Гостра променева хвороба людини: етіопатогенез, клініка, діагностика та лікування (лекція)
Ситуації, що призводили до розвитку гострої променевої хвороби. Фактори її розвитку у людини. Клітини організму, що мають високу чутливість до опромінення. Класифікація ГПХ, діагностика ступеня тяжкості. Симптоми первинної реакції. Лікування захворювання.
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| Вид | статья |
| Язык | украинский |
| Дата добавления | 24.07.2024 |
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гострий променевий хвороба клітина
Introduction
Acute radiation sickness (ARS) is a rather rare pathology. There are no such geographical areas on the globe in fact where people could be exposed to radiation from natural sources in doses that cause this disease. All situations that led to the development of ARS were the result of human activity. They can be divided into the following groups:
^ accidents at nuclear reactors of military and industrial facilities, including nuclear power plants (NPP);
^ violations of safety techniques during work at experimental nuclear facilities, accelerators, industrial gamma-ray installations or with radioactive materials;
^ use of atomic weapons of mass destruction or their testing;
^ exposure from closed artificial sources of radiation, found or stolen;
^ overexposure during medical procedures.
There are no official statistics on the number of people who fallen ill with ARS during the more than 125-year period since the discovery of radioactivity and X-rays. This is due to a number of reasons: firstly, not all cases of ARS were recognized and registered; secondly, in countries that worked on «nuclear projects», cases of exposure to people were not publicized due to the regime of secrecy, although there are separate publications about radiation accidents and the number of victims, which are based on information from open sources. So, according to R.F. Mould (2000), from 1945 to 1998, 68 radiation incidents were recorded in the world, in which more than 600 people were exposed to radiation, and for 121 of them the exposure was fatal. According to the materials of the russian register, in the period from 1949 to 2014 in the territory of the former USSR, and after 1991 in the russian federation, there were 349 radiation incidents accompanied by the exposure of people, as a result of which ARS were diagnosed in 352 people.
For the first time, the term «radiation sickness» was proposed by Takashi Nagai, a Japanese doctor, researcher and humanist who in the first days and weeks after the atomic bombing, treated the victims of Nagasaki city, despite the fact that he himself received a high dose of radiation. Staying true to his vocation as a scientist, he made a report to the president of Nagasaki Medical University, in which he described and classified the symptoms of «radiation sickness» for the first time.
In the decades after the tragedy of Hiroshima and Nagasaki, humanity has made significant progress in understanding the mechanisms of radiation damage and gained experience in the treatment of ARS. Nuclear energy has become safer, thanks to the use of protection systems that prevent the fission chain reaction of the uranium nucleus from getting out of control. At the same time, there are gradually increasing in the world the number of countries that have nuclear weapons and pursue an aggressive foreign policy. The russia's war against Ukraine is accompanied by direct threats to use nuclear weapons and provocative actions at the Zaporizhia NPP, which can lead to the release of radioactive elements of nuclear fuel into the environment. All this makes the risk of exposure of Ukrainian citizens and the development of ARS in them quite real. According to calculations made by the Hazard Prediction Assessment Capability Program, version 3.21 (Defense Threat Reduction Agency, Fort Belvoir, VA, USA), a 1-kiloton nuclear explosion in a city of 2 million people would result in the exposure of 18,000 people at a dose > 10 Gy, 19,500 -- at a dose of 5-10 Gy, 33,000 -- at a dose of 3-5 Gy and 66,000 people -- at a dose of 1-3 Gy.
This forecast dictates the need to once again explain to doctors of primary, secondary and tertiary levels of medical care modern views on the clinic and diagnosis of ARS with the aim of more effective and timely treatment of victims.
Etiopathogenesis
A combination of two factors is necessary for the development of ARS in a person: (1) exposure to ionizing radiation, which has a high penetrating ability in the soft tissues of the body, and (2) a radiation dose exceeding a cetain threshold level should be accumulated by the body within a short time.
Of all the known types of ionizing radiation used in medicine and industry, only X-rays (wavelength from 100 to 0.01 nm) and y-radiation (wavelength < 0.02 nm), as well as neutrons (n) are able to pass through the human body, delivering to it a part of its energy. For a- and в-particles, the skin is a barrier that prevents them from penetrating into the body, so they cannot cause ARS when exposed externally. Exposure to y-neutron radiation on a person causes a complex set of changes at the cellular and molecular level, which can lead to the death of body cells due to their necrosis or apoptosis.
Polypotent hematopoietic stem cells (HSC) are the progenitors of all hematopoietic lines and they are the most sensitive to ionizing radiation. They located in the red bone marrow and in small quantities circulate in the peripheral blood. In the process of division-maturation and only maturation, the radiosensitivity of hematopoietic tissue cells decreases. T. Flidner et al. (1994), provide data on the D0 dose [more detailed information about D0 is in the publication of S.P. Yarmonenko, A.A. Wainson (2004)] for the population of CFU GEMM (promyeloblast derived from the common polypotent HSC progenitor), which is 0.54 Gy (F.M. Uckun and C.W Song. 1989) or 0.91 Gy (according to H.A. Neumann et al., 1981).
Cells that are also highly sensitive to irradiation include lymphocytes, the bone marrow immature cells and intestinal epithelium. Cells of eye lens, mucous membrane cells of stomach, esophagus and oral cavity, and epidermis basal layer cells are less sensitive. Cells of medium sensitivity to radiation include cells of the liver, kidneys, lungs, thyroid gland, and connective tissue. Mature erythrocytes, myocytes, as well as bone, chondral tissues and nervous system cells have a low sensitivity to radiation. It can be assumed that irradiation of whole human body with absorbed dose of about 1 Gy will lead to the death of high radiosensitivity cells. When the dose increases, other cells and organs will be affected, which will change the symptoms of the irradiated person (The international Chernobyl project. Technical report, 1991).
The death of red bone marrow cells under radiation was called acute radiation bone marrow syndrome (BMS), which main clinical manifestations are associated with suppression of immunity (lymphocytopenia), infectious complications (neutropenia) and internal bleeding (thrombocytopenia). The response of bone marrow to radiation exposure has a clearly expressed dose dependence. If doses from 1 to 6 Gy cause the death of mainly HSC, then total irradiation in the dose range from 6 to 10 Gy is able not only completely deplete the pool of HSC, but also lead to death young committed cells in dividing-maturing pool. After a day, only macrophages, mature granulocytes, cells of the stroma and blood vessels remain in the bone marrow. Dead cells are removed by macrophages within 1-2 days, and the depleted bone marrow is filled with blood. Exposure to a dose of 20 Gy or higher leads to stroma damage and bone marrow irreversible aplasia with its replacement by fatty and fibrous tissue.
The lifespan the oral cavity and pharynx epithelium is 3-5 days, which indicates the need to maintain a high rate of cell proliferation to ensure the integrity of the epithelium. Irradiation, causing the death of mucous membrane cells, leads to changes in oropharynx, which has received the name of radiation stomatitis, or oropharyngeal syndrome (OPS). Depending on a dose of whole body radiation or head region, the clinical picture of OPS will vary from simple catarrhal mucositis at doses of the threshold level (1-2 Gy) to the appearance of necrotic foci at doses of more than 20 Gy.
It was established experimentally on animals that the stem cells radiosensitivity in the small intestine (SI) crypts can be compared with that of HSC. During humans lifetime it is practically impossible to study in SI the kinetics of mucous membrane cells, but the use of biomathematical modeling methods allows to imagine it at least schematically. As it is known, the two main structural units of SI mucosa are the villi and the crypts of Lieberkun. There are from 4 to 7 crypts for each villi in a person. The crypts are lined with a singlelayer cylindrical epithelium. The bottom of the crypt reaches the muscular layer of the mucous membrane, and the throat opens into the lumen between the villi. Undifferentiated enterocytes are located at the crypts bottom, which actually play the role of stem cells, divide intensively and are a source of replenishment of the crypt cells itself and villi. A pool of proliferating and maturing cells is also secreted in the crypt. Each division of an undifferentiated enterocyte produces, on average, one daughter cell and one cell that enters the proliferating pool.
When exposed to radiation, the SI crypts stem cells die first, although it is quite possible that lethal damage can be observed in the proliferating pool cells. This leads to a decrease in the total cellularity of SI, flattening of the villi, impaired absorptive function of the surviving enterocytes. At the level of SI as an organ, there is a violation of the epithelium barrier function, as a result of which the body loses water, electrolytes and proteins. The reabsorption of bile, which enters SI lower section and colon upper section, causing diarrhea. Currently, it is believed that although there is a possibility of microflora and toxins entering the body from SI lumen, it cannot significantly affect the clinical picture of severe ARS.
Clinical observations have shown that with a total body irradiation dose of 6-8 Gy, clinical phenomena of SI damage may occur, which are reversible due to the great compensatory capabilities of the SI stem cell pool. This symptom complex was called «intestinal syndrome» (IS) of ARS. At doses from 8 to 10 Gy, IS significantly complicates ARS hematological manifestations, and in the range of doses from 10 to 20 Gy, it plays a major role as the cause of the patient's death.
The skin as an organ has a multi-layered structure and belongs to the hierarchical type of tissue, that is it contains stem cells. They are located on the basement membrane in one row with the cells of the basal layer. Rarely dividing, stem cells give rise to new basal cells, which in turn also divide, and the average duration of their mitotic cycle is quite long having 10-16 days. Part of the basal cells loses the ability to divide and turns into a layer of spiny cells consisting of 3-6 rows. When aging, the spinous cells pass into the granular layer, and those, in turn, into the layer of horny cells, which gradually exfoliate, performing cleansing and bactericidal functions.
Among the skin cells, the epidermis basal cells, the dermis vessels endothelium, and the epithelium of the hair follicles are the most radiosensitive. The epithelium of the ducts of free sebaceous glands and hair sebaceous glands is relatively radiosensitive, and that of sweat glands is relatively radioresistant.
Skin reactions to irradiation begin with a dose of 8-12 Gy, when the affected area shows not only primary erythema due to irritation of dermis nerve receptors, but also secondary (true) inflammation of skin, the so-called dry epidermitis. Changes in hair follicles under radiation lead to epilation, which is transient at doses of 3-5 Gy, and irreversible after 7 Gy. Fast-growing beard hair and head is more radiosensitive than hair in other locations. Radiation damage of skin, which received the name «skin syndrome» (SS), can occur only in extremely severe ARS, complicating the general condition of patients together with BMS, OPS and SS.
ARS classification
It is common to distinguish ARS depending on the distribution of the radiation dose in the human body. If the difference in doses to different parts of the body does not exceed 2.5-3 times, then the exposure is considered relatively uniform (A.K. Gus'kova et al., 1987). If any part of the body received a significantly higher dose of ionizing radiation and clear signs of ARS appeared, then we will be talking about ARS from non-uniform exposure. Often, non-uniform irradiation ARS is combined with radiation damage of skin.
ARS is divided into four clinical forms in dependence of what body organ or system plays a leading role in a person death. Each form develops in a certain range of doses: typical or bone marrow (1-10 Gy), intestinal (10-20 Gy)), toxemic or vascular (20-80 Gy), cerebral (80-120 Gy). The indicated range of absorbed doses for ARS forms are indicative but not absolutely precise. The last three forms are incurable: patients develop severe multiple organ failure incompatible with life.
So, ARS may be defined as an independent nosological unit, which develops under external y- or y-neutron short-term (from a second to 3 days) exposure of whole body or it the most great part with accumulation of doses higher than 1 Gy and accompanying with damage of radiosensitive body cells (those that are divided), and under the lethal doses also obviously radioresistant cells.
The bone marrow form of ARS is characterized by a combination of the syndromes that develop after a short-term relatively uniform general irradiation of the body in the dose range from 1 to 10 Gy, with the obligatory presence of hematopoiesis suppression and the period of manifestation of main pathological changes that limited to 2--3 months.
According to the severity of clinical manifestations, ARS is divided into 4 degrees, which are characterized by certain ranges of radiation doses:
V ARS degree I (mild) -- 1--2 Gy
V ARS degree II (moderate) -- 2--4 Gy
V ARS degree III (severe) -- 4--6 Gy
V ARS degree IV (extremely severe) -- 6--10 Gy.
In ARS clinical presentation of any severity,
4 consecutive periods are distinguished: primary reaction, latent (hidden or feigned wellbeing), manifestation and recovery one. The duration of each period depends on ARS severity (Fig. 1).
Figure 1. Duration of ARS periods depending on its severity
Clinical picture Primary reaction
The primary reaction after irradiation (it is also called prodromal syndrome, post-radiation prostration, X-ray hangover) was firstly described by D. Walsh in 1897 as the appearance of dizziness, light headache, vomiting, diarrhea, high temperature and prostration. He observed it in a person who worked with X-rays. In the future, ideas about the symptoms of the primary reaction were expanded and, at present, it is characterized by the following pathological manifestations:
^ dyspepsia -- anorexia, nausea, vomiting, diarrhea, intestinal colic;
^ neuromotor reactions -- quick fatigue, apathy, weakness;
^ neurovascular reactions -- sweating, initial hyperthermia, headache, arterial hypo- or hypertension.
With radiation dose increase and ARS severity, the period from the moment of irradiation to an appearance of primary reaction the first signs is shortened, the number of symptoms increased, as well as their severity and duration of manifestation.
As a rule, the first reaction to radiation is the appearance of nausea, vomiting, which intensifies after taking liquid. At the same time, the victims experience a headache, general weakness, lethargy, drowsiness, and loss of appetite. Starting from ARS II degree skin and visible mucous membranes hyperemia is observed in patients, the body temperature rises to subfebrile, and with ARS III degree to febrile.
The duration of dyspeptic symptoms during the primary reaction usually does not exceed 1--2 days.
However, even with a very severe lesion, the maximum nausea and vomiting intensity is noted during the first 5--6 hours after exposure. Intestinal colic and diarrhea, as a rule, occur only in patients with ARS IV degree. They may also experience adynamia, a sharp drop of blood pressure, up to collapse and fainting.
The most objective and important diagnostic criterion is vomiting. The time of its appearance after irradiation and its expressiveness depends on the ARS degree of severity. At ARS I degree it occurs in 30--50 % of irradiated patients, at II degree -- in 80--100 % and at III and IV degree -- in 100 % of patients.
In ARS IV degree patients whose radiation absorbed dose close to 10 Gy, saliva secretion may be disturbed, they complain of dryness in the mouth, saliva becomes viscous, parotid salivary glands are enlarged and painful during palpation (radiation sialoadenitis).
During the first 2-3 days after total short-term irradiation, peripheral blood leukocytes number increases (leukocytosis of the first day) and lymphocytes decreases (early lymphocytopenia). Hyperbilirubinemia, increased glucose level, and hypoalbuminemia may be observed in ARS III-IV patients.
The intensity of the primary reaction symptoms is used to diagnose the severity of ARS (Table 1).
Table 1. Diagnosis ARS severity during the primary reaction (A.K. Gus'kova, 1987)
|
Symptoms |
ARS degree |
||||
|
І |
ІІ |
ІІІ |
IV |
||
|
Vomiting |
In 2 hours or later; single |
After 1-2 hours, repeated |
After 30-60 minutes, repeated |
After 5-20 minutes, intractable |
|
|
Diarrhea |
Absent |
Absent |
Absent or probable |
Probable |
|
|
Headache |
Short |
Moderate |
Moderate |
Intensive |
|
|
Consciousness |
Clear |
Clear |
Clear |
Confused |
|
|
Body temperature |
Normal |
Subfebrile |
Subfebrile |
Febrile (38-39 °С) |
|
|
Skin and mucosa |
Normal |
Slight transient hyperemia |
Moderate transient hyperemia |
Prolonged transient hyperemia |
|
|
Duration of primary reaction |
Lasts several hours |
Up to 1 day |
Up to 2 days |
More than 2-3 days |
However, it should be noted that 5-7 % of people, even with doses of 3-4 Gy, may not show any symptoms of the primary reaction. At the same time, more emotional people react to exposure harder and longer. Observation of Chernobyl accident victims showed that some patients without clinical and hematological signs of ARS demonstrated the primary reaction in the form of nausea, vomiting, headache, general weakness and even diarrhea.
Latent period
In 1-3 days after irradiation, the symptoms of the initial reaction disappear and the patients' wellbeing improves. There is a latent period. Its duration depends on ARS severity and ranges from 8 to 30 days.
General weakness decreases, drowsiness and headache disappears, and appetite increases in patients Only some of the victims have increased sweating, poor appetite, slight asthenia, some lability of pulse and blood pressure, sometimes with a tendency to increase the latter.
In cases where the radiation dose is equal to or exceeds the epilation dose (about 3 Gy), baldness develops and progresses in patients from the 15 th day.
Table 2. Diagnosis of ARS severity in the latent period
|
Indices |
ARS degree |
||||
|
І |
ІІ |
ІІІ |
IV |
||
|
Peripheral blood lymphocytes on the 3rd-6,h day, 109/l |
1,0-0,6 |
0,5-0,3 |
0,2-0,1 |
0,1 і нижче / and less |
|
|
Peripheral blood leukocytes on the 8th-9th day, 109/l |
4,0-3,0 |
2,9-2,0 |
1,9-0,5 |
0,5 і нижче / and less |
|
|
Diarrhea that starts from 7-9 days |
Absent |
Absent |
Absent |
Present |
|
|
Epilation, start time |
Invisible |
It can be on the 15th-20th day |
In most cases on the 10th-15th day |
In most cases, on the 7th-10th day |
|
|
Duration of the latent period |
28-30 days |
15-25 days |
8-17 days |
Absent or less than 6-8 days |
In the first days after radiation the most patients already complain of sore throat when swallowing, swelling of the gums and tongue. These symptoms pass by the end of the second week in case of ARS I degree, but continue with ARS II degree and above. They are classified as manifestations of OPS.
In the peripheral blood, by the 2nd--4th day of the disease, the number of leukocytes usually decreases due to number of neutrophils decrease (the first decrease). Lymphocytopenia, which was observed in the early stages, persists or even progresses somewhat. Starting from day 6--10, the number of neutrophils in the blood may increase. This phenomenon was called «abortive» rise. There is an assumption that the mechanism of the «abortive» rise is caused by increased proliferative activity of bone marrow myelocytes and normoblasts that have survived the irradiation, that is cells with limited possibilities of proliferation and self-maintenance of the pool. This, for some time, restrains the process of reducing neutrophils in the peripheral blood. «Abortive» rise is actually not registered at doses over 4-5 Gy. The end of the latent period is characterized by the progressive elimination of neutrophils and platelets from the peripheral blood. Any significant 5 changes in red blood, except for reticulocytopenia, are usually not observed during this period.
As in the period of primary reaction, clinical and hematological indicators of the latent period are used to assess the ARS severity (Table 2). The former include epilation and diarrhea, and the latter include the lymphocytes count on 3rd-6th days after irradiation, and granulocytes on 8th--9th days. However, it should be taken into account that the prediction of the disease severity that based on these criteria is only indicative, as it cannot be compared in accuracy with the criteria of ARS manifestation period, and therefore serves to correct the treatment tactics that chosen on the basis of primary reaction symptoms.
Manifestation period
In the dose range of 1-10 Gy the transition from the latent period to the period of apparent clinical manifestations is determined quite clearly by the leading pathogenetic mechanism and the resulting clinical syndrome of deep damage to the hematopoietic system. It is associated with the suppression of immunity and the detection of hemorrhagic syndrome, the severity of which may become incompatible with the normal functioning of the body.
By the end of ARS latent period, patient's wellbeing deteriorates sharply: general weakness increases, appetite worsens, body temperature rises, skin changes appear. The intensity of the temperature reaction depends on the severity of radiation damage and varies from short-term subfebrile in ARS II degree to hectic fever (38-40 °C) in patients with ARS IV degree, while the clinical picture looks like sepsis.
Skin while ARS I degree usually remain clean, but petechial rashes may appear in some patients, such as thrombocytopenic purpura, which in ARS II degree and, especially, III-IV degree are located in groups, have a tendency to merge into large hemorrhages.
Symptoms of radiation stomatitis or OPS in patients with ARS I degree occur even in the latent period, whereas in ARS II-III degree their maximum expression occurs during the peak period. The gums acquire a pearly color, become swollen, loose and bleed at the slightest pressure on them; hemorrhages and erosions appear on the mucous membrane of the cheeks, hard and soft palate.
There are four degrees of OPS severity:
I degree -- desquamation edematous mucositis. It is typical for ARS I--II degree;
II degree -- erosive mucositis. It is most often observed in patients with ARS II--III degree;
III degree -- ulcerative mucositis. It can develop in patients with ARS III degree, especially if the head region has been slightly more exposed to radiation, but it is more often noted in ARS IV degree or in ARS intestinal form.
IV degree -- necrotic mucositis. Deep necrosis of the lamina propria with edema is the result of uneven exposure, where the head region receives a radiation dose that, if distributed evenly throughout the body, would lead to rapid death of the patient from toxemia or central nervous system damage.
Along with OPS phenomena, in patients with ARS signs of tonsils bacterial damage (the so- called agranulocytic tonsillitis) can be observed that caused by conditionally pathogenic microorganisms of autoflora and environment flora.
The pulse becomes more frequent parallel to the temperature rise. Blood pressure, especially diastolic, decreases. Mutting heart sounds are heard during auscultation. With a severe ARS clinical course electrocardiograms show signs of myocardial dystrophy, caused primarily by toxemia and electrolyte disturbances due to significant fluid loss when vomiting, diarrhea, prolonged fever.
Neurological symptoms in cases of severe ARS are non-specific and appear as a result of general infection, intoxication and anemia. Muscle tone gradually decreases. Tendon and periosteal reflexes are usually high, with intermittent asymmetry. Pathological reflexes may be observed. Psychic changes, if they occur, are typical of infectious or toxic delirium. In cases of extremely severe ARS, patients' consciousness may be confusional, meningeal symptoms of varying severity appear, and in the terminal stage, intoxication and hypoxemic encephalopathy with signs of cerebral edema develop.
The development of clinical symptoms during the manifestation period coincides in time with the onset of critical neutropenia (agranulocytosis) and thrombocytopenia. In the peripheral blood, there is a second sharp decrease of leukocytes count caused mainly by a drop of neutrophils number. In the most severe cases, they completely disappear from the peripheral blood. Lymphocytes and monocytes remain the main elements of the leukocyte formula. In the preserved neutrophils, toxic granularity is noted. Plasma and reticular cells may appear in the peripheral blood. The time of appearance and duration of neutropenia and thrombocytopenia are very indicative for assessing the disease severity. In the most severely sick patients, platelets completely disappear from the peripheral blood, which is accompanied by a significant slowing of blood coagulation and impaired retraction of the blood clot.
At ARS I-II degree a decrease of erythrocytes content in the circulating blood can be observed, while ARS III-IV degree characterized by the presence of pronounced anemia, anisocytosis of erythrocytes and the absence of reticulocytes.
The occurrence of infectious complications and hemorrhages, or massive bleeding in vital organs are the main threat for patients' life at this time. The development of infectious complications during this period should be considered as characteristic of severe radiation injuries. The greatest importance in the occurrence of these complications should be given to the infectious process, which develops according to the type of autoinfection and acquires pathogenic significance in connection with the marked inhibition of hematopoiesis and a drop in the general immunobiological reactivity of the body. Clinically, a bacterial- viral infection takes the form of pneumonia, septicemia, and the appearance of herpes.
Hemorrhages can be observed both in the skin and subcutaneous tissue, and in the mucous membranes of the gastrointestinal tract, respiratory and urinary tracts, in the heart muscle, brain and other organs and tissues. It is significantly difficult to determine the localization of hemorrhages in the brain against the background of the general a patient's severe condition and preceding brain edema, even in the presence of seemingly clear focal neurological symptoms.
Changes in the hematopoietic system depend on the radiation dose and ARS severity. The first signs of recovery are observed relatively early and appear primarily in the lymphoid tissue. In the period when lymphocytopenia is still sharply expressed, lymphoblasts and young lymphocytes appear in the lymph nodes and spleen. However, complete repair of lymphoid tissue is carried out slowly, and therefore the number of lymphocytes in the peripheral blood remains at a low level for a long time. With a more severe injury, regeneration may initially have a somewhat distorted character. In cases ending in death, signs of recovery can sometimes not be noted during the course of the disease. With a lighter injury, regeneration is restored quite quickly.
Table 3 presents a combination of ARS different syndromes depended on of its severity.
Table 3. Typical ARS: combination of syndromes and their expressiveness
|
Dose, Gy |
ARS degree |
|||||
|
ARS degree |
BMS |
OPS |
IS |
SS |
||
|
1-2 |
I |
Mild |
Absent or mild |
Absent |
Absent |
|
|
2-4 |
II |
Moderate |
Mild |
Absent |
Absent |
|
|
4-6 |
III |
Severe |
Mild or moderate |
Absent or mild |
Absent |
|
|
6-10 |
IV |
Extremely severe |
Moderate or severe |
Moderate |
Mild |
Changes in the bone marrow after irradiation can be characterized by four successively periods, which correspond to a certain morphological pattern:
Phase of degenerative-necrotic changes. It is characterized by disorganization of the bone marrow structure, devastation of hematopoietic tissue, expansion of bone marrow sinuses, and hemorrhage. The total number of cells according to trepanobiopsy data one day after irradiation decreases according to the dose: 1-2 Gy - by 10-20 %, 3-4 Gy - by 25-30 %, 5-7 Gy - by 50-60 %, 8-10 Gy - by 80-85 %. Within 1-2 days, macrophages almost completely remove all products of necrosis. One day after irradiation, a 3fold increase in histiocytic, macrophage and stromal elements is determined in the bone marrow.
Stabilization phase. It is characterized by some increase in neutrophils and platelets in the peripheral blood due to preserved cells in bone marrow pool, dividing and maturing. Signs of true regeneration of hematopoietic tissue appear 4-6 days after radiation exposure as the appearance of undifferentiated cells clones. The total number of undifferentiated cells increases over time and reaches a maximum approximately 14-20 days after irradiation. It happens regardless of how irradiation was uniformly distributed on bone marrow individual areas.
Phase of pronounced aplasia. It is characterized by the presence of clones having undifferentiated cells in bone marrow, by edema and hyperemia of parenchyma, increasing fatty atrophy and persistent cytopenia. During this period, lymphocytes, monocytes, and plasma cells predominate in the bone marrow punctate. By the end of the period, there is a decrease in the number of undifferentiated cells due to their entry into the path of differentiation. There is a pronounced focality in the restoration of germ hematopoiesis.
Regeneration phase. It is determined by the number of surviving stem cells and the rate of their proliferation. The recovery phase begins earlier, the higher the radiation dose. This depends primarily on the fact that the stem hematopoietic cell divides at the maximum possible rate and upon reaching a certain level, the process of comitation occurs. The recovery of germinal hematopoiesis in the bone marrow precedes the normalization of peripheral blood parameters by approximately a week.
The beginning of regeneration can be indicated by the appearance or a significant increase in the number of reticulocytes in the peripheral blood, as well as an increase in the number of leukocytes with a sharp left shift up to myeloblasts.
In addition to the above-mentioned changes, hypoproteinemia and hypoalbuminemia, as well as a slight increase in the residual nitrogen content and a decrease in the amount of blood chloride, are observed in the blood picture of seriously sick patients during the disease manifestation.
Hematological and clinical indicators in the period ARS manifestation are the most reliable criteria for determining ARS degree of severity (Table 4).
Table 4. Diagnostics of the degree of severity of ARS during the manifestation period
|
Indices |
ARS degree |
||||
|
І |
ІІ |
ІІІ |
IV |
||
|
Clinical signs |
Asthenia |
Infectious complications, bleeding, epilation |
Infectious complications, bleeding, epilation |
General intoxication, fever, is, hypotension |
|
|
Leukocytes of peripheral blood, 109/l |
3.0-1.5 |
1.5-0.5 |
0.5-0.1 |
< 0.5 or the patient dies earlier |
|
|
Thrombocytes of peripheral blood, 109/l |
100-60 |
50-30 |
< 30 |
< 20 or the patient dies earlier |
|
|
Beginning of agranulocytosis |
Absent |
20th-30th day |
8th-20th day |
6th-8th day |
|
|
Beginning of thrombocytopenia |
Absent or on 25th-28th day 17th-24th day |
10th-16th day |
Before 10th day |
||
|
ESR, mm/h |
10-25 |
25-40 |
40-80 |
60-80 |
Recovery period
The immediate recovery period usually lasts 4-8 weeks, during which the repair processes in hematopoietic system although are not completely finished but reach such a level of functional activity that allows us to talk about clinical recovery from ARS.
The beginning of the recovery period coincides with the normalization of the temperature. At the same time, general well-being improves, appetite appears, sleep normalizes, general weakness decreases. Patients significantly gain weight, with the exception of severely affected patients, in whom weight recovery occurs much later. Swelling, looseness and bleeding gums are significantly reduced and gradually disappear completely.
The petechial rash turns pale and then disap - pears completely. The remaining hair fades, becomes dry, brittle, the growth of new hair at the place of baldness is restored somewhat later (3-4 months from the moment of irradiation), while sometimes the hair color and the degree of curliness change. If the radiation dose was higher than 7 Gy, the alopecia will be irreversible.
The pulse decreases to normal, although its lability remains significant, which is manifested during physical exertion. Systolic blood pressure, as a rule, is equalized, moderate hypotension can often persist for a long time. The tones of the heart become clearer.
As a rule, dyspeptic phenomena are not observed during the recovery period, although at its beginning there may still be a decrease in appetite, intermittent dull pains in the abdomen and the presence of moderate pain during palpation of the colon.
At the end of manifestation period and the beginning of recovery, a gradual recovery of peripheral blood parameters is observed: the number of reticulocytes, leukocytes (primarily neutrophils), platelets and erythrocytes increases, but their number may not reach the lower limit of normative values.
Treatment
Primary reaction
Vomiting relief. To eliminate nausea and prevent vomiting, it is enough to prescribe per os or intramuscular (im) metoclopramide The most common commercial name of a drug is given in parentheses. Author's note. (Cerucal) as dopamine and serotonin receptor blocker if bone marrow form of ARS I degree. At ARS II and III grade it is necessary to inject parenterally metoclopramide or the more effective ondansetron and tropisetron as highly selective 5-HT3 (serotonin) receptor antagonists. At ARS IV degree, when vomiting is violent and is accompanied by abdominal pain, pronounced asthenia or, on the contrary, psychomotor excitement, it is advisable to start treatment with intramuscular or intravenous (iv) administration of chlorpromazine (Aminazine) as neuroleptic.
If the victim has an ulcer then atropine sulfate or platyphylline hydrotartrate can be used subcutaneously (sc) to eliminate vomiting. These drugs in combination with antispasmodics drotaverin are also recommended to be prescribed for intestinal colic with diarrhea in patients with ARS III-IV degree.
Correction of hemodynamic disorders. Phenomena of acute insufficiency of peripheral blood circulation, up to the development of collapse, can be observed in ARS IV degree. If the patient has diseases of the cardiovascular system, hemodynamic disturbances may develop even with a milder course of ARS.
To prevent the development of collapse, the appointment of niketamide (Cordiamine-Zdorovya) or sulfocamphocaine im or sc is indicated. Phenylephrine (Mezaton) is administered in case of a colaptoid condition, and in the case of heart failure in persons with a history of cardiac pathology cardiac glycosides are administered.
Detoxification and replacement therapy. In order to relief intoxication caused by massive cell death and restore the water-electrolyte balance under repeated vomiting, infusion therapy is carried out using saline solutions (Ringer's lactate or Hartmann's), reosorbilact and 5 % glucose solution. In some cases forced diuresis is performed according to indications, taking into account hemodynamic state.
Parenteral nutrition is indicated for patients with ARS III and IV degree. For this purpose, solutions containing amino acids and trace elements (Aminol), as well as fat emulsions (Lipofundin MCT/LCT) are used.
Toxemia and microcirculation disorders in the first days after irradiation are partially associated with the activation of proteolytic enzymes and the development of disseminated intravascular coagulation syndrome. To prevent the mentioned violations during the first 2-3 days after irradiation with ARS II-IV degree development the administration of the proteinase inhibitor aprotinin (Kotriven, Gordox) and low molecular weight heparins as enoxaparin (Clexane, Novoparin, Flenox) and nadroparin (Fraxiparin) is shown.
Hematopoietic growth factor. For the restoration of hematopoiesis and correction of granulocytopenia in patients with presumed ARS III-IV degree it is necessary to start therapy with filgrastim (Grastim, Zarsio, Tevagrastim, Filstim) on the first day after irradiation. This drug is a recombinant granulocyte colony-stimulating factor (G-CSF), which stimulates the formation of functionally active granulocytes and their release into the blood from bone marrow. It is administered sc (the main route) or im daily at a dose of 10 pg per kg of body weight until the level of granulocytes is restored above 1.0 x 109/l, which is maintained for at least 2--3 days. The duration of treatment is 10--27 days.
Pegfilgrastim can be used instead of filgrastim. Its first dose of 6 mg is administered as soon as possible after suspected or confirmed radiation exposure. The second dose of 6 mg is administered a week after the first.
Latent period
After eliminating the symptoms of the primary reaction, the main efforts of medical staff should be directed to the prevention of pathological conditions that may occur during the disease manifestation.
As a primary measure, remediation of chronic infection foci should be carried out: purulent- inflammatory diseases of the skin, oral cavity, nasopharynx (tonsillitis, rhinitis, sinusitis), ear (external and middle otitis), eyes, genitourinary, respiratory systems, etc. If necessary, surgical specialists, dentists, and dermatologists are involved in the treatment of patients.
In patients with ARS I-III degree it is necessary to carry out a bacteriological study of the materials from the foci of chronic infection to determine a microflora sensitivity to antibiotics. For patients with ARS IV degree antibacterial therapy should be prescribed immediately after the elimination of primary reaction symptoms.
In the latent period patients with ARS I--III degree should receive sedatives and antihistamines, analgesics and multivitamins. Pronounced emotional disorders and insomnia require the appointment of anxiolytics (fabomotizolum, gidazepam, diazepam) and tranquilizers (phenazepam).
Manifestation period
Isolation of patients and arrangement of aseptic conditions. Patients with ARS II-IV degree are placed in boxed wards where ultraviolet air sterilizers are installed. Aseptic blocks with air cleanliness class 100 are ideal for patients with ARS III-IV degree.
In order to minimize the likelihood of infectious complications during the disease manifestation it is necessary to keep the following measures:
^ sanitation of medical personnel that contact with the patient;
^ use of sterile hospital gowns, shoe covers, masks and caps by staff when entering the ward;
^ treatment of hands with an antiseptic solution; use of disposable medical gloves before performing medical manipulations;
^ steam treatment and food sterilization;
^ daily change of sterile bed linen.
Antibacterial and antiviral therapy. During the period of agranulocytosis, as well as with deep thrombocytopenia, subcutaneous and intramuscular injections are canceled; intravenous administration of the drug through a catheter is preferred.
Empiric antibacterial therapy should be prescribed according to the protocol for the treatment of febrile neutropenia. This protocol provides for the treatment of infectious complications in patients with ARS and is carried out taking into account risk groups. The low-risk group includes patients who do not have the following symptoms: ^ level of neutrophils below 1.0 x 109/l ^ hemodynamic disorders;
^ organ failure;
^ severe wounds and infections of soft tissues;
^ pneumonia.
The high-risk group includes patients who have one or more of the listed risk factors. It should be noted that agranulocytosis will be present in 25 % of patients with ARS II degree and in 100 % of ones with ARS III--ІV degree. Patients with afebrile neutropenia with clinical signs of infection are also candidates for antimicrobial therapy.
The empirical scheme of antibacterial therapy with a drug from the fluoroquinolones group of the III-IV generation (levofloxacin, moxifloxacin) or the semisynthetic penicillin amoxicillin in combination with clavulanic acid (Amoxiclav, Amoxii-K) provides a wide range of coverage of gram-positive streptococci and staphylococci, as well as gramnegative Pseudomonas and Enterobacteriaceae (National stockpiles for radiological and nuclear emergencies: policy advice, 2023). As an alternative to empirical antibiotic therapy, broad-spectrum antibiotics with extended gram-negative activity can be used parenterahy. It is cephalosporins of the III-IV generations (Ceftriaxone, Ceftazidime, Cefoperazone, Cefepime), protected cephalosporins (Ceftazidime/Avibactam), synthetic carbapenems (Meropenem or Imipenem with Cilastatin sodium, the drug, which blocks the metabolism of the antibiotic in the kidneys, that significantly increases its concentration in the urinary tract) or the semi-synthetic broad-spectrum penicillin Piperacillin with Tazobactam, which is a sulfone derivative of triazolylmethylpenicilanic acid, an inhibitor of many (3-lactamases. Combined antibiotic therapy may also include aminoglycosides (Amikacin, Tobramycin), tricyclic glycopeptide antibiotics (Vancomycin) or synthetic antimicrobial drug of the oxazolidinone class, Linezolid.
Fluconazole is used to prevent systemic fungal infection. With resistance of candida and the development of systemic aspergillosis, viriconazole is prescribed for a long period.
Acyclovir, Valciclovir, Valganciclovir are used to treat a viral infection, usually caused by viruses of herpes group, depending on the causative agent obtained by polymerase chain reaction.
The effectiveness of empiric antibiotic therapy is assessed no earlier than 48--72 hours after its initiation. After receiving the results of a bacteriological examination, it is possible to change antibacterial therapy. Cancellation of the antimicrobial drug is possible on the 3rd--5rd day of the afebrile period.
Hemotransfusion therapy. When the level of platelets in the peripheral blood drops to 20 x 109/l in patients with ARS III-IV degree, there is a threat of spontaneous thrombocytopenic hemorrhagic syndrome development. It is enough to carry out 2-3 transfusions of platelet concentrate containing from 2 to 2.8 x 1011 platelets in 200 ml of plasma for patients with ARS III degree. In patients with ARS IV degree myelosuppression requires more frequent transfusions of platelet concentrate.
Moderate erythrocytopenia is already observed in patients with ARS I degree. Severe anemia is observed only under ARS IV degree, less often in patients with ARS III degree. The indication for the introduction of erythrocyte mass is a hemoglobin level of 80 g/l and below, provided that the patient does not have a violation of cerebral and coronary blood circulation. Instead of erythro-mass, you can use erythrocyte concentrate (hematocrit index 0.85--0.95).
All cellular products should be leukoreduced and irradiated to 25 Gy to prevent a graft-versus-host transfusion reaction in the irradiated (and therefore immunosuppressed) patient. Leukoreduction is known to reduce febrile nonhemolytic reactions and the immunosuppressive effects of blood transfusion. In addition, leukoreduction helps protect against platelet alloimmunization and cytomegalovirus infections (J. K. Waselenko et al., 2004).
Detoxification therapy and nutrition of patients are the same as described for the period of primary reaction and latent period. The volume of infusion is determined taking into account the severity of the disease and hemodynamic indicators.
In patients with severe and extremely severe ARS, 3 to 5 sessions of plasmapheresis (mainly membrane plasmapheresis) are indicated.
Treatment of OPS. When swelling of the mucous membrane of oral cavity appears, rinsing with a 0.5-2 % solution of sodium bicarbonate is recommended. To prevent bacterial infection in the case of loosening and bleeding gums, erosive-ulcerative lesions, antiseptic and antimicrobial drugs are prescribed in solutions for rinsing and in the form of inhalations (Rotokan, Nitrofural, etc.). Treatment is continued until the symptoms of radiation stomatitis disappear. In some cases of severe OPS under ARS I-II degree, when there is no need to transfer a patient to parenteral nutrition, it is advisable to feed the patient through a nasogastric tube with the use of enzyme preparations.
Bone marrow transplantation under ARS is a controversial topic. There are both opponents of HSC transplantation and cautious supporters. The first put forward the following arguments against: (1) since ARS in the vast majority of cases occurs as a result of radiation accidents and incidents, the time factor is included that is the impossibility of quickly selecting the most compatible donor bone marrow; (2) in patients with extremely severe ARS, who are considered as candidates for bone marrow transplantation, this procedure does not reduce the mortality associated with other toxic effects such as burns, lung, gastrointestinal tract and central nervous system damage (R.P. Gale, 1987; R.P. Gale, Y. Reisner, 1988); (3) even with the selection of the most compatible donor (for example, from among first-line relatives), the risk of death remains high, due to toxic immunosuppressants are used during transplantation, developing «graft-versus-host disease» (GVHD) or interstitial pneumonia may develop (A. Baranov et al., 1986; J.-C. Nenot, D. Thierry, 1995).
Some authors believe that the treatment of ARS requires innovative approaches, which include mesenchymal cell transplantation. It can be useful for treatment in various clinical conditions, as they directly replenish lost tissue, indirectly creating a microenvironment necessary for tissue regeneration (R. Fukumoto, 2016). There is also a more cautious approach: hematopoietic stem cell therapy may be considered for patients in whom 2 weeks of supportive hematological therapy, including cytokine therapy and blood transfusion, has been ineffective, and who have limited, potentially curable damage to the body's non-hematopoietic systems (N. Dainiak et al., 2011).
Dividing one or another point of view on HSC transplantation, it should be taken into account that with the mass influx of patients with ARS, it will be very difficult to use this method of treatment.
Recovery period
With mild and moderate lesions, recovery is usually complete, although moderate asthenia can persist for a long time, many years after a severe illness. After the elimination of life-threatening conditions in the hospital, the victims undergo rehabilitation in sanatorium-resort conditions.
For patients with severe weight loss there are prescribed drugs from the group of anabolic steroids (Methandienone, Nandrolone) to stimulate anabolic processes. It is advisable to prescribe multivitamin complexes with trace elements during this period. In the recovery period of AES there is no need to sterilize food. Before restoring the normal functioning of the digestive tract, it is recommended to follow a diet characterized by an increased amount of consumed proteins, mainly dairy, as well as vitamins and minerals.
Prognosis
According to S.P. Yarmonenko and A.A. Winson (2004), after general, relatively uniform exposure and development of ARS I degree it is predicted full recovery in 100% of cases, even in the absence of treatment. The same prognosis was done for patients with ARS II degree, but already in the presence of qualified treatment. Under ARS III degree the recovery is possible in 50--80% of people under the condition of specialized treatment. As a result of the ARS IV degree 30--50% of patients possibly survive only with early treatment in a specialized hospital (A.K. Guskova et al., 1985).
It should be taken into account that this forecast was made in 1985. In the past more than 35 years, medicine began to have new pharmacological agents, which are already successfully used in hematology for the restoration of hematopoiesis, the treatment of heart failure, and antibacterial therapy. There are worked out more accurate and effective methods of diagnosing pathological conditions, which gives hope for successful treatment of patients with ARS III--IV degree. The prognosis for life with intestinal, toxemic and cerebral forms of ARS, as before, remains extremely negative, without hope for survival.
Список використаних джерел
1. Массовые радиационные поражения и вопросы организации медицинской помощи / А К. Гуськова и др. М.: Медицина, 1987. 80 с.
2. Ярмоненко С.П., Вайнсон А.А. Радиобиология человека и животных. М.: Высшая школа, 2004. 549 с.
3. First global consensus for evidence-based management of the hematopoietic syndrome resulting from exposure to ionizing radiation / N. Dainiak, R.N. Gent, Z. Carr et al. Disaster Med. Public Health Prep. 2011. Vol. 5, № 3. P. 202-212.
4. Baranov A., Gale R.P., Guskova A., Piatkin E. Bone marrow transplantation after the Chernobyl nuclear accident. N Engl J Med. 1986;321(4):205-212.
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