Shank2 identifies a subset of glycinergic neurons involved in altered nociception in an autism model.

BACKGROUND: Autism Spectrum Disorders (ASD) patients experience disturbed nociception in the form of either hyposensitivity to pain or allodynia. A substantial amount of processing of somatosensory and nociceptive stimulus takes place in the dorsal spinal cord. However, many of these circuits are not very well understood in the context of nociceptive processing in ASD. METHODS: We have used a Shank2-/- mouse model, which displays a set of phenotypes reminiscent of ASD, and performed behavioural and microscopic analysis to investigate the role of dorsal horn circuitry in nociceptive processing of ASD. RESULTS: We determined that Shank2-/- mice display increased sensitivity to formalin pain and thermal preference, but a sensory specific mechanical allodynia. We demonstrate that high levels of Shank2 expression identifies a subpopulation of neurons in murine and human dorsal spinal cord, composed mainly by glycinergic interneurons and that loss of Shank2 causes the decrease in NMDAR in excitatory synapses on these inhibitory interneurons. In fact, in the subacute phase of the formalin test, glycinergic interneurons are strongly activated in wild type (WT) mice but not in Shank2-/- mice. Consequently, nociception projection neurons in laminae I are activated in larger numbers in Shank2-/- mice. LIMITATIONS: Our investigation is limited to male mice, in agreement with the higher representation of ASD in males; therefore, caution should be applied to extrapolate the findings to females. Furthermore, ASD is characterized by extensive genetic diversity and therefore the findings related to Shank2 mutant mice may not necessarily apply to patients with different gene mutations. Since nociceptive phenotypes in ASD range between hyper- and hypo-sensitivity, diverse mutations may affect the circuit in opposite ways. CONCLUSION: Our findings prove that Shank2 expression identifies a new subset of inhibitory interneurons involved in reducing the transmission of nociceptive stimuli and whose unchecked activation is associated with pain hypersensitivity. We provide evidence that dysfunction in spinal cord pain processing may contribute to the nociceptive phenotypes in ASD.

Individualized flow-controlled versus conventional pressure-controlled ventilation in on-pump heart surgery (FLOWVENTIN HEARTSURG): study protocol for a randomized controlled trial.

BACKGROUND: In on-pump cardiac surgery, lungs are at high risk of periprocedural organ impairment because of atelectasis formation, ventilator-induced lung injury, and hyperinflammation due to the cardiopulmonary bypass which results in postoperative pulmonary complications in half of this patient population. The new ventilation mode flow-controlled ventilation (FCV) uniquely allows full control of ins- and expiratory airway flows. This approach reduces the mechanical power of invasive ventilation as a possible cause of ventilator-induced lung injury. The scope of FLOWVENTIN HEARTSURG is to compare perioperative individualized FCV with best clinical practice pressure-controlled ventilation (PVC) modes in patients with elective on-pump cardiac surgery procedures. We hypothesize that the postoperative inflammatory response can be reduced by the perioperative application of FCV compared to PCV. METHODS: FLOWVENTIN HEARTSURG is a single-center, randomized, parallel-group trial with two intervention arms: perioperative PCV modes (n = 70, PCV group) with an individualized positive end-expiratory pressure (PEEP) and a tidal volume of 6-8 ml/kg predicted bodyweight compared to perioperative FCV (n = 70, FCV group) with an individualized PEEP and driving pressure, resulting in a liberal tidal volume. As the primary study endpoint interleukin 8 plasma level is assessed 6 h after cardiopulmonary bypass as a surrogate biomarker of systemic and pulmonary inflammation. As secondary aims clinically relevant patient outcomes are analyzed, e.g., perioperative lung function regarding oxygenation indices, postoperative pulmonary and extra-pulmonary complications, SIRS-free days as well as ICU and total inpatient stays. As additional sub-studies with an exploratory approach perioperative right ventricular function parameters are assessed by echocardiography and perioperative lung aeration by electrical impedance tomography. DISCUSSION: Current paradigms regarding protective low tidal volume ventilation are consciously left in the FCV intervention group in order to reduce mechanical power as a determinant of ventilator-induced lung injury in this high-risk patient population and procedures. This approach will be compared in a randomized controlled trial with current best clinical practice PCV in FLOWVENTIN HEARTSURG. TRIAL REGISTRATION: German Clinical Trials Register DRKS00018956 . Registered on 12 June 2020 (Version 1), last update on 22 August 2022 (Version 4).

Phenotype- and species-specific skin proteomic signatures for incision-induced pain in humans and mice.

BACKGROUND: Acute pain after surgery is common and often leads to chronic post-surgical pain, but neither treatment nor prevention is currently sufficient. We hypothesised that specific protein networks (protein-protein interactions) are relevant for pain after surgery in humans and mice. METHODS: Standardised surgical incisions were performed in male human volunteers and male mice. Quantitative and qualitative sensory phenotyping were combined with unbiased quantitative mass spectrometry-based proteomics and protein network theory. The primary outcomes were skin protein signature changes in humans and phenotype-specific protein-protein interaction analysis 24 h after incision. Secondary outcomes were interspecies comparison of protein regulation as well as protein-protein interactions after incision and validation of selected proteins in human skin by immunofluorescence. RESULTS: Skin biopsies in 21 human volunteers revealed 119/1569 regulated proteins 24 h after incision. Protein-protein interaction analysis delineated remarkable differences between subjects with small (low responders, n=12) and large incision-related hyperalgesic areas (high responders, n=7), a phenotype most predictive of developing chronic post-surgical pain. Whereas low responders predominantly showed an anti-inflammatory protein signature, high responders exhibited signatures associated with a distinct proteolytic environment and persistent inflammation. Compared to humans, skin biopsies in mice habored even more regulated proteins (435/1871) 24 h after incision with limited overlap between species as assessed by proteome dynamics and PPI. Immunohistochemistry confirmed the expression of high priority candidates in human skin biopsies. CONCLUSIONS: Proteome profiling of human skin after incision revealed protein-protein interactions correlated with pain and hyperalgesia, which may be of potential significance for preventing chronic post-surgical pain. Importantly, protein-protein interactions were differentially modulated in mice compared to humans opening new avenues for successful translational research.

Conditioned pain modulation and offset analgesia: Influence of sex, sex hormone levels and menstrual cycle on the magnitude and retest reliability in healthy participants.

BACKGROUND: Conditioned pain modulation (CPM) and offset analgesia quantify impairment of endogenous pain modulation, but magnitude and reliability vary broadly between studies, indicating influencing factors that are not currently controlled for. The aim of this study was to quantify magnitude and retest reliability of CPM and offset analgesia in healthy participants, while investigating the influence of sex and sex hormone levels. METHODS: Sixty-two participants (30 female) completed the study. We tested CPM (heat-cold paradigm) and offset analgesia on 6 days within two menstrual cycles (tests were performed in each phase of two subsequent menstrual cycles, with similar time points for men). RESULTS: Median offset effect was -29.4% in female and - 22.5% in male participants (as change from initial stimulus). Median early CPM effects were - 16.7% for women versus -13.3% for men. Reliability (intra-class correlation coefficient [ICC]) was similar between the main measures, offset effect (female: 0.48, male: 0.47) and early CPM effect (female: 0.49, male: 0.43). There was significant variance between individual experimental parameters within protocols but not between sexes or menstrual phases. While oestradiol and progesterone did not correlate with the magnitude of effect within sexes, we found that testosterone levels explained an estimated 5%-10% of variance within individual responses in all sexes. CONCLUSIONS: Our results show that the reliability of both CPM effect and offset analgesia was independent of sex and menstrual cycle phase. The magnitude of CPM and offset effects was weakly influenced by sex and testosterone levels, indicating an area for future research, rather than clinical significance. SIGNIFICANCE: This study investigated CPM and offset analgesia in parallel, across sexes and during two menstrual cycles while assessing the impact of sex hormones. Reliability seems to depend on experimental parameters rather than participant characteristics, while the magnitude of effect could be weakly linked to sex hormones and sex.

Efficacy of Auricular Acupuncture and Lavender Oil Aromatherapy in Reducing Preinterventional Anxiety in Cardiovascular Patients: A Randomized Single-Blind Placebo-Controlled Trial.

Introduction: Auricular acupuncture at the "relaxation point" and lavender oil aromatherapy can reduce preoperative anxiety associated with increased mortality and morbidity. Data on the effect of combined auricular acupuncture and lavender oil aromatherapy in patients undergoing cardiovascular interventions with the use of local anesthesia or under conscious sedation are sparse. The authors sought to evaluate the efficacy of auricular acupuncture and lavender oil aromatherapy in reducing preinterventional anxiety in cardiovascular patients. Materials and Methods: Data of 80 consecutive patients undergoing diagnostic coronary angiography (n = 56) with or without percutaneous coronary intervention (n = 9) and right heart catheterization (n = 6), transcatheter aortic valve replacement (n = 17) and percutaneous mitral valve repair (MitraClip; n = 2) were analyzed. Patients were prospectively randomized to receive either preinterventional auricular acupuncture and lavender oil (Lavandula angustifolia) aromatherapy (verum group, n = 39) or combined sham auricular acupuncture and placebo oil aromatherapy (placebo group, n = 41). For the verum group bilateral auricular acupuncture was performed at the "relaxation point." State anxiety and blood pressure were assessed before and at 30 min after acupuncture and presternal oil application. State anxiety was defined as primary outcome measure and assessed using the Spielberger State Anxiety Inventory (STAI) for Adults form Y6. Intervention-specific anxiety was assessed by a 10-point numerical rating scale, and perceived treatment success by a single dichotomous question. Clinical blood pressure was further assessed. Results: After the intervention, the verum group had significantly decreased anxiety on the STAI compared with the placebo group (Δ = -4.18; 95% confidence interval = -8.31 to -0.05; p = 0.047). Significantly more patients reported subjective treatment success in the verum group (87.2%) than in the placebo group (65.9%, p = 0.035). No significant differences were observed regarding intervention-specific anxiety and blood pressure between the two groups. No serious adverse events occurred in any group. Conclusions: Combined auricular acupuncture and lavender oil aromatherapy can decrease preinterventional anxiety in cardiovascular patients and requires further investigation. German Clinical Trials Register (registration no. DRKS00023686).

Perioperative ketamine for postoperative pain management in patients with preoperative opioid intake: A systematic review and meta-analysis.

STUDY OBJECTIVE: Postoperative pain management in opioid users remains challenging. The perioperative administration of ketamine might lead to favourable pain outcomes in these patients. STUDY DESIGN: A systematic review of randomised controlled trials (RCT) with meta-analysis and assessment of the quality of evidence by GRADE was performed. SETTING: Perioperative pain treatment. PATIENTS: Adult opioid users undergoing surgery. INTERVENTIONS: Perioperative administration of ketamine. MEASUREMENTS: Primary outcomes were postoperative acute pain at rest/during movement after 24 h and number of patients with ketamine-related adverse events. MAIN RESULTS: Nine RCTs (802 patients with at least two weeks opioid-intake) were included. There is low-quality evidence that ketamine may slightly reduce postoperative pain during movement after 24 h (mean difference: -0.79; 95% confidence interval (CI): -1.22 to -0.36). Based on a very low-quality of evidence, we are uncertain on any effect of ketamine on pain at rest after 24 h and incidences of adverse events like hallucinations and confusion within 48 h. However, perioperative ketamine reduced cumulative mean opioid consumption by 97.3 mg (95%CI: -164.8 to -29.7) after 24 h and 186.4 mg (95%CI: -347.6 to -25.2) after 48 h. The relative risks (RR) for opioid-related adverse events were significantly different for sedation within 24 h (RR: 0.54; 95%CI 0.37 to 0.78). CONCLUSIONS: There is currently limited evidence for a reduced postoperative pain intensity using perioperative ketamine in preoperative opioid-consuming patients. However, a clinically relevant opioid-sparing effect was evident associated with a reduced risk for postoperative sedation and without increased harm. Therefore, ketamine might be a useful anti-hyperalgesic adjuvant in these patients. Nevertheless, with clinical heterogeneity being considerable, it's too premature to suggest any specific ketamine protocol. Furthermore, many questions (like ideal dosing, treatment duration and more favourable patient-related outcome measures including long-term effects) remain open and need to be addressed in future studies. PROTOCOL REGISTRATION: Prospero CRD42020185497.

Chronic Pain Following Fracture-Related Surgery: Posttraumatic Rather Than Postsurgical Origin Promotes Chronification-A Prospective Observational Study With 1-Year Follow-up.

BACKGROUND: Chronic posttraumatic/postsurgical pain (CPSP) is common after traumatic or surgical damage. Exposure to both trauma and surgery, with the potential for repeated bone and nerve damage, may increase the risk of CPSP after fracture-related surgery. But the (long-term) incidences of CPSP and neuropathic CPSP and the ensuing burdens are unknown. Therefore, the patients were prospectively assessed within 1 year, and the patient-specific characteristics were explored. METHODS: Between 2017 and 2018, 127 patients (age: 52.9 ± 17.1 years, male: 55.1%) with traumatic fractures needing osteosynthesis (extremities: 91.3%) were assessed posttrauma (before surgery), postsurgery at days 1 to 5, 6 weeks, 3 and 12 months. The primary outcomes are as follows: incidence at 3 and 12 months of CPSP (defined as pain intensity on a numerical rating scale [NRS: 0-10] ≥3), secondary exploration: neuropathic CPSP (NRS ≥3 and Douleur Neuropathique 4 interview [DN4i] score ≥3 [Douleur Neuropathique interview: 0-7]); burden: quality of life (QoL, the EuroQOL five dimensions questionnaire [EQ-5D-3L] descriptive system); and inter alia, the number of analgesics (trial registration: DRKS00011601). RESULTS: The incidence of CPSP was 57.1% (52/91, n/N) at 3 and 42.7% (35/82) at 12 months postsurgery, including neuropathic CPSP 7.7% (4/52) and 17.1% (6/35), respectively. Descriptively, posttraumatic higher pain intensity at rest (difference of 0.9 ± 1.8 NRS) and the need for more frequent analgesics (by 34.3%) were associated with CPSP a year after surgery compared to those without. As soon as week 6, these patients had developed descriptively a 15% more impaired QoL, with 25% more impairment after 1 year. The patients with CPSP presented with at least 1 neuropathic symptom 12 months later in 68.6% (24/35) of cases, mainly with an early posttraumatic occurrence (without fulfilling the definition of neuropathic CPSP). CONCLUSIONS: After early fracture-related surgery, high incidences of CPSP (43%) were prospectively observed 1 year postsurgery, up to approximately 1 in 5 patients who had neuropathic CPSP. At the same time, CPSP was accompanied with an impacted QoL and analgesic dependence, both indicating clinical relevance. Moreover, the high incidence and the early posttraumatic occurrence of more intense pain suggest that the initial fracture-related trauma, rather than the surgical trauma, may predominantly trigger CPSP at Y1 (1 year). Therefore, these exploratory results set the direction of required future research. A future clinical hypothesis might be: treat first what hurts first.

Isoflurane not at the expense of postoperative nausea and vomiting in cardiac anesthesia - an observational study.

OBJECTIVES: Inhalative anesthesia is of common use, but is generally known to potentiate postoperative nausea and vomiting (PONV). With an internal change of anesthesia regimen from total intravenous anesthesia (TIVA) to isoflurane (in terms of myocardial protection) in cardiac anesthesia a higher incidence of PONV was to be expected. Therefore, we evaluated the incidence of PONV after the simultaneous implementation of PONV prophylaxis. METHODS: The incidence of PONV, prospectively assessed in 197 cardiac surgery patients (68 y ± 10.4, 66.5% male) having isoflurane plus dual PONV prophylaxis with dexamethasone and droperidol, was compared with previous data of 190 controls (67 y ± 9.6, 71% male) having TIVA without and with single or dual PONV prophylaxis (n = 64 dexamethasone and droperidol, n = 25 dexamethasone, n = 101 only TIVA), and the Apfel-scoring (0-4 depending on PONV-risk). DRKS00014275. Statistics: Chi2-test, p < .05 (Bonferroni). RESULTS: The incidence of PONV under isoflurane with antiemetic prophylaxis was 20.8% (95% confidence interval (CI) 15.4; 27.4) compared to 30.5% (95%CI 24; 37.6) under TIVA (p = .029; dexamethasone and droperidol 23.4% (95%CI 13.8; 35.7); dexamethasone 32% (95%CI 14.9; 53.5); only TIVA 34.7% (95%CI 25.5; 44.8)), but was not lower in high-risk patients than predicted according to Apfel-scoring 4 (71.4 vs. 78%). CONCLUSION: In cardiac anesthesia, the use of isoflurane is not at the expense of PONV when using a risk-independent two-drug-prophylaxis. It is even beneficial resulting surprisingly in a lower incidence of PONV than under TIVA unless with and without prophylaxis. Patients with the highest risk for PONV and receiving isoflurane should receive a third antiemetic prophylactic drug.

Efficacy and adverse events of selective serotonin noradrenaline reuptake inhibitors in the management of postoperative pain: A systematic review and meta-analysis.

STUDY OBJECTIVE: Selective-serotonin-noradrenaline-reuptake inhibitors (SSNRI) might be an interesting option for postoperative pain treatment. Objective was to investigate postoperative pain outcomes of perioperative SSNRI compared to placebo or other additives in adults undergoing surgery. DESIGN: Systematic review of randomised controlled trials (RCT) with meta-analysis and GRADE assessment. SETTING: Acute and chronic postoperative pain treatment. PATIENTS: Adult patients undergoing surgery. INTERVENTIONS: Perioperative administration of SSNRI. MEASUREMENTS: Primary outcomes were postoperative acute pain at rest/during movement (measured on a scale from 0 to 10), number of patients with chronic postsurgical pain (CPSP) and with SSNRI-related adverse events. MAIN RESULTS: Fourteen RCTs (908 patients) were included. We have high-quality evidence that duloxetine has no effect on pain at rest at 2 h (MD: -0.02; 95% confidence interval (CI) -0.51 to 0.47), but probably reduces it at 48 h (MD: -1.16; 95%CI -1.78 to -0.54). There is low- and moderate-quality evidence that duloxetine has no effects on pain during movement at 2 h (MD: -0.42; 95%CI -1.53 to 0.69) and 48 h (MD: -0.91; 95% CI -2.08 to 0.26), respectively. We have very low-quality evidence that duloxetine might reduce pain at rest (MD: -0.45; 95%CI -0.74 to -0.15) and movement (MD: -1.19; 95%CI -2.32 to -0.06) after 24 h. We have low-quality evidence that duloxetine may reduce the risk of CPSP at 6 months (RR:0.35; 95%CI 0.14 to 0.90). There is moderate-quality evidence that duloxetine increases the risk of dizziness (RR:1.72; 95%CI 1.26 to 2.34). CONCLUSION: At the expense of a higher risk for dizziness, SSNRI may be effective in reducing postoperative pain between 24 and 48 h after surgery. However, the results of the meta-analyses are mostly imprecise and duloxetine might only be used in individual cases. Protocol registration: CRD42018094699.

Place of Death Trends and Utilization of Outpatient Palliative Care at the End of Life­Analysis of Death Certificates (2001, 2011, 2017) and Pseudonymized Data From Selected Palliative Medicine Consultation Services (2017) in Westphalia, Germany.

BACKGROUND: The largest German study on place of death was performed for deaths in selected regions of Westphalia in the years 2001 and 2011. In the period thereafter, provision of palliative care was regionally expanded. This upgrade included the establishment of palliative medicine consultation services (PMCS), combining general and specialized palliative care on an outpatient basis. A follow-up place of death survey took place in 2017. The aim was to depict the trends in place of death between 2001 and 2017. A second goal was to determine how often outpatient PMCS were used by persons who died in 2017. METHODS: Descriptive analysis of place of death as specified in all death certificates (2001, 2011, 2017) issued in the cities of Bochum and Münster and the districts of Borken and Coesfeld. Comparison of pseudonymized data on deceased patients (2017) treated by the PMCS of Münster and Coesfeld with the place of death database to ascertain the rate of PMCS care at the end of life. RESULTS: A total of 38 954 death certificates were analyzed, and 5887 deaths were compared with PCMS data. The distribution of place of death was as follows: (2001, 2011, 2017; age standardized; %): own residence 27.8; 23.3; 21.3; hospital: 55.8; 51.8; 51.8; palliative care unit: 0.0; 1.0; 6.2; hospice: 1.9; 4.5; 4.8; nursing home: 13.1; 18.6; 20.4; other: 1.2; 1.2; 1.5. The rate of PMCS use was 28.8% (1694/5887). CONCLUSION: Over the period 2001-2017, the proportion of people who died at home or in the hospital went down, while the number who died in a palliative care unit, hospice, or nursing home increased. In the city of Münster and the district of Coesfeld, one fourth of the people who died in 2017 received PMCS care at the end of life.

Prevalence of therapeutic and diagnostic procedures in the last 14 days of life in hospital patients: a single-center observational study from Germany.

BACKGROUND: The opportunities available for maintaining and prolonging life in modern medicine give rise to medical-ethical dilemmas in patients at the end of life, raising the question of whether intensified treatment and diagnosis is appropriate in these patients. This affects hospital patients in particular. METHODS: This single-center cross-sectional study from Germany analyzed hospital records of all deceased patients of a university hospital who died between October 2016 and September 2017. The prevalence of therapeutic and diagnostic procedures during the last 14 days before death was determined. In-hospital transfer practices shortly before patients' deaths were also examined. RESULTS: A total of 468 hospital patients died. The mean age at death was 76.3±13.7 years; 47.0% [220] were female; 12.0% [56] died on the day of hospital admission, 41.9% [196] 1 to 6 days and 46.1% [216] more than 6 days later; the case mix index (CMI) was 4.6. The majority of patients {57.1% [267]} died on intensive care unit (ICU). Therapeutic and diagnostic procedures within the last 14 days before death: 30.3% [142] resuscitation, 28.6% [134] surgery, 10.9% [51] extracorporeal membrane oxygenation (ECMO), 23.7% [111] renal replacement therapy, 4.3% [20] tracheostomy, 2.8% [13] PTCA/cardiac stenting, 1.9% [9] chemotherapy, 29.3% [137] transfusion of packed red blood cells, 13.7% [64] transfusion of prothrombin complex concentrate, 5.3% [25] cardiac catheter examination, 7.5% [35] upper gastrointestinal endoscopy, 79.1% [370] chest X-ray, 41.9% [196] computed tomography. In-hospital transfer from ICU to PCU before patients' death: 1.5% (4/274 ICU patients). CONCLUSIONS: Intensified therapeutic and diagnostic procedures are often performed at the end of life in hospital patients. Closer interdisciplinary cooperation between intensive care and palliative care would be beneficial to improve in-patient care for these patients.

Assessing outcome in postoperative pain trials: are we missing the point? A systematic review of pain-related outcome domains reported in studies early after total knee arthroplasty.

ABSTRACT: The management of acute postoperative pain remains suboptimal. Systematic reviews and Cochrane analysis can assist with collating evidence about treatment efficacy, but the results are limited in part by heterogeneity of endpoints in clinical trials. In addition, the chosen endpoints may not be entirely clinically relevant. To investigate the endpoints assessed in perioperative pain trials, we performed a systematic literature review on outcome domains assessing effectiveness of acute pain interventions in trials after total knee arthroplasty. We followed the Cochrane recommendations for systematic reviews, searching PubMed, Cochrane, and Embase, resulting in the screening of 1590 potentially eligible studies. After final inclusion of 295 studies, we identified 11 outcome domains and 45 subdomains/descriptors with the domain "pain"/"pain intensity" most commonly assessed (98.3%), followed by "analgesic consumption" (88.8%) and "side effects" (75.3%). By contrast, "physical function" (53.5%), "satisfaction" (28.8%), and "psychological function" (11.9%) were given much less consideration. The combinations of outcome domains were inhomogeneous throughout the studies, regardless of the type of pain management investigated. In conclusion, we found that there was high variability in outcome domains and inhomogeneous combinations, as well as inconsistent subdomain descriptions and utilization in trials comparing for effectiveness of pain interventions after total knee arthroplasty. This points towards the need for harmonizing outcome domains, eg, by consenting on a core outcome set of domains which are relevant for both stakeholders and patients. Such a core outcome set should include at least 3 domains from 3 different health core areas such as pain intensity, physical function, and one psychological domain.

Incidence, Time Course and Influence on Quality of Life of Intensive Care Unit-Acquired Weakness Symptoms in Long-Term Intensive Care Survivors.

PURPOSE: Intensive care unit-acquired weakness (ICUAW) can manifest as muscle weakness or neuropathy-like symptoms, with diagnosis remaining a challenge. Uncertainties surround the long-term cause and sequelae. Therefore, the purpose was to assess incidence, time course and long-term influence on quality of life (QoL) of symptoms in ICU survivors. METHODS: After ethical approval and registration (www.drks.de: DRKS00011593), in a single-center cohort study all patients admitted to the ICU in 2007-2017 in a German university hospital were screened. Out of 1,860 patients (≥7d ICU care including ventilation support for ≥72 h, at least 6mo-10y after ICU) 636 were deceased, 912 survivors were contacted. RESULTS: 149 former patients (age: 63.5 ± 13.1y; males: 73%; duration in ICU: 20.8 ± 15.7d; duration of ventilation: 16.5 ± 13.7 h; time post-ICU: 4.4 ± 2.7y, 5-10y: 43%) consented to be interviewed concerning occurrence, duration, recovery and consequences of ICUAW-associated muscle weakness or neuropathy-like symptoms after ICU. In 75% at least 1 persistent or previous symmetrical symptom was reported (myopathy-like muscle weakness: 43%; neuropathy-like symptoms: 13%; both: 44%) and rated as incidence of ICUAW. However, only 18% of participants had received an ICUAW diagnosis by their physicians, although 62% had persistent symptoms up to 10y after ICU (5-10y: 46%). Only 37% of participants reported a complete recovery of symptoms, significantly associated with an initially low number of symptoms after ICU (p < 0.0001), myopathy-like symptoms (p = 0.024), and younger age at the time of ICU admission (55.7 ± 13.1 vs. 62.6 ± 10.6y, p < 0.001). ICUAW still impaired the QoL at the time of the interview in 74% of affected survivors, with 30% reporting severe impairment. CONCLUSION: ICUAW symptoms were disturbingly common in the majority of long-term survivors, indicating that symptoms persist up to 10y and frequently impair QoL. However, only a small number of patients had been diagnosed with ICUAW. Trial registry: Deutsches Register Klinischer Studien (DRKS), https://www.drks.de/drks_web/navigate.do?navigationId=trial.HTML&TRIAL_ID=DRKS00011593, registration number: DRKS00011593.

Hemoadsorption: effective in reducing circulating fragments of the endothelial glycocalyx during cardiopulmonary bypass in patients undergoing on-pump cardiac surgery?

BACKGROUND: The vascular endothelial glycocalyx is susceptible to ischemia and hypoxia. Released soluble components of the endothelial glycocalyx (EG) have been identified as potential damage associated molecular patterns (DAMPs) able to enhance an ongoing inflammatory response. Shedding of the EG has been associated with released atrial-natriuretic peptide (ANP) during cardiac surgery procedures. A novel hemoadsorption technique (CytoSorb®) has been shown to effectively remove molecules up to 55 kDa unspecifically from circulation. It is not known whether ANP or glycocalyx components can be removed successfully by this technique. METHODS: In 15 patients undergoing on-pump cardiac surgery, the hemoadsorption device was integrated in the cardiopulmonary bypass (CPB) circuit. Pre- and post-adsorber concentrations of ANP, heparan sulphate (HEP), syndecan-1 (SYN) and hyaluronan (HYA) were measured at 10 (T1), 30 (T2), and 60 (T3) minutes after aortic cross-clamping and complete CPB. RESULTS: Hemoadsorption significantly reduced mean HEP concentrations (-157.5 [333.4] ng/mL; P<0.001) post adsorber. For ANP and SYN no statistically significant changes were detected whereas mean [SD] HYA concentrations even increased significantly (+21.6 [43.0] ng/mL; P<0.001) post adsorber. CONCLUSIONS: In this study representing a real-life scenario, we could demonstrate that the novel hemoadsorption device (CytoSorb®) was able to effectively adsorb HEP from the circulation if integrated in a CPB circuit. However, blood concentrations of HYA, SYN, and ANP could not be reduced during CPB in our investigation.

Pectoral nerve blocks for breast surgery: A meta-analysis.

BACKGROUND: Pectoral nerve blocks (PECS block) might be an interesting new regional anaesthetic technique in patients undergoing breast surgery. OBJECTIVE: The aim of this meta-analysis was to investigate postoperative pain outcomes and adverse events of a PECS block compared with no treatment, sham treatment or other regional anaesthetic techniques in women undergoing breast surgery. DESIGN: We performed a systematic review of randomised controlled trials (RCT) with meta-analysis and risk of bias assessment. DATA SOURCES: The databases MEDLINE, CENTRAL (until December 2019) and clinicaltrials.gov were systematically searched. ELIGIBILITY CRITERIA: All RCTs investigating the efficacy and adverse events of PECS compared with sham treatment, no treatment or other regional anaesthetic techniques in women undergoing breast surgery with general anaesthesia were included. RESULTS: A total of 24 RCTs (1565 patients) were included. PECS (compared with no treatment) block might reduce pain at rest [mean difference -1.14, 95% confidence interval (CI), -2.1 to -0.18, moderate quality evidence] but we are uncertain regarding the effect on pain during movement at 24 h after surgery (mean difference -1.79, 95% CI, -3.5 to -0.08, very low-quality evidence). We are also uncertain about the effect of PECS block on pain at rest at 24 h compared with sham block (mean difference -0.83, 95% CI, -1.80 to 0.14) or compared with paravertebral block (PVB) (mean difference -0.18, 95% CI, -1.0 to 0.65), both with very low-quality evidence. PECS block may have no effect on pain on movement at 24 h after surgery compared with PVB block (mean difference -0.56, 95% CI, -1.53 to 0.41, low-quality evidence). Block-related complications were generally poorly reported. CONCLUSION: There is moderate quality evidence that PECS block compared with no treatment reduces postoperative pain intensity at rest. The observed results were less pronounced if patients received a sham block. Furthermore, PECS blocks might be equally effective as PVBs. Due to mostly low-quality or very low-quality evidence level, further research is warranted. PROTOCOL REGISTRATION: CRD42019126733.

Prevalence of resuscitation in cancer patients at the end of life-a population-based observational study from Germany.

BACKGROUND: Cardiopulmonary resuscitation (CPR) is a medical emergency intervention aimed at ending a life-threatening cardiovascular arrest as quickly as possible. However, the medical ethics of starting CPR in patients who have incurable and terminal disease is a matter of controversy. This ethical dilemma affects cancer patients in particular, as they are often suffering from advanced disease in a palliative situation. Few data are as yet available concerning the prevalence of CPR in patients with terminal cancer. METHODS: A population-based cross-sectional study was carried out on the basis of death certificates of two large cities in Germany evaluated for 2017. Medical data on resuscitation and cause of death were analyzed. Cancer patients with or without a palliative situation were identified, and the prevalence of resuscitation in these patients was determined. In addition, factors influencing resuscitation were calculated using binary multivariate regression. RESULTS: A total of 8,496 persons died, 32.1% of whom [2,723] were cancer patients. A palliative situation was present in 80.9% of the cancer patients [2,202]. A total of 163 cancer patients and 1,006 individuals without cancer were resuscitated at the end of life, representing prevalences of 6.0% (95% CI, 5.1-6.9%) and 17.4% (95% CI, 16.4-18.4%), respectively. Cancer patients with a palliative disease status received CPR in 3.4% of cases (95% CI, 2.6-4.2%). More than half of the resuscitations were performed in hospital (57.7% of resuscitated persons and 68.7% of cancer patients). Sex, age, presence of a palliative situation, and care provided by a specialized outpatient palliative service were found to be independent influencing factors. CONCLUSIONS: Six in 100 cancer patients, and slightly more than three in 100 cancer patients with a palliative disease status, undergo CPR at the end of their lives. Thus, the indication for resuscitation in advanced cancer patients is handled with care and responsibility in Germany.

Transcutaneous spinal direct current stimulation shows no effect on paired stimulation suppression of the somatosensory cortex.

Transcutaneous spinal direct current stimulation (tsDCS) is a safe and convenient method of neuromodulation. It has been proven to alter sensory processing at cervicomedullary level by amplitude changes of the P30 response of tibial nerve somatosensory evoked potentials (TN SEPs). With knowledge that tsDCS affects cortical circuits, we hypothesized that tsDCS may also affect intracortical excitability of the somatosensory cortex assessed by paired stimulation suppression (PSS). Fourteen healthy men were included in this prospective, single-blinded, placebo-controlled crossover study. Single (SS) and paired stimulation (PS) TN SEPs were recorded over the scalp before, immediately as well as 30 and 60 min after applying 15 min of tsDCS over the twelfth thoracic vertebra. Each volunteer underwent three independent and randomized sessions of either cathodal, anodal or sham stimulation. tsDCS showed no effect on peak-to-peak amplitudes or latencies of cortical P40-N50 response after SS. Furthermore, tsDCS failed to induce significant changes on amplitude ratios of PSS, thus showing no impact on intracortical excitability of the somatosensory cortex in healthy subjects. Further research is required to reveal the different mechanisms and to strengthen clinical use of this promising technique.