The influence of peroperative dobutamine infusion on the blood flow of the DIEP-flap

Breast cancer is the most common form of cancer in women. In 2008 the amount of
new cases of an invasive form of breast cancer was 1.56 per 1.000 women
(absolutely 13.005 new cases), in 2009 this amount was already 13.177. [BRON:
NATIONAAL KOMPAS].

With the increasing percentage of breast cancer, the amount of women who want a
breast reconstruction increases as well, specifically the reconstruction with
own tissue in the form of a DIEAP-flap for its natural, soft result. The
negative publications about silicone implants attributes to this increase.

In de DIEAP-flap is the blood flow in the microanastomosis most crucial for
flap survival. Of previously performed studies we know that dobutamine
increases the blood flow. This data however comes forth out of cardiologic or
small, non-randomized nor controlled trials. Dobutamine is standardly used in
performing DIEP-flap reconstruction although till now no randomized controlled
trial has proven its effectiveness or even its ineffectiveness. For this reason
this research will be performed. Hence, it is not an experimental treatment.

Primary Objective:
To investigate in a prospective randomized controlled trial whether intravenous
infusion of low doses dobutamine solely peroperative or for 18 more hours
postoperative in women undergoing a breast reconstruction by means of a DIEP
flap, increases the blood flow in arterioles and decreases the amount of fat
necrosis postoperative after dobutamine infusion as compared to placebo (NaCl
0.9% infusion) measured by means of laser doppler for the blood flow and
ultrasound for the fat necrosis?

A double-blind, randomized placebo-controlled pilot study with a duration of at
least one year performed in the hospital during DIEP-flap reconstruction. The
control group has the same characteristics as the investigational group en will
receive the placebo on the same time as the investigational product is given to
its group.

In case of severe hypotension (<80mmHg systemic pressure) which can not be
corrected with fluid infusion and is not related to the dose of anesthesia, one
can use the escape medication (ephedrine). If the tension remains low in the
placebo group dobutamine can be given and these patients will be left included
due to the intention-to-treat analysis performed. The rationale for this
analysis is to estimate the effect of allocating an intervention in practice
instead of the effect in the subgroup of the participants who adhere to it. In
case of ongoing low tension in the intervention group despite dobutamine and
ephedrine given, the anesthesiologist can give phenylephrine or noradrenalin.

1. Dobutamine 5microgram/kg/min peroperative, 18hours postoperative 0.9% NaCl
infusion
2. Dobtuamine 5microgram/kg/min until 18hours postoperative
3. 0.9% NaCl infusion both per- and 18hours postoperative

One investigational group will receive intravenous dobutamin in a dose of
5migrogram/kg/min, while the other investigational group will receive
dobutamine 5 microgram/kg/min until 18hours postoperative. This catecholamin
can stimulate the *1-, *2- and **adrenergic receptors. The combined *1- and
*1*adrenergic receptor stimulation leads to an inotropic effect, while *2-
receptor stimulation induces a peripheral vasodilatory effect. Dobutamin will
be given during dissection of the artery and during the performed
microanastomosis.

The comparator (placebo) group will not receive dobutamine infusion, but NaCl
0.9% solution. Blood flow will be measured at the same time as done in the
investigational group.

The patients in all the groups will receive medication infusion at the same
time, so in the postoperative hours that one investigation group receives
dobutamine, the other groups receive placebo infusion. This to preserve
blinding. The medication preparation and distribution is done by the clinical
pharmacologist.

With the Laser doppler the blood flow will be measured during the operation on
standard moment (by dissecting the inferior epigastric artery, before the micro
anastomosis, during the micro anastomosis, after the micro anastomosis and at
the end of the operation. Postoperative the blood flow will be measured at
18.00hrs, 00.00hrs and 8.00hrs in the morning. 24hours postoperative patient
are on the ICU where the nursing staff can do the measurement and note it on
the research status of the patient.

The potential value of the research * namely increasing the rate of flap
survival * is in proportion to the potential risk to and burden for the
patient. The potential risk is mainly related to the use of dobutamine (among
them increased heart frequency, increased blood pressure, supraventricular
extra systole, ventricular tachycardia, chest pain, bronchospasm, dyspnoea).

The most feared risk of the DIEP-flap operation is flap failure due to problems
with the anastomosis. Since dobutamine is thought to increase the blood flow in
the anastomosis making it easier to perform the anastomosis and increasing the
flap survival rate, this study is expected to be beneficial to the patient.

This is in proportion to the risks which are restricted to the already
cardiologic registered medicine dobutamine with a known vasodilatory action.

In conclusion: the theoretically action of dobutamine should lead to the
desired effect but it still has to be proven for this specific research
population and operation.