Discussion:
The syndrome of hypoxic-ischemic encephalopathy (HIE), also referred to
as anoxic encephalopathy, is often caused by brain injury due to
asphyxia; it can be divided into acute and subacute classes. The patient
discussed in this report was admitted due to an acute case of
intentional benzodiazepine poisoning, presenting in a comatose state
with type II acute respiratory failure, hypotension, metabolic acidosis,
seizures, and developed hypoxic-ischemic encephalopathy (HIE) secondary
to benzodiazepine poisoning. In most cases, HIE is seen in adults who
are patients of cardiac arrest.
Common symptoms of benzodiazepine overdose include ataxia and
unresponsiveness, and a physical examination often reveals nystagmus,
respiratory depression, hypotension, and coma. These symptoms are seen
as a result of central nervous system (CNS) depression due to the
agonist action of benzodiazepines on GABA-A receptors, causing an influx
of chloride ions into the neuron and facilitating hyperpolarization.
Due to the hypercapnic state of the patient, possessing a PaCO2 of more
than 50 mmHg, acute respiratory failure was established and is followed
by hypoxemia if air at atmospheric pressure is breathed in. Hence
patients often require intubation and ventilation. Due to the necessity
for intubation and ventilation, the patient was supplied with oxygen via
a P-SIMV mode ventilator, which aided in maintaining a set number of
breaths, allowing for the reversal of hypercapnia and restoring PaCO2
and pH levels to normal.
MRI findings in our case presented abnormal bilateral signal intensity
areas, particularly in the globus pallidus of the basal ganglia, and
attenuated cerebral blood flow in the right vertebral artery. No other
forms of damage were noted. Such findings align with MRI assessments of
previous adult hypoxic-ischemic brain injury cases. As stated in the
literature, increased signal intensities in the basal ganglia,
cerebellar hemispheres, or the peri Rolandic and occipital cortices of
the cerebral cortex are seen in DWI taken in the initial 24 hours of the
injury [9]. Certain studies have also mentioned that regions of the
thalami, hippocampi, or brain stem may also be involved [9,10,11].
The reason why such specific regions of the brain are involved in the
damage is because hypoxic-ischemic injury particularly attacks the
sensitive grey matter of the brain, which is abundant in the cerebral
cortex, cerebellum, basal ganglia, thalami, and hippocampi [9,12].
Due to the abundance of glutamate receptors on the post-synaptic
dendrites, these regions are particularly susceptible to glutamate
excitotoxicity, providing an explanation for the pathophysiology behind
grey matter injury. When placed concerning age groups, cerebellar damage
is seen more commonly among the elderly, despite its presence in
neonates as well. This is due to the presence of immature Purkinje
cells, which protect the neurons of the cerebellar cortex from ischemic
damage [13].
CT findings of hypoxic-ischemic brain injury seen in adults generally
present with edema formation in spaces containing cerebrospinal fluid,
decreased attenuation of the cortical grey matter, and reduced to
complete loss of the grey-to-white matter differentiation [12]. None
of these findings were seen in our patient. This may be due to the
underlying fact that our patient is, firstly, of a younger age group
than patients that showed such symptoms, and secondly, the extent of the
injury was relatively mild. Adults who suffer a severe hypoxic injury
often display symptoms of reversal sign and white cerebellum sign
[11]. The reversal sign presents with hypoattenuation of white
matter and diffuse cortical swelling. In contrast, the white cerebellum
sign presents with elevated attenuation of the brain stem and cerebellum
compared to that of the cerebral cortex due to the posterior shunting of
blood following anoxia; the prognosis for both, the reversal sign and
the white cerebellum sign are poor [14]. Our patient presented with
neither of these findings on his CT scan, suggesting that his level of
injury was far from severe.
It is well understood that the main treatment method for benzodiazepine
poisoning is supportive care and management, which is necessary as
mortality second to sedative-hypnotic overdose is commonly seen due to
cardiorespiratory arrest. For effective systemic maintenance,
immunoassay screening is paramount, along with the test for arterial
blood gas (ABG), electrocardiogram (ECG), blood glucose level
(especially if the patient is in an altered state of mind), serum
electrolytes, ethanol concentrations, and acetaminophen levels. Upon
conducting a urine analysis, the patient presented positive for
benzodiazepines alone, with an absence of acetaminophen and ethanol. As
previously stated, benzodiazepines do not present fatal symptoms on
their own, however in the case of our patient, HIE secondary to
poisoning was diagnosed, revealing a new understanding of the various
toxic presentations of benzodiazepine overdose.
The patient was also tested for HIV antibodies and the presence of HBV
and HCV, which all revealed negative results. Along with being used as
an anticonvulsant, benzodiazepines are commonly abused and used for
recreational purposes. Patients brought in with benzodiazepine overdose
are screened for HIV and HCV to verify if the patient presents
’risk-taking behaviors’ and often indulges in the misuse of drugs,
unsafe injection usage, and unprotected sexual behaviors [16,17].
According to a study conducted in 2015, Because the mentioned patient
presented a negative result for the HIV antibodies, and HBV and HCV
tests, it can be assumed that the patient is not a frequent drug user,
and even if so, does not part-take in acts of misuse or drug abuse.
Further highlighting the aspect of treatment, single-dose activated
charcoal, and orogastric lavage are known treatment options when
considering benzodiazepine poisoning; however, these methods are greatly
discouraged and not considered as first-line treatment as the extent of
risk outweighs their benefits. Additionally, flumazenil is an
FDA-approved benzodiazepine antagonist which is used to reverse the
sedative action of benzodiazepines under conscious sedation and general
anesthesia [18,19]. It acts by competitively inhibiting the binding
of benzodiazepines to the benzodiazepine receptor on the GABA receptor
complex, and it is known to reverse the effects of sedation, antagonize
memory loss, and recover psychomotor activity. However, there are great
contraindications and adverse effects linked to flumazenil, including
hypertension, bradycardia, nausea, hypersensitivity reactions, hearing
loss, panic attacks, psychotic disorders, diaphoresis, seizures, and
arrhythmias [20]. Furthermore, the patient requires extensive
monitoring after administration in case of respiratory depression,
benzodiazepine withdrawal, and other residual effects, especially for
the first 2 hours [21]. Due to this reason, flumazenil is not
commonly used to treat benzodiazepine overdose. Due to self-extubation
and the various adverse effects listed above, the patient mentioned in
this report was not given flumazenil. His poisoning was entirely treated
by monitoring and managing ABGs, electrolytes, and seizures until the
patient recovered.
Pathophysiology of hypoxic-ischemic encephalopathy (HIE)
The syndrome of hypoxic-ischemic encephalopathy (HIE), also referred to
as anoxic encephalopathy, is often caused by brain injury due to
asphyxia; it can be divided into acute and subacute classes. HIE can be
caused by various conditions or insults, including cardiac arrest,
hypoxic arrest, and carbon monoxide (CO) poisoning. In this section, the
pathophysiology of HIE due to a purely hypoxic event will be discussed,
and how it applies to the patient involved in this report.
Due to its rapid decline in activity and response as a result of poor
oxygen supply, metabolic instabilities, and energy indigence, the brain
parenchyma is seen as vulnerable to any sort of injury or insult. It
begins with the blockage of blood flow to the brain parenchyma via the
cerebral arteries, which is generally a result of poisoning (drug
overdose or carbon monoxide poisoning), vascular injury, and in certain
cases, cardiac arrest [22].
Generally, encephalopathy is often reworded as HIE following an event of
resuscitation. However, HIE can be further divided into brain injury
following cardiac arrest, brain injury due to hypoxic arrest, and brain
injury following carbon monoxide intoxication; each subsets’
pathogenesis and etiology are relatively different. Furthermore, the
extent of hypoxia is determined by the duration and type of
insult/injury; cardiac arrest is a common cause of global hypoxia,
whereas vascular injury commonly presents a localized extent to the
hypoxia [23].
In the case of a purely hypoxic event, severe brain damage is rare,
especially when global circulation is maintained, but the difference in
neuronal function and microscopic damage is commonly seen. It is due to
this reason that patients presented in the emergency department
following a pure hypoxic event are unresponsive or in a comatose state.
Obstruction of the airway and intoxication/overdose (due to drugs or
toxins) are common causes of a purely hypoxic syndrome. Partial
pressures of carbon dioxide in the blood increase, decreasing the pH as
a consequence of hypoxia, inducing acidosis. Vasodilation is seen due to
cerebral homeostatic autoregulation, increasing the flow of blood to
continually supply the neurons with glucose and other nutrients while
removing the toxin or drug and their metabolites from the surrounding
tissue fluid. In addition, astrocytic swelling of glial cells due to
increased acidosis and hypercapnia is also a common phenomenon that
leads to brain edema [24]. A hypoxic attack generally acts on the
synapse of neurons, creating a deficit of GABA molecules, due to which
seizures and myoclonus often follow.
Global brain ischemia is also commonly seen due to the shift from
aerobic to anaerobic respiration, leading to the fall of ATP levels in
the cerebral blood and an accumulation of lactic acid. This leads to
membrane damage. Furthermore, an influx of calcium ions into the
postsynaptic neurons leads to further membrane damage, activation of
various cytotoxic processes, and triggering the membrane phospholipase,
producing oxygen free radicals. Mitochondrial membrane damage may
insure, causing the leakage of cytochrome enzymes. The extent of ATP
depletion is a contributing factor to the death of the cell; if the
depletion is grand, the cell often dies via necrosis; however, if the
neurons survive the initial hypoxic insult and the extent of energy
depletion is far less, apoptosis ensues after a certain period.
Another syndrome under HIE is delayed post-hypoxic leukoencephalopathy;
an uncommon condition that develops in patients exposed to hypoxia for a
considerable period, inciting severe damage to the brain cortical and
deep white matter [25,26]. When presented, patients are generally
comatose but soon recover and reestablish neuronal function and maintain
normal cognitive behavior, however these later decline, following a
period of approximately 10 days, after which the patient shows poor
motor function and a sudden change in personality (agitated, confused
and easily irritable). Tests reveal extensive demyelination of neurons
within the white matter while maintaining sufficient cerebral blood
flow, leading to leukoencephalopathy. Edema formation during
demyelination is uncommon as it subsides naturally 2 to 4 days following
the initial hypoxic insult [25]. The true pathogenesis of
demyelination is not yet understood and requires further attention. In
the case of our patient, no personality or cognitive changes were noted
upon follow-up, suggesting that the patient did not suffer from
post-anoxic leukoencephalopathy following the initial hypoxic insult.
Mechanism of action of benzodiazepines
The mechanism of action of benzodiazepines and the extent of their
effects have been well studied. Benzodiazepines belong to a class of
drugs that act agonistically on the gamma-aminobutyric acid (GABA)
receptors, specifically the GABA-A receptors, by acting on the
benzodiazepine receptors, which are formed by the extracellular portions
of the alpha and gamma subunits of the GABA-A receptors.
Benzodiazepines are known agonists of the gamma-aminobutyric acid (GABA)
receptors, specifically the GABA-A receptors. They bind to the
benzodiazepine binding sites formed by the alpha and gamma subunits of
the GABA-A receptors (ligand-gated ion channels), causing a
conformational change in the central pore structure of the GABA-A
receptors, channeling an influx of chloride ions in the neuron,
resulting in hyperpolarization of the neuron and generalized depression
of the central nervous system (CNS) [27]. An inhibitory effect is
seen due to a decrease in the resting potential of the neuron because of
the increased inclusion of a negative charge. It is worth noting that
benzodiazepines are nearly non-functional in the absence of GABA
molecules and require the presence of GABA on the GABA-A receptors to
initiate the increased influx of chloride ions [28].
Decreased concentrations of GABA between neurons results in an increased
occurrence of psychiatric conditions such as anxiety, schizophrenia,
autism spectrum disorder, and major depressive disorder. At a level of
clinical significance, GABA-A receptor agonists are not considered to be
the first line of treatment for psychiatric disorders linked to GABA
suppression due to their addictive properties and major consequences of
overdose (intentional or accidental) [29,30].
A study conducted by Schur et al. investigated the relation between
known patients of psychiatric illnesses and altered brain GABA levels
measured using proton magnetic resonance spectroscopy (1H-MRS) across 40
(N=1,591), involving cases of bipolar disorder, major depressive
disorder, schizophrenia, autism spectrum disorder, panic disorder,
posttraumatic stress syndrome, and attention-deficit/hyperactivity
disorder. It was concluded that patients with autism spectrum disorder
and major depressive disorder were the only groups to show visible
depression in brain GABA levels. Patients with autism spectrum disorder
(p-value: 0.001) and major depressive disorder who are actively
depressed (p-value: 0.005) were statistically significant and showed
lower brain GABA levels when compared to healthy controls, whereas
remitted patients of major depressive disorder showed no significance
(p-value: 0.310) [30].
The link to Suicide
The relation between psychiatric illnesses and decreased levels of
brain GABA is an underlying cause for the prevalent usage of
benzodiazepines as a mode of treatment; however, due to their sedative
nature and ease in accessibility, the use of benzodiazepines is often
abused for self-pleasure leading to addiction or suicide. The patient
mentioned in this article stated that he had intentionally overdosed on
benzodiazepines Alprazolam due to unemployment and familial pressures.
Statistics regarding the total number of deaths due to suicide,
particularly suicide by poisoning, are unreliable because Pakistan, a
developing Muslim country, is scarce and neither compiles such reports
nor publishes them annually [31]. Approximately 19,331 deaths were
estimated by the WHO in 2019, with acts of self-harm possessing an
elevation of approximately 10 to 20 times the estimated number of deaths
[32]. Furthermore, the act of suicide or any other form of self-harm
is disparaged and denounced religiously and considered illegal in the
country, such that survivors can be prosecuted in a court of law. In
Pakistan, all suspected cases of suicide or parasuicide are titled
”medicolegal” and must be investigated by medicolegal officers (MLOs)
that are stationed at medicolegal centers (MLCs) within all
government-funded hospitals. In contrast, privately funded hospitals are
given leverage as to whether they wish to report such cases, providing a
reason why most cases of attempted suicide are predominantly found in
privately funded hospitals.
A study conducted by Khan et al. investigated the use of
benzodiazepines, such as diazepam, among attempted suicide cases over
the course of 5 years. Results showed that from the total of 447
patients, 73% of the cases were through the overdose of
over-the-counter medication. Of the total 274 patients who overdosed on
benzodiazepines (69% used diazepam), 91% overdosed on benzodiazepines
alone, whereas only 9% used it in concomitance with other drugs or
physical methods. 80% of patients that overdosed on benzodiazepines
showed no signs of complication and were discharged within 3 days. None
of these cases led to mortality [33]. This further verifies that
overdose on benzodiazepines alone is rarely fatal, and most studies show
that if mortality has been exhibited, it is due to the overdose of
benzodiazepines in concurrence with other drugs such as opioids,
alcohol, and amphetamines.
Conclusion:
The symptoms and adverse effects regarding benzodiazepine poisoning
alone are poorly understood and require further investigation as to what
symptoms present upon immediate action of the drug and the progression
of symptoms over the course of time. Furthermore, it is worth
investigating the extent of acute benzodiazepine overdose-induced anoxia
on the various sections of the brain, particularly the gray matter, and
the extent of behavioral deterioration seen over a period following the
initial hypoxic injury.