The Journal of Emergency Medicine, Vol. -, No. -, pp.

1–5, 2018
Ó 2018 Elsevier Inc. All rights reserved.
0736-4679/$ - see front matter

https://doi.org/10.1016/j.jemermed.2018.09.015

Selected Topics:
Toxicology

REFRACTORY HYPOTENSION CAUSED BY PRAZOSIN OVERDOSE COMBINED

WITH ACETAMINOPHEN AND NAPROXEN TOXICITY: A CASE REPORT AND
REVIEW OF THE LITERATURE

Cory Anderson, MD,* Timothy Lynch, MD,* Ronish Gupta, MD,† and Rodrick K. Lim, MD*
*Department of Pediatrics at Schulich School of Medicine, University of Western Ontario, and the Children’s Health Research Institute,
Children’s Hospital at London Health Sciences Centre, London, Ontario, Canada and †Department of Pediatrics, McMaster University,
Hamilton, Ontario, Canada
Corresponding Address: Rodrick K. Lim, MD, Department of Pediatrics, Children’s Hospital at London Health Sciences Centre, 800
Commissioners Rd E, London, ON, Canada, N6C 2V5

, Abstract—Background: Pediatric exposure to prazosin INTRODUCTION

is unusual because it is most commonly indicated for the
treatment of hypertension. Prazosin’s increase in popularity
as a treatment for posttraumatic stress disorder makes it
important for emergency physicians to be aware of how to
manage potential toxic ingestion because of prazosin over-
dose. Case Report: A 16-year-old, 76-kg female presented
after ingesting 110 mg of prazosin, 209.3 g of acetamino-
phen, and 55 g of naproxen. She was admitted to the pediat-
ric intensive care unit for rapidly deteriorating hypotension
(lowest blood pressure 47/19 mm Hg) refractory to aggres-
sive fluid resuscitation and infusions of epinephrine and
norepinephrine each at 0.5 mcg/kg/min. Stabilization of
blood pressure was eventually achieved, and associated
with use of a vasopressin infusion of 0.004 units/kg/min.
Why Should an Emergency Physician Be Aware of This?:
Because of the increasing exposure of children to prazosin,
clinicians should be aware of the pharmacology behind
alpha-1 antagonist overdose and consider treatment options,
such as vasopressin, when hypotension is resistant to stan-
dard fluid and catecholamine therapy. Ó 2018 Elsevier
Inc. All rights reserved.
, Keywords—alpha-1 antagonist; alpha-1 blockade; hypo-
tension; overdose; prazosin; refractory hypotension; vaso-
pressin
Reprints are not available from the authors.
Pediatric exposure to prazosin is unusual because it is
most commonly indicated for the treatment of hyperten-
sion. However, it is gaining popularity as a treatment for
nightmares in the context of posttraumatic stress disorder
as a replacement for tricyclic antidepressants and is there-
fore important for emergency physicians to be aware of
its toxicity (1).
Prazosin is a relatively fast-acting alpha-adrenergic
antagonist that works by competitively binding to the
postsynaptic alpha-1 adrenergic receptors to inhibit bind-
ing by norepinephrine. This results in a net vasodilatory
response and a decrease in systemic vascular resistance
to lower systemic blood pressure. It typically takes effect
within 2 h of ingestion and achieves its peak effect within
2–4 h before wearing off after 10–24 h postingestion (1).
The half-life of prazosin ranges from 2–4 h in healthy
adults. The majority of drug metabolism occurs in the
liver via demethylation and glucuronidation. Only 6–
10% of the active drug is eliminated by the kidneys (2,3).
Acetaminophen and naproxen are common over-the-
counter medications that provide analgesia and antipyre-
sis. Both are commonly seen in ingestion-related suicide
attempts, with 75% of fatal acetaminophen ingestions re-
sulting from suicidal intent (4). Acetaminophen is known

RECEIVED: 15 June 2018; FINAL SUBMISSION RECEIVED: 10 August 2018;

ACCEPTED: 1 September 2018

1
2 C. Anderson et al.

to cause liver damage through saturation of glutathione- An initial electrocardiogram revealed a sinus tachy-
mediated conjugation and subsequent conversion into cardia at 104 with a prolonged, corrected QT-interval of
toxic metabolites by CYP450-dependent pathways. 536 ms. The acetaminophen level was 4140 mmol/L
Although nonsteroidal antiinflammatory drugs are nor- (625 mg/dL) at 4.5 h postingestion. Ethanol, acetylsali-
mally benign, doses exceeding 400 mg/kg have been asso- cylic acid, and tricyclic antidepressant screens were nega-
ciated with acidosis, renal failure, coma, and death (5). tive.
Given the paucity of literature describing the toxicity Given her presentation with altered level of con-
of alpha-antagonist agents and their management, we sciousness, hypotension, and a prolonged QT interval,
aim to report the case of a patient demonstrating refrac- a decision was made to consult the pediatric critical
tory hypotension and discuss vasopressin as a potential care team. In the following 2 h, she experienced a
therapeutic option. slow but progressive decline in her level of conscious-
ness. She received an additional 1-L bolus of normal
CASE REPORT saline once again with improvement in her blood pres-
sure as it was being infused. Given the anticipation for
A 16-year-old, 76-kg female with a history of generalized deterioration at this point, the patient was transferred to
anxiety disorder, depressive symptoms, and cluster B per- the pediatric critical care unit (PCCU) for ongoing
sonality traits presented to the pediatric emergency management.
department. She stated that 90 min earlier she ingested Upon transfer to the PCCU, the patient became signif-
55 2-mg tablets of prazosin (110 mg) along with a bottle icantly more somnolent and hypotensive. An arterial line
of naproxen (220 mg, 250 tablets, total 55 g), a bottle of was placed, and additional fluid boluses of lactated
acetaminophen (500 mg, 325 tablets), and a bottle of Ringers solution were given while central access and
extended release acetaminophen (650 mg, 72 tablets) catecholamine infusions were prepared. Repeat blood-
totaling 209.3 g of acetaminophen. She vomited both at work revealed a worsening metabolic acidosis with a
home and in the emergency department. pH of 7.31, a partial pressure of carbon dioxide of
The patient notified her family who called emergency 27 mm Hg, bicarbonate of 14.4 mmol/L, base excess of
medical services. She remained hemodynamically stable 11.3, and lactate of 6.4 mmol/L (57.7 mg/dL). Epineph-
and neurologically intact during transport to the emer- rine and norepinephrine infusions were initiated and
gency department via ambulance. rapidly escalated to 0.5 mcg/kg/min each. The patient
She was first prescribed prazosin 5 weeks before presen- also received an additional 4 L of Ringers solution in
tation to help her sleep because she had been experiencing
nightmares. Her current dose was 2 mg nightly. She had
also been treated with fluoxetine 40 mg/day until 2 weeks Table 1. Initial Bloodwork
earlier, when it was discontinued by her psychiatrist. Investigation Results
She was noted to be somnolent on initial assessment in
the emergency department. Her airway was patent. Her Complete blood cell count
White blood cells 7.4  109/L
respiration rate was 15 breaths/min and her oxygen satu- Hemoglobin 115 g/L (11.5 g/dL)
ration was 100% in room air. There was no increased Platelets 159  109/L
work of breathing. Her initial heart rate was 126 beats/ Electrolytes
Sodium 134 mmol/L
min with a blood pressure of 98/59 mm Hg; a repeat blood Potassium 2.8 mmol/L
pressure measurement was 83/40 mm Hg. Her pupils Chloride 99 mmol/L
were reactive to light. Her initial Glasgow Coma Scale Carbon dioxide 20 mmol/L
Total calcium 2.07 mmol/L (8.28 mg/dL)
score was 14 (eye opening 3, verbal response 5, and motor Magnesium 0.73 mmol/L (1.77 mg/dL)
response 6). Her oral temperature was 36.7 C and there Renal function
were no signs of trauma. Urea 2.4 mmol/L (6.7 mg/dL)
Creatinine 48 mmol/L (0.6 mg/dL)
She was given supplemental oxygen and was initially Enzymes
fluid resuscitated with 1 L of normal saline. Her blood Aspartate transaminase 17 units/L
pressure transiently responded measuring 94/45 mm Hg Alanine transaminase 16 units/L
Alkaline phosphatase 43 units/L
but then fell to 87/53 mm Hg. Another liter of normal sa- Gamma glutamyl transferase 10 units/L
line raised her blood pressure to 93/45 mm Hg but it then Lipase 24 units/L
dropped again to 77/49 mm Hg. The Ontario Poison Con- Lactate dehydrogenase 115 units/L
Blood gas
trol Centre was contacted, and the patient’s management pH 7.37
was discussed. Initial investigations are detailed in Partial pressure of carbon dioxide 35 mm Hg
Table 1. A lactate assessment was not completed with Bicarbonate 21.3 mmol/L
Base excess 4.5
initial bloodwork.
Refractory Hypotension Caused by Prazosin Overdose 3

the PCCU, totaling 7 L of crystalloid since emergency
department presentation. Despite these therapies, the pa-
tient remained hypotensive (lowest blood pressure 47/
19 mm Hg).
A vasopressin infusion was initiated and quickly
increased from 0.0005 units/kg/min to a maximum of
0.004 units/kg/min. A significant and steady improve-
ment in blood pressure was observed in association
with the commencement and escalation of the vaso-
pressin infusion. Systolic blood pressures were able to
be maintained in the 75–90 mm Hg range, with good
urine output. Extracorporeal circulatory life support
(ECLS) was also being considered, given the borderline
hemodynamic status on maximum medical therapy. Ulti-
mately it was decided that in light of the improvement
with vasopressin, the anticipated short-acting toxicity,
and difficulties in achieving adequate circulatory flow
with primary alpha-blockade, ECLS was not pursued.
The patient’s blood pressure continued to gradually
improve to systolic measurements of 110–120 mm Hg
in the following hours (Figure 1).
Inotropic and vasoactive supports begun to be reduced
at 16 h postingestion, beginning with epinephrine and
norepinephrine. Vasopressin was left as the last support
to be weaned. All pharmacologic circulatory supportive
medications were discontinued by 43 h postingestion.

1830h Time of IngesƟon

2130h HR: 126bpm BP: 98/54mmHg

pH: 7.37 PCO2: 35mmHg HCO3: 21.3mmol/L BE: -4.3

2L 0.9%NaCl

2400h HR: 105bpm BP: 83/46mmHg

pH: 7.31 PCO2: 27mmHg HCO3: 14.4mmol/L BE: -11.3

lactate: 6.4mmol/L (57.7mg/dL)

1L ringers lactate
epi 0.05mcg/kg/min
0130h HR: 130bpm BP: 52/32mmHg

pH: 7.17 PCO2: 17mmHg HCO3: 6.7mmol/L BE: -20.4

lactate: 10.8mmol/L (97.4mg/dL)

3L ringers lactate
epi 0.5mcg/kg/min
norepi 0.5mcg/kg/min

0330h** HR: 125bpm BP: 68/33mmHg

pH: 7.09 PCO2: 17mmHg HCO3: 5.7mmol/L BE: -22.7

lactate: 12.2mmol/L (110mg/dL)

1L 0.9%NaCl
epi 0.5mcg/kg/min
norepi 0.5mcg/kg/min
vaso 0.001 units/kg/min
HCO3 50mmol bolus
0530h HR: 111bpm BP: 86/35mmHg

pH: 7.02 PCO2: 17mmHg HCO3: 4.6mmol/L BE: -25 LEGEND:

lactate: 12.1mmol/L (109mg/dL) HR (heart rate)
epi 0.5mcg/kg/min BP (blood pressure)
norepi 0.5mcg/kg/min HCO3 (bicarbonate)
vaso 0.004 units/kg/min BE (base excess)
HCO3 50mmol bolus epi (epinephrine)
norepi (norepinephrine)
0900h HR: 122bpm BP: 110/43mmHg vaso (vasopressin)
bpm (beats per minute)
pH: 7.09 PCO2: 17mmHg HCO3: 4.6mmol/L BE: -23.6 ** - central venous access
lactate: 6.6mmol/L (59.5mg/dL) obtained here

Figure 1. Stepwise progression of management for refractory hypotension in our patient.

4 C. Anderson et al.
Serial electrocardiograms demonstrated normalization of
the QTc interval.
Given the initial need to dedicate available intravenous
access to fluid resuscitation and acute circulatory support,
initiation of the N-acetylcysteine (NAC) infusion for the
acetaminophen ingestion was delayed and eventually
started at 7 h postingestion once central venous access
was obtained. The patient completed the hospital proto-
col of 150 mg/kg NAC run over the first hour, followed
by 50 mg/kg run over 4 h and then 100 mg/kg run over
the next 16 h. Since the patient’s serum acetaminophen
level 24 h postingestion remained elevated at 655 mmol/
L (98.9 mg/mL), a NAC infusion was continued at
12.5 mg/kg/h until 72 h postingestion when the acetamin-
ophen level returned to normal. The patient’s interna-
tional normalized ratio peaked at 1.6, 48 h
postingestion. This returned to normal by 85 h postinges-
tion.
The patient was transferred from the PCCU to the gen-
eral pediatrics floor 3 days after her admission. She re-
mained there for 2 days while the team monitored her
liver and renal function. Once these were found to be
normal and stable the patient was transferred to the pedi-
atric psychiatry service.
DISCUSSION
Prazosin is an antihypertensive medication that acts by
competitively blocking norepinephrine at the site where
it binds to the alpha-1 adrenergic receptor. Although the
toxic effects of prazosin have yet to be fully characterized
in the literature, toxic doses are documented as ranging
from 285 mcg/kg to 1.7 mg/kg on the Material Safety
Data Sheet (6). This is consistent with the dose of
1.45 mg/kg ingested by our patient.
Other reports of intentional alpha-1 antagonist over-
dose include a 75-year-old man with a terazosin overdose
and a 22-year-old man and a 19-year-old woman with
overdoses on doxazosin (7,8). Similar to those cases,
our patient initially presented with somnolence and
hypotension. Hypotension may be easily attributed to
direct drug effect, but the patient’s decreased level of
consciousness may have been multifactorial in nature.
Although somnolence could be explained by the
patient’s circulatory compromise, others have
postulated that changes in consciousness may be related
to toxic effects at the level of central alpha-adrenergic re-
ceptors (8).
Where our case differs, however, is in the severity and
duration of symptoms. Whereas the terazosin and doxa-
zosin intoxications were treated supportively with fluid
boluses, our patient developed profound, refractory hypo-
tension that required multiple pharmacologic supports.
One possible explanation for this is the relatively greater
potency of prazosin when compared with the other med-
ications (8). Satar et al. reported that prazosin was twice
as potent as doxazosin in a weight for weight comparison.
This higher potency may have accounted for the degree of
hypotension experienced by our patient.
Both the 75-year-old man and 19-year-old woman
from previous cases were noted to have resolved the
bulk of their hypotension by 48 h postingestion. While
this time course is similar to the 43 h it took our patient
to be weaned from vasoactive medications, neither of
the other patients required active treatment past the 12-
h mark. Although the half-life of prazosin is documented
as being 2–4 h, it is possible that the longer duration of
effect seen in our patient was related to her multidrug
ingestion. Where the other patients ingested only the
alpha-1 antagonist, the fact that our patient also ingested
acetaminophen could have impaired the ability of the
liver and kidneys to eliminate the circulating prazosin.
Acetaminophen is metabolized primarily through glucur-
onidation with secondary metabolism occurring via the
CYP450 pathway (specifically 3A4, 1A2, 2D6, and
2A6) (9,10). Given that prazosin is also primarily
metabolized through glucuronidation, it is possible that
the pharmacokinetics of both medications were altered
as they competed for clearance, although this
interaction has not been documented in the literature
previously (3). It is also possible that the even mild degree
of liver impairment (international normalized ratio 1.6,
aspartate transaminase 128 units/L, and alanine transam-
inase 169 units/L 48 h postingestion) affected her ability
to clear the prazosin, which is extensively metabolized by
the liver (2).
Another interesting observation regarding our pa-
tient’s hypotension was the general lack of improvement
in blood pressure despite high-dose infusions of epineph-
rine and norepinephrine. While not the definitive cause of
improvement, the patient’s blood pressure improved and
stabilized in temporal association with initiation and
escalation of vasopressin. No previous cases in the litera-
ture have required pharmacologic circulatory support,
and therefore there exists no data with which to compare
the effectiveness of various agents in alpha-1 antagonist
overdose. One possible explanation for the lack of
response to epinephrine and norepinephrine is prazosin’s
mechanism of action (Figure 2). By blocking the alpha-1
receptor, prazosin directly inhibits the ability of epineph-
rine and norepinephrine to cause peripheral vasoconstric-
tion. Vasopressin on the other hand, directly stimulates
vasoconstriction via intracellular calcium release by
binding to the V1 receptor in the systemic circulation,
thereby bypassing the blockade of the alpha-1 receptor
(11). This provides vasopressin a potential mechanism
to increase systemic vascular resistance and raise blood
pressure in the presence of direct alpha blockade.
Refractory Hypotension Caused by Prazosin Overdose
Figure 2. Prazosin’s mechanism of action and its effect on
inotrope choice (Figure credit M. Lim).
Although our patient eventually responded to medical
therapy, the possibility of ECLS use was initially explored.
No literature exists regarding the use of ECLS in the
context of alpha-1 blockade. In the context of refractory
septic shock, however, the use of ECLS has been associated
with favorable outcomes in pediatric patients (survival to
discharge 50–75%) (12,13). Studies have been less
favorable in adults, with recent literature showing a
survival to discharge of 15–22% in patients receiving
ECLS for refractory septic shock (14,15). Several key
differences exist between our patient and patients
suffering from refractory septic shock, including but not
limited to the presence of inflammatory cytokines,
endotoxins, impaired cardiac contractility, and expected
duration of hypotension. Nonetheless, from a physiologic
basis, ECLS could still be considered for cases of
refractory hypotension secondary to alpha-1 blockade. If
pursued, a cannulation strategy aimed at producing high
flows should be planned.
WHY SHOULD AN EMERGENCY PHYSICIAN BE
AWARE OF THIS?
To our knowledge, our report details the first documented
case of alpha-1 antagonist toxicity requiring pharmaco-
logic support. Our patient experienced profound hypoten-
sion refractory to fluid resuscitation as well as high-dose
infusions of epinephrine and norepinephrine before ap-
pearing to respond to a vasopressin infusion. The ability
of vasopressin to bypass the direct alpha blockade makes
5
it an important potential therapeutic option for patients
with alpha-1 antagonist overdose. It is possible that the
coingestion of acetaminophen with prazosin saturated
the ability of the liver to conjugate both medications via
glucuronidation. This may have impaired hepatic clear-
ance of prazosin and contributed to liver damage from
acetaminophen overdose, both of which may explain
the severity of our patient’s symptoms. With the support-
ive treatment described, her hypotension corrected and
her liver function returned to within normal limits. She
was discharged home 6 days after admission with sched-
uled psychiatric follow-up as an outpatient.
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