Acute Radiation Syndrome- Avinesh Shrestha

This presentation topic discussed a rare but devastating phenomenon/ disaster than can occur due to high exposure to radiation, known as Acute radiation syndrome (ARS)/Radiation sickness. Although radiation(X-Ray's) is used in medical diagnosis as well as treatment regularly, radiation does come with risk, one being ARS. This presentation explains certain aspects of ARS such as what are the conditions required for ARS. it stages and its various subsyndromes. It also covers some of the historical events in mankind which caused ARS as well as some of the medical accidents which resulted in ARS. Some related topics like mean lethal dose, Cutaneous Radiation Injury/ Syndrome and Mean Survival Time are also covered breifly.

1. Acute Radiation Syndrome

2. Overview

3. Introduction When the whole body (or large portion of the body) is subjected to a high acute radiation dose, there are a series of characteristic clinical responses known collectively as the acute radiation syndrome (ARS)/Radiation Sickness. ARS is an organismal response quite distinct from isolated local radiation injuries such as epilation or skin ulcerations. The primary cause of ARS is the destruction of immature parenchymal stem cells in the affected tissues. It refers to a group of subsyndromes occurring in stages over a period of hours to weeks after the exposure as the injury to various tissues and organ systems is expressed. These subsyndromes result from the differing radio-sensitivities of the organ systems.

4. Introduction ARS in human is only academic interest in diagnostic radiology. Diagnostic x-ray beams are neither intense enough nor large enough to cause death. The required conditions for ARS are as follows: The dose must be large. The dose is usually external. The dose is from penetrating radiation (e.g., X- and gamma rays). The majority of the body receives the dose. The entire dose is received in a short time.

5. Sequence of Events: STAGES OF ARS The clinical manifestation of each of the subsyndromes occurs in a predictable sequence of events that includes the prodromal, latent, manifest illness, and, if the dose is not fatal, recovery stages or Death

6. Prodromal Stage This immediate response of radiation sickness is the prodromal period. The onset of prodromal symptoms is dose dependent and can begin within minutes to hours after the exposure. As the whole-body exposure increases above a threshold of approximately 0.5 to 1 Gy , the prodromal symptoms, which (depending on dose) can include anorexia, nausea, lethargy, fever, vomiting, headache, diarrhea and altered mental status, begin earlier and are more severe. It may last from a few hours to a couple of days. The severity of the symptoms is dose related; at doses in excess of 10 Gy (1000 rad), symptoms can be violent. At still higher doses, the duration of the prodromal syndrome becomes shorter until it is difficult to separate the prodromal syndrome from the period of manifest illness. A severe prodromal response to a whole body dose will usually indicate a poor clinical prognosis.

7. Prodromal Period

8. Latent Period After the period of initial radiation sickness, a period of apparent well-being occurs, which is called the latent period. It is the time after exposure during which there is no sign of radiation sickness. It’s duration is shorter for higher doses and may last for up to 4 weeks for modest exposures less than 1 Gy . The latent period extends from hours or less (at doses in excess of 50 Gy ) to weeks (at doses rom 1 to 5 Gy ). The latent period can be thought of as an “incubation period” during which the organ system damage is progressing.

9. Manifest Illness The latent period ends with the onset of the clinical expression of organ system damage, called the manifest illness stage, which can last for approximately 2 to 4 weeks or in some cases even longer. This stage is dependent on the specific clinical syndrome (hematopoietic, gastrointestinal, central nervous system) and may last for hours up to several months. This stage is the most difficult to manage from a therapeutic standpoint, because of the overlying immuno-incompetence that results from damage to the hematopoietic system. Therefore, treatment during the first 6 to 8 weeks after the exposure is essential to optimize the chances for recovery.

10. Death/Recovery If the patient survives the manifest illness stage, recovery is likely; however, the patient will be at higher risk for cancer and, to a lesser extent, his or her future progeny may have an increased risk of genetic abnormalities.

11. Sequence of Events: STAGES OF ARS At very high radiation doses, the latent period disappears altogether. At very low radiation doses, there may be no prodromal period at all.

12. MEAN LETHAL DOSE (LD 50 ) The mean lethal dose is defined as the amount of dose necessary to cause fatality in 50% of a population within a specified period of time. Because various clinical syndromes run their course in different time periods, the LD 50 is assessed at different time periods. The time period in which death is assessed is denoted by a subscript denoting the number of days that has elapsed. For example, the LD 50/30 is the dose necessary to kill 50% of the exposed population within 30 days, whereas the LD 100/2 would be the dose necessary to kill the entire population within 2 days.

13. MEAN LETHAL DOSE (LD 50 ) Being a statistical quantity, the LD 50 varies between species and is not an absolute within the species, as it also depends on body weight and general health of the individual. The LD 50 is only a guide in assessing the prognosis in any individual or animal. The LD 50/30 for human whole body irradiation without medical intervention is approximately 5 Gy . However, as with any other clinical reaction, individual patients will respond differently to the same dose based on their overall health.

14. MEAN LETHAL DOSE (LD 50 ) In the absence of medical care, the human LD 50/60 is approximately 3.5 to 4.5 Gy to the bone marrow. The LD 50/60 may extend to 5 to 6 Gy with supportive care such as the use of transfusions and antibiotics and may be as high as 6 to 8 Gy with effective use of hematopoietic growth factors in an intensive care setting.

15. MEAN LETHAL DOSE (LD 50 )

16. CLINICAL SYNDROMES OF ARS There are, three separate syndromes that are dose related and that follow a rather distinct course of clinical responses. These syndromes are hematologic syndrome, gastrointestinal (GI) syndrome, and central nervous system (CNS) syndrome.

17. Hematologic Syndrome The hematopoietic syndrome is the primary acute clinical consequence of an acute radiation dose between 0.5 and 10 Gy . Healthy adults with proper medical care almost always recover from doses lower than 2 Gy , whereas doses greater than 8 Gy are almost always fatal unless advanced therapies such as the use of colony-stimulating factors or bone marrow transplantation are successful. Even with effective stem cells therapy, however, it is unlikely that patients will survive doses in excess of 12 Gy because of irreversible damage to the gastrointestinal tract and the vasculature. The prodromal symptoms associated with the hematopoietic syndrome can occur within a few hours after exposure and may consist of nausea, vomiting, headache, and diarrhea.

18. Hematologic Syndrome If these symptoms appear early and severe diarrhea occurs within the first 2 days, the radiation exposure may prove to be fatal. The prodromal and latent periods may each last for weeks. Although the nausea and vomiting may subside during the latent period, patients may still feel fatigued and weak. Overall, the systemic effects that can occur from the hematopoietic syndrome include mild to profound immunologic compromise, sepsis, hemorrhage, anemia, and impaired wound healing. It is important to appreciate that even at doses within the hematopoietic syndrome dose range (2 to 10 Gy ), damage to the gastrointestinal tract is occurring. It is responsible for many of the prodromal symptoms.

19. Hematologic Syndrome

20. Hematologic Syndrome In the left image (Normal Marrow), we see a dense population of purple-stained cells — these are bone marrow stem cells actively producing blood cells. The white circular spaces are normal fat vacuoles. In contrast, the right image (Irradiated Marrow, shows loss of these stem cells; the marrow looks empty with mostly large fat spaces and only a few surviving cells. Many of these show pyknosis —meaning shrunken, dark, condensed nuclei, which is a hallmark of cell death. Thus, the irradiated marrow is functionally unable to produce new blood cells.

21. Hematologic Syndrome White blood count (WBC) as a function of time after exposure. The figure shows plots of white blood cell count over time following exposure to different doses of ionizing radiation. These plots summarize data from the Chernobyl accident.

22. Gastrointestinal (GI) Syndrome At higher doses (10-50 Gy ) the clinical expression of the gastrointestinal syndrome becomes the dominant component of the radiation response, the consequences of which are more immediate, severe, and overlap with those of the hematopoietic syndrome. At doses greater than 12 Gy , this syndrome is primarily responsible for lethality. Its prodromal stage includes severe nausea, vomiting, watery diarrhea, and cramps occurring within hours after the exposure and persist for hours to as long as a day. A latent period of 3 to 7 days follows, during which no symptoms are present. Radiation exposure kills the most sensitive cells— stem cells; this controls the length of time until death.

23. Gastrointestinal Syndrome The manifest illness stage begins with the return of the prodromal symptoms that are often more intense than during their initial presentation. Crypt stem cell death: no replacement of villus epithelial cells. Villi denudation: mucosal barrier breakdown. Consequences: Malabsorption of electrolytes & nutrients. Entry of bacteria, antigens, digestive enzymes = radiation-induced mucositis. Increased risk of Sepsis (due to both GI barrier loss & bone marrow leukopenia).

24. Gastrointestinal Syndrome Overall, intestinal pathology includes mucosal ulceration and hemorrhage, disruption of normal absorption and secretion, alteration of enteric flora, depletion of gut lymphoid tissue, and disturbance of gut motility. The systemic effects include malnutrition resulting from malabsorption; vomiting and abdominal distention from paralytic ileus; anemia from gastrointestinal bleeding; sepsis resulting from invasion of intestinal bacteria into the systemic circulation; and dehydration and acute renal failure from fluid and electrolyte imbalance.

25. Gastrointestinal Syndrome Lethality from the gastrointestinal syndrome is essentially 100%. Measurable and even severe hematologic changes occur. It takes a longer time for the cell renewal system of the blood to develop mature cells from the stem cell population; therefore, there is not enough time for maximum hematologic effects to occur. Death occurs within 3 to 10 days after the exposure if no medical care is given or as long as 2 weeks afterward with intensive medical support.

26. Central Nervous System (CNS) syndrome After a radiation dose in excess of approximately 50 Gy (5000 rad) or higher is received, a series of signs and symptoms occur that lead to death within a matter of hours to days. This is the central nervous system (CNS) syndrome. Doses in this range result in cardiovascular shock with a massive loss of serum and electrolytes into extravascular tissues. The ensuing circulatory problems of edema, increased intracranial pressure, and cerebral anoxia cause death before damage to other organ systems and tissues can become clinically significant.

27. Central Nervous System (CNS) syndrome Severe nausea and vomiting begins, usually within a few minutes of exposure. During this initial onset, the patient may become extremely nervous and confused, may describe a burning sensation in the skin, may lose vision, and can even lose consciousness within the first hour. This may be followed by a latent period that lasts up to 12 hours, during which earlier symptoms subside or disappear, followed by a severe manifest illness stage. The prodromal symptoms return with even greater severity, coupled with respiratory distress and gross neurologic changes (including tremors and convulsions) that inevitably lead to coma and death. Many other aspects of this syndrome are not understood because human exposures to supralethal radiation are rare. Experimental evidence suggests that the initial hypotension may be caused by a massive release of histamine from mast cells, and the principal pathology may result from massive damage to the microcirculation

28. Central Nervous System (CNS) syndrome At doses sufficient to produce CNS damage, damage to all other organs of the body is equally severe. The classic radiation-induced changes in the GI tract and the hematologic system cannot occur, because there is insufficient time between exposure and death for them to appear. The ultimate cause of death in CNS syndrome is elevated fluid content of the brain

29. Mean Survival Time As the whole-body radiation dose increases, the average time between exposure and death decreases. This time is known as the mean survival time . As the radiation dose increases rom 2 to 10 Gy (200–1000 rad), the mean survival time decreases from approximately 60 to 4 days; this region is consistent with death resulting from the hematologic syndrome. Mean survival time is dose dependent with the hematologic syndrome. In the dose range associated with GI syndrome, however, the mean survival time remains relatively constant, at 4 days. With larger doses, those associated with CNS syndrome, the mean survival time is again dose dependent, varying from approximately 3 days to a matter of hours.

30. Summary of Clinical Features During the Manifest Illness Phase of the Acute Radiation Syndrome

31. Summary of Clinical Features During the Manifest Illness Phase of the Acute Radiation Syndrome

32. DOI: 10.1016/j.rpor.2011.06.001 Radiobiology of the acute radiation syndrome

33. DOI: 10.1016/j.rpor.2011.06.001 Radiobiology of the acute radiation syndrome

34. DOI: 10.1016/j.rpor.2011.06.001 Radiobiology of the acute radiation syndrome

35. DOI: 10.1016/j.rpor.2011.06.001 Radiobiology of the acute radiation syndrome

36. Cutaneous Radiation Injury/Syndrome Phases of CRS are the same as for the other 3 ARS subsyndrome, and can occur due to: Exposure of the skin from whole or partial body radiation which penetrates deeply into tissues (e.g., gamma, neutron) Exposure of very large areas of skin from high energy beta radiation, which usually does not penetrate deeply enough in tissue to cause the 3 other subsyndromes of ARS (hematopoietic, gastrointestinal, neurovascular) but can cause major skin effects known as beta burns. Medical literature provides wide ranges of  minimal  threshold radiation doses necessary to produce ionizing radiation-induced skin injury (e.g., 3-5 Gy )

37. Cutaneous Radiation Injury/Syndrome Differences between CRS and CRI CRI need not occur in the context of ARS. CRI may occur when radiation injury (from therapeutic or unintentional exposure) is more localized or if radiation dose is insufficient to penetrate to deeper organs and cause ARS. CRS and CRI may be confused or used interchangeably (though incorrectly) in the medical literature.

38. Cutaneous Radiation Syndrome Source: Cutaneous Radiation Syndrome - Radiation Emergency Medical Management

39. Sequence of images shows progression of radiation injury in 40-year-old man who underwent multiple coronary angiography and angioplasty procedures. Image at left is six to eight weeks after exposure and shows prolonged erythema with mauve central area, suggestive of ischemia. Image at center is 16 to 21 weeks following exposure; depigmented skin with central area of necrosis is seen. At right, image at 18 to 21 months shows deep necrosis with atrophic borders. This sequence is available on the U.S. Food and Drug Administration (FDA) Web site and is in the public domain. Source: New paper updates guidelines on fluoro radiation injuries | AuntMinnie

40. Source: Figure 3 | Scientific Reports ( a ) A 52-year-old man (case 6) presented with a typical fluoroscopic radiation-induced skin lesion as a target-like plaque with three differently-colored rims and central ulceration. ( c ) Immediate reconstruction with local rotation fasciocutaneous flap was done. Wound healed smoothly one month after surgery. No recurrence was noted in the following 15 months.

41. ARS Incident Most of the data we have regarding ARS are taken from the survivors of the Hiroshima and Nagasaki atomic bombings in 1945. Atomic bomb  mushroom clouds  over Hiroshima (left) and Nagasaki (right)

42. ARS Incident An explosion at the Chernobyl Nuclear Power Plant in April 1986 resulted in the hospitalization of 237 patients identified as overexposed persons. One hundred thirty-four of them developed ARS. Of these 134 exposed persons, 28 eventually died of ARS-associated injury. Reactor 4 several months after the Chernobyl disaster.

43. ARS Incident In September 1987, a shielded radioactive cesium-137 source (50.9 TBq ) was removed from the protective housing of an abandoned teletherapy machine in Goiânia , Brazil. Subsequently, the source was ruptured. As a result, many people incurred large doses of radiation by both external and internal contamination. Four of the casualties ultimately died, and 28 people developed local radiation injuries and radiation burns. A photograph of the radioactive source involved in the 1987 accident.

44. ARS Incident In 1989, a radiological accident occurred at an industrial sterilization facility in San Salvador, El Salvador. The accident occurred when the cobalt-60 source became stuck in the open position. Three workers were exposed to high radiation doses and developed ARS. The immediate acute effects were limited by specialized treatment. Nonetheless, two of the men were so seriously injured that their legs had to be partly or completely amputated. The most highly exposed worker died 6.5 months later, his death attributed to residual lung damage and other injuries.

45. ARS Incident Litvinenko at  University College Hospital Litvinenko in 2002 Accidental internal or external contamination with radioactive material is unlikely to result in a sufficiently acute dose to produce the ARS in the organ systems. However, as the widely publicized death of Alexander Litvinenko in 2006 from Po-210 (an alpha emitter) poisoning demonstrated, ARS can be observed when internal contamination with large quantities of highly radiotoxic material (~2 GBq in this case) are widely distributed in the body. Mr. Litvinenko died approximately 3 weeks after the poisoning from the complications of profound pancytopenia( low blood cell counts) that is characteristic of severe hematopoietic damage.

46. ARS Incident Litvinenko at  University College Hospital Litvinenko in 2002 The European Court of Human Rights (ECHR) and the UK inquiry concluded that the assassination was likely approved by Russian President and the poisoning was an act of state-sanctioned assassination.

47. Notable medical ARS incidents Therac-25 accidents (1985–1987): The Therac-25, a computer-controlled radiation therapy machine, suffered from a software bug that caused at least six cancer patients in the US and Canada to receive massive radiation overdoses. These incidents led to severe injuries and deaths from ARS. The patients received doses far greater than intended in a very short time, which is one of the key conditions for ARS. A newspaper cut showing the real Therac-25 Accident prevention in case of radiotherapy equipment malfunction | IAEA

48. Notable medical ARS incidents Zaragoza, Spain (1990): After a repair was performed on a linear accelerator, operator failed to notice a problem with the display. As a result, 27 patients with Hodgkin's disease were overexposed to radiation. The incident was attributed to a combination of machine malfunction and human error. Twenty of these patients died, and others suffered severe injuries due to the resulting ARS. Images courtesy of Rune Hafslund Source: Zaragoza Radiotherapy Accident

49. Notable medical ARS incidents Costa Rica (1996): The accident occurred in the radiotherapy Alcyon II unit of the radiotherapy facility at the San Juan de Dios Hospital in San Jose, Costa Rica. On august 22, 1996, a Co-60 radiation source had been replaced, but when it was calibrated, an error was made in calculating the dose rate. The team found that, "the exposure rate had been greater than assumed, by about 50%- 60%“. There were 7 fatalities and 81 injuries due to this accident. Source:Radiation Overdose in Costa Rica, 1996 San Juan de Dios Hospital in San Jose, Costa Rica.

50. Notable medical ARS incidents Panama (2001): A treatment planning error that was not caught, causing a large group of patients to receive massive overdoses of radiation. Many died from the gastrointestinal effects of the radiation, and survivors have suffered from long-term side effects. 28 patients were identified as overexposed with absorbed dose errors ranging from +10% to +105%. By 2005, 23 of the 28 overexposed patients had died, with at least 18 deaths attributed to radiation effects. Source:14--ESPEC--Borras--173-187 The  National Oncologic Institute

51. Notable medical ARS incidents Białystok , Poland (2001): Following a power cut at the Białystok Oncology Centre, five patients (Breast Ca) received significant radiation overdoses. An investigation revealed a fault in the linear accelerator's dose monitoring and safety systems. All five patients developed local radiation injuries of varying severity. Source: STI/PUB/1180 Białystok Oncology Centre poland

52. Conclusion ARS is an condition caused due to high radiation exposure to the whole body or major parts of the body at a short amount of time. The radiation dose in diagnostic imaging is highly unlikely to produce such effects of ARS, however, although very rare, it is a possibility in therapeutic radiation. CRI can occur in complicated and long intervention/ fluoroscopy procedure.

53. References Bushberg J. The essential physics of medical imaging. 3rd ed. Philadelphia, PA: Wolters Kluwer / Lippincott Williams & Wilkins; 2012 Bushong S. Radiologic science for technologists : physics, biology, and protection. 11 th ed. Elsevier Health Sciences; 2016. Kelsey C. Radiation biology of medical imaging. Hoboken, NJ: Wiley Blackwell; 2014. Macià i Garau M, Lucas Calduch A, Casanovas López E. Radiobiology of the acute radiation syndrome. Reports of Practical Oncology and Radiotherapy. 2011;16(5):161-168. doi:10.1016/j.rpor.2011.06.001 . Wei, KC., Yang, KC., Chen, LW.  et al.  Management of fluoroscopy-induced radiation ulcer: One-stage radical excision and immediate reconstruction.  Sci Rep   6 , 35875 (2016). https://doi.org/10.1038/srep35875 https://remm.hhs.gov/cutaneoussyndrome.htm https://www.auntminnie.com/clinical-news/digital-x-ray/article/15594249/new-paper-updates-guidelines-on-fluoro-radiation-injuries