respiratory physiology in sleep ritu grewal, md. states of mammalian being wake non-rem sleep...

Respiratory Physiology In Sleep

Ritu Grewal, MD

States of Mammalian Being

• Wake

• Non-REM sleep

– brain is regulating bodily functions in a movable body

• REM sleep:

- highly activated brain in a paralyzed body

Electrographic State Determination

• Wake

• NREM

• REM

• EEG - Desynchronized• EMG - Variable

• EEG - Synchronized• EMG - Attenuated but present

• EEG - Desynchronized• EMG - Absent (active paralysis)

Normal Sleep Histogram

• Rapid eye movements

• Mixed frequency EEG

• Low tonic submental EMG

Stage REM

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

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 ponsintegrate many peripheral and centralrespiratory and non-respiratory inputsand modulate the cells of the medullary rhythm and pattern generator.

Main pontomedullary respiratory neurons

Influences on Respiration in Wake State

• Metabolic control /Automatic control– Maintain blood gases

• Voluntary control/behavioral – Phonation, swallowing

(wakefulness stimulus to breathing)

Respiration during sleep

• Metabolic control/automatic control– Controlled by the medulla

• on the respiratory muscles

– Maintain pCO2 and pO2

Changes in Ventilation in sleepChanges in Ventilation in sleep

• Decrease in Minute Ventilation (Ve)(0.5-1.5 Decrease in Minute Ventilation (Ve)(0.5-1.5 l/min)l/min)

• Decrease in Tidal Volume)Decrease in Tidal Volume)• Respiratory Rate unchangedRespiratory Rate unchanged

• ↑↑ UA resistance (reduced activity of pharyngeal UA resistance (reduced activity of pharyngeal dilator muscle activity)dilator muscle activity)

• Reduction of VCO2 and VO2 (reduced Reduction of VCO2 and VO2 (reduced metabolism)metabolism)

• Absence of the tonic influences of wakefulnessAbsence of the tonic influences of wakefulness• Reduced chemosensitivityReduced chemosensitivity

Changes in Blood BasesChanges in Blood Bases

• Decrease in CO2 production (less than Decrease in CO2 production (less than decrease in Ve)decrease in Ve)

• Increase in pCO2 3-5 mm HgIncrease in pCO2 3-5 mm Hg

• Decrease in pO2 by 5-8 mm HgDecrease in pO2 by 5-8 mm Hg

• O2 saturation decreases by less than 2%O2 saturation decreases by less than 2%

Chemosensitivity and SleepChemosensitivity and Sleep

Chemosensitivity and SleepChemosensitivity and Sleep

MetabolismMetabolism

• Metabolism slows at sleep onsetMetabolism slows at sleep onset

• Increases during the early hours of the Increases during the early hours of the morning when REM sleep is at its morning when REM sleep is at its maximummaximum

• Ventilation is worse in REM sleep Ventilation is worse in REM sleep

REM sleepREM sleep

• Worse in REM sleepWorse in REM sleep

• Hypotonia of Intercostal muscles and Hypotonia of Intercostal muscles and accessory muscles of respirationaccessory muscles of respiration

• Increased upper airway resistanceIncreased upper airway resistance

• Diaphragm is preservedDiaphragm is preserved

• Breathing rate is erraticBreathing rate is erratic

Arousal responses in sleepArousal responses in sleep

• Reduced in REM compared to NonREMReduced in REM compared to NonREM

• Hypercapnia is a stronger stimulus to Hypercapnia is a stronger stimulus to arousal than hypoxemiaarousal than hypoxemia– Increase in pCO2 of 6-15 mmHg causes Increase in pCO2 of 6-15 mmHg causes

arousal arousal – SaO2 has to decrease to below 75%SaO2 has to decrease to below 75%

• Cough reflex in response to laryngeal Cough reflex in response to laryngeal stimulation reduced (aspiration)stimulation reduced (aspiration)

Overview of Sleep and Respiratory Physiology

I. CNS Ventilatory Control

II. Respiratory Control of the Upper Airway

III. Obstructive Sleep Apnea

Anatomy of the Upper Airway

The Upper Airway is a Continuation of the Respiratory System

20

The Upper Airway is a Multipurpose Passage

• It transmits air, liquids and solids.

• It is a common pathway for respiratory, digestive and phonation functions.

21

Collapsible Pharynx Challenges

the Respiratory System• Airflow requires a patent upper airway.

• Nose vs. mouth breathing must be regulated.

• State of consciousness is a major determinant of pharyngeal patency.

22

Components of the Upper Airway

• Nose

• Nasopharynx

• Oropharynx

• Laryngopharynx

• Larynx

23

Anatomy of the Upper Airway• Alae nasi

(widens nares)

• Levator palatini (elevates palate)

• Tensor palatini (stiffens palate)

24

Anatomy of the Upper Airway

• Genioglossus (protrudes tongue)

• Geniohyoid (displaces hyoid arch anterior)

• Sternohyoid (displaces hyoid arch anterior)

• Pharyngeal constrictors (form lateral pharyngeal walls)

25

Pharyngeal Muscles are Activated during Breathing

Mechanical Properties and Collapsibility of Upper Airway

Reflexes Maintaining an Open Airway and Effects of Sleep

Respiratory Control of the Upper Airway

Upper airway muscles modulate airflow1. Primary Respiratory Muscles (e.g., Diaphragm, Intercostals)

Contraction generates airflow into lungs2. Secondary Respiratory Muscles (e.g., Genioglossus of tongue)

Contraction does not generate airflow but modulates resistance

Upper Airway(collapsible tube)

Respiratory Pump

Respiratory pump muscles generate airflow

Awake

Genioglossus+++

Intercostals+++

Diaphragm+++

Non-REM

++

++

++

REM

++

+

+

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)

Sleep reduces upper airway muscle activity more than diaphragm activity

Sleep and respiratory muscle activity

The pharynx is a collapsible tube vulnerable to closure in sleep – especially when supine

Tendency for Airway Collapse:Reduced muscle activation in sleepWeight of tongueWeight of neck - worse with obesityWorse when supine

+Diaphragm

++

Sleep

GenioglossusGenioglossus

Diaphragm+++

+++

Awake

Tongue movement

Clinical Relevance:SnoringAirflow limitation (hypopneas)Obstructive Sleep Apnea (OSA)

Tendency for upper airway collapse in sleep

Tonic and respiratory inputs summate to determine pharyngeal muscle activity

Hypoglossal Motoneuron

Tonic Inputs Inspiratory Drive

GenioglossusEMG

Lung Volume

Inspiratory pre-activationof genioglossus

Trigeminal Motoneuron

Tonic Inputs

Tensor veli palatini EMG

Inspiratory Drive

Insp. Lung Volume

Insp.

Hypoglossal Motoneuron

Tonic Inputs Inspiratory Drive

GenioglossusEMG

Lung Volume

Inspiratory pre-activationof genioglossus

Trigeminal Motoneuron

Tonic Inputs

Tensor veli palatini EMG

Inspiratory Drive

Insp. Lung Volume

Insp.

Genioglossus muscle: Respiratory-related activity

superimposed upon background tonic activity

Tensor veli palatini (palatal muscle): Mainly tonic activityEnhances stiffness in the airspace

behind the palate

Determinants of pharyngeal muscle activity

Pharyngeal Muscles are Activated during Breathing

Mechanical Properties and Collapsibility of Upper Airway

Reflexes Maintaining an Open Airway and Effects of Sleep

Overview of Sleep and Respiratory Physiology

The airway is narrowest in the region posterior to the soft palate

RetropalatalAirspace

GlossopharyngealAirspace

Airway anatomy and vulnerability to closure

Redrawn from Horner et al., Eur Resp J, 1989

Retropalatal Airspace Glossopharyngeal Airspace

Normal

Normal

OSA

OSA

InspirationExpiration

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)

Upper airway size varies with the breathing cycle

Redrawn from Schwab, Am Rev Respir Dis, 1993

The upper airway is narrowest at end-expiration and so vulnerable to collapse on inspiration

Upper airway at end-expiration is most vulnerable to collapse on inspirationTonic muscle activity sets baseline airway size and stiffness ( in sleep)Any factor that airway size makes the airway more vulnerable to collapse

Retropalatal Airspace Glossopharyngeal Airspace

Normal

Normal

OSA

OSA

Upper airway size varies with the breathing cycle

Redrawn from Schwab et al., Am Rev Respir Dis, 1993

OSA patients have larger retropalatal fat depositsand narrower airways

Fatdeposit

Magnetic resonance image showing large fat deposits lateral to the airspace These fat deposits are larger in OSA patients compared to weight matched controlsWeight loss decreases size of fat deposits and increases airway size

Retropalatalairspace

Fat deposits around the upper airspace

From Horner, Personal data archive

Mechanics of the upper airway and influences on collapsibility

The upper airway has been modeled as a collapsible tube with maximum flow (VMAX) determined by upstream nasal pressure (PN) and resistance (RN).

●

PN (cmH2O)

0

100

200

300

400

500

0 4 8-4-8

PCRIT

RN = 1/slope

V M

AX

(ml/s

ec)

●

Airflow ceases in the collapsible segment of the upper airway at a value of critical pressure (PCRIT). VMAX is determined by:

VMAX = (PN - PCRIT) / RN

●

●

Lungs

PN RN

PCRITVMAX

●

Determinants of upper airway collapsibility

Redrawn from Smith and Schwartz,Sleep Apnea: Pathogenesis, Diagnosis and Treatment, 2002

Mechanics of the upper airway influences airway collapsibility

PN (cmH2O)

V MAX

(ml/sec)

0

500

150 105-5-10-15

NormalSnorer

HypopneaOSA

●

PN (cmH2O)V

MA

X (m

l/se

c)

0

100

200

300

400

500

0 4 8-4-8

Passive Upper Airway

Active Upper Airway PCRIT

V MAX

●

●

PCRIT 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 VMAX and decrease PCRIT, i.e., make the airway less collapsible.

●

Influences on upper airway collapsibility

Redrawn from Smith and Schwartz,Sleep Apnea: Pathogenesis, Diagnosis and Treatment, 2002

Pharyngeal Muscles are Activated during Breathing

Mechanical Properties and Collapsibility of Upper Airway

Reflexes Maintaining an Open Airway and Effects of Sleep

Overview of Sleep and Respiratory Physiology

Sub-atmospheric airway pressures cause reflex pharyngeal muscle activation

Sub-atmospheric airway pressures cause short latency (reflex) genioglossus muscle activation in humansReflex thought to protect the upper airway from suction collapse during inspirationReflex is reduced in non-REM sleep and inhibited in REM sleep

Genioglossus Electromyogram

Suction Pressure(cmH2O)

0

-25

100 msec

Reflex responses to sub-atmospheric pressure

From Horner, Personal data archive

Major contribution of nasal and laryngeal afferents to negative pressure reflex in humans

0

Genioglossus Electromyogram

Suction Pressure(cmH2O) -25

100 msec

Normal response

Anesthesia of nasal afferents

Anesthesia of laryngeal afferents

Afferents mediating reflex response

From Horner, Personal data archive

Upper airway trauma may impair responses to negative pressure and predispose to OSA

Sleeping normal subject

Narrower than normal airwayStructural (e.g., obesity, position)

muscle activity (e.g., alcohol)

Exaggerated negative airway pressure

Reflex pharyngeal dilator muscle activation (e.g., genioglossus)

Small responder Big responder

Snoring, hypopneas and occasional OSA

Decrement in upper airwaymucosal sensation to pressure

Decrement in upper airway reflex

Worsening snoringand OSA

Any decrement in reflexe.g., age, alcohol

No change in reflex

Remain normal

Upper airway reflex and clinical relevance

Redrawn from Horner, Sleep, 1996

Chemoreceptor stimulation cause reflex pharyngeal muscle activation

Wakefulness

Non-REM sleep

REM sleepRes

pir

ato

ry-R

elat

edG

enio

glo

ssu

s A

ctiv

ity

(mV

)

Inspired CO2 (%)

Chemoreceptor stimulation increases genioglossus muscle activityReflex is reduced in sleep, especially REM sleep

Responses to hypercapnia in 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

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.

State-dependent respiratory disorders - 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

100

80

15 sec

EEG (V) 100

200

200

EMG (V) 50

OxygenSaturation (%)

RibCage(ml)

Abdomen (ml)

Snoring Sound

Arousal Sleep Arousal

ObstructionObstruction

100

80

15 sec

EEG (V) 100

200

200

EMG (V) 50

OxygenSaturation (%)

RibCage(ml)

Abdomen (ml)

Snoring Sound

ArousalArousal Sleep ArousalArousal

ObstructionObstruction

Polysomnographic tracings in OSA

Redrawn from Thompson et al., Adv Physiol Educ, 2001

The site of obstruction varies within and between patients with obstructive sleep apnea

All patients obstruct at level of soft palate

~50% of patients: obstruction behind tongue in non-REM

REM: Obstruction extends caudally

Site of obstruction in 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).

State-dependent respiratory disorders - OSA

SummarySummary

• Increased upper airway resistance-OSASIncreased upper airway resistance-OSAS

• Circadian changes in airway muscle toneCircadian changes in airway muscle tone

• Reduced ventilationReduced ventilation– COPDCOPD– Neuromuscular diseasesNeuromuscular diseases– Interstitial lung diseaseInterstitial lung disease

COPDCOPD

• Hyperinflated diaphragm(reduced Hyperinflated diaphragm(reduced efficiency)efficiency)

• ABG’s deteriorate during sleepABG’s deteriorate during sleep

• Coexisting OSAS-severe hypoxemiaCoexisting OSAS-severe hypoxemia

• Pulmonary hypertensionPulmonary 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 O2 supply and CO2 removal.

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