U.S. patent number RE38,081 [Application Number 09/776,144] was granted by the patent office on 2003-04-15 for method of hemodilution facilitated by monitoring oxygenation status.
Invention is credited to Nicholas Simon Faithfull, Ronald M. Hopkins, Peter E. Keipert, Duane J. Roth.
United States Patent |
RE38,081 |
Faithfull , et al. |
April 15, 2003 |
Method of hemodilution facilitated by monitoring oxygenation
status
Abstract
A method for hemodiluting a patient is disclosed which includes
the steps of administering a biocompatible oxygen carrier in
conjunction with surgery or organ ischemia or infarct while
assessing the patient's PvO.sub.2 or other oxygenation indices, and
administering to the patient additional oxygen carrier or
autologous blood in response to the PvO.sub.2 value if necessary to
maintain the PvO.sub.2 at or above the desired level.
Inventors: |
Faithfull; Nicholas Simon (La
Jolla, CA), Keipert; Peter E. (San Diego, CA), Roth;
Duane J. (La Jolla, CA), Hopkins; Ronald M. (Escondido,
CA) |
Family
ID: |
23923030 |
Appl.
No.: |
09/776,144 |
Filed: |
February 2, 2001 |
Related U.S. Patent Documents
|
|
|
|
|
|
|
Application
Number |
Filing Date |
Patent Number |
Issue Date |
|
Reissue of: |
484166 |
Jun 7, 1995 |
05865784 |
Feb 2, 1999 |
|
|
Current U.S.
Class: |
604/4.01;
604/6.14 |
Current CPC
Class: |
A61K
31/025 (20130101); A61K 33/00 (20130101); A61K
31/02 (20130101); A61P 7/08 (20180101); A61K
33/00 (20130101); A61K 2300/00 (20130101); A61K
31/025 (20130101); A61K 2300/00 (20130101); A61K
31/02 (20130101); A61K 2300/00 (20130101) |
Current International
Class: |
A61K
31/02 (20060101); A61K 38/41 (20060101); A61K
38/42 (20060101); A61K 31/025 (20060101); A61M
037/00 () |
Field of
Search: |
;604/4.01,5.01,6.01,6.14,6.11,6.15,16,19,27-8,48,59,503,506-508,514,518
;514/532,6,99,109,449,743,749,759 ;422/44-45 |
References Cited
[Referenced By]
U.S. Patent Documents
Foreign Patent Documents
|
|
|
|
|
|
|
091 183 |
|
Oct 1983 |
|
EP |
|
0 231 070 |
|
Aug 1987 |
|
EP |
|
0 627 913 |
|
Apr 1998 |
|
EP |
|
2515198 |
|
Apr 1983 |
|
FR |
|
58 32 829 |
|
May 1983 |
|
JP |
|
60 166 626 |
|
Jan 1986 |
|
JP |
|
WO 81/00002 |
|
Jan 1981 |
|
WO |
|
Other References
Messmer et al. "Oxygen Supply to the Tissues During Limited
Normovolemic Hemodilution" Res. Exp. Med. 159:152-166 (1973). .
Colt, "The use of stroma-free hemoglobin solution for partial
exchange transfusion in aortic resection in dogs", American J. of
Surgery, 135:656-663 (1978). .
Rice et al., "Blood and Blood Substitutes: Current Practice,"
Advances in Surgery, vol. 13, pp. 93-114, 1979. .
Homer et al., "Oxygen Gradients Between Red Blood Cells in the
Microcirculation," Microvascular Research, 22:308-323 (1981). .
K. Fukushima et al., "Clinical Experience of Hemodilution with
Fluosol-DA," Jpn. J. Anesthesiol, vol. 30, No. 7, pp. 741-745
(1981). .
Riess et al., "Reassessment of Criteria for the Selection of
Perfluorochemicals for Second-Generation Blood Substitutes:
Analysis of Structure/Property Relationships," Artificial Organs,
8(1):44-56 (1984). .
Winslow, R., "A Model for Red Cell O.sub.2 Uptake," International
J. of Clinical Monitoring and Computing, 2:81-93 (1985). .
Federspiel et al., "A Theoretical Analysis of the Effect of the
Particulate Nature of Blood on Oxygen Release in Capillaries,"
Microvascular Research, 32:164-189 (1986). .
Gutierrez, "The Rate of Oxygen Release and its Effect on Capillary
O.sub.2 Tension: A Mathematical Analysis," Respiration Physiology,
63:79-96 (1986). .
Messmer et al., "Present State of Intentional Hemodilution," Eur.
Surg. Res., 18:254-263 (1986). .
Gould et al., "Fluosol-DA As a Red Cell Substitute in Acute
Anemia," New England Journal of Medicine, 314(26): 1653-1656
(1986). .
Biro et al., "The Effect of Hemodilution with Fluorocarbon or
Dextran on Regional Myocardial Flow and Function During Acute
Coronary Stenosis in the Pig," Am. J. Cardiovascul. Pathol,,
1:1:99-114 (1987). .
Light et al., "Perfluorochemical Artificial Blood as a Volume
Expander in Hypoxemic Respiratory Failure in Dogs," Chest,
9:3:444-449 (1987). .
Riess et al., "Design, Synthesis and Evaluation of Fluorocarbons
and Surfactants for in Vivo Applications: New Perfluoroalkylated
Polyhydroxylated Surfactants" Int'l Symposium on Blood Substitutes,
Montreal pp. 421-430 (1987). .
Faithfull et al., "Peripheral Vascular Responses to Fluorocarbon
Administration," Microvascular Research, 33:183-193 (1987). .
Faithfull et al., "Critical Levels of O.sub.2 Extraction Following
Hemodilution with Dextran or Fluosol-DA," J. of Critical Care,
3:1:14-18 (1988). .
Greenwalt et al., "Perioperative Red Blood Cells Transfusion,"
JAMA, 260:18:2700-2703 (1988). .
Von Bormann, "Blutsparende Verahren--anasthesiologisch Aspekte,"
Unfallchirurgie, 4:194-200 (1989). .
Zauder, "Preoperative Hemoglobin Requirements," Anesthesiology
Clinics of North America, 8:3:471-480 (1990). .
Zuck et al., "Autologous Transfusion Practice," Vox Sang,
58:234-253 (1990). .
Vlahakes et al., "Hemodynamic Effects on Oxygen Transport
Properties of a New Blood Substitute in a Model of Massive Blood
Replacement," J. Thorac. Cardiovasc. Surg., 100:379-388 (1990).
.
Sheffield et al., "Preparation and in Vivo Evaluation of Two Bovine
Hemoglobin-Based Plasma Expanders," Biotechnol. Appl. Biochem.,
12:6:630-642 (1990). .
Trouwborst et al., "Blood Gas Analysis of Mixed Venous Blood During
Normoxic Acute Isovolemic Hemodilution in Pigs," Anesth. Analg.,
70:523-9 (1990). .
Riess, "Fluorcarbon-Based in Vivo Oxygen Transport and Delivery
Systems," Vox Sang, 61:225-239 (1991). .
Stehling, "Acute Normovalemic Hemodilution," Transfusion,
31:9:857-868 (1991). .
Mercuriali et al., "Autologous Blood," Transmedica Europe Limited,
pp. 1-30 (1991). .
Giordano et al., An Autologous Blood Program Coordinated by a
Regional Blood Center: A 5-Year Experience, Transfusion, 31:6:
509-512 (1991). .
Riess, "Overview of Progress in the Fluorocarbon Approach to In
Vivo Oxygen Delivery," Biomater. Artif. Cells Immobilization
Biotechnol., 20:2-4:183-202 (1992). .
Fennema et al., Myocardial Oxygen Supply Under Critical Conditions,
The Effects of Hemodilution and Fluorocarbons, Adv. Exp. Med.
Biol., 317:527-544 (1992). .
Keipert et al., "Enhanced Oxygen Delivery by Perflubron Emulsion
During Acute Hemodilution," Artif. Cells Blood Substit. Immobil.
Biotechnol., 22:4:1161-67 (1994). .
Weiskoff, "Mathematical Analysis of Isovlemic Hemodilution
Indicates That it Can Decrease the Need for Allogeneic Blood
Transfusion," Transfusion, 35:1:37-41 (1995). .
NIH Consensus Conference "Perioperative Red Blood Cell Transfusion"
JAMA 260(18): 2700-2703 (1988)..
|
Primary Examiner: Jastrzab; Jeffrey R.
Assistant Examiner: Bianco; Patricia
Claims
What is claimed is:
1. A method of hemodiluting a patient, comprising the steps of:
removing and storing a portion of the patient's blood .[.while
intravenously.]. .Iadd.and .Iaddend.administering a biocompatible
oxygen carrier, after which the patient undergoes a further loss of
blood wherein the removal and further loss of blood reduces the
patient's .[.hematocrit value.]. .Iadd.hemoglobin concentration
.Iaddend.to about 8 g/dL or below; monitoring the patient's tissue
oxygenation status during said removal and further loss of blood,
whereby the patient's .[.hematocrit value.]. .Iadd.hemoglobin
concentration .Iaddend.is maintained at a level of about 8 g/dL or
below; and administering additional biocompatible oxygen carrier to
the patient during or after said further loss of blood in response
to said oxygenation status to maintain said oxygenation status at
or above a desired value.
2. The method of claim 1, further comprising the step of
readministering blood removed during said removing step to said
patient.
3. The method of claim 1, wherein the oxygen carrier is derived
from human, animal, plant, or recombinant hemoglobin.
4. The method of claim 1, wherein the oxygen carrier is a
fluorocarbon emulsion.
5. The method of claim 4, wherein said fluorocarbon emulsion has a
concentration of at least 40%, w/v.
6. The method of claim 4, wherein the concentration of said
fluorocarbon emulsion is at least 60%, w/v.
7. The method of claim 1, further comprising the step of
administering oxygen breathing gas to the patient during said
method.
8. The method of claim 1, wherein the amount of oxygen carrier
administered is between about 0.5 and 10 ml/kg, based on the body
weight of the patient.
9. The method of claim 1, wherein said monitoring step is performed
by assessing PvO.sub.2.
10. The method of claim 9, wherein said assessing of said patient's
PvO.sub.2 is performed using a pulmonary artery catheter.
11. The method of claim 9, wherein said desired value of PvO.sub.2
is about 40 mmHg.
12. The method of claim 1, wherein said monitoring step is
performed periodically.
13. The method of claim 1, wherein said monitoring step is
performed continuously.
14. A method of hemodiluting a patient, comprising the steps of:
removing and storing a portion of the patient's blood .[.while
intravenously.]. .Iadd.and .Iaddend.administering a biocompatible
oxygen carrier; simultaneously monitoring the patient's tissue
oxygenation status, wherein biocompatible oxygen carrier is
administered so that said tissue oxygenation status is maintained
at or above a desired value; stopping removal of the patient's
blood when the hemoglobin concentration in the patient reaches a
point corresponding to .[.a hematocrit value of.]. about 8 g/dL or
below; continuing to monitor the patient's tissue oxygenation
status while allowing the patient to undergo a further loss of
blood, whereby the patient's .[.hematocrit value.].
.Iadd.hemoglobin concentration .Iaddend.is maintained at a level of
about 8 g/dL or below; and .[.intravenously.]. readministering
blood removed during said removing step in an amount sufficient to
maintain said oxygenation level at or above a desired value and
concomitantly increasing said .[.hematocrit value.].
.Iadd.hemoglobin concentration .Iaddend.above 8 dg/L.
15. The method of claim 14, further comprising the step of
administering additional biocompatible oxygen carrier to said
patient following said further loss of blood.
16. The method of claim 14, wherein the oxygen carrier is derived
from human, animal, plant, or recombinant hemoglobin.
17. The method of claim 14, wherein the oxygen carrier is a
fluorocarbon emulsion.
18. The method of claim 17, wherein said fluorocarbon emulsion has
a concentration of at least 40%, w/v.
19. The method of claim 17, wherein the concentration of said
fluorocarbon emulsion is at least 60%, w/v.
20. The method of claim 14, further comprising the step of
administering oxygen breathing gas to the patient during said
method.
21. The method of claim 14, wherein the amount of oxygen carrier
administered is between about 0.5 and 10 ml/kg, based on the body
weight of the patient.
22. The method of claim 14, wherein said monitoring step is
performed by assessing PvO.sub.2.
23. The method of claim 22, wherein said assessing of said
patient's PvO.sub.2 is performed using a pulmonary artery
catheter.
24. The method of claim 22, wherein said desired value of PvO.sub.2
is about 40 mmHg.
25. The method of claim 14, wherein said monitoring step is
performed periodically.
26. The method of claim 14, wherein said monitoring step is
performed continuously.
Description
FIELD OF THE INVENTION
The present invention relates to improved medical procedures
involving hemodilution. The improved method includes the
administration of an oxygen carrier, the continuous monitoring of
the mixed venous partial pressure of oxygen (PvO.sub.2) or other
tissue oxygenation indices, and the administration of autologous
blood or additional oxygen carrier to maintain the PvO.sub.2 or
other indices at or above a predetermined level.
BACKGROUND OF THE INVENTION
More than 13 million units of blood are collected each year in the
United States alone, and about 10 million of these units are
transfused into 4 million recipients. Of the transfused units,
about two-thirds are used during surgical procedures, and the
remainder are used primarily for treating severe anemia or in
emergency indications. Experience from clinical studies suggests
that postoperative recovery can be shortened if hemoglobin
concentrations are not allowed to fall to below 10 g/dL, the
previously generally accepted indication for transfusion (Zauder,
Anesth. Clin. North Amer. 8:471-80 (1990)). This criterion,
however, is currently being reevaluated due in part to a recent
increase in awareness of the risks associated with allogeneic blood
transfusion (NIH Consensus Conference JAMA 260:2700-2703 (1988)).
This has also resulted in a renewed interest in the use of
autologous blood transfusion techniques, in particular predonation
and cute normovolemic hemodilution (ANH).
Although autologous blood transfusion (i.e., reinfusion of the
patient's own blood) was first employed over 170 years ago, it was
not until the early 1970s that its use became more widespread
because of growing concerns about the transmission of hepatitis.
More recently, interest in autologous transfusions on the part of
both patients and physicians has been stimulated by the emergence
of AIDS. Despite an increased awareness and acceptance of the
benefits of autologous blood transfusion, recent studies have
revealed the widespread underutilization of autologous predonation
(which is estimated to represent only 2-5% of all units drawn
nationwide).
ANH is a procedure whereby several units of blood are withdrawn
from the patient at the beginning of surgery and simultaneously
replaced with either a crystalloid or a colloid plasma volume
expander (Stehling et al. Transfusion 31:857 (1991)). The basic
mechanism that compensates for most of the decreased oxygen
capacity of the diluted blood is the rise in cardiac output and
increased organ blood flow, factors that result from the improved
fluidity of blood (i.e., lower viscosity) at lower hematocrit
levels (Messmer et al Eur. Surg. Res. 18:254-263 (1986)).
Weisskopf, Transfusion 35(1):37-41 (1995) describes a mathematical
analysis of acute isovolemic hemodilution prior to surgical blood
loss, which was used to determine the magnitude of potential
reductions in allogeneic transfusion. Weisskopf concluded that
isovolemic hemodilution prior to surgery can obviate allogeneic
blood transfusion or diminish the amount transfused.
Predonation typically involves withdrawal of several units of a
patient's blood during the six weeks prior to surgery. To avoid
excessive anemia, the amount of blood that can be safely predonated
in the weeks before surgery is limited, as is the amount of blood
that can be removed during ANH.
Quite apart from ANH and predonation, it has been suggested that
red cell substitutes, or blood substitutes, could be used in place
of allogeneic blood (i.e., blood from other humans) during surgery.
Methods for facilitating autologous blood use which employ a
synthetic oxygen carrier or blood substitute are disclosed in U.S.
Pat. No. 5,344,393 (Roth et al). Extensive research in the field of
such blood substitutes over the past two decades has resulted in
several candidate compositions. These include perfluorocarbon
emulsions, such as FLUOSOL (Green Cross Corporation, Japan) and
OXYGENT (Alliance Pharmaceutical Corp., San Diego, USA), and
hemoglobin compositions, such as those derived from human, animal,
or recombinant sources.
Traditional thinking has been that a red cell substitute would be
given in volumes equal to the amount of whole blood that would be
used for the same purpose. The use of such blood substitutes in
large volumes to replace blood used in transfusions has not been
entirely satisfactory in earlier applications. For example, early
studies using FLUOSOL as a large volume blood substitute found that
following blood loss, FLUOSOL was "unnecessary in moderate anemia
and ineffective in sever anemia." Gould, et al., New Engl. J. Med.
314:1653 (1986). In this study, the average increase in arterial
oxygen content with the drug was only 0.7 ml/deciliter. Thus, it
was concluded that use of fluorocarbon emulsions as blood
substitutes would not provide a significant benefit in severely
anemic and bleeding patients. Indeed, although the U.S. Food &
Drug Administration approved FLUOSOL in 1989 for use as a perfusion
agent to enhance myocardial oxygenation during percutaneous
transluminal coronary angioplasty (PTCA), it did not approve an
earlier application for use as a large volume blood substitute for
general use.
The problem in using fluorocarbon emulsions and hemoglobin
compositions as red cell substituted or blood substitutes to
compensate for blood loss from surgery, disease, or trauma lies in
the relatively short circulating blood half life of those materials
in vivo. Healthy humans typically require about two weeks to
manufacture new red cells and increase their hematocrit to normal
levels following blood loss. In contrast, the intravascular half
life of fluorocarbon emulsions and hemoglobin substitutes in vivo
is typically less than 72 hours, most often much less than 24
hours. Thus, even if sufficient quantities of a red cell substitute
are administered during and/or after surgery, for example, to
provide adequate oxygen delivery, the oxygen carrying capacity will
drop significantly long before the body can compensate by making
new red cells. One aspect of the current invention therefore
defines an improved method to use red cell substitutes or blood
substitutes for temporary short-time perioperative use in
conjunction with autologous blood conservation strategies as a
means of reducing or eliminating allogeneic blood transfusions.
Treatment of intracoronary thrombotic events such as myocardial
infarcts usually involves systemic administration of thrombolytic
agents, for example tissue plasminogen activator (tPA) or
streptokinase. Mechanical intervention using percutaneous coronary
angioplasty (PTCA) is also used. Under no circumstance during
current treatment methods is blood purposefully diluted, as this
would dilute the concentration of red blood cells and thus impair
the delivery of oxygen to the hearts. Many cellular elements of
blood, however, are detrimental in the case of myocardial
infarction. For example, it is well known that platelets are
necessary for the process of thrombus formation; reduction in the
number of platelets would result in attenuation of the rate of
thrombus formation following infarction. Further, certain white
blood cells, polymorphonuclear leukocytes (neutrophils), are known
to be activated at the site of the infarct to release cytotoxic
components including oxygen free radicals, which, upon successful
opening of the stenosed artery, are responsible for damaging normal
cells through a phenomenon known as reperfusion injury. It would be
beneficial, therefore, to dilute blood during and for a specified
time after treatment of a myocardial infarction in order to reduce
the number of platelets and neutrophils that exacerbate the effects
of the infarct. Hemodilution is not done, however, because it is
also necessary to maintain high red blood-cell levels to deliver
oxygen to the myocardium.
The current invention therefore also defines an improved method to
use red cell substitutes or blood substitutes for temporary
short-term use in conjunction with treatment of myocardial
infarction as a means of reducing or eliminating the detrimental
effects associated with the infarct while providing enhanced oxygen
delivery to the tissues.
SUMMARY OF THE INVENTION
The present invention provides a method for facilitating autologous
blood use by a patient facing a loss of blood, comprising the steps
of: removing and storing a portion of the patient's blood while
intravenously administering a biocompatible liquid in sufficient
quantity to bring the patient's blood hemoglobin level to a desired
concentration; intravenously administering a biocompatible oxygen
carrier, while periodically or continuously assessing the patient's
tissue oxygenation, after which the patient undergoes a further
loss of blood; and intravenously readministering the stored blood
to the patient in response to the oxygenation measurements to
maintain oxygenation measurements at or above a desired value. In
one embodiment, the biocompatible liquid comprises a hemodiluent.
In another embodiment, the hemodiluent is administered separately
from the oxygen carrier. The method further comprises the step of
administering additional oxygen carrier in response to the
oxygenation assessments to maintain oxygenation assessments at or
above a desired value prior to readministering the stored blood.
The oxygen carrier is preferably derived from human, animal, plant,
or recombinant hemoglobin, or it may be a fluorocarbon
emulsion.
When the oxygen carrier is a fluorocarbon emulsion, the volume of
the administered oxygen carrier is advantageously less than 50% of
the volume of the biocompatible liquid. The fluorocarbon emulsion
preferably has a concentration of at least 40%, preferably 50% or
60% w/v.
The biocompatible liquid is advantageously selected from the group
consisting of a crystalloid, a colloid, a biocompatible oxygen
carrier, and combinations thereof. The method also may further
comprise the step of administering oxygen breathing gas to the
patient during the procedure. The blood loss is often blood loss
associated with surgery. Alternatively, the blood loss is
associated with trauma.
The amount of oxygen carrier administered is usually between about
0.5 and 10 ml/kg, based on the body weight of the patient. The
desired concentration of hemoglobin may advantageously be about 8
g/dL. The assessing of the patient's tissue oxygenation can be
performed by assessing PvO.sub.2, such as by using a pulmonary
artery catheter. Preferably, the desired value of PvO.sub.2
referred to above is about 40 mmHg.
The present invention also includes a method for the treatment of
organ ischemia or infarct, including myocardial infarction,
comprising the steps of removing a portion of the blood of a
patient in need of treatment for organ ischemia or infarct and
intravenously administering a biocompatible liquid in sufficient
quantity to reduce the patient's blood hemoglobin level to a
desired concentration; and intravenously administering a
biocompatible non-red cell oxygen carrier in conjunction with the
removing step to maintain oxygenation of the patient's tissues at
or above a predetermined level. In one embodiment, the
biocompatible liquid comprises a hemodiluent. In another
embodiment, the hemodiluent is administered separately from the
oxygen carrier. The oxygen carrier and biocompatible liquid may be
the same or different, and may be as described above. The method
advantageously also includes the step of administering oxygen
breathing gas to the patient during the method. The amount of
oxygen carrier administered is preferably between about 0.5 and 10
ml/kg, based on the body weight of the patient. As above, one
preferred concentration of hemoglobin after hemodilution is about 8
g/dL. In order to assure adequate oxygenation of tissue including
myocardium, the method further comprises the step of assessing the
patient's tissue oxygenation by assessing PvO.sub.2, as discussed
above, to maintain a desired value of PvO.sub.2 at a value, for
example, of about 40 mmHg. In one modification of the method, the
oxygen carrier constitutes at least a part of the biocompatible
liquid.
In addition to the foregoing, the invention comprises a method of
hemodiluting a patient, comprising the steps of removing and
storing a portion of the patient's blood while intravenously
administering a biocompatible oxygen carrier and periodically or
continuously assessing the patient's tissue oxygenation, after
which the patient undergoes a further loss of blood, and
administering additional oxygen carrier to the patient in response
to the oxygenation assessments to maintain the oxygenation
assessments at or above a desired value. The method may further
comprise the step of readministering the stored blood to the
patient. The oxygen carrier and the desired values of oxygen
carrier delivery and oxygenation may be as described above. The
method may also include the step of administering oxygen breathing
gas to the patient during the method.
Yet another aspect of the present invention comprises a method of
hemodiluting a patient, comprising the steps of removing and
storing a portion of the patient's blood while intravenously
administering a biocompatible oxygen carrier and periodically or
continuously assessing the patient's tissue oxygenation, after
which the patient undergoes a further loss of blood. The method may
further comprise the step of readministering the stored blood to
said patient. The oxygen carrier and the desired values of oxygen
carrier delivery and oxygenation may be as described above. The
method may also include the step of administering oxygen breathing
gas to the patient during the method.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 is a graph showing acceptable blood loss during surgery
without hemodilution, administration of allogeneic blood, or
administration of a synthetic oxygen carrier, assuming a normal
hemoglobin (Hb) concentration of 14 g/dL in the patient at the time
of surgery, and a concentration of 10 dg/L being required at the
end of operation. The calculated permitted blood loss before
transfusion is deemed necessary amounts to 1682 l.
FIG. 2 is a graph showing acceptable blood loss during surgery
using conventional hemodilution methods. It is assumed that no
allogeneic blood is to be given, that initial ANH is to a Hb of 10
gm/dL. Intraoperative transfusion of ANH blood occurs at a Hb of 8
gm/dL and a Hb of 10 gm/dl is given at the end of operation. The
calculated permitted blood loss amounts to 2366 ml.
FIG. 3 is a graph showing acceptable blood loss during surgery
using the method of isovolemic hemodilution described by Weisskopf,
Transfusion 35(1) :37-41 (1995). This method allows a blood loss of
2500 ml.
FIG. 4 is a graph showing acceptable blood loss during surgery
using the method of the present invention, which allows a blood
loss of 4000 ml. The present example uses 1.8 gm/Kg of a perflubron
emulsion given at 8 gm/dL hemoglobin concentration. This method
assumes that initial ANH is to a Hb concentration of 8 gm/dL. As
surgical blood loss starts, ANH blood is transfused to keep the Hb
at 8 gm/dL.
FIG. 5 is a graph showing the relationship between the O.sub.2
delivery from the hemoglobin in blood and cardiac output under
normal conditions (hematocrit=45%). Total O.sub.2 utilization (or
consumption; VO.sub.2) is equal to the product of cardiac output
times the arterial--venous O.sub.2 content difference, and is
indicated by the cross-hatched area. OxyHb dissociation curves were
generated from data provided by the model developed by Winslow,
Int. J. Clin. Monitor Comp. 2:81-93 (1985).
DETAILED DESCRIPTION OF THE INVENTION
A. Overview of the Invention
The invention described below combines the use of limited
intravascular half-life oxygen carriers (blood substitutes) with
hemodilution methods to increase allowable blood loss during
surgery. Increasing the allowable blood loss decreases the need for
autologous or allogeneic blood transfusion, thereby reducing or
eliminating the attendant risks and complications. The invention
also provides a method for adjunctive treatment of organ ischemia
or infarct, including myocardial infarction, using hemodilution and
administration of intravascular oxygen carriers.
In one method of the present invention, blood is removed from the
patient prior to initiation of a surgical procedure, and the
removed blood is stored for later readministration to the patient.
The removed blood is replaced with an asanguineous fluid, generally
crystalloid and/or colloid-based solutions which may also be the
oxygen carrier red cell substitute based on hemoglobin (Hb) or
fluorocarbon, to maintain normovolemia, while bringing the red cell
contained hemoglobin concentration down to a predetermined level.
At this point, the oxygen carrier is administered if not already
administered as the hemodiluent during ANH. Additional blood is
removed from the patient while monitoring the mixed venous partial
pressure of oxygen (PvO.sub.2) or other indices of global or
regional tissue oxygenation. Tissue oxygenation can be assessed by
use of oxygen electrodes, NADH fluorescence, or other means. When
the PvO.sub.2 or other index reaches a certain trigger level,
surgery is initiated. During the surgical procedure PvO.sub.2 or
other oxygenation indices are continuously or periodically
monitored and the autologous blood is added back to the patient in
response to the oxygenation level to maintain that level at or
above the trigger level. Alternatively, additional doses of the
oxygen carrier can be administered until the maximum tolerated dose
is reached.
The oxygen carrier is administered to the patient to supplement the
oxygen-carrying capacity of the blood during or after hemodilution
with crystalloid and/or colloid-based solutions, or the oxygen
carrier can serve as the hemodiluent itself. In this clinical
solution an additional margin of safety is afforded to the
hemodiluted patient, by augmenting total oxygen delivery.
The combined use of autologous and blood substitute infusion
technologies to avoid allogeneic transfusion is emphasized. The
present invention contemplates use of both predeposit and
perioperative autologous technologies with preferably less than
one-to-one volume infusions of various oxygen-carrying blood
substitute formulations. This invention includes use of any or all
of these technologies in whatever order or of whatever magnitude
they may be clinically useful in the preioperative clinical setting
described.
Another aspect of the present invention provides a method useful in
the treatment of organ ischemia or infarct, including myocardial
infarction. Both blood oxygenation and dilution are accomplished
for more beneficial adjunctive treatment. This aspect of the
invention involves the hemodilution of the patient suffering organ
ischemia with a generally crystalloid and/or colloid-based
solutions. Blood is removed from the patient and replaced with an
asanguineous fluid, while at the same time, the patient is
administered an oxygen carrier red cell substitute, such as a
fluorocarbon emulsion or hemoglobin solution. As before, the
crystalloid or colloid-based solution may also be the oxygen
carrier red cell substituted based on hemoglobin (Hb) or
fluorocarbon. The administration of the oxygen carrier ensures
adequate delivery of oxygen to the heart and other tissues, while
hemodilution reduces the number of platelets, neutrophils and other
cellular components that exacerbate the effects of the myocardial
infarction. PvO.sub.2 or other oxygenation indices are continuously
or periodically monitored and additional doses of the oxygen
carrier are administered until the maximum tolerated dose is
reached in response to the oxygenation level to maintain that level
at or above the trigger level.
The oxygen carrier is administered to the patient to supplement the
oxygen-carrying capacity of the blood during hemodilution with
crystalloid and/or colloid-based solutions. In this clinical
situation total oxygen delivery is augmented while the number of
detrimental cells in the blood is reduced.
One unique feature of the present invention is of particular
importance. By monitoring the mixed venous partial oxygen pressure
or other oxygenation indices during surgery or organ ischemia
(rather than using conventional hemoglobin or hematocrit
measurements), and by using a non-blood oxygen carrier, increased
amounts of blood can safely be removed (below a conventional
hematocrit-based transfusion trigger in the case of surgery). The
present invention therefore increases the margin of safety of
existing autologous transfusion technologies, by increasing the
amounts of blood which can safely be lost during surgery, and more
accurately determining the oxygenation status of the tissues. It
also provides a method for augmenting oxygen delivery to the
myocardium and other organs and tissues while reducing the number
of cells in the blood which exacerbate the damaging effects of the
ischemia or infarct.
B. Materials
A large number of materials suitable for use in the present
invention are already known in the art. Without limiting the scope
of the invention, certain representative materials are discussed
below.
Several compositions have been proposed or demonstrated to function
as intravenous oxygen carriers. These include fluorocarbon
emulsions, including but not limited to perfluorocarbon emulsions.
Such emulsions are typically fluorocarbon-in-water emulsions having
a discontinuous fluorocarbon phase and a continuous aqueous phase.
The emulsions typically include emulsifying agents and osmotic
agents, together with buffers and electrolytes.
The fluorocarbon emulsion may be selected from a wide range of
suitable emulsions. Preferably, it is a fluorocarbon-in-water
emulsion, having a preferred fluorocarbon concentration of about 5%
to about 125% weight per volume (w/v) that is used.
Fluorocarbons are fluorine substituted hydrocarbons that have been
used in medical applications as imaging agents and as blood
substitutes. U.S. Pat. No. 3,975,512 to Long discloses
fluorocarbons, including brominated perfluorocarbons, used as a
contrast enhancement medium in radiological imaging. Brominated
fluorocarbons and other fluorocarbons are known to be safe,
biocompatible substances when appropriately used in medical
applications.
It is additionally known that oxygen, and gases in general, are
highly soluble in some fluorocarbons. This characteristic has
permitted investigators to develop emulsified fluorocarbons as
blood substitutes. For a general discussion of the objectives of
fluorocarbons as blood substitutes and a review of the efforts and
problems in achieving these objectives see "Reassessment of
Criteria for the Selection of Perfluorochemicals for
Second-Generation Blood Substitutes: Analysis of Structure/Property
Relationship" by Jean G. Reiss, Artificial Organs 8:34-56,
(1984).
The fluorocarbon, in one preferred embodiment, is a perfluorocarbon
or substituted perfluorocarbon. Fluorocarbon molecules used in
these emulsions may have various structures, including straight or
branched chain or cyclic structures, as described in Reiss, J.,
Artificial Organs 8(1): 44-56 (1984). These molecules may also have
some degree of unsaturation, and may also contain bromine or
hydrogen atoms, or they may be amine derivatives. The fluorocarbons
may be present in the emulsion in any useful concentration, but
usually range from about 5% to 125% W/V. As used throughout,
concentrations defined as weight/volume are understood to represent
grams/ml and % weight per volume to represent grams/100 ml.
Although concentrations as low as 5% w/v are contemplated, in a
preferred embodiment the concentrations are at least 25% or 30%,
preferably at least 40%, 50%, 55%, 60%, 75% or 80% w/v. Emulsions
of 60%, 85%, 90%, and 100% are particularly preferred. Preferred
fluorocarbon emulsion formulations are those disclosed in U.S. Pat.
Nos. 4,865,836, 4,987,154, and 4,927,623, which are hereby
incorporated by reference.
There are a number of fluorocarbons that are contemplated for use
in the present invention. These fluorocarbons includes bis
(F-alkyl) ethanes such as C.sub.4 F.sub.9 CH.dbd.CH.sub.4 CF.sub.9
(sometimes designated "F-44E"), i-C.sub.3 F.sub.9 CH.dbd.CH.sub.6
F.sub.13 ("F-i36E"), and C.sub.6 F.sub.13 CH.dbd.CHC.sub.6 F.sub.13
("F-66E") ;cyclic fluorocarbons, such as C10F18 ("F-decalin",
"perfluorodecalin" or "FDC"), F-adamantane ("FA"),
F-methyladamantane ("FMA"), F-1,3-dimethyladamantane ("FDMA"),
F-di- or F-trimethylbicyclo[3,3,1]nonane ("nonane"); perfluorinated
amines, such as F-tripropylamine ("FTPA") and F-tri-butylamine
("FTBA"), F-4-methyloctahydroquinolizine ("FMOQ"),
F-n-methyl-decahydroisoquinoline ("FMIQ"),
F-n-methyldecahydroquinoline ("FHQ"), F-n-cyclohexylpurrolidine
("FCHP") and F-2-butyltetrahydrofuran ("FC-75" or "RM101").
Other suitable fluorocarbons may be selected from brominated
perfluorocarbons, such as 1-bromo-heptadecafluoro-octane (C.sub.8
F.sub.17 Br, sometimes designated perfluorooctylbromide. "PFOB", or
"perflubron"), 1-bromopenta-decafluoroheptane (C.sub.7 F.sub.15
Br), and 1-brmotridecafluorohexane(C.sub.6 F.sub.13 Br, sometimes
known as perfluorohexylbromide or "PFHB") Other brominated
fluorocarbons are disclosed in U.S. Pat. No. 3,975,512 to Long,
Also contemplated are fluorocarbons having nonfluorine
substituents, such as perfluorooctyl chloride, perfluorooctyl
hydride, and similar compounds having different numbers of carbon
atoms, e.g., 6-12 carbon atoms.
Additional fluorocarbons contemplated in accordance with this
invention include perfluoroalkylated ethers or polyethers, such as
(CF.sub.3).sub.2 CFO(CF.sub.2 CF.sub.2).sub.2 OCF(CF.sub.3).sub.2,
(CF.sub.3).sub.2 CFO(CF.sub.2 CF.sub.2).sub.3 OCF(CF.sub.3),
(CF.sub.3)CFO(CF.sub.2 CF.sub.2)F, (CF.sub.3).sub.2 CFO(CF.sub.2
CF.sub.2).sub.2 F, (C.sub.6 F.sub.13).sub.2. Further,
fluorocarbonhydrocarbon compounds, such as, for example compounds
having the general formula C.sub.n F.sub.2n+1 C.sub.n,F.sub.2n+1,
C.sub.n F.sub.2n+1 OC.sub.n F.sub.2n'+1, or C.sub.n F.sub.2n+1
CF.dbd.CHC.sub.n' F.sub.2n+1' where n and n' are the same or
different and are from about 1 to about 10 (so long as the compound
or a mixture containing the compound is a liquid at room
temperature). Such compounds, for example, include C.sub.8 F.sub.17
C.sub.2 H.sub.5 and C.sub.6 F.sub.13 CH.dbd.CHC.sub.6 H.sub.13. It
will be appreciated that esters, thioethers, and other variously
modified mixed fluorocarbonhydrocarbon compounds are also
encompassed within the broad definition of "fluorocarbon" materials
suitable for use in the present invention. Mixtures of
fluorocarbons are also contemplated. Additional "fluorocarbons" not
listed here, but having those properties described in this
disclosure that would lend themselves to use in vivo in accordance
with the present invention are also contemplated.
Emulsifying agents used in the emulsions of this invention may be
anionic, cationic or non-ionic surfactants or combinations thereof
as are well known to those in the chemical arts, or they may be
mixtures of synthetic compounds such as Pluronic F-68, a condensate
of ethylene oxide with propylene glycol, as used in U.S. Pat. No.
4,073,879 to Long. Fluorosurfactants, such as those described by J.
Riess et al. Int'l Symposium on Blood Substitutes, Montreal, (May
1987), are particularly suitable and can also be used. Emulsifying
agents may also be mixtures of the above agents. Particularly
suitable emulsifiers may include natural amphipathic compounds such
as phospholipids, particularly phosphatidylcholine, wherein
combined hydrophilic and hydrophobic properties enable the molecule
to interface with both aqueous and fluorocarbon systems, thereby
forming the emulsion droplets. There are various species of each
class of phospholipids, such as the phospholipid cholines,
comprising various pairings of saturated and unsaturated fatty
acids in the glycerol structures. Phosphatidylcholine is an
abutment natural material (lecithin) which may be purified from egg
yolk, or may be produced synthetically (Avanti Polar Lipids,
Pelham, Ala.). Phospholipid emulsifiers, particularly egg yolk
phospholipid and lecithin, are particularly preferred.
The phospholipid emulsifying agent is typically included in the
range of from 2 to 14% w/v, usually increasing the phospholipid
concentration with increasing fluorocarbon concentration. The
preferred amount for an emulsion comprising 75% w/v
bromofluorocarbon is 2.5 to 5% w/v and 3.5 to 10% w/v of
phospholipid for an emulsion with 100% w/v bromofluorocarbon. In a
preferred embodiment, the phospholipid comprises at leas 2% w/v of
the emulsion.
Emulsification requires large amounts of energy to convert a
two-phase immiscible system into a suspension of discontinuous
small droplets of hydrophobic fluid in an aqueous continuous phase.
Fluorocarbon emulsification may be carried out generally by either
of two general processes which provide energy to the system to
break up the fluorocarbon volume into small droplets. In sonication
emulsification, a probe is inserted into the mixture of
fluorocarbon, emulsifier, and aqueous phase, and bursts of energy
are released from the tip of the probe. In a mechanical
emulsification process, such as that performed by a MICROFLUIDIZER
apparatus (Microfluidics, Newton, Mass. 02164), streams of the
mixed emulsion components are directed through the apparatus at
high velocity and under high pressure (e.g. 15,000 psi), and the
high shear forces or cavitation resulting from the mechanical
stress applied to the fluid produce the emulsion.
The aqueous phase of the emulsion may have components dissolved
therein which give the emulsion desirable properties. For example,
it may comprise an osmotic agent to bring the emulsion to
physiological isotonicity. The osmotic agent may be sodium
chloride, or it may be a polyhydroxyl compound, such as a sugar or
mannitol. The aqueous phase will also contain soluble buffering
agents.
The liquid phase of the emulsion may also have components dissolved
therein. For example, a phosphatidyl choline emulsifier may have
glycerol, phosphatidyl glycerol, other phospholipids or cholesterol
admixed, and further contain an antioxidant substance, such as a
tocopherol, to protect against lipid oxidation.
Several fluorocarbon emulsions have been produced commercially for
use as intravascular oxygen carriers. These include a mixed decalin
emulsion formerly sold by Alpha Therapeutics Corp., Los Angeles,
Calif. under the trademark FLUOSOL and perflubron-based emulsions
produced by Alliance Pharmaceutical Corp. of San Diego, Calif.,
under the trademark OXYGENT.
One exemplary perflubron emulsion is a 90% (w/v) perflubron
emulsion (Alliance Pharmaceutical Corp., San Diego, Calif.) having
the following Formula I:
FORMULA I PERFLUBRON EMULSION Component Percent (w/v) Perflubron
90.000 Egg Yolk Phospholipid 4.000 NaH.sub.2 PO.sub.4.H.sub.2 O,
USP 0.052 Na.sub.2 HPO.sub.4.7H.sub.2 O, USP 0.355 NaCl, USP 0.280
EDTA, USP 0.020 d-.alpha.-tocopherol, USP 0.002 Water for injection
48.400
Hemoglobin compositions contemplated for use in the present
invention are well known. Such compositions are disclosed, for
example, in the following U.S. Patents, which are hereby
incorporated by reference: U.S. Pat. Nos. 4,911,929; 4,861,867;
4,857,636; 4,777,244; 4,698,387; 4,600,531; 4,526,715; 4,473,494;
and 4,301,144.
Various materials have been used successfully as plasma expanders
in connection with hemodilution procedures. These include the
well-known categories of crystalloid compositions (exemplified by
Ringers-lactate and saline (0.9%) both from Baxter Healthcare
Corp., Deerfield, Ill.) and colloid compositions. Colloid
compositions include (1) modified fluid gelatins, such as those
sold under the following trademarks: PLASMAGEL (R. Bellon Lab.,
Neuilly-sur Seine, France), GELIFUNDOL (Biotest, Frankfurt,
Germany), GELOFUSINE (Braun, Melsungen, Germany) and HAEMACEL
(Hoechst-Roussel Pharmaceutical Inc., Sommerville, N.J.); (2)
dextran solutions, such as those sold under the trademarks MACRODEX
(dextran-70) and RHEOMACRODEX (dextran-40) both from Pharmacia,
Piscataway, N.J.; (3) albumin solutions, such as those sold under
the trademark ALBUTEIN (Alpha Therapeutics, Los Angeles, Calif.)
and human serum albumin (5%) from Abbott Labs. North Chicago, Ill.;
(4) starch solutions such as Hetastarch (Hydroxyethylstarch), HAES
(Fresenius, Hamburg, Germany) and HESPAN (DuPont, Willimington,
Del.). These are administered in various volumes to maintain the
patient's blood volume in the normal range and to encourage the
increase in cardiac output that accompanies hemodilution
procedures. In general, crystalloid-based solutions need to be
given in volume ratios of 2:1 or 3:1 to blood withdrawn; colloids
are usually given in lesser amounts.
C. Procedures
Autologous blood use virtually eliminates the possibility of
contracting blood-borne diseases associated with transfusions as
well as transfusion reactions occurring as a result of
incompatibility between donor and recipient blood. Autologous blood
for use in subsequent transfusions can be obtained in a number of
ways, including one or more of the following: predeposit,
perioperative isovolemic hemodilution; and intraoperative
salvage.
Predeposit requires that the surgery be planned well in advance of
the actual date. Blood is donated by the patient during the weeks
before surgery, and is stored for subsequent administration to the
patient. Phlebotomies of 350-400 ml are typically preferred at 2-7
day intervals, with the last collection more than 72 hours before
surgery. The blood may be stored in the liquid state as whole
blood, or it may be divided into red cells and plasma which can be
frozen to preserve labile components.
Perioperative isovolemic hemodilution is the process of collecting
blood immediately before a surgical procedure with the concomitant
replacement by a sufficient volume of crystalloid or colloid
solution. This practice decreases blood viscosity during surgery,
thereby reducing the work load on the heart allowing cardiac output
to rise and improving microcirculatory oxygen flow and
distribution. Typically, sufficient blood is removed to reduce the
hemoglobin concentration from a typical normal value of
approximately 14 g/dL to about 10 g/dL. This blood is stored for
readministration to the patient during or after surgery. After
removal of some of the blood, or simultaneously with the removal, a
crystalloid or colloid plasma expander (or both) is administered to
the patient to maintain blood volume at a desired value, typically
at the normal value.
Intraoperatively blood salvage involves collecting blood lost from
a wound or body cavity during surgery, processing it, and
reinfusing the processed blood into the same patient. This
procedure is safe and effective if certain basic precautions are
followed to ensure against contamination of the blood with bacteria
or other pathogens, or malignant cells. Autotransfusion devices for
collecting, filtering, and reinfusing the blood are commercially
available. Also, some devices separate and wash the red blood
cells, thereby avoiding administration of blood contaminated by
debris, irrigating solutions, activated factors, anticoagulants,
and free hemoglobin. Suitable devices of this type are exemplified
by the Haemonetics Cell Separator and Cell Washer, Haemonetics
Corp., Braintree, Mass.
Detailed reviews of autologous blood procedures and acute
isovolemic or normovolemic hemodilution are found, for example, in
Stehling, et al., Transfusion 31:857 (1991) and Mercuriali, et al,
Autologous Blood, Transmedica Europe Limited, Eastbourne, United
Kingdom (1991), which are hereby incorporated by reference.
In the practice of the present invention, autologous blood
procedures (preferably involving perioperative hemodilution) are
combined with administration of non-blood oxygen carriers,
including hemoglobin compositions and, more preferably,
fluorocarbon emulsions, together with the monitoring of the partial
oxygen pressure in the venous blood (PvO.sub.2) or other
oxygenation indices in the patient.
Though it is generally acceptable that venous blood oxygen tension
reflects, but does not measure, PO.sub.2 of the tissue from which
it is issuing, it is generally impractical, except under unusual
circumstances, to monitor PO.sub.2 in venous blood draining from
individual tissues or organs. Hence, the mixed venous PO.sub.2
(PvO.sub.2) is usually taken as an acceptable estimator of the
oxygen delivery/consumption ration in the whole body and is used as
a guide to the oxygenation status of the whole body. It would be
logical therefore to use PvO.sub.2 as an indication for the need
for blood transfusion during surgical procedures and in the trauma
situation.
During the perioperative period, blood transfusions are routinely
administered when a "critical" hemoglobin (Hb) concentration or
hematocrit is reached. This level has traditionally been at a Hb
concentration of 10 g/dL. To determine the lowest acceptable Hb
level and the level of suitable transfusion trigger, it is
necessary to first consider the changes that take place during
hemodilution as blood is removed and normovolemia is
maintained.
As a patient is hemodiluted, either intentionally as part of an
autologous blood conservation program, or following surgical
bleeding with maintenance of normovolemia, both Hb concentration
and arterial O.sub.2 content (CaO.sub.2) decrease. As the red cell
concentration falls, a reduction in whole blood viscosity occurs;
this, together with the simultaneously occurring increase in venous
return, causes a rise in cardiac output (CO) and in improvement in
total O.sub.2 transport to the tissues (PO.sub.2). The degree to
which this physiological compensation occurs will primarily depend
on the response of CO to the reduction in red cell mass. Some
authorities have concluded that the relationship between decrease
in Hb concentration and CO is linear whereas others have maintained
that it follows a curvilinear relationship; the degree of curvature
found is very minimal, causing many researchers to perform
calculations that assume a linear relationship.
In man, the extent to which cardiac output increases as Hb
concentration decreases varies between 0.25 liters per minutes per
gm of Hb change to 0.70 L/min/g. Hence, the cardiac output response
to hemodilution differs between patients and this will affect the
Hb level at which additional oxygen carrying capacity in the blood
will be needed. The necessity for transfusion of red blood cells
will also vary depending on such factors as vascular tone, which
will cause the viscosity contribution to total systemic resistance
to vary, and the ability of the myocardium to function at low Hb
levels. During moderate hemodilution, myocardial blood flow
increases proportionately more than total cardiac output and hence,
in the absence of significant coronary atherosclerosis, no
myocardial ischemia occurs. It has been shown, however, that low
postoperative hematocrit (Hct) may be associated with postoperative
myocardial ischemia in patients with generalized atherosclerosis.
Though attempts have been made to define a critical Hct level, an
empiric automatic transfusion trigger should be avoided and red
cell transfusions should be tailored to the individual patient and
be triggered by his or her own response to anemia.
As arterial blood passes through the tissues, a partial pressure
gradient exists between the PO.sub.2 of the blood in the arteriole
entering the tissue and the tissue itself. Oxygen is, therefore,
released from hemoglobin in the red blood cells and also from
solution in the plasma; the O.sub.2 then diffuses into the tissue.
The PO.sub.2 of the blood issuing from the venous end of the
capillary cylinder will be a reflection of, but not necessarily
equal to, the PO.sub.2 at the distal (venous) end of the tissue
through which the capillary passes. Under normal conditions this is
essentially the same as that of interstitial fluid in contact with
the outside of the capillary. The degree of equilibration between
blood and tissue may depend on the speed of passage of blood
through the capillary bed and under conditions of critical oxygen
delivery caused by extreme anemia, there may not be time for
equilibration of tissue and blood PO.sub.2 levels; this may lead to
higher than expected mixed venous PO.sub.2 (PvO.sub.2).
Nevertheless, in the clinical situation, it is generally accepted
that probably the most reliable single physiological indicator for
assessing the overall balance between oxygen supply and demand is
mixed venous oxygen tissues. It is therefore sensible to use
PvO.sub.2 as an indication of the overall adequacy of tissue
oxygenation and to use it as a transfusion trigger rather than to
use the traditional "10/30 rule" as an indication for red blood
cell transfusion.
If PvO.sub.2 is accepted as a reasonable indicator of patient
safety, the question arises as to what can be considered a "safe"
level of this parameter. Though much data exists on critical oxygen
delivery levels in animals, there is little to indicate what a
critical PvO.sub.2 might be in the clinical situation. The
available data indicates that the level is extremely variable. For
instance, in patients about to undergo cardiopulmonary bypass,
critical PvO.sub.2 varied between about 30 mm Hg and 45 mm Hg; the
latter value is well within the range of values found in normal,
fit patients. Furthermore, shunting of blood in the tissues will
cause elevated levels of PvO.sub.2, such as is found in patients in
septic shock, and will result in O.sub.2 supply dependency.
A PvO.sub.2 value of 35 mm Hg or more may be considered to indicate
that overall tissue oxygen is adequate, but this is implicit on the
assumption of an intact and functioning vasomotor system. This
PvO.sub.2 level is reached at a Hb of about 4 g/dL in patients with
good cardiopulmonary function; even lower PvO.sub.2 levels are
tolerated in some patients when increased fractional inspired
O.sub.2 concentrations (FiO.sub.2 S) are employed. In each
situation it is necessary to maintain a good margin of safety and
it is best to pick a PvO.sub.2 transfusion trigger at which the
patient is obviously in good condition as far as oxygen dynamics
are concerned.
Physiological and clinical studies involving measurement and
calculation of oxygenation parameters are usually carried out using
cardiac output measurements obtained by thermodilution using a
pulmonary artery catheter such as a Swan-Ganz catheter. Oxygen
delivery and oxygen consumption (VO.sub.2) are then derived from
measured or calculated arterial and mixed venous oxygen contents by
using the Fick equation. The Fick equation allows the determination
of oxygen consumption based on the difference between arterial and
venous oxygen content times cardiac output. The equation is as
follows:
where VO=oxygen consumption, C.sub.a O.sub.2 =arterial oxygen
content, C.sub.v O.sub.2 =venous oxygen content, and CO=cardiac
output.
Accordingly, one embodiment of the present invention involves
removal of a portion of the patient's blood, and administration of
an intravenous fluid to reduce the patient's hemoglobin
concentration from about the normal level of about 14 g/dL to a
first "trigger" point. The intravenous fluid preferably includes a
plasma expander, such as a colloid or crystalloid solution which
may also be the oxygen-carrier red cell substitute or blood
substitute based on Hb or PFC. This blood removal is usually
deliberate, although the invention may also be used with trauma
victims or other patients suffering involuntary blood loss. With
deliberate removal, the blood is stored for readministration to the
patient at a later time.
When the hemoglobin level reaches the first "trigger" point, an
oxygen carrier is administered intravenously if not already done as
part of the ANH procedure. Additional blood is then removed, and
PvO.sub.2 and/or other indicators of tissue oxygenation is
continuously or periodically monitored, for example by using a
pulmonary artery catheter, until the oxygenation reaches a second
trigger point. At that time, autologous blood can be administered
to the patient to maintain oxygenation at or above the second
trigger point, or additional doses of the oxygen carrier can be
given until the maximum tolerated dose is reached. In some
instances, the patient will not reach the second trigger point as
the initial dose of oxygen carrier is sufficient to maintain
oxygenation above the second trigger point, and no additional
oxygen carrier or autologous blood need be administered.
The oxygen carrier used is one other than red blood cells,
preferably a biocompatible fluorocarbon emulsions of the type
previously discussed, although hemoglobin compositions are also
contemplated, as are other oxygen carriers.
Another aspect of the present invention provides for the use of a
combination of hemodilution and administration of oxygen carrier as
adjunctive treatment of organ ischemia or infarct, including
myocardial infarction. Frequently, higher concentrations of
inspired oxygen are given to a patient who has suffered a
myocardial infarct to assure maximum saturation of hemoglobin in
red blood cells and thereby maximum delivery of oxygen to damaged
and potentially damageable myocardial tissue. Under no
circumstance, however, is the blood purposefully diluted, as this
would dilute the concentration of red blood cells and the ability
of the blood to carry oxygen to the heart. This is so even though
it is known that other cellular elements of the blood are
detrimental, contributing to the damage caused by the myocardial
infarct. Platelets, for example, are necessary for the process of
thrombus formation. Neutrophils are known to be activated at the
site of the infarct to release cytotoxic components, including free
radicals, which are responsible for damaging normal cells.
Accordingly, it would be beneficial to dilute blood during and for
a specified period of time after treatment of a myocardial infarct
in order to reduce the number of platelets and neutrophils that
exacerbate the effects of the myocardial infarct, provided that
adequate oxygen delivery to the myocardium and other tissues can be
maintained.
The method of the present invention provides for the hemodilution
of a patient suffering from organ ischemia or infarct using a
crystalloid- or colloid- based hemodiluent and intravenously
administering a non-blood oxygen carrier such as a hemoglobin
composition or a fluorocarbon emulsion. Alternatively, the
hemodiluent may be the oxygen carrier. During hemodilution and the
administration of the oxygen carrier, the patient's PvO.sub.2 or
other oxygenation indices is monitored, and the oxygen carrier is
administered to maintain the PvO.sub.2 or other oxygenation indices
at or above a predetermined level.
This embodiment of the present invention involves removal of a
portion of the patient's blood during and/or for a specified time
during treatment of organ ischemia or infarct, and administration
of an intravenous fluid to reduce the patient's hemoglobin
concentrations from about the normal level of about 14 g/dL to a
first "trigger" point. The intravenous fluid preferably includes a
plasma expander, such as a colloid or crystalloid solution which
may also be the oxygen-carrier red cell substitute or blood
substitute based on Hb or PFC. The blood is stored for optional
readministration to the patient at a later time. In one embodiment,
where the intravenous fluid contains an oxygen carrier, no further
hemodilution is done and the hemodilution procedure of the present
invention is complete. The procedure reduces the quantity of
circulating platelets and neutrophils, decreases the viscosity of
the blood, and assures adequate perfusion of the tissue due to the
added presence of the oxygen carrier.
In an optional embodiment of the organ ischemia or infarct
treatment of the present invention, when the hemoglobin level
reaches the first "trigger" point, an oxygen carrier is
administered if not already done as part of the ANH procedure.
Additional blood is then removed, and PvO.sub.2 and/or other
indicators of tissue oxygenation is continuously or periodically
monitored, for example by using a pulmonary artery catheter, until
the oxygenation reaches a second trigger point. At that time,
additional doses of the oxygen carrier can be given until the
maximum tolerated dose is reached to maintain oxygenation at or
above the second trigger point, or the autologous blood can be
administered to the patient.
In either hemodilution associated with surgery or hemodilution
associated with the treatment of organ ischemia or infarct, the
volume of intravenous fluid administered to the patient is at least
about equal to 75%, preferably at least about 100% of the volume of
blood removed from the patient. More preferably, the volume of
intravenous fluid is between about 150% and 300% of the volume of
blood removed, depending on whether the fluid is predominantly a
colloid or a crystalloid and depending on whether it consists of or
contains the oxygen carrier. Alternatively, the volume of
intravenous fluid administered to the patient is adequate to reduce
the hemoglobin concentration of the patient to the trigger levels
discussed above.
In one embodiment of the invention, the intravenous fluid comprises
a major portion of a plasma expander and a minor portion of oxygen
carrier. The volume ratio of administered expander to an oxygen
carrier will range from 0:1 to at least 10:1, depending on whether
the fluid is a crystalloid or a colloid, and on the composition of
the oxygen carrier, the concentration of the oxygen carrier,
PO.sub.2 and cardiac output. These ranges are most desirable when
using a high concentration fluorocarbon emulsion, having at least
about 40%, preferably at least about 50% or 60% fluorocarbon,
w/v.
In one preferred embodiment, where a fluorocarbon emulsion such as
perflubron-based emulsion is used as the oxygen carrier, the total
amount of actual perfluorocarbon administration to the patient is
advantageously from about 0.5 g/kg to about 10 g/kg, preferably 1-6
g/kg, based on the weight of the patient. When a 90% w/v or 100%
w/v fluorocarbon emulsion is used, the volume of emulsion necessary
to deliver the desired dosage is about 0.25 or 0.255 ml/kg to about
10 or 11 ml/kg, preferably about 1 to 6 ml/kg. Simple calculation
provides the preferred volume of emulsion when different
concentrations of fluorocarbon are used.
The hemodiluted patient is preferably administered a breathing gas
enriched in oxygen, preferably at least 50-60%, and most preferably
75% or 100% oxygen. The effects of the enriched breathing gas,
increased cardiac output due to hemodilution, the oxygen carrier,
and the dissolved oxygen in the aqueous phase of the circulating
intravascular fluid and plasma all combine to supply enhanced
levels of oxygen to the patient. The collective contributions of
these factors to oxygen delivery in the patient are discussed in
more detail in section D, below.
During or after the surgical procedure or other condition resulting
in blood loss, or following treatment of organ ischemia or infarct,
the autologous blood removed from the patient (or the red cell
portion thereof) can be readministered to the patient to maintain
PvO.sub.2 and/or other indices of oxygenation at or above the
second trigger point. The oxygen carrier, meanwhile, is cleared
from the circulation in a relatively short time, and its
oxygen-carrying functions is supplanted by the autologous
transfusion of red cells, if required.
Accordingly, there are various trigger points that are important to
the use of the present invention. One is the hemoglobin or
PvO.sub.2 value at which oxygen carrier is infused if not already
administered during the ANH. Others are the PvO.sub.2 values at
which additional doses of the oxygen carrier or transfusion with
autologous blood are initiated. Appropriate values in any
particular instance or for any particular type of procedure will be
determined with consideration of such variables as age, sex,
weight, cardiac status, disease state, and so forth. In general,
however, one would expect that the first trigger point would occur
during hemodilution at a hemoglobin level of between about 7 and 10
g/dL, typically at about 8 g/dL. (Alternatively, it could occur at
a PvO.sub.2 value of about 35 mm Hg to about 45 mm Hg, preferably
at about 40 mm Hg). One would expect that the second trigger point
would occur at a PvO.sub.2 value of about 30 mm Hg to about 50 mm
Hg, preferably at a value of about 40 mm Hg.
A comparison of the acceptable blood loss levels using conventional
methods and the method of the present invention is shown in FIGS.
1-4.
FIG. 1 is a graph showing acceptable blood loss during surgery
without hemodilution, administration of allogeneic blood, or
administration of a synthetic oxygen carrier, assuming a normal
hemoglobin concentration of 14 g/dL in the patient at the time of
surgery, and a concentration of 10 g/dL being required at the end
of surgery. The hemoglobin concentration is generally not allowed
to fall postoperatively below about 10 g/dL. This allows a blood
loss of 1682 mL before transfusion is deemed necessary.
FIG. 2 is a graph showing acceptable blood loss during surgery
using conventional hemodilution methods, wherein the hemoglobin
concentration is allowed to fall to a level of about 8 gm/dL. This
method allows for blood loss up to about 2366 mL.
FIG. 3 is a graph showing acceptable blood loss during surgery
using the mathematical analysis described by Weisskopf. Transfusion
35(1):37-41 (1995). Assuming that hemodilution is completed before
surgical blood loss is begun and that transfusion of removed blood
is begun when surgical blood loss begins and lost blood is replaced
at a rate that maintains the target hematocrit, this method allows
for blood loss of 2500 mL.
FIG. 4 is a graph showing acceptable blood loss during surgery
using the method of the present invention. By monitoring PvO.sub.2
levels or other indices of tissue oxygenation and using them as an
indicator of the overall oxygenation status of the patient, rather
than hemoglobin or hematocrit measurements, and by administering an
oxygen carrier, blood loss can safely-be increased to 4000 mL. The
present examples uses 1.8 gm/Kg of a perflubron emulsion given at 8
gm/dL hemoglobin concentration. This method assumes that initial
ANH is to a Hb concentration of 8 gm/dL. As surgical blood loss
starts, ANH blood is transfused to keep the Hb at 8 gm/dL.
D. Oxygen Delivery to Tissues
Although not intending to be bound by any particular theory of
operation, the following discussion provides a framework for
understanding the physical and physiological mechanisms
contributing to the function of the present invention.
Oxygen transport to tissues can be considered to occur via two
processes. The first is the convective (bulk) delivery of oxygen to
tissues; the second is the delivery of oxygen to tissues via a
diffusive process.
(1) Convective Oxygen Delivery
The first process, convective O.sub.2 is described by the Fick
equation:
Although the Fick equation is quite straightforward, a number of
physiological variables of importance are imbedded in it. For
example, the arterial-venous differential in oxygen content
CAO.sub.2 -CvO.sub.2 is determined by the O.sub.2 content of both
arterial (CaO.sub.2) and venous (CvO.sub.2) blood, respectively,
which, in turn, are directly related to the hemoglobin (Hb)
concentration and the O.sub.2 saturation and the contact of O.sub.2
in the plasma. Oxygen saturation is determined by the PO.sub.2 and
by the position of the oxyHb (oxygenated form of Hb) dissociation
curve. The PO.sub.2 is determined by the O.sub.2 tension in the
inspired air and the capacity of the lung to oxygenate pulmonary
capillary blood. Finally, the position of the oxyHb dissociation
curve is determined by 2.3-diphosphoglycerate (2.3-DPG) as well as
pH and pCO.sub.2, which differ between arterial and venous blood
and the temperature.
Similarly, cardiac output (CO) is controlled by many factors,
including heart rate, the left ventricular filling volume and
ejection fraction (i.e., stroke volume), and the demand for O.sub.2
in tissues (i.e., oxygen consumption, VO.sub.2). Assuming a
constant blood volume and under stable hemodynamic conditions, the
left ventricular filling volume is proportional to the blood
viscosity, which, in normal humans, is primarily a function of the
hematocrit (percent of red cells in blood).
Some of these complex relationships can be shown graphically (see
FIG. 5). In FIG. 5, O.sub.2 content is placed against O.sub.2
tension, PO.sub.2 FIG. 5 presents data for a normal, 70 kg man at
rest with a hemoglobin concentration of 14.4 g/dl (hematocrit=45%).
The data for the oxyHb dissociation curve used to create this
graphic representation were generated by the model developed by
Winslow (1985), which calculates the total O.sub.2 contents
dissolved in the plasma and bound to hemoglobin. For a given
arterial and venous PO.sub.2 of 100 and 40 torr, respectively, the
arterial to venous oxygen content difference (CaO.sub.2 -CvO.sub.2)
is 5 mL/dL. At a normal cardiac output of 5 L/min, the O.sub.2
consumption (VO.sub.2, represented by the cross-hatched area) is
approximately 250 mL/min or 5 mL/kg/min.
Normally, more O.sub.2 is delivered to tissue than is utilized,
providing a "margin of safety". When the convective (bulk) delivery
of O.sub.2 decreases below a certain critical point, tissue
function may be compromised, with various consequences such as
tissue bypoxia, production of lactic acid, infarction, necrosis,
etc. Once this critical oxygen delivery level is reached (i.e.,
when O.sub.2 delivery is severely limited), then VO.sub.2 (oxygen
consumption) will be supply-limited. The actual value for the
critical oxygen delivery level is very difficult to specify, since
there are likely to be different values for different organs or
different capillary beds.
When O.sub.2 consumption is not supply-limited, changes in O.sub.2
content of the arterial blood can be compensated for by other
normal physiological mechanisms. For example, in anemia, the
cardiac output becomes elevated (see below), as does the level of
red cell 2.3-DPG. The latter serves to shift the oxyHb dissociation
curve to the right (reduced affinity, increased P.sub.50 [the
PO.sub.2 at which hemoglobin is 50% saturated with O.sub.2 ])
A similar compensatory mechanism (with respect to the cardiac
output) occurs during acute normovolemic hemodilution (Messmer et
al. Res. Exp. Med. 159:152-56 (1986)). As the hematocrit decreases
during the hemodilution, blood viscosity also decreases
significantly, which allows the cardiac output to increase without
any significant changes in the work load on the heart. In this way,
total oxygen transport (DO.sub.2) can be maintained.
Work by Guyton et al. (Cardiac Output and its Regulation, 2nd Ed.
Saunders, Philadelphia (1973)) has shown that over a broad range,
the cardiac output varies inversely with hematocrit. A hematocrit
within the range of approximately 40 to 45% for normal, resting
humans is considered most appropriate. When hematocrit values
exceed 45%, blood viscosity limits cardiac output such that there
is little beneficial effect from the additional O.sub.2 carrying
capacity of the increased number of circulating red cells. When the
hematocrit is less than about 40%, the lower viscosity results in a
decreased total peripheral resistance to blood flow which allows
cardiac output to increase in order to maintain normal oxygen
delivery.
It should be noted that augmenting O.sub.2 transport by
administration of a cell-free oxygen carrier differs from simple
transfusion in several important ways. A key point in understanding
the value of a low-dose acellular "blood substitute" is that plasma
O.sub.2 is increased, rather than red cell O.sub.2, as is the case
with transfusion of blood. Transfusion of red cells will increase
bulk blood viscosity, which can cause a decrease in cardiac output
and therefore may not increase the bulk O.sub.2 delivery.
Addition of a cell-free O.sub.2 carrier, on the other hand, will
increase bulk O.sub.2 delivery by elevating the O.sub.2 content of
the plasma and potentially increasing the cardiac output (since
overall blood viscosity would be reduced). This additional
contribution to DO.sub.2 is primarily due to an increased amount of
O.sub.2 dissolved in the plasma compartment. DO.sub.2 can be
further increased by addition of a dose of perflubron emulsion or
other oxygen carrier under these conditions which would provide an
even greater margin of safety.
As a result, the hematocrit and hemoglobin levels can be
significantly decreased when compared with the prior art methods,
since the hemoglobin and hematocrit measurements do not adequately
reflect oxygen carried in the added liquid volume and carried by
the oxygen carrier. Nor do they account for increased cardiac
output which follows from hemodilution. PvO.sub.2 measurement,
therefore, is a better indicator of the oxygenation status of the
patient.
(2) Diffusion Oxygen Delivery
Oxygen transport to tissue also occurs via diffusion. There are a
series of diffusion boundaries through which O.sub.2 must pass on
its way from the red cell to the tissues. Fick's law of diffusion
states that the overall rate of diffusion of a gas from one
compartment to another is governed by the diffusion gradient, the
difference between the gas concentrations (P.sub.1 -P.sub.2) within
the two compartments, and a diffusion constant, K.sub.d, which is a
lumped-sum reflection of many factors including properties of the
boundary layers, temperature, etc. ##EQU1##
The process of O.sub.2 diffusion can be simply illustrated by
considering the movement of water through holes in a wall
separating a higher elevation reservoir and a lower level
reservoir. Water is supplied initially at one elevation (P.sub.1),
and flows to a second lower level (P.sub.2). The hydrostatic
pressure driving this movement is the vertical difference in height
between the two reservoirs. The total rate of water movements is
also limited by the cross-sectional area of the holes in the
barrier which provide resistance to flow from compartment 1 to 2.
In this analogy, the two water levels correspond to the two O.sub.2
pressures (P.sub.1 and P.sub.2) in Fick's law of diffusion, shown
above, and the cross-sectional area of the holes in the barrier
(through which the water flows) would be represented by the
diffusion constant, K.sub.d.
Experimental work has shown that there are probably two barriers to
diffusion of O.sub.2 from the red cell to the tissues; the layer of
unstirred plasma surrounding the red blood cell, and the collective
membranes separating the plasma space from the cellular cytosol of
adjacent tissue. Raising the PO.sub.2 in the plasma will have the
effect of increasing the rate of diffusion into tissues, since the
plasma represents an "intermediate level reservoir" in the
preceding analogy. In fact, if there is not a limiting supply of
O.sub.2 in red cells, then the rate of movement of O.sub.2 from
plasma to tissues will be proportional to this plasma reservoir.
This represents the essence of the proposed use of low-dose O.sub.2
carriers to reduce the need to transfuse allogeneic blood.
The proposed mechanism assumes that a small reduction of the
reservoir of available O.sub.2 (e.g., hemodilution) will not
appreciably change the overall rate of diffusion because it is
assumed that the barrier to diffusion represented by the membranes
between the plasma and tissue cytosol space is rate-limiting.
Experimental evidence exists to support this assumption.
Increasing the diffusive delivery of O.sub.2 to tissue is sometimes
called "diffusion facilitation", and could increase O.sub.2
delivery to tissues under conditions where O.sub.2 delivery might
be otherwise supply-limited. In other words, increasing the
dissolved (plasma) O.sub.2 concentration is expected to decrease
the level at which critical O.sub.2 delivery occurs and thereby
increase the margin of safety in terms of prevention of tissue
hypoxia. Experimental evidence suggests that this is, in fact, the
case. In a study by Faithfull & Cain (J. Crit. Care 3:14-18
(1988)), dogs were initially hemodiluted with either 6% dextran
(average molecular weight 70,000, in Tyrode's solution), or the
perfluorocarbon emulsion, FLUOSOL, and then progressively
hemorrhaged to determine the critical O.sub.2 extraction ratios.
FLUOSOL-treated dogs had lower mixed venous PO.sub.2 levels and
higher O.sub.2 extraction fractions at the critical O.sub.2
delivery point. This indicated that perfluorochemicals in FLUOSOL
may have promoted diffusion of O.sub.2 into the tissues. This
effect was very evident in these FLUOSOL studies since these dogs
likely had a compromised microcirculation due to the severe
capillary flow inhomogeneity that occurs in dogs immediately
following injection of only 1 to 2 mL of the FLUOSOL emulsion
(Faithfull et al. Microvasc. Res. 33:183-93 (1987)).
It should be noted that transfusion of red cells will not affect
O.sub.2 diffusion in the same manner as described. In fact, an
additional physiological effect described by Federspiel et al.
(Microvasc. Res. 32:164-89 (1986)), refers to the fact that in
normal capillary beds, red cells are separated by considerable
distances as they individually traverse the capillary network. The
O.sub.2 would be expected to transfer from red cells to tissue
predominantly across the area where the red cell is closely in
contact wit the endothelial cells lining the vasculature. Addition
of a cell-free O.sub.2 carrier might increase the rate of O.sub.2
transfer, simply on the basis that more O.sub.2 would be in contact
with the endothelial cells.
In general, improvement of blood fluidity by hemodilution has been
shown to increase mean tissue PO.sub.2 in various organs (Messmer
et al. Res. Exp. Med. 159:152-56 (1973)). This increase in tissue
PO.sub.2 was attributed to more even flow distribution at the
microcirculatory level and was interpreted as improved tissue
oxygenation. On the other hand, Homer Microvasc. Res. 22:308-23
(1981), argued that in acute anemia there may be large differences
between red blood cell PO.sub.2 and the plasma PO.sub.2. This would
occur as a result of O.sub.2 diffusion from the red cell being
slowed by passage through the plasma (which has very low O.sub.2
solubility characteristics). With hemodilution, the spacing between
red blood cells in tissue capillaries is increased so that outward
diffusion of O.sub.2 from red cells is slowed further by the
increased diffusional barrier of plasma. The resultant gradient for
PO.sub.2 may not be resolved (i.e., not all the oxygen has time to
unload) during the short time that the red cell dwells in the
capillary and O.sub.2 extraction may be diminished accordingly
(Gutierrez, Respirat. Physiol. 63:79-96 (1985)).
The presence of an additional O.sub.2 carrier such as a
perfluorochemical in the plasma will increase the total O.sub.2
content in the plasma compartment of blood and may facilitate the
diffusion of O.sub.2 from the red cell into the tissues. The
addition of a relatively small dose (3 mL [2.7 g perflubron]/kg BW)
of a concentrated 90% w/v perflubron emulsion will result in a
significant increase in the total O.sub.2 content in the plasma.
When performed during respiration with 100% O.sub.2 and in the
presence of acute normovolemic hemodilution (to a hematocrit of
25%), the net result would represent an increase in the available
oxygen. Normal oxygen consumption would come preferentially from
the perflubron and the plasma, since this O.sub.2 is physically
dissolved and therefore readily available (compared to the O.sub.2
that is chemically bound to hemoglobin as a ligand). The remaining
O.sub.2 carried by the red cells would therefore represent an
available reservoir of extra O.sub.2 that would supply additional
oxygen, when needed, to prevent certain sensitive tissues from
reaching a critical level of O.sub.2 delivery.
A low-dose cell-free oxygen carrier is therefore superior, in terms
of tissue oxygenation, to additional red cell transfusion. Such an
oxygen carrier is used for the temporary enhancement of oxygen
delivery during the acute phase of surgery or following organ
ischemia or infarct. None of the currently available oxygen
carriers can be considered effective "blood substitutes" because of
their short retention time in the circulation (hours) compared to
red cells (months). With routine use, especially in uncomplicated
elective surgery combined with acute normovolemic hemodilution
procedures, the "transfusion trigger" can be reduced. With the
method of the present invention, wherein PvO.sub.2 or other indices
of tissue oxygenation is continuously or periodically monitored and
autologous blood or additional oxygen carrier administered to the
patient in response to PvO.sub.2 levels, the "transfusion trigger"
can be reduced even further. This can eliminate the need for
translation of allogeneic red blood cells in many cases and thereby
significantly reduce the risk of transfusion-borne disease and
transfusion reaction. The present invention also provides for
hemodilution as an adjunctive therapy for organ ischemia or
infarct, by maintaining adequate delivery of oxygen to the tissues
while reducing the number of cells known to excaberage the effects
of ischemia and infarct.
EXAMPLE 1
Enhancement of O.sub.2 Delivery by Perfluorocarbon Emulsion
Immediately prior to undergoing surgery, a patient is subjected to
perioperative isovolemic hemodilution. The removed blood is stored
for later use. Blood is removed with the concomitant intravenous
replacement by a crystalloid solution. During this time, the
patient's fractional inspired oxygen concentration (FiO.sub.2) is
increased to 1. The patient is hemodiluted until the hemoglobin
concentration reaches 8 gm/dL, with each aliquot of the removed
blood being replaced by 3 volumes of Ringer-lactate. A 90% w/v
perflubron emulsion having the composition of Formula I is
administered intravenously to a total dose of 1.8 gm/kg body
weight, while the patient's PvO.sub.2 is monitored using a
Swan-Ganz catheter. Hemodilution and administration of perflubron
emulsion is continued until the PvO.sub.2 reaches 40 mm Hg
(hemoglobin level is 2 gm/dL). Surgery is then initiated, with an
attendant blood loss of up to 3 liters. Autologous blood is then
re-administered to the patient to maintain the PvO.sub.2 at 40 mm
Hg or above.
Although the invention has been described with reference to
particular preferred embodiments, the scope of the invention is
defined by the following claims and should be construed to include
reasonable equivalents.
* * * * *