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Acetaminophen, bupivacaine, Duramorph, and Toradol: A comparison of chondrocyte viability and gene expression changes in osteoarthritic human chondrocytes.
Cooke, C, Osborne, J, Jackson, N, Keating, P, Flynn, J, Markel, D, Chen, C, Lemos, S
The Knee. 2020;(6):1746-1752
Abstract
BACKGROUND A multitude of chemical agents are currently used intra-articularly to decrease pain after orthopaedic procedures including total knee arthroplasty. However, the possible deleterious effects of these injectable chemicals on chondrocyte viability have not been weighed against their potential benefits. Using a human osteoarthritic chondrocyte model, the purpose of this study was to assess the potential for cartilage damage caused by bupivacaine, Toradol, Duramorph, and acetaminophen from surgical local anesthesia. METHODS Human distal femur and proximal tibia cross sections were obtained during total knee arthroplasty and divided into control group and experimental groups treated by bupivacaine, Toradol, Duramorph, and acetaminophen respectively. Chondrocytes obtained from enzymatically digested cartilage were cultured using a 3D alginate bead culture method to ensure lower rates of dedifferentiation. Chondrocyte bead cultures were exposed to the study chemicals. The gene expression and chondrocyte viability were measured by RT-PCR and flow cytometry, respectively. RESULTS Compared with untreated group bupivacaine treatment led to the greatest cellular apoptosis with 30.5 ± 11% dead cells (P = 0.000). Duramorph and acetaminophen did not result in a significant increase in cell death. Bupivacaine treatment led to an increase in Caspase 3 gene expression (P = 0.000) as well as the acetaminophen treatment (P = 0.001) when compared to control. CONCLUSION Our data demonstrated that Duramorph and Toradol were not cytotoxic to human chondrocytes and may be better alternatives to the frequently used and more cytotoxic bupivacaine. Acetaminophen did not result in increased cell death; however, it did show increased caspase 3 gene expression and caution should be considered.
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Early acetaminophen-protein adducts predict hepatotoxicity following overdose (ATOM-5).
Chiew, AL, James, LP, Isbister, GK, Pickering, JW, McArdle, K, Chan, BSH, Buckley, NA
Journal of hepatology. 2020;(3):450-462
Abstract
BACKGROUND & AIMS Acetaminophen-protein adducts are specific biomarkers of toxic acetaminophen (paracetamol) metabolite exposure. In patients with hepatotoxicity (alanine aminotransferase [ALT] >1,000 U/L), an adduct concentration ≥1.0 nmol/ml is sensitive and specific for identifying cases secondary to acetaminophen. Our aim was to characterise acetaminophen-protein adduct concentrations in patients following acetaminophen overdose and determine if they predict toxicity. METHODS We performed a multicentre prospective observational study, recruiting patients 14 years of age or older with acetaminophen overdose regardless of intent or formulation. Three serum samples were obtained within the first 24 h of presentation and analysed for acetaminophen-protein adducts. Acetaminophen-protein adduct concentrations were compared to ALT and other indicators of toxicity. RESULTS Of the 240 patients who participated, 204 (85%) presented following acute ingestions, with a median ingested dose of 20 g (IQR 10-40), and 228 (95%) were treated with intravenous acetylcysteine at a median time of 6 h (IQR 3.5-10.5) post-ingestion. Thirty-six (15%) patients developed hepatotoxicity, of whom 22 had an ALT ≤1,000 U/L at the time of initial acetaminophen-protein adduct measurement. Those who developed hepatotoxicity had a higher initial acetaminophen-protein adduct concentration compared to those who did not, 1.63 nmol/ml (IQR 0.76-2.02, n = 22) vs. 0.26 nmol/ml (IQR 0.15-0.41; n = 204; p <0.0001), respectively. The AUROC for hepatotoxicity was 0.98 (95% CI 0.96-1.00; n = 226; p <0.0001) with acetaminophen-protein adduct concentration and 0.89 (95% CI 0.82-0.96; n = 219; p <0.0001) with ALT. An acetaminophen-protein adduct concentration of 0.58 nmol/ml was 100% sensitive and 91% specific for identifying patients with an initial ALT ≤1,000 U/L who would develop hepatotoxicity. Adding acetaminophen-protein adduct concentrations to risk prediction models improved prediction of hepatotoxicity to a level similar to that obtained by more complex models. CONCLUSION Acetaminophen-protein adduct concentration on presentation predicted which patients with acetaminophen overdose subsequently developed hepatotoxicity, regardless of time of ingestion. An adduct threshold of 0.58 nmol/L was required for optimal prediction. LAY SUMMARY Acetaminophen poisoning is one of the most common causes of liver injury. This study examined a new biomarker of acetaminophen toxicity, which measures the amount of toxic metabolite exposure called acetaminophen-protein adduct. We found that those who developed liver injury had a higher initial level of acetaminophen-protein adducts than those who did not. CLINICAL TRIAL REGISTRATION Australian Toxicology Monitoring (ATOM) Study-Australian Paracetamol Project: ACTRN12612001240831 (ANZCTR) Date of registration: 23/11/2012.
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Environmental risk factors, protective factors, and peripheral biomarkers for ADHD: an umbrella review.
Kim, JH, Kim, JY, Lee, J, Jeong, GH, Lee, E, Lee, S, Lee, KH, Kronbichler, A, Stubbs, B, Solmi, M, et al
The lancet. Psychiatry. 2020;(11):955-970
Abstract
BACKGROUND Many potential environmental risk factors, environmental protective factors, and peripheral biomarkers for ADHD have been investigated, but the consistency and magnitude of their effects are unclear. We aimed to systematically appraise the published evidence of association between potential risk factors, protective factors, or peripheral biomarkers, and ADHD. METHODS In this umbrella review of meta-analyses, we searched PubMed including MEDLINE, Embase, and the Cochrane Database of Systematic Reviews, from database inception to Oct 31, 2019, and screened the references of relevant articles. We included systematic reviews that provided meta-analyses of observational studies that examined associations of potential environmental risk factors, environmental protective factors, or peripheral biomarkers with diagnosis of ADHD. We included meta-analyses that used categorical ADHD diagnosis criteria according to DSM, hyperkinetic disorder according to ICD, or criteria that were less rigorous than DSM or ICD, such as self-report. We excluded articles that did not examine environmental risk factors, environmental protective factors, or peripheral biomarkers of ADHD; articles that did not include a meta-analysis; and articles that did not present enough data for re-analysis. We excluded non-human studies, primary studies, genetic studies, and conference abstracts. We calculated summary effect estimates (odds ratio [OR], relative risk [RR], weighted mean difference [WMD], Cohen's d, and Hedges' g), 95% CI, heterogeneity I2 statistic, 95% prediction interval, small study effects, and excess significance biases. We did analyses under credibility ceilings, and assessed the quality of the meta-analyses with AMSTAR 2 (A Measurement Tool to Assess Systematic Reviews 2). This study is registered with PROSPERO, number CRD42019145032. FINDINGS We identified 1839 articles, of which 35 were eligible for inclusion. These 35 articles yielded 63 meta-analyses encompassing 40 environmental risk factors and environmental protective factors (median cases 16 850, median population 91 954) and 23 peripheral biomarkers (median cases 175, median controls 187). Evidence of association was convincing (class I) for maternal pre-pregnancy obesity (OR 1·63, 95% CI 1·49 to 1·77), childhood eczema (1·31, 1·20 to 1·44), hypertensive disorders during pregnancy (1·29, 1·22 to 1·36), pre-eclampsia (1·28, 1·21 to 1·35), and maternal acetaminophen exposure during pregnancy (RR 1·25, 95% CI 1·17 to 1·34). Evidence of association was highly suggestive (class II) for maternal smoking during pregnancy (OR 1·6, 95% CI 1·45 to 1·76), childhood asthma (1·51, 1·4 to 1·63), maternal pre-pregnancy overweight (1·28, 1·21 to 1·35), and serum vitamin D (WMD -6·93, 95% CI -9·34 to -4·51). INTERPRETATION Maternal pre-pregnancy obesity and overweight; pre-eclampsia, hypertension, acetaminophen exposure, and smoking during pregnancy; and childhood atopic diseases were strongly associated with ADHD. Previous familial studies suggest that maternal pre-pregnancy obesity, overweight, and smoking during pregnancy are confounded by familial or genetic factors, and further high-quality studies are therefore required to establish causality. FUNDING None.
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Impact of Preoperative Acetaminophen and Carbohydrate Loading on Pain and Functional Status in Patients Undergoing Mohs Micrographic Surgery for Nonmelanoma Skin Cancers.
Aleisa, A, Naccarato, L, Gramz, M, Patel, J, Nguyen, B
Dermatologic surgery : official publication for American Society for Dermatologic Surgery [et al.]. 2020;(7):863-867
Abstract
BACKGROUND Preoperative acetaminophen and carbohydrate loading has been shown to improve the functional recovery of surgical patients. OBJECTIVE To determine the effects of preoperative acetaminophen and carbohydrates on functional outcomes and the use of pain medications after surgery in patients undergoing Mohs Micrographic Surgery (MMS) for nonmelanoma skin cancer (NMSC). MATERIALS AND METHODS One hundred patients treated with MMS for NMSC at an academic center were randomized into a control group receiving standard preoperative care or an intervention group receiving acetaminophen and carbohydrate drinks immediately before surgery. Patients rated levels of pain, thirst, hunger, anxiety, and fatigue on the day of surgery on a scale of 0 to 100, and reported through a phone interview the use of pain medications within 48 hours of surgery. RESULTS There was no significant difference between intervention and control groups in maximum pain score on the day of surgery; maximum pain score 48 hours after surgery; use of nonopioid pain medications; and use of opioids. However, the intervention group had lower anxiety levels during and at the end of surgery. CONCLUSION Patients undergoing MMS for NMSC reported very low levels of pain during and after surgery. Preoperative acetaminophen and carbohydrate loading had no impact on pain levels or the use of pain medications but did reduce levels of anxiety.
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Comparing the effects of ketorolac and Paracetamol on postoperative pain relief after coronary artery bypass graft surgery. A randomized clinical trial.
Javaherforooshzadeh, F, Abdalbeygi, H, Janatmakan, F, Gholizadeh, B
Journal of cardiothoracic surgery. 2020;(1):80
Abstract
INTRODUCTION Pain management after coronary artery bypass graft (CABG) surgery remains challenging. OBJECTIVE This study aimed to compare the effects of Ketorolac and Paracetamol on postoperative CABG pain relief. METHOD This double-blind randomized clinical trial study was conducted in Ahvaz, Iran, from September 2018-December 2019. Two consecutive groups of 60 patients undergoing elective on-pump coronary artery bypass graft surgery. INTERVENTION The patients were divided into 0.5 mg/kg of ketorolac mg/dl and 10 mg/kg of Paracetamol after surgery for pain management. Primary outcomes were: visual analog pain scale (VAS) at the time point immediately after extubation (baseline) and at 6, 12, 24 and 48 h and the total dose of morphine consumption. Secondary outcomes included the hemodynamic variables, weaning time, chest tube derange, in-hospital mortality and myocardial infarction. STATISTICAL ANALYSIS The data were analyzed using SPSS version 22(SPSS, Chicago, IL). The Mann-Whitney U-test was used to compare demographic data, VAS scores, vital signs, and side effects. Repeated measurements were tested within groups using Friedman's ANOVA and the Wilcoxon rank-sum test. Values were expressed as means ± standard deviations. Statistical significance was defined as a p-value < 0.05. RESULTS Compared with baseline scores, there were significant declines in VAS scores in both groups throughout the time sequence (P< 0.05). The statistical VAS score was slightly higher in the Paracetamol group at most time points, except for the time of 6 h. However, at 24 and 48 h, the VAS score in group Paracetamol was significantly higher than in group Ketorolac. There were no significant differences between groups about hemodynamic variables. CONCLUSION The efficacy of ketorolac is comparable to that of Paracetamol in postoperative CABG pain relief. TRIAL REGISTRY IRCT20150216021098N5. Registered at 2019-09-12.
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Prophylactic intravenous paracetamol use in extremely premature infants for patent ductus arteriosus.
Silahli, M, Gokmen, Z, Tekin, M
Journal of basic and clinical physiology and pharmacology. 2020;(5):943-950
Abstract
OBJECTIVES Patency of ductus arteriosus (PDA) is a very common problem among extremely low birth weight infants (ELBW). Hemodynamic instability caused by PDA is associated with important morbidities. This study aims to evaluate the effects of prophylactic intravenous paracetamol on the hemodynamically significant patent ductus arteriosus (hsPDA). METHODS A total of 75 infants of <28 week-gestational age were enrolled into the study which was retrospective. Prophylactic paracetamol as the experimental group and none-prophylaxis group as the control group were compared in the study. RESULTS There were 35 subjects in the prophylactic paracetamol group (PPG), and 40 in the control group. Primary outcome measures were ductal closure, ductal diameter, grade 3-4 IVH, and repeated ibuprofen need for the treatment of hsPDA. At the time of the evaluation by echo, hsPDA, and the diameter of the ductus higher than 1 mm were found significantly lower in the PPG (p=0.004 and p=0.013). Additionally, the repeated course of ibuprofen was significantly lower in the PPG (p=0.025). Secondary outcomes were the other perinatal morbidities. According to the results of the study, the male gender is 6.6, and the paracetamol use is 5.5 times more likely to suffer from ROP. CONCLUSIONS The results of the study indicated that prophylactic paracetamol use in ELBW infants decreases the likelihood of hsPDA. The repeated course of ibuprofen for the treatment of hsPDA can be reduced. Furthermore, it can be understood that while prophylactic use of paracetamol is preventive for intraventricular hemorrhage, it does not function in the same way for retinopathy of prematurity or bronchopulmonary dysplasia. It might even worse the retinopathy of prematurity. Further prospective randomized controlled and larger sample-sized studies are needed.
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Analgesic efficacy of ketorolac associated with a tramadol/acetaminophen combination after third molar surgery - a randomized, triple-blind clinical trial.
Martins, LD, Rezende, M, Loguercio, AD, Bortoluzzi, MC, Reis, A
Medicina oral, patologia oral y cirugia bucal. 2019;(1):e96-e102
Abstract
BACKGROUND This study compared the efficacy of ketorolac alone versus its combination with tramadol/acetaminophen for pain control after mandibular third molar surgery. MATERIAL AND METHODS A randomized, triple-blind clinical trial was carried out with 52 patients divided into 2 groups: Group K+T+A (1 tablet of Ketorolac 10 mg plus and 1 capsule of Tramadol 37.5 mg/acetaminophen 325 mg) and Group K (1 tablet of Ketorolac 10 mg plus and 1 placebo capsule). The treatments were given 1 h before the surgery and was repeated 4 times per day, for 48 h. The difference in postoperative pain was assessed by 4 primary end-points: pain intensity (VAS 100mm, for 48 h), rescue medication, overall assessment and adverse effects. RESULTS Significant differences in pain intensity were observed in the different times (p < 0.05). The comparison of groups in each time showed significant differences only of 9 h, with lower level of pain intensity for group K+T+A (p = 0.005). The need of analgesics was higher in Group K (p < 0.001), the need of antiemetic were greater in Group K+T+A (p < 0.0001). No significant difference between groups were observed in overall assessment. The adverse effects was higher in Group K+T+A. CONCLUSIONS The current study showed that both ketorolac and the combination of ketorolac plus tramadol/acetaminophen showed good control of pain after the extraction of the lower third molars. Although the combination group showed lower pain at 9 h, the difference is small and not clinically relevant.
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Intravenous dexketoprofen versus paracetamol in non-traumatic musculoskeletal pain in the emergency department: A randomized clinical trial.
Demirozogul, E, Yilmaz, A, Ozen, M, Turkcuer, I, Seyit, M, Arikan, C
The American journal of emergency medicine. 2019;(12):2136-2142
Abstract
INTRODUCTION Although acute musculoskeletal pain has a wide range of causes from tendinitis, muscle spasm, to bone and joint injuries, it is a frequent occurrence in emergency services. Paracetamol and non-steroidal anti-inflammatory analgesics (NSAID) are common used in the treatment of musculoskeletal pain. This study sets out to compare the effectiveness of intravenous dexketoprofen and paracetamol in musculoskeletal pain relief. METHODS This prospective, randomized, double blind, controlled study was carried out in a university emergency room. The participating patients were randomized into two groups to receive either 50 mg of dexketoprofen or 1000 mg of paracetamol intravenously by rapid infusion in 150 ml of normal saline. Visual analogue scale (VAS), Numeric Rating Scala (NRS) was employed for pain measurement at baseline, after 15, after 30 and after 60 mins. RESULTS 200 patients were included in the study, excluding 7342 of them. The mean age of the patients was calculated as 32,6. Paracetamol and dexketoprofen intervention decreases NRS pain scores over time. When compared to all pain locations, the NRS pain score of the patients was found to be statistically more effective in dexketoprofen than in paracetamol (p = 0.001). Paracetamol and dexketoprofen intervention reduces pain VAS scores over time. When the VAS pain score of the patients was compared to all pain locations, dexketoprofen was found to be statistically more effective than paracetamol (p = 0.001). CONCLUSION Intravenous dexketoprofen seemed to achieve superior analgesia to intravenous paracetamol when compared with all pain locations in patients with non-traumatic musculoskeletal pain.
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Postoperative pain and bleeding after adenotonsillectomy versus adenotonsillotomy in pediatric obstructive sleep apnea: an RCT.
Borgström, A, Nerfeldt, P, Friberg, D
European archives of oto-rhino-laryngology : official journal of the European Federation of Oto-Rhino-Laryngological Societies (EUFOS) : affiliated with the German Society for Oto-Rhino-Laryngology - Head and Neck Surgery. 2019;(11):3231-3238
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Abstract
PURPOSE Our previous randomized controlled trial (RCT) of children with obstructive sleep apnea (OSA) showed no significant differences between adenotonsillectomy (ATE) and adenotonsillomy (ATE) in improving nocturnal respiration and symptoms after one year. This is the continuous report with the evaluation of postoperative morbidity concerning bleeding and pain. METHODS A double-blinded RCT including 79 children, aged 2-6 years, with moderate to severe OSA, randomized to either ATE (n = 40) or ATT (n = 39). From one to ten days postoperatively, parents filled in a logbook with six pain-related outcomes (parent and child grading pain at different levels, days of analgesic use and return to normal diet). Peri- and postoperative bleeding were also registered. RESULTS 63 patients (80%) returned the logbook. There were significant differences between groups in only two of the six pain-related outcomes in favor of the ATT group; first day when the children graded themselves as pain free (p = 0.021, Log Rank Test), and first day the caregiver estimated pain VAS ≤ 5 (p = 0.007, Log Rank Test). Two (5%) cases of postoperative bleeding occurred in the ATE group, one of which needed a return to theatre. No case of postoperative bleeding was seen in the ATT group. CONCLUSIONS The results from this RCT are in line with previous comparative studies between ATT and ATE. Children operated with ATT had significantly less postoperative pain in one-third of the outcomes, and less bleeding than ATE. However, as the differences in morbidity between the surgical methods were minor the clinical significance is uncertain. TRIAL REGISTRATION This study was approved by the Swedish Regional Ethics Board in Stockholm, Sweden (Dnr 2011/925-32 and 2013/2274-32) and registered at ClinicalTrials.gov (Trial registration number NCT01676181).
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Administering analgesia sublingually is a suitable option for children with acute abdominal pain in the emergency department.
Cozzi, G, Zanchi, C, Chiaretti, A, Tipo, V, Cernich, M, D'Anna, C, Fantacci, C, Conversano, E, Zanon, D, Ronfani, L, et al
Acta paediatrica (Oslo, Norway : 1992). 2019;(1):143-148
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AIM: Acute abdominal pain is a frequent complaint in children attending emergency departments. The aim of this study was to investigate the pain score reductions when children with acute abdominal pain received medication sublingually. METHODS We carried out a multicentre randomised controlled trial in three children's hospitals in Italy between March 2015 and June 2017. Children from four to 18 years of age with acute abdominal pain were recruited if their self-reported pain was at least six on a scale from 0-10. The children were randomised to receive ketorolac 0.5 mg/kg (n = 70) or tramadol 2 mg/kg (n = 70) sublingually or a melt in the mouth powder of 20 mg/kg paracetamol (n = 70). The main study outcome was the pain scores for the three drugs after two hours. RESULTS The 210 children (58.6% girls) had a median age of 12 years with an interquartile range of 9-14.3. The median pain scores at two hours were not significantly different between ketorolac 2.0 (interquartile ranges, IQR 0.0-4.3) and tramadol 3.0 (IQR 1.0-5.0) vs paracetamol 3.0 (IQR 0.8-5.0). The median pain reductions were all 5.0 points. CONCLUSION Delivering analgesia sublingually was a suitable option for pain relief in children with acute abdominal pain in the emergency department.