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Voluntary control

  1. Voluntary control
  2. This is from the cortex directly to the spinal cord
  3. Automatic control : In medulla & pons
  1. MEDULLA – has pre botzinger complex  (between nucleus ambiguous and lateral rectal nucleus) which acts as pacemaker for spontaneous respiration, also contains DRG & VRG (DORSAL &VENTRAL RESPIRATORY GROUP OF NEURONS)

a. DRG - contains inspiratory neurons which supply inspiratory muscles

b. VRG  - both inspiratory & expiratory neurons


  1. PONS – contain 2 centres  
    1. Apneustic centre (in lower pons) :  stimulates inspiratory neurons. If not inhibited by vagus and pneumotaxic centre will cause apneusis .
    2. Pneumotaxic centre (in upper pons) : inhibit apneustic centre .Near Parabranchial Nucleus (NPBL)

Effect of Lesion/ Transection of brainstem on respiration


Section A: Above pons :
Normal tidal respiration but voluntary control is lost. If vagus also cut then slow & deep breathing because vagus inhibits apneustic centre .

Section B: At Mid pons :
loss of inhibitory action of pneumotaxic centre on apneustic centre there is stimulation of inspiratory neurons by apneustic resulting in slow and deep breathing. If vagus also cut then APNEUSIS .

Section C: Between Pons & Medulla
: Spontaneous respiration continues, although somewhat- irregular and gasping Q because respiration is produced by medulla but made rhythmic & regular by pontine centres .

Section D: Below medulla:
No respiration. Q


Factors affecting the respiratory centre

1. Chemical

        CO2 / O2 / H+


2. Non – chemical

a.   Vagal afferents from airways / lungs

b.  Pons / hypothalamus / limbic system

c.   Proprioceptors
d.  Baroreceptors


3.  Hemical control

The chemoreceptors for chemical control are the

  • Peripheral chemoreceptors Viz the carotid and the aortic bodies
  • Central chemoreceptors situated in the ventral surface of the medulla
  1. Peripheral chemoreceptors
    These chemoreceptor are located in - (a) Carotid bodies  → at the birfurcation of the common carotid artery (bilaterally) Afferent fibers via  Hering’s Nerve of IX CN  to the dorsal respiratory area of the medulla.
    1. Aortic bodies located in arch of Aorta afferent fiber via X CN to dorsal respiratory area of the medulla.
  2. These receptors are stimulated by: -

a. a rise in PCO2 of arterial blood

b. a rise in H+ conc.

c. a decline in the PO2

  1. Each carotid and aortic body (glomus) contains 2 types of cells, type I and type II cells. The type I (glomus cells) respond to hypoxia; they have O2 – sensitive K+ channels
  2. Blood flow in each 2 mg carotid body is about 0.04 mL/min. or 2000 ml/100gm of tissue/min.
  3. Because the blood flow per unit of tissue is so enormous, the O2 needs of the cells can be met largely by dissolved O2 alone. Therefore, the receptors are not stimulated in conditions such as Anemia and Carbon Mono oxide poisoning
  4. Maximally stimulated by KCN (cyanides)

4. Central chemoreceptors

There respond to H+ only.

They are sensitive to the H+ in the CSF and the brain interstitial fluid. CO2 can influence these central chemoreceptors only indirectly by getting converted into H+. By virtue of this, CO2 is able to act on both central (60-70% of the effect of CO2) as well as on peripheral (30-40% of the effect of CO2) chemoreceptors.

Apnea point :
   pCO2 levels at which respiration stops. A CO2 drive is needed to maintain the respiration. Normal 37 mmHg.


5. Ventilatory response to CO2

The link between metabolism and ventilation is CO2 and not O2

There is a linear relationship between respiratory minute volume and alveolar pCO2        


6. Ventilatory response to O2 lack

There is no increase in ventilation till the PAO2 (alveolar PO2) becomes less than 60 mmHg. The reasons for this

lack of response are :

  1.  Hb is a weaker acid than HbO2; therefore with less O2, there is more Hb which by being weaker acid tends to inhibit the ventilation
  2.  Also, as ventilation increases, the CO2 that is washed out counters the increase in ventilation

7. Ventilatory response to CO2 and O2

This exhibits a complex relationship, the effect of CO2 excess and O2 lack is more than additive. If one were to plot a curve between CO2 and ventilation at different fixed O2 levels, one would get a fan of curves. The slope of the curve (between CO2 and ventilation) would increase significantly with decreased O2 levels.


The intersection of these fan of curves is at one single point.

Since this point of intersection is below the normal value of PACO2 of 40 mmHg, it shows that there is normally a slight but definite CO2 drive of the respiratory centre.

Ventilatory response to H+ and CO2

Here, the effect is simply additive


8. Breath Holding

The breaking point is the point at which breathing can no longer be voluntarily inhibited (because of increase in CO2 and decrease in O2)

Breath holding can be prolonged by:

  1. Removal of carotid bodies
  2. Breathing 100% O2 before breath holding
  3. Hyperventilating room air (because of the initial in CO2 of arterial blood)
  4. By breathing gas mixture low in O2 and high in CO2, breath holding can be prolonged for an additional 20 seconds
  5. Encouragement

Non–chemical influences

  1. Responses mediated by receptors in the airways and lungs (all are vagally mediated)

Vagal innervation

Type of receptors

Location in interstitium




Slowly adapting

Among airway smooth muscle

Lung inflation

i. Inspiration time ed

ii. Hering - Breuer reflexes

iii. Bronchodilation

iv. Tachycardia


Rapidly adapting

Among airway epithelial cells

i. Lung hyper inflation

ii. Irritants

i. Hyperpnoea

ii. Cough

iii. Bronchoconstriction

iv. Mucus secretion

Unmyelinated C fibres

Pulmonary C fibres (J receptors) Bronchial C fibres

Close to blood vessels

i. Lung hyper – inflation

ii. Irritants


i.  Apnoea followed by rapid breathing

ii. Bronchoconstriction

iii.  HR

iv.  BP

v. Mucus secretion


1. Hering-Breuer Reflexes:

a. Hering-Breur Inflation reflex is an increase in the duration of expiration - produced by steady lung inflation.          

b. Hering-Breuer deflation reflex is a decreased in the duration of expiration produced by marked deflation of the lung .

J-Receptors (Juxtracapillary):They are present in alveolar interstitium, supplied by Unmyelinated C fibres of vagus. They are stimulated by hyperinflation of the lung, but they respond as well to intravenous or intracardiac administration of chemicals such as Capsaicin, Increased fluid in alveolar interstitium. The reflex response that is produced is apnea followed by rapid breathing, bradycardia and hypotension (pulmonary chemoreflex). Eg. CHF, Pulmonary odema, Heavy exercise etc

Head's paradoxical reflex:

a. Inflation of lungs lead to further inflation. Helps in 1st breath of child.

b. Seen during labour. Clamping of umbilical cord results in a fall in arterial oxygen and slight rise in carbon dioxide tension. These factors stimulate the respiratory centre directly and via the chemoreceptors in carotid body.


4. Baroreceptors stimulation

Inhibits respiration ; the effect is almost of no physiologic importance


5. Effect of sleep

There is a decrease in sensitivity to CO2 during slow wave sleep; during REM sleep ,there is even further decrease in sensitivity to CO2


V. Hypoxia






Underlying cause

PaO2 is ed

Amount of

available Hb


O2 carrying capacity is

normal but O2 delivery

is decreased

No utilization at

tissue level


High altitude, lung


Anaemic, CO


Heart failure shock









O2 Content dissolved





Combined (with








Stimulated (+)

Not stimulated

Strongly stimulated



stimulated (+++)

Amount of

reduced Hb


Total Hb ed, HHb





Can be present


Can be present


2. C.O. poisoning

Produces anaemic type of hypoxia. The uptake of CO is diffusion limited  as it has very high affinity for Hb  so it crosses the alveolar membrane and maximally binds to Hb and very little dissolves in blood. Therefore the partial pressure of CO in the blood entering the pulmonary capillaries is zero.  The affinity of hemoglobin for CO is 210 times its affinity for O2, and COHb liberates CO very slowly .

C.O. poisoning is especially dangerous because

a. Less Hb is available for carrying O2

b. It does not stimulate the chemoreceptors

c. There is a shift of the O2 – Hb dissociation curve to the left


3. High altitude

a. High altitude pulmonary edema is a serious form of mountain sickness à pulmonary edema prone to occurs in individual who ascend quickly to altitudes above 2500m and engage in heavy physical acitvity during the first 3 days after arival. It is associated with marked pulmonary hypertension due to vasoconstriction . The edema is patchy in nature. It is due to increased capillary permeability , increased filtration pressure but left atrial pressure is normal . Nifedipine, Steroids & Carbonic Anhydrase inhibitor are of value in the t/t and prevention of the condition, also rest and O2. Q

Acute mountain sickness  in unacclimatized persons: -

  1. At 3700m (12000 feet) symptoms :irritability, drowsiness, lassitude, mental and muscle fatigue.
  2. Above 18,000 feet seizures
  3. Above 23,000 feet (conciousness lost)

Cause cerebral edema due to arteriolar dilation

 T/t for Alkalosis Acetazolamide and for cerebral edema gluco-corticoids


c. Acclimatization refers to changes in the body tissues in response to long term exposure to hypoxia i.e. at high altitude for days, weeks or years the person becomes more and more acclimatized to low PO2. The principal means by which acclimatization comes about are: -

  1. A great increase in pulmonary ventilation  → on immediate exposure to very low Po2, the hypoxic stimulation of the chemoreceptors increase alveolar ventilation about 65% above normal. This is immediate compensation for the high altitude.”
  2. Increased in RBC  → Due to hypoxia → ↑ erythropoietin → polycythemia
  3. Increased diffusion capacity of lungs  → it increased three folds above the normal; and Increased T.L. capacity.
  4. Pulmonary Hypertension  → Note that hypoxia causes vasoconstriction in lungs.
  5. Increased vascularity of the tissue  à density ↑es in skeletal and cardiac muscle.
  6. Increase alkalization of urine.
  7. Increased ability of the cells to use O2, despite the low PO2  → due to ↑ed conc of oxidative enzymes and ↑ed density of mitochondria at cellular level.

The alkalosis tends to shift the O-HDC to the left; recall that alkalosis also favours formation of red cell. 2,3 DPG which tends to shift the O-HDC to the right. The net effect is a slight shift of the O-HDC to the right (i.e the P50 increase slightly)


d. Other points

  1. PB (the atmospheric pressure) decrease
  2. Composition of the air remains the same
  3. PH2O remain the same
  4. PAO2 decreases
  5. PACO2 decreases (because of hyperventilation)
  6. The sensitivity of the carotid body to hypoxia does not increase; in fact, prolonged hypoxia decrease the sensitivity

4. P(A – a) O2 gradient

This is affected in hypoxic hypoxia, in other types of hypoxia, it is normal

In hypoxic hypoxia due to high altitude and hypoventilation, it is decreased, in hypoxic hypoxia due to diffusional defect and night to left shunt, it is increased.


Latest Trends

  1. Hypoxia-inducible factors (HIFs) are transcription factors that respond to HYPOXIA.
    1. Hypoxia promotes the formation of blood vessels, and is important for the formation of a vascular system in embryos. The hypoxia in wounds promotes the formation of blood vessels, but also the migration of keratinocytes and the restoration of the epithelium.In general, HIFs are vital to development.
    2. Therapeutic Potential: Recently several drugs have been developed which act as selective HIF prolyl-hydroxylase inhibitors. Eg.FibroGen's compounds FG-2216 and FG-4592. By inhibiting HIF prolyl-hydroxylase, the activity of HIF-1α in the bloodstream is prolonged, which results in an increase in endogenous production of erythropoetin.
  2. OXIDATIVE STRESS: It is due to various free oxygen radicals which dameages the lipid membrane, proteins, nucleus etc.

Methods of Measuring Oxidative stress

There are several methods for measuring Oxidative stress that includes
  1. The measurement of lipid oxidation products such as malonaldehyde in blood on urine ;
  2. In vivo oxidizability of blood fractions (such as LDL)
  3. Vitamin E or vitamin C levels in blood fractions (including LDL)
  4. Catalase or Superoxide dismutase levels in blood fractions
  5. Lipid peroxides in blood
  6. Volatile compounds such as ethane and pentane in expired breath
  7. Glutathione/glutathione disulfide in blood factions
  8. Eicosanoids in urine
  9. Autoxidative, non-cyclooxygenase-denived eicosanoids in plasma
  10. The “TRAP” assay that measures the total peroxyl radical-trapping antioxidant power of blood serum
  11. BMR
    1. Energy expenditure in resting state is given by RMR or the Resting Metabolic Rate.
    2. The metabolic rate determined at rest in a room at a comfortable temperature in the thermoneutral zone 12–14 hours after the last meal is called the basal metabolic rate (BMR).
    3. Katch-McArdle formula is most accurate for its calculatiom on the basis of lean body mass:    
    4. P=370 +b(21.6. LBM) where LBM is the lean body mass in kg.
    5. This value falls about 10% during sleep and up to 40% during prolonged starvation.
    6. The rate during normal daytime activities is, of course, higher than the BMR because of muscular activity and food intake.
    7. The maximum metabolic rate reached during exercise is often said to be 10 times the BMR.

Factors Affecting the Metabolic Rate

The metabolic rate is affected by many factors. One of the most important is muscular exertion. O2 consumption is elevated not only during exertion but also for as long afterward as is necessary to repay the O2 debt .


Factors Affecting the Metabolic Rate.

Muscular exertion during or just before measurement

Recent ingestion of food (SDA)

High or low environmental temperature

Height, weight, and surface area






Emotional state

Body temperature

Circulating levels of thyroid hormones

Circulating epinephrine and norepinephrine levels

Effect of Height, weight, and Body surface area (BSA)on BMR

  1. BMR has a stronger correlation with body weight than with any other nutritional anthropometric index used as a single independent variable.
  2. BMR has highest correlation with Lean body mass as compared to Total weight (fat + Lean body weight), BSA & Height.
  3. ince BMR is the energy consumption in resting state in metabolic active tissue i.e lean body mass (adipose tissue is metabolically inert) BMR depends very much on LBM. By far the main determinant of resting metabolic rate is fat-free mass
  4. In a very tall thin and short obese person BMR differs but BSA can be similar so low correlation. Same way BMI depends more on Body weight rather Lean body weight so again low correlation.
    1. Recently ingested foods also increase the metabolic rate because of their specific dynamic action (SDA). The SDA of a food is the obligatory energy expenditure that occurs during its assimilation into the body.
    2. Another factor that stimulates metabolism is the environmental temperature. The curve relating the metabolic rate to the environmental temperature is U-shaped. When the environmental temperature is lower than body temperature, heat-producing mechanisms such as shivering are activated and the metabolic rate rises.
    3. When the temperature is high enough to raise the body temperature, metabolic processes generally accelerate, and the metabolic rate rises about 14% for each degree Celsius of elevation.
  5. Nitrogen narcosis
    1. Nitrogen narcosis( inert gas narcosis, raptures of the deep, Martini effect) is a reversible alteration in consciousness that occurs while scuba diving at depth as under high pressure nitrogen becomes soluble in blood and reaches the brain.
    2. Apart from helium, and probably neon, all gases that can be breathed have a narcotic effect, which is greater as the lipid solubility of the gas increases.
    3. The precise mechanism is not well understood, but it appears to be the direct effect of gas dissolving into nerve membranes and causing temporary disruption in nerve transmissions. 
    4. Some of these effects may be due to antagonism at NMDA receptors and potentiation of GABAA receptors. Similar to the mechanism of ethanol's effect, the increase of gas dissolved in nerve cell membranes may cause altered ion permeability properties of the neural cells' lipid bilayers.
    5. An early theory, the Meyer-Overton hypothesis suggested that narcosis happens when the gas penetrates the lipids of the brain's nerve cells, causing direct mechanical interference with the transmission of signals from one nerve cell to another.

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