|
Clinical Studies
A New Effective
Intraoperative Hemostat – Superstat
P.N. Sawyer, B. Stanczewski, J.
Fitzgerald,
P.P. Sivasubramanian, F. Mistry, J. Landi
A positively charged collagenous
hemostatic agent, Superstat, has been found to have superior hemostatic
characteristics while at the same time undergoing solvation during the
hemostatic event.
When this group began studies of
collagen approximately 15 years ago, efforts were initially directed towards
modifying collagen as a polymeric material for vascular surgical bypasses 1-4 .
It was obviously necessary to decrease the thrombotic characteristics of
collagen which was done by selectively neutralizing the positively charged end
amino acids of the collagen helices, while simultaneously manipulating collagen
(an elegant polymeric material which replicated every 1,000 moieties).
When this work commenced it was
obvious that making collagen a more potent blood coagulation surface by making
it “more positive,” to potentiate the thrombotic effect, might be possible. It
was not initially obvious how to carry out this objective. However, three
factors immediately became apparent when the development of a modern hemostatic
agent was dealt with conceptually: 1) the material had to be an effective
hemostat, 2) it had to have a large surface area to carry out its task rapidly,
and 3) it had to solvate while carrying out hemostasis.
Materials & Methods
A specially prepared small
polypeptide collagen derivative, acid washed collagen, was used as the initial
hemostatic agent. Several concentrations of calcium were added to measure the
effect to potentiate hemostasis.
The material was brought into
solution by adding it in stoichiometric amounts to water at 40° C. Calcium was
added in appropriate physiological concentration.
Following this, freeze drying was
carried out, using two methods:
1) Shell freeze drying of the
centrifuged spun out hemostat, and
2) Shelf freeze drying technique – pouring the liquefied Supertat into dishes
for freezing, followed by freeze drying.
The pads of Superstat, once freeze
drying was completed, were placed into marked packages, first for animal studies
and then ultimately for human use. The packages were sterilized using either ETO
or gamma irradiation. Sterility is ascertained by multiple cultures of both
native Superstat and sporestrips placed in the hemostatic containers sterilized
in the same ambient condition as was the hemostatic agent itself. The
characteristic structure of the microcavitated Superstat was monitored
microscopically with each batch of the material.
Development
It was found that both the initial
shell freeze dried and shelf freeze dried material solvated rapidly in producing
hemostasis. Prior to developing effective application techniques, it was not at
all certain that material could be used effectively. However, application to a
bleeding site in concentrations up to Superstat 5%, subsequently packing off
with a laparotomy pad, resulted in rapid hemostasis (Table I).
Application in Animals
The material was first evaluated
in 30 dogs (Tables I & II). Incisions were made in spleen and liver. Healing
characteristics, in comparison with several other hemostatic agents included
Avitene, Surgicel, Gelfoam, Collatamp and Kolagen Haemostyptikum Vlies in both
subcutaneous healing sites as well as in the overt incisional areas in spleen,
liver, skin were performed (Figure 1).
Initially it was very difficult to
effectively apply Superstat since no solvating hemostatic agent had previously
been tested. It ultimately became obvious that an effective technique for
application of this material involved placing it on the point of bleeding and
packing the whole area off with a gauze Laparotomy pad.
Chronic Studies – Animals
Chronic studies were carried out
measuring the healing characteristics of Superstat, in comparison with the other
hemostatic agents described above, by placing them in subcutaneous pouches and
serially excising the intact pouches at 2 hours, 2 days, 7, 14, and 21 days
(Figure 1).
Application in Man
The initial description of the
effectiveness of Superstat in man has come from more than 130 applications in
man (Table III). The ultimate efficacy of Superstat in man is described in 5
anecdotal experiences in the operating room. It was impossible to produce
hemostasis using any other material available to the operating surgeons. This
involved two neurosurgical and three peripheral vascular experiences by people
who have since joined the multicenter trial by Superstat. In each instance,
hemostasis was obtained very rapidly by using Superstat.
Application in man in the majority
of instances has been to arterial and anastomotic sites following reconstruction
in heparinized patients. No evidence of diffuse intravascular coagulopathy,
fibroplasia, infection, persistence of physical residue of Superstat,
nonhealing, nor adhesions have been found in any instance in which Superstat had
been used, as is often seen with other hemostatic agents clinically.
___________________________________________________________________________________________________________________
From the Electrochemical and Biophysical Laboratories of the Vascular Surgical
Services, Department of Surgery and Surgical Research, Downstate Medical Center
, Brooklyn , New York.
*This work was supported in part by a Grant from the Sawyer Foundation.
Vol.XXVI Trans Am Soc Arcif Intern Organs 1980
Table I
Comparative Evaluation of
Hemostatic Agents
 |
| |
|
% Reduction in
|
% Tissue Healing in
|
|
|
|
Hemostats
|
Bleeding Time
|
Shed Blood
|
2 days
|
7 days
|
14 days
|
21 days
|
|
|
|
Control
|
0
|
0
|
40
|
90
|
95
|
99
|
|
|
|
Avitene
|
14.4
|
1.9
|
16
|
18
|
22
|
50
|
|
|
|
Gelfoam
|
20.6
|
28.7
|
20
|
43
|
55
|
70
|
|
|
|
Surgicel
|
25.6
|
35.5
|
11
|
28
|
30
|
60
|
|
|
|
Collatamp
|
9.4
|
18.5
|
25
|
30
|
50
|
80
|
|
|
|
Kollangen Haemo Vlies
|
9.8
|
14.3
|
20
|
25
|
35
|
70
|
|
|
|
Superstat
|
66.7
|
47.4
|
40
|
90
|
95
|
99
|
|
|
|
|
|
|
|
|
|
|
|
Table II
Wound Healing After Applying
Superstat Based on Histochemical Studies
on 2, 7, 14 and 21 days Observation Postoperatively
|
|
|
|
Days After
Surgery
|
Clot in
Wound
|
Fibrin
Strands
|
Scab. Form.
|
Basal
Epith.
Migr.
|
Mono-
Cytes
|
Poly-
morpho-
nuclear
Leuko-
cytes
|
Mesen-
chymal
Cells
|
Fibro-
blasts
|
Collagen
Matura-tion
|
Revascu-
larization
|
|
|
2
|
++
|
+++
|
+
|
+
|
++++
|
++
|
+++
|
+
|
0
|
0
|
|
|
7
|
+
|
++
|
++++
|
++
|
+
|
++
|
++
|
++++
|
+++
|
+
|
|
|
14
|
0
|
+
|
0
|
+++
|
0
|
0
|
0
|
+++
|
+++
|
++
|
|
|
21
|
0
|
0
|
0
|
++++
|
0
|
0
|
0
|
+
|
++++
|
++++
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
KEY:
|
0
|
=
|
None/None
|
|
|
|
|
|
|
|
|
|
+
|
=
|
Poor/Minimal
|
|
|
|
|
|
|
|
|
|
++
|
=
|
Good/Medium
|
|
|
|
|
|
|
|
|
|
+++
|
=
|
Very Good/Severe
|
|
|
|
|
|
|
|
|
|
++++
|
=
|
Excellent/Maximal
|
|
|
|
|
|
|
| |
|
|
|
|
|
|
|
|
|
|
Table III
Effect of Superstat on Coagulation
Profiles in 131 Patients
Total Number of Superstat Applications
|
|
|
|
|
|
|
|
|
No. of Patients
|
% Superstat
|
|
Intraoperative
Hemostasis
Time (minutes)
|
|
|
|
P.T. Thrombin Time (seconds)
|
|
|
P.T.T. Partial Thromboplastin Time (seconds)
|
|
|
|
Mean
|
±
|
SD*
|
SEM+
|
|
Mean
|
±
|
SD*
|
SEM+
|
|
Mean
|
±
|
SD*
|
SEM+
|
|
22
|
1
|
3.04
|
±
|
2.65
|
0.61
|
|
11.76
|
±
|
0.74
|
0.17
|
|
29.66
|
±
|
10.87
|
2.43
|
|
|
|
|
|
|
|
|
12.27
|
±
|
0.34
|
0.08
|
|
28.31
|
±
|
3.52
|
0.79
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
79
|
2
|
3.77
|
±
|
1.7
|
0.19
|
|
14.08
|
±
|
11.93
|
1.42
|
|
27.39
|
±
|
10.57
|
1.23
|
|
|
|
|
|
|
|
|
11.94
|
±
|
0.35
|
0.04
|
|
26.55
|
±
|
2.28
|
0.27
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
19
|
3
|
3.78
|
±
|
2.85
|
0.67
|
|
11.69
|
±
|
0.76
|
0.19
|
|
25.46
|
±
|
4.72
|
1.18
|
|
|
|
|
|
|
|
|
11.97
|
±
|
0.36
|
0.09
|
|
26.10
|
±
|
2.48
|
0.62
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
11
|
5
|
6.20
|
±
|
3.11
|
0.98
|
|
10.75
|
±
|
3.26
|
1.03
|
|
25.94
|
±
|
3.01
|
0.95
|
|
|
|
|
|
|
|
|
12.36
|
±
|
0.25
|
0.08
|
|
27.41
|
±
|
4.96
|
1.57
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
Total 131
|
1,2,3,5
|
4.20
|
±
|
1.38
|
0.69
|
|
12.07
|
±
|
1.42
|
0.71
|
|
27.11
|
±
|
1.89
|
0.94
|
|
|
|
|
|
|
|
|
12.14
|
±
|
0.21
|
1.11
|
|
27.09
|
±
|
0.98
|
0.49
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
Intra-Abdominal Cases
|
|
|
|
|
|
|
|
Total 47
|
1,2,3,5
|
5.30
|
±
|
1.74
|
0.87
|
|
12.02
|
±
|
0.69
|
0.35
|
|
25.37
|
±
|
0.57
|
0.29
|
|
|
|
|
|
|
|
|
12.10
|
±
|
0.20
|
0.10
|
|
27.08
|
±
|
1.14
|
0.57
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
Extra-Abdominal Cases
|
|
|
|
|
|
|
|
Total 84
|
1,2,3,5
|
3.51
|
±
|
1.19
|
0.60
|
|
11.93
|
±
|
0.42
|
0.21
|
|
27.67
|
±
|
3.27
|
1.64
|
|
|
|
|
|
|
|
|
11.94
|
±
|
0.34
|
0.17
|
|
27.06
|
±
|
0.86
|
0.43
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
SD* - Standard Deviation
|
SEM+ - Standard Error of the Mean
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
Results
1. Avitene 5 , one of the most
effective hemostatic agents available, suffers from two problems. Once it is
packed into a wound to produce hemostasis, it is extremely difficult to remove
mechanically and will not go into solution. If left in place, it tends to
produce cutaneous fistuli (Figure 2). *
2. Gelfoam 6 , formalin-tanned
gelatin, is difficult to manipulate and impossible to fold. It is softened in a
limited way by application to tissues and to blood. It appears to be less
effective than Surgicel, Avitene, or Superstat (Figure 3, Top), and generates
foreign body reaction.
3. Surgicel 7 , (Figure 3, Bottom)
* appears to produce its hemostatic effects largely due to pH changes it
develops in tissues, usually yielding moderately effective hemotasis. However,
it also produces tanning and browning of tissues due to the release of nitrous
acid (Figure 3). This material probably should not be left in wounds, as there
is information suggesting abscess formation if the material is not removed
following hemostasis.
4. Collatamp – Collagen tampon
(Figure 4, Top) *, is somewhat similar to Gelfoam but is less hemostatic; it has
larger vacuoles and less surface exposure of collagen per unit weight. It
appears to generate a foreign body reaction identical to that of Gelfoam.
5. Kollagen Haemostyptikum Vlies
(Figure 4, Bottom) * - This material consists of compressed fibers of collagen.
It is a moderately effective hemostatic agent, but does not solvate once it is
placed in wounds. Its removal results in recurrent bleeding.
6. In general, it was found that
Superstat, though it has no tensile strength, produced hemostasis at least as
rapidly or more rapidly than any of the other hemostatic agents evaluated. In
five instances it produced hemostasis when all other hemostatic agents failed.
In experimental animals it produced rapid hemostasis in both spleen and liver
incisions as well as in skin incision (Table II). It is available in several
concentrations for different applications. The most concentrated, 5%, is used in
serious bleeding areas where no conformation is necessary. On the other end of
the scale, 1% flexes around anastomotic points. Two percent is for conventional
applications in small bleeding sites (Figure 5) *. Three percent and 5%
Superstat, on the other hand, are used for persistent bleeding (Figure 6) *.
Superstat is a good hemostatic
agent since it dissolves while producing hemostasis, leaving no residue; it
displays no foreign body effect, permits normal healing, does not appear to
produce major adhesions and useful in heparinized patients.
*Figures 1 through
6 not reproduced.
Discussion
A preliminary report of the
initial animal and clinical experiences with a new ultra-positively charged,
calcium containing, self dissolving hemostatic agent, Superstat, is presented.
The material produces rapid hemostasis due to its extremely high surface area
and positive charge, while dissolving during the performance of its activities.
The available evidence suggests
that Superstat works by acting as a very potent “electron sink” due to its
special charge characteristics, interacting with shed blood to rapidly convert
fibrinogen to fibrin. This appears to be in part due to interaction between the
alpha helix amino acid side chains of collagen and fibrinogen.
Summary
A new effective solvating
hemostatic agent, Superstat, has been developed and evaluated in animals and
man. It appears to work in part because of its large electron absorbing surface
and in part due to the physiologic concentration of calcium. The available
information from the first 130 patients in which it had been evaluated suggest
that it had few, if any, side effects, leaves no residue following use, and is
an extremely effective hemostat under most conditions and in all tested
operative areas in man. |
