Endometriosis is a common gynecological disorder that causes inflammation and pelvic pain. Endometriosis-related pain is best captured with patient-reported outcome (PRO) measures, however, assessment of endometriosis-related pain in clinical trials has been difficult in the absence of a reliable and valid PRO instrument. We describe the development of the Endometriosis Pain Daily Diary (EPDD), an electronic PRO developed as a survey instrument to assess endometriosis-related pain and its impact on patients’ lives.The EPDD was initially developed on the basis of an existing Endometriosis Pain and Bleeding Diary, a targeted review of relevant literature, clinical expert interviews, and open-ended (concept elicitation) patient interviews in the United States (US) and Japan which captured patients’ experience with endometriosis. Cognitive interviews of patients with endometriosis were conducted to evaluate patient comprehension of the EPDD items. A conceptual model of endometriosis was developed, and meetings with US and European regulatory authorities provided feedback for validating the EPDD in the context of clinical trials. Translatability assessments of the EPDD were conducted to confirm its appropriate interpretation and ease of completion across 17 languages.The iterative development progressed through three versions of the instrument. The EPDDv1 included 18 items relating to dysmenorrhea/pelvic pain, dyspareunia and sexual activity, bleeding, hot flashes, daily activities, and use of rescue medication. The EPDDv2 was a larger 43-item survey tested in cognitive interviews and subsequently revised to yield the current 11-item EPDDv3, consisting of five core items relating to dysmenorrhea, non-menstrual pelvic pain, and dyspareunia, and six extension items relating to sexual activity, daily activities, and use of rescue medication.The EPDD is a PRO for the evaluation of endometriosis-related pain and its associated impacts on patients’ lives. The EPDD represents an important step in providing a PRO that is relevant to patients with endometriosis-related pain in the context of a clinical study setting , designed to evaluate pain associated with endometriosis, including regulatory agency support for its further exploration in clinical trials. Endometriosis is a common gynecological disorder characterized by the presence of endometrial glands and tissue outside of the uterus, resulting in chronic inflammation, dysmenorrhea, dyspareunia, and chronic pelvic pain . The preEndometriosis-related pain and its impact on patients’ lives are best captured through the use of direct reports from patients regarding their experience, that is, patient-reported outcome (PRO) measures. PROs are widely used in evaluating pain; three PROs are commonly used in studies of endometriosis. The Composite Pelvic Signs and Symptoms Score (CPSSS) is a modified version of the Biberoglu and Behrman Scale  and measThus, the CPSSS, EHP, and EPBD have their limitations as a fit-for-purpose tool for evaluating endometriosis-related pain in the context of supporting labeling claims of a treatment benefit, as outlined in the US FDA PRO Guidance for Industry . TherefoGiven its development process, the EPBD was an appropriate starting place for the EPDD. The FDA guidance emphasizes the importance of demonstrating evidence of the relevance  of the PRO instrument to the target patient population, and ensuring that the population studied in the PRO instrument development and documentation process is comparable with that in the clinical study setting in which the instrument is to be used .This paper describes the initial steps of the development of the EPDD. Specifically, this paper describes the process undertaken for establishing content validity of the EPDD, providing evidence that it measures relevant concepts and experiences relating to pain associated with endometriosis, is homogenously interpretable, and is easily comprehendible. The processes described herein represent the first steps of development of an instrument that is ‘fit-for-purpose’.The EPDD was developed through a series of procedures, including the development of an evidence-supported conceptual model of disease, all of which followed regulatory guidance set forth by the European Medicines Agency’s (EMA) Committee for Medicinal Products for Human Use (CHMP) reflection paper on the use of health-related quality of life measures in the evaluation of medicinal products  and the The EPDD was designed to be administered using an electronic platform, asking patients to record their endometriosis-related pain experiences over the previous 24 h. To date, the EPDD has been administered using a small hand-held electronic device that queries the patient each evening for a recording. The device allows patient compliance to be tracked and is designed to minimize incomplete records, as the programming does not allow patients to skip questions.The initial version of the EPDD EPDDv1) was developed on the basis of the conceptual framework of the existing Endometriosis Pain and Bleeding Diary (EPBD) , availab was deveA targeted literature review to identify the most important and relevant symptoms and impacts related to endometriosis. The MEDLINE database was searched for human studies published in English; search terms included targeted phrases such as ‘endometriosis sign’, ‘endometriosis symptom’, ‘endometriosis impact’, ‘endometriosis’ and ‘quality of life’, ‘Activities of Daily Living (ADL)’, ‘interview’, and ‘focus group’.Individual interviews with five clinical experts in endometriosis to collect further input regarding important and relevant health concepts  for women with endometriosis.n = 17) were recruited if they were aged 18–45 years and had surgically confirmed diagnosis of endometriosis within 5 years. Patients from Japan (n = 17) were recruited if they were aged 20–45 years with a diagnosis of endometriosis; because surgical diagnosis is uncommon in Japan, surgical diagnosis was not required if diagnosis was confirmed by a blood test, internal examination, or a magnetic resonance imaging or computed tomography scan. During the interviews, patients were first asked to spontaneously report any symptoms they experienced as a result of endometriosis, and thereafter were asked if they experienced any specific symptoms from a predefined list of symptoms known to be associated with endometriosis (based on literature and expert input).Concept elicitation interviews with adult women in the US and Japan to identify and confirm the symptom and impact concepts from the EPDDv1 that were the most important and relevant to women with endometriosis-related pain. Patients from the US  software program for coding . Data coInformation obtained from these exercises resulted in the development of a conceptual disease model of endometriosis. This conceptual disease model served to facilitate an item refinement and generation meeting, during which the EPDDv1 was updated to include relevant findings from the literature review and patient and expert interviews. The outcome of the item refinement and generation meeting was the EPDDv2.n = 16) and Japan (n = 15) were identified via clinical record review (US) and patient self-reporting (Japan), and subsequently recruited and screened at three US centers  and one market research firm in Tokyo, Japan, to participate in the cognitive interviews. Patients completed the EPDDv2 and participated in face-to-face individual semi-structured interviews.The EPDDv2 was tested in additional cognitive interviews with patients. Patients with endometriosis from the US  among 19 countries. When countries/languages are selected for the pivotal trials, the full translation and linguistic validation process would be conducted for each language. Overall, results from the translatability assessment demonstrated that the EPDDv3 is a robust tool and has utility among all translated languages. No significant issues were identified. Furthermore, additional regulatory feedback was obtained from the FDA and the EMA and a second item refinement and generation meeting was held during which the current version of the EPDD (EPDDv3) was developed.The EPDDv1 included 18 items in six categories: pelvic pain (including dysmenorrhea and NMPP), dyspareunia and sexual activity, bleeding, hot flashes, daily activities, and rescue medication/protection. The EPDDv1 was developed to be administered electronically with a 24-h recall period. In the phase 2 TERRA trial, it was implemented with a small hand-held device.A total of 14 patients from the US participated in the face-to-face, semi-structured cognitive interviews in three waves, with 4–5 patients in each wave. During the first wave, wording modifications were made to two instructions and 7 items of the EPDDv1. During the second wave, wording modifications were made to one item. No modifications were made during the third wave. Demographic data are presented in Table A total of 30 peer-reviewed articles were retrieved from the search; seven articles contained qualitative data. Five types of pain were identified, and bleeding and gastrointestinal disturbance were also highlighted as being related to endometriosis.n = 1; Germany, n = 2) and Japan (n = 2) and completed a semi-structured interview. Interviews with the Japanese experts were conducted in English via typed text to minimize language misinterpretation. All five clinical experts highlighted the key symptom of endometriosis as pain; specifically, pain during menstruation, NMPP, pain during and after sexual intercourse, and pain during defecation. Pain during or after sexual intercourse was more associated with ‘deep’ pain rather than ‘superficial’ pain. A less common symptom not related to pain was bleeding. All clinical experts stated that a primary concern related to endometriosis is infertility. The most common impacts on patients’ daily lives, as perceived by clinical experts, were role functioning, especially attendance at work and school, performance of daily activities, sexual function, and partner relationships; missed work/school was consistently reported as having the greatest impact.Five clinical experts were recruited from Europe  of patients who reported these symptoms (Table n = 17) and 64.7% of Japanese patients (n = 17), and ‘having problems at work’, spontaneously reported by 58.8% of US patients and 41.2% of Japanese patients. Japanese patients also commonly reported ‘dropping other daily activities’ (41.2%)  informed a conceptual model of disease Fig. , which sPatients were recruited and screened at three US centers  and through a market research firm in Tokyo, Japan. The cognitive interviews were conducted in four waves in the US and three waves in Japan. Patient demographics are presented in Table The EPDDv2 items were tested in three waves of cognitive interviews in the US, and wording modifications were made to items after each wave. During Wave 1 (US), wording modifications were made to three items pertaining to pain, sexual intercourse and pain, and bleeding; no items were added or removed. During Wave 2 (US), wording modifications were made to one item, and alternate questions for nine items were proposed and tested in Wave 3. During Wave 3 (US), one item was removed from the survey, and an alternate question was proposed for one other item for further testing.The EPDDv2 was then translated to Japanese and tested in two waves of interviews in Japan. The Japanese translation was slightly modified after each wave to ensure the accuracy and understandability of the language used. Based on Japanese patient feedback, translation modifications were necessary for the phrases ‘deep pain or penetration’, ‘spotting’, ‘social activities’, sexual ‘interest’, and ‘during the past 24 h’, which are not common terminology in Japan. Four items were evaluated and found to be better understood by patients and subsequently replaced the original items.Following the two waves of interviews in Japan, and based on feedback from the FDA and EMA regarding the length of the survey, the EPDDv2 was reduced from 43 to 11 items consisting of five core items relating to dysmenorrhea, NMPP, and dyspareunia, and six extended items relating to sexual activity, daily activities, and use of rescue medication, yielding the EPDDv3. This 11-item EPDDv3 was evaluated in a third wave of interviews in Japan and the fourth wave of interviews in the US. During Wave 3 of the Japanese interviews, translation modifications were made to 12 items and wording modifications were made to two items. During Wave 4 of the US interviews, all patients confirmed comprehension of all items. After the final wave of interviews, the EPDDv3 was sent for translation and linguistic validation into 17 languages (including Japanese). The EPDDv3 is displayed in Table In the absence of a fit-for-purpose PRO for the measurement of endometriosis-related pain, we developed an instrument to support evaluation of biopharmaceutical products and to measure key signs and symptoms associated with endometriosis. To accomplish this, a conceptual model of endometriosis and the EPDD was developed on the basis of three sources of evidence: a structured literature review, clinical expert opinion, and qualitative patient concept elicitation interviews. In addition, translation and linguistic validation and patient cognitive interviews facilitated the refinement of the items to ensure patient comprehension and understanding, as well as the ability to respond to items as intended. Through these exercises, the items of the EPDD were revised and refined to ensure relevance to patient pain experience as well as comprehension by patients as intended. Translation and testing in Japanese patients allowed for development of a harmonized instrument.The EPDD resulting from this content validity work consists of five core items relating to dysmenorrhea, NMPP, and dyspareunia, and six extended items relating to sexual activity, daily activities, and use of pain medication, and will serve as a daily, electronic, patient-reported measure of endometriosis-related pain. In particular, the instrument was designed and developed for the purpose of detecting a treatment response in the context of drug development. Content validity of the EPDD was demonstrated via a rigorous process consisting of several waves of cognitive interviews. In addition, the translatability assessment confirmed its utility in 17 languages, allowing for the potential use of the EPDD in global clinical trials in endometriosis. The 17 languages included in the translatability assessment were chosen based on anticipated countries that would be selected for enrollment in future phase 3 clinical trials. If any of those countries/languages are selected, then a full translation and linguistic validation process would be conducted for each language. The phase 2 TERRA study, a double-blind, randomized, parallel-group, placebo-controlled clinical trial, used the EPDD to assess the efficacy of a GnRH receptor antagonist, ASP1707, in women with endometriosis-associated pelvic pain. To determine a clinically meaningful threshold of improvement, as measured by the EPDD, anchor-based analyses of the degrees of improvement in endometriosis-related pain on the Patient Global Impression of Change, the Brief Pain Inventory, the modified Biberoglu and Behrman, and the European quality of life 5-dimension 5-level scale were performed using the EPDDv1. Results suggested that an improvement of 60%  and 70% (for dysmenorrhea), as measured by the EPDD, would be considered clinically meaningful . The successful completion of this study, which achieved its primary endpoint of reducing endometriosis-associated pelvic pain after 12 weeks of treatment, demonstrates the internal validity and reliability of the EPDDv1 in a clinical trial context.The PRO reported here has three key advantages over existing measures. First, to our knowledge, the EPDD is the only PRO for endometriosis-related pain that was developed in accordance with guidance set forth by the EMA and FDA. Second, the electronic format allows for convenient, real-time completion of the instrument by the patient, without the requirement for involvement of investigative research site staff. Third, the requirement for daily entry ensures accurate data collection and precludes inaccuracies associated with lengthy recall periods. Conversely, limitations of the EPDD are noteworthy and should be considered. As the instrument was designed specifically for use in clinical trials for the assessment of patient response to treatment, important items relating to patient personal experience with endometriosis  were removed from the final version. In addition, the EPDD does not address pain during defecation or exercise, or other non-pain symptoms that are important to patients, such as bloating, dizziness, nausea, vomiting, difficulties with physical functioning, work/school limitations, relationship interference, or emotional functioning . Together, these characteristics limit the use of the EPDD within clinical practice; however, opportunities exist for expansion of the EPDD to broaden its clinical application.Although the EPDDv3 can be considered content valid, the remaining psychometric properties of the instrument, including reliability, construct validity, and ability to detect change have not been established. Such psychometric data and quantitative validation can be obtained through the administration of the EPDD with other validated PRO measures  in a longitudinal intervention study, and are required for endorsement  of the EPDD as fit-for-purpose for use in clinical trials of endometriosis interventions.The EPDD is a PRO for the evaluation of endometriosis-related pain. The EPDD represents an important step in providing an effective PRO to evaluate pain associated with endometriosis and its related impacts on patients.


Herein we show that low IPP and WH gas may decrease inflammation in the laparoscopic surgical environment, resulting in better clinical outcomes. Low IPP and/or WH gas significantly lowered expression of inflammation-related genes in peritoneal tissues compared to the standard IPP and/or CD gas. The odds ratios of a visual analogue scale (VAS) pain score >30 in the ward was 0.18  at 12 hours and 0.06  at 24 hours in the low IPP group versus the standard IPP group, and 0.16  at 0 hours and 0.29  at 12 hours in the WH gas group versus the CD gas group.Laparoscopic surgery technology continues to advance. However, much less attention has been focused on how alteration of the laparoscopic surgical environment might improve clinical outcomes. We conducted a randomized, 2 × 2 factorial trial to evaluate whether low intraperitoneal pressure (IPP) (8 mmHg) and/or warmed, humidified CO Laparoscopic surgery technology has evolved dramatically over the past 3 decades, and continues to advance. However, much less attention has been focused on how alteration of the laparoscopic surgical environment might improve clinical outcomes.2 pneumoperitoneum on expression levels of 84 genes known to encode extracellular matrix and adhesion molecules and 84 genes that encode inflammatory cytokine signaling molecules in peritoneal tissues using two real-time polymerase chain reaction (PCR)-based assay panels2. We hypothesized that a high IPP during a CO2 pneumoperitoneum might adversely affect gene expression of extracellular matrix, adhesion and inflammatory cytokine signaling molecules in peritoneal tissues4, if the high IPP caused higher rates of peritoneal dissemination, peritoneal tissue hypoxia and post-operative adhesion formation, as demonstrated in animal studies8. We identified several differentially expressed genes  in peritoneal tissues in the standard IPP (12 mmHg) group compared with the low IPP (8 mmHg) group. Our previous findings suggested that a low IPP (8 mmHg) might minimize the adverse impacts of IPP on the fibrinolytic system, inflammation, peritoneal fibrosis, and generation of hyaluronan (HA) fragments2. However, our previous studies were not randomized2. In addition, we did not evaluate whether a low IPP (8 mmHg) could improve clinical outcomes2. A Cochrane review concluded that no evidence is currently available to support the use of a low-pressure pneumoperitoneum in low–anesthetic-risk patients undergoing elective laparoscopic cholecystectomy9. Regarding temperature and humidity, previous animal and in vitro experiments demonstrated that a cool and dry CO2 (CD) gas, which we use in a clinical setting, might adversely affect the surgical peritoneal environment13. However, a Cochrane review concluded that during laparoscopic abdominal surgery, heated gas insufflation, with or without humidification, minimally impacts patient outcomes14. However, no studies have yet evaluated the impact of the combined use of a warmed, humidified CO2 (WH) gas pneumoperitoneum and low IPP during laparoscopic surgery on the peritoneal environment and postoperative clinical outcomes.We previously investigated the impact of IPP during a CO2 pneumoperitoneum on the surgical peritoneal environment during laparoscopic abdominal surgery and improving postoperative clinical outcomes, compared to the standard IPP and CD gas. To test this hypothesis, we conducted the present randomized, 2 × 2 factorial trial.In the present study, we hypothesized that combined use of low IPP and WH gas may be better for minimizing the adverse impact of a CO2. Secondary objectives were to compare the impacts of low IPP versus standard IPP, and CD gas versus WH gas, on the quality of postoperative recovery, postoperative pain, intraoperative core body temperature, and intraoperative and postoperative complications.The primary objective of this study was to compare the impact of low IPP (8 mmHg) versus standard IPP (12 mmHg), and CD gas versus WH gas, on expression levels of 12 genes  in peritoneal biopsy specimens according to our previous studiesThe study was designed as a prospective, 2 × 2 factorial, four–parallel-group, single-center, single-blinded (patients), superiority randomized trial. Patients were recruited at CHU Clermont-Ferrand from September 2013 through June 2016. The study protocol was approved by the Consultative Committee for Protection of Persons in Biomedical Research (CPP) of the Auvergne (France) region and registered by the competent French authority . Informed written consent was obtained from each patient prior to surgery. Methods were carried out in accordance with the approved guidelines and regulations. This trial is registered with ClinicalTrials.gov on 24/06/2013, trial number NCT01887028.https://www.randomizer.at/) using an algorithm with BMI (<25 vs. ≥25), height (<160 vs. ≥160 cm), and age (<65 vs. ≥65 years) as minimization covariates. This randomized trial employed a 2 × 2 factorial design, with IPP and types of CO2 gas as factors, resulting in four experimental arms: 1) 12-mmHg IPP with CD gas, 2) 12-mmHg IPP with WH gas, 3) 8-mmHg IPP with CD gas, and 4) 8-mmHg IPP with WH gas. After randomization, patients can only be excluded if pathological peritoneal tissues such as adhesions are detected just after insertion of the four trocars, a different surgical technique is needed because the sacral promontory is not clearly identified, IPP is changed during the surgery, conversion to laparotomy, or withdrawal of consent. Enrollment in this study is voluntary and patients are allowed to withdraw at any time.During study recruitment, all patients who underwent laparoscopic sub-total hysterectomy with promontofixation for uterine prolapse were assessed for eligibility to participate by the principal investigators (S.M. and R.B.). The full trial protocol can be found in the Supplement (see Supplementary Methods). After obtaining informed written consent, participants are allocated in a 1:1:1:1 ratio by a remote 24-hour-a-day computer-generated randomization system hosted at the Institute for Medical Informatics, Statistics and Documentation, Medical University of Graz, in Graz, Austria  and the ward nurses, who evaluated postoperative pain using a visual analogue scale (VAS), were also blinded. The database was submitted for analysis to independent statisticians who were blinded and were neither involved in the trial management nor employed by the trial sponsor.Anesthetic management was performed by 8 staff anesthesiologists  and anesthesiology residents or nurse anesthetists under their supervision. In the operating room, standard ASA anesthetic monitors were placed. All patients received a standardized general anesthetic consisting of premedication with oral administration of 1 mg/kg hydroxyzine hydrochloride suspension 1 hour preoperatively and induction with target-controlled infusion of 0.2 mcg/kg sufentanil and 3 to 5 mg/kg IV propofol. Two mg/kg IV cisatracurium were used to facilitate tracheal intubation. The patient’s lungs were ventilated with a 40:60 mixture of oxygen to nitrous oxide. Desflurane and target-controlled infusion of sufentanil were added for maintenance. To assure suitable operating conditions, neuromuscular blockade was maintained using cisatracurium. After induction of anesthesia, all patients received intraoperative forced-air warming, which was placed on the patient by the anesthesia staff. Intraoperative core temperature was measured at 15-minute intervals using an esophageal probe. For prevention of postoperative nausea and vomiting, 8 mg IV dexamethasone at the beginning of intervention, and 1 mg IV droperidol 1 and 4 mg IV ondansetron at the end of intervention were administrated. 30 minutes before the end of intervention, all patients received 1 g IV paracetamol and 50 mg IV ketoprofene for prevention of postoperative pain.2 gas was performed using a Storz electronic endoflator . CO2 gas was warmed to 37 °C and humidified to 98% RH using the Fisher & Paykel MR860 Laparoscopic Humidification System . For the groups receiving WH gas, 180 mL sterile water was added to the chamber and the humidifier was switched on. For the groups receiving standard CD gas, sterile water was not added to the chamber and the humidifier was not switched on, and CO2 gas was delivered at room temperature (21 °C) and 0% relative humidityThis study involved 1 staff surgeon (R.B.) who performed all operations with the assistance of a gynecological surgical resident. Insufflation of CO15. Macroscopically normal peritoneum was collected from the anterior parietal wall at the beginning of surgery and every 60 minutes thereafter as previously described2.When the IPP reached 15 mmHg, four trocars were inserted, immediately after which the IPP was decreased to 12 or 8 mmHg and then maintained at these levels throughout surgery. For all patients, 5 mL ropivacaine hydrochloride solution (2 mg/mL) were infiltrated around the trocar wounds. All incisions were made after ropivacaine infiltration. In addition, 20 mL ropivacaine solution (2 mg/mL) were infused at the beginning of the operation under the right hemidiaphragm. Laparoscopic sub-total hysterectomy with promontofixation used the same surgical technique previously described by our group was performedAll patients received our standardized post-operative pain management. On arrival in the PACU, patients were asked to rate their pain at rest using a VAS. After the initial rating, pain ratings were repeated every 20 minutes during the remainder of the PACU stay. When the pain score was >30 of 100, postoperative pain was treated with an IV bolus of 2 to 3 mg morphine, and then 1 to 2 mg IV every 10 minutes to achieve a pain score ≤30 of 100. Intravenous patient-controlled analgesia (IV-PCA) was prepared using morphine (1 mg/mL) and droperidol (0.05 mg/mL). On arrival in the ward, patients were asked to rate their pain at rest using a VAS. Then, the intensity of postoperative pain at rest and/or on moving was assessed using a VAS every 4 hours until 24 hours postoperatively, then 3 times/day until discharge. All patients received 1 g paracetamol and 50 mg of ketoprofene IV every 6 hours until 24 hours postoperatively. Then, pain was managed using oral paracetamol and ketoprofene.16. The QoR-40 was originally designed to assess recovery in five dimensions 24 h after surgery 16. It may be most suitable for use in clinical trials or for inpatients17. The QoR-40 was administered four times, the day before surgery , 24 hours and 48 hours postoperatively, and at the first postoperative visit (30 days after surgery). Intraoperative and postoperative complications were recorded and postoperative complications were classified according to the Clavien-Dindo classification18.The quality of postoperative functional recovery was assessed using the QoR-40 questionnaireQuality of surgical conditions, including the operative technical difficulty, working space, visibility, and pain experienced by the surgeon such as shoulder pain, backache, and hand/finger joint pain during surgery, was rated by the operating surgeon at the end of each procedure using visual analogue scales consisting of 100-mm lines anchored at both ends with 0 and 100.2.mRNA levels of 12 genes  ligand 2 [CXCL-2], E-selectin, interleukin-10 [IL-10], hyaluronic acid synthase-1 [HAS-1], HAS-2, HAS-3, and hyaluronidase-1 [Hyal-1]) were measured by quantitative real-time RT-PCR with a Light Cycler  as previously described2 and our pilot study. The standard deviation was calculated from these gene expression level results for 12 genes and differences that we considered biologically plausible with a significance level of 0.05; 40 patients for each group enabled a power of 91–95% for each gene.The STATA program version 13.1  was used for statistical analysis. The power calculation of the present trial was based on our previous studies2 gas, and time point. The results were summarized as the mean difference in scores between groups, after adjusting for levels at baseline.The global QoR-40 scores and the dimensions of the QoR-40 questionnaire were analyzed using the generalized linear mixed model to allow for repeat measurements over time from each patient. The baseline score was considered as a covariate in the analysis, and three main factors were used in the analysis: IPP, type of CO19. During the PACU stay, the maximum pain score before receiving morphine was assessed at a single time point. Logistic regression was used for the analysis. During the inpatient ward stay, pain scores were measured at multiple time points. To allow for multiple measurements over time, the analysis was performed using mixed logistic regression methods. Two-level models were used, with individual measurements nested within patients. To allow for varying pain scores over time, terms for time were included in the regression model. Linear, squared, and cubic terms for time were all included to allow modelling of a flexible relationship between time and pain score. Interactions between the two treatments (IPP and type of CO2 gas) and time were included to allow the treatment effects to vary over the course of the inpatient stay. The regression models were simplified to omit non-significant interactions from the final model. Mixed logistic regression was used for the analysis.VAS pain scores were grouped into three categories; ≤30, 31–70, and >70. A study showed that grouping VAS scores into categories  provides greater clinical relevance for comparisons than using the full spectrum of measured values or changes in value, when pain is an outcome measure in postoperative patients2 pneumoperitoneum. This analysis approach considered the 1- and 2-hour values as separate outcomes, which were thus analyzed separately. Linear regression was used for the analysis, with the baseline (0 hours) values included as a covariate.The gene expression levels in peritoneal biopsy specimens relative to levels of a reference gene (GAPDH) were assessed at 0 hours, and at 1 and 2 hours during a COFor the remaining analyses, groups were compared using Fisher’s exact test for categorical variables, the Mann-Whitney U test for nonparametric continuous variables, and the t test for parametric continuous variables. Statistical significance was accepted at the 0.05 level.The datasets generated during and/or analysed during the current study are available from the corresponding author on reasonable request.2 volume used during CO2 pneumoperitoneum between the 12-mmHg and 8-mmHg groups: the CO2 volume used in the 8-mmHg group was significantly smaller than that used in the 12-mmHg group . No significant differences in global QoR-40 scores were observed between the CD gas and WH gas groups. “Psychological support” was significantly higher in the 8-mmHg group than in the 12-mmHg groups (p = 0.04). However, the mean difference was only 0.07 between groups. For the “pain” dimension, a significant time by IPP interaction was observed (p = 0.008), but no significant time by type of CO2 gas interaction was noted. The score for the “pain” dimension was significantly higher in the 8-mmHg group than in the 12-mmHg group at 24 hours  and at 48 hours  postoperatively. No significant difference in “pain” was observed between the 8-mmHg and 12-mmHg groups 30 days postoperatively. Furthermore, no significant difference in “pain” was observed between the CD gas and WH gas groups.Results are shown in Table There were no patients with a VAS score >30 the day before surgery . In the present analysis, we only analyzed VAS pain scores at rest, because during the early postoperative period up to 12 hours, many patients stayed at rest; thus, pain scores on movement could not be sufficiently evaluated during this period. No patients had shoulder pain. We have been systematically performing infusion of ropivacaine solution under the right hemidiaphragm for over 10 years. During this time, we have had no or few complaints about shoulder pain after laparoscopic surgery.19.In the present study, there were very few patients with a VAS score >70 postoperatively. Thus, pain scores were categorized as either ≤30 (no or mild pain) or >30 , giving a binary measure2 gas (p = 0.81). Neither IPP nor the type of gas was associated with the likelihood of a high VAS pain score >30 in the PACU   Table .Table 5O2 gas and time (p = 0.21), and a non- significant-two-way interaction was observed between IPP and type of CO2 gas (p = 0.22). No significant difference was observed in the likelihood of a VAS pain score >30 between the 8-mmHg and 12-mmHg groups at 0 hours (p = 0.29)  Fig. , Table 629) Fig. , Table 629) Fig. , Table 629) Fig. , Table 629) Fig. , Table 629) Fig. , Table 6No significant differences in the start, minimum, maximum, mean, or final intraoperative core body temperatures were observed between the CD gas and WH gas groups Table .One patient in the 8-mmHg with CD gas group had an intraoperative complication (perforation of the stomach by the Veress needle). Postoperatively, the patient had an uneventful recovery and was discharged on postoperative day 3. No patients had postoperative complications.Scores rated by the surgeon for operative technical difficulty and working space for dissection and suturing were significantly worse in the 8-mmHg group than in the 12-mmHg group  compared to laparotomy22. The present findings and a previous meta-analysis21 suggest that a WH gas may be effective in reducing pain scores during the immediate postoperative period after laparoscopic surgery. The present molecular analysis indicated that low IPP significantly decreased expression of pro-inflammatory genes  and significantly increased that of anti-inflammatory genes  compared to the standard IPP. In addition, low IPP and WH gas significantly increased the HA synthase genes HAS-1 and HAS-2 compared to the standard IPP and CD gas. HA, a major component of the extracellular matrix (ECM), plays a key role in regulating inflammation23. HAS-1 and HAS-2 encode high–molecular-weight HA, which suppresses the inflammatory response23. These findings suggest that low IPP and WH gas decreased the likelihood of a clinically significant high VAS pain score in the first 24 hours after laparoscopic surgery by reducing inflammation in the surgical laparoscopic peritoneal environment. Further studies to investigate the molecular mechanisms underlying the different effects of low IPP and WH gas on postoperative pain may provide useful information for developing strategies to reduce pain after laparoscopic abdominal surgery. A limitation of the present molecular analysis is that it is unclear whether similar effects of a low IPP and/or WH gas on these 12 genes would be observed, if the surgical procedure was much longer than that in the present study. In addition, it is ethically impossible to perform serial laparoscopies to collect peritoneal biopsy specimens and/or to evaluate the clinical significance of the present molecular findings on clinical outcomes such as postoperative adhesion formation.Effects of low IPP may be clinically significant for “pain” among the five dimensions of the QoR-409. The surgeon’s laparoscopic skills represent a risk factor for perioperative complications of laparoscopic surgery24. A major advantage of low IPP is that it requires no additional cost during laparoscopic surgery if the duration of surgery is not affected. The results of the present study and previous studies suggested that experienced surgeons may not need a longer duration of surgery at low IPP even if they realize that surgical conditions may be worse9. The present findings may support a clinical benefit of low IPP; however, use of low IPP should be recommended only for skilled, experienced surgeons.A major disadvantage of using a low IPP is that surgical conditions are worse than with the standard IPP. A Cochrane review concluded that the safety of low-pressure pneumoperitoneum has yet to be established2 gas used for VAS pain scores. In addition, the present molecular analysis showed that adhesion-formation–related and inflammation-related gene expression levels were less affected when using WH gas at the standard IPP. Thus, when low IPP may not be feasible, use of WH gas at the standard IPP may be a clinically useful alternative for reducing postoperative pain and minimizing adverse effects of a CO2 pneumoperitoneum at the standard IPP on the surgical peritoneal environment. However, a major disadvantage of using WH gas is the additional cost. Further studies are required to perform a cost-benefit analysis on the use of WH gas during laparoscopic abdominal surgery.In contrast, use of a WH gas requires no technical effort and could be applied to any abdominal laparoscopic surgery and by any surgeon. In the present study, no significant interactions were observed between IPP and the type of CO26. In the present study, all patients were informed about the expected discharge 3 days after operation.The present study showed no significant difference in the length of hospital stay between the 12-mmHg IPP and 8-mmHg IPP groups or between the WH gas and CD gas groups. However, length of hospital stay after surgery would be influenced by many different factors such as preoperative counseling regarding expected length of stay, supports in place at home for patient upon discharge and distance from the hospital to home27. Previous studies have also suggested that a low IPP may reduce postoperative pain compared to the standard IPP29. However, almost all of these previous studies were conducted during laparoscopic cholecystectomy;29 thus, it is not clear whether the present findings may be generalized to different surgical procedures for other pathologies. In the present study, only patients with a macroscopically normal peritoneum were included. Whether low IPP and/or WH gas would have the same impact on peritoneal gene expression levels and postoperative pain in patients with pathological peritoneum remains to be clarified.The external validity of randomized controlled trials (RCTs) is often lowIn conclusion, the present randomized 2 × 2 factorial trial showed that low IPP and/or WH gas significantly lowered expression of inflammation-related genes in peritoneal tissues compared to the standard IPP and/or CD gas. Low IPP and WH gas independently decreased the likelihood of a high VAS pain score (>30) after surgery.Supplementary info


The U.S. opioid epidemic has highlighted the need to identify patients at risk of opioid abuse and overdose. We initiated a novel emergency department- (ED) based interventional protocol to transition our superuser patients from the ED to an outpatient chronic pain program. The objective was to evaluate the protocol’s effect on superusers’ annual ED visits. Secondary outcomes included a quantitative evaluation of statewide opioid prescriptions for these patients, unique prescribers of controlled substances, and ancillary testing.Patients were referred to the program with the following inclusion criteria: ≥ 6 visits per year to the ED; at least one visit identified by the attending physician as primarily driven by opioid-seeking behavior; and a review by a committee comprising ED administration and case management. Patients were referred to a pain management clinic and informed that they would no longer receive opioid prescriptions from visits to the ED for chronic pain complaints. Electronic medical record (EMR) alerts notified ED providers of the patient’s referral at subsequent visits. We analyzed one year of data pre- and post-referral.A total of 243 patients had one year of data post-referral for analysis. Median annual ED visits decreased from 14 to 4 . We also found statistically significant decreases for these patients’ state prescription drug monitoring program (PDMP) opioid prescriptions (21 to 13), total unique controlled-substance prescribers (11 to 7), computed tomography imaging (2 to 0), radiographs (5 to 1), electrocardiograms (12 to 4), and labs run (47 to 13).This program and the EMR-based alerts were successful at decreasing local ED visits, annual opioid prescriptions, and hospital resource allocation for this population of patients. There is no evidence that these patients diverted their visits to neighboring EDs after being informed that they would not receive opioids at this hospital, as opioid prescriptions obtained by these patients decreased on a statewide level. This implies that individual ED protocols can have significant impact on the behavior of patients. In the early 1990s there was a concerted effort by the Veterans Health Administration (VHA) and The Joint Commission to target pain management with opioids.3Emergency department (ED) visits related to prescription opioid abuse have risen dramatically from 173,000 in 2004 to 416,000 in 2009 and now are over 500,000 annually.The purpose of this study was to examine and present the outcomes of a novel interventional chronic pain program established in a metropolitan ED. The protocol was designed to transition superuser opioid-seeking patients out of the ED and into a chronic taper-to-abstinence pain program. We primarily hypothesized that visits to the ED post-referral would decrease. We hypothesized that secondary outcomes would similarly decrease, such as statewide opioid prescriptions, number of opioid prescribers, number of electrocardiographs (ECG), laboratory tests, radiographs, and computed tomography (CT) imaging.This study is a retrospective analysis of a novel preexisting, administrative chronic pain management program at Methodist Hospital in Indianapolis, IN. This is an urban teaching hospital with an annual ED volume of approximately 102,000 patients per year. Patients were drawn from the existing administrative database of frequent opioid recidivists who had been prospectively identified for inclusion into the program as outlined below. The study is designed as a one-way crossover intervention, with patients serving as their own controls in the year prior to their referral in the program. The protocol was approved as an administrative policy four years prior to the collection of any research data. Research data gathering was separately approved and registered by the Indiana University (IU) Institutional Review Board (1409177708).Population Health Research CapsuleWhat do we already know about this issue?Opioid prescriptions and overdoses have increased significantly in the past 30 years. Superuser patients may use the Emergency Department (ED) as a source for opioids.What was the research question?Does ED referral to a pain management group – with subsequent EMR-based reminders to ED practitioners - decrease annual visits from superuser patients?What was the major finding of the study?Superuser patients had fewer overall ED visits after the intervention, decreasing annual visits from 14 to 4.How does this improve population health?Enrollment in a chronic pain program with EMR-based provider reminders appeared to decrease overall visits to the ED post-intervention.Inclusion criteria into the chronic pain program were as follows: 1) Frequent use of the ED, defined as ≥ 6 visits per year; 2) At least one visit identified by the treating attending physician as primarily driven by opioid-seeking behavior; and 3) Chart review by ED administration and case management for evidence of ED misuse. Patients meeting all three of these criteria were referred to the chronic pain program unless they met exclusion criteria below.Exclusion criteria for the chronic pain program were preexisting chronic disease processes expected to cause frequent and uncontrollable visits to the ED, such as cancer or sickle cell disease. Pregnancy and age were not exclusion criteria.We excluded patients from the retrospective data analysis if they had not been part of the chronic pain program for at least a year. These patients would not have a full year of data post-intervention to compare to the year prior. Demographic characteristics of the participants can be found in After medical director approval, patients were referred to a free, outpatient taper-to-abstinence pain management clinic. A chronic pain management and addiction specialist runs the clinic. Patients were notified by an administrator either in person at their next visit or by telephone that they had been referred into a chronic pain program. They were also informed that they would no longer routinely receive opioids or opioid prescriptions for their chronic painful conditions from the ED. Additionally, they received written instructions and information either in person or by certified mail.Exceptions were made for acute pain not related to a chronic condition, such as new fractures. Those patients non-compliant with follow-up with the pain management program were contacted on subsequent ED visits and referred again. Treatment with opioids, both parenteral and prescribed, remained at the discretion of the treating ED provider, with a reminder in place that the patient had already been given outpatient follow-up.To reinforce the program to emergency physicians, an electronic medical record- (EMR) based notification was implemented, which was activated any time the patient arrived in the ED. This notification is three-fold. On the ED tracking screen, a flag is placed to alert providers to the patient’s referral to the program. Upon opening the patient’s chart, a pop-up alert indicates the patient’s chronic pain management, with instructions to refer to the case management notes for specific details. If opioids are chosen as a treatment modality, a separate notification activates to ensure that the provider is aware that the patient has been referred to pain management.We collected and managed study data using REDCap electronic data capture tools hosted at IU.Data regarding controlled substance prescriptions pre- and post-referral into the program was captured via the Indiana Board of Pharmacy Prescription Monitoring System or INspect. All pharmacies are mandated to report any controlled substance filled to this database. The few exceptions are entities and clinics governed by federal regulations . Data included in the database are the following: Patient demographics , prescriber, prescriber demographics, date of prescription filled, pharmacy demographics, prescribed substance, strength, quantity, intended days, and date written. We obtained data regarding ED visits pre- and post-referral via Indiana University Health’s (IUH) EMR (Cerner), which connects approximately 32 hospitals, rehabilitation facilities, and clinics across the greater Indianapolis area. Data were collected on a data abstraction form by blinded, trained abstractors. As this was a retrospective chart review, a random sample of 10% of the charts was reassessed by one of the investigators (reassessed by one of the investigators [ZPK]). We performed a kappa analysis for the primary outcome, which was found to be 0.91, indicating excellent inter-rater reliability.The primary outcome of interest was the difference between annual ED visits to an annual ED visits to an IUH ED pre- and post-referral into the chronic pain program. Secondary outcomes included their statewide opioid prescriptions, number of unique prescribers of controlled substances, as well as ancillary testing: number of ECGs, laboratory tests, radiographs, and CTs.We performed statistical analysis using the R statistical software package with the Rstudio frontend . Descriptive analyses are reported where appropriate. Mean values are reported for normal data with standard deviations, with significance between results analyzed with Student’s t-test for unpaired values and Student’s paired t-test for paired values. Non-normal data is reported in medians with interquartile ranges (IQR), with significance analyzed by Mann-Whitney U test for unpaired values and Wilcoxon signed-rank test for paired values. As most of the data is non-normal, the primary analysis method used was the Wilcoxon signed-rank test for paired medians. We calculated data to a significance of α=0.05 and β=0.20 where appropriate. There was no formal sample size calculated, as this was a retrospective study performed on all eligible existing patients in the program. A priori to capture and analysis of our data, we identified annual ED visits as our primary outcome, with secondary outcomes as described in outcomes and analysis.At the time of data gathering, 278 patients had been referred into the program. Of those patients, 243 had been in the program for one year or greater, and therefore had 12 months of data both pre- and post-intervention. Demographics of the participants are shown in The primary outcome was the number of ED visits pre- and post-intervention. This data is represented visually in Given the skewness of the data, our data is primarily reported in median values, although mean values are also reported in Median ED visits to hospitals in our health system decreased from 14 to 4 . We evaluated visits as paired data, with each patient serving as their own control. Mean visits decreased from 19 to 6, implying a rightward skewness of the data. When assessing the highest quartile, we found that median visits decreased from 25 to eight. The outlier patient decreased annual visits to our ED from 131 to 13.Secondary outcomes were similarly significant. Total median number of opioid prescriptions filled statewide decreased from 21 to 13 , as did median number of statewide prescribers 11 to seven .In this study, we present the outcomes of a novel, administratively instituted “no-opioid” policy for 243 patients at a large metropolitan hospital. These patients had been identified as over-using the ED, primarily to obtain opioids for chronic pain. It has been previously estimated that approximately 5% of patients account for 25% of all ED visits, and chronic pain and addiction is often a driving force behind this recidivism.14. We believe that this implies that there is a significant degree of local bias in care for these patients – that is, patients preferentially seek care at the closest ED to their home. When access to opioids is fettered at that site, these patients did not appear to supplement by simply visiting neighboring EDs. This may be the understated strength of our administrative policy; our results imply that our ED was a major source of these patients’ legal access to opioids. Further, when opioid prescriptions are restricted from the ED, this patient population decreases ED visit frequency.Our study demonstrated decreased visits to our facility from these patients by 58%, a decrease in the number of unique prescribers for their controlled substances by 31%, and a decrease in the number of prescriptions these patients received statewide by 30%. Of note, our intervention appears to have decreased overall opioid prescriptions and prescribers statewide for these enrolled patients, despite being implemented at only one facilityTo date, there is no standardized definition of frequent users of the ED. Various authors have proposed anywhere from 3–10 visits as “frequent.”Several researchers have evaluated ED pain protocols prior to this study.With regards to the first point, emergency providers often feel obligated to acquiesce to patient demands for fear of lowered patient satisfaction scores, or simply to avoid a complaint.As only a handful of patients followed up with the pain management clinic, this component of the intervention is unlikely to have changed ED visit frequency or prescription volume. Instead, the authors believe that the EMR-based reminders to physicians were the key component. These reminders occurred at every visit for each provider who interacted with the patient. Thus, prior to the administration or prescription of an opioid, the EMR reinforced the behavior of physicians and therefore patients. Many hospitals use a provider-initiated system for opioid management; that is, a provider must go looking for a care management note, chronic pain policy, or must do a chart review manually.Our EMR-based alerts were active, informing the patient’s ED provider of their chronic pain referral at every visit. When a patient’s chart is initially accessed at each visit, a reminder screen is displayed prior to chart access and order entry. This ensured that every provider who interacted with the patient was aware of the referral to the clinic. A secondary alert was triggered if providers ordered opioids.Ancillary testing decreased proportionally to the decrease in ED visits. If our intervention had biased physicians against these patients, causing physicians to assume that they were never “sick,” one would expect a comparatively greater decrease in the quantity of ancillary services used. Instead, there was strong correlation between both the decrease in ED visits and most of the secondary outcome variables, implying that these patients received the same amount of testing at each visit. To a degree, this is surprising; if a patient routinely presents with opioid-seeking behavior, one would plausibly expect providers to decrease testing.Of all 278 patients referred into the program, to date only seven have followed up with the referral outpatient clinic. Of these, only three have continued to follow up with the clinic, and the other four were discharged for noncompliance with controlled substance covenants. The remaining 271 patients either already had a primary care physician or missed all scheduled appointments with the clinic. We posit that this extremely poor compliance is a direct function of the patient population included in our protocol; prior to referral in the protocol these patients had a 14:1 median ratio of ED visits to clinic visits. Our chronic pain clinic ensured that these patients had guaranteed follow-up for their chronic pain, and thus the ED was no longer an acceptable mechanism to fill this need.There has been much research into maintenance therapy, adjunct therapy, and replacement therapy for opioid cessation.One of our main concerns is that when cut off from a source of opioids, these patients may resort to illicit methods to supply their addiction. Recently there was an HIV outbreak in Southern Indiana among Opana (oxymorphone) users who were sharing needles to inject their prescriptions.There are several limitations to this study. This was a retrospective observational analysis of a preexisting administrative database at a large metropolitan hospital, which is part of a wide-reaching health system. While the data itself were not prospectively collected, the administrative protocol was performed in a prospective fashion. Thus, this study was a retrospective analysis of a prospective protocol, which we feel improved the robustness of the data. However, fundamentally this study was a retrospective review of existing data, and limitations exist for this form of study protocol. There is a potential for sampling bias in any retrospective review, although our abstractors followed strict rules and were transcribing concrete data points. We do note that we were unable to blind abstractors, but given the cohort nature of the study, all patients were “case” and blinding would be impossible.While the EMR connects most of the hospitals in our healthcare system, we were unable to assess visits at most urgent visit centers, or EDs within other health systems. However, the use of our state PDMP does act as a surrogate for whether subjects simply shifted their ED use to other health systems. We were unable to determine total morphine equivalents for our patients. Thus, the decrease in annual prescriptions may in fact represent consolidation of prescriptions to fewer providers, with increased pill quantities per prescription. As there was no interview component to this study, we cannot determine if these patients went on to use illicit drugs at an increased rate.One potential confounder is the increased national attention on restriction of opioid prescription at the same time as the study period. However, the study authors feel that it is unlikely that national attention alone resulted in a 58% decrease in opioid prescriptions for these patients.A second confounder may be a natural decrease in opioid usage as painful conditions improve. However, prior studies have demonstrated that patients on long-term opioid therapy are unlikely to discontinue usage.In summary, this study demonstrates the efficacy of an interventional protocol intended to decrease ED visits among ED superusers. These patients were selected as those who frequently presented for the primary purpose of obtaining opioids for chronic pain. While only a handful took advantage of the chronic pain clinic to which they were referred, our protocol resulted in a decrease in ED visits, fewer statewide opioid prescriptions for the cohort, and less ancillary testing such as ECGs, CTs and radiographs. Implementing this protocol is fairly straightforward, requiring only an EMR flag and a task force willing to steward the database. We believe that this protocol streamlines patient care, decreases unnecessary visits to the ED, improves patient safety and can be one tool to help EDs combat our current opioid epidemic.


Objective. The aim of this study was to compare the accuracy and efficacy of sonographically guided lumbar periradicular injections through in-plane or out-of-plane approach techniques for patients with unilateral lower lumbar radicular pain. The feasibility and accuracy of these techniques were studied by means of computed tomography (CT). Methods. A total of 46 patients with chronic unilateral lumbar radicular pain were recruited and randomly assigned to either the in-plane or out-of-plane injection group. A mixture of 3 mL 1% lidocaine and 7 mg betamethasone was injected. The visual analog scale (VAS) was used to assess pain before and after treatment. Results. The pain intensity, as measured by VAS, significantly decreased in both in-plane and out-of-plane injection groups. Conclusions. The sonographically guided periradicular injections are feasible and effective in treating lumbar unilateral radicular pain. Unilateral radicular pain is thought to be induced by inflammation or irritation of an exiting spinal nerve root originated from degeneration of intervertebral disc . Nerve rWith the real-time guidance of ultrasound, the spinous process and adjacent structures such as lamina, zygapophyseal articulations, and transverse process can by clearly identified. Several injection procedures have been introduced, including transforaminal injection through in-plane approach , medial n = 25) or out-of-plane approach  techniques, respectively. A mixture of 3 mL 1% lidocaine and 7 mg betamethasone was injected.The study protocol was approved by the Institutional Review Board of Sun Yat-sen Memorial Hospital of Sun Yat-sen University, and written informed consent was obtained from all patients. There were 52 eligible patients with chronic unilateral lower lumbar radicular pain for more than 3 months and 46 patients participated in this randomized, single-blind study. The patients were recruited consecutively between January 2015 and September 2016. They were randomly assigned into two groups and received one sonographically periradicular injection through either in-plane approach , or magnetic resonance imaging (MRI). The excluded criteria were systemic inflammatory disease, uncontrolled diabetes, infections, previous injections within 3 months, taking oral anti-inflammatory medication, receiving physical therapy or other injection therapy during this study, and having underwent surgery. The demographic data for patients were demonstrated in Ultrasound-guided selective nerve root block was conducted for 25 patients in 25 nerve roots. The patients were lying in the prone position with a pillow under the abdomen. The areas of injection treatment were disinfected and a sterile cover was placed on a curved array transducer. One experienced physician performed the ultrasound-guided injections using an Q9  device . The spiThe patients' position and sterilization were described previously. The transducer was placed longitudinally; the sacral spinous process and the fifth lumbar spinous process were identified. The lamina, facet joint, and transverse process were identified when moving the transducer from midline laterally. Then the transducer was moved back to visualize the edge of the zygapophyseal joints . After iPatients were prepared as specified above for the US procedure. A radiopaque marker was placed at the indicated level. A low-dose topogram through the area of interest was obtained at 3 mm increments for a precise definition of the needle pathway by ultrasound guidance. A representative image for confirmation of the needle pathway is demonstrated in  t-test was used for measurement data. P < 0.05 was considered statistically significant.The data were analyzed using SPSS version 11.0 software . Analysis of variance was used to compare the demographic characteristics of the patients, and aA total of 46 patients completed this study. The patients had comparable pain intensity assessed by VAS between IP (7.26 ± 1.00) and OP (7.34 ± 1.08) technique groups before injections. The spinal level of injections was located at L4 or L5. The demographic data of patients are present in The blocking procedures were tolerable for all the patients. None of the patients had any treatment-related complications. The pain was significantly reduced after injection in both IP and OP technique groups. There were no significant differences in the VAS before and after the injections between IP and OP technique groups .Radicular low back pain is commonly caused by intervertebral disc herniation, spinal stenosis, and intervertebral disc degeneration. Selective nerve root blocking is one of the most frequently performed mini-invasive interventions. Ultrasonography has been used broadly in evaluation and treatment of musculoskeletal disorders. Ultrasound has proved to be reliable and accurate in the demonstration of paravertebral anatomy and sonographically guided lumbar injections for the treatment of unilateral lower lumbar radicular pain have been previously studied for feasibility and accuracy , 13. TheThe success ratio of the lumbar nerve root blocking is over 95% in our study; this indicates that, in both approaches, the drug is able to be delivered at the periradicular space. Relief of symptoms has been the gold standard for evaluating the success of US-guided injection . HoweverIn our study, there was no significant difference in VAS evaluation between IP and OP injection techniques. This indicates that, in both approaches, the medication is able to reach the periradicular space. The long-term pain relieving effect needs further investigation.In comparison with CT, ultrasonography has several advantages. There is no radiation exposure for the physician. And the device is portable; it can be used in outpatient and at bedside. Despite the above advantages, it is has limitations in showing good quality view of spinal structures and the quality depends on experiences of the physician. It has been demonstrated that the reproducibility among physicians is low .This study had some limitations: first, the sample size was small and the long-term effects were not evaluated; second, the outcome of injections was only pain score and functional tests of lumbar spine should be conducted in further researches.The sonographically guided periradicular injections are feasible and effective in treating lumbar unilateral radicular pain.


Protocol based care is known to improve the outcomes of patients admitted with recent onset chest pain. The aim of this clinical review was to investigate chest pain management, using newly published guidance from NICE, in the emergency department of a regional hospital in New Zealand.All admissions with chest pain during the period of September-October 2010 were identified retrospectively (n = 599), and a sufficiently powered random sample (n = 120) taken. Relevant data was identified from patient notes, including basic demographics and specific management details.One hundred and eighteen patients were analysed , 99.2% received an ECG on admission, yet only 59.3% of patients had documented evidence of a repeat ECG, with admissions during the day less likely to receive one compared to those admitted overnight . Younger patients (< 39 years) appeared less likely to receive aspirin than older patients , 21.3% of patients failed to receive 300 mg aspirin, and 45.6% of patients received oxygen despite normal saturations.Despite good performance in a number of areas, this clinical review has highlighted that some standards, such as repeat ECGs, administration of aspirin therapy and appropriate use of oxygen are not being met in all patients with chest pain. A chest pain management pathway is to be implemented for all relevant admissions, to ensure that essential aspects of care are not missed. Timely dissemination and implementation of new clinical guidelines remains a challenge in clinical practice. Chest pain is a common and often non-specific symptom that can be caused by a number of underlying conditions, one of the most serious being acute myocardial infarction. Whilst only around a third of these presentations are cardiac in origin , the potIn New Zealand, cardiovascular disease is the leading cause of mortality, with coronary artery disease responsible for 23% of all deaths in 1999. Over 52% of these deaths were due to myocardial infarction .Furthermore, mortality associated with coronary artery disease in Maori’s under the age of 65 is almost three times that found in Europeans of a similar age . CardiovThe National Institute for Health and Clinical Excellence (NICE) is an independent UK organisation which provides national guidance on promoting health and preventing and treating poor health. They published updated guidelines for the management of recent onset chest pain in March 2010 . This doThe College of Emergency Medicine (UK) established standards for the treatment of suspected acute coronary syndrome . In theiIn recent years, cost reduction strategies have led to emergency departments worldwide admitting only those patients deemed essential for monitoring, and reducing a patient’s length of stay in hospital where possible, whilst maintaining a high standard of care. The focus of emergency medicine has now shifted to the development and implementation of high quality protocol based care, to ensure that all patients are screened in a systematic manner, and management is optimal.Despite this, it is estimated that between 2 - 5% of acute myocardial infarction patients are discharged inappropriately . These iWhilst there are New Zealand based guidelines for the management of established acute coronary syndrome, there was no available comparable guideline for the initial management of recent onset chest pain. The aims of this clinical review were to assess baseline clinical standards in a regional emergency department in New Zealand, and to ascertain whether current practice had adapted to incorporate recent published developments in chest pain management.Tauranga Hospital has one of the largest emergency departments in New Zealand, treating 45000 patients each year, including around 4000 presentations with chest pain.All admissions to the emergency department of Tauranga Hospital between 01/09/10 and 31/10/10 were screened for the presenting complaint of ‘chest pain’ using the medical records database. Patients were included if they had either ongoing chest pain, or recent chest pain (< 12 hours) which was now resolved. Those under the age of 18 were excluded, as were presentations which were known to be non-cardiac at an early stage and therefore not managed on an appropriate pathway for audit.This search generated records of 599 patients that fitted the inclusion criteria. After the population was identified, a sample size calculation was performed. As this audit is based on standards of 100%, the likelihood of a positive response for measured criteria is high, therefore a response distribution of 90% was chosen. To detect a statistical effect with a confidence level of 95%, and 5% margin of error, the minimum sample size required is 113. Using the statistical package for social sciences (SPSS) version 18.1, a simple randomisation scheme was employed, and 120 patients were identified.Data was obtained from patient notes by the principal researcher and collected using an audit proforma consisting of 32 different variables (Appendix 1). Results were then compiled in a spread sheet. Data was handled using SPSS, and assessed for normality. Appropriate statistical tests were employed as detailed in the results section. The level of statistical significance was deemed (P < 0.05) for all calculations.All patients were allocated a number, and data was recorded anonymously to ensure confidentiality was maintained. This research was exempt from formal ethical committee procedure, however, it was approved by the Research Manager of the Bay of Plenty District Health Board.From the original population of 599, 120 patients were identified at random. Two cases identified by the randomisation scheme were not eligible for inclusion as their presentations were not considered to be cardiac in origin at time of admission, leaving a total number of 118 eligible cases .Ages of those in the sample were found to be normally distributed. Women were older than men . Time of admission was also found to be normally distributed within the sample. Results highlighting the performance of the department compared to NICE standards are shown in Results comparing the department to the College of Emergency Medicine (UK) guidelines for pain management, aspirin prescription and time to ECG are summarised in Time of admission was investigated as a potential influencing factor on the management of patients with chest pain. As hospitals have fewer staff at night, it was hypothesised that those admitted outside of normal working hours (17:30 - 08:00) would wait longer for clinical management and investigation. Further investigations sought to establish the effect of patient age on management decisions. Formal statistical testing was applied, with results as shown in This clinical review has identified several areas for discussion. Compliance with recent NICE standards was noted in establishing pain status and pain characteristics, eliciting previous episodes of chest pain, recording blood pressure, and completing a detailed physical examination. Furthermore, 99.2% of patients received an ECG during their presentation to the emergency department. It is likely that these measures would identify the vast majority of patients presenting with an acute coronary syndrome.However, some areas for improvement were identified. Risk factor documentation was incomplete in a proportion of patients and a repeat ECG was frequently not undertaken. Aspirin was generally under prescribed and oxygen therapy was given outwith the recent guidelines. Trends involving time of admission, patient age and management decisions were also identified, and may require further exploration.An ECG was recorded in the vast majority of patients in this cohort 99.2%). However, a single normal 12 lead resting ECG does not exclude a diagnosis of ACS, and NICE guidance recommends that all patients should have serial ECGs and continuous monitoring with telemetry when clinically appropriate. This study has found that only 59.3% of patients admitted with chest pain received more than one ECG, and only 57.6% were continuously monitored with telemetry. Serial ECGs improve the outcomes of patients later diagnosed with both ACS and MI, and their use is recommended in high risk patients [9.2%. HowIt has been suggested that failure to repeat ECGs may lead to an increase in the number of missed cardiac diagnoses, however, there was no evidence this happened during the study. It is possible that the actual number of repeat ECGs was higher than found in this study, yet due to a combination of poor recording in the notes, and ECGs not being filed, the numbers appear lower.The local policy on continuous telemetry suggests that those diagnosed with either AMI or unstable angina should be monitored, excluding those without a definitive diagnosis. On two occasions, telemetry was indicated but clinicians commented that it was unavailable. Unfortunately these comments are likely to be a true reflection of the financial constraints on the emergency department.Aspirin is indicated in the initial management of patients with suspected cardiac chest pain. However in this cohort the use of aspirin appeared to be poor. Aspirin is frequently given en route by paramedic staff, and it is possible that this was not always documented. Furthermore, after discussion with staff members, it appears that some clinicians favour the prescription of clopidogrel over aspirin in the acute setting.= 0.002) [No systematic reviews or randomised controlled trials studying the use of aspirin versus clopidogrel in patients with acute current chest pain could be identified in the literature. NICE base their guidance on a cohort study assessing the efficacy of aspirin when given pre or post hospital admission. A lower mortality rate was found in patients that received aspirin pre admission compared to post admission at 7 days,  , and thiNICE recommend that other anti-platelet agents, such as clopidogrel, should only be given after patients have had an initial assessment which has refined the likely diagnosis, and they suggest that those diagnosed with AMI or ACS should be managed in line with other relevant guidelines .The Scottish Intercollegiate Guidelines Network (SIGN) guidelines state that patients with acute ECG changes should receive a combination of both aspirin and clopidogrel, as this improves patient outcomes despite an increase in secondary bleeding .Oxygen is indicated in patients with low oxygen saturations (< 94%) on air. Recent guidelines from NICE and the British Thoracic Society agree that supplementary oxygen has not been shown to be beneficial to these patients, and may indeed be harmful , 12. In However, clinical practice has been slow to change in this regard and routine use of oxygen therapy persists despite these guidelines. The rate of oxygen prescription in those with normal saturations in this cohort was high, with 45.6% of individuals receiving oxygen inappropriately. Education of all members of staff may help to address this issue, improve patient care and allow resources to be allocated elsewhere.Published research has shown that patients with myocardial infarction admitted to hospital overnight or at the weekend are managed less efficiently than daytime admissions , 13, 14.In this current study the only significant correlation between time of admission and management was the use of the repeat ECG. Results show that patients admitted during the day were less likely to receive a repeat ECG than those admitted overnight (P = 0.032). It is possible that due to a larger number of general attendees to the emergency department during normal working hours, there is an increased demand for routine ECGs, and therefore admissions with chest pain were not monitored as often as they should be. However, it is also possible that repeat ECGs were performed, but were not recorded or filed within the medical record. Regardless, this would seem to imply that perhaps additional staffing is required during busy periods.Further published research has highlighted associations between patient age and management of chest pain. Younger patients admitted with chest pain are significantly less likely to receive therapeutic aspirin (300 mg), than older counterparts .Whilst we have also found trends between patient age and aspirin prescription, these narrowly failed to reach significance. It is likely that this result is due to the small numbers available for statistical testing once stratified into age appropriate groups, and an adequately powered study is likely to have confirmed such a relationship. There is limited evidence to suggest that this lack of prescription is detrimental to patient care, and indeed this may be clinically appropriate decision making. As outcome data was not available within our study, this is unknown, however it would be interesting to explore this relationship in future work.This was a retrospective audit, however the use of an audit data collection tool ensured that a complete dataset was obtained, and maintained consistency in recording data between patients. There was a low rate of exclusion within the study cohort, as only two of the original 120 identified were omitted from analysis. This improves the validity of the results.As this was single centre study the results may not be fully generalisable, however, the setting in a typical busy general hospital is likely to be representative of other centres.In order to standardise the assessment and treatment of patients with acute chest pain, a new admission proforma has been implemented into the department. The current general admission document used within the emergency department does not contain a pre-written checklist section to be completed regarding risk factors, and this has also been updated.As yet, there have been no published audit findings which discuss the uptake of new guidance on the management of recent onset chest pain, in particular the delivery of oxygen, and this paper highlights issues that still need to be addressed. As with all changes in medical practice, these guidelines will take time to become fully implemented. This early clinical review serves to raise awareness of the challenges which must be overcome in order to comply with new standards.Despite good performance in a number of areas, this clinical review has highlighted that some standards are not being met in patients with chest pain. Clinicians must be aware of up to date guidance regarding oxygen therapy in chest pain, and aspirin should be used in all eligible patients when clinically appropriate. Serial ECGs must be used as a single 12 lead ECG does not exclude a diagnosis of acute coronary syndrome.


This study aimed to translate and culturally adapt a Greek version of the Shoulder Pain and Disability Index (SPADI) questionnaire and to validate its usage in Greek patients.A forward and backward translation was performed, and the final version of the Greek questionnaire was administered to 134 outpatients (mean age 47.4 ± 14.5) with rotator cuff tear under conservative treatment. The questionnaire was re-administered 2–5 days later to assess test–retest reliability. Patients completed the Greek SPADI, the Greek version of the Quick DASH  and the EuroQoL EQ-5D. 102 of the 134 questionnaires were considered valid.r = 0.66), “common activities” (r = 0.58), and “pain/discomfort” (r = 0.49), and a weaker correlation with the “mobility” variable (r = 0.20). Factor analysis (PAF method) revealed a bidimensional formation of the SPADI. Eight items (five pain/three disability) weighted the first factor by >0.5, and five disability items weighted the second factor.The internal consistencies of the SPADI total and its subscales measured with Cronbach’s alpha coefficient were high . Intraclass correlation coefficients showed excellent test–retest reliability . A significantly high positive correlation was found between the SPADI total score and its subscales, and Quick DASH for Pain and Disability. Significant correlations were also found between SPADI scales and EQ-5D variables. There was a moderate positive correlation with the variables “self-reliance” (The Greek SPADI represents a valid and reliable tool for measuring pain and disability in patients with painful shoulder disorders.Level 3. Shoulder pain has a significant cost for health care and a serious impact on quality of life which influences the social and the working aspects of living . An estiOne of the easiest ways to obtain information about musculoskeletal pain is through the use of appropriately designed, self-assessment questionnaires, which collect specific information from the participants and are also used as patient-reported outcome measures (PRO) . Μore thTherefore, the aim of this study was to translate and culturally adapt a Greek version of the SPADI questionnaire and to validate its usage in Greek patients with partial rotator cuff tear. For that reason, we performed a thorough investigation of the SPADI scale, in terms of internal consistency (reliability) and validity , in a population-based study of patients with self-reported symptoms related to their shoulders.The SPADI is a self-administered questionnaire  created The EuroQoL (EQ)-5D is a widely used questionnaire developed in order to record information about quality of life of a certain population . It has The DASH was advanced by the Institute for Work and Health and the American Academy of Orthopaedic Surgeons (AAOS) . It was The study took place after obtaining approval by the Ethics Committee of both the 401 Army General Hospital of Athens and the “Attikon” University Hospital. The linguistic validation process was initiated after communication with the original developer of the questionnaire , in ordeInformed consent was obtained from all individual participants included in the study. The study has been approved by the ethics committee of the institutions involved, and the ethical standards are in accordance with the Declaration of Helsinki. The participants were all Greek citizens, patients of the 401 Army General Hospital of Athens and the “Attikon” University Hospital, aged 20–80 years, and suffering from a rotator cuff tear of more than 3 months duration. The rotator cuff tear was confirmed by clinical testing combined with magnetic resonance imaging (MRI) and ultrasound. All patients had been treated conservatively. Patients had a negative history of neurological and psychiatric issues, and they had not undergone previous surgery on the affected or the ipsilateral shoulder. The questionnaire was administered to 134 patients, but only 102 questionnaires were considered valid, with all questions answered. These patients re-completed the questionnaire within 2–5 days.The first section of the study collected information related to sex, age, weight, presence of coexisting diseases, pharmacological treatment of these diseases, and recording of the affected and the dominant upper limb. The patients also completed two numerical analogue scales. One was about the previous week’s pain and the other evaluated the pain while filling the questionnaires. The second part of the study comprised the completion of the Greek version of the EQ-5D  in orderP values less than 0.05 were considered statistically significant [p value of 0.2 was obtained (>0.05), showing acceptance of the null hypothesis .The statistical analysis was performed using SPSS 17.0 for Windows  . P valuenificant . The SPAt test was performed for the equality of means between men and woman and the hypothesis was rejected evidently (p > 0.05).To examine whether the difference between men and women in the total SPADI scores was statistically significant, the In order to evaluate differences in SPADI scores regarding different functional status and different ages of patients, we classified the total SPADI score into four classes , and age into three different subgroups .The internal consistency of the SPADI scale and the EQ-5D questionnaire was assessed using Cronbach’s alpha coefficient, which represents a measure of how well each question (item) of the scale is correlated with the sum of the remainders. Values of Cronbach’s alpha equal to or greater than 0.7 indicate good reliability, while values >0.9 indicate excellent reliability , 24, 43.In order to quantify the test–retest reliability or the stability over time, the intraclass correlation coefficient (ICC) was used  . The ICCThe construct validity of the SPADI score was examined by determining how well SPADI scores correlated with those other instruments, such as the Quick DASH , 38. As p value <0.001), and so items were analyzed by factor analysis (FA) with the extraction method of principal axis factoring (PAF) with Varimax Rotation. Factors were elicited according to the Kaiser criterion of maintaining eigenvalues larger than 1 [Structural validity refers to the degree to which a measure evaluates the domain of concern of the SPADI and was inspected through factor analysis   men and 58.8 % (n = 60) women, of mean age 47.4 ± 14.5 years (range 20–80 years). Descriptive characteristics of patients revealed that 52 % of them had a higher level of education, 13.7 % post-secondary education, and 22.5 % and 4.9 % higher and lower secondary education, respectively, and only 6.9 % had a primary level of education. The mean values of SPADI scores and Quick DASH for the total sample of patients, as well as separately for men and women, are given in Table One hundred and thirty-four patients were studied, resulting in 102 valid questionnaires. The sample consisted of 41.2 %  and in the Quick DASH, but these differences were not significant. Additionally, the majority of patients (>86 %) demonstrated SPADI total scores between 25 and 75, while almost the same proportion exhibited pain scores >50 %. On the other hand, more than 61 % of patients showed low disability scores, as shown in Table The internal consistency was quite high for the SPADI scale 0.932). For the two subscales (Pain and Disability) Cronbach’s alpha coefficient was 0.905 and 0.899, respectively. Regarding the EQ-5D items, Cronbach’s alpha was 0.723. Item-to-total correlations ranged from 0.57 to 0.83, showing high correlations between the questions of the questionnaire. Reliability data are presented in Table 2. For thIntraclass correlation coefficient (ICC) of SPADI subscales was found to be 0.902  for Pain and 0.899 (95 % CI 0.866–0.926) for Disability , while a value of 0.929 (95 % CI 0.907–0.948) for the total SPADI score was found.r = 0.719, p < 0.01), as well as the correlations with the total SPADI score (r = 0.877 for Pain and r = 0.964 for Disability). We found a strong positive correlation between the Quick DASH and the SPADI total , and the same applied to the SPADI subscales (r = 0.764 for Pain and r = 0.684 for Disability), as well as with the third variable of EQ-5D, “common activities” .The correlation between the scores of the SPADI subscales was quite high (r = 0.66), “common activities” (r = 0.58), and “pain/discomfort” (r = 0.49), and a weak correlation with the “mobility” variable (r = 0.20). No significant correlation was observed regarding the variable “anxiety/grief”. A moderate positive correlation was also observed between the Quick DASH “self-reliance” (r = 0.588) and “pain/discomfort” (r = 0.564). Correlations between the SPADI and its subscales with the Quick DASH and the five variables of EQ-5D are given in Table The total SPADI scores were shown to have a significant relationship with each of the five EQ-5D variables: a moderate positive correlation with the variables “self-reliance”  for these two factors are presented in Table There are various scales used in clinical practice designed to elicit initial information about a disease, monitor the possible changes of symptoms, and evaluate the effectiveness of the therapeutic process . The SPAThese results are consistent with those obtained by the original testing of the questionnaire in English, as demonstrated in several studies , 31, 32,In its original form, the SPADI lists 13 questions for “pain” and “disability” , but theAnother interesting observation from this study was that women exhibited higher total pain scores compared to men, and higher levels in disability scores. Generally, in musculoskeletal problems, women tend to report pain more often, with longer duration and greater severity, in comparison with men , 63. TheThe necessity of measurement of health-care needs and assessment of health status by using different social, economic, and psychological indicators imposed the use of the EQ-5D and the Quick DASH concomitantly with the SPADI . The SPAA main limitation of our results is that the sample size would have been higher if all of the patients who had been given the questionnaire answered all of its questions. Specifically, 102 of the 134 questionnaires were considered valid. Another limitation is the absence of a correlation between SPADI and other questionnaires, since several tools have the ability to elicit different aspects of pain and functionality regarding the same pathology .To conclude, a satisfactory test–retest reliability, internal consistency, and construct and structural validity were displayed by this study of the Greek version of the SPADI questionnaire. Therefore, it represents a reliable and valid tool that can record the pain and incapacity caused by shoulder pain in the Greek population. This translation and cultural adaptation of the SPADI questionnaire, in addition to its validation in patients with rotator cuff tears, will significantly help Greek scholars and researchers to obtain data regarding disorders of the shoulder, and to design new studies for improving treatment and the quality of patients’ lives. However, further research is required in this area in order to validate the SPADI questionnaire in other shoulder diseases and patient populations.