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.

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.

Dabigatran: review of pharmacology and management of bleeding complications of this novel oral anticoagulant.

Dabigatran (Pradaxa) is a competitive direct thrombin inhibitor approved by the US FDA for prevention of embolic stroke in patients with nonvalvular atrial fibrillation. Dabigatran has a pharmacokinetic profile that produces predictable anticoagulation responses, does not undergo CYP 450 metabolism, has few drug-drug and drug-food interactions, and does not require frequent laboratory monitoring of clotting parameters. Clinicians are rapidly prescribing this agent as a replacement for warfarin therapy. However, no therapeutic agent has been accepted to reliably reverse the hemorrhagic complications of dabigatran. As of yet, there is no solid evidence to guide management of bleeding complications; management should start with local control of bleeding when possible and transfusion of pRBCs if needed. Transfusion of FFP would not be expected to help control bleeding. Limited and mixed data exist for transfusion of factor VIIa and prothrombin complex concentrates; these therapies should be considered as well as dialysis, which will increase elimination in patients with life-threatening or closed-space bleeding due to dabigatran. We present an article that reviews the pharmacokinetics, clinical trial literature, and consensus guidelines regarding this novel oral anticoagulant.

Exertional rhabdomyolysis--when should we start worrying? Case reports and literature review.

Exertional rhabdomyolysis (ER) is a serious medical issue usually seen in individuals or patients after engaging in heavy exertion and physical activity. The incidence, natural course, and recurrence of ER are, by and large, unknown. Given the lack of rigorous scientific data that are specific for ER, most of the patients with ER receive treatment in an inpatient setting even with only a mild elevation of creatine phosphokinase (CPK) level. Often, patients receive inpatient treatment solely on the basis of elevated CPK (<3000 IU) even in the absence of other serious signs and symptoms of ER. We intent to describe 2 case reports that involve patients who developed ER after an intense physical exertion and were managed in an outpatient setting with close follow-up. In the discussion part, we point suggest that in patients with a relatively mild CPK elevation (<15,000 IU) and normal creatinine value and in the absence of factors such as profound dehydration, sickle cell trait, concomitant infectious cause, underlying metabolic syndrome, and current and ongoing use of analgesics, the complications after ER are low. Patients who develop ER, who can be reliably followed up, and who fulfills these criteria can be managed as outpatients.

Hyperbaric oxygen reduces acetaminophen toxicity and increases HIF-1alpha expression.

OBJECTIVES: To investigate the effect of hyperbaric oxygen (HBO2) on acetaminophen (APAP)-induced hepatotoxicity. The authors further evaluated the effects of APAP poisoning and HBO2 on the expression and function of hypoxia-inducible factor 1-alpha (HIF-1alpha) in an effort to further describe the mechanisms of APAP-induced hepatotoxicity. In vitro assays were performed to better understand the effects of HBO2 on HIF-1alpha function. METHODS: In vivo, four groups of C57BL/6 mice were treated as follows: APAP only, APAP followed by HBO2, HBO2 only, and untreated shams. Plasma alanine aminotransferase activity was measured, and hepatic HIF-1alpha induction was determined by Western blot. In vitro, cultured HEP G2 hepatocytes were exposed to HBO2, hypoxia (2.5% O2), or normoxia. HIF-1alpha DNA-binding and transcriptional activity were assessed. RESULTS: Alanine aminotransferase activity was reduced in the APAP+HBO2 group (2,606 IU/L +/- 4,080; vs. APAP: 6,743 +/- 3,397, p = 0.01 at 6 hours). APAP-only, HBO2-only, and APAP+HBO2 treatments all increased HIF-1alpha expression relative to shams (p = 0.02, p = 0.02, and p < 0.01, respectively). HBO2 increased HIF-1alpha DNA binding 5.7 (+/- 1.2)-fold relative to controls (p < 0.01); however, a parallel increase in HIF functional transcriptional activity did not occur. CONCLUSIONS: Hyperbaric oxygen reduced early APAP-induced hepatocellular injury. APAP poisoning increases HIF-1alpha protein levels and functional activity. HBO2 increases HIF-1alpha protein levels and DNA binding without a corresponding increase in transcriptional activity.

Endothelially derived nitric oxide affects the severity of early acetaminophen-induced hepatic injury in mice.

OBJECTIVES: The precise mechanism of hepatocellular toxicity following acetaminophen (APAP) poisoning remains unclear. Nitric oxide is implicated in APAP toxicity as an inflammatory signaling molecule and as a precursor to the free radical peroxynitrate. The effects of inducible nitric oxide synthase (iNOS)-derived NO in APAP toxicity are known; however, the role of endothelial nitric oxide synthase (eNOS)-derived NO is unknown. The authors sought to evaluate the effect of eNOS-derived NO during APAP toxicity. METHODS: C57BL6/J mice deficient in eNOS (eNOS KO) or iNOS (iNOS KO) and wild-type mice (WT) were treated with 300 mg/kg APAP. Alanine aminotransferase levels and plasma nitrate and nitrite levels were measured. Hypoxia inducible factor (HIF)-1alpha and Glucose Transporter 1 (Glut-1) levels were determined by Western blot. RESULTS: Alanine aminotransferase levels were significantly elevated in all treated animals. Alanine aminotransferase levels were significantly lower in eNOS KO and iNOS KO than in treated WT animals. Plasma nitrate/nitrite levels were significantly higher in WT animals than in iNOS KO and eNOS KO animals. HIF-1alpha expression was increased in WT mice and decreased in iNOS KO mice. Glut-1 is a downstream, indirect marker of HIF function. Glut-1 expression was increased in WT and eNOS KO mice. CONCLUSIONS: Deficiency of either iNOS or eNOS results in decreased NO production and is associated with reduced hepatocellular injury following APAP poisoning. HIF-1alpha and Glut-1 levels are increased following APAP poisoning, implying that HIF-1alpha is functional during the pathogenic response to APAP poisoning.

The relationship between pre-hospital and emergency department Glasgow coma scale scores.

INTRODUCTION: Pre-hospital GCS scores are used to make critical patient care decisions and to fill in gaps in hospital-based TBI surveillance, but they may not be accurate. OBJECTIVE: To determine the relationship between pre-hospital (EMS-GCS) and emergency physician GCS scores (ED-GCS). METHODS: Prospective observational study of 60 TBI patients with a field GCS of 8-13 and age > 18. ED-GCS, EMS-GCS, time of GCS and vitals signs were recorded. ANALYSIS: Simple and multiple linear regression. RESULTS: The median EMS-GCS was 13 and that for ED-GCS was 15. There was a significant linear relationship between ED-GCS and EMS-GCS (r = 0.45, p = 0.003). There was improvement in the prediction of ED-GCS when alcohol/drug use and age (but not time) were added to EMS-GCS. CONCLUSION: EMS-GCS is usually two points lower than ED-GCS, but the correlation between them is strong and independent of the time between score determinations. These results could prevent unnecessary procedures based on the EMS-GCS and improve the accuracy of TBI surveillance.

Management of calcium channel antagonist overdose.

Calcium channel antagonists are used primarily for the treatment of hypertension and tachyarrhythmias. Overdose of calcium channel antagonists can be lethal. Calcium channel antagonists act at the L-type calcium channels primarily in cardiac and vascular smooth muscle preventing calcium influx into cells with resultant decreases in vascular tone and cardiac inotropy and chronotropy. The L-type calcium channel is a complex structure and is thus affected by a large number of structurally diverse antagonists. In the setting of overdose, patients may experience vasodilatation and bradycardia leading to a shock state. Patients may also be hyperglycaemic and acidotic due to the blockade of L-type calcium channels in the pancreatic islet cells that affect insulin secretion. Aggressive therapy is warranted in the setting of toxicity. Gut decontamination with charcoal, or whole bowel irrigation or multiple-dose charcoal in the setting of extended-release products is indicated. Specific antidotes include calcium salts, glucagon and insulin. Calcium salts may be given in bolus doses or may be employed as a continuous infusion. Care should be exercised to avoid the administration of calcium in the setting of concomitant digoxin toxicity. Insulin administration has been used effectively to increase cardiac inotropy and survival. The likely mechanism involves a shift to carbohydrate metabolism in the setting of decreased availability of carbohydrates due to decreased insulin secretion secondary to blockade of calcium channels in pancreatic islet cells. Glucose should be administered as well to maintain euglycaemia. Supportive care including the use of phosphodiesterase inhibitors, adrenergic agents, cardiac pacing, balloon pump or extracorporeal bypass is frequently indicated if antidotal therapy is not effective. Careful evaluation of asymptomatic patients, including and electrocardiogram and a period of observation, is indicated. Patients ingesting a nonsustained-release product should be observed in a monitored setting for 12 hours, while those who ingest a sustained-release preparation should be observed for no less than 24 hours. Charcoal should be given to the asymptomatic patient with a history of calcium channel antagonist overdose.

Use and analysis of field triage criteria for mass gatherings.

INTRODUCTION: Mass gatherings may result in an acute increase in the number of people seeking medical care potentially causing undue stress to local emergency medical services (EMS) and hospitals. Often, temporary medical facilities are established within the mass gathering venue. Emergency Medical Services providers encountering patients in the field should be equipped with effective protocols to determine transport destination (venue facility vs. hospital). HYPOTHESIS: Paramedics are capable of appropriately using triage criteria written specifically for a particular mass gathering. The use of triage criteria, when applied correctly, decreases over-triage to the venue facility and undertriage to the hospital. METHODS: Paramedics triaged patients at a mass gathering to a temporary venue facility or to a single emergency department using criteria specific for the event. Cases were reviewed to determine if the patients transported went to an appropriate facility and if the triage criteria were applied appropriately. RESULTS: Transport destination was consistent with that dictated by the criteria for 78% of cases. Analysis of these cases shows that the criteria had a sensitivity of 100% (95% CI = 58-100%) and a specificity of 90% (95% CI = 73-98%) for predicting which patients needed hospital services and which could be cared for safely in the temporary clinic setting. CONCLUSIONS: Triage by paramedics at the point of patient contact may reduce transporting of patients to hospitals unnecessarily. Patients in need of hospital services were identified. Point-of-contact triage should be applied in mass gatherings.