Position paper: Single-dose activated charcoal.

Single-dose activated charcoal therapy involves the oral administration or instillation by nasogastric tube of an aqueous preparation of activated charcoal after the ingestion of a poison. Volunteer studies demonstrate that the effectiveness of activated charcoal decreases with time. Data using at least 50 g of activated charcoal, showed a mean reduction in absorption of 47.3%, 40.07%, 16.5% and 21.13%, when activated charcoal was administered at 30 minutes, 60 minutes, 120 minutes and 180 minutes, respectively, after dosing. There are no satisfactorily designed clinical studies assessing benefit from single-dose activated charcoal to guide the use of this therapy. Single-dose activated charcoal should not be administered routinely in the management of poisoned patients. Based on volunteer studies, the administration of activated charcoal may be considered if a patient has ingested a potentially toxic amount of a poison (which is known to be adsorbed to charcoal) up to one hour previously. Although volunteer studies demonstrate that the reduction of drug absorption decreases to values of questionable clinical importance when charcoal is administered at times greater than one hour, the potential for benefit after one hour cannot be excluded. There is no evidence that the administration of activated charcoal improves clinical outcome. Unless a patient has an intact or protected airway, the administration of charcoal is contraindicated. A review of the literature since the preparation of the 1997 Single-dose Activated Charcoal Position Statement revealed no new evidence that would require a revision of the conclusions of the Statement.

Poison control centers and state-specific poisoning mortality rates.

OBJECTIVE: The purpose of this study was to compare poisoning mortality rates of states served by a poison control center certified by the American Association of Poison Control Centers (AAPCC) to those that are not served by a certified center because health policy has been based on certification status. METHODS: Poisoning mortality rates from 1993 to 1997 were obtained from a public use database of death certificates and were stratified by state and circumstance. Each state was classified as being fully served, partially served, or not served by an AAPCC-certified center. States in one category of service for the entire 5 years were selected for analysis. RESULTS: During this 5-year period, 39 states exhibited a consistent category of poison control center services. The mortality rates per 100,000 population during these 5 years were 5.93, 6.12, 6.01, 6.23, and 6.68 respectively (P <0.05) for all 39 states. The mean 5-year mortality rate for states with certified poison control center services (7.08 +/- 2.59; n = 17) was higher (P <0.05) than those with noncertified service (5.17 +/- 1.46; n = 15) but not significantly different from those with partial certified service (6.25 +/- 1.75; n = 7). CONCLUSION: Increased poisoning mortality rates were associated with AAPCC certification status and year. Poisoning mortality rates may not be an appropriate outcome measure of the impact of poison control centers, AAPCC-certification notwithstanding, at this time. Basing poison control center-related policy on state-specific poisoning mortality rates can not be supported by these findings.

Ferrous sulfate adsorption by activated charcoal.

Although activated charcoal is thought to not appreciably adsorb iron salts, previous in vitro work indicates some adsorption of iron. This study characterized the adsorptive capacity of activated charcoal for ferrous sulfate at 3 pH environments. Langmuir adsorption isotherms were determined with a fixed amount of iron in the reaction vessels. Activated charcoal USP (20, 40, 60, 80, 100, or 120 mg) was placed in plastic tubes to which were added 1 of 3 different simulated gastrointestinal fluids (pH = 1.5, 4.5, or 7.5) and 1.49% ferrous sulfate in water. The reaction vessels were agitated and immersed in a water bath at 37 C for 30 min. Each series was performed in triplicate. Following temperature eQuilibration filtration yielded an aliquot that was assayed for iron by atomic absorption spectrophotometry. Adsorptive capacities (mean +/- SD) of activated charcoal for ferrous sulfate (mg elemental iron/g charcoal) at pH 4.5 (102.96+/-4.49) and pH 7.5 (100.94+/-19.02) were higher (P<0.01) than at pH 1.5 (-0.01+/-0.26). At pH 1.5 iron was not appreciably adsorbed by activated charcoal. Activated charcoal adsorbed ferrous sulfate to a greater extent at pH environments where iron is typically absorbed from the gastrointestinal tract. These results indicate that activated charcoal may prove an effective therapy for acute iron poisoning and further investigation is warranted.

How many deaths occur annually from adverse drug reactions in the United States?

PURPOSE: The numbers of deaths attributed to adverse drug reactions by death certificates and by the Food and Drug Administration's (FDA) spontaneous postmarketing surveillance system (MedWatch) were compared in order to characterize national mortality statistics. METHODS: Mortality statistics related to adverse drug reactions were obtained from national public-use databases of death certificates based on appropriate International Classification of Disease (ICD-9) codes and from MedWatch during 1995. The number of deaths, frequency distributions of sex and age groups, and rankings of drug categories associated with adverse reactions were compared. RESULTS: During 1995, 206 deaths were attributed to adverse drug reactions on death certificates in the United States, whereas MedWatch tabulated 6,894 fatalities. The proportions of men and women were similar, and the majority of deaths involved persons 60 years of age and older, in both data sets. The rankings of drug categories associated with adverse drug reactions differed in the two data sets. CONCLUSION: The numbers of deaths reported in these data sets varied 34-fold and were up to several 100-fold less than values based on extrapolations of surveillance programs. These differences indicate that better and more comprehensive data are needed to develop appropriate health care policies to improve drug safety.

Reporting of adverse drug reactions by poison control centres in the US.

BACKGROUND: Although US poison control centres manage approximately 30,000 adverse drug reactions each year, the extent of voluntary reporting of these events to the US Food and Drug Administration (FDA) MedWatch spontaneous surveillance programme is unknown. METHODS: A survey was mailed to directors of all 72 US poison control centres during April 1999 to determine their practices and opinions on reporting adverse drug reactions. The survey requested information on the poison control centre staff's practices in reporting adverse drug reactions to the FDA MedWatch programme during 1998. RESULTS: A total of 56 fully completed surveys were returned. Of the respondents, 30 had not directly submitted adverse drug reaction reports to the FDA, 22 had submitted 10 or less, and 4 had submitted a total of 47 during 1998. Reasons given for not routinely reporting adverse drug reactions included adverse drug reactions reporting is not part of the regular routine (20%), lack of time to complete forms (15%), inability to determine causality (13%), most reactions are already reported and not unique (10%), reporting to the FDA is too much work (9%), and responsibility rests with the attending physician (7%). Direct reporting to MedWatch of any cases of adverse drug reactions was more likely when the poison control centre was certified by the American Association of Poison Control Centers (p < 0.05; odds ratio = 5.1; 95% confidence interval 1.1 to 23.5); however, this practice was not associated with documenting deaths associated with adverse drug reactions, having more than 75% of the staff of the Poison Information Specialists composed of pharmacists or nurses, or managing greater than 20,000 or 34,000 human exposure cases during 1998. Approximately half of the poison control centres directly or indirectly reported some adverse drug reactions to the FDA by virtue of contacting the manufacturer or cooperating with postmarketing surveillance. CONCLUSION: Poison control centres represent an underutilised source of reporting to MedWatch, but several internal and external obstacles limit the direct reporting of adverse drug reactions routinely.

Poisoning mortality in the United States: comparison of national mortality statistics and poison control center reports.

STUDY OBJECTIVE: To determine whether the distributions of age and poisoning categories for poisoning deaths are similar in death certificates as compiled by the National Center for Health Statistics (NCHS) and US poison control centers as reported by the Toxic Exposure Surveillance System (TESS). METHODS: Data from both databases for 1994 were examined. Mortality data from NCHS were identified by applicable E-codes of the International Classification of Diseases-ninth revision (ICD-9). All fatalities described in the TESS report were coded to conform to the ICD-9 system. RESULTS: A total of 16,527 poisoning deaths were recorded by NCHS; 766 deaths were reported by TESS. For NCHS and TESS, respectively, the age distribution of unintentional drug poisonings (N=7,823; 155) and unintentional non-drug poisonings (N=1,234; 102) differed (P <.001), whereas those for intentional poisonings (N=5,320; 413) did not differ significantly. In the NCHS and TESS data sets, respectively, the relative distribution of death circumstances differed (P <.001) for unintentional drug poisonings (47% versus 20%), unintentional non-drug poisonings (8% versus 14%), intentional poisonings (32% versus 54%), and unknown or other circumstances (13% versus 12%). The distributions of poisoning circumstances and age categories were dependent on the data source (P <.001). There was no statistical agreement between the data sets in rankings of the 12 most frequent ICD-9 codes and toxins associated with poisoning deaths. CONCLUSION: Deaths reported in TESS represent 5% of the poisoning deaths tabulated by NCHS. Differences observed in the 2 data sets may lead to differing health policies to address poisoning hazards.

Utility of acetylcysteine in treating poisonings and adverse drug reactions.

As recognition of the role of free radicals and reactive toxins in the pathogenesis of disease, poisoning, and adverse drug reactions has evolved, interest in the use of acetylcysteine as a modulator of these effects has steadily increased in recent years. Acetylcysteine is commonly thought to serve as a glutathione precursor and consequently can increase or sustain intracellular glutathione which scavenges reactive oxygen species caused by toxins or subsequent tissue injury. At least 10 additional mechanisms of action for acetylcysteine have been demonstrated in various laboratory models, but a unifying framework of its actions is still to be proposed. This paper reviews the current experimental and therapeutic status of acetylcysteine for the treatment of poisonings and adverse drug reactions. Of the 45 potential uses of acetylcysteine that were identified for the treatment of poisonings or adverse drug reactions, 14 of the toxic effects have little support for its use while promising results have been demonstrated for 27 toxicities. Currently, treatment of acute paracetamol (acetaminophen) poisoning is the only widely accepted clinical indication for acetylcysteine as a treatment for poisoning or adverse drug reactions. In many clinical situations acetylcysteine is used empirically utilising modifications of dosage regimens employed for paracetamol poisoning. Often it is difficult to determine the benefit of therapy with acetylcysteine owing to the nature of the toxicity being treated, the use of other therapies, the presence of comorbid conditions, and the small number of patients studied. The diverse and positive nature of the investigations suggest that there is considerable promise in acetylcysteine as a research tool and pharmacological agent.

Interactions of warfarin with garlic, ginger, ginkgo, or ginseng: nature of the evidence.

OBJECTIVE: To review and characterize the evidence describing potential interactions between warfarin and garlic, ginger, ginkgo, or ginseng. DATA SOURCES: Searches of MEDLINE (1966-1999), other bibliographic databases, several abstracting services, and tertiary references were conducted. STUDY SELECTION AND DATA EXTRACTION: Articles were examined by each author, and additional citations were obtained from the references of these articles. Preference was given to Englishlanguage articles of human studies. DATA SYNTHESIS: Evidence is lacking for an interaction of warfarin wth galic or ginger. One case report associates ginseng use with decreased warfarin-maintained anticoagulation effect. Another case report links concomitant use of ginkgo and warfarin with the development of intracerebral hemorrhage. Hemorrhage and tendencies were noted in four cases with ginkgo use and in three cases with garlic; in none of these cases were patients receiving warfarin. CONCLUSIONS: The true risks of these interactions and effects are difficult to characterize due to the limited number and nature of existing reports.

Role of US poison centers in adverse drug reactions monitoring.

Poison centers are a valuable source of adverse drug reaction reporting in the US based on their ready access, familiarity with adverse events, the training of staff health care professionals, and computerized case documentation. During 1997, 35,563 suspected adverse drug reactions were reported by poison centers to their national database. Of these, 71% involved individuals over 19 y of age, 62% were treated at a non-health care facility, 64% experienced no effect or a minor effect, and 6% were potentially symptomatic but lost to follow-up. There were 18 fatalities. Although US poison centers currently provide input to reporting adverse drug reactions, the data collection system could be better integrated with the FDA MedWatch spontaneous adverse drug reactions reporting program on a more systematic basis to allow greater input and harmonization of the 2 datasets.

The history of poisoning in the future: lessons from Star Trek.

BACKGROUND: The Arts are replete with examples of presaged events of the future. Since a unique glimpse of the 23rd century is afforded by the television series Star Trek, a survey of the toxin-related events as chronicled by the crew of the USS Starship Enterprise may provide insight to prepare toxicologists for the future. METHODS: An investigation of the logs of the Enterprise was undertaken for the years 2266 to 2269 which were part of its first 5-year mission. Internet sites, published databases, and selected recorded episodes from the original Star Trek television series were searched for poisonings or toxin-related incidents. RESULTS: Out of the 79 Star Trek episodes, 28 (35%) involved toxin-related incidents. A total of 31 poisoning incidents were documented with 13 environmental, 9 intentional, 5 unintentional, and 4 homicidal circumstances. Biotoxins (10 incidents) were the most frequently involved toxin followed by neurotoxins (9), radiation (3), cytotoxins (3), temporal toxins (3), acids (2), and phytotoxins (1). Of these cases, 2 involved hazardous materials incidents, 1 was contamination of food, and 3 involved therapeutic misadventures. CONCLUSIONS: Many of the circumstances encountered in poisonings of the future will likely be similar to contemporary reasons, but the nature of the toxins will differ. Clinical toxicologists should prepare for the future by increasing their study of molecular biology, comparative medicine, physics, and history.

Methylene blue by intraosseous infusion for methemoglobinemia.

Intraosseous administration of methylene blue may be an emergency alternative to intravascular administration. A 6-week-old female infant (3 kg) presented to the emergency department after a 1-week illness and appeared cyanotic and listless. Oxygen saturation by oximetry was 86% while the patient was receiving oxygen. Vital signs were blood pressure, 107/80 mm Hg; pulse, 190; respirations, 47; temperature, 39.0 degreesC. A metabolic acidosis and a methemoglobin level of 29.3% were present. After several unsuccessful attempts to establish intravenous access, an intraosseous needle was placed in the infant's left tibia. Methylene blue, 1 mg/kg, normal saline solution, and sodium bicarbonate were given intraosseously. The patient's oxygen saturation rose to 98% to 100%, and her cyanosis improved. Three hours later, her methemoglobin level was 8.2%. The child recovered uneventfully and was sent home after 3 days. Intraosseous administration of standard intravenous doses of methylene blue rapidly terminated the effects of acquired methemoglobinemia.

Problems in assessment of acute melatonin overdose.

Melatonin is sold in the United States as a dietary supplement and is promoted primarily as an aid for insomnia, stress, jet lag, and aging. Cases of acute poisoning have not been reported, partially because of problems in assessment of toxicity. We report the case of a 66-year-old man who became lethargic and disoriented after taking 24 mg melatonin to aid relaxation and sleep the evening before prostate surgery. He recovered uneventfully, and after the scheduled surgery he resumed his regular practice of taking 6 mg melatonin with prescription sedative drugs. Although melatonin is not regulated as a drug, it may interact with benzodiazepines, be antagonized by naloxone and flumazenil, and interact with melatonin receptors in the central nervous system and elsewhere in the body. Melatonin appears to be pharmacologically active and should not be considered a benign agent on overdose.

Position statement: single-dose activated charcoal. American Academy of Clinical Toxicology; European Association of Poisons Centres and Clinical Toxicologists.

In preparing this Position Statement, all relevant scientific literature was identified and reviewed critically by acknowledged experts using agreed criteria. Well-conducted clinical and experimental studies were given precedence over anecdotal case reports and abstracts were not usually considered. A draft Position Statement was then produced and subjected to detailed peer review by an international group of clinical toxicologists chosen by the American Academy of Clinical Toxicology and the European Association of Poisons Centres and Clinical Toxicologists. The Position Statement went through multiple drafts before being approved by the boards of the two societies and being endorsed by other societies. The Position Statement includes a summary statement for ease of use and is supported by detailed documentation which describes the scientific evidence on which the Statement is based. Single-dose activated charcoal should not be administered routinely in the management of poisoned patients. Based on volunteer studies, the effectiveness of activated charcoal decreases with time; the greatest benefit is within 1 hour of ingestion. The administration of activated charcoal may be considered if a patient has ingested a potentially toxic amount of a poison (which is known to be adsorbed to charcoal) up to 1 hour previously; there are insufficient data to support or exclude its use after 1 hour of ingestion. There is no evidence that the administration of activated charcoal improves clinical outcome. Unless a patient has an intact or protected airway, the administration of charcoal is contraindicated.

Serum iron concentrations and symptoms of acute iron poisoning in children.

STUDY OBJECTIVE: To determine whether serum iron concentrations correlate with the development of symptoms of iron poisoning in children. DESIGN: A retrospective study of medical records from January 1976 through June 1992. SETTING: A tertiary care children's medical center. PATIENTS: Criteria for patient selection included an acute ingestion of iron-containing drugs, measurement of serum iron prior to deferoxamine administration, and a serum iron concentration (obtained within 2-9 hours of exposure) that was greater than 150 micrograms/dl (27 mumol/L). Of the 128 children who were hospitalized for acute iron poisoning, 92 patients (mean age 2.3 +/- 2.2 years) met the selection criteria. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: The mean (+/-SD) serum iron concentrations (microgram/dl) of patients who exhibited cardiovascular instability (725 +/- 555, n = 6; p < 0.001) differed from those categorized with central nervous system changes (373 +/- 77, n = 30), gastrointestinal symptoms (334 +/- 83, n = 44), and no symptoms (368 +/- 102, n = 12). Serum iron concentrations in patients with cardiovascular instability ranged from 205-500 micrograms/dl (37-269 mumol/L), whereas those with no symptoms ranged from 170-513 micrograms/dl (30 to 92 mumol/L) demonstrating considerable overlap of ranges. CONCLUSIONS: Serum iron concentrations do not necessarily relate to acute toxicity, and further study is needed to demonstrate the value of serum iron concentrations and to identify alternative strategies in the emergency assessment of the acutely poisoned child.

Relationship of serum iron and nonprotein-bound iron concentrations following administration of ferrous sulfate in pigs.

A prospective analytical study was conducted to determine the relationship between nonprotein-bound iron and serum iron concentrations following gastric instillation of ferrous sulfate. Four female pigs (20-22 kg) with indwelling central venous lines and gastrostomy tubes were studied. A 5% solution of ferrous sulfate (20 mg elemental iron/kg bwt) was administered through the gastrostomy tube over 1 to 2 min. Six hourly blood samples were collected, and serum samples were subjected to ultrafiltration with the filtrate representing nonprotein-bound iron. Iron concentrations were determined by atomic absorption spectrophotometry. Baseline (mean +/- SD) iron concentrations were 73 +/- 25 micrograms/dL as the serum total and 21 +/- 4 micrograms/dL as nonprotein-bound iron. The serum iron and nonprotein-bound iron concentrations achieved a peak of 191 +/- 66 and 23 +/- 10, respectively, at 2 h and declined to near baseline values at 6 h. The mean ratio of filtrate to serum iron concentration was 0.16 +/- 0.08 and ranged from 0.08 to 0.29. Nonprotein-bound iron did not increase as the serum iron concentration increased (r = 0.18) within the ranges achieved in the study. The absence of protein, particularly transferrin and albumin, was verified by electrophoresis. A form of apparent nonprotein-bound iron was isolated from serum by ultrafiltration and its concentration was relatively constant despite the rise and fall of total serum iron concentrations during the 6 h. These observations warrant further investigation to understand the development of toxicity in acute iron poisoning.

Relational database for drug-use review of Tennessee Medicaid claims.

The development of a relational database from Tennessee Medicaid files for the purpose of retrospective drug-use review (DUR) and application of the database for DUR of angiotensin-converting-enzyme inhibitors (ACEIs) are described. Computer queries were designed to create profiles of physicians' or pharmacies' experiences from claims data and other Medicaid data. Outlying patients (patients for whom at least one DUR criterion was unmet) were grouped according to their physicians or pharmacies. Thresholds for defining outlying physicians and pharmacies (i.e., those with more than a specified number of outlying patients) were based on the provider population instead of the patient population as a whole; aggregating patient outliers by provider allowed trends of inappropriate practices to be detected. As the threshold for outlying providers rose, the number of such providers fell, as did the number of outlying patients with whom they were associated. Stratification of the outliers by provider for specific drug-drug interactions and drug-disease complications afforded the option to set individual thresholds for outlying providers based on individual subsets; for example, for ACEIs, a threshold of greater than five patient outliers could be set for the criterion of no concurrent potassium supplements and a threshold of greater than three, for the criterion of no unmonitored concurrent lithium therapy. Tennessee patients formerly covered by Medicaid are now enrolled in managed care plans, and the flexibility of the database has allowed it to be modified accordingly. The relational database allows flexibility in the analysis of certain patterns of drug use. Such a database may be useful to other Medicaid programs that are converting to managed care models.

Benefits of extracorporeal membrane oxygenation for hydrocarbon pneumonitis.

OBJECTIVE: To review the therapeutic benefits of extracorporeal membrane oxygenation for the management of hydrocarbon pneumonitis. METHODS: A search of the medical literature was conducted through Medline and the bibliographies of relevant articles and a search of patient databases maintained by the Extracorporeal Life Support Organization and the American Association of Poison Control Centers was performed. All articles and case reports on the use of extracorporeal membrane oxygenation in patients with hydrocarbon pneumonitis were selected. The data were abstracted without judgments about study design. RESULTS: There is some evidence that pulmonary parenchymal tissue can recover from hydrocarbon pneumonitis, but the degree of injury and recovery are variable. In the Extracorporeal Life Support Organization Registry 19 children with hydrocarbon pneumonitis were treated with extracorporeal membrane oxygenation during 1985 to 1994 and 68% survived compared to the 52% overall survival of 883 pediatric cases who had a diagnosis of a respiratory condition. A review of the American Association of Poison Control Centers data for 1993 and 1994 identified five cases of hydrocarbon pneumonitis in which extracorporeal membrane oxygenation was used and two survived. There are two full case descriptions in the literature with both children surviving, but one child developed persistent moderate left hemiparesis and seizure activity. CONCLUSIONS: The need for extracorporeal membrane oxygenation is rare owing to the generally good outcome of most cases of hydrocarbon ingestions and pneumonitis. Only with further research on the nature and clinical course of severe hydrocarbon pneumonitis, refinement of extracorporeal membrane oxygenation criteria, and evaluation of alternative therapies, will the benefits of extracorporeal membrane oxygenation be better defined.

Use of telephone recording devices by poison centers in the United States.

To determine the extent of and rationale for the use of telephone recording devices by poison centers, a survey was distributed to 93 poison centers in the US during September 1991. Of the 62 respondents, 23 (37%) utilized and 39 did not utilize a telephone recording device. Telephone recording devices were primarily installed to address liability concerns followed by use for quality assurance, staff evaluation and training. The most frequent reason for not using a telephone recording device was the high cost and lack of funds (19) followed by considering it an unnecessary practice (8) and liability concerns (7). Poison centers certified by the AAPCC were more likely to record telephone conversations (p < 0.05) and accounted for 70% of centers with a recording device. A telephone recording device is employed by 1/3 of poison centers primarily to address liability concerns.