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• Fever is an induced increase of the body core temperature caused by a regulated elevation of the temperature set point evoked by changes in the neuronal activity of components localized in the preoptic area of the hypothalamus
• Categorization of fever


  • Low-grade: 37.3 to 38.0 C (99.1 to 100.4 F)
  • Moderate-grade: 38.1 to 39.0 C (100.6 to 102.2 F)
  • High-grade: 39.1 to 41 C (102.4 to 105.8 F)
  • Hyperthermia: Greater than 41 C (105.8 F)
• The Wealth of Nations was written in 1776
• Homeostasis of body temperature


  Body temperature is one of the physiological parameters continuously monitored and has a particular set point (a value around which the normal range fluctuates). The maintenance is achieved through negative feedback at all times.
• Thermoregulation


  • The human body regulates body temperature through thermoregulation (body thermostat: hypothalamus), in which the body can maintain its temperature within certain boundaries, even when the surrounding temperature is very different. The core temperature of the body remains steady at around 36.5–37.5 °C (or 97.7–99.5 °F).
• In the process of ATP production by cells throughout the body, approximately 60 percent of the energy produced is in the form of heat, which is used to maintain body temperature.
• Normal body temperature fluctuations


  Normal fluctuation is between 1°C and 1.3°C daily with: Lowest-noted temperature between 2 am and 8 am, Highest-noted temperature between 4 pm and 9 pm
• Body temperature measurement sites

  • Axillary temperature reading is 36o C
  • Oral is 36.5o C
  • Urine and tympanic is 36.6o C
  • Rectal is 37o C
• Factors influencing body temperature

  • Age
  • Activity level
  • Hormonal changes
  • Hydration status
  • Emotional state
  • Clothing and insulation
• Physiological response to increased body temperature

  1. Activating sympathetic cholinergic fibers innervating sweat glands, leading to increased sweat and increased heat loss

  2. Inhibiting sympathetic activity in blood vessels of the skin, causing blood to be shunted to the skin (vasodilatation) and an increased heat loss

  3. Decreasing the release of catecholamines from the adrenal glands and thyroid hormones from the hypothalamus, leading to a reduced metabolic rate

  4. Behavioural changes include reducing movements, adopting an open body position, removing clothing, and reducing appetite
• Physiological response to decreased body temperature

  1. Activating the sympathetic nervous system which causes vasoconstriction of skin arterioles, causing blood to bypass the skin and leading to a decreased loss of heat

  2. Piloerection (goosebumps) also occur, leading to heat-trapping

  3. Adrenal glands will release catecholamines (epinephrine, norepinephrine) and hypothalamus releasing thyroid hormones, leading to increased metabolic rate and heat production

  4. Activating the primary motor center in the posterior hypothalamus causes skeletal muscle contraction and shivering, leading to increased heat production

  5. Non-shivering thermogenesis using brown adipose tissue (BAT heat production) in the first six months of life

  6. Behavioural changes include increased movements, adopting a closed body position, adding clothing, and an increased appetite
• Body temperature is always "fairly close to normal level" by maintaining a balance between heat production and heat loss
• Basic physics of heat loss from the skin surface

  • Blood vessels are distributed profusely beneath the skin. Especially important is a continuous venous plexus that is supplied by inflow of blood from the skin capillaries. A high rate of skin flow causes heat to be conducted from the body core to the skin with great efficiency, whereas reduction in the rate of skin flow can decrease heat conduction from the core to very little.
• Clothing entraps air next to the skin in the weave of the cloth, thereby increasing the thickness of the so-called private zone of air adjacent to the skin and decreasing the flow of convection air currents. Consequently, the rate of heat loss from the body by conduction and convection is greatly depressed.
• Fever


  Fever is defined as a measured body temperature of at least 37.5℃. Fever is caused by circulating endogenous and/or exogenous pyrogens that increase levels of prostaglandin E2 in the hypothalamus. This process increases the physiologic "set-point" of body temperature.
• Etiologies of fever


  • Infectious (most common)
  • Drug-induced (drug-fever: penicillin, cephalosporins, antitubercular, quinidine, procainamide, methyldopa, and phenytoin; adjuvants in vaccines; synthetic lipopeptides)
  • Non-infectious (neurogenic, hyperthyroid, adrenal insufisiensi)
• Characteristics of febrile conditions

  • Chills: When the set-point of the hypothalamic temperature-control center is suddenly changed from the normal level to higher than normal (as a result of tissue destruction, pyrogenic substances, or dehydration), the body temperature usually takes several hours to reach the new temperature setpoint
  • Crisis, or "Flush": If the factor that is causing the high temperature is removed, the set-point of the hypothalamic temperature controller will be reduced to a lower value—perhaps even back to the normal level
• Hypothalamus


  The portion of the brain that maintains the body's internal balance (homeostasis). The hypothalamus is the link between the endocrine and nervous systems. The hypothalamus produces releasing and inhibiting hormones, which stop and start the production of other hormones throughout the body.
• Role of the Anterior Hypothalamic-Preoptic Area in Thermostatic Detection


  • Warmth & cold receptors from skin, deep tissues, spinal cord and hypothalamus
  • Heat loss center – Pre-optic & Anterior Hypothalamus
• Hypothalamus


  The portion of the brain that maintains the body's internal balance (homeostasis)
• Hypothalamus


  • It is the link between the endocrine and nervous systems
  • It produces releasing and inhibiting hormones, which stop and start the production of other hormones throughout the body
• Processes the hypothalamus helps stimulate or inhibit

  • Heart rate and blood pressure
  • Body temperature
  • Fluid and electrolyte balance, including thirst
  • Appetite and body weight
  • Glandular secretions of the stomach and intestines
  • Production of substances that influence the pituitary gland to release hormones
  • Sleep cycles
  • Behavioural and emotional responses
  • Coordination of the autonomic nervous
• Thermostatic detection


  1. Role of the Anterior Hypothalamic-Preoptic Area in Thermostatic Detection of Temperature

  2. Receptors - warmth & cold receptors from skin, deep tissues, spinal cord and hypothalamus

  3. Heat loss center – Pre-optic & Anterior hypothalamic nuclei

  4. Heat gain center – Posterior hypothalamus

  5. Preoptic region of the anterior hypothalamus is regarded as the thermostat. SET POINT is maintained by this region

  6. Injury abolishes heat loss/production
• Fever Pathway


  Neuronal Effector Mechanism that Changes Body Temperature
• Beneficial effects of fever

  • Endogenous pyrogens influence the recruitment and function of many types of immune cells
  • Endogenous pyrogens decrease the levels of trace metals available (iron and zinc) to help inhibit microbial reproduction
  • High temperatures (39°C–41°C) directly inhibit the growth of some bacteria and may also inhibit motility and capsule/cell wall formation
  • Increases antimicrobial activity of some antibiotics
• Adverse effects of fever

  • Direct cellular damage by cytokines and inflammation causes both local and systemic effects
  • Local effects: Cytokine stimulation, Inflammatory response, Vascular stasis, Extravasation, Edema
  • Systemic effect: Endotoxemia, Gut bacterial translocation, May provoke sepsis syndrome
  • Very high fevers (> 41°C) increase host metabolic demands and may result in congestive heart failure (CHF) and ischemia
• Acute neurologic and cognitive function may occur after an episode of hyperthermia. Specifically, the Purkinje cells in the cerebellar cortex are sensitive to heat damage, which can lead to long-lasting cerebellar dysfunction.
• Acutely, a hyperthermic patient will tend to be hypotensive with a high cardiac output due to blood redistribution and nitric-oxide-induced vasoconstriction. In severe fever, such as heatstroke, an electrocardiogram may show T-wave abnormalities, QT and ST changes, and conduction defects. In addition, serum troponin I levels may be significantly raised.
• Above 40 C (104 F), there is a reduction in blood flow to the GI tract. In addition, oxidative stress, denatured proteins, and damaged cell membranes are evident, increasing the potential for releasing pro-inflammatory cytokines, GI inflammation, and edema
• Elevated liver enzymes (AST/ALT) are observed in individuals with body temperatures above 40 C, with severe cases leading to permanent hepatocellular damage requiring a liver transplant.
• Patients with an increased body temperature are at a significantly greater risk for acute kidney injury (AKI). An increase in body temperature by only 2 C leads to a decrease in the glomerular filtration rate (GFR), which continues to fall with a further rise in temperature. Lab studies will show an increase in plasma creatinine and urea. Additionally, a hyperthermic state stimulates the renin-angiotensin-aldosterone system (RAAS), leading to a subsequent reduction in blood flow to the kidney
• Types of infection fever patterns


  • See link 1
  • See link 2
• Non-Infection causes of increased body temperature

  • Dehydration/hypohydration
  • Exercise
• Dehydration/hypohydration


  Hypohydration increases heat storage and reduces one's ability to tolerate heat strain. The increased heat storage is mediated by reduced sweating rate (evaporative heat loss) and reduced skin blood flow (dry heat loss) for a given core temperature.
• Exercise


  As exercise intensity increases: Heat production increases, Linear increase in body temperature (core temperature proportional to active muscle mass), Higher net heat loss (lower convective and radiant heat loss, higher evaporative heat loss)
• Pyrogens (fever-inducing agents)


  • Exogenous pyrogens: Microbial (Gram-negative bacteria, Gram-positive bacteria, Virus, Fungi), Non-microbial (Antigen-antibody complexes, Drugs)
  • Endogenous pyrogens: Interleukin-1 (IL-1), Interleukin-6 (IL-6), Tumour Necrosis Factor alpha (TNF-α), Interferon (INF)
• Prostaglandins (PGs)


  Eicosanoids derived from eicosa (20-carbon) polyenoic fatty acids (>2 cis double bonds). They include Prostanoids (Prostaglandins, Prostacyclins, Thromboxanes), Leukotrienes, and Lipoxins.
• Prostaglandin Biosynthesis


  1. PLA2: Phospholipase A2

  2. COX-1: cyclooxygenase-1 (Constitutive)

  3. COX-2: cyclooxygenase-2 (Inducible)

  4. Lipoxygenase

  5. cortisol, NSAID
• Four principal bioactive PGs generated in vivo: PGD2, PGE2, PGF2, PGI2
• Comparison of the COX-1 and COX-2 Isoforms. Note the cell who expresses COX-2. This concept is used for anti-inflammatory drugs development