Which of the following statements is true of the differences between methohexital and midazolam

Barbiturates (Thiopental, Methohexital, and Pentobarbital)

Barbiturates are primarily used for sedating children younger than 3 years of age to perform diagnostic imaging. They are relatively safe but are contraindicated in patients with porphyria. Major side effects include respiratory depression with apnea and hypotension, both of which are more common when barbiturates are used in combination with opiates or benzodiazepines.

Thiopental (Pentothal) is a short-acting barbiturate with an onset of action of 30 to 60 seconds when given intravenously and only 5 to 8 minutes when given rectally. It has a duration of effect of 15 minutes when given intravenously but up to 1 hour when given rectally. Given intravenously at doses of 20 to 25 mg/kg, thiopental is generally given rectally to children at a dosage of 5 to 10 mg/kg. Thiopental has the notable side effect of decreasing intracranial pressure; it is therefore particularly useful in patients for whom increased intracranial pressure is a concern.

Methohexital (Brevital) is an ultra-short-acting agent with an onset of action of 30 to 60 seconds and duration of effect of 5 to 10 minutes. It is twice as potent as thiopental and can be administered intravenously at a dose of 0.5 to 1.0 mg/kg to children older than 12 years. It should not be administered in younger children and is contraindicated in children with temporal lobe epilepsy because it can cause seizures in this subgroup. Methohexital is rarely used in the emergency department anymore because of a single study (Zink, 1991) of 102 patients, in which 22 patients developed respiratory depression requiring bag-valve-mask assistance. Five of these 22 patients developed transient apnea. If combined with an analgesic medication, respiratory depression is minimized by first administering the analgesic to control pain and then titrating methohexital to needed effect.

Pentobarbital (Nembutal) is a useful barbiturate sedative for longer radiologic procedures such as magnetic resonance imaging and positron emission tomography scans. It has an onset of action of 3 to 5 minutes when given IV and a duration of effect of 30 to 45 minutes. For children and infants older than 6 months, it can be given intravenously at a dosage of 1 to 3 mg/kg and titrated every 3 to 5 minutes to a maximum dosage of 100 mg or intramuscularly at a dosage of 2 to 6 mg/kg to a maximum dosage of 100 mg.

Uses

Pentobarbital

Nembutal and generics

Barbiturate

Injection: 50 mg/mL (20, 50 mL); contains propylene glycol and 10% alcohol

Hypnotic

Child:

IM: 2–6 mg/kg/dose.Max. dose: 100 mg

Adult:

IM: 150–200 mg

Reduction in Elevated ICP (adjunct therapy; patient must to be intubated): Barbituate coma may be used if needed.

Child and adolescent:

IV/IO: 1–3 mg/kg/dose

IM/PR: 2–6 mg/kg/dose

Max. dose: 100 mg/dose

Barbiturate coma

Child and adult:

IV: loading dose: 10–15 mg/kg given slowly over 1–2 hr

Maintenance: Begin at 1 mg/kg/hr. Dose range: 1–3 mg/kg/hr as needed.

Short-Acting Barbiturates: Pentobarbital

Pentobarbital is water soluble. If released into air, with an estimated vapor pressure of 3 × 10−10 mmHg (25 °C), it will exist solely as in particulate phase in the atmosphere and as a particulate pentobarbital will be removed from the atmosphere by wet or dry deposition. Pentobarbital is not susceptible to photolysis from sunlight as pentobarbital does not contain chromophores that absorb wavelengths of light greater than 290 nm. If pentobarbital is released into soil, a pKa of 7.8 indicates that it will exist partially as an anion, which does not absorb strongly to soils containing organic carbon or clays. Pentobarbital is not expected to volatilize from moist soil based upon an estimated Henry's law constant of 8.4 × 10−13 atm-cu m mol−1. If released into water, pentobarbital is not expected to adsorb to suspended sediment and solids in the water based upon the estimated Koc. Volatilization from water is not expected to be an important fate process based upon the estimated Henry's law constant. Pentobarbital has an estimated biological concentration factor (BCF) of 11 suggesting the potential for bioconcentration in aquatic organisms is low. Pentobarbital lacks functional groups that hydrolyze easily and hydrolysis is not expected to be an important environmental fate process.

Seizure Clusters and Status Epilepticus

Seizure clusters, also calledacute repetitive seizures andserial seizures, are closely grouped seizures representing an increase in seizure frequency compared to baseline, usually occurring over the span of minutes to a couple days. Seizure clusters may include any type of seizure and may vary in severity, but by definition there is complete recovery in between seizures. Seizure clusters are more common in patients with drug-resistant epilepsy, particularly those with remote symptomatic epilepsy and extratemporal epilepsy. Patients with seizure clusters are more likely to have a history of status epilepticus. Seizure clusters themselves may or may not progress to prolonged seizures or even status epilepticus. Such progression may be predictable for individual patients, based on their seizure history. This may determine the most appropriate treatment for seizure clusters. Mild clusters can be treated with oral doses of benzodiazepines. However more severe clusters, particularly those known to progress to severe prolonged seizures or status epilepticus, may require other routes of administration. Rectal diazepam was the only FDA-approved treatment for out-of-hospital administration by nonmedical caregivers (Cereghino et al., 1998), until intranasal midazolam spray was approved in 2019 (Detyniecki et al., 2019). Buccal midazolam is in wide clinical use in Europe and various countries (Nakken and Lossius, 2011), but has not been approved in the United States. Intranasal diazepam was approved by the US FDA in 2020. The efficacy of intramuscular diazepam delivered by autoinjector was demonstrated in a blinded controlled trial (Abou-Khalil et al., 2013), but this did not lead to FDA approval or marketing. Other approaches that were evaluated include buccal diazepam and staccato midazolam.

Status epilepticus was previously broadly defined as seizure activity that continues for 30 minutes, or recurrent seizures without recovery between attacks. The 30-minute duration has been the subject of debate, since it may delay aggressive therapy, particularly when prolonged duration can be predicted in the absence of therapy. Experimental evidence suggests that irreversible neuronal injury may start after 20–30 minutes of generalized convulsive status epilepticus (GCSE) (Fujikawa, 1996;Meldrum and Brierley, 1973), so every effort has to be made to stop seizure activity prior to that. A large body of evidence suggests that the bilateral tonic-clonic phase if focal or generalized onset seizures does not last longer than 2 minutes (Jenssen et al., 2006a;Theodore et al., 1994) except when it evolves into status epilepticus. As a result, it has been suggested that vigorous therapy for statusepilepticus be initiated after 5 minutes of bilateral tonic-clonic activity (Lowenstein et al., 1999). There is also evidence that FIAS that last longer than 10 minutes will likely evolve into status epilepticus (Jenssen et al., 2006a). Based on the above, the ILAE defined status epilepticus as a condition “resulting from the failure of the mechanisms responsible for seizure termination or from the initiation of mechanisms which lead to abnormally prolonged seizures (after time point t1), and can have long-term consequences (after time point t2)” (Trinka et al., 2015). The time point t1 for status epilepticus was 5 minutes for bilateral tonic-clonic seizures, 10 minutes for focal seizures, and 10–15 minutes for absence seizures.

Barbiturates

Pentobarbital is an oxybarbiturate analog of barbituric acid. Pentobarbital can be utilized as a sedative–hypnotic, anesthetic, and anticonvulsant. Pentobarbital’s mechanism of action is similar to that of benzodiazepines and propofol in that GABAA receptors are activated resulting in enhanced GABA binding and opening of transmembrane chloride channels leading to cellular hyperpolarization within the central nervous system. Administration of pentobarbital produces dose-dependent sedation, hypnosis, muscle relaxation, and depression of the sensory cortex and reticular activating system.

As with all GABAA agonists, pentobarbital has little or no analgesic activity. Pentobarbital produces dose-dependent respiratory depression which may require respiratory assistance (Peeters et al., 1988). At higher doses, pentobarbital possesses anticonvulsant and hypotensive properties. Hypotension results from vasodilation, diminished myocardial contractility, and reduced cardiac output. These and other cardiovascular effects depend upon the route of administration and tend to be less pronounced with IP rather than IV administration. This is due to the fact that peak blood concentration is reached more slowly than with IV administration and the portion of drug absorbed into the portal system is subject to early destruction in the liver. Hypothermia is common and has been reported in gerbils (Weinandy et al., 2005). Hypothermia is most likely a result of decreased basal metabolism and vasodilation. Additive sedation and respiratory depression can occur if pentobarbital is administered in conjunction with tranquilizers, benzodiazepines, opioids, alpha2-agonists, propofol, and inhalant anesthetic agents. Animals administered pentobarbital should be supplied supplemental oxygen or monitored with pulse oximetry. General anesthetic doses may require respiratory support or endotracheal intubation.

When pentobarbital is administered, a supplemental heat source should be applied to the animal during the surgical period and continued until full recovery to prevent hypothermia. Pentobarbital can be administered intraperitoneally or intravenously. When used as a general anesthetic, pentobarbital can be administered as a bolus (Borkowski et al., 1990) or CRI. Commercial solutions commonly contain propylene glycol, which can cause pain upon injection and thrombophlebitis. For this reason, the subcutaneous and intramuscular routes of injection are not recommended.

Pentobarbital.

Pentobarbital (or thiopental) can provide a definitive treatment for refractory SE. Short-acting barbiturates are rapid but necessitate intensive care unit treatment. Loading doses of 3 to 5 mg/kg followed by infusion of 1 to 3 mg/kg/hour are typical; some studies suggest that many patients need at least 3.5 mg/kg/hour. Effectiveness is measured as the effect on the electroencephalogram, with an attempt to eliminate seizures or aim for a burst suppression or flat record; most reviewers seek a burst suppression pattern. The half-life of pentobarbital is approximately 20 hours but may be extended at higher levels. Accordingly, prolonged coma after pentobarbital treatment should not be attributed to a "burnt out" brain before the medication has had time to dissipate. Pentobarbital levels are more useful to indicate residual toxicity than they are in assessing therapeutic effect.

All SE should be suppressible with adequate pentobarbital dosages, but hypotension is very common. Usually, volume replacement and low doses of vasopressors are sufficient. Myocardial function and temperature regulation can be impaired. Most reports of pentobarbital use show a very high mortality, usually attributed to the severe underlying diseases causing SE refractory enough to necessitate pentobarbital. An advantage of pentobarbital, besides its invariable effectiveness when used in large enough doses, is a reduction of cerebral metabolism and blood flow. The infusion is also easy to adjust. The optimal duration of barbiturate-induced coma has not been established. Recommendations range from 4 to 72 hours; at least 24 hours may be helpful. Patients probably should have therapeutic levels of two other anticonvulsants before pentobarbital withdrawal.

Beta-adrenoceptor antagonists

Pentobarbital increases the clearances and reduces the plasma concentrations of some beta-blockers, such as alprenolol [100,101], with loss of beta-blockade. In six healthy subjects pentobarbital 100 mg reduced the plasma concentrations of steady-state oral alprenolol 200 mg/day for 10 days and its metabolite 4-hydroxyalprenolol, without changes in half-lives [102].

In eight healthy subjects pentobarbital 100 mg/day for 10 days reduced the AUC of metoprolol 100 mg by 32%, with considerable interindividual variability (2–46%) [103].

Pentobarbital

Barbiturates

Pentobarbital, a barbituric acid derivative, has been used extensively for anesthesia of nonhuman primates, but it causes marked cardiovascular and respiratory depression and its effects are cumulative. Recovery from pentobarbital is prolonged and often associated with involuntary excitement and prolonged ataxia. Pentobarbital is better replaced by other agents except for terminal (nonrecovery) procedures such as perfusion-fixation, when the depressant effects of this drug are considered unimportant. Thiopental is a useful induction agent, but maintenance of anesthesia by continued infusion or administration of successive doses results in very prolonged recovery times, and it is better replaced with propofol or alphaxalone.