During the study period, 1,392,365 cases of exposure were recorded by French Poison Centers, or approximately 199,000 per year. Initially, 56,388 cases of poisoning mentioning the use of an antidote (recommended or administered) were extracted from the FNDP. After excluding (a, b, c), we included 25,289 cases (mean ± SD age: 35.0 ± 25.1 years; 59.6% were females) in the study, representing patients for whom a French PC was contacted and who received at least one antidote between January 1, 2015, and December 31, 2021 (Fig. 1).
Flowchart of the case selection process based on the use of an antidote from the French national database of poisonings.
Over the 7-years study period, poisoning cases requiring antidote administration were intentional in more than three quarters of cases (77.0%) (Table 1). Poisoning severity was assessed as none in 16.8% of cases, minor in 35.1%, moderate in 27.1%, and severe in 19.6%. The overall mortality rate was 1.7% (n = 436).
Figure 2 presents for all antidotes used from 2015 to 2021, the poisoning circumstances, the implicated agents, as well as severity and outcomes.
Circumstances, implicated agents, severity and outcomes of poisonings requiring an antidote. The circumstances of poisoning are represented by stacked bar graphs, separating the types of unintentional circumstances from the intentional ones. The subdivisions represent the share (%) of each circumstance in each diagram. The agents involved and their frequencies are represented by pie charts. Severity and outcomes are represented by stacked bar charts. Severity is represented in red when high, orange when moderate, yellow when low, green when absent and gray when unknown. The outcome is represented in red when death, orange when sequelae, green when recovery and gray when unknown.
The Fig. 3 provides a descriptive summary of the data presented in (Fig. 2). For unintentional circumstances, the most common were accidental (mean = 45.4%) and therapeutic error/accident (mean = 35.1%). In contrast, indoor air pollution (mean = 0.3%) and practical work (mean = 0.1%) were rarely reported. Regarding intentional circumstances, suicide attempt was by far the most frequent (mean = 76.9%), while criminal/malicious act was rare (mean = 1.7%). The most commonly involved agents were drugs (mean = 47.4%), chemical products (mean = 13.1%), and other agents (mean = 15.3%). Less frequently reported were animals (mean = 3.8%), illicit drugs (mean = 2.8%), and plants (mean = 1.4%). In terms of severity, cases were most frequently classified as severe (mean = 31.5%) or moderate (mean = 30.6%). The absence of severity (none) was less common (mean = 12.9%). For outcomes, recovery was the most frequent conclusion (mean = 71.3%), followed by unknown outcomes (mean = 21.7%). Death and sequelae were rare, with means of 4.9 and 2.0%, respectively.
Bar plots representing (A) unintentional circumstances, (B) intentional circumstances, (C) involved agents, (D) severity, and (E) outcomes. Each bar represents the mean proportion of cases for each category, with the observed minimum and maximum values as a proxy for the confidence interval.
Eight antidotes were used more than 500 times during the study period, in descending order: N-acetylcysteine (NAC) (n = 13,555), flumazenil (n = 3,012), naloxone (n = 1,740), antivenoms (n = 1,131), phytomenadione (vitamin K) (n = 871), glucagon (n = 709), pyridoxine (vitamin B6) (n = 673), and fomepizole (n = 638) (Fig. 4a,b and Supplementary Tables 2–9). While the recorded proportion of NAC use increased from 48% in 2015 to 61% in 2021, the absolute number of uses remained relatively stable or slightly declined. This means that despite a relatively stable absolute number of cases requiring the administration of NAC, the proportion of this antidote out of the total number of administrations has increased over the period. In contrast, the use of other antidotes decreased both in absolute numbers and proportions over the same period. Fomepizole accounted for 2.6% of all antidote administrations recorded in 2015, falling to 1.8% in 2021. Over the period, the use of flumazenil fell from 14.8 to 9.2%, pyridoxin fell from 3.8 to 1.4%, phytomenadione from 5.4 to 2.2% and glucagon from 3.4 to 2.2%.
Trends in antidotes use from 2015 to 2021. (A) Values of antidotes used in at least 500 cases. (B) Proportions of antidotes used in at least 500 cases. (C) Values of antidotes used less than 500 cases. (D) Proportions of antidotes used less than 500 cases.
Eighteen antidotes were used less than 500 times during the study period: digoxin-specific antibodies (n = 454), silymarin (n = 327), high-dose insulin euglycemic therapy (n = 287), ethanol therapy (n = 272), methylthioninium chloride (n = 246), hydroxocobalamin (n = 243), L-carnitine (n = 223), folic acid (vitamin B9) (n = 222), dantrolene (n = 157), calcium gluconate (n = 93), calcium salts (n = 85), pralidoxime (n = 74), octreotide (n = 61), cyanocobalamin (vitamin B12) (n = 54), physostigmine (n = 51), deferoxamine (n = 50), protamine (n = 33), and reversal agents for DOACs (n = 28) (Fig. 4c,d and Supplementary Tables 10–27). The observed use of methylthioninium chloride, hydroxocobalamin, cyanocobalamin and DOAC reversal agents increased, both in terms of absolute numbers and proportions. Conversely, the observed use of ethanol-based therapy, L-carnitine, and dantrolene decreased over time. Pralidoxime, octreotide, physostigmine, deferoxamine and protamine tended to decrease in both absolute numbers and proportions. For certain antidotes, such as silymarin and digoxin-specific antibodies, trends were more difficult to define due to significant year-to-year variations or a decline in absolute numbers despite an increase in proportional use. Among these antidotes, folic acid appeared to be the only one with stable use both in absolute numbers and proportion over time.
Of the 26 antidotes analyzed, they were used in both voluntary and involuntary circumstances. In fact, 13 antidotes were mainly used for deliberate poisonings (insulin, methylthioninium chloride, carnitine, calcium salts, pralidoxime, cyanocobalamin, physostigmine, octreotide, NAC, flumazenil, naloxone, phytomenadione, glucagon and pyridoxin) in relation with suicide attempts or addictive behavior. Interestingly, among the reported uses of flumazenil (n = 3012), 196 (6.5%) involved multiple intoxications with benzodiazepines and other proconvulsant drugs such as escitalopram (N = 76), amitriptyline (N = 59), fluoxetine (N = 51), clozapine (N = 8) and methylphenidate (N = 2).
Eleven antidotes were mainly indicated for unintentional poisoning (digoxin-specific antibodies, folic acid, silymarin, antivenom, hydroxocobalamin, protamine, reversal agent for DOAC, deferoxamine, calcium gluconate gel, dantrolene), involving exposure to natural toxins (fungi, snakes) or environmental phenomena (fires), but also exposure to drugs with narrow therapeutic index (digoxin or methotrexate). Fomepizole and ethanol, both indicated in the treatment of toxic alcohol poisoning, were used equally in cases of voluntary or involuntary poisoning.
Observed mortality rates above 5% concerned poisonings requiring the following antidotes: digoxin-specific antibodies (7.3%), insulin (7.7%), methylthioninium chloride (6.5%), hydroxocobalamin (21.5%), dantrolene (5.1%), calcium salts (11%), pralidoxime (10%), protamine (15%) and reversal agents for DOAC (14%).
For additional details, the complete dataset is available for each antidote in the supplementary materials (Supplementary Tables 2–27). A description of each tables is available in additional results.