Inflammation is a major feature of sickle cell disease (SCD). Low-dose methotrexate (MTX) has long been used in chronic inflammatory diseases. This pilot study examined the MTX effect on acute vaso-occlusive pain crises (VOC) in SCD patients.Fourteen adults on hydroxyurea with severe and refractory VOC received one intramuscular injection of 10 mg of MTX per week for 12 weeks. A single weekly dose of 5 mg of leucovorin was administered orally 48 h after each MTX injection. The primary outcome was reduction in number/intensity of acute pain episodes. The secondary outcomes were improvement of quality of life (QOL) and reduction of the inflammatory status.P = 0.6240) or the median McGill pain index . However, there was a decrease of ≥50% in chronic pain resulting from avascular osteonecrosis (AVN) in 5 out of 7 patients with radiologic evidence of AVN, with the perception of longer pain-free periods. There was a 44.4% median gain in physical function in the SF-36 QOL questionnaire (P = 0.0198). MTX treatment up-regulated two C-X-C motif chemokines (CXCL), CXCL10 (P = 0.0463) and CXCL12 (P < 0.0001), without significant effect on 14 additional plasma inflammatory markers. Adverse events: One individual had fever of unknown origin. Respiratory tract infections were recorded in five patients. Among the latter, one also had dengue fever and another had a central venous line infection and died of pneumonia and septic shock. Three patients with previous history of hydroxyurea-induced hematological toxicity developed low blood platelet counts while receiving simultaneously MTX and hydroxyurea.MTX did not significantly change the median VOC frequency  contains supplementary material, which is available to authorized users. Vaso-occlusive crises (VOC) are important features of sickle cell disease (SCD), which is characterized by ischemic injury of potentially all major organs in the body –3. TissuAnother important aspect of SCD is the chronic hemolysis occurrence , 7. IntrFor decades, nonsteroidal anti-inflammatory drugs (NSAID) have been recommended for treatment of light and moderate pain in SCD patients , 14. SimThis was a prospective pilot study that enrolled young adult patients with sickle cell disease who were under chronic hydroxyurea treatment and had more than 3 severe VOC episodes/year, that were refractory to opioids for periods longer than 3 weeks duration. For inclusion purposes, a VOC episode was defined as any severe acute pain episode demanding emergency admission for opioid parenteral administration. Pregnancy and concomitant infection were exclusion criteria. Contraceptive measures were routinely advised for fertile female patients under chronic hydroxyurea. The study was conducted in the city of Campinas in the Brazilian Southeast region. The population in this metropolitan area is prevalently white but includes close to 25% individuals self-described as multiracial or black. About 230 SCD patients ≥18 years of age attend Boldrini Children’s Center each year. Recruitment for this study was opened for 10 months, during which 14 patients had severe disease and met the inclusion criteria. None of them declined to participate. Eleven carried HbSS and 3 had HbSC. There were 9 men and 5 women, with a median age of 23.5 years (range 18–32 years). Clinical and demographic data are presented in Table The experimental treatment consisted of one intramuscular injection of 10 mg of methotrexate per week for 12 weeks. A single weekly dose of 5 mg of leucovorin was administered orally 48 h after each methotrexate injection. Sickle cell disease is a condition characterized by hemolysis and increased erythropoiesis, which may compromise folate levels . The ratThe primary endpoint was the decrease in frequency and intensity of severe acute pain episodes that required emergency medical assistance during the 12-week long study, compared to an equivalent period preceding the MTX treatment.http://www.who.int/ictrp/en/ and http://www.ensaiosclinicos.gov.br .The secondary endpoints were the blood levels of inflammatory markers and the quality of life (QOL), which were evaluated at three time points  of MTX treatment. Each patient was considered as his/her own control. S.R.B, P.O.C.L., R.A., J.A.Y., and A.B.A.L. analyzed and had access to primary clinical data. This study followed the Declaration of Helsinki, was approved by the Institutional Ethics Committee, and was registered in the Brazilian National Ethics Database/Plataforma Brasil (CAAE: 36641414.9.0000.5376). All participants gave written informed consent. This study was registered at The general effectiveness of methotrexate treatment was evaluated by the patients in a scale of 0–10 at the last follow-up visit. Pain quantification was performed with the Brazilian validation of the McGill Pain Questionnaire, which contains 68 pain descriptors , 22. ConQuality of life was assessed according to the Brazilian Portuguese validation of the SF-36 Questionnaire, which contains four 0–100 subscales for the physical and mental domains , 24. Symhttp://www.rndsystems.com). White blood cell counts, hemoglobin F, reticulocytes, biochemical markers of kidney and liver function, and C-reactive protein were measured in freshly collected blood samples.Blood samples (20 ml) were collected in EDTA tubes before the first meal. Plasma aliquots were kept frozen at −70 °C until the end of the study, when they were analysed. Measurements of cytokines, C-X-C motif chemokines (CXCL), and adhesion molecules  were performed with Quantikine ELISA kits , according to the manufacturer’s instructions. sP-Selectin was measured with the human sP-Selectin/CD62P immunoassay kit from R&D Systems. Details regarding the sensitivity, specificity, linearity, and intra-/inter-assay precision are available in the manufacturer’s website  are presented.The statistical analysis was performed with GraphPad Prism software version 6 . The Wilcoxon matched-pairs signed rank test was used whenever two experimental groups were compared. When indicated, the one-sample Wilcoxon signed rank test was used to compare the median of a group to a specified value. Nonparametric analysis of data from paired groups obtained in three time points was performed by the Friedman test, followed by the Dunn’s post test. P = 0.6240; Fig. P = 0.0469, n = 8, Fig. P = 0.931).The number of VOC episodes during the 12-week methotrexate treatment was not significantly different from that recorded in a preceding trimester: the medians were 12 (95% CI 6–26) and 10.5 (95% CI 6–21), respectively, (P = 0.015). Only 2 patients (#6 and #7) did not perceive any benefit at week 12 . This response was heterogeneous, probably reflecting the overlapping occurrence of acute and chronic pain Table . Three pPatient #8 had bilateral osteonecrosis of the femoral and humeral heads, with previous hip joint replacement on the right side. His clinical picture improvement during MTX therapy allowed him to walk without crutches.It is interesting that there were two patients (#4 and #9) who did not experience pain reduction associated to acute VOC episodes, but had ≥50% decrease in chronic osteonecrosis pain. Patient #4 illustrates well this category of response: at the end of the study, her MPI was 19% higher. However, the chronic pain completely disappeared in her right shoulder and reduced 50% in her hips. She also regained mobility of the gleno-humeral joint that had been greatly compromised by the humeral head necrosis. Patient #9 had a similar MPI before and after MTX treatment, but had 50% reduction of the osteonecrosis pain intensity in his left hip joint.P = 0.0020, n = 12]. Six of the participants said that they felt continuous persistent pain all the time before the MTX treatment, four of whom  admitted gaining pain-free days under MTX therapy.To all 10 patients that were classified in Table P = 0.004, n = 7], while those without avascular osteonecrosis scored similarly at weeks 0 and 12   (Table P = 0.002) and trended upward in nonresponders (P = 0.125), irrespectively of the presence of avascular osteonecrosis   Table ; Fig. 2aP = 0.0753)  Common Terminology Criteria for Adverse Events v3.0 (CTCAE) , three pTen out of fourteen patients exhibited some degree of response to methotrexate, ranging from mild pain improvement (Patient #14) to dramatic outcomes . The best responders were often among those with osteonecrosis . Furthermore, pain relief was accompanied by functional gain, most notably in those who had osteonecrosis. It is worth mentioning that the SF-36 physical functioning subscale used in this study has also been applied as a stand-alone assessment tool in similar conditions, that may involve physical limitation and pain, including peripheral arterial disease and hip fracture , 31. TheThe use of MTX was associated to the patient’s perception of occurrence of longer uninterrupted pain-free periods in between crises. It is not surprising that any pain-free period produced by MTX use would be seen as a tremendous gain, notably for those that previously had continuous chronic pain.Although not evaluated in this study, the MTX beneficial effect is likely to be independent of a mechanism of reduction of sickling episodes similar to that induced by hydroxyurea , 34. MetRheumatoid arthritis and sickle cell disease are similar in that they both have an inflammatory component –13, 15. 1R, A2AR, A2BR, and A3) and is a powerful immune modulator to different cells known to participate of the inflammatory response in rheumatoid arthritis and sickle cell disease, such as M1 macrophages and neutrophils [Extracellular AMP is converted into adenosine by the ecto-5′-nucleotidase CD73 expressed on the endothelial surface . Adenositrophils , 13, 41.trophils , 42. A sP = 0.075 for week 6 and P = 0.899 for week 12; Additional file 2a receptor activation and heterologous desensitization of CXCR3 [A decrease in plasma levels of TNF-α, the master inflammatory regulator, was observed in weeks 6 and 12 of the MTX treatment, with a more pronounced down-regulation in the middle of the study but it did not reach significance in either time point (of CXCR3 –46.The up-regulation of CXCL12 may be a central point to the understanding of the MTX clinical impact on SCD patients. CXCL12 is a powerful angiogenic factor that recruits endothelial progenitor cells from the bone marrow and have regenerative and tissue protective effects in ischemic conditions, such as myocardial infarction , 48. ImpIt is not known how MTX activates the above-mentioned chemokines in SCD, nor if it is a direct or indirect effect. Nevertheless, MTX has shown promise in reducing the often opioid-resistant osteonecrosis-associated pain in this present series. Our findings suggest CXCL12 as a putative marker that could mediate a possible MTX-induced limitation of ischemia–reperfusion damage in sickle cell disease.The long-term implications of the MTX treatment in sickle cell disease are unknown. There is mounting evidence that deregulated angiogenesis may be an important component of a complex pathophysiology, affecting the course of complications as varied as leg ulcers, proliferative retinopathy, pulmonary hypertension and moyamoya syndrome –58. The 1 receptor was shown to reduce central nociceptive signaling in the spinal cord and it is possible that the MTX-induced systemic release of adenosine may decrease the neuropathic pain component in SCD patients [Finally, activation of the Apatients –61.Methotrexate did not change significantly the number and intensity of acute pain episodes in SCD patients but reduced chronic pain from avascular osteonecrosis, with perception of longer pain-free periods, and quality of life improvement. This is a pilot study that should be interpreted cautiously because of the small number of patients included and the fact that it has not being designed in a blinded, randomized format. It remains to be determined if a better clinical outcome could be achieved by recruiting younger and less compromised patients, prolonging the treatment period, and optimizing dosing and administration route. These are all relevant points that can only be meaningfully addressed in a larger prospective clinical trial. Methotrexate has been around for almost 80 years , 35, and


In the summer of 1919, a slight but otherwise healthy 15-year-old English Navy recruit succumbed to epileptic fits so severe, his doctor wrote, “he threw five strong men about like kittens.” Navy medics exhausted options to treat the boy, and sent him home. His family doctor prescribed a testicular extract on the theory that the boy’s seizures could be related to his delayed sexual development. The doctor also allowed that some pharmacologists dismissed such extracts “as having only a psychotherapeutic value as placebos,” though he thought the effect was real.  The placebo-response biomarker identified in the first trial again emerged in scans of placebo responders in the second. The finding of the same biomarker indicates that brain biology can indeed predict a placebo response, which can be identified even before the placebo is given. Roughly half the patients who took the placebo in both trials reported feeling significantly less pain.The authors also created a model to assess how a patient’s predicted placebo response might interact with the active drug. They found that for a third of the patients the drug may actually inhibit pain relief by blocking the placebo response.“Given the enormous societal toll of chronic pain,” the authors write, “being able to predict placebo responders in a chronic pain population could both help the design of personalized medicine and enhance the success of clinical trials.” Knowing in advance that a patient might experience pain relief on a placebo, for example, suggests the placebo itself might be a useful treatment option. And the finding that FDA-approved pain medications might actually have an adverse effect by diminishing placebo-mediated relief suggests that clinical researchers should account for this possibility when designing pain treatment trials.The study, like most studies of this phenomenon, does have limitations, including the small number of participants and the possibility that placebo-related improvements could be a function of spontaneous healing or symptom fluctuation.Such limitations have long plagued researchers trying to disentangle the effects of a treatment drug from those of a placebo . RandomiPLOS Biology study to a surgical procedure that simulates a therapeutic intervention by, for example, drilling a hole in a patient’s skull without injecting a healing agent into the brain. A recent review of such “sham” surgery clinical trials in the Annals of Medicine and Surgery [The nature of the placebo used also raises ethical questions. Placebos can come in many forms of varying risk, from the sugar pill used in the  Surgery  found seBMC Surgery [Researchers have devoted considerable attention to understanding how the doctor-patient relationship influences the placebo effect. A good or bad rapport can color a patient’s expectations, which can also be affected by suggestions or conditioned responses associated with a trial’s experimental design . But eve Surgery  found thPLOS ONE [Confusion over the use of placebos and their effects also crops up in surveys of patients. A small survey of patients and health professionals involved in clinical trials published in PLOS ONE  found thBMC Medical Ethics [In a larger study published in l Ethics , researcWhen Beecher found himself running out of pain killers while tending to U.S. soldiers on the Italian front, the story goes, he told the wounded soldiers that a saline-filled syringe held morphine. Many soldiers, thus deceived, were comforted. The ethical quicksand involved in deceiving patients was not lost on Beecher, though some have argued that the placebo effect is less a form of deception than a product of positive expectations . Two decTrying to explain what placebos are to patients and even to aspiring researchers, why they’re used in clinical research, and how they might work is clearly challenging. But few would argue that it’s not worth the effort.For more detailed reading please see the associated PLOS Collection .


The efficacy of ALO-02, an abuse-deterrent formulation containing extended-release oxycodone and sequestered naltrexone, in the treatment of chronic low back pain (CLBP) was studied in a 12-week randomized controlled trial. Primary efficacy endpoint results have been published previously . The current paper focuses on patient-reported outcomes for health-related quality of life (HRQL), work productivity, and activity impairment that were assessed during this study.This was a double-blind, placebo-controlled, randomized withdrawal study in patients with moderate-to-severe CLBP. After a screening period (≤2 weeks), patients entered an open-label titration period (4–6 weeks). Treatment responders were then randomized to a double-blind placebo-controlled treatment period (12 weeks). HRQL was assessed using changes in the Short Form-36 v2 Health Survey (SF-36v2) and the EuroQol-5 Dimensions Health Questionnaire 3-Level version (EQ-5D-3L). Work productivity and regular activities were evaluated using the Work Productivity and Activity Impairment Questionnaire: Specific Health Problem (WPAI:SHP).p < 0.005) and the EQ-5D-3L summary index and visual analog scale (p < 0.0001) during the titration period. Improvement was also significant (p < 0.0001) for all WPAI:SHP outcomes except ‘work time missed due to CLBP’ for the titration period. Significant differences favoring ALO-02 compared with placebo were only observed for the SF-36v2 Bodily Pain subscale  during the double-blind treatment period and the overall study period (screening to the end of the double-blind treatment period). The percentage change in activity impairment due to low back pain subscale of the WPAI:SHP significantly favored ALO-02 compared with placebo for the ITT population when considering the overall study period (p = 0.0040).A total of 410 patients received ALO-02 during the open-label titration period, of which 280 (intent-to-treat (ITT) population) were treated during the double-blind placebo-controlled treatment period . Significant improvement was observed for all SF-36v2 subscales and component scores (HRQL, work productivity, and activity impairment may be improved with ALO-02 treatment.NCT01571362, registered April 3, 2012.ClinicalTrials.gov  Chronic pain is a major public health challenge owing, in part, to its prevalence and economic burden . In 2012The long-term management of chronic pain with opioids should only be initiated when other pain treatments, such as non-opioid pain medicines or immediate-release opioid medicines, are ineffective or are not tolerated , 5. GuidAbuse-deterrent opioids (ADOs) have been developed as part of a multifaceted approach to enable safer use of opioids . ADOs inThe efficacy and safety results of a phase III clinical trial to evaluate the analgesic efficacy of ALO-02, when compared with placebo, in patients with moderate-to-severe chronic low back pain (CLBP) have been published . This stThe current paper focuses on secondary objectives of this study that relate to additional patient-reported outcomes of ALO-02 in treating CLBP. Assessments of HRQL, work productivity, and activity impairment in patients treated with ALO-02 for the management of moderate-to-severe CLBP are reported here.This was a double-blind, placebo-controlled, randomized withdrawal study in patients from the United States with moderate-to-severe CLBP . Informed consent and institutional review board approval were obtained before study initiation.Patients (aged ≥18 years) with a documented diagnosis of nonspecific moderate-to-severe CLBP present for at least three months requiring continuous around-the-clock opioid analgesic treatment and an average daily NRS-Pain score for low back pain of ≥5 and ≤9 were included in the study. Major exclusion criteria were history (within the past 2 years) of lumbosacral radiculopathy, spinal stenosis, documented drug or alcohol abuse, or a positive urine drug test for illicit substances or opioid medications not prescribed to the patient.This study consisted of four periods, starting with an initial screening period lasting ≤2 weeks during which standard medical assessments were conducted to determine patient eligibility. Eligible patients entered an open-label ALO-02 conversion titration period (4–6 weeks) during which pain management was individualized by titrating ALO-02. At the end of the open-label titration period, patients tolerating ALO-02 and with NRS-Pain scores of 4 or lower were then randomized to either continue on active ALO-02 treatment or placebo. Patients were randomized in a 1:1 ratio using an interactive voice or web response system to receive a randomization number and blinded treatment assignment. Randomization was stratified by prior pain analgesic (opioid or non-opioid) and study center. Patients, investigators and clinic personnel were blinded to the randomized drug. The double-blind randomization period included a two-week blinded taper for both the treatment and placebo arms to ensure integrity of blinded data, followed by 10 weeks of treatment with ALO-02 or placebo. During the two-week post-treatment follow-up period, patients were tapered off ALO-02 and converted to standard of care treatment.HRQL was measured using the Short Form-36v2 Health Survey (SF-36v2)  and the The SF-36v2 is a self-administered questionnaire measuring physical functioning, role limitations due to physical problems, social functioning, bodily pain, mental health, role limitations due to emotional problems, vitality, and general health perception. These eight domains also combine to form two component summary scores, the Physical Component Summary and the Mental Component Summary. Scores range from 0 to 100, with higher scores indicating better health states.The EQ-5D-3L is a self-completed standardized instrument used as a generic measure of health status using a simple descriptive profile consisting of five dimensions , each of which is assessed on a three-level severity scale . These scores are combined to form a single index utility value with higher scores indicating better health. Additionally, a standard vertical 20 cm visual analog scale (VAS) was used to record an individual’s rating of their current health status.Work productivity and activity impairment were measured using the Work Productivity and Activity Impairment Questionnaire: Specific Health Problem (WPAI:SHP) . The WPAThe endpoints assessed were mean changes in the SF-36v2, EQ-5D-3L, and the WPAI:SHP from screening period to the end of titration period (open-label titration period), from randomization baseline to the end of study (double-blind treatment period), and from screening period to the end of double-blind treatment period .t test was used on observed data. For changes during the double-blind treatment period and overall study period, analysis of covariance was used, with treatment and prior pain analgesic (opioid or non-opioid) as categorical factors and the screening or baseline score and final total daily dose of the titration period  as covariates. Last observation carried forward was used for missing data at the end of the treatment or study period.Analysis of patient-reported outcomes was conducted on all patients during the titration period and on the intent-to-treat (ITT) population, consisting of all randomized patients who received at least one dose of study medication after randomization. For changes during the open-label titration period, a paired n = 134; ALO-02, n = 146). Detailed demographic data from this study have been published [2. Of the patients randomized to the double-blind treatment period, 57.5% were non-opioid users prior to the start of this study. These patients reported a mean NRS-Pain score of 7.1 and a mean BPI-sf score of 6.7 at screening. Overall, patient demographics were similar between the placebo and ALO-02 groups. The most common reasons for patients not entering the double-blind treatment period were AEs (13.9%) and “did not meet entrance criteria” (10.0%), which included those unable to tolerate ALO-02 and not meeting treatment response criteria for randomization.Of the 410 patients who received ALO-02 during the open-label titration period, 280 (ITT population) were treated during the double-blind treatment period  and ITT patients . Improvement was also statistically significant for all patients (p < 0.0001) and the ITT population (p ≤ 0.0017) for all WPAI:SHP outcomes, except the work time missed due to low back pain subscale for all patients (p = 0.3822).During the open-label titration period, changes on the SF-36v2 showed statistically significant improvement for all subscales for all patients  for patients treated with ALO-02 compared with those on placebo.For the overall study period, the difference between patients randomized to placebo and patients randomized to continue ALO-02 for the mean change in SF-36v2 was statistically significant only for the bodily pain subscale (Patient-reported outcomes are useful in evaluating treatment efficacy and interpreting clinical outcomes . This stThe primary efficacy and safety data from this study showed that ALO-02 was superior to placebo in reducing pain in patients with CLBP and exhibited a safety profile similar to that of other opioids . In the The bodily pain subscale of the SF-36v2 significantly favored patients randomized to continue ALO-02 compared with patients randomized to placebo during the double-blind treatment period, but other measures of HRQL, work productivity, and activity impairment did not show significant differences. This may be due to effects of ALO-02 persisting from the open-label period in patients randomized to placebo for the double-blind period. The specific design of randomized withdrawal trials, where the outcome of the double-blind treatment period is assessed on the worsening of pain with placebo relative to the active arm, may also contribute to the lack of significant differences between placebo and ALO-02 treatments .When considering the overall study period, the bodily pain subscale of the SF-36v2 showed a significant difference. This is supported by the significant difference between ALO-02 and placebo in the WPAI:SHP measure of activity impairment due to low back pain during the overall study period.There are limitations of this study that should be taken into consideration. First, the results may not be generalizable to a wider population because the placebo-controlled double-blind treatment period included a population enriched with treatment responders, whereas the open-label period of the study, which included all eligible patients, was uncontrolled. Second, improvements on various patient-reported outcome measures in the open-label titration period were based on comparison to baseline only, as this portion of the study by design was not placebo-controlled. Finally, the study was powered for the primary efficacy endpoint of NRS-Pain and not these secondary outcome measures.ALO-02 may improve HRQL, work productivity, and activity impairment in patients with chronic low back pain. Improvement was generally maintained during the randomized double-blind treatment period, although few treatment differences were observed. ALO-02 appears effective for pain relief and potentially also functional improvement in this chronic pain population. Further studies are needed to evaluate patient-reported functional outcomes as a primary or secondary endpoint in chronic pain populations.


Background and Aim. First-line treatment strategy for managing cervical disc herniation is conservative measures. In some cases, surgery is indicated either due to signs/symptoms of severe/progressive neurological deficits, or because of persistence of radicular pain despite 12 weeks of conservative treatment. Success for treatment of cervical disc herniation using ACDF has been successfully reported in the literature. We aim to determine the outcome of ACDF in treatment of cervical disc herniation among Iranians. Methods and Materials/Patients. In a retrospective cohort study, we evaluated 68 patients who had undergone ACDF for cervical disc herniation from March 2006 to March 2011. Outcome tools were as follows: (1) study-designed questionnaire that addressed residual and/or new complaints and subjective satisfaction with the operation; (2) recent (one week prior to the interview) postoperative VAS for neck and upper extremity radicular pain; (3) Japanese Orthopaedic Association Myelopathy Evaluation Questionnaire (JOACMEQ) (standard Persian version); and (4) follow-up cervical Magnetic Resonance Imaging (MRI) and lateral X-ray. Results. With mean follow-up time of 52.93 (months) ± 31.89 SD (range: 13–131 months), we had success rates with regard to ΔVAS for neck and radicular pain of 88.2% and 89.7%, respectively. Except QOL functional score of JOAMEQ, 100% success rate for the other 4 functional scores of JOAMEQ was achieved. Conclusion. ACDF is a successful surgical technique for the management of cervical disc herniation among Iranian population. Cervical radiculopathy could be caused by disc herniation, spondylosis, instability, and trauma or on rare occasions by tumors . MajoritFrom April 2003 to June 2014, 1280 cases of spine surgeries were performed by the senior author at a single centre. Surgical indications for cervical disc herniation (CDH) were (1) progressive myelopathy; (2) persistence or worsening of radiculopathy despite 12 weeks of medical treatment; and (3) motor deficit or intractable pain. Our inclusion criteria were (1) single- or multilevel CDH and (2) more than 12 months of postoperative follow-up. Cases were excluded due to (1) coexistent spine pathologies; (2) history of previous spine surgery; and (3) less than 12 months of postoperative follow-up.Sixty-eight cases of CDH that were managed by ACDF were included in this series. The outcome instruments were (1) study-designed questionnaire that addressed residual and/or new complaints and subjective satisfaction with the operation; (2) recent (one week prior to the interview) postoperative VAS for neck and upper extremity radicular pain; (3) Japanese Orthopaedic Association Myelopathy Evaluation Questionnaire (JOACMEQ) (standard Persian version); and (4) follow-up cervical Magnetic Resonance Imaging (MRI) and lateral X-ray.Preoperative medical information which consisted of preoperative symptoms, duration of pain (from onset up to surgery), physical examination, and pain severity using Visual Analogue Scale (VAS) was recorded at the time of operation by the senior author. The operation notes were reviewed for intraoperative complications. The follow-up notes were read for the postoperative course. Our study population was contacted by phone and informed about the research project and invited for a follow-up visit. A physician working in the field of spine research carried out the follow-up visits.This is the first study that addresses the long-term clinical and radiographic outcome and influential factors among Iranian patients who underwent ACDF for herniated cervical disc using polyetheretherketone (PEEK) cage stand-alone technique.U test).Data analysis was performed with SPSS version 16.0 . Statistical significance was set at level of 0.05. For descriptive statistics, central and dispersion tendencies were performed. For comparison between qualitative variables, nonparametric test (chi-square) test was done. Comparing qualitative and quantitative variables was analysed by using nonparametric test (Mann-Whitney Our mean follow-up time was 52.93 (months) ± 31.89 SD (range: 13–131 months). 68 cases (99 segments) were studied. 42 cases had one-level disc herniation and 21 and 5 patients were operated on for two- and three-level involvements, respectively. 34 were men and 34 were female. Study population mean age was 47.26 ± 11.138 SD. Majority  of cases had a sedentary job. Most were nonsmokers, 64 (94.1%). Mean preoperative VAS (one week prior to operation) for neck pain and radicular pain were 9.32 ± 2.40 SD and 9.29 ± 2.41 SD, respectively. Mean postoperative VAS (at the time of follow-up) for neck and radicular pain were 1.28 ± 2.50 SD and 1.03 ± 2.22 SD. Most  of our cases had disc herniation at the level of C5-C6. Two-level disc herniation was mostly  encountered at C5-C6/C6-C7. Other patient data is presented in Subjective satisfaction with the surgery was 95.6%. Success rates for clinical outcome with regard to VAS for neck and radicular pain were 88.2% and 89.7%, respectively . Success rates for 5 scores of JOAMEQ are shown in We had no intraoperative complications. Early postoperative complications were hoarseness , C5 root palsy , and dysphagia . Late postoperative complications were 8 (19%) cases of subsidence, 6 (14.3%) cases of adjacent segment degeneration, 2 (2.94%) cases of adjacent segment disease, 1 (1.5%) case of right upper broken screw, 1 (1.5%) case of screw loosening, and one (1.5%) case of graft extrusion. Among cases who were diagnosed with subsidence, 6 (75%) had undergone single-level ACDF  and 2 had undergone 2-level ACDF.During the follow-up time, none of the patients complained of symptoms recurrence. 47.1% of patients complained of residual complaints at the time of the follow-up. The most common  residual complaint was sensory deficits, followed by cases 6, 8.8%) who still suffered from both upper extremity radicular pain and sensory deficits at the final follow-up. Four (5.8%) reported new complaints. These were neck pain , contralateral to preoperative side of radicular pain , limitation of shoulder abduction , and sensory deficits . Figures , 8.8% whp value: 0.039) better for men (mean rank: 38.09) in comparison to women (mean rank: 30.91). Older patients had lower scores in UEF , LEF , BF , and QOL . Presence of preoperative radicular pain affected UEF  . Preoperative Hoffmann's sign affected LEF , BF , and QOL . Preoperative Babinski sign had an effect on LEF and BF .The outcome of surgery did not differ by type of job, smoking, preoperative neck pain or sensory complaints, preoperative hypoesthesia, duration of pain, or level of disc herniation. The surgical outcome was significantly  has been documented in literature for the incidence of C5 root palsy after anterior decompression and fusion . In our Incidence of adjacent segment degeneration (ASdeg) after ACDF has been reported to range from 16 to 51 , 39. 21.The prevalence of subsidence in our study was 19%, which is higher than Cabraja et al.'s  series tKao et al.  found th mean follow-up of 28.4 months, Cabraja et al. [Kulkarni et al.  reporteda et al.  achieveda et al.  observeda et al.  had 78.9a et al. , fusion a et al.  achievedACDF is a successful surgical technique for the management of cervical disc herniation among Iranian population.


Telenursing triage and advice services are increasingly being used to deliver health advice. Medication-related queries are common, however little research has explored the medication-related calls made to these services. The aim of this study was to examine the profile of medication-related calls to a national telenursing triage and advice service and the medications involved.This was a retrospective cohort study of medication-related calls received by Australia’s national helpline  in 2014, which provides free advice from registered nurses. We examined the volume of medication-related calls over time, user profiles for patients and callers, and call characteristics and we also investigated medications involved in the calls by their generic names and therapeutic classes.n = 25,744) were medication-related, which was the largest category of calls. The average call length was 10 min. Over half of callers (55.4%) were advised to deliver self-care. Of 7,459 calls where the callers reported they did not know what to do prior to calling, 56.8% were advised to self-care and 3.5% were transferred to the Poisons Information Centre immediately. Of 1,277 calls where callers reported that they had originally intended to call an ambulance or attend an emergency department (ED), none were advised to do so. Advice most frequently requested was about analgesics and antipyretics, followed by non-steroidal anti-inflammatory agents.Of 675,774 calls, 3.8% (The telenursing triage and advice helpline offered quick and easily accessible advice, and provided reassurance to patients and callers with medication-related queries. The service also potentially diverted some patients from attending an ED unnecessarily. Increasing demands on healthcare systems have led to changes in healthcare delivery . InformaTelenursing triage and advice services are increasingly being used to deliver health advice, and have been shown to have high levels of acceptability to callers . The genFor decades, nurses have performed the task of triaging patients to assess their level of care needs. More recently, there has been an increase in telephone-based triage by nurses, both in general medical practices and emergency departments. This practice has been effective in reducing doctor workload  and imprMedication prescription, therapy and advice form a large part of healthcare, and calls to these telephone lines often comprise medication queries. Callers regularly require quick advice about medications, such as actions to take when doses are omitted or taken accidentally, side effects, whether different medications will interact, or whether medications are safe for patients with certain conditions. Past research has focused on medication advice over the telephone targeting the public or healthcare professionals, provided by clinical pharmacologists, clinical pharmacists, poison specialists and clinical anaesthetists –16. LitePrevious studies have also examined telephone based medication therapy management, adherence and prescriptions. An American study , 18 examResearch has shown that nurses are capable of safely and effectively handling general medical queries and providing advice , 19. NHSResearch on telephone consultation and triage helplines is expanding, with several studies and reviews published in the past decade , 20, 21.This study had two main aims: 1) to examine the profile of medication-related calls, including characteristics of patients, callers and calls, and 2) to investigate the medications involved in these calls.This retrospective cohort study examined medication-related calls received by the healthdirect helpline in Australia in 2014. Staffed by registered nurses, the healthdirect helpline provides free 24 h/seven day telephone health advice to people calling from four states and two territories, serving 54.9% of Australia’s total population . The regDe-identified call records are collected routinely by the healthdirect helpline. The data includes demographics of callers and patients, the relationship between callers and patients, time of calls, callers’ original intentions before contacting the service (including not knowing what to do), care advice  and the free text entered by nurses about a patient’s presenting problem. Nurses might transfer calls to NPS Medicine Wise for further medication information after providing care advice (this data was not available for this study).Registered nurses document the presenting problem as described by a caller in a free text field. From the free text field, we identified medications involved and then coded medication names into their generic names and therapeutic classes based on the Monthly Index of Medical Specialties (MIMS) Australia database . The MIMWe conducted a detailed descriptive analysis of 2014 data over time, specifically examining the volume of medication-related calls, the profiles of patients and callers , and call characteristics . Based on the data extracted from the patient presenting problems, we analysed the frequency of medications by their generic names and therapeutic classes for the month of November.In 2014, there were 675,774 calls recorded in the healthdirect helpline database. The largest number of calls were made in January, followed by August, March and December. There were 416 call categories. Among these calls, 25,744 calls (3.8%) for 23,254 patients were medication-related, which represented the largest single category of calls in the database. Other frequent call categories included abdominal pain/discomfort (3.0%), paediatric vomiting (3.0%), chest pain/discomfort (2.8%), paediatric trauma - head (1.9%), paediatric fever (1.7%) and paediatric colds (1.5%).n = 4078, Fig. The percentage of medication-related calls received in each month varied between 3.4 and 4.2%. April, May and June had the highest proportion of medication-related calls Fig. . Of all n = 17,467) were female. Patients aged between 26 and 45 years were the most frequent clients of the service , followed by those aged 46–65 years , as shown in Table The majority of patients , 1,057 patients used the service twice (4.5%) and 360 patients (1.5%) called three or more times.Of 23,254 patients, most patients only used the service once in 2014  of medication-related calls were made by patients themselves and 14.1%  were made by a parent of the patient  were made by female callers. Aboriginal and Torres Strait Islander people made 947 calls .In 2014, 73.1% , 5.0%  called twice, and 1.8% (n = 406) made three or more (up to 19 times) medication-related calls.There were 23,254 people who made medication-related calls in total. Most people made a single medication-related call  were the busiest and Sundays  were the quietest.The number of medication-related calls was distributed evenly across weekdays. Although there was little variation in call numbers between the days of the week, Wednesdays . The busiest hours were 17:00–22:00 with 34.8%  of all medication-related calls made during this period.The volume of calls fluctuated over the day Fig. . More thThe duration of calls varied from 2 to 55 min with an average length of 10 min (median 9 with the interquartile range (IQR) from 7 to 12 min). There were few differences in the duration of calls by other related characteristics, including patient demographics , caller relationship to patient, final care advice given by the nurses, caller’s age, gender or time of call.n = 14,263; Fig. n = 10,629) ended with the advice to see a health provider or doctor within 24 h. Advice to see another health provider includes advice to speak to a local pharmacist. While no caller was advised to call an ambulance or attend an ED, 850 callers (3.3%) were transferred to the Poisons Information Centre immediately.Callers received care advice from the healthdirect helpline nurses. More than half of the calls , callers reported they did not know what to do prior to calling the service. More than half of these calls  ended with the advice of home/self-care and 39.7% of these calls  ended with the advice to see a health provider or doctor within 24 h. Importantly, 259 of these calls (3.5%) ended with a transfer to the Poisons Information Centre immediately.For nearly one third of calls , callers had planned to visit the GP or another healthcare provider prior to calling the healthdirect helpline. Nearly half of these callers  were advised to stay home or administer self-care.For another nearly one third of calls , callers had planned to stay home or administer self-care. Nearly two thirds of these calls  ended with the same recommendation, however, 3.1% (n = 161) of these callers were transferred to the Poisons Information Centre immediately.For one fifth of calls  where the caller had originally intended to attend an ED or call an ambulance but other advice was given for these calls.Of 55,653 healthdirect helpline calls in November 2014, 1,835 (3.4%) were classified as medication-related by nurses. Of these calls, 204 (11.2%) had no medication information included in the presenting problem data and 380 medication names  were unable to be extracted and classified despite efforts by the research team. The remaining 1,631 calls (88.8%) had up to 12 medications mentioned in a call. More than half of calls (55.3%) involved only one medication.n = 207 times; 8.2% of all medications involved in medication-related calls; Fig. n = 112, for 4.4% of medications), and paracetamol and codeine .We identified 2536 medications from our analysis of the free text data for calls made during November. We were able to classify 2,156 (85.0%) medications into 384 generic names. The most frequent medications enquired about were paracetamol , and antidepressants .We were able to classify 2,299 (90.7%) medications into 118 therapeutic classes. Table Medication-related calls constituted 3.8% of total calls to the healthdirect helpline service and made up the largest individual category of calls. More than half of these callers (55.4%) were advised by nurses to stay home and administer self-care. Of 7,459 calls where the callers did not know what to do prior to calling the helpline, 56.8% were advised to stay home and administer self-care. A significant proportion of calls ended with the advice of home/self-care providing reassurance to callers and patients that more serious intervention was not required. The average length of a call was 10 min indicating that on average the nurse telephone helpline was able to provide quick advice to patients who had medication queries.n = 7,537), callers had planned to visit the GP or another healthcare provider and nearly half of these callers were advised to stay home and administer self-care. Importantly, there was also evidence that the service was able to quickly direct a small proportion (3.5%) of callers requiring urgent, specialised advice, who rang uncertain of what to do, to the Poison Information Centre immediately. However, a limitation of this study was that we have no information on patients’ actual compliance with the advice.The results provide some evidence that advice received diverted unnecessary use of more costly health services. Of 1,277 calls (5%) where callers had originally intended to ring an ambulance or to attend an ED, none were advised to do so. Our findings are consistent with a recent study on medication-related queries received by an ‘after hours GP helpline’, which showed that less than 2.3% of callers were directed to the ED despite 10.6% of people originally calling with this intention . For oneThe results from this study could be useful for the service provider to plan and manage services according to the community need for the medication advice. The need for medication advice appeared to be consistent across day of the week while it fluctuated over hour of the day. About one third of calls (34.8%) were made between 17:00 and 22:00 when there is less access to a caller’s regular GP or local pharmacist.Reported disadvantages of telephone consultation include both over- and under-utilisation of the service by different population groups , nuisancAboriginal and Torres Strait Islander people comprise 3% of the Australian population . They apThe medications about which callers most frequently enquired correspond with health conditions of high prevalence in the population. A 2001 study  found thAntidepressants and antipsychotics were the third and fourth most frequently enquired about medications respectively in this study. A National Review in 2014  found thThere was a disparity between the most frequently enquired about medications in our study and the most commonly dispensed drugs to Australians, as reported by the Pharmaceutical Benefits Scheme (PBS) . The mosPrescription medications in Australia come with detailed consumer information leaflets, including information about dosage, interactions and side effects, yet research suggests these leaflets are not the preferred source of information for consumers. In a German study, Stahl et al. interviewed pharmacy customers regarding their use of product information leaflets . They obWhile call characteristics were examined for the entire year 2014, only the November call data were examined in relation to the specific medication advice given, which may somewhat limit the representativeness of those findings due to seasonal variation in medications used. This may particularly be the case regarding medications such as antihistamines, however, seasonal variation is unlikely to significantly affect the rate of use of most other medications.To our knowledge, this is the first study to provide a profile of medication-related calls to a telenursing triage and advice service and the medications involved. The telenursing triage and advice helpline offered quick and easily accessible advice to patients with medication-related queries. Medication advice provided by telenursing services can effectively refer more serious cases to the Poisons Information Centre. The service provided reassurance to patients/callers, especially those who did not know what to do, and also potentially diverted patients from attending an ED or general practitioner where it was not medically necessary.


People from family-oriented societies in particular, in addition to having a post-traumatic stress disorder (PTSD) suffer from chronic pain and physical complaints. Such people have a different understanding of physical illness and pain and, compared to patients from western societies, have different ideas on healing, even when confronted with the therapist. Hitherto, these factors have not been sufficiently taken into account in modern, multi-module therapy approaches. Trauma can be perceived via pain and physical complaints, whereby the pain is not restricted to one part of the body but is seen as covering the body as a whole. Therefore, in the treatment and above all in the patient-therapist relationship, it is necessary to understand what importance is attached to the perceived pain in relation to the trauma. The afflicted body expresses the trauma in the shape of its further-reaching consequences such as the patient’s social, collective, economic and cultural sensitivity. Therefore, for the effective treatment of trauma and chronic pain, it is necessary to use a multi-modal, interdisciplinary, and culture-sensitive approach when treating patients from traditional cultural backgrounds. As a result of the increasing numbers of people from other cultures who flee and migrate for political, religious or economic reasons or because of war—in recent years, mainly refugees from Asia and Africa—doctors and therapists are reporting that traumatized refugees from family-oriented societies—such as Syria, Iraq, or Afghanistan—in addition to mental complaints caused by traumatization, complain of pain more than patients from the western world ,2. They Unlike the western society, which puts impetus on ‘individualism’, the traditional family oriented society is ‘collectivistic’ in that it promotes interdependence and co-operation, with the family forming the focal point of this social structure. The traditional family oriented society families like in Syria, Iraq, Afghanistan and some part of south European countries are therefore far more involved in caring of its members, and also suffer greater illness burden than their western counterparts.In family-oriented societies the mention of psychotherapy can give rise to the feeling that they are in some way ‘mad’ and that they are ostracized and that medication or ‘resting the body’ can reduce the pain. A further reason for rejecting psychotherapy is the collective thinking in which the family plays a superordinate role. For this reason, personal feelings and inner mental symptoms are often not expressed; to adapt to the social environment is considered a sign of personal maturity . The humThe literature describes the treatment and relationship structure of patients with PTSD and a pain disorder from family-oriented societies as difficult ,4,6 and The diagnostics of mental disorders and the consequences of PTSD orient towards the criteria of ICD-10 and DSM-V. This assumes that all people display comparable stress and reactions following a traumatic experience. This is, however, not substantiated by clinical experience and the findings of transcultural psychiatry .The link between PTSD and chronic pain has been proven in numerous studies. In a study with general psychiatric outpatients Villano and colleagues  found thAccording to Otis and colleagues  the prevA study by Norman and colleagues  with patThe literature indicates a high degree of co-occurrence between pain and PTSD, regardless of whether the pain is being assessed in patients with PTSD or PTSD is being assessed in patients with chronic pain. Also, they may interact in such a way as to negatively affect the course and outcome of treatment of either disorder . The higEvery culture has developed its own management strategies appropriate to their own values and norms to cope with physical ailments in connection with pain. The Irish, for example, shrank rather from any contact with others because they thought it was indelicate to show pain . North APsychological problems following trauma manifest themselves, amongst other things, in the form of physical disorders appropriate to the person’s cultural imprint . NigeriaPatients from family-orientated societies, predominantly from rural Turkey, Iraq, or Syria, report pain disorders significantly more often than western patients and this explains the high number of pain diagnoses . Those aThis severe fixation with total-body pains, the cause of which is often difficult to elicit, frequently leads to problems of diagnosis and treatment .Fundamentally, the concepts of PTSD and cognitive behavioral therapy are applicable to all ethnic groups. However, the varying perceptions of health and disease and the cultural, traditional, medical treatment for dealing with traumatic experiences require alternative concepts or additions.The culture-specific aspects of patients from traditional cultures are their knowledge of the anatomy and physiology of their own body and their concept of pain . The experiencing of pain is not limited to one part of the body but is seen holistically i.e., over the body as a whole. Therefore, even when initially documenting the pain—i.e., localization, quality, time pattern, and cause—the patients give other details than those to be expected from northern European patients . For exaUnderstanding illness is especially important, both for the diagnosis and for the treatment. The comparative study on ethnic Turkish and German patients in a psychosomatic clinic revealed that significantly fewer ethnic Turkish patients were able to describe their illness . It is nHowever, this pain patient must feel that his complaints and ailments are being taken seriously; otherwise he will stop the therapy . In geneThe aim of psychological pain therapy is to reduce the patient’s impairment since this normally leads to a reduction in the subjective pain intensity. Since patients from traditional societies have a pain model reduced to somatic variables and a specific understanding of anatomy, the treatment setting has to be somewhat modified for them. Their causal and control attributions are determined in part, for example, by simple biomedical assumptions originating in the Arabic—Greek medicine of the “Four Humours Theory” and magical connotations . The wayOn the whole, in the case of a large number of patients from family-oriented societies the activity spectrum appears to be significantly limited. As a result, their life revolves around the pain; it becomes the focus of their thinking and behavior ,19. TheiOwing to the various ways pain is presented, the passive relieving posture, language problems, and possible ethnic-cultural behavioral differences, it is important to form a relationship based on trust with the patient. With patients from family-oriented societies the physician  is traditionally seen as a father-like family friend . He reprWhereas with a German patient the main focus is on mobilising the individual’s potential, the patients mentioned above expect more help from the person in authority and this must be offered . This meThe traditional exposition therapy is not always effective with victims of political oppression and with people suffering from complex and cumulative traumatization ,21. It cYasemin is a Yazidi and her family were persecuted and taken hostage by the “Islamic State” (ISIL). She was repeatedly raped and sold before she was able to escape from the hands of her tormentors. She reports how the IS fighters took her prisoner; she talks of violence, rape, escape, and unimaginable suffering. She says she was sold 12 times to IS fighters in Iraq and Syria, and beaten and raped again and again.Finally, after eight months of captivity, she managed to flee from Syria. She says more than 20 members of her family were murdered by the ISIL. She had to watch her husband being executed. She is nervous, desperate and shows me a bag full of pain killers and sleeping pills because she has pain all over her body and cannot sleep. “If only I didn’t have this pain, I would be much better. The doctors say my body is all right. The pains are due to my mental state. I don’t understand that. I am in pain, I can feel it all over my body.” As regards the pain, she has the feeling that her body is besmirched. She feels she has to shower several times every day and yet she still has the feeling that her body is unclean.Just how far psychotherapeutic trauma work is possible seems also to depend on how a society deals with the topic of sexualized violence. In this context, patients often report of a considerable feeling of insecurity, not to say viewing the topic as an absolute taboo. High moral ideas and restrictions, especially in women, lead to considerable worry and fear since they are particularly at risk of being ostracized by the collective. In this respect, feelings of shame play a special part. This is due to the fact that, in a so-called shame culture, the actual event and the violation of a norm are of less importance than the desire to keep one’s face. For example, the collective may regard the rape of a young woman as shameful and the victim ostracized. The fact that the perpetrator is also seen as violating a norm is of secondary importance in the collective.statements of pain [From the psychodynamic perspective, discussing traumatic incidents via  of pain  offers p of pain ,11.In addition to feelings of mental and physical tension, the perception of pain is also influenced by increased inactivity and avoidance behavior. As a result, the fear of possible consequences, so-called “catastrophe thinking” and “fear avoidance beliefs” the cycle of pain results in an increase of inactivity, avoidance behavior and depression.The crucial link between the PTSD and the pain chain is avoidance/inactivity and the associated depression. These factors have a crucial influence on the development and maintenance of both the PTSD and chronic pain ,26.Following the diagnostics, a further treatment model is psycho-education as a necessary integral part of the therapy. Psycho-education is designed to reinforce the patient’s own self-efficacy beliefs. This can be in the form of media such as self-help brochures and videos in the patient’s mother tongue. One essential target of this education is to demonstrate to the patient that physical and mental processes are intertwined. In doing so, the culture-specific aspects and the patient’s level of education should be taken into account .A culture-sensitive approach to the treatment of traumatized individuals with chronic pain and physical ailments from family-oriented societies is indicated when the patient is severely restricted and needs medical help; when psychological factors influence his perception of pain and this impairment can be verified in the diagnosis; when conventional treatment does not work sufficiently well on the patient due to his different understanding of illness and how to cope with trauma and pain.An individual and culture-sensitive treatment which takes the relationship structure between the patients and therapist into consideration is especially important, whereby traumatologists and doctors co-operate with other professional groups  and look at the patient’s state of the art cultural imprint ,17.If language, cultural, and migration-specific aspects are included in the consultation, treatment and social support of patients from family-oriented societies with PTSD and chronic pain, it is possible to fundamentally improve their care and integration . TherefoTreating patients with PTSD and chronic pain from family-oriented societies is not about learning a new form of psychotherapy. It is about registering and learning skills of the culture-sensitive use of psychotherapeutic treatment in general and especially in behavioral trauma therapy and chronical pain methods . IndividWhen dealing with patients from family-oriented societies with PTSD and chronic pain it is necessary to consider cultural, historical (trauma) and socio-political aspects, the perception of illness and dealing with it and the way in which a relationship can be formed with the patient ,25. In a


We studied the value and correlation of NIRS and EC in monitoring hemodynamic status in children with SCD during pain crisis. We monitored EC and NIRS continuously for 2 h after presentation and during management. Forty-five children participated in the study. CO (D = 1.72), CI (D = 1.31), rSO2 (D = 11.6), and rCO2 (D = 9.3), all increased over time. CO max and CI max were achieved 1 h after starting resuscitation. rCO2 max attainment was quicker than rSO2, as monitored by NIRS. CI max correlated with rCO2 max (r = −0.350) and rSO2 max (r = −0.359). In adjustment models, initial CI significantly impacted initial rCO2 (p = 0.045) and rCO2 max (p = 0.043), while initial CO impacted rCO2 max (p = 0.030). Cardiac output monitoring and NIRS monitoring for cerebral and splanchnic oxygenation were feasible and improved the monitoring of therapeutic interventions for children with SCD during pain crisis.Pain crisis in children with sickle cell disease (SCD) is typically managed with intravenous fluids and parenteral opioids in the pediatric emergency department. Electrical cardiometry (EC) can be utilized to measure cardiac output (CO) and cardiac index (CI) non-invasively. Near-infrared spectroscopy (NIRS) measuring cerebral (rCO Pain crises account for 79–91% of pediatric emergency department (PED) visits and up to 70% of hospitalizations in patients with sickle cell disease (SCD) ,3. Vaso-Non-invasive measurements of hemodynamic status, particularly cardiac output (CO), have been studied and found to be useful in SCD children undergoing plasmapheresis . ChildreWe hypothesize that the monitoring of hemodynamics and tissue oxygenation for SCD patients while receiving IV fluid and analgesics for pain crisis, will be feasible and add valuable information. Therefore, we sought to evaluate the utility of non-invasive monitoring of CO by EC and monitoring of cerebral oxygenation by cerebral oximeter and splanchnic oxygenation by NIRS in children with SCD presenting with pain crisis in a PED setting.This was a prospective, observational, convenience sample study of pediatric patients with SCD presenting to the ED. After approval from the institutional review board of the University of Louisville, School of Medicine, children with SCD aged 3–18 years who were treated for pain crisis at Norton Children’s Hospital ED, Louisville, KY, from May 2010 to December 2013 were included in the study. These patients were considered high priority at the ED, ensuring the facilitation of rapid assessment and management. All subjects received the standard management of sickle cell pain crisis with administration of IV fluids  and analgesia—morphine 0.1–0.15 mg/kg with repeat doses 50–100% of original dose depending on pain control.The exclusion criteria included subjects with pre-existing neurological conditions such as cerebral palsy or developmental delay, cyanotic heart disease, or history or risk of an adverse skin reaction due to dermatological hypersensitivity. Patients who were suspected to have hypoxemia (less than 90% on pulse oximetry) due to concurrent infections or comorbidities other than sickle cell pain crisis were also excluded.Once subjects met the eligibility criteria, informed and written (when applicable) consent was obtained. Relevant clinical data including age, weight, height, pain duration, pain score, home medications, baseline mental status, vital signs, perfusion status , fever, chest pain, presence/absence of difficulty breathing, and initial pulse oximetry were obtained. All components of ED evaluation and treatment, including laboratory data, medications, and IV fluids, were recorded using a standardized data collection form. Cardiac output , cerebral oximetry , and splanchnic oxygenation measured using NIRS probe were measured continuously for two hours. These measurements were recorded every 15 min for 2 h after initiation of IV fluids and/or analgesics. Age-appropriate pain scores on a scale of 1–10  ,10 were 2 and rSO2), over time, for pediatric SCD patients experiencing a pain crisis. To realize this goal, n = 45 pediatric SCD patients who experienced a pain crisis and were administered intravenous IV fluids and parenteral opioids, were monitored during their management. Initially, a descriptive analysis was performed on the demographic data, as well as on the baseline physiological disease markers and associated outcomes. Subsequently, repeated-measures ANOVA techniques were used to test if intravenous IV fluids and parenteral opioids affected outcomes over time. Poisson regression techniques were used to measure the rate of change of each measuring parameters rates over time . The test significance level was set at 0.05 and no alpha-splicing was performed since each output CO was viewed as important in isolation. Lastly, exploratory analyses were conducted, in which generalized estimating equation (GEE) models where pain scores were made a function of time and disposition status, were developed.The current study aimed to examine the impact of IV fluids and parenteral opioids on CO, CI and oxygenation  with a mean age of 12.1 years . p < 0.01), Cardiac Index , Splanchnic Oxygenation  and Cerebral Oxygenation , all increased over time.The majority of the 45 subjects were male (p = 0.812). While it took over an hour to reach rSO2 max (70.0 min), it took less time to reach rCO2 max (44.3 min). The difference between the two times were significant . Although the overall increase in rSO2 and rCO2 was similar , the rate at which these levels were reached was 59% higher for the cerebral area . That is, while both areas eventually reached similar levels, the improvement in cerebral oxygenation was significantly faster.The time to reach CO and maximum CI (CI max) max was approximately one hour  and splanchnic oxygenation max . Unadjusted, time until splanchnic oxygenation max was correlated with initial CO , CO min , CO max , initial CI , CI min , and CI max .The correlations between the studied variables are presented in 2 (p = 0.045) and rCO2 max (p = 0.043), while initial CO impacted rCO2 max (p = 0.030).In adjustment models . For the time to achieve CI max, the average time was 70 min for the admitted group and 55 min for the discharged group (p = 0.22). For the time to achieve CO max, the average was 72 min for the admitted group and 52 min for the discharged group (p = 0.03). Pain scores trend lower with time  in pain scores over the first hour ) was approximately 18 min earlier than the attainment of peak CO. An established physiologic principle is that flow and oxygenation are selective towards vital organs and, in particular, the brain, yet the peak in rCO2 occurred much earlier, before the maximal CO. This could, in part, be because the cerebral oximetry monitoring based on the principles of NIRS measures mixed venous oxygen saturation, which reflects both oxygen delivery (like pulse oximetry) and oxygen utilization. In addition, the variation could be related to altered neuro-humoral reactions in SCD. Pain control combined with a decreased level of consciousness/induction of sleep , will reduce oxygen utilization and improve tissue oxygen availability, which is detected by cerebral oximeter as an increase in cerebral oxygenation, similar to prior studies [Cerebral oxygenation, as measured by a cerebral oximeter, improved much earlier than splanchnic oxygenation, at a rate faster by almost 26 min. Interestingly, although one would assume that improvements in oxygenation would follow similar changes in CO/CI, maximal cerebral oxygenation (rCO studies .Cardiac output is dependent on four important elements: stroke volume, heart rate, preload, and afterload. As previously noted, children with SCD have baseline differences in cardiac hemodynamic parameters compared to healthy children. In SCD, echocardiography has demonstrated a higher CI at baseline ,16. ChilThe incidence of adverse events in pain crisis in SCD in well-controlled, tertiary care settings is low. While CI/CO changes may not have been significant in this study, other SCD-related serious complications, such as acute chest syndrome, and procedures, such as exchange transfusions, may be situations where such monitoring will be of significant value. The fact that the time to maximum CO/CI measurements by EC were shorter for discharged than for admitted patients, though not statistically significant, could be reflective of milder symptomatology in the discharged patients and the need for less aggressive hydration.In conclusion, our study supports the current clinical practice of hydration and use of potent opiod analgesics in the management of sickle cell pain crises in the ED. Use of non-invasive monitoring with EC may be considered as an adjunctive in the assessment of patients, especially for those at risk of cardiovascular complications. Additional studies are required to see the impact of such monitoring on patient care, especially in the early identification of potentially critical issues.


Introduction: Intramedullary nailing has been used frequently for the treatment of tibial diaphyseal fractures. Chronic anterior knee pain has been considered the most frequent post-operative complication of this technique. We investigated the relationship between anterior knee pain and position of nail tip in proximal tibia.Methods: 103 patients were selected among patients who underwent interlocking nailing in our institution. Patients with other factors that might cause anterior knee pain were excluded. In all patients intramedullary nailing was done using transpatellar approach. The patients were evaluated in two groups, 42 patients had anterior knee pain (Grup A), whereas 61 patients did not have pain (Group B). The distance from nail tip from tibial plateau was measured on lateral radiographs. Nail prominence from anterior tibial cortex was also measured.Results: The two groups were similar with respect to gender and follow up period. Out of 42 patients who had knee pain 21 (50%) had nail tip within proximal third distance from plateau to tibial tuberosity. Twenty-four patients (42%) among knee pain group had nail prominence of more than 5mm from anterior tibial cortex followed by 12 patients (29%) within 5mm and 12 patients (29%) nail tip buried within the anterior cortex.Conclusion: A greater incidence of knee pain was found when nail was prominent more than 5mm and when it is in the proximal third distance from tibial plateau to tuberosity. Patients should be aware of high incidence of knee pain when the nail tip is placed in proximal third and prominence of more than 5mm. Many complications like non-union, infection, malunion, deep venous thrombosis, thermal necrosis and compartment syndrome are reported following tibial nailing, but are relatively low when compared with other procedures6. Chronic anterior knee pain is the most common problem associated with tibia nailing. In literature, incidence of knee pain after tibia nailing has been reported as high as 86%9. Multiple factors like skin incision, damage to intra-articular structures, gender, size of tibial platue, and presence of implant in medullary cavity have been reported to be the cause of anterior knee pain6. Often combinations of these factors are responsible for pain. Hence, it is difficult to predict based on single factor which patient is going to develop knee pain after tibia nailing.Intramedullary nailing is the most common treatment used for tibial shaft fracture management12. We find various suggestions regarding the correlation between position of nail and knee pain. In this study, we investigated the relationship of knee pain with the position of the nail tip in proximal tibia as seen in lateral radiograph.Many studies have suggested prominence of nail as the major factor in the causation of anterior knee painWe retrospectively evaluated patients who underwent tibia intramedullary nailing for displaced tibia shaft fracture in our hospital from 2008 to 2012. Patients aged above 50 years, patients having other factors that might cause anterior knee pain like infection post operatively, broken implants, non-union, associated meniscal injury were excluded from the study. The information regarding presence of anterior knee pain was obtained retrospectively from clinical notes. A total of 103 patients were included in the study. These patients were divided into two groups, Group A with 42 patients having anterior knee pain and Group B consisting of 61 patients without knee pain. A few patients in whom the nail was removed because of anterior knee pain after fracture union were also included in Group A. Mean follow up in group A was 30 months (range 16 - 48 months) and in group B was 24 months (range 14 - 42 months).All patients were operated by two trauma surgeons in our hospital using the same nail design. In all patients transtendinous approach was used for entry point. In all patients the nail was locked proximally and distally. Patient’s case notes were reviewed for details of surgery and for demographic data. In Group A there were 13 female and 29 male patients with mean age of 38, and in Group B there were 16 female and 45 male patients with mean age of 36. Measurement in radiograph was done by two resident doctors. As the measurements were done on digital radiograph, correction of magnification was not required. The observers were blinded and final measurement was taken as avereage of three measurements.12. These zones were named as zone I, zone II and zone III from top to bottom respectively. The height of the nail was noted in both groups by marking position of the nail tip with respect to these zones on lateral radiograph.To evaluate the height of nail, the distance between the tibial articular surface and tip of tibial tuberosity in the lateral radiograph was divided into three equal zones by two horizontal lines . The hei12. It was measured by drawing a line over the anterior cortex of tibia and measuring the distance in millimeters between this line and anterior tip of nail (The anterior cortex nail (ACN) is the distance between the anterior cortex of tibia and the anterior nail tip of nail . Based oStatistical analysis was performed using SPSS version 19. Results were represented in percentage and proportion. The association between nail position and anterior knee pain was assessed using Pearson Chi-square Test and the probability (P) value less than 0.05 was considered statistically significant.One hundred and three patients were included in the study, age ranging between 18 years to 49 years. Out of the 42 patients in Group A, visual analogue score (VAS) was noted between 4 to 7. In this group the majority of patients complained of knee pain while kneeling. Thirty patients (71%) had pain while kneeling which is followed by other activities like walking, climbing stairs, squatting, and sitting crossed leg. Four patients had pain at rest (10%).In Group A, 21 out of 42 patients (50%) had nail tip in zone I followed by 11 (26%) in zone II and 10 (24%) in zone III. In Group B, 39 patients (49%) had nail tip in zone III followed by 16 patients (26%) in zone I and 15 patients (25%) in zone II.The difference was found to be statistically significant .Twenty-four patients (57%) in Group A had ACN distance of more than 5mm, followed by ten patients (24%) within 5mm and eight patients (19%) with nail tip buried within the anterior cortex. Fourty-one patients (67%) in Group B had ACN distance within 5mm, 14 patients (23%) buried within cortex. Only six patients (10%) had ACN of more than 5mm.The difference was found to be statistically significant .4. Many factors like damage to articular surface and meniscus, injury to the infrapatellar branch of the saphenous nerve, infrapatellar fat pad, nail prominence, thigh muscle weakness, and small plateau width contribute to the pain11. Incidence of anterior knee pain has been noted between 31% to 86% in various studies20. Fourty-two patients (41%) developed anterior knee pain in this study which is comparable to other similar studies.Anterior knee pain is a common complication of intramedullary nailing for tibia fractures21. All patients included in this study were operated by the transtendinous approach.Present litrature is not clear about correlation between type of surgical approach and knee pain. No study has provided definitive evidence of decrease in knee pain using a single approach. From available literature and meta-analysis, it is evident that paratendinous and transtendinous approaches for entry point do not make any differences cause of anterior knee pain10. Keating et al in their study had observed that anterior knee pain was more related to ACD (of more than 5mm) rather than the height of nail10. However, Bhattacharyya et al reported that both anterior and superior nail prominence caused pain11. In their study the greater incidence of rest pain was seen in anterior nail prominance, whereas superior nail prominence was associated with pain while kneeling11.The protrusion of nail tip (anterior and superior prominence) has been reported as one of the contributing factors for knee painWe observed that half of the patients with knee pain in our study had nail tip prominent superiorly (50% in zone I) and ACD was more than 5mm (57%) . These cMost of the patients in our study complained pain while kneeling, sitting crossed legged and squatting, irrespective of superior or anterior nail prominence. Pain may be due to irritation of patellar tendon by the protruded nail as these activities required high knee flexion. In a few patients knee pain was noted in spite of the nail tip being not prominent. The causes of knee pain are multifactorial and protruded nail alone cannot be blamed.24. Hernigou et al in their study noticed that structures like medial meniscus, lateral tibial plateau and transverse ligament were at risk of damage while making entry point. Hence they recommend entry point anterior to the transverse ligament and anterior horn of each meniscus23. McConnell et al, based on their study on cadaveric knees recommended entry point medial to the lateral tibial spine and anterior to articular margin to avoid articular cartilage damage24. Both these studies suggest that the closer the entry point was to the tibial articular surface there was greater risk of damage to the intra-articular structures. This is evident in the current study . Hence, we recommend the burying of the nail tip up to zone II.Many intra-articular and extra articular structures are believed to be responsible for knee pain after tibia nailing11. The tibial plateau size is also variable among different patients. Hence, while measuring the height of nail we prefered to divide it into zones rather than taking linear measurement. We observed that the height of nail correlated with anterior knee pain as half of the patients with knee pain had tip of nail in zone I, close to the tibial articular surface. This relationship was found statistically significant. We believe that injury to adjacent structures like synovium, meniscus, intermeniscus ligament or articular cartilage damage may contribute to the pain.It is evident that the smaller size of the tibial plateau is associated with knee painOur study suggests that anterior nail prominence of more than 5mm and superior prominence of nail closer to tibial articular surface are associated with anterior knee pain. Hence we recommend extra-articular entry point, burying the nail tip and avoiding nail tip proximity to tibial plateau.