Most patients with xenobiotic exposures do well with supportive care and close attention to vital physiology. However, one of the fundamental principles of managing an acutely poisoned patient is appropriate and timely antidotal administration when indicated. According to the last available US Poison Control Center data, a therapeutic intervention which includes specific antidotes was used in 18.5% of all poisoning exposures (Chap. 130).^16,41

Sufficient antidote stocking is a best practice; failure to do so presents a clear and present danger to patient safety. Death and serious harm resulted from the delay to administer appropriate antidotes, reversal agents, and rescue agents.²⁸ Many poisonings are acute unanticipated emergencies, which would presumably invoke the protections of the Emergency Medical Treatment and Labor Act of 1986, which mandates public access to emergency services regardless of ability to pay. The Joint Commission (TJC) is the accrediting body for hospitals. The Joint Commission’s elements of performance require that “emergency medications and their associated supplies are readily available,” as well as written criteria determining which medications are available for dispensing or administering to patients.^55,56 The Joint Commission also recognizes the difficulties presented by medication shortages and requires staff communication, written medication substitution protocols approved by leadership and the medical staff, and review of the impact of substitutions (eg, medication errors and adverse drug events).⁵⁷ It is an Institute for Safe Medication Practices best practice to “ensure all appropriate antidotes, reversal agents, and rescue agents are readily available.”²⁸ The World Health Organization devotes an entire section to antidotes and other substances used in poisonings that are considered of paramount importance in its model list of essential medicines.⁶⁵ Because many antidotes are used in practice to reverse potential medication errors, overdoses, or adverse clinical conditions, the Department of Veterans Affairs (VA) National Center for Patient Safety considers it mandatory that reversal agents such as flumazenil, naloxone, protamine, and others are available in the clinical setting.⁶⁰ Antidotes are a fundamental aspect of response (as medical countermeasures) to chemical, biological, and radiologic terrorism. As such, provisioning and antidotal administration are Critical Target Capabilities in the US National Preparedness Guidelines.⁵⁹ These national Preparedness Measures include quarterly updates to the federal government on the status of critical items; memoranda of understanding to determine collective inventory accessibility and to ramp up manufacturing capability; and maintenance by pharmaceutical manufacturers and distributors of increased inventory amounts of critical items.⁵⁹ Many professional organizations such as the American Heart Association, American Hospital Association, American Medical Association, American College of Medical Toxicology, and American Academy of Clinical Toxicology consider drug and antidote shortages a significant threat to public health and patient outcomes.^5,6,8,9

Decades of research have consistently documented inadequate stocking of antidotes, which are required at critical instances. In 1986, the lack of any antidotal capacity within a 50-mile radius to treat a case of pyrinuron (Vacor) overdose was reported, with ultimate patient mortality.²⁶ A 1996 study of Colorado, Montana, and Nevada pharmacies found that only 1 of 108 (0.9%) responding hospitals had adequate supplies of eight antidotes (Crotalidae antivenin, cyanide kit, deferoxamine, digoxin immune Fab, ethanol, naloxone, pralidoxime chloride, and pyridoxine).¹⁷ A 1997 survey of Massachusetts hospitals found that only 8 of 82 hospitals (9.8%) stocked all of 14 common antidotes.⁶⁴ A 1999 study determined that no Alabama hospital had adequate supplies of all nine essential antidotes (digoxin-specific antibody fragments [DSFab], pyridoxine, ethanol, pralidoxime, Crotalidae antivenin, deferoxamine, cyanide antidote, naloxone, and fomepizole).⁵³ In 1999, a tertiary care New Mexico hospital was unable to adequately respond to three separate poisoning episodes (ethylene glycol, organic phosphorus compounds, and rattlesnake envenomation).⁴⁷ Rural hospitals are even more likely to lack antidotes.^15,16,22 To complicate medication management, multiple antidotes, such as bromocriptine, carnitine, cyproheptadine, glucagon, octreotide, and high-dose insulin, are not specifically labeled for use as such or are used at different dosages than that of the labeled indication.

With its small vial size, pyridoxine was particularly problematic in the past. Only half of the hospitals with pediatric emergency medicine (EM) fellowships and only two-thirds of hospitals with EM residencies had adequate pyridoxine stores, and of those that did, more than 70% of the time it was stored away from the emergency department (ED) in the hospital’s pharmacy.⁴⁹ One isoniazid overdose case depleted the intravenous pyridoxine supply for a significant region of a state (Nebraska).⁴⁰ A similar isoniazid overdose case left a patient continually seizing because of an inadequate supply at a treating hospital and three of four surrounding hospitals.³⁸ In one study of 21 patients, 85% of patients failed to receive adequate initial intravenous pyridoxine because of inadequate hospital stocking, with resultant severe toxicity to one patient until antidote procurement.¹³

Antidotes specific to known chemical disaster scenarios are equally poorly accessible. Evaluations of a US city’s preparedness in 1996 and 2000 determined that only 4.8% of local hospitals had sufficient atropine and pralidoxime to address a nerve agent incident, and none had sufficient cyanide antidotal capacity.³¹ In a survey of Philadelphia hospitals in 2002, 87% of ED directors did not believe or did not know if adequate antidote stores for nerve agent and cyanide poisoning were available onsite.²³ This antidotal preparedness gap had not narrowed by 2013, when a report of US hospitals determined that only 16% of emergency care hospitals had sufficient cyanide antidote to treat just two 100-kg patients.²¹

The failure to adequately stock antidotes is also well described internationally. In a survey of Quebec hospital pharmacies, the number of adequately stocked antidotes ranged from 0 to 9 (of 13) and was correlated with N-acetylcysteine and naloxone utilization, annual ED visits, and weekend pharmacy coverage, suggesting that smaller hospitals were poorly positioned to adequately care for poisoned patients.¹² Ontario hospitals were no better; only 1 of 179 hospitals (0.6%) stocked adequate amounts of 10 basic antidotes, and more than half were stocked less than 50% of the time.²⁹ A 2003 study of British Columbia hospitals found zero hospitals with adequate stocking of 14 antidotes, with poor availability of DSFab, glucagon, pyridoxine, and antivenom.²² In follow-up in 2005, only 51% to 70% had adequate folic acid, glucagon, methylene blue, atropine, pralidoxime, leucovorin, pyridoxine, and deferoxamine; fewer than 50% had adequate DSFab; and only 7 (8.9%) hospitals sufficiently stocked 21 essential antidotes.⁶³ Similar deficiencies in antidote stocking are reported in Greece,⁴⁸ Lebanon,³⁴ Malaysia,² Spain,⁴⁵ sub-Saharan Africa,⁵² and Taiwan.⁴⁶ Hospitals in the United Kingdom generally had access to N-acetylcysteine, activated charcoal, dantrolene, desferrioxamine, naloxone, flumazenil, and vitamin K but lacked cyanide antidotes, cyproheptadine, ethanol, fomepizole, pralidoxime, succimer, and viper antivenom.⁵⁴ Antidote stocking in New Zealand was generally robust, with only very rarely used antidotes being unavailable (eg, Prussian blue).¹

National shortages can impede institutional attempts to obtain and sustain necessary antidotes. The underlying causes of antidote shortages are complex and include a constricted supplier and manufacturer pool, supply chain disruptions, manufacturing delays, demand issues, economic factors, legal decisions, and the unintended consequences of well-intentioned regulatory approaches (eg, regulatory inspections and the Food and Drug Administration {FDA} Unapproved Drugs Initiative).^24,37,58 Novel regulatory requirements present a particular threat to antidotes that are not specifically labeled for toxicologic use or are used at different dosages than the FDA-approved labeling. The 2011 American Hospital Association survey on drug shortages reported that 99.5% of hospitals reported experiencing one or more drug shortage in the previous 6 months, 82% of hospitals had to delay patient treatment as a result of a drug shortage, and hospitals rarely or never received advance notice of drug shortages and were not informed of the cause or the expected duration of the shortage.⁷ To address this crisis, the 2012 Food and Drug Administration Safety and Innovation Act¹¹ required manufacturers to notify the Secretary of Health and Human Services of significant medications disruptions, required the development and implementation of a plan to prevent and mitigate drug shortages, and required the Comptroller General of the United States to conduct a study to examine the reasons for drug shortages and formulate recommendations on remediation.⁵ Tragically, US national drug shortages continue to number in the hundreds of medications.¹⁰ Certain shortages do challenge credulity. Salt, sugar, and baking soda do not suffer from a lack of raw materials or natural abundance, but 0.9% saline, dextrose, and sodium bicarbonate for parenteral administration are intermittently difficult to obtain.¹⁰ Other specific antidote shortages have included atropine, benzodiazepines, black widow spider (Latrodectus mactans) antivenin, CaNa₂EDTA, dexrazoxane, digoxin immune Fab, epinephrine, ethanol, lipid emulsion (20%), leucovorin, methylene blue, N-acetylcysteine, naloxone, North American coral snake (Micrurus fulvius) antivenin, octreotide, and vitamin K.⁵ In one study, 141 of 1,751 (8.1%) drug shortages were products used to treat poisoned patients.³⁷ Associated medications for critical care such as inotropes, analgesics, induction agents and paralytics for intubation, and sedatives for mechanical ventilation have not been spared.^10,36,62 This pervasive systemic failure to provide basic medications undermines adequate “modern” health care. Internationally, entire countries have reported a substantial rise in hard endpoints such as mortality because of an inability to obtain of antidotes. For example, death rates rose threefold when digoxin immune Fab stocks were exhausted in Sri Lanka.¹⁸

The use of substitute or atypical medications can engender side effects or toxicity that would require alternative antidotes. One study of directors of pharmacy found multiple adverse events associated with drug shortages, including omission, wrong dose dispensing and administration, wrong drug dispensing and administration, treatment delays, and requirements for increased patient monitoring.³⁹ Most patients want to be informed of drug shortages and the side effects of substitutes, and drug shortages lead to patient complaints.^27,39 Antidote shortages are particularly vexing because of a relatively narrow number of agents “in class,” or appropriate to the poisoning. In many situations, suitable alternatives either do not exist or create new benefit–side effect conundrums. For example, sodium acetate substitution for sodium bicarbonate is limited by ceilings in acute dosing and the side effects of myocardial depression, hypotension, hypopnea, and hypoxemia.^43,44

Cost can present a significant barrier to antidote acquisition, particularly for those that are infrequently used. The reasons for this are complex and include market exclusivity, generic availability, development costs, and “what the market will bear.”³² However, even simple antidotes that are years since introduction are associated with massive cost increases. Without significant new research, the original cyanide antidote kit, containing amyl nitrite, sodium nitrite, and sodium thiosulfate, was rebranded and released as “new” Nithiodote without amyl nitrite, with subsequent market exclusivity and elimination of generic competition.¹⁹ In one of the most egregious examples, Valeant Pharmaceuticals raised the price of CaNa₂EDTA from $950 to $26,927 within a year.⁵⁰ Similar massive increases in the cost of vital drugs such as epinephrine and naloxone are described.²⁰ In a broader analysis, the average wholesale price of 15 of 33 antidotes had a greater than 50% price increase, and 8 of 33 had greater than $1,000 increase from 2010 to 2015.²⁵ Similar marked cost increases are detailed in in the position statements of toxicologic organizations.⁴ Even in the hospital setting, where providers and patients are typically insulated from cost, massive price increases (sometimes upwards of 70 times) have led to medication abandonment and presumably alternative medication use.³³ Shortages themselves exacerbate cost pressures, as pharmacy directors reported a 300% to 500% markup on medications on shortage lists.¹⁴ Although factors other than cost such as frequency of use, shelf life, and outdated product returns or recycling factor into decision making, hospital emphasis on cost alone might cause EDs to forgo the most appropriate antidote.⁵¹ To address these costs and provide economies of scale, standardized, regional antidote collections with online administration guidelines have demonstrated success in providing antidote coverage.⁴²