The effect of ARTISS on latissimus dorsi donor site seroma formation after breast reconstruction: a randomised controlled trial.

Yearly the plastic surgery department of the Isala Clinics performs about 23
pedicle-based musculocutaneous latissimus dorsi flaps (LD) used in immediate
breast reconstruction surgery. One of the most frequent and dreaded
complications of these interventions is production of seroma. The incidence of
donor-site seroma is seen up in 80% of the patients. The amount of seroma can
differ from 0mL until almost 3500 mL. Seroma can occur at the donor site at
the back, but also in the chest wall after mastectomy. Formation of seroma can
result in seroma related morbidity such as infection, formation of a capsule
around seroma resulting in deformity, skin flap necrosis or impaired wound
healing. As a consequence, patients suffer from increased postoperative pain,
delay of adjunctive treatments, longer hospital stays and therefore increased
costs. Potential treatments for seroma are frequent needle aspiration, *benign
neglect*, and even doxycyline or bleomycine sclerotherapy.
Avoiding seroma production seems to be of great importance for both patients
and plastic surgeons. Since a couple of years, ARTISS© (Baxter Healthcare
Corporation, Utrecht, NL), a human fibrin sealant, is available as a treatment
option to reduce or even prevent donor site seroma formation. ARTISS is a
mixture of fibrinogen, human thrombin, aprotinin and calcium chloride solution.
Therefore, it facilitates haemostasis, seal leaky lymph vessels, and manage
tissue adherence2. In a rodent model, after harvesting the LD and using fibrin
sealant, seroma formation was even decreased from 90% to 20%.
So far, no large randomized controlled trials are conducted describing the
effectiveness of ARTISS on seroma production after LD procedures in breast
reconstruction surgery. Therefore, this prospective, single-blinded randomized
controlled trial aims to determine the effect of ARTISS in preventing donor
site seroma production compared with the current standard care.
*

The aim of this study is to investigate the effect of ARTISS compared with our
standard care on total volume of donor site seroma after harvesting a LD in
immediate breast reconstruction. Seroma is diagnosed, when >= 20 mL can be
punctuated after fine needle aspiration or when >= 20 mL can be diagnosed with
the help of ultrasound, after removal of all drains.

A prospective, single-blinded, randomized controlled trial in one teaching
hospital (Isala Clinics, location Zwolle) will be carried out from 1st July
2015 until 1st July 2020. The recruited patients will be allocated in one of
the two groups: ARTISS and suction drains or suction drains alone. The program
*research manager* will allocate the patients in groups.

Firstly, the general surgeon will perform a mastectomy. One drain will be
inserted in the cavity of the amputated breast. Hereafter, the LD flap is
harvested by a qualified plastic surgeon using the following technique. Beside
the latissimus dorsi musle, a transverse skin paddle will be included in the LD
flap. The LD flap size is designed in reference to the removed breast tissue.
Dissection of the flap is performed using electrocautery. All adipose tissue is
included in the flap and the thoracodorsal nerve is dissected. Therefore, the
flap could be transposed anteriorly. A mamma prothese can be used in breast
reconstruction. Haemostasis is performed using electrocautery. The wound site
is irrigated with saline solution. Before closure, two suction drains are
inserted at the same location at the back in every patient. In the ARTISS
group, the entire cavity is dried and than sprayed with ARTISS. Pressure is
applied for three minutes to ensure the obliteration of the cavity. The drains
are not activated before these three minutes after the fibrin sealant is
sprayed, to avoid disturbing the gluing process. Hereafter, the wound is closed
using vicryl and monocryl sutures. Our control group will have the same wound
closure technique, besides the ARTISS spraying in the cavity.
Starting on day one, all volumes and duration of wound drainage will be
recorded. Suction drains are removed if drainage < 50 cc/ 24hours. When the
drains are removed, seroma formation is diagnosed with clinical examination of
the back and/ or with ultrasound. Seroma can be aspirated with fine needle
aspiration and the aspirated volume will be recorded if aspiration had
occurred. Standard out clinic examination will be performed at one, two and six
weeks after discharge. At six weeks after discharge, an ultrasound will be
performed of the donor site in our included cases, to objectivize the volume of
seroma formation. Our last measurement will be at 12 weeks postoperative.
In case of discomfort caused by donor site seroma, patients will visit our out
clinic department more often than our check-ups at 1, 2, 6 and 12 weeks. The
volume and frequency of these aspirations are also recorded during these extra
examinations.
Our secondary outcomes are drainage volume and duration of drainage, length of
hospital stay of a patient, other postoperative complications besides donor
site seroma (such as infection), pain measured by the Visual Analog Scale
(VAS), and costs in euros.

All included patients in the ARTISS group can experience the benefits of the
fibrin sealant. So, patients can experience less donor site seroma and seroma
related complications.
In line with the manufacturer*s guide, a few risks are associated with the use
of ARTISS:
a. Hypersensitivity Reactions
Hypersensitivity reactions, including anaphylaxis, can occur. Cases have been
reported in post-marketing experience with fibrin sealant. In specific cases,
these reactions have progressed to anaphylaxis. Such reactions may especially
be seen if product is applied repeatedly over time or in the same setting, or
if systemic aprotinin has been administered previously; however, these
reactions may also occur in patients receiving ARTISS for the first time. Even
if the first treatment was well tolerated, a subsequent administration of
ARTISS or systemic aprotinin may not exclude the occurrence of an allergic
reaction. Symptoms associated with allergic anaphylactic reactions include:
Flush, urticaria, pruritus, nausea, drop in blood pressure, tachycardia or
bradycardia, dyspnea, severe hypotension and anaphylactic shock.
The product contains aprotinin for its antifibrinolytic properties. Aprotinin,
a monomeric polypeptide, is known to be associated with anaphylactic reactions.
Even in the case of strict local application of aprotinin, there is a risk of
anaphylactic reactions to aprotinin, particularly in the case of previous
exposure.
Discontinue administration in the event of hypersensitivity reactions. Remove
the already applied, polymerized product from the surgical field. Mild
reactions can be managed with antihistamines. Severe reactions and reactions
involving hypotension require immediate resuscitative intervention.
b. Air or Gas Embolism
Air or gas embolism has occurred with the use of spray devices employing
pressure regulator to administer fibrin sealants. This event appears to be
related to the use of the spray device at higher than recommended pressures and
in close proximity to the tissue surface.
When using a spray device, be sure to use the pressure within the pressure
range recommended by the spray device manufacturer. In the absence of a
specific recommendation avoid using pressure above 20-25 psi. Do not spray
closer than the distance recommended by the spray device manufacturer. In the
absence of a specific recommendation avoid spraying closer than 10-15 cm from
the surface of the tissue. When spraying, changes in blood pressure, pulse,
oxygen saturation and end tidal CO2 should be monitored because of the
possibility of occurrence of air or gas embolism. When using the Easyspray
device, or an equivalent spray device cleared by FDA, use the pressure within
the pressure range recommended by the spray device manufacturer. Spray only on
to visible application sites.
c. Protein Denaturation
The sealer protein and thrombin solutions can be denatured by alcohol, iodine
or heavy metal ions (e.g., antiseptic solutions). If any of these substances
have been used to clean the wound area, the area must be thoroughly rinsed
before application of ARTISS and made as dry as possible.
d. Transmission of Infectious Agents
ARTISS is made from human plasma. Because this product is made from human
blood, it may carry a risk of transmitting infectious agents, e.g., viruses,
the variant Creutzfeldt-Jakob disease (vCJD) agent, and theoretically, the
Creutzfeldt-Jakob disease (CJD) agent. All infections thought by a physician
possibly have been transmitted by this product should be reported by the
physician or other healthcare provider to Baxter Healthcare Corporation,
telephone no. 1-866-888-2472.
Some viruses, such as parvovirus B19, are particularly difficult to remove or
inactivate at this time. Parvovirus B19 most seriously affects pregnant women
(fetal infection), immune-compromised individuals or individuals with an
increased erythropoiesis (e.g., hemolytic anemia).