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.