Clinical trial NCT04904081: Feasibility of Use of Indocyanine Green in Pediatric Colorectal Surgery
Official title: The Use of Indocyanine Green Angiography in Pediatric Colorectal Surgery: A Feasibility Randomized Controlled Trial
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE3
Conditions: Hirschsprung Disease
Anorectal Malformations
Lead sponsor: London Health Sciences Centre Research Institute OR Lawson Research Institute of St. Joseph's
Sponsor class: OTHER
First posted: 2021-05-27
Enrollment: 12
Sex: ALL
Minimum age (years): 1
Maximum age (years): 7
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: Hirschsprung's Disease (HD) and anorectal malformations (ARM) are both paediatric diseases of the colon and rectum. Both of these conditions require surgery in order to correct them, frequently needing sections of the bowel to be removed. Some complications of removing parts of the bowel include forming a stricture (a narrowing of the place where the bowel is reattached), and leak from the join. These can be devastating complications, and can significantly impact a patient's quality of life. Indocyanine green (ICG) is a medication that binds to blood vessels and can be visualized using special cameras in the operating room. Once it binds, it "lights up" green on this equipment. This lends the advantage of being able to better see which parts of the bowel get good blood flow. The theory is that good blood flow can reduce the risks of previously mentioned complications. This has been shown to be true in a variety of bowel surgeries in adults. ICG has also been shown to be safe in children. Given that HD and ARM are both relatively rare conditions (\~1/5000 live births), research in this area needs to be strategic. The investigators want to ensure that the investigators can recruit enough patients to the study using this protocol such that if this were to be scaled up to a multi-centre trial in the future, the investigators could demonstrate feasibility. The investigators will collect data both on the feasibility of recruitment as the primary outcome and secondary outcomes including stricture, leak, length of stay in hospital, and return to hospital.

Detailed description: Pediatric colorectal conditions, such as Hirschsprung's disease (HD) and anorectal malformations (ARM), result in significant disease burden in pediatric populations in Canada. Both conditions are present in approximately 1 in 5000 live births. Surgical correction of these anomalies is typically performed in Children's Hospitals in Canada. Postoperative complications, such as anal stricture and anal stenosis, have been reported to occur in 2-35% and 2-10%, after posterior-sagittal anorectoplasty (PSARP) and laparoscopic-assisted pull through for ARM and HD, respectively. In addition, anastomotic leaks and dehiscence are life-threatening, and should be avoided at all costs. The literature estimates the rate of anastomotic leak in HD to be approximately 2%, but have been reported in as high as 10% in neonatal patients. Wound dehiscence post ARM repair has been estimated as high as 30-40%. It is hypothesized that the above post-operative complications occur due to compromised vascular supply to the bowel undergoing coloanal anastomosis at the time of pull-through.

Traditionally, surgeons evaluate bowel viability with tactile and visual means, including discoloration, bleeding from the cut edge, and peristalsis after resection. With the push towards minimally invasive surgeries over recent decades, the adoption of surgical technology which can replace open or tactile assessments is necessary. One such example is the use of indocyanine green (ICG) for assessing bowel perfusion in laparoscopic surgery. ICG is a nontoxic, nonimmunogenic, water-soluble intravascular imagine agent. It has a short half-life (approximately 3-5 minutes) and when injected intravenously, it binds to plasma proteins and proteins in the lymph fluid keeping it in the intravascular compartment. ICG absorbs light in the near-infrared region (806 nm) and emits fluorescent light at 830 nm. ICG was approved by the Food and Drug Administration (FDA, New Drug Application \[NDA\] 211580 505(b)(2) via fda.gov) for use in adults in the late 1950s and has since been approved for use in adults by Health Canada.

A review article published in 2012 identified over 200 manuscripts describing safe and reliable use of ICG in surgical procedures in adults. More specifically, qualitative analysis of bowel perfusion enhanced by ICG in colorectal cancer patients has been shown to reduce rates of anastomotic leak by approximately 4%. Practically speaking, the use of ICG florescence technique can be useful in identifying clinical vascular anatomy in colorectal surgery, both via open and laparoscopic approaches, allowing surgeons to better preserve important structures.

Several studies have shown that ICG is safe among pediatric populations, with utility demonstrated in cases of difficult cholecystectomy, hydrocele repairs, and localizing metastatic disease. As such, the FDA has approved the use of ICG in paediatric patients. Research studies from the US, have examined the intravenous application of ICG for more than 60 years in adults and children with few reported adverse effects. However, Health Canada has not reported on the safety and efficacy of ICG and does not authorize an indication for its use.

To our knowledge, there have only been two studies that have looked at intraoperative ICG to visualize intestinal perfusion for primary pull-through in Hirschsprung Disease and anorectal malformation repair patients and both were retrospective studies. A previous study included eight patients, diagnosed with HD undergoing transanal, open or laparoscopically-assisted pull-through procedures after biopsy confirmation of aganglionosis. Patients were given a dose of 1.25mg (\<2 mg/kg) of ICG intraoperatively in the operating room. In five of the eight patients, the level of the bowel transection was changed based on the ICG visualization. In the other three patients, ICG confirmed the surgeon's assessment of where the resection should occur. There were no intraoperative complications or complications noted at two-week, one-month, and three-month follow-up visits. Further no leaks, incontinence, or strictures were noted at any of these follow-up visits. Another study 16 included 13 patients in total, nine undergoing cloacal reconstruction, four with HD and one with an ARM. ICG was used to predict the vascular supply during the reconstruction procedure and patients were given an intravenous dose of ICG between 0.1 to 0.3mg/kg in the operating room. There were no intraoperative adverse events or side effects from the ICG. ICG changed the operative plan in four out of 13 cases (31%), one of those four cases being a pull-through for HD. For this HD case, ICG resulted in the detection of 10cm of non-viable colon which may not have previously been detected. Although the level of evidence is limited by study design and small sample sizes, these studies help to provide rationale for the continued study of ICG use in paediatric patients.

Despite the results from these studies, future work is needed before he investigators can determine the effectiveness of ICG in reducing rates of post PSARP and pull-through complications. Practically speaking, the main inhibitors to widespread adoption of ICG in these surgeries is the cost of the technology, and lack of data to support that it truly reduces the rates of complications associated with these surgeries. Our research team, looks to be the first group to explore the feasibility of using ICG in a paediatric population with Hirschsprung's Disease and anorectal malformations. The investigators hope that the results from the study will help to initiate future multicenter, randomized controlled trials to provide high level evidence to support the use of ICG in colorectal surgeries in paediatric patients.

Eligibility criteria: Inclusion Criteria:

1. All patients with Hirschsprung's disease or anorectal malformations, diagnosed by:

   1. Clinical evaluation and physical examination
   2. Radiologic studies including abdominal x-rays and/or contrast enemas
   3. Pathologic diagnosis after rectal biopsies (HD only)
2. Patients greater than one-month of age to 7 years of age at the time of surgery
3. Patient requires surgical management for their diagnosis
4. Patient/Substitute decision maker (SDM) able to read/write/understand English

Exclusion Criteria:

1. Those patients and SDM unwilling to provide consent
2. Pregnant and/or women who are breast feeding
3. Patients with a known iodine allergy

Primary outcomes:
measure: The number of eligible paediatric patients treated for HD or ARM at the local institute that would qualify for participation in this trial.
timeFrame: 12 months
measure: The number of eligible paediatric patients treated for HD or ARM that enroll in this study during the recruitment period of this study.
timeFrame: 12 months
measure: The number of eligible paediatric patients treated for HD or ARM that enroll in this study and attend al required study visits.
timeFrame: 12 months
measure: The number of eligible paediatric patients treated for HD or ARM that enrolled in this study but are lost to attrition/drop-out during the study
timeFrame: 12 months
Secondary outcomes:
measure: If the use of ICG alters the intraoperative management of the patient, resulting in the surgeon resecting a longer segment of bowel.
timeFrame: 5 hours
measure: If the use of ICG alters the length of operative time between ICG and control group
timeFrame: 5 hours
measure: If the use of ICG alters the length of stay in hospital between ICG and control group
timeFrame: 2 weeks
measure: Rates of anastomotic dehiscence
timeFrame: Up to 6 months post surgery
measure: Rates of anal stricture (mild) not requiring anal dilatations
timeFrame: Up to 6 months post surgery
measure: Rate of anal stricture (moderate or severe) requiring anal dilatations
timeFrame: Up to 6 months post surgery
measure: Rate of hospital readmission in the first 30 days postoperatively
timeFrame: Up to 6 months post surgery
measure: Rate of an additional related procedure under general anaesthesia (i.e. return to the operating room or interventional radiology)
timeFrame: Up to 6 months post surgery
Other outcomes:
measure: Adverse reaction to ICG resulting in anaphylaxis
timeFrame: Up to 2 weeks post-op
measure: Adverse reaction to ICG resulting in urticarial reactions
timeFrame: Up to 2 weeks post-op
measure: Adverse reaction to ICG resulting in drug interactions
timeFrame: Up to 2 weeks post-op
measure: Adverse reaction to ICG resulting in adverse events/complications
timeFrame: Up to 2 weeks post-op
Locations:
city: London
country: Canada
facility: Children's Hospital, London Health Sciences Centre
state: Ontario
Study officials:
affiliation: Pediatric Surgeon, Children's Hospital, LHSC
name: Andreana Butter, MD
role: PRINCIPAL_INVESTIGATOR
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