Biología y características clínicas de la lesión por radiación de los adultos

Sabias que?

Para que sea util el ioduro de potasion en la prevencion del cancer de tiroides por radiacion externa debe ser adminsitrado antes de las doce horas de la exposcion y hasta el cese de la misma?

Que igual que la intensidad del sonido. La intensidad de la radiación desde una fuente nuclear accidental se reduce como el cuadrado de la distancia?

Que de los estudios a proposito de las experiencias de explosiones y accidentes nucleares surge que quienes tenian mas de 15 años al momento de la exposicion no tuvieron cancer de tiroides, en cambio si lo tuvieron los que recibieron irradiacion del cuello por razones terapeuticas?

Que la radiacion habitual en Roma es 6.25 veces mayor que la de la embajada italiana en Roma en estos momentos?

La noticia original de la RAI:

"Roma più radioattiva di Tokyo. E' la sorpresa delle analisi effettuate dalla squadra della Protezione civile italiana, composta da sei persone, giunta oggi nella capitale nipponica.

I rilievi fatti dai tecnici - comunica l'ambasciata italiana - danno una radioattività di fondo misurata sul tetto dell'ambasciata di 0.04 microsievert/ora. Per riferimento, il valore di radioattività ambientale tipico della città di Roma è di 0.25 microsievert/ora."

Dicha medición ofrece unos valores de 0,04 mSv/h en la embajada italiana en Tokyo, mientras que la radiación ambiental "habitual" en Roma se sitúa en 0,25 mSv/h.

http://lafocamonje.blogspot.com/2011/03/mas-radiacion-en-roma-que-e....

Biology and clinical features of radiation injury in adults
 
Author
Nicholas Dainiak, MD, FACPSection Editor
Nancy Berliner, MDDeputy Editor
Stephen A Landaw, MD, PhD
 
Last literature review version 18.3: septiembre 2010 | This topic last updated: marzo 29, 2010

INTRODUCTION — The occurrence of industrial and medical radiation accidents and the threat of terrorist events involving radioactive material mandate the development and implementation of an appropriate medical response. Medical professionals who would logically be involved in such events include, among others, radiation safety officers, radiation oncologists, nuclear medicine physicians, emergency department physicians, hematologists, medical oncologists, infectious disease specialists, and gastroenterologists. All will be asked to play a significant role in evaluating and treating victims of an accidental or deliberate exposure to radiation. Due to their experience in managing patients with cytopenias and/or marrow aplasia, hematologists and medical oncologists will most likely be asked to take primary responsibility or a consultative role for the medical treatment of individuals exposed to a moderate or high dose of radiation.
However, all physicians, and especially medical triage personnel, must have an understanding of how radiation alters the function of cells, tissues, and organ systems, how radiation levels are quantified, and how victims receiving a significant radiation dose can be recognized and treated. In addition, all medical facilities should have a radiation emergency contingency plan with which their employees are familiar. Emergency personnel and hospital personnel must also be aware of local, state, and national resources that may be employed in the case of a radiological event [1].
A basic understanding of radiation physics is requisite for understanding the principles of injury and the fundamentals of medical management of those suffering radiation-induced injury. This subject is reviewed separately. (See "Clinical features of radiation exposure in children", section on 'Radiation Physics'.) Building on a rudimentary understanding of these principles, the general aspects of radiation biology and the clinical features of radiation injury in the adult will be discussed here.
Triage and treatment of adults involved in radiation accidents are discussed separately. (See "Treatment of radiation injury in the adult".) These subjects are also covered in the Pediatrics section of UpToDate [2]. (See "Clinical features of radiation exposure in children" and "Management of radiation exposure in children following a nuclear disaster".)
UNITS OF RADIATION DOSE — The amount of radiation (ie, radiation dose) absorbed by the patient's tissues is highly predictive of its biological effects. Such doses are defined as the amount of energy of ionizing radiation deposited per unit of tissue mass at a specific point [3-5].
It is important to distinguish ionizing radiation (eg, x-rays, gamma rays, proton beams used for radiation therapy) from non-ionizing radiation (eg, microwaves, radio waves, infrared light). Nonionizing radiation generally causes damage through direct or indirect transfer of thermal (heat) energy; sunburn and microwave heating are classic examples of such exposures. On the other hand, ionizing radiation acts at the cellular level and has the potential to cause structural and chemical damage to vital targets such as nucleic acids and proteins.
The terms most often used for quantifying radioactivity, radiation dose, and radiation injury are described in the table (table 1). Those that will be employed in this review are defined below.
Absorbed Dose — The rad (radiation absorbed dose) is the traditional unit of absorbed dose, and is defined as the transfer of 100 ergs per gram of tissue. The rad has been superseded in the SI (Système International) by the Gray (Gy). One Gy, the unit most commonly used to measure radiation therapy dose, is equivalent to 100 rad (1 joule/kilogram), while one cGy is equivalent to 1 rad or 1000 mrad.
Dose Equivalent — The rem (Roentgen equivalent in man) is a unit for the dose equivalent and represents the product of the absorbed dose (in rads) and weighting factors that take into account the differential sensitivity among tissues as well as the biological effectiveness ("quality factor") of various sources of ionizing radiation (see 'Cellular effects of radiation' below). The rem has been superseded in the SI by the Sievert (Sv). One Sv is equivalent to 100 rem.
For most therapeutic radiation exposures (eg, x-rays, gamma rays) the Sievert and Gray are approximately equal. However, when there is exposure to highly ionizing particles (eg, neutrons, alpha particles) the radiation dose equivalent reflects resulting tissue damage better than the absorbed dose. As an example, the quality factor for x-rays, gamma rays, and beta particles is 1, while that for alpha particles is 20, and can range from 4 to 22 for neutrons, depending on neutron energy.
Dose rate — The "dose rate" refers to the amount of radiation delivered per unit of time and is most often measured in rads/hour or Gy/hour. Geiger counters typically provide an estimate of dose rate that may, in turn, be used to estimate the degree of hazard in a particular environment (eg, accident scene, patient clothing or bodily wastes). Common, hand-held Geiger counters are suitable for monitoring radioactive sources emitting gamma rays, but more specialized equipment is required for sources emitting certain low energy beta particles, neutrons, and alpha particles.
For cases involving exposure to x-rays, gamma rays and beta particles, a reduction in the radiation dose rate results in a decreased radiation response. For example, it is believed that the carcinogenic effect of these radiations delivered at a lower dose rate is less than that of the same total dose delivered at a higher dose rate. Similarly, a dose of 1 Gy delivered over 1 minute might cause signs and symptoms of acute radiation injury, whereas the same dose delivered over 100 days would not [2].
Examples of possible radiation exposures — The average annual dose to persons residing in the United States is approximately 3.6 mSv (360 mrem) [4]. The majority of this dose (55 percent) is due to exposure to radon daughter products from the earth and construction materials, with man-made sources of radiation (eg, medical imaging studies), cosmic radiation, and natural radiation from endogenous sources (eg, the naturally occurring radioactive isotope of potassium, potassium-40) contributing the majority of the rest.
Examples of the ranges of exposures that might be seen following medical imaging procedures include the following [6-8]:
A standard chest x-ray delivers a dose of 6 to 11 mrem (0.06 to 0.11 mSv, 0.06 to 0.11 mGy).
Interventional cardiologists working in a high-volume catheterization laboratory may have collar badge exposures exceeding 600 mrem (6 mSV) per year [7].
A barium enema with 10 spot images delivers a dose of approximately 0.7 rem (700 mrem, 7 mSv, 7 mGy). Similar doses (7 to 8 mSv) are delivered from a CT scan of the chest or a PET scan, while a combined PET/CT scan is estimated to deliver a dose of 25 mSv [8].
The biologic effect of radiation doses higher than those achieved after routine medical imaging procedures are outlined below:
The lowest radiation dose resulting in an observable effect on bone marrow depression in man, with a resultant decrease in blood cell counts, is in the range of 10 to 50 rem (100 to 500 mSv, 0.1 to 0.5 Gy).
The lowest total body dose at which the first deaths may be seen following exposure to ionizing radiation is in the range of 1.0 to 2.0 Gy. Depending upon the type of support given, 50 percent of people exposed to a dose of 3 to 4 Gy will be expected to die of radiation-induced injury. (See 'Lethal dose of radiation' below.)
There is virtually no chance of survival following a total body exposure in excess of 10 to 12 Gy.
The risk of radiation-induced carcinogenesis and other adverse health effects from medical imaging is controversial and is discussed separately. (See "Radiation dose and risk of malignancy from cardiovascular imaging", section on 'Health risks of radiation exposure'.)
Lethal dose of radiation — Estimation of the dose associated with death in 50 percent of those similarly exposed (ie, the LD 50) have been made in various scenarios. As an example, virtually all survivors of the explosion of a nuclear device at Hiroshima had estimated exposures of less than 3 Gy [9]. Depending on the incident, estimates for the LD 50 have ranged from 1.4 Gy among atomic bomb survivors in Japan to 4.5 Gy following uniform total-body exposure to external photons [10,11]. Several factors determine the lethality of ionizing radiation. These include:
Dose rate — doses received over a shorter period of time cause more damage.
Distance from the source — For point sources of radiation, the dose rate decreases as the square of the distance from the source (inverse square law).
Shielding — Shielding can reduce exposure, depending upon the type of radiation and the material used [12]. As examples, alpha particles can be stopped by a sheet of paper or a layer of skin, beta particles by a layer of clothing or less than one inch of a substance such as plastic, and gamma rays by inches to feet of concrete or less than one inch of lead. (See "Clinical features of radiation exposure in children", section on 'Ionizing radiation'.)
Available medical therapy — The availability of supportive therapy (eg, antibiotics, transfusion, use of cytokines, hematopoietic cell transplantation) is critical for those exposed to moderately high doses of radiation. These subjects are discussed separately. (See "Treatment of radiation injury in the adult".)
Based upon an analysis of all available data, the LD 50 at 60 days (LD 50/60) for humans has been estimated to be approximately 3.5 to 4.0 Gy in persons managed without supportive care, 4.5 to 7 Gy when antibiotics and transfusion support are provided, and potentially as high as 7 to 9 Gy in patients with rapid access to intensive care units, reverse isolation, and hematopoietic cell transplantation [13-16].
ASSESSMENT OF RADIATION DOSE — Radiation dose from external exposure can be assessed by physical, biological, and clinical dosimetric techniques.
Physical measurement — Physical dosimetry can provide an estimate of individual dose, using a whole-body radiation dosimeter. While sensitive and precise measurements of dose can be made, few whole-body dosimeters are available for rapid assessment of dose. Reconstruction of dose can be made with considerable sensitivity, using environmental measurements combined with time-integrated activity [17,18]. Measurements of radioactivity in the air, plants, buildings, and ground are combined with an individual activity over time to reconstruct a dose for the purpose of epidemiological studies. However, this is a time-consuming process that is impractical in an emergency situation, particularly when there are many potentially exposed persons.
Estimation of internal radiation dose from the deposition of radioactive materials, such as alpha emitters (eg, plutonium, americium, californium), and beta-gamma emitters (eg, cesium, cobalt, iodine) into the lungs, gastrointestinal tract, and other tissues, requires detection with special instrumentation (such as ion chambers and spectroscopes). In this case, measurements are made on body fluids (blood, urine, saliva), nasal swipes, fecal samples, and/or expired air [19].
Biologic and clinical markers — Individual "biomarkers" for evaluation of radiation exposure have been sought from the beginning of the nuclear age. Currently, the three most clinically useful markers are the time to onset of emesis, lymphocyte depletion kinetics, and chromosomal aberrations (table 2). These will be described below.
Chromosomal changes — A landmark observation was the observation that the frequency of chromosomal aberrations (eg, dicentrics, chromosomal rings) in lymphocytes correlated well with radiation dose [20]. In this setting, the formation of dicentrics involves an interchange between two separate chromosomes damaged by ionizing radiation, while ring formation involves a break in the arm of a single damaged chromatid, followed by rejoining to form a ring and a fragment [21].
At low doses, chromosomal breakage results from the passage of a single charged particle through the cell's nucleus, damaging one or more chromosomes in the process, and is a linear function of dose. At high doses, chromosomal breaks are caused by the passage of multiple charged particles, resulting in an interaction that is a quadratic function of dose [3].
The presence of chromosomal aberrations is currently the "gold standard" for biodosimetry. Their detection is facilitated by the application of hybridization probes for centromeres and automated metaphase detectors [22,23]. The sample is not drawn until 24 hours after the exposure. For triage purposes, as few as 20 metaphases may be scored to provide a preliminary estimate of dose [24]. However, such testing typically requires several days of processing time, including sample collection, cell separation and incubation, metaphase finding, and scoring of dicentrics and ring forms.
Biological dosimetry — Other forms of biological dosimetry include the determination of absolute lymphocyte counts, lymphocyte depletion kinetics, interphase aberrations (eg, premature chromosome condensation [25]), and electron spin resonance of dental enamel. Of these methods, monitoring the decrease in absolute lymphocyte count has been found to be the most practical method to assess the radiation dose within hours or days following a radiation exposure (table 2) [26,27]. A simple algorithm has been developed for estimating whole-body dose in the range from 0.5 to 10 Gy from acute exposure to gamma radiation, using the rate of decline in circulating lymphocytes [27].
The importance of documenting clinical signs and symptoms has been emphasized in assigning risk from radiation exposure [28]. These include the time of onset and intensity of nausea and vomiting, the appearance and type of skin changes, development of anorexia and fatigue, and the severity of depression in circulating blood counts, including the absolute lymphocyte, neutrophil, and platelet counts [29-31].
Of these clinical features, the time to emesis and lymphocyte depletion kinetics are dose-related and are amenable to quantitative analysis with respect to dose (table 2) [32]. As an example, at doses >6 Gy, virtually all victims will develop vomiting, with the time to vomiting being inversely proportional to the absorbed dose. However, at doses <4 Gy, vomiting is less common and its presence/absence, and timing cannot be reliably used to estimate dose. A reassessment of reported times to emesis showed a relative error of 200 percent for the prediction of a dose of 2Gy [33].
An international consensus document developed with the assistance of the World Health Organization has recommended that clinicians use as many sources of information on radiation dose as available in order to assess prognosis and guide therapy [34]. Whenever possible, incorporation of data from three key elements (ie, time to onset of vomiting, lymphocyte depletion kinetics, and chromosome aberrations) should be sought for the most accurate assignment of prognosis and selection of therapy (table 2). As a practical matter, however, only the time of onset of vomiting and lymphocyte depletion may be available within the first 24 hours following exposure.
CELLULAR EFFECTS OF RADIATION — Ionizing radiation may interact directly with intracellular targets or may interact with other molecules (eg, water) to produce free radicals that, in turn, reach and damage a target (eg, DNA, mRNA, proteins, plasma membrane). Depending upon the amount of ionization deposited along a unit length of track of radiation, the chance of achieving a "hit" on a critical cellular target will vary. Low linear energy transfer (LET) sources of radiation (eg, x-rays, gamma-rays) produce sparse ionization, while high LET radiation sources (eg, alpha particles, neutrons) are characterized by dense ionization.
The following observations have been made concerning the effects of ionizing radiation on human tissue:
Radiosensitivity varies directly with the rate of cellular proliferation. Rapidly dividing cells are more profoundly affected (see below).
Radiosensitivity varies directly with the number of future divisions. Long-lived gonadal and hematopoietic stem cells fall into this category.
Radiosensitivity varies indirectly with the degree of morphologic and functional differentiation. As an example, cells at the growth plate in bone, which have not yet developed into bone or cartilage, are more sensitive than those of the diaphysis. Accordingly, growth arrest of bone is commonly seen after radiation exposure to the growth plate in children, as may occur in the treatment of malignancy. (See "Overview of the outcome of acute lymphoblastic leukemia in children", section on 'Late effects'.)
Variation in sensitivity to radiation is an inherited genetic trait, although candidate gene studies have been largely unsuccessful in identifying the genetic variants underlying most phenotypes [35,36].
While all tissues composed of short-lived cells are directly and indirectly affected by radiation, the most critically affected tissues in adults include the following:
Spermatocytes in the testis
Hematopoietic precursor cells in the bone marrow
Crypt cells in the intestines
Depending upon the dose and dose rate, effects on these cells are primarily exerted through inhibition of cell renewal and triggering of cell death (apoptosis) [37]. However, most cell types do not manifest evidence of damage until mitosis occurs, and several divisions may ensue before actual cell death.
Survival curves for normal clonogenic hematopoietic cells have been derived using the spleen colony forming unit (CFU-S) assay [38]. A single-exponential radiation survival curve is evident for murine hematopoietic stem cells, with 37 percent surviving a dose of 0.95 Gy. Such mitotically active cells have a limited ability to divide after a whole body exposure greater than 2 to 3 Gy [39,40].
Nevertheless, some CFU-S appear to be extremely radioresistant, perhaps because they are in a resting or G(0) phase, surviving doses as high as 6 Gy [39,40]. Such radioresistant stem cells may play a role in spontaneous hematologic recovery and/or the hematopoietic response observed in exposed individuals receiving cytokine therapy. In addition, hematopoietic reconstitution may occur from unirradiated (or relatively under-irradiated) areas of bone marrow that have been partially shielded from the source of radiation by physical materials (eg, lead, other metals), heavy clothing, or other body tissues.
Based on a mathematical model, it has been suggested that an absolute neutrophil count less than 200 to 300/microL at five to six days following radiation exposure indicates that no stem cells remain from which a spontaneous regeneration could occur [41]. Such patients would therefore be candidates for hematopoietic cell transplantation. (See "Treatment of radiation injury in the adult", section on 'Hematopoietic cell transplantation'.)
Dose-dependent effects on various organs have also been identified. They are of two types, deterministic and stochastic:
A deterministic effect is one in which the severity is determined by the dose (eg, depression of blood counts). A dose threshold (ie, a dose below which an effect is not seen) is characteristic of this effect. As an example, the threshold absorbed dose for a "deterministic effect" on bone marrow (0.5 Gy) is lower than that for all other organs, except for the testis (0.15 Gy).
A stochastic effect represents an outcome for which the probability of occurrence (rather than severity) is determined by the dose. An example is radiation-induced carcinogenesis, which occurs after a prolonged and variable delay (latency) after exposure. These effects do not have an apparent threshold dose.
The mechanisms underlying deterministic and stochastic effects remain unknown. Studies showing the impact of radiation on gene function may shed light in this area [42-44]. In addition, studies employing cDNA microarrays and protein arrays may help to identify gene expression and protein profiles that may ultimately serve as biomarkers for an exposure to radiation [43-47]. (See "Overview of gene expression profiling and proteomics in clinical oncology".)
Sources of data on radiation effects — Our initial understanding of the acute effects of total-body radiation is derived from analysis of the clinical course of individuals exposed to radiation after the detonation of two atomic bombs over Japan in 1945, as well as radiation accidents that have occurred throughout the world since that time. In some cases, this includes a large affected population (eg, the Marshallese exposed in 1954 and individuals in the former Soviet Union and Europe exposed during the Chernobyl nuclear power plant disaster in 1986). As examples:
The Chernobyl reactor explosion in the former Soviet Union resulted in high levels of exposure, with 28 people receiving doses >6 Gy, 23 receiving 4 to 6 Gy, and 53 receiving 2 to 4 Gy [48]. There were 115 cases of acute radiation syndrome and 28 deaths.
In 1987, in Goiania, Brazil, an abandoned Cesium-137 teletherapy source was breached, with hundreds of people exposed to gamma and beta radiation [49]. There were 48 hospitalizations for radiation injury and four deaths.
In contrast, the reactor breach at Three Mile Island in the United States was calculated to result in no more than 50 to 70 mrem of additional exposure to any individual within range [50].
In other cases, relatively low numbers of individuals have been exposed. The registry of serious radiation accidents maintained by the Radiation Emergency Assistance Center/Training Site (REAC/TS) [51] has been updated [52]. Since December 1990, over 50 accidents have occurred worldwide, involving more than 650 individuals. Of these, more than 250 had a significant exposure and more than 30 have died. This information is periodically updated at Advanced Radiation Research Workshops in Europe and elsewhere [53-56].
PHASES OF ACUTE RADIATION INJURY — Irradiation of human cells leads to acute as well as delayed effects, which may involve every major organ system. Chronic changes, which may take many months or years to become evident, include the development of malignancy (eg, thyroid cancer, leukemia), growth retardation in children, cataracts, infertility, and fetal abnormalities. These stochastic effects of ionizing radiation will not be discussed here.
The ensuing damage results from the sensitivity of cells to radiation, with the most rapidly dividing cells being the most sensitive to the acute effects of radiation. The inherent sensitivity of these cells results in a constellation of clinical syndromes that occur within a predictable range of doses after a whole-body or significant partial-body exposure. Symptoms arising from such exposures are referred to as radiation sickness or acute radiation syndrome (ARS). Classically, the threshold dose for ARS is a whole-body or significant partial-body irradiation of greater than 1 Gy delivered at a relatively high dose rate.
Acute changes, which are seen within the first two months following exposure, include signs and symptoms resulting mainly from damage to the skin, central nervous system, lung, gastrointestinal tract, and hematopoietic tissues. Classic clinical syndromes associated with ARS include the hematopoietic, gastrointestinal, and cerebrovascular (formerly known as cardiovascular and central nervous) syndromes, although there is significant clinical overlap.
Local radiation injury, sometimes called the Cutaneous Syndrome (CS), is especially common and important in patients with ARS consequent to a non-uniform exposure. The CS may include changes ranging from epilation to radionecrosis (see 'Cutaneous syndrome' below).
The presence of ARS complicates the management of CS, due to poor wound healing, infections, and bleeding, while the converse is also true. As an example, severe CS dramatically affected the course of victims of the Chernobyl accident, and was the main cause of death in more than half of the lethal cases [57].
There are four main phases to the acute radiation syndrome [58]:
The prodromal phase usually occurs in the first 48 hours following exposure, but may develop up to six days after exposure.
The latent phase is a short period characterized by improvement of symptoms. However, this effect is transient, lasting for several days to a month. The duration of this phase is inversely related to the dose of radiation received, and may be absent at the highest, fatal doses.
The stage of manifest illness may last for weeks, and is characterized by intense immunosuppression. It is the most difficult to manage. If the person survives this stage, recovery is likely.
Death or recovery phase — Those patients who recover will require close follow-up for the first year, owing to the risk for unusual infections, as aberrant immune reconstitution is probable in those with significant exposure. Survivors will require life-long follow-up to monitor for long-term complications, such as organ dysfunction and carcinogenesis.
The onset, duration, and dominant pattern of the acute radiation syndrome depend upon the dosage of radiation received (table 3) [59]. As examples, the prodromal syndrome is often minimal in those exposed to doses of ≤1 Gy, while those exposed to doses of 10 to 20 Gy may have a rapid compression of phases and proceed from the prodromal phase to death in two days or less.
Prodromal phase — Early symptoms resulting from an acute total-body exposure constitute the prodromal radiation syndrome. The time of onset, duration of symptoms and signs, and mortality rate are all dependent on the magnitude of radiation dose and the presence or absence of additional injury (such as trauma or burns). These early symptoms include anorexia, apathy, nausea, vomiting, diarrhea, fever, tachycardia, and/or headache. The following general observations concerning the relationship between this phase and the absorbed dose include:
The prodromal syndrome is generally mild or absent at total body doses of 1 Gy or less.
Patients whose symptoms begin more than two hours after exposure were probably exposed to doses <2 Gy. They can be expected to fully recover within one month, although long-term sequelae may develop.
Onset of symptoms within the first two hours usually indicates significant and potentially lethal exposures exceeding 2 Gy. At these doses, sloughing of the gastrointestinal epithelium also occurs (ie, the gastrointestinal syndrome), adding to the symptomatology (see below). At doses between 2 to 10 Gy, it is difficult to establish a prognosis based solely on the existence and/or severity of the prodromal syndrome.
At high doses (eg, 10 to >20 Gy), prodromal symptoms occur in virtually all patients within minutes of exposure [60-62]. These gradually merge into loss of consciousness and hypotension, components of the cerebrovascular syndrome. Death often occurs within a few days to weeks after such exposures.
Accordingly, a rapid and severe prodromal response is the harbinger of a poor clinical outcome that may be later complicated by a severe form of the gastrointestinal and hematopoietic syndromes. As noted previously, the time of onset of vomiting in the prodromal phase, when present, can be used to estimate radiation dose (table 2), (see 'Biological dosimetry' above).
Evaluation of signs and symptoms specific to these organ systems is required for triage of victims, selection of therapy, and determination of prognosis. These component syndromes are discussed below. It is important to emphasize the following:
Almost all patients who present with the cerebrovascular syndrome will die. Those who live long enough will also develop a severe form of the gastrointestinal and hematologic syndromes before death.
Those patients who do not present with the cerebrovascular syndrome but develop the gastrointestinal syndrome may survive with appropriate medical support. However, all will also develop the hematologic syndrome if they survive long enough. Presentation with mild gastrointestinal symptoms limited to one or two episodes of diarrhea with associated abdominal pain is accompanied by virtually certain recovery.
Those with minimal gastrointestinal signs and symptoms may still develop the hematologic syndrome, with a potentially fatal outcome. Those with mild to moderate prodromal symptoms, absence of the gastrointestinal syndrome, and minimal evidence of bone marrow suppression have an estimated survival in excess of 90 percent.
The cutaneous syndrome may develop in any of the above scenarios and will complicate management. Consultation with specialists in CS is necessary.
Cerebrovascular syndrome — The cerebrovascular syndrome, also called the neurovascular syndrome or CNS syndrome, results from localized changes in the central nervous system. These include impaired capillary circulation with damage to the blood-brain barrier, interstitial edema, acute inflammation, petechial hemorrhages, inflammation of the meninges, and hypertrophy of perivascular astrocytes [63]. Paroxysmal spike and wave discharges may be evident on the EEG [64], and the presence of swelling and edema may be documented by CT scans and MRI of the head.
In general, cerebrovascular symptoms only occur at whole-body doses in excess of 10 Gy. Its stages from prodrome through to death are usually compressed (table 4). As examples:
The early presence, within minutes of exposure, of fever, hypotension, and major impairment of cognitive function, along with severe prodromal symptoms (eg, anorexia, nausea, vomiting) suggests that the victim has been exposed to a supralethal dose of radiation (ie, more than 20 to 30 Gy) [65].
Those with lesser, but still fatal, exposures to the central nervous system, in the range of 10 to 20 Gy, present with persistent and severe nausea and vomiting, accompanied by headache, neurologic deficits, and abnormal cognition. Signs and symptoms include disorientation, confusion, loss of balance, and seizures. Physical examination may show papilledema, ataxia, and reduced or absent deep tendon and corneal reflexes.
There may be a latent period of a few hours in which there is apparent improvement, but within five to six hours watery diarrhea, secondary to severe gastrointestinal syndrome (see below), respiratory distress, fever, and cardiovascular collapse ensue. The final picture, which may mimic that of sepsis, includes hypotension, cerebral edema, increased intracranial pressure, and cerebral anoxia, with death in about two days time.
Gastrointestinal syndrome — The gastrointestinal syndrome typically develops within five days of the initial exposure (table 5). At doses <1.5 Gy, only the prodromal phase of nausea, vomiting, and gastric atony are observed [66].
More severe symptoms develop at doses between 5 and 12 Gy [67], secondary to loss of intestinal crypt cells and breakdown of the mucosal barrier, with sloughing of the epithelial cell layer and denudation of the bowel wall. These changes result in crampy abdominal pain, diarrhea, nausea and vomiting, gastrointestinal bleeding with resultant anemia, and abnormalities of fluid and electrolyte balance. This early phase is often followed by a latent phase lasting five to seven days, during which symptoms abate. Vomiting and severe diarrhea accompanied by high fever make up the manifest illness. Systemic effects at this time may include malnutrition from malabsorption.
Impaired barrier function of the gastrointestinal tract results in the passage of bacteria and their toxins through the intestinal wall into the bloodstream, predisposing to infection and sepsis, which may be further compromised by immunosuppression and cytopenias secondary to development of the hematopoietic syndrome (see below).
Other severe complications include ulceration and necrosis of the bowel wall, leading to stenosis, ileus, and perforation. In the latter case, recovery is most unlikely, as radiosensitive stem cells in the crypts of the gastrointestinal tract are permanently damaged. Consequently, there is no replacement of cells that are lost from the surface of the villi through the sloughing process, precluding recovery [26,68].
However, mild gastrointestinal symptoms limited to one or two episodes of diarrhea with associated abdominal pain are accompanied by virtually certain recovery, provided that the hematopoietic syndrome that follows is reversible (see below).
Hematopoietic syndrome — The hematopoietic syndrome develops at doses exceeding 1 Gy and is rarely clinically significant at doses <1 Gy [3,61,62,65,67].
Mitotically active hematopoietic precursors have a limited capacity to divide after whole-body doses greater than 2 to 3 Gy. In addition to inducing apoptosis, whose effect is not seen before the first cell cycle following radiation exposure, radiation alters recirculation properties of lymphocytes [41,69,70]. Neutropenia and thrombocytopenia reach a nadir at two to four weeks and may persist for months. Anemia inevitably ensues, due to the combined effects of gastrointestinal blood loss from the gastrointestinal syndrome, hemorrhage into organs and tissues secondary to thrombocytopenia, and, ultimately, bone marrow aplasia.
In the ensuing weeks to months after exposure, hypoplasia or aplasia of the bone marrow occurs, resulting in pancytopenia, predisposition to infection, bleeding, and poor wound healing, all of which may contribute to death in the absence of appropriate supportive care.
Two important points warrant discussion here:
Inhomogeneity of dose, afforded by partial shielding or a more ventral exposure may imply bone marrow sparing. Indeed, most active bone marrow sites are present dorsally, in the spine, dorsal ribs, and pelvis. Such sparing may contribute to the reestablishment of hematopoiesis.
Selectively radioresistant subpopulations of stem cells and/or accessory cells exist. These may play an important role in recovery of hematopoiesis after exposure to doses as high as 6 Gy, albeit with a reduced capacity for self-renewal.
Lymphocytopenia — Lymphopenia is common and occurs before depression of the other cellular elements, and may develop within the first 6 to 24 hours after exposure to a moderate or high dose [26,71,72]. (See "Secondary immune deficiency due to miscellaneous causes", section on 'Ionizing radiation'.) As examples:
A 50 percent decline in the absolute lymphocyte count within the first 24 hours after exposure, followed by a further more severe decline within 48 hours, characterizes a potentially fatal exposure in the range of 5 to 10 Gy.
An absolute lymphocyte count that remains within 50 percent of normal during the first week following exposure suggests an exposure of <1 Gy and a survival probability in excess of 90 percent.
As noted above, there is a highly predictable relationship between the absolute lymphocyte count and absorbed dose (table 2) and (see 'Biologic and clinical markers' above). However, since lymphopenia can also result from stresses accompanying burns and trauma [73-75], it is always important to examine more than one biodosimetry element (eg, prodromal symptoms, lymphocyte dicentrics) whenever possible.
Neutrophil counts — Because of the profound lymphocytopenia that occurs shortly after exposure, the absolute neutrophil count and the total white blood cell count become nearly identical. The initial neutrophil nadir occurs at approximately one week following exposure, after which there may be an abortive, transient rise in the absolute neutrophil count following exposure to doses less than 5 Gy. Presence of this abortive rise may indicate a survivable exposure [76]. As noted above, a more profound and longer-lasting neutrophil nadir occurs at two to four weeks post-exposure, and may last for many weeks (figure 1).
The mechanism for the transient neutrophilia is unknown but may be related to demargination and/or enhanced release of preformed neutrophils from marrow. In addition, radiation is known to cause endothelial cell damage and/or death, resulting in interruption of the marrow-peripheral blood barrier [37].
Based on the overall levels of lymphocyte, neutrophil, and platelet counts, as well as the presence or absence of infection and blood loss, the relative severity of toxicity to the hematopoietic system can be evaluated (table 6). Approaches to therapy for different levels of severity, including the use of transfusions, antibiotics, colony-stimulating factors, and allogeneic hematopoietic cell transplantation, are described separately. (See "Treatment of radiation injury in the adult".)
Cutaneous syndrome — The cutaneous syndrome may develop early following exposure (eg, one to two days). However, it may take years before becoming fully manifest. Unlike the syndromes discussed above, which are related to the whole body radiation dose, the localized dose to the skin is critical for determining the type of skin lesions that occur.
Early lesions include erythema, edema, and dry desquamation of the skin (table 7). Such lesions may be isolated or may appear simultaneously in several locations, depending on the amount of skin receiving direct exposure. More advanced lesions include bullae, moist desquamation, ulceration, and onycholysis [77,78].
Target cells of radiation reside at multiple levels within the skin (ie, epidermis, dermis, hair follicle canals, subcutaneous tissues). Hence, the severity of the cutaneous reaction depends upon the depth dose distribution of the radiation source [63]. Ulceration may be limited to the epidermis or may involve deeper structures, such as the dermis, subcutaneous tissue, and even muscle and/or bone. Estimated dose responses to localized skin exposures include:
Blisters and bullae with or without necrosis appear one to three weeks after localized exposure to doses of >30 Gy [10,79]
Moist desquamation and ulceration are seen with localized doses of 20 to 25 Gy [79]
The estimated threshold for erythema is a localized exposure dose of 10 to 15 Gy
Epilation occurs 10 to 20 days after a single localized exposure to 3 to 4 Gy or greater

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