A Pilot Study into the Use of Intraoperative Indocyanine Green Fluorescence Angiography in Young Infants & Neonates

A fluorescence imaging device, in combination with intravenous injection of
indocyanine green (ICG), can visualize perfusion in real-time during surgery.
[1] Perfusion assessment is of major importance for prevention of complications
in gastrointestinal surgery. Specifically, a fluorescence imaging device can
determine the tissue perfusion rate of anastomoses. [2,3]. Therefore, such a
device can reduce the risk of complications such as anastomotic leakage,
stricture and bowel ischemia. [4-6] Furthermore, it has the potential of
improving intraoperative decision-making regarding anastomotic location. A
review on the use of ICG-fluorescence angiography (FA) for assessment of
colorectal anastomosis perfusion rate has shown that ICG-FA use causes on
intraoperative change in surgical plan in 10.8% of cases as well as a 4%
leakage reduction. [7] Furthermore, a 2020 RCT showed an intraoperative change
in transection line in 19.3% of patients undergoing colorectal resection
surgery, as well as a leakage reduction for low colorectal anastomoses. [8]

Although these results in the adult population are promising, the use of ICG-FA
for assessment of intestinal perfusion in neonates has barely been researched
in this particularly vulnerable patient group. However, in neonates, severe
gastrointestinal diseases associated with a decreased perfusion can occur. One
might think of necrotizing enterocolitis (NEC), a fulminant and often
life-threatening disease mostly occurring in preterm infants, during which
intestinal ischaemia and subsequent perforation can occur. Resection of the
avital tissue followed by either a primary anastomosis (when bowel vitality
allows) or ostomy creation is required. Resection of too much bowel is
undesirable as it can cause severe complications such as Short Bowel Syndrome
(SBS). [9] The decision whether bowel is still viable is a subjective one,
based on the surgeons macroscopic assessment of perfusion. Other intestinal
diseases in the newborn requiring surgery and are e.g. intestinal atresia,
malrotation/volvulus and spontaneous intestinal perforation (SIP). In all of
these disorders, assessment of the viability of the resection margins which are
subsequently anastomosed is paramount yet subjective. An objective measurement
to assess bowel perfusion, outlining which intestine is still viable and which
is not adequately perfused, can therefore significantly increase our surgical
abilities. In the future such a tool might significantly decrease complications
such as anastomotic leakage or stricture, as well as prevent unnecessary
resection of viable tissue thereby decreasing the risk for short bowel
syndrome. ICG-FA might be such a tool, as has been demonstrated in adults.

A review of current literature has confirmed the lack of available studies on
indocyanine green fluorescence angiography (ICG-FA) use in pediatric
gastrointestinal surgery. However, the available literature does show that its
use might be safely used for intraoperative decision-making as well as for
intraoperative perfusion assessment. It may even be more useful than
conventional clinical assessment of intestinal perfusion. The safety profile of
ICG in neonates furthermore looks promising, as no serious complications or
adverse events have been reported to date. [10] Prospective studies are
necessary to further investigate the feasibility of ICG-FA in neonatal
gastrointestinal surgery [10]. The goal of this study is to follow up on the
review by further investigating the feasibility and safety of ICG-FA in
neonatal gastrointestinal surgery in two academic pediatric surgical centers
with a wide experience in such surgery.

This study aims to investigate whether the intraoperative use of indocyanine
green fluorescence angiography (ICG-FA) is feasible and safe in neonates.
Feasibility is therein defined as practically possible use of ICG-FA, resulting
in clear and interpretable results, with the future potential to improve
clinical outcome and benefits for the patient.

Specifically, the feasibility and safety for use of ICG-FA in neonates
undergoing laparotomy as treatment for necrotizing enterocolitis (NEC),
intestinal atresia, spontaneous intestinal perforation (SIP) and malrotation
will be investigated.

If ICG-FA turns out to be feasible and safe for the population investigated in
this study, a follow-up study will be conducted with the aim to explore the
potential benefits of this technique on the postoperative outcome and
intraoperative decision-making.

This is a prospective single-arm multicenter feasibility study, including all
neonates undergoing laparotomy for intestinal diseases within the first three
months of life. The study will be performed in two academic pediatric surgical
centers: University Medical Center Groningen (UMCG) and University Medical
Center Utrecht (UMCU). Due to the exploratory nature of the study, there is no
control group.

This clinical investigation is a drug-device combination study. The objective
is to visualize perfusion in the bowel using a hand-held imaging device
(SPY-PHI, Stryker® Endoscopy) with the aid of the fluorescent dye indocyanine
green (Verdye®, Diagnostic Green)
As the visualization of perfusion in the bowel is the main objective, the
SPY-PHI® medical device has the primary functionality in the study and the
study is therefore considered a medical device study. This decision is further
supported by the medical device being used off-label in this study (not
indicated for use in neonates), while the fluorescent dye (Verdye®) is being
used on label.

After the standard-of-care visual bowel inspection, study participants will
undergo an additional 5-10 minutes of bowel fluorescence angiography (FA) with
the aid of intravenous indocyanine green (ICG) injection (on-label,
non-investigational) and a specific imaging camera, the SPY-PHI (Stryker®
Endoscopy) - the investigated medical device. There will be no physical contact
between the study participant and the SPY-PHI camera, and heat release and
radiation exposure are not applicable. In principle, the obtained ICG-FA images
will not have any therapeutic implications as this is a safety and feasibility
study. An unexpected signifcant discrepancy between visual inspection and
ICG-FA may prompt a change in surgical plan as ICG-FA has already been proven
superior to visual assessment only in adults.

The investigational device does not touch the patient at all and therefore does
not constitute many potential risks for participants in this trial. For the use
of the SPY-PHI camera, the potential risks are:
- Minimal prolonged OR time
- Device malfunction
- Non-sterile drapes

If the device malfunctions (ADE), no results of the participant involved will
be available afterwards. However, the patient will still receive the same care
all other participants and non-participants receive. The only change in
treatment that occurs when a child participates in this study is the injection
of ICG and limited prolongation of operative time. The assessment of vitality
of the bowel and further surgical and therapeutic management of the patient
does not change.

The device is always covered in sterile drapes before use during the surgery.
To mitigate any risk of contamination of the surgical field, in case the drapes
are touched by the device they will be immediately replaced by new sterile
drapes.
Last, the use of the device prolongs the operative time with approximately 5-10
minutes. Prolonged operative time may cause additional risks, such as
development of a surgical site infection (SSI). However, the mean operating
time for the diseases studied is 120 minutes. A 10-minute extension is thus
less than 10% additional operating time. This will have a negligible effect on
the complication risks. A 2020 systematic review on the incidence of abdominal
surgical site infections after abdominal birth defects surgery in infants
showed the total proportion of wound infection in these surgeries is 6%, which
is a low risk already. [14]

More importantly, the length of procedure does not seem to determine this risk
in this systematic review. For example, the Kasai procedure for biliary atresia
takes approximately 4 hours, whereas pull-through surgery for Hirschsprung*s
disease takes approximately 2.5 hours. Still, the individual SSI rate for
biliary atresia surgery is lower than the individual SSI rate for
Hirschsprung*s disease. A <10% extension of operating time for this study is
thus not expected to cause an additional risk in SSI. However, to mitigate any
risk, ICG-FA will not be performed if the patient is assessed unstable by the
operating team intraoperatively. If so, the patient will be excluded.