Review of Propofol and Auxiliary Medications Used for Sedation

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Marsha L. Ellett, PhD, RN

ABSTRACT The sedative-hypnotic propofol (2,6-diisopropylphenol) is being increasingly used for sedation during painful diagnostic and therapeutic procedures in adults and children. The purpose of this article is to present a general overview of the use of propofol for endoscopic sedation. Advantages and disadvantages of using propofol for sedation, as well as its pharmacokinetics, preparation for use, dosing for endoscopic sedation, auxiliary sedative and analgesic medication options, methods of administering, adverse effects with interventions, recovery, and patient–physician satisfaction are discussed. Finally, next steps necessary to optimize future use of propofol are suggested.

ropofol (2,6-diisopropylphenol, Diprivan; Pharmacokinetics AstraZeneca, Wilmington, DE), a rapid-acting Propofol pharmacokinetics involves a three-compart- sedative–hypnotic medication, was introduced ment model: plasma, rapidly equilibrating tissues, and clinically by Pecaro and Houting in 1985 slowly equilibrating tissues (Schnider et al., 1998). P(Pecaro & Houting, 1985) and approved by the U.S. Propofol is 98% plasma-protein bound (American Food and Drug Administration (FDA) in 1989 for the Society for Gastrointestinal Endoscopy [ASGE], 2004). induction and maintenance of general anesthesia and The rapid onset of anesthesia and sedation, approxi- sedation in ventilated patients. In addition to its seda- mately 40 seconds after an intravenous induction dose, is tive and hypnotic properties, propofol provides amne- due to the rapid equilibration between plasma and the sia but minimal levels of analgesia. As case reports of highly perfused tissue of the brain (Schnider et al., 1998). propofol infusion syndrome (PRIS) surfaced (discussed Peak effect is 1-2 minutes, and duration of effect is 4- later under serious adverse effects), a serious adverse 8 minutes (SedationFacts.org, 2010). Propofol decreases effect warning against the long-term use of propofol in cerebral metabolism specifically in the frontal, parietal, pediatric patients was issued (American Academy of and occipital lobes and hippocampus that involve areas Pediatrics Committee on Drugs, 1992). This led to a belonging to the sensory (auditory, visual, and voluntary change in the package insert provided by somatosensory), motor, and limbic systems (Kikuchi, AstraZeneca. At first, the FDA chose not to issue a Wang, Sato, & Okumara, 1998; Sanna et al., 1999). It warning, citing that its review of the data failed to find exerts its effect by modulating the inhibitory function of a link between propofol infusion and deaths in chil- the main neurotransmitter ␥-aminobutyric acid (GABA)

dren (FDA, 1992); however, in 2001, the FDA did mainly through GABAA receptors (Trapani, Altomare, issue a recommendation that propofol not be used for Sanna, Biggio, & Liso, 2000). GABAA receptors are pediatric sedation. The FDA has not changed its rec- ligand-gated ion channels coupled to an integral chloride ommendation in the interim. channel (Sieghart, 1995). Propofol has no direct effect on either the sinoatrial Received July 31, 2009; accepted November 29, 2009. or atrioventricular (AV) node conductivity of the heart; however, it does decrease heart contractility and after- About the author: Marsha L. Ellett, PhD, RN, is Professor, Indiana University School of Nursing, Indianapolis. load reduction leading to hypotension (Romano et al., Correspondence to: Marsha L. Ellett, PhD, RN, Indiana University 1994). A decrease in cerebral blood flow by up to 50%, School of Nursing, 1111 Middle Drive, Room 439, Indianapolis, IN with a simultaneous decrease in intracranial pressure, 46202 (e-mail: [email protected]). has been seen following propofol use (Marinella, DOI:10.1097/SGA.0b013e3181eac371 1997).

Review of Propofol and Auxiliary Medications Used for Sedation

Propofol has dose-dependent, radical-scavenging or should not used if there is evidence of sedimentation activities similar to the endogenous antioxidant vitamin or discoloration (Leffler, 2004). Propofol is incompatible E (Vanlersberghe & Camu, 2008). It also demonstrates with polyvinyl chloride infusion tubing. Compatible anti-inflammatory properties and mild bronchodilating intravenous solutions include: Ringer’s lactate solution capabilities and has been shown to be useful in the (RL), 5% dextrose (D5), D5/RL, D5/0.45 sodium chlo- management of refractory seizures and severe delirium ride (NS), and D5/0.25NS (AstraZeneca, 2001; Levadouz, tremens (Marik, 2004). Propofol does not trigger Sautou, Bazin, Schoeffler, & Chopineau, 1996; Sautou- malignant hypothermia (Fruen, Mickelson, Roghair, Miranda, Levadoux, Groueix, & Chopineau, 1996). Litterer, & Louis, 1995). Depending on the manufacturer, ethylenediaminete- Because the half-life of propofol is very short, recov- traacetic acid (Diprivan) or sodium metabisulfite (generic ery from sedation with propofol is quick and smooth propofol) are added to retard microbial growth (Kang, with little nausea and vomiting (Bryson, Fulton, & 2002; Marik, 2004). In spite of these additives, propofol Faulds, 1995). Propofol is metabolized in the liver by supports bacterial growth from extrinsic contamination the cytochrome P450 system into four inactive once the ampule or vial is accessed. Because even small metabolites, 1-quinol glucuronide, 4-quinol glu- numbers of organisms may result in clinical infections, curonide, propofol glucuronide, and 4-quinol sulfate, strict aseptic techniques, including disinfecting appropri- and eliminated in the urine (Bryson et al., 1995; Cillo, ately the neck of ampules or the rubber stopper of vials 1999; Schnider et al., 1998; Trapani et al., 2000; before use, using careful technique when preparing a Vanlersberghe & Camu, 2008). syringe of the medication immediately before use, The pharmacokinetic parameters of propofol are restricting the use of an ampule or vial to a single patient, altered by factors including weight (SedationFacts.org, and discarding any unused medication after 6 hours, are 2010). A prolonged effect may be observed in patients essential during the handling of propofol to prevent extrin- with high proportions of adipose tissue compared with sic contamination and dangerous infectious complications overall body weight (Steinbacher, 2001). The presence (Bryson et al., 1995). of cirrhosis or renal dysfunction does not significantly alter the pharmacokinetics of propofol (Bryson et al., Recommendations of 1995; Weston et al., 2003). Professional Organizations Propofol rapidly crosses the placenta and may lead According to the American Society of Anesthesiologists to neonatal depression (Bryson et al., 1995; Rex, (ASA, 2006), all deep sedation should be provided by Overley, & Walker, 2003). It has reportedly been trained anesthesia providers. On the other hand, the found in human milk, but the effects of small amounts American Gastroenterological Association, the of propofol on infants are not known; therefore, American College of Gastroenterology, and the ASGE propofol should be used during pregnancy and lacta- issued a joint statement that propofol can safely be tion only if clearly needed (SedationFacts.org, 2010). administered by specially trained nurses under the supervision of an endoscopist. Preparation for Use Propofol is lipophilic (i.e., fat soluble) and is prepared The Society of Gastroenterology Nurses and as an oil–water emulsion consisting of 1% propofol, Associates, Inc. support the position that regis- 10% soybean oil, 2.25% glycerol, and 1.2% egg lecithin tered nurses trained and experienced in gastroen- (ASGE, 2004). It is available in 20-, 50-, or 100-mL terology nursing and endoscopy can administer vials containing 10 mL/mg propofol (SedationFacts.org, and maintain moderate sedation and analgesia 2010). The patent for Diprivan expired in 1999 (Kang, by the order of a physician. In addition, the 2002). In collaboration with Baxter Healthcare gastroenterology registered nurse can be given Corporation (Deerfield, IL), Gensia-Sicor received the responsibility for the administration of reversal FDA approval for generic propofol the same year. agents prescribed by the physician. (2008, Although propofol can cause allergic reactions, it is p. 250) generally safe from anaphylactic reactions because it does not promote the release of histamine from mast Currently, state boards of nursing in 30 states allow cells (Stellato et al., 1991). Patients who are allergic to registered nurses to administer moderate (conscious) eggs, soy products, or sulfites as well as those having sedation under the direct supervision of a physician known mitochondrial or lipid metabolism disorders (SedationFacts.org, 2010). should not receive propofol (Marik, 2004). Because propofol is a lipid-based medication, neither Dosing for Endoscopic Sedation refrigeration nor freezing are recommended. It must be According to SedationFacts.org (2010), ASA Classes I shaken well prior to use and should be uniformly white (healthy) and II (limited disease) adults younger than

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Review of Propofol and Auxiliary Medications Used for Sedation

55 years should receive an initial dose of 10-40 mg midazolam postcolonoscopy, provides great amnesia, propofol followed by incremental intravenous bolus and has high patient preference (Rex et al., 2002; Sipe, doses of 10-20 mg at 3- to 5-minute intervals as need- Latinovich, Bratcher, & Rex, 2001), it produces syner- ed or a continuous drip of 25-75 ␮g/kg per minute iv. gistic activity when administered concurrently with In children, the unfamiliar environment, fear of sepa- benzodiazepines and opioids allowing smaller doses to ration from parents, and painful events often lead to a be used with fewer and milder adverse effects stress response. Also of note, the volume of propofol’s (Steinbacher, 2001). Cohen, Hightower, Wood, Miller, central distribution is larger in children than in adults and and Aisenberg (2004) combined propofol with mida- clearance is higher (Roelofse, 2000); therefore, children zolam and fentanyl (or meperidine) in 100 ASA Classes require 1.5 times higher doses of propofol per kilogram I-II adult patients undergoing esophagogastroduo- to achieve the same level of sedation and hypnosis as denoscopy (EGD) or colonoscopy. This combination of adults (Bryson et al., 1995; Hanna & Ramundo, 1998). medications allowed a moderate level of sedation in Children (3 years and older) can receive 1-2 mg/kg of which the endoscopy procedure was performed safely propofol iv bolus administered over 30 seconds initially and effectively. Mean recovery time was 16 minutes for followed by 0.5-1 mg/kg doses at 3- to 5-minute intervals EGD and 14 minutes for colonoscopy; these times as needed or alternatively receive a continuous infusion of compare favorably with those obtained when higher 50-150 ␮g/kg per minute following the initial bolus dose. doses of propofol alone were used. Patient satisfaction Older patients show a greater sensitivity to the hypnotic with sedation remained at 90% or more. The results of effect of propofol as a result of a smaller central compart- the study of Rudner et al. (2003) support the results of ment and a lower rate of clearance, possibly because of Cohen et al. (2004); therefore, the benzodiazepines decreased cardiac output and hepatic blood flow (Bryson midazolam and diazepam, and the narcotics fentanyl et al., 1995; Chan & Chung, 1996; Gan, 2006; Schuttler and meperidine will be presented in the following text & Ihmsen, 2000; Vanlersberghe & Camu, 2008). Twenty as possible auxiliary medications. The reversal agents percent lower doses of propofol for moderate sedation are flumazenil and naloxone will also be discussed. needed for endoscopic procedures in patients 50 years or older (Byrne & Baillie, 2002). A gender difference has Midazolam been noted, with older women needing a larger dose of Midazolam hydrochloride (Versed; Roche Pharmaceuticals, propofol than men (Vuyk, Oostwouder, Vletter, Burm, & Nutley, NJ), a water-soluble, short-acting benzodiazepine Bovill, 2001). Chan and Chung (1996) found that propo- that is a central nervous system (CNS) depressant, is a fol and fentanyl administered by a slower rate of contin- widely used drug that has the following characteristics: uous infusion resulted in a lower total dose of propofol sedative–hypnotic, anxiolytic, muscle relaxant, anticon- being needed, greater hemodynamic stability during the vulsant, and anterograde amnesia (Sievers, Yee, Foley, procedure, and more rapid return to wakefulness and pre- Blanding, & Berde, 1991); however, it lacks analgesic procedure mental orientation. According to SedationFacts. properties. When used for sedation in painful procedures, org (2010), elderly debilitated or ASA Class III and above a narcotic must usually be added (Kotash, Johnston, patients should receive a smaller bolus dose, with longer Bailey, Konopad, & Guthrie, 1994). Midazolam is water intervals between doses. The assistance of an anesthesiol- soluble at an acidic pH Ͻ 3. After intravenous adminis- ogist is encouraged in these patients. tration, it undergoes an intramolecular reconfiguration Propofol has no analgesic properties; thus, adminis- at physiological pH 7.4, increasing its lipid solubility tration in sufficient doses to eliminate pain during endo- (SedationFacts.org, 2010). Midazolam was approved scopic procedures or to eliminate gagging and coughing by the USFDA in 1986 for intravenous use in induction during and after esophageal intubation is often associat- of general anesthesia and to induce moderate sedation ed with deep sedation. Deep sedation is defined as a state during short diagnostic or therapeutic procedures of depressed consciousness or unconsciousness from (Arrowsmith, Gerstman, Fleischer, & Benjamin, 1991). which the patient is not easily aroused. There may be Oral midazolam used as a premedication may be pre- partial or complete loss of protective reflexes and may pared from a 1:1 ratio of 2.5 mg/ml of injectable mida- include the inability to maintain a patent airway and zolam hydrochloride (5 mg/ml) and a colorless, flavored respond purposefully to physical stimulation or verbal syrup (Liacouras, Mascarenhas, Poon, & Wenner, 1998). command (American Academy of Pediatrics Committee In this study, children were given 0.5 mg/kg of the oral on Drugs, 1992). There is no reversal agent for propofol. midazolam (maximum of 20 mg [10 mg of midazolam]) approximately 20 minutes before intravenous catheter Auxiliary Amnestic and Analgesic placement and 35 minutes before beginning intravenous Medication Options sedation for endoscopy. These researchers found it easier Although propofol used alone reduces mean recovery to insert the intravenous catheter and to separate the time by 31 minutes compared with meperidine and child from the parent. Premedication with midazolam

Review of Propofol and Auxiliary Medications Used for Sedation

also extended the child’s amnesia for preprocedure events be injected slowly, taking at least 1 minute for each leading to increased child and parent satisfaction. 5 mg injected. The onset of action is 2-3 minutes, with Midazolam oral premedication did not affect intravenous peak effect in 3-5 minutes and the duration of effect is 6 moderate sedation dosage or vital signs (Liacouras et al., hours. Children should receive 0.2-0.3 mg/kg with a 1998). maximum dose of 10 mg orally or 5 mg iv in a large Midazolam is 1.5-3.5 times more potent than vein infused slowly over a 3-minute period, with dosage diazepam following intravenous administration not to exceed 0.25 mg/kg followed by 2.5 mg as an (SedationFacts.org, 2010). The recommended initial additional dose after 15-30 minutes as needed to achieve dose in adults is 1-2 mg, with 1 mg additional doses and maintain moderate sedation. The efficacy and safe- administered at 2-minute intervals as needed. The onset ty of parenteral diazepam have not been established in of action is 1-2 minutes and reaching peak effect in neonates (Յ30 days of age), apparently because of their 3-4 minutes. The duration of effect is 15-80 minutes. inability to biotransform the drug into inactive metabo- In general, children require higher doses of midazolam lites. Adolescents should receive 10 mg orally or 5 mg iv, (mg/kg) than do adults. For children 6 months to 12 years with a 2.5-mg repeat dose if needed. Diazepam should of age, the recommended initial dose is 0.05 mg/kg, not be mixed with other medications. More than 50% with additional 0.05 mg/kg doses at 3-minute intervals of the diazepam in the infusate may be adsorbed onto as needed. The maximum dose at one time is 2.5 mg, the walls of plastic containers. Severe hypotension and and the maximum total dose is the lesser of 0.3 mg/kg seizures have been reported following rapid intravenous or 15 mg. The dose should be reduced by 30% if nar- administration of midazolam, particularly with con- cotics or other CNS depressants are given in conjunc- comitant use of fentanyl (SedationFacts.org, 2010). tion with midazolam. Dosage in obese children should In elderly and chronically ill patients, the initial dose be calculated on the basis of ideal body weight of diazepam should be small and gradually increased. (SedationFacts.org, 2010). Extreme care should be exercised in administering The main drawback of midazolam is the potential diazepam to elderly patients with limited pulmonary for accumulation of the drug resulting in prolonged reserve (SedationFacts.org, 2010). When diazepam is sedation and a hangover effect (Gan, 2006). In elderly used with a narcotic analgesic, the dosage of the nar- and obese patients and those with hepatic impairment, cotic should be reduced by at least one-third and midazolam has a reduced clearance and prolonged administered in small increments (SedationFacts.org, half-life; therefore, in elderly patients (Ն65 years) and 2010). those with chronic disease(s), initial and subsequent Manifestations of diazepam overdosage include dosing should be half of the adult dosing (Gan, 2006). somnolence, confusion, coma, and diminished reflexes (SedationFacts.org, 2010). An increased risk of con- Diazepam genital malformations associated with the use of minor Diazepam (Valium; Roche Pharmaceuticals) is an intra- tranquilizers including diazepam during the first venous and orally active benzodiazepine. Like midazolam, trimester of pregnancy has been suggested in several its pharmacological effects include anxiolysis, sedation, studies; therefore, the use of diazepam should be amnesia, anticonvulsant, muscle relaxation, and anesthesia avoided during pregnancy (SedationFacts.org, 2010). (SedationFacts.org, 2010). In adults, oral diazepam has been approved by the FDA for induction of moderate seda- Fentanyl tion in people undergoing gastrointestinal endoscopy Fentanyl (Sublimaze; Baxter Healthcare Corporation) is (Arrowsmith et al., 1991). Martinez et al. (2002) recom- a short-acting synthetic opioid narcotic that primarily mended an oral dose of 0.3 mg/kg, with a maximum dose undergoes hepatic metabolism. It was first approved for of 10 mg be given as a premedication. In children, although hospital use in 1992 (Chuang, William, Wenner, & diazepam promotes decreased anxiety, it has been associ- Picolli, 1995). Fentanyl has a high lipid solubility that ated with increased nausea, vomiting, and headache (van allows quick penetration of the blood–brain barrier der Walt, Jacob, Murrell, & Bentley, 1990). resulting in rapid pain relief, more sedative effect than Diazepam is not water soluble; the propylene glycol meperidine, and faster recovery (Ali, Davidson, & solvent may cause pain and irritation with intravenous Gremse, 2004; Chuang et al., 1995). injection (Sievers et al., 1991). Furthermore, diazepam In adults, the suggested initial dose for endoscopy is has a long elimination half-life (24-57 hours), with an 50-100 ␮g fentanyl with additional doses of 25 ␮g active plasma metabolite, desmethyl diazepam, occa- administered every 2-5 minutes until adequate sedation sionally causing mild prolonged psychomotor impair- and pain relief is achieved (SedationFacts.org, 2010). ment (Sievers et al., 1991). In children older than 12 years, an initial dose of Adults can receive 5-10 mg of diazepam as an initial 0.5-1 ␮g/kg of fentanyl is recommended, with a maxi- dose (SedationFacts.org, 2010). The medication should mum dose of 5 ␮g/kg or 250 ␮g (whichever is less)

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Review of Propofol and Auxiliary Medications Used for Sedation

(SedationFacts.org, 2010). A reduction of at least 50% with meperidine use include respiratory, myocardial, of the recommended adult dose is indicated for elderly and CNS depression; histamine-releasing effects; light- patients. headedness; dizziness; nausea; vomiting; and sweating Because there are no adequate and well-controlled (Ali et al., 2004; SedationFacts.org, 2010). studies in pregnant women, fentanyl should be used in pregnant women only if the potential benefit justifies Flumazenil the potential risk to the fetus (SedationFacts.org, Flumazenil (Romaxicon; Roche Pharmaceuticals) is 2010). Fentanyl should be administered with caution structurally related to benzodiazepines but acts as an to patients with liver and kidney dysfunction because antagonist to reverse the sedative effects of these med-

of the importance of these organs in its metabolism ications (SedationFacts.org, 2010). It acts at the GABAA and excretion. Fentanyl is contraindicated in patients receptor complex to competitively inhibit the activity of with myasthenia gravis (SedationFacts.org, 2010). benzodiazepines at the receptor sites. Flumazenil is Adverse effects associated with fentanyl include venti- administered intravenously to counteract the effect of latory depression, nausea, vomiting, muscular rigidity, benzodiazepines including sedation, memory loss, psy- bradycardia, and pruritus (Yaster, Nichols, Deshpande, & chomotor impairment, and respiratory depression. It is Wetzel, 1990). In neonates, fentanyl can produce bradycar- more effective in reversing sedation and amnesia than dia secondary to central vagal stimulation leading to pro- respiratory depression. Its action is highly specific; there- longation of the refractory period of the AV node. When fore, it cannot be used to reverse the effects of opioids fentanyl is administered too rapidly, chest wall rigidity can (SedationFacts.org, 2010). occur rarely leading to cardiac arrest (Yaster et al., 1990). In adults of all ages, the recommended initial dose is Opioid infusion should be discontinued 10-20 min- 0.2 mg iv administered over 15 seconds (SedationFacts. utes before propofol infusion (Jenstrup, Nielson, org, 2010). If desired consciousness is not reached Fruergard, Moller, & Wiber-Jorgensen, 1990). If this within 45 seconds, up to four additional 0.2-mg doses lag time is not implemented, opioid-induced respira- may be administered at 1-minute intervals. The onset tory depression may be a problem (Steinbacher, 2001). of action is 1-2 minutes, with a peak effect at 3 minutes A dose of 100 ␮g of fentanyl is approximately equal in and a duration effect of 10-15 minutes. If sedation reoc- analgesic activity to 75 mg of meperidine. curs, repeated doses can be administered at 20-minute intervals. No more than a maximum of 1 mg (given Meperidine 0.2 mg/minute) should be administered at any one time. Meperidine (Demerol; Abbott Laboratories, North No more than 3 mg should be given in any 1 hour Chicago, IL) is an opioid analgesic indicated for the (SedationFacts.org, 2010). relief of moderate to severe pain. It was commonly used In children (1-17 years of age), the recommended for endoscopy in the United States, although its popu- initial dose is 0.1 mg/kg administered intravenously larity has waned in the last few years (Arrowsmith et al., over 15 seconds (SedationFacts.org, 2010). If desired 1991). Meperidine is a synthetic narcotic–analgesic that consciousness is not reached within 45 seconds, up to undergoes hepatic metabolism with an active metabo- four additional doses of 0.01 mg/kg (maximum 0.2 mg) lite, normeperidine, which has half its analgesic effect. can be administered at 1-minute intervals. The maxi- Seizures can occur in patients developing high levels of mum total dose is 0.05 mg/kg or 1 mg, whichever is less normeperidine (Ali et al., 2004). (SedationFacts.org, 2010). In adults, the initial recommended dose is 25-50 mg Excessive doses of flumazenil may cause anxiety, followed by additional doses of 25 mg administered agitation, increased muscle tone, and the possibility of every 2-5 minutes until moderate sedation is achieved seizure activity (SedationFacts.org, 2010). Because of (SedationFacts.org, 2010). The onset of action is 3-6 min- the possibility of seizures, flumazenil should be admin- utes with peak effect occurring in 6-7 minutes and the istered with caution in patients with head injuries and duration of effect lasting 1-3 hours. In children weighing those receiving benzodiazepines to control seizures. less than 50 kg, the initial recommended dose is 1 mg/kg, The clearance of flumazenil is reduced 25%-60% in with additional doses of the same magnitude adminis- patients with hepatic dysfunction; therefore, repeat tered every 2-4 minutes as needed to a maximum dose doses of the reversal agent should be reduced in size of 3 mg/kg. The half-life of meperidine in children may and frequency. The effects of flumazenil may wear off be as long as 3-4 hours. The initial dose of meperidine before a longer-acting benzodiazepine is completely should be reduced in elderly and debilitated patients and cleared from the body (SedationFacts.org, 2010). those with severe impairment of hepatic or renal function, sickle cell anemia, hypothyroidism, Addison disease, Naloxone pheochromocytoma, and prostatic or urethral stricture Naloxone hydrochloride (Narcan; Hospira, Inc., Lake (SedationFacts.org, 2010). Adverse effects associated Forest, IL.) is indicated for the complete or partial

Review of Propofol and Auxiliary Medications Used for Sedation

reversal of narcotic depression including respiratory 1998; Struys, Versichelen, Thas, Herregods, & Rolly, depression, sedation, and hypotension induced by 1997). opioids (SedationFacts.org, 2010). Although the mechanism of action is not fully understood, the pre- Continuous Infusion ponderance of evidence suggests that naloxone antag- In contrast, the continuous infusion mode of delivery onizes the opioid effect by competing for the same steadies the plasma propofol concentration by mini- receptor sites (SedationFacts.org, 2010). mizing the “peaks and valleys” of blood concentration In adults, the recommended initial dose of naloxone seen with manual bolus titration (Cillo, 1999). This is 0.1-0.2 mg iv, with additional doses of 0.2-0.4 mg iv tends to decrease the amount of drug given, permits administered every 2-3 minutes until the desired response better control of the depth of sedation, and allows for is attained (SedationFacts.org, 2010). The onset of action faster recovery (Cillo, 1999; Steinbacher, 2001). is 1-2 minutes, with a peak effect at 5 minutes and a To address the need for target-controlled infusion duration effect of 30-45 minutes. In children, the rec- (TCI), propofol delivery technology has progressed ommended initial dose is 1 ␮g/kg, with additional doses rapidly. Mechanically driven pumps and computer- of 2-4 ␮g/kg if no response is seen within 90 seconds. controlled infusion systems are being increasingly used The maximum dose is 400 ␮g. When naloxone is admin- for induction and maintenance of sedation. Several istered intravenously, the onset of action is generally appropriate miniperfusers for the administration of apparent within 2 minutes. The onset of action is only propofol, including the Diprifusor (AstroZeneca) and slightly less rapid when it is administered subcuta- 360 Infuser (Beckton, Dickinson, and Co., Franklin neously or intramuscularly; however, the duration of Lakes, NJ), are available (Yusoff, Raymond, & Sahai, effect is prolonged (SedationFacts.org, 2010). 2004). The healthcare provider sets the pump for a Naloxone should be used with caution in patients desired blood concentration. The computer uses the with preexisting cardiac disease (SedationFacts.org, incorporated pharmacokinetic data set to calculate the 2010). Also, this medication should administered cau- infusion rate required to reach and maintain the desired tiously to people (including newborns of mothers) who blood concentration. The pump will run initially at a are known or suspected to be physically dependent on high rate providing a loading dose. After the loading opioids because withdrawal symptoms such as nausea, dose, the calculated maintenance infusion rate decreases vomiting, sweating, tachycardia, hypertension, tremu- logarithmically to maintain a constant blood concen- lousness, seizures, and even cardiac arrest could occur tration as the three pharmacokinetic compartments (SedationFacts.org, 2010). Use of naloxone in patients discussed previously reach saturation. When the target receiving an opioid for pain control long term is con- rate is reduced by the healthcare provider, the computer traindicated, as it can exacerbate their pain levels. will stop the infusion until the clearance and redistrib- ution of the drug reach the desired concentration Methods of Administering Propofol (Lichtenbelt, Mertens, & Vuyk, 2004). Propofol can be administered by manual bolus titration, continuous infusion, and/or patient-controlled Patient-Controlled Infusion sedation (PCS). Patients have different sensitivities to sedative drugs and different preferences for the level of sedation Manual Bolus Titration required during a procedure (Cillo, 1999). Bright et al. There is no set propofol dose requirement to prepare (2003) conducted a randomized controlled trial of adults for the initiation of EGD or colonoscopy proce- 67 adults undergoing colonoscopy who either controlled dures; doses can vary from 30 mg to more than 200 mg their sedation of propofol and alfentanil or received a (Rex et al., 2003). After a loading dose in adults (depend- bolus of midazolam and pethidine. The patient-con- ing on weight), boluses are given as needed. Proponents trolled sedation (PCS) group recovered significantly of manual bolus injections state that “peaks and faster (median time 5 minutes vs. 35 minutes; p Ͻ valleys” can be avoided by the use of a dedicated spe- .00001) and left the endoscopy unit more quickly (medi- cially trained endoscopy team member whose only an 40 minutes vs. 75 minutes; p Ͻ .00001). Patients in duties are administering propofol and visually monitor- the PCS group, who received propofol (4.8 mg) and ing the patient’s chest wall excursions and spontaneous alfentanil (12 ␮g) per 0.5 ml delivered over 7 seconds movement (Rex et al., 2003). Opponents contend that four times initially and whenever they felt discomfort, repeated bolus administration often produces fluctu- had significantly higher pain scores and significantly ating plasma concentrations, resulting in a greater like- more recall of the procedure than those receiving the lihood of hypotension and respiratory depression in bolus dose of midazolam (2.5 mg) and pethidine addition to increasing the amount of drug that needs (50 mg) initially, with the midazolam dose repeated to be administered (Bennett, Shafer, Efaw, & Goupil, during the procedure at the endoscopist’s discretion.

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Review of Propofol and Auxiliary Medications Used for Sedation

Only one procedure failed because of poor patient The use of propofol commonly results in some tolerance; this patient was in the midazolam and pethi- decline in arterial blood pressure, but cardiac output dine group (Bright et al., 2003). The anesthesiologist is nearly always maintained (Rex et al., 2003). A high- intervened on one occasion giving atropine to a patient er incidence of hypotension has been associated with in the midazolam and pethidine group when the systolic advanced age, female gender, poor physical status, blood pressure fell to 58 mmHg and the heart rate to and concomitant use of opioids or benzodiazepines 45 beats/minute. All patients in both groups were sat- (Hug et al., 1993). Additional intravenous fluids may isfied with the sedation they received, and all were pre- be used to treat a 20% or more decrease in systolic or pared to undergo the procedure again if needed using diastolic blood pressure from baseline, with or with- the same form of sedation. The researchers concluded out Trendelenburg positioning and/or holding a bolus that PCS with propofol and alfentanil provides an dose or reducing the propofol infusion rate (Martinez acceptable alternative to bolus sedation with midazolam et al., 2002; Steinbacher, 2001). Should bradycardia and pethidine (Bright et al., 2003). This study would (Ͻ50 beats/minute in adults) occur, it can be controlled have been stronger had the same sedation regimen by the administration of atropine (Langley & Heel, been used for both groups so that only the method of 1988). Other rare mild to moderate adverse effects administration was different. include retching, vomiting, aspiration, laryngospasm during the procedure, and itching and wheezing Adverse Effects and Interventions postprocedure (Rex et al., 2003; Wurz & Bernstein, Adverse effects of propofol may be mild, moderate, or 2008). severe. These commonly include pain on injection, respiratory depression including apnea, hypotension, Severe and/or occasionally bradycardia (Hug et al., 1993; Acute Pancreatitis Picard & Tramer, 2000). Premedication, underlying Rare cases of acute pancreatitis attributed to propofol cardiopulmonary disease, and advanced age have been have been reported and appear to be caused by hyper- cited as risk factors for adverse effects (Kotash et al., triglyceridemia (Jawaid, Presti, Neuschwander-Tetri, 1994). & Burton, 2002). Mild Neuroexcitory Reactions Pain on injection, attributed to propofol’s solvent Rarely occurring (Յ1%) excitatory reactions to Intralipid 10%, is the most frequently observed local propofol, can be divided into two groups: seizure-like adverse effect; however, its incidence varies from 28.5% (tonic–clonic or grand mal) or dystonic (abnormal for small veins to 6% for larger veins (Pastuovic, Cohen, hypertonicity in the limbs). Seizures may occur in & Burton, 1996). Despite the discomfort sometimes patients with and without a history of epilepsy. They associated with propofol administration, the drug does tend to occur during changes in propofol levels in not induce phlebitis. Injecting 1 ml of lidocaine before brain tissue—induction and emergence from sedation. injecting propofol can decrease or eliminate this pain. Delayed seizures have occurred from 33 minutes to 6 days after the use of propofol (Walder, Tramer, & Moderate Seeck, 2002). The origin of these reactions is unknown Propofol is a respiratory depressant that can lead to because propofol has anticonvulsant properties apnea. It impairs ventilation by reducing the ventila- (Lowenstein & Alldredge, 1998; Vanlersberghe & tory response to hypercapnia and the ventilatory adap- Camu, 2008). These researchers propose that propo- tation to hypoxia at sedative doses (Vanlersberghe & fol inhibits epileptic dampening that is most likely to Camu, 2008). Because the duration of effect of propo- occur during rapid changes in propofol concentration fol is so short, in patients with oxygen desaturation of at the induction of or emergence from anesthesia. less than 90%, an increase in supplemental oxygen by These seizures should be managed in the same manner nasal cannula or mask while withholding further as in any generalized seizure. The dystonic reactions propofol until desaturation resolves usually remedies may be attributed to an imbalance of cholinergic the problem. In patients with oxygen desaturation of (excitatory)–dopaminergic (inhibitory) neurotransmit- less than 85%, use of chin lift or jaw thrust to open the ters in the basal ganglia. Propofol is assumed to airway and/or administration of continuous positive air- increase cholinergic output. Dystonic reactions may way pressure using a Jackson–Rees bag and mask can be treated with benzotropine (Cogentin) 2 mg iv (for be used to treat hypoxemia (Martinez et al., 2002). All adults) repeated every 30 minutes until symptoms healthcare providers administering propofol must be resolve (Schramm & Orser, 2002). Adverse effects of prepared to intubate the patient endotracheally should benzotropine include sedation, tachycardia, and dry this become necessary. mouth.

Review of Propofol and Auxiliary Medications Used for Sedation

Propofol Infusion Syndrome has avoided death in a few adults and children with Propofol infusion syndrome is the most well-known PRIS (Bray, 1998; Rosen et al., 2007). severe adverse effect. It first appeared in case reports Pepperman and Macrae (1997) conducted a retro- that described fatalities in children undergoing prospective study comparing the safety of propofol with longed sedation with propofol (Parke et al., 1992). The other sedative agents used in critically ill patients. early reports were mainly about children younger than One hundred ninety-eight patients were evaluated: 4 years with infections of the upper respiratory tract 106 received propofol and 92 received other sedatives who received high and escalating doses of propofol including midazolam. Sixty-two percent of the propo- (Bray, 1998; Cray, Robinson, & Cox, 1998; Fudickar, fol group participants and 68% of the other sedative Bein, & Tonner, 2006; Kelly, 2001; Pate & Steelman, group participants were younger than 3 years. The 2007). The children developed metabolic acidosis, mean propofol dose was 3.38 mg/kg per hour but refractory bradycardia (even after high doses of posi- ranged from 0.4 to 30 mg/kg per hour, with infusion tive inotropes), lipidemia, rhabdomyolysis, fever, and durations ranging from 30 minutes to 156 hours. refractory heart failure leading to death. Propofol infu- Forty-one children developed metabolic acidosis dur- sion syndrome is now known to occur in both adults ing sedation: 17 received propofol and 24 received and children (Rosen, Nicoara, Koshy, & Wedderburn, other sedatives. Of these, two children in the propofol 2007; Vasile, Rasulo, Candiani, & Latronico, 2003). group and three in the other sedative group developed The occurrence of PRIS has been associated with clinically significant metabolic acidosis defined as a high-dose propofol infusions, as well as prolonged pH Յ 7.2 and a base excess Ͼ10. Of the children who administration of lower doses (Rosen et al., 2007). developed metabolic acidosis, 22% of those receiving Theories of its causality include metabolic derangements propofol and 27% of those receiving other sedatives leading to mitochondrial toxicity and impaired tissue were younger than 3 years. Four children developed oxygenation and carbohydrate deficiency (Ahlen, lipemia; three of whom (two in the propofol group Buckley, Goodale, & Pulsford, 2006). The mechanism and one receiving midazolam) were concurrently receiv- for the metabolic derangements has been postulated to ing an intravenous fat emulsion as part of their par- be related to a defect in the mitochondrial respiratory enteral nutrition. No patient with clinically significant

chain. Increased plasma malonyl carnitine and C5-acyl- metabolic acidosis had lipemic serum. The researchers carnitine may indicate the inhibition of beta-oxidation concluded that there was no association between the by propofol, leading to an increase in plasma free fatty use of propofol and clinically significant metabolic acids (Fudickar et al., 2006; Marik, 2004). Impaired acidosis or lipemic serum (Pepperman & Macrae; fatty acid oxidation due to reduced mitochondrial entry Susla, 1998). This study was underpowered to detect of long-chain fatty acids leads to respiratory chain fail- a rare adverse event; however, some of these children ure and impaired tissue oxygenation (Rosen et al., may have been developing early signs of impending 2007). Carbohydrate deficiency may also be a contribut- PRIS. ing factor in PRIS because energy demand is maintained Although PRIS is unlikely to occur as a result of a by lipolysis if the carbohydrate supply is also low, result- relatively short endoscopic procedure requiring propo- ing in an accumulation of free fatty acids (Ahlen et al., fol sedation, it is prudent to assess laboratory values 2006). It has also been suggested that PRIS occurs in prior to procedures in patients who are currently or individuals with a genetic predisposition—an inborn have recently received propofol for sedation for early error of mitochondrial fatty acid oxidation (Fudickar signs of PRIS including metabolic acidosis, lipidemia, et al., 2006). According to Vasile et al. (2003), CNS and increased levels of creatinine kinase, myoglobin, activation with production of catecholamines and glu- and blood lactate (Kelly, 2001; Marik, 2004). costeroids and systemic inflammation with cytokine production are priming factors for cardiac and periph- Recovery and Patient–Physician eral muscle dysfunction. Not only high-dose propofol Satisfaction but also supportive treatments with catecholamines Within 20 minutes or less after cessation of propofol, and corticosteroids act as triggering factors. patients were reported to be fully alert with normal Vernooy et al. (2006) found that a pattern of ST- neuropsychological function and to experience fewer segment elevation in leads V1-V3 (Brugada-like pat- postprocedure complications (Rex et al., 2003). tern) of the electrocardiogram was the first indicator Adults, children and their parents, and physicians per- of electrical instability, and this occurrence was high forming the procedure reported satisfaction of 90% or risk for imminent sudden death. Immediate cessation more with the level of sedation provided by propofol of propofol sedation, and prompt hemodialysis to alone or in combination with auxiliary medications clear lactic acid and toxic metabolites from the blood, (Weston et al., 2003).

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Summary maintained system in which target levels of propofol are Propofol possesses many properties crucial to an ideal delivered in response to patient demand. Theoretically, anesthetic drug. These characteristics include rapid onset the use of TCI systems and PCS should decrease the of action, short duration of effect, fast clearance rate, total dose of propofol required, thereby increasing minimal tendency for drug accumulation, and no active patient safety. metabolites (Bennett et al., 1998). Propofol is a global Patient-controlled sedation using propofol has the CNS depressant leading to decreased cerebral oxygen potential to greatly influence the manner in which consumption and reduced intracranial pressure (Marik, endoscopic procedures are performed in adults. It can 2004). It also demonstrates potent anticonvulsant prop- be set up and supervised by specially trained registered erties, is a potent antioxidant, has anti-inflammatory nurses who monitor respiratory effort continuously. properties, and is a bronchodilator (Marik, 2004). When controlling their level of sedation, adults chose Propofol has a narrow therapeutic window between to be less sedated and all were satisfied with their level moderate sedation, deep sedation, and general anesthe- of sedation. The greater recollection of the procedure sia. Thus, adverse effects have been reported. The most and discomfort did not influence their overall satisfac- common mild adverse effect is pain on intravenous tion with the method of sedation, nor their willingness injection. The most common moderate adverse effects to undergo repeat colonoscopy using PCS if needed. are dose-dependent respiratory depression and hypoten- Rapid patient turnaround would increase the effi- sion (Marik, 2004). These and other common mild to ciency of endoscopy units (Byrne & Baillie, 2002). In moderate adverse effects can be detected early through this fast-paced world, patients opting for PCS may be careful monitoring and can be managed successfully willing to exchange greater discomfort during a short when detected early. Although propofol can be used diagnostic or therapeutic procedure for more rapid alone, auxiliary medications allow a lower dose of propo- recovery post-procedure with good cognitive function fol to be used, with a resulting decrease in the frequency and early discharge so that they can return to their and severity of adverse effects (Elitsur, Blankenship, & normal activities quicker. Lawrence, 2000). Of the three methods of administering propofol, manual bolus injections, continuous infusion, ACKNOWLEDGMENT and patient-controlled infusion, recent research appears to be leaning toward the use of continuous infusion to The author thanks Erin Calloway, BSN student, for maintain consistent plasma levels. help in procuring and managing the literature used in this review. Next Steps One glaring omission in support of the use of propofol REFERENCES for endoscopy is that propofol has never been approved Ahlen, K., Buckley, C. J., Goodale, D. B., & Pulsford, A. H. (2006). by the FDA for use as sedation for painful diagnostic or The propofol infusion syndrome: The facts, their interpretation therapeutic procedures including endoscopy. It is hoped and implications for patient care. European Journal of that the FDA will review the abundant literature Anaesthesiology, 23(12), 990-998. demonstrating the safety and efficacy of using propofol Ali, S., Davidson, D. L., & Gremse, D. A. (2004). 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Review of Propofol and Auxiliary Medications Used for Sedation

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Weston, B. R., Chadalawada, V., Chalasani, N., Kwo, P., Overley, C. Yaster, M., Nichols, D. G., Deshpande, J. K., & Wetzel, R. C. A., Symms, M., et al. (2003). Nurse-administered propofol (1990). Midazolam-fentanyl intravenous sedation in children: versus midazolam and meperidine for upper endoscopy in Case report of respiratory arrest. Pediatrics, 86(3), 463-467. cirrhotic patients. American Journal of Gastroenterology, 98(11), Yusoff, I. F., Raymond, G., & Sahai, A. V. (2004). Endoscopist 2440-2447. administered propofol for upper-GI EUS is safe and effective: A Wurz, S., & Bernstein, B. (2008). Propofol or process: What really prospective study in 500 patients. Gastrointestinal Endoscopy, affects efficiency? Gastroenterology Nursing, 27(2), 69-73. 60(3), 356-360.

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