Ann Hematol (2006) 85: 671–679 DOI 10.1007/s00277-006-0153-x
CONFERENCE REPORT
N.-C. Gorin . T. M. Fliedner . P. Gourmelon . A. Ganser . V. Meineke . B. Sirohi R. Powles . J. Apperley
Consensus conference on European preparedness for haematological and other medical management of mass radiation accidents Received: 12 May 2006 / Accepted: 20 May 2006 / Published online: 1 August 2006 # Springer-Verlag 2006
Preface A consensus conference on the medical management of mass radiation accidents was held by the European Group for Blood and Marrow Transplantation (EBMT), the Institute for Radioprotection and Nuclear Safety (France) and the University of Ulm (Germany) at Vaux de Cernay Abbey (France) on October 25–27, 2005. This consensus on the diagnosis and treatment strategy in the event of accidental overexposure to ionising radiation has been established by a working group of 65 physicians and health ministry representatives from the 25 European Union countries with representation from the fields of haematology, radiopathology and dosimetry. The authors of this consensus conference report wish to acknowledge the competent and constructive contribution of the following speakers and discussion group leaders who were extremely helpful in establishing a common knowledge platform regarding the effects of radiation exposure on human beings and guided the
N.-C. Gorin (*) . P. Gourmelon Institut de Radioprotection et de Sureté Nucléaire (IRSN), Fontenay aux Roses, France e-mail:
[email protected] N.-C. Gorin . B. Sirohi . R. Powles . J. Apperley European Cooperative Group for Blood and Marrow Transplantation (EBMT), Paris Office, Université Pierre et Marie Curie, Paris VI, Paris, France T. M. Fliedner University of Ulm, Ulm, Germany A. Ganser Hannover Medical School, Hannover, Germany V. Meineke Institut für Radiobiologie der Bundeswehr, München, Germany
group discussions: Dr. M. Akashi (Japan), Dr. B. AllenetLepage (France), Dr. D. Blaise (France), Dr. J.F. Bottollier (France), Dr. A. Bushmanov (Russia), Dr. N. Chao (USA), Dr. J.M. Cosset (France), Dr. F. Frassoni (Italy), Dr. M.H. Gaugler (France), Dr. N. Griffiths (France), Dr. D. Lloyd (UK), Dr. A. Nikiforov (Russia), Dr. A.R. Oliveira (Brazil), I. B. Resnick (Israel), Dr. G. Seitz (Germany), Dr. J. Sierra (Spain) and Dr. Leif Stenke (Sweden).
Context Radiation accident management has, until now, been designed for sites where the risks are totally identifiable and likely to involve a limited number of victims. However, any guidelines on radiation or nuclear accident management should now take into account the threat of terrorist attacks that aim to cause mass human losses at unpredictable locations using high technology combined with suicidal behaviour. In the context of this new threat, certain aspects of accident management by the healthcare services are not, as yet, completely satisfactory. In particular, the approaches to be implemented in the event of acute whole body irradiation, where a very large number of victims is exposed to very high doses of radiation, a situation that could arise if one or more highly radioactive sources were to be intentionally released into the environment, are unclear and not widely disseminated. In spite of the diversity of existing and valuable treatment options, there is indeed no real consensus at the present time regarding the definition of a coherent plan for treating mass radiation accidents. Up to now, radiation accidents have occurred only very rarely and the fact that victim care management has, in the past, often been influenced by the opinions of experts with very different professional backgrounds explains the current lack of consensus. A typical example is the lack of guidance as to the use of haematopoietic stem cell transplantation after a myeloablative dose of whole body radiation. In the case of a major accident or terrorist attack, a very large number of victims (upwards of several hundreds) would require emergency hospital admission and treatment.
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The medical teams involved in “initial management” are unlikely to be adequately trained in the handling of patients suffering from severe acute radiation syndrome (ARS). Without appropriate preparation for such an unfamiliar situation, they will be under enormous pressure to define appropriate responses and treatment options. It is therefore essential to set out standard protocols to help make the right decisions in such an extraordinary situation. Faced with the growing threat of a terrorist attack, establishing a European consensus on treatment protocols for mass accidental radiation exposure has therefore become a priority.
Problems involved in radiation accidents in terms of medical management Radiation accidents present certain unique characteristics which explain why healthcare management is so complex and why it is difficult to harmonise and standardise the methods of diagnosis and treatment. Cases of accidental radiation exposure cannot, by their very nature, be compared to whole body therapeutic irradiation and, while there may be some similarities between them, their clinical and biological modalities are extremely different. This specificity is manifested in six areas: (1) Patients who have been diagnosed with malignant tumours or haematological diseases receive treatment involving the use of cytotoxic agents including whole body or partial body irradiation. Such exposure to radiation is carried out in a controlled environment according to standardised protocols which often include lung shielding to prevent pulmonary radiation lesions. This is not the case in accidental radiation exposure where the radiation fields and doses are a priori unknown. (2) The clinical consequences of bone marrow failure as observed in patients with “malignant haematology”, on the one hand, and with an ARS, on the other hand, appear to be similarly characterised by infection (granulocytopenia), bleeding (thrombocytopenia), anaemia, etc. However, there are distinct differences. In patients with “malignant haematology”, the pathophysiology can be traced back to a qualitatively impaired stem cell pool. In patients with ARS, the hemopoietic tissue was unimpaired until the time of exposure and the course of events including regeneration is determined by the number of stem cells that were unaffected or repaired. If the exposure dose was in the LD50 range (per 60 days), one can expect a fully recovered marrow by about 60 days after exposure. (3) A Historical analysis of radiation accidents shows that, unlike in cases of therapeutic whole body irradiation, the dose of irradiation delivered is, in practice, almost always heterogeneously dispersed. As certain areas of the bone marrow are under-exposed and relatively protected, the presence of functional residual haematopoiesis is possible or even probable. The existence of such residual haematopoiesis in a radiation victim can
radically affect decisions as to whether haematopoietic stem cell transplantion is indicated. (4) In cases of very high doses, the prognosis of accidental radiation exposure depends mainly on the extent of damage to organs other than the bone marrow (lungs, gastrointestinal tract and skin) as there is an increased risk of fatal multi-organ failure, even if the bone marrow aplasia has been successfully controlled. (5) Radiation accident victims may, depending on the circumstances, present a combination of radiationinduced lesions, including traumatic injuries and/or burns, thus rendering the prognosis less optimistic and making treatment considerably more complicated. (6) Lastly, dose assessment, which has traditionally been considered essential information in determining the management of accidental irradiation, cannot be relied upon. In an operational situation and especially one which involves a large number of victims, physical dosimetric assessment will not be available immediately and, moreover, cannot provide sufficient information to assess the extent of biological damage to the various organs upon which the definitive prognosis depends.
Methodology to achieve a qualified consensus The first part of the meeting was devoted to oral presentations of past radiological accidents throughout the world together with current knowledge of dosimetry techniques, radiation organ injuries (bone marrow, neurovascular system, gastrointestinal tract and skin) and the genesis of the radio-induced multi-organ failure (MOF) syndrome. Furthermore, the “METREPOL” document established for the EU DG XII in 2000 [1] which scores the severity of the radiation-induced damage was presented as a teaching and work tool to reach a subsequent general consensus. METREPOL identifies 1–4 response categories (RC) based on the grading of the effects observed in the four most important organ systems (neurovascular, hemopoietic, skin and gastrointestinal tract). After these presentations, the second part of the meeting was devoted to working group discussions. The participants were split in five working groups of 12–14 persons and asked to answer 20 identical question sets. A synthesis of all the answers of the working groups was established and for each question a consensus was reached, if no more than one group answer was different from the others.
Consensus report This “consensus conference report” frequently uses the term “triage”. It should be noted that this consensus document is designed for the clinician who is faced with the diagnosis and treatment of radiation accident victims once they have reached a specialised hospital setting. This “clinical triage” which directs the patient to the most appropriate medical services should be clearly distinguished from the “primary triage” which is conducted “in
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the field” by emergency and rescue teams. The primary triage identifies those patients who require emergency admission and decontamination, if necessary. A second group in the “primary triage” is that of the “bystanders” who were not affected. A third group is comprised of persons who are so severely injured, that death is inevitable and only palliative therapy is possible. This “primary triage” is beyond the scope of this paper.
Scoring the severity of the acute radiation syndrome Timing of scoring The consensus was that it is possible to score the severity of the radiation exposure effects in the first 24–72 hours. It necessitates sequential examination after the radiation accident is confirmed (or suspected). Criteria for scoring The score relies on clinical symptoms, physical examination (detailed below) and laboratory data including blood counts, chemical profile with serum amylase and cytogenetics, in addition to information about the accident and the exposure settings. Relevance of the prodromal phase
Applicability of the GVHD model There is no consensus that, after accidental irradiation, a scoring model based on the same principles as the GVHD scoring model can be used to predict MOF. Scoring by organs or multi-organ score The METREPOL multi-organ score based on neurological, skin, haematological and gastrointestinal system damages was found to be indispensable. However, the consensus was that other organ damage (not presently included in METREPOL) should also be considered (lungs, kidneys, liver, cardiovascular system and fertility) [2]. Summary There was consensus on the need to identify bystanders that did not receive any irradiation (score “0”). There was consensus that for hospitalised patients, the present METREPOL grading system with four grades is adequate. There was also, however, consensus that, to help the primary emergency triage (performed by emergency squads) of large patient populations (not covered by METREPOL), three levels for a transitory scoring would be enough to sort it out: –
score “1” corresponding to patients that can be followed on an outpatient basis or by a day care hospital structure score “2” corresponding to patients needing maximum medical effort to be rescued score “3” corresponding to patients predicted to develop MOF unfortunately beyond any curative therapeutic measures
The prodromal phase is of considerable importance but can be missed in case of unknown exposure. All symptoms should be carefully recorded and graded with the exact time of occurrence. Monitoring of the prodromal phase will be essential for the subsequent triage and management of victims (Table 1).
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Criteria for early assessment of the risk of multiple organ failure
Clinical data and biological sample collection within the first 48 h
The severity of the prodromal clinical features is of major importance (particularly high fever, hypotension, extensive and immediate erythema, immediate diarrhoea and early transient incapacitation syndrome).
Clinical data collection
Prognosis value of the scoring: usefulness as a guideline for clinical management The consensus was that the most important value of such a score would be to predict early and accurately for the occurrence of the multi-organ failure syndrome. This would help to identify victims unlikely to be rescued. It would simultaneously improve the efficacy of the early triage and the management of the other victims.
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As previously mentioned, there was consensus that all symptoms should be carefully recorded with the exact time of occurrence. Monitoring the prodromal phase is essential for the triage and subsequent management of the victims. Clinicians should refer to the summary list in the METREPOL compendium (Table 1).
674 Table 1 Summary list of clinical data (from METREPOL compendium C18)
Laboratory samples within the first 48 h There was consensus that the following samples should be collected and sent to the appropriate laboratory for analysis: – – –
Repeated blood cell counts (lymphocytes, granulocytes and platelets) if possible every 4–8 h for the first 24 h , then every 12–24 h (+ reticulocytes) Chromosome aberration analysis on blood lymphocytes (biodosimetry) Red cell group typing
– – –
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Store serum and cells or DNA for future analyses including HLA typing upon request from clinical teams Standard biochemical tests + amylasemia As far as needed: 24 Na measurement after exposure to neutrons. If there is suspicion of a neutron exposure, a blood sample of 20 ml should be taken to measure the content of radioactive sodium (24Na). Urine and faeces if radionuclide contamination is suspected
675 Table 1 (continued)
Value of physical dosimetry An important debating point was whether the physician should delay further medical management until the physical dosimetry is available: the consensus was that they should not but it was recognised that the physical dosimetry data and the dose assessment should be transmitted as soon as it is known (especially for internal contamination) to all authorised persons (medical, public health and coordination teams). The physical data allow the establishment of on-site cartography of the perimeters of exposure around the causative source. It may also help later to evaluate the dose distribution within the body in case of heterogeneous external irradiation. For physical characterisation of the radiation field, there is a need to collect: –
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Information about the source characteristics such as the type of irradiation (α, β, γ, neutrons and mixed), whether the source is sealed (irradiating) or not (releasing radionuclides) and the physico-chemical properties of radionuclides Information on the exposure characteristics such as geometry and duration of the exposure, daily dose rate,
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shielding and possibility of homogeneous/heterogeneous irradiation Garments, biological material (hair, nails, urine, faeces...)
This information/material should be collected as soon as possible preferably on site by physicists and trained personnel.
Clinical organ damage assessment for triage Neurovascular system The neurological system should be evaluated daily using Table C3 from the METREPOL compendium (Table 2). Skin A repeated evaluation (once per day) of degree and distribution of the involved body surface is essential. Photographs might help to document changes over time. Use Table 1 in combination with C4 cutaneous system METREPOL (Table 3).
676 Table 2 Guide in the evaluation of the neurological system (from METREPOL compendium C3) N Symptom
Degree 1
Degree 2
Degree 3
Degree 4
Nausea Vomiting
Mild Occasional, 1/day
Tolerable Intermittent, 2–5/day
Intense Persistent, 6–10/day
Anorexia
Able to eat, reasonable intake Significantly decreased intake but No significant intake able to eat Able to work or perform Interferes with work or normal Needs some assistance for normal activity activity self-care 40°C for less than 24 h
Excruciating Refractory >10/dor parenteral nutrition Parenteral nutrition
Fatigue syndromea Fever
Prevents daily activity
>40°C for more than 24 h or accompanied with hypotension Headache Minimal Tolerable Intense Excruciating Hypotension HR>100/BP>100/70 BP
