Memorandum of Understanding - COST B14

HYPERBARIC OXYGEN THERAPY

Proposer Country: BELGIUM

Action Proposer:

COST National Co-ordinator:

Date of proposal: (June 5, 1998)

1. BACKGROUND

1. Introduction

Oxygen is a gas, which is normally present in inhaled air. It is transported by haemoglobin, at a near-maximal saturation capacity while breathing 1 atmosphere air. When administered at supra-atmospheric pressures, oxygen is dissolved in large quantities in the blood plasma. This way, an appreciable extra quantity of oxygen is transported by the blood. Apart from an increase in peripheral oxygen delivery, hyperoxia causes certain cardiovascular and cellular reactions that give it all of the properties of a pharmaceutical drug.

Besides penetrating much further into the tissues adjacent to the capillary - and thus permitting the survival of cells otherwise insufficiently oxygenated - high pressures of oxygen induce a generalised arteriolar vasoconstriction, promote fibroblast growth and differentiation, and exerce an antibacterial effect. All these effects add to the therapeutical value of HBO, whether alone or combined with "classical" therapeutical measures.

2. Indications for Hyperbaric Oxygen Therapy

Indications for HBO have already been validated in various fields of modern medicine. They include among others: carbon monoxide intoxication, clostridial myonecrosis, diving decompression sickness, and cerebral arterial gas embolism. For a number of other diseases or illnesses, HBO is likely to represent a very important adjunctive therapy, optimising the effects of the "classical therapy" and thus providing a major therapeutical benefit. Among those diseases, several represent a high burden on personal and national health care budgets. Also, these diseases usually severely compromise the social and personal integrity of the affected person, as well as his economic potential. In the end, these diseases carry a high financial and social impact, also on a national scale.

The systematic involvement of HBO in the therapeutic protocol would most certainly reduce all of these deleterious effects, by limiting the extent of the damage (when applied early in the disease course), and accelerating recovery and healing. For many of these therapeutic fields, abundant case reports are available and limited clinical studies have already been performed, but in order to clarify more the precise action and benefits of HBO, further research is absolutely necessary. Some of these fields are: oncology (enhancement of radiotherapy or chemotherapy protocols), crush trauma (combined vascular, nervous, bone injury to extremities), thermal burns, acute traumatic ischaemia, cluster headache and migraine.

3. Technological Aspects

Hyperbaric Oxygen Therapy involves the administration of oxygen at pressures between 1.5 and 3 ATA (atmospheres absolute). To breathe these high-pressure gasses, the patient must be placed in a hyperbaric pressure chamber during treatment, in order to ensure an equipression between the physical environment and the inhaled gas mixture.

Hyperbaric chamber technology has been evolving gradually from a diving industry oriented, to a clinically (hospital treatment) oriented industrial science. Although the technology itself is not much prone to changes, the design and functionality of the hyperbaric treatment facility is.

Depending on the type of patient that will be treated inside the hyperbaric chamber, the technical and design characteristics of the chamber itself will have to be adapted. Many of the diseases for which HBO may prove to be extremely effective when integrated in the global treatment protocol, require the use of large, air-compressed hyperbaric chambers, capable of providing at the same time a full intensive care environment as well as hyperbaric oxygen inhalation.

Finally, the actual use of HBO at this moment comes nowhere close to its potential and probably optimal use. Therefor, increasing the knowledge on HBO may have also a purely economic dimension, via an effect on R&D and manufacturing effort in this highly specific field of technology.

4. Limitations to the progress of research

Research into the therapeutic mechanisms and the clinical usefulness of Hyperbaric Oxygen Therapy is hindered by several limitations, inherent to the pathology and also to the clinical characteristics of hyperbaric treatment centres.

First, although the prevalence of the diseases for which HBO offers substantial benefits, is not negligible, the stratification and classification of these diseases is difficult, and because of the great variability in the clinical pictures, comparable clinical courses are rare. This makes it virtually impossible for any individual HBO centre to perform a sound therapeutic research protocol, due to a lack of includable cases. Pan-European co-operation seems invaluable to achieve a sufficient number of study subjects.

Secondly, the "classical" therapeutic approaches to the various diseases to be studied, are differing considerably from one country to another, and even within one country, major treatment centres may adopt different and sometimes contradictory strategies. To extract from this generally diverse therapeutic information the possible influence of HBO in a single or limited clinical trial, is impossible. The need for large-scale multicentric clinical trials is obvious.

Thirdly, the mechanisms of action of oxygen under pressure are themselves incompletely understood. Basic research is being performed at several research and clinical institutions, but internationally published reports are rare, and are many times not available to hyperbaric scientists. Interaction and close integration with these basic research groups will be sought, as both parties will be benefiting.

Fourth, the scale to which HBO has been applied and the amount of basic and clinical research being undertaken, differ largely between Western and Central/Eastern European Countries. There is a marked discrepancy between the scarceness of the use of HBO in the Western European countries, and the more liberal and early use of this therapeutic modality in Central/Eastern Europe. Therefore, it can be assumed that in Eastern Europe there is a vast area of clinical experience. This experience, however, is not often exploited in a way that other HBO researchers and clinicians can benefit from.

Not only are they not published or only published in local medical papers, but also do the reports themselves suffer from either methodological inaccuracies or incompleteness of data. The reason for this is obvious: a lack of basic reference articles and books, and the inaccessibility of recently published data and research directions. Through an improved accessibility of current scientific literature and specific guidance, quality enhancement of Eastern European scientific publications will be achieved.

Fifth, although several multicentric studies are already being performed, the progress of these investigations is slowed by the use of conventional communication means. Many other prospective multicentric studies never leave the embryonic stage, due to a lack of easy contact between partners.

Other studies suffer from methodological problems, or are being set up to investigate phenomena that have been studied already, but of which the data and conclusions are either not available or simply not known. There is a clear necessity for an optimisation both in the ease and speed of communication between HBO centres in Europe.

In conclusion, although the HBO researchers themselves are convinced of the need for large-scale clinical and experimental studies, essentially due to a lack of communication means, it is, at the moment, very difficult to set up or conduct such studies or even to share the available information, within Western Europe, from East to West, and even more from West to East.

No other European Forum or Programme is providing support or funding for this type of international research co-operation or its support actions.

2. OBJECTIVES AND BENEFITS

The main objective of the Action is to improve the knowledge required for a rational use of Hyperbaric Oxygen Therapy (HBO), to a level making it possible to set out specific guidelines for the implantation and development of clinical HBO centres and to provide scientifically sound recommendations for HBO treatment of various diseases and conditions.

For many accepted indications for HBO, a more detailed knowledge of the precise actions of HBO and the optimum dosage, will greatly enhance the therapeutic results and will make possible an optimal selection of patients who will mostly benefit from this treatment. Examples are:

• Carbon monoxide poisoning:
  Up until now, only patients who are severely intoxicated are commonly referred for HBO. However, there are some clinical reports and only a few animal studies indicating that also patients with only a mild to moderate carbon monoxide intoxication could benefit from HBO. HBO would in these patients also reduce the incidence of delayed neuropsychologic sequelae due to the hypoxic insult to the brain. However, referral for HBO is not often considered in these patients, as they seem to have recovered "sufficiently" after a short course of 100% 1 ATA oxygen by mask. Some animal studies however indicate a positive effect of HBO on biochemical brain damage, opposed to no effect of normobaric oxygen. These finding need to be further clarified.
  
• Bone and soft tissue radionecrosis:
  Here, the optimal treatment schedule for the various categories of patients needs to be defined. Since these diseases have a slow course and need a long follow-up (several years), follow-up studies are at the moment very scarce. Fundamental research on the actions of HBO on the cellular level might accelerate the definition of the optimal treatment regimen.
  
• Anaerobic soft tissue infections:
  The precise interaction between HBO and various antibiotics, as well as the effects of various dosages (i.e. treatment pressures) of HBO on the infecting agent, needs to be clarified further.

For other indications, treatment with HBO seems promising, but no definite acceptance can be made because of a lack of sufficient clinical and/or experimental data. Focused large-scale research projects are the only way to obtain these data. Possible research projects to be initiated or enlarged include:

• Oncology:
  The possibility to enhance the efficacy of oncologic therapy protocols, especially in cancer states with a very poor prognosis, by combining conventional therapy with HBO schedules, has aroused new interest in this field of application. The development of specific treatment schedules, alternating oncologic treatment and HBO according to precise time-related schedules, seems an extremely promising therapeutic advance in cancers that up until now still suffer near 100% mortality (e.g. stage IV neuroblastoma).
  Also, the preventive use of HBO in the post-therapeutic period of radiation therapy, in order to limit the appearance of long-term secondary bone and soft tissue necrosis, is a field of application that merits further study and development. In these diseases, not only better survival rates could be obtained, but also a reduction of the incidence of invalidating complications of radiotherapy. Large-scale multicentric studies have to be conducted, to result in internationally published medical reports. HBO is, as yet, the only treatment available for (bony and soft) tissue radiation damage. The number of patients that actually benefit from this treatment is however only a fraction of those that could possibly benefit.

• Crush trauma:
  "Crush", defined as extensive soft tissue, bone and vascular injury to extremities, is usually arising from traffic accidents. These injuries often result in a long hospitalisation, a long rehabilitation period, and because of the high frequency of infection and ischaemia, an important risk of residual invalidity (amputation) and mortality (sepsis, shock, renal insufficiency). By a supplementation of oxygen to swollen tissues, a reduction of oedema formation by hyperoxia-induced vasoconstriction, and a preventive effect on the development of anaerobic infections, HBO can reduce healing time and residual invalidation.

• Thermal burns:
  Although there is experimental proof that HBO would be of utmost benefit if consistently used in the treatment of severe burns, sufficient clinical data is apparently lacking to make this an accepted indication among the burn treatment centres. However, HBO has been shown to reduce the progression of severe burns during the first 24 hours, and to accelerate revascularisation and reepithelialisation. Burn injuries are characterised by a long hospitalisation, a considerable degree of physical invalidity, and the resulting scars represent a psychological burden.

This COST Action will aim at the co-ordination and optimisation of research in this and other areas of HBO, in order to direct research efforts to specifically defined targets, and to avoid incomplete or duplicate research efforts by isolated HBO groups.

The results of the research conducted under this COST Action will be disseminated through existing and where appropriate, new channels. On a European level, the guidelines and recommendations that will be produced may have an impact on European Regulations and Directions in this field.

3. SCIENTIFIC PROGRAMME

The proposed COST Action will be initially implemented through the work of three Working Groups.

These will lay out the necessary structural and quality guidelines for the research to be conducted. These will include the development of:

• a "Computer Information Network", that will be maintained throughout the duration of the Action. It will take the form of an Internet Website, allowing the easy retrieval of information, the participation to discussion groups and the consultation of a bibliographic database pertinent to HBOT.
• a "Research Guidance Document" specifying the quality criteria desired for any new and ongoing research projects on HBOT, based on the analysis of existing research data and of the weight of the available scientific data.
• a "Research Priority Report", defining areas needing further clarification urgently, that will serve as a basis for directed clinical and experimental research.

On the basis of these three achievements, specific research projects will be initiated or adapted. While the general subject of these research projects will be in the scope of the previously outlined areas, it is possible that other research areas are also selected.

D. ORGANISATION AND TIMETABLE

Within the proposed COST Action, three phases can be distinguished.

D.1. PHASE 1: Preparation Phase (1 year)

During this phase, different Working Groups will be constituted, that will each tackle one of the limitations set out in Section A.

Working Group A

Will develop an efficient communication network for HBO centres in Europe. It will focus both on the creation of a practical and updated information database and on the development of data acquisition software that makes possible the integration of medical data from different centres in different countries.

To achieve this, contacts will be made with other European actions, e.g. for the security aspects of medical data transmission.

A sustained and substantial secretarial effort can however be predicted in relation to this specific task. This secretarial effort, and the hardware costs of maintaining an efficient and accessible Internet connection via a protected and secure server system, cannot be carried by one of the active research programmes.

Working Group B

Will develop an outline of the quality criteria desired for new and ongoing research. As a first step, a uniform classification of the possible indications for HBOT, based on current international consensus and conventions will be proposed. This will make possible the development of multi-centric studies, based on the same objective selection and evaluation criteria, according to current scientific standards.

Working Group C

Will inventarise the existing and ongoing isolated and multicentric clinical and experimental studies, and will propose directions for focused research. It will also propose possible participant HBOT centres, according to the information obtained via the communication network set-up by Working Group A.

D.2. PHASE 2: Active Research Phase (3 years)

During this phase, Working Group A will continue to operate for the maintenance and updating of the communication network.

A Scientific Supervising Committee will be constituted, that will actively encourage and assist new research projects as proposed by Working Group C.

Regular reports (at least once per year) will be collected from the different research projects’ leaders, and theoretic and/or practical suggestions will be offered. Common interactions will take place via the remote communication. A yearly symposium will permit to summarise the progress of the different co-ordinated research projects, and will allow a larger feedback and input from researchers from other projects.

D.3. PHASE 3: Finalisation Phase (1 year)

At the end of the previous phase, a General Meeting will be organised, and the results of research projects that have terminated will be examined. Small complementary research projects may be proposed at this stage. Intermediate reports or reports from finished research projects may by then already have been published in international medical or scientific journals. Research projects that have not yet been finalised will be encouraged to do so within 6 months. Possible problems will be tackled in order to achieve this.

During the last 6 months of the course of this Action, the Final Reports will be prepared.

A global Conference, open to HBOT researchers world-wide and also to other interested parties, will be organised at the end of this phase. At this Conference, several Consensus Reports should ideally be presented, and subsequently, publication of these reports will be sought in leading medical journals.

The duration of this Action will be 5 years.

E. ECOMONIC DIMENSIONS

The following COST countries have actively participated in the preparation of the Action or otherwise indicated their interest:

Belgium, France, Spain, Switzerland, Austria, Finland, Denmark, Poland, United Kingdom, Slovenia, Germany, Italy, The Netherlands, Czech Republic, Sweden.

Other European non-COST countries have expressed their interest.

E.1. Personnel costs:

On the basis of estimates, provided by representatives from these countries, the total amount of concerned research personnel corresponds to:

• Phase 1: 60 persons
• Phase 2:
  • scientific personnel: 100 persons/year
  • technical personnel: 100 persons/year
• Phase 3:
  • scientific personnel: 100 persons
  • technical personnel: 100 persons

The overall cost of the activities to be carried out under the Action can be estimated at 39MECU.

E.2. Technical costs:

These costs, which will consist of the acquisition of medical and technical apparatus required for the carrying out of the research projects, are estimated at 300 KECU/year.

E.3. Co-ordination costs:

The funding required for the co-ordination of the research activities, and which will be carried by the COST Action, can be estimated as 75 KECU/year

The global economic dimension of the COST Action can thus be estimated at 41 MECU.