In modern anesthesia, the dosing of both hypnotics and analgesics is by titration to clinical effect, measured either by effects on the cardiovascular system or the EEG (or one of its surrogates). The changes in heart rate and blood pressure tend to be "agent specific" (for most IV agents, increasing depth of anesthesia causes a reduction in heart rate and blood pressure, although with ketamine, the heart rate may increase with increasing plasma drug concentrations). However, of all the markers of inadequate anesthesia, patient movement remains the most reliable.
Despite the availability of pharmacokinetic-based infusion regimens, it is the dynamic responses of the individual patient to any given surgery that governs the rate of drug infusion. No single plasma drug concentration results in satisfactory anesthetic and surgical conditions for all patients and all operations.
Titration of the infusion rate should reflect the anticipated intensity of the applied stimulus and likely observed patient responses. In general, drug requirements are greatest during endotracheal intubation and decrease during surgical preparation and draping. The infusion rates will need to be increased before skin incision, whereas during anesthesia, drug dosing should be titrated according to signs of patient movement, hemodynamics, and autonomic responses. In the absence of any response over a given period of time, the anesthesiologist may consider reducing the infusion rate by 15% to 20%.
Table 43-8 shows typical infusion regimens used to achieve the steady drug concentrations required to provide analgesia using IV analgesic drugs given by infusion. If the dose of drug administered is clearly too high in the presence of continuing signs of inadequate anesthesia, then the anesthesiologist should examine for a disconnection of the delivery system or delivery to a subcutaneous rather than vascular site. Other causes could include incorrect programming of pumps or mechanical errors of the delivery systems.
During TIVA, use of combinations of drugs poses questions over which one to increase or decrease and for what reasons. In general, the dosing of opiates should be aimed at achieving analgesic drug concentrations at the effect site, whereas the hypnotic infusion should be titrated to individual patient requirements and to the intensity of the surgical stimulation. At the end of surgery, the anesthesiologist should reduce the infusion rates of the hypnotic and analgesic during skin closure to allow restoration of spontaneous respiration by the end of surgery.
Early recovery from thiopental occurs because of a decline in the blood (and brain) concentrations as a result of drug redistribution. After bolus doses and after short or low-dose infusion regimens, thiopental is eliminated by first-order kinetics, and the patient promptly awakens. However, at rates in excess of 300 μg/kg/min, thiopental concentrations increase nonlinearly because of the peripheral tissue stores becoming saturated. Maintaining anesthesia with infusions of thiopental requires rates of 150 to 300 μg/kg/min in combination with an opiate. This will achieve thiopental concentrations of 15 to 25 μg/mL.27 In the absence of an analgesic supplement, thiopental concentrations of the order of 40 to 50 μg/mL are needed to abolish the response to squeezing the trapezius muscle (which has been equated with the initial surgical incision). Besides the changes in pharmacokinetics, high doses of thiopental also lead to the formation of significant blood concentrations of its active metabolite, pentobarbital. Other inactive metabolites occur after C5 side-chain oxidation. Renal excretion of thiopental is very low (approximately 0.3%).
Possible advantages to the use of thiopental infusions include minimal cardiovascular depression and cerebral protection during ischemic episodes, with blood thiopental concentrations on the order of 70 μg/mL resulting in EEG burst suppression.97
When given by continuous infusion for TIVA, thiopental has a low systemic clearance (2.2-5.5 mL/kg/min) and an apparent volume of distribution at steady state of 1.3 to 2.4 L/kg.26,98-100 Larger volumes of distribution, coupled with altered kinetics, have been observed after prolonged or high-dose infusions.97
Plasma methohexital concentrations of 3 to 4 μg/mL result in hypnosis, and concentrations between 10 and 12 μg/mL cause EEG burst suppression. Based on dose–response data from Sear and Prys-Roberts,101-103 infusion rates of 50 to 65 μg/kg/min supplemented by opiates or of 100 μg/kg/min methohexital alone are required for anesthesia. Methohexital infusions depress both blood pressure and cardiac output; they also decrease baroreceptor reflex sensitivity with a resetting of the response to allow a more rapid heart rate at lower arterial pressures than when awake.104 Side effects include excitatory movements, pain on injection, and predisposition to convulsions. Epileptiform activity has been recorded by EEG, but clinical fitting is rare. Methohexital also causes pain if accidentally injected into arteries, but unlike thiopental, this does not normally lead to thrombosis.
The combination of methohexital and opiates can cause significant respiratory depression. No untoward effects of methohexital infusions on liver, renal, or adrenal function have been described.
Continuous infusions of midazolam have been used to provide both sedation and maintenance of anesthesia. When used as the hypnotic component to supplement alfentanil in a TIVA technique and compared with propofol, Vuyk et al observed similar hemodynamic effects but slower recovery.105 For the maintenance of anesthesia, infusions on the order of 10 mg/h (resulting in plasma drug concentrations of 200-350 ng/mL) are needed to supplement opiate infusions.7,16,78,80,106 There are few data describing the disposition of midazolam during TIVA for noncardiac surgery; typical clearance estimates range from 5.0 to 11.0 mL/kg/min and distribution 1.3 to 1.7 L/kg.107-110
Several of these studies showed that infusions of midazolam and opiates together may cause myocardial depression; this does not appear to be dose dependent, and there is an apparent ceiling effect at midazolam concentrations greater than 100 ng/mL. Clinically relevant rates of infusion of midazolam in combination with alfentanil have no significant effect on the plasma cortisol response during lower abdominal surgery.111 A major disadvantage of midazolam for TIVA is the slow recovery. Awakening occurs at drug concentrations of approximately 50 to 80 ng/mL. Nilsson et al82 showed that recovery can be improved by reversal with bolus doses of flumazenil, but re-sedation may subsequently occur as a consequence of the faster elimination of the antagonist and rebinding of the agonist.
Although widely used throughout the world for the maintenance of anesthesia, there are few concentration-effect data for continuous infusions of ketamine. Most studies suggest that hypnotic and analgesic thresholds are approximately 1.5 to 2.5 μg/mL and 150 to 200 ng/mL, respectively. Awakening from anesthesia occurs in the concentration range 600 to 1100 ng/mL. As sole agent, infusion rates of 60 to 80 μg/kg/min will provide clinical anesthesia.
The use of TCI ketamine for sedation and maintenance of anesthesia was described by Bowdle et al112 and Gray et al.113 For examination of the psychomimetic effects of ketamine, Bowdle et al designed a BET delivery scheme based on the kinetic parameters of Domino et al114 to achieve a stepwise series of plasma target concentrations between 0 and 200 ng/mL. Bowdle et al showed a good correlation and relationship between the targeted and observed drug concentrations. Increasing ketamine concentrations were associated with greater psychedelic effects for a variety of symptoms. Interestingly, there was no apparent threshold concentration and no concentration at which these effects plateaued.112
In the second study, Gray et al113 developed a TCI scheme for ketamine to provide the analgesic component of a TIVA technique with propofol in spontaneously breathing patients undergoing body-surface surgery, using the kinetic parameters of Wieber et al.115 The target concentration of ketamine was 300 ng/mL, with propofol delivered according to the manual BET scheme of Roberts et al.14 Clinically this combination provided good cardiovascular control throughout the surgery, with an average end-tidal carbon dioxide of 5.8 kPa. There were episodes of involuntary movements (although these did not interfere with the surgery being undertaken) and no episodes of recall. However, recovery to giving date of birth was prolonged in some patients. There were no reports of unpleasant dreams or other psychomimetic side effects.
Schuttler et al116 described a similar technique in patients undergoing lower abdominal surgery under propofol-ketamine anesthesia. They describe satisfactory anesthesia without any significant psychic disturbances or cardiovascular stimulation. Recovery was not significantly delayed.
A major development in the use of ketamine as part of TIVA has been the separation of the hypnotically active S(+) ketamine enantiomer from the racemic mixture.94 In a crossover volunteer study, White et al96 examined the pharmacologic effects of infusions of racemic, S(+), and R(–) ketamine, with measurement of cardiovascular parameters, the raw EEG, and a battery of psychometric tests. S(+) ketamine was approximately 2 times more potent in terms of anesthesia and was associated with faster recovery compared with both the racemic mixture and the R(–) isomer. This is in agreement with subsequent kinetic studies showing inhibition of metabolism of S(+) ketamine by its R(–) isomer.117 Ketamine enantiomer concentrations at time of regaining consciousness and orientation are consistent with an S-to-R potency ratio of 4:1, whereas for impairment of psychomotor function, the ratio was between 3:1 and 5:1. When administered at equipotent doses, S(+) ketamine produces longer hypnosis than the R(–) isomer, with the racemate being intermediate. Improved recovery was seen after S(+) ketamine by infusion compared with the racemate. However, cardiovascular stimulation and psychotomimetic effects are seen with both stereoisomers.
When the racemate is given by infusion, the terminal or elimination half-life of ketamine is 2.2 to 3.5 hours and clearance 14.0 to 20.0 mL/kg/min.118-120 Similar values have been described for the S+ enantiomer.121,122
When given alone as part of an anesthetic technique to surgical patients, ketamine can cause considerable side effects. Emergence reactions are commoner after infusions of the R(–) enantiomer than after the racemate and S(+) isomer. However the incidences of dreaming with all 3 treatment groups were comparable.123 There are no apparent differences between the enantiomers and racemate in their hemodynamic effects, but recovery is faster after the S(+) isomer. The EEG effects of both racemic ketamine and the S(+) isomer are similar; both cause increased fast activity (21-30 Hz) with an accompanying reduction in Δ power. The IC50 (concentration that inhibits 50%; in this instance, the plasma ketamine concentration necessary to achieve a 50% depression of the maximal EEG median frequency reduction) was 0.8 μg/mL for S(+) ketamine, compared with 1.8 and 2.0 μg/mL, respectively, for the R(–) and the racemic preparations.95 The concentration–effect relationships show the curve for S(+) ketamine to lie to the left of the racemate and to be steeper.
Propofol is the most widely used hypnotic for the maintenance of TIVA. Infusion rates of 2 to 10 mg/kg/h are needed when administered with bolus doses or an opiate infusion, whereas drug concentrations > 8 μg/mL will be necessary if propofol is used as a sole anesthetic agent. Recovery occurs rapidly after cessation of an infusion at blood concentrations of approximately 1.0 μg/mL.91 Because of the wide variability in the therapeutic drug concentration window (related to both age and type of surgery) and intersubject drug kinetics, propofol dosing must be titrated to effect. This is easily achievable as it has a short blood–brain equilibration time (t½ke0).
The disposition of propofol has been studied extensively during TIVA or for sedation during regional anesthesia.48,87,124-126
A number of other formulations (apart from Diprivan) are either available or undergoing clinical evaluation (Table 43-9). The efficacy of these newer formulations has not been evaluated in large outcome studies, but there appears to be little difference in their kinetic and dynamic properties.
Table 43-9 Different Formulations of Propofol (di-Isopropyphenol) Presently in Preclinical Trials, Current Clinical Practice, or under Developmenta ||Download (.pdf)
Table 43-9 Different Formulations of Propofol (di-Isopropyphenol) Presently in Preclinical Trials, Current Clinical Practice, or under Developmenta
Original preclinical formulation: 2% propofol in 16% Cremophor EL and 8% ethanol (withdrawn after initial preclinical evaluation)
1% propofol in 16% Cremophor EL (preclinical and early phase I use only; withdrawn after administration to 1151 patients because of adverse reactions)
1% propofol in lipid emulsion (containing 10% soybean) [= Diprivan]; emulsion preservatives include ethylenediaminetetracetic acid (EDTA), metabisulfite.
0.5% formulation for use in pediatrics.127
Modified lipid emulsions containing medium-chain triglycerides (MCTs) and 1% propofol; IDD-D propofol (Skye Pharma Inc., New York, NY)128 and Propofol-lipuro (B Braun, Meslungen, Germany).129 The latter formulation is not presently available in the United States due to the lack of EDTA or metabisulfite in the solvent.
6% propofol in MCTs-LCTs (long-chain triglycerides) (Lipofundin, B Braun).
AM 149 (Amrad Operations Pty Lyd, Richmond, Victoria, Australia): 1% propofol in MCT alone.
1% "Aquafol" micro-emulsion.130,131
Albumin-containing emulsions (under development).132
Non-emulsion formulations (under development): β cyclodextrin,133,134 micelle formulations.135
Propofol prodrugs formulated as the hemisuccinate, hemiglurate, hemiadipate, mono- or di-phosphate.136,137
When used to maintain anesthesia, infusions of propofol cause dose-related decreases in blood pressure, cardiac output, and systemic vascular resistance.91 One important difference when compared with methohexital is that infusions of propofol do not show the normal baroreflex increase in heart rate to a decreased blood pressure. Propofol causes a resetting of the baroreceptor reflex such that slower heart rates are seen for a given arterial blood when compared with awake values.91,138 As well as these central hemodynamic effects of propofol by infusion, other cardiac effects, including severe bradycardia, sinus arrest, heart block, and asystole, have been reported, which usually occur when propofol is coadministered with vagotonic drugs.91,132 During TIVA, propofol affects ventilatory control, causing a reduction in the ventilatory response to carbon dioxide and in the acute ventilatory response to isocapnic hypoxia.139,140
Although bolus doses of propofol have no effect on renal or portal venous blood flows, dose-related changes in liver blood flow have been reported in dogs during graded infusions to concentrations greater than those needed clinically in people.141 However, in patients, clinically relevant infusion rates of propofol appear to cause no significant changes of liver blood flow or liver function tests.142
Propofol–Drug Interactions during TIVA
Because TIVA normally depends on the coadministration of more than 1 IV drug, there is always the potential for drug–drug interactions, which may result in changes to drug distribution, metabolism and elimination, or drug dynamics. In vitro, propofol inhibits drug metabolism at clinical concentrations.143-145 The magnitude of this inhibition varies from 30% to 71%, with the greatest effect on biotransformations mediated by hepatic isocytochrome P450 2B1. Other cytochromes (P450 1A1 and 2A1) are also inhibited, and Chen et al146 showed that clinical concentrations of propofol inhibit renal monooxygenase and defluorinase activities. There are 4 types of drug interaction in vivo between propofol and opioids. Besides the interaction of propofol and cytochrome P450 to inhibit drug metabolism, there is also competition between propofol and fentanyl for pulmonary binding sites.
As infusions of propofol decrease liver blood flow,141 they also decrease clearance of flow-dependent drugs. Capacity-limited drug clearance is also decreased by action of propofol on the hepatic extraction ratio.33 These findings are relevant during TIVA, because propofol may decrease the systemic clearance of other coadministered drugs through changes in effective liver blood flow or in the hepatic extraction ratio. However, simulation studies by Schnider et al21 suggest that significant changes will not be associated with propofol infusion rates used in clinical practice, as the kinetics of propofol appear linear with regard to infusion rate at those concentrations. Schnider's simulations are in general agreement with the data of Sear and colleagues141 in an open-chested dog model.
In vivo there are significant interactions between propofol and alfentanil that lead to alterations in drug clearance.147 Pavlin et al148 found that an infusion of alfentanil caused an increase in the predicted propofol concentration and led to greater than predicted alfentanil concentrations when compared with those when alfentanil was infused alone. In male volunteers, Mertens et al147 showed that addition of a propofol infusion (at a steady-state concentration ranging between 0.85 and 1.75 μg/mL) to alfentanil infused at 25 μg/kg/h resulted in a decrease in mean arterial pressure. In turn, this influenced the disposition of the alfentanil, resulting in a 15% decreased systemic clearance, a 68% reduction in the rapid distribution clearance, and a 51% reduction in slow distribution clearance.
A similar interaction is seen with the combination propofol-remifentanil, where there is a significant reduction in the initial volume of distribution of the opiate and reductions in both systemic clearance and the intercompartmental distributional clearance. Because this effect is not concentration dependent, it does affect the dosing strategy when using this opiate.19,149
Of greater importance, however, are the dynamic interactions between the hypnotics and opiates during the maintenance phase of anesthesia. One of the earliest studies examining the hypnotic–opiate interaction was by Smith et a49 (Fig. 43-2). Other clinical studies and computer simulations by Vuyk et al50,150-152 from Leiden, the Netherlands, confirm a synergism between these groups of drugs. They also indicate that regardless of an opiate's relative potency, the optimal effect-site concentration should be one that (1) prevents responses to noxious stimulation and (2) allows the rapid recovery of spontaneous ventilation at the end of anesthesia and surgery. Although the original interaction studies focused mainly on the combination propofol-alfentanil,147,148,150-152 more recent studies confirm similar interactions for propofol with remifentanil and sufentanil.39,149 A further dynamic interaction is seen between the 2 groups of drugs, with the frequent need for vasoconstrictor drugs to correct hypotension after the induction of anesthesia.
Increasing concentrations of fentanyl reduces the propofol concentration at which 505 patients (95%) did not move at skin incision (Cp50i and Cp95i, respectively). Solid lines, logistic regression solution. [Adapted with -permission from Smith C, McEwan AL, Jhaveri R, et al. The interaction of fentanyl on the Cp50 of propofol for loss of consciousness and skin incision. Anesthesiology. 1994;81:820-828.]
Adverse Effects of Propofol during TIVA
Although widely used as the main hypnotic component of TIVA, propofol exhibits a number of significant adverse effects, including pain on injection (especially when given into small veins and to children), hypotension and bradycardia (which are exaggerated in the presence of other vagotonic drugs, such as opioids and hypovolemia), apnea in up to 40% of patients after induction, and reports of epileptiform movements and true convulsions.
Nonhypnotic Effects of Propofol
In addition to its anesthetic effects, propofol has other properties that may be advantageous. These include:
Mood-altering effects: Subhypnotic doses of propofol administered by a patient-controlled analgesia (PCA) system (10 mg with a 1- to 5-minute lockout) exert sedative and anxiolytic effects in anxious patients presenting for ambulatory surgery and thus can be useful as premedication in ambulatory patients.153
Antiemetic effects: Although several authors have suggested an antiemetic effect of propofol (in both hypnotic and subhypnotic doses), the site of this action of the drug remains uncertain.154 It is probable that propofol does not act at dopaminergic receptors. Subhypnotic infusions of the hypnotic are also effective in the prevention of nausea and emesis after cisplatin chemotherapy.154
Antipruritic effects: Again, subhypnotic doses (10-20 mg IV) of propofol are equally as effective as naloxone in relieving pruritus caused by both epidural and spinally administered opiates.155,156
Effects on the cerebral circulation and metabolism: Although in vitro studies demonstrate a vasodilating effect of propofol, in vivo measurement shows that infusions of propofol act to decrease cerebral blood flow and intracranial pressure (ICP) and decrease the cerebral metabolic rate. Infusions of propofol have no effect on cerebrovascular autoregulation to carbon dioxide, although the slope of the curve is decreased. There is some evidence for a cerebral protective effect of propofol, and high doses of propofol have been used to afford protection during cerebral aneurysm surgery in patients requiring cardiopulmonary bypass and deep hypothermic arrest, as well as in patients undergoing nonpulsatile bypass for cardiac surgery.157,158
α2-Agonists and Other Sedative Drugs
α2-Agonist drugs are widely used as part of TIVA techniques in veterinary practice; however, few of these agents are presently licensed for clinical use for sedation or hypnosis in people. Dexmedetomidine (DMD) is presently undergoing evaluation for both its sedative and hypnotic properties. It also has analgesic properties in animals.
In humans, DMD interacts with both opiates and hypnotics to reduce drug requirements needed to maintain sedation or anesthesia. Peden et al159 examined the combination DMD and propofol. They found that an infusion of 3 ng/kg/min of DMD reduced the median effective (ED50) infusion rate of propofol for loss of consciousness from 5.79 to 3.45 mg/kg/h and the resulting plasma median effective concentration (EC50) from 2.3 to 1.69 μg/mL. However, at these infusion rates, DMD caused significant side effects (with 2 cases of sinus arrest and 1 case of severe postural hypotension persisting for 24 hours postanesthesia). Sinus arrest has also been observed in other studies. Consequently, it is appropriate to pretreat patients (especially those younger than 40 years) with an anticholinergic agent. At an infusion rate of 3 ng/kg/min, DMD blunted the hemodynamic responses to intubation and surgical incision, with the blood pressure and heart rate remaining stable throughout surgery and into the recovery period.
In a separate study, Dutta et al160 determined the EC50 of propofol for loss of motor response to an electrical stimulus to be 6.63 μg/mL; when DMD was infused to a steady plasma concentration of 0.66 ng/mL, the EC50 of propofol was reduced by 41% to 3.89 μg/mL.
A number of other clinical studies describe the use of DMD as part of TIVA techniques. Ramsey and Luterman161 used variable-rate DMD infusions to provide hypnosis for surgery in patients with upper airway pathology. When infused at rates up to 10 μg/kg/h, DMD caused no respiratory depression, none of the patients experienced severe hypotension or bradycardia, and recovery was not excessively prolonged (although the patients, who were ages 50 to 66 years, required 2 to 3 hours for complete recovery).
Clomethiazole (a derivative of the thiazole part of vitamin B1) can be used by continuous IV infusion to supplement both regional and spinal anesthesia. It permits ease of titration of the depth of sedation and anesthesia, with minimal cardiovascular effects. However, widespread use is limited because of the large fluid loads that occur when administered as a 0.8% infusion in 4% glucose; increased red cell fragility when given as infusions of greater than 5%; a high incidence of peripheral thrombophlebitis, necessitating central venous administration; and minor side effects of nasal irritation and stuffiness. After prolonged infusions, recovery may be delayed.162
When used in TIVA, the opiates act synergistically with most hypnotic agents. Studies by Vuyk et al,6,19,50,147,150-152 Smith et al,49 and Lentschener et al163 show that even very small doses of opiates can markedly reduce the requirements of the hypnotic component. These studies also demonstrate a significant "ceiling effect"—such that above a given opiate dose or plasma concentration, little further reduction in hypnotic requirement can be achieved. During TIVA, the ability to prevent autonomic responses appears to be largely dependent on increasing the amount of the opiate drug.164 Examples of "useful" interactions between the hypnotic and analgesic components of TIVA can be found in the cited work of Vuyk et al and Mertens et al (see earlier). Table 43-8 shows the typical plasma opiate concentrations needed to obtund responses to noxious stimuli during TIVA (and the associated opiate concentrations needed for adequate spontaneous ventilation in the recovery room), together with the regimens needed to achieve other drug concentrations.