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Nociception monitoring devices are designed to estimate nociception during general anaesthesia. We evaluated the predictive accuracy of heart rate and three nociception indices to predict postoperative pain before emergence from general anaesthesia.In patients undergoing trauma or orthopaedic surgery, HR, Surgical Pleth Index® (SPI), Pupillary Pain Index® (PPI), and Nociception Level® (NOL) were simultaneously recorded for 5 min after the end of surgery but before return of consciousness. After admission to the recovery room, pain scores were assessed regularly for 2 h. HR, SPI, PPI, and NOL were analysed for their predictive accuracy of postoperative pain and opioid consumption with assessment of area under the receiver operating characteristic (AUC) curves, Spearman rank-correlation coefficient, and regression modelling.Data for 60 subjects were analysed. The AUC (95% confidence interval [95% CI]) of the predictive accuracy for moderate-to-severe postoperative pain differed between nociception indices (HR=0.46 [0.29-0.64], P=0.671; SPI=0.46 [0.31-0.61], P=0.621; PPI=0.52 [0.36-0.68], P=0.770; NOL=0.66 [0.51-0.81], P=0.038). In a multivariable logistic regression model, a higher predictive accuracy was found for a multivariable predictor combining NOL values with ASA physical status and information about use of regional anaesthesia (AUC=0.83 [0.72-0.94], P0.001).Heart rate, Surgical Pleth Index, Pupillary Pain Index, and Nociception Level measured before emergence from general anaesthesia do not yet have sufficient diagnostic accuracy for prediction of postoperative pain.NCT05063227.

Purpose Postoperative complications after major liver surgery are common. Thoracic epidural anesthesia may provide beneficial effects on postoperative outcome. We strove to compare postoperative outcomes in major liver surgery patients with and without thoracic epidural anesthesia. Methods This was a retrospective cohort study in a single university medical center. Patients undergoing elective major liver surgery between April 2012 and December 2016 were eligible for inclusion. We divided patients into two groups according to whether or not they had thoracic epidural anesthesia for major liver surgery. The primary outcome was postoperative hospital length of stay, i.e., from day of surgery until hospital discharge. Secondary outcomes included 30-day postoperative mortality and major postoperative complications. Additionally, we investigated the effect of thoracic epidural anesthesia on perioperative analgesia doses and the safety of thoracic epidural anesthesia. Results Of 328 patients included in this study, 177 (54.3%) received thoracic epidural anesthesia. There were no clinically important differences in postoperative hospital length of stay (11.0 [7.00–17.0] vs. 9.00 [7.00–14.0] days, p = 0.316, primary outcome), death (0.0 vs. 2.7%, p = 0.995), or the incidence of postoperative renal failure (0.6 vs. 0.0%, p = 0.99), sepsis (0.0 vs. 1.3%, p = 0.21), or pulmonary embolism (0.6 vs. 1.4%, p = 0.59) between patients with or without thoracic epidural anesthesia. Perioperative analgesia doses — including the intraoperative sufentanil dose (0.228 [0.170–0.332] vs. 0.405 [0.315–0.565] μg·kg−1·h−1, p < 0.0001) — were lower in patients with thoracic epidural anesthesia. No major thoracic epidural anesthesia-associated infections or bleedings occurred. Conclusion This retrospective analysis suggests that thoracic epidural anesthesia does not reduce postoperative hospital length of stay in patients undergoing major liver surgery — but it may reduce perioperative analgesia doses. Thoracic epidural anesthesia was safe in this cohort of patients undergoing major liver surgery. These findings need to be confirmed in robust clinical trials.

The intraoperative dosing of opioids is a challenge in routine anesthesia as the potential effects of intraoperative overdosing and underdosing are not completely understood. In recent years an increasing number of monitors were approved, which were developed for the detection of intraoperative nociception and therefore should enable a better control of opioid titration. The nociception monitoring devices use either continuous hemodynamic, galvanic or thermal biosignals reflecting the balance between parasympathetic and sympathetic activity, measure the pupil dilatation reflex or the nociceptive flexor reflex as a reflexive response to application of standardized nociceptive stimulation. This review article presents the currently available nociception monitors. Most of these monitoring devices detect nociceptive stimulations with higher sensitivity and specificity than changes in heart rate, blood pressure or sedation depth monitoring devices. There are only few studies on the effect of opioid titration guided by nociception monitoring and the possible postoperative benefits of these devices. All nociception monitoring techniques are subject to specific limitations either due to perioperative confounders (e.g. hypovolemia) or special accompanying medical conditions (e.g. muscle relaxation). There is an ongoing discussion about the clinical relevance of nociceptive stimulation in general anesthesia and the effect on patient outcome. Initial results for individual monitor systems show a reduction in opioid consumption and in postoperative pain level. Nevertheless, current evidence does not enable the routine use of nociception monitoring devices to be recommended as a clear beneficial effect on long-term outcome has not yet been proven.

This pilot study investigated the effect of sufentanil titration by 3 different analgesia monitoring devices or clinical signs during general anesthesia.Forty-eight patients undergoing radical retropubic prostatectomy with sevoflurane/sufentanil anesthesia were randomly assigned into 4 groups and received sufentanil guided either by 1 of 3 analgesia monitoring devices (Surgical Pleth Index [SPI], Pupillary Pain Index [PPI], Nociception Level [NoL]) or by clinical judgment (control). The primary end point was intraoperative sufentanil consumption. Adrenocorticotropic hormone (ACTH) and cortisol were measured at 4 time points during the day of surgery. Data were analyzed by Kruskal-Wallis and Mann-Whitney U tests and by mixed model and area under the curve (AUC) analyses for group comparisons and time effects of stress hormones.The total amount of sufentanil administration (μg·kg·minute·10) differed between the groups (median [quartiles]: control = 5.6 [4.4-6.4], SPI = 7.2 [4.8-8.4], PPI = 2.0 [1.8-2.9], NoL = 3.8 [3.3-5.1]; PPI versus SPI, -5.1 [-6.6 to -1.3], P.001; NoL versus SPI, -3.0 [-5.2 to 0.2], P = .024; control versus SPI, -1.6 [-3.7 to 1.7], P = .128; NoL versus PPI, 1.7 [0.6-3.4], P.001; control versus PPI, 3.4 [2.0-4.6], P.001; control versus NoL, 1.6 [-0.2 to 3.3], P = .017) (Hodges-Lehmann estimator [99% confidence interval {CI}], P values). The AUC analysis indicated differences among groups in cumulative ACTH levels (ng·liter·minute, natural logarithm (ln)-transformed data) of NoL versus PPI (-1.079 [-1.950 to -0.208], P = .001) and PPI versus SPI (1.192 [0.317-2.068], P= .001), as well as differences in cortisol levels (µg·liter·minute) for PPI versus SPI (46,710 [21,145-72,274], P.001), NoL versus SPI (27,645 [3163-52,126], P = .003), and control versus SPI (31,824 [6974-56,675], P = .001) (differences in means [99% CI], P value). Secondary end points (postoperative recovery, pain level, and analgesia medication) showed no differences.The type of analgesia nociception monitoring affected the total amount of sufentanil administered. Lower sufentanil doses in the PPI group were associated with an increased endocrine stress response. Titration by SPI caused no opioid reduction compared to the control but was associated with a reduced endocrine stress response.

Background Sedative premedication with benzodiazepines has been linked with prolonged recovery and inadequate emergence during the immediate postoperative period. We aimed to analyze the association between postanesthesia care unit (PACU) delirium and sedative premedication with oral midazolam. Methods We performed a secondary analysis of prospectively collected data before (midazolam cohort) and after (non-midazolam cohort) implementation of a restrictive strategy for oral premedication with midazolam. From March 2015 until July 2018, we included patients 60 years and older, who underwent elective radical prostatectomy for prostate cancer. Exclusion criteria were contraindications to premedication with midazolam, preoperative anxiety, and a history of neurological disorders. Patients, who were scheduled for postoperative admission to the intensive care unit, were excluded. Between 2015 and 2016, patients received 7.5 mg oral midazolam preoperatively (midazolam cohort). Patients included between 2017 and 2018 did not receive any sedative medication preoperatively (non-midazolam cohort). The primary endpoint was the incidence of PACU delirium. Results PACU delirium rates were 49% in the midazolam cohort (n = 214) and 33% in the non-midazolam cohort (n = 218). This difference was not statistically significant on multivariable logistic regression analysis (OR 0.847 [95% CI 0.164; 4.367]; P = 0.842). Age (OR 1.102 [95% CI 1.050; 1.156]; P < 0.001), the cumulative dose of sufentanil (OR 1.014 [95% CI 1.005; 1.024]; P = 0.005), and propofol-sufentanil for anesthesia maintenance (OR 2.805 [95% CI 1.497; 5.256]; P = 0.001) were significantly associated with PACU delirium. Conclusion Midazolam for sedative premedication was not significantly associated with PACU delirium. The reduction in the incidence of PACU delirium throughout the study period may be attributable to improvements in perioperative management other than a more restrictive preoperative benzodiazepine administration.

Intermittent hypoxia and various pharmacological compounds protect the heart from ischemia reperfusion injury in experimental approaches, but the translation into clinical trials has largely failed. One reason may lie in species differences and the lack of suitable human in vitro models to test for ischemia/reperfusion. We aimed to develop a novel hypoxia-reoxygenation model based on three-dimensional, spontaneously beating and work performing engineered heart tissue (EHT) from rat and human cardiomyocytes. Contractile force, the most important cardiac performance parameter, served as an integrated outcome measure. EHTs from neonatal rat cardiomyocytes were subjected to 90 min of hypoxia which led to cardiomyocyte apoptosis as revealed by caspase 3-staining, increased troponin I release (time control vs. 24 h after hypoxia: cTnI 2.7 vs. 6.3 ng/mL, ** p = 0.002) and decreased contractile force (64 &plusmn, 6% of baseline) in the long-term follow-up. The detrimental effects were attenuated by preceding the long-term hypoxia with three cycles of 10 min hypoxia (i.e., hypoxic preconditioning). Similarly, [d-Ala2, d-Leu5]-enkephalin (DADLE) reduced the effect of hypoxia on force (recovery to 78 &plusmn, 5% of baseline with DADLE preconditioning vs. 57 &plusmn, 5% without, p = 0.012), apoptosis and cardiomyocyte stress. Human EHTs presented a comparable hypoxia-induced reduction in force (55 &plusmn, 5% of baseline), but DADLE failed to precondition them, likely due to the absence of &delta, opioid receptors. In summary, this hypoxia-reoxygenation in vitro model displays cellular damage and the decline of contractile function after hypoxia allows the investigation of preconditioning strategies and will therefore help us to understand the discrepancy between successful conditioning in vitro experiments and its failure in clinical trials.

Background This RCT investigated the effect of opioid titration by three different nociception monitoring devices or clinical signs during general anaesthesia. Methods Ninety-six patients undergoing radical retropubic prostatectomy with propofol/remifentanil anaesthesia were randomised into one of four groups to receive remifentanil guided by one of three nociception monitoring devices (surgical pleth index [SPI], pupillary pain index [PPI], or nociception level [NOL]) or by clinical judgement (control). Intraoperative remifentanil requirement was the primary endpoint, whereas recovery parameters and stress hormone levels were secondary endpoints. Results The mean [95% confidence interval {CI}] remifentanil administration rate differed between the groups: control 0.34 (0.32–0.37), SPI 0.46 (0.38–0.55), PPI 0.07 (0.06–0.08), and NOL 0.16 (0.12–0.21) μg kg−1 min−1(P Conclusions The nociception monitoring devices and clinical signs reflect the extent of nociception differently, leading to dissimilar doses of remifentanil. Very low remifentanil doses were associated with an increase and higher remifentanil doses were accompanied by a decrease in serum cortisol concentrations. Use of nociception monitoring devices for guiding intra-operative opioid dosing needs further validation. Clinical trial registration NCT03380949.

Summary Energy metabolism is a key aspect of cardiomyocyte biology. Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) are a promising tool for biomedical application, but they are immature and have not undergone metabolic maturation related to early postnatal development. To assess whether cultivation of hiPSC-CMs in 3D engineered heart tissue format leads to maturation of energy metabolism, we analyzed the mitochondrial and metabolic state of 3D hiPSC-CMs and compared it with 2D culture. 3D hiPSC-CMs showed increased mitochondrial mass, DNA content, and protein abundance (proteome). While hiPSC-CMs exhibited the principal ability to use glucose, lactate, and fatty acids as energy substrates irrespective of culture format, hiPSC-CMs in 3D performed more oxidation of glucose, lactate, and fatty acid and less anaerobic glycolysis. The increase in mitochondrial mass and DNA in 3D was diminished by pharmacological reduction of contractile force. In conclusion, contractile work contributes to metabolic maturation of hiPSC-CMs., Graphical Abstract, Highlights • Higher mitochondrial mass, protein, and DNA content in 3D versus 2D hiPSC-CMs • Similarity of mitochondrial proteomes between 3D hiPSC-CMs and adult human heart • Preference for oxidative metabolism in favor of anaerobic glycolysis in 3D hiPSC-CMs, Ulmer et al. show that 3D-cultured human iPSC-derived cardiomyocytes replicate metabolic aspects of developmental hypertrophy, indicating maturation of hiPSC-derived cardiomyocytes.

Background This study compares the analgesic indices Analgesia Nociception Index (heart rate variability), Surgical Pleth Index (photoplethysmography), and pupillary dilatation, to heart rate, mean arterial pressure, and bispectral index, with regard to diagnostic accuracy and prediction probability for nociceptive response. The primary endpoint was the correlation between Δ values and the remifentanil dose administered. Methods We anesthetized 38 patients with propofol and increasing doses of remifentanil and applied standardized tetanic and intracutaneous electrical painful stimulations on each analgesic level. Baseline and Δ values of the Analgesia Nociception Index, the Surgical Pleth Index, pupillary dilatation, heart rate, mean arterial pressure, and bispectral index and their relation to remifentanil doses were analyzed by receiver operating characteristic curves, prediction probability (PK), and mixed-model analysis. Results Under propofol sedation, sensitivity and specificity of the Analgesia Nociception Index (PK = 0.98), the Surgical Pleth Index (PK = 0.87), and pupillary dilatation (PK = 0.98) for detecting both painful stimulations were high compared to heart rate (PK = 0.74), mean arterial pressure (PK = 0.75), and bispectral index (PK = 0.55). Baseline values had limited prediction probability toward the nociceptive response (Analgesia Nociception Index: PK = 0.7; Surgical Pleth Index: PK = 0.63; pupillary dilatation: PK = 0.67; and bispectral index: PK = 0.67). The remifentanil dose had an effect (P < 0.001) on all parameters except for bispectral index (P = 0.216). Conclusions The Analgesia Nociception Index, the Surgical Pleth Index, and pupillary dilatation are superior in detecting painful stimulations compared to heart rate and mean arterial pressure but had limited predictive value. These effects are attenuated by increasing dosages of remifentanil. Our data confirm that bispectral index is not a marker of analgesia.

Long non-coding RNAs (lncRNAs) have potential as novel therapeutic targets in cardiovascular diseases, but detailed information about the intercellular lncRNA shuttling mechanisms in the heart is lacking. Here, we report an important novel crosstalk between cardiomyocytes and fibroblasts mediated by the transfer of lncRNA-enriched extracellular vesicles (EVs) in the context of cardiac ischemia. lncRNA profiling identified two hypoxia-sensitive lncRNAs: ENSMUST00000122745 was predominantly found in small EVs, whereas lncRNA Neat1 was enriched in large EVs in vitro and in vivo. Vesicles were taken up by fibroblasts, triggering expression of profibrotic genes. In addition, lncRNA Neat1 was transcriptionally regulated by P53 under basal conditions and by HIF2A during hypoxia. The function of Neat1 was further elucidated in vitro and in vivo. Silencing of Neat1 in vitro revealed that Neat1 was indispensable for fibroblast and cardiomyocyte survival and affected fibroblast functions (reduced migration capacity, stalled cell cycle, and decreased expression of fibrotic genes). Of translational importance, genetic loss of Neat1 in vivo resulted in an impaired heart function after myocardial infarction highlighting its translational relevance., Graphical Abstract

Hemodynamic instability is frequent and outcome-relevant in critical illness. The understanding of complex hemodynamic disturbances and their monitoring and management plays an important role in treatment of intensive care patients. An increasing number of treatment recommendations and guidelines in intensive care medicine emphasize hemodynamic goals, which go beyond the measurement of blood pressures. Yet, it is not known to which extent the infrastructural prerequisites for extended hemodynamic monitoring are given in intensive care units (ICUs) and how hemodynamic management is performed in clinical practice. Further, it is still unclear which factors trigger the use of extended hemodynamic monitoring. In this multicenter, 1-day (November 7, 2013, and the preceding 24 h) cross-sectional study, we retrieved data on patient monitoring from ICUs in Germany, Austria, and Switzerland by means of a web-based case report form. One hundred and sixty-one intensive care units contributed detailed information on availability of hemodynamic monitoring. In addition, detailed information on hemodynamic monitoring of 1789 patients that were treated on due date was collected, and independent factors triggering the use of extended hemodynamic monitoring were identified by multivariate analysis. Besides basic monitoring with electrocardiography (ECG), pulse oximetry, and blood pressure monitoring, the majority of patients received invasive arterial (77.9 %) and central venous catheterization (55.2 %). All over, additional extended hemodynamic monitoring for assessment of cardiac output was only performed in 12.3 % of patients, while echocardiographic examination was used in only 1.9 %. The strongest independent predictors for the use of extended hemodynamic monitoring of any kind were mechanical ventilation, the need for catecholamine therapy, and treatment backed by protocols. In 71.6 % of patients in whom extended hemodynamic monitoring was added during the study period, this extension led to changes in treatment. Extended hemodynamic monitoring, which goes beyond the measurement of blood pressures, to date plays a minor role in the surveillance of critically ill patients in German, Austrian, and Swiss ICUs. This includes also consensus-based recommended diagnostic and monitoring applications, such as echocardiography and cardiac output monitoring. Mechanical ventilation, the use of catecholamines, and treatment backed by protocol could be identified as factors independently associated with higher use of extended hemodynamic monitoring.

Background:Xenon and isoflurane are known to have cardioprotective properties. We tested the hypothesis that these anesthetics positively influence myocardial remodeling 28 days after experimental perioperative myocardial infarction and compared their effects.Methods:A total of 60 male Sprague–Dawley rats were subjected to 60min of coronary artery occlusion and 120min of reperfusion. Prior to ischemia, the animals were randomized for the different narcotic regimes (0.6 vol% isoflurane, 70 vol% xenon, or intraperitoneal injection of s-ketamine). Acute injury was quantified by echocardiography and troponin I. After 4 weeks, left ventricular function was assessed by conductance catheter to quantify hemodynamic compromise. Cardiac remodeling was characterized by quantification of dilatation, hypertrophy, fibrosis, capillary density, apoptosis, and expression of fetal genes (α/β myosin heavy chains, α-skeletal actin, periostin, and sarco/endoplasmic reticulum Ca2+-ATPase).Results:Whereas xenon and isoflurane impeded the acute effects of ischemia-reperfusion on hemodynamics and myocardial injury at a comparable level, differences were found after 4 weeks. Xenon in contrast to isoflurane or ketamine anesthetized animals demonstrated a lower remodeling index (0.7±0.1 vs. 0.9±0.3 and 1.0±0.3g/ml), better ejection fraction (62±9 vs. 49±7 and 35±6%), and reduced expression of β-myosin heavy chain and periostin. The effects on hypertrophy, fibrosis, capillary density, and apoptosis were comparable.Conclusions:Compared to isoflurane and s-ketamine, xenon limited progressive adverse cardiac remodeling and contractile dysfunction 28 days after perioperative myocardial infarction.