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Anti-Inflammatory properties of Insulin and its Use in Critical Care Patients

March 25, 2016

Anti-Inflammatory properties of Insulin and its Use in Critical Care Patients

Apart from its use in the management of hyperglycemia, insulin has recently been associated with attenuation of systemic inflammatory response owing to its anti-inflammatory properties hence making it an important drug in critical care patients. This discussion explores anti-inflammatory effect of insulin in critical care patients. The discussion details the documented impacts of insulin on critical care populations as well as the beneficial effects of insulin in critical care. Analysis of relevant literature is applied to determine the anti-inflammatory causes of insulin as well as the manner in which insulin therapy could be applied in enhancing the end results for patients in intensive care units experiencing an inflammatory response to illness. From Pender’s Health Promotion Model (HPM), prevention and early detection of inflammatory response is viewed. Pender’s Health promotion Model explores the complex relationship between pathological, sociological, as well as psychological functions that hinder or encourage intensive insulin therapy for patients in need of critical care.

Insulin has long been applied in regulating hyperglycemia as well as in the treatment of diabetes mellitus since its discovery in 1921 by Banting and Best (Dandona, 2011). Hyperglycemia, which refers to high blood sugar, is a frequent impediment that occurs in critical care patient populations leading to a number of health issues. In addition to its ability to lower blood glucose levels, insulin has recently been associated with anti-inflammatory properties (Chaudhuri et al., 2004). The mechanism of action, however, is still unknown and is under investigation (Chaudhuri et al., 2004).
Several patients with critical health problems, principally the septic patients as well as ones with injuries to the myocardium, portrays an inflammatory reaction following an infarct to the myocardial tissue (Chaudhuri et al., 2004). The inflammatory surge in the critical care population is triggered by inflammation, trauma as well as infection. As a result of the inflammatory process, the systemic inflammatory response syndrome (SIRS) develops initiated by internal and external toxins. Interleukin-1 and (IL-1) tissue necrosis factor-a (TNF-a) are initially produced and triggers numerous cascades. IL-1 & TNF-a impacts the endothelial surfaces causing the production of tissue factor, that facilitates coagulation by prompting thrombin formation. Despite it being a coagulatory mediator, tissue factor is a pro-inflammatory mediator and is associated with the development of SIRS in critically injured patients. Systemic inflammatory response syndrome (SIRS) is advanced by the correlation between inflammation and coagulation (Burdette, Parilo, Kaplan, & Bailey, 2010).
A study by Paresh Dandona (2001) found that insulin could be anti-atherogenic since atherosclerosis is a chronic inflammation of the arterial wall. In order to prevent all of these inflammatory cascades, an administration of insulin is found to be beneficial. The infusion of insulin also reduces the size of the infarct and improves myocardial function. From previous studies, it is clear that high-dose insulin therapy is not only secure but also successful in sustaining peri-operative normoglycemia in patients with coronary artery bypass transplant (Albacker, Carvalho, Schricker, & Lachapelle, 2008). Moreover, research has shown that the administration of insulin may also have immunemodulatory impacts and ability to minimize the pro-inflammatory cytokines as well as C – reactive protein formation (Koskenkari et al., 2006). Vanhorebeek et al. (2006) examined the connection amid intensive insulin therapy and cortisol levels. He concluded that the cortisol levels were less for patients exposed to intensive insulin therapy.
Problem Statement
As mortality and morbidity rates of critically ill patients continue to climb owing to secondary health complications such as multiple organ failure and infectious complications, health care professionals and researchers alike are struggling to work out strategies to reverse the situation. The main cause of organ failure and infectious complications in critically ill patients is Systemic Inflammatory Response Syndrome. One strategy for minimizing further health complications in the ICU is intensive insulin therapy aimed at controlling blood glucose to levels between 80 to 110mg.dL-1 (Sengupta, et al., 2008). The result of intensive insulin therapy has been shown to have a positive in critical care patient populations by lessening the mortality as well as morbidity in ICUs. Intensive insulin therapy can also decline the intensity of serum cortisol (Vanhorebeek et al., 2006). Yet, most health care practitioners are still unaware of the positive role of insulin as an anti-inflammatory modulator in critical care patients. The relationship existing amid hyperglycemia, inflammation and possible effects of insulin on patient outcomes are still under investigation. The purpose of this review was to examine the anti-inflammatory properties of insulin and how these properties could be applied to progress effects on patients in intensive care units with an inflammatory reaction to disease. The review of literature was guided by Pender’s Health Promotion Model.
Background and Significance
Systemic inflammatory response syndrome and insulin resistance are common among patients with severe illnesses, including the ones lacking previous history of diabetes (Dandona et al., 2005). From research, it is clear that blood glucose normalization using insulin therapy, progresses the prognosis of such patients and minimizes their mortality as well as morbidity. Studies have also revealed that hyperglycemia elevates pro-inflammatory markers and often lead to SIRS and sepsis (Dandona et al., 2005). Systemic Inflammatory Response Syndrome (SIRS) refers to a clinical response against an inflammatory or traumatic prompt of an indefinite etiology (Talmor, Hydo, & Barie, 1999). According to Talmor et al. (1999), based on the American College of Chest Physicians and the Society of Critical Care Medicine,
SIRS is diagnosed if two or more of the following criteria are met: 1) Temperature greater than 380C or less than 360C; 2) Heart rate greater than 90 beats per minute; 3) Respiratory rate greater than 20/minute or a PACO2 less than 32 mmHg and; 4) white blood cell count greater than 12.0x 109/L or less than 4.0×109/L or the presence of more than 10 immature bands. (p. 81)
There are several factors that are known to trigger these symptoms. These factors are broadly categorized into modifiable and non-modifiable risk factors (Burdette et al., 2010). Modifiable risk factors for SIRS include bacterial, viral, fungal as well as parasitic infections. These may consist of toxic shock syndrome, community acquired pneumonia, diabetic foot ulcer, gas gangrene, cellulites, cholecystitis, meningitis, and influenza (Burdette et al., 2010). Burdette et al. (2010) also summarized non-modifiable risk factors, which comprises of drug reaction, trauma, pancreatitis, myocardial infection, burns, adrenal insufficiency, cirrhosis, dehydration, chemical aspirations, hemorrhagic shock, and pancreatitis among others (Burdette et al., 2010). .
The management of Systemic Inflammatory Response Syndrome in critical care patients include: oxygen antibiotics supplement in case of infectious etiology, small steroid therapy dosage, IV fluid for hypotensive and intensive insulin therapy for hyperglycemia. Deep venous thrombosis as well as gastrointestinal stress-ulcers prophylactics can be applied in the management of SIRS. Modifiable risk factors are minimized through timely infection diagnosis, comprehensive evaluation and most importantly, timely diagnosis of the malignancy (Burdette et al., 2010).
Anti-inflammatory insulin characteristics involve the capacity to safeguard the myocardium from reperfusion damage & ischemia as well as myocardial cells apoptosis. Das (2003) maintains that a blend of sufficient insulin quantity in patients having acute myocardial infarction, carcinogenic shock, congestive heart failure, as well as severe health problems sustains myocardial function and protection that guarantees a speedy recovery. In addition, insulin counteracts catabolic state erupted from illness and partially corrects the abnormal serum lipid profile. Added non-metabolic anti-inflammatory role of insulin includes the deterrence of unnecessary inflammation while its anti-apoptotic role involves myocardial protection (Vanhorebeek, Langouche, & Van den Berghe, 2005).
However, insulin’s mechanisms of action are debatable, but it is ascertained to minimize mortality as well as prevention of occurrence of multi-organ failure in patients with severe illnesses (Jeschke, Klein, & Herndon, 2004). A study by Jeschke et al. (2004) explored the anti-inflammatory role of insulin and its effects on severely ailing patient populations. Besides, they determined the resemblance and distinction in an array of setups to identify discrepancies of insulin and the anti-inflammatory response. The results of their study revealed that insulin indeed has beneficial effects in lowering morbidity and mortality arising from Systemic Inflammatory Response Syndrome in critically ill patient populations. They also suggested a need to explore this topic further to establish the mechanisms of action in the beneficial effect of insulin as an anti-inflammatory modulator. This review, therefore, intended to fill this gap by exploring this topic further (Chinsky, 2004).
Theoretical framework
This study addressed anti-inflammatory effects of insulin with the aim of promoting its use in critical care patients. Pender’s Health Promotion theory analyses the intricate communication amid the psychological, biological and pathological processes involved in inflammation in critically ill individuals (Chaudhuri et al., 2004).
Biological processes refer to individual characteristics and experiences including age, gender, and genetics among others (Pender et al., 2002). Biological factors are generally non-modifiable and can either pose as a barrier or benefit to health promotion. In critical care nursing practice, biological processes are considered as the non-modifiable risk factors to inflammatory response syndrome. Psychological processes are behavior specific effects and cognitions, which generate apparent advantages and obstructions to health wellbeing (Pender et al., 2002). This basically refers to health provision behaviors of critical care health practitioners. Their behavior can either embrace or discourage the use of insulin as anti-inflammatory modulator in critical care patients. Finally, sociological processes are the situational and interpersonal factors, which influence health promotion behaviors (Pender et al., 2002). In this paper, these are considered as the professional relationships between health care practitioners. For instance, is there any cooperation between the physician and the critical care nurse in the administration of insulin therapy?
According to Srof and Velsor-Friedrich (2006), these three important processes in Pender’s health promotion model interact in a complex manner forming a multi-faceted network as opposed to linear progression. As Pender maintained, health promotion behavior is a tripod concept that cannot be achieved unless all three legs are secure (Pender et al., 2002), which are commonly referred to as the determinants of health promotion behavior including the sociological, biological, and psychological processes.
The remaining sections of this paper provide a literature review guided by this model and eventually highlight these determinants in detail. The biological processes will be highlighted in the discussion of the ‘advanced pathology and pharmacology’ as well as ‘human diversity’ that are beyond the patient’s personal control. The health policy and ethical decision making discussions will examine the sociological processes, which either encourage or discourage the use of insulin as an anti-inflammatory modulator in critical care patients. Finally, health promotion section will discuss the increasing professional awareness of the significance of insulin as an anti-inflammatory modulator in critical care patients.
Inflammatory responses and critical illness
Critical care patients are at a high risk of developing further injuries including organ failure as their bodies respond to illness (Ward, Casserly, & Ayala, 2008). One of the common responses to illness among critical care patients is inflammation. Why inflammatory response to illness in critical care patients? During severe injury or bacterial infection, the body utilizes homeostatic mechanisms to fight foreign microbial agents, a process that also involves the activation of both anti and pro-inflammatory pathways (Ward et al., 2008). In most critically ill patients, the body finds it difficult to maintain a balance between pro and anti-inflammatory mediators with pro-inflammatory mediators being in excess. Pro-inflammatory mediators arise to fight pathogens and dead tissue, but often cause injury to the host body as they promote the development of systemic inflammatory response syndrome and sepsis in critically ill patients (Ward et al., 2008).
Systemic inflammatory reaction is important in organ dysfunction pathogenesis. Some of the stress factors, which trigger these pro-inflammatory responses, include surgical operation procedures, and the subsequent intensive care procedures such as ICU resuscitations. Sepsis is present in about 40% (forty percent) of ICU patients. Besides, it is linked to 30% mortality (Gustot, 2011). This is is interrelated to the extent of inflammatory response syndrome as well as several organ failures.
Severe host inflammatory response to pathogens progresses in three stages. The first one is sepsis, while the second and third one is severe sepsis and sepsis shock respectively. Systemic inflammatory response syndrome has an affinity to develop into severe sepsis or shock (Alberti et al., 2004). This extreme response stimulates microthrombi production and RBCs capillary blockage affecting their deformity. Additionally, there are microcirculatory modifications, capillary leakage to cause tissue edema, as well as neutrophil engagement resulting to multiple tissue injuries, organ failures, and ultimate fatalities (Gustot, 2011). Organ failures increase length of stay in the Intensive Care Unit. In addition, Systemic inflammatory response syndrome can lead to severe sepsis and death among critically ill patients. The scholars, Saibeni, Spina, & Vecchi (2004) ascertained that Systemic Inflammatory Response Syndrome eases the coagulation gush in the case of inflammatory bowel illnesses.
Anti-inflammatory responses, on the other hand, occur when the homeostatic balance is upset in favor of anti-inflammatory mediators resulting into Compensatory Anti-Inflammatory Response Syndrome (CARS). Unlike pro-inflammatory responses, anti-inflammatory responses aim at limiting damage by counterchecking pro-inflammatory forces. Compensatory Anti-Inflammatory Response Syndrome is a positive immune response associated with improved outcomes in critical care patients (Ward et al., 2008). Compensatory anti-Inflammatory response syndrome is a counter-balance response, which occurs to countercheck pro-inflammatory forces and hence limit further injury of the host’s body organs. According to Ward et al. CARS is characterized by the following symptoms:
cutaneous energy, apoptotic decline in lymphocytes through minimal cytokine reaction of monocytes to stimulus, lessening of the level of human leukocyte antigen (HLA), antigen presenting receptors (APC) on monocytes as well as cytokines recruitment such as IL-10 that restrain the expression of TNF (2008, p. 618).
Even though Compensatory anti-Inflammatory response syndrome may occur as a natural body immuno-response to SIRS, it is very rare in critically ill patients hence critical care practitioners often have to induce it through administration of drugs with anti-inflammatory properties. Besides, untimely anti-inflammatory response is equally dangerous as it may interfere with the elimination of pathogens making the host body susceptible to future infections. Studies have revealed that patients who develop Compensatory Anti-Inflammatory Response Syndrome to Systemic Inflammatory Response Syndrome are more susceptible to infections (Takahashi et al., 2006). For this reason, health practitioners have to come up with strategies for timely diagnosis and management of Systemic Inflammatory Response Syndrome in a manner that does not interfere with elimination of pathogens, but at the same time moderates sepsis. Anti-inflammatory response should only be induced when there is a need as it may as well cause mortality in critical care patients. In this regard, health care practitioners administer several drugs with anti-inflammatory properties to induce Compensatory Anti-Inflammatory Response and increase patient outcomes. One of these drugs is insulin. Originally used in the management of hypoglycemia, insulin has become a significant anti-inflammatory drug in critical care. The role of insulin as an anti-inflammatory drug will be discussed in the succeeding paragraphs of this section.
Risk factors associated with systemic inflammatory response to illness
As had been mentioned earlier in the discussion, pro-inflammatory response is a natural body reaction to infection or tissue injury. Therefore, pro-inflammatory response is triggered by risk factors, which are either modifiable or non modifiable. The risk factors involved in Systemic Inflammatory Response Syndrome are trauma, inflammation. The presence of these risk factors in the host body activates the inflammatory cascade, which is instigated by both internal and external toxins. Burdette et al. (2010) summarized the modifiable risk factors of SIRS to include meningitis, influenza, diabetic foot infection, cholecystitis, internal abdominal infection, bacterial sepsis, arthritis, infective endocarditis, pneumonia, cellulites among others. Burdette et al. (2010) also classified cirrhosis, seizure, hemorrhagic shock, pancreatitis, burns, adrenal insufficiency, hematologic malignancy, drug reaction, myocardial infarction, dehydration, autoimmune disorders, and electrical injuries as non-modifiable risk factors of SIRS.
Clinical management of SIRS in the ICU
The management of systemic inflammatory response syndrome in critical care patients include: oxygen supplement, administration of antibiotics if there is an infectious etiology, low dose steroid therapy, IV fluid in hypotensive patients, or intensive insulin therapy in patients with hyperglycemia. Both deep venous thrombosis and Gastro Intestinal stress ulcer prophylaxis also should be considered to manage SIRS. Modifiable risk factors can be reduced through early detection of infection, complete history and physical examination, and by early detection of malignancy (Burdette et al., 2010).
According to Lewis et al. (2004), critical care patients are often diagnosed with hyperglycemia mainly due to the medications used in the ICU and other related critical care procedures. A study carried out by Dandona et al. (2005) revealed that while glucose has pro-inflammatory effect, insulin has anti-inflammatory effect.
Since the medical breakthrough regarding insulin in 1921, it continues to be utilized to regulate hyperglycemia as well as in the treatment of diabetes mellitus (Dandona, 2011). From recent studies, it is clear that insulin can be utilized not only in the treatment of hyperglycemia, but also as an anti-inflammatory mediator (Koskenkari et al., 2006; Vanhorebeek et al., 2006; Albacker et al., 2008; Jeschke et al., 2004; Chaudhuri et al., 2004; Hoedemaekers et al., 2005). A number of previous studies ascertain that insulin is not only helpful in regulating hyperglycemia and glucose homeostasis, but also implicated with the distinctive role of safeguarding the myocardium from reperfusion injury & ischemia as well as putting check on check on myocardial cells’ apoptosis (Das, 2003). Research has concentrated on animals and man to assess the anti-inflammatory properties of insulin. Brix-Christiansen et al. (2004) has done research on pigs and inferred that insulin has anti-inflammatory role and progresses neutrophillic activity by lessening the concentrations of blood glucose. Moreover, research on burned chickens ascertained that insulin declines fatty acids as well as serum triglycerides (Jeschke et al., 2004). As a result, various scholars have deduced that insulin eases the inflammatory response through lessening pro-inflammatory surge while rising anti-inflammatory surge therefore, re-establishing systemic homeostasis, implicated with organ function as well as survival in patients that are severely ill (Jeschke et al., 2004). From the literature used, it is notable that there are contradictory outcomes that question the anti-inflammatory role of insulin. From the laboratory research on macrophages, it was supposed that the inflammatory cascade would be deterred by the impact of insulin (Burdette et al., 2010).
In human populations, clinical studies have also yielded contradicting results, although many of them report findings that embraces the theory that insulin apply a form of anti-inflammatory impact in critically ill patients. Others depict a restraint of the systemic inflammatory reaction in patients undergoing cardiac surgery administered with high-dose insulin (Albacker et al., 2008; Koskenkari et al., 2006; Chaiudhuri et al., 2004). However, research conducted on cardiac surgery patients by Hoedemaekers et al., (2005) goes against the hypothesis which shows that stern glucose control would trigger a change from a pro-inflammatory condition to a further steady anti-inflammatory state. Some of the severely ailing patients have helped to determine the link among insulin, inflammatory markers, as well as patient’s results (Jeschke et al., 2004; Vanhorebeek et al., 2006). Intensive insulin therapy has been linked to lesser levels of serum cortisol in these patients that was implicated with enhanced patient’s results (Vanhorebeek et al., 2006). Conversely, the sample numbers of cardiothoracic patients in the study was not proportional (206 out of 451) making generalization hard since particular patient subpopulation outcomes failed to be discussed. Due to technical limitations, the authors were unable to investigate the factors accountable for the disparity in circulating cortisol, for instance, the consequence of insulin therapy on cortisol formation/clearance (Vanhorebeek et al., 2006). Dandona (2011), illustrates that insulin can be utilized as anti-atherogenic given that atherosclerosis is a chronic inflammation of the arterial wall. Besides, insulin infusion minimizes the extent of the infarct as well as enhancing the myocardial function.
Most recently, insulin is asserted to cause a suppression of amyloid precursor protein that facilitates the pathogenesis of Alzheimer’s disease as well as IL-4, which is a significant cytokine that facilitates the pathogenesis of asthma. That aside, it is possible that the scope regarding the anti-inflammatory role of insulin will progress in future (Dandona, 2011). On the same note, efforts are being invested in formation of analogs of insulin that will have the capacity to induce anti-inflammatory reaction with less glucose lessening effect for insulin to be utilized as an effective anti-inflammatory drug with minimal or no probable risk of hypoglycemia (Dandona, 2011). As a result, it can be deduced that insulin impacts a number of successive intricate cellular/physiological communications. These communications perhaps fail to be isolated and replicated autonomously in a laboratory study or be precisely clarified by the existing clinical trial outcome. Hence, various questions need to be answered with regard to the topic to erase the controversies that exist. Most importantly, further advanced studies are required to establish insulin’s anti-inflammatory role so as to attain optimized care for patients that have severe illnesses under intensive care.

Review of Literature
The literature was searched based on the anti-inflammatory characteristics of insulin, as well as the manner in which the properties affect the outcomes in various critical care patient populations. The literature was retrieved in September 2010 through May of 2011. The sources accessed included online sources such as Google Scholar, American Association of Critical Care Nurses website among others. The search terms were narrowed to ‘insulin,’ ‘inflammation’, ‘inflammatory,’ ‘critical care’, ‘hyperglycemia’ and ‘surgery’. In the beginning, the search gave out a number of study articles although it was condensed through merging the search terms. The criterion for inclusion was based on whether the study material linked insulin to inflammation as well as the analysis of individuals in need of critical care. Moreover, the research population was not restricted to man since a number of literature material studied other subjects like pigs. However, most of the populations were human. Most of the study materials utilized in this research paper emphasized on significance of intensive insulin therapy in individuals in need of critical care.
This literature review aims at analyzing the anti-inflammatory characteristics of insulin as well as the way intensive insulin therapy could be exploited to enhance the wellbeing of intensive care patients depicting inflammatory reactions against disease. The review of literature followed the theoretical framework of Pender’s Health Promotion Model (Pender, Murdaugh, & Parsons, 2002).
Albacker, T., Carvalho, G., Schricker, T., & Lachapelle, K. (2008). High dose insulin therapy attenuates systemic inflammatory response in coronary artery bypass grafting patients. The Annals of Thoracic Surgery, 86, 20-27.
Alberti, C., Brun-Buisson, C., Chevret, S., Antonelli, M., Goodman, S. V., Martin, C., & Le Gall, J. R. (2004). Systemic inflammatory response and progression to severe sepsis in critically ill infected patients. American Journal of Respiratory and Critical Care Medicine, Vol. 171, 461-468.
Brix-christensen, V., Anderson, S. K., Anderson, R., Mengel, A., Dyhr, T., Anderson, N. T., & Tonnesen, E. (2004). Acute hyperinsulinemia restrains endotoxin induced systemic inflammatory response. Anesthesiology, Vol. 100(4), 861-870.
Burdette, S. D., Parilo, M. A., Kaplan, L. J., & Bailey, H. (2010). Systemic Inflammatory Response Syndrome. Journal of Investigative Medicine, Vol. 58: 28-31.
Chaudhuri, A., Janicke, D., Wilson, M. F., Tripathy, D., Garg, R., Bandyopadhyay, A., & Dandona, P. (2004). Anti inflammatory and profibrinolytic effect of insulin in acute ST segment elevation Myocardial infarction. Circulation, Vol. 109(4), 849-854.
Chinsky, K. (2004). The Evolving paradigm of Hyperglycemia and Critical illness. Chest, Vol. 126(3), 674-676.
Dandona, P. (2011). Anti-Inflammatory and cardio protective effects of insulin. Mol Med., Vol. 8: 443–450.
Dandona, P., Mohanty, P., Chaudhuri, A., Garg, R., & Aljada, A. (2005). Insulin infusion in acute illness. The Journal of Clinical Investigation, Vol. 115(8), 2069-2072.
Das, U. N. (2003). Insulin: an endogenous cardioprotector. Current Opinion in Critical Care, Vol. 9(5), 375-383.
Gustot, T. (2011). Multiple organ failure in sepsis: prognosis and role of systemic inflammatory response. Current Opinion in Critical Care, Vol. 17(2), 153-159.
Hoedemaekers, C. W., Pickkers, P., Netea, M. G., Deuren, M., & Van der Hoeven, J. G. (2005, 16th November). Intensive insulin therapy does not alter the inflammatory response in patients undergoing coronary artery bypass grafting: a randomized controlled trial. Critical Care, Vol. 9(6), 790-797.
Hyatt, T. C., Phadke, R. P., Hunter, G. R., Bush, N. C., Muñoz, J. A., & Gower, B. A. (2009). Insulin sensitivity in African-American and white women: Association with inflammation. Obesity, Vol. 17(2), 276-282.
Jeschke, M. G., Klein, D., & Herndon, D. N. (2004). Insulin treatment improves the systemic inflammatory reaction to severe trauma. Annals of Surgery, Vol. 239(4), 553-560.
Kelly, J. C., & Lie, D. (2011). ACP guideline discourages intensive insulin therapy. Mediscape Education Clinical Briefs. Retrieved June 16, 2011 from
Koskenkari, J. K., Kaukoranta, P. K., Rimpilainen, J., Vainionpaa, V., Ohtonen, P. P., & Surcel, H. M. (2006). Anti inflammatory effect of high dose insulin treatment after urgent coronary revascularization surgery. Acta Anesthesiologica Scandinavica, Vol. 50(8), 962-969.
Kurtzhals, P. (February 2006). Insulin Detemir: From Concept to Clinical Experience. Informa Healthcare, Vol. 7, (3), 325-343 (doi:10.1517/14656566.7.3.325).
Malesker, M. A., Foral, P. A., McPhillips, A. C., Christensen, K. J., Chang, J. A., & Hilleman, D. (2007). An efficiency evaluation of protocols for tight glycemic control in intensive care units. America Journal of Critical-Care Nurses, Vol. 16(6), 589-598.
Pender, N. J., Murdaugh, C. L., & Parsons, M. A. (2002). Health promotion in nursing practice, 4th edition. Upper Saddle River, New Jersey: Prentice Hall.
Saibeni, S., Spina, L., & Vecchi, M. (2004). Exploring the relationship between inflammatory response and coagulation cascade in inflammatory bowel disease. European Review for Medical and Pharmacological Sciences, Vol. 8(5), 205-208.
Srof, B. J., & Velsor-Friedrich, B. (2006). Health promotion in adolescents: a review of Pender’s health promotion model. Nursing Science Quarterly, Vol. 19(4), 366 – 373.
Talmor, M., Hydo, L., & Barie, P. S. (1999). Relationship of systemic inflammatory response syndrome to organ dysfunction, Length of stay, and mortality in critical surgical illness. Arch Surg, Vol. 134(1), 81- 87.
Van Den Berghe, G., Wouters, P., & Weekers, F. et al. (2001). Intensive insulin therapy in critically ill patients. N Engl J Med, Vol. 345, 11359–1367.
Vanhorebeek, I., Langouche, L., & Van den Berghe, G. (2005). Glycemic and nonglycemic effects of insulin: how do they contribute to a better outcome of critical illness? Current Opinion in Critical Care, Vol. 11(4), 304-311.
Vanhorebeek, I., Peeters, R. P., Vander Perre, S., Jans, I., Wouters, P. J., Skogstrand, K., & Van Den Berghe, G. (2006). Cortisol response to critical illness: Effect of intensive insulin therapy. The Journal of Clinical Endocrinology and Metabolism, Vol. 91(10), 3803-3813.
Ward, S. N, Casserly, B., & Ayala, A. (2008). The compensatory anti-inflammatory response syndrome (CARS) in critically ill patients. Clinics in Chest Medicine, Vol. 29 (4), 617-6.

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