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1.
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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2.
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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3.
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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4.
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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5.
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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6.
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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7.
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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8.
Oral Diclofenac Potassium Versus Intravenous Acetaminophen in Acute, Isolated, Closed-Limb Trauma.
Momeni, M, Vahidi, E, Badrizadeh, M, Naderpour, Z, Saeedi, M
Advanced emergency nursing journal. 2019;(1):48-55
Abstract
Pain control is an important concern in limb trauma. The most ideal agent for this purpose varies among different hospitals. The objective of this study was to compare the analgesic effect of oral diclofenac potassium versus intravenous acetaminophen in patients with limb trauma. This was a double-blind randomized clinical trial conducted on 60 adult patients. Oral diclofenac potassium (50 mg) was given in Group D, and intravenous acetaminophen (1 g in 500 ml normal saline over 20 min) was administered in Group A. Patients' pain scores (visual analogue scale) were recorded and compared at baseline, 5, 15, 30, 60 min, and 4 hr after drug administration. The mean age was 42.62 ± 15.42 and 38.04 ± 17.48 years in Group A and Group D, respectively. No significant change was observed between the 2 groups (p = 0.11). In this study, both drugs could decrease the pain score effectively and safely in isolated limb trauma.
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9.
Multimodal opioid-sparing postoperative pain regimen compared with the standard postoperative pain regimen in vaginal pelvic reconstructive surgery: a multicenter randomized controlled trial.
Petrikovets, A, Sheyn, D, Sun, HH, Chapman, GC, Mahajan, ST, Pollard, RR, El-Nashar, SA, Hijaz, AK, Mangel, J
American journal of obstetrics and gynecology. 2019;(5):511.e1-511.e10
Abstract
BACKGROUND Postoperative pain control after urogynecological surgery has traditionally been opioid centered with frequent narcotic administration. Few studies have addressed optimal pain control strategies for vaginal pelvic reconstructive surgery that limit opioid use. OBJECTIVE The objective of the study was to determine whether, ice packs, Tylenol, and Toradol, a novel opioid-sparing multimodal postoperative pain regimen has improved pain control compared with the standard postoperative pain regimen in patients undergoing inpatient vaginal pelvic reconstructive surgery. STUDY DESIGN This was a multicenter randomized controlled trial of women undergoing vaginal pelvic reconstructive surgery. Patients were randomized to the ice packs, Tylenol, and Toradol postoperative pain regimen or the standard regimen. The ice packs, Tylenol, and Toradol regimen consists of around-the-clock ice packs, around-the-clock oral acetaminophen, around-the-clock intravenous ketorolac, and intravenous hydromorphone for breakthrough pain. The standard regimen consists of as-needed ibuprofen, as-needed acetaminophen/oxycodone, and intravenous hydromorphone for breakthrough pain. The primary outcome was postoperative day 1 pain evaluated the morning after surgery using a visual analog scale. Secondary outcomes included the validated Quality of Recovery Questionnaire, satisfaction scores, inpatient narcotic consumption, outpatient pain medication consumption, and visual analog scale scores at other time intervals. In all, 27 patients in each arm were required to detect a mean difference of 25 mm on a 100 mm visual analog scale (90% power). RESULTS Thirty patients were randomized to ice packs, Tylenol, and Toradol and 33 to the standard therapy. Patient and surgical demographics were similar. The median morning visual analog scale pain score was lower in the ice packs, Tylenol, and Toradol group (20 mm vs 40 mm, P = .03). Numerical median pain scores were lower at the 96 hour phone call in the ice packs, Tylenol, and Toradol group (2 vs 3, P = .04). Patients randomized to the ICE-T regimen received fewer narcotics (expressed in oral morphine equivalents) from the postanesthesia care unit exit to discharge (2.9 vs 20.4, P < .001) and received fewer narcotics during the entire hospitalization (55.7 vs 91.2, P < .001). At 96 hour follow up, patients in the ice packs, Tylenol, and Toradol group used 4.9 ketorolac tablets compared with 4.6 oxycodone/acetaminophen tablets in the standard group (P = .81); however, ice packs, Tylenol, and Toradol patients required more acetaminophen than ibuprofen by patients in the standard arm (10.7 vs 6.2 tablets, P = .012). There were no differences in Quality of Recovery Questionnaire or satisfaction scores either in the morning after surgery or at 96 hour follow up. CONCLUSION The ice packs, Tylenol, and Toradol multimodal pain regimen offers improved pain control the morning after surgery and 96 hours postoperatively compared with the standard regimen with no differences in patient satisfaction and quality of recovery. Ice packs, Tylenol, and Toradol can significantly limit postoperative inpatient narcotic use and eliminate outpatient narcotic use in patients undergoing vaginal pelvic reconstructive surgery.
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10.
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.