In vitro analysis of n-acetylcysteine (NAC) interference with the international normalized ratio (INR).

BACKGROUND: Previous literature suggests a laboratory interference of n-acetylcysteine (NAC) with prothrombin time (PT) and the international normalized ratio (INR). Early publications focused on this interaction in the setting of an acetaminophen overdose and evaluated the INR of patients receiving intravenous NAC. However, there is limited literature describing the concentration-effect relationship of NAC to INR measurement in the absence of acetaminophen-induced hepatotoxicity at therapeutic NAC concentrations. The purpose of the study is to quantify the degree of interference of NAC on INR values at therapeutic concentrations correlating to each infusion of the regimen (ex. bag 1: 550 mcg/mL, bag 2: 200 mcg/mL, bag 3: 35 mcg/mL, double bag 3: 70 mcg/mL) and at supratherapeutic concentrations in vitro. METHODS: Blood samples were obtained from study volunteers. Each blood sample was transferred into vials containing 0.3 mL buffered sodium citrate 3.2% and spiked with various concentrations of NAC for final concentrations of 0, 35, 70, 200, 550, 1000, 2000, and 4000 mcg/mL. The samples were centrifuged and tested to determine PT and INR on two separate machines: Siemens CS-2500 and Stago SN1114559. We would require a sample size of 6 to achieve a power of 80% and a level of significance of 1.7% (two-sided). Differences between INRs at varying concentrations were determined by Friedman's test. For multiple comparisons, post hoc analysis was performed using Wilcoxon signed-rank test with Bonferroni adjustment. Analyses were performed with SAS version 9.4 (SAS Institute, Cary, NC). RESULTS: Participants included 11 healthy subjects: 8 males, 3 females, median age 30 years (range 25 - 58). Median and interquartile ranges (IQR) INR for the baseline samples were 1.09 (IQR 1.05, 1.16) for Siemens and 1.03 (IQR 0.99, 1.11) for Stago analyzers. There was a significant difference in INR between the therapeutic concentrations (baseline, 35, 70,200, or 550 µg/mL) (Siemens p = .0008, Stago p < .0001). The 550 µg/mL concentration with the Siemens analyzer was the only one compared separately and found to be significantly greater than the baseline (1.07 vs 1.22, p = .02). For the Stago analyzer the 200 µg/mL and 500 µg/mL were compared and found to be significantly different from baseline (1.00 vs 1.07 and 1.19, adjusted p = .02 and p = .03, respectively). The largest INR increase seen was in one subject from a baseline of 1.07-1.32 with the 550 µg/mL concentration. Increases in concentrations to supratherapeutic levels resulted in a statistically significant non-linear increase in INR for all concentrations (Siemens p < .0001, Stago p < .0001). All of these concentrations were found to be significantly different from baseline (all adjusted p < .05). CONCLUSION: Although it was found that at therapeutic concentrations the in vitro presence of NAC affects INR measurements on two different machines, the change is of little clinical relevance. Supratherapeutic concentrations of NAC affect INR significantly, but the clinical utility of those results is limited by the rarity of those concentrations being measured.

Clinical effects and outcomes of perampanel overdoses reported to U.S. poison centers.

INTRODUCTION: Perampanel is indicated for partial onset seizures in children and adults. The mechanism is unique among antiepileptic agents as it inhibits glutamate activity on AMPA receptors. Currently, there are few published case reports describing overdose. METHODS: This is a retrospective observational study of all single substance perampanel ingestions from January 2014 to December 2019 reported to the national poison data system (NPDS). The primary outcome is to describe the clinical effects of perampanel exposures. Secondary outcomes include evaluation of management and investigation of a dose-effect relationship for the purpose of triaging acute unintentional exposures. RESULTS: A total of 138 exposures were reported to NPDS since the release of the agent. Median age was 20 years (IQR 10-38) with 68 (49.3%) males. The reason for exposure was most commonly therapeutic error (80, 58.0%), followed by exploratory ingestion (24, 17.4%), and suicidal ingestion (14, 10.1%). A total of six (4.3%) patients developed major effects, 20 (14.5%) moderate, 32 (23.2%) minor effects and 22 (15.9%) no effect. An additional 54 (39.1%) cases were not followed. Almost half of cases were managed at home. Of those that were in a healthcare facility (HCF) (n = 72), most were treated/evaluated and released (31, 43.1%), followed by admission to a non-critical care unit (20, 27.8%), and critical care unit (13, 18.1%). Most frequently reported symptoms were drowsiness (27, 19.6%), agitation (20, 14.5%), ataxia (13, 9.4%), and confusion (12, 8.7%). The most common therapies provided in a HCF were intravenous fluids (22,30.6%), followed by benzodiazepines (14, 19.4%), then other types of sedation (9, 12.5%). There were too few cases to determine a dose cut off for triaging. CONCLUSIONS: While drowsiness, agitation, ataxia, and confusion were the most often reported symptoms, close to 19% developed moderate/major effects and almost 4% of patients received potentially life-saving interventions.

Time to Peak International Normalized Ratio Rise in Acute and Acute-on-Chronic Warfarin Overdoses.

ABSTRACT: Guidelines exist on the management of supratherapeutic/subtherapeutic international normalized ratio (INR) values for patients on warfarin. However, there is a paucity of the literature relating to an acute overdose of warfarin. This is a retrospective cohort study for all acute and acute-on-chronic (AOC) warfarin overdoses reported to the Maryland Poison Center in patients ≥12 years between January 1st, 2000, until October 31st, 2019, managed in a health care facility. The primary outcome was to determine the time after presentation to peak INR. Secondary outcomes included risk factors associated with INR >10 and describing patient characteristics. A total of 163 overdoses were included, 68 acute and 95 AOC. In patients who did not receive reversal therapies, INR peaked at a median value of 3.8 (interquartile range 2.6-5.5) between 24 and 36 hours. The median time to phytonadione was 22.0 hours. Most patients received phytonadione (62.0%), with fewer receiving blood products (16.6%). The median warfarin dose ingested was 75 mg. The AOC group had a greater mean age (56 vs. 43 years), median INR value (2.4 vs. 1.4), and men (62.1% vs. 41.2%). Factors associated with an INR > 10 included initial INR and reported quantity ingested. Peak INR was greater in the AOC than the acute overdose group (6.1 vs. 3.4), although the bleeding rate was similar. Peak INR values after warfarin overdose occur between 24 and 36 hours after presentation. Initial INRs and reported quantity ingested may be useful to predict those needing treatment.

Predictors of Serious Opioid-Related Adverse Drug Events in Hospitalized Patients.

OBJECTIVE: Opioids are high-risk medications in the inpatient setting because of their potential for significant patient harm. The primary objective was to identify risk factors that predispose inpatients to develop opioid-related adverse drug events (ORADE) requiring the use of naloxone. METHODS: In a retrospective case-control study, patients were included according to the following criteria: 18 years or older, 1 administered opioid doses or more, and admitted for 24 hours or more. Patients were excluded if they had a prehospital drug overdose, other indications for naloxone use, or were admitted to an intensive care unit, psychiatric medical unit, or in the emergency department. Patients were classified as cases if naloxone was administered and a selection of controls were frequency matched 2:1 based on medical or surgical status. A logistic regression model was used to evaluate for risk factors for ORADE. RESULTS: A total of 275 cases and 592 control patients were included into the final analysis. Variables that were associated with greater odds of naloxone administration included age of 65 years or older, female, length of stay, pulmonary diagnoses, use of gabapentinoids, and patient-controlled analgesia use. Antihistamines, continuous infusion, and intermittent nurse administered intravenous bolus routes had a negative association with naloxone use. CONCLUSIONS: Several risk factors were found to be associated with ORADE supporting many of the previously described risk factors, and the discovery of potential new ones, such as gabapentinoid use. Health care providers should consider the risk factors for hospitalized patients receiving opioids who may warrant lower doses, additional monitoring, or alternative agents.

Amphetamine and Clonidine Toxicity Resulting in Posterior Reversible Encephalopathy Syndrome.

ABSTRACT: Amphetamine toxicity typically presents with hypertension and tachycardia. Conversely, clonidine acts as an agonist at central α2 and imidazoline receptors, which may cause brief initial hypertension followed by hypotension and bradycardia in overdose. We report a case of mixed ingestion resulting in posterior reversible encephalopathy syndrome (PRES) successfully treated with phentolamine.A 17-year-old male adolescent presented to the emergency department 2 hours after ingesting up to 25 each of clonidine 0.1-mg tablets and dextroamphetamine 10 mg extended-release capsules. He reported nausea and fatigue with initial blood pressure (BP) 145/95 mm Hg and heart rate (HR) 52 beats per minute (bpm). Nine hours postingestion (HPI), the patient developed headache, photophobia, and confusion with BP 182/111 mm Hg and HR 48 bpm. A computed tomography scan of the head revealed generalized fullness of the cerebellum, upward bulging of the tentorial leaflets, effacement of the fourth ventricle, and crowding of the foramen magnum, suspicious for an atypical presentation of PRES. The patient's systolic BP rose over 200 mm Hg and treated with 2 mg of intravenous phentolamine at 14 HPI. Blood pressure decreased to 133/82 mm Hg, and HR increased to 56 bpm with improvements in headache. Following repeat doses of phentolamine, nicardipine was initiated and increased to 2.5 mg/h for 12 hours. The patient was stable with normal vital signs at 36 HPI.The delayed presentation of hypertensive emergency with PRES may have been due to the actions of extended-release dextroamphetamine and the α2-agonistic effects of clonidine. Phentolamine was chosen for its α1-antagonism and was effective in managing symptoms.

Evaluation of opioid requirements in the management of renal colic after guideline implementation in the emergency department.

PURPOSE: Evaluate opioid prescribing before and after emergency department (ED) renal colic guideline implementation focused on multi-modal pain management. METHODS: Retrospective study of ED patients who received analgesia for urolithiasis before and after guideline implementation. The guideline recommends oral acetaminophen, intravenous (IV) ketorolac, and a fluid bolus as first line, IV lidocaine as second line, and opioids as refractory therapy to control pain. Opioid exposure, adverse effects, length of stay (LOS), and ED representation were evaluated. Comparisons were made with univariate analyses. Backwards stepwise binomial multivariate logistic regression to identify factors related to opioid use was performed. RESULTS: Overall, 962 patients were included (451 pre- and 511 post-implementation). ED and discharge opioid use decreased; 65% vs. 58% and 71% vs. 63% in pre- and post-implementation groups, respectively. More post-implementation patients received non-opioid analgesia (65% vs. 56%) and non-opioid analgesia prior to opioids (50% vs. 38%). A longer ED LOS and higher initial pain score were associated with ED opioid administration. Guideline implementation, receiving non-opioid therapy first, and first renal colic episode were associated with decreased ED opioid administration. Seventeen adverse events (1.8%) were reported. There was no difference in change in ED pain score between groups, but patients in the post-implementation group were admitted more and had a higher 7-day ED representation (11% vs. 7%). CONCLUSIONS: A multimodal analgesia protocol for renal colic was associated with decreased opioid prescribing, higher rates of admission to the hospital, and a higher 7-day ED representation rate.

Outcomes of acute exploratory pediatric lithium ingestions.

Objectives: To date, very little literature describes the outcomes of acute unintentional ingestions of lithium in young children. This study aimed to describe the clinical effects and outcomes reported in these patients reported to the National Poison Data System (NPDS).Methods: This is a retrospective observational study of acute unintentional lithium ingestions in children <6 years of age. The primary intent of the study was to characterize acute unintentional exposures to lithium in children in this age group. As a secondary outcome, we sought to identify a weight-based threshold to empirically refer patients into a healthcare facility for symptoms consistent with moderate effect or worse. The American Association of Poison Control Centers' NPDS was queried for all acute ingestions of lithium salts in children <6 years of age from 2000 to 2018. Inclusion criteria were single substance ingestions, unintentional-general exposure (i.e., exploratory ingestion), and followed to a known outcome or coded as potentially toxic exposure unable to follow and the patient was experiencing symptoms.Results: A total of 3045 single-substance exploratory ingestions of lithium were reported to poison centers that showed a decrease over time, consistent with decreasing use of lithium and decreasing calls to poison centers. Of the 3045 cases, we excluded 1178 leaving 1863 cases for analysis. Median age was 2 years (IQR: 1.5, 2) with 51% male cases. Management site was primarily non-health care facility (n = 808; 43.4%) with 569 (30.5%) already in a healthcare facility (HCF) when the Poison Control Center (PCC) was called and 477 (25.6%) referred to a HCF. The route of exposure was most commonly ingestion (n = 1853; 99.5%) and site of exposure was primarily home (1743; 93.6%). Medical outcomes were predominantly no effect and minor effect. There were 262 related clinical effects were reported in 184 patients (10%). The most frequently reported were vomiting (n = 76), drowsiness/lethargy (n = 58), other (n = 22), and ataxia (n = 20). Clinical effects lasted ≤2 h for 65 (33%), 2-8 h for 57 (28.9%), 8-24 h for 51 (25.9%), 1-3 days for 11 (5.6%), and >3 days to ≤1 week for 1 (0.5%); no cases resulted in clinical effects thought to be permanent and no deaths were reported. There were 1173 treatments provided to 857 patients. The most common treatments were basic and are readily performed at home; dilution (n = 492) and food/snack (n = 180). A smaller subset of patients received care that could likely only be provided in a healthcare facility including IV fluids (n = 173), other (n = 120), whole bowel irrigation (n = 46), single dose activated charcoal (n = 41), syrup of ipecac (n = 34), and lavage (n = 31). No patients received hemodialysis. A total of 425 of the exposures were referred to a healthcare facility by the PCC which had a dose coded. There was no difference in dose that resulted to referral to a healthcare facility over time (p = 0.2747). Due to the small number of moderate/major effect cases with dose information, we were unable to identify a dose-based threshold for referral to HCF.Conclusions: Severe outcomes after unintentional ingestion of lithium in pediatric patients are rare. It is likely that most asymptomatic pediatric patients <6 years do not need to be referred to the hospital after ingestion of lithium.