IV Tci Propofolthedoseofpropofol2012

The dose of Propofol during TCI

Dr. A. Alisher MD PhD

AL SABAH & ZAIH HOSPITALS, MOH, KUWAIT

Propofol 2 μg/mL Induces a Non-Uniformity in rCBF

• Margaret J. Rose, M.D., Maolin Qui, Ph.D., R. Todd Constable, Ph.D., Ramachandran Ramani, M.D. Propofol 2 μg/mL Induces a Non-Uniformity in rCBF- fMRI Study in Volunteers. ASA, October 17, 2011. A800.

• Yale New Haven Hospital, New Haven, Connecticut, United States

• Alteration in rCBF is a reflection of neuronal activity in the brain, because of the property of flow-metabolism coupling in the brain.

• With Propofol anesthesia flow-metabolism coupling is maintained over a broad dose range.

• It has been reported a non-uniformity in rCBF change with both 0.25 MAC1 and 0.5 MAC SV.

• A study to measure the alteration in rCBF with Propofol 2 μg/mL plasma level (0.5 MAC equivalent) in healthy volunteers.

• 19 healthy ASA I volunteers (19-35 years). • Basic standards of monitoring and • Propofol anesthesia was administered

through a TCI device (Stanpump pump connected to a Harvard 22 syringe pump).

• TCI Propofol level was 2 μg/mL.

• PR level was confirmed by drawing a blood sample at the beginning and end of the infusion period.

• Regional CBF was measured in a 3 Tesla Siemens Trio by the PASL technique.

• CBF was measured in subjects while awake and under anesthesia.

• The difference in rCBF between the awake and anesthetized states was calculated (δ CBF).

• Vital signs of all the subjects were within normal limits during Propofol infusion.

• With Propofol 2 μg/mL plasma level, 18/19 subjects were asleep with OAA/S score of ≤ 2 (no response to call) and none had any memory of the event.

• The total duration of anesthesia was 75 min. With 2 μg/mL plasma level Propofol there was a significant drop in rCBF in most of the regions (frontal, parietal, occipital, temporal cortices and thalamus).

• In the thalamus and occipital cortex decrease in CBF was close to 40-50%.

• In the anterior cingulated (ACC), insula and parahippocampal gyrus there was a modest rise in rCBF.

• PR causes a non-uniformity in rCBF.

• Regions manifesting a rise in rCBF (ACC, insula & parahippocampal gyrus) showed a similar response with 0.5 MAC SV also.

• 2 ACC & insula are linked to pain processing while parahippocampal gyrus is related to memory, whereas the thalamus is associated consciousness.

• The regional decrease in CBF was significantly more with PR than that seen with sevoflurane.

• With Propofol 2 μg/mL, there is a non-uniformity in rCBF;

• A response observed with Sevoflurane also.

• Because the flow response with Propofol is indirect (linked to a decrease in CMRO2) the CBF alteration is more pronounced as compared to Sevoflurane.

Target-controlled infusion (TCI)

• Target-controlled infusion (TCI) is useful for anesthetic management using Propofol because a TCI system can automatically adjust the dose to keep the predicted concentration of Propofol at the target concentration that was input into the TCI system by an anesthesiologist.

• T. Kunisawa, A. Kurosawa, S. Hanada, H. Iwasaki: Attention should be paid to the dose of propofol during target-controlled infusion. The Internet Journal of Anesthesiology. 2010 Volume 24 Number 2

• However, human error such as inputting incorrect weight can cause administration of Propofol at an inappropriate dose.

• Therefore, attention should be paid to whether the dose is appropriate or inappropriate against a target concentration.

• It has been calculated the dose of propofol during TCI with 3 μg/mL of the target propofol concentration and found that the dose converged to 4.884 (mg/kg/h);

• And that the dose can be calculated in many periods by multiplying the target concentration (μg/mL) by 1.7-2.3.

• Since the concentration of Propofol depends on only the dose independent of personal characteristics;

• The dose that should be administered (mg/kg/h) can be estimated by doubling the target concentration (μg/mL);

• And we should therefore repeatedly confirm that the appropriate dose is being administered.

A TCI system

• A TCI system is very convenient because a syringe pump with a built-in DiprifusorTM can adjust the Propofol dose by means of just inputting the expected target concentration of Propofol during anesthetic management after inputting the patient’s characteristics such as weight and age before starting administration.

A TCI system

• However, confirmation of matching dose with predicted plasma concentration (Cp) displayed on the syringe pump is thought to be always necessary for preventing human errors such as inputting incorrect weight.

A TCI system

• It has been calculated the predicted Cp using TIVAtrainerTM (http://www.eurosiva.org/; accessed on May 1, 2010) with Marsh’s parameter when it was assumed that Propofol was administered using TCI with 3 μg/mL of the target concentration in a 40-year-old male with a height of 170 cm and weight of 70 kg (Figure 1).

Target plasma concentration and dose of Propofol with time

• I. Concentration(ug/ml)= a x dose (mg/kg/min)

• II. a = Weight (kg):CL1 (L/min)

• III. Dose (mg/kg/h) = b x concentration (ug/ml)

• IV. b = 1.628

• The patient a 40-year-old male ; • Height of 170 cm;• Weight of 70 kg. • Propofol dose decreases with time during

administration of Propofol at the target plasma concentration of 3 μg/mL;

• And converges to ~ 4.884 mg/kg/h.

• Cp: plasma concentration, prop: Propofol.

• Cp of intravenous anesthetics in a steady state can be predicted using the following equation:

• Cl1 is metabolic clearance.

• Cl1 of Propofol is affected only by weight and varies in proportion to weight .

• Therefore, value “α” is constant in all patients and the value is 36.84.　

• Formula (I) can be written as the following formula:

• I. Concentration(ug/ml)= a x dose (mg/kg/min)

TCI : Target plasma concentration and dose of Propofol with time

• Value β is also constant in all patients. We can confirm that the dose is appropriate against the target concentration by using formulas (III) and (IV) in the steady state:

• III. Dose (mg/kg/h) = b x concentration (ug/ml)

• IV. b = 1.628

• However, in the case of Propofol, much time is needed until a steady state is reached.

• Thus, if value β is calculated from the data infusing formula (3);

• Value “β” falls below 2.3 at about 40 min after starting administration,

• Reaches 2.0 at about 2 hours and 7 min after starting administration;

• And falls below 1.7 at about 10 hours and 9 min after starting administration.

• These values are the same regardless of the patient’s characteristics or target concentration as long as the patient has not been administered Propofol before starting TCI and target concentration has not been changed.

• It can be approximate the appropriate dose (mg/kg/h) by means of doubling concentration (μg/ml).

• It should constantly be confirmed during TCI that the administered dose (mg/kg/h) of Propofol matches the value calculated by doubling the target concentration (μg/ml).

Effect-site concentration of RF for Nasotracheal vs. Orotracheal

intubation during TCI PR

• Kwak HJ, Min SK, Kim DH, Kang M, Kim JY. Effect-site concentration of remifentanil for nasotracheal versus orotracheal intubation during target-controlled infusion of propofol. J Int Med Res. 2011;39(5):1816-23.

• Department of Anaesthesiology and Pain Medicine, Gachon University of Science and Medicine, Gil Medical Centre, Incheon, Republic of Korea.

Effect-site concentration of RF for Nasotracheal vs. Orotracheal

intubation during TCI PR• The concentration of Remifentanil required

for acceptable nasotracheal intubation in adults after TCI Propofol without NMBA was compared with that required for orotracheal intubation.

RF for Nasotracheal vs. Orotracheal intubation during TCI PR

• 250 patients undergoing oral and maxillofacial surgery received nasotracheal intubation and

• 150 undergoing ear, nose and throat surgery received orotracheal intubation.

RF for Nasotracheal vs. Orotracheal intubation during TCI

• Anaesthesia was induced with Propofol TCI at a target effect-site concentration of 5.0 - 10 μg/ml.

• RF EC(50): and RF EC(95): for Remifentanil, calculated using isotonic regression, were 5.40 and 6.85 ng/ml, respectively,

• TCI RF: 5.75 ng/ml In the orotracheal group;

• TCI RF: 7.43 ng/ml in the nasotracheal group;

• The EC(50) (± SD) values for Remifentanil, calculated using a modified Dixon's up-and-down method, were:

• 6.08 ± 0.75 for nasotracheal intubation;

• 5.58 ± 0.75 ng/ml for orotracheal intubation;

• Effect-site remifentanil concentrations did not differ significantly between the two groups of patients.

• Coadministration of Propofol and Remifentanil can provide acceptable conditions for Nasotracheal intubation without neuromuscular blockade.

Conventional Rate Controlled Infusion (RCI)

• Conventional Rate Controlled Infusion (RCI) -Propofol infusion rate(shown in green) is constant at 40 mcg/kg/min.

• Drug concentration in blood (shown in blue) increases with time.

• With TCI, software within the pump models the distribution and elimination of a particular drug in an average patient.

• To achieve and maintain a set drug concentration in the blood, a TCI system will calculate, and deliver with a short rapid infusion, the amount of drug required to reach the target rapidly.

• Thereafter the TCI system will automatically reduce the infusion rate over time, delivering sufficient drug to compensate for loss from the circulation by redistribution and elimination.

• Thus the blood concentration is constant and the infusion rate decreases over time (see Fig 2).

Target Controlled Infusion

• Target Controlled Infusion - Calculated blood propofol concentration indicated by TCI system is constant at 1000ng/ml.

• Propofol infusion rate (shown in green) decreases over time.

Target Controlled Infusion• If an increase in drug concentration is required,

a further small bolus is administered by the TCI system and the maintenance rate adjusted to maintain this new target.

• If a decrease in target concentration is requested, the TCI system will stop the infusion until the model within the pump calculates that the blood concentration will have fallen to the new target.

Target Controlled Infusion

• Infusion then recommences automatically at a lower rate to maintain this lower target.

• Thus with TCI, when a given target setting is changed, the response in the blood concentration occurs more rapidly and more reproducibly than with RCI (see Fig 3).

Advantages of TCI

• A. Benefits to Pharmaceutical Companies1. Maintenance of a desired drug concentration may improve therapeutic effect and minimise toxicity or undesirable effects associated with high peak concentrations obtained with bolus dosing.2. Use of TCI in drug development allows early determination of concentration/effect data. A number of stepped drug concentrations can be studied in the same subject. Early availability of PK/PD data may help to shorten drug development times.3. Simplification of dosing strategy and improved ease of use

TCI : Benefits to User• 1. Dose titration to achieve a desired effect is

facilitated• 2. Simplification of dosage and improved ease of

use• 3. Advisory information on the calculated drug

concentration is provided• 4. Improved individualisation of dosage if a

complex PK model is available using covariates for age or other patient characteristics.

Drug for TCI and Therapeutic Areas

• Drugs Suitable for TCI:• 1. Drugs administered by intravenous infusion• 2. Drugs with a short or moderate duration of

action if given as a single bolus• 3. Drugs which can be titrated to a recognizable

or measurable pharmacodynamic end point• 4. Drugs where maintenance of a steady

therapeutic concentration is desirable

TCI: Possible therapeutic areas

• 1. Hypnotic and analgesic drugs used in anaesthesia. Infusion devices for the delivery of the iv hypnotic, propofol and the short acting analgesic, remifentanil are currently available.2. Antibacterial agents used in the critical care environment.3. Antifungal agents used in the critical care environment4. Anticancer chemotherapeutic agents5. Inotropic agents used in cardiac surgery and coronary care units6. Antiarrhythmic agents used in coronary care units and other critical care areas.7. Short acting beta-blocking agents for control of heart rate intraoperatively or in the ICU.

TCI RF vs. TCI PR for awake fiber-optic intubation with LTA

• Zhang X, He W, Wu X, Zhou X, Huang W, Feng X. TCI remifentanil vs. TCI propofol for awake fiber-optic intubation with limited topical anesthesia. Int J Clin Pharmacol Ther. 2012 Jan;50(1):10-6.

• Department of Anesthesiology, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong, China.

• It has been compared the effects of TCI Propofol and TCI Remifentanil on awake fiber-optic intubation with limited local anesthesia.

• 36 patients requiring Fiberoptic intubation were randomized to receive Propofol (P) or Remifentanil (R) effect-site TCI.

• Target concentrations; • Sedation levels; • Pulse Oximetry;• Hemodynamic change; • Duration; • Number of adjustments; • Intubating conditions; • And recall after surgery • were recorded at each stage.

• The target intubation concentration of Remifentanil was very close to the sedation concentration;

• The intubation concentration of Propofol was more than double its sedation concentration:

• 5.83±1.46 μg/ml • vs. • 2.60±0.47 μg/ml

• Vocal cord opening was better in TCI Remifentanil-treated patients.

• More adjustments; and

• A longer duration were required in TCI Propofol-treated patients.

• Recall was significantly more frequent in TCI Remifentanil-treated patients.

• It has been concluded that compared to TCI Propofol;

• TCI Remifentanil provide safer and better intubating conditions for fiber-optic intubation with limited local anesthesia.

TCI Remifentanil vs TCI Propofol for awake fibreoptic intubation:

• Rai MR, Parry TM, Dombrovskis A, Warner OJ. Remifentanil target-controlled infusion vs propofol target-controlled infusion for conscious sedation for awake fibreoptic intubation: a double-blinded randomized controlled trial. Br J Anaesth. 2008 Jan;100(1):125-30. Epub 2007 Nov 23.

• Nuffield Department of Anaesthetics, Oxford Radcliffe NHS Trust, Headley Way, Headington, Oxford OX3 9DU, UK.

TCI Remifentanil vs TCI Propofol for awake fibreoptic intubation::

• Awake fibreoptic intubation (AFOI) is a technique used in patients with difficult airways.

• A study of the suitability of TCI Remifentanil to TCI Propofol for conscious sedation during AFOI in patients with bona fide difficult airways.

• 240 , ASA I-III patients, who were undergoing sedation for elective AFOI.

• Patients were randomized to one of the two groups, Group P (n=120) received Propofol TCI and Group R (n=120) received Remifentanil TCI.

• Primary outcome measures were conditions achieved at endoscopy, intubation, and post-intubation, which were graded using scoring systems.

• Other parameters measured were:• The endoscopy time, • Intubation time, • And number of attempts at intubation.

• A postoperative interview was conducted to determine recall of events and level of patient satisfaction.

• Endoscopy scores (0-5) and intubation scores (0-5) were significantly different:

• Group P 3 (1-4) vs • Group R 1 (0-3) • P<0.0001;

• Group P 3 (2-4) • vs • Group R 1 (0-3) • P<0.0001,• With much better conditions in Group R;

• Endoscopy times and intubation times were also significantly different:

• Being shorter in Group R (P<0.007 and P<0.023, respectively).

• Patient tolerance of the procedure, judged by the discomfort scores (P<0.004);

• And the post-intubation scores (P<0.08),

• It was significantly better in Group R.

• The level of recall for events was higher in Group R.

• No significant differences in the patient satisfaction scores.

• TCI Remifentanil appears to provide better conditions for AFOI when compared with TCI Propofol .

• The disadvantage of TCI Remifentanil in this setting:

• A higher incidence of recall.

TCI Propofol

A comparison of three different TCI RF rates during TCI PR for oocyte retrieval.

• Coskun D, Gunaydin B, Tas A, Inan G, Celebi H, Kaya K. A comparison of three different target-controlled remifentanil infusion rates during target-controlled propofol infusion for oocyte retrieval. Clinics (Sao Paulo). 2011;66(5):811-5.

• Department of Anaesthesiology and Reanimation, Faculty of Medicine, Gazi University, Ankara, Turkey. dcoskun@gazi.edu.tr

TCI RF rates during TCI PR for oocyte retrieval.

• It has been evaluated the effects of three different TCI Remifentanil infusion rates during TCI Propofol:

• Hemodynamic Parameters, • Pain, • Sedation, • Recovery Score during oocyte retrieval.

• 210 women were scheduled for oocyte retrieval.

• TCI Propofol at an effect-site concentration of 1.5 μg/mL.

• The patients were to receive Remifentanil at an effect-site concentration of either:

• 1.5 ng/mL (group I, n = 70), • 2 ng/mL (group II, n = 70) or • 2.5 ng/mL (group III, n = 70).

• Hemodynamic variables, • Sedation, • Pain, • The Aldrete recovery score, and • Side effects • Were recorded.

TCI RF rates during TCI PR for oocyte retrieval

• Hemodynamic variables, • Sedation and • Pain scores and • The number of patients with the maximum Aldrete

recovery score 10 min after the procedure • Were comparable among the groups.

• The number of patients in group III with the maximum Aldrete recovery score 5 min after the procedure was significantly lower than that in groups I and II.

• One patient in group II and one patient in group III suffered from nausea.

• Similar pain-free conscious sedation conditions without significant changes in hemodynamic parameters were provided by all three protocols.

• However, TCI of Remifentanil at TCI RF -1.5 or TCI RF 2 ng/mL proved superior at providing early recovery;

• Compared to TCI RF - 2.5 ng/mL.

Reliability of TCI Propofol in obese patients

• Igarashi T, Nagata O, Iwakiri H, Negishi C, Ozaki M.

• Reliability of propofol target-controlled infusion in obese patients.

• Masui. 2009 Oct;58(10):1226-31.• Department of Anesthesia, Saiseikai Kawaguchi

General Hospital, Kawaguchi 332-8558.

• TCI Propofol is now commonly used for induction and maintenance of anesthesia.

• It has been measured the Propofol plasma concentrations in obese patients in order to test our hypothesis that Propofol TCI is reliable for use in obese patients.

• It has been measured plasma concentrations of propofol in 100 obese patients undergoing elective general anesthesia.

• Propofol TCI was commenced at a target plasma concentration of 4ug/ml using a TCI pump.

• The target concentration was kept at 4ug/ml for at least 3 hours.

• Arterial blood samples were drawn for measurement of the propofol plasma-concentration analysis at 30, 60, 90, 120 and 180 minutes after the induction of anesthesia, and at the emergence from anesthesia.

• The measured plasma concentrations of the drug were not significantly different from the target plasma concentrations and they showed no tendency to increase during the 3 hours of anesthesia.

• The measured plasma concentration at emergence was lower than the estimated value.

• TCI Propofol is a reliable method for maintaining anesthesia in obese patients.

• However, at emergency, the plasma concentrations lower than the estimated values in obese patients.

IV Tci Propofolthedoseofpropofol2012

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