Pathophysiology of

Dyspnea &
Its Treatment
台北醫學大學附設醫院
胸腔內科 游元方 2009 Mar 20
 Regulation of Respiration

• Nervous system
– adjusts the rate of alveolar ventilation almost
exactly to the demands of the body

→ PaO2 & PaCO2 are hardly to altered,

even during heavy exercise & most other
types of respiratory stress
 Regulation of Respiration
• Respiratory Center (RC)
– several groups of neurons located bilaterally in
the medulla & pons of the brainstem

– divided into 3 major collections of neurons

• dorsal respiratory group (DRG) → dorsal medulla
• ventral respiratory group (VRG) → ventrolateral
medulla
• pneumotaxic center (PTC) = pontine respiratory group
(PRG) → dorsosuperior pons
Regulation of Respiration
• DRG: mainly causes
inspiration
• VRG: mainly causes
expiration
• PTC:
dorsosuperior pons,
controls rate & depth of
breathing (rhythmicity)
• DRG plays the most
fundamental role in the
control of respiration
 Regulation of Respiration

• DRG
– most: located within the solitary nucleus (SN)
– additional: adjacent reticular substance (RS)
– SN: the sensory termination of both vagal &
glossopharyngeal n. (which transmit sensory
signals into the RC from chemoreceptors,
baroreceptors, several types of receptors in
the lungs)
→ control inspiration!! control Resp Rhythm!!
 Regulation of Respiration

• PTC (pneumotaxic center)

– located dorsally in the nucleus parabrachialis
of the dorsosuperior pons
– primary effect: basic oscillatory mechanism to
control the switch-off point of the inspiratory
ramp
→ to limit inspiration!! to increase Resp Rate!!
• controlling the duration of the filling phase of the
lung cycle
• signal strong: inspiration 0.5 sec
signal weak: inspiration 5 sec
 Regulation of Respiration
• VRG
– found in the nucleus ambiguus & nucleus
retroambiguus
– remain almost totally inactive during normal-quiet
respiration
– no evidence of participating in the basic rhythmical
oscillation that controls resp
– contributes extra inspiratory drive, if high insp drive
→ “ spill over ” from DRG
– provide powerful expiratory signals to abdominal m.
during very heavy expiration → overdrive
mechanism!! (esp during heavy exercise)
Chemical Control of Respiration
• Direct chemical control
by CO2 & [H+]
– Chemosensitive area:
highly sensitive to
changes in
blood PCO2 & [H+]
– BBB: not permeable to H+,
very permeable to CO2
→ blood CO2 > blood H+
control (more potent effect)
Chemical Control of Respiration
• Peripheral chemoreceptor
system

– chemoreceptors in several
areas outside the brain
– important for detecting changes
in PaO2
– also respond to a lesser extent
to changes in CO2 & [H+]
– transmit nervous signals to the
RC in the brain
– carotid bodies, aortic bodies,
other a. of thoracic &
abdominal regions
Chemical Control of Respiration
• Low PaO2 stimulate
alveolar ventilation

– when PCO2 & [H+] kept

constant at normal levels

→ almost no effect on
ventilation as long as
PaO2 remains >
100mmHg
→ ventilation doubles
when PaO2 falls to
60mmHg
 Other Factors Affecting Respiration

• Volutary control
– for short periods of time, one can hyper- or hypo-
vent to serious derangements in PCO2, pH, PO2
• Irritant receptor in the airways
– stimulated by many incidents → causing cough,
sneeze, bronchoconstriction
• J receptor in alveolar wall, juxtaposition to pulmonary capillaries
– stimulated when pc engorged with blood, when
pul edema occurs → causing dyspnea
 Other Factors Affecting Respiration

• Brain edema
– activity of RC depressed or inactivated
– damaged brain tissue swell, compressing the cerebral a.,
partially blocking cerebral blood supply
– hypertonic solution: remove fluids in brain, ↓ICP, re-
establishing respiration within mins

• Anesthesia
– pentobarbital: depress RC strongest
– morphine: only as an adjunct to anesthetics, because
greatly depress RC, while lessly anesthetize cerebral
cortex
 O2 or CO2 for control of RC?
• changes in PO2:
– no direct effect on RC itself to alter resp drive
– only indirect effect acting through peripheral
chemoreceptors
– Hb-O2 buffer system delivers almost exactly normal
amounts of O2 even when PO2 changes from 60 to
1000mmHg
– adequate DO2, despite changes in pulmonary ventilation
• changes in PCO2:
– both blood & tissue PCO2 changes inversely with the
rate of pulmonary ventilation
– animal evolution → CO2: THE MAJOR CONTROLLER
OF RESPIRATION
 Dyspnea = SOB ≒ Air Hunger
• Definition: subjective mental anguish
associated with inability to ventilate enough
to satisfy the demand for air causing
experience of breathing discomfort
• Sensation of dyspnea have 2 components:
– Urge to breathe = air hunger
– Excessive effort sensation = perception of
sensation
• Can be separated experimentally →
in voluntarily hyperventilating normal subjects,
addition of CO2 results in ↑ sense of urge to breathe
BUT ↓ awareness of effort of breathing
 Dyspnea = SOB ≒ Air Hunger
• Urge to breath
– Sensory input to the cerebral cortex: consists of
information form mechanoreceptors
• Resp apparatus (predominantly the upper airways)
• & face
– BUT, no specific area in CNS identified as
sensory locus for dyspnea
• Excessive effort sensation
– Interpretation of information arriving at
sensorimotor cortex
– Depends on psychological makeup of the person
 Dyspnea = SOB ≒ Air Hunger
• A range of sensation:
from awareness of breathing to resp distress
• The wide range of meanings on several
counts:
– Subjective complaint w/o consistency in objective signs
(eg tachypnea)
– Few physicians have experienced the resp discomfort
a/w chest dz (extrapolations from normal breathlessness,
eg after strenuous exercise)
– Most experimental observations based on the study of
normal subjects or animals under artificial circumstances
– Apply the term loosely, based on the predominant pt
population the physicians served
 Dyspnea = SOB ≒ Air Hunger

• Results from some pathophysiologic event

• influenced by psychological state, bodily
preoccupation, level of awareness, usual
level of physical activity, body weight, state
of nutrition, medications
• Many modifying factors → variable
correlation between dyspnea ratings – airflow
limitation – exercise performance
 Dyspnea = SOB ≒ Air Hunger
• Three factors: development of this sensation
– Abnormality of resp gases in the body fluid, esp
hypercapnia (a much less extent, hypoxia)
→ excess buildup of CO2 in the body fluid, a person becomes very
dyspneic
– Amount of work performed by the resp m. to
provide adequate ventilation
→ at times, CO2 & O2 level in body fluids are normal, but to attain
this normality of resp gases, the person has to breathe forcefully
– State of mind
→ person’s resp functions is normal & still dyspnea: neurogenic or
emotional dyspnea, eg, psychological fear of not being able to
receive a sufficient quantity of air on entering small or crowed rooms
 Mechanisms of Dyspnea

afferent

efferent

• Activation of resp complex → efferent command to breathe to lungs & CW

• Voluntary output from 1° motor cortex → ventilation → coactivation of 1°
sensory cortex
• Input from lung & CW → 1° sensory cortex → affect the perception
• Emotions, cognition, personality → affect central experience of dyspnea
 Mechanisms of Dyspnea
• As with all sensations, result from changes
in neural activity within the cortical structures
that are responsible for sensory perception
• Unlike localized sensations (eg touch,
temperature, arise from peripheral receptor stimulation),
dyspnea is a vague visceral sensation
(analogous to thirst or hunger), more dependent
on neural activity arising from within CNS;
exercise, breath-holding, anemia causing dyspnea → do not have a
common pattern of peripheral receptor stimulation
 Mechanisms of Dyspnea
• Imaging of brain function (PET, fMRI)
– Dyspnea perception → neural activity → activation of
limbic & paralimbic structures (phylogenically ancient regions of
cerebral cortex) → also seen in brain imaging studies of pain,
thirst, hunger
– So dyspnea is a primal experience associated with
behaviors intended to counteract a threat to survival
– Interestingly, increasing resp effort + mild insp load →
insufficient to provoke urge to breath → activation of
sensory cortex & not limbic structure
– Good evidence: dyspnea sensation depends on, to a
large extent, the degree to which resp-related neurons in
the brainstem are stimulated
 Mechanisms of Dyspnea
• Dyspnea with lung disease
– Increased central resp drive necessary to
achieve adequate ventilation by a mechanically
contrained resp apparatus
– eg, COPD → progressive hyperinflation /c increasing dyspnea,
as ventilatory demands require greater resp m. activity 1. to
overcome increased elastic work at high lung volume 2. to offset
foreshortening of insp m. that places them at a mechanical
disadvantage
– LVRS successful lessening of dyspnea, consistent with
improvement in both lung & resp m. mechanics → alleviation of
hyperinflation of lungs & decrease in neural drive to diaphragm
 Mechanisms of Dyspnea
• Dyspnea without primary lung disease
– eg, HF → a heightened resp drive secondary to expiratory flow
limitation or a peripheral m. reflex
– eg, deconditioning → similar phenomenon, exercise
training → mediated in part by changes in peripheral m. function
– other conditions: could be accounted for by increased resp
drive → resp m. weakness, late-stage pregnancy,
anemia, thyroid disorders, panic disorder,
anxiety
 Mechanisms of Dyspnea
• role of afferent feedback from lungs & CW in
the genesis of dyspnea is complex
– RASRs (rapidly adapting strech receptors) ← atelectasis
Pulmonary C-fibers ← pulmonary edema
stimulate breathing & contribute to dyspnea via vagal stimulation
• alleviation of dyspnea via vagotomy or vagal blockade: consistent with
this concept

– SASRs (slowly adapting strech receptors) ← lung inflation

inhibit central resp drive & ameliorate dyspnea
• immediate relief of dyspnea with thoracic movement following breath-
holding BUT without improvements in ABG status: consistent with this
concept

– receptors outside the chest ← cold air blowing on face

 Diagnostic Approach of Dyspnea
• Intermittent dyspnea → reversible conditions
– eg, bronchoconstriction, HF, pleural effusion, acute PTE,
hyperventilation syndrome
• Persistent/progressive dyspnea → chronic conditions
– eg, COPD, interstitial fibrosis, chronic PTE, dysfunction of diaphragm
or chest wall
• Nocturnal dyspnea
– eg, asthma, HF, GER, OSA, nasal obstruction
• Dyspnea in the recumbent position (orthopnea)
– eg, left ventricular failure, abdominal processes (ascites),
diaphragmatic dysfunction
• Dyspnea worsening in the upright position (platypnea)
– eg, cirrhosis, interatrial shunts
 Diagnostic Approach of Dyspnea
• To simplify conceptualization of the
pathophysiology of dyspnea, 3 components can be
independently discerned (multifactorial)
– WOB:
• Increased effort required for breathing against increased resistance,
eg COPD
• OR breathing w/ weakened muscles, eg NMD, cachexia
– Chemical:
• Medullary chemoreceptors predominantly sense hypercapnia
• Carotid & aortic chemoreceptors preominantly sense hypoxemia
• Hypoxemia seems to have a less significant role than hypercapnia in
dyspnea
– Neuromechanical dissociation
• Mismatch btw what brain desires for resp & sensory feedback it receives,
dyspnea is increased
 Symptomatic Tx of Dyspnea

• Cumulative effects of Tx on exercise endurance time at a set

workload & dyspnea measured by a visual analogue scale
(VAS)
– Endurance time gradually improves /c cumulative Tx using bronchodilator by MDI,
O2, exercise training
– Dyspnea relative to workload gradually relieved both at rest and relative to time
on treadmill
– Improvement on exercise testing should translate into improvement with ADL →
should experience less dyspnea with ADL
 Symptomatic Tx of Dyspnea

• Reducing respiratory effort & improving

respiratory m. function
• Decreasing the respiratory drive
• Altering central perception
• Exercise training
 Symptomatic Tx of Dyspnea
• Reducing respiratory effort & improving
respiratory m. function
– Energy conservation: pacing → reduce physical effort
– Breathing technique: pursed-lip → slowing breathing &
impoving O2 saturation
– Strenthening resp. m. → improve max. ventilation &
exercise performance, esp. documented resp m weakness
– Nutritional repletion → improve resp m strength, esp
cachectic pt
– NIV → improve exercise performance in COPD, not in HF
nocturnal bilevel nasal ventilation: more effective in NMD
than obstructive lung dz
– Medication: theophylline → increase m contractility, esp
persistently dyspneic COPD
 Symptomatic Tx of Dyspnea
• Decreasing the respiratory drive
– Supplemental O2 → reduce carotid body activation resulting in
prolonged breath-holding time, decrease ventilation /c exercise,
direct central effect on dyspnea, improved ventilatory m function, LV
contractility, PAP
– Opiates → reduce resp drive
– Furosemide inhalation → reduce dyspnea elicited both by breath-
holding & loaded breathing, valuable for terminal malignancy,
(topical anesthesia of airway receptors affects neither ventilatory
responses nor dyspnea)
– A fan blowing air on the face
– Vibration of the chest → directed at peripheral receptors
– Surgical approaches: vagal n section, carotid body resection → not
currently available
 Symptomatic Tx of Dyspnea
• Altering central perception
– Education including m relaxation → understand their dz
& develop feelings of mastery over it
– Psychotherapy → reduce intensity of dyspnea & distress
associated with it
– Central acting agents: limited role in treating dyspnea
• Anxiolytics: no benefit for unselected COPD, useful in selected
COPD /c psychiatric disorder
• Antidepressants: sertraline, amitriptyline may have positive result
• Opiates: reduce dyspnea in ventilation /c exercise or hypoxia,
affect an individual’s experience as they do pain, inhalation of
opiates anecdotally to help pt with terminal lung dz, HF, terminal
malignant dz. BUT, controlled studies have been disappointing.
IV morphine → alleviate dyspnea of acute LVF
 Symptomatic Tx of Dyspnea
• Exercise training
– A critical part of pulmonary rehabilitation program
– Decrease dyspnea even when exercise performance or
mechanical efficiency is not improved
– Treadmill training /c or /s nurse coaching: equally
effective in reducing dyspnea during exercise testing and
during ADL
– Many mechanisms (neither pul mechanics nor resp m strength is usually
affected)
• True conditioning with decreased lactate production & resulting
decreased stimulation of ventilation
• Relaxation & increased mechanical efficiency: lower O2
consumption & ventilation
• Improve self-confidence, thereby reducing anxiety & dyspnea
• Desensitization of repeated exercise
 Indications for O2 Therapy
• Short-term O2 therapy
– Tissue hypoxia /c arterial hypoxemia → most common, esp VQ
mismatch
– Tissue hypoxia /c normal PaO2 → PaO2 is an inadequate index
of the need for O2 therapy
– Acute myocardial infarction → double-blinded studies of value of
O2 in uncomplicated MI demonstrated no significant effects on
morbidity or mortality
– Inadequate CO (low-flow states) → no proof, used in conjunction
/c inotropes & other devices
– Trauma & hypovolemic shock → best treated by increasing
supply of circulating Hb
– Carbon monoxide intoxication
– Miscellaneous disorders: sickle cell crisis, pneumothorax
 Indications for O2 Therapy
• Long-term O2 therapy
– Most are pt /c arterial hypoxemia, COPD represent the largest
group of pt
• Continuous supplemental O2 for 4-8 wks → decreased Hb,
improved exercise tolerance, lowered pul vascular pressures
• Nocturnal O2 (> 15h/d) is better than O2, continuous O2 imparts the
most benefit
– Resting hypoxemia from a variety of cardiopulmonary dz: eg,
restrictive lung dz, cystic fibrosis, chronic cardiac dz
– Exercise-induced hypoxemia → improves exercise endurance,
as measured by either treadmill walking or bicycle ergometry
– Hypoxemia during sleep: eg, primary sleep-disordered breathing
(OSA, OHS), primary lung dz exhibiting nocturnal desaturation
 Techniques of O2 administration
• Choice of delivery system, based upon
– Degree of hypoxemia
– Requirement for precision of delivery
– Patient comfort
– Cost
• The devices discussed below are reserved
primarily for conscious pt
 Techniques of O2 administration
• Oxygen delivery system in acute setting
– Rebreathing is avoided through use of one-way valve
to sequester expired from inspired gases
– Inspired gas mixtures must be presented in sufficient
volume & at flows to allow compensation for the high-
flow demands often exhibited by critically ill pt
– Can deliver humidified, heated inspired gases
• Low-flow oxygen devices
• High-flow oxygen devices
Low-Flow Oxygen devices
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Low-Flow Oxygen devices
Low-Flow
Low-Flow Oxygen devices
Low-Flow
Low-Flow Oxygen devices
Low-Flow
High -Flow Oxygen devices
High-Flow
High -Flow Oxygen devices
High-Flow
Clinical Syndromes of O2 Toxicity
• Acute toxicity: tracheobronchitis & ARDS
– Normal vlunteers exposed to 100% O2 in 12-24h
• Earliest: effects on tracheobronchial mucosa → substernal
chest pain, nonproductive cough, decreased particle
clearance as early as 6h
• Systemic symptoms: malaise, nausea, anorexia, headache
• Latest: severe dyspnea, marked decrease in pul function,
acute resp failure, longest report is 110h
• Chronic pulmonary syndrome
– Newborns: NRDS /c O2 Tx → bronchopul. dysplasia
– Adults: can tolerate 100% O2 at sea level for 24h
without serious pulmonary injury