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Fever thermometer 1.Introduction 2.Causes and mechanisms of fever

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1 Fever thermometer 1.Introduction 2.Causes and mechanisms of fever
3.Febrile phases and the characteristics of thermo-metabolism 4.Functional and metabolic changes induced by febrile response 5.Pathophysiological basis of prevention and treatment for fever

2 1. Introduction Set point of hypothalamic thermostat:
(1) Normal body temperature ~37℃(98.6 F)with a variation ~1C Axillary C Oral C Rectal C (2)Regulation of normal body temperature (homeostasis) Thermoregulatory center: mainly located in hypothalamus Set 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℃)

4 An elevation of body temperature is fever?
36 ℃ 40 ℃ Physiologic elevation of body temperature

5 A pathologic elevation of body temperature is fever?
Hyperthermia Heatstroke Hyperthyroidism Central nervous system damage

6 (4) Types of body temperature elevation
Physiological elevation before menstruation severe exercise stress Pathological elevation Fever(发热), e.g. Infection diseases Hyperthermia(过热), e.g. heatstroke

7 (5) Fever Fever 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 pyrogens Regulated 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 heat impediment in heat loss dysfunction of body temperature center Features: Passive increase of body temperature >0.5 C Body temperature beyond the unchanged setpoint

9 Comparison between hyperthermia and fever
Arising from changes within the body or by changes in environment Resulting from pyrogen Set-point remains unchanged or damaged, or effector organs fails Ability to regulate set-point remains intact, but is turned up at a high level functionally Body temperature may rise to a very high level Rise of body temperature has an upper limit Treatment with water-alcohol bathing Treatment with antipyretics and measures, and drugs to eliminate the causes

10 2. 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 activator fever-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.

12 Category of pyrogenic activator
Infectious factors: microbes and microbial products G- bacteria: Lipopolysaccharide (LPS)/Endotoxin G+ bacteria: Exotoxins; Peptidoglycans, Lipoteichoic acid (LTA) Viruses Other microorganisms Non-infectious factors: Antigen-Antibidy complexes Components of the complement cascade Non-infectious inflammation-genesis irritants Certain steroids: etiocholanolone(本胆烷醇酮)

13 (2)Endogenous pyrogen (EP)
Concept of EP EPs 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.

14 EP generating cells Category of EPs Monocyte Macrophage T lymphocyte
Kupffer cells Endothelia cells Some tumor cells Category of EPs Interleukin-1 (IL-1) Tumor necrosis factor (TNF) Interferon (IFN) Macrophage inflammatory protein-1 (MIP-1) Interleukin-6 (IL-6) Others

15 Endogenous Pyrogenic cytokines
EPs Principle source Inducers IL-1a IL-1b Macrophages and other cell types LPS,TNF, Other microbial products TNF-a TNF-b Macrophages Lymphocytes(T&B) LPS, Other microbial products antigen, mitogen stmulation IFN- a IFN- b IFN-g Leukocytes Fiboblasts T-lymphocytes LPS, viral infection IL-6 Many cell types LPS, TNF MIP-1a MIP-1b LPS IL-8 LPS, TNF, IL-1

16 Production 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 release Exotoxin (G+ bacteria)---APC/T cell receptor (TCR)---PTK---pathway:PLC, Ras


18 (3)Mechanisms of setpoint elevation by EP
Thermoregulation center Positive regulation center Preoptic region of anterior hypothalamus (POAH,视前区-下丘脑前部): Temperature-sensitive neurons ---Cold sensitive neuron ---Warm sensitive neuron Negative regulation center Medial amygdaloid nucleus (MAN,中杏仁核) Ventral septal area (VSA,下丘脑腹隔区)

19 The routes for EP signals into
the thermoregulatory center of hypothalamus Organum 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 barrier Vagal afferent nerve fibers

20 The Role of OVLT in pathogenesis of fever
EP Macrophage OVLT neuron POAH neuron Supraoptic recess Third ventricle of brain Chiasma of optic nerves Capillary OVLT area PGE2 Cells of ventricle tubal membrane

21 The 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.

22 Central mediators of fever
The positive regulatory mediators  Prostaglandins (PGE2)  Corticotropin releasing hormone (CRH) The ratio of central Na+/Ca2+ cAMP Nitric oxide (NO) The negative regulatory mediators Febrile 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)

23 (4) Pathogenesis of fever
Pyrogenic activators: microorganisms, non-microbial pyretic substances Fever Heat conservation; heat production EP-producing cells: Monocytes/macrophages, endothelial cells, etc Elevated thermoregulatory set point Hypothalamus thermoregulatory center: Central mediators of fever (Positive:PGE2,CRH,cAMP,Na+/Ca2+,NO; Negative: AVP, α-MSH, Lipocortin-1) Endogenous pyrogens (EP)/ pyrogenic cytokines: IL-1,6, TNF, IFN,MIP-1,etc OVLT , BBB, Vagus nerve

24 3. Febrile phases and the characteristics of thermo-metabolism

25 Three stages of fever (typical)
The setpoint is restored to the normal level The setpoint is raised to a higher level Effervescence period Heat production↑ heat loss ↓ 体温上升期 Defervescence period Heat loss ↑ heat production↓ 体温下降期 Persistent febrile period Heat equipoise at a higher level 体温持续期

26 Manifestations of fever
Effervescence period Heat production↑: shivering, brown adipose tissue, basal metabolic rate Heat loss ↓: feeling of being cold, skin is cold and pale (vasoconstriction), piloerection, goose flesh Persistent febrile period Heat equipoise at a higher level: shivering ceases, sensation of warmth, cutaneous vasodilation occurs, skin becomes warm and flushed. Defervescence period Heat loss ↑, heat production↓:sweating, etc.

27 Fever patterns Intermittent 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.

28 4.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 changes Central nervous system: excitability Cardiovascular 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 metabolism Generally, the basal metabolic rate increases 13% while 1 oC elevation in body temperature. Consumption and catabolism of nutrients increase during fever: Carbohydrates, Lipid, Protein, Walter, Salts, Vitamines

30 5. Pathophysiological basis of prevention and treatment for fever
Basic principles for fever treatment Eliminate the cause of a fever: e.g., antibiotics; Antipyretic therapy: High fever, children, pregnant wommen, patients with severe cardiopathy Support measures: fluid and nutrients Physical measures

31 Case study

32 A 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?

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