Hospital Management of Trauma

*Emergency Medicine and Trauma*

emj.2009.087486

CD009228.pub3

[16] Butler DP, Anwar I, Willett K. Is it the H or the EMS in HEMS that has an impact on trauma patient mortality? A systematic review of the evidence. Emergency Medicine Journal. 2010;**27**:692-701. DOI: 10.1136/

[17] Galvagno SM Jr, Sikorski R, Hirshon JM, Floccare D, Stephens C, Beecher D, et al. Helicopter emergency medical services for adults with major trauma. Cochrane Database of Systematic Reviews. 2015;(12). Article ID: CD009228. DOI: 10.1002/14651858.

[18] Frink M, Probst C, Hildebrand F, et al. The influence of transportation mode on mortality in polytraumatized patients. An analysis based on the German Trauma Registry. Der Unfallchirurg. 2007;**110**(4):334-340. DOI: 10.1007/s00113-006-1222-2

**42**

**45**

**Chapter 4**

**Abstract**

**1. Introduction**

Treatment Toxicity: Radiation

*Matthew Iandoli, Ameer Elaimy, James Shen, Peter Lee,* 

*Alexander Lukez, Lakshmi Shanmugham, Beth Herrick,* 

*Jon Glanzman and David Goff*

interrelate with immediate and long-term care.

*Thomas J. FitzGerald, Maryann Bishop-Jodoin, Fran Laurie,* 

Radiation exposures, both intentional and unintentional, have influence on normal tissue function. Short-term and long-term injuries can occur to all cell systems of both limited and rapid self-renewal potential. Radiation effects can last a lifetime for a patient and can produce complications for all organs and systems. Often invisible at the time of exposure, the fingerprints for cell damage can appear at any timepoint after. Health-care providers will need comprehensive knowledge and understanding of the acute and late effects of radiation exposure and how these

**Keywords:** radiation exposure, cell damage, toxicity, radiation dose/volume

Radiation exposure can occur during diagnosis and primary treatment of a cancer or during a nuclear incident. These exposures increase our need to educate health-care providers and first responders on assessing and managing patients [1–8]. Although effects on tissue may not be meaningful from a clinical perspective during an evaluation for healthcare, identification of radiation exposure from a dose and volume perspective is an important piece in the patient's past medical history. Invisible fingerprints relevant to medical situations can declare themselves decades after exposure in spite of careful periodic evaluation. The dose and volume of the intentional exposure is usually well documented in the radiation therapy treatment record. Shadow parallel radiation records that are not entered into electronic health system records may not be available at the time of a related healthcare evaluation, and important clinical information may be too brief or inadequate. Many current electronic medical records (EMR) do not have a module for radiation oncology. Data acquisition and management of radiation oncology are conducted with proprietary software systems and are not directly included in the modern electronic record. Interfaces can be built to move small portions of records to the EMR; however these are not reliable modes of data transfer and, if transferred, often cannot be easily retrieved when needed in the acute care setting. Unintentional exposure including exposure from diagnostic imaging is more challenging to document as it is provider-dependent and limited reliable information is documented during a radiology procedure. Radiation dose exposure is estimated using distance and duration models from the primary source as victims, unlike health-care providers, are

#### **Chapter 4**

## Treatment Toxicity: Radiation

*Thomas J. FitzGerald, Maryann Bishop-Jodoin, Fran Laurie, Matthew Iandoli, Ameer Elaimy, James Shen, Peter Lee, Alexander Lukez, Lakshmi Shanmugham, Beth Herrick, Jon Glanzman and David Goff*

#### **Abstract**

Radiation exposures, both intentional and unintentional, have influence on normal tissue function. Short-term and long-term injuries can occur to all cell systems of both limited and rapid self-renewal potential. Radiation effects can last a lifetime for a patient and can produce complications for all organs and systems. Often invisible at the time of exposure, the fingerprints for cell damage can appear at any timepoint after. Health-care providers will need comprehensive knowledge and understanding of the acute and late effects of radiation exposure and how these interrelate with immediate and long-term care.

**Keywords:** radiation exposure, cell damage, toxicity, radiation dose/volume

#### **1. Introduction**

Radiation exposure can occur during diagnosis and primary treatment of a cancer or during a nuclear incident. These exposures increase our need to educate health-care providers and first responders on assessing and managing patients [1–8]. Although effects on tissue may not be meaningful from a clinical perspective during an evaluation for healthcare, identification of radiation exposure from a dose and volume perspective is an important piece in the patient's past medical history. Invisible fingerprints relevant to medical situations can declare themselves decades after exposure in spite of careful periodic evaluation. The dose and volume of the intentional exposure is usually well documented in the radiation therapy treatment record. Shadow parallel radiation records that are not entered into electronic health system records may not be available at the time of a related healthcare evaluation, and important clinical information may be too brief or inadequate. Many current electronic medical records (EMR) do not have a module for radiation oncology. Data acquisition and management of radiation oncology are conducted with proprietary software systems and are not directly included in the modern electronic record. Interfaces can be built to move small portions of records to the EMR; however these are not reliable modes of data transfer and, if transferred, often cannot be easily retrieved when needed in the acute care setting. Unintentional exposure including exposure from diagnostic imaging is more challenging to document as it is provider-dependent and limited reliable information is documented during a radiology procedure. Radiation dose exposure is estimated using distance and duration models from the primary source as victims, unlike health-care providers, are

frequently unmonitored [1–4, 6, 8]. While these estimation models may be useful, accuracy can be compromised, particularly in calculating the integral or total body dose as there are often multiple sources of radiation at the time of the unintended exposure along with thermal injury. With the increasing rate of cancer survivors and the transition of pediatric patients to adult care systems, there is a multilevel knowledge gap of the toxicities caused by radiation exposure and how the acute and late effects relate to patient care.

#### **2. Radiation toxicity**

#### **2.1 Normal tissue damage**

We arbitrarily categorize radiation injury into phases: acute injury (3 months from exposure), subacute (from 3 to 24 months from exposure), and late or chronic (>24 months from exposure). There is considerable overlap in these definitions, and acute injury can be less and non-predictive of chronic injury [1–4]. Acute intentional injuries, both expected and unanticipated, related to radiation therapy management of cancer are best managed by the responsible treating physicians during radiation treatment. These professionals are cognizant of the intended target and normal tissues in the treatment field. Their knowledge of radiation treatment's impact on normal tissue is coupled with established and less well-established toxicities with various applications of chemotherapy and targeted therapy. Unintentional radiation exposure requires additional support and evaluation by emergency services working together with radiation safety experts, who are trained in managing radiation effects and assessing the dose received by the victims using models of time and distance from the epicenter of the event. This also includes evaluating the risk to caregivers of the victim if radioactive particles/elements remain on or in the victim. The acute phase of injury can affect many cell systems. This includes toxicity to limited and rapid self-renewal potential tissues such as the central nervous system, bone marrow, skin, and mucosal surfaces lining the head/neck and gastrointestinal system. Death can occur soon after exposure if it is not recognized in a timely manner and appropriate support is not provided. Although injury to reticulum systems is less common from radiation exposure due to limited self-renewal of these cell systems, injury to these systems including thermal injury eliminate the scaffolding needed for structural repair of cell systems with rapid self-renewal potential as disorderly repair can severely limit cell function.

From an individual cellular perspective, radiation therapy has direct impact on intracellular molecules and can cause both single-strand and double-strand DNA breaks which are repaired through multiple mechanisms. Because water is an important intracellular compound, oxygen compounds including free radical formation creates injury to cells through ionization from radiation exposure. These processes are important for cells and groups of cells near each other. The significance of the injury is directly related to the volume of tissue injured from the exposure as well as the degree of injury to support cells (stroma) that often have a more limited self-renewal capacity. If stroma is significantly damaged, cells with rapid self-renewal potential will not have a support architecture to reorganize and maintain function. The seriousness of acute and late injury is also proportional to the dose and volume of tissue exposed. Late injury is manifested by accelerated fibrosis coupled with limited blood vessel proliferation. The mechanism of late injury is multifactorial in origin including damage to rapid and limited self-renewal potential tissues, blood vessels, and intrinsic repair capacity of the cell system injured mitigated by mechanisms that accelerate fibrosis including TGF beta [9].

**47**

*Treatment Toxicity: Radiation*

deterioration [1, 5–8].

*DOI: http://dx.doi.org/10.5772/intechopen.88192*

Radiation exposure symptoms differ with the severity of the exposure. At very high single-fraction total body doses (>10 Gy (Gray)), near-immediate death will occur through cerebrovascular syndrome despite medical care. The syndrome is due to profound edema within the brain and meninges associated with collapse of all neuromuscular processes due to swelling and herniation of the brain through the foramen magnum. At total body doses of 5–12 Gy, death without support will occur within a few weeks as a result of profound fluid loss and diarrhea due to denudation and destruction of the gastrointestinal system. This can affect both stem cells and cause secondary injury to subdermal structures deforming the architecture of the bowel inhibiting absorption and promoting fluid loss. Patient survival is directly correlated with gastrointestinal (fluid/nutrition) and bone marrow (blood/blood product) support during this phase after exposure. A single total body dose of 10 Gy will eradicate a large segment of the stem cells within the gastrointestinal crypts. Although this dose does not directly affect differentiated adult cells, the exposure eliminates the stem cell self-renewal potential; therefore, the gastrointestinal tract mucosal surface becomes denuded, and the reticulum architecture supporting cell organization can be damaged. As a result, with no barrier for fluid and blood loss, clinical deterioration will occur often within days. At total body exposure doses of 2–5 Gy, death occurs from destruction to the hematopoietic system with primary damage to both stem cells and cells of established lineation. Cells cannot sustain self-renewal, and clinical deterioration can occur with primary marrow failure and secondary infection. Lymphocytes may die an intermitotic death; thus the degree of lymphopenia can provide indirect assessment of dose from exposure [1, 5–8]. During exposure, symptoms consistent with a radiation syndrome will be developed by the victim and can be seen as early as 15 minutes from the initial exposure [1, 6, 8]. Symptom severity is proportional to dose. At higher doses, victims can experience severe gastrointestinal fluid loss, secondary fever from exposure to homeopathic pathogens, and hypotension due to fluid loss suggesting significant toxicity. Often identified at lower dose exposure, the prodromal phase is followed by a latent interval during which the person may look and feel clinically well for days to weeks. After this gastrointestinal and hematopoietic damage may become visible and require intervention to prevent further acute clinical

If the total body exposure is <4–5 Gy, most experts currently recommend no immediate intervention other than symptomatic treatment with fluids and blood support. This would include periodic hydration and antiemetic therapy for nausea and vomiting. As needed, infection can be treated with antibiotics. Death associated with the hematopoietic syndrome becomes a real concern for exposure >5 Gy. Barrier nursing intervention and appropriate blood product support may improve survival. Experience from recent nuclear events suggest that efforts to limit bleeding, infection, and physical trauma during the blood count nadir may improve the

Dermal surfaces can receive much higher doses than internal organs, particularly if the exposure is related to particles. Dermal injuries can be primitive dose biomarkers with epilation/erythema at 3–6 Gy and wet desquamation, bullae, ulceration, and necrosis visible at increased doses [1, 10]. However, if the exposure is a contaminate of radioactive particle and photon exposure, dermal dose may not be an accurate assessment of total body dose. Dermal injuries can be life-threatening due to concurrent infection. Injuries should be managed with the same care offered to burn victims with care taken to monitor health-care staff in case there are residual particles which can transmit unintentional dose to health-care providers. Residual exposure can be identified with careful monitoring with dosimeters as

LD 50/30 (50% survival at 30 days) to and possibly beyond 7 Gy.

done in brachytherapy treatments for health-care providers.

#### *Treatment Toxicity: Radiation DOI: http://dx.doi.org/10.5772/intechopen.88192*

*Emergency Medicine and Trauma*

late effects relate to patient care.

**2. Radiation toxicity**

**2.1 Normal tissue damage**

disorderly repair can severely limit cell function.

frequently unmonitored [1–4, 6, 8]. While these estimation models may be useful, accuracy can be compromised, particularly in calculating the integral or total body dose as there are often multiple sources of radiation at the time of the unintended exposure along with thermal injury. With the increasing rate of cancer survivors and the transition of pediatric patients to adult care systems, there is a multilevel knowledge gap of the toxicities caused by radiation exposure and how the acute and

We arbitrarily categorize radiation injury into phases: acute injury (3 months from exposure), subacute (from 3 to 24 months from exposure), and late or chronic (>24 months from exposure). There is considerable overlap in these definitions, and acute injury can be less and non-predictive of chronic injury [1–4]. Acute intentional injuries, both expected and unanticipated, related to radiation therapy management of cancer are best managed by the responsible treating physicians during radiation treatment. These professionals are cognizant of the intended target and normal tissues in the treatment field. Their knowledge of radiation treatment's impact on normal tissue is coupled with established and less well-established toxicities with various applications of chemotherapy and targeted therapy. Unintentional radiation exposure requires additional support and evaluation by emergency services working together with radiation safety experts, who are trained in managing radiation effects and assessing the dose received by the victims using models of time and distance from the epicenter of the event. This also includes evaluating the risk to caregivers of the victim if radioactive particles/elements remain on or in the victim. The acute phase of injury can affect many cell systems. This includes toxicity to limited and rapid self-renewal potential tissues such as the central nervous system, bone marrow, skin, and mucosal surfaces lining the head/neck and gastrointestinal system. Death can occur soon after exposure if it is not recognized in a timely manner and appropriate support is not provided. Although injury to reticulum systems is less common from radiation exposure due to limited self-renewal of these cell systems, injury to these systems including thermal injury eliminate the scaffolding needed for structural repair of cell systems with rapid self-renewal potential as

From an individual cellular perspective, radiation therapy has direct impact on intracellular molecules and can cause both single-strand and double-strand DNA breaks which are repaired through multiple mechanisms. Because water is an important intracellular compound, oxygen compounds including free radical formation creates injury to cells through ionization from radiation exposure. These processes are important for cells and groups of cells near each other. The significance of the injury is directly related to the volume of tissue injured from the exposure as well as the degree of injury to support cells (stroma) that often have a more limited self-renewal capacity. If stroma is significantly damaged, cells with rapid self-renewal potential will not have a support architecture to reorganize and maintain function. The seriousness of acute and late injury is also proportional to the dose and volume of tissue exposed. Late injury is manifested by accelerated fibrosis coupled with limited blood vessel proliferation. The mechanism of late injury is multifactorial in origin including damage to rapid and limited self-renewal potential tissues, blood vessels, and intrinsic repair capacity of the cell system injured mitigated by mechanisms that accelerate fibrosis including TGF beta [9].

**46**

Radiation exposure symptoms differ with the severity of the exposure. At very high single-fraction total body doses (>10 Gy (Gray)), near-immediate death will occur through cerebrovascular syndrome despite medical care. The syndrome is due to profound edema within the brain and meninges associated with collapse of all neuromuscular processes due to swelling and herniation of the brain through the foramen magnum. At total body doses of 5–12 Gy, death without support will occur within a few weeks as a result of profound fluid loss and diarrhea due to denudation and destruction of the gastrointestinal system. This can affect both stem cells and cause secondary injury to subdermal structures deforming the architecture of the bowel inhibiting absorption and promoting fluid loss. Patient survival is directly correlated with gastrointestinal (fluid/nutrition) and bone marrow (blood/blood product) support during this phase after exposure. A single total body dose of 10 Gy will eradicate a large segment of the stem cells within the gastrointestinal crypts. Although this dose does not directly affect differentiated adult cells, the exposure eliminates the stem cell self-renewal potential; therefore, the gastrointestinal tract mucosal surface becomes denuded, and the reticulum architecture supporting cell organization can be damaged. As a result, with no barrier for fluid and blood loss, clinical deterioration will occur often within days. At total body exposure doses of 2–5 Gy, death occurs from destruction to the hematopoietic system with primary damage to both stem cells and cells of established lineation. Cells cannot sustain self-renewal, and clinical deterioration can occur with primary marrow failure and secondary infection. Lymphocytes may die an intermitotic death; thus the degree of lymphopenia can provide indirect assessment of dose from exposure [1, 5–8].

During exposure, symptoms consistent with a radiation syndrome will be developed by the victim and can be seen as early as 15 minutes from the initial exposure [1, 6, 8]. Symptom severity is proportional to dose. At higher doses, victims can experience severe gastrointestinal fluid loss, secondary fever from exposure to homeopathic pathogens, and hypotension due to fluid loss suggesting significant toxicity. Often identified at lower dose exposure, the prodromal phase is followed by a latent interval during which the person may look and feel clinically well for days to weeks. After this gastrointestinal and hematopoietic damage may become visible and require intervention to prevent further acute clinical deterioration [1, 5–8].

If the total body exposure is <4–5 Gy, most experts currently recommend no immediate intervention other than symptomatic treatment with fluids and blood support. This would include periodic hydration and antiemetic therapy for nausea and vomiting. As needed, infection can be treated with antibiotics. Death associated with the hematopoietic syndrome becomes a real concern for exposure >5 Gy. Barrier nursing intervention and appropriate blood product support may improve survival. Experience from recent nuclear events suggest that efforts to limit bleeding, infection, and physical trauma during the blood count nadir may improve the LD 50/30 (50% survival at 30 days) to and possibly beyond 7 Gy.

Dermal surfaces can receive much higher doses than internal organs, particularly if the exposure is related to particles. Dermal injuries can be primitive dose biomarkers with epilation/erythema at 3–6 Gy and wet desquamation, bullae, ulceration, and necrosis visible at increased doses [1, 10]. However, if the exposure is a contaminate of radioactive particle and photon exposure, dermal dose may not be an accurate assessment of total body dose. Dermal injuries can be life-threatening due to concurrent infection. Injuries should be managed with the same care offered to burn victims with care taken to monitor health-care staff in case there are residual particles which can transmit unintentional dose to health-care providers. Residual exposure can be identified with careful monitoring with dosimeters as done in brachytherapy treatments for health-care providers.

An accurate assessment of dose is very important during the triage and care of victims with unintended exposure. Health-care workers are often monitored with dosimeters; however, the public will not have access to these tools. Therefore, radiation exposure and dose assessment experts are important early in the evaluation including analysis of the population at risk. As radiation dose increases, the time to emesis decreases, and rapid onset of nausea and vomiting suggests higher exposure. As indicated, a decline in lymphocyte count or abnormal lymphocyte cytogenetics can be an indirect estimate of dose within 1–2 days of exposure. [1, 6–8, 11]. The Radiation Emergency Assistance Center for the United States (US) Department of Energy is operated by Oak Ridge Institute for Science and Education. Medical and radiation safety support is available through a 24-hour consultation service. Resources include radiation dose assessment in laboratory facilities and computation of dose from radionucleotide expertise. The 24-hour emergency telephone number is 865.576.3131, and the website is https://orise.orau.gov/reacts/resources/index.html.

Recognized as an important clinical endeavor since nuclear weapons have been developed, there is keen interest in finding the chemical compounds that can protect normal tissues against radiation injury. Radiation protectors are compounds applied or administered prior to exposure or in selected circumstances soon thereafter, to limit the impact and subsequent damage from exposure upon normal tissue. Compounds that can influence and promote the health of normal tissue after exposure are referred to as radiation mitigators. These therapeutic compounds are applied once the injury has occurred. Sulfhydryl compounds (SHs) have been shown to be effective radioprotectors. The simplest of these compounds, cysteine, contains a natural amino acid [11, 12]. The mechanism is thought to be related to the augmentation of amino acids in generating repair proteins at a higher level. Once the compound becomes intracellular, it loses the phosphate group and is thought to also serve as a free radical scavenger limiting intracellular damage.

Amifostine (ethyol) has been used to prevent xerostomia in patients receiving radiation therapy for head and neck cancer [13]. Several clinical trials have used amifostine to evaluate the effectiveness in protecting multiple mucosal surfaces as well as protecting pulmonary injury in patients undergoing total body irradiation therapy as part of bone marrow transplant [13]. Amifostine was associated with improvement in patient assessment of mouth dryness and swallowing in a trial managed by the National Clinical Trial Network [13, 14]. The intrinsic fear of applying radiation protectors and mitigators in cancer therapy is the possible simultaneous tumor protective effect of these compounds in situ potentially limiting the usefulness of the compounds. In this trial, it is important to note there was no difference in tumor control between patients receiving amifostine and patients receiving placebo. Nitroxides have been identified by Citrin and colleagues [11] as radioprotection agents in clinical development. Stable nitroxide free radicals and their specific electron reduction products, hydroxylamines, protect cells when exposed to oxidative stress. Accordingly, similar compounds are under review and evaluation. Antioxidants, such as alpha-tocopherol and beta-carotene, are under review for clinical application but to date have not been shown to be of clinical benefit [15, 16]. Investigators explored using gene therapy vectors with superoxide dismutase (SOD) to improve the intracellular component of SOD. The purpose is to limit damage caused by superoxide radicals. Investigators have demonstrated improved normal tissue tolerance to multiple organs including the esophagus with this approach [17, 18]. Captopril is a sulfhydryl containing analog of proline and inhibits angiotensin-converting enzyme and limits vasoconstriction. In animal models, it has been shown to benefit renal and pulmonary function with total body irradiation by limiting endothelial dysfunction, fluid exudation, and the subsequent development of pulmonary fibrosis. It also appeared to improve recovery

**49**

*Treatment Toxicity: Radiation*

*DOI: http://dx.doi.org/10.5772/intechopen.88192*

gene expression after radiation [25, 26].

of hematoprogenitor cells [19–21]. ON 01210 (chlorobenzylsulfone derivative) is a small molecule kinase inhibitor which potentiates recovery of peripheral blood elements when administered before radiation. This may be of benefit to the general public and first responders in an unanticipated event if received early postexposure [22]. Animal models have shown a positive repopulation effect of gastrointestinal stem cells with R-spondin 1, a 263 amino acid protein [23]. CBLB502 is an agent that binds to toll-like receptor 5 (TLR5) activating NF-kB signal pathways. It is derived from the flagellin protein of *Salmonella* bacteria. It promotes recovery and regeneration of multiple organ system stem cells after TBI therapy including GI, oral mucosa, skin, and bone marrow progenitors. IL-6 and other bone marrowassociated colony-stimulating factors likewise appear to work in parallel with this compound. The compound has a potential role as both a protectant and a mitigator [24]. Gamma-tocotrienol is an isomer of vitamin E and supports survival in animal models during total body irradiation in part by promoting bone marrow colonystimulating factors and IL-6. It also may play a role in upregulating anti-apoptotic

The role of mitigators is to limit injury from radiation exposure prior to the clinical manifestations of acute and late toxicities of the exposure and treatment. These compounds are generally thought to influence metabolic events occurring after exposure and limit radiation-associated damage. To date, cytokines and growth factors directed to stimulate stem cell proliferation are the most common tools used for this purpose. In clinical practice, these are commonly used to balance the inhibition of stem cell growth induced by chemotherapy and radiation to the hematopoietic, dermal, and gastrointestinal systems. These include granulocyte colony-stimulating factor (G-CSF) and keratinocyte growth factor (KGF) [27]. The factors contribute to many aspects of cell recovery. KGF has positive influence in the recovery of mucosal surfaces during the acute phase of toxicity as well as limits the late effects of radiotherapy, including xerostomia [11]. This is thought to potentially be of benefit to patients undergoing primary management for head and neck tumors. Mitigators of late toxicity are largely directed to limit fibrosis, which is thought to be a primary factor in late pulmonary injury and other tissues of more limited self-renewal potential [11, 15–18, 28–32]. Transforming growth factor beta (TGF-B) is the primary target to limit fibrosis [33–35]. Several compounds in development prevent late effects to either directly or indirectly target the TGF-B signaling pathway [33–35]. Tumor protection remains a concern when evaluating treatments associated with this parallel pathway for patients being treated for a malignancy, identical to compounds associated with radiation protection. There has been increasing interest in the use of stem cell therapy to repair both acute and chronic injuries. Mesenchymal stem cells modified with extracellular superoxide dismutase have been shown to improve survival of irradiated mice [36]. There is evidence these progenitors have a pleuripotent role and can be called upon by organ systems for differentiation along multiple pathways. Bone marrow stromal cells and myeloid progenitors are also under evaluation to mitigate radiation response. The survival benefit in mice with infusion of myeloid progenitors could be seen days after exposure [37–40]. The role of these infusional therapies in this circumstance remains to be optimally defined. The role of transplant and stem cell infusion during the Chernobyl crisis was uncertain; however these techniques have improved

and remain to be optimized in similar situations moving forward.

Neutrophil inhibition has the potential of limiting the severity of response to injury, and this has been evaluated in a series of experiments determining the potential role of these strategic compounds applied after radiation exposure. Experiments evaluated interleukin-1 alpha (IL-1α) as a mitigator of dermal damage after radiation exposure. Interleukin-1 (IL-1) inhibits neutrophil infiltration

#### *Treatment Toxicity: Radiation DOI: http://dx.doi.org/10.5772/intechopen.88192*

*Emergency Medicine and Trauma*

An accurate assessment of dose is very important during the triage and care of victims with unintended exposure. Health-care workers are often monitored with dosimeters; however, the public will not have access to these tools. Therefore, radiation exposure and dose assessment experts are important early in the evaluation including analysis of the population at risk. As radiation dose increases, the time to emesis decreases, and rapid onset of nausea and vomiting suggests higher exposure. As indicated, a decline in lymphocyte count or abnormal lymphocyte cytogenetics can be an indirect estimate of dose within 1–2 days of exposure. [1, 6–8, 11]. The Radiation Emergency Assistance Center for the United States (US) Department of Energy is operated by Oak Ridge Institute for Science and Education. Medical and radiation safety support is available through a 24-hour consultation service. Resources include radiation dose assessment in laboratory facilities and computation of dose from radionucleotide expertise. The 24-hour emergency telephone number is 865.576.3131, and the website is https://orise.orau.gov/reacts/resources/index.html. Recognized as an important clinical endeavor since nuclear weapons have been developed, there is keen interest in finding the chemical compounds that can protect normal tissues against radiation injury. Radiation protectors are compounds applied or administered prior to exposure or in selected circumstances soon thereafter, to limit the impact and subsequent damage from exposure upon normal tissue. Compounds that can influence and promote the health of normal tissue after exposure are referred to as radiation mitigators. These therapeutic compounds are applied once the injury has occurred. Sulfhydryl compounds (SHs) have been shown to be effective radioprotectors. The simplest of these compounds, cysteine, contains a natural amino acid [11, 12]. The mechanism is thought to be related to the augmentation of amino acids in generating repair proteins at a higher level. Once the compound becomes intracellular, it loses the phosphate group and is thought to

also serve as a free radical scavenger limiting intracellular damage.

Amifostine (ethyol) has been used to prevent xerostomia in patients receiving radiation therapy for head and neck cancer [13]. Several clinical trials have used amifostine to evaluate the effectiveness in protecting multiple mucosal surfaces as well as protecting pulmonary injury in patients undergoing total body irradiation therapy as part of bone marrow transplant [13]. Amifostine was associated with improvement in patient assessment of mouth dryness and swallowing in a trial managed by the National Clinical Trial Network [13, 14]. The intrinsic fear of applying radiation protectors and mitigators in cancer therapy is the possible simultaneous tumor protective effect of these compounds in situ potentially limiting the usefulness of the compounds. In this trial, it is important to note there was no difference in tumor control between patients receiving amifostine and patients receiving placebo. Nitroxides have been identified by Citrin and colleagues [11] as radioprotection agents in clinical development. Stable nitroxide free radicals and their specific electron reduction products, hydroxylamines, protect cells when exposed to oxidative stress. Accordingly, similar compounds are under review and evaluation. Antioxidants, such as alpha-tocopherol and beta-carotene, are under review for clinical application but to date have not been shown to be of clinical benefit [15, 16]. Investigators explored using gene therapy vectors with superoxide dismutase (SOD) to improve the intracellular component of SOD. The purpose is to limit damage caused by superoxide radicals. Investigators have demonstrated improved normal tissue tolerance to multiple organs including the esophagus with this approach [17, 18]. Captopril is a sulfhydryl containing analog of proline and inhibits angiotensin-converting enzyme and limits vasoconstriction. In animal models, it has been shown to benefit renal and pulmonary function with total body irradiation by limiting endothelial dysfunction, fluid exudation, and the subsequent development of pulmonary fibrosis. It also appeared to improve recovery

**48**

of hematoprogenitor cells [19–21]. ON 01210 (chlorobenzylsulfone derivative) is a small molecule kinase inhibitor which potentiates recovery of peripheral blood elements when administered before radiation. This may be of benefit to the general public and first responders in an unanticipated event if received early postexposure [22]. Animal models have shown a positive repopulation effect of gastrointestinal stem cells with R-spondin 1, a 263 amino acid protein [23]. CBLB502 is an agent that binds to toll-like receptor 5 (TLR5) activating NF-kB signal pathways. It is derived from the flagellin protein of *Salmonella* bacteria. It promotes recovery and regeneration of multiple organ system stem cells after TBI therapy including GI, oral mucosa, skin, and bone marrow progenitors. IL-6 and other bone marrowassociated colony-stimulating factors likewise appear to work in parallel with this compound. The compound has a potential role as both a protectant and a mitigator [24]. Gamma-tocotrienol is an isomer of vitamin E and supports survival in animal models during total body irradiation in part by promoting bone marrow colonystimulating factors and IL-6. It also may play a role in upregulating anti-apoptotic gene expression after radiation [25, 26].

The role of mitigators is to limit injury from radiation exposure prior to the clinical manifestations of acute and late toxicities of the exposure and treatment. These compounds are generally thought to influence metabolic events occurring after exposure and limit radiation-associated damage. To date, cytokines and growth factors directed to stimulate stem cell proliferation are the most common tools used for this purpose. In clinical practice, these are commonly used to balance the inhibition of stem cell growth induced by chemotherapy and radiation to the hematopoietic, dermal, and gastrointestinal systems. These include granulocyte colony-stimulating factor (G-CSF) and keratinocyte growth factor (KGF) [27]. The factors contribute to many aspects of cell recovery. KGF has positive influence in the recovery of mucosal surfaces during the acute phase of toxicity as well as limits the late effects of radiotherapy, including xerostomia [11]. This is thought to potentially be of benefit to patients undergoing primary management for head and neck tumors. Mitigators of late toxicity are largely directed to limit fibrosis, which is thought to be a primary factor in late pulmonary injury and other tissues of more limited self-renewal potential [11, 15–18, 28–32]. Transforming growth factor beta (TGF-B) is the primary target to limit fibrosis [33–35]. Several compounds in development prevent late effects to either directly or indirectly target the TGF-B signaling pathway [33–35]. Tumor protection remains a concern when evaluating treatments associated with this parallel pathway for patients being treated for a malignancy, identical to compounds associated with radiation protection. There has been increasing interest in the use of stem cell therapy to repair both acute and chronic injuries. Mesenchymal stem cells modified with extracellular superoxide dismutase have been shown to improve survival of irradiated mice [36]. There is evidence these progenitors have a pleuripotent role and can be called upon by organ systems for differentiation along multiple pathways. Bone marrow stromal cells and myeloid progenitors are also under evaluation to mitigate radiation response. The survival benefit in mice with infusion of myeloid progenitors could be seen days after exposure [37–40]. The role of these infusional therapies in this circumstance remains to be optimally defined. The role of transplant and stem cell infusion during the Chernobyl crisis was uncertain; however these techniques have improved and remain to be optimized in similar situations moving forward.

Neutrophil inhibition has the potential of limiting the severity of response to injury, and this has been evaluated in a series of experiments determining the potential role of these strategic compounds applied after radiation exposure. Experiments evaluated interleukin-1 alpha (IL-1α) as a mitigator of dermal damage after radiation exposure. Interleukin-1 (IL-1) inhibits neutrophil infiltration

into the initial inflammatory response to injury. Assuming the initial inflammatory phase can be titrated, short-term and long-term injuries could be influenced. Knockout mice deficient in IL-1α or the IL-1 receptor demonstrated both decreased dermal injury and more rapid healing after superficial radiation exposure with both electrons and a strontium applicator. This demonstrated the potential importance of this cytokine in generating and ameliorating radiation-associated skin damage associated with neutrophil inhibition. In a separate group of experiments, investigators demonstrated that hyperspectral optical imaging (HSI) can reveal acute and late oxygenation and perfusion changes in dermal tissue with changes occurring as early as 12 hours after radiation exposure [41, 42]. Imaging changes in oxygenation and perfusion were seen within 12 hours of exposure and predated clinical visible skin change by 14 days [42]. Data sets from this group as part of an approved Institutional Review Board clinical trial for breast cancer patients receiving radiation therapy have shown that changes in imaging correlate well with radiation dose and dose asymmetry in the treated volume. Areas of increased dose associated with patient topography, and chest wall separation demonstrated changes consistent with increased dose and daily fractionation.

In response to the need of developing compounds for radioprotection and mitigation, the Radiation Research Program of the National Cancer Institute in collaboration with the Small Business Innovation Research program has funded a series of contracts since 2010 to support the development of radiomodulators. To date, five of the funded applications have successfully transitioned to phase II funding. Eight clinical trials have been developed to establish safety and efficacy. Two drugs on trial are under evaluation as radioprotectors, and two are also being evaluated for anticancer properties. The sites of interest being studied include CNS injury, mucositis, proctitis/enteritis, bone marrow failure, and lung injury [43].

#### **3. Conclusions**

Researchers are developing a targeted pharmacologic response to protect and mitigate issues surrounding intentional and unintentional radiation exposure. A knowledge of normal tissue response to radiation injury will be important for all health-care providers moving forward. Radiation therapy patients, accident victims, and first responders will benefit from the growing body of knowledge.

**51**

*Treatment Toxicity: Radiation*

**Author details**

Matthew Iandoli2

Thomas J. FitzGerald1

Lakshmi Shanmugham4

Worcester, MA, USA

\*, Maryann Bishop-Jodoin2

, Beth Herrick<sup>5</sup>

UMass Memorial Managed Care Network, Worcester, MA, USA

3 University of Massachusetts Medical School, Worcester, MA, USA

UMassMemorial Managed Care Network, Fitchburg, MA, USA

UMassMemorial Managed Care Network, Brighton, MA, USA

UMassMemorial Managed Care Network, Foxborough, MA, USA

UMassMemorial Managed Care Network, Methuen, MA, USA

thomas.fitzGerald@umassmed.edu

provided the original work is properly cited.

\*Address all correspondence to: tj.fitzgerald@umassmemorial.org;

, James Shen3

1 Department of Radiation Oncology, University of Massachusetts Medical School,

2 Department of Radiation Oncology, University of Massachusetts Medical School,

4 Department of Radiation Oncology, University of Massachusetts Medical School,

5 Department of Radiation Oncology, University of Massachusetts Medical School,

6 Department of Radiation Oncology, University of Massachusetts Medical School,

7 Department of Radiation Oncology, University of Massachusetts Medical School,

© 2019 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium,

, Ameer Elaimy3

, Fran Laurie2

, Peter Lee3

, Jon Glanzman6

,

and David Goff <sup>7</sup>

, Alexander Lukez<sup>3</sup>

,

*DOI: http://dx.doi.org/10.5772/intechopen.88192*

#### **Conflict of interest**

The authors have no conflict of interest.

### **Author details**

*Emergency Medicine and Trauma*

with increased dose and daily fractionation.

**3. Conclusions**

**Conflict of interest**

The authors have no conflict of interest.

into the initial inflammatory response to injury. Assuming the initial inflammatory phase can be titrated, short-term and long-term injuries could be influenced. Knockout mice deficient in IL-1α or the IL-1 receptor demonstrated both decreased dermal injury and more rapid healing after superficial radiation exposure with both electrons and a strontium applicator. This demonstrated the potential importance of this cytokine in generating and ameliorating radiation-associated skin damage associated with neutrophil inhibition. In a separate group of experiments, investigators demonstrated that hyperspectral optical imaging (HSI) can reveal acute and late oxygenation and perfusion changes in dermal tissue with changes occurring as early as 12 hours after radiation exposure [41, 42]. Imaging changes in oxygenation and perfusion were seen within 12 hours of exposure and predated clinical visible skin change by 14 days [42]. Data sets from this group as part of an approved Institutional Review Board clinical trial for breast cancer patients receiving radiation therapy have shown that changes in imaging correlate well with radiation dose and dose asymmetry in the treated volume. Areas of increased dose associated with patient topography, and chest wall separation demonstrated changes consistent

In response to the need of developing compounds for radioprotection and mitigation, the Radiation Research Program of the National Cancer Institute in collaboration with the Small Business Innovation Research program has funded a series of contracts since 2010 to support the development of radiomodulators. To date, five of the funded applications have successfully transitioned to phase II funding. Eight clinical trials have been developed to establish safety and efficacy. Two drugs on trial are under evaluation as radioprotectors, and two are also being evaluated for anticancer properties. The sites of interest being studied include CNS injury, mucositis, proctitis/enteritis, bone marrow failure, and lung injury [43].

Researchers are developing a targeted pharmacologic response to protect and mitigate issues surrounding intentional and unintentional radiation exposure. A knowledge of normal tissue response to radiation injury will be important for all health-care providers moving forward. Radiation therapy patients, accident victims, and first responders will benefit from the growing body of knowledge.

**50**

Thomas J. FitzGerald1 \*, Maryann Bishop-Jodoin<sup>2</sup> , Fran Laurie2 , Matthew Iandoli<sup>2</sup> , Ameer Elaimy3 , James Shen3 , Peter Lee3 , Alexander Lukez<sup>3</sup> , Lakshmi Shanmugham4 , Beth Herrick<sup>5</sup> , Jon Glanzman6 and David Goff <sup>7</sup>

1 Department of Radiation Oncology, University of Massachusetts Medical School, UMass Memorial Managed Care Network, Worcester, MA, USA

2 Department of Radiation Oncology, University of Massachusetts Medical School, Worcester, MA, USA

3 University of Massachusetts Medical School, Worcester, MA, USA

4 Department of Radiation Oncology, University of Massachusetts Medical School, UMassMemorial Managed Care Network, Fitchburg, MA, USA

5 Department of Radiation Oncology, University of Massachusetts Medical School, UMassMemorial Managed Care Network, Brighton, MA, USA

6 Department of Radiation Oncology, University of Massachusetts Medical School, UMassMemorial Managed Care Network, Foxborough, MA, USA

7 Department of Radiation Oncology, University of Massachusetts Medical School, UMassMemorial Managed Care Network, Methuen, MA, USA

\*Address all correspondence to: tj.fitzgerald@umassmemorial.org; thomas.fitzGerald@umassmed.edu

© 2019 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

#### **References**

[1] Hall EJ, Giaccia AJ. Radiobiology for the Radiologist. 7th ed. Philadelphia: Lippincott Williams and Wilkins; 2012. p. 576

[2] Miller DL, Balter S, Cole PE, Lu HT, Berenstein A, Albert R, et al. Radiation doses in interventional radiology procedures: The RAD-IR study: Part II: Skin dose. Journal of Vascular and Interventional Radiology. 2003;**14**:977-990

[3] Miller DL, Balter S, Wagner LK, Cardella J, Clark TW, Neithamer CD Jr, et al. Quality improvement guidelines for recording patient radiation dose in the medical record. Journal of Vascular and Interventional Radiology. 2004;**15**:423-429

[4] Shope TB. Radiation-induced skin injuries from fluoroscopy. RadioGraphics. 1996;**16**:1195-1199

[5] Donnelly EH, Nemhauser JB, Smith JM, Kazzi ZN, Farfan EB, Chang AS, et al. Acute radiation syndrome: Assessment and management. Southern Medical Journal. 2010;**103**:541-546. DOI: 10.1097/SMJ.0b013e3181ddd571

[6] Turai I, Veress K. Radiation accidents: Occurrence, types, consequences, medical management, and lessons learned. Central European Journal of Occupational and Environmental Medicine. 2001;**7**:3-14

[7] Baranov A, Gale RP, Guskova A, Piatkin E, Selidovkin G, Muravyova L, et al. Bone marrow transplantation after the Chernobyl nuclear accident. The New England Journal of Medicine. 1989;**321**:205-212. DOI: 10.1056/ NEJM198907273210401

[8] Contributors W. Acute Radiation Syndrome Wikipedia, The Free Encyclopedia [Internet]. 2014. Available from: http://en.wikipedia.

org/w/index.php?title=Acute\_ radiation\_syndrome&oldid=608982279 [Accessed: April 1, 2019]

[9] Williams JP, McBride WH. After the bomb drops: A new look at radiation-induced multiple organ dysfunction syndrome (MODS). International Journal of Radiation Biology. 2011;**87**:851-868. DOI: 10.3109/09553002.2011.560996

[10] Fitzgerald TJ, Jodoin MB, Tillman G, Aronowitz J, Pieters R, Balducci S, et al. Radiation therapy toxicity to the skin. Dermatologic Clinics. 2008;**26**:161-172

[11] Citrin D, Cotrim AP, Hyodo F, Baum BJ, Krishna MC, Mitchell JB. Radioprotectors and mitigators of radiation-induced normal tissue injury. The Oncologist. 2010;**15**:360-371. DOI: 10.1634/theoncologist.2009-S104

[12] Patt HM, Tyree EB, Straube RL, Smith DE. Cysteine protection against x irradiation. Science. 1949;**110**:213-214

[13] Brizel D, Overgaard J. Does amifostine have a role in chemoradiation treatment? The Lancet Oncology. 2003;**4**:378-381

[14] Brizel DM, Wasserman TH, Henke M, Strnad V, Rudat V, Monnier A, et al. Phase III randomized trial of amifostine as a radioprotector in head and neck cancer. Journal of Clinical Oncology. 2000;**18**:3339-3345

[15] Chitra S, Shyamala Devi CS. Effects of radiation and alpha-tocopherol on saliva flow rate, amylase activity, total protein and electrolyte levels in oral cavity cancer. Indian Journal of Dental Research. 2008;**19**:213-218

[16] Bentzen SM. Preventing or reducing late side effects of radiation therapy: Radiobiology meets molecular pathology. Nature Reviews. Cancer. 2006;**6**:702-713

**53**

2000;**109**:563-570

[22] Suman S, Datta K, Doiron K, Ren C, Kumar R, Taft DR, et al. Radioprotective effects of ON 01210. Na upon oral administration. Journal of Radiation Research. 2012;**53**:368-376

[23] Bhanja P, Saha S, Kabarriti R, Liu L, Roy-Chowdhury N, Roy-Chowdhury J,

*Treatment Toxicity: Radiation*

Physics. 1999;**43**:169-181

2000;**7**:1011-1018

*DOI: http://dx.doi.org/10.5772/intechopen.88192*

et al. Protective role of R-spondin1, an intestinal stem cell growth factor, against radiation-induced gastrointestinal syndrome in mice. PLoS One. 2009;**4**:e8014. DOI: 10.1371/

[24] Vijay-Kumar M, Aitken JD, Sanders CJ, Frias A, Sloane VM, Xu J, et al. Flagellin treatment protects against chemicals, bacteria, viruses, and radiation. Journal of Immunology.

[25] Suman S, Datta K, Chakraborty K, Kulkarni SS, Doiron K, Fornace AJ Jr, et al. Gamma tocotrienol, a potent radioprotector, preferentially

upregulates expression of anti-apoptotic genes to promote intestinal cell survival.

[26] Kulkarni S, Ghosh SP, Satyamitra M, Mog S, Hieber K, Romanyukha L, et al. Gamma-tocotrienol protects hematopoietic stem and progenitor cells in mice after total-body irradiation. Radiation Research. 2010;**173**:738-747.

[27] Farrell CL, Rex KL, Kaufman SA, Dipalma CR, Chen JN, Scully S, et al. Effects of keratinocyte growth factor in the squamous epithelium of the upper aerodigestive tract of normal and irradiated mice. International Journal of Radiation Biology.

[28] Soule BP, Hyodo F, Matsumoto K, Simone NL, Cook JA, Krishna MC, et al. Therapeutic and clinical applications of nitroxide compounds. Antioxidants & Redox Signaling. 2007;**9**:1731-1743

[29] Hyodo F, Matsumoto K, Matsumoto A, Mitchell JB, Krishna MC. Probing the intracellular redox status of tumors with magnetic resonance imaging and redox-sensitive contrast agents. Cancer

Research. 2006;**66**:9921-9928

Food and Chemical Toxicology. 2013;**60**:488-496. DOI: 10.1016/j.

journal.pone.0008014

2008;**180**:8280-8285

fct.2013.08.011

DOI: 10.1667/RR1824.1

1999;**75**:609-620

[17] Epperly MW, Bray JA, Krager S, Berry LM, Gooding W, Engelhardt JF, et al. Intratracheal injection of adenovirus containing the human MnSOD transgene protects athymic nude mice from irradiation-induced organizing alveolitis. International Journal of Radiation Oncology, Biology,

[18] Epperly MW, Defilippi S, Sikora C, Gretton J, Kalend A, Greenberger JS. Intratracheal injection of manganese superoxide dismutase (MnSOD) plasmid/liposomes protects normal lung but not orthotopic tumors from irradiation. Gene Therapy.

[19] Moulder JE, Cohen EP, Fish BL. Captopril and losartan for mitigation of renal injury caused by single-dose totalbody irradiation. Radiation Research. 2011;**175**:29-36. DOI: 10.1667/RR2400.1

[20] Ghosh SN, Zhang R, Fish BL, Semenenko VA, Li XA, Moulder JE, et al. Renin-angiotensin system suppression mitigates experimental radiation pneumonitis. International Journal of Radiation Oncology, Biology, Physics. 2009;**75**:1528-1536. DOI: 10.1016/j.ijrobp.2009.07.1743

[21] Chisi JE, Briscoe CV, Ezan E, Genet R, Riches AC, Wdzieczak-Bakala J. Captopril inhibits in vitro and in vivo the proliferation of primitive haematopoietic cells induced into cell cycle by cytotoxic drug administration or irradiation but has no effect on myeloid leukaemia cell proliferation. British Journal of Haematology.

#### *Treatment Toxicity: Radiation DOI: http://dx.doi.org/10.5772/intechopen.88192*

[17] Epperly MW, Bray JA, Krager S, Berry LM, Gooding W, Engelhardt JF, et al. Intratracheal injection of adenovirus containing the human MnSOD transgene protects athymic nude mice from irradiation-induced organizing alveolitis. International Journal of Radiation Oncology, Biology, Physics. 1999;**43**:169-181

[18] Epperly MW, Defilippi S, Sikora C, Gretton J, Kalend A, Greenberger JS. Intratracheal injection of manganese superoxide dismutase (MnSOD) plasmid/liposomes protects normal lung but not orthotopic tumors from irradiation. Gene Therapy. 2000;**7**:1011-1018

[19] Moulder JE, Cohen EP, Fish BL. Captopril and losartan for mitigation of renal injury caused by single-dose totalbody irradiation. Radiation Research. 2011;**175**:29-36. DOI: 10.1667/RR2400.1

[20] Ghosh SN, Zhang R, Fish BL, Semenenko VA, Li XA, Moulder JE, et al. Renin-angiotensin system suppression mitigates experimental radiation pneumonitis. International Journal of Radiation Oncology, Biology, Physics. 2009;**75**:1528-1536. DOI: 10.1016/j.ijrobp.2009.07.1743

[21] Chisi JE, Briscoe CV, Ezan E, Genet R, Riches AC, Wdzieczak-Bakala J. Captopril inhibits in vitro and in vivo the proliferation of primitive haematopoietic cells induced into cell cycle by cytotoxic drug administration or irradiation but has no effect on myeloid leukaemia cell proliferation. British Journal of Haematology. 2000;**109**:563-570

[22] Suman S, Datta K, Doiron K, Ren C, Kumar R, Taft DR, et al. Radioprotective effects of ON 01210. Na upon oral administration. Journal of Radiation Research. 2012;**53**:368-376

[23] Bhanja P, Saha S, Kabarriti R, Liu L, Roy-Chowdhury N, Roy-Chowdhury J,

et al. Protective role of R-spondin1, an intestinal stem cell growth factor, against radiation-induced gastrointestinal syndrome in mice. PLoS One. 2009;**4**:e8014. DOI: 10.1371/ journal.pone.0008014

[24] Vijay-Kumar M, Aitken JD, Sanders CJ, Frias A, Sloane VM, Xu J, et al. Flagellin treatment protects against chemicals, bacteria, viruses, and radiation. Journal of Immunology. 2008;**180**:8280-8285

[25] Suman S, Datta K, Chakraborty K, Kulkarni SS, Doiron K, Fornace AJ Jr, et al. Gamma tocotrienol, a potent radioprotector, preferentially upregulates expression of anti-apoptotic genes to promote intestinal cell survival. Food and Chemical Toxicology. 2013;**60**:488-496. DOI: 10.1016/j. fct.2013.08.011

[26] Kulkarni S, Ghosh SP, Satyamitra M, Mog S, Hieber K, Romanyukha L, et al. Gamma-tocotrienol protects hematopoietic stem and progenitor cells in mice after total-body irradiation. Radiation Research. 2010;**173**:738-747. DOI: 10.1667/RR1824.1

[27] Farrell CL, Rex KL, Kaufman SA, Dipalma CR, Chen JN, Scully S, et al. Effects of keratinocyte growth factor in the squamous epithelium of the upper aerodigestive tract of normal and irradiated mice. International Journal of Radiation Biology. 1999;**75**:609-620

[28] Soule BP, Hyodo F, Matsumoto K, Simone NL, Cook JA, Krishna MC, et al. Therapeutic and clinical applications of nitroxide compounds. Antioxidants & Redox Signaling. 2007;**9**:1731-1743

[29] Hyodo F, Matsumoto K, Matsumoto A, Mitchell JB, Krishna MC. Probing the intracellular redox status of tumors with magnetic resonance imaging and redox-sensitive contrast agents. Cancer Research. 2006;**66**:9921-9928

**52**

*Emergency Medicine and Trauma*

p. 576

**References**

2003;**14**:977-990

2004;**15**:423-429

[1] Hall EJ, Giaccia AJ. Radiobiology for the Radiologist. 7th ed. Philadelphia: Lippincott Williams and Wilkins; 2012. org/w/index.php?title=Acute\_

[Accessed: April 1, 2019]

radiation\_syndrome&oldid=608982279

[10] Fitzgerald TJ, Jodoin MB, Tillman G, Aronowitz J, Pieters R, Balducci S, et al. Radiation therapy toxicity to the skin. Dermatologic Clinics. 2008;**26**:161-172

[11] Citrin D, Cotrim AP, Hyodo F, Baum BJ, Krishna MC, Mitchell JB. Radioprotectors and mitigators of radiation-induced normal tissue injury. The Oncologist. 2010;**15**:360-371. DOI: 10.1634/theoncologist.2009-S104

[12] Patt HM, Tyree EB, Straube RL, Smith DE. Cysteine protection against x irradiation. Science. 1949;**110**:213-214

amifostine have a role in chemoradiation treatment? The Lancet Oncology.

[14] Brizel DM, Wasserman TH, Henke M, Strnad V, Rudat V, Monnier A, et al. Phase III randomized trial of amifostine as a radioprotector in head and neck cancer. Journal of Clinical Oncology.

[15] Chitra S, Shyamala Devi CS. Effects of radiation and alpha-tocopherol on saliva flow rate, amylase activity, total protein and electrolyte levels in oral cavity cancer. Indian Journal of Dental

[13] Brizel D, Overgaard J. Does

2003;**4**:378-381

2000;**18**:3339-3345

Research. 2008;**19**:213-218

2006;**6**:702-713

[16] Bentzen SM. Preventing or reducing late side effects of radiation therapy: Radiobiology meets molecular pathology. Nature Reviews. Cancer.

[9] Williams JP, McBride WH. After the bomb drops: A new look at radiation-induced multiple organ dysfunction syndrome (MODS). International Journal of Radiation Biology. 2011;**87**:851-868. DOI: 10.3109/09553002.2011.560996

[2] Miller DL, Balter S, Cole PE, Lu HT, Berenstein A, Albert R, et al. Radiation doses in interventional radiology procedures: The RAD-IR study: Part II: Skin dose. Journal of Vascular and Interventional Radiology.

[3] Miller DL, Balter S, Wagner LK, Cardella J, Clark TW, Neithamer CD Jr, et al. Quality improvement guidelines for recording patient radiation dose in the medical record. Journal of Vascular and Interventional Radiology.

[4] Shope TB. Radiation-induced skin injuries from fluoroscopy. RadioGraphics. 1996;**16**:1195-1199

[5] Donnelly EH, Nemhauser JB, Smith JM, Kazzi ZN, Farfan EB, Chang AS, et al. Acute radiation syndrome:

Assessment and management. Southern Medical Journal. 2010;**103**:541-546. DOI:

10.1097/SMJ.0b013e3181ddd571

[6] Turai I, Veress K. Radiation accidents: Occurrence, types,

Journal of Occupational and

NEJM198907273210401

consequences, medical management, and lessons learned. Central European

Environmental Medicine. 2001;**7**:3-14

[7] Baranov A, Gale RP, Guskova A, Piatkin E, Selidovkin G, Muravyova L, et al. Bone marrow transplantation after the Chernobyl nuclear accident. The New England Journal of Medicine. 1989;**321**:205-212. DOI: 10.1056/

[8] Contributors W. Acute Radiation Syndrome Wikipedia, The Free Encyclopedia [Internet]. 2014. Available from: http://en.wikipedia.

[30] Guo H, Seixas-Silva JA Jr, Epperly MW, Gretton JE, Shin DM, Bar-Sagi D, et al. Prevention of radiation-induced oral cavity mucositis by plasmid/ liposome delivery of the human manganese superoxide dismutase (SOD2) transgene. Radiation Research. 2003;**159**:361-370

[31] Stickle RL, Epperly MW, Klein E, Bray JA, Greenberger JS. Prevention of irradiation-induced esophagitis by plasmid/liposome delivery of the human manganese superoxide dismutase transgene. Radiation Oncology Investigations. 1999;**7**:204-217

[32] Burdelya LG, Krivokrysenko VI, Tallant TC, Strom E, Gleiberman AS, Gupta D, et al. An agonist of toll-like receptor 5 has radioprotective activity in mouse and primate models. Science. 2008;**320**:226-230. DOI: 10.1126/ science.1154986

[33] Anscher MS, Thrasher B, Rabbani Z, Teicher B, Vujaskovic Z. Antitransforming growth factor-beta antibody 1D11 ameliorates normal tissue damage caused by high-dose radiation. International Journal of Radiation Oncology, Biology, Physics. 2006;**65**:876-881

[34] Anscher MS, Thrasher B, Zgonjanin L, Rabbani ZN, Corbley MJ, Fu K, et al. Small molecular inhibitor of transforming growth factorbeta protects against development of radiation-induced lung injury. International Journal of Radiation Oncology, Biology, Physics. 2008;**71**:829-837. DOI: 10.1016/j. ijrobp.2008.02.046

[35] Massague J. TGF beta in cancer. Cell. 2008;**134**:215-230. DOI: 10.1016/j. cell.2008.07.001

[36] Abdel-Mageed AS, Senagore AJ, Pietryga DW, Connors RH, Giambernardi TA, Hay RV, et al. Intravenous administration of

mesenchymal stem cells genetically modified with extracellular superoxide dismutase improves survival in irradiated mice. Blood. 2009;**113**:1201-1203. DOI: 10.1182/ blood-2008-07-170936

[37] Saha S, Bhanja P, Kabarriti R, Liu L, Alfieri AA, Guha C. Bone marrow stromal cell transplantation mitigates radiation-induced gastrointestinal syndrome in mice. PLoS ONE. 2011;**6**:e24072. DOI: 10.1371/journal. pone.0024072

[38] Singh VK, Christensen J, Fatanmi OO, Gille D, Ducey EJ, Wise SY, et al. Myeloid progenitors: A radiation countermeasure that is effective when initiated days after irradiation. Radiation Research. 2012;**177**:781-791

[39] Singh VK, Brown DS, Kao TC, Seed TM. Preclinical development of a bridging therapy for radiation casualties. Experimental Hematology. 2010;**38**:61-70. DOI: 10.1016/j. exphem.2009.10.008

[40] Rosen EM, Day R, Singh VK. New approaches to radiation protection. Frontiers in Oncology. 2014;**4**:381. DOI: 10.3389/fonc.2014.00381

[41] Chin MS, Freniere BB, Bonney CF, Lancerotto L, Saleeby JH, Lo YC, et al. Skin perfusion and oxygenation changes in radiation fibrosis. Plastic and Reconstructive Surgery. 2013;**131**:707-716. DOI: 10.1097/ PRS.0b013e3182818b94

[42] Chin MS, Freniere BB, Lo YC, Saleeby JH, Baker SP, Strom HM, et al. Hyperspectral imaging for early detection of oxygenation and perfusion changes in irradiated skin. Journal of Biomedical Optics. 2012;**17**:026010. DOI: 10.1117/1.JBO.17.2.026010

[43] Zakeri K, Narayanan D, Vikram B, Evans G, Coleman CN, Prasanna PGS. Decreasing the toxicity of

**55**

*Treatment Toxicity: Radiation*

ijrobp.2018.12.027

*DOI: http://dx.doi.org/10.5772/intechopen.88192*

radiation therapy: Radioprotectors and radiomitigators being developed by the National Cancer Institute through Small Business Innovation Research contracts. International Journal of Radiation Oncology, Biology, Physics. 2019;**104**:188-196. DOI: 10.1016/j.

*Treatment Toxicity: Radiation DOI: http://dx.doi.org/10.5772/intechopen.88192*

*Emergency Medicine and Trauma*

2003;**159**:361-370

science.1154986

2006;**65**:876-881

ijrobp.2008.02.046

cell.2008.07.001

[30] Guo H, Seixas-Silva JA Jr, Epperly MW, Gretton JE, Shin DM, Bar-Sagi D, et al. Prevention of radiation-induced oral cavity mucositis by plasmid/ liposome delivery of the human manganese superoxide dismutase (SOD2) transgene. Radiation Research.

mesenchymal stem cells genetically

[37] Saha S, Bhanja P, Kabarriti R, Liu L, Alfieri AA, Guha C. Bone marrow stromal cell transplantation mitigates radiation-induced gastrointestinal syndrome in mice. PLoS ONE. 2011;**6**:e24072. DOI: 10.1371/journal.

[38] Singh VK, Christensen J, Fatanmi OO, Gille D, Ducey EJ, Wise SY, et al. Myeloid progenitors: A radiation countermeasure that is effective when initiated days after irradiation. Radiation Research. 2012;**177**:781-791

[39] Singh VK, Brown DS, Kao TC, Seed TM. Preclinical development of a bridging therapy for radiation casualties. Experimental Hematology.

2010;**38**:61-70. DOI: 10.1016/j.

[40] Rosen EM, Day R, Singh VK. New approaches to radiation protection. Frontiers in Oncology. 2014;**4**:381. DOI:

[41] Chin MS, Freniere BB, Bonney CF, Lancerotto L, Saleeby JH, Lo YC, et al. Skin perfusion and oxygenation

exphem.2009.10.008

10.3389/fonc.2014.00381

changes in radiation fibrosis. Plastic and Reconstructive Surgery. 2013;**131**:707-716. DOI: 10.1097/

[42] Chin MS, Freniere BB, Lo YC, Saleeby JH, Baker SP, Strom HM, et al. Hyperspectral imaging for early detection of oxygenation and perfusion changes in irradiated skin. Journal of Biomedical Optics. 2012;**17**:026010. DOI: 10.1117/1.JBO.17.2.026010

[43] Zakeri K, Narayanan D, Vikram B, Evans G, Coleman CN, Prasanna PGS. Decreasing the toxicity of

PRS.0b013e3182818b94

modified with extracellular superoxide dismutase improves survival in irradiated mice. Blood. 2009;**113**:1201-1203. DOI: 10.1182/

blood-2008-07-170936

pone.0024072

[31] Stickle RL, Epperly MW, Klein E, Bray JA, Greenberger JS. Prevention of irradiation-induced esophagitis by plasmid/liposome delivery of the human manganese superoxide dismutase transgene. Radiation Oncology Investigations. 1999;**7**:204-217

[32] Burdelya LG, Krivokrysenko VI, Tallant TC, Strom E, Gleiberman AS, Gupta D, et al. An agonist of toll-like receptor 5 has radioprotective activity in mouse and primate models. Science. 2008;**320**:226-230. DOI: 10.1126/

[33] Anscher MS, Thrasher B, Rabbani

Antitransforming growth factor-beta antibody 1D11 ameliorates normal tissue damage caused by high-dose radiation. International Journal of Radiation Oncology, Biology, Physics.

[34] Anscher MS, Thrasher B, Zgonjanin

Fu K, et al. Small molecular inhibitor of transforming growth factorbeta protects against development of radiation-induced lung injury. International Journal of Radiation Oncology, Biology, Physics. 2008;**71**:829-837. DOI: 10.1016/j.

[35] Massague J. TGF beta in cancer. Cell. 2008;**134**:215-230. DOI: 10.1016/j.

[36] Abdel-Mageed AS, Senagore AJ,

Pietryga DW, Connors RH, Giambernardi TA, Hay RV, et al. Intravenous administration of

Z, Teicher B, Vujaskovic Z.

L, Rabbani ZN, Corbley MJ,

**54**

radiation therapy: Radioprotectors and radiomitigators being developed by the National Cancer Institute through Small Business Innovation Research contracts. International Journal of Radiation Oncology, Biology, Physics. 2019;**104**:188-196. DOI: 10.1016/j. ijrobp.2018.12.027

**57**

**Chapter 5**

**Abstract**

therapy, may occur.

**1. Introduction**

and labor accidents [1, 2].

future prognosis.

injury, iatrogenic vascular trauma, aortic injury

**2. Prehospital care in patients with vascular injury**

**2.1 On-site emergency procedures and medical transport**

Vascular Trauma

*Krzysztof Szaniewski, Tomasz Byrczek and Tomasz Sikora*

Trauma is a leading cause of death and disability in young adults in developed countries with the high impact on future patient quality of life and productivity. The traumatic injury of the vessels is one of the most dangerous types of injury, requiring a fast and reliable diagnosis and, in vast majority of cases, immediate surgical treatment. In this chapter, the authors describe various types of vascular injuries according to injury types and locations. The prehospital care algorithms in patients with vascular trauma are proposed with the emphasis on bleeding control techniques and transportation technique to the nearest hospital. In the next subsection, the various peripheral vascular injuries of specific body areas are described. The truncal vessel trauma is discussed in the next subsection, focusing on fast diagnosis and decision on surgery. In the last subsection, a problem of iatrogenic vascular injury is described due to a rapid increase of minimally invasive techniques in which a vascular injury, as a complication of

**Keywords:** vascular trauma, vascular injury, peripheral vessels injury, truncal vessels

Trauma has become a leading cause of death among young adults in industrialized nations. In the United States in 2010, trauma was the cause of death in 63% of patients aged 1–24 years and 42% of the patients in the ages 25–44. Furthermore, trauma results with lowered patient's productivity with high economic impact. A vascular trauma incidence is estimated between 1.6 and 2% in adults during peace and between 6 and 12% during war. Most of the civilian casualties are injured by penetrating objects like firearm bullets, blades, or machine parts. In Europe, where access to firearms is limited, most of the penetrating vascular injuries result from criminal acts (e.g., knife stabbing), traffic,

Fast initial diagnosis, patient's vital signs stabilization together with effective bleeding control, and quick transport to the hospital are crucial factors influencing

After the evaluation of the overall security condition on trauma site (traffic accident, disaster site, explosion area), it is important to predetermine a possible

### **Chapter 5**
