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P. ZACHEEMD PhD
ALGEMEENZIEKENHUIS
STUIVENBERG
UNIVERSITAIREZIEKENHUIZENLEUVEN
HEM/91000P
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William Harvey (1578-1657)Exercitatio Anatomica de Motu Cordis
et Sanguinis in Animalibus"... Door een bloedvat af te binden, kunnen we aantonen dat het bloed van de slagaders naar de aders stroomt, reden om aan te nemen dat het bloed continu circuleert met het hart als aandrijfkracht.De vraag is nu of dit is bedoeld voor de voeding ofvoor het behoud van bloed en longen door warmte tetransporteren , zodat het in armen en benen afgekoelde bloed in het hart opnieuw wordt opgewarmd. ..."
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Transport and communication system
Host DefenceCoagulationOncotic pressureNutrient & wasteThermoregulationOxygen carrier
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Cell membrane
O2
2,3 DPG
a1
a2 b
2
b1
molecule
(tetramer)
O2
2,3 DPG
a1
a2 b2
b1
Hemoglobin molecule(tetramer)
HEM/90213P
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Bloodtransfusion
�Goal:� increase in D02 and VO2
�Strategy:� fluid ---> to optimalise the fillingpressure� RBC-mass ---> to increase the DO2
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Pulmonary factorsdiffusion
Pa02 VentilationPerfusion
FiO2 (altitude)
HB concentration
Sa02
(=220-age)Sinus node dysfunctionDrugs ( B-blockers)
Genetic factorsHeart size
Conditioning factorsContractilityAfter LoadPreload
Disease factorsWall motionVentricular functionValve stenosis or regurgitation
500 ml/min/m2
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Influence of packed cell volume (PCV) on the relative oxigen transport capacity of blood
110
90
70
50
30
10
200
150
100
50
0
20.0
15.0
10.0
5.0
10 30 50 70
Relative oxigen transport capacity
Viscosity
Hemoglobin
Hem
oglo
bin
(%)
Visc
osity
(cP)
PCV
Rel
ativ
eox
igen
tran
spor
t cap
acity
(%)
HEM/90221P
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Pulmonary factorsdiffusion
Pa02 VentilationPerfusion
FiO2 (altitude)
HB concentration
Sa02
(=220-age)Sinus node dysfunctionDrugs ( B-blockers)
Genetic factorsHeart size
Conditioning factorsContractilityAfter LoadPreload
Disease factorsWall motionVentricular functionValve stenosis or regurgitation
Skeletal musclesAerobic enzymesFiber typeMuscle disease
Capillary density
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Cardiogenic shock Septic shock
800600400200
015010050
06420
DO2ml/min/M2
VO2ml/min/M2
lactatemEq/L
Pretransfusion Posttransfusion
HEM/90222P
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Why increase in DO2 and not in VO2?
• Low 2,3-DPG in packed cell• reduction in RBC deformability• Increase in blood viscosity• dysfunction in the microcirculation• Heterogenicity in vascular conductivity
• High flow (vasodillatation) increase in DO2 when high HT• Low flow (vasoconstriction) increase in DO2 when low HT
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BLOOD substitution Clinical situation
• Preoperative status• Chronic anaemia• Acute anaemia
• Bleeding• Acute operation• Sepsis ICU patiënt
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Jehovah’s Witnesses
� Agree with EPO, IV Fe, folinic acid, PFC, human HBOC, recombinant HBOC, PFC
� Not agree with transfusion allo or auto, mammalian HBOC
� General rule: avoid risk situations for your patients
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Preoperative status
• Cardiopulmonary evalutation• Correction of anaemia before operation• Correction of coagulation disorders: anamnesis, PTT,
APTT, fibrinogen, PFA, platelet count• If large bloodloss is expected: 4 U PC
• Pre-op IV EPO 300-500U/Kg IV D-3 to D+2• folinic acid 15 mg IV /d D-3 to D+5• IV iron 200 mg D-3 to D0
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Hem
atoc
rit(1
/1)
Tfr/f
tn
1500
1000
500
0
0 5 10 15 20 25Time (days)
0.46
0.44
0.42
placebo (n=10)rHuEpo (n=19)
Gareau et al, 1996 HEM/70675M
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45
35
25
150 4 8 12 16
Weeks of rHuEpo Therapy
Hem
atoc
rit(%
)500 U/kg
150 U/kg
50 U/kg
15 U/kg
Brown et al, 1993 ACZA 2 PZ
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Pharmacokinetics of EPO
300 E/Kg SC op D1EPO in serum (mE/ml) 300 E/Kg IV op D1
10000
1000
100
108 24 36 48185 15 302 12
Tijd (uren)
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FLUORESENCE INTENSITY FLUORESENCE INTENSITY
BEFORE: rH-EPO AFTER: rH-EPOfr
eque
ncy
f req
uenc
y
Effect of EPO on reticulocyte age in CHD patients
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RBC enzymes during EPO therapy
10067.637.588 +/- 70Retic X109/L
16.9514.6710.7210.6-16.2DPG umol/g Hb
3.363.53.61.97-3.29ATP umol/gHb
7.195.955.654,10-7.90G6PD U/gHb
9.849.097.893.80-12.0PK U/gHb
1.711.521.090.64-0.90Hx U/gHb
During EPOAfter 1 mthBefore EPONl Limits
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Chronic anaemia
�Hematological consult + adapted treatment�Hematological growth factors, substitution of
deficiencies�Pharmacological agents for prophylaxis and treatment
of bleeding (e.g tranexamic acid, epsilon-aminocaproic acid, aprotinine, desmopressin)
�Restricted phlebotomy for laboratory tests�Hormone manipulation to control menstrual blood loss�Supplemental oxygen to alleviate symptoms of anaemia�(Oxygen-carrying red-cell substitutes) no effect
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Pulmonary factorsdiffusion
Pa02 VentilationPerfusion
FiO2 (altitude)
HB concentration+ P50
Sa02
(=220-age)Sinus node dysfunctionDrugs ( B-blockers)
Genetic factorsHeart size
Conditioning factorsContractilityAfter LoadPreload
Disease factorsWall motionVentricular functionValve stenosis or regurgitation
Skeletal musclesAerobic enzymesFiber typeMuscle disease
Capillary density
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Acute Anaemia
• Maintain Q, peroperativ hemodilution• Reduction of transfusion trigger
• except: cardio&pulmonary disease, old age, betablockers• Normovolemic hemodilution
• Pre-op 750-1500 ml, compensation with colloÏd:cristaloid• decrease in bloodviscosity, increase of Q, increase of coronary
flow, increase in O2 extraction• When 20% loss of RCM is expected• Except: cardio&pulmonary disease, old age, betablockers, renal
disease, coagulation disorders, fever, pain, or when VO2 is increased.
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Acute Anaemia• Blood cell salvage per and post operatively
• Except in the presence of infection• Reduction in bleeding
• Anesthesical and surgical techniques: controled hypotension, loco-regional, endoscopic, operation field on the top, disection with laser or electro-cauter, bone waks.
• Pharmacological agents for prophylaxis and treatment of bleeding
• Resticted phlebotomy for laboratory tests• Hormone manipulation to control menstrual blood loss
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Acute Anaemia
• Supplemental oxygen to alleviate symptoms of anaemia• IV EPO 300-500U/Kg IV • folinic acid 15 mg IV /d• IV iron if needed (cave infection)
• Oxygen cariers
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• Can be used immediately• Can be stored in a ready-for-use• formulation for years• Without transfusion reactions (non-antigenic, non-
toxic, non-pyrogenic, virus free)• The same O2 carrying capacity and delivery to the
tissues as RBC's• Adequate colloid oncotic pressure• Adequate survival in the circulation
HEM/90846P
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�
�
HEM/90851P
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O2
2,3 DPG
a 1
a2 b2
b1
HAEMOGLOBIN
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0 20 40 60 80 100 120
Partial pressure of oxygen (mmHg)
0
20
40
60
80
100
Hb
Sat u
ratio
n (%
)
2,3 DPG 2,3 DPG
pH pH
arterialvenous
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-COOPERATIVITY (heme/heme interaction)- 16 mmHg
-2,3 DPG-BOHR effect :
-CO2-Cl--PH
-HILL number (log function of the slope at P50)-2,7-3,1
-TEMPERATURE
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������
��� ���
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O2
2,3 DPG
a 1
a2 b2
b1
HAEMOGLOBIN
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O O +H Hb HbO + H +HbO H Hb+O O
2CO 2CO2CO
H O2
3H CO2
22 22
+
+2 2
ERYTHROCYTETISSUES LUNGS
CA
+
Cl - Cl-3HCO-
3HCO-3HCO-
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DPG
��� ���
��� ���DPG
��� ���
��� ���2
���
���
���
���
���
���
���
���
DPG
��� ���
������
2
22
NL= 2,7 – 3,1
1= high affinity Hb
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OXY-Hb --> DEOXY-HbP50 > 30 mmHg
-COOPERATIVITY <16 mmHg
-2,3 DPG-BOHR effect
-Low PH-High CL-
-High C02-HILL number (log function of the slope at P50)
>2,7-3,1-TEMPERATURE
-High temperature
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High-affinity, noncooperative, cell-free hemogobin
P50
H+CO22,3-DPGCl-temperature
0 20 40 60 80 100 120 140 PO2 (Torr)
Saturation (fraction) Normal blood
0.8
0.6
0.4
0.2
0.0
ACZA 1PZ
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O2
a1 b1• Low P50 (no 2,3-DPG)• Tetramer to Dimers• Low half-life (1-2hrs)• Iso-oncotic at 7 g/dl• Renal toxicity• Vasoconstriction
a2 b2
a1b1
a2 b2
HEM/70565P
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Hypertension & gastrointestinal• Stroma• NO
Ca2+ NO synthase activity
NO Citrulline L-Arginine
Endothelial cell
Guanylate cyclase activity (Fe 2+ )
Smooth muscle cell
blood
GTP cGMP Ca2+ Vasodilation
Hb Fe2+ Stimuli (Ach)
HEM/90872P
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• To decrease oxygen affinity
• To prolong intravascular retention
• To decrease colloid osmotic activity
• To prevent toxicity (renal & extravasation & hypertension & gastrointestinal)
HEM/90850P
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bis-(3.5-dibromosalicyl) fumaratecross-link two a subunitsmodifying the 2.3-DPG pocket (increase in P50)Diaspirin cross-linked tetrameric Hb Phase III trials
O 2
a 1
a 2 b2
b1
O 2
O 2 O 2
HEM/90857P
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• engineered in E-coli• prevent breakdown of the tetramers• high P50
b2
b1a1
a2
HEM/90858P
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• glutaraldehyde cross-linking• pyridoxal phosphate increase the P50
• bovine poly Hb P50 is controlled by Cl
a1
a 2 b 2
b1
PLPPLP
a1
a 2 b 2
b1
PLPPLP
a1
a 2 b 2
b1
PLPPLP
Tetrameric Hb < 1%
HEM/90856P
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O2
a1
a 2 b2
b1
O2
O2 O2
PLPPLP
POE POE
POEPOE
POE
POE
POE
POE
O 2
a 1
a 2 b2
b1
O 2
O 2 O 2
PLPPLP
POE POE
POEPOE
POE
POE POE
O 2
a 1
a 2 b 2
b1
O 2
O 2 O 2
PLPPLP
POE POE
POEPOE
POE
POE
• dextran• polyoxyethylene• polyethylene glycol
HEM/90859P
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� Limiting binding of NO by extravascular Hb� Half-life reduced due to removing by spleen and liver� Interaction with granulocytes and immune system
2,3 DPG
a1
a2 b2
b1
2,3 DPG
a1
a2 b2
b1
2,3 DPG
a1
a2 b2
b1
2,3 DPG
a1
a2 b2
b1
2,3 DPG
a1
a2 b2
b1
2,3 DPG
a1
a2 b2
b1
2,3 DPG
a1
a2 b2
b1
0.2µm NO
HEM/90866P
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P50 of some new hemoglobins
49.5 mmHg5.6 g/dlNeo Red Cells® Terumo (human Hb)
Encapsulated Hb
ca. 15 mmHg6 g/dlPEG-Hb Enzon (bovine Hb)
Polymerized-conjugated Hb
38 mmHg13 g/dlHemopure® Biopure / Upjohn (bovine Hb)
34 mmHg10 g/dlHemolink® Hemosol (human Hb)
28-30 mmHg10 g/dlPolyHeme® Northfield (human Hb)
Polymerized Hb
32 mmHg5-8 g/dlOptro® Somatogen / Eli Lilly (rHu-Hb)
32 mmHg10 g/dlHemAssist® Baxter (human Hb)
Crosslinked Hb (intramolecular)P50Hb concentration
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Hill coefficient of some new hemoglobins
n.a.5.6 g/dlNeo Red Cells® Terumo (human Hb)Encapsulated Hb
16 g/dlPEG-Hb Enzon (bovine Hb)Polymerized-conjugated Hb
n.a.13 g/dlHemopure® Biopure / Upjohn (bovine Hb)110 g/dlHemolink® Hemosol (human Hb)
n.a.10 g/dlPolyHeme® Northfield (human Hb)Polymerized Hb
2.275-8 g/dlOptro® Somatogen / Eli Lilly (rHu-Hb)n.a.10 g/dlHemAssist® Baxter (human Hb)
Crosslinked Hb (intramolecular)Hill coefficientHb concentration
HEM/00492M
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COP of some new hemoglobins
25 mmHg5.6 g/dlNeo Red Cells® Terumo (human Hb)
Encapsulated Hb
ca. 100 mmHg6 g/dlPEG-Hb Enzon (bovine Hb)
Polymerized-conjugated Hb
17 mmHg13 g/dlHemopure® Biopure / Upjohn (bovine Hb)
24 mmHg10 g/dlHemolink® Hemosol (human Hb)
n.a.10 g/dlPolyHeme® Northfield (human Hb)
Polymerized Hb
16 mmHg5-8 g/dlOptro® Somatogen / Eli Lilly (rHu-Hb)
43 mmHg10 g/dlHemAssist® Baxter (human Hb)
Crosslinked Hb (intramolecular)
COPHb concentration
HEM/00493M
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Circulation storage shelf life & half life
ca. 44 h1 year frozenPEG-Hb Enzon (bovine Hb)Polymerized-conjugated Hb
ca. 24 h2 years room temperature
Hemopure® Biopure / Upjohn (bovine Hb)
ca. 14 h2 years refrigeration
Hemolink® Hemosol (human Hb)
24 h12 months refrigeration
PolyHeme® Northfield (human Hb)Polymerized Hb
4-5 h18 months refrigeration
Optro® Somatogen / Eli Lilly (rHu-Hb)ca. 14 hn.a.HemAssist® Baxter (human Hb)
Crosslinked Hb (intramolecular)CirculationShelf life storage
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Viscosity of some new hemoglobins
2 cP5.6 g/dlNeo Red Cells® Terumo (human Hb)Encapsulated Hb
n.a.6 g/dlPEG-Hb Enzon (bovine Hb)Polymerized-conjugated Hb
1.3 cP13 g/dlHemopure® Biopure / Upjohn (bovine Hb)1 cP10 g/dlHemolink® Hemosol (human Hb)n.a.10 g/dlPolyHeme® Northfield (human Hb)
Polymerized Hbn.a.5-8 g/dlOptro® Somatogen / Eli Lilly (rHu-Hb)
1.1 cP10 g/dlHemAssist® Baxter (human Hb)Crosslinked Hb (intramolecular)
ViscosityHb concentration
HEM/00495M
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Clinical Use
Phase IIRadiosenstive, chemosensitive tumors; volume
expansion
PEG-Hb Enzon (bovine Hb)Polymerized-conjugated Hb
Phase IIIElective surgery, sickle cell crisis
Hemopure® Biopure / Upjohn (bovine Hb)
Phase IIICardiac, orthopedic surgery;
erythropoiesis
Hemolink® Hemosol (human Hb)
Phase IIITrauma, elective/emergency
surgery
PolyHeme® Northfield (human Hb)Polymerized Hb
preclinicalCardiac bypassOptro® Somatogen / Baxter (rHu-Hb)Crosslinked Hb (intramolecular)
Regulatory phase
Potential clinical use
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Artificial O2 carriersThe modified hemoglobin-based solutions are grouped by the
source of the hemoglobin• Modified Hemoglobin-Based Solutions
• Derived from Outdated Human Red Cells• Polymerized hemoglobin (PolyHeme®, Northfield) (phase III clinical trials)• Polymerized and cross-linked hemoglobin (Hemolink®, Hemosol) (phase III clinical
trials) • Pyridoxalated hemoglobin polyoxyethylene conjugate (PHP, Apex Bioscience)
(phase III clinical trials) • Diaspirin cross-linked hemoglobin (HemAssist®/DClHb®, Baxter) (discontinued)
• Derived from Bovine Red Cells• Polymerized Purified Bovine Hemoglobin (HemoPure®, Biopure) (phase III clinical
trials) • Polyethylene-Glycol Modified-Bovine Hemoglobin (PEG-Hgb®, Enzon) (phase Ib
clinical trials)• Recombinant Human Hemoglobin
• E. coli46 (Optro® /rHb1.1, Somatogen/Baxter) (discontinued) Transgenic tobacco47
(preclinical)HEM/00501M
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�
�
HEM/90870P
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O2
PERFLUOROCARBON40-50% O2 dissolvingcapacity for 100% pure oxygen
HEM/90211P
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High gas-dissolving capacity(O and CO )Low viscosityChemical and biologic inertInsoluble in water
,
,,,
F
F
C
C
C
C
C
C
C
C
C
C
F2F2
F2
F2 F2
F2
F2
F2
F-decalin (Fluosol-DA)
C
C
C
C
C
C
C
F3
F2 F2F2 F2
F2 F2 F2
Br
F-octylbromide (oxygent)
2 2
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Emulsion of 0.1-0.3 umSurface active agent (surfactant)
poloxamer:Pluronic F-68 (Fluosol-DA) (allergic reactions)egg-yolk phospholipide
T 1/2: 4 to 7 daysexhalation or phagocytosis (RES)Problem: coalescence of the emulsion
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Compared solubilities of the respiratory gases in perfluorocarbons and their emulsion
15.350% Emulsion of perfluorooctylbromide (perflubron)707.520% Emulsion of F-decalin (Fluosol)
50Perfluorooctylbromide C8F17Br13045F-decalin16645.3F-tripropylamin N (C4F7)3
14240.3F-tributilamin N (C4F9)3
7020Blood652.3H2O, plasma
CO2O2
O2 and CO2 solubilities in fluorochemicals and their emulsions(ml/dL, 37°C, 1 atm)
Clark et all, 1982HEM/00483M
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Comparisons between 1st and 2nd generation in perfluorocarbon emulsions
Egg yolk phospholipidsEmulsifierPluronic F-18 +++
Egg yolk phospholipids
17.2 ml/dlO2 carrying capacity5-7 ml/dl1.96Density1.96
30% vol/volConcentration10-11% vol/vol
Perfluoro-octylbromidePFCPerfluoro-
tripropylamidePerfluoro-
decalin
7
7.5 (10ml/kg)14.5 (20ml/kg)22 (30ml/kg)
< 600 nM
7 (1.8g/kg)Half-live tissues (days)65
4 (2.7g/kg)Half-life iv (hours)
< 250 nmSize of micelles
PerflubronFluosol DA
HEM/00485M
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Oxygen equilibrium curves Hemoglobin attains nearly complete saturation at the
arterial oxygen partial pressure 100 mmHgBlood 14g/dl
Hemogobin 7g/dl
100 200 300 400 PO2 (Torr)
25
20
15
10
5
PFOB
Fluosol-DA 20%O2
cont
ent (
ml/d
l)
HEM/00489M
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Artificial O2 carriersThe modified hemoglobin-based solutions are grouped by the
source of the hemoglobin
• Perfluorocarbon (PFC) Emulsions• Perflubron (Oxygent®, Alliance/Baxter) (phase III clinical trials) • Emulsified perfluorodichlorooctane (Oxyfluor® ,
HemaGen/PFC) ( discontinued)
• ‘First-Generation’ PFC emulsions• Fluosol® (Green Cross, Japan) (discontinued)• Perftoran (Russia)
HEM/00502M
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Future• Blood poisoning: CO, CN-,etc.• Converting hypoxic cells in the center of the tumor to
aerobic metabolism, increasing susceptibility to radiation and chemotherapy
• Temporary vitreal replacement• Organ preservation• Radiology (CTscan, NMR) perfluorooctyl bromide• Assessment of tissue oxygenation• Ischaemia and microcirculatory disturbances• Liquid ventillation
HEM/90871P
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Advantages and disadvantages of hemoglobin-based solutions
• Advantages• Carries and unloads O2
• Sigmoidal O2 dissociation curve• 100% FiO2 is not mandatory for maximal potency• Easy to measure
• Disadvantages• Side effects
• Vasoconstriction• Interference with colorimetric laboratory methods
HEM/00503M
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Advantages and disadvantages of perfluorocarbon (PFC)
• Advantages• Carries and unloads O2• Few and mild side effects• No known organ toxicity
• Disadvantages• 100% FiO2 is mandatory for maximal efficacy• Additional colloid often necessary with potential
side effects
HEM/00504M
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Albert Einstein
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25 to 30 %
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Limit of efficacy
• intravascular persistence only a few hours & days
• colloid osmotic activity• vasoactive• oxidation to methemoglobin• reperfusion injury
HEM/90862P
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• Hemostasis: Hb binds NO � vasoconstriction and increased platelet adhesion
• Vasoactivity• execessive delivery of O2 to arterioles � increase in endothelin
� vasoconstriction • Binding of NO
• Gastrointestinal side effects (NO)• Immunosuppression• Interference with laboratory assays
HEM/90861P
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PFC side effects
• Flu-like symptoms
• Sequestration in spleen and liver• Hepato & splenomegaly• thrombocytopenia