0dbepropofol study orlando1.ppt
TRANSCRIPT
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Diprivan (Propofol) SequestrationDuring Cardiopulmonary Bypass
Gerard J Myers CCP , Cheri Voorhees BAH(ASCP)SH ,
Bob Eke BA and Ren Ren Johnston
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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)
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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
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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)
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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
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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
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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
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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
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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
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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?
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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)
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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
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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
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Mean ACT >1500 seconds
4.5 LPM Blood flow
Line pressure maintained 150 5mmHg
Total Propofol and UnboundPropofol
Management
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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)
21 ml sample taken 20 min, 40 min and 60 min
3rdstage Extreme Dose Propofol356 mg(214 mcg/ml)
21 ml sample taken 20 min, 40 min and 60 min
Study Protocol
Propofol 1% (10mg/ml)
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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
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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
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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)
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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)
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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)
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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)
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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)
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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)
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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)
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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)
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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
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Coating of extracorporeal surfaces withPhosphorylcholine does notprevent
the adsorption of Propofol under in
vitroconditions
Adsorption Conclusion
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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
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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
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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
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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
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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