Propofol is an intravenous sedative-hypnotic that was introduced for clinical use in 1977 and for commercial use in the United States in 1989 (Astra Zeneca, 2003; Larson, 2005). Since the introduction of propofol into clinical practice, it has become the intravenous induction agent of choice for anesthesia providers. The main advantages of propofol over existing anesthetic induction agents include rapid induction of general anesthesia, rapid return of consciousness, minimal residual effects on the central nervous system (CNS), and a decreased incidence of postoperative nausea and vomiting (Stoelting & Miller, 2000).

Pharmacology

Propofol is commonly used for conscious sedation, as an anesthetic induction agent, for the maintenance of general anesthesia, and short-term sedation for intensive care patients who are intubated and mechanically ventilated. Propofol is a substituted isopropylphenol formulated as a 1% aqueous solution (Stoelting & Miller, 2000). The propofol emulsion formulation contains soybean oil, glycerol, and egg lecithin (derived from egg yolk). This emulsion may result in pain during injection, especially when injected into small veins. Discomfort may be reduced by mixing 2 ml of 1% lidocaine in 18 ml of propofol. An alternative formulation of 1% propofol in 16% polyoxyethylated castor oil, may decrease discomfort associated with injection (Morgan, Mikhail, & Murray, 2002). Strict aseptic technique must be adhered to as the emulsion can support microbial growth. Sepsis and death have been linked to contaminated propofol. Administration should be completed within 6 hours of opening an ampule. For administration in the intensive care unit (ICU), the bottle should be used for only 12 hours and then discarded along with any intravenous tubing (Bedford Laboratories, 2005; Morgan et al.).

The mechanism of action of propofol is related to its interaction with gamma-aminobutyric acid (GABA), which is the principal inhibitory neurotransmitter in the CNS. Specifically, propofol interacts with the GABA-receptor complex to decrease the rate of dissociation of GABA from its receptors (Stoelting & Miller, 2000). The onset of action of propofol is within 40 seconds with a peak effect of 1 minute (Omoigui, 1995). The high lipid solubility of propofol is responsible for its rapid onset (Morgan et al., 2002). Its duration of action is 5-10 minutes (Omoigui). Rapid awakening from a single bolus dose is due to a short distribution half life. Lower doses of propofol are recommended for elderly patients (Morgan et al.).

Propofol is rapidly removed from the plasma due to redistribution and rapid metabolism by the hepatic system. Currently there is no evidence that moderate hepatic dysfunction impairs the metabolism of propofol. Inactive and water soluble metabolites are excreted by the kidneys. Less than 0.3% is excreted unchanged in the urine (Stoelting & Miller, 2000). Chronic renal failure does not appear to affect the clearance of propofol (Morgan et al., 2002). As propofol is rapidly cleared and metabolized, there is little cumulative effect when administered by short-term continuous infusion (Stoelting & Miller). Long-term use in critically ill children and young adults, however, has been associated with case reports of lipemia, metabolic acidosis, and death (Morgan et al).

Effects of Propofol on Organ Systems

There are three organ systems affected by propofol: the cardiovascular system, the CNS, and the respiratory system. Propofol affects the cardiovascular system by decreasing systemic blood pressure. This effect is due to three mechanisms: decreased systemic vascular resistance due to inhibition of vasoconstrictor activity of the sympathetic nervous system, decreased cardiac contractility, and decreased preload. Exaggerated blood pressure responses may be seen in patients who are hypovolemic, in the elderly, in patients with compromised left ventricular function, with the administration of large doses, and with rapid injection (Morgan et al., 2002; Stoelting & Miller, 2000). In addition, propofol impairs the normal arterial baroreflex response to hypotension. Heart rate is generally unaffected in healthy patients; however, there have been reports of asystole in patients who are at the extremes of age, patients taking medications that exert a negative chronotropic effect, and procedures associated with the oculocardiac reflex (Morgan et al.).

In addition to the effects on GABA receptors, propofol has a number of effects on the CNS. Excitatory reactions may occur with the administration of propofol including spontaneous movement and movements that mimic tonic-clonic seizures. Propofol has anticonvulsant properties, however, and can be safely administered to patients with a history of seizures (Morgan et al., 2002). Propofol also decreases intracranial pressure, cerebral blood flow, and cerebral metabolic rate for oxygen (Stoelting & Miller, 2000).

The respiratory system is profoundly affected by propofol, producing a dose-dependent depression of ventilation and apnea (Stoelting & Miller, 2000). Infusions of propofol in doses commonly employed for conscious sedation inhibit the normal protective respiratory reflexes including the hypoxic ventilatory drive and normal response to hypercarbia (Morgan et al., 2002). Concomitant use of opioids intensifies the inhibition of these reflexes (Stoelting & Miller). In addition, there is a dose-dependent relationship to the propensity of upper airway collapse. Upper airway collapse is associated with an inhibition of the genioglossus muscle in combination with a depression of central respiratory output to the upper airway dilator muscles and reflexes (Eastwood, Platt, Shepherd, Maddison, & Hillman, 2005). Contraction of the genioglossus muscle causes the tongue to extrude and relieves upper airway obstruction in the oropharynx.

During sedation, propofol can cause airway obstruction at the soft palate and the epiglottis. When midazolam and propofol are used to induce similar levels of sedation, propofol is more likely to cause an upper airway obstruction (Litman, 2005).

The use of propofol by practitioners who are not trained in the use of general anesthesia and medications that cause deep sedation has resulted in respiratory arrest and death. The administration of propofol may have unpredictable and profound effects on the respiratory system even when administered in low doses. There is currently no reversal agent for propofol (Institute for Safe Medication Practice (ISMP) Medication Safety Alert, 2005). These facts support the joint statement of the American Association of Nurse Anesthetists (AANA) (2004) and American Society of Anesthesiologists (ASA) regarding propofol administration. The package insert explicitly states that the administration of propofol should be limited to practitioners who are trained in the administration of general anesthesia or for the sedation of critically ill patients who are intubated and mechanically ventilated and monitored by practitioners who are trained in cardiovascular resuscitation and airway management (Bedford Laboratories, 2005). In addition to the aforementioned respiratory effects, propofol may cause histamine release, but has a low incidence of bronchoconstriction and is not contraindicated in the asthmatic patient (Morgan et al., 2002). Formulations with sulfite, however, may cause a bronchospasm in patients with asthma (Stoelting & Miller, 2000).

Allergic reactions may occur after the administration of propofol and are related to the iso-propylphenol structure, the solvent used, or the sulfite preservative (Stoelting & Miller, 2000). Propofol is contraindicated in patients with a history of an allergy to propofol or the components of the emulsion (Astra Zeneca, 2003). A history of egg allergy does not necessarily contraindicate the use of propofol. Most egg allergies are related to a reaction to the egg white (albumin) (Morgan et al., 2002); and not to the egg yolk (lecithin). However, a patient who has an egg allergy should be carefully questioned.

Conclusion

Propofol has greatly influenced anesthesia practice. Its rapid induction, rapid elimination, minimal residual effects, and decreased incidence of postoperative nausea and vomiting have been beneficial for patients undergoing procedures that require sedation or general anesthesia. From a patient-safety standpoint, its administration is limited to practitioners who are trained to administer deep sedation and general anesthesia. This limitation is supported by the current research that highlights its profound and rapid effects on the respiratory system.

References