Lecture 22: Regulation of Respiration Flashcards
What is the importance of respiration?
Maintaining O2 levels
Eliminating CO2 waste
pH regulation (by extension of CO2)
Managing respiratory work and expenditure
How does respiration regulate pH?
CO2 + H2O H2CO3 HCO3- + H+
CO2 build up (hypercapnia) = respiratory acidosis
Excessive clearance of CO2 = respiratory aklalosis
Respiratory control organisation
See figure
What are the respiratory control centres?
Neurons in the brain stem
Medullary rhythmic centre
Pons respiratory centres
See figure
Functions of the neurons in the brain stem as respiratory control centres
Generate rhythm of breathing (exhalation and inspiration cycles)
Stimulate respiratory muscles
Integrate feedback signals
What are the components of the medullary rhythmic centre?
Pre-Botzinger complex
Dorsal respiratory group
Ventral respiratory group
What are the components of the pons respiratory centres?
Apneustic area
Pneumotaxic area
Pre-Botzinger complex (PBC) - what? Function?
Basal pacemaker and initiation
Generates some neural activity (even in the absence of all external signals, under significant pharmacological blockage and in severe brain damage)
Not a stable, rhythmic output (needs outside help)
Does not directly stimulate inspiration, but ensures activation of the dorsal respiratory group
Dorsal Respiratory Group (DRG) - Function
Exerts primary control over basal breathing (at rest)
Principal Inspiratory centre
Critical integrator/effector of respiratory control
What are oscillations and/or maintenance in DRG activity due to?
Multiple sensory inputs
Pre-Botzinger complex
Apneustic centre
Graph of DRG activity
DRG activity ramps up over 2 seconds to cause inspiration (slow and gradual crescendo)
Somewhat self-inhibitory
Halting of activity over 3 seconds causes passive expiration
See figure
DRG downstream innervation
Phrenic nerve -> diaphragm (contraction)
External intercostal nerves/muscles -> ribcage expansion (open chest)
See figure
Phrenic nerve and regulation of breathing
Bursts of phrenic nerve activity contract principal inspiratory muscles
More rapid firing, bigger and deeper breaths (active ventilation)
More frequent bursts, faster breathing rate
See figure
What type of breathing is driven by the ventral respiratory group (VRG)?
Inactive during normal, quiet breathing
Principally drives active expiration during exercise, dyspnea, some lung diseases (failure of passive expiration - COPD, asthma, emphysema)
Also provides supplementary inspiratory control (pectorals, scalene)
What efferent activity does the VRG control?
Internal intercostal nerves/muscles -> ribcage compression
Abdominal muscles -> push diaphragm up
How is the VRG engaged?
Activated by spillover from the DRG
The VRG is only activated AFTER the DRG (the two cannot be activated at once) = the expiration is delayed and out of phase
Bursts of internal intercostal nerve activity contract the expiratory muscles
See figure
When is activation of the VRG required?
Under periods of high respiration
When there is failed passive expiration
Function of the Apenustic centre (APC)
Activates DRG
APC actively prolongs inspiration: prevents DRG from switching off, maintained phrenic nerve activity, longer/deeper breaths, shortened expiration
Function of the pneumotaxic centre (PRG)
Inhibits APC
Turns off inspiration, allows expiration
Routinely activated by DRG: delayed and out pf phase, key part of flip-flop circuit
Characteristics of apneustic breathing
Gasping
Prolonged inspiration, shallow expiration
See figure
How can apneustic breathing come about?
Brainstem injury (severe stroke or trauma)
Loss of input from mechanoreceptors
Simple respiratory centre feedback
See figure
What is responsible for central chemoreception in regulation of breathing?
Neurons of retrotapezoid nucleus (RTN)
Seem to interface with pre-Botzinger complex
How do the central chemoreceptors modulate respiration?
Minute-by-minute ventilatory control (not fast, but slow, gradual changes)
Most sensitive to PaCO2
Somewhat sensitive to pHa (indirectly)
Insensitive to PaO2 (oxygen is not a primary regulator)
How does the central chemoreceptor sense changes in respiratory system?
Through pH of CSF (does not directly measure CO2)
CO2 diffuses across the BBB, into the cerebrospinal fluid.
H+, H2CO3 and HCO3- cannot cross the BBB
In the CSF, CO2 is converted into HCO3- and H+.
Change in pH is sensed by the RTN
See figure
What is the normal pH of the CSF?
7.32
Weakly buffered = High change in pH for small changes in CO2
Sensitive and linear
RTN chemoreceptor CO2 response graph
- Room CO2 (0.4 %)
- CO2 goes up to 10% (takes 5 minutes for RTN to kick in)
- CO2 decreased back to room air = allow decrease in firing
See figure
How can the RTN system get confused?
When there are long term changes of CO2 in the system, there can be an adaptation of CSF bicarbonate
Choroid plexus releases more HCO3- into the CSF to account for the high CO2, which is causing high H+. pH changes are no longer detectable.
Patients begin to tolerate the hypercapnia and start hypoventilating
H+ builds up in the blood and there is respiratory acidosis
See figure
What are the peripheral chemoreceptors? Role?
Carotid body
Aortic body
Sense arterial blood at high flow sites
How does the carotid body sense and transmit signals?
Sensor: type I glomus cell
Glossopharyngeal nerve (IX) transmits
Afferent interface to DRG
See figure
What does the carotid body respond to
Principally: Low PaO2
NOT THE O2 CONTENT
Also responds to: PaCO2, pHa (CO2 independent)
Non adapting (should always be able to respond to O2)
Carotid body response mechanism
Carotid body has low basal firing rate
When PaO2 goes below 60 mmHg = dramatic increase
Typical of emergency mechanism (oxygen falls, but there is no problem. Suddenly, threshold is reached and there is a massive stimulus from cells)
NOTE: integrated respiratory response is still heavily dependent on PaCO2
See figures
Importance of aortic body in central chemoreception? Where is it important?
Less important than carotid body
Aortic body response is weak, but it can adapt/increase if the carotid body is damaged
Principal role is baroreception for blood pressure
How does the aortic body sense and transmit signals?
Sensor: Type I gloms cells
Interfaces and activates DRG
Afferent through vagus nerve (X)
Comparison of chemoreceptors - role in normal and emergency breathing, transmission, interface site, primary and secondary stimuli, no stimuli, response speed, response type, adaptation
See figure
What do pulmonary receptors and nerves help regulate?
Inspiration
Expiration
Emergency or protective responses
What do the pulmonary receptors and nerves operate through? What stimulates them? Outcomes?
Vagus nerve
Stimuli: Mechanical, chemical
Outcomes: inhibitory, excitatory
Lung mechanoreceptors - respond to? Types?
Respond to stretch
Slowly adapting receptors (SARs): continual firing during normal, slow inspiration
Rapidly adapting receptors (RARs): fire during rapid inspiration
See figure
What are the hiring-breuer reflexes?
Classic respiratory control discovered in 1868
Inflation reflexes and deflation reflexes
Hering Breuer reflexes - inflation
Mechanoreceptors terminate at APC and DRG
Inhibitory neurons
Act to suppress inspiratory activity (stop stretching of lungs)
SARs help turn gentle inspiration to expiration
RARs prevent lung overinflation
See figure
Hering Breuer Reflexes - deflation
Small group of mechanoreceptors
Excitatory neurons
Terminate at DRG
Compression acts to restart inflation at low lung volumes
See figure
Where are irritant and cough receptors located? Nerve?
Airway epithelium
Afferent through vagus nerve
Where are cough receptors located? What do they respond to?
Nerves in trachea and high bronchi
Respond to mechanical and chemical stimuli
Where are irritant receptors located? What do they respond to?
Nerves in bronchioles
Respond to chemical stimuli only
What does stimulation of irritant and cough receptors cause?
Stimulation causes spasm of multiple effector muscles
No clearly defined cough centre
Comparison of mechano- and irritant- receptors- location, transmission, nerve ty[e, interface site, stimuli, reflex action
See figure
What are the components of cortical control of breathing?
Conscious control of muscles: singing and talking, holding breath
Subconscious control of respiratory centres: emotion, pain, fear, temperature
When can hypercapnia be tolerated?
If respiratory effort is high, possible situations:
High gas pressure/density
Heavy weight on chest
What wins in a fight: autonomic or cortical control?
Autonomic
Spinal cord damage and effects on breathing
See figure
What happens if C1-C4 phrenic and intercostal nerves are severed?
Full ventilator dependency
What happens if C4-C6 are damaged, but phrenic nerve is intact
Weak but functional breathing driven by diaphragm
What happens is T6-T12 afferent nerves are severed?
Loss of cough reflex (efferent)
Mechano- and chemo- reception intact (vagus and glossopharyngeal nerves are outside spine)
What happens during altitude sickness?
Low inspired pO2 = hypoxemia at carotid bodies
Acute hyperventilation may help to improve PaO2
Excessive CO2 loss = respiratory alkalosis and suppression of central chemoreceptors
Symptoms arise from hypoxemia and/or alkalosis: nausea, lightheadedness, headaches, fatigue and confusion, insomnia
Altitude feedback loop
See figure
Adaptation to altitude
Chronic adaptation (1-2 days) comes from kidneys
Therapeutic options
Increased O2 carrying capacity of blood
How does chronic adaptation to altitude occur?
Comes from kidneys
Normally: HCO3- retention, H+ consumed/excreted, CO2 expired
Hypoxia: HCO3- secreted, H+ retention, pHa falls
What is the therapeutic option for adaptation to altitude?
Acetazolamide
Carbonic anhydrase inhibitor = forces HCO3- secretion, pHa falls
May assist CO2 retention in the brain
How does increased O2 carrying capacity of the blood occur during adaptation to altitude?
EPO secretion downstream of hypoxia inducible factors
PaO2 stays low, so hypoxemia-driven respiration remains high
Combined benefits are essentially altitude training
Adapted altitude feedback loop
See figure
What happens if there is failed adaptation to altitude?
High altitude pulmonary deem (HAPE)
High altitude cerebral deem (HACE)
Characteristics of HAPE?
Chronic hypoxic vasoconstriction in lungs (V/Q matching)
Fluid build up in alveoli
Treatment as for pulmonary hypertension (nifedipine)
Characteristics of HACE?
Chronic hypoxic vasodilation in brain (improve O2 delivery)
Cerebral endothelium becomes leaky
VEGF; NO and other molecules implicated
Dexamethasone treatment, steroidal, anti-inflammatory, vasoconstrictive
What ventilation occurs during metabolic acidosis? Causes?
Hyperventilation
Longstanding diarrhea (HCO3- loss)
Diabetic type 1 - ketoacidosis
Some kidney dysfunctoins
What ventilation occurs during metabolic alkalosis? Causes?
Hypoventilation
Excessive vomiting (H+ loss)
Chronic diuretic use (HCO3- retention)
Some kidney dysfunctions
What occurs in the respiratory system of people with chronic lung disease (Emphysema, chronic bronchitis)
Persistent mild hypercapnia and hypoventilation
Central chemoreceptor adaptation
Supplemental O2 often necessary: suppresses emergency breathing, additional risk factors, sudden respiratory failure
What happens during exercise?
Increased O2 consumption, increased CO2 production
Anticipatory breathing precedes exercise (learned/trained feed-forward response, subconscious and conscious)
Mechanoreceptors in exercising muscles (type III/IV afferent fibers, interface in medulla, possible DRG)
Circulating catecholamines (dopamine, adrenaline, noradrenaline)
Activation/spillover from aortic body baroreceptors (hypoxia-like response under normal O2 conditions)
Limit to exercise is mostly cardiac output
What do opiates do to respiration?
Suppress multiple aspects of rhythm generation (especially DRG)
Suppress cortical control
Reversed by opioid antagonist: naloxone
See figure
What are typical findings in sudden infant death syndrome
SIDS
Infant 1-12 months
Asleep on stomach
Soft bed and tight blankets or in bed with parents
No sign of struggle
Triple risk model of SIDS
Critical period (1-12 months, rapid changes in homeostatic control)
Vulnerable infant (abnormalities in brain stem)
Outside stressors (smoke, infection, overheating, mechanical factors)
What is the key pathology in SIDS?
Poor ventilation
CO2 rebreathing
Poor response to PaCO2
Emergency responses fail
What are other stressors and vulnerabilities in SIDS?
Serotonin deficiency in SIDS group
RTN defects in 71% of cases (faulty interface between central chemoreceptors and PBC)
Peripheral chemoreceptors under-developed and possibly abnormal
SIDS feedback loop
See figure
What occurs in CO poisoning
CO prevents hemoglobin from releasing O2
Reduces oxygen carrying capacity, but not PaO2
O2 delivery to tissue drops without triggering carotid body
No change in PaCO2 or pHa
Slowly suffocate without a gasp/rescue response
Treatment: 100% O2 or hyperbaric O2 therapy
