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Effect of a preoperative warming intervention on the acute phase response of surgical stress

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Effect of a preoperative warming intervention on the acute phase response of surgical stress
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Wagner, Vanda Doreen
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Hypothermia
Forced-air warming
Catecholamine
Cytokine
Innate immunity
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ABSTRACT: When a patient is exposed surgical stress, the endocrine system secretes hormones in response to that stress. These hormones further activate the immune system to release cytokines and other acute phase reactions. These processes are supposed to protect the body by upregulating the innate immune system and producing an inflammatory response that acts to protect and heal. However, uncontrolled surgical stress may cause a weaker immune response that may lead to delayed wound healing. The phenomenon of unplanned perioperative hypothermia is known to expose patients to additional surgical stress. The purpose of this preliminary experimental study was to determine the effect of a preoperative warming intervention on the acute phase response of surgical stress in surgical patients.Specifically, the aim of this study was to evaluate the effect of a prewarming intervention using a forced-air warming (FAW) device versus routine care (RC) using warmed cotton blankets on the development of unplanned hypothermia, cytokine production, and endocrine responses. It was hypothesized that 1) the FAW participants would experience less unplanned perioperative hypothermia than the RC participants; 2) the FAW participants would experience lower catecholamine and cortisol levels than the RC participants; and 3) the FAW participants would experience higher proinflammatory cytokine and CRP production intra- and postoperatively than the RC participants. Infrared tympanic temperatures and 4 blood samples were taken at 4 time intervals from each of the 28 (n = 14 each group) randomized participants that underwent routine general anesthesia surgery.Serum concentrations of CRP, cortisol and IL-1beta, IL- 6, TNF-alpha, and IFN-gamma, and plasma concentrations of epinephrine and norepinephrine were measured. To test the hypotheses across time and between groups, a repeated measures ANOVA design was used. Though FAW was not associated with a differential endocrine or inflammatory response in this small, preliminary study, further study of forced air warming as a preoperative nursing intervention is warranted. The finding of higher than expected IL-6 levels in the preoperative period suggests a potential role for anxiety, an important factor in psychoneuroimmunological pathways, that could affect recovery and healing. The relationship between surgical stress, anxiety, and preoperative IL-6 deserves further study.
Thesis:
Dissertation (Ph.D.)--University of South Florida, 2007.
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Includes bibliographical references.
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by Vanda Doreen Wagner.
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Includes vita.

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Effect of a Preoperative Wa rming Intervention on the Acute Phase Response of Surgical Stress by Vanda Doreen Wagner A dissertation submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy College of Nursing University of South Florida Major Professor: Maureen Gror, R.N., Ph.D., FAAN Jason Beckstead, Ph.D. Clyde Gwinn, M.D. Barbara Holtzclaw, Ph.D., R.N., FAAN Date of Approval: October 31, 2007 Keywords: hypothermia, forced-air warming, catecholamine, cytokine, innate immunity Copyright 2007, Vanda Doreen Wagner

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Dedication I dedicate this dissertation to Brent and Karla with all my love. You made this worthwhile journey so much easier.

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Acknowledgements I would not have been able to comple te this mind-expanding adventure without the guidance and support of many people. Firs t and foremost, I want to express my heartfelt gratitude to Dr. Maureen Gror. As my dissertation chairperson, she provided me with unlimited support, guidance, and enc ouragement. Dr. Gror has been my mentor and has taught me what it takes to be a nurse scientist. My career as a nurse researcher will only benefit from her gracious gifts of knowledge. Secondly, I would like to individually thank my committee members for their support and assistance in making this disserta tion a reality. I would like to especially thank Dr. Jason Beckstead for his patience a nd direction in my search for understanding statistics. Heartfelt appreciation for his en couragement and feedback goes to Dr. Clyde Gwinn. I would also like to recognize and th ank Dr. Barbara Holtzclaw for sharing her thermoregulation expertise with me. She will always be the “Temperature Lady!” Special thanks are given to Dr. Nagwa Dajani for be ing moderating Chairperson at my defense. I also want to thank Dr. Mary Evans fo r her advisement and unfailing support. Warm thanks go to Alison Jones Montpetit and Marianne Chanti-Ketterl for the many hours of assistance, crises intervention, and friendship they gave so freely. Last, but not least, I am very happy to acknowledge the financial funding I received from the Association of periOperat ive Registered Nurses and from the Linda Moody Doctoral Dissertation Scholarship of U SF. This monetary support allowed me to reach for higher goals in my research efforts.

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i Table of Contents List of Tables iv List of Figures v Abstract vi Chapter One: Introduction 1 Statement of the Problem 3 Focus of Inquiry 3 Definition of Terms 4 Purpose 8 Specific Aim 8 Significance 8 Summary 9 Chapter Two: Context of the Study 11 Review of the Literature 11 Search Strategy 11 Physiology of Temperature Regulation 12 Etiology of Perioperative Hypothermia 14 Immune Responses to Surgery 16 Immune Responses to Hypothermia 19 Therapeutic Effects of Prewarming 23 Discussion 26 Conceptual Model 27 Study Hypotheses 29 Summary 30

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ii Chapter Three: Method 31 Research Design 31 Protection of Human Participants 32 Study Approval 32 Recruitment Process 32 Informed Consent Process 32 Benefits and Risks of Participation 32 Sample Selection 34 Study Setting 35 Inclusion and Exclusion Criteria 35 Data Collection 36 Intervention Protocol 37 Serum Collection Protocol 37 Assay Protocol 38 Data and Safety Monitoring 40 Data Analysis 41 Summary 42 Chapter Four: Results 43 Data Preparation 43 Profile of Study Sample 44 Statistical Analyses 46 Test Assumptions 47 Hypotheses, Statistical Pr ocedures, and Results 47 Hypothesis 1 47 Hypothesis 2 49 Cortisol 50 Epinephrine 51 Norepinephrine 53 Hypothesis 3 55 IL-1 55

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iii IL-6 56 TNF58 IFN60 CRP 61 Summary 63 Chapter Five: Discussion 64 Specific Aim of the Study 64 Hypothesis 1 65 Hypothesis 2 68 Cortisol 69 Catecholamines 70 Hypothesis 3 72 Study Limitations 74 Implications for Nursing 75 Implications for Future Research 76 Summary 77 References 78 Appendices 88 Appendix A: IRB Approval 89 Appendix B: Recruitment Flyer 91 Appendix C: Informed Consent Form 92 Appendix D: Surgeon Letter 101 Appendix E: Anesthesia Provider Letter 102 Appendix F: Data Collection Forms 103 About the Author End Page

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iv List of Tables Table 1 Descriptive Statistics Calc ulations on Temperature Across Time 44 Table 2 Participant Characteristics 45 Table 3 Descriptive Statistics of Temperature (F) Across Time 49 Table 4 Raw Mean Values of Cortisol (ng/ml) Across Time 50 Table 5 Raw Mean Values of Epinephrine (pg/ml) Across Time 52 Table 6 Raw Mean Values of Norepinephrine (pg/ml) Across Time 54 Table 7 Raw Mean Values of IL-1 $ (pg/ml) Across Time 55 Table 8 Raw Mean Values of IL-6 (pg/ml) Across Time 57 Table 9 Correlation Coefficients for IL-6 and TNFAcross Time 57 Table 10 Raw Mean Values of TNF(pg/ml) Across Time 59 Table 11 Raw Mean Values of IFN(pg/ml) Across Time 60 Table 12 Raw Mean Values of CRP (pg/ml) Across Time 62 Table 13 Correlations Between BMI and CRP Across Time 63 Table 14 Total Mean Temperature (F) of Hypothermic Participants at Time 3 66 Table 15 Total Mean Temperature (F) of Hypothermic Participants at Time 4 66

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v List of Figures Figure 1 Conceptual Model 28 Figure 2 Flow Diagram of Par ticipant Status During the Study 34 Figure 3 Mean Temperature Values (F) Across Time 48 Figure 4 Raw Mean Values of Cortisol (ng/ml) Across Time 51 Figure 5 Raw Mean Values of Epinephrine (pg/ml) Across Time 53 Figure 6 Raw Mean Values of Norepinephrine (pg/ml) Activity Across Time 54 Figure 7 Raw Mean Values of IL-1 $ (pg/ml) Across Time 56 Figure 8 Raw Mean Values of IL-6 (pg/ml) Across Time 58 Figure 9 Raw Mean Values of TNF(pg/ml) Activity Across Time 59 Figure 10 Raw Mean Values of IFN(pg/ml) Across Time 61 Figure 11 Raw Mean Values of CRP (pg/ml) Across Time 62

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vi Effect of a Preoperative Warming Intervention on the Acute Phase Response of Surgical Stress Vanda Doreen Wagner ABSTRACT When a patient is exposed surgical stress, the endocrine system secretes hormones in response to that stress. These hormones fu rther activate the immune system to release cytokines and other acute phase reactions. These processes are supposed to protect the body by upregulating the innate immune system and producing an inflammatory response that acts to protect and heal. However, unc ontrolled surgical stress may cause a weaker immune response that may lead to delayed wound healing. The phenomenon of unplanned perioperat ive hypothermia is known to expose patients to additional surgical stress. The pur pose of this preliminary experimental study was to determine the effect of a preopera tive warming intervention on the acute phase response of surgical stress in surgical patien ts. Specifically, the aim of this study was to evaluate the effect of a prewarming inte rvention using a forced-air warming (FAW) device versus routine care (RC) using warm ed cotton blankets on the development of unplanned hypothermia, cytokine produc tion, and endocrine responses. It was hypothesized that 1) the FAW participants would experience less unplanned perioperative hypothermia than the RC participants; 2) th e FAW participants w ould experience lower catecholamine and cortisol levels than the RC participants; and 3) the FAW participants

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vii would experience higher proinflammatory cyt okine and CRP producti on intraand postoperatively than the RC participants. Infrared tympanic temperatures and 4 blood samples were taken at 4 time intervals from each of the 28 (n = 14 each gr oup) randomized participants that underwent routine general anesthesia surgery. Serum concentrations of CRP, cortisol and IL-1 IL6, TNF, and IFN, and plasma concentrations of ep inephrine and norepinephrine were measured. To test the hypotheses across tim e and between groups, a repeated measures ANOVA design was used. Though FAW was not associated with a di fferential endocrine or inflammatory response in this small, preliminary study, further study of forced air warming as a preoperative nursing intervention is warranted. The finding of higher than expected IL-6 levels in the preoperative peri od suggests a potential role fo r anxiety, an important factor in psychoneuroimmunological pathways, that could affect recovery and healing. The relationship between surgical stress, anxiety, and preopera tive IL-6 deserves further study.

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1 Chapter One: Introduction Perioperative patients commonly dominate the care provided by hospitals and freestanding facilities in the United States as shown by Vital Health Statistics from the Centers for Disease Control and Prevention (CDC). According to summary findings for 1996, more than 40 million surgical procedures were performed for hospitalized patients with 30% of those surgerie s considered elective proce dures. In both hospitals and freestanding surgical centers, another 31.5 million patients had ambulatory surgery that year (CDC, 1998). Because of cost containm ent measures and technological advances, patients are sent home earlier or consider ed for ambulatory surgery that leads to discharge within hours of surgery completion. However, even with an earlier discharge home, patients still have to recover for weeks to several months afte r a surgical procedure because of the impact that surgical stress has on the body systems. An increased understanding of how surgical stress affects patients has occurred in the last 70 years with much evidence indicating that physiologic stress reduction decreases complications and improves periope rative outcomes (Kehlet & Wilmore, 2002; Wilmore, 2002). In the last decade alone, preventive therapies recognized to reduce complications have led to changes in practi ce and standardized perioperative strategies, such as minimally invasive procedures, timi ng of preoperative antibiotics, perioperative insulin therapy, and postoperative throm boembolic prophylaxis (Kehlet & Wilmore, 2002; Meiler, 2006).

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2 Surgery is a threatening experience becau se of multiple stressful components. Stress is a term used to refer to “forces or factors that cause disequilibrium to an organism and therefore threaten homeostas is” (Wilmore, 2002). Surgical stress results from cellular and organ system insult, tissu e injury, and nociceptiv e stimulation that impact endocrine and metabolic processes. The central nervous system, hypothalamicpituitary-adrenal axis, and the peripheral autonomic nervous sy stem are all involved in an integrated response, known co llectively as the stress respon se, in order to return the patient to homeostasis following surgery. When a patient is exposed to surgical stre ss, the endocrine system secretes various hormones, such as cortisol and catechol amines, in a response mediated by the hypothalamic-pituitary-adrenal (H PA) axis and the autonomic nervous system. It is well established that both external and internal stressors, such as pre operative anxiety, tissue injury, and anesthesia medications, associated with the surgical e xperience activate the HPA axis and that the HPA axis plays a key role in stress responses (Haddad, Saade, & Safieh-Garabedian, 2002). Cytokines, such as interleukin-1 beta (IL-1 ), interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF), are released in response to signals produced by surgical tissue damage, anesth esia, sympathetic activ ation, and psychosocial stress. IL-6 in particular is a multifunctional cy tokine that is the major stimulator of acute phase reactants, including C-reactive protein ( CRP) and other hepatic proteins (Ogawa et al., 2000). This complicated response is intended to protect the body by producing an inflammatory state that acts to protect and heal. Any continued stimulation of the stress response, however, may lead to reduced car diac function, a diminished immune response to infection, delayed wound h ealing, and a general loss of energy stores necessary to

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3 promote healing (Edwards, 2003). An imbalance between inflammatory and antiinflammatory cytokines causes immunosuppressi on. Restoration of an adequate balance between inflammatory and anti-inflammato ry immune cell function is the key to decreasing surgical stress. With recognition that perioperative nu rsing practices could prevent later complications comes the need to reassess exis ting practices and how those practices may or may not impact patient risks. To provide best practice, it is sometimes necessary to question traditional interventions in order to look for new approaches to reduce surgical stress. For example, unplanned perioperat ive hypothermia is still accepted as commonplace and even just expected. The trad itional practice is to treat perioperative hypothermia, rather than preventing its developm ent. It is well esta blished that unplanned hypothermia contributes to the stress respons e and increases the risk for postoperative infections (Beilin et al., 1998; Kurz, Sessl er, & Lenhardt, 1996). Since all surgical patients are potentially at risk for developing hypothermia, they are routinely put at risk for developing surgical stress induced complications such as infection. Statement of the Problem Focus of Inquiry In order to study the reduction of su rgical stress related to unplanned perioperative hypothermia, a focused inquiry into how a nursing intervention would impact the initial phase of surgical stress wa s selected. The specific intervention used in this focused study was a preoperative forced-air warming intervention. Perioperative hypothermia, a core body temperature less than 96.8 F (36 C), happens during surgical procedures in tw o ways: planned or unplanned (AORN, 2007;

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4 Sessler, 1997a, 1997b). Planned hypot hermia is used during surg eries that benefit from a lessened metabolic demand and organ protectio n during low blood flow periods, such as cardiac and neurological surg ery. Conversely, unplanned hypothermia occurs because of the inherent heat loss in the operating room (OR), of anesthesia-induced thermoregulation impairment, and the actual surgery itself. Ot her factors that place patients at risk for unplanned hypothermia include major fluid or blood loss, infusion of cold fluids/blood, large volume of non-warmed irrigation, expos ure of a large body cavity, patient’s age (pediatric or geriatric speci fically), and the patient’s phys ical status (Forstot, 1995; Sessler, 2000). Unplanned hypothermia is c onsidered one of the most common and expected complications that pa tients experience during surgery. There is a large amount of literature a ddressing the numerous complications that occur because of unplanned perioperative hypothermia (Beilin et al., 1998; Connor & Wren, 2000; Guest, Vanni, & Silbert, 2004; Holtzclaw, 1997; Kurz, Sessler, & Lenhardt, 1996; Lee, Battistella, & Go, 2001; Lenhardt et al., 1997; Leslie & Sessler, 2003; Schein, Rucinski, & Wise, 1996). However, there is li ttle research focusing on the prevention of unplanned perioperative hypothermia as a preoperative nursing intervention. Therefore, a preliminary investigation of preoperative warming as a nursing intervention to reduce surgical stress was conducted. Definition of Terms The definitions listed below provide the re ader with a lexicon that will be useful in reading this dissertatio n. These terms are used frequently throughout this document and are standard definitions in the field.

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5 Acute Phase Proteins (APPs) Proteins whose plasma concentration increases or decreases by at least 25% in order to defend the host during inflammatory processes. Cytokines are the primary stimulators of the liver to produce the APPs. Acute Phase Response (APR) The metabolic, physiologic, and beha vioral changes that accompany the organism’s response to inflammation and inf ection. The major cell i nvolved in generating the APR is the macrophage. Active Warming The application of conductive, convec tive or radiative warming devices to clinically increase th e body temperature. Catecholamines A group of aromatic amines (norepinephr ine, epinephrine, dopamine, and their derivatives) that act as hormones and neurotransmitters. Epinephrine. An amine that functions as both a neurotransmitter in the central nervous system (CNS) and a hormone when released from the adrenal medulla. It mobilizes the body for action. Norepinephrine. An amine released by both the adrenal medulla and neurons in the CNS and the sympathetic nervous sy stem (SNS), which induces arousal. C-Reactive Protein (CRP) An alpha globulin synthesized in the liv er and normally present in trace amounts in circulating blood. CRP is one of the acute-phase proteins, le vels of which rise during

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6 responses to varied stimuli, such as rheuma toid arthritis, inflammatory diseases, and surgical trauma. It is used as an indi cator of the inflammatory process. Core Temperature The temperature in the thermal compar tment of the body that is composed of highly perfused tissues and major organs where the temperature is uniform and high compared with the rest of the body. Cortisol The main corticosteroid secreted in humans by the adrenal cortex with the main biological effects of gluconeogenesis, increa sed glucose concentration, fat metabolism, anti-inflammatory, and anti-immune actions. Cytokines Proteins that are clas sified into interferons, lymphokines, monokines, and chemokines that influence the ac tivity of other cells by intercellular signa ls. Cytokines, as a group, are responsible for the multidirecti onal communication among cells engaged in host defense, tissue repair and other immune responses. IL-1 Pro-inflammatory monokine that play s a major role in the induction of acute phase reactant synthe sis. Stress induced IL-1 activation of the HPA axis is modulated by IL-6. IL-6. Pro-inflammatory lymphokine that has a role in stress-in duced activation of the HPA axis. Its main function is to stim ulate the production of most acute phase proteins and potentiate the effects of other cytokines IFN. Proinflammatory interferon that amp lifies acute phase response. Secretion of IFN is a hallmark of Th1 lymphocytes.

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7 TNF. A proinflammatory paracrine that ha s a major role in mediation of the inflammatory response and the i nduction of acute phase proteins. Forced-air warming (FAW) Convection warming technology that disper ses a “blanket” of warm air over the patient’s skin in a controlled manner. Hypothermia A core temperature less than 96.8F (36C). Normothermia A core temperature range of 96.8F (36C) to 100.4F (38C). Passive warming Insulation type warming approaches, such as warmed cotton blankets, socks, and head coverings, used to insulate th e body from heat lo ss through radiation. Redistribution Hypothermia A decrease in body temperature occurring as heat is exchanged from the body’s core compartment to the peripheral tissues. Stress A physiologic response from physical or psychological factors that cause disequilibrium to an organism a nd therefore threatens homeostasis. Surgical Stress An invasive action that caus es cellular and organ system insult, tissue injury, and nociceptive stimulation that impacts endocrine and metabolic processes. Thermoregulation The action of monitoring a nd regulating body temperature.

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8 Purpose The overall objective of this preliminary experimental study was to determine the effect of a preoperative warming interventi on on the initial acute phase response of surgical stress in perioperative patients. The use of either a FAW or routine practice of preoperative warming intervention served as th e independent variable. The effects of this manipulation on thermoregulation and acute phase stress response were examined. Specifically, three questions were addressed: 1) What is the effect of type of preoperative warming on the occurrence of unplanned perioperative hypothermia? 2) What is the effect of type of preopera tive warming on the acute phase response of surgical stress during the periope rative period (i.e., changes in cortisol, CRP, IL-1, IL-6, IFN, TNF, epinephrine and norepinephrine)? and 3) Is there a difference in the level of surgical stress response between the FAW group of patients versus the routine care (RC) group of participants? Specific Aim The overreaching objective of the study wa s to obtain new information about a nursing intervention that could possibly decrease surgical stress. The specific aim of this preliminary study was to examine the effect of a preoperative warming intervention using a FAW device versus routine care using warm ed cotton blankets on the development of unplanned perioperative hypothermia, proinflammatory cytokine production, and neuroendocrine responses. Significance Perioperative nurses provide patient care during the preoperative, intraoperative, and postoperative phases of a surgical proc edure. Throughout these phases of care, the

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9 professional nurse takes on the vital role of patient advocate with an emphasis on the maintenance of a patient’s psychological and physical well being. Nurses are educationally prepared to provide organized patient care planne d on an individualized basis and encompassing the biophysiological, psychological, and social components of the patient’s response or adjustment to physic al alterations. Thus, perioperative nursing is a specialized area of practi ce that provides continuity of care and treatment necessary to provide comfort to the patient, to assist the patient in promotion and maintenance of health, and the prevention, detection, and treatment of illness. The significance of this research was in the development of a new understanding of surgical stress and how the perioperat ive nurse may impact and perhaps reduce surgical stress. The focus of this study cr eated opportunities to learn more about the phenomenon of redistribution hypothermia and su rgical stress. This study evaluated the effect of a FAW intervention that was hypot hesized to lead to less perioperative hypothermia, lower levels of stress hormone production, a heightened inflammatory response and less immunosuppression, that woul d ultimately impact overall surgical stress of the perioperative patient. Th e knowledge gained from the benefits of a preventive nursing intervention could potential ly provide evidence a nd direction for best practices during the entire perioperative experience. Summary Perioperative nurses care for patients be fore, during and after surgery. The known problem of unplanned hypothermia adds to the surg ical stress that all patients experience. Numerous studies have provi ded an increased understand ing of how surgical stress affects patients and that prevention measur es can be used to reduce perioperative

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10 complications. A lack of specific evidence related to the prevention of unplanned perioperative hypothermia and how it may be a possible surgical stress reduction strategy was recognized and the need for a nursi ng intervention study was determined. A preliminary investigation of preoperative FA W intervention and its effect on surgical stress was conducted to answer the posed research questions. The following chapters provide a discussion about the context of th e study, the research method, results of the study, and an in depth discussion of the study findings.

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11 Chapter Two: Context Of Study In this chapter, the revi ew of literature and concep tual framework underlying the study is discussed. A brief review of the stra tegies undertaken for literature search is followed by a discussion of specific literature pertaining to the physiology of temperature regulation, etiology of perioperative hypot hermia, cellular immune responses to hypothermia, immune responses to surgery, a nd the therapeutic effects of prewarming. The evidence provided support that preventi on of unplanned hypothermia could be used as an effective nursing strategy to significan tly reduce the stress of surgery and improve patient outcomes. The conceptual model used to provide the framework for this research is discussed prior to the outline of th e research questions and study hypotheses. Review of Literature Search Strategy Several literature search strategies were used. The standard online searches with Medline, Pubmed, and Biomed Central came up with over 20,000 hits for the key words perioperative hypothermia. The author f ound surgical hypothermia studies being conducted in the 1950’s and that animal studi es prompted the quest ions still studied today. Further search for terms acute phase reaction and surgery delivered 56 hits and surgical stress alone came up with 724 hits. With limits placed to English language only and the elimination of pediatric, dental, obs tetric and cardiac surgeries, and exercise physiology, a reasonable retrie val of literature occurred. Fu rther review of reference sections and bibliographies of all retrieved ar ticles were examined for additional studies.

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12 After reviewing articles for specificity to perioperative hypothermia and surgical stress, the literature search finally yielde d 156 articles for intense review. Physiology of Temperature Regulation The human body temperature is a tightly controlled physiological parameter that is normally controlled within 0.36 F (0.2 C). Even small variations in the core body temperature incite aggressi ve thermoregulatory defenses, because maintenance of body temperature is necessary for life. The precisi on of thermoregulatory control is similar in men and women, but declines in the elderly (Lopez, Sessler, Walter, Emerick, & Ozaki, 1994; Vassilieff, Rosencher, Se ssler, & Conseiller, 1995). The three major autonomic thermore gulatory defenses in humans are vasoconstriction, shivering, and sweating (Sessler & Akca, 2002) Each of these defenses has a threshold (triggering core temperature), a gain (incremental change in response), and a maximum intensity response (Sessl er, 1997b). Sweating and vasoconstriction thresholds are separated only by a few tent hs of a degree centigrade, whereas, the shivering threshold is a full degree centigrade below the vasoconstriction threshold. This inter-threshold range defines the normal ra nge of body temperature and is based on the individual’s “set point” which ranges from approximately 97.5 to 99.14 F (36.4 to 37.3 C) (Holtzclaw, 1993; Sessler, 1997b). The thermoregulatory system consists of a sensory component, a control center, and effector mechanisms. The control center, situated in the h ypothalamus, maintains normothermia by balancing heat production, heat conservation, and heat loss. The hypothalamus regulates temperature hormonally. Peripheral thermoreceptors in the skin and central thermoreceptors in the hypothala mus, spinal cord, abdominal organs, and

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13 other central locations provide the hypothala mus with information about skin and core temperatures (Buggy & Crossle y, 2000; Sessler, 1997b, 2000). If skin and core temperatures are low, the hypothalamus responds by triggering heat production and heat cons ervation mechanisms. Increased heat production is initiated by a series of hormonal mechanisms involvi ng the hypothalamus and its connections with the endocrine system. The heat producing mechanism begins with a hypothalamic hormone, thyrotropin-stimulating hormone re leasing hormone (TSH-RH). TSH-RH in turn stimulates the anterior pituitary to re lease thyroid-stimulating hormone (TSH), which acts on the thyroid gland, stimulating releas e of thyroxine (T4), one of the thyroid hormones. This hormone then acts on th e adrenal medulla, causing the release of epinephrine (a catecholamine and vasopres sive hormone) into the bloodstream (Silva, 2005). Epinephrine causes vasoconstriction, stimulates glycolysis, and increases metabolic rates, thus increasing heat production (Buggy & Crossley, 2000; Sessler, 1997b, 2000). Other hormonal changes influence te mperatures, such as ovulatory cycles of women and the diurnal variations that occur in all people. Plasma cortisol concentrations are thought to influence the 24-hour cir cadian variations in human temperatures by 0.2 to 0.3C with temperatures falling during sleep and peaking in the late afternoon (Holtzclaw, 1993). The hypothalamus also triggers heat c onservation. The mechanisms of heat conservation involve stimulating the sympathe tic nervous system, which is responsible for stimulating the adrenal cortex, increasing sk eletal muscle tone, initiating the shivering response, and producing vasoconstriction. The hypothalamus also functions in raising body temperatures by relaying information to the cerebral corte x. Awareness of cold

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14 provokes voluntary responses such as in creased body movement (Buggy & Crossley, 2000; Holtzclaw, 1993; Sessler, 1997b, 2000). Etiology of Perioperative Hypothermia Unplanned perioperative hypothermia is a common and potentially preventable occurrence in surgical patients. Hypothermia is one of the most common complications that surgical patients expe rience (Sessler, 1997b). Numerous clinical trials have demonstrated that unplanned hypothermia increases the incidence of serious complications including surgical site in fections, (Flores-Mald onado, Medina-Escobedo, Rios-Rodriguez, & Fernandez-Dominguez, 2001; Kurz, Sessler, & Lenhardt, 1996) adverse cardiac events, (Frank et al., 1993) in creased blood loss, (Schmied, Kurz, Sessler, Kozek, & Reiter, 1996) altered drug metabolis m, (Heier et al., 2002) and extended postanesthesia recovery time (Lenhardt et al., 1997). When a surgical patient undergoes general anesthesia for periods longer than one hour, hypothermia is expected because an esthesia disrupts th e behavioral and physiological mechanisms of thermoregul ation (Buggy & Crossley, 2000; Sessler & Akca, 2002). During that first hour of anesthes ia, the patient’s core temperature usually drops 0.9 F to 2.7 F (0.5 C to 1.5 C) (Matsukawa et al., 1995). This drop in core temperature can be explained by redistribution of heat from the body’s core to periphery. Redistribution occurs because anesthetics i nhibit thermoregulatory control and therefore disrupt the tonic vasocons triction that normally maintains a core-to-peripheral temperature gradient. This re distribution is not a clear exchange of heat with the environment, but a heat flow from the actual core to the periphery, thereby reducing core temperature (Matsukawa et al., 1995; Sessler & Akca, 2002).

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15 The next phase of the hypothermic action is a slower, linear decrease in core temperature. Simply, it results from heat lo ss exceeding heat produc tion. This phase lasts approximately 2-3 hours and depends on the di fference between heat loss and metabolic heat production. Approximately 90% of heat loss is through the sk in surface, with convection and radiation usually contributing more to the pr ocess than evaporation or conduction (Kurz, Sessler, Christense n, & Dechert, 1995; Sessler, 2000), After 3 to 5 hours of anesthesia, there is a plateau phase in hypothermic patients. This may reflect a steady state of heat loss equaling heat production and seen in patients who are well insulated. However, if a pati ent is quite hypothermic, the halt to the temperature decline results from activation of thermoregulatory vasoconstriction, which decreases cutaneous heat lo ss and acts to hold metabolic heat in the body core. Characteristically, this happens when the patient’s core temperature is around 93.2 F (34 C) (Kurz, Sessler, Chri stensen, & Dechert, 1995). The risk of unplanned hypothermia is greater in certain patients, such as neonates, trauma patients, and patients with extens ive burns (Caldwell, Wallace, & Cone, 1994; Gentilello, Jurkovich, Stark, Hassantash, & O'Keefe, 1997; Macario & Dexter, 2002; Rutherford et al., 1998; Tander et al., 2005). Other factors that place patients at risk for unplanned hypothermia development include ma jor fluid loss, infusion of cold fluids, exposure of a large body cavity, increased duration of anesthes ia time, and the patient’s co-morbidity status (For stot, 1995; Sessler, 1993).

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16 Immune Responses to Surgery Cytokines mediate and regulate immune and inflammatory responses. The complex interaction that exists between cytokines, inflammation and the adaptive response in maintaining homeostasis is crucia l to survival just lik e it is in the stress response. Most studies examining imm une responses to surgery focus on the intraoperative and postoperative pha ses of the surgical experience. During inflammation, the initiation of the st ress system, because of the effect of cortisol, protects the organism from syst emic “overshooting” with proinflammatory cytokines (Elenkov, Iezzoni, Daly, Harris, & Chrousos, 2005). Homeostasis relies on cytokines as they play vita l roles in mediating inflammatory and immune responses. Cytokines may act in a paracrine, autocrine or endocrine manner in order to control the proliferation, differentiation and activity of immune cells (Elenkov, Iezzoni, Daly, Harris, & Chrousos, 2005; Elenkov, Papanicolaou, Wilder, & Chrousos, 1996). In one of the first studies that demons trated changes in cytokine serum levels after surgery related to the extent and durati on of the surgical procedure and the type of disease process, Baxevanis and others (1994) studied 80 patients sc heduled for elective surgery. Serum levels of IL-2, IL-1 IL-6, TNF, and prostaglandin E2 (PGE2) were measured serially preand postoperatively to determine the surgical stress differences between surgery types and relative immune responses. The data suggested that overproduction of inflammatory cytokines in vivo together with a decrease of IL-2 levels were responsible for post operative immunosuppression and ope ned the possibility of using immune specific interventions for th e prevention of post operative infections (Baxevanis, Papilas, Dedoussis, Pavlis, & Papamichail, 1994)

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17 IL-6 is a T cell helper 2 (Th2) cytokine and the main mediator of acute phase response and also has many biol ogic activities such as the stimulation of hepatocytes and the production of acute phase reactants such as CRP. The increase of IL-6 seen during tissue injury can be interprete d as being related to the pr edominance of Th2 cells caused by surgical stress (Ogawa et al., 2000). In a study of 20 gastrointestinal cancer patients age 44-66, Ogawa and others (2000) measured hormones, cytokines and acute phase reactants from the preoperative to postopera tive time frames. The researchers found that during the perioperative period, catecholamines and cortisol were significantly increased during and after the operation. The serum IL-6 was increased after the surgery whereas CRP was decreased intraoperatively with onl y a postoperative increase. Th cells were decreased by surgical stress and the Th1 to Th2 balance was upset, with Th2 cells predominant due to the hypersecretion of cortisol (Ogawa et al., 2000). Biffl and colleagues (1996) performed a review of literature in order to summarize origins, actions, and biologic effects of IL-6 as well as the IL-6 response to injury. Prolonged and excessive elevations of circulating IL -6 levels in patients after elective surgery have been associated w ith complications and even death. Findings included the role of IL-6 in the acute phase response to surgery a nd it was suggested that IL-6 is a more accurate indicator of infla mmatory status than acute phase proteins, especially in patients with liver disease. Su rgery provoked increases in IL-6 levels within 1 to 3 hours postoperatively which remained el evated for up to 72 hours in uncomplicated cases. It was also found that the magnitude of elevation was related directly to the degree of surgical insult. An interest ing result of the review was th e finding that IL-6 response to tissue injury in septic patients appeared to be independent of commonly summoned

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18 mediators, such as TNF, IL-1 and endotoxin. The most confirmatory finding in this review was that surgery causes a paradox. This paradox occurs when the hyperinflammatory state predisposes patient s to the development of immunosuppression. When there is tissue insult, physiologic re sponse involves an early hyperinflammatory response, which is complemented by a degree of compensatory anti -inflammatory effect. If this early inflammatory response is exces sive, an inappropriat e persistence of antiinflammatory compensation will result in im munosuppression (Biffl, Moore, Moore, & Peterson, 1996). The initiation of the inflammatory re sponse and the cessation of this process during the perioperative experience are not well understood (Bjornsson et al., 2007). Bjornsson and colleagues (2007) studied the ear ly phase of acute inflammatory reaction and the course of proand an ti-inflammatory cytokines in re lation to the adrenal response to surgical stress. They measured IL-1 IL-6, TNF, IL-8, IL-12 and IL-10 in 13 patients (67 + 9 years) undergoing total hip repl acement due to osteoarthritis. The measurement of cortisol was interpreted to be related to the operative stress level of each patient. There was a significant inverse correl ation between the cortis ol secretion and IL6 response during the first 24 hours after surger y that demonstrated cortisol as having a slowing effect on the acute infl ammatory response. Five patien ts had significantly higher cortisol levels preoperati ve than those 8 patients who had double their cortisol concentration postoperatively; 580 + 128 nmol/l versus 33 + 123 nmol/l (p = .003). This led the researchers to question if IL-6 drove cortisol producti on or if cortisol could be a negative feedback loop in the inflammato ry system (Bjornsson et al., 2007).

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19 In a study that examined CRP levels afte r different hip surgeries in 349 patients, researchers found CRP levels could be used to quantify the degree of tissue damage and invasiveness of a procedure. Peak CRP leve ls were reached on the second postoperative day in each group (median range of CRP leve ls 8.716 mg/dL). Significant differences were found between each of the 5 types of hip surgeries and high CRP values on the second postoperative day was found to indi cate a major inflammatory response to the surgery and reflected the level of tissue da mage. The highest levels of mean CRP and resultant surgical stress were found in the hemiarthroplasty (16mg/dL; p = <0.001) and total hip arthroplasty patients (16mg/dL; p = <0.001) (Neumaier, Metak, & Scherer, 2006). Ruzic and colleagues (2004) studied the di fferences in systemic stress responses in 80 patients undergoing 3 different types of surgery for benign prostatic hyperplasia by measuring urinary cortisol, and CRP, and fibr inogen as well as antioxidants from serum samples. The researchers found significantly hi gher levels of cortisol, CRP and total antioxidant status in all three study groups after surgery. A strong systemic stress response intraand postoperatively was re lated to the surgery and blood loss. The researchers also commented that cortis ol could be increased by fear, smoking, hypovolemia and endocrine dysfunc tion (Ruzic et al., 2005). Immune Responses To Hypothermia A study by Beilin and others (1998) investig ated the postoperative impact of mild intraoperative hypothermia in comparison to normothermia in terms of cellular immune responses. Sixty patients undergoing abdomin al surgery (hysterectomy, colorectal surgery, and open cholecystectomy) were randoml y assigned to either routine care (n=30)

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20 or FAW (n=30). The routine care group (hypothermia group) did not receive any active warming nor warmed fluids during th e perioperative period. The FAW group (normothermia group) received active warming th at began 45 minutes before anesthesia induction and continued throughout the surger y as well as 1 hour postoperatively. The normothermia group also received warmed (98.6 F /37C) intravenous (IV) fluids. Anesthesia care was standardized for all patients. Venous blood samples were collected 90 minutes before anesthesia induction, at the end of surgery, and at 24 and 48 hours postoperatively. Within 1 hour after the bl ood was drawn, PBMC were isolated and suspended in calf serum and then frozen unt il use within 1 month’s time. After quick thaw, cells were washed and viability test ed by trypan blue dye exclusion. Cells were used only if viability was >95%. PBMCs were used to test cytokine production IL-1, IL2, and IL-6, TNF mitogen-induced pro liferation and NK cell cy totoxicity. Plasma cortisol levels were also determined. Statis tical analysis was done by repeated measures ANOVA with probability values <0.05 cons idered significant (Beilin et al., 1998). Mean core temperature was signifi cantly less in the hypothermia group throughout the surgery and until 3 hours afte r surgery. Mitogen induced proliferation assay results showed significant suppressi on with the hypothermic group that suggests suppressive effects involve various lymphocyte subpopulations. The mitogen proliferation in the normothermia group remain ed stable at all time periods. Production of IL-1 and IL-2 was significantly higher 24 hour s after surgery in the normothermia group compared to the hypothermia group. The researchers state that because IL-2 plays such a central role in various immune responses, a reduction of this cytokine would impair immune defense mechanisms and increase susceptib ility to surgical site infections (SSIs).

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21 The proinflammatory cytokine IL-1 increase noted in the normothermia group confirms other studies; and suggests that delayed w ound healing found after hypothermia could be partially accounted for by reduced IL-1 production in hypothermic patients. No significant differences were found in NK cell cy totoxicity between th e two groups at any repeated measurement. Lastly, there were signi ficant elevations in the cortisol levels in the hypothermic group as compared to the normothermia group at 24 hours after surgery. The researchers conclude that these findi ngs indicate periopera tive hypothermia may contribute to the suppression of immune res ponse in the perioperati ve period (Beilin et al., 1998). Frank and colleagues (1995) examined the relationship between perioperative changes in body temperature and plasma levels of stress hormones in 74 elderly patients undergoing abdominal, thoracic, or lower ex tremity vascular surgical procedures. Randomly assigned to FAW (n=37) or routin e care (n=37), the two groups had core temperatures, skin temperatures, and plasma concentrations of epinephrine, norepinephrine, and cortisol measured and compared throughout the perioperative period. In addition, heart rate and ar terial blood pressure were compared between groups. The mean core temperature was lower in the rout ine care group on admission to the recovery area (35.3C + 0.1C) compared to the FAW (36.7C + 0.1C; p = 0.02) and remained lower during the early postoperative peri od. Forearm minus fingertip skin-surface temperature gradient (an index of peripheral vasoconstriction) was gr eater in the routine care group in the early postoperative period. The mean norepinephrine concentration (pg/ml) was higher in the routine care group immediately postoperative (480 + 70pg/ml versus 330 + 30pg/ml; p=0.02) while mean epinephrine concentrations were not

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22 significantly different between gr oups. The mean cortisol leve ls were increased in both groups during the early postope rative timeframe, but the differences between groups were not significant. Systolic, mea n, and diastolic arterial blood pressures were significantly higher in the routine care group. Researchers concluded that hypothermic patients had a greater degree of peripheral vasoconstr iction, higher blood pr essures, and higher norepinephrine levels during the early postopera tive phase of care and that these findings suggest cardiovascular morbidity may be re lated to hypothermia in the perioperative period (Frank et al., 1995). In another study, Wenisch and others ( 1996) tested the hypothesis that mild intraoperative hypothermia decreases both pha gocytic capacity and the generation of reactive oxygen intermedia tes in polymorphonuclear leukocytes. Random assignment was conducted with 10 surgical patients assi gned to intraoperative core temperatures ranging from 33 to 37C. The production of re active oxygen intermediates and neutrophil phagocytosis were measured using flow cyto metry. Phagocytic capacity was evaluated by uptake of fluorescein isothiocyanate labele d with Escherichia coli. Reactive oxygen production was estimated by the intracellula r conversion of dihydrorhodamine 123 to rhodamine 123. Arterial blood samples were take n preoperatively, one hour after surgery started and 2 hours postoperatively. Results sh owed that mild intraoperative hypothermia reduced the generation of oxygen-free radi cals by more than 50% and neutrophil phagocytosis by 72% from preoperative levels Serum cortisol increased during surgery, and increased more during the postoperative phase. However, there was no relationship between neutrophil phagocytosis or reactive oxygen intermediate production and serum concentrations of acute phase reactants or pl asma cortisol levels. Production of reactive

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23 oxidative intermediates was closely linked to body temperature and found to be linear, varying approximately fourfold over a 4C range of core temperatures. Researchers concluded that since neutr ophil oxidative function is one of the important defenses against bacteria that cause typical surgical site infections, impaired neutrophil oxidative killing may be a contributing factor hypothe rmia-induced reduction in resistance to infection (Wenisch et al., 1996). Therapeutic Effects Of Prewarming There is recent research documenting the therapeutic effects of preoperatively warming surgical patients. Prewarming rais es mean body temperature by increasing the energy content in the peripheral thermal co mpartment of the body. This is important because it is difficult to tr eat the core hypothermia that occurs immediately after induction of general and regional anesthesia due to an internal core-to-peripheral redistribution of body heat. Discussion of f our of these studies provided evidence that prewarming is beneficial. Fossum and colleagues (2001) determined the effect of prewarming for 30 minutes with FAW (treatment group; n = 50) versus warmed cotton blankets (control group; n = 50) on core body temperature. The treatment group had significantly higher temperatures (35.97C + 0.52) on arrival to PACU than did the control group (35.54C + 0.5; p < .001). Of interest, the control gr oup of patients also self-reported a higher incidence of shivering and thermal disc omfort (Fossum, Hays, & Henson, 2001). In a prospective, randomized and blinde d study by Vanni and others (2003), 30 patients undergoing abdominal surgery were placed in one of three groups according to the thermal management administered. In 10 patients, no special precautions were used to

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24 avoid hypothermia, whereas the other two groups received both preoperative and intraoperative active warming (n = 10) or only intraoperative active warming (n = 10). In the group that received only prewarming for 60 minutes, mean skin (3.7 C), mean body (1.9 C) and core temperature (1.0 C) increased significantly (p < .05) before induction of anesthesia. Intraoperatively, the core temp erature of prewarmed patients remained significantly higher (36.2C + 0.5C; p <.05) than that of the other two groups. All patients warmed intraoperatively were normother mic at the end of surgery. In contrast, all unwarmed patients were hypothermic at the end of surgery and 5 of those patients suffered from postoperative shivering (Vanni, Braz, M odolo, Amorim, & Rodrigues, 2003). In a randomized, pretest/posttest experime nt conducted to compare the effects of two preoperative warming approaches on perc eptions of thermal comfort and anxiety, 118 preoperative patients were placed either in a forced-air warming (FAW) group or routine care (RC) group The FAW group (n =60) had significantly higher thermal comfort levels in relation to their overall body temperature (p=.016), shivering (p=.010), and chest warmth (p=.003) in comparison to the RC group (n=58). Of interest, only the FAW group experienced a signi ficant reduction in preope rative anxiety (t=2.77, p=.007) compared to the RC group (t=.790, p=.431). The researchers suggested that preoperative warming is a positive nursing intervention fo r both temperature management and anxiety reduction Melling, Ali, Scott and Leaper (2001) conducted a randomized controlled study investigating the effects of preoperative warming on the incidence of SSI after clean surgery. The sample included 416 patients under going elective hernia repair, varicose

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25 vein surgery or breast surgery that would resu lt in a scar longer th an 3 cm in length. Random assignment occurred with 139 assigne d to standard treatment (non-warmed), 138 allocated to local warming (wound area warm ed with radiant heat), and the last 139 patients assigned to systemic warming (f orced air warming to whole body). Warming interventions lasted at least 30 minutes w ith staff nurses applying warming devices. Demographics and surgical variables were documented with core temperatures before treatment, after any warming, and after surg ery. A single observer, unaware of treatment allocation, reviewed all patients at 2 and 6 weeks postoperative. He observed wounds and interviewed patients for wound history. Wounds were swabbed for microbiological analysis if purulent drainage was present at time of observation. Wounds were classified as infected if there was pus or a painful eryt hema that lasted for at least 5 days and was treated with antibiotics within the 6 weeks of surgery. The overall rate of SSI was 8% with a statistically higher rate of w ound infection in the non-warmed group (14%) compared to the combined warmed groups (5%; p = .001). There was also statistical significance on the rate of wound infecti on when the two warmed groups were considered individually (systemic p = .026; local p = .003). The researchers concluded that prewarming patients, if done according to manufacturer’s inst ructions, appears to have no adverse side effects. There were no st atistical differences in outcome between the two types of warming interventions, alt hough local warming resulted in 2% fewer infections. Of interest, the suggestion was made by the res earchers that the hour before surgery may be of equal importance as the ‘decisive period’ of during and immediately postoperative because of the prevention of vasoconstriction by preoperative warming intervention (Melling, Ali, Sc ott, & Leaper, 2001).

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26 Discussion The need to undertake more human outc ome studies was apparent during the literature review. It was also apparent that there are num erous differences in design, definitions of hypothermia, site and method of temperature measurement, and numerous other confounding variables related to the relationsh ip between perioperative hypothermia and surgical stress. The literatu re review measurements of cytokines, catecholamines, and acute phase proteins, di d not provide a solid basis from which to compare biologic values, especially from a pr eoperative perspective. Perhaps conduct of repeat studies to see if eviden ce is reproducible is another a pproach that could be taken, as that was not evident in this review of lite rature Future studies need to show sufficient power through large enough sample sizes, and develop reproducible methodological approaches in order to detect clinically im portant outcomes. The preoperative phase of care was not a focus in studies reviewed, ther efore it would be releva nt to suggest that future studies examine changes that occu r preoperatively and even target early preoperative warming as an intervention agai nst the risk of perioperative hypothermia. There were numerous studies that disc ussed complications that have been associated with unplanned perioperative hypot hermia, such as shivering, increased cardiac morbidity, coagulopathy, enhanced dr ug effects, venous stasis, and delayed recovery from anesthesia. This long lis t of complications alone should warrant the perioperative warming of all surgical patients, however, the evidence was so spread out and slim amongst each of these complications, th at patients are still suffering due to a lack of strong cause and e ffect quantification for each.

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27 Most of the evidence discussed above s upported the hypotheses that preoperative warming reduces perioperative hypothermia as we ll as reduces surgical stress in patients. Perioperative warming is bene ficial as it increases perfus ion, oxygenation and cellular immune responses. Intraoperative warming dur ing major surgeries is becoming more of a routine practice in many instit utions; however, evidence review ed in this paper suggests that all surgical procedures warrant perioperative warmi ng beginning in the preoperative phase of care. It was also apparent that nursing intervention studies are needed to find new approaches that decrease surgical st ress and thereby improve immunocompetence postoperatively. Conceptual Model The perioperative experience includes elem ents such as the fear of surgery, anesthetic medications, tissu e injury, and unplanned hypothermia – to name a few. The immune system provides an excellent biol ogic model to generate and test hypotheses related to perioperative care issues. Consider ing that anesthesia and surgery have broad effects on the immune system and provoke proinflammatory as well as immunosuppressive responses, it is reasonable that preventi on of possible intraoperative and postoperative complications could begi n during the preoperative phase of the patient’s surgical experience. This study was a preliminary effort in determining the effect of prewarming on redistribution hypothermia and th e initial acute phase response of surgical stress. The conceptual framework for this study, de picted in Figure 1, was based on the FAW intervention providing a moderating effect on unplanned hypothermia that would lead to decreased surgical stress.

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28 Anesthesia and Surgery Surgical Stress Response Figure 1: Conceptual Model Note : The conceptual model illustrates the moderating effect of a preoperative FAW intervention on unplanned hypothermia and the ac ute phase response of surgical stress. The perioperative immune system responds to multiple insults from the start of the surgical experience in order to preserve life, heal incised/excised tissues and fight infection. The FAW preoperative interv ention was hypothesized as decreasing the catecholamine and cortisol levels of stress wh ile increasing the healing processes of the initial acute phase response. Any continued stimulation of the st ress response leads to possible reduced cardiac function, reduced immunocompetence, delayed wound healing, and a general loss of sufficient energy st ores to promote healing (Edwards, 2003). Preoperative FAW was theorized as one way to decrease surgical stress by allowing more normal temperature levels during surgery and th ereby interacting with the stimulation of the stress response. Unplanned Hypothermia level of hypothermia temp FAW Preoperative Intervention stress hormones APR Decreased Surgical Stress cytokines CRP

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29 The FAW intervention was also hypoth esized to lessen the unplanned hypothermia that routinely o ccurs intraoperatively. The broken line coming from the unplanned hypothermia represents a decrease d hypothermia from the FAW intervention and as an interaction with the surgical stre ss response. The patient that receives a FAW intervention would ultimately have decrease d surgical stress demonstrated by higher proinflammatory cytokine and CRP producti on that would reflect a functional acute phase response intraand post operatively. This conceptual m odel reflects the intervention as an action intended to prot ect the body by ensuring an upre gulation of the inflammatory response that acts to protect and heal wit hout decreasing the competence of the immune system. Study Hypotheses This study was developed from research questions and direct ional hypotheses. In order to answer the research question, the following hypotheses were tested: 1) What is the effect of type of preoperati ve warming on the occurrence of intraoperative redistribution hypothermia? Hypothesis 1: The FAW group will e xperience less unplanned perioperative hypothermia than the RC group. 2) What is the effect of type of preope rative warming on the acute phase response of surgical stress during th e perioperative period Hypothesis 2: The FAW group will experience lower catecholamine and cortisol levels than the RC group. 3) Is there a difference in th e level of surgical stress re sponse between the FAW group of patients versus the routin e care group of patients?

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30 Hypothesis 3: The FAW group will experien ce higher pro-inflammatory cytokine and CRP production intra and postoperatively than the RC group. Summary The literature review provided evidence of support for this preliminary study and the conceptual framework. This evidence was discussed from the perspective of temperature physiology, the etiology of unplanned hypothermia and the cellular responses to surgery and hypothermia, as well as the therapeutic effects of prewarming. The lack of nursing studies that focus on FAW as a preoperative intervention for decreasing surgical stress was recogni zed. The conceptual framework guided the development and organization of the study as well as led to the hypotheses used to answer the research questions posed at th e start of the study process. This chapter provided discussion about the overall context for the phenomenon under study.

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31 Chapter Three: Method This chapter describes the research plan and includes the research design, selection of setting, power analys is and sample size, and selec tion criteria for participants in this study. Institutional Review Board approval and the confidentiality and anonymity of participants’ data are discussed. Data collection pro cedures and analysis methods are also found in this chapter. Research Design The method used was a randomized, equivale nt group, experimental design to test the following hypotheses: 1) The FAW group will experience less unplanned perioperative hypothermia than the RC group. 2) The FAW group will experience lower catecholamine and cortisol levels than th e RC group. 3) The FAW will experience higher pro-inflammatory cytokine and CRP production intra and post-operatively than the RC group. The use of either an experimental or routine practice of preoperative warming intervention served as the independent vari able. The effects of this manipulation on thermoregulation and acute phase stress respon se were examined. Confounding variables, such as ambient temperatures, blanket te mperatures, surgery duration, and patient’s physical status were measured on each patient.

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32 Protection of Human Participants Study Approval Approval for this study was obtained from the Institutional Review Board (IRB) of the University of South Florida (Appendi x A: IRB Approval Letter) and verbal permission was received from the Research Co mmittee at the surgical facility where the study was conducted. Recruitment Process The recruitment flyer was made available to all patients in the Preadmission and Testing Department minimized perception of coer cion and the recruits we re told that their participation was voluntary (Appendix B: Recrui tment Flyer). The large print recruitment flyer briefly described the nursi ng study and asked for interested participants. If a patient stated an interest in part icipating in the study to their preadmissions nurse, then the investigator approached the pa tient to further describe the study, ascertain if the patient met inclusion criteria, and obtained informed consent. Informed Consent Process Written informed consent was obtained from each eligible participant prior to participation in the research process (Appendix C: Informed Consent Form). Understanding was assured by asking if th e participant had qu estions and if the participant could verbalize accurately what he/s he had agreed to do as a participant in the study. Benefits and Risks of Participation At this facility, different teams of hea lth professionals see the patient at each phase of perioperative care. The main benefit of participation was the opportunity to have

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33 one familiar person (the nurse researcher) with them throughout their surgical experience. Participants were withdrawn from the st udy when they requested to be withdrawn and at no time was the surgery delayed for th e sake of the study. The forced-air warming blanket posed very low risk of thermal injury and is made of a non-woven medical fabric manufactured by Dupont. The blanket material s are latex free and biocompatible. There were no adverse events during the FAW inte rventions. The FAW blanket can make an occasional patient feel too warm, and when this occurred, the temperature of the air entering the blanket was adjusted. Core temperature monitoring also enabled the researcher to decrease the temperature of the blanket if overwarming of the participant occurred. There were two instances where the blanket airflow was too warm for the patient and the temperature was adjusted on one case and turned off earlier than the 30minute intervention in another case. Thes e types of events were documented for statistical control. Antecubital venipuncture was used to obtain eight tubes (10ml and 4mL x 4 collections) of venous blood and the particip ant was told that th ere could be mild discomfort and possibly a small amount of bruising. A separate intermittent IV access (INT) to use for all 4 blood draws was used to decrease multiple venipunctures for each participant. It was placed at the same time as the routine IV line in the preoperative setting. This decreased the amount of po ssible discomfort and bruising involved. Assessment of the site and removal of th e access line was documented on each patient after the last blood sample was taken in PACU.

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34 15 RC Group Participants 1 participant dropped due to serum sample error 29 participants randomized 14 FAW Group Participants Included in analysis N= 14 Included in analysis N= 14 Sample Selection A power analysis was conducted during th e planning of the study that showed a total of 116 participan ts with 50% in the FAW treatment group (n=58), and 50% in the routine care group (n=58) would provide suffici ent power. This power analysis was based on type I error rate of .05, a type II error ra te of .20, and an effect size of r = .30 based on past research of a prewarming intervention study. After the first set of assays were run and preliminary analysis was conducted on 9 participant samples in the laboratory, it was de termined that high sensitivity assay plates were needed. Due to the increased cost of the different assay plates, it was cost prohibitive to continue with a large sample size. The decision to conduct a preliminary study with approximately 30 participants was made at that time. Figure 2 depicts the flow of participant status during the conduct of the study. Figure 2 Flow Diagram of Partic ipant Status During the Study

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35 Study Setting This study was conducted over a 5 and one half month period at a public, 98-bed acute care facility with 6 OR’s. All patie nts coming into the preadmission and testing area were given a recruitment flyer. If a patient stated an interest in participating in the study, the investigator described the study, as certained if the patient met inclusion criteria, and obtained informed consent. Prior to starting the study, an inservice was given to the surgical services staff so they would be aware of the res earch and its purpose as well as their role in continuing to practice in their usual manner when involved in a study patient case. The surgeons and anesthesia providers were all given a lett er describing the study (Appendix D: Surgeon Letter; Appendix E: Anesthesia Provider Le tter). Verbal permission was obtained in order to use the hospital laboratory’s centr ifuge so blood samples could be handled appropriately for assay. Inclusion and Exclusion Criteria Inclusion criteria include d any patient 18 to 65 year s of age, competent and undergoing general anesthesia with a schedul ed clean or clean-contaminated surgical procedure. Exclusion criteria included mini mally invasive surgery involving scopes (e.g., arthroscopy, laparoscopy) and any patient exhi biting the following: pa ralysis or a known paresthesia, hyper/hypothyroidi sm, immunosuppression drug or radiation therapy within the past 6 months, febrile status (temperature > 38C ), and inability to tolerate tympanic temperatures. Non-English speaking patient s were excluded due to the lack of interpreters.

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36 Data Collection On the day of surgery and after arrival in the preoperative holding area, patients were assigned to one of two groups using a set of computer-gener ated random numbers. Demographic and health status data were gathered to cont rol for confounding variables. The data collection forms are in Appendix F. A peripheral venous access device (IV line designated for blood samples) was inserted by the investigator, using hospital procedure, in order to decrease the amount of periphe ral punctures for serum collection. The access site was placed in the opposite ar m from the surgical IV access. A minimum of four timed measurements throughout the peri operative period was recorded. The first set of measurements was recorded just before the warming intervention started and incl uded vital signs with the core temperature taken by an infrared tympanic thermometer (Bra un Thermoscan IRT 4520, Exac Temp). The following technique was used each time a te mperature was taken was insertion of the probe into the ear, on the same side as th e study IV access site, with the tip pointed toward the nose with the auricle pulled up and back. The ambient temperature was determined and recorded at each measurement with the use of an indoor/outdoor digital thermometer (Radio Shack Thermometer, M odel 63-1009) that had a temperature range of + 32 to + 122 F. Two tubes (10 mL seru m separator and 4 mL plasma separator) of venous blood were collected for measuremen t of CRP, pro-inflammatory cytokines, catecholamines, and cortisol levels. A second set of the same measurements was obtained at least 30 minutes after the start of interventi on, and recorded befo re entering the OR suite and induction of anesthesia. The third blood sample and data measurements were taken 1 hour after induction of anesthesia. Upon arrival to the Post Anesthesia Care Unit

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37 (PACU), the investigator obtained the last se t of measurements within a 30-minute time frame of admission to the PACU. Intervention Protocol Both groups put on a hospital gown and f ooties with a non-warmed cotton blanket placed over the legs for privacy prior to initia l measurements being taken. After the initial set of measurements, those in the FAW group were covered with a forced-air warming blanket (Bair Hugger, model 111, Arizant Hea lthcare, Inc., Eden Prairie, MN) that connects to a warming unit (Bair Hugger, model 505) set on medium (38 + 3C or 100.4 + 5.4F) at that time. The warming equi pment and blankets were donated and incurred no cost to the patient or facility. Once started, use of the warming blanket was continued for at least a 30 minute warming intervention. After initial measurements were taken on the participants in the RC group, they were covered with one warmed cotton bath bl anket. The blanket temperature was taken, at the time of placing it on the patient, with a handheld digital infrared thermal scanner (OS951, Omega, Stamford, CT) that has an ope rating temperature range of 0 to 50 C (32 to 122 F) with only 1% reading emissivity error. The warmed cotton bath blanket was replaced twice at 15-minute intervals during the 30 minutes of intervention. Each replacement blanket had a documented thermal reading. The post intervention measurements were taken at least 30 minutes af ter the start of the c ontrol intervention. Serum Collection Protocol Two tubes of venous blood (14 m/L) were collected for measurement of CRP, pro-inflammatory cytokines, catecholamines, and cortisol levels at each of the four collection times. All blood samples were placed on ice a nd transported to the lab within

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38 2 hours and processed for immediate freezing. The serum and plasma separator tubes were spun at 3500 rpm for 10 minutes at 4C in one of two hospital laboratory centrifuges (Beckman Spinchron 15 N-414880), and the end products aliquoted into Eppendorf tubes and frozen at -20C. Periodically, samples were shipped on dry ice to the USF biological laboratory for the investigator to analyze wh ere they were stored at – 80 C until analysis. Assay Protocol Analyses of biological variables were done in duplicate with appropriate controls and standards within 3 months of collec tion. For the cytokines (IL-1 , IL-6, TNF, & IFN), the samples were analyzed using a high sensitivity human cytokine LINCOplex 4-plex immunoassay kit utilizing Luminex technology. Luminex technology measures multiple analytes simultaneously in a single reaction vessel. Less than 50 L of sample is needed to test for these analytes at a single testing time. The assays are highly reliable and precise and were purchased as kits from Linco Research where this investigator’s dissertation chai rperson, Dr. Groer, was traine d in the use of the Luminex analyzer. This investigator received training in the opera tion of the Luminex and was supervised by Dr. Groer. The catecholamines, epinephrine and norepinephrine, were measured in plasma by research ELISA’s (Rocky Mountain Dia gnostics, Colorado Springs, CO) using a microtiter plate format with acylated catecholamines from the sample and the solid phase of the microtiter plate competing for a fi xed number of antiserum binding sites. The antibody bound to the solid phase catecholam ine was detected by an anti-rabbit IgGperoxidase conjugate using TMB as a subs trate. The reaction was monitored at 450

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39 nanometers with the amount of antibody bound to the solid phase catecholamine being inversely proportional to the catecholamine concentration of the plasma sample. Cortisol levels were measured by ELIS A (DRG, Germany) with lower limits of detection at 2.5ng/mL and high interand intra-assay specificity. The assay kit was a solid phase enzyme-linked immunosorbent as say based on the principle of competitive binding. The microtiter wells we re coated with monoclonal antibody directed towards an antigenic site on the cortisol molecule. Endoge nous cortisol of a patient sample competes with a cortisol-horseradish peroxidase conj ugate for binding to the coated antibody. After incubation, the unbound conjugate was washed off and the amount of bound peroxidase conjugate was then inversely pr oportional to the concentration of cortisol in the serum sample. Absorbance was measured spect rophotometrically at 450 nanometers. The C-reactive protein (DRG, Germany) in serum samples were measured using a high sensitivity assay system utilizing a uni que monoclonal antibody directed against a distinct antigenic determinant on the CRP molecule. A mouse monoclonal anti-CRP antibody was used for solid phase immobilization. A goat anti-CRP antibody wass in the antibody-enzyme conjugate solution. The test sample was allowed to react simultaneously with the two antibodies, resulting in the CRP molecules being sandwiched between the sold phase and enzyme-linked antibodies. A tetramethylbenzidine (TMB) reagent was adde d and incubated for 20 minutes, resulting in the development of blue color. After de velopment was stopped, the concentration of CRP was directly proportional to the color intensit y of the test sample. Absorbance was then measured spectrophotometrically at 450 nanometers.

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40 Data from the ELISAs were converted fr om optical densities to concentrations and analyzed by Graph Pad. The Luminex instrument converted and analyzed the fluorescence intensity of the cytokine concen trations in the samples and provided one mean value of the duplicate samples. For each assay, a standard curve was obtained through the measurement of a set of standard samples. The concentrations of the experimental samples were then determined by comparison with this st andard curve. The raw assay data were then entered on the st atistical spreadsheet with the other data for analysis. Data and Safety Monitoring All data was kept confidential with all data locked in a file cabinet in the researcher’s office during the conduct of the study. Privacy was insured by the use of a code number and computer files were set up to require passcodes for access. Only the student PI and the Faculty Advisor have access to the data. Consent forms were kept separate from data gathering forms during the conduct of the study. Consents and data we re then stored in a locked fi le cabinet that will be kept for 5 years in the researcher’s office at hom e. Computer files were also placed on a CD for storage. Shredding of the paper files and the CD will be completed at the end of 5 years. Participant safety was monitored on an ongoing individual basis. Protective measures to ensure the participant’s privacy are outlined on the consent form (Appendix C) and confidentiality was maintained. The participant was withdrawn from the study at any time they requested to be withdrawn. Th e surgical procedure was not delayed for the sake of the study. The use of inclusion and exclusion criteria for determining

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41 participation status of patients was another monitoring tool for maintaining participant safety and control. Data collection tools were tested on 6 patie nts at the start of the study to confirm usability, clarity, and process orientation of the forms. Adjustments were minor to the collection tools. Documentati on of research activities will be kept in a lab notebook for review purposes as well as data integrity. Analyses of biological samples were done in duplicate with ap propriate controls and standards within 3 months of collecti on. Thermometers, blanket warming units, and the FAW equipment were continually mon itored for function and calibration. The monitoring information was documented in a lab notebook for ease in review and maintenance of data integrity. Data Analysis To test the hypotheses that the independent variable of a FAW intervention would impact the dependent variables of temperat ure and acute phase re sponse across time and between groups, the statistical analysis pl an was a (2 x 4) repeated measures ANOVA design. The 4 time points used for assessmen t were the following: before warming treatment (Time 1); after warming treatment (Time 2); one hour after induction of anesthesia (Time 3); and upon admission to th e PACU (Time 4). Sample characteristics regarding demographic and hea lth characteristics were gath ered from the participants. Data was coded, entered and analyzed using St atistical Package for the Social Sciences version 15 (SPSS, Inc., Chicago, IL). All statis tical tests were eval uated for significance at the .05 level.

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42 Summary This chapter provided an overview of the research plan that included the design, participant protections, setti ng and sample, as well as se lection criteria. A discussion about the data collection was provided through th e use of specific prot ocols. A review of the data and safety monitoring processes as we ll as the data analysis method were also discussed.

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43 Chapter Four: Results Analysis of the collected data led to a view of the effect of a FAW intervention compared to routine care on the initial acute phase response of surgical stress. This chapter discusses data prepara tion, the profile of study partic ipants, statistical analyses procedures. The test results of each hypothe sis are discussed base d on statistical test findings. The use of tables and figures disp lay the raw data at each time point of measurement. Data Preparation All data entries were entered with frequent data veri fications by visual comparison of the data printout against the original data collection sheets. All errors in entry were corrected at that time. Outli ers were also inspected using frequency distributions and boxplots. There we re no outliers found between groups. Histograms of each timed temperature reading (Time 1 to Time 4) were used to examine distributions for normality. Time 1 and Time 2 were positively skewed whereas Time 3 and Time 4 were negatively skewed. Computation of t-tests for each value of skewness was done and there were no signifi cant values found. The decision to use raw temperature data in analysis procedures was made. Table 1 displays the descriptive statistics calculated on temperature data.

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44 Table 1: Descriptive Statistics Calc ulations on Temperature Across Time Statistics (N = 28) T1 Temp T2 Temp T3 Temp T4 Temp Mean Standard Deviation 98.3 .6150 98.3 .6566 97.4 1.0758 97.5 1.0167 Skewness Std. Error of Skewness t-test of skewness .464 .441 1.052 .635 .441 1.439 -.552 .441 -1.251 -.591 .441 -1.340 Missing data were also assessed among th e biologic variables. One participant’s blood samples were not labeled appropriately, so a listwise deletion of this participant’s data was completed. Other missing biologic data points were valid missing values because of no serum/plasma available at that specific time frame due to technical difficulties or the inability to draw a blood sample at a particular time point. Raw data from the biological assays were entered and a non-normal distribution was determined. Because these variables show their effects on a logarithmic scale, a log 10 transformation was conducted to achieve a normal distribution before repeated measures ANOVA were computed. However, for ease in discussing and comparing data, the raw data values were used to plot and e xplain mean values in the tables and figures displayed in this report. Profile of Study Sample There were no significant differenc es between the RC and FAW groups. Participants in this study (N = 28) were basically healthy an d not considered at risk for surgery by the assignment of a physical level 1 or 2 (P1 or P2), as designated by the

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45 American Society of Anesthesiologists (ASA) and used by the anesthesiologists routinely during this study. The participants were sc heduled for either a clean or a cleancontaminated invasive surgical procedure. The types of surgery included gynecologic and genitourinary, hernia repair with mesh, nasopharyngeal, open reduction fracture repair, and laminectomy procedures. Women comprised 75% (n = 21) of the entire sample. There were both African American (n = 10) a nd Caucasian (n = 19) participants in the sample, but no other racial groups responded to recruitment. Ten participants were hypertensive and 2 diabetic with even di stribution between groups. A display of the baseline characteristics of the study participants is found in Table 2. Table 2: Participant Characteristics (N = 28) Characteristic Min Max Mean SD Age 22 64 44 11 Height 61 76 66.5 3.4 Weight 125 340 194 50 BMI 21 58 31 8 Anesthesia duration 33 207 113 39 Surgery duration 21 189 88 38 PACU duration 45 100 66 16 All participants routinely received pre operative anxiolysis with the medication midazolam usually within 15 minutes prior to being transported to the OR. All underwent balanced general anesthesia that routinely included fentanyl, propof ol, and nitrous oxide

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46 and were intubated for the procedure. It was also routine practice to provide warmed IV fluids in all perioperative se ttings. Intraoperative FAW wa s provided for 17 out of the 28 participants (n = 8 in RC group; n = 9 in FAW group) by Anesthesia Providers. The Anesthesia Providers were neither deterred nor encouraged to provide intraoperative FAW. There were a total of 9 (32%) hypot hermic participants at Time 4 with postoperative shivering documente d on 3 patients. Two of the pa rticipants with shivering were in the RC group with the ot her participant in the FAW group. Of particular interest, th e overall body mass index (BMI) of the participants was 31 + 8 with approximately 71% of the samp le population in the overweight to obese range. There were only 8 participants not ed as within normal range on the body mass index. Statistical Analyses A 2 (warming type) x 4 (Time 4) re peated measure ANOVA was conducted using a probability value of p = < .05 to test the following hypotheses: 1. The FAW group will experience less unplanne d perioperative hypothermia than the RC group. 2. The FAW group will experience lower catecholamine and cortisol levels than the RC group. 3. The FAW group will experience higher pro-inflammatory cytokine and CRP production intra and post-operatively than the RC group. Pearson product moment co rrelation coefficients we re also calculated to determine relationships between temperatures, catecholamines, cortisol, CRP and

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47 cytokines, as well as other confounding variables, such as BMI and ambient temperatures. Test Assumptions The assumption of normal distribution of the dependent variables was reviewed and using a log 10 transformation of the biol ogical data, that assumption was met. With repeated measures, there is correlation betw een the measures because they are from the same people, so the assumption of sphericity must be met. Specifica lly, the equality of variances of the differences between treatment levels in this ex perimental study were tested by Mauchly’s Test, which tests the hypothe sis that the variance s of the differences between conditions are equal (Fie ld, 2005). If the test statistic was significant (p = < .05) then there were significant differences be tween the variances of differences and the condition of sphericity was not met. When the assumption of sphe ricity was violated, then the Greenhouse-Geisser correction was used. Levene’s Test was used to test for the assumption of equality of error variances between groups. When this test is non-signi ficant, it indicates the assumption was met. When pairwise differences among treatment le vels for a main effect was assessed, the Bonferroni post-hoc procedure was performe d with a p = .008 level of significance. Hypotheses, Statistical Procedures, and Results Hypothesis 1 Hypothesis 1 predicted that the group of participants that received FAW would experience less unplanned perioperative hypother mia than the group of participants that received routine care. The results of a repeated measures ANOVA test showed a significant effect over time (F (3, 78) = 19.374, p = < .001), a non-si gnificant effect

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48 within subjects (F (1, 26) = 1.439, p = .241), a nd a non-signifi cant interaction effect (F (3, 78) = .390, p = .656). Since there was a si gnificant effect of temperature across time, pairwise comparisons were analyzed. The mean difference ( M) between temperatures from Time 1 and 3 ( M = .964, SE = .191, p = < .001) and Time 2 and 3 ( M = .939, SE = .190, p = < .001) were found statistically signifi cant. Further comparison analysis also revealed Time 1 and 4 ( M = .864, SE = .184, p = < .001) as well as Time 2 and 4 ( M = .839, SE = .188, p = .001) to be statistically significan t. Figure 3 as well as Table 3 shows the descriptive statistics for each group at the four time points. Figure 3: Mean Temperature Values (F) Across Time 94.5 95 95.5 96 96.5 97 97.5 98 98.5 99 99.5 1234 TimeTemperature (F) Routine Care Group FAW Group There were neither significant differences nor correlations be tween groups related to length of anesthesia, surgery duration, or ambient temperatures. Since the statistical

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49 analysis of interaction was not significant, this evidence s howed a lack of statistical support for the first hypothesis. Table 3: Descriptive Statistics of Temperatures (F) Across Time Time Reading of Temperature Group Assignment Mean (F) Std. Deviation Time 1 temperature RC group (n = 14) 98.2 .7 FAW group (n = 14) 98.4 .5 Total Mean 98.3 .6 Time 2 temperature RC group (n = 14) 98.1 .7 FAW group (n = 14) 98.5 .6 Total Mean 98.3 .7 Time 3 temperature RC group (n = 14) 97.3 1.2 FAW group (n = 14) 97.5 1.0 Total Mean 97.4 1.1 Time 4 temperature RC group (n = 14) 97.3 1.2 FAW group (n = 14) 97.7 .8 Total Mean 97.5 1.0 Hypothesis 2 Hypothesis 2 predicted that the FAW group would experience lower catecholamine and cortisol levels than the RC group. The results of repeated measures ANOVA testing on cortisol, epinephrine, and norepinephrine will be presented separately.

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50 Cortisol. There were no significant findings over time (F (3, 75) = .272, p = .771), within subjects (F (1, 25) = .003, p = .959), or between groups (F (3, 75) = .073, p = .935. There were no relative correlations for the Co rtisol measurements across time. Table 4 and Figure 4 display the raw mean values of Cortisol across time. These results did not support the 2nd hypothesis. Table 4: Raw Mean Values of Cortisol (ng/ml) Across Time Time Group Assignment Mean (ng/ml) Std. Deviation Cortisol Time 1 RC group (n = 13) 127.85 104.32 FAW group (n = 14) 132.16 117.06 Cortisol Time 2 RC group (n = 13) 151.64 153.08 FAW group (n = 14) 146.31 124.64 Cortisol Time 3 RC group (n = 13) 160.08 140.54 FAW group (n = 14) 132.81 93.47 Cortisol Time 4 RC group (n = 13) 135.56 91.59 FAW group (n = 14) 151.96 124.41

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51 Figure 4: Raw Mean Values of Cortisol (ng/ml) Across Time -50 0 50 100 150 200 250 300 350 1234 TimeCortisol (pg/ml ) Routine Care Group FAW Group Epinephrine. There were incomplete sets of data (n = 9) for analysis in the routine care group compared to the FAW group (n = 14) due to missing data at different time points. The results of a repeated measures ANOVA test for transformed epinephrine data showed a significant effect over time (F (3, 63) = 7.874, p = .001), a non-significant within group effect (F (1, 21) = .500, p = .487) as well as no significa nt interaction effect (F (3, 63) = .068, p = .940). Since there was a significant effect of epinephrine across time, pairwise comparisons were analyze d. However, there were no statistically significant differences in the results. Table 5 illustrates the raw values of epinephrine activity within groups and between groups across time.

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52 Table 5: Raw Mean Values of Epinephrine (pg/ml) Across Time Time Group Assignment Mean (pg/ml) Std. Deviation Epinephrine Time 1 Routine Care group (n = 9) 41.01 31.47 FAW group (n = 14) 58.98 67.84 Epinephrine Time 2 Routine Care group (n = 9) 27.40 25.44 FAW group (n = 14) 37.04 26.48 Epinephrine Time 3 Routine Care group (n = 9) 68.52 55.53 FAW group (n = 14) 72.21 54.57 Epinephrine Time 4 Routine Care group (n = 9) 128.70 120.40 FAW group (n = 14) 121.57 85.03 There were no significant correlations between epinephrine and the other variables of interest. Overall, the presen tation of data showed the same type of catecholamine activity within and between grou ps. This data did not provide statistical support for hypothesis 2. Figure 5 shows the ra w values of epinephrine activity within subjects and between groups across time

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53 Figure 5: Raw Mean Values of Epinephrine (pg/ml) Across Time -50 0 50 100 150 200 250 300 1234 TimeEpinephrine (pg/ml ) Routine Care Group FAW Group Norepinephrine. Again, there were not complete sets of data (n = 10) for analysis in the routine care group when compared to the FAW group (n = 14). The results of a repeated measures ANOVA test for norepinephrin e showed a significant effect over time F (3, 66) = 5.580, p = .005), non-significance w ithin groups (F (1, 22) = .190, p = .667), and no statistically significant interaction effect (F (3, 66) = 1.300, p = .283). Pairwise comparisons were analyzed because there was a significant effect of epinephrine across time. The only pairwise comparison that wa s statistically significant was from Time 2 and 3 ( M= .245, SE = .061, p = .004). Table 6 and Figure 6 illustra te the levels of norepine phrine activity within groups and between groups across time. This statisti cal analysis did not support the hypothesis.

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54 Table 6: Raw Mean Values of Norepi nephrine (pg/ml) Activity Across Time Time Reading of Norepinephrine Group Assignment Mean (pg/ml) Std. Deviation Time 1 Routine Care group (n = 10) 216.91 171.96 FAW group (n = 14) 202.22 191.46 Time 2 Routine Care group (n = 10) 159.85 181.36 FAW group (n = 14) 169.34 163.53 Time 3 Routine Care group (n = 10) 253.61 300.77 FAW group (n = 14) 320.67 295.31 Time 4 Routine Care group (n = 10) 263.41 233.60 FAW group (n = 14) 509.81 432.57 Figure 6: Raw Mean Values of Norepinephrine (pg/ml) Across Time -200 0 200 400 600 800 1000 1234 TimeNorepinephrine (pg/ml ) Routine Care Group FAW Group

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55 Hypothesis 3 Hypothesis 3 predicted that the FA W group would experience higher proinflammatory cytokine and CRP production intra and postoperatively than the RC group. The results of a repeated measur es ANOVA tests on IL-1, IL-6, TNF, IFN, and CRP will be presented separately. The Time 1 upregulation of the cytokines were recognized as an item of interest and will be discussed in the next chapter. IL-1 For the measure of IL-1, there were no statistically significant main effects (F (3, 78) = 2.348, p = .124), between subjects effects (F (1, 26) = 2.446, p = .130), or interaction effects (F (3, 78) = 1.407, p = .253). The predicted hypothesis was not supported by the measurement values of IL-1. Table 7 and Figure 7 show the raw mean values of IL-1 between groups over time. Table 7: Raw Mean Values of IL-1 (pg/ml) Across Time Time Group Assignment Mean (pg/ml) Std. Deviation IL-1 Time 1 Routine Care group (n = 14) 5.78 3.43 FAW group (n = 14) 7.36 3.45 IL-1 Time 2 Routine Care group (n = 14) 5.30 3.61 FAW group (n = 14) 6.72 3.65 IL-1 Time 3 Routine Care group (n = 14) 5.43 3.51 FAW group (n = 14) 6.79 3.85 IL-1 Time 4 Routine Care group (n = 14) 4.51 3.53 FAW group (n = 14) 7.20 4.22

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56 Figure 7: Raw Mean Values of IL-1 (pg/ml) Across Time 0 2 4 6 8 10 12 1234 TimeIL-1 (pg/ml) Routine Care Group FAW Group IL-6. The results of a repeated measures ANOVA test for IL-6 showed a significant effect over time (F (3, 78) = 8.403, p = .004), no significant effect between subjects (F (1, 26) = .951, p = .339), and no si gnificant interaction effect (F (3, 78) = 2.593, p = .109). Since there was a significant e ffect of IL-6 across time, pairwise comparisons were analyzed. There were no st atistically significant findings in that comparison data. Table 8 and Figure 8 show the raw mean values of IL-6 between groups across time. Il-6 was correlated with TNFat times 1 through 3. Table 9 displays the correlation coefficients for IL-6 and TNFacross time.

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57 Table 8: Raw Mean Values of IL-6 (pg/ml) Across Time Time Group Assignment Mean (pg/ml) Std. Deviation IL-6 Time 1 Routine Care group (n = 14) 28.31 21.79 FAW group (n = 14) 25.06 18.24 IL-6 Time 2 Routine Care group (n = 14) 29.44 26.31 FAW group (n = 14) 22.97 18.12 IL-6 Time 3 Routine Care group (n = 14) 28.72 23.48 FAW group (n = 14) 23.85 17.52 IL-6 Time 4 Routine Care group (n = 14) 32.42 25.06 FAW group (n = 14) 31.35 15.73 Table 9: Correlation Coefficients for IL-6 and TNFAcross Time N = 28 TNF T1 TNF T2 TNF T3 TNF T4 IL-6 T1 Pearson Correlation .381(*) .377(*) .277 .256 Sig. (2-tailed) .045 .048 .154 .188 IL-6 T2 Pearson Correlation .372 .401(*) .276 .246 Sig. (2-tailed) .051 .034 .155 .208 IL-6 T3 Pearson Correlation .376(*) .386(*) .299 .249 Sig. (2-tailed) .048 .043 .123 .202 IL-6 T4 Pearson Correlation .113 .160 .049 .004 Sig. (2-tailed) .566 .417 .804 .985 *Correlation is significant at the 0.05 level (2-tailed).

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58 Figure 8: Raw Mean Values of IL-6 (pg/ml) Across Time 0 10 20 30 40 50 60 70 1234 TimeIL-6 (pg/ml ) Routine Care Group FAW Group TNF-. The results of a repeated measures ANOVA test for TNFshowed a significant effect over time (F (3, 78) = 4.309, p = .007), a non-significant between subjects effect (F (1, 26) = 1.248, p = .274), a nd no significant inter action effect (F (3, 78) = 1.847, p = .145). Since there wa s a significant effect of TNFacross time, pairwise comparisons were analyzed. There we re no statistically significant comparisons found in the comparisons analysis. Table 10 a nd Figure 9 display the raw mean values of TNFactivity between groups across time.

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59 Table 10: Raw Mean Values of TNFActivity Across Time Time Group Assignment Mean Std. Deviation TNFTime 1 Routine Care group (n = 14) 6.45 2.03 FAW group (n = 14) 8.95 5.70 TNFTime 2 Routine Care group (n = 14) 6.38 2.52 FAW group (n = 14) 8.25 6.07 TNFTime 3 Routine Care group (n = 14) 6.74 2.82 FAW group (n = 14) 8.50 5.73 TNFTime 4 Routine Care group (n = 14) 5.82 2.36 FAW group (n = 14) 8.25 5.29 Figure 9: Raw Mean Values of TNFActivity Across Time 0 2 4 6 8 10 12 14 16 1234 TimeTNF (pg/ml) Routine Care Group FAW Group

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60 IFN-. For the measure of IFNthere were no statistically significant main effects (F (3, 78) = 2.591, p = .077), no significa nt effects between subjects (F (1, 26) = .064, p = .802), or interaction effects (F ( 3, 78) = 1.621, p = .204). Table 10 and Figure 10 show the raw means of IFNactivity between groups across time. No evidence was found to support the hypothesis. Table 11: Raw Mean Values of IFN(pg/ml) Across Time Time Group Assignment Mean Std. Deviation IFNTime 1 Routine Care group (n = 14) 44.24 39.90 FAW group (n = 14) 44.45 50.26 IFNTime 2 Routine Care group (n = 14) 39.82 40.27 FAW group (n = 14) 42.71 53.58 IFNTime 3 Routine Care group (n = 14) 41.38 38.69 FAW group (n = 14) 47.31 58.25 IFNTime 4 Routine Care group (n = 14) 33.10 31.91 FAW group (n = 14) 45.85 59.57

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61 Figure 10: Raw Mean Values of IFN(pg/ml) Across Time -20 0 20 40 60 80 100 120 1234 TimeIFN (pg/ml) Routine Care Group FAW Group CRP For the measurement of CRP, there we re no statistically significant main effects (F (3, 75) = 1.852, p = .145), between subjects effects (F (1, 25) = 2.190, p = .151), or interaction effects (F (3, 75) = 1.645, p = .186). Table 12 and Figure 11 depict the total means of CRP measurements by gr oup over time. The statis tical analysis was not supportive of the hypothesis. Of clinical interest, there were signif icant findings related to CRP correlations with BMI across time. Table 13 shows these correlation coefficients.

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62 Table 12: Raw Mean Values of CRP (pg/ml) Across Time Time Group Assignment Mean Std. Deviation CRP Time 1 Routine Care group (n = 13) 6.22 7.20 FAW group (n = 14) 13.67 22.79 CRP Time 2 Routine Care group (n = 13) 3.33 5.51 FAW group (n = 14) 10.76 16.01 CRP Time 3 Routine Care group (n = 13) 3.43 5.06 FAW group (n = 14) 11.10 16.07 CRP Time 4 Routine Care group (n = 13) 3.42 5.05 FAW group (n = 14) 12.58 17.11 Figure 11: Raw Mean Values of CRP (pg/ml) Across Time -20 -10 0 10 20 30 40 1234 TimeCRP (pg/ml) Routine Care Group FAW Group

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63 Table 13: Correlations between BMI and CRP Across Time N = 27 CRPT1 CRPT2 CRPT3 CRPT4 BMI Pearson Correlation .706(**) .693(**) .709(**) .688(**) Sig. (2-tailed) .000 .000 .000 .000 Note: ** Correlation is significan t at the 0.01 level (2-tailed). Summary The analytical results of this preliminar y investigation into the effect of a FAW intervention on the acute phase response of surgical stress were presented. Data preparation, a profile of st udy participant characteristics and statistical analyses procedures were provided. There were no stat istically significant findings between the two groups of participants; therefore the proposed hypothese s were not supported. There were significant findings within groups acro ss time with the temperature measurements, catecholamine activity, IL-6, and TNF. Positive correlations between BMI and each time point for CRP were found statistically significant. The next and final chapter provides the discussion por tion of these findings.

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64 Chapter Five: Discussion The phenomenon of unplanned perioperat ive hypothermia exposes surgical patients to additional surgical stress. This has been determined by the large amount of evidence that shows the adverse perioperative effects on body systems and functions that occur in hypothermic patients (Beilin et al., 1998; Frank et al., 1997; Holtzclaw, 1997; Kurz, Sessler, & Lenhardt, 1996; Leslie & Se ssler, 2003; Wagner, Byrne, & Kolcaba, 2006). The more at risk the patient and the more significant the level of hypothermia, the greater the likelihood of advers e outcomes (AORN, 2007). Howeve r, what is the effect of surgical stress of unplanned hypothermia in patie nts that are relatively healthy and have elected to have a routine surgical procedure? There are approximately 70 million surgical procedures performed every year in the Unite d States and each patient may be subjected to an unwarranted surgical stress if unplanned hypothermia is allowed to occur (CDC, 1998) This chapter provides discussion on the fi ndings from a preliminary experimental study about the effect of a prewarming inte rvention on the acute phase response of surgical stress. Concluding comments about implications for both nursing and future nursing research follows a discussion regard ing study limitations and lessons learned as well as how this study has contribut ed to nursing and nursing science. Specific Aim of the Study The specific aim of this preliminar y study was to assess the effect of a preoperative warming intervention using a FAW device versus routine care using

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65 warmed cotton blankets on the developmen t of unplanned perioperative hypothermia proinflammatory cytokine production, a nd neuroendocrine responses. The following hypotheses were tested and analyzed: 1. The FAW group would experience less unpla nned perioperative hypothermia than the RC group. 2. The FAW group would experience lower catechol amine and cortisol levels than the RC group. 3. The FAW group would experience higher pr o-inflammatory cytokine and CRP production intra and post-operatively than the RC group. Each of the hypotheses will be discu ssed relative to the main findings. Hypothesis 1 Hypothesis 1 predicted that the group of participants receiving FAW would experience less unplanned perioperative hypother mia than the group of patients receiving routine care with warmed cotton blankets. A revi ew of specific temperatures by groups at Time 3 (intraoperative time frame) was conduc ted and there were 9 patients that had hypothermic temperatures at or below 96.8F (3 6C). Five of those 9 (36%) were in the FAW group with a mean group temperature of 96.3F. The RC group (29%, n = 4) were found hypothermic at Time 3 with mean temp erature of 95.8F. Clinically, this was observed as important, as the FAW group of participants were less hypothermic (96.3F) than the RC participants (95.8F) at Time 3 by .5F. A difference of .5 degree is of clinical importance. Table 13 displays the to tal mean temperatures at time 3 for both groups of participants that were hypothermic.

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66 Table 14: Total Mean Temperatures (F) of Hypothermic Participants at Time 3 Time Group Assignment Mean F Std. Deviation Time 3 Temperature RC Group (n = 4) 95.8 .90 FAW Group (n = 5) 96.3 .42 Total 96.1 .68 The PACU temperatures at Time 4 of the FAW group reflected faster recovery from the hypothermic state than the RC group. Upon admission to PACU, the FAW group only had 3 hypothermic patients with an average temperature of 96.7F whereas the RC group had 6 patients that were hypotherm ic with an average temperature of 96F. Table 14 shows the total mean temperatures of the hypothermic participants at Time 4. Table 15: Total Mean Temperatures (F) of Hypothermic Participants at Time 4 Time Group Assignment Mean F Std. Deviation Time 4 Temperature RC Group (n = 6) 96.0 .56 FAW Group (n = 3) 96.7 .10 Total 96.4 .57 The repeated measures ANOVA statistical test and separate t-tests showed no statistical significance between groups, however the particulars of the findings were considered clinically important. A clinical pa ttern of response relate d to temperature was also recognized in that FAW appeared to le ssen perioperative hypothermia in comparison to routine care.

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67 The reason that the FAW group of partic ipants became hypothermic along with the control group may be due to a preoperative impairment of thermoregulation related to the patients’ premedication with midazolam (Kurz et al., 1995; Matsukawa et al., 1997). An imbalance between heat production and sk in heat loss was not a large contributory predictor of hypothermia after midazolam ad ministration in the Kurz study, however, midazolam produced a concentration-dependent d ecrease in core temperature (.3 to .6C) and impaired thermoregulatory vasocons triction with hypothermic redistribution occurring 30 minutes af ter injection (Matsukawa et al., 1997). All but one participant in the study received midazolam and there wa s not a significant correlation between midazolam and the hypothe rmic participants. Another factor to take into consideration is the level of ambient temperature in the OR. The average Time 3 ambient temperature was 65.2F + 3.6F. Ambient temperature is a well known predictor of core hypothermia in the anesthetized patient that shows approximately a 50% average frequency of hypothermia occurring in ORs with temperatures of 20 to 23C (68 to 73.4 F) (Frank et al., 1992 ). The average OR temperature during this study was 18.4C, which is less than the known prediction temperature of ORs from the 20 – 23C range. However, there was not a statistically significant correlation found in this study fo r ambient temperature and hypothermic participants. It is difficult to treat in traoperative hypothermia because heat applied to the skin surface requires substantial time to reach th e core thermal compartment and impact the temperature gradient (Sessler 2000). The preoperative warming approach raises mean body temperature by increasing the energy conten t in the peripheral thermal compartment

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68 of the body. The amount of time needed for prew arming is still debated in the literature and ranges from 15 minutes to 120 minutes of time (Fossum, Hays, & Henson, 2001; Melling, Ali, Scott, & Leaper, 2001; Sessl er, 1997b; Vanni, Braz, Modolo, Amorim, & Rodrigues, 2003). Even the 15 minutes of prewarming made a difference in peripheral skin temperature and impacted unplanned hypothermia events (Sessler, 1997b). The mean amount of preoperative warming in tervention during this study was 39 minutes. According to Sessler and colleagues (1995) it is possible to reduce the time of prewarming from 2 hours to 30 minutes and up to 1 hour. The addition of at least 30 minutes of preoperative FA W warming made a clinical difference in temperature values across time and within the group w ith a higher level of temperature gain recognized postoperatively when compared to the RC group across time and within group measures. Preoperative ther mal status should be considered as an important assessment point for surgical pa tients and the active warming approach to increase skin temperature preoperatively shoul d be considered as a possible intervention to reduce unplanned hypothermia occurrence. As in this st udy, intraoperative warming is becoming more routine. There was no statis tically significant cova riance between groups related to intraoperative warm ing (F (1, 16) = 2.089, p = .169). Hypothesis 2 The prediction that the FAW group woul d experience lower catecholamine and cortisol levels than the RC group was not statistically suppo rted by any of the measurement variables. However, the raw da ta presented differences that warranted review. Each measurement will be discussed separately.

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69 Cortisol Usual serum values range from 50 ng/ml to 230 ng/mL during morning hours with a decrease seen in the afternoon/ evening hours (30 ng/ml to 150 ng/ml). This study was conducted in the early morning hours and usually participation was completed by 2:00 pm in the afternoon. So the values seen in both groups of patients at Time 1 were within the range of normal. Interestingly, the va lues did not vary much throughout the perioperative phases under study. Cortisol can down-regulate immune activit y, but acute stress has been shown to increase both cortisol and cytokine leve ls. In a study by Kunz-E brecht and colleagues (2003), a recent investigation of individual differences in cortisol and IL-6 responses during stress showed individual variations in neuroendocrine stress responsivity. Researchers concluded that in dividual responsivity to st ress might have an impact on proinflammatory cytokines, and that both hi gh and low cortisol stress responsiveness had potentially unfavorable effects (Kunz-Ebrech t, Mohamed-Ali, Feldman, Kirschbaum, & Steptoe, 2003). There are factors such as gender differences (Kirschbaum, Klauer, Filipp, & Hellhammer, 1995), effects of age (Ershler & Keller, 2000; Lutgendorf et al., 1999), personality factors (Pruessner et al., 1997; Smythe, 1999)and mood (Smythe, 1999) that have been found to influence cortisol as well as cytokine responses (Kunz-Ebrecht, Mohamed-Ali, Feldman, Kirschbaum, & Step toe, 2003). Findings s uggested that those who were cortisol responsive showed little cytokine response, while the cortisol unresponsive people possibly had autonomic ch anges that stimulated more cytokine response. It would be interesti ng to evaluate responsivity in later studies and see if there is an effect on cytokines by an alysis of the cytokines with a cortisol/catecholamine ratio, as this was not conducted in the present study.

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70 Opiods and benzodiazepines ha ve inhibitory effects on th e release of cortisol in patients undergoing surgery (H ogevold, Lyberg, Kahler, Ha ug, & Reikeras, 2000; RothIsigkeit, Dibbelt, Schmucker, & Seyfarth, 2000). In this study, a ll patients, but one, received the benzodiazepine mi dazolam preoperatively and fentanyl, an opiod type drug, intraoperatively. These medications confounde d the cortisol findings, however, there were opposite changes noted in cortisol leve ls intraoperatively as well as immediately postoperatively. The FAW group showed a decrease in cortisol levels at Time 3 whereas the RC group had increased cortisol levels. Interestingly, the opposite was seen in the Time 4 cortisol levels with the FAW group di splaying increased cort isol levels and the RC group showing decreased cortisol levels. Po stoperative Time 4 is when the patient may be experiencing pain as well as the ot her effects of inflammation. Pain was not measured during this study. Whereas the di fferences during Time 3 may reflect the impact of the warming intervention and the levels of hypothermia postoperatively, the Time 4 cortisol levels do not support th e hypothesis from a po stoperative standpoint. Impact of preoperative anxiety, pain, and indi vidual coping differences on these results may also be of importance, but these variables were not measured. Catecholamines. Catecholamines, norepinephrine and epinephrine help the body cope with acute stress when released. An in creased production of catecholamines can be found in both hypertensive and psychotic patie nts as well as in patients with chronic stressors. In several older st udies, catecholamines increase d in healthy non-anesthetized volunteers when subjected to cold ambient temperatures between 6.5C and 15C (Arnett & Watts, 1960; Lamke, Lennquist, Liljed ahl, & Wedin, 1972; Wilkerson, Raven, Bolduan, & Horvath, 1974). As expected in individuals with an active thermoregulatory

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71 response system, core temperature was not si gnificantly changed during cold exposure in these studies. However, mean skin temperature was decreased by 4C during a cold exposure of 15C. These results suggested skin surface cooling was responsible for initiating the adrenergic response. In co ld water exposure testing, norepinephrine increased twofold in the first 2 minutes of e xposure and increased thr ee to fourfold after 45 minutes of exposure. The rapid norepine phrine response preceded changes in core temperature. Rewarming effects of the same vol unteers resulted in a transient decrease in the first 5 minutes followed by a dramatic decr ease to baseline levels with 20 minutes of rewarming. The investigators concluded that skin temperature was strongly correlated with the catecholamine response (Johnson et al., 1977; Shum, Johnson, & Flattery, 1969). In a more recent study that assessed the relationship between body temperature, the neuroendocrine response, and hemodynamic changes in the perioperative timeframe found that patients receiving no active warm ing intraoperatively experienced higher norepinephrine concentrations postoperatively (Frank et al., 1995). These studies still provide support for hypothesis 2 in this study, but a lack of skin temperature measurements during this study make this association weaker. Evidence in the aforementioned studies suggests that cortisol and catecholam ine release are related to immediate threats, whereas actual immune ch anges are sensitive to more distant events that allows for adaptive responses. Perhaps one of the reasons that the participants in this preliminary study did not show differences betw een groups is that a ll but one participant received anxiolytic benzodiazepines during the interval between Time 1 and Time 2. Benzodiazepines have been shown to revers e stress-induced immunosuppression (Zavala, 1997). The threat surrounding preoperative prepar ation is an acute ev ent that preoperative

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72 warming might lessen and ther efore decrease the level of cortisol and catecholamine release. Issues of the lack of control over anesthesia medi cations, and a lack of power related to small number of participants and incomplete sets of data may have diluted possible effects from the warming interven tion in this study. There was no support for hypothesis 2 in these findings, however, with co ntrols in place, fu rther testing of how FAW may impact catecholamines remains warra nted because of the regulating effects on cytokine activity duri ng and after surgery. Hypothesis 3. Hypothesis 3 predicted that the participants rece iving FAW would experience higher pro-inflammatory cy tokine and CRP production intra and postoperatively than the RC group. There was a mixture of supportive versus nonsupportive findings related to this hypothesis. A number of characteristic s relative to surgery have been associated in the postoperative suppression of cell-mediated immunity including anesthesia agents, analgesic medications, hypothermia, tissue da mage, blood loss and transfusion, pain and preoperative anxiety (Shakhar & Ben-Eliyahu, 20 03). Another feature of immunity that is disturbed by surgical stress is the cytoki ne network, which regulates most immune functions and serves to communicate between leukocytes as well as between the immune system and other body systems. The cytokine reaction to surgery includes an immediate surge of proinflammatory cyt okines (IL-1, IL-6), which is connected to the development of postoperative infections (Elenkov, Papanicolaou, Wilder, & Chrousos, 1996). This preliminary surge of proinflammatory cyt okines is what this study investigated. Of greatest interest, this preliminar y study showed an overall preoperative upregulation of the proinflammatory cytokines an d a significant correlation across time with

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73 CRP and BMI. Inflammatory ma rkers are associated with obe sity (Vozarova et al., 2001), sleep disorders (Steptoe, Hamer, & Chida, 2007), older age (Cesari et al., 2003), and cardiac conditions. Acute psychological stress has been found to influence circulating inflammatory markers (Steptoe, Hamer, & Ch ida, 2007). In laborator y studies, evidence is showing that circulating levels of CRP, IL-6, and TNFmarkers respond to acute psycohological stress. In a meta-analysis of recent findings on the influences of acute psychological stress on circul ating inflammatory markers in humans, Steptoe and colleagues (2007) addressed which markers were sensitive to acute psychological stress, the timing of the responses, and if there were differences in response related to factors such as gender, age, health status, and the na ture of the acute stressor. The markers that they specifically looked at were also of interest related to this preliminary experiment. The meta-analysis procedure was performed for CRP, IL-1 IL-6, and TNF. The analysis indicated that circulating levels of IL-6 typically increased following acute stress. They reported similar findings for IL-1 and less vigorous effects for CRP. There were no significant effects for TNF. The overall conclusions s uggested that laboratoryinduced stressors moderately increased inflammatory markers. The non-significant findings were attributed to between study vari ability and effect sizes Another interesting finding was related to gender differences in cytokine stress responses. There were only two studies that examined gender differences and they showed inconsistent findings. Depression, work stress, and low socioeconomic status were associated with higher levels of cytokine responses. Of interest, the meta-analysis could fi nd no studies that investigated the effect of acute psycho logical stress on CRP gene expression and no evidence that there are other sources of circul ating levels other than hepatocytes (Steptoe,

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74 Owen, Kunz-Ebrecht, & Mohamed-Ali, 2002). Since laboratory studies differ from clinical studies, this was recognized as an area of great need for future study in order to provide insight into the role of psychone uroimmunological processes in both wellness and disease. In this study, the measured variables for Hypothesis 3 were upregulated at Time 1 for both the FAW and RC groups. This populat ion was overall healthy, but overweight to obese in regards to BMI. This may have cons iderable impact on the inflammatory process that is seen. Another strongly su spected factor is the preopera tive anxiety that is usual, was observed, but not measured. A couple of stud ies have also impli cated the effects of intravenous catheters and th e blood drawing procedures as confounding the values found in cytokines ((Haack et al., 2002; Haack et al., 2000). The findings just from Time 1 were found to be exciting and wa rranting further research. After the FAW treatment, the FAW group show ed more of an increase than the RC group with all variables with the exception of TNF. There was a noted trend of support for Hypothesis 3 even though the statis itical tests were not significant between groups. Again, this was a preliminary study a nd the findings were clinically, if not statistically, of great interest and warrant further research. Study Limitations This study was a preliminary field experi ment and had several limitations related to control. First the discovery that more expensive assays were required to determine values of the biologic measures made possi bility of having a large sample impossible from a budgeting viewpoint. The cost factor also disallowed the ability to conduct interassay assessments which impacts on the relia bility of the biologic assay readings.

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75 Secondly, the Anesthesia Providers rec ognized when participants had received FAW preoperatively and would ask if they we re to continue the pr actice. Just by this questioning, it was difficult to tell if the study activities influenced the decision to intraoperatively warm the patien t. Even though they were told to conform to their usual practice, the number of patients that rece ived intraoperative warming may have been impacted by the Anesthetists’ knowledge of the prewarming study. Another limitation of control was in regards to the incomplete sets of data for the catecholamine measurements. There were equipment problems during the first assay and two plates were run to get the first nine pa rticipants’ catecholamine values. The need for a replacement plate of sample led to some m easurement times with no plasma sample left for assay. The catecholamine kit was new to the researcher and quite complicated as well. This lack of control over the first 9 participant samples is a major limitation to adjust for in the future. The last of the limitations was a significan t issue in regards to internal validity. The infrared tympanic thermometer was chosen to take the core temperatures for this study based more on ease of route and level of non-invasiveness. The lack of skin temperature measurements to correlate with co re temperature gains or losses is also a limitation. However, the researcher was the on ly one using the thermometer and took the temperatures in the same manner and in the same ear at each reading to limit error. Implications for Nursing Attention to temperature has long been a nursing practice and one of the earliest focal points of scientific i nvestigation by nurses. The ther mometer was probably the first instrument of precision that nurses used to monitor and diagnose patients. In fact, the

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76 thermometer can be considered one of the t ools that led to the wo rk of nursing science (Sandelowski, 2000). Perioperative nurses should recognize the important role they can take in the prevention, or at least th e reduction, of unplanned hypothe rmia events by using the principles of thermoregulation and evid ence regarding prewarming. This study was conducted to determine the effect of pre operative FAW compared to RC on the acute phase response of surgical stress. Prelimin ary findings suggested that FAW is a positive intervention for better recovery from redist ribution hypothermia. One factor that should encourage research in this area is its obvious and immediate pr actical applicability. Prevention is more cost-effective than the treatment of complications from unplanned hypothermia. Implications for Future Research This preliminary study can be used to determine the feasibility of a larger psychoneuroimmunology study in the near future. Earlier data obtaine d in another study that assessed the impact of a prewarming in tervention on subjective thermal comfort and preoperative anxiety suggested that FAW provided thermal comfort while decreasing preoperative anxiety. To address the pr oblem of surgical stress from a psychoneuroimmunology approach would be the combining of these two studies. Lessons learned from both would only st rengthen the study model. Additional research is required to dete rmine whether the changes reported as clinically significant in this preliminary study are predictive of the positive perioperative outcomes of decreased surgical stress. The significance of this research was based upon the development of a better understanding of surgical stre ss and the poten tial protection

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77 from the harm of unplanned perioperative hypothermia. The need to better assess how FAW may impact the preoperative upregula tion of cytokines and if the level of preoperative anxiety is associated was an im portant realization duri ng the analysis phase of the study. A combination of this study and the previous thermal comfort study could potentially provide evidence for best practices during the entire perioperative experience. It seems appropriate to suggest multidisc iplinary team research to provide more substantial evidence to support global change in perioperati ve clinical practice since multiple professions care for the surgical patient. Summary A preliminary experimental study was conduc ted to investigate the effect of a preoperative warming intervention using FA W compared to the RC of warmed cotton blankets on the initial acute phase response of surgical stress. The focus of this study created an opportunity to examine how th e phenomenon of unplanned hypothermia might be impacted by a nursing intervention, which in turn may lead to a reduction in surgical stress. Though FAW was not associated with a di fferential endocrine or inflammatory response in this small, preliminary study, further study of forced air warming as a preoperative nursing intervention is warranted. The finding of higher than expected IL-6 levels in the preoperative peri od suggests a potential role fo r anxiety, an important factor in psychoneuroimmunological pathways that could affect recovery and healing. The relationship between surgical stress, anxiety, and preopera tive IL-6 deserves further study.

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78 References AORN. (2007). Recommended practices for the prevention of unplanned perioperative hypothermia. AORN Journal, 85 (5), 972-974, 976-984, 986-978. Arnett, E. L., & Watts, D. T. (1960). Catec holamine excretion in men exposed to cold. J Appl Physiol, 15 499-500. Baxevanis, C. N., Papilas, K., Dedoussis, G. V., Pavlis, T., & Papamichail, M. (1994). Abnormal cytokine serum levels correl ate with impaired cellular immune responses after surgery. Clin Immunol Immunopathol, 71 (1), 82-88. Beilin, B., Shavit, Y., Razumovsky, J., Wollo ch, Y., Zeidel, A., & Bessler, H. (1998). Effects of mild periope rative hypothermia on cellular immune responses. Anesthesiology, 89 (5), 1133-1140. Biffl, W. L., Moore, E. E., Moore, F. A., & Peterson, V. M. (1996). Interleukin-6 in the injured patient. Marker of injury or mediator of inflammation? Ann Surg, 224 (5), 647-664. Bjornsson, G. L., Thorsteinsson, L., Gudmundsson, K. O., Jonsson, H., Jr., Gudmundsson, S., & Gudbjornsson, B. (2007). Inflammatory cytokines in relation to adrenal response followi ng total hip replacement. Scand J Immunol, 65 (1), 99105. Buggy, D. J., & Crossley, A. W. (2000) Thermoregulation, mild perioperative hypothermia and postanaesthetic shivering. Br J Anaesth, 84 (5), 615-628.

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80 Flores-Maldonado, A., Medina-Escobedo, C. E ., Rios-Rodriguez, H. M., & FernandezDominguez, R. (2001). Mild perioperat ive hypothermia and the risk of wound infection. Arch Med Res, 32 (3), 227-231. Forstot, R. M. (1995). The etiology and management of inadvertent perioperative hypothermia. J Clin Anesth, 7 (8), 657-674. Fossum, S., Hays, J., & Henson, M. M. ( 2001). A comparison study on the effects of prewarming patients in the outpatient surgery setting. J Perianesth Nurs, 16 (3), 187-194. Frank, S. M., Beattie, C., Christopherson, R., No rris, E. J., Perler, B. A., Williams, G. M., et al. (1993). Unintentional hypothermia is associated with postoperative myocardial ischemia. The Perioperative Ischemia Randomized Anesthesia Trial Study Group. Anesthesiology, 78 (3), 468-476. Frank, S. M., Beattie, C., Christopherson, R., No rris, E. J., Rock, P., Parker, S., et al. (1992). Epidural versus general anesthes ia, ambient operating room temperature, and patient age as predictors of inadvertent hypothermia. Anesthesiology, 77 (2), 252-257. Frank, S. M., Fleisher, L. A., Breslow, M. J., Higgins, M. S., Olson, K. F., Kelly, S., et al. (1997). Perioperative maintenance of normothermia reduces the incidence of morbid cardiac events. A randomized clinical trial. Jama, 277 (14), 1127-1134. Frank, S. M., Higgins, M. S., Breslow, M. J., Fleisher, L. A., Gorman, R. B., Sitzmann, J. V., et al. (1995). The catecholamine, cortisol, and hemodynamic responses to mild perioperative hypothermia. A randomized clinical trial. Anesthesiology, 82 (1), 83-93.

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81 Gentilello, L. M., Jurkovich, G. J., Stark, M. S., Hassantash, S. A., & O'Keefe, G. E. (1997). Is hypothermia in the victim of major trauma protective or harmful? A randomized, prospective study. Ann Surg, 226 (4), 439-447; discussion 447-439. Guest, J. D., Vanni, S., & Silbert, L. (2004). Mild hypothermia, blood loss and complications in elective spinal surgery. Spine J, 4 (2), 130-137. Haack, M., Kraus, T., Schuld, A., Dalal, M., Koethe, D., & Pollmacher, T. (2002). Diurnal variations of interleukin-6 plasma levels are confounded by blood drawing procedures. Psychoneuroendocrinology, 27 (8), 921-931. Haack, M., Reichenberg, A., Kraus, T., Schuld, A., Yirmiya, R., & Pollmacher, T. (2000). Effects of an intravenous catheter on the local production of cytokines and soluble cytokine recep tors in healthy men. Cytokine, 12 (6), 694-698. Haddad, J. J., Saade, N. E., & Safieh-Gar abedian, B. (2002). Cytokines and neuroimmune-endocrine interacti ons: a role for the hypotha lamic-pituitary-adrenal revolving axis. J Neuroimmunol, 133 (1-2), 1-19. Heier, T., Clough, D., Wright, P. M., Sharma, M. L., Sessler, D. I., & Caldwell, J. E. (2002). The influence of mild hypothermia on the pharmacokinetics and time course of action of neostigmin e in anesthetized volunteers. Anesthesiology, 97 (1), 90-95. Hogevold, H. E., Lyberg, T., Kahler, H., Ha ug, E., & Reikeras, O. (2000). Changes in plasma IL-1beta, TNF-alpha and IL-6 af ter total hip replacement surgery in general or regional anaesthesia. Cytokine, 12 (7), 1156-1159. Holtzclaw, B. J. (1993). Monitoring body temperature. AACN Clin Issues Crit Care Nurs, 4 (1), 44-55.

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82 Holtzclaw, B. J. (1997). Perioperative problems: threats to thermal ba lance in the elderly. Semin Perioper Nurs, 6 (1), 42-48. Johnson, D. G., Hayward, J. S., Jacobs, T. P ., Collis, M. L., Eckerson, J. D., & Williams, R. H. (1977). Plasma norepinephrine responses of man in cold water. J Appl Physiol, 43 (2), 216-220. Kehlet, H., & Wilmore, D. W. (2002). Mult imodal strategies to improve surgical outcome. Am J Surg, 183 (6), 630-641. Kirschbaum, C., Klauer, T., Filipp, S. H., & Hellhammer, D. H. (1995). Sex-specific effects of social support on cortisol and subjective responses to acute psychological stress. Psychosom Med, 57 (1), 23-31. Kunz-Ebrecht, S. R., Mohamed-Ali, V., Feld man, P. J., Kirschbaum, C., & Steptoe, A. (2003). Cortisol responses to mild psychol ogical stress are inversely associated with proinflammatory cytokines. Brain Behav Immun, 17 (5), 373-383. Kurz, A., Sessler, D. I., Annadata, R., Decher t, M., Christensen, R., & Bjorksten, A. R. (1995). Midazolam minimally impairs thermoregulatory control. Anesth Analg, 81 (2), 393-398. Kurz, A., Sessler, D. I., Christensen, R., & Dechert, M. (1995). Heat balance and distribution during the core-temperature plateau in anesthetized humans. Anesthesiology, 83 (3), 491-499. Kurz, A., Sessler, D. I., & Lenhardt, R. ( 1996). Perioperative normothermia to reduce the incidence of surgical-w ound infection and shorte n hospitalization. Study of Wound Infection and Temperature Group. N Engl J Med, 334 (19), 1209-1215.

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83 Lamke, L. O., Lennquist, S., Liljedahl, S. O ., & Wedin, B. (1972). The influence of cold stress on catecholamine excretion an d oxygen uptake of normal persons. Scand J Clin Lab Invest, 30 (1), 57-62. Lee, S. L., Battistella, F. D., & Go, K. ( 2001). Hypothermia induces T-cell production of immunosuppressive cytokines. J Surg Res, 100 (2), 150-153. Lenhardt, R., Marker, E., Goll, V., Tschernic h, H., Kurz, A., Sessler, D. I., et al. (1997). Mild intraoperative hypothermia prolongs postanesthetic recovery. Anesthesiology, 87 (6), 1318-1323. Leslie, K., & Sessler, D. I. (2003). Periopera tive hypothermia in the high-risk surgical patient. Best Pract Res Clin Anaesthesiol, 17 (4), 485-498. Lopez, M., Sessler, D. I., Walter, K., Emer ick, T., & Ozaki, M. (1994). Rate and gender dependence of the sweating, vasoconstr iction, and shivering thresholds in humans. Anesthesiology, 80 (4), 780-788. Lutgendorf, S. K., Garand, L., Buckwalter, K. C., Reimer, T. T., Hong, S. Y., & Lubaroff, D. M. (1999). Life stress, mood disturbance, and elevated interleukin-6 in healthy older women. J Gerontol A Biol Sci Med Sci, 54 (9), M434-439. Macario, A., & Dexter, F. (2002). What are the most important risk factors for a patient's developing intraoperative hypothermia? Anesth Analg, 94 (1), 215-220, table of contents. Matsukawa, T., Hanagata, K., Ozaki, M., Iw ashita, H., Koshimizu, M., & Kumazawa, T. (1997). I.m. midazolam as premedicati on produces a concentration-dependent decrease in core temperature in male volunteers. Br J Anaesth, 78 (4), 396-399.

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84 Matsukawa, T., Sessler, D. I., Se ssler, A. M., Schroeder, M., Ozaki, M., Kurz, A., et al. (1995). Heat flow and distribution duri ng induction of general anesthesia. Anesthesiology, 82 (3), 662-673. Meiler, S. E. (2006). Long-term outcome afte r anesthesia and surgery: remarks on the biology of a newly emerging prin ciple in perioperative care. Anesthesiol Clin, 24 (2), 255-278. Melling, A. C., Ali, B., Scott, E. M., & L eaper, D. J. (2001). Effects of preoperative warming on the incidence of wound infec tion after clean surgery: a randomized controlled trial. Lancet, 358 (9285), 876-880. Neumaier, M., Metak, G., & Scherer, M. A. (2006). C-reactive protein as a parameter of surgical trauma: CRP response after di fferent types of surgery in 349 hip fractures. Acta Orthop, 77 (5), 788-790. Ogawa, K., Hirai, M., Katsube, T., Murayama, M., Hamaguchi, K., Shimakawa, T., et al. (2000). Suppression of cellular im munity by surgical stress. Surgery, 127 (3), 329336. Pruessner, J. C., Gaab, J., Hellhammer, D. H., Lintz, D., Schommer, N., & Kirschbaum, C. (1997). Increasing correlations between pe rsonality traits a nd cortisol stress responses obtained by data aggregation. Psychoneuroendocrinology, 22 (8), 615625. Roth-Isigkeit, A., Dibbelt, L., Schmucker, P., & Seyfarth, M. (2000). The immuneendocrine interaction varies with the dur ation of the inflammatory process in cardiac surgery patients. J Neuroendocrinol, 12 (6), 546-552.

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85 Rutherford, E. J., Fusco, M. A., Nunn, C. R., Bass, J. G., Eddy, V. A., & Morris, J. A., Jr. (1998). Hypothermia in critic ally ill trauma patients. Injury, 29 (8), 605-608. Ruzic, B., Tomaskovic, I., Tr nski, D., Kraus, O., Bekava c-Beslin, M., & Vrkic, N. (2005). Systemic stress responses in patients undergoing surgery for benign prostatic hyperplasia. BJU Int, 95 (1), 77-80. Sandelowski, M. (2000). Devices & Desires: Gender, Technology and American Nursing North Carolina: University of North Carolina Press. Schein, M., Rucinski, J., & Wise, L. (1996). Perioperative normothermia and surgicalwound infection. N Engl J Med, 335 (10), 748-749; author reply 749-750. Schmied, H., Kurz, A., Sessler, D. I., Koze k, S., & Reiter, A. (1996). Mild hypothermia increases blood loss and transfusion requi rements during total hip arthroplasty. Lancet, 347 (8997), 289-292. Sessler, D. I. (1993). Perianesthetic ther moregulation and heat balance in humans. Faseb J, 7 (8), 638-644. Sessler, D. I. (1997a). Mild perioperative hypothermia. N Engl J Med, 336 (24), 17301737. Sessler, D. I. (1997b). Perioperative thermoregulation and heat balance. Ann N Y Acad Sci, 813 757-777. Sessler, D. I. (2000). Perioperative heat balance. Anesthesiology, 92 (2), 578-596. Sessler, D. I., & Akca, O. (2002). Nonpharm acological prevention of surgical wound infections. Clin Infect Dis, 35 (11), 1397-1404.

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86 Shakhar, G., & Ben-Eliyahu, S. (2003). Potential prophylactic measures against postoperative immunosuppre ssion: could they redu ce recurrence rates in oncological patients? Ann Surg Oncol, 10 (8), 972-992. Shum, A., Johnson, G. E., & Flattery, K. V. (1969). Influence of ambient temperature on excretion of catecholamines and metabolites. Am J Physiol, 216 (5), 1164-1169. Silva, J. E. (2005). Thyroid hormone and the energetic cost of keeping body temperature. Biosci Rep, 25 (3-4), 129-148. Smythe, J., Ockenfels, M.C., Porter, L., Ki rschbaum, C., Hellhammer, D.H., Stone, A.A. (1999). Stressors and mood measured on a momentary basis are associated with salivary cortisol secretion. Psychoneuroendocrinology, 23 353-370. Steptoe, A., Hamer, M., & Chida, Y. (2007). The effects of acute ps ychological stress on circulating inflammatory factors in humans: a review and meta-analysis. Brain Behav Immun, 21 (7), 901-912. Steptoe, A., Owen, N., Kunz-Ebrecht, S., & Mohamed-Ali, V. (2002). Inflammatory cytokines, socioeconomic status and acute stress responsivity. Brain Behav Immun, 16 (6), 774-784. Tander, B., Baris, S., Karakaya, D., Aritur k, E., Rizalar, R., & Bernay, F. (2005). Risk factors influencing inad vertent hypothermia in in fants and neonates during anesthesia. Paediatr Anaesth, 15 (7), 574-579. Vanni, S. M., Braz, J. R., Modolo, N. S., Amor im, R. B., & Rodrigues, G. R., Jr. (2003). Preoperative combined with intraope rative skin-surface warming avoids hypothermia caused by general anesthesia and surgery. J Clin Anesth, 15 (2), 119125.

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87 Vassilieff, N., Rosencher, N., Sessler, D. I ., & Conseiller, C. (1995). Shivering threshold during spinal anesthesia is reduced in elderly patients. Anesthesiology, 83 (6), 1162-1166. Vozarova, B., Weyer, C., Hanson, K., Tataranni, P. A., Bogardus, C., & Pratley, R. E. (2001). Circulating interleukin-6 in re lation to adiposity, insulin action, and insulin secretion. Obes Res, 9 (7), 414-417. Wagner, D., Byrne, M., & Kolcaba, K. (2006). Effects of comfort warming on preoperative patients. AORN J, 84 (3), 427-448. Wenisch, C., Narzt, E., Sessler, D. I., Parschal k, B., Lenhardt, R., Kurz, A., et al. (1996). Mild intraoperative hypothermia reduces production of reactive oxygen intermediates by polymorphonuclear leukocytes. Anesth Analg, 82 (4), 810-816. Wilkerson, J. E., Raven, P. B., Bolduan, N. W., & Horvath, S. M. (1974). Adaptations in man's adrenal function in res ponse to acute cold stress. J Appl Physiol, 36 (2), 183-189. Wilmore, D. W. (2002). From Cu thbertson to fast-track surg ery: 70 years of progress in reducing stress in surgical patients. Ann Surg, 236 (5), 643-648. Zavala, F. (1997). Benzodiazepin es, anxiety and immunity. Pharmacol Ther, 75 (3), 199216.

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88 Appendices

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89 Appendix A: IRB Approval

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90 Appendix A: Continued

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91 Appendix B: Recruitment Flyer Interested in being WARM before your surgery? Then you might like to be involved in an important Nursing research study! If so, are you: Having surgery? Between the ages of 18 and 65? Without thyroid disease? The reason this research stud y is being done is to find out if warming a person’s skin before surgery can lower stress during surgery. We are asking you to take part in the study because you are going to have surgery. After talking with the research nurses to understand everything about the study, you will be asked to give wr itten consent to take part in this research study. You will only take part in the study on the day of your surgery. On the day of your surgery, you will be given either an electric warming blanket or a warmed cotton blanket while waiting for your surgery to start. Please check the box th at states your interest in this study: Yes, I am interested in being in this study. No, I am not interested at this time. If you want to contact the nurse researcher at any time, please call Doreen Wagner, RN, MSN at 404-401-4344 This nursing research has received appr oval from the Institutional Review Board at the University of South Florida, Tampa and from the Douglas Hospital Nursing Research Committee of the WellStar Health System.

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92 Appendix C: Informed Consent Form

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93 Appendix C: Continued

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94 Appendix C: Continued

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95 Appendix C: Continued

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96 Appendix C: Continued

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97 Appendix C: Continued

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98 Appendix C: Continued

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99 Appendix C: Continued

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100 Appendix C: Continued

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101 Appendix D: Surgeon Letter April 12, 2007 WellStar Douglas Hospital Surgeon: It is my pleasure to inform you about a nursing study soon to be implemented at Wellstar Douglas Hospital. This research is a dissertation stud y funded by a grant from the Association of periOperative Registered Nurses, Inc. The purpose of this experimental study is to de termine the effect of preoperative warming with forced-air warming blankets versus warmed cott on bath blankets on the acute phase response of surgical stress. All outpatient surgical patients will be recruited with “Interested” flyers. Inclusion criteria for subjects in this study are: Between 18 and 65 years of age English speaking Temperature WNL P1 or P2 ASA physical status classification No known cognitive impairments No paralysis or known paresthesia No known hypo/hyperthyroid disease General anesthesia surgery scheduled fo r >1hour and < 3 hours (no scope cases) Clean/clean-contaminated procedures only Approval was received from both the WellStar Medical Devices Review Committee and the Institutional Review Board of the University of S outh Florida,Tampa. This nursing study is to begin approximately on April 19, 2007 with data co llection completed by the end of June. Study results will be offered in a manuscrip t form for WellStar publications. The perioperative registered nurse researcher conducting this dissertation study is Doreen Wagner, RN, MSN, CNOR (principal investigator). A full proposal of this study is available per request. Please feel free to contact me for any con cerns or issues related to the inclusion of your patients in this study. Respectfully, Doreen Wagner, RN, MSN, CNOR 924 Chesterfield Place Marietta, Georgia 30064 770-919-9407/404-401-4344 doreen1799@aol.com

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102 Appendix E: Anesthesia Provider Letter April 12, 2007 Dear Anesthesia Providers: It is my pleasure to inform you about a nursing study soon to be implemented at Wellstar Douglas Hospital. This research is a dissertation stud y funded by a grant from the Association of periOperative Registered Nurses, Inc. The purpose of this experimental study is to de termine the effect of preoperative warming with forced-air warming blankets versus warmed cott on bath blankets on the acute phase response of surgical stress. All outpatient surgical patients will be recruited with “Interested” flyers. Inclusion criteria for subjects in this study are: Between 18 and 65 years of age English speaking Temperature WNL P1 or P2 ASA physical status classification No known cognitive impairments No paralysis or known paresthesia No known hypo/hyperthyroid disease General anesthesia surgery scheduled fo r >1hour and < 3 hours (no scope cases) Clean/clean-contaminated procedures only Approval was received from both the WellStar Medical Devices Review Committee and the Institutional Review Board of the University of S outh Florida,Tampa. This nursing study is to begin approximately on April 19, 2007 with data co llection completed by the end of June. Study results will be offered in a manuscrip t form for WellStar publications. The perioperative registered nurse researcher conducting this dissertation study is Doreen Wagner, RN, MSN, CNOR (principal investigator). A full proposal of this study is available per request. Please feel free to contact me for any con cerns or issues related to the inclusion of your patients in this study. Respectfully, Doreen Wagner, RN, MSN, CNOR 924 Chesterfield Place Marietta, Georgia 30064 770-919-9407/404-401-4344 doreen1799@aol.com

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103 Appendix F: Data Collection Forms Name ___________________________ Date___________________ Code number_____________ Does the Subject meet the fo llowing inclusion criteria ? > 18 to < 65 years of age __ English speaking __ No known hypo/hyperthyroid disease __ No cognitive impairment __ General anesthesia surgery scheduled __ Duration of procedure > 1h < 3 h __ Clean/clean-contaminated procedure scheduled __ P1 or P2 ASA classification __ Immunosuppressives > 6 mos ago __ No paralysis or known paresthesia __ Radiation therapy > 6 mos ago __ Temperature WNL __ Tolerates tympanic thermometry __ Informed Consent signed with copy given to patient: ___yes ___no Interview/Chart Review: Preoperative Diagnosis___________________________________________________________ Surgical Procedure _____________________________________________________________ Date of Surgery_________ Arrival Time to Preop ______ Time of Surgery ______ Surgeon Name ____________________ Other _______________________________________ Age: ____Sex: male female Weight: _____lbs. Height _____ R ace/Ethnicity: ______ List Chronic Illnesses : List routine medications at home (including alcohol, antipsychotics, antidepressants, OTC sedatives, etc):

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104 Appendix F: Continued Date___________________ Code number_______________ Time I: BEFORE INTERVENTION SURVEY (Upon Admission to Pre-operative Area) Gowned and covered with one non-warmed cotton bath blanket or cotton sheet. No activation of warming blanket nor application of warmed blanket at this time. Physical data: Preop Room # _____ Ambient temperature of preoperative room ___________ Preop Vital Signs: Tympanic T: ______ P ______ R ______ BP ______ O2 sat % ______ INT site _________ INT cath size _____ Blood samples drawn:____ Time drawn ______ Pre-op meds or prep (at home)__________________________________________________ At end of assessment session, provide preoperative warming intervention: Time warmed cotton blanket x 1 applied ( control group ) ________ Temperature of warmed cotton blanket ________ Blanket warmer temperature _________ Time Bair Hugger system activated ( treatment group ) _________ Control settings at Bair Hugger system activation: __off __cooler __medium __warmer Comments:

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105 Appendix F: Continued Date___________________ Code number_______________ Time II: AFTER INTERVENTION SURVEY *Before surgery (at least 30 after intervention) Completion of warming intervention – either warmed blanket(s) or FAW blanket Physical data: Ambient temperature of preoperative room __________ Preop Vital Signs: Tympanic T: ______ P ______ R ______ BP ______ O2 sat % _____ Blood samples drawn: _______ Time drawn __________ Other ____________________ Pre-op meds, preps, or treatments (giv en in preoperative room/holding area) Type/amount IV Fluid _________________ _________ ___ warmed ___ not warmed Time IV started ______ Type of IV antibiotics ________________________________________ Versed (dose/route) ____________________________________ Time given _________ ____ Pepcid (dose/route) ____________________________________ Time given ______________ Other preoperative medications given:_______________________________________________ _____________________________________________________________________________ Other observations/comments (use back of this page as necessary): ____________________ __ _____________________________________________________________________________ Check all warming information that apply in preoperative area: o Warmed cotton blankets Temperature of blanket at end of 30 minutes ______ o # of warmed blankets applied (if usual care group) ________ o Additional non-warmed blankets # of blankets __________ o Booties, socks, head covering o Warmed IV fluids o Bair Hugger™ blanket o Bair Hugger™ system setti ng: __off ___ cooler ___ medium ___ warmer o Other _________________________________________________________________

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106 Appendix F: Continued Date___________________ Code number_______________ Time III INTRAOPERATIVE SURVEY (Assessment at 1 Hour Intraoperatively) Duration of Surgical Procedure : Surgical Procedure: _____________________________________________________________ Anesthesia start time: ______________ Incision open time: ________________ Incision closure time: ______________ Anesthesia end time: _______________ Vital Signs: P ______ R ______ BP ______ O2 sat % _____ Tympanic temp OR ambient temp Time Temp @ 1 hour intraop Blood Samples Drawn Time OR Temp @ 1 hour intraop Active warming in OR : No___ Yes ___ Start time: ______ End time: ______ If yes, describe active warming approaches: ______________________________________________________________________________________ ____________________________________________________________________________ Passive warming in OR : No__ Yes ___ Start time: ______ # warmed blankets ______ If other than warmed blankets, describe passive warming approaches: ______________________________________________________________________________________ ____________________________________________________________________________ Circle Anesthesia Agents Provided: Propofol Sevoflurane Isoflurane Desflurane Succinylcholine Rocuronium Fentanyl Lidocaine Nitrous Oxide Oxygen Other _____________________________________________________________________ EBL:

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107 Appendix F: Continued Date___________________ Code number_______________ Time IV: ADMISSION TO PACU SURVEY Postoperative Assessment Physical Data: Time of Arrival to PACU: _______ Ambient temperature of bay area: _________ Postop Vital Signs: Tympanic T: ______ P ______ R ______ BP ______ O2 sat % _____ Blood samples drawn: _______ Time drawn __________ Other ____________________ Active warming in PACU : No___ Yes ___ Start time: ______ If yes, describe active warming approaches: ______________________________________________________________________________________ ______________________________________________________________________________________ ___________________________________________________________ Passive warming in PACU : No__ Yes ___ Start time: ______ If other than warmed blankets, describe passive warming approaches: ______________________________________________________________________________________ ______________________________________________________________________________________ ___________________________________________________________ Shivering in PACU : (circle the appropriate classification) 0 no shivering 1 mild fasiculations of face or neck 2 visible tremor involving more than one muscle group 3 gross muscular activity involving entire body Time of Discharge from PACU : _______

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About the Author V. Doreen Wagner has been a nurse for approximately 25 years with career roles including perioperative staff nursing to Surgical Services Educator, Patient Safety System Coordinator to Assistan t Professor of Nursing. At presen t, Doreen is nursing faculty at Kennesaw State University and a multi-y ear honoree in Who’s Who Among America’s Teachers. She has membership in the Sigma Theta Tau International Nursing Honor Society and the National Dean’s List. She also holds membership in the American Nurses Association, Southern Nurses Res earch Society, Georgia League for Nursing, with heavy volunteer activism in the Georgi a Nurses Association (GNA) and in the Association of periOperativ e Registered Nurses (AORN). She was honored with the AORN National Award for Outstanding Periop erative Nursing Research in 2005. Doreen has presented at numerous conferences loca lly to internationally and published many journal articles. Her research interests include thermoregulation issues of the perioperative patient, preoperativ e anxiety, and psychoneuroimmunology.


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Effect of a preoperative warming intervention on the acute phase response of surgical stress
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ABSTRACT: When a patient is exposed surgical stress, the endocrine system secretes hormones in response to that stress. These hormones further activate the immune system to release cytokines and other acute phase reactions. These processes are supposed to protect the body by upregulating the innate immune system and producing an inflammatory response that acts to protect and heal. However, uncontrolled surgical stress may cause a weaker immune response that may lead to delayed wound healing. The phenomenon of unplanned perioperative hypothermia is known to expose patients to additional surgical stress. The purpose of this preliminary experimental study was to determine the effect of a preoperative warming intervention on the acute phase response of surgical stress in surgical patients.Specifically, the aim of this study was to evaluate the effect of a prewarming intervention using a forced-air warming (FAW) device versus routine care (RC) using warmed cotton blankets on the development of unplanned hypothermia, cytokine production, and endocrine responses. It was hypothesized that 1) the FAW participants would experience less unplanned perioperative hypothermia than the RC participants; 2) the FAW participants would experience lower catecholamine and cortisol levels than the RC participants; and 3) the FAW participants would experience higher proinflammatory cytokine and CRP production intra- and postoperatively than the RC participants. Infrared tympanic temperatures and 4 blood samples were taken at 4 time intervals from each of the 28 (n = 14 each group) randomized participants that underwent routine general anesthesia surgery.Serum concentrations of CRP, cortisol and IL-1beta, IL- 6, TNF-alpha, and IFN-gamma, and plasma concentrations of epinephrine and norepinephrine were measured. To test the hypotheses across time and between groups, a repeated measures ANOVA design was used. Though FAW was not associated with a differential endocrine or inflammatory response in this small, preliminary study, further study of forced air warming as a preoperative nursing intervention is warranted. The finding of higher than expected IL-6 levels in the preoperative period suggests a potential role for anxiety, an important factor in psychoneuroimmunological pathways, that could affect recovery and healing. The relationship between surgical stress, anxiety, and preoperative IL-6 deserves further study.
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Dissertation (Ph.D.)--University of South Florida, 2007.
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Innate immunity.
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