Presentation on theme: "Fever thermometer 1.Introduction 2.Causes and mechanisms of fever"— Presentation transcript:
1Fever thermometer 1.Introduction 2.Causes and mechanisms of fever 3.Febrile phases and the characteristics of thermo-metabolism4.Functional and metabolic changes induced by febrile response5.Pathophysiological basis of prevention and treatment for fever
21. Introduction Set point of hypothalamic thermostat: (1) Normal body temperature～37℃（98.6 F）with a variation ～1CAxillary COral CRectal C（2）Regulation of normal body temperature (homeostasis)Thermoregulatory center: mainly located in hypothalamusSet point of hypothalamic thermostat:a hypothetic model for regulation of body temperature, which use the mechanic principle of thermostat of incubator to explain the process of body thermoregulation.The neurons in “set point” can sense the deviation of body temperature from its thermostat point and issue pulses to control the heat production and heat dissipation correspondently.
3(3)Elevation of body temperature An elevation of body temperature above the normal amplitude of daily variation(>0.5℃)
4An elevation of body temperature is fever? 36 ℃40 ℃Physiologic elevation of body temperature
5A pathologic elevation of body temperature is fever? HyperthermiaHeatstrokeHyperthyroidismCentral nervous system damage
6(4) Types of body temperature elevation Physiological elevationbefore menstruationsevere exercisestressPathological elevationFever（发热）, e.g. Infection diseasesHyperthermia（过热）, e.g. heatstroke
7(5) FeverFever is a complicated pathological process characterized by a regulated elevation of core body temperature that exceeds the normal daily variation (>0.5℃), in which pyrogens cause a temporary upward resetting of the hypothalamic thermostatic setpoint, inducing a complex physiologic and pathophysiologic febrile response.Caused by pyrogensRegulated increase of body temperature above 37.5℃Body temperature =the changed setpoint
8(6) Hyperthermia Causes: overproduction of heat An unregulated rise in body temperature beyond the unchanged hypothalamic thermostatic setpoint resulting from the dysfunction of body temperature center or impairment of heat production and/or heat loss mechanisms.Causes:overproduction of heatimpediment in heat lossdysfunction of body temperature centerFeatures:Passive increase of body temperature >0.5 CBody temperature beyond the unchanged setpoint
9Comparison between hyperthermia and fever Arising from changes within the body or by changes in environmentResulting from pyrogenSet-point remains unchanged or damaged, or effector organs failsAbility to regulate set-point remains intact, but is turned up at a high level functionallyBody temperature may rise to a very high levelRise of body temperature has an upper limitTreatment with water-alcohol bathingTreatment with antipyretics and measures, and drugs to eliminate the causes
102. Causes and mechanisms of fever Pyrogenic activator（发热激活物）(2)Endogenous pyrogen (EP，内生致热原)(3)Mechanisms of set point elevation caused by EP(4)Pathogenesis of fever
11(1) Pyrogenic activator Concept of pyrogenic activatorfever-inducing substances that can activate endogenous pyrogen(EP)-generating cells to generate and release EPs.Pyrogenic activator (exogenous pyrogen) →stimulate the cells → produce and release EPs.
12Category of pyrogenic activator Infectious factors: microbes and microbial productsG- bacteria: Lipopolysaccharide (LPS)/EndotoxinG+ bacteria: Exotoxins; Peptidoglycans, Lipoteichoic acid (LTA)VirusesOther microorganismsNon-infectious factors:Antigen-Antibidy complexesComponents of the complement cascadeNon-infectious inflammation-genesis irritantsCertain steroids: etiocholanolone(本胆烷醇酮)
13(2)Endogenous pyrogen (EP) Concept of EPEPs are fever-inducing cytokines, such as TNF, IL-1, IL-6 and IFN, via elevating the hypothalamic thermostatic setpoint, and derived from mononuclear cells, macrophages, Kupffer cell, endothelia cells and etc, under the action of pyrogenic activators.
14EP generating cells Category of EPs Monocyte Macrophage T lymphocyte Kupffer cellsEndothelia cellsSome tumor cellsCategory of EPsInterleukin-1 (IL-1)Tumor necrosis factor (TNF)Interferon (IFN)Macrophage inflammatory protein-1 (MIP-1)Interleukin-6 (IL-6)Others
15Endogenous Pyrogenic cytokines EPsPrinciple sourceInducersIL-1aIL-1bMacrophages and other cell typesLPS,TNF, Other microbial productsTNF-aTNF-bMacrophagesLymphocytes(T&B)LPS, Other microbial productsantigen, mitogen stmulationIFN- aIFN- bIFN-gLeukocytesFiboblastsT-lymphocytesLPS, viral infectionIL-6Many cell typesLPS, TNFMIP-1aMIP-1bLPSIL-8LPS, TNF, IL-1
16Production and release of EP LPS (G- bacteria) + LBP (LPS binding protein, serum) + sCD14---TLR (Toll-like receptors, EP-producing cells)+MD-2------MyD88---NF-κB---Target genes --- EP expression and releaseExotoxin (G+ bacteria)---APC/T cell receptor (TCR)---PTK---pathway:PLC, Ras
18(3)Mechanisms of setpoint elevation by EP Thermoregulation centerPositive regulation centerPreoptic region of anterior hypothalamus (POAH，视前区-下丘脑前部）:Temperature-sensitive neurons---Cold sensitive neuron---Warm sensitive neuronNegative regulation centerMedial amygdaloid nucleus (MAN，中杏仁核)Ventral septal area (VSA，下丘脑腹隔区)
19The routes for EP signals into the thermoregulatory center of hypothalamusOrganum vasculosum laminae terminalis (OVLT，下丘脑终板血管器)specialized neural regions along the margins of the cerebral ventricular system that have fenestrated capillaries (almost no blood-brain-barrier)Blood-brain barrierVagal afferent nerve fibers
20The Role of OVLT in pathogenesis of fever EPMacrophageOVLT neuronPOAH neuronSupraoptic recessThird ventricle of brainChiasma of optic nervesCapillaryOVLT areaPGE2Cells of ventricle tubal membrane
21The BBB can be broken down by: Hypertension: high blood pressure opens the BBB.Infection: exposure to infectious agents can open the BBB.Radiation: exposure to radiation can open the BBB.Development: the BBB is not fully formed at birth.
22Central mediators of fever The positive regulatory mediators Prostaglandins (PGE2) Corticotropin releasing hormone (CRH)The ratio of central Na+/Ca2+cAMPNitric oxide (NO)The negative regulatory mediatorsFebrile ceiling（热限）: The febrile response is controlled within a strict limit, the upper limit almost never exceeds 41.0℃.Endogenous cryogen: the endogenous antipyretic substances that antagonize the effects of pyrogens on thermosensitive neurons, including: Arginine vasopressin (AVP，精氨酸加压素) α-melanocyte-stimulating hormone (α-MSH，α黑素细胞刺激素)Lipocortin-1/Annexin A1（脂皮质蛋白-1/膜联蛋白A1）
243. Febrile phases and the characteristics of thermo-metabolism
25Three stages of fever (typical) The setpoint is restored to the normal levelThe setpoint is raised to a higher levelEffervescence periodHeat production↑heat loss ↓体温上升期Defervescence periodHeat loss ↑heat production↓体温下降期Persistent febrile periodHeat equipoise at a higher level体温持续期
26Manifestations of fever Effervescence periodHeat production↑:shivering, brown adipose tissue, basal metabolic rateHeat loss ↓:feeling of being cold, skin is cold and pale (vasoconstriction), piloerection, goose fleshPersistent febrile periodHeat equipoise at a higher level:shivering ceases, sensation of warmth, cutaneous vasodilation occurs, skin becomes warm and flushed.Defervescence periodHeat loss ↑,heat production↓:sweating, etc.
27Fever patternsIntermittent fever: temperature returns to normal at least once every 24h.Remittent fever: temperature does not return to normal and varies a few degrees in either direction.Sustained fever: temperature remains above normal with minimal variations.Recurrent or relapsing fever: there is one or more episodes of fever,each as long as several days, with one or more days of normal temperature between episodes.
284.Functional and metabolic changes induced by febrile response In addition to changes of the primary disease eliciting fever, a series of functional and metabolic alterations occur during fever because of the elevated body temperature.
29(2)Changes of metabolism (1)Functional changesCentral nervous system: excitabilityCardiovascular system: beat rate,cardiac output (1 oC beats/min)Respiratory system: hyperventilation/respiratory rate Digestive system: suppressed↓Immune system: anti-infection and anti-tumor activities (2)Changes of metabolismGenerally, the basal metabolic rate increases 13% while 1 oCelevation in body temperature.Consumption and catabolism of nutrients increase during fever:Carbohydrates, Lipid, Protein, Walter, Salts, Vitamines
305. Pathophysiological basis of prevention and treatment for fever Basic principles for fever treatmentEliminate the cause of a fever: e.g., antibiotics；Antipyretic therapy:High fever,children,pregnant wommen,patients with severe cardiopathySupport measures: fluid and nutrientsPhysical measures
32A 34-year-old man was well until 3 days prior to admission, where he noted the onset of fever, weakness, fatigue, headache, sore throat, and a cough productive of white sputum. One day prior to admission he awakened with burning chest discomfort that was made worse by coughing and by deep breathing. He developed shortness of breath and was seen at a university infirmary, where he appeared acutely ill with a fever. A chest radiograph demonstrated bilateral infiltrates consistent with pneumonia. An arterial blood gas analysis, done while the patient was breathing room air, was notable for significant hypoxemia. The patient’s shortness of breath increased markedly, and he was transferred to the hospital, where he was found to be cyanotic and febrile to C and to have a respiratory rate of 44/min with labored respirations. His sputum was grossly bloody with apparent clumps of tissure. Examination of the sputum revealed a grossly bloody background, numerous neutrophils, and sheets of gram-positive cocci in clusters. Despite appropriate antibiotic therapy and maximal intensive care support, the patient died.Questions:1.What disease did the patient suffer from: bacterial infection or viral disease?2. What pathogenic mechanism accounts for this patient’s fever?3. What alterations of metabolism and function may occur in a patient suffering from fever?