Human exposures to Phytolacca americana in Kentucky.

Phytolacca americana, known more commonly as "pokeweed", is a large perennial plant found ubiquitously throughout the United States. Despite known toxicities, characterization of pokeweed exposure demographics, symptoms, treatments, and outcomes is currently limited. The objective of this study is to describe human pokeweed exposures, treatments, and outcomes, in the state of Kentucky, between 2000 and 2019. The National Poison Database System was queried for all Phytolacca americana exposures in the state of Kentucky between 2000 and 2019. After the removal of non-human cases, investigators independently reviewed data to ensure all coding was appropriate per the standards set forth by NPDS. The primary objective of this study was to describe pokeweed exposure demographics within the state of Kentucky during the previously established timeframe. Secondary objectives included characterizing pokeweed treatment trends and evaluating their affiliated medical outcomes. 1669 cases of human pokeweed exposure were reported. Patients were predominantly young in age, with a median age of 3 years reported. The majority of patients were male (54.9%), with unintentional exposures representing most exposure reasons (97.2%). Oral ingestion of plant material represented the bulk of the exposure route (98.3%), with pokeberries most often implicated in these cases (93.9%). Exposures were generally well tolerated. 239 total adverse events were noted during the timeframe. Abdominal pain, nausea, vomiting, and diarrhea were most common. Dermal exposures resulted in cutaneous edema, pain, and swelling. Treatments were mainly supportive, with no deaths reported during the study timeframe. In conclusion, Phytolacca americana is commonly encountered in the United States. In this observational study, patients most heavily implicated in pokeweed exposures are young males. Oral ingestion was most commonly reported, with berries most often implicated. Exposures are generally well tolerated, with gastrointestinal symptoms most frequently reported. Cutaneous exposures represent an underappreciated exposure route. Treatments are largely supportive in nature.

Intravenous phytonadione administered orally in reducing warfarin-related coagulopathy.

INTRODUCTION: The cost of phytonadione tablets has increased markedly and is significantly higher than the intravenous formulation. The intravenous formulation given orally is a potential alternative but has not been directly evaluated in comparison to the commercially available tablet. The objective of this study was to evaluate the efficacy of phytonadione intravenous solution given orally compared to commercially available phytonadione tablets for reversal of coagulopathy related to warfarin. METHODS: We conducted a retrospective, observational study of adult patients who received phytonadione tablets and the IV formulation orally for warfarin-related coagulopathy. The international normalized ratio (INR) was measured before and after phytonadione administration. The primary outcome was INR <1.5 at 24 h after phytonadione administration. RESULTS: From January 1, 2015 to August 1, 2018 a total of 200 patients were identified. In total, 58% (n = 116) patients received IV phytonadione solution given orally and 42% (n = 84) patients received the tablets. The primary outcome of INR <1.5 at 24 h was not significantly different between groups (p = 0.321). DISCUSSION: The IV phytonadione solution given by mouth and the tablet formulation performed similarly.

Adverse effects associated with bupropion therapeutic errors in adults reported to four United States Poison Centers.

CONTEXT: Bupropion is a frequently used medication. Excessive doses may cause altered mental status, seizures, and dysrhythmias. There is a need for accurate estimate of seizure risk with therapeutic errors and determination if minor symptoms are harbingers of more severe effects. METHODS: A retrospective review of adult, acute, unintentional therapeutic error, single substance bupropion ingestions with known outcome reported to four poison centers from January 1, 2004 to December 31, 2016. Data included age, gender, single error dose, total bupropion dose over 18 h, prior history of seizure, management site, observation time, occurrence of an out-of-hospital adverse event, "jittery"/anxious/agitated, tachycardia/palpitations, seizures, and dysrhythmias. We recorded the total bupropion dose over 18 h if known; otherwise, we used the single error dose. We compared means for parametric data. We used Fisher's exact test and Mann-Whitney for nonparametric data. RESULTS: We identified 754 potential cases, of which 637 met inclusion criteria after case review. Median age was 42 years, and 76.1% were female. Cases were predominantly managed at home (56.2%). Outcomes were no effect (50.1%), minor (45.5%) and moderate (4.4%). The reported dose with no effect/minor outcome was 694 (±297) mg, and for moderate outcome was 1250 (±815) mg (p < 0.0001). Seizures occurred in four patients with median onset time of 7 h [range 2-21.5 h]. The median reported dose in patients who seized was 900 mg [range 600-3000 mg]. Of patients who developed a seizure and/or an out-of-hospital adverse event, 83% were "jittery"/anxious/agitated whereas "jittery"/anxious/agitated was present in 27% of cases that did not (p = 0.008). Tachycardia/palpitations was reported in 12% of cases; more serious dysrhythmias were not reported. CONCLUSIONS: Outcomes from single unintentional ingestions of bupropion in adults are overall mild and appear to be dose related. Home management may be an option with doses up to 900 mg in an appropriate patient population.

Evaluation of Dosing Strategies of N-acetylcysteine for Acetaminophen Toxicity in Patients Greater than 100 Kilograms: Should the Dosage Cap Be Used?

INTRODUCTION: Acetaminophen is a commonly used analgesic and antipyretic, with the potential to cause significant injury when ingested in toxic amounts. Although the antidote n-acetylcysteine (NAC) is available, evidence supporting dose recommendations for patients weighing over 100 kg are lacking. We performed a retrospective, multi-center analysis to determine if a capped NAC dosing scheme is similar to a non-capped dosing scheme in patients weighing over 100 kg. METHODS: Between January 2009 and January 2016, we identified patients presenting to 12 different centers who were evaluated for acetaminophen poisoning treatment. Patients must have weighed greater than 100 kg and were evaluated and identified as needing treatment for acetaminophen-related poisoning with NAC. The primary outcome was occurrence of hepatic injury, defined as an AST or ALT ≥ 100 IU/L. Secondary endpoints included number of drug-related adverse events, occurrence of hepatotoxicity, cumulative NAC dose, regimen cost, length of hospital and intensive care unit stays, and in-hospital mortality. RESULTS: There were 83 patients identified as meeting the pre-specified inclusion and exclusion criteria. A capped NAC dosing scheme resulted in no difference in hepatic injury when compared to a non-capped regimen (49.4% vs 50%, p = 1.000). The capped dosage regimen was associated with a lower cumulative dose (285.2 mg/kg vs 304.6 mg/kg, p < 0.001) and cost. No other statistically significant differences were identified among the secondary endpoints. CONCLUSION: A capped NAC dosing scheme was not associated with higher rates of hepatic injury or hepatotoxicity in obese patients in the setting of acetaminophen poisoning when compared to a non-capped regimen. Further research is needed to verify these results.

Trending gabapentin exposures in Kentucky after legislation requiring use of the state prescription drug monitoring program for all opioid prescriptions.

OBJECTIVE: Gabapentin is a gamma-aminobutyric acid (GABA) analog approved by the Food and Drug Administration (FDA) for partial seizures and post-herpetic neuralgia. Due to its wide therapeutic window and minimal adverse effects, it is frequently prescribed for additional off-label uses. The purpose of this study was to characterize the number, exposure reason, medical outcomes, and disposition of gabapentin exposures reported to one regional poison control center (PCC). METHODS: A retrospective cross-sectional review of exposures reported to one regional PCC was performed from January 1, 2012 to December 31, 2015. The primary outcomes were the number of gabapentin-only exposures and multi-agent exposures including gabapentin reported. Exposure reason, medical outcome, and disposition were identified for each exposure. RESULTS: There were 424 gabapentin-only exposures during the study period. The number of exposures increased each year, from 39 in 2012 to 160 in 2015. There were 1321 multi-agent exposures that included gabapentin. These exposures increased from 165 in 2012 to 440 in 2015. Comparatively, total human exposures reported to the regional PCC decreased during the study period. The majority of gabapentin-only and multi-agent exposures was intentional versus unintentional. Nine patients (2%) had a major medical outcome and three patients (1%) died in the gabapentin-only group. Comparatively, 76 patients (6%) had a major medical outcome and 12 patients (1%) died in the multi-agent group. Almost half of the multi-agent exposures required admission to the intensive care unit (ICU). CONCLUSIONS: Both gabapentin-only and multi-agent exposures increased significantly from 2012 to 2015, with the majority of cases intentional ingestion, specifically suspected suicide. The increased number of gabapentin exposures coincided with Kentucky's implementation of prescription opioid reform legislation. Providers are encouraged to call their local PCC, regardless of exposure type, to effectively monitor and evaluate exposure trends.

Diphenhydramine dose-response: a novel approach to determine triage thresholds.

CONTEXT: It is unclear how much diphenhydramine (DPH) is toxic in humans. Previous dose-response studies have had conflicting results. Objective. We sought to evaluate DPH dose-response using a unique method that utilizes acetaminophen (APAP) serum concentrations to estimate DPH doses in patients ingesting APAP/DPH in a fixed-combination product. METHODS: We retrospectively analyzed APAP/DPH-only exposures in patients 2-80 years of age using case data from 15 U.S. poison centers. DPH dose was extrapolated from measured serum APAP concentrations. A clinically significant response (CSR) was predefined in terms of eight specific manifestations (e.g., coma) that would warrant emergency department intervention. Nominal logistic regression was used to model the probability of each recorded manifestation across DPH dose ranges examining fits for mg, mg/kg, log10 mg, and log10 mg/kg DPH doses. The threshold value where patients reliably became symptomatic was determined by further examining receiver operating characteristic curves. RESULTS: There were 509 cases that met inclusion criteria. Forty-five patients (9%) developed CSRs. A higher percentage of patients developed CSR at ≥ 7.5 mg/kg DPH and ≥1 g total DPH cutoff points (p < 0.05, Fisher's exact test). The best model for predicting the probability of CSR was a logistic fit of log(10) mg/kg dose (p < 0.05). By this model, for every 1 log(10) unit increase of mg/kg DPH dose, the odds of developing a CSR increased 47-fold (95% CI 17, 154). Receiver operating characteristic analyses showed a dose-related progression of symptoms. The cut-point with greatest sensitivity (98%) versus 1-specificity (57%) corresponded to an extrapolated mg/kg DPH dose of 8.2 mg/kg (95% CI 5.6, 10.5). CONCLUSION: Our findings support the current American Association of Poison Control Centers' guideline recommendation to refer patients to the hospital for evaluation if they have ingested greater than or equal to 7.5 mg/kg of DPH.

Plasma membrane aquaporin activity can affect the rate of apoptosis but is inhibited after apoptotic volume decrease.

Apoptosis is characterized by a conserved series of morphological events beginning with the apoptotic volume decrease (AVD). This study investigated a role for aquaporins (AQPs) during the AVD. Inhibition of AQPs blocked the AVD in ovarian granulosa cells undergoing growth factor withdrawal and blocked downstream apoptotic events such as cell shrinkage, changes in the mitochondrial membrane potential, DNA degradation, and caspase-3 activation. The effects of AQP inhibition on the AVD and DNA degradation were consistent in thymocytes and with two additional apoptotic signals, thapsigargin and C(6)-ceramide. Overexpression of AQP-1 in Chinese hamster ovary (CHO-AQP-1) cells enhanced their rate of apoptosis. The AVD is driven by loss of K(+) from the cell, and we hypothesize that after the AVD, AQPs become inactive, which halts further water loss and allows K(+) concentrations to decrease to levels necessary for apoptotic enzyme activation. Swelling assays on granulosa cells, thymocytes, and CHO-AQP-1 cells revealed that indeed, the shrunken (apoptotic) subpopulation has very low water permeability compared with the normal-sized (nonapoptotic) subpopulation. In thymocytes, AQP-1 is present and was shown to colocalize with the plasma membrane receptor tumor necrosis factor receptor-1 (TNF-R1) both before and after the AVD, which suggests that this protein is not proteolytically cleaved and remains on the cell membrane. Overall, these data indicate that AQP-mediated water loss is important for the AVD and downstream apoptotic events, that the water permeability of the plasma membrane can control the rate of apoptosis, and that inactivation after the AVD may help create the low K(+) concentration that is essential in apoptotic cells. Furthermore, inactivation of AQPs after the AVD does not appear to be through degradation or removal from the cell membrane.