Natural Language Processing of Referral Letters for Machine Learning-Based Triaging of Patients With Low Back Pain to the Most Appropriate Intervention: Retrospective Study.

BACKGROUND: Decision support systems (DSSs) for suggesting optimal treatments for individual patients with low back pain (LBP) are currently insufficiently accurate for clinical application. Most of the input provided to train these systems is based on patient-reported outcome measures. However, with the appearance of electronic health records (EHRs), additional qualitative data on reasons for referrals and patients' goals become available for DSSs. Currently, no decision support tools cover a wide range of biopsychosocial factors, including referral letter information to help clinicians triage patients to the optimal LBP treatment. OBJECTIVE: The objective of this study was to investigate the added value of including qualitative data from EHRs and referral letters to the accuracy of a quantitative DSS for patients with LBP. METHODS: A retrospective study was conducted in a clinical cohort of Dutch patients with LBP. Patients filled out a baseline questionnaire about demographics, pain, disability, work status, quality of life, medication, psychosocial functioning, comorbidity, history, and duration of pain. Referral reasons and patient requests for help (patient goals) were extracted via natural language processing (NLP) and enriched in the data set. For decision support, these data were considered independent factors for triage to neurosurgery, anesthesiology, rehabilitation, or minimal intervention. Support vector machine, k-nearest neighbor, and multilayer perceptron models were trained for 2 conditions: with and without consideration of the referral letter content. The models' accuracies were evaluated via F1-scores, and confusion matrices were used to predict the treatment path (out of 4 paths) with and without additional referral parameters. RESULTS: Data from 1608 patients were evaluated. The evaluation indicated that 2 referral reasons from the referral letters (for anesthesiology and rehabilitation intervention) increased the F1-score accuracy by up to 19.5% for triaging. The confusion matrices confirmed the results. CONCLUSIONS: This study indicates that data enriching by adding NLP-based extraction of the content of referral letters increases the model accuracy of DSSs in suggesting optimal treatments for individual patients with LBP. Overall model accuracies were considered low and insufficient for clinical application.

Abuse, dependence and withdrawal associated with fentanyl and the role of its (designated) route of administration: an analysis of spontaneous reports from Europe.

PURPOSE: Fentanyl, a highly potent synthetic opioid used in cancer and non-cancer pain, is approved for various routes of administration. In Europe, fentanyl consumption increased substantially in the last decades but information on abuse, dependence and withdrawal associated with fentanyl is scarce, especially with respect to its different formulations. METHODS: We analysed case characteristics of spontaneous reports of suspected fentanyl-associated abuse, dependence or withdrawal from European countries recorded in the EudraVigilance database up to 2018 with respect to the (designated) routes of administration and potential indications. RESULTS: A total of 985 reports were included (mainly from France and Germany) with 43% of cases referring to transdermal fentanyl. Median age was 45 years (48.8% female) and 21.6% had musculoskeletal disorders. Only 12.6% of those using transdermal fentanyl had a cancer diagnosis compared to 40.2% and 26.8% of those using intranasal and oral transmucosal fentanyl, respectively. Depression was common (10.7%) and highest in cases with musculoskeletal disorders (24.9%) as was the use of benzodiazepines. Overall, 39.5% of reports resulted in a prolonged hospital stay and for 23.2% a fatal outcome was recorded. The respective proportions were especially high in cases with musculoskeletal disorders (56.3% with prolonged hospitalisation) and in those using transdermal fentanyl (35.2% fatalities). CONCLUSIONS: In suspected cases of abuse, dependence or withdrawal, fentanyl was mainly used for non-cancer pain indications and most often as transdermal formulations. Depression and prolonged hospitalisations were common, especially in patients with musculoskeletal disorders, indicating a vulnerable patient group and complex treatment situations.

Changes of the nociceptive flexion reflex threshold in patients undergoing cardiac surgery-a prospective clinical pilot study.

Opioid dosage for general anaesthesia and sedation relies on surrogate parameters such as heartrate and blood pressure. This implies the risk of both under- and overdosing. A promising tool to provide target-oriented opioid dosing is measuring the nociceptive flexion reflex threshold (NFRT). The aim of this study was to investigate the individual trajectories and to determine this methods' clinical practicability in the perioperative setting of cardiac surgery. NFRT was measured preoperatively (twice as baseline), immediately after surgery and later in the general ward (primary outcomes). No intraoperative measurements were performed since neuromuscular blockade hinders NFRT assessment. Administered analgesics and pain scores were also recorded (secondary outcomes). Data were collected from August 2019 to March 2020. 264 patients scheduled for cardiac surgery were screened for eligibility. 55 patients were included, 30 rendered datasets for analysis. Thresholds after conclusion of surgery [TICU: median (IQR), 31.1 mA (21.5-50.0 mA)] were significantly higher than preoperatively [Tpre: 9.2 mA (5.4-13.4 mA); P < 0.001]. In 11 patients (36.7%), no immediate postoperative reflex response was elicited. Later, all reflexes returned, but thresholds remained significantly higher than preoperatively [Tpost: 11.9 mA (9.2-16.6 mA); P = 0.043]. NFRT values after surgery were higher compared to baseline measurements. Subsequently they decreased but did not reach their baseline levels. There was no corresponding dose-dependency, suggesting multimodal effects on the nociceptive system. Unless measurements are not prevented by technical issues NFRT-assessment appears to be a future tool to target analgesics in patients not able to self-report pain. Trial registration Study registration: DRKS00021617. https://www.drks.de/drks_web/navigate.do?navigationId=trial.HTML&TRIAL_ID=DRKS00021617 (registered retrospectively).

Heart rate and heart rate variability in patients with chronic inflammatory joint disease: the role of pain duration and the insular cortex.

BACKGROUND: Chronic inflammatory joint diseases (CIJD) have been linked to increased cardiovascular morbidity and mortality. A decisive reason could be a dysregulation of the autonomic nervous system, which is responsible for the control of cardiovascular function. So far, the cause of changes in autonomic nervous system functions remains elusive. In this study, we investigate the role of chronic pain and the insular cortex in autonomic control of cardiac functioning in patients with CIJD. METHODS: We studied the autonomic nervous system through the assessment of heart rate and heart rate variability (HRV) at rest and under cognitive stimulation. Furthermore, we investigated insular cortex volume by performing surface-based brain morphometry with FreeSurfer. For this study, 47 participants were recruited, 22 individual age- and sex-matched pairs for the magnetic resonance imaging analyses and 14 for the HRV analyses. All available patients' data were used for analysis. RESULTS: Pain duration was negatively correlated with the resting heart rate in patients with chronic inflammatory joint diseases (n = 20). In a multiple linear regression model including only CIJD patients with heart rate at rest as a dependent variable, we found a significant positive relationship between heart rate at rest and the volume of the left insular cortex and a significant negative relationship between heart rate at rest and the volume of the right insular cortex. However, we found no significant differences in HRV parameters or insular cortex volumes between both groups. CONCLUSIONS: In this study we provide evidence to suggest insular cortex involvement in the process of ANS changes due to chronic pain in CIJD patients. The study was preregistered with the German Clinical Trials Register ( https://www.drks.de ; DRKS00012791; date of registration: 28 July 2017).

Replicability, Repeatability, and Long-term Reproducibility of Cerebellar Morphometry.

To identify robust and reproducible methods of cerebellar morphometry that can be used in future large-scale structural MRI studies, we investigated the replicability, repeatability, and long-term reproducibility of three fully automated software tools: FreeSurfer, CEREbellum Segmentation (CERES), and automatic cerebellum anatomical parcellation using U-Net with locally constrained optimization (ACAPULCO). Replicability was defined as computational replicability, determined by comparing two analyses of the same high-resolution MRI data set performed with identical analysis software and computer hardware. Repeatability was determined by comparing the analyses of two MRI scans of the same participant taken during two independent MRI sessions on the same day for the Kirby-21 study. Long-term reproducibility was assessed by analyzing two MRI scans of the same participant in the longitudinal OASIS-2 study. We determined percent difference, the image intraclass correlation coefficient, the coefficient of variation, and the intraclass correlation coefficient between two analyses. Our results show that CERES and ACAPULCO use stochastic algorithms that result in surprisingly high differences between identical analyses for ACAPULCO and small differences for CERES. Changes between two consecutive scans from the Kirby-21 study were less than ± 5% in most cases for FreeSurfer and CERES (i.e., demonstrating high repeatability). As expected, long-term reproducibility was lower than repeatability for all software tools. In summary, CERES is an accurate, as demonstrated before, and reproducible tool for fully automated segmentation and parcellation of the cerebellum. We conclude with recommendations for the assessment of replicability, repeatability, and long-term reproducibility in future studies on cerebellar structure.

Transversus abdominis plane block in urological procedures: A systematic review and meta-analysis.

BACKGROUND: Transversus abdominis plane (TAP) blocks have been shown to successfully reduce pain and opioid consumption after general and gynaecological surgery. OBJECTIVE: To evaluate whether TAP blocks alleviate pain and opioid consumption after urological procedures. DESIGN: A systematic review and meta-analysis. DATA SOURCES: MEDLINE, Embase and CENTRAL. ELIGIBILITY CRITERIA: Without language restriction, randomised controlled trials (RCTs) that compared the effects of TAP blocks with placebo or no treatment in urological surgery. MAIN OUTCOME MEASURES: Primary outcomes were pain intensities at rest and movement at 6, 12 and 24 h after surgery. Secondary outcomes were postoperative opioid consumption in the first 24 h after surgery and postoperative nausea and vomiting. We performed meta-analyses using random effects models. Effect sizes were expressed as mean differences for continuous variables. We used the Cochrane risk of bias tool (RoB 2.0) to assess risk of bias. RESULTS: We analysed 20 RCTs comprising a total of 1239 patients. The risk of bias of the studies was relatively high. TAP blocks significantly reduced postoperative pain at all time points compared with placebo or no treatment. Mean differences on an 11-point pain intensity scale were between 0.55 (95% CI: -0.90, to -0.21; P = 0.002; I2 = 94%) to 1.13 (95% CI: -1.62 to -0.65; P < 0.001; I2 = 95%) less at rest and 0.74 (95% CI: -1.25 to -0.23; P = 0.005; I2 = 79%) to 1.32 (95% CI: -1.83 to -0.81; P < 0.001; I2 = 68%) less on movements. TAP blocks also reduced opioid consumption in the first 24 h after surgery significantly by 12.25 mg (95% CI: -17.99 to -6.52 mg; P < 0.001; I2 = 99%) morphine equivalents. Possibly, this had no influence on postoperative nausea and vomiting (risk ratio: 0.98; 95% CI: 0.66 to 1.45; P = 0.91; I2 = 30%). CONCLUSION: TAP blocks seem to offer improved analgesia when used after urological surgery. However, due to the large heterogeneity between and the considerable risk of bias within the included studies results should be viewed with caution. SYSTEMIC REVIEW REGISTRATION: PROSPERO CRD42018112737.

Intranasal Analgesia and Sedation in Pediatric Emergency Care-A Prospective Observational Study on the Implementation of an Institutional Protocol in a Tertiary Children's Hospital.

OBJECTIVES: Children presenting with acute traumatic pain or in need of therapeutic or diagnostic procedures require rapid and effective analgesia and/or sedation. Intranasal administration (INA) promises to be a reliable, minimally invasive delivery route. However, INA is still underused in Germany. We hence developed a protocol for acute pain therapy (APT) and urgent analgesia and/or sedation (UAS). Our aim was to evaluate the effectiveness and safety of our protocol. METHODS: We performed a prospective observational study in a tertiary children's hospital in Germany. Pediatric patients aged 0 to 17 years requiring APT or UAS were included. Fentanyl, s-ketamine, midazolam, or combinations were delivered according to protocol. Primary outcome variables included quality of analgesia and/or sedation as measured on age-appropriate scales and time to onset of drug action. Secondary outcomes were adverse events and serious adverse events. RESULTS: One hundred pediatric patients aged 0.3 to 16 years were enrolled, 34 for APT and 66 for UAS. The median time onset of drug action was 5 minutes (ranging from 2 to 15 minutes). Fentanyl was most frequently used for APT (n = 19). Pain scores decreased by a median of 4 points (range, 0-10; P < 0.0001). For UAS, s-ketamine/midazolam was most frequently used (n = 25). Sedation score indicated minimal sedation in most cases. Overall success rate after the first attempt was 82%. Adverse events consisted of nasal burning (n = 2) and vomiting (n = 2). No serious adverse events were recorded. CONCLUSIONS: A fentanyl-, s-ketamine-, and midazolam-based INA protocol was effective and safe for APT and UAS. It should then be considered where intravenous access is impossible or inappropriate.

The value of pupillary dilation in pre-emptive analgesia: is there more to this than meets the eye?

The pupillary dilatation reflex may present an objective method of predicting whether sedated patients require additional analgesia for painful procedures. Behavioural pain assessment tools identify pain only once it has occurred and are unable to guide pre-emptive management. The pupillary dilatation reflex response to a tetanic stimulus has been utilised to assess analgesic requirements in patients under anaesthesia and for those with postoperative pain. This tool appears promising to assess pain in the critically ill; however, a number of questions remain unanswered regarding the influence of sedation on this response. These questions require further exploration before the pupillary dilatation reflex can be widely adopted into clinical practice.

Characteristics and completeness of spontaneous reports by reporter's role in Germany: An analysis of the EudraVigilance database using the example of opioid-associated abuse, dependence, or withdrawal.

Spontaneous reporting is based on the experience of all healthcare professionals (HCPs) but also consumers/non-HCPs and therefore reveals a broad picture of a drug's adverse reactions. Recent studies found substantial differences between reports from these varying sources including the reports' completeness. Using the example of opioid-associated abuse, dependence, or withdrawal, this study analyzed the completeness and characteristics of spontaneous reports from Germany focusing on the reporter. Based on EudraVigilance data, we included all cases of abuse, dependence, or withdrawal associated with opioids indicated for pain therapy and filed from Germany until 2018. Completeness and characteristics were analyzed by a reporter (physician, pharmacist, other HCPs, consumers/non-HCPs) and also by time period to account for other influencing factors. In total, 1721 cases were included, mainly filed by physicians (38.5%) and pharmacists (30.7%). Completeness of demographics varied from 74.5% (other HCPs) to 42.7% (consumers/non-HCPs). Consumers/non-HCPs most often provided any indication/comorbidity (75.2%), whereas this was the case for only 20.2% of pharmacists. Large differences between the reporters were found for almost all characteristics. Other HCPs far more often coded a history of drug abuse, dependence, or withdrawal than other reporters (46.9% vs. 11.6%-24.2%, respectively), and fatal outcomes were also mainly filed by other HCPs (68.1% vs. 14.8%-20.4% by all other reporters). Differences in completeness and characteristics were also observed over time. Studies analyzing spontaneous data should consider potential differences between the various reporting groups in terms of completeness and characteristics. Further, the impact of other influencing factors has to be assessed.

On pain - Virginia Woolf and the language of poets and patients.

Influenced by Virginia Woolf pain is traditionally believed to be a private object that defies language. However, our analysis of classical and contemporary works of British and American poets, in addition to our own clinical experiences, leads us to challenge this notion. In accordance with Wittgenstein we instead view pain as a concept and objective experience that should encourage interaction. Reasons why patients and healthcare providers often assume language to be insufficient to grasp the complexity of pain are manifold. Based on neuro-cognitive mechanisms we propose an important contributor might be that patients in pain speak a different language than their pain-free peers and doctors.

The influence of personal values and patient intoxication on nurses concerns about opioids: results of a prospective cross-sectional multi-centre study.

BACKGROUND: Nurses are the main administrators of opioids in hospitals and enjoy some autonomy when using them to manage pain. Nevertheless evidence suggests they exercise this freedom restrictively with the reasons for this self-limitation remaining unclear. Nurses are influenced by personal and professional values and by patients' attributes. Intoxicated patients pose a particular challenge. This study therefore investigated whether cautious attitudes towards opioids were aggravated in intoxicated patients and influenced by personal values. METHODS: A two-version questionnaire was developed. Each presented a case vignette describing a patient in acute pain who was either intoxicated or not intoxicated. Questionnaires contained identical case statements inquiring about concerns regarding opioids, preferred analgesics and statements about opioids and personal values. They were distributed prospectively in a cross-sectional, multi-centre design. Equal distribution of both questionnaires was achieved through randomization of wards. Regression analysis was employed to determine predictors for responses to the case statements. RESULTS: In total, n = 374 (26%) nurses returned questionnaires, 85% were female, 39% worked in surgery and 64% had >10 years experience. A total of 78% were concerned using opioids in the intoxicated patient and 70% preferred non-opioids instead. Most nurses agreed familiarity with an opioid gives them more confidence and they were more concerned in patients with a history of drug abuse. They neither associated opioids with helping patients to die nor with drug abuse. The majority endorsed value statements representing 'universalism', 'hedonism' and 'benevolence' while disagreeing with 'power' and 'stimulation'. Nurses concerns were predicted by values indicating 'conformity' and 'achievement'. CONCLUSION: Nurses were concerned giving opioids to intoxicated patients and preferred non-opioids instead. These concerns were predicted by personal values representing 'Conservation' ('conformity') and 'Self-Enhancement' ('achievement'). Therefore, stigmatizing mental models likely contribute to nurses' reluctance to use opioids. Interestingly, personal ambition might protect nurses from discriminatory thoughts and practice.

Noble gas xenon is a novel adenosine triphosphate-sensitive potassium channel opener.

BACKGROUND: Adenosine triphosphate-sensitive potassium (KATP) channels in brain are involved in neuroprotective mechanisms. Pharmacologic activation of these channels is seen as beneficial, but clinical exploitation by using classic K channel openers is hampered by their inability to cross the blood-brain barrier. This is different with the inhalational anesthetic xenon, which recently has been suggested to activate KATP channels; it partitions freely into the brain. METHODS: To evaluate the type and mechanism of interaction of xenon with neuronal-type KATP channels, these channels, consisting of Kir6.2 pore-forming subunits and sulfonylurea receptor-1 regulatory subunits, were expressed in HEK293 cells and whole cell, and excised patch-clamp recordings were performed. RESULTS: Xenon, in contrast to classic KATP channel openers, acted directly on the Kir6.2 subunit of the channel. It had no effect on the closely related, adenosine triphosphate (ATP)-regulated Kir1.1 channel and failed to activate an ATP-insensitive mutant version of Kir6.2. Furthermore, concentration-inhibition curves for ATP obtained from inside-out patches in the absence or presence of 80% xenon revealed that xenon reduced the sensitivity of the KATP channel to ATP. This was reflected in an approximately fourfold shift of the concentration causing half-maximal inhibition (IC50) from 26 +/- 4 to 96 +/- 6 microm. CONCLUSIONS: Xenon represents a novel KATP channel opener that increases KATP currents independently of the sulfonylurea receptor-1 subunit by reducing ATP inhibition of the channel. Through this action and by its ability to readily partition across the blood-brain barrier, xenon has considerable potential in clinical settings of neuronal injury, including stroke.

Chronic noncancer pain is not associated with accelerated brain aging as assessed by structural magnetic resonance imaging in patients treated in specialized outpatient clinics.

Chronic pain is often associated with changes in brain structure and function, and also cognitive deficits. It has been noted that these chronic pain-related alterations may resemble changes found in healthy aging, and thus may represent accelerated or premature aging of the brain. Here, we test the hypothesis that patients with chronic noncancer pain demonstrate accelerated brain aging compared with healthy control subjects. The predicted brain age of 59 patients with chronic pain (mean chronological age ± SD: 53.0 ± 9.0 years; 43 women) and 60 pain-free healthy controls (52.6 ± 9.0 years; 44 women) was determined using the software brainageR. This software segments the individual T1-weighted structural MR images into gray and white matter and compares gray and white matter images with a large (n = 2001) training set of structural images, using machine learning. Finally, brain age delta, which is the predicted brain age minus chronological age, was calculated and compared across groups. This study provided no evidence for the hypothesis that chronic pain is associated with accelerated brain aging (Welch t test, P = 0.74, Cohen's d = 0.061). A Bayesian independent-samples t test indicated moderate evidence in favor of the null hypothesis (BF01 = 4.875, ie, group means were equal). Our results provide indirect support for recent models of pain-related changes of brain structure, brain function, and cognitive functions. These models postulate network-specific maladaptive plasticity, rather than widespread or global neural degeneration.

Regional Differences in Opioid Prescribing in Germany - Results of an Analysis of Health Insurance Data of 57 Million Adult People.

BACKGROUND: Regional variations of opioid use have been reported from many countries. The objective of this study was to examine opioid prescribing patterns in Germany including low- and high-potency opioids (LPO and HPO) focusing on regional differences. METHODS: Data source was the "Information system for health care data" comprising statutory health insurance funds data for about 70 million Germans of all ages. For 2010, we received aggregated data (by age, sex, federal state and district) of Germans (18+) who had been prescribed at least one opioid including the number of prescribed packages. For each stratum, we further received the number of insured persons. We calculated LPO and HPO prevalences and the mean number of prescribed packages. RESULTS: Among 57 million adult Germans (mean age: 50.2 years, 53.8% female), opioid prevalences were 38.7 per 1000 persons for LPOs and 12.8 for HPOs. Prevalences rose with increasing age and were higher in women than in men. On average, LPO users were prescribed fewer packages than HPO users (3.5 vs 7.0). LPO use was highest in the eastern states ranging from 32.9 per 1000 persons (Hamburg) to 47.2 (Saxony-Anhalt). HPOs were most often prescribed in the North and in the East with prevalences varying between 10.6 per 1000 persons (Baden-Württemberg) and 16.9 (Mecklenburg-Western Pomerania). On the district level, prevalences varied by the factors 2.6 and 3.2 for LPOs and HPOs, respectively. CONCLUSION: We found large regional variations in opioid prescribing which probably cannot only be attributed to differences in patient characteristics.

Agranulocytosis attributed to metamizole: An analysis of spontaneous reports in EudraVigilance 1985-2017.

Despite ongoing debates about its safety, the use of metamizole (dipyrone) is still increasing in many countries. In this study, we analysed spontaneous reports of suspected metamizole-associated agranulocytosis recorded in EudraVigilance database from 1985 to 2017 with regard to patient and treatment characteristics as well as fatal vs non-fatal outcomes and compared these findings among countries. A total of 1448 reports from 31 different countries were included (Germany 42.0%; Spain 29.6%; Switzerland 13.1%; other countries 15.3%). Mean age of patients was 53.6 years (63.4% females). Differences among countries were observed, for example with respect to patient age, route of administration and daily doses. Overall, median time between starting metamizole and developing an agranulocytosis was 13 days with 34.7% of cases occurring up to 7 days. This time was much shorter in patients who had already received metamizole before (median: 6 vs 15 days). About 16% of cases ended fatally. Patients with fatal outcomes were older and more often had also received methotrexate compared to those with non-fatal outcomes. When adjusting for age and sex in a multivariable logistic regression, methotrexate was associated with an increased risk of fatal outcomes (odds ratio: 5.18; 95% confidence interval: 3.06-8.78). In conclusion, metamizole-associated agranulocytosis is still a life-threatening condition, especially in the elderly and those also receiving methotrexate. As agranulocytosis can develop weeks after last administration and independently of dose and duration of treatment, prescribers and patients should be aware of its signs and symptoms.

Regional Differences in Prescribing Patterns of Metamizole in Germany Based on Data from 70 Million Persons.

The non-opioid analgesic metamizole (dipyrone) is commonly used in Germany despite its narrow indications and market withdrawal from several countries. In this study we analyzed prescribing patterns of metamizole focusing on regional differences. The source of data was the "Information system for health care data" which includes data from the statutory health insurance funds for about 70 million Germans. We received aggregated data of individuals with at least one metamizole prescription in 2010 as well as the number of prescribed packages by age, sex, state and district along with the number of insured persons in each stratum. We calculated prescription prevalence stratified by age, sex, state and district. Among 68.4 million insured persons (mean age: 43.6 years; 53.0% female) 5.5 million received at least one metamizole prescription (8.1%, overall 12.2 million packages). Prevalence increased with age, and women received metamizole more often than men. In adults (total prevalence: 9.4%), levels varied between 7.0% (Saxony) and 11.1% (Schleswig-Holstein), whereas on a district level use ranged from 4.3% to 14.3%. In 2010, one of 12 individuals received metamizole at least once. Noticeable were the large regional variations which certainly cannot be explained by patient-related factors.

Neuronal preconditioning by inhalational anesthetics: evidence for the role of plasmalemmal adenosine triphosphate-sensitive potassium channels.

BACKGROUND: Ischemic preconditioning is an important intrinsic mechanism for neuroprotection. Preconditioning can also be achieved by exposure of neurons to K+ channel-opening drugs that act on adenosine triphosphate-sensitive K+ (K(ATP)) channels. However, these agents do not readily cross the blood-brain barrier. Inhalational anesthetics which easily partition into brain have been shown to precondition various tissues. Here, the authors explore the neuronal preconditioning effect of modern inhalational anesthetics and investigate their effects on K(ATP) channels. METHODS: Neuronal-glial cocultures were exposed to inhalational anesthetics in a preconditioning paradigm, followed by oxygen-glucose deprivation. Increased cell survival due to preconditioning was quantified with the 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide reduction test. Recombinant plasmalemmal K(ATP) channels of the main neuronal type (Kir6.2/SUR1) were expressed in HEK293 cells, and the effects of anesthetics were evaluated in whole cell patch clamp recordings. RESULTS: Both sevoflurane and the noble gas xenon preconditioned neurons at clinically used concentrations. The effect of sevoflurane was independent of K(ATP) channel activation, whereas the effect of xenon required the opening of plasmalemmal K(ATP) channels. Recombinant K(ATP) channels were activated by xenon but inhibited by halogenated volatiles. Modulation of mitochondrial K-ATP channels did not affect the activity of K(ATP) channels, thus ruling out an indirect effect of volatiles via mitochondrial channels. CONCLUSIONS: The preconditioning properties of halogenated volatiles cannot be explained by their effect on K(ATP) channels, whereas xenon preconditioning clearly involves the activation of these channels. Therefore, xenon might mimic the intrinsic mechanism of ischemic preconditioning most closely. This, together with its good safety profile, might suggest xenon as a viable neuroprotective agent in the clinical setting.

Corrigendum: The Influence of Chronic Pain and Cognitive Function on Spatial-Numerical Processing.

[This corrects the article DOI: 10.3389/fnbeh.2018.00165.].

Chronic Pain and Chronic Opioid Use After Intensive Care Discharge - Is It Time to Change Practice?

Almost half of patients treated on intensive care unit (ICU) experience moderate to severe pain. Managing pain in the critically ill patient is challenging, as their pain is complex with multiple causes. Pharmacological treatment often focuses on opioids, and over a prolonged admission this can represent high cumulative doses which risk opioid dependence at discharge. Despite analgesia the incidence of chronic pain after treatment on ICU is high ranging from 33-73%. Measures need to be taken to prevent the transition from acute to chronic pain, whilst avoiding opioid overuse. This narrative review discusses preventive measures for the development of chronic pain in ICU patients. It considers a number of strategies that can be employed including non-opioid analgesics, regional analgesia, and non-pharmacological methods. We reason that individualized pain management plans should become the cornerstone for critically ill patients to facilitate physical and psychological well being after discharge from critical care and hospital.