Full text of DOI:10.1177/021849230201000206

Svenarud
ORIGINAL CONTRIBUTION
Protamine Doses After Cardiopulmonary Bypass
Clinical Effects of Different
Protamine Doses After
Cardiopulmonary Bypass
NORWAY
Peter Svenarud, MD, Eivind Øvrum, MD
Oslo Heart Center
Oslo, Norway
ABSTRACT
The optimal dose of protamine needed to reverse the anticoagulant effect of
heparin after cardiopulmonary bypass is still not known. In this retrospective
cohort study, we investigated 3 different dose regimes in 300 patients undergoing
coronary artery bypass grafting. Group A patients (n = 100) were given protamine
in the ratio of 1.3 mg to 1 mg heparin, group B patients (n = 100) were given
0.75 mg protamine to 1 mg heparin, and group C patients (n = 100) were given
protamine in fractionated doses of 1 mg + 0.15 mg + 0.15 mg to 1 mg heparin.
The groups were comparable in all major clinical and operative variables. The
heparin dose was almost identical in the groups. The rate of red cell transfusion
was significantly higher in group B than in the other groups. A similar but
nonsignificant trend was observed in the incidence of resternotomy for postoperative
bleeding, mediastinal drainage, and postoperative hemoglobin loss. The study
demonstrates that a single bolus dose of 1.3 mg protamine to 1 mg heparin is safe
and efficient for neutralizing heparin after cardiopulmonary bypass.
(Asian Cardiovasc Thorac Ann 2002;10:119–23)
little is known about the optimal doses of protamine
required after CPB. Furthermore, the consequences of
too much or too little protamine remain unclear.
INTRODUCTION
From the very beginning of heart surgery with cardio-
pulmonary bypass (CPB), the dosage of heparin required
for anticoagulation and the protamine dose for reversing
its effect have often been estimated empirically.1 Bull and
associates2 in 1975 found that both inadequate heparin
reversal and excessive protamine administration were
common. They devised a technique for individualizing
heparin and protamine dosages based on dose-response
curves.3 Since then, several techniques for titrating the
protamine dose needed to neutralize circulating heparin
in each patient have been developed.1,4 In routine cardiac
surgery, however, individualized protamine/heparin
The aim of this study was to investigate the clinical
implications of different amounts of protamine given
to low-risk patients undergoing coronary bypass. Of
particular interest were the effects on postoperative
mediastinal drainage, hemoglobin loss during hospital
stay, the incidence of resternotomy for bleeding, and the
requirement for allogenic blood transfusion.
PATIENTS AND METHODS
titration is expensive and not necessary. Therefore, Over a period of 22 months, the scheme for protamine
standardized doses are very often administered, although administration to neutralize heparin after CPB was
For reprint information contact:
Peter Svenarud, MD Tel: 46 8 5858 6726 Fax: 46 8 5858 6740 email: peter.svenarud@thsurg.hs.sll.se
Department of Cardiothoracic Surgery and Anesthesiology (M85), Karolinska Institutet, Huddinge University Hospital,
Stockholm SE-14186, Sweden.
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changed in 3 successive time periods. A retrospective bypass, intra- and postoperative retransfusion of the
analysis of the first 100 consecutive patients undergoing oxygenator and circuit contents (without any cell
coronary artery bypass grafting in each period was
undertaken. To exclude personal bias, the patients were
selected from the experience of a single surgeon and a
single anesthetist. In the first cohort, protamine was given
in the ratio of 1.3 mg to 1 mg heparin (group A). In the
second period, the ratio was 0.75 mg protamine to 1 mg
heparin (group B). In the third period, the protamine dose
was divided into 3 boluses of 1 mg + 0.15 mg + 0.15 mg
to 1 mg heparin (group C) and given after CPB, after
retransfusion of the contents of the CPB circuit, and after
retransfusion of the autologous blood removed before
CPB, respectively.
processing), and postoperative autotransfusion of shed
mediastinal blood up to 18 hours postoperatively. If
possible, platelet inhibitors like aspirin were discontinued
7 days preoperatively.Antifibrinolytic or antiinflammatory
agents were not given to any patients.
The amount of postoperative bleeding was measured from
the time of sternal closure until the drains were removed.
The threshold for resternotomy was mediastinal drainage
exceeding 250 mL·h–1 for 2 hours. Normovolemic anemia
was defined as a hematocrit of 0.25 postoperatively, below
which allogenic red blood cell transfusion was indicated.
Hemoglobin concentration and platelet count were
determined preoperatively, at 3 hours and 18 hours
postoperatively, and at discharge on the 5th to 7th day.
All patients in the study were first-time candidates for
surgery, and most of them were of low operative risk. The
patients were selected in close collaboration with a
neighboring university department that manages cases of
severe renal dysfunction and ventricular aneurysms, as
well as patients in need of combined carotid and coronary
operations and acute operations after failed angioplasties.
All patient and laboratory data were recorded prospec-
tively. The groups were compared using the Kruskal-
Wallis test for continuous variables. Discrete variables
were tested by chi-square, with Yates’ correction and
Fisher’s test when one of the expected cell values was
less than 5. Data are expressed as mean ± standard
deviation. A p value < 0.05 was considered significant.
Standard operative procedures included median ster-
notomy, dissection of the internal mammary artery, and
CPB with a two-stage cannula in the right atrium and a
cannula in the ascending aorta. CPB was maintained with
a pulsatile flow at a rate of 2.4 L·m–2·min–1, and mild
hypothermia (blood temperature, 32°C to 34°C) was
instituted immediately after the start of bypass. The heart-
lung machine was primed with 2,000 mL of Ringer’s
acetate. The aorta was crossclamped and a crystalloid
cardioplegic solution (St. Thomas II) infused in the
antegrade fashion before distal anastomoses were
performed. Venous grafts were attached to the ascending
aorta using partial occlusion while rewarming the patient.
Cardiotomy suction was used throughout the CPB period.
RESULTS
The groups were comparable in all major clinical and
operative variables, except for a slightly higher mean age
in group C, which reflects the fact that patients admitted
for coronary bypass are getting older (Table 1).
The doses of heparin were almost identical in all the
groups (Table 2). The protamine dose was, according to
the protocol, statistically lower in group B, leading to a
protamine/heparin ratio of 0.75, compared with 1.3 in
groups A and C.
The activated clotting time (ACT) was measured (Hemo
Tec; HemoTec Inc., Englewood, CO, USA) preoperatively,
after heparin administration, before CPB, 10 minutes
after the start of CPB, every 20 minutes during CPB, after
protamine administration, and 2 hours postoperatively.
Heparin was given in a bolus dose of 4 mg·kg–1 to obtain
anACT above 480 seconds.Additional heparin was given
during CPB ifACT was below target level. The administra-
tion of supplemental doses of protamine was considered
when postoperative ACT exceeded 130 seconds.
In group B, given the lowest protamine dose, the rate of
red cell transfusion was significantly higher compared
with the other groups (Table 3). A similar but nonsignifi-
cant trend was seen in the incidence of resternotomy for
postoperative bleeding (p = 0.09). The amount of
mediastinal drainage did not differ significantly, nor did
postoperative hemoglobin loss, although a trend could be
seen towards higher figures for group B. For all other
relevant clinical variables, no significant differences were
observed.
The anesthetic technique, designed to permit early
extubation, included a combination of diazepam (0 to
0.2 mg·kg–1), midazolam hydrochloride (0 to 0.2 mg·kg–1),
fentanyl (6 to 8 µg·kg–1), and pancuronium bromide,
supplemented with isoflurane and nitrous oxide.
DISCUSSION
Although several laboratory techniques for determining
more accurate doses of protamine for neutralizing the
anticoagulant effect of heparin are available, most cardiac
surgical units use standardized doses of protamine after
Blood conservation before and after operation was CPB. The most common doses of heparin are 3 to
previously described in detail5,6 and included the removal 4 mg·kg–1, aiming at an ACT of 400 to 480 seconds,7 and
of autologous blood before bypass for retransfusion after a protamine/heparin ratio of 0.6–1.8 mg to 1 mg.8 Within
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Table 1. Demographic and Operative Details
Group A
Group B
Group C
Parameter
(n = 100)
(n = 100)
(n = 100)
p Value
Age (years)
58.5 ± 8.3
15
60 ± 8.1
22
61.1 ± 9.8
16
0.02
NS
NS
NS
NS
NS
NS
NS
NS
Female (%)
Body surface area (m3)
1.94 ± 0.15
65.9 ± 12.1
100
1.92 ± 0.16
64.7 ± 13.6
100
1.92 ± 0.19
65.1 ± 14.2
99
Ejection fraction (%)
At least 1 arterial graft (patients)
Number of distal anastomoses
Extracorporeal time (min)
Ischemic time (min)
3.8 ± 1.3
60.1 ± 20
28.7 ± 11.9
23.2 ± 2.5
3.9 ± 1.3
54.8 ± 17.1
26.7 ± 9.7
22.4 ± 2.6
4.1 ± 1.1
57.1 ± 16.8
29.8 ± 10.6
22.5 ± 2.1
Lowest hematocrit on bypass (%)
NS = not significant.
Table 2. Heparin and Protamine Doses
Drug
Group A (n = 100)
Group B (n = 100)
Group C (n = 100)
p Value
Heparin (mg)
323 ± 42
420 ± 54
1.3
318 ± 48
240 ± 38
0.75
318 ± 52
413 ± 52
1.29
NS
Protamine (mg)
Protamine/heparin
< 0.0001
< 0.0001
NS = not significant.
Table 3. Postoperative Data
Group A
Group B
Group C
Parameter
(n = 100)
(n = 100)
(n = 100)
p Value
Mediastinal drainage (mL)
Autotransfusion (mL)
629 ± 278
693 ± 340
648 ± 241
NS
NS
0.03
NS
NS
NS
NS
NS
NS
NS
611 ± 238
666 ± 332
622 ± 216
Red cells and/or plasma transfusion (patients)
Resternotomy for bleeding (patients)
Preoperative hemoglobin level (g·L–1)
Hemoglobin level at discharge (g·L–1)
Hemoglobin loss (g·L–1)
1
2
7
6
0
1
146 ± 13
122 ± 14
23.9 ± 1.2
1.1 ± 0.6
2
146 ± 11
118 ± 15
27.6 ± 1.3
1.2 ± 0.9
2
145 ± 10
120 ± 14
24.2 ± 1.1
1.1 ± 0.6
3
Postoperative intubation (hours)
Perioperative MI (patients)
Mortality (patients)
0
0
1
MI = myocardial infarction, NS = not significant.
the limitations of a nonrandomized study, the present data simple and convenient way of giving protamine, although
clearly show that the dose of 1.3 mg protamine to 1 mg care should be taken not to infuse the drug too fast as
heparin was very effective, causing moderate postoperative rapid administration may cause arterial hypotension and
mediastinal drainage, few reoperations for bleeding, and pulmonary hypertension.10
a very low incidence of allogenic transfusion. Although
Protamine acts by binding ionically to heparin, which
then remains as a stable precipitate. The protamine
molecule has 2 active sites: one binds to heparin and the
other has a mild anticoagulant effect. This anticoagulant
effect was demonstrated in vitro in 1937 by Chargaff and
a retrospective analysis, the results were obtained under
standardized conditions and all the patients underwent
identical treatment regimen performed by the same
surgeon and the same anesthetist.
There were no significant differences in any of the Olson,11 and it has been suggested that it is due to the
postoperative variables whether protamine was inhibition of platelet-induced aggregation.12 The impor-
administered in fractionated doses or in a bolus dose. tance of this effect in vivo is debatable. Administration
This is in contrast to the study by Aren and colleagues,9 of very large doses of protamine (600 mg·kg–1) to 6
who found that a two-dose protocol of protamine healthy volunteers (without prior heparin administration)
administration significantly reduced the level of circulating was found to cause a mild and transient 30-minute increase
plasma heparin. A single bolus appears to be the most in whole blood coagulation time, with no effect on the
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partial thromboplastin time.13 Other studies have shown
that protamine has a significant effect as an anticoagulant,
but only in nonclinical doses, usually 3 to 5 times the
dose normally used to neutralize heparin after CPB.14,15
This fact indicates that protamine has a large therapeutic
window. In this context, it should be noted that the quality
of different protamine and heparin preparations is not
consistent as the in vitro doses of protamine needed to
neutralize heparin are not the same as those shown in
vivo.16 This may also be due to different rates of heparin
metabolism.3,17 Patients’ response to heparin varies
considerably, depending on various factors such as the
body surface, sex, age, and antithrombin III concentration.
REFERENCES
1. Jobes DR, Schwartz AJ, Ellison N, Andrews R, Ruffini
RA, Ruffini JJ. Monitoring heparin anticoagulation and its
neutralization. Ann Thorac Surg 1981;31:161–6.
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therapy during extracorporeal circulation. I. Problems
inherent in existing heparin protocols. J Thorac Cardiovasc
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3. Bull BS, Huse WM, Brauer FS, Korpman RA. Heparin
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4. Despotis GJ, Joist JH, Hogue CW Jr, Alsoufiev A, Kater
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In the last 20 years, 4 of the 5 published studies that
investigated the effect of a reduced protamine dose on
postoperative blood loss or on the need for transfusion
showed no benefits of a reduced dose,1,7,8,18 while one
did.19
5. Øvrum E, Åm Holen E, Tangen G. Consistent non-
pharmacologic blood conservation in primary and
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thorac Surg 1995;9:30–5.
Keeler and associates8 compared a protamine titration
method with an empirical dose protocol for heparinization
reversal after CPB in 40 patients. All patients received
3 mg·kg–1 heparin, and additional heparin was given as
necessary during CPB to maintain the ACT above 400
seconds. The titration group received 2.1 to 7.4 mg·kg–1
compared with 5.3 to 9.3 mg·kg–1 in the empirical group.
Despite a significant reduction in the total protamine dose
in the titration group, postoperative bleeding did not
decrease.
6. Flom-Halvorsen HI, Øvrum E, Tangen G, Brosstad F,
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Anaesthesia 1991;46:925–8.
Shore-Lesserson and colleagues7 compared both heparin
and protamine titration systems to standard weight-based
strategies in 135 patients. Although they could predict a
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improved postoperative hemostasis.
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protocols for heparin neutralization by protamine after
cardiopulmonary bypass. J Thorac Cardiovasc Surg
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Ottesen’s group18 compared an individual heparin dose-
response curve technique for protamine dosing to a routine
protocol in 20 patients. The dose-response group received
1.18 mg protamine to 1 mg heparin compared to 2 mg in
the control group. They did not find any difference in the
amount of postoperative bleeding.
10. Øvrum E, Lindberg H, Åm Holen E, Abdelnoor M.
Hemodynamic effects of intraaortic versus intravenous
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man. Scand J Thorac Cardiovasc Surg 1992;26:113–8.
11. Chargaff E, Olson KB. Studies on the chemistry of blood
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In our study, no advantages were observed when the
protamine dose was reduced to 0.75 mg to 1 mg heparin.
All relevant bleeding variables tended to be negatively
affected, and the incidence of allogenic transfusion was
significantly higher. In fact, no reasons could be found to
reduce the protamine dose to less than 1.3 mg to 1 mg
heparin, and it appears safe and convenient to administer
protamine in a single bolus dose.
12. Ellison N, Edmunds LH Jr, Colman RW. Platelet
aggregation following heparin and protamine
administration. Anesthesiology 1978;48:65–8.
13. Ellison N, Ominsky AJ, Wollman H. Is protamine a
clinically important anticoagulant? A negative answer.
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estimating the required dose. J Lab Clin Med 1956;48:
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ACKNOWLEDGMENT
We would like to thank Einfrid Åm Holen, MD, former
chief anesthetist, for initiating the study.
15. Inagaki M, Goto K, Katayama H, Benson KT, Goto H,
Arakawa K. Activated partial thromboplastin time–
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protamine dose relation in the presence and absence of
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activated coagulation time in monitoring heparin therapy
during extracorporeal circulation. Scand J Thorac
Cardiovasc Surg 1984;18:123–8.
16. Hurt R, Perkins HA, Osborn JJ, Gerbode F. The
neutralization of heparin by protamine in extracorporeal
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and precision of heparin and protamine dosing reduces
blood loss and transfusion in patients undergoing primary
cardiac operations. J Thorac Cardiovasc Surg 1995;110:
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