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Original Research |
1 Department of Ultrasound, Chinese People's Liberation Army General Hospital,
28 Fuxing Rd., Beijing 100853, China.
2 Intensive Care Unit, Chinese People's Liberation Army General Hospital,
Beijing, China.
Received November 4, 2007;
accepted after revision March 17, 2008.
Supported by the Military Medical Science Program (No. 06G108).
Abstract
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MATERIALS AND METHODS. Fifteen mixed-breed dogs 2–3 years old
and weighing 17–20 kg were anesthetized with intramuscular pentobarbital
sodium (30 mg/kg). A special impacting device was used to induce hepatic
trauma with a mean force of 5.3 ± 0.3 kN. Twelve of the 15 dogs had
hepatic injuries with a grade of 3–4 or 4. The 12 dogs were divided into
treatment and control groups. In the treatment group, hemocoagulase atrox (1
Klobusitzky unit) and 
-cyanoacrylate (1 mL) were administered by
transcutaneous injection into the injury site and the bleeding site,
respectively, under the guidance of contrast-enhanced sonography. The control
group received injections of 0.9% normal saline solution.
RESULTS. After injection into the treatment group, no active bleeding was observed at the liver injury site. In the control group, evidence of active bleeding was present on contrast-enhanced sonograms. Laparotomy of the treatment group showed that hepatic injuries had been covered and adhered by clots and the glue membrane of the hemostatic agents and that free intraperitoneal blood volume was significantly less than in the control group (p < 0.001). Bleeding did not stop in the control group.
CONCLUSION. In dogs, transcutaneous local injection of hemostatic agents can effectively reduce blood loss due to severe liver trauma. Because it is simple, convenient, and effective, the technique may be an alternative for bedside and battlefield management of hepatic hemorrhage due to trauma.
Keywords: -cyanoacrylate • blunt abdominal trauma • contrast media • hemocoagulase atrox • hemostasis • injury • interventional radiology • liver • sonography
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The nonoperative management of hepatic injury, however, continues to be controversial. The main focus is that the incidence of delayed and uncommonly encountered complications, especially severe compli cations such as hemorrhage due to delayed rupture, has increased with the emergence of nonoperative management [6–8]. Studies are needed to develop minimally invasive techniques of rapid and easy control of hemorrhage due to hepatic injury.
Enhancement with contrast media improves the sensitivity of conventional sonography in the detection and characterization of focal hepatic lesions [9]. Owing to the current possibilities of low-mechanical-index, real-time contrast-specific systems, it is now possible to detect contrast leakage with sonography [10]. Contrast-enhanced sonography is an effective tool in the evaluation of blunt hepatic trauma, being more sensitive than and having better correlation with CT findings than does conventional sonography [11].
Hemostatic materials have been developed rapidly. Promising hemostasis
agents such as hemocoagulase atrox, fibrin sealant glue, and
-cyanoacrylate have been applied successfully and have played an
important role in stopping local blood loss
[12,
13]. For example, endoscopic
-cyanoacrylate injection is successful in controlling active bleeding
from gastric varices [14].
This experiment was designed to determine whether injecting hemostatic agents
directly into injury sites under the guidance of contrast-enhanced sonography
can effectively control hemorrhage due to hepatic trauma.
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Modeling Blunt Hepatic Trauma
Femoral arterial and femoral venous catheters were placed. The former were
used for detecting arterial pressure and the latter for resuscitation.
Balanced salt solution was administered IV for a mean arterial pressure no
less than 80 mm Hg.
An impacting device (Fig. 1) was used to induce blunt hepatic trauma [16]. This device consisted of a supporter, an impacting handle, a piston handle, a power bullet, and a powder-actuated fastening tool. Impacting force was recorded with the data recorder of a mechanical force transducer. The impacting procedure was as follows. A power bul let was loaded, and the powder-actuated fastening tool was fixed into a hole of the cross beam of the supporter. The impacting handle, which had a head 2 cm in diameter, was inserted into the gun barrel and aimed at the hepatic region, and the trigger was pulled. The force of the bullet pushed the piston handle and the impacting handle onto the designated target organ, which was located with conventional sonography before impact. The impacting force was based on the weight of the dog at 0.28 kN/kg. In this experiment, the force was 4.8–5.6 kN (mean, 5.3 ± 0.3 kN).
Contrast-enhanced sonography (Sequoia 512 unit, Siemens Medical Solutions) and CT (Sensation 64 scanner, Siemens Medical Solutions) were performed immediately after impact to confirm whether liver injury had occurred. The sonograms were assessed by a sonographer and the CT scans by a radiologist. If injuries were present, the size (orthogonal diameter), extent, and conspicuity were delimited. Conspicuity was graded according to the hepatic injury scale of the American Association for the Surgery of Trauma [17]. If the parenchymal laceration was more than 3 cm deep or intra parenchymal hematoma was larger than 10 cm or expanding, the injury was categorized grade 3. If the parenchymal disruption involved 25–75% of a hepatic lobe, the injury was categorized grade 4. Injuries between grades 3 and 4 were classified grade 3–4.
Sonographic Contrast Agent
The sonographic contrast agent used in this study was a microbubble
suspension (SonoVue, Bracco). In China, this second-generation contrast medium
has been approved for diagnostic imaging since 2003 and is under analysis by
the U.S. Food and Drug Administration. The agent consists of stabilized
microbubbles containing an inert gas (sulfur hexafluoride) and covered by a
phospholipid membrane. The reconstituted product provides 8 µL/mL of sulfur
hexafluoride microbubbles
[18]. The agent is
reconstituted with 5 mL of saline solution in a few seconds and can be
administered immediately [19].
There is no need for fasting or preliminary laboratory tests. Transvenous
inject ion of this contrast agent can be repeated. In this study, the contrast
agent was administered for diagnosis and again for guidance of the injections
of hemocoagulase atrox and -cyanoacrylate or normal saline solution and
evaluation of the efficacy of the local injections.
Direct Injection of Hemostatic Agent
Unenhanced and contrast-enhanced sonogra phy (Sequoia 512 scanner, Siemens
Medical Solutions) was performed with a 3-5–MHz trans ducer (4V1,
Acuson). Contrast-enhanced sonography was performed with contrast pulse
sequencing at low acoustic power (mechanical index, 0.15–0.17) and
microvessel density (MVD) imaging at a mechanical index of 0.39–0.42.
Contrast pulse sequencing was based on standard phase-inversion technology
with a low mechan ical index. This technique enables detection of not only the
nonlinear second harmonic response of microbubbles but also the strong
nonlinear funda mental component, increasing the signal-to-noise ratio
15–20 dB and providing a much stronger contrast signal than with
conventional sono graphy. In this study, we used contrast pulse sequencing to
identify the sites of hepatic injury and active hemorrhage.
MVD enhances nonlinear fundamental and second harmonic components with a middle mechanical index. In the MVD imaging procedure, MVD was reset, and a small dose of the sonographic contrast agent was transvenously injected to display the microvessels of abdominal parenchymal organs in real time. MVD technique was used to identify the site of bleeding from damaged microvessels and to guide injection of the hemostatic agents. The scan settings during this experiment (gain, scanning depth, and time gain control) were optimized independently for each region. The focus was set to the deeper aspect of the lesion being examined.
The microbubble contrast agent (0.05 mL/kg for contrast pulse sequencing,
0.02 mL/kg for MVD) was administered in a quick bolus through a femoral vein.
In the treatment group, once the location of active hemorrhage and the pathway
of transcutaneous puncture with an 18-gauge needle were confirmed with
real-time contrast pulse sequencing and MVD, 1 Klobusitzky unit of
hemocoagulase atrox in 2 mL of saline solution was transcutaneously injected
into the injury site with a 2-mL syringe under the guidance of contrast pulse
sequencing. Then 1 mL of -cyanoacrylate (Baiyun Medical Glue,
Guangzhou) was injected into the active hemorrhage with a 1-mL syringe under
the guidance of MVD. An injection of 3 mL of normal saline solution was
administered to the control group. For off-line analysis, digital images were
recorded on the scanner as single-frame pictures and multiple cine loops.
The dogs were sacrificed and subjected to laparotomy 30 minutes after injection treatment. Free intraperitoneal blood volume (calculated according to the weight of blood-soaked gauze and the density of dog blood) was recorded. The liver was collected to determine whether the wound was cohered and sealed and the hemorrhage was controlled. Hepatic tissue was collected for gross and histopathologic examinations.
Statistical Analysis
All measurements are presented as mean ± SD. Differences between
group means were determined with analysis of variance, Student's t
test, and nonparametric test as applicable (SyStat software, version 13.0,
SPSS). The differences were considered statistically significant at p
< 0.05.
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After laparotomy, the treatment group was found to have no active hemorrhage on the surface of the treated region. The control group had persistent bleeding from the injury site. Larger intraperitoneal blood volumes were found in the control group (103.8 ± 10.7 mL; range, 90–118 mL) than in the treatment group (15.8 ± 3.5 mL; range, 12.6–22 mL) (p < 0.001). In the treatment group, gross examination of the liver revealed that the injury sites were covered by clots and glue membrane (Fig. 5A) and that there was no hematoma in the treated region. Histopathologic examination showed adhesive glue covering and cohering with the wound, partial embolization of the microvessels (Fig. 5B), and inflammatory cell infiltration between hepatocytes.
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Hemocoagulase atrox is obtained by segregation and purification of venom of a Brazilian spearhead snake of the genus Agkistrodon. Hemocoagulase atrox can turn fibrinogen into fibrin monosomic I, which is turned into fibrin multimer I, which causes platelets to aggregate. In addition, the phospholipid-dependent factor X activator in hemocoagulase atrox causes blood coagulation factor X to turn thrombinogen into thrombin and fibrinogen into fibrin. The result is a decrease in bleeding. As a focal hemostatic agent, hemocoagulase atrox has been used clinically in the treatment of patients with low-flow hemorrhage. Alpha-cyanoacrylate is a quick-acting medical glue that acts as an adhesive and hemostatic agent by rapidly solidifying and forming a membrane. Alpha-cyanoacrylate has been used successfully in various operations for adhesion and hemostasis in the brain, trachea, esophagus, and blood vessels. This agent has played an important role in the management of variceal hemorrhage in patients with portal hypertension [23]. It also has been used for wound hemorrhage therapy. Camacho Alonso et al. [12] performed a study with 93 rats with tongue wounds and concluded that N-butyl-2-cyanoacrylate was a good hemostatic agent for managing oral mucosal wounds made using a steel scalpel.
Our findings in an earlier study (unpublished data) suggested that a single
injection of hemocoagulase atrox into the site of hepatic trauma resulted in
formation of soft blood clots accompanied by oozing. However, there was no
adhesive or seal effect on the bleeding site. Rebleeding at the injury site
necessitated repetition of treatment. Because -cyanoacrylate
polymerization and solidification are accelerated by bleeding
[24], when a single injection
of -cyanoacrylate was administered into the bleeding site, the agent
did not adhere to the wound because of the presence of overflowing blood,
resulting in incomplete hemostasis. In the treatment group in this study,
hemocoagulase atrox was injected into the injury site before
-cyanoacrylate to decrease or control bleeding so that when
-cyanoacrylate was injected into the hemorrhage site, glue adhesion and
solidification would occur to complete hemostasis and wound closure. The use
of the two agents together was complementary.
The efficacy of our approach was confirmed by the contrast-enhanced
sonographic finding of complete hemostasis in the treatment group and
persistent bleeding and larger intraperitoneal blood volume in the control
group. These findings showed the effectiveness of local injections of
hemocoagulase atrox and -cyanoacrylate in the management of hemorrhage
due to blunt hepatic trauma. The results of gross and histopathologic
examinations also showed that hemorrhage from hepatic lesions stopped, the
hepatic wound cohered and sealed, and parts of the microvessels were embolized
by the adhesive after injection of hemostatic agents.
This study of a novel form of hemorrhage control raises more questions than
it answers. First, the blunt hepatic injuries were induced by an impacting
device. Although this miniature device was simple, convenient, and effective
for blunt trauma to an abdominal parenchymal organ in this animal experiment,
the injury severity was not always as expected. Second, the efficacy of focal
injection was evaluated by immediate contrast-enhanced sonography and
laparotomy 30 minutes after the focal injection. Therefore, the long-term
effectiveness and adverse effects associated with injection of hemocoagulase
atrox and -cyanoacrylate are unclear, and further explorations are
needed. Our study results did indicate that direct injection of hemostatic
agents guided by contrast-enhanced real-time sonography is a simple and
effective therapy for grades 3–4 and 4 hepatic trauma.
Contrast-enhanced sonographically guided injection of hemocoagulase atrox
and -cyanoacrylate may be a feasible, fast, and effective method of
minimally invasive management of hemorrhage due to severe blunt hepatic trauma
in many treatment settings—battlefield and bedside.
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