Confirmed Fatal Colchicine Poisoning in an Adolescent with Blood and Bile Concentrations-Implications for GI Decontamination?

INTRODUCTION: Colchicine is commonly used to treat diseases like acute gouty arthritis. However, colchicine has a very narrow therapeutic index, and ingestions of > 0.5mg/kg can be deadly. We report a fatal acute colchicine overdose in an adolescent. Blood and postmortem bile colchicine concentrations were obtained to better understand the degree of enterohepatic circulation of colchicine. CASE REPORT: A 13-year-old boy presented to the emergency department after acute colchicine poisoning. A single dose of activated charcoal was administered early but no other doses were attempted. Despite aggressive interventions such as exchange transfusion and veno-arterial extracorporeal membrane oxygenation (VA-ECMO), the patient died 8 days later. Postmortem histology was notable for centrilobular necrosis of the liver and a cardiac septal microinfarct. The patient's blood colchicine concentration on hospital days 1 (~30 hours post-ingestion), 5, and 7 was 12ng/mL, 11ng/mL, and 9.5ng/mL, respectively. A postmortem bile concentration obtained during autopsy was 27ng/mL. DISCUSSION: Humans produce approximately 600mL of bile daily. Assuming that activated charcoal would be able to adsorb 100% of biliary colchicine, using the bile concentration obtained above, only 0.0162mg of colchicine per day would be able to be adsorbed and eliminated by activated charcoal in this patient. CONCLUSION: Despite supportive care, activated charcoal, VA-ECMO, and exchange transfusion, modern medicine may not be enough to prevent death in severely poisoned colchicine patients. Although targeting enterohepatic circulation with activated charcoal to enhance elimination of colchicine sounds attractive, the patient's low postmortem bile concentration of colchicine suggests a limited role of activated charcoal in enhancing elimination of a consequential amount of colchicine.

The Role of Dexmedetomidine in Pediatric Patients Presenting with an Anticholinergic Toxidrome.

BACKGROUND: We report two pediatric cases of anticholinergic toxidrome, including the youngest reported to date, in which standard therapeutic strategies were either contraindicated or ineffective, while treatment with dexmedetomidine was rapidly efficacious with no adverse effects. Moreover, with the recent shortage of physostigmine, we highlight an alternative treatment in this clinical setting. Case Summaries. In case 1, a two-year-old had an overdose presenting with an anticholinergic toxidrome. However, his hypopnea precluded the use of benzodiazepines due to the high likelihood of intubation. In case 2, a 14-year-old had a polypharmacy overdose inducing agitated delirium that was refractory to high-dose benzodiazepines. Due to the unknown ingestion, physostigmine was avoided. In both cases, dexmedetomidine helped the patient remain calm and metabolize the ingestions. CONCLUSION: Our experience suggests that dexmedetomidine may be a useful adjunct in anticholinergic presentations in the setting of polypharmacy, when standard therapy is proven ineffective, contraindicated, or unavailable.

Updated analysis of CALGB (Alliance) 100104 assessing lenalidomide versus placebo maintenance after single autologous stem-cell transplantation for multiple myeloma: a randomised, double-blind, phase 3 trial.

BACKGROUND: In the CALGB (Alliance) 100104 study, lenalidomide versus placebo after autologous stem-cell transplantation (ASCT) was investigated for patients with newly diagnosed myeloma. That study showed improved time to progression and overall survival and an increase in second primary malignancies for lenalidomide at a median follow-up of 34 months. Here we report an updated intention-to-treat analysis of CALGB (Alliance) 100104 at a median follow-up of 91 months. METHODS: Patients were eligible for this randomised, double-blind, placebo-controlled, phase 3 trial if they had symptomatic disease requiring treatment; had received, at most, two induction regimens; and had achieved stable disease or better in the first 100 days after ASCT. We randomly assigned patients to either lenalidomide or placebo groups using permuted block randomisation, with a fixed block size of six. Randomisation was stratified by three factors: normal or elevated ß2 microglobulin concentration at registration (≤2·5 mg/L vs >2·5 mg/L), previous use or non-use of thalidomide during induction therapy, and previous use or non-use of lenalidomide during induction therapy. The starting dose was two capsules (10 mg) per day, escalated to three capsules (15 mg) per day after 3 months. The primary endpoint was time to progression (time of progressive disease or death from any cause), with intention-to-treat analysis. This study is registered with ClinicalTrials.gov, identifier NCT00114101. New patients are no longer being recruited, but some patients remain on treatment and in follow-up. FINDINGS: Between April 14, 2005, and July 2, 2009, 460 patients were randomly assigned to receive either lenalidomide (n=231) or placebo (n=229). After three interim analyses, the study was unblinded at a median follow-up of 18 months, at which point 86 (67%) of 128 patients without progressive disease in the placebo group chose to cross over to the lenalidomide group. The median follow-up for the updated survival analysis, as of Oct 19, 2016, was 91 months (IQR 83·6-103·1). The median time to progression was 57·3 months (95% CI 44·2-73·3) for the lenalidomide group and 28·9 months (23·0-36·3) for the placebo group (hazard ratio 0·57, 95% CI 0·46-0·71; p<0·0001). The most common grade 3-4 adverse events were neutropenia (116 [50%] patients in the lenalidomide group and 41 [18%] patients in the placebo group) and thrombocytopenia (34 [15%] patients in the lenalidomide group and 12 [5%] patients in the placebo group). 18 (8%) haematological and 14 (6%) solid tumour second primary malignancies were diagnosed after randomisation and before disease progression in the lenalidomide group, compared with three (1%) haematological and nine (4%) solid tumour second primary malignancies in the placebo group. Three haematological and five solid tumour second primary malignancies in the placebo group were in the crossover subgroup. INTERPRETATION: Despite an increase in haematological adverse events and second primary malignancies, lenalidomide maintenance therapy after ASCT significantly improved time to progression and could be considered a standard of care. FUNDING: The National Cancer Institute.

The nature of emergency department interruptions and their impact on patient satisfaction.

OBJECTIVE: To explore the nature of interruptions that occur during clinical practice in the emergency department (ED). We determined the frequency, duration and type of interruptions that occurred. We then determined the impact on patient satisfaction of those interruptions occurring at the bedside. METHODS: This was a cohort study of ED physicians and physicians in training. Trained research associates were assigned to an individual provider during 4-hour blocks of time during day and evening shifts. The research associates recorded the activity that was interrupted, as well as the nature and the duration of the interruption. If the interruption occurred during the principal interaction with a patient, the patient's satisfaction score was recorded on a 10-point scale. RESULTS: Physicians were commonly interrupted in all clinical activities, but most frequently during reviewing of data (53%) and charting (50%). Bedside interruptions occurred 26% of the time, and had a negative impact on patient satisfaction. The majority of interruptions (60%) were initiated by another healthcare provider (physician or nurse). Interruptions only rarely resulted in a physician changing tasks before completion. CONCLUSION: Interruptions occur commonly during all clinical activities in the ED, and are frequently generated by providers themselves. These have a negative impact on patient satisfaction. The direct impact on medical errors or on provider satisfaction has not been determined.

Dedicated Shift Wrap-up Time Does Not Improve Resident Sign-out Volume or Efficiency.

OBJECTIVES: Sign-out (SO) is a challenge to the emergency physician. Some training programs have instituted overlapping 9-hour shifts. The residents see patients for eight hours, and have one hour of wrap-up time. This hour helps them complete patient care, leaving fewer patients to sign-out. We examined whether this strategy impacts SO burden. METHODS: This is a retrospective review of patients evaluated by emergency medicine (EM) residents working 9-hour (eight hours of patient care, one hour wrap-up time) and 12-hour shifts (12 hours patient care, no reserved time for wrap-up). Data were collected by reviewing the clinical tracker. A patient was assigned to the resident who initiated care and dictated the chart. SO was defined as any patient in the ED without disposition at change of shift. Patient turn-around-time (TAT) was also recorded. RESULTS: One-hundred sixty-one postgraduate-year-one resident (PGY1), 264 postgraduate-year-two resident (PGY2), and 193 postgraduate-year-three resident (PGY3) shifts were included. PGY1s signed out 1.9 patients per 12-hour shift. PGY2s signed out 2.3 patients on 12-hour shifts and 1.8 patients on 9-hour shifts. PGY3s signed out 2.1 patients on 12-hour shifts and 2.0 patients on 9-hour shifts. When we controlled for patients seen per hour, SO burden was constant by class regardless of shift length, with PGY2s signing out 18% of patients seen compared to 15% for PGY3s. PGY1s signed out 18% of patients seen. TAT for patients seen by PGY1s and PGY2s was similar, at 189 and 187 minutes, respectively. TAT for patients seen by PGY3s was significantly less at 175 minutes. CONCLUSION: The additional hour devoted to wrapping up patients in the ED had no affect on SO burden. The SO burden represented a fixed percentage of the total number of patients seen by the residents. PGY3s sign-out a smaller percentage of patients seen compared to other classes, and have faster TATs.

Resident productivity as a function of emergency department volume, shift time of day, and cumulative time in the emergency department.

OBJECTIVES: We sought to determine if resident productivity changed based on emergency department (ED) volume, shift time of day, or over time during a shift. METHODS: This is a retrospective review of patients evaluated in the ED by emergency medicine residents. Data were collected using the computerized tracker that provides time of physician assignment and daily volume. Regression analysis was used to determine relationship between productivity and volume as well as relationship between productivity and accumulated time in the ED. Analysis of variance was used to assess for productivity differences by shift time of day. RESULTS: One hundred sixty-one postgraduate year-1 (PGY-1), 264 PGY-2, and 193 PGY-3 shifts were included. PGY-1, PGY-2, and PGY-3 residents saw 0.85, 1.13, and 1.25 patients per hour, respectively. PGY-3 and PGY-2 productivity had a weak relationship to ED volume (R = 0.28, P = .03; and R = 0.36, P = .03), whereas PGY-1 productivity had a moderate relationship to ED volume (R = 0.44, P = .0001). There were no differences in productivity based on shift time of day. Accumulated time in the ED had a strongly negative relationship to productivity, with R values from -0.79 to -0.93 (P < .002 for all comparisons). CONCLUSIONS: Resident productivity is not strongly linked to volume or time of day. If specific times have statistically higher volume, they should be staffed with larger numbers of residents. In addition, emergency medicine resident productivity declines reliably over shift time. Therefore, scheduling should be adjusted to create larger shift overlaps to aid in smoother patient flow.

Wernicke encephalopathy complicating lymphoma therapy: case report and literature review.

Thiamine deficiency can occur in any disease that results in inadequate intake or excessive loss of vitamin B1. In addition to increased thiamine consumption secondary to high cell turnover, cancer patients frequently have reduced oral intake as a direct result of their cancer or from cancer treatments. However, Wernicke encephalopathy (cerebral Beriberi), a clinical manifestation of thiamine deficiency, has rarely been associated with cancer patients. We report a case of Wernicke encephalopathy in a nonalcoholic patient with lymphoma. Although thiamine deficiency rarely potentiates clinical sequelae in cancer patients, it is important to recognize the risk and the clinical signs and manifestations so that prompt therapy can be initiated to reverse morbidity.

Crystal structure of quinone reductase 2 in complex with resveratrol.

Resveratrol has been shown to have chemopreventive, cardioprotective, and antiaging properties. Here, we report that resveratrol is a potent inhibitor of quinone reductase 2 (QR2) activity in vitro with a dissociation constant of 35 nM and show that it specifically binds to the deep active-site cleft of QR2 using high-resolution structural analysis. All three resveratrol hydroxyl groups form hydrogen bonds with amino acids from QR2, anchoring a flat resveratrol molecule in parallel with the isoalloxazine ring of FAD. The unique active-site pocket in QR2 could potentially bind other natural polyphenols such as flavonoids, as proven by the high affinity exhibited by quercetin toward QR2. K562 cells with QR2 expression suppressed by RNAi showed similar properties as resveratrol-treated cells in their resistance to quinone toxicity. Furthermore, the QR2 knockdown K562 cells exhibit increased antioxidant and detoxification enzyme expression and reduced proliferation rates. These observations could imply that the chemopreventive and cardioprotective properties of resveratrol are possibly the results of QR2 activity inhibition, which in turn, up-regulates the expression of cellular antioxidant enzymes and cellular resistance to oxidative stress.