Steven B. Bird

A Randomized Trial of Alternative Two- and Three-Dose Hepatitis B Vaccination Regimens in Adolescents: Antibody Responses, Safety, and Immunologic Memory

Objectives. Hoping to increase hepatitis B (HB) vaccination of adolescents, we did the following: 1) studied if modified regimens of the recombinant HB vaccine, Recombivax HB (2 or 3 doses of 5 or 10 μg given over 4 or 6 months), induce protective anti-hepatitis B surface antibody [anti-HBsAb] levels (≥10 mIU/mL) comparable to the recommended regimen (5 μg at 0 and 1, and 6 months); 2) measured early antibody response after a single dose; and 3) assessed immunologic memory after 2- and 3-dose regimens. Design. One thousand twenty-six adolescents were randomized to 1 of 5 treatment groups (10 μg at 0 and 4 or 0 and 6 months; 5 μg at 0 and 6 or 0, 2, and 4 or 0, 1, and 6 months) in an open trial. Anti-HBsAb was measured in all participants just before and 1 month after the last dose, and at several other times in a subset of vaccinees. Anti-HBsAb response to a booster dose 2 years later was examined to assess immunologic memory in participants vaccinated with 5 μg at 0 and 6 or 0, 1, and 6 months. Results. All regimens induced ≥10 mIU/mL of anti-HBs in ≥95% of vaccinees. Geometric mean titers ranged from 674.8 to 3049.4 mIU/mL. Geometric mean titers were higher with regimens using the following: 1) 10 versus 5 μg; 2) 3 versus 2 doses; and 3) vaccination intervals of 6 versus 4 months. After 6 months, 63.8% of vaccinees given one 10-μg dose had ≥10 mIU/mL of anti-HBsAb versus 41.6% after one 5-μg dose. Participants vaccinated with either two or three 5-μg doses retained robust immunologic memory. Conclusions. The results of this study show that a 2-dose regimen of Recombivax HB is as immunogenic and induces immunologic memory as effectively as the recommended 3-dose regimen. A regimen of two 10-μg doses may be of significant benefit for vaccinees who are poorly compliant or deviate from the intended vaccination schedule.

OpdA, a bacterial organophosphorus hydrolase, prevents lethality in rats after poisoning with highly toxic organophosphorus pesticides

Organophosphorus (OP) pesticides poison more than 3,000,000 people every year in the developing world, mostly through intentional self-poisoning. Advances in medical therapy for OP poisoning have lagged, and current treatment is not highly effective with mortality of up to 40% in even the most advanced Western medical facilities. Administration of a broadly active bacterial OP hydrolase to patients in order to hydrolyze OPs in circulation might allow current therapies to be more effective. The objective of this work was to evaluate the efficacy of a new recombinant bacterial OP hydrolase (OpdA), cloned from Agrobacterium radiobacter, in rat models of two chemically distinct but highly toxic and rapidly acting OP pesticides: dichlorvos and parathion. Without OpdA treatment, median time to death in rats poisoned with 3x LD(50) of dichlorvos or parathion was 6 min and 25.5 min, respectively. Administration of a single dose of OpdA immediately after dichlorvos resulted in 100% survival at 24h, with no additional antidotal therapy. After parathion poisoning, OpdA alone caused only a delay to death. However, an additional two doses of OpdA resulted in 62.5% survival at 24 h after parathion poisoning. In combination with pralidoxime therapy, a single dose of OpdA increased survival to 75% after parathion poisoning. Our results demonstrate that OpdA is able to improve survival after poisoning by two chemically distinct and highly toxic OP pesticides.

Severe cholestatic hepatitis caused by thiazolidinediones: risks associated with substituting rosiglitazone for troglitazone

Troglitazone maleate (Rezulin) has been associated with severe hepatotoxicity, which led to its withdrawal from the U.S. market in March 2000. Rosiglitazone maleate (Avandia) is being marketed as a safe alternative in the treatment of type 2 diabetes mellitus. We report a case of severe thiazolidinedione-induced cholestatic hepatitis in a 56-year-old female patient at a university hospital who was given rosiglitazone, 8 mg/day, after she developed milder hepatotoxicity while taking troglitazone. Rosiglitazone was discontinued, and the patient was treated with prednisone, azathioprine, and ursodiol. Clinical evaluation and liver biopsy were performed and liver function tests were monitored. After being switched from troglitazone to rosiglitazone the patient developed a severe cholestatic hepatitis with marked jaundice and moderate increases in serum alkaline phosphatase and γ-glutamyltranspeptidase but only mild increases in serum aminotransferases. Discontinuation of rosiglitazone and treatment with prednisone, azathioprine, and ursodiol led to improvement, albeit with residual injury, dropout of intrahepatic bile ducts, and persisting elevations of serum alkaline phosphatase. Rosiglitazone is not always a safe alternative in patients who have had hepatotoxicity to troglitazone. It is important to monitor the serum alkaline phosphatase in addition to the serum aminotransferases in patients taking thiazolidinediones.

Monoamine Oxidase Inhibitor Poisoning Resulting from Internet Misinformation on Illicit Substances

The Internet may represent a new mechanism by which adolescents initiate the use of illicit substances. The existence of multiple partisan websites providing misinformation regarding the safety of these substances may lead to an increase in unsafe behavior among this age group. Adverse outcomes related to Internet‐based drug information are rarely identified. We report a case of an adolescent whose use of the Internet to obtain drug information led to severe poisoning from the combination of a monoamine oxidase inhibitor, harmaline, and a hallucinogenic tryptamine, 5‐methoxydimethyltryptamine (5‐MeO‐DMT).

Point-of-care ultrasonography by pediatric emergency medicine physicians

Emergency physicians have used point-of-care ultrasonography since the 1990s. Pediatric emergency medicine physicians have more recently adopted this technology. Point-of-care ultrasonography is used for various scenarios, particularly the evaluation of soft tissue infections or blunt abdominal trauma and procedural guidance. To date, there are no published statements from national organizations specifically for pediatric emergency physicians describing the incorporation of point-of-care ultrasonography into their practice. This document outlines how pediatric emergency departments may establish a formal point-of-care ultrasonography program. This task includes appointing leaders with expertise in point-of-care ultrasonography, effectively training and credentialing physicians in the department, and providing ongoing quality assurance reviews.

Diazepam Inhibits Organophosphate‐induced Central Respiratory Depression

OBJECTIVES Current evidence suggests that mortality from acute organophosphate (OP) poisoning is partially mediated through central nervous system (CNS) respiratory center depression (CRD). However, the exact mechanism of OP-induced CRD is unknown. In these studies, the authors investigated the hypothesis that OP-induced CRD is the result of overstimulation of CNS respiratory centers. METHODS Wistar rats received prophylaxis with either normal saline (controls), atropine, the peripherally acting anticholinergics glycopyrrolate (GLYC), ipratropium bromide (IB), or the CNS respiratory center attenuator diazepam. To determine if a dual CNS/peripheral cholinergic mechanism is responsible for animal death, two additional groups received combination treatment with diazepam plus either IB or GLYC. All treatments were completed 5 minutes before OP with subcutaneous dichlorvos. Differences in 10-minute and 24-hour mortality were assessed by the Fisher exact test. RESULTS Dichlorvos poisoning resulted in profound fasciculations without obvious seizure in all cohorts. In controls and animals treated with peripherally acting anticholinergics, fasciculations were followed by sedation and respiratory arrest (0% 10-minute survival in all cohorts). In contrast, pretreatment with either atropine or diazepam significantly improved 10-minute survival (100% and 44%, respectively). Although GLYC or IB afforded no protection when given alone, when delivered in conjunction with diazepam, the combination significantly improved survival (both groups 88% at 24 hours), suggesting a dual CNS/pulmonary muscarinic mechanism of lethality. CONCLUSIONS The central respiratory depressant diazepam paradoxically attenuates organophosphate-induced respiratory depression, and when combined with peripherally acting anticholinergic agents, reduces mortality in a rat model of severe acute OP poisoning.

Journal impact factors, h indices, and citation analyses in toxicology.

ConclusionOverall, toxicology journals have low impact factors compared to other scientific journals. As academic promotion boards increasingly use semiquantitative methods of determining academic productivity (such as the impact factor andh index of the journals in which a person has published), it could be expected that the toxicology journals in which many people in the fields of medical and clinical toxicology publish will see decreased submissions, as authors attempt to get their work published in journals with higher impact factors.

Outcome from severe accidental hypothermia with cardiac arrest resuscitated with extracorporeal cardiopulmonary resuscitation

PURPOSE This study aimed to identify factors of neurologic prognosis in severe accidental hypothermic patients with cardiac arrest. BASIC PROCEDURES This retrospective observational study was performed in a tertiary care university hospital in Sapporo, Japan (January 1994 to December 2012). We investigated 26 patients with accidental hypothermic cardiac arrest resuscitated with extracorporeal cardiopulmonary resuscitation (ECPR). We evaluated the neurologic outcome in patients who were resuscitated with ECPR at discharge from hospital. MAIN FINDINGS In those 26 patients, their median age was 50.5 years; and 69.2% were male. The cause of hypothermia was exposure to cold air in 46.1%, submersion in 46.1%, and avalanche in 7.8%. Ten (38.5%) of these patients survived to favorable neurological outcome at discharge. Factors associated with favorable neurological outcome were a cardiac rhythm other than asystole (P = .009), nonasphyxial hypothermia (P = .006), higher pH (P = .01), and lower serum lactate (P = .01). In subgroup analyses, the patients with hypothermic cardiac arrest due to submersion or avalanche (asphyxia group) showed no factors associated with good neurological outcome, whereas the nonasphyxia group showed a significantly lower core temperature (P = .02) and a trend towards a lower serum lactate (P = .09). PRINCIPAL CONCLUSIONS Patients with hypothermic cardiac arrest due to nonasphyxial hypothermia have improved neurologic outcomes when treated with ECPR compared to patients with asphyxial hypothermic cardiac arrest. Further investigation is needed to develop a prediction rule for patients with nonasphyxial hypothermic cardiac arrest to determine which patients would benefit from treatment with ECPR.

Diphenhydramine as a protective agent in a rat model of acute, lethal organophosphate poisoning

OBJECTIVE To evaluate the effects of diphenhydramine chloride (DPH) on mortality in a rat model of acute, severe organophosphate poisoning (OP). METHODS Wistar rats (n = 40) were randomized to pretreatment with either normal saline (controls), 5 mg/kg atropine, 3 mg/kg DPH, 15 mg/kg DPH, or 30 mg/kg DPH given as a single intramuscular injection 5 minutes prior to a subcutaneous injection of 25 mg/kg dichlorvos (n = 8 per group). The primary endpoint was 10-minute survival. Survival at 24 hours was a secondary endpoint. Comparison of survival rates between groups was carried out by ANOVA and the Student-Newman-Keuls test. RESULTS Dichlorvos exposure resulted in profound fasciculations within 2 minutes of injection in all cohorts. In controls, fasciculations were followed by respiratory arrest within 10 minutes (0% survival). The rats receiving atropine pre-treatment exhibited similar fasciculations (nicotinic effects) without subsequent respiratory arrest, resulting in a significant improvement in survival (88%, p < 0.001). The DPH-treated rats exhibited a significant dose-dependent reduction in mortality, with the 3 mg/kg, 15 mg/kg, and 30 mg/kg groups demonstrating 0%, 25%, and 100% survival, respectively. There was no additional mortality between 10 minutes and 24 hours in any group. There was no significant difference in survival between the high-dose DPH and the atropine groups. CONCLUSIONS Diphenhydramine chloride significantly reduced mortality in rats with acute, severe dichlorvos exposure.

Sodium Acetate as a Replacement for Sodium Bicarbonate in Medical Toxicology: a Review

Sodium bicarbonate is central to the treatment of many poisonings. When it was placed on the FDA drug shortage list in 2012, alternative treatment strategies to specific poisonings were considered. Many hospital pharmacies, poison centers, and medical toxicologists proposed sodium acetate as an adequate alternative, despite a paucity of data to support its use in medical toxicology. The intention of this review is to educate the clinician on the use of sodium acetate and to advise them on the potential adverse events when given in excess. We conducted a literature search focused on the pharmacology of sodium acetate, its use as a buffer in pathologic acidemia and dialysis baths, and potential adverse events associated with excess sodium acetate infusion. It appears safe to replace sodium bicarbonate infusion with sodium acetate on an equimolar basis. The metabolism of acetate, however, is more complex than bicarbonate. Future prospective studies will be needed to confirm the efficacy of sodium acetate in the treatment of the poisoned patient.