RESPIRATORY FAILURE RESPIRATORY FAILURE Mikl Mikl ós Molnár ós Molnár Semmelweis University Institute of Semmelweis University Institute of Pathophysiology Pathophysiology 2005 2005
Jan 29, 2016
RESPIRATORY FAILURERESPIRATORY FAILURE
MiklMiklós Molnárós Molnár
Semmelweis University Institute of Semmelweis University Institute of PathophysiologyPathophysiology
20052005
RespirationRespiration
Function of the respiratory system is to supply the Function of the respiratory system is to supply the body with oxygen for aerobic metabolism and to body with oxygen for aerobic metabolism and to remove its major metabolic waste product-carbon remove its major metabolic waste product-carbon dioxide dioxide (0.2-4 L/(0.2-4 L/minmin)). .
Does it by 3 Distinct Mechanisms: Does it by 3 Distinct Mechanisms: Ventilation: Ventilation: Delivery of ambient air to the alveoliDelivery of ambient air to the alveoli Diffusion: Diffusion: Movement of oxygen and carbon dioxide across the Movement of oxygen and carbon dioxide across the
alveolar air sac and capillary wallalveolar air sac and capillary wall Circulation: Circulation: Method by which oxygen is carried from site of gas Method by which oxygen is carried from site of gas
exchange to the cells where active metabolism occursexchange to the cells where active metabolism occurs
RespirationIs dependent on vital links of
various anatomic subcomponents
Central Nervous System
Thorax and Pleura
Neuromuscular System
Spinal Cord
Upper Airways
Cardiovascular Systemand Blood
Lower Airways and Alveoli
Seven anatomic subcomponents whose functions are vital to the maintenance Seven anatomic subcomponents whose functions are vital to the maintenance of normal respiration. Interruption in the function of any of the links has of normal respiration. Interruption in the function of any of the links has serious implications for the functioning of the system as a whole. serious implications for the functioning of the system as a whole. (adapted from Bone RC: Acute Respiratory Failure: Definition and Overview. In Bone R, ed: Pulmonary and (adapted from Bone RC: Acute Respiratory Failure: Definition and Overview. In Bone R, ed: Pulmonary and Critical Care Medicine. St. Louis: Mosby, 1997).Critical Care Medicine. St. Louis: Mosby, 1997).
Control of BreathingControl of Breathing
• Central chemoreceptorsCentral chemoreceptors• Respiratory centerRespiratory center – – medulla oblongatamedulla oblongata
•pH (pH (behind the blood-brain barrierbehind the blood-brain barrier))
• Peripheral chemoreceptors – Peripheral chemoreceptors – carotid carotid bodies bodies (carotis,(carotis, arch of aorta arch of aorta))
•pHpH/pCO/pCO22, pO, pO22
• mechanoreceptormechanoreceptorss ((lunglung, , chest wallchest wall))•mechanimechanicalcal strechstrech, , chemical irritationchemical irritation, ,
•J-receptorJ-receptorss
((juxtacapillarjuxtacapillar localization localization blood volume,blood volume, interstitial edemainterstitial edema))
Ventilatory Responses to Physiologic Ventilatory Responses to Physiologic StimuliStimuli
HypercapniaHypercapnia Gradual increase of frequencyGradual increase of frequency ((pCOpCO22=40-70 mmHg, linear=40-70 mmHg, linear -3 -3
l/min/mmHg)l/min/mmHg)
HypoxiaHypoxia normanormal PaOl PaO22=90 mmHg no effect=90 mmHg no effect, PaO, PaO22==550-55 mmHg yes0-55 mmHg yes
MetaboliMetabolicc acid acidosisosis activityactivity of the of the periperipheralpheral chemoreceptor chemoreceptor ↑↑
hyperventilation hyperventilation pCOpCO22↓↓,, later in thelater in the CNSCNS - 24-48 h.- 24-48 h.
Metabolic alkalosisMetabolic alkalosis activityactivity of the of the periperipheralpheral chemoreceptor chemoreceptor ↓↓
hypoventilation hypoventilation pCOpCO22 ↑↑, , later in thelater in the CNSCNS - 24-48 h.- 24-48 h.
Abnormality of the Control of Abnormality of the Control of BreathingBreathing
Abnormal Breathing PatternAbnormal Breathing Pattern
normal
tachypnoe
Kussmaul
Time (min)6 min
Air
flo
w
Apnoe: breathing stops at expirationApneusia: breathing stops at inspiration
Abnormal Breathing PatternAbnormal Breathing Pattern
Time (min)1 min
Cheyne Stokes
Cluster Breathing(Biot Breathing)
Abnormal Breathing PatternAbnormal Breathing Pattern ((AtaxiAtaxic breathing)c breathing)
Voluntary
Self-controlled
Time (min)1 min
Abnormal Breathing PatternAbnormal Breathing Pattern SleepSleep apn apneaea
Hypoventillation and an irregular respiratory pattern during sleep with apnea last for 15-20 sec during the REM phase, usually.
Types:Central apnea(complete cessation of respiratory efforts - encephalitis, central
ischemia)
Obstructive apnea(intermittent upper airway obstruction, morbid obesity, redundant
pharingeal soft tissue, reduced upper airway size due to enlarged lymphatic tissue)
Mixed apnea(Central apnea followed by obstructive one)
Types of ApneaTypes of Apnea
Obstructive apnea
Central apnea
Mixed apnea
Vol
um
e
Airflow
Muscle activity
Airflow
Airflow
Muscle activity
Muscle activity
Coronal section of the head and neck showing the segment Coronal section of the head and neck showing the segment over which sleep related narrowing can occur (arrows).over which sleep related narrowing can occur (arrows).
Anatomy of obstructive sleep apnea.Anatomy of obstructive sleep apnea.
An obese young woman with the short, thick neck typically An obese young woman with the short, thick neck typically seen in patients with obstructive sleep apnea.seen in patients with obstructive sleep apnea.
PathophysiologyPathophysiology
Enlarged uvula resting on the base of the tongue (large arrow), along with Enlarged uvula resting on the base of the tongue (large arrow), along with hypertrophied tonsils (small arrows). The posterior pharyngeal erythema hypertrophied tonsils (small arrows). The posterior pharyngeal erythema may be secondary to repeated trauma from snoring or gastroesophageal may be secondary to repeated trauma from snoring or gastroesophageal refluxreflux
PathophysiologyPathophysiology
Elongated soft palate (arrows). In this patient, an increased anteroposterior Elongated soft palate (arrows). In this patient, an increased anteroposterior dimension caused the soft palate to rest on the base of the tongue in the relaxed dimension caused the soft palate to rest on the base of the tongue in the relaxed position.position.
PathophysiologyPathophysiology
Family members or Family members or partners complaint partners complaint that the patient has that the patient has loud snoring, loud snoring, nocturnal gasping or nocturnal gasping or choking.choking.
Clinical ManifestationClinical Manifestation
Sleep Apnea Syndrome is profoundly Sleep Apnea Syndrome is profoundly associated with hypertension independent of associated with hypertension independent of all relevant risk factors.all relevant risk factors.
Arrhythmias from mild to severe.Arrhythmias from mild to severe.
Motor vehicle accident : Six time increased Motor vehicle accident : Six time increased accident rate compared to the general accident rate compared to the general population.population.
Pathophysiologic ConsequencesPathophysiologic Consequences
TreatmentTreatment
Carbon Carbon dioxidedioxide
Water Water vapourvapour
OxygenOxygen
NitrogeNitrogenn
Stephen Hawking“A Brief History of Time”: 1988.
Someone told me that each equation I Someone told me that each equation I included in the book would halve the included in the book would halve the sales.sales.
Pulmonary Gas ExchangePulmonary Gas Exchange
AlveolAlveolaar Or O22 tensiontension ( (PAOPAO22==1100 00 mmmmHgHg))
Capillary blood leaving the alveolusCapillary blood leaving the alveolus ( (Pc’OPc’O22==1100 00 mmHgmmHg))
ArterialArterial O O22 tensiontension ( (PaOPaO22==990 mm0 mmHgHg))Ideal Alveolar Gas EquationIdeal Alveolar Gas EquationCalculation of PAO2 (considering ideal alveolus):
PAO2 = PIO2 – PACO2 x FIO2 +
(1-FIO2)
R
FIO2 : fraction of inspired O2 (0.21 in room air)R: gas exchange ration – metabolic respiratory quotient (CO2 production/O2 consumption=0.7-1.0, typical value of about 0.8)
PIO2: pO2 of the inspired gas(PIO2= 0.21x(760-47)=150 mmHg)
PAO2= PIO2 – PaCO2 x 1.25
Representation of the Decrease in Partial Representation of the Decrease in Partial Pressure of OPressure of O22 from Inspired Air from Inspired Air
Effectiveness of Oxygene Exchange in the Effectiveness of Oxygene Exchange in the LungLung
(Alveolo(Alveololar-lar-ArtArteeririalal ox oxygen differenceygen difference))
AlveoloAlveolo-arte-arteririalal gr gragientagientIdeIdealal situationsituation P(A P(A--a)a)=0=0Right-to-left shuntRight-to-left shunt (2 (2-4 %), ventilation-perfusion -4 %), ventilation-perfusion mismatchmismatch..
P (P (AA –– a) = 2.5 + 0.21 x a) = 2.5 + 0.21 x (age in years(age in years))
IfIf P P (A(A - a) > 20 mmHg on room air is abnormal - a) > 20 mmHg on room air is abnormal usually due to a parenchymal abnormality of the usually due to a parenchymal abnormality of the lunglung
Oxygen Content of Blood Oxygen Content of Blood (CaO(CaO22))
Bound to hemoglobinBound to hemoglobin ((major partmajor part))
Dissolved in plasmaDissolved in plasma ((small amountsmall amount))
CaOCaO22 = Hb x 1.39 x + 0.0031 x PaO= Hb x 1.39 x + 0.0031 x PaO22SaO2
100
Hb: hemoglobin (g/100ml)
1.39 : oxygen-carrying capacity of Hb (ml O2/g Hb)
SaO2: % of Hb that is bound to O2 = (oxygen saturation)0.0031: solubility coefficient for O2 in plasma (ml O2/100 ml/mmHg)
PaO2: partial pressure of O2 in arterial blood
Dissociation Curve of OxyhemoglobinDissociation Curve of Oxyhemoglobin
% o
f S
O2
PO2 (mmHg)
Physiologiclyimportant
Clinicallyimportant
Adaptations
Right shift:acidosisfever, 2,3-DPG
Left shift:alkalosiscold
Why the OWhy the O22 content is so important ? content is so important ?
+ =
Hb=15 g% Hb=15 g% Hb=15 g%
100 ml100 ml 200 ml
PaO2
30 mmHgPaO2
96 mmHgPaO2
? mmHg
??? (30 + 96 )/2 = 63 mmHg ???
!! WRONG !!
Right AnswerRight Answer%
of
SO
2
PO2 (mmHg)
O2 c
onte
nt
(ml/
100
ml b
lood
)
((12.4 12.4 + 19.8) / 2 = 16.1 ml O+ 19.8) / 2 = 16.1 ml O22/ 100 ml / 100 ml PaO PaO22= 42 mmHg= 42 mmHg
Respiratory FailureRespiratory Failure
Impaired gas exchange:Impaired gas exchange:
Hypoxia with or without hypercapnia
Can be subclassified into acute and Can be subclassified into acute and chronic presentationschronic presentations
Acute respiratory failure occurs when:Acute respiratory failure occurs when: pulmonary system is no longer able to meet the pulmonary system is no longer able to meet the
metabolic demands of the bodymetabolic demands of the body
Hypoxemic respiratory failure:Hypoxemic respiratory failure: PaOPaO22 60 mmHg when breathing room air 60 mmHg when breathing room air
Hypercapnic respiratory failure:Hypercapnic respiratory failure: PaCOPaCO2 2 50 Hgmm 50 Hgmm
Definitions of Respiratory FailureDefinitions of Respiratory Failure HypoxemiaHypoxemia
Classification of Respiratory FailureClassification of Respiratory Failure
Predominant Hypercapnica Hypoxemiab
Type
Acute
Chronic
Minutes to hours; nocompensatory changes
Minutes to hours; nocompensatory changes
Days to months; compensatory changespresentpH and HCO3
Days to months; compensatory changespresenthemoglobin
a PaCO2 > 50 mmHgb PaO2 < 60 mmHg
Respiratory FailureRespiratory Failure
Pump failure Lung failure
Nervous System
Thoraciccage
Resp.muscle
Nervous System
Thoraciccage
Resp.muscle
Hypercapnia Hypoxemia
Breakdown of respiratory failure into its two major components:Breakdown of respiratory failure into its two major components:
Pump failure and lung failure. The end results of pump failure is Pump failure and lung failure. The end results of pump failure is hypercapnia, and the end result of lung failure is hypoxemia.hypercapnia, and the end result of lung failure is hypoxemia.
Examples of Disease that Causes Respiratory Examples of Disease that Causes Respiratory FailureFailure
BRAINBRAIN Drug overdoseDrug overdose Cerebrovascular accidentCerebrovascular accident
SPINAL CORD, SPINAL CORD, NEUROMUSCULARNEUROMUSCULAR Myastenia Gravis SyndromeMyastenia Gravis Syndrome PolioPolio Guillian-Barre’Guillian-Barre’ Spinal cord trauma or tumorSpinal cord trauma or tumor
CHEST WALLCHEST WALL Flail ChestFlail Chest KyphoscoliosisKyphoscoliosis
UPPER AIRWAYSUPPER AIRWAYS Vocal cord paralysis or Vocal cord paralysis or
paradoxicalmotionparadoxicalmotion Tracheal stenosis, Tracheal stenosis,
laryngospasmlaryngospasm
LOWER AIRWAYS & LOWER AIRWAYS & LUNGSLUNGS AsthmaAsthma BronchitisBronchitis Chronic Obstructive Chronic Obstructive
Pulmonary DiseasePulmonary Disease Pulmonary EmbolismPulmonary Embolism Acute Respiratory DistressAcute Respiratory Distress PreumoniaPreumonia Alveolar HemorrhageAlveolar Hemorrhage
HEARTHEART Congestive Heart FailureCongestive Heart Failure Valvular AbnormalitiesValvular Abnormalities
Pump FailurePump Failure Lung FailureLung Failure
Pathophysiology of Respiratory Pathophysiology of Respiratory FailureFailure
Diffusion abnormalities:Diffusion abnormalities: disturbances in gas transfer disturbances in gas transfer across the alveolar capillary bed across the alveolar capillary bed
Ventilation-perfusion imbalance and intrapulmonary Ventilation-perfusion imbalance and intrapulmonary shunt:shunt: problems with matching pulmonary blood flow problems with matching pulmonary blood flow and ventilation and ventilation
Alveolar hypoventilationAlveolar hypoventilation: decreased alveolar ventilation: decreased alveolar ventilation
Pathophysiologic mechanisms for respiratory failure include:
Diffusion AbnormalitiesDiffusion Abnormalities
The process by which OThe process by which O22 and CO and CO22 move passively move passively across the alveolar capillary membrane that across the alveolar capillary membrane that depends upon its physical properties (thickness, depends upon its physical properties (thickness, area, and diffusibility) and solubility of the gas area, and diffusibility) and solubility of the gas
Problem mainly in chronic, less so in acute Problem mainly in chronic, less so in acute respiratory failurerespiratory failure
Problems with Matching Pulmonary Problems with Matching Pulmonary Blood Flow and VentilationBlood Flow and Ventilation
Ideally each alveolar capillary exchange unit would Ideally each alveolar capillary exchange unit would have perfect matching of ventilation and perfusion to have perfect matching of ventilation and perfusion to ensure optimum gas exchange across each unit ensure optimum gas exchange across each unit
This does not happen even in normal individuals where This does not happen even in normal individuals where V/Q ranges in different lung regions from 0.6 to 3.0, V/Q ranges in different lung regions from 0.6 to 3.0, mean overall is 1.0 mean overall is 1.0
In disease states, balance of ventilation and perfusion In disease states, balance of ventilation and perfusion may be disturbed further: may be disturbed further: ventilation-perfusion inequality - imbalances of V/Q ventilation-perfusion inequality - imbalances of V/Q intrapulmonary shunt: mixed venous blood not exposed to the intrapulmonary shunt: mixed venous blood not exposed to the
alveolusalveolus
Problems with Matching Pulmonary Problems with Matching Pulmonary Blood Flow and VentilationBlood Flow and Ventilation
In disease states, balance of ventilation and perfusion In disease states, balance of ventilation and perfusion may be disturbed further: may be disturbed further: ventilation-perfusion inequality - imbalances of V/Q ventilation-perfusion inequality - imbalances of V/Q intrapulmonary shunt: mixed venous blood not exposed to the intrapulmonary shunt: mixed venous blood not exposed to the
alveolusalveolus
HypoventilationHypoventilation
To prevent the development of respiratory acidosis, the To prevent the development of respiratory acidosis, the carbon dioxide produced each day (17,000 meq acid) carbon dioxide produced each day (17,000 meq acid) must be exhaled by the lungs at the same rate must be exhaled by the lungs at the same rate
The relationship among alveolar ventilation (VA), The relationship among alveolar ventilation (VA), carbon dioxide production (VCOcarbon dioxide production (VCO22) and the partial ) and the partial pressure of carbon dioxide in the blood (PaCOpressure of carbon dioxide in the blood (PaCO22) is ) is expressed using a modification of the Fick principle of expressed using a modification of the Fick principle of mass balance that quantitates VCOmass balance that quantitates VCO22 as the product of as the product of VA and the fractional concentration of COVA and the fractional concentration of CO22 in the in the alveolar gasalveolar gas
Diagnosis of Respiratory FailureDiagnosis of Respiratory Failure
History and Physical Examination History and Physical Examination patient symptoms patient symptoms physical examination physical examination
Laboratory TestsLaboratory Tests
Patient Symptoms in Respiratory FailurePatient Symptoms in Respiratory Failure
Mental function: headache, visual disturbances, Mental function: headache, visual disturbances, confusion, memory loss, hallucinations, loss of confusion, memory loss, hallucinations, loss of consciousness. consciousness.
Dyspnea (resting vs. exertional). Dyspnea (resting vs. exertional).
Cough, sputum production, chest pain.Cough, sputum production, chest pain.
Arterial Blood Gas Analysis Arterial Blood Gas Analysis
The most important lab test to subclassify The most important lab test to subclassify respiratory failure respiratory failure
Provides an indication of the duration and Provides an indication of the duration and severity of respiratory failure severity of respiratory failure
Gives 3 Types of Information: Gives 3 Types of Information: presence and degree of hypoxemia (PaOpresence and degree of hypoxemia (PaO22) ) presence and degree of hypercapnia (PaCOpresence and degree of hypercapnia (PaCO22) ) arterial Acid-Base Status (pH)arterial Acid-Base Status (pH)
HypoxemiaHypoxemiaReduction of partial pressure of oxygen in the blood Reduction of partial pressure of oxygen in the blood
Resting PaOResting PaO22 normally 75-80mmHg, 60mmHg lower normally 75-80mmHg, 60mmHg lower limit of safety limit of safety
Oxygenation failure considered if PaOOxygenation failure considered if PaO22 < 50-60mmHg < 50-60mmHg on FiOon FiO22 40% or greater 40% or greater
Decreases in PaODecreases in PaO22 Occur Secondary To: Occur Secondary To: intracardiac or intrapulmonary shunting of blood intracardiac or intrapulmonary shunting of blood V/Q mismatch V/Q mismatch alveolar hypoventilation alveolar hypoventilation
Alveolar gas equation is helpful in sorting out causes of Alveolar gas equation is helpful in sorting out causes of hypoxemiahypoxemia
HypercapniaHypercapnia
Hypercapnia in an increase PaCOHypercapnia in an increase PaCO22 > 50 mmHg. > 50 mmHg.
PaCOPaCO22 = KVO = KVO22 * VA * VA
VCOVCO22 (carbon dioxide) is produced by the (carbon dioxide) is produced by the
oxidative metabolism of carbon containing food oxidative metabolism of carbon containing food products. products.
Any increase in VCOAny increase in VCO22 or decrease in VA will or decrease in VA will
result in hypercapnia. result in hypercapnia.
Respiratory Failure Examples of Lung Respiratory Failure Examples of Lung vs. Pump Failurevs. Pump Failure
Disorders causing respiratory failure can Disorders causing respiratory failure can usually be divided into those causing lung usually be divided into those causing lung failure (impaired oxygenation) vs. pump failure failure (impaired oxygenation) vs. pump failure (hypercapnia). (hypercapnia).
Adult Respiratory Distress Syndrome (ARDS) is Adult Respiratory Distress Syndrome (ARDS) is an example of lung failure, drug overdose is an an example of lung failure, drug overdose is an example of pump failure.example of pump failure.
ARDS - Clinical CaseARDS - Clinical Case
43 year old respiratory therapists with asthma, develops 43 year old respiratory therapists with asthma, develops acute exacerbation and aspirates during endotracheal acute exacerbation and aspirates during endotracheal intubation. Following intubation, progressive severe intubation. Following intubation, progressive severe hypoxemia refractory to 100% Ohypoxemia refractory to 100% O22 develops. develops.
Lab Data Lab Data ABG on 100% FiOABG on 100% FiO22, shows PaO, shows PaO22 114, PaCO 114, PaCO22 32, pH 7.47 on VT 32, pH 7.47 on VT
600cc, RR 18. A-a gradient=56mmHg. 600cc, RR 18. A-a gradient=56mmHg. CXR shows diffuse alveolar infiltrates. CXR shows diffuse alveolar infiltrates.
Management Management mechanical ventilation, AC ventilation, high FiOmechanical ventilation, AC ventilation, high FiO22 with increasing with increasing
levels of PEEP to decrease shunting. levels of PEEP to decrease shunting. Aggressive use of bronchodilators to alleviate bronchospasm. Aggressive use of bronchodilators to alleviate bronchospasm. Diuresis, enteral feeding, DVT and GI bleed prophylaxis.` Diuresis, enteral feeding, DVT and GI bleed prophylaxis.`
Respiratory Failure: Pump Failure CaseRespiratory Failure: Pump Failure Case
Case: 24 year old white female injected heroin 1/2 Case: 24 year old white female injected heroin 1/2 hour prior to presentation and presents comatose hour prior to presentation and presents comatose with shallow irregular respirations. Needle tracks with shallow irregular respirations. Needle tracks are present, gag reflex is absent. are present, gag reflex is absent.
Labs: Labs: ABG shows PaO2 40, PaCOABG shows PaO2 40, PaCO22 80, and pH 7.01. Alveolar 80, and pH 7.01. Alveolar
- arterial gradient = 10mmHg. CXR - clear lungs. - arterial gradient = 10mmHg. CXR - clear lungs.
Therapy: Therapy: Endotracheal intubation assisted ventilation Naloxone Endotracheal intubation assisted ventilation Naloxone
infusioninfusion
Diffusion abnormalitiesDiffusion abnormalities
Factors influencing diffusionFactors influencing diffusion thickness of membranethickness of membrane ((inverseinverse))
areaarea ((linearlinear))
constant of diffusionconstant of diffusion pressure gradientpressure gradient ((linearlinear))
Vgas=A x D x P1 - P2
T
A: area of membraneD: constantT: thickness of membraneP1-P2: pressure gradient
Possible causes of abnormal diffusionPossible causes of abnormal diffusion
Increase the thickness or decrease of areaIncrease the thickness or decrease of area fibrotic fibrotic tissue or alveolar cell proliferationtissue or alveolar cell proliferation thickening of capillary membranethickening of capillary membrane interstitial edema, exudatinterstitial edema, exudateses intraalveolintraalveolarar edema edema or exudates or exudates
Shorter contact timeShorter contact time 1/31/3 is enough for the normal diffusion so is enough for the normal diffusion so PaO PaO22
normal generallynormal generally CO increases CO increases PaO PaO22 if diffusion is effected if diffusion is effected
FIOFIO22 (P (P11 - P - P22) )
Changes of Gas exchange by exerciseChanges of Gas exchange by exercise
60
at rest
CO
SummarySummaryAbnormal diffusionAbnormal diffusion::
PAOPAO22 norm normaall but but PaO PaO22 decreaseddecreased
P(A - a)OP(A - a)O22 >>10 10 mmmmHgHg
Usually triggered by exercise Usually triggered by exercise
FIOFIO22 ↑↑ improves improves
Rarely the cause of hypoxiaRarely the cause of hypoxia
Mechanical component of breathingMechanical component of breathing
Mechanisms influencing inspiration and Mechanisms influencing inspiration and expirationexpiration elasticityelasticity
Lung parenchymaLung parenchyma Cavity of chestCavity of chest
resistance of airwaysresistance of airways other forces against the mechanism of other forces against the mechanism of
respirationrespiration
Lung volumesLung volumes
Spirometer
TV: tidal volumeERV: expiratory reserve capacityRV: residual volumeVC: vital capacityFRC: functional reserve capacityTLC: total lung capacity
Measurement of lung volumesMeasurement of lung volumes
SpiromSpiromeeter – ter – RV can not be determinedRV can not be determined
bodybody plethysmograph plethysmograph
Inert gas dilution testInert gas dilution test
FRC FRC can be estimated. can be estimated. RV = FRC-ERV
TLC = RV + VC
Static expiratory pressure-volume curves
Disruption of alveolar wallsFRC , RV elasticity
Interstitial or infiltration problem FRC , RV , elasticity
Factors influencing the elastic recoilFactors influencing the elastic recoil
Surface tensionSurface tension (surfactant (surfactant -dipalmit-dipalmitooddyyllphophosfatidilsfatidilchcholin, olin, other other
lipids and proteinslipids and proteins-- produced by type produced by type II.II. alveolar cells alveolar cells
Tissue elasticityTissue elasticity ((amount of amount of elastin elastin and collagen)and collagen)
The importance of surface tension.
If two connected alveoli have the same surface tension, then the smaller the radius, the greater the pressure tending to collapse the sphere. This could lead to alveolar instability, with smaller units emptying info larger ones. Alveoli typically do not have the same surface tension because surface forces vary according to surface area, due to the presence of surfactant. Since the relative concentration of surfactant in the surface layer of the sphere increases as the radius of the sphere falls, the effect of surfactant is increased at low lung volumes. This tends to counterbal ance the increase in pressure needed to keep alveoli open at diminished lung volume and adds stability to alveoli which might otherwise tend to collapse info one another. Surfactant thus protects against regional col lapse of lung units, a condition known as atelectasis, in addition to its other functions.
Pathological conditionsPathological conditions
respiratory distress syndrome in newbornsrespiratory distress syndrome in newborns Inadequate biosynthetic pathwaysInadequate biosynthetic pathways Inactivation of surfactantInactivation of surfactant Pathologic mechanical forces used up Pathologic mechanical forces used up
surfactantsurfactant metabolic problems:metabolic problems: acid acidosisosis, hypox, hypoxiaia, ,
decreased venous circulationdecreased venous circulation
Alveoli collapse, TLC, RV and FRC, elastic effort
(ARDS)(ARDS) -atelectas-atelectasyy, , lunglung edema edema
sshhoocckk trauma: trauma: burningburning, , fat embolismfat embolism, , crash of lung tissue, crash of lung tissue,
water aspirationwater aspiration Infections - SepsisInfections - Sepsis Inhalation of toxic gasInhalation of toxic gas Overdose of drugsOverdose of drugs: barbitur: barbiturates, sates, salalyyccyyllatesates, heroin, , heroin,
tthhiazidiazidss MetabolitesMetabolites: ketoacid: ketoacidosesoses, urem, uremic toxinsic toxins OthersOthers: pancreatitis, DIC, amnion-emb: pancreatitis, DIC, amnion-embolismolism, paraquat-, paraquat-
toxicationtoxication
Adult Respiratory Distress SyndromeAdult Respiratory Distress Syndrome
Decreased in elasticityDecreased in elasticity
Elasticity of lung parenchyma decreasesElasticity of lung parenchyma decreases lung fibrosislung fibrosis emphysemaemphysema
Elasticity of chest cavity decreasesElasticity of chest cavity decreases obesityobesity Deformity of chest wallDeformity of chest wall (ankylo spondilitis, (ankylo spondilitis,
scoliosis)scoliosis)
Elastic effort increases, TLC, FRC.
Changes of airflowChanges of airflow
CentrCentral obstructionsal obstructions Acute obstruction between the Acute obstruction between the glottis glottis andand
carinacarina.. Allergic reaction triggered by bite of Allergic reaction triggered by bite of insectsinsects
Slowly developing chronic forms:Slowly developing chronic forms: Constant obstruction e.g. tumorConstant obstruction e.g. tumor Temporary Temporary Laryngeal spasmLaryngeal spasm
Maximal expiratory volumeMaximal expiratory volume
Measures the mechanical status of Measures the mechanical status of airwaysairways
FVC - Forced Vital CapacityFVC - Forced Vital Capacity expirationexpiration::
PPalvalv = P= Pplpl + P + Pelel Ppl : pleural pressure, muscle workPel : pressure of elasticity
Important: The expiratory flow at the ¾ of the vital capacity dose notdepend on muscle forces, elasticity dependent
ForcedForced Vital CapacityVital Capacity(FVC)(FVC)
V (m L )
V (
L/m
in)
.
2 2
-22
4 5 0 0
E
I
V (m L )
V (
L/m
in)
.
2 2
-22
4 5 0 0
E
I
F ixá lt lég ú tio b stru ctio
N o rm á l
T érfo g a t-á ra m lá si g ö rb ék
V (m L )
V (
L/m
in)
.
2 2
-22
4 5 0 0
E
I
V (m L )
V (
L/m
in)
.
2 2
-22
4 5 0 0
E
I
V á lto zó ex tra th ora ca lislég ú ti o b stru ctio
V á lto zó in tra th ora ca lislég ú ti o b stru ctio
V (m L )
V (
L/m
in)
.
2 2
-22
4 5 0 0
E
I
V (m L )
V (
L/m
in)
.
2 2
-22
4 5 0 0
E
I
A stm a
E m p h ysem a
K e z e lé s e lő tt
K e z e lé s u tá n
Asthma
Volume-time curvesVolume-time curves
FVC plotted this way usuallyFVC plotted this way usually
FEF25-75
Functions of breathing musclesFunctions of breathing muscles
DiaphragmDiaphragm: : tidal volume (breathing at tidal volume (breathing at rest)rest)
IntercostaliIntercostali muscles muscles outerouter: : inspirationinspiration innerinner: : expirationexpiration
Scalenus Scalenus musclemuscle ((lifting ribslifting ribs)) tidal breathingtidal breathing
SternocleidomastoidSternocleidomastoid muscle muscle – – lifting the lifting the sternum sternum ((forced respirationforced respiration))
Frontal longitudinal musclesFrontal longitudinal muscles - - ((forced forced respirationrespiration))
MMechaniechanism of respiratory musclessm of respiratory muscles
Length - stretch correlationLength - stretch correlation Inspiratory muscles have the highest stretch at rest Inspiratory muscles have the highest stretch at rest Expiratory muscles have the highest stretch at Expiratory muscles have the highest stretch at TLCTLC
HyperinflatioHyperinflationn obstruobstructionction inflatesinflates efficacy increases during efficacy increases during
expiration; however more work needed during inspirationexpiration; however more work needed during inspiration
OO22 equilibrium (substitutedequilibrium (substituted//needed)needed) Similarly to brain and heart muscles needs oxygen. The Similarly to brain and heart muscles needs oxygen. The
inspiratory muscles are more sensitive because there are no inspiratory muscles are more sensitive because there are no
other help other help hypercapnhypercapnyy, hypox, hypoxemyemy
Evaluation of mechanical forcesEvaluation of mechanical forces
SpiromSpiromeeterter FVC, FEVFVC, FEV11, FEF, FEF25-7525-75,,
Diseases influence the mechanical forces Diseases influence the mechanical forces of lung decrease air ventilation and causeof lung decrease air ventilation and cause ObstruObstructive lung diseasesctive lung diseasesDecreases the amount of air holding unit Decreases the amount of air holding unit of lung causeof lung cause RestriRestrictive lung diseasesctive lung diseasesMixed form Mixed form ((fewfew))
FEV1
FVC
Restrictive pulmonary diseasesRestrictive pulmonary diseases FVCFVC, FEV, FEV11/FVC norm/FVC normaall
Obstructive pulmonary diseases,Obstructive pulmonary diseases, asthma, emphysemaasthma, emphysema etc. etc. FVCFVC, FEV, FEV11/FVC/FVC
““COPD”COPD”
EmphysemaEmphysema
Chronic BronchitisChronic Bronchitis
AsthmaAsthma
Cystic FibrosisCystic Fibrosis
Interstitial Lung Disease (ILD).Interstitial Lung Disease (ILD).
Obstructive Pulmonary DiseasesObstructive Pulmonary Diseases
Chronic Obstructive Pulmonary Chronic Obstructive Pulmonary Disease (COPD) Disease (COPD)
COPD is an accumulation of symptoms COPD is an accumulation of symptoms produced by respiratory diseases that produced by respiratory diseases that result in a diagnosis if COPD.result in a diagnosis if COPD.
Chronic bronchitis and emphysema.Chronic bronchitis and emphysema.
COPD is a respiratory disorder or COPD is a respiratory disorder or syndrome rather than a disease state.syndrome rather than a disease state.
COPDCOPD
Fourth leading cause of death in US.Fourth leading cause of death in US.
Approximately 18 million individuals. Approximately 18 million individuals.
Results in $440 billion in health care Results in $440 billion in health care costs annually.costs annually.
Surge of COPD in recent years.Surge of COPD in recent years.
COPD SymptomsCOPD Symptoms
COPD is characterized by two concepts:COPD is characterized by two concepts: Decreased expiratory air flow pressure, andDecreased expiratory air flow pressure, and Increased resistance to expiratory air flow.Increased resistance to expiratory air flow.
These problems are caused by airway These problems are caused by airway obstruction, determined by specific obstruction, determined by specific respiratory disease.respiratory disease.
Chronic Obstruction Pulmonary Chronic Obstruction Pulmonary DiseasesDiseases (COPD) (COPD)
Increased bIncreased bronchialronchial fluids fluids inflammations, thickening of brochial wall, inflammations, thickening of brochial wall,
hypertrophy of smooth muscleshypertrophy of smooth muscles
Thickening of Thickening of AcinAcini, discrepancy between i, discrepancy between protease – antiproteasesprotease – antiproteases alveol alveolar ar damagedamageNarrowing of small airways, inflammation, Narrowing of small airways, inflammation, fibrosisfibrosis resistance of airways increaseresistance of airways increaseUsually mixed formUsually mixed form
HHypercapnypercapnia in COPDia in COPD
PaCO2 = K x CO2 produced
alveolar gas exchange
PaCO2 = K xBMR + respir work
respir volume - residual
Respiratory work less then 2 % of BMR. can exceed 20%, in pathologic conditions.Hyperventilation can not decrease PCO2, because the rate of CO2
production is more
Progression of COPD and AsthmaProgression of COPD and Asthma
Normal
Failure
Time in Weeks, Months, Years
Possible compensatory mechanismsPossible compensatory mechanisms
With and increasedWith and increased a pCO a pCO22
alveolalveolaar hypoventilr hypoventillationlation pCO pCO22 CSF CSF
[HCO[HCO33]]-- stimulation decreasesstimulation decreases hypoxia, hypoxia,
cyanosis cyanosis pulmon pulmonalal hypertensio hypertensionn, , polycythaemia, cor pulmonale, edema polycythaemia, cor pulmonale, edema “Blue bloater”“Blue bloater”
TachTachyypnoe pnoe pCO pCO2, 2, PACOPACO22 norm normaal, nl, nonon
cyanotic, cyanotic, there is nothere is no polycythaemia polycythaemia nornor edema edema “Ping puffer”“Ping puffer”
Chronic BChronic Bronchitisronchitis
Chronic coughChronic cough associated with sputum production associated with sputum production more than more than 90 days 90 days on on 2 2 successive yearssuccessive years. Rule out. Rule out TBC, tumor, congestiveTBC, tumor, congestive heart heart failurefailureCauseCause:: smoking, smoking, air pollution. Occupational exposure, air pollution. Occupational exposure, etc.etc.
Pathologic changes:Pathologic changes: Increase in mucous glands in airwaysIncrease in mucous glands in airways Mucus accumulation in small airwaysMucus accumulation in small airways Small diameterSmall diameter,, <2mm, airways narrowing<2mm, airways narrowing Recurrent inflammations, infection, and subsequent scaring in the Recurrent inflammations, infection, and subsequent scaring in the
terminal airwaysterminal airways R Rawaw (resistance) (resistance) Blue bloater typeBlue bloater type: Hypoxaemi: Hypoxaemicc, , right heart failureright heart failure
(clinical diagnosis)
EmphysemaEmphysema
Abnormal permanent enlargement of the Abnormal permanent enlargement of the airspaces distal to the terminal bronchiole, with airspaces distal to the terminal bronchiole, with destruction of the wall,without obvious fibrosisdestruction of the wall,without obvious fibrosis
Site of injury is the septa-Site of injury is the septa- Elimination of pulmonary capillary bedElimination of pulmonary capillary bed Increase volume in acinus, with the development of Increase volume in acinus, with the development of
blebs (air spaces near pleura) and bulae (large air blebs (air spaces near pleura) and bulae (large air spaces)spaces)
Mechanical decrease in airway caliber Mechanical decrease in airway caliber (compression of acini)(compression of acini)
Loss of elastic recoilLoss of elastic recoil
TTypes of Emphysemaypes of Emphysema
CentrilobulCentrilobulaar (centriacinr (centriacinaar) emphysemar) emphysema Upper lobes and superior segments of the lower lobesUpper lobes and superior segments of the lower lobes.. Highly associated with smokingHighly associated with smoking
Panlobular (panacinPanlobular (panacinaar) emphysemar) emphysema Entire acinus, even in its earliest stages. Associated with Entire acinus, even in its earliest stages. Associated with
homozygous alpha1-antitrypsin deficiencyhomozygous alpha1-antitrypsin deficiency
Distal aciner (periacinDistal aciner (periacinaar, paraseptal, subpleural) r, paraseptal, subpleural) emphysemaemphysema Involves distal alveolar sacs and ducts, usually in the Involves distal alveolar sacs and ducts, usually in the
upper lobes and often subpleurally or along fibrous upper lobes and often subpleurally or along fibrous interlobular septa. Typically seen in a young adult with interlobular septa. Typically seen in a young adult with history of spontaneous pneumothoraxhistory of spontaneous pneumothorax
Emphysema
Pathogenesis of EPathogenesis of Emphysemamphysema
Inbalance between naturally occuring Inbalance between naturally occuring proteases and atiproteasesproteases and atiproteases Alveolar destruction occurs by the proteases Alveolar destruction occurs by the proteases
liberated from neutrophils, elastase liberated from neutrophils, elastase Smoking inhibitsSmoking inhibits 11--antitrypsinantitrypsin General alveolar General alveolar hyperventilatiohyperventilatio
““Pink puffer type”Pink puffer type”
EmphysemaEmphysemaPathogenesisPathogenesis
AsthmaAsthma
Reversible air flow obstruction manifested by Reversible air flow obstruction manifested by wheezing and caused by combinaton of airway wheezing and caused by combinaton of airway mucosal edema and inflammationmucosal edema and inflammation Increased secretions and smooth muscle constriction.Increased secretions and smooth muscle constriction.
Inflammatory Mechanism in AsthmaInflammatory Mechanism in Asthma Early (<15 min), Early (<15 min), IgEIgE-mediated-mediatedóó and late and late (4 (4-8 h), -8 h),
mechanism unknownmechanism unknown Multiple cells (Multiple cells (macrophagmacrophageses, eosinophil, eosinophilss, , hystiocytes andhystiocytes and
TT--lymphocytlymphocytes) and many mediators (cytokines, groth es) and many mediators (cytokines, groth factors, enzymes and superoxides) are involed following factors, enzymes and superoxides) are involed following various airway challenges (antigenes, chemical exposure, various airway challenges (antigenes, chemical exposure, exercise). At least six separate steps in this complex chain exercise). At least six separate steps in this complex chain of events have been identifiedof events have been identified
Allergen
Mast Cell
Degranulates
HistamineBradykininLeukotriene
ProstaglandinsThromboxane
Chemotactic factor
Releases
Mediators
*Airway smooth muscle contraction
*Increased vascular permeability
*Increased mucoussecretions
Peden, 2003
HistamineBradykininLeukotriene
ProstaglandinsThromboxane
Recruits
Eos
Eosinophils release
Mediators
Trashes Airway Epithelium and destroys cilia!!!
Loss of epithelium... 1. Exposes nerve endings2. Increased cytokine production3. More inflammation.4. Bronchospasm—inc. parasympathetic
Late asthmatic response—4-8hrs laterLate asthmatic response—4-8hrs laterPeden, 2003
Lung RemodelingLung Remodeling
Jeffery Am J. Resp. Crit Care Med. 2001
1
2
3
4
5
6
7
8
9
N o rm á l
E R V
V T V T
V T
V T
IR IR
VC
VC
FR
C FR
C FR
C
R V F R C T L CTeljes
d ila ta tio
Tér
foga
t (L
)
A stm a sú ly osb o d á saSeverity of Asthma
Total
dilatation
Pathophysiology of AsthmaPathophysiology of AsthmaTriggeringTriggering spec. antigspec. antigeen n IgE IgE h hystiocytesystiocytes tryptase, PGDtryptase, PGD22, LTC, LTC44
SignalingSignaling ccyytokintokinss T T--lymphocytlymphocyteses ( (intermediate messengerintermediate messenger) ) IL IL-2 -2 IL-2 IL-2
receptors receptors kemotaxis, kemotaxis, activation of immunsystemactivation of immunsystem IgE IgE
MigrMigrationation macrophagmacrophageses, eosinophil, eosinophilss, lymphocyt, lymphocyteses, monocyt, monocyteses LTB4, PAF, IL-LTB4, PAF, IL-
5, IL-8; 5, IL-8; ILIL-1, TNF-1, TNF ELAM-1, ICAM-1, Mac-1 adhesion molecules ELAM-1, ICAM-1, Mac-1 adhesion molecules inflammationinflammation
Inflammatory Cell ActivationInflammatory Cell Activation ccyytokinetokiness LTC4 LTC4 brochospa brochospasmsm, , increased increased permeabilpermeabiliittyy
Inflammation Causes BronchoconstrictionInflammation Causes Bronchoconstriction Damage of Damage of epitepithelial cellshelial cells az antig az antigen penetrates into deeper en penetrates into deeper
layerlayer strongerstronger bronchospa bronchospassm, m, smooth muscle cell smooth muscle cell ploriferationploriferation. . Inhibits mediators inducing dilatation Inhibits mediators inducing dilatation (PGE(PGE22, , NO)NO)
ResolutioResolutionn Although usually the episodic disease fully reversible, chronic form Although usually the episodic disease fully reversible, chronic form
becoming evidentbecoming evident
Pathophysiology of Asthma
BronchiectasisBronchiectasisPathogenesisPathogenesis
Bronchial obstruction Bronchial obstruction → Atelectasis→ AtelectasisDilatation of walls of patent airwaysDilatation of walls of patent airwaysInfection → Bronchial wall inflammation Infection → Bronchial wall inflammation → weakened walls → further dilation→ weakened walls → further dilationCystic fibrosis: squamous metaplasia Cystic fibrosis: squamous metaplasia with impaired mucociliary action, with impaired mucociliary action, infection, necrosis of bronchial and infection, necrosis of bronchial and bronchiolar wallsbronchiolar wallsKartagener’s syndrome: absent dynein Kartagener’s syndrome: absent dynein arms in cilia → lack of ciliary activityarms in cilia → lack of ciliary activity
Function of Cytoplasmic DyneinFunction of Cytoplasmic Dynein
BronchiectasisBronchiectasisMorphologyMorphology
GrossGross
Usually both lower Usually both lower lobeslobesMay be localisedMay be localisedDilated airwaysDilated airways
CylindroidCylindroid
FusiformFusiformSaccularSaccular
Cystic pattern on cut Cystic pattern on cut surface of lungssurface of lungs
HistologyHistologyAcute and chronic Acute and chronic inflammationinflammationDesquamation of Desquamation of epitheliumepitheliumNecrotising ulcerationNecrotising ulcerationSquamous metaplasiaSquamous metaplasiaNecrosis Necrosis → lung → lung abscessabscessFibrosisFibrosis
BronchiectasisBronchiectasisComputed TomographyComputed Tomography
BronchiectasisBronchiectasisGrossGross
BronchiectasisBronchiectasisHistologyHistology
BronchiectasisBronchiectasisComplicationsComplications
PneumoniaPneumonia
Lung abscessLung abscess
EmpyemaEmpyema
SepticaemiaSepticaemia
Cor pulmonaleCor pulmonale
Metastatic cerebral abscessesMetastatic cerebral abscesses
Secondary AmyloidosisSecondary Amyloidosis
Cystic FibrosisCystic Fibrosis
Genetic deficiency disease characterized Genetic deficiency disease characterized by recurrent respiratory tract infections.by recurrent respiratory tract infections.
Estimated 1 in 20 individuals carry trait Estimated 1 in 20 individuals carry trait for CF.for CF.
Typically diagnosed by age of 6 months.Typically diagnosed by age of 6 months.
Limits life expectancy to ~29 years.Limits life expectancy to ~29 years.
Cystic FibrosisCystic Fibrosis
Improper cellular retention of sodium Improper cellular retention of sodium chloride – lungs, pancreas. chloride – lungs, pancreas.
NaCl draws water from airways, NaCl draws water from airways, resulting in dry mucus.resulting in dry mucus.
Airway obstruction, resulting in Airway obstruction, resulting in respiratory infection and tissue damage.respiratory infection and tissue damage.
Cystic FibrosisCystic Fibrosis
Individuals can go asymptomatic until Individuals can go asymptomatic until adolescence.adolescence.
Later trigger, however, indicates more Later trigger, however, indicates more rapid decline in health.rapid decline in health.
Typically will also involve heptatic Typically will also involve heptatic system, including cirrhosis and jaundice.system, including cirrhosis and jaundice.
DiagnosisDiagnosis
PE and history of respiratory infections during PE and history of respiratory infections during infancy/childhood.infancy/childhood.
Sweat test – increased sodium marker.Sweat test – increased sodium marker.
DNA analysis.DNA analysis.
Currently, genetic engineering is attempting to Currently, genetic engineering is attempting to develop way to modify gene.develop way to modify gene.
PathomechaniPathomechanissmmClCl-- transport abnormality of bronchial cells on the luminal sitetransport abnormality of bronchial cells on the luminal site
Cl- diffuses into the cells normally. Influenced Cl- transport sodium accumulationViscosity of mucus increases, plugging airways infections (Pseudomonas aeruginosa) Respiratory failure, brochiectasis death
11 – – antitrypsin antitrypsin DeficiencyDeficiency (AAT) (AAT)
AutosomalAutosomal disease (more than 75 allels have been disease (more than 75 allels have been identified)identified), , decreased amount of antitrypsin decreased amount of antitrypsin produced. Aproduced. Antiprotentiprotease activity decreases ase activity decreases elastase activity elastase activity ↑↑ emphysema emphysema by age of by age of 4 40, 0, develops earlier in smokers.develops earlier in smokers.
Interstitial Lung DiseaseInterstitial Lung Disease
Inflammation of the alveolar walls inside Inflammation of the alveolar walls inside the lungs.the lungs.
Almost exclusively from industrial Almost exclusively from industrial irritants and agricultural byproducts.irritants and agricultural byproducts.
Numerous conditions coined in Numerous conditions coined in occupational health to describe ILD.occupational health to describe ILD.
Black lung – coal dust from mining.Black lung – coal dust from mining.Farmer’s lung – fungi exposure in moldy hay.Farmer’s lung – fungi exposure in moldy hay.Bird breeder’s lung – inhalation of avian Bird breeder’s lung – inhalation of avian proteins.proteins.Silicosis – inhalation of silicon dust.Silicosis – inhalation of silicon dust.Asbestosis – inhalation of asbestos.Asbestosis – inhalation of asbestos.
Exposure to wood products, detergents, metals, Exposure to wood products, detergents, metals, and other animal proteins.and other animal proteins.
Interstitial Lung DiseaseInterstitial Lung Disease
DiagnosisDiagnosis
PE.PE.
Evaluation of job site.Evaluation of job site.
X-ray of lungs.X-ray of lungs.
SpirometrySpirometry
PathomechanizmusPathomechanizmus
Interstitium is involvedInterstitium is involved. . Injury occurs initially to thype I alveolar epitelial cells or Injury occurs initially to thype I alveolar epitelial cells or capillary endotheliumcapillary endothelium edema, haemorrhage edema, haemorrhage fibrin fibrin is is deposited along alveolar wallsdeposited along alveolar walls (hyalin membrán) (hyalin membrán) Inflammatory phaseInflammatory phase infiltration of infiltration of neutrophilneutrophilss, , macrophagmacrophages andes and lymphocyt lymphocyteses c cyytokinetokiness influence influence the subsequent intensity and duration of disease process the subsequent intensity and duration of disease process and fibrosis and repair processand fibrosis and repair processInflammatory process subsides, proliferation of type II Inflammatory process subsides, proliferation of type II alveolar cells and organization of the fibrinous exudate alveolar cells and organization of the fibrinous exudate occuroccur collagen is deposited collagen is deposited distortion of lung distortion of lung architecture and enlargement of alveolar air spacesarchitecture and enlargement of alveolar air spacesSubsequent inflammatory process promote lung damageSubsequent inflammatory process promote lung damage
This should be enough for to
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