British Journal of Radiology (2005) Supplement_27, 196-200
© 2005 British Institute of Radiology
doi: 10.1259/bjr/25654769
British Journal of Radiology Supplement_27 (2005),196-200 © 2005 The British Institute of Radiology
Radiation-induced multi-organ involvement and failure: challenges for radiation accident medical management and future research
V Meineke, MD1 and
T M Fliedner, MD2
1 Bundeswehr Institute of Radiobiology, 80937 Munich and 2 Radiation Medicine Research Group, Faculty of Medicine, University of Ulm, Germany
Correspondence: Viktor Meineke, Institut für Radiobiologie der Bundeswehr, Neuherbergstrasse 11, 80937 München, Germany. E-mail: ViktorMeineke@bundeswehr.org
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Abstract
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A common feature of radiation accidents is the medical consequences of dose-dependent radiation-induced multi-organ involvement (RIMOI) and radiation-induced multi-organ failure (RIMOF). Both RIMOI and RIMOF contribute to the clinical outcome and prognosis of radiation accident victims. A most remarkable fact in this context is that the specific pathophysiological mechanisms involved in RIMOI and RIMOF as a function of time and in relation to the extent of radiation injury as well as the therapeutic ratios for specific treatment options based on our understanding of the roles of failure or the regenerative potential of different organs to a large extent remain unknown. A re-visit of the case reports of patients suffering from RIMOF as a consequence of RIMOI underlines the specific roles of individual organs, for example the haematopoietic system as one of the most sensitive and critical organs for early radiation-induced health impairments. The development of such radiation-induced impairments gains more and more attention, in particular after successfully coping with the consequences of haematopoietic failure using modern techniques such as stem cell transplantation and cytokine treatment to restore haematopoietic functions. Other equally important organs in the course of the development of RIMOF, such as the skin, neurovascular system, respiratory system or gastrointestinal system, need to be considered as contributors to the course and clinical outcome. The search for common denominators that are crucial in the pathogenesis of such a multi-organ functional impairment is of utmost importance. Thus, the pathophysiology of RIMOF is an extremely important and emerging challenge, and it is important to utilise the evolving new knowledge to develop new tools for the medical management of radiation accident victims. The "Advanced Research Workshop on Radiation-Induced Multi-organ Involvement and Failure" held at the Science Conference Center Schloss Reisensburg in November 2003 significantly contributed to the understanding of the role of RIMOI and RIMOF in the management of radiation accident victims. Moreover, it opened perspectives and challenges for future clinical and molecular–biological research in this specific area.
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Introduction
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Occasional accidental radiation exposure is no longer a reality only in industries or following occupational medicine exposure. Since 11 September 2001, the possibility of an accidental radiation exposure resulting from terrorist attacks has become clear. Scenarios involving the "dirty bomb" gain more and more attention. On the other hand, ways of dealing with the consequences of such a wide spectrum of potentialities of accidental radiation exposure are limited. To further exacerbate the situation, many aspects of the dynamics of radiation response both at the cellular and the organ level, in particular as a function of time and dose, still remain unclear up to now. Successfully coping with the consequences of any accidental radiation exposure would require a continuous update of knowledge regarding the pathophysiological mechanisms involved.
A common feature of accidental radiation exposure is the dose-dependent development of health impairments as a consequence of radiation-induced multi-organ involvement (RIMOI) and radiation-induced multi-organ failure (RIMOF). A re-visit of the case histories of patients showing RIMOI or even RIMOF underlines the specific and critical role of RIMOI in the prognosis and outcome of patients. Although there is not yet a full understanding of the pathogenesis of RIMOI and RIMOF, there are a limited number of organ systems critical for the evolution of RIMOF as well as common denominators in the development of the pathophysiological and the clinical course. New approaches and techniques are available in the study of health impairments as a function of dose of whole body irradiation at different levels of biological organisation (organism, organ system, cell renewal system, individual cells and subcellular components). In addition, the manifestation and course of the "radiation sickness" observed in two patients of the recent radiation accident in Tokai-mura (Japan) [1] who received extensive medical treatment and survived for 82 days and 211 days, respectively, after an essentially "supralethal" dose of whole body radiation exposure are a challenge for the study of the pathophysiological mechanisms involved.
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"Acute radiation sickness": the evolution of pathophysiological concepts
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A review of the evolution of pathophysiological concepts is also a reconsideration of the history regarding research in the field of RIMOF and RIMOI.
Whole body exposure to ionising radiation resulting in a "radiation sickness" was observed most dramatically following the use of nuclear bombs in Japan in 1945 [2]. In subsequent years, "radiation sickness" was observed after radiation accidents in industry or laboratories [3], after the Pacific Testing Ground accidents involving exposure to fallout radiation [4, 5] and after using whole body irradiation in the treatment of cancer [6, 7].
It became obvious that there are certain organs and organ systems that play an important role in the clinical consequences of RIMOI and RIMOF. The complexity of the signs and symptoms observed as a function of time, dose and dose rate as well as of radiation quality was first discussed extensively in 1960 [5] and in 1962 [8]. The health effects observed were described as "radiation syndromes" because of the prominence of clinical consequences manifesting themselves in characteristic changes in the most sensitive organ systems. Three major types of radiation sickness could be distinguished on the basis of prominent signs and symptoms: the haematopoietic form, the gastrointestinal form and the central nervous system (CNS) form [8]. More recently, and in consideration of the appearance and course of RIMOF, other organ systems such as the cutaneous system [9–11] have gained additional attention. The time course of the radiation reaction of the skin is variously described by several authors in different terms, so that the question arises how reliable the data in the literature are concerning the sequential appearance of skin reactions. Unpublished data (Dörr et al) lead to the conclusion that the sequence of characteristic radiation-induced skin symptoms in the human in vivo situation is somehow different from that described in the literature but nevertheless is an important prognostic factor. The description of skin reactions in recent radiation accidents such as Chernobyl 1986 [12], Lilo 1997 [13] and Tokai-mura 1999 [14] underline this fact.
A first approach to systematically analysing the radiation syndromes with respect to underlying pathophysiological mechanisms in man and animals resulted in the theory that "mammalian radiation lethality" can be viewed as a consequence of "a disturbance of cellular kinetics" [15]. It was shown that there is a characteristic survival pattern for mammals as a function of dose, the so-called "dose–effect survival curve". In the dose range up to approximately 1000 cGy, the mean survival time becomes progressively shortened to about a plateau region of approximately 3–6 days depending upon the species, which is seen as a consequence of the breakdown of the haematopoietic cell renewal system or, in other words, the "haematological syndrome". As the dose of radiation increases significantly beyond 1000 cGy, a relatively stable survival time is observed, which is attributed to a dose-independent denudation period of the intestinal mucosa resulting in a "gastrointestinal syndrome". The plateau in survival time of approximately 3.5 days was shown for conventional mice to be up to a radiation dose of approximately 5000 cGy, while it was about twice as long as for germ-free mice. Beyond this, survival progressively reduced to less than 24 h in relation to the dose. This third portion of the survival curve was attributed to the development of a "central nervous system syndrome". On this basis, it could be shown that the initial progressive reduction of life span was correlated with the extent of damage to the haematopoietic system and specifically, to injury of the stem cell pool. The plateau region of the survival curve was seen in relation to the cell turnover characteristics of the gastrointestinal mucosa and the difference in cellular turnover kinetics in conventional compared with germ-free mice, and the third part of the curve to the damage inflicted upon the CNS in terms of functional impairment of regulatory mechanisms of the organism. These considerations regarding the pathophysiology of RIMOF are still of utmost importance and in future research and concepts other organs such as the skin will have to be included.
In clinical terms, however, one has to treat individual patients with whole body exposure. The clinician has to "translate" the mammalian dose–effect survival pattern [15, 16] into an appropriate medical management scheme. As a consequence, it became apparent that the determination of dose as the major determining factor is not really meaningful for the clinical management of patients suffering from a radiation sickness. From a practical point of view, a classification of the extent of injury was proposed by Cronkite (1951) [2] and Fliedner (1964) [17] and in particular by Guskova [18, 19]. Thus, three to four categories of severity of the clinical response to whole body irradiation were distinguished that could be related to characteristic patterns of blood cell changes: survival improbable, survival possible and survival probable, or in other words very severe, severe, less severe and mild.
Survival was considered to be improbable if a pancytopenia developed within 1–6 days (severe aplastic anaemia) characterised by the disappearance of lymphocytes within 1–2 days, granulocytes within 5–6 days and platelets within 6–10 days. In these cases, only stem cell transfusion would be expected to rescue the haematopoietic system. However, in addition, other health impairments become apparent, such as seen in the Tokai-mura patients, including severe skin reactions and injuries as well as perturbation of neurovascular regulatory mechanisms [1], the significance of which were not recognised earlier because of the short survival time of whole-body-irradiated patients.
Survival would be possible if the evolution of a pancytopenia was slower and the clinically "critical phase" was associated with a severe granulocytopenia (infection) and/or thrombocytopenia (bleeding) and nadirs by 15–20 days. In these cases, the stem cell pool would, in principle, be able to regenerate autochthonously. The clinical management has to "bridge" the clinical consequences of pancytopenia by "reverse isolation" (prevention of infection), systemic antibiotic therapy, and platelet transfusion to combat bleeding or, more recently, by the administration of cytokines.
Survival would be probable if the changes in the haematopoietic system are compatible with the assumption of an autologous haematopoietic recovery potential on the basis of only mild and transient depression of granulocytes and platelets.
This overall attempt to correlate the pattern of clinical manifestations of the "acute radiation syndrome" to "indicators of effect" rather than "indicators of exposure" measured by physical dosemeters was used extensively in the development of a new semi-quantitative approach for the clinical management of radiation-exposed persons (Figure 1)
. A joint activity of European experts supported by the European Commission established the METREPOL approach (Medical Treatment Protocols for Radiation Accident Victims as a Basis for a Computerised Guidance System), which was published by the British Institute of Radiology [20].
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Figure 1. Indicators of radiation effects (symptoms) used to determine a grading of the most relevant organ systems as a function of time, and combination of "organ gradings 1–4" into a response category (RC) to guide subsequent clinical therapeutic decisions.
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This approach is built on "response categories" (RCs) taking into consideration 24 indicators of effect derived from early changes in the haematopoietic, cutaneous, gastrointestinal and neurovascular systems to classify an exposed person into one of four severity of effect classes: RC 4, autologous recovery most unlikely; RC 3, autologous recovery possible; RC 2, autologous recovery likely; and RC 1, autologous recovery certain (Figure 2).
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Figure 2. Assignment of a patient to a particular response category (RC) guides the general therapeutic interventions, the use of specific measures (e.g. stem cell transplantation (SCT)) as well as the assignment of a patient to a relevant hospital.
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The practical use of this scheme indicated that it is necessary but not sufficient to classify a patient according to his early haematopoietic response based on the impairments of cell systems, especially granulocytes, lymphocytes and platelets, as a basis for therapeutic strategies. Other indicators of effect must be considered.
The very early (within minutes) response after whole body radiation exposure of the vascular system and its regulation to ionising radiation was pointed out several years ago and was extensively reviewed by Cronkite and Bond [21] and Stodtmeister et al [22, 23]. It became evident that the radiation exposure of a mammalian organism results initially not only in an impairment of cellular replication and proliferation in actively renewing cell systems but primarily in an impairment of the capillary bed resulting in oedema (perturbation of permeability) and increased capillary fragility. In these early studies, there was consensus that there is a primary radiation effect on the capillaries (independent of other factors such as intoxication, infection etc.) but also an indirect influence (irradiation of the brain), which may result in increased peripheral increase of capillary permeability. The impairment of neurovascular regulatory mechanisms was discussed and stressed extensively at this conference (see Gourmelon et al [24] and Gaugler [25]).
Cell detriment caused by radiation-induced cell damage is another aspect that should not be underestimated in its consequences for RIMOF. Whole body radiation results in a burden of damaged cells that can be in the range of billions of cells within a short period of time. Apoptosis plays an important role here [26]. This detriment has to be cleared by macrophages and other immunocompetent cells. On the other hand, the physiological function of these scavenger cells can also be injured by ionising radiation. An impairment of this clearing reaction results in additional negative effects for the whole organism, thus possibly paving the way to RIMOF.
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Perspectives and challenges for future research in the field of RIMOI and RIMOF
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The fact that the mechanisms resulting in RIMOI and RIMOF remain unknown up to now is at the same time an obstacle and a challenge for the diagnosis and treatment of radiation damage at the multi-organ level. Therefore research in this area is of utmost importance. Future approaches must cover aspects that serve as common denominators of the radiation reaction at different levels of biological organisation as well as on organ systems of different origin. What might these common denominators be? To begin at the cellular level, the role of radiation-induced apoptosis [26] as well as cell–cell and cell–matrix interactions [27] modulated by integrins could serve as a model of a general pattern of reaction in all organs affected by radiation. Elucidation of the molecular mechanisms in the bystander effect [28] can help to understand the interaction between damaged and intact organ systems and thus the evolution of multi-organ involvement, which does not necessarily mean only interactions between radiation-damaged organs. An intensified search for biomarkers, at both the protein [29] and the genomic level [30], might help to quantify the radiation reaction and thus help to understand the development and time course in the special case of RIMOF and RIMOI. Understanding the repair of radiation-damaged cells as well as the regeneration of organ systems and organ interactions requires elucidation of the role of stem cells [31] in radiation injuries.
These are only a very few aspects where intensified research might significantly help to understand the pathogenetic mechanisms of RIMOF.
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RIMOI and RIMOF: a challenge for radiation accident medical management
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For radiation accident medical management [13], the development of RIMOF is a huge and sometimes even tremendous challenge. Recent radiation accidents have shown that large resources in the field both of logistics [13] and of medical treatment [1] are necessary. Even if only a small number of patients are affected, they utilise manpower around the clock as well as material resources, so that the limits of capabilities of hospitals may well be approached. Mass casualty scenarios, e.g. of terrorist origin, exacerbate these organisational demands to an extent that even a small-scale scenario (such as the dirty bomb) could lead to a situation of nearly total decompensation of available resources. To avoid this situation, pre-planning, continued training of medical and nursing staff, and field exercises are of utmost importance. Medical management requires an intensive planning and structuring of emergency plans as well as the provision of all necessary resources, such as decontamination facilities and capacities to analyse the radiation exposure characteristics and doses.
From the medical point of view, treatment of RIMOF patients requires an interdisciplinary approach. The medical management concept should not be based on the treatment of any one single organ but must consider the dynamics of the interaction between the different injured or non-impaired organ systems.
Again, recent radiation accidents have shown that no medical specialty alone can treat such patients, since RIMOF is not a problem for, for example, a haematologist or dermatologist alone, as it is neither a disease solely of the haematological system or the skin. Rather, RIMOF is a challenge for all specialties in the medical community. This approach, however, requires well-trained doctors and nurses in radiation medicine and the investigation and teaching of the complexity of radiation responses. Beyond that, central co-ordination of all diagnostic and therapeutic efforts by doctors or experts in the field of radiation medicine is essential. RIMOF is not an every day situation in clinical practice. Therefore, only a few experts worldwide will have the expertise to deal with this special condition. This is a strong argument in favour of strengthening international co-operation in the field of radiation accident medical management as well as the formation of an international radiation effects and medical management research network.
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Summary
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The "Advanced Research Workshop on Radiation-Induced Multi-organ Involvement and Failure" held at the Science Conference Center Schloss Reisensburg in November 2003 significantly contributed to the understanding of the role of RIMOI and RIMOF. Moreover, it opened perspectives and challenges for future clinical and molecular–biological research within this specific area.
Radiation accidents are relatively rare events compared with accidents of other origin; however, the consequence of accidental radiation exposure of human beings can be extensive, both physically and psychologically. The development of RIMOF very quickly demands a huge amount of logistic and medical resources. The treatment of patients suffering from the consequences of RIMOF is a difficult problem for all physicians involved and sometimes cannot be solved even with the use of all available modern techniques. These problems can only be overcome by bringing together all resources in the area of radiation accident medical management, together with an intensified support of specific research in the field of radiobiology and radiation medicine.
Strengthening science to help identify pathophysiological mechanisms involved in RIMOF might not only have benefit for the special condition of high dose whole body exposure by ionising radiation. RIMOF, as a clinically important but rare event, is the maximum extent of radiation-induced organ interaction. Research in the field of radiation injuries must pay attention to the specific role of RIMOI. This offers the opportunity to break through the vicious circle of RIMOF. However, the interaction of organs in an irradiated human being is a common feature of an almost every day situation, namely radiotherapy of cancer patients, which may well serve as an excellent model for routine RIMOI. Therefore identifying the mechanisms of RIMOF might also have a great benefit for patients in cancer treatment using ionising radiation. An understanding of organ interactions modulated by ionising radiation would logically give the chance to selectively influence all cell interactions modulated by ionising radiation and this includes the important interactions between tumour cells and normal tissues.
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Footnotes
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The Workshop was held from 12–15 November 2003 at the Science Conference Center Schloss Reisensburg of the University of Ulm and was supported by the German Armed Forces Medical Services, the Pharmacia Foundation and the University of Ulm. 
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Abstract
Introduction
