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About the Authors
Kenneth Lam is a fellow in Geriatrics at the University of Toronto. Ann Leung is a clinical pharmacist in the cardiac ICU at St.
Michaels Hospital. Trevor Jamieson is an assistant professor at the University of Toronto and a member of the Division of General
Internal Medicine at St. Michaels Hospital. Corresponding author kennethk.lam@mail.utoronto.ca
Submitted: April 20, 2017; Accepted: September 19, 2017. Published: June 25, 2018.
A Case of a Dispensing Error causing Iatrogenic
Orthostatic Hypotension
By Kenneth Lam, Ann Leung, and Trevor Jaimeson
Case
A 73-year-old man with a seven-year history of Parkinsons disease
(PD) presented with delirium and increasing falls for three weeks.
Past medical history included tinnitus, gout, depression, and
surgically corrected carotid artery stenosis. He had a one-year
history of orthostatic hypotension from PD for which he was
on a stable dose of midodrine 5mg by mouth in the morning
and noon, and 2.5 mg by mouth in the evening. His PD was
well controlled on levodopa/carbidopa. His other medications
were clopidogrel, paroxetine, and rosuvastatin; there was no
history of steroids. Medications had not changed recently and
were administered from weekly dosettes packaged by a private
caregiver. He denied cognitive changes, visual hallucinations,
bleeding, nausea, vomiting, or polyuria. He had delirium.
On physical examination, profound orthostatic hypotension
was noted; supine, his blood pressure was 191/93 and dropped to
119/75 mmHg when standing; his heart rate rose from 56 to 74
beats per minute. Cardiac and volume status examination were
otherwise normal. Neurological examination showed masked
facies but no other overt signs of PD. Cranial nerves, power,
reflexes, tone, cerebellar testing, and sensation were normal.
Initial bloodwork demonstrated mild hyponatremia
(131 mmol/L), hyperkalemia (5.6 mmol/L), and elevated
creatinine at 219 µmol/L (110 µmol/L one year prior). He had
no anemia. Urine output was normal and bladder scan did not
show retention. Computed tomography of the head showed mild
cortical atrophy, and hip radiographs were negative for fracture.
There were no signs of hyperpigmentation and 07:00 cortisol
was 670 nmol/L (normal 193-690 nmol/L).
Initial management of the patient involved intravenous
fluids and weaning paroxetine as a possible contributor to his
orthostatic hypotension. In the process of collecting a best
possible medication history (BPMH), the pharmacist reviewed
the dosette prepared by the caregiver. The pharmacist noted that
the midodrine 2.5-mg tablets were stamped with a “5” instead
of “2.5”. The caregiver remarked that the midodrine tablets had
changed from round white pills to diamond-shaped pills when
last dispensed 3 weeks ago. When the pharmacist reviewed an
online database, she found that the patient had been supplied
with 5-mg tablets of amiloride, a potassium sparing diuretic,
instead of midodrine. The patient had been taking a total of
25 mg of amiloride daily, above the maximum recommended
daily dose of 20 mg.
According to the patients pill bottle, his prescription had been
for midodrine (Figure 1). We notified the community pharmacy
and discovered that a dispensing error had occurred: amiloride
had mistakenly been supplied instead of midodrine, having
been shelved next to midodrine according to its brand name
(Midamor®). This pharmacy did not use bar-code technology.
The offending agent was stopped, and his orthostatic
hypotension, electrolyte abnormalities and delirium resolved
within two days. The patient was discharged in stable condition.
To avoid future dispensing errors, the community pharmacy
separated the two look-alike medications, held staff meetings to
discuss the error, and issued a reminder for pharmacy technicians
and pharmacists to both check the unique drug identification
number and document this step on the dispensing record.
Discussion
By consensus, the standard definition of orthostatic hypotension
is a sustained reduction of systolic blood pressure of at least
20 mmHg or of diastolic blood pressure of 10 mmHg within 3
Canadian Journal of General Internal Medicine
Volume 13, Issue 2, 2018 47
Case Report
Figure 1. Image of the patient’s pill bottle, labeled midodrine 2.5 mg, and the
diamond-shaped pills inside, (top inset) midodrine pills for comparison, (bottom
inset) diamond-shaped Midamor® pills.
minutes of standing, with or without symptoms. In 2011, the
definition was revised to include several distinct variants and
related conditions (Table 1).
1
Orthostatic hypotension is a common problem in the elderly.
A longitudinal observational study of 5037 healthy adults aged
50 and over in Ireland found orthostatic hypotension occurred
in 4.2% of patients aged 50–59 and 18.5% of patients over the age
of 80.
2
These results are consistent with older observational data
Table 1. Definitions of Disorders of Orthostatic Tolerance
Disorder Definition
Orthostatic hypotension
>20 mmHg drop in SBP or >10 mmHg drop in DBP within 3 minutes of standing, with or
without symptoms
Variants
Initial orthostatic hypotension >40 mmHg drop in SBP or >20 mmHg drop in DBP within 15 seconds
Delayed orthostatic hypotension Symptoms persisting beyond 3 minutes
Related disorders of orthostatic tolerance
Neurally mediated syncope
Transient loss of consciousness triggered by a change in autonomic activity (e.g., cough,
swallowing, micturition)
Postural tachycardia syndrome
Increase of >30 beats per minute within 10 minutes of standing without orthostatic
hypotension
* >40 beats per minute for those aged 12–19
DBP = diastolic blood pressure; SBP = systolic blood pressure (SBP).
reporting a prevalence of symptomatic orthostatic hypotension
ranging between 5 and 30%.
3
Postural dizziness is not a hallmark
symptom; neurologic symptoms more closely associated with
orthostatic hypotension are ataxia, vertigo, dizziness and falls.
The causes of orthostatic hypotension are varied (Table
2),
5
and an estimated 38% of chronic cases have no identifiable
cause. In this case, the relatively blunted heart rate response
despite a dramatic fall in blood pressure suggested an element
of autonomic dysfunction from the patients PD. His acute
renal failure with hyperkalemia and hyponatremia were more
suggestive of adrenal insufficiency once urinary retention had
been ruled out. Primary adrenal failure, though, was unlikely at
his age and no conventional secondary etiologies were present;
his morning cortisol was also well within the normal range.
Volume depletion was also unlikely as he lacked polyuria and
his symptoms were not fluid responsive.
The management of orthostatic hypotension involves non-
pharmacologic and pharmacologic strategies, with an aim to
improve symptoms and function (Table 3). Deprescribing potential
offending agents, adequate hydration, and salt intake, and cautious
transitions to a standing position are initial steps. If these fail,
compression stockings, abdominal binders, and raising the head
of the bed are the most effective non-pharmacological treatments
based on systematic review.
6
First-line pharmacotherapy includes
fludrocortisone, a mineralocorticoid which promotes fluid
retention and increases intravascular volume, and midodrine,
a peripherally acting alpha-1 agonist causing vasoconstriction.
7
Fludrocortisone may cause hypokalemia, fluid overload, and worsen
Canadian Journal of General Internal Medicine
48 Volume 13, Issue 2, 2018
A C a s e o f a D i s p e n s i n g E r r o r C a u s i n g I a t r o g e n i c O r t h o s t a t i c H y p o t e n s i on
n
Table 2. Common Causes of Orthostatic Hypotension
(n < 50), with no trial exceeding 200 participants, and symptoms
are not always included as an outcome of interest.
6
More recently,
droxidopa, a norepinephrine precursor, has been approved for
use in orthostatic hypotension associated with PD and other
Parkinson-plus syndromes, but is not yet available in Canada.
Our patients chronic orthostatic hypotension was appropriately
managed with midodrine, but he suffered an adverse drug event
when he was dispensed amiloride instead. Adverse drug events
are estimated to be the cause of 6.5% of hospital admissions.
8
Amiloride treats hypertension by blocking the epithelial sodium
channel in the renal collecting duct. Orthostatic hypotension
is a recognized side effect. For new admissions to hospital,
screening for adverse drug events involves conducting a BPMH.
Interviewing patients and caregivers to ascertain actual use of
medications, including recent changes, rather than relying solely
on medication lists is critical. As in this case, pharmacists have
an established role in conducting medication reconciliation/
BPMH,
9
yet it is still not usual practice to inspect and confirm the
identity of the actual pills in a dosette. Attention to detail by our
pharmacist, coupled with a keenly observant caregiver, allowed
us to make a diagnosis that would otherwise have been missed.
The community pharmacy completed root-cause analysis
internally and implemented changes to prevent similar errors
from occurring in the future. The dispensing process typically
involves multiple checks to ensure faithful delivery of the right drug
at the right dose to the right patient with the right instructions.
Dispensing errors are rarely the cause of adverse drug events;
error rates vary by setting, error definition and methodology
and roughly fall between 0.02 to 5% of dispensed items
10
. One
outlier study, which used covert patients prescribed warfarin,
carbamazepine or theophylline (all medications with baseline
high rates of dispensing error) reported an error rate of 24%, but
only 4% were clinically significant. A lack of automation (e.g.,
bar-coding), poor lighting, interruptions, and heavy workloads
likely increase the incidence of dispensing errors,
10
as do look-
alike drug names. Interestingly, midodrine and Midamor® do
not appear on lists of look-alike drugs released by the FDA and
Institute of Safe Medication Practices despite having similar
dosages.
This case illustrates how a dispensing error can be an
occult cause of an adverse drug event and emphasizes the value
of working in interdisciplinary teams as medicine becomes
increasingly complex. Fortunately, this error was caught and the
patient did not suffer any lasting sequelae. The feedback to the
community pharmacy was well received and led to meaningful
process change, highlight the importance of a culture of openly
acknowledging, investigating and mitigating/preventing error as
we strive for continuous quality improvement in patient safety
in the health care system.
congestive heart failure. Midodrine has side effects of pruritis,
paresthesias, piloerection and urinary retention. Both may cause
supine hypertension. Second-line agents include pyridostigmine
and octreotide. There is very limited evidence of the efficacy for
any of these treatments as most trials of interventions are small
C a n a d i a n J o u r n a l o f G e n e r a l I n t e r n a l M e d i c i n e V o l u m e 1 3 , I s s u e 2 , 2 0 1 8 49
Acute Causes of Orthostatic Hypotension
Hypovolemia (e.g., dehydration, bleeding, vomiting, diarrhea)
Cardiac (e.g., arrhythmia, myocardial infarction, valvular incompetence)
Endocrine (e.g., adrenal insufficiency, hypoaldosteronism)
Medication side effects
Antihypertensives (alpha blockers, RAAS blockers, beta blockers, and
diuretics)
Antipsychotics (first generation antipsychotics, clozapine,
risperidone, quetiapine)
Antidepressants (tricyclic antidepressants, SNRIs, MAOIs and SSRIs)
Anticholinergics (antispasmodics)
Marijuana
Chronic Causes of Orthostatic Hypotension
Primary autonomic dysfunction
Parkinson’s disease and other similar conditions (e.g., Lewy body
dementia, multi-system atrophy)
Pure autonomic failure (Bradbury-Eggleston syndrome)
Secondary autonomic failure
Diabetes mellitus
Syphilis
B
12
deficiency
Amyloidosis
Paraneoplastic neuropathy
Alcoholic neuropathy
Medication side effect (see above list)
MAOI = monoamine oxidase inhibitors; RAAS = renin–angiotensin–aldosterone system;
SNRI = serotonin and norepinephrine reuptake inhibitors; SSRI = selective serotonin reuptake
inhibitors.
(n < 50), with no trial exceeding 200 participants, and
symptoms
are not always included as an outcome of interest.
6
More recently,
droxidopa, a norepinephrine precursor, has
been approved for
use in orthostatic hypotension associated
with PD and other
Parkinson-plus syndromes, but is not yet
available in Canada.
L a m e t a l
(n < 50), with no trial exceeding 200 participants, and symptoms
are
not always included as an outcome of interest.
6
More recently,
droxidopa, a norepinephrine precursor, has been approved for
use
in orthostatic hypotension associated with PD and other
Parkinson-plus syndromes, but is not yet available in Canada.
Our patient’s chronic orthostatic hypotension was appropriately
managed with midodrine, but he suffered an adverse drug event
when he was dispensed amiloride instead. Adverse drug events are
estimated to be the cause of 6.5% of hospital admissions.
8
Amiloride
treats hypertension by blocking the epithelial sodium
channel in the
renal collecting duct. Orthostatic hypotension
is a recognized side
effect. For new admissions to hospital,
screening for adverse drug
events involves conducting a BPMH.
Interviewing patients and
caregivers to ascertain actual use of
medications, including recent
changes, rather than relying solely
on medication lists is critical. As
in this case, pharmacists have
an established role in conducting
medication reconciliation/
BPMH,
9
yet it is still not usual practice to
inspect and confirm the
identity of the actual pills in a dosette.
Attention to detail by our
pharmacist, coupled with a keenly
observant caregiver, allowed
us to make a diagnosis that would
otherwise have been missed.
The community pharmacy completed root-cause analysis
internally and implemented changes to prevent similar errors from
occurring in the future. The dispensing process typically
involves
multiple checks to ensure faithful delivery of the right drug
at the right
dose to the right patient with the right instructions. Dispensing
errors are rarely the cause of adverse drug events;
error rates vary
by setting, error definition and methodology
and roughly fall
between 0.02 to 5% of dispensed items
10
. One outlier study, which
used covert patients prescribed warfarin, carbamazepine or
theophylline (all medications with baseline
high rates of dispensing
error) reported an error rate of 24%, but
only 4% were clinically
significant. A lack of automation (e.g.,
bar-coding), poor lighting,
interruptions, and heavy workloads
likely increase the incidence of
dispensing errors,
10
as do look-alike drug names. Interestingly,
midodrine and Midamor® do not appear on lists of look-alike drugs
released by the FDA and
Institute of Safe Medication Practices
despite having similar
dosages.
This case illustrates how a
dispensing error can be an
occult cause of an adverse drug event
and emphasizes the value
of working in interdisciplinary teams as
medicine becomes
increasingly complex. Fortunately, this error
was caught and the
patient did not suffer any lasting sequelae. The
feedback to the community pharmacy was well received and led to
meaningful process change, highlight the importance of a culture of
openly
acknowledging, investigating and mitigating/preventing error
as
we strive for continuous quality improvement in patient safety in
the health care system.
T
Table 3. Non-pharmacologic and Pharmacologic Strategies For Treating
Orthostatic Hypotension
Non-pharmacologic Srategies
Deprescribe offending medications
Increase fluid and salt intake
Caution with changing position from supine to standing
Compression stockings (40–60 mmHg to ankles, 30–40 mmHg to hips)
Abdominal binders (20–30 mmHg)
Raising head of bed (by at least 6 inches)
Pharmacologic strategies
Fludrocortisone 0.1–0.3 mg PO daily
Midodrine 2.5–10 mg PO PRN or up to 3 times daily (during hours when
awake and upright)
Pyridostigmine 30–60 mg PO PRN
Octreotide 12.5–25 mcg SC PRN
Droxidopa 100 mg PO TID, up to 1800 mg max daily dose
Disclosure
The authors report no competing interests and received no funds
for the creation of this article.
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8. Pirmohamed M, James S, Meakin S, et al. Adverse drug reactions as cause
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9. Splawski J, Minger H. Value of the Pharmacist in the Medication
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Canadian Journal of General Internal Medicine
50 Volume 13, Issue 2, 2018
A Case o f a D i s p e n s i n g E r r o r C a u s i n g I a t r o g e n i c O r t h o s t a t i c H y p o t e n s i o n