title stringlengths 1 1.19k | keywords stringlengths 0 668 | concept stringlengths 0 909 | paragraph stringlengths 0 61.8k | PMID stringlengths 10 11 |
|---|---|---|---|---|
Materials and methods | GDM | GDM | This was a non-blinded, randomised controlled trial, that recruited 100 pregnant women diagnosed with GDM between 24 and 28 weeks of gestation at the 1st Department of Obstetrics and Gynaecology, Medical University of Warsaw. After meeting the inclusion criteria patients were randomly allocated to the study group (FGM, | PMC10359198 |
Results | There was no significant difference in mean glycaemia between the groups ( | PMC10359198 | ||
Supplementary Information | The online version contains supplementary material available at 10.1007/s00592-023-02091-2. | PMC10359198 | ||
Keywords | PMC10359198 | |||
Introduction | hyperglycaemia, GDM | GDM, HYPERGLYCAEMIA, GESTATIONAL DIABETES MELLITUS | Gestational diabetes mellitus (GDM) is the most common type of hyperglycaemia in pregnancy, with the incidence rate of 14% varying worldwide [ | PMC10359198 |
Materials and methods | macrosomia, weight gain, GDM | EVENTS, RECRUITMENT, GDM, SECONDARY, NEONATAL HYPOGLYCAEMIA, HYPERGLYCAEMIA | We performed a non-blinded, randomised controlled trial between March 2020 and October 2022, that recruited 100 pregnant women diagnosed with GDM between 24 and 28 weeks of gestation at the 1st Department of Obstetrics and Gynaecology, Medical University of Warsaw. A diagnosis of GDM was based on 2013 World Health Organisation criteria: (1) fasting plasma glucose 92–125 mg/dl (2) 1-h glucose concentration ≥ 180 mg/dl or (3) 2-h glucose concentration 153–199 mg/dl [After meeting the inclusion criteria patients were randomly allocated with a nested qualitative evaluation and 1:1 allocation ratio to the study (Study consisted of five visits, including recruitment and four follow-up visits. At the first visit all study participants were informed about glycaemic control, diet recommendations and physical activity. During the three follow up visits (2 weeks, 4 weeks after the recruitment visit and between 34–36 weeks of gestation) clinical and laboratory results were assessed, including: fasting and 1 h-postprandial glucose concentrations (after breakfast, lunch, and dinner), qualification to insulin therapy and dosage, diet control, physical activity and gestational weight gain. The qualification to insulin therapy was decided in case of hyperglycaemia, defined as fasting glycaemia ≥ 90 mg/dl or 1 h-postprandial glycaemia ≥ 140 mg/dl. At the second and third follow up visits Haemoglobin A1c (HbA1c) concentration and ultrasound estimated fetal weight (EFW) were measured. For the assessment of fetal birthweight percentile INTERGROWTH-21st Chart was implemented. At the last follow up visit (Visit 5; postpartum) patients were reviewed for perinatal outcomes: weeks of gestation and route of birth, newborn weight and neonatal hypoglycaemic events.As part of our study we analysed physical activity by daily footsteps measure with step counter app. After calculating daily steps, we divided participants into 4 groups–sedentary: < 5000; low active: 5000–7500; somewhat active: 7500–10,000 or active: > 10,000 steps.We also evaluated patient’s dietary habits and its modifications throughout pregnancy by using Eating Assessment Test (EAT) prepared by the Polish National Institute of Public Health–National Institute of Hygiene (Supplementary File 1). EAT contained a short questionnaire, with 20 items for diet assessment. Based on EAT, participants were assigned to one of four diet groups: good: 39–42; satisfactory: 30–38; demanding diet modification: 12–29 and not satisfactory: < 12 points.The primary outcome of the study was mean fasting and 1 h postprandial glycaemia during the first 28 days following GDM diagnosis. Additionally, we analysed variability pattern of glucose concentration inside the groups by using delta mean fasting and postprandial glucose concentration for each group, defined as difference between 3rd to 4th week mean glycaemia and 1st to 2nd week mean glycaemia. The secondary outcomes were maternal and neonatal outcomes, including: qualification to insulin therapy, insulin dosage, hypoglycaemic episodes (defined as glycaemia < 70 mg/dl), HbA1c concentration, pregnancy weight gain, physical activity and diet modifications, fetal birthweight and percentile, incidence of fetal macrosomia and neonatal hypoglycaemia.The detailed study protocol was already published in 2020 [ | PMC10359198 |
Sample size calculation | We performed a two-sided power analysis (power of 80%, significance level of 5%) and estimated a sample size of 80 patients (40 patients for each group). The sample size was further increased to 100 patients based on estimated drop-out rate of 10% participants. For the estimation, we used results of a previous study comparing target glycaemic range between FGM and SMBG [ | PMC10359198 | ||
Statistical analysis | REGRESSION | The statistical analysis was carried out using STATA, version 17.0 (Stata Corporation, TX, USA) and GraphPad Prism v9 (GraphPad Software, CA, USA). Continuous variables were presented as means ± standard deviation (SD) or medians ± interquartile range (IQR) and categorical variables were presented as frequencies (%) by treatment group. Normal distribution of continuous variables was assessed using the Shapiro–Wilk’s test. For the analysis of continuous variables either Mann–Whitney U test or t-test were used and for categorical variables Fisher exact test was applied. For the correlation analysis, we used Pearson correlation coefficient. To estimate correlation between method of glycaemic control and perinatal outcomes we performed binary logistic regression and presented results as odds ratio (OR) and 95% confidence interval (95% CI). We performed linear regression to analyse relationship between glucose concentration and continuous perinatal outcomes. All statistical tests applied were two-sided. A | PMC10359198 | |
Results | PLACENTA PRAEVIA, RECRUITMENT | Between March 2020 and October 2022, we recruited 100 patients that met the inclusion criteria. 50 patients were recruited to the study group, out of which 49 completed the study (one patient was excluded after recruitment process at the first follow up visit due to diagnosis of placenta praevia). 50 patients were allocated to the control group, with 50 women included in the statistical analysis. Maternal baseline characteristics did not differ significantly between the groups (Table Maternal baseline demographic and clinical characteristics24.65(21.65–27.24)22.95(20.80–26.03)Weeks of gestation at the recruitment visit (weeks),median (IQR)*BMI- Body mass index; **OGTT–Oral glucose tolerance test; *** not significant | PMC10359198 | |
Primary outcome | GDM | GDM, GESTATIONAL DIABETES MELLITUS | There was no significant difference in mean (SD) fasting glucose concentration during the first 4 weeks following GDM diagnosis between the groups (Glycaemic control in the first 4 weeks following inclusion to the studyDelta mean glucose concentrations were significantly reduced in the study group in comparison to the control group, with lower delta fasting (−0.69 mg/dl (7.89) vs. 2.52 mg/dl (3.53; Mean difference in glycaemia between 14–28 and 1–13 days following GDM diagnosis On the left: Mean difference in fasting glycaemia between 14–28 and 1–13 days following GDM diagnosis. On the right: Mean difference in postprandial glycaemia between 14–28 and 1–13 days following GDM diagnosis. Abbreviations: GDM: gestational diabetes mellitus. SMBG: self-monitoring of blood glucose. FGM: flash glucose monitoring | PMC10359198 |
Secondary outcomes | macrosomia, weight gain | EVENT, RECRUITMENT, NEONATAL HYPOGLYCAEMIA, REGRESSION, EVENTS, APPENDIX | FGM enabled to reveal all nocturnal hypoglycaemic events during the first month of the study in the study group (mean incidence of 15 events/month). In 6 out of 49 patients (12.24%) we recorded one episode of hypoglycaemic event level 2 (glucose concentration less than 54 mg/dl). We were not able to compare it with the control group, as participants from the control group measured glucose concentration only once between 2:00 and 4:00 at night. Therefore, in the control group the mean incidence of nocturnal hypoglycaemic events was 2 events per month, but the result was not comparable with the FGM group.We analysed HbA1c concentration at the 1st, 3rd and 4th visit and found no significant difference between the groups (Supplementary Appendix 1). Delta HbA1c concentration, defined as difference between HbA1c measured between 34–36 weeks of gestation and HbA1c measured at the recruitment visit also did not differ significantly between the groups (ΔHbA1c for SMBG group was 0.1% (−0.1–0.2) and for FGM group 0.05% (−0.2–0.2), We found no significant difference in incidence of caesarean section (OR 0.84, 95% CI 038–1.87) and weeks of gestation at birth between the groups (Logistic regression did not reveal strong association between mean glycaemia during the first month and incidence of neonatal hypoglycaemia, with OR 0.96 (95% CI 0.88–1.05) for fasting mean glycaemia and OR 0.99 (95% CI 0.91–1.08) for postprandial mean glycaemia, respectively. However, postprandial glucose concentration was correlated with the incidence of fetal macrosomia (ROC AUC 0.704, 95% CI 0.546–0.862) (Fig. Relationship between glycaemia during the first month of the study and birthweight We used Pearson’s correlation to analyse, whether mean glucose concentration during the first month of the study was correlated with birthweight, but we found no strong relationship between either fasting mean glycaemia (Gestational weight gain, defined as difference between weight at the 3rd follow up visit and weight at the recruitment visit, did not differ significantly between the groups (The study group more frequently modified their diet habits, when compared to the control group. Median (IQR) EAT score did not differ at the recruitment visit (34 points (28–36) for FGM compared to 33 points (28–35) for SMBG, | PMC10359198 |
Discussion | pre-gestational diabetes, macrosomia, diabetes, GDM, weight gain, hypoglycaemia | GESTATIONAL DIABETES MELLITUS, RECRUITMENT, GDM, DIABETES, NEONATAL HYPOGLYCAEMIA, EVENTS, HYPOGLYCAEMIA | Our study revealed, that FGM might improve glycaemic control, when compared to SMBG. Although mean glycaemia did not differ significantly between the groups, and when separately analysed, postprandial glycaemia was significantly lower in the control group, glycaemia through the first month of the study improved more significantly in the study group (delta mean glucose concentration showed a pattern of decreasing changes in glycaemia in FGM group). As in previous studies on pre-gestational diabetes population, we found that FGM system led to strict glycaemic control, that consequently decreased mean fasting and postprandial glycaemias at follow up visits.FLAMINGO revealed, that FGM had an impact on decreasing incidence of fetal macrosomia (birthweight > 4000 g) in GDM patients. It is consistent with the randomised controlled trial (RCT) by Murphy et al., evaluating effectiveness of CGM in pregnant women with type 1 and 2 diabetes [The CONCEPTT trial provided evidence that CGM led to clinically significant reduction in neonatal hypoglycaemia and NICU (neonatal intensive care unit) admission incidence [We found higher detection rate of hypoglycaemia in FGM group; however, these hypoglycaemic events were in most cases qualified as mild and none of them were symptomatic. As presented in previous studies continuous glucose monitoring detects masked hypoglycaemic events in pregnancy, that if qualified as mild, are clinically non-significant[Interestingly, we found, that the study group was more prone to modify their diet habits, compared to the control group; however, it had no impact on gestational weight gain and qualification to insulin therapy. Our data differ from the previous studies, in which these outcomes were improved, when CGM systems were used [Our study has several strengths. To our knowledge, this is the first study with such a long assessment of glycaemia with FGM system in gestational diabetes mellitus. The data were derived from a randomised controlled trial, that diminishes the risk of bias that might be the consequence of the recruitment process. Furthermore, the baseline characteristics of the participants did not differ significantly between the groups and therefore adjustments had no significant impact on the analysed outcomes. All the additional results, including diet modifications, physical activity, were assessed using standardised tools. For the control group, we used one type of glucose meters to diminish the influence of different types of devices on primary outcome [We also acknowledge some limitations. In FLAMINGO trial, the analysed time-period of glycaemic control was only 4 weeks, and therefore did not include glycaemic fluctuations occurring after the first month from GDM diagnosis till birth. Additionally, the EAT questionnaire was filled in by the patients and the diet scheme was not unified for all participants, that might produce the risk of bias. | PMC10359198 |
Conclusions | macrosomia, weight gain, GDM | GDM, NEONATAL HYPOGLYCAEMIA | In summary, FGM application resulted in significantly better improvement in glycaemic control in the 3rd and 4th week of the study. FGM led to higher EAT score, that might indicate better diet modifications after GDM diagnosis; however, it had no impact on lifestyle interventions including gestational weight gain, qualification to insulin therapy or dosage of insulin. FGM significantly decreased incidence of fetal macrosomia, but had no significant impact on birthweight percentile or neonatal hypoglycaemia incidence. Therefore, further studies are needed to analyse the impact of FGM on improving perinatal outcomes in GDM-complicated pregnancies.
| PMC10359198 |
Acknowledgements | RECRUITMENT | Thank you to our colleagues from the 1st Department of Obstetrics and Gynaecology, Medical University of Warsaw for helping us in the recruitment process. | PMC10359198 | |
Authors’ contributions | PJS | AM, PJS, BW and DBO conceived and planned the study. AM, PJS, JT, IR, MW and DBO recruited the participants to the study. AM, PJS, JT and DBO conducted the study and collected essential data. AM analysed data. AM, PJS and DBO drafted the manuscript. PJS and DBO revised the manuscript. All authors have contributed to refinement of the study protocol and have approved the final manuscript. | PMC10359198 | |
Funding | This study did not receive any funding from the public or commercial sector. | PMC10359198 | ||
Declarations | PMC10359198 | |||
Conflict of interest | The authors declare that they have no conflict of interest. | PMC10359198 | ||
References | PMC10359198 | |||
1. Introduction | obesity, metabolic syndrome, Obesity, TG | OBESITY, OBESITY, CARDIOVASCULAR DISEASES, INSULIN RESISTANCE, METABOLIC SYNDROME, TYPE 2 DIABETES, DISEASES | The aim of this study was to investigate the effects of 12 weeks of high-intensity training with astaxanthin supplementation on adipokine levels, insulin resistance and lipid profiles in males with obesity. Sixty-eight males with obesity were randomly stratified into four groups of seventeen subjects each: control group (CG), supplement group (SG), training group (TG), and training plus supplement group (TSG). Participants underwent 12 weeks of treatment with astaxanthin or placebo (20 mg/d capsule daily). The training protocol consisted of 36 sessions of high-intensity functional training (HIFT), 60 min/sessions, and three sessions/week. Metabolic profiles, body composition, anthropometrical measurements, cardio-respiratory indices and adipokine [Cq1/TNF-related protein 9 and 2 (CTRP9 and CTRP2) levels, and growth differentiation factors 8 and 15 (GDF8 and GDF15)] were measured. There were significant differences for all indicators between the groups (Obesity promotes co-morbid diseases such as cardiovascular diseases, type 2 diabetes, and metabolic syndrome [ | PMC9866205 |
2. Materials and Methods | After calling in public places such as gyms, medical clinics, hospitals and social networks, there were 101 participants who initially volunteered for the study, of whom 33 were ineligible, leaving 68 participants in the study (mean age: 27.6 ± 8.4 yrs; mean height: 167.8 ± 3.1 cm; mean weight: 94.7± 2.0 kg; mean BMI: 33.6 ± 1.4 kg/m | PMC9866205 | ||
2.1. Experimental Design | One week prior to the start of the training programs, the study procedures were explained and a familiarization session was completed by all participants. Height, weight, and body composition were assessed for all the participants, who were then randomly assigned into one of four equal groups ( | PMC9866205 | ||
2.2. Body Composition and Cardio-Respiratory Fitness Assessments | Body weights and heights were measured using a calibrated scale (Seca GmbH & Co., Hamburg, Germany) and stadiometer (Seca GmbH & Co., Hamburg, Germany), respectively. Then, the body mass index (BMI, kg/m | PMC9866205 | ||
2.3. Training Protocols | In the current study, a total of 36 sessions lasting up to 60 min each were included in the HIFT program using CrossFit. Crossfit training is stratified as high-intensity functional training with a mixed model of concurrent strength and endurance performance often containing various fitness components [ | PMC9866205 | ||
2.4. Supplementation of Astaxanthin and Placebo | Eligible participants in the SG and TSG received 20 mg/day of astaxanthin capsule (Marine Product Tech. Inc., Seongnam, Republic of Korea) or matching placebo capsule (20 mg/day of raw corn starch) once daily with breakfast for 12 weeks. Participants were considered adherent when ≥80% of their prescribed supplements were consumed. | PMC9866205 | ||
2.5. Nutrient Intake and Dietary Analysis | Before and after the experiment changes in habitual dietary intake over time were determined using three-day food records (two weekdays and one weekend day) [ | PMC9866205 | ||
2.6. Assessment of Blood Markers | MDD, TG | BLOOD, SENSITIVITY | Fasting blood samples were taken under standard conditions between 8 and 10 am from the right arm 12 h before the first exercise session and 72 h after the last session. Blood samples were transferred to EDTA-containing tubes, centrifuged for 10 min at 3000 rpm, and stored at −70 °C for later use for the following measurements:Plasma CTRP-9 was measured with an ELISA kit (Aviscera Bioscience, Santa Clara, CA, USA). Catalogue No: SK00081-02. Sensitivity: 1 ng/mL. Intra-coefficients of variation (CV) = 4%, inter-CV = 8%.CTRP-2 was measured using ELISA kits obtained from MyBioSource (San Diego, CA, USA) with a minimum detectable dose (MDD) of 0.039 ng/mL and detection range of 0.156–10 ng/mL (intra-assay CV: <8% and inter-assay < 10%).GDF-15 was measured using ELISA kits obtained from Thermo Scientific (Frederick, MD, USA) with a sensitivity of 2 pg/mL and detection range of 1.10–800 pg/mL (intra-assay CV < 10% and inter-assay CV < 12%).Plasma GDF8 was measured with an ELISA kit (R&D Systems, Minneapolis, MN, USA) Catalogue No: DGDF80. The sensitivity was 5.32 pg/mL. Intra-CV = 5.4%, inter-CV = 6%.Plasma total cholesterol (TC) and triglyceride (TG) were measured by enzymatic methods (CHOD-PAP). High-density cholesterol (HDL-C) and low-density cholesterol (LDL-C) were determined using a photometric method (Pars Testee’s Quantitative Detection kit, Tehran, Iran) with a coefficient and sensitivity of 1.8% and 1 mg/dL and 1.2% and 1 mg/dL, respectively.Insulin levels were measured with an ELISA kit (Demeditec, Kiel, Germany) with a sensitivity of 1 ng/mL and between and within CV of 5.1% and 8.4%, respectively. Glucose levels were measured with a colorimetric enzymatic kit (Paracetamol Glucose, Colorimetric Enzymatic kit, Parsazmun, Tehran, Iran) with a sensitivity of 5 mmol/L. HOMA-insulin resistance (HOMA-IR) was calculated from the ratio of insulin to glucose and the HOMA-IR index [HOMA-IR = fasting insulin (mU/L) × glucose (mmol/L)/22.5] [ | PMC9866205 |
2.7. Statistical Analysis | Descriptive statistics (means ± standard deviation) were used to summarize all data. The normality of the data was assessed by the Shapiro–Wilk test. A two-way ANOVA repeated measures test was used to determine group X time interactions. One-way ANOVA and Fisher LSD post-hoc tests were used for evaluation of baseline data for the four groups. When a significant difference was detected by ANOVA, mean differences were determined by pairwise comparisons. The sample size needed to detect a statistical difference between study variables with a 95% confidence interval (CI) and equal to or greater than 80% of the power value was calculated. Effect sizes (ES) were reported as partial eta-squared, where ES were considered trivial (<0.2), small (0.2–0.6), moderate (0.6–1.2), large (1.2–2.0) and very large (2.0–4.0). A | PMC9866205 | ||
3. Results | PMC9866205 | |||
3.1. Anthropometric Characteristics and Cardio-Respiratory Parameters | There were no between-group differences in baseline values for weight (Changes in BMI after 12 weeks were significantly decreased in the SG ( | PMC9866205 | ||
3.2. Lipid Profiles | There were no significant differences in the baseline levels of HDL ( | PMC9866205 | ||
3.3. Metabolic Factors | There were no significant differences in baseline levels of glucose ( | PMC9866205 | ||
3.4. Adipokines and Growth Differentiation Factors | TG | There were no significant differences in baseline levels of CTRP9 (A comparison of pre-test and post-test values indicated no differences in CTRP9 (The analysis of between-group differences for CTRP9 indicated a significance in TG (The decreases of CTRP2 in the SG (GDF8 decreased significantly in the SG (GDF15 significantly decreased in the TG ( | PMC9866205 | |
4. Discussion | obesity, obese, overweight | OBESITY, OBESE, INSULIN RESISTANCE | We examined the effects of 12 weeks of HIFT that was supplemented with astaxanthin on adipokine levels, insulin resistance and lipid profiles in males with obesity. Our findings indicate that 12 weeks of CrossFit exercise training supplemented with astaxanthin: (A) reduced anthropometric indices (body weight, BMI, FFM, body fat percent), (B) improved cardio-respiratory fitness (measured by VOThe release of GDF8 is increased in overweight and obese individuals, suggesting a role for GDF8 in the regulation of body fat and total energy metabolism [ | PMC9866205 |
5. Conclusions | obesity | OBESITY | Our findings indicate that 12 weeks of astaxanthin supplementation and exercise training decreased adipokines levels, body composition (weight, %fat), anthropometrical factors (BMI), and improved lipid and metabolic profiles. These benefits were greater in men with obesity who exercised and used astaxanthin supplementation. | PMC9866205 |
Author Contributions | All authors contributed equally to data collection. They read and approved the final manuscript. Finally, all authors agreed to be accountable for all aspects of the work. All authors have read and agreed to the published version of the manuscript. | PMC9866205 | ||
Institutional Review Board Statement | All procedures were performed according to the latest revision of the Declaration of Helsinki. The Research and Ethics Committee of the Islamic Azad University approved all procedures of this study (Ethics code: IR-IAU1400-47, 8 July 2021). | PMC9866205 | ||
Informed Consent Statement | Informed consent was obtained from all subjects involved in the study. | PMC9866205 | ||
Data Availability Statement | The data presented in this study are available within the manuscript. | PMC9866205 | ||
Conflicts of Interest | The authors declare no conflict of interest. | PMC9866205 | ||
References | TG | INSULIN RESISTANCE | Pre- and post-training values (mean ± SD) for CTRP9 in the control (CG), supplement (SG), training (TG), training + supplement (TSG) groups. Pre- and post-training values (mean ± SD) for CTRP2 in the control (CG), supplement (SG), training (TG), training + supplement (TSG) groups. Pre- and post-training values (mean ± SD) for GDF8 in the control (CG), supplement (SG), training (TG), training + supplement (TSG) groups. Pre- and post-training values (mean ± SD) for GDF15 in the control (CG), supplement (SG), training (TG), training + supplement (TSG) groups. Nutritional intakes in the four study groups.Data are mean (±SD) values of CG: Control group; SG: Supplement group; TG: Training group; TSG: Training supplement group; CHO: Carbohydrates.Mean (±SD) values of glucose, insulin, lipid profile, body composition, and VOCG: Control group; SG: Supplement group; TG: training group; TSG: training+ Supplement group BMI: Body Mass Index; FFM: Fat-Free Mass; HDL: High-density lipoprotein; LDL: Low-density lipoprotein; TC: Total cholesterol; TG: Triglyceride; HOMA-IR: Homeostatic Model Assessment of Insulin Resistance. | PMC9866205 |
Abstract | PMC10583133 | |||
Objective | To assess the clinical effectiveness of septoplasty. | PMC10583133 | ||
Design | Multicentre, randomised controlled trial. | PMC10583133 | ||
Setting | 17 otolaryngology clinics in the UK’s National Health Service. | PMC10583133 | ||
Participants | Nasal Obstruction, nasal obstruction | 378 adults (≥18 years, 67% men) newly referred with symptoms of nasal obstruction associated with septal deviation and at least moderate symptoms of nasal obstruction (score >30 on the Nasal Obstruction and Symptom Evaluation (NOSE) scale). | PMC10583133 | |
Interventions | Participants were randomised 1:1 to receive either septoplasty (n=188) or defined medical management (n=190, nasal steroid and saline spray for six months), stratified by baseline symptom severity and sex. | PMC10583133 | ||
Main outcome measures | nasal airflow | The primary outcome measure was patient reported score on the Sino-Nasal Outcome Test-22 (SNOT-22) at six months, with 9 points defined as the minimal clinically important difference. Secondary outcomes included quality of life and objective nasal airflow measures. | PMC10583133 | |
Results | bleeding, infections, nasal airflow | BLEEDING, INFECTIONS | Mean SNOT-22 scores at six months were 19.9 (95% confidence interval 17.0 to 22.7) in the septoplasty arm (n=152, intention-to-treat population) and 39.5 (36.1 to 42.9) in the medical management arm (n=155); an estimated 20.0 points lower (better) for participants randomised to receive septoplasty (95% confidence interval 16.4 to 23.6, P<0.001, adjusted for baseline continuous SNOT-22 score and the stratification variables sex and baseline NOSE severity categories). Greater improvement in SNOT-22 scores was predicted by higher baseline symptom severity scores. Quality of life outcomes and nasal airflow measures (including peak nasal inspiratory flow and absolute inhalational nasal partitioning ratio) improved more in participants in the septoplasty group. Readmission to hospital with bleeding after septoplasty occurred in seven participants (4% of 174 who had septoplasty), and a further 20 participants (12%) required antibiotics for infections. | PMC10583133 |
Conclusions | nasal obstruction | Septoplasty is a more effective intervention than a defined medical management regimen with a nasal steroid and saline spray in adults with nasal obstruction associated with a deviated nasal septum. | PMC10583133 | |
Trial registration | ISRCTN Registry ISRCTN16168569. | PMC10583133 | ||
Introduction | nasal airflow, nasal obstruction | Septoplasty is a common operation to alleviate nasal obstruction associated with deviation of the nasal septum. It may be accompanied by reduction of the inferior turbinate to increase airflow through the nasal cavities. Surgery is typically predicated on clinical history and a visual assessment of the nasal septum. To date, no objective nasal airflow measures have proven definitively beneficial in the selection of patients. Despite the lack of an evidence base, in 2019/20 about 16 700 septoplasty procedures were performed in EnglandMany UK clinical commissioning guidelines propose a trial of medical treatment before surgical referral.The Nasal Airways Obstruction Study (NAIROS) was designed to provide definitive evidence and recommendations for the clinical effectiveness of septoplasty, to inform guidance on which patients may benefit from this treatment, and to standardise treatment across the UK. | PMC10583133 | |
Methods | The Nasal Airways Obstruction Study was a multicentre, non-adaptive, open label randomised controlled trial conducted in 17 hospitals in the UK’s NHS. The regional ethics committee approved the trial protocol. | PMC10583133 | ||
Participants | Nasal Obstruction, nasal obstruction | Participants were adults (≥18 years) newly referred to otolaryngology clinics with symptoms of nasal obstruction associated with septal deviation and confirmed by endoscopic assessment. Participants were offered entry into the trial if their presenting Nasal Obstruction and Symptom Evaluation (NOSE) | PMC10583133 | |
Randomisation | The Newcastle Clinical Trials Unit Randomisation Service, an in-house bespoke internet based system, performed randomisation centrally using permuted random blocks of variable length. All allocations were generated by an automated process within the system. Participants were randomised 1:1 to receive either surgical intervention or medical management, stratified by sex and baseline severity of symptoms according to scores on the NOSE scale: 30-50 (moderate), 55-75 (severe), 80-100 (extreme). | PMC10583133 | ||
Interventions | PMC10583133 | |||
Outcome measures | PMC10583133 | |||
Primary outcome measure | CHRONIC RHINOSINUSITIS | The primary outcome measure was the score on the Sino-Nasal Outcome Test (SNOT-22) at six months (defined protocol time window −2 to 4 weeks for completion). SNOT-22 is a patient reported outcome measure that has been validated to assess symptoms related to chronic rhinosinusitis | PMC10583133 | |
Secondary outcome measures | ear/facial pain | SECONDARY | Four secondary patient reported outcome measures were assessed:• SNOT-22 score at 12 months.• SNOT-22 subscale (nose, sleep, ear/facial pain, psychological) score at baseline, six months, and 12 months.• Score on the NOSE scale at baseline, six months, and 12 months.• General quality of life, measured at baseline, six months, and 12 months using the physical component scores and mental component scores of the 36 item Short Form survey (SF-36), which assesses recall over the preceding week, with higher scores indicating better quality of life.Secondary clinical measures at baseline, six months, and 12 months were:• The double ordinal airway subjective scale, which is a subjective comparator of right and left nasal patency,• Objective assessments of nasal patency after decongestant use, including peak nasal inspiratory flow, measured using a peak nasal inspiratory flow meter (GM Instruments, Kilwinning, UK).• An imbedded economic evaluation is to be reported separately in a future publication. | PMC10583133 |
Statistical analysis | inferior turbinate reduction, airway blockage, enlargement of the inferior turbinate | REGRESSION, SECONDARY, RECRUITMENT | Analyses were performed according to a predetermined analysis plan.The planned population defining analyses included an ITT analysis, a per protocol analysis, and a per treatment analysis.
We explored the impact of the recruitment site on the primary outcome analysis by inserting the centre as a random effect with the mixed effect model.Analyses of the secondary outcome measures followed the same primary multiple linear regression modelling. Although inferior turbinate reduction was not a randomised intervention, its effect on the primary outcome was explored as a planned covariate in the linear regression model.Further planned multivariable linear regression sensitivity of the ITT analyses considered adjustment for other important baseline factors in the regression model. To utilise the full information from the continuous measure, model 2 adjusted for continuous baseline score on the NOSE scale rather than the three categories used at baseline. Model 3 included age, ethnicity, recruitment site (as a random effect), smoking history, double ordinal airway subjective scale, endoscopy findings (location of deviation, severity of airway blockage, and enlargement of the inferior turbinate), and four nasal patency variables. These variables were initially regressed univariately against the primary outcome measure to screen for independent relatedness. Any variable with P>0.1 was included for consideration in further modelling based on forward selection. Non-linear continuous covariates were considered for fractional polynomial transformations, if appropriate.The importance of baseline severity within the ITT population, as a continuous distribution of score on the NOSE scale at randomisation, was further explored graphically using a subpopulation treatment effect pattern plot (STEPP) analysis.All data were analysed using STATA, version 16. | PMC10583133 |
Missing data | SNOT-22 questionnaires with up to 20% of items missing were imputed with the average of the completed questions used for missing items. A sensitivity analysis using multiple imputation was also carried out that included all participants who provided consent and were randomised, including those with missing SNOT-22 scores at the primary endpoint. Baseline variables found to be predictive of missing data status were included in multiple imputation equations. To make the missing at random assumption as plausible as possible, the multiple imputation equation included baseline data on sex, NOSE scale categories, baseline SNOT-22 score, and predictors of missing data. Overall, 1000 multiple imputation datasets were created in STATA16 using chained equations. A conservative approach was adopted, and treatment group was included in the imputation model. | PMC10583133 | ||
Sample size calculation | The sample of 378 participants was based on 90% power to detect a minimal clinically important difference of 9 points on SNOT-22, | PMC10583133 | ||
Patient and public involvement | Patient and public involvement was integrated throughout the design and conduct of the trial. More than 20 patients were consulted about the primary outcome measure, with most favouring the items covered by SNOT-22 over NOSE scale questionnaire. Patients’ views were integrated into the design to encourage any crossover to septoplasty to occur after six months. All patient facing documents were reviewed for acceptability. | PMC10583133 | ||
Results | Nasal Obstruction | ADVERSE EVENTS, SECONDARY, RECRUITMENT | Between 26 January 2018 and 5 December 2019, 378 eligible participants (67% men) were randomised. Baseline personal characteristics were balanced across treatment groups (Baseline characteristics of recruited participants. Values are number (percentage) unless stated otherwiseIQR=interquartile range; NOSE Nasal Obstruction and Symptom Evaluation scale; SD=standard deviation.The onset of the covid-19 pandemic resulted in the suspension of all face-to-face clinics from 30 March 2020, therefore remaining trial participants were invited to complete the primary outcome six month SNOT-22 measure (n=8, 2%) and the secondary outcome 12 month SNOT-22 measure (n=25, 7%) remotely. By then recruitment had been achieved and all trial interventions had been completed. Information on adverse events was collected remotely by telephone at the six month and 12 month follow-ups. Only 66 participants in the septoplasty group and 72 in the medical management group completed the 12 month objective flow measures.Four SNOT-22 questionnaires had missing items at baseline—two in each treatment group (1%), five at the primary six month endpoint (2%) and four at the final 12 month data collection point (1%). All of these were imputed as each had <20% missing. One participant had one item missing from the NOSE scale questionnaire (20%) at the six month follow-up. This was also imputed, using the mean of the other four responses. | PMC10583133 |
Treatment received | Of the 378 participants randomised, 188 were assigned to receive septoplasty and 190 were assigned to receive medical management (Flow of participants through study | PMC10583133 | ||
Primary outcome analysis | Nasal Obstruction | Patient reported symptoms improved in both groups. In those participants randomised to receive septoplasty in the ITT population (n=152), mean SNOT-22 scores were 44.5 (95% confidence interval 41.1 to 47.8) at baseline and 19.9 (17.0 to 22.7) at six months. The corresponding scores for those participants randomised to receive medical management in the ITT population (n=155) were 44.1 (40.8 to 47.4) and 39.5 (36.1 to 42.9). Baseline SNOT-22 scores were approximately symmetrically distributed about the mean and were not transformed for the analysis (see supplementary material figures S2 and S3). In the primary ITT analysis, participants randomised to the septoplasty group reported on average 20.0 units greater improvement in symptoms compared with those randomised to the medical management group, as measured by SNOT-22 (95% confidence interval improvement 16.4 to 23.6, P<0.001; Patient reported SNOT-22 score at six months (primary outcome) adjusted for baseline SNOT-22 score and stratification variables sex and NOSE categories in 307 participants in intention-to-treat populationNOSE=Nasal Obstruction and Symptom Evaluation scale; SNOT-22=Sino-Nasal Outcome Test-22.Adjusted RThe planned population defining analyses all showed similar results and supported the primary ITT analysis (Forest plot of primary analysis and sensitivity analysis for intention-to-treat population. CI=confidence interval | PMC10583133 | |
Secondary outcomes | inferior turbinate reduction, Nasal Obstruction | SECONDARY | The improvement in SNOT-22 scores in the septoplasty group remained at 12 months but was less noticeable compared with those in the medical management group (Box plots showing summary statistics for SNOT-22 scores in intention-to-treat groups. Box represents middle 50% of data (lower quartile to upper quartile), horizontal line in box shows median (50th centile), whiskers show data that fall within 1.5× interquartile range, and points show data that fall outside these limits. SNOT-22=Sino-Nasal Outcome Test-22Supplementary table S3 shows that the secondary outcomes measured at six months improved more in the septoplasty group than in the medical management group, including the objective flow measures. A noticeable improvement in SNOT-22 scores was observed between six and 12 months for 29 of the 37 participants randomised to receive medical management and who chose to undergo septoplasty after six months, restricted to those who provided 12 months’ data. The SNOT-22 scores for these 37 participants had not improved between baseline and six months (see supplementary figure S5). The analysis between the groups in the 12 month objective assessments was affected by lack of face-to-face assessments during the covid-19 pandemic.For the ITT population (n=307) mean scores on the SF-36 physical component summary and mental component summary at six months were 2.74 (95% confidence interval 1.23 to 4.25) and 4.39 (2.43 to 6.36) units higher, respectively (better health), in the septoplasty group than in the medical management group (adjusted for baseline severity and stratification variables, P<0.001; see supplementary tables S5-S8 for full details).The STEPP analysis shows that for the 18 participants with moderate NOSE scores at baseline the average improvement in SNOT-22 score was around 5 units compared with medical management (Outcome data using subpopulation treatment effect pattern plot to assess individual changes in SNOT-22 scores from baseline to six months. Purple line shows average effect of being randomised to septoplasty for those with specific NOSE scores at baseline and shading represents 95% confidence intervals. Minimal clinically important difference is 9 points on SNOT-22. NOSE=Nasal Obstruction and Symptom Evaluation; SNOT-22=Sino-Nasal Outcome Test-22For the 148 participants who underwent septoplasty and had SNOT-22 scores at both baseline and six months, there was no difference in primary outcome scores between those chosen to receive inferior turbinate reduction and those chosen not to receive inferior turbinate reduction: 2.8 points difference (95% confidence interval −2.78 to 8.35 points difference; P=0.33).No other clinically relevant factors showed a statistically significant association with the primary outcome of patient reported SNOT-22 score at six months (see supplementary tables S1 and S2). The primary outcome SNOT-22 scores were not altered appreciably by the reported adherence rates in participants treated with medical management (see supplementary figure S6). | PMC10583133 |
Safety | ADVERSE EVENTS |
Reported serious adverse events and adverse events among all participants | PMC10583133 | |
Discussion | ear/facial pain, nasal obstruction, nasal airflow, nasal or sinus disease, inferior turbinate reduction | SECONDARY | Septoplasty results in significantly greater improvement in patient reported SNOT-22 scores at six months compared with a regimen of nasal steroid and saline sprays, and this improvement is sustained to 12 months. We therefore recommend that adults presenting with nasal obstruction associated with a deviated nasal septum, in the absence of coexistent nasal or sinus disease and with a baseline NOSE score >30, can reliably be offered surgery. The per protocol and per treatment analyses corroborated the ITT results, confirming the greater improvement in patient reported outcomes of those participants who received surgery compared with those treated medically.The STEPP analysis provided evidence of the increasing improvement in SNOT-22 scores as baseline NOSE score severity increased. This effect was observed in both male and female participants. This analysis can enable clinicians to quantify expected improvements in outcomes of patients considering septoplasty, predicated on baseline NOSE score. The STEPP analysis, in parallel with an understanding of the potential risks associated with both medical treatment and surgery, substantially improved the quality of information available to the clinician and patient in the decision making process around septoplasty.In 2014 when the National Institute for Health and Care Research commissioned this trial, no high level evidence existed for surgery compared with medical management for nasal obstruction associated with septal deviation. No specific guidance was available as to who should be referred for consideration of surgery, or the likely outcomes. The intervention was practice based, not evidence based. To our knowledge, in 2019 van Egmond et al reported the first randomised clinical trial assessing septoplasty.We estimated a superiority for septoplasty of 20 points on SNOT-22 at six months compared with 9.7 points at 12 months in the study by van Egmond et al. Their data transformation and variable non-surgical arm treatments make direct comparison with the current study difficult. The two clinical trials report concordant results in showing that septoplasty is clinically effective. The current study substantially enhances understanding of the role of quantitative patient reported data in the selection of patients for surgery by showing that the degree of improvement in symptoms (as measured by SNOT-22) is closely related to baseline severity stratification (as measured by NOSE score). This improvement in SNOT-22 score remained across each of the four SNOT-22 subdomains— nose, sleep, ear/facial pain, psychological. The impact of septal surgery in improving SNOT-22 scores is also found in studies of snoringIn the current study, although a greater and sustained improvement was observed in the surgical arm, we did note a potentially clinically important improvement in SNOT-22 scores in the medical management arm of 9.1 points between six and 12 months. In the ITT analysis, some of the improvement at 12 months in the medical management group may have been affected by 37 participants who were randomised to receive medical management undergoing septoplasty after six months. The primary outcome, SNOT-22 score at six months, did not improve from baseline in these 37 participants, suggesting that these participants undergoing septoplasty had an important impact on the medical management group.The benefits of septoplasty were also seen in the secondary outcome measures, including clinical airflow assessment, patient reported outcome measures, and objective measurements of peak nasal inspiratory flow and rhinospirometry. Absolute subjective double ordinal airway subjective scale, the subjective comparator of the worse versus the better nostril airflow, revealed a substantial treatment related shift from predominantly unilateral nasal airflow to equal airflow through both nostrils, more noticeable in magnitude in the surgical arm than in the medical management arm at both six and 12 months. It may be a useful tool to audit surgical outcomes, or future trials of nasal airway surgery.The results of the current study infer that turbinate surgery added no additional improvement to septoplasty alone. The decision to perform turbinate surgery was, however, pragmatic and left to the discretion of the operating surgeon. The results for inferior turbinate reduction may not be generalisable to other techniques or to bilateral reduction practices. The study by van Egmond et al similarly reported no additional benefit of turbinate surgery. | PMC10583133 |
Limitations of this study | nasal valve dysfunction, rhinitis, Nasal obstruction, nasal obstruction | CHRONIC RHINOSINUSITIS, SECONDARY, RHINITIS, ALLERGIC RHINITIS | The study has several limitations. At baseline, more than 80% of patients had NOSE scores in the severe or extreme category. This may reflect the population currently referred to secondary care. However, the conclusions for these two subgroups were strong. The benefits for those participants with moderate baseline symptoms was less clear, whereas those with moderate NOSE scores at baseline did not report an improvement that reached the minimal clinically important difference of 9 points on SNOT-22—only 18 participants were included in this subgroup of the STEPP analysis.Nasal obstruction is a non-specific symptom with many underlying possible causes (chronic rhinosinusitis, allergic rhinitis, non-allergic rhinitis, nasal valve dysfunction). As a pragmatic trial, the current study did not seek to diagnose or treat these conditions before randomisation. Also, surgical interventions were performed by experienced surgeons. In NHS practice, septoplasty is often performed by junior trainee surgeons, albeit many are supervised by more senior colleagues. The evidence is limited for septoplasty outcomes and surgeon experience. However, previous studies have found no association between grade of surgeon and septoplasty outcomes when assessing the need for revision surgeryThe current trial did not assess, and therefore cannot define, what should constitute an appropriate trial of medical management for patients and clinicians to consider before septal surgery is discussed. Participants in the medical management group reported an improvement in symptoms with mometasone nasal steroid and saline sprays. Participants with an element of underlying rhinitis contributing to the nasal obstruction in addition to the septal deviation may have responded to this treatment. Consensus opinion from the US recommends a course of medical management for four weeks before septoplasty is considered. | PMC10583133 |
Conclusions | nasal obstruction | Septoplasty is a superior treatment for nasal obstruction associated with septal deviation compared with a defined regimen of nasal steroid and saline sprays. Baseline NOSE scores can estimate the likely improvement in symptoms and guide decision making for patients and clinicians. The authors recommend that adults presenting with nasal obstruction associated with a deviated nasal septum should be offered septoplasty. | PMC10583133 | |
What is already known on this topic | SECONDARY | In 2014, the UK National Institute for Health and Care Research commissioned a randomised controlled trial to address the lack of high quality evidence to support nasal septoplastyA study in 2019 reported higher levels of general quality of life at 12 months in participants after septoplasty compared with those who received variable non-surgical managementIn that study, score on the Sino-Nasal Outcome Test (SNOT-22) was a secondary outcome, with greater improvement observed in participants after septoplasty | PMC10583133 | |
What this study adds | Leigh, Paget, nasal obstruction | LEIGH, RECRUITMENT | Septoplasty is a clinically effective treatment for nasal obstruction associated with septal deviation compared with a defined regimen of nasal steroid and saline spraysParticipants who underwent septoplasty had greater improvement in nasal obstruction and quality of life, as measured using the SNOT-22 questionnaireHowever, people with a deviated nasal septum and at least moderate nasal obstruction do tend to improve over time with medical treatmentWe thank the clinical research staff across the UK at the following centres: Aneurin Bevan University Health Board; Bradford Teaching Hospitals NHS Foundation Trust; County Durham and Darlington NHS Foundation Trust; Guy’s and St Thomas’s NHS Foundation Trust; James Paget University Hospital NHS Foundation Trust; Leeds Teaching Hospitals NHS Trust; Liverpool University Hospitals NHS Foundation Trust; Newcastle Upon Tyne Hospitals NHS Foundation Trust; NHS Grampian; NHS Lanarkshire; NHS Tayside; North Cumbria Integrated Care NHS Foundation Trust; Plymouth Hospitals NHS Trust; Salisbury NHS Foundation Trust; Stockport NHS Foundation Trust; University Hospitals Birmingham NHS Foundation Trust; Wrightington, Wigan and Leigh Teaching Hospitals NHS Foundation Trust. The Newcastle Clinical Trials Unit staff, including previous team members: Trial Manager, Ann-Marie Hynes; Clinical Trial Administrators, Eva-Maria Holstein, Wendy Banks; Secretary, Ruby Smith-Whelan; Data Manager, Alaa Abouhajar; Senior Trial Managers, Lesley Hall, Jared Thornton, Sonya Carnell. Maria Allen and Ian Campbell for providing clinical trials pharmacy guidance and review on behalf the sponsor. Joan Mackintosh for qualitative data collection. The patient and public involvement advisors who provided helpful advice and guidance when reviewing the trial and patient facing documents. The members of the NAIROS Trial Steering Committee: Valerie Lund (chair), Natalie Rowland (independent statistician), Helen Mason (independent health economist), Russell Cathcart (independent clinician), Tim Woolford (independent clinician), Andrea Anderson and Irene Soulsby (independent lay members). The members of the NAIROS Data Monitoring Committee; Steff Lewis (chair), Stephen Gerry (independent statistician), and Gerald McGarry (independent clinician). Most importantly, we would like to thank every participant who took part in the NAIROS trial.Extra material supplied by authorsSupplementary information: Inclusion and exclusion criteria, figures S1-S6, and tables S1-S8Contributors: All authors have contributed to writing, reviewing, and revising the manuscript. SC and JOH are joint first authors. SC is the corresponding author and NAIROS chief investigator.TF, DS, and DT performed the trial statistical analysis. TH and LT performed the trial health economic evaluation. NR and KL performed the qualitative research. KR, EC, and AS were the trial management team. NW managed the trial database. LR, JD, and CW performed the qualitative research that guided trial recruitment. AB and MD devised the nasal patency methodology and performed the related data analysis. DH and JW were co-applicants and contributed to the trial design and participant recruitment. YO contributed to the trial methodology design. JM acted as a co-applicant and primary care lead. QG, NK, SK, SL, SM, and PN were clinical co-applicants and contributed to participant recruitment. SC and JOH, as guarantors, accept full responsibility for the work and/or the conduct of the study, had access to the data, and controlled the decision to publish. The corresponding authors attests that all listed authors meet authorship criteria and that no others meeting the criteria have been omitted.Funding: The study was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (reference 14/226/07). The NIHR commissioned the research trial with some stipulation on the trial design. Thereafter, the funders were independent of the running of the trial, analysis and interpretation, and the decision to publish the results.Competing interests: All authors have completed the ICMJE uniform disclosure form at The lead authors (SC and JOH) affirm that the manuscript is an honest, accurate, and transparent account of the study being reported; that no important aspects of the study have been omitted; and that any discrepancies from the study as planned have been explained.Dissemination to participants and related patient and public communities: A lay summary of results will be available on the NAIROS website. Access to the Health Technology Assessment report will also be available through the trial website. Members of the patient and public involvement focus groups will review results and they will be involved in writing lay summaries of results for dissemination to relevant patient groups.Provenance and peer review: Not commissioned; externally peer reviewed. | PMC10583133 |
Ethics statements | PMC10583133 | |||
Ethical approval | The North East – Newcastle and North Tyneside 2 UK Health Research Authority Regional Ethics Committee (August 2017, study reference No 17/NE/0239). | PMC10583133 | ||
Data availability statement | The chief investigator and collaborators will act as custodians of the trial data and manage data sharing requests through ReShare, a UK online data repository recommended by the funder. Parties interested in data sharing will directly contact the chief investigator and collaborators and complete a project proforma and provide the rationale and the information required and comply with the regulation of responsibilities of users. If agreed to be appropriate, requested anonymised data will be made available. An access advisor who is independent of the trial team will periodically review access decisions. | PMC10583133 | ||
Background | postoperative pain, pain | Management of acute postoperative pain is one of the major challenges in pediatric patients. Oral oxycodone has shown good pain relief in postoperative pain relief in children, but no studies have investigated intravenous oxycodone in this context. | PMC10155412 | |
Objective | postoperative pain | whether oxycodone PCIA can provide adequate and safe postoperative pain relief, in comparison to tramadol as reference opioid drug. | PMC10155412 | |
Design | a randomized, double-blind, parallel, multi-center clinical trial. | PMC10155412 | ||
Setting | five university medical centers and three teaching hospitals in China. | PMC10155412 | ||
Participants | patients aged 3-month-old to 6-year-old undergoing elective surgery under general anesthesia. | PMC10155412 | ||
Intervention | patients were randomly allocated to either tramadol (n = 109) or oxycodone (n = 89) as main postoperative opioid analgesic. Tramadol or oxycodone were administered with a loading dose at the end of surgery (1 or 0.1 mg.kg | PMC10155412 | ||
Outcomes | postoperative pain, consolability | the primary outcome was adequate postoperative pain relief, defined as a face, legs, activity, cry, and consolability (FLACC) score < 4/10 in the post-anesthesia care unit (PACU), with no need for an alternative rescue analgesia. FLACC was measured 10 min after extubation then every 10 min until discharge from PACU. Analgesia was currently conducted with the boluses of either tramadol or oxycodone if FLACC was ≥ 3, up to three bolus doses, after what rescue alternative analgesia was administered. | PMC10155412 | |
Results | postoperative pain, nausea and vomiting | tramadol and oxycodone provided a similar level of adequate postoperative pain relief in PACU and in the wards. No significant differences were either noted for the raw FLACC scores, the bolus dose demand in PACU, the time between the first bolus dose and discharge from PACU, analgesic drug consumption, bolus times required in the wards, function activity score, or the parents’ satisfaction. The main observed side effects in both groups were nausea and vomiting, with no difference between groups. However, patients in the oxycodone group showed less sedation levels and had a shorter stay in the PACU, compared with the tramadol group. | PMC10155412 | |
Conclusions | postoperative pain | an adequate postoperative analgesia can be achieved with intravenous oxycodone, this with less side effects than tramadol. It can therefore be a choice for postoperative pain relief in pediatric patients. | PMC10155412 | |
Trial registration | The study was registered at | PMC10155412 | ||
Key points | postoperative pain, pain | Question: Can the intravenous administration of oxycodone provide adequate postoperative analgesia in children?Findings: Oxycodone can provide well postoperative pain control in children, similar to tramadol.Meanings: For the first time, we demonstrate that administration of oxycodone intravenously can provide well acute pain control in children after surgery, expanding our opioid drug choice for postoperative pain management in children patients. | PMC10155412 | |
Keywords | PMC10155412 | |||
Background | postoperative pain, nausea and vomiting | Acute postoperative pain is one of the major challenges for the anesthesiologists [Compared to adults, children should receive analgesia through the most comfortable and least painful method available. The oral administration of analgesics is straightforward and has demonstrated good effectiveness in various settings. However, the oral route is often unsuitable for postoperative pain relief immediately after surgery due to the risk of nausea and vomiting or a slow return to normal gastric function [Morphine is the most widely utilized opioid in PCA for children in western countries and serves as the benchmark against which other analgesics are evaluated in clinical trials [Oxycodone stands out among analgesics as a full agonist of both µ- and κ-opioid receptors [In this study, we propose that oxycodone-based PCIA can provide postoperative pain relief in pediatric patients effectively and safely. We chose not to use morphine as a positive control due to its low acceptance rate of only 14.8% among pediatric patients in China, compared to higher rates for sufentanil (70.4%), fentanyl (66.7%), and tramadol (59.3%) [ | PMC10155412 | |
Materials and methods | PMC10155412 | |||
Study design | This is a randomized, double-blind, parallel, multi-center clinical trial. This study was approved by the medical ethics committee, the second affiliated hospital of Xi’an Jiaotong University (2018024), and written informed consent was approved by each patient’s legal guardian. The study was registered at | PMC10155412 | ||
Patients | Patients [3-month-old to 6-year-old, Body Mass Index (BMI) 18-29.5 kg/m | PMC10155412 | ||
Randomization and blinding | BLIND | A biostatistician who is unaware of treatments and patient follow-up, generates the random numbers using the SAS software (SAS Institute, USA) in a ratio of 1:1, named group A and group B. The randomization sequence is stored online until the end of the study (Only the biostatistician was aware of the randomization sequence and did not participate in the conduct of the study or patient follow-up. The responsible anesthesiologist was aware of the drugs being used, oxycodone or tramadol, but was not involved in patient assignment, follow-up, or data analysis. The responsible anesthesiologist is aware of whether oxycodone or tramadol is used for the patients, however, he or she is not involved in the patient assignment, follow-up, and data analysis. The study drugs are prepared by the responsible anesthesiologist. The study drugs were prepared by the responsible anesthesiologist, diluted to the same volume with normal saline, and placed in similar PCIA devices without labeling. Throughout the study, all study personnel, patients, parents, and everyone except the responsible anesthesiologist, remained blind to the patients’ allocations.In an emergency, each center’s principal investigator can request the treatment allocation unmasking. The case should be documented and analyzed to evaluate any association with the treatment. | PMC10155412 | |
Procedures | postoperative pain, consolability, Pain, pain | Patients were fasting from clear liquids for 4 h and solid food for 6 h prior to undergoing anesthesia. No analgesic or antiemetic drugs were administrated before the procedure. Thirty minutes before the procedure, patients received an intramuscular administration of 0.01 mg.kgCisatracurium infusion was discontinued 30 min prior to the end of surgery, and 0.5 mg.kgAfter surgery, all patients were transferred to the post-anesthesia care unit (PACU). Extubation was performed after full recovery of spontaneous ventilation and consciousness. Ten min after extubation, pain intensity was firstly evaluated using the face, legs, activity, cry, consolability (FLACC) scale [Postoperative follow-up inwards was performed by research personnel or a healthcare member who was blinded to the allocation of the patient. Postoperative intensity at rest was evaluated using the FLACC scale by the parents. A bolus dose was given to the patient by parents immediately if the FLACC score was above 3. All parents were instructed on how to use the FLACC scale to evaluate postoperative pain intensity by research personnel face to face until they completely understood the method. Pain intensity in response to turning around in bed was evaluated using the functional activity score (FAS) [ | PMC10155412 | |
Outcomes | hypoxemia, postoperative pain | ADVERSE EVENTS, SECONDARY, BLIND | Outcome assessment was performed by researchers who were kept blind to the patient’s group assignments. The primary outcome was whether oxycodone could provide adequate postoperative pain relief after surgery in pediatric patients. The definition of adequate postoperative pain relief includes (1) the FLACC score< 4 in the PACU; (2) patients do not need alternatively rescue analgesia. Ten minutes after the extubation in the PACU, postoperative pain in PACU was firstly evaluated by research personnel unaware of the allocation of the patient according to the FLACC scale; the FLACC evaluation was repeated every 10 min until discharge from PACU. A bolus dose of oxycodone or tramadol is given to the patient immediately if the score ≥ 4 according to patient’s allocation. The procedures could be repeated after 10 min until the score ≤ 3. If postoperative pain relief is not satisfied after three continuous bolus doses, alternative rescue analgesia is administrated to the patient.The secondary outcomes included No. of boluses administered and bolus-administered amount of opioid in PACU (equal to morphine) in PACU and in the wards, time spent from PACU discharge to the first bolus dose, bolus analgesia rate in the wards, FAS scores in the wards, parents’ satisfaction with the PCIA. We also recorded and analyzed the consciousness recovery time, extubation time, the length of staying PACU, Ramsay scores, and adverse events, especially hypoxemia. | PMC10155412 |
Statistical analysis | A pilot observational study in our center showed that the FLACC scores between the oxycodone and tramadol groups in PACU were 3.71 ± 1.71 and 4.49 ± 1.74, respectively. The sample size required was 166 patients (83 patients in each group) after calculation with two-tailed α = 0.05 and β = 0.2 using the SAS software (SAS Institute Inc., USA). Considering the possible dropout cases, we increased the sample size to 240 for initial enrollment.GraphPad Prism 6.0 software (GraphPad Software Inc., USA) was used to perform the statistical analysis. The per-protocol analysis set consists of subjects who were randomly assigned to treatment, and have no major protocol violations such as violations of entry criteria, errors in treatment assignment and use of excluded medications. Gaussian distribution was tested using D’Agostino & Pearson analysis. Data was displayed as the median value (1st -3rd quartiles). An unpaired t test (if the data was normally distributed) or Mann-Whitney u test (if the data was not normally distributed) was used to analyze the numeric variables. FLACC scores, Ramsay sedation scores, and parent satisfaction scores were analyzed using a linear mixed-model to analyze the interaction and main effects of time and group. χ2 test or Fisher exact probability method (if the theoretical frequency was less than 5) was used to analyze the categorical variables were analyzed. A significant difference was defined as a value of P < 0.05. | PMC10155412 | ||
Results | postoperative pain, pruritus, CRF, nausea & vomiting | ADVERSE EVENTS, CRF | From October 2018 to September 2019, 240 patients were screened and 21 of them were excluded (Fig.
Trial profile. Data analysis included all patients in the groups to which they were randomly assigned. CRF: case report formWe did not find any significant difference in the demographic data between oxycodone and tramadol groups (P > 0.05, Table
Comparison of demographic data between oxycodone & tramadol groupsSurgery types(orthopedic/urinary/general/neuro/vascular)Neither oxycodone nor tramadol group needed alternative rescue analgesia in PACU. FLACC scores at different time points in PACU were analyzed using a linear mixed-model. Most of the patients from the oxycodone and tramadol groups had well immediate postoperative pain relief (FLACC scores < 4) after extubation in PACU, and there was no significant difference in FLACC scores at 10 min, 20 or 30 min after extubation (P > 0.05, Table After returning to the wards, all patients had adequate postoperative analgesia in the wards (FLACC scores < 4) after the bolus dose administration, and no alternative rescue analgesia was thereby recorded. There was no significant difference in the FAS scores (in response to turning around in bed), incidence rate of bolus analgesia, time spent from PACU discharge to the first bolus dose, No. of boluses administered, bolus-administered amount of opioid (equal to morphine) in the wards between the oxycodone and tramadol groups (P > 0.05, Table
Comparison the effect of postoperative pain relief between oxycodone & tramadol-PCIAPACU: postoperative anesthesia care unit; PCIA: parent control intravenous analgesiaParent satisfaction scores were analyzed using a linear mixed-model. There was no significant diffidence in parent satisfaction scores between the oxycodone and tramadol group at either 3 h (P = 0.553), 24 h (P = 0.553) or 48 h (P = 0.834) after surgery (Fig.
Comparison of parent satisfaction scores between oxycodone and tramadol group. * P < 0.05. +: mean; oxy: oxycodone group; tra: tramadol groupDuring the anesthesia recovery period, there was no significant difference in the consciousness recovery time, extubation time, incidence of nausea & vomiting or pruritus between the oxycodone and tramadol groups (P > 0.05, Table
Comparison of recovery and adverse events between oxycodone and tramadol in PACUPACU: postoperative anesthesia care unitPCIA: parent control intravenous analgesiaRamsay sedation scores were analyzed using a linear mixed-model. Patients from both oxycodone and tramadol groups showed a time-dependent reduction in Ramsay sedation scores in PACU (P < 0.05). Interestingly, patients from the oxycodone group showed significantly lower Ramsay sedation scores relative to the tramadol group 10 and 20 min after extubation in PACU (Fig.
Comparison of Ramsay sedation scores between oxycodone and tramadol group. Patient′s sedation level in the PACU (10, 20 and 30 min after extubation) and in the wards (3 h, 24 and 48 h after surgery) was assessed by Ramsay sedation scores. ** P ≤ 0.01. oxy: oxycodone group; tra: tramadol groupWe further compared the other PCIA-related adverse events in the wards. As shown in Table
Comparison of adverse events between oxycodone and tramadol-PCIA in wards | PMC10155412 |
Discussion | PONV, postoperative pain, nausea and vomiting, pain | ADVERSE EFFECTS, ADVERSE EFFECT | There are several reasons for the cautious use of opioids in pediatric postoperative pain management, one of which is the fear of potential severe adverse effects due to children’s young age and small size. Although oral oxycodone has been widely used for pain relief in children, there is no literature on the use of intravenous oxycodone for postoperative pain relief in pediatric. In this study, we investigated whether intravenous oxycodone can provide adequate and safe postoperative pain relief, in comparison to intravenous tramadol which has a well-established use in children [Oxycodone elimination is slower and its pharmacokinetics are more variable in neonates, particularly preterm newborns, and thus a lower dose with a longer dosing interval is recommended in these patients [Our study showed that children patients administrated with an equal dose of oxycodone or tramadol did not show any difference in the FLACC scores after extubation, the requirement for rescues analgesia in PACU. These results suggest that oxycodone could provide adequate transition analgesia compared with the equal dose of tramadol immediately after surgery, in line with previous studies conducted in adults [After returning to the wards, we did not record any requirements for the alternative rescue analgesia in either oxycodone or tramadol groups, suggesting that both oxycodone and tramadol-PCIA provide adequate postoperative pain control in children patients. Additionally, there was no significant difference in the bolus dose administration, including bolus dose times, the anesthetics consumption equivalent with morphine, the length between the first bolus dose and the discharge from PACU, and FAS scores between the two groups, demonstrating that oxycodone and tramadol have similar efficacy in providing postoperative analgesia in pediatric patients. Differently with the period of staying in PACU, we did not observe any cases of oversedation or significant differences in Ramsay scores between the oxycodone and tramadol groups in the ward. Considering the much lower dose administrated during PCIA infusion in the wards compared with the loading dose at the end of surgery, this result further illustrated that the higher sedation effect of tramadol relative to oxycodone observed in PCAU was dose-associated.Our results align with previous studies that show that nausea and vomiting (PONV) is the most frequently reported adverse effect in both the oxycodone and tramadol groups [This study has several limitations that need to be considered: firstly, we administered only a single dose of either oxycodone or tramadol. In another preliminary study we performed, 0.05, 0.1, and 0.15 mg.kg | PMC10155412 |
Acknowledgements | We appreciated that Prof. Krister Nilsson from Sweden kindly gave a lot of help for manuscript revision. | PMC10155412 | ||
Authors’ contributions | Zhengchen Li | Dr. Siyuan Li contributes to study design, project administration, data analysis, study conduction, data collection & analysis, and manuscript preparation; Drs. Hongfei Xiong, Yingping Jia, Zhengchen Li, Yexi Chen, Liang Zhong, Feng Liu, Shuangquan Qu, Zhen Du, Yuxia Wang, Suxia Huang, Yonghui Zhao contributed to study design, study conduction and data collection; Mrs. Jing Liu contributes to patients’ randomization & allocation, data input and statistical analysis; Dr. Lihua Jiang contributes to the project supervision, study design & administration, data analysis, manuscript preparation and revision. All authors read and approved the final manuscript. | PMC10155412 |
Subsets and Splits
No community queries yet
The top public SQL queries from the community will appear here once available.