Trajectories of pain and opioid use up to one year after surgery: analysis of a European registry.

BACKGROUND: Long-term opioid use after surgery is a crucial healthcare problem in North America. Data from European hospitals are scarce and differentiation of chronic pain has rarely been considered. METHODS: In a mixed surgical cohort of the PAIN OUT registry, opioid use and chronic pain were evaluated before surgery, and 6 and 12 months after surgery (M6/M12). Subgroups with or without opioid medication and pre-existing chronic pain were analysed. M12-chronic pain was categorised as chronic postsurgical pain (CPSP) meeting the ICD-11 definition, chronic pain related to surgery not meeting the ICD-11 definition, and chronic pain unrelated to surgery. Primary endpoint was the rate of M12 opioid users. Variables associated with M12 opioid use and patient-reported outcomes were evaluated. RESULTS: Of 2326 patients, 5.5% were preoperative opioid users; 4.4% and 3.5% took opioids at M6 and M12 (P<0.001). Chronic pain before operation and at M6/M12 was reported by 41.2%, 41.8%, and 34.7% of patients, respectively (P<0.001). The rate of M12 opioid users was highest in group unrelated (22.3%; related 8.3%, CPSP 1.5%; P<0.001). New opioid users were 1.1% (unrelated 7.1%, related 2.3%, CPSP 0.7%; P<0.001). M12 opioid users reported more pain, pain-related physical and affective interference, and needed more opioids than non-users. The predominant variable associated with M12 opioids was preoperative opioid use (estimated odds ratio [95% confidence interval]: 28.3 [14.1-56.7], P<0.001). CONCLUSIONS: Opioid use was low in patients with CPSP, and more problematic in patients with chronic pain unrelated to surgery. A detailed assessment of chronic pain unrelated or related to surgery or CPSP is necessary. CLINICAL TRIAL REGISTRATION: NCT02083835.

Cholinesterase activities and sepsis-associated encephalopathy in viral versus nonviral sepsis.

PURPOSE: There is evidence that cholinergic imbalance secondary to neuroinflammation plays a role in the pathophysiology of sepsis-associated encephalopathy (SAE). Blood acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) activities have been proposed as surrogate parameters for the cholinergic function of the central nervous system. Viral sepsis is associated with systemic inflammation and BChE has been reported to be of prognostic value in a small cohort of COVID-19 patients. Nevertheless, the prognostic value of AChE in patients with viral sepsis remains unclear. METHODS: We investigated the role of AChE and BChE activities as prognostic biomarkers of SAE and mortality in patients with viral vs nonviral sepsis enrolled in two prospective cohort studies. We quantified the AChE and BChE activities in whole blood of patients at two time points in the acute phase of viral sepsis (N = 108) and compared them with the activities in patients with nonviral sepsis (N = 117) and healthy volunteers (N = 81). Patients were observed until discharge from the intensive care unit (ICU). RESULTS: Three days after sepsis onset, the median [interquartile range] levels of AChE and BChE were reduced in both patients with viral sepsis (AChE, 5,105 [4,010-6,250] U·L-1; BChE, 1,943 [1,393-2,468] U·L-1) and nonviral sepsis (AChE, 4,424 [3,630-5,055] U·L-1; BChE, 1,095 [834-1,526] U·L-1) compared with healthy volunteers (AChE, 6,693 [5,401-8,020] U·L-1; BChE, 2,645 [2,198-3,478] U·L-1). Patients with viral sepsis with SAE during their ICU stay had lower AChE activity three days after sepsis onset than patients without SAE (4,249 [3,798-5,351] U·L-1 vs 5,544 [4,124-6,461] U·L-1). Butyrylcholinesterase activity seven days after sepsis onset was lower in patients with viral sepsis who died in the ICU than in surviving patients (1,427 [865-2,181] U·L-1 vs 2,122 [1,571-2,787] U·L-1). CONCLUSION: Cholinesterase activities may be relevant prognostic markers for the occurrence of SAE and mortality in the ICU in patients with viral sepsis. STUDY REGISTRATION: This study constitutes an analysis of data from the ongoing studies ICROS (NCT03620409, first submitted 15 May 2018) and ICROVID (DRKS00024162, first submitted 9 February 2021).

RéSUMé: OBJECTIF: Certaines données probantes soutiennent que le déséquilibre cholinergique secondaire à la neuroinflammation joue un rôle dans la physiopathologie de l'encéphalopathie associée au sepsis (EAS). Les activités de l'acétylcholinestérase (AChE) et de la butyrylcholinestérase (BChE) sanguines ont été proposées comme paramètres de substitution de la fonction cholinergique du système nerveux central. Le sepsis viral est associé à une inflammation systémique et il a été rapporté que la BChE possédait une valeur pronostique dans une petite cohorte atteinte de COVID-19. Néanmoins, la valeur pronostique de l'AChE chez les patient·es atteint·es de sepsis viral reste incertaine. MéTHODE: Nous avons étudié le rôle des activités de l'AChE et de la BChE en tant que biomarqueurs pronostiques de l'EAS et de la mortalité chez les patient·es atteint·es de sepsis viral vs non viral recruté·es dans deux études de cohorte prospectives. Nous avons quantifié les activités de l'AChE et de la BChE dans le sang total de patient·es à deux moments de la phase aiguë du sepsis viral (N = 108) et les avons comparées aux activités chez les patient·es atteint·es de sepsis non viral (N = 117) et chez des volontaires sain·es (N = 81). Les patient·es ont été observé·es jusqu'à leur sortie de l'unité de soins intensifs (USI). RéSULTATS: Trois jours après l'apparition du sepsis, les taux médians [écart interquartile] d'AChE et BChE étaient réduits tant chez la patientèle atteinte de sepsis viral (AChE, 5105 [4010­6250] U·L−1; BChE, 1943 [1393­2468] U·L−1) et de sepsis non viral (AChE, 4424 [3630­5055] U·L−1; BChE, 1095 [834­1526] U·L−1) par rapport aux volontaires sain·es (AChE, 6693 [5401­8020] U·L−1; BChE, 2645 [2198­3478] U·L−1). Les patient·es atteint·es de sepsis viral avec EAS pendant leur séjour aux soins intensifs avaient une activité AChE plus faible trois jours après l'apparition du sepsis que les personnes sans EAS (4249 [3798­5351] U·L−1 vs 5544 [4124­6461] U·L−1). L'activité de la butyrylcholinestérase sept jours après l'apparition du sepsis était plus faible chez les patient·es atteint·es de sepsis viral décédé·es à l'USI que chez les personnes ayant survécu (1427 [865­2181] U·L-1 vs 2122 [1571­2787] U·L-1). CONCLUSION: Les activités des cholinestérases pourraient constituer des marqueurs pronostiques pertinents pour la survenue d'EAS et la mortalité en soins intensifs chez la patientèle atteinte de sepsis viral. ENREGISTREMENT DE L'éTUDE: Cette étude constitue une analyse des données des études en cours ICROS (NCT03620409, première soumission le 15 mai 2018) et ICROVID (DRKS00024162, première soumission le 9 février 2021).

[What determines the overall quality of postoperative pain management? A question of perspective]. / Was ist ausschlaggebend für die Gesamtqualität der postoperativen Schmerztherapie? Eine Frage der Perspektive.

BACKGROUND: The outcome domains pain intensity, pain-related interference, side effects, (treatment) information, participation and personal interaction have all been identified as relevant factors in the management of perioperative pain. However, it is not yet clear which of these are particularly significant for the subjectively perceived overall quality of postoperative pain management. AIM: A newly developed questionnaire was used in this cross-sectional study to assess the relevance of these domains for patients and compare the relevance to healthcare professionals (HCP). METHODS: The patient survey (n = 40) was conducted on the first postoperative day at Jena University Hospital, Germany. In order to investigate group differences, 63 HCP (disciplines: n = 15 anaesthesiology, n = 17 surgery, n = 31 nursing) were recruited. The questionnaire primarily included all pairwise comparisons between the domains with regard to the overall quality of postoperative pain management. The resulting sum scores for each domain were the primary outcome measure, which were analysed using generalized estimating equations. RESULTS: Within the group of patients, there were significant differences in the prioritization of the six outcome domains, with personal interaction followed by intensity and interference having received the highest ratings. There were also significant differences within the domains between the perspectives of patients and HCP, as well as between the HCP themselves. CONCLUSIONS: The study demonstrates that personal interaction and the reduction of pain intensity and interference are three key factors that are significant for patients' experience of postoperative pain management. However, the extent to which the harmonisation of these three factors with those given prominence by HCP would positively impact postoperative pain management remains unclear and should be investigated further.

[Interdisciplinary multimodal pain therapy: does the dose make a difference? : A comparison from routine clinical care]. / Interdisziplinäre multimodale Schmerztherapie: Macht die Dosis einen Unterschied? : Ein Vergleich aus der klinischen Routineversorgung.

BACKGROUND: Interdisciplinary multimodal pain therapy (IMPT) is an established treatment for patients with severe chronic pain. Little evidence is available on the role of treatment dosage and, in particular, on the association between the duration of IMPT and treatment outcome. AIM: The aim of this retrospective study was to compare the medium-term treatment success of a short inpatient (SIT, 1 week) and a long outpatient (LOT, 4 weeks) IMPT with a comparable treatment concept and comparable therapy intensity (20 h/week) in patients with severe chronic pain. METHODS: Patients in both groups completed the German Pain Questionnaire at the beginning and end of IMPT as well as after 3 months. Primary outcome measures included pain-related impairment and average pain intensity at follow-up in patients of comparable sex, age as well as pain intensity and impairment at the beginning of the therapy. RESULTS: While both groups initially showed significant treatment effects in pain-related impairment and average pain intensity, LOT patients (n = 32) reported significantly better values in both variables at 3­month follow-up compared with SIT patients (n = 32). This was due to sustained positive effects in LOT patients and worsening in the SIT group. CONCLUSION: The results indicate that initial treatment effects can be observed in both treatment settings, but a longer duration of therapy seems to favour the long-term stability of treatment effects.

The Influence of Eye Closure on Somatosensory Discrimination: A Trade-off Between Simple Perception and Discrimination.

We often close our eyes to improve perception. Recent results have shown a decrease of perception thresholds accompanied by an increase in somatosensory activity after eye closure. However, does somatosensory spatial discrimination also benefit from eye closure? We previously showed that spatial discrimination is accompanied by a reduction of somatosensory activity. Using magnetoencephalography, we analyzed the magnitude of primary somatosensory (somatosensory P50m) and primary auditory activity (auditory P50m) during a one-back discrimination task in 21 healthy volunteers. In complete darkness, participants were requested to pay attention to either the somatosensory or auditory stimulation and asked to open or close their eyes every 6.5 min. Somatosensory P50m was reduced during a task requiring the distinguishing of stimulus location changes at the distal phalanges of different fingers. The somatosensory P50m was further reduced and detection performance was higher during eyes open. A similar reduction was found for the auditory P50m during a task requiring the distinguishing of changing tones. The function of eye closure is more than controlling visual input. It might be advantageous for perception because it is an effective way to reduce interference from other modalities, but disadvantageous for spatial discrimination because it requires at least one top-down processing stage.

Somatosensory Functions in Survivors of Critical Illness.

OBJECTIVES: There is growing evidence for increased levels of pain and reduced health-related quality of life in survivors of critical illness. Recent studies showed marked small nerve fiber pathology in critically ill patients, which may contribute to chronic pain states and reduced physical recovery after ICU discharge. Primary objective of this study was the comparison of somatosensory functions between survivors of critical illness 6 months after ICU discharge and controls. In post hoc analyses, we aimed to identify associations between small fiber deficits, pain, health-related quality of life, and clinical data. DESIGN: Cross-sectional study. SETTING: Study in critical illness survivors. PATIENTS: Critical illness survivors (n = 84) and controls (n = 44). INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Somatosensory functions were assessed with validated quantitative sensory testing. Pain and pain-related disability were assessed with the chronic pain grade questionnaire. Health-related quality of life was assessed by means of the Short Form-36. Compared with controls, former patients showed significantly increased thermal detection thresholds and more abnormal values in thermal testing, indicating reduced small fiber functioning. In addition, compared to patients without significant small fiber deficits (n = 46, 54.8%), patients with significant small fiber deficits (n = 38, 45.2%) reported higher average pain intensity, pain-related disability, and reduced physical health-related quality of life in the SF-36. CONCLUSIONS: A large portion of former critically ill patients show small fiber deficits which seem to be associated with increased pain and reduced physical health-related quality of life. Screening of somatosensory functions in the (post-) acute setting could possibly help to identify patients at risk of long-term impairments.

Prevalence and Characteristics of Chronic Intensive Care-Related Pain: The Role of Severe Sepsis and Septic Shock.

OBJECTIVE: There is only limited knowledge about chronic pain conditions resulting from critical care. Experimental and clinical data suggest a close relationship between inflammation and pain perception. Since sepsis is the most severe form of systemic inflammation, the primary objective was to evaluate chronic pain states and functional impairment of septic and nonseptic patients 6 months after discharge from ICU. Second, we aimed to obtain the total prevalence and characteristics of chronic ICU-related pain. DESIGN: Case-control study. SETTING: Observational study in long-term survivors of mixed surgical and medical ICUs. PATIENTS: Septic and nonseptic survivors of critical care (n = 207) and healthy controls (n = 46). INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: We collected comprehensive information on patients' past and present pain 6 months after ICU discharge by means of the German pain questionnaire. Pain intensity levels and pain interference ratings were compared between septic and nonseptic patients and healthy controls. We found no differences in prevalence, severity, and interference of pain between septic and nonseptic patients. However, both patient groups differed significantly from controls. In secondary analysis, a third of all patients reported chronic clinically relevant pain associated with the ICU stay 6 months after ICU discharge. Half of these patients experienced chronic pain conditions before ICU admission and reported additional sources of pain. Most important, 16% of all patients had no preexisting pain condition and now experience chronic ICU-related pain. The majority of patients with chronic ICU-related pain reported a high degree of disabling pain, limiting daily activities. CONCLUSIONS: A high percentage of former ICU patients develop chronic pain conditions associated with critical care. These patients differ significantly from control data in terms of pain intensity and show high levels of interference with pain. The presence of sepsis per se seems to play a marginal role for the development of chronic ICU-related pain.

Cell-free DNA in patients with sepsis: long term trajectory and association with 28-day mortality and sepsis-associated acute kidney injury.

Introduction: Outcome-prediction in patients with sepsis is challenging and currently relies on the serial measurement of many parameters. Standard diagnostic tools, such as serum creatinine (SCr), lack sensitivity and specificity for acute kidney injury (AKI). Circulating cell-free DNA (cfDNA), which can be obtained from liquid biopsies, can potentially contribute to the quantification of tissue damage and the prediction of sepsis mortality and sepsis-associated AKI (SA-AKI). Methods: We investigated the clinical significance of cfDNA levels as a predictor of 28-day mortality, the occurrence of SA-AKI and the initiation of renal replacement therapy (RRT) in patients with sepsis. Furthermore, we investigated the long-term course of cfDNA levels in sepsis survivors at 6 and 12 months after sepsis onset. Specifically, we measured mitochondrial DNA (mitochondrially encoded NADH-ubiquinone oxidoreductase chain 1, mt-ND1, and mitochondrially encoded cytochrome C oxidase subunit III, mt-CO3) and nuclear DNA (nuclear ribosomal protein S18, n-Rps18) in 81 healthy controls and all available samples of 150 intensive care unit patients with sepsis obtained at 3 ± 1 days, 7 ± 1 days, 6 ± 2 months and 12 ± 2 months after sepsis onset. Results: Our analysis revealed that, at day 3, patients with sepsis had elevated levels of cfDNA (mt-ND1, and n-Rps18, all p<0.001) which decreased after the acute phase of sepsis. 28-day non-survivors of sepsis (16%) had higher levels of cfDNA (all p<0.05) compared with 28-day survivors (84%). Patients with SA-AKI had higher levels of cfDNA compared to patients without AKI (all p<0.05). Cell-free DNA was also significantly increased in patients requiring RRT (all p<0.05). All parameters improved the AUC for SCr in predicting RRT (AUC=0.88) as well as APACHE II in predicting mortality (AUC=0.86). Conclusion: In summary, cfDNA could potentially improve risk prediction models for mortality, SA-AKI and RRT in patients with sepsis. The predictive value of cfDNA, even with a single measurement at the onset of sepsis, could offer a significant advantage over conventional diagnostic methods that require repeated measurements or a baseline value for risk assessment. Considering that our data show that cfDNA levels decrease after the first insult, future studies could investigate cfDNA as a "memoryless" marker and thus bring further innovation to the complex field of SA-AKI diagnostics.

Pain After Outpatient Surgical Procedures.

BACKGROUND: Approximately 8.1 million outpatient surgical procedures were performed in Germany in 2021. Little is known about the quality of postoperative pain treatment in the outpatient sector. METHODS: The AQS1 project comprises a combined survey of patients and staff in the framework of quality control for ambulatory surgery. The primary endpoint of this study was the prevalence of relevant incisional pain (≥ 4/10 on the numerical rating scale) up to postoperative day 3. Secondary endpoints included prognostic variables for pain and pain-associated outcomes, based on the AQS1 patient questionnaire. Moreover, mixed regression models were used to analyze potential prognostic variables and associations of pain with other outcomes (study registration number DRKS00028052). RESULTS: Data from 330 008 patients were evaluated (from 1 July 2001 to 31 December 2021). The overall prevalence of relevant incisional pain up to postoperative day 3 was 22.5%, with major differences between different types of procedure (3.2%-51.2%). Pain was most common after hemorrhoid surgery (51.2%) and the laparoscopic lysis of large and small bowel adhesions (45.4%). The main associations of relevant pain were with younger age (odds ratio [OR] 1.87, 95% confidence interval [1.82; 1.91]), early postoperative pain (1.34, [1.30; 1.39]), inadequate provision of analgesics (2.90, [2.71; 3.09]), and surgical wound infections (2.60, [2.43; 2.78]). Patients with pain reported lower overall satisfaction with the procedure and a longer inability to work. CONCLUSION: These data have not been tested for representativeness. They can serve as a point of departure for the optimization of individualized perioperative pain therapy and for the planning of prospective studies.

The Incidence and Risk Factors of Persistent Opioid Use After Surgery­a Retrospective Secondary Data Analysis.

BACKGROUND: The risk of persistent postoperative opioid use (PPOU) and its association with the type of surgery are still unclear in Germany. METHODS: We conducted a nationwide retrospective cohort study on the basis of claims data from BARMER, a statutory health insurance carrier in Germany. Opioid-naive adults who did not have cancer and who underwent inpatient surgery in 2018 were included in the study. The operations were divided into 103 categories. PPOU was defined as the prescribing of opioids between postoperative days 1 and 90 and also between postoperative days 91 and 180 after hospital discharge. Patient-associated risk factors in the 12 months before surgery were investigated. RESULTS: 203 327 patients were included. 1.4% had PPOU (95% confidence interval [1.4; 1.5]). There were major differences between operation groups: major amputations and orthopedic procedures carried the greatest risk for the development of PPOU. The type of surgery had a larger effect on the risk of PPOU than pre-existing risk factors (explained variance 22.3% vs. 14.3%). Among such factors, alcohol abuse and pre-existing treatment with antidepressant drugs were associated with the highest risk for PPOU (odds ratios [OR] 1.515 [1.277; 1.797] and 2.131 [1.943; 2.336]). CONCLUSION: The incidence of PPOU in Germany is low (1.4%). The type of surgery plays an important role in its development.

Cost-effectiveness of the Perioperative Pain Management Bundle a registry-based study.

Introduction: The Perioperative Pain Management Bundle was introduced in 10 Serbian PAIN OUT network hospitals to improve the quality of postoperative pain management. The Bundle consists of 4 elements: informing patients about postoperative pain treatment options; administering a full daily dose of 1-2 non-opioid analgesics; administering regional blocks and/or surgical wound infiltration; and assessing pain after surgery. In this study, we aimed to assess the cost-effectiveness of the Bundle during the initial 24 h after surgery. Materials and methods: The assessment of cost-effectiveness was carried out by comparing patients before and after Bundle implementation and by comparing patients who received all Bundle elements to those with no Bundle element. Costs of postoperative pain management included costs of the analgesic medications, costs of labor for administering these medications, and related disposable materials. A multidimensional Pain Composite Score (PCS), the effectiveness measurement, was obtained by averaging variables from the International Pain Outcomes questionnaire evaluating pain intensity, interference of pain with activities and emotions, and side effects of analgesic medications. The incremental cost-effectiveness ratio (ICER) was calculated as the incremental change in costs divided by the incremental change in PCS and plotted on the cost-effectiveness plane along with the economic preference analysis. Results: The ICER value calculated when comparing patients before and after Bundle implementation was 181.89 RSD (1.55 EUR) with plotted ICERs located in the northeast and southeast quadrants of the cost-effectiveness plane. However, when comparing patients with no Bundle elements and those with all four Bundle elements, the calculated ICER was -800.63 RSD (-6.82 EUR) with plotted ICERs located in the southeast quadrant of the cost-effectiveness plane. ICER values differ across surgical disciplines. Conclusion: The proposed perioperative pain management Bundle is cost-effective. The cost-effectiveness varies depending on the number of implemented Bundle elements and fluctuates across surgical disciplines.

Following Evidence-Based Recommendations for Perioperative Pain Management after Cesarean Section Is Associated with Better Pain-Related Outcomes: Analysis of Registry Data.

Women who have had a Cesarean Section (CS) frequently report severe pain and pain-related interference. One reason for insufficient pain treatment might be inconsistent implementation of evidence-based guidelines. We assessed the association between implementing three elements of care recommended by guidelines for postoperative pain management and pain-related patient-reported outcomes (PROs) in women after CS. The analysis relied on an anonymized dataset of women undergoing CS, retrieved from PAIN OUT. PAIN OUT, an international perioperative pain registry, provides clinicians with treatment assessment methodology and tools for patients to assess multi-dimensional pain-related PROs on the first postoperative day. We examined whether the care included [i] regional anesthesia with a neuraxial opioid OR general anesthesia with wound infiltration or a Transvesus Abdominis Plane block; [ii] at least one non-opioid analgesic at the full daily dose; and [iii] pain assessment and recording. Credit for care was given only if all three elements were administered (= "full"); otherwise, it was "incomplete". A "Pain Composite Score-total" (PCStotal), evaluating outcomes of pain intensity, pain-related interference with function, and side-effects, was the primary endpoint in the total cohort (women receiving GA and/or RA) or a sub-group of women with RA only. Data from 5182 women was analyzed. "Full" care was administered to 20% of women in the total cohort and to 21% in the RA sub-group. In both groups, the PCStotal was significantly lower compared to "incomplete" care (p < 0.001); this was a small-to-moderate effect size. Administering all three elements of care was associated with better pain-related outcomes after CS. These should be straightforward and inexpensive for integration into routine care after CS. However, even in this group, a high proportion of women reported poor outcomes, indicating that additional work needs to be carried out to close the evidence-practice gap so that women who have undergone CS can be comfortable when caring for themselves and their newborn.

The Perioperative Pain Management Bundle is Feasible: Findings From the PAIN OUT Registry.

OBJECTIVES: The quality of postoperative pain management is often poor. A "bundle," a small set of evidence-based interventions, is associated with improved outcomes in different settings. We assessed whether staff caring for surgical patients could implement a "Perioperative Pain Management Bundle" and whether this would be associated with improved multidimensional pain-related patient-reported outcomes (PROs). METHODS: "PAIN OUT," a perioperative pain registry, offers tools for auditing pain-related PROs and obtaining information about perioperative pain management during the first 24 hours after surgery. Staff from 10 hospitals in Serbia used this methodology to collect data at baseline. They then implemented the "Perioperative Pain Management Bundle" into the clinical routine and collected another round of data. The bundle consists of 4 treatment elements: (1) a full daily dose of 1 to 2 nonopioid analgesics (eg, paracetamol and/or nonsteroidal anti-inflammatory drugs), (2) at least 1 type of local/regional anesthesia, (3) pain assessment by staff, and (4) offering patients information about pain management. The primary endpoint was a multidimensional pain composite score (PCS), evaluating pain intensity, interference, and side effects that was compared between patients who received the full bundle versus not. RESULTS: Implementation of the complete bundle was associated with a significant reduction in the PCS ( P < 0.001, small-medium effect size [ES]). When each treatment element was evaluated independently, nonopioid analgesics were associated with a higher PCS (ie, poorer outcome, and negligible ES), and the other elements were associated with a lower PCS (all negligible small ES). Individual PROs were consistently better in patients receiving the full bundle compared with 0 to 3 elements. The PCS was not associated with the surgical discipline. DISCUSSION: We report findings from using a bundle approach for perioperative pain management in patients undergoing mixed surgical procedures. Future work will seek strategies to improve the effect.

Variations and Predictors of Post-COVID Syndrome Severity in Patients Attending a Post-COVID Outpatient Clinic.

A relevant proportion of patients suffer from long-lasting impairments following an acute SARS-CoV-2 infection. The proposed post-COVID syndrome (PCS) score may improve comparison in the course and classification of affected patients. A prospective cohort of 952 patients presenting to the post-COVID outpatient clinic at Jena University Hospital, Germany, was enrolled. Patients received a structured examination. PCS score was calculated per visit. A total of 378 (39.7%) and 129 (13.6%) patients of the entire population visited the outpatient clinic two or three times, respectively (female: 66.4%; age: 49.5 (SD = 13) years). The initial presentation took place, on average, 290 (SD = 138) days after acute infection. The most frequently reported symptoms were fatigue (80.4%) and neurological impairments (76.1%). The mean PCS scores of patients with three visits were 24.6 points (SD = 10.9), 23.0 points (SD = 10.9) and 23.5 points (SD = 11.5) (p = 0.407), indicating moderate PCS. Female sex (p < 0.001), preexisting coagulation disorder (p = 0.021) and coronary artery disease (p = 0.032) were associated with higher PCS scores. PCS is associated with a multitude of long-lasting problems. The PCS score has proven its capability to objectify and quantify PCS symptoms in an outpatient setting. The influence of therapeutic measures on various PCS aspects should be the subject of further analyses.

Functional connectivity and neurotransmitter impairments of the salience brain network in chronic low back pain patients: a combined resting-state functional magnetic resonance imaging and 1 H-MRS study.

ABSTRACT: Functional reorganisation of the salience network (SN) has been proposed as one of the key pathomechanisms associated with central nociceptive processing in the chronic pain state. Being associated with an altered functional connectivity within the SN, these processes have been hypothesized to result from a loss of inhibitory function leading to node hyperexcitability and spontaneous pain. Combined resting-state BOLD functional magnetic resonance imaging (MRI) and 1 H-MR spectroscopy was applied to chronic back pain patients and healthy subjects to assess deviations from functional integrity (weighted closeness centrality [wCC], derived from resting-state functional MRI), oscillatory BOLD characteristics (spectral power), and neurotransmitter levels (GABA + , glutamate+glutamine) in 2 key SN nodes, anterior insular (aIns R ) and anterior mid-cingulate cortices. In addition, examinations were repeated in chronic back pain patients after a 4-week interdisciplinary multimodal pain treatment and in healthy subjects after 4 weeks to explore longitudinal, treatment-mediated changes in target variables. The aIns R and, to a lesser extent, the anterior mid-cingulate of patients exhibited significantly reduced wCC accompanied by a spectral power shift from a lower to a higher frequency band, indicating a desynchronization of their neuronal activity within the SN, possibly because of increased spontaneous activations. Without revealing neurotransmitter differences, patients alone showed significant positive associations between local GABA + levels and wCC in aIns R , suggesting a stronger dependence of node synchronization on the inhibitory tone in the chronic pain state. However, this needs to be explored in the future using magnetic resonance spectroscopy techniques that are more sensitive to detecting subtle neurotransmitter changes and also allow multifocal characterization of neurotransmitter tone.

Identification of cardiovascular and molecular prognostic factors for the morbidity and mortality in COVID-19-sepsis (ICROVID): Protocol for a prospective multi-centre cohort study.

INTRODUCTION: Severe COVID-19 constitutes a form of viral sepsis. Part of the specific pathophysiological pattern of this condition is the occurrence of cardiovascular events. These include pulmonary embolism, arrhythmias and cardiomyopathy as manifestations of extra-pulmonary organ dysfunction. Hitherto, the prognostic impact of these cardiovascular events and their predisposing risk factors remains unclear. This study aims to explore this question in two cohorts of viral sepsis-COVID-19 and influenza-in order to identify new theragnostic strategies to improve the short- and long-term outcome of these two diseases. METHODS AND ANALYSIS: In this prospective multi-centre cohort study, clinical assessment will take place during the acute and post-acute phase of sepsis and be complemented by molecular laboratory analyses. Specifically, echocardiography and cardiovascular risk factor documentation will be performed during the first two weeks after sepsis onset. Aside from routine haematological and biochemical laboratory tests, molecular phenotyping will comprise analyses of the metabolome, lipidome and immune status. The primary endpoint of this study is the difference in 3-month mortality of patients with and without septic cardiomyopathy in COVID-19 sepsis. Patients will be followed up until 6 months after onset of sepsis via telephone interviews and questionnaires. The results will be compared with a cohort of patients with influenza sepsis as well as previous cohorts of patients with bacterial sepsis and healthy controls. ETHICS AND DISSEMINATION: Approval was obtained from the Ethics Committee of the Friedrich Schiller University Jena (2020-2052-BO). The results will be published in peer-reviewed journals and presented at appropriate conferences. TRIAL REGISTRATION: DRKS00024162.

Body composition, mitochondrial oxygen metabolism and metabolome of patients with obesity before and after bariatric surgery (COMMITMENT): protocol for a monocentric prospective cohort study.

INTRODUCTION: Obesity, defined as a body mass index ≥30 kg/m2, is one of the most prevalent health conditions worldwide. It is part of the metabolic syndrome, which encompasses arterial hypertension, dyslipoproteinaemia and diabetes. Obesity is viewed as a systemic disease with pathophysiological mechanisms on the molecular level. Dysfunction of the mitochondrion and systemic low-grade inflammation are among the proposed causes for the metabolic changes. In severe cases of obesity, laparoscopic sleeve gastrectomy, a bariatric operation, can achieve the desired weight loss and has been associated with clinical outcome improvement. Hitherto, the influence of patients' body composition on mitochondrial function and concomitant metabolic changes has not been fully understood. This study aims to quantify the patient's body composition before and after laparoscopic sleeve gastrectomy and to correlate these findings with changes in mitochondrial oxygen metabolism, metabolome and immune status. METHODS AND ANALYSIS: In this prospective monocentric cohort study, patients undergoing laparoscopic sleeve gastrectomy (n=30) at Jena University Hospital (Germany) will be assessed before surgery and at four time points during a 1-year follow-up. Body composition will be measured by bioimpedance analysis. Non-invasive assessment of mitochondrial oxygen metabolism using protoporphyrin IX-triplet state lifetime technique (PPIX-TSLT) and blood sampling for, among other, metabolomic and immunological analysis, will be performed. The primary outcome is the difference in relative fat mass between the preoperative time point and 6 months postoperatively. Further outcomes comprise longitudinal changes of PPIX-TSLT and metabolic and immunological variables. Outcomes will be assessed using paired t-tests, Wilcoxon signed-rank tests and regression analyses. ETHICS AND DISSEMINATION: The study was approved by the Ethics Committee of Friedrich Schiller University Jena (2018-1192-BO). Written informed consent will be obtained from all patients prior to enrolment in the study. The results will be published in peer-reviewed journals and presented at appropriate conferences. TRIAL REGISTRATION NUMBER: DRKS00015891.

Infliximab in the treatment of patients with severe COVID-19 (INFLIXCOVID): protocol for a randomised, controlled, multicentre, open-label phase II clinical study.

BACKGROUND: Despite the intense global research endeavour to improve the treatment of patients with COVID-19, the current therapy remains insufficient, resulting in persisting high mortality. Severe cases are characterised by a systemic inflammatory reaction driven by the release of pro-inflammatory cytokines such as IL-6 and tumour-necrosis-factor alpha (TNF-α). TNF-α-blocking therapies have proved beneficial in patients with chronic inflammatory diseases and could therefore pose a new treatment option in COVID-19. Hitherto, no results from randomised controlled trials assessing the effectiveness and safety of infliximab-a monoclonal antibody targeting TNF-α-in the treatment of COVID-19 have been published. METHODS: In this phase-2 clinical trial, patients with COVID-19 and clinical and laboratory signs of hyperinflammation will be randomised to receive either one dose of infliximab (5 mg/kg body weight) in addition to the standard of care or the standard of care alone. The primary endpoint is the difference in 28-day mortality. Further assessments concern the safety of infliximab therapy in COVID-19 and the influence of infliximab on morbidity and the course of the disease. For the supplementary scientific programme, blood and urine samples are collected to assess concomitant molecular changes. The Ethics Committee of the Friedrich Schiller University Jena (2021-2236-AMG-ff) and the Paul-Ehrlich-Institute (4513/01) approved the study. DISCUSSION: The results of this study could influence the therapy of patients with COVID-19 and affect the course of the disease worldwide, as infliximab is globally available and approved by several international drug agencies. TRIAL REGISTRATION: The trial was registered at clinicaltrials.gov ( NCT04922827 , 11 June 2021) and at EudraCT ( 2021-002098-25 , 19 May 2021).

The Right Hemisphere Is Responsible for the Greatest Differences in Human Brain Response to High-Arousing Emotional versus Neutral Stimuli: A MEG Study.

Studies investigating human brain response to emotional stimuli-particularly high-arousing versus neutral stimuli-have obtained inconsistent results. The present study was the first to combine magnetoencephalography (MEG) with the bootstrapping method to examine the whole brain and identify the cortical regions involved in this differential response. Seventeen healthy participants (11 females, aged 19 to 33 years; mean age, 26.9 years) were presented with high-arousing emotional (pleasant and unpleasant) and neutral pictures, and their brain responses were measured using MEG. When random resampling bootstrapping was performed for each participant, the greatest differences between high-arousing emotional and neutral stimuli during M300 (270-320 ms) were found to occur in the right temporo-parietal region. This finding was observed in response to both pleasant and unpleasant stimuli. The results, which may be more robust than previous studies because of bootstrapping and examination of the whole brain, reinforce the essential role of the right hemisphere in emotion processing.