`
`Steven L. Shafer, M.D.
`Donald R. Stanski M.D.
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`
`
` Propofol
`
` Thiopental
`
`While the topic of this refresher course is "Techniques and New Drugs" there is only one new drug to discuss:
`PROPOFOL. Propofol (DIPRIVAN®, Stuart Pharmaceuticals, Wilmington, Del.) was approved by the FDA for use in
`the United States in October, 1989 and has been available to anesthesiologists since November, 1989. Prior to the US
`release, it had been used extensively in many other countries.
`
`Propofol, 2,6,-diisopropylphenol, has been in use in the Unites States since November, 1989. Propofol is a low
`molecular weight (178D) molecule that is virtually insoluble in water and is highly soluble in fat. Propofol is marketed
`as Diprivan® by Stuart Pharmaceuticals. Diprivan® is 1% propofol mixed in an emulsion of soybean oil, glycerol and
`purified egg lecithin (Intralipid®). The handling of Diprivan® should be the same as the handling of Intralipid®: always
`use strict aseptic technique.1 The fat in Diprivan® provides one calorie per ml.
`
`Propofol Pharmacokinetics
`
`Propofol has a unique pharmacokinetic profile relative to the
`other intravenous anesthetics. The table to the right compares
`the pharmacokinetics of propofol and thiopental using propofol
`data generated in the authors' laboratory (unpublished) and
`recently published pharmacokinetics for thiopental.2
`
`The metabolic clearance of propofol is ten times as fast as the
`metabolic clearance of thiopental. In fact, the metabolic
`clearance of propofol exceeds hepatic blood flow, suggesting
`that propofol has extrahepatic 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 intravenous anesthetic drug is a measure of the movement of 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 liters.minute-1.70 kg-1, a value
`that is approximately 60 to 80% of the cardiac output. This suggests that propofol and thiopental distribution to body
`tissues will be governed by cardiac output and regional blood flow. The large steady state volumes of distribution for
`propofol and thiopental suggest extensive partitioning into muscle
`and fat tissue. The long (and clinical irrelevant) elimination half-
`lives of propofol and thiopental result from the slow elimination of
`drug from the large stores in fat and muscle.
`
`Figure 1 shows simulated declines in blood thiopental and propofol
`concentration as a percentage of the initial peak concentration
`following an intravenous bolus. This simulation is based on the
`pharmacokinetic parameters shown in the table on page 1. Plasma
`concentrations decline rapidly for both drugs in the first few minutes.
` The similar shapes of the curves over the first few minutes reflect
`the similar distribution clearances of propofol and thiopental.
`However, after the first few minutes the propofol concentration
`declines faster than the thiopental concentration. This is due to the
`very rapid hepatic, and possibly extrahepatic, clearance of propofol
`
`Initial Volume (l)
`
`Steady-State Volume (l)
`
`Metabolic Clearance (l/min)
`
`Rapid Dist. Clearance (l/min)
`
`Slow Dist. Clearance (l/min)
`
`Total Clearance (l/min)
`
`Elimination Half-Life (hr)
`
`
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`
`
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`6.3
`
`530
`
`1.7
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`1.7
`
`2.1
`
`5.5
`
`6.3
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`
`
`
`
`
`
`
`
`
`
`
`
`
`
`12.7
`
`120
`
`0.2
`
`2.6
`
`0.6
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`3.4
`
`12.7
`
`Figure 1: Propofol and thiopental concentrations, as a percentage
`of the initial concentration, following bolus injection.
`
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`Figure 2: Curves showing time required for 50% decrease in
`propofol and thiopental concentration following discontinuation of
`a continuous infusion.
`
`
`
`relative to thiopental.
`
`Figure 2 shows a simulation of the time required for the plasma
`concentration of thiopental and propofol to decline by 50% following
`discontinuation of a continuous infusion. This quantitates the
`increasing time required for recovery with increasing infusion
`duration.
` When
`the
`infusion
`is
`terminated,
`the propofol
`concentration decreases by 50% far more rapidly than the thiopental
`concentration. Moreover, the time required for a 50% decline once
`the infusion is stopped increases far more with infusion duration for a
`thiopental infusion than for a propofol infusion. This is consistent
`with clinical experience that when thiopental is used for maintenance
`of anesthesia, recovery may be unacceptably slow. By contrast, even
`after a 6 hour infusion of propofol, only 15 minutes are required for a
`50% decrease in drug concentration. This finding has been confirmed
`in clinical studies using propofol as a sedative in intensive care
`units.3
`
`Figure 3 on the following page compares the relationship between
`infusion duration and recovery time for propofol (as also shown in
`figure 2) with alfentanil and sufentanil, based on the published
`pharmacokinetics of alfentanil4 and sufentanil.5 Even though
`alfentanil has more rapid half-lives than sufentanil, for infusions of
`less than 8 hours the plasma alfentanil concentrations may not
`decline as rapidly the plasma sufentanil concentrations when the
`infusion is terminated. This concept is more fully presented in a
`recent manuscript.6
`
`Propofol infusions are often combined with opioid infusions during
`anesthesia. Since the decline in propofol concentration is several
`fold faster than the decline in opioid concentration, it makes
`pharmacokinetic sense to titrate the propofol while maintaining a
`constant opioid concentration. Thus, if a drug overdose occurs, it
`will be with the drug most quickly eliminated from the blood.
`Clinically, it is our impression that titration of propofol produces the desired increase or decrease in anesthetic 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.” Sufentanil was selected because its
`pharmacokinetic properties suggest that after infusions of less than 6 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 induction and maintenance of
`anesthesia.
`
`Induction of anesthesia
`
`The induction dose of propofol ranges from 1-2.5 mg/kg, administered as several divided doses (2-3 cc 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 1 minute. The blood pressure usually falls by 20-40%,
`while the heart rate remains stable. Intubation should be attempted 60-90 seconds following the induction dose. The
`blood pressure usually returns to within 10-20% of the baseline blood pressure following intubation. The heart rate tends
`to remain stable throughout the entire induction and intubation.
`In some elderly patients, the blood pressure may fall by 50% and remain rather low, even after intubation. This usually
`
`Figure 3: Curves showing time required for 50% decrease in
`propofol, alfentanil, and sufentanil concentration following
`discontinuation of a continuous infusion.
`
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`responds to 5-10 mg of ephedrine, and is a sign of relative hypovolemia. Fluid administration will usually resolve the
`hypotension. Patients in hypovolemic shock should not be induced with propofol.
`
`Premedication with opioids decreases the propofol dose necessary for induction of anesthesia, decreases the
`hemodynamic response to noxious stimuli such as laryngoscopy and intubation, and increases the likelihood of
`hypotension following induction. Some practice is required to find the correct doses of opioid and propofol that offer
`smooth hemodynamics for different categories of patients.
`
`Maintenance of Anesthesia
`
`Appended to this syllabus is our dosing guideline for maintenance of anesthesia with a continuous infusion of propofol.
`This is the handout which we give residents at Stanford.
`
`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 the maintenance of the anesthetic.
`The guidelines are intended to serve as a starting point, beyond which the anesthesiologist must titrate the maintenance
`infusion rate to the desired degree of 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 ten minutes and at two hours.
`
`When propofol is used without N2O or a potent vapor, there is the possibility of intraoperative awareness. Although
`intraoperative awareness can also occur when using a N2O/opioid anesthetic technique, N2O is a sufficiently potent
`analgesic that intraoperative awareness of pain almost never occurs during when using N2O with an opioid. This is not
`the case with propofol. Intraoperative awareness during a propofol/opioid technique (e.g. during total intravenous
`anesthesia) may include awareness of intraoperative pain. To prevent awareness:
`
`1.
`
`2.
`
`3.
`
`4.
`
`Remain vigilant for signs of light anesthesia. A rapid change in heart rate, even if only from 60 to 70
`BPM, may signal impending awareness. If the patient is not fully paralyzed, nonspecific movements may
`occur virtually simultaneously with the change in heart rate.
`
`Treat light anesthesia with a 1-2 cc bolus of propofol. One major advantage of an intravenous hypnotic
`over an inhaled hypnotic is the ability to administer an intravenous bolus. When signs of light anesthesia
`develop, this is the time to take advantage of the rapid deepening of anesthetic state that is possible with
`an intravenously administered drug. For this reason, we recommend keeping the propofol syringe
`attached to the I.V. line during the entire anesthetic.
`
`Note that several minutes of light anesthesia are usually required before the patient is sufficiently aware
`that recall is possible. In each case of intraoperative awareness with which we are familiar, the patient
`was allowed to remain light for a substantial period of time. Even if patients clearly demonstrate
`purposeful movement, prompt treatment with a bolus of propofol will prevent postoperative recall.
`
`At the end of the case, turn off the infusion several minutes prior to the desired time of emergence.
`However, remain vigilant for signs of light anesthesia during placement of the last sutures, etc. If signs of
`light anesthesia develop prior to the desired time of emergence, administer one or more small boluses (1-2
`cc) of propofol. This will prolong the anesthetic without causing excessive sedation.
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`Propofol boluses are much more suitable for briefly extending an anesthetic by a few minutes than thiopental boluses. It
`is our experience that patients wake up slowly, and are quite sedated, if a small bolus of thiopental is used to extend an
`anesthetic. For this reason, we suggest having a syringe of propofol, not thiopental, ready to extend the anesthetic by a
`few minutes when necessary at the end of the case.
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`Cardiovascular, Respiratory and Cerebrovascular Effects
`
`Propofol causes a decrease in mean arterial blood pressure. The decrease is usually greater than seen following induction
`with thiopental. The primary mechanism appears to be venous and arterial vasodilation. There is controversy about the
`direct cardiovascular depressant effects of propofol. However, it appears to be a mildly negative inotrope. Propofol
`usually causes a mild decrease in heart rate. With the exception of the effect on heart rate, the cardiovascular effects of
`propofol are very similar to the cardiovascular effects of isoflurane. Patients who respond with excessive decrease in
`blood pressure following propofol administration should be treated with volume administration.
`
`Propofol causes apnea in hypnotic doses. The respiratory depression is enhanced by concurrent administration of
`opioids. Spontaneously breathing patients who receive propofol should be constantly monitored to assure the adequacy
`of ventilation. Equipment for controlling ventilation is essential whenever propofol is used. As seen with other
`intravenous hypnotics, even small doses of propofol may cause apnea in sensitive individuals.
`
`The effects of propofol on the CNS are similar to the effects of thiopental. Propofol decreases cerebral blood flow,
`increases cerebral vascular resistance and decreases cerebral metabolic oxygen consumption. The EEG initially activates
`during propofol administration. Consciousness is lost at the time of peak activation. The EEG then slows until burst
`suppression is reached. Further administration of propofol causes isoelectricity. Clinical experience in patients with
`raised intracranial pressure is limited, and propofol is currently not approved for use in patients with raised intracranial
`pressure.
`
`Clinical Dosing Guidelines
`
`Figure 4 shows the "therapeutic ranges" of propofol concentrations
`needed to achieve varying degrees of CNS depression, based upon
`propofol concentrations presented in several recent manuscripts.7-12
`Very high propofol concentrations may be required when propofol is
`used as a sole anesthetic drug because propofol lacks intrinsic
`analgesic properties. Much lower propofol concentrations suffice
`when propofol is combined with drugs that provide analgesia, such
`as nitrous oxide or opioids. When combined with opioids, increasing
`the plasma opioid concentration reduces the amount of propofol
`needed to provide adequate clinical anesthesia.
`
`The first page of the propofol guidelines show the infusion rates
`Figure 4: Propofol therapeutic ranges for different anesthetic
`required to maintain concentrations in the therapeutic ranges shown
`techniques. TIVA refers to Total IntraVenous Anesthesia.
`in figure 4. The second page contains a series of caveats in an effort to spare the reader many of the traps that the authors
`discovered while learning how to use this novel drug. Additional information about propofol can be found in several
`excellent reviews.13-16
`
`References
`
`1)
`
`
`
`Postsurgical infections associated with an extrinsically contaminated intravenous anesthetic agent-California,
`Illinois, Maine and Michigan, 1990. Mortality, Morbidity World Report, Vol. 39(25), June 29,1990.
`Stanski DR, Maitre PO: Population pharmacokinetics and pharmacodynamics of thiopental: the effect of age
`revisited. Anesthesiology 72:412-422, 1990
`Beller JP, Pottecher T, Lugnier A. Mangin P, Otteni JC: Prolonged sedation with propofol in ICU
`patients:Recovery and blood concentration changes during periodic interruptions in infusion. Br. J. Anaesth.
`61:583-588,1988
`Scott JC, Stanski DR: Decreased fentanyl and alfentanil dose requirements with age. A simultaneous
`pharmacokinetic and pharmacodynamic evaluation. J Pharm Exp Ther 240:159-166, 1987
`Hudson RJ, Bergstrom RG, Thomson IR, Sabourin MA, Rosenbloom M, Strunin L. Pharmacokinetics of
`sufentanil in patients undergoing abdominal aortic surgery. Anesthesiology 70:426-431, 1989
`
`2)
`
`3)
`
`4)
`
`5)
`
`Fresenius Ex. 2003
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`Shafer SL, Varvel JR. Pharmacokinetics, pharmacodynamics, and rational opioid selection. Anesthesiology
`74:53-63, 1991
`Shafer A, Doze VA, Shafer SL, White PF. Pharmacokinetics and pharmacodynamics of propofol infusions
`during general anesthesia. Anesthesiology 69:348-356, 1988
`Adam HK, Kay B, Douglas EG. Blood disoprofol levels in anaesthetized patients. Anaesthesia 37:536-540,
`1982
`Schuttler J, Kloos S, Schwilden H, Stoeckel H. Total intravenous anesthesia with propofol and alfentanil by
`computer-assisted infusion. Anaesthesia 43 Suppl:2-7, 1988
`Tackley RM, Lewis GT, Prys-Roberts C, Boaden RW, Dixon J, Harvey JT. Computer controlled infusion of
`propofol. Br J Anaesth 62:46-53, 1989
`Russell GN, Wright EL, Fox MA, Douglas EJ, Cockshott ID. Propofol-fentanyl anesthesia for coronary artery
`surgery and cardiopulmonary bypass. Anaesthesia 43:205-208, 1989
`Glass PSA, Markham K, Ginsberg B, Hawkins ED. Propofol concentrations required for surgery.
`Anesthesiology (abstract) 71:A273, 1989
`Langley MS, Heel RC. Propofol: A review of its pharmacodynamic and pharmacokinetic properties and use as an
`intravenous anesthetic. Drugs 35:334-372, 1988
`Dundee JW, Clarke RSJ: Propofol. Eur J Anaesth 6:5-22, 1989
`Kanto JH: Propofol, the newest induction agent of anesthesia. Int J Clin Pharmacol Ther Tox 26:41-57, 1988
`Sebel PS, Lowdon JD: Propofol: A new intravenous anesthetic. Anesthesiology 71:260-277, 1990.
`
`Adapted from the 1990 ASA refresher course:
`New Intravenous Anesthetics by Donald R. Stanski and Steven L. Shafer
`
`6)
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`7)
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`8)
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`9)
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`10)
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`11)
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`12)
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`13)
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`14)
`15)
`16)
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`Propofol Dosing Guidelines
`
`Induction:
`
`
`
`I.
`
`
`
`A.
`B.
`C.
`
`Initial Bolus: 2.0-2.5 mg/kg.
`Give in 2-3 divided doses.
`Patient will be apneic within 30-90 seconds.
`
`
`
`
`II. Maintenance:
`
`For adults, the infusion rate, in cc/min, is approximately equal to the % isoflurane you
`would use for the comparable technique at the same time point.
`
`
`
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`Propofol:
`
`Initial Bolus: 0.8-1.2 mg/kg
`
`(1-2 minutes after sufentanil)
`Infusions:
`Start at 0.75-1.5 cc/min
`At 10 minutes: 0.5-1.0 cc/min
`After 2 hours: 0.3-0.5 cc/min
`
`
`
`Turn off propofol infusion
`about 5 minutes prior to the
`desired time of emergence.
`
`III. Total Intravenous Anesthesia:
`
`Sufentanil:
`
`Initial Bolus: 25-50 µg
`
`(will cause apnea)
`Infusions: (Suggest 5 µg/ml)
`None for first 25 minutes
`At 25 minutes: 40 µg/hr (8 cc/hr)
`At 2 hours: 35 µg/hr (7 cc/hr)
`At 4 hours: 25 µg/hr (5 cc/hr)
`
`Turn off sufentanil infusion
`10-15 minutes prior to the
`end of surgery.
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`Propofol Dosing Caveats
`
`Induction:
`
`A.
`B.
`
`Even small boluses (1-2 cc) may cause apnea, especially following a premed.
`Reduce propofol doses by 40-60% for elderly patients, sick patients, or following a
`heavy premed.
`
`
`
`I.
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`
`
`
`
`
`II. Maintenance:
`
`A.
`
`B.
`
`C.
`
`D.
`E.
`F.
`
`G.
`
`H.
`
`I.
`
`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. If the infusion stops for more than a few
`minutes, your patient will awaken during the operation.
`Propofol is not amnestic, so patients must be kept completely unconsciousness with
`propofol to prevent intraoperative awareness.
`Infuse the propofol through a t-piece connected immediately proximal to the IV
`catheter to minimize dead space.
`The infusion rate must be turned down over time, or the patient will be overdosed.
`The infusion can be titrated to blood pressure and heart rate.
`If your patient is too deep, turn off the propofol 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 1-4
`cc bolus of propofol, and increase the infusion rate.
`The infusion rates are intended for adults in the normal weight range (60-80 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 the operation is finished, or your patient may
`awaken before the last sutures are in place.
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`III. TIVA:
`
`A.
`
`B.
`C.
`
`D.
`
`Anticipate that the blood pressure will drop following the propofol/sufentanil
`induction. It usually returns promptly with intubation.
`Reduce the doses 25-50% for elderly, sick, or heavily premedicated patients.
`TIVA means no N2O and no isoflurane! If you turn on the isoflurane, you will alter
`the technique, and the patient may awaken slowly.
`Titrate the propofol infusion rate, not the sufentanil infusion rate. The sufentanil
`infusion has been designed to permit spontaneous respiration postoperatively with
`reasonable analgesia.
`As with propofol, the sufentanil infusion rate was designed for adults of average
`weight (60-80 kg). Adjust upward or downward for larger or smaller patients.
`Movement is a good sign of light anesthesia, so complete paralysis should be
`avoided if possible.
`H. Watch the pupils for signs of opioid overdose. If the pupils become pinpoint, stop
`the sufentanil infusion until the pupils are slightly larger.
`
`F.
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`G.
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`
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`
` //
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