Table 6.1. Comparison of Sedatives and Analgesics
Midazolam
Midazolam is a rapid-acting benzodiazepine that has become the most widely used drug for ED conscious sedation. It has 3 to 4 times the potency of diazepam with peak onset of action occurring within 2 to 3 minutes of intravenous administration. It is rapidly redistributed and has a short duration of action (20 to 30 minutes). Being highly soluble in water at physiologic pH, it does not require propylene glycol as an additive to facilitate solubility (as does diazepam), and thus is nonirritating to veins. There is high hepatic first-pass metabolism of midazolam resulting in 50% loss of efficacy using the oral or rectal route of administration. The drug binds g-aminobutyric acid receptors in the central nervous system, inhibits spinal afferent pathways, and produces skeletal muscle relaxation, amnesia, and anxiolysis. It, as with all benzodiazepines, alters the response to pain but does not reduce pain perception. It does have the advantage of producing both anterograde and retrograde amnesia of the event. When used for painful procedures, however, it is recommended that it be combined with an analgesic. Midazolam can be reversed with
flumazenil.
The dosage of midazolam is 0.05 to 0.1 mg/kg intravenous. The drug is also effective via the intranasal, sublingual, oral, or rectal routes. Physicians should be aware that this medication is “off-label” and the PDR is not an adequate source for information regarding its use ( 20A).
Morphine
Morphine has long been the gold standard by which all other analgesics are judged. It is analgesic, reduces anxiety, and is sedating. Morphine has been shown to be more effective for continuous dull pain than for sharp or lancinating types. It has poor lipid solubility and, as such, penetrates the central nervous system with difficulty. This property limits its usefulness as a sedative although it can still be effectively used as an analgesic. It produces significant histamine release and hypotension. Despite its slow onset of action (5 minutes intravenous, 10 to 15 minutes intramuscularly) and a prolonged duration of action (3 to 4 hours), it works well with benzodiazepines to produce analgesia. The preferred route is intravenous with dosage of 0.1 mg/kg titrated to effect. Naloxone will reverse effects of excessive dosage.
Meperidine
Meperidine is the most commonly used narcotic analgesic in emergency medicine. It is a synthetic opiod with one-tenth the potency of morphine. It too produces histamine release, but unlike morphine has a direct myocardial suppressant effect at therapeutic doses. Through its metabolite normeperidine, it has the potential to cause central nervous system excitation with possible seizure development. Meperidine is poorly titratable with an onset in 15 to 30 minutes and a duration of action of 2 to 3 hours when given in doses of 1 to 2 mg/kg. Because of its central nervous system excitation and its poor titratability, it has limited usefulness in the setting of conscious sedation although it remains widely used by many practitioners who have long experience with its use and side-effect profile.
Fentanyl
Fentanyl is a synthetic narcotic 100 times as potent as morphine and 7,000 times as lipophilic. Because of its significant lipid solubility, it is rapidly taken up by
lipid-rich brain tissue within 30 to 60 seconds of intravenous injection and reaches peak effect in 2 to 3 minutes. It is redistributed rapidly to peripheral skeletal muscle and adipose tissue resulting in short duration of action of between 20 to 30 minutes. It has been called “the twenty minute drug for the twenty minute procedure.” The adverse effects of fentanyl are related to either rate of administration or total dosage (greater than 8 to 10 mcg/kg). Too rapid administration of fentanyl can cause rigidity of the chest wall inspiratory muscles and result in sustained inspiration (i.e., the “tight chest syndrome”). Central vagal stimulation results in bradycardia,
sometimes significant. All adverse effects of fentanyl are reversible with naloxone.
Despite the fact that metabolism in infants is prolonged, children are less likely than adults to suffer respiratory depression from fentanyl administration. In higher doses, fentanyl has sedative properties as well as its primary analgesic effects.
Dosage of fentanyl is 2 to 4 mg/kg at 1 mg/kg increments spaced 2 to 3 minutes apart. The finding by Pohlgeers et al. (21) that when mixed with diazepam, reduced saturation of oxygen was more likely if dosage was above 2 mg/kg. Therefore, with combinations, the dosage should be 2 mg/kg or less.
Thiopental
Thiopental is an ultrashort-acting barbiturate hypnotic that reaches the brain within 30 seconds of intravenous administration. It produces profound hypnosis and sedation that lasts 10 to 15 minutes at doses below those that produce respiratory suppression. Because of its propensity to stimulate histamine release, it must be used with great caution in the asthmatic population. In addition, it can produce significant hypotension through peripheral venodilation and suppression of the baroreceptor reflex. Its' effects on the central nervous system are dose-dependent and consist of reduction in central nervous system metabolism, intracranial
pressure, and cerebral blood flow making it an ideal agent for use in the head injured patient. Its sedative dose is 1 mg/kg intravenous every 1 to 2 minutes titrated to effect or total dose of 3 to 5 mg/kg. Because of its extreme alkalinity and the potential for tissue necrosis, care must be taken not to extravasate the solution.
Pentobarbital
Pentobarbital is a short-acting barbiturate that produces sleep within 30 seconds when given intravenously in doses of 3 to 5 mg/kg. It produces sedation within 5 minutes and has a duration of action of 30 to 60 minutes. It is ideally suited for nonpainful diagnostic studies such as computed tomography and magnetic resonance imaging. The major problem with pentobarbital is hypoxia due to respiratory suppression.
Methohexital
Methohexital is similar to thiopental when given in doses of 0.5 to 1.0 mg/kg intravenous. It has a more rapid onset and shorter duration of action.
Propofol
Propofol is an ultrashort-acting intravenous sedative-hypnotic with a rapid onset, rapid emergence and return to baseline. It also has the added benefit of being an antiemetic. As with barbiturates, propofol produces dose-dependent depression of respiration, apnea, and hypotension. It has no amnestic or analgesic effects and must be used in combination with other agents to produce these desired actions. Propofol can be administered either as repeat boluses or at a constant infusion of 25 mg/kg per minute and titrated up to a total dose of 100 mg/kg per minute. Propofol has been reported to cause pain at the intravenous injection site.
Ketamine
Ketamine is unique to conscious sedation as it is the only agent that functions as a dissociative anesthetic. It produces a trancelike state, cataleptic in appearance in which there is interference with the sensory perception of painful stimuli. It is completely amnestic and significantly sedative. It gives meaning to the expression “the lights are on but no one is home” as the patients frequently will have their eyes open, staring blankly into space. It can be quite disconcerting to parents watching the procedure as patients will frequently move their extremities involuntarily, moan unrelated to the procedure and appear to be awake, but in effect are completely disconnected from reality. Ketamine has been proven safe and effective in over 11,000 children.
Ketamine is a positive inotrope and increases heart rate, blood pressure, cardiac output, and intracranial pressure. Although it increases bronchial secretions, it affords bronchodilation making it particularly useful in the asthmatic population. It does not depress airway reflexes. Rarely, it has been reported to produce laryngospasm, which is reversible by positive airway pressure using an ambu-bag. Ketamine requires pretreatment with atropine (0.01 mg/kg) to counteract its tendency to increase oral secretions.
The dose of ketamine is 1 to 2 mg/kg intravenous or 2 to 4 mg/kg intramuscular. It is the only sedating agent which is consistently effective by the intramuscular route and can be mixed in a syringe with atropine (0.01 mg/kg) and given intramuscularly. For prolonged sedation and to combat dysphoria on emergence, midazolam (0.05 to 0.1 mg/kg) can be administered by intramuscular injection in the same syringe or preferably given intravenously.
Contraindications to ketamine include head injury with increased intracranial pressure, age less than 3 months or greater than 10 years (although it has been used safely in multiple adult trials), upper respiratory infections, and mental illness. Rarely, recovery has been prolonged for up to several hours (more likely to occur with concomitant administration of sedatives), and emergence hallucinations also occur. Vomiting occurs in up to 40% of patients on emergence and can be treated with antiemetics.