Intravenous S-ketamine's analgesic efficacy in third molar surgery. A randomized placebo-controlled double-blind clinical trial.

Background: In most cases, a combination of paracetamol and ibuprofen are the optimal treatment for postoperative pain in third molar surgery. If stronger analgesia is required, opioids are traditionally administered. In day-case, surgery; however, opioids should be avoided. Thus, the anaesthetic agent S-ketamine in analgesic doses might be preferred. Methods: The study was designed as a randomized placebo-controlled double-blind clinical trial. The study enrolled healthy subjects according to the American Society of Anaesthesiologists classification; I or II (ASA), aged 18 to 44 years, with a body weight between 50 and 100 kg. The patients were randomized into three groups where two doses of S-ketamine were compared (high: 0.25 mg/kg or low: 0.125 mg/kg) with placebo (saline). Results: A primary outcome of the study was that VAS at 4 h postoperatively, showed no significant difference between the placebo and high-dose S-ketamine group or in the low-dose group. We found a significant difference between the groups for the first 24 h, with a lower VAS-score in the high-dose S-ketamine group. The time to when 50% had taken their first rescue medication was 12 min later in the high-dose ketamine group. Conclusions: Pre-emptive S-ketamine 0.25 mg/kg gave a global significant reduction of pain by VAS during the first 24 h postoperatively. The time from end of surgery to first rescue medication were longer in the high-dose ketamine group compared to both low-dose ketamine and placebo groups.

Real-world outcomes in spinal cord stimulation: predictors of reported effect and explantation using a comprehensive registry-based approach.

Introduction: Despite advancements in implanted hardware and development of novel stimulation paradigms in Spinal Cord Stimulation (SCS), real world evidence suggests a large variation in patient reported outcomes and a proportion of patients are later explanted due to loss of analgesia. Possible predictors for outcome have been explored in smaller short-term evaluations, but few clinically applicable robust measures for long term outcome have emerged. Methods: We performed a comprehensive retrospective study based on an assembled patient-level aggregated database from multiple local and national registries in Sweden. Variables associated with risk of explantation (due to insufficient analgesia) and analgesic effect was analyzed using a Cox regression analysis and an ordered logit regression model, respectively. Results: We found the accumulated risk of explantation due to loss of analgesia to be 10% and 21% at two and ten years follow up, respectively. The use of 10 kHz spinal cord stimulation (compared with Tonic waveform; p = 0.003), and being 60 years or older (reference 18-40 years; p = 0.003) were associated with an increased risk of explantation.At a mean follow up at 1 year, 48% of patients reported a pain intensity reduction from baseline of at least 30%. Secondary (p = 0.030) and post-secondary (p = 0.001) education (compared with primary education) was associated with an increased probability of successful patient reported outcomes. Conclusion: This study suggests that a higher educational level and being employed are associated with successful treatment outcome in patients with chronic pain treated with SCS in Sweden.

Psychometric Assessment of the Swedish version of the Work Ability Index in Patients with Chronic Pain in Specialized Care.

OBJECTIVE: To evaluate the construct validity and internal consistency of the Work Ability Index (WAI) in patients with chronic pain in secondary and tertiary care. METHODS: Cross-sectional study based on 200 patients with chronic pain (> 3 months), with a final sample of 118 participants, 18-64-years-old. Construct validity was assessed by exploratory factor analysis for the structural validity of the WAI, and by correlating the WAI with EuroQol EQ-5D, Brief Pain Inventory pain severity and interference, Patient Health Questionnaire and Generalized Anxiety Disorder scales. The study also assessed the discriminant validity of the WAI for occupational status, and the validity of the single-item work ability score. Reliability was assessed by internal consistency. RESULTS: A single-factor model of WAI was supported. Internal consistency was good. Moderate correlations were found, except for Brief Pain Inventory pain severity, where the correlation was weak; hence, both convergent and divergent validity of the WAI were supported. The work ability score correlated strongly with the total WAI, and the discriminant validity for both was good. CONCLUSION: In patients with chronic pain in specialized care, the WAI and the work ability score displayed acceptable construct validity and internal consistency, supporting their use in a clinical context and research.

Impact of spinal cord stimulation on sick leave and disability pension in patients with chronic neuropathic pain: a real-world evidence study in Sweden.

ABSTRACT: Current research indicates that spinal cord stimulation (SCS) has a positive short-term impact on outcomes, such as quality of life, pain, and productivity in patients with chronic neuropathic pain. However, there is a need for studies on larger population samples. This study used data from Swedish national registers to analyze change and predictors of sick leave and disability pension 2 years before and after SCS treatment. Patients with SCS implanted between 2006 and 2017, and a reference group consisting of 5 individuals matched to each SCS patient without replacement with respect to age, sex, and region of residence, were included. A difference-in-difference approach was used to compare the average change (2 years after treatment vs 2 years before treatment) in net disability days and indirect cost related to disability days for the SCS group, compared with the average change for the reference group. The results showed that SCS treatment in Sweden is associated with a decrease of 21 disability days and consequent decrease in indirect cost of €4127 in working age patients. Large work loss prior to index date was also demonstrated (average 214 days before 1 year), indicating a significant burden on the patient, employers, and the society at large. The number of disability days varied considerably depending on age, sex, socioeconomic variables, and comorbidities; however, the effect of SCS seemed to have little association with patient characteristics. This economic benefit needs to be considered, as well as the clinical outcome, when evaluating the full societal value of SCS.

U-PAIN cohort study among patients with chronic pain in specialised pain care: a feasibility study.

OBJECTIVES: To examine acceptability of study participation and feasibility of (1) recruitment, (2) data collection and (3) outcome measures for the prospective U-PAIN cohort. DESIGN: Internal feasibility study of a prospective cohort. PARTICIPANTS AND SETTING: 64 patients, >18 years, with chronic pain at a multidisciplinary pain centre at a university hospital in Sweden. OUTCOME MEASURES: Acceptability of study participation was measured with a study-specific 10-item Likert scale. A score <3 was considered feasible, for the two items that assessed respondent burden a higher score indicated lesser participant burden and a score >3 was feasible. Recruitment was assessed by participation rates at baseline and retention at the 1-year follow-up, with threshold values for feasibility at 75% and 80%, respectively. Data collection and outcome measures were examined by completions rates of study procedures (90% was considered feasible), sample scores, internal consistency (α>0.70 was considered feasible), and agreement between self-reported data and data retrieved from medical records on opioid use (ICC or κ>0.60 was considered feasible). RESULTS: Acceptability for study procedures was feasible, but participation rates were low: 25%. The retention rate at 1-year follow-up was 81% for those included in the feasibility study, that is, filling out computerised patient-reported outcome measures, and 65% for those using paper and pencil format. The completion rates for the different data collection methods ranged from 83% to 95%. Agreement between self-reported opioid use and prescribed dose and between opioid use disorder according to Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5), and clinical International Classification of Diseases-10 (ICD-10) diagnoses for opioid dependence were almost perfect (κ=0.91 and κ=0.90, respectively). CONCLUSIONS: This feasibility study has helped to explore and improve methods for recruitment, data collection and use of outcome measures for the U-PAIN cohort. Low participation rate and high refusal rate at baseline is a challenge that needs to be further addressed.

Swedish Chronic Pain Biobank: protocol for a multicentre registry and biomarker project.

INTRODUCTION: About 20% of the adult population have chronic pain, often associated with psychological distress, sick leave and poor health. There are large variations in the clinical picture. A biopsychosocial approach is used in investigation and treatment. The concept of personalised medicine, that is, optimising medication types and dosages for individual patients based on biomarkers and other patient-related factors, has received increasing attention in different diseases but used less in chronic pain. This cooperative project from all Swedish University Hospitals will investigate whether there are changes in inflammation and metabolism patterns in saliva and blood in chronic pain patients and whether the changes correlate with clinical characteristics and rehabilitation outcomes. METHODS AND ANALYSIS: Patients at multidisciplinary pain centres at University Hospitals in Sweden who have chosen to participate in the Swedish Quality Registry for Pain Rehabilitation and healthy sex-matched and age-matched individuals will be included in the study. Saliva and blood samples will be collected in addition to questionnaire data obtained from the register. From the samples, proteins, lipids, metabolites and micro-RNA will be analysed in relation to, for example, diagnosis, pain characteristics, psychological distress, body weight, pharmacological treatment and clinical rehabilitation results using advanced multivariate data analysis and bioinformatics. ETHICS AND DISSEMINATION: The study is approved by the Swedish Ethical Review Authority (Dnr 2021-04929) and will be conducted in accordance with the declaration of Helsinki.The results will be published in open access scientific journals and in popular scientific relevant journals such as those from patient organisations. Data will be also presented in scientific meetings, meeting with healthcare organisations and disseminated in different lecturers at the clinics and universities.

Behavioral Medicine Physiotherapy in the Context of Return to Work for Chronic Pain: A Single-Case Experimental Design Study.

Effective interventions are needed for return-to-work (RTW) for individuals with chronic pain on long-term sick leave. In this study, a behavioral medicine physiotherapy protocol was systematically replicated and added to workplace components. The intervention was evaluated for fidelity and effects on target activities and work ability. A single-case experimental design was used with five participants. Daily and weekly ratings of personalized target activities at work as well as work ability were carried out throughout the study period of 26-28 weeks. Effects of the behavioral medicine physiotherapy intervention were evaluated for each individual using visual analysis of displayed graphs and quantitative non-overlap methods. Goal achievement for target activities was reviewed. Three participants completed the intervention. The results indicated an effect from the behavioral medicine physiotherapy intervention on task-specific self-efficacy for target activities, but no consistent effect on experience of target activities or work ability. All three participants had increased function in target activities in line with pre-defined goals. Fidelity to the intervention manual was good. Behavioral medicine physiotherapy can be successfully adapted to work disability and was here replicated in an RTW context for individuals with chronic pain. The intervention protocol should be further evaluated in large-scale studies.

Prolonged time of after-sensation after experimental pain stimuli despite efficient conditioned pain modulation in patients with chronic neuropathic pain after traumatic nerve injuries in upper extremity.

BACKGROUND: As yet, there is limited research that can identify factors that differentiate between painful and nonpainful neuropathies after traumatic nerve injury. The aim of this study was to compare subjects with pain and without pain, all after operative nerve repair in the upper extremities. METHODS: Subjects in both groups (pain, n = 69; painless, n = 62) underwent clinical assessment of sensory nerve function and psychophysical tests: quantitative sensory testing and conditioned pain modulation (CPM). Conditioned pain modulation was assessed by pain ratings to 120 seconds pressure stimuli administered before and after a 60 seconds noxious 4°C cold conditioning stimulus (CS). Time of recovery (time off) of pain intensity from peak VASmaxc after CS was recorded. Questionnaires about the quality of life (RAND-36) and disability of the extremity (QuickDash) were completed. RESULTS: There were no significant differences between groups for CPM (P = 0.19). Time off was 42 seconds in subjects with pain in comparison with 28 seconds in those without pain (P < 0.0001). Compared with individuals reporting no pain, participants with neuropathic pain after nerve injuries had 1.8 times the odds of recovering later after CS, gain of function findings at sensory examination (P < 0.0001), lower scores of the physical component of RAND-36 (P < 0.0001), and increase arm disability (P < 0.0001). Hyperesthesia to cold pain stimulation (P = 0.03) and lowered pain pressure threshold (P = 0.01) were found in the pain group. CONCLUSION: Recovery after the pain induced by cold CS indicates changes in central processing of pain and provides a potential measurement of endogenous pain modulation in individuals with chronic neuropathic pain.

Chronic neuropathic pain after traumatic peripheral nerve injuries in the upper extremity: prevalence, demographic and surgical determinants, impact on health and on pain medication.

Background and aims Aside from the long term side effects of a nerve injury in the upper extremity with devastating consequences there is often the problem of chronic neuropathic pain. The studies concerning the prevalence of persistent pain of neuropathic origin after peripheral nerve injuries are sparse. The prevalence and risk factors associated with chronic neuropathic pain after nerve injuries in the upper extremity were assessed. Methods A standardized data collection template was employed prospectively and retrospectively for all patients with traumatic nerve injuries accepted at the Hand Surgery Department, Uppsala, Sweden between 2010 and 2018. The template included demographic data, pain diagnosis, type of injured nerve, level of injury, date of the lesion and repair, type of procedure, reoperation, time since the procedure, S-LANSS questionnaire (Self report-Leeds Assessment of Neuropathic Symptoms and Signs), RAND-36 (Item short form health survey), QuickDASH (Disability of Shoulder, Arm and Hand) and additional questionnaires concerned medication, pain intensity were sent to 1,051 patients with nerve injuries. Partial proportional odds models were used to investigate the association between persistent pain and potential predictors. Results More than half of the patients undergoing a surgical procedure developed persistent pain. Prevalence of neuropathic pain was 73% of the patients with pain (S-LANSS ≥ 12 or more). Multivariate analysis indicated that injury of a major nerve OR 1.6 (p = 0.013), years from surgery OR 0.91 (p = 0.01), younger age OR 0.7 (p < 0.001), were the main factors for predicting pain after surgery. The type of the nerve injured was the strongest predictor for chronic pain with major nerves associated with more pain (p = 0.019). Conclusions A high prevalence of chronic pain and neuropathic pain with a negative impact on quality of life and disability were found in patients after traumatic nerve injury. Major nerve injury, younger age and less time from surgery were predictors for chronic pain.

Detection of systemic inflammation in severely impaired chronic pain patients and effects of a multimodal pain rehabilitation program.

Background and aims Recent research indicates a previously unknown low-grade systemic or neurogenic inflammation in groups of chronic pain (CP) patients. Low-grade inflammation may have an important role in symptoms that have previously not been well depicted: widespread pain, tiredness and cognitive dysfunctions frequently seen in severely impaired CP patients. This study aimed to investigate the plasma inflammatory profile in a group of very complex CP patients at baseline and at a 1-year follow-up after participation in a cognitive behavior therapy (CBT)-based multimodal pain rehabilitation program (PRP). Methods Blood samples were collected from 52 well-characterized CP patients. Age- and sex-matched healthy blood donors served as controls. The samples were analyzed with a multiple Proximal Extension Analysis allowing a simultaneous analysis of 92 inflammation-related proteins consisting mainly of cytokines, chemokines and growth-factors. At follow-up, 1-year after participation in the RPR samples from 28 patients were analyzed. The results were confirmed by a multi-array technology that allows quantitative estimation. Results Clear signs of increased inflammatory activity were detected in the CP patients. Accepting a false discovery rate (FDR) of 5%, there were significant differences in 43/92 inflammatory biomarkers compared with the controls. In three biomarkers (CXCL5, SIRT2, AXIN1) the expression levels were elevated more than eight times. One year after the PRP, with the patients serving as their own controls, a significant decrease in overall inflammatory activity was found. Conclusions Our results indicate that the most impaired CP patients suffer from low-grade chronic systemic inflammation not described earlier with this level of detail. The results may have implications for a better understanding of the cluster of co-morbid symptoms described as the "sickness-syndrome" and the wide-spread pain seen in this group of patients. The decrease in inflammatory biomarkers noted at the follow-up after participation in the PRP may reflect the positive effects obtained on somatic and psycho-social mechanisms involved in the inflammatory process by a rehabilitation program. Besides the PRP, no major changes in medication or lifestyle factors were implemented during the same period. To our knowledge, this is the first study reporting that a PRP may induce inflammatory-reducing effects. Further studies are needed to verify the objective findings in CP patients and address the question of causality that remains to be solved. Implications The findings offer a new insight into the complicated biological processes underlying CP. It may have implications for the understanding of symptoms collectively described as the "sickness-syndrome" - frequently seen in this group of patients. The lowering of cytokines after the participation in a PRP indicate a new way to evaluate this treatment; by measuring inflammatory biomarkers.

The utility/futility of medications for neuropathic pain - an observational study.

Background and aims The RELIEF (Real Life) study by AstraZeneca was designed as an observational study to validate a series of Patient Reported Outcome (PRO) questionnaires in a mixed population of subjects with neuropathic pain (NP) coming from diabetes, neurology and primary care clinics. This article is an analysis of a subset of the information to include the medications used and the effects of pharmacological treatment over 6 months. The RELIEF study was performed during 2010-2013. Methods Subjects were recruited from various specialty clinics and one general practice clinic across Canada. The subjects were followed for a total of 2 years with repeated documentation of their status using 10 PROs. A total of 210 of the recruited subjects were entered into the data base and analyzed. Of these, 123 had examination-verified painful diabetic neuropathy (PDN) and 87 had examination-verified post-traumatic neuropathy (PTN). To evaluate the responsiveness of the PROs to change, several time points were included and this study focusses primarily on the first 6 months. Subjects also maintained a diary to document all medications, both for pain and other medical conditions, including all doses, start dates and stop dates, that could be correlated to changes in the PRO parameters. Results RELIEF was successful in being able to correlate the validity of the PROs and this data was used for further AstraZeneca Phase 1, 2, and 3 clinical trials of NP. To our surprise, there was very little change in pain and low levels of patient satisfaction with treatment during the trial. Approximately 15% of the subjects reported improvement, 8% worsening of pain, the remainder reported pain unchanged despite the use of multiple medications at multiple doses, alone or in combination with frequent changes of medications and doses over the study. Those taking predominantly NSAIDs (COX-inhibitors) did no worse than those taking the standard recommended medications against NP. Conclusions Since this is a real-life study, it reflects the clinical utility of a variety of internationally recommended medications for the treatment of NP. In positive clinical trials of these medications in selected "ideal" subjects, the effects are not overwhelming - 30% are 50% improved on average. This study shows that in the real world the results are not nearly as positive and reflects information from non-published negative clinical trials. Implications We still do not have very successful medications for NP. Patients probably differ in many respects from those subjects in clinical trials. This is not to negate the use of recommended medications for NP but an indication that success rates of treatment are likely to be worse than the data coming from those trials published by the pharmaceutical industry.

Identifying characteristics of the most severely impaired chronic pain patients treated at a specialized inpatient pain clinic.

BACKGROUND AND AIMS: Patients suffering from chronic nonmalignant pain constitute a heterogeneous population in terms of clinical presentation and treatment results. Few data are available about what distinguishes different groups in this huge population of patients with chronic persistent pain (CPP). A subgroup that is poorly studied, consists of the most severely impaired chronic pain patients. At the Uppsala University Hospital Pain Clinic, there is a specialized department accepting the most complex patients for rehabilitation. In the endeavour to improve and evaluate treatment for this subgroup, a better understanding of the complex nature of the illness is essential. This prospective study aimed to describe the characteristics of this subgroup of patients with CPP. METHODS: Seventy-two consecutive patients enrolled in the Uppsala programme were evaluated. We collected data on demographics, type of pain and experienced symptoms other than pain using a checklist of 41 possible symptoms. Psychiatric comorbidity was assessed by a psychiatrist using a structured clinical interview. Quality of life (QoL), pain rating and medication/drug/alcohol usage were measured by validated questionnaires: SF-36, NRS, DUDIT and AUDIT. Concerning physical functioning and sick leave, a comparison was made with data from the Swedish Quality Register Registry for pain rehabilitation (SQRP). RESULTS: The cohort consisted of 61% women and the average age was 45 (range 20-70) years. For this cohort, 74% reported being on sick leave or disability-pension. In the SQRP 59% were on sick leave at the time they entered the rehabilitation programmes [1]. On average, the study-population reported 22 symptoms other than pain, to be at a high rate of severity. Patients treated in conventional pain-rehabilitation programmes reported a mean of 10 symptoms in average. Symptoms reported with the highest frequency (>80%), were lethargy, tiredness, headache and difficulties concentrating. Seventy-six percent were diagnosed with a psychiatric disorder. Sixty-nine fulfilled the criteria for depression or depression/anxiety disorder despite that most (65%) were treated with psychotropic medication. Alcohol/drug abuse was minimal. Seventy-one percent were on opioids but the doses were moderate (<100mg) MEq. The pain rating was ≥7 (out of a maximum of 10) for 60% of the patients. CONCLUSION: This study describes what makes the subgroup of pain patients most affected by their pain special according to associated factors and comorbidity We found that they were distinguished by a high degree of psychiatric comorbidity, low physical functioning and extreme levels of symptom preoccupation/hypervigilance. Many severe symptoms additional to pain (e.g. depression/anxiety, tiredness, disturbed sleep, lack of concentration, constipation) were reported. The group seems hypervigilant, overwhelmed with a multitude of different symptoms on a high severity level. IMPLICATIONS: When treating this complex group, the expressions of the illness can act as obstacles to achieve successful treatment outcomes. The study provides evidence based information, for a better understanding of the needs concerning these pain patients. Our result indicates that parallel assessment and treatment of psychiatric comorbidities and sleep disorders combined with traditional rehabilitation, i.e. physical activation and cognitive reorganization are imperative for improved outcomes.

The changing face of acute pain services.

BACKGROUND AND AIMS: Acute Pain Services have been implemented initially to treat inadequate postoperative pain. This study was undertaken to prospectively review the current challenges of the APS team in an academic hospital assessing the effects of its activity on both surgical and medical pain intensity. It also define the characteristics of the patients and the risk factors influencing the multiple visits from the APS team. METHOD: This prospective cohort study was conducted at Uppsala University Hospital (a Swedish tertiary and quaternary care hospital) during one year. All the patients referred to the APS team were enrolled. A standardized data collection template of demographic data, medical history, pain diagnosis, associated diseases, duration of treatment, number of visits by the APS team and type of treatment was employed. The primary outcomes were pain scores before, after treatment and the number of follow-ups. The patients were visited by APS at regular intervals and divided by the number of visits by APS team into several groups: group 1 (one visit and up to 2 follow ups); group 2 (3 to 4 follow-ups); group 3 (5 to 9 follow-ups); group 4 (10 to 19 follow-ups); group 5 (>20 followups). The difference between groups were analyzed with ordinal logistic regression analyses. RESULTS: Patients (n=730) (mean age 56±4, female 58%, men 42%) were distributed by service to medical (41%) and surgical (58%). Of these, 48% of patients reported a pain score of moderate to severe pain and 27% reported severe pain on the first assessment. On the last examination before discharge, they reported 25-30% less pain (P=0.002). The median NRS (numerical rating scores) decreased significantly from 9.6 (95% confidence interval, 8.7-9.9) to 6.3 (6.1-7.4) for the severe pain (P<0.0001), from 3.8 (3.2-4.3) to 2.4 (1.8-2.9) for the moderate pain. The odds ratio for frequent follow-ups of the patients between 18 and 85 years (n=609) was 2.33 (95% CI: 1.35-4.02) if the patient had a history of chronic neuropathic pain, 1.80(1.25-2.60) in case the patient had a history of chronic nociceptive pain, 2.06(1.30-3.26) if he had mental diseases, and 3.35(2.21-5.08) if he had opioid dependency at the time of consultation from APS. Strong predictors of frequent visits included female gender (P=0.04). CONCLUSIONS: Beside the benefits of APS in reducing pain intensity, this study demonstrates that the focus of APS has been shifted from the traditional treatment of acute surgical pain to the clinical challenges of treating hospitalized patients with a high comorbidity of psychiatric diseases, opioid dependency and chronic pain. IMPLICATIONS: The concept of an APS will ultimately be redefined according to the new clinical variables. In the light of the increasing number of patients with complex pain states and chronic pain, opioid dependency and psychiatric comorbidities it is mandatory that the interdisciplinary APS team should include other specialties besides the "classical interdisciplinary APS team", as psychiatry, psychology, rehabilitation and physiotherapy with experience in treating chronic pain patients.

Outcome among VF/VT patients in the LINC (LUCAS IN cardiac arrest) trial-A randomised, controlled trial.

INTRODUCTION: The LINC trial evaluated two ALS-CPR algorithms for OHCA patients, consisting of 3min' mechanical chest compression (LUCAS) cycles with defibrillation attempt through compressions vs. 2min' manual compressions with compression pause for defibrillation. The PARAMEDIC trial, using 2min' algorithm found worse outcome for patients with initial VF/VT in the LUCAS group and they received more adrenalin compared to the manual group. We wanted to evaluate if these algorithms had any outcome effect for patients still in VF/VT after the initial defibrillation and how adrenalin timing impacted it. METHOD: Both groups received manual chest compressions first. Based on non-electronic CPR process documentation, outcome, neurologic status and its relation to CPR duration prior to the first detected return of spontaneous circulation (ROSC), time to defibrillation and adrenalin given were analysed in the subgroup of VF/VT patients. RESULTS: Seven hundred and fifty-seven patients had still VF/VT after initial chest compressions combined with a defibrillation attempt (374 received mechanical CPR) or not (383 received manual CPR). No differences were found for ROSC (mechanical CPR 58.3% vs. manual CPR 58.6%, p=0.94), or 6-month survival with good neurologic outcome (mechanical CPR 25.1% vs. manual CPR 23.0%, p=0.50). A significant difference was found regarding the time from start of manual chest compression to the first defibrillation (mechanical CPR: 4 (2-5) min vs manual CPR 3 (2-4) min, P<0.001). The time from the start of manual chest compressions to ROSC was longer in the mechanical CPR group. CONCLUSIONS: No difference in short- or long-term outcomes was found between the 2 algorithms for patients still in VF/VT after the initial defibrillation. The time to the 1st defibrillation and the interval between defibrillations were longer in the mechanical CPR group without impacting the overall outcome. The number of defibrillations required to achieve ROSC or adrenalin doses did not differ between the groups.

Biomarker of extracellular matrix remodelling C1M and proinflammatory cytokine interleukin 6 are related to synovitis and pain in end-stage knee osteoarthritis patients.

Little is known about local and systemic biomarkers in relation to synovitis and pain in end-stage osteoarthritis (OA) patients. We investigated the associations between the novel extracellular matrix biomarker, C1M, and local and systemic interleukin 6 (IL-6) with synovitis and pain. Serum C1M, plasma, and synovial fluid IL-6 (p-IL-6, sf-IL-6) were measured in 104 end-stage knee OA patients. Contrast-enhanced magnetic resonance imaging was used to semiquantitatively assess an 11-point synovitis score; pain was assessed by the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) and the Neuropathic Pain Questionnaire (NPQ). Linear regression was used to investigate associations between biomarkers and synovitis, and biomarkers and pain while controlling for age, sex, and body mass index. We also tested whether associations between biomarkers and pain were confounded by synovitis. We found sf-IL-6 was associated with synovitis in the parapatellar subregion (B = 0.006; 95% confidence interval [CI] 0.003-0.010), and no association between p-IL-6 and synovitis. We also observed an association between C1M and synovitis in the periligamentous subregion (B = 0.013; 95% CI 0.003-0.023). Furthermore, sf-IL-6, but not p-IL-6, was significantly associated with pain, WOMAC (B = 0.022; 95% CI 0.004-0.040), and NPQ (B = 0.043; 95% CI 0.005-0.082). There was no association between C1M and WOMAC pain, but we did find an association between C1M and NPQ (B = 0.229; 95% CI 0.036-0.422). Lastly, synovitis explained both biomarker-NPQ associations, but not the biomarker-WOMAC association. These results suggest that C1M and IL-6 are associated with synovitis and pain, and synovitis is an important confounding variable when studying biomarkers and neuropathic features in OA patients.

Per-Protocol and Pre-Defined population analysis of the LINC study.

OBJECTIVE: To perform two predefined sub-group analyses within the LINC study and evaluate if the results were supportive of the previous reported intention to treat (ITT) analysis. METHODS: Predefined subgroup analyses from the previously published LINC study were performed. The Per-Protocol population (PPP) included the randomized patients included in the ITT-population but excluding those with violated inclusion or exclusion criteria and those that did not get the actual treatment to which the patient was randomized. In the Pre-Defined population (PDP) analyses patients were also excluded if the dispatch time to ambulance arrival at the address exceeded 12 min, there was a non-witnessed cardiac arrest, or if it was not possible to determine whether the arrest was witnessed or not, and those cases where LUCAS was not brought to the scene at the first instance. RESULTS: After exclusion from the 2589 patients within the ITT-population, the Per-Protocol analysis was performed in 2370 patients and the Pre-Defined analysis within 1133 patients. There was no significant difference in 4-h survival of patients between the mechanical-CPR group and the manual-CPR group in the Per-Protocol population; 279 of 1172 patients (23.8%) versus 281 of 1198 patients (23.5%) (risk difference -0.35%, 95% C.I. -3.1 to 3.8, p=0.85) or in the Pre-Defined population; 176 of 567 patients (31.0%) versus 192 of 566 patients (33.9%) (risk difference -2.88%, 95% C.I. -8.3 to 2.6, p=0.31). There was no difference in any of the second outcome variables analyzed in the Pre-Protocol or Pre-Defined populations. CONCLUSIONS: The results from these predefined sub-group analyses of the LINC study population did not show any difference in 4h survival or in secondary outcome variables between patients treated with mechanical-CPR or manual-CPR. This is consistent with the previously published ITT analysis.

Experiences with an adaptive design for a dose-finding study in patients with osteoarthritis.

Dose-finding studies in non-oncology areas are usually conducted in Phase II of the development process of a new potential medicine and it is key to choose a good design for such a study, as the results will decide if and how to proceed to Phase III. The present article has focus on the design of a dose-finding study for pain in osteoarthritis patients treated with the TRPV1 antagonist AZD1386. We describe different design alternatives in the planning of this study, the reasoning for choosing the adaptive design and experiences with conduct and interim analysis. Three alternatives were proposed: one single dose-finding study with parallel design, a programme with a smaller Phase IIa study followed by a Phase IIb dose-finding study, and an adaptive dose-finding study. We describe these alternatives in detail and explain why the adaptive design was chosen for the study. We give insights in design aspects of the adaptive study, which need to be pre-planned, like interim decision criteria, statistical analysis method and setup of a Data Monitoring Committee. Based on the interim analysis it was recommended to stop the study for futility since AZD1386 showed no significant pain decrease based on the primary variable. We discuss results and experiences from the conduct of the study with the novel design approach. Huge cost savings have been done compared to if the option with one dose-finding design for Phase II had been chosen. However, we point out several challenges with this approach.

Mechanical chest compressions and simultaneous defibrillation vs conventional cardiopulmonary resuscitation in out-of-hospital cardiac arrest: the LINC randomized trial.

IMPORTANCE: A strategy using mechanical chest compressions might improve the poor outcome in out-of-hospital cardiac arrest, but such a strategy has not been tested in large clinical trials. OBJECTIVE: To determine whether administering mechanical chest compressions with defibrillation during ongoing compressions (mechanical CPR), compared with manual cardiopulmonary resuscitation (manual CPR), according to guidelines, would improve 4-hour survival. DESIGN, SETTING, AND PARTICIPANTS: Multicenter randomized clinical trial of 2589 patients with out-of-hospital cardiac arrest conducted between January 2008 and February 2013 in 4 Swedish, 1 British, and 1 Dutch ambulance services and their referring hospitals. Duration of follow-up was 6 months. INTERVENTIONS: Patients were randomized to receive either mechanical chest compressions (LUCAS Chest Compression System, Physio-Control/Jolife AB) combined with defibrillation during ongoing compressions (n = 1300) or to manual CPR according to guidelines (n = 1289). MAIN OUTCOMES AND MEASURES: Four-hour survival, with secondary end points of survival up to 6 months with good neurological outcome using the Cerebral Performance Category (CPC) score. A CPC score of 1 or 2 was classified as a good outcome. RESULTS: Four-hour survival was achieved in 307 patients (23.6%) with mechanical CPR and 305 (23.7%) with manual CPR (risk difference, -0.05%; 95% CI, -3.3% to 3.2%; P > .99). Survival with a CPC score of 1 or 2 occurred in 98 (7.5%) vs 82 (6.4%) (risk difference, 1.18%; 95% CI, -0.78% to 3.1%) at intensive care unit discharge, in 108 (8.3%) vs 100 (7.8%) (risk difference, 0.55%; 95% CI, -1.5% to 2.6%) at hospital discharge, in 105 (8.1%) vs 94 (7.3%) (risk difference, 0.78%; 95% CI, -1.3% to 2.8%) at 1 month, and in 110 (8.5%) vs 98 (7.6%) (risk difference, 0.86%; 95% CI, -1.2% to 3.0%) at 6 months with mechanical CPR and manual CPR, respectively. Among patients surviving at 6 months, 99% in the mechanical CPR group and 94% in the manual CPR group had CPC scores of 1 or 2. CONCLUSIONS AND RELEVANCE: Among adults with out-of-hospital cardiac arrest, there was no significant difference in 4-hour survival between patients treated with the mechanical CPR algorithm or those treated with guideline-adherent manual CPR. The vast majority of survivors in both groups had good neurological outcomes by 6 months. In clinical practice, mechanical CPR using the presented algorithm did not result in improved effectiveness compared with manual CPR. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00609778.