Perfluorocarbons (PFC) are liquids with unique properties which make them feasible for medical applications in different fields. To give researchers and clinicians who are involved in PFC-associated research a platform for exchange of ideas, the symposium on perfluorocarbon application was established. The first meeting took place in Germany at the Charité Berlin in 1999, followed by Bilbao (2000), Berlin (2002) and Dresden (2004).
The recent “5th European Symposium on Perfluorocarbon application” was held in Milano, Italy, at the School of Engineering of the Politecnico di Milano on March, 17th and 18th 2006. This was the first time the Symposium took place at a technical school, to show the importance of a synergic cooperation between clinicians and biomedical engineers to reach results in the field of PFC application and liquid ventilation. The first day of the Symposium was dedicated to oral and poster presentations dealing with research updates and various applications of PFC liquids, while the second day mainly focused on discussion about future PFC applications and the steps to be accomplished. Four main topics were discussed: (1) PFC for respiratory therapy, (2) PFC for other applications, (3) Introduction of a new therapy in clinical practice, and (4) Does it make sense to bring PFC into clinical practice? Participants were 103 colleagues from 7 different countries, including Canada and Japan.
Presentations and discussions focused on several new and promising issues of PFC application. Participants were convinced that PFCs have a great potential for clinical application in various fields. There were promising trials of partial liquid ventilation in the past (e.g., in infants with congenital diaphragmatic hernia), nevertheless perflubron was not approved by the FDA as a respiratory medium. Due to some methodological weakness and the exceptionally good outcome in conventionally treated patients, the last large ARDS trial failed to show a benefit of partial liquid ventilation over conventional therapy. To avoid similar problems in future studies, the next steps to get medical approval for PFC were discussed. The main aspects of the discussion are summarized below.
What will be the best PFC?
Samuel Schürch (Canada) gave “A biophysical point of view”. He argued that in patients with disturbed pulmonary surfactant, each PFC will improve surface tension. However, if administered into healthy lungs, some PFCs could impair function of endogenous surfactant. From a “biological point of view” (Marla Wolfson, USA), there will be little difference between PFC liquids if administered as total liquid ventilation; however, if used for partial liquid ventilation, variations in viscosity and vapour pressure have to be considered. If used as a carrier for pulmonary drug administration, a rapidly evaporating PFC will be beneficial. With respect to anti-inflammatory properties, significant differences between various PFCs were observed. To choose the appropriate PFC, the molecular mechanisms of action have to be understood. Walter Navarrini (Italy) expressed his “chemical point of view” and argued that a proper PFC can be designed according to specific requirements. Therefore, first, the needed properties have to be defined, and thereafter, the appropriate PFC can be produced.
Participants agreed that future research should focus on understanding the molecular mechanism of PFC effects and correlating this activity to its biophysical properties. Perflubron, which has been tested in clinical trials, is not necessarily the only PFC for future use; some others could be even better. However, for clinical application, PFC liquids must be of medical grade. Therefore, a major company is required dedicated to the development of appropriate PFC liquids and subsequent clinical application. According to industrial representatives, different types of PFC applications can be distinguished: (1) PFC as a drug (e.g., for liquid ventilation), (2) device (e.g., for eye surgery), (3) biomaterial (e.g., for brain cooling), or (4) as a diagnostic tool (e.g., contrast agent).
What are the “target populations” for PFC administration?
Gunnar Sedin (Sweden) gave “a neonatologist′s point of view” and argued that – regardless of the population that is studied – a close follow up of PFC treated patients is needed to obtain data on long term outcome and potential side effects. In a neonatal population, infants with meconium aspiration syndrome, congenital diaphragmatic hernia and surfactant non-responder could benefit from liquid ventilation. Furthermore, it was discussed, whether extremely preterm infants (below 26 weeks of gestation) could benefit, since mortality in that population is very high. “an intensivists point of view” was presented by Gama de Abreu (Germany), who argued that PFC could alleviate severe respiratory insufficiency and avoid the progression of ARDS. For future clinical studies, other end points than those previously used should be considered, such as duration of mechanical ventilation, need for ventilatory support and long term lung functions.
The subsequent discussion distinguished between prophylactic and therapeutic approaches of PFC administration. David Steinhorn (USA) differentiated between a strategy for future application that uses a simple, minimally invasive approach in a low morbidity population to show the beneficial effects of PFC and a “heroic” approach in a high mortality population to show the life saving effect of PFC. It could be considered to use PFC instead of normal saline for broncho-alveolar lavage, since PFC could prevent hypoxic periods during the lavage process. According to Roland Wauer (Germany), a well defined target population is needed, which also will be of interest for industry.
What will be the best modality for PFC administration?
Ronald Hirschl (USA) compared partial and total liquid ventilation. Partial liquid ventilation is a rather simple approach for PFC application, and has, therefore, been used in previous clinical trials. However, a simple method is not always the best method. Hirschl criticized the approach of the FDA, that used figures obtained from adult and pediatric patients to show a higher mortality in liquid ventilated patients. However, the number of newborn patients was very low, and the results in patients with congenital diaphragmatic hernia were very promising. Therefore, he suggested continuing with that indication in future clinical trials. With respect to total liquid ventilation, Hirschl argued that the ventilators for total liquid ventilation still need some technical improvement to ensure a safe and simple clinical application. However, for further improvement, an industrial partner is required. Furthermore, further research is required to understand and refine the weaning process and the effect of PFC on oxygen induced lung toxicity. Hirschl suggested using liquid ventilation in a population at high risk of mortality.
“A nebulized point of view” was presented by Michael Kandler (Germany), who pointed out that PFC nebulization is an easy approach that improves not only oxygenation and ventilation but also reduces inflammation. “a vapour point of view” was presented by Jörg Bleyl (Germany). Due to the simple administration, PFC-vapour offers the opportunity of an early treatment or even prophylaxis due to its mechano-cytoprotective effects. During the discussion, it was argued that the mode of action of inhaled PFC is still poorly understood, and future studies should focus on that aspect.
In summary, participants were convinced that PFC liquids and vapors have a great potential for medical application, including fields not yet studied in detail, such as drug carrier, anti-adhesive, pulmonary gene therapy, brain cooling, organ and cell preservation. To understand the molecular mechanism of PFC activity, further research is mandatory but requires significant financial support. Since no major company can afford to develop medical grade PFC, other sources of funding are needed. If, however, there is no financial support, the lesson of previous PLV trial has not been learned, and a potentially beneficial substance will not have the chance to enter medical application.
Finally, it was announced, that “The 6th International Symposium on Perfluorocarbon Application” will be organized by Herve Walti in Canada for early October 2007.