Lecture 4 Flashcards
To explain and describe the different components of whole body metabolic responses and which of these components are influenced by acute cold exposure.
a
To explain and describe the afferent and efferent
limbs of the cold response including the neural pathways involved in this response.
a
To explain the physiological mechanisms underlying the shivering and non shivering thermogenesis responses.
a
To explain the local as well as central effects of
reductions in body temperatures on cutaneous blood vessel responses.
a
To define hypothermia, its clinical aspects as well as the different types of freezing and non freezing cold injuries.
a
Define Obligatory Energy Expenditure (EE) or Thermogenesis
heat from normal functions of cells and organs, including obligatory part of diet induced thermogenesis (DIT) aka Thermal Effect of Feeding (TEF) that is the nrg cost to digest & absorb food.
Define Facultative EE or Thermogenesis
- an inc in nrg expenditure in response to cold or diet; regulated by hypothalamic integration of skin & core temp plus visceral inputs
Define Adaptive EE or Thermogenesis
the capacity for heat production becomes larger when the organism stays for a prolonged time (days, weeks, months) in the cold; we will look at this in the cold acclimation lecture
What are the components for Obligatory Energy Expenditure (EE) or Thermogenesis
- Standard metabolic rate
- Diet-induced thermogenesis 1
- Physical activity
What are the components for Facultative EE or Thermogenesis
- Cold-induced shivering thermogenesis
- Voluntary activity thermogenesis (exercise)
- Non-exercise activity thermogenesis (fidgeting)
- Cold-induced nonshivering thermogenesis
- Diet-induced thermogenesis 2 (facultative part)
Define ganglion
Group of neuron cell bodies
Define Dorsal Root Ganglia
Group of neuron cell bodies specifically outside SC in the dorsal area and carry efferent info
Define ventral root Ganglia
Group of neuron cell bodies specifically outside SC in the ventral area and carry efferent info
Define Glutamate
Glutamate is the most prominent NT in the body, and is the main excitatory NT
Define glutmateric
Glutamatergic neurons produce glutamate, which is one of the most common excitatory NTs in the CNS
Define Lateral parabrachial nucleus
: one of three main parabrachial nuclei, located at the junction of the midbrain and pons. It receives information from the caudal solitary tract and transmits signals mainly to the medial hypothalamus but also to the lateral hypothalamus and many of the nuclei targeted by the medial parabrachial nucleus
Define Dorsal medial hypothalamus
a nucleus of the hypothalamus. It is involved in feeding, drinking, body-weight regulation and circadian activity
Define GABA
gamma-Aminobutyric acid is the main inhibitory NT
Define Median pre optic subnucleus
Nuclei located in preoptic area of AH, this is most dorsal of the 3, involved in osmoregulation, thermoregulation
Define GABAergic
Synapse uses GABA as it’s NT. If a neuron is GABAERGIC = produces GABA.
Define Subnucleus
Secondary nucleus
Define Rostral ventromedial
Group of neurons located on floor of oblongata and form part of descending pathway. Transmit nociceptive info. 3 categories (on, off, and —)
Define Intermediolateral nucleus
: region of grey matter found in one of the three grey columns of the spinal cord, the lateral grey column. This is Rexed lamina VII
Describe the central integration pathway in response to cold
a
Describe the central integration pathway in response to hot
a
Describe shivering thermogenesis (pathway of receptor in skin to brain structures back to musles)
- facilitatory motor pathways
- skin cold receptors to myelinated afferent A fibers, group III delta, group IV Dorsal Root, and central temperature sensitive neurons
- descends via lateral columns in SC from brainstem
- alpha and gamma motor neurons excite skeletal muscles
- Increased tone stretches muscle spindles that are in series w/muscle fibres; gives stretch reflex induced contractions
- Gives oscillations of contractions of skeletal muscle
Where is the primary motor center for shivering thermogenesis
Dorsomedial hypothalamus
What is shivering thermogenesis inhibited by
Warm signal
Name 2 ways shivering can be blocked?
- Consciously suppressed
2. Blocked by CURARE that competes w/Ach for nicotinic receptors at the NMJ in skeletal muscle
Out of carbs, lipids, and protein, what is the most important shivering fuel source?
If you have more glycogen available, you can oxidize more glycogen and shiver for longer
What would be the optimal fuel mix for sustaining shivering?
In glycogen loaded men, glycogen utilization rate is higher and estimated time before muscle glycogen depleted is longer (longer time until u deplete). The burst rate (contraction of fibres) is lower in glycogen loaded men (contract less).
What promoted a renewed interest in NST (non-shivering thermogenesis)
- Recent identification of fxnal BAT in adult humans
- ß3 receptors, SNS, NE, brown adipose tissue, uncoupling proteins (UCP-1 to UCP-5).
Brown adipose tissue (BAT) thermogenic functions are primarily mediated by what proteins?
Uncoupling proteins (UCP-1 to UCP-5)
What is the basic mechanism for NST, specifically in BAT
- NE binds to adrenergic beta 3 receptor in BAT
- Leads to degradation of intracellular TG
- FFA are released & interact with UCP1
- This interaction overcomes the inhibition of UCP 1 by cytosolic purine nucleotides (e.g. ATP, ADP, GTP & GDP)
- Leads to respiration in the
mitochondria that is uncoupled from ATP synthesis - All combusted food nrg is released as heat
- Therefore without shivering facultative nrg transfer occurs to warm the animal
Does NST occur in skeletal muscles & other tissues?
a
Is NST obligatory, facultative, or adaptive EE or both? How can it be acutely induced?
NST is a facultative (meaning that it can be turned on and off within minutes), adaptive (meaning that it needs weeks to develop) form of thermogenesis that can be acutely induced by NE injection (i.e. an adrenergic thermogenesis)’
Discuss the role of thyroid hormone in shivering thermogenesis
- Thyroid Hormones (mainly T3) give slow response to metabolic rate, has small role in shivering in an interaction with SNS; mxn not complete
- T3 needed for maximal responsiveness to SNS
- T3 & SNS said to act via mitochondrial uncoupling in adult skeletal m., as seen in BAT thermogenesis
- suggests on cold exposure that mitochondrial uncoupling in skeletal m., is a major contributor to increase RMR in humans
What happens to hypothyroid humans
- Become quasi-poikilothermic (will use behaviour to regulate)
- Resting EE is reduced in hypothyroid
How do hypothyroid rats vs. euthyroid rat differ with heat generation during mechanical work
Hypothyroid rats generate less heat during mechanical work than euthyroid (normal fxning thyroid gland) rats
Is just BAT or other tissues involved in NST?
- unknown, active debate on the tissues responsible for NST in adult humans
- Some argue there are uncoupling proteins other than BAT that may be contributing to overall thermogenesis
How does sympathectomy (surgical cutting) or pharmocological block affect skBF? What is this evidence of?
- increased SkBF in cold
- evidence of active tone
What molecular events occur for vasoconstriction?
NE acts on alpha adrenergic (a1 & a2 receptors)
What did Pre-junctional bretylium tosylate block in hypothermia do?
Pre-junctional bretylium tosylate block in hypothermia gave no decrease of SkBF with body cooling (bretylium tosylate typically blocks the release of adrenergic transmitters)
Although the main NT acting on A1 and A2 receptors to cause vasoconstriction if NE, what does new evidence suggest?
Newer evidence suggests NPY and ATP act as NTs and participate in noradrenergic vasoconstriction (non human) or in vitro w/human vascular smooth muscle (vsm) contraction
complete a1 & a2 as well as beta block did not prevent vasoconstriction induced by hypothermia, suggesting what?
Possibly there is a co-transmitter system like in active cutaneous vasodilatation
Neuropeptide cotransmitter neuropeptide Y (NPY) has been shown to be involved in active vasoconstriction and works through what receptors
NPY acts on postjunctional Y1 receptors to aid in vasoconstriction
Temperature dependent _____ vasoconstriction (i.e. local temp) depends on intact _______ cutaneous active _______ nerves
Temperature dependent LOCAL vasoconstriction (i.e. local temp) depends on intact NORADRENERGIC cutaneous active VASOCONSTRICTOR nerves
What does pre-junctional bretylium tosylate (BT) do?
Bretylium tosylate blocks the NT release; prevents cold-induced vasoconstriction of cutaneous vessels; eventually w/continued cooling vasoconstriction is evident at BT treated sites
How did complete a1 and a2 as well as B block or bretylium tosylate alter cutaneous blood flow responses
Gave an initial vasodilation in cold eventually followed by a vasoconstriction with continued cooling
What does the antagonist BIBP-3226 act on? Outcome?
Antagonist BIBP-3226 acting on NPY on Y1 receptors had no influence on vasoconstriction
What are the 2 vasoconstriction phases
- Initial (NE/SNS/alpha/NPY on Y1) phase
- Prolonged (NPY on Y1; non neurogenic as well) phase
** mxns need to be resolved
Describe the local cooling responses and vasoconstrictor mechanisms in human skin
- Dec in local temp of cutaneous blood vessels reduces SkBF thru mechanisms that require intact sympathetic noradrenergic innervation.
- Effects of local temp dec are independent of any change in core temp.
- Local temp reductions are sensed by cold-sensitive afferent nerves.
- These nerves effect release of NE from sympathetic active vasoconstrictor nerves.
- NE acts thru a and b receptors to produce initial vasoconstriction
- Local cooling also mediates initial vasodilation that competes w/initial noradrenergically mediated vasoconstriction.
- This dilation is mediated thru nonneural mechanisms that is observed when release or postjxnal effects of NE are blocked
- Finally, continued local cooling effects a prolonged vasoconstriction thru nonneural mechanisms. The nature of the nonneural mechanisms is unknown to humans
- Initial vasoconstriction due to NORADRENERGIC MECHANISMS
- Initial vasodilation due to NON-NEURAL MECHANISM
- Prolonged vasoconstriction due to NON-NEURAL MECHANISM
What is the Lewis Hunting Response
- alternating vasoconstriction & vasodilatation in extremities exposed to cold
- starts w/ 5-10 min of local cooling if the body is not hypothermic
- evident in tissues w/abundant AVAs including palmar hand & fingers surfaces
What is cold-induced vasodilation
- occurs after cold exposure, possibly to reduce the risk of injury
- can take place in several locations in the human body but is observed most often in the extremities
- fingers are esp common because they are exposed most often
- When the fingers are exposed to cold, vasoconstriction occurs first to reduce heat loss, resulting in strong cooling of the fingers
- 5-10 mins after the start of the cold exposure of the hand, the blood vessels in the finger tips will suddenly vasodilate. This is probably caused by a sudden decrease in the release of neurotransmitters from the sympathetic nerves to the muscular coat of the arteriovenous anastomoses due to local cold. The CIVD increases blood flow and subsequently the temp of the fingers. This can be painful and is sometimes known as the ‘hot aches’ which can be painful enough to bring on vomiting
What are the 4 proposed mxns for CIVD?
- Lewis 1930 Axon reflex or antidromic (aka opposite than normal conduction) vasodilation
- Dilating substance released (prob NO)
- Decreased NE released** (so NE released = constriction, less NE released = dilation, cyclic path)
- Cold effects VSM (intermittently contracts then release)
What are the 3 ways to measure CIVD?
- Skin temp (most common but slower responses than LDF)
- Strain gauge plethysmography (put cuff around arm and inflate to over 40 mmHg so blood can’t escape from hand and it ends up swelling and u measure how much it swells and that gives u index of volume change)
- Laser Doppler flowmetry (LDF)
Other names for piloerection (goosebumps)
- Horripilation
2. Pilomotor reflex
Is piloerection seen in mammals and non mammals?
Only mammals since they have hair covering the body
Fxn of piloerection/horripilation?
in animals covered with fur or hair the erect hairs trap air to create a layer of insulation
Describe the mxn of piloerection
- tiny muscles at base of each hair (arrectores pilorum) contract & pull the hair erect.
- reflex is started by the SNS with cold/emotion
Describe the piloerection reflex in regards to humans
- piloerection is a vestigial response to cold or fear
- we retain very little body hair
- the reflex now provides no known benefit
Describe the stages of hypothermia in relation to range of temp
Stages of Hypothermia
TCORE
･37°C - Normal body temperature (which varies each day from 36.5-37.5°C
･36°C - Mild to moderate shivering (it drops this low during sleep). May be a normal body temperature.
･35 °C -Intense shivering, numbness and bluish/grayness of the skin.
There is the possibility of heart irritability.
･34°C - Severe shivering, loss of movement of fingers, blueness and confusion. Some behavioural changes may take place.
･33°C - Moderate to severe confusion, sleepiness, depressed reflexes, progressive loss of shivering, slow heart beat, shallow breathing. Shivering may stop. Subject
may be unresponsive to certain stimuli.
･32°C - Medical emergency- Hallucinations, delirium, complete confusion, extreme sleepiness that is progressively becoming comatose. Shivering is absent (subject may even think they are hot). Reflex may be absent or very slight.
･31°C - Comatose, very rarely conscious. No or slight reflexes. Very shallow breathing and slow heart rate. Possibility of serious heart rhythm problems.
･28°C - Severe heart rhythm disturbances are likely and breathing may stop at any time.
Patient may appear to be dead.
･≤24-26°C Death usually occurs due to irregular heart beat or respiratory arrest;
- Lowest TCORE was 14.2°C (2 yo Karlee Kosolofski Feb 23, 1984; 6 h @ -22˚C) 27
What are the 4 types of hypothermia
- Mild
- Moderate
- Severe
- Profound
Describe what occurs during mild hypothermia (Tcore, BP, glucose levels etc.)
- dec Tcore, inc shivering, inc BP, tachycardia, tachypnea (rapid breathing), vasoconstriction
- cold induced diuresis (if vasoconstrict u produce more urine), confusion, lethargy (lack of nrg)
- possibly hyperglycemia due to dec insulin secretion/dec glucose uptake, and inc SNS mediated release from liver glycogen stores
Describe what occurs during moderate hypothermia (Tcore, behavioural problems, muscle skeletal problems etc.)
- behavioral and physiological changes, GREAT dec Tcore, GREAT vasoconstriction
- apathy (lack of interest), withdrawal, irritable, pale complex, blue lips, ears/fingers/toes
- ataxia (uncoordinated movements), speech and gait problems (similar symptoms to a cerebrovascular stroke), start of skeletal m. rigidity
Describe what occurs during severe hypothermia (Tcore, behavioural problems, cardiovascular problems)
- GREAT dec Tcore, loss of voluntary control and reflexes and consciousness, amnesia, paradoxical undressing, finally skeletal muscle rigidity
- dec CO/Q, dec Ventilation (VE)
- risk of ventricular fibrillation at low cardiac temp; likely due to:
1. >reduced conduction velocity of Purkinje f. vs myocardial f.
2. Myocardial hypoxia
Describe what occurs with profound hypothermia (electrical activity, BP, skeletal muscle problems)
- inaudible cardiac sounds, due to circulatory depression
- electrical activity of heart (EKG) and brain (EEG) are unmeasurable
- no pulse and BP due to circulatory depression
- extensive muscular rigidity, like rigor mortis
- clinically dead but some revived from Tcore ~17˚C or lower
What is the “rule of thumb” for hypothermia
Nobody is dead until they are warm and dead
How is death caused by hypothermia
- death is from cessation of respiration and failure of cardiac pump
- depressed renal tubular mechanism w/cold… impairs Na reabsorption giving diuresis, dehydration and hypovolemia.
- Q and VE depressed more than MR = metabolic and respiratory acidosis w/CO2 retention and lactic acid accumulation
- RIGHT shift O2-hemoglobin curve (Hb more tightly bound to O2 and harder to off load to tissues, contributes to dec pH inc CO2. Attempt for body to preserve its health)
How to treat mild to moderate hypothermia
passive warming by increasing insulation
How to treat severe hypothermia
active rewarming (hands/feet or forced warm air such as Bear Hugger etc)
What should be avoided when treating hypothermic patients
Always avoid posture changes; sudden collapse possible
What is one CV problem that may arise with rewarming a hypothermic patient and why
VFib in during rewarming may arise as cool/acidic blood from the periphery returns to the core; gives transient drop to Tcore and pH and this may precipitate VFib
2 other names for non-freezing cold injury
- Immersion foot
2. Trench foot
What is non-freezing cold injury? How does it develop?
- develops at non-freezing temp usually at < 10˚C
- longstanding immersion >12 h often for several days
- coldness, wind, damp, assisted by immobility, dependency on the limbs and constrictive clothing or footwear
- circulatory and neuralgic injury
- develops w/out tissue actually freezing
In the first World War, what were symptoms of non-freezing cold injury
- numb feet and the skin would turn red or blue
- gangrenous, amputation
Describe the 3 stages of immersion foot/trench foot (aka non-freezing cold injury)
(i) Pre-Hyperaemic Stage: tissue is COLD, BLUE and NUMB
(i) Rewarming Stage- a hyperaemia (excess blood) may last 3 months; tingling pain, swelling, blisters, sometimes ulcers and superficial gangrene
(i) Post-Hyperaemic Stage: can last many years vasoneuropathy produces post-injury sequelae,
e. g. Raynaud´s syndrome (white coloured fingers), cold sensitivity, hypo-/hyper-hidrosis, dry, scaly skin, leg spasms and persistent pain or other debilitating local symptoms, such as chronic ulceration.
What is the mxn of trench foot/immersion foot
- Absorption and retention of water results in swelling, thickening and fragmentation of corneal layer.
- One hypothesis is ischemia and anoxia are due to vasospasm and stasis of venous flow.
- Another more recent hypothesis is cold damages cells < 22-24˚C tissue temp.
- Severe endothelial damage in true capillaries and venous vessels shown in non-freezing cold injuries of test animals
Treatment/prevention of trench foot?
- Whale oil
2. Dry socks/boots if possible
What are the 3 types of Freezing Injury
- Frost nip
- Superficial frostbite
- Deep frostbite
Where and when does frostbite occur
- Usually feet, toes, nose, ears, chin, cheeks, forehead, fingers, hands, & wrists
- tissue freezing temperature is not resolved; btwn -0.6 and -5-10˚C or lower
- super-cooling
Describe Frost nip
- mild form of frostbite
- no tissue destruction
- crystals dissolve as soon as skin is warmed
- skin turns pale and numb or tingly until warming begins
Describe superficial frostbite
- reddish (light-skinned) or grayish (dark-skinned) area on exposed skin
- sudden blanching/whitening of affected area
- tingling sensation, followed by numbness
Describe deep frostbite
- total lack of feeling in affected (frozen) tissue
- Pale, yellowish, waxy-looking skin
- solid flesh (feels wooden to the touch)
- red-violet discoloration, deep, blood-filled blisters and sloughing of affected skin may occur 1-5 days after initial injury
Treatment and prognosis for freezing injury (4)
- reduce cold
- slow warming
- hyperbaric oxygen possibly
- amputation possible
What is Raynaud’s disease or syndrome?
vasospastic disorder causing discoloration of the fingers, toes, and occasionally other extremities, named for French physician Maurice Raynaud
What is the difference btwn Raynaud’s disease and Raynaud’s syndrome? Example of how each may be caused
Raynaud’s disease (primary Raynaud’s), where the phenomenon is idiopathic aka arise spontaneously from unknown cause, and Raynaud’s syndrome (secondary Raynaud’s), where it is secondary to something else
- Raynaud’s disease: someone whos never worked with tools and we don’t know why it happens.
- Raynaud’s syndrome: barber damages hands when working w/vibration
What is the Rate of Heat Exchange (S)
this is the net of the different rates of heat exchange via the different avenues
Eqn for Rate of Heat Exchange (S)
S = +QM +/- QCD(Tb-Ts) Qconv(Ts-Ta) +/- Qrad(Ts-Tsur) -QE(PSKIN-PAMB)
Where:
Qx x ΔT= rate of heat exchange, where x = avenue of heat exchange
and ΔT = difference in temperature
- Qx= heat transfer coefficient for that avenue of heat exchange
- Tb = temperature of body contacting the skin
- Ts = skin temperature
- Ta = air temperature
- Tsur = temperature of an object emitting radiation
- P = Pressure
What is the 1st line of defence to a change in ambient temp.
Behavioral Responses
Example of Behavioral Responses to Changes in Body Temperatures
- In hot/cool climates we choose appropriate clothing, activities, and locations to minimize the changes in our body temp
e. g. in deserts we look for shade, drink water, wear shorts and sandals
e. g. in winter we stay inside, are more active to generate heat, wear warm insulated clothing
What is Hyperthermia
inc of core temp by ~1ºC above resting normothermic levels
What is hypothermia
dec in core temp by ~1ºC below resting normothermic levels
What is vasodilation
Inc in caliber of a blood vessel
What is vasoconstriction
an actively mediated dec in peripheral BF by various mxn(s)
What is vasomotion
changes in caliber of vessels by vasoconstriction or vasodilation actions
What are arteriovenous anastomoses (AVAs)
Direct arterial to venous conduit in a capillary bed that connects arterioles and venules; allows bypassing of capillary beds; useful for heat conservation in cold climates
What are the diameter of capillaries vs. AVAs
Capillaries = 5-10µ, AVA 20-70µ
What are eccrine sweat glands
produce sweat that is employed in body cooling after increases in body temp
What are apocrine sweat glands
produce sweat often after an emotional event
What is a set point
– point of core temps about which core temp is regulated
What is null zone
a zone of core temp with no sweating or shivering and just vasomotion
What is core temp
– temp of the bodys core, usually measured in the esophagus, GI tract, rectum or on the tympanic membrane
What is skin temp
– temp on the surface of the body, usually measured w/a thermocouple or thermistor taped to the skin surface at multiple sites
What is the periphery
– describes the peripheral tissues; there are
no definite boundaries for the periphery; and its size inc or dec depending on the peripheral vessels states
What is the core
– describes the central tissues, there are no
definite boundaries for the core and its size inc or dec depending on the peripheral vessels states
What is the Hypothalamus
centre for temp regulation
What are cold sensitive neurons
dec’s in their temps cause inc firing rates
What are Warm sensitive neurons
inc in their temps cause inc firing rates
Discuss the control of room temp when there is a disturbance (include what is the receptor, control centre, effector)
E.g. if room temp rises, the thermometer (RECEPTOR) located inside the thermostat (CONTROL CENTER) sends this info to the thermostat which sends the command of the AC (EFFECTOR) to turn on. A thermostat stabilizes room temp by turning on AC (or heater) as needed to keep room temp near desired set point. When room temp rises, thermostat turns on AC, and room temp returns to normal lvls. With this regulatory system room temp oscillates around set point
Describe the POAH
- has neurons that inc in firing with increased temp = stimulates heat loss
- this output is inhibited by cold input from skin
Describe the DMPH
has neurons that increase in firing with decrease temp
- this output is inhibited by warm input from skin
As core temp drops, metabolic rate ____
inc
Who identified a null zone of core temp with no sweating or shivering responses
Mekjavic
What are responses to cold environment
- shivering (inc metabolic rate) and vasoconstriction
- sympathetic response to catecholamines via ß1 &
ß2 receptors; also thyroxine over long term increases metabolic rate - Non-shivering thermogenesis
What is involved in non shivering thermogenesis and what receptor
- brown adipose & other tissues via ß3 receptors
- uncoupling proteins UCP1, UCP2 and UCP3
- J. Himms-Hagen /Mary-Ellen Harper in Ottaw
In regulation of Regulation of Body Heat Content, what does the time constant (tau) represent
– represents the time it takes a system’s step response to reach 1-1/e that is approximately 63.2% of its final asymptotic value
Describe indirect calorimetry
Computer interfaces with:
- A flow-measuring device that records air volume breathed
- O2 & CO2 analyzers that measure the composition of the expired gas mixture
- Mouth piece/nose clip or hood
