Ritu Grewal, MD

• Wake
• Non-REM sleep
– brain is regulating bodily functions in a movable body
• REM sleep :
highly activated brain in a paralyzed body

• Wake
• EEG - Desynchronized
• EMG - Variable
• NREM
• REM
• EEG - Synchronized
• EMG - Attenuated but present
• EEG - Desynchronized
• EMG - Absent (active paralysis)

Stage REM
• Rapid eye movements
• Mixed frequency EEG
• Low tonic submental EMG

Overview of Sleep and Respiratory Physiology
I. CNS Ventilatory Control
II. Respiratory Control of the Upper Airway
III. Obstructive Sleep Apnea

Ventilatory pump and its central neural control

Main pontomedullary respiratory neurons

Dorsal view of the brainstem and upper spinal cord showing the medullary origin of the descending inspiratory and expiratory pathways that control major respiratory pump muscles , such as the diaphragm and intercostals .

Central respiratory neurons form a network that ensures reciprocal activation and inhibition among the cells to be active during different phases of the respiratory cycle.

Respiratory-modulated cells in the pons integrate many peripheral and central respiratory and non-respiratory inputs and modulate the cells of the medullary rhythm and pattern generator.

• Metabolic control /Automatic control
– Maintain blood gases
• Voluntary control/behavioral
– Phonation, swallowing
(wakefulness stimulus to breathing)

• Metabolic control/automatic control
– Controlled by the medulla
• on the respiratory muscles
– Maintain pCO2 and pO2

• Decrease in Minute Ventilation (Ve)(0.5-1.5 l/min)
• Decrease in Tidal Volume)
• Respiratory Rate unchanged
• ↑ UA resistance (reduced activity of pharyngeal dilator muscle activity)
• Reduction of VCO2 and VO2 (reduced metabolism)
• Absence of the tonic influences of wakefulness
• Reduced chemosensitivity

• Decrease in CO2 production (less than decrease in Ve)
• Increase in pCO2 3-5 mm Hg
• Decrease in pO2 by 5-8 mm Hg
• O2 saturation decreases by less than 2%

• Metabolism slows at sleep onset
• Increases during the early hours of the morning when REM sleep is at its maximum
• Ventilation is worse in REM sleep

• Worse in REM sleep
• Hypotonia of Intercostal muscles and accessory muscles of respiration
• Increased upper airway resistance
• Diaphragm is preserved
• Breathing rate is erratic

• Reduced in REM compared to NonREM
• Hypercapnia is a stronger stimulus to arousal than hypoxemia
– Increase in pCO2 of 6-15 mmHg causes arousal
– SaO2 has to decrease to below 75%
• Cough reflex in response to laryngeal stimulation reduced (aspiration)

Overview of Sleep and Respiratory Physiology
I. CNS Ventilatory Control
II. Respiratory Control of the Upper Airway
III. Obstructive Sleep Apnea

The Upper Airway is a Continuation of the Respiratory System
20

• It transmits air, liquids and solids.
• It is a common pathway for respiratory, digestive and phonation functions.
21

• Airflow requires a patent upper airway.
• Nose vs. mouth breathing must be regulated.
• State of consciousness is a major determinant of pharyngeal patency.
22

• Nose
• Nasopharynx
• Oropharynx
• Laryngopharynx
• Larynx
23

• Alae nasi
(widens nares)
• Levator palatini
(elevates palate)
• Tensor palatini
(stiffens palate)
24

• Genioglossus
(protrudes tongue)
• Geniohyoid
(displaces hyoid arch anterior)
• Sternohyoid
(displaces hyoid arch anterior)
• Pharyngeal constrictors
(form lateral pharyngeal walls)
25

Respiratory Control of the Upper Airway
Pharyngeal Muscles are Activated during
Breathing
Mechanical Properties and Collapsibility of
Upper Airway
Reflexes Maintaining an Open Airway and
Effects of Sleep

Respiratory pump muscles generate airflow
Upper airway muscles modulate airflow
1. Primary Respiratory Muscles ( e.g.
, Diaphragm, Intercostals)
Contraction generates airflow into lungs
2. Secondary Respiratory Muscles ( e.g., Genioglossus of tongue)
Contraction does not generate airflow but modulates resistance
Upper Airway
(collapsible tube)
Respiratory
Pump

Sleep and respiratory muscle activity
Sleep reduces upper airway muscle activity more
Awake than diaphragm activity
Non-REM REM
Genioglossus
+++ ++ +
Intercostals
+++
++ +
Diaphragm
+++
++ ++
Consequences:

Lung ventilation in sleep caused by both

Upper airway resistance (major contributor) and
 pump muscle activity
Clinical Relevance: Airway narrowing in sleep
(potential for hypopneas and obstructions)

Tendency for upper airway collapse in sleep
The pharynx is a collapsible tube vulnerable to closure in sleep – especially when supine
Awake Sleep
Genioglossus
+++
Genioglossus
+
Diaphragm
+++
Diaphragm
++
Tongue movement
Tendency for Airway Collapse :
Reduced muscle activation in sleep
Weight of tongue
Weight of neck - worse with obesity
Worse when supine
Clinical Relevance:
Snoring
Airflow limitation (hypopneas)
Obstructive Sleep Apnea (OSA)

Determinants of pharyngeal muscle activity
Tonic and respiratory inputs summate to determine pharyngeal muscle activity
Genioglossus muscle:
Respiratory-related activity superimposed upon background tonic activity
Tensor veli palatini (palatal muscle):
Mainly tonic activity
Enhances stiffness in the airspace behind the palate

Overview of Sleep and Respiratory Physiology
Pharyngeal Muscles are Activated during
Breathing
Mechanical Properties and Collapsibility of
Upper Airway
Reflexes Maintaining an Open Airway and
Effects of Sleep

Airway anatomy and vulnerability to closure
The airway is narrowest in the region posterior to the soft palate
Retropalatal
Airspace
Glossopharyngeal
Airspace
Redrawn from Horner et al., Eur Resp J, 1989

Upper airway size varies with the breathing cycle
Retropalatal Airspace Glossopharyngeal Airspace
Normal
Normal
OSA
Expiration
OSA
Inspiration
The upper airway is:
(1) Narrowest in the retropalatal airspace
(2) Narrower in obstructive sleep apnea (OSA) patients vs. controls
(3) Varies during the breathing cycle (narrowest at end-expiration)
Redrawn from Schwab, Am Rev Respir Dis, 1993

Upper airway size varies with the breathing cycle
The upper airway is narrowest at end-expiration and so vulnerable to collapse on inspiration
Retropalatal Airspace Glossopharyngeal Airspace
Normal
Normal
OSA
OSA
Upper airway at end-expiration is most vulnerable to collapse on inspiration
Tonic muscle activity sets baseline airway size and stiffness (
 in sleep)
Any factor that
 airway size makes the airway more vulnerable to collapse
Redrawn from Schwab et al., Am Rev Respir Dis, 1993

Fat deposits around the upper airspace
OSA patients have larger retropalatal fat deposits and narrower airways
Fat deposit
Retropalatal airspace
Magnetic resonance image showing large fat deposits lateral to the airspace
These fat deposits are larger in OSA patients compared to weight matched controls
Weight loss decreases size of fat deposits and increases airway size
From Horner, Personal data archive

Determinants of upper airway collapsibility
●
V
MAX
Mechanics of the upper airway and influences on collapsibility
P
N
R
N
500
R
N
= 1/slope
P
CRIT
400
300
Lungs
The upper airway has been modeled as a collapsible tube with maximum flow
●
( V
MAX
) determined by upstream nasal pressure (P
N
) and resistance (R
N
).
200
● 100 P
CRIT
0
-8 -4 0 4 8
P
N
(cmH
2
O)
Airflow ceases in the collapsible segment of the upper airway at a value of critical
● pressure (P
CRIT
). V
MAX is determined by:
●
V
MAX
= (P
N
- P
CRIT
) / R
N
Redrawn from Smith and Schwartz,
Sleep Apnea: Pathogenesis, Diagnosis and Treatment, 2002

Influences on upper airway collapsibility
Mechanics of the upper airway influences airway collapsibility
V
●
MAX
(ml/sec)
500
Normal
Snorer
Hypopnea
OSA
●
500
400
300
200
100
0

●
V
MAX

P
CRIT
Active Upper Airway
Passive Upper Airway
0
-15 -10 -5 0 5
P
N
(cmH
2
O)
10 15 -8 -4 0 4 8
P
N
(cmH
2
O)
P
CRIT is more positive (more collapsible airway) from groups of normal subjects, to snorers, and patients with hypopneas and obstructive sleep apnea (OSA).
Increases in pharyngeal muscle activity
(passive to active upper airway) increase
●
V
MAX and decrease P
CRIT
, i.e., make the airway less collapsible.
Redrawn from Smith and Schwartz,
Sleep Apnea: Pathogenesis, Diagnosis and Treatment, 2002

Overview of Sleep and Respiratory Physiology
Pharyngeal Muscles are Activated during
Breathing
Mechanical Properties and Collapsibility of
Upper Airway
Reflexes Maintaining an Open Airway and
Effects of Sleep

Reflex responses to sub-atmospheric pressure
Sub-atmospheric airway pressures cause reflex pharyngeal muscle activation
0
Suction
Pressure
(cmH
2
O)
-25
Genioglossus
Electromyogram
100 msec
Sub-atmospheric airway pressures cause short latency (reflex) genioglossus muscle activation in humans
Reflex thought to protect the upper airway from suction collapse during inspiration
Reflex is reduced in non-REM sleep and inhibited in REM sleep
From Horner, Personal data archive

Afferents mediating reflex response
Major contribution of nasal and laryngeal afferents to negative pressure reflex in humans
0
Suction
Pressure
(cmH
2
O)
-25
Genioglossus
Electromyogram
Normal response
100 msec
Anesthesia of nasal afferents
Anesthesia of laryngeal afferents
From Horner, Personal data archive

Upper airway reflex and clinical relevance
Upper airway trauma may impair responses to negative pressure and predispose to OSA
Sleeping normal subject
Structural (e.g., obesity, position)
Narrower than normal airway
 muscle activity (e.g., alcohol)
Exaggerated negative airway pressure
Small responder
Snoring, hypopneas and occasional OSA
Reflex pharyngeal dilator muscle activation (e.g., genioglossus)
Any decrement in reflex e.g., age, alcohol
Big responder
No change in reflex
Remain normal
Decrement in upper airway mucosal sensation to pressure
Decrement in upper airway reflex
Worsening snoring and OSA
Redrawn from Horner, Sleep, 1996

Responses to hypercapnia in sleep
Chemoreceptor stimulation cause reflex pharyngeal muscle activation
Wakefulness
Non-REM sleep
REM sleep
Inspired CO2 (%)
Chemoreceptor stimulation increases genioglossus muscle activity
Reflex is reduced in sleep, especially REM sleep
Modified from Horner, J Appl Physiol, 2002

Overview of Sleep and Respiratory Physiology
I. CNS Ventilatory Control
II. Respiratory Control of the Upper Airway
III. Obstructive Sleep Apnea

State-dependent respiratory disorders - OSA
Obstructive Sleep Apnea (OSA) Syndrome
•
Very common; affects 2-5% of middle-aged persons, both men and women.
• The initial cause is a narrow and collapsible upper airway (due to fat deposits, predisposing cranial bony structure and/or hypertrophy of soft tissues surrounding the upper airway).

State-dependent respiratory disorders - OSA
•OSA patients have adequate ventilation during wakefulness because they develop a compensatory increase in the activity of their upper airway dilating muscles (e.g., contraction of the genioglossus, the main muscle of the tongue, effectively protects against upper airway collapse). However, the compensation is only partially preserved during SWS and absent during REMS. This causes repeated nocturnal upper airway obstructions which in most cases require awakening to resolve.

Polysomnographic tracings in OSA
OSA is characterized by cessation of oro-nasal airflow in the presence of attempted
(but ineffective) respiratory efforts and is caused by upper airway closure in sleep
Hypopneas are caused by reductions in inspiratory airflow due to elevated upper airway resistance
Redrawn from Thompson et al., Adv Physiol Educ, 2001

Site of obstruction in OSA
The site of obstruction varies within and between patients with obstructive sleep apnea
REM: Obstruction extends caudally
All patients obstruct at level of soft palate
~50% of patients: obstruction behind tongue in non-REM

State-dependent respiratory disorders - OSA
• In severe OSA, 40-60 episodes of airway obstruction and subsequent awaking occur per hour; due to overwhelming sleepiness, the patient is often unaware of the nature of the problem.
• In light OSA, loud snoring is associated with periods of hypoventilation due to excessive airway narrowing.

State-dependent respiratory disorders - OSA
•Sleep loss, sleep fragmentation and recurring decrements of blood oxygen levels
(intermittent hypoxia) have multiple adverse consequences for cognitive and affective functions, regulation of arterial blood pressure
(hypertension), and metabolic regulation
(insulin resistance, hyperlipidemia).

• Increased upper airway resistance-OSAS
• Circadian changes in airway muscle tone
• Reduced ventilation
– COPD
– Neuromuscular diseases
– Interstitial lung disease

• Hyperinflated diaphragm(reduced efficiency)
• ABG’s deteriorate during sleep
• Coexisting OSAS-severe hypoxemia
• Pulmonary hypertension

Decreased ventilatory responses to hypoxia, hypercapnia, and inspiratory resistance during sleep, particularly in REM sleep, permit
REM hypoxemia in patients with chronic obstructive pulmonary disease, chest wall disease, and neuromuscular abnormalities affecting the respiratory muscles. They may also contribute to the development of the sleep apnea/hypopnea syndrome.

CNS Ventilatory Control – Summary 1
• The respiratory rhythm and pattern are generated centrally and modulated by a host of respiratory reflexes.
• The basic respiratory rhythm is generated by a network of pontomedullary neurons, of which some have pacemaker properties.
• The central controller is set to ensure ventilation that adequately meets demand for O
CO
2 removal.
2 supply and

CNS Ventilatory Control – Summary 2
• Pharyngeal muscles are activated during breathing
• Upper airway size varies during breathing
• Mechanical properties of the upper airway influences collapsibility
• Reflexes modulate pharyngeal muscle activity, but reflexes are reduced in sleep
• These mechanisms contribute to normal maintenance of airway patency and are relevant to obstructive sleep apnea