Intra-operative visualization and treatment of salivary glands affected by sjögren*s syndrome using contrast enhanced ultrasound sialendoscopy (ceuss): a pilot study

Sjögren*s syndrome (SS) is an autoimmune inflammatory disorder of the exocrine
glands highly associated with rheumatoid arthritis. The prevalence of SS is
estimated at 0.15-1% of the worldwide population with a female preference
(female:male ratio 9:1). SS is therefore the second most common autoimmune
disease.
SS particularly affects the lacrimal and salivary glands. Severe dry mouth and
eyes are frequently reported as presenting symptoms. In SS, the quantity and
quality of saliva reduces progressively. Next to a reduced saliva production of
the glands, also the saliva-transporting ducts are often occluded. Due to
hyposalivation the patients suffer from progressive dental decay, dental
erosion, severe dry mouth complaints (i.e. eating and swallowing problems, lack
of taste), inflammation of the oral mucosa and lack of retention of removable
dentures. Overall, this may lead to a marked reduction in the quality of life.

In recent years, we established a promising approach to use endoscopic
irrigation of the glands (sialendoscopy). In this technique the ducts of the
salivary glands are rinsed with saline and cortisone and strictures (i.e.
occlusions or blockades) are dilated. We showed alleviation of the oral
symptoms of patients suffering from SS and restoration of salivary flow to
adequate levels. However, limitations of this technique include: only a few
ducts can be visualized per treatment, no diagnostic imaging (occlusions, flow)
available at time of treatment and effect assessment only in follow-up.

To tackle these issues and improve our therapy, we will employ
contrast-enhanced ultrasound (US) using commercially available sulphur
hexafluoride microbubbles (SonoVue; Bracco SpA, Milan, Italy) combined with
classic sialendoscopy. These microbubbles, consisting of 5-10 µm gas-filled
particles, are used as contrast agents to demonstrate (occlusions of) fluid
flow in several organs.

In our approach, the microbubbles will actually serve multiple purposes:
* We expect that the µm-size of the microbubbles facilitates penetration of
virtually all ducts, thereby allowing non-invasive high-resolution US imaging
of the glands, and in particular duct occlusions (where microbubbles will
accumulate). Based on previous research, we expect that stasis of the contrast
agent can be seen in front of the stenosis, indicating the occurrence of a
stricture. The passing of the contrast agent will result in elongation of the
stricture.
* The effect of the classic sialendoscopic treatment can be imaged directly by
re-infusion of microbubbles, and assessing the *new* distribution pattern.
Even though the treatment we exert in the current study is technically spoken a
symptomatic solution, we have provided evidence that sialendoscopy is able to
restore saliva flow significantly, reducing the burden of the SS patient.
Sialendoscopy is a minimal invasive technique, which is clinically accepted in
the Netherlands to treat obstructive salivary gland diseases. Sialendoscopy is
performed under local anaesthesia. The current project has the added value over
classic sialendoscopy that it encompasses non- invasive intra-operative
visualization and diagnostic imaging with no radiation exposure of the patient,
and we hypothesize that the irrigation-induced local hydrostatic pressure may
dissolve ductal occlusions and enhance saliva flow.

Microbubbles are widely used for various applications, both as contrast agent
and as treatment modality. The use of microbubbles is also described for
salivary glands but not for US-assisted contrast imaging in salivary glands
affected by Sjögren*s syndrome. Therefore, and because it concerns an
intervention with a registered medicine with a different indication, it is
imperative that this new application is first tested for its feasibility and
safety in this category of patients.

our aim is to investigate practical applicability and safety of contrast
enhanced ultrasound sialendoscopy (CEUSS) in salivary Parotid and Submandibular
glands affected by Sjögren*s Syndrome

This is a single center, single-arm trial. The study will be conducted with
patients diagnosed with Sjögren*s syndrome (SS) and will encompass a
recruitment period of 8 months and a patient follow-up time of 16 weeks
(excluding medical ethical approval, data analysis etc).

Contrast enhanced ultrasound sialendoscopy: A mixture of 0.3 ml of a second
generation contrast agent (SonoVue®, Bracco, Milan, Italy), consisting of
stabilized microbubbles of sulfur hexafluoride and 9.5 ml (0.9% NaCl) will be
prepared (irrigation solution).

At the start of the treatment, local anaesthesia is introduced, upon which the
endoscope is properly positioned in the salivary duct (figure 1) under
echoscopic guidance. Sialendoscopy with continuous ultrasound imaging will be
performed using 0.8 or 1.1 mm diameter Erlangen sialendoscopes. Sialendoscopy
is always started by flushing the salivary duct system and filling it with
approximately 2 ml irrigation solution to unfold the ducts. During
sialendoscopy, irrigation fluid will continuously drain in a retrograde manner
from the duct system via the ostium into the oral cavity and it is removed from
the oral cavity by suction. Therefore, the irrigation fluid has to be
replenished regularly throughout the procedure. For this, a small volume will
be applied whenever the ducts collapse. This strategy results in an average
application rate of about 0.5 ml irrigation fluid per minute (23). Stronger and
longer-lasting bursts of irrigation may be necessary during endoscopy to flush
out plaques and microsialoliths from the salivary duct system and open
stricture. On the surgeon*s instruction, the assisting nurse will perform
intermittent flushing by manual pressure on the 10 ml syringe. Finally, an
intraductal bolus injection of the remaining irrigation solution will be
administered intraductally under direct vision into the salivary glands and
maintained in the glands by temporarily (±10 min) occluding the ductal orifices
with a microvascular clamp.
During the procedure, continuous ultrasound imaging will be performed using a
local transdermal ultrasound device to visualize the glands, including the
location of strictures and occlusions. This will be performed at a fixed US
resonance frequency of 9 MHz, performed under low US mechanical index settings
(MI: 0.1) to avoid disruption and premature activation of the bubbles (see
reference #13 in the protocol). It will be monitored how far and how quick the
microbubbles enter the ductal system of the salivary glands and the effect of
the sialendoscopic rinsing procedure on strictures (i.e. occlusions or
blockades) will be monitored. The application of the microbubbles concerns an
intervention with a registered medicine with a different indication.

The burden for participating volunteers is two consultation visits followed by
a visit on which the intervention is performed under local anaesthesia and
several follow up visits. At every visit (except the intervention visit) the
patient has to donate saliva, and the patient has to fill out questionnaires.
At T-4, T1 and T16 the major salivary glands are evaluated by ultrasound using
the Ho*evar scoring system.
A reported side effect of sialendoscopy is post-operative swelling.
Postoperative swelling usually occurs during the initial 48 hours and may last
for 3-5 days after the procedure. A possible but rare complication is
perforation of the salivary duct and the creation of a passage due to the
application of excessive force.
Ultrasound is a safe and non-invasive imaging technique. The use of contrast
enhanced ultrasound in salivary glands is described before in non-SS patients,
either by intraductal or by venous application (12*14). Zengel et al described
that the intraductal application of Sonovue microbubbles was easily to perform
and no patient inconvenience, pain or side effects were detectable. About the
safety and side effects of the systematic use of microbubbles there is a large
body of literature available, mainly from the field of cardiology. According
the EMA (European Medicines Agency) guideline, the most common side effects
when SonoVue is injected into a vein (seen in up to 1 in 100 patients) are
headache, nausea (feeling sick) and reactions at the injection site. In
literature, a low incidence of adverse reactions to the use of Sonovue
microbubbles as an ultrasound contrast agent for clinical applications in
abdominal and superficial organs is found. It should be emphasized that in our
study the microbubbles will not be injected intravenously but into the ducts of
the salivary glands. Therefore, the microbubbles will not enter the bloodstream
and we presume that the occurrence of adverse reactions, as described below, is
even more limited compared to intravenous infection.
The benefit for the participating patient is a possible reduction of dry-mouth
complaints and (partial) restoration of salivary flow. The application of the
microbubbles concerns an intervention with a registered medicine with a
different indication.