- Email: [email protected]
Advances in propofol pharmacokinetics and pharmacodynamics
Department of Anesthesia, Stanford University School of Medicine, Stanford, 5%; Anesthesiology Service, Palo Alto Veterans Administration Medical Center, Palo Alto, CA. s: Anesthesia-ambulatory, Intravenous; opioids; propofol.
local, regional;
anesthetics-
The availability of intravenous (IV) sedatives, hypnotics, opioads, an8n muscle relaxants with more evanescent drug effects has facilitated the 3e of IV anesthetic techniques in the ambulatory setting. No new drug impact on the practice of outpatient anesthesia than propofol its introduction into clinical practice in the United States, prop an increasingly important role for the induction and maintenance of general anesthesia for outpatients undergoing ambulatory procedures. In addition to .its use in the induction and maintenance of general anesthesia, recently approved by the Food and Drug ‘~drniu~§trat~ou for se local and regional anesthesia and for sedation of mechanically veu~~at~d patients in the intensive care unit (HCU). In this article, ret t advances in pharmacology are reviewed. our understanding of propofol advances, dosing and titration guidelines for propofoi are the integration of pharmacokinetic and pharmacodynamic models.
*Assistant
Professor
Address reprint requests to Dr. Shafer at the Anesthesiology Service (112A), Palo Alto Veterans Administration Medical Center, 3801 Miranda Avenue, Palo Alto, CA 94304, USA. Received for publication on August 26, 1993; revised manuscript accepted for publication September 10, 1993. 0 1993 Butterworth-Heinemann J. Glin. Anesth. B(Supp1 1):14%?1S,
14s
j. Gin.
Anesth.,
1993.
vol. 5 (Suppl
roPiie relative :o :he other IV arresue pharmacokinetic t,hetics. Table 1 compares the pharmaco inetics of propofol’ and thiopental sodium.* The metabolic clearance of propofol is ten times as fast as the metabolic clearance of thiopental. In fact, the meta olic clearance of pro exceeds hepatic blood Row, suggesting that propofol has extsahepatic sites of metabolism and elimination. This rapid metabolic clearance is one of the most important characteristics that makes propofol clinically and pharmacokinetically different from thiopental. The distribution clearance of an IV anesthetic drug is a measure of the movement of the drug from the central compartment (the instantaneously equilibrating tissues, including the blood and highly perfused vessel-rich tissues) into tissues with lower blood flow. The total distribution clearance of propofol and thiopental ranges from 3 to 4 Unkdkg, a value that is approximately 60% to 80% of the cardiac output (619). This suggests that propofol and thiopental distribution to Sody tissues will be governed by CO and regional blood Row. The large steady-state volumes of distribution for propofol and thiopental suggest extensive partitioning into muscle and fat tissue. The long (and clinically irrelevant) elimination half-
I), November/December
1993
lives of propof& arnd thiopental result from elimination 0B the drugs from the large stores
the in
sl0W
fat
and
KkUSCk.
Figure P show simulated declines in blood lhiopental and propofol concentration as a percentage of the initial peak concentration following an IV bolus dose. This simulation is based on the pbarmacokinetic parameters shown in Taable I. Plasma concentrations decline rapidly for both drugs in the first few minutes. The similar shapes of the curves over the first few minutes reflect rhe-similar distribution clearances of propofol and thiopental. However, after the first few minutes, the propofol concentration declines more rapidly than the thiopental concentration. This is due to the very rapid hepatic, and possibly extrahepatic, clearance of propofol relative to rhiopental. Figure 2 shows a simulation of the time required for e effect site concentration ofthiopental and propofol to decline by 50% following discontinuation of a continuous infusion. The simulations shown in Figure 2 are based on the pharmacokinetics of each drug and the rate of equilibration between the plasma and the effect site. Fig-
0
Thiopentd
-
6.3 530 1.7 1.7 2.1 5.5 6.3
Initial volume (L) Steady-state volume (L) etabolic clearance (Limin) pid distribution clearance (Limin) Slow distribution clearance (Limin) Total clearance (Limin) Elimination half-life (hr)
PICJS~CI revels
Following
c 100 2 E? t; u” G 0
__ -----
12.7 120 0.2 2.6 0.6 3.4 12.7
Bolus Propofol Thiopental
IO -_-___
3 .z 5
CL0.7
/
/
0
60
---__
--_-___
Minutes
---------_____________
120 Since
180 Bolus
ure 1. Propofol and thiopental concentrations, percentage of the initial concentration, following injection.
Prcpofol
-----
Tnicpentol
240
360
Infusion
Duration
480
600
uli& 2. Curves showing time required for 50% decrease in propofol and thiopental concentration foliowing discontmuation of a continuous infusion.
le 1. Relative Fharmacoklnelics of Propofo: and pental Sodium Bropofol
120
_
240
as a bolus
u7-e2 relates tne increasing time requIrea for recovery with increasing infusion duration. When the infusion is terminated, the effect site propofol concentration decreases by 50% far more rapidly than does the thiopental concentration. Moreover, the time required for a 50% decline in propofol concentration once the infusion is stopped increases far more with infusion duration for thiopental than for propofol. This is consistent with clinical experience showing that when thiopentai is used for maintenance of anesthesia, recovery may be unacceptably slow. By contrast, even after a G-hour infusion of 9ropofo1, only I5 minutes are require for a 50% decrease in drug concentration. This finding has been confirmed in clinical studies using propofol as a sedative in ICLJS.~ 3f course, if the drug is precisely titrated so that the percent decrease required for recovery is less than SS%, he time required will be less than that shown in PZguz 2 and will asymptotically approach XX-Q for a 0% decrease. Figure 3 compares the relationship between infusion An-ation and recovery time for propofol (as also shown tn Figure 2) with alfentanii and sufentanii: based on the xblished pharmacokinetics of aKentanil* and sufen,:anil .j Even tho.ugh alfentanil has more rapid distribution and terminal half-lives than sufentani8, for infusions of ess than 8 hours, the plasma alfentan;! concentration sufentanil conrzay not decline as rapidly as the @asma rentration when the infusion is terminated. This concept is explained fully in a recent article.s Propofol infusions are often combined with opioid mfusions during anesthesia. Since the decline in propofol concentration is several-fold faster than the decline in 3pioid concentration, it makes ~~armacoki~et~c sense to titrate the propofol while maintai&g a constant opioid concentration. Thus, if a drug overdose occurs, it w be with the drug more quickly elimin.ated from the bloo Slinically, it is my impression that titrahn of propofol oroduces the desired increase or decrease in anesthetic
8. Clin. -be&.,
vol. 5 (Suppi I), FiovenberiDecember
I993
95s
Orfginai
Contrzbution,s
goscopy and mtubation, and increases the irk&hood ~fd‘ hypotension following induction. Some practice is required to find the correct doses of opioid and prop&l that offer smooth hemodynamics for different categories of patients.
Recovery Curves: Propofol vs Opioids
240 Infusion
360
480
600
Duration
Figure 3. Curves showing time required for 50% decrease in propofol, alfentanil, and sufentanil concentration following discontinuation of a continuous infusion.
depth more quickly and reliably than titration of the opioid. The clinical dosing guidelines contain a recommendation for combining sufentanil with propofol to achieve total intravenous anesthesia (TIVR). Sufentanil was selected because its pharmacokinetic properties suggest that after infusions of less than 8 hours, patients will awaken more quickly from a sufentanil infusion than from an alfentanil infusion, as shown in Figure 3. In summary, propofol’s pharmacokinetic characteristics of extremely rapid metabolism and large distribution clearances relative to distribution volumes result in a unique disposition that is well suited to both the induction and maintenance of anesthesia.
The induction dose of propofol ranges from 1 to 2.5 mgikg, administered as several divided doses (2 to 3 ml per dose). Elderly patients and patients receiving opioids prior to induction should receive doses closer to 1 _mg/ kg. Following the induction dose, patients will lose consciousness in approximately I minute. Blood pressure (BP) usually decreases by 20% to 40%, while heart rate (IN) remains stable. Intubation should be attempted 60 to 90 seconds following the induction dose. Following intubation, BP usually returns to within IO% to 20% of baseline. HR tends to remain stable throughout induction and intubation. In some elderly patients, BP may decrease by 50% and remain rather low, even after intubation. This usually responds to 5 to 10 mg of ephedrine and is a sign of relative hypovolemia, which resolves with fluid administration. Patients in hypovolemic shock should not be induced with propofol. Premeditation with opioids decreases the propofol dose necessary for induction of anesthesia, decreases the hemodynamic response to noxious stimuli such as larynJ. Glin. Anesth., vol. 5 (Suppl l), November/December i993
Intermittent boluses of propofol produce oscillations in propofol concentration and anesthetic depth. Therefore, the dosing guidelines assume that propofol will be given by continuous infusion during maintenance of the anesthetic. (See Appendices A and B far dosing guidelines for maintenance of anesthesia with a contmuous mfusion of propofooi.) The guidelines are intended to serve as a starting point, beyond which the ane~thes~o~~g~st must titrate the maintenance infusion rate to the desired degree of central nervous system (CNS) depression. To maintain reasonably constant propofol blood concentrations, the maintenance infusion rate should be decreased during the operation. The guidelines recommend downward adjustments at 10 minutes and 2 hours. When propofol is used without nitrous oxide (N&r) or a potent vapor, intraoperative awareness is possible. Although intraoperative awareness also can occur when using a N@-opioid anesthetic technique, N@ is a sufficiently potent analgesic that intraoperative awareness of pain almost never occurs when it is used with an opioid. This is not the case with propofol. Intraoperative awareness during a propofol-opioid technique (e.g., during total IV anesthesia) may include awareness ofintraoperalive pain. Following are some suggestion5 for preventtng awareness. Rem& rjigilant for signs cf light anesthesia. Arr abr~p change in HP., even if only from SO to 70 beats per minute (bpm), may signal impending awareness. If the patient is not fully paralyzed, nonspecific movements may occur virtually simultaneously with the HR change. Treat light anesthesia with a ! to 2 ml boius of~ro~ofo~. One major advantage of an IV hypnotic over an inhaled hypnotic is the ability to administer an IV bolus. Wren signs of light anesthesia develop, this is the time to take advantage of the rapid deepening of the anesthetic state that is possible with an IV drug. For this reason, I keep the propofol syr-inge attached to the ZV line during the entire anesthetic. Note that several minutes of light anesthesia are usua& required before the patient 3s sufficiently aware that recai2 is possible. In each case of intraoperative awareness with which I am familiar, the patient was allowed to remain lightly anesthetized for a substantial period of time. 1 have frequentfy observed patients showing movement in response to light propofol anesthesia. I have treated these patients with a smal: propofosii bo1us and on postoperative questioning have not had them report any recall. At the end of th,e case, turn off the infusion several minutes prior to the desired time of emergence. owever, remain
vigilant for signs of light anesthesia during, for examp!e, placement of the last sutures. If signs of light anesthesia develop prior eo the desired time of emergence, administer one or more small boluses (I to 2 ml) of propofol. This will prolong the anesthetic without causing excessive sedation or emergence. 5. 1: recent innovakvz is the use of propofol combined with Retamine, as reported by Guit et al.’ These investigators compared propofol-fentanyl with propofol-ketamine and found that propofol-ketamine provided stable hemodynamics and was not associated with dreaming or abnormal behavior. They concluded that propofol effectively eliminated the untoward side effects of ketamine and the propofol-ketamine was a useful combination for TWA. Ketamine also has the advantage of being a potent analgesic. My TIVA guidelines have been revised to reflect a propofol-opioid-ketanine technique. (See Appendices A and B.) My own two cases of in:raoperative awareness with propofol-opioid TIVA are instructive. In the first case, the patient abruptly developed tachycardia at a rate of 120 to 130 bpm during the surgical prep. I observed the tachycardia for aSout IO minutes prior to treating her with a bolus of propofol. She could vividly recall the last I to 2 minutes prior to the bolus, despite 3 mg of midazolam given prior to induction. In the second case, a patient was given a large bolus of esmolol, resulting in bradycardia and hypotension. In response, the propofol infusion was turned off intraoperatively for about 15 minutes. The patient could clearly recall several minutes of abdominal exploration. In both case, the patients were totally paralyzed and reported their frustrated attempts to move. The lessons from these two cases are (I) additional vigilance is required in totally paralyzed patients; (2) midazolam is not a substitute for adequate hypnosis; (3) there is a period of several minutes between light anesthesufficient awareness in which patients can subserecall events and during which the anesthetic with a bolus of propofol; (4) depth can be sup$emented don’t turn the propofol infusion off during the operation, 2s the “ciearheaded” emergence that is desirable following surgery is considerably less desirable in the middle of a procedure. Propofol &uses are much more suitable than thiopental boluses for extending an anesthetic by a few minutes. It is my experience that patients wake up slowly, and are quite sedated, if 2 small bolus of thiopental is used to extend an anesthetic. For this reason, 1 suggest having a syringe of propofol, not thiopental, ready at the end of an anesthetic if a few additional minutes are necessary.
InJanuary
i992, propofool was approved for use in moni-
tored anesthesia car efits of propofo? for
midadam,
inch_&
AC) sedation. The potential benC sedation, when compared with more rapid titration of the level of
sedation and faster return of ciearheadechess. Figure 4 shows the effect site concentrations over ti.me following a bolus injection of propofol or midazolam, based on an integrated ~harmacokinetic-~harmacodynamic model for each drug that was developed in our laboratory. The more rapid blood-brain equilibration of propofol (I to 2 minutes)’ compared with midazolam (2 to 4 minutes)8~g means that the level of sedation can be increased more rapidly with propofol in anticipation of an imminent noxious stimulus. Following a bolus, the effect of fol is far more evanescent than that of midazolam. once the stimulus has ended, the patient can be returned to a Lighter level of sedation more rapidly with propofol than with midazolam. A continuous propofol infusion can be used to maintain a steady level of sedation throughout a case. The siower pharmacokinetics of midazolam permit a technique of small intermittent boluses that IS easier to administer than a propofol infusion. However, if a steady concentration is maintained, we can use the integrated pharmacokinetic-pharmacodynamic model to compare ihe time to the offset of drug effect for propofol and midazolam, as shown in Figure 5. Tiae model demonstrates that recovery from propofol will be far faster than recovery from midazolam. The rapid recovery from a propofol infusion is particularly important if the patient must occasionally interact with the surgeon or if the patient’s condition requires very precise control of the level of sedation. As of June 1992, a ne search of every =.eference to both propofol an azoiam confirmed *his prediction in every publication that examined rates of recovery from sedation.‘k16 The introduction of patient-con:rolled sedation per,mits the patient to titrate his or her level of sedation by sressing a button to receive additional drug, which is analogous to patient-controlled analgesia. In two recent studies,6,‘T patients were very satisfied with patient-
0 0
1
2 3 MinutesSince Bolus
4
Figure 4. Rise to peak concentration in the effect site following a bolus injection of propofol and midazolam, as predicted from an integrated ?la;trmacokiwetic-plarmacodynamic model.
infusions (usuaIly in the %CLj, rhe Znirairpid ve&le .mal cause hyperlipidemia. Therefore, it is necessary to monitor triglycerides during prolonged infusions, particular+ if rapid rates are used. Lastly, the Intraiipid v&i& contains no preservatives and supports growth of microorganisms.*r Therefore, it is necessary to draw up and administer Diprivan in a manner that minimizes the possibility of contamination.
-
Propofal - - . Midozoiam
.* z
0
120
240 Infusion
360 Duration
480
Although large doses of opioids are commonly used for cardiac anesthesia, propofol has several properties that make it an attractive alternative. Unlike thiopental, the propofol concentrations that induce cerebral isoelectricity are well below the propofol concentrations that intrinsicaliy decrease contractility. This may make cerebral protection with propofol more clinically attractive than with thiopental. Several recent reports have examined the direct influence of pro Gon.?‘-26 Using in vitro myoca al.*2 found that propofol had a m dial contractility, Park and Lynch?” found a moderate effect (although less than with thiopentai), and Stowe et ~1.~1reported that the negative inotropic properties of propofol exceeded those of thiopental (although it must be noted that the electroencephalographic depressant effect of propofol also exceeds that of thiopental.). The latter group also reported that propofol a nary autoregulation. In clinical studies, and Vermeyen et aLz6 both reported goo with propofol infusions for cardiac surgery. The latter group also reported no change in coronary sinus flow, myocardiai O2 consumpticn; or myocardial lactate extraction. By avoiding bolus injections, most investigators have shown that propofol use in cardiac surgery IS not associated with the hypotension usually observed following bolus doses used for rapid induction of anesthesia.
600
(min)
ure 5. The pharmacokinetic models show that recovery from an infusion that maintains a steady propofol concen:ration will be far faster than from a similar infusion of midazolam.
controlled sedation, no complications were found, and recovery times were rapid. In considering propofol for sedation, it must be emphasized that propofol is a potent respiratory depressant, Propofool should be administered for sedation only by anesthesiologists or other personnel trained in acute airway management. IC U Sedation PropofoE is also being investigated for sedation of rntubated patients in 4CUs following cardiac surgery18,1g and standard In for long-term ventilation. 2o The current many hospitals is a continuous infusion of midazolam and an opioid. This regimen can lead to substantial accumulation of midazolam, resulting in prolonged sedation when the infusion is terminated. The high clearance of propofol permits a rapid decrease in propofol concentraLion upon terminating the infusion, even following infusions of 1 to 2 weeks. This allows the patient to be awakened at regular intervals, enabling frequent assessment of neurologic status. Provided that the patient has adequate filling pressures and the level of sedation is approached by judicious titration, propofol sedation in ICU patients is usually not associated with the hypotension that accompanies induction of anesthesia in the operating room. Additional benefits ofpropofol in critically ill patients are a decrease in metaboiic oxygen (0,) requirements, with a concomitant increase in mixed venous Q saturation and a decreased need for vasodilators or beta-blockers in hyperdynamic patients. Since propofol has no intrinsic analgesic requirements, it is helpful to administer a small amount of opioid concurrentiy. This action substantially reduces the amount of propofol required to produce the desired level of sedation. Whenever administering propofol, it is important to remember that Diprivan is 1% propofol in a 10% soybean oil emulsion (Intralipid 10%) vehicle. The lntralipid provides B calorie per milliliter of Diprivan. During long 18s
J. Gin. Anesth., vol. 5 (Suppl I), November/December
Two separate studies have deter-marred that the ~~d~c~~o~ dose of propofol in infants and young children was 2.5 to 3 mg/kg.27,ZHBoth studies concluded that the frequency of pain on injection was quite high (25% to .W%), but the pain was attenuated bv injecting through an antecubitai vein. Decreases in BP’in children were similar to in adults. Thus? the major difference between pro _n adults and propofol in children was a slightly h induction dose requirement (per kg), especially in infants. The need for IV access prior to induction remams a major impediment to widespread use of propofol in uediatric anesthesia.
A recent study by Borgeat eEai.‘” demonstrated thai subanesthetic doses possess intrinsic antiemetic properties. In this study, 81% of patients with nausea and vomiting had symptomatic improvement with 10 mg of propofol, 1993
as opposed to 3.5% of placebo-treated patients~ Propofoi also is effective in treating chemotherapy-induced emeother work suggests that propofoi may be effecventing refractory chemotherapy-induced vomiting. The propofol concentrations that ctive in treating nausea are wet1 below the concentrations associated with sedation. This subject is now being studied further, owing to the importance of reducing chemotherapy-induced nausea and the high cost of ondansetron.
9
‘0
Therapeutic
1
Ganges
I
Pr
B ve+s
usalne
With the 1ntroducLion of desflurane into clinncal praceice, propofool’s position as the maintenance anesthetic with the fastest recovery profile may be seriously chaiienged. Two recent studies compared propofol with desflur~1.~~studied 60 patients and found desflurane maintenance was faster propofol maintenance, a finding that was confirmed by Van Hemelrijck et al.32 Both investigators noted that inhalation induction with desflurane is quite difficult due to airway irritability. The latter investigators also noted that propofol maintenance was associated with less nausea and vomiting (15%) than desflurane maintenance (more than 507%). Additional studies will help determine w ether the more rapid emergence with desflurane (about 3 minutes faster than with propofol) justifies the increased nausea and vomiting associated with desflurane maintenance.
Veroli et a1.33 conclusively demonstrated chat propofol does indeed have extrahepatic routes of metabolism. s administered propofool to patients atic phase of orthoptic liver transnd propofol metabolites in the urine while the liver was still excluded from the circulation. The extrahepatic sites of propofol metabolism have yet to be determined.
utic ranges of propofol coneve varying degrees of CNS depression for various anesthetic techniques, based on studies of propofool concentrations.34-3g Because propofol lacks intrinsic analgesic properties, very high concentrations may be required when propofol is used as the sole anesthetic drug. Much lower propofol concentrations suffice when propofol is combined with analgesics, such as IV@ or opioids. When propofol is combined with opioids, increasing the plasma opkoid concentration reduces ropofol needed to provide adequate clinical anesthesia. Appendix A shows the infusion rates required to rnaintain concentrations in the therapeutic ranges shown pendix B contains a series of caveats in in Figure 4. aii effort to s re the reader many of the traps that I
i
0 Sedation
TIVA: Propofoi/ 0p;oid
Minor: Fropofo!/ %O
TWA:
iAajor: Propcfol/
Propofol
b;,O
Only
Propofol therapeutic ranges for different anesthetic techniques. TIVA = total intravenous anesthesia.
discovered while learning how LOuse :hls versatile drug. Additional information about propofol can be found in several excellent reviews.4G43
Shis manuscript was adapted and updated from the 1990 and 199 I. ASA Refresher Courses ‘“Intravenous Anesthes and New Drugs” by Steven L. Shafer Stanski and the 1992 ASA Refresher Course “Intravenous Anesthetic Techniques” by Steven 1. Shafer. The manuscript has been modified to remain consistent with new information regarding appropriate Arug dosing for MAC sedation and tota! IV anesthesia, and it reflects studies in additional popu!ations.
IIyckJB, Shafer SL. Effects of age on propoiol pharmacokinetits. Semin An& 1992;11:2-4. Stanski DR, Maitre PO: Population pharmacokinetics and pharmacodynamics of thiopental: the effect ofagerevisited. An&e.30z0gl 1990;72:412-22. Seller JP. Pottecher T, Lugnier A, Mangin P, Otteni JC: Prolonged sedation with propofo? in BCU patients: recovery and ‘Yood concentration changes d2ring periodic interruptions in ,nfusion. BrJ Anaesth 1988;61:583-8. Scott JC, Stanski DR: Decreased fentanyl and alfentanil dose requiremenes with age. A simultaneous phrrmacokinetic and oharmacodynamic evaluation. J Phav&oi Exp Ther 198’7; 140: 159-66. IHudson RJ, Bergstrom RG, Thomson IR, Sabourin MA, Rosenbloom M, Strunin L: Pharmacokinetics of sufentanil in patients undergoing abdominal aortic surgery. ArLesthesiolo~ 1989;70:426-31. Shafer SL, ‘Varvel JR: Pharmacoknnetics, pharmacodynamics, and rational opioid selection. AnestF.eszolo,~ 1991;74:53-63. Suit JE, @ConingHM, Caster ML, Niemeijer RP, Mackie DP: Ketamine as analgesic for total intravenous anaesthesia with aropofo!. Anaesthesia 1991:46:24-T. Suhrer M, biaitre PO, Hung 0, San&i DR: Etectroencephalographic effects of henzodiazepines. I: Choosing an electroen-
L)r@nal
C’ontrihutzons
artery anaestbesia with propofoi and ali‘emami for coronary bypass grafting. BrJ Anaesik 1991;66:716-8. 26 Vermeyen KM, De Hert SG, Erpels FA, Adriaensen IIF: Myocardial metabolism during anaesthesia witb propofol-low dose fentanyl for coronary artery bypass surgery. BrjAnaesUr 1991; 66:504-M. 27 Westrin P: The induction dose of propofol in infants I-6 months of age and in children IQ-16 years of age.P,n&hesinlog 1991;74:455-8. 28. Hannallah RS, Baker SB, Casey W, McGilI WA, Broadman
cephaiographic parameter to measure the effect of midazolam oo the central nervous system. Clin Phamacol Thcr 1990; 48:344-54. 9. Bl;hrer M, Maitre PO, Crevoisier C, Stanski DR: Electroencephalographic effects of benzodiazepines. II: Pharmacodynamic modeling of the electroencephalographic effects of midazolam and diazepam. Clin Pharmacol Ther 1990; 48:555-67. io. Kestin IG, Harvey PB, Nixon C: Psychomotor recovery after three methods of sedation during spinal anaesthesia. BrJ Anaesth 1990;64:675-81. 1:. Wilson E. David A, MacKenzie N, Grant IS: Sedation during spinal anaesthesia: comparison of propofol and midazolam. Br ,/ Anaesth 1990;64:48-52. 12. Osborne GA, Rudkin GE, Curtis NJ: Vickers D, Craker AJ: Inn-a-operative patient-controlled sedation. Comparison of patient-controlled propofol with anaesthetist-admmlstered midazolam and fentanyl. Anaesthesia 1991;46:553-6. 13. Patterson KW, Casey PB, Murray JP, O’BoyleCA, Cunningham AJ: Propofol sedation for outpatient upper gastrointestinal endoscopy: comparison with midazolam. Br i Anaesth 1991; 67:108-11. l4. Forrest P, Galletly DC: Comparison of propofoi and antagonised midazolam anaesthesia for day-case surgery. Anaesth Intensive Care 1987;15:394-401. 15. Snellen F, Lauwers P, Demeyere R, Byttebier G, Van Aken H: ‘The use of midazolam versus propofol for short-term sedation following coronary artery bypass grafting. Intensive Care Med 1990;16:312-6. !6. White PF, Negus JB: Sedative infusions during local and regional anesthesia: a comparison of midazolam and propofol. / Clin Anesth 1991;3:32-9. 17. Rudkin GE, Osborne GA, Curtis NJ: Intra-operative patientcontrolled sedation. Anaesthesia 1991;46:90-2. 18. McMurray TJ, Collier PS, Carson IW, Lyons SM, Elliott P: Propofol sedation after open heart surgery. A clinical and pharmacokinetic study. Anaesthesia 1990;45:322-6. 19. “wart MC, Yau KW, Morgan M: 2% propofol for sedation in the intensive care unit. A feasibility study. Anaesthesia 1992; 47: 146-8. 20. Aitkenhead ilR, Pepperman ML, Willatts SM, et al: Comparison of propofol and midazolam for sedation in critically ill patients. Lancet 1989;2(8665):704-9. 21. Postsurgical infections associated with an extrinsically contaminated intravenous anesthetic agent-California, Illinois, Maine and Michigan, 1990. Mortality, Morbidi World Report, Vol. 39(25), June 29, 1990. Y, Viars P: In vitro effects of 22. Riou B; Besse S. Lecarpentier propofol on rat myocardium. Anesthesiology 1992;76:609-16. depression of 23. Park WK, Lynch C 3d: Propofol and thiopental myocardial contractility. A comparative study of mechanical and electrophysiologic effects in isolated guinea pig ventricular muscle. Anesth Analg 1992;74:395-405. ofetomidate, 24. Stowe DF, Bosnjak ZJ, Kampine JP: Comparison ketamine, midazolam, propofol, and thiopental on function and metabolism of isolated hearts. Anesth Analg 1992; 74:547-58. 25. Manara AR, Monk CR, Bolsin SN, Prys-Roberts C: Total iv.
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Anesth.,
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l), November/December
LM, Norden JM: Propofol: effective dose and induction characteristics in unpremeditated children. Anesthesiology 1991; 74:217-9. 29. Borgeat A, Wilder-Smith OH, Saiah M, Rifat K: Subhypnotic doses of propofol possess direct antiemetic properties. Anath Analg 1992;74:539-41. 30. Sher C, McDowall R, Barst S: Propofol for the prevention of chemotherapy induced nausea and vomiting in pediatric cancer patients [Abstract]. Anesthesiology I991 ;75:AI050. 31. Wrigley SR, Fairfield JE, Jones RM, Black AE: Induction and recovery characteristics of desflurane in day case patients: a comparison with propofol. Anaesthesia 1991;46:615-22. 32. Van Hemelrijck J, Smith I, White PF: Use of desflurane fol outpatient anesthesia. A comparison with propofol and nitrous oxide. Azesthesioloa 1991;75:197-203. 33. Veroli P, O’Kelly B, Bertrand F, Trouvin JH, Farinotri R, Ecoffey C: Extrahepatic metabolism of propofol in man during the anhepatic phase of orthotopic liver transplantation. r7rf Anaestk 1992;68:183-6. 34. Shafer A, Doze VA, Shafer SL. White PF: Pharmacokinetics and pharmacodynamics of propofol infusions during general anesthesia. AnesthesioZog?l 1988;69:348-56. 35. Adam HK, Kay 13, Douglas EJ: Blood disoprofol levels in anaesthetised patients. Correlation of concentrations after single or repeated doses with hypnotic activity. Anaesthesia 1982; 37:536-40. 36. Schuttler J, Kioos S, Schwilden H, Stoeckel H: Total intravenous anaesthesia with propofol and alfentanil by comp-uterassisted infusion. Anaesthesia 1988:(43 §uppl):2-7. 37. Tackley Rh4, Lewis GT, Prys-Roberts C, Boaden RW, Dixon J, Harvey JT: Computer controlled infusion of propofol. Brj Anaesth 1989;62:46-53. 38. Russell GN, Wright EL, Fox MA, Douglas EJ, Cockshott ID: Propofol-fentanyl anaesthesia for coronary artery surgery and cardiopulmonary bypass. Anaestkesia 1989;43:205-8. K, Ginsberg B, Hawkins ED: Propofoi 39. Glass PSA, Markham concentrations required for surgery [Abstract]. An&&&~ 1989;iI:A273. A review of its pbarmacody40. Langley MS, Heel RC: Propofol. namic and pharmacokinetic properties and use as an intravenous anesthetic. Drugs 1988;35:334-72. 4:. Dundee JW, Clarke RS: Propofol. Eur J Anaesthesiol 1989; 6:5-22. agent of anesthesia. 42. Xanto JH: Propofol, the newest induction Int J Clin Pharmacol Ther Toxicol 1988;26:41-57. 43. Sebel PS, Lowdon JD: Propofol: Anesthesioloa 1990;71:260-77.
I993
a new intravenous
anesthetic.
.Or~~o~o~pharmacokinetics and @arlrLaco&namics.
1 Dosing
Guideli Induction:
:.
Even small Soluses
A.
Initial Bolus: 1.5-2.3 mgikg.
B.
c.
Give in 2-3 divided doses. Patient will be apneic within 30-90
II
Maintenance:
seconds.
300
250
2
\
s
Minutes
to 2
250
liours
200
200 150
& =_ 150 Q
100
100
50
Sedation
III.
Total
200-400
3 3'
50
3-
TIVA: Propofoi
TIVA: Propofoi/
Only
Opioid
Intravenous
t_~g2-3
Anesthesia
mm p:ior
MillOr: Propofo1/ f-%0
Major: Propofol/
Lo
N,O
(propofoliketamine):
to induction
Ketamine: No initial holus In&ion: Start at I mgimin At I hour: 0.6 mgimin At 4 hours: 0.4 mgimin Turn
off kecamine
ml) may cause
apnea,
especially
patients,
Maintenance:
300
<
(1-2
following a premed. Reduce propofol doses by 40-60s for elderly sick patients, or following a heavy premed.
For adults, the infusion rate, in mlimin, is approximately equal COthe % isoflurane you would use for the comparable technique at the same time point.
.’
Shafer
mfusion
Check repeatedly that the infusion is running. Continuous infusions are prone to equipment problems, such as the clamps left on the line, running out of drug, excessive backpressure in the line, etc. IJfthe i?;fmion stops for more than afew minutes, Jourpatient will awaken during the operation. Propofol is not ainnestic, so patients must be kept completely unconsciousness with prapofoi to prevent intraoperative awareness. Infuse the propofol through a T-piece connected immediately proximal to the IV catheter to minimize dead space. If the infusion rate is not turned down over time, the patient wiil be overdosed. ?he infusion can be titrated to blood pressure and heart rate. If your patient is too deep, turn off the psopofol for a minute or two. (Remember to turn it back on, or your patient will wake up!) If your- patient is too light, give a l-4 ml boius of propofol, and increase the infusion rate. The infusion rates are intended for adults in the normal weight range (SO-SO kg). The infusion rates should be increased for larger patients and decreased for smaller patients. For sedation, start with an infusion only (no bolus) and titrate to level of wakefulness, respiratory rate, etc. Don’t turn off the infusion until 5-10 minutes before the operation is ftnished. Once the infusion is off, be prepared to give l-2 ml boluses of propofol for signs of light anesthesia. ‘This allows assessment of anesthetic depth, and thus facilitates rapid emergence at the end of surgery. TWA:
lS-30
minutes
prior to the end of
surgery.
Propofol:
0.8-1.2 mgikg (1-2 minutes after fentanyl) I?@&: Start at 140-200 ugikglmin At 10 minutes: IOO-140 pgikgimin After 2 hours: 80-120 bglkglmin Turn off propofol infusion about 5-10 minutes prior to the desired time of emergence. Give 1-2 ml boluses as needed to keep patient asleep until the desired time of emergence.
.4ntlcipate that the blood pressure will drop foliowing the xopofolifentanyl induction. It usually returns promptly -with intubation. Reduce the doses 2%50% for elderly, sick, or heavily prenedicated patients. TIVA means no N,O and no isoflurane. Titrate the propofol infusion rate, not the ketamine infusion rate. If the patient seems to require a lot of propofol, give 25-50 t_~gfentanyl boluses. As with propofol, the ketamine infusion rate was designed for adults of average weight (SO-SO kg). Adjust upward or downward for larger or smaller patients. Movement is a good sign of light anesthesia, so complete naralysis should be avoided if possible. batch the pupils for signs of opioid overdose. If the pupils become pinpoint, don’t administer add?tional opioid. TIVA with propofoliketamine has not been associated with awareness. Propofol effectively blocks she psychotomimetic effects of ketamine.
J. Clin. Anesth.,
vol. 3 (Suppl
I), i\P’ovemberiDecerruber
19%
41s
local, regional;
anesthetics-
The availability of intravenous (IV) sedatives, hypnotics, opioads, an8n muscle relaxants with more evanescent drug effects has facilitated the 3e of IV anesthetic techniques in the ambulatory setting. No new drug impact on the practice of outpatient anesthesia than propofol its introduction into clinical practice in the United States, prop an increasingly important role for the induction and maintenance of general anesthesia for outpatients undergoing ambulatory procedures. In addition to .its use in the induction and maintenance of general anesthesia, recently approved by the Food and Drug ‘~drniu~§trat~ou for se local and regional anesthesia and for sedation of mechanically veu~~at~d patients in the intensive care unit (HCU). In this article, ret t advances in pharmacology are reviewed. our understanding of propofol advances, dosing and titration guidelines for propofoi are the integration of pharmacokinetic and pharmacodynamic models.
*Assistant
Professor
Address reprint requests to Dr. Shafer at the Anesthesiology Service (112A), Palo Alto Veterans Administration Medical Center, 3801 Miranda Avenue, Palo Alto, CA 94304, USA. Received for publication on August 26, 1993; revised manuscript accepted for publication September 10, 1993. 0 1993 Butterworth-Heinemann J. Glin. Anesth. B(Supp1 1):14%?1S,
14s
j. Gin.
Anesth.,
1993.
vol. 5 (Suppl
roPiie relative :o :he other IV arresue pharmacokinetic t,hetics. Table 1 compares the pharmaco inetics of propofol’ and thiopental sodium.* The metabolic clearance of propofol is ten times as fast as the metabolic clearance of thiopental. In fact, the meta olic clearance of pro exceeds hepatic blood Row, suggesting that propofol has extsahepatic sites of metabolism and elimination. This rapid metabolic clearance is one of the most important characteristics that makes propofol clinically and pharmacokinetically different from thiopental. The distribution clearance of an IV anesthetic drug is a measure of the movement of the drug from the central compartment (the instantaneously equilibrating tissues, including the blood and highly perfused vessel-rich tissues) into tissues with lower blood flow. The total distribution clearance of propofol and thiopental ranges from 3 to 4 Unkdkg, a value that is approximately 60% to 80% of the cardiac output (619). This suggests that propofol and thiopental distribution to Sody tissues will be governed by CO and regional blood Row. The large steady-state volumes of distribution for propofol and thiopental suggest extensive partitioning into muscle and fat tissue. The long (and clinically irrelevant) elimination half-
I), November/December
1993
lives of propof& arnd thiopental result from elimination 0B the drugs from the large stores
the in
sl0W
fat
and
KkUSCk.
Figure P show simulated declines in blood lhiopental and propofol concentration as a percentage of the initial peak concentration following an IV bolus dose. This simulation is based on the pbarmacokinetic parameters shown in Taable I. Plasma concentrations decline rapidly for both drugs in the first few minutes. The similar shapes of the curves over the first few minutes reflect rhe-similar distribution clearances of propofol and thiopental. However, after the first few minutes, the propofol concentration declines more rapidly than the thiopental concentration. This is due to the very rapid hepatic, and possibly extrahepatic, clearance of propofol relative to rhiopental. Figure 2 shows a simulation of the time required for e effect site concentration ofthiopental and propofol to decline by 50% following discontinuation of a continuous infusion. The simulations shown in Figure 2 are based on the pharmacokinetics of each drug and the rate of equilibration between the plasma and the effect site. Fig-
0
Thiopentd
-
6.3 530 1.7 1.7 2.1 5.5 6.3
Initial volume (L) Steady-state volume (L) etabolic clearance (Limin) pid distribution clearance (Limin) Slow distribution clearance (Limin) Total clearance (Limin) Elimination half-life (hr)
PICJS~CI revels
Following
c 100 2 E? t; u” G 0
__ -----
12.7 120 0.2 2.6 0.6 3.4 12.7
Bolus Propofol Thiopental
IO -_-___
3 .z 5
CL0.7
/
/
0
60
---__
--_-___
Minutes
---------_____________
120 Since
180 Bolus
ure 1. Propofol and thiopental concentrations, percentage of the initial concentration, following injection.
Prcpofol
-----
Tnicpentol
240
360
Infusion
Duration
480
600
uli& 2. Curves showing time required for 50% decrease in propofol and thiopental concentration foliowing discontmuation of a continuous infusion.
le 1. Relative Fharmacoklnelics of Propofo: and pental Sodium Bropofol
120
_
240
as a bolus
u7-e2 relates tne increasing time requIrea for recovery with increasing infusion duration. When the infusion is terminated, the effect site propofol concentration decreases by 50% far more rapidly than does the thiopental concentration. Moreover, the time required for a 50% decline in propofol concentration once the infusion is stopped increases far more with infusion duration for thiopental than for propofol. This is consistent with clinical experience showing that when thiopentai is used for maintenance of anesthesia, recovery may be unacceptably slow. By contrast, even after a G-hour infusion of 9ropofo1, only I5 minutes are require for a 50% decrease in drug concentration. This finding has been confirmed in clinical studies using propofol as a sedative in ICLJS.~ 3f course, if the drug is precisely titrated so that the percent decrease required for recovery is less than SS%, he time required will be less than that shown in PZguz 2 and will asymptotically approach XX-Q for a 0% decrease. Figure 3 compares the relationship between infusion An-ation and recovery time for propofol (as also shown tn Figure 2) with alfentanii and sufentanii: based on the xblished pharmacokinetics of aKentanil* and sufen,:anil .j Even tho.ugh alfentanil has more rapid distribution and terminal half-lives than sufentani8, for infusions of ess than 8 hours, the plasma alfentan;! concentration sufentanil conrzay not decline as rapidly as the @asma rentration when the infusion is terminated. This concept is explained fully in a recent article.s Propofol infusions are often combined with opioid mfusions during anesthesia. Since the decline in propofol concentration is several-fold faster than the decline in 3pioid concentration, it makes ~~armacoki~et~c sense to titrate the propofol while maintai&g a constant opioid concentration. Thus, if a drug overdose occurs, it w be with the drug more quickly elimin.ated from the bloo Slinically, it is my impression that titrahn of propofol oroduces the desired increase or decrease in anesthetic
8. Clin. -be&.,
vol. 5 (Suppi I), FiovenberiDecember
I993
95s
Orfginai
Contrzbution,s
goscopy and mtubation, and increases the irk&hood ~fd‘ hypotension following induction. Some practice is required to find the correct doses of opioid and prop&l that offer smooth hemodynamics for different categories of patients.
Recovery Curves: Propofol vs Opioids
240 Infusion
360
480
600
Duration
Figure 3. Curves showing time required for 50% decrease in propofol, alfentanil, and sufentanil concentration following discontinuation of a continuous infusion.
depth more quickly and reliably than titration of the opioid. The clinical dosing guidelines contain a recommendation for combining sufentanil with propofol to achieve total intravenous anesthesia (TIVR). Sufentanil was selected because its pharmacokinetic properties suggest that after infusions of less than 8 hours, patients will awaken more quickly from a sufentanil infusion than from an alfentanil infusion, as shown in Figure 3. In summary, propofol’s pharmacokinetic characteristics of extremely rapid metabolism and large distribution clearances relative to distribution volumes result in a unique disposition that is well suited to both the induction and maintenance of anesthesia.
The induction dose of propofol ranges from 1 to 2.5 mgikg, administered as several divided doses (2 to 3 ml per dose). Elderly patients and patients receiving opioids prior to induction should receive doses closer to 1 _mg/ kg. Following the induction dose, patients will lose consciousness in approximately I minute. Blood pressure (BP) usually decreases by 20% to 40%, while heart rate (IN) remains stable. Intubation should be attempted 60 to 90 seconds following the induction dose. Following intubation, BP usually returns to within IO% to 20% of baseline. HR tends to remain stable throughout induction and intubation. In some elderly patients, BP may decrease by 50% and remain rather low, even after intubation. This usually responds to 5 to 10 mg of ephedrine and is a sign of relative hypovolemia, which resolves with fluid administration. Patients in hypovolemic shock should not be induced with propofol. Premeditation with opioids decreases the propofol dose necessary for induction of anesthesia, decreases the hemodynamic response to noxious stimuli such as larynJ. Glin. Anesth., vol. 5 (Suppl l), November/December i993
Intermittent boluses of propofol produce oscillations in propofol concentration and anesthetic depth. Therefore, the dosing guidelines assume that propofol will be given by continuous infusion during maintenance of the anesthetic. (See Appendices A and B far dosing guidelines for maintenance of anesthesia with a contmuous mfusion of propofooi.) The guidelines are intended to serve as a starting point, beyond which the ane~thes~o~~g~st must titrate the maintenance infusion rate to the desired degree of central nervous system (CNS) depression. To maintain reasonably constant propofol blood concentrations, the maintenance infusion rate should be decreased during the operation. The guidelines recommend downward adjustments at 10 minutes and 2 hours. When propofol is used without nitrous oxide (N&r) or a potent vapor, intraoperative awareness is possible. Although intraoperative awareness also can occur when using a N@-opioid anesthetic technique, N@ is a sufficiently potent analgesic that intraoperative awareness of pain almost never occurs when it is used with an opioid. This is not the case with propofol. Intraoperative awareness during a propofol-opioid technique (e.g., during total IV anesthesia) may include awareness ofintraoperalive pain. Following are some suggestion5 for preventtng awareness. Rem& rjigilant for signs cf light anesthesia. Arr abr~p change in HP., even if only from SO to 70 beats per minute (bpm), may signal impending awareness. If the patient is not fully paralyzed, nonspecific movements may occur virtually simultaneously with the HR change. Treat light anesthesia with a ! to 2 ml boius of~ro~ofo~. One major advantage of an IV hypnotic over an inhaled hypnotic is the ability to administer an IV bolus. Wren signs of light anesthesia develop, this is the time to take advantage of the rapid deepening of the anesthetic state that is possible with an IV drug. For this reason, I keep the propofol syr-inge attached to the ZV line during the entire anesthetic. Note that several minutes of light anesthesia are usua& required before the patient 3s sufficiently aware that recai2 is possible. In each case of intraoperative awareness with which I am familiar, the patient was allowed to remain lightly anesthetized for a substantial period of time. 1 have frequentfy observed patients showing movement in response to light propofol anesthesia. I have treated these patients with a smal: propofosii bo1us and on postoperative questioning have not had them report any recall. At the end of th,e case, turn off the infusion several minutes prior to the desired time of emergence. owever, remain
vigilant for signs of light anesthesia during, for examp!e, placement of the last sutures. If signs of light anesthesia develop prior eo the desired time of emergence, administer one or more small boluses (I to 2 ml) of propofol. This will prolong the anesthetic without causing excessive sedation or emergence. 5. 1: recent innovakvz is the use of propofol combined with Retamine, as reported by Guit et al.’ These investigators compared propofol-fentanyl with propofol-ketamine and found that propofol-ketamine provided stable hemodynamics and was not associated with dreaming or abnormal behavior. They concluded that propofol effectively eliminated the untoward side effects of ketamine and the propofol-ketamine was a useful combination for TWA. Ketamine also has the advantage of being a potent analgesic. My TIVA guidelines have been revised to reflect a propofol-opioid-ketanine technique. (See Appendices A and B.) My own two cases of in:raoperative awareness with propofol-opioid TIVA are instructive. In the first case, the patient abruptly developed tachycardia at a rate of 120 to 130 bpm during the surgical prep. I observed the tachycardia for aSout IO minutes prior to treating her with a bolus of propofol. She could vividly recall the last I to 2 minutes prior to the bolus, despite 3 mg of midazolam given prior to induction. In the second case, a patient was given a large bolus of esmolol, resulting in bradycardia and hypotension. In response, the propofol infusion was turned off intraoperatively for about 15 minutes. The patient could clearly recall several minutes of abdominal exploration. In both case, the patients were totally paralyzed and reported their frustrated attempts to move. The lessons from these two cases are (I) additional vigilance is required in totally paralyzed patients; (2) midazolam is not a substitute for adequate hypnosis; (3) there is a period of several minutes between light anesthesufficient awareness in which patients can subserecall events and during which the anesthetic with a bolus of propofol; (4) depth can be sup$emented don’t turn the propofol infusion off during the operation, 2s the “ciearheaded” emergence that is desirable following surgery is considerably less desirable in the middle of a procedure. Propofol &uses are much more suitable than thiopental boluses for extending an anesthetic by a few minutes. It is my experience that patients wake up slowly, and are quite sedated, if 2 small bolus of thiopental is used to extend an anesthetic. For this reason, 1 suggest having a syringe of propofol, not thiopental, ready at the end of an anesthetic if a few additional minutes are necessary.
InJanuary
i992, propofool was approved for use in moni-
tored anesthesia car efits of propofo? for
midadam,
inch_&
AC) sedation. The potential benC sedation, when compared with more rapid titration of the level of
sedation and faster return of ciearheadechess. Figure 4 shows the effect site concentrations over ti.me following a bolus injection of propofol or midazolam, based on an integrated ~harmacokinetic-~harmacodynamic model for each drug that was developed in our laboratory. The more rapid blood-brain equilibration of propofol (I to 2 minutes)’ compared with midazolam (2 to 4 minutes)8~g means that the level of sedation can be increased more rapidly with propofol in anticipation of an imminent noxious stimulus. Following a bolus, the effect of fol is far more evanescent than that of midazolam. once the stimulus has ended, the patient can be returned to a Lighter level of sedation more rapidly with propofol than with midazolam. A continuous propofol infusion can be used to maintain a steady level of sedation throughout a case. The siower pharmacokinetics of midazolam permit a technique of small intermittent boluses that IS easier to administer than a propofol infusion. However, if a steady concentration is maintained, we can use the integrated pharmacokinetic-pharmacodynamic model to compare ihe time to the offset of drug effect for propofol and midazolam, as shown in Figure 5. Tiae model demonstrates that recovery from propofol will be far faster than recovery from midazolam. The rapid recovery from a propofol infusion is particularly important if the patient must occasionally interact with the surgeon or if the patient’s condition requires very precise control of the level of sedation. As of June 1992, a ne search of every =.eference to both propofol an azoiam confirmed *his prediction in every publication that examined rates of recovery from sedation.‘k16 The introduction of patient-con:rolled sedation per,mits the patient to titrate his or her level of sedation by sressing a button to receive additional drug, which is analogous to patient-controlled analgesia. In two recent studies,6,‘T patients were very satisfied with patient-
0 0
1
2 3 MinutesSince Bolus
4
Figure 4. Rise to peak concentration in the effect site following a bolus injection of propofol and midazolam, as predicted from an integrated ?la;trmacokiwetic-plarmacodynamic model.
infusions (usuaIly in the %CLj, rhe Znirairpid ve&le .mal cause hyperlipidemia. Therefore, it is necessary to monitor triglycerides during prolonged infusions, particular+ if rapid rates are used. Lastly, the Intraiipid v&i& contains no preservatives and supports growth of microorganisms.*r Therefore, it is necessary to draw up and administer Diprivan in a manner that minimizes the possibility of contamination.
-
Propofal - - . Midozoiam
.* z
0
120
240 Infusion
360 Duration
480
Although large doses of opioids are commonly used for cardiac anesthesia, propofol has several properties that make it an attractive alternative. Unlike thiopental, the propofol concentrations that induce cerebral isoelectricity are well below the propofol concentrations that intrinsicaliy decrease contractility. This may make cerebral protection with propofol more clinically attractive than with thiopental. Several recent reports have examined the direct influence of pro Gon.?‘-26 Using in vitro myoca al.*2 found that propofol had a m dial contractility, Park and Lynch?” found a moderate effect (although less than with thiopentai), and Stowe et ~1.~1reported that the negative inotropic properties of propofol exceeded those of thiopental (although it must be noted that the electroencephalographic depressant effect of propofol also exceeds that of thiopental.). The latter group also reported that propofol a nary autoregulation. In clinical studies, and Vermeyen et aLz6 both reported goo with propofol infusions for cardiac surgery. The latter group also reported no change in coronary sinus flow, myocardiai O2 consumpticn; or myocardial lactate extraction. By avoiding bolus injections, most investigators have shown that propofol use in cardiac surgery IS not associated with the hypotension usually observed following bolus doses used for rapid induction of anesthesia.
600
(min)
ure 5. The pharmacokinetic models show that recovery from an infusion that maintains a steady propofol concen:ration will be far faster than from a similar infusion of midazolam.
controlled sedation, no complications were found, and recovery times were rapid. In considering propofol for sedation, it must be emphasized that propofol is a potent respiratory depressant, Propofool should be administered for sedation only by anesthesiologists or other personnel trained in acute airway management. IC U Sedation PropofoE is also being investigated for sedation of rntubated patients in 4CUs following cardiac surgery18,1g and standard In for long-term ventilation. 2o The current many hospitals is a continuous infusion of midazolam and an opioid. This regimen can lead to substantial accumulation of midazolam, resulting in prolonged sedation when the infusion is terminated. The high clearance of propofol permits a rapid decrease in propofol concentraLion upon terminating the infusion, even following infusions of 1 to 2 weeks. This allows the patient to be awakened at regular intervals, enabling frequent assessment of neurologic status. Provided that the patient has adequate filling pressures and the level of sedation is approached by judicious titration, propofol sedation in ICU patients is usually not associated with the hypotension that accompanies induction of anesthesia in the operating room. Additional benefits ofpropofol in critically ill patients are a decrease in metaboiic oxygen (0,) requirements, with a concomitant increase in mixed venous Q saturation and a decreased need for vasodilators or beta-blockers in hyperdynamic patients. Since propofol has no intrinsic analgesic requirements, it is helpful to administer a small amount of opioid concurrentiy. This action substantially reduces the amount of propofol required to produce the desired level of sedation. Whenever administering propofol, it is important to remember that Diprivan is 1% propofol in a 10% soybean oil emulsion (Intralipid 10%) vehicle. The lntralipid provides B calorie per milliliter of Diprivan. During long 18s
J. Gin. Anesth., vol. 5 (Suppl I), November/December
Two separate studies have deter-marred that the ~~d~c~~o~ dose of propofol in infants and young children was 2.5 to 3 mg/kg.27,ZHBoth studies concluded that the frequency of pain on injection was quite high (25% to .W%), but the pain was attenuated bv injecting through an antecubitai vein. Decreases in BP’in children were similar to in adults. Thus? the major difference between pro _n adults and propofol in children was a slightly h induction dose requirement (per kg), especially in infants. The need for IV access prior to induction remams a major impediment to widespread use of propofol in uediatric anesthesia.
A recent study by Borgeat eEai.‘” demonstrated thai subanesthetic doses possess intrinsic antiemetic properties. In this study, 81% of patients with nausea and vomiting had symptomatic improvement with 10 mg of propofol, 1993
as opposed to 3.5% of placebo-treated patients~ Propofoi also is effective in treating chemotherapy-induced emeother work suggests that propofoi may be effecventing refractory chemotherapy-induced vomiting. The propofol concentrations that ctive in treating nausea are wet1 below the concentrations associated with sedation. This subject is now being studied further, owing to the importance of reducing chemotherapy-induced nausea and the high cost of ondansetron.
9
‘0
Therapeutic
1
Ganges
I
Pr
B ve+s
usalne
With the 1ntroducLion of desflurane into clinncal praceice, propofool’s position as the maintenance anesthetic with the fastest recovery profile may be seriously chaiienged. Two recent studies compared propofol with desflur~1.~~studied 60 patients and found desflurane maintenance was faster propofol maintenance, a finding that was confirmed by Van Hemelrijck et al.32 Both investigators noted that inhalation induction with desflurane is quite difficult due to airway irritability. The latter investigators also noted that propofol maintenance was associated with less nausea and vomiting (15%) than desflurane maintenance (more than 507%). Additional studies will help determine w ether the more rapid emergence with desflurane (about 3 minutes faster than with propofol) justifies the increased nausea and vomiting associated with desflurane maintenance.
Veroli et a1.33 conclusively demonstrated chat propofol does indeed have extrahepatic routes of metabolism. s administered propofool to patients atic phase of orthoptic liver transnd propofol metabolites in the urine while the liver was still excluded from the circulation. The extrahepatic sites of propofol metabolism have yet to be determined.
utic ranges of propofol coneve varying degrees of CNS depression for various anesthetic techniques, based on studies of propofool concentrations.34-3g Because propofol lacks intrinsic analgesic properties, very high concentrations may be required when propofol is used as the sole anesthetic drug. Much lower propofol concentrations suffice when propofol is combined with analgesics, such as IV@ or opioids. When propofol is combined with opioids, increasing the plasma opkoid concentration reduces ropofol needed to provide adequate clinical anesthesia. Appendix A shows the infusion rates required to rnaintain concentrations in the therapeutic ranges shown pendix B contains a series of caveats in in Figure 4. aii effort to s re the reader many of the traps that I
i
0 Sedation
TIVA: Propofoi/ 0p;oid
Minor: Fropofo!/ %O
TWA:
iAajor: Propcfol/
Propofol
b;,O
Only
Propofol therapeutic ranges for different anesthetic techniques. TIVA = total intravenous anesthesia.
discovered while learning how LOuse :hls versatile drug. Additional information about propofol can be found in several excellent reviews.4G43
Shis manuscript was adapted and updated from the 1990 and 199 I. ASA Refresher Courses ‘“Intravenous Anesthes and New Drugs” by Steven L. Shafer Stanski and the 1992 ASA Refresher Course “Intravenous Anesthetic Techniques” by Steven 1. Shafer. The manuscript has been modified to remain consistent with new information regarding appropriate Arug dosing for MAC sedation and tota! IV anesthesia, and it reflects studies in additional popu!ations.
IIyckJB, Shafer SL. Effects of age on propoiol pharmacokinetits. Semin An& 1992;11:2-4. Stanski DR, Maitre PO: Population pharmacokinetics and pharmacodynamics of thiopental: the effect ofagerevisited. An&e.30z0gl 1990;72:412-22. Seller JP. Pottecher T, Lugnier A, Mangin P, Otteni JC: Prolonged sedation with propofo? in BCU patients: recovery and ‘Yood concentration changes d2ring periodic interruptions in ,nfusion. BrJ Anaesth 1988;61:583-8. Scott JC, Stanski DR: Decreased fentanyl and alfentanil dose requiremenes with age. A simultaneous phrrmacokinetic and oharmacodynamic evaluation. J Phav&oi Exp Ther 198’7; 140: 159-66. IHudson RJ, Bergstrom RG, Thomson IR, Sabourin MA, Rosenbloom M, Strunin L: Pharmacokinetics of sufentanil in patients undergoing abdominal aortic surgery. ArLesthesiolo~ 1989;70:426-31. Shafer SL, ‘Varvel JR: Pharmacoknnetics, pharmacodynamics, and rational opioid selection. AnestF.eszolo,~ 1991;74:53-63. Suit JE, @ConingHM, Caster ML, Niemeijer RP, Mackie DP: Ketamine as analgesic for total intravenous anaesthesia with aropofo!. Anaesthesia 1991:46:24-T. Suhrer M, biaitre PO, Hung 0, San&i DR: Etectroencephalographic effects of henzodiazepines. I: Choosing an electroen-
L)r@nal
C’ontrihutzons
artery anaestbesia with propofoi and ali‘emami for coronary bypass grafting. BrJ Anaesik 1991;66:716-8. 26 Vermeyen KM, De Hert SG, Erpels FA, Adriaensen IIF: Myocardial metabolism during anaesthesia witb propofol-low dose fentanyl for coronary artery bypass surgery. BrjAnaesUr 1991; 66:504-M. 27 Westrin P: The induction dose of propofol in infants I-6 months of age and in children IQ-16 years of age.P,n&hesinlog 1991;74:455-8. 28. Hannallah RS, Baker SB, Casey W, McGilI WA, Broadman
cephaiographic parameter to measure the effect of midazolam oo the central nervous system. Clin Phamacol Thcr 1990; 48:344-54. 9. Bl;hrer M, Maitre PO, Crevoisier C, Stanski DR: Electroencephalographic effects of benzodiazepines. II: Pharmacodynamic modeling of the electroencephalographic effects of midazolam and diazepam. Clin Pharmacol Ther 1990; 48:555-67. io. Kestin IG, Harvey PB, Nixon C: Psychomotor recovery after three methods of sedation during spinal anaesthesia. BrJ Anaesth 1990;64:675-81. 1:. Wilson E. David A, MacKenzie N, Grant IS: Sedation during spinal anaesthesia: comparison of propofol and midazolam. Br ,/ Anaesth 1990;64:48-52. 12. Osborne GA, Rudkin GE, Curtis NJ: Vickers D, Craker AJ: Inn-a-operative patient-controlled sedation. Comparison of patient-controlled propofol with anaesthetist-admmlstered midazolam and fentanyl. Anaesthesia 1991;46:553-6. 13. Patterson KW, Casey PB, Murray JP, O’BoyleCA, Cunningham AJ: Propofol sedation for outpatient upper gastrointestinal endoscopy: comparison with midazolam. Br i Anaesth 1991; 67:108-11. l4. Forrest P, Galletly DC: Comparison of propofoi and antagonised midazolam anaesthesia for day-case surgery. Anaesth Intensive Care 1987;15:394-401. 15. Snellen F, Lauwers P, Demeyere R, Byttebier G, Van Aken H: ‘The use of midazolam versus propofol for short-term sedation following coronary artery bypass grafting. Intensive Care Med 1990;16:312-6. !6. White PF, Negus JB: Sedative infusions during local and regional anesthesia: a comparison of midazolam and propofol. / Clin Anesth 1991;3:32-9. 17. Rudkin GE, Osborne GA, Curtis NJ: Intra-operative patientcontrolled sedation. Anaesthesia 1991;46:90-2. 18. McMurray TJ, Collier PS, Carson IW, Lyons SM, Elliott P: Propofol sedation after open heart surgery. A clinical and pharmacokinetic study. Anaesthesia 1990;45:322-6. 19. “wart MC, Yau KW, Morgan M: 2% propofol for sedation in the intensive care unit. A feasibility study. Anaesthesia 1992; 47: 146-8. 20. Aitkenhead ilR, Pepperman ML, Willatts SM, et al: Comparison of propofol and midazolam for sedation in critically ill patients. Lancet 1989;2(8665):704-9. 21. Postsurgical infections associated with an extrinsically contaminated intravenous anesthetic agent-California, Illinois, Maine and Michigan, 1990. Mortality, Morbidi World Report, Vol. 39(25), June 29, 1990. Y, Viars P: In vitro effects of 22. Riou B; Besse S. Lecarpentier propofol on rat myocardium. Anesthesiology 1992;76:609-16. depression of 23. Park WK, Lynch C 3d: Propofol and thiopental myocardial contractility. A comparative study of mechanical and electrophysiologic effects in isolated guinea pig ventricular muscle. Anesth Analg 1992;74:395-405. ofetomidate, 24. Stowe DF, Bosnjak ZJ, Kampine JP: Comparison ketamine, midazolam, propofol, and thiopental on function and metabolism of isolated hearts. Anesth Analg 1992; 74:547-58. 25. Manara AR, Monk CR, Bolsin SN, Prys-Roberts C: Total iv.
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LM, Norden JM: Propofol: effective dose and induction characteristics in unpremeditated children. Anesthesiology 1991; 74:217-9. 29. Borgeat A, Wilder-Smith OH, Saiah M, Rifat K: Subhypnotic doses of propofol possess direct antiemetic properties. Anath Analg 1992;74:539-41. 30. Sher C, McDowall R, Barst S: Propofol for the prevention of chemotherapy induced nausea and vomiting in pediatric cancer patients [Abstract]. Anesthesiology I991 ;75:AI050. 31. Wrigley SR, Fairfield JE, Jones RM, Black AE: Induction and recovery characteristics of desflurane in day case patients: a comparison with propofol. Anaesthesia 1991;46:615-22. 32. Van Hemelrijck J, Smith I, White PF: Use of desflurane fol outpatient anesthesia. A comparison with propofol and nitrous oxide. Azesthesioloa 1991;75:197-203. 33. Veroli P, O’Kelly B, Bertrand F, Trouvin JH, Farinotri R, Ecoffey C: Extrahepatic metabolism of propofol in man during the anhepatic phase of orthotopic liver transplantation. r7rf Anaestk 1992;68:183-6. 34. Shafer A, Doze VA, Shafer SL. White PF: Pharmacokinetics and pharmacodynamics of propofol infusions during general anesthesia. AnesthesioZog?l 1988;69:348-56. 35. Adam HK, Kay 13, Douglas EJ: Blood disoprofol levels in anaesthetised patients. Correlation of concentrations after single or repeated doses with hypnotic activity. Anaesthesia 1982; 37:536-40. 36. Schuttler J, Kioos S, Schwilden H, Stoeckel H: Total intravenous anaesthesia with propofol and alfentanil by comp-uterassisted infusion. Anaesthesia 1988:(43 §uppl):2-7. 37. Tackley Rh4, Lewis GT, Prys-Roberts C, Boaden RW, Dixon J, Harvey JT: Computer controlled infusion of propofol. Brj Anaesth 1989;62:46-53. 38. Russell GN, Wright EL, Fox MA, Douglas EJ, Cockshott ID: Propofol-fentanyl anaesthesia for coronary artery surgery and cardiopulmonary bypass. Anaestkesia 1989;43:205-8. K, Ginsberg B, Hawkins ED: Propofoi 39. Glass PSA, Markham concentrations required for surgery [Abstract]. An&&&~ 1989;iI:A273. A review of its pbarmacody40. Langley MS, Heel RC: Propofol. namic and pharmacokinetic properties and use as an intravenous anesthetic. Drugs 1988;35:334-72. 4:. Dundee JW, Clarke RS: Propofol. Eur J Anaesthesiol 1989; 6:5-22. agent of anesthesia. 42. Xanto JH: Propofol, the newest induction Int J Clin Pharmacol Ther Toxicol 1988;26:41-57. 43. Sebel PS, Lowdon JD: Propofol: Anesthesioloa 1990;71:260-77.
I993
a new intravenous
anesthetic.
.Or~~o~o~pharmacokinetics and @arlrLaco&namics.
1 Dosing
Guideli Induction:
:.
Even small Soluses
A.
Initial Bolus: 1.5-2.3 mgikg.
B.
c.
Give in 2-3 divided doses. Patient will be apneic within 30-90
II
Maintenance:
seconds.
300
250
2
\
s
Minutes
to 2
250
liours
200
200 150
& =_ 150 Q
100
100
50
Sedation
III.
Total
200-400
3 3'
50
3-
TIVA: Propofoi
TIVA: Propofoi/
Only
Opioid
Intravenous
t_~g2-3
Anesthesia
mm p:ior
MillOr: Propofo1/ f-%0
Major: Propofol/
Lo
N,O
(propofoliketamine):
to induction
Ketamine: No initial holus In&ion: Start at I mgimin At I hour: 0.6 mgimin At 4 hours: 0.4 mgimin Turn
off kecamine
ml) may cause
apnea,
especially
patients,
Maintenance:
300
<
(1-2
following a premed. Reduce propofol doses by 40-60s for elderly sick patients, or following a heavy premed.
For adults, the infusion rate, in mlimin, is approximately equal COthe % isoflurane you would use for the comparable technique at the same time point.
.’
Shafer
mfusion
Check repeatedly that the infusion is running. Continuous infusions are prone to equipment problems, such as the clamps left on the line, running out of drug, excessive backpressure in the line, etc. IJfthe i?;fmion stops for more than afew minutes, Jourpatient will awaken during the operation. Propofol is not ainnestic, so patients must be kept completely unconsciousness with prapofoi to prevent intraoperative awareness. Infuse the propofol through a T-piece connected immediately proximal to the IV catheter to minimize dead space. If the infusion rate is not turned down over time, the patient wiil be overdosed. ?he infusion can be titrated to blood pressure and heart rate. If your patient is too deep, turn off the psopofol for a minute or two. (Remember to turn it back on, or your patient will wake up!) If your- patient is too light, give a l-4 ml boius of propofol, and increase the infusion rate. The infusion rates are intended for adults in the normal weight range (SO-SO kg). The infusion rates should be increased for larger patients and decreased for smaller patients. For sedation, start with an infusion only (no bolus) and titrate to level of wakefulness, respiratory rate, etc. Don’t turn off the infusion until 5-10 minutes before the operation is ftnished. Once the infusion is off, be prepared to give l-2 ml boluses of propofol for signs of light anesthesia. ‘This allows assessment of anesthetic depth, and thus facilitates rapid emergence at the end of surgery. TWA:
lS-30
minutes
prior to the end of
surgery.
Propofol:
0.8-1.2 mgikg (1-2 minutes after fentanyl) I?@&: Start at 140-200 ugikglmin At 10 minutes: IOO-140 pgikgimin After 2 hours: 80-120 bglkglmin Turn off propofol infusion about 5-10 minutes prior to the desired time of emergence. Give 1-2 ml boluses as needed to keep patient asleep until the desired time of emergence.
.4ntlcipate that the blood pressure will drop foliowing the xopofolifentanyl induction. It usually returns promptly -with intubation. Reduce the doses 2%50% for elderly, sick, or heavily prenedicated patients. TIVA means no N,O and no isoflurane. Titrate the propofol infusion rate, not the ketamine infusion rate. If the patient seems to require a lot of propofol, give 25-50 t_~gfentanyl boluses. As with propofol, the ketamine infusion rate was designed for adults of average weight (SO-SO kg). Adjust upward or downward for larger or smaller patients. Movement is a good sign of light anesthesia, so complete naralysis should be avoided if possible. batch the pupils for signs of opioid overdose. If the pupils become pinpoint, don’t administer add?tional opioid. TIVA with propofoliketamine has not been associated with awareness. Propofol effectively blocks she psychotomimetic effects of ketamine.
J. Clin. Anesth.,
vol. 3 (Suppl
I), i\P’ovemberiDecerruber
19%
41s