Basics
Description
- Potentiates the activity of γ-aminobutyric acid (GABA), the major inhibitory neurotransmitter, by binding to its own specific site
- Also facilitates GABA binding to its site
- Results in chloride influx, membrane hyperpolarization, and inhibition of cellular excitation:
- Benzodiazepines (BZDs) increase the frequency of chloride channel opening.
- Depresses spinal reflexes and reticular activating system
- Rapidly absorbed from GI tract:
- Highly protein bound
- Large Vd
- Hepatic metabolism
- Duration of action is inversely proportional to lipophilicity with highly lipophilic drugs penetrating the CNS more rapidly.
- Duration of lorazepam > diazepam > midazolam.
- Synergistic with other sedative-hypnotic medications (e.g., ethanol, barbiturates, propofol)
Diagnosis
Signs and Symptoms
- CNS:
- Sedation/drowsiness
- Slurred speech
- Midrange or small pupils
- Delirium
- Coma
- Neuromuscular:
- Incoordination
- Slowed voluntary movements
- Ataxia
- Hypotension
- Hyporeflexia/areflexia
- Cardiovascular:
- Mild depression
- Rarely lethal if ingested alone
- Respiratory:
- Mild depression but less than barbiturates
- Short acting and IV have higher depression
- GI:
- Nausea, vomiting, diarrhea
- Other:
- Hypothermia
- Complications may include cerebral hypoxia, rhabdomyolysis, pressure-induced neuropathies.
- No long-term organ toxicity
Rarely may cause paradoxical restlessness and agitation �
Essential Workup
Diagnosis based on: �
- History of ingestion or recent injection
- Clinical findings associated with CNS depression
- No response to naloxone
Diagnosis Tests & Interpretation
Lab
- Pulse oximetry
- Electrolytes, BUN, creatinine, serum glucose
- Thyroid studies
- Urinalysis (UA) for myoglobin if coma present or down for prolonged period of time
- ABG
- Qualitative urine screen:
- May confirm exposure, but does not indicate or measure intoxication or correlate clinical state.
- False-negative test results reported
- Qualitative immunoassays detect only BZDs that are metabolized to oxazepam.
- BZDs that do not produce this metabolite (clonazepam, lorazepam, midazolam, alprazolam) are not detected on qualitative screen.
- Serum levels not acutely practical
- Clinical signs and symptoms more important than theoretic LD50 or serum levels
- Alcohol(s) level
- Barbiturate level (e.g., Phenobarbital)
- Acetaminophen and salicylate levels
- Pregnancy test
Imaging
- EKG
- CXR for aspiration pneumonia
- Consider CT head
Diagnostic Procedures/Surgery
Core body temperature �
Differential Diagnosis
- Drugs and toxins causing decreased level of consciousness:
- Hypoglycemics
- Other sedative-hypnotics (barbiturates, chloral hydrate, GHB, bromides)
- Antidepressant-antipsychotics
- Narcotics
- Anticonvulsants
- Carbon monoxide/cyanide
- Alcohols
- Nontoxic medical conditions:
- Hypoxemia
- Hypothermia
- Head trauma (intracranial bleeding)
- Infection (meningitis or encephalitis)
- Electrolyte and metabolic abnormalities
Treatment
Pre-Hospital
- Attention to airway and breathing
- Cardiac monitor
- IV access
- Rapid glucose determination
- Obtain pill bottles/pills in suspected overdose
Initial Stabilization/Therapy
- ABCs:
- Secure airway and assist ventilation with supplemental oxygen to prevent hypoxemia and shock.
- IV access with 0.9% NS
- Cardiac monitor
- Administer naloxone, thiamine, and dextrose if altered mental status/comatose.
Ed Treatment/Procedures
- Consider gastric lavage when presenting within 1 hr of life-threatening ingestion with protected airway but should be done cautiously
- Activated charcoal (AC) PO or via nasogastric tube (NGT) if airway protected
- No role for diuresis, dialysis, or charcoal hemoperfusion
- Flumazenil (FZ):
- Competitive BZD-receptor inhibitor
- Rapidly reverses BZD-induced coma
- Onset within 1-2 min; peak at 6-10 min; duration 1-2 hr (repeated dosing may be indicated)
- Efficacy dependent on dose of BZD being antagonized and dose of FZ used
- Do not administer empirically as part of "coma cocktail"� or unknown ingestion
- May help avert need of airway intubation but has not consistently reversed respiratory depression
- May be beneficial in shortening hospital stay or as diagnostic maneuver
- Indications include isolated BZD overdose in nonhabituated user with CNS depression, normal EKG, normal vital signs, and normal neurologic exam.
- Most useful to reverse iatrogenic poisoning (conscious sedation)
- Contraindications include:
- Coingestions that might lower seizure threshold (tricyclic antidepressants [TCAs])
- Seizure history or activity
- Allergy
- Neuromuscular blockade
- Do not use if hypotension, hypoxia, dysrhythmias, or increased intracranial pressure is present.
- May precipitate withdrawal state including seizures, for which BZDs can no longer be used to treat
Medication
- AC: 1 g/kg PO/NG (ideal is 10:1 ratio of AC:dose of drug)
- Dextrose: D50W 1 ampule: 50 mL or 25 g (peds: D25W 2-4 mL/kg) IV if hypoglycemic
- FZ (Romazicon):
- Initial: 0.2 mg IV over 30 sec (adult)
- If no response: 0.3 mg IV after 30 sec
- If still no response: 0.5 mg IV and repeat q1min if needed, to max. dose of 3 mg
- Continuous infusion at 0.1-1 mg/h if multiple repeated doses required to maintain response. Continuous infusion not FDA approved
- Pediatric dosing: Titrate to max. cumulative dose of 0.05 mg/kg/d. Continuous infusion at 0.005-0.01 mg/kg/h has been used.
- Only use in selected patients (see above) as may precipitate seizures or dysrhythmias
- Monitor after use for resedation (occurs between 20 and 120 min after use)
- Naloxone (Narcan): 0.4-2 mg (peds: 0.1 mg/kg) IV or IV initial dose
- Thiamine (vitamin B1): 100 mg IV/IM
Follow-Up
Disposition
Admission Criteria
- Persistent or profound CNS depression
- Cardiovascular or respiratory compromise
- Coingestants with potential delayed toxicity
Discharge Criteria
- Can discharge after 4-hr observation period if no signs or symptoms of BZD poisoning.
- If FZ administered, observe for additional 2-4 hr for recurrent sedation.
Issues for Referral
Psychiatry consultation for intentional overdoses. �
Followup Recommendations
Habituated patients may experience BZD withdrawal after cessation: �
- Autonomic instability, tremor, paresthesias, seizures
Pearls and Pitfalls
IV formulations of certain BZDs (e.g., lorazepam) may contain propylene glycol diluent that can produce elevated osmolar gap and anion gap metabolic acidosis. �
Additional Reading
- Isbister �GK, O'Regan �L, Sibbritt �D, et al. Alprazolam is relatively more toxic than other benzodiazepines in overdose. Br J Clin Pharmacol. 2004;58:88-95.
- Lee �DC, Ferguson �KL. Sedative-hypnotics. In: Nelson �LS, Lewin �NA, Howland �MA, et al., eds. Goldfranks Toxicologic Emergencies. 9th ed. New York, NY: McGraw-Hill; 2011:1060-1077.
- Olkkola �KT, Ahonen �J. Midazolam and other benzodiazepines. Handb Exp Pharmacol. 2008;182:335-360.
- Seger, �DL. Flumazenil - treatment or toxin. J Toxicol Clin Toxicol. 2004;42:209-216
- Tenore �PL. Advanced urine toxicology testing. J Addict Dis. 2010;29(4):436-448.
See Also (Topic, Algorithm, Electronic Media Element)
Barbiturate Poisoning �
The author would like to provide special thanks to the author of the prior edition, Matthew Valento. �
Codes
ICD9
969.4 Poisoning by benzodiazepine-based tranquilizers �
ICD10
- T42.4X1A Poisoning by benzodiazepines, accidental, init
- T42.4X2A Poisoning by benzodiazepines, intentional self-harm, init
- T42.4X4A Poisoning by benzodiazepines, undetermined, init encntr
SNOMED
- 81914009 Poisoning by benzodiazepine-based tranquilizer (disorder)
- 216530001 Accidental poisoning by benzodiazepine-based tranquilizers (disorder)
- 242832005 Intentional benzodiazepine overdose (disorder)