Midodrine exposures reported to United States poison centers: 2000–2023

Abstract

Introduction

Midodrine is an oral alpha-1 adrenergic agonist used to treat orthostatic hypotension. Its vasoconstrictive properties can lead to hypertension and reflex bradycardia. We characterized midodrine exposures reported to United States poison centers from 2000 to 2023.

Methods

We performed a retrospective analysis of single-substance midodrine exposures reported to the National Poison Data System^®. Descriptive statistics were used to characterize temporal trends, demographics, exposure reasons, level of healthcare, and medical outcomes. National estimates of retail outpatient midodrine prescriptions during 2002–2023 were obtained from IQVIA Total Patient Tracker.

Results

The number of patients dispensed midodrine from retail pharmacies increased 695%, from 55,300 in 2002 to 439,659 in 2023. There were 1,935 midodrine exposures reported to the National Poison Data System^® from 1 January 2000 to 31 December 2023. Exposures increased 714%, from 21 calls in 2000 to 171 calls in 2023. The most common features reported were hypertension in 277 (14.3%) and bradycardia in 197 (10.2%). Therapeutic errors accounted for most cases in most age groups except adolescents aged 13–19 years, in which suspected suicide was the most commonly reported reason (50.2%). Most exposures were managed at home. Among 866 patients who sought medical care, 437 (50.5%) were treated/evaluated and released, but 115 (13.3%) were admitted to a critical care unit.

Discussion

Midodrine exposures increased over time, particularly among individuals aged 20–59 years and 60 years and older, with a concomitant increase in retail midodrine dispensing. Although most exposures were managed at home, severe adverse effects have been reported, especially among patients with suspected suicidal ingestions compared to those with therapeutic errors. The National Poison Data System^® is limited by its passive surveillance design, and not all exposures are reported.

Conclusions

Better understanding of midodrine exposures and associated outcomes can inform poison center triage and medical management. Improved surveillance and clinician awareness may reduce morbidity and mortality associated with midodrine toxicity.

Introduction

Midodrine is an orally administered alpha-1 adrenergic agonist approved by the United States (US) Food and Drug Administration for the treatment of symptomatic orthostatic hypotension. Since its approval, midodrine has been used off-label for various hypotensive conditions, including hemodialysis-associated hypotension, autonomic dysfunction, and spinal cord injury-related hypotension. It is also used in patients with heart failure with reduced ejection fraction, to allow for optimization of medical therapy.

Midodrine is absorbed from the gastrointestinal tract and is metabolized in the liver via deglycination to form an active metabolite, desglymidodrine, which is an alpha-1 adrenergic agonist. It is relatively selective for vascular postjunctional alpha-1-adrenoreceptors, increasing peripheral vascular resistance primarily by arteriolar constriction, with some venous constriction in capacitance vessels [Citation 1].

Clinically, midodrine increases the standing, sitting, and supine systolic and diastolic blood pressures in patients with orthostatic hypotension, and is used to treat many different etiologies of orthostatic hypotension, including neurogenic orthostatic hypotension [Citation 2], neurocardiogenic syncope [Citation 3], hemodialysis-related hypotension [Citation 4], and more recently, postural orthostatic tachycardia syndrome, particularly in adolescents [Citation 5–7].

Despite its therapeutic utility, the pharmacologic properties of midodrine can be potentially toxic. Specifically, the vasoconstrictive effects of midodrine can lead to hypertension and reflex bradycardia in overdose. Although rare, these clinical effects in overdose are often significant, leading to hospitalization and intensive care unit stay [Citation 7,Citation 8].

Although there are multiple case reports of midodrine overdose [Citation 9–11], there has not been a large longitudinal national poison center-based study to describe the characteristics of exposures to midodrine over time. United States poison centers provide free, 24/7 professional advice on poisonings and adverse effects from substances, including pharmaceutical products and chemicals. This study characterizes single-substance exposures to midodrine reported to the National Poison Data System^® (NPDS^®) of America’s Poison Centers^® from 2000 to 2023, including overall trends in midodrine exposures, the types of exposures (intentional versus unintentional), demographics, and medical outcomes.

Methods

We conducted a retrospective analysis of data from NPDS^®, an electronic surveillance system that is owned and operated by America’s Poison Centers^®. The NPDS^® collects exposure and information call data from all poison centers in the US. Data are uploaded into NPDS^® in near-real-time, approximately every 5 min. We queried NPDS^® for single-substance human exposures to midodrine from 1 January 2000 to 31 December 2023. We excluded calls with multiple exposures (i.e., midodrine and another substance) and in which the exposure was not responsible for the effect (coded as "unrelated effect" or "confirmed non-exposure").

We conducted descriptive analyses of single-substance midodrine exposures by year, age, sex, medical outcome, the highest level of healthcare facility, and reason for exposure using SAS 9.4 (SAS Institute Inc, Cary, NC) and Excel (Microsoft Corporation, Redmond, WA). We conducted an overall test of trend using Poisson regression to determine whether counts of exposures to midodrine had changed significantly during the study period, and whether the rate of exposure had changed after adjusting for the number of recipients of dispensed prescriptions. Fisher’s exact test was used to compare frequencies of clinical effects among suspected suicides and therapeutic errors.

We categorized age (in years) by NPDS^® age categories with infants/toddlers (0–5 years), children (6–12 years), adolescents (13–19 years), adults (20–59 years), and older adults (60+ years). As defined in the NPDS^® database, medical outcomes were organized in categories including no effect, minor effect, moderate effect, major effect, not followed, and unable to follow, potentially toxic exposure. Level of healthcare facility categories included admitted to critical care unit, admitted to noncritical care unit, treated and released, patient lost to follow-up/left against medical advice, and patient refused referral. Reason for exposure was defined as the underlying reason, purpose, or intent for which the exposure occurred. Reasons can be categorized as unintentional, intentional, or adverse reaction, with specific codes within each category such as "unintentional - therapeutic error" or "intentional - suspected suicide." We limited collected clinical effects and therapies information to effects and therapies that we thought were relevant to midodrine exposure. Clinical effect data obtained included bradycardia, hypertension, lethargy, chest pain, nausea, vomiting, central nervous system depression, seizure, slurred speech, headache, dizziness, syncope, and dysrhythmia. Selected therapies included intravenous fluid administration, atropine, oxygen, activated charcoal, endotracheal intubation, and administration of antihypertensive medications.

To contextualize the numbers of poison center calls relative to overall midodrine exposure, we obtained national estimates of the number of unique persons dispensed midodrine prescriptions at outpatient retail pharmacies in 2002–2023 from IQVIA Total Patient Tracker. IQVIA tracks national medication dispensing trends and activity for pharmaceutical products, aggregates medication dispensing data from participating US pharmacies, and uses a proprietary algorithm to project national-level estimates of unique patients receiving dispensed prescriptions. The IQVIA sample included pharmacy records from nearly 49,000 retail pharmacies across the US, representing approximately 93% of all retail prescription activity from independent and chain pharmacies and pharmacies in food and mass merchandise stores, with over 3.5 billion transactions annually. Overall retail pharmacy midodrine exposure estimates were further analyzed by age group and time period.

Results

There were 1,935 single-substance exposures to midodrine reported to NPDS^® from 2000 to 2023. Exposures have increased over time, from 21 exposures in 2000 to 171 in 2023, an increase of 714% over the past 23 years (Figure 1). This increase persisted after adjusting for the number of patients receiving dispensed midodrine prescriptions.

Figure 1.

Number of midodrine exposures reported to NPDS^® from 2000 to 2023.

Age was recorded in 95% of calls. There were 367 exposures (19.0%) reported among children less than 5 years old, 53 (2.7%) among those aged 6–12 years, 223 (11.5%) in those 13–19 years, 564 (29.2%) in those aged 20–59 years, and 632 (32.7%) in those aged 60 years or older. Most individuals were female (60.0%), and 53.2% of exposures were managed on site (Table 1). Single-substance exposures to midodrine reported to NPDS^® increased during the study period, with a statistically significant test for trend (P < 0.0001). The largest increases were reported in those aged 20–59 years and 60 years and older (Figure 2).

Table 1:

Characteristics of patients with single substance exposures to midodrine (n=1,935).

Characteristic	Number of cases (%)
Age (y)
<5	367 (19.0%)
6–12	53 (2.7%)
13–19	223 (11.5%)
20–59	564 (29.1%)
60+	632 (32.7%)
Unknown	96 (5.0%)
Sex
Female	1160 (60.0%)
Male	771 (39.8%)
Unknown	4 (0.2%)
Exposure Reason
Adverse reaction	88 (4.5%)
Intentional – abuse/misuse	27 (1.4%)
Intentional – suspected suicide	276 (14.3%)
Unintentional – general	467 (24.1%)
Unintentional – therapeutic error	1029 (53.2%)
Other/Unknown	48 (2.5%)
Management Site
Managed on site (non-healthcare facility)	1030 (53.2%)
Patient already in (enroute to) healthcare facility	552 (28.5%)
Patient referred to healthcare facility	314 (16.2%)
Other/Unknown	39 (2.0%)
Level of healthcare facility (n=866)
Admitted to critical care unit	115 (13.3%)
Admitted to noncritical care unit	76 (8.8%)
Admitted to psychiatric facility	81 (9.4%)
Patient lost to follow-up / left against medical advice	100 (11.5%)
Patient refused referral / did not arrive at healthcare facility	57 (6.6%)
Treated/evaluated and released	437 (50.5%)
Medical Outcome
Major effect	11 (0.6%)
Moderate effect	351 (18.1%)
Minor effect	184 (9.5%)
No effect	556 (28.7)
Not followed	706 (36.5%)
Unable to follow, potentially toxic exposure	127 (6.6%)

Figure 2.

Single-substance exposures to midodrine from 2000 to 2023 per National Poison Data System^® age group category.

The most common effects were hypertension (14.3%) and reflex bradycardia (10.2%). Patients also experienced vomiting (3.6%), headache (3.41%), nausea (3.4%), lethargy (2.3%), dizziness (2.7%), chest pain (1.5%), mild central nervous system depression (0.9%), moderate central nervous system depression (0.4%), confusion (0.4%), seizure (0.2%), slurred speech (0.2%), and syncope (0.2%). One patient had a dysrhythmia. Of therapies provided, 149 (7.7%) were administered intravenous fluids, 115 (5.9%) were given activated charcoal, 46 (2.4%) were given antihypertensives, 20 (1.0%) were given supplemental oxygen, 20 (1.0%) were administered atropine, and five (0.3%) were endotracheally intubated.

The clinical effects reported among patients whose reason for exposure was suspected suicide were compared to patients exposed due to therapeutic error (Table 2). Hypertension, bradycardia, vomiting, nausea, lethargy, chest pain, headache, central nervous system depression, seizure, and slurred speech were reported with significantly greater frequency among patients with suspected suicide attempts compared to patients exposed due to therapeutic error. Differences in reported frequencies of dizziness, confusion, syncope, and dysrhythmias were not statistically significant between the two groups.

Table 2.

Comparison of frequency of clinical effects between suspected suicides and therapeutic errors.

Clinical effect	Suspected suicides, number of cases (%) (n=409)	Therapeutic error, number of cases (%) (n=1029)	P value (Fisher’s Exact Test)
Hypertension	127 (46.0%)	94 (9.1%)	<0.0001
Bradycardia	125 (45.3%)	33 (3.2%)	<0.0001
Vomiting	44 (15.9%)	13 (1.3%)	<0.0001
Nausea	29 (10.5%)	27 (2.6%)	<0.0001
Lethargy	21 (7.6%)	11 (1.1%)	<0.0001
Chest pain	12 (4.4%)	13 (1.3%)	0.0023
Headache	20 (7.3%)	28 (2.7%)	0.0010
Dizziness	9 (3.3%)	32 (3.1%)	0.8475
Central nervous system depression (Mild)	8 (2.9%)	6 (0.6%)	0.0033
Central nervous system depression (Moderate)	4 (1.5%)	2 (0.2%)	0.0205
Confusion	3 (1.1%)	3 (0.3%)	0.1130
Seizure	3 (1.1%)	0 (0%)	0.0094
Slurred speech	3 (1.1%)	0 (0%)	0.0094
Syncope	0 (0%)	2 (0.2%)	1.0000
Dysrhythmia	1 (0.4%)	0 (0%)	0.2115

Within the less than 6 years age group, unintentional (general) exposures represented the largest reason for exposure (97.3%). Unintentional therapeutic errors accounted for the largest category among persons aged 6–12 years (52.8%) and aged 20–59 years (58.2%), as well as in those aged 60 years and older (81.7%). In the 13–19 years age group, suspected suicide attempts accounted for 50.2% of exposures, while therapeutic error accounted for 39% (Figure 3).

Figure 3.

Reasons for midodrine exposure per age group.

*Other reasons for exposure include other unintentional use reasons, as well as intentional exposures such as abuse or misuse.

There was a known medical outcome in 1,102 of 1,935 exposures: 556 (28.7%) exposures resulted in no clinical effects, 184 (9.5%) were minor, 351 (18.1%) were moderate, and 11 (0.6%) were major. Seven hundred and six persons (36.5%) were not followed and judged to have minimal clinical effects, and 127 (6.6%) could not be followed but were judged to have a potentially toxic exposure (Table 1). There were no deaths. Of those with major clinical effects, one patient was in the 6–12 years age group, three patients were in the 13–19 years age group, five patients were in the 20–59 years age group, and two patients were in the 60 years and older age group (Table 3). Of the three exposures with major clinical effects that had a scenario reported, one was an iatrogenic error, and two were a wrong medication taken/given scenario.

Table 3.

Medical outcomes by age group

Medical Outcome	Age ≤ 5	Age 6–12	Age 13–19	Age 20–59	Age ≥ 60	Unknown Age	Total
No effect	245 (66.8%)	18 (34.0%)	43 (19.3%)	83 (14.7%)	154 (24.4%)	13 (13.5%)	556 (28.7%)
Minor effect	21 (5.7%)	8 (15.1%)	34 (15.3%)	76 (13.5%)	40 (6.3%)	5 (5.2%)	184 (9.5%)
Moderate effect	15 (4.1%)	2 (3.8%)	84 (37.7%)	137 (24.3%)	107 (16.9%)	6 (6.3%)	351 (18.1%)
Major effect	0 (0%)	1 (1.9%)	3 (0.2%)	5 (0.9%)	2 (0.3%)	0 (0%)	11 (0.6%)
Not followed	61 (16.6%)	19 (35.9%)	47 (21.1%)	221 (39.2%)	304 (48.1%)	54 (56.3%)	706 (36.5%)
Unable to follow, judged as potentially toxic exposure	25 (6.6%)	5 (9.4%)	12 (5.4%)	42 (7.5%)	25 (4.0%)	18 (18.8%)	127 (6.6%)
Total	367 (19.0%)	53 (2.7%)	223 (11.5%)	564 (29.1%)	632 (32.7%)	96 (5.0%)	1935 (100%)

The level of healthcare was documented in 44.7% of exposures. Approximately half of these were treated/evaluated and released. One hundred and fifteen (13.3%) were admitted to a critical care unit, 81 (9.4%) to a psychiatric facility, and 76 (8.8%) to a noncritical care unit (Table 1).

Figure 4 displays the level of healthcare by age group. The 13–19 years age group represented the largest percentage of those admitted to psychiatric facilities, accounting for 52.5% of patients. Patients in the 20–59 years age group represented the largest percentage of those admitted to critical and noncritical care units.

Figure 4.

Level of healthcare in patients by age group.

Midodrine retail dispensing has increased almost 700% based on IQVIA Total Patient Tracker data, with an estimated 55,300 patients being dispensed midodrine by retail pharmacies in 2002, compared to 439,659 in 2023. Patients aged ≥65 years represented the largest group being dispensed midodrine in all years with available age data (2006–2023). In this age group, midodrine dispensing increased an estimated 730%, from 30,712 patients in 2006 to 255,065 in 2023. The 0–17 years age group was the smallest group dispensed midodrine, with an estimated 1,343 patients in 2006 and 7,158 in 2023, an increase of 433%. These findings are summarized in Figure 5.

Figure 5.

(a) Estimated number of persons receiving midodrine dispensed from United States retail pharmacies, 2006–2023, by age group.

Data from 2002–2006 did not specify age group. Patients whose age was not known are not displayed, accounting for an average of 0.02% of patients per year.

Data source: IQVIATotal Patient Tracker, 2006–2023.

(b) Estimated number of persons in the 0–17 year age group receiving midodrine dispensed from US retail pharmacies

Discussion

Midodrine exposures reported to NPDS^® have increased over time, particularly in the 20–59 years and 60+ years age groups. A similar increase in midodrine dispensing by retail pharmacies across the US was also observed based on IQVIA Total Patient Tracker data. Unintentional exposures accounted for most cases in most age groups except adolescents (ages 13–19 years), in which suspected suicide attempt was the most commonly reported reason.

Multiple smaller studies have demonstrated an increase in midodrine prescribing by clinicians in both inpatient and outpatient settings [Citation 12–14]. Our findings indicate an increasing trend in exposures, likely reflecting growing clinical use, both on- and off-label. After approval by the US Food and Drug Administration of midodrine in 1996 for symptomatic orthostatic hypotension, other uses emerged. Midodrine began to be used as a pre-treatment medication for chronic hypotension associated with hemodialysis and in the hepatorenal syndrome to improve renal blood flow [Citation 15]. Hypertension was the most common clinical manifestation, consistent with the pharmacologic mechanism of midodrine, although other adrenergic and neurologic symptoms were also observed.

Among patients aged 13–19 years, intentional ingestions – suspected suicide attempts accounted for 50.2% of reported midodrine exposures, despite the IQVIA data showing that the 0–17 years age group had the smallest estimated number of persons receiving midodrine prescriptions in all years with age group dispensing information and the smallest percentage increase over time from 2006 to 2023. Midodrine may be prescribed to patients in the 13–19 years age group for medical problems such as postural orthostatic tachycardia syndrome, among other causes of orthostatic hypotension. It is unclear if there is any causal relationship between patients in this age range with certain diagnoses that are prescribed midodrine, including postural orthostatic tachycardia syndrome, and suicidality. However, one small survey study comparing postural orthostatic tachycardia syndrome patients and controls without the condition demonstrated that patients with postural orthostatic tachycardia syndrome had a significantly higher risk of suicide [Citation 16].

We hypothesize that the more severe clinical effects reported among patients with intentional suicide attempts may be due to larger doses ingested, compared to patients with therapeutic errors. However, NPDS^® data do not include detailed information about ingested doses. Case reports of midodrine exposure in the literature allude to severe clinical effects with large exposures, including posterior reversible encephalopathy syndrome and subarachnoid hemorrhage [Citation 17,Citation 18].

The findings of this report are subject to several limitations. Because NPDS^® relies on data that are voluntarily reported to poison centers by healthcare providers and the public, NPDS^® may not capture all midodrine exposures, and the true incidence of exposure to midodrine is not known. Moreover, these exposures were not confirmed analytically. In addition, NPDS^® data contain no information about the amount of drug to which the individuals were exposed. Patients with midodrine exposure and healthcare providers taking care of patients with midodrine exposure may be less inclined to report these exposures to NPDS^® because of a lack of symptoms or preconceived notions that midodrine exposure is benign. Data entry error leading to inaccurate coding in poison centers, as well as in NPDS^® is also possible. Some coded sections had large numbers of missing data. For example, 1,069 patients (55.3%) did not have a level of healthcare facility coded. If all these patients were not coded because they were observed at home, the proportion of patients admitted to noncritical and critical care units, as well as other categories of healthcare, may be overrepresented. Finally, IQVIA Total Patient Tracker estimates do not include persons receiving midodrine prescriptions dispensed from mail order or long-term care pharmacies.

Conclusion

Midodrine exposures reported to NPDS^® have increased over the past two decades, along with a concomitant increase in prescriptions. While most cases were associated with minor outcomes, serious adverse effects requiring critical medical interventions, such as endotracheal intubation, have occurred. Patients with suspected suicide attempts as the reason for exposure developed clinical effects at higher frequencies than patients with therapeutic errors. Adverse clinical effects were also seen with certain exposure scenarios, such as double doses and taking the medication too soon after an initial dose. Increased clinician awareness and ongoing surveillance are essential, particularly given the expanding use of midodrine beyond US Food and Drug Administration-approved indications. A clearer understanding of midodrine exposures and their associated outcomes can improve clinical decision-making, including poison center triage and patient care.