Carbon Monoxide Poisoning Effectively Treated with High-flow Nasal Cannula.

Carbon monoxide (CO) poisoning is typically treated by administration of oxygen via non-rebreather mask (NRB). High-flow nasal cannula (HFNC) is an alternative to NRB in a variety of disease states. We report a case of the novel use of HFNC in the treatment of acute CO poisoning. A 29-year-old man presented with a carboxyhemoglobin (COHb) level of 29.8%. He was treated with HFNC, and COHb levels declined to 5.4% in 230 minutes. Given several theoretical advantages of HFNC relative to NRB, HFNC is a potential option for use in the treatment of CO poisoning.

Metabolomic analysis of acetaminophen induced subclinical liver injury.

Introduction: This study examines the metabolomic profile in humans following acetaminophen (APAP) induced subclinical hepatoxicity in the presence and absence of propylene glycol (PG), a cytochrome P450 2E1 inhibitor.Methods: Plasma samples were collected during a previously performed randomized, cross-over trial where 21 subjects received APAP, four grams daily for two weeks in one arm and APAP, four grams daily with 20 mL PG in a second arm. Plasma collected at baseline and at day nine of each arm(time of peak elevation of liver function tests) underwent metabolomic analysis.Results: There were reduced phase two metabolites in subjects who displayed liver injury. There was also decreased sulfonation capacity in all subjects as well as in subjects displaying liver injury relative to subjects not displaying liver injury as evidenced by decreased sulfonation of hepatically derived steroids. There were decreased levels of acylcarnitines in subjects who displayed liver injury relative to subjects not displaying liver injury, indicating inhibition of mitochondrial fatty acid ß-oxidation.Conclusions: Daily APAP dosing led to saturation of metabolic pathways and inhibition of mitochondrial function in subjects displaying subclinical liver injury.

Inhibition of CYP2E1 With Propylene Glycol Does Not Protect Against Hepatocellular Injury in Human Acetaminophen Daily-Dosing Model.

Acetaminophen (APAP)-induced liver injury is initiated by metabolism of APAP by the cytochrome P-450 (CYP) system, primarily CYP2E1. We previously demonstrated CYP inhibition following administration of a liquid APAP formulation containing propylene glycol, a CYP2E1 inhibitor, and other excipients. This study was undertaken to determine if propylene glycol specifically inhibits production of CYP-derived metabolites and if propylene glycol reduces the rise in alanine aminotransferase (ALT) seen following prolonged APAP dosing. Human subjects were randomized to receive 4 g of APAP daily in one arm of the study or 4 g of APAP with 5 mL of 99% propylene glycol in the other arm, both for 14 days. After a washout period of at least 14 days, subjects were crossed over between arms. Outcomes were rise of ALT greater than 2 times baseline (responders) and proportion of randomly sampled CYP-derived metabolites relative to total metabolites produced. There was no difference in percentage of responders between treatment groups: 6 of 21 in the APAP group (29%) compared with 8 of 20 in the APAP + propylene glycol group (40%); chi-square, P = .59. For all subjects, the mean percentage of CYP-derived metabolites produced was 5.8% (APAP) versus 4.3% (APAP + propylene glycol); P = .018. This effect was solely attributable to the responders: the mean percentage of CYP metabolites of responders was 7.7% (APAP) versus 4.6% (APAP + propylene glycol), P = .050, whereas there was no difference for the nonresponders. Five subjects were responders in both arms (2% probability of random occurrence). Our data indicates that propylene glycol inhibits CYP2E1 metabolism of APAP in some subjects but does not effect hepatocellular indury at the dose given.

Acute dyskinesia, myoclonus, and akathisa in an adolescent male abusing quetiapine via nasal insufflation: a case study.

BACKGROUND: Although the benefits of antipsychotic pharmacotherapy can be pronounced, many patients develop unwanted adverse effects including a variety of movement disorders. Compared with the traditional antipsychotics, the atypical antipsychotics have a decreased risk for associated movement disorders. Drug-induced movement disorders can occur, however, and the risk of adverse events can increase significantly when medications are abused. CASE PRESENTATION: We describe the case of a 13-year-old male who presented to an emergency department with acute movement disorders after nasal insufflation of crushed quetiapine. The patient was admitted and successfully treated for neuroleptic toxicity with intravenous antihistamine pharmacotherapy. His primary care provider and psychiatrist were notified of the abuse, quetiapine was discontinued, and the patient was discharged and referred to a drug and alcohol awareness and abuse program. CONCLUSIONS: The abuse of quetiapine has unfortunately become more common. This unique case report of acute movement disorders following nasal insufflation of quetiapine highlights the need for heightened vigilance when prescribing quetiapine and for increased awareness and education regarding medication-abuse.

CD39 modulates hematopoietic stem cell recruitment and promotes liver regeneration in mice and humans after partial hepatectomy.

OBJECTIVE: To study molecular mechanisms involved in hematopoietic stem cell (HSC) mobilization after liver resection and determine impacts on liver regeneration. BACKGROUND: Extracellular nucleotide-mediated cell signaling has been shown to boost liver regeneration. Ectonucleotidases of the CD39 family are expressed by bone marrow-derived cells, and purinergic mechanisms might also impact mobilization and functions of HSC after liver injury. METHODS: Partial hepatectomy was performed in C57BL/6 wild-type, Cd39 ectonucleotidase-null mice and in chimeric mice after transplantation of wild-type or Cd39-null bone marrow. Bone marrow-derived HSCs were purified by fluorescence-activated cell sorting and administered after hepatectomy. Chemotactic studies were performed to examine effects of purinergic receptor agonists and antagonists in vitro. Mobilization of human HSCs and expression of CD39 were examined and linked to the extent of resection and liver tests. RESULTS: Subsets of HSCs expressing Cd39 are preferentially mobilized after partial hepatectomy. Chemotactic responses of HSCs are increased by CD39-dependent adenosine triphosphate hydrolysis and adenosine signaling via A2A receptors in vitro. Mobilized Cd39 HSCs boost liver regeneration, potentially limiting interleukin 1ß signaling. In clinical studies, mobilized human HSCs also express CD39 at high levels. Mobilization of HSCs correlates directly with the restoration of liver volume and function after partial hepatectomy. CONCLUSIONS: We demonstrate CD39 to be a novel HSC marker that defines a functionally distinct stem cell subset in mice and humans. HSCs are mobilized after liver resection, limit inflammation, and boost regeneration in a CD39-dependent manner. These observations have implications for monitoring and indicate future therapeutic avenues.

Hemorrhagic complications in emergency department patients who are receiving dabigatran compared with warfarin.

STUDY OBJECTIVE: Dabigatran is a reversible direct thrombin inhibitor recently approved for stroke prevention in patients with atrial fibrillation. An increasing number of patients receiving dabigatran present to the emergency department (ED) with bleeding complications. Unlike vitamin K antagonists, there are no accepted reversal agents for dabigatran and the data on course and management of bleeding complications are limited. The study objective is to describe the course of bleeding complications in patients admitted through the ED who are prescribed dabigatran in comparison with warfarin therapy. METHODS: This was a prospective observational study of ED patients under treatment with dabigatran or warfarin who were admitted with bleeding complications during a 6-month period. Patient demographics, laboratory results, bleeding site, interventions, and outcomes are reported. RESULTS: There were 15 and 123 patients admitted with dabigatran and warfarin-induced bleeding complications, respectively. Of the warfarin patients, 25 charts were randomly chosen for extraction. Patients with dabigatran-induced bleeding had a shorter length of stay (3.5 versus 6.0 days) and were older (77 versus 70 years). Patients receiving dabigatran were more likely to have gastrointestinal bleeding (80% versus 48%) and less likely to have intracranial bleeding (0% versus 32%) than those receiving warfarin. Of patients with dabigatran-induced bleeding, 53% presented with an acute kidney injury. CONCLUSION: Our patients with dabigatran-induced bleeding had a more benign clinical course with a shorter length of stay compared with patients with warfarin-induced bleeding. As was the case in previous published reports, there were fewer intracranial hemorrhages in patients receiving dabigatran than warfarin. Sustaining an acute kidney injury potentially predisposes patients to bleeding while receiving dabigatran.

Effect of excipients on acetaminophen metabolism and its implications for prevention of liver injury.

Acetaminophen poisoning is the most frequent cause of acute hepatic failure in the US. Toxicity requires reductive metabolism of acetaminophen, primarily via CYP2E1. Liquid acetaminophen preparations contain propylene glycol, a common excipient that has been shown to reduce hepatocellular injury in vitro and in rodents. Children are less susceptible to acetaminophen toxicity for unclear reasons. We conducted a pharmacokinetic single-blinded crossover study of 15 healthy adult volunteers comparing the CYP2E1 and conjugative metabolism of a 15 mg/kg dose of liquid versus solid preparations of acetaminophen. Measured AUC's for the CYP2E1 metabolites were 16-17% lower and extrapolated AUC's were 25-28% lower in the liquid formulation arm while there was no difference in conjugative metabolite production. The formation rate constants for reductive metabolites were equivalent between solid and liquid formulations indicating that enzyme inhibition was competitive. Propylene glycol, an established CYP2E1 competitive antagonist, was detected in the liquid formulation but not solid formulation arm. Since children tend to ingest liquid preparations, the protective effect of this excipient could explain their decreased susceptibility to acetaminophen toxicity. A less hepatotoxic formulation of acetaminophen could potentially be developed if co-formulated with a CYP2E1 inhibitor.

Amatoxin poisoning: case reports and review of current therapies.

BACKGROUND: Diagnosis and management of Amanita mushroom poisoning is a challenging problem for physicians across the United States. With 5902 mushroom exposures and two resultant deaths directly linked to Amanita ingestion in 2009, it is difficult for physicians to determine which patients are at risk for lethal toxicity. Identification of amatoxin poisoning can prove to be difficult due to delay in onset of symptoms and difficulty with identification of mushrooms. Consequently, it is difficult for the Emergency Physician to determine proper disposition. Further, treatment options are controversial. OBJECTIVES: To review current data to help health care providers effectively identify and treat potentially deadly Amanita mushroom ingestions. CASE REPORTS: We present two cases of Amanita mushroom ingestion in the northeastern United States treated with N-acetylcysteine, high-dose penicillin, cimetidine, and silibinin, a semi-purified fraction of milk thistle-derived silymarin, as part of their treatment regimen. The mushroom species was identified by a consultant as Amanita Ocreata. CONCLUSIONS: We present the successful treatment of 2 patients who ingested what we believe to be an Amanita species never before identified in the northeastern United States.

Increased plasma levels of microparticles expressing CD39 and CD133 in acute liver injury.

BACKGROUND: We have previously demonstrated that CD133 and CD39 are expressed by hematopoietic stem cells (HSC), which are mobilized after liver injury and target sites of injury, limit vascular inflammation, and boost hepatic regeneration. Plasma microparticles (MP) expressing CD39 can block endothelial activation. Here, we tested whether CD133 MP might be shed in a CD39-dependent manner in a model of liver injury and could potentially serve as biomarkers of liver failure in the clinic. METHODS: Wild-type and Cd39-null mice were subjected to acetaminophen-induced liver injury. Mice were sacrificed and plasma MP were isolated by ultracentrifugation. HSC and CD133 MP levels were analyzed by fluorescence-activated cell sorting. Patients were enrolled with acute (n=5) and acute on chronic (n=5) liver injury with matched controls (n=7). Blood was collected at admission and plasma CD133 and CD39 MP subsets were analyzed by fluorescence-activated cell sorting. RESULTS: HSC and CD133 MP levels were significantly increased only in the plasma of wild-type mice with acetaminophen hepatotoxicity (P<0.05). No increases in CD133 MP were noted in Cd39-null mice. Plasma MP increases were observed in patients with liver injury. These MP were characterized by significantly higher levels of CD39 (P<0.05). CONCLUSIONS: HSC and plasma CD133 MP levels increase in a CD39-dependent manner during experimental acute liver injury. Increased levels of CD39 MP are differentially noted in patients with liver injury. Further research is needed to determine whether MP fluxes are secondary to pathophysiologic insults to the liver or might reflect compensatory responses.