There have been controversial voices on if hepatitis B virus infection decreases the risk of colorectal liver metastases or not. This study aims to the find the association between HBV infection and postoperative survival of colorectal cancer and the risk of liver metastases in colorectal cancer patients.Patients who underwent curative surgical resection for colorectal cancer between January 2011 and December 2012 were included. Patients were grouped according to anti-HBc. Differences in overall survival, time to progress, and hepatic metastasis-free survival between groups and significant predictors were analyzed.P < .001), time to progress , and hepatic metastasis-free survival  than the low-titer group. Multivariate model showed anti-HBc ≥ 8.8 S/CO was correlated with poor overall survival , time to progress , and hepatic metastasis-free survival  in the anti-HBc positive cases.Three hundred twenty-seven colorectal cancer patients were comprised of 202 anti-HBc negative cases and 125 anti-HBc positive cases, and anti-HBc positive cases were further divided into high-titer anti-HBc group (39) and low-titer anti-HBc group (86). The high-titer anti-HBc group had significantly worse overall survival (5-Yr, 65.45% vs. 80.06%; Higher titer anti-HBc predicts a potential higher risk of liver metastases and a worse survival in anti-HBc positive colorectal cancer patients.The online version contains supplementary material available at 10.1186/s12957-021-02369-1. Colorectal cancer (CRC) is the third most common carcinoma in the world . The 5-yInflammation has close relationship with the forming of tumor. In the nineteenth century, German doctor Rudolf Virchow  first obHBV is the virus that leads to inflammation and necrosis of hepatocytes during infection, and it is one of the leading public health problems in China . As a coAs almost all of the patients generate hepatitis B core antibody (anti-HBc) after HBV infection, hepatitis B core antibody (anti-HBc) is recognized as the most sensitive serum marker  in the cA retrospective analysis was conducted by reviewing the clinicopathological data of CRC patients who underwent curative resection from January 2011 to December 2012 at the Tianjin Union Medical Center. Patients who met the following criteria were enrolled: (1) histologically confirmed colorectal malignancy, (2) TNM stage II or III, (3) no evidence of distant metastases was found before the operation, (4) R0 resection for primary lesion, and (5) aged between 40 and 75 years. All clinicopathological data, including clinicopathological features, tumor characteristics, and laboratory examinations, were obtained from medical records and follow-up system of Tianjin Union Medical Center. All the patients included were staged according to AJCC Cancer Staging Manual, 7th edition.Patients with colon cancer received imaging examinations consisting of thoracic, abdominal, and pelvic computed tomography (CT), abdominal ultrasound, abdominal and/or pelvic magnetic resonance imaging (MRI) (if necessary), and colonoscopy before operation.Patients with rectal cancer received imaging examinations consisting of thoracic, abdominal, and pelvic CT, abdominal ultrasound, pelvic MRI, abdominal MRI (if necessary), and colonoscopy before operation.The primary colorectal malignancy was radically resected from all eligible patients according to the principle of total mesorectal excision (TME) or complete mesocolic excision (CME). Depending on patients’ conditions, neoadjuvant therapy and adjuvant treatment was determined by the multidisciplinary team (MDT). For colon cancer, neoadjuvant FOLFOX or CAPEOX was considered for bulky nodal disease or clinical T4b; neoadjuvant radiation therapy (RT) with concurrent fluoropyrimidine (FU)-based chemotherapy was considered for initially unresectable or medically inoperable tumor to aid resectability; adjuvant treatment consisting FOLFOX, or CAPEOX, or capecitabine alone, or 5-FU/leucovorin, or observation was considered according to the pathologic stage. For the rectal cancer, neoadjuvant therapy consisting long-course chemotherapy/RT or short-course RT was considered according to clinical stage; FOLFOX, or CAPEOX, or infusional 5-FU/RT, or capecitabine/RT followed by FOLFOX or CAPEOX, or observation was considered for adjuvant treatment according to pathologic stage and clinical stage.All of the cases were grouped based on anti-HBc. Firstly, all cases were grouped into anti-HBc positive group and anti-HBc negative group. Moreover, the anti-HBc positive group was grouped into the high-titer anti-HBc group and the low-titer anti-HBc group by the cutoff point of 8.8 S/CO which was calculated based on time to progress (TTP).All laboratory results, including biochemical tests, serum tumor markers, and HBV infection tests, were obtained within 1 week before the operation. Hepatitis B surface antigen (HBsAg), antibodies to hepatitis B surface antigen (anti-HBs), and anti-HBc were detected by electrochemical luminescence. Carcinoembryonic antigen (CEA) levels above 5 ng/ml, carbohydrate antigen 19-9 (CA19-9) levels above 37 U/ml, and anti-HBc levels above 1S/CO were considered to be elevated.All patients were followed up after hospital discharge. The patients were followed up every 3 months in the first 2 years after surgery and then semi-annually during the third to the fifth year. The follow-up evaluation included a routine physical, blood test, tests for the tumor markers CEA and CA19-9, and abdominal ultrasonography. Thoracic, abdominal, and pelvic computed tomography (CT) were performed annually. Colonoscopy was performed in 1 year after surgery except if no preoperative colonoscopy due to obstructing lesion, colonoscopy in 6 months. If advanced adenoma was founded, repeat it in 1 year; otherwise, repeat it in 3 years, then every 5 years. Magnetic resonance imaging (MRI) was performed when necessary. The follow-up period was terminated in July 2019.The following fibrosis 4 score (FIB-4) equations was used to evaluate the extent of fibrosis , 15. Calyte109/L . The cutt test or Mann-Whitney U test. Chi-square test and Fisher’s exact test was performed for the categorical variables. Overall survival (OS), TTP, and hepatic metastasis-free survival (HMFS) outcomes were compared using Kaplan-Meier curves. Log-rank test was used to determine statistical differences between curves. Univariate and multivariate analyses were performed by Cox proportional hazards regression models to determine the hazard ratio of each factor. Variables that were showed a significant univariate relationship with outcome were entered into the multivariate analysis. OS was defined from the date of surgery to the date of death or last follow-up. TTP was defined from the date of surgery to the date of disease progression. HMFS was defined from the date of surgery to the date of occurrence of hepatic metastases. The optimal cutoff point of NLR and anti-HBc are determined by X-tile 3.6.1 software  based on TTP. All statistical analyses were performed using SPSS 22.0 statistical software  and GraphPad Prism version 8.01 . A two-tailed P value < .05 was interpreted as statistically significant.Continuous variables are presented as means ± standard deviation (SD). Categorical variables are shown as the number of cases and percentages. Comparisons for continuous variables were performed using Student’s P = .027). Besides, no significant difference was identified between the high-titer and low-titer anti-HBc group.A total of 327 cases were qualified for the analyses. Among them, 202 61.8%) cases were anti-HBc negative and 125 (38.2%) cases were anti-HBc positive including 8 (2.4%) HBsAg positive cases. The 125 anti-HBc positive cases were divided into two groups according to optimal cut-off point of anti-HBc titer (8.8 S/CO): 39 (31.2%) cases were classified into the high-titer anti-HBc group, while the remaining 86 (68.8%) cases were classified into the low-titer anti-HBc group. The comparisons of baseline characteristics were shown in Table .8% casesP = .395; Fig. P = .524; Fig. P = .739; Fig. P < 0.001; Fig. P < 0.001; Fig. P = .029; Fig. The mean follow-up period was 61.2 ± 28.8 months. Recurrence was observed in 84 (25.7%) of 327 patients until the last follow-up. There were 30 (9.2%) hepatic recurrences, 37 (11.3%) lung recurrences, 11 (3.36%) bone recurrences, 11 (3.36%) pelvic recurrences, and 5 (1.5%) instances of brain recurrences. The OS, TTP, and HMFS curves for the anti-HBc positive and negative groups are shown in Fig. P = .016), CA19-9 > 37 U/ml , and stage III  were associated with worse OS; NLR ≥ 3.4  and stage III  were associated with worse TTP; NLR ≥ 3.4  and stage III  were associated with worse HMFS (Table P = .001) and stage III  were associated with worse OS; anti-HBc ≥ 8.8  and stage III  were associated with worse TTP; only anti-HBc ≥ 8.8  was associated with worse HMFS  [P < .05), and the prognosis of infected patients was better [Our data showed no statistical difference between the anti-HBc positive group and anti-HBc negative group about the incidence of CRLM. Prior to this, Utsunomiya T et al. analyzed the association of hepatitis virus infection and the incidence of CRLM in 1999. He found that the incidence of CRLM of the infected group was significantly lower than non-infected group  . Howevers better .P < 0.05, and 61.1% vs. 28.7%, P < 0.05, respectively) [Some studies reached the opposite conclusion. Huo T et al. performed a cross-sectional study about CRC patients and reported that chronic HBV infection increased the risk of CRLM. Also, the study found that the incidence of CRLM of the HBeAg-positive patients was higher than it of the HBeAg-negative patients . It indiOur outcome differs from previous studies. The probably reason is the recognition of HBV infection in our study differs from other studies in which “HBV infection” was characterized by positive HBsAg. Therefore, the composition of “HBV-infected patients” in this study varies from other studies. Also, HBV replication activity of anti-HBc positive cases varies from the “HBV-infected” cases in previous studies. Additionally, both Wei X and Huo T have observed a likely correlation between the activity of HBV replication and liver metastases of malignant tumors.In 1974, Hoofnagle JH et al.  proposedFusobacterium which could promote CRC by upregulating tumor-associated macrophages (TAMs) [It is worth mentioning that Caviglia GP et al.  reporteds (TAMs) , 40.Some previous studies suggest that cirrhosis could inhibit CRLM. As early as 1975, Hamaya K et al.  conducteIn this study, we used FIB-4 as predictors of fibrosis to evaluate its impact on CRLM. But no statistical difference was identified. This is probably because in spite of 81 cases with FIB-4 > 1.45 was identified, 77 cases of them were in the 1.45–3.25 interval which was not clearly defined so far , and onlWe found that NLR ≥ 3.4, CA19-9 > 37 U/ml, and stage III were the predictors of adverse outcomes, which strongly support previous reports –54 and cThere are several limitations in our approach. First, this is a retrospective single-institution study with relatively small sample size and multi-center, prospective, large-scale trials are needed in the future. Second, some clinical data such as serum HBV DNA, intrahepatic HBV DNA, and cccDNA were not available in the study. As a retrospective study, we are unable to obtain these data. Finally, we did not analyze the usage of antivirals which may affect the outcomes.Of note, we developed a basis for understanding the relationship between HBV infection, prognosis, and liver metastases in CRC patients using anti-HBc as the criterion for distinguishing HBV infection, avoiding errors generated by using HBsAg as the criterion for grouping. Moreover, we first established a link between the anti-HBc titer and the prognosis and liver metastases of CRC patients. Notably, we excluded patients who were infected with HAV, HCV, and HEV and patients with liver metastases before surgery to ensure the uniformity of baseline data to the greatest extent.Our data demonstrated that higher titer anti-HBc predicts a higher risk of liver metastases and worse survival in anti-HBc positive patients with colorectal cancer undergoing curative surgical resection, which implies the close relationship between highly active replication of HBV and occurrence of CRLM. This gives us some enlightenment on the management of CRC patients. For the management of CRC, we should pay more attention to the status of HBV, especially those whose serum anti-HBc are above 8.8 S/CO, because this may pose great impact to improving the prognosis of such patients. Moreover, we can draw up more personalized follow-up plans for patients based on their anti-HBc titers.Additional file 1: Supplementary Figure 1. Flow diagram of the retrospective analysis with adequate data.Additional file 2: Supplementary Figure 2. X-tile plots of the anti-HBc. Notes: X-tile plots showing χ2 values with cut-off points to generate the low-titer and high-titer anti-HBc subgroups. (A) The optimal cutoff value of the anti-HBc was 8.8 at the maximum χ2 value of 18.44. (B) Histogram of the entire cohort divided into low-titer anti-HBc and high-titer anti-HBc subgroups according to the optimal cutoff value of 8.8. Blue bars represent the low-titer anti-HBc group, and gray bars represent the high-titer anti-HBc group.


Introduction Opioids are the mainstay of pain management in critically ill patients. However, recent attention to their adverse effects in the intensive care unit (ICU) has led to the use of strategies that aim to reduce these side effects. Among these strategies, there are multimodal analgesia protocols, which prioritize pain management and employ a combination of different analgesics to spare excessive doses of opioids and sedatives in continuous infusion.ObjectiveThe objective of this study is to evaluate the impact of a multimodal analgesia protocol on clinical outcomes and consumption of sedatives and analgesics in two intensive care units.Methods We conducted a single-center, quasi-experimental, retrospective, and prospective cohort study comparing clinical outcomes and consumption of sedatives and analgesics before and after the implementation of a multimodal pain management protocol in critically ill adult patients. We included 465 patients in 2017 (pre-intervention group) and 1508 between 2018 and 2020 (post-intervention group).ResultsIn the analysis of the primary outcome, there was a significant reduction in mortality between 2017 and 2020 . There was no statistical difference in mechanical ventilation time or concerning the infection rate. Patients who received the multimodal analgesia protocol had a decrease of 24% regarding mean fentanyl intake and a progressive reduction in morphine milligram equivalents (MME) (8.4% - 19%). There was an increasing trend in the use of adjuvant analgesics and morphine in preemptive and therapeutic analgesia.ConclusionThe implementation of a multimodal pain control protocol significantly reduced morbidity and mortality and the use of opioids in the ICU. Patients admitted to the intensive care unit (ICU) are vulnerable to severe pain as a result of tissue injury due to serious illnesses, inflammation, major surgeries, and traumas, which require invasive monitoring, mechanical ventilation, immobility, and prolonged hospitalization. Pain, despite being a frequent symptom in the ICU, is underdiagnosed, especially in sedated and intubated patients. It is present in up to 50% of patients at rest and in up to 80% of patients receiving routine care procedures, such as tracheal aspiration, punctures, and drain removal . Up to 7Under-treated pain leads to prolonged mechanical ventilation, increased ICU stay, hypoxemia, thromboembolic and pulmonary complications, self-removal of tubes and catheters, violence against caregivers, patient-ventilator asynchrony, immunosuppression, readmission for additional pain control, agitation, myocardial ischemia, delirium, and chronic pain .The main class of drugs used to control pain in the ICU comprises opioid analgesics. Recent guidelines recommend that intravenous opioids be considered as first-line treatment for non-neuropathic pain in critically ill patients . ObservaAlthough the consequences of inadequate pain control are significant, overuse of opioid analgesics and sedatives is often accompanied by unwanted side effects such as hypotension, gastrointestinal hypomotility, paralytic ileus, gastric bleeding, renal dysfunction, immunosuppression, tolerance, hyperalgesia, dependence abstinence syndrome, arousal delay, dependence, risk of developing withdrawal symptoms, prolonged mechanical ventilation and associated problems such as ventilator-associated pneumonia, post-traumatic stress disorder, delirium, unnecessary tests for altered mental status, prolonged ICU stay, decubitus bedsores, nerve compression, respiratory depression, and iatrogenic coma .Multimodal analgesia, due to the significant reduction of opioids, gained great notoriety and evidence in the treatment of postoperative pain . It refeThis study examines the effects of implementing a multimodal analgesia protocol in critically ill patients. We imagine that a multimodal approach through a protocol for pain control in critical adult patients may: (1) decrease mortality, time of mechanical ventilation, and infection rate by reducing pain-related complications and overdose of opioid and sedative analgesics; (2) decrease opioid consumption, measured as morphine milligram equivalents (MME), and consumption of sedatives due to increased consumption of adjuvant analgesics.This investigation was designed as a single-center quasi-experimental study conducted in the modality of pre-post cohorts, comparing the impact of an unpublished multimodal analgesia protocol before and after its implementation in two Brazilian ICUs with a total of 14 beds. The protocol below was developed by the researchers of this study and approved by the institution Clinical Hospital of the Faculty of Medicine of Ribeirão Preto of the University of São Paulo (HCFMRP-USP) Table , 3.This research was carried out in the emergency unit of the Clinical Hospital of the Faculty of Medicine of Ribeirão Preto of the University of São Paulo (HCFMRP-USP), having been approved by the Research Ethics Committee of the institution.All critical adult patients hospitalized between 2017 and 2020 were included in the study, with a uniform distribution of the number of patients each year. Patients with COVID-19 admitted in 2020 were excluded from clinical outcome data analyses, although all received multimodal analgesia according to the protocol. Data from all patients was collected and recorded by nursing technicians, nurses, and physiotherapists from the ICU database of the HCFMRP-USP emergency unit, from January 2017 to December 2020. Data from 2017 was collected retrospectively, and data from 2018, 2019, and 2020 were prospectively collected. The baseline variables evaluated included: age, gender, and pathological causes of hospitalization. In addition, a simplified acute physiology score, the Simplified Acute Physiology Score 3 (SAPS 3), was calculated in patients during the first 24 hours of hospitalization to analyze the severity of the disease.The primary outcome was mortality. Secondary outcomes were duration of mechanical ventilation (excluding patients who died), infection rate, and use of sedative and analgesic drugs, both opioid and non-opioid: fentanyl, morphine, morphine, methadone, midazolam, gabapentin, propofol, dexmedetomidine, clonidine, and dextroketamine.The patients were divided into two groups: the PRE group, composed of patients who were admitted in 2017, before the implementation of the protocol; and the POST group, composed of patients who were admitted between 2018 and 2020, after the beginning of the implementation of the protocol, in January 2018.Until December 2017, there was no protocoled strategy for pain management and sedation in mechanically ventilated critical patients in the ICUs of the emergency unit of HCFMRP-USP. There were no standardized and validated methods of pain assessment in critically ill patients. Analgesia and sedation, in general, were based on the infusion of fentanyl and midazolam in increasing doses, a common practice in Brazil.As this study involved all eligible patients (by inclusion/exclusion criteria) during the pre-specified period, a prior calculation of sample size was not performed.2 and Eta2 based on the statistic H, being considered small (~0.01), medium (~ 0.06) and large (~ 0.14), and Cramer’s V, being considered small (~ 0.2), medium (~0.3) and large (> 0.3). All procedures were performed using Software R version 4.1.1 .Categorical data was presented as frequency and percentage, while continuous data such as mean were displayed as standard deviation or 95% confidence interval. The correlations between the years for continuous variables were obtained by means of analysis of variance (ANOVA) with post-test (post hoc) of Tukey Honestly Significant Difference (HSD) or, alternatively, Kruskal-Wallis test with Dunn's post-test whenever not possible to meet the assumptions of parametric statistics. All proportions were tested between years, using the Chi-Square test, and the post-test was examined by standardized residual analysis. Additionally, the effect size was reported: generalized EtaThe sample of this study comprised 1973 patients. There were 465 patients in 2017 (pre-intervention), 656 in 2018, 433 in 2019, and 419 in 2020, totaling 1508 post-intervention patients  between the types of annual occurrences, and the analysis of standardized residuals showed differences in the causes "Other" in 2018 (p=0.0096) and "Cardiovascular" in 2017 (p=0.0187) and 2018 (p<0.0001). There was no difference in age p=0.13) and gender of participants (p=0.51).  Figure . Regarding the primary outcome, the mortality rate fell between 2017 and 2020 . There was a statistical difference in the death rate in relation to the years studied p=0.0116). The death rate was different in 2020 compared to the others (p=0.0134) . There was no difference between the years in relation to the number of days of mechanical ventilation (p=0.75). Regarding the infection rate between the years, there was a difference between 2017  and the others , but no statistical difference in relation to the years studied (p<0.56).Until 2017, the sedation and analgesia regimen in the ICUs studied was based on the continuous infusion of Fentanyl and Midazolam. After the implementation of the protocol, we observed a progressive decrease in the consumption of fentanyl ampoules in subsequent years  Table .The difference between the fentanyl intake of the PRE group (28915 ampoules) and the mean fentanyl intake of the POST group (22869 ampoules) was 6046 ampoules (a decrease of 20.9%). The decrease in midazolam consumption was progressive from 2017 to 2019; however, there was an increase in 2020   with the average consumption per patient in the POST group (35.09 tablets per patient) revealed an increase of 97.13% . Lidocaine at 2% consumption per patient increased by 1316,26% in 2020, compared to 2017 (pre-intervention)  as the consumption metric for opioid analgesics. MMEs are responsible for the potency of the opioids consumed. There was a progressive decrease in total consumption of MMEs from 2017 to 2020 Table .In relation to the pre-intervention year (PRE group), there was an 8.4% drop in the consumption of MMEs in the first year after the intervention (2018), followed by a drop of 11.83% in 2019 and 19% in 2020  but increased considerably in subsequent years (2019 and 2020). The increase in morphine consumption was very significant in the third year after the intervention (2020), with an increase of 122.62% in consumption per patient in relation to the PRE group.The present study, through a multimodal, preemptive, and preventive analgesic approach, using a validated behavioral scale for pain assessment (BPS), showed that an intervention with the objective of improving pain management can generate favorable results. This way, we value the possible benefits of the management of protocoled multimodal analgesia. Our main finding was the decrease in the mortality rate in the 2020 subgroup compared to the other years, including the decrease by 6% compared to the pre-protocol subgroup of 2017  (p=0.0134). In a prospective pre-post study methodology, Skrobik et al. , 9. PainCritically ill adults experience moderate to severe pain at rest and during standard care procedures ,10. UntiAlthough pain assessment is strongly recommended by the guidelines, its broad adoption is not universal . Even thPatient-focused analgesia algorithms are multidisciplinary, including the training and development of physicians, nurses, physiotherapists, and pharmacists. Implementing algorithms in ICUs is a challenging process for which sufficient resources should be allocated. In a prospective, observational, non-randomized study, the implementation of a multidisciplinary protocol of analgesia, sedation, and delirium lasted 13 months . In the Ideal analgosedation in patients who are victims of severe trauma on mechanical ventilation is often challenging. ICUs from the HCFMRP-USP Emergency Unit constantly receive trauma patients. During the period of this study, severe trauma was the main reason for ICU admission in 330 patients (16.7%). Our study did not specifically analyze this subgroup, but Robinson et al., in a retrospective pre-post study with 143 critically ill trauma victims, found shorter mechanical ventilation and hospitalization times in the group that received multidisciplinary analgesia, sedation, and delirium protocol .In our study, 51.2% of the patients underwent mechanical ventilation. Although we observed a decrease in opioid consumption over the years and increased consumption of adjuvant drugs, in relation to the time of mechanical ventilation, there was no significant difference between the years studied and between the PRE and POST subgroups of the protocol. Regarding the infection rate, we demonstrated a decrease of 2.9% between the PRE group and the mean of the three subgroups POST, but without statistical significance. Published sedation protocols have been tested in controlled clinical trials, often demonstrating benefits such as shorter duration of mechanical ventilation, reduced length of ICU stay, and/or better management of sedation, compared to the usual treatment . ChanqueOur protocol implemented changes in the routine of the ICUs studied, requiring systematic and periodic evaluation of pain through the BPS scale. Our study showed that a multimodal pharmacological intervention aimed at improving pain management may reduce opioid consumption, according to suggestions from the Society of Critical Care Medicine guidelines of 2018 that support the use of multimodal pharmacotherapy as a component of an analgesia approach to save and/or minimize opioids and sedatives. According to the guidelines, the multimodal analgesia strategy probably improves pain control, reduces opioid consumption, and improves patient-centered outcomes ,19. In aThe use of adjuvant drugs, in addition to opioids, can help provide effective analgesia while minimizing unwanted side effects. There is evidence for the use of non-opioid analgesics in other acute care environments, such as emergency departments and post-anesthetic treatment units, but the efficacy and degree of use of non-opioid analgesics in the ICU are not well-documented ,21. Our There are few studies to date that suggest positive impacts on critical patient care, such as the reduction of opioid consumption with the use of multimodal analgesia protocols in the ICU. Nevertheless, protocols that, at least, required systematic evaluations with validated scales of pain and sedation consistently reduced opioid and sedative consumption . Our stuThe pre-post study of Skrobik et al. demonstrated superior analgesia and significantly lower mean doses of opioids (four times lower) in the post-protocol of analgesia sedation and delirium group . Both coThe practice of analgosedation in the ICU, that is, first using analgesia instead of sedation, are new paradigms in the management of patients on mechanical ventilation and form the basis of the current practice of sedation. The results of a retrospective pre-post study demonstrated that an analgosedation protocol was associated with a lighter level of sedation than a previous sedative-based strategy. In addition, the authors found a shorter duration of mechanical ventilation time and length of stay in the ICU. The study also demonstrated a significant decrease in the use of sedative agents in continuous infusion (fewer benzodiazepines and more dexmedetomidine), a significant increase in opioid analgesics, and a potential reduction in the costs of associated drugs . In our Pain management is not only a strategy to improve patient comfort and outcomes, but also a means of reducing sedation. The decrease in the use of sedatives can also be a useful intervention in reducing opioid consumption, provided that the appropriate assessment of pain precedes it . Our finThe reduction in opioid consumption in MME was predicted in our study. While Faust et al. showed that a better pain assessment increased the use per patient of fentanyl, others revealed opposite results ,19. Our Limitations of the StudyAmong the limitations of this study, we can highlight the following: (1) it was an observational, non-randomized study. The pre-post design was chosen to better simulate real-life clinical situations due to concern that a randomized model would be contaminated by culture change over time and because observational studies can provide valuable evidence, even when compared to randomized trials. These findings may show only association and no causality. The design of this study prevents any attribution of causality between analgesia management and mortality, even comparing homogeneous populations. At the very least, our findings suggest that the protocol does not pose any risk. The association of the protocol with a decrease in mortality should be validated with a randomized clinical trial. (2) The variables chosen were limited to only those available before the intervention. It was merely possible to include patients of the year 2017 in the PRE group due to the lack of data concerning the previous years. (3) We adjusted the analyses to compare the two periods, but we could not do it for all possible confounding factors; other variations in care and secular tendency may also have contributed to the observed results, especially mortality, infection rate, and duration of mechanical ventilation (MV). Nonetheless, the substantial reduction in opioid consumption is a clinically significant result that may have led to a significant reduction in complications and unnecessary expenses and may have had an impact on outcomes. (4) We do not have pain measurements available for the purposes of this study, so we cannot prove that patients had adequate pain control. However, the entire ICU team was trained to adequately assess pain, with special attention to the BPS scale and pre-procedure analgesia. (5) Our results are from a single-center study and may not be generalizable, although these findings may help other centers to evaluate their pain management protocols, which may have an impact on clinical outcomes. (6) We were not able to evaluate the side effects of opioids with our methodology. (7) The presence of multiple pharmacological interventions limits the assignment of results to one intervention or another. (8) We did not evaluate the incidence of delirium, agitation, and level of sedation; however, a multimodal analgesia protocol probably reduces iatrogenic coma, delirium, and agitation of mechanically ventilated patients, and further studies are needed to confirm these hypotheses. A multimodal analgesia protocol in the ICU, characterized by routine evaluation of pain with validated behavioral scale, increased use of adjuvant analgesics, and use of preemptive analgesia substantially, decreased the use of fentanyl and the consumption of MMEs in the intensive care unit. This strategy was associated with increased use of adjuvant analgesics  and propofol and a significant decrease in mortality three years after the beginning of the intervention. There were no changes regarding mechanical ventilation time and infection rates. The protocol developed in our study proved to be efficient for the study proposal, and our results are consistent with previous research. Randomized clinical trials are needed to confirm these findings.


COVID-19 has caused a certain proportion of patients to be hospitalized in intensive care units (ICU) and may cause musculoskeletal and neurological deficits following intubation and mechanical ventilation. The aim of this study was to quantify and describe the presence of shoulder pain in patients released from hospitals after suffering COVID-19. Patients with positive Apley tests were sent to a physiatrist for a clinical evaluation, ultrasound and electromyography (EMG). This evaluation was completed with a pain scale, joint range and shoulder muscle strength evaluations. Of the one-hundred-sixteen patients, seventy eight entered the respiratory rehabilitation program. Twenty patients were sent to the multidisciplinary shoulder team for positive Apley scratch tests. Of these twenty patients, one had only an EMG, ten had only ultrasounds, seven had an EMG and ultrasound and two did not need complementary tests. The twenty patients were sent to the physical therapist, with all presenting pain and diminished joint range and muscle strength in the affected shoulder. In this context, shoulder pain could be associated with the prone position in the ICU. We suggest time control and position change for patients on mechanical ventilation in a prone position with COVID-19. COVID-19 was first identified in Wuhan, China, in December 2019 and rapidly extended worldwide. By June 2021, there were already over 178 million cases diagnosed around the world [In the ICU, the prone decubitus (PD) position has been used to improve oxygenation. While the impact of the PD position is proven regarding increased oxygen (2), care must be taken when positioning patients since the pressure applied on specific body regions for prolonged time periods may cause nerve and muscle injuries, apart from the well-known risk of pressure ulcers .Movement difficulties in the ICU due to the need to minimize health personnel exposure could increase joint rigidity risk . Along wSome COVID-19 patients’ SARS progressed rapidly, needing prolonged ICU treatments. Some complications linked to these temporalities are polyneuropathy and myopathy, which compromise sensory and motor axons, respectively, and generally present as flaccid and symmetrical paralysis . Apart fPost-ICU syndrome covers certain complications throughout all areas of daily life following hospital discharge. On the physical side, the high rate of chronic musculoskeletal pain is notable . In thisIn the present study, a cross-sectional design was used. All patients hospitalized in the ICU during the period of May–August 2020 were considered. After leaving hospital care, the patients enrolled in the post-COVID-19 cardiopulmonary rehabilitation program. The physical therapist in charge of the cardiorespiratory rehabilitation room entered all patients with positive Apley scratch tests  into theFrom the electronic clinical records , we obtained sociodemographic data, medical backgrounds and clinical history, as well as days on MV and in prone position. Evaluations were divided in two: (i) The physical therapist from the respiratory rehabilitation program, as part of the entry evaluation, did an Apley scratch test . This teSince the loss of shoulder mobility in patients was important (inclusion criteria: Apley scratch test ), a modiA numerical rating scale was used. Patients were asked about their pain perception on a scale of 0 to 10, where 0 was the absence of pain and 10 was the worst pain imaginable. Patients were also asked to differentiate between pain while lying down and while performing daily activities .To evaluate glenohumeral joint flexing and abduction, a universal goniometer was used . All measurements were performed by the same physiotherapist (RA). For both measurements, the patient was placed in a supine decubitus position with their hip and knee joints flexed, the soles of their feet on the bed and their hands and forearms in pronation. In the glenohumeral joint, the goniometer axis was located at the humeral head, with the fixed arm on the lateral line of the trunk aligned with the greater femoral trochanter, and the mobile arm in the median longitudinal line of the humerus in alignment with the lateral epicondyle of the humerus. Following this, the patient was asked to perform a maximum flexing of their shoulder to the point that it hurt. For the glenohumeral abduction, the goniometer axis was located in the anterior margin of the acromion, with the fixed arm on the anterior axillar line parallel to the sternum and the mobile arm on the longitudinal line of the humerus. Following this, the patient was asked to perform a maximal shoulder abduction to the point that it hurt .To evaluate strength in the muscles used to perform abduction and flexing in the glenohumeral joint, we used the Daniels Scale which goes from 0 to 5. At 0, there is no muscular contraction. One presents palpable or visible contraction of the muscle group without movement. Two presents muscle contraction and the entire movement performed with assistance due to not being able to overcome gravitational force. At 3 the muscle can perform the movement, with gravity as the only resistance. At 4, the muscle contracts and performs the entire movement against gravity and moderate manual resistance. At 5, the muscle contracts and performs the entire movement against gravity and maximal manual resistance simultaneously .® Sammons Preston Inc., Salt Lake City, UT, USA). This test was done with the patient in a bipedal position, with their shoulder and forearm in a neutral position and their elbow at a 90-degree flex angle. The participant applied maximum pressure force for three seconds, making two attempts with a one-minute rest between each try, with the best value being selected [We used a hydraulic dynamometer .® program. The results are presented as averages ± standard deviation or percentage.The data were tabulated and analyzed in the GraphPad Prism 52). During MV, 100% of the sample were sedated and on neuromuscular blockers , 15% had mellitus diabetes and 45% were obese . Although there is little literature about shoulder pain in ICU patients suffering COVID-19-related pneumonia, recent results associate shoulder pain presence after leaving the ICU with various factors including age, previous pain, medical comorbidities and spending over 15 days in the ICU, which could be explained by diminished joint mobility and muscle mass loss .Prolonged prone decubitus is used in MV patients to improve oxygenation during COVID-19-related pneumonia . HoweverThe results of this study coincide with those of Puentes-Gutiérrez et al. (2020). This research group proposed to quantify shoulder pain presence two months after ICU discharge in patients hospitalized for SARS-CoV-2. In this way, out of 120 patients hospitalized in this unit, 38 received follow-up in the rehabilitation service following hospital discharge. Evaluations after two months showed that 18 people (47.4%) presented shoulder pain. The researchers attributed this pain to age, illness severity, prolonged opioid use, MV ≥ 12 days, ICU stay ≥ 15 days and the prone position . ResultsThis study used an upper-limb EMG and a shoulder ultrasound, helping to locate the origin of the shoulder pain more precisely in the patients evaluated. Results indicated that four patients presented pain with a nerve origin, while another four had pain with both nerve and osteoarticular origins. This is similar to the findings of O’Sullivan et al. (2021) who described the location, severity and prevalence of upper limb nerve injuries linked to acute COVID-19 rehabilitation. Between March and June 2020, out of 256 patients entering the ICU, 15 patients with shoulder problems were selected. All patients with shoulder issues were on MV 32.5 days) and in PD position (7.3 cycles), as well as presenting significant muscle weakness and neuropathic pain, suggesting more proximal than distal nerve damage. Thirteen patients (87%) had multiple nerve injuries in their upper limbs. Most of them had injuries on the ulnar nerve, at the level of the cubital tunnel. The most common nerve injury site was the infraclavicular level, on the brachial plexus fascicles [2.5 days In this context, positioning guides from the Faculty of Intensive Care Medicine (FCIM) suggest that the shoulder and elbow in the prone position should be at 80 and 90 degrees, respectively . Howeverp < 0.001), regardless of dose or duration [p = 0.032) [Furthermore, the pharmacotherapy used for COVID-19 patients in ICUs has also been shown to cause physical aftereffects . In pati= 0.032) . In the = 0.032) .The results from the clinical indicators used gave evidence of decreased movement range and muscle strength. In this regard, most of the disorders observed in the shoulder ultrasound indicated inflammation or breakage of the muscle group comprising the rotator cuff. Shoulder joint abduction biomechanics indicate that beyond 90° the decomposition of the force applied on the glenoid cavity tends to luxate it upwards and laterally, which makes rotator muscles contract against this luxation . Along wThis study has some limitations which must be clarified. (i) The number of participants was small. However, it coincides with the prevalence of recent studies ,4. (ii) In summary: several patients discharged from the ICU presented shoulder pain, which needed to be identified with EMG and ultrasound tests. In this context, we suggest time control and position changing in prone COVID-19 patients on MV. We also recommend that earlier ultrasound examinations be considered in patients in the PD position on MV.


The systematic collection of disease-specific symptoms and impacts on the lives of patients with Fabry Disease (FD) can offer unique insights into the patient experience, yet no disease-specific tool to measure FD symptoms exists. This study describes the development of the Fabry Disease Patient-Reported Outcome (FD-PRO).A targeted literature search, interviews with key opinion leaders (KOLs), and concept elicitation (CE) interviews with patients identified the most frequent signs and symptoms associated with FD and their impact on daily life. Cognitive interviews evaluated patients’ ability to understand the FD-PRO instructions and respond to the items on the draft FD-PRO instrument.The targeted literature search identified key signs and symptoms in domains that were confirmed in KOL interviews. In CE interviews with 37 treated and treatment-naïve patients, neuropathic pain symptoms , temperature intolerance , energy difficulties , hearing/vision impairment , and gastrointestinal symptoms  were most frequently mentioned. Results were similar for men and women in both treated and treatment-naïve groups. While treatment-naïve patients in general expressed fewer and milder symptoms compared to treated patients, the overall sets of symptoms expressed by the two groups were similar. The most severe symptoms were neuropathic pain, stomach pain, burning pain, and fatigue. The most bothersome symptoms were stomach pain, breathing difficulty, fatigue, neuropathic pain, and constipation. The most frequent impacts were in the work/school limitations domain for both treated and treatment-naïve patients. The impacts with the highest difficulty ratings were stress, limited outdoor activity, and guilt. Cognitive interviews with 14 treated and treatment-naïve patients resulted in the refinement of FD-PRO items and language.The FD-PRO is a novel, disease-specific instrument that measures the patient experience in Fabry disease. Such tools are valuable in capturing the burden of disease in patients with FD and demonstrating the value of treatment in clinical trials. Fabry Disease (FD) is a rare genetic disorder caused by mutations in the lysosomal enzyme α-galactosidase A  that lead to the progressive accumulation of globotriaosylceramide (GL-3) and other products in the lysosomes of cells , 2. OverThe systematic collection of disease-specific symptoms and the impact of these symptoms on the lives of patients with FD can offer unique insights into the patient experience. Since symptoms and disease impacts are feelings that are experienced by the patient, not observable by clinicians, and not optimally evaluated in a standard clinical trial setting, they are best measured by asking the patient to evaluate them using disease-specific patient-reported outcome (PRO) instruments . PRO insImproving and preventing symptom burden is an important clinical goal and treatments for FD can alleviate symptoms and reduce the impact that they have on health-related quality of life (HRQOL) . A systeThough other PROs have been developed in FD, these questionnaires are specific in scope or population  –7. ThereThe content validity of the instrument was established based on the process outlined by the Food and Drug Administration (FDA) Guidance for Industry and expert guidelines , 8. The CE was comprised of 3 main steps: a targeted literature review, interviews with KOLs, and patient interviews. The goal of the targeted literature review was to identify the most relevant and most important signs, symptoms, and impacts of FD from the patient perspective. The identified sign, symptom, and impact concepts were used to develop the FD-PRO instrument. The targeted literature review was conducted in PubMed and ClinicalTrials.gov in May and June 2013 using the key word “Fabry” and additional search terms . The targeted literature review was used to create the interview guides prior to patient and KOL interviews.The interviews with 7 KOLs were conducted to identify the priority signs, symptoms, and impacts of FD that were frequently experienced by patients, used as endpoints in clinical trials, and/or improved by enzyme replacement therapy (ERT). Telephone interviews were conducted with KOLs from the United States (US) (n = 3), Brazil (n = 1), the United Kingdom (UK) (n = 1), and Denmark (n = 1). In addition, an in-person interview was conducted with a KOL from Japan (n = 1). The interviews evaluated the experiences of patients dealing with the symptoms of FD, how symptoms change over time, and how the experience differed by age, sex, and treatment.Thirty-seven CE interviews with patients from the US aimed to qualitatively assess the experiences that patients had with the signs and symptoms of FD and the impact that these signs and symptoms had on their daily lives. The CE interviews included patients ≥ 18 years of age with a diagnosis of Fabry Disease. Male patients’ diagnoses were confirmed by leukocyte α-GAL A activity assay of < 4 nmol/h/mg OR documented plasma α-GAL A activity < 1.5 nmol/h/mL AND a documented causative α-GAL A mutation. Female patients’ diagnoses were confirmed by a documented causative α-GAL A mutation. Both treated and treatment-naïve as well as classic and late-onset patients were included in the study. To be eligible for enrollment as a treated patient, treatment with Fabrazyme 1 mg/kg q2w for ≥ 6 months was required.The study excluded patients who had a history of, or active, clinically significant organ disease (except for symptoms related to FD) that, in the opinion of the Investigator, precluded participation in the study or interfered with the interpretation of the interview data. Patients were also excluded if they had a positive test result for hepatitis B surface antigen (HBsAg), anti-hepatitis C virus (anti-HCV) antibodies, and/or anti-human immunodeficiency virus 1 and 2 antibodies (anti-HIV1 and anti HIV2 antibodies), or had participated in a study of an investigational drug within 30 days of the start of the study.A semi-structured CE interview guide was used to identify the terms that patients used to describe the signs, symptoms, and impacts associated with their condition. Interviews were transcribed and coded in ATLAS.ti (version 7.0) to identify themes in the data . The sigCognitive debriefing interviews were conducted to evaluate the ability of patients with FD to understand the FD-PRO instructions and respond to the items on the draft FD-PRO instrument. These interviews also helped to identify potentially problematic terminology that prevented patients from understanding the instructions and responding to the items of the instrument.Inclusion and exclusion criteria for the cognitive interviews were the same as for the CE interviews. Cognitive interviews were conducted in 3 waves, with revisions at each wave, to produce the final list of concepts for the FD-PRO. Overall, 14 patients participated in the cognitive debriefing interviews and all patients were from the US.The targeted searches identified 677 abstracts, from which 30 articles were identified for full text review. Review of studies on the ClinicalTrials.gov website identified 84 studies, of which 16 had FD signs, symptoms, or impacts as primary or secondary outcome measures. The signs/symptoms and impacts relevant to patients with Fabry Disease identified by these searches are listed in Table The KOLs confirmed that while symptom experience varies among patients, all the symptoms identified in the targeted search were relevant, and that the same PRO instrument could be used to capture the experience of both men and women and of both treated and treatment-naive patients. The KOLs noted that renal, cardiac, and cerebrovascular complications are not commonly experienced in early disease, and that symptoms such as angiokeratomas and corneal verticillata are common, but less bothersome than other symptoms. Impacts including productivity, work or school performance, activity limitations, and perception of health were mentioned by KOLs and further explored in the CE interviews.A total of 37 patients with FD met the eligibility criteria and were interviewed at 6 US clinical sites. Patients ranged from 23 to 74 years of age with a mean age of 45.7 years; 22 (59.5%) patients were women, and 32 (86.5%) were White. Thirty-four patients had classic FD and 3 patients had late-onset FD . Burning pain was worsened by triggers, such as exercise or extreme temperatures. One patient experienced burning pain in the hands during cold weather, stating “they are burning, like they are on fire … It's just like I touched a hot, that cold ice stuff [dry ice]” (Participant 8104). While burning pain was similar in presentation to neuropathic pain, patients primarily characterized their pain as “burning” which resulted in the separate concept. The term “neuropathic pain” was mentioned by only 10% of treated patients and one patient noted, “I use the word neuropathy with people who know what it means” (Participant 8109).Crisis pain occurred in 60% of treated patients and 29.4% of treatment-naïve patients and were described as recurring, sudden attacks of pain of varying duration. Pain would move up the body for one patient whose crisis pain began in the hands and feet and noted that “every fifth burning dart or so, it goes up to my elbows and up to my knees” (Participant 8103). Patients also described pain in specific locations, primarily in the extremities. For one patient, pain occurred intermittently and was described as “somebody is just stabbing me with a sharp object, you know just consistently. And that pain will last approximately I will say ten or fifteen, maybe thirty seconds. It would go away, then it would come back” (Participant 6102). Patients also reported tingling, described as “somebody lit a sparkler in my feet and my hands” (Participant 8001). A patient noted that the tingling varied in severity, stating “mildly, it's a feeling of when you know your hand falls asleep. And when it's actually painful … it's like a burning” (Participant 7002).85% of treated patients and 47.1% treatment-naïve patients reported experiencing heat intolerance, the most frequently experienced concept within this domain. Heat intolerance was experienced typically at 90 degrees Fahrenheit or higher, and was described by a patient as a tingling feeling on the skin which caused the patient to feel “sluggish … I feel like I'm coming down with the flu” (Participant 7001). Many patients would cope with consistent use of air conditioning and avoiding going outdoors on hot days. Additionally, some patients reported experiencing both heat and cold intolerance. One patient would “turn my heater on at work even in the summer because I’m always freezing” (Participant 8102). Lastly, 65% of treated patients and 52.9% of treatment-naïve patients reported a lack of sweating. A patient noted the differences in amount of sweat compared to others, stating “if their armpits might be soaking wet and their chest might be wet and it might be visible through their shirt … hardly any sweat there on my skin” (Participant 8106).Many patients reported feeling tired  and fatigued . One patient who experienced both symptoms described fatigue as “my body just feels like it doesn't have the energy to continue doing that activity and my arms and legs feel heavy” whereas tiredness was associated with the need to sleep, such as “if we get in the car, I'm usually sleeping within five minutes. In class, I would always just put my head down and fall right asleep” (Participant 3103). Another patient described fatigue as running out of energy for daily activities and “get to where I start taking short cuts” (Participant 6104). While running errands, this patient would “sit in the truck for thirty minutes just to get up enough energy to go in and get the groceries” (Participant 6104). For many patients, taking breaks and naps throughout the day were necessary to have enough energy to get through the day.Eighty percent of treated patients and 58.8% of treatment-naïve patients experienced GI symptoms, including diarrhea, constipation, and stomach pain. A patient noted that his/her stomach pain was particularly severe, stating that “I noticed that I would get like trapped gas to the point to where I would end up in the emergency room for my stomach because it wouldn't go anywhere, it would just sit there and then the ER gave me every medicine possible and as much as they could give me to try and relieve the pain, but it did nothing” (Participant 3002). Another patient experienced alternating constipation and diarrhea, noting that “constipation will usually last a couple days… And then that turns into diarrhea. And then I feel like I just flush out my system in one day” (Participant 3103). For some patients, their GI symptoms required significant planning or avoidance of daily activities. One patient noted that he/she would not plan long activities, stating “I can't do it … I wouldn't want to do it if I had diarrhea or something like that” (Participant 3101). Another patient with severe GI symptoms stated, “I would have gas, unbelievable gas that I could not get rid of. … I just had so much pain. I couldn't go anywhere” (Participant 2101). This patient expressed concern that the consistent constipation and diarrhea was so severe that “there is something else got to be going wrong. … it's dysfunctional” (Participant 2101).A number of patients experienced some to total hearing loss , with or without tinnitus. A patient who experienced both hearing loss and tinnitus stated “I lost like fifty percent of my hearing. And the ringing in my ears, most of the time when I wake up in the morning, the ringing is like, is really like twice as loud as it normally is” (Participant 6104). The patient sat in a car in the driveway during the interview, stating “I didn't want any distractions. Because if any, if I hear, if there is any noise in the room anywhere, then I can't hear you” (Participant 6104). Fifty percent of treated patients and 17.6% of treatment-naïve patients experienced vision impairment which similarly varied in severity. One patient described seeing halos and glowing lights, which caused discomfort and watery eyes. Another patient occasionally experienced double vision, stating “If I close one eye I’m fine but with the two I walk like I’m drunk …it just starts out like almost instantaneously I’m seeing double” (Participant 3104). Lastly, a patient who had greater sight impairment lost vision in one eye for 10 days, describing swelling and pain whenever he/she moved the eye. Half of the vision was lost, described as “if you were looking at TV it would, half of it would go gray” (Participant 3101).The most severe symptoms as reported by the patients (N = 37) (rated from 0 = none to 10 = extremely severe) were neuropathic pain , stomach pain , burning pain , and fatigue .The most bothersome symptoms  were stomach pain , breathing difficulty , fatigue , neuropathic pain , and constipation . Table Nearly all of the patients who were interviewed expressed impacts related to FD. Ninety-five percent of treated patients reported experiencing at least one impact in each of the following domains: physical activity limitations, difficulty with daily activities, social and lifestyle limitations, and emotional health. When asked to describe how FD impacted their daily lives, the most frequent impacts reported were in the work/school limitations domain for both treated (85%) and treatment-naïve (65%) patients. Other predominant impact domains were exercise limitations (80%), social activity (75%), and difficulty with household responsibilities (75%) for treated patients. For treatment-naïve patients, the most frequently reported impacts were depression (59%), memory problems (59%), worry/fear (54%), and exercise limitations (54%). Notably, a number of patients in both groups expressed significant emotional impacts, including stress, concerns about perception of health, and difficulty with self-image.Patients were asked to rate how difficult each impact was to cope with . The impacts with the highest difficulty ratings were stress, irritability, limited outdoor activity, and guilt. Table Many patients noted that their FD symptoms, including pain crises, tinnitus, and fatigue, impacted their ability to work or be productive at work and/or school. One patient “lost two jobs because I was fatigued, and I would get pain crisis and lay on the floor in the break room” (Participant 3103). Another patient who experienced sudden pain crises at work noted that “it just comes on really fast where I feel sick and I run a fever and then I'm like in crippling pain … I can't even walk out of work, which is embarrassing, so I have to be carried because my feet hurt so bad” (Participant 8109). Another patient’s tinnitus affected his/her ability to listen to others at work, stating “I have to be very alert and attentive to [redacted] and it’s very hard to hear what they’re saying to me when the ringing starts” (Participant 2002).Heat intolerance was one of the key symptoms that affected patients’ physical activities. While roller skating, one patient mentioned that “I always had to immediately take my skates off … It could be the dead of winter and I would walk on the cement to cool my feet off. It felt like they were on fire” (Participant 2101). Similarly, another patient mentioned participating less in physical activities because “I feel like I’m overheating … I need to manually cool myself down quite often” (Participant 8103). Other symptoms that impacted physical activities included fatigue, neuropathic pain, and burning pain. A patient noted that he/she would feel more fatigued than usual during physical activities, describing it as “my legs and my whole body just feels like feel like I’m about 90 years old” (Participant 8110).Patients reported a number of limitations in the types of social activities that they were able to participate in as well as relationships with others. For one patient, the extent of his/her social activities depended on whether others knew about the patient’s condition, stating “I won't go running or work out with people … I don't wanna sit and explain it” (Participant 7002). Many linked the impact on social activities to symptoms of fatigue and pain. A patient noted that it was difficult for friends to understand that he/she didn’t have the same amount of energy as others might, and so they would “wonder if I’m mad at them, or am I mad at the world … It is hard not to be isolated or isolate yourself” (Participant 8109). Some patients chose to limit themselves to close relationships, such as one patient who stated “I don’t even try to have a relationship like a friendship or relationship with anyone other than my family … it’s been bothersome with the pain and the ringing in the ear and the burning because I can’t do what the average person could do” (Participant 2002).Based on the data acquired through the targeted literature search, the KOL interviews, and the CE interviews, an initial draft of the FD-PRO was developed. The initial draft contained the following concepts: pain, burning, numbness or tingling (assessed separately for hands and feet), abdominal pain, abdominal discomfort, headache, cold and heat intolerance, swelling in the lower extremities, tinnitus, tiredness/fatigue, hearing impairment, exposure to activities that would lead to sweating, and lack of sweating.The draft FD-PRO was evaluated through 3 waves of cognitive interviews with a total of 14 patients, with changes made to the draft FD-PRO after each wave. Of the 14 patients, 11 had received treatment for ≥ 6 months, 1 had received treatment for ≤ 6 months, and 2 were treatment-naïve. As shown in Table Changes made based on the first wave of interviews (n = 4) included improving the specificity of the intended recall period to “the past 24 h”; changing “burning” to “burning feeling”; and adding descriptors for the location of abdominal pain/discomfort. Changes made based on the second wave of interviews (n = 5) included adding “arms” with “hands” and “legs” with “feet” on several items to include the entire extremity; adding an item on vision impairment; and revising the descriptors of the location of abdominal pain/discomfort to provide alternatives for wave 3 testing. A final 5 patients evaluated the FD-PRO in wave 3, during which the revised terminology was confirmed. Patients indicated no difficulty in comprehension of the items and confirmed their relevance, and one of the alternative descriptors for the location of abdominal pain/discomfort was chosen. After the final wave of interviews, the selected items were pain, burning, numbness or tingling (assessed separately for hands or arms and feet or legs), abdominal pain, headache pain, heat intolerance, swelling in the feet or legs, tinnitus, tiredness/fatigue, hearing impairment, visual impairment, exposure to activities that would lead to sweating, lack of sweating, and engaging in physical activities.In FD, the progressive accumulation of GL-3 and other products in lysosomes causes a constellation of signs and symptoms that can start as early as childhood and gradually progress to organ failure and death , 2. EarlThis study was done using robust methodology in accordance with the FDA guidance and expert guidelines for establishing content validity , 8. The The symptoms most commonly reported by patients, regardless of sex or treatment status, were neuropathic symptoms, temperature intolerance, energy difficulties, digestive/GI symptoms, and hearing/vision impairment. The most severe symptoms reported by patients were neuropathic pain, stomach pain, burning pain, and fatigue, and the most bothersome symptoms were stomach pain, breathing difficulty, fatigue, neuropathic pain, and constipation. Diarrhea and constipation were not included in the FD-PRO because assessment of these experiences may need to occur episodically , which is not possible with the daily FD-PRO. Additionally, standard measures, such as the Bristol Stool Form Scale, exist to measure these GI symptoms . CliniciWhen asked how FD impacted their daily lives, patients reported that work/school limitations were the most common impacts, regardless of whether they were treated or treatment-naïve. Other common impacts were exercise limitations, social activity, and difficultly with household responsibilities in treated patients and depression, memory problems, worry/fear, and exercise limitations in treatment-naïve patients. The impacts with the highest difficulty ratings were stress, limited outdoor activity, and guilt.The strengths of this study lie in the robust methodology used to develop the FD-PRO and incorporating the patient perspective of the constellation of symptoms that characterize FD. The spectrum of symptoms assessed by the FD-PRO is especially important in accounting for the heterogeneity of disease presentation, as it is well documented that symptoms vary by patients and phenotype. The FD-PRO is complementary to other PROs that assess specific symptoms of FD, such as the Brief Pain Inventory to assess neuropathic pain or the Bristol Stool Form Scale to assess GI symptoms. At the time of this publication, other PROs have been developed that assess specific components of FD. These include the FABry Disease Patient-Reported Outcome-GastroIntestinal which evaluates FD-related GI signs and symptoms ; the Fabry-Specific Pediatric Health and Pain Questionnaire which evaluates the frequency of disease-specific symptoms in children; and the Patient Needs Questionnaire Fabry which assesses patient needs and expectations towards their treatment –7. TheseLimitations include the potential that some signs and symptoms reported by patients in the treated group might instead be side effects of ERT. Indeed, some symptoms were reported more commonly in treated patients, and these were retained for quantitative testing. It was also hypothesized that the symptom pattern would differ between male and female patients. However, while there were numerical differences between male and female patients for several symptoms, the overall pattern was very similar between the sexes. Patient recall can be a limitation in any patient-reported instrument, so questions on the FD-PRO were phrased to focus on the “past 24 h” to address this potential limitation. Finally, the number of items in the FD-PRO may pose a burden that would influence the accuracy or completeness of patient reports. It is anticipated that the results of quantitative testing will be key in adjusting the final number of items in the FD-PRO.The next step in the development of the FD-PRO will be to evaluate its psychometric properties in terms of reliability and validity, and to assess patient compliance and burden in using the instrument.


Cancer diagnosis and treatment are drastic events for patients and their families. Besides psychological aspects of the disease, patients are often affected by severe side effects related to the cancer itself or as a result of therapeutic interventions. Particularly, chemotherapy-induced peripheral neuropathy (CIPN) is the most prevalent neurological complication of oral or intravenous chemotherapy. The disorder may require dose reduction of chemotherapy and is accompanied by multiple symptoms with long-term functional impairment affecting quality of life (QoL), e.g., sensory and functional deteriorations as well as severe pain. Although CIPN may reverse or improve after termination of the causative chemotherapy, approximately 30–40% of patients are faced with chronicity of the symptoms. Due to the advantages in cancer diagnosis and treatments, survival rates of cancer patients rise and CIPN may occur even more frequently in the future. In this review, we summarize current recommendations of leading national and international societies regarding prevention and treatment options in CIPN. A special focus will be placed on current evidence for topical treatment of CIPN with high-dose capsaicin. Finally, an algorithm for CIPN treatment in clinical practice is provided, including both pharmacologic and non-pharmacologic modalities based on the clinical presentation.The online version contains supplementary material available at 10.1007/s00520-021-06042-x. According to the International Association of the Study of Pain (IASP) neuropathic pain is defined as pain caused by a lesion or disease of the somatosensory  nervous system and comprises a loss of sensory function or sense as well as an increased pain sensitivity or spontaneous pain , 2. CancSymptoms of CIPN usually decline after termination of the neurotoxic therapy. However, depending on the administered substance , further progression or new development of symptoms for several months post-therapy is possible (coasting phenomenon), and symptoms can persist for many years or even lifelong . Since cApproximately 50–90% of patients under chemotherapy are affected by CIPN and bear a high risk of chronicity (approx. 30–40%) –13. A reSensory nerve fibers are generally more vulnerable to toxic effects of anticancer drugs and patients affected by CIPN usually experience greater sensory than motor or autonomic symptoms. CIPN-specific symptoms commonly manifest in feet and hands in typical sock and/or glove-like pattern. They may cause adjustments of therapy as well as subsequent reduction in treatment efficacy .The pathophysiology of CIPN upon administration of anticancer therapies has been analyzed in detail by a variety of studies and reviews , 15, 16.In general, prevalence and incidence of CIPN vary according to the chemotherapeutic agent, dose, duration of exposure, and method of assessment . AccordiBesides specific risk factors such as diabetes, hypothyroidism, renal insufficiency, alcohol abuse, and preexisting neuropathy , there are tumor-associated and therapy-related factors that contribute to the individual risk for CIPN . HoweverCIPN is predominantly a sensory neuropathy that may be accompanied by motor and autonomic deficits, depending on the chemotherapy regimen Table , Fig. 2.hyperalgesia allodynia , resulting from thermal and mechanical  stimulispontaneous  shooting pain, electric shocks, or burning paindysesthesia paresthesia Positive sensory symptoms can be stimulus-evoked or spontaneous and include:hypoesthesia or hypoalgesia) causing a feeling of numbnessreduced responses to either normally non-painful or painful stimuli in the damaged nerve territory disturbance of vibratory and proprioceptive sensationsNegative sensory symptoms include:The longest peripheral axons are more vulnerable to toxic drugs, and sensory symptoms usually begin in the lower limbs followed by the upper extremities, spreading from toes and fingertips in a distal symmetric sock- and glove-like distribution pattern. Most patients (approx. 68%) are simultaneously affected at upper and lower limbs, although presence of symptoms exclusively in the feet is also possible . AdditioCIPN-associated QoL deteriorations including increased risk of falling are burdensome for patients and often underestimated by physicians , 25, 26.Guidelines by national and international societies recommend neurological examination of cancer patients prior to initiation of potentially neurotoxic cancer therapies in order to obtain a neurological baseline status and identify patients at risk of CIPN , 7. ImpoOnce CIPN is presumed, further diagnosis is made by history and clinical presentation , 6. BedsAs some chemotherapeutic substances can provoke polyneuropathy-like symptoms, differential diagnoses, e.g., palmoplantar erythrodysesthesia  after treatment with capecitabine or pegylated doxorubicin or paraneoplastic neuropathy mediated by onconeural antibodies targeting peripheral nervous system epitopes, should be considered to ensure appropriate treatment , 17. FurSeveral compounds have been investigated in clinical studies for their efficiency in prevention of CIPN, including anticonvulsants, antidepressants, vitamins, minerals, and other chemoprotectants without reliable or conclusive clinically meaningful benefits , 7, 38. Upon initiation of potential neurotoxic anticancer therapies, regular functional exercises  should be considered , which iNational and international guidelines provide recommendations for non-pharmacological as well as pharmacological treatment options of manifest CIPN. The pharmacological recommendations are summarized in Table Conventional systemic treatment options for neuropathic pain include antiepileptic agents, antidepressants, including selective serotonin and norepinephrine reuptake inhibitors (SNRIs), and tricyclic antidepressants, as well as opioids. However, only the SNRI duloxetine is recommended for treatment of CIPN in existing guidelines , 7, 44, Systemic drugs need to be slowly titrated from a low starting dose to a dose providing best efficacy and limited side effects. Of special note in this context is the interaction potential of systemically acting substances in case of co-administration with chemotherapeutic and other therapies.Topical treatment options for neuropathic pain and CIPN include the lidocaine patch (700 mg), the capsaicin patch (179 mg), and various gel formulations.The German S3 guideline for supportive therapy in oncology patients highly recommends functional exercises  .I.Duloxetinen = 231) found that duloxetine treatment resulted in greater reduction of CIPN-associated pain, particularly when induced by platinum derivatives [II.VenlafaxineIn patients with peripheral neuropathy of other origin than CIPN, duloxetine is administered due to established efficacy. In addition, a phase III, randomized double-blind, placebo-controlled crossover study  indicating significant benefit vs. placebo, albeit occurrence of several side effects [Venlafaxine may be considered for CIPN therapy in individual cases , 44. The effects . In addi effects .I.Amitriptyline/nortriptylinen = 114 and n = 44, respectively) revealed negative results or only discrete improvements of symptoms in CIPN patients [n = 51) revealed only modest and questionable benefit [Two randomized placebo-controlled studies of amitriptyline  revealed no improvement in either pain intensity or sensory neuropathy [Although both gabapentin and pregabalin have been shown to be effective in the treatment of polyneuropathies, only limited scientific evidence for CIPN treatment exists. A phase III, randomized, double-blind, placebo-controlled crossover study of gabapentin in patients with CIPN , metamizole, or paracetamol display low efficacy in the treatment of neuropathic pain and are considered to be associated with a variety of potential side effects , 44. HowClinical trials provide little medical evidence that cannabinoid-based medicines are effective for the treatment of neuropathic pain , 63. DatI.LidocaineII.CapsaicinThe lidocaine patch (700 mg) is approved for the treatment of postherpetic neuralgia but have also been suggested by guidelines for the treatment of localized neuropathic pain of other origins, including CIPN , 44, 65.n = 18 and n = 16, respectively) [In Europe, the capsaicin patch (179 mg) is approved for topical treatment of peripheral neuropathic pain as monotherapy or in combination with other pharmaceutical products for pain treatment . The guictively) , 68. HowI.Baclofen (0.8%), amitriptyline (3%) and ketamine (1.5%)/amitriptyline (4%), and ketamine (2%)II.Menthol (1%)Topical therapy of CIPN with a gel formulation containing baclofen (0.8%), amitriptyline (3%), and ketamine (1.5%) may be suggested as it was beneficial in comparison to placebo in a randomized, double-blind, placebo-controlled trial in 208 CIPN patients. However, the overall effect was modest and not clinically relevant . FurtherSignificant reduction of pain as well as some improvement in functionality and sensitivity was detected upon topical therapy of CIPN with 1% menthol in a proof-of-concept study with 51 patients. However, the patient cohort was small, and the study was non-blinded .+, Ca2+) with subsequent release of vasoactive neuropeptides, depolarization, and propagation of action potentials into spinal cord and brain. Patients may experience this as various sensations at the application site  [Capsaicin is a highly selective agonist of the transient receptor potential vanilloid 1 (TRPV1) ion channel and induces activation of TRPV1-expressing cutaneous nociceptors. Upon activation, TRPV1 opens transiently resulting in an ion influx (Naitching) . Importaitching) , 69. Treitching) . Re-treaitching) , 71.Exposure to the capsaicin 179 mg patch reduced the density of epidermal nerve fibers (ENF) and induced modest but significant changes in tactile thresholds as well as sharp mechanical pain detection in healthy volunteers. Tactile and sharp pain sensations returned to normal within 12 weeks after application, and ENF density was regenerated 24 weeks after exposure. The latter suggests that the proximal dermal origins of ENFs remained intact and that only the distal dermal nerve segments and epidermal nerve endings are affected .n = 15) within the open-label, clinical observational QUEPP study [n = 1044 patients with various peripheral neuropathic pain conditions). The average pain intensity assessed by the 11-point numeric pain rating scale (NPRS) continuously decreased over the course of the study  revealed that the analgesic effect of the capsaicin patch is higher and lasts longer in patients with shorter durations of preexisting neuropathic pain. The highest response to capsaicin treatment was achieved within 6 months of onset of peripheral neuropathic pain. Therefore, treatment should be initialized as early as possible [Analyses of the total QUEPP population  as these drugs might induce dizziness and subsequently increase the risk of falling.Consequently, and in view of patients with comorbidities or at risk of cancer recurrence, topical treatment options with a non-systemic mode of action should be preferred for patients with CIPN-associated pain due to the low rate of systemic side effects and systemic drug interactions.CIPN represents a major concern in cancer therapy. There is limited evidence-based data available for prophylaxis and treatment of this condition. Early start of functional exercises during chemotherapy is recommended.Existing data on pharmaceutical treatment of CIPN allow weak recommendations for duloxetine. Given the paucity of available alternative treatment strategies and extrapolating efficacy data from other neuropathic pain conditions, certain antidepressants (amitriptyline), and anticonvulsants  may be considered. If appropriate, opioids may be used on the basis of clinician’s experience.Systemic treatments are associated with a typical tolerability profile and carry the risk of drug interactions. Study results from open-label trials provide evidence for successful topical treatment of CIPN with capsaicin 179 mg patch. The patch provides significant reduction of CIPN-related pain and symptoms as shown in the literature for other neuropathic disorders, while displaying low rates of side effects , 67, 70.ESM 1(DOCX 186 kb)