Reversal of sedation
Flumazenil for midazolam, and naloxone for fentanyl: how to dose them, and why to be careful in neurocritical care and stroke.
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 depends on the indication (overdose vs reversal of procedural sedation); it is given intravenously.
| Step | Reversal of conscious sedation or general anesthesia | Benzodiazepine overdose |
|---|---|---|
| Initial dose | 0.2 mg IV over 15 seconds (if overdose, the initial dose can be as high as 0.3 mg IV) | 0.2 mg IV over 30 seconds |
| Subsequent doses | If the desired level of consciousness is not reached after 45 seconds, repeat 0.2 mg at 1-minute intervals | If not obtained after 30 seconds, give 0.3 mg IV over 30 seconds |
| Further titration | Up to 4 additional doses | If necessary, repeat 0.5 mg IV over 30 seconds at 1-minute intervals |
| Maximum | Total cumulative dose 1 mg | Cumulative dose 3 mg (no response after 5 mg suggests sedation is likely not benzodiazepine-related) |
| Resedation | Repeat doses at 20-minute intervals (no more than 1 mg per dose or 3 mg per hour) | — |
Cautions
- Seizure risk: flumazenil can precipitate seizures, which may be intractable. 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) — and patients with a known seizure disorder.
- Resedation: the half-life of flumazenil is about 54 minutes, often shorter than that of midazolam, so patients may become re-sedated as it wears off. Monitor for respiratory depression and residual sedation for at least 2 hours after administration.
- Traumatic brain injury: flumazenil may alter cerebral blood flow or precipitate convulsions in patients with head injuries; use with caution.
Neurocritical care and stroke
Risk: acute stroke patients have an inherently elevated seizure risk from cerebral ischemia; flumazenil can lower the seizure threshold further.
Indication: in neurocritical care, restrict flumazenil strictly to isolated, confirmed benzodiazepine over-sedation causing respiratory compromise that cannot be managed with supportive measures alone.
Naloxone (Narcan) — reversal of fentanyl
Reversal of narcotic-induced respiratory depression. Mechanism of action: naloxone is a competitive antagonist at μ, δ, and κ opioid receptors, antagonizing opioids including fentanyl, morphine, and heroin.
| Use | Dose |
|---|---|
| Supplied as | 0.4 mg/mL (1 mL ampoule) or 1 mg/mL (2 mL vial) |
| Bolus | 0.1–0.2 mg IV direct; give doses 2–3 minutes apart until the desired effect |
| More severe | 0.4–2 mg IV direct |
| Maintenance infusion | Loading dose 0.4 mg, then 0.1–0.4 mg/h, titrated to patient effect — useful for patients who needed high doses, prolonged therapy, or multiple doses of opioids |
Adverse effects
- Hypertension or hypotension
- Ventricular ectopic rhythms
- Pulmonary edema (most common in post-operative patients with pre-existing cardiac disease or hypertension, and in patients on β2-agonist therapy)
- Nausea, vomiting, sweating — from abrupt reversal of the narcotic
- Tremors
- Hyperventilation or respiratory depression
When respiratory depression is reversed with naloxone, monitor closely for rebound respiratory depression.