Unit 4
Hemostasis as a perfusion
problem
Jeff Acsell “*”
Rick Kunz “*”
Chad Smith “*”
Juan Tucker “*”
Mindy Valleley
Tammy Murray
Grant Catlett
University of Nebraska Medical Center
Eric Rauch
Clinical Perfusion Education
Mark Brown
CLPR 775 – Fall 2004
Hemostasis as a perfusion problem
Is there a problem more central to the practice of
perfusion? Perhaps gas exchange. Yet
extracorporeal gas exchange cannot occur without
some understanding and control over the process of
hemostasis.
It is a problem we all struggle with each day we
practice our craft. A problem that we often only
understand minimally, yet treat cavalierly. It is easy
as a Perfusionist to get into the automaticity of
giving every patient 400 iu/kg because, “that’s what
we’ve always done”.
Hemostasis as a perfusion problem
It is a big problem
Chapter 22 of Gravelee: Cardiopulmonary
bypass. Principles and Practices is titled,
Anticoagulation for Cardiopulmonary Bypass, is
one of five chapters that try to address
various issues involved in hemostasis. This
one chapter alone contains over 350
references to the scientific literature, in an
effort to address this complex topic.
Hemostasis as a perfusion problem
• A search on Google for Hemostasis yielded
about 145,000 “results”
• A further search for the British version
Haemostasis revealed another 95,800 “results”
• Clicking on definition brought up 5 American
definitions and 3 British, all of which were
various forms of “stoppage of the flow of
blood” or “arrest of bleeding”.
Hemostasis as a perfusion problem
• It is obvious to every Perfusionist that the
definition of the word, doesn’t fairly express
what it is that makes hemostasis so
important for extracorporeal circulation.
• Surely there isn’t another profession that is
more concerned with the arrest of, control of,
preservation of, and restoration of
hemostasis.
Hemostasis as a perfusion problem
• The first problem with hemostasis, in this forum, is
its size and scope. There are many sub-topics within
this broad subject that should spawn examinations
as perfusion problems.
• In an effort to “whittle a little off the tree” we
narrowed the scope a bit in choosing a topic worthy
of inspection.
• My fear is that we only saw the root, and may be
trying to cut down a sequoia with a butter knife.
Heparinization (and Protamine
Neutralization)
As a Perfusion Problem
There are hundreds of thousands surgeries
performed each year in the US requiring
cardio-pulmonary bypass. In the vast
majority of these cases the patient is
anticoagulated with heparin and later the
heparin is neutralized with protamine
–Source: STS Adult CV Surgery national database, Spring 2004
The heparin-protamine regimen has been the
method of choice for extracorporeal circulation
since 1939 when John Gibbon used this
combination approach on laboratory animals, and
then humans in 1953
In the intervening 51 years, much research has been
conducted on how to safely use heparin and
protamine.
Research continues today.
Heparin / protamine administration has
become an automatic process in the daily
routine of cardiac surgery.
Often, little thought goes into this aspect of the
surgery
– Protocols are written
– The reasons are forgotten
This is what prompted this
project
Through experience and observation, these
authors hypothesize that:
Many surgeons, anesthesiologists and
Perfusionists administer these drugs with such
regularity, that the reasons behind their protocols
have become clouded by the passing of time.
Through experience and observation, these
authors hypothesize that:
Only when confronted by deviations from the
normal case Such as:
• Heparin resistance
• Heparin allergy (HIT, HITT)
• Protamine reaction
do clinicians question the processes with which
they have become so comfortable.
“Familiarity with its use has led to the assumption on
the part of many that the control of heparin during,
and the neutralization of heparin after,
extracorporeal circulation are straightforward
matters which can be adequately handled by means
of set protocols.”
– Brian S. Bull, M.D. 1974 Heparin therapy during
extracorporeal circulation I. Problems inherent in existing
heparin protocols. The Journal of Thoracic and
Cardiovascular Surgery:1975;69(5)674-684
The intent of this project is to:
• review the literature in an effort to elucidate the
reasons behind the protocols in use today,
• to re-acquaint ourselves with these reasons so that
we can evaluate our own protocols,
• informally poll the perfusion “World” to discover the
range of, similarities of, and differences in
hemostasis management in use,
• and, let’s not kid ourselves; get a good grade in
CLPR775.
Heparin
• Glucosaminoglycan
(polysaccharide)
• Found most commonly
in mast cells
• Strongest
macromolecular acid in
the body
Heparin Acts as a catalyst for ATIII to
accelerate the neutralization of :
– Thrombin
– XIa
– Xa
– XIIa
– IXa
– VIIa/TF complex
Jack Hirsh, et al. Heparin and Low-Molecular-Weight
Heparin Mechanisms of Action, Pharmacokinetics,
Dosing, Monitoring, Efficacy, and Safety. Chest.
2001;119:64S-94S
Heparin
Yep, that’s about all we’re going to go into the
specifics of it’s chemical interaction and
function with respect to the clotting cascade.
This and related problems would provide
another excellent topic for inspection.
Heparin
• Normally Unfractionated
– heterogeneous mixture of molecules from 3,000 to
40,000 daltons (mean ~ 15,0000)
– batch to batch heparin preparations may have
different activity levels per milligram
– standardized activity levels reported in units
• 100 units = 1 mg
– 1 unit will maintain anticoagulation of 1 ml of
recalcified sheep serum for 1 hour
Sources of Heparin
• First isolated from liver extract (hepatic)
• Porcine intestinal mucosa
• Bovine lung
Problem: What heparin should we
use?
• Porcine
• Bovine
– Lower molecular weight
– Higher molecular weight
– More cross linked
structure
– Less cross linking
– Higher content of binding
sites for ATIII
– Lower content of ATIII
binding sites
Problem: What heparin should we
use?
• Porcine
– Higher incidence
of delayed
hemorrhage?
• Bovine
– Lower incidence
of heparin
rebound?
Abbott WM, Warnock DF, Austen WG. The relationship of heparin
source to the incidence of delayed hemorrhage. Surg Res
1977:22:593-597.
Problem: What heparin should we
use?
• Porcine
– Higher doses
needed for CPB?
• Bovine
– Perhaps lower
doses needed?
Stewart SR, Gaich PA. Clinical comparison of two brands of heparin
for use in cardiopulmonary bypass. J Extracorporeal Technology
1980:12:29-33.
Problem: What heparin should we
use?
• Porcine
– 25-30% less
protamine needed
compared to
bovine?
• Bovine
– May need more
protamine to
neutralize?
Novak E, Sekhar NC, Dunham NW, et al. A comparative study of
the effect of lung and gut heparins on platelet aggregation and
protamine neutralization in man. Clin Med 1972:79:22—27.
Lowary LR, Smith FA, Coyne E, et al. Comparative neutralization
of lung- and mucosal-derived heparin by protamine sulfate using
in vitro and in vivo methods. / Pharm Sci 1971;60: 638-640.
Problem: What heparin should we
use?
• Porcine
• Bovine
– Inhibits factor Xa more
effectively than Bovine
– Inhibits factor IIa more
effectively than Porcine
– (only partially neutralized
by protamine)
– (totally neutralized by
protamine)
Barrowcliffe TW, Johnson EA, Eggleton CA, et al.
Anticoagulant activities of lung and mucosal heparins. Thromb
Res 1977; 12:27-36.
Problem: What heparin should we
use?
• Porcine
– Lower incidence of
HIT with porcine
• Rao AK, White GC,
Sherman L, et al; Arch
Intern Med
1989:149:1285-1290
• Bovine
– Cannot rule out
bovine spongiform
encephalopathy
transmission
• Bolt J, Zickmann B,
Ballesteros m, Scholz D,
Dapper F, Hempelmann
G, J of Cardiothorac and
Vasc Anest 1991:5:449453
Problem: What heparin should we
use?
• Porcine
– Longer lasting
• Bovine
– Shorter lasting
– Renal elimination of
bovine and porcine
does not differ
Bolt J, Zickmann B, Ballesteros m, Scholz D, Dapper F, Hempelmann
G, Does the Preparation of Heparin Influence Anticoagulation During
Cardiopulmonary Bypass, J of Cardiothorac and Vasc Anest
1991:5:449-453
Problem: What heparin should we
use?
The answer to this problem may have already
been made for us, as there have been several
reports from Perfusionists around the United
States being unable to obtain bovine lung
heparin.
With the increased awareness of “mad cow”
disease, certain countries (Canada) have
imposed restrictions on its use.
Additional information to help answer this
problem will follow later in this presentation.
Heparin
• Half life of heparin is
dose dependent.
– Olsson P, Lagergren H,
Ek S. The elimination
from plasma of
intravenous heparin.
An experimental study
on dogs and humans.
Acta Med Scand
1963:173:619-630.
• And Highly variable
between patients
Dose
Half life
400 u/kg
Minutes
126 +- 24
200 u/kg
93 +-6
100 u/kg
61 +-9
Problem: How should we monitor
heparin therapy?
Problem: How should we monitor heparin therapy?
Historical Monitoring of Heparin Effect
• 1953 Extension of the bleeding time
• Lee-White clotting time
• 1958 Kaolin clotting time - plasma
• 1964 Celite clotting time – plasma
• 1966 ACT of whole blood
• 1977 Automated ACT
Problem: How should we monitor heparin therapy?
Activated Clotting Time
• Hattersley 1966:
– Introduced ACT for whole blood
“probably technique of choice in the control of
therapeutic heparin”, “quick and more reliable
than the Lee-White.”
• Hattersley PG, Activated Coagulation Time of Whole Blood.
JAMA 1966:196(5)150-154
Problem: How should we monitor heparin therapy?
The ACT
• Hattersly found that
– room temp values were 60 sec longer than 37o.
– variables that showed no appreciable variation in
ACT:
• quantity of celite, tube diameter, volume of blood between 1
and 3 ml, number of inversions of the tube
– 0.1 u of heparin increased ACT in 1ml of blood by
~45 seconds
Problem: How should we monitor heparin therapy?
The ACT
• Hattersly
“simple, reliable, and reasonably sensitive bedside
test of the coagulation mechanism.”
– He did not use it for extracorporeal circulation
monitoring
– His test has lasted as the standard of care for 51+
years
Problem: How should we monitor heparin therapy?
Heparin Management
Empiric management – Primary method for the first 30
years of bypass
– Based on knowledge of effect of heparin
– Applied to general population
– No individualization
– No assessment needed
– Example
• Bolus 300 mg/kg heparin and follow with 1.5 mg/kg/hr until end
of bypass
• Reverse with 3.6 mg/kg protamine
Problem: What is an adequate
dosage?
The method was as simple as that. Administer
the heparin, do the surgery and reverse with
a set quantity of protamine. If there was still
bleeding they would give more protamine.
For many years the determination of safe
anticoagulation was the lack of observed clot
in the extracorporeal circuit.
Problem: How should we monitor heparin therapy?
Empiric management - Problems
There is a wide range of variability
between patients in
– Patient Response to heparin
– Half life of heparin
Bolt J, Zickmann B, Ballesteros m, Scholz D, Dapper F,
Hempelmann G, Does the Preparation of Heparin Influence
Anticoagulation During Cardiopulmonary Bypass, J of
Cardiothorac and Vasc Anest 1991:5:449-453
Culliford AT, Gitel SN, Starr N, et al. Lack of Correlation Between
Activated Clotting Time and Plasma Heparin during
Cardiopulmonary Bypass. Ann. Surg. 1981: 105-111
Problem: How should we monitor heparin therapy?
Empiric management - Advocates
Metz S, Keats AS. Low activated coagulation time
during cardiopulmonary bypass does not increase
postoperative bleeding. Annals of Thoracic Surgery.
1990:49(3):440-444
– 300 U/kg heparin to 193 patients
– No additional heparin given
– 51 patients had ACTs less than 400
– 4 patients had ACTs less than 300
– No postoperative bleeding
– No clots in the circuits
Problem: How should we monitor heparin therapy?
The ACT
Landmark paper by Bull, et al in 1975
– Analyzed 30 different protocols of anticoagulation
from around the country
– Using bovine heparin, he defined ranges
• < 180 seconds – unsafe
– as determined by observations from long term bypass
• < 300 seconds – insufficient heparin
• 300 – 600 seconds “Safe Zone”
– As determined by observations of lack of clot in circuit
• Above 600 seconds – Excess heparin
Bull BS, Korpman RA, Huse WM, et al. Heparin therapy during
extracorporeal circulation. I. Problems inherent in existing
heparin protocols. J Thoracic Cardiovascular Surg 1975:69:674684.
Problem: How should we monitor heparin therapy?
Bull, Brian MD
• Recommended the ACT as the standard for
monitoring anticoagulation on CPB
• Recommended that sufficient heparin be
administered to raise the ACT to 8 minutes (480
seconds)
– easily remembered arbitrary number, approximately
between 300 and 600 seconds, which falls in the “safe
zone”.
• 480 seconds is still the most common target ACT
today
Problem: How should we monitor heparin therapy?
Bull, Brian MD
Introduced the concept of heparin dose
response to individualize heparin and
protamine dosages (HDR) CPB
Bull BS,. Huse W M, Brauer FS, Korpman RA, Heparin therapy
during extracorporeal circulation II. The use of a dose-response
curve to individualize heparin and protamine dosage. The
Journal of Thoracic and Cardiovascular Surgery. 1975:69(5)685689
Problem: How should we monitor heparin therapy?
Bull, Brian MD
HDR protocol
– Perform ACT prior to surgery
– Administer 2 mg/kg dose and perform ACT
– Construct a dose response curve
– Calculate dose needed to reach 480 seconds
– Calculate dose of protamine needed from last ACT
on CPB
Problem: How should we monitor heparin therapy?
ACT-HDR method
Comparing the empiric approach to the ACT
– Group I – 3mg/kg plus 1.5 mg/kg/45 minutes
– Group II – 2.0 mg/kg and maintain at ACT of 400 seconds
Group II results
1. Decrease in postoperative blood loss
2. Decrease in heparin administered
3. Lower dose of protamine required
With the ACT-HDR method
Babka R. Colby C. El-Etr A. Pifarre R. Monitoring of
intraoperative heparinization and blood loss following
cardiopulmonary bypass surgery. Journal of Thoracic &
Cardiovascular Surgery. 1977;73(5):780-782
Problem: How should we monitor heparin therapy?
ACT-HDR method
Comparing 58 historic cases using empiric method to
56 cases monitored by automated ACT
• In the automated ACT cases.
– Protamine to heparin ratio was 25%less
– Postoperative blood loss was 48% less
Verska JJ. Control of heparinization by activated clotting time
during bypass with improved postoperative hemostasis.
Annals of Thoracic Surgery. 1977:24(2);170-173
Problem: How should we monitor heparin therapy?
ACT monitoring and change in
clinical practice
• The introduction of the ACT in the 1960s and 1970s brought
about a significant change in the practice of perfusion.
• The test is easy to perform, especially when automated
• Studies comparing dosage based on patient weight or BSA
verses ACT demonstrated a reduction in post-operative
bleeding when ACTs were used or no difference.
• This was compelling evidence that the ACT should become the
standard of care.
• By the late 1970s and continuing until today the ACT became
the most common method of determining heparin dosage and
effect
Problem: What is a safe ACT?
1978 Young, et al, using an animal model, bovine
heparin, experimented to determine the minimum
safe ACT
• Used the appearance of fibrin monomer as indicator
of coagulation
– “The lower limit as measured by the ACT...is at least 400
seconds”
Young JA, Kisker TC, M.D., Doty DB Adequate
Anticoagulation During Cardiopulmonary Bypass Determined
by Activated Clotting Time and the Appearance of Fibrin
Monomer. The Annals of Thoracic Surgery 1978:26(3)231-237
Problem: What is a safe ACT?
• The study by Young, is often reported as the first
controlled study that used a biological marker to
determine a safe level of anticoagulation. It was
another step in solving this problem
• The appearance of fibrin monomer in blood indicated
that coagulation had been initiated and that there
was a consumption of fibrin occurring, which meant
that there was not enough heparin circulating to
totally inhibit thrombin.
• This reinforced the work of Bull, and more
Perfusionists began to adopt the protocol of
maintaining ACTs greater than 400 seconds.
Problem: What is a safe ACT?
Problems with ACT-HDR?
Heparin administration by ACT can be problematic
– ACT values are altered by temperature
– ACT values are altered by hemodilution
– ACT does not measure units of heparin
– ACT does not accurately reflect the protamine needed
1. Culliford AT, et al. 1981;191(1):105-111
2. G. J. Despotis, et al. J Thoracic Cardiovascular Surg 1994;108:10761082
3. Tian L, et al. JECT 1995:27(4)192-196
4. Fox DJ, Gaines J, Reed G. JECT;11(4):137-142
Problem: What is a safe ACT?
Problem: with ACT-HDR
These inherent inconsistencies in ACT driven
HDR could lead to;
– Overestimation of the actual heparin level
– Under heparinization
– Consumption of coagulation factors
– Increased transfusion requirements
Problem: What is a safe ACT?
What is needed?
Hypothesis: The inherent inconsistencies with the ACT
based heparin management might be overcome with
a method to monitor the concentration of heparin
circulating in the plasma.
• Protamine titration
– Automatic heparin-protamine titration device (AHPT)
Hepcon A-10
Hill AG, Lefrak EA. Monitoring heparin and protamine therapy
during cardiopulmonary bypass procedures. Proceedings,
American Society of Extra-Corporeal Technology. 1978;6:10-13
Problem: How should we monitor heparin therapy?
Hepcon
In 1979 two studies, Hill and Lefrak, Fox et al,
compared anticoagulation monitoring by the
Hemochron device (AACT), and the Hepcon device
(AHPT).
– The ACTs by the manual method correlated with the AACT
– The ACTs did not correlate with AHPT
– The AHPT “…more precise in determination of heparin
levels and the doses required to facilitate reversal.”
Fox DJ, Gaines J, Reed G. Vehicles of heparin management: A
comparison. JECT;11(4):137-142
Problem: Does heparin concentration
make a clinical difference?
• Investigators began to wonder if there would be a
clinical difference in maintaining anticoagulation by
heparin concentration or by ACT or by the empiric
method
• Several studies were published showing variable
results
Problem: Does heparin concentration
make a clinical difference?
Patient assigned to one of 3 groups using bovine heparin
1.
300 iu/kg and ACT >400 sec
2.
250 iu/kg and ACT >400 sec
3.
350 iu/kg and heparin concentration of 4.1 iu/ml
Results
–
Sub clinical coagulation occurred in all 3
–
Post-op drainage correlated with increased heparin levels
–
ACT > 350 seconds results in acceptable hemostasis
Gravlee GP. Haddon WS. Rothberger HK. Mills SA. Rogers AT. Bean VE. Buss DH.
Prough DS. Cordell AR. Heparin dosing and monitoring for cardiopulmonary bypass. A
comparison of techniques with measurement of sub clinical plasma coagulation.
Journal of Thoracic & Cardiovascular Surgery. 1990;99(3):518-527.
Problem: Does heparin concentration
make a clinical difference?
1. Used porcine heparin
2. Control group, 250U/kg + heparin to ACT of 480sec,
protamine 0.8:1
3. Intervention group, HDR to 480sec, protamine by HDR
–
Higher heparin concentrations are maintained by
anticoagulation by heparin concentration
–
Higher heparin concentrations result in more effective
suppression of coagulation
Despotis GJ. Joist JH. Hogue CW Jr. Alsoufiev A. Joiner-Maier D. Santoro
SA. Spitznagel E. Weitz JI. Goodnough LT. More effective suppression of
hemostatic system activation in patients undergoing cardiac surgery by
heparin dosing based on heparin blood concentrations rather than ACT.
Thrombosis & Haemostasis. 1996:76(6):902-908.
Problem: Does heparin concentration
make a clinical difference?
1. Used porcine heparin
2. Control group, “conventional” to ACT of 400sec,
protamine “conventional”
3. Intervention group, HDR to 400sec, protamine by HDR
–
Intervention group received slightly larger heparin doses
and significantly lower protamine dosages
–
Chest tube drainage was less in the intervention group
–
Donor exposures less in the intervention group
Jobes DR. Aitken GL. Shaffer GW. Increased accuracy and precision of
heparin and protamine dosing reduces blood loss and transfusion in
patients undergoing primary cardiac operations.
Journal of Thoracic & Cardiovascular Surgery. 1995;110(1):36-45
Problem: Does heparin concentration
make a clinical difference?
1.
Used porcine heparin
2.
Control group, celite ACT
3.
Intervention group, kaolin ACT and heparin concentration
measurement
–
Intervention group had higher heparin concentrations than the
control group
–
Intervention group had lower fibrinopeptide A and D-dimer levels
after bypass
–
Intervention group had higher levels of factors V, and VIII,
fibrinogen and ATIII after bypass
Despotis GJ. Joist JH. Hogue CW Jr. Alsoufiev A. Joiner-Maier D. Santoro
SA. Spitznagel E. Weitz JI. Goodnough LT. More effective suppression of
hemostatic system activation in patients undergoing cardiac surgery by
heparin dosing based on heparin blood concentrations rather than ACT.
Thrombosis & Haemostasis. 1996:76(6):902-908.
Problem: Does heparin concentration
make a clinical difference?
1.
94 patients undergoing DHCA for aortic surgery, aprotinin and 3
mg/kg heparin given to all
2.
During CPB
–
Group A. 49 patients were given additional 1 mg/kg heparin
–
Group B. 45 patients were given 1 mg/kg heparin if ACT fell below 500
seconds
•
Heparin dose was higher in Group A
•
Levels of TAT, fibrinogen, DD,PF-4, beta-TG were lower in Group A
•
Intra and post-operative platelet count was higher in Group A
Okita Y. Takamoto S. Ando M. Morota T. Yamaki F. Matsukawa
R. Kawashima Y. Coagulation and fibrinolysis system in
aortic surgery under deep hypothermic circulatory arrest with
aprotinin: the importance of adequate heparinization.
Circulation. 1997 ;96(9 Suppl):II-376-381
Problem: Does heparin concentration
make a clinical difference?
Comparing the porcine heparin concentration (HC) with ACT,
during hypothermia and DHCA
1.
Maintained ACT >400seconds
•
2.
Maintained heparin concentration at 3 mg/kg
•
–
Resulted in
Higher blood concentrations were maintained by the HC method
•
–
Or
and
Better suppression of the coagulation system
Shirota K. Watanabe T. Takagi Y. Ohara Y. Usui A. Yasuura K.
Maintenance of blood heparin concentration rather than activated
clotting time better preserves the coagulation system in
hypothermic cardiopulmonary bypass. Artificial Organs. 2000;
24(1):49-56
Problem: Does heparin concentration
make a clinical difference?
Results of surgery on 487 patients using multiple
logistic and linear regression on variables that may
have an association on blood loss and/or
transfusion.
• Female gender, lower heparin dose, pre-op ASA use,
and number of transfusions were associated with
increased chest tube drainage.
Despotis, George J. MD; Filos, Kriton S. MD; Zoys, Timothy N. MD;
Hogue, Charles W. Jr., MD; Spitznagel, Edward PhD; Lappas, Demetrios
G. MD. Factors Associated with Excessive Postoperative Blood Loss and
Hemostatic Transfusion Requirements: A Multivariate Analysis in Cardiac
Surgical Patients. Anesthesia & Analgesia 1996:92(1)12-21
Problem: Does heparin concentration
make a clinical difference?
In a Anesthesiology 1999 review of the available literature
published, the following statements were made
• “Because generation of FPA and inhibition of clot-bound
thrombin have been shown to relate inversely to heparin
concentration, maintenance of heparin concentrations that
more effectively inactivate thrombin may preserve hemostasis
during prolonged CPB”
and
• “..maintenance of higher patient-specific heparin
concentrations should be considered to reduce thrombin –
mediated activation and consumption of platelets in patients
requiring longer CPB intervals.”
Despotis GJ, Gravlee G, Filos K, Levy J. Anticoagulation Monitoring
during Cardiac surgery; A Review of Current and Emerging Techniques.
Anesthesiology 1999:(91)1122-1151
Problem: When should the baseline
sample be taken?
Though Bull, et al. suggested that the baseline ACT
should be determined prior to the start of surgery,
there is evidence to the contrary.
• Baseline ACTs decrease with anesthesia and
surgery.
• Therefore an ACT baseline found prior to surgery,
could lead to the mistaken diagnosis that all heparin
had been neutralized after protamine administration.
Gravlee GP. Whitaker CL. Mark LJ. Rogers AT. Royster RL. Harrison GA.
Baseline activated coagulation time should be measured after surgical
incision. Anesthesia & Analgesia. 1990;71(5):549-553
Problem: How much time should elapse
between heparin administration and ACT to
confirm anticoagulation?
The answer to this question requires us to
know:
• how fast is the onset of action for heparin?
• what is the circulation time of heparin?
• how heparin is distributed in the body?
Problem: How much time should elapse
between heparin administration and ACT to
confirm anticoagulation?
The onset of action is very fast
– In one study Using bovine heparin
– Peak arterial ACT occurred within 30 seconds
– Peak venous ACT occurred within 60 seconds
Heres EK. Speight K. Benckart D. Marquez J. Gravlee GP.
The clinical onset of heparin is rapid. Anesthesia & Analgesia.
2001;92(6):1391-1395
Problem: How much time should elapse
between heparin administration and ACT to
confirm anticoagulation?
The onset of action is very fast
– In a second study Using bovine heparin
– ACT of 400 seconds was obtained within one minute
– There was a progressive increase for 4 minutes followed by a slow
decline where the one minute ACT is essentially equivalent to the
10 minute ACT
– An ACT taken at one minute will save time and approximate a long
term ACT which is a better indicator of heparinization.
E.T. Coleman, M. Hargrove, H.P. Singh, T. Aherne, Estimation of Minimum
Heparin Circulation Time for Activated Clotting Time Determination.
Journal of Extra-Corporeal Technology. 1994;26(2):61-63
Problem: How much time should elapse
between heparin administration and ACT to
confirm anticoagulation?
How is heparin distributed in the body?
•
Heparin is a highly polarized molecule
•
This pre-disposes it to stay within the plasma and not cross into any
lipid bearing tissues
•
Some portion of administered heparin moves into an attaches to
vascular endothelial cells.
•
There is also some degree of sequestration in reteculoedothelial cells
and vascular smooth muscle.
•
This may account for the relatively quick fall in the ACT seen within
the first few minutes after administration.
Hiebert LM. McDuffie NM. The internalization and release of heparins by cultured
endothelial cells: the process is cell source, heparin source, time and
concentration dependent Artery. 1990;17(2):107-118
Have we found solutions to any of
our identified problems?
With respect to: What heparin should we use?
• On slide #27 we suggested that the decision may have already been
made for us in favor of porcine heparin.
• In our exploration of the monitoring of heparin, several papers were
discovered, hinting that porcine heparin administered and maintained
at high concentrations resulted in less post-operative blood loss, better
preserved coagulation factors, and better platelet function.
• Porcine heparin has a higher anti Xa activity that is not completely
reversed by protamine administration, which may be a potential cause
of heparin rebound. Another problem to be investigated.
• With respect to HIT porcine heparin may be a better choice. For this
reason alone, The Medical University of SC switched the entire
hospital formulary to porcine heparin three years ago.
• For now – porcine heparin has an edge
Have we found solutions to any of
our identified problems?
With respect to: How should we monitor heparin
therapy?
• It is obvious to most, that strict empiric therapy should not
be utilized these days. The advent of the automated ACT,
with its proven benefits of reducing post-operative
bleeding, and catastrophic coagulation, reduction of
transfusion requirements, and reduced protamine dosages,
has hopefully put an end to that practice.
• The ACT is known to fall short of being the perfect
monitoring regimen. It fails to correlate well with
circulating heparin concentrations, mainly due to the
effects of hemodilution and hypothermia.
Have we found solutions to any of
our identified problems?
With respect to: How should we monitor heparin therapy?, What is
a safe ACT?, and Does heparin concentration make a clinical
difference?
• Most of the studies that compared heparin management by the ACT or
heparin concentration, favor maintaining heparin concentration or
show no difference.
• At the time of most of these studies (late 1970s – 1990s) most CPB
involved diluting patients to lower hematocrit levels, and utilizing
deeper hypothermia than is practiced today. (We don’t have a printed
reference for this)
• With the current trends toward smaller circuits, retrograde autologous
prime, and the resulting higher hematocrits, along with tepid or
normothermic bypass, there seems to be an opportunity to investigate
whether the ACT better correlates with heparin concentration, under
these seemingly more favorable conditions.
Have we found solutions to any of
our identified problems?
With respect to: How should we monitor heparin therapy?, What is
a safe ACT?, and Does heparin concentration make a clinical
difference?
• In the book, Cardiopulmonary bypass : principles and practice, the
authors conclude that “in most situations” they see no clinical
advantage to heparin concentration monitoring. They advocate using
the ACT maintained at 400 – 480 seconds. This also seems to be the
level accepted by the perfusion community as reflected by our informal
survey. (see Chart)
• That having been said, one of the editors and co-author of the chapter
that this was written in, has conducted research, mainly using bovine
heparin, that showed few of the benefits found in other investigations.
Dr Gravlee is an expert in the field, but could be considered to be
biased in his opinion.
“World” Target ACT for Bypass
11%
5%
480 sec
400 sec
16%
350 sec
500 sec
68%
N=19
Have we found solutions to any of
our identified problems?
With respect to: How should we monitor heparin therapy?, What is
a safe ACT?, Does heparin concentration make a clinical
difference?
• It is difficult to deny that monitoring the concentration of circulating
heparin has distinct advantages over the ACT method. From our
informal poll of “World” Perfusionists, extrapolated to the perfusion
community at large, the technology to perform protamine titration and
monitor heparin concentration, has been embraced by a significant
percentage of practitioners
• The following chart indicates that 69.6% of the Perfusionists
responding to our survey, that indicated what instrument they use for
heparin monitoring, have the technology to perform protamine titration
for heparin concentration, by using the Hepcon system or the RXDX
system.
“World” Anticoagulation Monitoring Instruments Reported
Hemochron 21.7%
RXDX 8.7%
Hepcon 60.9%
ACT II 8.7%
N=23
Have we found solutions to any of
our identified problems?
With respect to: How should we monitor heparin therapy?, What is a safe
ACT?, and Does heparin concentration make a clinical difference?
•
The previous slide provides evidence that the standard of care in perfusion
today is, maintaining the technology for heparin concentration determination,
and utilization of the ACT.
•
This seems to be an appropriate choice. For many procedures that are
relatively quick and performed at normothermia or tepid temperatures, the
ACT is probably adequate.
•
It also seems reasonable that if the procedure is long and/or requires deep
hypothermia, heparin concentrations should be checked and/or additional
heparin should be administered.
•
However, the protocol best supported by the literature reviewed is to maintain
both adequate heparin concentration and a corresponding ACT.
•
From the survey data collected, it isn’t possible to tell how many Perfusionists
are actually using protamine titration for heparin management.
Have we found solutions to any of
our identified problems?
With respect to: What is an adequate dosage?, and Does heparin
concentration make a clinical difference?
•
Again the answer not crystal clear, though there seems to be an advantage to
the patients maintained with heparin concentrations between 3iu/ml and
5iu/ml, and achieving ACTs between 400 and 480 seconds.
•
This seems to be achievable with loading doses of 300 to 400 iu/kg, which is
the range of loading dosages that the majority of Perfusionists in our survey
use. (see the chart)
•
Most importantly though, Perfusionists must be aware that the circulating
concentration of heparin poorly correlates with the ACT, because of
hemodilution, hypothermia, and individual patient differences.
•
For these reasons, an ACT that seems adequate may not be enough to stop the
coagulation cascade, and prevent the consumption of factors.
“World” heparin loading doses
5%
27%
49%
150/kg
1
200/kg
1
300/kg
11
350/kg
2
400/kg
6
600/kg
1
N=22
9%
5% 5%
Have we found solutions to any of
our identified problems?
With respect to, Problem: When should the
baseline sample be taken?
• The evidence that was elucidated by Gravlee
provides the best answer that we could find.
• The baseline should be taken after anesthesia and
surgery has been initiated.
Have we found solutions to any of
our identified problems?
With respect to, Problem: How much time should elapse between
heparin administration and ACT to confirm anticoagulation?
• Considering onset of action, circulation time, and
redistribution the most common recommendation is to take
a sample 3 to 5 minutes after administration of the initial
dose.
• However in emergency situations, where speed is of
utmost importance, a sample taken one minute after the
loading dose should provide a reasonable ACT value.
• At the very least it will confirm whether the heparin dose
was delivered into the patients circulatory system, which
could be missed at any time but especially in the confusion
that sometimes accompanies an emergent case.
Have we found solutions our original problem:
Heparinization (and Protamine neutralization)
• As it is so many times when looking for the solutions of problems, we
soon discovered many related problems.
• First: it was quickly revealed that “Heparinization” alone is a complex
problem of a scale much larger than was first imagined.
• Therefore we have addressed the problem of protamine neutralization,
only peripherally.
• The topic of “protamine administration as a perfusion problem” would
make another excellent topic for inclusion in subsequent classes of
CLPR 775.
• We all should be cognizant that the potential answers hinted at in this
forum should not be considered the final word. By inspection of the
other branches of the hemostasis tree, we may well need to alter our
present conclusions.
Have we found solutions our original problem:
Heparinization (and Protamine neutralization)
• There are many sub-topics and side branches to the original problem
that we would have liked to include in this project. They were
excluded, not by desire, but by time and space constraints. (“beam me
up Scotty”)
• Some of the identified topics are:
– Heparin rebound
– Heparin resistance
– Heparin bonded circuits (as well as non-heparin coatings)
– Pharmacology (aprotinin, amicar, LMWH, alternative anticoagulants, etc.)
– Hemoconcentration
– Review of available instruments for monitoring coagulation
– HIT, HITT
Have we found solutions our original problem:
Heparinization (and Protamine neutralization)?
• There are very few true solutions to most complex
problems. What is important is a close inspection of the
problems, to try to get a handle on as many pieces of
potential solutions that we can.
• This is especially true of any profession where decisions
made, on seemingly mundane issues, can have life and
death consequences.
• We hope we have made a reasonable attempt to inspect the
problem of heparinization, but realize that the work is not
done. This is just one small area of the ‘jigsaw puzzle”, and
the pattern is only beginning to be fully revealed.
Have we found solutions our original problem:
Heparinization (and Protamine neutralization)?
The truth is that the original problem posed
was,
Hemostasis as a perfusion problem
We have placed the first piece of that puzzle in
the corner.
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