chni

Department of Anesthesiology and Pain Management, western Medical Center, Dallas, TX.

Before

anesthesia was achieved with inha%ational techthat this approach was inadequate in many ects, leading to the search for better anesthetics. In 3933, thiopental m was introduced into clinical practice by Waters and Eundy for the induction of anesthesia. It was expected th his new intravenous (IV) drug would be used for “total anesthesia,“1 t is, to provide hypnosis, analgesia, and muscle relaxation. Unfortuna y, no single IV drug (with the possible exception of ketamine) exists that provides a ponents of anesthesia with an acceptable margin of safety.2 The initial experiences with IV drugs for maintenance of anesthesia were disappointing. Following the use of thiopentai at Pearl Harbor, its administration was described as “an ideal form of euthanasia.“” Since that time, many more IV anesthetics have been introduced into clinical practice, each with its own advantages and disadvantages. Currently, the most popular method of induction of anesthesia is via the IV route. Until recently, maintenance of anesthesia has been accomplished almost exclusively with volatile anesthetics, supplemented by IV and analgesics. Inhaled anesthetics remain extremely they are generally considered to be more controllab’re and hence easier to administer during surgery .* Older IV drugs such as thiopental, morphine, and pancuronium can accumulate during an infusion and prolong recovery. The availability of newer IV drugs that have m,ore acceptable pharmacokinetic profiles (i.e., more rapid onset and shorter acting) has led to increased interest in maintaining anesthesia with IV anesthetic techni9ues.j These newer IV drugs are more controilabie, and drug accumulation is minimized compared with more traditional drugs. niques.

*Visiting Assistant Professors iProfessor

and x%cDermott Chair

Address reprint requests to Dr. White at the Department of Anesthesioiogy and Pain Management. University of Texas Southwestern ?tiedical Center. 5201 Harry Hines Boulevard. Dallas, TX 75235, USA. 0 :Y92 Eutterworth-Heinemann

1930,

L~mversity of Texas South-

general

It was clear: however,

J. Clin. Anesth.,

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I), SeptemberlCPc:ober

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45s:

hen using IV drugs, anesthesia can be achieved in one of two manners: intermittent bolus or continuous infusion administration Intermittent bolus dosing can lead to excessive levels immediately after the bohas is administered and inadequate levels during the interval between bolus injections (Figure I). As a consequence, the depth of anesthesia may oscillate above and below the desired level and result in inadequate surgical conditions.4,” When smaller bolus doses are administered at more frequent intervals, the oscillations around the desired blood drug concentration are smaller. Taken to its logical conclusion, the desired blood concentration can be maintained by administering very small incremental bolus doses at extremely short time intervals, approaching a continuous IV infusion. This leads to decreased oscillations in drug blood concentrations, thereby decreasing side effects.738 For example, fentanyl by continuous infusion provides for more precise regulation of analgesic dose, and hence drug effect, compared with conventional intermittent injection techniques. 5,? Similar results were obtained when comparing continuous infusions of alfentanil or fentanyl with the “conventional” incremental injection technique.8 It has also been shown that the duration of postoperative analgesia is longer and the degree of respiratory depression is reduced when an infusion of fentanyl is compared with incremental bolus mjections.7 It would be advantageous if the infusion rate could be altered to accommodate the variable stimuli that

occur during an operatnon. Varyrng the Grug’s inalinsion rate according to a patient’s individuai needs prevents unnecessary accumuiation of the drug (an hence rolonged recovery! that woul result from using onstant rate infusion sufficient to block the patient’s responses to all surgical stimuli.” In a study comparing a variable-rate infusion of fentanyl with a continuous infusion, the constant infusion group manifested more acute hemodynamic responses than did the variable-rate group despite the fact that the constant infusion group received more fenranyl.7 ‘The investigators reported that the plasma fentanyl concentration in the constant infusion grou 50% lower than the level needed to hemodynamic responses to specific surgical stimuli. Thus, a variable rate infusion is clinically more useful than a constant rate infusion.

The ability to titrate the dose more close+ when the indication for additional drug disa resents one of the major advantages of the i over the intermittent bofus technique. The v rate infusion technaque is similar to altering anesthetic depth by varying the inspired concentration of the volatile anesthetic. With the availability of more rapid and shorter-acting IV drugs, continuous variable-rate infusions of anesthetics can be made as controllable as ~~halatio~a~ anesthetics. However, to use IV technintly, a basic knswle armacodynamics is r As described b ost,” pharmacokinetrc the mathematics n of the processes relating the site of administration tion and elimi g concentration

and the clinical

effect. In more s refers to “what th

Drug Concentration

Time

iglnre 1. lntermiltent bolus injections of a drug to maintain anesthesia can lead to excessive levels immediately after the boius is administered and inadequate levels during the interval between bolus injections.

6s

a steady-state plasma drug level takes four to five a constant rate of krfusion is elimination half-fives used.r4 For drugs wit long e~irni~~t~on haif-life valrecess. The neues, it can therefore be a very slo cessity of rapidly achieving an anesthesia makes this practice un

J. Clin. Anesth., vol. 4 (Suppl I), September/October 1992

hiemer

propose

Anesthetic infusion techniques--how

tration of a loading dose (LD) followed by an exponentially declining infusion rate to maintain a constant plasma level of a drug. l5 The LD can be administered rapidly to achieve the required therapeutic blood level. To calculate the loading dose, one needs to know the desired plasma drug concentration (Cp) and the drug’s volume of d~s~rib~t~o~ (Vd) according to the following equation: LD(pg/kg) = Cp+g/ml) x Vd(ml/kg). The LD can be administered as either a bolus or as a rapid ‘“priming” infusion. In 1974, Wagner proposed an administration scheme consisting of two consecutive infusions. The first (or priming) infusion loaded the central compartment, whereas the second maintained the drug level at the desired plasma concentration. The loading infusion helps to minimize the acute side effects associated with a bolus injection.4316 lasma concentration is achieved, y continuous infusion. This main) can be calculated from tenance infusion rate ( R (pg/kg/min) = Cp (pgi the following equation: clearance of the drug (Cl) ml) x C1 (mlikgimin). T from population kinetics and is influis determine enced by age and coexisting diseases. The situation is lex because there are two clinically important volumes of distribution, the Vd of the central compartment (Vc) and the steady-state volume of distribution (Vdss). In the equation used to calculate LD, ay underestimate the required LD the smaller Vc whereas the larger Vdss will result in drug levels that transiently exceed those desired.4 Thus, if the initial loading dose is based on the central compartment volume, a higher initial maintenance infusion rate is required to offset drug redistribution {Figure 2). The initial redistribution of the drug from the circulation to the tissues (or eripherai compartments) plays an important part i the initial decline in plasma con. Thereafter, it becomes centration following the less important and the needed to maintain the of drug required to reCp decreases to the amou place the drug that is being eliminated. Computer programs can be used to calculate the required infusion rates.17-lg One of the main problems with using “averaged” population pharmacokinetic data is that they may lead to inaccuracies in individual patients. For instance, prediction errors of 22% to 33% occurred when using average alfentanil pharmacokinetic data in a computer-assisted infusion pnmp to predict alfentanil plasma concenhrations.g As a result, the investigators concluded that it was unwise to rely totally on predicted values when using a computer-regulated inump. Preexisting disease states, the presence of other drugs, as well as the age and gender of the patient, may significantly alter pharmacokinetic vari-

to do it: Pace et al.

msrna Dw

i

,.:’

; :;.’

2. Simulated drug level curves when a continuous infusion is administered following a “Ml” loading dose equal to Cp times Vdss (A), a smaller loading dose equal to Gp times Vc (B), or in the absence of a loading dose (

Figure

abies. For example, it has been shown that Vdss and clearance rates for propofol’O and midazolamzl are higher in women. Clearance rates for most anesthetic and analgesic drugs are significantly decreased in the elderly. As a result of marked interpatient differences, the rate of IV drug administration should be titrated according to the clinical situationS availability of pharmacokinetic-based in nology, it is the pharmacodynamic res timately determines the rate of drug infusion in anesthesia.

When using a total intravenous anesthetic (TIVA) technique, hypnosis, analgesia, amnesia, and muscle relaxation are achieved by a combination sf IV drugs. In designing an infusion regimen involving a combination of IV anesthetics, drugs with similar pharmanetic profiles and compatible pharmacodynamic C cts should be chosen to achieve optimal surgical e and anesthetic conditions.* The availability of newer muscle relaxan mivacurium) with more predictable and rapi of recovery of neuromuscular block than other available nondepolarizing relaxants makes it possible to use IV infusions of muscle relaxants with of accumulation. The degree of muscle relaxation can be accurately controlled during surgery at a level that is compatible with rapid recovery at any time during the operation Portable corn~~~e~-controlled closedsions, using electromyography (EMG) as the loop, have been developed. They can effectively control the degree of ~~~ro~~sc~la~ block, thereby simplifying the rna~ag~rne~~ of TIVA techniques.22 Based on numerous clinical reports in the

j. Clin t\nesth.,

vol. 4 (Suppi I), SeptemberiOctober

1992

47s

Original Contributions

anesthesia literature, recommended LD and initial MIR for the commonly used IV anesthetics, analgesics, and muscle relaxants are listed in Table 1.23

a. calibrated

@ion, Inc., Watertown, C Automated drug delivery requires the use of Entegrated units, as illustrated in FigAre 3, thesiologist must specify the desired set representing a particular plasma drug con a degree of muscuiar relaxation, or an EEG-derived spectral edge (or median) frequency). A computer determines the optimal infusion scheme to achieve this predetermined setpoint, based on a previously calculated algorithm and population pharmacokinetic data. Feedback from the patient is used to calculate how much more or less drug needs to be administered. The desired setpoint can be changed as frequently as required by the anesthesiol commodate differing surgical stimuli. In terns, the feedback signal is an actual me of the variable of interest. For example, when infusing a muscle relaxant, the feedback signal could be a measurement of the degree of muscle blockade from a neuromuscular function monitor. Similarly, when infusing sodium nitroprusside, the fee

ickford used an amplified, rectified, and integrated electroencephalographic (EEG) voltage to drive a stepper motor connected to a syringe that automatically produced both IV and inhaled anesthesia in animals and humans.z4 All modern infusion pumps are capable of being programmed to deliver a set dose of drug. Because the infusion rate equation to maintain a constant plasma level is too complex to be calculated manually and changes constantly over time, Schwilden suggested that a microprocessor could be used to calculate the instantaneous infusion rate rapidly and to change the infusion pump rate as required.z5 Furthermore, a computer programmed with the population pharmacokinetic data can be used to calculate the LD and initial MIR for several different drugs administered concurrently. This pharmacokinetic model-driven infusion technology is referred to as CACI, an acronym for computer-assisted contin-

Table 1.

infu~ion.~~ These

systems are aamalogsIas eo nskng vaporizer to administer the ~~~~~~atio~~~ anesthetic.17.26 A user-friendly kinetic-based infusion enny using an Ohmeda system has been developed b ) and Psiorn corn pump (Ohmeda, Madison,

uous

Recommended Loading and Initial Maintenance Infusion Rates

for Intravenous Technique

Anesthetics

When Used as Part of a “Balanced” or TVA

gnotics-Anesthesia

Hypnotics--Sedation opofol dazolam Ketamine Methohexital

50-150 5-15 1-3

uscle Relaxants Mivacurium Atracurium Vecuronium

150-250 200-400 40-80

TIVA

= total intravenous

Used

4%

J.

from

Fragen

25-75 0.25-l IO-20 IO-50

250- 1000 25-100 500-1000 250-- 1000

pioid Analgesics lfentanil FentanyI Sufentanil

Adapted

75-200 0.25-1.5 50-150

1000-2500 50-100 1500-2500

Midazolam Methohexital

RJ:

anesthetic Drug

0.5-3 0.03-O. I Q.O1-0.05 5-io 4-8 0.5-I.7

technique.

Infuszon inAnestlmkhgy.

with permission.

Clin. Anesth., vol. 4 (Suppl i), September/October

1992

New

York:

Raven

Press,

1991.

Anesthetic

Figure 3. The integrated units of an automated drug deIivery system.

the systemic blood pressure (BP). Hence, this type of system can be described as being closed-loop. On the other band, when one infuses an IV anesthetic such as propofol, the feedback signal is usually a mathematically computed plasma drug level. Closed-loop control of plasma drug concentrations is not yet possible because it is not possible to rapidly rug concentrations, such that these measure plasma ed as the feedback signal. Hence: values could be the only computer-controlled method available for infusing drugs such as propofol, midazoiam, and alferatanil is the mathematically based pharmacokinetic delivery system, the accuracy of which is essentially the accuracy of the pharmacokinetic model. Although there is some disagreement regarding the usefulness of these techniques, there is preliminary evidence suggesting that CACI offers clinical advantages over conventional dosing techniques.10 As ou p receiving a variable-rate mentioned earlier, a d greater hemodynamic stainfusion of fentanyl uvant drug interventions, and d significantly Cewer hypotensive and hyepisodes than did a manual, intermittent .I0 Closed-loop administration of muscle relaxants has been available for some time.27.28 The development of transportable systems allows for their more widespread use (e.g., transporting critically ill patients).“” Closed-loop systems have also been developed to deliver and achieve setpoint end-tidal gas concentrations for enflurane, halothane, and isoflurane.*g However, it has not been the lack of appropriate delivery systems for inhalational anesthetics that has led to the current renewed interest in IV anesthetics, but rather the availability of‘ drugs such as propofol, alfentanil, and mivacurium, which are relatively rapid and shortacting drugs that are ideally suited for administration by continuous, variable-rate infusion.

&fusiontechniques-how

to do it: Pace et al.

As mentioned earlier, one a vantage of an inhalational technique is the ability to correlate t tb brain concenconcenrration of the volatile drug tration and clinical effect (e.g., re iratory rate and minimum alveolar concentration). On the other hand, one problem associated with the tinuous infusion technique is difficulty judging h of anesthesia, which may lead to inadequate anesthesia and intraoperative awareness. No universally act is available to indicate depth of anestbesx awareness during anesthesia. It h sudden increases in the am could indicate s frontalis muscle EMC acti enhanced patient responsiveness.30 and coworkers showed that EMG a iP;g did not significantly improve t ability to titrate an IV infusion of methohexital during outpatient anesthesia. 3L The EMC changes often occurred 5 to 10 seconds after the patient moved and were therefore of little predictive value in adjusting the maintenance infusion. On the other hand, changes in the respiratory rate and pattersi were a more useful measure of anesthetic depth because they occurred before changes in EMO; activity were 1.5 to 30 se recorded. usly, this clinical sign is only useful if the patient is breathing spontaneously, as the administration of muscle relaxants obliterates these signs. The BP response to surgical stimulation is not as reliable a predictor of anesthetic depth when esthetics and analgesics are used (as with inhalational anesthetics). It may be that changes in peripheral vascular resistance may be more useful in monitoring anesthetic depth during “balanced” or TIVA.32 The development of the IV equivaient of the minimum alveolar concentration (MAC) values would clearly be of clinical value. This has led to the development of the concept of the Iminimum infusion rate. This is defined as the minimum infusion rate that suppresses movement of the patient in response to the initial and subsequent sustained surgical stimulation.“” When propofol was used to supplement nitrous oxide 67% in oxygen, a minimum infusion rate of 51 + 4 ,u,g!kglmin was required. correlating to a plasma concentration of 1.5 1. 0.2 ,~g/mP.“”Additional work is required to establish the minimum infusion rate as part of a TIVA techniqne. Glinica! data defining therapeutic plasma drug concemrations for a variety of surgical stimuli are becoming more readily available.34

nt advances in infusion pump technology have ted in the ability to administer IV drugs more safely and easily over prolonged periods of time. Malion and Edelist suggest that use of a TIVA technique requires a dedicated IV line.2 The future of pharmacokinetic-based IV drug delivery systems will depend on their safety, reliability, cost-effectiveness, and ‘user friendliness.

Day surgical procedures can be performed safely under local, regional, or general anesthesia, with the choice depending in part on the surgical procedure and in part on the preference of the patient and anesthesiologist. If a local or regional technique is chosen, IV sedation, anxiolysis, and amnesia may be desirable. Midazolam has many properties that make it a useful adjuvant when administered by continuous infusion during local or regional anesthesia.3j-37 It is a water-soluble drug with an elimination half-life of 2 to 4 hours.38 A plasma concentration between 100 and 200 ngiml results in a sedated but easily arousable patient. The sedative and amnesic properties persist until the midazolam concentration falls below 75 ng/ ml. However, the time taken to achieve sedation can be as long. as 24 minutes.36 Furthermore, of greater significance is the fact that recovery of cognitive function after midazolam can be delayed.3”-“’ When the sedative, amnesic, and recovery characteristics of methohexital, etomidate, and midazolam infusions were compared during regional anesthesia, it was shown that, although midazolam provided more effective intraoperative sedation and amnesia, recovery of psychomotor function was slower with midazoiam than with either methohexital or etomidate.3j However, patient evaluation of residual sedative effects and discharge times from the recovery room were similar in all three groups. Subhypnotic infusions of propofol ( 1- 10 mg/min) also provide effective sedation during regional anesthesia3g and appear to have significant advantages over midazolam with respect to recovery parameters.35 Flumazenil, a specific benzodiazepine antagonist, can be used to reverse the effects of a midazolam sedative infusion.** However, due to the pharmacokinetic profile of flumazenii, the duration of antagonism is brief and resedation can occur.41 When used as a sedative infusion during local and regional anesthesia in outpatients, propofol was as-

50s

sociated with less postoperatnve sedation, drowsiness, confusion, clumsiness, and amnesia, as well as more rapid recovery of cognitive function, than was midazofam. However, discharge times were similar in the . Choice reaction time, a sophisticated nt of recovery from anesthesia, was imropofol compared paired for only 30 minutes after with 3 hours after midazolam.36 It woul ear that Vf3 the optimal technique for sedation in administration of midazolam, 2 mg IV, followed titrated propofol infusion, 25-108 ~gikglmin.~~ If a general anesthetic technique is administered for outpatient surgery, ideally it should provide for a rapid and pleasant loss of consciousness, adequate depth of anesthesia without significant cardiores atory changes, and rapid recovery without side fects. The introduction of IV drugs with and shorter duration of effect, such as p fentanil, and mivacurium, has brought this to achievement. When used with 67% nitrous oxide and fentanyl, i pglkg, propofol (La-12 mg/min) compared favorably in) for outpatient aneswith methohexital(311 mg stoperative nausea and thesia. The low incidence o vomiting with rapid return a “clear-headed” state contributed to shorter ambulation and discharge times.4” opofol infusion (2.5-15 mgimin) has also compar favorably to t~iopental-iso~~~ra~e when used for longer outpatient procedures.“-’ When administered by a variable-rate infusion as an adjuvant to nitrous oxide for maintenance of general anesthesia, propofol (Z-10 mgimin) was associated with cardiovascular effects similar to those produced by methohexital and thiopental-isoflurane but with signiftcantly shorter times to awakening, orientation, and recovery of psychomotor and cognitive ~~~ct~o~i~g.~~ The routine use of propofool as the primary anesthetic significantly decreased nausea and a postoperative complication of minor ou necologic surgery.” Recent studies suggest that propofol has a direct antiemetic action.lj-47 In the outpatient setting, this can be very useful in decreasing both recovery times and unanticipated admissions.48,49 Although an equianalgesic dose of alfentani! may be associated with a shorter duration of respiratory depression than fentanyl,a,iO recovery times foIlowing alfentanil have been either sirnilarjl~jz or shorte+j” than those reported following the use of fentanyf in the outpatient setting. However, one of the main problems with alfentaniI appears to be the high incidence of side effects such as nausea and vomiting when combined with natrous oxide.8 To supplement nitrous oxide anesthesia, the mean effective maante-

J. @fin. ipnesth., vol. 4 (Sup@ l), September/October 1992

Ane.rthPtrc iry%sion technzquPi-haul

nance infusion i-ate of alfentanil can vary from 0.25 depending on the type of surgical to 2.5 pgkgimin, stimulus. These rates are associated with alfentanil concentrations ranging from IO0 to 500 ng/ml.s~Y~53 It has been suggested that individual variability in serum drug levels, despite similar surgical stimuli, may reflect different individual sensitivities to this analgesic drug.8 Perhaps simultaneous infusions of propofol and alfentanil as part of a total IV technique may represent the optimal combination5fi utilizing the anesthetic and antiemetic effects of propofol together with the analgesic effects of alfentanil, thereby decreasing the anesthetic and analgesic requirement, as well as the deleterious side effects.

The combination

of existing infusion pump technolbarmacokinetic data in the form very systems may facilitate clinical use of IV anesthetic, analgesic, and muscle relaxant drugs. As suggested in a recent editorial in the Canadian ,~ournal of Anaesthesin, total IV anesthesia is a concept whose time has come.* Problems remain, such as the question of monitoring depth of anesthesia and whether such systems are cost-effective. The delivery systems ust be “as easy to use as vaporizers for inhalational anaesthetics.” A new generation of anesthesiologists who are familiar with pharmacokinetic factors and pump technology may find the use esthetic techniques as acceptable as the curpular inhalational techniques. Although constant vigilance is mandatory, one of the advantages of pharmacoki~etic-based delivery systems is that they free the anesthesiologist from carrying out complex dosage regimens when multiple alterations in infusion rates are required to achieve a specific effect. The commercial introduction of the TITRATQR (IVAC Corporation, San Diego, CA), a device implementing closed-loop administration of sodium nitroprusside, indicates a significant advance in the field of automated drug delivery. This should lead to much more Widdgi utomated drug delivery systems for drugs onofol, a?fentanil, and mivacurium as part technique for outpatient anesthesia.

W: Total intravenous anaesthesia. Br] Anuesth 1978;50:89-90. 2. Mallon JS, Edehst G: Total intravenous anaesthesia. Can] Anaesth 1990;37:279-81.

io do it: Pace it al.

3. Halford FJ: A critique o:‘intravenous anesthesia in war surgery. Anesthesiology 1943;4:67-9. 4. White PF: Chnical uses of intravenous anesthetic and analgesic infusions. An&h An&g 1989;68:161-71. 5. Gnnawardene RD, White DC: Propofoi and emesis. Annesthesia 1988;43(Suppl):65-7. 6. White PF: Use of continuous infusion versus intermittent bolus administration of fentanyl or ketamine during outpatient anesthesia. Anesstheszolog?1983;59:294300. 7. Pathak KS; Brown RH, Nash GLJr, Gascorbi HF: Gontinuous opioid infusion for scoliosis fusion surgery. Anesth Analg 1983;62:841-5. 8. White PF, Coe If, Shafer A, Sung M-L: Comparison of aifentanil with fentanyl for outpatient anesthesia. Anesthesiology 1986;64:99i 06. 9. Ausems ME, Stanski DR, Hug CC Jr: An evaluation of the accuracy of pharmacokinetic data for the computer assisted infusion of alfentanil. Br J Anaesth 1985; 57:1217-25. LO. f&is JM, Reves JG, Govier AV, et ai: Computer-assisted continuous infusions of fentanyl during cardiac anesthesia: comparison with a manual method. Anesthesiolo_q 1985;63:41-9. !I. Cook DR, Chopyk J-B: Infusion of narcotics and relaxants as an adjunct to nitrous oxide-oxygen anesthesia. Semin Anesth 1988;3:226-34. abaufe in der 12. Dost IH: Kinetic der Konzertrations Krieslauffiussigkeit. Der Blutspiegel 1953;224, Leipzig: l-. i nieme. and dy13. Holford NC, Sheiner E : Pharmacokinetic namic modelling in vivo. CRC Crit Rezi Bioeng 1981; 5:273-322. rug therapy. Clinical 14. Greenblatt DJ; Koch-Weser J: pharmacokinetics. N EnglJ Me 15~ Kruger-Thiemer E: Continuous intravenous infusion and multicompartment accumulation. Eur J Pharmacol 1968;4:317-24. 16. Wagner JG: A safe method for rapidiy achieving plasma concentration. plateaus. Clin Phamacol Ther 1974; 16:691-700. 17. Glass P, Jacobs JR, Hawkins ED, et al: Accuracy and efficacy of a pharmacokinetic model-driven device to infuse fentanyl for anesthesia during general surgery [Abstract]. Anesthesiology 1988;69:A290, 18. Kenny GN, White M: A portable computerised infusion system for propofol. Anaesthesia 1990:45:692-3. 19. Kenny GNG: Practical experience with computer-conof01 infusion. Semin Anesth J992; 1I( I,Suppl 1):12-13. PF: Pharmaco20. Shafer A, Doze VA, Shafer SL, kinetics and pharmacodynamics pofol infusions during general anesthesia. P,nesthesi&Kj 1988;69:34856. 21. Greenbiatt DJ, Abernethy D , Locniskar A, Harmatz J#S; kimjuco RA, Shader RI: Effect of age, gender, and obesity on midazolam kinetics. Armthesiolo~ 1984;6 1:27-35.

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Original Contributaons Webster KK, Cohen AT: Closed-loop administration of atracurium. Steady-state neuromuscular blockade during surgery using a computer controlled closed-loop atracurium infusion. Anaesthesia 1987;42:1085-91. 23. Fragen RJ: Drug Infusion in Anesthesiology. i’dew York: Raven Press, 1991. 24. Bickford RG: Automatic electroencephalographic control of general anesthesia. EEG Clin Neurojkysiol 22.

1950;2:93-6.

Schwilden H: A general method for calculating the dosage scheme in linear pharmacokinetics. Eur] Clin F’harmacol 1981;20:379-86. 26. Ausems ME, Vuyk J, Hug CC Jr, Stanski DR: Comparison of a computer-assisted infusion versus intermittent bolus administration of alfentanil as supplement to nitrous oxide for lower abdominal surgery. Anesthesiolog3; 1988;68:851-61. 27. Bradlow HS, Rametti LB, Uys PC, Coetzee WP: Microcomputer-based muscle relaxation monitor and controller for clinical use. Med BiolEng Comput 1985;23:54725.

55. 28.

Bradlow HS, Uys PC, Rametti LB: On-line control of atracurium induced muscle relaxation. / Biomed Eng

29.

Westenskow DR, Wallroth CF: Closed-loop control for anesthesia breathing systems. J Clin Monit 1990;6:249-

30.

Fink BR: Electromyography in general anesthesia. Br J Anaesth 1961;33:555-9. Chang T, Dworsky WA, White PF: Continuous electromyography for monitoring depth of anesthesia. Anesth Analg 1988;67:521-5. White PF, Boyle WA: Relationship between hemodynamic and electroencephalographic changes during general anesthesia. Anesth Analg 1989;68: 177-8 1. Prys-Roberts C, SearJW, Adam HK: Pharmacokinetics of continuous infusions of althesin, minaxolone and ICI 35 868 to supplement nitrous oxide anaesthesia in man. BTJ Anaesth 1981;53:115P. Glass PSA,Jacobs JR, Reves JG: Intravenous anesthetic delivery. In Miller RD, ed. Anesthesia. 3rd ed. New York: Churchill Living-stone, 1990:367-88. Urquhart ML, White PF: Comparison of sedative infusions during regional anesthesia-methohexital, etomidate and midazolam. Anesth Analg 1989;68:249-

1986;8:72-5.

56.

31.

32.

33.

34.

35.

37.

38.

39.

1983,55:

Wilson E, David A, Mackenzie X, Grant I§: Sedation during spinal anaesthesia: comparison of propofol and midazolam. BrJ Anaesth 1990;64:48-52. White PF, Negus JB: Sedative infusions during local and regional anesthesia: a comparison of midazolam and propofol. J Clin Anesth 1991;3:32-9. Greenblatt DJ, Locniskar A, Ochs HR, Lauven PM: Automated gas chromatography for studies of midazolam pharmacokinetics. AnesthesioloB 1981;55: 176-9. MacKenzie N, Grant IS: Comparison of propofol with _methohexitone in the provision of anaesthesia for surgery under regional blockade. Br J Anaesih 1985;57: 1167-72.

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169S-71s.

Shafer A, Sung ML, White PF: Pharmokinetics and pharmacodynamics of alfentanil infusions during general anesthesia. An&h Analg 1986;65:1021-8. 56. Monk JG, Ding Y, White PF: Total intravenous anesthesia: effects of opioid versus hypnotic suppiementation on autonomic responses and recovery. A?~esthAnalg (in press). 57. Schuttler J, Kloos S, Schwilden H, Stoeckel II: Total intravenous anaesthesia with propofol and alfentanil by computer-assisted infusion. AncLesthe.sia 1988;43 (Suppi):2-7. 55.

54. 36.

40. Ghouri AF, Ramirez-Ruiz M, White PF: %nmazenii after midazolam sedation decreases outpatient recovery times. Anesthesiology (in press). 41. Kestin IG, Harvey PB, Nixon C: Psychomotor recovery after three methods of sedation during spinal anaesthesia. RrJ Anaesth 1990;64:675-81. 42. Taylor E, Ghouri AF, White PF: Midazolam in combination with propofol for sedation during local anesthesia.J Clin Anesth 1992;4:213-16. 43. Doze VA, Westphai LM, White PF: Comparison of propofol with methohexital for outpatient anesthesia. Alzesth An&g 1986;65: 1189-95. 44. Doze VA, Shafer A, White PF: Propofol-nitrous oxide versus thiopental-isoflurane-nitrous oxide for general anesthesia. Anesthesiology 1988;69:63-7 I. 45. McCollum JSC, Milligan KR, Dundee JW: The antiemetic action of propofol. Anaesthesia i988;43:239-40. 46. Watcha MF, Simeon RM, White PF, Stevens JL: Effect of propofol on the incidence of postoperative vomiting after stabismus surgery. Anesthesiology 1991;75:204-9. 47. Borgeat A, Wilder-Smith OHG, Saiah M, Rifat K: Subhypnotic doses of propofol possess direct antiemetic properties. Anesth Analg 1992;74:539-41. 48. Doze VA, Shafer A, White PF: Nausea and vomiting after outpatient anesthesia-effectiveness of droperidol and in combination with metoclopramide [Abstract]. Anesth Analg 1987;66:S41. 49. Gold BS, Kitz DS, Lecky JN, Neuhaus JM: Unanticipated admission to the hospital following ambu!atory surgery.jAMA 1989;262:3008-IO. 50. Scamman FL, Ghoneim MM, Korttila and mental effects of alfentanil and fentanyl. Acta Anaesthesiol Stand 1984;28:63-7. 5 1. Hull GJ, Jacobson L: A clinical trial of alfentanil as an adjuvant for short anaesthetic procedures. BrJi Anaesth 1983;55: 173%8s. 52. Cooper GM, O’Connor M, MarkJ, HarveyJ: Effect oI alfentanil and fentanyl on recovery from brief anaesthesia. BrJ Anaesth 1983;55: 179%82s. 53. White PF, Coe V, Shafer A, Sung ML: Comparison of alfentanil with fentanyl for outpatient anesthesia. ;anesthesioloa 1986;64:99-106. 54. Kay B, Venkataraman P: Recovery after fentanyl and alfentanil in anaesthesia for minor surgery. BrJ Anaesth

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