0dbepropofol study orlando1.ppt

8/10/2019 0dbePropofol study Orlando1.ppt

1/34

Diprivan (Propofol) SequestrationDuring Cardiopulmonary Bypass

Gerard J Myers CCP , Cheri Voorhees BAH(ASCP)SH ,

Bob Eke BA and Ren Ren Johnston
http://images.google.ca/url?source=imgres&ct=tbn&q=http://www.sportnovascotia.ca/Portals/0/images/sponsor/sidebar/mhc_side.jpg&usg=AFQjCNFrg_7w0MWus_2aIalwI5Eyc_VVGwhttp://images.google.ca/url?source=imgres&ct=tbn&q=http://www.rjrinnovations.com/edocs/UserGroups/images/CHlogoColor.jpg&usg=AFQjCNE6ei4ENZFrL1uORh7CZGEPspsb1Ahttp://images.google.ca/url?source=imgres&ct=tbn&q=http://www.teamt.us/images/SorinGroup_Logo.jpg&usg=AFQjCNFWmzsmztnvbDx3nyNFiBM_8A5smghttp://images.google.ca/url?source=imgres&ct=tbn&q=http://skrueger-3.physiology.dal.ca/%257EActiveZone/img/Logo.jpg&usg=AFQjCNF3GkgU5ebrfzCkVml64piLHGScLA


2/34

Intravenous hypnotic agent that is estimated to be

used in 1 of every 2 operations undertaken

worldwide

(making it the world`s leading I.V general anesthetic agent)

White oil in water emulsion with a pH 6.0-8.5. Oil

made of soybean (100 mg/ml), glycerol (22.5mg/ml) and egg phospholipid (12.0 mg/ml). Also

contains disodium edetate and sodium hydroxide.

Diprivan (Propofol)


3/34

Propofol

Induction (1.5-3.0 mg/kg)

Maintenance 2.0-6.0 mg/kg/hr)

Highly fat soluble and widely distributed

throughout body and tissues Rapidly acting (< 60 sec.)

Metabolized by the liver/excreted in urine

97-98% protein bound

Unbound fraction is < 3-4%

Renal disease, liver dysfunction andhypothermia can alter drug pharmacokenetics


4/34

Extraneous Propofol Concerns ??

The styrene based plastic luer lock collar was shattered by what

was believed to be the constant infusion of the Propofol

emulsion. Exact reason was not fully understood.(Rutherford, JS et al: Effect of Propofol on plastic components Anesth 2005, 60:1046)

Plastic upper casing of two syringe pumps (used exclusively for

propofol infusions) developed multiple cracks. Pump

manufacturer stated Propofol was originally developed asplasticizer and not an anesthetic.

(Fujise, K et al: Damage to a syringe pump by Propofol Anesth 2005, 60:1045)


5/34

Sequestration of Propofol in an Extracorporeal Circuit

Methods:First in vitro study using 4 Uncoated Cobe CML oxygenatorswith uncoated tubing and arterial filters. 2000 ml Hartmanns solution/ 2

units PRBC. Hct was 21-25%. Blood flows 5 lpm at 37oC. Propofol 10

mg was added to perfusate to achieve concentration of 2-4 mcg/ml.

Samples taken 18 times over 4 hour period. Total propofol

measurements were done using HPLC method.

Conclusion:They found that the total propofol levels at the start of CPBfell by an amount greater than 50% in 15 minutes. This was more than

the decrease predicted by hemodilution alone, and therefore surface

sequestration was an important factor. Total propofol continued todecrease during the course of the study.

Tarr, TJ and Kent, AP : J Cardiothoracic Anes 1989 3(1):75


6/34

Propofol sequestration within the extracorporeal circuit

Methods: Study consisted of in vitro and in vivo groups. In vitro groupconsisted of three uncoated membranes with uncoated silicone and PVC

tubings, with no arterial filter. Total prime volume was 2000 mls (Ringers

and 2 units whole blood). Pump flow was 4 lpm at 28oC for 120 minutes.

Propofol 4 mg was infused to achieve a level of 2 mcg/ml and Total

Propofol was measured using HPLC. In vivo group consisted of 14 patients

undergoing CPB and Propofol infusion was between 3-10 mg/kg/hr

throughout cases.

Results: After infusion, in vitro total Propofol decreased by 35% after 5

minutes and 75% after 120 minutes of circulation. Similar decreases in totalpropofol levels were found with the in vivo study group. Hemodilution

contributes to decreases in total propofol, but continued decrease due to

sequestration.

Hynynen M et al: Can J Anaesth 1994; 41(7):583-8


7/34


8/34

Total Propofol vs Unbound Propofol

Measurement of Total drug concentrations in plasma during

CPB may fail to elucidate the true picture of changes in

drug effect unless measurement of the Unboundconcentration is also reported

The ability of a drug to produce its effect on the body

depends on the ability of the Unbound drug to reach itsreceptor and bind with that receptor to transduce its

signal


9/34

The effects of cardiopulmonary bypass on total and

unbound plasma concentrations of propofol

Methods:Twelve patients undergoing cardiac surgery were given 1mg/kg Propofol preop followed by 3 mg/kg/hr intraop. Membrane

oxygenation with a prime that consisted of Plasmalyte and Haemaccel

and temp maintained at 30oC. Total propofol measured by HPLC

method and Unbound propofol measured by ultrafiltration.

Conclusion: At the start of CPB, total propofol levels dropped by >58%but after 6 minutes, the unbound propofol levels actually increased from

1.97 0.36 ng/ml to 2.18 0.43 ng/ml (9.7%). They concluded that total

propofol decreases were consistent with hemodilution and sequestration.

Unbound increases were believed to be due to hemodilution of protein

and displacement of bound drug by protein binding site competition

from plasma free fatty acids

Dawson PJ et al: J Cardiothorac Vasc Anesth 1997 Aug;11(5):556-61


10/34

Changes in the effect of propofol in response to

altered plasma protein binding during normothermic

cardiopulmonary bypass

Methods:Randomized study included 30 patients undergoing CPB forcardiac surgery. Prime consisted of 1600 mls Ringers with flows 2.4

l/m2/min at temps >35oC. Total propofol measured by HPLC and unbound

propofol measured by equilibrium dialysis. Measurements done at intervalsup to 60 minutes after start of CPB.

Conclusion:Initial drop in total propofol levels at the start of CPB, butreturned to prebypass values after 30 minutes. They concluded that

variations in total propofol levels were consistent with the effects of

hemodilution of albumin/erythrocytes and volume distribution. There was

also a two fold increase in the unbound propofol concentration during CPB.

Takizawa E et al: Brit J Anaesth 2006; 96(2):179-85


11/34

Propofol adsorption has been studied onuncoated and heparin coated circuitry

Propofol is a lipid emulsion

Is Propofol adsorption reduced by

Phosphorylcholine (phospholipid) coated

surfaces during extracorporeal circulation?

Does Propofol affect oxygenation and CO2

removal in PC coated membranes?


12/34

Phospholipid based synthetic polymer

Industry only biomimetic (mimics endothelial

surfaces) coating made of both positive/negative PChead groups (zwitterionic)

Hydrophilic head groups adsorb water molecules and

render surface nonthrombogenic or biologically inert

to native circulation

Used on extracorporeal blood surfaces, coronary

stents, urological devices and tympanostomy tubes

Phosphorylcholine(PC, PHISIO, Mimesys)


13/34

3 hardshell PrimO2X oxygenatorswithout filters

3 hardshell PrimO2X oxygenators withDideco D732 (27 ) arterial filters

Lengths of circuits identical all

experiments All oxygenators/circuits were coated

with Phosphorylcholine

Study Circuit


14/34

1250 ml fresh bovine blood/750 ml

normal saline (total 2000 mls)

Mean hematocrit of 411.0%

Mean Total protein 3.7 0.5g/dl

Mean Lipids 81.6 19.0mg/dl Mean Temperature 34 degrees C

Mean Glucose 217 mg/dl

Circuit Prime


15/34

Mean ACT >1500 seconds

4.5 LPM Blood flow

Line pressure maintained 150 5mmHg

Total Propofol and UnboundPropofol

Management


16/34

1ststage - Low Dose Propofol4 mg (2.0 mcg/ml)

21 ml sample taken 20 min, 40 min and 60 min

2ndstage High Dose Propofol40 mg (22.7 mcg/ml)


3rdstage Extreme Dose Propofol356 mg(214 mcg/ml)


Study Protocol

Propofol 1% (10mg/ml)


17/34

Collected samples were placed in 10 ml blood

tubes containing 143 units Sodium Heparin

and centrifuged for 10 minutes at 3000 RPMand 4oC within 5 minutes of collection.

Separated plasma was then placed in LowTemperature Freezer Vials tubes and stored at

70 degrees C until assayed.

Sample Preparation


18/34

Both Total and UnboundPropofol testing was done by anindependent GMP/GLP laboratory in Colorado

All samples were analyzed on an Applied Biosystems 4000QTrap tandem mass spectrometer equipped with two

Shimadzu LC-20AD pumps and a Leap HTC PALautosampler. Chromatography was performed on a 50 mm x

4.6 mm Sunfire C18column

Unbound Propofol was determined through diffusion, by adding500 L of plasma to a Nanosep 3,000 daltons centrifugal filter.

The plasma was centrifuged for 10 minutes at 13,000 rpm

High Performance Liquid ChromatographySample Assay


19/34


20/34

0.330.41

2

1.66

1

2

0.36 0.280.4

2

0.44

0

0.5

1

1.5

2

2.5

Calc 20 40 60

minutes

mcg/ml

Oxy 1 Oxy 2 Oxy 3

Total PropofolWith Arterial Filter

(2 mcg/ml)


21/34

22.7

9.789.79

12.7

22.7

11.5

11.510.5

9.6910.1

22.7

11.3

0

5

10

15

20

25

Calc 20 40 60

minutes

mcg/ml

Oxy 4 Oxy 5 Oxy 6

Total Propofol

No Arterial Filter(22.7 mcg/ml)


22/34

13.515.1

11

22.7

11.1

11.611.1

22.7

11.9

22.7

11.49.4

0

5

10

15

20

25

Calc 20 40 60

minutes

mcg/ml

Oxy 1 Oxy 2 Oxy 3

Total Propofol

With Arterial Filter(22.7 mcg/ml)


23/34

119117

214214

121

132

214

132

214

136

153

150

0

50

100

150

200

250

Calc 20 40 60

minutes

mcg/ml

Oxy 4 Oxy 5 Oxy 6

Total PropofolNo Arterial Filter

(214 mcg/ml)


24/34

136

119

214

132

214150

108

155

131

122

214

150

0

50

100

150

200

250

Calc 20 40 60

minutes

mcg/ml

Oxy 1 Oxy 2 Oxy 3

Total PropofolWith Arterial Filter

(214 mcg/ml)


25/34

20 minutes

%

40 minutes

%

60 minutes

%

No Arterial

Filter

45.0 14.5 22 12.1 47 34

Arterial

Filter

19.9 3.2 21 27.3 16.3 64

Low Dose(2 mcg/ml)Percent of Total Propofol remaining in blood

(Bound + Unbound)


26/34

20 minutes

%

40 minutes

%

60 minutes

%

No Arterial

Filter

50.7 5.1 44.5 6.2 43.1 3.1

Arterial

Filter

52.4 7.1 51.1 14.1 48.5 7.3

High Dose(22.7 mcg/ml)Percent of Total Propofol remaining in blood

(Bound + Unbound)


27/34

20 minutes%

40 minutes%

60 minutes%

No Arterial

Filter

70.1 29.1 61.7 9.8 56.5 6.9

Arterial

Filter

70.1 9.8 61.2 8.8 57.0 6.5

Extreme Dose(214 mcg/ml)

Percent of Total Propofol remaining in blood

(Bound + Unbound)


28/34

0.46

0.61

0.35

0.66

0.43

0.31

0.17

0.52

0.34

0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

P

e

r

c

e

n

t

20 40 60

Minutes

2.0 mcg/ml 22.7 mcg/ml 214 mcg/ml

Unbound PropofolPercent of Total


29/34

Coating of extracorporeal surfaces withPhosphorylcholine does notprevent

the adsorption of Propofol under in

vitroconditions

Adsorption Conclusion


30/34

Does Propofol alter the gas exchange in

membrane oxygenators?

In vitro (n=10) and in vivo (n=10) studies into gas exchange and

oxygenation during clinically relevant doses of Propofol during

extracorporeal circulation.

In vivostudy involved BGA 30 min after infusion of 125 mg

Propofol on bypass.In vitrostudy used crystalloid primed

oxygenators, with an FiO2 of 100% and a gas:blood ratio of 1:1.

In vitroBGA were collected 30 sec. after 100 mg bolus of

Propofol and 30 sec. after bolus dose of 200 mg Propofol.

In both arms, they concluded that at clinically relevant doses,

Propofol does not adversely affect gas exchange or oxygenation.

Nader-Djalal, N et al: Ann Thorac Surg 1998;66:298-99


31/34

Blood Gas Analysis

Radiometer ABL500 Blood Gas analyzer

BGs done at 20, 40 and 60 minutes after each

Propofol injection on each oxygenator studied

FiO2 was 21% and flow was 3.1 Lpm Air with

0.4 Lpm CO2 throughout experiment

Mean pH 7.38, PCO2 41.8, PO2 119,BE -0.8


32/34

OxygenAfter 180 Minutes of Circulation

119.5

118.2

117.3

118.7

116

117

118

119

120

1 2 3 4 Baseline 60 min 120 min 180 min

PO2mmH

g

p=ns

00


33/34

Carbon DioxideAfter 180 Minutes of Circulation

42.5

41.741.6

40.8

39

40

41

42

43

1 2 3 4 Baseline 60 min 120 min 180 min

PCO2mm

H

p=ns


34/34

Gas Exchange Conclusion

After 180 minutes of circulation and

exposure to 400 mg Propofol, there is

no in vitro evidence to suggest that

Propofol interferes with oxygenation

or carbon dioxide removal in the PCcoated PrimO2X oxygenator

0dbepropofol study orlando1.ppt

Documents