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Propofol: A Review of the Pharmacology and Applications of an Intravenous Anesthetic Agent
Propofol: A Review of the Pharmacology and Applications of an Intravenous Anesthetic Agent ROBERT
J.
DEEGAN, MB, BCH, BSe
KEY INDEXING TERMS: Anesthetic; Intravenous; Propofol. [Am J Med Sci 1992; 304 (1):45-49.]
M
odem anesthetic practice has been largely based on the use of volatile/gaseous agents administered by inhalation, with the intravenous agents generally confined to anesthetic induction. Inhalational agents cause pollution of the operating room environment, which may be related to impaired psychomotor performance, liver damage, and miscarriages among surgical, anesthesiology, and nursing personnel. The goal of intravenous anesthesia has long been considered desirable but available agents, for reasons of pharmacokinetics or side effects, were not suitable for maintenance of anesthesia. This situation has changed with the introduction of propofol, a novel intravenous anesthetic chemically unrelated to previous compounds. Pharmacokinetics
Propofol obeys first order kinetics through a range of infusion rates capable of maintaining anesthesia over a number of hours. Due to high lipophilicity and extensive tissue binding, the volumes of distribution are very high, and the steady state and elimination phase volumes of distribution exceed total body water. In general, the concentration time data are best fitted by a triexponential function. The tI!2(¥ of 2-5 minutes is attributed to distribution from blood into tissues; a t1f2{3 of 0.5-1 hour represents metabolic clearance from Prepared for Vanderbilt University Medical Center Pharmacy and Therapeutics Committee, Vanderbilt University, Nashville, Tennessee. Editors: Renata E. Bluhm, MD, PhD, Philip E. Johnston, PharmD, Jason D. Morrow, MD. The author thanks Dr. Margaret Wood, MD, Division of Anesthesiology, Vanderbilt University School of Medicine, for her assistance in reviewing this article. Correspondence: Department of Pharmacology, Division of Clinical Pharmacology, Vanderbilt University, School of Medicine, Nashville, TN 37332. THE AMERICAN JOURNAL OF THE MEDICAL SCIENCES
blood; a t l l20 of 3-9 hours is explained by the slow return of propofol from a poorly perfused deep compartment (probably fat) acting as a rate-limiting factor for elimination. Even after several hours of infusion however one can still expect a rapid initial decline in plasm~ concentration due to redistribution, and recovery can remain independent of the long terminal half-life. 1 The liver is the most important site of elimination,2 and very high clearance values, of the order of 70-140 L/ hr have been reported. 3 A number of factors that might affect propofol pharmacokinetics have been investigated. Sex,4 hepatic cirrhosis,5 and renal failure 6 have no significant effect. With increasing age, induction and maintenance dose requirements are reduced. 7,8 Propofol pharmacokinetics are also altered by coadministration of other drugs. Cockshott and colleagues9 found that blood propofol levels were 50% higher following induction in patients receiving 2 Jlg/kg of the opioid, fentanyl. Clinical Use and Effects of Propofol
Propofol has been found useful for three different clinical applications: (1) IV bolus for anesthesia induction; (2) IV infusion or repeated bolus for maintenance of anesthesia; and (3) IV infusion or repeated bolus for sedation. Induction
Its high degree of lipophilicity and short half-life make propofol suitable for IV induction with rapid access to the brain and subsequent rapid recovery due to redistribution and elimination. The effective induction dose of propofol is 2-2.5 mg/kg in healthy unpremedicated adults. 10 In those over 60 years old, 1.5 mg/kg is adequate. 7 The induction dose is also reduced by premedication with benzodiazepines or opiates. l l Loss of consciousness is achieved within one arm-brain circulation time (< 40-50 seconds), as has been shown for thiopental and methohexital. 12 ,13 Ideally, an induction agent should achieve rapid loss of consciousness smoothly without significant cardiovascular or respiratory effects. The decrease in blood pressure and the increase in heart rate with propofol
45
Propofol
induction are generally greater than with thiopental or methohexital. l2- 14 To some extent this may be advantageous, counteracting the reflex hypertension with endotracheal intubation. The hypotension may, however, be deleterious. In one study of beta-blocked patients for coronary artery surgery,15 propofol induction reduced systolic blood pressure to less than 100 mm Hg in 8 of 10 patients and to less than 70 mm Hg in 2 of 10 patients. In contrast, thiopental induction caused systolic pressure to fall below 100 mm Hg in only 1 of 10 patients and no patient in the thiopental group had a systolic pressure below 90 mm Hg. Earlier studies in both animals 16 and man17 have attributed propofol-induced hypotension to a decrease in systemic vascular resistance; cardiac output was either maintained or increased. The latter observation may, in some cases,17 have resulted from elevated PaC02 values, as a significant reduction in cardiac output by propofol induction has been demonstrated in the presence of normocarbia. 18 In addition, there are now a number of studies which indicate that propofol has a negatiye inotropic effect in vitro19 and in vivo. 14.20 Depression by propofol of both systemic vascular resistance and cardiac output might be partly the result of the marked sympathetic inhibition, which has been demonstrated by percutaneous sympathetic nerve recording in man 21 and by assessment of norepinephrine kinetics in dogs 22 following propofol administration. Propofol induction causes higher incidences of excitatory phenomena (hypertonus, spontaneous movement, twitching, tremor), apnea, and pain on injection than does thiopental. Local pain is related to injection site and can be minimized by use of large antecubital veins (incidence 6.0%) rather than small dorsal hand veins (incidence 28.5%) or by coadministration of lidocaine. 23 A greater respiratory depressant effect of propofol versus thiopental has been suggested by some studies,13,24 but not by others.25 The reported incidence . of apnea of greater than 60 seconds duration varies widely, from about 20_90%.25.26 Some of the variability may be explained by differences in premedication. Coadministration of or premedication with opioids increases the respiratory depression25 but reduces excitatory movements and pain on injection. Anesthesia Maintenance
Propofol is the only currently available IV anesthetic that is well-suited for maintenance of anesthesia. This is due to its favorable pharmacokinetic profile, which avoids the accumulation seen with prolonged thiopental administration, to its preservation of adrenal steroidogenesis26.27 (inhibition of which leads to increased patient mortality with etomidate infusions), and to its ability to provide extremely smooth maintenance with easily controlled depth of anesthesia and relative freedom from the excitatory effects, which occur with alternative agents such as methohexita1. 28
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While repeated bolus administration is feasible, continuous infusion provides more stable blood propofol concentrations with better control of anesthetic depth and adverse effects. When administered together with 60-70% nitrous oxide in oxygen, a propofol infusion rate of about 6-8 mg/kg- 1 hr- 1 is required, depending on the extent of surgery. When nitrous oxide is undesirable (eg, jet ventilation or pneumothorax), anesthesia can be adequately maintained by propofol infusion alone (usually with benzodiazepine or opioid premedication). Rates of up to 12 mg/kg- 1 hr- 1 are then required. 17.29 More commonly, total IV anesthesia is achieved by combined infusions of propofol and an opioid. Both fentanyl and alfentanil have been found suitable in this context.28.30 The characteristic rapid, smooth recovery after propofol maintenance still occurs, provided that the opioid infusion is discontinued 10-20 minutes before the propofol infusion. 28.29 Otherwise, opioid-induced respiratory depression may be a problem. The potential for respiratory or cardiovascular depression during propofol maintenance is significant but rarely causes problems when adequate precautions are taken. Some authors have used propofol infusions without controlled ventilation for periods of up to 1 hour without major increases in PaC02,17.29 but apnea of more than 30 seconds occurred in 72% of cases in one such report. 29 Opioid co-infusions increase this risk, thus requiring controlled ventilation. When an induction dose of 2 mg/kg propofol is followed by a fixed infusion rate (3-6 mg/kg-1 hr-1), a 25-45% reduction in systolic pressure can be expected. 17.31 Knowledge of propofol's pharmacokinetic profile has allowed development of computer-driven infusion systems, which attain the desired blood propofol concentration very rapidly with little overshoot, and then maintain the level over long periods by calculating an exponentially decreasing infusion rate to match the decreasing rate at which the drug leaves the central compartment by distribution and elimination.32 Such regimens and their manually-applied equivalents33 achieve very stable propofollevels and remarkably stable hemodynamics. Sedation
Sedation of critically ill patients in the intensive care setting traditionally involves the use of benzodiazepines, opiates, or the major tranquilizers (phenothiazines, butyrophenones) , which is limited by prolonged recovery, respiratory depression, and gastrointestinal stasis. There have been a number of reports of the successful use of propofol by continuous infusion for sedation in intensive care patients with a variety of illnesses, including cardiac surgery,34 head injury,35 acute respiratory failure, septic shock, and acute tubular necrosis,27.36 for durations of 8-189 hours. The mean dosages used vary from 0.79 to 2.88 mg/kg-1 hr-1, reflecting the different ages and conditions of the patients in the studies. In each study, adequate sedation was achieved July i992 Volume 304 Number 1
Deegan
without difficulty. Supplemental opioid boluses were required in each case but significantly less than with midazolam (a short-acting benzodiazepine) sedation. 34 Recovery was also very satisfactory. Grounds and colleagues34 reported a mean time to tracheal extubation of 25 minutes following cessation of an 8-hour infusion of propofol, while a comparable group sedated with midazolam required 226 minutes on average. Even with the relatively low doses required for sedation, potential cardiovascular depression is still a concern in critically ill patients treated with propofol. This is exemplified in a study by Newman et al27 in which 6 to 10 patients had mean arterial pressures of less than 60 mm Hg at some point during an 8 hour infusion of propofol. It is very important that hemodynamic parameters be carefully monitored to minimize such events. Outside of the intensive care unit, administration of propofol by continuous infusion or intermittent bolus has been found to be suitable for sedation during regional anesthesia37,38 or during day case endoscopies,39 comparing favorably with midazolam and methohexital. In a series by Gepts and colleagues,4o however, apnea occurred in 48% of patients receiving propofol for sedation during colonoscopy. It is clear that special vigilance is required when propofol is administered by nonanesthesiologists and in locations other than the intensive care unit or the operating room. Recovery Characteristics
In keeping with its high lipid solubility and high clearance rate, rapid emergence from propofol anesthesia may be expected. Propofol has a lesser influence on recovery when it is used only for induction with subsequent maintenance by an inhalational agent. 4l ,42 However, even in this context, more rapid recovery has been demonstrated with propofol induction compared to thiopental or methohexital induction when the period of inhalational anesthesia is short.43 When used for both induction and maintenance of anesthesia, the benefit of improved recovery with propofol is more obvious. More rapid, smooth recovery has been demonstrated following maintenance of anesthesia by repeated bolus or continuous infusion of propofol compared to all of the other major alternatives44-47 and for procedures of durations ranging from 15 minutes to a few hours. Patients recovering from propofol are relatively clearheaded and have a low incidences of depression, tremulousness, nausea, and vomiting. 44 ,48,49 These features significantly improve patient well-being in the postoperative period and may be especially advantageous in the context of ambulatory surgery. There may also be economic benefits. An analysis by Marais and colleagues50 has suggested that switching from thiopentaljisoflurane anesthesia to propofol anesthesia would reduce nurse staffing requirements in the recovery room. THE AMERICAN JOURNAL OF THE MEDICAL SCIENCES
Use of Propofol in Special Settings
Propofol has been found suitable for anesthesia during Caesarean section5l and appears safe in patients with porphyria52 or with susceptibility to malignant hyperthermia.53 As with thiopental, propofol induction reduces intraocular pressure, and propofol is more effective than thiopental in inhibiting the increase in intraocular pressure associated with intubation. 54 The use of total IV anesthesia for neurosurgical patients avoids the cerebral vasodilating action of inhalational agents. Rapid recovery from propofol compared to thiopental infusion can avoid prolonged delays in neurologic assessment. Further, propofol alleviates cerebral hypertension,55 and, when combined with a small bolus of fentanyl, attenuates the usual increase in cerebrospinal fluid pressure in response to intubation and other noxious stimuli. 56 However, the reduction in cerebral perfusion pressure that is related to decreased mean arterial pressure may be marked and potentially deleterious, especially following bolus administration of propofol.55 The influence of propofol on the coupling between cerebral metabolism and blood flow has not been adequately defined. 57 Cost
Propofol is available in 200-mg (20 ml) ampules at $9.97 each. An average induction dose, thus, costs almost $10 (compared to about $2 for thiopental); anesthesia maintenance by propofol alone would cost up to $42 per hour for a 70-kg patient but less than $28 per hour for the lower infusion rates required in combination with nitrous oxide. Sedation can be achieved with rates ranging from 1 to 3 mg/kg-lhr-l, which costs approximately $3-10 per hour for a 70-kg patient. Conclusion
Propofol is a relatively new IV anesthetic agent whose pharmacokinetic profile renders it suitable not only for induction, but also for infusion to maintain anesthesia or sedation. A remarkable feature of propofol is a rapid, smooth recovery which, during administration, allows rapid titration of effect and, after cessation, allows relatively early discharge to the ward or home. Thus, propofol can be expected to facilitate the increasing trend toward day-cease surgery. The apparent safety of propofol in patients with porphyria or malignant hyperthermia susceptibility suggests that propofol may be a valid alternative where barbiturates or inhalational anesthetics are contraindicated. Propofol may also have advantages for opthalmic and some neurologic surgery. Minor problems of pain on injection and some excitatory phenomena at induction do not significantly limit propofol's use. However, cardiovascular and respiratory depression are potentially more serious. Adequate attention to dosage (reduced in elderly), rate of administration of boluses, and concomitant medications (opioids enhance both cardiovascular and respiratory adverse effects) minimizes these prob47
Propofol
lems. Pharmacokinetics-based computer-driven infusion regimens allow maintenance of stable hemodynamics and will contribute to the increasing use of propofol. Nevertheless, the potential for profound respiratory and cardiovascular depression with propofol requires that its use be largely restricted to situations such as the intensive care unit or operating room where trained personnel and resuscitation equipment are at hand. For these reasons, propofol is not a substitute for the benzodiazepines as an agent for conscious sedation under supervision of the nonanesthesiologist. References 1. Gepts E, Camu F, Cockshott !D, Douglas EJ: Disposition of propofol administered as constant-rate infusions in humans. Anesth Analg 66:1256-1263,1987. 2. Simons PJ, Cockshott!D, Douglas GJ, Gordon EA, Hopkins K, Rowland M: Disposition in male volunteers of a subanaesthetic intravenous dose of an oil in water emulsion of 14C-propofol. Xenobiotica 18:429-440, 1988. 3. Sebel PS, Lowdon JD: Propofol: A new intravenous anesthetic. Anesthesiology 71:260-277,1989. 4. Kay NH, Sear JW, Uppington J, Cockshott ID, Douglas EJ: Disposition of propofol in patients undergoing surgery. A comparison in men and women. Br J Anaesth 58:1075-1079, 1986. 5. ServinF, HabererJP, Cockshott ID, Farinotti R, DesmontsJM: Propofol pharmacokinetics in patients with cirrhosis (abstract). Anesthesiology 65:A554, 1986. 6. Morcos WE, Payne JP: The induction of anaesthesia with propofol ('Diprivan') compared in normal and renal failure patients. Postgrad Med J 61(Suppl):62-63, 1985. 7. Dundee JW, Robinson FP, McCollum JSC, Patterson CC: Sensitivity to propofol in the elderly. Anaesthesia 41:482-485, 1986. 8. Doze VA, Shafer A, White PF: Propofol-nitrous oxide versus thiopental-isoflurane-nitrous oxide for general anesthesia. Anesthesiology 69:63-71,1988. 9. Cockshott JD, Briggs LP, Douglas EJ, White M: Pharmacokinetics of propofol in female patients. Br J Anaesth 59:11031110,1987. 10. Cummings GC, Dixon J, Kay NH, Windsor JPW, Major E, Morgan M, Sear JW, Spence AA, Stephenson DK: Dose requirements of ICI 35,868 (propofol, 'DIPRIVAN') in a new formulation for induction of anaesthesia. Anaesthesia 39:1168-1171, 1984. 11. Thomas VL, Sutton DN, Saunders DA: The effect of fentanyl on propofol requirements for day case anesthesia. Anaesthesia 43(Suppl):73-75,1988. 12. Mackenzie N, Grant IS: Comparison of the new emulsion formulation of propofol with methohexitone and thiopentone for induction of anesthesia in day cases. Br J Anaesth 57:725-731, 1985. 13. Gold MI, Abraham EC, Herrington C: A controlled investigation of propofol, thiopentone and methohexitone. Can J Anaesth 34: 478-483,1987. 14. Lippmann M, Paicius R, Gingerich S, Owens R, Mok MS, Appel P: A controlled study of the hemodynamic effects of propofol versus thiopental during anesthesia induction. Sem Anesth 7(Suppl 1):116-122, 1988. 15. Patrick MR, Blair IJ, Feneck RO, Sebel PS: A comparison of the hemodynamic effects of propofol ('Diprivan') and thiopentone in patients with coronary artery disease. Postgrad Med J 61(Suppl):23-27, 1985. 16. Glen JB, Hunter SC: Pharmacology of an emulsion formulation of ICI 35, 868. Br J Anaesth 56:617-626, 1984. 17. Claeys MA, Gepts E, Camu F: Haemodynamic changes during anaesthesia induced and maintained with propofol. Br J Anaesth 60:3-9, 1988.
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18. Stephen H, Sonntag HD, Schenk D, Kettler D, Khambatta HJ: Effects of propofol on cardiovascular dynamics, myocardial blood flow and myocardial metabolism in patients with coronary artery disease. Br J Anaesth 58:969-975, 1986. 19. Roewer N, Winguth TH, Proske 0, Dziadzka A, Schulte am Esch J: Inotropic and electrophysiological effects ofpropofol on isolated ventricular myocardium (abstract). Anesthesiology 73: A381,1990. 20. Briissel T, Theissen JL, Vigfusson G, Lunkenheimer PP, Van Aken H, Lawin P: Hemodynamic effects ofpropofol and etomidate. Negative inotropic properties of propofol. Anesth Analg 68:35-40, 1989. 21. Ebert TJ, Berens RJ, Muzi M, Kampine JP: Direct comparison of etomidate and propofol on sympathetic neural outflow and baroreflex function in man. Anesth Analg 72:S61, 1991. 22. Deegan R, He HB, Wood AJJ, Wood M: Effects of anesthesia on norepinephrine kinetics. Comparison of propofol and halothane anesthesia in dogs. Anesthesiology 75:481-488,1991. 23. Stark RD, Binks SM, Dutka VN, O'Connor KM, Arnstein MJA, Glen JB: A review of the safety and tolerance of propofol ('Diprivan'). Postgrad Med J 61(Suppl 3):64, 1985. 24. Perry SM, Bullington J, Davis L, Fisher K, Ramsay S, Wood M: A comparison of DIPRIVAN (propofol) and thiopental for the induction and recovery of anesthesia. Sem Anesth 7(Suppl 1):91-93, 1988. 25. Streisand JB, Stanley TH: The respiratory effects of DIPRIVAN (propofol) with and without fentanyl. Sem Anesth 7(Suppl 1): 123-126, 1988. 26. Kay NH, Uppington J, Sear JW, Allen MC: Use of an emulsion of ICI 35868 (Propofol) for the induction and maintenance of anaesthesia. BrJ Anaesth 57:736-742,1985. 27. Newman LH, McDonald JC, Wallace PGM Ledingham I McA: Propofol infusion for sedation in intensive care. Anaesthesia 42: 929-937, 1987. 28. Kay B: Propofol and alfentanil infusion. A comparison with methohexitone and alfentanil for major surgery. Anaesthesia 41: 589-595, 1986. 29. McLeod B, Boheimer N: Propofol ('Diprivan') infusion as main agent for day case surgery. Postgrad Med J 61(Suppl 3):105107,1985. 30. Jenstrup M, Nielsen J, Fruergard K, Mq,ller A-M, Wiberg-. Jq,rgensen F: Total IV anaesthesia with propofol-alfentanil or propofol-fentanyl. Br J Anaesth 64:717-722, 1990. 31. Monk CR, Coates DP, Prys-Roberts C, Turtle MJ, Spelina K.: Hemodynamic effects of a prolonged infusion of propofol as a supplement to nitrous oxide anesthesia. Br J Anaesth 59:954960,1987. 32. Tackley RM, Lewis GTR, Prys-Roberts C, Boaden RW, Dixon J, Harvey JT: Computer controlled infusion of propofol. Br J Anaesth 62:46-53, 1989. 33. Perry SM, Smith D, Wood M: Propofol for induction and maintenance of anesthesia: Recovery characteristics. Proc World Congress Anaesthes, 1988. 34. Grounds RM, Lalor JM, Lumley J, Royston D, Morgan M: Propofol infusion for sedation in the intensive care unit. Br Med J 294:397-400, 1987. 35. Farling PA, Johnston JR, Coppel DL: Propofol infusion for sedation of patients with head injury in intensive care. Anaesthesia 44:222-226, 1989. 36. Harris CE, Grounds RM, Murray AM, Lumley J, Royston D, Morgan M: Propofol for long-term sedation in the intensive care unit. A comparison with papaveretum and midazolam. Anaesthesia 45:366-372, 1990. 37. Mackenzie M, Grant IS: Comparison of propofol with methohexitone in the provision of anaesthesia for surgery under regional blockade. Br J Anaesth 57:1167-1172, 1985. 38. Fanard L, Van Steenberge A, van der Puyl F: Comparison between propofol and midazolam as sedative agents for surgery under regional anaesthesia. Anaesthesia 43(Suppl):87-88, 1988. July 1992 Volume 304 Number 1
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39. Dubois A, Balatoni E, Peeters JP, Bandoux M: Use of propofol for sedation during gastrointestinal endoscopies. Anaesthesia 43(Suppl):75-80, 1988. 40. Gepts E, Claeys MA, Camu F, Smekens L: Infusion of propofol ('Diprivan') as sedative technique for colonoscopies. Postgrad Med J 61(Suppl 3):120-126, 1985. 41. Valanne J, Kortilla K: Comparison of methohexitone and propofol ('Diprivan') for induction of enflurane anaesthesia in outpatients. Postgrad Med J 61 (Suppl 3):138-143, 1985. 42. Sanders LD, Isaac PA, Yeomans WA, Clyburn PA, Rosen M, Robinson JO: Propofol-induced anaesthesia. Double-blind comparison of recovery after anaesthesia induced by propofol or thiopentone. Anaesthesia 44:200-204, 1989. 43. Grant IS, Mackenzie N: Recovery following propofol ('Diprivan') anaesthesia-a review of three different anaesthetic techniques. Postgrad Med J 61(SuppI3):133-137, 1985. 44. Kortilla K, Ostman PL, Faure E, Apfelbaum JL, Ekdawi M, Roizen MF: Randomized comparison of outcome after propofolnitrous oxide or enflurane-nitrous oxide anaesthesia in operations of long duration. Can J Anaesth 36:651-657, 1989. 45. Milligan KR, O'Toole DP, Howe JP, Cooper JC, Dundee JW: Recovery from outpatient anaesthesia: A comparison of incremental propofol and propofol isoflurane. Br J Anaesth 59:11111114,1987. 46. Gold MI, Sacks DJ, Grosnoff DB, Herrington CA: Comparison of propofol with thiopental and isoflurane for induction and maintenance of general anesthesia. J Clin Anesth 1:272-276, 1989. 47. Sear JW, Shaw I, Wolf A, Kay NH: Infusion ofpropofol to supplement nitrous oxide-oxygen for the maintenance of anaesthesia. Anaesthesia 43(Suppl):18-22, 1988.
THE AMERICAN JOURNAL OF THE MEDICAL SCIENCES
48. Doze VA, Westphal LM, White PF: Comparison of propofol with methohexital for outpatient anesthesia. Anesth Analg 65:11891195,1986. 49. McCollum JSC, Milligan KR, Dundee JW: The antiemetic action of propofol. Anaesthesia 43:239-240, 1988. 50. Marais ML, Maher MW, Wetchler BV, Kortilla K, Apfelbaum JL: Reduced demands on recovery room resources with propofol ('Diprivan') compared to thiopental-isoflurane. Anesthes Review XVI:29-40, 1989. 51. Gregory MA, Gin T, Yau G, Leung RK, Chan K, Oh TE: Propofol infusion anaesthesia for Caesarean section. Can J Anaesth 37: 514-520, 1990. 52. McLougin C: Use of propofol in a patient with porphyria. Br J Anaesth 62:114-116, 1989. 53. Cartwright DP: Propofol in patients susceptible to malignant hyperpyrexia (letter). Anaesthesia 44:173, 1989. 54. Mirakhur RK, Elliott P, Shepherd WFI, Archer DB: Intraocular pressure changes during induction of anaesthesia and tracheal intubation. A comparison of thiopentone and propofol followed by vecuronium. Anaesthesia 43(Suppl):54-57, 1988. 55. Van Hemelrijck J, Van Aken H, Plets Ch, Goffin J, Vermaut G: The effects of propofol on intracranial pressure and cerebral perfusion pressure in patients with brain tumors. Acta Anais Belgica 40:95-100, 1989. 56. Ravussin P, Guinard JP, Railey F, Thorin D: Effect of propofol on cerebrospinal fluid pressure and cerebral perfusion pressure in patients undergoing craniotomy. Anaesthesia 43(Suppi) 3741,1988. 57. Van Hemelrijck J, Fitch W, Mattheussen M, Van Aken H, Plets C, Lauwers T: Effect of propofol on cerebral circulation and autoregulation in the baboon. Anesth Analg 71:49-54, 1990.
49
J.
DEEGAN, MB, BCH, BSe
KEY INDEXING TERMS: Anesthetic; Intravenous; Propofol. [Am J Med Sci 1992; 304 (1):45-49.]
M
odem anesthetic practice has been largely based on the use of volatile/gaseous agents administered by inhalation, with the intravenous agents generally confined to anesthetic induction. Inhalational agents cause pollution of the operating room environment, which may be related to impaired psychomotor performance, liver damage, and miscarriages among surgical, anesthesiology, and nursing personnel. The goal of intravenous anesthesia has long been considered desirable but available agents, for reasons of pharmacokinetics or side effects, were not suitable for maintenance of anesthesia. This situation has changed with the introduction of propofol, a novel intravenous anesthetic chemically unrelated to previous compounds. Pharmacokinetics
Propofol obeys first order kinetics through a range of infusion rates capable of maintaining anesthesia over a number of hours. Due to high lipophilicity and extensive tissue binding, the volumes of distribution are very high, and the steady state and elimination phase volumes of distribution exceed total body water. In general, the concentration time data are best fitted by a triexponential function. The tI!2(¥ of 2-5 minutes is attributed to distribution from blood into tissues; a t1f2{3 of 0.5-1 hour represents metabolic clearance from Prepared for Vanderbilt University Medical Center Pharmacy and Therapeutics Committee, Vanderbilt University, Nashville, Tennessee. Editors: Renata E. Bluhm, MD, PhD, Philip E. Johnston, PharmD, Jason D. Morrow, MD. The author thanks Dr. Margaret Wood, MD, Division of Anesthesiology, Vanderbilt University School of Medicine, for her assistance in reviewing this article. Correspondence: Department of Pharmacology, Division of Clinical Pharmacology, Vanderbilt University, School of Medicine, Nashville, TN 37332. THE AMERICAN JOURNAL OF THE MEDICAL SCIENCES
blood; a t l l20 of 3-9 hours is explained by the slow return of propofol from a poorly perfused deep compartment (probably fat) acting as a rate-limiting factor for elimination. Even after several hours of infusion however one can still expect a rapid initial decline in plasm~ concentration due to redistribution, and recovery can remain independent of the long terminal half-life. 1 The liver is the most important site of elimination,2 and very high clearance values, of the order of 70-140 L/ hr have been reported. 3 A number of factors that might affect propofol pharmacokinetics have been investigated. Sex,4 hepatic cirrhosis,5 and renal failure 6 have no significant effect. With increasing age, induction and maintenance dose requirements are reduced. 7,8 Propofol pharmacokinetics are also altered by coadministration of other drugs. Cockshott and colleagues9 found that blood propofol levels were 50% higher following induction in patients receiving 2 Jlg/kg of the opioid, fentanyl. Clinical Use and Effects of Propofol
Propofol has been found useful for three different clinical applications: (1) IV bolus for anesthesia induction; (2) IV infusion or repeated bolus for maintenance of anesthesia; and (3) IV infusion or repeated bolus for sedation. Induction
Its high degree of lipophilicity and short half-life make propofol suitable for IV induction with rapid access to the brain and subsequent rapid recovery due to redistribution and elimination. The effective induction dose of propofol is 2-2.5 mg/kg in healthy unpremedicated adults. 10 In those over 60 years old, 1.5 mg/kg is adequate. 7 The induction dose is also reduced by premedication with benzodiazepines or opiates. l l Loss of consciousness is achieved within one arm-brain circulation time (< 40-50 seconds), as has been shown for thiopental and methohexital. 12 ,13 Ideally, an induction agent should achieve rapid loss of consciousness smoothly without significant cardiovascular or respiratory effects. The decrease in blood pressure and the increase in heart rate with propofol
45
Propofol
induction are generally greater than with thiopental or methohexital. l2- 14 To some extent this may be advantageous, counteracting the reflex hypertension with endotracheal intubation. The hypotension may, however, be deleterious. In one study of beta-blocked patients for coronary artery surgery,15 propofol induction reduced systolic blood pressure to less than 100 mm Hg in 8 of 10 patients and to less than 70 mm Hg in 2 of 10 patients. In contrast, thiopental induction caused systolic pressure to fall below 100 mm Hg in only 1 of 10 patients and no patient in the thiopental group had a systolic pressure below 90 mm Hg. Earlier studies in both animals 16 and man17 have attributed propofol-induced hypotension to a decrease in systemic vascular resistance; cardiac output was either maintained or increased. The latter observation may, in some cases,17 have resulted from elevated PaC02 values, as a significant reduction in cardiac output by propofol induction has been demonstrated in the presence of normocarbia. 18 In addition, there are now a number of studies which indicate that propofol has a negatiye inotropic effect in vitro19 and in vivo. 14.20 Depression by propofol of both systemic vascular resistance and cardiac output might be partly the result of the marked sympathetic inhibition, which has been demonstrated by percutaneous sympathetic nerve recording in man 21 and by assessment of norepinephrine kinetics in dogs 22 following propofol administration. Propofol induction causes higher incidences of excitatory phenomena (hypertonus, spontaneous movement, twitching, tremor), apnea, and pain on injection than does thiopental. Local pain is related to injection site and can be minimized by use of large antecubital veins (incidence 6.0%) rather than small dorsal hand veins (incidence 28.5%) or by coadministration of lidocaine. 23 A greater respiratory depressant effect of propofol versus thiopental has been suggested by some studies,13,24 but not by others.25 The reported incidence . of apnea of greater than 60 seconds duration varies widely, from about 20_90%.25.26 Some of the variability may be explained by differences in premedication. Coadministration of or premedication with opioids increases the respiratory depression25 but reduces excitatory movements and pain on injection. Anesthesia Maintenance
Propofol is the only currently available IV anesthetic that is well-suited for maintenance of anesthesia. This is due to its favorable pharmacokinetic profile, which avoids the accumulation seen with prolonged thiopental administration, to its preservation of adrenal steroidogenesis26.27 (inhibition of which leads to increased patient mortality with etomidate infusions), and to its ability to provide extremely smooth maintenance with easily controlled depth of anesthesia and relative freedom from the excitatory effects, which occur with alternative agents such as methohexita1. 28
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While repeated bolus administration is feasible, continuous infusion provides more stable blood propofol concentrations with better control of anesthetic depth and adverse effects. When administered together with 60-70% nitrous oxide in oxygen, a propofol infusion rate of about 6-8 mg/kg- 1 hr- 1 is required, depending on the extent of surgery. When nitrous oxide is undesirable (eg, jet ventilation or pneumothorax), anesthesia can be adequately maintained by propofol infusion alone (usually with benzodiazepine or opioid premedication). Rates of up to 12 mg/kg- 1 hr- 1 are then required. 17.29 More commonly, total IV anesthesia is achieved by combined infusions of propofol and an opioid. Both fentanyl and alfentanil have been found suitable in this context.28.30 The characteristic rapid, smooth recovery after propofol maintenance still occurs, provided that the opioid infusion is discontinued 10-20 minutes before the propofol infusion. 28.29 Otherwise, opioid-induced respiratory depression may be a problem. The potential for respiratory or cardiovascular depression during propofol maintenance is significant but rarely causes problems when adequate precautions are taken. Some authors have used propofol infusions without controlled ventilation for periods of up to 1 hour without major increases in PaC02,17.29 but apnea of more than 30 seconds occurred in 72% of cases in one such report. 29 Opioid co-infusions increase this risk, thus requiring controlled ventilation. When an induction dose of 2 mg/kg propofol is followed by a fixed infusion rate (3-6 mg/kg-1 hr-1), a 25-45% reduction in systolic pressure can be expected. 17.31 Knowledge of propofol's pharmacokinetic profile has allowed development of computer-driven infusion systems, which attain the desired blood propofol concentration very rapidly with little overshoot, and then maintain the level over long periods by calculating an exponentially decreasing infusion rate to match the decreasing rate at which the drug leaves the central compartment by distribution and elimination.32 Such regimens and their manually-applied equivalents33 achieve very stable propofollevels and remarkably stable hemodynamics. Sedation
Sedation of critically ill patients in the intensive care setting traditionally involves the use of benzodiazepines, opiates, or the major tranquilizers (phenothiazines, butyrophenones) , which is limited by prolonged recovery, respiratory depression, and gastrointestinal stasis. There have been a number of reports of the successful use of propofol by continuous infusion for sedation in intensive care patients with a variety of illnesses, including cardiac surgery,34 head injury,35 acute respiratory failure, septic shock, and acute tubular necrosis,27.36 for durations of 8-189 hours. The mean dosages used vary from 0.79 to 2.88 mg/kg-1 hr-1, reflecting the different ages and conditions of the patients in the studies. In each study, adequate sedation was achieved July i992 Volume 304 Number 1
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without difficulty. Supplemental opioid boluses were required in each case but significantly less than with midazolam (a short-acting benzodiazepine) sedation. 34 Recovery was also very satisfactory. Grounds and colleagues34 reported a mean time to tracheal extubation of 25 minutes following cessation of an 8-hour infusion of propofol, while a comparable group sedated with midazolam required 226 minutes on average. Even with the relatively low doses required for sedation, potential cardiovascular depression is still a concern in critically ill patients treated with propofol. This is exemplified in a study by Newman et al27 in which 6 to 10 patients had mean arterial pressures of less than 60 mm Hg at some point during an 8 hour infusion of propofol. It is very important that hemodynamic parameters be carefully monitored to minimize such events. Outside of the intensive care unit, administration of propofol by continuous infusion or intermittent bolus has been found to be suitable for sedation during regional anesthesia37,38 or during day case endoscopies,39 comparing favorably with midazolam and methohexital. In a series by Gepts and colleagues,4o however, apnea occurred in 48% of patients receiving propofol for sedation during colonoscopy. It is clear that special vigilance is required when propofol is administered by nonanesthesiologists and in locations other than the intensive care unit or the operating room. Recovery Characteristics
In keeping with its high lipid solubility and high clearance rate, rapid emergence from propofol anesthesia may be expected. Propofol has a lesser influence on recovery when it is used only for induction with subsequent maintenance by an inhalational agent. 4l ,42 However, even in this context, more rapid recovery has been demonstrated with propofol induction compared to thiopental or methohexital induction when the period of inhalational anesthesia is short.43 When used for both induction and maintenance of anesthesia, the benefit of improved recovery with propofol is more obvious. More rapid, smooth recovery has been demonstrated following maintenance of anesthesia by repeated bolus or continuous infusion of propofol compared to all of the other major alternatives44-47 and for procedures of durations ranging from 15 minutes to a few hours. Patients recovering from propofol are relatively clearheaded and have a low incidences of depression, tremulousness, nausea, and vomiting. 44 ,48,49 These features significantly improve patient well-being in the postoperative period and may be especially advantageous in the context of ambulatory surgery. There may also be economic benefits. An analysis by Marais and colleagues50 has suggested that switching from thiopentaljisoflurane anesthesia to propofol anesthesia would reduce nurse staffing requirements in the recovery room. THE AMERICAN JOURNAL OF THE MEDICAL SCIENCES
Use of Propofol in Special Settings
Propofol has been found suitable for anesthesia during Caesarean section5l and appears safe in patients with porphyria52 or with susceptibility to malignant hyperthermia.53 As with thiopental, propofol induction reduces intraocular pressure, and propofol is more effective than thiopental in inhibiting the increase in intraocular pressure associated with intubation. 54 The use of total IV anesthesia for neurosurgical patients avoids the cerebral vasodilating action of inhalational agents. Rapid recovery from propofol compared to thiopental infusion can avoid prolonged delays in neurologic assessment. Further, propofol alleviates cerebral hypertension,55 and, when combined with a small bolus of fentanyl, attenuates the usual increase in cerebrospinal fluid pressure in response to intubation and other noxious stimuli. 56 However, the reduction in cerebral perfusion pressure that is related to decreased mean arterial pressure may be marked and potentially deleterious, especially following bolus administration of propofol.55 The influence of propofol on the coupling between cerebral metabolism and blood flow has not been adequately defined. 57 Cost
Propofol is available in 200-mg (20 ml) ampules at $9.97 each. An average induction dose, thus, costs almost $10 (compared to about $2 for thiopental); anesthesia maintenance by propofol alone would cost up to $42 per hour for a 70-kg patient but less than $28 per hour for the lower infusion rates required in combination with nitrous oxide. Sedation can be achieved with rates ranging from 1 to 3 mg/kg-lhr-l, which costs approximately $3-10 per hour for a 70-kg patient. Conclusion
Propofol is a relatively new IV anesthetic agent whose pharmacokinetic profile renders it suitable not only for induction, but also for infusion to maintain anesthesia or sedation. A remarkable feature of propofol is a rapid, smooth recovery which, during administration, allows rapid titration of effect and, after cessation, allows relatively early discharge to the ward or home. Thus, propofol can be expected to facilitate the increasing trend toward day-cease surgery. The apparent safety of propofol in patients with porphyria or malignant hyperthermia susceptibility suggests that propofol may be a valid alternative where barbiturates or inhalational anesthetics are contraindicated. Propofol may also have advantages for opthalmic and some neurologic surgery. Minor problems of pain on injection and some excitatory phenomena at induction do not significantly limit propofol's use. However, cardiovascular and respiratory depression are potentially more serious. Adequate attention to dosage (reduced in elderly), rate of administration of boluses, and concomitant medications (opioids enhance both cardiovascular and respiratory adverse effects) minimizes these prob47
Propofol
lems. Pharmacokinetics-based computer-driven infusion regimens allow maintenance of stable hemodynamics and will contribute to the increasing use of propofol. Nevertheless, the potential for profound respiratory and cardiovascular depression with propofol requires that its use be largely restricted to situations such as the intensive care unit or operating room where trained personnel and resuscitation equipment are at hand. For these reasons, propofol is not a substitute for the benzodiazepines as an agent for conscious sedation under supervision of the nonanesthesiologist. References 1. Gepts E, Camu F, Cockshott !D, Douglas EJ: Disposition of propofol administered as constant-rate infusions in humans. Anesth Analg 66:1256-1263,1987. 2. Simons PJ, Cockshott!D, Douglas GJ, Gordon EA, Hopkins K, Rowland M: Disposition in male volunteers of a subanaesthetic intravenous dose of an oil in water emulsion of 14C-propofol. Xenobiotica 18:429-440, 1988. 3. Sebel PS, Lowdon JD: Propofol: A new intravenous anesthetic. Anesthesiology 71:260-277,1989. 4. Kay NH, Sear JW, Uppington J, Cockshott ID, Douglas EJ: Disposition of propofol in patients undergoing surgery. A comparison in men and women. Br J Anaesth 58:1075-1079, 1986. 5. ServinF, HabererJP, Cockshott ID, Farinotti R, DesmontsJM: Propofol pharmacokinetics in patients with cirrhosis (abstract). Anesthesiology 65:A554, 1986. 6. Morcos WE, Payne JP: The induction of anaesthesia with propofol ('Diprivan') compared in normal and renal failure patients. Postgrad Med J 61(Suppl):62-63, 1985. 7. Dundee JW, Robinson FP, McCollum JSC, Patterson CC: Sensitivity to propofol in the elderly. Anaesthesia 41:482-485, 1986. 8. Doze VA, Shafer A, White PF: Propofol-nitrous oxide versus thiopental-isoflurane-nitrous oxide for general anesthesia. Anesthesiology 69:63-71,1988. 9. Cockshott JD, Briggs LP, Douglas EJ, White M: Pharmacokinetics of propofol in female patients. Br J Anaesth 59:11031110,1987. 10. Cummings GC, Dixon J, Kay NH, Windsor JPW, Major E, Morgan M, Sear JW, Spence AA, Stephenson DK: Dose requirements of ICI 35,868 (propofol, 'DIPRIVAN') in a new formulation for induction of anaesthesia. Anaesthesia 39:1168-1171, 1984. 11. Thomas VL, Sutton DN, Saunders DA: The effect of fentanyl on propofol requirements for day case anesthesia. Anaesthesia 43(Suppl):73-75,1988. 12. Mackenzie N, Grant IS: Comparison of the new emulsion formulation of propofol with methohexitone and thiopentone for induction of anesthesia in day cases. Br J Anaesth 57:725-731, 1985. 13. Gold MI, Abraham EC, Herrington C: A controlled investigation of propofol, thiopentone and methohexitone. Can J Anaesth 34: 478-483,1987. 14. Lippmann M, Paicius R, Gingerich S, Owens R, Mok MS, Appel P: A controlled study of the hemodynamic effects of propofol versus thiopental during anesthesia induction. Sem Anesth 7(Suppl 1):116-122, 1988. 15. Patrick MR, Blair IJ, Feneck RO, Sebel PS: A comparison of the hemodynamic effects of propofol ('Diprivan') and thiopentone in patients with coronary artery disease. Postgrad Med J 61(Suppl):23-27, 1985. 16. Glen JB, Hunter SC: Pharmacology of an emulsion formulation of ICI 35, 868. Br J Anaesth 56:617-626, 1984. 17. Claeys MA, Gepts E, Camu F: Haemodynamic changes during anaesthesia induced and maintained with propofol. Br J Anaesth 60:3-9, 1988.
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18. Stephen H, Sonntag HD, Schenk D, Kettler D, Khambatta HJ: Effects of propofol on cardiovascular dynamics, myocardial blood flow and myocardial metabolism in patients with coronary artery disease. Br J Anaesth 58:969-975, 1986. 19. Roewer N, Winguth TH, Proske 0, Dziadzka A, Schulte am Esch J: Inotropic and electrophysiological effects ofpropofol on isolated ventricular myocardium (abstract). Anesthesiology 73: A381,1990. 20. Briissel T, Theissen JL, Vigfusson G, Lunkenheimer PP, Van Aken H, Lawin P: Hemodynamic effects ofpropofol and etomidate. Negative inotropic properties of propofol. Anesth Analg 68:35-40, 1989. 21. Ebert TJ, Berens RJ, Muzi M, Kampine JP: Direct comparison of etomidate and propofol on sympathetic neural outflow and baroreflex function in man. Anesth Analg 72:S61, 1991. 22. Deegan R, He HB, Wood AJJ, Wood M: Effects of anesthesia on norepinephrine kinetics. Comparison of propofol and halothane anesthesia in dogs. Anesthesiology 75:481-488,1991. 23. Stark RD, Binks SM, Dutka VN, O'Connor KM, Arnstein MJA, Glen JB: A review of the safety and tolerance of propofol ('Diprivan'). Postgrad Med J 61(Suppl 3):64, 1985. 24. Perry SM, Bullington J, Davis L, Fisher K, Ramsay S, Wood M: A comparison of DIPRIVAN (propofol) and thiopental for the induction and recovery of anesthesia. Sem Anesth 7(Suppl 1):91-93, 1988. 25. Streisand JB, Stanley TH: The respiratory effects of DIPRIVAN (propofol) with and without fentanyl. Sem Anesth 7(Suppl 1): 123-126, 1988. 26. Kay NH, Uppington J, Sear JW, Allen MC: Use of an emulsion of ICI 35868 (Propofol) for the induction and maintenance of anaesthesia. BrJ Anaesth 57:736-742,1985. 27. Newman LH, McDonald JC, Wallace PGM Ledingham I McA: Propofol infusion for sedation in intensive care. Anaesthesia 42: 929-937, 1987. 28. Kay B: Propofol and alfentanil infusion. A comparison with methohexitone and alfentanil for major surgery. Anaesthesia 41: 589-595, 1986. 29. McLeod B, Boheimer N: Propofol ('Diprivan') infusion as main agent for day case surgery. Postgrad Med J 61(Suppl 3):105107,1985. 30. Jenstrup M, Nielsen J, Fruergard K, Mq,ller A-M, Wiberg-. Jq,rgensen F: Total IV anaesthesia with propofol-alfentanil or propofol-fentanyl. Br J Anaesth 64:717-722, 1990. 31. Monk CR, Coates DP, Prys-Roberts C, Turtle MJ, Spelina K.: Hemodynamic effects of a prolonged infusion of propofol as a supplement to nitrous oxide anesthesia. Br J Anaesth 59:954960,1987. 32. Tackley RM, Lewis GTR, Prys-Roberts C, Boaden RW, Dixon J, Harvey JT: Computer controlled infusion of propofol. Br J Anaesth 62:46-53, 1989. 33. Perry SM, Smith D, Wood M: Propofol for induction and maintenance of anesthesia: Recovery characteristics. Proc World Congress Anaesthes, 1988. 34. Grounds RM, Lalor JM, Lumley J, Royston D, Morgan M: Propofol infusion for sedation in the intensive care unit. Br Med J 294:397-400, 1987. 35. Farling PA, Johnston JR, Coppel DL: Propofol infusion for sedation of patients with head injury in intensive care. Anaesthesia 44:222-226, 1989. 36. Harris CE, Grounds RM, Murray AM, Lumley J, Royston D, Morgan M: Propofol for long-term sedation in the intensive care unit. A comparison with papaveretum and midazolam. Anaesthesia 45:366-372, 1990. 37. Mackenzie M, Grant IS: Comparison of propofol with methohexitone in the provision of anaesthesia for surgery under regional blockade. Br J Anaesth 57:1167-1172, 1985. 38. Fanard L, Van Steenberge A, van der Puyl F: Comparison between propofol and midazolam as sedative agents for surgery under regional anaesthesia. Anaesthesia 43(Suppl):87-88, 1988. July 1992 Volume 304 Number 1
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39. Dubois A, Balatoni E, Peeters JP, Bandoux M: Use of propofol for sedation during gastrointestinal endoscopies. Anaesthesia 43(Suppl):75-80, 1988. 40. Gepts E, Claeys MA, Camu F, Smekens L: Infusion of propofol ('Diprivan') as sedative technique for colonoscopies. Postgrad Med J 61(Suppl 3):120-126, 1985. 41. Valanne J, Kortilla K: Comparison of methohexitone and propofol ('Diprivan') for induction of enflurane anaesthesia in outpatients. Postgrad Med J 61 (Suppl 3):138-143, 1985. 42. Sanders LD, Isaac PA, Yeomans WA, Clyburn PA, Rosen M, Robinson JO: Propofol-induced anaesthesia. Double-blind comparison of recovery after anaesthesia induced by propofol or thiopentone. Anaesthesia 44:200-204, 1989. 43. Grant IS, Mackenzie N: Recovery following propofol ('Diprivan') anaesthesia-a review of three different anaesthetic techniques. Postgrad Med J 61(SuppI3):133-137, 1985. 44. Kortilla K, Ostman PL, Faure E, Apfelbaum JL, Ekdawi M, Roizen MF: Randomized comparison of outcome after propofolnitrous oxide or enflurane-nitrous oxide anaesthesia in operations of long duration. Can J Anaesth 36:651-657, 1989. 45. Milligan KR, O'Toole DP, Howe JP, Cooper JC, Dundee JW: Recovery from outpatient anaesthesia: A comparison of incremental propofol and propofol isoflurane. Br J Anaesth 59:11111114,1987. 46. Gold MI, Sacks DJ, Grosnoff DB, Herrington CA: Comparison of propofol with thiopental and isoflurane for induction and maintenance of general anesthesia. J Clin Anesth 1:272-276, 1989. 47. Sear JW, Shaw I, Wolf A, Kay NH: Infusion ofpropofol to supplement nitrous oxide-oxygen for the maintenance of anaesthesia. Anaesthesia 43(Suppl):18-22, 1988.
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48. Doze VA, Westphal LM, White PF: Comparison of propofol with methohexital for outpatient anesthesia. Anesth Analg 65:11891195,1986. 49. McCollum JSC, Milligan KR, Dundee JW: The antiemetic action of propofol. Anaesthesia 43:239-240, 1988. 50. Marais ML, Maher MW, Wetchler BV, Kortilla K, Apfelbaum JL: Reduced demands on recovery room resources with propofol ('Diprivan') compared to thiopental-isoflurane. Anesthes Review XVI:29-40, 1989. 51. Gregory MA, Gin T, Yau G, Leung RK, Chan K, Oh TE: Propofol infusion anaesthesia for Caesarean section. Can J Anaesth 37: 514-520, 1990. 52. McLougin C: Use of propofol in a patient with porphyria. Br J Anaesth 62:114-116, 1989. 53. Cartwright DP: Propofol in patients susceptible to malignant hyperpyrexia (letter). Anaesthesia 44:173, 1989. 54. Mirakhur RK, Elliott P, Shepherd WFI, Archer DB: Intraocular pressure changes during induction of anaesthesia and tracheal intubation. A comparison of thiopentone and propofol followed by vecuronium. Anaesthesia 43(Suppl):54-57, 1988. 55. Van Hemelrijck J, Van Aken H, Plets Ch, Goffin J, Vermaut G: The effects of propofol on intracranial pressure and cerebral perfusion pressure in patients with brain tumors. Acta Anais Belgica 40:95-100, 1989. 56. Ravussin P, Guinard JP, Railey F, Thorin D: Effect of propofol on cerebrospinal fluid pressure and cerebral perfusion pressure in patients undergoing craniotomy. Anaesthesia 43(Suppi) 3741,1988. 57. Van Hemelrijck J, Fitch W, Mattheussen M, Van Aken H, Plets C, Lauwers T: Effect of propofol on cerebral circulation and autoregulation in the baboon. Anesth Analg 71:49-54, 1990.
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