You have a new patient!
A 21-year-old female with no significant past medical history was brought to the emergency department by ambulance after her friends found her unresponsive in her bedroom. According to her friends, she had been experiencing significant anxiety related to an upcoming exam. The only notable finding in her room was a half-empty bottle of alcohol.
On arrival, the patient was arousable only to painful stimuli. Despite slurred speech, she admitted to taking “a few pills” provided by a friend to help her relax. Physical examination revealed nystagmus, but a complete neurological assessment was limited as the patient was not following commands. Her condition rapidly deteriorated, and she became obtunded with a Glasgow Coma Scale (GCS) score of 3/15. The vital signs are as follows: Respiratory rate: 10 breaths per minute, oxygen saturation (SpO₂): 92%, blood pressure: 60/45 mmHg, heart rate: 48 beats per minute, temperature: 36.1°C, and blood glucose at triage: 110 mg/dL.
How would you proceed with further evaluation for this patient?
What do you need to know?
Benzodiazepines are modulators of gamma-aminobutyric acid-A (GABA-A) receptors, which mediate the main inhibitory neurotransmitter in the central nervous system (CNS). By binding to GABA-A receptors, benzodiazepines indirectly potentiate the inhibitory action of GABA by increasing its affinity for the receptor [1].
Benzodiazepines are among the safest drugs within the sedative-hypnotic class. They are widely used in emergency medicine for seizure management, sedation of agitated patients, alcohol withdrawal, and procedural sedation. Additionally, benzodiazepines are commonly prescribed for various conditions, including anxiety and sleep disorders. However, their widespread availability poses a risk of misuse, whether intentional or accidental [2].
Benzodiazepines are the most commonly prescribed psychiatric medications and rank as the third most misused drug class among adults and adolescents in the United States. While data from the Middle East are limited, benzodiazepine misuse is recognized as a significant concern in the region [3,4]. Policies are being implemented to restrict inappropriate prescriptions and raise awareness about their safe use. Patients should be educated on the proper use of benzodiazepines to mitigate risks [5]. When taken alone, benzodiazepine overdoses are rarely lethal, unlike opioids. However, abrupt withdrawal after prolonged use can carry a high risk of mortality, particularly due to the potential for withdrawal seizures.
Benzodiazepines can be administered orally, intramuscularly, intravenously, or rectally. Oral administration is the most common route due to rapid absorption. Intramuscular administration has erratic absorption but may be useful in emergencies when IV access is unavailable. Rectal administration is primarily used in pediatric patients, providing faster and more predictable effects than the IM route. After absorption, benzodiazepines distribute readily throughout the body and rapidly penetrate the blood-brain barrier due to their high lipophilicity. Most benzodiazepines are highly protein-bound in plasma [6].
Benzodiazepines are metabolized in the liver into active or inactive compounds. Based on their elimination half-life, they are classified as short-acting (e.g., midazolam), intermediate-acting (e.g., alprazolam, lorazepam), and long-acting (e.g., diazepam, chlordiazepoxide, clonazepam). The duration of a benzodiazepine’s effect can be prolonged in the presence of active metabolites, liver dysfunction, or co-ingestion of substances that inhibit their metabolism (e.g., alcohol, cytochrome P450 inhibitors) [7].
Chronic benzodiazepine use can lead to tolerance, characterized by reduced receptor sensitivity. Abrupt discontinuation or dose reduction after tolerance develops can cause a pro-excitatory state, increasing the risk of seizures. The risk of tolerance and withdrawal is dose- and duration-dependent, though specific thresholds have not been clearly established.
Medical History
Taking a medical history from an intoxicated or withdrawing patient can be challenging due to their altered mental status. In such cases, information from family members, bystanders, or emergency medical services (EMS) can be invaluable in filling gaps in the patient’s history [8].
As with any toxidrome, the most critical aspect of the medical history is identifying the causative agent—or agents, as co-ingestion of multiple substances is common. Clues such as empty medication bottles or blister packs found near the patient can be helpful.
If benzodiazepine use is suspected, it is crucial to determine the specific agent, dosage, and duration of use to guide management effectively. Signs and symptoms of benzodiazepine overdose often mimic ethanol intoxication. Mild to moderate cases may present with drowsiness, slurred speech, nystagmus, and ataxia, which is the most common symptom in pediatric patients. Severe cases, particularly those involving co-ingestion, may present with hypotension and hypoventilation. Symptoms of benzodiazepine withdrawal, such as tremors, anxiety, hallucinations, dysphoria, psychosis, seizures, and autonomic instability, should also be investigated [9].
Past medical history is significant, especially for conditions like epilepsy, liver disease, or the use of medications that inhibit liver enzymes (e.g., cimetidine, valproate, fluoxetine, ciprofloxacin), as these factors can prolong the half-life of benzodiazepines. Psychiatric history is equally important, as conditions like depression, previous withdrawal episodes, intoxication, or suicide attempts may provide insights into the likely ingested compounds [10].
Physical Examination
The initial assessment begins with vital signs, including temperature, as severe benzodiazepine ingestion can cause hypothermia. Blood glucose levels should also be measured to exclude easily treatable causes of AMS, such as hypoglycemia. An ECG is recommended to assess for potential cardiac involvement.
A comprehensive head-to-toe examination is essential. This includes checking the skin for needle tracks and unusual odors, performing a full neurological examination (pupil size, signs of seizures, or meningeal irritation), and looking for indications of head trauma, drug toxicity, or metabolic disturbances. Specific attention should be given to acute limb ischemia, which can occur after accidental arterial injection of benzodiazepines; severe limb pain or agitation warrants a focused limb examination.
If the patient is responsive, a mental status examination can be conducted. Once the patient is stable and oriented, a thorough psychiatric evaluation should be undertaken.
Alternative Diagnoses
Benzodiazepine overdose is primarily a clinical diagnosis. Pure overdoses typically present with a depressed mental state while maintaining hemodynamic stability, and the history of benzodiazepine ingestion may align with a sedative-hypnotic toxidrome.
Co-ingestion or altered mental status may complicate the clinical picture and necessitate consideration of alternative diagnoses. Focal neurological deficits, seizures, or severe hemodynamic instability could point to intracranial pathologies (e.g., head trauma, intracerebral hemorrhage, stroke, meningitis, encephalitis) or other co-ingested substances (e.g., opiates, ethanol, tricyclic antidepressants, gamma-hydroxybutyrate). Delirium or sedation due to non-toxicological causes, such as hypoglycemia, should also remain part of the differential diagnosis.
Acing Diagnostic Testing
Pure benzodiazepine overdose presents with a characteristic sedative-hypnotic toxidrome and is primarily a clinical diagnosis. Diagnostic testing is often aimed at ruling out alternative causes of depressed consciousness.
Essential tests include blood glucose to exclude hypoglycemia and a CT head scan if head trauma is suspected. Testing for common co-ingestants such as paracetamol, salicylates, and ethanol may be warranted. ECG should be performed, as transient first- and second-degree heart blocks or QT prolongation may be seen in benzodiazepine toxicity. Patients with such ECG changes should be monitored for progression to arrhythmias. Arterial blood gas (ABG) analysis may be indicated for patients with hypoventilation. Basic laboratory tests, including electrolytes, liver function tests (which may show mild elevation), and creatine kinase levels, are recommended to monitor for rhabdomyolysis in severe cases.
Benzodiazepine detection in urine is possible via qualitative immunoassay, though this method is not diagnostic of overdose [11]. False negatives can occur as not all benzodiazepines are detected, and a positive result only indicates exposure without providing timing or dosage information. False positives may result from medications such as efavirenz and sertraline. Urine tests can detect benzodiazepines within three hours of ingestion and remain positive for up to two weeks. Serum benzodiazepine levels are rarely needed except in forensic cases, as they do not correlate well with the ingested dose.
Risk Stratification
Patients presenting with benzodiazepine overdose or withdrawal must be thoroughly assessed before discharge, even if they remain asymptomatic or their symptoms have been controlled in the ED. Psychiatric consultation is recommended in all cases, regardless of whether the overdose was intentional or accidental.
Suicidal ideation and suicide risk should be evaluated using tools like the SAD PERSONS score (Table 1) [12]. Patients with high scores require admission for further evaluation and intervention. Patients in withdrawal need to be referred for rehabilitation, with the choice of inpatient or outpatient care determined by the psychiatric assessment.
Table 1: SAD PERSONS Score
S | Male sex | 1 |
A | Age (<19 or >45 years) | 1 |
D | Depression | 1 |
P | Previous attempt | 1 |
E | Excessive alcohol or substance use | 1 |
R | Rational thinking loss | 1 |
S | Social supports lacking | 1 |
O | Organized plan | 1 |
N | No spouse | 1 |
S | Sickness | 1 |
0-4 | Low risk | Consider discharge to home with follow-up. |
5-6 | Medium risk | Admit or discharge based on clinical judgment, ensuring appropriate follow-up arrangements. |
7-10 | High risk | Admit to hospital |
Management
Initial Stabilization
Management of a patient with altered mental status (AMS) and suspected overdose begins with resuscitation. The ABCDEFG approach in toxicology is a structured method [13]:
A: Airway/C-Spine
- Endotracheal intubation should be promptly performed in severely intoxicated patients or those unable to maintain their airway.
- Nasopharyngeal or oropharyngeal airways may be used temporarily.
- C-spine immobilization is indicated if head trauma is suspected.
B: Breathing
- Hypoventilation is a critical sign of severe overdose, often indicating co-ingestion with alcohol or other central nervous system (CNS) depressants.
- Monitor respiratory rate and oxygen saturation. Administer oxygen for hypoxemia. Consider ventilatory support in cases of hypoventilation (e.g., Bag-valve-mask ventilation).
C: Circulation
- Two large-bore intravenous lines should be placed, and fluid resuscitation with isotonic solutions (e.g., 0.9% saline or Ringer’s lactate) initiated for hypotension.
- Monitor for signs of shock and consider vasopressors if hypotension persists despite adequate fluid resuscitation.
D: Disability/Decontamination/Draw Bloods
- Perform a rapid neurological exam; pupillary changes and other symptoms can help identify the toxidrome.
- Decontamination measures: Activated charcoal (1 g/kg for children or 50–100 g for adults) can be effective if administered within an appropriate timeframe. Multiple doses are not typically beneficial. Gastric lavage, hemodialysis, and urine alkalinization are ineffective for benzodiazepine toxicity.
- Draw blood samples for complete blood count (CBC), renal and liver function tests (U&E, RFT, LFT), creatine kinase (CK), arterial blood gases (ABG), osmolality, and a toxicology screen (ethanol, acetaminophen, salicylate).
E: Exposure
- Examine for track marks, odors, nasal septum erosion, and signs of trauma or assault. The lack of signs of trauma or assault does not totally rule out in patients with altred mental status.
- Check for evidence of seizures (incontinence, tongue biting) or meningeal irritation.
- Ensure the patient is kept warm.
F: Full Monitoring
- Continuous monitoring of vital signs, end-tidal carbon dioxide, and ECG is essential.
G: Give Antidote
- Administer antidotes based on the identified or suspected toxic agent.
- The universal antidotes—dextrose, oxygen, naloxone, and thiamine—can be administered as appropriate. Administer dextrose for hypoglycemia and oxygen for hypoxemia, as indicated. Naloxone, administered intranasally or intravenously, is beneficial for any patient with respiratory depression suggestive of opioid exposure. With a rapid onset of action (~1 minute), it serves both diagnostic and therapeutic purposes. Administer thiamine to prevent Wernicke’s encephalopathy in at-risk patients. If glucose administration is indicated but thiamine is unavailable, glucose should not be delayed.
- Most benzodiazepine overdoses can be effectively managed with supportive care alone, without the need for specific antidotes. In rare cases where specific treatment is required, flumazenil, unlike naloxone, should not be administered empirically.
Flumazenil
Adult
- Initial Dose: 0.2 mg over 1-2 minutes
- Frequency: 0.3 – 0.5 mg IV every 1-2 minutes
- Maximum Dose: 1 mg
- Cautions / Comments:
- Category C in Pregnancy.
- Short duration of action (45–75 minutes); re-sedation may require re-dosing or continuous infusion (0.25 to 1.0 mg/h).
- Adverse reactions include seizures (treat with barbiturates or propofol) and arrhythmias.
- Adverse drug reactions are less common in pediatric patients.
Paediatrics
- Initial Dose: 0.01 mg/kg over 1-2 minutes
- Frequency: Up to 4 doses of 0.005 – 0.01 mg/kg
- Maximum Dose:
- 0.2 mg per dose.
- Should not exceed 1 mg total or 0.05 mg/kg.
Flumazenil, a competitive antagonist of the benzodiazepine receptor, is primarily used in benzodiazepine-naïve patients [14]. Common scenarios include iatrogenic overdoses during monitored procedural sedation to reverse respiratory depression and pediatric accidental ingestion.
Flumazenil administration in patients with chronic benzodiazepine use can precipitate withdrawal symptoms, including intractable seizures and status epilepticus. Flumazenil is contraindicated in the following situations:
- Chronic benzodiazepine use (e.g., for seizure disorders or in known substance use).
- In patients where the cause of altered mental status is unknown or seizure activity is suspected.
- Co-ingestion with pro-convulsant agents, such as tricyclic antidepressants, cocaine, diphenhydramine, carbamazepine, chloral hydrate, or bupropion.
- Iatrogenic overdose during management of status epilepticus.
Benzodiazepine withdrawal syndrome can occur in chronic users following flumazenil administration or abrupt cessation of the drug. The risk is proportional to the dose and duration of benzodiazepine use, increasing significantly after 3–4 months of regular use.
Acute withdrawal requires resuscitation aligned with the standard ABCDE approach:
- Administer long-acting benzodiazepines (e.g., diazepam or chlordiazepoxide) in mild or moderate cases to alleviate symptoms and allow tapering under medical supervision.
- Seizures during withdrawal should be treated with propofol or barbiturates rather than benzodiazepines [6].
Special Patient Groups
In the elderly, liver metabolism can be significantly impaired, necessitating dose adjustments [15]. For patients with known liver disease, benzodiazepines without active metabolites are preferred (e.g., lorazepam, oxazepam, temazepam—LOT).
In children under 5 years of age, accidental benzodiazepine ingestion may present primarily with ataxia, which is more common than AMS [16]. Both children and elderly patients may experience paradoxical reactions following benzodiazepine administration for procedural sedation.
When To Admit This Patient
In cases of suspected suicidal attempts, a psychiatric evaluation should be conducted in the emergency department (ED) [17]. Patients with mild, accidental, or pure benzodiazepine overdoses successfully managed in the ED who remain asymptomatic for 4–6 hours can be discharged. However, if mild symptoms persist, admission to a general ward for observation may be warranted until symptom resolution. Patients with severe overdoses requiring monitoring, oxygen therapy, or ventilatory support should be admitted to the ICU [1].
Revisiting Your Patient
The patient was rapidly transferred to the resuscitation room and connected to a monitor. A structured A to E approach was used for further assessment.
Airway: With a GCS of 3/15, a nasopharyngeal airway (NPA) was inserted as a precaution, and an intubation kit was prepared. There were no visible signs of airway trauma, foreign body obstruction, or excessive secretions.
Breathing: The patient was bradypneic with oxygen saturation below 94%. Oxygen at 10 L/min via a non-rebreather mask was administered, improving her saturation to 98%. End-tidal CO₂ measured 35 mmHg.
Circulation: To address hemodynamic instability, two large-bore intravenous cannulas were placed, blood samples were drawn, and an intravenous bolus of 0.9% NaCl was administered. Continuous monitoring showed an improvement in her blood pressure to 85/50 mmHg and her heart rate to 52 bpm. An ECG revealed sinus bradycardia.
Disability: Neurological examination showed constricted pupils. Activated charcoal was not administered, as the ingestion was presumed to have occurred 2–5 hours earlier.
Exposure: On physical examination, no track marks or septal erosion were noted. A mild odor of alcohol was detected. There were no overt signs of seizures, trauma, or assault. However, given the altered mental state, trauma or assault could not be definitively ruled out.
Management included supportive care with oxygen and a trial of naloxone (0.4 mg IV), which had no effect within two minutes. Thiamine (100 mg IV) was administered as part of the standard protocol. Flumazenil was withheld due to concerns about potential withdrawal seizures in the context of possible chronic benzodiazepine use, particularly since the patient was improving with supportive treatment alone.
Further questioning of her friends revealed that they had given her Xanax (alprazolam), though they were unsure of the quantity. They also confirmed that she had consumed alcohol. Laboratory investigations were largely unremarkable, apart from a blood ethanol level of 150 mg/dL.
The patient’s condition showed gradual improvement in the emergency department. Her GCS increased to 9/15 (E3V2M4), and intubation was deferred as she maintained her airway. Hemodynamic stability was achieved, with a blood pressure of 90/55 mmHg, a heart rate of 62 bpm, and oxygen saturation of 95% on a 5 L face mask. Although she remained confused and unable to provide a detailed history, her overall status warranted further supportive care. She was admitted to the telemetry ward for ongoing monitoring and management.
Authors
Gina Rami Abdelmesih
Emergency Department, Zayed Military Hospital
Rauda Alnuaimi
Emergency Department, Zayed Military Hospital
Listen to the chapter
References
- Overbeek DL, Erickson TB. Sedative-Hypnotics. In: Walls RM, Hockberger RS, Gausche-Hill M, Erickson TB, Wilcox SR, ed. Rosen’s Emergency Medicine Concepts and Clinical Practice, 10th edition. Philadelphia, PA, USA: Elsevier; 2023: 1986-1993.
- United Nations Office on Drugs and Crime. Non-medical use of benzodiazepines: a growing threat to public health? https://www.unodc.org/documents/scientific/Global_SMART_Update_2017_Vol_18.pdf Published September 2017. Accessed December 11, 2024.
- AlMarri TS, Oei TP. Alcohol and substance use in the Arabian Gulf region: a review. Int J Psychol. 2009;44(3):222-233.
- El Zahran T, Kanaan E, Kobeissi L, et al. Benzodiazepine use disorder: A cross-sectional study at a tertiary care center in Lebanon. Medicine (Baltimore). 2022;101(38):e30762.
- Naja WJ, Pelissolo A, Haddad RS, Baddoura R, Baddoura C. A general population survey on patterns of benzodiazepine use and dependence in Lebanon. Acta Psychiatr Scand. 2000;102(6):429-431.
- Greller H, Gupta A. Benzodiazepine poisoning and withdrawal. UpToDate. https://www.uptodate.com/contents/benzodiazepine-poisoning Updated July 11, 2022. Accessed May 1, 2023.
- Yin S. Sedatives and Hypnotics. In: Cydulka RK, Fitch MT, Wang VJ, Cline DM, Ma, OJ, ed. Tintinalli’s Emergency Medicine Manual, 8th Edition. New York, NY, USA: McGraw-Hill Education; 2018: 574-579.
- National Poisons Information Service. Street Benzodiazepines. TOXBASE. https://www.toxbase.org/poisons-index-a-z/s-products/street-benzodiazepines/. Updated August, 2022. Accessed May 1, 2023.
- Wright SL. Benzodiazepine withdrawal: clinical aspects. In: Peppin J, ed. The Benzodiazepines Crisis. New York, NY: Oxford University Press; 2020. doi:10.1093/med/9780197517277.003.0008. Accessed December 17, 2024.
- Rockett IRH, Caine ED, Connery HS, et al. Discerning suicide in drug intoxication deaths: paucity and primacy of suicide notes and psychiatric history. PLoS One. 2018;13(1):1-13. doi:10.1371/journal.pone.0190200.
- DeRienz RT, Holler JM, Manos ME, Jemionek J, Past MR. Evaluation of four immunoassay screening kits for the detection of benzodiazepines in urine. J Anal Toxicol. 2008;32(6):433-437. doi:10.1093/jat/32.6.433.
- Bolton JM, Spiwak R, Sareen J. Predicting suicide attempts with the SAD PERSONS scale: a longitudinal analysis. J Clin Psychiatry. 2012;73(6):735-741. doi:10.4088/JCP.11M07362.
- Emergency Management of Poisoning. Haddad and Winchester’s Clinical Management of Poisoning and Drug Overdose. 2007;13-61. doi:10.1016/B978-0-7216-0693-4.50007-4
- Brogden RN, Goa KL. Flumazenil: a reappraisal of its pharmacological properties and therapeutic efficacy as a benzodiazepine antagonist. Drugs. 1991;42(6):1061-1089. doi:10.2165/00003495-199142060-00010.
- Cook PJ. Benzodiazepine hypnotics in the elderly. Acta Psychiatr Scand. 1986;74:149-158. doi:10.1111/j.1600-0447.1986.tb08992.x.
- Friedrich JM, Sun C, Geng X, et al. Child and adolescent benzodiazepine exposure and overdose in the United States: 16 years of poison center data. Clin Toxicol (Phila). 2020;58(7):725-731. doi:10.1080/15563650.2019.1674321.
- Ronquillo L, Minassian A, Vilke GM, Wilson MP. Literature-based recommendations for suicide assessment in the emergency department: a review. J Emerg Med. 2012;43(5):836-842. doi:10.1016/j.jemermed.2012.08.015.
Reviewed and Edited By
Elif Dilek Cakal, MD, MMed
Arif Alper Cevik, MD, FEMAT, FIFEM
Prof Cevik is an Emergency Medicine academician at United Arab Emirates University, interested in international emergency medicine, emergency medicine education, medical education, point of care ultrasound and trauma. He is the founder and director of the International Emergency Medicine Education Project – iem-student.org, chair of the International Federation for Emergency Medicine (IFEM) core curriculum and education committee and board member of the Asian Society for Emergency Medicine and Emirati Board of Emergency Medicine.
