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Multi-organ failure aspects of a fatal radiation accident in Norway in 1982

¹ Department of Oncology, The Norwegian Radium Hospital, Oslo, ² Section of Haematology, Medical Department, The National Hospital, Oslo and ³ Department of Pathology, The National Hospital, Oslo, Norway

	Abstract

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A fatal radiation accident with a 2.43 PBq (65 kCi) ⁶⁰Co radiation source occurred in Norway in 1982. The patient was estimated to have received an inhomogeneous whole body dose of approximately 10–30 Gy and he died on day 13 after the accident. The clinical features in general were consistent with a haematological syndrome variant of the acute radiation syndrome (ARS). Gastrointestinal symptoms were modest compared with the estimated dose. More recent insights cast doubt about the classical descriptions and interpretation of ARS, which show many similarities to the multi-organ failure (MOF) of otherwise severely traumatised patients. This report discusses the features of ARS in this case in relation to commonly accepted features of MOF, based on clinical and autopsy data.

	Introduction

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Acute radiation syndrome (ARS) following total body irradiation has been described in many textbooks, e.g. by Young [1]. Reactions may occur in any irradiated organ in severely irradiated individuals, but the most prominent symptoms are assumed to originate mainly from tissue damage in the bone marrow and the gastrointestinal tract. However, physiological alterations of the cardiovascular and central nervous systems also play important roles. In the classical descriptions of ARS, the different organ tissues are often treated as separate cell compartments, and the signs and symptoms are schematically described as if they follow the cell kinetics of depletion and restoration of the isolated organ in question. This is in contrast to general pathophysiological processes, where the interplay between organs and tissues is crucial. Moreover, the clinical course in the few meticulously observed cases does not always follow the picture of classical ARS, but shows similarities to multi-organ failure (MOF) of otherwise severely traumatised patients [2].

Published cases of accidental life threatening total body irradiation are fairly rare. The total clinical experience is based on only a limited number of cases with a more complete follow-up [3, 4]. In 1982, a fatal external -irradiation accident occurred in Norway. This radiation accident has been described thoroughly in a number of previous reports [5–10]. This paper concentrates on the MOF aspects of the accident.

	Case report

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The accident occurred in a -irradiation plant near Oslo, used for sterilising medical equipment. The 2.43 PBq (65 kCi) ⁶⁰Co source could be raised to various positions above the shielded position in the concrete floor [5, 8]. Owing to technical and human error, the operator entered the irradiation room although the source was not in the shielded position. His stay in the irradiation room may have lasted a few minutes.

Shortly afterwards he was found sitting, clearly sick, outside the plant. With a previous history of coronary heart disease, he was first admitted to the local hospital with a suspicion of myocardial infarction. Immediately before admission he experienced chills. On admission, the patient reported that sudden retrosternal pain and pain in the left arm was the reason why he had left the irradiation room. Shortly afterwards it was realised that an irradiation accident had occurred. When confronted with the irradiation, he realised that the source had been in an unshielded position and estimated that he had been in the room for 30 s. Later he said that he had walked around the source and was therefore no longer sure that he had been in the irradiation room for only 30 s. He was afebrile on admission, but in the afternoon his temperature rose to 38.5°C. On admission he showed slight posterolateral ischaemia on the electrocardiogram. Later, however, it was normal. His blood pressure was initially 180/120 mmHg, the following day it was 90/60 mmHg, but later it retuned to normal. On admission he suffered nausea and vomiting; according to the clinical charts, vomiting started within the first hour. A facial erythema was noted.

The patient was then transferred to The National Hospital. 1 day after irradiation he felt soreness and dryness in the throat and itching of the eyes. He was red faced, with erythema covering the upper part of the body. On inspection, conjunctival redness and dullness were noted and the corneas were also affected. The mucosa in the mouth and throat was red but without sera or haemorrhages. Dryness of the mouth was noted about 1 day after the accident, but no swellings of the salivary glands were noted on examination. Serum amylase analyses were not performed. Over the next 4 days he had persistent nausea and increasing oral mucositis. Microbiological investigation showed concomitant infection with candida in the mouth, and he was treated with crystal violet and topical amphotericin. The abovementioned conjunctival and corneal reactions subsided.

After a week, haematological values were markedly reduced, with only 600 leukocytes, 20% of which were lymphocytes, and the platelet count fell to 60 000 (Figure 1). Excluding the initial short rise, the temperature remained around 37.3°C. On day 8, however, he developed tachycardia and his temperature rose to 39.6°C. Over the following days, the temperature rose further to 40.0°C (Figure 1). He was treated with penicillin and gentamycin in dosages as for septicaemia, as well as partial intestinal decontamination with neomycin, nalidixic acid and nystatin. Bacteriological cultures showed Staphylococcus epidermidis in the mouth and nose, but blood cultures were persistently negative. The stools were loose but no real diarrhoea evolved. Serum bilirubin varied between 32 µmol l^–1 and 39 µmol l^–1.

View larger version (20K): [in this window] [in a new window]   Figure 1. Blood cell levels and temperature in the patient following the radiation accident.

Based on the exposure rate in the irradiation room, a dose level of approximately 5–6 Gy was initially assumed. However, electron spin resonance (ESR) investigations of nitroglycerin tablets in his front trouser pocket showed a dose of approximately 40 Gy [5]. Large lymphocyte chromosome aberrations indicated a dose in the saturation range for this system [7, 9], i.e. above 10 Gy, and the skewed distribution indicated dose inhomogeneities. The prompt nausea, vomiting and transient fever indicated a high dose, whereas the distribution of the initial erythema and skin reactions described at autopsy, and the lack of more pronounced diarrhoea, strongly indicated dose inhomogeneities. The higher dose on the upper half of the body may indicate that the patient has bent over the source and held his left hand somewhat behind (ESR dose estimate of 15 Gy from synthetic rubies in his wrist watch). A discussion of the dosimetry is given in previous reports [5, 10].

	Autopsy

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At autopsy, there was erythema on the front of the thorax and on both shoulders, with epidermal desquamation, most extensive on the right side. There were early signs of hair loss and the conjunctivae were red bilaterally. Oral and perioral white incrustations were found, probably partly due to Candida infection.

The entire gastrointestinal tract showed desquamated epithelium. Desquamation of the mucosa could not unequivocally be related to irradiation necroses, since some autolysis may have occurred. Microscopically, the desquamation was nearly total except in the large intestine, but there the mucosal epithelium was also lacking. Occasional leukocytes were seen, mainly plasma cells, most frequently in the large intestine. Microscopy of the submandibular gland showed reduced parenchyma, but preserved ductuli and collecting tubes. There were few leukocytes, mainly resembling plasma cells.

In the airways the bronchial mucosa was pale and partly desquamated, as well as the trachea and larynx. Microscopically, there were very few leukocytes, mainly plasma cells. The lungs showed slight oedema, dilated vessels and some fresh thrombi. The heart showed coronary arteriosclerosis with an old, but no recent, myocardial infarction.

The kidneys were enlarged, with a total weight of 430 g. The surface was speckled with red, grey and pale areas. On section, the cortex was oedematous and 1.3 cm thick with small haemorrhages. The glomeruli were normal but the distal tubules contained hyaline eosinophilic casts. The ureters were open, but the urothelium was red, with early desquamation. More pronounced desquamation was found in the bladder. The small number of leukocytes present were mainly plasma cells.

The lymph nodes were few, small and cell deficient. There were some lymphocytes but they were mainly plasma cells and some macrophages. The spleen was enlarged to 420 g and was nearly black and congested. The architecture was preserved and had remnants of follicles. In these were some lymphocytes, mainly plasma cells. Bone marrow from the spine was grey and cell deficient. Some megakaryocytes were seen. The bone marrow of the femur had the same appearance.

The brain was apparently normal and without oedema, apart from the adenohypophysis, which showed marked epithelial reduction with empty sinusoids and a spongy appearance. The neurohypophysis was also partly spongy. The thyroid gland and the pancreas were apparently normal. The testes were of normal size but soft and showed absence of spermatogenesis.

	Discussion

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In several radiation accidents with ARS there appears to be some similarities to MOF seen after surgical and/or infectious trauma [2]. According to the literature, these similarities have been partly overlooked compared with the extensive work on classification into the classical subtypes of ARS of haematopoietic syndrome, gastrointestinal syndrome, etc. In many instances, such subclassification does not really fit with the clinical picture encountered. In general, the present case fits with the description of a haematopoietic syndrome. There are, however, discrepancies, including death under a scenario resembling MOF. The symptoms, signs and findings may be discussed according to the main organ systems involved and their relative contribution to the clinical situation. Scoring systems of the clinical picture of multiple organ dysfunction (MOD) have been proposed, e.g. that of Marshall et al [11] based on the worst registered value. MOD must be assumed to represent the situation progressing directly to the failing situation of MOF. This scoring system includes a scoring from 0 (least severe) to 4 (most severe) for reactions in the haematopoietic system, the cardiovascular system, the respiratory system, the renal system, the gastrointestinal and hepatic systems, and the nervous system. The Chernobyl accident brought attention to involvement of the skin as a serious component of irradiation damage, but skin was not included in that scoring system.

Haematopoietic system
The clinical course of a manifest haematological syndrome with leukopenia and thrombocytopenia was more or less characteristic. The post-mortem examination showed marked cell depletion of the bone marrow, with mainly plasma cells remaining, as often seen after intensive chemotherapy for haematological malignancies. The lymph nodes and spleen were also affected, with mostly plasma cells remaining. Some older data indicate that plasma cells may tolerate radiation better than other lymphocyte subtypes [12]. The plasma cell frequency in this case was so striking that a subclinical myelomatosis might have been suspected. However, a bone marrow smear on day 1 after the accident showed a normal plasma cell percentage, which makes this diagnosis highly unlikely. If classified according to the MOD score system, a reaction grade 4 was found owing to the low platelet count.

Cardiovascular system
The patient initially complained of chest pain resembling that of acute myocardial infarction. These symptoms may have evolved due to his autopsy-proven coronary arteriosclerosis if a transient radiation-induced hypotension had occurred [13]. The significance of the electrocardiographic hypoxaemia on admission was rather dubious, and the blood pressure was not particularly low at that time. For a short period after admission he had a low blood pressure, but no chest pain at that time. The MOD score system recommend the determination of pressure adjusted heart rate (PAR) based on right atrial (central venous) and mean arterial pressure. Central venous pressure was not registered, but neither blood pressure nor heart rate posed any serious clinical problems.

Respiratory system
Lung complications after accidental irradiation appear to be frequent but not very well studied [14]. A latent period between irradiation and the onset of early pneumonitis varies between 1 week to a few months, depending on dose. In the first days, hyperaemia, oedema and leukocyte infiltration predominate, progressing to increased secretion, endothelial sloughing, capillary thrombosis and bleeding. The data from the patient fit well with this description. Pulmonary complications are also significant contributors to early mortality after irradiation for bone marrow transplantation. However, the interpretation in relation to accidental irradiation is difficult, as these patients may also suffer from, for example, graft-versus-host reactions, and the correlation between mortality and irradiation may be weak [14–16]. Moreover, effects on even non-irradiated lung volumes in radiotherapy points to a complicated pathogenesis, probably with several cytokines being involved [14, 17].

In this patient, blood gas analyses were only performed once, probably because respiration did not pose a serious problem. In the experimental setting, severe interstitial changes do not necessarily involve ventilation to the same extent [18]. The pO₂/FIO₂ (which describes the ratio between measured oxygen tension in blood, pO₂, and the fraction of O₂ in the inhaled atmosphere, FIO₂ [11]) calculated from the clinical data is 304, consistent with grade 0 in the MOD score system.

Urinary/renal system
The terminal anuria was apparently not due to hypotension but to renal disturbances. Eosinophilic casts, oedema and bleeding were found. Following total body irradiation in conjunction with bone marrow transplantation, late nephropathy is a well known complication [19]. It should be noted that the patient was treated with gentamycin, a potentially nephrotoxic drug, which may interact with a radiation-induced nephropathy. In the experimental setting, however, gentamycin, in contrast to busulfan, does not seem to interact with total body irradiation at radiation doses relevant for marrow transplantation [20]. However, possible interactions between tubular and interstitial autocrine and paracrine functions [19], and the large number of drugs given to this patient, cannot be excluded. It may be that a very high radiation dose can precipitate an earlier and more severe effect than dose ranges used for bone marrow transplantation. The serum creatinine rose to 250 µmol l^–1 the day before death, and to 416 µmol l^–1 on the last day, qualifying for grade 3 in the MOD score system.

Gastrointestinal and hepatic systems
The modest gastrointestinal symptoms are difficult to reconcile with the common description of ARS in the dose range of 10–20 Gy, where a gastrointestinal death should have been expected [1]. The patient received intensive symptomatic treatment with intravenous fluid and electrolytes under close laboratory control. He also received numerous transfusions with blood cell concentrates, and the partial intestinal decontamination and other antibiotics may have had some beneficial influence. At autopsy the mucosa was generally denuded, probably owing to clonogenic depletion, but other pathophysiological changes, e.g. of the microvasculature [21] and processes involving thrombomodulin and proteases [22], may also have importance. Gastrointestinal dysfunction was excluded from the MOD score system because of the inherent difficulties in developing a reliable descriptor, although hepatic dysfunction was included [11]. Serum transaminases and serum albumin remained normal. Serum bilirubin, chosen as the MOD score descriptor, was only slightly elevated, giving a score of 1.

The nervous system
No real neurovascular syndrome was present [1], although the patient initially appeared disoriented. However, a more or less transient cerebral dysfunction may have occurred. The central nervous system showed no signs of oedema or other changes at autopsy, although the blood–brain barrier is known to be damaged by radiation [23], making the brain tissues susceptible to the abundance of drugs given in this case. The peculiar pituitary findings at autopsy may be seen as part of a cerebral effect. When treating brain lesions by external radiation or with a gamma-knife, late pituitary side effects, especially growth hormone deficiency, have been observed [24, 25]. In rat brain irradiation, Robinson et al [26] have shown that pituitary weight reduction is time- and dose-dependent. It may be that the high dose in this case depleted the pituitary cells after just 1 week. Comparison of whole brain irradiation with strict locally pituitary irradiation from ⁹⁰Y implants indicates that the effect may be more related to irradiation of the hypothalamus than the pituitary itself [27]. The pathogenesis of radiation-induced brain damage is not very well understood. In addition to the classical view of effects originating in the microvasculature and of glial damage and apoptosis, other tissue constituents and cytokine releases have been proposed [28, 29]. In this case, the prompt nausea, early vomiting and early rise in temperature indicated a high radiation dose, probably affecting the brain. The MOD score system recommend the use of "Glasgow Coma Score", but the patient was not evaluated with this instrument.

	Conclusion

Top Abstract Introduction Case report Autopsy Discussion Conclusion References

 
Evaluation from autopsy alone following irradiation accidents must be done with caution. Only one time point is registered; moreover, it cannot unequivocally be assumed that the person was completely healthy at the time of irradiation, and several findings may represent subclinical, or at least undetected, disease processes already present. Post-mortem autolysis may further complicate the assessment. The autopsy findings must therefore be seen in conjunction with the clinical data.

If the single cell/organ compartment description of ARS must be replaced by identification of an overall mechanism common to all organs, several system candidates exists. The microvasculature is a ubiquitous organ system having a major role in the pathogenesis of radiation damage, and acute vascular changes including endothelial cell swelling, increased vascular permeability and oedema have been observed as early as 24 h after radiation exposure [30]. Second, a generalised imbalance between pro-inflammatory and anti-inflammatory responses leading to "non-infectious sepsis" is a strong candidate [2, 31]. Clinically, this case had a sepsis-like appearance but with negative blood cultures. One might speculate whether immunoglobulins produced by the plasma cells found in most of the organ systems in this case may have contributed to this imbalance, but so far it is not possible to draw any conclusion regarding a generalised immunological factor. Third, one may speculate that all other major regulatory organ systems such as the central nervous system, the cardiovascular system and/or the hormonal systems may be considered as common pathway factors of the pathophysiology. Standard post-mortem findings, exclusively based on light microscopic morphology, can only identify the organ(s) affected. It can be expected that new molecular techniques currently under development for analysis of tissue specimens may contribute to a new understanding of the underlying pathophysiological mechanisms of ARS.

The clinical features of the case show many similarities to the MOF syndrome. Data are not available to make a full MOD score according to the proposal of Marshall et al [11]. A high MOD score describes only an increased risk of death, and patients may pass away even with low scores. Some of the scores for this patient may indicate a low risk, but there were high scores in selected parameters. The characteristics were mainly in accordance with Young's [1] description of a haematopoietic syndrome after total body irradiation of more than 10 Gy. It may therefore be discussed whether a full-blown ARS syndrome is simply one way of developing MOF, or whether there are certain peculiarities distinguishing ARS from MOF. The data on the present patient do not allow any conclusion to this question.

	References

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