**7. Impact of radiation therapy on normal tissues**

#### **7.1. Accidents and weapons: unintended exposure**

entered the room with two other workers to try and free the equipment. The exposure was so high that one worker died within 6 months of exposure and the two other workers sustained

The modern linear accelerator has a vast array of safety features including computer override systems which prevent improper application of therapy and internal monitoring diodes which monitor dose application. Safe operation of linear accelerators is a challenging task and users of modern equipment have to assume greater responsibilities for safe execution of patient care. Complex treatment plans and delivery system require thorough hands on understanding of machine operations and safety systems. Continuous process monitoring ensuring safe delivery of care is essential to mission to prevent abhorrent behavior of equipment. This includes well trained staff who can detect potential issues and report concerns to appropriate individuals for next step action to mitigate potential problems. Nevertheless, significant errors have occurred which continue to haunt patient care delivery. Advancement in therapy application often require tools that are developed by different companies and the tools must be harmonized through hardware and software adjustments to provide appropriate patient care. This has led to serious and life-threatening injuries when not applied appropriately. The most common errors in computer override situations are software flaws that indicate that a situation is safe when it is unsafe. Examples of software flaws include unintentionally reporting that multileaf jaws are moving appropriately during treatment when they are not and assuring the individual delivering therapy that system delivery is compliant to plan and calculation when the situation may be less secure. Treatments now require thousands of dynamic motions of individual leaves hidden in the gantry of the machine. Linear accelerators and radiation therapy treatment planning have become exceptionally complex. Treatment delivery capability has become exceptionally precise in its capability to deliver very high doses of treatment to small areas with submillimeter precision. The power of the new equipment is extraordinary; however, the power is often used as a marketing tool and does not recognize that new systems including training of personnel have not been appropriately vetted. This represents both the strength and weakness of modern care. The instrument is powerful; however, if not applied appropriately can cause significant harm. If not calibrated and executed properly, life-threatening injuries occur. In recent reporting through the New York Times, Walter Bogdanich accurately reported on misadministration of radiation therapy to multiple patients in several separate situations causing severe injury and death including injuries to tissues that could not be repaired. These are the innocent victims of our technology and their injuries are a sobering reminder that we must maintain

Although software matters can be addressed, we must improve on right patient and right treatment. Human error remains too frequent in treatment delivery. Technology cannot resolve all causes of error and department processes including double identification and time out must be documented and validated to ensure patient safety. More sophisticated digital identification processes may be implemented into clinical operation including iris and fingerprint strategies

injuries requiring amputation [6, 7, 9].

12 Essentials of Accident and Emergency Medicine

a culture of safety [12].

**6. Modern accelerator safety issues**

In these circumstances, injuries imposed are related to strength of the radiation source and distance to the source of radiation. Thermal and mechanical injuries are immediately lifethreatening. Within 15 minutes of exposure, victims exposed to high dose radiation can experience symptoms associated with the event. These symptoms are manifest with high exposure by neuromuscular changes and gastrointestinal effects. At very low-level exposure, the victim may appear well; however, gastrointestinal and bone marrow symptoms may become more visible in the upcoming month post exposure. Intermediate dose exposure results in upper abdominal symptoms and lassitude seen within hours of the exposure. High dose exposure results in more extreme symptoms including rapid fluid loss and hypotension associated with more pronounced neuromuscular symptoms. Often normal tissue sequelae associated with exposure can be divided into acute injury, sub-acute injury, and chronic injury. Unintentional exposure requires evaluation by a trained group of experts who can assess both injury to the victim and risk to others with continued exposure of radioactive sources either on or inhaled/ingested by the victim. The initial screening of victims requires evaluation by trained radiation safety officers and members of emergency services who can begin to apply best supportive care. In the initial phase of the evaluation, it is important to ascertain as accurate assessment of dose exposure as possible. Lymphocyte counts due to intermitotic death and chromosomal damage assessment can be qualitative surrogates for exposure in the early phase of response assessment. Healthcare workers will likely be monitored for exposure; however, the general public will not be monitored, therefore involving experts in radiation exposure early in response assessment is essential to mission in order to appropriately define the extent of the damage and risk of injury [7, 9, 15].

Acute injury occurs within 90 days of exposure, sub-acute injury occurs from 90 days to 2 years after exposure, and chronic injury occurs 2 years after exposure. All organ systems are affected by radiation exposure. At very high exposures of 10 Gy, death will occur within 24–48 hours due to unrelenting swelling within the central nervous system which compromises all neural processes. At exposure of 5–10 Gy, death will occur within 1–2 weeks due to de-population of gastrointestinal stem cells and bone marrow progenitors. Profound and uncontrollable fluid losses compounded by infection are the cause of death. Victims have survived exposures to this level if they can afford maximal supportive care with fluid replacement and bone marrow support. The term LD 50/30 is a term initially used in pharmacology to determine lethal dose (LD) in 50% of the population within 30 days. Historically, the LD 50/30 for radiation exposure was believed to be 2 Gy; however, with modern support services it is believed that this can be increased to 5 Gy.

assigned to amifostine. There are complexities to outpatient clinical application which can be manifested as hypotension and nausea, therefore patients need to be carefully monitored both before and after administration. It is unusual in clinical practice for patients to receive every assigned dose each day. The success is well documented; however, with improvements in radiation dose delivery across salivary tissue, amifostine is not as commonly used in clinical practice as it was a decade earlier. Citron and colleagues have identified nitroxides as agents for protection. These function as well through a free radical scavenger mechanism. Superoxide dismutase (SOD) compounds with gene therapy applications have also been explored. The gene therapy vector has been used in animal models to enhance intracellular accumulation of

Essentials in Accident and Emergency Medicine Radiation Injury: Response and Treatment

http://dx.doi.org/10.5772/intechopen.76863

15

Mitigators are compounds that potentially limit damage of radiation exposure once the event has occurred without clinical manifestation of injury. These compounds influence the metabolic cascade of events that occur post exposure. These compounds include those that can stimulate bone marrow and dermal progenitors. These include granulocyte stimulating growth factor (G-CSF) and keratinocyte growth factor (KGF). KGF also appears to influence the recovery of mucosal surfaces as well as improve dermal integrity. Mitigators of late toxicity center around limiting fibrosis and the primary target is transforming growth factor beta (TGF beta) and interruption of the signaling pathway that promotes expression. Investigators at the University of Massachusetts have evaluated the use of interleukin 1 alpha to limit neutrophil infiltration into the site of radiation injury to limit the extent of injury in damaged dermal tissue. Knockout mice deficient in IL-1 alpha demonstrated both decreased dermal injury to radiation and more rapid time to repair injury. In another series of experiments, investigators at the University of Massachusetts studied optical imaging as a tool to evaluate radiation injury and determine if changes in metrics associated with oxygenation and deoxygenation can be related to dose. Optical imaging demonstrated that changes in dermal tissue associated with radiation within 12 hours of exposure and imaging defined consistent metrics for acute and chronic injury. In a separate patient breast cancer treatment protocol optical imaging successfully defined radiation dose and dose asymmetry (hot spots) in patients undergoing serial imaging during breast cancer radiation therapy. Chronic

changes were likewise well defined on images obtained post treatment [18, 22, 23].

website is http://www.orau.gov/reacts [9, 13–16, 24, 25].

With increased risk of nuclear weapons and exposure to radiation through accident and future air/space travel, it is of increasing importance that emergency services become more familiar with the management of radiation exposure and injury. Radiation experts and safety officers likewise need to be aware and available to support colleagues in emergency services to optimize care for those affected by unintended exposure in time of crisis. There have been numerous incidents of unintended radiation exposure with victims exposed to both partial and total body X-ray. The Medical Science Division of the Oak Ridge Institute for Science and Education operates a Radiation Emergency Assistance Center for the US Department of Energy. The center is a 24-hour consultation service with both medical and health physics support for issues associated with radiation and X-ray exposure. The resources are comprehensive and include expertise for dose assessment, computation of dose from radionucleotides, and laboratory support. The 24-hour emergency telephone is 865 576 3131 and the

SOD with SOD functioning as a free radical scavenger [18–21].

If the exposure is determined to be at or below 5 Gy, most experts recommend no immediate intervention other than best supportive care and symptom management. The victim will need to be carefully monitored for manifestations of acute and sub-acute injury as well as chronic events that can appear at any point in later life including the development of malignancy. If the exposure is determined to be greater than 5 Gy, then death by hematopoietic syndrome including loss of bone marrow progenitors becomes a visible concern. Intervention with barrier nursing and appropriate blood product support is needed to move the victim through this phase into recovery. Recent nuclear accidents have suggested that infection control and vigorous supportive care may help victims survive an exposure dose of up to 7 Gy. The role of bone marrow transplantation in this effort remains to be established. It is likely of benefit in selected patients [15–17].

#### **7.2. Response applications**

Since the development of nuclear weapons and need for response metrics to injury, there is been a scientific interest in identifying compounds that can protect normal tissue from the effects of radiation exposure. Protectors are given either prior to or immediately thereafter exposure. Mitigators are compounds given after exposure to influence and diminish the impact of the exposure to normal tissue. Therapeutic compounds are applied when the event has occurred. After WWII, it has been known that sulfhydryl groups can function as radiation protectors with the simplest compound being cysteine which contains a natural amino acid. Sulfhydryl groups are toxic which can be decreased by the addition of a phosphate group. Once the compound enters the cell, the phosphate group is released, and the sulfhydryl group becomes a free radical scavenger. Sulfhydryl groups have been shown to protect mice from lethal doses of total body radiation. The only compound approved by the US Food and Drug Administration is amifostine (WR-2721). It is sold as ethyol and has been used to prevent xerostomia in patients treated with radiation therapy for head and neck malignancies. In clinical trials, the use of the compound has been shown to improve quality of life scores for patients undergoing radiation therapy. It has also been used to protect other mucosal surfaces (rectum) and pulmonary parenchyma in patients undergoing total body radiation therapy in preparation for bone marrow transplant. To date, there has been no defined tumor protective effect assigned to amifostine. There are complexities to outpatient clinical application which can be manifested as hypotension and nausea, therefore patients need to be carefully monitored both before and after administration. It is unusual in clinical practice for patients to receive every assigned dose each day. The success is well documented; however, with improvements in radiation dose delivery across salivary tissue, amifostine is not as commonly used in clinical practice as it was a decade earlier. Citron and colleagues have identified nitroxides as agents for protection. These function as well through a free radical scavenger mechanism. Superoxide dismutase (SOD) compounds with gene therapy applications have also been explored. The gene therapy vector has been used in animal models to enhance intracellular accumulation of SOD with SOD functioning as a free radical scavenger [18–21].

Acute injury occurs within 90 days of exposure, sub-acute injury occurs from 90 days to 2 years after exposure, and chronic injury occurs 2 years after exposure. All organ systems are affected by radiation exposure. At very high exposures of 10 Gy, death will occur within 24–48 hours due to unrelenting swelling within the central nervous system which compromises all neural processes. At exposure of 5–10 Gy, death will occur within 1–2 weeks due to de-population of gastrointestinal stem cells and bone marrow progenitors. Profound and uncontrollable fluid losses compounded by infection are the cause of death. Victims have survived exposures to this level if they can afford maximal supportive care with fluid replacement and bone marrow support. The term LD 50/30 is a term initially used in pharmacology to determine lethal dose (LD) in 50% of the population within 30 days. Historically, the LD 50/30 for radiation exposure was believed to be 2 Gy; however, with modern support services

If the exposure is determined to be at or below 5 Gy, most experts recommend no immediate intervention other than best supportive care and symptom management. The victim will need to be carefully monitored for manifestations of acute and sub-acute injury as well as chronic events that can appear at any point in later life including the development of malignancy. If the exposure is determined to be greater than 5 Gy, then death by hematopoietic syndrome including loss of bone marrow progenitors becomes a visible concern. Intervention with barrier nursing and appropriate blood product support is needed to move the victim through this phase into recovery. Recent nuclear accidents have suggested that infection control and vigorous supportive care may help victims survive an exposure dose of up to 7 Gy. The role of bone marrow transplantation in this effort remains to be established. It is likely of benefit in

Since the development of nuclear weapons and need for response metrics to injury, there is been a scientific interest in identifying compounds that can protect normal tissue from the effects of radiation exposure. Protectors are given either prior to or immediately thereafter exposure. Mitigators are compounds given after exposure to influence and diminish the impact of the exposure to normal tissue. Therapeutic compounds are applied when the event has occurred. After WWII, it has been known that sulfhydryl groups can function as radiation protectors with the simplest compound being cysteine which contains a natural amino acid. Sulfhydryl groups are toxic which can be decreased by the addition of a phosphate group. Once the compound enters the cell, the phosphate group is released, and the sulfhydryl group becomes a free radical scavenger. Sulfhydryl groups have been shown to protect mice from lethal doses of total body radiation. The only compound approved by the US Food and Drug Administration is amifostine (WR-2721). It is sold as ethyol and has been used to prevent xerostomia in patients treated with radiation therapy for head and neck malignancies. In clinical trials, the use of the compound has been shown to improve quality of life scores for patients undergoing radiation therapy. It has also been used to protect other mucosal surfaces (rectum) and pulmonary parenchyma in patients undergoing total body radiation therapy in preparation for bone marrow transplant. To date, there has been no defined tumor protective effect

it is believed that this can be increased to 5 Gy.

14 Essentials of Accident and Emergency Medicine

selected patients [15–17].

**7.2. Response applications**

Mitigators are compounds that potentially limit damage of radiation exposure once the event has occurred without clinical manifestation of injury. These compounds influence the metabolic cascade of events that occur post exposure. These compounds include those that can stimulate bone marrow and dermal progenitors. These include granulocyte stimulating growth factor (G-CSF) and keratinocyte growth factor (KGF). KGF also appears to influence the recovery of mucosal surfaces as well as improve dermal integrity. Mitigators of late toxicity center around limiting fibrosis and the primary target is transforming growth factor beta (TGF beta) and interruption of the signaling pathway that promotes expression. Investigators at the University of Massachusetts have evaluated the use of interleukin 1 alpha to limit neutrophil infiltration into the site of radiation injury to limit the extent of injury in damaged dermal tissue. Knockout mice deficient in IL-1 alpha demonstrated both decreased dermal injury to radiation and more rapid time to repair injury. In another series of experiments, investigators at the University of Massachusetts studied optical imaging as a tool to evaluate radiation injury and determine if changes in metrics associated with oxygenation and deoxygenation can be related to dose. Optical imaging demonstrated that changes in dermal tissue associated with radiation within 12 hours of exposure and imaging defined consistent metrics for acute and chronic injury. In a separate patient breast cancer treatment protocol optical imaging successfully defined radiation dose and dose asymmetry (hot spots) in patients undergoing serial imaging during breast cancer radiation therapy. Chronic changes were likewise well defined on images obtained post treatment [18, 22, 23].

With increased risk of nuclear weapons and exposure to radiation through accident and future air/space travel, it is of increasing importance that emergency services become more familiar with the management of radiation exposure and injury. Radiation experts and safety officers likewise need to be aware and available to support colleagues in emergency services to optimize care for those affected by unintended exposure in time of crisis. There have been numerous incidents of unintended radiation exposure with victims exposed to both partial and total body X-ray. The Medical Science Division of the Oak Ridge Institute for Science and Education operates a Radiation Emergency Assistance Center for the US Department of Energy. The center is a 24-hour consultation service with both medical and health physics support for issues associated with radiation and X-ray exposure. The resources are comprehensive and include expertise for dose assessment, computation of dose from radionucleotides, and laboratory support. The 24-hour emergency telephone is 865 576 3131 and the website is http://www.orau.gov/reacts [9, 13–16, 24, 25].

#### **7.3. Injury with diagnostic and therapeutic X-rays**

There is an increasing number of cancer survivors. It is estimated that in each primary care practice by 2025 that 20% of the panel of patients in every primary care practice will be a cancer survivor. This creates a challenge for both the primary care and oncology community as management of the normal tissue imprint of therapy on the survivor does not have clear definition as providers differ in their perceived responsibilities and expertise. Historically, the focus of cancer management was driven to tumor control as a sole endpoint. Today, success brings new challenges. With survivorship improving, more patients now live in symbiosis with the known and unknown sequelae of management. Accordingly, cancer survivorship is beginning to mature as a sub-specialty service defined in oncology and executed through primary care. Gaps in both anticipation of injury and responsibility of management often are initially recognized in crisis by emergency services and often are not easily recognized as sequela of management. Unfortunately, electronic medical records are often insufficient in providing necessary information to facilitate problem solving and management. Most radiation therapy equipment and radiation therapy planning volumetric archives reside in proprietary software systems that are used to operate and validate daily treatment operations. Commercial electronic record systems do not have access to this information as the information in radiation oncology resides in proprietary systems. Although interfaces can be built to facilitate note transfer and medical billing documentation, in evaluation of a patient, the volumetric imaging, and radiation dose information is an essential aspect of problem solving in the emergency environment. For example, in the cancer survivor being evaluated for new onset chest pain, it is essential that dose/volume relationships to cardiac subsegments be available for review for analysis of risk assessment. The evolving field of oncocardiology requires an accurate record of radiation dose volume analysis to specific subsegments including pericardium, vessels, myocardium, cardiac valves, and the electrical conducting system. Each area can be affected by specific dose volume review and this information becomes essential for evaluation of the modern patient. Radiation is not a drug and has specific residual fingerprints on the area treated. Modern management of the cancer survivor requires comprehensive understanding of the impact of treatment on normal tissue by those who evaluate the patient after treatment is completed. The imposition of therapy on normal tissue lasts for the lifetime of the patient, therefore information on treatment needs to be available and in an easily retrievable format for all providers. In the next section, we will evaluate injury to tissue that is both acute and chronic. Acute effects of radiation exposure affect cells of rapid self-renewal potential such as skin, bone marrow, and gastrointestinal progenitors. Every organ system can manifest a late effect from radiation exposure [9, 13, 14, 24–26].

exceptionally high doses to skin surfaces, especially in procedures that are highly complicated. Patients would unintentionally receive higher daily dose and accordingly, dermal sequela of management was and still can be highly visible and a significant problem. Modern linear accelerator equipment delivers dose below the skin surface, therefore skin sequelae with traditional treatment fractionation models are less visible in the modern world. However, from an emergency services perspective, radiation beams resonate on dermal surfaces in skin folds and intertriginous regions. These include skin folds in the breast and regional lymph node regions and inguinal/gluteal regions of patients treated for pelvic and anal malignancies. Dose to these areas is higher daily, therefore may have desquamation, both moist and dry, as a consequence of management. Uninformed providers refer to this issue as a "burn". This is inaccurate. Daily treatment limits the self-renewal capacity of stem cells and injury to the basement membrane exposes the dermis to air with resultant moist changes. Although this can be a future site of infection, conservative treatment measures uniformly outpace any barrier application applied in thermal injury, therefore symptom management is often the best approach in this situation. With interest in compressed fractionation schedules for selected patients, the degree of injury during the acute management phase may be more pronounced, therefore from an emergency services perspective, it is important to ask what for the daily dose, not just whether the patient has been treated. The skin is often hyperpigmented during this phase of treatment. Chronic changes appear as hypopigmentation and thinning of dermal tissue associated with fragments of visible surface blood vessels known as telangiectasia. In the chronic phase, the skin is functional; however, if injured, repair may be more protracted. Modern intensity modulation techniques can limit both the extent and volume of radiation dose asymmetry, thus ameliorating the extent of acute and chronic dermal injury for modern patients. It is also to recognize recall of injury by many medications including antibiotics. Modern targeted therapies including epidermal growth factor receptor (EGFR), B-Raf Proto-Oncogene (BRAF), and mechanistic target of rapamycin (mTor) therapies also result in dermal injury and the integrated use of radiation therapy may augment the reaction, even in areas not irradiated. Radiation oncology is evaluating the use of more compressed treatment strategies for outpatient care including stereotactic therapy. There are reports of dermal injury to patients due to equipment augmenting dose to

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17

skin. Treatment planning needs to limit this risk [19, 21–23, 27–33].

Acute effects of radiation therapy affect marrow elements with rapid self-renewal potential. Lymphocytes die an intermitotic death, therefore can be used as a highly qualitative biomarker for radiation dose during exposure. Neutrophils self-renew on a near daily basis, therefore are highly sensitive to X-ray exposure like platelets. Red cells do not have nucleus, therefore decreased red cell count requires further evaluation to rule out a source of cell loss or limitation in production. It is interesting that the use of intensity-modulated radiation therapy (IMRT) for patients with pelvic malignancies is demonstrating an increase in issues associated with blood counts in patients treated with standard chemotherapy for gynecologic and rectal malignancies. This is due to the fact that most radiation oncologists have applied tighter bowel constraints for attenuation of small and large bowel sequelae of management. This brings dose further into pelvic marrow elements and away from bowel. Radiation oncologists must be conscientious on these points. Modern investigators are using advanced technology MRI and metabolic imaging tools to distinguish between red and yellow marrow elements

**7.5. Bone marrow**

#### **7.4. Skin**

Skin is the visible site of acute reactions to X-ray and harbors chronic changes from therapy. Dermal stem cells reside at the basement membrane of the epidermis and the self-renewal process for the epidermis is 3 weeks in tissues that are uninjured. Prior to the use of linear accelerators for patient care, diagnostic X-ray equipment was used to treat patients for malignancies. This resulted in a much higher dose to superficial tissues including skin. Both acute and late effects of radiation therapy are influenced by daily dose and fractionation. In this circumstance, the skin would receive significantly high dose to skin surfaces relative to target. This has importance because fluoroscopy used in interventional radiology and cardiology can deliver exceptionally high doses to skin surfaces, especially in procedures that are highly complicated. Patients would unintentionally receive higher daily dose and accordingly, dermal sequela of management was and still can be highly visible and a significant problem. Modern linear accelerator equipment delivers dose below the skin surface, therefore skin sequelae with traditional treatment fractionation models are less visible in the modern world. However, from an emergency services perspective, radiation beams resonate on dermal surfaces in skin folds and intertriginous regions. These include skin folds in the breast and regional lymph node regions and inguinal/gluteal regions of patients treated for pelvic and anal malignancies. Dose to these areas is higher daily, therefore may have desquamation, both moist and dry, as a consequence of management. Uninformed providers refer to this issue as a "burn". This is inaccurate. Daily treatment limits the self-renewal capacity of stem cells and injury to the basement membrane exposes the dermis to air with resultant moist changes. Although this can be a future site of infection, conservative treatment measures uniformly outpace any barrier application applied in thermal injury, therefore symptom management is often the best approach in this situation. With interest in compressed fractionation schedules for selected patients, the degree of injury during the acute management phase may be more pronounced, therefore from an emergency services perspective, it is important to ask what for the daily dose, not just whether the patient has been treated. The skin is often hyperpigmented during this phase of treatment. Chronic changes appear as hypopigmentation and thinning of dermal tissue associated with fragments of visible surface blood vessels known as telangiectasia. In the chronic phase, the skin is functional; however, if injured, repair may be more protracted. Modern intensity modulation techniques can limit both the extent and volume of radiation dose asymmetry, thus ameliorating the extent of acute and chronic dermal injury for modern patients. It is also to recognize recall of injury by many medications including antibiotics. Modern targeted therapies including epidermal growth factor receptor (EGFR), B-Raf Proto-Oncogene (BRAF), and mechanistic target of rapamycin (mTor) therapies also result in dermal injury and the integrated use of radiation therapy may augment the reaction, even in areas not irradiated. Radiation oncology is evaluating the use of more compressed treatment strategies for outpatient care including stereotactic therapy. There are reports of dermal injury to patients due to equipment augmenting dose to skin. Treatment planning needs to limit this risk [19, 21–23, 27–33].

#### **7.5. Bone marrow**

**7.3. Injury with diagnostic and therapeutic X-rays**

16 Essentials of Accident and Emergency Medicine

There is an increasing number of cancer survivors. It is estimated that in each primary care practice by 2025 that 20% of the panel of patients in every primary care practice will be a cancer survivor. This creates a challenge for both the primary care and oncology community as management of the normal tissue imprint of therapy on the survivor does not have clear definition as providers differ in their perceived responsibilities and expertise. Historically, the focus of cancer management was driven to tumor control as a sole endpoint. Today, success brings new challenges. With survivorship improving, more patients now live in symbiosis with the known and unknown sequelae of management. Accordingly, cancer survivorship is beginning to mature as a sub-specialty service defined in oncology and executed through primary care. Gaps in both anticipation of injury and responsibility of management often are initially recognized in crisis by emergency services and often are not easily recognized as sequela of management. Unfortunately, electronic medical records are often insufficient in providing necessary information to facilitate problem solving and management. Most radiation therapy equipment and radiation therapy planning volumetric archives reside in proprietary software systems that are used to operate and validate daily treatment operations. Commercial electronic record systems do not have access to this information as the information in radiation oncology resides in proprietary systems. Although interfaces can be built to facilitate note transfer and medical billing documentation, in evaluation of a patient, the volumetric imaging, and radiation dose information is an essential aspect of problem solving in the emergency environment. For example, in the cancer survivor being evaluated for new onset chest pain, it is essential that dose/volume relationships to cardiac subsegments be available for review for analysis of risk assessment. The evolving field of oncocardiology requires an accurate record of radiation dose volume analysis to specific subsegments including pericardium, vessels, myocardium, cardiac valves, and the electrical conducting system. Each area can be affected by specific dose volume review and this information becomes essential for evaluation of the modern patient. Radiation is not a drug and has specific residual fingerprints on the area treated. Modern management of the cancer survivor requires comprehensive understanding of the impact of treatment on normal tissue by those who evaluate the patient after treatment is completed. The imposition of therapy on normal tissue lasts for the lifetime of the patient, therefore information on treatment needs to be available and in an easily retrievable format for all providers. In the next section, we will evaluate injury to tissue that is both acute and chronic. Acute effects of radiation exposure affect cells of rapid self-renewal potential such as skin, bone marrow, and gastrointestinal progenitors.

Every organ system can manifest a late effect from radiation exposure [9, 13, 14, 24–26].

Skin is the visible site of acute reactions to X-ray and harbors chronic changes from therapy. Dermal stem cells reside at the basement membrane of the epidermis and the self-renewal process for the epidermis is 3 weeks in tissues that are uninjured. Prior to the use of linear accelerators for patient care, diagnostic X-ray equipment was used to treat patients for malignancies. This resulted in a much higher dose to superficial tissues including skin. Both acute and late effects of radiation therapy are influenced by daily dose and fractionation. In this circumstance, the skin would receive significantly high dose to skin surfaces relative to target. This has importance because fluoroscopy used in interventional radiology and cardiology can deliver

**7.4. Skin**

Acute effects of radiation therapy affect marrow elements with rapid self-renewal potential. Lymphocytes die an intermitotic death, therefore can be used as a highly qualitative biomarker for radiation dose during exposure. Neutrophils self-renew on a near daily basis, therefore are highly sensitive to X-ray exposure like platelets. Red cells do not have nucleus, therefore decreased red cell count requires further evaluation to rule out a source of cell loss or limitation in production. It is interesting that the use of intensity-modulated radiation therapy (IMRT) for patients with pelvic malignancies is demonstrating an increase in issues associated with blood counts in patients treated with standard chemotherapy for gynecologic and rectal malignancies. This is due to the fact that most radiation oncologists have applied tighter bowel constraints for attenuation of small and large bowel sequelae of management. This brings dose further into pelvic marrow elements and away from bowel. Radiation oncologists must be conscientious on these points. Modern investigators are using advanced technology MRI and metabolic imaging tools to distinguish between red and yellow marrow elements and use IMRT for conformal avoidance to address this point. Prior to the use of modern tools for image guidance, radiation oncologists used more generous planning target volumes, and this likewise contributed to the problem. Pancytopenia and bone marrow aplasia and dysfunction are becoming a common consequence of therapy including secondary liquid malignancies. Often, these are first identified in the acute care setting. Bone marrow deficiencies can often take years and decades to develop as a consequence of therapy, therefore vigilance remains important in this area as part of patient management moving forward [19–21, 33].

therapy volumetric objects do not reside in a standard electronic medical record (EMR). This makes communication to the patient/family as well as disease assessment problematic including the delivery of intravascular therapy. In a chaotic vascular system, one can never be certain that dose intent is dose delivered. Efforts are made with external radiation therapy to limit mean liver dose and in an otherwise healthy liver to 30 Gy to 30% volume [19–21, 33–35].

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Similar to the liver, the kidney is a sensitive late responding critical organ. Radiation doses greater than 20 Gy in 2 Gy fractions can result in renal damage with downstream consequence of anemia and hypertension. Although not validated through clinical trials, the tolerance dose is lower is patients who have also received chemotherapy. With advanced treatment technologies, modern radiation oncologists can optimize dose to the kidney using intensity modulation; however, even modern technologies leave a footprint which can limit future function. In comparison with siblings, cancer survivors have a higher likelihood of renal failure. We need to be aware of the tolerance dose as we design care plans with imaging

Similar to the liver and kidney, the lung is a sensitive intermediate to late responding organ. In extreme situations, radiation injury to the lung is life-threatening. The period of active inflammation generally occurs 2–6 months post completion of therapy. Fibrosis can occur years after therapy and this can create distortions in pulmonary anatomy relative for the region treated and dose delivered. During the active inflammatory period, changes consistent with inflammation are visible on thoracic imaging. Interestingly, changes on imaging are often more frequent than symptoms, nevertheless, when symptoms occur at times management is challenging. Injury outside the radiation treatment field is often ascribed to radiation therapy and often we dismiss this as an event without merit. Recent investigations have demonstrated that nitric oxide gas is produced as a by-product of treatment which may explain, in part, why changes in untreated lung can be seen. It is important for radiation therapy treatment objects be available for acute care providers. Although the most recognized metric for pulmonary injury is the volume of parenchyma receiving 20 Gy, in selected situations, the volume of parenchyma receiving 10 and 5 Gy may be of equal importance in determining root cause of pulmonary dysfunction. Oncology treatment records are important for review as chemotherapy agent, targeted therapies and immunotherapy can significantly contribute to pulmonary toxicity. Cancer survivors have a higher risk of chronic pulmonary disease compared to

siblings; therefore need to be vigilant to their long-term pulmonary health [21, 33, 36].

Although historically, the heart and large vessels were thought to be a late responding tissue to injury, modern cardiovascular evaluation and imaging have demonstrated that radiation therapy has an impact on all cardiac structures including coronary arteries, valves, myocardium, and the electrical conduction system. Although efforts in planning radiation therapy now focus on cardiac avoidance and compartment dose volume analysis, there are multiple

**7.8. Renal**

[19, 21, 33].

**7.9. Lung**

**7.10. Cardiovascular**

#### **7.6. Gastrointestinal tract**

The cells that line the gastrointestinal tract have a rapid self-renewal potential with gastric lining undergoing renewal every day and the small bowel every 3 days. The mucosa is dynamic and is responsible for absorption of nutrition and water. Without mucosal lining, body fluid is readily lost and with intermediate level total body exposure, repopulation of mucosa cannot keep pace with fluid loss, hence the genesis of gastrointestinal death from exposure. Infection is also an issue as the barrier is denuded and intestinal flora autoinfect the victim. Therefore, barrier nursing, blood and fluid support are essential to survival in victims who have received an intermediate dose of X-ray. Investigators have demonstrated that bone marrow progenitors may repopulate and differentiate in the gastrointestinal system, indicating a potential benefit to bone marrow transplantation in victims of radiological exposure.

Therapeutic X-ray impact on the gastrointestinal tract is influenced by several factors including co-morbidities and previous surgery. Sequelae can be seen in patients who receive intermediate therapeutic dose to large segments of bowel as well as those who receive high dose to small bowel segments. Strictures are not thought to be a direct effect from treatment; however, if a bowel segment is fixed in position by adhesions, if irradiated, this segment of the GI tract can be further injured and may require surgical removal if symptoms become too demanding and life-threatening. Late effects from management include every tissue component of the gastrointestinal tract. Atrophy of mucosa exposures underlying submucosal tissues to external injury can lead to chronic infection and malabsorption with pain as nerve roots become exposed in the unprotected internal environment. Insufficiency syndromes including the exocrine pancreas are now being observed [19–21, 33].

#### **7.7. Liver**

With the marked increase in viral- and diet-induced liver disease, there is a significant increase in primary hepatic malignancies. Coupled with the improved efficacy of radiation therapy for metastatic disease to the liver, hepatic and diaphragmatic injury from radiation treatment is now well described. Although hepatic parenchyma does not have a rapid self-renewal component, injury to the hepatic reticulum results in disorderly repair limiting blood flow to parenchyma. This limits filtration of both nutrients and toxins. With increased vascular stasis due to disorganized repair, veno-occlusive disease (VOD) becomes an insidious issue and serves to complicate the delivery of care. Metrics for the degree of pre-existing VOD influence the radiation therapy approach to radiosurgery for both primary and metastatic patients. This is important in assessing hepatic disease in the acute care setting. One of the more challenging issues for emergency room providers and primary healthcare delivery teams is the fact that radiation therapy volumetric objects do not reside in a standard electronic medical record (EMR). This makes communication to the patient/family as well as disease assessment problematic including the delivery of intravascular therapy. In a chaotic vascular system, one can never be certain that dose intent is dose delivered. Efforts are made with external radiation therapy to limit mean liver dose and in an otherwise healthy liver to 30 Gy to 30% volume [19–21, 33–35].

#### **7.8. Renal**

and use IMRT for conformal avoidance to address this point. Prior to the use of modern tools for image guidance, radiation oncologists used more generous planning target volumes, and this likewise contributed to the problem. Pancytopenia and bone marrow aplasia and dysfunction are becoming a common consequence of therapy including secondary liquid malignancies. Often, these are first identified in the acute care setting. Bone marrow deficiencies can often take years and decades to develop as a consequence of therapy, therefore vigilance remains important in this area as part of patient management moving forward [19–21, 33].

The cells that line the gastrointestinal tract have a rapid self-renewal potential with gastric lining undergoing renewal every day and the small bowel every 3 days. The mucosa is dynamic and is responsible for absorption of nutrition and water. Without mucosal lining, body fluid is readily lost and with intermediate level total body exposure, repopulation of mucosa cannot keep pace with fluid loss, hence the genesis of gastrointestinal death from exposure. Infection is also an issue as the barrier is denuded and intestinal flora autoinfect the victim. Therefore, barrier nursing, blood and fluid support are essential to survival in victims who have received an intermediate dose of X-ray. Investigators have demonstrated that bone marrow progenitors may repopulate and differentiate in the gastrointestinal system, indicating a potential

Therapeutic X-ray impact on the gastrointestinal tract is influenced by several factors including co-morbidities and previous surgery. Sequelae can be seen in patients who receive intermediate therapeutic dose to large segments of bowel as well as those who receive high dose to small bowel segments. Strictures are not thought to be a direct effect from treatment; however, if a bowel segment is fixed in position by adhesions, if irradiated, this segment of the GI tract can be further injured and may require surgical removal if symptoms become too demanding and life-threatening. Late effects from management include every tissue component of the gastrointestinal tract. Atrophy of mucosa exposures underlying submucosal tissues to external injury can lead to chronic infection and malabsorption with pain as nerve roots become exposed in the unprotected internal environment. Insufficiency syndromes including the exo-

With the marked increase in viral- and diet-induced liver disease, there is a significant increase in primary hepatic malignancies. Coupled with the improved efficacy of radiation therapy for metastatic disease to the liver, hepatic and diaphragmatic injury from radiation treatment is now well described. Although hepatic parenchyma does not have a rapid self-renewal component, injury to the hepatic reticulum results in disorderly repair limiting blood flow to parenchyma. This limits filtration of both nutrients and toxins. With increased vascular stasis due to disorganized repair, veno-occlusive disease (VOD) becomes an insidious issue and serves to complicate the delivery of care. Metrics for the degree of pre-existing VOD influence the radiation therapy approach to radiosurgery for both primary and metastatic patients. This is important in assessing hepatic disease in the acute care setting. One of the more challenging issues for emergency room providers and primary healthcare delivery teams is the fact that radiation

benefit to bone marrow transplantation in victims of radiological exposure.

crine pancreas are now being observed [19–21, 33].

**7.7. Liver**

**7.6. Gastrointestinal tract**

18 Essentials of Accident and Emergency Medicine

Similar to the liver, the kidney is a sensitive late responding critical organ. Radiation doses greater than 20 Gy in 2 Gy fractions can result in renal damage with downstream consequence of anemia and hypertension. Although not validated through clinical trials, the tolerance dose is lower is patients who have also received chemotherapy. With advanced treatment technologies, modern radiation oncologists can optimize dose to the kidney using intensity modulation; however, even modern technologies leave a footprint which can limit future function. In comparison with siblings, cancer survivors have a higher likelihood of renal failure. We need to be aware of the tolerance dose as we design care plans with imaging [19, 21, 33].

#### **7.9. Lung**

Similar to the liver and kidney, the lung is a sensitive intermediate to late responding organ. In extreme situations, radiation injury to the lung is life-threatening. The period of active inflammation generally occurs 2–6 months post completion of therapy. Fibrosis can occur years after therapy and this can create distortions in pulmonary anatomy relative for the region treated and dose delivered. During the active inflammatory period, changes consistent with inflammation are visible on thoracic imaging. Interestingly, changes on imaging are often more frequent than symptoms, nevertheless, when symptoms occur at times management is challenging. Injury outside the radiation treatment field is often ascribed to radiation therapy and often we dismiss this as an event without merit. Recent investigations have demonstrated that nitric oxide gas is produced as a by-product of treatment which may explain, in part, why changes in untreated lung can be seen. It is important for radiation therapy treatment objects be available for acute care providers. Although the most recognized metric for pulmonary injury is the volume of parenchyma receiving 20 Gy, in selected situations, the volume of parenchyma receiving 10 and 5 Gy may be of equal importance in determining root cause of pulmonary dysfunction. Oncology treatment records are important for review as chemotherapy agent, targeted therapies and immunotherapy can significantly contribute to pulmonary toxicity. Cancer survivors have a higher risk of chronic pulmonary disease compared to siblings; therefore need to be vigilant to their long-term pulmonary health [21, 33, 36].

#### **7.10. Cardiovascular**

Although historically, the heart and large vessels were thought to be a late responding tissue to injury, modern cardiovascular evaluation and imaging have demonstrated that radiation therapy has an impact on all cardiac structures including coronary arteries, valves, myocardium, and the electrical conduction system. Although efforts in planning radiation therapy now focus on cardiac avoidance and compartment dose volume analysis, there are multiple generations of patients treated with traditional technologies that may remain at higher risk for cardiovascular injury. Chemotherapy agents also contribute to this risk and targeted therapies may unintentionally add to risk. For example, breast cancer patients are often treated with Adriamycin on an adjuvant basis. This agent has an established history of cardiotoxicity. After administration of Adriamycin, the recovering myocardium expresses Her 2 Neu. Her 2 Neu positive breast cancer patients will receive Herceptin after initial chemotherapy, therefore these patients are at higher risk for cardiac injury without radiation therapy. Modern radiation technologies including optical tracking of position, breath hold, and intensity modulation contribute to decreasing mean heart dose and limit radiation dose to specific cardiac volumes including the left ventricle which is an issue for left breast patients. The field of oncocardiology is an important field of study. Cancer survivors have a higher risk of cardiovascular disease compared to siblings and introducing cardiac-oriented survivorship plans as patients complete their primary therapy needs to become the standard of care. Long-term radiation injury is noted to the microvasculature in all organ systems; however, large vessels were thought to be less susceptible to injury. However, as we move to treatments that include non-traditional fractionation protocols and overlap of previous areas of radiation therapy, evaluation of large vessels with surveillance imaging including the carotid vessels for patients treated for head and neck cancer. With more patients being retreated for secondary events, conformal avoidance to cardiovascular structures as part of primary management and avoidance of radiation dose asymmetry will be important to optimize outcome moving forward [37–43].

vulnerable to injury with unintended exposure and a source of secondary malignancies due to exposure. Gonadal exposure leads to both fertility issues and endocrine dysfunction, which can affect every organ system including growth and development in children. Atrophy and dysfunction of multiple organ systems is identified in patients where limitations in estrogen and testosterone function are not identified. Pituitary dysfunction is well described in multiple disease systems especially in patients treated with high retropharyngeal adenopathy or primary disease in the nasopharynx. Modern survivorship plans need to include strategies

Essentials in Accident and Emergency Medicine Radiation Injury: Response and Treatment

http://dx.doi.org/10.5772/intechopen.76863

21

Children are a highly vulnerable population. Although treated at a young age, late effects often become more visible when these cancer survivors transfer their long-term care into adult medicine. At radiation doses of 20 Gy, limitations in musculo-skeletal development are seen and at dose of 55 Gy bone necrosis can occur, especially in patients treated with chemotherapy. Exit dose from cranio-spinal radiotherapy can impose changes in cardiovascular and pulmonary health and development. Treatment for Wilms tumor makes children vulnerable to renal health problems as adults. Because these children are treated as infants and young children, even low dose therapy affects gonadal function and other gastrointestinal injuries including maldevelopment of bowel segments. With advanced imaging techniques, structures once thought immune to radiation effects now are known to be more vulnerable to injuries. Sacral insufficiency fractures are now visible at radiation doses of 50 Gy. Stereotactic body radiosurgery is now associated with injuries once thought historical in nature including rib fractures from pulmonary therapy. Often childhood patients do not have survivorship plans that can detail what is needed when they become adult patients and adult physicians need to detail a plan when caring for these patients as they become adults to provide a comprehensive survivorship plan. Intentional and unintentional radiation exposure can have significant impact on normal tissue, both immediate and late. In assessing acute exposure, it is essential to determine exposure and dose. Optical imaging may be a tool moving forward which can validate computational extrapolation of dose as injury can be seen within 12 hours of exposure. Appropriate support needs to be applied to victims of acute exposure and intentional therapy needs to be mitigated by strategic planning and application of therapy. Survivorship plans for those exposed to radiation including those with unintentional exposure need to be developed. An understanding of these effects is essential for modern healthcare providers in the acute care setting [19–21, 26, 33, 45].

It has been more than 100 years since the discovery of X-rays and radium. The power of radiation is significant and appropriate application of radiation has saved lives and become an extraordinary source of energy. The devastating side of radiation is equally visible. Both intentional and unintentional injury remains at significant risk in spite of a century worth of knowledge concerning radiation safety and application of safety measures. Radiation therapy and diagnostic imaging remain tools that are essential to mission for patient care, nevertheless we must remain vigilant and apply continuous process improvements in practice to ensure

for endocrine malfunction [33, 26].

**7.13. Pediatrics**

**8. Conclusions**

#### **7.11. Central nervous system**

The brain has multiple cell systems susceptible to injury uniformly viewed as late responding tissues. Necrosis can occur after radiation therapy, especially in circumstances of compressed fractionation and stereotactic radiosurgery and radiotherapy. Although highly unusual, demyelinating syndromes can occur both in the brain and spinal cord associated with both radiation dose and volume treated. Toxicity is also increased with chemotherapy agents including but not limited to Ara-C and Methotrexate, both used in multiple disease settings due to penetrance beyond the blood-brain barrier. There are injuries noted to tissues with end arterial vascular systems. The optic chiasm is susceptible to injury with radiation therapy due to the unique arterial system at doses of 54 Gy. The cochlea is susceptible to injury especially when cis-platinum is used as part of the care plan. Brachial plexus injury was described in breast cancer patients at doses of 54 Gy; however, this is an issue which identification of this dose may be inaccurate. At the time of description of the injury, radiation therapy techniques unintentionally created overlap with anterior and posterior fields under the lateral third of the clavicle where the entire nerve plexus enters the upper extremity. It is rare to see plexopathy in head and neck patients, therefore the experience with the breast cancer population and regional treatment may have related to technique rather than radiation dose. This again point to the importance of increasing the knowledge of radiation therapy in the general medical community and acute care providers [33, 44].

#### **7.12. Endocrine**

Hypothyroidism is exceptionally common in patients treated with both surgery and radiation therapy to the upper thorax and neck. This can have significant health issues and is often overlooked and underappreciated in the acute care environment. The thyroid is also highly vulnerable to injury with unintended exposure and a source of secondary malignancies due to exposure. Gonadal exposure leads to both fertility issues and endocrine dysfunction, which can affect every organ system including growth and development in children. Atrophy and dysfunction of multiple organ systems is identified in patients where limitations in estrogen and testosterone function are not identified. Pituitary dysfunction is well described in multiple disease systems especially in patients treated with high retropharyngeal adenopathy or primary disease in the nasopharynx. Modern survivorship plans need to include strategies for endocrine malfunction [33, 26].

#### **7.13. Pediatrics**

generations of patients treated with traditional technologies that may remain at higher risk for cardiovascular injury. Chemotherapy agents also contribute to this risk and targeted therapies may unintentionally add to risk. For example, breast cancer patients are often treated with Adriamycin on an adjuvant basis. This agent has an established history of cardiotoxicity. After administration of Adriamycin, the recovering myocardium expresses Her 2 Neu. Her 2 Neu positive breast cancer patients will receive Herceptin after initial chemotherapy, therefore these patients are at higher risk for cardiac injury without radiation therapy. Modern radiation technologies including optical tracking of position, breath hold, and intensity modulation contribute to decreasing mean heart dose and limit radiation dose to specific cardiac volumes including the left ventricle which is an issue for left breast patients. The field of oncocardiology is an important field of study. Cancer survivors have a higher risk of cardiovascular disease compared to siblings and introducing cardiac-oriented survivorship plans as patients complete their primary therapy needs to become the standard of care. Long-term radiation injury is noted to the microvasculature in all organ systems; however, large vessels were thought to be less susceptible to injury. However, as we move to treatments that include non-traditional fractionation protocols and overlap of previous areas of radiation therapy, evaluation of large vessels with surveillance imaging including the carotid vessels for patients treated for head and neck cancer. With more patients being retreated for secondary events, conformal avoidance to cardiovascular structures as part of primary management and avoidance of radiation

dose asymmetry will be important to optimize outcome moving forward [37–43].

The brain has multiple cell systems susceptible to injury uniformly viewed as late responding tissues. Necrosis can occur after radiation therapy, especially in circumstances of compressed fractionation and stereotactic radiosurgery and radiotherapy. Although highly unusual, demyelinating syndromes can occur both in the brain and spinal cord associated with both radiation dose and volume treated. Toxicity is also increased with chemotherapy agents including but not limited to Ara-C and Methotrexate, both used in multiple disease settings due to penetrance beyond the blood-brain barrier. There are injuries noted to tissues with end arterial vascular systems. The optic chiasm is susceptible to injury with radiation therapy due to the unique arterial system at doses of 54 Gy. The cochlea is susceptible to injury especially when cis-platinum is used as part of the care plan. Brachial plexus injury was described in breast cancer patients at doses of 54 Gy; however, this is an issue which identification of this dose may be inaccurate. At the time of description of the injury, radiation therapy techniques unintentionally created overlap with anterior and posterior fields under the lateral third of the clavicle where the entire nerve plexus enters the upper extremity. It is rare to see plexopathy in head and neck patients, therefore the experience with the breast cancer population and regional treatment may have related to technique rather than radiation dose. This again point to the importance of increasing the knowledge of radiation therapy in the general medical community and acute care providers [33, 44].

Hypothyroidism is exceptionally common in patients treated with both surgery and radiation therapy to the upper thorax and neck. This can have significant health issues and is often overlooked and underappreciated in the acute care environment. The thyroid is also highly

**7.11. Central nervous system**

20 Essentials of Accident and Emergency Medicine

**7.12. Endocrine**

Children are a highly vulnerable population. Although treated at a young age, late effects often become more visible when these cancer survivors transfer their long-term care into adult medicine. At radiation doses of 20 Gy, limitations in musculo-skeletal development are seen and at dose of 55 Gy bone necrosis can occur, especially in patients treated with chemotherapy. Exit dose from cranio-spinal radiotherapy can impose changes in cardiovascular and pulmonary health and development. Treatment for Wilms tumor makes children vulnerable to renal health problems as adults. Because these children are treated as infants and young children, even low dose therapy affects gonadal function and other gastrointestinal injuries including maldevelopment of bowel segments. With advanced imaging techniques, structures once thought immune to radiation effects now are known to be more vulnerable to injuries. Sacral insufficiency fractures are now visible at radiation doses of 50 Gy. Stereotactic body radiosurgery is now associated with injuries once thought historical in nature including rib fractures from pulmonary therapy. Often childhood patients do not have survivorship plans that can detail what is needed when they become adult patients and adult physicians need to detail a plan when caring for these patients as they become adults to provide a comprehensive survivorship plan.

Intentional and unintentional radiation exposure can have significant impact on normal tissue, both immediate and late. In assessing acute exposure, it is essential to determine exposure and dose. Optical imaging may be a tool moving forward which can validate computational extrapolation of dose as injury can be seen within 12 hours of exposure. Appropriate support needs to be applied to victims of acute exposure and intentional therapy needs to be mitigated by strategic planning and application of therapy. Survivorship plans for those exposed to radiation including those with unintentional exposure need to be developed. An understanding of these effects is essential for modern healthcare providers in the acute care setting [19–21, 26, 33, 45].
