Midterm II Flashcards
Functional residual capacity
- net work is zero (no inspiratory/expiratory)
- point at end of normal exhale (not forced exhale)
- pressure lungs = pressure of ribcage (pressure of ribcage wants to pop open = lungs wanting to collapse)
- can’t be measured with spirometer
- increases in COPD vs healthy
Dead space
- air in trachea
- inhaled but not participating in gas exchange (atmospheric air)
- body weight in lbs (ideal) = dead space in mls
Non steroidal anti-inflammatory drugs (NSAIDs)
- inhibit COX I and COX II (cyclooxygenase)
- stomach ulcers issue because COXI involved in muscosal lining of stomach
- COXII related to inflammation
Neuromuscular transmission failure
- impairment of AP across neuromuscular membrane (diaphragm)
- not seen in vivo with human/animal models for respiratory failure
- can only be produced in vitro using supra physiological stimulation rates
High frequency fatigue
- occurs due to some sort of load
- recovers quickly with rest
- related to ion imbalance (K+)
- measured using stimulation frequencies above 50Hz
Z line streaming
- normal muscle zline vertical
- no longer straight with damage, pulled in one direction
- evidence of fatigue or injury
- ultrastructural
Protein Oxidation
- increase in protein oxidation with fatigue/mechanical ventilation
- when a protein is oxidized, biological function decreases
- proteasome pathway removes oxidized proteins
2a)
What is the function of CK in a cell?
- 1 mark
- creatine kinase
- transfers “high energy” phosphate from ATP to creatine or phosphocreatine to ADP
2b)
why is ck NOT a good marker for skeletal muscle injury?
- 3 marks
- lacks specificity (found in every cell of the body)
- lacks sensitivity (low damage = no increase)
- control range for population is large (40-500 units/L - adults only), making small increase in any one individual (need baseline; individual increase +/- 10 units/L)
- CK detectable in everyone, better to have a maker that is only detectable when the disease/injury is present
2c)
despite problems, why was it used in clinical study to strongly suggest respiratory muscle in patients with acute exacerbations of asthma?
- 4 marks
- load on respiratory muscles increases as FEV1 decreases
- increased load = increased muscle damage
- increased damage = more CK is released from damaged muscle
- levels of CK reflect degree of load on respiratory muscles
- with decreases in FEV1, there are increases in CK
FEV1
- forced expiratory volume
- indicator of airway resistance
- normal/healthy range 70-80%
- decrease FEV1 correlated with increase CK (indicating increased muscle injury)
3)
Problem associated with ventilator
- 4 marks
- atrophy (fast in diaphragm)
- decrease cross sectional area (CSA) proportional to muscle force
- CSA proportional to time on ventilator - ultrastructural damage (myofibrils)
- swollen mitochondria
- myofibril damage
- z line streaming - Altered mechanical signals (decreased blood flow, loss of negative intrathoracic pressure)
- decreased protein synthesis (MHC mRNA - myosin heavy chain **indicator)
- increased oxidative proteins
- increased protein degradation (calpain II)
- increased protease activity (calpain II - ATP independent) + (Ubiquitin-proteasome - ATP dependent)
Oxidation is associated with
loss of proteins’ biological function
- classical assay: formation of aldehydes and ketones
- proportional to damage
- oxidative stress caused by mechanical ventilation
Stress increases the production of?
why does this increase CK production?
“Damaged” proteins
CK aids ATP dependent proteasome pathways
- transfers “high energy” phosphate from ATP to creatine or phosphocreatine to ADP
CrP + ADP –> CK + ATP
- more CK in blood
3 ATP dependent pathways
1 ATP independent proteasome
*Ubiquitin-pathway
Sumo
Nedd (can be used in combination)
Calpain II
- targets myofilament proteins
4a)
Skeletal muscle “fatigue” definition
- 2 marks
- loss in capacity for developing force and/or velocity
- resulting from muscle activity under “load”
- reversible by rest
4b)
Force (pressure) / Frequency graph
describe how one would be generated in a human subject
Y: force (Pdi / Pdi max) % 0-100
X: frequency (Hz) 0-100
control and post fatigue
25-30mins
- low frequency still a gap (damage / injury to muscles, hours-days recovery)
- high frequency (60hz) minimal gap (ion homeostasis K+, fast recovery)
— 2 pressure catheters need to be inserted through the nose into stomach (Pab) and esophagus (Pes) to measure Pdi (Pdi = Pab - Pes)
stimulate phrenic nerve while the airway is occluded
4c)
explain why force frequency curve can’t be used to detect central failure
- 2 marks
- not measuring action potential or nerve stimulation (not measuring brain activity or phrenic nerve)
- measuring force in diaphragm; central failure could be present and not know it
4d)
what technique is used to detect central failure
twitch occlusion
5)
how are both CO2 and O2 perfusion limited when the pressure gradient for CO2 is 1/10th of O2?
- 3 marks
Vgas = A/T x D x (p1 - p2)
D = Sol/ MW^-2
CO2 is approximately 20x more soluble than O2
MW is approximately the same
CO2 greater D (diffusion coefficient)
VCO2 > VO2 despite the pressure
Perfusion limitation
P1 = P2
with Vgas = A/T x D x P1-P2
6
reasons why resp. muscle failure techniques aren’t used clinically
- 4 marks
invasive - patient discomfort technologically demanding - equipment and staff expensive time consuming non-specific non-sensitive requires training need control value
8a)
why does pulmonary blood flow in a capillary depend on its vertical position in the chest relative to the heart
- 4 marks
Top: PA > Pa > Pv (closed)
Mid: Pa > PA > Pv (partially closed)
Bot: Pa > Pv > PA (open)
Pa is working against gravity in the upper portions of the lung.
8b)
graph how alveolar hypoxia affects pulmonary blood flow
Y: percent blood flow
X: Alveolar PO2
Blood flow decreases with decrease alveolar blood flow below normal levels (PO2 decreases below 100 mmHg)
80% at 100mmHg
gradual increase above
steep decline below
Blood flow shunted from non-ventilated regions to ventilated regions
Shunting blood
mechanisms
from non-ventilated to ventilated regions
- Drop in PO2 causes vasoconstriction
- when sick, phlegm inhibits ventilation
- Nitric Oxide
- ET-1
- methods not well known
mechinisms have no effect with global hypoxia
- COPD patients affect the whole lung
8c)
when is shunting blood useful? when is it counter productive?
useful:
local non-ventilatory regions (mucus, atelectasis)
not:
whole lung hypoxia (COPD) - no where to shunt blood
Two factors determining blood flow?
Q = P1-P2/R
pressure gradient and resistance
R = 1/r^4
what holds vessels open around alveoli?
Elastin (spiny)
Respiratory failure
(pump failure)
- inability to sustain an expected level of pressure (force) production, sometimes evident as apnea
Ventilatory failure
(hypercapnic failure)
alveolar ventilation “insufficient” to achieve adequate “CO2” elimination resulting in hypercapnia
Hypercapnia
pCO2 > 50mmHG
- caused by ventilatory failure
- insufficient CO2 elimination through alveoli
Central failure
decrease in central neural output “despite” adequate or even increased stimuli
Neuromuscular transmission failure
impaired transmission of action potential across neuromuscular junction
- not possible in vivo
Problems vs causes
Problems
- respiratory failure
- ventilatory failure
Causes
- central failure
- peripheral muscle fatigue
- neuromuscular junction failure (not possible in vivo)
Peripheral muscle fatigue
impaired output
ex. diaphragm weakens like muscles do during exercise (Rare)
Blood flow pulmonary circuit 4 relationships (graphs)
- change with articular or venous pressure
- Increase pressure / decrease resistance
- mechanisms: distension and recruitment - height of the lung
- BF vs height - Lung volume
- Volume vs vascular resistance
- Increase resistance above and below FRC - Alveolar PO2
- Alveolar PO2 vs % blood flow
- Bf decreases in hypoxic vascular region (<100mmHg)
- shunting of blood
Main reasons for lack of studies that have clearly identified cause of respiratory failure in patients
- No standard model of respiratory muscle dysfunction
- Development of respiratory failure poorly characterized
- Central “failure” or peripheral “fatigue” appear separately or in combination depending on specific situation (no agreement in contributions)
- lack of “specific” and “sensitive” marker of peripheral muscle fatigue that is clinically useful
One method to test for peripheral fatigue
3 problems?
Elevated serum creatine levels following acute exacerbations of asthma
- ck levels correlated with severity of airway obstruction (FEV1)
- not tissue specific
- not sensitive (+/- 10 units/L)
- only adults
- wide baseline of a population (40-500 units/L)
biomarker sensitivity vs specificity
sensitivity - positive test when disease is present (no false negatives)
specificity - negative when disease is not present (no false positives)
Measures of skeletal muscle injury
direct
- muscle biopsy (histology)
indirect
- muscle soreness (DOMS)
- max pressure / force generation
- serum markers (CK, myoglobin, LDH, aldolase)
different types of creatine kinase
CKm - muscle
CKb - brain
CKmit - mitochondria
Combinations: ADP --> ATP -CKmm -CKmb -CKbb
ATP –> ADP
CKmit
Fatigue
- lost capacity for developing force/velocity of a muscle
- result from muscle activity under load
- reversible by rest
Weakness
NOT reversible by rest
- nerve damage
- genetic disorder
Factors affecting surface area
disease*
emphysema (effects of smoking) atelectasis (collapsed alveoli) cancer age (emphysema) mucus / pulmunary edema
collapsed alveoli
atelectasis
factors affecting pressure gradient
- altitude
- increase Vd (dead space volume)
- decrease ventilation
- non-disease
atelectasis
collapsed alveoli
- effects surface area when calculating Vgas
- surfactan opens alveoli
- released during lung stretch (deep breathes)
srufactan
opens alveoli
- released during lung stretch
- deep breathes therefor make it easier to breathe
- surgery (anesthetic) prevents this response
factors affecting thickness of alveolar membrane
- mucus / pulmonary edema
2. fibrosis –> collagen (12 dif types), elastin etc
Perfusion limited
P1 = P2
diffusion stops
O2
approx. 0.25 sec
CO2
approx .125
Perfusion diffusion limitations graph
partial pressure / distance (time)
up to .75
perfusion occur .25 for both O2 and CO2
large reserve capacity
Extreme athletes Pr / distance graph
time less than .2sec
can become “diffusion” limited
Abnormal perfusions graphs
no problem at rest
become “diffusion limited” with exercise
(exercise shortens time, lowers reserve capacity
Reserve capacity
extra time/distance of blood in alveoli after gas exchange
- shortens with exercise in healthy individual
Approx. time for blood to travel through alveoli
.75sec
perfusion limited .25sec
Gas exchange in alveoli at elevation
steep curve no longer exists (pressure gradient decreased)
-healthy individual still perfusion limited, take longer to reach
circulatory functions of lungs
- immune
- gas exchange
- clear blood clots
- skin cells
- metabolism of vasoactive substances
a) activation of
AI –(ACE in lung)–> AII (incr. BP)
b) inactivation of NE/epi seratonin brodykinin PGs
archidonic acid –> PG (sensitize pain/inflammation control)
- needs cyclogene (cox 1 and 2)
- NSAIDS inhibit
mean pressure in pulmonary circuit / systemic circuit
pulm 15mmHg
syst 100mmHg
Flow of pulmonary and systemic circuits
BOTH
rest: 6 L/min
exercise: 20 L/min
Pressure gradients of pulmonary and systemic circuits
systemic
rest: 100-2 – 98mmHg
exercise: 120mmHg
pulmonary
rest: ~10mmHg
exercise: ~16mmHg
Resistance of pulmonary and systemic circuits
systemic
rest: 16.7
exercise: 6
pulmonary (VERY LOW)
rest: 1,7
exercise: 0.8
mmHg/L/min**
To increase flow
increase pressure gradient
decrease resistance
two methods
- recruitment
- distension (when Pv greater than PA
Lung volume / vascular resistance relationship
resistance lowest at FRC (95-140 ish)
resistance increases below - capillaries are in series, expansion of capillaries will increase resistance of others
resistance increases above - capillaries stretch from expansion of alveolar space, increasing resistance
- COPD increases work of breathing above FRC
Alveolar PO2 / Blood Flow relationship
Graudual increase above 100mmHg (above 80%)
steep decline below
below 100mmHg "hypoxic vasoconstriction region" Local shunting of blood - from non to ventilated regions 2 mechnisms - Nitric oxide - ET-1
NO effect with global hypoxia
- COPD patients
COPD can die from what unrelated problem?
“right” heart failure (pulmonary side)
too much pressure to deal with increased resistance
2 reasons:
global hypoxia
- No where to shunt blood
increased lung volume
- increases resistance
Respiratory failure objective (3)
- describe the limitation of current models in respiratory failure
- species, anesthetic, age, health status, gas, type of load (resistive ex. straw, threshold ex. pressure, elastic ex. ballon), size of load, end point
- NO Consistancy, failure poorly characterized in humans - describe the limitations of current markers of respiratory fatigue
- CK (40-500units/L, every tissue, adults only)
- myoglobin, LDH, aldolase - how can central failure and peripheral fatigue be determined in a patient
- central “twitch occlusion” (failure when twitch at max effort - phrenic nerve)
very accurate, too long, expensive equipment, few trained people
- peripheral
diaphragm fatigue, ultrastructual injury, power spectrum, detection of sarcolemmal damage (procion orange), biomarkers (CK), weaning from mechanical ventilation
**occur in combination or separate, no agreement
clinical studies of muscle fatigue
- elevated serum CK acute exacerbations of asthma
2. weaning from mechanical ventilation
low vs high frequency fatigue
high
- ion homeostasis (K+)
- buildup in t-tubules, can’t get cells to depolarize
- quick recovery
low
- damage/injury to muscle
- hours to days recovery
Diaphragmatic fatigue test
measure Pdi and Ephr
60min cardiogenic shock
- Pdi and ePhr go up
140min
- Pdi down, Ephr up
indicates peripheral failure but central not determined
Shift in power spectrum
average frequency decreases
- muscle fatigue
- change in ion homeostasis
- need baseline
- not all changes from muscle fatigue
EMG —–> Power spectrum
(fast fornia transformation FFT)
Ultrastructual injury
biopsy
z-line streaming
swollen mitochondria
posse of muscle
risk of death from biopsy
2 day process
shows only one area of diaphragm
Detection of sarcolemmal damge
procion orange stains damaged cells
- healthy has existing damaged cells
- need baseline
Diaphragm life expectancy
only 3 days
- high turnover
- looking for ways for diaphragm to stimulate the diaphragm to regenerate itself
COPD before and after 2010
pre
- not reversible
- treatment limited success reserving lung function
post
- not “fully” reversible
- airflow limitation progressive and associated with abnormal inflammatory response of the lung to noxious particles or gas
COPD def
chronic (repeated exposure) of inflammation
chronic decrease in flow
heterogeneous disorder of emphysema and/or chronic bronchitis
pathogenesis of COPD
noxious agent (tobacco smoke, pollutants, occupational agent)
- -> inflamation (chronic exposure)
- -> COPD
other factors:
- genetics (alpha1-antitrypsin deficiency)
- respiratory infection as a child, or chronic pneumonia
- age
Chronic bronchitis
excess mucus production (3 months of year for 2 successive years) sufficient to cause expectoration of septum
- partially blocked lumen
- thickening of airway wall
Emphysema
anatomic alteration of lung characterized by enlargement of the air spaces distal to the terminal bronchioles with destruction of alveolar walls
- determined only by biopsy
- 2% chance of death
loss of radial traction
Chronic bronchitis and emphysema similarities
treated the same way - no benefit distinguishing between the two
Exercise intolerance caused by 2? how to distinguish?
heart failure or COPD
- FEV1, decrease with COPD
Partially blocked lumen
chronic bronchitis
- mucus in airspace
- increase resistance = decrease flow
Thickening of airway wall
chronic bronchitis
- mucus gland hypertrophy
- mucus buildup suffocates cell of bronchial wall
- decrease # of cilia
Loss of radial traction
emphysema
- air trapping
- elastin lost, nothing to hold airways open
- reduced radial traction
- SA decrease –> # capillaries decrease
Diagnosing COPD
irreversible progressive airflow limitation
FEV1.0
normal - 80% FVC in 1 sec (~4L)
COPD - 60% FVC in 1 sec (~2.5L)
FVC
Forced Vital Capacity
- termination of vital capacity with the maximum force used
- approx 5% less than VC
FEV1.0
Forced expiratory capacity
% volume of air expired in 1sec with maximal force of the FVC
- decrease indicates COPD
Angiotensin II
vasoactive substance activated by the lung which has 50x vasocontrictive affect of angiotensin I
- ACE (angiotensin converting enzyme)
3 mechanisms of airway obstruction
- partially blocked lumen
- thickening of airway wall
(chronic bronchitis) - loss of radial traction
(emphysema)
hyperplasia
increase number of mucus cells (thickening of airway wall)
reid index
size of cluster of mucus glands with respect to airway wall
- healthy < 0.4
- COPD > 0.4
