Published ahead of print on June 23, 2004, doi:10.1164/rccm.200404-438CR
© 2004 American Thoracic Society doi: 10.1164/rccm.200404-438CR
Fluorescein-enhanced Autofluorescence Thoracoscopy in Primary Spontaneous PneumothoraxInterventional Endoscopy Clinic, Anaesthesiology Department and Respiratory Division, University Hospital AZ VUB, Brussels, Belgium Correspondence and requests for reprints should be addressed to Marc Noppen, M.D., Ph.D., Head, Interventional Endoscopy Clinic, University Hospital AZ VUB, 101, Laarbeeklaan, B 1090 Brussels, Belgium. E-mail: marc.noppen{at}az.vub.ac.be
The exact site of air leakage in a patient with primary spontaneous pneumothorax is difficult to determine and locate. In particular, the role of rupture of emphysema-like changes (blebs and bullae) versus that of enhanced porosity of lung parenchyma in the pathophysiology of primary spontaneous pneumothorax remains unclear. This is the first description of a patient with recurrent primary spontaneous pneumothorax in whom inhalation of aerosolized fluorescein followed by autofluorescence thoracoscopy allowed in vivo localization of various lung areas of extensive subpleural fluorescein accumulation which were not, or only partly, visibly abnormal during normal white light thoracoscopy. No air leak was present at the time of thoracoscopy. No emphysema-like changes were seen. Our findings suggest substantial areas of parenchymal abnormality that remain unnoticed by white light thoracoscopic inspection of the parenchymal surface. In this respect, fluorescein-enhanced autofluorescence thoracoscopy may become an exciting tool in the study of the pathophysiology of primary spontaneous pneumothorax, and could prove useful in clinical practice in determining the sites of surgical staple resection whenever this treatment modality is considered.
Key Words: autofluorescence • fluorescein • pathophysiology • spontaneous pneumothorax • thoracoscopy Most journal and textbook authors (1, 2) believe that rupture of emphysema-like changes (i.e., blebs and/or bullae) is the cause of primary spontaneous pneumothorax. We (3, 4) and others (5, 6) have proposed that air leaks may occur at diseased portions of the lung characterized by visceral pleural porosity (7, 8), which may occasionally be associated with emphysema-like changes, but which also may be localized elsewhere at the visceral lung surface. Understanding the exact pathophysiology of primary spontaneous pneumothorax in an individual patient is important because recurrence prevention treatment may differ accordingly (e.g., blebectomy with or with or without pleurodesis versus pleurodesis alone) (9). We describe a patient with recurrent primary spontaneous pneumothorax in whom autofluorescence thoracoscopy using the DAFE autofluorescence system (developed by R. Wolf, Knitlingen, Germany) (10), performed after inhalation of aerosolized fluorescein, allowed in vivo localization of areas on the lung surface with extensive subpleural fluorescence accumulation. This visualization in the blue light excitation mode revealed a much larger area of parenchymal abnormality than was visible with white light inspection. In addition, satellite areas of parenchymal abnormality could only be identified with blue light inspection. Fluorescein (sodium fluorescein) is used in the diagnosis and treatment of a wide range of ocular disorders. Its visible fluorescence on leaking from dammaged vessels makes it particularly useful in the diagnosis of retinal vascular disorders and monitoring of treatment of conditions amenable to laser photocoagulation. Fluorescein is injected intravenously, and serial retinal photographs using a special camera equipped with an exciter/barrier filter set are taken through the pupil (11). Sodium fluorescein is a relatively low-molecular-weight, highly water-soluble compound which, when exposed to light of wavelengths between 465 and 490 nm (blue, which is exactly the wavelength used by the DAFE system), emits light at a wavelength of 520 to 530 nm (green-yellow, which also is detectable by the DAFE system). In more than 30 years of clinical use, the intravenous injection of fluorescein is proven safe, although mild side effects occasionnaly have been reported. Serious or life-threatening complications are extremily rare. To our knowledge, inhalation of fluorescein has not been reported yet in controlled series, although it has been used safely in the past under white light thoracoscopic conditions (12). The results of fluorescein inhalation in white light illumination conditions for detecting air leaks, however, are disappointing (M. Noppen, unpublished observations). Illumination with blue light, taking advantage of the physical fluorescence properties of fluorescein, seems to dramatically increase its usefulness, as this study illustrates.
A 28-year-old man with a 15–pack-year smoking history presented with a second recurrence of a right-sided primary spontaneous pneumothorax. Previous episodes had been treated by chest tube drainage only. A 16-Fr chest tube coupled to a water-seal device was inserted, and a thoracoscopic talc poudrage was proposed. Twenty-four hours after admission, and after oral informed conscent, the patient inhaled an aerosolized 10% fluorescein solution (5 ml; Novartis Pharma, Vilvoorde, Belgium) for about 10 minutes under VT conditions. The fluorescein aerosol was delivered via a pressure-driven nebulizer (Micro Mist; Hudson RCI, Vasby, Sweden) attached to a mask. Ten minutes later total intravenous anesthesia was induced, and medical videothoracoscopy was performed under single-lumen intubation with High Frequency Jet ventilation delivered through the endotracheal tube. A 7-mm trocar was used for introduction of the telescope, and a 5-mm trocar was used for introduction of accessories. At the time of thoracoscopy (24 hours after admission), an air leak was no longer present. We used the DAFE autofluorescence endoscopy unit (Richard Wolf, Knitlingen, Germany) equipped with a filtered 300-W xenon lamp with an IR blocking filter allowing for inspection with either white light or violet-blue light (ranging from 390–460 nm) as the excitation source. The light is transmitted from the lamp to the endoscope via a liquid light guide. Photodetection relies on the use of a CCD camera and a dual detection range: 500 to 590 nm, and 600 to 700 nm. A system of dichroic mirrors and filters allows for superimposition of the signals and false color image reconstruction displayed on a trinitron color monitor (10). Switching from white to blue light and back is accomplished instantaneously by means of a foot pedal switch. At white light inspection, one approximately 6 cm2 region of visceral pleural irregularity was seen at the lateral part of the lung apex (region of interest [ROI]1 in Figure 1A). There were no blebs or bullae, nor any other abnormalities seen during complete white light inspection of the lung and pleural cavity. During the blue light excitation mode, however, extensive subpleural fluorescein accumulation was seen over an area that largely exceeded the abnormal lung area detected with white light (ROI1), covering a total area of about 35 cm2 (ROI2 in Figure 1B). Furthermore, two small satellite zones of fluorescein accumulation were seen in the vicinity of the original lesion (ROI3 and ROI4, figure not shown, but visible on videoclip in the online supplement) and, importantly, a second approximately 9 cm2 area of fluorescein accumulation was seen apicoposteriorly (ROI5 in Figure 2). None of the latter zones of fluorescein accumulation (ROI3–ROI5) were identifiable under white light inspection. Both under white and blue light inspection, some foam was observed on top of the area of abnormality ROI1 (under blue light inspection this appeared somewhat more clearly as a yellow foam). Although such foam is suggestive of a recent active air leak, actual air leakage was no longer present at the time of thoracoscopy (as inferred from the absence of air bubbling in the water seal).
After white and blue light inspection, talc poudrage was performed using two grams of sterile, calibrated, asbestos-free talc (Novatech, Aubagne, France), and a new chest tube was inserted. The chest tube was removed 18 hours later, and the patient was discharged that same day. Follow-up at 1 and 8 weeks showed complete lung reexpansion.
This is the first report of an in vivo visualization of abnormal lung regions that most likely play an important role in the pathophysiology of primary spontaneous pneumothorax, by use of fluorescein-enhanced autofluorescence thoracoscopy (FEAT). FEAT revealed regions of extensive subpleural fluorescein accumulation, some of which were either partly or not at all identifiable as "abnormal" during conventional white light thoracoscopy. These regions may be considered as plausible sites where air leakage can originate. Although, at the time of thoracoscopy, no actual air leak was present, some yellowish foam on the surface of an abnormal region was suggestive of a possible recent air leakage. Interestingly, there were no other lesions (i.e., blebs or bullae) present. The pathophysiologic significance of the observed phenomenon remains to be explored. We can only speculate on several possibilities, while realizing that fluorescence measurements are planar measurements with light intensity not only depending on the local concentration of the fluorophore, but also on how deep the fluorophore is penetrating in the lung tissue (13). In addition, the shape of the emitted light spectrum may be affected by a differential absorption of different frequencies (10). In this respect our data may only be interpreted in a semiquantitative fashion, i.e., referring to abnormal versus normal fluorescence intensity. Our speculation will concern the reason for enhanced fluorescein accumulation in ROI1–ROI5. One possibility is that the inhaled fluorescein aerosol got accumulated in certain areas of the lung due to localized areas of air trapping, which is one of the plausible mechanisms leading to spontaneous air leakage and pneumothorax (9). Interestingly, this interpretation could be brought in agreement with the observation of a wedge-shaped region of increased helium signal in the lung parenchyma subjacent to the site of air leakage in an animal model of pneumothorax, using 3D MRI imaging of laser-polarized 3He gas (14). Another possibility is that fluorescein leaked through the crater-like abnormalities (ROI1) (as suggested by the presence of the foam), and spread on the surface of the lung adjacent to the air leak. However, this mechanism would not explain the satellite spots of accumulated fluorescein (ROI3–ROI4) in different places on the lung surface that are not in contact with ROI1. The high solubility of fluorescein in water could favor its spread over the parenchymal surface around the leak. The presence of fluorescein-containing foam on top of a region of subpleurally accumulated fluorescein, in the absence of blebs, might be explained by the presence of pleural porosity (the presence of pleural pores several microns in width) (15). Either the aerosol itself (with 78.5% of its mass in the < 5 µm range for Micro Mist nebulizer [Hudson RCI]) could have passed right through, or the fluid molecules (once the fluorescein aerosol droplets deposit) may have penetrated preferentially in the more porous pleural areas with a detectable fluorescence intensity as a result. Note that the fluorescein clearly accumulated under the visceral pleural surface of the lung because it could not be washed away or aspirated during thoracoscopy. Our findings are interesting for the following reasons. First, abnormal regions susceptible to visceral pleural air leakage could be identified with FEAT in the absence of emphysema-like changes, and in regions which appeared completely normal at white light thoracoscopy. This demonstrates that patients with primary spontaneous pneumothorax may suffer from a more extensive disease process of parenchymal inflammation and destruction than previously thought, and suggests that ELC-rupture is not necessarily involved in the pathogenesis of every case of primary spontaneous pneumothorax. Second, FEAT may have important therapeutic implications because it allows for in vivo identification of all diseased lung regions, and, if still present at the time of thoracoscopy, of actual air leaks. The alternative leakage identification technique, i.e., submersion of the lung in fluid during thoracoscopy, is cumbersome, rarely allows for complete inspection, and is useless if the air leak has already closed spontaneously. When thoracoscopic resection of blebs or bullae is the preferred treatment technique for recurrence prevention—which often is the case in surgical departments caring for pneumothorax patients—FEAT may allow improved selection of lung regions to be resected. Our observations indeed may explain why bleb resection alone (blebs identified by white light thoracoscopy) currently is still followed by a 5 to 10% recurrence rate, whereas a pleurodesis technique alone, or in association with bleb resection, decreases recurrence rate to 0 to 5% (9). Confirmation of the present findings in larger patient groups may indeed reveal that systematic resection of diseased areas identified by conventional white light thoracoscopy alone may not be the best recurrence prevention treatment, unless true air leaks are visible (9). A limitation of this article is that we report FEAT findings in a single case of primary spontaneous pneumothorax only, and that it is unknown whether our observations actually represent an abnormal finding. We are therefore initiating a prospective study on FEAT in three patient cohorts (i.e., patients with spontaneous pneumothorax, patients with normal lungs undergoing thoracoscopic sympathectomy for treatment of essential hyperhidrosis, and patients with other lung or pleura disorders such as malignant pleural effusion undergoing diagnostic or therapeutic thoracoscopy). Preliminary findings in normal subjects suggest that the aforementioned findings in primary spontaneous pneumothorax indeed are abnormal. Finally, FEAT is well tolerated and safe (no side effects except for a yellow discoloration of the mouth which is otherwise asymptomatic and which spontaneously resolves within 24–48 hours). It is easy to perform, with pedal-switch alternation between white and blue light inspection prolonging thoracoscopy by a few minutes only. Although the DAFE autofluorescence endoscopy unit has been developed for the bronchoscopic detection of early or preneoplastic bronchial lesions (10), and is easily adaptable to commercially available bronchoscopes, it can also easily be adapted to the rigid telescope used in thoracoscopy. Further studies in large numbers of patients with primary spontaneous pneumothorax with various degrees of emphysema-like changes in combination with other parenchymal abnormalities are necessary to document the usefulness of the FEAT technique in the study of the pathophysiology and treatment of primary spontaneous pneumothorax.
This article has an online data supplement, which is accessible from this issue's table of contents online at www.atsjournals.org Conflict of Interest Statement: M.N. does not have a financial relationship with a commercial entity that has an interest in the subject matter of this manuscript; G.S. does not have a financial relationship with a commercial entity that has an interest in the subject matter of this manuscript; S.V. does not have a financial relationship with a commercial entity that has an interest in the subject matter of this manuscript; J.D. does not have a financial relationship with a commercial entity that has an interest in the subject matter of this manuscript; M.M. does not have a financial relationship with a commercial entity that has an interest in the subject matter of this manuscript; W.V. does not have a financial relationship with a commercial entity that has an interest in the subject matter of this manuscript. Received in original form April 1, 2004; accepted in final form June 16, 2004
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