School of Medicine

Control of Breathing

1. Control of breathing is effected by intrinsic rhythmicity modified by neural and chemical input.
2. Final common pathway: phrenic nerves, nerves to intercostals, etc., Pulmonary ventilation is therefore determined by:
3. The interval between successive groups of nerve discharges to the muscles of inspiration (and expiration, if active). This determines the rate of respiration.
4. The frequency of the nerve impulse transmitted by the individual nerve fiber to its motor unit.
5. The duration of nerve fiber activity.
6. The number of motor units activated during each inspiration or expiration.
7. Respiratory center - anatomically diffuse, functionally integrated.
8. Rhythmic pattern of breathing
9. Medullary Center
10. Inspiratory and expiratory neurons located in reticular formation of medulla beneath the lower part of the fourth ventricle.
11. Spontaneous activity - can section brain above the respiratory center and still get rhythmic inspiration and expiration
12. These do not appear to be discrete areas of expiratory and inspiratory neurons (as often seen in texts) but are anatomically intermingled. There appear to be two dense bilateral aggregations of respiratory neurons.
13. Dorsal respiratory groups (DRG). Located in the ventrolateral portion on the nucleus of the tractus solitarius. Primarily inspiratory cells.
14. These inspiratory neurons project primarily to the contralateral spinal cord and drive the diaphragm via the phrenic nerves. DRG units also project to the VRG.
15. The nucleus of the tractus solitarius is a primary projection site of visceral afferents from the 9^th and 10^th cranial nerves, including input from the arterial chemoreceptors, baroreceptors, stretch receptors in the heart and lungs, and many others. The location of the DRG within this tract suggests that the DRG may function to integrate afferent information for the control of breathing.
16. Two types of inspiratory neurons in the DRG: type Ia are inhibited by lung inflation and Type Ib are excited by lung inflation. These appear to be related to the Hering-Breuer inflation and deflation reflexes, respectively.
17. Ventral respiratory groups (VRG) - associated with nucleus ambiguus, para-ambiguus, nucleus retromabigualis - both inspiratory and expiratory cells. Function of VRG neurons is to project to distant sites and drive either spinal respiratory motorneurons (primarily intercostal and abdominal) or the auxiliary muscles of respiration innervated by the vagi, including structures of the larynx and pharynx. A few fibers from Bötzinger complex project to DRG.
18. Respiratory rhythm generation - mechanism is still unknown, but cells in pre-Btzinger complex may act as pacemakers.
19. Apneustic Center
20. Location: In reticular formation of pons above the medullary respiratory center.
21. If the brain is sectioned immediately above this level and the vagus nerves are transected get prolonged inspiratory efforts interrupted by occasional expiratory efforts (apneusis).
22. Apneusis only occurs if the vagus nerves are also transected. This suggests that afferent information, from the vagus nerves (and possibly the spinal cord) may be important in preventing apneusis.
23. Apneusis is probably a general phenomenon involving sustained discharge of medullary inspiratory neurons.
24. The apneustic center may be the site of the normal "inspiratory cutoff switch." It is the site of projection of the various inputs that can terminate inspiration. Apneusis arises from inactivation of this inspiratory cutoff mechanism.
25. Thus the apneustic center must stimulate inspiratory neurons and directly or indirectly inhibit expiratory neurons.
26. Pontine Respiratory Groups (Pneumotaxic Center)
27. Located in the upper pons (nucleus parabrachialis medialis; Kölliker-Fuse nucleus)
28. If the brain is transected immediately above the pneumotaxic center, the pattern of respiration shows an essentially normal balance between inspiration and expiration.
29. Electrical stimulation of the above structures results in synchronization of phrenic activity with the stimulus and premature switching of respiratory phases. Pulmonary inflation afferent information inhibits pneumotaxic center respiratory activity.
30. The pneumotaxic center probably functions to "fine tune" the respiratory pattern, whether by setting the timing of the inspiratory cut off or by modulating the respiratory system's response to stimuli such as hypercapnia, hypoxia, and lung inflation. In any case, respiratory rhythmicity can exist without the pneumotaxic center.
31. The pneumotaxic center then inhibits inspiration either by direct effects on the inspiratory neurons, or more likely by inhibiting the apneustic center.
32. Spinal Pathways:
33. Projecting axons from the DRG, VRG, cortex, and other supraspinal sites descend in the spinal white matter to influence phrenic, intercostal, and abdominal motorneurons of respiration
34. At the level of the spinal respiratory motorneurons, there is integration of descending influences as well as the presence of local spinal reflexes that can affect these motorneurons. Ascending pathways in the cord can also influence respiration.
35. Inspiratory and expiratory components appear to be separated in the cord.
36. Descending axons with inspiratory activity excite external intercostal motorneurons and also inhibit internal intercostal motorneurons by exciting spinal inhibitory interneurons.
37. Reflex mechanisms of respiratory control (See Levitzky pages 196-197 for complete list)
38. Respiratory reflexes from pulmonary stretch receptors. (Hering-Breuer reflexes)
39. Hering-Breuer inflation reflex:
40. Stimulus - pulmonary inflation (a "stretch reflex")
41. Receptor site - large and small airways (within smooth muscle)
42. Afferent pathway - vagus
43. Effect - apnea; bronchodilatation; (increased H.R., decreased SVR)
44. Show very little adaptation
45. Controversial whether the pulmonary stretch reflex is important in determining rate and depth of ventilation in adult man, since the central threshold is high (VT's > lL) during eupnea.
46. May be important in babies.
47. Hering -Breuer deflation reflex:
48. Stimulus - pulmonary deflation
49. Receptor site - lungs (probably also in airways)
50. Afferent pathway - vagus
51. Effect - hyperpnea
52. Probably not too important under normal circumstances
53. Paradoxical reflex of Head (partial block of vagus)
54. Stimulus - pulmonary inflation
55. Receptor site - lungs
56. Afferent pathway - vagus
57. Effect - inspiration
58. First breath of newborn; sigh
59. Other pulmonary reflexes affecting respiration:
60. Mechanical or chemical irritation of airways (and alveoli?) Cause cough or hyperpnea and bronchoconstriction.
61. Pulmonary embolism causes apnea or rapid shallow breathing; pulmonary vascular congestion causes hyperpnea. Receptors in pulmonary vessels (Type J receptors)
62. Diving reflex (see Lecture on Diving Physiology).
63. Cardiovascular - respiratory reflexes
64. Arterial chemoreceptors
65. Stimulus - low PaO₂, high PaCO₂, low pHa
66. Receptor - carotid bodies, aortic bodies
67. Afferent pathways - glossopharyngeal (carotid body) and vagus
68. Effect - Hyperpnea, bronchoconstriction
69. Arterial Baroreceptors (minor influence on respiration)
70. Stimulus - high arterial blood pressure
71. Receptors - carotid sinus, aortic arch
72. Afferent pathway - glossopharyngeal, vagus
73. Effect - Apnea
74. Pharyngeal dilator reflex
75. Stimulus - negative pressure in upper airway
76. Receptor sites unknown - in nose, mouth, upper airway
77. Afferent pathway - trigeminal, laryngeal, glossopharyngeal
78. Effect - contraction of pharyngeal dilator muscles
79. Important in preventing obstructive sleep apnea
80. Muscle and tendon influences on respiration
81. Receptors in diaphragm, intercostal muscles and tendons and joints of limbs can stimulate respiration.
82. Pain - somatic pain causes hyperpnea:
83. The vagus nerve and breathing
84. Afferents
85. Hering - Breuer and paradoxical reflex
86. Sensory innervation of airways
87. Aortic chemoreceptors and baroeceptors
88. Efferents - bronchomotor, bronchial secretion (below recurrent laryngeals). Glottis (above recurrent laryngeals).
89. Respiration after vagal section- slower and deeper due to loss of stretch reflexes. Main danger due to difficulty in swallowing and loss of cough reflex.
90. Influences of higher center on breathing
91. Maximum voluntary ventilation - highest E attainable
92. Speech, singing, etc.
93. Emotional states
94. Chemical control of breathing - a negative feedback system
95. Arterial PO₂, PCO₂ and pH
96. CSF pH and PCO₂
97. CO₂
98. Regulation of PaCO₂ the most important input in the control of ventilation. (Remember, however, that CO₂ changes will produce pH changes.)
99. Powerful stimulus - The greatest respiratory stimulation that can be produced in nonexercising individuals is that produced by increasing PICO₂. Much greater than lowering PIO₂.
100. Sensitive control - PaCO₂ changes little (< lmmHg), if at all, during exercise even though ECO₂ may be 10 times normal.
101. Response to inspired CO₂
102. Increased PICO₂ Increased E
103. Note steepest slope is between 5-10% CO₂ in inspired air (PaCO₂ 38-70 mmHg). Levels off above 10%.
104. Above approximately 7% CO₂ in inspired air effects become quite pronounced: vigorous respiratory stimulation, dyspnea, faintness, severe headache, and dulling of consciousness.
105. Above about 15% CO₂ inspired unconsciousness, muscular rigidity, tremors.
106. With 20-30% CO₂ inspired generalized convulsions.
107. Although CO₂ is normally a respiratory stimulant, acute very high PaCO₂'s (> 60-70 mmHg) produce respiratory depression.
108. The response to lower inspired CO₂ concentrations:
109. Concentrations of CO₂ producing PACO₂'s of 38-50 ( PaCO₂'s in same range) linearly increase E. Young man: E = 2-5L/min/mmHg PaCO₂; decreases with age: about ½ at 70 years of age.
110. Note effect of PaO₂: curve steeper and shifted to the left.
111. Response may be decreased by chronic airway obstruction, sleep, and especially anesthesia, barbiturates, opiates.
112. Metabolic acidosis shifts the curve to the left.
113. Increasing E increases removal of metabolically produced CO₂.
     PaCO₂
     Therefore, under normal circumstances: increased PACO₂ Increased E decreased PaCO₂.
114. Mechanism of CO₂ influence on control of respiration:
115. Both the peripheral chemoreceptors (carotid and aortic bodies) and central chemosensitive sites are stimulated by CO₂.
116. CO₂ effects at each chemosensitive site may be due to either a (local) rise in PCO₂ or H⁺ concentration.
117. Central effects of PACO₂ are much greater than the peripheral chemoreceptor effects. Probably about 80% is central, 20% is from arterial chemoreceptors. The breath to breath response originates from the arterial chemoreceptors.
118. Arterial chemoreceptors:
119. At normal levels of arterial PCO₂, pH and PO₂ there is considerable chemoreceptor impulse traffic over the carotid sinus nerve. All have similar response patterns to a given stimulus. No recruitment.
120. In single fiber recordings each fiber appears to transmit the activity generated by decreased pHa, increased PaCO₂ and decreased PaO₂.
121. Response nearly linear over PCO₂ range of 20-60 mmHg
122. Also stimulated by decreased blood pressure and by increased sympathetic activity, which presumably acts by causing a vasoconstriction, thereby reducing blood flow to the chemoreceptor.
123. Central sites of CO₂-induced stimulation:
124. Central chemosensitive sites appear to be on the brain side of the blood-brain barrier. Response takes about 60 sec.
125. CO₂ can easily diffuse through the blood - brain barrier, but H⁺ ions and HCO^-₃ ions do not pass through easily. However, any change in PCO₂ in the brain will lead to a proportional change in the H⁺ concentration. Thus the chemosensitive cells may actually be responding to H⁺ concentration changes.
126. Under normally circumstances the brain is producing CO₂. Brain CO₂ level will be higher than that of arterial blood.
127. In certain states (e.g. metabolic acidosis or alkalosis) blood H⁺ concentration and central H⁺ concentration may change in opposite directions. This is because of the extreme slowness with which fixed acids and bases cross the blood-brain barrier and the great ease with which CO₂ traverses it. There may be active transport of HCO^-₃ across the blood brain barrier but it is slow.
128. Hydrogen Ions
129. Role of changes in H⁺ concentration on regulation of respiration are difficult to separate from CO₂ effects.
130. Response to H⁺ nearly linear from 20-60 nanequivalents per liter.
131. O₂.
132. Response to alveolar hypoxia
133. Little effect on respiration until PAO₂ < 50 - 60 mmHg.
134. Interaction with PACO₂; response is enhanced when hypoxia is simultaneous with hypercapnia.
135. The peripheral chemoreceptors appear to be entirely responsible for the ventilatory response to hypoxia.
136. In the absence of the carotid chemoreceptors the effect of increasing degrees of hypoxia is a progressive depression of the central mechanisms of respiratory control, leading to complete respiratory failure.
137. It appears that the aortic arch chemoreceptors alone are not able to sustain the increased ventilation in hypoxia.
138. When the peripheral chemoreceptors are intact, the depressant effects of hypoxia on respiration can by overcome by the influences of nerve impulses reaching the respiratory centers from the chemoreceptors.
139. The degree of the respiratory response to hypoxia is related to the change in O₂ tension (PaO₂) rather than the O₂ content of arterial blood.
140. Hypoxia alone (as in altitude) increases E which leads to decreased PaCO₂ and subsequent respiratory alkalosis.
141. Mechanism of chemoreception by the carotid body unknown
142. Certain enzyme poisons that block the formation of ATP stimulate the carotid body - Hypoxia may act in a similar manner.
143. Carotid body has a very high blood flow (2000 ml/100 grams of tissue/min) and very small A-V O₂ difference (0.15 ml O₂/100 ml blood), even though is has one of the highest metabolic rates in the body.
144. Two types of cytochrome a₃ in the carotid body: One with a high affinity for O₂ (which may maintain normal metabolism) and one with a low affinity for O₂ (which may be associated with impulse generation).
145. Relation between structure and generation of impulses.
146. Glomus cells with nerve fiber in close proximity. Form reciprocal synapses so glomus cells are both pre- and post-synaptic to the sensory afferent nerves.
147. Glomus cells high in dopamine, acetylcholine
148. Ventilatory response to exercise:
149. Immediate response - "neural component"
150. Central Command
151. Learned or conditioned reflex
152. Direct connections from motor cortex-collaterals from motor neurons to muscles.
153. Coordination in hypothalamus
154. Proprioceptors or mechanoreceptors in limbs (probably not muscle spindles or Golgi tendon organs.)
155. Subsequent Increase
156. During moderate exercise
157. Arterial chemoreceptor
158. PO₂ - usually no change in mean
159. PCO₂ - usually no change in mean
160. [H⁺] - usually no change unless cross anaerobic threshold
161. [K⁺] - minor role
162. Oscillations in arterial PO₂ and PCO₂ probably important
163. Metaboreceptors in exercising muscles
164. Nociceptors - H⁺, K⁺, bradykinin, arachidonic acid
165. Cardiac receptors
166. Venous chemoreceptor - venous PO₂, pH, PCO₂
167. Temperature receptors - temperature stimulates breathing
168. During exercise severe enough to exceed anaerobic threshold (lactic acid buffered by HCO^-₃ produces CO₂)
169. Arterial chemoreceptors
170. PCO₂
171. [H⁺]
172. Central chemoreceptors PCO₂ H⁺
173. Potentiation of chemoreceptor responses during exercise.

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Last updated Tuesday, November 25, 2003 2:47 PM

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