Advantages Of Maintenance Phase Infusions Compared To Intermittent Bolus Dose

During an infusion, the effect-site concentration mirrors plasma concentration, except following changes in rates or following supplemental boluses. This is due to the fact that either from a high loading dose or a long infusion time (Table III-7), the different compartments of the three-compartment model have been filled. Therefore, the kinetics are now mostly on the lower end of the decay curve (i.e., beta slope). Indications for the intravenous infusion of an opioid for anesthesia are as follows:

• When duration of effect is the key consideration

• When overdose effects are undesirable

• When rapid onset time is not critical

• For malignant hyperthermia patients, for patients with high risk of post operative nausea and vomiting, or for use in an ICU sedation setting

The advantages of a continuous opioid infusion in anesthesia are as follows:

• Decreased total dose of a drug

• Greater hemodynamic stability

• Decreased side effects (e.g. rigidity with opioids)

• Decreased need for supplementation with other anesthetics

• More predictable recovery of consciousness

• Possible less pain in the post-operative period

• Possible decreased discharge time

For continuous intravenous infusion one therefore needs to know the target infusion rates to achieve a desired plasma concentration by replacing what is lost to elimination. Cp50 is the concentration that prevents reaction to stimulus in 50% of the population (analogous to minimal alveolar concentration or MAC). Infusion rates are calculated based upon elimination kinetics only. The initial part of the infusion will have to overcome redistribution kinetics prior to achieving its desired target concentration. So, initially, one would woefully be in the subtherapeutic range due to redistribution of the infusion rate. And unless a higher rate is used, the target Cp 50 may never be reached since elimination is still occurring at the

Table III-8. The approximative effective drug plasma levels at different situations when combined with 65%-70% nitrous oxide in order to reach sufficient effect site concentrations. Effective plasma concentrations may differ markedly depending on premedictation and intraoperative drug combinations

Drug (ng/ml)

Skin incision

Major surgery

Minor surgery

Recovery

Analgesia-sedation

Alfentanil

200-300

250-450

100-300

-

50-100

Fentanyl

3-6

4-8

2-5

-

1-2

Sufentanil

1-3

2-5

1-3

-

0.02-0.2

Remifentanil

4-8

2-4

2-4

-

1-2

Propofol

2000-6000

2500-7500

2000-6000

800-1800

2000-3000

Methohexital

5000-10.000

5000-

5000-

1000-3000

2000-3000

15.000

10.000

Thiopental

7.500-12.500

10.000-

10.000-

4000-8000

7.500-15.000

20.000

20.000

Etomidate

-

500-1000

300-600

200-350

100-300

Midazolam

400-600

50-250

50-250

20-70

40-100

(+opioid)

(+opioid)

(+opioid)

Ketamin

-

-

1000-2000

-

100-1000

Adapted from [79]

same time as redistribution. But loss to compartments is greatest initially, and then decreases with time. Eventually accumulation of drug will occur due to saturated peripheral compartments returning drug to central compartment plus the ongoing fixed rate infusion. So the infusion must adapt or be either ineffective or eventually toxic. When choosing the appropriate infusion rate in order to achieve the proper target Cp 50 (Tables III-7 and III-8) the following considerations have to be taken into account:

1. What kind of agent is being used?

2. What kind of stimulus has to be blocked (i.e., skin incision, intubation, major/minor surgery, etc.)

3. What kind of reaction is one trying to prevent (i.e., movement, tachycardia/hypertension, pain in the postoperative care unit, etc.)

4. What kind of synergy exists with other anesthetics being given (i.e., nitrous oxide, volatile agents, other i.v. agents, premedication, etc.)

One cannot simply start an infusion rate and expect the plasma concentration (Cp) to stay at the correct level!

The initial bolus should establish a therapeutic level. The bolus would rapidly fill compartments to get to the elimination kinetic part of the curve primarily, while the infusion must replace what is lost through:

• Elimination clearance (i.e. liver, kidney, enzymes)

• Transfer to compartment 1 (Fast)

• Transfer to compartment 2 (Slow)

Unfortunately, the last two processes are changing exponentially with time. Fortunately, inter-individual pharmacokinetic variability is large since parameters are derived from population studies. And since pharmacodynamics are also highly variable especially for narcotics (a good Cp for one patient may not be a good Cp for another). Therefore, a large adjustment factor or tolerance margin is available during infusion, and precision is not absolutely required. The therapeutic window for opioids is large (a little overdose is o.k.) during anesthesia since patients can be mechanically ventilated. The anesthesiologist therefore must titrate to effect by recognizing signs of inappropriate depth. One can always add a bolus and can always titrate the infusion rate to meet one's clinical targets. However, there is no current direct measurement real time monitor for plasma concentrations. Clinical monitors such as bispectral index or BIS, EEG, and anesthetic MAC titration currently being used, are all indirect measurements of Cp.

One also has to consider that combinations of narcotic infusions and inhalational anesthetics or other hypnotics allow synergistic interactions, which will reduce the required doses of both agents. Lower doses allow faster and more dependable recovery/emergence times. Infusions can be titrated to keep anesthetic MAC low throughout surgery and allow rapid elimination on emergence.

In summary, the following points have to be considered when using an infusion regimen for maintenance of anesthesia:

1. The effect site concentrations closely parallel plasma concentration in intravenous infusions.

2. Steady Cp is not achieved by steady infusion rate. Patients vary in terms of the infusion patterns required for given Cp (pharmacokinetics) and also the required Cp for a given desired drug effect (pharmacodynamics).

Use of Target Controlled Infusion (TCI) Systems in Anesthesia

Computerized pumps are used for infusions containing pharmacokinetic data based on population studies for various drugs. They deliver combinations of boluses and variable infusions to achieve a specified target Cp. The target Cp can be changed to match varying degrees of required depth throughout surgery. They have not been used frequently due to cost and design issues. The computerized pump Diprifusor® for instance requires proprietary propofol ampules/syringe cassettes. What is important is to know the Cp required for surgery and emergence. To awaken the patient one must decrease Cp from the initial surgical Cp to the emergence Cp that results in awakening. Therefore it is necessary to consider:

• If a higher Cp is maintained during the case, then expect a longer recovery.

• If a very low Cp is required for awakening and spontaneous ventilation, then a longer recovery is also expected.

For opioids, one needs a Cp low enough to awaken, but also high enough for postoperative analgesia. The goal is to coincide achievement of target Cp for emergence with intended time of awakening. The rate at which the body eliminates drug is relatively steady so the percent decrease required to awaken will affect greatly recovery time. The percent decrease in opioid concentrations required for emergence may vary from about 50% (balanced anesthesia) to 80% or more (opioid based technique). In this context recovery time depends on a number of things, among which the following are the most important:

• What is the Cp (initial), for maintenance anesthesia,

• the duration of infusion,

• the different drug pharmacokinetic characteristics

• and lastly the interpatient variability.

Within this framework the greatest drawback is that there is no real-time Cp monitor which may give a clue of what the necessary Cp is, and when to reduce the infusion rate in order to have a recovery at a certain time (Fig. III-22).

For recovery the principle of Context Sensitive Half Time (CSHT) can be used. The context Sensitive Half Time is the time required for a drug to reach to half its plasma concentration following termination of infusion. The "context" is the duration of the infusion and assumes that the infusion was designed to maintain target plasma concentration (e.g., with a computerized pump). Essentially, the longer the infusions, the longer the time needed to take to reduce its plasma concentration by V2. But Context Sensitive Half Time behavior varies between drugs, especially since it cannot be predicted at all by drug's terminal elimination half-life. Even though there is a no relationship between elimination half-life and Context Sensitive Half Time, elimination half-life will always exceed Context Sensitive Half Time, regardless of Context Sensitive Half Time being derived from computer modeling of known pharmacokinetic parameters. It takes into account drug behavior in compartments and redistribution (Figure III-23).

CSHT can be used to support a choice of drug for infusion depending on its projected duration of infusion. Note the propofol, midazolam and thiopental slopes. Propofol's CSHT is under 50min, even after 9h infusion. Midazolam has a slower CSHT (60min) but seems constant after a 6h infusion. So one can choose the drug with which to infuse for 2h, 6h, or 24 h and then allow for expedient awakening.

Fentanyl has a rapid increase in CSHT with infusions even over a short time frame. This causes slow recovery after an infusion due to large reservoirs in fat. However, it still can be used knowing that one must turn off infusions earlier to allow awakening. It would be similar to using halothane or isoflurane vapours. Among opioids, sufentanil may be a good choice for infusions lasting less than 8 h. Alfentanil may be a good choice for infusions over 8 h because its CSHT slope crosses over at around 600 min, while alfentanil's CSHT is fairly flat after 2h sufentanil's slope continues to rise. Because remifentanil is metabolized by plasma

Figure III-22. The different decay curves of opioids after intravenous injection with similar elimination half-lives

esterases it always has a CSHT of only 3-6 min. It rapidly attains target concentration following change in infusion rate and lacks any significant accumulation, i.e. steady infusion rate = steady effect-site concentration. However, it provides no postoperative analgesia. Remifentanil is by far the best opioid for rapid equilibration

Figure 111-23. Context-Sensitive Half Times (CSHT) as a function of infusion duration (the context) derived from pharmacokinetic models of fentanyl, sufentanil, propofol, midazolam, and thiopental (Adapted from [80])

and recovery but one must add a postoperative analgesic such as bolus of fentanyl or morphine.

In summary the following points have to be considered for recovery times when using an opioid infusion:

• It depends on the type of drug being used.

• It depends on the duration of infusion.

• It depends on the effect-site concentration required for surgery.

• It depends on the effect-site concentration required for awakening.

The weak correlation between plasma levels and pharmacodynamic effects can be visualized in the spectral edge frequency of the electroencephalographic recording, where the opioid was administered in volunteers. There, the EEG represents the biophase of pharmacodyamic effects of the opioid, while the plasma concentration reflects the circulating amount of the drug outside the CNS. It can be seen during fentanyl and sufentanil infusion, there is a drop in spectral edge frequency. Being due to a dominance of delta-waves, there is a lag of peak plasma concentration and central changes. And even after rapid decline of plasma levels, there is only a gradual change in pharmacodynamic effect (Figure III-24).

Such lag in effects is in contrast to two other fentanyl analogues, alfentanil and remifentanil. There is a parallel decline of plasma concentration and the

Figure III-24. Opioid plasma concentrations and their corresponding electroencephalographic changes, the spectral edge frequency, following a 5-min infusion of fentanyl (150 |ig/min) and sufentanil (15 |ig/min) respectively Adapted from [81, 82]

centrally mediated sedative effect, as visualized in a computerized EEG spectral edge frequency (Figure III-25).

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