CNS Physiology Temperature Regulation PDF

RCSI Royal College of Surgeons in Ireland Coláiste Ríoga na Máinleá in Éirinn Temperature Control [email protected] Class Year 2 Semester 1 Course CNS Code CNS Title Temperature Control Lecturer...

RCSI Royal College of Surgeons in Ireland Coláiste Ríoga na Máinleá in Éirinn Temperature Control [email protected] Class Year 2 Semester 1 Course CNS Code CNS Title Temperature Control Lecturer Prof David Henshall (RCSI-IE): Dr. Colin Greengrass (RCSI-BH) Date 30.11.2023  LEARN THE MECHANISM /SYSTEM/ PROVIDES CONTEXT OR LINKED LEARN THE CONTENT OF PRINCIPLE SHOWN ON THIS SLIDE, BUT CONTEXT. READ ONCE TO THIS SLIDE NOT ALL THE DETAILS ESTABLISH CONTEXT DON’T FORGET THE SIGNS ALO387 Recognise the main mechanisms of heat transfer ALO388 Discuss the mechanisms of heat gain and loss in the body ALO389 Describe how heat is sensed (warm and cold receptors) ALO390 Describe the role of the hypothalamus in regulating temperature ALO391 Explain the coordinated response to hot and cold ALO392 Explain the causes of temperature change in fever Learning Objectives  Thermoregulation: The process of maintaining an Thermoregulation internal balance between heat production and heat loss. Thermoregulation is a complex homeostatic function involving multiple body systems. It is essential for preserving the optimal conditions for biochemical reactions and physiological processes, crucial for health and survival.  Homeothermic refers to the ability of the human body to HOMEOTHERMIC maintain a relatively constant internal body temperature regardless of external environmental conditions  Homeotherms maintain a stable internal temperature. Poikilotherms’ body temperature varies with the environment.  ADVANTAGES TO BEING HOMEOTHERMIC Homeothermic animals (and humans) can adapt metabolically to environmental challenges. The advantages of homeothermy include the ability to sustain metabolic processes and adapt to environmental challenges Homeotherms are relatively unaffected by changes to ambient temperature Can function in subzero conditions Disadvantages – Expend (chemical) energy to maintain homeothermic condition – Complex regulatory systems Normal Human Body Temperature The average normal body temperature for a healthy adult human when taken orally is approximately 37°C (98.6°F). The 37°C set-point is an average; individual variations exist. Understanding the factors affecting this set-point is essential for clinical assessment and management of thermoregulatory disorders. Temperature regulation: first principals Humans ~37oC (98.6F)* Daily variation in range 35.5oC -37.7oC Above 37.8: protein denaturation, cell damage Below 35.5oC: compromised metabolic function (but generally less harmful) *taken by mouth – temperature varies internally from organ to organ Consequences of Deviations in Body Temperature Temperature (°C) Consequence 40-44 Heat stroke, brain lesions 38-40 Fever or exercise 36-38 Normal range 34-36 Mild hypothermia 30-34 Impairment of temperature regulation 27-29 Cardiac fibrillation 30-34 [hypothermia] at these temperatures, the body's physiological responses to maintain normal temperature begin to fail. This impairment can include reduced or ineffective shivering, diminished consciousness, and a slowing of metabolic processes.  Variation in Body Temperature Body temperature fluctuates daily between 35.5°C and 37.7°C, influenced by circadian rhythms. Body temperature is at its lowest in the early morning and peaks in the late afternoon. Circadian fluctuations are driven by changes in metabolic rate and hormone levels, such as cortisol and melatonin.  Measuring Body Temperature Body temperature can be measured orally, axillary (armpit), rectally, and in the ear Each temperature measurement method has implications for clinical interpretation. For example, rectal temperatures are closer to core temperature (averages 0.56oC) higher. Rectal ToC can accurately assess hypothermia or hyperthermia but can be inconvenient.  Typical Site of Measurement Temperature Range Advantages Disadvantages Easily accessible, relatively Can be affected by recent food Oral 36.5°C to 37.5°C accurate for core or drink intake; not suitable for temperature patients who are unconscious Less accurate, can be Non-invasive, safer for use in Axillary (Armpit) 35.9°C to 37.0°C influenced by external factors children like room temperature Considered most accurate Rectal 37.0°C to 38.1°C Invasive, uncomfortable, for core body temperature Can be affected by earwax, ear Quick and easy to use, less Tympanic (Ear) 35.8°C to 38.0°C infections, or improper invasive placement of the thermometer Core vs. Shell Temperature The core (vital organs and CNS) maintains a stable temperature, while the shell (skin and extremities) is more variable. The core-shell model of temperature regulation is vital for understanding different heat exchange mechanisms. The core is protected by vasoconstriction and countercurrent heat exchange in the extremities to minimise heat loss.  Enzyme activity fluctuates as a Maintaining stability of core function of changes in temperature Heat input: We need to maintain body External environment temperature at a level optimal for Internal heat production (main) cell metabolism Metabolic activity Movement-generated heat Heat Output Exposed body surfaces Balance affected by: – Changes to internal heat production (e.g. exercise) – Changes in external environment To If Core To decreases: heat production increases, heat loss minimized If Core To increases: increase heat loss, decrease heat production Heat Production: Muscular Activity Muscle contractions during physical activity significantly increase heat production. Muscular thermogenesis, including both exercise-associated and shivering-induced heat production, is a critical response to cold stress. It is increased by thyroxine and catecholamines. During exercise, tremendous heat production due to (friction) caused by contraction of muscles (up by 2.3oC)  Heat Production: Metabolism Heat is a byproduct of metabolic reactions, predominantly during the breakdown of food and muscle use. Metabolic heat production is a function of basal metabolic rate and the thermic effect of food. Thyroid hormone levels and sympathetic nervous system activity are key regulators of these metabolic processes. Heat produced during metabolic oxidation of foods and exercising muscles (friction-generated heat). ~333 kilojoules/h at rest = this will raise the temperature of a 70kg human by 1.4 oC ΔT=334,720J/ (70kg×3470J/kg°C) Heat Input and Output Heat balance is a dynamic process involving heat input from metabolic processes and external environment, and heat output through various mechanisms." Thermal equilibrium is maintained by the balance between heat produced internally and heat lost to the environment. This balance is orchestrated by the central nervous system, integrating internal and external thermal signals. Model of energy transfer from the body to the environment Heat Transfer Principles The body follows the same physical principles of heat transfer as inanimate objects, moving heat from warmer to cooler areas. Heat is gained or lost through: Radiation Conduction Convection Evaporation Understanding the principles of heat transfer is essential for clinical scenarios such as managing hypothermia, burns, or fever. Body Heat Emission and Invisible Photons (Infrared) This body scan Metabolic Heat Generation: Cellular metabolism measures intensity of predominantly involves exothermic reactions, such infrared light (heat) as oxidative phosphorylation, which is accompanied by colour and not by heat generation. frequency of light The thermal energy elevates the vibrational energy Otherwise, you would have a glowing orange back states of intracellular water molecules and other biomolecules. These molecules return to their ground state, they emit photons in the infrared spectrum (700 nm to 1 mm wavelength), a form of electromagnetic radiation beyond the visible light spectrum. Mechanisms of Heat Transfer: Radiation Radiation: The human body constantly emits infrared radiation, Body heat is emitted as infrared radiation and is a significant source of heat loss. sun Body emits (heat loss) and absorbs (heat gain) radiant energy Net transfer depends on ambient temperature Transfers from warmer to cooler Sources of gain: sun, heater Sources of loss: furniture, building walls Humans tend to lose ~50% heat energy through radiation  Mechanisms of Heat Transfer: Conduction Transfer of heat between objects of differing temperature that are in direct contact Warmer object transfers to cooler Faster-moving “warmer” molecules agitates cooler molecule and warms it up, in turn losing some thermal energy – actually, it transfers some of it’s kinetic energy Rate according to Temperature difference Thermal conductivity (air is poor, water is good) In clinical practice, conductive heat loss is relevant in situations where patients are in contact with colder surfaces, as in operating rooms or when immobilized on cold surfaces.  Mechanisms of Heat Transfer: Convection Transfer of heat by air (or H2O) currents Warm air is less dense than cold air Warm air rises away [from skin], replaced by cooler air Process carries heat away from body Can be enhanced by forced air movements Wind, fan, riding a bike “wind chill factor” Mechanisms of Heat Transfer: Evaporation Heat loss from an object through evaporation of water from its surface Heat needed to transform water from liquid to gaseous state is absorbed from the skin – an endothermic process Cools the body Sites: respiratory airways, lining of mouth, skin “insensible” water loss – not subject to control Mechanisms of Heat Transfer: Evaporation Evaporative heat loss is critical during hypermetabolic states, fever, or exercise. The effectiveness of evaporative cooling is modified by ambient humidity and air flow.  Heat Loss Through Breathing Pulmonary Heat Loss: When we inhale, the air entering our respiratory system is typically cooler and drier than the conditions within our body. As this air travels through the respiratory tract, it gets warmed and humidified before reaching the lungs. This process of warming and adding moisture to the inhaled air requires energy, which is in part derived from the body's heat. As a result, heat is lost from the body to the air during this process.  Thermoregulatory system Homeostatic system > requires anticipatory controls and negative feedback Thermal sensors Afferent pathways Integration system in CNS Efferent pathways Target organs that control heat muscles, sweat glands  Core vs shell From thermoregulatory viewpoint body has core & shell Core: heat-generating. Internal organs, CNS and skeletal muscle (37.8oC) To in core is quite constant & subject to precise regulation – Contains sites of internal heat production & set point control Shell: insulating & exchanging: Skin & subcutaneous fat Exchanges heat according to ambient To and momentary insulating capacity of shell To in shell generally cooler & varies substantially – E.g. skin 20oC-40oC, without damage – Peripheral effector site(s) of thermoregulatory mechanisms  MAIN PHYSIOLOGIC MECHANISMS FOR REGULATING TEMPERATURE Metabolic activity Vasomotor responses constriction & dilation of skin vessels Sweating involuntary Shivering “Brown fat” metabolism Hair-raising Behavioural voluntary  VASOMOTOR RESPONSES To conserve heat: Skin vessels (arterioles) constrict (vasoconstriction) to reduce (warm) blood flow skin is excellent insulator To lose heat: Heat-induced vasodilation enhances blood flow to the skin, promoting heat loss. controlled by the inhibition of sympathetic vasoconstrictor activity.  VASOMOTOR RESPONSES Regulating blood flow through small vessels in skin by adjusting calibre – Heat loss/gain by radiation and conduction- convection To conserve heat: Skin vessels (arterioles) constrict (vasoconstriction) to reduce (warm) blood flow (range: 400-2,500 ml/min) Keeps blood in central core Cold, relatively bloodless skin is excellent insulator To lose heat: Vasodilation – active process to reduce temperature Thermoneutral zone Range within which core To maintained by vasomotor responses alone – without the need for shivering/sweating  SWEATING Physiological Responses to Heat Active evaporative heat-loss process – Regulated, continually adjusted Sweat: dilute salt solution extruded by sweat glands – Glands can produce 2L/hr Sweat cools body when water evaporates Affected by relative humidity of surrounding air High humidity means air is saturated with H 20 Limits ability to take up additional moisture  Physiological Responses to Heat SWEATING Sweat gland innervated by an acetylcholine- secreting sympathetic nerve. A primary protein-free secretion is formed by the glandular portion, but most of the electrolytes are reabsorbed in the duct, leaving a dilute, watery secretion.  Physiological Responses to Heat SWEATING Sweat Production in Glandular Cells: Primary Sweat Formation: In the secretory coil of the eccrine gland, the glandular cells actively transport ions like sodium and chloride into the lumen, creating an osmotic gradient that draws water into the lumen through osmosis. Isotonic Fluid: Initially, the sweat is an isotonic fluid, similar in composition to plasma. Modification in Ducts: Ion Reabsorption: As sweat moves through the gland's ducts towards the skin surface, some ions, particularly sodium, are reabsorbed, making the sweat hypotonic (less salty) by the time it reaches the skin surface. Excretion onto Skin Surface: Pore Release: The diluted sweat is then excreted onto the skin surface through the pores. Influence of Humidity on Thermoregulation Humidity affects the body's ability to lose heat through evaporation. High humidity levels can significantly impair this mechanism, leading to heat retention and possible heat stress. Physiological Responses to Heat Responses to Shivering is an involuntary muscle activity triggered Cold: Shivering by the hypothalamus in response to cold. Primary involuntary mechanism of heat production Skeletal muscle activity generates heat Body “harnesses” principal to generate heat by “shivering” Rhythmic, oscillatory (10-20/s) skeletal muscle contractions and increased muscle tone All [chemical] energy liberated converted to heat because no work is accomplished Can increase internal heat 2-5 fold in sec-min Physiological Responses to Cold  Other mechanisms Physiological Responses to Cold Stimulating “brown fat” metabolism Heat-generating chemical activity Animals and newborns Role in adult human undetermined Hair-raising (piloerection) Animals w/fur or feathers Contraction of tiny muscles at base of hair/feather Lifts hair off skin, traps air which warms Low density of hair in humans means ineffective Responses to Cold: Behavioural Changes Heat-avoiding behaviour Find shade, water Heat-generating behaviour More clothing etc Change physical activity Decrease movement Increase skeletal activity (hand-clapping, jumping up and down) Metabolic Rate and Thermoregulation The basal metabolic rate influences heat production; a higher metabolic rate produces more heat. The basal metabolic rate (BMR) is influenced by factors such as thyroid hormone levels, which in turn affect heat production. A higher BMR results in greater heat generation. Thermoregulatory Feedback Mechanisms The body uses feedback mechanisms to regulate heat production and heat loss to maintain a stable core temperature. Thermoregulatory feedback involves afferent signalling to the hypothalamus, integration of thermal information, and efferent responses to adjust heat production and loss, maintaining thermal homeostasis. Thermoregulation: central control & detection Temperature detection and set-point controlled by peripheral and central nervous system. Comprises peripheral & core thermoreceptors and a central control (hypothalamus) Peripheral thermoreceptors: monitor skin To Core thermoreceptors: located in hypothalamus, CNS and internal abdominal organs Send afferents to hypothalamus Peripheral Thermoreceptors Peripheral thermoreceptors in the skin sense external temperatures and relay information to the hypothalamus. Peripheral thermoreceptors located in the skin, mucous membranes, and other tissues provide the CNS with critical information about external temperature conditions.  Central (or Core) Thermoreceptors Central thermoreceptors, located in the hypothalamus and other internal organs, monitor the body's core temperature. Central thermoreceptors, including those in the hypothalamus, spinal cord, and abdominal organs, monitor the temperature of the blood and internal tissues, providing feedback on internal thermal states. Mechanisms of Signal Transduction Thermal Sensitivity: The terminal endings of these neurons contain ion channels that are sensitive to temperature changes. These are known as Transient Receptor Potential (TRP) channels. Different types of TRP channels respond to different TRPM8 temperature ranges. For example, TRPV1 is activated by high temperatures, while TRPM8 responds to cold. Activation of TRP Channels: When the ambient temperature reaches the threshold that a particular TRP channel is sensitive to, the channel opens. This opening allows the flow of ions (such as calcium and sodium) into the neuron, leading to depolarization of the membrane. TRPV1 What is the mechanism of Temperature sensitivity? (Cold fibres) 2+ TRPM8 is a Ca -permeable nonselective cation channel TRPM8: Transient receptor potential melastatin 8 channel, is a non- selective cation channel that can be activated by cold temperatures and menthol. TRPM8 contains temperature-sensitive “Free” non-specialized nerve endings, slower conducting fibres. Temperature sensitivity arises from receptor/channel domains that undergo a conformational openings in nerve endings change in response to cold. It is likely that the warmth causes a fluctuation in the open-closed state, but cold stabilises the open state (exact mechanism still unknown) What is the mechanism of Temperature sensitivity? (ex. Cold fibres) TRPM8+/+ (Wild Type) Mice with two copies of the functional TRPM8 gene. Exhibit normal TRPM8 expression and function. Show robust firing rates in response to decreasing temperatures, indicating functional cold sensing. TRPM8+/- (Heterozygous) Mice with one functional copy and one non-functional or deleted copy of the TRPM8 gene. Exhibit reduced TRPM8 expression compared to wild type. Show an intermediate firing rate response to cold, indicating partial +/+ = both copies functionality of cold sensing. +/- = only one copy -/- = no copies TRPM8-/- (Knockout) Mice with both copies of the TRPM8 gene non-functional or deleted. Lack functional TRPM8 channels. Do not show a firing rate response to cold, indicating a loss of cold sensing through the TRPM8 pathway.  Heat Receptors Receptor General MoA Temperature Range Other Responses Distribution Activated by capsaicin, Found in nociceptive neurons Opens in response to heat, allowing cation influx, TRPV1 >43°C protons, and inflammatory in the peripheral nervous primarily Ca2+ and Na+. mediators. system. Located in the CNS and PNS, Similar to TRPV1 but with a higher threshold for Sensitive to stretch and TRPV2 >52°C also in macrophages and activation. pressure. vascular smooth muscle cells. Responds to warm temperatures, gating allows Warm temperatures (>33°C to Activated by skin care Expressed in skin TRPV3 cation influx. 40°C) pancreatic β-cells. Temperature sensitive neurons Generation of Action Potentials: If the depolarization is sufficient to reach the threshold potential, it will trigger an action potential. This is an all-or-nothing electrical signal that travels along the neuron's axon to the central nervous system. Temperature- sensitive neuron firing changes (eg. Cold fibres) Thermoregulatory Centre: The Hypothalamus The hypothalamus acts as the body's thermostat, integrating signals from the body and initiating responses. The hypothalamus integrates inputs from peripheral and central thermoreceptors and orchestrates an appropriate thermoregulatory response via the autonomic nervous system, endocrine system, and behavioural mechanisms. Detectors of temperature located in hypothalamus Thermoregulatory Continuously receive Centre: The info from core & periphery, adjusting Hypothalamus mechanisms to keep core stable Can respond to changes of as little as 0.01oC The hypothalamic neurons’ firing depends on local temperature warm-sensitive neurons and cold-sensitive neurons also respond to signals from periphery (e.g. skin thermoreceptors) Anterior Hypothalamus Role Thermal Sensitivity: Detects heat. Heat Dissipation: Neurons sensitive to increased blood temperature. Initiates responses like vasodilation and sweating. Posterior Hypothalamus Cold Response: More involved in cold temperature responses. Activates heat-conservation and generation mechanisms (e.g., shivering, vasoconstriction). Hypothalamus: thermoregulatory integrating centre Anterior region: mediates decreases in body temperature Triggers heat loss reflexes Posterior region: mediates increases in body temperature Triggers heat production & conservation Evidence? – Electrical stimulation of AH causes dilation of blood vessels, panting and stops shivering – Ablation/lesion of AH cause chronic hyperthermia – Electrical stimulation PH produces shivering (etc) – Ablation/lesion of PH cause hypothermia (when animal is exposed to colder-than-room temperature) *some studies report cold-sensitive neurons also in posterior hypothalamus  Skin To Core To Peripheral Central thermoreceptors thermoreceptors Post. Hypothalamus Behavioural Motor neurones Sympathetic NS Sympathetic NS adaptations Skeletal muscles Skin blood vessels Sweat glands Muscle tone, Skin shivering vasoconstriction Sweating Control of heat production/loss Control of heat production heat loss heat loss  Skin To Core To Peripheral Central thermoreceptors thermoreceptors Ant. Hypothalamus Behavioural Motor neurones Sympathetic NS Sympathetic NS adaptations Skeletal muscles Skin blood vessels Sweat glands Muscle tone, Skin shivering vasodilation Sweating Control of heat production/loss Control of heat production heat loss heat loss  Age-Related Differences in Thermoregulation Age can affect thermoregulatory efficiency, with the very young and elderly being more vulnerable to temperature extremes. Age affects thermoregulatory efficiency. The young and the elderly have less efficient thermoregulatory responses, making them more susceptible to temperature extremes.  Diurnal Variations in Body Temperature Body temperature varies throughout the day, with the lowest temperatures in the early morning and the highest in the late afternoon. Core body temperature exhibits diurnal variations, typically lower in the morning and higher in the evening. These variations are driven by circadian rhythms that regulate body temperature independently of activity or external temperature.  The Menstrual Cycle and Body Temperature Women may experience an increase in basal body temperature during the luteal phase of the menstrual cycle. Body temperature follows a biphasic pattern during the menstrual cycle, with a rise in temperature during the luteal phase due to the thermogenic effect of progesterone. Menstrual cycle Core raised ~0.5oC during last half of cycle  Hypothermia Fall in core body To below normal accepted range Causes: Accidental: Mountaineering, diving, old age Secondary: Hypothyroidism, hypopituitarism, malnutrition, stroke, trauma, drugs, burns, surgery Generalized cooling exceeds ability of heat-producing and heat-causing mechanisms – Metabolic processes slow down – Higher cerebral functions affected quickly Loss of judgment, apathy, disorientation – Progresses to depression of respiratory centres: Reduced breathing Reduced cardiac output Hyperthermia Elevation in body To beyond normal range When core temp. >39oC get heat stroke Exercise-induced – Tremendous heat production by exercising muscles – Triggers heat-loss mechanisms (e.g. sweating) Treatment - Active/passive cooling: ice pack, water spray, fan Pathologic hyperthermia – Abnormally high thyroid hormone, adrenaline (epinephrine) – Malfunction of hypothalamus (tumour, lesion) Fever as an Adaptive Response Fever is an adaptive and regulated immune response, raising the body's set- point temperature to combat infection. Many pathogens, such as bacteria and viruses, have optimal temperatures for replication that are close to the human body's normal temperature. Increasing body temperature can slow down or inhibit the growth and reproduction of bacteria and can break down toxins. The Role of Pyrogens in Fever Pyrogens are released in response to pathogens and act on the hypothalamic thermoregulatory centre to elevate the hypothalamic set-point for body temperature. Pyrogens such as interleukins (interleukin-1b (IL1β), and tumour necrosis factor-alpha (TNF-α) trigger the hypothalamic release of prostaglandins, which then elevate the set-point for body temperature, inducing fever. Fever Step 1: Recognition of Pathogens 40.5 The body detects the presence of 40.0 (oC) pathogens (like bacteria or viruses) through immune system cells. These cells identify unique 39.5 molecules from the pathogens, known as antigens. 39.0 Step 2: Release of Pyrogens In response to these antigens, 38.5 immune cells release pyrogenic cytokines, such as interleukin-1 (IL- 38.0 1), interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF-alpha). 37.5 These cytokines act as endogenous pyrogens, substances that induce fever. 37.0  Fever 40.5 Step 3: Signal Transmission to the 40.0 (oC) Hypothalamus Pyrogens travel through the 39.5 bloodstream to the brain, reaching the hypothalamus, 39.0 the body's thermostat. They induce the production 38.5 of prostaglandins, which reset the hypothalamic set point to a higher 38.0 temperature. 37.5 During fever, the hypothalamic set point for body temperature is raised to create an 37.0 environment that's less favourable for pathogens and to enhance the immune response Fever 40.5 Step 4: Induction of Fever 40.0 (oC) To reach the new set point, the body initiates thermogenic mechanisms, 39.5 including: Vasoconstriction: Reduces 39.0 blood flow to the skin and extremities to decrease heat loss. 38.5 Shivering: Involuntary muscle contractions 38.0 generate additional heat. Piloerection: Minimal effect in humans but aims 37.5 to trap more heat closer to the skin. 37.0 Hormonal changes: Such as increased epinephrine release to boost metabolic heat production. Fever 40.5 Step 5: Maintenance of Elevated Set Point 40.0 (oC) The body maintains the higher temperature, which can inhibit 39.5 pathogen replication and enhance immune function. During this phase, the 39.0 individual may feel warm and have an elevated body 38.5 temperature. Step 6: Resolution of Infection 38.0 As the immune system combats the infection, the 37.5 level of pyrogens decreases. The hypothalamus recognizes 37.0 the reduction in pyrogens and lowers the temperature set point back to normal. Fever Step 7: Initiation of 40.5 Cooling Mechanisms ("Crisis") 40.0 (oC) To reduce the body temperature to the new 39.5 (original) set point, the body initiates cooling 39.0 processes: 38.5 Vasodilation: Increases blood flow to the skin, allowing more heat to 38.0 dissipate. Sweating: Evaporative 37.5 cooling removes heat from the body. 37.0 Behavioural changes: Such as seeking cooler environments or removing excess clothing. Pharmacological Management of Fever Antipyretic medications such as paracetamol and aspirin reduce fever by acting on the hypothalamus to lower the set-point temperature. Antipyretics like paracetamol and NSAIDs inhibit prostaglandin synthesis, lowering the hypothalamic set-point back toward the normal range and reducing fever. Fever 40.5 Step 8: Return to Normal Temperature 40.0 (oC) As the fever breaks and body temperature returns 39.5 to normal, the individual may experience sweating 39.0 and a sensation of being chilled as the body 38.5 dissipates the excess heat. 38.0 This return to normal temperature signals the 37.5 end of the febrile response, assuming the 37.0 infection has been effectively managed by the immune system. Step 8: Return to baseline – Resolution of infection or another cycle begins  FEVER & ENDOGENOUS PYROGENS Aspirin* Paracetamol Ibuprofen Paracetamol, aspirin (and anti-pyretics) blocks pathway used by pyrogens to alter set-point *aspirin not recommended for children (Reye’s syndrome)