Faculty Bibliography

CASE REPORT/UNASSIGNED:A 12-month-old (former 24 week gestational age), 8.7 kg male was hospitalized after an uneventful colostomy reversal. In the postoperative unit, the patient unintentionally received 1000 mg IV (114.9 mg/kg) acetaminophen instead of the intended 100 mg IV. Serial acetaminophen concentrations were drawn. The patient received IV Nacetylcysteine and ultimately had no adverse outcomes. DISCUSSION/UNASSIGNED:This case report adds to the existing literature regarding toxicokinetics of IV APAP in infants. Our patient had a calculated ke of 0.263 h-1, correlating with a half-life of 2.63 hours. Based on current available data, the half-life of IV APAP in infants varies (2.6 to 4.9 hours). The reason for this variation is unknown and further research is needed in this area.

OBJECTIVE:Although hemodialysis is recommended for patients with severe metformin-associated lactic acidosis (MALA), the amount of metformin removed by hemodialysis is poorly documented. We analyzed endogenous clearance and hemodialysis clearance in a patient with MALA. METHODS:A 62-year-old man with a history of type II diabetes mellitus presented after several days of vomiting and diarrhea and was found to have acute kidney injury (AKI) and severe acidemia. Initial serum metformin concentration was 315.34 μmol/L (40.73 μg/mL) (typical therapeutic concentrations 1-2 μg/mL). He underwent 6 h of hemodialysis. We collected hourly whole blood, serum, urine, and dialysate metformin concentrations. Blood, urine, and dialysate samples were analyzed, and clearances were determined using standard pharmacokinetic calculations. RESULTS:The total amount of metformin removed by 6 h of hemodialysis was 888 mg, approximately equivalent to one therapeutic dose. Approximately 142 mg of metformin was cleared in the urine during this time. His acid-base status and creatinine improved over the following days. No further hemodialysis was required. CONCLUSION/CONCLUSIONS:We report a case of MALA likely secondary to AKI and severe volume depletion. The patient improved with supportive care, sodium bicarbonate, and hemodialysis. Analysis of whole blood, serum, urine, and dialysate concentrations showed limited efficacy of hemodialysis in the removal of metformin from blood, contrary to previously published data. Despite evidence of acute kidney injury, a relatively large amount of metformin was eliminated in the urine while the patient was undergoing hemodialysis. These data suggest that clinical improvement is likely due to factors besides removal of metformin.

Objective: We present a patient who developed prolonged coma following treatment of ethanol withdrawal with large doses of diazepam and demonstrated prolonged elimination toxicokinetics. Case report: A 68-year-old man who drank 5-6 alcoholic beverages/day was admitted for an elective transcatheter aortic valve replacement. Two days post-procedure, he developed agitation and was presumptively treated for ethanol withdrawal with diazepam (470 mg IV over 24 hours). He remained comatose for four days prompting a toxicology consult. On day 7 of persistent coma from presumed benzodiazepine excess, flumazenil (0.5 mg) was administered; he opened his eyes for the first time, began speaking, and answering simple questions, but 30 minutes later was comatose again. Flumazenil infusion 0.25mg/h was trialed with unclear effect. His hospitalization was complicated by gastrointestinal bleeding and mild ischemic stroke deemed noncontributory to his clinical status. The flumazenil infusion was discontinued 1 week later. His evaluation was extensive (brain magnetic resonance imaging and computerised tomography, lumbar puncture, and blood cultures) and unremarkable. On hospital week 4, he became only gradually more awake, and was eventually discharged to a rehabilitation facility on hospital week 6, awake, conversive but still confused. Six weeks later, he was discharged home fully recovered. He remains amnestic to his hospitalization. Serum diazepam and nordiazepam concentrations were determined via liquid-chromatography mass-spectrometry. Concentrations obtained four days after the last dose were: diazepam 963 mug/L (therapeutic: 200-1000 mug/L) and nordiazepam 240 mug/L (therapeutic: 100-1500 mug/L). Elimination kinetics were calculated with apparent half-lives of 294 hours and 797 hours for diazepam and nordiazepam, respectively. Genotyping of CYP3A4 and CYP2C19, the two primary metabolizers of diazepam, demonstrated no abnormalities.
Conclusion(s): Diazepam demonstrated extremely atypical elimination kinetics despite normal renal and hepatic function. Acute tolerance which is expected after prolonged benzodiazepine exposure was not clearly demonstrated. The relationship between his serum concentration and clinical status is unclear at this time

Background: The "Pollyanna Phenomenon," an optimism for useful interventions appearing as efficacious as useless ones, was first described in 1992[1]. An editorial written in 1997 highlighted this phenomenon regarding passive data collection from Poison Control Centers (PCCs) and its limitations related to minimally symptomatic or asymptomatic patients[2]. PCCs continue to collect data passively with an immense data pool. Despite these "big data," limitations to PCC research persist. The term toxicovigilance was borne from this editorial and suggestions were made to improve PCC data fidelity and to overcome the "Pollyanna Phenomenon." We investigated PCC research over the past 40+ years to determine the impact of this editorial on toxicovigilance[2].
Method(s): We searched PubMed and EMBASE for PCC research from 1978 to 2020 using these search terms: "Poison Center", "Poison Control Center", "Poison Centre", "Poison Control Centre." Research articles before 1997 established a baseline for research quality[2]. Research articles from 1997 to April 2020, served as the intervention group assessing for changes in the quality of research and were examined for evidence of toxicovigilance. Articles were included in this study based on the following criteria: written in English; classified as original research; performed in a PCC setting, and the study objective was focused on an identifiable xenobiotic or xenobiotics. Each article was assessed for toxicovigilance based on the following criteria: confirmation of said xenobiotic(s) either qualitatively or quantitatively, study methodology (retrospective or prospective), and clinical recommendations made "beyond the scope of study methodology." If a study did not confirm xenobiotics' presence analytically, the study was considered to make recommendations beyond the scope of the study methodology.
Result(s): Our search initially identified 1614 articles. A random sample of 400 articles was chosen for review. From 1978-1997, 88 articles were initially identified. Twenty-five studies met inclusion criteria. Fifteen were retrospective and ten were prospective. Two studies confirmed exposure confirmation analytically in each group. Ten retrospective studies made clinical recommendations based on their conclusions, none of which confirmed the analytical presence of xenobiotic(s). Ten prospective studies made clinical recommendations with only two analytically confirming the presence of the xenobiotic. From 1998-2020, 138 research studies met inclusion criteria of which 117 were retrospective and 19 were prospective. Of these two groups, 19 and 7 had analytically confirmed xenobiotic presence in the retrospective and prospective studies, respectively. Sixty-eight retrospective studies and ten prospective studies made clinical recommendations without analytically confirming xenobiotic exposures. Comparing the baseline and intervention groups, we observed an increase in the frequency of retrospective studies with a similar proportion making clinical recommendations while lacking confirmation of exposures. There was an increase in rates of xenobiotic confirmation by 2% in the intervention period.
Conclusion(s): Toxicovigilance appears to be lacking in many PCC studies. Despite vast advancements in analytical techniques and the ability to gather and record data, the "Pollyanna Phenomenon" remains vibrant in PCC research. Efforts towards improving the frequency of analytical testing and confirmation of xenobiotic exposure are essential to improve PCC data collection and research and must be considered prerequisites for journal publication. (Table Presented)

BACKGROUND:We report a patient with a massive hydroxychloroquine overdose manifested by profound hypokalemia and ventricular dysrhythmias and describe hydroxychloroquine toxicokinetics. CASE REPORT/METHODS:A 20-year-old woman (60 kg) presented 1 h after ingesting 36 g of hydroxychloroquine. Vital signs were: BP, 66 mmHg/palpation; heart rate, 115/min; respirations 18/min; oxygen saturation, 100% on room air. She was immediately given intravenous fluids and intubated. Infusions of diazepam and epinephrine were started. Activated charcoal was administered. Her initial serum potassium of 5.3 mEq/L decreased to 2.1 mEq/L 1 h later. The presenting electrocardiogram (ECG) showed sinus tachycardia at 119 beats/min with a QRS duration of 146 ms, and a QT interval of 400 ms (Bazett's QTc 563 ms). She had four episodes of ventricular tachydysrhythmias requiring cardioversion, electrolyte repletion, and lidocaine infusion. Her blood hydroxychloroquine concentration peaked at 28,000 ng/mL (therapeutic range 500-2000 ng/mL). Serial concentrations demonstrated apparent first-order elimination with a half-life of 11.6 h. She was extubated on hospital day three and had a full recovery. CONCLUSION/CONCLUSIONS:We present a massive hydroxychloroquine overdose treated with early intubation, activated charcoal, epinephrine, high dose diazepam, aggressive electrolyte repletion, and lidocaine. The apparent 11.6 hour half-life of hydroxychloroquine was shorter than previously described.