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Supplemental Digital Content is available in the text., OBJECTIVES: Clinical trials evaluating the safety and effectiveness of sedative medication use in critically ill adults undergoing mechanical ventilation differ considerably in their methodological approach. This heterogeneity impedes the ability to compare results across studies. The Sedation Consortium on Endpoints and Procedures for Treatment, Education, and Research Recommendations convened a meeting of multidisciplinary experts to develop recommendations for key methodologic elements of sedation trials in the ICU to help guide academic and industry clinical investigators. DESIGN: A 2-day in-person meeting was held in Washington, DC, on March 28–29, 2019, followed by a three-round, online modified Delphi consensus process. PARTICIPANTS: Thirty-six participants from academia, industry, and the Food and Drug Administration with expertise in relevant content areas, including two former ICU patients attended the in-person meeting, and the majority completed an online follow-up survey and participated in the modified Delphi process. MEASUREMENTS AND MAIN RESULTS: The final recommendations were iteratively refined based on the survey results, participants’ reactions to those results, summaries written by panel moderators, and a review of the meeting transcripts made from audio recordings. Fifteen recommendations were developed for study design and conduct, subject enrollment, outcomes, and measurement instruments. Consensus recommendations included obtaining input from ICU survivors and/or their families, ensuring adequate training for personnel using validated instruments for assessments of sedation, pain, and delirium in the ICU environment, and the need for methodological standardization. CONCLUSIONS: These recommendations are intended to assist researchers in the design, conduct, selection of endpoints, and reporting of clinical trials involving sedative medications and/or sedation protocols for adult ICU patients who require mechanical ventilation. These recommendations should be viewed as a starting point to improve clinical trials and help reduce methodological heterogeneity in future clinical trials.

Background Unintentional dural puncture with an epidural needle complicates approximately 1% of epidural anaesthetics and causes an acute headache in 60–80% of these patients. Several retrospective studies suggest an increased risk of chronic headache. We assessed the relationship between unintentional dural puncture and chronic disabling headache, defined as one or more functionally limiting headaches within a 2-week interval ending 2, 6, and 12 months postpartum. Methods In this prospective observational study, parturients who experienced unintentional dural puncture were matched 1:4 with control patients. Patients completed questionnaires regarding characteristics of headache and back pain pre-pregnancy, during pregnancy, immediately postpartum, and at 2, 6, and 12 months postpartum. The primary outcome was prevalence of disabling headache in the past 2 weeks, assessed at 2 months postpartum. Secondary outcomes included prevalence and characteristics of headache and back pain at these time points. Results We enrolled 99 patients. At 2 and 6 months postpartum, the prevalence of disabling headache was greater among patients with unintentional dural puncture than matched controls (2 months, 74% vs 38%, relative risk 1.9, 95% confidence interval 1.2–2.9, P=0.009; 6 months, 56% vs 25%, relative risk 2.1, 95% confidence interval 1.1–4.0, P=0.033). There was no difference in the prevalence of back pain at any time point. Conclusions Our prospective trial confirms retrospective studies that chronic headache is more prevalent among women who experienced unintentional dural puncture compared with controls who received uncomplicated neuraxial anaesthesia. This finding has implications for the. patient consent process and recommendations for long-term follow-up of patients who experience unintentional dural puncture.

Background A gender-based compensation gap among physicians is well documented. Even after adjusting for age, experience, work hours, productivity, and academic rank, the gender gap remained and widened over the course of a physician's career. This study aimed to examine if a significant gender pay gap still existed for anesthesiologists in the United States. Methods In 2018, we surveyed 28,812 physician members of the American Society of Anesthesiologists to assess the association of compensation with gender and to identify possible causes of wage disparities. Gender was the primary variable examined in the model, and compensation by gender was the primary outcome. Compensation was defined as the amount reported as direct compensation on a W-2, 1099, or K-1, plus all voluntary salary reductions (eg, 401[k], health insurance). The survey directed respondents to include salary, bonuses, incentive payments, research stipends, honoraria, and distribution of profits to employees. Respondents had the option of providing a point estimate of their compensation or selecting a range in $50,000 increments. Potential confounding variables that could affect compensation were identified based on a scoping literature review and the consensus expertise of the authors. We fitted a generalized ordinal logistic regression with 7 ranges of compensation. For the sensitivity analyses, we used linear regressions of log-transformed compensation based on respondent point estimates and imputed values. Results The final analytic sample consisted of 2081 observations (response rate, 7.2%). This sample represented a higher percentage of women and younger physicians compared to the demographic makeup of anesthesiologists in the United States. The adjusted odds ratio associated with gender equal to woman was an estimated 0.44 (95% confidence interval, 0.37-0.53), indicating that for a given compensation range, women had a 56% lower odds than men of being in a higher compensation range. Sensitivity analyses found the relative percentage difference in compensation for women compared to men ranged from -8.3 to -8.9. In the sensitivity analysis based on the subset of respondents (n = 1036) who provided a point estimate of compensation, the relative percentage difference (-8.3%; 95% confidence interval, -4.7 to -11.7) reflected a $32,617 lower compensation for women than men, holding other covariates at their means. Conclusions Compensation for anesthesiologists showed a significant pay gap that was associated with gender even after adjusting for potential confounding factors, including age, hours worked, geographic practice region, practice type, position, and job selection criteria.

Experimental and clinical acute pain research in relation to biological sex and genetics started in the 1980s. Research methods became more powerful and sensitive with the advancement in affordable gene sequencing methods and high-throughput genetic assays. Decades of research has identified several potential pharmaceutical targets, providing insights into future research direction, and understanding of acute pain and opioid analgesic effects in the clinical setting. However, there is insufficient evidence to make generalized recommendations for using genetic tests for clinical practice of acute pain management.

Objective. Evidence to date, while sparse, suggests that patients taking long-term opioids require special considerations and protections to prevent potential iatrogenic harms from opioid de-prescribing, such as increased pain or suffering. Following this study protocol, the EMPOWER study seeks to address multiple unmet needs of patients with chronic pain who desire to reduce long-term opioid therapy, and provide the clinical evidence on effective methodology. Methods. EMPOWER applies patient-centered methods for voluntary prescription opioid reduction conducted within a comprehensive, multi-state, 3-arm randomized controlled comparative effectiveness study of three study arms (1) group cognitive behavioral therapy for chronic pain; (2) group chronic pain self-management; and (3) usual care (taper only). Specialized electronic data capture systems collect patient reported symptoms and satisfaction data weekly and monthly during the taper, with real-time clinical alerts and electronic feedback loops informing, documenting, and steering needed care actions. Conclusion. The EMPOWER study seeks to provide granular evidence on patient response to voluntary opioid tapering, and will provide evidence to inform clinical systems changes, clinical care, patient satisfaction, and patient outcomes for opioid reduction.

Background Back pain is more prevalent among women than men. The association with sex could be related to pregnancy and childbirth, unique female conditions. This association has not been thoroughly evaluated. Methods Using a retrospective cohort design, we evaluated the relationship between history of childbirth on the prevalence and severity of functionally consequential back pain in 1069 women from a tertiary care pain management clinic. Interactions among preexisting, acute peripartum, and subsequent back pain were evaluated as secondary outcomes among the parous women using logistic and linear regression as appropriate. Results The women who had given birth had a higher risk for functionally significant back pain compared to women who had not given birth (85% vs 77%, p p = 0.002). Women who recalled severe, acute postpartum back pain had a higher prevalence of current debilitating back pain (89% vs 75%, Risk Ratio 1.19 (1.08-1.31), p = 0.001). Twenty-eight percent of acute postpartum back pain never resolved and 40% reported incomplete resolution. Conclusions A history of pregnancy and childbirth is a risk factor for chronic functionally significant back pain in women. Severe acute postpartum back pain is a risk factor for future disability suggesting that the peripartum period may provide an important opportunity for intervention. Early recognition and management may mitigate future disability. Trial registration The study was registered with clinicaltrials.gov as “Association Between Chronic Headache and Back Pain with Childbirth” (NCT04091321) on 16/09/2019 before it was initiated.

To assess the feasibility, patient tolerance, pharmacokinetics, and potential effectiveness of a randomized controlled trial protocol investigating intravenous calcium chloride for the prevention of uterine atony during cesarean delivery.Double-blind, randomized controlled pilot trial with nested population pharmacokinetic analysis.This study was performed at Lucile Packard Children's Hospital, from August 2018 to September 2019.Forty patients with at least two risk factors for uterine atony at the time of cesarean delivery.One gram of intravenous calcium chloride (n = 20 patients) or a saline placebo control (n = 20 patients), in addition to standard care with oxytocin, upon umbilical cord clamping.The primary efficacy-related outcome was the presence of uterine atony defined as the use of a second-line uterotonic medication, surgical interventions for atony, or hemorrhage with blood loss1000 mL. Blood loss, uterine tone numerical rating scores, serial venous blood calcium levels, hemodynamics, and potential side effects were also assessed.The study protocol proved feasible. The incidence of atony was 20% in parturients who received calcium compared to 50% in the placebo group (relative risk 0.38, P = 0.07, 95% CI 0.15-1.07, NNT 3.3). Calcium recipients tolerated the drug infusion well, with no adverse events and an equal incidence of potential side effects in the calcium and placebo groups. Ionized calcium concentration rose significantly in all patients who received calcium infusion, from baseline 1.18 mmol/L to peak levels 1.50-1.60 mmol/L. One-compartment population pharmacokinetics established clearance of 0.93 (95% CI 0.63-1.52) L/min and volume of distribution 76 (95% CI 49-94) L.In this pilot study, investigators found that intravenous calcium chloride was well-tolerated by the 20 patients assigned to receive the study drug and may be effective in prevention of uterine atony. A 1-g dose was sufficient to substantially increase calcium levels without any critically elevated lab values or concern for adverse side effects. These encouraging findings warrant further investigation of calcium as a novel agent to prevent uterine atony with an adequately powered clinical trial. Clinical trial registry NCT03867383 https://clinicaltrials.gov/ct2/show/NCT03867383.

Objective This narrative literature review examines the long-term impact of postdural puncture headache (PDPH) in postpartum women following an unintended dural puncture (UDP) with a large bore needle commonly used for epidural catheter placement. It seeks to bridge the knowledge gap for the neurologist as to the mounting body of obstetric anesthesia literature on the development of chronic headache after PDPH with this unique needle. Background Headache is the most common complication of dural puncture, and the risk is greatest in the parturient population. Preexisting risk factors for this population include youth and sex, and after UDP with a large bore needle, almost 70%-80% report a headache. Additionally, there appears to be a significant cohort who experience long-term, persistent headache after UDP. Methods We performed a narrative review of literature using PubMed, searching terms that included long-term follow-up after UDP with a large bore needle in the postpartum population. Results In women who had UDP with a large bore needle used for epidural catheter placement at delivery, the rate of chronic debilitating headache is around 30% in the months following delivery and may persist for up to a year or longer. Conclusion Based on the existing literature, we have mounting evidence that UDP with the large bore needle used to place an epidural catheter should be understood as a high-risk inciting event for the development of long-term headaches not simply a high risk of acute PDPH. Additionally, consideration should be given to stratifying the etiology of PDPH, based on needle type, and recognizing the entity of chronic PDPH, thus allowing for improvements in research and diagnosis.

Objectives: Since the uprising in 2011, there have been limited health-care data from inside Syria regarding women’s health. This study aimed to provide an updated account of women’s health, including pregnancy, perinatal care, childbirth, and other conditions to identify obstacles and challenges to health-care delivery in Northwestern Syria. Methods: This is a prospective data registry study, using a medical electronic records system that builds on the International Classification of Diseases, Tenth Revision (ICD-10) codes. We collected data from one medical center in Northwestern Syria during 2017. We conducted a survey to understand patients’ knowledge of and barriers limiting antenatal care (ANC). Results: We studied 7213 patients’ health status and surveyed 134 regarding ANC. Prenatal care, delivery, and miscarriage treatment represented the most common (70%) reasons for women’s health-care visits, followed by menstrual disorders (17%). From 2057 delivery records, 70% delivered vaginally and 30% required cesarean delivery. Our findings showed that 1169 (24%) of the pregnant women (4936) in 2017 were adolescents, of them 22 (0.44%) were 14 years old. Regarding ANC visits, 85% of respondents did not have a single ANC visit in the first trimester, 82% had no visits in the second trimester, and 44% had no visits in the third trimester. Thirty-one percent had no ANC visit throughout the entire pregnancy. Only 13% had postnatal care (PNC) visits. Women who live in the refugee camp are 2.7 times less likely to meet the World Health Organization (WHO) criteria for focused ANC (FANC = 4 visits) compared to those who reside in town (P < 0.001), with only 14% having met the FANC. The major barrier to ANC is related to transportation (34%), followed by factors related to the study center (29%) and knowledge and education (19%). We estimated the number of obstetrics-gynecology doctors per 1000 populations to be 0.02. Conclusions: We found a huge deficiency in ANC and PNC visits, a high adolescent birth rate, and a higher cesarean-to-vaginal delivery ratio than what is recommended by the WHO. We also found a severe shortage in the number of obstetrician-gynecologists serving this population.

Patient-centred care and factors associated with patient satisfaction with anaesthesia have been widely studied. However, the most important considerations in the setting of obstetric anaesthesia are uncertain. Identification of, and addressing, factors that contribute to patient dissatisfaction may improve quality of care. We sought to identify factors associated with 100% satisfaction with obstetric anaesthesia care. At total of 4297 women treated by anaesthetists provided satisfaction data 24 h after vaginal and 48 h after caesarean delivery. As 78% of women were 100% satisfied, we studied factors associated with the dichotomous variable, 100% satisfied vs.100% satisfied. We evaluated patient characteristics and peripartum factors using multivariable sequential logistic regression. The following factors were strongly associated with maternal dissatisfaction after vaginal delivery: pain intensity during the first stage of labour; pain intensity during the second stage of labour; postpartum pain intensity; delay 15 min in providing epidural analgesia and postpartum headache (all p 0.0001). Pruritus (p = 0.005) also contributed to dissatisfaction after vaginal delivery, whereas non-Hispanic ethnicity was negatively associated with dissatisfaction (p = 0.01). After caesarean delivery, the intensity of postpartum pain (p 0.0001), headache (p = 0.001) and pruritus (p = 0.001) were linked to dissatisfaction. Hispanic ethnicity also had a negative relationship with dissatisfaction after caesarean delivery (p = 0.005). Thus, inadequate or delayed analgesia and treatment-related side-effects are associated with maternal dissatisfaction with obstetric anaesthesia care. Development of protocols to facilitate identification of ineffective analgesia and provide an appropriate balance between efficacy and side-effects, are important goals to optimise maternal satisfaction.

BackgroundThe phase III research evaluating migraine prophylaxis therapy (PREEMPT) protocol was developed in low-risk migraine patients. We studied longitudinal response to treatment in a sequential retrospective observational cohort to evaluate predictors of effectiveness in patients with multiple overlapping pain syndromes treated in a quaternary pain management clinic.MethodsWe evaluated indicators of individual response in 402 consecutive chronic migraine patients who provided demographic information and used the Collaborative Health Outcomes Information Registry.ResultsThe patients were middle aged 47 (38–56) median (IQR) years old and 83% women. They reported multiple complex pain problems with 11 (6–18) regions represented on a pain body map. Evaluated with National Institutes of Health Patient-Reported Outcomes Measurement Information System measures, they reported higher scores for sleep impairment and disturbance, anxiety, depression, fatigue, pain behavior, pain interference and worse function and satisfaction with social roles compared with the general US population; pConclusionsOur findings point to the importance of identifying and addressing pain interference and depression early in chronic migraine management and, more broadly, highlights the importance of multidisciplinary evaluation and treatment in chronic migraine.

Objective This study aims to assess the feasibility of digital perioperative behavioral pain medicine intervention in breast cancer surgery and evaluate its impact on pain catastrophizing, pain, and opioid cessation after surgery. Design and Setting A randomized controlled clinical trial was conducted at Stanford University (Palo Alto, CA, USA) comparing a digital behavioral pain medicine intervention (“My Surgical Success” [MSS]) with digital general health education (HE). Participants A convenience sample of 127 participants were randomized to treatment group. The analytic sample was 68 patients (N = 36 MSS, N = 32 HE). Main Outcomes The primary outcome was feasibility and acceptability of a digital behavioral pain medicine intervention (80% threshold for acceptability items). Secondary outcomes were pain catastrophizing, past seven-day average pain intensity, and time to opioid cessation after surgery for patients who initiated opioid use. Results The attrition rate for MSS intervention (44%) was notably higher than for HE controls (18%), but it was lower than typical attrition rates for e-health interventions (60–80%). Despite greater attrition for MSS, feasibility was demonstrated for the 56% of MSS engagers, and the 80% threshold for acceptability was met. We observed a floor effect for baseline pain catastrophizing, and no significant group differences were found for postsurgical pain catastrophizing or pain intensity. MSS was associated with 86% increased odds of opioid cessation within the 12-week study period relative to HE controls (hazard ratio = 1.86, 95% confidence interval = 1.12–3.10, P = 0.016). Conclusions Fifty-six percent of patients assigned to MSS engaged with the online platform and reported high satisfaction. MSS was associated with significantly accelerated opioid cessation after surgery (five-day difference) with no difference in pain report relative to controls. Perioperative digital behavioral pain medicine may be a low-cost, accessible adjunct that could promote opioid cessation after breast cancer surgery.

Chorioamnionitis is associated with an increased risk of cesarean delivery and uterine atony. We hypothesized that the onset of maternal fever is temporally associated with decreased uterine contractility.Retrospective cohort.Academic center.Term participants who developed a fever in the setting of an intrauterine pressure catheter.Montevideo units (MVUs) and oxytocin dose at time 0 (first oral temperature ≥38°C) and in the five 1--hour blocks preceding and following T0.Montevideo units relative to the onset of fever. Results were adjusted for oxytocin dose and parity in a mixed-effects model.One hundred participants were included. Uterine contractility was maintained for 2 hours after the onset of maternal fever but thereafter significantly and steadily declined by an average of 6.9 ± 3.2 MVU/h ( P = .03), despite the absence of a parallel decline in oxytocin exposure. Multiparas and nulliparas showed a similar pattern of waning uterine contractility. Patients who delivered vaginally maintained contractility, while those who delivered via cesarean had diminishing contractility ( P = .01). The postpartum hemorrhage (PPH) rate (postpartum bleeding requiring treatment) was 32%.A decline in myometrial contractility occurs 2 hours following the onset of maternal fever. Increased risk of cesarean delivery appears to be directly associated with waning uterine contractility and decreased uterine responsiveness to oxytocin. Clinically, close attention should be given to maintaining adequate uterine contractions following a diagnosis of suspected chorioamnionitis. The likelihood of successful vaginal delivery may decrease over time, and the risk of PPH is clinically significant.

Patients with chronic pain experience stigma within the healthcare system. This stigma is compounded for those taking long-term prescription opioids. Often, public messaging and organizational policies have telegraphed that opioid treatment is a problem to be solved by focusing only on medication reduction efforts. Lack of data has contributed to misperceptions and poor opioid policies. In part, data collection remains poor because patients feel fractured from systems of care and are often not interested in engaging with opioid reduction mandates and research. Similarly, clinicians may fail to engage with opioid stewardship and research due to complexities that exceed their training or capacities. The EMPOWER study applies a coproduction model that engages researchers, patients, clinicians, managers, and other health system users. Key stakeholders shaped the design of the study to best ensure acceptability and engagement of the “end users”—patients who enroll in the study and the clinicians who implement the opioid tapers. Targeting the needs of any stakeholder group in isolation is suboptimal. Accordingly, we detail the EMPOWER patient-centered opioid tapering clinical research framework and specific strategies to address stakeholder concerns. We also discuss how this framework may be applied to enhance engagement in healthcare research broadly.

Background Severe acute post-cesarean delivery (CD) pain has been associated with an increased risk for persistent pain and postpartum depression. Identification of women at increased risk for pain can be used to optimize post-cesarean analgesia. The impact of labor prior to CD (intrapartum CD) on acute post-operative pain and opioid use is unclear. We hypothesized that intrapartum CD, which has been associated with both increased inflammation and affective distress related to an unexpected surgical procedure, would result in higher postoperative pain scores and increased opioid intake. Methods This is a secondary analysis of a prospective cohort study examining opioid use up to 2 weeks following CD. Women undergoing CD at six academic medical centers in the United States 9/2014-3/2016 were contacted by phone two weeks following discharge. Participants completed a structured interview that included questions about postoperative pain scores and opioid utilization. They were asked to retrospectively estimate their maximal pain score on an 11-point numeric rating scale at multiple time points, including day of surgery, during hospitalization, immediately after discharge, 1st week, and 2nd week following discharge. Pain scores over time were assessed utilizing a generalized linear mixed-effects model with the patient identifier being a random effect, adjusting for an a priori defined set of confounders. A multivariate negative binomial model was utilized to assess the association between intrapartum CD and opioid utilization after discharge, also adjusting for the same confounders. In the context of non-random prescription distribution, this model was constructed with an offset for the number of tablets dispensed. Results A total of 720 women were enrolled, 392 with and 328 without labor prior to CD. Patients with intrapartum CD were younger, less likely to undergo repeat CD or additional surgical procedures, and more likely to experience a complication of CD. Women with intrapartum CD consumed more opioid tablets following discharge than women without labor (median 20, IQR 10–30 versus 17, IQR 6–30; p = 0.005). This association persisted after adjustment for confounders (incidence rate ratio 1.16, 95% CI 1.05–1.29; p = 0.004). Pain scores on the day of surgery were higher in women with intrapartum CD (difference 0.91, 95% CI 0.52–1.30; adj. p = Conclusion Intrapartum CD is associated with worse pain on the day of surgery but not other time points. Opioid requirements following discharge were modestly increased following intrapartum CD.

Background We performed a systematic review using Consensus Based Standards for the Selection of Health Measurement Instruments (COSMIN) guidelines to identify the best available patient-reported outcome measure (PROM) of postpartum pain. Methods This review follows COSMIN guidelines. We searched four databases with no date limiters, for previously identified validated PROMs used to assess postpartum pain. PROMs evaluating more than one author-defined domain of postpartum pain were assessed. We sought studies evaluating psychometric properties. An overall rating was then assigned based upon COSMIN analysis, and the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach was used to assess the level of evidence for psychometric properties of included PROMs. These assessments were used to make recommendations and identify the best PROM to assess postpartum pain. Results We identified 19 studies using seven PROMs (involving 3511 women), which evaluated postpartum pain. All included studies evaluated ≥1 psychometric property of the included PROMs. An adequate number of pain domains was assessed by the Brief Pain Inventory (BPI), Short Form-BPI (SF-BPI), and McGill Pain Questionnaire (MPQ). The SF-BPI was the only PROM to demonstrate adequate content validity and at least a low-level of evidence for sufficient internal consistency, resulting in a Class A recommendation (the best performing instrument, recommended for use). Conclusion SF-BPI is the best currently available PROM to assess postpartum pain. However, it fails to assess several important domains and only just met the criteria for a Class A recommendation. Future studies are warranted to develop, evaluate, and implement a new PROM designed to specifically assess postpartum pain.

Study findings reveal continued opioid reduction and enduring pain stability for a substantial fraction of patients, 2 to 3 years after a patient-centered voluntary opioid tapering program., Objective: We previously reported promising results for a 4-month patient-centered voluntary opioid tapering study. Key questions remain about the durability of effects and possible risks after opioid reduction. We provide the longest follow-up data to date for prospective opioid tapering: 2- to 3-year follow-up for pain intensity and daily opioid use in a subset of patients from our original 4-month opioid tapering study. Methods: Twenty-three patients (44% of original sample) responded to contact attempts through telephone and reported their average pain intensity and current opioid use. Opioid doses were converted to morphine equivalent daily dose (MEDD). Data were analyzed within a repeated-measures model where time (baseline, 4 months, and 2–3 years) was the within-subject factor. Results: Among reachable patients, the effect of time on change in MEDD from baseline to 4 months to 2 to 3 years was significant. Since baseline, 20 (95%) of the current sample reduced MEDD, and 15 (71%) further reduced MEDD at 2- to 3-year follow-up. There was no effect of time on change in pain intensity from baseline to 4 months to 2 to 3 years. Since baseline, 11 (52%) of the current sample reported pain reduction, and 12 (57%) reported reduced pain from the 4-month follow-up to the 2- to 3-year follow-up. Five (24%) reported increased pain intensity. Conclusion: Study findings reveal continued MEDD reduction and enduring pain stability 2 to 3 years after a patient-centered voluntary opioid tapering program for a substantial fraction of patients. Notably, we were not able to verify current opioid use through medical records and were limited by self-report.

Background Nicotine and nicotinic acetylcholine receptors (nAChRs) have been explored for the past three decades as targets for pain control. The aim of this review is to introduce readers particularly to α7 nAChRs in a perspective of pain and its modulation. Methods Developments for α7 nAChR modulators and recent animal studies related to pain are reviewed. Results Accumulating evidences suggest that selective ligands for α7 nAChRs hold promise in the treatment of chronic pain conditions as they lack many of side effects associated with other nicotinic receptor types. Conclusion This review provides the reader recent insights on α7 nAChRs from structure and function to the latest findings on the pharmacology and therapeutic targeting of these receptors for the treatment of pain and inflammation.

Item does not contain fulltext OBJECTIVE: To update and expand the 2013 Clinical Practice Guidelines for the Management of Pain, Agitation, and Delirium in Adult Patients in the ICU. DESIGN: Thirty-two international experts, four methodologists, and four critical illness survivors met virtually at least monthly. All section groups gathered face-to-face at annual Society of Critical Care Medicine congresses; virtual connections included those unable to attend. A formal conflict of interest policy was developed a priori and enforced throughout the process. Teleconferences and electronic discussions among subgroups and whole panel were part of the guidelines' development. A general content review was completed face-to-face by all panel members in January 2017. METHODS: Content experts, methodologists, and ICU survivors were represented in each of the five sections of the guidelines: Pain, Agitation/sedation, Delirium, Immobility (mobilization/rehabilitation), and Sleep (disruption). Each section created Population, Intervention, Comparison, and Outcome, and nonactionable, descriptive questions based on perceived clinical relevance. The guideline group then voted their ranking, and patients prioritized their importance. For each Population, Intervention, Comparison, and Outcome question, sections searched the best available evidence, determined its quality, and formulated recommendations as "strong," "conditional," or "good" practice statements based on Grading of Recommendations Assessment, Development and Evaluation principles. In addition, evidence gaps and clinical caveats were explicitly identified. RESULTS: The Pain, Agitation/Sedation, Delirium, Immobility (mobilization/rehabilitation), and Sleep (disruption) panel issued 37 recommendations (three strong and 34 conditional), two good practice statements, and 32 ungraded, nonactionable statements. Three questions from the patient-centered prioritized question list remained without recommendation. CONCLUSIONS: We found substantial agreement among a large, interdisciplinary cohort of international experts regarding evidence supporting recommendations, and the remaining literature gaps in the assessment, prevention, and treatment of Pain, Agitation/sedation, Delirium, Immobility (mobilization/rehabilitation), and Sleep (disruption) in critically ill adults. Highlighting this evidence and the research needs will improve Pain, Agitation/sedation, Delirium, Immobility (mobilization/rehabilitation), and Sleep (disruption) management and provide the foundation for improved outcomes and science in this vulnerable population.

Summary A systematic literature search was performed to identify studies that reported risk factors for persistent pain after childbirth. Many studies have sought to identify risk factors for post-delivery pain in different populations, using different methodologies and different outcome variables. Studies of several different but interrelated post-partum pain syndromes have been conducted. Factors strongly and specifically associated with persistent incisional scar pain after Caesarean delivery include a coexisting persistent pain problem in another part of the body and severe acute postoperative pain. For persistent vaginal and perineal pain, operative vaginal delivery and the magnitude of perineal trauma have been consistently linked. History of pregnancy-related and pre-pregnancy back pain and heavier body weight are robust risk factors for persistent back pain after pregnancy. Unfortunately, limitations, particularly small samples and lack of a priori sample size calculation designed to detect specific effect sizes for risk of persistent pain outcomes, preclude definitive conclusions about many other predictors and the strength of outcome associations. In future studies, assessments of specific phenotypes using a rigorous analysis with appropriate predetermined sample sizes and validated instruments are needed to allow elucidation of stronger and reliable associations. Interventional studies targeting the most robustly associated, modifiable risk factors, such as acute post-partum pain, may lead to solutions for the prevention and treatment of these common problems that impact a large population.

Background The majority of parturients in the United States first return for evaluation by their obstetric practitioner 6 weeks after delivery. As such, there is little granular data on the pain experience, analgesic requirements, and functional recovery during the postpartum period. This prospective observational study was performed to evaluate these factors to provide expectations for patients. Methods A total of 213 nulliparous women were enrolled and assessed daily until they completed 3 outcomes: (1) pain resolution; (2) opioid cessation; and (3) self-assessed functional recovery from delivery. The primary endpoint, pain- and opioid-free functional recovery, was the time required to reach all three of the endpoints. Pain burden was assessed as the area under the curve created by plotting the daily numerical pain rating scale against the days required to attain pain resolution. Times to attain study endpoints after cesarean delivery and vaginal delivery were compared using survival analysis. Results After vaginal delivery, days required for pain and opioid-free functional recovery (median [interquartile range (IQR)]) were 19 [11 to 26], for opioid cessation 0 [0 to 2], termination of all analgesic (including nonsteroidal antiinflammatories and acetaminophen) 11 [5 to 17], and pain resolution 14 [7 to 24]. Achievement of these endpoints after cesarean delivery required 27 [19 to 40], 9 [5 to 12], 16 [11 to 24], and 21 [14 to 27] days, respectively. Conclusions There is clinically significant variability between healthy nulliparous parturients in the pain experience, opioid use, and functional recovery after childbirth following vaginal and cesarean delivery. Recovery to predelivery function is similar after vaginal and cesarean delivery, and approximately half of the variance was explained by pain burden.

To define the amount of opioid analgesics prescribed and consumed after discharge after cesarean delivery.We conducted a survey at six academic medical centers in the United States from September 2014 to March 2016. Women who had undergone a cesarean delivery were contacted by phone 2 weeks after discharge and participated in a structured interview about the opioid prescription they received on discharge and their oral opioid intake while at home.A total of 720 women were enrolled; of these, 615 (85.4%) filled an opioid prescription. The median number of dispensed opioid tablets was 40 (interquartile range 30-40), the median number consumed was 20 (interquartile range 8-30), and leftover was 15 (interquartile range 3-26). Of those with leftover opioids, 95.3% had not disposed of the excess medication at the time of the interview. There was an association between a larger number of tablets dispensed and the number consumed independent of patient characteristics. The amount of opioids dispensed did not correlate with patient satisfaction, pain control, or the need to refill the opioid prescription.The amount of opioid prescribed after cesarean delivery generally exceeds the amount consumed by a significant margin, leading to substantial amounts of leftover opioid medication. Lower opioid prescription correlates with lower consumption without a concomitant increase in pain scores or satisfaction.

Routine pain assessment and the procurement of effective analgesics are of paramount importance to critical care patients. Constant evaluation underpins the important balance between pain relief and the pharmacological side effects of administered agents. The significance of these issues was highlighted during the production of the most recent Society of Critical Medicine’s (SCCM) Pain, Agitation, Delirium, Immobility, and Sleep (PADIS) Guidelines [1]. Patients who partnered as authors and contributors in the SCCM PADIS effort ranked this dimension of clinical care as essential to their well-being, leading to its prioritization for these guidelines [2].

The availability of labor analgesia is highly variable in the People's Republic of China. There are widespread misconceptions, by both parturients and health care providers, that labor epidural analgesia is harmful to mother and baby. Meanwhile, China has one of the highest cesarean delivery rates in the world, exceeding 50%. The goal of the nongovernmental No Pain Labor & Delivery (NPLD) is to facilitate sustainable increases in vaginal delivery rates by increasing access to safe neuraxial labor analgesia, thereby decreasing the cesarean delivery rate. NPLD was launched in 2008 with the stated goal of improving labor outcome in China by increasing the absolute labor epidural analgesia rate by 10%. NPLD established 10 training centers over a 10-year period. We hypothesized that increased availability of labor analgesia would result in reduced requests for cesarean delivery and better labor outcomes for mother and baby. Multidisciplinary teams of Western clinicians and support staff traveled to China for 8 to 10 days once a year. The approach involved establishing 24/7 obstetric anesthesia coverage in Chinese hospitals through education and modeling multidisciplinary approaches, including problem-based learning discussions, bedside teaching, daily debriefings, simulation training drills, and weekend conferences. As of November 2015, NPLD has engaged with 31 hospitals. At 24 of these sites, 24/7 obstetric anesthesia coverage has been established and labor epidural analgesia rates have exceeded 50%. Lower rates of cesarean delivery, episiotomy, postpartum blood transfusion, and better neonatal outcomes were documented in 3 impact studies comprising approximately 55,000 deliveries. Changes in practice guidelines, medical policy, and billing codes have been implemented in conjunction with the modernization of perinatal practice that has occurred concurrently in China since the first NPLD trip in 2008.

BackgroundDisagreement among many underpowered studies has led to an equivocal understanding of the efficacy of the 5-HT3 antagonist ondansetron in preventing the consequences of sympathectomy after subarachnoid anesthesia. The authors assessed the efficacy of ondansetron with respect to the overall quality and statistical power of the meta-analyses.MethodsThe authors used a standard and a newer method of meta-analysis, trial sequential analysis (TSA), to estimate adjusted CIs based on how much information has been accrued. They also used random-effects meta-analyses techniques, small trial bias assessment, selection models, sensitivity analyses, and the Grading of Recommendations on Assessment, Development, and Evaluation system. These results from the aforementioned techniques were compared, and importance of consideration of these factors was discussed.ResultsFourteen randomized placebo-controlled trials (1,045 subjects) were identified and analyzed. By using conventional meta-analyses, the authors determined that ondansetron was associated with reduction in the incidence of hypotension (relative risk = 0.62 [95% CI, 0.46 to 0.83], P = 0.001; TSA-adjusted CI, 0.34 to 1.12; I2 = 60%, P = 0.002) and bradycardia (relative risk = 0.44 [95% CI, 0.26 to 0.73], P = 0.001; TSA-adjusted CI, 0.05 to 3.85; I2 = 0%, P = 0.84). However, the authors found indications of bias among these trials. TSAs demonstrated that the meta-analysis lacked adequate information size and did not achieve statistical significance when adjusted for sparse data and repetitive testing. The Grading of Recommendations on Assessment, Development, and Evaluation system showed that the results had low to very low quality of evidence.ConclusionsThe analyses fail to confirm evidence that ondansetron reduces the incidence of hypotension and bradycardia after subarachnoid anesthesia due to the risk of bias and information sizes less than the required. As results from meta-analysis are given significant weight, it is important to carefully evaluate the quality of the evidence that is input.

OBJECTIVES: To describe novel guideline development strategies created and implemented as part of the Society of Critical Care Medicine's 2018 clinical practice guidelines for pain, agitation (sedation), delirium, immobility (rehabilitation/mobility), and sleep (disruption) in critically ill adults. DESIGN: We involved critical illness survivors from start to finish, used and expanded upon Grading of Recommendations, Assessment, Development and Evaluation methodology for making recommendations, identified evidence gaps, and developed communication strategies to mitigate challenges. SETTING/SUBJECTS: Thirty-two experts from five countries, across five topic-specific sections; four methodologists, two medical librarians, four critical illness survivors, and two Society of Critical Care Medicine support staff. INTERVENTIONS: Unique approaches included the following: 1) critical illness survivor involvement to help ensure patient-centered questions and recommendations; 2) qualitative and semiquantitative approaches for developing descriptive statements; 3) operationalizing a three-step approach to generating final recommendations; and 4) systematic identification of evidence gaps. MEASUREMENTS AND MAIN RESULTS: Critical illness survivors contributed to prioritizing topics, questions, and outcomes, evidence interpretation, recommendation formulation, and article review to ensure that their values and preferences were considered in the guidelines. Qualitative and semiquantitative approaches supported formulating descriptive statements using comprehensive literature reviews, summaries, and large-group discussion. Experts (including the methodologists and guideline chairs) developed and refined guideline recommendations through monthly topic-specific section conference calls. Recommendations were precirculated to all members, presented to, and vetted by, most members at a live meeting. Final electronic voting provided links to all forest plots, evidence summaries, and "evidence to decision" frameworks. Written comments during voting captured dissenting views and were integrated into evidence to decision frameworks and the guideline article. Evidence gaps, reflecting clinical uncertainty in the literature, were identified during the evidence to decision process, live meeting, and voting and formally incorporated into all written recommendation rationales. Frequent scheduled "check-ins" mitigated communication gaps. CONCLUSIONS: Our multifaceted, interdisciplinary approach and novel methodologic strategies can help inform the development of future critical care clinical practice guidelines.

Background Consensus panels regularly recommend aerobic exercise for its health‐promoting properties, due in part to presumed anti‐inflammatory effects, but many studies show no such effect, possibly related to study differences in participants, interventions, inflammatory markers, and statistical approaches. This variability makes an unequivocal determination of the anti‐inflammatory effects of aerobic training elusive. Methods and Results We conducted a randomized controlled trial of 12 weeks of aerobic exercise training or a wait list control condition followed by 4 weeks of sedentary deconditioning on lipopolysaccharide (0, 0.1, and 1.0 ng/mL)‐inducible tumor necrosis factor‐α (TNF‐α) and interleukin‐6 (IL‐6), and on toll‐like receptor 4 in 119 healthy, sedentary young adults. Aerobic capacity by cardiopulmonary exercise testing was measured at study entry (T1) and after training (T2) and deconditioning (T3). Despite a 15% increase in maximal oxygen consumption, there were no changes in inflammatory markers. Additional analyses revealed a differential longitudinal aerobic exercise training effect by lipopolysaccharide level in inducible TNF ‐α ( P =0.08) and IL‐6 ( P =0.011), showing T1 to T2 increases rather than decreases in inducible (lipopolysaccharide 0.1, 1.0 versus 0.0 ng/mL) TNF‐ α (51% increase, P =0.041) and IL‐6 (42% increase, P =0.11), and significant T2 to T3 decreases in inducible TNF‐ α (54% decrease, P =0.007) and IL‐6 (55% decrease, P TNF‐ α or IL‐6. Conclusions The failure to support the primary hypotheses and the unexpected post hoc findings of an exercise‐training–induced proinflammatory response raise questions about whether and under what conditions exercise training has anti‐inflammatory effects. Clinical Trial Registration URL : http://www.clinicaltrials.gov . Unique identifier: NCT 01335737.

Author(s): Devlin, John W; Skrobik, Yoanna; Gelinas, Celine; Needham, Dale M; Slooter, Arjen JC; Pandharipande, Pratik P; Watson, Paula L; Weinhouse, Gerald L; Nunnally, Mark E; Rochwerg, Bram; Balas, Michele C; van den Boogaard, Mark; Bosma, Karen J; Brummel, Nathaniel E; Chanques, Gerald; Denehy, Linda; Drouot, Xavier; Fraser, Gilles L; Harris, Jocelyn E; Joffe, Aaron M; Kho, Michelle E; Kress, John P; Lanphere, Julie A; McKinley, Sharon; Neufeld, Karin J; Pisani, Margaret A; Payen, Jean-Francois; Pun, Brenda T; Puntillo, Kathleen A; Riker, Richard R; Robinson, Bryce RH; Shehabi, Yahya; Szumita, Paul M; Winkelman, Chris; Centofanti, John E; Price, Carrie; Nikayin, Sina; Misak, Cheryl J; Flood, Pamela D; Kiedrowski, Ken; Alhazzani, Waleed

We previously reported the rapid and robust clinical effects of ketamine versus saline infusions in a proof-of-concept crossover trial in unmedicated adults with obsessive-compulsive disorder (OCD). This study examined the concurrent neurochemical effects of ketamine versus saline infusions using proton magnetic resonance spectroscopy ((1)H MRS) during the clinical proof-of-concept crossover trial. Levels of the inhibitory neurotransmitter gamma-aminobutyric acid (GABA) and the excitatory neurochemicals glutamate+glutamine (Glx) were acquired in the medial prefrontal cortex (MPFC), a region implicated in OCD pathology. Seventeen unmedicated OCD adults received two intravenous infusions at least 1 week apart, one of saline and one of ketamine, while lying supine in a 3.0 T GE MR scanner. The order of each infusion pair was randomized. Levels of GABA and Glx were measured in the MPFC before, during, and after each infusion and normalized to water (W). A mixed effects model found that MPFC GABA/W significantly increased over time in the ketamine compared with the saline infusion. In contrast, there were no significant differences in Glx/W between the ketamine and saline infusions. Together with earlier evidence of low cortical GABA in OCD, our findings suggest that models of OCD pathology should consider the role of GABAergic abnormalities in OCD symptomatology.

Objective The aim of this study is to determine the relationship between heart rate and/or blood pressure variability, measured at 28 weeks' gestation, and the incidence of pregnancy-induced hypertension or preeclampsia. Study Design Secondary analysis of data from a prospectively enrolled cohort of 385 active military women in whom spectral analysis of continuous heart rate and variability was measured at 28 weeks' gestation. The primary outcome was the predictive value of spectral analysis of heart rate and blood pressure for hypertensive diseases of pregnancy. Results High-frequency heart rate variability was reduced and low-frequency variability of systolic and diastolic blood pressure increased in women who would develop pregnancy-induced hypertension but not preeclampsia. Low-frequency variability of diastolic blood pressure remained a significant predictor of pregnancy-induced hypertension but not preeclampsia after adjustment for age, weight, and blood pressure in a multivariate model. Conclusion Early identification of pregnancy-induced hypertension can facilitate treatment to avoid maternal morbidity. Understanding the physiological underpinnings of the two very different diseases may lead to improved treatment and prevention. If proven effective in a broader population, the ability to differentiate pregnancy-induced hypertension from preeclampsia may reduce unnecessary iatrogenic interventions or inappropriate preterm delivery.

This chapter reviews the pharmacology of the intravenously administered opioids in the practice of geriatric anesthesiology. These drugs include morphine, meperidine, hydromorphone, fentanyl, sufentanil, and methadone. It is important that anesthesiologists understand the differences in pharmacology of opioids in elderly patients, in order to choose the appropriate drug and titrate precisely to achieve the desired analgesic effects while minimizing the risks of opioid toxicity. The key points for this chapter are as follows: (1) Elderly patients need about half the dose as younger patients, (2) The primary reason is pharmacodynamics (the elderly brain is more sensitive to opioids), (3) The pharmacokinetic changes with age are modest, (4) Studies in elderly animals show reduced numbers of μ receptors with increased age. That does not explain the reduction in dose, as decreased receptor density should decrease sensitivity to opioids. The enhancement in drug effect seen in the clinic is more likely attributable to changes in cyclonucleotide coupling and other downstream changes that occur in aging, and (5) Mepiridine should be used with caution in elderly patients due to its effects on myocardium, pharmacokinetics related to its metabolites, and its delirogenic properties.

The physiology that underlies pain perception is complex and clearly influenced by both genetic and environmental factors. This issue of Anesthesia & Analgesia includes 2 articles that identify relationships between single nucleotide polymorphisms (SNPs) in the gene for Catechol-O-methyltransfer

Objective To develop a model that uses cervical effacement, fetal station, and parity to predict progress during the first stage of labor. Study Design This was a secondary analysis of a cohort of 1,128 parturients delivering after 34 weeks. Timed cervical exams from each patient were fit with a biexponential model. Methods for consideration of fetal station, cervical effacement and parity were developed and validated. Results The biexponential model fit the data in an unbiased manner with a median absolute prediction error of 1.1 cm. Although nulliparous women had slower active labor, they did not differ from multiparous women in their rate of latent labor or the cervical dilation at which they transitioned to active labor. In addition, nulliparous women began laboring with a more effaced cervix (45 vs. 31%) and lower fetal station (–2.8 vs. –3.2). Conclusion We validated a biexponential model for labor progress using a large mixed parity cohort. We demonstrated that parity and initial fetal station add important clinical information that can be used to make a labor model more accurate. As such, parity and fetal station can be utilized in such structural models to predict normal labor progress and potentially identify abnormalities in labor progress.

Background Prediction models to identify parturients who experience protracted pain, prolonged opioid use, and delayed self-assessed functional recovery are currently inadequate. Methods For this study, 213 nulliparous women who planned vaginal delivery were enrolled and assessed daily until they completed three outcomes: (1) pain resolution; (2) opioid cessation; and (3) self-assessed functional recovery to predelivery level. The primary composite endpoint, ‘pain and opioid-free functional recovery' was the time required to reach all three endpoints. The subjects were divided into two categories (the worst (longest time) 20% and remaining 80%) for reaching the primary composite endpoint, and each individual component. Prediction models for prolonged recovery were constructed using multivariate logistic regression with demographic, obstetric, psychological, and health-related quality of life characteristics as candidate predictors. Results Labour induction (vs spontaneous labour onset) predicted the worst 20% for the primary composite endpoint in the final multivariate model. Labour induction and higher postpartum day 1 numerical rating score for pain were predictors for being in the worst 20% for both functional recovery and pain burden. Labour type, delivery type, Patient-Reported Outcomes Measurement Information System (PROMIS) anxiety score, RAND 36 Item Health Survey 1.0 (SF-36) physical health composite score, and postpartum breastfeeding success were predictive of delayed opioid cessation. Conclusions Labour induction and elevated numerical rating score for pain are predictive of poor recovery after childbirth. Further research is necessary to determine whether modification would benefit mothers at risk for poor recovery.