Respiratory Physiology During Sleep
BY
AHMAD YOUNES
PROFESSOR OF THORACIC MEDICINE
Mansoura Faculty of Medicine
The respiratory system provides continuous homeostasis
of PaO2, PaCO2, and pH levels during constantly changing
physiologic conditions.
• This elegant system responds promptly to subtle
variations in metabolism occurring in both health and
disease.
• During wakefulness, volitional influences can override
this automatic control.
• Modifications occur in the regulation and control of
respiration with the onset of sleep. Furthermore, these
changes differ significantly with specific sleep stages.
• Consequences of these alterations of respiratory control
can result in the pathogenesis of sleep-related breathing
disorders and limit the usual respiratory compensatory
changes to specific disease states.
Most patients who have arterial oxygen
desaturation in the sleep center do so
from apnea or hypopnea.
• Patients with respiratory disorders may have sleeprelated arterial oxygen desaturation and/or
hypoventilation without a significant number of
discrete apnea or hypopnea events
• These abnormalities in gas exchange can occur
because the normal effects of sleep on ventilation
and oxygenation are magnified by abnormal
function of the lung, chest wall, respiratory
muscles, or ventilatory control centers.
NORMAL CHANGES IN VENTILATION
DURING SLEEP
Sensors primarily include central and peripheral
chemoreceptors, vagal pulmonary sensors, and chest wall
and respiratory muscle afferents. Data from these sensors
regarding dynamic oxygen and CO2 levels, lung volumes, and
respiratory muscle activity are continuously transmitted to the
central controller.
Within the medulla, the central controller generates an
automated rhythm of respiration that is constantly modified in
response to an integrated input from the various receptors.
The controller modulates motor output from the brainstem to
influence the activity of the effectors, namely respiratory
motoneurons and muscles. These effectors then alter minute
ventilation and gas exchange accordingly.
The central pattern generator is composed of
predominately three neuronal groups
1- Drsal respiratory group
2- Ventral respiratory group
3- Pontine respiratory group.
– The dorsal respiratory group is in the ventrolateral
subnucleus of the nucleus tractus solitarius. This
neuronal group is primarily active during inspiration
receiving input from pulmonary vagal afferents.
Many of these neurons excite lower motor cranial
nerves that dilate the upper airway prior to excitation of
the contralateral phrenic and intercostal neurons in the
spinal cord. This coordinated output must occur in the
correct timed sequence to permit the movement of air
through a patent airway.
Ventral respiratory group
• The ventral respiratory group is located in the ventral lateral
medulla from the top of the cervical cord to the level of the
facial nerve.
• This group contains the Botzinger complex, the preBotzinger
neurons, the rostral portion of nucleus ambiguous, and
nucleus retroambigualis.
• The Botzinger complex contains neurons that are active
during expiration and inhibit inspiration.
• The preBotzinger complex contains propriobulbar neurons that
participate in generating the rhythm of respiration.
• The caudal portion of this group is primarily composed of
expiratory neurons that project to intercostal, abdominal, and
external sphincter motor neurons.
Ventilatory control
• The medullary centers respond to direct influences from
the upper airways, intra-arterial chemoreceptors, and
lung afferents by the 5th, 9th, and 10th cranial nerves,
respectively.
• The dorsal respiratory group seems to be active
primarily during inspiration .
• The ventral respiratory group, contains both inspiratory
and expiratory neurons. Ventral respiratory group
output increases in response to the need for forced
expiration occurring during exercise or with increased
airways resistance.
• Respiratory effector muscles are innervated from the
ventral respiratory group by phrenic, intercostal, and
abdominal motoneurons.
Pontine respiratory centers
• The pneumotaxic center in the rostral pons consists of the
nucleus parabrachialis and the Kolliker-Fuse nucleus.
• This area seems primarily to influence the duration of inspiration
and provide tonic input to respiratory pattern generators.
• The apneustic center, located in the lower pons, functions to
provide signals that terminate smoothly inspiratory efforts.
• The pontine input serves to fine tune respiratory patterns and
may additionally modulate responses to hypercapnia, hypoxia, and
lung inflation.
• The automatic central control of respiration may be influenced and
temporarily overridden by volitional control from the cerebral
cortex for a variety of activities, such as speech, singing,
laughing, intentional and psychogenic alterations of
respiration, and breath holding.
Central chemoreceptors
• Central chemoreceptors, located primarily within the
ventrolateral surface of medulla, respond to changes in
brain extracellular fluid [H1] concentration.
• Other receptors have been recently identified in the
brainstem, hypothalamus, and the cerebellum.
• These receptors are effectively CO2 receptors because
central [H1] concentrations are directly dependent on
central PCO2 levels.
• Central [H1] may differ significantly from arterial [H1]
because the blood-brain barrier prevents polar solute
diffusion into the cerebrospinal fluid. This isolation results
in an indirect central response to most peripheral acidbase disturbances mediated through changes in PaCO2.
• Central responses to changes in PCO2 levels are also
slightly delayed for a few minutes by the location of
receptors in the brain only, rather than in peripheral
vascular tissues.
Peripheral chemoreceptors
• Peripheral chemoreceptors include the carotid bodies
and the aortic bodies.
• The carotid bodies, located bilaterally at the bifurcation
of the internal and external carotid arteries, are the
primary peripheral monitors.
• They are highly vascular structures that monitor the
status of blood about to be delivered to the brain and
provide afferent input to the medulla through the 9th
cranial nerve.
• The carotid bodies respond mainly to PaO2, but also to
changes in PaCO2 and pH.
• They do not respond to lowered oxygen content from
anemia or carbon monoxide toxicity.
Other afferent pathways
• Pulmonary stretch receptors are located in proximal
airway smooth muscles, and respond to inflation,
especially in the setting of hyperinflation. Pulmonary
stretch receptors mediate a shortened inspiratory
and prolonged expiratory duration.
• Additional input is also provided by rapidly adapting
receptors that sense flow and irritation. J receptors
are located in the juxtacapillary area and seem to
mediate dyspnea in the setting of pulmonary vascular
congestion.
• Bronchial c-fibers also affect bronchomotor tone and
respond to pulmonary inflammation.
Other afferent pathways
• Afferent activity from chest wall and respiratory
muscles additionally influences central controller
activity.
• Feedback information regarding muscle stretch,
loading, and fatigue may impact both regulatory
and somato-sensory responses.
• Upper airway receptors promote airway patency
by activation of local muscles including the
genioglossus.
During sleep
• During sleep, the metabolic rate falls (hence,
decreased CO2 production), but this is offset by
a proportionately greater fall in minute
ventilation with the result that the PaCO2
increases slightly.
• The fall in ventilation is due to increased upper
airway resistance and decreased
chemosensitivity as well as the loss of the
wakefulness stimulus to breathe.
• The result is that the PaCO2 rises and the PaO2
falls slightly
Because of the normal position on the flat portion of the O2Hb
dissociation curve, there is little change in the SaO2 as a result of the
fall in PO2 associated with sleep . If the baseline awake PaO2 is lower,
the fall in SaO2 will be greater for the same drop in PaO2.
• In patients with lung disease and a lower awake PO2,
even a normal sleep-related drop in PO2 will be
associated with a larger decrease in the SaO2.
• The change in ventilation with sleep is due to a fall in Vt
with minimal change in the RR.
• During the transition from wake to stage N1 and early
stage N2, the ventilation can be slightly irregular.
However, in stable stage N2 and stage N3, the Vt and RR
are nearly constant.
• During REM sleep, ventilation is irregular with periods of
decreased Vt associated with bursts of eye movements.
• The FRC decreases from wake to sleep.
• During sleep, the hypercapnic ventilatory response
and hypoxic ventilatory response are reduced during
NREM compared with wake and decreased in REM
sleep compared with NREM sleep .
• Both hypoxia and hypercapnea may trigger
arousals from sleep, resulting in a return to the
more tightly regulated ventilatory control
associated with wakefulness.
• Arousal thresholds for hypercapnia range
between 65 and 66 mmHg and do not vary
consistently among the different sleep stages.
• The threshold for arousal in response to hypoxia
is more variable and seems less reliable. Severe
oxygen desaturations in some individuals do not
uniformly result in arousals.
Alveolar hypoventilation
• Alveolar hypoventilation during wakefulness is defined as an
PaCO2 of 45 mm Hg or higher.
• If the sleeping PaCO2 is ≥10 mm Hg above the awake value,
Sleep hypoventilation is said to be present.
Hypoxemia is defined as a low arterial partial pressure of
oxygen (PaO2) relative to predicted values.
A PaO2 < 55 mm Hg while breathing room air is considered
severe and an indication for chronic 24-hour supplemental
oxygen therapy.
Milder degree of hypoxemia can be identified by comparing a
PaO2 with a predicted value for age.
• A simple estimate of a normal predicted PaO2
Pao2=105 – 1/2 age (yr).
Alveolar gas equation
•
The alveolar gas equation allows one to compute the
alveolar (ideal) partial pressure of oxygen (PAO2) from the
fractional concentration of oxygen in inspired gas (FIO2),
which is 0.21 when breathing room air ,and the PaCO2.
• The respiratory exchange ratio (R) is the CO2 elimination
divided by the O2 uptake. At steady state, R is equal to 0.8.
• Computation of the PAO2 and the A-a gradient
PAO2 = FIO2(PB - PH2 O) - PaCO2/R
R=VCO2/VO2 ( assumed to be 0.8)
VCO2= CO2 elimination . VO2 = O2 uptake
• FIO2 = 0.21 (breathing room air), PB is the barometric
pressure (760 mm Hg at sea level), and PH2O is the partial
pressure of water vapor (47 mm Hg at 37°C).
Alveolar gas equation
• The A-a gradient is the difference between the ideal PAO2 and
the actual (measured) PaO2. (usually <20 mm Hg).
PAO2 = 0.21 (760-47) – PaCO2/0.8 = 150- PaCO2/0.8
A-a gradient = PAO2 -PaO2
In patients with hypoventilation of unclear etiology, calculating
an A-a gradient can provide an important clue as to whether
the hypoventilation is due to lung disease or due totally to
hypoventilation.
A normal A-a gradient in a patient with hypoventilation would
suggest a disorder of ventilatory control or muscle weakness.
In a patient with COPD with evidence of both hypoxemia and
hypercapnia , the A-a gradient is increased. The hypoxemia is
due to both V/Q mismatch and hypoventilation.
patient with sickle hemoglobin (Hb S) will have a higher arterial
partial pressure of oxygen (PaO2) associated with a given
SaO2. Hb A = hemoglobin A.
FO2Hb = O2Hb X 100 /(O2Hb+RHb
+COHb + MetHb)
FO2Hb=O2Hb X 100 /Hbt
• where O2Hb, RHb, COHb, and MetHb are the
concentrations of the types of Hb and equal the
total Hb concentration (Hbt).
• For example, if the FO2Hb = 85%, FCOHb = 8%,
FmetHb = 1%, then the FRHb is 6%.
• Using these numbers the SaO2 equals 85 ×
100/(85 + 6) or 93%, which is considerably
higher than FO2Hb of 85%.
The FO2Hb is sometimes called the
fractional saturation and the SaO2 the
functional or effective saturation.
• The PaO2 depends on the SaO2, not the FO2Hb.
That is, the oxyhemoglobin saturation curve
expresses the ratio of oxygenated Hb to the
total Hb available for oxygen binding.
• Neither COHb nor MetHb binds oxygen.
• The position of the oxyhemoglobin saturation curve
is shifted to the left by the presence of COHb or
MetHb.
The previous four fractions of Hb can be accurately
measured by co-oximeters that measure the absorption of 4
or more wavelengths of electromagnetic radiation by blood.
• This is possible because the four forms of Hb differ
in their absorption for the different wavelengths of
radiation.
• In contrast, pulse oximetry uses only two
wavelengths: 660 nm (red) and 940 nm (infrared)
to measure the O2Hb and RHb.
• COHb has about the same absorbance at 660 as
O2Hb and, if present, increases the measured
SpO2 value.
In normal individuals, FCOHb is 2% or
less but can be 8% or more in cigarette
smokers.
• Patients with SCD often have FCOHb values of
4% or more due to production of CO from chronic
hemolysis.
• In patients who are heavy smokers, it is important
to remember that the SpO2 may overestimate the
FO2Hb.
If a patient has a lower than expected SpO2 while awake in
the sleep center, a number of possibilities should be
considered including a faulty oximetry probe, poor signal
quality due to poor perfusion, a shift in the O2Hb
saturation curve or an abnormal Hb.
• If oximetry issues are ruled out, an arterial blood
gas is needed to determine whether hypoxemia is
really present.
• In this situation, co-oximetry analysis could also
determine whether significant COHb or MetHb is
present and determine a true SaO2 and the
fraction of Hb that is oxygenated.
PULMONARY FUNCTION TESTING
• Pulmonary function testing is often needed to evaluate
patients with a low awake PaO2 (or SaO2) or to
determine the etiology of unexpected daytime
hypoventilation or dyspnea on exertion.
• Sometimes pulmonary function testing is ordered after a
sleep study reveals an unexplained low sleeping
baseline SaO2 without discrete apneas or
hypopneas. Therefore, some knowledge of pulmonary
function testing can be very useful for the sleep clinician.
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OVD versus RVD
OVD is associated with a reduced FEV1/FVC ratio, whereas
the ratio is normal or increased in RVD .
In very mild disease, the FEV1 may be normal but the
FEV1/FVC reduced.
The RVD pattern of spirometry is characterized by a normal
FEV1/FVC ratio and a reduced FVC.
American Thoracic Society criteria for a significant
bronchodilator response include an increase in the FEV1 or
FVC by 12% AND an absolute increase of at least 200 mL.
A large improvement of 15% to 40% is suggestive of asthma.
Patients with COPD typically have no response (predominant
emphysema) or a modest response of 10% to 12%
(predominant chronic bronchitis).
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Obesity
In obesity, the FRC is either reduced or reduced in
relation to the RV. Therefore, in simple obesity,
the most common pulmonary function finding is
a reduced ERV. Usually, the TLC and RV are
normal, as is the VC.
In contrast, the obesity hypoventilation syndrome
may be associated with reductions in the TLC
and VC.
The finding of a reduced TLC in a patient with
severe obesity and OSA could be a clue that the
obesity hypoventilation syndrome might be
present.
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MUSCLE STRENGTH
• Inspiratory muscle weakness causes a low TLC.
Expiratory muscle weakness causes an
increased RV.
• Typically, muscle weakness affects both the
inspiratory muscles (diaphragm and intercostal
muscles) and the expiratory muscles
(abdominal muscles) at the same time.
• This results in a pattern of low TLC, high RV,
and low VC
Maximum Inspiratory Pressure and
Maximum Expiratory Pressure
• The MIP is usually performed at RV, and the
MEP is performed at TLC.
• The published normal ranges are wide and
vary considerably between studies.
• For clinically significant changes in the FVC to
begin to occur, the MIP is usually < 60 cm H2O.
• An MEP less than 60 cm H2O is associated with a
reduced ability to cough and clear secretions.
• An American College of Chest Physicians (ACCP)
Consensus group recommended NPPV for
progressive neuromuscular disorders when the MIP
was < 60 cm H2O (or FVC < 50% of predicted).
Respiratory Pressure Meter for
measurements of (MIP/MEP)