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.

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.

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.

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.

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.

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.

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 ).

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).

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).

The effect of low- versus normal-pressure pneumoperitoneum during laparoscopic colorectal surgery on the early quality of recovery with perioperative care according to the enhanced recovery principles (RECOVER): study protocol for a randomized controlled study.

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.

Visualising improved peritoneal perfusion at lower intra-abdominal pressure by fluorescent imaging during laparoscopic surgery: A randomised controlled study.

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.

Early postoperative pain after laparoscopic donor nephrectomy predicts 30-day postoperative infectious complications: a pooled analysis of randomized controlled trials.

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.

Monitoring patient-ventilator breath contribution in the critically ill during neurally adjusted ventilatory assist: reliability and improved algorithms for bedside use.

The patient-ventilator breath contribution (PVBC) index estimates the relative contribution of the patient to total tidal volume (Vtinsp) during mechanical ventilation in neurally adjusted ventilator assist mode and has been used to titrate ventilator support. The reliability of this index in ventilated patients is unknown and was investigated in this study. PVBC was calculated by comparing tidal volume (Vtinsp) and diaphragm electrical activity (EAdi) during assisted breaths (Vtinsp/EAdi)assist and during unassisted breaths (Vtinsp/EAdi)no-assist. Vtinsp was normalized to peak EAdi (EAdipeak) using 1) one assisted breath, 2) five consecutive assisted breaths, or 3) five assisted breaths with matching EAdi preceding the unassisted breath (N1PVBC2, X5PVBC2, and PX5VBCEAdi-matching2 , respectively). In addition, PVBC was calculated by comparing only Vtinsp for breaths with matching EAdi (PVBCß2). Test-retest reliability of the different PVBC calculation methods was evaluated with the intraclass correlation coefficient (ICC) using five repeated PVBC maneuvers performed with a 1-min interval. In total, 125 PVBC maneuvers were analyzed in 25 patients. ICC [95% confidence interval] values were 0.46 [0.23-0.66], 0.51 [0.33-0.70], and 0.42 [0.14-0.69] for N1PVBC2, X5PVBC2, PX5VBCEAdi-matching2 , respectively. Complex waveform analyses showed that insufficient EAdi filtering by the ventilator software affects reliability of PVBC calculation. With our new EAdi-matching techniques reliability improved (PVBCß2 ICC: 0.78 [0.60-0.90]). We conclude that current techniques to calculate PVBC exhibit low reliability and that our newly developed criteria and estimation of PVBC-using Vtinsp of assisted breaths and unassisted breaths with matching EAdi-improves reliability. This may help implementation of PVBC in clinical practice. NEW & NOTEWORTHY The patient-ventilator breath contribution (PVBC) index estimates the relative contribution of the patient to tidal volume generated by the patient and the mechanical ventilator during mechanical ventilation in neurally adjusted ventilator assist mode. It could be used to titrate ventilator support and thus to limit development of diaphragm dysfunction in intensive care unit patients. Currently available methods for bedside assessment of PVBC are unreliable. Our newly developed criteria and estimation of PVBC largely improve reliability and help to quantify patient contribution to total inspiratory effort.

Influence of a Tourniquet on Opioid Consumption After Local Infiltration Analgesia for Total Knee Arthroplasty.

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.

Spinal anesthesia-induced hypotension is caused by a decrease in stroke volume in elderly patients.

BACKGROUND: Hypotension is common during spinal anesthesia (SA) and is caused by a decrease in systemic vascular resistance (SVR) and/or cardiac output (CO). The effect of the dose of bupivacaine administered intrathecally on the changes in CO in elderly patients is largely unknown. This study investigated the hemodynamic effect of SA in elderly patients by studying the effect of two different dosages of intrathecal bupivacaine. METHODS: This prospective cohort study included 64 patients aged >65 years scheduled for procedures under SA; the patients received either 15 mg bupivacaine (the medium dose [MD] group) or 10 mg bupivacaine and 5 µg sufentanil (the low dose [LD] group). Blood pressure and CO were monitored throughout the procedure using Nexfin™, a noninvasive continuous monitoring device using a finger cuff. RESULTS: Thirty-three patients received MD and 31 received LD and there was no mean difference in baseline hemodynamics between the groups. On an average, the CO decreased 11.6% in the MD group and 10.0 % in the LD group. There was no significant change in SVR. Incidence of a clinically relevant decrease in stroke volume (SV) (>15% from baseline) was 67% in the MD and 45% in the LD groups (P<0.05). CONCLUSION: CO and blood pressure decreased significantly after the onset of SA in elderly patients. This is mainly caused by a decrease in SV and not by a decrease in SVR. There was no difference in CO and blood pressure change between dosages of 10 or 15 mg bupivacaine.

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.