Regulation of Breathing

The regulation of breathing is based in the body's acid/base balance. The Central Chemoreceptors (CCR), primarily responsible for the breathing stimulation, are affected by the PaCO_2. The responsiveness of the peripheral receptors is tied to the level of pH and PaCO₂. Together these provide the ultimate in servo-control - sensors provide feedback that increase or decrease breathing.

Medullary Respiratory Center

The rhythmic cycle of breathing originates in the medulla. Higher brain centers (voluntary control), systemic receptors, and reflexes modify the medulla's output. However, no truly separate inspiratory and expiratory centers have been identified.

The medulla does contain several widely dispersed groups of respiratory-related neurons that form dorsal and ventral respiratory groups.

Fig-Schematic illustration of the respiratory components of the lower brainstem (pons and medulla oblongata).
PNC = pneumotaxic center; APC = apneustic center; DRG = dorsal respiratory group; VRG = ventral respiratory group; CC = central chemoreceptors.

Dorsal respiratory groups (DRG)

Composed mainly of inspiratory neurons located bilaterally in the medulla, the DRG controls the basic rhythm of breathing by triggering inspiratory impulses.

These neurons send impulses to the motor nerves of diaphragm and external intercostal muscles.

DRG nerves extend into the VRG, but the VRG neurons do not extend into the DRG.

Vagus and glossopharyngeal nerves bring sensory impulses to the DRG from the lungs, airways, peripheral chemoreceptors, and joint proprioceptors.

Input modifies the breathing pattern.

Ventral respiratory groups (VRG)

Contain both inspiratory and expiratory neurons located bilaterally in the medulla and primarily active in exercise and stress.

VRG sends inspiratory impulses to

Laryngeal and pharyngeal muscles - (from neurons located in the nucleus ambiguus)

Diaphragm and external intercostals - (from neurons located in the rostral area of the nucleus retroambigualis)

Other VRG neurons send expiratory signals to abdominal muscles and internal intercostals - (from neurons in the caudal area)

 

Inspiratory ramp signal: Interaction between the DRG and VRG inspiratory neurons:

Signal starts low and gradually increases to produce a smooth inspiratory effort instead of a gasp.

Fig-Neural impulses from the respiratory center travel to the diaphragm by way of the right and left phrenic nerves. The cervical, thoracic, and lumbar motor nerves stimulate the external intercostal muscles (accessory muscles of inspiration).

Pontine Respiratory Centers

The pons modifies the output of medullary centers.

Two pontine centers are the apneustic and pneumotaxic.

Apneustic center

Stimulates the inspiratory neurons of the DRG and VRG.

Its function only identified by cutting connection to medullary centers (don't know what you've got till its gone!)

Over stimulation from the apneustic center results in apneustic breathing which is characterized by long gasping inspirations interrupted by occasional expirations.

Pneumotaxic center

Sends inhibitory signals to the inspiratory center of the medulla

Controls "switch-off," so controls inspiratory time.

Increased signals increase RR, while weak signals prolong IT and increase V_T.

Reflex Control of Breathing

The Hering-Breuer Inflation Reflex

Receptors located in the visceral pleura, walls of the bronchi and bronchioles.

Lung distention causes stretch receptors to send inhibitory signals to DRG, stopping further inspiration.

In adults active only on large VT (>800 ml)

Regulates rate and depth of breathing during moderate to strenuous exercise

Viewed as a protective mechanism.

Deflation reflex

Sudden lung collapse results in hyperpnea as seen in pneumothoraces.

Head's paradoxic reflex

May maintain large V_T during exercise and deep sighs

May be responsible for babies first breaths at birth

Irritant receptors

Subepithelial mechanoreceptors in the trachea bronchi and bronchioles

Stimulated by inhaled irritants or mechanical factors

Cause bronchospasm, cough, sneeze, tachypnea, and narrowing of glottis

These are vasovagal reflexes.

In hospital triggered by

Suctioning, bronchoscopy, endotracheal intubation

Irritation reponse can be anesthetized by instilling lidocaine into the airway through the endotracheal (breathing) tube.

J-receptors

C-fibers - located in the small airways, blood vessels, interstitial tissues between the pulmonary capillaries and alveolar walls

J-fibers - Located in lung parenchyma juxtacapillary

Stimulated by pneumonia, CHF, pulmonary edema

Cause rapid, shallow breathing and dyspnea

Peripheral proprioceptors

Found in muscles, tendons, joints, and pain receptors

Movement stimulates hyperpnea.

Moving limbs, pain, cold water all stimulate breathing in patients with respiratory depression

Chemical Control of Breathing

Body works to maintain proper levels of O₂, CO₂, and pH through mediation of chemoreceptors as it affects V_E

 

Central chemoreceptors

Fig-The relationship of the blood-brain barrier (BBB) to CO2, HCO3, and H+. CO2 readily crosses the BBB. H+ and HCO3 do not readily cross the BBB. H+ and HCO3 require the active transport system to cross the BBB.  CSF = cerebrospinal fluid.

 

Located bilaterally in the medulla

Stimulated directly by H⁺ ions in the cerebrospinal fluid, indirectly by CO₂ 

The BBB is almost impermeable to H⁺ and HCO₃^– but CO₂ freely crosses from the blood to the cerebrospinal fluid.

In CSF, CO₂ is hydrolized, releasing H⁺.

An increased CO₂ therefore increases H+ in CSF which stimulates the neurons to cause hyperventilation to restore normal levels pH and CO₂.

 increased 2–3 L/min for 1–mm Hg rise in PaCO₂.

In normal circumstances our primary stimulus to breaths is PaCO₂. This is an important point to remember as it is not unusual for patients on mechanical ventilation to be over-ventilated. If their CO₂ is less than the level it takes to stimulate the central chemoreceptors then they will not initiate a breath on their own, and this can be misinterpreted as an apneic period.

Peripheral chemoreceptors

Located in the aortic arch and bifurcations of common carotid arteries

Fig- Location of the carotid and aortic bodies (the peripheral chemoreceptors).

 

Peripheral chemoreceptors' response to ⇓ PaO2

The carotid bodies more responsive to a decrease in PaO₂ than the aortic bodies.

This response is frequently referred to as the "Hypoxic drive" however current research indicates that Hhypoxemia increases receptors sensitivity for H+, and it is this that stimulates a increse in minute ventilation.

⇓PaO2 causes ⇑ for any pH, and vice versa.

In severe alkalosis, hypoxemia has little affect on .

 

Only affected by PaO₂, not CaO₂ (so in conditions such as anemia or COHb, even though the patient's total O₂ content is reduced, the periperhal chemoreceptor's are not stimulated)

Not a significant response until PaO₂ falls to ~60 mm Hg (corresponds to an SaO₂ of 90%) A further fall results in sharp increase in VE. However this response limits out at a PaO₂ of 30 mm Hg, with suppression of respiration occuring below that level.

This means the under normal circumstances, oxygen plays no role in drive to breathe.

 

Fig. 9-5.  Schematic illustration showing how a low PaO2 stimulates the respiratory components of the medulla to increase alveolar ventilation.

 

Once the PaO₂ fall to 60 then, hypoxemia is the most common cause of hyperventilation.

Fig. 9-6.  The effect of low PaO2 levels on ventilation.

 

Peripheral chemoreceptors' response to ⇑PaCO2 and [H+] - 20 to 30% of the ventilatory response to hypercapnia.

Less responsive than central chemoreceptors (CCRs)

One-third of hypercapnic response, but a more rapid response to changes in [H+]

Influenced by fixed acids such as Lactic acid, ketones

In hyperoxia, PCRs are almost totally insensitive to changes in PaCO₂, so any response is due to CCRs responding to changes in CSF [H+].

Low PaCO₂ renders PCRs almost unresponsive to ⇓PaO2.

 

Fig. 9-7.  The effect of PaO2 on ventilation at three different PaCO2 values. Note that as the PaCO2value increases, the sensitivity of the peripheral chemoreceptors increases.

 

Fig. 9-8.  The accumulation of lactic acids leads to an increased alveolar ventilation primarily through the stimulation of the peripheral chemoreceptors. 

Coexisting acidosis, hypercapnia, and hypoxemia maximally stimulate PCRs

Low PaCO₂ renders PCRs almost unresponsive to ⇓PaO2

PCR are also stimulated by:

Hypoperfusion (stagnant or circulatory hypoxia)

Increased temperature

Nicotine - which also causes

Peripheral vasoconstriction

Increased pulmonary vascular resistance

Systemic arterial hypertension

Tachycardia

Increased left ventricular performance

Control of breathing in chronic hypercapnia

A sudden rise in PaCO₂ in the normal person causes an immediate rise in V_E. In slow-rising PaCO₂ (such as seen in the development of severe COPD), the kidneys retain HCO₃–, which maintains CSF pH, so no hyperventilation response is trigger by the chronically elevated CO₂.

Hypoxemia seen with hypercapnia becomes the minute-to-minute breathing stimulus via altered response to [H+].

Hypoxemia is always present in severe COPD due to severe mismatches in V/Q.

An increased F_IO₂ raises the PaO₂ making the PCR less sensitive to [H+] resulting in a higher PaCO₂

Oxygen-induced hypercapnia

O₂ therapy may cause a sudden rise in PaCO₂ in severe COPD with chronic hypercapnic. This rise in CO2 may be significant enough to cause a condition known as CO2 narcosis - the patient becomes obtunded and non-responsive, further hypoventilation occurs, and can lead to coma and death.

Possible explanations include

Hypoxic drive is removed (traditional view).

⇑FIO2 may worsen V/Q mismatch

Hypoxic pulmonary vascoconstriction is reversed to poorly ventilated alveoli

⇑FIO2 may make patient susceptible to absorption atelectasis.

 

A. Low V/Q unit: Hypoxia and hypercapnia on room air (0.21) causes pulmonary vasocontriction which directs blood to alveolus with better ventilation.

B. Increased FIO2 to 0.50 results in absorbtion atelectasis in poorly ventilated unit which further diminishes ventilation while blood flow (perfusion) is increased due to the relief of hypoxic vasoconstriction. This results in further V/Q imbalances: redistributes blood flow to underventilated unit, and ventilation to already well-ventilated unit which is now receiving less perfusion (increased dead space)

Oxygen-induced Hypercapnia: KEY POINTS

The diagnosis of "COPD" does NOT signify chronic hypercapnia or that O₂ therapy will induce hypoventilation. Only an arterial blood gas can show CO₂ retention and compensation by the kidneys.

These characteristics are only in end-stage disease.

Present in small percent of COPD patients

 Concern about O2-induced hypercapnia and acidemia is not warranted in most COPD patients.

 O2 should NEVER be withheld in hypoxemic COPD patients as tissue oxygenation is an overriding priority.

 Be prepared to provide MV to the rare COPD patient who does have severe hypoventilation due to oxygen therapy.

CCR response to acute CO2 increase in chronic hypercapnia

Acute rises in PaCO₂ continues to stimulate the CCRs.

Resulting ventilatory response is depressed due to chemical and mechanical reasons.

Increased HCO₃– prevents as large a fall in pH, as would be seen in a healthy patient.

Abnormal mechanics impair lung ability to increase V_E.

Ventilatory Response to Exercise

Strenuous exercise can increase CO₂ production and O₂ consumption 20-fold.

Ventilation normally keeps pace so all ABG values are held constant.

Mechanism for increased V_E poorly understood: may be

CNS sends concurrent signals to skeletal muscles and to medullary respiratory centers.

Joint movement stimulates proprioceptors, which send excitatory signals to medullary centers.

May also be due to repeated experience causing anticipatory changes in ventilation

Fig. 9-9.  The respiratory center coordinates signals from the higher brain region, great vessels, airways,
lungs, and chest wall. (+) = increased ventilatory rate; (-) = decreased ventilatory rate.

Abnormal Breathing Patterns

Apnea

Absence of breathing. (Ap-knee-a)

Eupnea

Normal breathing (Eup-knee-a)

Orthopnea

Only able to breathe comfortable in upright position (such as sitting in chair), unable to breath laying down, (Or-thop-knee-a)

Dyspnea

Subjective sensation related by patient as to breathing difficulty

Paroxysmal nocturnal dyspnea - attacks of severe shortness of breath that wakes a person from sleep, such that they have to sit up to catch their breath - common in patient's with congestive heart failure.

Hyperpnea

Figure 2-38  Hyperpnea: Increased depth of breathing (Hi-perp-knee-a)

Increased volume with or without and increased frequency (RR), normal blood gases present.

Hyperventilation

Figure 2-39  Hyperventilation. Increased rate (A) or depth (B), or combination of both.

"Over" ventilation - ventilation in excess of the body's need for CO₂ elimination. Results in a decreased PaCO₂, and a respiratory alkalosis.

Hypoventilation

Hypoventilation.  Decreased rate (A) or depth (B), or some combination of both.

"Under" ventilation - ventilation that is less than needed for CO₂ elimination, and inadequate to maintain normal PaCO₂. Results in respiratory acidosis.

_{Can be a slow rate with normal tidal volumes such that the total minute ventilation is inadequate.}

_{Can be a normal rate but with such low tidal volumes that air exchange is only in the dead space and not effective.}

Tachypnea

Increased frequency without blood gas abnormality

Kussmaul's Respiration

Kussmaul's respiration. Increased rate and depth of breathing over a prolonged period of time. In response to metabolic acidosis, the body's attempt to blow off CO₂ to buffer a fixed acid such as ketones. Ketoacidosis is seen in diabetics.

Cheyne-Stokes respirations (CSR)

Gradual increase in volume and frequency, followed by a gradual decrease in volume and frequency, with apnea periods of 10 - 30 seconds between cycle. Described as a crescendo - decrescendo pattern. Characterized by cyclic waxing and waning ventilation with apnea gradually giving way to hyperpneic breathing.

Seen with low cardiac output states (CHF) with compromised cerebral perfusion

Creates lag of CSF CO₂ behind arterial PaCO₂ and results in characteristic cycle. Delayed sensitivity to CO₂ changes- during apnea the CO₂ increase above the threshold for stimulus but the brain is slow to respond, then it over shoots by hyperventilating and the signal to reduce ventilation is slow to be recognized.

Biot's respiration

Similar to CSR but V_T is constant except during apneic periods. Short episodes of rapid, deep inspirations followed by 10 - 30 second apneic period.

Seen with patients with elevated ICP as seen in meningitis

Apneustic breathing (previously described)

Indicates damage to pons

Central neurogenic hyperventilation

Persistent hyperventilation

May be caused by head trauma, severe brain hypoxia, or lack of cerebral perfusion

Mid brain and upper pons damage

Central neurogenic hypoventilation

Medulla respiratory centers are not responding to appropriate stimuli.

Associated with head trauma, cerebral hypoxia, and narcotic suppression

CO₂ and Cerebral Blood Flow (CBF)

CO₂ plays an important role in autoregulation of CBF  mediated through its formation of H⁺.

 Increased CO₂ dilates cerebral vessels and vice versa.

 In traumatic brain injury (TBI), the brain swells acutely. Head is a fixed volume container - cannot expand. When bleeding or swelling occurs in the brain pressures rapidly increase. Raising ICPs exceed cerebral arterial pressure and brain perfusion stops.

Cerebral hypoxia/ischemia - brain death

 Mechanical hyperventilation can lower PaCO₂, which results in vasoconstriction in cerebral vessels, reduction of swelling and ICP.

Controversial as reduces O₂ and CBF to injured brain.

Only effective for the first 24 hours.

Current practice is to treat perfusion pressures pharmacologically rather then use hyperventilation.

All agree must avoid hypoventilation in TBI patients.