Length of stay and intubation were shorter on average among patients who received bupivacaine, but these differences were not statistically significant after adjusting for potential confounders. The study results seem to suggest that the perioperative administration of bupivacaine may reduce opioid usage among children post-cardiotomy.Postoperative pain treatment affects immediate and long-term outcomes in children undergoing cardiac surgery. Opioids, as part of multimodal analgesia, are effective in treating pain, however, they can be disadvantageous due to adverse side effects. Therefore, we assessed whether the local anesthetic bupivacaine as a parasternal nerve block in children post-cardiac surgery is an effective adjunct to pain management. This was a retrospective cohort study of all patients who underwent cardiothoracic surgery via median sternotomy at a large children’s hospital between November 2011 and February 2014 with and without bupivacaine following the introduction of perioperative bupivacaine in late 2012 on a single unit. 62 out of 148 patients (age 3–17 years) who received bupivacaine demonstrated decreased postoperative opioid use. Within one day of surgery, patients who received bupivacaine required, on average, 0.57 mg/kg  of total morphine equivalent compared to 0.93 mg/kg  for patients who did not receive bupivacaine. This difference was statistically significant after adjusting for potential confounders ( Pain in hospitalized children remains common, under-assessed, and under-treated, with 24 to 80 percent of hospitalized pediatric patients experiencing moderate to severe pain ,6,7,8. HAn effective perioperative pain control regimen not only improves the quality of life of children undergoing open-heart surgery but facilitates the process of early extubation and assists with maintaining stable hemodynamics ,21. FollMost advanced pediatric cardiac centers now appear to employ the concept of multimodal analgesia, i.e., combining modalities, which act synergistically for more effective (opioid-sparing) pediatric pain control with fewer side effects than a single analgesic or modality ,26. Addin = 34 children) reported improved analgesia as a result of continuous local infusion in a post-surgical pediatric population ) has 25 beds and performs more than 400 open-heart surgeries annually.In addition to employing multimodal analgesia, triggered by clinical experience and emerging data , 2 cardiTo assess potential clinical outcomes of this change of practice occurring in late 2012, patients prior and post-addition of bupivacaine were included. A chart review was conducted on pediatric patients undergoing cardiac surgery between 1 November 2011, and 1 February 2014. Eligible patients were between the ages of 3 and 17 years at the time of surgery, required a median sternotomy, and whose parents or caregivers consented to the general use of their medical information for research. Patients undergoing delayed sternal closure were excluded. Following surgery, all patients were admitted to the CVCC for postoperative care.Specifically, there were 679 total cardiac cases during this time period, with 254 meeting the age requirement. The case total was verified by using the STS national database, which is an externally verified database. The chart review identified among those who were between 3 and 17 years of age 148 patients who had an initial operation at admission, a median sternotomy, and without ECMO support or further interventions. Those patients who met the study criteria had their information extracted from electronic medical records. Pre-exposure data included demographic information , medical history , and description of the cardiac procedure . The exposure of interest was whether a patient received bupivacaine as a parasternal nerve block during surgery (bupivacaine group) or no bupivacaine (control group). Post-operative outcomes included length of intubation and hospital stay following surgery and the daily amount of medications administered.Current pediatric pain trial recommendations include comparing opioid use in the intervention and control group as a proxy for the efficacy of an analgesic modality . As suchDaily measurements of pain, sedation, and withdrawal were also recorded ; however, they were excluded from this analysis because of inconsistent reporting into the electronic medical record system.Based on pediatric opioid equivalent and conversion tables ,39,40, tThe analysis was a comparison of the bupivacaine group to the control group. Pre-exposure characteristics were compared in order to assess potential confounding factors. Unadjusted analysis of the post-operative outcomes used the non-parametric Mann-Whitney test. Linear regression models were used to account for differences in patient characteristics between the 2 groups and incorporate important prognostic information. Outcome variables were transformed  to satisfy standard regression assumptions, which were checked via diagnostic plots. Wald tests were used to test associations with the use of bupivacaine, adjusting for potential confounders. Both adjusted and unadjusted estimates of within-group averages were reported on the original scale. Adjusted estimates of transformed outcomes were back-transformed under standard regression assumptions; standard errors and confidence intervals were calculated via the bootstrap procedure.Sensitivity analyses were performed. One compared different formulas for computing the amount of morphine equivalent (including adult opioid conversion tables) in order to ensure results were not dependent on the opioid used. Additional sensitivity analyses examined the impact of outliers. No specific subgroups or interactions were examined because an analysis of effect modification was beyond the scope of this study.n = 0/8 (0%) children received bupivacaine, in 2012 n = 11/88 (12.5%), in 2013 n = 46/57 (81%), and in January 2014 n = 5/5 (100%). The bupivacaine and control groups had similar ages, and the majority were white/non-Hispanic. The bupivacaine group had a higher percentage of females  combined) and exclusively via nurse- or patient-controlled analgesia (PCA)-pumps, on the day of surgery and the following day, and usage dropped off quickly in subsequent days see . The larPatients in the bupivacaine group were intubated for 5.8 h  following surgery compared to 8.9 h  within the control group. This difference was not statistically significant after adjusting for confounding factors using linear regression models see . Two patAn effective perioperative pain control regimen not only improves the quality of life of children undergoing open-heart surgery but also advances their clinical outcomes ,21. The Multi-modal analgesia, i.e., combining modalities that act synergistically for more effective (opioid-sparing) pediatric pain control with fewer side effects than single analgesic or modality, is now the key approach in treating and preventing pain after cardiac surgery ,26. MultThis retrospective cohort study, exploring the practice change occurring on a large pediatric cardiac intensive care unit, seems to suggest that the perioperative administration of the local anesthetic bupivacaine as a parasternal nerve block may reduce opioid usage among children following cardiotomy.There is limited evidence regarding the perioperative use of sodium-channel blockers in patients undergoing open-heart surgery. One recent study by Mattila et al. in 49 children aged 1–9 years could not demonstrate that a continuous ropivacaine wound infusion reduced morphine consumption, pain score or values, or nausea and vomiting in children who underwent atrium septum defect closure with median sternotomy and mediastinal drain . One aduLimitations of this study stem from collecting observational data from a retrospective open-enrollment cohort. A clinical practice change occurred in late 2012 with the addition of perioperative bupivacaine administration, and the majority of the control group consists of children prior to this point in time, as well as a few children who were not expected to be extubated within 24 h. As such, there are differences in terms of comorbidities and gender. An adjusted analysis accounting for these observed differences and other prognostic factors attempted to control for these differences. However, there may be other potential confounding factors that were not measured, and that might explain the observed associations. We were unable to account for daily measurements of pain and sedation via commonly used instruments , due to inconsistent reporting. Clinicians in this study charged with managing patient pain post-surgery were not blinded to the use of a parasternal nerve block. This information may have influenced their decision to provide certain types and amounts of analgesics. However, the opioid analgesia was patient- or nurse-administered, and it appears less likely that the knowledge of a perioperative block may have influenced analgesia administration.Despite the use of multi-modal analgesia, adequate pain treatment and prevention after pediatric cardiac surgery continues to represent the challenge of balancing effective pain control with limiting opioid-induced side-effects, sedation, and respiratory effects ,18,19,20


The aim of this study was to assess the prevalence and characteristics of breakthrough cancer pain (BTcP) in patients receiving low doses of opioids for background pain. This prospective study showed that in this population, BTcP prevalence was 69.8%. Many patients did not achieve a sufficient level of satisfaction with BTcP medications, particularly with oral morphine. Data also suggest that better optimization of background analgesia, though apparently acceptable, may limit the number of BTcP episodes.p = 0.036), short duration of BTcP (p = 0.005), poorer efficacy of BTcP medication (none or mild) (p = 0.001), and late meaningful pain relief (p = 0.024). The poor efficacy of BTcP medication was independently associated with a higher number of episodes/day (OR = 0.22). In patients who were receiving low doses of opioids, BTcP prevalence was 69.8%. Many patients did not achieve a sufficient level of satisfaction with BTcP medications, particularly with oral morphine. Data also suggest that better optimization of background analgesia, though apparently acceptable, may limit the number of BTcP episodes.The aim of this study was to assess the prevalence and characteristics of breakthrough cancer pain (BTcP) in patients receiving low doses of opioids for background pain. A consecutive sample of advanced cancer patients receiving less than 60 mg/day of oral morphine equivalent (OME) was selected. Epidemiological data, background pain intensity, and current analgesic therapy were recorded. The presence of BTcP was diagnosed according to a standard algorithm. The number of BTcP episodes, intensity of BTcP, its predictability and triggers, onset duration, interference with daily activities, BTcP medications, satisfaction with BTcP medication, and time to meaningful pain relief were collected. A total of 126 patients were screened. The mean intensity of background pain was 2.71 (1.57), and the mean OME was 28.5 mg/day (SD15.8). BTP episodes were recorded in 88 patients (69.8%). The mean number/day of BTP episodes was 4.1 . In a significant percentage of patients, BTcP was both predictable and unpredictable (23%). The BTcP onset was less than 20 min in the majority of patients. The mean duration of untreated episodes was 47.5 (SD 47.6) minutes. The mean time to meaningful pain relief after taking a BTcP medication was >20 min in 44.5% of patients. The efficacy of BTcP medication was not considered good in more than 63% of patients. Gender  (OR = 4.16) and lower Karnofsky (OR = 0.92) were independently associated with BTcP. A higher number of BTcP episodes/day was associated with gender  ( Pain is one of the most common and feared symptoms of cancer, with a prevalence largely differing according to the stage of the disease . Other tAt present, BTcP is understood to be an episode of severe pain, of variable duration, that occurs in patients with chronic pain who are receiving a stable opioid-based analgesic regimen and who describe their baseline pain as both stable and mild to moderate in intensity for most hours of the day ,7. The dThe principal characteristic of BTcP episodes is the temporal pattern of a short onset and offset, that should be clearly distinguished from the background pain. In pioneer surveys of BTcP, a set of characteristics for the purpose of identifying the phenomenon ,7 has beThe principal finding of studies published in the last decade was that BTcP is a variegate phenomenon, often presenting in different ways in individuals that may change its presentation during the course of the patient’s disease in the same individual ,16,17,18Indeed, there is typically no distinction made between BTcP that can be clearly attributed to an etiology associated with increased pain and BTcP that could be related to insufficient opioid therapy, as long as the stable dose of the opioid is associated with controlled baseline pain. In many epidemiological studies of BTcP, patients receiving non-opioids or opioids for moderate pain were indistinctly included ,11,12,21n = 25) or inpatients . The study was approved by the ethical committee of the University of Palermo , and written informed consent was obtained from each patient.This was a prospective, cross-sectional, multicenter study performed during a period of one year in three palliative care centers , from January to December 2019. Patients were seen as outpatients , and unstable or uncontrolled background pain (>4/10).Data were collected by experienced palliative care physicians. Age, gender, primary cancer, stage of disease, and Karnofsky status were recorded. The following data were collected: pain mechanisms , neuropathic, or mixed), average pain intensity in the last 24 h , opioids used for background pain and their doses, expressed as OME, and the presence of BTcP. The diagnosis of BTcP was based on a previously reported algorithm : a peak n) and relative (%) frequencies; mean and standard deviation (SD) summarized continuous variables. To compare patients with or without BTcP, bivariate analyses were conducted. The differences between clinical characteristics of patients with or without BTcP were assessed by the chi-square test or Fisher exact test, as needed for categorical variables, and by the independent Student t test for continuous parameters if the data were normally distributed. All variables that were found to be significantly associated with the presence of BTcP (p ≤ 0.05) at the bivariate analysis were included in a multivariate regression model in order to avoid any potential confounding effects. We also evaluated, using a bivariate analysis, the factors associated with BTcP by categorizing the patients into two groups (with <4 and ≥4 episodes). Again, the factors found to be significantly associated were evaluated by a multivariate regression analysis. Data were analyzed by the IBM SPSS Software 22 version . All p-values were two-sided, and p < 0.05 was considered statistically significant.Categorical variables were described as absolute , visceral (n = 28), neuropathic (n = 6), or mixed (n = 54). In three patients, data were missed. The mean intensity of background pain was 2.71 (SD 1.57). Opioids used for background pain management are listed in Pain mechanisms were somatic (p = 0.144). The mean doses of opioids (OME) used for background analgesia in patients with BTcP were 28.3 mg/day (SD 17.6). No differences in OME in patients with or without BTcP were found (p = 0.814).BTcP episodes were reported by 88 of patients (69.8%). The mean intensity of background pain in these patients was 2.6 (SD 1.5), and no differences in background pain intensity with patients without BTcP were found . BTcP was euther predictable, unpredictable, both predictable and unpredictable, or missed in 28.4%, 47.3%, 23%, and 1.3% of patients, respectively. The main triggers were in a rank order: movement (56.8%), feeding (13.6%), urination (4.5%), hygienic procedures (2.4%), and others (22.7%). The BTcP onset was 5–10, 11–15, 16–20, and >20 min in 49.2%, 16.9%, 20.1%, and 13.8% of patients, respectively. The mean duration of untreated episodes was 47.5 (SD 47.6) min.Drugs and doses used for BTcP are reported in p = 0.034), age (p = 0.025), lower Karnofsky (p < 0.0005), and some primary tumors  were associated with the probability to have BTcP. At multivariate analysis, gender   and lower Karnofsky  were independently associated with BTcP.Gender , as well as short duration of BTcP (p = 0.005), poorer efficacy of BTcP medication (none or mild) (p = 0.001), and late meaningful pain relief (p = 0.024). At the multivariate analysis, the poor efficacy of BTcP medication was independently associated with more than four episodes/day .More than four episodes/day were more likely in females  weak or strong opioids, those who had or did not have stable, well-controlled background pain, and those with different levels of BTP intensity ,11,12,21Specifically, no study has ever assessed the prevalence of BTcP in patients receiving low doses of OME that is less than the traditional 60 mg/day, which is commonly considered the cut-off point of the third step of the WHO analgesic ladder. Although the distinction between weak and strong opioids seems to be obsolete, as strong opioids can be used early at low doses, this is considered the minimal dose requested to prescribe fentanyl products for BTcP. This category of drugs commonly used for BTP has been shown to be superior in onset and efficacy in comparison with placebo and oral opioids . In thisOther features regarding the characteristics of BTcP presentation have been taken into consideration. In this study of patients receiving low doses of opioids for background pain, there were not only patients with predictable or unpredictable pain, but also patients presenting both conditions. This aspect has been poorly described in the general population and deserves further study. Potentially, this subgroup of patients may have more therapeutic options, rendering the treatment more complex. Indeed, more than half of the patients were reported to experience more than one type of BTcP, although it is unclear what kind of different BTcP, with 4.3% of patients presenting with four or five different types of BTcP .BTcP onset and duration did not present relevant differences in comparison with the general population , while aMoreover, having a higher number of episodes was associated with limited efficacy of BTcP medications. As a consequence, patients receiving low OMEs could also have a suboptimal management of BTcP, as reported in recent secondary analysis of a large study . One canIn this study, patients receiving lower OMEs were less likely to be prescribed a BTcP medication in comparison with patients receiving higher doses, and about 30% of patients of them were prescribed oral morphine . In the There are some limitations in this study. The number of patients was not as high as in other recent studies  and was In conclusion, about 70% of patients receiving low doses of OME experienced BTcP episodes. This subgroup of patients is worthwhile of specific attention, as they could often receive suboptimal management of BTcP. Further studies should be performed to better assess the risk factors for BTcP, for example in females, and to find an explanation for that.


Many studies have shown a global efficacy of laparoscopic surgery for patients with endometriosis in reducing painful symptoms and improving quality of life (QoL) in the short and long-term. The aim of this study was to analyze the different trajectories of long-term evolution in QoL and symptoms following surgical treatment for endometriosis, and to identify corresponding patient profiles. This prospective and multicenter cohort study concerned 962 patients who underwent laparoscopic treatment for endometriosis. QoL was evaluated using the Short Form (SF)-36 questionnaire and intensity of pain was reported using a visual analog scale prior to surgery and at 6, 12, 18, 24 and 36 months after surgery. Distinctive trajectories of pain and QoL evolution were identified using group-based trajectory modeling, an approach which gathers individuals into meaningful subgroups with statistically similar trajectories. Pelvic symptom trajectories  correspond to (1) patients with no pain or pain no longer after surgery, (2) patients with the biggest improvement in pain and (3) patients with continued severe pain after surgery. Our study reveals clear trajectories for the progression of symptoms and QoL after surgery that correspond to clusters of patients. This information may serve to complete information obtained from epidemiological methods currently used in selecting patients eligible for surgery. Many studies have shown the efficacy of laparoscopic surgery for patients with endometriosis in reducing painful symptoms and improving quality of life (QoL) in the short term ,3,4,5,6 Institutional Review Board approval was obtained in 2003 (PHRC 2003 R.05-04).This prospective multicenter study was previously presented ,18 and cHaving obtained informed written consent, data on epidemiology and medical history were collected prospectively at the time of inclusion using a case report form. Surgeons completed operative reports, precisely detailing diagnostic lesions and grading in accordance with revised American Fertility Society (rAFS) scores, and treatment given. Symptoms , quality of life and fertility self-report written questionnaires were collected at different time points: prior to surgery (t0), 6, 12, 18, 24 and 36 months after surgery.Patients were either recruited when scheduling surgery or the day before surgery. Of the 1237 patients operated on for suspected endometriosis between January 2004 and December 2012, 962 patients were enrolled, 92 patients had no histological confirmation of endometriosis, 25 did not fulfill inclusion criteria, 139 refused participation in the study and 19 had missing data for the trajectory analysis. The response rate was 79% at 12 months after surgery . PatientOur surgical technique has been previously described . LaparosAll analyses were performed using Stata software  for a two-sided Type I error of 5%. Patient characteristics were expressed as mean ± standard-deviation or median and interquartile range, for continuous data  and as numbers and associated percentages for categorical parameters.To identify distinctive trajectories for evolution of pain and QoL, a group-based trajectory model (GBTM) was performed. GBTM involves an approach that gathers individuals into meaningful subgroups that show statistically similar trajectories, i.e., identify groups based on distinctive trajectories ,26. ThisContinuous variables were compared between independent trajectory groups by ANOVA, or Kruskal—Wallis test when assumptions for ANOVA were not met. Homoscedasticity was analyzed using the Bartlett’s test. When appropriate, post-hoc tests were performed taking into account multiple comparisons . Comparisons between independent trajectories were carried out using Chi-squared or Fisher’s exact tests for categorical variables. When appropriate, a post-hoc test was performed (Marascuillo procedure). Relationships between pain, quality-of-life trajectories and outcomes were analyzed as mentioned above.These tests were completed by multiple correspondence analysis (MCA) and a mixed unsupervised classification  in order to determine patient profiles  categorized according to relationships between modalities of the variables. The parameters included in the MCA were selected by clinical relevance: demographic data, gynecological and digestive symptoms, psychological disorders, QoL, fertility, rAFS Stage and preoperative medical treatment. Finally, the association between trajectories (determined by GBTM) and patient profiles (determined by MCA) was studied.Performing the MCA necessitates a complete data set, i.e., no missing data for any variable used in the analysis. A sensitivity analysis was carried out to evaluate representativeness and compared the MCA dataset with that of all the patients. As recommended by several statisticians , particuCharacteristics of the population are detailed in p < 0.001)  A. Mean V< 0.001) B. TrajecFor dysmenorrhea, 35.3% of patients were in trajectory 1 (Stable +), 23.0% in trajectory 2 (Improvement +) and 41.7% in trajectory 3 (Stable −) (observed probabilities), with posterior probabilities of 29.9%, 32.2%, 38.0%, average posterior probabilities of 79.0%, 83.4% and 78.9% (expected >70%) and odds of correct classification based on posterior probabilities of group membership of 6.9, 16.9 and 5.2 (expected >5)  [29]. FoFor PCS and MCS , trajectPelvic symptom trajectories correspond to (1) patients with no pain or pain no longer after surgery (Stable +), (2) patients with the biggest improvement in pain (Improvement +), (3) patients with continued severe pain after surgery (Stable −).PCS and MCS trajectories correspond to: (1) patients with the highest QoL score which remained stable over a period of years (Stable +); (2) patients with the biggest improvement in QoL score (Improvement +); and (3) patients with a poor QoL score maintained after surgery (Stable −).Dysmenorrhea: 40% of patients in the PCS Stable + trajectory were also in the dysmenorrhea Stable + trajectory; 24% of patients in the PCS Improvement + trajectory were also in the dysmenorrhea Improvement + trajectory; 56% of patients in the PCS Stable − trajectory were also in the dysmenorrhea Stable – trajectory A.Cpp: 45%, 41% and 69% of patients in the PCS Stable +, Improvement + and Stable − trajectories respectively were also in the Cpp Stable +, Improvement + and Stable − Cpp trajectories respectively A.Dyspareunia: 42%, 26% and 63% of patients in the PCS Stable +, Improvement + and Stable – trajectories respectively were also in the dyspareunia Stable +, Improvement + and Stable − trajectories respectively A.Dysmenorrhea: 43%, 25% and 64% of patients in the MCS Stable +, Improvement + and Stable − trajectories respectively were in the dysmenorrhea Stable +, Improvement + and Stable − trajectories respectively B.Cpp: 47%, 38% and 61% of patients in the MCS Stable +, Improvement + and Stable − trajectories respectively were also in the dysmenorrhea Stable +, Improvement + and Stable − trajectories respectively B.Dyspareunia: 47%, 26% and 57% of patients in the MCS Stable +, Improvement + and Stable − trajectories respectively were in the dysmenorrhea Stable +, Improvement + and Stable − trajectories respectively B.n = 76) included only 20% of patients under 29 years old, 45% with infertility antecedents, 37% for whom pain was the main reason for intervention, 22%, 1% and 6% for whom VAS scores for pelvic pain  were superior or equal to 7; 17% and 24% of patients reported a PCS score <50 and a MCS score <40 respectively. Cluster 2 (n = 182) included 36% of patients under 29 years old, 57% with infertility antecedents and 65% with pregnancy desire, 52% for whom pain was the main reason for intervention, 86%, 4% and 15% for whom VAS scores for pelvic pain  were superior or equal to 7; 42% and 37% reported a PCS score <50 and a MCS score <40 respectively. Cluster 3 (n = 102) included 35% of patients under 29 years old, 45% with infertility antecedents and 52% with pregnancy desire, 4% with a family history of endometriosis, 60% for whom pain was the main reason for intervention, 42% who had preoperative medical treatment, 39% reported digestive symptoms (dyschezia or constipation), 18% reported painful urination, 77%, 32% and 33% for whom VAS scores for pelvic pain  were superior or equal to 7; 67% and 53% reported a PCS score <50 and a MCS score <40 respectively. Cluster 4 (n = 62) included 42% of patients under 29 years old, 29% with infertility antecedent and 52% with pregnancy desire, 18% with a family history of endometriosis, 76% for whom pain was the main reason for intervention, 45% who had preoperative medical treatment, 48% and 37% reported digestive symptoms (dyschezia and constipation respectively), 15% reported painful urination, 87%, 73% and 32% for whom VAS scores for pelvic pain  were superior or equal to 7; 84% and 69% reported a PCS score <50 and a MCS score <40 respectively. rAFS was not significantly different between the 4 clusters .More than 50% of patients from Clusters 1 and 2 and none from Clusters 3 and 4 were in the dysmenorrhea trajectory 1 (Stable +) . By contp = 0.16).Most patients from Clusters 2, 3 and 4  were in the Cpp trajectory 3 (Stable −) though this result was not statistically significant (p = 0.001).A majority of patients from Cluster 1 were in dyspareunia trajectory 1 (Stable +) and most patients from Clusters 2, 3 and 4 were in the dyspareunia trajectory 3 (Stable −) (Patient profiles from trajectory 3 (Stable −) for each pelvic symptom and including PCS and MCS scores revealed patients to be younger (most were single), the majority were smokers, patients with severe symptoms and the highest VAS scores for pelvic, digestive and urinary symptoms. These patients also took the most analgesics, reported the most mental disorders  and had the most altered physical and mental QoL . PatientThis study highlights the heterogeneity of long-term symptoms and quality of life experienced by patients having undergone a first surgery for endometriosis. For pelvic pain, the group-based trajectory modeling method revealed three categories of patients: 25–36% of patients experienced improvement in pelvic pain six months after surgery, 28–41% of patients continued to report moderate pelvic pain after surgery over a period of years. The remaining patients (approximately 35–37%) with little or no pain prior to surgery, had no postoperative pain over a period of years. Overall, each trajectory corresponded to 1/3 of patients: 1/3 with considerable improvement, 1/3 with moderate improvement but persistent symptoms and 1/3 of stable patients with little or no remaining symptoms.For QoL, the group-based trajectory modeling method also revealed three categories of patients: a few patients (5–11%) for whom poor QoL remained unchanged after surgery, 28–35% of patients who after surgery reported the greatest improvement in quality-of-life scores and a majority of patients (53–67%) with the highest QoL scores before surgery remaining stable over a period of years. The benefits of surgery are mostly experienced by patients in trajectory 2 for pelvic pain and QoL. Our analysis included only PCS and MCS; it would also be interesting to include all dimensions of PCS , role limitations—physical (RP) and bodily pain (BP) and MCS , social functioning (SF), role limitations—emotional (RE), mental health (MH) and general health (GH)).The MCA method revealed four Clusters of patients before surgery. The majority of patients in Clusters 1 and 2 were older and presented with infertility antecedents and pregnancy desire. They reported few low-intensity symptoms (notably Cluster 1) and good QoL. Most patients in Cluster 3 and Cluster 4 were younger, had a pregnancy desire and had fewer infertility antecedents (notably Cluster 4); they reported the most severe symptoms (notably Cluster 4), a greater use of antalgics and an altered QoL. A comparison between clusters and trajectories revealed similar tendencies: a majority of patients from Cluster 1 and Cluster 2 who had little or no pelvic pain prior to surgery no longer experienced pain after surgery. The remaining small number of patients had persistent pain after surgery. Among patients from Cluster 3 and Cluster 4, a majority of those who reported severe dysmenorrhea prior to surgery experienced relief from symptoms after, however a majority of those who reported Cpp and dyspareunia continued to experience intense/moderate pelvic pain after surgery.Although surgery is effective for most patients, some patient profiles (notably in trajectory 2) appear to be more eligible for surgery than others as they experience greater benefits ,30. In aWe also previously suggested that differing patient evolutions in pain and QoL after surgery may be explained by postoperative side effects, complications, disease recurrences and persistent and recurrent pain after surgery . RecurreThis study revealed a further finding of interest: although a correlation exists between improvement in pain and QoL see , the impPain is multifactorial and painful symptoms do not only arise due to endometriotic lesions. Key to patients benefiting from the long term positive effects of laparoscopic surgery is a multidisciplinary pre assessment and a post-operative follow-up  and alternative medicines ) ,35,36,37n = 422 vs. n = 962 respectively). Representativeness analysis however confirmed that the two samples were comparable. Despite missing data, sensitivity analyses provided strong support for our conclusions. Furthermore, although the SF-36 questionnaire has been validated for use with endometriosis and has been largely used in studies [The main limitation of our study relates to missing data. GBTM analysis was based on the assumption that each patient required at least two time-points for evaluation, but due to missing data the same time-points were not possible for all patients. A sensitivity analysis carried out using a last observation carried forward (LOCF) missing data approach, however, confirmed our results. For example, LOCF applied to dysmenorrhea similarly highlighted three trajectories, revealing the following posterior probabilities: 31.3%, 32.7% and 36%  with more than 75% of patients classified in the same trajectories. Secondly, due to missing data, MCA was not carried out with the same sample as for GBTM ( studies , it rema studies . Thirdly studies .Certain patient profiles are more likely to undergo surgery than others, however it remains difficult to accurately predict which patients will benefit from improvement in pain and quality of life. We have revealed, for the first time, clear trajectories for the progression of symptoms and quality of life after surgery that correspond to clusters of patients. This information may serve to complete that obtained from epidemiological methods currently used in selecting patients eligible for surgery. Future research is required to develop mathematical models or the use of artificial intelligence, so as to both exploit the data from these trajectories and to allow patients to be associated with a trajectory at the time of preoperative consultation.


Long bone fractures are common painful conditions often managed in the pediatric emergency department (PED). Delay to providing effective pediatric pain management is multifactorial. There is limited information regarding how the issue of language spoken impacts the provision of adequate and timely institution of analgesia. We sought to determine whether there is a difference between English-speaking and non-English speaking patients with respect to time to pain management for long bone fractures in a multi-ethnic urban PED.We conducted a retrospective cohort study of consecutive cases over 29 months of children <18 years old who presented to the PED with a first-time long bone fracture. A correlation of multiple clinical variables with timeliness to providing analgesia as a primary outcome was determined. We performed regression analysis to eliminate confounding and to determine the magnitude of each variable’s effect on the outcome.p < 0.001). There was a significant difference in median time to triage measurement of pain score (1 minute vs 4 minutes for English vs non-English speakers [p < 0.001]); median time to initial analgesia (4 minutes vs 13 minutes for English vs non-English speakers (p < 0.001]); and median time to opioid analgesia (32 minutes vs 115 minutes for English vs non-English speakers (p < 0.001]), respectively. All measurements of time were from the creation of a patient’s electronic health record. Just 30% of all patients received an opioid analgesic for treatment of long bone fractures, including only 37% with moderate triage pain scores.We analyzed a total of 753 patient cases (power 0.95). Regression analysis showed that the variable of English vs non-English language spoken was the most significant predictor of timeliness to pain management (Delay to receiving analgesic medications in pediatric patients with long bone fractures can be augmented by language barriers. Time to providing analgesia for long bone fractures is significantly delayed in non-English speaking families, contributing to disproportionate care in the PED. Furthermore, use of opioid analgesia for fractures in children remains poor. Pain is one of the most common complaints encountered in the emergency department (ED).7Extremity injury is one of the more common painful conditions for which appropriate and timely management of pain is important. However, a prior study of long bone injuries in children reported that just 29% of patients received analgesia and the mean time to receiving analgesia was two hours.6Pain is a subjective, self-reported process, which can often vary in its manifestation among children of different cultural and ethnic backgrounds.To our knowledge, only one prior published study has documented an association between limited parental English proficiency and oligoanalgesia in hospitalized children. In postoperative patients, children from limited English proficiency households were less likely to receive opioid analgesia compared to children from English-proficient households with comparable pain scores.We conducted a retrospective cohort study, reviewing electronic health record (EHR) charts from January 2011–May 2013. This time period was chosen due a change in the PED’s triage system that was initiated on June 1, 2013. Long bone fractures were selected for study due to the common nature of this complaint, potential for inducing significant pain, and the need for rapid analgesia and general care for these conditions.This study was conducted in an urban PED in Brooklyn, NY, with an annual patient volume of 37,500, approximately 1400 long bone fractures per year, and a high volume of families not proficient in English. Per protocol, patients were initially triaged by a nurse, who recorded vital signs and initial pain score. Triage pain score was attained via patient self-report, using the Wong-Baker FACES scale or the Numeric Pain Rating Scale for patients aged ≥6 years. For younger patients, the FLACC  behavior scale was recorded. Initial analgesia, typically acetaminophen at 15 milligrams per kilogram (mg/kg) or ibuprofen at 10 mg/kg, could be given by the nurse at that time by standing order. If no analgesia was administered at triage, the treating physician in the PED could order either one of these or an opiate medication in place of or in addition to acetaminophen or ibuprofen.What do we already know about this issue?Oligoanalgesia remains a common occurrence in the emergency department (ED), especially in children, with ethnic minorities at highest risk.What was the research question?Does language play a role in timeliness of pain assessment and analgesia in a pediatric ED?What was the major finding of the study?Children from non-English speaking families were more likely to experience a delay in analgesia for fractures.How does this improve population health?Greater knowledge about healthcare disparities can inform future work in settings providing care for families with limited English proficiency.The opiate generally favored by our PED staff was intravenous morphine at 0.05–0.1mg/kg. On-site hospital interpreters are available by request for Spanish, Mandarin, Cantonese, and Russian-speaking families. The EHR was created, with vital signs and pain score documented by the triage nurse, only once an interpreter was present to assist non-English speaking families. If on-site interpretation was unavailable, phone-based interpretation was accessible for all other languages typically encountered in our PED, with language phone lines present for use both in triage and within the PED. This study was approved and conducted in accordance with guidelines from the hospital’s institutional review board.International Classification of Diseases, 9th revision, codes corresponding to long bone fractures of both upper and lower extremities, excluding injuries to the clavicle, hands, feet, fingers and toes as these were determined as less likely to need urgent intervention for pain. We also excluded other orthopedic conditions of torus or avulsion fractures, nursemaid’s elbow and patella dislocations, as they are not typically treated with analgesia on the same sustained basis as performed with long bone fractures. Diagnosis of long bone fracture was confirmed by a positive radiograph report in the health record as read by an attending-level radiologist. We further excluded any cases for which patients had prior history of chronic medical conditions that predisposed to limb pain (sickle cell disease and osteogenesis imperfecta) and those patients with conditions who may alter pain perception or accurate communicability . Patients who received pain medications for their acute injury prior to hospital arrival were excluded, as were patients who indicated routine use of pain medication . In addition, we excluded patients with abnormal mental status, hypotension for age, multi-organ trauma or triage status of “resuscitation,” as their serious medical conditions could potentially have precluded pain management as a primary goal. Finally, any patient who arrived without a parent or legal guardian present was excluded because of the natural delay in care that would result while attempting to obtain consent for treatment.We initially screened charts for Data collected included information on clinical variables that could possibly affect timely ED pain management: patient demographics ; and clinical or circumstantial data relevant to treatment of their extremity injury and pain . Spoken language was determined as a routine part of the triage process on all patients; interpreter usage was noted where available.The primary outcomes measured were time intervals from creation of a patient’s EHR to each of the following pain management endpoints: time to measuring initial pain score; time to administration of initial pain medication ; and time to administration of opiate pain medication. Baseline time zero was the timestamp for the creation of the EHR; each endpoint measurement of pain management was compared to this baseline. Thus, the times to administration of pain medications already included the time to measurement of the initial pain score in triage and were not sequential time periods. Timely administration of analgesic agents was the focus of study due to the importance of rapid care for long bone fractures. Secondary outcomes analyzed related to quality of ED pain management for fractures.We conducted a retrospective health record review in accordance with criteria set forth by prior articles.We performed statistical tests using Microsoft Excel and SPSS 19.0 . Analysis included descriptive statistics and chi-square test for categorical variables. Since the variable of time would likely not follow a normal distribution curve, univariate analysis of factors  related to timing of analgesia used non-parametric statistics, specifically Mann-Whitney and Kruskal-Wallis tests. Finally, we performed a regression analysis to control for potential confounders.p < 0.05. To maximize accuracy, we determined a sample size allowing a power of 95% to detect a minimal difference of five minutes to pain assessment and analgesic provision (750 patients). We set a higher standard than the traditionally used 80% limit in order to capture even the slightest difference possible between the two groups; if such a small difference was present at this level of statistical significance and power, then it would certainly be present in any larger time difference that would be more clinically relevant in the ED.Statistical significance was set at We screened a total of 3426 charts for the child’s first fracture-related visit, and 753 met inclusion criteria . Charactp < 0.001); median time to initial analgesia was 4 minutes vs 13 minutes for English vs non-English speakers (p < 0.001); and median time to opioid analgesia was 32 minutes vs 115 minutes for English vs non-English speakers (p < 0.001), respectively. There was a significant difference between English vs non-English speaking patients/families in median time to triage measurement of pain score and median time to administering analgesia medications.The median times to initial triage measurement of pain scores, initial administration of analgesia, and opioid medication are depicted in Secondary measures related to quality are summarized in 2: 0.054–0.178, p < 0.001].Factors independently associated with enhanced timeliness to pain management included having commercial insurance, non-Asian ethnicity, non-Hispanic ethnicity, and race identified as White. The results of the linear regression show that English-speaking language was ultimately the most significant predictor of timeliness to pain management [RProviding analgesia for children is important to help relieve suffering, decrease anxiety, facilitate success in examination and diagnosis, increase patient satisfaction, and to avoid long-term neuro-psychological sequelae to painful stimuli.This is the first known study to address language-related barriers causing delays to analgesia administration in the PED. Among non-English speakers, there was an additional nine minutes of median wait times for initial analgesia in our ED and an additional 83 minutes of median wait times for opioid analgesia. This disparity existed despite a lack of significant difference between the two groups in terms of actual receipt of pain scores, initial analgesia, opioid analgesia, or procedural sedation for fracture or dislocation reduction. This difference was present despite the baseline time being the creation of the EHR, which would not be done for non-English speakers until there was an interpreter available to assist the patient or their family. Hence, our study design would not capture any additional delay in first obtaining an interpreter to start the registration process.Interestingly, the one disparity in quality of pain management that existed in our study was that English speakers were more likely to receive an opiate as their first-line pain medication. It is possible that language barriers between patient and providers make it more likely that English-speaking patients would more effectively communicate degree of pain to ED providers. Also, at the time of this study, there was no intranasal formulation for rapid-onset opioid pain relief available in this institution. The extra step of explaining placement of an intravenous line for medication administration to non-English patients’ families may have been perceived as an additional barrier for staff, especially if the interpreter would need to be recalled to the ED to explain this procedure. We found no correlation between higher level of triage acuity, older patient age, or higher initial pain score with respect to timing to pain score, analgesia, or opioid analgesia.There were some demographic differences between the two groups, with non-English speaking families more likely to have Medicaid insurance and be of Hispanic or Asian ethnicity. These differences were also independently associated with delays in pain management, which support prior studies that demonstrate minority ethnicity and Medicaid patients have less optimal pain management compared to their White and commercially-insured counterparts.21Overall, 92.4% of our patient population received a pain score, which parallels a prior study of long bone fractures in children and is evidence of our hospital’s standardized practice of pain assessment as mandated by the Joint Commission.26One area for quality improvement in pain management is short-term acute use of opiates for long bone fractures. We found that our overall rate of opiate administration (30%) to be just as sub-par as previously documented.8The ongoing opioid crisis in the US and concern that even legitimate pediatric exposure to opioids could be associated with subsequent abuse may be the reason that providers limit use of opiates for pain control in the scenario of long bone fractures.The retrospective nature of the study created a reliance on accurate recordkeeping in our EHR. There was no indication in the medical record whether the provider could speak the patient’s language; thus, we did not control for any ability of staff or treating physicians to speak the patient’s native language. Future prospective studies may serve to clarify whether or not these concerns played a role in the language barriers noted by this current study. A prospective study could also explore other barriers to pain management specific to the system used in our ED, such as whether arrival during peak time is a more important factor than language issues.Separate from the concerns that result from the retrospective nature of the study, we must acknowledge the older age of our data, which were collected from January 2011–May 2013. As noted, this time period was chosen due to a change in the ED triage process that occurred in June 2013, which would have adjusted the time intervals to the pain management variables collected for the purpose of this study. The desire to maintain uniformity in the information collected among ED staff was the primary driver of setting this cutoff date. However, we must note that major improvements in technology, access to interpreter services via video chat devices, and overall improvement in internet speed since then could yield different results had a similar study been performed in this same ED in present time. However, as a historical benchmark, this study presents important information about healthcare disparities in a non-English speaking population.As this was a single-center study, we can only comment on the delivery of analgesia at this site alone. A prospective, multicenter study could further delineate whether language serves as a barrier to pain management and address whether this single site had any flaws in its system of administering analgesia, such as variance in triage nursing delivery of pain medication, which was the source of the differences found. Finally, further management of fractures with splinting would always occur after the initial triage process was complete, generally once the patient had already received some initial form of pain medication and radiographic studies were obtained.As this study was focused on the initial assessment of pain and delivery of analgesia, we did not assess further means of caring for these long bone fractures and pain score reassessment. We felt that timeliness to delivery of analgesia served as a reasonable surrogate to these patient-oriented factors, despite being a more process-driven measure. Future study efforts could focus more on standardized measurements of pain score at multiple time intervals in order to assess whether the initial effect of language spoken persists throughout a patient’s ED or hospitalization course.Delay to providing analgesics presents a problem for non-English speaking families in the pediatric emergency department. Our study demonstrates significant delays in time to pain score (three minutes), providing initial analgesia (nine minutes), and providing opiate analgesia (83 minutes), all of which were primarily attributed to language barriers. Measures to provide translation services when needed can augment diagnostic accuracy and timeliness of patient care, as well as decrease disproportionate care to these patients. Furthermore, use of opiates overall for long bone fractures was uncommon in children, as just 30% of patients in this study received them, including 37% with moderate triage pain scores.


ObjectivePostoperative recovery process following laparoscopic cholecystectomy depends on many factors such as pain, fatigue and exhaustion. The objective of this study was to investigate whether the administration of dexamethasone, a glucocorticoid, has positive effects of postoperative patient comfort in patients who underwent laparoscopic cholecystectomy in our clinic.MethodsPatients who presented to the general surgery clinic of our hospital and scheduled for laparoscopic cholecystectomy due to cholelithiasis were included in this study. Patients in Group 1 received dexamethasone 90 minutes before the skin incision, while patients in Group 2 were given placebo . Pain scores, presence of nausea and vomiting in the postoperative period were compared between the study and control groups.ResultsNo statistically significant difference was observed between the groups in terms of incisional pain at rest and in motion and visceral pain at rest at postoperative 6th, 12th and 24th hours. Although there was a difference between the groups in terms of visceral pain in motion at the postoperative 12th and 24th hours, this was not statistically significant (p > 0.05). Although the need for additional analgesics and antiemetic drugs was lower in the study group compared to the control group, the difference between the groups was not statistically significant (p > 0.05).ConclusionWe can expect better results with the use of multimodal analgesic and anti-emetic combination instead of a single agent in studies to be performed about the prevention of postoperative pain, nausea and vomiting. Gallstone disease is a commonly seen problem in developed countries. Autopsy and clinical investigations have shown that at least 10% of adults have gallstones. Whereas 40-60% of people with gallstones exhibit a symptomatic clinical course, the majority of patients with symptomatic cholelithiasis have an asymptomatic period. Twenty percent of symptomatic patients with gallstones present with acute cholecystitis picture, while 10% present with complicated cholecystitis , and 60-70% with chronic cholecystitis symptoms [Surgery is a trauma applied on a patient. The organism produces a metabolic and endocrine response against trauma as a result of the stimulation of hypothalamus-pituitary-adrenal axis and sympathetic nervous system . StudiesRecently, a golden page was opened in gallstone disease with the introduction of endoscopy in surgical operations and laparoscopically performed cholecystectomy. Laparoscopy is attractive due to several reasons: laparoscopic cholecystectomy is more cosmetic, postoperative pain is less, length of stay in hospital is shorter and return to normal activity and work is earlier with laparoscopic cholecystectomy .Postoperative recovery process following laparoscopic cholecystectomy depends on many factors such as pain, fatigue and exhaustion. Pain and exhaustion are marked especially on the day of operation and next day, while nausea and vomiting mostly occur on the day of surgery, and rarely prolong postoperative recovery process.Various agents are used in the management of postoperative process. Among these, glucocorticoids, although their mechanism of action has not yet been fully clarified, are known for their analgesic, antiinflammatory, antiemetic and immunomodulatory effects. Dexamethasone is a synthetic glucocorticoid used for its analgesic and antiinflammatory effects. In addition to these indications, this agent is also recommended for nausea and vomiting treatment which may occur during the postoperative process.The objective of this study was to investigate whether preoperative dexamethasone administration will have positive effects of postoperative patient comfort in patients who underwent laparoscopic cholecystectomy in our clinic.Patients who presented to the general surgery clinic of our hospital and scheduled for laparoscopic cholecystectomy due to cholelithiasis were included in this study. Patients with an American Society of Anesthesiologists (ASA) score of III or IV, those aged over 75 years, patients who underwent papillotomy with endoscopic retrograde cholangiopancreatography (ERCP) one month before the operation or later and pregnant women were excluded from the study. In addition, patients with additional diseases other than cholelithiasis that may cause pain, those with hepatic, renal, endocrine and immunologic diseases, patients who used opioids or tranquilizer for longer than one week before the operation and those with alcohol and/or substance abuse were also excluded.Patients were randomly divided into two groups with computer generated random numbers. Patients in Group 1 received dexamethasone  90 minutes before the skin incision, while patients in Group 2 were given placebo . The patients, surgeon and anesthetists were blind to the drugs administered.Similar drugs were used in the anesthesia process of all patients. Vital findings of the patients were monitored in the postoperative recovery room. All patients were administered intramuscular nonsteroidal anti-inflammatory drugs (NSAID) and intravenous metoclopramide HCL in the postoperative recovery room at the postoperative 4th hour. Oral paracetamol tablet was initiated after the postoperative 8th hour and patients were advised to use it regardless of the presence of pain. Other additional analgesic and anti-emetic drugs were systematically recorded for the first 24 hours. Recovery time was defined as the time from wound closure to the decision of taking patients to the ward following vital findings in the postanesthesia care unit.Pain was daily recorded at the postoperative 6th, 12th and 24th hours and postoperative 1st week. Incisional pain was defined as superficial pain localized in the wound site or abdominal pain. Visceral pain was considered as blunt intraabdominal pain, which was difficult to locate. These pains were separately recorded as at rest and in motion at above specified periods of time. Total pain was evaluated as the sum of incisional and visceral pains at rest and in motion beginning from the postoperative first day for one week. Visual analogue scale (VAS) was used for pain scoring. Patients were asked to choose the most appropriate number describing their condition for a scale involving numbers between 1 and 10  ,6.Nausea and vomiting periods were evaluated at two distinct intervals as postop 0-6 hours and 6-12 hours. Nausea was evaluated with verbal rating scale (VRS) . Vomiting was recorded according to the number of vomiting  -7.Ethics statementBefore the beginning, the study protocol was approved by the local ethics committee of our hospital. Patients were informed about the objectives of the study and possible side effects in details and gave written consent. The study was conducted in accordance with the ethical principles of the Declaration of Helsinki.Statistical analysisData obtained in the study were statistically analyzed using SPSS for Windows version 10.0 statistical package software. Besides descriptive statistical methods , in the comparison of quantitative variables, student t test was used in the comparison of normally distributed data between the study and control groups, and Mann-Whitney U test in the comparison of non-normally distributed data. Qualitative variables were compared between the groups with Chi-square test. p < 0.05 values were considered statistically significant.The study was conducted in the general surgery clinic of our hospital with 60 patients. Of all patients, 43 (71.7%) were female and 17 (28.3%) male. Patients were divided into two groups as the study and control groups with 30 patients in each. The mean age of the patients was 46.13 ± 14.12 (min-max: 20-71 years).No statistically significant difference was found between the groups in terms of age and height (p > 0.05). No significant difference was observed between both groups in terms of gender (p > 0.05). The number of female patients was higher than male patients in both groups. There was no statistically significant difference between the groups in terms of ASA scores (p > 0.05). Majority of patients had an ASA score of I in both groups. Demographic data of the groups are given in Table There was no statistically significant difference between the groups in terms of anesthesia duration and operation time (both p > 0.05). Recovery time was statistically significantly lower in the study group compared to the control group (p < 0.05). No statistically significant difference was found between both groups in terms of the duration of hospitalization (p > 0.05). Clinical features of the groups are shown in Table No statistically significant difference was observed between the group in terms of incisional pain at rest at postoperative 6th, 12th and 24th hours. Again, no statistically significant difference was observed between the group in terms of incisional pain in motion at postoperative 6th, 12th and 24th hours.No statistically significant difference was observed between the groups in terms of visceral pain at rest at postoperative 6th, 12th and 24th hours. There was no statistically significant difference between both groups in terms of visceral pain in motion at the postoperative 6th hour (p > 0.05). Although there was a difference between the groups in terms of visceral pain in motion at the postoperative 12th and 24th hours, this was not statistically significant (p > 0.05). Although not statistically significant, remarkably visceral pain in motion was lower in the study group at the postoperative 12th and 24th hours. Distributions of incisional and visceral pain scores between the groups at rest and in motion are given in Figure Although the need for additional analgesic was lower in the study group (25.8%) compared to the control group (44.8%), the difference between the groups was not statistically significant (p > 0.05).No statistically significant difference was found between the groups in terms of the presence of nausea at postoperative 0-6 hours and postoperative 6-24 hours (p > 0.05). Again, no statistically significant difference was found between the groups in terms of the presence of vomiting at postoperative 0-6 hours and postoperative 6-24 hours (p > 0.05).The need for additional anti-emetic medication was lower in the study group (19.4%) compared to the control group (37.9%), although the difference was not statistically significant (p > 0.05).No statistically significant difference was found between the groups in terms of pain evaluated at postoperative 1st, 2nd, 3rd, 4th, 5th, 6th and 7th days (p > 0.05). Scoring in this evaluation was carried out by sum of the incisional and visceral pain scores at rest and in motion.Glucocorticoids regulate humoral mediators triggered by trauma and modify postoperative physiologic, inflammatory, humoral and immunologic responses , 6. C-reIn the present study, no statistically significant difference was observed between the groups in terms of incisional pain at rest at postoperative 6th, 12th and 24th hours (p > 0.05). Again no statistically significant difference was observed between the groups in terms of visceral pain at rest at postoperative 6th, 12th and 24th hours (p > 0.05).There was no significant difference between the groups in terms of incisional pain at rest, namely when the patient was mobilized at the postoperative 6th, 12th and 24th hours (p > 0.05). There was no statistically significant difference between both groups in terms of visceral pain in motion at the postoperative 6th hour (p > 0.05). Although there was a difference between the groups in terms of visceral pain in motion at the postoperative 12th and 24th hours, this was not statistically significant (p > 0.05). Although not statistically significant, remarkably visceral pain in motion was lower in the study group at the postoperative 12th and 24th hours.There was no statistically significant difference between the groups in terms of total pain obtained by sum of incisional and visceral pain scores from postoperative 1st day through 7th day (p > 0.05).Postoperative 24-hour period mostly involves hospitalization. Although no significant difference was found between the groups in terms of the need for additional analgesic support other than anesthesia protocol applied in all patients (p > 0.05), the need for additional analgesic was markedly lower in the study group (25.8%) compared to the control group (44.8%).In a study by McKenzie et al., perioperative single dose dexamethasone was found to decrease pain following abdominal surgery . In anotAlthough it is not fully understood how antiemetic effects of glucocorticoids occur, they are thought to affect centrally through the inhibition of prostaglandin synthesis or the inhibition of endogenous opioids release .Glucocorticoids bind to intracellular glucocorticoid receptors and exert their effects through protein synthesis and gene transcription . TherefoBecause the activation of early mediators of the metabolic response occurring against surgery begins with skin incision, it is crucial to administer glucocorticoids 1-2 hours before the operation in order to obtain desired effects postoperatively. In the present study, dexamethasone was preoperatively administered 90 minutes before skin incision.In the current study, nausea and vomiting were evaluated as two periods. Looking at the obtained data, no statistically significant difference was found between the groups in terms of the presence and severity of nausea at 0-6 hours and 6-24 hours intervals (p > 0.05).Again no statistically significant difference was found between the groups in terms of the presence and severity of vomiting at 0-6 hours and 6-24 hours intervals (p > 0.05).Although the need for additional antiemetic drugs was lower in the study group (19.4%) compared to the control group (37.9%), the difference was not statistically significant.In a meta-analysis, 17 placebo-controlled studies were reviewed, and it was demonstrated that a combination of 5-HT3 receptor antagonist and single dose dexamethasone can decrease postoperative nausea and vomiting. However, as a result of these studies there are still questions that have not been elucidated about optimal dose of the combination and necessity of 5-HT3 receptor antagonist , 16.In a study by Aouad et al., preoperative 0.5 mg/kg dexamethasone was given to 110 children aged between 2-12 years who were scheduled for adenotonsillectomy operation, and it was found that postoperative nausea and vomiting decreased by 50% compared to placebo group .In a study by Wang et al., dexamethasone administered at doses of 10 and 5 mg in 180 patients after cesarean section decreased postoperative nausea and vomiting, and the need for additional antiemetic drugs .In this study, when studies on several parameters including pain, nausea and vomiting were statistically analyzed, although no significant, the need for analgesics and anti-emetic drugs was lower in the study group which received dexamethasone compared to the control group.We can expect better results with the use of multimodal analgesic and anti-emetic combination instead of a single agent in studies to be performed about the prevention of postoperative pain, nausea and vomiting.


Thalamocortical dysrhythmia is a key pathology of chronic neuropathic pain, but few studies have investigated thalamocortical networks in chronic low back pain (cLBP) given its non-specific etiology and complexity. Using fMRI, we propose an analytical pipeline to identify abnormal thalamocortical network dynamics in cLBP patients and validate the findings in two independent cohorts. We first identify two reoccurring dynamic connectivity states and their associations with chronic and temporary pain. Further analyses show that cLBP patients have abnormal connectivity between the ventral lateral/posterolateral nucleus (VL/VPL) and postcentral gyrus (PoCG) and between the dorsal/ventral medial nucleus and insula in the less frequent connectivity state, and temporary pain exacerbation alters connectivity between the VL/VPL and PoCG and the default mode network in the more frequent connectivity state. These results extend current findings on thalamocortical dysfunction and dysrhythmia in chronic pain and demonstrate that cLBP pathophysiology and clinical pain intensity are associated with distinct thalamocortical network dynamics. Thalamocortical dysrhythmia is a key pathology of chronic pain. Here, the authors propose an analytical pipeline to study dynamic fMRI brain networks and demonstrate that chronic low back pain pathophysiology and clinical pain intensity are associated with distinct thalamocortical network dynamics. Current treatment regimens are ineffective in a significant number of individuals, and few nonopioid and nonaddictive pain medications have been developed over the past five decades3. cLBP is characterized by a range of biophysical, psychological, and social factors with extreme variability in genesis4. This complexity and the limited understanding of the neural mechanisms responsible for the development, maintenance, and experience of cLBP hinder the development of new treatments.Chronic low back pain (cLBP) is the number one cause of disability globally5. Multiple lines of evidence suggest a critical role of the thalamus in chronic pain processing. Electrophysiological studies have shown altered thalamocortical rhythm, termed thalamocortical dysrhythmia (TCD)6, in chronic pain9. The abnormal, internally generated low-frequency oscillations in the thalamo-cortico-thalamic network disrupts the normal state-dependent flow of information between the thalamus and cortex. This in turn leads to disturbances of sensation, motor performance, and cognition in patients with chronic pain7. Studies using functional magnetic resonance imaging (fMRI) have also demonstrated that abnormal low-frequency oscillations and connectivity in thalamocortical networks underpin the constant perception of pain11. However, this evidence is mainly found in neuropathic pain (NP), and the role of thalamocortical networks in cLBP is still unknown. Unlike NP, cLBP is not necessarily sustained by peripheral nerve injury, and rarely can a specific cause of cLBP be identified4. Investigating the neural mechanisms of thalamocortical networks in cLBP is challenging but important for potential therapeutic targets.The brain of the chronic pain patient is continuously processing background pain by integrating information between multiple brain regions related to sensory, cognitive, and emotional functions15, and such time-varying characteristics may represent spontaneous alterations in the underlying networks and thus may reveal neural mechanisms that cannot be discovered through static rsFC alone18.In past decades, fMRI resting-state functional connectivity has provided high spatial resolution for studying brain networks. Challenging the conventional assumption that functional interactions remain constant throughout the entire resting-state scan, recent studies have shown that rsFC can vary considerably in different temporal scales20 since previous studies have suggested that neural dynamics discriminating cLBP patients from HCs may be distinct from neural dynamics sensitive to pain intensity changes21. We applied a novel analytical framework combining sliding-window cross-correlation, clustering state analysis, and graph-theory methods to capture abnormal thalamocortical network dynamics and their relationships with clinical symptoms in cLBP patients under two different conditions . The global and local efficiency of information transfer in large scale brain networks was also investigated and compared between cLBP and HCs. In addition, we tested the validity of the findings using an independent dataset consisting of 30 cLBP patients (each patient had two fMRI scans separated by about 2 weeks to explore test–retest reliability) and 30 HCs. We also replicated the findings from a dataset of 25 cLBP patients and 25 HCs with a similar attention/vigilance level, as demonstrated by a multisource interference task (MSIT), to rule out the confounding effect of vigilance.In this study, we examined dynamic rsFC in 90 cLBP patients and 74 healthy controls (HCs) using fMRI. We hypothesized that cLBP would be associated with dynamic connectivity abnormalities of the thalamocortical networks, which would be correlated with clinical symptoms. Patients underwent two resting-state fMRI scans before and after physical maneuvers aimed to exacerbate their spontaneous LBP. This allowed us to separate brain patterns associated with chronic pain pathophysiology (as compared with HCs) and temporal intensity alternations of clinical pain (high pain vs. low pain)22 and our research23 have suggested that cLBP may modulate brain functions beyond the pain system itself in ways that may be maladaptive, affecting patients’ daily experiences and diminishing their quality of life. In addition, patients were required to rate their current pain intensity  prior to the two resting-state fMRI scans, between which they performed pain-exacerbating maneuvers to increase their LBP intensity. Across 90 cLBP patients, the current pain intensities were increased from 31.7 ± 20.1 to 51.5 ± 20.1, while 14 of them had the same or decreased levels of pain intensity. These 14 patients were excluded from the following fMRI analyses comparing dynamic rsFC and thalamocortical networks between low-pain and exacerbated-pain conditions. The remaining 76 patients had current pain intensities increased from 31.3 ± 18.7 to 55.2 ± 19.6.For exploration and validation, we used three independent cohorts of subjects Table . The firThe second cohort (Dataset 2) consisted of 30 cLBP patients  and 30 HCs . Patients had an average pain intensity of 5.8 ± 1.5 (0–10 NRS) for the past 7 days before the first resting-state fMRI scan, and an average current pain intensity of 44.0 ± 23.1 and 44.1 ± 23.1 (0–100 NRS) prior to the first and second resting-state fMRI scans, respectively (these two sessions were separated by about 2 weeks). Please note that one of the independent cohorts measured pain severity using the Pain Bothersomeness scale over the past 7 days (Dataset 1) and the other cohort measured pain intensity using the NRS over the past 7 days (Dataset 2). Although each cohort used a different measure, pain intensity and pain severity are likely to be highly correlated and both were used to distinguish chronic pain from acute clinical pain .24 . Patients had an average past pain intensity of 6.1 ± 5.8 (0–10 NRS).The third cohort (Dataset 3) consisted of 25 cLBP patients  and 25 HCs  from an independent site that performed a MSIT25. Previous studies have typically conducted GICA on the exploratory dataset and have identified targeted independent components (ICs) as intrinsic connectivity networks (ICNs). However, due to the differences between datasets , the traditional GICA-identified ICNs are variable and not necessarily consistent across studies, which limits the replicability of the findings. In this study, we adopted a method capable of identifying reliable ICNs that can be compared across datasets26. The group template of ICNs was identified from two independent datasets (Human Connectome Project [HCP] and Genomics Superstruct Project [GSP]) with large sample sizes (N = 1005 for GSP and N = 823 for HCP) and different temporal resolutions 31, frontoparietal network (FPN)32, subcortical network (SCN)33, visual network (VSN)34, and auditory network22, which have been widely studied in chronic pain. The detailed component labels and peak coordinates of each ICN are provided in Supplementary Figs. We parcellated the brain into regions and networks of interest using group independent component analysis (GICA), a powerful data-driven approach for capturing individual differences of real functional boundaries in the brainrks Fig. , includiz-transformation to each correlation coefficient, resulting in static functional network connectivity (sFNC). We did not observe strong thalamocortical connectivity across participants  detrending linear, quadratic, and cubic trends; (2) nuisance regression of head-motion-related points detected by artifact detection toolbox (ART) in fMRI preprocessing; (3) de-spiking detected outliers; and (4) low-pass filtering with a cutoff frequency of 0.15 Hz. After these additional quality control steps, we calculated 45 × 45 correlation matrices for each subject and applied the Fisher nts Fig. .35. In addition to the Yeo atlas, we added six regions in the SCN  and six regions in the SMN  from the automated anatomical labeling (AAL) atlas to match the regions identified from GICA. Details of the parcellation can be found in Supplementary Note To further increase the validity of our study, we tested an additional parcellation strategy of using the established and extensively validated functional atlas by Yeo and colleaguesk-mean clustering on the dFNC estimates to identify recurring functional states36. We performed a cluster number validity analysis using a silhouette method to identify the optimal number of clusters ranging from 2 to 1037, and it was determined to be 2  among ICNs using a sliding-window approach with graphical LASSO and then conducted a p < 0.05 false discovery rate [FDR] corrected). We did not find any significant differences in fraction rate and dwell time between low-pain and exacerbated-pain conditions. The significant differences of fraction rate and dwell time between cLBP patients (in both Session 1 and Session 2) and HCs were also observed in Dataset 2 , and the significant differences were further validated using the Yeo parcellation strategy  are shown in Fig. In a further analysis of relationships between dFNC and clinical symptoms in cLBP patients, we found that the fraction rate and dwell time of State 2 were significantly correlated with pain severity/intensity of cLBP patients in the past 7 days Fig. , indicatFigure 38. Figure p < 0.05 FDR corrected; two sample t-test), suggesting that the average parallel information transfer in the brain networks of State 2 was less efficient in patients with chronic pain. However, the global efficiency of State 1 was not significantly different in cLBP compared with HCs . In contrast to the findings of global efficiency deficits in cLBP patients, the local efficiency, measuring the average efficiency between critical nodes within a neighborhood, was less affected . Interestingly, direct comparisons between patients before and after the maneuver did not show a significant difference of global and local efficiencies of dFNC in the two states, indicating that temporary pain exacerbation may not affect efficiencies of brain networks in cLBP patients.To investigate the topologic organizations of the dFNC states and compare them between groups , we applied a graph-theory analysis. Two established and widely validated measures, global and local network efficiencies, were employed to evaluate local and global information transfer in functional brain networkshttp://www.thehumanbrain.info/brain/brain_navigator.php) (see “Methods” for details). We found that these two ICNs included the ventral lateral/posterolateral (VL/VPL) nucleus and dorsal/ventral medial (DM/VM) nucleus . These results support our hypothesis that abnormal thalamocortical networks may underlie chronic pain pathophysiology in State 2.Figure Direct comparisons of VL/VPL and DM/VM-based whole-brain dFNC between pre- and post-maneuver conditions showed that cLBP patients had significantly decreased connectivity between the VL/VPL and visual cortex  but had increased connectivity between the VL/VPL and PoCG and DMN  in State 1 Fig. . TherefoUsing conventional static seed-to voxel connectivity, we only found significant differences in DM/VM-based connectivity between cLBP and HCs 44. The findings from the sub-thalamic atlas were consistent with those using ICA-derived nuclei, but we also found thalamocortical connectivity differences from other nuclei  into the following seven large cortical areas: primary motor, somatosensory, occipital, prefrontal, pre-motor, parietal, and temporal . We observed decreased connectivity between the putamen and several brain regions within emotional/affective  and cognitive networks  in cLBP patients .To further validate our findings, and more importantly, to account for the potential confounding effect of vigilance on dFNCIn summary, we found that cLBP patients and HCs performed better (higher accuracy (Acc) and shorter reaction time (RT)) in control trials  of brain functional connectivity, even during “rest,” time-varying characteristics of rsFC may reveal neural mechanisms/pathophysiology that cannot be discovered through static rsFC alone. In the present study, we identified two reoccurring dFNC states characterized by different connectivity patterns. Of these two dFNC states, the less frequent state, characterized by strong negative connectivity between the SCN and SMN, is associated with the following characteristics: (1) the occurrences of this state were significantly higher in cLBP patients and correlated with pain severity, (2) patients exhibited significantly lower efficiency of information transfer in functional brain networks in this state, and (3) patients had abnormal thalamocortical networks in this state. In contrast, the altered clinical pain intensity was associated with thalamocortical networks in the other more frequent state, which was characterized by sparsely connected within-network dFNC.51 and have suggested that temporal organization of dynamic rsFC patterns follow specific sequential orders in awake rats and humans52. Therefore, it is believed that rsFC brain networks may have several reoccurring states throughout the entire fMRI scan36. In this study, we found that both patients and HCs had two dFNC states. State 1, the more frequent and sparsely connected state, was characterized by within-network connectivity and was similar to sFNC patterns. A dFNC state that resembles sFNC patterns typically accounts for the largest percentage of windows and time53. It is speculated that such a weak and diffused state represents the average of a large number of additional states with less variability54 and may be associated with self-referential processing and even drowsiness55. This state may be considered a steadier state and signifies the average of less variable rsFC, thereby sharing similar connectivity patterns with sFNC.Recent studies have shown the neuronal origins of dynamic rsFC56, and this was confirmed by our subsequent analyses . Interestingly, a similar dFNC state was identified in previous studies on healthy and diseased populations, including those with schizophrenia17, migraine15, bipolar disorder53, and Parkinson’s disease37. Although these diseases have different pathophysiologies, they share a common TCD model8. The dFNC patterns in this state were always characterized by connectivity between the SCN and other disease-related networks; for example, between the SCN and VSN in migraine15, between the SCN and SMN/VSN in schizophrenia14, and between the SCN and SMN in chronic pain in the present study. Several studies have shown that the temporal properties and dFNC patterns in this state have associations with clinical symptoms that cannot be observed between sFNC and the same clinical scores57. Thus, this transient dFNC state may be better for revealing a disease’s pathophysiology by excluding non-relevant steady dFNC states .State 2 was a less frequent but more strongly interconnected state that was represented by negative connectivity between the SCN and SMN. Patients tended to spend more time in this state, and the state’s occurrence showed significant correlation with pain severity. We speculated that the increased occurrence of State 2 for cLBP patients may be due to abnormal cortical-subcortical interaction59. In our study, we applied topologic measures for examining the global and local efficiencies and provided direct evidence of disrupted functional segregation and integration in brain networks of State 2 but not in State 1. The loss of brain efficiency in chronic pain patients in State 2 may lead to more occurrences/time spent in this state.The importance of State 2 in revealing cLBP pathophysiology was further supported by reduced efficiency of global information transfer in functional brain networks. Previous studies have found global dysfunction of multisensory information processing and integration in chronic pain patients6 underlies multisensory dysfunction in chronic NP9. fMRI evidence also suggests that NP is associated with disturbed thalamocortical activity10. We demonstrated that cLBP patients, compared with HCs, had disrupted connectivity between the VL nucleus and PoCG/ParaCL, as well as between the DM and insula. Interestingly, we found that the abnormalities were only observed in State 2, not in State 1. The VL, especially the VPL nucleus, is the principal somatosensory nucleus of the thalamus, which sends projections to PoCG and ParaCL for somatosensation. The dysfunction of the VL/VPL and its projections have been observed in experimentally induced pain in humans 40 and chronic pain in rats41. On the other hand, the DM plays a role in cognitive functions together with other cortical brain areas 60 and is involved in the cognitive deficits of several neurological and psychiatric disorders42. These findings suggest abnormal thalamocortical networks of both sensory and cognitive domains in cLBP patients, which is consistent with studies demonstrating that chronic pain may modulate brain functions beyond the pain/somatosensory system itself23.Evidence from electrophysiological studies has shown aberrant intrinsic electrical activity in the thalamocortical loop and suggests that the TCDPrevious studies investigating resting-state brain activity/connectivity in chronic pain patients normally lack any concomitant experimental manipulation and therefore may mix abnormalities stemming from intrinsic brain dysfunction and those stemming from the intensity of clinical pain. To better understand the specific relationships between chronic pain and thalamocortical networks, we experimentally manipulated levels of spontaneous LBP on patients to create two conditions: a low back pain and a high back pain condition. Our results provide direct evidence that increasing spontaneous back pain only alters thalamocortical networks (between the VL/VPL nucleus and PoCG/DMN) in State 1 but not in State 2. Taken together, our results suggest that thalamocortical networks, which underlie chronic pain pathophysiology, may be reflected in State 2, while clinical pain may modulate thalamocortical networks in State 1.56 and may result in altered integration of sensorimotor responses, cognitive impairment, and emotional processing.It is worth mentioning that our exploratory analysis with the putamen as a seed extended the findings from thalamocortical networks to thalamo-cortico-BG networks. The altered function of thalamo-cortico-BG loops in chronic pain has been reported previously61.There are several limitations to this study. First, although we have performed substantial quality control analyses to rule out the potential effect of vigilance differences between cLBP patients and HCs, and we have included an independent dataset to validate our findings, future studies could include EEG, cardiac, respiratory, or eye-tracking data to monitor vigilance level during scans. Second, our present study focuses on thalamus-related sensory system dysfunction in chronic pain . Future studies with specific experimental designs and hypotheses are needed to explore the abnormal brain dynamics in associative and limbic systems. Third, clinical utility was not explored in this study. Because patients from the three cohorts exhibited consistent abnormalities in rsFC time-varying characteristics and thalamocortical networks, it is plausible that they can be indicators/markers of evaluating treatment effects, especially for those approaches targeting thalamocortical networks The present study included three independent datasets with a total of 274 participants. The first dataset (Dataset 1) included 90 patients diagnosed with cLBP with a duration of at least 6 months confirmed by a clinical evaluation and 74 matched HCs. The second dataset (Dataset 2) included 30 cLBP and 30 HCs. The third dataset  included 25 cLBP and 25 HCs. All patients in the three datasets met the same inclusion criteria and had no other chronic pain comorbidities. Details of the inclusion criteria can be found in Supplementary Note 62. After the maneuvers, which took ~10–15 min, patients entered the scanner for another identical MRI session. All patients were required to rate their pain intensity before and after the two MRI sessions. HCs did not perform maneuvers and underwent only one MRI session.In the first dataset, all cLBP patients underwent two resting-state fMRI scan sessions. After the first MRI session, patients stepped out of the scanner and performed pain-exacerbating maneuvers to increase their LBP so that we could investigate the brain activity/connectivity changes following temporary back pain intensification. The maneuvers were tailored to each patient based on what the patient reported would exacerbate his or her LBP, such as lumbar flexion, extension, or rotationIn the second dataset, cLBP patients did not perform maneuvers, and they underwent two MRI sessions separated by about 2 weeks. HCs underwent only one MRI session.24 before and after the MRI scan to measure and increase their attention level. The attention and cognition components of MSIT are closely related to vigilance/arousal level63, and other similar visual attention tasks have been used to study subjects before and after sleep deprivation65, suggesting that a drowsy state/insufficient sleep may reduce visual attention task performances. The MSIT was presented by e-prime 2.0 . In brief, subjects were given response boxes  and were required to view sets of three numbers  in the center of the screen lasting for 1.75 s, with one number always being different from the other two numbers. Subjects were instructed to report, via button press, the number that was different from the other two items. There were two different tasks: a control task in which the distractors were zeros (0) and target numbers were always aligned with the same position as on the response box, and an interference task in which the distractors were other numbers  and target numbers were not aligned with the same position as on the response box . Subjects in Dataset 1 and Dataset 2 had 6-min and 8-min resting-state fMRI scans, respectively. High-resolution brain structural images were also acquired with a T1-weighted three-dimensional multi-echo magnetization-prepared rapid gradient-echo sequence .The MRI data in the third dataset were acquired at the First Affiliated Hospital of Xian Jiao Tong University using an 8-channel head coil in a 3-T GE scanner . The structural images were acquired with a T1-weighted 3-dimensional fast-spoiled gradient-echo sequence .https://www.nitrc.org/projects/conn). The first five scans were removed for signal equilibrium and participants’ adaptation to the scanner’s noise. Preprocessing steps included a standard pipeline . ART (http://www.nitrc.org/projects/artifact_detect/) was also applied to detect motion during the resting-state fMRI scan. Time points in subjects’ images were marked as outliers if the global signal exceeded three standard deviations from the mean or if scan-to-scan motion deviation exceeded 0.5 mm. Those outliers, in addition to the linear and polynomial trends of six head-motion parameters50, were included as nuisance regressors during the denoising procedure in the post-processing steps of GICA. Note that we did not perform global signal regression in the preprocessing.fMRI data were preprocessed using CONN toolbox version 17f  conduct a GICA with spatial reference 54 to decompose whole-brain resting-state fMRI data into multiple ICs and select ICNs from ICs; (2) calculate dFNC among ICNs using a sliding-window approach with graphical LASSO; (3) conduct a k-mean clustering on the dFNC estimates to identify distinct states (dFNC states) and the fraction rate/dwell time; and (4) apply graph-theory measures on each dFNC state to demonstrate the efficiency of information transfer in functional brain networks. The technical details pertaining to each step are described in the 55.The framework for characterizing dFNC to detect atypical thalamocortical networks in cLBP patients is shown in Supplementary Fig. t value > 10 and confined by the AAL thalamus atlas). In addition to BrainNavigator, we also compared our masks to locations of FSL sub-thalamic atlas and Morel atlas66. Given the potential limitations of ICA technique in brain parcellation, the nuclei obtained from ICA may cover a relatively larger area compared with parcellations based on cyto- and myelo-architecture information67, as well as other noninvasive thalamic parcellations using probabilistic diffusion tractography44 and using functional connectivity-based winner-take-all strategy68. We therefore defined the nucleus based on its most predominant anatomical location in the thalamus.To explore the abnormal thalamocortical networks, we performed the thalamus-to-whole-brain connectivity analysis within each dFNC state  for each window; (2) averaged the connectivity maps within each state ; and (3) performed statistical comparisons between different groups , thresholded at p < 0.005 at voxel level and pFDR < 0.05 at cluster level.Then, we (1) calculated the correlations between the time series of the thalamus and time series of all other voxels in the brain within each sliding window, resulting in a connectivity map (Fisher Further information on research design is available in the Supplementary InformationReporting Summary