Untitled

Abstract

221COX-2 = cyclooxygenase-2; HSF = heat shock factor; HSP = heat shock protein; ICU = intensive care unit; IL = interleukin; NF = nuclear factor; OVLT = organum vasculosum of the laminae terminalis; TNF-α = tumor necrosis factor alpha.Available online http://ccforum.com/content/7/3/221 Fever occurs commonly in hospitalized patients. It is estimated that nosocomial fevers occur in approximately one-third of all medical patients at some time during their hospital stay [1]. In patients admitted to the intensive care unit (ICU) with severe sepsis, the incidence of fever is more than 90% [2]. As there is variation in the incidence of reported fevers, the etiology of fever in critically ill patients is similarly diverse-both infectious and noninfectious etiologies are common [1,3,4].The definition of fever is arbitrary. The mean body temperature (oral) in healthy individuals is approximately 36.8°C (98.2°F), with a range of 35.6°C (96°F) to 38.2°C (100.8°F) and a slight diurnal variation [5]. The Society of Critical Care Medicine and the Infectious Disease Society of America, in a recent consensus statement, suggested that a temperature of above 38.3°C (101°F) should be considered a fever and should prompt a clinical assessment [4].Physician and staff response to fever varies institutionally. Besides evaluating the patient and initiating a workup based on the clinical evaluation, it is common for the patient to receive either pharmacologic or mechanical antipyretic therapy. However, there is little evidence that would support such routine practice. The traditional view, at least in pediatrics, is that an exuberant febrile response is inherently dangerous and can, in the worse case, lead to seizures and brain damage [6]. Adult nonhealthcare workers (i.e. patient family members) also have significant misconceptions regarding the perceived detrimental effects of fever [7]. In this complicated psychosocial setting, it is easy for the physician to merely treat the fever. However, there are costs associated with such therapies. It is estimated that when either paracetamol, icepacks or cooling blankets are used, it can cost one 18-bed ICU between $10,000 and $29,000 per year [8]. Pharmacological means to reduce fever cause renal and hepatic dysfunction in patients who are volume depleted or who have underlying kidney or liver disease [9]. Additionally, there is evidence, at least in animal models, that fever is a beneficial host response to infection [10][11][12]. AbstractFever is a common response to sepsis in critically ill patients. Fever occurs when either exogenous or endogenous pyrogens affect the synthesis of prostaglandin E 2 in the pre-optic nucleus. Prostaglandin E 2 slows the rate of firing of warm sensitive neurons and results in increased body temperature. The febrile response is well preserved across the animal kingdom, and experimental evidence suggests it may be a beneficial response to infection. Fever, however, is commonly treated in critically ill patients, usually with antipyretics, without good data to ...

Toll-Like Receptor (TLR) Response Tolerance: A Key Physiological “ Damage Limitation ” Effect and an Important Potential Opportunity for Therapy

“…PBMC and endothelial cells ↓ NF-κB activation & cytokine production [191] Lung surfactant protein A Murine monocytes /macrophages ↓IL-10 production ↓TNF-α, IL-1α, IL-1β, NF-κB activation [192,193] Extracellular ATP Human monocytes ↓ MCP-1, TNF-α, increased IL-10 production [194] Filarial nematode protein ES-62 Murine macrophages ↓ TLR4 dependent IL-12 production [195] Bacterial superantigen Human monocytes ↑ TLR4 expression & LPS responsiveness [196] timepoints restores TNF-α production in low dose (0.5-10ng/ml) LPS tolerised human PBMC [180]. IL-12 can enhance IFN-γ production and partially restore TNF-α production in LPS tolerised PBMC.…”

“…Another aspect of the inflammatory response is fever; proinflammatory cytokines such as IL-1 act via the hypothalamus to increase body temperature. Hyperthermia is associated with the release of heat shock proteins, which have been identified by a number of groups as potential ligands for TLR4 [42,230] ; hyperthermia is also associated with reduced NF-κB activity and diminished cytokine production, as seen in endotoxin tolerance [191]. Thus, it may be that the regulation of MyD88 dependent signalling serves a homeostatic role in limiting the febrile response.…”

Randomized trial of the effect of intravenous paracetamol on inflammatory biomarkers and outcome in febrile critically ill adults

“…Fever, defined as an increase in body temperature above 38.3°C (100.4°F), is among the most frequently detected abnormal physical signs in critically ill patients related either to SIRS or infections [1,2]. Fever is associated with increased length of stay in general ICU patients and poorer outcomes in certain patient groups such as those with Traumatic Brain Injury (TBI), Subarachnoid Hemorrhage (SAH) or pancreatitis [3,4].…”

Fever and the thermal regulation of immunity: the immune system feels the heat

“…For example, the use of antipyretic drugs to diminish fever correlates with a 5% increase in mortality in human populations infected with influenza virus and negatively affects patient outcomes in the intensive care unit. 3–5 Preclinical studies in rabbits infected with rinderpest virus also found an increase in mortality when fever was inhibited with the antipyretic drug acetylsalicylic acid — 70% of acetylsalicylic acid-treated animals died as a result of infection as compared with only 16% of animals with a normal febrile response. 6 However, fever is not universally beneficial, particularly in cases of extreme inflammation where lowering, rather than raising body temperature has evolved as a protective mechanism.…”