Reversal of Sedation

Reversal Agent: Flumazenil (Anexate) - Reversal of Midazolam

Mechanism of Action: Flumazenil is a competitive antagonist that inhibits the activity of benzodiazepines (like midazolam) at the GABA/benzodiazepine receptor complex.

Dosing Protocols

The dosing depends on the clinical indication (overdose vs. reversal of procedural sedation). Flumazenil is administered intravenously (IV).

1. Reversal of Conscious Sedation or General Anesthesia (Adults)

• Initial Dose: 0.2 mg IV administered over 15 seconds. Initial dose, if overdose can be as high as 0.3 mg IV

• Subsequent Doses: If the desired level of consciousness is not reached after 45 seconds, repeat 0.2 mg doses at 1-minute intervals.

• Maximum Dose: Up to 4 additional doses may be given, with a maximum total cumulative dose of 1 mg.

• Resedation: If sedation recurs, repeat doses may be given at 20-minute intervals (do not exceed 1 mg per dose or 3 mg per hour).

2. Management of Benzodiazepine Overdose (Adults)

• Initial Dose: 0.2 mg IV administered over 30 seconds.

• Subsequent Doses: If the desired level of consciousness is not obtained after 30 seconds, administer 0.3 mg IV over 30 seconds.

• Further Titration: If necessary, repeat doses of 0.5 mg IV over 30 seconds at 1-minute intervals.

• Maximum Dose: The maximum cumulative dose is 3 mg. (Note: If there is no response after 5 mg, the sedation is likely not benzodiazepine-related).

Seizure Risk: Flumazenil can precipitate seizures, which may be intractable. This risk is highest in:

    ◦ Patients who chronically use benzodiazepines (it can precipitate acute withdrawal).

    ◦ Patients who have co-ingested pro-convulsant drugs, specifically tricyclic antidepressants (TCAs).

    ◦ Patients with a known seizure disorder.

• Resedation: The half-life of flumazenil is approximately 54 minutes, which is often shorter than that of midazolam. Consequently, patients may become re-sedated after the flumazenil wears off. Patients require monitoring for respiratory depression and residual sedative effects for at least 2 hours after administration.

• Traumatic Brain Injury: Flumazenil may alter cerebral blood flow or precipitate convulsions in patients with head injuries and should be used with caution.

Considerations in Neurocritical Care and Stroke

• Risk: Acute stroke patients have an inherently elevated risk of seizures due to cerebral ischemia. Administering flumazenil can lower the seizure threshold further.

• Indication: In neurocritical care, flumazenil should be restricted strictly to cases of isolated, confirmed benzodiazepine over-sedation resulting in respiratory compromise that cannot be managed with supportive measures alone.

Reversal Agent: NALOXONE (Narcan) - Reversal of Fentanyl

-reversal of narcotic induced respiratory depression
-Mechanism of Action: Naloxone is a competitive antagonist at the μ, δ, and κ opioid receptors. It competitively antagonizes opioid xenobiotics, including fentanyl, morphine, and heroin

Dose:
Supplied as: 0.4 mg/ml (1 mL amp) or 1 mg/ml (2 mL vial)

Bolus:

0.04  IV Direct - can be repeated Q3 min
until desired effect.

If more severe - 0.4 - 2mg IV direct - if Cardiac/Respiratory Arrest

Patient may need an infusion - Maintenance Infusions:
loading dose: 0.4mg
0.1 - 0.4mg/h
rate of administration titrated to the patient effect
useful in patients requiring high doses or prolonged therapy or multiple doses of opiates given

Adverse Effects:
hypertension or hypotension
ventricular ectopic rhythms
pulmonary edema (most common in post-operative patients with pre-existing cardiac disease, hypertension and patients receiving B2 agonist therapy)
nausea, vomiting, sweating: secondary to abrupt cessation/reversal of narcotic
tremors
hyperventilation or respiratory depression
in respiratory depression that is reversed with naloxone, monitor closely for rebound respiratory depression