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Respiratory failure

The major function of the lung is to get oxygen into the


body and carbon dioxide out.

nability to transfer oxygen and/or carbon dioxide


between the atmosphere and the blood
Definitions
 acute respiratory failure occurs when:
 pulmonary system is no longer able to meet the
metabolic demands of the body
 hypoxaemic respiratory failure:
 PaO2 ≤ 50 mm Hg when breathing room air
 hypercapnic respiratory failure:
 PaCO2 ≥ 50 mm Hg.
Oxygen in
 Depends on
 PAO2
 Diffusing capacity
 Perfusion
 Ventilation-perfusion matching
Carbon dioxide out
 Largely dependent on alveolar ventilation
 Anatomical deadspace constant but
physiological deadspace depends on
ventilation-perfusion matching
•Respiratory rate
•Tidal volume
•Ventilation-perfusion matching
Respiratory Failure
inadequate blood oxygenation or CO2 removal
A syndrome rather than a disease
PaO 2 < 60 mmHg or PaC O2 > 50 mmH g

Hypoxemic Hypercapnic
PaO 2 < 5 5~6 0 mmHg or Sa O2 < 90 % PaCO 2 > 4 5~5 0 mmHg
wit h FiO 2 > = 6 0%

This two types of respiratory failure always coexist

Ac ute: develops in minutes to hours, pH < 7.30


Chro nic: develops over several days or longer
Tr ansfe r o f o xygen o f inh aled air into t he
blood and
of wast e c ar bon diox ide of blo od int o t he
lungs
Vent ilatio n

Gas Exchang e Hypercapnic respiratory failure

Hypoxemic respiratory failure


Ventilation
CNS PNS Respiratory Muscles Airways
Efferents Chest Wall

Dysfunction of any component


CNS
Afferents/
of the ventilation system may Alveoli
Intergration result in ventilat ory fai lur e

Chemoreceptors PaO2 Alveolar Minute


PaCO2 Ventilation Ventilation
Control of Ventilation
Mechanical stimuli, Chemical stimuli, Higher CNS input

Medulla
Pneumotaxic center
Dorsal respiratory group
Ventral respiratory group Dorsolateral pons
Nucleus parabrachialis medialis

Ventral and Lateral columns


of the spinal cord
Switching between the
inspiratory and expiratory phase
Phrenic n.  diaphragm
Intercostal n.  intercostal
m.

rhythm, rate, depth of breathing


Chemical Stimuli
 Peripheral chemoreceptors
 Carotid bodies, Aortic bodies
 Stimulus: PaO2, Acidemia (pH), PaCO2

 Central chemoreceptors
 Near the ventrolateral surface of the medulla
 Stimulus: H+ of brain ECF (pH), PaCO2
Chemical Stimuli
 Hypoxia  peripheral receptors
 Hypercapnea  central receptors (80%)

 For the same pH change, the ventilatory


response to respiratory acidosis is
greater than metabolic acidosis:
 CO2 (gas) readily crosses the BBB, but H+
and HCO3- (ion) cross the BBB more slowly.
Respiratory Muscles
 Inspiration: active
 Diaphragm:
 phrenic n. (C3-5)
 Intercostal muscles:
 T (their own level)
 Accessory muscles

 Expiration: passive
 Abdominal muscles:
(active expiration)
 Lower T and L level
 Intercostal muscles:
 T (their own level)
Respiratory drive
O2 demand Motor neuron/nerve function
CO2 production Muscle strength
Dead space Respiratory mechanics

Ve nti lator y De man d Ve nti lat or y S up ply

Ventilatory Demand > Ventilatory Supply  Ve nti lator y F ai lur e


Low I nsp ire d Oxy ge nAlv eolar Hy po ventil atio nSh un t
V-Q misma tch
Diffusion im pairment

Hypoxe mic R espiratory Fa ilure


Resp onse we ll t o oxy gen t herapy
Hypoxic Respiratory Failure

1. Low inspired oxygen


 High altitudes

2. Hypoventilation
 Conditions described in hypercapnic
respiratory failure
 Oxygen therapy improve hypoxemia but may
worsen the hypoventilation
Hypoxic Respiratory Failure

3. Shunt (right-to-left shunt)


 Normal shunting: (2~3% of C.O.)
 Some of the bronchial arterial blood
 Some of the coronary venous blood

 Abnormal shunting:
 Congenital defects in the heart or vessels
 ASD, VSD, Pulmonary AVM
 Lung atelectasis or consolidation

Pneumonia, Cardiogenic or Non-cardiogenic pulmonary edema
 Resistant to O2 supply when shunt fraction of CO > 30%
 Hypercapnia develops when shunt fraction > 60%
Hypoxic Respiratory Failure

4. Ventilation-Perfusion Mismatch
 Vascular obstruction
 Pulmonary embolism
 Air-space consolidation
 Pneumonia, Pulmonary edema
Hypoxic Respiratory Failure

5. Diffusion Impairment
 Interstitial lung disease
 Pulmonary fibrosis, Connective tissue
disease, Interstitial pneumonia, interstitial
pulmonary edema
 ARDS. RDS
 Obstructive lung disease
 Emphysema, Asthma
↓FIO2

Ventilation
without
perfusion Hypoventilation
(deadspace
ventilation)

Diffusion
abnormality
Normal

Perfusion
without
ventilation
(shunting)
Hypercapnic Respiratory Failure

Increase carbon dioxide production


 Fever, sepsis, seizure, obesity, anxiety
 Increase work of breath (Asthma, COPD)
 high carbohydrate diet with underlying lung
disease (high RQ)
Hypercapnic Respiratory Failure
Decreased minute ventilation
 CNS disorders
 stroke, brain tumor, spinal cord lesions, drug overdose
 Peripheral nerve disease
 Guillain-Barre syndrome, botulism, myasthenia gravis
 Muscle disorders
 muscular dystrophy, respiratory muscles fatigue
 Chest wall abnormalities
 scoliosis, kyphosis, obesity
 Metabolic abnormalities
 myxedema, hypokalemia
 Airway obstruction
 Upper airway obstruction, Asthma, COPD
Hypercapnic Respiratory Failure

Increase dead space


 Airway obstruction
 Upper airway obstruction
 Asthma, COPD
 Foreign body aspiration (check-valve)

 ARDS, Pulmonary embolism


 Chest wall disorder
Brainstem

Spinal
Airway cord root
Nerve

Lung Nerve

Pleura

Neuromuscular
Chest junction
wall
Respiratory
muscle

Sites at which disease may cause ventilatory disturbance


Respiratory Failure Symptoms

 Respiratory compensation
 Sympathetic stimulation
 Tissue hypoxia
 Haemoglobin desaturation

•Often nonspecific (and unrecognized)


•Dyspnea
•Cynosis
Dyspnea
 Short of breath
 Abnormally uncomfortable awareness of
breathing
 subjectively
 Increased work of breath
Cynosis
 Cyanosis is a blue coloration of the skin and
mucous membranes due to the presence of
deoxygenated hemoglobin in blood vessels
near the skin surface.
 It occurs when the oxygen saturation of
arterial blood falls below 85-90% (>5 g/dl
deoxyhemoglobin).
Asthma

Definition
 Chronic inflammatory disorder
of bronchi characterized by
episodic, reversible
bronchospasm resulting from
an exaggerated
bronchoconstrictor response to
various stimuli
Asthma
Etiology
 Allergens  Fumes, smoke,
 Occupational sprays
chemical  Diurnal variation
 Viruses  Exercise, cold air
 Genetic factors  Fog
 Prematurity  Emotion
 Lack breast feeding  Allergens,
 Smoking anaphylaxis
 Viruses
 Drugs - NSAID, Beta
Types of asthma
 Extrinsic (Allergic/Immune)
 Atopic - IgE
 Occupational – IgG

 Intrinsic (Non immune)


 Aspirin induced
 Infections induced
Mechanisms of asthma
Risk Factors
(for development of asthma)

Airway
Hyperresponsiveness Airflow Limitation

Risk Factors
(for exacerbation) Symptoms
Mechanisms of asthma
 Edema
 Excesive mucus
 Bronchospasm
 Obstructed
bronchiole
Factors in inflammatory
process
 MEDIATORS  CELL TYPES
 HISTAMINE  MAST CELLS
 LEUCOCYTE C F  MACROPHAGES
 PROSTAGLANDINS  EOSINOPHILS
 LEUKOTRIENES  T LYMPHOCYTES
 PAF
 KININS
Mast cell in asthma
Mast cell in asthma
Eosinophils in asthma
EOSINOPHIL RECRUITMENT IN ASTHMA

IL-5
Th2 cell Survival
IL-3, IL-5,
IL-4
Adhesion GM-CSF
VCAM-1
VLA4
Chemotaxis
Eotaxin,
RANTES, MCP-4
Activation

Bone
marrow CCR3
Basic
proteins
Airway vessel
Mediators

AIRWAY HYPERRESPONSIVENESS
T cell in asthma
Neural mechanisms

PARASYMPATHETIC
AFFERENT SENSORY
HISTAMINE
KININS
EFFERENT
BRONCHOCONSTRICTOR
MUCUS SECRETION
PATHOPHYSIOLOGY OF ASTHMA
Allergen

Macrophage Mast cell

Th2 cell Neutrophil

Eosinophil
Mucus plug
Epithelial shedding
Nerve activation

Subepithelial
fibrosis

Plasma leak Sensory nerve


Oedema activation
Mucus Cholinergic
Vasodilatation
hypersecretion reflex
New vessels
hyperplasia Bronchoconstriction
Hypertrophy/hyperplasia
COPD

Definition
 COPD is a disease state characterised by
airflow limitation that is not fully reversible.
The airflow limitation is usually both
progressive and associated with an abnormal
inflammatory response of the lungs to
noxious particles or gases.
 Includes
 Emphysema
 Chronic bronchitis
Risk factors for COPD

Endogenous factors Genes (e.g. alpha1-antitrypsin deficiency)


Hyperresponsiveness
Lung growth

Exogenous factors Tobacco smoke


Occupational dusts and chemicals
Infections
Socioeconomic status
Chronic bronchitis
 Persistent cough
with sputum
production for at
least 3 months in ≥
consecutive years
Chronic bronchitis
• Mucosa of the lower respiratory passages
becomes severely inflamed
• Mucus production increases

• Pooled mucus impairs ventilation and gas


exchange
• Risk of lung infection increases

• Pneumonia is common

• Hypoxia and cyanosis occur early


Chronic bronchitis
 Hypersecretion of mucus in large airways
 Submucosal gland hypertrophy
 Increase in goblet cells in small airways
 Excessive mucus → airway obstruction
 Cigarette smoke predisposes to infection
Emphysema
 Emphysema is
defined by
destruction of
airways distal to the
terminal bronchiole.
Emphysema
• Alveoli enlarge as adjacent chambers break
through
• Chronic inflammation promotes lung fibrosis

• Airways collapse during expiration

• Patients use a large amount of energy to


exhale
• Overinflation of the lungs leads to a
permanently expanded barrel chest
• Cyanosis appears late in the disease
CELLULAR MECHANISMS OF COPD

Cigarette smoke

? Alveolar macrophage
CD8+
MCP-1
lymphocyte
Neutrophil chemotactic factors
Cytokines (IL-8)
Mediators (LTB4)4))

Neutrophil

PROTEASE Neutrophil elastase


INHIBITORS PROTEASES Cathepsins
- Matrix metalloproteinases

Alveolar wall destruction Mucus hypersecretion


(Emphysema) (Chronic bronchitis)
PROTEASE-ANTIPROTEASE IMBALANCE IN COPD

α 1-Antitrypsin
SLPI

Neutrophil elastase
Cathepsins
MMP-1
Granzymes
Perforins
Alpha1-Antitrypsin
Deficiency
 Enzyme prevents loss of lungs’
elastic fibers
 Deficiency – Pan-lobular
emphysema
 Homozygous – PiZZ – 15-30% of
normal AAT levels (PiMM) Earlier
development of COPD
 Airflow obstruction in early 40s
 Accelerated by 10 to 15 years
 occurs in 1:5000
 Heterozygous – PiMZ – 50-80% -
smokers
 Z allele – 3-5% population
MUCUS HYPERSECRETION IN COPD

Epithelium
Mucus • Acetylcholine
• Tachykinins
• Proteinases
neutrophil elastase
Goblet cell
hyperplasia
SP
• Cytokines
(TNF-α )
Cholinergic
nerve ACh
Sensory nerve
• Oxidants
N
Mucus gland hyperplasia
Cytokines • Growth factors
E ROS
• ↑ MUC genes
INFLAMMATION MUC5a, MUC8
Neutrophils
OVERLAP BETWEEN COPD AND ASTHMA

COPD ASTHMA
Neutrophils
Eosinophils

No AHR ~10%
AHR

No steroid response Steroid response

“Wheezy bronchitis”
Asthma and COPD
Inflammation ASTHMA COPD

CELLS Mast cells Neutrophils


Eosinophils CD8 T cells
CD4 T cells Macrophages++
macrophages

MEDIATORS LTD4,histamineIL­ LTB4’


4,IL­5,  IL­8, TNFa,
ROS + ROS+++

EFFECTS All airways Periph airways


Little fibrosis Lung destruction
Ep shedding Fibrosis +
Sq metaplasia
Response steroids +++ ±