Fig. 11.1
Drug distribution in various tissues over time after an intravenous bolus dose
This rapid metabolism of propofol minimizes any residual effects after wakening. This lack of “hangover” effect makes propofol an ideal agent in ambulatory settings, where propofol induction has been associated with a more rapid recovery (Table 11.1) and earlier discharge when compared to induction with thiopental. The use of propofol for sedation for endoscopy is also associated with quicker recovery when compared to midazolam. Elderly patients have decreased clearance rates, while women have been shown to have greater clearance rates and volumes of distribution than men and therefore awaken faster from propofol anesthesia.
Table 11.1
Pharmacokinetics properties of IV anesthetic agents
Agent | Induction dose (mg/kg) | Onset of action (s) | Duration of action or awakening (min) |
|---|---|---|---|
Propofol | 1–2.5 | <30 | 2–8 |
Thiopental | 3–5 | <30 | 10–15 |
Methohexital | 1–1.5 | <30 | 10–12 |
Etomidate | 0.2–0.3 | <30 | 5–10 |
Ketamine | 1–2 | 45–60 | 12–15 |
Cardiovascular Effects
Of all the induction agents, propofol has the most profound cardiovascular depressant effects (Table 11.2). It causes the largest reduction in mean arterial pressure (MAP) and does so via several mechanisms. The primary cause of hypotension is venous and arterial vasodilation, resulting in a reduction in cardiac preload and afterload. It also inhibits baroreceptor reflexes, thereby preventing the increase in heart rate which would typically accompany these changes, further compromising MAP. Vagally mediated reflex bradycardia, and rarely asystole, may occur due to a marked decrease in preload.
Table 11.2
Cardiovascular effects of IV anesthetic agents
Agent | MAP | HR | CO | Contractility | Venodilation |
|---|---|---|---|---|---|
Propofol | ↓↓ | ↓ | ↓ | ↓ | ↓↓ |
Thiopental | ↓ | ↑ | ↓ | ↓ | ↓↓ |
Etomidate | 0 | 0 | 0 | 0 | 0 |
Ketamine | ↑↑ | ↑↑ | ↑ | ↑/↓ | 0 |
Hypotension may be exacerbated by rapid injection, large doses, old age, and impaired cardiac function. Adequate intravascular volume hydration, as well as slow and titrated dosing, can minimize the reduction in MAP in susceptible individuals, such as the elderly. However, neither the duration of fasting nor the rate of administration has been shown to make a significant difference in young, healthy patients.
Respiratory Effects
Propofol causes profound respiratory depression, consistently producing apnea at induction doses. At lower doses, such as those used for sedation, minute ventilation is reduced, with greater decreases in tidal volume than respiratory rate. The ventilatory response to hypoxia and hypercarbia is reduced as well. Propofol is generally considered the most effective agent at blocking upper airway reflexes during direct laryngoscopy or laryngeal mask airway placement. It has also been shown to decrease the incidence of bronchospasm when compared to thiopental and etomidate in healthy patients, asthmatics, and smokers. In addition, smokers anesthetized with propofol experience less coughing upon extubation than those anesthetized with sevoflurane. Propofol does not inhibit hypoxic pulmonary vasoconstriction.
Central Nervous System Effects
Propofol depresses the central nervous system (CNS) as well, resulting in a decreased cerebral metabolic rate of oxygen consumption (CMRO2). This, along with cerebral vasoconstriction, reduces cerebral blood flow (CBF) and cerebral blood volume (CBV). The reduction in CBV reduces intracranial pressure (ICP) and effectively “shrinks” the brain to improve the neurosurgical field (Table 11.3). Despite the cerebral vasoconstriction, propofol does maintain cerebrovascular autoregulation in response to changes in MAP (within the normal range) and changes in pCO2.
Table 11.3
Central nervous system effects of IV anesthetic agents
Agent | CMRO2 | CBF | CPP | ICP |
|---|---|---|---|---|
Propofol | ↓↓ | ↓↓ | ↓ | ↓ |
Thiopental | ↓↓ | ↓↓ | ↑/↓ | ↓↓ |
Etomidate | ↓↓ | ↓↓ | ↑ | ↓ |
Ketamine | ↑ | ↑↑ | ↑/↓ | ↑ |
Like barbiturates, propofol affords neuroprotection from focal ischemia. All of these properties make propofol a popular choice for neuroanesthesia, though it must be realized that propofol can decrease cerebral perfusion pressure (CPP) given its depressant effects on MAP. Propofol is not an ideal choice for implantation of deep brain stimulation, as it leads to a significant decrease in the neuronal activity of the subthalamic nucleus, thereby interfering with the identification of this structure.
Propofol has anticonvulsant effects, producing burst suppression on the electroencephalogram (EEG), and can also be used to break status epilepticus when other treatments have failed. Induction with propofol sometimes produces excitatory phenomenon producing muscle twitching, spontaneous movement, or hiccupping. Propofol produces a dose-dependent decrease in the bispectral index (BIS), and this effect is additive with that of volatile anesthetics. As is the case with surgery and general anesthesia in general, propofol has been shown to disrupt circadian sleep structure by altering melatonin secretion. It has been shown to produce an equal degree of amnesia compared to midazolam when used at equal levels of sedation. When compared to midazolam, propofol has been associated with significantly more dreaming when used for sedation. Propofol decreases intraocular pressure, and tolerance is not known to develop after long-term propofol infusions.
Dosage and Uses
A.
Induction of anesthesia: 1–2.5 mg/kg. Children usually require higher doses than adults, while elderly patients require lower dosages. Women may require a higher induction dosage than men.
B.
Sedation: 25–100 mcg/kg/min. Sedation with propofol is provided in the operating room, emergency room, intensive care unit, and other procedural units.
C.
Maintenance of anesthesia: 50–200 mcg/kg/min. Maintenance of anesthesia can be provided with or without the addition of a volatile inhalational agent. Patients with contraindication to the use of an inhalational agent (malignant hyperthermia, muscular dystrophies) are often maintained with a propofol infusion.
D.
Antiemetic effect: Propofol is known to have an antiemetic effect, which is in contrast to the pro-emetic effect of thiopental and etomidate. It can be given as a low-dose intraoperative infusion (10–20 mcg/kg/min) to prevent postoperative nausea and vomiting (PONV) and can also be used as a rescue drug with 10 mg doses followed by a 10 mcg/kg/min infusion to treat refractory PONV. Though it has been shown to decrease lower esophageal sphincter pressure during high-dose infusions, the clinical significance of this is unknown.
E.
Antipruritic effect: Propofol is also unique among the induction agents, in that it has antipruritic effects.
F.
Other effects: Unlike volatile agents, propofol does not seem to impair glucose tolerance, thereby potentially leading to less intraoperative hyperglycemia.
Side Effects
A.
Pain on injection: Pain on injection is a common, undesirable effect of propofol administration, with reported incidences ranging between 30 and 90 %. Many recent studies have examined ways to eliminate or lessen this pain. Effective techniques include dilution, slow injection, injection into larger veins, pretreatment with intravenous analgesics (opiates, ketamine, dexmedetomidine, acetaminophen), or pretreatment or mixing with lidocaine (30–50 mg of 1 % lidocaine/200 mg propofol).
Tourniquet-controlled pretreatment with lidocaine is more effective than mixing propofol with lidocaine, and combination of pretreatment with opiates and lidocaine is more effective than either technique alone. A 0.5 ml priming dose of propofol injected slowly over 30 s, 2 min prior to the main induction dose, has also been shown to decrease injection pain with the main dose. In addition, a new solvent consisting of a mix of medium- and long-chain triglycerides, as opposed to the standard long-chain formulation, has been shown to cause decreased pain on injection.
B.
Egg allergy: Formulations of propofol contain egg lecithin, and therefore, propofol use is sometimes cited as a contraindication in egg-allergic individuals. However, the vast majority of egg-allergic individuals react to proteins found in egg white (ova albumin), and not to egg lecithin, which is found in egg yolk. Indeed, a recent review of patients with documented egg allergy who received propofol found that nearly all individuals had no reaction to the drug.
C.
Bacterial growth: The current commonly used lipid emulsion formulation of propofol can support bacterial and fungal growth, and therefore, it is recommended that propofol should be used within 6 h of opening the vial to reduce the risk of infection from extrinsic contamination. Current formulation of propofol may contain 0.025 % of sodium metabisulfite or 0.005 % edetate to confer antimicrobial properties. Lidocaine, which possesses bacteriostatic properties, can be added to propofol to confer these properties to the mixture and potentially further reduce the risk of infection. A new bioequivalent microemulsion of the drug has been recently developed, which may be safer to use than the current formulation.
D.
Propofol infusion syndrome: Prolonged infusions can rarely result in a condition called propofol infusion syndrome, characterized by lipemia, metabolic acidosis, rhabdomyolysis, renal failure, and cardiac failure. Children and critically ill patients, especially those receiving corticosteroids, appear to be at greatest risk.
E.
Propofol abuse: Propofol abuse in academic anesthesiology has become a problem in recent years. Eighteen percent of all academic anesthesiology departments with training programs reported at least one incident of abuse or diversion in the past 10 years. There appears to be an association between lack of pharmacy accounting and the incidence of propofol abuse.
Thiopental
With the increasing use of propofol, thiopental is now much less frequently used than it was in the past. In fact, it is no longer available for use in the United States. Methohexital, a shorter-acting barbiturate, is still used for anesthesia for electroconvulsive therapy. Barbiturates are acidic drugs, but are manufactured as sodium salts which have a pH > 10. With this basic pH of greater than 10, thiopental precipitates when mixed with acidic drugs, such as nondepolarizing neuromuscular blockers, which can completely occlude intravenous lines. Thiopental is available as a 2.5 % solution and the induction dose is 3–5 mg/kg in adults.
Mechanism of Action
Thiopental, being a barbiturate, shares many characteristics with other drugs of that class, including its mechanism of action: activation of GABA channels, causing increased duration of inhibitory chloride channel opening. In addition to its hypnotic actions in the brain, it also depresses the response to noxious stimuli in the dorsal horn of the spinal cord.
The onset of action of thiopental after a bolus dose has been shown to be slightly faster than that of propofol, though any clinical relevance of this is doubtful. Thiopental is highly lipid soluble and highly protein bound, but with a greater nonionized fraction, which leads to rapid initiation of action (30 s). Termination of action or awakening (10–15 min) occurs via redistribution (alpha elimination). Like propofol, thiopental also undergoes hepatic metabolism to inactive metabolites, but at a much slower rate (4–12 h beta elimination). Though emergence still occurs very rapidly after a bolus dose by redistribution, total recovery is much slower than with propofol. Indeed, a “hangover” effect from a single induction dose can last for hours, making thiopental a less attractive choice for ambulatory surgery. Compared to thiopental, methohexital is metabolized in the liver about three times faster than thiopental. Therefore, psychomotor recovery is faster with methohexital than with thiopental.
Related posts:
Stay updated, free articles. Join our Telegram channel
Full access? Get Clinical Tree
