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Time-series assessment of function | hypermobility | Qualitative visual evaluation of the kinematic and kinetic time-series plots showed some differences between joint hypermobility and non-joint hypermobility participants. The joint hypermobility group demonstrated greater hip flexion than the non-joint hypermobility group throughout the entire DVJ (Fig. Kinematic time-series plots for joint hypermobility vs. non-hypermobility during drop vertical jump taskKinetic time-series plots for joint hypermobility vs. non-hypermobility during drop vertical jump task | PMC10626644 | |
Discussion | hypermobility, decreased joint stiffness, chronic musculoskeletal pain, pain, joint hypermobility, chronic pain | CHRONIC PAIN, SECONDARY | The results of this pilot study suggest that adolescents with JFM and joint hypermobility show similar clinical pain intensity levels to those with JFM without joint hypermobility; however, those with joint hypermobility had lower levels of overall physical impairment. We found small differences in biomechanics between joint hypermobility groups during a landing and jumping task (e.g., hip [sagittal] angle; hip [frontal and transverse] and knee [transverse] moments). Specifically, those with joint hypermobility may demonstrate greater hip flexion (Fig. Our preliminary findings indicate among adolescents with JFM, those with joint hypermobility may demonstrate decreased joint stiffness during landing, a biomechanical feature that is consistent with excessive joint laxity [This pilot study has several limitations. First, the small sample size may not have provided enough power to detect significant group differences. Additionally, this study was a secondary analysis involving participants with a primary diagnosis of JFM, and results may not generalize to other chronic musculoskeletal pain conditions or those with joint hypermobility without chronic pain at all. In addition, joint hypermobility group classifications were based on adolescents’ Beighton scores, and there is some debate over appropriate clinical cut-off scores to use in pediatric populations [ | PMC10626644 |
Conclusion | joint hypermobility, hypermobility, chronic musculoskeletal pain | These results tentatively support the use of neuromuscular training and exercise programming in adolescents with chronic musculoskeletal pain, regardless of joint hypermobility status; though, additional work is needed to address concerns regarding our study findings being attributed to error alone. However, findings also do suggest subtle differences in biomechanics in adolescents with JFM who also have joint hypermobility. Based on these preliminary findings, these differences in body biomechanics may be worth examining in more definitive studies with larger samples, to determine how exercise programs can be best modified for patients with joint hypermobility. | PMC10626644 | |
Acknowledgements | No acknowledgments of note beyond the study team. | PMC10626644 | ||
Financial disclosure | Other than disclosed funding (see below), the authors have no other financial disclosures in relation to this study. | PMC10626644 | ||
Author’s contributions | CAD, MP, GDM | GDM, CAD | All authors contributed to this manuscript. WRB, LAW, CAD, and SKZ contributed a majority of the writing of this manuscript, while ST, MP, KK, TVT, SEW, and GDM provided expert-informed modifications and edits to the text. CAD, ST, KK, and GDM conducted and analyzed biomechanical data, and provided expert feedback and guidance form Sports Medicine, and WRB, SEW, and SKZ integrated biomechanics findings into clinical interpretation. | PMC10626644 |
Funding | Arthritis, Musculoskeletal | ARTHRITIS, SKIN DISEASES | This study was funded by the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), R21AR063412 and K24AR056687 to the last author (SKZ). Funding source R21AR063412 provided support for SKZ to design the study, staff support for data collection, analysis, and manuscript writing. Funding source K24AR056687 provided supports for SKZ to oversee the project and completion of the manuscript.The project described was also supported by the National Institutes of Arthritis and Musculoskeletal Skin Diseases under Award - Number P30AR076316. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. | PMC10626644 |
Availability of data and materials | Given the size and complexity of the biomechanics files, data may be provided and shared upon a reasonable request. | PMC10626644 | ||
Declarations | PMC10626644 | |||
Ethics approval and consent to participate | This study was approved by the Institutional Review Board at Cincinnati Children’s Hospital and Medical Center. Written informed consent was obtained by parents/guardians and written assent from participants. | PMC10626644 | ||
Consent for publication | No individual consent for publication is required for this study. | PMC10626644 | ||
Competing interests | The authors have no financial disclosures or competing interests to report relevant to this study. | PMC10626644 | ||
References | PMC10626644 | |||
Keywords | PMC10570009 | |||
Abbreviations: | differencetype-2 diabetes | VASODILATION | Akt substrate 160 kDacapillaries per individual fibrecapillary contactscapillary-to-fibre-perimeter exchangeconfidence limitsnon-protein isocaloric controlcytochrome citrate synthaseendothelial nitric oxide synthaseglucose clearance rateglucose transporter 4glutathioneglutathione disulphideglutathione peroxidase 1insulin receptor substratekeratin-derived proteinkeratin-derived protein with wheymicrovascular blood flowmicrovascular vasodilation, representing tissue sectional blood volumemoderate-to-vigorous physical activityN-Ethyl maleimidenuclear factor kappa light chain enhancer of activated B cellsNAD(P)H oxidasenuclear factor erythroid 2–related factor 2one-repetition maximumoxidised peroxiredoxin 2oxidised peroxiredoxin 3p21 activated kinasepeak powersharing factorsuperoxide dismutase 1smallest important effectsmallest standardised differencetype-2 diabetes mellituswhey protein isolate | PMC10570009 |
Introduction | We recently developed a novel edible keratin-derived protein (KDP) containing uniquely high concentrations of cysteine, glycine, and arginine [Glutathione is part of the thiol/disulfide system centred around the selenium-containing glutathione peroxidases (GPx) and thiol reductases, which in conjunction with peroxide scavenging enzymes (e.g., catalase and superoxide dismutase, SOD) and proteins, such as the highly abundant peroxiredoxins (PRX) mediate the transfer of redox state to cell signalling and metabolism [In a pilot study over 28-d in sedentary overweight mice, the ingestion of a 50/50 KDP/casein blend vs 100% casein lowered blood glucose (11 vs 19 mmol/L; difference 8 mmol/L, 90% confidence interval 5 to 11 mmol/L) [ | PMC10570009 | ||
Materials and Methods | T2DM | Men and women with T2DM (n = 35; see Results section for cohort descriptive statistics) completed a 14-wk placebo-controlled randomised trial comprising standardised exercise 5 d/wk and 2×20 g protein/d dietary supplementation in three arms: KDP-whey blend (KDPWHE), whey (WHEY), non-protein isocaloric control (CON). The preparation and nutritional properties of the novel KDP protein were evaluated for the first time in humans. The experiment derived outcomes from pre-post (week 0 and week 15) measures of tissue redox status and cell signalling in blood and insulin-stimulated (hyperinsulinaemic-isoglycaemic clamp) skeletal muscle. | PMC10570009 | |
Preparation, analysis and reducing potential of the keratin-derived protein (KDP) and whey protein isolate | PMC10570009 | |||
Preparation of KDP isolate | HEAT | Double-scoured wool (Wool Services International, Christchurch, New Zealand) was solubilized and degraded for nutritional application using a novel process in which a reaction mixture was formed containing food grade citric acid (90 mM) and ascorbic acid (6 mM) at pH 2.3. Ascorbic acid acts as a stabilizing and reducing agent preventing repolymerization of keratin protein through reformation of keratin disulphide bonds. The reaction mixture was processed by microwave radiation, heat and pressure, using a temperature-controlled 20 kW, 2450 MHz magnetron microwave into a reaction mix with a pH of 4.1. The reaction mix was centrifuged to generate three separate fractions: a liquid fraction (supernatant), emulsified fraction (precipitate), and solid fraction (plug). The supernatant, containing high concentrations of soluble components: citric acid, ascorbate and free amino acids, were discarded. The high molecular-weight precipitate and plug were freeze dried, ground to a fine powder, combined (50:50 ratio), and vacuum packed for storage prior to use. The full KDP production process is described in Ref. [ | PMC10570009 | |
Proximate analysis of KDP and WHEY | SEPARATION, ASH, TAG | Proximate analysis was carried out according to the 1990 Association of Official Analytical Chemists methods. Amino acids were analysed in triplicate with a standard hydrochloric acid hydrolysis followed by RP HPLC separation using AccQ Tag derivatization. Cysteine/methionine were analysed using performic acid oxidation (AOAC 994.12). The moisture, ash, fat, and protein contents (g/100 g) in the samples were determined as follows; the protein content was determined using Kjeldahl (AOAC Method 991.20), moisture content was determined by drying at 106 °C for 24 h (ISO R-1442) and ashing was done at 550 °C for 24 h (ISO R-936). The fat content was measured according to Soxhlet method (ISO R 1443) using a Foss Tecator AB Soxtec 2050. Carbohydrates was determined by subtracting the sum of moisture, ash, fat and protein content from 100. The caloric value was calculated as described by Karp et al. [ | PMC10570009 | |
Protein extraction and solubilization of KDP and WHEY | Dried dietary protein powder (10 mg) of KDP and WHEY were extracted overnight by rotation (Mini Labroller, Labnet International Inc) at room temperature in 1 ml of extraction buffer (8 mM urea, 0.05 M Tris, 50 mM TCEP, pH 4). Extracted protein was spun down at 3000 g for 5 min and the absorbance of the supernatant was measured at 280 nm (Nano photometer, Implen) against the appropriate blank after dilution (1:10). The protein solutions were kept at 4 °C until assessment of thiol groups. | PMC10570009 | ||
Reduction potential of KDP and WHEY | The accessible thiol content was determined in KDP and WHEY to assess the reduction potential. The proteins were extracted, and the diluted protein solutions were assayed by reaction with monobromobimane (MBB) and comparison to a GSH standard curve. 1 mM GSH (in 1 mM TCEP, 2.7 mM KCl, 0.14 M NaCl, 8 mM Na | PMC10570009 | ||
Human trial | PMC10570009 | |||
Participants | T2DM | MAY | Males and females of any ethnicity diagnosed with T2DM were recruited at medical centres and from the local community in Wellington (New Zealand) from January 2016 to January 2017 with final testing in May 2017. Inclusion criteria were non-insulin dependent T2DM for > one year (HbA | PMC10570009 |
Study design | The study was a multi-arm, double-blind, parallel group, randomized controlled trial comprising 14 wk of standardized exercise combined with dietary protein supplementation conducted in University and Hospital gyms, labs, and clinics. Participants all completed the same controlled exercise regimen and were randomized to protein treatment by an external researcher accounting for baseline glucose clearance rate (GCR), age, peak power (PP) and leg press 1RM, stratified by sex [ | PMC10570009 | ||
Dietary protein intervention | gluten free flour) | Protein treatments were a non-protein isocaloric placebo control (CON, blend of 50% maltodextrin and 50% low protein gluten free flour); isoenergetic whey protein isolate as active control (WHEY, 40 g WPI-A895; Fonterra, New Zealand), or a blend of KDP isolate and whey protein isolate (KDPWHE, 17 g KDP+23 g whey protein isolate) (Supplementary Material, SM, | PMC10570009 | |
Hyperinsulinemic-isoglycaemic clamp | INSULIN SENSITIVITY | Participants underwent a 2-h hyperinsulinaemic-isoglycaemic clamp at weeks 0 and 15 after an overnight fast. Using dietary recall, the diet was equal the day before the clamps, and participants were provided with 250-300 ml of water in the morning prior to procedures. The post-intervention clamp was performed 46-50 h after the last exercise session to minimise influences of acute exercise induced increases in insulin sensitivity. An insulin infusion of 80 mU/mA space correction was applied to the glucose infusion rate to correct non-steady state [glucose] using: (Glucose2-Glucose1)⋅0.095 [ | PMC10570009 | |
Skeletal muscle blood flow and vasodilation | VASODILATION | Basal and insulin-stimulated skeletal muscle blood flow (mBF) and vasodilation (blood volume, mBV) were measured during the clamp using continuous-wave near infrared spectroscopy (NIRS) [The measurements were performed before obtaining the muscle biopsies, and great care was taken to ensure that the participants lay still in a relaxed position without moving the leg while measurements were performed. mBV was calculated using the average tHb concentration (μM) over 5 min, at rest before (basal) and 120 min after insulin infusion. Using a custom and automated occlusion device, mBF was determined from the average slope of the [tHb] signal during four 15-s venous cuff occlusions (90 mmHg) with 45 s rest separating the occlusions as validated previously [ | PMC10570009 | |
Skeletal muscle and erythrocyte collection and analysis | Skeletal muscle, ∼100 mg frozen weight) from | Skeletal muscle tissue (∼100 mg frozen weight) from | PMC10570009 | |
Blood analysis | Samples for HbA | PMC10570009 | ||
Immunofluorescence protocol | SECONDARY, -20 | Samples were cut at 7 μm in transverse orientation using a microtome cryostat at -20 °C (Leica CM1850, Wetzlar, Germany). Sections were mounted on superfrost microscope slides (Sigma-Aldrich, catalogue #Z692255), then air-dried for 1 h. Slides were then either stored at -80 °C, or transferred straight into 1 × TBS, pH 7.6 for initiation of a staining protocol. The following antibodies were used for visualization of insulin signalling: 1:250 anti-GLUT4 rabbit polyclonal primary antibody (Abcam, catalogue # ab654) [Tissue samples were blocked for 30 min in 1% bovine serum albumin (BSA), then after washing for 3×5 min in 1 × TBS, samples were incubated in primary antibodies overnight at 4 °C. Next, samples were washed 3×5 min with 1 × TBS, 3×5 min with 2 × TBS and 3×5 min with 1 × TBS. Samples were then incubated with appropriate secondary antibodies, washed thoroughly and subsequently incubated for 1 min in TrueBlack (Lab Supply, NZ, catalogue #23007) to mask tissue autofluorescence. Finally, the samples were washed thoroughly, mounted in 50/50 TBS/glycerol and coverslipped. | PMC10570009 | |
Image capture | Images of immunostained muscle fibres were captured using a Spot-RT slider (SPOT Imaging Solutions: Diagnostic Instruments, Inc., Sterling Heights, MI) cooled digital microscope camera mounted on a compound widefield fluorescence microscope (Olympus BX-50, Olympus Corporation, Tokyo, Japan) equipped with a CoolLED illuminator (CoolLED Ltd, UK). Illumination and exposure times were optimized for each antibody and kept consistent throughout the acquisition. The Alexafluor 594 was excited using Olympus U-MWIY (540-580 nm) excitation filter, the Alexafluor 488 and UEA-I-FITC were excited using Olympus U-MWIG (465-495 nm) excitation filter and the WGA-350 was excited using narrow band UV filter (Olympus U-MNU-BP, 330-385 nm). All images were taken using a 20 × oil immersion objective. | PMC10570009 | ||
Image analysis | Three images per sample were taken and Image J (National Institutes of Health, Bethesda, MD) was utilized for analysis. GLUT4 translocation with the plasma membrane was measured as the mean grey value within the plasma membrane region, which was determined by masking the dystrophin-positive area [ | PMC10570009 | ||
Preparation of skeletal muscle tissue samples for biochemical and Western blot analyses | COLD | For GSH/GSSG and oxiPRX2/3, muscle tissue proteins were extracted as adapted from Kumar et al. [For Western blot analyses of NRF2, GPx1, SOD1, Akt, AS160, and PAK1/2, 30 mg of snap-frozen muscle tissue was homogenized in ice cold RIPA buffer (15 mM Tris, 167 mM NaCl, 0.5% sodium, deoxycholate, 0.1% SDS, 1% Triton X-100), containing complete protease and phosphatase inhibitor cocktail (at 25 μl per mg tissue, using an automatic homogenization blender (IKA) for 1 min. Sample lysates were placed in an orbital shaker for 1 h at 4 °C before centrifuging at 600× | PMC10570009 | |
Preparation of erythrocytes for GSH/GSSG analysis and SDS-electrophoresis | LYSED | Frozen packed erythrocytes treated with NEM, were lysed with 270 μl deionized water, vortexed and split into three parts for further analysis. For analysis of GSH/GSSG, 200 μl of lysate was mixed with 300 μl of precipitation solution to denature the proteins (5.37 mM EDTA, 5.13 M NaCl, and 0.17 M orthophosphoric acid). After 5 min incubation at room temperature, the samples were centrifuged at 12,000 g for 10 min, and supernatants were collected for further analysis. For gel electrophoresis, 100 μl lysate were diluted further with 100 μl deionized water, and half of this dilution was added to 200 μl 3x non-reducing sample buffer, before diluting it by an additional factor of 50 with 1x sample buffer (6.6 mM Tris, 93 μM bromophenol blue, 675 mM glycerol and 0.5% SDS, pH 6.8). To calculate haemoglobin content, 5 μl of the diluted lysate was added to 1 ml Drabkin's reagent (2 mM KCN, 1 mM K | PMC10570009 | |
GSH/GSSG analysis | GSH (as its NEM derivative) and GSSG were analysed by liquid chromatography tandem mass spectrometry as adapted from Harwood et al. [ | PMC10570009 | ||
Western blot protocols | Protein extracts from skeletal muscle (4 μg for PRX2/3) and erythrocytes (6 μg for PRX2) were separated by SDS-PAGE under non-reducing conditions. Extracts from skeletal muscle (30 μg for NRF2, GPx1, SOD1 or 40 μg for Akt, AS160, and PAK1/2) were separated by SDS-PAGE under reducing conditions. Separated proteins were transferred to PVDF membranes, stained and imaged for total protein using Ponceau S (Sigma-Aldrich, Cat. P3504) prior to blocking for 1h in Tris-Buffered Saline/0.1%Tween-20 (TBS-T) containing 3% BSA. Blocked membranes were then incubated overnight at 4 °C with the following antibodies diluted in TBS-T/3%BSA; rabbit polyclonal anti-human PRX2 at 1:10,000 (R8656, Sigma-Aldrich, RRID: | PMC10570009 | ||
Nuclear factor kappa light chain enhancer of activated B cells (NF-κB) p50/p65 DNA-binding assay in skeletal muscle nuclear extract | The nuclear fraction was isolated using a Nuclear Extraction kit (ab113474, Abcam) and the DNA-binding activity of p65 and p50 NF-κB subunits in the lysates was evaluated by colorimetric enzyme-linked immunosorbent assay (ELISA) using the NF-κB Transcription Factor Assay kit (ab207216, Abcam), according to the manufacturer's instructions. DNA-binding activity of combined p50/p65 was expressed as intensity based on absorbance measurement at 450 nm. | PMC10570009 | ||
Body composition, cardiometabolic risk factors, physical performance, daily physical activity level and gastrointestinal symptoms questionnaire | nausea, belching, diarrhoea, flatulence, Diabetes | DIABETES | Fat and fat-free mass were measured using bioelectrical impedance (Bodystat 1500 analyzer, UK) on the morning of the hyperinsulinaemic-isoglycaemic clamp. Waist circumference was measured at baseline and again prior to the final exercise session according to the International Diabetes Federation. Systolic and diastolic blood pressure was measured at baseline and again prior to the final exercise session using a Pulsecor Cardioscope (Uscom, Sydney Australia). Physical performance (cycling PP and lift 1-RM) were measured to calibrate weekly exercise load progression to 2% and 1.5%, respectively. Gastrointestinal symptoms were measured using 0-15 cm for abdominal or epigastric discomfort, or a 7-point Likert scale for nausea, belching, flatulence, and diarrhoea at the end of study week 1 and 14 [ | PMC10570009 |
Exercise procedures | In the morning after an overnight fast and rest day, peak power (PP) was established using cycle ergometry (Velotron, WA) with resistance increasing 1 W/3 s until exhaustion [ | PMC10570009 | ||
Statistical analysis | PMC10570009 | |||
Sample size | Sample size was calculated [ | PMC10570009 | ||
General statistical method | Data were analysed using mixed model longitudinal analysis of covariance for change scores adjusted for the baseline value [Thresholds for interpreting the magnitude of effect sizes (relative to clinical thresholds or the standardized difference/Glass's Baseline characteristics of the participants who completed the clinical trial (per protocol dataset).All values are raw mean (SD). BMI, body mass index; CON, non-protein isocaloric control; GCR, glucose clearance rate; KDPWHE, keratin-derived protein with whey; WHEY, whey protein isolate. | PMC10570009 | ||
Results | PMC10570009 | |||
Protein and supplement composition | The macronutrient and amino acid composition of the KDP and WHEY protein isolates, and supplement composition are in SM | PMC10570009 | ||
Participant disposition, gastrointestinal symptoms, and supplement acceptability | Of the 43 randomized participants, 35 completed (8 dropouts, 19%) (see Consort flow diagram | PMC10570009 | ||
Glucose clearance, nutrient delivery, and sarcoplasmic GLUT4 translocation | Skeletal muscle microvascular, type-2 diabetes mellitus, skeletal muscle microvascular blood flow | INS | In response to insulin stimulation (hyperinsulinaemic-isoglycaemic clamp), there was good and very good evidence for substantial (moderate standardized effect size) increases in whole-body glucose clearance rate (GCR) and skeletal muscle microvascular blood flow (mBF), respectively, and for good evidence for moderate increases in GLUT4 translocation with KDPWHE supplementation vs CON, and vs WHEY (The effect of 14-weeks of CON, WHEY or KDPWHE treatment in adults with type-2 diabetes mellitus on measures of glucose clearance, nutrient delivery to tissue microvasculature and cells, and glycaemic control. (A) Glucose clearance rate (GCR) during the last 20 min of the hyperinsulinemic-isoglycaemic clamp at weeks 0 and 15. Skeletal muscle microvascular (B) blood volume (mBV), and (D) blood flow (mBF) as measured by near-infrared spectroscopy (NIRS), expressed as basal fasted (INS -) and during the last 20 min of the hyperinsulinemic-isoglycaemic clamp (INS +) at weeks 0 and 15. (C) Fasting blood [HbA1c] at weeks 0 and 15. (E) Representative immunofluorescence images of cross-sectional skeletal muscle fibres stained for glucose transporter 4 (GLUT4). GLUT4 was measured as staining intensity in the plasma membrane area (SM The effect of 14-weeks of KDPWHE, WHEY, or CON supplementation in adults with type-2 diabetes mellitus on whole-body and skeletal-muscle glucoregulatory phenotype responses: haemoglobin A1c, basal and insulin-stimulated glucose clearance rate and, nutrient delivery to skeletal muscle microvasculature, and sarcoplasmic membrane GLUT4 content and translocation.Refer to Data are least-squares mean Week 15-0 change score in percent with 90% confidence limits (90%CL) for single point observations or insulin-stimulated values, where the latter is the insulin-stimulated (measured during isoglycaemic clamp) minus baseline (measured pre-clamp) difference score. Data are baseline-covariate adjusted values.Effect statistics are baseline-adjusted estimates of the treatment effects on the week 15-0 change score with 90%CL expressed as percent.Magnitude of effect estimates were interpreted from the lower and upper CLs, consistent with an alpha of 0.05 (maximum error rate of 5%) for rejection of substantial (superiority) hypotheses, referenced against the smallest effect threshold. The thresholds for interpreting effect magnitudes are based on the modified Cohen | PMC10570009 |
Discussion | hormesis, T2DM | INSULIN RESISTANCE, INSULIN SENSITIVITY | There was good evidence to suggest that the ingestion of the cysteine-rich keratin-derived combinatorial protein blend (KDPWHE) for 14 weeks by adults with T2DM produced a clinically relevant increase in whole-body glucose clearance rate (GCR), relative to a non-protein placebo control (CON), based on the mean effect size (24%) being comparable to pioglitazone + metformin intervention of similar duration [The GCR response following KDPWHE supplementation was supported mechanistically by association with good to very-good level evidence for enhanced nutrient-delivery phenotype and insulin sensitivity within the skeletal muscle – the largest tissue mass responsible for glucose disposal and metabolism [The good evidence for improved insulin-stimulated skeletal muscle microvascular blood flow (mBF) and for increased GLUT4 translocation provides for a candidate tissue-level mechanism responsible for the enhanced GCR, because tissue glucose delivery and uptake is partially regulated by insulin-stimulated mBF [The current data also provide the first indicative evidence to suggest a change in dietary protein pattern can modify insulin-stimulated sarcolemmal GLUT4 density in humans with T2DM. The increase in GLUT4 translocation with KDPWHE supplementation was accompanied with good evidence for a substantially higher IRSAt study onset, we believed that the KDPWHE would increase GSH synthesis, potentially increasing its endogenous antioxidant tissue levels to boost cellular reducing capacity and improve insulin sensitivity, as indicated in prior literature by association [The small-moderate change in basal redox state with KDPWHE may have accumulated over time to drive a comparatively greater adaptive response (hormesis) [Several limitations should be noted. The study was an exploratory pilot with the motivation to study based by the only prior evidence of any possible glycaemic effect from a mouse trial and from interpolation of a role for redox and tissue glutathione depletion in insulin resistance [Our insulin-sensitivity analysis focus was on traditional and established regulatory processes of relatively macro-level redox markers. However, a myriad of other possible evolutionarily conserved post-translational protein modifications at redox sensitive protein sites may be functional in insulin-signalling or sensitivity processes [ | PMC10570009 |
Conclusions | death, T2DM | CARDIOVASCULAR DISEASE, INSULIN SENSITIVITY | The pilot trial provided good evidence to suggest that chronic dietary supplementation with a novel cysteine-rich keratin protein blend may produce a clinically-relevant improvement in whole-body glucose clearance and aspects of muscle insulin sensitivity in humans with T2DM. These changes were associated within good evidence for redox-state shifts responding to insulin, increased antioxidant protein expression, GLUT4 translocation, and higher microvascular blood flow responses within the skeletal muscle tissue. The keratin protein was largely acceptable within baked products and capsules. As cysteine, glycine, and arginine are inversely correlated with cardiovascular disease - the primary cause of death in people with T2DM [ | PMC10570009 |
Funding disclosure | Ministry of Business, Innovation and Employment, NZ [UOOX1404]; Wool Industrial Research Ltd, NZ. | PMC10570009 | ||
CRediT authorship contribution statement | Peeters, WM: Conceptualization, Data curation, Investigation, Project administration, Writing - original draft, review & editing, revisions. Gram, M: Conceptualization, Data curation, Formal analysis, Investigation, Methodology, Project administration, Writing - original draft, review & editing. Dias, GJ: Conceptualization, Data curation, Funding acquisition, Methodology, Project administration. Vissers, MCM: Conceptualization, Funding acquisition, Methodology, Project administration, Writing - review & editing. Hampton, MB: Conceptualization, Methodology. Dickerhof, N: Data curation, Investigation, Methodology. Bekhit, AE: Conceptualization, Investigation, Methodology. Black, MJ; Bond, J: Investigation. Oxbøll, J; Bayer, S; Dickens, M; Vitzel, K; Sheard, PW; Perry, BG: Investigation, Methodology. Hodges, LD; Cornwall, J: Conceptualization, Funding acquisition, Project Administration. Brønd, JC: Data curation, Methodology. Stoner, L: Conceptualization, Funding acquisition, Methodology, Writing - review & editing. Rowlands, DS: Conceptualization and overall project management, Research design, Data curation, Statistical analysis, Funding acquisition, Methodology, Project administration, Supervision, Writing – original and final drafts, revisions. | PMC10570009 | ||
Declaration of competing interest | We were unable to get the Elsevier online DOI working, so this document covers declarations.George Dias, David Rowlands, and Margreet Vissers received a grant to conduct the study from the New Zealand Ministry of Ministry of Business, Innovation and Employment, NZ [UOOX1404].David Rowlands received additional funding for the project from Wool Industrial Research Ltd, NZ.There is no new patents or other intellectual property files arising from this research.All figures and tables are the authors own and original work.The authors declare not further conflicts of interest. | PMC10570009 | ||
References | PMC10570009 | |||
Supplementary data | The following are the Supplementary data to this article: | PMC10570009 | ||
SM Fig. 1 | CONSORT style summary of participant flow through the trial. | PMC10570009 | ||
SM Fig. 2 | Effect of keratin-derived protein on measures of skeletal muscle capillarization. | PMC10570009 | ||
SM Fig. 3 | Representative widefield images of skeletal muscle eNOS, p-eNOS | PMC10570009 | ||
Acknowledgements | Shanggari Venugopal, Brandon Woolley, William Pickup, Stephanie Bozonet, Adam Lucero, Henry Jones. The participants.Supplementary data to this article can be found online at | PMC10570009 | ||
Amendments from Version 1 | INFILTRATION | [version 2; peer review: 1 approvedNo competing interests were disclosed.
This revised article features notable improvements. The title has been refined to "Ketamine infiltration improves analgesia after thyroid surgery," accurately encapsulating the essence of the study. Methodologically, difficult airways were considered as an exclusion criterion, and we specified the ketamine concentration used, which was 50mg/ml. We defined that rescue analgesic during hospitalization was Nefopam in the case of VAS values greater than 30. The randomization method was specified. Our data, including age and type of surgery, have been carefully validated. We improved the discussion according to the recommendations of the reviewers. | PMC10835105 | |
Introduction | postoperative pain | THYROID, INFILTRATION | Thyroid surgery is known to be responsible for mild to moderate postoperative pain during the first 24 hours after surgery.
Ketamine has a high affinity for N-methyl-D-aspartate receptors; it can also bind to opioid mu and sigma receptors that provide central and peripheral analgesic effects.
The purpose of this study was to assess the impact of local wound infiltration using ketamine at the end of thyroid surgery on postoperative pain and opioid requirement. | PMC10835105 |
Methods | PMC10835105 | |||
Selection of patients, ethical approval and consent | allergic reactions, allergy, cardiac or respiratory disease, unstable diabetes | BLEEDING, ALLERGY, ALLERGIC REACTION, COMPLICATIONS | Ethical approval for this study was given by the Committee for the Protection of People in Southern Tunisia (approval number 0117/18). This randomized double-blind study was achieved through collaboration between the ENT department and the anesthesia department of the university hospital, Habib Bourguiba in Sfax, Tunisia.Patients scheduled for thyroid surgery were enrolled after having provided written informed consent, which they also gave for publication of their data, in de-identified form.Patients aged 18 to 65 years were included in this study if they had an ASA score (American Society of Anesthesiology) of I or II. Patients with unstable diabetes, an allergy to study drugs, a history of previous cervical surgery, or a history of cardiac or respiratory disease, as well as patients on long-term analgesics or corticosteroids and patients with predictable difficult airways were not included in this study. Patients who had major complications, such as allergic reactions to anesthetic drugs and major bleeding, as well as patients whose intubation required more than 2 attempts or whose surgery duration exceeded 3 hours, were excluded from this study. Patients who underwent a neck dissection associated with thyroid surgery were also excluded from the study. | PMC10835105 |
The patients and randomization | postoperative pain, pain | The patients were informed about the anesthetic protocols and were educated about the use of the visual analog scale (VAS) to evaluate the severity of the pain. All patients in the study were blinded to the drug they received for postoperative pain.The patients were randomly assigned to the following two groups using an online random list generator (
| PMC10835105 | |
General anesthesia procedure | STERILE, INFILTRATION, INFILTRATING | After 3 minutes of preoxygenation, anesthesia was induced with an injection of 3 μg/kg of Fentanyl followed by 3 mg/kg of Propofol; and with intubation using a silicone wire-reinforced tracheal tube with 0.2 mg/kg Cisatracurium. Anesthesia was maintained using isoflurane with a minimum alveolar concentration (MAC) of 1% in a 50% oxygen/air mixture. A 0.03 mg/kg Cisatracurium bolus was administered every 40 min, and a Fentanyl bolus of 0.1 μg/kg was injected whenever there was an increase of 20% of the base values in heart rate or systolic arterial blood pressure.Before surgery, an anesthesiologist, not involved in the study, prepared an unlabeled sterile syringe using 10 ml of ketamine (2 m/kg) or 10 ml of a saline solution. After wound closure, the infiltration was performed by a blinded surgeon. The needle was introduced to a depth of 0.5 cm, an aspiration was then performed to avoid an intravascular injection followed by infiltrating the wound. The content of the syringe was used for homogenous infiltration of the subcutaneous wound sides by the surgeon. | PMC10835105 | |
Analgesic protocol | Thirty minutes before the end of the surgery, all patients received 1 g of paracetamol ad then were extubated before being moved to the post-anesthetic care unit (PACU) for close monitoring for 2 hours. In the PACU, intravenous morphine titration (2 mg every 5 min) was performed until the VAS value was less than 30. All patients were admitted for at least 24 hours postoperatively in the ENT department. They all received 1 g of paracetamol systematically every 6 hours during the first 24 hours. Nefopam (NEFOMED 20 mg in 30 minutes) was administered when VAS was greater than 30. An anesthesiologist blinded to the study groups collected intraoperative and postoperative parameters. | PMC10835105 | ||
Evaluation criteria | pain | The primary outcomes were to determine the intensity of the pain using VAS from 0-100 in the first 24 hours. The VAS score was assessed every 10 minutes in the PACU for 2 hours and every 6 hours during the first 24 hours after the operation in the ENT department. Nefopam was administered in the cases where VAS exceeded 30. Opioid requirements were recorded during the PACU admission period. The occurrence of side effects of opioids and ketamine was noted. | PMC10835105 | |
Statistical analysis | In each group, a total number of 27 patients was required to obtain a difference on the VAS scale of 20 mm (standard deviation of 25 mm), with a power of 0.9 and an α=0.05. To allow for some margin of error in the underlying assumptions, the baseline sample size was increased by 10 % to 32 patients per group. χ
| PMC10835105 | ||
Results | PMC10835105 | |||
Study population | The study lasted for a total of 6 months from September 2018 to March 2019. Sixty-four patients were included. Two patients were withdrawn from the study for prolonged surgery (more than 3 hours). The flow of patients is represented in the CONSORT diagram of the study, which is shown in
| PMC10835105 | ||
CONSORT 2010 flow chart for the patients in the study. | PMC10835105 | |||
Demographic characteristics and intraoperative anesthetic characteristics of both groups. | Values are mean±standard deviation.S: physiological serum, K: ketamine, cm: centimeters, kg: kilograms, HR: heartbeat, bpm: beats per minute, SBP: systolic blood pressure, MAP: mean arterial pressure, DBP: diastolic blood pressure, SpO
Student t-test.Fisher exact test.χ
| PMC10835105 | ||
Assessment of postoperative pain | Pain | Pain scores during swallowing were significantly lower for group K in the PACU at 0, 10, and 20 minutes (
| PMC10835105 | |
Mean VAS values in group S and group K at rest and during swallowing in the PACU admission period. | Group S: saline solution group, group K: ketamine group, VAS: visual analog scale, PACU: post anesthetic care unit.Regarding the first 24-hour postoperative hospitalization period in the ENT department, the mean VAS values were higher in group S compared to group K; either at rest or during swallowing, but the difference was not statistically significant (p>0.05) (
| PMC10835105 | ||
Mean VAS values in group S and group K at rest and during swallowing in the first 24 hours postoperatively. | Dizziness, Respiratory distress, vomiting, hallucinations, Nausea, hematoma | HEMATOMA | Group S: saline solution group, Group K: ketamine group, VAS: visual analog scale.None of the patients in group K received morphine while it was administered to four patients in group S. The mean morphine consumption in the PACU was 0.71 mg and 0 mg respectively in group S and group K. The difference in morphine consumption between both groups was statistically significant (p=0.04). Nefopam was not administered to any of our patients.No patient presented a hematoma at the injection points of the product. A patient in group K showed hallucinations during the stay in the PACU. Dizziness was recorded in three patients of group K and one patient of group S. No patients presented postoperative shivers.Respiratory distress was not recorded in any of our patients. Nausea and vomiting were observed in a total of 11 patients but without significant differences between both groups. | PMC10835105 |
Discussion | cleft palate, postoperative pain, pain, respiratory distress, nausea, vomiting | INFILTRATE, THYROID, INFILTRATION, INFILTRATING | Acute pain is one of the most common complaints after surgery. Thyroid surgery is known to be responsible for mild to moderate postoperative pain during the first 24 hours, with a mean VAS score of 6.9 (±1.7).
The attempted locoregional anesthetic approaches to reduce post-thyroidectomy pain have included mainly bilateral superficial cervical plexus block and local wound infiltration with a local anesthetic agent.
Wound infiltration with a local anesthetic agent is a simple and safe procedure to reduce postoperative pain with fewer side effects in comparison with cervical plexus block.
Diclofenac has also been reported as an effective molecule to infiltrate the wound prior to surgery compared to Bupivacaine in reducing postoperative pain.
Ketamine also belongs to the molecules whose local wound analgesic effect has been studied. The local ketamine analgesic effect is related to different mechanisms: blocking sodium, calcium, and potassium channels, as well as binding to opioid, cholinergic, D2, and 5-HTE receptors and monoamine transporters.
In our study, ketamine (2 mg/kg) was injected into the wound after skin closure. It was associated with a significant reduction in VAS scores during swallowing compared to the saline solution group in PACU at 0, 10, and 20 minutes. In a prospective, controlled, double-blind, randomized study, Abd EL-Rahman
We also demonstrated that local injection of ketamine significantly reduced the average morphine requirement compared to the saline solution group. The use of opioids can be associated with severe side effects such as nausea, vomiting, and respiratory distress.
Kim
The use of ketamine as a local wound infiltration agent was studied more frequently in oral, tonsillar, and abdominal surgeries. In their meta-analysis, Cho
Infiltrating the surgical site using ketamine in pediatric patients undergoing cleft palate surgery was superior to Bupivacaine with respect to analgesic requirements, quality of sleep after surgery, and speed of recovery.
Regarding abdominal surgeries, Honarmad
In a randomized double-blind study, patients undergoing cholecystectomy who received subcutaneous ketamine infiltration at a dose of 2 mg/kg or intravenous ketamine at a dose of 1 mg/kg 15 minutes before surgical incision reported enhanced analgesia for 24 hours after surgery.
Our study has several limitations. First, thyroid surgeries were performed by different surgeons. Second, we did not consider the size of the resected thyroid gland which can reflect the extent of surgery and influence postoperative pain. | PMC10835105 |
Conclusions | INFILTRATION | In conclusion, local wound infiltration using 2 mg/kg of ketamine is an effective approach to reduce opioid requirements after thyroid surgery without increasing the side effects of ketamine. | PMC10835105 | |
Acknowledgments | We would like to thank all nurses and the personnel of the operating unit, in the otolaryngology and anesthesiology departments for their assistance and cooperation. | PMC10835105 | ||
Data availability | PMC10835105 | |||
Underlying data | INFILTRATION | Figshare: Underlying data for ‘Ketamine infiltration decreases opioid requirement after thyroid surgery’,
This project contains the following underlying data:
data ketamine thyroidectomy.sav (SPSS format; all datasets have been de-identified in accordance with the Safe Harbor method)CONSORT checklist
Data are available under the terms of the
| PMC10835105 | |
References | Postoperative pain, hallucinations, tachycardia, pain | SAID |
1. The study design: - Random grouping is unequal: The proportion of patients undergoing total thyroidectomy or partial thyroidectomy is much different between the two groups. Different types of surgery result in different level of pain. It make great influence on research results. - The post-operative pain relief design is not appropriate. When VAS score > 30, author used Nefopam. Nefopam is a strong pain relief but it causes a tachycardia so it needs to be infused slowly, with an infusion time is 30 minutes or more. So, this medicine is not suitable for pain relief. An NSAID group such as Ketorolac can be used. Furthermore, when using Nefopam, the dose must also be controlled, not exceeding 120mg per day. So if the patient has already taken 120 mg and still has pain, what is the next treatment? - Patients were assessed for pain both at rest or swallowing, but when swallowing, the VAS score was very high in the group not using Ketamine. This is not clinically appropriate in the first 120 minutes, because when author knew the patients were in pain, author still force the patient to perform swallowing for research without giving any additional pain relief. It can be said that author did not respect research ethics. 2. Data results - It need to add a table of results about side effects of pain relief methods, especially hallucinations when using Ketamine. The research object and method section should clearly state: Criteria for diagnosing hallucinations, prevention and treatment. 3. Discussion and conclusion - Discussion does not focus on the question research or the research results.Is the work clearly and accurately presented and does it cite the current literature?YesIf applicable, is the statistical analysis and its interpretation appropriate?PartlyAre all the source data underlying the results available to ensure full reproducibility?PartlyIs the study design appropriate and is the work technically sound?PartlyAre the conclusions drawn adequately supported by the results?YesAre sufficient details of methods and analysis provided to allow replication by others?PartlyReviewer Expertise:AnesthesiologistI confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard, however I have significant reservations, as outlined above.
The authors have addressed the requested revisions.Is the work clearly and accurately presented and does it cite the current literature?YesIf applicable, is the statistical analysis and its interpretation appropriate?YesAre all the source data underlying the results available to ensure full reproducibility?YesIs the study design appropriate and is the work technically sound?YesAre the conclusions drawn adequately supported by the results?YesAre sufficient details of methods and analysis provided to allow replication by others?YesReviewer Expertise:Regional anesthesia, Anesthesiology, critical care, cardiac anesthesia, artificial intelligenceWe confirm that we have read this submission and believe that we have an appropriate level of expertise to confirm that it is of an acceptable scientific standard.
Postoperative opioid requirements were assessed only in the PACU. Postoperative pain is your primary outcome. Please rephrase your title.Difficult airways should be considered as an exclusion criteria because you had assessed VAS during swallowing.Please precisely include which ketamine concentration was used.Baseline characteristics should be comparable between the two groups. Please verify your data (age, performed surgery).You have many VAS assessments exceeding 3/10. What was your rescue analgesia?The choice of ketamine dosage should be discussed."However, the use of ropivacaine was not associated with an analgesic effect.
VAS was considered as a limitation while it is a validated tool.Please put “to reduce” instead of “to reducing”.Is the work clearly and accurately presented and does it cite the current literature?YesIf applicable, is the statistical analysis and its interpretation appropriate?PartlyAre all the source data underlying the results available to ensure full reproducibility?PartlyIs the study design appropriate and is the work technically sound?YesAre the conclusions drawn adequately supported by the results?YesAre sufficient details of methods and analysis provided to allow replication by others?YesReviewer Expertise:Anesthesia and intensive careI confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard, however I have significant reservations, as outlined above. | PMC10835105 |
References | Postoperative pain, postoperative pain, pain | ADVERSE EFFECTS, INFILTRATION |
Title:
Postoperative opioid requirements were assessed only in the PACU. Postoperative pain is your primary outcome. Please rephrase your title. Methods:
Difficult airways should be considered as an exclusion criteria because you had assessed VAS during swallowing.Please precisely include which ketamine concentration was used.
Baseline characteristics should be comparable between the two groups. Please verify your data (age, performed surgery).You have many VAS assessments exceeding 3/10. What was your rescue analgesia?
The choice of ketamine dosage should be discussed.
"However, the use of ropivacaine was not associated with an analgesic effect.
VAS was considered as a limitation while it is a validated tool.
Conclusion:
Please put “to reduce” instead of “to reducing”.
In this study, researchers investigated the effects of local ketamine wound infiltration versus saline placebo on postoperative pain and opioid consumption in patients undergoing thyroid surgery. After randomizing 64 patients to receive either ketamine or saline infiltration, the researchers found that the ketamine group had lower VAS pain scores during the PACU stay for static pain at rest and dynamic pain on swallowing. The ketamine group consumed significantly less morphine in the PACU than the saline group. No adverse effects were reported. The authors concluded that local ketamine can reduce postoperative opioid use without increasing side effects. This study is well-designed and addresses an important clinical question. We recommend you to :
Provide more details regarding the randomization process: Was a computer random number generator used? Were block randomization or stratification techniques used?Presenting VAS scores graphically could better visualize trends.Is the work clearly and accurately presented and does it cite the current literature?YesIf applicable, is the statistical analysis and its interpretation appropriate?YesAre all the source data underlying the results available to ensure full reproducibility?YesIs the study design appropriate and is the work technically sound?YesAre the conclusions drawn adequately supported by the results?YesAre sufficient details of methods and analysis provided to allow replication by others?YesReviewer Expertise:Regional anesthesia, Anesthesiology, critical care, cardiac anesthesia, artificial intelligenceWe confirm that we have read this submission and believe that we have an appropriate level of expertise to confirm that it is of an acceptable scientific standard.
In this study, researchers investigated the effects of local ketamine wound infiltration versus saline placebo on postoperative pain and opioid consumption in patients undergoing thyroid surgery. After randomizing 64 patients to receive either ketamine or saline infiltration, the researchers found that the ketamine group had lower VAS pain scores during the PACU stay for static pain at rest and dynamic pain on swallowing. The ketamine group consumed significantly less morphine in the PACU than the saline group. No adverse effects were reported. The authors concluded that local ketamine can reduce postoperative opioid use without increasing side effects. This study is well-designed and addresses an important clinical question. We recommend you to : Provide more details regarding the randomization process: Was a computer random number generator used? Were block randomization or stratification techniques used?
Presenting VAS scores graphically could better visualize trends.
| PMC10835105 |
Objective | knee arthroplasty, TKA | Academic Editor: Vahid Rakhshan The purpose of the present study (a randomized clinical trial) was to evaluate the preemptive analgesic effects of pregabalin combined with celecoxib in total knee arthroplasty (TKA). | PMC9851777 | |
Methods | From January 2019 to June 2021, we enrolled 149 patients who underwent TKA and divided them into four groups: the placebo group ( | PMC9851777 | ||
Results | pain | The pain scores upon movement were significantly lower in the combination group than in the other three groups at 6, 12, 24, and 48 hours after surgery ( | PMC9851777 | |
Conclusion | pain | The preemptive analgesia regimen of pregabalin combined with celecoxib had positive effects on improving acute pain and reducing the cumulative dose of opioids after TKA. This trial is registered with | PMC9851777 | |
1. Introduction | postoperative pain, inflammation, pain, knee arthroplasty, TKA, trauma | ADVERSE EFFECTS, INFLAMMATION, KNEE OSTEOARTHRITIS | Total knee arthroplasty (TKA), a surgical method for the treatment of terminal stage knee osteoarthritis, can effectively relieve pain and restore knee function. However, patients experience moderate to severe pain after TKA. Acute pain after TKA can have a negative effect on enhanced recovery after surgery among patients [The mechanism of postoperative pain is complicated. In the past, it was believed that postoperative pain after TKA was mainly nociceptive pain caused by surgical trauma and tissue inflammation [The use of oral analgesics in advance is a convenient and effective method for preemptive analgesia after TKA. Celecoxib or other cyclooxygenase-2 (COX-2) inhibitors selectively inhibit the activity of COX-2, reduce prostaglandin production and inflammatory reactions, and achieve effective control of pain and anti-peripheral pain sensitization effects. In particular, it has a positive effect on reducing nociceptive pain mediated by inflammatory mechanisms after TKA [The purpose of our study was to evaluate the effectiveness of pregabalin combined with celecoxib as TKA preemptive analgesia by compared the pain score, cumulative dosage of opioids, high-sensitivity C-reactive protein (hs-CRP) level, and adverse effects after TKA. We hypothesised that the effectiveness of pregabalin combined with celecoxib as TKA preemptive analgesia would lead to satisfactory clinical outcomes. | PMC9851777 |
2. Materials and Methods | PMC9851777 | |||
2.1. Ethical Approval | The present study was a double-blind randomized clinical trial and was conducted in the affiliated hospital of our university. The study was approved by the ethics committee of the affiliated hospital of our university and conducted in accordance with the Declaration of Helsinki. In addition, the study was retrospectively registered at | PMC9851777 | ||
2.2. Inclusion and Exclusion Criteria | mental illness, allergy, cognitive impairment, liver and kidney insufficiency | ALLERGY, CARDIOPULMONARY DISEASE, DIGESTIVE TRACT DISEASE | From January 2019 to June 2021, 201 patients who underwent TKA were subjected to a strict eligibility review. The inclusion criteria were as follows: patients who received elective, initial, and single TKA. The exclusion criteria were as follows: (1) patients with an American Society of Anesthesiologists (ASA) classification of grade 4 or higher, (2) patients with a history of liver and kidney insufficiency, severe cardiopulmonary disease, severe digestive tract disease, and mental illness, (3) patients with an allergy to celecoxib or pregabalin or to anesthetic drugs, (4) patients who had taken celecoxib or pregabalin within 2 weeks before surgery, and (5) patients with cognitive impairment. A total of 160 patients were finally included in the study. | PMC9851777 |
2.3. Design and Conduct of the Study | postoperative nausea and vomiting, pain, dizziness, PONV, urinary retention | INFILTRATION, DEEP VEIN THROMBOSIS (DVT), ADVERSE EFFECTS, GASTROINTESTINAL HEMORRHAGE, COMPLICATIONS | Pregabalin and celecoxib are produced by Pfizer in the United States under the trade names Lyrica and Celebrex, respectively. Pregabalin, celecoxib, and the placebo were packaged in the same opaque packaging by the University Hospital Health Research Center pharmacy. The placebo capsule contained a mixture of 50% cellulose and 50% starch. An assistant from the Clinical Research Center used a random number table to divide the patients into four groups: the control group, celecoxib group, pregabalin group, and combination group. The patient group assignments were sealed in envelopes. Anesthesiologists who did not participate in the study opened the envelope 12 hours before the surgery, distributed drugs according to the patient group assignment, and distributed the same drugs again 2 hours before the surgery. The researchers involved did not know the patient group assignment during the surgery or data analysis. The medication program was as follows: placebo group: 200 mg + 150 mg placebo; pregabalin group: 150 mg pregabalin + 200 mg placebo; celecoxib group: 200 mg celecoxib + 150 mg placebo; and pregabalin combined with celecoxib group: 150 mg pregabalin + 200 mg celecoxib. Each group was given the same medication program again 2 hours before surgery. The patients were closely monitored for adverse effects after each administration of the medicine. All patients were given general anesthesia by senior anesthesiologists in our hospital. All operations were performed by two senior doctors with more than ten years of experience in TKA. Periarticular infiltration of the cocktail ingredient (0.5% ropivacaine + 10 mg/ml triamcinolone acetonide acetate + 0.1% epinephrine hydrochloride) was performed before closed the incision. Afterwards, the four groups of patients received patient-controlled intravenous analgesia (PCIA) immediately after the laryngeal mask was removed. The analgesic formula was sufentanil 2 The main observation indicators included the following:(1) VAS pain score at rest and upon movement at 6, 12, 24, and 48 hours after the surgery (from 0: no pain to 10: worst possible pain; pain upon movement was pain upon maximum flexion of the knee); (2) cumulative dose of opioids within 48 hours (including total sufentanil and morphine remedial analgesic dosages, all converted to sufentanil equivalent); (3) the hs-CRP level before and after the surgery; (4) time of first successful straight leg elevation: the standard is that the patient can maintain a flexed ankle joint and straight leg raise at least 40 cm above the bed for more than 4 s; (5) maximum knee flexion range of motion (ROM) at 24, 48, and 72 hours after surgery; (6) time to first remedial analgesia after surgery; and (7) complications including postoperative nausea and vomiting (PONV), dizziness, gastrointestinal hemorrhage, urinary retention, deep vein thrombosis (DVT), and severity of sedation. | PMC9851777 |
2.4. Statistical Analysis | Power analysis was performed based on the data from a previous study [ | PMC9851777 | ||
3. Results | vomiting reaction | A total of 160 patients were enrolled in the study, 7 patients discontinued PCIA because of severe vomiting reaction to sufentanil. 2 patients asked to withdraw from the study and 2 patients were suspended surgery. Consequently, 149 patients were included in the final data analysis. The CONSORT study participant flow diagram is shown in | PMC9851777 | |
3.1. Patient and Surgical Characteristics | There were no significant differences in the patient and surgical characteristics among the four groups ( | PMC9851777 | ||
3.2. VAS Pain Scores and the Cumulative Dose of Sufentanil | As shown in | PMC9851777 | ||
3.3. hs-CRP Level, Knee Function Indicator, and Incidence of Postoperative Complications | As shown in | PMC9851777 | ||
3.4. Linear Regression Analysis | pain | REGRESSION | In the linear regression analysis, the mean pain score upon movement within 48 hours after surgery (4.78 ± 1.02) was the independent variable ( | PMC9851777 |
4. Discussion | postoperative pain, nausea and vomiting, pain, urinary retention, TKA, drug dependence | CHRONIC PAIN, RESPIRATORY DEPRESSION, POSTOPERATIVE COMPLICATIONS | Perioperative pain management is key to the smooth implementation of enhanced recovery after surgery (ERAS), which has rapidly become a popular concept in the field of orthopedics. Although the combined application of various postoperative analgesia methods can improve the postoperative acute pain of TKA patients, many still suffer from moderate or even severe pain [Preemptive analgesia is an important part of multimodal analgesia, and its value is increasingly recognized by clinicians and researchers. Some studies have found that preemptive analgesia can further improve postoperative pain in TKA patients [In the present study, we observed that the combination group had better improvement in pain scores at rest and upon movement than the other three groups. The pain scores at rest in the combined group were always low level within 48 hours, and unlike the placebo group, there were no large fluctuations in pain scores, which indicated that the analgesic effect of the combination regimen was stable and relatively durable. However, the pain upon movement was more significant than that at rest because all of the patients need to exercise as soon as possible after TKA to enhance recovery. In the study of Lee et al. [Currently, analgesia after TKA mainly involves a variety of opioids, such as sufentanil, tramadol, and morphine. Opioids mainly act on opioid receptors in the pain center of the brain to inhibit the generation and amplification of pain signals. However, opioids have significant side effects, such as nausea and vomiting, drug dependence, urinary retention, excessive sedation, and respiratory depression. The majority of TKA patients are elderly patients, and the incidence of opioid side effects is significantly higher in elderly patients than in young and middle-aged patients [The key core of preemptive analgesia is to reduce the degree of peripheral and central pain sensitization and to improve the pain threshold of patients in advance [Our study has some limitations. First, our research was limited to within 72 hours after surgery, so we cannot be sure whether control of acute postoperative pain can promote long-term knee function recovery and reduce the possibility of long-term chronic pain. Second, we did not accurately estimate sample size, which may affect the efficacy of the present study. Third, according to the relevant study [Last, in terms of postoperative complications, our sample size was too small to comprehensively and objectively evaluate the safety of analgesia programs. | PMC9851777 |
5. Conclusion | pain | The preemptive analgesia regimen of pregabalin combined with celecoxib had positive effects on improving acute pain and reducing the cumulative dose of opioids after TKA. | PMC9851777 | |
Acknowledgments | The authors thank the trial patients and the trial site personnel who assisted with the trial. | PMC9851777 | ||
Data Availability | The data used to support the findings of this study are available from the corresponding author upon request. | PMC9851777 |
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