ACMT Positions, Guidelines and Recommendations
 Caring for patients with Opioid Use Disorder During Coronavirus Disease Pandemic |
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July 7, 2020 |
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| Maintenance of Certification in Coronavirus Pandemic |
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June 19, 2020 |
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| Medication Administration and Safety During the Response to COVID-19 Pandemic |
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June 5, 2020 |
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| Limiting Harms of Vaping and E-cigarette Use |
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May 22, 2020 |
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| Off-Label Prescribing during COVID-19 Pandemic |
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May 3, 2020 |
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| Prescription Drug Shortages |
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Link to Statement April 2020
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| Medication Shortages During Coronavirus Disease Pandemic |
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April 2020 |
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| Interpretation of Urine for Tetrahydrocannabinol Metabolites |
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| Recommending Removing The Waiver Requirement For Prescribing Buprenorphine For Opioid Use Disorder |
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| Addressing Pediatric Cannabis Exposure |
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| Buprenorphine Administration in the Emergency Department |
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| Addressing the Rising Cost of Prescription Antidotes |
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| Alternative or Contingency Countermeasures for Acetylcholinesterase Inhibiting Agents |
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| The Role of Clinical Pharmacists in the Emergency Department |
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| Sodium Bicarbonate Shortage Recommendations |
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| Preventing Occupational Fentanyl and Fentanyl Analog Exposure to Emergency Responders |
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| Safety Data Sheets |
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The American College of Medical Toxicology supports the intent of the Federal Regulations which requires Safety Data Sheets (formerly Material Safety Data Sheets) as part of communications to improve safety in the workplace.1 It is the position of ACMT that the format of the SDS should not be expanded to serve as a mechanism to communicate to practitioners of medicine advice on treatment of the health effects of chemical exposure other than first aid measures. As an alternative, the SDS should include a referral mechanism through which advice on treatment is available from a physician board-certified in medical toxicology. If one is not available, advice can be obtained from a poison control center. First aid recommendations should be intended for first responders and include specific treatment only when there is an antidote or intervention generally accepted as effective, and early administration could substantially improve outcome. The first aid section should be developed under the supervision of a physician. Additionally, SDS should include a complete listing of preservatives in Section 3 and allergens/sensitizers in Sections 2, 3, 11, 15, or 16.2,3 For complete and accurate information, special attention should be given to engineered nanoparticles. This information should be reported on the SDS within three months of being discovered.4,5 The individual or organization responsible for the content should be identified and the source of listed health hazards should be cited. Disclaimer While individual practitioners may differ, this is the position of the College at the time written, after a review of the issue and pertinent literature. References
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| Determining Brain Death in Adults After Drug Overdose |
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The position of the American College of Medical Toxicology, endorsed by the American Academy of Clinical Toxicology and the Society of Critical Care Medicine, is as follows: We agree with the American Academy of Neurology (AAN) recommendation that the clinical determination of brain death should only be made in the absence of drug intoxication or poisoning. However, a drug screen and clearance calculation using five drug half-lives (T1/2) are not sufficient to exclude intoxication in all cases. Drug screens are not sufficiently comprehensive to detect all drugs that may cause mental status depression. Even when the specific drugs are quantitatively identified, the use of kinetic data to determine clinical effects is limited because drugs often have prolonged half-lives in overdose. For certain drugs and toxins, the duration of effect may extend beyond their detected presence in the vascular space. We recommend identification of drugs or toxins by careful history and targeted testing. An observation period of longer than five half-lives is appropriate when there is a possibility of an extremely large drug overdose, delayed drug absorption, delayed elimination, or interaction with another agent. In cases where brain death is considered but intoxication is unclear, consultation with a medical toxicologist or clinical toxicologist is recommended to guide decision making regarding the timing or appropriateness of clinical testing, as clinical brain death determination cannot take place until intoxication is excluded.
While individual practitioners may differ, these are the positions of the ACMT, AACT, and SCCM at the time written, after a review of the issue and scientific literature.
The American Academy of Neurology (AAN) offers guidance for the diagnosis of brain death. Brain death is diagnosed clinically when an irreversible and proximate cause of brain injury is identified and no brain function is present upon clinical assessment [1, 2]. A prerequisite of the practice parameters for clinical testing is the absence of "drug intoxication or poisoning." The only evidence available regarding brain death determination in the setting of intoxication derives from case reports. To determine the extent to which inaccurate brain death determination by clinical testing may occur in this setting, we conducted a review of the literature in MEDLINE and SCOPUS using the search terms "brain death mimic" and "brain death drug overdose" for the dates January 1, 1960 to June 10, 2015. A total of 1394 titles were reviewed for relevance to the topic, and only ten case reports of brain death mimicry were found (three baclofen [3, 4], two snake bites [5, 6], and one each of valproic acid [7], amitriptyline [8], mixed diazepam + ethylene glycol [9], bupropion [10], and phorate [11], an organic phosphorous compound).
"Evidenced-Based Guideline Update: Determining Brain Death in Adults" suggests that the clinician should exclude the presence of a central nervous system (CNS)-depressant drug effect by "history, drug screen, and calculation of clearance using five times the drug’s half-life." [2] However, there may be limitations to this approach. The specific drug responsible for intoxication may not be identified by history or drug screening. Drug screening in the clinical setting is not comprehensive, so a negative drug screen does not exclude intoxication. Routine urine toxicologic immunoassays have limited sensitivity, even for common drugs, and a "negative" urine drug screen should not be used to exclude drug intoxication, and a "positive" urine drug screen cannot be used to assess the extent or degree of intoxication. For example, a typical opiate screen does not reliably identify oxycodone and hydrocodone and does not identify synthetic opioids such as fentanyl or buprenorphine, and a typical benzodiazepine screen does not reliably identify clonazepam. In contrast, a "positive" urine drug screen by itself is not confirmatory, but in the setting of an appropriate history, clinical presentation and physical examination can support intoxication.
Although most hospital laboratories can readily measure serum concentrations of some common drugs in overdose, including lithium, digoxin, phenobarbital, phenytoin, and valproic acid, there are many drugs that cannot be measured in a clinically relevant time frame. When drug concentrations are available, the distribution of the drug into tissues may complicate the relationship between concentration and clinical effect.
In cases in which drug concentrations are not available but a specific drug is suspected, experts recommend waiting five half-lives prior to clinical determination of brain death [2]. This figure is likely derived from the mathematical observation that 0.55 (50% elimination, five times) equals 0.03125, suggesting that only 3% of a drug remains following five half-lives. However, this approach may not be appropriate in every case. If a patient was exposed to an exceedingly large quantity of drug or toxin, 3% of the original dose could potentially still have clinical effects. In addition, the pharmacokinetics of many drugs will be altered in patients with organ failure [12, 13]. Furthermore, the pharmacokinetics of absorption and elimination of a drug in large dose may be different than published pharmacokinetic data suggest, which are typically obtained following therapeutic dosing, generally in healthy subjects without co-exposures [14].
The reasons for prolonged half-lives in overdose are numerous. Delays in gastric emptying and gut hypomotility may result from fasting status, from overdose itself, or from coingestion of opioids or anticholinergic drugs, and controlled release drugs have a prolonged absorption phase [15, 16]. Hypoperfusion of the gastrointestinal tract, secondary to hypotension and/or splanchnic vasoconstriction, can slow absorption [17]. Hypothermia may slow drug metabolism [18]. Enterohepatic recirculation may play a role in elimination of certain drugs. Mechanisms of metabolism may be saturated in overdose [14]. As an example of prolonged half-life in overdose, many references indicate the half-life of baclofen is approximately 2–4 h, but in overdose, the duration of effect far exceeds the recommended five half-life calculation [3]. Reported cases of coma mimicking brain death secondary to baclofen overdose have described a duration of coma of up to 7 days [3, 4]. Furthermore, pharmacokinetic elimination (i.e., "normal" or negative serum concentration) does not equate to pharmacodynamic duration of effect (i.e., drug remaining at the target organ receptor). Finally, published pharmacokinetic data may not account for pharmacodynamic or pharmacokinetic interactions [19].
Ancillary testing to assess cerebral blood flow, including cerebral angiography, transcranial Doppler, and single photon emission computed tomography, has been used to assist in the determination of death when the examination is felt to be potentially unreliable [2]. No publication was found to suggest that a drug or toxin could be the sole cause of cessation of cerebral blood flow and it is unlikely that such a drug effect exists; however, no study has been performed to answer this question.
The requirement to identify a proximate and irreversible cause of brain injury should prevent clinical brain death determination in overdose patients [4]. Therefore, we recommend identification of drugs or toxins by careful history and targeted testing. Five drug half-lives should be considered an absolute minimum period to ensure clearance. A longer period is necessary when there is a possibility of an extremely large drug or toxin exposure, likelihood for delayed drug absorption or elimination (relevant organ failure), pharmacokinetic or pharmacodynamic interactions, saturable elimination kinetics, or interactions with another agent. In cases where brain death is considered but intoxication is unclear, a medical toxicologist or clinical toxicologist can be consulted to guide decision-making regarding clinical testing, as clinical brain death determination cannot begin until intoxication is excluded. In the absence of an on-site toxicologist, one can be consulted via a local poison center at 1-800-222-1222.
Compliance with Ethical Standards
Source of Funding for the Project None.
Conflicts of Interest None.
References 1. Practice parameters for determining brain death in adults (summary statement). The quality standards subcommittee of the American Academy of Neurology. Neurology. 1995;45(5):1012–1014.
2. Wijdicks EF, Varelas PN, Gronseth GS, Greer DM. American Academy of N. Evidence-based guideline update: determining brain death in adults: report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology. 2010;74(23):1911–8. 3. Ostermann ME, Young B, Sibbald WJ, Nicolle MW. Coma mimicking brain death following baclofen overdose. Intensive Care Med. 2000;26(8):1144–6.
4. Sullivan R, Hodgman MJ, Kao L, Tormoehlen LM. Baclofen overdose mimicking brain death. Clin Toxicol. 2012;50(2):141–4.
5. John J, Gane BD, Plakkal N, Aghoram R, Sampath S. Snake bite mimicking brain death. Cases J. 2008;1(1):16.
6. Sodhi R, Khanduri S, Nandha H, Bhasin D, Mandal AK. Brain death—think twice before labeling a patient. Am J Emerg Med. 2012;30(7):1321. e1321-1322
7. Auinger K, Muller V, Rudiger A, Maggiorini M. Valproic acid intoxication imitating brain death. Am J Emerg Med. 2009;27(9): 1177. e1175-1176
8. Yang KL, Dantzker DR. Reversible brain death. A manifestation of amitriptyline overdose. Chest. 1991;99(4):1037–8.
9. Marik PE, Varon J. Prolonged and profound therapeutic hypothermia for the treatment of "brain death" after a suicidal intoxication. Challenging conventional wisdoms. Am J Emerg Med. 2010;28(2): 258. e251-254
10. Mundi JP, Betancourt J, Ezziddin O, Tremayne B, Majic T, Mosenifar Z. Dilated and unreactive pupils and burst-suppression on electroencephalography due to buproprion overdose. J Intensive Care Medicine. 2012;27(6):384–8.
11. Peter JV, Prabhakar AT, Pichamuthu K. In-laws, insecticide—and a mimic of brain death. Lancet. 2008;371(9612):622.
12. Philips BJ, Lane K, Dixon J, MacPhee I. The effects of acute renal failure on drug metabolism. Expert Opin Drug Metab Toxicol. 2014;10(1):11–23.
13. Verbeeck RK. Pharmacokinetics and dosage adjustments in patients with hepatic dysfunction. Eur J Clin Pharmacol. 2008;64(12): 1147–61.
14. Sue YJ, Shannon M. Pharmacokinetics of drugs in overdose. Clin Pharmacokinet. 1992;23(2):93–105.
15. Adams BK, Mann MD, Aboo A, Isaacs S, Evans A. Prolonged gastric emptying half-time and gastric hypomotility after drug overdose. Am J Emerg Med. 2004;22:548–54. doi:10.1016/j.ajem. 2004.08.017.
16. Buckley NA, Dawson AH, Reith DA. Controlled release drugs in overdose. Clinical considerations Drug Safety. 1995;12(1):73–84.
17. Howland MA. Pharmacokinetic and toxicokinetic principles. In: Hoffman RS, et al., editors. Goldfrank’s toxicologic emergencies. 10th edition. New York: McGraw-Hill; 2015. p. 110–23.
18. van den Broek MP, Groenendaal F, Egberts AC, Rademaker CM. Effects of hypothermia on pharmacokinetics and pharmacodynamics: a systematic review of preclinical and clinical studies. Clin Pharmacokinet. 2010;49(5):277–94.
19. Jann M, Kennedy WK, Lopez G. Benzodiazepines: a major component in unintentional prescription drug overdoses with opioid analgesics. J Pharm Prac. 2014;27(1):5–16.
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| Duration of Intravenous Acetylcysteine Therapy Following Acetaminophen Overdose |
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Click here for a .pdf of this statement
Disclaimer
While individual practitioners may differ, this is the position of the American College of Medical Toxicology (ACMT) at the time written, after a review of the issue and pertinent literature.
Acetylcysteine (previously called N-acetylcysteine (NAC)—the abbreviation NAC is used throughout to avoid confusion with activated charcoal) for the treatment of potentially toxic acetaminophen (APAP) ingestion is available in oral and intravenous (IV) formulations. The FDA approved a 72-h oral NAC regimen in 1985. However, evidence supports using shorter oral NAC courses provided that liver enzymes and synthetic function are normal or improving, and plasma APAP concentration is undetectable [1, 2]. Intravenous NAC (Acetadote®, Cumberland Pharmaceuticals) was approved by the FDA in 2004 and is indicated to prevent or lessen hepatic injury after potentially toxic APAP ingestion.
The prescribing information for IV NAC recommends administering the drug within 8 h of APAP ingestion for maximal efficacy, and to administer as soon as possible for patients who present later than 8 h [3]. The NAC treatment regimen described in the prescribing information was developed in the UK in the 1970s and delivers NAC 300 mg/kg, with half given as a loading dose, and the remainder infused over 20 h. The primary mechanism of action involves enhanced detoxification of N-acetyl-p-benzoquinone imine, a hepatotoxic APAP metabolite. Later investigations demonstrated improved mortality in APAP-induced liver failure, presumably via other mechanisms, even when IV NAC was administered after APAP had been eliminated from the blood [4, 5].
Since approval of IV NAC in the USA, several reported cases have documented rising hepatic aminotransferase concentrations or persistent serum APAP concentrations despite 21 h of treatment [6–8]. With a short elimination half-life after therapeutic dosing, APAP is typically eliminated within 21 h after an acute overdose. However, hepatic injury can slow acetaminophen metabolism and prolong its apparent half-life [9]. In addition, altered absorption following massive ingestion [6] or coingestants that slow gastrointestinal motility [7] can result in persistently elevated acetaminophen concentrations.
In APAP poisoning, elevations in aminotransferases (AST or ALT equal or greater than 1000 U/L) precede laboratory markers of hepatic dysfunction. In APAP poisoning, many predictors of poor prognosis have been described. In practice, decreased pH, increases in phosphate, increased lactate, increases in prothrombin time/INR, and increases in serum creatinine are the most readily available predictors of poor prognosis [8, 10, 11]. Treatment with 21 h of IV NAC is highly effective at preventing hepatotoxicity in most patients following acute APAP overdose and in reducing mortality in those with established hepatotoxicity [12].
The administration of an additional NAC bolus or extending the duration of the 6.25 mg/kg/h infusion may be appropriate in certain clinical scenarios [13–16]. Treatment beyond 21 h is indicated when patients have evidence of hepatotoxicity evidenced by elevations in aminotransferases, abnormalities in predictors of poor prognosis, or persistent APAP detected by laboratory testing. Laboratories use different reporting limits for APAP concentrations. Because the scientific literature does not establish one APAP reporting cutoff to be superior to another (e.g., 5 versus 15 μg/mL), we recommend the use of Bundetectable^ APAP as an indication to stop therapy.
The presence of rising liver aminotransferases, markers of poor prognosis, or persistent acetaminophen concentrations should prompt continued IV NAC administration.
The American College of Medical Toxicology (ACMT) strongly recommends all of the following criteria be present for discontinuation of IV NAC: & Undetectable acetaminophen concentration & Improving hepatic aminotransferases & Improving prognostic markers (e.g., creatinine, lactate, pH, prothrombin time/INR, phosphate) ACMT supports the principle of individualizing therapy, guided by patients’ clinical condition, in consultation with a medical toxicologist or other expert.
The development of hepatotoxicity or liver failure despite IV NAC therapy should prompt evaluation and monitoring of acid–base status, coagulation parameters, renal function, and level of consciousness. Consider consultation with a medical toxicologist, a regional poison center (1-800-222-1222), and/ or individual or institution with expertise in managing patients with severely compromised hepatic function.
Acknowledgments ACMT would like to acknowledge the members of the Position Statement and Guidelines Committee for the authorship of this statement: Andrew Stolbach (Chair), Jeffrey Brent, Peter Chase, Howard Greller, Ronald Kirchner, Thomas Kurt, Charles McKay, Sean Rhyee, Silas Smith, Brandon Warrick.
Compliance with Ethical Standards
Conflict of Interest None
Sources of Funding None
References 1. Woo OF, Mueller PD, Olson KR, Anderson IB, Kim SY. Shorter duration of oral N-acetylcysteine therapy for acute acetaminophen overdose. Ann Emerg Med. 2000;35:363–8.
2. Betten DP, Cantrell FL, Thomas SC, Williams SR, Clark RF. Prospective evaluation of shortened course oral N-acetylcysteine for acute acetaminophen poisoning. Ann Emerg Med. 2007;50: 272–9.
3. United States Food and Drug Administration. Acetadote (acetylcysteine) Package Insert.http://www.accessdata.fda.gov/ drugsatfda_docs/label/2006/021539s004lbl.pdf). Accessed 8/11/ 15
4. Harrison PM, Keays R, Bray GP, Alexander GJ, Williams R. Improved outcome of paracetamol-induced fulminant hepatic failure by late administration of acetylcysteine. Lancet. 1990;335: 1572–3.
5. Keays R, Harrison PM, Wendon JA, Forbes A, Gove C, Alexander GJ, et al. Intravenous acetylcysteine in paracetamol induced fulminant hepatic failure: a prospective controlled trial. BMJ. 1991;303: 1026–9.
6. Smith SW, Howland MA, Ho ffman RS, Nelson LS. Acetaminophen overdose with altered acetaminophen pharmacokinetics and hepatotoxicity associated with premature cessation of intravenous N-acetylcysteine therapy. Ann Pharmacother. 2008;42:1333–9.
7. Hendrickson RG, McKeown NJ, West PL, Burke CR. Bactrian ("double hump") acetaminophen pharmacokinetics: a case series and review of the literature. J Med Toxicol. 2010;6:337– 44.
8. O’Grady JG, Alexander GJ, Hayllar KM, Williams R. Early indicators of prognosis in fulminant hepatic failure. Gastroenterology. 1989;97:439–45.
9. Prescott LF, Wright N. The effects of hepatic and renal damage on paracetamol metabolism and excretion following overdosage. A pharmacokinetic study. Br J Pharmacol. 1973;49:602–13.
10. Cholongitas E, Theocharidou E, Vasianopoulou P, Betrosian A, Shaw S, Patch D, et al. Comparison of the sequential organ failure assessment score with King’s College Hospital criteria and the model for end-stage liver disease score for the prognosis of acetaminophen-induced acute liver failure. Liver Transpl. 2012;18:405–12.
11. Schmidt LE, Dalhoff K. Serum phosphate is an early predictor of outcome in severe acetaminophen-induced hepatotoxicity. Hepatology. 2002;36(3):659–65.
12. Heard KJ. Acetylcysteine for acetaminophen poisoning. N Engl J Med. 2008;359(3):285–92.
13. Doyon S, Klein-Schwartz W. Hepatotoxicity despite early administration of intravenous N-acetylcysteine for acute acetaminophen overdose. Acad Emerg Med. 2009;16:34–9.
14. Klein-Schwartz W, Doyon S. Intravenous acetylcysteine for the treatment of acetaminophen overdose. Expert Opin Pharmacother. 2011;12:119–30.
15. Smilkstein MJ, Bronstein AC, Linden C, Augenstein WL, Kulig KW, Rumack BH. Acetaminophen overdose: a 48-hour intravenous N-acetylcysteine treatment protocol. Ann Emerg Med. 1991;20: 1058–63.
16. Rumack BH, Bateman DN. Acetaminophen and acetylcysteine dose and duration: past, present and future. Clin Toxicol. 2012;50:91–8. J. Med. Toxicol. |
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| Safety Issues Regarding Prescription Fentanyl Products |
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Click here for a .pdf of this statement
This position statement addresses several specific areas regarding the safety of transdermal and transmucosal fentanyl.
The position of the American College of Medical Toxicology (ACMT) is as follows:
Fentanyl products must be prescribed with caution. Outpatient fentanyl products, including transmucosal and transdermal (patch) forms, should only be prescribed to patients with uncontrolled chronic pain and opioid tolerance. ACMT supports the FDA’s decision to require a Risk Evaluation and Mitigation Strategy (REMS) for transmucosal immediate-release fentanyl (TIRF) products. Transmucosal fentanyl products should be prescribed at the lowest possible dose. Patients should be educated on the appropriate use, safe storage and disposal, and the risks associated with misuse of fentanyl products.
While individual practitioners may differ, these are the positions of the ACMT at the time written, after a review of the issue and pertinent literature.
Use of Prescription Fentanyl Products
Though primarily used intravenously in inpatient settings, fentanyl is available in a variety of formulations for outpatient chronic pain treatment. Fentanyl is commonly prescribed as a transdermal patch intended to administer the drug at a fixed hourly rate. It may also be used in a transmucosal form for rapid relief of pain, typically breakthrough pain in patients with malignancy-related pain. Similar to other prescription opioids, medical complications related to fentanyl have increased as fentanyl availability has expanded [1].
Toxicity from the use of a fentanyl transdermal patch can result through several distinct means. For example, patients and healthcare providers may inappropriately use fentanyl patches for acute pain management. This indication is not appropriate because upon initial application of a fentanyl transdermal patch, therapeutic drug concentrations may not be achieved for approximately 12 h or more. Substantial pharmacokinetic variability exists between individuals [2]. Therefore, a patient could potentially apply multiple patches due to a perceived lack of efficacy initially, with excessive drug delivery occurring hours later. Furthermore, given its high potency, transdermal fentanyl use is also recommended only in patients who are previously tolerant to opioids and require continuous (round-the-clock) opioid analgesic administration [1]. Hence, initiation of therapy in a non-tolerant individual increases the risk of toxicity. Additionally, drug delivery can be facilitated through several means, including increases in surface skin temperature or extracting the fentanyl from the transdermal patch. In experimental volunteer studies, heating fentanyl patches to 41 °C increased the rate of initial drug absorption and shortened the time to steady state serum concentrations [3]. Fentanyl overdose has been reported with inadvertent placement of a heating pad over a 75 μg/h patch [4]. Since the stratum corneum represents the primary barrier to transdermal absorption, placement of patches onto non-intact skin or onto mucosal surfaces can lead to dramatically increased absorption rates [5]. The clinician should thoroughly examine the opioidpoisoned patient in search of patches. In a case series of deaths involving fentanyl, 45 % of cases involved routes of exposure other than transdermal application; oral exposure accounted for the largest fraction of non-dermal routes [6]. Fentanyl’s formulation as a transdermal patch also raises unique safety issues surrounding its disposal after use. Patches can contain a total of 1.25 to 10 mg of fentanyl with up to 82 % of drug remaining after normal therapeutic application [1]. Proper disposal of a used patch involves folding the adhesive surface together and then flushing it down a toilet. Failure to follow these procedures leaves the possibility of misuse or inadvertent pediatric exposures. The U.S. Food and Drug Administration’s (FDA) advisory concerning the safe use of fentanyl patches includes information regarding appropriate patient and physician education, limiting use to opioid tolerant patients, and avoiding heating a patch once applied [7].
Fentanyl is also available in immediately active transmucosal formulations, including oral lozenges and buccal tablets, sublingual sprays, and films. These transmucosal formulations have mainly been studied in the treatment of breakthrough pain in patients with chronic pain who are maintained on opioids, primarily cancer patients [8–10]. In clinical studies, these formulations appear to be efficacious with low incidence of severe toxicity. However, there are limited data on adverse events outside of controlled studies. The FDA has released a safety advisory concerning fentanyl buccal tablets due to reports of adverse events [11].
The U.S. Food and Drug Administration has implemented the Transmucoal Immediate Release Fentanyl (TIRF) Risk Evaluation and Mitigation Strategy (REMS) for use with transmucosal fentanyl formulations [12]. Under this program, only certified prescribers may prescribe transmucosal fentanyl products outside of the hospital. Certification involves enrollment in an access program which consists of training, a knowledge assessment, and signed prescriber agreement. According to the REMS, these products should be prescribed only to opioid-tolerant cancer patients with chronic pain resistant to other therapies. To minimize risk of adverse events, patients should be started on the lowest possible dose, unless there is product-specific dose conversion information available.
Acknowledgments ACMT would like to acknowledge the Members of the Position Statement and Guidelines Committee for authorship of this statement: Andrew Stolbach (Chair), Jeffrey Brent, Peter Chase, Howard Greller, Ronald Kirschner, Charles McKay, Thomas Kurt, Lewis Nelson, Sean Rhyee, Silas Smith, and Brandon Warrick.
Compliance With Ethical Standards
Conflicts of Interest None.
Sources of Funding None
References
1. Nelson LS, Schwaner R. Transdermal fentanyl: pharmacology and toxicology. J Med Toxicol. 2009;5:230–41. 2. Gourlay GK, Kowalski SR, Plummer JL, et al. The transdermal administration of fentanyl in the treatment of postoperative pain: pharmacokinetics and pharmacodynamic effects. Pain. 1989;37: 193–202.
3. Shomaker TS, Zhang J, Ashburn MA. Assessing the impact of heat on the systemic delivery of fentanyl through the transdermal fentanyl delivery system. Pain Med. 2000;1:225–30.
4. Rose PG, Macfee MS, Boswell MV. Fentanyl transdermal system overdose secondary to cutaneous hyperthermia. Anesth Analg. 1993;77:390–1.
5. Roy SD, Flynn GL. Transdermal delivery of narcotic analgesics: pH, anatomical, and subject influences on cutaneous permeability of fentanyl and sufentanil. Pharm Res. 1990;7:842–7.
6. Martin TL, Woodall KL, McLellan BA. Fentanyl-related deaths in Ontario, Canada: toxicological findings and circumstances of death in 112 cases (2002–2004). J Anal Toxicol. 2006;30:603–10.
7. U.S. Food and Drug Administration. Fentanyl Transdermal Patch, Important Information for the Safe Use of Fentanyl Transdermal System (patch). Last Updated: 06/18/2009. Available at: http://www.fda.gov/Drugs/DrugSafety/ PostmarketDrugSafetyInformationforPatientsandProviders/ DrugSafetyInformationforHeathcareProfessionals/ PublicHealthAdvisories/ucm048721.htm. Accessed December 1, 2011.
8. Mystakidou K, Katsouda E, Parpa E, et al. Oral transmucosal fentanyl citrate: overview of pharmacological and clinical characteristics. Drug Deliv. 2006;13:269–76.
9. Nalamachu SR, Narayana A, Janka L. Long-term dosing, safety, and tolerability of fentanyl buccal tablet in the management of noncancer-related breakthrough pain in opioid-tolerant patients. Curr Med Res Opin. 2011;27:751–60.
10. Uberall MA, Muller-Schwefe GHH. Sublingual fentanyl orally disintegrating tablet in daily practice: efficacy, safety and tolerability in patients with breakthrough cancer pain. Curr Med Res Opin. 2011;27:1385–94.
11. U.S. Food and Drug Administration. Information for Healthcare Professionals: Fentanyl Buccal Tablets (marketed as Fentora). Last Updated: 09/29/2010. Available at: http://www.fda.gov/ Drugs/DrugSafety/ PostmarketDrugSafetyInformationforPatientsandProviders/ ucm126082.htm. Accessed April 21, 2014.
12. 12.U.S. Food and Drug Administration. Transmucoal Immediate Release Fentanyl (TIRF) Risk Evaluation and Mitigation Strategy (REMS). http://www.fda.gov/downloads/Drugs/DrugSafety/ PostmarketDrugSafetyInformationforPatientsandProviders/ UCM289730.pdf . Accessed April 21, 2014. J. Med. Toxicol. |
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| The Use of Methadone as an Analgesic |
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Click here for a .pdf of this statement
The position of the American College of Medical Toxicology (ACMT) is as follows:
Use of methadone as an analgesic It is the position of ACMT that providers exercise caution when prescribing methadone as an analgesic and preferably avoid this use. Methadone should not be prescribed on an as-needed basis. Clinicians should recognize the risk of overdose (e.g., dose stacking) during the initial induction period for chronic use and titrate very slowly. Patients should be educated on potential risks of methadone at the time of initiation of therapy. Clinicians should obtain a baseline ECG before methadone treatment is initiated in patients with risk factors for QT prolongation such as use of other medications that prolong QT interval, structural heart disease, or a history of arrhythmia. In such higher-risk patients, a follow-up ECG should be obtained approximately 30 days after starting therapy. ACMT supports the FDA’s decision to require a Risk Evaluation and Mitigation Strategies program for extended-release/long-acting (ER/LA) opioid medications, including methadone. It is the position of ACMT that the FDA assess the value of this program and make adjustments to ensure reaching the goal of improved safety balanced with effective pain relief.
While individual practitioners may differ, these are the positions of the ACMT at the time written, after a review of the issue and pertinent literature.
Use of Methadone as an Analgesic
The use of methadone as an analgesic (not for treatment of opioid dependence) has grown dramatically in recent years [1]. Nationally, methadone-related deaths have mirrored prescriptions trends, increasing nearly sevenfold between 1996 and 2006 [2]. When comparing data from individual US states, higher rates of methadone prescribing have correlated with increased frequency of opioid-related deaths [3]. While these trends suggest that increased mortality is a function of increased drug availability, some studies implicate methadone in a disproportionate share of overdose events. Investigations of opioid overdose deaths have reported methadone accounting for up to 35 to 40 % of cases [4, 5]. This proportion is striking since sales of other opioids such as codeine and hydrocodone exceed that of methadone. Methadone accounts for a relatively small proportion of opioid prescriptions, but is responsible for a disproportionate number of opioidassociated fatalities [3].
Methadone’s pharmacology is responsible in part for the apparent excess mortality risk. Volunteers achieve maximum serum methadone concentrations approximately 4 h after oral dosing [6]. In contrast, maximum serum concentration of hydrocodone occurs approximately 90 min after ingestion [7]. Patients with methadone prescribed on an as-needed basis might take multiple doses, perceiving a lack of efficacy due to delayed analgesic onset. This behavior, in combination with the drug’s prolonged elimination, may lead to excessive methadone accumulation and toxicity. The duration of methadone’s analgesic effect also appears to be significantly shorter than its elimination half-life, which could also prompt too-frequent patient dosing and excessive drug accumulation [8].
Methadone’s cardiovascular effects also contribute to toxicity. Methadone’s (S)-enantiomer (dextromethadone) inhibits the potassium-dependent, delayed rectifier current in cardiac cells. This inhibition risks QT prolongation and the development of torsades de pointes (TdP) [8, 9]. The risk of dysrhythmia is likely to be higher when combined with other drugs that have similar ion channel effects on the heart. Methadone was the second most frequently mentioned drug in cases of druginduced TdP in a 4-year analysis of FDA Adverse Event Reporting System data [10]. In a community-based series of sudden cardiac death cases in which a therapeutic blood level of methadone (less than 1 mg/L) was detected at autopsy, among 22 total subjects, 17 cases (77.3 %) lacked any evidence of structural heart disease such as ventricular hypertrophy, coronary artery disease, etc. [11]. In contrast, among 106 control cases of sudden death without detectable methadone post-mortem, 60 % had significant structural heart disease. These data Bstrongly suggested^ to the study’s authors a causative role for methadone in the development of sudden cardiac death. Actual estimates of QT prolongation in individuals taking methadone have varied depending on populations studied as well as study design. Two cross-sectional studies of patients receiving methadone maintenance therapy (MMT) found frequencies of prolonged corrected QT (defined as greater than 500 ms) of 2.2 and 4.6 %, respectively [12, 13]. Corrected QT prolongation was seen only in patients taking more than 120 mg methadone daily. A much higher prevalence has been noted in other retrospective and prospective studies. Retrospectively evaluated hospitalized patients with a history of IV drug use receiving MMT had a 16.2 % rate of QTc >500 ms (29.9 % had QTc >460 ms) [14]. Corrected QT exceeding 500 ms was observed at methadone doses as low as 30 mg daily. Only 10 % of non-methadone patients had QTc >460 ms, and none had QTc >500 ms [14]. A prospective study evaluated subjects entering a MMT program and compared ECG at baseline to 6 and 12 months later [15]. At both 6 and 12 months, approximately 12 % of patients had prolonged corrected QT (>450 ms in males and >470 ms in females) compared to 5 % at baseline. The authors noted a significant increase in average corrected QT at 6 months compared to baseline which was sustained at 12 months. Frequencies of corrected QT prolongation (>470 ms in males and >490 ms in females) as high as 23 % are reported in patients initiated in MMT [16]. Significant increases in average, corrected QT over baseline were observed after only four weeks of therapy.
A SAMHSA organized expert panel addressed issues relating methadone use and QT prolongation but did not reach a consensus that baseline ECG screening was appropriate for all patients [17]. However, the panel agreed that baseline and 30- day ECGs were recommended for patients with risk factors for QT prolongation, including cardiac arrhythmia, prolonged QT interval, episodes of syncope, dizzy spells, palpitations or seizures, or other clinical features suggestive of risk of dysrhythmia. The panel recommended annual ECGs when methadone dose exceeds 120 mg/day.
In consideration of these risks, experts recommend conservative initial methadone dosing and dose escalation. When converting a patient’s pain regimen from high doses of another opioid to methadone, experts in pain management recommend calculating the equianalgesic methadone dose, reducing by as much as 90 %, and dividing into three daily doses [18, 19]. For both pain management and maintenance pharmacotherapy, authors have recommended 30 mg as a maximum initial total daily methadone dose [18–21]. The Institute of Medicine Committee on Federal Regulation of Methadone Treatment recommends raising the daily dose for maintenance pharmacotherapy by no more than 10 mg every week [20]. American Pain Society Guidelines recommend increasing the daily methadone dose by no more than 10 mg every 5–7 days in patients with chronic pain who changed from other opioids to methadone [20].
The FDA’s Information for Healthcare Professionals also details methadone safety concerns, including both the risk of QT prolongation and the disparity between duration of analgesia, methadone’s half-life, and peak respiratory depressant effects [22]. Providers are advised to educate patients not to take methadone more frequently than prescribed.
The Food and Drug Administration Amendments Act of 2007 authorized the FDA to require drug manufacturers to implement a risk evaluation and mitigation strategy (REMS) when necessary to ensure that the benefits of a drug outweigh the risks. The FDA has implemented a REMS for extendedrelease/long-acting (ER/LA) opioids, including methadone. The main component of the REMS is optional provider education on the potential risks of ER/LA opioids. A blueprint for the education program has been made available [23].
Acknowledgments ACMT would like to acknowledge the Members of the Position Statement and Guidelines Committee for authorship of this statement: Andrew Stolbach (Chair), Jeffrey Brent, Peter Chase, Howard Greller, Ronald Kirschner, Charles McKay, Thomas Kurt, Lewis Nelson, Sean Rhyee, Silas Smith, and Brandon Warrick.
Compliance with Ethical Standards Conflicts of Interest None
Sources of Funding None
References
1. Zerzan JT, Morden NE, Soumerai S, et al. Trends and geographic variation of opiate medication use in state Medicaid fee-for-service programs, 1996 to 2002. Med Care. 2006;44:1005–10.
2. Warner M, Chen LH, Makuc DM. Increase in fatal poisonings involving opioid analgesics in the United States 1999–2006. NCHS data brief, no 22. Hyattsville: National Center for Health Statistics; 2009.
3. Paulozzi. MMWR. 2012; 61: 493–7.
4. Paulozzi LJ, Logan JE, Hall AJ, et al. A comparison of drug overdose deaths involving methadone and other opioid analgesics in West Virginia. Addiction. 2009;104:1541–8.
5. Hall AJ, Logan JE, Toblin RL, et al. Patterns of abuse among unintentional pharmaceutical overdose fatalities. JAMA. 2008;300:2613–20.
6. Wolff K, Rostami-Hodjegan A, Shires S, et al. The pharmacokinetics of methadone in healthy subjects and opiate users. Br J Clin Pharmacol. 1997;44:325–34.
7. Baselt RC. Hydrocodone. Disposition of toxic drugs and chemicals in man. 7th ed. Foster City: Biomedical Publications; 2004. p. 546–7.
8. Andrews CM, Krantz MJ, Wedam EF, et al. Methadone-induced mortality in the treatment of chronic pain: role of QT prolongation. Cardiol J. 2009;16:210–7.
9. Ehret GB, Desmeules JA, Broers B. Methadone-associated long QT syndrome: improving pharmacotherapy for dependence on illegal opioids and lessons learned from pharmacology. Expert Opin Drug Saf. 2007;6:289–303.
10. Poluzzi E, Raschi E, Moretti U, et al. Drug-induced torsades de pointes: data mining of the public version of the FDA Adverse Event Reporting System (AERS). Pharmacoepidemiol Drug Saf. 2009;18:512–8.
11. Chugh SS, Socoteanu C, Reinier K, et al. A community-based evaluation of sudden death associated with therapeutic levels of methadone. Am J Med. 2008;121:66–71.
12. Peles E, Bodner G, Kreek MJ, et al. Corrected-QT intervals as related to methadone dose and serum level in methadone maintenance treatment (MMT) patients—a cross-sectional study. Addiction. 2006;102:289–300.
13. Anchersen K, Clausen T, Gossop M, et al. Prevalence and clinical relevance of corrected QT interval prolongation during methadone and buprenorphine treatment: a mortality assessment study. Addiction. 2009;104:993–9.
14. Ehret GB, Voide C, Gex-Fabry M, et al. Drug-induced long QT syndrome in injection drug users receiving methadone. Arch Intern Med. 2006;166:1280–7.
15. Martell BA, Arnsten JH, Krantz MJ, et al. Impact of methadone treatment on cardiac repolarization and conduction in opioid users. Am J Cardiol. 2005;95:915–8.
16. Wedam EF, Bigelow GE, Johnson RE, et al. QT-interval effects of methadone, levomethadyl, and buprenorphine in a randomized trial. Arch Intern Med. 2007;167:2469–75.
17. Martin JA, Campbell A, Killip T, et al. QT interval screening in methadone maintenance treatment: report of a SAMHSA expert panel. Addict Dis. 2011;30:283–306.
18. Soto E, Hao J, Knotkova H, Cruciano RA. Prescribing methadone safely. In: Cruciano RA, Knotkova H, editors. Handbook of methadone prescribing and buprenorphine therapy. New York: Springer; 2013. p. 1–14.
19. Chou R, Cruciani RA, Fiellin DA, Compton P, Farrar JT, Haigney MC, et al. Methadone safety: a clinical practice guideline from the American Pain Society and College on Problems of Drug Dependence, in collaboration with the Heart Rhythm Society. J Pain. 2014;15:321–37.
20. Institute of Medicine (US) Committee on Federal Regulation of Methadone Treatment. Treatment standards and optimal treatment. In: Rettig RA, Yarmolinksy A, editors. Federal Regulation of Methadone Treatment. Washington (DC): National Academies Press (US); 1995.
21. Webster LR, Fine PG. Review and critique of opioid rotation practices and associated risks of toxicity. Pain Med. 2012;13(4):562–70.
22. Food and Drug Administration. Information for healthcare professionals methadone hydrochloride text version http://www.fda.gov/ Drugs/DrugSafety/PostmarketDrugSafetyInformation forPatientsandProviders/ucm142841.htm. Accessed: April 20, 2015.
23. Food and Drug Administration. FDA blueprint for prescriber education for extended-release and long-acting opioid analgesics http:// www.fda.gov/downloads/Drugs/DrugSafety/ InformationbyDrugClass/UCM277916.pdf. Accessed: April 20, 2015. J. Med. Toxicol. |
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| Safety Issues Regarding Prescription Opioids |
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Click here for a .pdf of this statement
Disclaimer
This position statement addresses several specific areas regarding prescription opioid safety: (a) acetaminophen-opioid combination products; (b) total daily opioid dosage; (c) abusedeterrent opioids. Outpatient fentanyl use and the use of methadone as an analgesic are discussed in separate position statements. The position of the American College of Medical Toxicology (ACMT) on each topic is as follows: Acetaminophen-Opioid Combination Products It is the position of ACMT that when prescribing opioids, a risk-benefit analysis for both acetaminophen toxicity and opioid misuse should direct the choice of a combination analgesic. An acetaminophen-free product should be considered for those at risk for supratherapeutic dosing to avoid acetaminophen hepatotoxicity. Overall, ACMT supports the decision of the FDA to limit the acetaminophen content in opioid combination products.
Total Daily Opioid Dosage The risk of drug-related overdose increases with increased opioid dosing, and there is no threshold dividing "safe" from "toxic" dosing. It is the position of ACMT that providers always exercise caution when prescribing outpatient opioids, especially in doses that exceed 50 mg daily (in morphine equivalents), due to the increased risk for drug-related overdose or death. Abuse-Deterrent Opioid Formulations ACMT supports the development of tamper-resistant and abuse-deterrent formulations as part of a comprehensive program to decrease opioid misuse. However, deterrence of abuse does not equate to full prevention of abuse. ACMT recognizes that abuse-deterrent formulations may have a limited impact on addiction and death, because in most cases, substance misuse involves oral administration of the intact drug and injection accounts for a small percentage of misuse. In addition, the impact on non-oral misuse will be limited because users may defeat the abuse-deterrent or tamper-resistant mechanism or shift to other legal or illicit opioid formulations, such as heroin. While individual practitioners may differ, these are the positions of the ACMT at the time written, after a review of the issue and pertinent literature. Background The USA and Canada have witnessed a dramatic rise in the use of prescription opioids, especially in the treatment of noncancer chronic pain [1–3]. This trend is particularly notable, as it has not been accompanied by a proportional increase in total physician encounters [1]. According to the United States Substance Abuse and Mental Health, 4.3 million Americans age 12 or older report current nonmedical use of prescription pain relievers [4]. The expanded use of prescription opioids has coincided with rising morbidity and mortality related to these medications [5]. The age-adjusted death rate attributable to prescription opioids increased fourfold from 1999 to 2009 [6]. In 2010, prescription opioids were involved in 75.2 % of US pharmaceutical overdose deaths [7]. The United States Centers for Disease Control and Prevention reported that, from 2011 to 2013, the heroin overdose death rate doubled in the USA. The same report showed that past-year use of opioid pain relievers was related to past-year heroin use or dependence [8]. Mortality rates show significant correlation with the total number of prescriptions for oxycodone, hydromorphone, and methadone, when data from individual US states are compared [9]. A. Acetaminophen-Opioid Combination Products Acetaminophen remains the leading cause of acute liver failure in the USA [10, 11]. Oxycodone and hydrocodone are frequently prescribed as combination immediate-release formulations containing acetaminophen. Although malnutrition and glutathione-depleted states are risk factors for acetaminophen hepatotoxicity, increased acetaminophen dose is the principle cause of hepatic injury [12, 13]. Patients who develop tolerance to an opioid analgesic may increase their analgesic consumption, concomitantly increasing acetaminophen exposure. One national study reported that acetaminophenopioid combinations were related to 63 % of unintentional acetaminophen overdose cases producing acute liver failure [10]. Historically, most combination products contained 325 mg acetaminophen per tablet, so an individual would only need to take about 12 tablets in a 24-h period to reach the maximum adult daily dose of 4 g. In 2009, an FDA advisory panel voted in favor of eliminating of acetaminophen-opioid combination products as a means of decreasing risk of acetaminophen toxicity [14]. While the FDA did not ultimately recommend elimination of these products, in January 2011, the agency did request that the acetaminophen content of opioid combination products be limited to 325 mg per unit dose (tablet, capsule, etc.). It is the position of ACMT that when prescribing opioids, a risk-benefit analysis for both acetaminophen toxicity and opioid misuse should direct the choice of a combination analgesic. An acetaminophen-free product should be considered for those at risk for supratherapeutic dosing to avoid acetaminophen hepatotoxicity. Overall, ACMT supports the decision of the FDA to limit the acetaminophen content in opioid combination products. B. Total Daily Opioid Dose Patients maintained on chronic opioid therapy may require an increasing dose over time due to the development of tolerance. However, recent studies have demonstrated an increased risk for morbidity and mortality with escalating dose even in tolerant individuals. One study of patients receiving treatment for chronic, non-cancer-related pain reported an increased risk of overdose in those receiving opioid doses greater than 50 mg daily (of morphine equivalents) compared to patients receiving less than 20 mg daily [15]. Patients receiving doses between 50 and 100 mg daily experienced a hazard ratio of 3.73 for overdose, while patients receiving greater than 100 mg had a hazard ratio of 8.87. A subsequent study reported similar findings, even when study outcome was limited to unintentional death due to opioid overdose [16]. Patients with chronic pain who receive doses between 50 and 100 mg daily (of morphine equivalents) had a hazard ratio of 4.63 for overdose death compared to patients receiving less than 20 mg daily. Patients receiving greater than 100 mg daily had a hazard ratio of 7.18. Of note, patients treated for acute pain demonstrated similar outcomes. Similarly, a large case-control study of patients receiving opioids for nonmalignant pain determined odds ratio of death for patients taking 50–99 mg/d of morphine equivalents, compared to be those taking The risk of drug-related overdose increases with increased opioid dosing, and there is no threshold dividing "safe" from "toxic" dosing. It is the position of ACMT that providers always exercise caution when prescribing outpatient opioids, especially in doses that exceed 50 mg daily (in morphine equivalents), due to the increased risk for drug-related overdose or death. C. Tamper-Resistant and Abuse-Deterrent Opioid Formulations
Tamper-resistant and abuse-deterrent formulations of opioid have been employed to decrease misuse by the non-oral route, such as intravenous injection or nasal insufflation. Types of deterrents include physical/chemical barriers, co-formulation with opioid antagonists, drug release designs, new molecular entities and prodrugs, and aversive additives [18, 19]. Physical barriers are materials that limit the ability to crush or inject tablets. Opioid antagonist combination formulations consist of an opioid antagonist in a sequestered form that is not systemically available unless the product is tampered or taken by a route other than indicated. Drug release designs include sustained-release depot injectable formulations or subcutaneous implants that are difficult to manipulate. New molecular entities and prodrugs include entities that require enzymatic activation, provide different receptor binding profiles, or achieve slower central nervous system penetration. Aversive additives create an unpleasant sensation if the product is insufflated. OxyContinTM (oxycodone hydrochloride) was reformulated in 2010 to complicate tablet tampering. Following clinical trials, FDA permitted an abuse-deterrent designation on the label. After the introduction of the new formulation, surveys indicating past month misuse decreased from 45.1 to 26.0 % [20]. In subsequent months, misuse remained between 25 and 30 %. This residual abuse involved defeating the abuse-deterrent mechanism, misusing the drug in oral form, and shifting to other opioid formulations, including heroin [21]. Other opioids such as Hysingla™ ER (hydrocodone bitartrate) have been granted the abuse-deterrence designation by demonstrating a decrease in "drug liking," a purported measure of abuse potential [22]. ACMT supports the development of tamper-resistant and abuse-deterrent formulations as part of a comprehensive program to decrease opioid misuse. However, deterrence of abuse does not equate to full prevention of abuse. ACMT recognizes that abuse-deterrent formulations may have a limited impact on addiction and death, because in most cases, substance misuse involves oral administration of the intact drug and injection accounts for a small percentage of misuse. In addition, the impact on non-oral misuse will be limited because users may defeat the abuse-deterrent or tamper-resistant mechanism or shift to other legal or illicit opioid formulations, such as heroin [23]. Acknowledgements ACMT would like to acknowledge Members of the Position Statement and Guidelines Committee for authorship of this statement: Andrew Stolbach (Chair), Jeffrey Brent, Peter Chase, Howard Greller, Ronald Kirschner, Charles McKay, Thomas Kurt, Lewis Nelson, Sean Rhyee, Silas Smith, Brandon Warrick.
References
1. Caudill-Slosberg MA, Schwartz LM, Woloshin S. Office visits and analgesic prescriptions for musculoskeletal pain in US: 1980 vs. 2000. Pain. 2004;109:514–9. 2. Boudreau D, VonKorff M, Rutter CM, et al. Trends in long-term opioid therapy for chronic non-cancer pain. Pharmacoepidemiology and Drug Safety. 2009;18:1166–75. 3. Zerzan JT, Morden NE, Soumerai S, et al. Trends and geographic variation of opiate medication use in state Medicaid fee-for-service programs, 1996 to 2002. Medical Care. 2006;44:1005–10. 4. Hedden SL, Kennet J, Lipari R, Medley G, Tice P, Copello EAP, Kroutil LA.Behavioral health trends in the United States: results from the 2014 National Survey on Drug Use and Health. http://www.samhsa.gov/data/sites/default/files/NSDUH-FRR1-2014/ NSDUH-FRR1-2014.pdf. Accessed 29 Sept 2015. 5. Centers for Disease Control and Prevention (CDC). Vital signs: overdoses of prescription opioid pain relievers—United States, 1999–2008. MMWR Morbidity and Mortality Weekly Report. 2011;60:1487–92. 6. Calcaterra S, Glanz J, Binswanger IA. National trends in pharmaceutical opioid related overdose deaths compared to other substance related overdose deaths: 1999–2009. Drug and Alcohol Dependence. 2013;131:263–70. 7. Jones CM, Mack KA, Paulozzi LJ. Pharmaceutical overdose deaths, United States, 2010. The Journal of the American Medical Association. 2013;309:657–9. 8. Jones CM, Logan J, Gladden RM, Bohm MK. Vital signs: demographic and substance use trends among heroin users—United States, 2002–2013. MMWR Morbidity and Mortality Weekly Report. 2015;64:719–25. 9. Paulozzi LJ, Ryan GW. Opioid analgesics and rates of fatal drug poisoning in the United States. American Journal of Preventive Medicine. 2006;31:506–11. 10. Larson AM, Polson J, Fontana RJ, et al. Acetaminophen-induced acute liver failure: results of a United States multicenter, prospective study. Hepatology. 2005;42:1364–72. 11. Ostapowicz G, Fontana RJ, Schiodt FV, et al. Results of a prospective study of acute liver failure at 17 tertiary care centers in the United States. Annals of Internal Medicine. 2002;137:947–54. 12. Whitcomb DC, Block GD. Association of acetaminophen hepatotoxicity with fasting and ethanol use. The Journal of the American Medical Association. 1994;272:1845–50. 13. Kim Y, Sim S, Kwon J, et al. Effects of cysteine on amino acid aconcentrations and transsulfuration enzyme activities in rat liver with protein-calorie malnutrition. Life Sciences. 2003;72:1171–81. 14. Lee WM. The case for limiting acetaminophen-related deaths: smaller doses and unbundling the opioid-acetaminophen compounds. Clinical Pharmacology and Therapeutics. 2010;88:289–92. 15. Dunn KM, Saunders K, Rutter CM, et al. Opioid prescriptions for chronic pain and overdose. Annals of Internal Medicine. 2010;152: 85–92. 16. Bohnert ASB, Valenstein M, Blair MJ, et al. Association between opioid prescribing patterns and opioid overdose-related deaths. The Journal of the American Medical Association. 2011;305:1315–21. 17. Gomes T, Mamdani MM, Dhalla IA, Paterson JM, Juurlink DM. Opioid dose and drug-related mortality in patients with nonmalignant pain. Archives of Internal Medicine. 2011;171:686–91. 18. Alexander L, Mannion RO, Weingarten B, et al. Development and impact of prescription opioid abuse deterrent formulation technologies. Drug and Alcohol Dependence. 2014;138:1–6. 19. United States Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research. Abuse-deterrent opioids—evaluation and labeling: Guidance for industry. http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ default.htm. Accessed 20 July 2015 20. Cicero TJ, Ellis MS. Abuse-deterrent formulations and the prescription opioid abuse epidemic in the United States: lessons learned from OxyContin. The Journal of the American Medical Association Psychiatry. 2015. 21. Dart RC, Surratt HL, Cicero TJ, et al. The New England Journal of Medicine. 2015;372:241–8. 22. [No authors listed]. Extended-release hydrocodone (Hysingla ER) for Pain. Med Lett Drugs Ther. 2015;57:71–2. 23. Maxwell JC. The pain reliever and heroin epidemic in the united states: shifting winds in the perfect storm. Journal of Addictive Diseases. 2015;34(2-3):127–40. doi:10.1080/10550887.2015. 144 J. Med. Toxicol. (2016) 12:142–144 |
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| ACMT Ethics Statement |
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Click here for a .pdf of this statement
Preamble
This document outlines specific tenets of ethical behavior for medical toxicologists as promulgated by the American College of Medical Toxicology (the College). It is not meant to be all-inclusive, and thus, activities in areas not covered by these guidelines should not be considered to be deemed a priori ethical. These guidelines are meant to supplement and not to supplant the Code of Medical Ethics of the American Medical Association referred to as the BCode of the AMA^) [1]. This Code of Ethics is meant to be specifically applicable to medical toxicologists. A medical toxicologist is defined, for the purposes of this document, as a physician who is qualified to be a member of the College. The purpose of these guidelines is to delineate principles constituting the ethical foundations upon which the medical toxicologist should rely in fulfilling his/her responsibilities to his/her patients, society, and other health professionals. Except under circumstances delineated in this document, or as required by law, the medical toxicologist’s primary responsibility is to his/her patients. As a physician, a medical toxicologist should strive to exemplify the highest standards of moral character. These guidelines apply to the practice of medical toxicology. Any medical toxicologist whose ability to practice is physically, mentally, or emotionally impaired should not continue to function in those aspects of practice which may be affected by his/her impairment.
It is recognized that this Code of Ethics cannot encompass the entire range of possible circumstances. These guidelines are applicable to the vast majority of foreseeable circumstances but may not apply when extenuating circumstances are present.
The College may censure, deny, or revoke membership to members who are in violation of these guidelines, in accord with established policies and procedures. Membership in the
College is contingent upon compliance with this Code of Ethics. Medical Toxicologists and the Public Health Medical toxicologists are stewards of the public health. In this role, they have a responsibility to assure that appropriate public health authorities are informed of situations or occurrences that may represent an imminent and unrecognized risk to public health. If such information is privileged by a physician patient relationship or by law, the decision to reveal it to appropriate authorities may only be made to the extent permitted by applicable law and the Code of the AMA. If the medical toxicologist determines that a patient’s condition renders him/her dangerous when driving, operating heavy equipment, or taking part in other safety-sensitive activities, there is an obligation to intervene, to the extent permitted by applicable law and the Code of the AMA, balancing the patient’s best interest with any danger to society. This may mean direct confrontation of the patient or the patient’s family. For cases in which the patient’s dangerous behavior persists despite this intervention, appropriate authorities should be notified. However, the latter should be considered to be a last resort to be employed only after other measures, as described
above, fail. To the extent permitted by applicable law and the Code of the AMA, if a medical toxicologist has reasonable suspicion of domestic violence, including child or elder abuse, there is an ethical responsibility to report these concerns, or assure that other appropriate parties make such reports, to governmental or other appropriate authorities.
When a medical toxicologist determines that there is an ethical responsibility to inform authorities about a patient’s behavior or limitations, it should be done in a way that maintains as much patient confidentiality as possible, revealing only the minimal amount of information necessary. When embarking on such an activity, or considering the need to do so, the medical toxicologist should make reasonable attempts to inform the patient of his/her ethical and/or legal responsibilities to make such reports.
Physicians are encouraged to participate in activities aimed at enhancing the public health. They should not participate in any activity contrary to the public good.
Relationships with Other Professionals Society confers a special level of trust, respect, and deference to physicians. Medical toxicologists should always act in a dignified and honorable way respectful of this public trust. Relationships with physicians, nurses, and other health care professionals should live up to the faith that the public-at-large has in physicians and be characterized by fairness, honesty, respect, and integrity.
Cooperation with other health care professionals and institutions should occur to the extent necessary to serve the patient’s and society’s best interests.
To the extent permitted by applicable law and the Code of the AMA, concerns about physicians or other health professionals acting in an apparently impaired, incompetent, unethical, or negligent fashion are guided by the principle of nonmaleficence and thus should be reported to appropriate authorities, regional medical societies, and/or hospital medical staff officials, quality assurance, or peer-review programs. Fraud or deceptive behavior is considered unethical and should be reported per these guidelines. All such reports should be done with the utmost discretion. In the event that a medical toxicologist is being investigated by any of the bodies enumerated in this paragraph, they should honestly and openly cooperate with the investigation. Where possible, medical toxicologists should constructively assist colleagues who appear to be impaired, incompetent, or acting in an unethical fashion. This may include advice for
self-referral for treatment. Sexual harassment of a staff member or another health care professional is unethical. Sexual harassment is defined here as physical or verbal intimation of a sexual nature involving a staff member, a colleague, or a subordinate when such conduct creates an unreasonable, intimidating, hostile, or offensive workplace environment.
The Physician-Patient Relationship The physician-patient relationship must be founded on mutual trust, cooperation, and respect. All patients should be treated with compassion and dignity. The welfare of the patient is central to all considerations in the patient-physician relationship. The medical toxicologist must have freedom to choose patients whom she/he will serve. However, the medical toxicologist should not refuse to accept patients because of the patient’s race, sexual orientation, creed, color, sex, gender identification, national origin, medical condition, or disability. In emergencies, if reasonable to do so, a medical toxicologist should make her/his services available to all patients. However, if the scope of the required care is outside of the competence of the medical toxicologist, it is appropriate to decline the role of being a treating physician. A medical toxicologist is never justified in abandoning a patient. Rather, the toxicologist should attempt to give due notice in writing to the patient, or to those responsible for
the patient’s care, when she/he withdraws from the case so that another physician may be engaged. In such cases, the medical toxicologist must continue to provide acute care for a reasonable period of time while the patient makes alternative care arrangements. A sexual or romantic relationship between a physician and a current or recent patient is unethical. When a patient’s parent, guardian, spouse, partner, or proxy mediates the patient-physician relationship, a sexual or romantic relationship between a physician and such individuals is unethical.
To the extent permitted by applicable law and the Code of the AMA, the medical toxicologist shall keep confidential all individual medical information, releasing such information only as follows: (1) when required by law or overriding public health considerations, (2) to other health care professionals according to accepted medical practice, or (3) to others at the request of the individual patient. Requests to release records by the patient, or legal surrogate, should not be denied based on outstanding unpaid bills. To the extent permitted by applicable law and the Code of the AMA, disclosure of detailed information to insurance carriers or other interested third parties must be restricted to instances where the patient provides informed consent to do
so, and any significant inadvertent breaches of patient confidentiality should be revealed to the patient. No medical toxicologist shall advertise or solicit patients directly or indirectly through the use of materials or activities that are false or misleading, nor should a medical toxicologist provide or bill for services that are not medically justifiable. Bills for services should not be based on any contingency, such as successful outcome of therapy or other positive end points. Medical toxicologists should not engage in intentional "fee splitting" with any referral sources or health care provider/facility to whom they refer
patients, nor should they accept finders’ fees for referring a patient to another practitioner or facility. Fees charged for services should not be excessive. Fees should be commensurate with the time of service, difficulty of services involved, and the quality of service. No fees should be charged by a medical toxicologist for patient care services not performed either by him/her or under his/her direct supervision. Although it is appropriate for medical toxicologists to charge for their services, the physician should use compassion when considering the patient’s ability to pay. A medical toxicologist should not charge for billing third party payers unless this activity requires an excessive amount of time. In the latter case, charges consistent with those customary in the same community are appropriate. Unless prior arrangements are made to the contrary, if charges for laboratory or other studies done at an external facility are included in the medical toxicologist’s bill, the actual
laboratory costs and any additional add-on charges should be clearly specified. It is generally expected that patients will provide consent before treatment is rendered. Where consent is absent because of an emergent medical situation, it is expected that the med ical toxicologist will provide all necessary treatments within the scope of his/her expertise. The patient has the right of self-decision. When helping a patient to make a treatment decision, the medical toxicologist should consider the patient’s ability to receive information, given the patient’s condition and time available. The medical toxicologist should inform the patients of all treatment alternatives, including non-intervention, consistent with good medical practice. The medical toxicologist’s personal belief should not prevent him or her from informing the patient of medically recognized treatment alternatives. Obligations to Patients Who Are Medically Indigent Medical toxicologists are free to choose whom to serve. However, the paradigm of the medical profession implies responsibility to society as a whole. This includes an obligation to provide emergent care, irrespective of the patient’s ability to pay or his/her legal status. Informed Consent and the Suicidal Patient The medical toxicologist is likely to be called upon to evaluate and care for individuals who suffer from, or are believed to suffer from, attempted self-injury using one or more chemical substances. Under these circumstances, the medical toxicologist is unlikely to have a preexisting relationship with the patient or his/her family and often has a limited window of time in which to make critical decisions regarding patient care. Because the toxic exposure may pose an ongoing threat to patient’s well-being, rapid assessment and immediate medical intervention (often based on limited information) may be required without a formal determination of patient’s competency. To the extent permitted by applicable law and the Code of the AMA, in such situations, the treating physician must determine, to the best of his/her ability, the present decisionmaking capability of the patient, and act in the patient’s best interest, even if this is contradictory to the patient’s current expressed or implied wishes. Thus, evaluation, treatment, and disposition of the patient must be such that the psychiatric and physical well-being of the patient can be reasonably assured in the face of expressed or implied self-harm. Allowing self-destruction or even serious self-injury is not in the long-term best interests of the patient and should be avoided. Yet, the wishes of the patient regarding treatment, confidentiality, and other medico-legal decisions must thus be respected to the maximal extent possible, consistent with appropriate medical care and psychiatric assessment. To the extent permitted by applicable law and the Code of the AMA, physicians may investigate or treat without securing informed consent, even in the face of refusal, when immediate intervention is deemed necessary to prevent potential death or serious harm to the patient. This should only occur when treatment or evaluation cannot be delayed without seriouspotential harm. While it may be necessary to physically or pharmacologically restrain a patient to assure that essential medical services are provided, such restraints should be applied in a stepwise manner and only to the degree necessary to protect the patient and those around him or her, with the necessary minimum violation of patient rights. The use of restraints should comply with applicable guidelines. Responsibilities When Conducting Independent Medical Evaluations or Occupational Examinations Medical toxicologists may evaluate patients on behalf of a third party as part of independent medical evaluations (IMEs) or as part of occupational health examinations. In all instances, the role of a medical toxicologist as a physician must be the paramount guiding principle. Conduct During Independent Medical Examinations
When conducting IMEs, medical toxicologists should
Occupational Health Examinations
Despite the absence of a traditional doctor-patient relationship, the medical toxicologist still has the responsibility to divulge to the examinee any medical conditions identified during the examination and should treat the examinee with dignity. During the course of an occupational surveillance examination, the medical toxicologist may acquire information beyondthat which is relevant to the occupational examination’s requirements. Such information should not be divulged to the employer unless required by statute or regulation. Expert Testimony It is recognized that the discipline of medical toxicology has a unique relationship with judicial matters. This is because medical toxicologists specialize in being knowledgeable about the capacity of chemical substances to do harm. Because of their unique knowledge base, the provision of legal testimony is considered to be a component of the practice of medical toxicology. It is important that the medical toxicologist consistently bear in mind the purpose of an expert witness within the legal system. The expert is not present as an advocate nor is he/she present to adjudicate the matter at hand. Rather, he/she is present exclusively to assist the trier of fact via the presentation of factual knowledge and scientifically based opinion and the conveyance of understanding regarding the matter under consideration. All testimonies must be objective and impartial. It is unethical to give false or misleading testimony. Compensation of the expert should be reasonable and commensurate with the time and effort invested by the expert as well as his/her experience, unique expertise, and ability. An expert should not, under any circumstances, link compensation of any kind to the outcome of the case.
The physician expert witness should, in general, not make such activities the sole focus of his/her professional practice. Consideration can, however, be given to special circumstances such as retirement from or temporary interruption of clinical practice, so long as the expert can demonstrate that these circumstances do not materially diminish the expert’s competency to address the issues at hand.
Research
Research undertaken by medical toxicologists should be conducted with the aim of advancement in the treatment of patients and for the well-being of society. Such activities should follow the guidelines outlined by the applicable versions of the Declaration of Helsinki and the National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research. Additionally, such research should comply with relevant federal, institutional, and professional regulations and guidelines. All human subjects or animal research activities should be approved by a recognized human subject or animal review board. Medical toxicologists must be diligently aware of real and potential sources of bias when conducting research. This is particularly relevant where the stipulations and interest of the funding agency (e.g., pharmaceutical firms, foundations, government, industry, and educational institutions) are potential sources for bias. In no circumstances should a medical toxicologist resort to research on human subjects in an alternative location with the specific intent of avoiding restrictive patient safeguards. Analyzing and communicating the results of research must be timely, accurate, and truthful. The principal investigator of a research project must take full responsibility for the design, execution, and reporting of the results of the study. The investigator must assure that all relevant investigators in the research project receive recognition for their contributions. If the medical toxicologist has any potential or real financial benefit associated with their research, this must be disclosed to the research institution and to any potential publishers of the research. If a medical toxicologist is serving in the role of a clinical investigator of a commercial product, it is unethical to buy or sell equity in the company that may financially benefit or suffer from the results of the research until the study is completed and the results are made public. Reasonable requests for access to raw data should be respected, provided doing so does not create an unduly onerous task for the investigator and that there are no contractual obligations to the contrary. Before embarking on a clinical trial, medical toxicologists in the USA should pre-register applicable studies at trial with www.clinicaltrials.gov.
Educational Activities
The medical toxicologist has had the privilege of unique training and medical education and thus is encouraged to teach his/her knowledge to medical students, physicians in graduate medical education, other health care professionals, patients, and society. When providing such education, the medical toxicologist should strive to do so without the bias of outside influences. Maintenance of Professional Competency Medical toxicologists should strive to obtain and maintain certification in medical toxicology. It is recommended that medical toxicologists who are eligible to do so actively participate in the American Board of Medical Specialties Medical Toxicology Maintenance of Certification process. Use of Non-Accepted Therapies A medical toxicologist must never use personal gain as a motivating factor in choosing a therapy, nor should he/she ever use therapies that have been established to be of no benefit. Where possible, a medical toxicologist who uses a therapy that is unlikely to be of benefit must inform the patient of the status of the therapy, give the patient the rationale leading to that choice, inform the patient of the costs, possible lack of coverage by medical insurance (if applicable), and risks, and obtain informed consent from the patient before initiating therapy.
It is unethical for a medical toxicologist to use therapies that are contrary to accepted principles of medical practice. Conflict of Interest The ethical practice of medicine demands that the physician’s obligations to the patient must not be influenced by any conflicts of interest that detract from the physician’s core obligation to the patient. The medical toxicologist must assure that the use of any medication, treatment, or device is based solely on the potential for patient’s benefit and not on any direct or indirect benefit to the practitioner or other parties. The practitioner must be aware that any commercial or financial relationship with third parties, such as pharmaceutical companies or other businesses, carries a potential for conflict of interest. While such relationships should not be prohibited, the practitioner must maintain awareness of such potential conflict. When questions arise in this regard, consultation with an ethics board is encouraged. The medical toxicologist must disclose conflicts of interests. The toxicologist should disclose conflicts to the medical institution where the toxicologist practices, to journals where he or she is submitting research, and to patients who may receive treatments that involve conflicts. Patients must be made aware of and have the ability to refuse service with any such potential conflict of interest. Any disputes regarding potential conflicts of interest between the physician and the patient should be resolved with the patient’s best interest as the primary motive. If a satisfactory resolution of a disclosure of conflict of interest cannot be established, the medical toxicologist should withdraw from the relationship with the patient in a manner consistent with the principles outlined in the section on the Physician-Patient relationship of these guidelines. In these instances, the medical toxicologist should assist the patient in making arrangements for care by another appropriate practitioner. Conflict of Interest None.
References
1. American Medical Association. AMA’s Code of Ethics. American http://www.ama-assn.org/ama/pub/physician-resources/medicalethics/ code-medical-ethics.page). Accessed: April 29, 2015 |
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| Guidance Document: Management Priorities in Salicylate Toxicity |
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Click here for a .pdf of this statement
Disclaimer
While individual practitioners may differ, this is the position of the College at the time written, after a review of the issue and pertinent literature. This document identifies critical management priorities for the salicylate-poisoned patient. It is not intended as a clinical guideline or substitute for clinical consultation with a medical toxicologist and a nephrologist.
Introduction Salicylate toxicity is a complex problem that may develop with either acute or chronic exposure to salicylates. Salicylates are found in over-the-counter medications including aspirin, bismuth subsalicylate, effervescent antacids, ointments, liniments and oil of wintergreen (methyl salicylate) and alternative medication products (e.g., willow bark) as well as numerous prescription medications. Patients with salicylate toxicity may have involvement of multiple organ systems including particularly the central nervous system (cerebral edema, coma, agitation, tinnitus, seizures), the pulmonary system (hyperventilation/tachypnea, acute lung injury), and the gastrointestinal system (nausea, vomiting). Salicylate-poisoned patients are almost universally volume depleted at the time of presentation to medical care (as much as 4-6 L in most symptomatic adults) from both sensible (e.g., vomiting and natriuresis) and insensible (e.g., fever, increased respiratory losses) losses. Volume resuscitation should be addressed early in the course. Acid-base disturbances including respiratory alkalosis, elevated anion gap metabolic acidosis, and mixed abnormalities are common. Serum salicylate concentrations should be interpreted in the context of the acuity of the exposure and the overall clinical condition.Significant toxicity with chronic salicylate exposure can occur at relatively low serum concentrations. Once the diagnosis of salicylate toxicity is seriously considered, treatment should begin promptly. While an abundance of case reports, case series and textbook chapters serve to identify critical issues and provide recommendations for therapy, there have not been direct comparisons of specific treatment regimens. The following document highlights clinically important issues that both demand attention in the salicylate-poisoned patient and suggest avenues for future clinical research.Management Priorities The management of salicylate toxicity can be difficult due to its complex pathophysiology. There is no specific antidote for salicylate poisoning. Good supportive care and attention to the following specific issues are important.1. Salicylate Concentration
Initial and subsequent frequent salicylate concentrations should be determined and interpreted in the individual clinical context. Factors that may influence the interpretation of the salicylate concentration include exposure acuity, product formulation, coingestions, comorbidities and clinical condition, particularly acid-base status. The Done nomogram is not reliable for interpretation of concentrations in either acute or chronic toxicity.1-3 Furthermore, while the earliest time-concentration plot on the Done nomogram is six hours post ingestion, earlier salicylate determinations are typically advisable and clinically useful. Attention to reported salicylate concentration units is important as they may be reported as mg/dL, mg/L, or mmol/L (e.g., 100 mg/dL is equal to 1000 mg/L or 7.24 mmol/L). Clinical laboratories are encouraged to standardize their reporting of salicylate units. Serial concentrations should be determined until they are clearly declining, documenting lack of ongoing absorption. However, the patient’s overall clinical condition, and not the salicylate concentration alone, should guide management. Clinical deterioration, even in the setting of a falling serum concentration, is ominous, suggestive of increasing central nervous system (CNS) salicylate concentration. As blood pH falls, there is an increased proportion of nonionized salicylate that more readily distributes into the cerebrospinal fluid (CSF) and other tissues.4,5 Therefore, blood pH must be considered in conjunction with the salicylate concentration. There are some substances (e.g., diflunisal) that can interfere with the laboratory quantitation of salicylate concentration.6 Consultation with the laboratory and/or medical toxicologist will help identify the most appropriate specific analytic methodology and may assist in the clinical interpretation of laboratory findings, particularly when they are inconsistent with the clinical condition.
2. Acid-Base Status, Volume Status and Electrolytes
The evaluation of the salicylate-poisoned patient requires measurement of serum/plasma electrolytes and arterial blood gas analysis. The use of electrolytes to identify an abnormally high anion gap is not a reliable screen for salicylate toxicity as many chemistry analyzers report a false elevation of the chloride measurement in the presence of salicylates.7 Acidemia should be avoided. Continuous intravenous infusion of sodium bicarbonate is also indicated in the presence of mild alkalemia. Alkalemia is a function of salicylate-induced respiratory alkalosis and is almost universally associated with a bicarbonate deficit and paradoxical aciduria, limiting salicylate excretion. The reduction in serum bicarbonate is caused both by concomitant metabolic acidosis and by an initial respiratory alkalosis-induced bicarbonaturia. A slightly alkalemic blood pH limits an increase in CNS salicylate concentration by shifting the ionization equilibrium of salicylate in the blood to the charged form and decreasing passage of salicylate into the CNS. Clinical severity is predicted by the acid-base status, with those adult patients exhibiting only respiratory alkalosis expected to have mild toxicity, while those with a normal or near normal serum pH (7.40 ± 0.05) with underlying respiratory alkalosis and metabolic acidosis are expected to have moderate poisoning. Acidemia (pH < 7.35) is seen in severe poisoning, and the pH itself also worsens the expected course. Euvolemia should be achieved. Hypovolemia is often underappreciated, and worsens salicylate toxicity as well as impairing treatment measures, especially alkalinization of the urine. Hypovolemia contributes to electrolyte and acid-base abnormalities through enhanced renal sodium and bicarbonate resorption and potassium excretion. Electrolyte balance should be restored. Particular attention should be paid to glucose supplementation as CNS glucose utilization is increased, and CNS glucose concentration may be lower than the serum glucose. Hypokalemia is multifactorial in etiology and potassium supplementation should be made early. A normal to high-normal serum potassium is believed to facilitate urinary alkalinization. Electrolytes and acid-base status should be closely monitored in order to avoid excessive electrolyte replacement and/or alkalinization, particularly as salicylate toxicity resolves during treatment.
3. Gastrointestinal Decontamination
Gastrointestinal decontamination techniques including administration of activated charcoal administration or even whole bowel irrigation may be considered in specific cases, particularly in those patients with early presentation after ingestion or in cases with rising levels or other signs of incomplete absorption. The use of multiple-dose activated charcoal is controversial. The data from animal and some volunteer studies demonstrated enhanced salicylate clearance with multiple-dose activated charcoal; the data from human overdose cases are mixed in their results. The relative roles of decreased absorption (gastrointestinal decontamination), enhanced adsorption of salicylate within the small bowel, and so-called gastrointestinal dialysis (enhanced elimination) are not clear. Clinical risk/benefit considerations are important given the potential for aspiration in the sick salicylate-poisoned patient with a deteriorating mental status.8,9
4. Airway Protection and Respiratory Status
Endotracheal intubation may be indicated in the salicylate-intoxicated patient with deteriorating mental status or acute lung injury and should be considered in those with significant, uncontrollable agitation. Hyperventilation is not itself an indication for intubation. However, endotracheal intubation and mechanical ventilation can be associated with rapid worsening of clinical salicylate toxicity and increased mortality unless a normal or slightly alkalemic blood pH is maintained via hyperventilation and achievement of a low PCO2 and/or intravenous sodium bicarbonate. Once airway control has been established, it is imperative that the increased minute ventilation and low PCO2 usually seen with salicylate intoxication are maintained.5 The acts of sedation and/or induction of paralysis lead to retention of carbon dioxide and respiratory acidosis. Rapid distribution of salicylate into the CNS can occur consequent to the blood pH decrease associated with the loss of normal or slightly alkalemic (7.45-7.50) blood pH. Administration of sodium bicarbonate by intravenous bolus at the time of intubation in a sufficient quantity to maintain a blood pH of 7.45-7.50 over the next 30 minutes is a reasonable management option during this critical juncture; intravenous sodium bicarbonate bolus and/or bag valve mask hyperventilation should be employed in any patient who is acidemic with a spontaneously ventilating PCO2 of <20 mm Hg as further deterioration in acid-base status can be expected during intubation. Clinical studies demonstrating benefit from various empiric dosing regimens have not been reported. Coingestion or therapeutic administration of CNS/respiratory depressant drugs may also suppress hyperventilation and thereby precipitate clinical deterioration in salicylate toxicity.
5. Enhanced Elimination
Techniques for enhanced elimination should be utilized in managing patients with salicylate toxicity. Extracellular volume depletion should be corrected and diuresis should be induced with large volumes of relatively isotonic sodium bicarbonate-containing intravenous fluids, as renal excretion of salicylates is more dependent on urine pH than on urine flow. Urine alkalinization to a pH of 7.5 - 8.0 increases urinary excretion of salicylates more than 10-fold and should be considered for significant salicylate toxicity in patients with intact renal function, alone or in combination with hemodialysis (see below).10 Intravenous (not oral) administration of sodium bicarbonate as a crystalloid preparation should be used. One commonly utilized intravenous solution consists of one liter of D5W to which three 50 mL-ampules of 7.5% or 8.4% sodium bicarbonate (for a total of 132-150 mEq) and 30-40 mEq of potassium chloride per liter are added. The rate of infusion should be sufficient to induce a urine output of 2-3 mL/kg/hr. Urine pH should be checked frequently. Achievement of the goal urine pH may be difficult in the setting of metabolic acidosis and hypobicarbonatemia, hypokalemia, renal insufficiency, predominant respiratory alkalosis (which also causes hypobicarbonatemia), volume depletion, or volume limitations to intravenous fluid administration (e.g., patients with congestive heart failure, cerebral edema, and/or pulmonary edema). Hemodialysis is very effective in the treatment of patients with salicylate toxicity since an increased fraction of free salicylate occurs in the serum following saturation of protein binding.3Hemodialysis may be life-saving in certain circumstances and it typically resolves toxicity in hours rather than days that may be required with alkaline diuresis. Charcoal hemoperfusion is also very effective at removing salicylate, but is now rarely used. Advantages of hemodialysis over hemoperfusion include correction of acid-base and fluid and electrolyte disturbances in addition to enhancing elimination of the salicylate, and being a much more widely available technique. Peritoneal dialysis is not an efficient means of salicylate removal. Urine alkalinization should be initiated while preparing for hemodialysis and continued during this procedure. Indications for hemodialysis vary depending on the age of patient, acuity of the toxicity, serum salicylate concentration, associated ingestions or other co-morbidities, and ability to tolerate sodium bicarbonate and fluid administration but may include:
References 1. Done AK. Salicylate intoxication. significance of measurements of salicylate in blood in cases of acute ingestion. Pediatr 1960;26:800-807.2. Dugandzic RM, Tierney MG, Dickinson GE, Dolan MC, McKnight DR. Evaluation of the validity of the Done nomogram in the management of acute salicylate intoxication. Ann Emerg Med 1989;18(11):1186-90.3. Alvan G, Bergman U, Gustafsson LL: High unbound fraction of salicylate in plasma during intoxication. Br J Clin Pharmacol 1981; 11:625.4. Hill JB. Experimental salicylate poisoning: observations on the effects of altering blood pH on tissue and plasma salicylate concentrations. Pediatr 1971;47:658-665.5. Stolbach AI, Hoffman RS, Nelson LS. Mechanical ventilation was associated with acidemia in a case series of salicylate-poisoned patients. Acad Emerg Med 2008;15(9):866-9.6. Adelman HM, Wallach PM, Flannery MT. Inability to interpret toxic salicylate levels in patients taking aspirin and diflunisal. J Rheumatol 1991;18(4):522-523.7. Jacob J, Lavonas EJ. Falsely normal anion gap in severe salicylate poisoning caused by laboratory interference. Ann Emerg Med 2011;58(3):280-281.8. Bradberry SM, Vale JA. Multiple-dose activated charcoal: A review of relevant clinical studies. J Toxicol Clin Toxicol 1995;33: 407.9. Juurlink DN, McGuigan MA: Gastrointestinal Decontamination for enteric-coated aspirin overdose: What you do depends on who you ask. J Toxicol Clin Toxicol 2000;38:465.10. Proudfoot AT, Krenzelok EP, Vale JA. Position Paper on Urinary Alkalinization. J Toxicol Clin Toxicol 2004;42:1.11. Fertel BS, Nelson LS, Goldfarb DS. The underutilization of hemodialysis in patients with salicylate poisoning. Kidney Int 2009;75(12):1349-1353.Related Positions Statements American Academy of Clinical Toxicology and European Association of Poisons Centres and Clinical Toxicologists. Position Statement and Practice Guidelines on the Use of Multi-Dose Activated Charcoal in the Treatment of Acute Poisoning. J Toxicol Clin Toxicol 1999;37:731. American Academy of Clinical Toxicology and European Association of Poisons Centres and Clinical Toxicologists. Position Paper: Single-Dose Activated Charcoal Clin Toxicol 2005;43:61. Proudfoot AT, Krenzelok EP, Vale JA. Position Paper on Urine Alkalinization. J Toxicol Clin Toxicol 2004;42:1. |
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| Medical Toxicologist Participation in Medication Management and Safety Systems |
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Disclaimer While individual practitioners may differ, this is the position of the American College of Medical Toxicology (ACMT) at the time written, after a review of the issue and pertinent literature. Background Hospital committees are regularly meeting working groups either required by regulatory agencies, oversight organizations, or accrediting bodies, or established by hospital administration as critical elements to the safe practice and monitoring of healthcare delivery. Examples of working groups that address medication management and medication safety systems include the Pharmacy and Therapeutics (P&T) Committee (also known as the Formulary and Therapeutics, Formulary Committee, or Pharmaceutical Stewardship Committee, et al.) and the Medication Safety Committee (MSC) (also known as the Medication Safety Improvement, Drug Safety Committee, et al.). Within a specific institution, other organizational structures (Departments and/or Committees) may address or support these missions, such as Quality, (Patient) Safety, Performance Improvement, and Risk Management. The P&T committee (or equivalent) commonly determines the hospital formulary and manages medication utilization.1 Medications are included or excluded based on factors such as efficacy, safety, cost, dosing, the needs of the organization, and the patient population served. The P&T Committee may perform pharmacoeconomic assessments or financial evaluations to minimize pharmacy budget impact. The MSC (or equivalent) commonly reviews medication errors and adverse drug events and develops systematic solutions to mitigate the risk of recurrent episodes and similar incidents. Medication errors are mistakes involving substances used for medical treatment (including, but not limited to, prescription and nonprescription pharmaceuticals, biologics, relevant devices, respiratory therapy treatments, diagnostic and contrast agents, parenteral nutritional and concentrated electrolytes solutions, vitamins, and blood derivatives, et al.), whether or not patient harm results. According to the National Coordinating Council for Medication Error Reporting and Prevention, “Such events may be related to professional practice, health care products, procedures, and systems, including prescribing; order communication; product labeling, packaging, and nomenclature; compounding; dispensing; distribution; administration; education; monitoring; and use."2 Adverse drug events may result not only from (preventable) medication errors, but also from known side effects, drug-drug interactions, drug-alternative medicine interactions, unique patient-specific factors such as pharmacogenetics or underlying comorbidities, and idiopathic reactions. Data are usually collected by hospital pharmacies, quality improvement and risk management departments, and physician peer review systems, although under-reporting is common. Medication errors and adverse drug reactions are common and costly.3-13 Medical Toxicologists have unique knowledge, training, and experience that may aid both the P&T and MSC committees (or equivalent) in fulfilling their duties.14 1. Medical Toxicologists are physicians involved in clinical care of patients. They have expertise in pharmacotherapeutics, pharmacokinetics, adverse drug reactions, drug-drug interactions, overdose, and risk-assessment. Medical Toxicologists can make recommendations regarding the admission, change in status, or deletion of a medication to the formulary based on this expertise. 2. Medical toxicologists are in a unique position to identify, investigate, and treat the consequences of medication errors and adverse drug reactions. They may assist in decreasing the incidence of errors in their institutions through identification and elimination of systems errors and aggressive education of health care providers. 3. Medical Toxicologists may aid healthcare organizations in preparing guidelines for safe use of high-risk medications15 such as antithrombotic agents, glycemic control agents, chemotherapeutics, opioids, procedural sedation agents, and others. 4. Medical Toxicologists may aid their medication management committees on the policies, protocols, or guidelines for off-label uses of FDA-approved medications and for restricted use policies, protocols, or guidelines of certain medications and therapies. 5. Medical Toxicologists are uniquely qualified to discuss the antidotes and therapies for poisonings from adverse medication events, therapeutic misadventures, or overdoses. Medical Toxicologists may aid hospitals in developing guidelines for their safe use in appropriate situations. 6. Medical toxicologists may aid their hospitals in improving often underreported adverse events by ensuring their appropriate and precise capture through such channels as the U.S. Food and Drug Administration’s MedWatch Program, appropriately certified Patient Safety Organizations, health care systems databases, or ACMT’s ToxIC Registry.16,17 Conclusion Due to Medical Toxicologists’ unique knowledge, training, and experience, it is ACMT’s position to encourage hospitals to utilize Medical Toxicologists in their medication management and medication safety systems. This may include membership on relevant committees or consultative roles to these committees. ACMT encourages its members, where relevant, to be involved in local medication management systems. Medical Toxicologists should assist in the development, adoption, and monitoring of error preventative and detection measures such as computerized order entry, bar coding of medications, etc. in their institutions whenever practicable.18-20 ACMT encourages these practices among its members, as well as reporting of medication errors which may be encountered. References 1. American Society of Health-System Pharmacists. ASHP guidelines on the pharmacy and therapeutics committee and the formulary system. Am J Health-Syst Pharm. 2008;65:1272-83. 2. National Coordinating Council for Medication Error Reporting and Prevention. About Medication Errors. What is a Medication Error? National Coordinating Council for Medication Error Reporting and Prevention: published online, ©1998-2012. Available at: http://www.nccmerp.org/aboutMedErrors.html. Accessed June 22, 2012. 3. Bates DW, Cullen DJ, Laird NM, et al. Incidence of adverse drug events and potential adverse drug events: implications for prevention. JAMA. 1995;274:29-34. 4. Bates DW. Frequency, consequences and prevention of adverse drug events. J Qual Clin Pract. 1999;19:13-17. 5. Beckett RD, Sheehan AH, Reddan JG. Factors associated with reported preventable adverse drug events: a retrospective, case-control study. Ann Pharmacother. 2012;46:634-41. 6. Brennan TA, Leape LL, Laird NM, et al. Incidence of adverse events and negligence in hospitalized patients- results of the Harvard Medical Practice Study I. N Engl J Med. 1991;324:370-376. 7. Budnitz DS, Lovegrove MC, Shehab N, Richards CL. Emergency hospitalizations for adverse drug events in older Americans. N Engl J Med 2011;365:2002-12. 8. Dormann H, Muth-Selbach U, Krebs S, et al. Incidence and costs of adverse drug reactions during hospitalization. Drug Safety. 2000;22:161-168. 9. Hug BL, Keohane C, Seger DL, Yoon C, Bates DW. The costs of adverse drug events in community hospitals. Jt Comm J Qual Patient Saf. 2012;38:120-6. 10. Kohn LT, Corrigan JM, Donaldson MS, eds. To Err is Human: Building a Safer Health System. Washington, D.C.: National Academy Press, 2000. 11. Leape LL, Brennan TA, Laird N, et al. The nature of adverse events in hospitalized patients: results of the Harvard Medical Practice Study II. N Engl J Med. 1991;324:377-384. 12. Leape LL. Errors in medicine. Clin Chim Acta. 2009;404:2-5. 13. Thomas EJ, Struddert DM, Burstin HR, et al. Incidence and types of adverse events and negligent care in Utah and Colorado. Med Care. 2000;38:261-271. 14. Perrone JM, Nelson LS. Pharmacy and Therapeutics Committees: Leadership opportunities in medication safety for medical toxicologists. J Med Toxicol. 2011;7:99-102. 15. Institute for Safe Medication Practices. ISMP’s List of High-Alert Medications. Published online: ISMP, 2012. Available at: https://www.ismp.org/tools/highalertmedications.pdf. Accessed June 22, 2012. 16. Emmendorfer T, Glassman PA, Moore V, Leadholm TC, Good CB, Cunningham F. Monitoring adverse drug reactions across a nationwide health care system using information technology. Am J Health Syst Pharm. 2012;69:321-8. 17. U.S. Food and Drug Administration. MedWatch: The FDA Safety Information and Adverse Event Reporting Program. Last Updated: 06/21/2012. Available at: http://www.fda.gov/Safety/MedWatch/default.htm. Accessed June 22, 2012. 18. Nwulu U, Nirantharakumar K, Odesanya R, McDowell SE, Coleman JJ. Improvement in the detection of adverse drug events by the use of electronic health and prescription records: An evaluation of two trigger tools. Eur J Clin Pharmacol. 2012 Jun 17 [Epub ahead of print]. 19. Ferner RE. Medication errors. Br J Clin Pharmacol. 2012;73:912-6. 20. Menendez MD, Alonso J, Rancaño I, Corte JJ, Herranz V, Vazquez F. Impact of computerized physician order entry on medication errors. Rev Calid Asist. 2012 Mar 30 [Epub ahead of print]. |
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| Antidote Shortages: Impact and Response |
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Disclaimer While individual practitioners may differ, these are the positions of the ACMT and the AACT at the time written, after a review of the issue and pertinent literature. Background The recently passed 2012 Food and Drug Administration Safety and Innovation Act1 requires manufacturers to notify the Secretary of Health and Human Services of any significant disruption in the availability of emergency, life-supporting medications. The Act also requires the Secretary to establish a task force to develop and implement a strategic plan for enhancing the response to preventing and mitigating drug shortages and requires the Comptroller General of the United States to conduct a study to examine the cause of drug shortages and formulate recommendations on how to prevent or alleviate such shortages. Inadequate antidote and antivenom supply to treat poisonings and envenomations has long been recognized by the toxicology and emergency medicine communities.2-8 A recent worsening trend of antidotes and antivenoms in critically short or absent supply places patients at increased risk for adverse outcomes. Shortages have included, but have not been limited to, atropine, benzodiazepines (diazepam, midazolam, et al.), black widow spider (Latrodectus mactans) antivenin, CaNa2EDTA, dexrazoxane, digoxin immune Fab, epinephrine, ethanol, etomidate, intravenous fat emulsion (20%), leucovorin, methylene blue, N-acetylcysteine, naloxone, North American coral snake (Micrurus fulvius) antivenin, octreotide, sodium bicarbonate, and vitamin K.9,10 Significant economic disincentives exist to produce rarely used drugs (such as antidotes). While the FDA’s Orphan Drug program provides some inducement, many antidotes and antivenoms are provided by a single entity. In the event a manufacturer is unable to meet demand, a critical shortage is likely to develop. Shortages are particularly concerning because the administration and provision of antidotes are identified as National Preparedness Critical Target Capabilities11 and treatment sites already demonstrate deficiencies.12,13 Further complicating this issue is the assignment of expiration dates as required under federal statute,14 which is intended to insure medication stability and safety under the conditions which they are tested. However, manufacturers are not required to test for extended stability, although permitted to do so, and economic incentives may preclude extending expiration dates. However, testing has shown that some pharmaceuticals are stable far past their labeled expiration dates.15,16,17 Except for a tetracycline formulation no longer in circulation, there is little evidence that expired medications deteriorate to unsafe constituents, although potency may decrease.15,16,17 While potency is especially important for medications that have a narrow therapeutic window, many antidotes and antivenoms are titrated to effect. For these drugs, there is insufficient evidence to support that a minimally decreased potency results in clinically significant difference. This is particularly true of biologicals, such as antivenoms, where the primary risks are related to anaphylactoid or anaphylactic reactions. Additionally, legislation intended to deter the diversion of drugs of abuse may proscribe criminal sanctions on practitioners and facilities that utilize expired medications and antivenoms, even in the event of medical necessity. Drugs or devices whose expiration date has passed are considered adulterated by some states’ statutes, and thus their delivery, sale, holding, or receipt is illegal per se.18 This is despite the evidence that such drugs may not be less potent, merely untested. Thus, faced with the need to provide lifesaving medications for which the only available supply is past expiration or without precise documentation of production and storage, such as antivenoms for exotic snakebites, practitioners and health care facilities must choose between providing potentially life-saving treatment and abiding by the law. Poison centers and organizational consortiums have responded to antidotal insufficiencies in a number of ways, including maintaining lists of regional antidote availability and formal institutional-sharing agreements. An Antivenom Index19 has been established to help locate scarce antivenoms for rare indigenous and non-indigenous venomous animals, although sourced antivenoms may still encounter regulatory obstacles to administration. For other agents, particularly medical countermeasures for chemical, biological, radiological, nuclear, and public health emergencies, cooperation between the DOD, the FDA, and pharmaceutical companies has resulted in programs to extend the shelf-life of existing supplies – for example, outdated potassium iodide (KI)20 and the Shelf Life Extension Program (SLEP) for ciprofloxacin, nerve agent antidote autoinjectors, Prussian Blue, and others.21 However, SLEP is limited to specific items and participating organizations, places official limitations on sharing testing and extension data, and exposes non-SLEP organizations utilizing SLEP data to violations of Federal law.14 Thus, opportunities to extend shelf-life of other critical antidotes and antivenoms are not assured, although not impossible (e.g., as demonstrated with the recent successful extension of the North American coral snake antivenin “out-date”).10 Conclusion ACMT and AACT encourage the Secretary of Health and Human Services, the Food and Drug Administration, The Comptroller General of the United States, and manufacturers, under the newly granted authority and mandates of the Food and Drug Administration Safety and Innovation Act of 2012, to immediately evaluate and address access to antidotes and antivenoms. In particular, experts in these areas, including medical toxicologists and other physicians, pharmacists, pharmacologists, scientists, and regulators, in cooperation with manufacturers, should be accessed to generate uniform guidelines that should address: 1) Including antidotes (including those with established antidotal benefit, but potentially without specific toxicological labeling indication)22 within the statutory scope of emergency, life-supporting medications; 2) Monitoring the use and availability of life-sustaining medications requiring emergent or intra-operative use and early notification of antidotes and medication classes facing shortages; 3) Establishing a systematic mechanism for ascertaining clinically relevant, realistic “out-dating” procedures based on biologic and storage condition principles, and determining if presumption of adulteration based solely on a date determined by a manufacturer’s choice of a testing regimen is appropriate; 4) Exploring and addressing extending dating standards or Emergency Use Authorizations In cases where the public’s health may be compromised by shortages of specific, critical therapeutics or unavailable antidotes; 5) Countermeasures to address and preclude hoarding and price-gouging; 6) Local and regional strategies to facilitate antidote sharing and delivery; 7) Mechanisms to encourage development, testing and delivery of rare antidotes and antivenoms.
References 1. Food and Drug Administration Safety and Innovation Act (FDASIA). Public Law 112-144, 126 Stat. 993. Available at: http://www.govtrack.us/congress/bills/112/s3187/text> 2. Burda AM, Sigg T, Haque D, Bardsley CH. Inadequate pyridoxine stock and its effect on patient outcome. Am J Ther. 2007;14(3):262-264. 3. Dart RC, Borron SW, Caravati EM, et al. Expert consensus guidelines for stocking of antidotes in hospitals that provide emergency care. Ann Emerg Med. 2009;54(3):386-394.e1. 4. Dart RC, Stark Y, Fulton B, Koziol-McLain J, Lowenstein SR. Insufficient stocking of poisoning antidotes in hospital pharmacies. JAMA. 1996;276(18):1508-1510. 5. Morrow LE, Wear RE, Schuller D, Malesker M. Acute isoniazid toxicity and the need for adequate pyridoxine supplies. Pharmacotherapy. 2006;26(10):1529-1532. 6. Teresi WM, King WD. Survey of the stocking of poison antidotes in Alabama hospitals. South Med J. 1999;92(12):1151-1156. 7. Woolf AD, Chrisanthus K. On-site availability of selected antidotes: results of a survey of Massachusetts hospitals. Am J Emerg Med. 1997;15(1):62-66. 8. McFee RB, Caraccio TR, Gamble VN. Understocking antidotes for common toxicologic emergencies: A neglected public health problem. Johns Hopkins Advanced Studies in Medicine. 2005;5(5):262-263. 9. American Society of Health-System Pharmacists. Drug Shortages: Current Drugs. 2012. Available at: http://www.ashp.org/menu/DrugShortages/CurrentShortages.aspx> 10. Azoulay S. Antivenin (Micrurus fulvius) (Equine Origin). North American Coral Snake Antivenin. Further Extension of Expiration Dating To October 31, 2012. LOT No. 4030026. [Dear Health Care Provider Letter]. New York, NY: Pfizer Inc.; 2011. 11. U.S. Department of Homeland Security. Target Capabilities List. A companion to the National Preparedness Guidelines. 2007. Available at http://www.fema.gov/pdf/government/training/tcl.pdf> 12. Greenberg MI, Jurgens SM, Gracely EJ. Emergency department preparedness for the evaluation and treatment of victims of biological or chemical terrorist attack. J Emerg Med. 2002;22(3):273-278. 13. Keim ME, Pesik N, Twum-Danso NA. Lack of hospital preparedness for chemical terrorism in a major US city: 1996-2000. Prehosp Disaster Med. 2003;18(3):193-199. 14. Code of Federal Regulations. Title 21 (Food and Drugs). Chapter 1 (Food and Drug Administration Department of Health and Human Services). Subchapter C (Drugs: General). Part 211 (Current Good Manufacturing Practices for Finished Pharmaceuticals). Available at: http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?CFRPart=211&showFR=1> 15. Lyon RC, Taylor JS, Porter DA, Prasanna HR, Hussain AS. Stability profiles of drug products extended beyond labeled expiration dates. J Pharm Sci. 2006;95(7):1549-1560. 16. [No author listed]. Drugs Past Their Expiration Date. Med Lett Drugs Ther. 2009;51(1327/1328):100-101. 17. Hoffman RS, Mercurio-Zappala M, Bouchard N, Ravikumar P, Goldfrank L. Preparing for chemical terrorism: a study of the stability of expired pralidoxime (2-PAM). Disaster Med Public Health Prep. Mar 2012;6(1):20-25. 18. The 2012 Florida Statutes. Florida Drug and Cosmetic Act; 499.006(9), 499.005(1), and 499.005(3). Available at: http://www.leg.state.fl.us/statutes/index.cfm?App_mode=Display_Statute&URL=0400-0499/0499/0499.html> 19. American College of Medical Toxicology. ACMT Position Statement: Institutions housing venomous animals. 2012. Available at http://www.acmt.net/cgi/page.cgi?aid=4005&_id=462&zine=show> 20. Food and Drug Administration CfDEaR. Guidance for federal agencies and state and local govenments. Potassium iodide tablets shelf life extension. Rockville, MD: U.S. Department of Health and Human Service; 2004. 21. Department of Defense. Shelf Life Management Manual. DOD 4140.27-M / DLA J-373. 2003. Available at https://www.shelflife.hq.dla.mil/policy_DoD4140_27.aspx> 22. Marraffa JM, Cohen V, Howland MA. Antidotes for toxicological emergencies: a practical review. Am J Health Syst Pharm. 2012;69(3):199-212. |
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| Pressure Immobilization After North American Crotalinae Snake Envenomation |
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Click here for a .pdf of this statement
Background Historically, many first aid measures have been employed in the treatment of snake bites, but none have been shown to improve patient outcome. Pressure immobilization is a technique routinely employed in the prehospital management of neurotoxic snake species in Australia. First described by Sutherland and colleagues in the 1970s, pressure immobilization involves wrapping the entire extremity with a bandage and then immobilizing the extremity with a splint [6]. The bandage should generate a pressure between 40 and 70 mmHg in the upper extremity and 55 and 70 mmHg in the lower extremity in order to effectively delay systemic absorption of venom [7]. Several animal studies have demonstrated delayed systemic absorption of venom with pressure immobilization [6–8]. However, studies have also revealed that pressure immobilization bandages are commonly applied incorrectly, even in a simulated setting following provider instructions and training [9–12]. Although the more common error is to apply the bandage too loosely, when applied too tightly, the bandage may function as a tourniquet, causing limb ischemia, and may also increase systemic absorption of the venom [7]. Animal models of North American Crotalinae envenomation demonstrate delayed systemic absorption of venom and delayed mortality following application of pressure immobilization bandages [13–15]. However, the local effects of sequestering cytotoxic venom in the extremity are less clear. In a swine model of pressure immobilization following Crotalus atroxlower extremity envenomation, intracompartmental pressure increased significantly compared to controls, from a nonsurgical range to levels that would prompt fasciotomy [13]. Position Given that the primary toxic effect of envenomation is local tissue injury, mortality is not an ideal outcome measure to extrapolate to human crotaline envenomation. Available evidence fails to establish the efficacy of pressure immobilization in humans, but does indicate the possibility of serious adverse events arising from its use. The use of pressure immobilization for the prehospital treatment of North American Crotalinae envenomation is not recommended. Acknowledgments The organizations acknowledge the efforts of Michael Levine, MD and Michelle Ruha, MD in creating this position statement. References
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| The Role of a Medical Toxicologist for Assistance in the Treatment of Alcohol Withdrawal Syndrome |
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Click here for a .pdf of this statement While individual practitioners may differ, this is the position of the American College of Medical Toxicology at the time written, after a review of the issue and pertinent literature. Background Alcohol (ethanol) withdrawal syndrome is a complex disorder which may present with a spectrum of clinical scenarios, including simple physical or mental discomfort, tremulousness, hallucinations of a tactile, auditory, or visual nature, discrete withdrawal seizures, status epilepticus, and delirium tremens. The clinical presentation and therapy may differ significantly from that of medically intended or planned substance dependence treatment (“detox”). Clinical presentation and management may also vary according to the age of the patient, duration of use, concomitantly abused substances, prescribed pharmaceuticals, and acute or chronic underlying medical, surgical or psychiatric illness. The clinician treating the patient with alcohol withdrawal syndrome should have a comprehensive understanding of the pathophysiology of alcohol withdrawal and be prepared to administer treatment carefully adapted to the clinical scenario(s) present and its (their) severity. The differential diagnosis of alcohol withdrawal syndrome includes withdrawal from other sedative-hypnotic agents such as barbiturates, benzodiazepines, or gamma-hydroxybutyrate; drug-induced, agitated delirium or acute intoxication with stimulants or pro-convulsant agents such as cocaine, amphetamines, phencyclidine, methylxanathines, anticholinergics, or ethylene glycol; delirium secondary to toxicological hyperthermias such as serotonin syndrome; and other deliriums and encephalopathies of toxic or nontoxic origin. The presence of complicating infections, such as meningitis, encephalitis or pneumonia, which may also be entertained as part of the differential diagnosis, may make the diagnosis more difficult and significantly complicate management. Concomitant illness such as meningitis, encephalitis, pneumonia, sepsis, ketoacidoses, pancreatitis, and gastrointestinal hemorrhage may precipitate alcohol withdrawal. As the condition progresses, the ethanol-dependent individual decreases or ceases ethanol intake. The decision to diminish or abstain from ethanol intake may originate voluntarily or occur secondary to a lack of funds. Additionally, patients hospitalized for other reasons (medical illness, planned surgical interventions, or unanticipated traumatic injury) may either choose not disclose or lack the capacity to disclose the full extent of their alcohol intake, and therefore may present in a delayed fashion. Morbidity and Mortality While the mortality of alcohol withdrawal syndrome has decreased with improvements in intensive care, a significant minority of these patients will die or experience significant morbidity either from the effects of withdrawal itself or from its complications, including cerebral hypoxia, infection, and rhabdomyolysis. Failure to recognize and rapidly treat thiamine deficiency, intercurrent hypoglycemia, agitated delirium, and volume depletion may result in irreversible central nervous system damage, other organ systems injury, or persistent psychosis. Benefits of Medical Toxicology Participation in Alcohol Withdrawal Syndrome Treatment Medical Toxicologists have education, training, clinical experience, and practice in the pharmacotherapy, intensive care principles, diagnosis and management of alcohol withdrawal and other withdrawal syndromes. Given (1) the spectrum of alcohol withdrawal presentations; (2) a differential diagnosis which involves primarily drug intoxications or other forms of substance withdrawal; (3) the potential for rapid escalation of symptoms, significant morbidity, and mortality; (4) the potential requirement for "heroic" quantities of sedative-hypnotics or central nervous system depressants in treatment; (5) the dangers of using medications which may mask or exacerbate withdrawal, which may be inappropriately applied to withdrawal manifestations, may interact with other pharmacotherapy, or may complicate the underlying illness; and (6) the need for intensive monitoring – early involvement of a medical toxicologist may be of significant benefit in the care of patients with alcohol withdrawal. The American College of Medical Toxicology strongly recommends participation by a medical toxicologist in the direct or indirect care of patients with suspected or confirmed alcohol withdrawal syndrome. References
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| Interpretation of Urine Analysis for Cocaine Metabolites |
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Click here for a .pdf of this statement The following represents the position of the American College of Medical Toxicology (ACMT). The original Position Statement on this topic, produced and approved in 2000, was re-examined by ACMT in 2011 in light of any new and relevant medical and scientific information. The College may, at its discretion, re-assess this position at any time if and when new relevant data emerges. Background Urine drug screening in the workplace (particularly pre-placement screening) has been associated with a decline in absenteeism, workplace theft, and on the job accidents. Administratively, positive results in "for-cause" and post-accident testing have been taken as presumptive evidence of impairment in most jurisdictions. The American College of Medical Toxicology agrees with the ideal of a chemically unimpaired workforce, but wishes to emphasize that there is no scientifically or medically valid method to equate the mere presence (or quantitation) of cocaine or one if its metabolites in a particular person's urine with clinical impairment due to that drug. The clinical circumstances and condition of the individual must also be evaluated as part of the medical interpretation of the urine drug screen. The Department of Health and Human Services standard for a positive urine test for use of cocaine is: 1) a positive screening test for cocaine metabolites at or above 150 ng/ml with a confirmation of the presence of benzoylecgonine at or above 100 ng/ml using gas chromatography/mass spectroscopy. A positive test by these criteria should be interpreted as establishing the introduction of cocaine into the body by any route at some time prior to the collection of the urine specimen. The most probable time frame is within five days. Thus, metabolites of cocaine may be present for time periods beyond that for which its use may be associated with impairment. It is also possible that they may also be present after the exposure to cocaine at doses that are insufficient to cause significant impairment. Conclusions Equating a positive urine test for cocaine metabolites to the presence of impairment at a particular time prior to the urine collection is without scientific merit. Nothing herein should be construed to condone the use of cocaine nor to suggest that cocaine cannot induce impairment. References 1. Substance Abuse and Mental Health Services Administration, HHS. Mandatory Guidelines for Federal Workplace Drug Testing Programs. Fed Regist. 2008 Nov 25;73(228):71858-71907. 2. Ambre J, Rhu T, Nelson J, and Balknap S. Urinary Excretion of Cocaine, Benzoylecgonine, and Ecgonine Methyl Ester in Humans. J Anal Toxicol. 1988;12(6):301-306. 3. Baselt RC. Cocaine. In: Disposition of Toxic Drugs and Chemicals in Man, 9th edition. Biomedical Publications: Seal Beach, CA, 2011; 390-394. 4. Weiss RD, Gawin FH. Protracted Elimination of Cocaine Metabolites in Long Term, High Dose Cocaine Abusers. Amer J Med. 1988;85(6):879-880. 5. Jackson GF, Saady JJ, Poklis A. Urinary Excretion of Benzoylecgonine Following Ingestion of Health Inca Tea. Forensic Sci Intern. 1991;49(1):57-64. 6. Bruns AD, Zieske LA, Jacobs AJ. Analysis of the Cocaine Metabolites in the Urine of Patients and Physicians During Clinical Use. Otolaryngol Head Neck Surg.1994;111(6):722-726. 7. Watson WA, Wilson BD, Roberts DK. Clinical Interpretation of Urine Cocaine and Metabolites in Emergency Department Patients. Ann Pharmacol. 1995;29(1):82. 8. Burke WM, Ravi NV, Dhopesh V, Vandegrift B, Maany I. Prolonged Presence of Metabolite in Urine After Compulsive Cocaine Use. J Clin Psychiatry. 1990;51(4):145-148. |
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| Institutions Housing Venomous Animals |
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Click here for a .pdf of this statement While individual practitioners may differ, this is the position of the American College of Medical Toxicology at the time written, after a review of the issue and pertinent literature. Background There are no published standards regarding the responsibilities of institutions housing venomous animals. Manifestations and management of the envenomations of non-native venomous animals are unfamiliar to most potential local treating physicians. Optimal planning for such envenomations includes ensuring proper storage, transport, and use of licensed and non-FDA approved antivenoms, coordination with regional Emergency Medical Services and potential receiving medical facility, regional poison center involvement, and the involvement of an appropriately trained or experienced clinician(s).2 Therefore: When an institution houses, displays, transports, or otherwise has possession of venomous animals, it is incumbent upon that institution to assure that the likelihood of human envenomation is minimized and that there is a written, implemented plan, reviewed at regular intervals, to respond to any envenomation that might occur. 1. Acquisition and Housing: Venomous animals with significant envenomation risks should only be acquired and maintained by institutions that have the resources and capabilities to properly care for them and where the local and regional resources and capabilities exist to manage envenomations and potential animal escape. Venomous animals should be housed and displayed in properly designed enclosures. 2. Antivenom Acquisition: When antivenom is available, it should be obtained prior to the institution's acquisition of the venomous animal. When an FDA approved species-specific antivenom is available, the institution should procure an amount adequate to treat a moderately to severely envenomated victim. When FDA approved antivenom is unavailable, an antivenom that is approved for use in another country is preferred over antivenom with no governmental regulatory approval. Decisions regarding which antivenom to obtain and in what amounts should be made by the physician or clinical toxicologist identified below. When only non-FDA approved species-specific antivenom(s) are available, it is the responsibility of the institution to obtain an importation permit and FDA investigational new drug (IND) application for appropriate antivenom. Replacement antivenom should be obtained prior to expiration of old stock. 3. Antivenom Storage: Antivenom may be stored at the institution where the venomous animal is housed or at the intended medical receiving facility. If the antivenom is to be stored at the institution, storage conditions should meet manufacturers' recommendations and standards of hospital pharmacy storage (i.e., refrigeration with back-up power supply, temperature monitoring, and expiration date surveillance). 4. Venomous Animal Handling and Identification: Written procedures regarding staff training, venomous animal handling, and feeding should be created to minimize envenomation risk. Procedures should be in place to assure accurate identification of potentially envenomating animals. 5. Consultations: A clinical toxicologist or a physician knowledgeable and experienced in the management of envenomations should be responsible for the policies and procedures regarding first aid and ongoing medical management of envenomations. At the medical receiving facility, victims of envenomation should be treated or managed in consultation with clinical toxicologists or physicians with expertise defined above. 6. Poison Center Collaboration: Collaboration with the nearest American Association of Poison Control Centers (AAPCC)-certified regional poison center should occur during the process of medical response planning. 7. Patient Transport and Treatment Plan: A pre-existing written agreement should exist with emergency medical transport agencies and receiving medical facilities. There should be a written plan for timely and appropriate first aid to be administered to an envenomated individual and timely evacuation and transport of the victim (and antivenom if stored at the institution) to the designated medical receiving facility. A copy of mutually-agreed upon (institution and medical receiving facility) management guidelines, including preparation and use of any antivenom, should accompany the patient. 8. Medical Receiving Facility: The institution should designate a medical receiving facility to receive victims of envenomation. The facility should have the capability to properly care for any possible adverse reactions to envenomation or treatment with antivenom. The receiving facility should have written policies and procedures for patient assessment and management of envenomations, for appropriate antivenom receipt (if sent with the patient), storage, preparation and administration. Because of the extensive and specialized preparations and skills required in the management of envenomations, the medical receiving facility should have policies in place to accept envenomation victims regardless of the facility's diversion status. 9. IRB Approval: If non-FDA-approved antivenoms are intended for use, investigational review board (IRB) approval for emergency use must be obtained at the medical receiving facility. Mechanisms to expedite IRB review for emergency use should be in place. 10. Antivenom Index Participation: It is encouraged that any institution that procures non-FDA approved antivenom be listed in the Antivenom Index, (developed by the Association of Zoos and Aquariums (AZA) in collaboration with AAPCC and administered by the University of Arizona College of Pharmacy).3, 4 This resource lists common and scientific names, antivenoms effective for various species, participating institutions, antivenom manufacturers and sources, procedures for importing non-licensed antivenoms, emergency procedures and first aid, recommendations for handling of venomous animals, and general management of elapid and crotaline envenomations). If an institution consents to the use of its antivenom by another medical facility, replacement or reimbursement is expected. References 1. Seifert SA, Keyler D, Isbister G, McNally J, Martin TG. ACMT Position Statement: Institutions housing venomous animals. J Med Toxicol. 2006;2(3):118-119. 2. Vohra R, Clark R, Shah N. A pilot study of occupational envenomations in North American zoos and aquaria. Clin Toxicol (Phila). 2008;46(9):790-793. 3. Association of Zoos and Aquariums and American Association of Poison Control Centers. The Antivenom Index. Administered by the University of Arizona College of Pharmacy. Available via URL: http://www.pharmacy.arizona.edu/avi/index#top [secured site]. Access verified 6 August 2012. 4. McNally J, Boesen K, Boyer L. Toxicologic information resources for reptile envenomations. Vet Clin North Am Exot Anim Pract. 2008;11(2):389-401, viii. |
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| Recognition of Medical Direction and Support of Poison Center Activities |
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Click here for a .pdf of this statement It is the position of the American College of Medical Toxicology that medical direction of poison centers be provided by at least a full-time equivalent (1.0 FTE) board-certified medical toxicologist. In order for this commitment to be filled, poison centers must provide direct salary support for these positions in proportion to the physician time commitment. Poison Centers serve as an important component of the health care system and the American College of Medical Toxicology supports their role. A necessary and essential element to the functioning of poison centers is the provision of medical direction by qualified physician medical toxicologists. Medical toxiocologists who provide medical direction or who provide professional on-call coverage for poison centers are encouraged to do so as a component of their medical practice and thus are entitled to appropriate compensation for their professional services. Medical Directors of regional poison information centers are physician toxicologists responsible for providing medical direction and supervision of these centers. As providers of medical diagnostic and treatment consultative services, physicians, in concert with a staff of expert Doctors of Pharmacy, pharmacists, nurses, educators, and other health care professionals, provide the medical oversight of these centers. However, the Medical Director must assume final responsibility for the clinical activities of the staff. Other responsibilities of the Medical Director include the establishment and periodic review of triage and treatment protocols; quality assurance; education of staff, health professionals and students; daily case reviews; and other operation activities. In addition, the Medical Director or designee must be available at all times to provide consultation to the center staff and to other health care professionals seeking advice from the center on medical toxicology issues. This responsibility can only be fulfilled by a physician qualified in medical toxicology, and these physicians should be routinely consulted for all critical poisonings. Poison Center Medical Directors must be board certified in medical toxicology, either by the American Board of Medical Toxicology, the Subboard of Medical Toxicology of the American Board of Medical Specialties, or the American Osteopathic Board of Emergency Medicine’s Certification of Added Qualifications in Medical Toxicology. Physicians designated on-call for consultations to the poison center must also be similarly board-certified or board-prepared as defined by meeting qualifications for sitting for the examination and accepted by the Board in writing. Toxicology fellows-in-training may provide on-call consultations with appropriate back-up of board-certified or board-prepared medical toxicologists. The scope of responsibilities for Medical Directors is so extensive for operational activities, oversight, and direction, plus the requirement of continuous on-call, that the total time commitment per center must be at least one physician FTE (1.0 FTE). The on-call commitment alone requires more than a single physician. However, there must be an on-site Medical Director who devotes a minimum of one-half FTE solely to operational activities, exclusive of on-call time. The remaining one-half FTE could be filled by additional Medical Director time and/or other qualified physicians. In order for this commitment to be filled, poison centers must provide direct salary support for these positions in proportion to the physician time commitment. One of the stated indications for federal funding under the Poison Center Stabilization and Enhancement Act from the United States Department of Health and Human Services (USDHHS) is to support “medical direction” of poison centers. Consistent with the need for committed oversight and medical direction by medical toxicologists, the American Association of Poison Control Centers (AAPCC) identified the provision of medical direction at a sufficient level of effort to ensure appropriate medical oversight as a criterion for designation as a certified center. This has been codified as a minimum of 0.5 FTE plus 0.25 FTE for every 25,000 poison center calls. The availability of medical direction is certainly germane to guideline development and support of recommendations made in complex medical cases. The Institute of Medicine in its 2004 report “Forging a Poison Prevention and Control System” noted that the median supported time of medical direction to poison centers at the time of a survey in 2000, was only 0.5 FTE. The USDHHS recently reported that, between 2000 and 2002, median supported time for medical direction grew slightly to 0.76 FTE. They also noted that many poison centers “count unpaid medical toxicologist backup…as volunteers.” “All centers use consultants as back-up medical toxicologists and other medical experts, and these are often not paid.” The provision of medical “back up” as an unpaid volunteer activity is inconsistent with the required commitment and responsibilities of physicians supplying these services. Despite the fundamental importance of physician participation in the proper functioning of poison control centers and some improvements in the funding for medical directors, it is still true that many medical toxicologists who provide toxicology medical direction, do so on a voluntary basis. A recent survey (Offerman SR, Brent J, Wax PM. Medical toxicologist attitudes on compensation for services provided to poison control centers J Med Toxicol 2010;6:79-80) conducted by members of the American College of Medical Toxicology indicated that only 49% of responding toxicologists reported being fully compensated for their poison center work while 28% were never compensated. Only 40% of surveyed toxicologists who were poison center directors felt that they were fairly compensated for their work. This is despite all respondents (100%) feeling that toxicologists provide a useful service and 97% who feel that toxicologists should be compensated for their work. The American College of Medical Toxicology’s mission is to “…advance quality care of poisoned patients and public health through physicians who specialize in consultative, emergency, environmental, forensic, and occupational toxicology.” Physicians who provide medical direction to specialists in poison information at the nation’s poison control centers should undertake this activity as a component of the practice of medical toxicology, and strive to improve the development of a system of poison prevention and information. Doing so on an unpaid and volunteer basis is inconsistent with this paradigm. ACMT encourages individual poison centers and their funding agencies to recognize the quality medical oversight and expertise provided by their medical directors and medical toxicology consultants by providing financial support consistent with the time and effort expended. |
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| Interim Guidance for the Use of Lipid Resuscitation Therapy |
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Click here for a .pdf of this statement Lipid resuscitation therapy (LRT) refers to the administration of a lipid emulsion with the intent of reducing the clinical manifestations of toxicity from excessive doses of certain medications. This therapy has shown very promising results in experimental (animal) models of poisoning by lipid-soluble cardiotoxic medications.1,2 The data deriving from experience with similarly poisoned humans is highly anecdotal, although they do suggest that LRT may be beneficial.1,2 The choice of if, and when, to initiate LRT is one that is solely discretionary and is based on the clinical judgement of the treating physician. Given the uncertainty of its beneficial effect in human poisonings, it is the opinion of the American College of Medical Toxicology that there are no standard of care requirements to use, or to choose not to use, LRT. However, in circumstances where there is serious hemodynamic, or other, instability from a xenobiotic with a high degree of lipid solubility, LRT is viewed as a reasonable consideration for therapy, even if the patient is not in cardiac arrest. The purpose of this document is to propose a treatment guideline if LRT is used as a component of the treatment of poisoned patients. If LRT is used, it should be instituted for patients with hemodynamic, or other (e.g intractable seizures), instability, not responsive to standard resuscitation measures, such as fluid replacement, inotropes, and pressors, where appropriate. The decision to use LRT instead of, or in conjunction with, other therapies, such as euglycemic-insulin therapy, is to be based on the clinical judgement of the treating physician. Where possible, it is recommended that these therapies be administered in consultation with a medical toxicologist. RECOMMENDED GUIDELINE If the decision is made to initiate LRT, the following guideline is recommended. This suggested guideline is a modification of the ones posted on LipidRescue.org1, the UK Resuscitation Council3, and Association of Anesthetists of Great Britain and Ireland4. However, it is completely appropriate if the treating physician, based on his/her clinical judgement, chooses to alter the manner in which LRT is administered. 20% lipid emulsion (e.g. Intralipid*) should be administered as a 1.5 ml/kg bolus. This can be accomplished by drawing the appropriate volume of 20% lipid emulsion into 50 ml syringes and administering it through an intravenous catheter. The bolus should be administered over 2-3 minutes. The bolus should be followed immediately by an infusion of 20% lipid emulsion at a rate of 0.25 ml/kg/min. This can be accomplished by attaching the lipid emulsion bag to an intravenous pump. Blood pressure, heart rate, and other available hemodynamic parameters, should be recorded at least every 15 minutes during the infusion. For asystolic patients, or those with pulseless electrical activity, who do not respond to the bolus, the dose may be repeated. If there is an initial response to the bolus followed by the re-emergence of hemodynamic instability, the infusion rate could be increased or, in severe cases, the bolus could be repeated. Where possible, LRT should be terminated after 1 hour, or less, if the patient’s clinical status permits. In cases where the patient’s stability is dependent on continued lipid infusion, longer periods of treatment may be appropriate. References
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| American College of Medical Toxicology Code of Ethics for Medical Toxicologists |
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AMERICAN COLLEGE OF MEDICAL TOXICOLOGY CODE OF ETHICS
FOR MEDICAL TOXICOLOGISTS
Click here for a .pdf of the Code of Ethics Preamble This document outlines specific tenets of ethical behavior for medical toxicologists as promulgated by the American College of Medical Toxicology (the College). It is not meant to be all-inclusive and thus activities in areas not covered by these guidelines should not be considered to be deemed a priori ethical. These guidelines are meant to supplement and not to supplant the Code of Medical Ethics of the American Medical Association (referred to as the “Code of the AMA”). This Code of Ethics is meant to be specifically applicable to medical toxicologists. A medical toxicologist is defined, for the purposes of this document, as a physician who is qualified to be a member of the College. The purpose of these guidelines is to delineate principles constituting the ethical foundations upon which the medical toxicologist should rely in fulfilling his/her responsibilities to their patients, society, and other health professionals. Except under circumstances delineated in this document, or as required by law, the medical toxicologist's primary responsibility is to his/her patients. As a physician, a medical toxicologist should strive to exemplify the highest standards of moral character. These guidelines apply to the practice of medical toxicology. Any medical toxicologist whose ability to practice is physically, mentally, or emotionally impaired should not continue to function in those aspects of practice which may be affected by their impairment. It is recognized that this Code of Ethics cannot encompass the entire range of possible circumstances. These guidelines are applicable to the vast majority of foreseeable circumstances but may not apply when extenuating circumstances are present. The College may censure, deny, or revoke membership to members who are in violation of these guidelines, in accord with established policies and procedures. Membership in the College is contingent upon compliance with this code of Ethics. Medical Toxicologists and the Public Health Medical toxicologists are stewards of the public health. In this role they have a responsibility to assure that appropriate public health authorities are informed of situations or occurrences that may represent an imminent and unrecognized risk to public health. If such information is privileged by a physician-patient relationship or by law, the decision to reveal it to appropriate authorities may only be made to the extent permitted by applicable law and the Code of the AMA. If the medical toxicologist determines that a patient's condition renders them dangerous when driving, operating heavy equipment, or taking part in other safety-sensitive activities there is an obligation to intervene, to the extent permitted by applicable law and the Code of the AMA, balancing the patient's best interest with any danger to society. This may mean direct confrontation of the patient, or the patient's family. For cases in which the patient's dangerous behavior persists despite this intervention, appropriate authorities should be notified. However, the latter should be considered to be a last resort to be employed only after other measures, as described above, fail. To the extent permitted by applicable law and the Code of the AMA, if a medical toxicologist has reasonable suspicion of domestic violence, including child or elder abuse, there is an ethical responsibility to report these concerns, or assure that other appropriate parties make such reports, to governmental or other appropriate authorities. When a medical toxicologist determines that there is an ethical responsibility to inform authorities about a patient's behavior or limitations, it should be done in a way that maintains as much patient confidentiality as possible, revealing only the minimal amount of information necessary. When embarking on such an activity, or considering the need to do so, the medical toxicologist should make reasonable attempts to inform the patient of their ethical and/or legal responsibilities to make such reports. Physicians are encouraged to participate in activities aimed at enhancing the public health. They should not participate in any activity contrary to the public good. Relationships With Other Professionals Society confers a special level of trust, respect, and deference to physicians. Medical toxicologists should always act in a dignified and honorable way respectful of this public trust. Relationships with physicians, nurses, and other health care professionals should live up to the faith that the public-at-large has in physicians and be characterized by fairness, honesty, respect, and integrity. Cooperation with other health care professionals and institutions should occur to the extent necessary to serve the patient's and society's best interests. To the extent permitted by applicable law and the Code of AMA, concerns about physicians or other health professionals acting in an apparently impaired, incompetent, unethical or negligent fashion are guided by the principle of non-maleficence and thus should be reported to appropriate authorities, regional medical societies, and/or hospital medical staff officials, quality assurance, or peer-review programs. Fraud or deceptive behavior is considered unethical and should be reported per these guidelines. All such reports should be done with the utmost discretion. In the event that a medical toxicologist is being investigated by any of the bodies enumerated in this paragraph they should honestly and openly cooperate with the investigation. Where possible, medical toxicologists should constructively assist colleagues who appear to be impaired, incompetent, or acting in an unethical fashion. This may include advice for self referral for treatment. Sexual harassment of a staff member, or another health care professional is unethical. Sexual harassment is defined here as physical or verbal intimation of a sexual nature involving a staff member, or a colleague or subordinate when such conduct creates an unreasonable, intimidating, hostile or offensive workplace environment. The Physician-Patient Relationship The physician-patient relationship must be founded on mutual trust, cooperation, and respect. All patients should be treated with compassion and dignity. The welfare of the patient is central to all considerations in the patient-physician relationship. The medical toxicologist must have freedom to choose patients whom she/he will serve. However, the medical toxicologist should not refuse to accept patients because of the patient's race, sexual orientation, creed, color, sex, national origin, medical condition, or disability. In emergencies, if reasonable to do so, a medical toxicologist should make her/his services available to all patients. However, if the scope of the required care is outside of the competence of the medical toxicologist it is appropriate to decline the role of being a treating physician. A medical toxicologist is never justified in abandoning a patient. Rather they should attempt to give due notice in writing to the patient, or to those responsible for the patient's care, when she/he withdraws from the case so that another physician may be engaged. In such cases, the medical toxicologist must continue to provide acute care for a reasonable period of time while the patient makes alternative care arrangements. A sexual or romantic relationship between a Physician and a current or recent patient is unethical. To the extent permitted by applicable law and the Code of the AMA, the medical toxicologist shall keep confidential all individual medical information, releasing such information only: 1) when required by law or overriding public health considerations; 2) to other health care professionals according to accepted medical practice; or 3) to others at the request of the individual patient. Requests to release records by the patient, or legal surrogate, should not be denied based on outstanding unpaid bills. To the extent permitted by applicable law and the Code of the AMA, disclosure of detailed information to insurance carriers or other interested third parties must be restricted to instances where the patient provides informed consent to do so, and any significant inadvertent breaches of patient confidentiality should be revealed to the patient. No medical toxicologist shall advertise or solicit patients directly or indirectly through the use of materials or activities that are false or misleading; nor should a medical toxicologist provide or bill for services which are not medically justifiable. Bills for services should not be based on any contingency, such as successful outcome of therapy or other positive end points. Medical toxicologists should not engage in fee splitting with any referral sources or health-care provider/facility to whom they refer patients; nor should they accept finders-fees for referring a patient to another practitioner, or facility. Fees charged for services should not be excessive. No fees should be charged by a medical toxicologist for services not performed either by them or under their direct supervision. Although it is appropriate for medical toxicologists to charge for their services, compassionate decisions concerning patients' ability to pay are encouraged. A medical toxicologist should not charge for billing third party payers unless this activity requires an excessive amount of time. In the latter case, charges consistent with those customary in the same community are appropriate. Unless prior arrangements are made to the contrary, if charges for laboratory, or other, studies done at an external facility are included in the medical toxicologist's bill, the actual laboratory costs and any additional add-on charges should be clearly specified. It is generally expected that patients will provide consent before treatment is rendered. Where consent is absent because of an emergent medical situation it is expected that the medical toxicologist will provide all necessary treatments within the scope of their expertise. Obligations to Patients Who Are Medically Indigent Medical toxicologists are free to choose whom to serve. However, the paradigm of the medical profession implies responsibility to society as a whole. This includes an obligation to provide emergent care, irrespective of their ability to pay, or their legal status. Informed Consent and the Suicidal Patient The medical toxicologist is likely to be called upon to evaluate and care for individuals who suffer from, or are believed to suffer from, attempted self-injury using one or more chemical substances. Under these circumstances, the medical toxicologist is unlikely to have a preexisting relationship with the patient or their family and often has a limited window of time in which to make critical decisions regarding patient care. Because the toxic exposure may pose an ongoing threat to patient well-being, rapid assessment and immediate medical intervention (often based on limited information) may be required without a formal determination of patient competency. To the extent permitted by applicable law and the Code of the AMA, in such situations, the treating physician must determine, to the best of their ability, the present decision making capability of the patient, and act in the patient's best interest, even if this is contradictory to the patient's current expressed or implied wishes. Thus, evaluation, treatment, and disposition of the patient must be such that the psychiatric and physical well-being of the patient can be reasonably assured in the face of expressed or implied self harm. Allowing self-destruction or even serious self-injury is not in the long term best interests of the patient and should be avoided. Yet the wishes of the patient regarding treatment, confidentiality, and other medico-legal decisions must thus be respected to the maximal extent possible, consistent with appropriate medical care and psychiatric assessment. To the extent permitted by applicable law and the Code of the AMA, physicians may investigate or treat without securing informed consent, even in the face of refusal, when immediate intervention is deemed necessary to prevent potential death or serious harm to the patient. However, this should only occur when treatment or evaluation cannot be delayed without serious potential harm. While it may be necessary to physically or pharmacologically restrain a patient to assure that essential medical services are provided, such restraints should be applied in a stepwise manner and only to the degree necessary to protect the patient and those around him or her, with the necessary minimum violation of patient rights. The use of restraints should comply with applicable guidelines. Responsibilities When Conducting Independent Medical Evaluations or Occupational Examinations Medical toxicologists may evaluate patients on behalf of a third party as part of independent medical evaluations (IMEs) or as part of occupational health examinations. In all instances the role of a medical toxicologist as a physician must be the paramount guiding principle. Conduct During Independent Medical Examinations When conducting IMEs the Medical Toxicologist should:
Despite the absence of a traditional doctor-patient relationship the medical toxicologist still has the responsibility to divulge to the examinee any medical conditions identified during the examination and should treat the examinee with dignity. During the course of an occupational surveillance examination the medical toxicologist may acquire information beyond that which is relevant to the occupational examination's requirements. Such information should not be divulged to the employer unless required by statute or regulation. Expert Testimony It is recognized that the discipline of medical toxicology has a unique relationship with judicial matters. This is because medical toxicologists specialize in being knowledgeable about the capacity of chemical substances to do harm. Because of their unique knowledge base the provision of legal testimony is considered to be a component of the practice of medical toxicology. It is important the medical toxicologist consistently bear in mind the purpose of an expert witness within the legal system. The expert is not present as an advocate nor are they present to adjudicate the matter at hand. Rather, he/she is present exclusively to assist the trier of fact via the presentation of factual knowledge and scientifically-based opinion and the conveyance of understanding regarding the matter under consideration. All testimony must be objective and impartial. Compensation of the expert should be reasonable and commensurate with the time and effort invested by the expert as well as their experience, unique expertise, and ability. An expert should not, under any circumstances, link compensation of any kind to the outcome of the case. The physician expert witness should, in general, not make such activities the sole focus of their professional practice. Consideration can, however, be given to special circumstances such as retirement from or temporary interruption of clinical practice, so long as the expert can demonstrate that these circumstances do not materially diminish the expert's competency to address the issues at hand. Research Research undertaken by medical toxicologists should be conducted with the aim of advancement in the treatment of patients and for the well-being of society. Such activities should follow the guidelines outlined by the applicable version of the Declaration of Helsinki and the National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research. Additionally, such research should comply with relevant federal, institutional and professional regulations and guidelines. All human subjects or animal research activities should be approved by a recognized human subjects or animal review board. Medical toxicologists must be diligently aware of real and potential sources of bias when conducting research. This is particularly relevant where the stipulations and interest of the funding agency (e.g., pharmaceutical firms, foundations, government, industry, and educational institutions) are potential sources for bias. In no circumstances should a medical toxicologist resort to research on human subjects in an alternative location with the specific intent of avoiding restrictive patient safeguards. Analyzing and communicating the results of research must be timely, accurate and truthful. The principal investigator of a research project must take full responsibility for the design, execution, and reporting of the results of the study. The investigator must assure that all relevant investigators in the research project receive recognition for their contributions. If the medical toxicologist has any potential or real financial benefit associated with their research this must be disclosed to the research institution and to any potential publishers of the research. If research is being done on a commercial product, or one that is likely to become commercial, it is unethical to buy or sell equity in the company that may financially benefit or suffer from the results of the research until the study is completed and the results are made public. Reasonable requests for access to raw data should be respected, provided doing so does not create an unduly onerous task for the investigator and that there are no contractual obligations to the contrary. Before embarking on a clinical trial medical toxicologists in the U.S. should pre-register applicable studies at trial with www.clinicaltrials.gov. Educational Activities The medical toxicologist has had the privilege of unique training and medical education and thus is encouraged to teach their knowledge to medical students, physicians in graduate medical education, other health care professionals, patients, and society. When providing such education, the medical toxicologist should strive to do so without the bias of outside influences. Maintenance of Professional Competency Medical toxicologists should strive to obtain and maintain certification in medical toxicology. It is recommended that medical toxicologists who are eligible to do so actively participate in the American Board of Medical Specialties Medical Toxicology Maintenance of Certification process. Use of Non-Accepted Therapies A medical toxicologist must never use personal gain as a motivating factor in choosing a therapy, nor should they ever use therapies that have been established to be of no benefit. Where possible, a medical toxicologist who uses a therapy that is unlikely to be of benefit must inform the patient of the status of the therapy, give the patient the rationale leading to that choice, inform the patient of the costs, possible lack of coverage by medical insurance (if applicable), and risks, and obtain informed consent from the patient before initiating therapy. It is unethical for a medical toxicologist to use therapies that are contrary to accepted principles of medical practice. Conflicts of Interest The ethical practice of medicine demands that the physician's obligations to the patient must not be influenced by any conflicts of interest that detract from the physician’s core obligation to the patient. The medical toxicologist must assure the use of any medication, treatment or device is based solely on the potential for patient benefit and not on any direct or indirect benefit to the practitioner or other party. The practitioner must be aware that any commercial or financial relationship with third parties, such as pharmaceutical companies or other businesses, carries a potential for conflict of interest. While such relationships should not be prohibited, the practitioner must maintain awareness of such potential conflict. When questions arise in this regard, consultation with an ethics board is encouraged. Patients must be made aware of and have the ability to refuse service with any such potential conflict of interest. Any disputes regarding potential conflicts of interest between the physician and the patient should be resolved with the patient's best interest as the primary motive. If a satisfactory resolution of a disclosed conflict of interest cannot be established, the medical toxicologist should withdraw from the relationship with the patient in a manner consistent with the principles outlined in the section on the Physician-Patient relationship of these guidelines. In these instances the medical toxicologist should assist the patient in making arrangements for care by another appropriate practitioner.
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| Post-Chelator Challenge Urinary Metal Testing |
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American College of Medical Toxicology Position Statement on Post-Chelator Challenge Urinary Metal TestingHeavy metals, such as lead and mercury, are ubiquitous in the environment [1-4]. Exposure in human populations is constantly occurring, and detectable levels of lead and mercury are commonly found in blood and urine of individuals who have no clinical signs or symptoms of toxicity and may be considered background or reference values [1-5]. Although urine testing for various metals in an appropriate clinical context, using proper and validated methods, is common and accepted medical practice, the use of post-challenge (a.k.a., post-provocation) urine metal testing, wherein specimens are typically collected within 48 hours of chelation agent administration, is fraught with many misunderstandings, pitfalls and risks. The American College of Medical Toxicology issues this position statement in disapproval of the use of post-challenge urinary metal testing in clinical practice and the use of such test results as an indication for further administration of chelating agents.In current evidence-based medical practice, urinary testing is commonly used in the biomonitoring of exposure to certain metals such as arsenic and inorganic mercury and the severity of their associated toxicity. It is accepted practice to conduct such testing, e.g., in exposed individuals with clinical evidence of peripheral neuropathy, as long as validated collection and analytical methods are employed prior to, or after, a sufficiently long time interval (e.g., 3-5 days) following administration of a chelating agent, i.e., applied to non-challenge urine specimens, and the results are compared to appropriate reference values [5, 6]. In some non-evidence-based medical practices, however, assessment of metal poisoning is frequently based on non-validated post-challenge urine metal testing, which invites inappropriate comparison to normal urine reference ranges [4-7]. Chelating agents such as dimercaptosuccinic acid (DMSA), dimercaptopropanesulfonic acid (DMPS), dimercaprol (BAL), and edetate calcium disodium (CaNa2-EDTA) bind metallic and metalloid elements and have been shown to increase their elimination from the body. Chelating agents have been found to mobilize metals in healthy individuals who have a body burden considered normal for a standard reference population, as well as in those who are determined to have a high body burden of the same metallic species [4, 8-11]. More specifically, urine specimens collected in relatively close temporal proximity to administration of chelating agents, i.e., post-challenge specimens, are expected to have increased concentrations of metallic elements. This includes elements, such as zinc, that are essential to normal physiologic functions and maintenance of good health. Normal reference values for non-challenge urine metal test results vary among and within different populations. Ranges for these values have been established in nationally certified laboratories that meet proficiency standards for urinary metal testing [5]. However, scientifically acceptable normal reference values for post-challenge urine metal testing have not been established [10]. In addition, scientific investigation to date has failed to establish a valid correlation between prior metal exposure and post-challenge test values [10]. Despite the lack of scientific support to do so, it is also a common practice of some laboratories and care providers to provide or apply non-challenge normal reference values as a comparative means of interpreting results of post-challenge urine metal testing [5]. Currently available scientific data do not provide adequate support for the use of post-challenge urine metal testing as an accurate or reliable means of identifying individuals who would derive therapeutic benefit from chelation. Unfortunately, the practice of post-challenge urine metal testing and its application to assessment of metal poisoning often leads to unwarranted and prolonged oral and/or intravenous administration of chelating agents, in response to the results of serial post-challenge testing that remain elevated above non-challenge reference values. Chelation therapy based on such laboratory values, in addition to being of no benefit to patient outcome, may actually prove harmful [5, 12]; catastrophic outcomes such as acute fatal hypocalcemia have been reported following the improper use of a chelating agent, edetate disodium (Na2-EDTA) [13]. In addition, the safer formulation of this agent, CaNa2-EDTA, has been demonstrated to increase urinary excretion of essential minerals such as iron, copper and zinc [8, 14]. There is published experimental evidence that deleterious effects may occur when chelation is applied in the absence of prior lead exposure. [15] Other chelating agents such as DMSA and DMPS may also increase the elimination of certain essential elements, as well as promote target organ redistribution of metallic elements of concern such as mercury [16-18]. It is, therefore, the position of the American College of Medical Toxicology that post-challenge urinary metal testing has not been scientifically validated, has no demonstrated benefit, and may be harmful when applied in the assessment and treatment of patients in whom there is concern for metal poisoning. References
This statement has been developed by members of the ACMT with principal contribution in writing by Nathan Charlton, M.D. and Kevin L. Wallace, M.D., F.A.C.M.T., reviewed and approved by the ACMT Practice Committee and Board of Directors, and opened to comment by all members of the College. Disclosure statements for participating members of the ACMT Practice Committee and ACMT Board of Directors are available. June 2009 |
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| Dietary Supplements |
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Written by: Thomas L. Kurt, M.D., MPH Previous version dated August 30, 2007 Edited by: Alan H. Hall, M.D. Charles McKay, M.D. Disclaimer While individual practitioners may differ, this is the position of the College at the time written, after a review of the issue and pertinent literature. Introduction In 2004 the Practice Committee of American College of medical Toxicology (ACMT) composed a Position Statement on Dietary Supplements which was posted for member comment, edited, and published in the Journal of Medical Toxicology in 2006. This original Position Statement arose out of increased poison center calls about dietary supplements, a greater number of case reports of herbal toxicity and herb-drug interactions and surveys showing rapid growth of dietary supplement use among the lay public after passage of the Dietary Supplement and Health Education Act (DSHEA) in 1994. As well, the Eisenberg report in the American Medical Association (1998) stated that 42% of those surveyed used some alternative forms of medical therapy, increased from 34% in his 1991 survey. While the percentage of herbals was relatively low at 12% in 1998, this was dramatically increased from 2.5% in 1991. Historically passage of the Food Drug & Cosmetics Act in 1938 “grandfathered” pre-existing plant-based drugs, such as atropine, codeine and morphine into approved use along with everything listed in the United States Pharmacopoeia-National Formulary. Herbals were exempted from registration as drugs following a review commissioned by the FDA (authorized by the Kefauver-Harris amendments in 1962) and by the National Academy of Sciences. In 1994 DSHEA designated the US Food and Drug Administration’s (FDA’s) Center for Food Safety and Applied Nutrition (CFSAN) with responsibility for developing regulations for dietary supplements, which include amino acids, biological extracts, herbals, minerals and vitamins. In 1995, a National Center for Complementary and Alternative Medicine was established at the US National institute of Health with a growing budget for sponsored research. Then in May, 1998, the dietary supplement branch of CFSAN published a container-labeling requirement; and, a 10-year plan was issued in January, 2000, for the total regulation of dietary supplements. Demonstrating enforcement powers, since the original position statement, the FDA later in 2004 took dramatic action to remove ephedra-containing dietary supplements from the market in response to reports of cardiovascular risks of cardiac arrhythmias. And, in May, 2006, based on reports of hepatotoxicity in Europe, a warning was issued on kava. More recently in 2007, FDA has issued guidance directives on filing serious adverse event reports for both dietary supplements and over-the-counter products as well as Good Manufacturing Practices for dietary supplements; and, a pathway has been established in the Center for Drug Evaluation and Research for bringing botanical substances to market as drugs with approval of a green tea extract for the treatment of genital warts. There are also three trade organizations, including the American Herbal Products Association and the Council for Responsible Nutrition, which self-regulate members according to established codes of ethics. Applying principles of evidence-based medical practice to dietary supplements, as well as educating health professionals and the lay public concerning hazards associated with their use is vitally important. Among the concerns of the American College of Medical Toxicology is that patients may choose dietary supplements rather than pharmaceutical agents that are established to be safe and effective. Although there may be case-control study data that demonstrates varying degrees of therapeutic effectiveness of single agents such as ginger, St. John’s wort, saw palmetto and ginkgo biloba, there are also multi-ingredient herbal preparations such as those from Traditional Chinese Medicine and of Ayurvedic (Indian subcontinent) origin that can introduce significant confounding issues into this type of risk to benefit analysis. In this regard, medical toxicology is primarily focused on the risk of harm to human health related to recommended use as well as overdose of these preparations and adverse interactions with other agents including pharmaceuticals, rather than their therapeutic effectiveness. Direct Harm Aside from single agent toxicity of the marketed preparation, toxicity from contamination/adulteration of the source product with heavy metals, such as lead and arsenic, has been, as well as misidentified plant material being substituted for the botanical agent that is, thus, falsely identified as present in that product. In addition, the inclusion of pharmaceuticals such as butazolidine in antiarthritics and benzodiazepines in calmatives has occurred in preparations purported to be nonpharmaceutical dietary supplements. There were certain naturally-occurring substances withdrawn due to hepatotoxicity by the time of the original position statement, such as comfrey tea, chaparral and pennyroyal. There have also been reports that some ingredients in supplements are potential central nervous system toxicants. These include henbane, jimson weed and mandrake. In addition, there have also been reports that chan su, foxglove, oleander and squill may be cardiovascular toxicants. Commercially available dietary supplements can also be abused with adverse effects, such as the gastrointestinal use of aloe, buckthorn, cascara, pokeweed and senna for dyspepsia and constipation, where systemic electrolyte deficits and other problems can occur. This can result in secondary complications from concurrent use of prescription medications, such as cardiac drugs and diuretics. Potentially Harmful Interactions Reports of herb-drug interactions with the 6 isomers in ephedra-containing Ma huang have led to the FDA’s withdrawal of herbal ephedra from the market, with the exception of their use in traditional Chinese medicines. Other herbal supplements with adverse interaction potential include St. John’s wort through its induction of CYP 3A4-mediated metabolism of antiretroviral drugs and oral contraceptives, as well as its associated risk of serotonin syndrome if combined with drugs that inhibit postsynaptic serotonin reuptake (e.g., sertraline, trazodone, nefazodone). Ongoing collection of reports from the FDA’s MedWatch system at www.fda.gov/medwatch and the American Association of Poison Control Centers surveillance system helps update this information. Conclusions Dietary supplement use has become increasingly common with the implementation of the DSHEA in 1994. The National Center for Complementary and Alternative Medicine at NIH is sponsoring clinical trials which have prompted as well as answered questions. Clinicians not only need to specifically ask for dietary supplement histories, but be aware of the potential for product contamination and misidentification of the ingredients therein, as well as herb-drug interactions. The American College of Medical Toxicology strongly recommends consultation with a medical toxicologist in cases of suspected or confirmed toxicity, adverse effects or interactions from dietary supplements, and other issues relating to product safety. In addition to establishing requirements for “Supplement Facts” label information on dietary supplement bottles marketed in the US, FDA has taken regulatory action to withdraw ephedra-containing supplements and is instituting Good Manufacturing Practices. The ACMT strongly supports further review and regulation, as well as augmentation of clinical education and scientific information and enhanced awareness of potential harm from dietary supplement use. Disclosure This statement has been developed by members of the ACMT with principal contribution in writing by Tom Kurt, MD, reviewed and approved by the ACMT Practice Committee and Board of Directors, and opened to comment by all members of the College. Disclosure statements for participating members of the ACMT Practice Committee and ACMT Board of Directors will be available soon. References
Weblinks The Federal Drug Administration at www.fda.gov |
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| IOM Report on Thimerosal and Autism |
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Disclaimer While individual practitioners may differ, this is the position of the College at the time written, after a review of the issue and pertinent literature. The American College of Medical Toxicology (ACMT) is a professional society composed of physician toxicologists who focus on the diagnosis, management of acute and chronic adverse health effects due to medications, chemical, occupational and environmental toxicants and biological hazards. The ACMT commends the efforts of the IOM report of Immunization Safety Review:Vaccines and Autism. (1) The ACMT notes that the Immunization Safety Review Committee, while comprised of many competent academicians, had none with the special skill set of a medical toxicologist, a critical criterion when the adverse effects of an organomercurial are being considered. The IOM is encouraged to include medical toxicologists on committees that focus on potential toxicologic exposures. Indeed, in the past, a medical toxicologist has stepped forward on this issue. (2) The IOM concludes that the body of epidemiological evidence indicates that there is no causal relationship between thimerosal containing vaccines and autism. The ACMT provides the following background and comments. Thimerosal is a mercury-containing organic compound (sodium ethylmercuric thiosalicylate, also known as Merthiolate, Mercurothiolate) which contains approximately 50% mercury by weight. (3) The United States Code of Federal Regulations (CFR) requires the addition of a preservative to multi-dose vials of vaccines. Since the 1930’s, thimerosal has been widely used as a preservative in a number of biological and drug products, to help prevent contamination from microbes. When the Food, Drug and Cosmetic Act was passed in 1938, thimerosal was placed on the GRAS (generally recognized as safe) list. Thimerosal in concentrations of 0.001% (1 part in 100,000) to 0.01% (1 part in 10,000) has been shown to be effective in clearing a broad spectrum of pathogens. Placed in perspective, a vaccine containing 0.01% thimerosal as a preservative contains 50 micrograms of thimerosal per 0.5 mL dose or approximately 25 micrograms of mercury per 0.5 mL dose, in the form of ethyl mercury. As the number of vaccinations given to infants has increased, so has the cumulative exposure to Thimerosal as the organomercurial preservative. (3) In 1999, with a recognized increase in the prevalence of autism spectrum syndromes, attention was called to thimerosal as a potential risk factor, especially in combination with measles, mumps and rubella (MMR) vaccination (4-9). At that time the Public Health Service (including the Food and Drug Administration (FDA), National Institutes of Health, and the Centers for Disease Control and Prevention (CDC)), and the American Academy of Pediatrics (AAP) called for the withdrawal of thimerosal from further use in vaccines targeted for children. However, thimerosal in existing vaccine inventory was allowed to be used.Much of this concern was based on methylmercury-related neurotoxicity, the timing of vaccination during the first year of life when the blood-brain barrier is more permeable to heavy metals, and a model that equated intermittent exposure to ethylmercury to cumulative dosing of methylmercury. Recent research has confirmed that the ethylmercury component found in Thimerosal is less hazardous than methylmercury. These are different compounds and should not be considered as equivalent neurotoxins. Experimental conditions can be created that result in neurological cell dysfunction (10,11) However, current literature supports the contention that childhood vaccinations do not deliver a sufficient dose to produce these neurological injuries. Several large epidemiological studies have been completed in an attempt to clarify the issue of childhood immunizations and the risk of neurodevelopmental disorders. The CDC reviewed computer-based vaccination records and ICD-9 codes of autistic spectrum disorders for over 124,000 infants at two health maintenance organizations (HMOs) in California. (12) In 2003, a published comparison of imputed thimerosal dose in Sweden, Denmark and the United States found no correlation with the rise in prevalence of autism spectrum disorders occurring in all three countries. (13) The Institute of Medicine (IOM) of the National Academy of Sciences assembled an Immunization Safety Review Committee that held hearings and provided a series of reports, culminating in their 2004 Immunization Safety Review: Vaccines and Autism.(1) Although a number of potential concerns have been raised (14) regarding the adequacy of the IOM review (7 months, rather than one year catchment period, and procedural issues such as cutoff age and ICD-9 diagnostic listings), the ACMT believes that the IOM’s conclusions are justified. In fact, in conjunction with epidemiological data from Europe, Australia, and the United States, the IOM report stands as reassurance to parents concerned about the risk of previous vaccinations for their children. Although the AAP and the combined Public Health Service agencies (CDC, NIH and FDA) have taken a precautionary approach in encouraging vaccination of infants with Thimerosal-free products when available (particularly for the most susceptible infants - those that are very premature and undernourished), the ACMT wishes to emphasize that these are also those infants most at risk of vaccine-preventable diseases. The restriction of vaccine access is inappropriate and results in real, as opposed to theoretical, harm. (15,16) The ACMT further discourages chelation therapy in autistic children, a practice that is not supported by clinical evidence either of mercury toxicity or therapeutic effect, and which can have hazardous consequences. (17) Lastly, the ACMT commends the IOM report’s conclusions encouraging research funding to investigate adverse vaccine concerns, evaluating autistic disorders up through a pre-school catchment age, and related epidemiologic surveillance.
Bibliography (1) Immunization Safety Review Committee: Vaccines and Autism. Institute of Medicine. National Academies Press, 2004. http://www.iom.edu/report.asp?id=20155 http://www.nap.edu/catalog;10997.html (2) Brent J. Toxicologists and the Assessment of Risk: The Problem with Mercury. J Toxicol/Clin Toxicol 2001;30:707-710. (3) Thimerosal in Vaccines (Mercury in Plasma-Derived Products). Center for Biologics Evaluation and Research, FDA. http://fda.gov/cber/vaccine/thimerosal.htm (4) Madsen KM, Hviid A, Vertergaard M, Schendel D, Wohlfahrt J, Thorsen P, Olsen J, Melbye M. A Population-Based Study of Measles, Mumps and Rubella Vaccination and Autism. N Engl J Med 2002;19:1477-1482. (5) Morris SAS, Bernstein HH. Immunizations, Neonatal Jaundice and Animal-Induced Injuries. Current Opinion in Pediatrics 2004;16:450-460. (6) Newschaffer CJ, Falb MD, Gurney JG. National Autism Prevalence Trends from US Special Education. Pediatrics 2005;115:277-282. (7) Parker SK, Schwartz B, Todd J, Pickering LK. Thimerosal-Containing Vaccines and Autistic Spectrum Disorder: A Critical Review of Published Original Data. Pediatrics 2004;114:793-804. (8) Ruther M. Incidence of Autism Spectrum Disorders: Changes Over Time and Their Meaning. Acta Paediatrica 2005;94:2-15. (9) Chez NG, Chin K. Hung PC. Immunizations, Immunology and Autism (Review). Seminars Ped Neurol 2004;11:214-217. (10) Burbacher TM, Shen DD, Liberato N, Grant KS, Cernichiari E, Clarkson T. Comparison of Blood and Brain Mercury Levels in Infant Monkeys Exposed to Methylmercury or Vaccines Containing Thimerosal. Environmental Health Perspectives 2005;112:1015-1021 (11) Parran DK, Barker A, Ehrich M. Effects of Thimerosal on NGF Signal Transduction and Cell Death in Neuroblastoma Cells. Toxicol Sci 2005;86:132-140. (12) Verstraeten T, Davis RL, DeStefano F, Lieu TA, Rhodes PH, Black SB, Shinefield H, Chen RT. Safety of Thimerosal-Containing Vaccines: A Two-Phased Study of Computerized Health Maintenance Databases. Pediatrics 2003;112:1039-1048. http://pediatrics.aappublications.org/cgi/content/full/112/5/1039?ijkey=ed4b4475a8522 (13) Stehr-Green P, Tull P, Stellfeld M, Mortenson PB, Simpson D. Autism and thimerosal-containing vaccines: lack of consistent evidence for an association. American Journal of Preventive Medicine. 2003;25(2):101-6. (14) Verstraeten T. Thimerosal, the Centers for Disease Control and Prevention, and GlaxoSmith Kline. Pediatrics 2004;113:932 (letter). http://pediatrics.aappublications.org/cgi/content/full113/4/932 (15) Bigham M, Copes R. Thiomersal in vaccines: balancing the risk of adverse effects with the risk of vaccine-preventable disease. Drug Safety. 2005;28(2):89-101, 2005. (16) Elliott VS. Anti-thimerosal laws vex flu shot planners. American Medical News. 2004;49(16):1,4. (17) Boy with Autism Dies after Chelation Therapy: 5-Year-Old Was Receiving Controversial Treatment in Doctor’s Office. Associated Press. MSNBC, August 25, 2005. http://msnbc.msa.com/id/9074208 Prepared by the ACMT Practice Committee. Primary author: Tom L Kurt Disclosure forms on file at ACMT Last reviewed June 2006 |
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| Hospital Privileges for Physicians Practicing Medical Toxicology |
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Disclaimer While individual practitioners may differ, this is the position of the College at the time written, after a review of the issue and pertinent literature. Introduction In September, 1992, Medical Toxicology was accepted by the American Board of Medical Specialties as a sub-board of the American Board of Emergency Medicine, the American Board of Preventive Medicine, and the American Board of Pediatrics. Currently there are several hundred physicians certified by ABMS, or the American Board of Medical Toxicology in this specialty. As poisonings, intoxications, and environmental issues become more prevalent and appreciated by our medical colleagues and the general public, there may be an increased desire for the medical toxicology consultation. Because of greater acceptance and appreciation of the valuable input Medical Toxicology can contribute, it is appropriate that this body develop standards on how Medical Toxicology may interface in the hospital venue. Credentials Prior certification in a primary specialty will be required. These specialties will primarily include Internal Medicine, Pediatrics, Emergency Medicine, or Preventive (Occupational) Medicine but could include any clinical specialty. Completion of a two year medical toxicology fellowship, or certification as a diplomate of the American Board of Medical Toxicology, or ABMS certification by the sub-board of Medical Toxicology will be an additional requirement for granting of staff privileges in the subspecialty of medical toxicology. Privileges
The credentials specified above should be required for a physician to be eligible for admitting and/or consultative privileges in Medical Toxicology for adult and pediatric inpatient or outpatient services. Inpatient services include the provision of medical care in emergency and critical care units. Scope of Practice Medical Toxicology is a medical subspecialty focusing on the diagnosis, management and prevention of poisoning and other adverse health effects due to medications, occupational and environmental toxins, and biological agents. Medical Toxicology is officially recognized as a medical subspecialty by the American Board of Medical Specialties. Several examples of medical problems evaluated by Medical Toxicologists include:
ACMT Recommended Clinical Privilege FormQualifications
Adults ____ Requested
____ Approved with observation ____ Denied Pediatrics ____ Requested ____ Denied
Procedures
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| Institute of Medicine Report on Damp Indoor Spaces and Health |
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Disclaimer While individual practitioners may differ, this is the position of the College at the time written, after a review of the issue and pertinent literature.
INSTITUTE OF MEDICINE REPORT ON DAMP INDOOR SPACES AND HEALTH The American College of Medical Toxicology (ACMT) is a professional society composed of physician toxicologists who focus on the diagnosis, management and prevention of acute and chronic health effects due to medications, chemicals, occupational and environmental toxicants, and biological hazards. The ACMT has reviewed the Institute of Medicine (IOM) report on Damp Indoor Spaces and Health,(1) and has prepared additional background and comments relating to this document. The ACMT considers this review to be valuable, because the IOM committee did not include input from physicians with training and board certification in the subspecialty of medical toxicology. The ACMT commends the IOM for recognizing that damp indoor spaces present health risks to humans, in association with allergic mechanisms resulting from fungi, dust mites, bacteria, cockroach, and possibly other antigens that proliferate in moist environments. The ACMT concurs with the IOM that residences, schools, offices, and other buildings should be designed to prevent water intrusion, and that when water damage or chronic moisture is identified it should be remediated as soon as possible. While the allergic effects of fungi are well-summarized in the IOM report, there are still a number of misperceptions relating to mycotoxins or other chemicals produced by certain species of fungi, and their role in adverse health effects from exposures in water-damaged buildings. Although several epidemiological studies of building-related illness have implicated mycotoxins as a cause of health effects in water-damaged environments, their interpretation is complicated by limitations in their study design, exposure and dose assessment methods, and confounding effects. In fact, these issues have cast doubt on the causative role of inhaled mycotoxins for any toxic health effects in the indoor residential environment. (2-5) The ACMT believes that an improved understanding of the role of mycotoxins in damp indoor spaces should begin by acknowledging that both fungi and their mycotoxin prodcuts are ubiquitous in the outdoor environment. Human exposure to fungi can occur from contact with the soil as well as outdoor air, where fungal spores are normally present in much higher concentrations than indoor environments (with seasonal variability, e.g. cold, snow). Epidemiological studies of mold in indoor environments should include appropriate comparisons with outdoor air, and studies should be designed to consider our aggregate and cumulative exposure to fungi and mycotoxins from indoor and outdoor environments. The ACMT would like to emphasize the importance of distinguishing exposure to mycotoxins from exposure to the fungi that are capable of producing them. Toxigenic fungi and mycotoxins are not synonymous hazards. It is well established that for many fungal species, the production of mycotoxins is significantly influenced by genetics and the environmental conditions of their growth. The isolation of a toxigenic fungal species in the environment does not necessarily indicate that mycotoxins are also present, or that they are present at doses that pose health risks from environmental exposure. For this reason, if epidemiological studies of damp indoor spaces are to include hypotheses relating to mycotoxins, then exposure assessment methods should utilize validated techniques to detect and quantify mycotoxins directly in environmental samples. The interpretation of such environmental measurements should consist of a plausible, complete exposure pathway and an assessment of the dose-response relationship. The ACMT would also like to emphasize the importance of acknowledging that the diet is the most important source of human exposure to mycotoxins. The vast majority of scientific data on the adverse health effects of mycotoxins is derived from their presence as natural and unavoidable contaminants of foods and beverages that are consumed as part of a healthy diet. Mycotoxins of known dietary importance include aflatoxins (in corn, ground nuts, and dairy products), trichothecenes (in corn, cereals and fermented beverages) and ochratoxins (in coffee, wine, and dried fruits). Risk assessments have been conducted for several mycotoxins that are of relevance to human health,(6) and these studies should be used as a benchmark for interpreting the relative role of exposures occurring from other sources and pathways in addition to dietary ingestion. With respect to mycotoxins in indoor air, exposure modeling studies have concluded that even in moldy environments, the maximum inhalation dose of mycotoxins is generally orders of magnitude lower than demonstrated thresholds for adverse health effects.(3,7,8) The results of human studies in agricultural environments provide additional consistency for this finding, demonstrating that in moldy environments inhalation exposure to mycotoxins results in a dose that is far less than what is normally encountered from dietary exposure.(9,10) Studies that quantify human exposure utilizing validated biomarkers as indicators of internal dose will provide additional information to assess cumulative exposure to mycotoxins. There have been significant advances in the research on biomarkers of exposure to important mycotoxins,(11-13) and the ACMT recommends that future studies utilize these methods in the assessment of the dose-response relationship. The ACMT is aware of other types of clinical laboratory tests that have recently been utilized in epidemiological studies of damp indoor spaces, including “mycotoxin antibody testing.” Identification or measurement of antibodies to mycotoxins, rather than biomonitoring of mycotoxins directly, is not an accepted method to assess human exposure. This method has not been validated in well-designed epidemiological studies, and is not recommended for the assessment of human exposure to mycotoxins.(14) Fungal immunoassay tests (including immunoglobulin testing for IgG and IgE) can be clinically useful in the assessment of immunological conditions from exposure to fungal antigens (including common allergies and hypersensitivity pneumonitis), but they do not provide any information about exposure to mycotoxins and therefore they have no role in exposure assessment in this context. The American Academy of Asthma, Allergy, and Immunology (AAAAI) has addressed some of these issues in their recent position statement on health effects from mold exposure (15). In comparison to the low-level indoor exposures of general public concern, a syndrome known as Organic Dust Toxic Syndrome (ODTS) has been described in association with microbial exposures in agricultural environments, consisting of fever, malaise, myalgia, headache, dyspnea, chest tightness, dry cough, and nausea.(16) While the pathogenesis of this transient condition is not well-understood, it has been hypothesized to develop from acute inhalation exposure to high concentrations of bacterial endotoxins, fungal mycotoxins, and possibly other cellular components of microorganisms that proliferate in agricultural environments. The epidemiology of this disorder is uncertain, but the levels of microbial exposure that have been measured in association with its occurrence are generally orders of magnitude greater what has been measured in moldy home, school, or office environments. It should be noted that symptoms from ODTS are transient in nature, and generally resolve within hours to days from the time of acute exposure. There is no documented evidence that inhalation exposure to fungi or mycotoxins in indoor environments causes a chronic toxic encephalopathy. Similarly, the role of volatile organic compounds produced by mold (mVOCs), and responsible for the musty odor, can be addressed from a toxicological perspective. In sufficient dose, mVOCs can produce transient irritive symptoms and subjective complaints such as nasal and eye discomfort, headache and dizziness. However, the concentrations of mVOCs produced by mold in indoor spaces are very low, on the order of nanograms to micrograms per cubic meter or part per billion (ppb) range (17). On the other hand, the levels that can induce sensory irritation are in the milligram per cubic meter (mg/m3) or parts per million (ppm) range in the air (18). Additionally, volatile organic compounds are volatile, thus having short environmental half-lives (minutes to hours), and their effects are transient. In cases where individuals complain of persistent neurological, cognitive, or non-specific symptoms week or months after the putative exposure, these symptoms should not be attributed to irritant effects; other causes should be sought. In conclusion, the ACMT generally concurs with the IOM’s assessment of the relationship between damp indoor spaces and human health effects. The ACMT recommends that public health responses to damp indoor spaces be based upon what is known and generally accepted with respect to their association with allergic disease. Public health responses should not be solely based upon the presence of fungi or mycotoxins, because from a toxicological perspective, the available scientific evidence does not provide any compelling data to conclude that they pose significant health risks via inhalation in these settings. The risks from inhalation exposure are minimal in comparison to other sources and pathways, including the diet, which in themselves are rarely of health consequence in the United States. Furthermore, the use of unapproved diagnostic studies and therapeutic modalities based on unproven infection or mold-related toxicity (as opposed to allergic phenomena) are medically inappropriate and costly. Reference List
(1) Institute of Medicine, Committee on Damp Indoor Spaces and Health. Damp Indoor Spaces and Health. Washington, D.C: National Academies Press; 2004. http://www.nap.edu/books/0309091934/html/>> > (2) Update: Pulmonary hemorrhage/hemosiderosis among infants--Cleveland, Ohio, 1993-1996. MMWR Morb Mortal Wkly Rep 2000 March 10;49(9):180-4. http://www.cdc.gov/mmwr/preview/mmwrhtml/mm4909a3.htm>> > (3) American College of Occupational and Environmental Medicine. Evidence Based Statement: Adverse Human Health Effects Associated with Molds in the Indoor Environment. 2002. http://www.acoem.org/guidelines/article.asp?ID=52>> > (4) Fung F, Clark RF. Health effects of mycotoxins: a toxicological overview. J Toxicol Clin Toxicol 2004;42(2):217-34. (5) Page EH, Trout DB. The role of Stachybotrys mycotoxins in buildings related illness. AIHAJ 2001 September;62(5):644-8. (6) Food and Agriculture Organization/ United Nations Expert Committee on Food Additives. Safety evaluation of certain mycotoxins in food. Geneva: World Health Organization; 2001. (7) Kelman BJ, Robbins CA, Swenson LJ, Hardin BD. Risk from inhaled mycotoxins in indoor office and residential environments. Int J Toxicol 2004 January;23(1):3-10. (8) Islam Z, Harkema JR, Pestka JJ. Satratoxin G from the black mold Stachybotrys chartarum evokes olfactory sensory neuron loss and inflammation in the murine nose and brain. Environmental Health Perspectives. [online Feb 27, 2006] Available at http://dx.doi.org/10.1289/ehp.8854>;.(9) Halstensen AS, Nordby KC, Elen O, Eduard W. Ochratoxin A in grain dust--estimated exposure and relations to agricultural practices in grain production. Ann Agric Environ Med 2004;11(2):245-54.
(10) Skaug MA. Levels of ochratoxin A and IgG against conidia of Penicillium verrucosum in blood samples from healthy farm workers. Ann Agric Environ Med 2003;10(1):73-7. (11) Gilbert J, Brereton P, MacDonald S. Assessment of dietary exposure to ochratoxin A in the UK using a duplicate diet approach and analysis of urine and plasma samples. Food Addit Contam 2001 December;18(12):1088-93. (12) Meky FA, Turner PC, Ashcroft AE, Miller JD, Qiao YL, Roth MJ, Wild CP. Development of a urinary biomarker of human exposure to deoxynivalenol. Food Chem Toxicol 2003 February;41(2):265-73. (13) Young CL, Sclafani AG, Croley TR, Lemire SW, Barr JR. Simultaneous detection of trichothecene mycotoxins in human urine by LC-APCI/MS/MS. Abstracts of Papers, 229th ACS National Meeting, San Diego, CA, United States, March 13-17, 2005. (14) Centers for Disease Control and Prevention. Case Definitions for Chemical Poisoning. 2005 Jan 14. Report No.: 54(RR01). http://www.cdc.gov/mmwr/preview/mmwrhtml/rr5401a1.htm>;;
(15) Bush RK, Portnoy JM, Saxon A, Terr AI, Wood RA. The medical effects of mold exposure. Journal of Allergy Clinical Immunology 2006;117(2):326-333. (16) Seifert SA, Von ES, Jacobitz K, Crouch R, Lintner CP. Organic dust toxic syndrome: a review. J Toxicol Clin Toxicol 2003;41(2):185-93.
(17) Claeson AS, Levin JO, Blomquist G, Sunesson AL. Volatile metabolites from microorganisms grown on humid building materials and synthetic media. Journal of Environmental Monitoring. 2002;4(5):667-72. (18) Doty RL, Cometto-Muniz JE, Jalowayski AA, Dalton P, Kendal-Reed M, Hodgson M. Assessment of upper respiratory tract and ocular irritative effects of volatile chemicals in humans. Critical Reviews in Toxicology 2004;34(2):85-142.
Prepared by the ACMT Practice Committee and approved June, 2006. Primary authors: Daniel Sudakin and Tom Kurt Disclosure forms on file at ACMT |
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All position statements will be edited by the committee and then referred to the board. Any comments will be reviewed by the authors and the committee. Once endorsed by the board, they will be posted on the ACMT web site and published in an issue of JMT. All position statements will be introduced by a disclaimer indicating that while individual practitioners may differ, this is the position of the college at the time written, after a review of the issue and pertinent literature. All statements should be reviewed on a periodic basis (every 3 years) and as needed when new data or questions arise. The original author(s) will be asked to address any questions, indicating the date of any revisions on the statement. Each author must sign a disclosure form discussing any potential sources of bias and conflict of interest.
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