SEARCH

SEARCH BY CITATION

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References

Aliment Pharmacol Ther31, 548–552

Summary

Background  Confocal laser endomicroscopy (CLE) is rapidly emerging as a valuable tool for gastrointestinal endoscopic imaging. Fluorescent contrast agents are used to optimize imaging with CLE, and intravenous fluorescein is the most widely used contrast agent. Fluorescein is FDA-cleared for diagnostic angiography of the retina. For these indications, the safety profile of fluorescein has been well-documented; however, to date, fluorescein is not cleared for use with CLE.

Aims  To estimate the rate of serious and total adverse events attributable to intravenous fluorescein when used for gastrointestinal CLE.

Methods  We performed a cross sectional survey of 16 International Academic Medical Centres with active research protocols in CLE that involved intravenous fluorescein. Centres using i.v. fluorescein for CLE who were actively monitored for adverse events were included.

Results  Sixteen centres performed 2272 gastrointestinal CLE procedures. The most common dose of contrast agent was 2.5–5 mL of 10% sodium fluorescein. No serious adverse events were reported. Mild adverse events occurred in 1.4% of individuals, including nausea/vomiting, transient hypotension without shock, injection site erythema, diffuse rash and mild epigastric pain. The limitation is that only immediate post procedure events were actively monitored.

Conclusions  Use of intravenous fluorescein for gastrointestinal CLE appears to be safe with few acute complications.


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References

Confocal laser endomicroscopy (CLE) is a new gastrointestinal endoscopy method that provides imaging of the mucosal layer at resolution of approximately 1 micron, and visualization of the cellular and subcellular structures, as well as capillaries and single red blood cells. Potential applications include detection of neoplasia with targeting of biopsies, confirmation of non-diseased tissue with avoidance of random biopsy, and detection of inflammatory bowel disease, coeliac sprue and microscopic colitis.1

There are currently two systems for CLE available; one that is integrated into an endoscope (eCLE, Pentax corporation, Tokyo, Japan), and another that is integrated into a small calibre probe that can be passed through standard endoscope accessory channels (pCLE, Mauna Kea Technologies, Paris, France). Both systems are optimized with the use of a contrast agent, and intravenous fluorescein is the most widely used agent.

The United Stated Food and Drug Administration approved the use of intravenous fluorescein for ophthalmological imaging of blood vessels, in conjunction with a laser scanning opthalmoscope. Common side effects for ophthalmological use include hypotension, syncope, nausea, vomiting, hypersensitivity, headache and bronchospasm. Rare serious side effects include arterial ischaemia, shock, thrombophlebitis, anaphylaxis and seizure.2–5 For our study, we surveyed international experts in CLE to determine the rate of serious and non-serious adverse events for intravenous fluorescein for gastrointestinal confocal laser endomicroscopy.

Methods

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References

All adverse event data were collected prospectively at each centre. We identified active CLE research programmes using published manuscripts and a recent users group meeting (International Conference of Cellvizio Users, Miami, Nov, 2008) to identify sixteen centres with active Human Safety Committee-approved research protocols involving CLE following intravenous administration of fluorescein. The period of recruitment includes the active dates for IRB approved clinical trials at each centre, spanning January 2003 to November 2008. Patients were excluded if they were examined after topical administration of other fluorescent agents such as cresyl violet or acriflavin. All centres excluded patients with known fluorescein allergy, pregnancy, or who were breast feeding. No other specific groups were excluded for fluorescein purposes except for a multicentre pilot study including three French centres (Nantes, Marseille, Toulouse) which also considered beta-blocker treatment as exclusion criteria. We distributed a clinical report form in the format of an excel spreadsheet (Microsoft Co, Redmond, WA, USA), to each investigator by email. Sites and patients were included if patients were enrolled in an IRB-approved clinical trial using CLE with only intravenous fluorescein contrast and all adverse events were tracked as part of the clinical trial. If they met these inclusion criteria, the data collection form was completed including summary data such as total number of patients treated, dose and formulation of drug used and incidence of serious and non-serious adverse events. All centres followed standard procedures for adverse event collection and reporting.

The specific protocol at each centre varied slightly, but each investigator used either eCLE or pCLE systems for gastrointestinal applications. All patients were enrolled in a protocol approved by the local institutional review board (IRB) and they were actively monitored for serious adverse events. Adverse events were tracked using procedures consistent with policies for management of unanticipated problems involving risk to subjects or others (UPIRTSO) as defined by U.S. Code of Federal regulations [45 CFR 46.103(b)].5 Serious adverse events were those considered by the investigator or subject to be potentially life-threatening. All other adverse events were considered non-serious.

All patients were monitored for a minimum of 2 h after each procedure in the endoscopy laboratory for adverse events including blood pressure, heart rate and pulse oximetry. Patients were evaluated by the discharge nurse for any potentially attributable adverse events prior to discharge. Any such events were reported to the principal investigator at each site and added to the clinical report form. After discharge, adverse events were reported by the patient to each principal investigator or study staff, but we did not perform active interrogation at 30 days for adverse events. Criteria for adverse events included any systemic allergic symptoms including rash, hive, shortness of breath, wheezing or any other new symptoms reported by the patient. For this study, only patients who received intravenous fluorescein for CLE were included. Rates of adverse events were calculated as binomial proportions. For reasons of the small number of complications, exact 95% confidence intervals were calculated.6

Adverse events were collated on a ‘centre’ level (each centre reported total number of adverse events and total number of procedures), thus individual correlations with age and disease predictors were not performed. Data are reported as proportions with 95% confidence intervals. Given the small number of adverse events in subgroups, it was not meaningful to make inferential (P-value) statements of each subgroup. We do report absolute adverse event rates in the total and each subgroup.

Results

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References

Sixteen centres contributed data involving 2272 unique patients undergoing CLE procedures from January 2003 to November 2008. The indications for enrolment in clinical trials included evaluation of Barrett’s oesophagus, colon polyps, colitis, biliary stricture, coeliac disease, and Helicobacter pylori.

Four primary formulations of fluorescein sodium were used; 10% with doses ranging from 0.5 to 10 mL. (AK-Fluor, Acorn Pharmaceuticals, Lake Forest, IL, USA; Novartis, E Hanover, NJ, USA; Fluorescein, Serb, Paris, France; Alcon Labs, Ft. Worth, TX, USA) and 1% fluorescein at 0.1 mL/kg. A vast majority (2087/2272; 92%) of patients received 2.5–5 mL of 10% fluorescein sodium.

All patients experienced transient yellowish discolouration of the skin lasting 1 to 2 h. No serious adverse events were reported. Minor adverse events occurred in 1.4% (Table 1). These were primarily nausea, transient decrease in blood pressure without shock, and injection site erythema. None of the adverse events required significant interventions other than short-term out-patient observation, intravenous fluid supplementation (for low blood pressure), and anti-emetics (for nausea).

Table 1.   Adverse events among 2272 patients undergoing i.v. fluorescein for CLE
Serious adverse events0/22720% (95% confidence interval; 0–0.16%)
Transient hypotension12/22720.5% (0.27–0.92%)
Nausea9/22720.39% (0.18–0.75%)
Injection site erythema8/22720.35% (0.15–0.69%)
Self-limited diffuse rash1/22720.04% (0–0.24%)
Mild epigastric pain2/22720.09% (0.01–0.32%)
Total32/22721.4% (0.97–1.98%)

Although the small number of adverse events did not allow statistically relevant comparisons of sub-groups, we explored the effect of drug formulation, dose and site or study. Of the two most commonly used formulations, no significant differences were seen in mild adverse events (1.4%; 29/1962 Alcon Lab or 0.4%; 1/279 Akorn Pharmaceutical). Of the two primary doses, there was no significant difference in mild adverse events [1.4%; (30/2087) for 2.5–5 mL of 10% vs. 1.1%; (2/185) for 0.1 mg/kg of 1%]. The adverse events occurred at four different institutions, with most data from the largest (author RK) centre representing 29 events among 1671 procedures. Each of three other centres reported 1/8, 1/7, and 1/191.

Discussion

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References

Intravenous fluorescein appears to be safe for gastrointestinal confocal laser endomicroscopy. The safety of intravenous fluorescein is well established for its use in ophthalmological angiography. In a study of 150 patients undergoing ophthalmoscopy with 10% i.v. fluorescein at 2 and 5 mL dose, three patients experienced mild side effects (nausea in two, vomiting in one)5 at the higher dose of 5 mL. Although the size of the study did not allow comparison of side effects between the two doses, the authors concluded that the minor side effects at 5 mL were outweighed by the superior image quality at the higher dose. In the ophthalmological literature, mild nausea and vomiting occurred in up to 2–10% of individuals.3, 7 Severe adverse reactions such as cardiovascular, respiratory, or neurological compromise were reported in 0.05% of individuals. The higher rate of minor side effects in this trial compared to our study may be as a result of variability in attributing mild nausea as a side effect, particularly after a sedated endoscopy where mild nausea is common and not typically attributed to a new study medication. In a recent study of more than 11 000 patients, with very similar survey design to ours, minor adverse events were reported in 1.1% and none had severe adverse events,8 results nearly identical to our study. Allergic reactions and anaphylaxis are extremely rare; estimated to occur in 1 in 222 000,2 although even patients with known allergy have been successfully desensitized when angiographic imaging is needed.4 The route of administration, formulation, concentration, rate and general indication (vascular imaging) are identical when used for gastrointestinal CLE.

While opthalmological uses of i.v. fluorescein have clearly demonstrated an excellent safety profile, it is still valuable to measure safety specific to CLE as the patient population for endoscopy (Barrett’s, screening colonoscopy, colitis) is different from those undergoing retinal angiography (long standing diabetes, macular degeneration) particularly with regard to renal function in chronic diabetic patients.

Pharmacologically, intravenous fluorescein has very rapid distribution in the vasculature, with visualization on confocal imaging with seconds after administration. It is 80% protein-bound and diffuses quickly into the interstitial spaces. Fluoresecin is quickly metabolized to fluorescein monoglucuronide and then renally cleared.9

Fluorescein-based confocal laser endomicroscopy is becoming an increasingly important tool in both research and clinical settings for gastrointestinal disease. Kiesslich et al.10 published the first report of using confocal endomicroscopy in 42 patients during ongoing colonoscopy in diagnosing intraepithelial neoplasia and colorectal cancer. A total of 134 small lesions (mean size 4 mm) were identified during colonoscopy after staining, with an overall accuracy of 99.2% using both intravenous fluorescein and topical staining.

The potential applications of this technology extends beyond the discrimination of neoplastic and non-neoplastic (hyperplastic) colon polyps, to detection of other pathologies such as squamous cell oesophageal cancer,11 Barrett’s oesophagus, oesophagitis, gastritis, coeliac disease, etc.10, 12–14 In a study of 63 patients with Barrett’s oesophagus using fluorescein-aided endomicroscopy (eCLE), Kiesslich et al.15 predicted Barrett's oesophagus (BO) with a sensitivity of 98.1% and specificity of 94.1%.

A new high resolution probe-based confocal endomicroscopy (pCLE) has recently been developed (Mauna Kea Technologies). These probes have further expanded the potential of CLE use in gastroenterology as they can be passed through the accessory channel of any endoscope and can be used as needed in any endoscopy case, including passage into the bile and pancreatic ducts. Clinical studies with pCLE technology have shown promise in Barrett’s oesophagus,16, 17 biliary cancer,18 and colonic neoplasia.10, 19

The optimal dose and timing of i.v. fluorescein injection has also been reported. Becker et al. reported time-dependant imaging with pCLE showing an optimal window from 0 to 8 min after injection, with interpretable images for up to 30 min.20 Our group has evaluated the preliminary assessment of dose optimization studies from 0.5 to 5 mL of 10% fluorescein, showing 5 mL to be better than lower doses.21

A limitation of our study is the lack of a 30-day active follow-up, which could lead to underestimation of risk. While possible, we believe it is unlikely that significant adverse events occurred beyond the immediate post procedure time. Previously reported reactions are usually observed in the immediate post-injection period.2, 4, 5 Furthermore, all patients participated in approved research studies with active mechanisms for patients to report adverse events to the study centre. Another limitation as well as strength is the large number of centres, each with slightly different protocols and methods of assessment for adverse events. Although this could lead to some variability in adverse event rate detection, it also provides a robust cross sectional view of the worldwide use and safety of fluorescein for CLE. There is certainly potential for variability in reporting and attribution of events, particularly mild adverse events such as nausea which is also common after narcotic analgesics used for sedation during endoscopy. It is likely that some of the variability in these side effects was because of site-specific variability in report of mild events. It is unlikely in our view, however, that there would be substantial variability in reporting serious adverse events.

The current study demonstrates that side effects of intravenous fluorescein are rare and generally mild. Serious side effects, although reported in non-gastrointestinal applications, have not yet been reported to date, but these should be anticipated and prepared for as with any drug. The use of i.v. fluorescein for gastrointestinal confocal laser endomicroscopy appears to be safe and effective in current clinical doses.

Acknowledgements

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References

Declaration of personal interests: Dr Michael B Wallace has received research funding from Mauna Kea Technologies. Declaration of funding interests: This study was funded in part by Mayo Clinic Foundation for research to purchase confocal equipment.

References

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References
  • 1
    Wallace MB, Fockens P. Probe-based confocal laser endomicroscopy. Gastroenterology 2009; 136: 150913.
  • 2
    Yannuzzi LA, Rohrer KT, Tindel LJ, et al. Fluorescein angiography complication survey. Ophthalmology 1986; 93: 6117.
  • 3
    Lopez-Saez MP, Ordoqui E, Tornero P, et al. Fluorescein-induced allergic reaction. Ann Allergy Asthma Immunol 1998; 81(5 Pt 1): 42830.
  • 4
    Knowles SR, Weber EA, Berbrayer CS. Allergic reaction to fluorescein dye: successful one-day desensitization. Can J Ophthalmol 2007; 42: 32930.
  • 5
    Moosbrugger KA, Sheidow TG. Evaluation of the side effects and image quality during fluorescein angiography comparing 2 mL and 5 mL sodium fluorescein. Can J Ophthalmol 2008; 43: 5715.
  • 6
    Pezullo J. Available at: http://statpages.org; 2009.
  • 7
    Jennings BJ, Mathews DE. Adverse reactions during retinal fluorescein angiography. J Am Optom Assoc 1994; 65: 46571.
  • 8
    Kwan AS, Barry C, McAllister IL, Constable I. Fluorescein angiography and adverse drug reactions revisited: the Lions Eye experience. Clin experiment ophthalmol 2006; 34: 338.
  • 9
    Mandava N, Reichel E, Guyer D. Fluorescein and ICG Angiography, 2nd edn. St Louis: Mosby, 2004.
  • 10
    Kiesslich R, Burg J, Vieth M, et al. Confocal laser endoscopy for diagnosing intraepithelial neoplasias and colorectal cancer in vivo. Gastroenterology 2004; 127: 70613.
  • 11
    Manner H, May A, Pech O, et al. Early Barrett’s carcinoma with “low-risk” submucosal invasion: long-term results of endoscopic resection with a curative intent. Am J Gastroenterol 2008; 103: 258997.
    Direct Link:
  • 12
    Sakashita M, Inoue H, Kashida H, et al. Virtual histology of colorectal lesions using laser-scanning confocal microscopy. Endoscopy 2003; 35: 10338.
  • 13
    Kiesslich R, Hoffman A, Goetz M, et al. In vivo diagnosis of collagenous colitis by confocal endomicroscopy. Gut 2006; 55: 5912.
  • 14
    Kiesslich R, Goetz M, Burg J, et al. Diagnosing Helicobacter pylori in vivo by confocal laser endoscopy. Gastroenterology 2005; 128: 211923.
  • 15
    Kiesslich R, Gossner L, Goetz M, et al. In vivo histology of Barrett’s esophagus and associated neoplasia by confocal laser endomicroscopy. Clin Gastroenterol Hepatol 2006; 4: 97987.
  • 16
    Pohl H, Rosch T, Vieth M, et al. Miniprobe confocal laser microscopy for the detection of invisible neoplasia in patients with Barrett’s oesophagus. Gut 2008; 57: 164853.
  • 17
    Miehlke S, Morgner A, Aust D, Madisch A, Vieth M, Baretton G. Combined use of narrow-band imaging magnification endoscopy and miniprobe confocal laser microscopy in neoplastic Barrett’s esophagus. Endoscopy 2007; 39(Suppl 1): E316.
  • 18
    Meining A, Frimberger E, Becker V, et al. Detection of cholangiocarcinoma in vivo using miniprobe-based confocal fluorescence microscopy. Clin Gastroenterol Hepatol 2008; 6: 105760.
  • 19
    Buchner A, Murli K, Wolfsen H, Michael M. High resolution confocal endomicroscopy probe system for in vivo diagnosis of colorectal neoplasia [abstract]. Gastroenterology 2008; 135: 295.
  • 20
    Becker V, Von Delius S, Bajbouj M, Karagianni A, Schmid RM, Meining A. Intravenous application of fluorescein for confocal laser scanning microscopy: evaluation of contrast dynamics and image quality with increasing injection-to-imaging time. Gastrointest Endosc 2008; 68: 31923.
  • 21
    Wallace M, Buchner A, Becker V, Meining A. Determination of the optimal fluorescein dose of probe-based confocal laser endomicroscopy in colonic imaging. Gastrointest Endosc 2009; 69: AB375.