Introduction

Overview

• Humans have a normal core internal temperature of approximately 37ºC (98.6ºF).
• Thermoregulation:
  • Regulation of body temperature is independent of external temperature.
  • 3-step pathway:
    • Afferent sensing
    • Central control
    • Efferent responses
• The hypothalamus Hypothalamus The hypothalamus is a collection of various nuclei within the diencephalon in the center of the brain. The hypothalamus plays a vital role in endocrine regulation as the primary regulator of the pituitary gland, and it is the major point of integration between the central nervous and endocrine systems. Hypothalamus is the main thermoregulatory center in the brain.

Physiologic processes related to thermoregulation

• Fever Fever Fever is defined as a measured body temperature of at least 38°C (100.4°F). Fever is caused by circulating endogenous and/or exogenous pyrogens that increase levels of prostaglandin E2 in the hypothalamus. Fever is commonly associated with chills, rigors, sweating, and flushing of the skin. Fever:
  • Controlled increase in body temperature most commonly due to an infection
  • Triggered by pyrogens (e.g., bacterial and nonbacterial molecules)
  • Pyrogens reaching the preoptic area (POA) of the hypothalamus Hypothalamus The hypothalamus is a collection of various nuclei within the diencephalon in the center of the brain. The hypothalamus plays a vital role in endocrine regulation as the primary regulator of the pituitary gland, and it is the major point of integration between the central nervous and endocrine systems. Hypothalamus stimulate cyclooxygenase-2 (COX-2).
  • COX-2 expression in the endothelial cells of the POA of the hypothalamus Hypothalamus The hypothalamus is a collection of various nuclei within the diencephalon in the center of the brain. The hypothalamus plays a vital role in endocrine regulation as the primary regulator of the pituitary gland, and it is the major point of integration between the central nervous and endocrine systems. Hypothalamus results in prostaglandin (PG)E₂ production.
  • PGE₂ acts through local EP3 receptors to inhibit the activity of the hypothalamic POA neurons that function to reduce body temperature, resulting in fever.
• Sleep Sleep Sleep is a reversible phase of diminished responsiveness, motor activity, and metabolism. This process is a complex and dynamic phenomenon, occurring in 4-5 cycles a night, and generally divided into non-rapid eye movement (NREM) sleep and REM sleep stages. Physiology of Sleep: 
  • Sleep Sleep Sleep is a reversible phase of diminished responsiveness, motor activity, and metabolism. This process is a complex and dynamic phenomenon, occurring in 4-5 cycles a night, and generally divided into non-rapid eye movement (NREM) sleep and REM sleep stages. Physiology of Sleep onset coincides with a decline in body temperature.
  • During sleep phases (i.e., REM phase), thermoregulation is significantly inhibited.
• Appetite and regulation of food intake: Energy generated from food is used for temperature homeostasis.
• Fluid homeostasis: Adequate hydration is necessary for effective sweat production.

Afferent Thermoregulatory Pathway

Peripheral temperature sensing

• Afferent signaling starts from the peripheral tissues.
• Tissues that provide thermoregulatory input:
  • Skin
  • Spinal cord
  • Abdominal viscera
  • Brain:
    • The POA of the hypothalamus Hypothalamus The hypothalamus is a collection of various nuclei within the diencephalon in the center of the brain. The hypothalamus plays a vital role in endocrine regulation as the primary regulator of the pituitary gland, and it is the major point of integration between the central nervous and endocrine systems. Hypothalamus is the most thermosensitive site in the body.
    • The POA of the hypothalamus Hypothalamus The hypothalamus is a collection of various nuclei within the diencephalon in the center of the brain. The hypothalamus plays a vital role in endocrine regulation as the primary regulator of the pituitary gland, and it is the major point of integration between the central nervous and endocrine systems. Hypothalamus receives signals from the peripheral tissues and also acts as an autosensor.
• There are 2 classes of temperature-sensitive afferent sensory neurons:
  • Neurons activated by warmth (approximately 34–42ºC (93–107ºF))
  • Neurons activated by cold (approximately 14–30ºC (57–86ºF))
  • Sensory neurons have cell bodies located in:
    • Trigeminal ganglion (for innervation of the head and face)
    • Dorsal root ganglia (for innervation of the rest of the body)
  • Axons split into 2 branches:
    • The 1st branch innervates the skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Structure and Function of the Skin or viscera.
    • The other branch projects to the dorsal horn of the spinal cord Spinal cord The spinal cord is the major conduction pathway connecting the brain to the body; it is part of the CNS. In cross section, the spinal cord is divided into an H-shaped area of gray matter (consisting of synapsing neuronal cell bodies) and a surrounding area of white matter (consisting of ascending and descending tracts of myelinated axons). Spinal Cord or the trigeminal nucleus in the brainstem.

Circumventricular organs (CVOs)

• Areas of the brain with absent or very limited blood-brain barrier
• Can sense signals in the blood and pass that information neurally to other areas of the brain
• Permeable to PGs
• 2 CVOs important for thermoregulation due to their proximity to the hypothalamus Hypothalamus The hypothalamus is a collection of various nuclei within the diencephalon in the center of the brain. The hypothalamus plays a vital role in endocrine regulation as the primary regulator of the pituitary gland, and it is the major point of integration between the central nervous and endocrine systems. Hypothalamus:
  • Subfornical organ
  • Organum vasculosum of the lamina terminalis (OVLT)
• Other CVOs:
  • Median eminence
  • Posterior pituitary gland Pituitary gland The pituitary gland, also known as the hypophysis, is considered the "master endocrine gland" because it releases hormones that regulate the activity of multiple major endocrine organs in the body. The gland sits on the sella turcica, just below the hypothalamus, which is the primary regulator of the pituitary gland. Pituitary Gland
  • Pineal gland
  • Area postrema

Central Control and Efferent Responses

Central control

• The preoptic area and anterior hypothalamus Hypothalamus The hypothalamus is a collection of various nuclei within the diencephalon in the center of the brain. The hypothalamus plays a vital role in endocrine regulation as the primary regulator of the pituitary gland, and it is the major point of integration between the central nervous and endocrine systems. Hypothalamus are key control sites for thermoregulation in the brain.
• Efferent pathways to thermoregulatory effectors activate negative feedback responses if the core body temperature deviates from 37ºC (98ºF).

Efferent responses

Four physiologic effectors are particularly important for thermoregulation in mammals:

• Brown adipose tissue Adipose tissue Adipose tissue is a specialized type of connective tissue that has both structural and highly complex metabolic functions, including energy storage, glucose homeostasis, and a multitude of endocrine capabilities. There are three types of adipose tissue, white adipose tissue, brown adipose tissue, and beige or "brite" adipose tissue, which is a transitional form. Adipose Tissue (BAT):
  • Specialized organ for the rapid production of heat
  • Highly innervated by sympathetic nerves
  • Norepinephrine release induces a mitochondrial leak that produces heat.
  • The rostral raphe pallidus is the primary site within the preoptic nucleus where descending signals to BAT exit the brain.
• Control of blood flow to the skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Structure and Function of the Skin:
  • Heat exchange between the skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Structure and Function of the Skin and the environment is dependent on blood flow to the skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Structure and Function of the Skin.
  • Vasoconstriction prevents heat loss in cold environments.
  • Vasodilation allows for heat loss in hot environments.
  • Controlled by adrenergic and cholinergic innervation of blood vessels in the skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Structure and Function of the Skin
• Shivering:
  • Fast, repetitive contraction of skeletal muscle to generate heat (“chills”)
  • Occurs when the core body temperature falls below 35ºC (95ºF)
• Evaporative heat loss:
  • Thermoregulatory strategy to dissipate heat
  • Achieved primarily by sweating
  • Occurs through stimulation of the sweat glands by cholinergic postganglionic innervation

Conditions That Affect Thermoregulation

• Age: Aging is associated with diminished cold-induced thermoregulation, which is due to a combination of increased heat loss and decreased metabolic heat production.
• Exercise
• Extreme environmental conditions leading to:
  • Hypothermia Hypothermia Hypothermia can be defined as a drop in the core body temperature below 35°C (95°F) and is classified into mild, moderate, severe, and profound forms based on the degree of temperature decrease. Hypothermia
  • Heatstroke Heatstroke Heatstroke is an illness characterized as a core body temperature exceeding 40°C (104°F) with accompanying neurological symptoms including ataxia, seizures, and/or delirium. Heatstroke is usually due to the body's inability to regulate its temperature when challenged with an elevated heat load. Heatstroke
• Hormone levels: Menopause Menopause Menopause is a physiologic process in women characterized by the permanent cessation of menstruation that occurs after the loss of ovarian activity. Menopause can only be diagnosed retrospectively, after 12 months without menstrual bleeding. Menopause is associated with impaired thermoregulation and occurs due to estrogen depletion and elevated central sympathetic stimulation.
• Drugs can impair thermoregulation through:
  • Diuresis and electrolyte imbalance
  • Sedation and cognitive impairment
  • Reduced thirst recognition
  • Reduced sweat production
  • Hypotension Hypotension Hypotension is defined as low blood pressure, specifically < 90/60 mm Hg, and is most commonly a physiologic response. Hypotension may be mild, serious, or life threatening, depending on the cause. Hypotension and reduced cardiac output
  • Commonly implicated drugs:
    • Diuretics
    • ACE inhibitors
    • ARBs
    • Anticholinergics
    • Psychotropics
• Alcohol use:
  • Impaired sweating and skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Structure and Function of the Skin vasodilation
  • Behavioral changes
• Metabolic conditions:
  • Diabetes mellitus Diabetes mellitus Diabetes mellitus (DM) is a metabolic disease characterized by hyperglycemia and dysfunction of the regulation of glucose metabolism by insulin. Type 1 DM is diagnosed mostly in children and young adults as the result of autoimmune destruction of β cells in the pancreas and the resulting lack of insulin. Type 2 DM has a significant association with obesity and is characterized by insulin resistance. Diabetes Mellitus
  • Hypothyroidism Hypothyroidism Hypothyroidism is a condition characterized by a deficiency of thyroid hormones. Iodine deficiency is the most common cause worldwide, but Hashimoto's disease (autoimmune thyroiditis) is the leading cause in non-iodine-deficient regions. Hypothyroidism
  • Hyperthyroidism Hyperthyroidism Thyrotoxicosis refers to the classic physiologic manifestations of excess thyroid hormones and is not synonymous with hyperthyroidism, which is caused by sustained overproduction and release of T3 and/or T4. Graves' disease is the most common cause of primary hyperthyroidism, followed by toxic multinodular goiter and toxic adenoma. Thyrotoxicosis and Hyperthyroidism
  • Hypoadrenalism
  • Hypopituitarism Hypopituitarism Hypopituitarism is a condition characterized by pituitary hormone deficiency. This condition primarily results from a disease of the pituitary gland, but it may arise from hypothalamic dysfunction. Pituitary tumors are one of the most common causes. The majority of cases affect the anterior pituitary lobe (adenohypophysis), which accounts for 80% of the gland. Hypopituitarism

Temperature Measurement

Clinical Relevance

The following conditions occur when thermoregulation mechanisms are overwhelmed by environmental conditions:

• Hyperthermia: occurs when the core body temperature increases due to intensive physical stress and the mechanisms of heat emission are insufficient. In its extreme state, hyperthermia is referred to as heatstroke and is accompanied by a systemic inflammatory response causing multiple organ dysfunction that can lead to death. Treatment includes rapid external and internal cooling.
• Hypothermia Hypothermia Hypothermia can be defined as a drop in the core body temperature below 35°C (95°F) and is classified into mild, moderate, severe, and profound forms based on the degree of temperature decrease. Hypothermia: A decrease in core body temperature to < 35ºC (95ºF) can be classified as mild (32–35ºC (90–95ºF)), moderate (28–32ºC (82–90ºF)), or severe (< 28ºC (82ºF)) hypothermia. Symptoms progress from shivering to confusion, lethargy, coma Coma Coma is defined as a deep state of unarousable unresponsiveness, characterized by a score of 3 points on the GCS. A comatose state can be caused by a multitude of conditions, making the precise epidemiology and prognosis of coma difficult to determine. Coma, and ultimately death. Individuals with alcohol- or substance-use disorders who lose consciousness in cold environments are particularly susceptible. Treatment requires passive and active rewarming.
• Frostbite Frostbite Injuries due to cold weather are common among children and athletes who are involved in sports played in cold conditions. Frostbite is a direct freezing injury to the peripheral tissues and occurs when the skin temperature drops below 0°C (32°F). Common sites of frostbite include the nose, ears, fingers, and toes. Frostbite: a direct freezing injury to peripheral tissues that occurs when the skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Structure and Function of the Skin temperature drops below -0.5ºC (31.1ºF). Common sites of frostbite include the nose Nose The nose is the human body's primary organ of smell and functions as part of the upper respiratory system. The nose may be best known for inhaling oxygen and exhaling carbon dioxide, but it also contributes to other important functions, such as tasting. The anatomy of the nose can be divided into the external nose and the nasal cavity. Anatomy of the Nose, ears, fingers, and toes. Gangrene may develop and severely affected tissue may autoamputate. Treatment is with rewarming and local tissue care. Surgery is sometimes necessary if necrosis occurs.