Rosen & Barkin's 5-Minute Emergency Medicine Consult (98 page)

• 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 V
    _d
    
  • 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

• 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

Diagnosis based on:

• History of ingestion or recent injection
  
• Clinical findings associated with CNS depression
  
• No response to naloxone
  

• 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 LD
    ₅₀
    or serum levels
    
• Alcohol(s) level
  
• Barbiturate level (e.g., Phenobarbital)
  
• Acetaminophen and salicylate levels
  
• Pregnancy test
  

• EKG
  
• CXR for aspiration pneumonia
  
• Consider CT head
  

Core body temperature

• 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

• Attention to airway and breathing
  
• Cardiac monitor
  
• IV access
  
• Rapid glucose determination
  
• Obtain pill bottles/pills in suspected overdose
  

• 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.
  

• 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
      

• AC: 1 g/kg PO/NG (ideal is 10:1 ratio of AC:dose of drug)
  
• Dextrose: D
  ₅₀
  W 1 ampule: 50 mL or 25 g (peds: D
  ₂₅
  W 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 B
  ₁
  ): 100 mg IV/IM
  

FOLLOW-UP

• Persistent or profound CNS depression
  
• Cardiovascular or respiratory compromise
  
• Coingestants with potential delayed toxicity
  

• 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.
  

Psychiatry consultation for intentional overdoses.

Habituated patients may experience BZD withdrawal after cessation:

• Autonomic instability, tremor, paresthesias, seizures
  

IV formulations of certain BZDs (e.g., lorazepam) may contain propylene glycol diluent that can produce elevated osmolar gap and anion gap metabolic acidosis.

• 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.
  Goldfrank’s 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.
  

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