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British Journal of Radiology (2003) 76, 246-253
© 2003 British Institute of Radiology
doi: 10.1259/bjr/82373369
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Full Paper

Initial medical management of patients severely irradiated in the Tokai-mura criticality accident

T Hirama, MD, PhD 1 S Tanosaki, MD, PhD 1 S Kandatsu, MD, PhD 2 N Kuroiwa, MD 1 T Kamada, MD, PhD 2 H Tsuji, MD, PhD 2 S Yamada, MD, PhD 2 H Katoh, MD, PhD 2 N Yamamoto, MD, PhD 2 H Tsujii, MD, PhD 2 G Suzuki, MD, PhD 3 and M Akashi, MD, PhD 1

1 Research Center for Radiation Emergency Medicine, 2 Research Center for Charged Particle Therapy, National Institute of Radiological Sciences, Chiba, Japan and,3 Radiation Effect Research Foundation, Hiroshima, Japan

Correspondence: Toshiyasu Hirama, Research Center for Radiation Emergency Medicine, National Institute of Radiological Sciences, 4-9-1 Anagawa, Inage-ku, Chiba 263-8555, Japan


   Abstract
Top
 Abstract
Introduction
 Patients and methods
 The accident
 Evaluation of patients
 Clinical course
 Discussion
 Conclusion
 References
 
A nuclear criticality accident occurred in Japan on September 30, 1999, which resulted in severe exposure of three victims to mixed flux of neutrons and {gamma}-rays. Estimated average doses for the three victims were 5.4 Gy of neutrons and 8.5 Gy of {gamma}-rays for Patient A, 2.9 Gy of neutrons and 4.5 Gy of {gamma}-rays for Patient B, and 0.81 Gy of neutrons and 1.3 Gy of {gamma}-rays for Patient C. They then suffered the consequences of the effects of ionizing radiation resulting in acute radiation syndrome. In Patients A and B, bone marrow failure was so severe that they received haematopoietic stem cell transplantation. The graft initially took successfully in both patients, although in Patient B it was later taken over by his own haematopoietic cells. They also suffered from severe skin lesions, later exhibited gastrointestinal bleeding and eventually died of multiple organ failure 82 and 210 days after the accident, respectively. The survival of these patients beyond the period of agranulocytosis means that bone marrow failure per se caused by exposure to ionizing radiation may now be overcome. Patient C also developed bone marrow failure and was treated with granulocyte colony-stimulating factor as well as supportive care. He recovered without major complications and is now under periodical follow-up. Remarkably, during the prodromal phase, all the patients exhibited hypoxaemia, two of whom also showed interstitial oedema of the lungs. In Patient C these manifestations improved within a week. The circumstances of the accident and the initial medical treatment of the victims are described.


   Introduction
Top
 Abstract
 Introduction
Patients and methods
 The accident
 Evaluation of patients
 Clinical course
 Discussion
 Conclusion
 References
 
Since the advent of the nuclear industry, more than 40 accidents associated with nuclear criticality in undesired manners have occurred [1, 2]. Most occurred before 1970, on which our knowledge of the medical outcomes of such accidents is mainly based. Criticality accidents differ from other types of radiation accidents in that they cause exposure to neutrons and {gamma}-rays in quite a short period, often a moment, and can be lethal for those within several metres of the source of radiation, who are often those who triggered the chain reaction. Those who were in the immediate vicinity of the source of radiation exhibit symptoms reflecting the severe damaging effects of high-dose ionizing radiation to many organ systems, such as the bone marrow, gastrointestinal tract, cardiovascular system and skin, which are collectively described as a severe form of acute radiation syndrome (ARS). Typically, survival terms of such patients after a criticality accident have been less than 10 days [3, 4]. For instance, in a reported criticality accident in 1946 in the United States [5], the victim who was directly handling the critical assembly survived 9 days. In another recent criticality accident in Russia, the victim survived 66.5 h [6]. Earliest clinical manifestations in such patients, following non-specific prodromal symptoms such as nausea and vomiting, have been early and severe leukopenia and painful oedema of the upper extremities, which in most cases had been closest to the source of radiation. Thus, for the survival chance of patients with a severe form of ARS to ever exist, therapeutic intervention to support general physical condition as well as bone marrow failure is of the utmost importance. In contrast, in the survivors of previous criticality accidents, radiation-induced skin damage has typically been absent, except localized epilation, and the decrease in leukocytes has been slower and milder.

In the criticality accident in Tokai-mura, Japan, which occurred in 1999, three victims were exposed to high doses of neutrons and {gamma}-rays. Two of the victims exhibited extremely severe damage to the bone marrow as well as to the skin, which was comparable with a severe form of ARS. However, state of the art therapy, including haematopoietic stem cell transplantation, enabled them to survive 82 days and 210 days after the accident, illustrating that bone marrow failure per se may no longer be the limiting factor for the survival of such patients. In the present report, we describe the circumstances in which the victims were irradiated, their medical condition and the therapeutic strategy in the initial period. We also show that arterial blood gas analysis and CT of the chest may be of diagnostic value, at least in criticality accidents, even when the symptoms of ARS are still subtle.


   Patients and methods
Top
 Abstract
 Introduction
 Patients and methods
The accident
 Evaluation of patients
 Clinical course
 Discussion
 Conclusion
 References
 
Patients
Patients A, B and C, all male, were 35 years old, 39 years old and 54 years old, respectively, at the time of the accident. Disclosure of any information related to the patients in this report is based on written informed consent.

CT
CT was performed with a HighSpeed Advantage (GE Medical Systems, Milwaukee, WI) scanner. Scans were obtained at end inspiration using 10 mm collimation and at 10 mm intervals through the chest, with the patient in a supine position. CT was performed at 140 kVp and 200 mAs.


   The accident
Top
 Abstract
 Introduction
 Patients and methods
 The accident
Evaluation of patients
 Clinical course
 Discussion
 Conclusion
 References
 
A nuclear criticality accident occurred in Tokai-mura, located approximately 120 km northeast of Tokyo. It occurred in a company that had been manufacturing nuclear fuel for power plants in Japan. On September 30, 1999, three workers were mixing together seven batches (2.4 kg uranium per batch) of individually prepared uranyl nitrate solution, one of the final steps in the process of producing 18.8% uranium for an experimental fast reactor in Tokai-mura. Previously they had used a container with a controlled geometry for this purpose to prevent criticality. On that day, however, they decided to mix the batches in a larger container, the precipitation tank, of which the mass limit to prevent criticality was 2.4 kg uranium. At 10:35 am on September 30, when they were pouring the seventh batch of solution into the tank and its uranium content reached approximately 16 kg, criticality was triggered. The positions and postures of the workers at the scene were reconstructed by interviewing them (Figure 1Go). Worker A, who was the most severely irradiated, apparently was standing beside and facing the tank holding a funnel with at least his right hand. Worker B, who was also severely irradiated, was crouching on a stage with his right foot on a stair, pouring the solution from a bucket into the tank, with his face and right hand very close to the tank. Worker C, who was less severely irradiated, was sitting at his desk a few metres away from the tank separated by a thin wall. At the moment that criticality was triggered, all three workers saw a flash of blue light. Workers A and B then ran to the next building, where Worker A collapsed and lost consciousness for some 20 s. He then experienced vomiting and diarrhoea. The stools were not described. Worker C stayed at the scene for approximately 5 min trying to contact the radiation safety personnel of the facility by telephone. He then joined the other two workers. The three workers (hereafter referred to as patients) were initially transported to National Mito Hospital. Because the patients were radioactive by routine radiological survey and their granulocytosis and lymphopenia were already marked, physicians of the hospital readily recognized the severity of the circumstances and decided to send the patients to the National Institute of Radiological Sciences (NIRS) in Chiba, which had been assigned, as the hospital in charge of medical treatment of victims of radiation accidents in Japan's Basic Plans for Disaster Prevention. The three patients arrived at the NIRS at 15:10. While the physicians of the NIRS were evaluating the medical condition of the patients, our health physicists and radiation safety staff made radiological analyses. Their body surface was significantly radioactive as surveyed by Geiger–Muller survey meter, but not by alpha survey meter. The vomitus of Patient A was analyzed and 24Na detected [7], which is produced by neutron activation of stable 23Na and emits ß- and {gamma}-rays and has been routinely utilized to calculate neutron flux to estimate doses in previous criticality accidents. It was thus known that these were victims of a criticality accident.



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  		Figure 1. The positions and postures of the victims of the accident at the moment when criticality was triggered, reconstructed by interviewing Workers B and C.

 

   Evaluation of patients
Top
 Abstract
 Introduction
 Patients and methods
 The accident
 Evaluation of patients
Clinical course
 Discussion
 Conclusion
 References
 
Within hours of total body irradiation, radiation accident victims exhibit symptoms such as nausea, vomiting, diarrhoea, fever and in severe cases, hypotension and even loss of consciousness, which might reflect an acute response of the neurovascular system [8]. Although none of these symptoms are specific for ARS, collectively their promptness and severity have been described to reflect the extent of damage that the body had received from ionizing radiation and have often been compatible with the dose of radiation estimated by physical methods [9]. Therefore, we carefully observed the initial symptoms and physical signs of the patients to get a rough picture of the severity of the effect of irradiation and thereby formulate reasonable therapeutic strategies [10].

Patient A experienced nausea, vomiting and a transient loss of consciousness minutes after the exposure, and diarrhoea within 1 h. The type of stools at the accident scene was not reported, but during his 3-day admission at the NIRS, stools were watery and negative for occult blood, which meant that the intestinal epithelium was still intact. On admission, the patient was febrile without any evidence of infection, slightly drowsy and hypotensive with a systolic blood pressure of 70 mmHg. The patient also had diffuse erythema on the ventral body surface, facial oedema, injection of the conjunctiva bulbi and painful bilateral parotid swelling. He complained of diffuse tenderness of the abdominal wall by palpation and difficulty in voiding. These findings strongly indicated that the patient had received serious damage from the irradiation, comparable with the victims of reported accidents with fatal outcome.

Patient B also experienced nausea and vomiting within 1 h of exposure, but without early diarrhoea. Although Patient B was normotensive on the day of the accident, his blood pressure was rather low for the next several days (lowest recorded 80/44 mmHg). The patient was also slightly drowsy, febrile, had erythema on the ventral body surface and salivary gland swelling, and complained of mild epigastralgia on admission. These findings indicated that he would also undergo a severe form of ARS, although to a lesser degree than Patient A.

Patient C experienced only mild nausea several hours after exposure. On admission, his skin had slight but diffuse erythema. Otherwise, the patient was asymptomatic and appeared to be in a good physical condition. If we utilize the published table by the International Atomic Energy Agency that correlates symptoms of ARS during its prodromal phase with results of dosimetry, the symptoms and signs in Patients A, B and C would correspond to the degrees of damage caused by more than 8 Gy, between 6 and 8 Gy and less than 4 Gy, respectively, of ionizing radiation [9].

Lymphocytes represent one of the most sensitive types of cells to ionizing radiation; the rapidity and extent of the decrease of lymphocytes are known to correlate with the severity of exposure. Baranov et al have formulated a function between the lymphocyte count and the corresponding exposure dose in ARS [11]. Although the method can be influenced by the baseline numbers of lymphocytes, which vary from one individual to another, it provides information about the severity of ARS in the first 24 h, when the results of dosimetry are typically not yet available. Because their data were based on {gamma}-ray accidents, we plotted the patients' lymphocyte counts in the formula and obtained values equivalent to {gamma}-rays. The resultant values for Patients A, B and C were more than 10 Grey Equivalent (GyEq), between 6 GyEq and 10 GyEq, and between 1 GyEq and 4.5 GyEq, respectively. In Patient A, the lymphocyte counts were far outside the range of the graph.

The results of dosimetric analyses by specialists came 2 days after the accident and were refined thereafter. They agreed fairly well with the above values. Doses based on the 24Na content in the peripheral blood were 5.4 Gy of neutrons and 8.5 Gy of {gamma}-rays for Patient A, 2.9 Gy of neutrons and 4.5 Gy of {gamma}-rays for Patient B and 0.81 Gy of neutrons and 1.3 Gy of {gamma}-rays for Patient C 12]. Chromosome analyses of the patients' lymphocytes, utilizing the prematurely condensed ring method, resulted in doses equivalent to {gamma}-rays, which were more than 20 GyEq for Patient A, 7.4 GyEq for Patient B and 2.3 GyEq for Patient C [13].

Laboratory analyses revealed several remarkable findings (Table 1aGo). All three patients showed granulocytosis and degrees of lymphocytopenia on the day of the accident (day 0). Serum amylase increased after admission and peaked on the day following the accident (day 1). It then decreased and, in Patient C, returned to within the normal range on day 4. Isoenzyme analyses of serum amylase revealed a predominant S-fraction, indicating damage to the salivary glands. Serum uric acid also increased in Patients A and B on day 1. Arterial blood gas was analyzed in all of them and invariably showed hypoxaemia, with partial pressure of oxygen in arterial blood (PaO2) values of approximately 60 mmHg (Table 1bGo). In Patient C, PaO2 gradually improved to 79.8 mmHg by day 5. Respiratory function was assessed on Patient C and initially revealed a slightly decreased diffusion capacity of the lung for carbon monoxide (DLCO) value of 13.36 ml min-1 mmHg-1. The value had returned to normal when the test was repeated 3 months later. Respiratory function was not assessed on Patients A and B because of the impracticality of doing so under reverse isolation.


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  		Table 1. (a) Blood counts and serum chemistry on admission (5.5 h after exposure) to the NIRS. Values marked with an asterisk are of the following day of the accident. (b) Arterial blood gas analyses on the day of admission. For Patient C, chronological change is also shown.

a)

 

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Remarkably, in Patient C, CT of the chest peformed on day 1 revealed a crescent-shaped subpleural thickening in the dorsum of the lower lobes of the lung, and adjacent reticular shadows in the lung parenchyma, together suggesting interstitial oedema of the organ (Figure 3aGo, arrow). In accordance with the improvement of PaO2, a CT scan taken on day 6 showed remarkable recovery, with only minimal reticular shadows (Figure 3bGo), which further became almost insignificant on day 60 (Figure 3cGo). Similar findings were observed initially in Patient A (Figure 3d)Go. Also, in Patient B, mild subpleural thickening was observed (not shown).



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  		Figure 3. CT image of the chest of Patients A and C. Arrows show the relevant areas stated below. (a) Day 1, Patient C. Note bilateral subpleural thickening, more severe in the right side, in the dorsum of the lower lobes of the lung. Adjacent to the thickening, restiform or rough reticular shadow can be seen. These findings were also observed in the dorsum of the upper lobes (not shown). (b) Day 6, Patient C. Remarkable improvement of the initial findings is obvious. (c) Day 60 of Patient C. Only equivocal reticular shadow remains. (d) Day 1, Patient A. Note bilateral crescent form shadows. The density of the area is higher than that of water, indicating proteinacious exudate or soft tissue thickening.

 

   Clinical course
Top
 Abstract
 Introduction
 Patients and methods
 The accident
 Evaluation of patients
 Clinical course
Discussion
 Conclusion
 References
 
On admission, Patients A and B were kept under reverse isolation. Initial therapeutic measures that were taken common for all three patients included strict maintenance of body fluid balance with the infusion of electrolytes and plasma under central venous pressure monitoring and selective digestive tract decontamination with oral administration of kanamycin sulfate (3 g day-1), polymyxin B (3 000 000 units day-1) and amphotericin B (400 mg day-1). On day 4, vancomycin was substituted (2 g day-1) for kanamycin. Prophylactic systemic administration of antibiotics (imipenem 1 g day-1), antiviral (acyclovir 1 g day-1) and antifungal (fluconazole 200 mg day-1) reagents was also started on day 1. Below the clinical picture of each patient is described separately.

Patient A
Granulocyte colony-stimulating factor (G-CSF, 100 µg) was administered intravenously on the evening of day 1. Shortly after it was infused, the patient complained of mild dyspnea and systemic rash. The symptoms resolved after inhaled oxygen concentration was increased to 50%. Electrocardiogram was normal on day 1, but evolved inverted T waves in leads II, III and aVF on day 2, possibly suggesting damage to the inferior myocardium. Bone marrow taps were taken from the sternum and iliac crest on day 1 and showed marked hypocellularity in both the erythroid and myeloid lineages (not shown). The myelogram of the smear from the sternum was as follows: myeloblast 1%; promyelocyte 1%; myelocyte 3.6%; metamyelocyte 4%; band 32.4%; segmented 54.4%; eosinophil 1.4%; monocyte 0.8%; lymphocyte 1%; and plasma cell 0.2%. Some cells had intranuclear vacuolations, which have also been reported in previous accidents [5]. White blood cells (WBC) of Patient A slightly increased on day 2, then rapidly decreased and almost disappeared by day 7 (Figure 2aGo). Later we were informed that he had been warned of leukocytosis for at least 2 years. Lymphocytes kept decreasing and disappeared on day 3 (Figure 2aGo). Platelets also decreased steeply, necessitating platelet transfusion starting from day 5 (Figure 2aGo). Haemoglobin was rather elevated initially (Table 1aGo), possibly reflecting haemoconcentration, but then decreased rather steeply by day 7 (Figure 2aGo, lower right panel, diamond) without documented bleeding. From our evaluation of the severity of his disease based on his symptoms and signs in comparison to the victims of previous accidents and the preliminary results of dosimetry that we received on day 2, the spontaneous recovery of the bone marrow of Patient A was judged to be quite unlikely. Therefore on day 2 it was decided to treat the patient with haematopoietic stem cell transplantation and to transfer him to the University of Tokyo Hospital, which was one of our collaborators. G-CSF was discontinued for several days. While in the NIRS hospital, the patient's facial oedema slightly improved. However, he complained of painful forearm swelling on the right side on day 2, which subsequently became tenser. Although the patient continued to have watery diarrhoea and complained of diffuse abdominal tenderness by palpation, he was apparently well on days 1 and 2, following which his general condition rapidly deteriorated. He received peripheral blood stem cell transplantation on days 6 and 7. His progressive hypoxaemia necessitated endotracheal intubation on day 10. Although the graft took, the patient continued to have respiratory failure, subsequently exhibited severe skin lesion and gastrointestinal bleeding, and died of multiple organ failure on day 82. The detail of his therapy has been published elsewhere [14].



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  		Figure 2. Haematologic data of the patients. (a) Peripheral blood counts of Patients A, B and C during the first 11 days are depicted with diamonds, rectangles and triangles, respectively. (b) Haematologic data of Patient C during the whole admission period. The dynamics of neutrophil (upper left), platelet (middle left), lymphocyte (lower left), haemoglobin (upper right), reticulocyte (middle right) and serum iron (lower right) are shown.

 
Patient B
G-CSF (100 µg, intravenous infusion) was started on day 1. This patient also exhibited systemic rash after the infusion, it was decided to administer the growth factor through round the clock infusion from day 2 (500 µg day-1). Bone marrow aspirates from the sternum and iliac crest on day 1 were markedly hypocellular with some intranuclear vacuolations. The myelogram of the smear from the sternum was as follows: promyelocyte 0.4%; myelocyte 2.2%; metamyelocyte 2.0%; band 32.4%; segmented 58%; eosinophil 1.2%; lymphocyte 2.2%; and phagocyte 1.6%. WBC slightly increased on day 2, almost stabilized on day 3 and then rapidly decreased and almost disappeared by day 7 (Figure 2aGo). Lymphocytes also rapidly decreased and disappeared on day 7 (Figure 2aGo). Platelets and haemoglobin decreased rather gradually (Figure 2aGo). We anticipated that Patient B, although obviously having been less severely irradiated than Patient A, would suffer at least a prolonged period of severe leukopenia. As the patient may have exhibited severe skin injury and gastrointestinal lesion during that period, we reasoned that it should be more beneficial than detrimental to support his leukopenic period with haematopoietic stem cell transplantation. He was transferred to the Institute of Medical Science, University of Tokyo, which was another of our collaborating hospitals, and received umbilical cord blood transplantation on day 9. The graft initially took, and then was gradually replaced by his own haematopoietic cells. The patient also had oedema in the right forearm in the first several days, and later evolved severe skin lesions involving the large part of his body surface, in particular the face and extremities. Although the skin lesions were extensively treated with skin grafts, he later evolved gastrointestinal bleeding and infectious complications, which caused him to die of multiple organ failure on day 210. The detail of his therapy has been published [15].

Patient C
Judging from Patient C's symptoms and signs, as well as the preliminary results of dosimetry, we expected his bone marrow to recover spontaneously. Therefore, he remained at the hospital of the NIRS and was treated without haematopoietic stem cell transplantation. The bone marrow aspirates from the sternum and iliac crest on day 1 showed decreased erythroid series and well preserved myeloid series. The myelogram of the smear from the sternum was as follows: myeloblast 0.4%; promyelocyte 2.8%; myelocyte 5.2%; metamyelocyte 4.6%; band 17.3%; segmented 32.6%; eosinophil 3.4%; monocyte 1.8%; lymphocyte 17.2%; plasma cell 1%; phagocyte 0.4%; basophilic normoblast 1%; polychromatic normoblast 5%; and orthochromatic normoblast 6.8%. Some morphologically abnormal megakaryocytes were also seen (data not shown). The patient's WBC count returned to normal on day 1, then increased in response to G-CSF, which was started on the evening of day 2 (Figure 2aGo). Neutrophils then started to decrease following a stairwise pattern, and reached a nadir of 1.09 x 109 l-1 on day 20 (Figure 2bGo). The patient was kept under reverse isolation while having neutropenia. Following the recovery of the neutrophil count, G-CSF was reduced and eventually discontinued on day 28. The decrease in platelets was slower than that of the other two patients (Figure 2aGo), but necessitated platelet transfusion on days 17, 20 and 23 (Figure 2bGo). Platelets made a gradual recovery thereafter. The number of lymphocytes was lowest on day 2 and also made a slow recovery (Figure 2aGo). Haemoglobin slowly decreased from above 150 g l-1 to 102 g l-1 without any evidence of bleeding (Figure 2bGo). Serum iron concentration steeply increased from 134 µg dl-1 on day 0 to 235 µg dl-1 on day 1, presumably reflecting the halting of erythropoiesis (Figure 2bGo). It then decreased abruptly in the second month, coinciding with the recovery of reticulocytes, which had decreased during the first week and had then undergone two transient rises (Figure 2bGo). During admission the patient exhibited spotty epilation as well as marked diminution in the growth of beard. In addition, he had a localized painless defect of the oral mucosa without his knowing, which was pointed out on day 19. The lack of pain might be attributable to inefficient inflammation because of the neutropenia that peaked on day 20. These symptoms were presumed to have been caused by irradiation and improved gradually. He is now being followed up in the outpatient clinic of the NIRS.


   Discussion
Top
 Abstract
 Introduction
 Patients and methods
 The accident
 Evaluation of patients
 Clinical course
 Discussion
Conclusion
 References
 
This accident caused ARS in three patients, who were heavily exposed to mixed flux of neutrons and {gamma}-rays. ARS develops when a large part of one's body is exposed to a high dose of ionizing radiation and has two characteristics. First, its clinical manifestation depends upon the absorbed energy of ionizing radiation: with increasing energy, symptoms resulting from the damage to the haematopoietic, gastrointestinal, cardiovascular or central nervous system prevail. Second, the syndrome has distinct clinical phases; exposure is followed by the initial prodromal phase with nausea and vomiting, followed by the latent phase, during which the patient is asymptomatic, and eventually the symptomatic phase. In the literature, the latent phase has been described to be absent in patients who were exposed to more than 8 Gy [9]. However, Patient A, who obviously exceeded this dose, was apparently well for a few days except for the tenderness on the abdominal wall and diarrhoea, suggesting that the initial evolution of symptoms in even a severely irradiated patient may be overcome by managing the medical condition appropriately.

After exposure to ionizing radiation, the severity of damage to a given organ and the degree of the resultant organ-specific clinical manifestations should be dependent upon the absorbed energy of ionizing radiation. Accordingly, early clinical manifestations of a radiation accident victim are quite valuable for predicting the degree of ARS and thereby formulating a reasonable therapeutic strategy. Extensive efforts have been made to formulate methods to predict the severity of ARS based on clinical manifestations, in particular the dynamics of haematopoietic parameters [8, 11, 16], which outweigh other clinical parameters in its ease of measuring, sensitivity and quantitativeness. Looking at the blood counts of the present patients would therefore be meaningful. The lymphocyte count of Patients A and B decreased steeply in the first 48 h (Figure 2aGo). In Patient A, its rate of decrease was quicker than in Patient B, and so extreme that it might be best comparable with that of a victim of the Los Alamos accident in 1946 [5] who died 9 days after exposure. In contrast, its decrease in Patient C was relatively mild. Thus the degrees of lymphocyte decrease correlated well with the order of severity of ARS among the three patients, and was compatible with our initial reasoning that Patient A had received supralethal dose of radiation. In addition, the predicted doses obtained in the first 24 h relying on the graph by Baranov et al, which were more than 10 GyEq, between 6 and 10 GyEq and between 1 and 4.5 GyEq for Patients A, B and C, respectively, seemed to be reasonable and were quite valuable.

The dynamics of WBC also differed significantly amongst the patients (Figure 2aGo). Although initial leukocytosis, which reflected granulocytosis, was obvious in all of them, WBC of Patients A and B further increased on the morning of day 1, whereas that of Patient C returned to normal. In addition, its increase in response to G-CSF was only mild in Patients A and B (day 2), while that of Patient C was quite significant (day 3). In Patients A and B, WBC then decreased rapidly and almost disappeared on day 7, whereas in Patient C it was favourably maintained for another 10 days. Although the dynamics of the WBC count differed between Patients A and B, we have to take into account some conditions. (1) Patient A had been warned of granulocytosis before the accident, which had not been evaluated as to its exact pathology. His leukocytosis after the accident, which was obviously more severe than that of the other two, might partly reflect his higher baseline reservoir of granulocytes. (2) In patient A, the administration of G-CSF was discontinued on day 2 and restarted on day 7, whereas in Patient B it was continued. The quicker decline of WBC in Patient A on days 3 to 7, compared with that in Patient B in the same period, might reflect the lack of G-CSF stimuli. Due to these two limitations, we would not consider the difference of the WBC dynamics between Patients A and B significant. Platelets decreased rather slowly when compared with neutrophils or lymphocytes (Figure 2aGo). However, if we look at the first 7 days, its rate of decline clearly separated the three patients. For instance, platelet count of Patient A turned below 50 G l-1 on day 5, which again was comparable with case 3 of 1946 Los Alamos accident. In Patient B, the platelet count turned below 50 G l-1 on day 8, which might be comparable with case V of the 1958 Vinca accident [17], who was the most severely irradiated among the six victims in the accident and survived for 1 month. However, in the previous patient, the decrease in lymphocytes and granulocytes were obviously milder than those in Patient B. In Patient C the decrease was even milder and fell below 50 G l-1 on day 16. In this regard, this patient might be comparable with case 1 of the 1945 Los Alamos accident who died 24 days after irradiation. Because the use of G-CSF or other growth factors that mobilize myeloid cells is now an important therapeutic option in the treatment of ARS, the platelet count, which is not supposed to be influenced by such reagents, might make a reliable indicator of the severity of the disease after several days. Interestingly but quite reasonably, the dynamics of reticulocytes in Patient C showed a precisely flipped pattern of that of serum iron. It started to recover in the second week and exhibited two humps of transient increase before its full recovery in the second month. The transient rises of the reticulocyte count are seemingly analogous to those of his neutrophil count, although they came several days after those of the neutrophil count. They might together represent limited proliferations of damaged progenitor cells in the respective lineages.

During the initial period, the three patients exhibited hypoxaemia. One explanation for this symptom would be because ionizing radiation generates a certain amount of ozone in the human body, which reportedly transforms haemoglobin into methaemoglobin in vitro [18]. An increased level of methaemoglobin in the blood would then decrease PaO2. However, this is not likely to be the case as studies have shown exposure of intact red cells or rabbits to ozone did not result in a significant increase of methaemoglobin [19, 20]. Another explanation would be based on radiation damage to the lungs themselves. Arterial blood gas analyses in the three patients showed increased alveolar–arterial gradients of oxygen tension, suggesting inefficient gas exchange (calculated results not shown). In addition, respiratory function test in Patient C revealed a transient decrease of the diffusion capacity of the lungs. CT of the chest performed on day 1 showed interstitial infiltration accompanied by subpleural thickening in two of them. In Patient C, the hypoxaemia gradually improved, together with the CT findings. These findings indicate the emergence of interstitial oedema of the lungs caused by the damage to the endothelial cells in the organ. Lung oedema has been observed in a recent fatal criticality accident in Sarov 2 days after exposure [6] and in the Los Alamos accidents in the post-mortem investigation [5]. Hypoxaemia shortly after a radiation accident has a precedent in the Soreq accident in 1990 [21]. However, this is the first time that the characteristic CT findings of the chest and hypoxaemia in the very early phase of ARS are described in a patient who has received a non-lethal dose of radiation that does not cause any prodromal symptoms of ARS. Hypoxaemia and the CT findings of interstitial oedema of the lungs might make valuable early clinical indicators of acute high dose irradiation.

The loss of consciousness in Patient A can be explained as early transient incapacitation (ETI), which has been observed in animals after whole body exposure to a very high dose of radiation. According to Franz, ETI in monkeys evolves 3–8 min after a whole body irradiation and lasts for 5–20 min [22]. It is associated with a sudden decrease in the cerebral blood flow and systemic hypotension [23, 24]. The cause of the symptom has not been elucidated, but might reflect the response of the neurovascular system [8] and might be related to a rapid release of histamine [25]. MRI of the head of the patients on day 1 did not show any signs of cerebral oedema or focal lesions (data not shown).

Elevation of serum uric acid has been described in two lethally irradiated victims of the criticality accidents in 1946 and 1958 [3, 5]. Although we do not know the mechanisms that underlie this phenomenon, we speculate that it reflects non-specific and massive cell death caused by high dose irradiation. In addition, increases in serum amylase have been encountered after therapeutic irradiation of the head and neck region and planned irradiation of the whole body before haematopoietic stem cell transplantation. The increase in amylase was mainly of salivary origin, as has been described [26, 27]. As to its degree, Patient B marked the highest level of serum amylase amongst the three patients on day 1 after the accident, followed by Patients A and C. Although the estimated average dose in Patient B was lower than in Patient A, the head of Patient B might have been very close to the source of radiation (Figure 1Go). Thus, the extent of the amylase elevation might have roughly reflected the severity of the exposure to the head and neck in the three patients. Serum uric acid and amylase should be measured in cases of suspected exposure to ionizing radiation.


   Conclusion
Top
 Abstract
 Introduction
 Patients and methods
 The accident
 Evaluation of patients
 Clinical course
 Discussion
 Conclusion
References
 
Our experience presented in this report is an important example of applying state of the art therapy and extremely intensive care to patients of ARS. It confirmed the value of the early clinical signs as well as haematologic parameters for predicting the severity of the disease. We have learned that, even in a severe form of ARS, the initial hypotensive period can be properly managed and that the damage to the haematopoietic system may no longer be the direct cause of death. Because a severe form of ARS involves multiple organ systems, the rescuing of the bone marrow would subsequently confront us with the failures of other organ systems such as the gastrointestinal tract, skin or lungs. Successful treatment of the failures of such organ systems in an ARS patient awaits further progress in the relevant fields at the moment and will continue to challenge transplantation medicine in the future. Finally, hypoxaemia and interstitial oedema of the lungs may be considered an early indicator of ARS, not only in severe cases but also in otherwise asymptomatic cases.


   Acknowledgments
 
We thank Dr Misao Hachiya for her general support, and Ms Rika Hara for her secretarial help. We also thank Drs Hiroyuki Watanabe, Yoshihiro Yamaguchi, Toru Iseki and Hideharu Tanaka and Professor Kazuhiko Maekawa for generously providing us with their expertise in the treatment of the three patients, and the Dose Estimation Working Group for Three Victims, National Institute of Radiological Sciences for sharing the results of dosimetry.

Received for publication November 12, 2001. Revision received October 4, 2002. Accepted for publication November 11, 2002.


   References
Top
 Abstract
 Introduction
 Patients and methods
 The accident
 Evaluation of patients
 Clinical course
 Discussion
 Conclusion
 References
 

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