Introduction:
Benzodiazepines are a class of sedative-hypnotic drugs often used by
people suffering from anxiety, sleep disorders, stress reactions, panic
disorders, obsessive-compulsive disorders, and mania due to their
anticonvulsant, anxiolytic, and muscle relaxant properties [1,2].
Between the year 1996 to 2013, the percentage of US adults filling
benzodiazepine prescriptions rose from 8.1 million to 13.5 million (67%
increase), and the cumulative quantity of benzodiazepines served over
the years surged by 140% [3]. However, this rise in treatment using
benzodiazepines heavily contributed to an increase in the number of
cases of benzodiazepine overdose-related deaths, from 0.58 to 3.07 per
100,000 adults. This value soon reached a plateau in early 2010 but
continued to increase among the elderly and the Hispanic and African
American communities [3]. It is worth noting that nearly 75% of
these deaths were not caused by benzodiazepines alone but by the added
effects of alcohol, opioids, or amphetamines [3].
In mention to its relation with age, the use and misuse of
benzodiazepines vary, with individuals between the ages of 50 to 64
years having the highest prescription-based use, whereas young adults of
ages 18 to 25 years presented with the highest statistics for
non-prescription based use, highlighting the misuse and abuse of
benzodiazepines, according to a study conducted in the United States
[4].
Overdoses induced by benzodiazepines rarely present as an emergency and
are often aggravated further by additional ingestion of other drugs
[5]. In people with long-term benzodiazepine use, immediate
retirement from the drug may induce a severe withdrawal syndrome,
resulting in anxiety, confusion, sleep disorders, and in extreme cases,
seizures [6]. The most widely used benzodiazepine, Alprazolam, has
much greater side effects from withdrawal, including mania, psychosis,
delirium, and hyperadrenergic states [7]. Furthermore, tapering of
benzodiazepines has been linked to Takotsubo cardiomyopathy [8].
This article reports a case regarding a Pakistani patient with no
previous history of drug abuse that voluntarily overdosed on
benzodiazepines (Alprazolam) alone and was later diagnosed with
hypoxic-ischemic (anoxic) encephalopathy.
Case Presentation:
A 32-year-old Pakistani male was presented to the emergency department
in an unconscious and gasping condition. His mother had found him in an
unresponsive, comatose state. The patient had a history of epilepsy,
anxiety, and depression. The remainder of his past medical history was
unremarkable, and any admissions made during childhood had no recrudesce
in adulthood.
At the emergency department, the patient suffered multiple seizure
episodes, and remained unconscious, maintaining a GCS of 3/15. Upon
physical examination, unresponsive bilateral pinpoint pupils were noted;
the neck of the patient was found to be supple, and the bilateral
plantar reflexes were normal, suggesting active involuntary movement.
His abdomen was soft and nontender, and his chest was found to be
unremarkable.
On the first day of admission, a complete blood count revealed a low
hemoglobin count of 12.9 g/dl, leukocytosis (white blood cell count of
14.0 x 10^9/L), neutrophilia (neutrophil at 93%), hyperglycemia
(glucose concentration at 93 mg/dl) and hyperproteinemia (proteins: 66.1
mg/dl), while displaying a minor decrease in the hematocrit levels. The
test for plasma lactate levels was normal, resting at 15.5; however,
lactate dehydrogenase levels produced a low result of 21 U/L (the normal
range is 135 – 225 U/L). The above-mentioned laboratory investigations
have been summarized in Table 1. Arterial blood gases revealed high
anion gap metabolic acidosis. On the second day of admission, a urine
test revealed a positive result for benzodiazepine overdose
(>200 ng/ml) while testing negative for amphetamines,
cannabinoids, barbiturates, and cocaine metabolites, as mentioned in
Table 2. Enzyme-linked immunosorbent assay for human immunodeficiency
virus (HIV) antibodies and tests for the presence of Hepatitis B and C
virus revealed negative results. The gram stain showed no organisms. On
the fifth day, a test for C-reactive protein (CRP) revealed a CRP of
15.62 mg/l (normal range is less than 6), suggesting the presence of an
inflammation reaction. His respiratory examination displayed acute
hypercapnic respiratory failure (type II).
A CT scan, which was also conducted on the first day, revealed no
intraparenchymal hemorrhage, cerebral edema, or midline shift. Grey and
white matter differentiation were intact, and the basal ganglia and
thalami showed normal density. This was viewed through multiple axial
images obtained from the base up to the vertex of the skull without
intravascular contrast.
Initial treatment for hypercapnic respiratory failure and seizures was
initiated, as these were the presenting symptoms when our patient had
arrived in the ER. He was intubated, aided by a pressure-synchronized
intermittent mandatory ventilation (P-SIMV) mode ventilator, and
transferred to the ICU for intensive care and monitoring. The patient
was administered anti-inflammatory glucocorticoids, intravenous lactam
antibiotics (meropenem, and tazobactam with piperacillin), levetiracetam
for the treatment of seizures, and half normal saline with 2 amps of KCL
at 75 ml/hr via a nasogastric tube as an immediate course of
treatment.
On the third day, the patient had self-extubated but maintained an
oxygen saturation of 99% and was supplied with 5 L/min oxygen via
facemask at a respiratory rate of 22/min. The patient’s GCS topped
15/15, and reintubation was considered unnecessary. The patient was
drowsy, but was physically responsive and fully capable of conversing
with the consultant. On this day the patient was diagnosed with
benzodiazepine poisoning. The patient admitted to intentionally
overdosing on Alprazolam, a type of benzodiazepine, with suicidal
intentions, despite not having any history of using the drug or any
other illicit substances previously. He was later diagnosed with major
depressive disorder by the neurologist that overlooked the case.
Further in regards to the patient’s condition, anion gaps returned to
normal, and no further seizures occurred. The patient remained fatigued,
but mobilization out of bed was prescribed. The patient had a
physiotherapy session in which chest physiotherapy was conducted. The
patient was kept in an ICU setting for another day before being
transferred to a normal monitoring setup.
In regards to the radiological tests taken following the initial CT
scan, an echocardiography, electroencephalography (EEG) and a general
abdomen ultrasound were taken on the third day. Echocardiography
revealed atypical septal motion and an ejection fraction of 55%;
however, all other findings were normal, with an absence of thrombi or
pericardial effusions. EEG reported fast beta activity of 15-18 Hz in
the background rhythm and muscle stiffness due to ventilation; however,
photic stimulation was normal, and no focal or generalized epileptic
discharges were noted. Since idiopathic epilepsy appears normal on an
interictal EEG, the technician had advised that a diagnosis be made
after clinical correlation. The abdominal ultrasound showed a slightly
altered texture with raised echogenicity of the liver; however, the rest
of the abdomen was unremarkable. On the fifth and sixth days of
admission, a brain MRV/DWI and MRA were conducted to accurately view the
condition of the brain. MRA revealed a comparatively attenuated right
vertebral artery with normal hyperintensity within the right and left
vertebral, basilar, and bilateral posterior cerebral arteries. No
evidence of stenosis or abnormal dilation of the hyperintense arteries
was seen. The MRV presented evidence of bilateral symmetrical abnormal
signal intensity areas seen in the basal ganglia, predominantly in the
globus pallidus, which appears hyperintense on T2/FLAIR images while
showing restriction on the DWI images. The superior sagittal, inferior
sagittal, transverse, and straight sinuses appeared unremarkable, and no
venous segment filling was detected to show signs of thrombosis. Another
MRV, which was taken 24 hours after the first one, presented the Dural
sinuses as normal. The MRI, MRA, and MRV imaging, with DWI protocol,
demonstrates ischemic hypoxic insult involving bilateral globus
pallidus, which was later understood to be linked to the benzodiazepine
intoxication.
Upon gaining consciousness, the patient admitted to intentionally
overdosing on Alprazolam with suicidal intentions, despite not having
any history of using the drug or any other illicit substances
previously. He was later diagnosed with major depressive disorder by the
neurologist that overlooked the case.
On the final day, the patient possessed the following vitals: blood
pressure of 130/80, a pulse of 76/min, respiratory rate of 21/min, and
oxygen saturation of 99% in the absence of oxygen support. The abdomen,
respiratory and cardiovascular examinations were completely normal. The
patient had fully gained consciousness, was well-oriented in time,
place, and person, and held a GCS of 15/15, with an attenuated right
vertebral artery under CNS findings. He was discharged after staying at
the hospital for 6 days and was instructed to return for a follow-up
after 1 week.
During the follow-up, the patient presented with no cognitive
deterioration and was completely responsive and healthy. The patient
presented with no personality changes and sustained a GCS of 15/15.