QT prolongation, torsades des pointes, and cardiac arrest after 4 mg of IV ondansetron.

Ondansetron is a commonly used antiemetic in the emergency department despite a 2011 FDA warning regarding dose-related QTc prolongation and torsades des pointes (TdP). Cases of TdP from small ondansetron doses administered in the emergency department are lacking. A 41-year-old-woman with alcohol use disorder on no medications or supplements presented to an emergency department with one day of nausea, vomiting, and epigastric pain. Examination revealed a pulse of 77 beats/min and epigastric tenderness. The patient received 4 mg IV ondansetron, 30 mg IV ketorolac, and was placed on cardiac monitoring. ECG obtained one minute after ondansetron demonstrated premature ventricular contractions with QTc = 653 ms. Thirteen minutes after receiving ondansetron she suffered TdP and cardiac arrest. She received immediate CPR and IV epinephrine with successful defibrillation at one minute. She then received IV magnesium. Post-arrest ECGs demonstrated persistent QTc prolongation immediately and at three hours post-arrest. Laboratory studies, drawn prior to arrest, demonstrated hypokalemia (3.2 mEq/L), hypomagnesemia (1.3 mg/dL), and elevated lipase (4918 IU/L). She received no additional QT-prolonging agents. Transthoracic echocardiogram and troponins were normal; ECG intervals completely normalized within 12 h and she was discharged neurologically intact. The patient returned 18 months later with recurrent pancreatitis and similar electrolyte abnormalities; QT-prolonging drugs were avoided at that time and her course was uncomplicated. QT prolongation with subsequent torsades des pointes and cardiac arrest may occur in high-risk patients receiving small doses of ondansetron. Further studies are warranted to determine the safest antiemetic for use in the emergency department.

Is Two Better Than Three? A Systematic Review of Two-bag Intravenous N-acetylcysteine Regimens for Acetaminophen Poisoning.

Introduction: Acetaminophen poisoning is commonly treated by emergency physicians. First-line therapy is N-acetylcysteine (NAC), traditionally administered intravenously via a US Food and Drug Administration (FDA)-approved three-bag protocol in which each bag has a unique concentration and infusion duration. Recently, simplified, off-label two-bag NAC infusion protocols have become more common. The purpose of this review is to summarize the effectiveness and safety of two-bag NAC. Methods: We undertook a comprehensive search of PubMed, EMBASE, and MEDLINE from inception to December 13, 2022, for articles describing human acetaminophen poisonings treated with two-bag NAC, defined as any regimen involving two discrete infusions in two separate bags. Outcomes included effectiveness (measured by incidence of liver injury); incidence of non-allergic anaphylactoid reactions (NAAR); gastrointestinal, cutaneous, and systemic reactions; treatments for NAARs; incidence of NAC-related medication errors; and delays or interruptions in NAC administration. Results: Twelve articles met final inclusion, 10 of which compared two-bag NAC to the three-bag regimen. Nine articles evaluated the two-bag/20-hour regimen, a simplified version of the FDA-approved three-bag regimen in which the traditional first and second bags are combined into a single four-hour infusion. Nine articles assessed comparative effectiveness of two-bag NAC in terms of liver injury, most commonly assessed for by incidence of hepatotoxicity (aspartate aminotransferase or alanine aminotransferase >1,000 international units per liter). No difference in liver injury was observed between two-bag and three-bag regimens. Of nine articles comparing incidence of NAARs, eight demonstrated statistically fewer NAARs with two-bag regimens, and one showed no difference. In seven articles evaluating treatment for NAARs (antihistamines, corticosteroids, epinephrine), all showed that patients received fewer medications for NAARs with two-bag NAC. Three articles evaluated NAC-related medication errors; two demonstrated no difference, while one study evaluating only children showed fewer errors with two-bag NAC. Two studies evaluated delays and/or interruptions in NAC infusions; both favored two-bag NAC. Conclusion: For patients with acetaminophen poisoning, two-bag NAC regimens appear to have similar outcomes to the traditional three-bag regimen in terms of liver injury. Two-bag NAC regimens are associated with fewer adverse events and fewer treatments for those events than the three-bag regimen and fewer interruptions in antidotal therapy.

Vasodilation in patients with calcium channel blocker poisoning treated with high-dose insulin: a comparison of amlodipine versus non-dihydropyridines.

Background: High dose insulin (HDI), an inotrope and vasodilator, is a standard therapy for calcium channel blocker (CCB) poisoning. HDI causes vasodilation by stimulating endothelial nitric oxide synthase (eNOS). Most literature supporting HDI for CCB poisoning involves verapamil toxicity; however, amlodipine now causes more CCB poisonings. Unlike other CCBs, amlodipine stimulates eNOS and may cause synergistic vasodilation with HDI. The purpose of this study was to determine if amlodipine-poisoned patients treated with HDI had more evidence of vasodilation than similarly treated patients with non-dihydropyridine (non-DHP) poisoning.Methods: This was a retrospective study from a single poison center. Cases were identified via the generic code "Calcium Antagonists" in which the therapy "High Dose Insulin/Glucose" was "performed, whether or not recommended" from 2019-2021. Evidence of vasodilation was assessed via maximum number of vasopressor infusions per case, vasopressor doses, and use of rescue methylene blue to treat refractory vasoplegia.Results: Thirty-three patients were enrolled: 18 poisoned with amlodipine, 15 with non-DHPs (verapamil n = 10, diltiazem n = 5). The median number of maximum concomitant vasopressors in the amlodipine group was 3 (IQR: 2-5; range 0-6) and 2 in the non-DHP group (IQR: 1-3; range 0-5; p = 0.04); median difference in maximum concomitant vasopressors between groups was 1 (95% confidence interval: 0-2). Median maximum epinephrine dosing was higher in the amlodipine group (0.31 mcg/kg/min) compared to non-DHPs (0.09 mcg/kg/min; p = 0.03). Use of rescue methylene blue was more common in the amlodipine group (7/18 [39%]) than in the non-DHP group (0; p = 0.009).Conclusions: Amlodipine poisoned patients treated with HDI required more vasopressors, higher doses of epinephrine, and more often received rescue methylene blue than similarly treated patients with verapamil or diltiazem poisoning. These differences suggest amlodipine-poisoned patients had more evidence of vasodilation. Further study is warranted to determine if synergistic vasodilation occurs when HDI is used to treat amlodipine poisoning.

Nipple-sparing Mastectomy: What the Radiologist Should Know.

Nipple-sparing mastectomy (NSM) is increasingly offered to patients undergoing treatment of breast cancer and prophylaxis treatment for reduction of breast cancer risk. NSM is considered oncologically safe for appropriately selected patients and is associated with improved cosmetic outcomes and quality of life. Accepted indications for NSM have expanded in recent years, and currently only inflammatory breast cancer or malignancy involving the nipple is considered an absolute contraindication. Neoplasms close to and involving the nipple areolar complex are common, and cancer of the lactiferous ducts can spread to the nipple. Therefore, accurate determination of nipple involvement at imaging examinations is critical to identifying appropriate candidates for NSM and preventing local recurrence. Multiple imaging features have been described as predictors of nipple involvement, with tumor to nipple distance, enhancement between the index malignancy and the nipple, and nipple retraction demonstrating the highest predictive values. These features can be assessed at multimodality breast imaging, particularly at breast MRI, which demonstrates high specificity and negative predictive value for determining nipple involvement in malignancy. Online supplemental material is available for this article. ©RSNA, 2022.

CRISPR-Cas9 cytidine and adenosine base editing of splice-sites mediates highly-efficient disruption of proteins in primary and immortalized cells.

CRISPR-Cas9 cytidine and adenosine base editors (CBEs and ABEs) can disrupt genes without introducing double-stranded breaks by inactivating splice sites (BE-splice) or by introducing premature stop (pmSTOP) codons. However, no in-depth comparison of these methods or a modular tool for designing BE-splice sgRNAs exists. To address these needs, we develop SpliceR ( http://z.umn.edu/spliceR ) to design and rank BE-splice sgRNAs for any Ensembl annotated genome, and compared disruption approaches in T cells using a screen against the TCR-CD3 MHC Class I immune synapse. Among the targeted genes, we find that targeting splice-donors is the most reliable disruption method, followed by targeting splice-acceptors, and introducing pmSTOPs. Further, the CBE BE4 is more effective for disruption than the ABE ABE7.10, however this disparity is eliminated by employing ABE8e. Collectively, we demonstrate a robust method for gene disruption, accompanied by a modular design tool that is of use to basic and translational researchers alike.

Point-of-sale Naloxone: Novel Community-based Research to Identify Naloxone Availability.

INTRODUCTION: Expanding naloxone availability is important to reduce opioid-related deaths. Recent data suggest low, variable urban naloxone availability. No reports describe naloxone availability at the point of sale (POSN). We characterize POSN without prescription across a Midwestern metropolitan area, via a unique poison center-based study. METHODS: Pharmacies were randomly sampled within a seven-county metropolitan area, geospatially mapped, and distributed among seven investigators, who visited pharmacies and asked, "May I purchase naloxone here without a prescription from my doctor?" Following "No," investigators asked, "Are you aware of the state statute that allows you to dispense naloxone to the public under a standing order?" Materials describing statutory support for POSN were provided. Responses were uploaded to REDCap in real time. We excluded specialty (veterinary, mail order, or infusion) pharmacies a priori. POSN availability is presented as descriptive statistics; characteristics of individual sites associated with POSN availability are reported. RESULTS: In total, 150 pharmacies were prospectively randomized, with 52 subsequently excluded or unavailable for survey. Thus, 98 were included in the final analysis. POSN was available at 71 (72.5%) of 98 pharmacies. POSN availability was more likely at chain than independent pharmacies (84.7% vs 38.5%, p<0.001); rural areas were more commonly served by independent than chain pharmacies (47.4% vs 21.5%, p = 0.022). Five chain and five independent pharmacies (18.5% each) were unaware of state statutory support for collaborative POSN agreements. Statutory awareness was similar between independent and chain pharmacies (68.8% vs 54.6%, p = 0.453). Rationale for no POSN varied. CONCLUSION: POSN is widely available in this metropolitan area. Variability exists between chain and independent pharmacies, and among pharmacies of the same chain; awareness of statutory guidance does not. Poison centers can act to define local POSN availability via direct inquiry in their communities.

The Incidence of QT Prolongation and Torsades des Pointes in Patients Receiving Droperidol in an Urban Emergency Department.

INTRODUCTION: Droperidol carries a boxed warning from the United States Food and Drug Administration for QT prolongation and torsades des pointes (TdP). After a six-year hiatus, droperidol again became widely available in the US in early 2019. With its return, clinicians must again make decisions regarding the boxed warning. Thus, the objective of this study was to report the incidence of QT prolongation or TdP in patients receiving droperidol in the ED. METHODS: Patients receiving droperidol at an urban Level I trauma center from 1997-2001 were identified via electronic health record query. All patients were reviewed for cardiac arrest. We reviewed electrocardiogram (ECG) data for both critically-ill and noncritical patients and recorded Bazett's corrected QT intervals (QTc). ECGs from critically-ill patients undergoing resuscitation were further risk-stratified using the QT nomogram. RESULTS: Of noncritical patients, 15,374 received 18,020 doses of droperidol; 2,431 had an ECG. In patients with ECGs before and after droperidol, the mean QTc was 424.3 milliseconds (ms) (95% confidence interval [CI], 419.7-428.9) before and 427.6 ms (95% CI, 424.3-430.9), after droperidol (n = 170). Regarding critically-ill patients, 1,172 received droperidol and 396 had an ECG. In the critically-ill group with ECGs before and after droperidol mean QTc was 435.7 ms (95% CI, 426.7-444.7) before and 435.8 ms (95% CI, 427.5-444.1) after droperidol (n = 114). Of 337 ECGs suitable for plotting on the QT nomogram, 13 (3.8%) were above the "at-risk" line; 3/136 (2.2%; 95% CI, 0.05-6.3%) in the before group, and 10/202 (4.9%; 95% CI, 2.4%-8.9%) in the after group. A single case of TdP occurred in a patient with multiple risk factors that did not reoccur after a droperidol rechallenge. Thus, the incidence of TdP was 1/16,546 (0.006%; 95% CI, 0.00015 - 0.03367%). CONCLUSION: We found the incidence of QTc prolongation and TdP in ED patients receiving droperidol to be extremely rare. Our data suggest the FDA "black box warning" is overstated, and that close ECG monitoring is useful only in high-risk patients.

GazeMetrics: An Open-Source Tool for Measuring the Data Quality of HMD-based Eye Trackers.

As virtual reality (VR) garners more attention for eye tracking research, knowledge of accuracy and precision of head-mounted display (HMD) based eye trackers becomes increasingly necessary. It is tempting to rely on manufacturer-provided information about the accuracy and precision of an eye tracker. However, unless data is collected under ideal conditions, these values seldom align with on-site metrics. Therefore, best practices dictate that accuracy and precision should be measured and reported for each study. To address this issue, we provide a novel open-source suite for rigorously measuring accuracy and precision for use with a variety of HMD-based eye trackers. This tool is customizable without having to alter the source code, but changes to the code allow for further alteration. The outputs are available in real time and easy to interpret, making eye tracking with VR more approachable for all users.

Pneumocystis jiroveci pneumonitis complicating ruxolitinib therapy.

Ruxolitinib is a novel inhibitor of the Janus kinase (JAK) pathway that has become available for the treatment of myelofibrosis. There are increasing reports of opportunistic infections associated with ruxolitinib therapy. We present a case of Pneumocystis jiroveci pneumonitis complicating ruxolitinib therapy. Clinicians should consider the use of pneumocystis prophylaxis when using ruxolitinib.

Comparison of toxicity associated with nonmedical use of benzodiazepines with buprenorphine or methadone.

BACKGROUND: Polysubstance use is prevalent in individuals using buprenorphine or methadone nonmedically, with benzodiazepines being a common co-ingestant. The objective of this study was to compare the severity of buprenorphine and methadone toxicity with concomitant use of benzodiazepines. METHODS: A retrospective analysis of buprenorphine and methadone cases from November 1, 2002 to December 31, 2010 reported to the American Association of Poison Control Centers' National Poison Data System (NPDS) was conducted. INCLUSION CRITERIA: age ≥ 18 years, nonmedical use of methadone with benzodiazepines (methadone-BZD) or buprenorphine with benzodiazepines (BUP-BZD), and case followed to a documented outcome. Cases with co-ingestants other than benzodiazepines were excluded. Clinical effects, treatments, disposition and final medical outcomes were evaluated. RESULTS: There were 692 methadone-BZD cases and 72 BUP-BZD cases. Clinical effects in methadone-BZD and BUP-BZD groups were lethargy (71.1%, 59.7%), respiratory depression (29.0%, 15.3%), coma (22.4%, 5.6%), respiratory arrest (4.5%, 0), hypotension (11.8%, 2.8%) and cardiac arrest (1.9%, 0), respectively. Patients in the methadone-BZD group were four-times more likely to receive naloxone (60.4% vs 15.3%) or be intubated (16.3% vs 4.2%) than in the BUP-BZD group. Hospitalization rates were highest for methadone-BZD patients with 67.3% receiving medical admissions compared to 43.3% of BUP-BZD patients. Outcomes were more serious for methadone-BZD cases (p<0.0001); while there were no BUP-BZD deaths, exposure to methadone-BZD yielded 16 deaths. CONCLUSIONS: Nonmedical use of benzodiazepines with methadone is associated with higher hospitalization rates, greater ICU utilization rates and considerably worse medical outcomes when compared to nonmedical use of benzodiazepines with buprenorphine.

Evaluation of the use and safety of octreotide as antidotal therapy for sulfonylurea overdose in children.

OBJECTIVES: The objectives of this study were to evaluate the effect of octreotide on number of hypoglycemic episodes and blood glucose concentrations (BGCs) in a case series of young children who received octreotide for treatment of sulfonylurea-induced hypoglycemia and to identify the frequency of adverse effects associated with octreotide's use for this indication. METHODS: A retrospective review of 9 years of National Poison Data System pediatric sulfonylurea overdoses treated with octreotide was conducted. Inclusion criteria were age younger than 6 years with acute sulfonylurea overdose managed in a health care facility. Redacted poison center charts were obtained, and data on pretreatment and posttreatment number of hypoglycemic episodes and BGCs as well as medical outcomes and adverse reactions were extracted and analyzed. RESULTS: There were 121 octreotide cases. Patients experienced a median of 2.0 and 0.0 hypoglycemic episodes before and after treatment, respectively (P < 0.0001). The median lowest BGC was significantly higher after octreotide administration (P < 0.001). In 73% of children, only 1 dose of octreotide was given. Hyperglycemia was noted in 3 children who also received dextrose in whom adverse effects to therapy were coded. CONCLUSIONS: Octreotide administration decreases number of hypoglycemic events and increases BGCs. The majority of children who receive octreotide require only 1 dose. There were no adverse effects documented in these children who received octreotide as an antidote for sulfonylurea-induced hypoglycemia.

Comparison of citalopram and other selective serotonin reuptake inhibitor ingestions in children.

CONTEXT: In adults, citalopram is more likely to cause seizures and ECG changes than other selective serotonin reuptake inhibitors (SSRIs). Data in children are lacking, yet the 2007 American Association of Poison Control Centers out-of-hospital citalopram consensus guideline mirrors the guideline for other SSRIs. OBJECTIVE: To compare the clinical effects and hazard index of citalopram with other SSRIs in pediatric ingestions. METHODS: An 11-year retrospective analysis of national poison center data was conducted. Acute, known-type SSRI ingestions in children younger than 6 years with known outcome were included. Clinical effects and hazard index (number of major or fatal outcomes/1000 SSRI ingestions) were compared. Citalopram dose-response was evaluated. RESULTS: The 35 296 included cases by SSRI type were citalopram (3747), escitalopram (4815), fluoxetine (5946), fluvoxamine (273), paroxetine (7157), and sertraline (13 358). The overall hazard index was 0.340. The hazard index for citalopram (0.801) was 2.8-fold higher than for non-citalopram SSRIs (0.285). Comparing seizures (single or multiple discrete) and cardiac effects (conduction disturbances, other ECG changes or other dysrhythmia) of citalopram with the other SSRIs, pediatric citalopram ingestions were more likely to develop seizures (5 of 3747 [0.13%] vs. 10 of 31 549 [0.03%], OR = 4.2; 1.4-12.3) and cardiac toxicity (9 of 3747 [0.24%] vs. 25 of 31 549 [0.08%], OR = 3.0; 1.4-6.5). Clinical effects occurring more frequently with other SSRIs included tachycardia (p = 0.0236), oral irritation (p = 0.0412), vomiting (p = 0.0036), agitation/irritability (p = 0.0104), and hyperthermia (p = 0.0314). There was a dose response only for single or multiple discrete seizures, mydriasis and clinically significant responses (a predetermined subset of CNS and cardiopulmonary clinical effects). Meaningful triage thresholds for citalopram could not be determined due to the low frequency of significant clinical effects. CONCLUSION: Children develop minimal toxicity with SSRI ingestions. Seizures and ECG changes, while uncommon, occur more frequently with citalopram. Doses associated with significant outcomes suggest that the triage guideline for citalopram does not need to be modified.