Prophylactic Intravenous Acetaminophen in Extremely Premature Infants: Minimum Effective Dose Research by Bayesian Approach.

BACKGROUND: Patent ductus arteriosus (PDA) in preterm infants is associated with increased morbidities and mortality. Prophylactic treatment with cyclooxygenase inhibitors, as indomethacin or ibuprofen, failed to demonstrate significant clinical benefits. Acetaminophen may represent an alternative treatment option. OBJECTIVE: This study evaluated the minimum effective dose of prophylactic acetaminophen to close the ductus and assessed the safety and tolerability profile in extremely preterm infants at 23-26 weeks of gestation. METHODS: A dose finding trial with Bayesian continual reassessment method was performed in a multicenter study with premature infants hospitalized in neonatal intensive care unit. Infants of 23-26 weeks of gestation and post-natal age ≤ 12 h were enrolled. Four intravenous acetaminophen dose levels were predefined. The primary outcome was the ductus arteriosus closing at two consecutive echocardiographies or at day 7. The main secondary objectives included the safety of acetaminophen on hemodynamics and biological hepatic function. RESULTS: A total of 29 patients were analyzed sequentially for the primary analysis with 20 infants assigned to the first dose level followed by 9 infants to the second dose level. No further dose level increase was necessary. The posterior probabilities of success, estimated from the Bayesian logistic model, were 46.1% [95% probability interval (PI), 24.9-63.9] and 67.6% (95% PI, 51.5-77.9) for dose level 1 and 2, respectively. A closing or closed pattern was observed among 19 patients at the end of treatment [65.5% (95% confidence interval (CI), 45.7-82.0)]. No change in alanine aminotransferase values was observed during treatment. A significant decrease in aspartate aminotransferase values was observed with postnatal age. No change in systolic and diastolic blood pressures was observed during treatment. CONCLUSIONS: Minimum effective dose to close the ductus was 25 mg/kg loading dose then 10 mg/kg/6 h for 5 days in extremely preterm infants. Acetaminophen was well tolerated in this study following these doses. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04459117.

Dolor local durante la administración de paracetamol endovenoso que tiene como excipiente ácido acético / Local pain during the administration of intravenous paracetamol with acetic acid as excipient

Objetivo: evaluar la presencia de dolor local durante la administración endovenosa de paracetamol con ácido acético respecto a la administración de paracetamol sin ácido acético en los pacientes intervenidos en el bloque quirúrgico.Métodos: se realizó un ensayo clínico controlado aleatorizado doble ciego de dos grupos. Se incluyeron los pacientes mayores de edad intervenidos en el bloque quirúrgico de la Fundació Salut Empordà (Girona, España) durante los meses de agosto a noviembre de 2020, que precisaron administración de paracetamol endovenoso. Se requerían 60 pacientes por grupo (paracetamol con acetato frente a paracetamol sin acetato). Se recogieron variables sociodemográficas, relativas al catéter venoso, tratamiento, presencia de dolor y momento, valoración del dolor según escala numérica verbal (0 sin dolor a 10 peor dolor imaginable). Análisis descriptivo y bivariado. Comparación de grupos según el protocolo asignado.Resultados: se incluyeron 60 pacientes en cada grupo. La media de edad fue de 56,6 años (DE=15,6), el 56,7% fue varón. Los grupos fueron homogéneos y comparables en el momento basal. Se identificó presencia de dolor en el 48,3% (n= 29) de los pacientes del grupo de infusión de paracetamol con ácido acético, mientras que en el grupo sin acetato no se dio ningún caso de dolor (p< 0,001).Conclusiones: se observaron diferencias estadísticamente significativas entre el grupo de pacientes intervenidos del bloque quirúrgico a los que se les administró paracetamol sin ácido acético, que no presentaron dolor, frente al grupo de paracetamol con ácido acético, con presencia de dolor casi en la mitad de los pacientes.(AU)

Objective: to evaluate the presence of local pain during the intravenous administration of paracetamol with acetic acid compared with the administration of paracetamol without acetic acid in patients undergoing a procedure in the surgical unit.Methods: a double-blind randomized controlled clinical trial was conducted on two groups. All patients of age who underwent a procedure in the surgical unit of the Fundació Salut Empordà (Girona, Spain) from August to November 2020 and who needed the administration of intravenous paracetamol were included in the study. Sixty (60) patients were required per group (paracetamol with acetate vs. paracetamol without acetate). Sociodemographic variables were collected, as well as those related to the venous catheter, treatment, presence and time of pain, pain assessment according to the verbal numerical scale (from 0=no pain to 10=the worst pain imaginable). Descriptive and bivariate analysis. Comparison between arms according to the assigned protocol.Results: sixty (60) patients were included in each arm. Their mean age was 56.6 years (SD =15.6), and 56.7% were male. Arms were homogeneous and comparable at baseline. The presence of pain was detected in 48.3% (n= 29) of patients in the group receiving infusion of paracetamol with acetic acid, while there were no cases of pain in the group without acetate (p< 0.001).Conclusions: statistically significant differences were observed between the group of patients undergoing procedures in the surgical unit who were administered paracetamol without acetic acid, who did not present pain, vs. the group receiving paracetamol with acetic acid, where pain was present in almost half of the patients.(AU)

Comparison of intravenous paracetamol (acetaminophen) to intravenously or intramuscularly administered non-steroidal anti-inflammatory drugs (NSAIDs) or opioids for patients presenting with moderate to severe acute pain conditions to the ED: systematic review and meta-analysis.

OBJECTIVE: Paracetamol, non-steroidal anti-inflammatory drugs (NSAIDs) and opiates/opioids, administered parenterally via intravenous or intramuscular route, are widely used to provide analgesia for patients with moderate to severe pain. This systematic review and meta-analysis evaluated the level of analgesia provided by intravenous paracetamol (IVP) alone compared with NSAIDs (intravenous or intramuscular), or opioids (intravenous) alone in adults attending the ED with acute pain. METHODS: Two authors independently searched PubMed (MEDLINE), Web of Science, Embase (OVID), Cochrane Library, SCOPUS and Google Scholar (3 March 2021-20 May 2022) for randomised trials without any language or date restriction. Clinical trials were evaluated using the Risk of Bias V.2 tool. The primary outcome was mean difference (MD) for pain reduction at 30 min (T30) post analgesia delivery. The secondary outcomes were MD in pain reduction at 60, 90 and 120 min; the need for rescue analgesia; and the occurrence of adverse events (AEs). RESULTS: Twenty-seven trials (5427 patients) were included in the systematic review and 25 trials (5006 patients) in the meta-analysis. There was no significant difference in pain reduction at T30 between the IVP group and opioids (MD -0.13, 95% CI -1.49 to 1.22) or IVP and NSAIDs (MD -0.27, 95% CI -1.0 to 1.54. There was also no difference at 60 min, IVP group versus opioid group (MD -0.09, 95% CI -2.69 to 2.52) or IVP versus NSAIDs (MD 0.51, 95% CI 0.11 to 0.91). The quality of the evidence using Grading of Recommendations, Assessments, Development and Evaluations methodology was low for MD in pain scores.The need for rescue analgesia at T30 was significantly higher in the IVP group compared with the NSAID group (risk ratio (RR): 1.50, 95% CI 1.23 to 1.83), with no difference found between the IVP group and the opioid group (RR: 1.07, 95% CI 0.67 to 1.70). AEs were 50% lower in the IVP group compared with the opioid group (RR: 0.50, 95% CI 0.40 to 0.62), whereas no difference was observed in the IVP group compared with the NSAID group (RR: 1.30, 95% CI 0.78 to 2.15). CONCLUSION: In patients presenting to the ED with a diverse range of pain conditions, IVP provides similar levels of pain relief compared with opiates/opioids or NSAIDs at T30 post administration. Patients treated with NSAIDs had lower risk of rescue analgesia, and opioids cause more AEs, suggesting NSAIDs as the first-choice analgesia and IVP as a suitable alternative. PROSPERO REGISTRATION NUMBER: CRD42021240099.

Paracetamol and ibuprofen combination for the management of acute mild-to-moderate pain in children: expert consensus using the Nominal Group Technique (NGT).

BACKGROUND: Acute pain is a common symptom in children of all ages, and is associated with a variety of conditions. Despite the availability of guidelines, pain often remains underestimated and undertreated. Paracetamol and ibuprofen are the most commonly used drugs for analgesia in Pediatrics. Multimodal pain management by using a combination of paracetamol and ibuprofen results in greater analgesia. METHODS: An investigation using the Nominal Group Technique was carried out between May and August 2022. Two open (non-anonymous) questionnaires were consecutively sent to a Board of ten clinicians to understand their opinions on the use of the oral paracetamol and ibuprofen association. Answers were examined in a final meeting where conclusions were drawn. RESULTS: The board achieved a final consensus on a better analgesic power of paracetamol and ibuprofen in fixed-dose combination as compared to monotherapy, without compromising safety. Strong consensus was reached on the opinion that the fixed-dose combination of paracetamol and ibuprofen may be a useful option in case of inefficacy of one or other drug as monotherapy, especially in case of headaches, odontalgia, earache, and musculoskeletal pain. The use of the fixed combination may be also considered suitable for postoperative pain management. CONCLUSIONS: The use of the fixed-dose combination may represent advantage in terms of efficacy and safety, allowing a better control of the dose of both paracetamol and ibuprofen as monotherapy, thus minimizing the risk of incorrect dosage. However, the limited evidence available highlights the need for future well designed studies to better define the advantages of this formulation in the various therapeutic areas.

Association of FDA Mandate Limiting Acetaminophen (Paracetamol) in Prescription Combination Opioid Products and Subsequent Hospitalizations and Acute Liver Failure.

Importance: In January 2011, the US Food and Drug Administration (FDA) announced a mandate to limit acetaminophen (paracetamol) to 325 mg/tablet in combination acetaminophen and opioid medications, with manufacturer compliance required by March 2014. Objective: To assess the odds of hospitalization and the proportion of acute liver failure (ALF) cases with acetaminophen and opioid toxicity prior to and after the mandate. Design, Setting, and Participants: This interrupted time-series analysis used hospitalization data from 2007-2019 involving ICD-9/ICD-10 codes consistent with both acetaminophen and opioid toxicity from the National Inpatient Sample (NIS), a large US hospitalization database, and ALF cases from 1998-2019 involving acetaminophen and opioid products from the Acute Liver Failure Study Group (ALFSG), a cohort of 32 US medical centers. For comparison, hospitalizations and ALF cases consistent with acetaminophen toxicity alone were extracted from the NIS and ALFSG. Exposures: Time prior to and after the FDA mandate limiting acetaminophen to 325 mg in combination acetaminophen and opioid products. Main Outcomes and Measures: Odds of hospitalization involving acetaminophen and opioid toxicity and percentage of ALF cases from acetaminophen and opioid products prior to and after the mandate. Results: In the NIS, among 474 047 585 hospitalizations from Q1 2007 through Q4 2019, there were 39 606 hospitalizations involving acetaminophen and opioid toxicity; 66.8% of cases were among women; median age, 42.2 (IQR, 28.4-54.1). In the ALFSG, from Q1 1998 through Q3 2019, there were a total of 2631 ALF cases, of which 465 involved acetaminophen and opioid toxicity; 85.4% women; median age, 39.0 (IQR, 32.0-47.0). The predicted incidence of hospitalizations 1 day prior to the FDA announcement was 12.2 cases/100 000 hospitalizations (95% CI, 11.0-13.4); by Q4 2019, it was 4.4/100 000 hospitalizations (95% CI, 4.1-4.7) (absolute difference, 7.8/100 000 [95% CI, 6.6-9.0]; P < .001). The odds of hospitalizations with acetaminophen and opioid toxicity increased 11%/y prior to the announcement (odds ratio [OR], 1.11 [95% CI, 1.06-1.15]) and decreased 11%/y after the announcement (OR, 0.89 [95% CI, 0.88-0.90]). The predicted percentage of ALF cases involving acetaminophen and opioid toxicity 1 day prior to the FDA announcement was 27.4% (95% CI, 23.3%-31.9%); by Q3 2019, it was 5.3% (95% CI, 3.1%-8.8%) (absolute difference, 21.8% [95% CI, 15.5%-32.4%]; P < .001). The percentage of ALF cases involving acetaminophen and opioid toxicity increased 7% per year prior to the announcement (OR, 1.07 [95% CI, 1.03-1.1]; P < .001) and decreased 16% per year after the announcement (OR, 0.84 [95% CI, 0.77-0.92]; P < .001). Sensitivity analyses confirmed these findings. Conclusions and Relevance: The FDA mandate limiting acetaminophen dosage to 325 mg/tablet in prescription acetaminophen and opioid products was associated with a statistically significant decrease in the yearly rate of hospitalizations and proportion per year of ALF cases involving acetaminophen and opioid toxicity.

Indicación de N-acetilcisteína en distintas formas de toxicidad por paracetamol / Indication of n-acetylcysteine in differents forms of paracetamol toxicity

Introducción: la hepatotoxicidad por paracetamol está relacionada con la formación del metabolito N-acetil-parabenzoquinoneimina (NAPQI) y su falta de detoxificación a través del glutatión, cuyas reservas se deplecionan en el contexto de una sobredosis. La administración de N-acetilcisteína (NAC) como sustancia dadora de grupos tioles (-SH) contribuye a la prevención del daño hepático que puede desarrollarse con dosis terapéuticas o tóxicas. Métodos: se comentan 5 casos de exposición a paracetamol en los cuales se administró NAC por alteración de la función hepática. La gravedad de los cuadros varió en función de las dosis y del tiempo de latencia hasta la consulta. Resultados: cuatro pacientes ingirieron una única dosis tóxica y una paciente recibió la dosis diaria máxima de paracetamol de 4000 mg/día durante 5 días. La paciente que consultó dentro de las 4 horas posteriores a la ingesta no presentó elevación de transaminasas. Todas las pacientes recibieron NAC y sus valores de enzimas hepáticas se normalizaron al momento del alta. Conclusión: la administración temprana de NAC puede ser útil para prevenir daño hepático tanto en ingestas de dosis tóxicas, como en casos de utilización de dosis terapéuticas máximas durante varios días. (AU)

Introduction: paracetamol hepatotoxicity is related to the formation of the metabolite N-acetyl-parabenzoquinoneimine (NAPQI) and its lack of detoxification through glutathione, whose reserves are depleted in paracetamol overdose. The administration of N-acetylcysteine (NAC) as a donor of sulfhydryl groups (-SH) can prevent liver damage that could even occur with therapeutic or toxic doses. Methods: 5 cases of exposure to paracetamol are discussed, in which NAC was administered due to impaired liver function. These manifestations presented different severity depending on the drug doses and the time until medical consultation. Results: four patients ingested single toxic doses and one patient received the maximum daily dose of paracetamol of 4000 mg/day for 5 days. The patient who consulted within 4 hours after ingestion did not present elevation of transaminases. All patients received NAC, with normal liver enzymes at discharge. Conclusion: the early administration of NAC may be useful to prevent liver damage both in toxic dose intakes and in cases of use of maximum therapeutic doses for several days. (AU)

Metabolomic Evaluation of N-Acetyl-p-Benzoquinone Imine Protein Adduct Formation with Therapeutic Acetaminophen Administration: Sex-based Physiologic Differences.

BACKGROUND: Acetaminophen (APAP)-associated transaminase elevation, induced by N-acetyl-p-benzoquinone imine (NAPQI) protein adduction, remains an area of research interest. Distinct from known genetic, physiologic, and dosage associations dictating severity of hepatic injury, no known factors predict an absence of protein adduct formation at therapeutic APAP dosing. HYPOTHESIS: Sex-based physiology is predictive of APAP-induced protein adduct formation and differential metabolite expression at therapeutic doses. METHODS: This retrospective study interrogated serum samples collected for a prior study investigating fluctuations of alanine aminotransferase (ALT) over time with 4G daily APAP dosing for ≥ 16 days in subjects from Denver, Colorado. Subjects were grouped by adduct formation (n = 184) vs no adducts (n = 20). Samples were run on ultra-high-performance liquid chromatography mass spectrometry from study days 0, 7, 16, and 31. Significant metabolite expressions were identified using t-tests with false discovery rate correction (FDR), partial least squares discriminant, and ANOVA simultaneous comparison analyses. Demographic and clinical data were explored using t-tests with FDR (age, weight, BMI, ALT) and Chi-square (sex, ethnicity, race) analyses. RESULTS: In pre-treatment samples, relative quantitation caprylic acid was expressed ninefold higher and 6-carboxyhexanoate was expressed threefold lower in subjects who did not develop adducts. Lactate had greater expression in the no adducts group (p = 0.001). Using absolute quantitation, glutathione was expressed 2.6-fold greater among no adduct subjects. Odds of males developing NAPQI protein adducts at therapeutic APAP dosing were 5.91 times lower than females (95% CI = 2.3-14.9; p = 0.0001). CONCLUSION: Multiple metabolites were differentially expressed based on adduct group and sex. Metabolites were identified unique to adduct development independent of sex. At therapeutic APAP dosing, males were less likely to develop APAP protein adducts. Further research into lipid biosynthesis and metabolism may provide further insight into physiology associated with adduct production.

Sensitivity of dose-estimations for acute acetaminophen overdose in predicting hepatotoxicity risk using the Rumack-Matthew Nomogram.

Timely assessment of acetaminophen concentration in overdose situations is not always available in resource-poor settings. The 150 mg/kg dose-estimate for acetaminophen is widely considered as criterion for acetaminophen overdose. Its sensitivity and specificity when compared to the 150 mg/L treatment line on the Rumack-Matthew Nomogram (150-treatment line) has rarely been evaluated. This is a retrospective chart review of acute acetaminophen overdose patients. We evaluated the sensitivity and specificity of the 150, 200 mg/kg and 8- and 10-g dose-estimates by plotting the serum acetaminophen levels and using 150-treatment line on the Nomogram as the treatment cut-off. A comparison of medical care costs was performed. We enrolled 784 cases for analysis. Median (IQR) age was 23 (20-28) years (81.9% female). There were 545 cases (69.5%) where the estimated ingested acetaminophen dose were ≥150 mg/kg and 406 cases (51.8%) with concentrations ≥150-treatment line. Hepatotoxicity and acute liver injury (ALI) occurred in 7.3% and 23.9%, respectively. The sensitivity and specificity of 150 mg/kg dose-estimate for the 150-treatment line were 92.6% (95% CI 89.6, 94.8) and 55.3% (95% CI 50.3, 60.2). Among patients with dose-estimate below150 mg/kg, none developed hepatotoxicity and 17 (7.1%) develop ALI. The administration of activated charcoal significantly decreased the risk of being above the 150-treatment line by half. In resource-poor setings, the use of 150 mg/kg dose-estimate as a stand-alone criteria for initiation of N-acetylcysteine therapy is satisfactory, especially when combined with decontamination with activated charcoal and follow up of aminotransferase at 24 h.

Effect of dexamethasone as an analgesic adjuvant to multimodal pain treatment after total knee arthroplasty: randomised clinical trial.

OBJECTIVE: To investigate the effects of one and two doses of intravenous dexamethasone in patients after total knee arthroplasty. DESIGN: Randomised, blinded, placebo controlled trial with follow-up at 90 days. SETTING: Five Danish hospitals, September 2018 to March 2020. PARTICIPANTS: 485 adult participants undergoing total knee arthroplasty. INTERVENTION: A computer generated randomised sequence stratified for site was used to allocate participants to one of three groups: DX1 (dexamethasone (24 mg)+placebo); DX2 (dexamethasone (24 mg)+dexamethasone (24 mg)); or placebo (placebo+placebo). The intervention was given preoperatively and after 24 hours. Participants, investigators, and outcome assessors were blinded. All participants received paracetamol, ibuprofen, and local infiltration analgesia. MAIN OUTCOME MEASURES: The primary outcome was total intravenous morphine consumption 0 to 48 hours postoperatively. Multiplicity adjusted threshold for statistical significance was P<0.017 and minimal important difference was 10 mg morphine. Secondary outcomes included postoperative pain. RESULTS: 485 participants were randomised: 161 to DX1, 162 to DX2, and 162 to placebo. Data from 472 participants (97.3%) were included in the primary outcome analysis. The median (interquartile range) morphine consumptions at 0-48 hours were: DX1 37.9 mg (20.7 to 56.7); DX2 35.0 mg (20.6 to 52.0); and placebo 43.0 mg (28.7 to 64.0). Hodges-Lehmann median differences between groups were: -2.7 mg (98.3% confidence interval -9.3 to 3.7), P=0.30 between DX1 and DX2; 7.8 mg (0.7 to 14.7), P=0.008 between DX1 and placebo; and 10.7 mg (4.0 to 17.3), P<0.001 between DX2 and placebo. Postoperative pain was reduced at 24 hours with one dose, and at 48 hours with two doses, of dexamethasone. CONCLUSION: Two doses of dexamethasone reduced morphine consumption during 48 hours after total knee arthroplasty and reduced postoperative pain. TRIAL REGISTRATION: Clinicaltrials.gov NCT03506789.

Effect of Acetaminophen use during pregnancy on adverse pregnancy outcomes: a systematic review and meta-analysis.

INTRODUCTION: A high number of women are exposed to acetaminophen during pregnancy worldwide. This drug safety during pregnancy regarding preterm birth, birth weight, and fetal development has not been well described. This study investigated the effect of acetaminophen use during pregnancy on selected adverse pregnancy outcomes. AREAS COVERED: Databases were searched to identify studies reporting the effects of acetaminophen use during pregnancy on preterm birth, low birth weight, and small for gestational age. The studies' quality was assessed by the Newcastle-Ottawa Scale and the Methodological Index for Non-Randomized Studies. Risk ratios with 95% confidence intervals were estimated using a fixed or random-effects model. Six studies were included for final review, four cohort and two case-control studies. We found no increased risk of preterm birth (RR 0.97; 95% CI 0.59-1.58), and decreased risks of low birth weight (RR 0.65; 95% CI 0.59-0.72) and small for gestational age (RR 0.69; 95% CI 0.50-0.97). Acetaminophen exposure during the third trimester revealed non-significantly in the outcomes. EXPERT OPINION: Exposure to acetaminophen during pregnancy appears to not increase the risk of the outcomes analyzed. However, there is a lack of information regarding the exposure dose and frequency of acetaminophen use.

Perioperative Buprenorphine Management: A Multidisciplinary Approach.

Buprenorphine formulations (including buprenorphine/naloxone) are effective treatments of pain and opioid use disorder (OUD). Historically, perioperative management of patients prescribed buprenorphine involved abstinence from buprenorphine sufficient to allow for unrestricted mu-opioid receptor availability to full agonist opioid (FAO) treatment. Evidence is mounting that a multimodal analgesic strategy, including simultaneous administration of buprenorphine and FAO, nonopioid adjuncts such as acetaminophen and nonsteroidal anti-inflammatory drugs, and regional anesthesia, is a safe and effective perioperative strategy for the patient prescribed long-term buprenorphine treatment of OUD. This strategy will likely simplify management and more seamlessly provide continuous buprenorphine treatment of OUD after hospital discharge.

Pain Management Following Otological Surgery: A Prospective Study of Different Strategies.

OBJECTIVES: The aim of this study was to prospectively assess pain and associated analgesic consumption after otological surgery comparing two prescription patterns. STUDY DESIGN: A prospective nonrandomized consecutive cohort study. METHODS: 125 adult patients undergoing ambulatory otologic surgery-cochlear implantation and endaural middle ear surgery, were assigned (according to surgeon's preference) and prospectively studied in two arms: 1) acetaminophen 500 mg + ibuprofen 400 mg; 2) acetaminophen 500 mg + codeine 30 mg. Pain levels, medication dose, disposal patterns of opioids, and suspected side effects were evaluated. RESULTS: All patients reported mild to moderate pain. There was a statistically significant reduction of pain from day to day, which was on average 0.26 lower than the day before. Sufficient pain control could be achieved with both drug regimens with no significant difference in pain levels. Only 50% of patients who were prescribed opioids used them. Additionally, the median tablet intake was 3 tablets while 10 to 20 tablets were prescribed. The majority of patients (97%) did not dispose of these drugs safely. CONCLUSION: Adequate analgesia was achieved in both arms of this study. Pain control following otologic surgery with a combination of acetaminophen and nonsteroidal anti-inflammatory drugs is recommended unless contraindications or chronic opioid use are present. If opioids such as codeine (30 mg) are prescribed, the amount should be reduced as low as possible, such as five tablets, based on our studied population. LEVEL OF EVIDENCE: 3 Laryngoscope, 132:204-211, 2022.

Opiate vs non-opiate prescription medication for pain control after endoscopic sinus surgery for chronic rhinosinusitis.

PURPOSE: Research indicates that most providers give opiates after endoscopic sinonasal surgery. The effectiveness of non-opiate medications after sinonasal surgery is poorly understood and most studies do not assess medication failure. This study compares oral opiate, oral opiate and topical steroid, and oral non-opiate pain control. Patient call-backs are used as a proxy for pain medication failure. MATERIALS AND METHODS: This study compares three medication regiments after sinonasal surgery for 180 adults with chronic rhinosinusitis. Patients were instructed to take acetaminophen for mild pain. For moderate/severe pain, patients used: 1) oxycodone-acetaminophen, 2) oxycodone-acetaminophen + budesonide nasal rinses, or 3) meloxicam + acetaminophen. Patients were instructed to call clinic if pain was not controlled. Descriptive statistics compared cohorts. Chi-square tests compared call-backs between cohorts. Logistic regression adjusted for baseline differences in covariates, comorbidities, and operative sites. RESULTS: Cohorts had similar age, sex distribution, disease features, and extent of surgery. The meloxicam cohort had less subjects with pain disorders. The oxycodone cohort had less subjects with diabetes, septoplasty, and turbinate reduction. After adjusting for baseline differences and using oxycodone as the reference group (n = 50), the odds of calling clinic for poorly controlled pain was 0.18 (95% Confidence Interval (CI): 0.05-0.6) in the meloxicam cohort (n = 45) and 0.19 (95% CI:0.07-0.5) in the oxycodone + budesonide rinses cohort (n = 85). CONCLUSION: In this study, both meloxicam and oxycodone + budesonide rinses were more effective at controlling pain after sinonasal surgery than oxycodone alone.

Short-Term Safety of Repeated Acetaminophen Use in Patients With Compensated Cirrhosis.

Current guidelines recommend restricting acetaminophen (APAP) use in patients with cirrhosis, but evidence to support that recommendation is lacking. Prior studies focused on pharmacokinetics (PK) of APAP in cirrhosis but did not rigorously examine clinical outcomes, sensitive biomarkers of liver damage, or serum APAP-protein adducts, which are a specific marker of toxic bioactivation. Hence, the goal of this pilot study was to test the effects of regularly scheduled APAP dosing in a well-defined compensated cirrhosis group compared to control subjects without cirrhosis, using the abovementioned outcomes. After a 2-week washout, 12 subjects with and 12 subjects without cirrhosis received 650 mg APAP twice per day (1.3 g/day) for 4 days, followed by 650 mg on the morning of day 5. Patients were assessed in-person at study initiation (day 1) and on days 3 and 5. APAP-protein adducts and both conventional (alanine aminotransferase) and sensitive (glutamate dehydrogenase [GLDH], full-length keratin 18 [K18], and total high-mobility group box 1 protein) biomarkers of liver injury were measured in serum on the mornings of days 1, 3, and 5, with detailed PK analysis of APAP, metabolites, and APAP-protein adducts throughout day 5. No subject experienced adverse clinical outcomes. GLDH and K18 were significantly different at baseline but did not change in either group during APAP administration. In contrast, clearance of APAP-protein adducts was dramatically delayed in the cirrhosis group. Minor differences for other APAP metabolites were also detected. Conclusion: Short-term administration of low-dose APAP (650 mg twice per day, <1 week) is likely safe in patients with compensated cirrhosis. These data provide a foundation for future studies to test higher doses, longer treatment, and subjects who are decompensated, especially in light of the remarkably delayed adduct clearance in subjects with cirrhosis.

Assessing efficacy of intravenous acetaminophen for perioperative pain control for oocyte retrieval: a randomized, double-blind, placebo-controlled trial.

OBJECTIVE: To compare the effect of preoperative intravenous (IV) acetaminophen versus oral (PO) acetaminophen or placebo on postoperative pain scores and the time to discharge in women undergoing oocyte retrieval. DESIGN: Randomized, double-blind, placebo-controlled trial. SETTING: Single academic fertility center. PATIENT(S): Women aged 18-43 years undergoing oocyte retrieval. INTERVENTION(S): Randomization to preoperative 1,000 mg IV acetaminophen and PO placebo (group A), IV placebo and 1,000 mg PO acetaminophen (group B), or IV and PO placebo (group C) MAIN OUTCOME MEASURE(S): Difference in patient-reported postoperative visual analog scale pain scores from baseline and the time to discharge. RESULT(S): Of the 159 women who completed the study, there were no differences in the mean postoperative pain score differences or the time to discharge. Although not statistically significant, the mean postoperative opioid dose requirement in group A was lower than that in groups B and C (0.24 vs. 0.59 vs. 0.58 mg IV morphine equivalents, respectively) due to fewer women in group A requiring rescue pain medication (8% vs. 19% vs. 15%, respectively). Group A also reported less constipation when compared with groups B and C (19% vs. 33% vs. 40%, respectively). The rates of postoperative nausea were similar, and there were no differences in embryology or early pregnancy outcomes between the study groups. CONCLUSION(S): Preoperative IV acetaminophen for women undergoing oocyte retrieval did not reduce postoperative pain scores or shorten the time to discharge when compared with PO acetaminophen or placebo and, thus, cannot currently be recommended routinely in this patient population. CLINICAL TRIAL REGISTRATION NUMBER: NCT03073980.

Biomarkers in neonates receiving potential nephrotoxic drugs.

OBJECTIVE: Novel biomarkers, such as kidney injury molecule-1 (KIM-1), cystatin, and neutrophil gelatinase-associated lipocalin (NGAL) were shown to predict acute kidney injury (AKI) earlier than serum creatinine in critically ill. We carried out the present study to evaluate these biomarkers in addition to conventional in our neonates. PATIENTS AND METHODS: We recruited 70 neonates of various gestational age groups receiving one or more potential nephrotoxic drug/s. Daily urine samples were collected for estimating KIM-1, cystatin, and NGAL. Modified neonatal kidney disease improving global outcomes (mKDIGO) classification was used in defining AKI. RESULTS: A significant trend in increased urine concentrations of KIM-1, cystatin, and NGAL were observed as we proceed from term to preterm categories. Strong positive correlation was observed between urine albumin and urine albumin creatinine ratio (ACR), and strong negative correlations between urine creatinine and urine cystatin, and between urine creatinine with urine NGAL. A moderate positive correlation was observed between urine KIM-1 and urine cystatin, between urine KIM-1 and urine NGAL, and between urine cystatin and urine NGAL; and a moderate negative correlation was observed between urine creatinine and urine KIM-1. Seven neonates met the mKDIGO criteria for AKI and ROC plot revealed that baseline KIM-1 and NGAL can significantly predict possible drug-induced AKI in neonates. CONCLUSIONS: Urine KIM-1, cystatin, and NGAL are significantly correlated with several other conventional biomarkers that reflect renal function in critically ill neonates. Baseline urine KIM-1 and NGAL concentrations can predict the AKI following potential nephrotoxic drug use in this population.

Association of Intravenous Acetaminophen Administration With the Duration of Intravenous Opioid Use Among Hospitalized Pediatric Patients.

Importance: Adoption of multimodal pain regimens that incorporate nonopioid analgesic medications to reduce inpatient opioid administration can prevent serious opioid-related adverse effects in children, including tolerance, withdrawal, delirium, and respiratory depression. Intravenous (IV) acetaminophen is in widespread pediatric use; however, its effectiveness as an opioid-sparing agent has not been evaluated in general pediatric inpatients. Objective: To determine if IV acetaminophen administered prior to IV opioids is associated with a reduction in the total duration of IV opioids administered compared with IV opioids administered without IV acetaminophen in general pediatric inpatients. Design, Setting, and Participants: This comparative effectiveness research study included data on pediatric inpatients from 274 US hospitals between January 2011 and June 2016 collected from a national database. Outcomes were compared with a propensity score-matched analysis of pediatric inpatients administered IV opioids without IV acetaminophen (control) and those administered IV acetaminophen prior to IV opioids (intervention). Data were analyzed from January 2020 through October 2021. Exposures: Patients in the intervention group received IV acetaminophen prior to IV opioids. Patients in the control group received IV opioids without IV acetaminophen. Main Outcomes and Measures: Total duration of all IV opioids administered during a patient's hospitalization. Results: Of 893 293 pediatric inpatients, a total of 104 579 were included in analysis (median [IQR] age, 1.3 [0-14.7] years; 59 806 [57.2%] female; 21 485 [21.5%] African American, 56 309 [53.8%] White), of whom 18 197 (2.0%) received IV acetaminophen, and 287 504 (34.0%) received IV opioids. After applying exclusion criteria, among patients who received IV acetaminophen, 1739 (10.8%) received IV acetaminophen prior to IV opioids within a median (IQR) treatment time of 1.5 (0.02-7.3) hours. After propensity score matching produced comparable groups in the control and intervention groups (with 839 patients in each group), the multivariable model estimated a 15.5% shorter duration of IV opioid use in the intervention group, with an absolute IV opioid reduction of 7.5 hours (95% CI, 0.7-15.8 hours). Conclusions and Relevance: In this comparative effectiveness study, IV acetaminophen administered prior to IV opioids was associated with a reduction in IV opioid duration by 15.5%. Multimodal pain regimens that use IV acetaminophen prior to IV opioids could reduce IV opioid duration.

COVID Arm After Moderna Booster in Healthcare Worker: A Case Report.

SARS CoV-2 virus has infected more than 200 million people worldwide and more than 4.4 million in Indonesia. The vaccination program has become one of the solutions launched by many countries globally, including Indonesia, to reduce the transmission rate of COVID-19. Various vaccination platforms are produced, such as inactivated, viral vector, mRNA, and protein subunit. The vaccination booster program with mRNA platform (Moderna) was launched by the Indonesian government to give better protection for health care workers, particularly from delta variant. In this case report, we discuss one of the typical side effects of Moderna vaccine, which is referred to as the COVID arm.