Use of 5-Aminolevulinic Acid to Assess Bone and Tissue Profusion in Orthopaedic Infection Patients

The focus of this study is to explore the variability distribution of 5-Aminolevulinic Acid (ALA)associated with bone and soft tissue perfusion in infection patients, using 5-ALA fluorescence imaging. In additional this study plans to evaluate the change in 5-ALA distribution from pre to post debridement and to preliminarily determine whether an orally administered dose of 20mg/kg 5-ALA can predict recurrent infection/treatment failure.

Study Overview

• Status: Withdrawn
• Conditions: Trauma; Infection; Bone Fracture
• Intervention / Treatment: Procedure: Imaging using 5-Aminolevulinic Acid (5-ALA) during surgery

Detailed Description

The focus of this study is to (1) Explore variability in distribution of 5-Aminolevulinic Acid (ALA) in bone and soft tissue infection (2) Evaluate the change in 5-ALA distribution from pre to post debridement (3) Preliminarily determine whether 5-ALA has the possibility predict infection / treatment failure

Infection following trauma is one of the most prevalent and challenging complications faced by orthopedic surgeons in both military and civilian populations, occurring after up to 60% of open bone fractures. Several factors specific to this trauma place patients at high risk for infectious complications, including: traumatized tissues, open contaminated fracture, soft tissue coverage issues, catabolic state due to poly-trauma, prolonged hospitalization with exposure to nosocomial bacteria, and presence of metallic implants8. Infection requires one or more unplanned surgical procedures and leads to prolonged morbidity, loss of function, and potential loss of limb1. Failed treatment for bone infection results in recurrent infection, requiring repeat surgical procedures in approximately 30% of patients.

Studies are currently being conducted to evaluate the utility of first window Indocyanine Green (ICG) to identify areas of deficient perfusion. This is based upon the concept deficient perfusion prevents delivery of antibiotics and endogenous immune cells to traumatized tissues. In the setting of established infection, poorly perfused bone can be a nidus for biofilm formation creating resistance to antibiotics. However, in the context of this work it is becoming increasingly clear that acute (rather than chronic) infections display hyper vascularity with increased blood flow and neovascularization. Infection is known to display the enhanced permeability and retention effect with increased vascular permeability.

There are currently no accepted intraoperative tools that can be used to make objective decisions about which bone and tissue is infected and which is normal. Methods currently used to guide debridement are quite rudimentary. Clinical judgement is based on the gross appearance of soft tissue and bone, including color, turgor, and extent of soft tissue stripping. A burr may be used to look for bleeding bone. More extensive debridement is thought to minimize risk of index infection or reduce the rate of persistent infection; however, this comes at the cost of increasingly complex reconstructive procedures to fill bony defects. Clearly what is needed is a functional imaging system which can identify infected tissues to guide surgeons in the amount of tissue to debride. In turn, this will lead to fewer infections and a more effective treatment of surgical site infections (SSIs) at the fracture site. Both scenarios will allow patients to return to duty or work sooner.

• Study Type: Observational

Contacts and Locations

Study Locations

• United States
  • New Hampshire
    • Lebanon, New Hampshire, United States, 03756
      • Dartmouth Hitchcock Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 100 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

• Sampling Method: Non-Probability Sample

Study Population

Patients 18 years of age or older who present to Dartmouth-Hitchcock Medical Center with an orthopaedic infection

Description

Inclusion Criteria:

1. Patients 18 years of age or older.
2. History of an extremity fracture.
3. Prior definitive fracture management with external fixation, internal fixation, or joint fusion.
4. Superficial, deep, or organ space surgical site infection (SSI) (as per Center for Disease Control criteria) at the fracture site that requires operative management.
5. Will have all planned SSI care surgeries performed by a participating surgeon or delegate.
6. Provision of informed consent.

Exclusion Criteria:

1. Fractures of the hand cannot be imaged.
2. Iodine allergy.
3. Burns at the SSI site.
4. Incarceration.
5. Expected survival of less than 90 days.
6. Problems, in the judgment of study personnel, with maintaining follow-up with the patient.
7. Adults unable to consent or whom do not have a legal authorized representative
8. Individuals who are not yet adults (infants, children, teenagers)
9. Pregnant or breastfeeding women
10. History of cutaneous photosensitivity, porphyria, hypersensitivity to porphyrins, photodermatosis, exfoliative dermatitis.
11. History of liver disease within the last 12 months.
12. Elevated liver function tests (aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase or bilirubin levels greater than 2.5 times the normal limit) from laboratory tests conducted within 30 days prior to surgery.
13. Serum creatinine in excess of 180 µmol/L within 30 days prior to surgery.
14. Inability to comply with the photosensitivity precautions associated with the study

Study Plan

How is the study designed?

Design Details

• Observational Models: Case-Only
• Time Perspectives: Prospective

Number of groups / cohorts

1

Cohorts and Interventions

Group / Cohort

Intervention / Treatment

Orthopedic infection; Subjects who have undergone previous trauma surgeries and have developed an infection will be assessed for protocol inclusion criteria. Patients will be administered a single, oral, 20mg/kg dose of 5-Aminolevulinic Acid (ALA) by a qualified member of their care team. This dose will be administered ideally 3 hours prior to surgery. Fluorescent imaging will be obtained pre and post irrigation and debridement.

Procedure: Imaging using 5-Aminolevulinic Acid (5-ALA) during surgery; Patients will be administered FDA approved oral 5-ALA and imaged by a FDA approved surgical fluorescence imaging device (Spy Elite) which is 0.5 meter away from the subject.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
5-Aminolevulinic Acid distribution variability	Distribution of 5-Aminolevulinic Acid in the bone and soft tissue of infection patients, measured using fluorescent imaging.	One Day

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
5-Aminolevulinic Acid distribution pre and post debridement.	Distribution of 5-Aminolevulinic Acid in bone and soft tissue prior to and following debridement, measure using fluorescent imaging	One Day

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
5-Aminolevulinic Acid Dose Effectiveness	Number of patients who do not experience a recurrent infection following the experimental dose of 5-Aminolevulinic Acid.	6 months

Collaborators and Investigators

• Sponsor: Dartmouth-Hitchcock Medical Center
• Investigators: Principal Investigator: Ida L Gitajn, Dartmouth-Hitchcock Medical Center

Study record dates

Study Major Dates

• Study Start (Actual): August 13, 2021
• Primary Completion (Anticipated): August 30, 2022
• Study Completion (Actual): November 21, 2022

Study Registration Dates

• First Submitted: June 2, 2021
• First Submitted That Met QC Criteria: July 14, 2021
• First Posted (Actual): July 26, 2021

Study Record Updates

• Last Update Posted (Actual): November 28, 2022
• Last Update Submitted That Met QC Criteria: November 22, 2022
• Last Verified: November 1, 2022

More Information

Terms related to this study

• Keywords: 5-Aminolevulinic Acid, infection, orthopedics, imaging
• Additional Relevant MeSH Terms: Pathologic Processes; Wounds and Injuries; Disease Attributes; Infections; Communicable Diseases; Fractures, Bone; Photosensitizing Agents; Dermatologic Agents; Aminolevulinic Acid
• Other Study ID Numbers: STUDY02000990

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No