendation (1a level of evidence) in favor of low IAP during laparoscopic surgery.

Muscle Ultrasound Abnormalities in Individuals with RYR1-Related Malignant Hyperthermia Susceptibility.

BACKGROUND: Variants in RYR1, the gene encoding the ryanodine receptor-1, can give rise to a wide spectrum of neuromuscular conditions. Muscle imaging abnormalities have been demonstrated in isolated cases of patients with a history of RYR1-related malignant hyperthermia (MH) susceptibility. OBJECTIVE: To provide insights into the type and prevalence of muscle ultrasound abnormalities and muscle hypertrophy in patients carrying gain-of-function RYR1 variants associated with MH susceptibility and to contribute to delineating the wider phenotype, optimizing the diagnostic work-up and care for MH susceptible patients. METHODS: We performed a prospective cross-sectional observational muscle ultrasound study in patients with a history of RYR1-related MH susceptibility (n = 40). Study procedures included a standardized history of neuromuscular symptoms and a muscle ultrasound assessment. Muscle ultrasound images were analyzed using a quantitative and qualitative approach and compared to reference values and subsequently subjected to a screening protocol for neuromuscular disorders. RESULTS: A total of 15 (38%) patients had an abnormal muscle ultrasound result, 4 (10%) had a borderline muscle ultrasound screening result, and 21 (53%) had a normal muscle ultrasound screening result. The proportion of symptomatic patients with an abnormal result (11 of 24; 46%) was not significantly higher compared to the proportion of asymptomatic patients with an abnormal ultrasound result (4 of 16; 25%) (P = 0.182). The mean z-scores of the biceps brachii (z = 1.45; P < 0.001), biceps femoris (z = 0.43; P = 0.002), deltoid (z = 0.31; P = 0.009), trapezius (z = 0.38; P = 0.010) and the sum of all muscles (z = 0.40; P < 0.001) were significantly higher compared to 0, indicating hypertrophy. CONCLUSIONS: Patients with RYR1 variants resulting in MH susceptibility often have muscle ultrasound abnormalities. Frequently observed muscle ultrasound abnormalities include muscle hypertrophy and increased echogenicity.

Neuromuscular symptoms in patients with RYR1-related malignant hyperthermia and rhabdomyolysis.

Malignant hyperthermia and exertional rhabdomyolysis have conventionally been considered episodic phenotypes that occur in otherwise healthy individuals in response to an external trigger. However, recent studies have demonstrated a clinical and histopathological continuum between patients with a history of malignant hyperthermia susceptibility and/or exertional rhabdomyolysis and RYR1-related congenital myopathies. We hypothesize that patients with a history of RYR1-related exertional rhabdomyolysis or malignant hyperthermia susceptibility do have permanent neuromuscular symptoms between malignant hyperthermia or exertional rhabdomyolysis episodes. We performed a prospective cross-sectional observational clinical study of neuromuscular features in patients with a history of RYR1-related exertional rhabdomyolysis and/or malignant hyperthermia susceptibility (n = 40) compared with healthy controls (n = 80). Patients with an RYR1-related congenital myopathy, manifesting as muscle weakness preceding other symptoms as well as other (neuromuscular) diseases resulting in muscle weakness were excluded. Study procedures included a standardized history of neuromuscular symptoms, a review of all relevant ancillary diagnostic tests performed up to the point of inclusion and a comprehensive, standardized neuromuscular assessment. Results of the standardized neuromuscular history were compared with healthy controls. Results of the neuromuscular assessment were compared with validated reference values. The proportion of patients suffering from cramps (P < 0.001), myalgia (P < 0.001) and exertional myalgia (P < 0.001) was higher compared with healthy controls. Healthcare professionals were consulted because of apparent neuromuscular symptoms by 17/40 (42.5%) patients and 7/80 (8.8%) healthy controls (P < 0.001). Apart from elevated creatine kinase levels in 19/40 (47.5%) patients and mild abnormalities on muscle biopsies identified in 13/16 (81.3%), ancillary investigations were normal in most patients. The Medical Research Council sum score, spirometry and results of functional measurements were also mostly normal. Three of 40 patients (7.5%) suffered from late-onset muscle weakness, most prominent in the proximal lower extremity muscles. Patients with RYR1 variants resulting in malignant hyperthermia susceptibility and/or exertional rhabdomyolysis frequently report additional neuromuscular symptoms such as myalgia and muscle cramps compared with healthy controls. These symptoms result in frequent consultation of healthcare professionals and sometimes in unnecessary invasive diagnostic procedures. Most patients do have normal strength at a younger age but may develop muscle weakness later in life.

Deep neuromuscular block reduces the incidence of intra-operative complications during laparoscopic donor nephrectomy: a pooled analysis of randomized controlled trials.

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 ).

The neuromuscular and multisystem features of RYR1-related malignant hyperthermia and rhabdomyolysis: A study protocol.

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).

Positive end-expiratory pressure affects geometry and function of the human diaphragm.

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 cmH2O. 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 cmH2O 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).