"Fever Chapter 6 professor Deng yu bin department of pathophysiology ????? ?????????????? set point ?????????"
Fever Chapter 6 professor Deng yu bin department of pathophysiology 发热的概念 由于致热原的作用使体温调定点 (set point)上移而引起的由调节性 体温升高（超过0.5℃）的全身性病 理过程。 Definition : fever refers to a pathologic sustained or intermittent elevation of body temperature occurring in the course of disease . Cause : set-point↑(hypothalamic) thermostat temperature↑(>0.5℃), hyperthermia : set-point at normothermic level Heat stroke ( heat production >heat loss) Normal body temperature is the result of a maintained balance between heat production and heat loss. The hypothalamus act as a thermostat or set –point . Core temperature is defined as the temperature of the blood at the hypothalamic level . Oral and rectal temperature can reflect core temperature . Hypothalamic temperature control is more often regulating the amount of heat loss by vasodilation and evaporation . Pathological Elevation of body temperature A pathologic elevation of the body temperature above the normal range is called fever in general or hyperthermia in special cause .Three basic mechanisms can produce an elevation of the body temperature above the normal range : ①elevation of the set-point ②heat production and /or gain of heat from the external environment exceeding the body’S capacity for heat loss; or ③primary failure of temperature regulation . Fever is an elevation of temperature above the normal amplitude of daily variation , and results from the malfunction of temperature regulating control center . Hyperthermia is an elevation of body temperature that occurs regardless of the hypothalamic set-point . Hyperthermia may result from changes within the body (endogenous) or by changes in the environment (exogenous). The comparison between hyperthermia and fever Hyperthermia fever 1) Arising from changes 1) resulting from within the body pryrogens or by changes in 2)ability to regulate environment set-point remains 2)set-point remains intact ,but is turned unchanged or damaged up at a high levels or effector organs fails functionally 3)body temperature may 3) body temperature rise to very high Level reaches higher level 4) treatment with water- 4)treatment with alcohol bathing antipyretics and drugs to eliminate the cause 发热的原因 感染性发热：各种病原体 发热 非感染性发热 发热的原因 细菌 病毒 感染性发热： 支原体 各种病原体 立克次体 螺旋体 真菌 寄生虫 发热的原因 机械、理化因素损害 无菌性坏死 血管闭塞 非 组织的吸收 溶血 感 染 性 肿瘤 发 变态反应 热 其它 Etiology and classification of fever In most instances fever is cause by pyretic substances. 1)infectious fever The infectious fever is caused by various kinds of infectious microorganisms such as bacterium, virus, mycoplasma, rickettsia, fungus and spirochete. Endotoxin 2. Non –infectious fever 1) neoplasm Hodgkin’s leukemia 2) hypersensitivity diseases collagen vascular disease 3)bacteria–free inflammation burns ,trauma , operation , radiation 内生致热原 概念： 产EP细胞在发热 种类： 激活物的作用下，产 1.白细胞介素-1 生和释放的能引起体 2.肿瘤坏死因子 温升高的物质，称为 3.干扰素 内生致热源。 4.白细胞介素-6 Pathogenesis of fever Pyrogen is a substance that can cause fever. Exogenous pyrogen are derived from outside the host . The characteristics of fever induced by these agents vary with respect to time of onset (latency) and duration ,but the mechanisms involved in the production of fever appear to be quite similar in most instances . ①large molecular LPS > 3000000daltons ②can not penetrate blood-brain barrier ③target cell – WBC ④ endotoxin – heat resistant all gram-negative bacteria endotoxin LPS Gram –positive organisms exotoxins ; antibodies; antigen-antibody complexes Endogenous pyrogen Source: macrophages monocyte ; T lymphocyte activation ① small molecules , 15000daltons ② easy to pass brain –brain blood barrier ③ heat –irresistible Endogenous pyrogen cytokines Il-1 and TNF are the most potent EPs in humans. Il-1 acts on many types of cell and result of these actions is to produce fever, tissue catabolism, IL-1 has pyrogenic activity . Tumor necrosis factor Interferon Interleukin 6 Macrophage inflammatory protein-1. The endogenous pyrogens cause fever by their ability to initiate metabolic changes in the hypothalamic thermoregulatory center. Site of action of endogenous pyrogen EP hypothalamic thermoregulatory center (OVLT) organ vasculosa lamina terminals . Cytokine cascade It is now established that pyrogenic cytokines stimulate release of the arachidonic acid product , prostaglandin E2 (PGE2 ), which apparently up-regulates the set-point of the thermoregulatory center in hypothalamus to produce fever . Once the PGE2 levels in hypothalamus is elevated , a cascade of changes in monoamines , cAMP , and calcium ion is triggered that raise the set-point in hypothalamus . Prostaglandins Monoamines Cyclic adenosine monophosphate (cAMP) Na+/Ca ++ ratio↑ fever Serotonin (5-HT) Neuronal Mechanisms The activities of thermally sensitive neurons after systemic injection of endotoxin or endogenous pyrogens are so changed that warm-sensitive neurons decrease their activity (heat loss mechanisms are depressed ) while cold sensitive neurons increase their activity , and as a result , fever occurs . In summary , microbial agents, inflammatory agents and other exogenous pyrogens induce the synthesis and release of endogenous pyrogens (pyrogenic cytokines ) from a variety of cells . These cytokines , in turn , trigger specialized endothelial cells of the hypothalamic vascular organs to release PGE2 , which then brings about increases in cAMP , monoamines , and calcium ion in the thermoregulatory center of the hypothalamus , resulting in a resetting of the thermostatic temperature from normothermia to febrile levels . These neurotransmitters then activate the vasomotor center , which bring about vasoconstriction (heat conservation ) and increased heat production , both resulting in an increase in blood temperature . Upper limit of fever upper limit of fever ①warm-sensitive neurons reach peak at 42℃,cold -sensitive neurons reach nadir at 42 ℃ ②antipyretics arginine vasopressin (AVP) and α-melanocyte-stimulating hormone . It is clear that human core temperature is almost never permitted to raise higher than 41℃~42℃ . The firing rates of warm-sensitive neurons reach their peak and cannot be increased further in response to temperature of 42℃. Similarly, the firing rates of cold-sensitive neurons reach their nadir at 42℃ and cannot decrease further if temperature increase above 42℃. It is also possible that antipyretic substances that antagonize the actions of endogenous pyrogens play an important role in this process. arginine vasopressin(AVP) and α- melanocyte-stimulating hormone(α- MSH) 发 体温上升期 产热>散热 热 调定点上移 的 高温持续期 产热＝散热 时 相 体温下降期 产热<散热 调定点恢复正常 发热的时相 39.5 ℃ 37.5℃ Manifestations of Fever Periods of fever (1)The fervescence period ①feels cold.Sweating ceases,vasoconstriction occurs ②the skin is cold and pale. metabolism increases, muscle tone increases, and shivering ③chills ④the tidal volume decreases ⑤hypotension (2) The persistent febrile period. At this point the person has no subjective feeling of being cold or hot, but the skin may feel warm to touch. therefore the rate and depth of breathing and the heart rate increase to deliver more oxygen to the tissues. Cutaneous vasodilation proceeds rapidly, and the flush phase begins. The respiratory activity increases during fever. The respiratory alkalosis is the more common finding. The cardiac output is increased due to rises of rate and force of heart-beats. Insensible water loss increases due to the increased body temperature and increased ventilation. water deficit convulsive seizures Headache Anorexia increased utilization of fat and increased breakdown of body proteins for energy, The increased protein catabolism causes increased urinary excretion of nitrogen,muscle wasting,and weakness. (3)The defervescence period. Therefore the person feels hot and mechanisms to decrease heat production and increase heat loss are instituted. sweating skin is warm and flushed. If water supply is not sufficient, dehydration may occur in this period. Types of fever ① Remittent fever ② Irregular fever ③ Sustained fever ④ Intermittent fever Grades of fever low fever (37.5-38℃), mild fever( 38-39℃ ) high fever(39-41℃ ) superhigh fever >41 ℃. Abnormal laboratory findings The laboratory changes in febrile patients include changes in white blood cells, proteins and certain hormones. Acute phase response ①polymorphonuclear leukocytosis ②increases in plasma levels of fibrinogen, C-reactive protein, haptoglobin, ceruloplasmin, and alpha-l-acid glycoprotein . ③ increases in plasma levels of lactoferrin . ④ decreases in plasma iron and zinc levels and increases in plasma copper levels. Erythrocyte sedimentation rate(ESR) neutrophil count Low iron an increase in urinary calcium. Aminoaciduria and proteinuria 发热时的代谢变化 代谢加强 糖代谢 脂肪代谢 蛋白质代谢 水盐代谢 维生素代谢 发热时机体功能改变 中枢神经系统 循环系统 呼吸系统 消化系统 防御功能 Role of Fever 1)It appear likely that a functional interrelation occurs between the two biological properties pyrogenicity and T- cell mitogenecity of IL-1 . 2) Fever provides an internal environment that can inhibit proliferation of infecting microorganisms . Iron and zinc During fever ,plasma iron and zinc ion levels fall sharply . However,If the fever is overhigh or very prolonged , It is harmful to body . Beneficial ①T cell miigene city of IL-1 . ②Temperature↑ inhibit proliferation of harmful microorganisms , overhigh , very prolong 发热治疗的病理生理学基础 处理原则 1.治疗原发病。 2.一般发热不必急于解热 必须及时解热的病例 解热措施 1.药物 2.物理降温 Principles of Therapy for fever In view of the fact fever may be of some benefits , perhaps one should be less enthusiastic about lowering milder levers of fever . Aspirin lowers fever by preventing pyrogen-induced prostagladin synethesis from phagocyte . The most common is ice water or alcohol sponging 发热激活物 发 刺激 产EP细胞 热 合成释放 EP 的 体温调节中枢 机 合成 制 中枢发热介质（正调介质、负调介质） SP上移 运动神经 交感神经 骨骼肌 皮肤血管 产热增多 散热减少 体温上升 重要的急性期反应蛋白 成分 分子量 血浆浓度（mg/ml) 炎症浓度 C-反应蛋白 105000 <0.5 >1000倍 血清淀粉样A蛋白 160000 <10 >1000倍 α1-酸性糖蛋白 40000 55~140 2~3倍 α1-抗糜蛋白酶 68000 30~60 2~3倍 结合珠蛋白 100000 40~180 2~3倍 补体 180000 80~120 50%