James B. Mowry

2014 Annual Report of the American Association of Poison Control Centers’ National Poison Data System (NPDS): 32nd Annual Report

ABSTRACT Background: This is the 32nd Annual Report of the American Association of Poison Control Centers’ (AAPCC) National Poison Data System (NPDS). As of 1 January 2014, 56 of the nation’s poison centers (PCs) uploaded case data automatically to NPDS. The upload interval was 7.82 [7.02, 11.17] (median [25%, 75%]) minutes, creating a near real-time national exposure and information database and surveillance system. Methodology: We analyzed the case data tabulating specific indices from NPDS. The methodology was similar to that of previous years. Where changes were introduced, the differences are identified. Poison center cases with medical outcomes of death were evaluated by a team of medical and clinical toxicologist reviewers using an ordinal scale of 1–6 to assess the Relative Contribution to Fatality (RCF) of the exposure to the death. Results: In 2014, 2,890,909 closed encounters were logged by NPDS: 2,165,142 human exposures, 56,265 animal exposures, 663,305 information calls, 6,085 human confirmed nonexposures, and 112 animal confirmed nonexposures. US poison centers (PCs) also made 2,617,346 follow-up calls in 2014. Total encounters showed a 5.5% decline from 2013, while health care facility human exposure cases increased by 3.3% from 2013. All information calls decreased by 17.7% and health care facility (HCF) information calls were essentially flat, decreasing by 0.04%, medication identification requests (Drug ID) decreased 29.8%, and human exposures reported to US PCs decreased 1.1%. Human exposures with less serious outcomes have decreased 3.40% per year since 2008 while those with more serious outcomes (moderate, major or death) have increased by 4.29% per year since 2000. The top 5 substance classes most frequently involved in all human exposures were analgesics (11.3%), cosmetics/personal care products (7.7%), household cleaning substances (7.7%), sedatives/hypnotics/antipsychotics (5.9%), and antidepressants (4.4%). Sedative/Hypnotics/Antipsychotics exposures as a class increased the most rapidly (2,368 calls (12.2%)/year) over the last 13 years for cases showing more serious outcomes. The top 5 most common exposures in children age 5 years or less were cosmetics/personal care products (14.0%), household cleaning substances (11.0%), analgesics (9.3%), foreign bodies/toys/miscellaneous (6.7%), and topical preparations (5.8%). Drug identification requests comprised 43.3% of all information calls. NPDS documented 1,835 human exposures resulting in death with 1,408 human fatalities judged related (RCF of 1-Undoubtedly responsible, 2-Probably responsible, or 3-Contributory). Conclusions: These data support the continued value of PC expertise and need for specialized medical toxicology information to manage more serious exposures, despite a decrease in calls involving less serious exposures. Unintentional and intentional exposures continue to be a significant cause of morbidity and mortality in the US. The near real-time, always current status of NPDS represents a national public health resource to collect and monitor US exposure cases and information calls. The continuing mission of NPDS is to provide a nationwide infrastructure for surveillance for all types of exposures (e.g., foreign body, viral, bacterial, venomous, chemical agent, or commercial product), the identification of events of public health significance, resilience, response and situational awareness tracking. NPDS is a model system for the real-time surveillance of national and global public health. NOTE: Comparison of exposure or outcome data from previous AAPCC Annual Reports is problematic. In particular, the identification of fatalities (attribution of a death to the exposure) differed from pre-2006 Annual Reports (see Fatality Case Review – Methods). Poison center death cases are described as all cases resulting in death and those determined to be exposure-related fatalities. Likewise, Table 22 (Exposure Cases by Generic Category) since year 2006 restricts the breakdown of included deaths to single-substance cases to improve precision and avoid misinterpretation.

2012 Annual Report of the American Association of Poison Control Centers’ National Poison Data System (NPDS): 30th Annual Report

Abstract Background: This is the 30th Annual Report of the American Association of Poison Control Centers’ (AAPCC) National Poison Data System (NPDS). As of July 1, 2012, 57 of the nations poison centers (PCs) uploaded case data automatically to NPDS. The upload interval was 7.58 [6.30, 11.22] (median [25%, 75%]) min, creating a near real-time national exposure and information database and surveillance system. Methodology: We analyzed the case data tabulating specific indices from NPDS. The methodology was similar to that of previous years. Where changes were introduced, the differences are identified. Poison center cases with medical outcomes of death were evaluated by a team of 34 medical and clinical toxicologist reviewers using an ordinal scale of 1–6 to assess the Relative Contribution to Fatality (RCF) of the exposure to the death. Results: In 2012, 3,373,025 closed encounters were logged by NPDS: 2,275,141 human exposures, 66,440 animal exposures, 1,025,547 information calls, 5,679 human confirmed nonexposures, and 218 animal confirmed nonexposures. Total encounters showed a 6.9% decline from 2011, while healthcare facility (HCF) exposure calls increased by 1.2%. All information calls decreased by 14.8% and HCF information calls decreased by 1.7%, medication identification requests (Drug ID) decreased by 22.0%, and human exposures reported to US PCs decreased by 2.5%. Human exposures with less serious outcomes have decreased by 3.7% per year since 2008, while those with more serious outcomes (moderate, major, or death) have increased by 4.6% per year since 2000. The top five substance classes most frequently involved in all human exposures were analgesics (11.6%), cosmetics/personal care products (7.9%), household cleaning substances (7.2%), sedatives/hypnotics/antipsychotics (6.1%), and foreign bodies/toys/miscellaneous (4.1%). Analgesic exposures as a class increased the most rapidly (8,780 calls/year) over the last 12 years. The top five most common exposures in children aged 5 years or less were cosmetics/ personal care products (13.9%), analgesics (9.9%), household cleaning substances (9.7%), foreign bodies/toys/ miscellaneous (7.0%), and topical preparations (6.3%). Drug identification requests comprised 54.4% of all information calls. NPDS documented 2,937 human exposures resulting in death with 2,576 human fatalities judged related (RCF of 1-Undoubtedly responsible, 2-Probably responsible, or 3-Contributory). Conclusions: These data support the continued value of PC expertise and need for specialized medical toxicology information to manage the more severe exposures, despite a decrease in calls involving less severe exposures. Unintentional and intentional exposures continue to be a significant cause of morbidity and mortality in the US. The near real-time, always current status of NPDS represents a national public health resource to collect and monitor US exposure cases and information calls. The continuing mission of NPDS is to provide a nationwide infrastructure for public health surveillance for all types of exposures, public health event identification, resilience response, and situational awareness tracking. NPDS is a model system for the nation and global public health.

2013 Annual Report of the American Association of Poison Control Centers’ National Poison Data System (NPDS): 31st Annual Report

ABSTRACT Background: This is the 31st Annual Report of the American Association of Poison Control Centers’ (AAPCC) National Poison Data System (NPDS). As of January 1, 2013, 57 of the nations poison centers (PCs) uploaded case data automatically to NPDS. The upload interval was 8.08 [7.10, 11.63] (median [25%, 75%]) minutes, creating a near real-time national exposure and information database and surveillance system. Methodology: We analyzed the case data tabulating specific indices from NPDS. The methodology was similar to that of previous years. Where changes were introduced, the differences are identified. Poison center (PC) cases with medical outcomes of death were evaluated by a team of 38 medical and clinical toxicologist reviewers using an ordinal scale of 1–6 to assess the Relative Contribution to Fatality (RCF) of the exposure to the death. Results: In 2013, 3,060,122 closed encounters were logged by NPDS: 2,188,013 human exposures, 59,496 animal exposures, 806,347 information calls, 6,116 human-confirmed nonexposures, and 150 animal-confirmed nonexposures. Total encounters showed a 9.3% decline from 2012, while health care facility human exposure calls were essentially flat, decreasing by 0.1%.All information calls decreased 21.4% and health care facility (HCF) information calls decreased 8.5%, medication identification requests (drug ID) decreased 26.8%, and human exposures reported to US PCs decreased 3.8%. Human exposures with less serious outcomes have decreased 3.7% per year since 2008 while those with more serious outcomes (moderate, major or death) have increased by 4.7% per year since 2000. The top five substance classes most frequently involved in all human exposures were analgesics (11.5%), cosmetics/personal care products (7.7%), household cleaning substances (7.6%), sedatives/hypnotics/antipsychotics (5.9%), and antidepressants (4.2%). Sedative/hypnotics/antipsychotics exposures as a class increased most rapidly (2,559 calls/year) over the last 13 years for cases showing more serious outcomes. The top five most common exposures in children of 5 years or less were cosmetics/personal care products (13.8%), household cleaning substances (10.4%), analgesics (9.8%), foreign bodies/toys/miscellaneous (6.9%), and topical preparations (6.1%). Drug identification requests comprised 50.7% of all information calls. NPDS documented 2,477 human exposures resulting in death with 2,113 human fatalities judged related (RCF of 1, undoubtedly responsible; 2, probably responsible; or 3, contributory). Conclusions: These data support the continued value of PC expertise and need for specialized medical toxicology information to manage the more severe exposures, despite a decrease in calls involving less severe exposures. Unintentional and intentional exposures continue to be a significant cause of morbidity and mortality in the United States. The near real-time, always current status of NPDS represents a national public health resource to collect and monitor US exposure cases and information calls. The continuing mission of NPDS is to provide a nationwide infrastructure for public health surveillance for all types of exposures, public health event identification, resilience response and situational awareness tracking. NPDS is a model system for the nation and global public health.

The EXTRIP (EXtracorporeal TReatments In Poisoning) workgroup: Guideline methodology

Abstract Extracorporeal treatments (ECTRs), such as hemodialysis and hemoperfusion, are used in poisoning despite a lack of controlled human trials demonstrating efficacy. To provide uniform recommendations, the EXTRIP group was formed as an international collaboration among recognized experts from nephrology, clinical toxicology, critical care, or pharmacology and supported by over 30 professional societies. For every poison, the clinical benefit of ECTR is weighed against associated complications, alternative therapies, and costs. Rigorous methodology, using the AGREE instrument, was developed and ratified. Methods rely on evidence appraisal and, in the absence of robust studies, on a thorough and transparent process of consensus statements. Twenty-four poisons were chosen according to their frequency, available evidence, and relevance. A systematic literature search was performed in order to retrieve all original publications regardless of language. Data were extracted on a standardized instrument. Quality of the evidence was assessed by GRADE as: High = A, Moderate = B, Low = C, Very Low = D. For every poison, dialyzability was assessed and clinical effect of ECTR summarized. All pertinent documents were submitted to the workgroup with a list of statements for vote (general statement, indications, timing, ECTR choice). A modified Delphi method with two voting rounds was used, between which deliberation was required. Each statement was voted on a Likert scale (1–9) to establish the strength of recommendation. This approach will permit the production of the first important practice guidelines on this topic.

Increased adolescent opioid use and complications reported to a poison control center following the 2000 JCAHO pain initiative

Context. Adolescents are at risk to abuse opioid analgesics for many reasons, including inaccurate perception of risk and increased drug availability. In 2000, the Joint Commission on Accreditation of Healthcare Organizations (JCAHO) released pain management standards that emphasized pain control as a patient rights issue. This focus on analgesia may have increased both the prescribing and use of opioid analgesics, thereby increasing availability. Objective. Using data from a US poison center, this study aims to compare the number of adolescent opioid cases and their outcome severity before and after the 2000 JCAHO pain initiative. Methods. Retrospective case series of opioid exposures involving persons 12–18 years of age reported to a US poison center from 1994 to 2007. The main outcome measure was the number of adolescent opioid cases reported for 1994–2000 compared to 2001–2007. Secondary outcomes included outcome severity, number of cases involving specific opioids, and correlation between the number of cases and the amount of opioids distributed to the state. Results. There were 1634 adolescent opioid-related cases with 187 cases developing medical complications. Compared with 1994–2000, the rate ratio of cases involving adolescents and opioid analgesics for the years 2001–2007 was 1.69 (95% CI: 1.53, 1.86), and these cases were 2.84 (95% CI: 2.06, 3.91) times more likely to have had medical complications. Medical complications involving methadone (p =0.001) increased after the JCAHO initiative, while complications related to codeine (p =0.001) and propoxyphene (p =0.030) decreased. There were 15 deaths in 2001–2007 and none in 1994–2000 (p =0.012). Lastly, there was a correlation between the rate of adolescent opioid cases and the amount of opioids distributed to the state (r2 =0.90; p < 0.001). Conclusion. In the 7 years following the JCAHO pain standards, there was an increase in the number and severity of adolescent opioid-related poison center cases. The increase correlates with statewide availability of opioids. These data may prove useful in drug education and prevention programs targeting adolescents.

Trends in toxic alcohol exposures in the United States from 2000 to 2013: a focus on the use of antidotes and extracorporeal treatments

Morbidity and mortality from toxic alcohols like ethylene glycol and methanol remain prevalent worldwide. The introduction of fomepizole, a potent blocker of alcohol dehydrogenase, has modified current practice over the last 15 years. The aim of the study was to describe the characteristics of toxic alcohol poisoning reported to US poison centers, the trends in the incidence of antidote use and hemodialysis treatment, as well as the related mortality. A retrospective study of all electronic entries from the AAPCC National Poison Data System database, from the years 2000 to 2013 was reviewed. When considering all exposures, the great majority of patients had a benign outcome. Major effects (e.g., life threatening) occurred in 2.1% and 4.9% of methanol and ethylene glycol cases, respectively. Mortality rates were similar for both toxic alcohols, approximately 0.6%. When only considering ingestions reported to healthcare facilities, a major effect was reported in 9.5% and 20.5%, and the mortality rate was 2.9% and 2.4% for methanol and ethylene glycol exposures, respectively, and remained constant over time. The use of fomepizole increased statistically over the study period while that of ethanol decreased, until it became proportionally negligible by 2012‐2013. The use of hemodialysis significantly decreased in “Early” ethylene glycol exposures during the study period. Similar to other reports, it appears that the use of fomepizole has largely supplanted ethanol as the antidote of choice in toxic alcohol exposures and may decrease the requirements for hemodialysis in patients poisoned with ethylene glycol who have no acidosis and normal kidney function.

Practice Trends in the Use of Extracorporeal Treatments for Poisoning in Four Countries.

Extracorporeal treatments (ECTRs) such as hemodialysis (HD), enhance the elimination of a small number of toxins. Changes in overdose trends, prescribing practices, antidotes, and dialysis techniques may alter the indications and rates of ECTR use over time. This study analyzed trends in ECTR for poisonings in four countries. A retrospective study of national poison center databases from the United States, Denmark, United Kingdom, and five regional databases within Canada was performed. All cases of patients receiving an ECTR were included. ECTR cases were totalled annually and reported as annual rates per 100,000 exposures with stratification per types of ECTR and toxins. The data collection varied by countries. United States, 1985–2014; United Kingdom, 2011–2013; Denmark, 2005–2014, and regions of Canada as follows: Alberta, 1991–2015; Saskatchewan, 2001–2015; Nova Scotia‐PEI, 2006–2015; Quebec, 2008–2014; Ontario‐Manitoba, 2009–2015; British Columbia, 2012–2015. During the study period, the total number of ECTRs and rates per 100,000 exposures, respectively, were: United States, 40,258 and 65.7; United Kingdom, 343 and 232.6; Denmark, 616 and 305.5; Canada, 2709 and 177.5; case rates increased over time for the United States, Denmark, and Canada, but decreased in the United Kingdom. Across the United States and Denmark, HD was the preferred modality used. Toxins for which ECTR was most often used were: United States, ethylene glycol; Canada, methanol; United Kingdom, ethylene glycol; Denmark, salicylates. A high number of ECTRs were performed for atypical toxins such as acetaminophen and benzodiazepines. These data demonstrate a growing use of HD for poisoning with significant regional variations in the overall rates and indications.

Acute tacrolimus toxicity in a non-transplant patient

Introduction. Tacrolimus is an immunosuppressant widely used in recipients of solid organ transplants to prevent rejection. Toxicity is usually reported in transplant patients. We report the first case of tacrolimus toxicity in a non-transplant patient. Case report. A 42 year-old, 48 kg woman complained of neck pain following a motor vehicle collision and was admitted for observation. On examination, her pulse was 112 beats/minute and her blood pressure 188/134 mmHg. Because the hypertension and tachycardia might be ethanol withdrawal, she was admitted and treated with multivitamins, folate, and thiamine in her maintenance fluids. She was discharged after 4 days in hospital. The day after her discharge, she was asked to return after it was discovered that she had inadvertently received tacrolimus (total of 400 mg) instead of thiamine. She was admitted with non-oliguric renal failure and metabolic acidosis. A tacrolimus concentration 27 hours after her last exposure was 96.8 ng/mL (therapeutic 5 to 20 ng/mL). Treatment was supportive and she was discharged after 4 days without sequellae. Discussion. Our patients tacrolimus dose was 2.1 mg/kg/day for 4 days (therapeutic 0.03 to 0.05 mg/kg/day). Her tacrolimus elimination half-life was 16.5 hours, compared to a mean half-life in healthy volunteers of 34.2 ± 7.7 hours. Conclusion. Clinical toxicity, similar to that seen in transplant patients, can develop in non-transplant patients following intravenous administration of supra-therapeutic doses of tacrolimus.

Evaluation of toxicity after acute accidental methotrexate ingestions in children under 6 years old: a 16-year multi-center review

Abstract Context: There is little data on the frequency of adverse events following acute methotrexate ingestions in pediatric patients. Likewise, recommendations for observation length, site and management strategies in this population are not well established. Therefore, most recommendations are modeled after management of chronic overdose in patients with underlying medical conditions. Objective: The primary objective of this study is to determine the frequency of acute toxicity after acute methotrexate accidental unsupervised ingestions in patients less than six years. In addition, we describe the frequency of late toxicity and characterize the management site and approaches. Materials and Methods: This is a retrospective cohort study of pediatric accidental unsupervised methotrexate ingestions reported to six poison centers in the United States over a 16 year period. Demographic information, exposure details, signs, symptoms, treatments, length and location of observation and outcomes were collected. Results: 103 patients met inclusion criteria. Methotrexate dose was reported in 86 patients (84%) and ranged from 1.3 mg–75 mg. The majority of cases (97%) ingested a dose ≤20 mg. The significant majority of cases experienced no clinical effects (99 of 103 cases; 96%). Three children experienced minor outcome (3%). There were no patients with a major outcome or death. Conclusions: The incidence of toxicity from pediatric single, acute ingestions of methotrexate is rare and when it occurs is generally limited to no or only minimally concerning effects. Because concentrations from single ingestions were consistent with low subtoxic exposures, we believe that home monitoring without hospital referral and without methotrexate specific therapy is reasonable in those with acute ingestions up to 20 mg.

In vitro release of fentanyl from transdermal patches in gastric and intestinal fluid

Abstract Context. Fentanyl patches are intended for transdermal use to treat pain. However, these patches have been abused by ingestion, offering a unique mode of drug delivery with unknown drug release characteristics. Objectives. In vitro fentanyl release from patches in simulated gastric and intestinal fluid was evaluated. Materials and methods. Ten 75 mcg/hr fentanyl transdermal patches (Mylan Pharmaceuticals Inc., Morgantown, WV), simulated gastric fluid without enzymes, and USP simulated intestinal fluid (Ricca Chemical Company, Arlington, TX) were obtained. Each fentanyl patch was placed into either 100 mL of simulated gastric fluid or 100 mL of simulated intestinal fluid. Flasks were agitated at 24 rpm while incubated at 36.8°C. Fluid was sampled at time zero and 5, 15, 30, 60, 120, and 180 min after submersion. Fentanyl was assayed using ultra performance liquid chromatography coupled with tandem mass spectrometry (AIT Laboratories, Indianapolis, IN). Results. An average of 239 mcg and 1,962 mcg of fentanyl was released into gastric fluid and 338 mcg and 3,139 mcg into intestinal fluid in 5 min and 3 h, respectively. An average of 26% and 41% of 7.65 mg of fentanyl contained within the 75 mcg/hr patch was released into gastric and intestinal fluid in 3 h, respectively (p = 0.169, Students t-test). Discussion. Our results demonstrate fentanyl release within 5 min of submersion. Conclusion. These results help support the potential rapid onset of clinical compromise reported and are relevant to the design of future pharmacokinetic studies of fentanyl release from transdermal patches.