Mortality Outcomes for Treating a Fever - Yola



Mortality Outcomes for Treating a FeverAshley PeczkowskiWright State UniversityNUR 7203Mortality Outcomes for Treating a FeverIntroductionPatients admitted to the Intensive Care Units (ICU) commonly develop a febrile event during their stay, often related to an infectious process. For many years it has become common practice to treat these fevers with some type of antipyretic. Recently, the treatment of fevers in non-traumatic brain injury patients has come into question related to an increase in mortality rates (Launey, Nesseler, Malledant, & Seguin, 2011). Brain injury patients have been excluded because it has been well researched and documented that a febrile event in a brain injury patient can often be detrimental (Mrozek, Vardon, & Geeraerts, 2012). Researchers have discerned a possible increase in mortality rates in septic patients who have been treated with antipyretics, especially in the elderly. Critically ill patients are likely to develop a fever due to an infectious or non-infectious process and there are currently no guidelines for treatment (Ho Lee et al., 2012). By definition a fever is an up regulation of the preset hypothalamic temperature outside of the female hormonal-induced variation and diurnal variation. While the exact point of which the fever begins is not universally standard, many studies have developed a threshold of ≥38.2?C (Launey et al., 2011). In the elderly the development of a fever of unknown origin commonly includes an infectious process or malignancy (Cunha, Hage, & Nouri, 2011). A fever is the body’s natural defense against infection and produces many favorable effects. An infectious or non-infectious response can trigger an up regulation of the pre-optic area of the hypothalamus thus causing the febrile response. Activation of this area can be caused by: exogenous pyrogens to stimulate leukocytes which produce cytokines causing secretion of prostaglandin E2 in the organum vasculosum of the lamina propria below the hypothalamus; also IL-1β causes a ceramide production which replaces the prostaglandin E2 causing and earlier rise in core temperature; lastly a pathway not cytokine produced but neuronal in nature with Kupper cells producing prostaglandin E2 after they are stimulated by lipoply saccharides and then mediated by the vagus nerve and nucleus tractus solitaries (Launey et al., 2011). The variety of methods to induce a febrile response indicates how important this response is to maintaining normal body function. Allowing the body to mount a fever below a fatal temperature (some studies suggest below 40-41?C) enhances the immunes’ response, reduces and slows bacterial growth, increases synthesis of antibodies and cytokines while activating T-cells, neutrophils, and macrophages (Ho Lee et al., 2012; Launey et al., 2011). Some studies have indicated that there is an increase in both mortality and morbidity in infectious septic patients in the ICU when fevers were suppressed with antipyretics. Possible causes for this are reducing the fever inhibits the beneficial effects of inhibiting bacterial and viral activity (Carey, 2010). Other theories are that antipyretics (NSAIDS and acetaminophen) are associated with hypotension and renal dysfunction which is often already present in a critically ill patient thus causing further damage. Fevers are protective and the inability to produce a fever is linked to a significantly higher mortality rate by as much as 66% in a study by Ho Lee et al. (2012). Fever, however, also imparts extensive demand on a body. This is in addition to a body that is already stressed from an infection, surgical event, or other medical event. Some studies have indicated that treating the fever is more important due to a higher benefit than risk ratio. A febrile event causes an increased metabolic demand in a compromised oxygen delivery system; reduces myocardial function and intensifies vasodilatory shock; and finally a fever may cause additional difficulty with oxygen exchange in lung injury patients. Treatment of fevers to prevent this circulatory collapse has become a common practice within the ICU (Mohr & Doerschug, 2013). Discussion of the IssueThe use of antipyretics to treat a febrile event in a critically ill septic patient has become common practice until recently. Current studies performed on non-acute neurological injury septic patients were showing an increase in morbidity and mortality rates when antipyretic were given. Since this discovery, research studies specific to the effect of antipyretics in the septic patient have been conducted. The concern is that because fevers are a beneficial defense mechanism, prevention of such inhibits the body’s ability to fight the infection are blunted. The question is, are healthcare providers preventing the body from effectively killing the invasive organism or are they helping. Due to the critical illness of the patient, many of the normal functions of the body are typically disrupted. This raises the concern for increased risk of side effects from the use of antipyretics and is this contributing to the increase in mortality. Benefits to allowing permissive hyperthermia were found to have limited clinical evidence but felt the per se argumented benefits were helpful. The main issue to debate is how fevers could influence to outcome of septic patients. The literature reviews found the benefits to allowing permissive febrile events to be retarded microorganism growth, with optimal pathogen growth found between 35-37?C temperature (Ferguson, 2007). Other studies found that increasing the temperature inhibited parasite growth, increased activity from antimicrobial agents, and reduce the minimum inhibitory concentration levels. Immunity and heat shock responses were also examined and found to have reduced the severity of infection by preventing CD4 counts, B cells, and proinflammatory cytokine TNF α from being reduced. Another study showed an increased mobility of polymorphonuclear cells, increased phagocytosis speed, lymphocyte recruitment, T-helper lymphocyte adherence to L-selectin, increased immunoglobulin levels and TNF α cytotoxicity. Also important are heat shock proteins which reduce endothelial and organ damage. Data showed a heat shock response reduced mortality and organ injury while prolonging survival time in animal trails. Other clinical data reviewed in the study showed that patients with gram-negative bacilli bacteremia had higher survival rates when a fever was present, morality rate were reduced in spontaneous peritonitis when the temperature was greater than 38, and overall survival increased in spontaneous peritonitis as the body temperature increased. In contrast elderly patients with pneumonia who failed to develop a fever had a 29% mortality rate compared to the 4% who developed a febrile event (Jefferies, Weatherall, Young, Eyers, & Beasley, 2012; Launey et al., 2011). Other studies were identified in having mortality rate of 80% in hypothermic patients compared to 47% who developed a fever in Candida infections as did a higher incident of inflammatory response in hypothermic patients compared to febrile patients leading to a likely protective effect of fevers. Continued re-iteration of improved survival rates, decreased inflammatory markers, and decrease in bacterial counts were also seen in several animal studies (Launey et al., 2011). Disadvantages to allowing a permissive febrile event to occur include increased metabolic demand, reduce oxygen delivery to all organs and can worsen pre-existing disease. It has been well documented that a fever post ischemic stroke causes a secondary brain injury and increases the morbidity and mortality rate by 20%. The heart has also shown negative effects after a fever. The trials obtained were only in swine studies but the swine showed an increase in myocardial infarction when a fever was induced. Other non-data supported claims to treating a fever include: patient discomfort, febrile seizure prevention in children, and possible collateral tissues damage from microbial consumption. Collateral damage was seen in rat studies who developed vascular pulmonary injury and it is now thought that in a high fever over 40-41?C the benefits do not out weight the metabolic and inflammatory effects (Launey et al., 2011). Finally the study looked at the side effects of antipyretic treatments and physical cooling. Concern for antipyretic use include: delay in diagnosis and therapy for infections or side effects such as bleeding, hypotension, hepatic and renal toxicity. A meta-analysis of eight studies on patients with the influenza virus showed an increased mortality rate with antipyretics (odds ration= 1.34, 95% confidence interval= 1.04 to 1.73) (Eyers, Weatherall, Shirtcliffe, Perrrin, & Beasley, 2010; Launey et al., 2011). Other effects of antipyretic administration found were longer viral shedding, suppressed serum-neutralizing antibody response, prolonged parasite clearance, delayed and lower antibody response post vaccination, and increased infection rate (Walsh, 2014). These findings are indirect data but show that antipyretic use negatively impacts the morbidity rate. Paracetamol (acetaminophen) has had well documented hepatic necrosis with overdose due to N-acetyl-p-benzo-quinoneimine metabolite which can be life threatening. Even with normal use, a critically ill patient may have reduced glutathione reserves (alcoholics/malnourished) which can induce a hepatitis increasing the risk of hepatic damage. The same metabolic pathway is also implicated in nephrotic injury and possibly playing a role in analgesic associated nephropathy. Another unclear yet concerning finding is a threefold increase in alanine aminotransferase in healthy individuals who took four grams for 14 days. Intravenous paracetamol has been found to inhibit platelet aggregation along with lowering critically ill febrile patient’s blood pressure which in most cases required both fluid boluses and/or norepinephrine administration. The latter three finding require more extensive studies to fully appreciate their effects. In contrast, non-steroidal anti-inflammatory drugs (NSAIDS) are known to have side effects of gastrointestinal bleeding, inhibit cyclooxygenases-1 causing the bleeding risk, inhibit prostaglandin synthesis causing adverse effects on the kidneys, and possibly vasospasms in patient with coronary artery disease. These side effects are seen more commonly when higher doses are used, used in the elderly, with steroids or anticoagulants, or in short course therapy. Lastly physical cooling data was looked at. This found that physical cooling can cause sympathetic activation, shivering, dermal vasoconstriction, limited core cooling, elevated oxygen consumption by up to 40%, increased catecholamine’s , rebound hypothermia, and large temperature fluctuation. The use of a myo-relaxant medication is recommended to prevent shivering and excessive oxygen consumption (Launey et al., 2011).The role of the nurse practitioner in treatment of septic patients and especially elderly is growing. Sepsis has a high mortality rate in the elderly and a leading cause of overall global mortality. Mastering care for these individuals is complicated and requires new strategies and knowledge. Nurse practitioners are uniquely qualified for optimizing new knowledge and use protocols to rapidly diagnosis and treat early sepsis. This in turn reduces morbidity and mortality outcomes in the elderly (Hans Jurgen, Seiber, Walger, Bahrmann, & Singler, 2012; Kleinpell, Aitken, & Schorr, 2013)Review of Literature In a prospective observational investigation study to evaluate if there was an independent involvement between fever and antipyretics with mortality rate in infected critically ill patients (Ho Lee et al., 2012). The study was performed in 25 hospitals, ten in Korea and 15 in Japan with a total of 1,002 intensive care units (ICU) with a mean of 20 beds per ICU. Twenty of the hospitals were tertiary and five were community hospitals. There were 1,425 adult patients included in the study who had been in the ICU for at least 48 hours from September 2009 to November 2009. Those excluded include “post-cardiac arrest, post craniotomy, traumatic brain injury, central nervous system infection, subarachnoid hemorrhage, intra-cerebral hemorrhage, or stroke (Ho Lee et al., 2012, p. 2)”. The remaining group of patients was then divided into with and without sepsis based on identifiable organisms found. Data collected included age, sex, reason for admission, mechanical ventilation usage, Acute Physiology and Chronic Health Evaluation (APACHE) II score, and hourly temperature from either: pulmonary artery catheter thermistors (3%), bladder catheter thermometers (16%), tympanic membrane thermometers (9%), or axillary thermometers (72%). Treatment data collected was not standardized throughout the hospitals and included non-steroidal anti-inflammatory drugs, acetaminophen, and physical cooling. Statistical analysis used to compile data was the chisquare test, mean or median of continuous variables, Student’s t-test, or Wilcoxon rank-sum test. The confidence interval was at 95%. Results were: mean APACHE II score of 17, a 28 day mortality rate of 12%, median ICU stay of seven days, median hospital stay of 26 days, and 606 patients with sepsis while 819 patients were not septic. Results in septic patients: 28 day mortality (22.3%; P-value <0.001), Gender (male) (63.5%), Age (67), APACHE II score 21, Mechanical ventilation (70.8%), cardiac admission (18.0%), respiratory admission (56.6%), metabolic admission (10.0%), gastrointestinal admission (11.2%), length of stay mean 8 days, MAX ICU <36.5 ?C (0.7%), MAX ICU 36.5-37.4 ?C (16.2%), MAX ICU 37.5-38.4 ?C (39.1%), MAX ICU 38.5-39.4 ?C (30.5%; odds ratio 5.13 (P-value <0.007) and 13.4 (P-value<0.001), MAX ICU ≥39.5 ?C (13.5%), NSAIDs: Given (31 patients, 5.1%), Acetaminophen: Given (116 patients, 19.1%), Physical Cooling: Given (307 patients, 50.7%). Non septic patients data results included a mortality rate of 4.4%, APACHE II sore of mean 14, more likely to be admitted for postoperative (65.7%), cardiac (53.1%), or gastrointestinal (13.1%) reasons, lower length of stay at mean 5 days, more likely to have a MAX ICU temperature of 37.5-38.4 ?C (52%) and more likely to be treated with NSAIDS (12.1%) (Ho Lee et al., 2012). Limitations of the study included lack of standardized protocols; body temperature monitoring methods were not standardized and included mostly axillary (non-core), higher severity of illness patients were more likely to have invasive monitoring methods (core) with higher values, and finally NSAIDs were more likely to be given in non-septic patients, acetaminophen was given more often in septic patients, and physical cooling was used more frequently as compared to other studies which may alter mortality rates (Ho Lee et al., 2012). The interpretation of the results of the study concluded that there is a significantly higher 28 day mortality rate in septic patients, the use of NSAIDS or acetaminophen was associated with higher mortality rates only in septic patients (odds ratio: NSAIDS 2.32, P=0.02; acetaminophen 2.30, P=0.002), and it is recommended that further study be conducted to refute or confirm these finding as it is common that septic patients develop fevers and are treated the antipyretics (Ho Lee et al., 2012). A literature review done in 2011 set out to evaluate advantages and disadvantages of allowing septic patient to have a fever. Also viewed were the side effects the antipyretics to evaluate the risk/benefit ratio (Launey et al., 2011). Throughout this study the overall conclusion is that the risk and benefits should be assessed for every patient on the need for antipyretics. While more research is needed current recommendation are to sub stain from using antipyretics in septic patients absent of any neurological or cardio insult. If needed, physical cooling may be useful in a select patient subgroup. Limitations of this study were that they did not specify how many research articles were used and the type of research reviewed (Launey et al., 2011). Finally a recent (2013) systematic review and meta-analysis conducted on the effects of mortality when antipyretics are given in critically ill non-acute neurologically injured adult patients were reviewed (Niven, Stelfox, & Laupland, 2013). Preferred Reporting Items for Systemic Reviews and Meta-analyses (PRISMA) and Cochrane Collaboration guidelines were used for article inclusion and data analysis. There were five articles filtered from 755 articles used and obtained from different medical journal sites such as OVID, MEDLINE, CINAHL, EMBASE, and Cochrane. Findings included that there have been few randomized control studies which were limited by small populations, different types of interventions, and variable length of therapy given. They recommend urgently performing large randomized trials to effectively study mortality rates. Limitations of this study include the small number of randomized control studies to review and only one reported mortality as a specific outcome (Niven et al., 2013). Summary of StatementsSepsis is a concerning event commonly seen in older critically ill patients in the ICU that carry a significantly higher mortality rate. Small and limited studies have alluded to the fact the fevers are the body’s natural defense mechanisms against infectious organisms and are better for the patients survival. Negative findings associated with treating febrile events below fatal temperatures with antipyretics are numerous related to both the blunting of the therapeutic effects of the fever and also to the drugs sided effect profile. Deleterious effects of allowing the fever to continue in non-acute brain injury patients are nominal in comparison and need to be considered. Current recommendations are to allow permissive hyperthermia below fatal temperatures in septic non-acute brain injury patients who are able to withstand the deleterious effects of the fever itself. The use of antipyretics and physical cooling should be kept to a minimum if possible. As more IUC’s adopt this standard of thinking, large randomized control trials should be conducted to effectively prove this new standard of care. ReferencesCarey, J. (2010). Literature review: Should antipyretic therapies routinely be administered to patient fever? Journal of Clinical Nursing, 19, 2377-2393. , B., Hage, J., & Nouri, Y. (2011). Recurrent fever of unknown origin (FUO): Aseptic meningitis, hepatosplenomegaly, pericarditis, and a double quotidian fever due to juvenile rheumatoid arthritis (JRA). Heart and Lung, 41, 177-180. , S., Weatherall, M., Shirtcliffe, P., Perrrin, K., & Beasley, R. (2010). The effect on mortality of antipyretics in the treatment of influenza infection: Systematic review and meta-analysis. Journal of the Royal Society of Medicine, 103, 403-411.Ferguson, A. (2007). Evaluation and treatment of fever in intensive care unit patients. Critical Care Nursing Quarterly, 30(4), 347-363. Retrieved from Jurgen, H., Seiber, C., Walger, P., Bahrmann, P., & Singler, K. (2012). Infections in the elderly. Critical Care Clinics, 29, 757-774. fromHo Lee, H., Inui, D., Suh, G., Kim, J., Kwon, J., Park, J., ... Koh, Y. (2012). Association of body temperature and antipyretic treatments with mortality of critically ill patients with and without sepsis: Multi-centered prospective observational study. Critical Care, 16(33), 1-13. , S., Weatherall, M., Young, P., Eyers, S., & Beasley, R. (2012). Systematic review and meta-analysis of effects of antipyretic medications on mortality in Streptococcus pneumoniae infections. Postgraduate Medical Journal, 88, 21-27. , R., Aitken, L., & Schorr, C. (2013). Implications of the new international sepsis guidelines for nursing care. American Journal of Critical Care, 22(3), 212-222. , Y., Nesseler, N., Malledant, Y., & Seguin, P. (2011). Clinical review: Fever in septic ICU patients- friend of foe? Critical Care, 15(222). , N., & Doerschug, K. (2013). Point: Should antipyretic therapy be given routinely to febrile patients in septic shock? Yes. Chest, 144(4), 1096-1098. , S., Vardon, F., & Geeraerts, T. (2012). Brain Temperature: Physiology and pathophysiology after brain injury. Anesthesiology Research and Practice, 2012(989487), 1-13. , D., Stelfox, T., & Laupland, K. (2013). Antipyretic therapy in febrile critically ill adults: A systematic review and meta-analysis. Journal of Critical Care, 28, 303-310. , A. (2014). Available evidence does not support routine administration of antipyretics to reduce duration of fever or illness. Evidence-Based Nursing, 14(2). ................
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