Children with osteogenesis imperfecta (OI) experience pain and impaired physical functioning. The longitudinal effect of cyclic bisphosphonate treatment on these symptoms has not been described. We serially evaluated pain and functioning in pediatric patients with OI treated with intravenous bisphosphonate therapy.Pain and physical functioning were assessed at multiple time-points over two infusion cycles in 22 OI patients  receiving cyclic intravenous bisphosphonate therapy. Pain was assessed using the FACES® visual analogue scale; physical functioning, including self-care, was assessed using the PedsQL™ Generic Core inventory.F = 25.00, p < 0.001). Physical functioning scaled scores improved 4 weeks after infusion and declined before subsequent infusion across patients . Exploratory analyses indicated significantly different effects between mild and moderate-severe OI types for pain, but not for physical functioning. No fractures occurred during the study.Pain scores decreased significantly immediately following infusion and remained reduced at 4 weeks post-infusion, increasing before and decreasing again after subsequent infusion (In children with OI, cyclic intravenous bisphosphonate therapy transiently reduces pain and improves functional abilities. Pain relief occurs immediately following infusion with functional improvements observed 4 weeks later. Both pain and physical functioning return to pretreatment levels by the subsequent infusion. COL1A1 or COL1A2 gene encoding the alpha 1 and alpha 2 chains of type 1 collagen, producing either defective type 1 collagen or a deficient quantity of normal type 1 collagen; more than 200 mutations in multiple genes have been identified [Osteogenesis imperfecta (OI) is a genetic disorder that affects type 1 collagen and has variable manifestations including low bone mineral density, skeletal deformities, recurrent bone fractures, scoliosis, and chronic pain . The majentified , 5. The entified –8. Regarentified , 9. The entified . Chronicentified , 12. Furentified .Table 1SThe current mainstay of pharmacologic treatment for OI is nitrogen-containing bisphosphonate therapy, which has been shown to decrease bone turnover, improve bone mineral density and reduce fracture rates , 15. BisThe sample in this prospective longitudinal cohort study consisted of 22 children with a diagnosis of OI receiving intravenous bisphosphonate therapy at the Monroe Carell Jr. Children’s Hospital at Vanderbilt between November 2014 and February 2016. Patients that had experienced at least 2 fragility fractures within the 12 months prior to starting therapy were included and patients naïve to bisphosphonate treatment were excluded. All patients approached agreed to be enrolled.OI Type  was defined clinically, and one patient had genetic testing consistent with OI Type VIII. Patients were followed under real-world conditions through two cycles of bisphosphonate treatment with pain assessed by patient report immediately before and after each infusion and 4 weeks following the initial infusion. Physical functioning was assessed immediately before each infusion and 4 weeks after the first infusion by a parent-completed survey. This study was approved by the Institutional Review Board at Vanderbilt University Medical Center. The authors have no conflicts of interest to disclose.Patients received either pamidronate or zoledronic acid per their chronic regimen. Pamidronate was administered in a single-day infusion dosed in a weight- and age-dependent manner. Children ages 2–3 years received 1.1 mg/kg every 3 months and those > 3 years received 1.5 mg/kg/dose every 4 months (maximum dose ≤45 mg/infusion and 4.5 mg/kg/year). Zoledronic acid was administered in a single-day infusion of 0.05 mg/kg every 6 months for all ages. The treatment regimen was selected prior to study participation by patients and families after discussion about long-term knowledge of the effects of pamidronate compared with ease of administration of zoledronic acid.Pain was evaluated using the FACES® visual analogue scale, a validated tool for assessing patient-perceived pain on a scale of 0–10 with 0 indicating no pain and 10 indicating worst possible pain . The speDescriptive analyses were conducted to determine the means and standard deviations of the measures at each time point. To assess changes in pain and physical functioning over time (within subjects), we conducted repeated measures analysis of variance. The repeated measures design provides greater statistical power to detect effects with a smaller number of patients by controlling for individual differences. We also conducted exploratory analyses to determine whether there were differences in changes in pain across OI types (Type I vs. Types III and IV). Analyses were performed using IBM SPSS software, version 23 .N = 8) while 64% had moderate-severe OI , as defined by clinical characteristics (Sillence classification (Table N = 16) of patients were treated with pamidronate, while 27% (N = 6) were treated with zoledronic acid. There were no significant differences between patients treated with pamidronate and zolendronic with respect to child age, sex, or OI Type. No fractures occurred during the study.Clinical characteristics of the 22 children analyzed in this study are presented in Table Eighteen patients completed the pre- and immediately post- infusion pain assessments, 12 patients completed the 4-week post-infusion assessment, and eight patients completed the subsequent pre-infusion pain assessment. One patient sustained acute trauma by falling from a chair during his infusion and his pain scores were excluded.n = 6), there was a significant change in self-reported pain scores over time associated with bisphosphonate infusion  . Pain scores decreased from 2.17 ± 1.53 prior to infusion to 0.42 ± 0.79 post-infusion and remained decreased from baseline at 4 weeks post-infusion, with a mean score of 0.50 ± 0.67. It is notable that there was a significant difference between pre-infusion pain scores at the first visit and follow-up visit .For patients who had data for all time points : children with more severe forms of OI  reported significantly higher levels of pain at baseline, and a greater decrease in pain following bisphosphonate infusion, than children with milder OI . In patients with Types III/ IV OI, mean pain scores decreased from 3.33 ± 2.08 pre-infusion to 1.00 ± 1.00 post-infusion, and remained decreased at 1.33 ± 0.58 4 weeks post-infusion. In patients with Type I OI, mean pain scores decreased from 0.67 ± 0.58 pre-infusion to 0.00 ± 0.00 post-infusion, and remained decreased at 0.00 ± 0.00 4 weeks post- infusion. A similar pattern was seen with the second infusion cycle. Children with more severe OI (Types III/IV) reported mean pain scores of 4.33 ± 2.08 prior to infusion, decreasing to 2.00 ± 1.00 immediately after the second infusion; children with milder OI (Type I) reported mean pain scores of 0.67 ± 0.58 pre-infusion, decreasing to 0.00 ± 0.00 immediately after infusion. These results must be interpreted with caution and are therefore considered exploratory; given the observed effect size and our sample of six participants measured across five time points, we had power of .24 to detect a significant effect. A sample size of 16 (8 per group) was needed to have sufficient power to detect significant effects.Exploratory subgroup analysis indicated that the effect of bisphosphonate infusion on pain scores differed according to type of OI Fig. . We idenParents of all 22 patients completed the pre-infusion physical functioning assessment, 12 parents completed the 4-week post-infusion assessment, and seven parents completed the subsequent pre-infusion physical functioning assessment.n = 12, Fig. F = 10.87, P = .007). Mean scaled score for physical functioning was 49.48 ± 25.49 before infusion, and increased to 57.03 ± 25.29 4 weeks after infusion.For the patients who had data for only the first two visits , such that physical functioning improved after the first infusion, and diminished to pre-infusion levels by Visit 3. Specifically, mean scaled score for physical functioning was 46.25 ± 31.59 before infusion, increased to 53.75 ± 29.60 4weeks after infusion, and returned to 46.88 ± 28.13 by the second infusion cycle. We were not able to evaluate differences in physical function between OI types due to small sample size.For the patients who had data from all time points , the current study did not have a large enough population to evaluate whether there was a significant difference in pain relief or improved functioning between these two groups. However, understanding both the exact time at which pain starts to worsen as well as whether analgesia is impacted by bisphosphonate type could be important in determining the duration and type of therapy which maximally reduces pain and improves physical functioning in these patients. Additionally, the exact locations of pain were not assessed, but would be useful to identify in future studies, in order to more specifically evaluate the impact of bisphosphonates. Physical functioning was not assessed by medical provider evaluation, but by parental survey. The PedsQL™ is an inventory not approved specifically for OI, but has been used in other chronic pediatric disease-specific populations , 29. TheOur data indicate that chronic cyclic treatment with single-day bisphosphonate infusions acutely reduces pain and improves parental reports of daily functioning, including ability to participate in self-care, in children with OI regardless of type. Effects on pain appear to differ according to type of OI. Pain relief occurs immediately following infusion with functional improvements observed 4 weeks later. Both pain and physical functioning return to pretreatment levels by the subsequent infusion.


Impaired cognition is a major risk factor for perioperative delirium. It is essential to provide good pain control in patients with hip fractures and especially important in patients with severely impaired cognitive status, as they receive less pain medication, have poorer mobility, poorer quality of life and higher mortality than patients with intact cognition. The purpose of this study was to examine the association between preoperative pain management with nerve blocks and cognitive status in patients with hip fractures during the perioperative period.One hundred and twenty-seven patients with hip fractures participating in a double-blind, randomised, controlled trial were included in this study. At hospital admission, a low-dose fascia iliaca compartment block (FICB) was administered as a supplement to regular analgesia. Cognitive status was registered on arrival at hospital before FICB and on the first postoperative day using the Short Portable Mental Status Questionnaire.Changes in cognitive status from arrival at hospital to the first postoperative day showed a positive, albeit not significant, trend in favour of the intervention group. The results also showed that patients with no or a moderate cognitive impairment received 50% more prehospital pain medication than patients with a severe cognitive impairment. FICB was well tolerated in patients with hip fractures.Fascia iliaca compartment block given to patients with hip fractures did not affect cognitive status in this study. Patients with a cognitive impairment may receive inadequate pain relief after hip fracture and this discrimination needs to be addressed in further studies.2008–004303-59 date of registration: 2008-10-24.EudraCT number  Globally, emergency healthcare faces a substantial increase in patients with hip fractures. Estimates indicate that, by 2050, there will there be six million patients with hip fractures annually . In SwedDelirium is one of the most common perioperative complications in patients with a fractured hip. The reported incidence of perioperative delirium in patients with a hip fracture ranges from 38 to 62% and increases with age, comorbidity and reduced preoperative cognitive status , 6. FurtStudies show that the clinical consequence for patients with hip fractures and cognitive impairment is that they have more pain than lucid patients, because they wait longer for pain relief and receive less than half the pain medication administered to cognitively intact patients , 16. PatThe risk of delirium increases with limited treatment of pain, so it is essential to provide good pain management . IntermiThe purpose of this study was to examine the association between preoperative pain management with nerve blocks and cognitive status in patients with hip fractures during the perioperative period. The primary aim was to examine the impact of preoperative FICB on cognitive status until the first postoperative day in patients with hip fractures. The secondary aim was to investigate the association between cognitive status and the amount of analgesia given in the preoperative phase of hip fracture care. The hypothesis was that FICB would have a positive impact on cognitive status in these patients as a result of improved pain management.The patients in this study were participants in a double-blind, randomised, controlled trial . In brieThe present study evaluated the perioperative effect of preoperative FICB on cognitive status in patients with a hip fracture.Patients aged 65 years or more were included consecutively after hospital admission, from October 2010 to February 2012. The inclusion criteria were: 1) patients with a single radiographically confirmed hip fracture and 2) FICB had to be administered less than one hour after hospital admission. The exclusion criteria were 1) multi-trauma; 2) fracture more than 12 h prior to FICB; 3) allergy to local anaesthetics and 4) infection in the injection area. Patients gave their written consent. Those patients who were unable to give their consent were included following presumed consent. Ethical approval and presumed consent were obtained from the Regional Ethics Board in Uppsala.Patients with a suspected hip fracture were transported by ambulance directly to the department of radiology. After X-ray verification of hip fracture, the patients were transferred to an orthopaedic ward where those included in the study were randomised to either an intervention group or a control group. The FICB was performed in accordance with Dalen’s technique and administered as a complement to regular analgesia . The medAll staff members were trained in using the pain assessment instrument, the Short Portable Mental Status Questionnaire (SPMSQ), filling out case report forms, randomisation and blinding according to the study protocol. All personnel involved in the study were blinded to the study medication. The study was conducted under the surveillance of an external monitor. Typical symptoms indicating adverse events (AE) associated with the injection of which the staff needed to be aware were hypotension, bradycardia, nausea, vomiting, paraesthesia, dizziness and headache.Morphine was given using an on-demand model with nurse-initiated analgesia. In Sweden, ambulances are staffed by prehospital emergency nurses (PENs). For PENs, it is standard procedure to titrate intravenous (iv) morphine for pain relief from the site of injury, during transport and until the time of admission to hospital. The titration of morphine was continued by nurses on the ward. Before surgery, paracetamol was prescribed on demand. This was a routine that was considered to work acceptably. There were no formal standards with regard to the preoperative dosage of either morphine or paracetamol. In hospital, preoperative iv morphine was usually prescribed as 1–2 or 2.5–5 mg on demand, repeated if necessary.spina iliaca anterior superior and os pubis, 1 cm lateral to the conjunction of the two thirds closest to the spina iliaca anterior superior. The insertion was made with a regular needle for intramuscular injections by loss of resistance when passing first the fascia lata and then the fascia iliaca (two pops). The investigation fluid was then injected [The FICB was administered to the affected hip by a perpendicular injection with a two-pop technique as a complement to preoperative analgesia by the orthopaedic surgeon who examined the patient. The insertion point was identified by drawing a line between the injected . Thirty-The following parameters, retrieved from the patients’ medical records, were used to characterise the study patients: age, gender, type of fracture, analgesia, pain, diagnosis of dementia prior to enrolment and the American Society of Anesthesiologists’ Physical Status Classification System (ASA). The ASA score system categorises comorbidity . The firFor the purpose of cognitive screening, the Short Portable Mental Status Questionnaire (SPMSQ) was used . This isThe SPMSQ consists of the following questions: 1. What date, month and year is it?; 2. What day of the week is it?; 3. What is the name of this place?; 4. What is your phone number?; 5. How old are you?; 6. When were you born?; 7. Who is the current prime minister?; 8. Who was the prime minister before him?; 9. What was your mother’s maiden name?; 10. Can you count backwards from 20 by 3’s? Every correct score gives one point. Mother’s maiden name is scored as correct if it is not the same as the patient’s surname.The scores on the SPMSQ were divided into four groups 0–2; 3–5; 6–7; 8–10. The scores of 0–2 are regarded as severe cognitive impairment; 3–5 and 6–7 are regarded as moderately or mildly impaired and 8–10 is considered cognitively intact . The SPMThe instrument used to assess pain was the Stockholm South General Hospital Pain Instrument (SSGHPI) . The SSGDescriptive statistics such as means, standard deviations (SD), median, range and proportions were used to summarise socio-demographic and clinical characteristics. For comparisons between the two groups with respect to categorical data, the chi-square test was used. When comparing groups with respect to morphine dose, we dealt with skewed distributions deviating from normal distribution, so we used non-parametric tests (the Mann-Whitney test). After establishing a classification of SPMSQ change from admission to postoperative period in three classes , we also used the chi-square test to compare the distribution of the classified categories between the two groups.p-value of < 0.05 was regarded as a statistically significant result. All analyses were performed with the IBM SPSS version 22 statistical package.A n = 66) or the control group (n = 61). The two study groups were well balanced, see the data presented in Table One hundred and twenty-seven patients were randomised to either the intervention group  than among patients with higher levels of cognitive status. However, no difference was found between the subgroups according to SPMSQ regarding the dose of morphine that was given after arrival in hospital Table .Table 5No serious adverse events were reported as a result of the FICB during the study period.The hypothesis that a preoperative nerve block after a hip fracture would improve cognitive status was not confirmed in this study. A report by Mouzopoulos et al.  shows thAnother reason may be a fading FICB effect when the waiting time (median 19 h) to operation exceeds the time window for the effect of the FICB. The effect of fascia iliaca compartment block has been shown to fade after eight hours . We therWe found that patients with a cognitive impairment received lower doses of morphine before arrival in hospital. Previous researchers have reported similar findings. Patients with dementia received only one third to half of the morphine dose that cognitively intact patients received , 16. CogIt is only possible to speculate on the reason for the discrimination of patients with a cognitive impairment regarding relief of pain. It seems reasonable to assume that, when titrating morphine, nurses have difficulty assessing the level of pain in cognitively impaired patients. Sometimes nurses need to rely on their own assessment of the patients’ pain . The nurIn spite of this, the ambulance nurses in this study were relatively liberal with the administration of morphine compared with other studies evaluating nurse-initiated analgesia –49. It tThe results highlight the need for more finely developed instruments for behavioural pain assessment and the need for more studies evaluating pain and its impact on patients with a cognitive impairment. For the future development of healthcare, this study is a simple reminder that the evaluation of pain is a complex and underestimated problem. Pain assessment, interventions for pain control and awareness of undertreated pain need to be improved, especially in emergency healthcare.If FICB is to be implemented with the intention of improving pain control, its high level of safety is supported by this study, due to the absence of serious adverse events.This study may have been underpowered in order adequately to address its primary aim. The main purpose of the original study was to examine pain control through FICB and sample size calculation was therefore performed using data on pain with a calculated power of 90% . The preWe evaluated cognitive function according to the SPMSQ. However, it would have been an advantage to have registered the incidence and prevalence of delirium in addition to SPMSQ scores. The SPMSQ score does not differentiate between delirium and/or dementia and it only shows the present status of a sometimes very fluctuating condition.The interval from hospital admission to the first postoperative day differed between individuals. However, the mean delay did not differ significantly between the two groups.Patients with displaced fractures are more likely to have severe pain. In this study, no data on displaced fractures were collected. It was therefore not possible to adjust the results for this potential confounder, which is a limitation.Finally, patients were only included in the study during daytime and until midnight. Although this may have created a selection bias, a bias of this kind could hardly affect the results in terms of pain relief.We found no impact on cognitive status by a single FICB after a hip fracture. Patients with a severe cognitive impairment received less pain medication before arrival in hospital than their lucid counterparts. This discrimination needs to be further addressed. Cognitively impaired patients in particular may benefit from improved pain control and quality of care with FICB, but this remains to be demonstrated.


To assess dose, characteristics, and coprescribed analgesics in patients newly prescribed pregabalin for neuropathic pain and fibromyalgia in Japan.  Based on the medical and prescription information present in the Medical Data Vision database, we analyzed the initial and maximum daily doses, prescription period, coprescribed analgesics, and neuropathic pain-related disorders of patients newly prescribed pregabalin between 01 July 2010 and 31 December 2013.  A total of 45,331 patients  were newly prescribed pregabalin during this period. The mean initial and maximum daily doses were 97.3 mg and 127.8 mg, respectively, and decreased yearly. The duration of the prescription period was 111.9 (mean) and 53 (median) days, and the frequently coprescribed analgesics included NSAIDs, opioids, and Neurotropin®. About one half of the patients had spinal disorders.  In Japan during the period examined, the number of newly prescribed pregabalin users increased, but the initial and maximum daily doses decreased yearly after pregabalin went on the market. The maximum daily dose in Japan was lower than those reported in the USA and Europe. These differences might be associated with patient age and physical status and with anxiety about possible adverse events. Neuropathic pain and fibromyalgia are intractable chronic pains. Neuropathic pain is defined as “pain caused by a lesion or disease of the somatosensory system” and is classified as peripheral or central neuropathic pain according to the site of the lesion or disease , 2. The α2δ subunit of the calcium channel and is used world wide to treat seizure, generalized anxiety disorder, neuropathic pain, and fibromyalgia. Pregabalin is a first- and/or second-line recommendation for neuropathic pain in many guidelines [Pregabalin is a ligand for the idelines –12 and widelines . PregabaPregabalin is approved to be started at 150 mg daily and titrated up to a maintenance daily dose range. In Japan and the USA, this dose range is 300–600 mg for neuropathic pain and 300–450 mg for fibromyalgia, and in Europe, 150–600 mg for neuropathic pain. However, the efficacy of 150 mg daily was inconsistent –16. In tAn interim report of postmarketing surveillance for peripheral neuropathic pain in Japan  showed tThis descriptive study was conducted using the data collected and aggregated by the Medical Data Vision (MDV) Co. Ltd. from the hospitals using a novel medical reimbursement system for hospitalization, the Diagnosis Procedure Combination/Per-Diem Payment System (DPC/PDPS) in Japan , 28. In Newly prescribed was defined as a first prescription in the database with no prescribed pregabalin in the previous 90 days. The date of newly prescribed pregabalin was designated as the first prescription date. Patients were excluded when the hospital's data collection had started within 90 days before the first prescription date. Records of prescribed pregabalin “as-needed” were excluded and patients whose first prescription was only “as-needed” were excluded.We selected patients newly prescribed pregabalin between 01 July 2010 and 31 December 2013. daily dose of pregabalin was calculated from the content and the daily number of capsules. When there were several records on the same prescription date, daily dose and the number of the days prescribed were estimated based on the number of days until the next pregabalin prescription date. The last prescription date was defined as the last date of pregabalin prescription in the database or as the first date with no pregabalin prescription after 30 days plus the number of days of the last prescription. The prescription period was set to be the time between the first prescription date and the end of the time prescribed by the last prescription. When the duration of the prescription period was over 365 days, this duration was set at 365 days.The Coprescriptions were defined as drugs that were coprescribed at the first prescription date of pregabalin, or before this first date but overlapping it and represcribed within 90 days after it. The number of kinds of coprescribed oral drugs was based on substance names. Coprescribed analgesic drugs were categorized as (1) first- and second-line drugs of the Japanese guideline , including tricyclic antidepressants , gabapentin, extract of cutaneous tissue of rabbit inoculated with vaccinia virus (Neurotropin), duloxetine hydrochloride, and mexiletine hydrochloride; (2) opioids, including fentanyl , oxycodone , morphine , buprenorphine , tramadol , and acetaminophen/tramadol combination ; and (3) nonsteroidal anti-inflammatory drugs . Opioids were subcategorized by strength (weak (tramadol and acetaminophen/tramadol combination) and strong (the others)) and route .Neuropathic pain-related disorders were classified as follows: (1) spinal disorders , (2) postherpetic neuropathy (ICD-10 code: B02.2), (3) diabetic neuropathy , (4) cancer-related pain , (5) trigeminal neuralgia (ICD-10 code: G50.0), (6) entrapment peripheral neuropathy of the upper limb , (7) other neuropathic pain , (8) fibromyalgia , and (9) others (not classified in the above categories).after pregabalin discontinuation period was defined as the time between the day after the last prescription date and 90 days after the end of the pregabalin prescription period. The prescriptions of the analgesic drugs described above in this period were then summarized. The prescriptions after the pregabalin discontinuation period were compared with those during the pregabalin prescription period and categorized as follows: (1) continued use: when the same drug had been prescribed during the pregabalin prescription period without prescriptions of other drugs of the same category, (2) new use: when a drug or other drugs of the same category had not been prescribed during the pregabalin prescription period, (3) changed/added drugs: the drugs prescribed after the pregabalin discontinuation period were different from or added to other drugs of the same category prescribed during the pregabalin prescription period, (4) changed/additions of the route: the routes of the drugs coprescribed during the pregabalin prescription period were changed or new administration routes for the same drugs were added after the pregabalin discontinuation period, and (5) changed/additions of the strength: different strengths of opioids were prescribed after the pregabalin discontinuation period to change from or add to opioids prescribed during the pregabalin prescription period.Patients were analyzed whose pregabalin prescription period duration was less than 365 days. The t-test for numerical data and the chi-square test for categorical data and were conducted using the SAS version 9.4 (SAS Institute Inc.) statistical package.Numerical data are presented as means ± their standard deviation, or as medians and their 25th and 75th percentiles, and categorical data are presented as numbers and percentages. Statistical comparisons were made using the We obtained the data of 148,593 patients from the MDV database who had been prescribed pregabalin; 45,331 of those patients met the necessary criteria, and their data were analyzed further . The numThe mean and median durations of the prescription period were 111.9 ± 124.2 and 53 days, respectively. The duration of the prescription period was longer for outpatients than that for inpatients. The fraction of patients who changed from the initial daily dose to at least one another dose during the prescription period (change in dose) was only 26.9%, and these changes were higher for inpatients than they were for outpatients. The mean number of coprescribed oral drugs was 4.2 ± 3.7, and the number for inpatients was higher than that for outpatients.The most frequently coprescribed analgesics for outpatients at the first pregabalin prescription date were NSAIDs (36.9%); the second most frequent was Neurotropin. Opioids were coprescribed for 5.7% of the outpatients, and most of these were oral formulas. For inpatients, the most frequently coprescribed analgesics were NSAIDs, followed by opioids; strong opioids were more frequently coprescribed than weak ones.About one half of the outpatients had spinal disorders; other disorders, in descending order of frequency, included postherpetic neuropathy, cancer-related pain, and diabetic neuropathy. About 30% of inpatients had spinal disorders and about 20% had cancer-related pain.To exclude the effects of short-trial pregabalin use on the results, a subgroup analysis of 12-month continuous users was conducted  as well as outpatients with trigeminal neuropathy and entrapment neuropathy of the upper limb were coprescribed NSAIDs.After the pregabalin discontinuation period , 10.2% oWhen individual pain disorders were analyzed separately , and decreased yearly; 60.8% of patients were prescribed less than the approved dose. The reason for this decrease may be due to the many adverse events observed early in the launch of pregabalin . A noticThe maximum daily dose was lower than both the approved initial (150 mg) and maintenance (≥300 mg) daily doses in Japan; the proportions of patients prescribed less than approved doses were 47.4% and 91.0%, respectively. In the subgroup analysis of 12-month continuous users, the maximum daily dose (153.5 mg) was comparable to the approved initial daily dose in Japan, and the proportions of patients prescribed less than the approved doses were 38.6% and 83.6%, respectively. Such low doses were also reported in another Japanese study 134.9 mg) . In USA .9 mg . IThe ratio of males, initial daily dose, maximum daily dose, and number of coprescribed opioids were higher in inpatients than in outpatients. The high ratio of males was considered to result from the high ratio of cancer-related pain patients and a low ratio of spinal disorders because there was a higher ratio of cancer-related pain in males and a lower ratio of males with spinal disorders. The higher ratio of coprescribed opioids in inpatients was observed for all disorders, including cancer-related pain. This may be because severer pain patients may more often be inpatients than outpatients.The 1-2-line drugs were coprescribed for about 15% patients with all disorders except cancer-related pain, and NSAIDs were coprescribed for 20% to 40% of patients. The high frequency of coprescribed NSAIDs may be due to many patients also having nociceptive pain, another component of pain. Approximately half of the patients with cancer-related pain were coprescribed opioids, and one half of the patients were coprescribed NSAIDs. NSAIDs and opioids were recommended for cancer pain, and pregabalin was coprescribed for adjuvant analgesics or relief of neuropathic pain from cancer or cancer treatment and/or the coexistence of these pains.This study had several strengths. First, a large population of patients who were prescribed pregabalin was analyzed about 10 times that of other drug-use investigations in Japan , and theThere were also some limitations. First, the follow-up of patients was limited because this was a database of hospital-based data. After discontinuation of pregabalin, other analgesics were prescribed for about 30% of patients. When there were no data of analgesic prescriptions, it was not possible to know whether no analgesics had been prescribed or the patients had consulted a different hospital. However, these patients were considered to be unsatisfied with the effectiveness of pregabalin. Second, the reasons for discontinuation were not confirmed because the effects and the most adverse drug reactions of pregabalin, such as dizziness and somnolence, were not collected for this database. Third, there is a possibility of bias in the patient population because many small scale hospitals have not introduced the DPC/PDPS . MoreoveIn Japan, the number of patients being newly prescribed pregabalin increased over the course of the study period, but the initial and maximum daily doses decreased yearly after pregabalin went on the market. The maximum daily dose in Japan was lower than those reported in the USA and Europe, which may be associated with differences in age and physical status and anxiety about possible adverse events.


Hemiplegic Shoulder Pain (HSP) is among common complications occurring after stroke leading to disability. This study was conducted to compare the effects of electrical Interferential Current stimulation (IFC) and Electrical Acupuncture (EAC) on pain intensity, range of motion, and functional ability in patients with HSP and also comparing the two modalities regarding improvement of above indices.In this randomized clinical trial, 46 patients with HSP caused by ischemic stroke were recruited and assigned into 2 groups. Conventional exercise trainings were applied for both groups. Group A received additional IFC with medium frequency of 4000 HZ, and Group B received additional EAC two times a week for a total of 10 sessions. Pain severity, daily function, and shoulder Range of Motion (ROM) were evaluated using Visual Analogue Scale (VAS), Shoulder Pain and Disability Index (SPADI), and goniometry, respectively before and 5 weeks after the treatment.Both groups showed relative improvement in pain severity, SPADI score, and its subscales, and also active and passive shoulder ROM after the treatment. However, IFC group compared to EAC group had higher mean changes of active ROM in abduction (28.00 ± 3.81 vs. 12.25 ± 2.39) and functional subscale of SPADI (11.45 ± 1.88 vs. 5.80 ± 1.66) after the treatment. On the contrary, EAC group showed higher percentage of VAS changes (46.14 ± 6.88 vs. 34.28 ± 5.52), indicating better pain improvement compared to IFC group. Other parameters did not show significant difference between two groups.Both IFC and EAC caused short term improvement in functional state, increased motion, and decreased pain in patients with HSP. Although pain control was more evident in acupuncture group, IFC resulted in better effects on function and active ROM of abduction, and seems to have higher efficacy.IRCT201602153217N10.This clinical trial was registered in the Iranian Registry of Clinical Trials at 2016-07-16 with a registry number of  Hemiplegic Shoulder Pain (HSP) is among main complications occurring after the stroke interfering with function of upper extremities and regular daily activities. Prevalence of shoulder pain in post stroke hemiplegia has been reported to range from 34 to 84% , 2. HSP Glenohumeral joint sub-laxation refers to increased translation of humeral head relative to glenoid fossa occurring in approximately half of stroke survivors with hemiplegia. It is considered as one of etiologies of HSP,but a causal relationship between subluxation and pain has remained controversial .HSP is associated with reduced motor recovery; therefore, it is critical for stroke patients to treat shoulder pain properly. Various treatments have been suggested including physical therapy, medications, nerve blocks, exercise, strapping, Transcutaneous Electrical Nerve Stimulation (TENS),and ultrasound , 6. On tRecently, two modalities have been recommended for pain control in these patients including acupuncture and one form of non-invasive electrotherapy; Interferential Current stimulation (IFC) . In IFC,Some studies have shown that IFC is useful for pain relief during movement and also increases pain-free passive range of motion of the shoulder in people with HSP .Acupuncture, as the other modality has been practiced since the ancient times,and is an important component of traditional Chinese medicine,and has been widely used to treat pain in various clinical conditions including musculoskeletal ,gastroinAcupuncture is a physical intervention, which involves placement of small needles in the skin at different acupoints, based on theoretical network of meridian system, and is supposed to restore the flow of vital energy in meridian channels and to bring the human body to a new balanced state . AcupuncIn this randomized clinical trial, 46 patients with hemiplegic shoulder pain caused by ischemic stroke seeking evaluation by expert neurologist, were referred to Physical Medicine and Rehabilitation Clinic of a university hospital and were recruited between February 2016 and March 2017. Inclusion criteria were as follows: 1) Patients aged between 35 and 85 years old suffering from HSP with or without subluxation caused by ischemic stroke in which cerebral lesions were verified by CT or MRI scans, 2) having had a first episode of unilateral stroke during 1 month to 1 year after accident, 3) being able to understand and follow simple verbal commands and participate in a rehabilitation program .Patients with a history of physiotherapy within the past 1 month; history of local injection of steroid/Botox into shoulder joint within the past 6 month; presence of pacemaker; skin lesions in shoulder area; intracerebral hemorrhage confirmed by neuroimaging; severe stroke with NIHSS  more than 21 at trial commencement ; impairen = 20 per condition) using the study by Suriya-amarit, et al. [Sample size was calculated , random numbers were produced and according to sample size, patients were enrolled into the study, divided into two groups, treated and were followed after the treatment  at baseline in both groups were recorded. Shoulder x-ray was taken if the patient was suspicious of subluxation  and presThe study protocol was approved by the Local Ethics Committee of our institution, and an informed consent was obtained from all study participants. This clinical trial was registered in the Iranian Registry of Clinical Trials with registry number of IRCT201602153217N10.Initially, all patients in both groups received superficial heat using infrared, followed by therapeutic exercises for muscles around shoulder joint area for a total of 30 min. Passive Range of Motion (PROM) exercises were performed for shoulder, elbow, and wrist joints in different directions. Shoulder PROM exercises were done in flexion, abduction, extension, gentle external rotation, and internal rotation with assistance of unaffected arm as well as the therapist. Active assistive exercises including tabletop circle movement around a water bottle for example, tabletop pushing movement, unweighted and weighted biceps curl, arm side movement, wrist curl and grip practices were also implemented. Each exercise was repeated 10 times. Sample of these exercises are presented as additional file in supplementary information at the end  were used in Group A (IFC). In one channel, 2 electrodes were placed onto infraspinatus and anterior deltoid muscles, and in the other channel, 2 electrodes were placed in posterior deltoid and supraspinatus muscles. The electrodes were positioned around the shoulder so that each channel was run perpendicular to the other, and the two current crossed at a midpoint in the center. Setup and interference of currents of these electrodes together constructed a cloverleaf pattern. So, IFC was conducted with following characteristics: isoplanar vector field with carrier frequency of 4 kHz; Beat frequency of 100 Hz,and sweep frequency of 150 Hz, on time/off time schedule of 10s:30s for a 20-min treatment period 0 mm were.In group B (electro-acupuncture or EAC), the materials used in the treatment were acupuncture needles, sterile silver-handle pre packed needles  with guide tubes and sizes of 0.25 × 25 mm, 0.3 × 25 mm,or 0.25 × 40 mm.In this study, the most common meridian-sinew sites recommended by Kung,et al. , 26 were1. GB21 (jianjing) in middle point of upper trapezius, 2. GB 20 (Fengchi): On the nape, below the occiput in depression between the upper portion of sternocleidomastoideus and trapezius muscles, 3.TW-15 (Tianliao) close to the TrP of levator scapulae, 4. SI-11 (Tianzong) in the region of subscapular fossa, level with the 4th thoracic vertebra, 5.SI-12 (Bingfeng) in the center of the suprascapular fossa, directly above SI 11, in the depression when the arm is lifted. 6. LI 14 (Binao) inferior to the deltoid muscle insertion point, 7.LI 11(quchi), lateral epicondyl, the point is on lateral end of the transverse cubital crease, at midpoint between biceps tendon and lateral epicondyle of the humerus.,8.LI 10 (shousanli), with the elbow flexed, the point is on the dorsal radial side of the forearm, 2 cun below the transverse cubital crease,9.LI 4 (Hegu), On the dorsum of the hand, between the 1st and 2nd metacarpal bones, in the middle of the 2nd metacarpal bone on the radial side., 10. Du 14 or GV 14 (Duzhui), on the posterior median line, in the depression below the spinous process of the 7th cervical vertebra; 11. Du 20(Baihui) On the top of head, at the midpoint of the line connecting the apexes of the two auricles. 12. 2 to 3 additional TrPs (trigger points) around involved shoulder and upper back was also inserted .A stimulation machine of EAC points (TENS Unit) delivers electrical current through 4 e-stim output channels and acupuncture needles. The 4 e-stim channels are separated into two groups  allowing each group to vary their frequency and pulse width independently. The unit is powered by a/c adapter and offers TENS  using 4 sets of lead wires connecting to needles, generating electrical stimulation for pain relief as well as twitch production aims upon plegic shoulder area and other determined acu-points for 20 min . TherapeThe whole therapy program in both groups was applied twice a week for a total of 10 sessions. However, 3 participants of each group discontinued the therapy and lost to follow up, so finally 20 patients in each group completed the intervention, data of which were analyzed.Primary outcome included 1.4 -point reduction in pain intensity at a 5-week period compared to the baseline  measuredSecondary outcome of the study included a 13 -point decrease  in shoulThe SPADI is a self-administered questionnaire created to assess shoulder functional abilities. It consists of 13 items assessing two different areas. The first 5 items measure the pain, and the next 8 items assess patients’ disability. To answer the questions, subjects place a mark on a numbered scale ranging from “0 (for no pain and difficulty) to 10 ” for each question . ValiditUsing a goniometer, ROM of shoulder was evaluated in active and passive abduction, flexion, external rotation, and internal rotation. Validity and reliability of this measuring device has been demonstrated by other researchers .Before and after the intervention, a blinded physiatrist assessed above-mentioned parameters.p-value of < 0.05 was considered as statistically significant.All data were analyzed using SPSS software . Results were expressed as Mean ± standard deviation or percentage. The Chi-Square and Fisher exact tests were used to compare categorical variables. AS the result of Shapiro-Wilk test for normal distribution and Leven’s test for homogeneity of variances were not significant, independent samples t-test was used to compare the continuous variables. Changes in variables before and after the intervention in each group were analyzed using Mixed ANOVA test. A In the present study, 40 patients with HSP were included and completed the intervention in IFC and electrical acupuncture groups. There were no significant differences in demographic and clinical characteristics between the two groups at baseline Table .Table 1p < 0.05), but only percentage and mean changes of functional subgroup were significantly higher in IFC group (p = 0.03).Mean SPADI score and its subgroups before and after the intervention and their percentage of changes in each group are shown in Table p = 0.49).MCID was considered ≥13 for SPADI questionnaire. According to this measure, 15 cases (75%) in IFC and 13 cases (65%) in electrical acupuncture groups reached this goal with no significant difference (p = 0.014) .We observed that in both groups pain using VAS was significantly reduced following intervention. The mean and percent change of VAS in electrical acupuncture group were 2.55 ± 0.29 and 46.14 ± 6.88; respectively, which were significantly higher than the mean and percent change of VAS in IFC group  (P = 0.216).Mean changes of pain severity among patients without shoulder subluxation within group EAC was equal to 2.87 ± 0.34 and among patients with subluxation was equal to 2.00 ± 0.85 points. Although improvement percentage according to mean changes of VAS was more in patients without shoulder subluxation than the patients with subluxation, however this difference was not statistically significant (p < 0.05) except passive ROM in internal (p = 0.09) and external rotation (p = 0.15) in IFC group and active ROM in abduction in EAC group (p = 0.08). Compared to EAC group, IFC group had significantly more active ROM in abduction, flexion, and external rotation after the intervention . Mean changes of other ROMs did not have significant difference between the two groups (P > 0.05).Table No adverse events including bleeding, infection or sustained pain related to EAC or IFC were seen at present study.Hemiplegic shoulder pain can affect up to 70% of stroke patients and can have an adverse effect on rehabilitation outcomes –35. TreaIn this randomized clinical trial, the effect of two modalities, namely IFC and EAC on pain and disability of patients with HSP was evaluated. All patients had weakness and Limitation of Movements (LOM) in shoulder caused by hemiplegia prior to the study. On the other hand, shoulder pain had exacerbated decreased ROM in different directions and the most limited ROM was in abduction and external rotation , 35.TherIFC is one of modalities used to control and alleviate the pain. The mechanism by which IFC exerts its effect is not exactly clear. It is suggested that its analgesic effects are similar to the effects of TENS with longer duration and higher intensity currents,which is suitable for patients with chronic pain and weak muscles . The advIFC has been shown to have significant effects in controlling pain in patients with shoulder and knee injuries , 39. ResThese results are in accordance with those of the study by Suriya-amarit, et al.  who indiAcupuncture stimulation works through transmission of signals to central nerve system, releasing opioid peptides, causing an increase in the threshold of pain receptors, and helping muscles to relax and move more passively, which in turn results in an increase in rehabilitation capacity . AcupuncIn our study, there was a significant improvement in pain severity, some shoulder joint free active and passive ROMs and SPADI score following treatment with EAC. In this regard, Lee,et al.  in a sysRegarding pain measurement using VAS, it should be mentioned that, mean changes in IFC group was equal to 1.60 ± 0.28 and in EAC group was equal to 2.55 ± 0.29, and since MCID has been estimated in a range of 1.4–1.5 cm of 10 cm scale in most of previous studies , so it cSeveral studies have suggested that Electrical Stimulation (ES) of shoulder girdle muscles can reduce shoulder subluxation, preventing HSP occurrence, and improving their function , 35. ResAlthough incidence of stroke has been reported to be higher among males , 5, in oIn summary, it was observed that, compared to electrical acupuncture, IFC accompanies with higher improvement in SPADI subgroups and ROM increase in abduction. It seems that, IFC is more effective than electrical acupuncture in improving functional status. This effect is partly attributed to more powerful electrical stimulations of IFC on motor performance because of deeper penetration, lower neural adaptation, and consequent positive effects on strength in this group, compared to TENS-like stimulations used in EAC devices , 24. On Finally, it should be mentioned that, EAC or IFC as complementary therapy not as a single protocol would be effective in treatment of HSP after stroke . PhysicaThere were some limitations in the present study. First, in this study elements which was used in both groups were not balanced together; 4 electrodes of IFC vs 12 points of needle insertion in EAC were applied, so may be placebo effects of more needle points or stimulation under electrodes impressed the patient’s satisfaction and positive perception rather than actual effect of treatment, although each group has a different kind of this effect but still placebo related-factors could not be ruled out . Second,Administering of both IFC and electrical acupuncture in patients with hemiplegic shoulder pain following ischemic stroke caused relative improvement in functional activities, shoulder joint ROM, and pain reduction after a 5 -week treatment period. Although pain control was more evident in electrical acupuncture group, IFC was accompanied by more improvement in functional state and active ROM of abduction, and seems to have higher efficacy.Additional file 1. Full body rehab exercises for stroke patients


Acute pain is a frequent symptom, but little is known about the frequency and causes of acute pain in the prehospital population. The objectives of this study were to investigate the frequency of moderate to severe pain among prehospital patients and the underlying causes according to primary hospital diagnose codes.This was a register-based study on 41.241 patients transported by ambulance. Information on moderate to severe pain [Numeric Rating Scale  > 3 or moderate pain or higher on 4-point likert scale] was extracted from a national electronic prehospital patient record. Patient information was merged with primary hospital diagnose codes based on the 10th version of the International Classification of Diseases (ICD-10) to investigate underlying causes of pain.11.430 patients (27.7%) reported moderate to severe pain during ambulance transport. As a measure of opioid demanding acute pain, 3.275 of 41.241 patients (7.9%) were treated with intravenous fentanyl. Underlying causes of pain were heterogenic according to ICD-10 chapters with injuries being the largest group of patients with moderate to severe pain (XIX: 42.8% of 8.041 patients), followed by non-specific diagnoses (XVIII: 28.5% of 7.101 patients and XXI: 31.6% of 5.148 patients), diseases of the circulatory system (IX: 22.1% of 4.812 patients) and other (20.3% of 16.139 miscellaneous patients).Due to the high frequency of moderate to severe pain affecting a wide range of patients, more attention on acute pain is necessary. Whether ambulance personnel have sufficient options for treating various pain conditions might be a subject of future evaluation. Non-specific diagnoses accounted for surprisingly many patients with moderate to severe pain, of which many were treated with intravenous fentanyl. This may be substance of further investigation.Moderate to severe pain is a highly frequent and probably underestimated symptom among patients transported by ambulance. Underlying causes of pain are heterogenic as described by primary hospital diagnose codes. More focus on the treatment of acute pain is needed. Prehospital emergency medical service is an evolving field essential in the initial phase of acute patient care. Focus has traditionally been on highly acute conditions such as cardiac arrest , 2, myocAcute pain is perhaps one of the most frequent symptoms felt by patients in emergency medicine –9. PropeThis is a register-based observational study of acute patients transported by ambulance to hospital in the Central Denmark Region over a 9-month period from 1 August 2015 to 30 April 2016.2 and provides healthcare for 1,303,000 individuals representing roughly 25% of the entire Danish population. Acute transports are dispatched through a common Emergency Medical Coordination Centre (EMCC) that receives 1-1-2 emergency calls and immediate requests from general practitioners . Table As a proxy of severe opioid demanding pain, 3.275 of 41.241 patients [7.9% (95% CI 7.7–8.2)] were treated with intravenous fentanyl, of which 2.886 patients had moderate to severe pain. Patients with the highest levels of pain were more likely to be treated with fentanyl compared with lower levels of pain [severe pain, number of patients with moderate to severe pain was injuries (XIX). Surprisingly, a high number of patients with non-specific (XVIII and XXI) diagnoses had moderate to severe pain. The ICD-10 chapters with the highest proportion of moderate to severe pain were diseases of the musculoskeletal system, injuries, digestive- and genitourinary diseases. Few other studies have investigated the frequency and causes of acute prehospital pain and these studies were less accurate in terms of describing missing data and classifying cause of pain.In this large prehospital population-based study, moderate to severe pain was experienced by at least 28% of more than 40.000 patients transported by ambulance, 10.3% had severe pain, and 7.9% were treated with intravenous fentanyl. According to primary hospital diagnosis, the underlying cause of pain was heterogenic with pain present in virtually all ICD-10 chapters. As expected, the ICD-10 chapter with the highest McLean and colleagues investigated 14.5 million ambulance transports over a 1-year period and found that 20% experienced moderate to severe pain. The most common reasons for hospital admission among patients with pain were injuries 27%), musculoskeletal symptoms 18%), chest pain (18%), digestive symptoms (11%) and respiratory symptoms (7%). Overall, 17% were treated with narcotic analgesics [%, muscul%, chest Acute pain is a complex subjective feeling that may not always be easily quantified by unidimensional tools , 37. AcuA high number of patients treated with intravenous fentanyl may reflect the fact that many prehospital patients have opioid demanding pain. There was a surprisingly high number and proportion of patients with moderate to severe pain among patients with non-specific diagnoses (e.g. ICD-10 chapters XVIII and XXI), which could be elucidated in future studies. Also, it may raise concerns whether few of these patients are malingering as part of a drug seeking behavior. While prehospital healthcare providers have to keep on relieving symptoms and not judging patient reliability, the prehospital EMS contribution to drug-seeking behavior may be substance of further investigation. Reports from the United States and Europe suggest an epidemic outbreak of opioid abuse that needs to be taken seriously , 47.In previous prehospital studies on the causes of pain –9, the cThe strength of this register-based study is first of all the sample size merged with validated national registries , 25. SecA number of limitations also need to be addressed. First, missing CPR numbers have hypothetically contributed to selection bias. Given the population of acute prehospital patients with potential acute diseases assessed in a limited timeframe, the risk of being unable to acquire precise information regarding some individuals is practically unavoidable , 52–54. Third, using unidimensional pain scales may not precisely reflect the highly nuanced and subjective sensation of pain experienced by acute patients. Baseline pain does not always mirror a treatment demand, and may be influenced by other factors such as anxiety. Though prone to inter-individual variation, simple pain scales are practical clinical tools widely adopted in prehospital- , emergenIn conclusion, moderate to severe pain is a frequent symptom in the prehospital setting, involving at least 28% of all acute patients transported by ambulance and present in nearly all ICD-10 chapters. The highest number of patients with moderate to severe pain occurred within injuries, non-specific diagnoses and diseases of the circulatory system. The highest proportion of moderate to severe pain occurs among patients with diseases of the musculoskeletal system, injuries and diseases of the digestive- and genitourinary system. More attention should be given to the management of acute pain, given the frequency and the broad range of causes in terms of main hospital diagnoses.


Background and Objectives: This study aims to identify reasons for unscheduled return visits (URVs), and risk factors for diagnostic errors leading to URVs, with comparisons to data from a similar study conducted in the same institution 9 years ago. Materials and Methods: This retrospective study included adult patients who attended the emergency department (ED) of a tertiary hospital in Singapore between January 2014 and June 2014, with re-attendance within 72 h for the same or similar complaint. The primary outcome was wrong or delayed diagnoses. Secondary outcomes include admission to the ED observation unit or ward on return visit. Findings were compared with the previous study performed in 2005 to identify trends. Results: Of 67,422 attendances, there were 1298 (1.93%) URVs from 1207 patients . The most common presenting complaint was abdominal pain (22.2%). One hundred ninety-one (15.8%) patients received an initial wrong or delayed diagnosis. Factors  associated with this were: presenting complaints of abdominal pain , fever , neurological deficit , and discharge without follow-up . Among re-attendances, 459 (38.0%) required admission. Factors  associated with admission were: male gender ; comorbidities of diabetes mellitus , asthma , and renal disease ; presenting complaints of abdominal pain , fever , and giddiness or vertigo . There was a reduction in URV rate compared to the previous study in 2005 (1.93% versus 2.19%). Abdominal pain at the index visit remains a significant cause of URVs (22.2% versus 25.1%). Conclusions: Presenting complaints of neurological deficits, abdominal pain, fever, and discharge without follow-up were associated with wrong or delayed diagnoses among URVs. Unscheduled return visits (URVs) to the emergency department (ED) are repeat presentations of patients, discharged from the ED, returning with related presenting complaints. While there is no worldwide consensus on the interval a return visit should fall within , studiesThis study aims to determine reasons for ED URVs in a tertiary healthcare institution, identify risk factors contributing to diagnostic errors leading to URVs, and factors leading to admission on repeat visit. Diagnostic error was defined according to the Institute of Medicine (IOM), as “the failure to establish an accurate and timely explanation of the patient’s health problem(s) or communicate that explanation to the patient” . A similThis retrospective study involved consecutive patients aged ≥16 years, who presented to the study site ED, a 1225 bed tertiary academic medical center in Singapore, between 1 January 2014 and 30 June 2014. Inclusion criteria for URVs were patients who presented to the ED and re-attended within 72 h of their index visit. The index visit was defined as the initial of two distinct visits made by a patient who returned within 72 h of discharge to the ED. We excluded patients who sought treatment for unrelated complaints during repeat visits, scheduled re-attendances, frequent attenders with >3 ED visits over the preceding 6-month period, and patients who attended due to alcohol intoxication with no other medical complaints. What was considered an “unrelated complaint” was decided a priori. Ambiguous cases were discussed among three independent reviewers  until consensus was reached.Medical records were reviewed through ED electronic medical records (ED Web). Variables collected included patient factors  and factors regarding index and re-attendance visits . In our institution, the majority of patients are seen by junior doctors . A senior doctor in our institution is defined as an emergency medicine senior resident or an attending emergency physician. Patients seen in our institution are triaged based on the Patient Acuity Category (PAC) scale: PAC 1 indicates life-threatening conditions requiring immediate medical attention, PAC 2 signifies serious conditions requiring early medical attention, and PAC 3 indicates acute conditions requiring non-urgent medical attention. Patients triaged to PAC 1 or 2 are reviewed by a senior doctor, whereas patients triaged to PAC 3 are only reviewed by a senior when deemed necessary by the primary physician. Electronic records were supplemented with written records from the medical records office. Ethics approval was obtained from the National Healthcare Group Domain Specific Review Board  for waiver of informed consent.Data were collected using a standardized data collection form by three investigators . To facilitate statistical analyses, presenting complaints were collected individually and then grouped under various clinically-relevant headings. For example, patients who presented with symptoms such as diarrhea and vomiting were grouped under “gastrointestinal symptoms”, symptoms such as cough, rhinorrhea, or sore throat were grouped under “upper respiratory tract infection”, and the main complaint of fever with no other significant symptoms were grouped under “fever” . The priU test. Multivariate stepwise logistic regression was performed for variables with p < 0.10 derived from univariate analyses with odds ratios (OR) and 95% confidence intervals (CI) presented. Statistical significance was set at p < 0.05.A formal sample size calculation was not performed, as this is a largely descriptive retrospective cohort study. Categorical variables are reported in proportions while continuous variables are reported in median with interquartile range (IQR) as appropriate. All data were populated in Microsoft Excel . Upon completion of data collection electronically, charts were reviewed for missing data, duplicate data and verification by two investigators independently . The data were then exported to Stata 14  for statistical analyses. Comparisons were made between URV patients with and without wrong or delayed diagnoses, and between patients who were admitted versus those who were not at their re-attendance visits. Differences in categorical variables were compared with a chi-square test or Fisher’s exact test. Skewed continuous variables were analyzed using the Mann–Whitney There were 67,422 unique patient attendances from 1 January 2014 to 30 June 2014 . Of thesp < 0.001). Of the re-attendances, 469 (38.9%) had abnormal vital signs at initial triage, and 326 (27.0%) had a documented pain score of ≥5 (There were 423 (35.0%) patients reviewed by senior ED doctors at index visits as compared to 589 (45.4%) during URVs , fever (21.0%), and gastrointestinal symptoms, including diarrhea, nausea, vomiting, and constipation (19.7%) . There wOne hundred ninety-one (15.8%) patients had an initial wrong or delayed diagnosis . There were six deaths; of which three were initially admitted to the ward or EDOU, one was discharged against medical advice, and two were discharged from the ED. Among them, five had delayed or wrong diagnoses during initial evaluation. The sixth patient discharged against medical advice during the index ED visit. One patient who died did not have any significant comorbidity and two had metastatic disease. Their ages ranged from 32 to 76 years.p = 0.73), regardless of whether the review was by a specialist (p = 0.70) or non-specialist (p = 0.64).Factors associated with initial wrong or delayed diagnosis are shown in p < 0.10 after univariate analysis, including gender, age, initial disposition, initial primary doctor designation, alcohol use, psychiatric history, presentation with abdominal pain, trauma, fever, renal colic, neurological deficit, and nausea/vomiting. After multivariate stepwise logistic regression, the following were associated with initial wrong or delayed diagnosis : presenting complaints of abdominal pain , fever , neurological deficit , and initial disposition of discharge without follow-up . URV patients between 21 and 30 years , and those with presentations related to trauma  were less likely to have an initial wrong or delayed diagnosis.The variables were adjusted for factors with p < 0.10 after univariate analysis, including age, gender, initial primary doctor designation, review or discussion with a senior doctor, initial disposition, patient mobility, Charlson comorbidity index, presence of caregiver, significant comorbidities, presentation with abdominal pain, trauma, fever, upper respiratory symptoms, giddiness, vertigo, cellulitis/abscess, chest pain, gynecological complaints, ophthalmological complaints, asthma, nausea/vomiting, shortness of breath, musculoskeletal pain, initial vital signs, and patient acuity status. After logistic regression analysis, factors  associated with admission were: male gender ; comorbidities of diabetes mellitus , asthma , and renal disease ; presenting complaints of abdominal pain , fever , and giddiness or vertigo . Conversely, younger patients from 16 to 20 years  and 21 to 30 years  and patients that had a Charlson comorbidity index of 0 to 3 ; initial disposition of being discharged from the ED with  or without  follow-up; presenting complaints related to upper respiratory tract infection , trauma , or obstetrics and gynecology  were less likely to be admitted.Among URV patients, 459 (38.0%) required admission to either EDOU or inpatient wards. Factors associated with this are shown in p = 0.006) despite a marked increase in patient attendances by 74% and reduction in admission rate from 36.2% in 2006 to 31.7% in 2014. Abdominal pain remains significant among URVs, with only a marginal decrease compared to 9 years ago (22.2% versus 25.1%). Similar to the previous study, younger patients aged 21 to 30 years constituted the majority of re-attendances but had a lower risk for wrong or delayed diagnoses  and admission on return visits . Patients who re-attended with fever continued to contribute to a large proportion (21.0%) of delayed diagnoses and were at a higher risk of admission  on URVs.A 2005 study in the same center allowed us to reassess trends after 9 years . URV ratIn our study, URVs comprised 1.93% of total patient attendances, similar to recent studies with the incidence rate of URVs ranging from 2.9% to 3.2% ,13. The Patients with abnormal vital signs and/or a pain score ≥5 at initial presentation were more likely to return. This is similar to other studies showing that pain is a common initial presenting complaint that may be associated with re-attendance . In our The URV rate has improved since 2005, which could be due to the implementation of various strategies conceived from our previous study. These include more streamlined protocols for common complaints in the ED and EDOU, structured discharge advice sheets, and an early referral system for specialist care via rapid access clinics for services such as colorectal surgery, urology, hand surgery, and otolaryngology. The use of the EDOU for complaints such as chest pain has been shown to reduce re-attendance rates as well as reduce the cost to the health service . In addiAbdominal pain remains significant among URVs, with only a marginal decrease compared to 9 years ago (22.2% versus 25.1%). Additional measures have been implemented since 2005, such as EDOU protocols for 24 h observation and serial evaluation of patients with abdominal pain and condition-specific structured discharge advice. Despite that, abdominal pain was independently associated with wrong or delayed diagnoses  and admission  during return visit. In recent years, ED point-of-care ultrasonography has been more commonly utilized for rapid identification of dangerous causes of abdominal pain  . ED physSimilar to the previous study, young patients aged 21 to 30 years constituted the majority of re-attendances but have a lower risk for wrong or delayed diagnoses  and admission on return visits . This may be due to increased health literacy among this age group, as compared to older counterparts . More neAn appreciable 15% of URVs demonstrated the primary outcome of either an initial wrong diagnosis or a delayed diagnosis. The presenting complaint of neurological deficit  was most significantly associated with this. Of 31 patients who attended for neurological deficits, 9 (29.0%) were initially triaged to PAC3. Neurological conditions may have subtle and non-specific initial presentations which make diagnosis challenging . New-onsPatients who re-attended with fever continued to contribute to a large proportion (21.0%) of delayed diagnoses compared to 9 years ago and were at a higher risk of admission  on their URVs. We postulate that patients may have initially presented early in their illness, where investigations were not clinically indicated or the source of fever was not obvious. Arranging follow-up care with primary physicians in the community may be a viable strategy to reduce URVs and wrong diagnosis . AnotherThirty-eight percent of patients required admission during the URVs. Factors independently associated were presentations with abdominal pain and fever. In addition, giddiness or vertigo , and comorbidities such as diabetes mellitus and renal disease were also independently associated with admission on return visit.An EDOU protocol for vertigo has been further streamlined in 2014 to incorporate vestibular rehabilitation and regular vestibular sedatives to decrease URVs. A possible strategy to manage patients presenting to the ED with vertigo with no indications necessitating admission would be the prescription of adequate vestibular sedatives, rapid access clinics with a vestibular rehabilitation specialist, and early follow-up in the outpatient setting [Patients with renal disease were most significantly associated with admission to the EDOU or ward on return visit . Renal patients, especially those on dialysis are known to have increased risk of mortality and are increasingly being considered as immunocompromised . They shThe main strength of this study is that it involved a large sample from a tertiary hospital with all adult subspecialties, across all PAC statuses and shift timings. An extensive set of variables were collected in order to identify factors associated with URVs. The ability to evaluate effectiveness of strategies put in place from the previous study over a corresponding period in 2005 is also an advantage.Our study has several limitations. First, being a single center study, our findings may not be representative of other EDs, which differ in patient demographics, sociocultural characteristics, physician practices, and healthcare resources. Second, the retrospective nature of the study is subjected to information bias from missing data in clinical documentation during index and return visits, especially information concerning socioeconomic status. We were also unable to evaluate communication of diagnosis, although the definition of diagnostic error used incorporates failure of communication to patients. Causal effects cannot be conclusively established. In order to minimize missing data, investigators reviewed all electronic records and hard copies of notes for data which could not be found electronically.Next, we were unable to obtain data on specific investigations and interventions during the index visit, which may have affected the URV rate, as the broad scope of presenting complaints made it difficult to collect all available investigations. Nevertheless, we collected a wide range of variables, such as mobility, status of activities of daily living, and comorbidities, and believe that the trends found in our study are useful.Third, while one of our aims was to compare with data from 2005, we were unable to gather the demographics of all patients who presented in 2005, as electronic data from that period was not accessible. Hence, we are unable to comment about secular trends and how the population has changed over this time period.Fourth, we did not study re-attendances after 72 h, and re-attendances to other hospitals, which could have led to missed cases and unknown outcomes. However, previous studies have described URVs within 72 h of initial visit as a high risk for diagnostic and management errors . InstituLastly, our definition of URV required similar presenting complaints for the first and subsequent visits. This may have resulted in inadvertent exclusion of URVs due to other presenting symptoms that developed from the same primary pathology. Consequently, we were only able to include in our results the patients’ presenting symptoms and complaints, rather than their eventual diagnoses at the initial visit and URV.URVs with wrong or delayed diagnoses are associated with presenting complaints of neurological deficits, abdominal pain, fever, and discharge without follow-up. URVs resulting in admission are associated with abdominal pain, fever, giddiness or vertigo, and comorbidities of diabetes mellitus and renal disease. Strategies to reduce URVs include better education for younger patients, and early review of patients with abdominal pain syndromes by primary healthcare providers.


The authors present a case of Wellen's syndrome, which has a characteristic T-wave on an electrocardiogram during a pain-free period in a patient with intermittent chest pain. The clinical presentation, pathophysiology, and management is discussed, and the importance of obtaining more than one electrocardiogram (ECG) is explained. What this case adds to the literature is the fact that Wellen’s syndrome patients may present atypically with active chest pain and, as such, should be managed similarly to acute myocardial infarction patients. However, because the diagnosis of Wellen’s syndrome depends on an ECG obtained during the ensuing pain-free period, serial ECGs are usually required to reveal T-wave abnormalities in this context and have been shown to be disposition-altering in the Emergency Department (ED). Support for the death-denying outcome preferred in Wellen’s syndrome by patients and providers alike depends on recognizing the diagnosis and consulting cardiology expediently. Wellen's syndrome (WS) captures the specific electrocardiogrphic (ECG) changes which indicate critical stenosis of the proximal left anterior descending (LAD) coronary artery. These ECG findings presage catastrophic myocardial infarction in patients presenting with unstable angina. The incidence of WS is estimated to be 10-15% of cases of acute coronary syndrome (ACS) . Timely A 51-year-old man with no history of coronary artery disease presented to the ED after he was awoken by sudden onset of left-sided chest pain. The pain escalated over 15 minutes. He described it as severe, radiating from the left anterior chest to his left scapula as well as down his left arm. The patient reported that he got out of bed and tried to "walk it off." At this time, he developed diaphoresis, nausea, and some light-headedness. He described his pain as 10/10 at its worst. His initial ECG was unremarkable. The patient was treated with aspirin, nitrates, and oxygen. His pain resolved within 15 minutes of arrival, or soon after vasodilators and anti-platelet therapy had been initiated. Repeat ECG Figure  upon resWellen's syndrome was first identified in 1982 by de Zwaan et al. when they found a subgroup of admitted patients 14-18%) that shared a pattern of ECG changes that distinguished them from the sample population presenting with unstable angina -4. Evolu-18% thatFurther cardiac enzymes are normal to minimally elevated in WS, and as was true in this case; there were no ECG changes noted on ED arrival with chest pain, but this developed during the pain-free interval and after acute coronary syndrome (ACS) management was instituted. While two ECGs usually are good and plenty, one is not enough in patients presenting with ongoing chest pain and treated for unstable angina. Here, the first ECG with pain was normal and biphasic T-waves in V2, V3, and V4 rapidly emerged with repeat ECG obtained once the patient was pain-free, consistent with WS. Also note biphasic T-waves in V2, V3 distribution may persist or gradually progress to an inverted pattern with time, but most importantly, these abnormalities don't disappear during the ED stay. Because biphasic T-waves and inverted T-waves can be a normal variant, they may give providers a false sense of security and lead to premature closure in the case of a patient with recent but not concurrent chest pain, normal physical exam, normal cardiac enzymes, and potentially only one ECG. The literature reports on a Wellen’s patient discharged home from the ED after an initial ECG and cardiac enzymes were considered normal and a determination of low-risk for an adverse cardiac event was made, but two days later, the patient returned to the ED arriving in cardiac arrest from a massive myocardial infarction . ReexamiThe pathophysiology of ECG changes associated with WS is unclear. LAD obstruction causing intermittency or destabilized blood flow has also been hypothesized to cause local edema or stunning that may lead to the development of ECG changes in WS . The difSince WS is very specific for LAD stenosis   consists of characteristic ECG findings in patients with unstable angina that are highly specific for critical LAD stenosis. The typical pattern includes biphasic T-waves in leads V2, V3, and V4. These T-wave abnormalities usually evolve into deeply inverted T-waves, and the pattern moves "down and out" extending across the precordium in an orderly fashion. Capturing T-wave changes in acutely asymptomatic patients is like finding trace evidence. It connotes a near miss with reperfusion artifact potentially the only detectable sign of a very precarious state: LAD preinfarction. Taking two ECGs to better inform the situation may save more lives than managing the case on the basis of just one ECG even when it is well-timed, because T-wave abnormalities can be subtle initially, incorrectly interpreted, or even missed. Maintaining a high level of suspicion and obtaining ECGs with and without chest pain in this case gave the emergency physician the additional insight needed to confidently proceed directly to cardiac catheterization as the lifesaving solution, best practice, and preferred clinical outcome. Thus, two ECGs are good and plenty, and not just one any more.