Benzodiazepine Poisoning


Benzodiazepine Poisoning:

 

Edited By :

Dr.Salim Al Mamun

MBBS(Raj);CCD(BIRDEM);

CMU(DU);DMUD(Course)

 

 

 

Benzodiazepines (BZD) are commonly used for a variety of situations that include seizure control, anxiety, alcohol withdrawal, insomnia, control of drug-associated agitation, as muscle relaxants, and as pre-anesthetic agents. Because of their widespread popularity, these drugs are commonly abused. In addition, BZDs frequently are used in overdose, either alone or in association with other substances especially in suicidal attempt and transport related poisoning.

The rate of onset of action is determined by rate of benzodiazepine absorption from the GI tract. Benzodiazepine absorption is especially rapid when ethanol is present and the stomach is empty. Peak blood concentrations of most agents occur within 1-3 hours. Benzodiazepines are metabolized predominantly in the liver by oxidation and/or conjugation. Most benzodiazepines are broken down into pharmacologically active metabolites, which may have longer half-lives than the parent compounds.

Mortality/Morbidity:

Benzodiazepines are generally thought to be safe and death is rare. Mortality from a pure benzodiazepine overdose is rare; it usually occurs in conjunction with concomitant alcohol ingestion or use of other sedative-hypnotics. Intravenous administration or overdose of ultrashort-acting benzodiazepines (eg, triazolam) is more likely to result in apnea and death. Elderly individuals and very young persons are more susceptible to the CNS depressant effects of benzodiazepines than people in other age groups. Intravenous administration is associated with greater degrees of hypotension than other routes of administration and occasional cardiac and respiratory arrest.

History: History should include the time, dose, and intent of the overdose. Determine if co-ingestants are present and the duration of benzodiazepine use. Symptoms include – Dizziness, Confusion, Drowsiness, Blurred vision, Unresponsiveness, Anxiety and Agitation.

Physical: The physical examination should focus on the patient’s vital signs and cardiorespiratory and neurologic function. The frequently found physical signs are- Nystagmus, Hallucinations, Slurred speech, Ataxia, Coma, Hypotonia, Weakness, Altered mental status, impairment of cognition, Amnesia, Paradoxical agitation, Respiratory depression and Hypotension

Workup: Qualitative screening of urine or blood may be performed but rarely influences treatment decisions. Obtain an arterial blood gas if respiratory depression is present. Following an intentional overdose, measure serum electrolytes, glucose, BUN, creatine clearance, and acetaminophen concentration. Obtain a pregnancy test in women of childbearing age. Obtain a chest x-ray if respiratory compromise is present. Evaluate for aspiration. Evaluate for acute respiratory distress syndrome (ARDS). Obtain an electrocardiogram (ECG) to evaluate for co-ingestants, particularly cyclic antidepressants.

Treatment:

Prehospital Care: 

  • Supplemental oxygen
  • Intravenous access
  • Rapid blood sugar
  • Naloxone, if the diagnosis is unclear or an opiate co-ingestion is suspected

Emergency Department Care:

  • Continue supportive care and monitoring (e.g., cardiac monitoring, IV, oximetry, vital signs).
  • Decontamination

o   Gastric lavage is not recommended but may be considered if the presence of a lethal co-ingestant is suspected and the patient presents within 1 hour of ingestion.

o   Single-dose activated charcoal is recommended for GI decontamination in patients who present within 1 hours of ingestion or in symptomatic patients when the time of ingestion is unknown.

  • Respiratory depression may be treated with assisted ventilation.

Medications:

Antidote:

Flumazenil is a selective competitive antagonist of the GABA receptor and the only available specific antidote for benzodiazepines; it will reverse effects of benzodiazepines but must be used with caution. In overdose situations, flumazenil may be used for patients with pure benzodiazepine overdose who are verbally unresponsive and have no history of long-term benzodiazepine use or seizure disorder. ECG should be performed before use to confirm the absence of cardiac conduction disturbances (which would suggest the presence of cyclic antidepressants). Use as a diagnostic and therapeutic agent for unsubstantiated drug-associated coma is controversial. A positive response to small titratable doses may obviate the need for endotracheal (ET) intubation and the search for other causes of coma.

The absence of clinical response to 2 mg of flumazenil within 5 to 10 minutes indicates that benzodiazepines poisoning may not be major cause of CNS depression or coma.

The patient regains consciousness within 15 to 30 seconds after injection of flumazenil, but since it is metabolised more rapidly than the benzodiazepines, recurrence of toxicity and CNS depression can occur and the patient should be carefully monitored after initial response to flumazenil therapy.

If the patient becomes unconscious again, flumazenil can be given by IV infusion 100‑400 micrograms/hour rate being adjusted according to level of arousal.

Adult Dose: 0.1-0.2 mg IV q1min to a total dose of 1 mg at one time or 3 mg in 1 h; infusion rates of 0.1 mg/min decrease disconcerting rapid arousal.

Pediatric Dose: 0.002-0.02 mg/kg IV q1min.

 

Contraindications:

Documented hypersensitivity; serious cyclic-antidepressant over dosage; patients using benzodiazepines to control a potentially life-threatening condition (eg, intracranial pressure, status epilepticus); chronic benzodiazepine use.

Pregnancy: category-C Safety for use during pregnancy has not been established.

Precautions:

Patients on benzodiazepines for prolonged periods may experience seizures; monitor for resedation and unmasking of seizures

Abusive Substance Poisoning

People abuse substances such as drugs, alcohol, and tobacco for varied and complicated reasons, but it is clear that our society pays a significant cost. Abused substances produce some form of intoxication that alters judgment, perception, attention, or physical control. Withdrawal of many of these can range from mild anxiety to seizures and hallucinations. Drug overdose may also cause death.

 

Few abusive substances, their toxic symptoms and management are enumerated below (alcoholic intoxication described elsewhere)–

Opiates: codeine, dihydrocodeine, morphine

Toxicity is enhanced if other CNS depressants such as alcohol are ingested as well.

Toxic dose: A toxic dose of opiate is difficult to assess as individual tolerances vary greatly. Therefore, the following doses are to be interpreted with care: Codeine: 350 mg. Dihydrocodeine: 420mg., Morphine: 30 mg (patients may be on higher doses in therapy; the clinical effects may occur if established dose is exceeded). Overdoses may present with nausea and vomiting. Some opioids may cause a rash, itching, flushing, drowsiness and pinpoint pupils. Fensidyl, commonly used recreational medicine in Bangladesh, contains high amount of codeine and dihydrocodeine.

In severe poisoning:

  • Unconsciousness, convulsions, hypotension.
  • Respiratory depression with cyanosis and respiratory arrest. Hypoxia due to respiratory depression is the most frequent cause of death from opioid poisoning. Serious complications include Non-cardiogenic pulmonary oedema, cardiovascular collapse, and renal failure.

 

Management:

  • Activated charcoal can be given within 1 hour of ingestion to reduce absorption unless the patient is drowsy, fitting or vomiting.
  • Naloxone can be given to reverse the signs of severe poisoning (coma, respiratory depression or convulsions) within a few minutes but it has a short life and the patient may relapse.
  • All patients who have taken an overdose of opioid analgesics should be transferred to hospital and observed for at least 6 hours. Patients who require naloxone should be observed for 24 hours. ECG monitoring and ventilation may be needed.

Marijuana (also known as ganja, grass, pot, weed, herb):

Marijuana comes from the plant Cannabis sativa. The plant produces delta-9-tetrahydrocannabinol (THC), the active ingredient associated with intoxication. Marijuana resin, called hashish, contains an even higher concentration of THC. The drug is usually smoked, but it can also be eaten. Common effects of marijuana use include pleasure, relaxation, and impaired coordination and memory. Often, the first illegal drug people use, marijuana is associated with increased risk of progressing to more powerful and dangerous drugs such as cocaine and heroin. It is virtually impossible to overdose from marijuana, which sets it apart from most drugs.

Heroin (also known as smack, horse): Effects of heroin intoxication include drowsiness, pleasure, and slowed breathing. Withdrawal can be intense and can include vomiting, abdominal cramps, diarrhea, confusion, aches, and sweating. Overdose may result in death from decreased breathing.

 

May present with:

  • Onset of effects within 30 minutes of ingestion or within seconds to minutes after IV injection. The peak effects last for about 10–30 minutes and continue in milder form for 2–4 hours.
  • Nausea, vomiting.
  • Dry mouth, constricted pupils, drowsiness, confusion, euphoria, a sense of calmness, flushing, sweating and a feeling of warmth.

In severe cases:

  • Hypotension, coma, bradycardia, respiratory depression with associated hypoxaemia and pulmonary oedema, cardiac arrhythmias. The pupils may be dilated if hypoxic cerebral damage has occurred.

 

Management:

  • Activated charcoal can be given within 1 hour of ingestion to reduce absorption unless the patient is drowsy, fitting or vomiting.
  • Naloxone can be given to reverse the signs of severe poisoning (coma, respiratory depression or convulsions) within a few minutes, but it has a short life and the patient may relapse.
  • All patients who have taken an overdose of opioid analgesics should be transferred to A&E and observed for at least 6 hours. Patients who require naloxone should be observed for 24 hours. ECG monitoring and ventilation may be needed.
  • Adult dose 0.4mg, can be repeated at intervals of 2-3 minutes to a maximum of 10mg.  (Naloxon ampoule, 0.4mg/ml).

 

Tricyclic antidepressants:

Includes: amitriptyline, amoxapine, clomipramine, dothiepin, doxepin, imipramine, lofepramine, nortriptyline, protriptyline and trimipramine.

Although the individual TCAs have differences in side-effects and kinetics, most behave similarly in an acute overdose. Peak plasma levels normally occur within 2–8 hours of a therapeutic dose because of delayed gastric emptying. After an overdose, peak levels may occur even later. Life-threatening signs usually develop within 6 hours of ingestion or not at all. The complications most often associated with a fatal outcome are severe hypotension and cardiac arrhythmias.

Toxic dose:

  • Hospital observation is recommended for ingestion > 5 mg/kg.
  • 10-20 mg/kg can be life threatening.
  • Anticholinergic effects, sedation and hallucinations can occur at doses
    < 5 mg/kg.

May present with:

  • Dry mouth, dilated pupils, urine retention, hallucinations, jerky movements, drowsiness.
  • Metabolic acidosis and hypokalaemia.

In severe poisoning:

  • Coma, hypotension, hypothermia, convulsions, respiratory depression, pulmonary oedema, cardiac arrhythmias, cardiac arrest. Arrhythmias may not respond to therapy.
  • Lofepramine is less likely to cause cardiac effects.
  • Amoxapine is more likely to cause arrhythmias and convulsions.

Management:

  • Activated charcoal can be given within 1 hour of ingestion to reduce absorption unless the patient is drowsy, fitting or vomiting.
  • Diazepam can be given to control fits if they are prolonged.
  • Because of the potential for serious toxicity, all patients should be transferred to A&E for observation and to monitor their ECG, pH and electrolytes for at least 6 hours post-ingestion.
  • In serious poisoning, ventilation and intensive care will be necessary.

Cocaine (also known as crack, coke, snow, rock):

Derived from the coca plant of South America, cocaine can be smoked, injected, snorted, or swallowed. Desired effects include pleasure and increased alertness. Short-term effects also include paranoia, constriction of blood vessels leading to heart damage or stroke, irregular heartbeat, and death. Severe depression and reduced energy often accompany withdrawal. Both short- and long-term use of cocaine has been associated with damage to the heart, the brain, the lung, and the kidneys.

The fatal dose of cocaine has been approximated 1.2 g, although severe toxic effects have been reported from doses as low as 20 mg.

Symptoms:

The symptoms of cocaine poisoning are referable to the CNS, namely the patient becomes excited, restless, garrulous, anxious and confused. Enhanced reflexes, headache, rapid pulse, irregular respiration, chills, rise in b.p, temperature, mydriasis, exophthalmos, nausea, vomiting, and abdominal pain are noticed in severe overdoses, delirium, Cheyne-Stokes respiration, convulsions, unconsciousness and death from respiratory arrest result. Acute poisoning by cocaine is rapid in developing.

Treatment:

The specific treatment of acute cocaine poisoning is the intravenous administration of a short-acting barbiturate or diazepam. Artificial respiration may be necessary. It is important to limit absorption of the drug. If entrance of the drug into circulation can be checked, and respiratory exchange maintained, the progress is favorable since cocaine is eliminated fairly rapidly.

Amphetamine and MDMA (ecstasy)

MDMA is an amphetamine derivative. It is taken as a tablet or powder enclosed in a capsule. Adverse effects more commonly occur after ‘recreational’ doses rather than with an overdose.

May present with:

  • Onset of symptoms from amphetamine according to the route of exposure.
  • Transient nausea, increased muscle tone, muscle pain, trismus (jaw-clenching), dilated pupils, blurred vision, sweating, dry mouth, agitation, anxiety, palpitations, vomiting, abdominal pain and diarrhoea.
  • Hypertonia, hyper-reflexia, hyperpyrexia, tachycardia, initial hypertension then hypotension, tachypnoea, and visual hallucinations.
  • Effects may be prolonged if a patient has alkaline urine.

In severe poisoning:

  • Delirium, coma, convulsions and cardiac dysrrhythmias that may be fatal.
  • A hyperthermic syndrome may develop with rigidity, hyper-reflexia and hyperpyrexia (>39°C) leading to hypotension, rhabdomyolysis, metabolic acidosis, acute renal failure, disseminated intravascular coagulation, hepatocellular necrosis, adult respiratory distress syndrome and cardiovascular collapse.
  • Death from intracerebral haemorrhage has also been reported in hyperthermic patients.
  • MDMA is also associated with hyponatraemia and cerebral oedema. This can occur in patients who have consumed excessive amounts of water (owing to drug-induced repetitive behaviour). These patients present with mild hypothermia and confusion; they may be unresponsive and staring.

‘Yaba’ is acombination of methamphetamine and caffeine. Yaba, which means crazy medicine in Thai, is produced is Southeast and East Asia. Yaba is produced as tablets. These tablets are generally no larger than a pencil eraser. They are brightly colored, usually reddish-orange or green.

Yaba has recently emerged as a drug of abuse among the young int affluent societies in  Bangladesh. Individuals who use Yaba face the same risks as users of other forms of methamphetamine: rapid heart rate, increased blood pressure, and damage to the small blood vessels in the brain that can lead to stroke. Chronic use of the drug can result in death. Individuals who use Yaba also may have episodes of violent behavior, paranoia, anxiety, confusion, and insomnia.

 

Management:

  • Activated charcoal can be given within 1 hour of ingestion to reduce absorption unless the patient is drowsy, fitting or vomiting.
  • All patients should be transferred to hospital and observed for at least 6 hours with electrocardiogram (ECG) monitoring and the monitoring of electrolytes balance
  • Give diazepam for convulsions.
  • If the rectal temperature > 39°C, instigate cooling measures (fan, sponging, ice packs, cool IV fluids). If this is unsuccessful, the patient will need to be paralysed and ventilated.

 

Follow-up:

Further Inpatient Care: Admit patients with hemodynamic instability, coma, or respiratory depression to the ICU. Watch for signs of withdrawal in patients who have been taking BZDs chronically before overdose.

Further Outpatient Care: Patients may be discharged if they remain asymptomatic 4-6 hours postingestion. Those with mild toxicity may be observed in the emergency department until they recover.

Transfer: Transfer patients who may require more advanced care than is available in inpatient setting.

 

Other Complications of abusive drugs:

  • Aspiration pneumonia
  • Rhabdomyolysis
  • Fatality (rare)

Treatment of Complications:

CNS stimulation may require sedation, usually with a benzodiazepine or a barbiturate. In pure amphetamine poisoning, chlorpromazine or a benzodiazepine may be used. To terminate seizures or prevent their recurrence, a benzodiazepine (eg, diazepam 5 to 10 mg for adults; 0.1 to 0.2 mg/kg for children) is given slowly IV, or Phenobarbital (100 to 200 mg IV or IM for adults; 4 to 7 mg/kg for children) is given. Ideally, phenytoin is avoided. O2 saturation should be closely monitored. Refractory seizures very rarely, if ever, require general anesthesia.

Severe CNS depression requires circulatory and ventilatory support.  Endotracheal intubation and, rarely, tracheostomy may be necessary. In suspected or known narcotic poisoning, naloxone should be used in repeated doses. Stimulants are ineffective and are generally contraindicated.

Cerebral edema is common in poisoning due to sedatives, carbon monoxide, lead, and other CNS depressants. A 20% mannitol solution (5 to 10 mL/kg) is given slowly IV over 30 to 60 min. Corticosteroids are also used (dexamethasone 1 mg/m2 of BSA q 6 h by IV drip). Intracranial monitoring with hyperventilation to try to alter the degree of cerebral edema is used less frequently.

Renal failure, if present, may require dialysis.

Hepatic failure may warrant transplantation.

Medical/Legal Pitfalls:

a.    Unmasking an underlying disorder, specifically seizures, with indiscriminate use of flumazenil

b.    Failure to anticipate withdrawal in a patient with chronic BZD use

c.    Failure to consider the possibility of co-ingestant use or secondary causes of treatable altered mental status (eg, hypoglycemia, meningitis).

 

 

 

 

 

 

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