Materials for classes study № 2 ACUTE AND CHRONIC RADIATION DISEASE
Victims of acute radiation events in radiological and nuclear incidents require prompt diagnosis and treatment of medical and surgical conditions as well as of conditions related to possible radiation exposure. Emergency personnel should triage victims using traditional military medical and trauma criteria. Radiation dose can be estimated early following the event using rapid-sort, automated biodosimetry and clinical parameters, such as the clinical history and timing of symptom complexes, the time to emesis (TE), lymphocyte depletion kinetics, and various multiparameter biochemical tests. Acute high-level radiation exposure should generally be treated as a case involving multiorgan failure (MOF). Various radiation severity grading schemes are currently used by the medical community.
Radiation-induced multiorgan dysfunction (MOD) and MOF refer to progressive dysfunction of two or more organ systems, the etiological agent being radiation damage to cells and tissues over time. Radiation-associated MOD appears to develop in part as a consequence of the systemic inflammatory response syndrome and in part as a consequence of radiation-induced loss of vital organs’ functional cell mass. A worldwide consensus conference considering many different historical radiation accidents has recently addressed radiation-related MOD and MOF. Besides providing modern guidance to medically managing radiation-induced MOF, the conference proceedings are also a comprehensive educational resource for the physician likely to be involved in managing patients in a radiation incident.
As a resource to physicians, the Strategic National Stockpile Radiation Working Group and other working groups have recently issued recommendations on medically managing acute radiation syndrome (ARS). ARS has been an important part of radiation medicine for many years and the basic pathophysiology and treatment protocols are summarized in various textbooks. In addition, the Radiation Emergency Assistance Center/Training Site, a medical asset of the US Department of Energy, sponsors periodic symposia and short courses on the medical management of radiation accidents.35“38 Likewise, the Armed Forces Radiobiology Research Institute (AFRRI) provides the Medical Effects of Ionizing Radiation course for military and ancillary personnel and has long been a guiding influence in developing improved treatment methods for ARS.
Radiation sensitivity data on humans and animals has made it possible to describe the symptoms associated with ARS. ARS results from high-level external
exposure to ionizing radiation, either of the whole body or a significant portion (> 60%) of it. For this purpose, “high-level” means a dose greater than 1 Gy delivered at a relatively high dose rate. From a physiological standpoint, ARS is a combination of syndromes. These syndromes appear in stages and are directly related to the level of radiation received. They begin to occur within hours after exposure and may last for several weeks. ARS includes a subclinical phase (< 1 Gy) and three syndromes resulting from either whole-body irradiation or irradiation to a significant fraction of the body: hematopoietic syndrome (approximately 1-8 Gy), gastrointestinal syndrome (approximately 6-20+ Gy), and neurovascular syndrome (20-50+ Gy).
Radiation accidents have historically fallen into certain major categories, including low-dose incidents in which the patient shows essentially no signs or symptoms; higher dose, acute whole- or partial-body incidents with significant systemic signs and symptoms associated with ARS and often MOF; local radiation injury arising primarily from lost radiation sources and involving a regional portion of the body, often the hands; and inhalation or ingestion of radioactive material, often without systemic signs and symptoms. In a tactical event, it is possible to have ARS from exposure to a lost or stolen source, from an improvised nuclear weapon, or from inhalation or ingestion of radioactive material. However, the latter is expected to be rare. This chapter will focus on evaluation and management of ARS, regardless of the etiology of the event, although high-level external radiation dose will most likely be the etiology. From a medical viewpoint, patient mortality from radiation exposure is generally associated with a high-level gamma or neutron dose delivered over a short period of time.
Goans has provided an analysis of the recent history of radiation medicine that shows many cases of delayed diagnosis, even with the presentation of classical symptoms. In a review of four recent major gamma radiation incidents involving lost high-level gamma sources (Goiania, Brazil [September 1987]; Tammiku, Estonia [October 1994]; Bangkok, Thailand [February 2000]; and Meet Halfa, Egypt [May 2000]), the average time from beginning of the accident until definitive diagnosis averaged 22 days. However, in the severe criticality event in
Radiation incidents will be seen by physicians in a dichotomous fashion: either soon after the event or 2
to 4 weeks or more later (as in the case of lost sources found in the public domain or stolen covertly), when the patient becomes ill secondary to radiation-induced
neutropenia or pancytopenia. The clinical presentation of the externally irradiated patient will be much different in these two scenarios.
PATHOPHYSIOLOGY
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The etiology of organ damage from high-level radiation exposure results from the radiosensitivity of certain cell lines. Cell radiosensitivity in various tissue systems is the basis for the distinction among the three acute radiation syndromes, as described below. Specifically, cells are radiosensitive if they replicate rapidly, are immature (eg, blast cells), and have a long mitotic future (law of Bergonie and Tribondeau). For example, spermatogonia, lymphocytes, blast cells (various types), other hematopoietic cells, and cells of the small intestine, stomach, colon, epithelium, and skin are radiosensitive, while cells of the central nervous system, muscle, bone, and collagen are much less sensitive. In addition, more highly differentiated cells are less radiosensitive. Lymphocytes are an exception to the law of Bergonie and Tribondeau because they have a long life span, but they do have a very large nucleus, encompassing almost all of the cytoplasm, thereby producing an excellent target for radiation damage.
In radiation medicine, ARS is classically divided into hematopoietic, gastrointestinal, and neurovascular syndromes, each with increasing dose, although there is some overlap, particularly within the first two. Each of these syndromes has been further divided into four clinical stages: prodromal, latent, manifest illness, and recovery or death. Prodromal symptoms begin a few hours after exposure and the time of onset is generally related to the severity of dose and dose rate. During the latent period, the patient may appear relatively clinically normal and generally symptom free. In the hematopoietic syndrome, during the period of manifest illness, significant issues to address are neutropenia and possibly pancytopenia. Therefore, medical treatment during the first 6 weeks after exposure to approximately 2 to 6 Gy is focused toward managing pancytopenia, controlling infection, and managing possible MOF in places other than the hematological system.
Hematopoietic Syndrome
Hematopoietic syndrome occurs after whole-body or significant partial-body irradiation of greater than 1 Gy delivered to the bone marrow. The radiosensitive cells of the hematopoietic tissue are the various lineages of stem cells. Their anatomical location in the bone marrow distributes them throughout the body. A
dose-dependent suppression of bone marrow at doses greater than 2 to 3 Gy leads to eventual neutropenia and possibly pancytopenia. Prompt radiation dose (within minutes to an hour) of approximately 3 to 8 Gy will cause significant damage to the bone marrow. A dose of approximately 3 to 4 Gy may result in death to 50% of exposed individuals without significant medical support. Radiation exposure causes the exponential biological death of bone-marrow stem and progenitor cells. If it is possible in tactical situations, shielding is the best method to protect bone marrow.
Prodromal symptoms after high-level radiation exposure often last for 1 to 3 days and include nausea, emesis, anorexia, and diarrhea. Generally, the earlier the onset of nausea and emesis, the higher the dose, if one excludes the possibility of psychogenic emesis. An approximate dose dependence for nausea and emesis was compiled from prior, unpublished research at Oak Ridge Associated Universities in the 1970s in conjunction with the
The prodromal symptoms are followed by 2 to 3 Percent of Patients Who Vomit After Exposure
ORAU Low-Dose Experiments
■Nausea
■Emesis
ED50 = 1.58 Gy
ED50 = 2.40 Gy
Dose (Gy)
Figure 2-1. Incidence of nausea and emesis as a function of dose. Research performed at Oak Ridge Associated Universities for the National Aeronautics and Space Administration. Adapted with permission from
Medical Consequences of Radiological and Nuclear Weapons
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weeks of latency, during which the patient will suffer from significant fatigue and weakness. The clinical symptoms of manifest illness appear approximately 21 to 30 days after exposure and may last up to 2 weeks. Sepsis associated with pancytopenia from bone-marrow suppression and severe hemorrhage from platelet loss are often the lethal factors in hematopoietic subsyndrome. Platelet counts of fewer than 20,000/ mm3, moderately decreased erythrocyte counts, and severely suppressed neutrophil counts (fewer than 500/mm3) may also be seen. The treating physician will consequently be required to use current medical therapy for severe neutropenia in the setting of МОЕ Clinical hematological profiles over the period of manifest illness generally follow a course similar to that shown in Figure 2-2. There is a progressive decrease in lymphocytes, neutrophils, and platelets with increasing radiation dose. From traditional medical guidance, a 30% to 50% decrease of absolute lymphocytes within the first 24 hours is suggestive of serious and potentially lethal injury. More recently developed guidelines have been presented for early determination of the severity of radiation injury using both hematological kinetics and the appearance and severity of various clinical symptoms. Subpopulations of selectively radioresistant stem cells or accessory cells often exist and play an important role in hematologic reconstitution. Moreover, the radiation exposure is often inhomogeneous. The patient’s physical environment and distance from the source may afford
Figure 2-2. Cellular kinetics for the hematopoietic syndrome as a function of days following irradiation. Graphic courtesy of the US Armed Forces Radiobiology Research Institute.
partial shielding, accounting for dose variability, and this may result in areas of viable hematopoietic stem cells. Such a reservoir of stem cells may contribute to the future reestablishment of hematopoiesis.
The onset of radiation-induced cytopenia is variable and dose dependent. Granulocytes may experience a transient rise prior to decrease in patients exposed to less than 5 Gy. The transient increase prior to decline is termed an “abortive” rise, a finding that may be clinically helpful because it may indicate a more sur-vivable exposure. The time to onset and duration of the nadir are variable. Indeed, the nadir may not occur for 3 to 4 weeks, particularly at lower doses. The duration of neutropenia is often extensive, requiring prolonged administration of hematopoietic growth factors, blood product support, and antibiotics. Patients with burns or wounds also experience poor wound healing, bleeding, and infection because of hematopoietic suppression. Impaired wound healing may be due in part to radiation-induced endothelial damage, which significantly depresses the revascularization of injured tissue.
Gastrointestinal Syndrome
Gastrointestinal syndrome and hematopoietic syndrome occur simultaneously at high radiation doses, beginning at 6 to 8 Gy. Consequences of gastrointestinal syndrome are more immediate and less amenable to treatment. The prodromal stage includes severe nausea, vomiting, watery diarrhea, and cramps occurring within hours after irradiation. At higher doses, bloody diarrhea, hypovolemia, shock, and death may ensue. At radiation doses above 10 to 12 Gy, patients will die sooner than if they just had hematopoietic syndrome. In a mass casualty event, these patients will likely be triaged expectant.
From a pathology viewpoint, the intestinal mucosa experiences severe radiation-induced damage following high-dose exposure. A shorter latent period is observed clinically because of the observed turnover time of 3 to 5 days for intestinal mucosal epithelial cells. Damaged crypt stem cells do not divide and therefore the damaged mucosal lining is shed and not replaced. The ability to absorb food is greatly reduced because of the disrupted mucosal lining and because of vascular coalescence. The damage to the mucosal lining also provides a portal for intestinal flora to enter the systemic circulation and serve as a nidus for sepsis. In addition, severe mucosal hemorrhage has been seen in experimental animal models. The overall intestinal pathology includes disturbance of absorption and secretion, glycocalyx disruption, mucosal ulceration, alteration of enteric flora, depletion of gut lymphoid
tissue, and motility disturbances.
Medical issues associated with the gastrointestinal syndrome include malnutrition resulting from mal-absorption, emesis, ileus, dehydration, possible acute renal failure, and cardiovascular collapse resulting from shifts in fluids and electrolytes. It is also possible to observe anemia from prolonged gastrointestinal bleeding and sepsis resulting from entry of bacteria into the systemic system via the damaged endothelial lining.
Neurovascular Syndrome
Neurovascular syndrome is less well defined than the others. Generally, patients with this syndrome have experienced a lethal dose over 30 Gy, but there is relatively little clinical experience at these doses for human exposure and the mechanism of death is unclear. Cardiovascular shock accompanies such high doses, resulting in a massive loss of serum and electrolytes through leakage into extravascular tissues. The ensuing circulatory problems of edema, increased intracranial pressure, and cerebral anoxia can bring death within 2 days.
The prodromal stages of the neurovascular syndrome are compressed. The patient may experience a burning sensation occurring within minutes; nausea
and vomiting within 1 hour; and confusion, prostration, and loss of balance (ataxia). During the latent period, apparent improvement for a few hours is likely to be followed by severe manifest illness. Within 5 to 6 hours, the overt clinical picture proceeds with the return of severe watery diarrhea, respiratory distress, and gross central nervous system signs. MOF is the final common pathway in the neurovascular syndrome.
The histopathology of the neurovascular syndrome appears to be due to massive endothelial damage in the microcirculation. This has been postulated as a causative mechanism in the damage of some organs. Preliminary experimental evidence indicates that the cause of initial hypotension may be an early, overwhelming surge of histamine released from de-granulated mast cells.34 The radiation threshold for the neurovascular symptom complex is not well defined. Experimental evidence in animals and in a few human radiation accidents indicates that 30 to 50 Gy will elicit the neurovascular syndrome and all doses in this range will eventually cause a lethal outcome.
The natural history of ARS shows that the time to death in an untreated patient is approximately 20 to 30 days in a severe hematopoietic case, 8 to 14 days in a patient with gastrointestinal syndrome, and 1 to 3 days with neurovascular syndrome.
DETERMINANTS OF RADIATION EFFECTS ON HUMANS
Radiation Lethality Curve
The slope of a radiation lethality curve is weighted heavily by data at each extreme of its distribution.34,52 This fact underscores the importance of reliable do-simetry, not only in the experimental situation but also in accurately determining the human exposure after a nuclear incident. In spite of the heterogeneity surrounding LD50 values, it is possible to conclude that the doses giving between 90% and 95% mortality in most animal experiments are about twice those giving 5% to 10% mortality. In a recent review of animal data, a uniform dose (D) normalized to the LD50 (D/ LD50) revealed that no deaths occurred when D/LD50 was less than 0.54. When D / LD50 was greater than 1.3, mortality was 100%. Therefore, total survival in a population can apparently be changed to total mortality by increasing the radiation dose by a factor of approximately 2.4. Relationships between dose and lethality, drawn from a large number of animal studies, emphasize two important points on extrapolation to the human radiation response: reliable dosimetry is extremely valuable, and either therapy or trauma can significantly shift the dose-response relationship. An
error in dosimetry of 0.5 to 1 Gy can result in large shifts along the dose-response curve, and effective therapy can increase the LD50 by 1 Gy or more. Radiation lethality appears to be a consequence of changes in the cellular kinetics of renewal systems critical for survival.
Factors such as trauma, stress, and poor nutritional status that compromise or damage the hematopoietic system or the immune system negatively affect the dose-response curve.
The goal of modern medical management of ARS is to shift the mortality curve to the right, which will result in saving more lives. This can be accomplished by good medical and nursing care, intravenous (IV) hydration, antibiotic coverage (as indicated), early use of cytokine growth factors, and possibly the use of stem cell transplants in the higher dose ranges (> 6-8 Gy).
Influence of Trauma on LD 50
A recent consensus committee has examined modern scientific aspects of combined injury (radiation plus burns or trauma).86 The combination of radiation exposure and trauma produces a clinical dilemma not encountered by most military and civilian physicians.
Medical Consequences of Radiological and Nuclear Weapons
In combined injury, two (or more) injuries that are sublethal or minimally lethal when occurring alone will act synergistically with radiation injury, resulting in much greater mortality than the simple sum of what all injuries would have produced.
Human radiation exposure events, such as the
The mechanisms responsible for combined injury sequelae are unknown, but they can significantly increase the consequences of radiation exposure across the entire dose-response curve. It must be emphasized that the survival of a patient following exposure in the hematopoietic dose range requires the following: (a) a minimum critical number of surviving stem cells to regenerate a competent host defense system, (b) the functional competence of surviving cells composing the specific and nonspecific immune system, or (c) effective replacement or substitution therapy during the critical postexposure cytopenic phase. Trauma alone, depending on its intensity, may also effectively depress host resistance to infection.
When trauma is imposed on a physiological system with even mild radiation injury, the outcome can be lethal. In most instances, trauma symptoms will either mask or exacerbate the first reliable signs of radiation injury. This will cloud the situation if one is relying on prodromal symptoms to estimate dose. In addition, the choice of treatment in these cases should include consideration of not only the patient’s initial status, but also the condition that will exist 7 to 21 days later, when the radiation effects are seen. An open skin wound (combined injury) markedly increases the chances of infection. Therefore, immediate wound closure has been recommended. Injuries to the abdomen may also present significant problems to the irradiated subject. Blast overpressure, blunt trauma, and penetrating trauma are all significant causes of abdominal injury in a tactical situation.
Effect of Clinical Support on the LD50 Dose Effect Curve
Modification of survival throughout the LD50 dose range is achievable using a simple regimen of clinical support to replace or substitute the depleted functional cells after stem cell destruction. Experimental work over the last 20 years showed the efficacy of supportive care centered on systemic antibiotics and transfusions of fresh platelets. Several canine studies indicated that antibiotics, individually or in combination, were successful in reducing mortality in the LD50 range. Combination antibiotics, in conjunction with fresh whole-blood transfusions and parenteral fluids, have been effective in controlling dehydration and thereby reducing mortality. These studies have been extended over a dose range that can determine the significant shift in LD50 that results from treatment. It must be emphasized that the practical application of these concepts requires that the damage to the stem cell system be reversible; that is, the surviving fraction of hematopoietic stem cells must be capable of spontaneous regeneration. Carefully controlled experiments clearly indicate that supportive treatment will elevate the estimate of the LD50 by as much as 30%. Based on the range of values discussed, the recommended value for the LD50 is approximately 3.6 to 3.9 Gy, but a mild dose-rate dependence has been demonstrated.
CLINICAL ASPECTS OF THE
Only a small number of radiation accidents in the
Two criticality events occurred with the same 6.2-kg, delta-phase plutonium sphere at Los Alamos National Laboratory in
Figure 2-3.
Reproduced with permission from Hempelmann LH, Lisco H, Hoffman JG. The acute radiation syndrome: a study of nine cases and a review of the problem. Ann Intern Med. 1952;36:279-510 (Plate XVIII). an average whole-body dose of approximately 5.1 Gy neutrons and gammas and a dose to the right hand of approximately 100 to 400 Gy. The patient died of sepsis 24 days later (Figure 2-3).
The second criticality accident occurred in 1946 during an approach-to-criticality demonstration at which several observers were present. The operator used a screwdriver as a lever to lower a hemispherical beryllium shell reflector into place. While holding the top shell with his left thumb in an opening at the spherical pole, the screwdriver slipped and caused a critical configuration. The operator received an estimated acute whole-body dose of approximately 21 Gy, with a dose to the left hand of 150 Gy and somewhat less to the right hand. Seven observers were exposed in the range of 0.27 to 3.6 Gy. The operator died 9 days later.A third
first neutron spike. The system was driven permanently subcritical by mixing the two layers. This accident resulted in the death of the operator 36 hours after the accident. The dose to the upper extremity is estimated to have been 120 Gy, plus or minus 50%. Two other persons received acute doses of 1.34 Gy and 0.53 Gy. The last fatal
Clinical Course of the Criticality Cases Radiation histopathology is an important adjunct to the clinical aspects of radiation medicine and has been examined by various authors.
Case Study 2-1: Los Alamos Plutonium Sphere (hema-topoietic syndrome; cutaneous radiation injury syndrome; whole-body dose approximately 5.1 Gy; dose to right hand 10CM-00 Gy). The patient was a 26-year-old male whose past
Figure 2-4. Wood River Junction,
Reproduced with permission from Karas JS, Stanbury JB. Fatal radiation syndrome from an accidental nuclear excursion. N Engl J Med. 1965;272:755-761. Article DOI:10.1056/ NEJM196504152721501.
Medical Consequences of Radiological and Nuclear Weapons
medical history was significant only for Wolff-Parkinson-White syndrome diagnosed 3 years prior to the incident. On admission to the hospital, his vital signs were withiormal limits and his only initial complaint was numbness and tingling of both hands. The initial physical examination was also withiormal limits.
Within 30 minutes after the accident, the patient’s right hand had become diffusely swollen. Emesis began approximately 1.5 hours after the event, and nausea continued intermittently for the next 24 hours. The patient experienced subjective improvement but had a mild temperature, mild gastric distress, and weakness during days 3 to 6. By day 5, the patient experienced a distinct rise in temperature with tachycardia and began to appear increasingly toxic. On day 10, he developed severe stomatitis, a paralytic ileus, and diarrhea. Clinical signs of pericarditis were noted on day 17, and the patient’s mental status became irrational. The clinical course is notable for progressive pancytopenia.
Within 36 hours after the accident, blisters were noted on the volar aspect of the right third finger, and within 24 hours thereafter, extensive blistering was noted on both palmar and volar surfaces of the hand. A decision was made on day 3 to surgically drain the blisters, but by the third week the right hand had progressed to a dry gangrene. Desquamation of the epidermis involved almost all of the skin of the dorsum of the forearm and hand. In addition, epilation was almost complete at the time of death. On day 24, the patient’s temperature had risen to
teria (Figure 2-5) and lymph nodes also showed significant lymphocyte depletion. The testes demonstrated significant atrophy with aspermia. A solitary ulcer was noted in the large colon, as was a right renal infarct.
Case Study 2-2: Los Alamos Plutonium Sphere (gastrointestinal syndrome; cutaneous radiation injury syndrome; acute dose approximately 21 Gy; dose to the left hand 150 Gy). The patient was a 32-year-old male, admitted to the hospital within 1 hour after the accident. His medical history is generally unremarkable. His occupational history is significant only for several prior, generally chronic occupational exposures, none exceeding 0.005 Gy in a week. The patient complained of nausea in the hour prior to admission and vomited once in that time.
The general condition of the patient was quite good in the first 5 days following the accident. On the fifth day, there was a precipitous drop in his leukocyte count, and his condition began to decline rapidly. The patient rapidly lost weight, became mentally confused on day 7, became comatose, and died in cardiovascular shock on the ninth day.
Medical therapy during the 9-day course was largely symptomatic. Penicillin was given (50,000 U every 3 hours intramuscularly) beginning on day 5 because of granulocy-topenia. Blood transfusions were also given daily after the fifth day. On day 6, fever and tachycardia developed, and on the seventh day, the patient developed a severe paralytic ileus. At the time of death, both hands showed extensive radiation damage. On autopsy, examination of the skin was remarkable for early vesicle formation in the abdominal skin and marked epidermal damage. The cardiorespiratory system was remarkable for cardiac hemorrhage and myocardial edema, and the terminal bronchi showed features of aspiration pneumonia. The spleen exhibited no germinal centers and mucosa of most of the gastrointestinal tract showed atrophy and sloughing, most pronounced in the jejunum and ileum (Figure 2-6). Widespread degenerative changes were noted in the adrenal cortex as well as hyaline degeneration in the
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Figure 2-5. Hypocellular marrow with bacteria present centrally (hematopoietic syndrome). Slide courtesy of the US Department of Energy.
Figure 2-6. Intestinal specimen illustrating villous atrophy, congestion, and hemorrhage (gastrointestinal syndrome). Slide courtesy of the US Department of Energy.
Figure 2-7. Neurovascular syndrome with brain peri vascular
edema (Virchow-Robins space).
Slide courtesy of the US Department of Energy. renal tubular epithelium. Examination of the red bone marrow showed it to be of liquid consistency.
Case Study 2-3: Los Alamos Liquid Criticality Event (central nervous system syndrome; dose to the upper extremity 120 Gy ± 50%). The patient was a 50-year-old male with no significant past medical history. The clinical course has been divided into four separate phases. Phase 1 (20-30 min after the event) included immediate physical collapse and mental incapacitation, progressing eventually into semiconscious-ness. Phase 2 (90 min after the event) consisted of signs and symptoms of cardiovascular shock accompanied by severe abdominal pain. Phase 3 (4 h after the event) included subjective minimal clinical improvement. Phase 4 (28 h after the event) was characterized by rapidly appearing irritability and mania, progressing to coma and death. The clinical course was remarkable for continuing, profound hypotension; tachycardia; and intense dermal and conjunctival hyperemia. The patient died 35 hours after exposure. On autopsy, examination of the bone marrow was most significant for absence of mitotic activity. The lungs showed pyknotic, degenerating cells in the pleura, degenerating
lymphocytes and neutrophils in the subpleural connective tissue, and many areas of focal atelectasis interspersed with foci of emphysema. All lymph nodes were markedly atrophic and lymphoid follicles in the spleen were greatly depleted. Examination of the heart showed acute myocarditis, myocardial edema, cardiac hypertrophy, and a fibrinous pericarditis. Examination of the brain demonstrated cerebral edema, diffuse vasculitis, and cerebral hemorrhage. The gastrointestinal system showed necrosis of the anterior gastric wall parietal cells, acute upper jejunal distention, mitotic suppression throughout the entire gastrointestinal tract, and acute jejunal and ileal enteritis.
Case Study 2-4: Wood River Junction (neurovascular syndrome; approximately 100 Gy). The patient was a 38-year-old male with a negative medical history. Following the initial criticality excursion, the patient appeared stunned, ran from the building, and immediately vomited. He also experienced immediate diarrhea and complained of severe abdominal cramping, headache, thirst, and profuse perspiration. His initial vital signs showed borderline blood-pressure elevation and tachycardia. Approximately 4 hours after the accident, the patient experienced transient difficulty in speaking, hypotension, and tachycardia. A portable chest radiograph 16 hours after admission showed hilar congestion. The physical examination also showed the left hand and forearm to be edematous, as well as left-sided conjunctivitis and periorbital edema. On day 2, the patient became disoriented, hypotensive, and anuric. The patient died 49 hours after the accident in cardiovascular shock.
At autopsy, interstitial edema of the left hand, arm, and abdominal wall was noted. Examination of the heart, lungs, and abdominal cavity revealed acute pulmonary edema, bilateral hydrothorax, hydropericardium, abdominal ascites, acute pericarditis, interstitial myocarditis, and inflammation of the ascending aorta. Examination of the gastrointestinal tract showed severe subserosal edema of the stomach and of the transverse and descending colon. The bone marrow was noted to be aplastic, and lymph nodes, spleen, and thymus were depleted of lymphocytes. The brain showed minimal change, with rare foci of microglial change and perivascular edema (Figure 2-7). The testes also showed interstitial edema and overt necrosis of the spermatogonia.
CURRENT TREATMENT OF ACUTE RADIATION SYNDROME
Radiation damage results from the inherent sensitivity of certain cell types to radiation, with the most undifferentiated and mitotically active cells being the most sensitive to acute effects. The inherent sensitivity of these cells results in a constellation of clinical syndromes that occur with radiation exposure. The clinical components of ARS include hematopoietic, gastrointestinal, and neurovascular syndromes and are reviewed above. The medical management of patients with acute, moderate to severe radiation exposure (effective whole-body dose > 3 Gy) should emphasize early initiation of colony-stimulating factor (CSF),
transfusion support as needed, antibiotic prophylaxis, and treatment of febrile neutropenia. Additional supportive medications may include antiemet-ics, antidiarrheals, fluid and electrolyte replacement, and topical burn creams. In the case of coexisting trauma (combined injury), wound closure should be performed within 24 to 36 hours.The merits of modern supportive care lie in its significant prolongation of survival. The LD50/60 (the dose at which 50% of the exposed population will die within 60 days) is approximately 3.5 Gy in persons managed without supportive care. The LD50/60may be
Medical Consequences of Radiological and Nuclear Weapons
increased to 4 to 5 Gy when antibiotics and transfusion support are provided. The lethal dose may also be somewhat higher with early initiation of CSFs. Casualties whose radiation doses are most amenable to treatment will be those who receive between 2 and 6 Gy. The primary goal of medical therapy is to shift the survival curve to the right by 2 Gy or more. Many casualties whose doses exceed 6 to 8 Gy will also have significant blast and thermal injuries that will preclude survival when combined with the radiation insult. If there is little to no trauma, some authorities would consider stem cell transplant (peripheral or cord blood) for victims in this dose range. Currently, the only hematopoietic CSFs that have marketing approval from the US Food and Drug Administration (FDA) for managing treatment-associated neutropenia are the recombinant forms of granulocyte-colony stimulating factor (G-CSF), granulocyte-mac-rophage-colony stimulating factor (GM-CSF), and the pegylated form of G-CSF. All have been explored and have some efficacy in irradiated preclinical models of radiation-induced marrow aplasia. The rationale for using CSFs in irradiated humans is derived from three sources: their enhancement of neutrophil recovery in oncology patients, their perceived benefit in a small number of radiation-accident victims, and several prospective trials in canines and nonhuman primates exposed to radiation.
The most convincing data, which provides the proof of principle, is the demonstration of not only enhanced neutrophil recovery, but more importantly a significant survival advantage ionhuman primates and canines if the CSF is given less than 24 hours after
irradiation (Figures 2-8 and 2-9) . However, there appears to be less efficacy with a delay in treatment, but the interval required before the survival advantage is lost is unknown. The current data strongly suggest that CSFs should be initiated as early as possible in those exposed to a survivable whole-body dose of radiation and who are at risk of the hematopoietic syndrome (> 3 Gy).These data collectively demonstrate that CSFs and extensive medical support may not only ameliorate radiation-induced neutropenia but also offer a survival advantage, especially if employed early. These data justify the treatment recommendations recently published by the Strategic National Stockpile Radiation Working Group.The following cytokines are choices available for patients expected to experience severe neutropenia:
• Filgrastim (G-CSF) 2.5-5 jUg/kg/d every day subcutaneously, or the equivalent (100-200
• Sargramostim (GM-CSF) 5-10 ]Ug/kg/d ev
ery day subcutaneously, or the equivalent
(200-400 ^g/m2/d)
• Pegfilgrastim (pegG-CSF) 6 mg once subcu
taneously
Treatment with CSFs for expected exposures greater than 2 Gy should begin within 2 days. CSFs have been associated with rare splenic rupture and, more commonly, bone pain. Allogeneic stem cell transplantation may have limited use due to severe morbidity and mortality associated with concurrent
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Canine Serum — G-CSF 10 цд/кд BID d1 -23 or G-CSF 10 цд/kg QD d1-23 or G-CSF5ng/kgQDd1-23 -*- G-CSF 5 цд/kg QD d10-23 or d9-23 — Severe Neutropenia |
300 400 500 600
Dose (cGy) i rhG- SF a rcSCF rcG-CSF A rcSCF + rcG-CSF Figure 2-8. Influence of clinical support and cytokine therapy
on canine mortality at 3.5 Gy. Graph courtesy of Dr Thomas MacVittie.
Various hospital issues are clinically important when managing patients who have sustained doses greater than 2 to 3 Gy, including:
• antibiotic prophylaxis, as well as antiviral and
antifungal agents;
• barrier isolation and gastrointestinal decontamination;
• early cytokine therapy;
• early surgical wound closure and avoidance of unnecessary invasive procedures;
• isolation rooms for ARS patients with whole-body doses greater than 2 to 3 Gy (medical personnel should also be aware of the need for rigorous environmental control, including potential laminar flow isolation, strict hand
washing, and surgical scrubs and masks for staff);
• physiological interventions, including main taining gastric acidity, avoiding antacids and H2 blockers, and using sucralfate for stress-ulcer prophylaxis, when indicated, to reduce gastric colonization and pneumonia (early oral enteral feeding is highly desirable when feasible); and povidone-iodine or chlorhexidine for skin disinfection and shampoo, as well as meticulous
oral hygiene.
Supportive Care
Transfusion of cellular components, such as packed red blood cells and platelets, is required for patients with severe bone-marrow damage and is an important component of clinical management. Fortunately, this complication does not typically occur for 2 to 4 weeks after the exposure unless losses from concur-
rent trauma are present. All cellular products must be leukoreduced and irradiated to 25 Gy. The latter prevents transfusion-associated graft-versus-host disease in immunosuppressed patients. Ionneutropenic patients, antibiotics should be directed toward the foci of infection and the most likely pathogens. For those who experience significant neu-tropenia (absolute neutrophil count < 500 cells/mm3), broad-spectrum prophylactic antimicrobials should be given during the potentially long duration of neutro-penia. Prophylaxis should include a fluoroquinolone (FQ), an antiviral agent (if indicated, as discussed below), and an antifungal agent. The justification for FQ prophylaxis includes preclinical and clinical studies demonstrating decreased infectious episodes in irradiated animals and neutropenic oncology patients, respectively. Streptococcal coverage with the addition of penicillin or amoxicillin should also be considered, if not inherently covered by the FQ, given the increased treatment failure observed due to this pathogen and the benefit demonstrated with expanded antistreptococcal coverage ieutropenic animals.13
Antimicrobials should be continued until the patient experiences a neutropenic fever and requires alternate coverage or experiences neutrophil recovery (absolute neutrophil count > 500 cells/mm3). In patients who experience fever first, traditionally the FQ is stopped and therapy is directed at gram-negative bacteria (in particular, Pseudomonas aeruginosa), as infections of this type may be rapidly lethal. Antipseudomonal coverage serves as the foundation antibiotic, and additional coverage is then added to address other foci of infection, such as mucosal or integument injury. Empiric therapy of patients with febrile neutropenia with or without a focus of infection should be guided by the current recommendations of the Infectious Diseases Society of America. Any focus of infection that develops during the neutropenic period will require a full course of therapy.
MEDICAL ISSUES IN PATIENT MANAGEMENT
ARS is seen to be a sequence of phased symptoms. It is characterized by the relatively rapid onset of nausea, vomiting, malaise, and anorexia. An early onset of prodromal symptoms in the absence of associated trauma suggests a large radiation exposure. The medical management of ARS has two primary goals: hematological support to reduce both the depth and duration of neutropenia, and prevention and management of neutropenic fever.
The onset and depth of neutropenia is directly determined by the severity of the accident. In order to gauge the severity of an incident, radiation dose
to a patient can be estimated early after the event using rapid-sort, automated biodosimetry and clinical parameters such as the onset of various clinical symptom complexes, TE, and lymphocyte depletion kinetics, and through combinations of various biochemical entities. No single technique is satisfactorily sensitive, but multiparameter techniques have been shown to have good predictive value. For external doses less than 1 Gy, the patient is generally asymptomatic and blood parameters will be within the normal range. Upon admission to
Medical Consequences of Radiological and Nuclear Weapons
emergency care following the incident, it is always appropriate to obtain a complete blood count with differential, either as a baseline level or as a beginning step for lymphocyte kinetic analysis. TE, measured from the irradiating event, generally decreases with increasing dose. For TE between 1 and 2 hours, the effective whole-body dose is likely at least 3 to 4 Gy. If TE is less than 1 hour, the whole-body dose likely exceeds 4 to 6 Gy. In a mass casualty tactical event, patients who experience emesis less than 4 hours after the accident should be triaged to professional medical care, while those with emesis after more than 4 hours can be instructed to receive delayed medical attention. Patients who experience radiation-induced emesis within 1 hour after a radiation incident will require extensive and prolonged medical intervention, and an ultimately fatal outcome will occur in many instances. Patient radiation dose and expected prognosis in a radiation event may be estimated from the medical history and timing of symptom complexes, serial lymphocyte counts, TE, and confirmatory chromosome-aberration cytogenetics. In addition, close collaboration with health physics experts is critical, since dose reconstruction personnel often have access to an array of sophisticated mathematical analysis techniques to estimate the dose field. The prodromal symptoms of nausea and emesis will be particularly troublesome to patients. The following dosages of selective 5-HT3 receptor antagonists are recommended for radiation-induced emesis:
• Ondansetron: initially 0.15 mg/kg IV; a con tinuous IV dose option consists of 8 mg fol lowed by 1 mg/h for the next 24 hours. Oral dose is 8 mg every 8 hours as needed.
• Granisetron (oral dosage form): dose is usually 1 mg initially, then repeated 12 hours after the first dose. Alternatively, 2 mg may be taken as one dose. IV dose is based on body weight; typically 10 jUg/kg (4.5 jUg/lb) of body weight.
The patient history, physical examination, and early estimate of the severity of the radiation incident may be rapidly analyzed, using multiple clinical and dosimet-ric parameters, into a clinically meaningful estimate of radiation exposure using the AFRRI Biodosimetry Assessment Tool software package, which is available at no cost (www.afrri.usuhs.mil). Estimation of dose purely from the lymphocyte depletion rate constant is a quantitative enhancement of the classical Andrews model.1,136,137 Two additional Web resources are useful to the physician charged with treating radiation casualties. The radiation event medical management Web site (http://www.remm.nlm.gov/) developed by the US
Department of Health and Human Services, National Cancer Institute, and the National Library of Medicine is an important resource in patient management. In addition, the Centers for Disease Control and Prevention has a useful compendium of radiation medicine information and protocols (http://www.bt.cdc.gov/ radiation/). As an additional medical resource, the recommendations of the Strategic National Stockpile Radiation Working Group12 are considered to be a primary reference document for modern medical management of ARS.
When the irradiated patient is first evaluated, the following laboratory test results are important to acquire, as time permits.
• Required initial laboratory test results (in the field or in the emergency department): о complete blood count with differential (repeat every 6 h) to evaluate lymphocyte kinetics and calculate the neutrophil-lym-phocyte ratio, and о serum amylase (baseline and daily after 24 h). A dose-dependent increase in amylase is expected after 24 hours.
• Other important laboratory test results to obtain: о blood FMS-like tyrosine kinase 3 ligand levels (marker for hematopoietic damage),
о blood citrulline (decreasing citrulline indicates gastrointestinal damage),
о cytogenetic studies with overdispersion index to evaluate for partial-body exposure,
о interleukin-6 (blood marker is increased at higher radiation doses), о quantitative G-CSF (blood marker is increased at higher radiation doses), and
о C-reactive protein (increases with dose as an acute-phase reactant; shows promise to discriminate early between minimally and heavily exposed patients). For a small-volume scenario (< 100 casualties), consider early cytokine therapy, fluid support, and antibiotic prophylaxis in the dose range of 2 to 6 Gy, if there is no significant trauma. At doses greater than 6 Gy without trauma, it is also prudent to consider stem cell transplantation therapy. With doses in the region of 2 to 6 Gy and with burns or trauma, cytokines and antibiotic therapy are warranted. For doses greater than 6 Gy with burns or trauma, the patient is probably expectant. The severely neutropenic patient must be evaluated carefully, using the Infectious Disease Society of America’s recommendations and other expert guidelines for the treatment of neutropenic fever.
Acute Radiation Syndrome in Humans
SELECTED ASPECTS OF CURRENT RESEARCH
The field of ARS research is progressing rapidly and any discussion is likely to be just as rapidly dated. However, many promising avenues of treatment have been shown in the preclinical phase or in early clinical evaluations.
AFRRI and a research partner recently achieved FDA clearance for 5-androstenediol (5-AED) to be evaluated in Phase 1 human clinical trials. Cytokines, as discussed above, are useful but costly to transport and store, unstable at room and high environmental temperatures, and must be used under the care of a physician. Those limitations make cytokines impractical for use in a mass casualty radiation scenario, which could leave many victims without access to physicians, hospitals, or roads to access either. Moreover, while G-CSF causes elevations in certain types of white blood cells, it does not stimulate production of platelets. AFR-RI’s preclinical trials for 5-AED showed an excellent safety and efficacy profile. Therefore it appears to be useful as a single therapy, without need for physician or medical support, in a mass casualty scenario. Research on 5-AED addresses two of the major problems causing mortality after irradiation—loss of infection-fighting white blood cells and loss of platelets—which lead to excessive bleeding. 5-AED also ameliorates the drop in red blood cells seen after high-level external irradiation (Figure 2-10).147“154 The AFRRI Radiation Countermeasures Branch continues to develop additional pharmacological countermeasures to radiation injury that can be used by military personnel and by emergency responders and to develop a better understanding of the biology of radiation injury and radiation countermeasure drugs. Knowledge of biochemical processes involved in radiation injury and countermeasures can be used to identify and assess novel drug candidates. AFRRI actively collaborates with other research institutions, pharmaceutical firms, and government agencies to develop and obtain approval for radiation countermeasures for use in the field and the clinic.
Possible countermeasures to ionizing radiation can be broadly categorized into three groups: (1) drugs that prevent the initial radiation injury (free-radical antioxidants, hypoxia-generating drugs, and enzymatic detoxification and oncogene targeting agents); (2) drugs that repair the molecular damage caused by radiation either by hydrogen transfer or enzymatic repair; and (3) drugs that stimulate proliferation of surviving stem and progenitor cells, such as immu-nomodulators and growth factors and cytokines. The availability of medical facilities for radiation casualties after a nuclear detonatioear a city will be problematic. In light of the logistical realities of likely nuclear disaster scenarios, much of the current focus is on drug candidates with extremely low toxicity and ease of administration, suitable for use outside the clinic without physician supervision. Radiation countermeasure candidates tested for efficacy at AFRRI are chosen based on extensive basic research, which increases the probability of eventual clinical success. All four ARS countermeasures currently with FDA investigational new drug status (2010) are AFRRI products. Two (5-AED and BIO 300 [Humanetics,
Figure 2-10. Bone marrow from a mouse treated with 5-an-drostenediol (right), compared with marrow from a mouse treated with placebo (left). The many small, round, dark objects in the control section are nuclei in progenitors of red blood cells. Progenitors of granulocytes (mostly neutrophils) and monocytes possess lighter nuclei, often horseshoe-shaped. Four days after 5-androstenediol treatment, there was a proliferation of granulocyte/ monocyte progenitors. Slide courtesy of the US Armed Forces Radiobiology Research Institute
didates. This screening program is supplemented by a robust research program that provides supporting data for approval of existing drugs and identification of potential drug targets. Radioprotectants are another class of drugs that are designed to be used before or shortly after exposure. These include antioxidants such as gamma tocotri-enol (a vitamin-E moiety) or genistein (a soy byproduct) to increase survivability. Assessed effects of genistein on hematopoietic progenitor cell recovery in irradiated mice have documented that genistein operates on radiation-responsive gene expression. Genistein also protects against delayed radiation effects in the lungs and induces cytokine production in whole-body gamma-irradiated mice. The use of advanced nutraceuticals as radioprotectants has shown that vitamin E is an effective radioprotectant. This research has also characterized the radioprotectant properties of soy-derived isoflavones and has demonstrated induction of cytokines by vitamin-E-related analogs. In addition, tocopherol succinate has been found to be a promising radiation countermeasure. A tocol antioxidant, gamma-tocotrienol, acts as a potent radioprotector, and alpha-tocopherol succinate has been shown to protect mice from gamma-radiation by induction of G-CSF and by preventing persistent DNA (deoxyribonucleic acid) damage. A recent review
article describes the history and scope of radioprotectants in research and in clinical radiation medicine. An entity important in the clinical management of ARS is severe mucositis, which often appears in patients with high-dose external irradiation. Keratinocyte growth factor (KGF) has been shown to decrease the incidence and duration of severe oral mucositis in patients with hematologic malignancies who are receiving myelotoxic therapy and require hematopoietic stem cell support. The safety and efficacy of KGF have not been established in patients with nonhematologic malignancies; however, it is likely that KGF would be of use in the treatment of ARS.
Another severe manifestation of high-level dose— gastrointestinal syndrome—has defied effective treatment over the years. Currently, mixed data is available for treating and mitigating gastrointestinal syndrome. Current treatment modalities include gastrointestinal decontamination with FQs, vancomycin, polymyxin B sulfate, and antifungals (as medically indicated). In addition, L-glutamine has been found to be a helpful adjunct, along with supportive care. Nutrition options include total parenteral nutrition, elemental diets, and fluid and electrolyte repletion. There is also active current research on the use of growth factors to protect intestinal stem cells from radiation-induced apoptosis.
SUMMARY
Victims of acute radiation events in radiological and nuclear incidents will require prompt diagnosis and treatment of medical and surgical conditions as well as conditions related to possible radiation exposure. Emergency personnel should triage victims using traditional military medical and trauma criteria. Radiation dose to military personnel can be estimated early after the event using rapid-sort, automated biodosimetry and clinical parameters, such as the clinical history and timing of symptom complexes, TE, lymphocyte depletion kinetics, and various multipa-rameter biochemical tests. Acute high-level radiation exposure should be clinically treated as a medical case
involving MOF. Radiation-induced MOD and MOF refer to progressive dysfunction of two or more organ systems with the etiological agent as radiation damage to cells and tissues over time. Radiation-associated MOD appears to develop in part as a consequence of the systemic inflammatory response syndrome and in part as a consequence of radiation-induced loss of the functional cell mass of vital organs. Modern guidance to the medical management of radiation-induced MOF is presented in this chapter and it is hoped that this will serve as a comprehensive educational resource for the physician likely to be involved in managing patients in a radiation incident.
It would be a mistake to conclude that high doses affect only the cerebrovascular tissues, lower doses only the gastrointestinal tract, and still lower ones the hematopoietic system. If we consider only radiosensitivity we have this order from most to least sensitive: hematopoietic, gastrointestinal, cerebrovascular. However, the sequence of promptness of manifestation is in the reverse order. Thus it follows that a person who receives 500 rads will not show the cerebrovascular syndrome because he has not received a dose high enough to induce it. On the other hand, a person who receives 5,000 rads dies before he can show the full picture of the gastrointestinal and hematopoietic syndromes; but he would show them in severe form if, somehow, he could be kept alive long enough to do so.
It should be recognized that figure 1 is only a rough approximation drawn from limited human experience and partially extrapolated from data obtained in other species. In many mammalian species there is a tendency to show these general patterns of response, but there are also rather prominent exceptions. A striking feature that tends to make radiation injury different from many other types of injury is that while the damage may all be incurred instantaneously, the manifestations of it, especially the hematopoietic syndrome, are not present immediately but develop inexorably over a period of days or weeks, with the rates of appearance being characteristic for the species. In general, the smaller species proceed through the sequence of damage and recovery more rapidly than the larger ones. For example, mice succumb to the hematopoietic syndrome within 10-12 days, while in man the time required is 25-35 days.
Cerebrovascular Syndrome
The cerebrovascular syndrome is what used to be known as the central nervous system syndrome. The effects are due to direct damage to brain cells, injury to blood vessels of the brain, and cardiovascular collapse with profound fall in blood pressure. Recent experiences have emphasized the importance of the vascular changes in producing this set of manifestations. Symptoms may develop within minutes after exposure and include mental disturbances, coma, and sometimes convulsions.
Gastrointestinal Syndrome
The gastrointestinal syndrome is manifested by persistent and severe vomiting and diarrhea, fluid loss, electrolyte disturbance, and terminal infections. Many mechanisms may be involved in this, and there is a difference of opinion about their relative importance. The epithelial cells which line the intestinal tract stop undergoing mitosis and after a period of time older cells die. Since there are no replacements for them, the surface is denuded. This situation contributes to severe abnormalities in electrolyte and fluid balance and provides sites for bacterial invasion.
In the mouse the gastrointestinal syndrome runs its course quite rapidly and death usually occurs within 3 or 4 days.
Hematopoietic Syndrome
The hematopoietic syndrome is of much greater importance than the other two because it is the one commonly seen, and because treatment for it is quite effective.
This syndrome is the only one that has been documented in man with a considerable number of well-studied cases. If a man who receives in a radiation accident an average absorbed dose of 300 rads, which might correspond to an air exposure of about 450 R, his injury is of a severity that might well prove lethal for some persons. Figure 2 gives the expected clinical and hematological effects of this dose.
The reductions in the numbers of circulating blood cells are caused mainly by radiation damage to precursor cells (stem cells) in bone marrow and lymphatic tissues. Primitive, undifferentiated cells are generally more radiosensitive than mature ones, and this is true for hematopoietic cells. Those already circulating (except for lymphocytes, which are quite radiosensitive even when mature) are generally not much affected by doses below those lethal for man.
The appearance in the blood picture of the effects of radiation damage to stem cells and other immature hematopoietic cells is quite complex; involved are the normal mitotic intervals, the time required for maturation, factors influencing release of cells from marrow into blood, and the normal and radiation-altered period in the blood and life span for each cell type. Much is yet to be learned about these relationships.
A sharp decrease in the number of lymphocytes occurs soon after irradiation and a return to normal levels usually does not take place for many months. The degree of depression in lymphocyte count constitutes one of the best and earliest biological indicators of degree of injury and, as shown in figure 3, most of the decrease occurs within 48 hours after exposure.
The neutrophil granulocytes may show a brief increase during the first day or so after exposure, due to release from the marrow of already mature cells in response to injury. Between days 2 and 10 the neutrophil count falls continuously but an “abortive” recovery may occur, reaching its peak at about day 15. This transient rise is thought to represent granulocytes from precursors which were so damaged that they and their offspring could undergo only a few mitoses before dying. After day 15 the granulocyte concentration goes progressively down, reaching a nadir at about day 30, with recovery beginning shortly afterward. The blood platelets (thrombocytes) may show some transient rise immediately after exposure; their numbers then remain stationary or decrease slightly for approximately a week. A more rapid decline follows, which reaches a nadir in about 30 days. A fairly prompt recovery which may include overshooting to values above normal completes the acute phase of platelet response.
The red blood cells are slow to show the effects of radiation damage to their precursors because of their long normal residence in the blood (about 120 days). The nadir is reached somewhat later than the 30 days that applies to platelets and granulocytes, and unless there is blood loss, which may occur due to thrombocytopenia, red cell values usually do not fall low enough to contribute in a major way to the clinical problem.
With doses lower than 300 but more than 150 rads the patterns are similar in timing to that given above, but they show lesser degrees of effect. At doses above 300 rads the depression of granulocytes and platelets becomes severe earlier, but if the patient does not die, the time of onset of recovery remains at slightly more than 30 days. At doses below 150 rads the hematological picture in the few human cases studied was quite inconsistent and the characteristic time course was not always seen.
LD50 CONCEPT
When groups of uniform, healthy animals are irradiated at doses near the lethal dose, a sigmoid curve is obtained which is quite steep in its mid portion (see figure 4). This means that for the great majority of animals the sensitivity is quite uniform. The upper and lower extremes of the curve are less steep, meaning that there is a small per cent of animals with more than the usual sensitivity and a small per cent with less. Quantitating these extremes of the curve is quite difficult and would require large numbers of animals. For practical purposes, in measuring sensitvity the point where the curve crosses 50% is used, and it is called the LD50 (lethal dose for 50%). If the animals vary in age, sex, genetic makeup, or state of health, a much less steep curve will be obtained, and for research purposes very little confidence can be placed in the reproducibility of the result. Pre-existing low-grade infections are a particularly common problem in research laboratories.
Since the curve is normally steep, it can be seen that the difference in dose that would reduce the mortality from 85 to 15% may be quite small. For example, in the evaluation of radiation-protective agents a report of a large change in mortality at a specific dose choseear the LD50 may artificially suggest a greater effect on resistance than actually occurs. A more helpful criterion is the change in the LD50 dose.
Most LD50 studies are carried out over the whole period during which acute radiation deaths may occur. Sometimes duration is explicitly stated by adding the number of days of the study to the term; that is, LD50 (30 days) means an LD50 study carried out for 30 days. In the mouse this would include all early deaths, and the meaning would be essentially the same as if the 30 days were omitted. However, if one were studying the cerebrovascular syndrome and referred to an LD50 (2 days), the 2 days would be a crucial part of the statement; the radiation dose producing 50% mortality in this short period would be a very high one, easily 100% lethal in a 30 day observation period.
For large animals, where manifestations of injury develop more slowly, the LD50 (60 days) is often used to cover the whole acute period through all hematopoietic deaths.
No one knows the LD50 for man. In considering this subject we must recognize that for animals in a base-line LD50 study no special post-treatment care is given to improve survival. It is widely believed that the human LD50 would be in the neighborhood of 450 R exposure to high-energy y-radiation. This would be equivalent to an average absorbed dose of about 300 rads and areas of minimal dose perhaps as low as 225 rads, depending on several variable factors, such as size of the man, direction of the beam of radiation, etc. Whether these figures are near the correct ones will probably never be known. It is certain, however, that man can survive much higher doses with modern care.
CLINICAL PICTURE ASSOCIATED WITH THE HEMATOPOIETIC SYNDROME
Consider again the person who received 300 rads (figure 2). The clinical course can be divided into well-defined periods:
Prodromal Period
During the first or second day after exposure, loss of appetite, nausea, and vomiting commonly occur. When vomiting is absent, it is usually but not always safe to conclude that the dose received was sublethal. If vomiting develops less than 1 hour after exposure, and persists in severe form, the prognosis is likely to be poor. Similarly the presence of severe and persistent diarrhea is likely to indicate a lethal dose, but mild diarrhea, perhaps psychic in origin can occur after relatively low doses. Psychogenic vomiting, on the other hand, is not a common occurrence unless the patient is in the presence of others who are vomiting or experiences other unpleasant sights or odors. Fear and anxiety alone rarely cause vomiting.
This complex of gastrointestinal symptoms, which usually subsides after 1 to 3 days, is not synonymous with the “gastrointestinal syndrome.” (Those persons who receive sufficient radiation to develop the gastrointestinal syndrome will, of course, have these prodromal symptoms in severe and persistent form.)
Latent Period
After the prodromal symptoms subside, the irradiated person is likely to have a period of perhaps 3 weeks, during which he feels relatively well and has no symptoms except mild weakness and apathy. During the latter part of the period he is likely to begin to note loss of hair. This alopecia is common at doses of around 300 rads or more to the skin, and it may begin from the thirteenth to the eighteenth day after exposure. Often it is preceded by mild soreness of the hair areas. The alopecia may be complete or partial, and in those patients who survive, is usually followed by regrowth of the hair beginning a few weeks later.
Period of Hematopoietic Depression
During the fourth and fifth weeks after exposure the patient may have a severe illness characterized by hemorrhage and infection. The mechanism of the hemorrhage is mainly the deficiency in blood platelets; the basis for the infection is complex, but the most important single factor is a lack of neutrophil granulocytes. Secondary factors include impaired antibody formation and disturbances in several cellular and humoral defense functions. When death occurs, it is more commonly caused by infection than by hemorrhage. A combination of the two is often involved and one may contribute to the other since infections may injure mucous membranes to produce bleeding sites, and hemorrhages, especially in the lungs, may provide areas where bacteria are likely to grow.
The hemorrhagic tendency is manifested clinically by the appearance of small hemorrhages in the skin (petechiae), bleeding around the teeth, nosebleeds, and hemorrhage from pre-existing injuries to the skin or mucous membranes. An early clinical means of detecting this tendency is to look for blood in urine or feces.
The infections may be of almost any type, but they may include certain kinds not common in persons with normal defense mechanisms, such as those due to gram-negative organisms, to organisms normally considered nonpathogenic, and to fungi. Antibiotics may be much less effective than they would be in persons with normal resistance, a fact contributing to fatal outcomes.
When death occurs during the period of severe marrow depression, and profound marrow hypoplasia is seen at autopsy, it is erroneous to conclude that the hematopoietic system has been irreversibly damaged. It is quite possible that a reversible injury is so severe that the patient cannot survive until recovery mechanisms can come into play.
Recovery Phase
During the fifth week after exposure the blood begins to show spontaneous increases in platelets and granulocytes, and with this there is cessation of bleeding. Most infections also tend to subside, but with abscesses or deep ulcers, healing may be unsatisfactory and late deaths can occur.
TREATMENT
For patients who have received doses high enough to produce severe damage to cerebrovascular tissues or gastrointestinal tract there is no known therapy that will make recovery possible. Treatment consists of providing comfort and attempting to achieve the communication with patient and family that will most nearly fulfill their humaeeds. Efforts to combat hypotension and to correct imbalances of electrolytes and fluids are likely to be made, perhaps in the faint hope that the injury will prove to be less severe than it appears.
When the clinical assessment indicates that the injury is less than surely lethal, that is, in the range characterized mainly by the hematopoietic syndrome, extensive treatment should be provided. The basic concept is to supply those supportive and replacement needs that will keep the patient alive until his inherent recovery mechanisms have time to become effectual. A brief outline of the methods and resources available follows:
1. Antimicrobial agents (mainly antibiotics) to control infection. The exact choices and timing for these agents is a complex problem. They should probably be given prophylactically in patients with severe bone marrow depression, that is, before clinical infections are apparent.
2. Fresh concentrated donor platelets to combat bleeding.
4. Certain auxiliary needs—variable—butalways including psychological support. Rest is probably of value, but it is not known whether complete confinement to bed is desirable. Symptomatic medications such as sedatives may be helpful. In the early phase of treatment, before the severe depression of blood elements has developed, it is desirable to look for local sites of low-grade pre-existing infection, such as in the gums, skin, and genitourinary tract, and to institute treatment before lowered resistance may make these sites dangerous as points of entry for systemic spread of infection.
When the injury is as severe as to make it appear that the above listed means of treatment may not be adequate, certain additional and experimental measures should be considered.
1. The administration of leukocytes from patients with chronic granulocytic leukemia. Normal granulocytes would be better but are not available in adequate numbers. The danger of a permanent graft of the leukemic process is very remote. The cells are promptly effective in controlling some infections that resist antimicrobials alone.
3. Cross circulation with another patient who has compatible red cell types and who might benefit from the irradiated patient’s kidney or liver function while providing white cells and platelets.
GENERAL COMMENTS
It is often pointed out that there is variability in human response to radiation; however, in the context of the variation in response to other kinds of injury, man’s early responses to radiation are perhaps more uniform than one might expect. Examples of really excessive sensitvity comparable to drug sensitivity are not known.
There is enough variation, and enough uncertainty about the dose in most radiation accidents, to make it mandatory to base therapy mainly upon biological evidence of injury rather than upon dose calculations. In addition to the hematological measurements described, cytogenetic changes may be useful as it appears that they may prove highly sensitive indicators of small amounts of injury. Biochemical changes in blood and urine have proved of limited value.
The late effects of irradiation are described in Chapter 6. They are not predictable in a given patient on the basis of dose; the effect is seen largely as a change in incidence of certain diseases and disorders which have multiple etiological factors.
5 RADIATION HAZARDS
Exposure of a mammal to ionizing radiation induces a complex series of physico-chemical changes within its tissues that may be repaired with no apparent harm to the organism, or be amplified and result in effects as transitory as vomiting or as serious as death. The type of lesion induced, and the probability that it will occur, depends on a variety of factors including the radiation dose, the rate at which it is delivered, and the portion of the body which is exposed.
Although the effects of these variables on the response of laboratory animals to ionizing radiation have been well documented, the human experience is limited largely to the survivors of the Hiroshima and Nagasaki detonations, radiation accident victims, and patients who have received radiation therapy for benign and, in some cases, malignant diseases. This chapter will outline the potential hazards of ionizing radiation, using human data wherever possible, and describe the current standards of safety for human populations.
The response of man to ionizing radiation may be divided into two broad categories: acute effects that manifest themselves within the first 60 days after exposure or not at all (e.g., serious depression of the peripheral leukocyte count) and late effects that either persist for extended periods after exposure (e.g., impaired fertility) or which require long periods for full manifestation (e.g., carcinogenesis). Acute and late effects differ not only in their time of occurrence, but also in terms of man’s resistance to their induction and the shape of their respective dose-response curves. These, as well as other differences, will be further discussed below. Unless otherwise stated, the radiation exposures referred to below are low linear energy transfer (LET) radiations, such as 250 Kvp x-rays, given as a single brief exposure.
ACUTE EFFECTS
As shown in figure 1, the dose-response curve for the acute effects of ionizing radiation is sigmoidal where low doses are incapable of eliciting the response in any individuals; intermediate doses induce the response in a fraction of the population and response is directly proportional to dose; and high doses induce the response in 100% of the population. The existence of a “no-response” region in the curve indicates that a threshold of latent injury exists which must be exceeded before the effect will express itself. Similarly, the lack of a sharp transition from no-response to 100% response indicates that the size of the threshold varies among individuals. The radioresistance of man to a specific effect is expressed as the ED50 or the dose that will induce the response in 50% of an exposed population. Table I lists the major acute effects of radiation that are encountered in human populations, the time period during which the effects will express themselves, and the respective ED50 doses expressed in rads.
Acute Effect Time of Appearance ED50, rads*
Anorexia < 2 days 120
Nausea < 2 days 170
Vomiting < 2 days 200
Diarrhea < 40 days 240
Death < 60 days
(without supportive therapy) 250
Erythema < 6 hours 575
Moist desquamation < 60 days 2000
*Dose which induces the acute effect in 50% of an exposed population.
The first three acute effects of ionizing radiation (anorexia, nausea, and vomiting) are transitory clinical disturbances that are thought to result from minor alterations ieural transmission. Diarrhea, in the immediate post-irradiation period, may also be due to this factor. Cell loss from the gastrointestinal epithelium and electrolyte imbalance, however, contribute in those instances in which the condition persists for many days after exposure.
Comparatively little information is available on the lethal radiation response of human populations, but the pathological changes that have been observed in radiation-accident victims and in others who received large doses indicate that man, like lower animals, dies from depletion of peripheral blood elements, secondary to bone marrow aplasia. The success of human bone marrow transplantation in radiation-accident victims provides direct support for this conclusion.
Included in Table I are two reactions of the skin to localized radiation: erythema and moist desquamation. Of all the acute radiation responses of humans, these two, especially the latter, have received the greatest attention. Prior to the development of supervoltage radiation equipment, they were often the limiting form of injury, and dictated the maximum allowable radiation dose in the therapy of certain malignancies.
The radiation doses given in Table I are those required to produce the effect if given as a single brief exposure. As discussed in Chapter 4, if the amount of time over which the dose is given is extended, the total radiation dose must be increased to achieve the same effect. Each of the acute effects listed in Table I responds in accordance with Strandquist’s equation of dose protraction, but the value of the recovery constant can only be approximated in most instances. The ED50 for a given acute effect also depends on the number of exposure fractions, the time between fractions, and the size of each fraction. One objective of experimental radiotherapy is to combine these variables in such a way that the ED50 for tumor control will be minimized, while the ED50 for acute effects will be maximized.
Great scientific and practical experience on the problem of the radiation deterministic effects in man was accumulated for last 50th years. The bone marrow form of the acute radiation disease (ARD) is described in greater details. The criteria of diagnostic, treatment on different stages of disease, the consequences of ARS are determined. In the conditions of chronic external radiation in large doses (significantly more than permissible dose) the injury of the high radiosensitive hemopoietic system is also developing.
In the beginning of 50th new nosological form of the radiation disease was found out in the atomic workers of the first atomic enterprise in
The results of the long-term observation include the evaluation of status of hemopoiesis, nervous, cardiovascular, respiratory, gastrointestinal systems and other systems and organs.
In 1948-1949 the reactor, radiochemical and plutonium production complex (PA “Mayak”) began its operation. The introduction of new complicated technologies, the short period for the production output, the absence of effective individual and collective protective means against radiation led to the excessive radiation exposure of the part of atomic workers. In 1949-1954 the annual radiation doses could achieve 1.0 – 4.0 Gy and the total doses were up to 4.0 – 10 Gy in the first 3-5 years of work. Beginning with the 60th the annual doses did not exceed the permissible dose (5 sZv per year). The part of the personnel also had the professional contact with plutonium 239 aerosols.
The medical control of the workers’ health status was begun in the starting of the enterprise operations. The medical examination included the primary examination before employment and the further periodical (monthly, quarterly, annually) examinations by therapeutist, neurologist, blood count investigations and other researchers, if it was necessary. The system of periodical medical examination allowed find out the early changes of any health status of atomic workers. In the first decade of atomic plant activity more than 1800 occupational diseases induced by radiation exposure were diagnosed. Chronic radiation disease (ChRD) compiled more than
80% of these diseases. In specialized hospital the additional investigations and treatment (hemostimulated measures, vitamin therapy, etc.) were carried out. After the diagnostic of ChRD atomic workers continued work without any contact with ionizing radiation sources
50 years passed since the PA “Mayak” started operations. The medical observation of most workers which had ChRD is continuing in the same medical center. The results of the long-term observation include the evaluation of status of hemopoiesis, nervous, cardiovascular, respiratory, gastrointestinal systems and other systems and organs. We estimated the health status of 632 atomic workers, which had the diagnosis of ChRD 49-50 years ago.
Many parameters of peripheral blood and bone marrow (sternal punction) for whole period of observation were analyzed. The local and common hemodynamic status (rheovasography, rheoencephalography, ophtalmoscopy), lung function, stomach function and morphological status of stomach mucous (aspiration gastrobiopsy) were studied. In late period of ChRD the immune investigations were carried out. The chromosome analysis of peripheral blood lymphocytes as the indicator of former radiation exposure was used.
The clinical syndromes of chronic external gamma-irradiation in total doses 1.0 – 10.0 Gy for the period 1-7 years of work have been estimated retrospectively. The maximal annual doses varied from 0.7 to 4.5 Gy.
The leading syndrome of ChRD was the injury of the hemopoietic system. The count of leukocytes fell to 30-65% of the initial level (primary analysis). There was the decrease of neutrophils mainly. The count of trombocytes fell to 50-60% from the initial level. During the period of forming of ChRD the leucopenia and trombocytopenia were observed in more than 90% of workers (Table).
The frequency of clinical syndromes of chronic radiation disease during the period of forming and late period of disease (%)
Clinical syndromes Initial parameters Period of disease
Forming Late
Leucopenia Amount leucocytes <4.9 x 109/l <4.0 x 109/l
11.6 0.8 95.0 26.0
43.5 5.1
Trombocytopenia (amount trombocytes less than 180 x 109/l)
24.0 91.8 11.0
Vegetative dystonia 9.0 78.0 4.0
Astenic syndrome
6.0 58.0 1.0
Syndrome of organic changes of nervous system of radiation
0 24.0 1.0
The erythrocytes count of peripheral blood in most cases remained at initial level and did not decrease below the normal level for the long period. However moderate anemia in some cases when the annual radiation doses were more than 2.0 Gy was observed. The character and depth of cytopenia depended on dose-rate and total doses of external radiation. The progressive hypoplasia of hemopoiesis was the cause of death of 3 workers which had the annual and summary doses more than 4.0 Gy and 7.0 Gy respectively
The changes of nervous system in most cases were observed simultaneously. These changes were characterized by following syndromes: vegetative dystonia (hypotonic type), astenic syndrome, organic changes of nervous system of radiation encephalomyelosis type. The character of changes of nervous system depended on dose-rate and total dose.
Vegetative dystonia syndrome was forming at maximal annual dose 1.3 Gy (total dose 2.6 Gy),
astenic syndrome – maximal annual dose 1.4 Gy (total dose 2.7 Gy)
syndrome of radiation encephalomyelosis – 2.3 and 4.5 Gy, respectively.
The dysfunction of thyroid (hyperfunction) and stomach dysfunction (hyposecretion) were observed in the same cases. During the period of forming of ChRD the radiation cataracts haven’t been diagnosed
After cessation contact with ionizing radiation sources the blood parameters in atomic workers gradually normalized. In the late period of ChRD the syndrome of moderate hypoplasia of hemopoiesis or moderate hypoplasia of granulocytopoiesis were observed in one out of ten cases of ChRD. The greatest amount hypoplasia (32%) was observed in workers, which had annual dose more than 2.0 Gy. In present time the hypoplasia of hemopoiesis is compensated and doesn’t require any special treatment.
In the late period of ChRD the changes of nervous system are characterized by the evaluated frequency of early cerebral atherosclerosis (before the age of 45) in cases when maximum annual dose was more than 1.5 -2.0 Gy and summary dose was more than 3.5 – 4.0 Gy. The frequency of cerebral atherosclerosis complications is not evaluated. We think than that cause of it is the intensive treatment and prophylactic measures (periodical prophylactic treatment in hospital, sanatorium, systematic vitamin therapy, etc).
Immune status in the late period of ChRD is characterized by reducing of the parameters of the cell immunity (T-helpers) in cases of high doses (more than 4.0 Gy) and by tendency of increasing of the infectious
syndrome frequency.
The chromosome aberrations are the indicator of former ionizing radiation. In present time most patients with ChRD (88%) have the chromosome aberrations of both unstable and stable types (in control 12%). The frequency of chromosome aberrations is evaluated to be 4-8 times of spontaneous level.
During long-term observation the clinical symptoms of radiation cataracts were not observed. The involutional cataracts were forming at the corresponding age.
The stomach function was estimated. In the late period of ChRD the frequency of cases of the hyposecretion of stomach and character of morphological changes of stomach mucous corresponds to the character of these changes in the common population of industrial countries
Malignant diseases (44.7%) and cardiovascular diseases (43%) occupy the leading place in the structure of death causes of patients. Lung cancer occupies one third in the structure of malignant diseases. It’s important to note that lung cancer was diagnosed at those patients, which has content of plutonium-239 body burden. Also it’s important to note that during first 3-7 years of the atomic plant operation the leukemia (acute myeloblust leukemia redominantly) was the leading disease in the structure of death causes in ChRD patients.
The chronic radiation disease (ChRD) is the syndromocomplex of the changes in most radiosensitive hemopoietic and nervous system evaluating after the chronic radiation exposure in doses significantly higher permissible dose (5sZv per year): maximal annual dose near 1.0 Gy, total external dose more than 2.0 Gy. In the late period of ChRD (after 40-50 years) there is the defect of the hemopoietic and immune system repair, unstability of somatic cells genome, acceleration of involutional process (the early cerebral atherosclerosis).
Chronic radiation doses
A chronic radiation dose is typically a small amount of radiation received over a long period of time. An example of a chronic dose is the dose we receive from natural background every day of our lives. The body’s cell repair mechanisms are better able to repair a chronic dose than an acute dose.
a. The body has time to repair damage because a smaller percentage of the cells need repair at any given time.
b. The body also has time to replace dead or non-functioning cells with new, healthy cells.
Biological effects of radiation exposure
Somatic effects refer to the effects radiation has on the individual receiving the dose.
Genetic effects refer to mutations due to radiation damage to the DNA of a cell. When this change is in the DNA of parental reproductive cells, it is called a heritable effect.
a. Somatic Effects
Somatic effects can best be described in terms of prompt and delayed effects as discussed below.
Prompt Effects
Although rare in the nuclear industry, large doses are typically acute radiation doses representing serious overexposures. The biological effects of large acute doses are as follows
Table 2-1
Prompt Biological Effects
Dose (rad) Effect
0-25 None detectable through symptoms or routine blood tests.
25-100 Changes in blood.
100-300 Nausea, anorexia.
300-600 (450 rem is considered the dose where 50% fatalities occur within 30 days with no medical help (lethal dose – LD 50/30)Diarrhea, hemorrhage, and possible death
Delayed Effects
Delayed effects may result from either a single large acute overexposure or from continuing low-level chronic exposure. Cancer in its various forms is the most important potential delayed effect of radiation exposure. Other effects noted include cataracts, life shortening and, for individuals exposed in the womb, lower IQ test scores.
b. Heritable Effects
A heritable effect is a physical mutation or trait that is passed on to offspring. In the case of heritable effects, the parental individual has experienced damage to some genetic material in the reproductive cells and has passed the damaged genetic material onto offspring.
Heritable effects from radiation have never been observed in humans but are considered possible. They have been observed in studies of plants and animals.
Heritable effects have not been found in the 77,000 Japanese children born to the survivors of
Risk from exposures to ionizing radiation
No increases in cancer have been observed in individuals who receive a dose of ionizing radiation at occupational levels. The possibility of cancer induction cannot be dismissed even though an increase in cancers has not been observed. Risk estimates have been derived from studies of individuals who have been exposed to high levels of radiation.
The risk of cancer induction from radiation exposure can be put into perspective. This can be done by comparing it to the normal rate of cancer death in today’s society. The current rate of cancer death among Americans is about 20 percent. Taken from a personal perspective, each of us has about 20 chances in 100 of dying of cancer. A radiological worker who receives 25,000 mrem over a working life increases his/her risk of cancer by 1 percent, or has about 21 chances in 100 of dying of cancer. A 25,000 mrem dose is a fairly large dose over the course of a working lifetime. The average annual dose to DOE workers is less than 100 mrem, which leads to a working lifetime dose (40 years assumed) of no more than approximately 4,000 mrem.
Comparison of risks
Table 2-2 compares the estimated days of life expectancy lost as a result of exposure to radiation and other health risks.
The following information is intended to put the potential risk of radiation into perspective when compared to other occupations and daily activities.
Table 2-2
Estimated Loss of Life Expectancy from Health Risks
Health Risk Estimated Loss of Life Expectancy
Smoking 20 cigarettes a day 6 years
Overweight (by 15%) 2 years
Alcohol consumption (
Agricultural accidents 320 days
Construction accidents 227 days
Auto accidents 207 days
Home accidents 74 days
Occupational radiation dose (1 rem/y), from
age 18-65 (47 rem total) 51 days
(Note: the average DOE radiation worker receives less than 0.1 rem/yr)
All natural hazards
(earthquakes, lightning, flood) 7 days
Medical radiation 6 days
Chronic Radiation Syndrome Chart
Criteria General Public Occupational Workers Astronauts
30-day limit 0.0004 Sieverts (0.4 milli-Sieverts) 0.004 Sieverts 1.5 Sieverts
annual limit Adult: 0.05, minor: 0.005 Sieverts 0.05 Sieverts 3 Sieverts
Male career limit N/A 2 + 0.075 x (age – 30) Sieverts 4 Sieverts
Female career limit N/A 2 + 0.075 x (age – 38) Sieverts 4 Sieverts
accident limit 0.25 Sieverts 1 Sievert N/A
acute limit N/A N/A 0.1 Sieverts
