Silas W. Smith

Acetaminophen Overdose with Altered Acetaminophen Pharmacokinetics and Hepatotoxicity Associated with Premature Cessation of Intravenous N-Acetylcysteine Therapy

Objective To report a case of erratic absorption, double peak serum concentrations, and hepatotoxicity following premature cessation of intravenous N-acetylcysteine (NAC) treatment in the setting of a massive acetaminophen overdose. Case Summary: A 78-year-old man reportedly ingested approximately 96 immediate-release acetaminophen 500-mg tablets (48 g) over a one-hour period in an apparent suicide attempt. The acetaminophen concentration at 2.25 hours was 264 μg/mL. Intravenous NAC was initiated 5 hours postingestion. At 6.25 hours postingestion, the acetaminophen concentration was 281 μg/mL. Following administration of intravenous NAC for 21 hours, therapy was discontinued despite a residual acetaminophen concentration of 116 μg/mL. The patient experienced hepatotoxicity, coagulopathy, and renal injury. Pharmacokinetic analysis revealed significantly prolonged acetaminophen absorption and a second peak acetaminophen concentration of 228 μg/mL approximately 48 hours post ingestion. Direct in-hospital monitoring of the patient made a second ingestion unlikely. Discussion: Acetaminophen overdose is usually effectively managed with NAC. Patients with massive ingestions may have altered absorption kinetics due to acetaminophens solubility being exceeded, physiologically or chemically altered gastrointestinal emptying or motility, or other factors. These patients may benefit from gastrointestinal decontamination and prolonged NAC therapy. Conclusions: In patients with massive acetaminophen ingestion, erratic absorption may occur, and toxic serum concentrations may persist beyond a standard 21–hour course of intravenous NAC therapy. Acetaminophen concentrations and aminotransferase levels should be evaluated at the completion of the intravenous NAC infusion to ensure complete elimination of acetaminophen and absence of hepatotoxicity and to exclude the need lor prolonged treatment.

Hemorrhagic complications associated with dabigatran use

Objective. Dabigatran is a direct thrombin inhibitor approved for anticoagulation in non-valvular atrial fibrillation and, in some countries, for thromboembolism prophylaxis following select orthopedic surgeries. Despite decreased rates of thromboembolism, bleeding remains a risk due to the inability to conveniently monitor anticoagulant effect and the lack of a reversal agent. Case series. We present four cases of dabigatran-related bleeding. A 79-year-old man on aspirin, clopidogrel, and dabigatran presented with rectal bleeding and epistaxis. He died despite transfusion and administration of prothrombin complex concentrate. A 73-year-old woman on dabigatran and aspirin survived after transfusion and an emergent sternotomy for cardiac tamponade. An 86 year-old man with kidney disease and thrombocytopenia received packed red blood cells, platelets, and fresh frozen plasma for rectal bleeding while on dabigatran. An 80 year-old man on dabigatran had a subdural hematoma after falling and hitting his head. Serial imaging showed no progression. Conclusion. The absence of a reversal agent for dabigatran raises concern for uncontrollable bleeding and death. Dabigatrans listed contraindications include active bleeding and a history of dabigatran hypersensitivity reaction. Wider use may result in bleeding rates higher than anticipated from clinical trials. Risks factors that may have contributed to bleeding in these patients include concomitant bleeding diathesis, antiplatelet agent use, renal insufficiency, advanced age, and fall risks.

Hemodialysis for the Treatment of Pulmonary Hemorrhage From Dabigatran Overdose

Dabigatran is an oral direct thrombin inhibitor indicated for thromboembolism prophylaxis in patients with nonvalvular atrial fibrillation. Since its approval in the United States in 2010, dabigatran-associated hemorrhages have garnered much attention because bleeding rates were higher than initially expected. Additionally, reversing anticoagulation remains challenging. Traditional modes of reversing warfarin-associated coagulopathies are ineffective in reversing anticoagulation from dabigatran. Although hemodialysis is proposed as a method to accelerate dabigatran elimination, evidence supporting its clinical utility remains unproved. We report the case of an 80-year-old man who presented with worsening hemoptysis in the setting of unintentional ingestion of excess dabigatran. Despite transfusion of 2 units of fresh frozen plasma, he continued to bleed, although his international normalized ratio improved from 8.8 to 7.2. He underwent hemodialysis, and serum dabigatran concentration decreased from 1,100 to 18 ng/mL over 4 hours, with an initial extraction ratio of 0.97 and blood clearance of 291 mL/min. Although his serum dabigatran concentration rebounded to 100 ng/mL 20 minutes after the cessation of dialysis, his bleeding stopped and he improved clinically. Hemorrhage in the setting of dabigatran anticoagulation remains a therapeutic predicament. Hemodialysis may play an adjunct role in accelerating the elimination of dabigatran in bleeding patients.

Paradoxical and Bidirectional Drug Effects

AbstractA paradoxical drug reaction constitutes an outcome that is opposite from the outcome that would be expected from the drug’s known actions. There are three types: 1A paradoxical response in a condition for which the drug is being explicitly prescribed.2Paradoxical precipitation of a condition for which the drug is indicated, when the drug is being used for an alternative indication.3Effects that are paradoxical in relation to an aspect of the pharmacology of the drug but unrelated to the usual indication. In bidirectional drug reactions, a drug may produce opposite effects, either in the same or different individuals, the effects usually being different from the expected beneficial effect. Paradoxical and bidirectional drug effects can sometimes be harnessed for benefit; some may be adverse.Such reactions arise in a wide variety of drug classes. Some are common; others are reported in single case reports. Paradoxical effects are often adverse, since they are opposite the direction of the expected effect. They may complicate the assessment of adverse drug reactions, pharmacovigilance, and clinical management. Bidirectional effects may be clinically useful or adverse. From a clinical toxicological perspective, altered pharmacokinetics or pharmacodynamics in overdose may exacerbate paradoxical and bidirectional effects. Certain antidotes have paradoxical attributes, complicating management.Apparent clinical paradoxical or bidirectional effects and reactions ensue when conflicts arise at different levels in self-regulating biological systems, as complexity increases from subcellular components, such as receptors, to cells, tissues, organs, and the whole individual. These may be incompletely understood. Mechanisms of such effects include different actions at the same receptor, owing to changes with time and downstream effects; stereochemical effects; multiple receptor targets with or without associated temporal effects; antibody-mediated reactions; three-dimensional architectural constraints; pharmacokinetic competing compartment effects; disruption and non-linear effects in oscillating systems, systemic overcompensation, and other higherlevel feedback mechanisms and feedback response loops at multiple levels. Here we review and provide a compendium of multiple class effects and individual reactions, relevant mechanisms, and specific clinical toxicological considerations of antibiotics, immune modulators, antineoplastic drugs, and cardiovascular, CNS, dermal, endocrine, musculoskeletal, gastrointestinal, haematological, respiratory, and psychotropic agents.

Attack rates assessment of the 2009 pandemic H1N1 influenza A in children and their contacts: a systematic review and meta-analysis.

Background The recent H1N1 influenza A pandemic was marked by multiple reports of illness and hospitalization in children, suggesting that children may have played a major role in the propagation of the virus. A comprehensive detailed analysis of the attack rates among children as compared with their contacts in various settings is of great importance for understanding their unique role in influenza pandemics. Methodology/Principal Findings We searched MEDLINE (PubMed) and Embase for published studies reporting outbreak investigations with direct measurements of attack rates of the 2009 pandemic H1N1 influenza A among children, and quantified how these compare with those of their contacts. We identified 50 articles suitable for review, which reported school, household, travel and social events. The selected reports and our meta-analysis indicated that children had significantly higher attack rates as compared to adults, and that this phenomenon was observed for both virologically confirmed and clinical cases, in various settings and locations around the world. The review also provided insight into some characteristics of transmission between children and their contacts in the various settings. Conclusion/Significance The consistently higher attack rates of the 2009 pandemic H1N1 influenza A among children, as compared to adults, as well as the magnitude of the difference is important for understanding the contribution of children to disease burden, for implementation of mitigation strategies directed towards children, as well as more precise mathematical modeling and simulation of future influenza pandemics.

Prolonged severe hypotension following combined amlodipine and valsartan ingestion

Introduction. Compared to other calcium channel blockers (CCBs), overdose with dihydropyridine CCBs are considered relatively benign due to their vascular selectivity. Although not a sustained-release preparation, amlodipines prolonged duration of effect is concerning following overdose. In addition, angiotensin II receptor blocker blunting of vasoconstrictive and sympathetic compensatory responses could exacerbate calcium channel blocker toxicity. We describe severe toxicity associated with an overdose of amlodipine and valsartan. Case Report. A 75-year-old woman presented to the ED 45 minutes after a witnessed suicidal ingestion of a “handful” of amlodipine and valsartan tablets. Hypotension, which appeared two hours after ingestion, was refractory to crystalloids and colloids, calcium gluconate, epinephrine, norepinephrine, phenylephrine, and vasopressin infusions. High-dose insulin euglycemia (HIE) therapy, and treatment with glucagon and naloxone were successful in improving her hemodynamic status. In this combined overdose, right heart catheterization demonstrated both negative inotropic effects and decreased systemic vascular resistance. Conclusion. Co-ingestion of amlodipine with valsartan produced profound toxicity. Early institution of HIE therapy may be beneficial to reverse these effects.

The Role of Chelation in the Treatment of Other Metal Poisonings

These proceedings will review the role of chelation in five metals—aluminum, cadmium, chromium, cobalt, and uranium—in order to illustrate various chelation concepts. The process of “chelation” can often be oversimplified, leading to incorrect assumptions and risking patient harm. For chelation to be effective, two critical assumptions must be fulfilled: the presumed “metal toxicity” must correlate with a given body or a particular compartment burden, and reducing this compartmental or the body burden (through chelation) attenuates toxicity. Fulfilling these assumptions requires an established dose–response relationship, a validated, reproducible means of toxicity assessment (clinical, biochemical, or radiographical), and an appropriate assessment mechanisms of body or compartment burden. While a metal might “technically” be capable of chelation (and readily demonstrable in urine or feces), this is an insufficient endpoint. Clinical relevance must be affirmed. Deferoxamine is an accepted chelator for appropriately documented aluminum toxicity. There is a very minimal treatment window in order to address chelation in cadmium toxicity. In acute toxicity, while no definitive chelation benefit is described, succimer (DMSA), diethylenetriaminepentaacetate (DTPA), and potentially ethylenediaminetetraacetic acid (EDTA) have been considered. In chronic toxicity, chelation is unsupported. There is little evidence to suggest that currently available chromium chelators are efficacious. Similarly, scant human evidence exists with which to provide recommendation for cobalt chelation. DTPA has been recommended for cobalt radionuclide chelation, although DMSA, EDTA, and N-acetylcysteine have also been suggested. DTPA is unsupported for uranium chelation. Sodium bicarbonate is currently recommended, although animal evidence is conflicting.

Solanaceous steroidal glycoalkaloids and poisoning by Solanum torvum, the normally edible susumber berry

Ingestion of immature, environmentally stressed, or cultivar-specific Solanum species (particularly the potato) has been previously associated with gastrointestinal and neurological symptoms caused by solanaceous steroidal glycoalkaloids (SGAs). We report on two geographically, temporally disparate outbreaks of poisoning by susumber berries (Solanum torvum- Solanaceae) and on detection of alkaloids not present in non-toxic berries. Five family members in New York City participated in a traditional evening meal containing Jamaican susumber berries. All those consuming berries were symptomatic the following morning with varying degrees of gastrointestinal distress, dizziness, slurred speech, cranial nerve deficits, and ataxia. The most seriously afflicted patient developed hypertension, confusion, proximal upper extremity weakness, and hypercapnic respiratory failure requiring prolonged mechanical ventilation. A separate cohort of six patients in Toronto ate unripe Jamaican susumber berries. They presented 14h post-ingestion with varying degrees of diarrhea, weakness, facial paralysis, slurred speech, ataxia, early hypertension, and proximal weakness. Two patients had ventilatory decompensation; one required intubation. Poisonous berries appeared indistinguishable from non-toxic varieties. We isolated solasonine, larger amounts of solamargine, and other steroidal glycoalkaloids in the toxic berry strains. S. torvum poisoning can produce significant neurological and gastrointestinal effects which appear to be mediated by SGAs present in the berries.

A novel approach to multihazard modeling and simulation.

OBJECTIVE To develop and apply a novel modeling approach to support medical and public health disaster planning and response using a sarin release scenario in a metropolitan environment. METHODS An agent-based disaster simulation model was developed incorporating the principles of dose response, surge response, and psychosocial characteristics superimposed on topographically accurate geographic information system architecture. The modeling scenarios involved passive and active releases of sarin in multiple transportation hubs in a metropolitan city. Parameters evaluated included emergency medical services, hospital surge capacity (including implementation of disaster plan), and behavioral and psychosocial characteristics of the victims. RESULTS In passive sarin release scenarios of 5 to 15 L, mortality increased nonlinearly from 0.13% to 8.69%, reaching 55.4% with active dispersion, reflecting higher initial doses. Cumulative mortality rates from releases in 1 to 3 major transportation hubs similarly increased nonlinearly as a function of dose and systemic stress. The increase in mortality rate was most pronounced in the 80% to 100% emergency department occupancy range, analogous to the previously observed queuing phenomenon. Effective implementation of hospital disaster plans decreased mortality and injury severity. Decreasing ambulance response time and increasing available responding units reduced mortality among potentially salvageable patients. Adverse psychosocial characteristics (excess worry and low compliance) increased demands on health care resources. Transfer to alternative urban sites was possible. CONCLUSIONS An agent-based modeling approach provides a mechanism to assess complex individual and systemwide effects in rare events.

An Approach to Chemotherapy-Associated Toxicity

The effects of chemotherapy in multiple organ systems may be challenging to discern from the sequelae of malignancy and systemic illnesses with concomitant immunocompromise. Chemotherapeutic agents typically affect multiple organ systems. Intrathecal medication errors may pose particularly devastating neurologic consequences and death, often requiring emergent intervention. This article provides an overview of commonly used chemotherapeutic drugs, indications for use, their adverse effects by organ system, and the management of commonly encountered toxicities. Intrathecal medication errors and specific antidotes are discussed in pertinent management sections. Emergency department management should focus on rapid patient assessment, immediate intervention following intrathecal medication errors, exclusion of infection, and excellent supportive care.