1. Joint hospital Surgical Grand Round Application of ICG in esophagectomy
Dr Lim Delon
Good morning professors, consultants and fellow colleagues, I am Dr Delon Lim from UCH.
Today I’d like to share with you about the use of Indo-cyanine green in esophagectomy.
First I’ll give you some introductions about ICG and some of its applications.
Then I’ll focus on its use on esophagectomy, mainly to assess the perfusion of the gastric tube, with the use of some current evidence for illustration.

2. Introduction ICG Methylene blue
a fluorophore that absorbed and emitted light in the near-infrared (NIR) spectrum  NIR probe
hydrodynamic diameter of 1.2 nm  very small
only NIR probe approved by the US Food and Drug Administration (FDA);
Methylene blue
another FDA-approved probe
not considered a pure NIR probe.
Indocyanine green (ICG) is a fluorophore that can bound to plasma protein and emits light in the near-intrared spectrum, therefore known as a NIR probe.
It has a very small size and is the only NIR probe so far to be approved by the US FDA.
Another commonly used probe is methylene blue, which is not a pure NIR probe.
Karol Polom et al, Current Trends and Emerging Future of
Indocyanine Green Usage in Surgery and Oncology, Cancer, 2010

3. Introduction ICG (NIR fluorescence imaging) has been used in :
ophthalmic angiography
determining cardiac output and hepatic function
New domains: Surgical oncology
SLN mapping (eg breast, gastric cancer, etc)
Tumor identification
Lymphedema
and assessment of tissue perfusion
ICG has been extensively used for more than 50 years, for example in ophthalmic angiography, determining cardiac output and most commonly known to us for assessing hepatic function.
New domains are being explored nowadays including SLN mapping in breast and gastrointestinal cancers. It can also aid in tumor identification, diagnosing lymphedema
Current Trends and Emerging Future of Indocyanine Green
Usage in Surgery and Oncology: An Update, Ann Surg Oncol (2015) 22:S1271–S1283

4. Introduction ICG (NIR fluorescence imaging) has been used in :
ophthalmic angiography
determining cardiac output and hepatic function
New domains: Surgical oncology
SLN mapping (eg breast, gastric cancer, etc)
Tumor identification
Lymphedema
and assessment of tissue perfusion
and assessing tissue perfusion, which is our main concern in today’s presentation.
Current Trends and Emerging Future of Indocyanine Green
Usage in Surgery and Oncology: An Update, Ann Surg Oncol (2015) 22:S1271–S1283

5. Introduction Assessment of tissue perfusion Reconstructive surgery
Assessment of microvascular circulation of anastomotic site
NIR fluorescence made visible with imaging technologies
Injected intravenously during operation
Tissue perfusion is one of The important parts in reconstructive surgery. Inadequate tissue perfusion may lead to ischemia and subsequent graft failure or anastomotic leakage. With this technology we hope to enhance the assessment of blood circulation during operation using NIR fluorescence coupled with specific imaging modalities.
For evaluation of tissue perfusion ICG is injected intravenously during operation and with special reprocessed images we can visualize distribution of blood supply and organ perfusion.

6. Introduction
This is one of the systems used to visualize ICG signals in laparoscopic surgery.
This is the picture showing SLN bx in breast surgery using ICG
This is the picture demonstrating perfusion in proximal margin in a colectomy
But today I’ll just focus on assessment of perfusion in esophagectomy
Mieog JS et al, Ann. Surg. Oncol. (2011)

7. Introduction Local (HA) figures of esophagectomy 09-10 10-11 11-12
12-13
13-14
14-15
No of cases
141
102 97 98 99
30-day crude mortality(%)
4.3
1.0
6.2
3.1 1
30-day crude morbidity(%)
62.4
58.8
53.6
57.1
68.4
48.5
Mean anastomotic leak(%)
13.5
12.7
7.2
9.2
6.1
Here is some background information about esophagectomy locally in HA.
According to the SOMIP database (next) 
SOMIP database

8. Introduction Local (HA) figures of esophagectomy 09-10 10-11 11-12
12-13
13-14
14-15
No of cases
141
102 97 98 99
30-day crude mortality(%)
4.3
1.0
6.2
3.1 1
30-day crude morbidity(%)
62.4
58.8
53.6
57.1
68.4
48.5
Mean anastomotic leak(%)
13.5
12.7
7.2
9.2
6.1
The rate of anastomotic leak ranges from % over the recent 6 years. Its still quite a substantial risk.
SOMIP database

9. Introduction Anastomotic leakage: Factors associated with leak
important cause of postoperative morbidity and
increased length of stay
Factors associated with leak
low flow or inadequate perfusion of the surgical site
procedure duration greater than 5 hours
type of procedure
obesity, heart failure, coronary disease, vascular disease,hypertension, steroids, diabetes, renal insufficiency, tobacco use
We understood that anastomotic leakage is an important cause of postop mortality/morbidity and prolonged hospital stay.
The cause of leakage is multifactorial. Examples of our concerns include inadequate perfusion, tension and surgical techniques, prolonged procedure, etc
Medical comorbidities like obesity, Heart failure, coronary disease, vascular disease and so on also have significant impact. And in fact these factors also contribute to poor tissue perfusion.
Apart from trying to shorten OT time, avoiding tension and meticulous surgical skills, to know whether the tissue itself is richly perfused or not may be able to help us minimizing the rate of anastomotic leakage
Edmund S. Kassis et al, Predictors of Anastomotic Leak After Esophagectomy: An Analysis of The Society of Thoracic Surgeons General Thoracic Database, Ann Thorac Surg 2013;96:1919–26

10. STUDY
To further look into the matter and find out whether or not it can help our patients, we did some literature search.

11. cervical or thoracic esophagectomy
, 40 patients
cervical or thoracic esophagectomy
ICG fluorescence was detected by a camera and recorded
One of the earliest studies was available in 2011 by the Japanese. In Yutaka’s study, they included 40 patients from the year , all of which esophagectomies were done. ICG flurorescence was detected by a camera system and recorded

12. Results
Their results were shown in a busy table. Basically they detected fluorescence easily at 1min in ALL patients after intravenous injection of ICG.

13. ICG (microcirculation in the stump)
Results
ICG (microcirculation in the stump)
Their results were shown in a busy table. Basically they detected fluorescence easily at 1min in ALL patients after intravenous injection of ICG.

14. ICG (microcirculation in the stump)
Results
Fluorescence was easily detected intra-operatively in all patients(40) at 1 min after ICG injection
ICG (microcirculation in the stump)
Their results were shown in a busy table. Basically they detected fluorescence easily at 1min in ALL patients after intravenous injection of ICG.

15. Results
And retrospectively they observed absence of small vessells in 18 out of 40 patients. They did not further elaborate how and when they did that.

16. ICG (small vessels in the stump) 18/40 -ve
Results
ICG (small vessels in the stump) 18/40 -ve
And retrospectively they observed absence of small vessells in 18 out of 40 patients. They did not further elaborate how and when they did that.

17. Results 3 out of 40  anastomotic leak Retrospectively:
Small vessels were not observed in the stump of the reconstructive organ’s wall in 18 cases
All the leakage cases belong to this group
All the 3 leakage cases belong to the 18 cases group.
There is no statistical calculations available so we really couldn’t draw any solid conclusion.

18. Conclusion? Imaging of ICG fluorescence
May be helpful in evaluating the blood supply of reconstructed organs
Microcirculation detected by ICG intraop =\= provide enough blood flow to maintain a viable anastomosis.
Additional and larger study is needed.
Therefore they commented that ICG MAYBE helpful in evaluating blood supply. And microcirculation demonstrated intraoperatively may not provide enough blood flow to maintain a viable anastomosis. And of course not to mention other risk factors that can affect the results.
Obviously additional and larger study is needed.

19. Other studies N=20 gastric pullup
Conclusions: ICG has potential usefulness for evaluation of blood flow in the gastric tube
After that more studies came out. But all were small observational studies.
N=33 thoracic esophagectomy
Conclusions: ICG fluorescence can be used to evaluate blood supply

20. N = 150 undergoing esophagectomy with gastric pull-up
N = 150 undergoing esophagectomy with gastric pull-up
Until last year, York from The US published a study including 150 patients with esophagectomy and gastric pull-ups.
They wanted to review the correlation between intraoperative perfusion assessment with subsequent anastomotic leakage

21. Real-time intraop perfusion assessment by ICG before bringing the graft up through the mediastinum
Fluorescence images of the graft captured using a charge coupled device video camera system
What they employed was a Laser-assisted angiography (LAA) with a receiving Imaging System (SPY). Basically after the gastric tube is formed, we illuminate the tissue using laser energy, so that the ICG molecules get excited and emit light in a longer wavelength. The energy was captured in the form of fluorescence images using a charge coupled device video camera system.

22. Method Transition site from
Rapid & bright  slow & less robust perfusion
Marked with suture
The location of the anastomosis relative to the suture compared with leakage rate
Outcome measurement:
Anastomotic leakage detected by videoesophagram or by upper endoscopy POD 5-7
So when they’ve found a transition from rapid and bright to slow & less robust perfusion, the site was marked with a suture
After that they pulled the gastric tube through the posterior mediastinum to the neck.
They tried to create the anastomosis proximal to the suture, ie closer to the well-perfused area.
If the length is inadequate, they marked down the location of the anastomosis relative to the suture and later compared the data with leakage rate.
Anastomotic leakage was detected using videoesophagram or by upper endoscopy around post-op D5-7

23. This figure showed a good perfusion in the entire gastric graft
This figure showed a good perfusion in the entire gastric graft. No transition seen

24. VIDEO

25. The figure showed a transition point between the bright and dark zones
Suture was placed at the arrow

26. Result Transition point +ve: 66% Overall leakage rate: 16.7%
This slide shows the result. A transition point was found in 66% of patients.
The overall leakage rate was 16.7%.
And it was significantly lower in the group with anastomosis proximal to the suture, ie transition point
On univariate analysis, anastomosis at or distal to suture and hx of HT were significantly a/w a leak.

27. Result Anastomosis at/distal to suture  significantly a/w leak
This slide shows the result. A transition point was found in 66% of patients.
The overall leakage rate was 16.7%.
And it was significantly lower in the group with anastomosis proximal to the suture, ie transition point
On univariate analysis, anastomosis at or distal to suture and hx of HT were significantly a/w a leak.

28. Result
This slide shows the result. A transition point was found in 66% of patients.
The overall leakage rate was 16.7%.
And it was significantly lower in the group with anastomosis proximal to the suture, ie transition point
On univariate analysis, anastomosis at or distal to suture and hx of HT were significantly a/w a leak.

29. Result
This slide shows the result. A transition point was found in 66% of patients.
The overall leakage rate was 16.7%.
And it was significantly lower in the group with anastomosis proximal to the suture, ie transition point
On univariate analysis, anastomosis at or distal to suture and hx of HT were significantly a/w a leak.
Multivariate analysis: Anastomosis at or distal to suture  the only significant factor associated with a leak

30. Conclusion
The use of ICG may lead to an altered surgical plan in some patients and contribute to reduced anastomotic morbidity and better overall patient outcomes
Intraop real-time assessment of perfusion correlated with the likelihood of an anastomotic leak
They concluded that the use of ICG may lead to an altered surgical plan in some patients and contribute to reduced anastomotic morbidity and better overall patient outcomes
And intraoperative realtime assessment of perfusion has correlations with the likelihood of an anastomostic leakage.

31. Conclusion Anastomosis was unlikely to leak in patients with
no transition point or
At proximal to the transition point when present
When anastomosis had to be placed at or distal to a transition point
 ~50% chance of leak
 should be monitored closely
 planned graft evaluation on POD 5-7
Anastomosis was unlikely to leak in patients with No transition point or when it was placed proximal to the transition point when present, in an area of good perfusion.
In cases where anastomosis had to be placed at or distal to a transition point, as there is 50% chance of leakage, the patients should be monitored closely.
A planned graft evaulation should be arranged on Postop D5-7

32. Limitation Evaluation of the images is largely qualitative
Overall small number of leaks
prohibited an evaluation of the impact of operative approach on anastomotic healing
masked the role of important comorbid conditions that contribute to leaks
Quantitative assessment?
The limitation of this study The evaluation is still largely qualitative
And The overall small number of leaks has prohibited an evaluation of the impact of operative approach on anastomotic healing.
Also it masked the role of important comorbid conditions that contribute to leaks
In the paper they mentioned that they are working on a more quantitative assessment with the refined system and study is underway.

33. Summary
Anastomotic leakage is an important cause of postop morbidity/mortality in esophagectomy
Tissue perfusion is one of the important factors affecting leakage rate
In summary, anastomotic leakage is an important cause of postoperative morbidity or mortalities in esophagectomy.
Tissue perfusion is one of The important factors affecting leakage rate

34. Summary
ICG is a safe, feasible way to assess perfusion and can potentially affect surgical decision
High cost (machine costs ~1 mil HKD)
More studies needed
Role of quantitative measurement
ICG is a safe, feasible way to assess perfusion and can potentially affect surgical decisions
However as this technology is still rather new, and the cost is quite high (around 1 million HKD for the machine) , more studies are needed to justify its use and certainly it would be even better if The assessment can be quantitative so it can be more objective.

35. Other Problems Universal application/ Selection criteria?
Training of staff?
Resources/ Cost-effectiveness?
Clear and non-ambiguous guideline?
More evidence and research is needed
Also some other considerations need to be sorted out, like patient selection criteria, staff training, resources, cost-effectiveness, guidelines, so on

36. THE FUTURE OF ICG??
There are also some areas of wilderness that ICG may have an effect on 

37. Future of ICG Sentinel LN biopsy in esophageal cancer?
Controversial
Problems with multidirectional, complicated lymphatic flow
?use in early superficial disease
LN dissection during esophagectomy
For example can we applied it to identify sentinel LNs in esophageal cancers?
The issues are still controversial as the lymphatic flow are multidirectional and complicated. Some studies tried to include use of ICG in SLN bx in early superficial esophageal cancer. But currently they are only small studies and results were inconclusive.
Yasuhiro et al. Sentinel Lymph Node Biopsy Using Intraoperative Indocyanine Green Fluorescence Imaging Navigated with Preoperative CT Lymphography for Superficial Esophageal Cancer, Ann Surg Oncol (2012) 19:486–493

38. Q & A This concludes my presentation.
Our centre: we are now trying to use a system called “Pinpoint”which makes use of the technology very similar to the US study but for perfusion assessment during minimally invasive or robotic procedures.

39. Thank you

41. Quantitative evaluation

42. Method
ICG emits light with a peak wavelength of 830 nm when illuminated with near-infrared light
Blood flow in the gastric tube was recorded by a Hyper Eye Medical System (HEMS, Mizuho Corporation)
Continuously recorded the data for 5 minutes

43. Method
Quantitative assessments of perfusion at 2 places in the gastric tube (Point A,
the last branch of the right GEA; Point B, 3 cm proximal to Point A

44. Method
Y = luminance
Blood perfusion determined by pattern of luminance change

45. Result

46. Result

47. Conclusion?
ICG fluorescence angiography may be used quantitatively to measure blood perfusion of the reconstructed gastric tube in patients undergoing esophagectomy.

48. Limitation Number of patients way too small
Unable to confirm any association between blood flow type and clinical outcomes (leakage)
The location of the anastomoses in the gastric tube differed among patients
Patients’ anatomy were variously biased