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Case Study 12
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History
A 60 year-old man with a history of hypertension, coronary artery disease, congestive heart failure, and chronic obstructive pulmonary disease was admitted to the hospital following an emergency department (ED) presentation for shortness of breath. Because no bed was available on the inpatient service, he was boarded in the ED for many hours. The ED physician who is no longer caring for the patient received a call from the laboratory that the patient’s serum potassium was 6.8 mEq/L in a nonhemolyzed specimen. A call was placed to the patient’s care team, but after several minutes there was no response.
Physical Examination A brief examination was performed, and the following vital signs were obtained: blood pressure, 166/92 mm Hg; pulse, 84 beats/minute; respiratory rate, 22 breaths/minute; temperature, 99.2°F (37.3°C); oxygen saturation, 93% on 4 L oxygen/minute via nasal cannula. The patient was awake and alert with a normal neurologic evaluation, and the chest examination revealed some wheezing and rhonchi and a regular heart rhythm with an S3 gallop. Electrocardiography (ECG) was obtained (Fig. CS12–1).
Immediate Management The ED physician ordered calcium gluconate (1 g), regular insulin (10 units), and dextrose (25 g) all to be given via the intravenous (IV) route to treat hyperkalemia. Shortly after the nurse administered the medications, the patient was noted to have a generalized seizure and lost consciousness. His pulse was noted to decrease and his QRS complex widened (Fig. CS12–2). The patient’s permanent pacemaker captured intermittently, and his blood pressure fell to 80/50 mm Hg. A bolus of 1 L of 0.9% sodium chloride was ordered and the patient was placed on 100% oxygen via a nonrebreather mask. A rapid reagent glucose was obtained and reported as 98 mg/dL.
What Is the Differential Diagnosis? The toxic syndrome that is characterized by a rapid onset of a seizure, hypotension, and a wide-complex dysrhythmia was highly suggestive of Na+ channel blockade. Common Na+ channel blockers are listed in Table CS12–1 and discussed in Chaps. 16, 48, 64, and 71. None of the ordered medications typically produce this effect. Additional considerations were that the administered xenobiotic would have to be available in an intravenous form and could be potentially confused with hypertonic dextrose since the patient’s glucose was not elevated as would have been expected following a bolus of D50W (Antidotes in Depth: A12).
Further Diagnosis and Treatment While the nurse was asked to review the medications given, the physician labelled and saved the syringes used to deliver the original medications and administered a bolus of 2 ampules (44 mEq each) of hypertonic sodium bicarbonate. Within 1 to 2 minutes the ECG returned to baseline, his hemodynamic parameters improved, and his mental status slowly normalized.
The nurse reported that the drawer in the automated medicine dispenser was filled with lidocaine instead of dextrose and, and that the vials looked similar (Fig. CS12–3). The patient may have received a bolus of lidocaine. This was confirmed with a serum lidocaine concentration of 4.9 mg/L taken about 1 hour after the event. Full disclosure was made to the patient and the pharmacy was informed of the error.
How Do Medication Errors Occur? Chapters 135, 136, 137, 138, Chapters 139, 140, and 141 deal with many issues of poison prevention and safety. This case highlights some of the key issues. System errors such as hospital and ED overcrowding that result in boarding of patients in busy areas remote from their primary care providers where teams turn over at relatively short intervals increase the likelihood of errors. Cognitive errors such as the urgency to treat a critically abnormal laboratory value (hyperkalemia), even in the absence of any characteristic ECG or clinical findings, may have been contributory. Improper filling of the storage device and purchasing of look alike medication vials added to the confusion. Finally, in this case, a simple error of not confirming that the medication that was ordered was the medication delivered, including proper dose and route, was nearly fatal. Fortunately, immediate recognition of the error and appropriate intervention proved to be life saving.
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Poison Prevention and Education
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Unintentional poisonings are a global health concern. According to the World Health Organization (WHO) Global Burden of Disease Project, in 2004 approximately 3,346,000 people died worldwide from unintentional poisoning.80 Nearly 1 million people die each year as a result of suicide. Approximately 350,000 deaths result from the deliberate ingestion of pesticides. In addition, an estimated 5 million snakebites occur annually.80 The WHO has undertaken initiatives in many countries, including the Bahamas, China, Ghana, Lebanon, Myanmar, Senegal, and Trinidad and Tobago to establish Poison Centers (PCs) and raise awareness about poison prevention. Worldwide, data on nonfatal poisoning rates are currently not available, although the increase in poison centers globally may result in improved research and surveillance programs.54 This chapter focuses on programs in North America that aim to prevent unintentional poisonings and improve access to PC services.
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Healthy People 2020 is a US federal program that outlines the health goals for the nation. These overarching goals are to attain high quality longer lives, achieve health equality and eliminate disparities, create social and physical environments that promote good health and promote quality of life, healthy development, and healthy behavior across all life stages. Two objectives in the Injury and Violence Prevention section relate to poison prevention. Objective IVP-9 is to reduce poisoning deaths and Objective IVP-10 is to reduce nonfatal poisonings.25 Community based public education programs at PCs are designed to help meet these other public health objectives.
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LEGISLATION AND POISON PREVENTION
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Since the first PC was established in 1953, a number of legislative efforts have improved poison prevention and awareness and reduced the number of unintentional poisonings in children. Public education programs at PCs have been influenced by these federal measures.71
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National Poison Prevention Week
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In 1961, President Kennedy signed Public Law 87–319, designating the third full week of March as National Poison Prevention Week (PPW) to raise awareness of the dangers of unintentional poisonings. Each year, during PPW, PCs and other organizations around the country organize events and activities to promote poison prevention.
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Child-Resistant Packaging Act
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In 1970, the Poison Prevention Packaging Act was passed. This law requires that the Consumer Product Safety Commission (CPSC) mandate the use of child-resistant containers for toxic household xenobiotics. In 1974, oral prescription medications were included in this requirement. A review of mortality data in children younger than 5 years of age shows a significant decrease in deaths after enforcement of the child-resistant packaging legislation.61,71,75
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Taste-Aversive Xenobiotics and Poison Prevention
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Nontoxic taste-aversive xenobiotics are frequently added to products such as shampoo, cosmetics, cleaning products, automotive products, and rubbing alcohol to discourage ingestion.24 This is done primarily to prevent poisoning in children except in the case of rubbing alcohol, where adults are also targeted. The most common taste-aversive xenobiotics are the denatonium salts, particularly denatonium benzoate (Bitrex, benzyldiethyl [(2,6-xylylcarbamoyl)methyl] ammonium benzoate), one of the most bitter-tasting xenobiotics known. The bitter taste of denatonium benzoate can be detected at 50 parts per billion (ppb). This aversive xenobiotic is used in concentrations of 6 to 50 parts per million (ppm), typically 6 ppm in cosmetic products and ethanol-containing household products and 30 to 50 ppm in methanol and ethylene glycol.8,53 Only limited data are available on the usefulness of taste-aversive xenobiotics for prevention of poisoning. Studies using denatonium benzoate added to liquid detergent and orange juice demonstrate that it can decrease the amount ingested by children.6,67 However, the degree of taste aversion is not universal. In one study, some children were noted to take more than one sip of denatonium benzoate-containing orange juice.67 Taste aversion is partially a learned response. Frequently young children do not find a bitter taste as offensive as do adults.7 It seems unlikely that taste-aversive xenobiotics will eliminate unintentional ingestions in children, because ingestion is required for aversive effects to occur. Taste-aversive xenobiotics may be most beneficial in the prevention of poisoning by toxic and nonaversive xenobiotics, such as ethylene glycol, methanol, paraquat, certain pesticides, acetonitrile, and bromate-containing cosmetics, where more than one or two sips of the product must be ingested to cause significant toxicity. In 1995, Oregon became the first state to mandate the addition of an aversive xenobiotic to ethylene glycol- or methanol-containing car products in its 1995 Toxic Household Products statute. Analysis on the incidence and severity of ethylene glycol and methanol exposures before and after the mandate could not demonstrate any difference in children under 6 years of age.49 Taste-aversive xenobiotics should therefore not be substitutes for other poison prevention modalities.
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Toll-Free Access to Poison Centers
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In 2000, the Poison Control Center Enhancement and Awareness Act (PL 106-174) was enacted with a goal of nationwide access to PCs. A toll-free number (1-800-222-1222) was established in 2001 for all US PCs.78Callers are connected to a regional PC based on the area code and telephone number exchange. Figure 135–1 displays the national logo incorporated into educational efforts.
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ROLE OF PUBLIC EDUCATORS IN POISON CENTERS
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Poison Center educators encompass a range of educational backgrounds including nurses, pharmacists, health educators, and teachers. The role of the public educator is based on social marketing concepts and encompasses two objectives: health promotion to change behavior, and marketing of the PC.69 Public education programs at PCs teach poison prevention techniques (primary prevention) and raise awareness about available services should a poisoning occur (secondary prevention). Education programs may utilize primary or secondary teaching or a combination of both.5,27,32,39 Public educators at PCs provide a range of community based programs ranging from workshops and health fairs to producing print materials, videos and or DVDs, and awareness campaigns through public service advertising using radio, television, print, and mass transit venues. Social media in health promotion offers an opportunity to further expand the dissemination of health information to diverse audiences through enhanced communication.47 Since underserved groups use mobile handheld devices frequently to access information,cell phones, mobile technology, and online resources provide new ways that educators can disseminate health messages to those in need.
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Educators also participate in community health coalitions, working in conjunction with other injury prevention groups such as National Safe Kids, and collaborate with a wide range of community health agencies. Caregivers of children younger than age 6 have often been the most important group to reach with education programs. Educators often work with national programs for families including Women, Infant and Children (WIC), Head Start, and the Red Cross.
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By contrast, older adults (individuals older than 65 years of age) have not been a priority population for PC education resources. However, this group represents a large number of fatalities reported nationally to PCs, primarily due to medication errors.10,27 Programs for older adults offer an educational opportunity to reach this high risk population. Collaborative programs with the American Association of Retired Persons (AARP), senior centers, and Departments for the Aging offer an opportunity to provide collaborations focusing on poison prevention and medicine safety programs through educational interventions conducted in senior centers, community agencies, and other groups that serve independently living older adults.
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The membership of the American Association of Poison Control Center’s Public Education Committee (PEC) includes the educators from PCs across the United States and Canada. The mission of the PEC is to provide poison prevention awareness programs in an effort to reduce morbidity and mortality associated with poisoning. Each year, the PEC provides educational sessions at the North American Congress of Clinical Toxicology. PEC workshops focus on program development, evaluation, grant writing, strategic planning, and other topics of interest to PC educators.27
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To develop successful poison education programs, educators must first analyze demographic data, call volume rates, cultural and language issues, and barriers to calling a PC. Geographic information systems (GIS) software offers a way for PCs to map demographic data. The use of this type of software is increasing in public health and can be applied to PC efforts. The coordination of data retrieval from various data entry programs and the use of GIS software by PC staff provides access to call rates by zip codes, counties, census tracts, or congressional districts to be used for planning programs. Health and social services for the targeted community may also be presented using GIS maps. Using GIS for population based programs is recommended for developing social marketing campaigns, health education programs, outreach efforts, and coalition building.60 The study of geographic areas with low call rates enhances the potential for targeted and focused educational programs.
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Focus groups, surveys, and interviews provide useful qualitative methods for PC educators to identify the perceptions of parents and caregivers about calling the PC. Barriers regarding PC utilization include not knowing the PC number, preference for calling 9-1-1 rather than the PC, fear of being reported to child welfare agencies, concerns with regard to confidentiality, language difficulties, lack of in person contact with health care providers, low self-efficacy, and concerns regarding the cost of the call.1,4,9,28,29,65,73 Each of these barriers must be considered and creatively addressed when planning new programs for reaching caregivers of young children. In one study, 51% of caregivers interviewed in a low income urban pediatric clinic said that they would immediately take their children to the emergency department (ED) after a possible poisoning exposure.63 In a separate study, focus group participants stated they would not call the PC in the case of a poison emergency. Their responses ranking was (1) call the pediatrician, (2) go to the ED, (3) read the label, and (4) call a friend after a poisoning exposure.28 A focus group with parents provided information to refine a telephone survey concentrating on hazardous household materials and health risks. Feedback from caregivers resulted in a more concise instrument with more targeted questions. In addition, perceptions of the PC and suggestions for future educational interventions were also gathered from participants.28 Involving the target audience in the development and testing of information is demonstrated to have improved outcomes when disseminating information.72
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Follow-up surveys provide a way to analyze factors related to PC access. English- and Spanish-speaking caregivers in Texas were contacted after an ED visit related to a poisoning exposure in a child. Findings showed that more than half had spoken to PC staff prior to the hospital visit. Of those who did not call the PC, 68% claimed prior knowledge of the PC, yet failed to use it. Significant demographic variables associated with a failure to call the PC were Hispanic (schooled in Mexico) and African American ethnicities.31 Findings from an ethnographic study of 50 Mexican-American mothers with children younger than 5 years of age demonstrated that none had the PC number in their home.46
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In person interviews were conducted with parents in the pediatric clinic about poison prevention strategies and awareness of the poison center.16,20 A pilot study to determine predictors of storage included acculturation, age, gender, and education among parents found that less acculturated parents were more likely to store medicines and cleaning products unsafely in the home.16 Another study conducted with 216 parents and caregivers reported that 80% were aware of the poison center services. However, none knew the 800 number specifically, although many stated they had the number in their home. Of the 42 participants (20% of the sample) unaware of the PC services, 57% were non-English speakers.20
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In order for educators to plan effective programs with older adults a needs assessment of the perceived barriers and benefits for this target group related to accessing the PC is required. Focus groups conducted with older adults show that most do not perceive the PC as an appropriate service for their concerns, but rather as a service for children and parents. Additionally, the participants expressed a very narrow view of what was considered a poison such as bleach and household products. Similar to caregivers of children, older adults repeatedly state that they would call 9-1-1 in an emergency.11
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POISON EDUCATION PROGRAMS
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Over half of the 2 million annual calls to PCs nationally involve children younger than 6 years of age.10 As a result, programs to teach caregivers about primary and secondary prevention techniques have been the major aim of education efforts. Typically, these programs focus on teaching poison prevention (Table 135–1) and raising awareness of PC services. Poison education programs designed to address barriers to accessing the PC through community interventions are reported in the literature. In one study, parents at two WIC centers reported an increased comfort level with calling the PC after a video based intervention.30 Interventions have demonstrated an increase in knowledge about PC messages and poison prevention in the study groups.30,38
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Interventions Targeting Health Behavior
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Unintentional poisonings frequently happen when children are left unattended for a brief period of time (< 5 minutes) and a toxic product in use or recently purchased is left within reach of the unattended child.51 A qualitative study conducted of 65 parents, some whose children had experienced an unintentional poisoning, showed that poison prevention strategies were not consistently implemented in the home. Recommendations included ongoing parent education to reemphasize that “child resistant” is not “childproof,” and reinforce safe storage of potentially toxic products, particularly those that are often used.22 When knowledge and behavior were measured through telephone surveys conducted 3 months after a poison prevention packet was mailed to families of young children who had experienced a poisoning, caregivers were more likely to have the PC number posted in the home.30,79
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The ED presents an opportunity for poison education programs to work with families to prevent further poisoning exposures.17 An injury prevention program provided to caregivers of young children after a home injury was effective, particularly regarding retention of poison prevention information and the use of safety devices.56 The use of a computer kiosk in an ED to provide personalized child safety information including specific advice of poison storage for parents showed increased knowledge scores on follow-up telephone surveys.23
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The effectiveness of poison prevention education for families who called the PC following a potential exposure in a young child was also studied. Poison prevention instructions, telephone stickers, and a cabinet lock were sent to the family one week after the initial call. Follow-up telephone interviews showed that intervention group recipients reported a higher use of the cabinet lock (59%) and were significantly more likely to post the telephone number for the PC (78%) than those in the control group who did not receive any poison prevention materials within 2 weeks of the incident.79
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Poison education programs developed to address caregiver barriers have also been evaluated. An educational video targeting low income and Spanish speaking mothers was developed and evaluated. Results showed increased knowledge about the services, staff, and appropriate use of the PC compared with a control group that attended the regularly scheduled WIC class.30
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Instructor training programs have been designed by a number of PCs to reach leaders or educators of community based organizations to incorporate poison education into their roles for the general population. An evaluation of the “Be Poison Smart” program showed an increase in knowledge and behavior change among service providers after a standardized training session. These reported changes included having the PC number visibly posted and keeping hazardous products out of reach.55 Working with community based services such as WIC presents an opportunity to reach the target population. Pretests and posttests administered to WIC staff and public health nurses showed increased understanding about poison prevention and increased awareness of PC services.57 Community health workers (promotoras) are involved in health promotion particularly in hard to reach communities. A train-the-trainer model evaluation demonstrated increased knowledge and behavior for teaching healthy homes promotion in the community setting.40
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Focus group participants identified pediatricians as a trusted source of health information for parents.28,65 The AAP includes a poison prevention counseling recommendation as part of The Injury Prevention Program (TIPP). TIPP is a safety education program for parents of children newborn through 12 years of age. The TIPP age related safety sheets include poison prevention advice for parents of children aged 6 to 12 month, 1 to 2 years, and 2 to 4 years.2 Each safety sheet encourages parents to call the toll-free number for PCs if the child ingests a potentially poisonous product. It is important that the AAP continues its support for efforts by PCs to prevent childhood poisonings.39 In another study, family practitioners and pediatricians were surveyed with respect to poison prevention counseling for parents. Although more than 80% of both groups reported that this was an important topic, family practitioners were less likely than pediatricians to provide poison information during a visit.21
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Education programs are designed for school-age curricula. The effectiveness of MORE HEALTH, a program to teach kindergarten and third-grade students about poison prevention, was studied.38 Posttests administered 1 to 2 weeks after the intervention showed increased knowledge in the intervention group of children. Parents of children in the intervention group also self reported that their homes were more likely to be “poison-proofed.”
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Recommendations have been made to develop programs targeting older adults, particularly about potential problems with medication use and storage.27,36,68 Efforts to teach nursing home staff about potential poisoning exposures are also recommended.36 There has been a shift in the priority of poison education programs to address this target population. An ED study of older adults showed that seniors had poor knowledge of their current medications. In addition, patients taking more medications were less likely to know the proper dose, name, and purpose of the medications.14,76
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Community-Wide Interventions
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A review of pediatric literature focusing on community based poisoning prevention programs showed that only four studies could be found using poisoning rates as the outcome measure. Additional creative studies to measure community based poison prevention efforts will be essential to determine the importance of these efforts.50
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In general, mass mailing of poison information is generally not an effective means to increase call volume for poison exposure or information requests nor is it cost effective.19,34 Similarly, a distribution of textbook covers with the national logo and PC information to elementary and secondary schools in low PC utilization counties was not an effective method for increasing PC calls.82 A hospital mailing that combined primary (poison prevention tips) and secondary (telephone stickers) messages were included in an established family health promotion magazine distributed widely in the PC regional area. This effort resulted in an increased call volume in areas where at least 5% of the residents received the information.32 In addition, another study result in that overall call volume increased by 11.2% after more than 1 million pieces of literature containing the toll-free number were distributed at sites including emergency departments, doctor offices, schools, and pharmacies.33
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An increased number of information calls to the PC was attributed to a campaign developed to raise community awareness.70 Media provide a venue for conducting educational activities. Direct mail, radio, television, newspapers, and magazines were incorporated into a media campaign developed to raise awareness in a particular Latino community. A telephone survey conducted pre- and post-media campaign showed an increase in awareness about the PC.1 Although developing this type of program is often costly compared with other education efforts, the potential audiences are vast. Mass media campaigns are powerful tools used in health promotion and disease prevention efforts.58 Research shows that a multilevel approach of media campaigns combined with community-based interventions and health education materials influence health behaviors and raise awareness. Additional factors that contribute to successful mass media campaigns include influencing the information environment to maximize exposure, using social marketing strategies, creating a supportive environment for the target audience to make health changes, and theory based process analyses to permit changes mid-campaign and assess outcomes and subsequent strategies in an iterative manner.58 Radio and television news stations often provide a way to broadcast poison prevention messages during PPW and during periods associated with perceived increased risks to a community. Social media is viewed as a communications tool rather than a factor in behavior change. Therefore, a process evaluation strategy is appropriate for measuring reach, context, delivery, and fidelity of application.47
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Multilingual Populations
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Language and culture must be addressed when planning community-based programs. Quantitative and qualitative research examining Latino communities and calls to the PC have been conducted. The findings from interviews with 206 Latino parents at a WIC site showed that 62% had not heard of the local PC and 77% did not know the PC services were free and offered in Spanish.74 Two other studies examined the call rates in communities with significant Latino populations. These areas had lower call rates than comparable areas based on demographic and socioeconomic factors.15,73 Furthermore, a number of studies demonstrate that Spanish speaking caregivers are less likely to call the PC because of concerns including confidentiality and language barriers.1,4,15,29,46 In a study conducted with 100 Mexican-American mothers of children younger than 5 years of age, 32% reported that a doctor or nurse would be the initial contact for health advice.43 Other sources include friends and family (29%), mother, grandmother, mother-in-law (21%), and spouses (17%). Most of the mothers (81%) acknowledged the use of home remedies to treat their childrens’ illnesses.43 New immigrant families from Mexico and Latin America are at high risk for poisoning exposures. PC education programs should target populations in communities where the impact has the potential to be consequential.66 Caution should be used when planning programs based on census data for demographic information as this data may not reflect the specific population or characteristic under study in community based programs. When ethnicity information is not collected from callers who contact the PC, there are severe limitations to the value of the data.15
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Qualitative research can help to identify cultural issues when planning targeted education efforts. Monolingual Spanish speaking mothers were more likely to report poor storage of household products and lack of protective placement of plants.1 Mexican-born mothers of children younger than 5 years of age were interviewed in their homes about poison prevention techniques. Safe storage was clearly a problem in these homes with 64% of homes having bleach stored within reach of children. The presence of multiple families living in the same home further impedes safe storage practices. In this study, families stored all personal products including medications and household cleansing agents with them in their bedrooms rather than in common areas such as the bathroom.46
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It is important to consider employment of bilingual staff as public educators when attempting to expand public awareness. The benefits of a bilingual educator include the ability to provide programs directly to an audience and eliminate the need for a translator. A lack of bilingual providers was the most significant barrier identified for Spanish speaking women interviewed about injury prevention techniques.26Recommendations for more effective outreach to Latino populations include television advertisements and distribution of written information at schools, churches, and doctor offices.74 Health education programs including mass media campaigns, designed to accurately reflect the cultural identity—language, beliefs, roles—of the targeted population are more likely to be accepted. Storytelling has also been a recommended strategy for health education among many cultures.44 When asked to provide suggestions for poison prevention education, responses included Spanish radio and video programs as well as brochures that incorporate culturally appropriate values. Including messages into widely recognized media such as telenovelas should also be considered when developing information dissemination channels. Most parents reported interest in learning from PC staff, doctor, or a teacher.16
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Field testing concepts and materials are important for the development and distribution of appropriate information for multicultural populations. Further work is needed to examine cultural beliefs related to poison prevention use of and access to the PC. It is important to address cultural beliefs related to use of herbal and other complementary medicines.30 New education programs are needed to reach multilingual and multicultural targeted populations communities across the country. Programs may be more successful if individuals trust and view a source as credible, particularly when cultural attitudes and beliefs closely resemble their own.16,35,44 In addition, promotoras or community health workers should be considered to deliver primary prevention information in the Hispanic community for building relationships with parents and overcoming cultural barriers.16,40
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Health Literacy/Numeracy
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Health literacy is defined as “the degree to which individuals have the capacity to obtain, process, and understand basic health information and services needed to make appropriate health decisions.”72 Health literacy encompasses the ability to read, understand, and discuss medical information. Research from the US Department of Education shows that only 12% of US English speaking adults have proficient health literacy skills.72 Older adults, Hispanic adults, immigrants, those with less than a high school degree or GED, and low income individuals are at highest risk for low health literacy.37 People with low functional health literacy abilities are less likely to understand written and verbal health information, medicine labels, and appointment information.37 This type of health information is often written at reading levels of at least tenth grade or higher.18 The recommended reading level for written information is sixth grade. Most Americans are able to understand medical information at this level.72 In addition to reading level, use of graphics, font style, color, type size, and layout are important components when developing print material.18,72 Recommendations for nonprint methods for communicating health information include visuals (posters, fotonovelas, pictographs), action-oriented activities (role-play, theater, storytelling), audiovisuals (videos, DVDs), and improving patient–provider communication.16,18,52,72
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Warning and medication labels are often difficult to understand. The inability to read these warning labels in English presents a barrier for safe storage and safe use of medication and products.46 Identification of products often includes brand recognition.45 Instructions for proper use and warnings may not be understood from the label independent of language.
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In order to address medication safety issues, particularly with medication labels, a number of studies have evaluated ways to simplify the information provided. New recommendations for standardized prescription medicine labels incorporate four specific time periods (morning, noon, evening, and bedtime) and plain language techniques on the container.76,77 Similarly, recommendations for nonprescription medicine labels have been developed.81
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The effects of health numeracy as a distinct component of health literacy are presented in the literature.48,64 Numeracy is an element of health literacy and involves the ability to use numeric information to make effective health decisions in daily life.3 This also includes concepts of risk, probability, and the communication of scientific evidence.48,62,64 Health-related tasks including measuring medications, scheduling appointments, and refilling prescriptions rely on applied numeracy skills.62,64 Patients managing multiple prescription and nonprescription regimens will lead to potential medication errors.76 Educators need to understand the importance of interventions that accurately assess numeracy levels and appropriately address health outcomes. Recommendations for techniques to improve understanding of numeric information include simplifying concepts, using plain language strategies, and utilizing “teach-back” patient understanding strategies.3,72
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Applying Health Education Principles to Poison Education Programs
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Health education involves planning, implementing, and evaluating programs based on theories and models. These models offer direction for educators with health promotion planning.42 There is a need to increase the number of poison educational programs incorporating health education principles. This includes educational efforts designed to reach individuals through community based programs and media campaigns.
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Both the Health Belief Model (HBM) and Social Cognitive Theory (SCT) incorporate the concept of “self-efficacy” and are applicable when designing poison prevention interventions and mass media campaigns. Self-efficacy is the individual’s belief that he or she will be able to accomplish the task requested.13,18,41,58 Many health educators believe that self-efficacy is necessary to enable behavior change. The SCT suggests that individuals, the environment, and behavior are intimately and inextricably interrelated.41 The HBM suggests that individuals are more likely to make health behavior changes based on perceived risk susceptibility, severity, potential barriers, and self-efficacy. These decisions are made when actions are seen as potentially more beneficial to the individual than the perceived risks associated with surmounting the current barriers.13
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In one study, the HBM approach was used as a framework for poison prevention and for the assessment of barriers to PC use. Questions for focus group participants were developed based on the principles of HBM—that is, perceived susceptibility, severity, benefits, barriers, and self-efficacy related to the health action requested. Most of the mothers viewed poisoning as an emergency and felt it was a health concern for their children. Cues to action are also a component of the model and involve discussions about poison prevention or related information. Participants recommended using community based venues and culturally appropriate information to expand awareness about poison prevention and the poison center.9
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The HBM and SCT approaches were used to develop the questions for focus groups in both English and Spanish. These questions addressed issues related to poison prevention (severity and susceptibility), the services of the PC (including barriers), and suggestions for education. Focus group participants suggested the use of modeling to reinforce real life scenarios in which a mother handles the poisoning emergency with the staff at the PC with a positive outcome.29 As a result, a video was developed addressing these ideas. Two poisoning situations in which a mother calls the center are depicted. One involves home management (ingestion of bleach) and the second involves taking the child to the emergency department (swallowing grandmother’s antihypertensive pill). The video and correlated teaching guides are available in English and Spanish.30
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It is important to develop questionnaires that will be accepted and understood by the target population. A Spanish language instrument that addresses home safety beliefs using the HBM framework was developed and tested. Low income, monolingual, Spanish speaking mothers of children younger than 4 years of age were interviewed about perceived susceptibility, severity, barriers, and self-efficacy factors affecting unintentional home injuries including poison prevention measures. Barriers identified include literacy skills and access to bilingual health information.26
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The HBM supports the idea that a “teachable moment” may be the ideal opportunity to present poison prevention interventions.23,56 People may be more open to health information after experiencing a traumatic experience.12 Events such as an unintentional poisoning exposure may motivate individuals to behavioral change. Applying HBM principles suggests that individuals will make changes in terms of poison prevention when or if they view the severity and susceptibility of a poisoning to be high in the home. Many languages are enriched by cultural variations that must be incorporated into poison education programs and best practices for outreach. Our goal as educators is to provide efforts using models that have been tested and evaluated for addressing focused community efforts in each population served by the PC.
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Poison center public education efforts must encompass needs assessments, program development, implementation, and evaluation.
Focus groups with caregivers of young children conducted across the country have consistently identified barriers to calling poison centers. These include calling 9-1-1, fear of being reported to child welfare agencies, and lack of confidence in handling poisoning emergencies.
Using health education theories and models, programs should be developed that address these barriers and encourage caregivers to use the services of the PC appropriately.
Education programs focusing on the needs of older adults and promoting using the poison center as a resource for medicine safety should be designed.
Cultural, health literacy, health numeracy, and language needs of target populations are important considerations when planning poison education programs.
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Poison Centers and Poison Epidemiology
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In 1950, the American Academy of Pediatrics created a Committee on Accident Prevention to explore methods to reduce injuries in young children. A subsequent survey by that committee demonstrated that injuries resulting from unintentional poisoning were a significant cause of childhood morbidity. Simultaneously came the realizations that a source of reliable information on the active ingredients of common household xenobiotics was lacking and that there were few accepted methods for treating poisoned patients. In response to this void, the first poison center was created in Chicago in 1953.102 Although initially designed to provide information to health care professionals, both the popularity and the success of this center stimulated a poison center movement, which rapidly spread across the country. The myriad of new poison centers not only offered product content information to health care professionals, but also began to offer first aid and prevention information to members of the community.
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In the 60 years that have since passed, countless achievements have been realized by a relatively small group of remarkably altruistic individuals. Throughout this time, poison services have remained free to the public, highlighting their essential role in the American public health system. Many of the legislative and educational accomplishments, which are chronicled in Chap. 1, have directly reduced the incidence and severity of poisoning in children.98,110,116 Concurrently, the number, configuration, and specific role of poison centers have shifted in response to public and professional needs.50,125
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Modern regional poison centers are staffed by highly trained and certified health professionals who are assisted by extensive information systems. Support is provided by 24 hour access to board certified medical toxicologists and consultants from diverse medical disciplines, the natural sciences, and industry. The role of the current American poison center can be best summarized as follows:
++
Maintaining and interpreting a database of xenobiotics
Reducing health care costs related to poisoning through:
Providing information and advice to the public to prevent unnecessary hospitalizations following exposure
Providing information and advice to health professionals to improve the diagnosis and care of patients who present to health care
Collecting epidemiologic data on the incidence and severity of poisoning
Integrating epidemiologic data as part of the public health surveillance system
Educating health care professionals on the diagnosis and treatment of poisoning
Contributing to the science of toxicology
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In the past, poison centers were evaluated based on number of incoming calls and measures of community awareness. Current emphasis should be placed on evaluating health outcomes such as admissions to the intensive care unit, length of stay in hospitals, and total health care expenditures. One crucial test of the utility of modern poison centers will be their ability to help reverse the current trend in the United States of increasing adult mortality from prescription drug poisoning.67 This chapter explores some of the critical roles of US poison centers and attempts to offer a vision of the future. An overview of the composition of poison centers worldwide can be found elsewhere.96 Unique issues facing poison centers in other countries are discussed in Chap. 137.
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MAINTAINING AND INTERPRETING A DATABASE OF XENOBIOTICS
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The first toxicology database created in the United States was a set of cumbersome 5 × 8-inch index cards produced in the 1950s by the US National Clearinghouse of Poison Control Centers.102 When it grew to include more than 16,000 cards, the sheer volume of space required to store this information, and the extensive time necessary to manually search these cards, created the necessity of a central repository, such as a poison center. As available information grew, a rapid expansion of information technology occurred, and the unwieldy index card database was privatized and transformed into microfiche. Although this resource was physically smaller, specialized equipment was required, and a search was still time consuming. Numerous encyclopedic and clinical textbooks were written to supplement the database and provide resources for the office or the bedside. With the growth of the computer age and the Internet, the computer program known as POISINDEX was established to replace the microfiche format as the major source of data on the contents of innumerable household and industrial products, drugs, and plant and animal xenobiotics. POISINDEX also provides uniform management strategies for many potentially toxic exposures. Over the years many proprietary competitors to POISINDEX such as TOXINZ and TOXBASE have gained recognition as valuable tools. Additionally, open source programs such as WIKITOX provide free information to both health care professionals and members of the public.
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With this evolution of information technology, poison centers are no longer perceived as the sole guardians of toxicology information. Although these services are still essential for the public at large, and those professionals away from their computers or smart phones, a predictable decline in poison center utilization has paralleled this growth in availability of information. A 1991 study in Utah demonstrated that 82.6% of emergency physicians who had POISINDEX available in their institutions no longer routinely consulted the poison center.27 A similar 1994 New York study suggested that 76% of physicians who had POISINDEX in their emergency departments (EDs) perceived that this decreased their own use of their poison center.121 These studies suggest that poison centers were more likely to be called for patients with acute and symptomatic overdose and less likely to be contacted for chronic toxicity, asymptomatic patients, and adverse drug reactions.
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An initial analysis might suggest that this is an acceptable trend for health care professionals in that it both allows physicians to respond more rapidly to patient needs and for poison centers to be more available to those individuals, especially non–health care professionals, who do not have access to this information system. In fact, one regional poison center model demonstrated that an integrated voice response (IVR) system effectively reduced human interactions for medication identification by more than one-half.75 By extension, it might be suggested that both the public and health care professionals can easily access the same information as poison specialists, making the human interaction nearly obsolete. However, this practice of “not calling” not only undermines the efforts of poison centers to gather epidemiologic data (see later) but also creates an understanding gap. In other words, the interpretation of the data is as essential (or more essential) than the data itself. For example, some commonly used sources of toxicology information such as the Physicians’ Desk Reference and material safety data sheets occasionally provide information that may be inaccurate, potentially misleading, or severely limited.19,56,87 Likewise, reviews of drug interaction programs designed for mobile devices demonstrated significant variability between individual programs and superiority of larger online resources.5,37,94,97 Although POISINDEX routinely provides more accurate information regarding overdose, it is only updated quarterly, cannot be expected to adapt to ongoing epidemiologic trends such as regional variations in substance use, and is incapable of judging adequacy or communications or the subtleties contained in natural language.
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The best source for essential new information is skilled professionals who specialize in poisoning. In addition, because most databases are designed to provide information about known entities, they perform poorly when dealing with unknown and unclear scenarios—especially long and complicated differential diagnoses. For example, consider the case of a clinician caring for a lethargic child whose only medication is Zantac syrup. After the other causes of altered mental status have been excluded, the clinician considers drug toxicity. Consultation with standard references suggests that altered consciousness would not be expected with use of this medication. However, a certified poison specialist at a regional poison center recognizes the potential for drug error, has the physician review the syrup bottle in question, and then calls the pharmacy where the drug was provided. The poison specialist learns that although the prescription was written for ranitidine (Zantac), the bottle actually contains cetirizine (Zyrtec syrup), which could account for the child’s symptoms.
++
Thus, although originally designed as providers of information, poison centers are in reality valued consultants, with staff members who not only provide content information but also interpret clinical material and link both to appropriate management strategies. This goal can only be achieved through rigorous training and certification and recertification criteria designed to provide valued up to date interactions with health care professionals. Access to computer programs can never be considered a substitute for a thoughtful human analysis. Computers do not recognize anxiety, inappropriate questions, and other subtle issues that can only be appreciated with human interactions.
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Another illustrative example of the value of poison centers can be drawn from the use of flumazenil for benzodiazepine overdose (Chap. 74 and Antidotes in Depth: A22). Although it may easily be determined by anyone capable of using a resource that flumazenil is an antidote for benzodiazepine overdoses, many subtle characteristics of the patient or the overdose often contraindicate its use. A prospective study determined that when flumazenil was used before consultation with the poison center, contraindications were present in 10 of 14 (71%) cases, resulting in one serious adverse event.22 In the study mentioned earlier, although physicians with access to POISINDEX were less likely to call the poison center, 86.7% still felt that using the poison center to gain access to a physician toxicologist was a valued resource.27 Many poison centers are linked with centers for poison treatment, which are health care facilities that can provide both bedside consultation and unique diagnostic and therapeutic interventions for a subset of patients with severe or complex poisoning.1 The benefits of consultation are discussed later in Health Care Savings.
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PROVIDING INFORMATION AND ADVICE TO THE PUBLIC AND TO HEALTH PROFESSIONALS
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In 2011, poison centers in the United States interacted with the public and health professionals more than 3.5 million times.18 While the financial value of these interactions will be discussed in the section on health care savings below, two major limitations to the success of poison centers were highlighted by recent studies. The first, which should be intuitively obvious, stems from the fact that poison centers are remote from the patient and can, therefore, only make decisions based on the information provided to them. Although poison information specialists are highly skilled and use a variety of communication styles to obtain the most accurate information,48 the quality of the information impacts on the utility of their recommendations. The greatest concern often is the estimation of the actual dose of an exposure. In a 3.5 year study of all children referred by a poison center to a health care facility for the determination of the presence of either a methanol or an ethylene glycol blood concentration because of the history of an exposure, only 21 of 102 children had a measurable concentration.78 While this has serious limitations on the interpretation of poison center data,62 the implications for clinical care are even greater. Likewise a human volunteer study demonstrated that adults are totally incapable of determining residual volumes in containers or describing the actual volume of semiquantitative descriptors such as “a small mouthful” or “a gulp.”61 Because critical decisions are made based on the history of ingestion or amount ingested, a clear challenge for poison centers is to develop methods to improve the accuracy of this information. Digital imagery may provide a useful method of assisting caregivers with determination of residual container volumes by allowing specialists to clarify container sizes and residual volumes.
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The second challenge involves the gap that exists between recommendations that are made by poison centers and those that are accepted. Two recent papers highlight this concern. In a 7 year analysis of poison center recommendations for the administration of high dose insulin and glucose therapy, the recommended treatment was actually administered only 50% of the time.49 Similarly, in a 5.5 year study of calcium channel blocker and β-adrenergic antagonist overdoses at a different poison center, high dose insulin and glucose therapy was only started in 42% of cases where it was recommended, and intravenous fat emulsion was only given in 33% of cases where it was recommended.41 Because both these therapies are considered effective and potentially life saving (Antidotes in Depth: A17 and A20), poison centers need to evaluate the reasons these recommendations are not accepted and explore methods to improve communication with providers. The use of on-site medical or clinical toxicology faculty liaisons may help reduce these gaps.
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COLLECTING POISON EPIDEMIOLOGY DATA
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In 2007, the US Centers for Disease Control and Prevention (CDC) reported that poisoning fatality surpassed both motor vehicle crashes and firearms to become the leading cause of injury related fatalities.93 This trend has continued and is largely influenced by an epidemic of prescription opioid abuse.67 Understanding the evolving trends in poisoning is essential to the development of enhanced surveillance, prevention, and education programs designed to improve medication prescribing, drug safety, and to reduce unintentional poisoning. Although data can be analyzed from numerous sources, such as death certificates, hospital discharge coding records, and poison centers, it is essential to recognize the biases that are inherent in each of these reports. Because not all significant poisonings result in either hospitalization or fatality, data from poison centers appear to offer a unique perspective.
++
Unfortunately, the term “poisoning” is often defined differently and therefore may be confusing. In this text, “poisoning” is used to denote any exposure to any xenobiotic (drug, toxin, chemical, or naturally occurring substance) that results in injury. Yet the data collected and disseminated by poison centers are defined by the term “exposures.”13, 14, 15, 16, 17, and 18,76,117, 118, and 119 Many exposures are of limited toxicologic consequence either because of the properties of the xenobiotic involved, the magnitude or duration of the exposure, or the uncertainties regarding whether an actual exposure has occurred. Therefore, data collected by poison centers represent a limited and ill-defined measure of poisoning.
++
The situation is further confounded by multiple biases that are introduced by the actual reporting process, which first and foremost is voluntary and passive. Because most calls concern self reported data from the home and are never subsequently confirmed, a significant percentage of the data generated to date may actually represent only potential or possible exposures, which can introduce large statistical errors into the database. This is highlighted by the 21 of 102 children who tested positive for a toxic alcohol discussed above.78 Despite the fact that only those 21 children were definitively exposed and potentially poisoned, all 102 were entered into the database as exposures. If these figures are representative of the rest of the data set, then they suggest that an actual ingestion does not occur in the vast majority of reported unintentional exposures in children. However, they do emphasize that in all of the cases a toxin was in an unacceptably close proximity to a child. Also, current events, hoaxes, and media awareness campaigns all may influence self-reporting rates.81 Furthermore, to report a possible exposure a caller must have a telephone, probably speak English, and have some degree of health literacy and numeracy.80,115 Although telecommunications devices for the hearing impaired and translation services exist, they are rarely used. Enhancement of technology to facilitate the accurate exchange of information between poison specialists and either hearing impaired callers or those who do not speak English is essential to the success of poison centers. While text message is an interesting option, preliminary data suggest that text messaging encounters take way too long to be productive.99 Another would be to entertain more active reporting systems automatically triggered directly by hospital laboratory values. Such a system would explore cognitive behavior of clinicians around reporting and develop a true understand of the epidemiology.
++
Under the present passive system, when hospitals report exposures to the poison center, a comparison of the hospital chart with the poison center record shows good agreement, demonstrating an accurate exchange of information.64 Unfortunately, a reporting bias similar to that described above is well recognized regarding professional utilization of poison centers and has been called the Pollyanna phenomenon.57 For example, in the spring of 1995, poison centers in the northeast United States began to receive numerous reports of severe psychomotor agitation and other manifestations of anticholinergic syndrome in heroin users. In the initial phase of the epidemic, most of the callers requested assistance in establishing a diagnosis, determining possible etiologies, and raised questions regarding treatment with physostigmine.58 Although the epidemic continued for many months, once the media announced that the heroin supply was tainted with scopolamine, and clinicians became familiar with the indications and administration of physostigmine, call volume decreased. Stated simply, health care professionals are less likely to call the poison center regarding issues with which they are familiar, are of little clinical consequence, or are not recognized as being related to a poison. Thus, a bias is introduced that results in a relative over reporting of new and serious events and a relative underreporting of the familiar or very common, unrecognized poisoning, and those exposures or poisonings that are apparently inconsequential. Numerous comparisons support this contention. Investigators who rely on published data from poison centers as a sole source of epidemiologic information demonstrate a failure to understand the complexity of poisoning data and the aforementioned consequential limitations of poison center–derived data.
++
A 4 year study compared deaths from poisoning reported to the Rhode Island medical examiner with those reported to the area poison center.79 Not surprisingly, the medical examiner reported many more deaths: 369 compared with 45 reported by the poison center. Although most of the cases not reported to the poison center were victims who died at home, were pronounced dead on arrival to the hospital, or those in whom poisoning was not suspected until the postmortem analysis, 79 patients who subsequently became unreported fatalities were actually admitted to the hospital with a suspected poisoning. In 10 of these cases, the authors concluded that a toxicology consultation might have altered the outcome. Examples of interventions that, if recommended and performed, might have resulted in a more favorable outcome included the proper use of antidotes such as naloxone for an opioid overdose, N-acetylcysteine for acetaminophen (APAP) poisoning, the cyanide antidote kit, sodium bicarbonate for a cyclic antidepressant overdose, hyperbaric oxygen for carbon monoxide poisoning, hemoperfusion for a theophylline overdose, and hemodialysis for a lithium overdose. While the xenobiotics may have changed since this study was performed, the fundamental principles highlighted remain relevant.
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Likewise, when medical examiner data were analyzed in Massachusetts, more than 47% of poison fatalities had not been reported to the poison center.107 A California study evaluating 358 poisoning fatalities reported to the medical examiner showed that only 10 poison center fatalities were reported over a similar time period, demonstrating an even more consequential reporting gap.7 Once again in this study, whereas the majority of underreporting was with respect to prehospital deaths (68%), only 5 of 113 hospitalized patients who ultimately died were reported to the poison center. Additionally, a cross-sectional comparison of national mortality data with poison center data for agricultural chemical poisoning demonstrated a similar trend of underreporting to poison centers of seriously poisoned admitted patients who became fatalities.72 Furthermore, when data for an entire year from the National Center for Health Statistics were compared with the same year of data from the American Association of Poison Control Centers (AAPCC), it was apparent that the AAPCC data captured only about 5% of annual poison fatalities.63
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More recent analyses have highlighted a remarkable trend. When 11 states evaluated trends in poison-related mortality from 1990 to 2001, an average increase of 145% was noted.106 A more comprehensive investigation of the National Vital Statistics System accessed via the CDC’s Web-based Injury Statistics Query and Reporting System database demonstrated a 5.5% increase in injury related mortality from 1999 to 2004. Mortality from poisoning accounted for 61.9% of the increase in unintentional injury, 28% of the increase in suicide, 81.2% of the increase in death from undetermined intent, and more than half of the total increase injury-related mortality.93 As of 2004, death from poisoning surpassed firearms and became the second most common cause of injury-related fatality. While most of the fatalities are in adults, a review of the entire 2010 AAPCC database only found 74 reported fatalities in children.23 Focusing on poison center data alone would produce the erroneous assumption that poisoning-related fatalities were not a significant public health concern. In actuality, poisoning is a significant concern in that other programs designed to reduce deaths from motor vehicle crashes and firearms have been largely successful whereas decades have gone by without a major intervention targeting poison related fatality.
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It is logical to assume that similar disparities exist regarding the reporting of nonfatal poisonings. The resultant gap in public health data needs to be addressed through improved definitions, epidemiology, reporting, and analysis of poison-related data systems. This inequity has developed through a long-standing tradition of poison centers to focus attention and concentrate on the largely benign exposures in children. The emphasis needs to be redirected toward seriously ill poisoning, utilization of the intensive care unit, and other markers of actual poisoning rather than health care utilization for benign events. The necessary data for such an evaluation may already exist, but the challenge will be in linking the data sets to provide a meaningful analysis.
++
An outreach study in Massachusetts determined that hospitals geographically close to a poison center reported their cases almost twice as often as hospitals remotely located (46% vs. 27% of total cases).28 Additionally, the authors noted that private physicians were less likely to report cases than residents in training. A one year retrospective review demonstrated that only 26% (123 of 470) of poisoned patients who were treated in a particular ED were reported to the poison center.59 Interestingly, only 3% of inhalational exposures were reported, compared with 95% of cyclic antidepressant ingestions. The authors also noted, as suggested above, that reporting decreased when comparable exposures occurred over a short period of time. Finally, in the physician survey study cited earlier, physicians reported that they would “almost never” contact the poison center for asymptomatic exposures (62.9%), chronic toxicity (50.4%), or simply to assist in establishing a reliable database (90.2%).27 This statement is most likely accurate even in jurisdictions in which the reporting of all or select exposures is incorporated into public health laws.
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Occupational Exposures
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Xenobiotic exposure occurs commonly in the workplace. As a result of the long-recognized association between occupational exposure and illness, several federal and state government funded agencies, such as the National Institute for Occupational Safety and Health, Occupational Safety and Health Act, and the Agency for Toxic Substances and Disease Registry (ATSDR), exist to prevent occupational illness, to educate the public, and to collect data on exposures to occupational xenobiotics. Legislation provides for mandatory reporting in some instances and offers workers job protection for voluntary reporting. Poison centers also provide information on occupational exposures and collect data. Once again, there are discrepancies between the poison information data and the data collected by governmental agencies. A six month survey in California noted that only 15.9% of the occupational cases reported to the poison center were captured by a state occupational reporting system.9 The most common occupational toxicologic illness—dermatitis—was even further underrepresented in these cases. A follow-up study by the same authors demonstrated that more than one-third of calls came directly from the individual worker, 70% of whom were unaware of the link between their occupation and their symptoms.8 Although these data suggest that poison centers can provide substantial assistance following occupational exposures, one author expressed concern, noting in a follow-up study that the poison center failed to provide an adequate epidemiologic assessment in that it did not identify an average of 12 other people per workplace who were also potentially exposed in addition to the index case.11 A 1999 survey of poison centers concluded that “responses to work-related calls are inadequate” and suggested that written protocols might be helpful.12
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Adverse Drug Events and Xenobiotic Errors
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Although the actual numbers are a source of controversy, data suggest that a striking number of adverse drug events (ADEs) occur each year in the United States, with many resulting in death.20,31,77 The ease of 24 hour telephone access, combined with the ability to consult with a health professional, make poison centers ideal resources for reporting of ADEs.30 Yet, more than 76% of physicians surveyed stated that they would “almost never” contact the poison center regarding adverse drug events.27 Moreover, 30 of the 56 (53.6%) poison centers surveyed stated that they had not submitted any of their ADE data to the US Food and Drug Administration’s MedWatch program.34 Many of the other centers reported only partial compliance with the MedWatch system.34 Biases may lead to disproportionate reporting of adverse events related to newer drugs skewing the interpretation of the data. For example, although bleeding may occur from both coumadin and dabigatran, it is easy to believe that reports would be more likely to be generated for the newer drug.
++
Prescription drug errors are another source of potential poisoning. Retrospective review of poison center data suggests that many of these errors are reported. In one report, the poison center provided valuable feedback to pharmacists and physicians about these errors. Ideally, reporting to the state board of pharmacy would assure that proper surveillance and counseling continue. The poison center would seem to be ideally suited to perform this function.104 Unfortunately, while pharmacists are ideally positioned to identify prescribing errors, data suggest that pharmacist utilization of poison centers is poor.2
++
Poison centers also collect data on exposures to drugs of abuse and misuse. These data consist largely of calls for information from the concerned public and reports of overdose requiring health care intervention. Although ethanol, tobacco, and caffeine are the most common xenobiotics used in society, these cases are rarely reflected in poison center data, with the exception of unintentional exposures in children. In fact, because most substance abuse does not result in immediate interactions with the health care system, other databases such as the National Institute of Drug Abuse Household Survey (now referred to as the Monitoring the Future Study) might better reflect substance abuse trends. Yet even this database has significant limitations.6,54 Because poison centers are more focused on immediate health care effects of exposures, it could be argued that only those cases in which health care interaction is required are of value in the database. Since poison centers collect data in real time, centers are ideally positioned to report on emerging trends and sentinel events. Recent examples include poison center experiences with trends opioid abuse in teenagers,51,111 bath salts,88 synthetic cannabinoid receptor agonists,89 and adulterated cocaine.112
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Grossly Underreported Xenobiotics
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As discussed previously, there is little doubt that ethanol and tobacco are the most common xenobiotics intentionally used in our society. Although their toxicologic manifestations can be acute and severe, chronic subclinical poisoning often goes unnoticed for many years. Similarly, more than 500,000 American children have lead concentrations above 10 μg/dL and polychlorinated biphenyls can be found in countless adults and children. We must remain cognizant of these large-scale exposures, such as bisphenol A, when we read that plants, cleaning products, and cosmetics comprise the most common exposures to xenobiotics18 are the most commonly “reported” exposures.
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Integrating Epidemiologic Data as Part of the Public Health Surveillance System
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With the current limitations of the poison center data, it should be clear that neither the numerator nor the denominator of the actual number of poisonings can be easily appreciated. However, analysis of these data for trends may be more useful because the inherent biases involved in poison center reporting are probably consistent over many years. Increasingly, poison center data are being used as part of surveillance and prediction models,46,123 often that extend beyond poisoning to other public health concerns.105 Rapid reporting in collaboration with the CDC highlights an essential partnership.38,55,89 Efforts should be directed to encourage reporting to poison centers by such enhanced access methods as Web-based forms for passive reporting, a direct interface between laboratory and hospital databases that actively transmits data to poison centers, and linkages to other agencies that collect reports of poisoning such as state and local health departments. Additional resources should be directed at improved case definitions (distinguishing asymptomatic exposure from poisoning) and integration with other essential databases such as MedWatch, the National Vital Statistics System, and the National Center for Health Statistics.
++
Despite its limitations, poison center data have significant utility. It is often an exposure rather than an actual poisoning that provides the impetus for contact with health care. For those exposures that are unlikely to be consequential, the poison center can intervene to prevent potentially harmful attempts at home decontamination and costly unnecessary visits to health care professionals. Interaction with parents at a time of perceived crisis also provides a “teachable moment” (Chap. 135) that may help prevent a more consequential exposure in the future. For those exposures that may result in poisoning, the period of time immediately following exposure is an ideal moment to initiate first aid measures designed to prevent or lessen the severity of poisoning. For both of these reasons the cost, benefits, and efficacy of poison centers especially regarding home calls must be measured in terms of exposures and not poisonings.
++
When visits to pediatric EDs for acute poisoning were analyzed, one study demonstrated that 95% of parents had not contacted the poison center before coming to the hospital and 64% of those children required no hospital services and could have therefore profited from a poison center interaction.29 By contrast, when parents called the poison center first, fewer than 1% sought emergency services afterward. When 589 callers to one poison center were surveyed, 464 (79%) stated that they would have used the emergency care system if the poison center were unavailable.69 In a similar study, 36% of callers would have selected a more costly alternative if the poison center were unavailable.10 Likewise, when primary care givers were surveyed, over 80% said that they would activate 9-1-1 if there were no poison center.3 Poison center data confirm that approximately 75% of reported exposures that originate outside of health care facilities can be safely managed onsite with limited telephone follow-up. Suggesting simple techniques or reassurance can successfully reduce hospital visits for patients who typically call poison centers which, as defined, may only represent a potential exposure. The use of established protocols, especially for unintentional exposures in children clearly reduces emergency department referral rates.60 These interactions can be followed by distribution of simply written prevention literature to improve use and retention. Unfortunately, this approach is less applicable to adults and the population as a whole.
++
Limited data suggest that direct bedside consultation and care help reduce length of hospital stay and health care costs.36 Yet poison centers operate remotely. In one assessment, consultation with a poison center reduced length of stay by nearly 3 days.114 Similarly, when the poison center was consulted for patients already in the hospital, length of stay and costs were reduced by 1.9 days and nearly $5000.21 This experience has been replicated outside the United States where poison center consultation resulted in a decreased length of stay of more than 3 days, respectively.52 Strongly encouraged or mandated interactions with poison centers might help reduce the cost of health care, hospital overcrowding, and access to limited resources such as antidotes and hemodialysis.
++
The national average cost to the poison center for a single human exposure call is on the order of $35.125 A federally funded study concluded that, in one year, poison centers reduced the number of patients who were treated but not hospitalized by 350,000 and reduced hospitalizations by an additional 40,000 patients, for a cost savings of more than $3 million in 1996 dollars.86 Each call to a poison center prevented at least $175 in subsequent medical costs, providing strong theoretical evidence to support the cost efficacy of poison centers. In fact, two natural experiments support these calculations. In 1988, Louisiana closed its state sponsored poison center. During the year that followed, the cost of emergency medical services for poisoning in Louisiana increased by more than $1.4 million. This additional expenditure represented a greater than threefold increase above the operating cost of that center.71 Similarly, because of financial disputes in California, direct access to the San Francisco poison center was electronically restricted for one major county, with a telephone recording referring callers instead to the county 9-1-1 system for assistance.95 The result of each blocked call was to increase health care costs by approximately $33. Moreover, these calculations cannot account for the unmeasured benefits to society from poison center interventions that reduce waiting times for ambulance availability and hospital treatments because of lower volumes, money saved by the prevention or reduction of injury from early intervention, or lives saved by enhancing access to or utilization of the health care system for seriously poisoned patients. In El Paso TX, cooperation between emergency medical services and the poison center was able to reduce ambulance dispatches by 1750 over 5 years.4 Overall estimates place the rate of return for poison center funding between 11 and 36:1.66,108
++
However, many barriers prevent a person from calling a poison center, including lack of familiarity with its available services, intellectual and cultural factors, language difficulties, and confidentiality concerns.35,70,80,115 Epidemiologic studies demonstrate that areas of increased population density, such as major urban communities, with high percentages of minority inhabitants have lower utilization of poison center services.113 Additional barriers include the absence of caregiver comfort with the extensive personal contact provided by the health care system and a concern regarding implications of child abuse or neglect when reporting to agencies such as poison center, many of which have governmental ties.103 Data demonstrate that public educators can help overcome some of these barriers.109 One good example of an effort to overcome reporting barriers was the institution of a single national toll-free number for poisoning (1-800-222-1222). Although it is clear that this intervention improved access and increased total calls to the poison center,74 it has yet to be determined if this has altered the patterns of use.
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PROVIDING EDUCATION FOR THE PUBLIC AND HEALTH PROFESSIONALS
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Poison center staff work closely with physicians, community health educators, community support groups, and parent–teacher associations to develop poison prevention activities.82Table 136–1 lists common strategies advocated to prevent poisoning. Poison centers are also actively involved in enhancing training programs for paramedics,47 medical students,68 pharmacy students,40 and resident physicians,40,91,122 and are an integral part of postgraduate training programs in medical toxicology fellowships.
++
++
As stated previously, there is an inherent risk in both enhanced public and professional education programs. Currently, the decreased telephone utilization of a poison center could be both the result of a decrease in the incidence of exposures or poisonings or an enhanced understanding of the prevention, diagnosis, and treatment of poisoning. Although education should never be viewed as detrimental, programs must include an emphasis on the continued use of poison centers to assure access to most current information in a rapidly changing discipline that only develops through an ongoing dialog between health care professionals and poison specialists. In actuality, as a result of the ongoing analysis of incoming calls, the knowledge base has the potential to change as rapidly as the calls are reported. This is far more rapid than can occur in any published literature or electronic database. Thus, additional emphasis should be applied to routine utilization of the poison center as a public health tool to improve the accuracy of epidemiologic data. Reporting of rare or suspected events can serve as sentinel efforts that help identify consequential adverse drug opportunities long before normal postmarketing surveillance tools identify areas of concern.
++
On the other hand, outreach programs that advise the public to access free services for inconsequential events can easily overwhelm an already stressed system of responding to incoming calls by demanding an immediate response to the less serious calls in an appropriate time frame. Public education and public health must both be considered to assure that poison centers are staffed with the appropriate number of skilled individuals to respond not only to daily events, but also to address surges in calls that may be the result of true epidemics or responses to media announcements. Increasing calls to demonstrate increased utilization offers no public health advantage if the utilization is inappropriate or if seriously ill or potentially ill callers lose access to timely responses.
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DEVELOPMENT OF FUTURE PUBLIC HEALTH INITIATIVES
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The initial public health efforts of poison centers focused on attempts to alter product concentration and to enhance product labeling and packaging. These clearly beneficial endeavors should continue and must evolve. However, current events have also increased poison center activities in preparedness for mass gatherings and disasters resulting from radiological, biological, and chemical terrorism.53,73 Additional links with governmental agencies such as the CDC and ATSDR will expand the role of medical toxicology in community health. The need for 24 hour rapid access to centralized information, existing data entry and retrieval systems, and links to experts in medical toxicology and emergency medicine helps to place poison centers in critical roles in both local and national initiatives. Important contributions have included development of triage and treatment protocols24, 25, and 26,32,33,39,43,60,83, 84, and 85,90,92,100,101,120,124 and assessments of antidote supplies.42,44,45Table 136–2 summarizes initiatives that require creation or enhancement to improve poisoning epidemiology data. Many of these are discussed extensively in a report from the Institute of Medicine.65
++
++
Public education efforts help reduce the likelihood of exposure.
Provision of basic management advice helps to diminish the consequences of a poisoning once an exposure has occurred.
Reassurance and proper basic management help to curtail unnecessary utilization of expensive health care.
Interactions with health care professionals streamline the care of poisoned patients saving hospital days and health care expenditures.
Collaboration with public health authorities will identify, inform, and help mitigate the consequences of ongoing toxicologic events.
Data on exposures have been effective to create legislation to further limit poisoning by altering contents or improving packaging or labeling.
++
Richard S. Weisman, PharmD, contributed to Table 136–1 in previous editions.
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++
International Perspectives on Medical Toxicology
++
Poisoning is a worldwide problem, but the major effects are felt in the developing world. At least 250,000 to 350,000 people die every year from acute pesticide poisoning,72 and an estimated 20,000 to 94,000 humans die each year from snake bites,97 the vast majority of whom lives in rural farming areas of lower and middle income countries. Hundreds of thousands of people are affected by groundwater arsenic contamination in Bangladesh and India,149 and outbreaks of poisoning from contaminated food40 and environmental pollution from poorly regulated industrial activity49,135 affect whole communities throughout the developing world.
++
The resources for dealing with these problems are limited in many countries. Public health education about poisons and infrastructure limiting access and exposure to the most highly toxic chemicals are practically absent in much of the developing world. Access to medical care is often limited for financial, cultural, and geographic reasons. Medical toxicology is frequently not a recognized specialty and patients are evaluated by general physicians with little training—although often with great experience. Diagnostic facilities are few, effective treatment options even more rare. Where antidotes exist, there is rarely enough knowledge or experience to use them effectively.30 Intensive care beds for invasive monitoring and long-term ventilation are scarce. This chapter outlines some of the major poisoning risks and challenges for medical toxicology in the developing world.
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POISONING AND THE GLOBAL BURDEN OF DISEASE
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The World Health Organization (WHO) has ranked injury, including poisoning, among the top 15 causes of death worldwide for persons aged 5 to 44 years.114,174 Recent reanalysis of data from the Global Burden of Disease project estimated that acute and chronic exposure to chemicals caused over 4.9 million deaths and 86 million disability-adjusted life years (DALYs) worldwide in 2004—more than cancer, sexually transmitted diseases, or diabetes.135,179 Children younger than 15 years of age bore more than one half of this burden.
++
Tremendous regional disparities in the health impact of poisoning are apparent. The global mortality burden from poisoning is disproportionately shouldered by lower and middle income countries. Overall, as much as 75% or more of all poisoning related deaths occur in the developing world,81 and an estimated 95% of children who die each year from acute poisoning live in low- and middle-income countries.174 Children living in Sub-Saharan Africa are at highest risk, with an estimated annual mortality rate of four children per 100,000 population. This is double the global average and higher than that in any other region.142
++
These figures are striking, yet most likely underestimate the contribution of poisoning to the global burden of disease and disability. Much of the existing data on poisoning epidemiology from lower income countries reflects the experience in larger hospital centers. By contrast, most of the population lives in rural areas, and many patients with poisoning may never reach such facilities for a variety of financial, cultural, or geographic reasons. For example, logistical difficulty with accessing health care facilities was responsible in part for the high mortality from snakebite noted in one community-based study in Nepal.146 Social or economic barriers often contribute to “healer shopping” within traditional or spiritual systems, with allopathic medical care delayed or avoided in many African countries.52,86,128
++
Unintentional poisoning risks from occupational, environmental, food, or medication sources may also be poorly recognized in communities, or by health care workers.123 The diagnosis of poisoning may not be suspected if a clear history of exposure is not given, because symptoms can mimic infectious or other processes and few medical centers have ready access to laboratory tests for specific poisons. When poisoning is suspect, many countries lack detailed injury surveillance systems or other standardized reporting mechanisms. The WHO has undertaken several initiatives to improve global poisoning surveillance, including support for poison center (PC) development in under represented regions worldwide, and the international efforts of the IPCS/INTOX programs to harmonize data collection and reporting terminology represent an important step toward this goal. However, the interpretation of PC data as evidence of epidemiologic trends must be approached with some caution (Chap. 136).
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COMMON XENOBIOTICS AND PATTERNS OF POISONING
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Agents commonly involved in acute poisoning differ substantially between communities, both within and among countries. For example, a comparison of poisoning cases seen at a major public teaching hospital in New York City with two large rural hospitals in Sri Lanka found striking differences in the classes of xenobiotics involved. A total of 70% of the patients in New York City were poisoned with pharmaceuticals, and 90% of patients in the Sri Lankan cohort were poisoned with nonpharmaceuticals, primarily pesticides and botanicals, such as yellow oleander, with a 10 times higher case fatality rate.81 A study comparing poisoning epidemiology in district (rural) and regional (urban) hospitals in Zimbabwe found that poisoning from pesticides was equally common in both settings, but animal envenomation was seen nearly twice as often at the district facilities compared to regional centers, and poisoning with pharmaceuticals was a problem seen uniquely at the regional hospital.156
++
Understanding the local patterns and specific risks for poisoning in particular communities is of critical importance since it provides an evidence base for designing and prioritizing strategies to prevent or limit harm. This section reviews some of the more common xenobiotics implicated in poisoning in developing countries worldwide.
++
A systematic review suggested that at least 250,000—but more likely 350,000—deaths occur each year from acute pesticide self-poisoning around the world.72 The WHO now considers pesticide poisoning to be the single most important means of suicide, accounting for more than one-third of all suicides worldwide.25 Most of these deaths occur in Asia, particularly in China and India.72 The annual number of deaths from occupational or unintentional pesticide poisoning is unknown but was estimated 20 years ago at 20,000.90
++
While many classes of pesticides are implicated (Chap. 113), organic phosphorous (OP) pesticides appear to be responsible for the majority of pesticide-related deaths in the developing world.56 Deliberate self-poisoning with OP pesticides puts a high cost on the health care system. In one study examining the experience in Sri Lanka, OP pesticide poisoning was responsible for 943 of 2559 (36%) admissions to a secondary hospital for poisoning.60 The case fatality for OP poisoning was 21%, and pesticide poisoned patients occupied 41% of all medical intensive care beds. Similar situations have been reported from across the world.56 In all likelihood, such studies underestimate the mortality associated with intentional pesticide ingestion as most are hospital based and do not include patients who die prior to hospital presentation.2
++
Factors contributing to the high mortality of self-poisoning with pesticides in the developing world include the intrinsic lethality of many pesticides, and health care systems that are poorly prepared to handle such critically ill patients (Table 137–1). Pesticides are often easily available in highly concentrated preparations in rural communities throughout the developing world. The ease of drinking liquid pesticides is also a factor facilitating massive intentional ingestions, as are inadequate pesticide storage systems.99 Outbreaks of unintentional poisoning from contaminated flour or old pesticide containers used to store food still occur in rural areas.54 The extraordinarily high human, economic, and social costs of pesticide-related mortality worldwide reinforce the importance of developing simple, economical, and evidence based strategies specifically designed to care for acutely poisoned patients in resource limited environments.26,32
++
++
Envenomation by snakes and other animals represents another significant cause of morbidity and mortality in the developing world. Few countries mandate the reporting of animal bites, making it difficult to estimate global incidence, severity, and outcome. Current data estimates that about 20,000 to 94,000 deaths occur globally each year from snakebite.97 The vast majority of deaths and serious envenomations occur in the developing world, with less than 100 snakebite deaths per year estimated to occur in Europe, the United States, Canada, and Australia combined.42,97
++
Because most rural people in the developing world may first consult traditional healers, hospital based studies of mortality and morbidity associated with snakebites likely underestimate the scope of the problem.42,150 For example, a study of rural Philippine rice farmers found that only 8% of cobra (Naja philippinensis) bite victims reached a hospital in the 1980s.170 However, changes in treatment seeking can occur. Studies over the last decade in Sri Lanka have shown that patients have started going to the hospital rapidly after common krait (Bungarus caeruleus) snakebite, bypassing traditional healers.103 A study in Ghana found that the incidence of snakebite victims at a district hospital increased significantly after the introduction of a new treatment protocol, possibly reflecting increased confidence in the ability of the health care system to manage these cases.168
++
Snakebites are most commonly occupational hazards in the rural tropics. Victims are just as likely to be women as men, reflecting rural farming practices. Working in large plantations and subsistence farms places rural people in frequent contact with venomous snakes. With simultaneous changes in global climate and expansion of human settlements, it is likely that the range of venomous snakes will enlarge to include urban areas and regions previously considered too temperate to support them.82,121 Snakebites from members of the Elapidae and Viperidae families are responsible for the majority of deaths worldwide, although several other families are also medically important (Colubridae and Atractaspididae species, in particular; Chap. 122 and Special Considerations: SC8).169,172
++
The burden of snake envenomation on local resources can be substantial. During the rainy season in Benin, snakebites account for up to 20% of all hospital admissions, with an estimated case fatality rate of 3% to 6%.43 In this region, the annual incidence of snake envenomation ranges from 200 to 100,000 in rural villagers to 1300 to 100,000 in sugar cane plantation workers.43 One study conducted in Nigeria in the late 1970s noted an incidence of 497 per 100,000 and a 12% case fatality (primarily due to envenomation by the carpet viper, Echis occelatus).136
++
After snakebites, the second most common cause of mortality and morbidity from venomous animals is scorpion stings88,169 (Chap. 118). Medically important scorpion species are widely distributed throughout the tropics, being particularly common causes of morbidity in North Africa, Mexico, India, and Brazil.44 The total number of medically significant scorpion stings that occurs annually is unknown; a recent review estimated 1.2 million stings, leading to more than 3250 deaths (case fatality 0.27%).44 Other venomous insects, such as Arachnida (spiders) and Hymenoptera (bees, ants, and wasps), are rarely sources of significant mortality on a global scale88 (Chap. 118).
+++
Herbal and Traditional Medicines
++
The use of traditional medicine (TM) to treat or prevent health problems is widespread. The WHO estimates that around 80% of the world’s population consults traditional healers regularly.177 Frequently cited reasons for this preference or reliance on TM include financial considerations, sociocultural preferences, beliefs about the relative safety and efficacy of TM compared to allopathic medicines, and mistrust or relative inaccessibility of doctors.86,128 Traditional practitioners still greatly outnumber medical professionals in many regions. For example, in 2004 there was one traditional healer but only 0.04 physicians per 500 inhabitants in Mali.71
++
Although TM also encompasses a variety of spiritual, religious, or physical manipulation therapies, it often includes administration of “herbal” remedies (muti) either orally or via enema. These are typically prepared using a combination of aqueous plant materials, sometimes mixed with insect or other animal parts, metallic salts, or both. While traditional medicinal preparations have usually been tested by generations of practitioners and the concentrations of active ingredients are generally low, both intentional and unintentional poisonings are common.38,94,153,157 In a 2-year retrospective review of acutely poisoned patients from South Africa, TM was the second most common cause of admission (15.8% of cases) and had the highest mortality rate (15.2%), accounting for over half of all deaths in the series.167 TM was the most common cause of admission (23% of cases) for acute poisoning in another 10-year retrospective review of cases from Zimbabwe, with a 6% mortality rate.95
++
The specific chemical constituents responsible for TM poisoning may vary widely between geographic and cultural areas. Laboratory analysis and ethnopharmacologic surveys in a number of countries have begun to elucidate some of the chemical constituents of commonly prescribed recipes. Interestingly, a review of 41 autopsies in South Africa for which the causative agent was presumed to be an herbal medicine found that cardiac glycosides were present in 44% of cases.109 Adulterants are also implicated in poisoning from TM formulations. For example, these are common in traditional Ayurvedic medicines (particularly heavy metals63 and corticosteroids75) and Asian medicines (particularly synthetic pharmaceuticals and heavy metals36 Chap. 45). A Taiwanese study of 2609 samples found that 23% were adulterated with pharmaceutical products such as caffeine, NSAIDs, acetaminophen, and diuretics.84
++
In many lower income countries, pharmaceuticals are relatively uncommon causes of acute poisoning. However, the incidence appears to be rising in conjunction with larger global demographic shifts toward increased urbanization and industrialization. Access to a wider array of medications is relatively greater among urban dwellers than in rural ones, and more people in urban communities may have the financial means to buy them. In a retrospective review of poisoning cases admitted to urban versus rural health centers in Zimbabwe, poisoning with pharmaceuticals was uniquely seen at the urban facilities, accounting for more than 15% of poisoning cases at regional hospitals surveyed and none of the cases presenting for care at the district level.156 The relative importance of pharmaceuticals in global poisoning trends is likely to continue over the next decades as the number of therapeutic drugs available for use in lower income countries expands, and more and more societies shift toward a “dual burden of disease” pattern, including chronic illnesses that require long-term drug therapy.21,120
++
The pharmacopeia available in low-income countries is often more restricted than in higher income countries, and this is reflected in the types of medications implicated in acute poisoning cases. The most common xenobiotics seen in the developing world are those used to treat tropical diseases. For example, self-poisoning with the antimalarial chloroquine (Chap. 59) has been widely reported in Sub-Saharan Africa,20,27,116,137 although this medication is now rarely used so the incidence may soon decrease. Intentional and unintentional poisoning with the leprosy drug dapsone, as well as the tuberculosis drug isoniazid (Chap. 58), are also well reported.132,158,159,165
++
Criminal poisoning of commuters to facilitate robbery is a common problem across South Asia.89,117,133 In the 1970s and 1980s, drinks containing extracts of Datura stramonium were given to unsuspecting commuters, resulting in anticholinergic poisoning.98 Practice has changed recently and benzodiazepines are now more commonly given for this purpose.108 As many as 300 people are admitted unconscious with this problem to a single university medical unit in Dhaka each year.108
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A more general issue of toxicologic concern is the prevalence of poor-quality medicines in use worldwide. Although data estimating the extent of the problem and its impact on health are limited, recent estimates suggest that more than one-third of all medicines on sale in Southeast Asia and Sub-Saharan Africa are substandard or counterfeit.23,118,119 The major problem with these medications is an absence or subtherapeutic concentration of active ingredient, leading to treatment failures and an increase in drug-resistant pathogens where antimicrobials are involved. However, substandard medications may sometimes contain more active ingredient than stated, leading to adverse drug effects,161 or contain harmful adulterants or contaminants.
++
Epidemic poisonings from such poor quality medicines underscore the dangers of inadequate regulation and oversight of pharmaceutical manufacture and sales. Recent examples include the deaths of more than 120 patients in Karachi from exposure to a batch of isosorbide mononitrate contaminated with pyrimethamine,15 the hospitalization of more than 50,000 infants in China with melamine poisoning from adulterated formula,87 and the numerous epidemics of diethylene glycol poisoning in multiple countries over the past few decades from contaminated glycerine, paracetamol syrups, cough syrups, toothpastes, teething mixtures, and other medications.22,79,125,127,140,148
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Household Products and Chemicals
++
Poisoning with common household products, such as fuels, cleansing products, rat poisons, insecticides, body care products, and cosmetics, is a global problem. This general category of diverse xenobiotics is consistently implicated as a significant source of unintentional childhood poisoning worldwide. The PC movement that began in the 1950s in North America grew out of an increasing recognition of the child health risks associated with exploratory household poison ingestions. Household chemicals are a similarly well recognized risk for unintentional childhood poisoning in Sub-Saharan Africa, accounting for up to 80% of all pediatric admissions for poisoning.21,41,45,96,126 Internationally, the specific risks are remarkably consistent, including age younger than 6 years (with toddlers younger than 3 years of age most affected), male sex, low socioeconomic status, and unsafe storage practices in the home.
++
Among specific household products, hydrocarbon poisoning from unintentional ingestion of kerosene (paraffin) is widely reported as the most common cause of pediatric admissions in low-income countries around the world.41,45,96,102,173 Kerosene is a common fuel used to power stoves and lamps in many relatively poor communities. It is pale in color with an appearance similar to water, and it is often purchased or stored in used beverage containers making it easy to misidentify (Chap. 108).62 In Sub-Saharan Africa, kerosene poisoning accounts for some 25% to 75% of all poisoning-related hospital visits among children younger than 6 years of age.122 Several studies document an increase in poisoning related admissions during the warmer months of the year, when children are more likely to become thirsty and to drink from any beverage container at hand.101,102
++
Caustics are another group of household products frequently implicated in poisoning in the developing world. The common form of caustic ingested varies between countries. In many countries, alkaline substances are most frequently implicated, whereas in others, such as Taiwan and Morocco, poisoning with hydrochloric or sulfuric acids may be more common.3,105,154,180 Acute poisoning carries substantial mortality risk, usually more than 10%. If the acute phase of caustic poisoning is survived, there also is a high rate of delayed complications, primarily esophageal strictures. Delayed complications may require surgical intervention, balloon dilatation of the esophagus (bougienage), or feeding tube placement. These treatments are expensive, require significant hospital resources, and have inherent morbidity and mortality (Chap. 106).
++
As with other categories of poison, patterns of self-harm using domestic products tend to demonstrate regional particularities. For example, in Hong Kong there is significant morbidity reported in association with self-poisoning using common household detergent products such as dettol (4.8% chloroxylenol, pine oil, and isopropyl alcohol) and savlon (cetrimide).34,37,39,46 Frequent use of potassium permanganate for self-harm has also been reported from Hong Kong.129,181 Fatal poisoning with hair dye (paraphenylenediamine) is known in the Middle East and North Africa.29,61,80,151 Barium sulfide, arsenic sulfide, and calcium oxide are contained in hair removal preparations146; poisoning from ingestion of these preparations has been reported from India and Iran.4 Rubigine is a domestic cleansing product containing hydrofluoric acid and ammonium difluoride that is used for self-harm in the Caribbean,85 while ingestion of sodium hydroxide is common in Malaysia.19
++
Poisonous plants have been used therapeutically to induce abortion, for recreational intoxication, in homicidal acts, and for self-harm throughout human history (Chap. 121). This section briefly mentions select toxic plants that are most commonly used in self-poisoning, or that have caused epidemic poisoning in the developing world.
++
Self-poisoning with seeds of two plants containing cardioactive steroids are important clinical problems in Asia. Yellow oleander (Thevetia peruviana) kills hundreds of people each year in Sri Lanka and India28,57 (Chap. 65). Sea mango (Cerbera manghas) has killed hundreds of people in Kerala, India,68 and is a focal problem in eastern Sri Lanka.58 Oduvan (Cleistanthus collinus) leaf contains the glycosides cleistanthin A and B, which produce severe hypokalemia and cardiac dysrhythmias.13 Self-poisoning has killed hundreds of people in Tamil Nadu, India.12,155 The superb lily (Gloriosa superba) contains colchicine alkaloids and has also been used for self harm in South Asia5,9,111 (Chap. 36).
++
Ackee tree fruit (Blighia sapida), which contains hypoglycin when unripe, is widely consumed as a food source. Epidemics of fatal poisoning with unripe Ackee fruit have occurred throughout the Caribbean and in Africa.64,92,110,112 Poisoning by castor beans (Ricinus communis) or other lectin containing plants such as Jatropha spp (African purging nut) is well reported from Africa and South Asia1,65,78,93 (Chap. 121).
++
Numerous plant species contain atropine like alkaloids, causing an anticholinergic syndrome when ingested. Reports of intentional ingestion of Datura species have been reported from Africa, Asia, and Latin America.78,143,152 Most commonly, the seeds are ingested as a recreational drug for their hallucinatory effects,67,138 or as part of traditional medical preparations.35
+++
Occupational and Environmental Sources
++
Poisoning from occupational and environmental sources is a significant global health problem, with disproportionate effects on persons living in lower income communities around the world. Exposure to “traditional” environmental health hazards, such as indoor air pollution from the combustion of solid fuels, and naturally occurring contaminants in groundwater, soil, and food, is still a major cause of morbidity and mortality in much of the world. Around 50% of the world’s people rely on solid fuels such as coal, dung, wood, or crop residues for cooking and heating.31 Resultant indoor air pollution was estimated to cause 1,965,000 deaths and 41,009,000 DALYs from lower respiratory tract infections, cancers, and COPD in 2004.178 In Bangladesh, arsenic contaminated groundwater contributed to 9100 deaths and 125,000 DALYs in 2001.107 Dental and skeletal fluorosis from excessive fluoride in drinking water is endemic in at least 17 countries worldwide.66
++
Increasingly, modern environmental health hazards (MEHHs) also play a large role in global poisoning risks.49,124 MEHHs include outdoor air pollution from automobiles and factories, soil and water contamination by plastics, heavy metals, pesticides and other industrial chemicals and wastes, radiation hazards, land degradation, and climate change produced by rapid urbanization and industrial development in the absence of strong regulatory controls.49 These are important sources of both occupational and environmental exposure to a wide range of toxins with acute and chronic health effects. Inadequate safeguards to control the selection, sale, and application of pesticides in parts of Africa and Asia are linked to pesticide poisoning both as an occupational hazard53,91 and from residues left on food.11,48,123 Occupational lead poisoning has largely been controlled in developed countries through improved working conditions and occupational health screens, but remains an enormous problem in developing countries where occupational and environmental health protection measures are often underdeveloped or practically nonexistent.164,171
++
Industrial factories are often placed in urban areas, or the areas around factories are rapidly urbanized, placing large numbers of people at risk not only from pollution but from industrial errors as well. The 1984 Bhopal tragedy in which a Union Carbide pesticide plant malfunctioned, releasing isocyanate gas into the surrounding community and causing an estimated 3787 deaths and 558,125 injuries, is emblematic of such disasters.14,145
++
Several international agreements on chemical safety provide legal frameworks to mitigate the human and environmental impact of global industrialization; however, the actual implementation of regulatory controls has lagged behind the expansion of toxic exposures. For example, at the level governance a total of 39 Sub-Saharan African countries have ratified the Rotterdam Convention on chemical safety. Yet industrial pollution is now becoming so highly concentrated in growing urban areas that the continent’s pollution intensity (pollution generated per unit of production output) is now rated among the world’s highest, attesting to significant regional difficulties in enforcing such regulations.166
++
The predominance of informal sector activity in agricultural and industrial work in lower income countries poses serious regulatory challenges. Fumes and dusts from small-scale domestic businesses involved in smelting, battery recycling or manufacture, welding, pottery, ceramic production, and artisanal mining are common sources of exposure to lead and other heavy metals in developing countries, and put not only workers but whole communities at risk.164 More recently, unregulated electronic waste (e-waste) recycling, in which salable metals are reclaimed from old electronics by burning, has emerged as a significant human and environmental health hazard in parts of China, West Africa, and India.7,104,160 Workers are often aware of the health risks, yet economic hardship and lack of alternative employment make them unwilling or unable to change.
++
Easy access to industrial chemicals from inadequate regulation of packaging and sales may also facilitate their use for intentional self-harm. For example, formic and acetic acids are used in the manufacture of rubber, and case series are reported from areas surrounding rubber factories in India and Sri Lanka.139 Copper sulfate is widely used for self-poisoning in parts of South Asia, and carries a high mortality rate due to direct damage to the gastrointestinal tract, hepatorenal failure, and hemolysis6,144 (Chap. 95). Cyanide has become a commonly used method in Korea over the last 20 years106 (Chap. 126).
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REDUCING THE GLOBAL IMPACT OF POISONING
++
Regulatory science and the coordinated actions of agencies and programs across multiple sectors play a vital role in preventing or reducing the impact of poisoning in society. Within the health sector, significant inter- and intraregional disparities in access to health care have a major impact on poisoning outcomes. Lack of human resources to provide acute care is an enormous problem in many parts of the developing world. In Mozambique, there is only one trained medical doctor for every 33,000 individuals, compared with 1 in 390 persons in the United States. Tanzania has a nurse to population ratio of 1:2700 individuals compared with 1:107 individuals in the United States. Policies and programs encouraging sustainable and equitable health workforce development are needed foundation to improve health care access globally.50
++
Beyond rectifying the raw numbers deficit, clinical training programs in many low and middle income countries must be upgraded to promote broad exposure and specialist development in clinical toxicology and acute care. Increasing local and international commitment to the growth of emergency medicine in low- and middle-income countries promises to support the dissemination of scientific knowledge and improve provider competence in advanced resuscitation techniques.8,16,70 Significant gaps in infrastructure and resources to provide basic critical care interventions and meet WHO minimum standards for essential emergency supplies must also be addressed.17,18,83
++
In addition to global disparities in acute care infrastructure generally, access to antidotes for specific poisons is either lacking or inadequate in much of the world.10,131,176 Poor antidote availability is not unique to the developing world,51 and many antidotes may be considered either adjunctive or unnecessary therapies. However, in certain cases they can significantly reduce the need for other medical interventions, and this may be particularly important in rural or underdeveloped areas where critical care facilities are not readily available.134 For example, the most important challenge to improving the treatment of patients with snakebite worldwide is poor antivenom availability, particularly in rural areas where it is most needed to reduce critical delays in administration.162,163 Currently, many available antivenoms are prohibitively expensive, ineffective, or have a high rate of adverse reactions. Equally important, some antivenoms must be refrigerated, making storage impractical in many rural areas where the need is most acute. Critical evaluation of existing antivenoms and development of new products are thus desperately needed24,30,76,77,105,162,163,172,175 (Special Considerations: SC8).
++
Where antidotes are available, knowledge and experience to know how to use them safely and effectively is often lacking.32 Input from experts in medical toxicology improves outcomes, reduces hospital stays and health care costs associated with acute poisoning,33,47,69 but practitioners in many parts of the world have limited or no access to consultation with such specialists. The mission of the International Union of Toxicology is to foster international scientific cooperation, ensure the development of toxicologists, and promote the dissemination of knowledge in toxicology worldwide.55 Through the collaborative efforts of this and other regional professional societies, an increasing number of online, regional, and international forums now offer educational and professional development opportunities in clinical toxicology around the globe. More work is needed to promote awareness and the growth of the specialty in all regions.
++
Improving health care access and health system preparedness is only one aspect of the coordinated, multilevel, national, and international public health responses needed to reduce the global impact of poisoning. Prevention and risk reduction efforts must involve locally appropriate community level education and awareness raising, strong governance to support the design, implementation, and monitoring of regulatory controls, and the involvement of multiple stakeholders and sectors including water, waste management, energy, agriculture, transportation, industry, and civil society. Effective legislative frameworks developed in countries with more advanced public health infrastructure have been successfully disseminated in some cases. For example, between 2000 and 2004 the proportion of people with blood lead concentrations above 10 μg/dL globally decreased from 20% to 14%, largely due to the widespread phase out of leaded gasoline.135 Other strategies, such as pharmaceutical and food safety regulations enacted through the US Food and Drug Administration, have influenced “duplicative legislation” in other countries but continue to pose significant implementation challenges in low and middle income countries that lack the necessary financing, human resources, and infrastructure to enforce them well.130
++
Many public health measures with proven efficacy, such as routine lead testing during childhood, the regulation of vehicle emissions, the detection of carbon monoxide, and the incorporation of childproof containers may seem prohibitively resource intensive in many parts of the world. The development of new, low-cost technologies such as solar heating and electrical sources, chemical assays and residue detectors, and electronic devices to identify and track pharmaceuticals hold some promise to reduce global risks for unintentional poisoning. More research is needed to propose and evaluate the effectiveness, acceptability, and sustainability of new and proven poison prevention techniques in resource-limited environments.
++
Recognizing that self-harm from pesticide ingestion is responsible for a majority of acute poisoning deaths worldwide, public health interventions specifically designed to limit access are an important goal. A minimum pesticide list, based on the WHO essential xenobiotic list initiative, has been proposed.59 Such a list would provide policy makers and farmers with unbiased information about relative risks. However, voluntary initiatives such as international policy statements and industry sponsored programs often suffer from a lack of resources, a shortage of political will, and nonexistent enforcement mechanisms.100,115 A dramatic illustration of an effective national program to reduce pesticide poisoning risks is the ban of all WHO high-risk OP insecticides and the organic chlorine endosulfan in Sri Lanka, which effectively arrested a previously exponential increase in the incidence of pesticide poisoning and halved the national suicide rate between 1995 and 2005.73 This program is estimated to have saved more than 20,000 lives in 10 years.73
++
Ironically, some programs to remove the most environmentally persistent and toxic chemicals from use have inadvertently replaced them with agents highly toxic to humans. The replacement of persistent organic chlorine compounds with carbamates in malaria control programs is an example. The opposite effect has also occurred, for example, by replacing OP insecticides with pyrethroids to reduce human toxicity.100 Coordinated pesticide harm reduction strategies should take into account concerns regarding both environmental and human toxicity, and anticipate which xenobiotics will enter into use as replacements as specific chemicals are phased out.141 A strategy based on industrial hygiene models of a hierarchy of controls has been proposed by several authors115,141
++
++
++
Poisoning is a common worldwide. Fatal poisoning is disproportionately concentrated in lower and middle income countries, where public health systems and acute care resources to detect, manage, prevent, and collect data on poisoning are often less well developed.
Global poisoning estimates are mostly derived from health care sources in a minority of developing world countries; current data may underrepresent the true burden and distribution of injuries from poisoning.
Efforts to develop international poisoning surveillance systems and establish harmonized definitions of poisoning cases will help generate a more complete picture to inform local, national, and international policies and interventions.
Pesticides are the most important cause of death from acute poisoning worldwide, with a majority of cases attributable to acts of deliberate self harm.
Improving access to health care and health system preparedness to provide acute care is essential to reduce global disparities in poisoning outcomes.
Randomized controlled trials and cost effectiveness research are needed to critically evaluate the utility of specific public health and treatment interventions in resource limited settings.
++
Michael Eddleston, MD, and Aaron Hexdall, MD, contributed to this chapter in previous editions.
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++
Principles of Epidemiology and Research Design
++
Advances in medical toxicology are achieved through the scientific method using observations, derived from cases of poisoning and nonpoisoning due to xenobiotic exposures, to generate hypotheses. Subsequent research questions are analyzed with epidemiological investigation, and preliminary studies are examined with methodological scrutiny. Initial analytical techniques are improved, and confirmatory studies are performed. Ultimately, models relating cause to effect are formulated.
++
To optimize patient care, it is useful to grade the quality of available scientific evidence used to justify treatment recommendations. Decisions about how strongly to recommend a medical action will be based on the careful consideration of the risks of leaving a patient untreated, the potential benefits and harms of treatment, the quality of the guiding evidence, a balanced view of resource utilization, and the values of the person to be treated. The Grading of Recommendations Assessment, Development, and Evaluation (GRADE) Working Group has provided a framework for assessing and communicating levels of scientific evidence (Table 138–1).22 An understanding of basic principles of research design and epidemiology is required to interpret published studies and to lay the groundwork for future investigation in toxicology.
++
+++
EPIDEMIOLOGIC TECHNIQUES AVAILABLE TO INVESTIGATE CLINICAL PROBLEMS
++
Table 138–2 lists the different study formats discussed below.
++
+++
Observational Design: Descriptive
++
A staggering array of xenobiotics are able to injure people, necessitating reliance of toxicologists on good descriptive data regarding toxic outcomes. Through 2011, the National Poison Data System (NPDS) of the American Association of Poison Control Centers (AAPCC) has amassed a database of more than 50 million human exposures (Chap. 136). Descriptive case reporting serves a valuable purpose in describing the characteristics of a medical condition or procedure and remains a fundamental tool of epidemiological investigation. A case report is a clinical description of a single patient or procedure in a unique context. Case reports are most useful for hypothesis generation. However, single case reports are not always generalizable, as the reported situation may be atypical. A number of case reports can be grouped on the basis of similarities into a case series. Case series can be used to characterize an illness or syndrome, but without a control group they are severely limited in proving cause and effect. In 1966, a case series of two patients with acute liver necrosis following overdose of acetaminophen (APAP)12 was accompanied by a case report of liver damage and impaired glucose tolerance after APAP overdose,40 which led to further study and the eventual creation of the Rumack-Matthew nomogram (Chap. 35). Similarly, a 1979 case report of “hypertension and cerebral hemorrhage after trimolets ingestion”24 led to subsequent animal studies, experimental human studies, and epidemiologic studies culminating in the decision by the US Food and Drug administration to remove phenylpropanolamine from nonprescription cold remedies and appetite suppressants (Chap. 42). The important role for descriptive data in guiding clinical research, focusing educational efforts, and formulating public policy are often underappreciated.
++
Cross-sectional studies assess a population for the presence or absence of an exposure and condition simultaneously. Such data often provide estimates of prevalence—the fraction of individuals in a population sharing a characteristic or condition at a point in time. These studies are particularly helpful in public health planning and have been extremely useful in monitoring common environmental exposures, such as childhood lead poisoning, or population-wide drug use, such as occurs with tobacco, marijuana, and alcohol. The US National Health and Nutrition Examination Survey demonstrated that the percentage of children with blood lead concentration greater than 10 μg/dL decreased from 88.2% to 4.4% between 1976 and 1991, with the highest rates of plumbism among African American, low-income, or urban children.5
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An analysis of secular trend is a study type that compares changes in illness over time or geography to changes in risk factors (ecological). These analyses often lend circumstantial support to a hypothesis; however, because of the ecologic nature of their design, individual data on risk factors are not available to allow exclusion of alternative hypotheses also consistent with the data. A prime example of an analysis of secular trends is the finding that reports of Reye syndrome declined between 1980 and 1985, coincident with a fall in sales of, or physician recommendations of, children’s salicylate products.4 This investigation suggested an etiologic role of salicylate in the development of Reye syndrome but could not exclude alternative hypotheses such as a change in viral epidemic patterns.
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Observational Design: Analytical
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Hypotheses that are generated by theoretical reasoning or anecdotal association require analytical testing. Case-control studies and cohort studies are analytical techniques that use observational data, and each technique has its own advantages and disadvantages (Table 138–2). Case-control studies compare affected, treated, or diseased patients (cases) to nonaffected patients (controls) and evaluate for a difference in prior risk factors or exposures (Fig. 138–1A). Because participants are recruited into the study based on prior presence or absence of a particular outcome, case-control studies are always retrospective in nature. They are especially useful when the outcome being studied is rare, and they enable the investigation of any number of potential etiologies for a single disease.
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The hypothesis, derived from multiple case reports and case series, that phenylpropanolamine might increase risk for hemorrhagic stroke was well suited to case-control study. Exposure to ingested phenylpropanolamine, as an ingredient in cold remedies and appetite suppressants, was common; but hemorrhagic stroke is rare among children and young adults. Other putative risk factors such as tobacco use, hypertension history, family history, cocaine use, and contraceptive use were identifiable and could be studied simultaneously. In a case-control analysis of 702 participants with hemorrhagic stroke and 1376 controls, the use of appetite-suppressant doses of phenylpropanolamine were found to be independently associated with the occurrence of hemorrhagic stroke.23
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Cohort studies compare patients with certain risk factors or exposures to those patients without the exposure, and then follow these cohorts to see which participants develop the outcome of interest (Fig. 138–1B). In this respect, they allow the comparison of incidence (the number of new outcomes occurring within a population initially free of disease over a period of time) between populations who share an exposure and populations who do not. They may be retrospective or prospective and enable the study of any number of outcomes from a single exposure. They are particularly well suited to investigations in which the outcome of interest is relatively common. In circumstances when an outcome of interest is very uncommon, such as the case with stroke after phenylpropanolamine use, the large number of study participants required might make a cohort study impractical. A cohort of 981 APAP overdose participants was used retrospectively to investigate whether administration of activated charcoal might be beneficial therapy for APAP poisoning.8 Participants were separated on the basis of whether or not they were treated with activated charcoal and were subsequently followed to see if they developed concentrations deemed toxic by the Rumack-Matthew nomogram. Perhaps the most famous cohort study was the Framingham Heart Study in which 5209 residents of Framingham, MA, aged 30 to 62 years, were followed for over 50 years. This study provided a useful tool for studying the incidence of lung cancer, stroke, and cardiovascular disease in those exposed to cigarette smoke and other hazardous xenobiotics.13
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Experimental studies are those in which the treatment, risk factor, or exposure of interest can be controlled by the investigator to study differences in outcome between the groups (Fig. 138–2). The prototype is the randomized, blinded, controlled clinical trial. Among epidemiologic study types, these provide the most convincing demonstration of causality. Clinical trials are used to measure the efficacy (the treatment effect within a controlled experimental setting) of treatment regimens and to draw inferences about the effectiveness of a treatment applied to the general population. Sometimes a trial can be designed to study drug treatments that are hampered by nonresponders to therapy, expensive drugs, or poorly tolerated regimens. Such trials are termed noninferiority trials, and operate on the null hypothesis that the new (study) drug is worse than the control (standard) drug. Thus, finding a difference between groups in a noninferiority trial means that the alternative hypothesis can be accepted that the new drug is not worse than the standard treatment.
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Unfortunately, interventional studies are the most complex to perform, and several questions must be addressed by investigators before performing a clinical trial (Table 138–3). Human clinical trials have been especially difficult to apply to the practice of toxicology. Table 138–4 lists characteristics of poisoned patients, which hamper attempts at clinical trials. Volunteer studies, using nontoxic xenobiotics or nontoxic doses of toxic xenobiotics, are often used to circumvent many of the problems in controlling human poisoning studies; but it is typically difficult to apply results from these studies to the actual context of toxic overdoses. In an experimental, human volunteer study, activated charcoal reduced absorption of ampicillin by 57%.39 Taken out of this artificial setting, a trial of single-dose oral activated charcoal was unable to prove benefit to outcome among 1479 heterogenous participants presenting to an emergency department (ED) for possible poisoning.29 Neither study was able to answer whether activated charcoal reduces morbidity from ingestion of dangerous xenobiotics if given while the xenobiotic is still in the stomach and amenable to adsorption.
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As toxicologists strive to find evidence for, or against, the traditions of clinical practice, several important clinical trials have been published. Among them are many important examples and lessons in epidemiologic study design. One trial attempted to evaluate whether or not corticosteroids might be beneficial in preventing esophageal strictures secondary to circumferential caustic injury of the esophagus.3 Because of the inherent difficulty in recruiting eligible patients from a single institution, only a small sample of 60 patients with esophageal injury were recruited over an 18-year period. Another study randomized hyperbaric oxygen therapy versus sham (placebo) therapy, among 152 victims of carbon monoxide poisoning, to investigate its effect on the development of neurocognitive injury.42 Certain concerns with the methodology and analyses of clinical studies are examined later in this chapter to illustrate epidemiologic concepts, and must be carefully considered when trying to apply the results of any clinical trial into the patient care setting.
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MEASURES USED TO QUANTIFY THE STRENGTH OF AN EPIDEMIOLOGIC ASSOCIATION
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The objective of analytical studies is to define and quantify the degree of statistical dependence between an exposure and an outcome. Such associations are ideally represented by the relative risk of developing an outcome if exposed in comparison to being unexposed. Thus, the relative risk can be defined as the incidence of outcome in exposed individuals compared to the incidence of outcome in unexposed individuals. The relative risk can be calculated directly from cohort or interventional studies. However, in a case-control study, an investigator chooses the numbers of cases and controls to be studied, so true incidence data are not obtained. In case-control studies an odds ratio can be calculated, and the odds ratio will provide an estimate for relative risk in situations in which the outcome is rare, such as when the outcome occurs in fewer than 10% of exposed individuals. Figure 138–3 demonstrates the calculation of relative risk or odds ratio from analytic studies.
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A relative risk of 1.0 signifies that an outcome is equally likely to occur whether an individual either is exposed or is not exposed and implies that no association exists between the exposure and the outcome. A relative risk approaching 0 suggests that an exposure is a marker of protection regarding the outcome, and a relative risk approaching infinity suggests the exposure predicts a tendency toward the outcome. Among men and women using phenylpropanolamine appetite suppressants, the odds ratio for development of hemorrhagic stroke was 15.9 which suggests a strong association.23
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MEASURES USED TO QUANTIFY THE SIGNIFICANCE OF AN EPIDEMIOLOGIC ASSOCIATION
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One of the essential features of research in medical toxicology is integration of the available data, whether clinical or experimental, into logical assumptions about how the overall system functions. Systems that are studied in medical toxicology research typically involve either elucidation of how a toxic insult influences normal physiology, or the mechanism and degree to which an antidote mitigates toxicity. Prior to undertaking a study, medical toxicology investigators may have no way of knowing whether their hypothesis is correct or applies at all. Thus, predictions made based on a priori hypotheses may be tested by performing experiments or by sampling observed data in an organized fashion. If the results are consistent with the predictions, then the hypothesis is retained. If they are not, then the prior hypothesis is rejected and a new hypothesis is formulated. This process is the basis of the scientific method and is also known as hypothesis testing.
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Determination of whether the observed data in a toxicology investigation allow us to retain or refute our a priori hypothesis depends on our ability to gauge the certainty that the data were arrived at by chance. When observing a set of data, investigators can never be 100% certain that what they observed actually happened; it is possible that confounding factors biased what was observed, and it is possible that the observation was made simply by chance. To deal with this problem of interpretation, researchers use statistical methods to evaluate whether their data were arrived at by chance. The presence of an association between two factors in any given study has a number of possible explanations (Table 138–5).
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To differentiate between differences due to chance and potentially real differences between comparison groups, researchers can use a philosophical trick known as the null hypothesis. The null hypothesis involves beginning experiments with the assumption that there is no difference between groups being compared. Thus, any significant deviation from observed and expected results under the null hypothesis allows the investigator to reject the null hypothesis and adopt the alternative hypothesis. The alternative hypothesis to the null is that the groups being compared are significantly different from one another (ie, not the same).
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To begin, one must assign a probability percentage or P value to the likelihood that their observed results are really the case assuming the null hypothesis to be true. With some exceptions, the standard P value deemed to represent ability to reject the null hypothesis has historically been set to 5% (or P<.05) in medical toxicology epidemiologic science. This value is also termed the alpha (α), the significance level, the type 1 error, and can also be thought of in layman terms as the chance of falsely finding a difference between groups when one does not exist.
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Because analytic studies involve only a sample of the total population, they contain two types of inherent error. Type 1 error, also referred to as an alpha (α) error, is the likelihood that an investigator may conclude that an association exists when none truly does. Type 2 error, or a beta (β) error, is the possibility that an investigator will be unable to find an association when one is really present. The most commonly reported measures of type 1 error in published toxicology studies are the P value and the confidence interval (CI). Statistical significance has customarily, but not necessarily, been defined as having less than a one in 20 chance of conducting a false-positive study. Therefore, a type 1 error of less than 5%, which corresponds to a P value of less than 0.05, is usually deemed “statistically significant.” In some cases investigators must use a significance level (P value) even lower than 0.05 when testing multiple hypotheses at once, for example, in genetic marker studies examining multiple genes across an entire genome. Such a correction is termed the Bonferroni correction, and is applied as the P value divided by the number of variables being tested at once: P= (significance level)/(# concurrent variables).37 The result is a smaller (ie, more stringent) corrected significance level for studies that test multiple hypotheses at once. For example, if a study protocol uses a genetic “chip” assay to evaluate 50 markers at once for an association with a predetermined disease in a population, the Bonferroni correction would require significance at (0.05)/(50) = 0.001 in order to deem any association to be statistically significant.
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Perhaps a more informative description of the significance of an association is provided through the CI. The CI not only provides a test of statistical significance, it also offers information pertaining to the degree (and possible range) of differences observed. In an unbiased study, the 95% CI provides a range between which, if the study could be repeated an infinite number of times, the observed point estimate would fall between the CI 95% of the time. For example, one study reported that no toddlers ingesting one or two calcium channel blocker tablets became seriously ill, but a subsequent analysis of the CI around this small set of data demonstrated that the true incidence could be as high as 18%.32 A CI around a relative risk or odds ratio is not statistically significant if it includes 1.0, and the narrower the CI the more precise the estimate of the magnitude of effect.
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The likelihood that a study will find a difference if one truly exists is termed statistical power and relates to the likelihood of a false-negative study (type 2 error). Power is usually artificially set by an investigator before a study is performed and is typically set at 80% or 90% to practically limit the number of study participants needed. Table 138–6 lists considerations applicable to choice of sample size. The sample size of a study is determined by the frequency of the exposure and outcome within the study population, the strength of association deemed clinically relevant, and the amount of error deemed acceptable in the study. Because power is often set relatively low, it is difficult to state that an association does not exist. It is more appropriate to state that a study was unable to reject the null hypothesis to find an association.
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The finding of a low P value indicates a statistically high level of confidence that a difference between study groups exists but offers no indication that the difference is clinically important. The interpretation of statistical versus clinical significance is often facilitated through calculation of CIs. Small actual differences between two groups can become statistically significant if large numbers of participants are studied. Likewise, impressive associations of cause and effect can seem trivial if few participants are in a study. The clinical significance of an association is left to the judgment of the individual interpreting a study. Ideally, a working definition of clinical significance is developed before a study is performed.
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METHODOLOGIC PROBLEMS FOUND WITHIN CLINICAL STUDIES
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The calculation of a P value or CI does nothing to assess the adequacy of study design. These measures are used to quantify the influence of random error, or chance, on research findings. Clinical research involving patients is particularly susceptible to bias, which can be defined as systematic error in the collection or interpretation of data. Because such error can lead to an inappropriate estimate of the association between an exposure and an outcome, careful evaluation of potential biases affecting a clinical study is of paramount importance.
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Selection bias refers to error introduced into a study by the manner in which participants are selected for inclusion in the study. This type of bias is most problematic for retrospective studies in which exposures and outcomes have both occurred at the time of participant recruitment. Selection bias may be introduced into a prospective clinical study if the study fails to enroll potential participants, or if potential participants refuse to participate, on a systematic basis. Selection bias may even influence the results of clinical trials. In a 1995 trial that found no difference in outcome between acutely poisoned patients treated with gastric emptying and patients from whom gastric emptying was withheld, all patients presenting to the ED after acute overdose were enrolled.35 Because most patients with poisoning exposure are likely to do well with minimal support, selection of patients on this basis might be expected to bias this study to find no effect. Reasoning suggests that the patients most likely to benefit from gastric emptying are those with life-threatening toxic ingestion presenting within the first hour after overdose. Indeed, subgroup review of the results of this paper suggests clinical benefit within this group of patients, but without conclusive power.
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Information bias refers to error introduced into a study as a result of systematic differences in the quality of data obtained between exposed and unexposed groups, or between those with and without the outcome of interest. Several distinct types of information bias may exist. Affected and nonaffected individuals may have differential memories regarding exposures, so recall bias is a concern in retrospective studies. The potential for recall bias may be cited as criticism of retrospective case-control studies of the association between phenylpropanolamine and hemorrhagic stroke, in which patients and families were asked to recollect their phenylpropanolamine use history. Stroke victims and their families might be more vigorous in their recall of exposures than control participants. Similarly, interviewer bias may occur if study personnel differ in how they solicit, record, or interpret information as a result of knowledge of participant status regarding exposures or outcomes.
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Prospective studies may be troubled by loss to follow-up, especially if participants are lost from the study for reasons relating to either exposure or outcome such as when participants withdraw from a study because they are feeling better, or are “lost” because they die. Misclassification bias occurs when investigators incorrectly categorize participants with respect to exposure or outcome. In a retrospective study of 378 children regarding the predictability of caustic esophageal injury from clinical signs and symptoms, it was found that 11 of 80 asymptomatic children had significant burns.14 There is a possibility that these “asymptomatic” children were misclassified because of lack of rigorous written documentation of symptoms or signs within the medical charts. In addition, studies that use “cause of death” as an outcome may be vulnerable to misclassification as well. In a large study comparing 414 poison center (PC) deaths with 7050 poisonings in the corresponding Vital Statistics database, the medical examiner and a medical toxicologist adjudication panel concurred on “cause of death” in only 66%, which the authors interpreted as only fair (ie, less than good) agreement.26 Thus, when investigators define “cause of death” as their study outcome, their results may be biased depending on which specialists are used to provide the “cause of death” interpretation.
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Bias is best minimized through careful study design. It is important to precisely define the study question and the population at risk and to carefully define rigorous inclusion and exclusion criteria. The outcome should also be defined precisely. During data acquisition the best way to reduce bias may be to keep study personnel gathering exposure data blinded to outcome, and vice versa. Often, it may also be advisable to keep study participants unaware of their status within a study to the extent that it is ethical (thus, “double-blinded”—neither investigators nor participants are aware of the participants’ status within a study). Use of placebos or “sham treatments” is a way to facilitate blinding. One of the strongest criticisms of a 1995 trial of HBO for the prevention of delayed neurologic syndromes after CO poisoning36 has been the failure to blind patients and investigators to the treatment in question,31 a flaw that was corrected in a follow-up study published in 2002.42 It is inevitable that some degree of potential bias will be present in any clinical study. Such bias should be reviewed in the analysis, and estimations of its magnitude and direction (bias toward or away from rejection of the null hypothesis) should be considered.
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Unlike selection and information biases, which are errors introduced into studies primarily by the investigators or participants, confounding is a special type of problem that may occur within a study as a result of interrelationships between the exposure of interest and another exposure. Confounding is a bias wherein an observed association is not a product of cause and effect but instead results from linking of the exposure of interest to another associated exposure. Studies pertaining to adverse effects of drugs of abuse are especially prone to confounding by variables such as concomitant caffeine use, alcohol use, tobacco use, nutritional deficiency, and/or psychiatric illness. Analytic studies may restrict characteristics of enrolled participants or match participant characteristics between comparison groups in an effort to reduce confounding. Accordingly, it has been suggested that future studies on delayed neuropsychiatric manifestations following CO poisoning control for potential confounding from depression and cyanide exposure.27 During data analysis, confounding can often be controlled through stratification of data into subgroups or through multivariate analysis techniques.
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Randomization is of central importance in clinical trials. It prevents selection bias and insures against unintended bias. It is also an important method to assure that unsuspected confounding factors are equally distributed between treatment groups within interventional studies. The four common types of randomization include (1) simple, (2) block, (3) stratified, and (4) unequal randomization. The simple method is equivalent to tossing a coin for each participant who enters a trial, such as heads = active, tails = placebo. Generally, a random number generator is used for this type of randomization. Block randomization is often used to guarantee balance in numbers during a clinical trial. The basic idea of block randomization is to divide potential patients into m blocks of size 2n, randomize each block such that n patients are allocated to A and n to B, and then to choose the blocks randomly. Less common is stratified randomization to prevent imbalance in prognostic factors that may confound estimating treatment effect. Stratified randomization achieves balance within important subgroups. For example, using block randomization separately for diabetics and nondiabetics in a cardiovascular trial. And finally, unequal randomization may be used when two or more treatments under evaluation have a cost difference such that it may be more economically efficient to randomize fewer patients to the expensive treatment and more to the cheaper one.
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In order to improve the reporting of clinical trials, and to improve the recognition and interpretation of biases within them, guidelines referred to as the Consensus Standards of Reporting Trials (CONSORT) have been adopted by many medical journals.30 The CONSORT guidelines provide a checklist to allow authors to systematically and uniformly report data and limitations. When interpreting published studies, it is also important to consider the potential for publication bias. Publication bias refers to the tendency for researchers, editors, and pharmaceutical companies to handle the reporting of studies with positive results differently from those with negative or inconclusive results.38 Many journals now require that researchers register all planned clinical trials into a registry as a prerequisite for subsequent publication.
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BIASES INHERENT IN STUDIES USING THE AMERICAN ASSOCIATION OF POISON CONTROL CENTERS DATABASE
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The NPDS database of the AAPCC is an ambitious effort to catalog and describe the epidemiology of poisoning in the United States and Canada. These data serve to help identify new poisoning epidemics, focus prevention and education efforts, guide demographic and economic poisoning analyses, and guide implementation of public health policies. It is a desirable goal to use this database in defining the scope of toxicity for particular xenobiotics and as a clinical research tool. In this regard, it is important to understand the biases inherent in the current database.
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It has been suggested that selection bias might exist within PC data if poisoning is unrecognized as a cause of illness or if a caregiver has no questions pertaining to the management of a recognized poisoning.22 Indeed, a survey of 170 emergency physicians in Utah found that 53% admitted to using a PC for symptomatic acute overdoses, and only 10% contacted PC for the purposes of reporting cases to the national database.10 Such selection might result in a bias of PC data toward more severe cases. On the other end of the spectrum, two large investigations have found selection bias in PC data suggesting that fatal poisonings may be severely underrepresented.19,26 It is interesting to note that in a 2004 report of the Institute of Medicine,21 the estimated range of annual fatal poisonings in the United States was from approximately 1000, derived from AAPCC data, to more than 30,000, derived from other databases. A study of potential spectrum bias in PC utilization found that one ED reported 95% of cyclic antidepressant overdoses, 33% of venomous snakebites, and only 3% of inhalation exposures.17 Further complicating the interpretation of PC data are the findings that such data may also be biased regarding geographic distribution of callers,2 age,34 ethnicity,2,11,34,41 and socioeconomic status.41
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Knowledge of information bias within NPDS data is less well characterized. Phone interviews of callers, many under duress, are certain to be subject to recall and interviewer bias. A comparison of rural hospital chart data to the NPDS database demonstrated deficiencies in PC reporting and in clinical information transfer to the NPDS database.20 Loss to follow-up remains a problem for many PCs, and misclassification of poisonings by health care professionals inadequately trained in medical toxicology remains too common. The clinical conundrum of the unwitnessed ingestion frequently becomes an issue in PC-derived studies designed to create triage policies. Some children having never ingested a xenobiotic of concern may be misclassified as an exposure and may be improperly analyzed.25
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Another potential weakness of PC data involves potential misclassification of substances considered by regional consultants and caregivers. Postmortem toxicology can be a surrogate marker for the accuracy of exposure information reported to PCs in fatal cases. Previously, a putative analysis was undertaken at the New Jersey PC to characterize the discordance between PC consultation and postmortem toxicology.16 The researchers found that in 41 of the 206 (19.9%) fatal cases receiving poison center consultation, substances were found at the time of postmortem examination that were not considered in the poison center consultation. This study highlights the potential for discordance between exposures considered and those confirmed by forensic toxicologists. The reasons for discordance may include a lack of thorough history taking or a cognitive bias to the substances initially reported.
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Despite the large volume of descriptive poisoning data available, it has proven difficult to derive valid, clinically useful conclusions from either the NPDS database or from published case reports.6 One suggested means through which to minimize information bias in descriptive toxicology is through the use of improved data collection charts.7 One large data collection effort underway to address this particular issue is the Toxicology Investigators’ Consortium (ToxIC), supported by the American College of Medical Toxicology, a prospectively collected data registry of patients seen by medical toxicologists at myriad hospitals and medical centers across the United States. Other researchers have found it useful in clinical studies to transform PC data collection from a passive to an active process through the use of specific research instruments.28 Further efforts are required to reduce and to quantify the impact of selection, interviewer, recall, misclassification, and information biases within PC data to optimize the value of this important resource.
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EVIDENTIARY CRITERIA USED TO LINK CAUSE AND EFFECT
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As was illustrated in Table 138–5, association of an exposure to an illness does not necessarily equate to cause and effect. In assessing causation, it must be determined if bias is present in the selection or measurement of exposure or outcome. If a study is unbiased, then the role of chance in the occurrence of the observed association must be explored. If an association is unbiased, unlikely to result from random error, and is not subject to confounding, then assumptions regarding to causation can be derived. Table 138–7 provides a list of evidentiary criteria, first proposed by Bradford Hill in 1965,18 that are often used to support causation.
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In medical toxicology it is virtually impossible to prove causal relationships beyond any doubt. The goal is to build empiric evidence so that associations can be confirmed or refuted with conviction. However, many toxicologists deem clinical trials indicating a lack of benefit from gastric emptying, or indicating a therapeutic benefit of HBO therapy for CO intoxication, unconvincing because of the degree of bias present in all relevant published clinical trials. To address this issue, some consensus works (from position papers to formal consensus studies) attempt to provide guidance to clinical toxicologists regarding interventions where equipoise remains despite published clinical trials. For example, the Appraisal of Guidelines for Research and Evaluation (AGREE) Instrument is widely used in consensus guidelines. The instrument in its present form has been updated as “AGREE II” and is composed of 23 items organized into six quality domains (scope, stakeholders, rigor, clarity, applicability, independence).1
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INFERENTIAL STATISTICAL TESTS
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As discussed previously, researchers must devise an appropriate statistical test to determine whether or not their data were arrived at by chance, a process known as inferential statistics. Once the significance level has been chosen, the inferential statistical test of choice depends on the type of data that are being collected. It should be noted that using the wrong statistical test for a given set of data will invalidate the results of a study; thus, choosing the correct statistical test is of paramount importance for research study design, as well as for toxicologists who try to interpret published medical studies.
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Once the significance level has been set, then the data must be classified by type. Generally, data are either: (1) categoric/nominal (≥ 2 categories of data with no intrinsic ordering, eg, presence/absence of medical comorbidities), (2) continuous/interval (data along a scale where each value is equidistant from one another, eg, dollar values), or (3) ordinal/ranked (≥ 2 categories of data with clear intrinsic ordering, eg, grade in high school). The method used to compare groups of data thus depends on whether data is categorical, continuous, or ordinal. Most commonly, categorical data are compared in terms of ratios/percentages (Chi-squared test) and continuous data are compared in terms of means (student’s t-test) or medians (Mann-Whitney U test). As a general rule of thumb, an ideal analysis involves comparing interval/ratio data between groups due to the fact that this data contains more information than any of the other forms of data. Finally, the number and relatedness of the independent variables for analysis must be determined. Most commonly, two unrelated samples are compared to assess for associations. However, there are times when groups are paired or related, such as in clinical trials with before/after data in the same participants. Additionally, it is possible to use more advanced techniques to compare three or more independent variables at once (Table 138–8).
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Inferential statistical tests are generally classified into parametric versus nonparametric techniques. This distinction is based on the fact that statistical tests make varying assumptions with regard to the population parameters that characterize the distributions for which the test is employed. Parametric tests generally make more stringent assumptions upon the data to produce valid results, while nonparametric tests make few if any assumptions about the data parameters and can thus be thought of as a “backup” test if the parametric assumptions are not met. For example, the t-test assumes that the two groups being compared are independent of each other, and that the dependent variable is continuous and normally distributed along a bell-shaped curve (also known as a Gaussian distribution). Similarly, the Chi-squared test assumes independent observation from a random selection of a given population with a large enough sample size such that any cell in the resultant 2 × 2 table is greater than five. A violation of one or more of these basic assumptions renders the test results invalid and mandates application of the nonparametric versions of these tests. A summary of common parametric and nonparametric tests based on data classifications is illustrated in Table 138–8.
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EVALUATION OF DIAGNOSTIC TESTS AND CRITERIA
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In clinical practice it is often useful to have a test, which may be a laboratory result or clinical paradigm, to help arrive at a diagnosis or predict an outcome. For instance, historical questionnaires, capillary blood lead concentrations, and venous blood lead concentrations might all be used to identify children at risk of neurocognitive injury from plumbism.9 However, each of these approaches is likely to have certain disadvantages in terms of effort, cost, discomfort, and/or accuracy. Targeting lead evaluation and therapy in children on the basis of exposure history is expected to be easy and inexpensive, but may not identify some children with significant poisoning; thus, the test may be susceptible to being falsely negative. Capillary blood testing is more costly and uncomfortable and may be susceptible to false-positive test results because of environmental lead dust present on fingertips. The possibility of false-positive or false-negative results must be considered with any diagnostic test (Fig. 138–4).
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The utility of diagnostic testing is often described in terms of sensitivity, specificity, predictive value of a positive test (PPV), and predictive value of a negative test (NPV). A cross-sectional design is often used to study diagnostic tests, as we seek to determine the prevalence of positive tests among the diseased (sensitivity), and the prevalence of negative tests among the healthy (specificity). A perfect test would be highly sensitive and specific, but this is seldom possible. A highly sensitive test (eg, D–dimer to assess for pulmonary embolism) is often used in screening programs because they rarely lead to false-negative diagnoses. Specific tests (eg, cardiac troponin to assess for acute coronary syndrome) are typically used to “rule-in” a diagnosis, as they rarely yield false-positive results. Whereas sensitivity and specificity are inherent properties of a diagnostic test applied to a given population, the probability of disease—based on the results of a test—is highly dependent on the prevalence of disease within the population being tested. The PPV is the probability of having disease in a patient with a positive test; the NPV is the probability of not having disease when the test result is negative. Numerous studies have tried to examine the utility of vomiting, leukocytosis, hyperglycemia, total iron-binding capacity, and radiographic findings in predicting toxicity after acute iron overdose. In a retrospective assessment of 40 adults with oral iron overdose, vomiting was found to predict a serum iron concentration above 300 μg/dL with a sensitivity rate of 84%, specificity of 50%, NPV of 44%, and PPV of 87%.33 This suggested that the presence of vomiting should raise concern for iron toxicity but that the lack of vomiting was not particularly reassuring. Figure 138–4 illustrates the calculation of the sensitivity and specificity rates, as well as the PPV and NPV. It is important to remember that these calculations, too, are subject to bias and are best presented with CIs.
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Galen, an influential physician from the second century, remarked of his clinical trial, “All who drink of this remedy recover in a short time, except those whom it does not help, who all die. Therefore, it is obvious that it fails only in incurable cases.” Unfortunately, error in contemporary clinical investigation of poisoning tends to be more insidious than the error in logic in Galen’s conclusion, and skillful scrutiny of published research remains an important endeavor.
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Medical toxicology has embraced the vision of incorporating “evidence-based, or literature-based, medicine” into practice.
Randomized clinical trials, although a noble goal, are rare and have proven difficult to perform within the discipline.
As toxicologists move beyond descriptive data reporting, there remains great potential for scientific advancement in the field of toxicology via observational, hypothesis-testing, clinical research.
Clinical investigators are charged with the imperative to perform studies based on sound epidemiologic principles.
All studies, by nature of population sampling, are at the mercy of chance, but such random error can be quantified using statistical techniques.
Systematic error (bias) can be limited, but not entirely excluded, through careful study design.
Clinicians interpreting published toxicologic research need to thoroughly evaluate a study’s research objectives, design, data acquisition, analysis, and conclusions before applying the results to patient care (Table 138–9).
Future epidemiological investigation should allow more valid conclusions to be drawn regarding the associations between exposures and outcomes, or regarding the value of treatments for poisonings, discussed in the preceding chapters of this text.
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acetaminophen overdose.
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Drug Development, Adverse Drug Events, and Postmarketing Surveillance
++
This chapter will focus on drug-induced diseases that occur as expected or unexpected adverse drug events (ADEs), as a drug–drug interaction or an ADE causing an untoward drug–disease interaction. Also included in this chapter is a discussion of an approach to the diagnosis of drug-induced disease, an overview of the new drug approval process in the United States, monitoring of drug safety postapproval, and the suggested role for the medical toxicologist in the discovery, reporting, and prevention of ADEs.
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ADEs are defined as untoward effects or outcomes associated with use of a drug. In this chapter, the word “drug” will be used for a pharmaceutical product and includes prescription and nonprescription medications, and dietary supplements.
++
In the United States, all new prescription and nonprescription medications must be shown to be both safe and effective in order to achieve approval by the US Food and Drug Administration (FDA), a prerequisite for marketing and sale. Dietary supplements fall outside of this legal requirement (Chap. 45).
+++
HISTORY OF THE UNITED STATES DRUG APPROVAL PROCESS
++
The evolution of drug product regulation in the United States has generally been reactionary; that is, most drug regulations were created in response to medicine related disasters at various times in our history. Prior to 1900, there was no requirement for a drug or medical device manufacturer to demonstrate that the product actually worked (efficacy), was safe when used as directed, or was made to be within precise manufacturing specifications. In addition, no laws existed that required labeled claims be proven valid. Any product could be sold as a company desired and it was left to the consumer or health care professional to determine if the products actually worked and were safe. Initiation of medicinal product regulation and the overall evolution of the US drug law and regulations are closely linked to specific medical product disasters that occurred during the twentieth century in the United States. Relatively recent changes in US drug approval law further changed drug review timelines and prioritization of drug application reviews. Most recently, specific provision of the FDA authorization has designated certain medication classes, such as antimicrobials, to receive extended patent protection as an incentive to develop new medications in an area where growing antibiotic resistance is on the rise and has become a public health concern.
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Examples of the pre-1900—or preregulation—marketed products include aspirin containing heroin sold as cough syrup and wine with cocaine to enhance sales of the alcoholic beverage. There was no legal requirement for systematic testing of products to determine content or the presence of possible adulterants in product formulations. The Pure Food and Drug Act of 1906 required pharmaceutical manufacturers to meet a standard for the concentration and purity of the drugs they marketed. However, the burden of proof was on the FDA to show that the drug was incorrectly labeled or that the advertising or label was false or misleading. To a large extent this is the current regulatory state for dietary supplements.
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The Food, Drug, and Cosmetic Act of 1938 resulted from a tragedy in which more than 100 patients (mostly children) died from poisoning by an excipient used in an oral solution of sulfanilamide, an antibiotic. Massengil, a pharmaceutical company, in an attempt to improve the palatability of a pediatric formulation of a sulfanilamide, added the solvent diethylene glycol to the formulation. Diethylene glycol is a sweet-tasting, but nephrotoxic hydrocarbon. Only after almost a full year of marketing were cases of renal failure and death reported in sufficient numbers to alert authorities to the extremely toxic nature of the product. The Food, Drug, and Cosmetic Act of 1938 accomplished the following:
++
Required companies to list the ingredients on each product label
Required companies to provide the known risks concerning use of the product to physicians or pharmacists
Made illegal the misbranding of food or medical products
For the first time, required companies to test their products for safety before being sold
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Drugs already marketed before 1938 were exempt from the requirement (Chap. 1).
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The Kefauver-Harris Amendments to the Food and Drug Act of 1962 resulted from the drug approval disaster that occurred in Europe and not in the United States. An application in the early 1960s for the approval of α-N-phthalylglutaramide (thalidomide), a sedative hypnotic already marketed in Europe at the time, was submitted to the FDA for review and approval. The sedative hypnotic had a rapid onset and short duration of action, did not affect ventilation, did not cause a morning-after effect, and was inexpensive. Dr. Frances Kelsey, a medical officer at the FDA, delayed approval by asking the sponsor to clarify several issues in the reportedly poorly organized new drug application (NDA). In the interim, an unusual teratogenic effect, phocomelia, or limb misdevelopment, was linked to the use of thalidomide in Europe. Congressional hearings on the “almost” approval for marketing in the United States resulted in the Kefauver-Harris Act of 1962, which required a drug manufacturer or sponsor to do the following:
++
File an investigational new drug (IND) application prior to initiating a clinical study with a drug in humans
Demonstrate that the drug was effective for the condition that it was being marketed to treat
Provide adequate directions for safe usage of the drug
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The act also was not retroactive and drugs that were already on the market were exempt from these new requirements. However, the Waxman-Hatch Act of 1983, among other things, incentivized companies to establish evidence in support of actual indications for an exempt drug. The effects of this incentivisation were demonstrated when a small pharmaceutical company studied the use of colchicine in gout which the company applied for, and subsequently received exclusivity leading to a 50 fold increase in the price of this ancient drug.17
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Subsequent US food and drug laws that have primarily affected FDA review and approval of products include the following:
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The Orphan Drug Act of 1983: The act provides financial incentives to drug manufacturers to develop drugs for the treatment of rare diseases and conditions (see http://www.fda.gov/orphan/designat/list.htm for a list of drugs that are approved under the Orphan Drug Act). A rare disease is defined as one in which there are less than 200,000 affected persons in the United States, or one affecting more people, but in which the cost of drug development is likely to exceed any potential sales of the drug (http://www.fda.gov/orphan/oda.htm). Some perverse outcomes due to marketing exclusivity have resulted. For example, colchicine received 7 years of marketing exclusivity after study of its use in patients with Familial Mediterranean Fever.17
The Prescription Drug User Fee Act (PDUFA) of 1992: The Act requires that manufacturers pay user fees to the FDA for NDAs and supplements to enable the FDA to hire additional reviewers and accelerate the review process. This Act, which has undergone several revisions (the latest in 2007), has proven to be controversial due to the new working relationships created between industry and regulators, and the concern that it may lead to compromises that are not in the best interest of public health.
The question remains as to whether or not the introduction of user fees and their associated mandate for shorter FDA review times for NDAs have had the desired impact.37 A recent comparison of review times over the first four Prescription Drug User Fee Act (PDUFA) authorizations did not find a substantial improvement.6 Compared with European Medicines Agency (EMA) and Health Canada, the analogous agencies to FDA in those regions, the FDA already had, and has maintained, significantly shorter review times over the past decade.6 Additionally, some believe that the shorter review times for FDA approval appear to be associated with an increased likelihood of drug withdrawal and black box label modification of the drug label postapproval,2 although others do not concur.40 The debate on this issue intensified during the controversy involving the cyclooxygenase-2 (COX-2) inhibitor antiinflammatory drugs. This widely publicized withdrawal and press coverage of the related litigation resulted in congressional hearings on the review practices and monitoring of drug safety by the FDA. The legislation has evolved to attempt to provide FDA with regulatory authority, adequate funding, and to encourage scientific exchange between the FDA and sponsors of drug products during the drug development process with the goal of improved quality and efficiency of the development process. PDUFA V, the fifth reauthorization of the FDA covering the period of 2013 to 2017, was recently approved.
The Dietary Supplement Health and Education Act (DSHEA amendment) of 1994: The Act removed from FDA the authority to require proof of safety or efficacy prior to marketing of products considered dietary supplements (including herbal remedies). Only when the manufacturer of a product makes a specific health claim, such as “treats congestive heart failure,” does the FDA have premarketing approval authority. That is, the use of structure or function claims, such as “supports heart function,” obviates the need for approval. Furthermore, rather than placing on the manufacturers the burden of proof for safety and efficacy of a product, the FDA is required to determine that a product is unsafe to prevent sale and distribution in the United States. Few dietary supplements have reached that benchmark.
The FDA Modernization Act of 1997: Among other things, the Act allowed for an accelerated drug approval process for the treatment of life-threatening illnesses such as AIDS and cancer if the drug has the potential to address medical needs unmet by currently available drugs. Many of the accelerated drug approvals rely on efficacy results derived from surrogate markers linked to the ultimate indication for the drug. For example, the protease inhibitors were approved on the accelerated track for the treatment of AIDS based on their demonstrated ability to reduce HIV viral load in preapproval clinical studies. Although practical, this may not be ideal and has led to additional authorities granted in later legislation (such as the Food and Drug Administration Safety and Innovation Act {FDSIA}).32
The Pediatric Research Equity Act of 2003: The Act requires manufacturers to study drugs being submitted for approval for a claimed indication in children. The FDA provides incentives such as patent extension and marketing exclusivity for performing these evaluations. As a result more data from children are being provided to guide therapeutic use of medications in this patient group, at the expense of allowances for marketing exclusivity to those manufacturers who provide such data.19
In 2007, the Food and Drug Administration Amendments Act (FDAAA) increased FDA responsibilities and authorizations primarily aimed at improving product safety. Specified deadlines for drug application reviews were added as well as the creation of a priority for FDA review based on indication and potential benefit of the candidate drug for a disease population. Four of the provisions of FDAAA reauthorize past legislation: PDUFA, the Medical Device User Fee Amendments of 2007 (MDUFA), the Pediatric Research Equity Act of 2007 (PREA), and the Best Pharmaceuticals for Children Act of 2007 (BPCA).
FDAAA gives authorization to FDA to require postmarketing studies, primarily of drug safety, including surveillance and clinical trials, as well as the requirement that sponsors incorporate Risk Evaluation and Mitigation Strategies (REMS) in their proposed marketing activities as a prerequisite for product approval. REMS are a mechanism to allow FDA to require proactive risk surveillance for newly approved products or those in which safety signals are detected. The elements of REMS vary considerably among products, and may be applied to both safety concerns and the potential for misuse, as in the case of prescription opioids.38 The impact of these new regulations remains unclear, particularly as to whether still stronger regulatory oversight is needed to protect the public health.
FDAAA also included a requirement for FDA to ensure that clinical trial information is provided to the National Institute of Health’s ClinicalTrials.gov Web site. However, despite the mandate, most trials are not reported within one year of their completion.29
Drug shortages, which have been present for decades, reached crisis levels in 2010. The reasons are multifactorial, but coincide with a time when an empowered FDA began enforcing high manufacturing standards at production sites around the nation and the world.16 Although many of the concerns leading to plant closure were not associated with patient harm, the proactive stance primarily affected generic drug manufacturers,3 initially mainly those producing oncology drugs that were unable or unwilling to respond to standard regulations. The shortage of important drugs had significant medical and ethical consequences including delays in care and medication errors. Furthermore, economic consequences of the use of more expensive (and potentially less effective) alternative drugs and development of a “gray” market led to higher costs.33 Some health systems turned to compounding pharmacies, which were largely unregulated. As this practice grew, new concerns such as interstate transport of compounded medications and safety risks from lax oversight became prominent.7
In 2012, the bipartisan passage of FDSIA again reauthorized PDUFA (now PDUFA V).31 This law included two noteworthy new FDA responsibilities and authorities: the establishment of a user fee requirement for generic drugs and for biosimilar (genericlike) biologic products similar to what is called the innovator product for drugs, and a new category of drug application designation called the “breakthrough therapy” designation. The breakthrough designation allows FDA to assist drug developers in an expedited review and approval process of a product application when there is preliminary clinical evidence that shows the drug may be a substantial improvement over existing therapies for treatment of patients with life-threatening diseases. Other new initiatives include an active effort to include patient groups representative of the affected populations in the overall FDA review processes and some yet to be determined measures to enhance the safety of the drug supply chain. This act allowed FDA to better regulate foreign drug manufacturing facilities to help alleviate shortages, and to require pharmaceutical companies to make the FDA aware of impending drug shortages. In addition, the provisions of the BCPA and PREA were made permanent.
++
A complete listing of the laws and statutes enforced by the FDA is found on the FDA Web site.10
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THE DRUG DEVELOPMENT PROCESS
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Figure 139–1 is a schematic overview of the process for drug development of a new molecular entity (NME). The process begins with the preclinical evaluation of the candidate drug. During this evaluation, preclinical toxicologic testing is performed in more than one animal species, and other testing includes product stability, good manufacturing methods, purity, and potential carcinogenicity. Dose–response relationships in animal models and in vitro receptor binding or surrogate marker effects are often determined at this phase of the evaluation. At this time many manufacturers determine the metabolism of the drug in animal and in vitro human systems. Following this preclinical testing, the sponsor submits an IND application to the FDA for approval to initiate human testing. This application contains all relevant data concerning animal and in vitro toxicology testing, product manufacturing and purity, and a protocol for using the drug in initial human investigation. Within 30 days, the FDA must review the IND application and either allow the proposed human study to proceed or inform the sponsor that additional data or preclinical (eg, animal) study is required before clinical testing of the candidate drug can begin.
++
++
The clinical study of new candidate drugs is divided into four basic phases.
++
Phase 1 clinical testing involves a relatively small number of participants with the primary aim of determining the safety and toxicity of the drug. Many phase 1 studies will also determine the human pharmacokinetics and metabolism of the drug. Phase 1 studies are normally conducted in 20 to 100 healthy volunteer participants, with the notable exception of phase 1 studies for cancer chemotherapeutics, which enroll only patients with cancer.
++
Phase 2 clinical testing is designed to determine the potential efficacy of the drug product in humans, usually at varying levels of exposure to the drug candidate. In this phase, approximately 100 to 300 participants are usually studied. In phase 2 clinical trials, participants generally have the diseases for which the drug is intended or are capable of demonstrating the appropriate, validated, biologic surrogate marker to indicate response to the drug. An example of this would be when a drug intended for early treatment of acute coronary syndrome is tested to show that it can inhibit in vivo platelet function after oral dosing in human study participants.
++
Phase 3 clinical drug studies usually involve large scale clinical trials in the actual population for which the drug is intended for use. Typically, this phase of drug development will involve testing a treatment cohort versus a control treatment of several hundred to several thousand patients who have the target disease, depending on both the prevalence of the disease and effectiveness of the drug. The primary goal of phase 3 studies is to determine the safety and efficacy of the candidate drug in the actual intended patient population in question, under conditions similar to the anticipated medical use. At the completion of phase 3, an NDA (request for approval to market) is submitted to the FDA. A candidate drug completing phases 1, 2, and 3 can thus be approved for marketing after study in only 2000 to 4000 patients. In the setting of a fast-track approval or under the Orphan Drug regulations, substantially fewer patients will receive the drug before its approval for marketing. The relatively small number of human exposures to a new chemical or biologic entity prior to approval for marketing is an important factor that limits the sensitivity of the drug approval process to detect uncommon ADEs.
++
Toward the end of the review cycle, the FDA often seeks the external advice of its constituted advisory committees prior to their approval decision, especially in the setting of an uncertain risk–benefit profile of a candidate drug. FDA advisory committees generally are organized by therapeutic areas and are composed of medical professionals, primarily from academia, as well as biostatisticians, a patient representative, a consumer representative, and a nonvoting industry representative. These same advisory committees also convene to consider postapproval safety or efficacy data when FDA is considering an important change to a drug label or other postapproval regulatory action. Generally, the FDA prepares questions for the committee members and provides an FDA briefing document containing a detailed data analysis and background of the issue from the FDA perspective as well as a briefing document prepared by the drug sponsor containing corresponding information. Committee members comment and vote on the FDA questions during the proceedings. For a new drug approval, one question generally includes a yes or no answer as to whether or not the committee member believes that the drug can be marketed with an adequate risk–benefit profile. The advisory committee vote is technically nonbinding for the FDA, but the FDA generally follows the advice of the committee. A recent issue of concern is the fact that some members of FDA advisory committees with perceived conflicts of interest are granted waivers by FDA to participate.23 The appearance of conflict of interest on an advisory committee can have a significant impact on the drug approval process, and the FDA has begun to decrease the number of committee member waivers.
++
At the conclusion of the NDA review process and, at times, following an Advisory Committee meeting on the application, the FDA may issue an approval for marketing the new product. On occasion, the FDA issues an “approvable” letter, indicating that the product is potentially approvable but additional data will be needed before final approval can be granted. Examples of additional data required in this setting include further clinical study of a specific drug interaction, use of the drug in a specific patient population, or extension of the submitted drug stability testing. Once approval of the drug is given by the FDA, the next phase of drug development begins as discussed separately below.
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Phase 4 Drug Development: Postmarketing Surveillance
++
Every drug, therapeutic biologic product, or medical device carries with it some potential risk. If society required that only “completely” safe drug products could be marketed, the drug approval process would likely take decades and few if any new drugs would be made available. Therefore, the FDA and the pharmaceutical industry rely significantly on postmarketing surveillance for further safety information regarding the toxicity of a medical product after approval. A postmarketing surveillance system is in place to monitor postapproval drug safety. These systems are intended to detect unanticipated or previously unrecognized adverse events or to identify an at-risk population in whom the safety profile differs from that which was expected prior to marketing. Individual pharmaceutical manufacturers are responsible for monitoring the safety of their products and regularly reporting any detected ADEs to the FDA. The FDA postmarketing surveillance program (MedWatch) for all medical products is a parallel system in place to monitor drug and medical device safety. This system relies on spontaneous reports by health care professionals or patients regarding the occurrence of deleterious effects associated with the use of a medical product.
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Because manufacturers are also required by law to report ADEs associated with use of their products to MedWatch, the FDA database contains one complete data set called FDA Adverse Event Reporting System (FAERS), that was renamed from AERS in 2010 following its enhancement and integration of device-related data.34 Because the MedWatch system is passive in nature, the estimated overall rate for adverse event reporting is estimated at only 1% to 10%. Despite this, the number of serious adverse events reported to MedWatch increased between 1998 and 2005,26 although the completeness of the reports remains poor.13 Improved attitudes toward reporting, perhaps due to an appreciation of the risk of error and adverse drug effects, leads to better MedWatch reporting.12 Both, the adverse event reports from MedWatch and those that are submitted from product manufacturers are entered into the FAERS database. This database is fully computerized and therefore easily searchable and contains adverse event reports from human drug and biologic products. The system contains more than 7 million reports, entered since 1969, and is growing substantially. In 2012 there were nearly 1 million reports submittedto FAERS. Approximately 95% of the total reports in the system are generated by the manufacturers and the remaining 5% are submitted via the MedWatch system.
++
The primary goals of the MedWatch system are the following:
++
To increase awareness of drug- and device-induced disease.
To clarify what should (and should not) be reported to the agency.
To facilitate reporting of adverse effects by creating a single system for health professionals to use in reporting ADEs and product problems to the agency.
To provide regular feedback to the health care community about safety issues involving medical products.9
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Establishing causality for a specific medical product is not required before submission of a MedWatch report. The FDA is primarily interested in the reporting of serious adverse events, or an ADE previously not associated with the drug being administered, whether or not a causal relationship is established. Although any potential ADE should be reported, an event is considered serious and must be reported when the patient outcome is one of the following:
++
Death: If the death is suspected to be a direct result of the adverse event
Life threatening: If the patient was considered to be at substantial risk of dying at the time of the adverse event or the use or continued use of the product would result in the patient’s death (eg, gastrointestinal hemorrhage, bone marrow suppression, pacemaker failure, and infusion pump failure that permits uncontrolled free flow and results in excessive drug dosing)
Hospitalization (initial or prolonged): If admission to the hospital or prolongation of a hospital stay resulted from the adverse event (eg, anaphylaxis, pseudomembranous colitis, bleeding that causes or prolongs hospitalization)
Disability: If the adverse event resulted in a significant, persistent, or permanent change, impairment, damage, or disruption in the patient’s body function/structure, physical activities, or quality of life (eg, cerebrovascular accidents caused by drug-induced coagulopathy, toxicity, peripheral neuropathy)
Congenital anomaly: If there is a suspicion that exposure to a medical product before conception or during pregnancy resulted in an adverse effect on the child (eg, vaginal cancer in female offspring from maternal exposure to diethylstilbestrol during pregnancy or limb malformations in the offspring from thalidomide use during pregnancy)
Requires intervention to prevent permanent impairment or damage if use of a medical product is suspected to result in a condition requiring medical or surgical intervention to preclude permanent impairment or damage to a patient (eg, acetaminophen overdose–induced hepatotoxicity requiring treatment with N-acetylcysteine to prevent permanent damage, burns from radiation equipment requiring drug therapy)
++
MedWatch reports are easily done through the MedWatch Web site, or by facsimile, telephone, or mail. Physician reports are given priority for review by the FDA in the MedWatch system. A well-documented case of a serious adverse event is a significant and useful contribution to the MedWatch system.
++
Reports of serious ADEs to the FDA or to the manufacturer can become an epidemiologically detectable signal that can trigger a more detailed investigation, several examples of which are provided later in this chapter. On occasion, serious ADEs detected in the AERS database have led to the withdrawal of products from the US market without conducting additional studies.
++
Reporting serious ADEs has periodically been encouraged by various health care groups in conjunction with the FDA. Currently, the MedWatch program is supported by more than 140 organizations, representing health care professionals and industry collaborating as MedWatch Partners to help achieve these goals. These organizations include medical societies and organizations such as the American Medical Association (AMA), the American College of Medical Toxicology (ACMT), and the American Academy of Pediatrics (AAP) that have encouraged their members to report to the MedWatch system. As a requirement for hospital accreditation, The Joint Commission mandates hospitals to collect, analyze, and report significant and unexpected ADEs to the FDA.
++
The primary limitation of the MedWatch system is the exclusive reliance on spontaneous reporting of ADEs. The system is passive in nature and therefore has several important limitations. Significant underreporting is known to occur in such systems. The uncertainty about the significance of a signal in the AERS database is exacerbated by the low estimated rate for adverse event reporting and the fact that the true incidence of the reported ADE is almost never precisely known because the denominator, which is the number of actual exposures to the drug, is rarely accurately known. Despite these limitations, the MedWatch system has detected significant ADEs during the postmarketing period.
++
Drug regulators must rely on passive surveillance systems like the AERS database to detect potential uncommon or rare but serious ADEs postapproval. This is primarily because a relatively small number of patients or participants are exposed to the drug during phases 1 to 3 prior to approval for marketing. For example, to detect an uncommon ADE occurring in approximately 1 of 5000 individuals exposed to a drug with 95% probability that the ADE resulted from exposure to that drug, approximately 15,000 patients would have to be exposed to the drug. In a balanced (equal numbers of drug and placebo recipients) placebo-controlled clinical trial, 30,000 participants would need to be enrolled. Premarketing clinical studies (phases 1, 2, and 3) are usually inadequate to detect rare ADEs, ADEs that are incorrectly diagnosed, or ADEs that result from a drug interaction that may not have been tested in the development program.
++
An example of a rare ADE not detected until postmarketing involves the drug felbamate, which was approved by the FDA in September 1993 and subsequently found to be associated with aplastic anemia during postmarketing surveillance. Felbamate induced aplastic anemia had not been detected during the drug development program. By July 1994, nine cases had been reported from an estimated 100,000 patients exposed to felbamate in the United States.28 Most of the aplastic anemia cases occurred in patients who had taken the drug for less than 1 year. The nine cases represented an approximate 50-fold increase in aplastic anemia over the expected rate in the population with the very low background rate of two to five cases per million per year allowing the FDA to attribute this rare condition to exposure to felbamate.
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The primary role of the MedWatch system is to generate a hypothesis for potential association of an ADE with a specific drug. These hypotheses are sometimes further tested in subsequent phase 4 investigations. An example of this “hypothesis generation” function of MedWatch was the question of whether phenylpropanolamine (PPA) caused hemorrhagic stroke in patients using nonprescription diet suppressants or cough and cold preparations containing PPA. In the early 1990s, the Spontaneous Reporting System (SRS; now AERS) detected a potential association of hemorrhagic stroke and nonprescription use of PPA. An industry-sponsored prospective, case-controlled study was designed to determine if such an association existed. The multicenter study demonstrated that an association did exist, especially for women aged 18 to 49 years. The Nonprescription Drug Advisory Committee (NDAC) of FDA reviewed this study and the associated MedWatch data in the fall of 2000 and decided that the evidence supported such an association. The committee advised the FDA to remove PPA from the market, which occurred a short time later. Although the entire process of signal identification from MedWatch to presentation of results from the prospective epidemiologic study required nearly a decade for PPA, the process demonstrates the value of the hypothesis-generating ability of the MedWatch system.
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Potential outcomes of a safety signal detection for a marketed drug include dose reduction in all or certain high risk patient populations, restriction of the sale of the specific drug to a more medically supervised environment or the development of a patient registry to more closely monitor use, and removal of the drug from the market. These options are further discussed later in this chapter.
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Other types of phase 4 safety investigations include clinical studies, comparative studies with the new drug versus a competitor, or a special population study or drug interaction study when suspicion is raised that there may exist a different risk–benefit relationship in certain clinical settings. The enhancement of safety information is the primary goal of most phase 4 studies. Other than the specific prospective study in patient subpopulations, the methods by which phase 4 safety studies are usually conducted are primarily observational and epidemiologic. Main sources of data for the postapproval monitoring of the safety of a drug are the spontaneous reports gathered by both the pharmaceutical manufacturer and FDA. The fields of pharmacovigilance and pharmacoepidemiology are typically employed in the conduct of phase 4 studies. Attributing a serious ADE to a drug solely from MedWatch reports does occur, but it is much more common for the AERS database to produce a signal, suggesting a possible drug-related safety problem.
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ESTABLISHING THE DIAGNOSIS OF DRUG-INDUCED DISEASE
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The recognition and diagnosis of a drug-induced disease, or an ADE, is an essential skill for all practitioners, and especially for medical toxicologists and clinical pharmacists and pharmacologists. The diagnosis of an ADE is typically established as the result of a systematic medical evaluation. One approach to establishing the diagnosis of drug-induced disease involves consideration of six related questions concerning the patient’s clinical presentation and available medical data, as shown in Table 139–1.
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The first question concerns the timing of the onset of the adverse event in relationship to the reported exposure to the drug. Perhaps because of publicity or word of mouth, ADEs are sometimes reported to the FDA MedWatch system even when the onset of the adverse event occurs before the first exposure to the suspect drug. A careful reconstruction of the time course of drug exposure and onset of adverse effects is extremely important in assessing causality. The time course differs considerably for different adverse clinical events. An anaphylactic reaction to a drug usually occurs within minutes of exposure, whereas renal insufficiency caused by a drug is not likely to be clinically detectable for up to several days after the exposure. A drug that causes cancer (a carcinogen) may not produce a clinically detectable effect for decades. Establishing a time course is an essential first step in the process of making the diagnosis of drug-induced disease.
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The second question is whether or not this adverse effect was reported previously for the suspect drug. An adverse drug effect that occurs commonly is likely to be known before the approval of the drug and therefore is typically found on the initial drug label. For example, respiratory depression and mental status changes were well known before the approval of fentanyl, an opioid agonist. Less common ADEs for drugs that have been on the market for a period of time are sometimes found in case reports in the literature, various medical databases, and in mention of safety related information. These will appear in a revised drug label for the medical product. Previous reports linking the observed adverse effect to drug exposure are very helpful to the clinician trying to establish a significant level of probability for causality in the setting of an ADE.
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However, in the setting of a newly approved drug or a previously unreported possible ADE, neither previous reports/medical literature nor the drug label will help establish causality. In this setting, the clinician must rely more on what is known of the pharmacology, the pharmacokinetics, and the anticipated pharmacodynamics of the suspect drug and the timing of the appearance and observed time course of the adverse event. The known pharmacology about the drug should include “target” effects as well as “off target” effects. It is important to put “drug-induced disease” in the differential diagnosis for most patients presenting for medical care. Someone has to be the first to report what is ultimately recognized as an adverse effect. Appropriate vigilance for the possibility of a new ADE significantly increases the probability that a finding can be made early after introduction of a new drug to prevent more widespread drug-induced morbidity or mortality.
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The next question to consider is: “Is there evidence of excessive exposure to the drug?” Most ADEs that occur are predictable on the basis of the known pharmacology of the specific drug. Such ADEs are referred to as type A ADEs.5 For example, antihistamines such as diphenhydramine are known to cause significant anticholinergic effects. When a patient presents with mental status changes and clinical findings consistent with the anticholinergic toxidrome after significant exposure to an antihistamine-containing product, the observed effects are consistent with an ADE attributable to the antihistamine. Occasionally, proof of drug excess can come from measurement of the drug in serum. In the case of the patient with a history of atrial fibrillation who exhibits nausea, vomiting, vision changes, and ventricular dysrhythmias, the measurement of an elevated serum digoxin concentration supports the diagnosis of digoxin toxicity or an ADE attributable to digoxin perhaps as an inadvertent or intentional overdose, drug interaction, or change in patient renal function resulting in excessive circulating digoxin concentration. In any case, knowing the pharmacology of the drug is important for establishing the diagnosis of an ADE.
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When an ADE is caused by an allergic mechanism or another mechanism unrelated to extent of the exposure to the drug, that is, a type B ADE, evidence of drug excess usually does not contribute to the diagnosis. In this setting, other factors such as allergy history or pharmacogenetic background are weighed more heavily to support the diagnosis of an ADE. Patients are usually not aware of their genetically determined ability to metabolize or react to medications but most patients will recall a previously experienced allergic reaction.
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The next issue to address in considering possible causality is whether there are other more likely etiologies that could be responsible for the observed effects. Although it is important to be appropriately vigilant for possible ADEs, it is equally important not to miss an alternative cause for the patient’s condition. There are certain clinical settings in which establishing an ADE becomes a diagnosis of exclusion. For example, in the case of persistent fever, the assignment of the diagnosis “drug fever” should not be made until a complete search for infectious causes has excluded this etiology.
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A very important factor to consider in contemplating a diagnosis of ADE is “What is the patient’s response to cessation of a suspect drug (dechallenge)?” In this case, the pharmacokinetics of the drug and the timing of resolution of the specific condition must be carefully considered. In some instances, the resolution of a type A ADE closely follows the pharmacokinetics of the suspect drug. For example, in the case of acute β-adrenergic antagonist poisoning, cardiac effects resolve in association with decreasing serum concentrations of the drug in question. However, in other instances, onset and resolution of the ADE may not correlate with drug concentrations in the body, for example, in the case of a penicillin rash, which may develop within 1 or 2 days or longer after starting the medication, but may take several days to weeks to completely resolve. In this example of a type B ADE, the resolution of the condition (rash) occurs over a much longer time period than would be predicted by the pharmacokinetics of the drug. When a suspected ADE resolves after discontinuation of exposure to the offending drug, along a predictable time course, the result of this dechallenge would support the diagnosis of ADE.
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Lastly, the clinician may have the opportunity or need to rechallenge the patient with the suspect drug. If the rechallenge results in the identical response or effect, this would be considered strong evidence to support a causal relationship for the suspect drug and the adverse event. In the setting of a serious or life-threatening adverse event, it is too dangerous to perform a rechallenge with the suspect drug, in which case the response to rechallenge will not be known. In this setting, the weight of evidence previously discussed will then be the only factors available to assign the probability of causality.
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FDA REGULATORY ACTIONS REGARDING SAFETY
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When new information about a safety issue for an already marketed drug raises concern at FDA, several regulatory options are available to either attempt to improve the safety of the drug or remove the drug from the US market. The most common regulatory action taken by the FDA is modification of the drug label. These modifications can include restrictions as to whom should receive the drug, what doses should be given for which indications or to which patient populations, what type of monitoring should be performed during therapy, and how long treatment should be administered. When potentially life-threatening safety information is discovered, and the FDA believes that the risk–benefit relationship remains in favor of continued availability of the drug, the FDA can require that a boxed warning (sometimes called a “black box” warning) be carried in the label. A black box warning is the most serious warning placed in the label of a prescription medication. If a black box warning is established, then health care professional advertisements regarding product availability are no longer permitted. Additionally, the manufacturer is required in most cases to send a “Dear Doctor” letter to potential prescribers informing them of the new black box warning. Dear Doctor letters may also be required when the FDA requires that prescribers be notified about a significant change in the drug label warning. An example of current medications with recently added black box warnings is antidepressant medication that now must warn about the increased risk of suicidality if children and adolescents are prescribed antidepressants. The antipsychotic medication clozapine currently has five black box warnings in its drug label for the following attributed ADEs: agranulocytosis, myocarditis, seizures, “adverse cardiovascular and respiratory effects,” as well as increased mortality in elderly patients with dementia-related psychosis.
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Another option employed by the FDA is the implementation of restricted availability measures to permit continued availability of the drug but only with specified restrictions. For example, use of the drug isotretinoin (Accutane) requires compliance with a multiple component REMS program called iPLEDGE that includes informed consent, prescriber and dispensing pharmacy registration, serial pregnancy testing if applicable, documentation of patient education, and completion of risk management programs by patients who will receive the medication.36 This option is more commonly used today when there is concern about “off-label” use. The FDA authority to require companies to submit, prior to drug approval, and execute, postapproval, an effective risk management plan is intended to improve both the monitoring and prevention of postapproval adverse drug events and their consequences.
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When the FDA believes that a drug can no longer be safely used despite modification of the drug label or any of the aforementioned restrictions, the regulatory threshold is reached to initiate removal of the drug from the market. This occurs when an acceptable risk–benefit relationship for continued availability of a drug product is no longer possible. Table 117–2 in the seventh edition of Goldfrank’s Toxicologic Emergencies contains a compilation of products that were withdrawn or removed from the market in the United States for reasons of safety or efficacy. Some recent additions to that list of drugs include valdecoxib (marketed as Bextra) and rofecoxib (marketed as Vioxx), withdrawn because of recognition of elevated cardiovascular risk associated with their use.11 In the case of the COX-2 inhibitor withdrawals, the precipitating factor for withdrawal was the findings of a strong safety signal for excess cardiovascular mortality and morbidity during the conduct of efficacy studies for other potential therapeutic indications for these drugs. The postmarketing surveillance system did not serve as the initial, precipitating data set for regulatory action in this instance.20,27 The manufacturers voluntarily withdrew these COX-2 inhibitors and the majority of the drugs deemed unsafe by FDA from the US market. In many cases, the manufacturer ceases marketing the specific drug after notification by the FDA that regulatory action is being initiated to remove their drug from the market. Only very rarely has the FDA itself actually removed a drug from the market. One example where the FDA did implement removal is the drug phenformin, which was removed by the FDA after due process was completed. In the case of ephedra-containing dietary supplements, the FDA removed these products from the market based on their analysis of safety data obtained from the medical literature and from analysis of cases reported to the MedWatch system. In some cases, the pharmaceutical manufacturers file suit against the FDA to fight or delay the planned regulatory action against the product. The manufacturer’s legal action generally prolongs the time the product remains on the market because the drug usually continues to be sold, while the legal proceedings and appeals proceed through the courts.
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Some feel that approval of a drug by FDA should preempt legal action for safety issues identified in the drug labeling. However, the FDA decision-making process regarding drug approval is largely reliant on efficacy and safety data provided by the manufacturer or in the publicly available medical literature. Plaintiff actions, taken against drug and device manufacturers, are sometimes a source of significant publicity and confidential disclosures regarding questionable behaviors practiced by companies that market medicinal products. The patient’s right to tort action against a product’s manufacturer provides an important mechanism to assure drug safety following approval and marketing.5 Recent US Supreme Court appeals have challenged this position seeking to reinforce the legal position of federal preemption. In the case of Wyeth v. Levine, the manufacturer appealed to the US Supreme Court to uphold the federal preemption status for FDA approved drugs.18 On March 4, 2009, the US Supreme Court ruled that federal law does not preempt this particular plaintiff from seeking and obtaining a judgment from the product manufacturer because the product was approved by the FDA. The case provided the opportunity to debate the extent of protection afforded by the FDA approval status and the issue of product liability litigation as a part of postmarketing surveillance of drug products in the United States. At the current time, medical devices are governed under a distinct statute in which FDA approval does preempt many forms of litigation.
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In recent years, there have been highly publicized drug withdrawals for risk of cardiovascular ADEs such as the COX-2 inhibitors and the recent market withdrawal for rosiglitazone and its subsequent relabeling and reauthorization of marketing for the product for the past two decades. Until recently, the most common reasons for FDA initiated drug withdrawals in the United States have been prolongation of the QTc interval followed by drug-induced hepatotoxicity. These ADEs, as well as the propensity to cause significant drug–drug interactions, are still the primary reasons for drug–safety-related regulatory action in the United States.
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Prolongation of the QT Interval
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Three significant drug withdrawals in the mid- to late 1990s exemplified a serious drug safety issue with regard to drug related prolongation of the QT interval when administered alone or as the result of increasing plasma concentrations due to inhibition of its metabolism by other medications. The three examples in this category are terfenadine (Seldane), astemizole (Hismanal), and cisapride (Propulsid). Several deaths were reported to the MedWatch system for patients taking these medications. In the case of terfenadine, the initial publication of a case report for polymorphic ventricular tachycardia in the setting of routine use of this nonsedating antihistamine with the self-administration of a known inhibitor of drug metabolism led to FDA funded small prospective clinical studies to confirm a previously unrecognized ability of terfenadine to dramatically alter cardiac repolarization, which can lead to torsade de pointes. The drug was marketed in 1985, cardiac toxicity was detected in clinical use in 1990,25 the FDA funded clinical cardiac safety research performed in 1991,15 and, ultimately, the drug was withdrawn from the market in 1998. The medicolegal course of the other two drugs is similar except that prospective controlled studies to document the extent of QT prolongation were not performed before regulatory action was taken. These early experiences led to new rigorous regulatory requirements and significant preclinical screening by manufacturers of all drugs worldwide.
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These three drug withdrawals demonstrated that the preapproval assessment of cardiac repolarization effects at that time was incapable of detecting even the most potent dysrhythmogenic drugs during their respective development and FDA review. Based on this dramatic systematic failure, FDA (as well as the European and Japanese drug regulatory agencies) now requires a thorough QT study (tQT) for all new molecular entities.24 These studies are designed to detect as little as a 5-millisecond increase in the corrected QT interval in healthy volunteer participants and must include a positive control to demonstrate the sensitivity of the study to detect this low-level change reliably. Since this new requirement was put in place, no newly approved drugs have subsequently been removed from the US market for QT safety reasons, although questions remain about its cost effectiveness.1
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SIGNIFICANT DRUG–DRUG INTERACTIONS
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Removal of mibefradil (Posicor) from the US market is an example of a drug withdrawn from the US market because of postmarketing discovery of a plethora of drug–drug interactions. Mibefradil, a pharmacologically unique calcium channel blocker, was approved by the FDA for the treatment of patients with hypertension and chronic stable angina. The FDA approved mibefradil for marketing in 1997 with the knowledge that the compound possessed the ability to inhibit certain hepatic CYP enzymes; these facts were included on the drug label. The initial labeling for mibefradil specifically listed three drug–drug interactions: astemizole, cisapride, and terfenadine (CYP3A pathway interactions). During the one year that mibefradil was marketed, information accumulated regarding drug–drug interactions with many other drugs and CYP pathways. As the in vitro and in vivo drug interaction data continued to accumulate for mibefradil, the FDA made labeling changes and issued a public warning for these potential drug interactions within 5 months of its initial approval. Additionally, the sponsor distributed a letter to health care professionals warning of drug–drug interactions. In the face of a growing and significant list of drug–drug interactions, and a 3 year international study demonstrating no clinical benefit of mibefradil over placebo for congestive heart failure, the FDA initiated regulatory action. In an unprecedented step for a drug with numerous drug interactions, the FDA requested that it be withdrawn from the market approximately a year after it was approved.30 The FDA felt that the extensive drug–drug interactions could not be addressed by standard drug label instructions and additional public warnings.
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Drug-Induced Hepatotoxicity
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Another category of ADE of recent concern is those drugs that cause hepatotoxicity. In June 1998, the manufacturer of the NSAID bromfenac sodium (Duract) withdrew this agent from the US market.14 The NDA was submitted for review to the FDA in 1994 and after 28 months of review was approved. The drug was withdrawn approximately 11 months later after postmarketing discovery of significant hepatotoxicity. Although no cases of serious liver injury were reported during premarketing clinical trials, after introduction to the market, a higher incidence of liver enzyme elevation was found in patients who were being treated with the drug. Postapproval exposure of patients to bromfenac generally resulted in longer periods of treatment than that of the participants in the clinical trials. Because of a preapproval concern by the FDA that long-term exposure to bromfenac could cause hepatotoxicity, bromfenac labeling specified that the product was to be used for 10 days or less. This dosing limitation appeared to be inconsistent with the initial approved drug indication for treatment of a chronic condition (eg, osteoarthritis). Information concerning elevated hepatic enzymes was actually included in the original product labeling. The postmarketing surveillance of this product identified rare cases of hepatitis and liver failure, including some patients who required liver transplantation, among those using the drug for more than 10 days specified on the label. In February 1998, approximately 6 months after approval for marketing, the FDA added a black box warning indicating that the drug should not be taken for more than 10 days. Nonetheless, severe injury and death from long-term use of bromfenac sodium continued to be reported, and ultimately, the sponsor agreed to voluntarily withdraw bromfenac sodium from the market. The withdrawal of bromfenac sodium raised several important questions concerning interpretation of “safety laboratory testing,” such as liver enzymes during the drug development program, and also raised questions concerning the effectiveness of drug labeling.
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The FDA has issued specific guidance on how to evaluate drug-induced liver injury (DILI) during drug development.8 As with many other adverse drug effects, severe DILI is uncommon so despite extensive study, few cases will be found prior to, and even after, marketing. Properly evaluated for evidence of lesser injury, drug databases may be able to offer insight into the potential for more severe liver injury. One of the common guidelines utilized by FDA is Hy’s law, which states that severe liver injury is predicted by laboratory assessment that includes an alanine aminotransferase of more than three times the upper limit of normal and a bilirubin of more than twice the upper limit of normal in a patient with no other reason for such an abnormality.22 Although imperfect, this is effective in preventing new drugs from obtaining approval and having others withdrawal from the market.
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Other Examples of Postmarketing Safety Problems Leading to Drug Withdrawal
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One voluntary withdrawal of two separate drugs used in combination serves as an important example of the discovery and publicizing of an unusual adverse event occurring years after individual drug approval but after a significant increase in the prescription use of the combination product. The drug fenfluramine was approved in 1973 after an FDA review period of 75 months. A significant increase in prescription use of a combination product of fenfluramine with phentermine, for weight loss (referred to as “fen-phen”), began in the 1990s when clinical data suggested that this drug combination was effective in a weight loss program.35 However, use of the fen-phen drug combination was never fully approved by the FDA and was therefore considered an “off-label” guideline usage of the product. The number of prescriptions for the drug combination soared in the mid-1990s. In July 1997, research from the Mayo Clinic reported 24 cases of an unusual form of cardiac valvular disease causing aortic and mitral regurgitation in patients using the fen-phen combination.4 The publicity surrounding the potential linkage of this drug combination to an unusual adverse event led to a significant increase in reports of possible adverse events associated with this drug combination. The FDA issued a public health advisory and initiated further epidemiologic studies to ascertain its prevalence. The FDA also encouraged echocardiographic studies of valvular diseases in patients taking fenfluramine or dexfenfluramine either alone or in combination with phentermine. Although at the onset the FDA, the product manufacturers, and the medical community did not expect valvular lesions to be associated with either fenfluramine or dexfenfluramine, the epidemiologic evidence suggested a possible association, leading the FDA to conclude that these agents should be removed from the US market. The potential association of valvular heart disease with these agents is an example of the use of a case-control study to explore a possible causal relationship between drug exposure and an ADE. In this case, it is unclear what the strength of the MedWatch signal was for the possible association of cardiac valvular disease with exposure to the fen-phen combination. The association between cardiac valvular lesions and exposure to the drug combination serves as an example of elucidation of a rare, unexpected ADE as the result of a dramatic increase in the number of exposed patients using a product.
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ROLE OF THE TOXICOLOGIST IN THE DETECTION AND PREVENTION OF ADVERSE DRUG EVENTS
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Toxicologists can play an extremely important role in ADE diagnosis and prevention, through efforts in patient care, education, and administrative functions. In patient care, it is common for the medical and clinical toxicologists to be the first medical specialists to be consulted for a patient with a potential ADE. Perhaps more than any other medical specialty, medical and clinical toxicologists are likely to include a thorough medication history that also includes prescription and nonprescription products, as well as dietary supplements. The medical toxicologist’s active involvement in the clinical arena, especially in settings in which the initial diagnosis of ADEs can be made, also serves to provide an important role model: the medical toxicologist as an educator to promote the detection and prevention of ADEs often in the academic setting of a medical school and affiliated teaching hospitals. Here, the academic toxicologist can champion the inclusion of education in therapeutics in the curriculum for medical and pharmacy students and house officers, and take an active role in the implementation of the instruction. Assuring that the curriculum in therapeutics includes recognition and prevention of ADEs and medical errors that lead to ADEs could have a significant beneficial impact on the ultimate outcome of the education process toward reduction of preventable ADEs. In addition to making sure that quality information is presented in the curriculum for trainees, the medical toxicologist can often create a special teaching opportunity for this type of education by establishing an elective or, in some cases, required experience in the curriculum for training in therapeutics. Participation in a quality learning experience can significantly impact the graduates’ knowledge of and attitudes toward therapeutics and risk reduction in patient care. Although the Institute of Medicine report on medical errors21 did not focus on education initiatives in its main recommendations for reduction of medical errors in the United States, it seems logical that education be considered an important (yet incomplete) tool to improve medication use and prevent ADEs and medical errors with therapeutic agents.
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The growth of the discipline of medication safety has provided new venues for involvement of toxicologists. Creation of interdisciplinary teams at many medical centers has allowed a system-oriented approach to the detection, mitigation, and prevention of adverse drug events. These take the form of pharmacy and therapeutics, medication safety, and quality improvement committees, and provide important opportunities to impact on the drug-induced disease problem. Interventions may be proactive and include targeted education programs, system modifications to reduce error rates, or a limitation of a specific drug usage to certain units of the organization or by certain specialties.
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A well-documented, complete report to MedWatch made by a health care professional is given priority review by the FDA. The toxicologist is likely to encounter a significant number of drug induced disease cases from a diagnostic and management standpoint, therefore practitioners of the specialty can make a significant impact on ADE reporting. All staff, including medical and clinical toxicologists and their trainees, should always submit an adverse event report locally for appropriate cases they encounter. Hospitals generally do not mandate or request that the reported event be “serious” as a requirement. The FDA MedWatch system requests that the reported events must be serious in nature or not previously associated with the medication involved. Other organizations that collect data on medication errors, such as the Institute for Safe Medication Practices, provide valuable insight and support to the drug safety community. They maintain a database, as do poison centers, and reporting is voluntary but important. In addition to reporting of the ADE, the medical toxicologist should promote publication of case reports of all new adverse events or adverse events occurring with newly approved products. Such publication often stimulates appropriate reporting of ADEs from other practitioners and generally raises awareness concerning a new ADE.
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An additional and very important role for toxicologists who work with poison centers is to facilitate the accurate reporting of poison center data to the National Poison Data System. Poison center data are invariably considered in the overall safety evaluation of approved and marketed drug. This is especially true for drugs with the potential for abuse and misuse. Accurate information and causality assignment for fatalities by the medical and managing directors of PCs can greatly aid regulatory decisions and guide efforts to improve drug safety at the national and international levels.
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Drug-induced disease is common in both inpatient and outpatient settings.
Despite significant advances in medical science applied to drug development and regulation, ADEs continue to occur and will continue to do so for the foreseeable future. ADEs have a significant impact on patient mortality and morbidity in addition to producing a significant burden on the health care system.
ADEs caused by newly approved drugs and ADEs resulting from a previously unrecognized association with drugs with a long marketing history continue to be a significant cause of mortality and morbidity.
The rapidly expanding number of approved drugs requires that the medical and clinical toxicologists and other practitioners have a continuing commitment to reduce the risk for ADEs in medical practice.
Active participation in clinical, teaching, and administrative roles that can improve ADE detection, analysis, and accurate reporting at the local and national levels by medical and clinical toxicologists has led to important advances in patient safety.
Maintaining a high level of commitment to these tasks as individuals and as a specialty will ultimately improve patient safety and benefit society.
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Medication Safety and Adverse Drug Events
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HISTORY AND EPIDEMIOLOGY
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Patient safety is of great interest to many regulatory groups, such as The Joint Commission, hospital administrations, health care professionals, and the general public. The interest has continued to grow since the publications of two reports by the Institute of Medicine. The first report, in 1999, focused on all medical errors and introduced measures necessary to ensure a safer health care system.85 The second report, in 2006, focused on reducing medication errors and adverse drug effects.83 These reports and others reveal that medications errors represent up to 25% of all medical errors.49 Many health care institutions address medication safety through their pharmacy and therapeutics (also commonly called drug and formulary), medication safety, patient safety, and quality improvement committees. Table 140–1 shows a timeline of some important developments in medication safety.
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Studies of medical errors, including those involving medications, are of a highly variable quality and usefulness. This occurs in large part because they address diverse populations, the definitions utilized vary, and a variety of data collection techniques, including observational studies and voluntary reporting, are employed.
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One study estimates that 180,000 people die each year of medical errors,64 and 60% of these injuries are probably preventable.17 The Institute of Medicine estimates that an additional 44,000 to 98,000 people die each year from medical errors.85 However, despite having methodologic differences, both studies establish that medical errors cause thousands of deaths each year. Studies like these illustrate the “Swiss Cheese Model of Error:”92 that is, multiple errors must align with an initial error to lead to harm.
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More than 1.5 million preventable adverse drug events (ADEs) may occur each year.83 An ADE is an untoward event or outcome associated with the use of a drug. The definition of ADEs includes medication errors as well as adverse reactions to a drug and drug interactions. A medication error is “any preventable event that may cause or lead to inappropriate medication use or patient harm while the medication is in the control of the health care professional, patient, or consumer.”81 An adverse drug reaction is a sign or symptom related to use of a medication that results in unpleasant effects when an error has not occurred. An adverse drug reaction is also an ADE.5 Those ADEs and medication errors with serious effects lead to 3.1% to 6.2% of all hospital admissions.62
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In 1997, the cost of a single ADE was estimated to be $2000 to $5000 at academic medical centers.10,22,23 Similarly, in 2012, a retrospective multi-center study of community hospitals estimated an increased cost of $3000 to overall care and increased length of stay of 3 days above expected when an ADE occurs.46 Other studies estimated that the annual cost of ADE morbidity and mortality was greater than $77 to 177 billion in the ambulatory care setting,33,50$2 billion in hospitals,10,23 and $4 billion in nursing homes.16 These costs exclude legal or other costs that accrue to the patient or their families.
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Deaths from Medication Errors and ADEs
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Although medication errors are the most common cause of iatrogenic patient injury, less than 2% result in injuries. Nevertheless, the incidence of ADEs in hospitalized patients is estimated to range from 2% to 20%22 resulting in 7000 deaths annually in the United States.85 A retrospective review of hospital death certificates by ICD 9 and ICD 10 codes from 1983 to 2004 revealed an increase of 361% in fatal medication errors and a 33% increase in deaths from ADEs occurring in a patient’s home.91 The hospital death certificate review also revealed an increase in fatal medication errors 32 times higher when prescription medications were combined with alcohol and or illicit xenobiotics.91 According to voluntary MedWatch reports to the US Food and Drug Administration (FDA), 17% of reported ADEs were associated with death, 7% were associated with permanent disability, and many others had serious complications. Women and elderly patients were at the highest risk.78
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National Coordinating Council for Medication Error Reporting and Prevention Taxonomy
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A useful medication error taxonomy, developed by the National Coordinating Council for Medication Error Reporting and Prevention (NCC MERP), classifies medication errors according to severity of outcome (Fig. 140–1).81 Importantly, the categories of least severity (A and B) describe circumstances or events in which the potential to cause error exists, or the error occurs but does not affect the patient. These “near misses” are so frequent that they serve as a critical source of information related to systems problems and education about medication error, but are typically underreported and underappreciated. In one study of 154,816 errors reported by hospitals and health systems to MEDMARX from 1999 to 2001, most of the errors were in category C (47%) and resulted in no patient injury, whereas there were 19 errors in category I, contributing to or resulting in patient death, comprising 0.01%.96 See Fig. 140–2 for a comparison of errors in the inpatient versus the emergency department (ED) setting based on the NCC MERP classification.
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FDA reports suggest that opioid analgesics and immune modulators are the most common medications in which errors resulted in death.78 The medications most frequently involved in errors and ADEs reported to MEDMARX were insulin, anticoagulants, morphine, and potassium chloride.96 These medications are considered high alert drugs according to the sentinel event alert system of The Joint Commission. Recently, The Joint Commission has focused more on all opioids (not just morphine) in order to promote safe use in the hospital setting.105 Identifying characteristics of high-risk drugs include low therapeutic index, pharmacokinetic interactions, inherent undesirable effects, newly approved or “off-label” use, and direct-to-consumer promotion.13Table 140–2 lists medications commonly reported and their classes of errors.
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The Medication Process
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The Medication Process comprises the five stages in the sequence of ordering a medication to its delivery to the patient. The stages are prescribing, transcribing, dispensing, administering, and monitoring.6 For patients discharged from the ED or hospital, discharge, and follow-up is the sixth stage.28 Although the medicating process has only six stages, there are multiple steps within each stage. The potential for error is high, increasing proportionately as the number of steps and their complexity increase. Figure 140–3 describes typical errors that occur at each stage in the process, along with prevention strategies.
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The greatest number of errors resulting in preventable ADEs (medication errors) occurs at the first prescribing stage.7 In a study of serious medication errors, 39% were found to occur at the prescribing stage, 12% at transcription, 11% at dispensing, and 38% at administration.65 In one study of 17,808 inpatient and ED medication orders, 6.2% of orders written involved a prescribing error and 30% of these were likely to harm the patient if they were not discovered.15 Another recent prospective study suggests that up to 43.8% of medications orders on hospital wards had a prescribing error discovered by ward-based pharmacists, despite the level of prescriber experience.98 In the ED, most errors occurred in either the prescribing or administration phase.89
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Transcribing errors usually involve poor communication due to illegible handwriting, the use of trailing zeroes, or inappropriate abbreviations. Poor handwriting can also lead to confusion, particularly with regard to look-alike and sound-alike medications.90 All information, whether printed, spoken, or otherwise communicated, must be transmitted in a clear, unambiguous, and timely fashion with avoidance of abbreviations. In its 2004 National Patient Safety Goals, The Joint Commission developed a minimum list of five sets of dangerous abbreviations, acronyms, and symbols that should not be used, and proposed preferred terms.104 The Institute for Safe Medication Practices (ISMP) also published a comprehensive list.48 By not using these abbreviations, the hope is that communication will be improved and that there will be no misinterpretation of poor physician handwriting.
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Dispensing errors are most commonly due to substitution and labeling errors.99 Errors at the stage of administering medications include incorrect drug, incorrect dose, incorrect route, and a drug given to the wrong patient. Computerized provider order entry (CPOE) was introduced to improve the medication process from prescribing to administering but has introduced new problems. See the Information Technology section for further discussion.
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Monitoring and discharging with follow up are associated with fewer errors. This phase involves attention to liver and kidney function, checking xenobiotic concentrations, and attention to and evaluation of drug interactions and pharmacokinetic interactions.28 Monitoring must be an ongoing process that begins when the patient receives the medication, regardless of where the patient is in the health care system, and continues as long as the individual continues to have the medication prescribed. In the acute stages of treatment, such as in the hospital or ED, the process is especially important and requires optimal three-way linkage between the pharmacy, laboratory, and physician.97 This process must be maintained throughout the individual’s continued relationship with the health care system. In the outpatient setting, providers must be aware of signs and symptoms related to adverse drug effects while they are monitoring and following up patients. In a study of 661 patients in four primary care practices, patient reports of medication side effects to their physicians led to changed therapies in 76% of cases. A failure to identify medication-related symptoms and change therapy resulted in 21% ameliorable and 2% preventable ADEs. Ameliorable ADEs were defined as those in which “the severity or duration could have been reduced substantially had different actions been taken.”112
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SPECIAL AT-RISK POPULATIONS
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Important medication safety issues exist for children and older adults, a problem that is exacerbated by their underrepresentation or exclusion from clinical trials. It is estimated, for example, that only a third of the medications used to treat children have been adequately tested in this population.25 Similar concerns apply to medications used in older adults and those individuals with specific underlying medical conditions that would have excluded them from trials.47
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Pediatric Considerations
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Pediatric adverse events involving medications may occur from the prenatal period and throughout childhood from the neonatal period through maturation. Errors may occur in all settings: the home, in ambulatory care, the ED, hospital floor, pediatric intensive care unit (PICU), and neonatal intensive care unit (NICU), and by all caregivers. Approximately 1 in 6.4 pediatric orders results in an error that reaches the child.72 Because of the greater need for dose calculations to allow for weight-based dosing, dose-related errors are more likely to occur in children.52 Errors also occur in the home environment with nonprescription medications, but the true incidence is unknown. In one survey, the errors associated with home antipyretic use were estimated at almost 50%.73 These errors were typically associated with underdosing, which is generally of little immediate harm.95 In the ambulatory care setting, the incidence is unknown but one study identified “numerous” errors in prescription writing in a pediatric clinic.110 In the ED setting, the error rate was estimated at 10% of all pediatric charts.57 There may be an increased risk of errors in children cared for in nonacademic or rural EDs compared with academic or pediatric EDs.55 A retrospective chart review of 177 pediatric charts in four rural EDs identified 84 different medication errors in 69 of the 135 patients who received medications. The outcomes of these errors were in NCC MERP categories A to D (Fig. 140–1).71 A study of 18 pediatric ED voluntary event/incident reporting data showed that 19% of all incidents were related to medication events. A total of 94% were medication errors and 6% were ADRs. Errors included using incorrect weights, duplicate dosing, and miscalculations. Human factors contributed to 84% of the medication errors in this study.100 See the Factors Affecting Human Performance section for further discussion.
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Hospitalized children experience up to three times the rate of medication errors and potential ADEs as do adults.53 The incidence of medication errors of hospitalized children is estimated at about 6% for all orders written; the majority (74%) of these occur at the prescribing stage and approximately 20% are classified as potentially harmful based on a 4-point Likert scale developed by the researchers instead of the NCC MERP classification previously described.38 Pharmacists based on pediatric hospital wards, discovered that 5.9% of orders contained a prescribing error and were able to intervene through the order entry system.30 Generally, children in the intensive care unit appear to be at higher risk for errors compared to adults and hospitalized children not in the ICU, presumably reflecting the increased complexity of disease and the medications used.55 Incorrect dosing, especially with the intravenous route, is the most commonly reported error. Dosing of antimicrobials and intravenous fluids are the most common medications involved.29,36,53 Errors and discrepancies found in hospital discharge instructions, with lack of complete medication reconciliation, could lead to patient harm51 (Chap. 32).
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Geriatric Considerations
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Medication errors in older adults also occur throughout the health care continuum: the home, ambulatory care, in nursing homes, in the assisted-living setting, and in the hospital (Chap. 33). Adults older than 65 years of age have a relative risk of 2.37 for drug complications and 4.12 for medication errors compared to adult patients younger than 65 years of age.17 The incidence of medication error at home with nonprescription medications is unknown but, for reasons outlined below, would be expected to exceed that of the younger adult population. Using a variety of methodologies, ADEs were evaluated for a 12 month period in a multispecialty ambulatory care practice in a cohort of 27,617 Medicare enrollees, equivalent to more than 30,000 person-years of observation. Extrapolating their findings, to the estimated 38 million Medicare enrollees (those ≥ 65 years), would predict nearly 2 million ADEs annually, of which more than 25% would be considered preventable and about 180,000 fatal or life threatening.43 A recent study estimates that there are about 265,802 ED visits in patients older than 65 years of age for ADEs and 99,628 of these patients require admission to the hospital. In the same study, patients older than 80 years of age constituted half of those admitted to the hospital. Medications or classes of medications involved in two-thirds of the hospitalizations were diabetic and antithrombotic medications.19
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There are more than 1.5 million nursing home residents in the United States. The average such resident uses six different medications, and 20% use ten or more.14 Extrapolating the findings of a study of 18 community-based nursing homes in Massachusetts over a 1 year period predicts 350,000 ADEs annually, more than one-half of which would be preventable.42 Fatal or life-threatening ADEs would represent 20,000 of these predicted events of which 80% would be preventable. Approximately one million other seniors live in assisted-living facilities, and are vulnerable to medication errors for a variety of reasons, including inadequate physician support, inadequately trained staff, and staffing shortages. ADEs cause 10.5% of hospital admissions for geriatric patients and are the most common type of adverse event occurring in hospitalized elderly patients.66,114 These drugs result in nearly 50% of ADE-related visits to the ED but are only prescribed during 9.4% of outpatient visits.20
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Addressing these issues is becoming ever more important as the US Census Bureau predicts a rise of 62 million in the number of Americans 65 years of age or older by the year 2025 and a 68% increase in the 85 years of age or older population that may be at an even higher risk.4 Advancing age brings with it several important considerations from the point of view of medication safety. Medical comorbidity increases with age, and therefore an increasing likelihood of receiving multiple medications. With more medications, the number of potential errors and interactions increases. Frailty and cognitive decline in older adults may result in errors following self-administration. Alterations in medication absorption, metabolism, distribution, and elimination may all affect the efficacy of the medication (Chaps. 9 and 33).
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Criteria were developed in both the United States (Beers)11,12,35 and Canada74 to determine appropriateness of medication prescribing for nursing home residents. Forty eight medications or classes of medications to avoid, and medications to avoid in the presence of 20 diseases/conditions were identified.35 The prevalence of inappropriate medication use in older adults is estimated to be in the 12% to 40% range.102 One in five prescriptions given to elderly individuals are considered inappropriate based on Beers criteria, with diphenhydramine and amitriptyline being the most common medications prescribed inappropriately.87 Older adult patients medicated with benzodiazepines, for example, have a four-fold increase in falls (Chap. 33).
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RESPONSE TO MEDICATION ERROR
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One of the leading causes of medication errors is human performance deficit. Almost invariably a human action will precede the ADE, and this temporal contiguity of action and consequence typically generates a tendency to blame someone. In most cases the blame will fall on the last person to have had contact with the patient. In recent years, however, a consensus has emerged that blaming people for errors is counterproductive. The number of ADEs that result from egregious behavior is very small, and more often than not an explanation for the fault will be found within the system that allowed the error to occur. Attempts to understand the nature of these faults, and to correct them, while being sensitive to the potential for unintended consequences, is the most appropriate response. Several processes can be used to respond to errors or system-problems. These include root cause analysis, clinical incident analysis, failure mode and effect analysis, and Lean Six Sigma (LSS).
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Root cause analysis (RCA), a term originally used to investigate major industrial events, is a technique that provides a structured, process-oriented analysis of sentinel events. The Joint Commission in accredited hospitals mandated its use in 1997. It is a time-consuming process requiring multidisciplinary teams with specialized training, and is subject to bias and methodologic limitations.108 Nevertheless, a judiciously conducted RCA may provide insights into systemic failures underlying the ADE, and identify areas that require change. An alternative approach, a clinical incident analysis protocol, was developed that more appropriately shifts the emphasis from the individual to the system.107 The clinical incident analysis protocol utilizes seven factors as the basis for an investigation. Some organizations have developed a hybrid combining these two approaches. Both RCA and clinical incident analysis are conducted retrospectively, and therefore subject to retrospective bias
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An alternative approach is failure mode and effect analysis (FMEA), which proactively attempts to identify potential errors, to initiate preventive measures. A multidisciplinary group is utilized in the FMEA approach to identify a process or subprocess that needs analysis, to identify the steps of the process and determine the risk/likelihood/severity of failure of each step. Once this phase is accomplished, the team prioritizes a high-risk step and conducts an RCA to make recommendations on redesigning the step. The establishment modifications are analyzed in their performance to determine change and decrease in risk. This process is designed as a quality control and assurance to protect the proceedings from legal investigation.3
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Other processes are being introduced into the health care industry to improve quality of care and safety and reduce costs. Two such approaches are Lean and Six Sigma, sometimes utilized together as LSS. Both were initially described in the Toyota Production System and have been adapted to health care. Define, measure, analyze, improve, and control are all steps related to LSS. It involves defining the process that needs evaluation, determining how to measure the process, analyzing the data collected based on the determined measures, forming an improvement plan based on the analysis, and putting a new process in place with the goals of developing a lasting culture regarding the newly improved process with elimination of waste.1,116 Each of these steps has principles to guide the use of LSS. The Agency for Healthcare Research and Quality has made specific forms to aid health care facilities when adopting these approaches to safety and improvement.63
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To reduce medication errors, each hospital should simplify, standardize, and stratify processes and communication. The medication process should be carefully automated with computer order entry and bar coding as extensively as the system will permit. While these information technology solutions will aid the medication process, nothing is perfect and each change introduces new problems. See the Information Technology section later. Limitations of attention and vigilance should be understood and the reporting of errors in a nonpunitive environment should be encouraged.65 Improving information access, error proofing, reducing reliance on memory, enhanced training, and the use of buffers or redundancy in an attempt to prevent errors should also be encouraged.64 Each time a medication is given, the focus should be “right drug, right dose, right route, right patient, at the right time.”
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In 2003, the American Academy of Pediatrics Committees on Drugs and on Hospital Care developed a position statement regarding the reduction of medication errors in the pediatric population. The recommendations can be adapted to all hospital settings and to patients of all ages. These recommendations include appropriate staffing, utilization of the resources in the pharmacy, standardization of hospital equipment and protocols, and the development of a nonpunitive, barrier-free system to report and easily track errors.103 Other more recent groups also encourage reduction of medication errors and participation in medication safety. The American College of Medical Toxicology encourages medical toxicologists to use their expertise and training to aid health care systems in reduction of errors and other pharmacy and therapeutics issues.2
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For older adults, prescribers should review medication indications and avoid age bias. Polypharmacy should be limited, with medications prescribed only as necessary. Dosing should be adjusted, as needed based on renal and hepatic function. Medication review by pharmacists can aid in decreasing the use of potentially inappropriate medications and in decreasing the number of medications prescribed (polypharmacy).76 In the hospital, outside of the emergency department and emergent situations, pharmacists review all medication orders, when available, and verify the medication as appropriate prior to it being dispensed. Pharmacists can also aid in medication reconciliation at transitions of care and upon hospital discharge to prevent complications of polypharmacy.40,59
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FACTORS AFFECTING HUMAN PERFORMANCE
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Human factors lead to many medication errors. In fact, it is not surprising that human performance deficits are the primary causes of medication errors in such an extremely complex medical environment. A performance deficit means that the individual making the error had the prerequisite knowledge to avoid the error but failed to do so. There are numerous variables that contribute to performance deficit, including many ergonomic issues such as workload, distractions, resource limitations, and staff shortages. This environment is both burdened and enriched by many inherited properties. Human factors and ergonomics theory draws on a variety of disciplines, including industrial engineering, industrial psychology, cognitive psychology, and information technology. Much can be done to optimize the interface between humans and the work environment and to ensure that systems operate more efficiently. As a general principle, it would be preferable if the dominant purpose in designing medical devices and processes was that they fit human users, and not the converse. Table 140–3 lists some of the more common human performance deficits. Such errors often manifest as simple slips of action, or execution failures, arising from distraction by something other than the task at hand.92 Vigilance is better maintained in individuals who are well rested and working without interruption or distraction in a well-designed environment. Fewer medication errors occur in optimally designed environments.65
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Human performance deficits such as diminished memory, sleep deprivation, depression, and distractions contribute to errors. Resident physician mood and lack of sleep are also factors in performance deficits. Depressed residents made 6.2 times as many medication errors as nondepressed residents.34 Sleep deprivation and improper supervision were highlighted initially after the Libby Zion case, in which a patient on phenelzine developed fatal serotonin toxicity following the administration of meperidine by a sleep-deprived and inadequately supervised intern. Interns working a traditional schedule of call every third night with extended work shifts (36 hours) made 35.9% more serious medical errors than those with the current reduced work schedule.60 In particular, there were 20.8% more serious medication errors during the older work schedules compared with the current reduced hour schedule.60 In 2008, an Institute of Medicine study addressed resident work hours and patient safety. This report recommended residents be provided with designated sleep time during each day and rest periods each week in order to decrease the risk of fatigue-related medical errors.84
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A particularly important goal for human performance deficit is the reduction of cognitive load and distractions. Many medication errors originate from cognitive failings because of interruptions, distractions, inexperience, or simple overloading—referred to as performance deficit. In the ED, increased cognitive load such as related to increased number of boarding patients, increased number of medication orders, and increased number of medications to be administered all lead to increased medication errors.89 Further efforts must be directed at strategies to reduce cognitive failure. The adoption of some very simple strategies based on human factors engineering principles will reduce error, such as simplification of the number of steps involved, reducing reliance on memory, applying cognitive forcing strategies,27 and using cognitive aids. Research into reducing distractions during medication administration has focused on adapting principles from the airline industry, “the sterile cockpit principle.”37 This principle limits interruptions and distractions that could interfere with proper performance of a critical task or tasks. In the airline industry, the use of this principle occurs during takeoff, taxi, and landing. In mediation administration, this principle involves the use of “do not disturb” signs or vests worn by the nurse administering medications, no conversations to disrupt the medication nurse during this important task, and the other nurses on the unit answering phone calls or patient/family questions. This approach reduces medication administration errors by improving human performance.37,93 One particularly useful aid to reduce cognitive load is the color-coded Broselow-Luten system, for pediatric medication dosing.69 This approach has the potential for further development to improve the safety of nonprescription medications and other potentially dangerous products used in the home.
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Another factor that contributes to errors is the assignment of a new role to a provider such as asking physicians to dispense or administer medications. Pharmacists are the only professional group formally trained and experienced in dispensing medication, and not surprisingly, their presence is associated with a lower medication-dispensing error rate.58,67 Nurses administer medications because they receive such training and the administration should be restricted to them except during specific circumstances such as procedural sedation.28