Richard F. Clark

Measuring Adherence to Antiretroviral Therapy in a Diverse Population Using a Visual Analogue Scale

Abstract Purpose: To examine the performance of an instrument to assess adherence based on a visual analogue scale, compared to an instrument based on 3-day recall, using unannounced pill counts in the place of residence as the gold standard. Method: We prospectively assessed adherence to antiretroviral therapy in 84 marginally housed indigent HIV-infected patients who were receiving stable antiretroviral therapy in San Francisco, California, with three adherence assessments over no more than 4 months. Results: Mean adherence using the visual analogue scale, 3-day recall, and unannounced pill count methods were 82.5%, 84.2%, and 75.9%, respectively. The correlation between visual analogue scale and unannounced pill count was high (r = 0.76) and was not statistically different from that between 3-day recall and unannounced pill count (r = 0.71; p = .52). Both methods were also similarly inversely correlated with HIV viral load (r = -0.49 and -0.34, respectively; p = .22 for the difference in the correlations). The visual analogue scale correlation with unannounced pill count was stable over time and remained high in all subpopulations examined. Conclusion: A visual analogue scale to assess adherence was performed as well as a more complicated 3-day recall instrument in this diverse population. Given its simplicity, the visual analogue scale adherence instrument will be useful in research and may be useful in routine patient care.

Midazolam: A review of therapeutic uses and toxicity

Midazolam is a familiar agent commonly used in the emergency department to provide sedation prior to procedures such as laceration repair and reduction of dislocations. Midazolam is also effective in the treatment of generalized seizures, status epilepticus, and behavioral emergencies, particularly when intravenous access is not available. Midazolam is often employed as an induction agent for rapid sequence endotracheal intubation. Midazolam has a rapid onset of action following intravenous, intramuscular, oral, nasal, and rectal administration. Only 50% of an orally administered dose reaches the systemic circulation due to extensive first-pass metabolism. Midazolam is metabolized by the cytochrome P450 enzyme system to several metabolites including an active metabolite, alpha-hydroxymidazolam. Cytochrome P450 inhibitors such as cimetidine can profoundly reduce the metabolism of midazolam. Midazolam has a half-life of approximately 1 h, but this half-life may be prolonged in patients with renal or hepatic dysfunction. Midazolam has been associated with respiratory depression and cardiac arrest when used in combination with an opioid, particularly in the elderly, although all ages are at risk for respiratory depression. Midazolam is relatively free of side effects when used alone and offers several advantages over traditional pharmacological agents such as chloral hydrate and the combination of meperidine, chlorpromazine, and promethazine. Hiccups, cough, nausea, and vomiting are the most commonly reported adverse effects. Many of the adverse effects associated with midazolam can be reversed rapidly by the administration of flumazenil, a competitive benzodiazepine receptor antagonist. Midazolam is a safe and effective agent for providing sedation in the emergency department.

Health effects of mycotoxins: A toxicological overview

Diseases caused by fungi are spread by direct implantation or inhalation of spores. Fungi can cause adverse human health effects to many organ systems. In addition to infection and allergy, fungi can produce mycotoxins and organic chemicals that are responsible for various toxicologic effects. We reviewed the published literature on important mycotoxins and systemic effects of mycotoxins. Scientific literature revealed a linkage between ingesting mycotoxin contaminated food and illness, especially hepatic, gastrointestinal, and carcinogenic diseases. Issues related to mycotoxin exposure, specific diseases, and management are discussed. Although there is agreement that diet is the main source of mycotoxin exposure, specific health effects and risk assessment from indoor nonagricultural exposure are limited by the paucity of scientific evidence currently available. Further research on the health effects of inhaling mycotoxins in indoor settings is needed.

Inadvertent ketamine overdose in children: Clinical manifestations and outcome

STUDY OBJECTIVE We sought to characterize the clinical manifestations, outcome, and etiology of inadvertent ketamine overdose in the emergency department. METHODS We investigated cases of inadvertent ketamine overdose in children seen in the ED solicited through electronic mail subscription lists or reported to the Institute for Safe Medication Practices. The clinical manifestations, outcome, and reported cause for each case are described. RESULTS We identified 9 cases of inadvertent ketamine overdose in children treated in the ED. Patients received either 5(n=3), 10(n=5), or 100(n=1) times the intended dose, either by the intramuscular (n=5) or intravenous (n=4) route. All 9 experienced prolonged sedation (3 to 24 hours). Four experienced brief respiratory depression shortly after administration, and assisted ventilation was performed in 2. Two children without respiratory difficulty or hypoxemia were intubated by their physicians as a precaution. In 5 children, the dosing error was not discovered until late in the sedation, often when the child was not waking at the expected time. No adverse outcomes were noted, and all children were normal neurologically on discharge and longer-term follow-up if available. CONCLUSION No adverse outcomes were noted in 9 healthy children treated in the ED who inadvertently received 5 to 100 times the intended dose of ketamine. Toxicity manifested as prolonged sedation in all 9 and brief respiratory depression in 4. The margin of safety in ketamine overdose may be wide, although less common and more serious outcomes cannot be excluded by this small, self-reported sample.

Affinity-Purified, Mixed Monospecific Crotalid Antivenom Ovine Fab for the Treatment of Crotalid Venom Poisoning

SUBJECT OBJECTIVE To test the efficacy and safety of a new antivenom, affinity-purified, mixed monospecific crotalid antivenom ovine Fab, in human subjects with minimal or moderate crotalid envenomation. METHODS We conducted a prospective multicenter clinical trial of 11 patients 10 years or older with progressive manifestations after mild to moderate crotalid snakebite. After giving their consent, subjects received four to eight vials of study drug and were then repeatedly examined over 48 hours and at 7 and 14 days after discharge. Each patients clinical condition was evaluated serially with the use of a validated severity score, as well as on the basis of the investigators assessment. RESULTS In all 11 subjects to the antivenom was judged by the investigator to have had a beneficial response. The severity score for each patient remained the same or decreased over the first 4 hours. However, two subjects demonstrated worsened condition 12 to 15 hours after antivenom administration. In no subject did an allergic reaction develop. CONCLUSION In this patient group, affinity-purified, mixed monospecific crotalid antivenom ovine Fab was associated with a halt of progressive crotalid venom poisoning. Initial safety data are promising but must be addressed further in subsequent studies.

Hyperthermia in Psychostimulant Overdose

Psychostimulant drugs such as amphetamines, amphetamine derivatives, and cocaine produce a variety of potentially lethal effects, and an understanding of these toxic effects is important for emergency physicians. While some effects of psychostimulant poisonings such as cardiovascular compromise and seizures have been discussed extensively, other metabolic derangements such as hyperthermia are less well characterized. In fact, hyperthermia is a common feature of severe-to-lethal poisonings and may be the primary mode of demise in some patients. Animal studies confirm that drug-induced hyperthermia alone can be lethal in some species, although other toxic effects may predominate at different drug doses or rates of administration. In non-lethal poisonings, hyperthermia can produce rhabdomyolysis, leading to further morbidity. Clinical reports and animal studies indicate that hyperthermia is a primary effect of psychostimulant drugs and can occur independently of seizures or increased motor activity. Furthermore, activation of particular dopamine receptors in the central nervous system appears to mediate psychostimulant-induced hyperthermia. The literature suggests cooling and tranquilization of psychostimulant-poisoned patients after cardiovascular stabilization. Paralysis and mechanical ventilation may be required. The involvement of dopamine receptor activation in psychostimulant toxicity suggests that dopamine-blocking neuroleptic drugs may be a useful adjunct to current treatment regimens. However, further studies are required to assess this approach. In summary, hyperthermia is a potentially lethal but treatable manifestation of severe psychostimulant poisoning.

Meperidine: Therapeutic use and toxicity

Meperidine is a synthetic opioid analgesic frequently prescribed in the emergency department. Meperidine is most often administered intramuscularly or intravenously, due to its poor oral bioavailability, and is metabolized extensively by the liver. Analgesic effects usually last 3-4 hours with parenteral administration, and some adverse effects such as nausea may be reduced when meperidine is combined with antiemetic or antihistaminic medications. Although meperidine is often a preferred analgesic by both patients and physicians in the treatment of disorders such as migraine headaches, its analgesic efficacy has rarely proven superior to alternative parenteral pain medications in controlled trials. In addition, meperidine can precipitate monoamine oxidase inhibitor reactions, and during metabolism it is demethylated to normeperidine, a compound with significant central nervous system (CNS) toxicity. Meperidine should be considered a second line agent in the treatment of pain when opioid analgesics are required.

COMA AND RESPIRATORY DEPRESSION FOLLOWING THE INGESTION OF GHB AND ITS PRECURSORS: THREE CASES

Gamma hydroxybutyrate (GHB) is a product of the metabolism of both gamma butyrolactone (GBL) and 1,4-butanediol (1,4-BD). Gamma hydroxybutyrate (GHB) is an illegal agent that causes central nervous system depression. Chemical precursors of GHB, such as GBL and 1,4-BD, have been available for purchase from many health food stores and Internet websites for mood-enhancement, sleep-induction, and stimulation of growth hormone release. We report three cases of ingestion of products containing GHB and chemical precursors of GHB. All three patients had severe presentations followed by full recoveries. Some products containing GBL were withdrawn from the market after the FDA issued a warning regarding these products. Products containing 1,4-butanediol remain on the market today.

Modeling the HIV Protease Inhibitor Adherence-Resistance Curve by Use of Empirically Derived Estimates

The standard view postulates a bell-shaped relationship between adherence to therapy and development of drug-resistant human immunodeficiency virus (HIV), with a resistance peak at a moderate level of adherence. This relationship has not been confirmed empirically. We statistically modeled the relationship between adherence and development of drug resistance, using empirically defined relationships of the rate of viral suppression and drug-resistance-mutation accumulation derived from patients receiving protease-inhibitor-based therapy. We found that the maximal rate of drug resistance occurs at 87% adherence and declines modestly at 100% adherence. Higher levels of viral suppression at 100% adherence (a marker of greater regimen potency) progressively reduce the overall population rate of drug resistance and shift the peak resistance rate to lower levels of adherence.

Prospective Evaluation of Mild to Moderate Pediatric Acetaminophen Exposures

STUDY OBJECTIVE To determine whether pediatric patients with acute, mild to moderate acetaminophen exposures, treated with home monitoring alone, develop systemic signs of hepatic injury. METHODS A prospective, observational study of calls to a regional poison center over a 25-month period was performed. Patients were eligible for the study if they were younger than 7 years and had an acute maximum possible acetaminophen exposure of up to 200 mg/kg. Exclusion criteria included previous decontamination measures, possibility of ingestion of an extended-release preparation, health or medication issues that could increase susceptibility to hepatotoxicity, current symptoms of hepatotoxicity, and indeterminable ingestions. Study protocol included reviewing the signs and symptoms of early and late acetaminophen toxicity, a 4- to 6-hour follow-up call, and a 72-hour follow-up call. Outcome measures were defined as a verbal report by the patients parent or guardian of the presence or absence of signs or symptoms of hepatotoxicity. RESULTS A total of 1,039 patients were enrolled in the study, including 519 girls and 520 boys, with exposures ranging from 20 to 200 mg/kg. Eighteen patients were lost to follow-up; data were incomplete for 2 patients. At 72-hour follow-up, the remaining 1,019 patients were all doing well, without signs or symptoms of hepatotoxicity. CONCLUSION On the basis of these data, pediatric patients with acute acetaminophen exposures of up to 200 mg/kg, treated with home monitoring alone, do not develop signs or symptoms of hepatic injury.