Dental general anesthesia (GA) is a day-stay procedure and is a suitable choice for complicated cases. It is undertaken in a controlled hospital setting that ensures the quality, safety, efficacy, and efficiency of dental treatment. The purpose of this study is to determine the prevalence, severity, duration, and factors related to the occurrence of postoperative discomfort in young children following GA in a general hospital. This study includes a minimum sample size of 23 children that were undergoing GA over a 1-month period. Informed consent was obtained from the parent prior to the treatment. A preoperative questionnaire via the Survey Monkey program was used for the purposes of recording the responses of the survey population. All data related to the immediate postoperative period while the child was in the post-anesthetic recovery room (PAR) was collected and assessed by one of the investigators using the Face, Legs, Activity, Cry, and Consolability (FLACC) pain assessment scale. Postoperative data was gathered using the Dental Discomfort Questionnaire (DDQ-8) and was performed by phone 3 days after the GA procedure. The participating 23 children ranged from 4 to 9 years old (mean 5.43 ± 1.53). A total of 65.2% were girls and 34.8% were boys, with 30.4% experiencing a recent history of pain. Delivering treatment to children can be difficult, particularly where extensive treatment is required ,2,3,4. IPediatric patients often experience fear and anxiety when undergoing local anesthesia, which can lead to increased pain perception. Various attempts have been made to reduce pain during local anesthesia in pediatric patients, including distraction techniques, topical anesthetics, and buffering of the anesthetic solution. Nitrous oxide, also known as laughing gas, has also been used as a form of analgesia for pediatric patients during local anesthesia procedures ,16,17,18Pain is an unpleasant sensory and emotional experience associated with, or described in terms of, actual or potential tissue damage . It is sTo assess the patient’s safety with regards to morbidity after comprehensive dental treatment, international studies are quoted due to insufficient local data on this topic . In addiThis was a prospective observational study that included a minimum sample size of 23 children who underwent GA at REU hospitals in Riyadh, Saudi Arabia over a 1-month period. All children were seen preoperatively at the Department of Pediatric Dentistry at REU. The Institutional Review Board at Riyadh Elm University (REU), Riyadh, Saudi Arabia authorized the protocol, which was carried out in accordance with the Helsinki Declaration . The written informed consent for involvement was provided by each patient and their guardians. Informed consent was obtained from the parent prior to data collection.Healthy (American Society of Anesthesiologists status I).Aged between 4 and 9 years old.Communicate well in Arabic.Require oral comprehensive treatment involving multiple dental procedures, for example: pulpotomies, pulpectomies, and extractions of at least one tooth.Developmentally delayed or congenitally impaired childrenBorn prematurely Currently using psychotropic medicationsUsing analgesics preoperatively on the day of the procedurep value of 0.05.Sample calculation: A sample of 23 participants were recruited to yield an 80% power to detect the effect of this sample size at a A preoperative questionnaire was used via the Survey Monkey program, which was sent via a link before the patient entered the GA appointment with an accompanying caregiver. The survey was composed of eight questions and contained information on demographic characteristics, past GA experience, recent use of medications for a dental issue, history of tooth discomfort, and the DDQ-8, which is an instrument to measure dental pain or discomfort in children. The range for the total score was from zero to 16; a score of three or higher was been determined to predict tooth-related discomfort in children  31]..31].All data related to the immediate postoperative period while the child was in the PAR was collected by one of the investigators. The child’s discomfort was assessed using the FLACC pain assessment scale. The range for the overall score was from 0 (no pain) to 10 (intense pain)  32]..32].Postoperative data was gathered by an investigator using the DDQ-8, and an inquiry about the use of medications, the child’s capability to eat a regular diet, and the severity/duration of pain; this process was performed using a phone 3 days after the GA procedure. A carer entered the dental surgical suite with the child for the induction of GA, which was administered intravenously. Three certified pediatric dentists supplied all of the dental care. For a few children who needed multiple extractions and crowns, infiltration local anesthesia  was used. Children were extubated in the surgical suite by the anesthesiologist after receiving their treatment, and were then immediately admitted to the PAR under the care of the PAR nurse. Children were to be released 15–30 min after awakening, as long as they were steady. The carers received postoperative instructions.p < 0.05 was considered significant for all statistical purposes. All data was analyzed using SPSS version 25 .The normality of the data was assessed using the Shapiro–Wilks test, and it was found to be not normally distributed. Hence, non-parametric tests were applied to the data. A descriptive statistic of mean and standard deviation values was calculated for the continuous variables, and frequency distributions were obtained for the categorical data. Mann–Whitney U and Wilcoxon’s sign rank tests were applied to the data. A value of p < 0.05).The participating 23 children ranged from 4 to 9 years old (mean 5.43 ± 1.53). Of this sample size, 65.2% were girls and 34.8% were boys, with 30.4% experiencing the maximum pain. The descriptive data and characteristics of the study of the children are reported in In p < 0.001  expressed discomfort by crying steadily, including screams, sobs or frequent complaints, while a few of the expressions were evaluated by the face, legs, activity, cry, and consolability scale (21.7%) . A compa < 0.001 . A different variable was used to indicate whether the child experienced discomfort during the dental treatment under GA in . As repoThis investigation was significant as it shed light on the factors that contribute to postoperative discomfort in young children, which can help improve their postoperative care after GA. Firstly, it provides valuable insights into the immediate and postoperative pain experienced by pediatric patients undergoing dental procedures under GA. The use of the FLACC pain assessment scale and the Dental Discomfort Questionnaire (DDQ-8) provide objective and subjective measures of pain, respectively, allowing for a more comprehensive understanding of the pain experienced by the children. Secondly, the study’s sample size of 23 children over a 1-month period is significant, as it provides a reasonable representation of the population being studied. This sample size also allows for statistical analysis and provides a basis for future studies and comparison with other similar studies. Thirdly, obtaining informed consent from the parent prior to treatment is an ethical requirement, and the use of a preoperative questionnaire via the Survey Monkey program ensures that the parent’s perspectives and concerns are taken into consideration. This shows that the study was conducted in an ethical and responsible manner. In addition, the study’s findings can help healthcare providers better understand and manage the pain experienced by pediatric patients undergoing dental procedures under GA. This can lead to improved pain management strategies and ultimately better outcomes for pediatric patients. Overall, the study provides valuable information that can contribute to the improvement of pediatric dental care under GA. The study also compared the differences in postoperative discomfort between genders, and found no significant difference. The results showed that restoration was the only variable that indicated discomfort. The study had a limited sample size, however, which may have impacted the results, suggesting the need for larger sample size studies to generalize the findings. Overall, the study contributes to a better understanding of the prevalence, severity, duration, and factors related to postoperative discomfort in young children following GA, which is essential for improving the quality of care provided to these children.Perception of pain in children is difficult due to their inability to communicate and describe pain . In thisBased on our results, all of the patients were released from the recovery room with discomfort according to the FLACC. A total of 56.5% expressed discomfort by crying steadily, including screams, sobs or expressing frequent complaints in the immediate postoperative period. In previous studies, postoperative pain was also a common finding ranging from 36% and 95%. While some studies reported it as an uncommon finding, this variation may be due to the time of pain assessment, type and quantity of the preformed procedures, and the age of the children . AnotherIn our study, the FLACC scale was used to assess pain because previous studies have demonstrated that this pain assessment scale is valid, easy and convenient to use. Postoperative analgesics were taken by 65.2% of the children. However, in one study 60% of the children took analgesics on day 1 while 33% did not, and their highest pain assessment was mild pain which concludes similar results .Our study revealed 78.3% of the children were eating a regular diet after 3 days and did not need any medications afterwards. El Batawi et al.  explaineA study mentioned in literature that we came across investigated similar objectives such as ours . The stuGA is a treatment method with intrinsic dangers and special advantages . It is nPostoperative complaints may be caused by a range of variables, including the type of procedure, the length of the general anesthetic, the use of a double throat pack, the patient’s pre-existing health, the expertise of the provider, and the use of local anesthetic . HoweverParents must watch over the child for 24 h after surgery . StructuAs far as limitations go, we believe the limited sample size of this study can be mentioned as one of its major flaws. Secondly, the use of the FLACC pain assessment scale and the Dental Discomfort Questionnaire (DDQ-8) may have limitations. The FLACC scale may not accurately assess pain in all children, as pain expression and perception can vary widely among individuals. The DDQ-8 may also be limited by recall bias, as it relies on the child’s memory of pain experienced 3 days after the GA procedure. The study’s design also did not include a control group, which limits the ability to make comparisons and draw definitive conclusions about the effectiveness of pain management strategies used during the GA procedure. In addition, the study only collected data related to the immediate postoperative period and 3 days after the procedure. Pain experienced beyond this time frame may not have been captured, limiting the overall understanding of pain experienced by pediatric patients undergoing dental procedures under GA. However, we would also like to mention that ours is a subset of a few studies that have attempted to analyze postoperative pain of pediatric patients undergoing dental treatment under general anesthesia. As such, the authors wish to emphasize the need for more studies to be undertaken in this regard, to validate ours as well as other studies’ observations.In this study, results were significant where the children commonly experienced postoperative symptoms such as pain, crying, and sleepiness after dental rehabilitations under GA; however, this significantly decreased over time. Therefore, none of the variables were predictors for the discomfort of the child. The limited sample size may, however, have had an impact on the results; hence, a larger sample size is required.


This study aimed to explore the value of the Charlson comorbidity index (CCI) in predicting ICU admission in patients with aortic aneurysm (AA).The clinical data of patients were obtained from the Medical Information Mart for Intensive Care-IV database. The association between CCI and ICU admission was explored by restricted cubic spline (RCS), threshold effect analysis, generalized linear model, logistic regression, interaction, and mediation analyses. Its clinical value was evaluated by decision curve analysis (DCA), receiver operating characteristic curve (ROC), DeLong's test, and net reclassification index (NRI) analyses.P = 0.005). Further, their nonlinear relationship was observed (adjusted P = 0.008), and a significant turning point of 6 was identified. The CCI had a favorable performance in predicting ICU admission (area under curve = 0.728) and achieved a better clinical net benefit. New models based on CCI significantly improved the accuracy of prediction. Besides the importance of CCI in ICU admission, CCI also exerted important interaction effect (rather than mediating effects) on the association of other variables (such as age and blood variables) with ICU admission requirements .The ICU admission was significantly associated with the thoracic AA (TAA), unruptured status, and surgery status. Therefore, 288 candidate patients with unruptured TAA who received surgery were enrolled in the further analysis. We found that CCI was independently associated with the ICU admission of candidates (The CCI is an important predictor of ICU admission after surgery in patients with unruptured TAA. Aortic aneurysm (AA) is the second most prevalent aortic disease after atherosclerosis and becomes the ninth-leading cause of death globally (1). AA mainly includes abdominal aortic aneurysm (AAA) and thoracic aortic aneurysm (TAA). Presently, surgical procedure remains the main choice for the treatment of AA. Open surgery repair (OSR) and endovascular aortic repair (EVAR) are the most common methods involved in AA treatment, especially the EVAR is used more often due to its superiority to some extent (2). Because of significant morbidity and mortality, many patients undergoing complex aortic surgical procedures were traditionally admitted to the intensive care unit (ICU) for the 1st postoperative day for close continuous monitoring and supportive therapies (3). Angela et al. study indicated that ICU admission within 24 h after noncardiac surgery occurred in 9.6% of patients , and these patients showed higher median age and burden of prehospital comorbidities  (4). They also found that the proportions of patients admitted to ICU were significantly related to the surgery types, and hysterectomy accounted for 0.9% as well as 90.8% for open AAA repair. However, Lawlor et al. showed that for the majority of elective infrarenal AAA patients undergoing open repair, postoperative ICU admission was unnecessary (5), and these patients can be safely admitted to the stepdown unit for postoperative management. Over 300 million surgical procedures are performed worldwide each year, and ICU resources become more limited, increasing constraints have been placed on ICU admissions.Therefore, early recognition and management contribute to effective ICU utilization (6). A key strategy for improving the management of ICU is to identify the subgroup of patients who are at high risk of adverse outcomes. At present, several tools have been used to determine which patients require ICU admission, such as quick Sequential Organ Failure Assessment (qSOFA) score, Systemic Inflammatory Response Syndrome (SIRS), and National Early Warning Score (NEWS). Stokes et al. indicated that a preoperative qSOFA score ≥ 2 can predict postoperative ICU admission in patients with obstructed infected ureteral stones (7). Goulden et al. showed that for predicting the ICU admission of patients with sepsis, the performance of sensitivity was NEW = SIRS > qSOFA and qSOFA > NEW > SIRS for specificity (8). It should be noted that no scoring system has both high sensitivity and specificity for predicting adverse outcomes. Hence, it was necessary to find a more useful tool to predict ICU admission, which contributes to the management of ICU resources and decreases health-care costs.Up to now, the previous studies only indicated that a high burden of prehospital comorbidities and AAA surgery showed a higher rate of ICU admission. However, no study reported a detailed association between CCI and ICU admission in patients with AA. In this study, we found that the patients with unruptured TAA undergoing the surgery, rather than AAA, were significantly related to the need for ICU admission. Therefore, we performed a series of analyses to evaluate the relationship between CCI of patients with TAA and ICU admission and the potential influence of CCI on the association of other significant variables with ICU admission. We also explored the clinical value of CCI to predict ICU admission in patients with TAA.In this study, the Medical Information Mart for Intensive Care-IV (MIMIC-IV), a publicly available single-center critical care database, was used to obtain the data. The platform can be accessed after finishing a web course offered by the National Institutes of Health (NIH).In this study, these patients were enrolled in the further analysis: diagnosed with abdominal aortic aneurysm  and thoracic aortic aneurysm ; had ICU data; had surgery records; aged ≥ 18 years old; and length of in-hospital stay ≥ 2 days. The patients missing Charlson comorbidity index (CCI) data were excluded. For patients with multiple admissions records, we only retained the record on the patient’s first admission to the ICU.2), normal weight (18.5–24.9 kg/m2), overweight (25.0–29.9 kg/m2), and obese (≥ 30.0 kg/m2). We also obtained the histories of hypertension, coronary heart disease (CHD), hyperlipidemia, and chronic obstructive pulmonary disease (COPD). In addition, these data within 24 h after admission, including systolic blood pressure (SBP), diastolic blood pressure (DBP), mean arterial pressure (MAP), platelet (K/μL), urea nitrogen (mg/dL), creatinine (mg/dL), anion gap (mEq/L), and red cell volume distribution width , were also collected.In this study, the outcome was the ICU requirement of patients with AA. The primary independent variable was the CCI. The demographical covariables included age, gender, marital status , and body mass index (BMI). The BMI was grouped into four groups, including underweight , disease progression (ruptured and unruptured), and surgery status (with and without). According to these results, the candidate patients for further analysis were determined. Baseline characteristics of final candidate patients were presented stratified by the ICU requirement (yes vs no). The continuous variables conforming to the normal distribution were presented as the means ± SD, and the independent t-test was used to compare the difference between the two groups. Whereas the median and quartiles were used for the nonnormal variables, and the Mann–Whitney U-test was used to compare the differences. Categorical variables were expressed as frequencies, and the distribution difference was analyzed by χP < 0.05 was considered statistically significant.Then, two models were established to explore the independent association between CCI and ICU admission requirements. Firstly, the restricted cubic spline (RCS) was performed to assess their association. The knots for RCS were set as 5. According to the book Regression Modeling Strategies by F. E. Harrell, the number of knots = 5 is a good choice when the sample size is > 100. To determine the significant reference point for RCS analysis, the threshold effect analysis was performed, and a significant inflection point affecting their association was obtained. Subsequently, the inflection point was set as the reference point in RCS analysis. Further, generalized linear model was performed to assess their association. In addition, we transformed the data of CCI as the log-CCI, and a linear relationship between log-CCI and ICU admission requirements was observed. Hence, the association between log-CCI and ICU admission requirements was also explored by the logistic regression analysis. The interaction effect of other variables on CCI was also evaluated both in two models. Next, we explored the clinical value of CCI for predicting the ICU requirement by decision curve analysis (DCA) and receiver operating characteristic curve (ROC) analysis. Based on CCI, we established three new models to predict the ICU requirement by introducing other variables. The DeLong's test and net reclassification index (NRI) analysis were performed to compare the performance of three models. In addition, we also assessed the potential role of CCI as the interaction factor and mediating factor on the association of other variables with ICU requirements by interaction and mediating analyses. All the data were analyzed using the SPSS and R software. P < 0.001), unruptured status , and those who underwent the surgery . Therefore, 288 patients with unruptured TAA who received the surgery were finally enrolled in the further analysis. Of whom, 226 patients (78.5%) had a record of ICU admission.In this study, a total of 1180 patients with aortic aneurysms were found. We first explored the association between CCI and ICU requirement (yes vs no) through subgroup analysis stratified by aortic aneurysm type, disease progression, and surgery status. The results , age (P = 0.009), CCI (P < 0.001), the levels of platelet (P = 0.008), urea nitrogen (P < 0.001), creatinine (P < 0.001), and RDW (P = 0.001). These six variables with statistical significance were selected for further analyses.The characteristics of patients with TAA are presented in Table P = 0.017). After adjusting related variables, their nonlinear relationship was still significant (P = 0.008) . In addition, threshold effect analysis also identified a significant turning point (Table P < 0.001). However, their relationship was insignificant when CCI > turning point. It followed that CCI may be significantly related to the ICU admission requirement in a certain range.The RCS analysis was firstly performed to evaluate the association between CCI and ICU requirements. A significant nonlinear relationship Fig. A betweenP < 0.05). Further, only CCI (P = 0.008) and creatinine (P = 0.022) were independently associated with the ICU requirement. Among these variables, age (P = 0.015) and creatinine (P = 0.014) showed the significant interaction effects with CCI involved in the ICU requirement.Then, the independent association between CCI and ICU requirement was explored by generalized linear model Table . The uniP = 0.062, data not shown), which supported the logistic regression analysis. We also used logistic regression analysis to further verify the independent role of CCI in ICU requirement (Table P < 0.001). Among these variables, age (P = 0.023) and creatinine (P = 0.048) displayed the interaction effects with log-CCI.Due to the nonlinear relationship between CCI and ICU requirement, we transformed the data of CCI as the log-CCI. After transformation, log-CCI showed a linear relationship with the ICU requirement by RCS analysis . The AUC value of CCI was also significantly higher than single age and blood variables (data not shown). In addition, a previous study has indicated that the age of 65 was related to the prediction performance of CACI in predicting ICU admission. Therefore, we also evaluated the prediction performance of CCI in subgroup patients (age ≤ 65 and age > 65) . These results highlighted that CCI may be more useful than CACI in predicting ICU admission in patients with TAA.The above results have demonstrated the significant association between CCI and ICU admission requirement, and we further explored its potential value in clinical application. As the importance of the age-adjusted CCI (CACI) has been confirmed, therefore, we evaluated the value of CCI in predicting ICU admission compared with the CACI. CACI was calculated as the CCI after adding 1 point for each time age exceeded 40 years by 10 years (9). The DCA analysis showed that both CCI and CACI can achieve a favorable clinical net benefit for predicting the ICU requirement Fig. A. ROC an65) Fig. C. The reP value of DeLong's test was all less than 0.001, suggesting the more favorable predicting performance of other models. We also performed the NRI analysis to evaluate the prediction performance of different models. The appropriate proportion of reclassification in three models was all improved  compared with the single CCI, indicating that the accuracy of new models was increased, and new models were superior to the single CCI for predicting the ICU requirement.We further established three new models based on CCI to predict the ICU requirement. The results showed that the AUC of CCI plus age (AUC = 0.724) was similar to that of single CCI Table . The AUCBesides the importance of CCI itself in predicting ICU admission, we found that CCI may also play a vital role in the association between other variables and ICU admission. The above two regression models showed that the age, CCI, RDW, platelet, urea nitrogen, and creatinine were all related to the ICU requirement. However, most of variables showed no associations with ICU need besides the CCI in the multivariable analysis. These results may suggest the potential influence of CCI on the association between these variables and ICU requirement. In this study, we performed interaction effect analysis and mediation analysis to clarify the potential effect of CCI involved in the association between other variables and ICU requirement.P < 0.001). Regarding subgroup analysis, its significant interaction effect was just observed on the association between platelet and ICU requirement in patients with CCI < 6 (P = 0.039). Although the interaction effect of CCI on the association between urea nitrogen/creatinine and ICU requirement was not found in whole populations , it was significant in CCI < 6 subgroup populations (P = 0.036 and P = 0.025). These results highlighted the important role of CCI in the association between these variables and ICU requirements, and its interaction effect may be related to the selection of a turning point. The interaction effect of CCI for these variables needs more investigations with larger samples to be verified.We initially performed the interaction effect analysis to explore the potential role of CCI. Based on the turning point of CCI = 6 in the adjusted model in threshold effect analysis, all the patients were divided into two subgroups (CCI < 6 and CCI ≥ 6). Then, the association between ICU requirement and these variables was explored by generalized linear model among whole populations and two subgroups Table . The resFurther, we performed the mediation analysis to explore the mediating effect of CCI on the association between these variables and ICU requirements Table . AccordiIn this study, we demonstrated a significant association of CCI with ICU admission in patients with TAA who had undergone the surgery. We also confirmed the favorable clinical value and accuracy of models based on CCI for predicting ICU admission. In addition, we found that CCI exerted significant interaction effect in the association between other variables and ICU admission. Until now, there was no study reported the value of CCI involved in ICU admission prediction, and this study initially disclosed the importance of CCI in TAA.CCI is an easy, inexpensive, and quick method of assessment. It was commonly used in different populations as a prognostic indicator in longitudinal studies to predict mortality  and postoperative complications (12). However, little research was conducted on the prediction of ICU admission using CCI. Our study initially reported its better performance for predicting ICU admission in patients with TAA undergone the surgery. The prediction role of age-adjusted CCI in ICU admission has been revealed in other aspects. St-Louis et al. showed that the age-adjusted CCI was associated with ICU admission in the emergency general surgery population, but it was not a good predictor (13). Vahapoğlu A et al. study showed that age-adjusted CCI was effective for determining the ICU indication in the preoperative evaluation process of patients aged > 65 who had elective surgery (14). In our study, we found that CCI had a more favorable performance for predicting ICU admission than age-adjusted CCI in patients with TAA over the age of 65 who had surgery. In addition, we found that the performance of new models based on CCI was significantly increased. These results all highlighted the promising value of CCI in predicting ICU admission in TAA.ICU admissions are usually related to serious conditions, illnesses, or complications associated with illness (15). In our study, 78.5% of patients with unruptured TAA undergone the surgery were admitted to the ICU, which may be due to the higher baseline number of patients with TAA. Hanna L et al. explored the trends in TAA hospital admissions and interventions, finding that the hospital admission incidence (mainly due to unruptured admissions) increased from 1998 (4.11/100 000) to 2020 (12.61/100 000), and operative interventions also increased mainly due to the increase in thoracic endovascular aortic repair (16). It followed that the hospital admissions of unruptured TAA and operative interventions increased objectively, which may promote ICU admission after surgery to some extent. In addition, the ICU admission was not only related to the patient’s health condition. Hicks et al. study reported that hospital-level factors including geographic location, hospital volume, teaching status, and urban/rural status, rather than patient-level factors, were the primary drivers of ICU admission after endovascular aortic aneurysm repair, and immediate ICU admission was currently overused (17). Hicks et al. study implies that it is the hospital practices that determine whether a patient needs ICU admission after surgery, whether it is warranted for the patient or not. Alshaikh et al. study found that patients admitted to the ICU not only had similar morbidity and mortality to those without admission to the ICU but also significantly correlated with increased hospital cost (18). In our study, we also found a longer length of in-hospital stay in ICU groups. The ICU is a crucial and expensive resource in the hospital and is also a special department dedicated to the most critically ill patients. Overused ICU admission and overcrowding increase morbidity and mortality (19), overworked staff, and even congestion of the patient flow as well as additional challenges in the management of ICU (20). Therefore, the requirement of ICU admission needs to be assessed reasonably and properly in preoperative.In addition, some limitations of this study should be acknowledged. This study focused on patients with or without ICU admission. However, we cannot confirm whether these patients admitted to ICU need admission. Therefore, the false positive may be inevitable. Meanwhile, this study did not consider the ICU types, and the influence of ICU types on the prediction performance may be ignored. Though some limitations existed, this study initially reported the association between CCI and ICU admission in TAA, which provided the reference value for further investigations about the evaluation of ICU admission in patients with TAA.This study initially disclosed the significant association between CCI and ICU admission in patients with TAA undergone the surgery. The CCI is a potential predictor for evaluating the ICU admission requirement in TAA. In addition, the potential role of CCI on the association between other variables and ICU admission requirements should not be ignored.


Rifaximin effectively treats symptomatic uncomplicated diverticular disease (SUDD) and has shown eubiotic potential  in other diseases. This study investigated changes in the fecal microbiome of patients with SUDD after repeated monthly treatment with rifaximin and the association of these changes with the severity of abdominal pain.This was a single-center, prospective, observational, uncontrolled cohort study. Patients received rifaximin 400 mg twice a day for 7 days per month for 6 months. Abdominal pain  and fecal microbiome (assessed using 16 S rRNA gene sequencing) were assessed at inclusion (baseline) and 3 and 6 months. The Spearman’s rank test analyzed the relationship between changes in the gut microbiome and the severity of abdominal pain. A p-value ≤ 0.05 was considered statistically significant.Akkermansia in the fecal microbiome was significantly higher at 3 (p = 0.017) and 6 (p = 0.015) months versus baseline. The abundance of Ruminococcaceae (p = 0.034), Veillonellaceae (p = 0.028), and Dialister (p = 0.036) were significantly increased at 6 months versus baseline, whereas Anaerostipes (p = 0.049) was significantly decreased. The severity of abdominal pain was negatively correlated with the abundance of Akkermansia  and Ruminococcaceae  but not with Veillonellaceae, Dialister, or Anaerostipes. After 3 months of rifaximin, abdominal pain was significantly less in patients with Akkermansia in their fecal microbiome than in patients without Akkermansia (p = 0.022).Of the 23 patients enrolled, 12 patients completed the study and were included in the analysis. Baseline abdominal pain levels decreased significantly after 3 (p = 0.036) and 6 (p = 0.008) months of treatment with rifaximin. The abundance of The eubiotic effect of rifaximin was associated with decreased abdominal pain in patients with SUDD. Diverticula are small sac-like protrusions that form in the large intestine wall and represent the most frequent anatomical alteration of the colon. The presence of diverticula in the intestine, defined as diverticulosis, may be asymptomatic or proceed as symptomatic uncomplicated or complicated diverticular disease . The maiClostridium cluster IX, Fusobacterium, and Lactobacillaceae . The Mann-Whitney test was used to assess differences between continuous variables. For differences between categorical variables, the Fisher’s exact test was used. Variations in the abundance of gut microbiome taxa were analyzed using the Wilcoxon test. The Spearman’s rank test was used to assess correlations between the variables computed. A p-value ≤ 0.05 was considered statistically significant. Statistical analysis was performed using STATISTICA 10 .Thirty patients were assessed for eligibility. Twenty-three patients were included in the study, and 12 patients completed the study , with improvement further pronounced at 6 months (p = 0.008) Fig. . None ofAkkermansia (phylum Verrucomicrobia) at both 3 months  and 6 months (both p = 0.015) compared with baseline levels. Significant increases were also observed at 6 months in the abundance of Ruminococcaceae (p = 0.034), Veillonellaceae (p = 0.028), and Dialister (p = 0.036) (family Veillonellaceae). In contrast, the abundance of Anaerostipes (p = 0.049) (family Lachnospiraceae) decreased significantly after 6 months of rifaximin compared with baseline levels. No significant differences in abundance were identified for the remaining taxa investigated.Analyses of the fecal microbiome Table  identifiAkkermansia was detected in the fecal microbiome in 2 of 12 (16.7%) patients at inclusion. This increased to 7 of 12  patients at 3 months, and 9 of 12  patients after 6 months of rifaximin.Akkermansia in the fecal microbiome at 3 months as follows; patients with Akkermansia  versus patients without Akkermansia .The patients were divided into subgroups based on the presence or absence of The severity of abdominal pain was significantly less in the Akkermansia[+] group than in the Akkermansia[-] group after 3 months  and 6 months  of rifaximin, whereas no significant between-group differences were identified at baseline .Akkermansia in their fecal microbiome.Significant decreases in abdominal pain were observed in the Akkermansia[+] group at 3 and 6 months compared with baseline (both p = 0.028) , Verrucomicrobia , and Ruminococcaceae  in the fecal microbiome. No significant correlation was identified between the severity of abdominal pain and the abundance of Veillonellaceae (p = 0.486), Dialister (p = 0.101), or Anaerostipes (p = 0.867).The severity of abdominal pain was negatively correlated with the abundance of Akkermansia, Verrucomicrobia, and Ruminococcaceae were observed and inversely correlated with the severity of abdominal pain.To the best of our knowledge, this study is the first to evaluate the long-term  effect of rifaximin on the gut microbiota in patients with SUDD. We show here that rifaximin significantly reduced the severity of abdominal pain, which is consistent with previous studies –12. WherVeillonellaceae, Dialister, and Anaerostipes were also observed after 6 months of rifaximin, however, they were not correlated with abdominal pain severity. Thus, it is likely that these bacteria are not involved in the development of abdominal pain in SUDD.Changes in the abundance of Akkermansia were identified in the fecal microbiome of 2 patients (16.7%) at inclusion and in 9 patients (75.0%) after 6 months of rifaximin, whereas these bacteria were detected in 90.5% of healthy individuals in a separate study (p < 0.001) . New larger studies should be performed to resolve this problem.In our study, ata from ). Howeveients 16.% at inclients 16.% at inclients 16.% at inclAkkermansia is the main representative of the Verrucomicrobia phylum in the gut microbiome. This bacterium has several beneficial properties, including an anti-inflammatory effect [Akkermansia increases the thickness of the mucin layer and improves the intestinal epithelial barrier, preventing the translocation of harmful bacteria and their components into the intestinal wall [Akkermansia in the mucosal microbiome [y effect –32. Specnal wall . This banal wall . Moreovecrobiome .Akkermansia on the epithelial barrier and mucous layer is believed to be because these bacteria degrade mucin to molecules that stimulate its formation by feedback and are used by bacteria from the family Ruminococcaceae that form butyrate [Akkermansia and Ruminococcaceae increased significantly after treatment with rifaximin. However, while the increase in the abundance of Akkermansia was significant at both 3 and 6 months, the increased abundance of Ruminococcaceae was only significant after 6 months of treatment with rifaximin. This result supports the hypothesis of the synergistic effect of these two groups of bacteria on decreasing intestinal permeability, bacterial translocation, low-level inflammation, and abdominal pain associated with patients with SUDD.The positive effect of butyrate , 31, whibutyrate , 34. In Ruminococcaceae family, there have been no published data to show that its use increases the abundance of Akkermansia [Citrobacter, and Coprococcus, and a deficiency of Mogibacteriaceae, Christensenellaceae, Dehalobacteriaceae, Pasteurellaceae, Anaerotruncus, Blautia, Eggerthella lenta, Dehalobacterium, SMB53, and Haemophilus parainfluenzae (p-adj < 0.05) reported. However, as patients received only 7 days of treatment with rifaximin, these results must be viewed with caution as they may not represent the long-term effect of rifaximin on the gut microbiota in patients with SUDD.Although rifaximin has been reported to increase the abundance of bacteria under the ermansia . In a prermansia , rifaximAkkermansia in the gut microbiome, counts of A. muciniphila species were numerically lower in patients with SUDD than in those with asymptomatic diverticulosis  [Akkermansia in patients with diverticulosis is associated with their transition from asymptomatic to symptomatic. Furthermore, a cohort study of patients with asymptomatic diverticulosis and periodic analysis of their gut microbiota may identify predictors of SUDD.Two small studies investigated the difference in the gut microbiome between patients with asymptomatic diverticulosis and SUDD , 7. AlthAll patients in our study consumed dietary fiber to prevent constipation, a risk factor for complications of diverticular disease. However, since we selected patients who had consumed dietary fiber for a minimum of 6 months before enrollment, this is unlikely to have influenced our results. In addition, we did not evaluate the severity of stool disturbances or bloating in our patients, since these may depend on dietary fiber intake.Several limitations of the present study must be acknowledged. Firstly, the number of participants was low, and a substantial proportion of patients were lost at follow-up. Nonetheless, our preliminary results are promising and may support the design of larger controlled studies. The small number of participants can also be explained by self-termination of rifaximin due to persistent improvement or other divergences that led to the exclusion of these patients from the study analysis. Another significant limitation of our study is the lack of a placebo control arm essential to demonstrate an unambiguous symptomatic benefit of rifaximin. Large randomized controlled trials are therefore required to support our findings.Akkermansia and Ruminococcaceae, which was associated with a decrease in the severity of abdominal pain. Our study also highlights the eubiotic effect of rifaximin from as early as 3 months after starting treatment.In conclusion, our study is the first to describe changes in the gut microbiome after multiple courses of rifaximin to treat SUDD and the association of these changes with the severity of abdominal pain. We show significant increases in the abundance of the beneficial bacteria,


ContextOver the past 60 years, several researchers have conducted extensive studies on the use of dexamethasone to reduce the postoperative complications of lower third molar surgery, namely, pain, edema, and trismus. In this study, we compared the oral and intramuscular methods of dexamethasone administration.PurposeThe aim of this research was to assess pain, edema, and trismus in the postoperative period following the surgical removal of the lower third molar using 8 mg of dexamethasone given orally or by intramuscular injection.MethodA split-mouth technique was employed for the study, in which each of the two bilaterally impacted mandibular third molars was removed one at a time, separated by at least two weeks. There were 26 participants in this experiment. Two groups were created from the research sample: group A (injection dexamethasone) and group B (tablet dexamethasone). The pain was assessed on the first, second, and third postoperative days. On the first, third, and seventh postoperative days, the parameters, such as edema and trismus, were evaluated.ResultsAs per our study, in terms of edema and trismus, there was less of a statistically significant difference between the two interventions at all time points. While the pain score had a significant difference between both interventions.ConclusionHence, we conclude that oral dexamethasone is an effective alternative to intramuscular dexamethasone. Oral dexamethasone is comparatively simple, less invasive, painless, and easy for the surgeon and for apprehensive patients, and it offers a cost-effective solution for the suffering often associated with the extraction of impacted lower third molars. The transalveolar extraction of the impacted third molars is one of the most frequently encountered minor surgical procedures in oral surgery. This procedure is often associated with considerable postoperative sequelae such as pain, edema, and trismus, which often cause discomfort to the patient . AccordiThe use of corticosteroids is an effective method that can alleviate the aforementioned postoperative sequelae. Classification of corticosteroids is based on their duration of action. Short-acting glucocorticoids have a duration of action of less than 12 hours, they include hydrocortisone and cortisone. Intermediate-acting glucocorticoids include prednisone and prednisolone with a duration of action of about 12-36 hours. Long-acting glucocorticoids include dexamethasone and betamethasone, with a duration of action greater than 36 hours [Dexamethasone is one of the most potent synthetic corticosteroids with a much greater anti-inflammatory effect and minimal unfavorable impact on leukocyte chemotaxis . It has There appears to be solidarity regarding the benefits of prophylactic antibiotics and the use of corticosteroids in decreasing postoperative complications after the third molar surgery ,11.This study compares the effect of intramuscular (IM) administration of dexamethasone (8 mg) in the deltoid muscle with that of oral dexamethasone (8 mg) on postoperative pain, swelling, and trismus after surgical removal of bilateral impacted mandibular third molars having similar difficulty indices.This study was conducted on 26 healthy patients  with an average age of 18 years (range = 15-30 years), with bilateral lower third molars in similar positions and with similar difficulty index, for which surgical removal had been indicated. Institutional Review Board and Ethics Committee’s approvals were obtained for conducting this study. The subjects were selected keeping in mind the following inclusion criteria: no history of allergy to dexamethasone, amoxicillin, or acetaminophen and a surgical site free of active infection. This study was conducted by a double-blind split-mouth technique wherein removal of the impacted mandibular third molars was done one at a time separated by a gap of at least two weeks.All patients were given preoperative antibiotics two hours prior to the surgery. Patients were given an information sheet and were explained in detail regarding the procedure and study. Written informed consent was taken from the patient before the procedure for publication of the study findings. A detailed case history was obtained from all the patients participating in the study, and standard sterilization protocol was followed throughout the study. All the patients were explained about the visual analog scale preoperatively, which was filled by the patients based on their experience postoperatively. All injections and third molar surgery were performed by the same surgeon and all the parameters were recorded by the same clinician. The same conventional surgical method was used for all lower third molar procedures, under the usual inferior alveolar nerve block and buccal nerve block. Painting and draping of the patient were done under an aseptic protocol. Local anesthesia with adrenaline in 1:200,000 was administered and inferior alveolar, lingual, and long buccal nerve blocks were given. An appropriate incision was taken, and the flap was reflected. The impacted tooth was sectioned and surgically removed. Flap was sutured with resorbable (3-0) Vicryl sutures . Each patient had to undergo two surgical extractions with an interval of at least two weeks.In the first appointment, the patient was given 8 mg 2 ml dexamethasone injection intramuscularly into the deltoid muscle following surgical removal of the impacted mandibular third molar. While in the second appointment, the surgical removal of the mandibular third molar was carried out on the same patient on the contralateral side and 8 mg of dexamethasone was given per oral immediately following the surgery. Given that the usual daily output of cortisol is 15 to 25 mg, but that it may be produced up to 300 mg during a crisis, and that the 8 mg of dexamethasone is nearly equivalent to this quantity of released cortisol, 8 mg of oral dexamethasone was the lowest dose with the best results that could be attained . DexametParameters such as swelling and trismus were recorded for the patients after surgical removal of bilaterally impacted mandibular third molars on the first, third, and seventh days postoperatively. The pain was evaluated on the first, second, and third days postoperatively (morning and evening). The swelling was measured using Matsumara and Gabka technique (in mm) with the help of a standard measuring tape from the lateral canthus of the eye to soft tissue gonion (LCG) line 1), as shown in Figure , as showThe second measurement for swelling was from the tragus to the corner of the mouth (TM) line 2), as shown in Figure , as showAnd the third imaginary line was from the tragus to the soft tissue pogonion (TP) line 3), as shown in Figure , as showThe preoperative measurements were used as baseline values. The difference between each postoperative evaluation and baseline indicated the swelling for that day. To eliminate the observer bias, only one observer measured the swelling in all the patients.Postoperative average pain was assessed over the next first, second, and third postoperative days once in the morning and at bedtime using a 10-point visual analog scale (VAS) with a graphic rating scale marked by the patient herself or himself as per the pain experienced by the patient. This is a numeric rating scale on which patients rate their current pain intensity, ranging from “0” (no pain) to “10” (worst possible pain).Trismus was evaluated by measuring the inter-incisal distance at maximum mouth opening (mm) using a calibrated scale between maxillary and mandibular incisal edges, as shown in Figure All the patients were given the same postoperative instructions and a course of antibiotics, i.e., tablet Augmentin 625 mg, which contains 500 mg amoxicillin + 125 mg clavulanic acid, and analgesic tablet Enzoflam, which contains diclofenac 50 mg + paracetamol 325 mg + serratiopeptidase 15 mg, following the surgical removal of impacted mandibular third molars for three days. The patient’s data were statistically analyzed. The level of significance used in the statistical decisions was p < 0.05.The mean value of facial swelling at line 1 for intramuscular dexamethasone on day one was 11.096 cm, and for oral dexamethasone, it was 12.392 cm, and the results were statistically significant. For day three, the mean for intramuscular dexamethasone was 9.826 cm, and for oral dexamethasone, it was 11.623 cm, and their difference using the independent t-test was found to be statistically significant as well. The result remained consistent for day seven, with the mean for intramuscular dexamethasone being 9.203 cm and for oral dexamethasone being 11.084 cm, and it was statistically significant too. The result implies that the facial swelling at line 1 was almost identical at all time points for the intramuscular dexamethasone and the oral dexamethasone intervention group  injection and 8 mg consumption of dexamethasone per oral immediately in the postoperative period on the day of the third molar surgery. This study used a case-control design with bias control and patients with bilateral lower third molars having similar difficulty index.The parameters evaluated for this study were pain, swelling, and trismus. In our study, the amount of pain experienced by the patient was recorded using VAS. In terms of severity of pain, less of a statistically significant difference existed between both interventions. The mean value of the VAS pain score on day one for intramuscular dexamethasone was found to be 6.88, and for oral dexamethasone, it was 7.96. These results indicate that the oral dexamethasone group had a greater pain score than the intramuscular dexamethasone group on the first postoperative day, which may have been due to the maximum plasma concentration of oral dexamethasone (8 mg) being 65% than that of intramuscular dexamethasone (8 mg). Therefore, we recommend patients receiving dexamethasone orally to take oral analgesics for the initial two days. On postoperative day two and day three, both groups produced almost similar pain scores.Overall, the results of the present study showed a reduction in the severity of the above-mentioned parameters at the test site on the first, third, and seventh days postoperatively. The result suggests that the measures of facial swelling for the intramuscular and oral dexamethasone groups were almost equivalent at all time points, and the outcomes were comparable. Trismus was evaluated by measuring the interincisal distance using a vernier caliper on the first, third, and seventh postoperative days. Both groups demonstrated the trismus' statistical relevance. The average values for each intervention group are quite comparable to one another, indicating that both of them may be employed to get effects that are expected to be similar. The parameters used in this study returned near to the normal baseline values on the seventh postoperative day in both oral and intramuscular dexamethasone groups.Our results were in correlation with the previous study of Boonsiriseth et al. , who empAs per our study, in terms of edema and trismus, there was less of a statistically significant difference between the two interventions. Comparatively, the mean VAS pain score on day one for intramuscular and oral administration of dexamethasone was 6.88 and 7.96, respectively. These findings show that on the first postoperative day, the oral dexamethasone group had a higher pain score than the intramuscular dexamethasone group, which may have been because the maximum plasma concentration of oral dexamethasone (8 mg) was 65% than that of intramuscular dexamethasone (8 mg).The present study demonstrated that oral dexamethasone (8 mg) is a successful substitute for dexamethasone intramuscular injection (8 mg). Oral dexamethasone (8 mg) can be prescribed along with analgesics in the initial two postoperative days. On days two and three following the surgery, both groups had essentially equal pain scores. The use of the intramuscular injection may be a discomforting and painful experience for the patient. On the other hand, oral dexamethasone is relatively straightforward, less intrusive, painless, easy for the surgeon and for apprehensive patients, and provides a reasonably priced remedy for the agony usually connected with the extraction of impacted lower third molars.To sum up, oral dexamethasone is an effective alternative to intramuscular dexamethasone. It can be given after surgical extraction of the third molar, which will aid in the postoperative management of pain, swelling, and trismus. Oral dexamethasone is comparatively simple, less invasive, painless, and easy for the surgeon and for apprehensive patients, and it offers a cost-effective solution for the suffering often associated with the extraction of impacted lower third molars.


Background and objectiveThe management and treatment of nociception remain one of the major challenges in anesthesiology, and hemodynamic variations may occur due to inadequate analgesia, which at times can be injurious. Pupillometry is a new noninvasive tool to assess nociception during anesthesia. The amount of pupillary reflex dilation (PRD) is directly proportional to the intensity of nociceptive stimuli and inversely proportional to the opioid dosage. This study aimed to assess the use of pupillometry as reflex pupillary dilatation in response to surgical stimulus in children under general anesthesia and to guide intraoperative opioid consumption.Materials and methods2 and N2O (50:50%), and fentanyl administration was guided by pupil diameter changes. The primary outcome was to measure pupillary dilatation in response to pain and fentanyl administration guided by it.After obtaining approval from the institutional ethics committee and written consent from parents, children with an American Society of Anesthesiology (ASA) classification of I and II and aged 2-12 years who were undergoing surgery under general anesthesia were enrolled in this prospective randomized observational study. General anesthesia was standardized with propofol, sevoflurane, and OResultsA total of 72 patients were included in the study. The mean pupil diameter significantly increased after surgical stimulus from 1.37 ±0.87 to 2.40 ±1.95 mm (p<0.001). The heart rate  and systolic BP  did not change significantly on stimulus. The mean fentanyl consumption was 2.4 ug/kg and the side effects were not remarkable.ConclusionBased on our findings, pain has a significant influence on the pupil dilatation reflex in anesthetized children, and opioid administration based on pupil diameter can be valuable in clinical settings. We recommend the use of pupillometry as a pain index in children undergoing surgery under general anesthesia, and it can be a beneficial tool for assessing intraoperative pain. Newer techniques and developments are required in this field. The evaluation and measurement of nociception are one of the major concerns among anaesthesiologists during and after surgery. Nociception refers to the neural encoding of noxious stimulation, while pain is a subjective feeling of tissue injury or trauma. The noxious stimuli of the surgical trauma generated due to mechanical stress, pressure, or inflammation activate nociception in neurons, reaching the cerebral cortex even under general anesthesia through A-delta and C fibers. The hemodynamic variations result from inadequate analgesia intraoperatively and postoperatively, which can be injurious. The frequent administration of opioids is associated with side effects like nausea, vomiting, pruritus, slowed breathing, urinary retention, etc. Thus, it is important to calculate the minimum effective dose of intraoperative opioids or other analgesics required for an individual.Hemodynamic parameters such as heart rate or blood pressure variations are commonly used to monitor analgesia intraoperatively. Many noninvasive devices have been developed in the past few years, with newer techniques, applications, and parameters, to check the balance between intraoperative algesia and analgesia. The dose of opioids should be individualized and effective to avoid overuse and underuse. Pupillometry is one such device and a reliable tool to monitor nociception. The pupillary diameter increases in response to painful stimuli. This phenomenon is called pupillary reflex dilation (PRD) and is observed in both conscious and anesthetized patients. The reflex dilation of the pupil in response to pain is correlated with the intensity of nociceptive stimuli and to the dose of administered opioids . During In light of this, we performed this study to assess pain by pupillometry in children under general anesthesia and opioid administration, to address the scarcity of data in the literature on the subject.This study was conducted after obtaining ethical clearance from the Institutional Ethics Committee, IGIMS, Patna, and registering the trial with Clinical Trials Registry (CTRI/2022/02/040112). This was a prospective observational single-blinded study of children in the age group of 2-12 years of both sexes with the American Society of Anaesthesiologists (ASA) physical status I and II who were scheduled to undergo surgeries for lower abdominal or urological issues and upper and lower limbs under general anesthesia. The pupil measurements were taken by another anesthetist who was unaware of the anesthetic agents delivered and procedures performed (blinded).The exclusion criteria were as follows: children whose parents declined to enroll in the study; children with a history of hypersensitivity to drugs, or use of anticholinergic drugs, opioids, and antiemetics recently; the presence of eye disease or any viral illness; a history of cardiovascular disease or anomaly; and those with a duration of surgery of more than two hours. Preanesthetic evaluation of all the patients was performed before admitting them to the ward.Out of 80 patients assessed for eligibility in the study, 72 children were included in the final analysis and eight were excluded due to several reasons, as shown in the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) diagram Figure .2), and respiration were instituted, and baseline values were noted. Intravenous access was established with a 20/22 G intravenous catheter on the dorsum of the nonoperative hand. The baseline eye examination was done to assess normal light reflex and rule out any pathology during the preanesthetic check-up. The pupil size was measured by pupillometer/digital vernier caliper after opening the eye with lid retractor , noninvasive arterial pressure (NIBP), pulse oximetry SPO, and res2 below 45 mmHg.No antiemetics were administered in the preoperative period and hypercarbia was avoided by keeping ETCO2 was kept between 32 and 40 mmHg. Intraoperative monitoring of NIBP, respiratory rate, heart rate, ETCO2, and SpO2 was done, and IV fluids were given as per protocol. Intraoperative analgesia was administered in the form of fentanyl bolus 1 ug/kg titrated to variations and changes in the pupil size recorded. After the completion of the surgery, the neuromuscular blockade was reversed with Inj. neostigmine and glycopyrrolate combination and Inj. ondansetron 0.1 mg/kg was given before reversal. An antibiotic (ofloxacin eye drop) was instilled in both eyes after the measurement was over. Vitals were recorded during the recovery period and the patient was observed for 30 minutes after surgery in the postoperative area. Any adverse effects were noted and treated symptomatically. The patients were followed up in the postoperative period and in the ward till discharge.After taking written informed consent from the parent or legal guardian of the child, the patient was taken to the operation theatre. Induction was done with Inj. propofol 2 mg/kg of body weight and Inj. atracurium 0.5 mg/kg of body weight. and oxygen 100%. Hypnosis was maintained with sevoflurane [minimum alveolar concentration (MAC): 1.5], 50% oxygen, and 50% nitrous oxide, and ETCOThe size of the pupil was recorded at different intervals , as mentioned above, in ambient light and not in bright light by separating the surgical field and head area with a screen. The other eye remained covered to prevent contralateral light reflex, and stimulation was stopped when pupil dilatation was more than 13% of the baseline. Inj. fentanyl 1 ug/kg was then administered, and the next measurement was recorded after two minutes.Sample size and statistical analysisContinuous variables were examined for normality using the Shapiro-Wilk test and were reported as mean (SD) or median (IQR) where appropriate. Normally distributed and non-normally distributed variables were analyzed using a one-way analysis of variance (ANOVA) or the Kruskal-Wallis test, respectively. Categorical data were analyzed using the Chi-squared test. A p-value <0.05 was considered statistically significant for all comparisons. Data were analyzed using IBM SPSS Statistics for Windows .Data related to 72 children who underwent surgeries for lower abdominal or urological issues and upper and lower limbs under general anesthesia were collected. The demographics of children are presented in Table The assessment and treatment of pain in children are difficult to evaluate as compared to adults, which often results in either undertreatment or overtreatment. The treatment of pain in children and adolescents is now focused on an interdisciplinary approach, with an equal emphasis on therapeutic, pharmacological, psychosocial, and behavioral aspects. The early evaluation and control of pain symptoms have improved with the emergence of newer techniques. The balance between nociception due to surgical stress and antinociception induced by anesthesia has an impact on the patient's homeostasis and postoperative recovery. Various nociceptive monitors are available to measure pain during anesthesia, such as analgesia nociception index (ANI), surgical pleth index (SPI), enhanced recovery after surgery (ERAS) nociception level (NOL), and pupillary pain index (PPI). Our study evaluated the use of a pupillometer as an alternative to other variables like heart rate and blood pressure in analyzing pain and depth of sedation during general anesthesia in children and in guiding intraoperative fentanyl requirements.In our study, we found that surgical stimulus causes reflex pupillary dilatation under anesthesia in children far more rapidly and greater than hemodynamic responses at two minutes after the stimulus Tables , 3. The Saboudrin et al.  demonstrWildemeersch et al.  and VideBoselli et al.  included2O:O2 (50:50) to allow hemodynamic response in the range of the depth of anesthesia, and the applied MAC was above the MAC for surgical stimulus.Julien-Marsollier et al.  assessedThe conventional way to assess pain during anesthesia is through heart rate and blood pressure changes, which are neither specific nor sensitive to intraoperative pain. But it depends on various other factors like bleeding, respiration, the position of the patient, volume status, cardiovascular drugs used, and body temperature. No changes in terms of these parameters were seen in children in our study on surgical stimulus and only four (5.5%) showed an increase in heart rate >20% after one minute of surgical stimulus. However, pupillary dilatation was seen in almost all patients on painful stimulus, and it was significant after the stimulus and after opioid use Tables . Thus, pOpioids cause miosis in a dose-dependent manner, whose mechanism of action is on the parasympathetic nervous system . Hence, In their study, Kegels et al.  included in their research, have shown the PPI score to be a predictive marker of pain response in sedated critically ill adults. Moreover, it has been proven that the administration of remifentanil reduces PPI scores. Our findings are similar to those of past research that shows that commonly monitored variables for analgesia like HR, SBP, and movement are less sensitive than PRD in adults as well as in children [Emery et al.  found grchildren Our study included a substantial number (n=72) of pediatric patients as it was an invasive procedure, but it has its limitations too. The sample size can be increased for better results with the use of noninvasive devices for pupil size measurement. Since we did not have an automated infrared pupillometer at our institute, the measurement may not have been very accurate. The variables of pain assessment like heart rate and blood pressure are dependent on other factors too, such as age, volume status of the patients, and depth of anesthesia. Given these facts, we maintained the volume status of the children as per protocol and MAC 1.5 of sevoflurane was maintained during the measurement of pupil size. The light in the operation theater was kept ambient so that no bright light fell directly on the measuring eye.Based on our findings, pain has a significant influence on the pupil dilatation reflex in anesthetized children, and opioid administration based on pupil diameter can be of value in clinical settings. Although many scales like the visual analog scale and numeric rating scales are used to identify and measure pain in the postoperative area in conscious and awake patients, it is difficult to measure it perioperatively. Some other modalities such as evoked potential, brain imaging, EEG, or BIS can be helpful in monitoring pain and depth of anesthesia, but they are not easily available at all centers and need qualified personnel to operate them. An automated infrared pupillometer is a device to measure pupil diameter more accurately. The pupil dilatation reflex can assess pain, albeit in a controlled environment and free of confounding variables such as bright light and the use of some drugs.The assessment of analgesia through pupil dilatation has definitive advantages over other autonomic responses to pain like heart rate and blood pressure, which are neither sensitive nor specific. Based on the above findings, we recommend that pupillary reflex dilatation be used to predict intraoperative pain and the requirement for opioids in anesthetized children. Further comparative studies are required to gain deeper insights into its sensitivity in predicting intraoperative pain and validate our results.


Severe dermal pain triggered by sweating stimuli, such as bathing, exercise, and mental stress, significantly affects patients’ daily lives. The pathomechanism underlying the sweating-induced dermal pain remains poorly understood and there exists no standard treatment for such pain. This study aims to evaluate the effectiveness of icatibant as an analgesic, a bradykinin B2 receptor antagonist, in treating sweating-induced dermal pain, and to establish the role of bradykinin in pain induction.A multicenter, exploratory, crossover, single-blinded, placebo-controlled randomized, comparative study will be conducted to evaluate the efficacy of subcutaneous icatibant injection (30 mg) in treating sweating-induced dermal pain. Ten patients will be enrolled and assigned randomly in a 1:1 ratio to either the icatibant-placebo or placebo-icatibant groups. The primary endpoint is the change in the visual analog scale scores for dermal pain induced by thermal load before and after treatment with icatibant or placebo. Secondary endpoints include changes in the duration of dermal pain, blood and plasma histamine levels, serum angiotensin-converting enzyme levels, and histological evaluation of skin tissue samples at the site of dermal pain.The effectiveness of icatibant against sweating-induced dermal pain would provide clear evidence for the involvement of the bradykinin-bradykinin B2 receptor pathway in the pathogenesis of this condition. This finding may contribute to a better understanding of the underlying mechanisms of dermal pain associated with sweating stimuli and has the potential to improve patients’ quality of life by suggesting potential treatment options, specifically, using drugs that inhibit bradykinin or suppress its production. When accompanied by such symptoms, the condition can also be referred to as cholinergic urticaria or acquired idiopathic generalized anhidrosis.,4 Such dermal pain predominantly affects young males in their teens and twenties and manifests immediately upon exposure to sweating stimuli, lasting typically for 5 to 10 minutes at a maximum visual analog scale (VAS) level of 100 mm. Although short lived, the pain is severe and significantly disrupts patients daily lives, resulting in absenteeism or withdrawal from school or work. Consequently, there is a substantial unmet need to understand the underlying mechanisms and develop effective treatments.In a certain population of individuals, the exposure to sweating stimuli such as bathing, exercise, or mental stress, leads to severe dermal pain.,3 However, these treatments fail to fully alleviate pain triggered by such stimuli.,5,6 The use of psychotropic drugs and neuropathic pain medications has also been explored, but their efficacy varies among patients.,5,6 The absence of a suitable animal model for sweating-induced dermal pain complicates the evaluation of therapeutic agents.Despite numerous attempts to treat sweating-induced dermal pain, no standard treatment has been established. Common nonsteroidal anti-inflammatory and analgesic drugs demonstrate little effect. As the condition frequently presents with transient eruptions and/or generalized hypohidrosis, antihistamines and systemic corticosteroids have been tested based on their effectiveness against cholinergic urticaria and acquired idiopathic generalized anhidrosis. support the potential involvement of histamine. However, antihistamines alone do not provide sufficient analgesia. Alternatively, bradykinin may serve as a mediator, inducing dermal pain triggered by sweating stimuli. Kininogen and kallikrein, which are involved in bradykinin production, are reportedly present in sweat glands. Additional study revealed that eccrine sweat gland stimulation by thermal load activated the bradykinin-forming enzyme in the sweat and the formation of bradykinin in the skin. The bradykinin-forming enzyme is shown to be tissue kallikrein, and contribute to generate Lys-bradykinin which acts on bradykinin B2 receptor.,10 Localization of kallikrein is detected in luminal ductal cells and in the peripheral rim of secretory coil segments. The stimulation of bradykinin B2 receptor is reported not to be associated with thermally- and pilocarpine-induced sweating itself; however, human sweat glands respond to bradykinin stimulation to increase cyclic AMP for flexible control of sweat gland function. Although the role of bradykinin-forming activity detected in sweat glands remains unclear, these suggest that increased bradykinin production in the skin during sweating stimulation could contribute to dermal pain.The precise pathomechanisms underlying sweating-induced dermal pain remain elusive. Short duration of the pain following sweating stimuli suggests the involvement of endogenous pain-producing substances with short lifetimes, such as histamine and bradykinin in the pathogenesis of sweating-induced dermal pain. High levels of histamine in sweat and elevated plasma histamine levels after thermal sweating in patients with dermal pain compared to healthy subjectsThis study aims to evaluate the analgesic effect of icatibant, a bradykinin B2 receptor antagonist, on patients experiencing sweating-induced dermal pain and to demonstrate a role of bradykinin in the pathomechanism of dermal pain. Its results are expected to contribute to the development of novel treatments for sweating-induced dermal pain targeting bradykinin and the kallikrein-kinin pathway.This is a multicenter, exploratory, crossover, single-blind, placebo-controlled, and randomized comparative study.Study participants include patients with sweating-induced dermal pain who visit Hiroshima University Hospital directly or are referred to Hiroshima University Hospital by collaborating institutions  to seek new treatment options. After obtaining consent from study participants at Hiroshima University Hospital, eligibility will be confirmed based on the inclusion and exclusion criteria. Upon enrollment, participants will be assigned to 1 of 2 groups (Icatibant-placebo group [Group A] or Placebo-icatibant group [Group B]). Treatment drugs will be administered in a single-blinded crossover manner, and dermal pain induced by thermal load will be evaluated before and after administration. To explore related mediators, blood and plasma histamine levels and plasma angiotensin-converting enzyme (ACE) levels will also be measured before and after thermal load.Male and female subjects aged ≥ 18 years and ≤ 50 years at the time of obtaining consent.Patients with severe dermal pain induced by thermal sweating stimuli , regardless of the presence or absence of cholinergic urticaria and hypohidrosis.Patients who have had symptoms of dermal pain for more than 3 months.Patients with a dermal pain degree ≥ VAS 60 mm in their daily life during the 2 weeks before obtaining consent.Patients who have not changed drugs* that may alleviate symptoms during the 2 weeks before obtaining consent and have no plans to change drugs until the end of this study . The asterisk refers to antihistamines, H2 receptor antagonists, leukotriene receptor antagonists, antipyretic analgesics, narcotics, antipsychotics, and drugs acting on the central and peripheral nervous systems.Patients whose consent for participation in this study can be obtained in writing.Patients with other causes for dermal pain.Patients with atopic dermatitis, Sjögren syndrome, hypothyroidism, Fabry disease, autonomic nervous system disorders, or drug-induced anhidrosis. To exclude these diseases, SS-A antibodies, SS-B antibodies, FT3, FT4, and TSH will be measured, and subjects with abnormal values will be excluded. In addition, α-galactosidase activity will be measured in patients who experience pain in their hands and feet, not related to temperature elevation, and hypohidrosis that appeared before school age. Genetic testing of α-galactosidase may need to be performed in women. Patients with these abnormalities would be excluded from the study.Patients with a history of allergy to icatibant.Patients who are pregnant or breastfeeding.The study procedures and schedule are shown in Figure Icatibant (30 mg) and placebo  will be subcutaneously injected in a defined order in a crossover manner. Dermal pain induced by thermal load will be assessed before and after administration of both drugs. For blinding, study participants wear an eye mask when receiving the drugs. The investigator will ensure that the study participant has properly donned the eye mask before preparing the drugs and giving them to the participants. After the used syringes are discarded, the participant will be allowed to remove the eye mask. The study will be conducted over 3 consecutive days under hospitalization. Scheduled examinations and blood sampling will be performed before and after thermal loading. The examinations include VAS for pain, distribution and duration of dermal pain, VAS for itching, and presence or absence of eruption. If unbearable dermal pain occurs during heating, the thermal load will be discontinued, and examinations and blood sampling will be performed. Icatibant (30 mg) or placebo  will be subcutaneously injected at least 90 minutes after the first thermal load or 30 minutes after the skin symptoms resolved, whichever occurs later. The second thermal load starts 45 ± 15 min after the drug administration, and the second scheduled examinations and blood sampling will be performed before and after the second thermal load.After collecting patients’ background data, both lower legs will be subjected to thermal load by placing them in warm water (~43°C) for 30 minutes to induce dermal pain. or longer.The same procedure as on Day 1 will be followed to administer the drug and conduct the (3rd and 4th) thermal load before and after drug administration. The placebo  will be subcutaneously injected into patients who receive icatibant on Day 1, while icatibant to those who receive placebo on Day 1. A washout period of ≥ 9 h will be allowed between drug administration on Day 1 and 2. The period was established as 5 times the half-life (T1/2 1.7 hours) of icatibantSubjects will be checked for adverse events.The primary endpoint is the change in the VAS score for thermally-induced dermal pain before and after treatment with icatibant or placebo.Changes in the duration of dermal pain induced by thermal load before and after administration of icatibant or placebo.Blood samples will be collected before and after treatment with icatibant or placebo to measure blood and plasma histamine, and serum ACE levels.In patients who consent to a skin biopsy, a skin tissue sample will be obtained to histologically evaluate the pathomechanism of dermal pain. In some patients, a prior skin biopsy may have been performed at the site of dermal pain beforehand in the past clinical practice. If the conditions for obtaining skin samples are consistent with those in this study, the previous specimens would be evaluated to avoid performing another biopsy with patients physical burden.Safety concerns in this study are assumed to be associated with the administration of icatibant and the induction of dermal pain by thermal stimuli. Safety will be assessed by monitoring adverse events, physical findings, and changes in vital signs. If an adverse event is clinically suspected, physicians will conduct a thorough examination and safety evaluation.Target number of patients is 5 patients in the icatibant-placebo group (Group A), and 5 patients in the placebo-icatibant group (Group B). Considering the minimum number of patients to achieve the study objectives and the rarity of sweating-induced dermal pain, total 10 eligible patients will be enrolled and evaluated in this proof-of-concept study.The population to be analyzed is defined as follows.Full analysis set (FAS): The FAS will comprise all study subjects who underwent randomization, excluding the following study subjects: cases that do not meet the eligibility criteria , cases that have never received any study treatment after randomization, and cases with no measurements made after randomization.Per protocol set (PPS): The PPS consisted of the FAS population, excluding the following study subjects: cases with unavailable measurements of the primary endpoint and cases with serious protocol violations .P < .05 (2-tailed). Paired t-tests will be performed to determine the significance of differences.The primary endpoint of the study is the change in the VAS scores for dermal pain induced by thermal load before and after treatment with icatibant or placebo. The FAS will be used as the analysis population to compare the changes in VAS scores between the 2 treatments at a significance of P < .05 between the icatibant and placebo treatment phases. Additionally, changes of blood and plasma histamine levels and serum ACE levels before and after treatment will be analyzed at a significance of P < .05 between both treatment phases. A secondary analysis will be performed using the PPS as the analysis population by the same statistical methods. Skin samples will be collected for the histological evaluation of dermal pain. In some patients, a prior skin biopsy may have been performed at the site of dermal pain in conditions consistent with those in this study. The previous specimens will be evaluated in those cases.The FAS will be the population to be analyzed. A comparison of the change in duration of dermal pain induced by thermal load will be examined at a significance of In the population of study subjects who receive at least 1 study treatment, the number and incidence of adverse events and the number of subjects suffering from adverse events will be investigated in each phase of the icatibant and placebo treatment.The principal investigator will designate monitoring personnel to monitor the study to ensure that the study is being conducted safely and in accordance with both the protocol and the Clinical Research Act, and that data are being collected accurately. The person in charge of monitoring will report the monitoring results to the principal investigator. No audit is applicable to this study.Adverse event is defined as illness, disability, death, or infection suspected to be attributed to conducting the study, including unintended physical signs, clinically significant changes in laboratory data, and worsening of symptoms or complications. In the event of harms, the principal investigator or sub-investigator will take appropriate actions to ensure the safety of study participants, including giving treatments and discontinuing administration of the research drugs to study participants.–3 It is transient but brings severe and heavy impacts on patients lives. The pathomechanism of sweating-induced dermal pain remains unclear, and no standard treatment has been established. Treatments may include antihistamines, steroid pulse therapy, psychotropic drugs, and the Ca2+ channel α2δ ligand, but their effectiveness is limited and varies among patients.Sweating-induced dermal pain is triggered by daily events, such as bathing, exercise, and mental stress. Since predominant kinin-producing activity is detected in the skin during thermal sweating, bradykinin may play a role in pain during sweating stimulation.–10 Icatibant, a bradykinin B2 receptor antagonist, has been approved for the treatment of acute attacks of hereditary angioedema,,16 but been off-label for dermal pain associated with sweating stimuli. Subcutaneous administration of 30 mg icatibant results in a rapid increase in blood icatibant levels (Tmax 0.63 hour) and effectively inhibits bradykinin activity. If a subcutaneous injection of icatibant effectively reduces sweating-induced dermal pain, it would provide clear evidence for the involvement of the bradykinin-bradykinin B2 receptor pathway in this condition.Bradykinin is an endogenous substance that causes pain.This study is a crossover, single-blind, placebo-controlled, randomized comparative study. Due to the rarity of patients with sweating-induced dermal pain, the number of patients capable to be enrolled in the study is limited. Moreover, the subjective nature of pain perception makes it difficult to compare pain levels across patients. To minimize these limitations, a crossover design is employed. Furthermore, to account for the potential placebo effect on dermal pain due to expectations of drug efficacy, the present study is designed as a single-blinded, placebo-controlled, randomized study. that is, 30 mg for an adult. Moreover, the approved dose of icatibant for hereditary angioedema is 30 mg/dose and has no frequent harmful events, except for transient local injection site reactions.,16 In this study, the same dosage of 30 mg used for hereditary angioedema is set for dermal pain. Since icatibant is typically administered as a single dose for hereditary angioedema attacks, the treatment in this study also includes a single administration of icatibant or placebo.The icatibant dose setting is based on its efficacy and safety. A pharmacodynamic analysis estimated the tolerated dosage needed to reduce bradykinin-induced reactions to be 0.4 mg/kg, This condition of loading is enough to induce sweating in healthy subjects, commonly experienced in daily life, and thus, non-excessive in terms of intensity and duration. The VAS score, a widely used pain rating scale, will be employed to measure the intensity of the pain.The primary endpoint is to assess the effectiveness of icatibant in treating sweating-induced dermal pain. Pain will be evaluated using a VAS score by inducing dermal pain with a thermal load before and after icatibant administration. This approach has been chosen due to the importance of evaluating pain in patients with the dermal pain and the subjective nature of pain perception. To induce dermal pain, both lower legs will be placed in warm water (~43°C) for 30 minutes. ACE is an enzyme involved in the kallikrein/kinin system that degrades and inactivates bradykinin. By analyzing the dynamics of these molecules before and after thermal sweating, we will evaluate the relationship between dermal pain occurrence, histamine in circulation, and the kallikrein-kinin system. Additionally, to explore the pathomechanism of dermal pain, we will examine histological changes of the eccrine sweat glands at the site of dermal pain in patients who provide consent for a skin biopsy. Histological analyses focus on pore obstruction, reduction in the number and atrophy of sweat glands, and surrounding inflammatory infiltration.,17–19Blood histamine and ACE levels will be measured as biomarkers. Similar to bradykinin, histamine causes skin pain and may be associated with dermal pain. This indicates that multiple administrations in a day are necessary for its clinical application. However, this is not realistic because icatibant is administered subcutaneously rather than orally and is expensive, thereby posing a high-cost burden for patients. Alternatively, this study may pave the way for novel treatments of dermal pain using kallikrein inhibitors. Kallikrein produces bradykinin by acting on high-molecular-weight kininogens; therefore, kallikrein inhibitors suppress the subsequent bradykinin-mediated responses. Kallikrein inhibitors berotralstat and lanadelumab are an oral formulation and a subcutaneous formulation with a considerably longer duration of effect, respectively.A limitation of this study is that a small number of patients are planned to be enrolled. Since this preliminary study is conducted for proof of concept, only ten patients will participate to explore the effect of blocking kinin-bradykinin pathway to sweating-induced dermal pain. Moreover, the efficacy of icatibant in this study does not necessarily imply that the use of icatibant is a practical treatment for the pain due to its short effective duration of action. According to pharmacodynamic analysis, icatibant exerts its effectiveness for only 5.5 to 6 hours.Overall, this study contributes to a better understanding of the underlying mechanisms of sweating-induced dermal pain and has the potential to improve the quality of life for patients experiencing this debilitating condition by suggesting potential treatment options.The study was approved on December 22, 2020. Participant recruitment will begin on July 8, 2021. The expected date of completion is the end of December 2024. Central ethical approval was obtained from the Hiroshima University Certified Review Board . The protocol and progress have been registered in Japan Registry of Clinical Trials (jRCT), jRCTs061210021 since July 8, 2022. Protocol version is v1.3 as on February, 2022.This study is conducted with the free supply of the research drug (Firazyl® subcutaneous injection 30 mg syringe) from Takeda Pharmaceuticals International AG, a subsidiary of Takeda Pharmaceutical Company Limited. It is supported by Clinical Research Center in Hiroshima. We offer a special thank you also to all the staff involved in this study.Conceptualization: Shunsuke Takahagi, Michihiro Hide.Funding acquisition: Shunsuke Takahagi, Michihiro Hide.Investigation: Shunsuke Takahagi, Yumi Aoyama, Atsushi Fukunaga, Hiroyuki Murota.Methodology: Shunsuke Takahagi, Michihiro Hide, Yumi Aoyama, Atsushi Fukunaga, Hiroyuki Murota.Resources: Shunsuke Takahagi, Michihiro Hide.Supervision: Michihiro Hide.Visualization: Shunsuke Takahagi.Writing – original draft: Shunsuke Takahagi.Writing – review & editing: Michihiro Hide, Yumi Aoyama, Atsushi Fukunaga, Hiroyuki Murota.


The letter to the editor was written in response to “The effect of ultrasound-guided intercostal nerve block on postoperative analgesia in thoracoscopic surgery: a randomized, double-blinded, clinical trial”, which was recently published by Li et al. (J Cardiothorac Surg 18(1):128, 2023). In this article, Li et al. showed that addition of a preoperative intercostal nerve block to the multimodal analgesic strategy significantly reduced the pain scores within 48 h after surgery. However, we noted several issues in this study that were not well addressed. They were no use of a standard opioid-sparing multimodal analgesic strategy recommended in the current Enhanced Recovery After Surgery protocols for thoracic surgery, the lack of clear description for reasonable selection of rescue analgesics, the interpretion of between-group differences in the postoperative pain scores based on only statistical differences rather than clinically meaningful differences, inclusion of patients who were not blinded to study intervention, not reporting cumulative opioid consumption and complications of intercostal nerve block. We believe that clarification of these issues is not only useful for improving design quality of randomized clinical trials which assess postoperative analgesic efficacy of nerve blocks, but also is helpful for the readers who want to use an opioid-sparing multimodal protocol including a nerve block in patients undergoing thoracoscopic surgery. By a randomized, double-blinded, clinical trial of 119 patients undergoing thoracoscopic pulmonary resection, Li et al. [First, this study actually used an opioid-based multimodal analgesic strategy, i.e., patient controlled analgesia (PCA) with intravenous sufentanil. This does not meet the requirements of the standard opioid-sparing multimodal analgesic strategy recommended in the current Enhanced Recovery After Surgery (ERAS) protocols for thoracic surgery, in which other than a nerve or fascial plane block, a serial of non-opioid basic analgesics with different mechanisms, such as paracetamol, nonsteroidal anti-inflammatory drugs or cyclooxygenase-2 specific inhibitors, gabapentin, dexamethasone, are included in order to achieve adequate co-analgesia and decrease opioid consumption. Most important, it is required that application of these non-opioid analgesics should be started before or during operation and regularly repeated after surgery, and opioids should be administered as rescue analgesia only when non-opioid basic analgesics are ineffective or contraindicated . Thus, wSecond, parecoxib sodium was intravenously given for rescue analgesia when postoperative rest pain VAS score in the ward was > 3. Furthermore, the need of rescue analgesia during 48 h postoperatively was significantly decreased in the patients receiving the ICNB compared with control patients. In fact, parecoxib sodium only is a weak basic analgesic. As a main goal of ERAS programs is to minimize opioid use, it may be better to use parecoxib sodium as a rescue analgesic for moderate pain. However, opioids should still be standard rescue analgesics for inadequate postoperative pain control with non-opioid basic analgesic [Third, pain VAS score at each observed point within 48 h postoperatively was statistically significantly lower in the patients receiving the ICNB compared to the control patients. Other than 0 and 4 h postoperatively, however, means of pain VAS scores at other time points postoperatively were 3 or less, indicating that most patients in the two groups only experienced mild postoperative pain, which achieves postoperative pain control goal of ERAS programs for thoracic surgery . Other tFinally, this study showed that duration of chest tube insertion, an outcome variable of the ERAS programs for thoracic surgery , was sig