Disorders of Gas Exchange

Physiology:
Control of Ventilation

Central ventilatory drive is affected by hypoxemia, hypercapnia, and acidemia, but may be modified by a
number of mechanical and irritant stimuli, as well as by conscious control. Input to the medullary respiratory
center comes from central and peripheral chemoreceptors, peripheral mechanical and irritant receptors, other
brainstem breathing centers, and the cerebral cortex. The respiratory centers of the brain then integrate this
information and provide the coordinated neuronal drive to respiratory muscles.
Overview of Gas Exchange

On a basic level, gas

exchange in the lungs consists
of the diffusion of O2 from the
alveoli into the pulmonary
capillary, and the diffusion of
CO2 from the pulmonary
capillary into the alveoli. This
process is summarized on the
right.

Adapted from: Costanzo, LS.

Physiology, 1st ed. 1998.

Gas exchange across the alveolar-capillary barrier can be described as either perfusion-limited or diffusion-
limited:

Perfusion-limited: The total amount of gas transported across the barrier is limited by blood flow, such that
equilibrium is reached between the partial pressures of the gas in the alveoli and in the pulmonary capillaries.
The rate of gas exchange can be increased by increasing blood flow. This is seen with O2 (under normal
conditions) and with CO2.

Diffusion-limited: The total amount of gas transported across the barrier is limited by the diffusion process, such
that as long as the partial pressure of the gas is maintained in the alveoli, diffusion will continue along the full
length of the capillary. In this process, equilibrium is not reached between the partial pressure of the gas in the
alveoli and its partial pressure in the capillary, and the rate of gas exchange can be increased by increasing its
partial pressure in the alveoli. Diffusion-limited gas exchange is generally seen only with O2 during strenuous
exercise, at high altitude, and in pathologic conditions such as emphysema and pulmonary fibrosis.

Mathematical Descriptions of Gas Exchange

The alveolar ventilation and alveolar gas equations are used to mathematically describe gas exchange in the
lungs. Their derivation is based upon the notion of conservation of mass, whereby the amount of a particular
gas that is either consumed or produced by the body must equal the net amount that either enters or leaves the
lungs (under steady-state conditions).

Rate of CO2 production by the body = Rate of CO2 removal by the lungs

VCO2 = VA x FACO2
 By Dalton’s law of partial pressures, PACO2 = PI x FACO2, therefore:

VCO2 = VA x (PACO2 / PI)

Because the alveolar membrane is thin, and CO2 is highly diffusible, PACO2 ≈ PaCO2.

Therefore: VCO2 = VA x (PaCO2 / PI)

With rearrangement: PaCO2 = (VCO2 x PI) / VA

Alveolar Ventilation Equation

Rate of O2 consumption by the body = Net rate of O2 entering the lungs

VO2 = (VA x FIO2) – (VA x FAO2)

O2 inhaled in. O2 exhaled out.

Rearrangement: VO2 = VA (FIO2 – FAO2)

By definition, the respiratory quotient (RQ) is the ratio of CO2 production : O2 consumption.

Therefore: RQ = VCO2/ VO2 = [VA x (FACO2)] / [VA (FIO2 – FAO2)] = FACO2 / (FIO2 – FAO2)

Further rearrangement: FAO2= FIO2 – (FACO2 / RQ)

Converting to partial pressures: PAO2 = PIO2 – (PACO2 / RQ)

Substituting PaCO2for PACO2, and converting PIO2 into values more easily measured:

PAO2 = [FIO2 (PI – PH2O)] – (PaCO2 / RQ)

Alveolar Gas Equation

Technically, the above equation is only an estimation of PAO2. As a greater volume of O2 is consumed per
minute than CO2 produced, there exists a small passive inflow of additional air (~50cc/min), which acts to boost
PAO2. The refined alveolar gas equation is:

PAO2 = [FIO2 (PI – PH2O)] – (PaCO2 / RQ) + {FIO2 x PaCO2 x [(1-R) / R]}

This additional corrective term is not clinically significant.

VCO2 – The minute production of CO2
VO2 – The minute consumption of O2
VA – Minute ventilation
FACO2 – Fractional concentration of CO2 in the alveoli
FAO2 – Fractional concentration of O2 in the alveoli
PAO2 – Partial pressure of O2 in the alveoli
PaCO2 – Partial pressure of CO2 in the arterial blood
PACO2 – Partial pressure of CO2 in the alveoli
PI – Pressure of inspired air
RQ – Respiratory Quotient (Normally assumed to
be approximately equal of 0.8)
FIO2 – Fractional concentration of O2 in inspired air
PIO2 – Partial pressure of O2 in inspired air
PH2O – The partial pressure of water
Additional Important Equations in Gas Exchange

Dalton’s Law: Px = PB Fx Px – Partial pressure of gas X

PB – Total barometric pressure
Fx – Fractional concentration of gas X

Henry’s Law: Cx = Px x Solubility Cx – Concentration of dissolved gas X in liquid

Fick’s Law: Vx = D A ΔP / Δx Vx – Rate of gas transfer

D – Diffusion coefficient of the gas
A – Membrane area available for diffusion
ΔP – Partial pressure gradient of the gas
Δx – Membrane thickness

Classic Shunt Equation: Qs/Qt = (CcO2 – CaO2) CcO2 – End capillary O2 content
(CcO2 – CvO2) CaO2 – Arterial O2 content
(Since CcO2 cannot be measured,
CvO2 – Mixed venous O2 content
patients are placed on 100% O2, PcO2 =
PAO2 is assumed, and ScO2 is assumed
to be 100%.)

Bohr Equation VD / VT = 1 – PECO2 VD – Volume of dead space

PaCO2 VT – Tidal volume
(Used to derive dead space ventilation)
PECO2 – Partial pressure of CO2 in mixed
expired gas (either directly measured, or
estimated from a capnogram)

Fick Equation
(Used to estimate cardiac output, if the
value of VO2 is assumed; or used to
calculate VO2, if CO is measured via
thermodilution)
SvO2 ≈ SaO2 – [VO2/(Hb x CO)]
SvO2 – Mixed venous O2 saturation
SaO2 – Arterial O2 saturation
VO2 – O2 consumption
Hb – Concentration of hemoglobin
CO – Cardiac output

Oxygen Extraction Ratio O2ER = VO2 ≈ 1 – SvO2 O2ER – Oxygen Extraction Ratio
D O2 S aO 2 DO2 – Oxygen Delivery
(When O2ER reaches its maximum
level, ~0.5-0.6, oxygen consumption
becomes supply-limited, a condition
known as dysoxia, and should be a
trigger to consider RBC transfusion.)

Oxygen Transport

Oxygen is carried in the blood in two forms: dissolved O2 (~2% of the total O2 content of blood) and O2 bound to
hemoglobin (~98% of the total). Hemoglobin is a globular protein consisting of 4 subunits (2 α and 2 β subunits
in adult Hb). Each subunit contains a heme moiety, which is an iron-binding porphyrin, which can bind to one
molecule of O2 (a total of 4 O2 molecules per molecule of hemoglobin).

Total O2 content of arterial blood (CaO2) = Dissolved O2 + Hemoglobin-bound O2

CaO2 = (PaO2 x solubility of O2 in blood) + (O2 binding capacity of Hb x [Hb] x SaO2)

For a person with normal gas exchange:

CaO2 = (100mmHg x 0.003mLO2/100mL blood/mmHg) + (1.34mLO2/1g Hb x 15g Hb/dL blood x 0.98)

CaO2 = (0.3mL O2 / 100mL blood) + (19.7mL O2 / 100mL blood)

As can be seen from this, the amount of oxygen present in dissolved form is clinically insignificant, and in
calculating O2 delivery to tissues, can generally be ignored. O2 delivery (DO2) = CO x CaO2.
The percent saturation of Hb is a function of
PaO2, and is expressed as the oxygen-
hemoglobin dissociation curve. Its sigmoidal
shape is due to the increasing affinity of the
remaining heme groups for O2 as each O2
molecule binds within a single molecule of
Hb. This curve helps to explain why O2 is
loaded into pulmonary capillary blood from
alveolar gas (where PaO2 ≈ 100mmHg) and
unloaded from systemic capillaries into the
tissues (where PaO2 ≈ 40mmHg).

The oxygen hemoglobin dissociation curve can be altered by changes in the affinity of Hb for O2 as a result in
changes in PCO2, pH, temperature, or concentration of 2,3-diphosphoglycerate (2,3-DPG). One example of the
advantage of these shifts is the rightward shift of the curve when PCO2 becomes elevated and pH drops (the
Bohr effect) which helps assure that unloading of O2 is greatest where metabolic need is greatest (e.g. in
exercising skeletal muscle). Another example exists in people living at high altitudes, where hypoxia drives the
production of 2,3-DPG which facilitates O2 delivery in a setting when O2 delivery is diminished.

Causes of shifts to the right Causes of shifts to the left

↑PCO2, ↓pH, ↑ temperature, ↑[2,3-DPG] ↓PCO2, ↑pH, ↓ temperature, ↓[2,3-DPG]

Carbon Dioxide Transport

Carbon dioxide is carried in the blood in three forms: dissolved CO2 (~5% of the total CO2 content of blood),
-
bound to terminal amino groups on hemoglobin (~3% of the total), and as HCO3 (~90% of the total). CO2 is
-
converted into HCO3 after diffusing into red blood cells (RBCs) and combined with H2O to form the weak acid
+ -
H2CO3. This reaction is catalyzed by the enzyme carbonic anhydrase. H2CO3 dissociates into H and HCO3 .
- -
The HCO3 is then transported into the plasma in exchange for Cl , a process accomplished by the cell
+
membrane protein, band three protein. The excess H is then buffered by the deoxyhemoglobin present in the
RBC. This process occurs in reverse in the lungs. A CO2 hemoglobin dissociation curve also exists, as it does
for oxygen. There is a rightward shift of the curve (i.e. decreased affinity of Hb for CO2) in the presence of high
SaO2 (The Haldane effect).
Ventilation/Perfusion Relationships

Pulmonary blood flow is regulated by altering the resistance of the pulmonary arterioles on a local level. The
most important stimulus for changing pulmonary vascular resistance is hypoxic vasoconstriction, in which
arterioles adjacent to alveoli with relatively low PAO2 constrict, increasing their individual resistance. This has
the effect of shunting blood flow to regions of the lungs which are receiving better ventilation. Vascular tone
does not become affected until PAO2 drops below 70mmHg. This mechanism is thought to act through inhibition
of nitric oxide (NO) or NO production, which is normally responsible for vascular smooth muscle relaxation.
Although hypoxic vasoconstriction as an adaptive mechanism is successful in mild, localized pulmonary
disease, if the pathologic process is widespread (e.g. multilobar pneumonia, ARDS), pulmonary hypertension,
systemic hypoxia, and right heart failure may develop.

Other vasoactive substances which play a minor role in regulating pulmonary vascular resistance:

Thromboxane A2 – Produced in response to certain types of lung injury, leading to vasoconstriction.

Prostacyclin – Acts as a local vasodilator.

Due to gravity, the distribution of blood flow within the lung is uneven, with the lung bases receiving the greatest
amount of blood, and the apices receiving the least. The pattern of blood flow in the lungs can be divided into 3
zones, depending on the relative relationships between pulmonary artery pressure (Pa), pulmonary venous
pressure (Pv), and alveolar pressure (PA).

Alveolar Blood
Lung Zones Ventilation Flow (Q) V/Q
(V)
In zone 1, the arterial pressure is below the
alveolar pressure; therefore the pulmonary
capillaries are compressed by the alveoli, and
blood flow is reduced. Normally, Pa is just high Lower Lowest Highest
enough to overcome PA, but in states of either (3.0)
hypotension or positive pressure ventilation, PA
may exceed Pa enough to cause zone 1 to become
part of the physiologic dead space.

In zone 2, PA is less than Pa but greater than Pv.

Although the pulmonary capillaries are not
compressed, blood flow is driven by the gradient - - -
between Pa and PA.

In zone 3, PA is less than Pv, so blood flow is

driven by the gradient between Pa and Pv, as it is in
systemic vascular beds.
Higher Highest Lowest
(0.6)

The ventilation/perfusion ratio (V/Q) is the ratio of alveolar ventilation to pulmonary blood flow. Matching
ventilation to perfusion is essential for ideal gas exchange. In the normal lung, the overall V/Q ratio is
approximately 0.8, which represents the average of V/Q ratio from different segments of lung. Regional
variations in ventilation and perfusion leave zone 1 with a relatively high V/Q ratio (3.0 in the normal lung) and
zone 3 with a relatively low V/Q ratio (0.6 in the normal lung).

Ventilation/perfusion mismatching is seen in a large number of pathologic processes (e.g. pneumonia, COPD,
pulmonary edema) which ultimately result in impaired gas exchange.
 Ventilatory Failure

Ventilatory failure is the inability to sustain a sufficient rate of CO2 elimination to maintain a stable pH.

Techniques for Measuring Carbon Dioxide:

Arterial CO2 can be measured via arterial blood gas analysis. In addition, a real-time measurement of PaCO2
can be estimated from infrared capnography. Infrared CO2 analyzers can be placed along the expiratory limb of
ventilator tubing. A light emitting diode generates a steady beam of infrared light which passes through the
expired gas and is picked up by a photodetector on the other side. The intensity of transmitted light is inversely
proportional to the concentration of CO2.

Infrared capnography can measure rapid changes of CO2

during a single expiration, which can be recorded as a
function of time (or more usefully as a function of expired
volume) in a waveform known as a capnogram. Near the
end of expiration, the PCO2 of expired gas, more
commonly referred to as end-tidal PCO2 (PETCO2),
approaches a plateau. In normal lungs, PETCO2 is within
5mmHg of PaCO2. The PaCO2 – PETCO2 gradient is
increased in any condition which increases either the
fraction of anatomic dead space (e.g. rapid shallow
breathing) or physiologic dead space (e.g. COPD, low
CO, PE). Although uncommon, PETCO2 can be greater The capnogram has four phases:
than PaCO2 is situations of very high FIO2 or in the
combination of high CO2 production and high CO. 1 – Exhalation of CO2-free gas present in the
Although PETCO2 is only a rough monitor of PaCO2, it can anatomic dead space.
be used to identify abrupt changes in gas exchange (e.g. 2 – Exhalation of mixed alveolar and dead
aspiration, PE), and to monitor changes in cardiac output space gas.
(changes in PETCO2 are roughly proportional to changes 3 – Exhalation of mostly alveolar gas
in CO). 4 – Inhalation

Etiologies of Hypercapnia:
A better understanding of the etiologies for elevations of PaCO2 can be found by reexamining and building upon
the alveolar ventilation equation:

PaCO2 = (VCO2 x PI) / VA

Since VA = RR (VT – VD):

PaCO2 = (VCO2 x PI) / [RR (VT – VD)]

Hypermetabolism (↑VCO2)
Fever
Sepsis
Acidosis
Seizures
Hyperalimentation
Decreased Minute Ventilation (↓VA)

Increased dead space (↑VD)

Pulmonary embolus
High PEEP (by increasing the size of lung zone 1)

Central hypoventilation (↓RR)

Opiates – These drugs act by stimulating µ-2 receptors in the medulla, which in turn decreases
the responsiveness of central chemoreceptors to rising PCO2.
Benzodiazepines – Act by stimulating GABA receptors in the brainstem. While alone,
benzodiazepines have only a modest affect on respiratory drive, they can enhance the
respiratory depression induced by other classes of medications (i.e. opiates).
Hypothyroidism – In mild to moderate hypothyroidism, there is a moderate reduction in hypoxic
ventilatory drive, whereas in severe hypothyroidism there is marked depression in both
hypoxic and hypercapnic ventilatory drive. Respiratory muscle weakness can also be a
contributing factor.
Metabolic alkalosis – Elevation in systemic pH blunt the stimulation from peripheral
chemoreceptors.
Brainstem lesions
Ondine’s Curse – A condition in which a patient has impaired autonomic control, but has intact
voluntary control of breathing. Typically, they become hypoxic when they fall asleep
because “they forget to breathe”. The congenital form has much overlap with congenital
central hypoventilation syndrome, however Ondine’s curse can also be due to surgery of
the brainstem or upper cervical spinal cord.
Congenital central hypoventilation syndrome – A disorder in which patients have a nearly
absent respiratory response to hypoxia and hypercapnia, no respiratory discomfort during
CO2 inhalation, mildly elevated PaCO2 during wakefulness, and markedly elevated PaCO2
during non-REM sleep. It often occurs in association with Hirschsprung’s disease.
Obesity-hypoventilation syndrome (aka the “Pickwickian syndrome”) – The constellation of
morbid obesity and alveolar hypoventilation while awake. In its classic form, it is also
characterized by hypersomnolence, dyspnea, hypoxemia, and pulmonary hypertension. In
this syndrome, usually due to the combination of obstructive sleep apnea and obesity, the
work of breathing becomes so great that it is more efficient to hypoventilate and to reset the
set-point of central chemoreceptors to tolerate a higher PaCO2.
Sleep deprivation

COPD – Some patients develop breathing patterns of high RR and low tidal volumes, leading to ↑VD to
compensate for V/Q mismatching and inefficient removal of CO2.

Neuromuscular disorders (↓VT)

Skeletal muscle weakness
Muscular dystrophy
Myopathies
Polymyositis
Severe malnutrition
Electrolyte disorders
Hypocalcemia
Hypokalemia
Hypomagnesemia
Hypophosphatemia
Impaired neuromuscular transmission
Myasthenia gravis
Guillain-Barre
Amyotrophic lateral sclerosis
Poliomyelitis
Diaphragmatic paralysis (usually from injury to the phrenic nerve)
Organophosphates – This class of drugs/toxins irreversibly inhibits
acetylcholinesterases, and includes sarin and VX gas.
Neuromuscular blocking agents (a.k.a. paralytics, e.g. succinylcholine, vecuronium)
Airflow Obstruction
Upper airway
Obstructive Sleep Apnea
Lower airway
Asthma
COPD
Bronchial stenosis
Excessive secretions

Decreased Lung/Chest Wall Compliance (↓VT)

Kyphoscoliosis
Pneumothorax
Pleural effusion
Hyperinflation (seen in COPD)
Auto-PEEP
Atelectasis
Pulmonary edema
Acute lung injury
Pneumonia

Signs of Ventilatory Failure:

Deteriorating mental status – In addition to acute cerebral acidosis (occurring just before arrest), other
contributing factors are likely sleep deprivation, muscle fatigue, and sustained high levels of
catecholamines.

Arterial pulsus paradoxus > 15-20mmHg – Pulsus paradoxus refers to the drop in systolic pressure
during inspiration (normally < 8mmHg). During inspiration, preload to the left ventricle is reduced,
leading to a transient decrease in cardiac output.

Severe hyperinflation – The increase in resting lung volume is due to air trapping. Air trapping is the inability
of narrowed airways to move air sufficiently at lower lung volumes to satisfy a necessary minute
ventilation, so therefore airways are kept open by breathing at higher volumes.

Acidemia – A sign that the normal compensatory mechanisms which prevent acidemia are being overwhelmed
by an acute rise in PaCO2.

Treatment:
Treatment for hypercapnic ventilatory failure is best directed at the precipitating cause. Non-invasive positive
pressure ventilation can improve most cases of hypercapnia, and is particularly useful in COPD and OSA.
Although intubation and mechanical ventilation is the definitive non-specific treatment for severe hypercapnia,
this should be avoided whenever possible in order to prevent ventilator-associated complications.
 Oxygenation Failure

Techniques for Measuring Oxygenation:

Oximetry

Oximetry is the application of spectrophotometry to the detection of oxygenated and deoxygenated hemoglobin
(Hb). Hb changes its structural confirmation in response to a chemical reaction, and each confirmation has a
different pattern of light reflection. Oxygenated Hb tends to reflect light more effectively at wavelengths of
660nm (red light), whereas deoxygenated Hb reflects light more effectively at 940nm (part of the infrared
spectrum). When both wavelengths of light are passed through blood, the intensity of light transmission at
660nm roughly correlates to the concentration of oxygenated Hb, whereas the intensity at 940nm corresponds
to deoxygenated Hb.

% Saturation = Oxygenated Hb x 100

(Oxygenated Hb + Deoxygenated Hb)

Pulse Oximetry

Pulse oximeters are oximeters in which the photodetectors are designed to sense only light of alternating
intensity (such as pulsating arteries), which reduces error from light reflection from soft tissue and veins. Pulse
oximeter probes consist of a photodetector and two diodes, one emitting light at 660nm and the other at 940nm.
The probes are most frequently placed on fingers or ear lobes such that the detector and emitters are positioned
facing each other through interposed tissue.

Factors affecting the accuracy of pulse oximetry:

1. Hypoxia – Inaccurate when SaO2 < 70%.

2. Dyshemoglobinemia – Carboxyhemoglobin (seen in smoke inhalation) absorbs roughly the same
wavelength of light as oxygenated hemoglobin, thus leading pulse oximeters to overestimate true SaO2,
with the degree of overestimation proportional to the level of carboxyhemoglobin. Methemoglobin
3+ 2+
(which occurs when Hb’s heme moiety is in the Fe rather than Fe state, is seen in high-dose
nitroglycerin or NO use, and which does not bind O2) absorbs light at both 660nm and 940nm. SpO2 (O2
saturation measured by pulse oximetry) drops by ½% for every 1% of metemoglobin present until
methemoglobin levels approach 20%, at which point SpO2 asymptotically approaches 85%. Fetal
hemoglobin and sickle-cell hemoglobin generally produce readings indistinguishable from normal
hemoglobin.
3. Severe hypotension – Inaccurate when MAP < 30mmHg. Accuracy in severe hemodynamic instability
may be increased by warming of the digit, or application of topical nitroglycerin.
4. Anemia – Inaccurate when Hb < 5g/dL.
5. Skin Pigmentation – Very dark skin can lead to occasional mild false reductions.
6. Fingernail polish – Blue or black colors can causes a mild false reduction.
7. Severe tricuspid regurgitation – This may cause venous pulsations with the pulse oximeter may mistake
for arterial.
8. Vital dyes (such as methylene blue) – These may cause falsely low SpO2 readings, but the effect is
transient as the dye is metabolized and cleared from the bloodstream.
9. Ambient EM radiation – There are reports that cellular telephones, electrocautery devices, and MRI
scanners may interfere with pulse oximetry.
10. Placement of the pulse oximeter on the same extremity as a blood pressure cuff or arterial line can give
erroneous readings and should be avoided.

Co-Oximetry

Co-oximeters transmit four wavelengths of light through a blood sample, detecting not only oxygenated and
deoxygenated Hb, but also methemoglobin and carboxyhemoglobin.
Measures of the Efficiency of Oxygenation

A-a gradient – The alveolar-arterial oxygenation gradient is the difference between PAO2 and PaO2. A normal A-
a gradient ≈ (age in yrs + 10) / 4. The source of this normal gradient is a physiologic shunt due to bronchial
blood flow (which bypasses the alveoli and is therefore not oxygenated) and a small portion of coronary venous
blood that drains directly into the left ventricle via the thebesian veins.

A-a oxygen ratio = PaO2 / PAO2 Normal Range > 0.77

Used to approximate the change expected in PaO2 for a given increase in FIO2.

PaO2/ FiO2 Ratio Normal Range = 300-500

Gas exchange derangement = 200-300
Severe hypoxia < 200

Etiologies of Hypoxia:
Low amount of inspired oxygen
High altitude (Decreased PI)
Suffocation (Decreased FIO2)
Increased CO2 production
(See causes of increased CO2 production under ventilatory failure)
Hypoventilation
(See causes of decreased minute ventilation under ventilatory failure)
Increased A-a gradient
Impaired diffusion capacity (Impaired diffusion is thought to have minimal effect on oxygenation at rest,
but rather affects oxygenation during exercise)
Decreased surface area
Emphysema
Increased membrane thickness
Early pulmonary edema
Pulmonary fibrosis
Shunt
Anatomic
Right to left intracardiac shunts
Pulmonary AVMs
Physiologic (can be considered a form of macroscopic V/Q mismatch)
Pneumonia
Atelectasis
Acute lung injury/ARDS
V/Q mismatch
Airway disease
COPD/Asthma
Alveolar disease
Pneumonia
Pulmonary edema
Diffuse alveolar hemorrhage
Vascular disease
Pulmonary embolus
Dysoxia (DO2/VO2 imbalance)
Hypermetabolic states
Anemia
Low cardiac output
Diagnosis:

Flow diagram for the work-up of hypoxia:

Radiographic Possible Etiologies Radiographic Possible Etiologies

Pattern Pattern

COPD/asthma Aspiration
Intracardiac shunt Pleural effusion
AV malformation Main bronchus intubation
Pulmonary embolism Mucus plug
Pneumothorax Re-expansion edema
Clear Hypoventilation Unilateral Pneumonia
Desaturated mixed Pulmonary contusion
venous blood Decubitus positioning +
hydrostatic edema

Lobar pneumonia ARDS

Occlusion (drowned Bronchopneumonia
lung) Hemorrhage
Pulmonary Infarction Hydrostatic edema
Aspiration
Lobar Diffuse
nd
Adapted from: Marini JJ, et al. Critical Care Medicine,2 ed. 1997.

Hypoxia combined with hypercapnia usually is due to COPD, asthma, or hypoventilation.

Treatment:
Basic techniques to improve tissue oxygenation:

1. Increase FIO2 by supplemental oxygen 4. Secretion management 7. Reduce O2 requirement

2. Increase mean lung volume and 5. Bronchodilation 8. (Increase CO)

alveolar pressure

3. Repositioning of the body 6. Diuresis 9. Increase Hb

Supplemental Oxygen

Hypoxia from any etiology (with the exception of large right to left shunts) respond well to supplemental oxygen.

Options for providing supplemental O2:

OXYGEN L/MIN OF MAXIMUM MAX. PAO2 NOTES

SUPPLY O2 DELIVERED AT SEA
DELIVERED F IO 2 LEVEL
(MMHG)
ROOM AIR - 0.21 100
NASAL 1-6 0.40 235 DELIVERED FIO2 IS INVERSELY
CANNULA PROPORTIONAL TO RR.
VENTURI MASK 1-4 0.50 305 DELIVERS FIXED FIO2.
OPEN FACE 1-15 0.60 375 CAN BE USED FOR PATIENTS WHO CANNOT
TENT TOLERATE NASAL CANNULA OR FACE
MASKS. FIO2 VARIES WIDELY WITH THE SET
FLOW RATE, MINUTE VENTILATION, AND
TENT POSITION.
SIMPLE FACE 6-10 0.60 375 FIO2 DEPENDS BOTH ON O2 FLOW RATE, AND
MASK (FM) ALSO ON PATIENT’S TIDAL VOLUME. CO2
CAN BUILD UP IN THE MASK AT FLOW RATES
<5L/MIN.
PARTIAL 5-7 0.70 450 RESERVOIR BAG MUST BE KEPT AT LEAST
REBREATHER PARTIALLY INFLATED TO PREVENT IT FROM
FM ACTING AS A SIMPLE FM.
NON- 5-15 > 0.80 >520 IF THE RESERVOIR BAG DEFLATES, AND THE
REBREATHER MASK IS WITHOUT A SAFETY RELEASE
FM MECHANISM FOR THE ONE-WAY VALVES, A
PATIENT COULD CONCEIVABLY SUFFOCATE.

Oxygen delivery systems are classified as either:

1. Low-flow – These provide a reservoir of oxygen for the patient to breathe (e.g. nasal canula, simple
face mask, masks with reservoir bags)
2. High-flow – These provide a constant FIO2, regardless of changes in ventilatory pattern (e.g. Venturi
masks). Their major advantage over low-flow systems is that they prevent inadvertently giving too
great an FIO2 to patients with chronic hypercapnia.

Additional notes regarding O2 supplementation:

O2 must be humidified if given at ≥ 4L/min.

An FIO2 > 60% sustained for >48 hours increases the risk of developing pulmonary oxygen toxicity. If high FIO2
is required for a longer time, consideration should be given to mechanical ventilation or non-invasive
positive pressure ventilation (NIPPV).
O2 supplementation should only be given in the following situations (the latter two being evidence of ongoing
tissue hypoxia):
PaO2 < 60 or SaO2 < 92%
Myocardial ischemia
Lactic acidosis
PvO2 < 50%

Increasing lung volume and alveolar pressure

Both PEEP and inverse ratio ventilation can be beneficial in lung volume recruitment in intubated, hypoxic
patients. In addition, periodic deep breathing can help improve hypoxia associated with plate and
microatelectasis. In awake, non-intubated patients this is best accomplished by incentive spirometry and by
adequate control of any chest wall pain.

Repositioning

Alert patients should be kept upright whenever possible. Alternating lateral decubitus positions improves
secretion drainage from the uppermost lung. When one lung is affected differentially in the process leading to
hypoxia, oxygenation may improve by placing the good lung in the dependent position, however care must be
given to prevent secretions from the infiltrated lung spilling into the good one. Intermittent shifts from the supine
position to the prone position can significantly help the hypoxemia that accompanies the early stages of ARDS.

Secretion Management

Suctioning and chest therapy in both intubated and non-intubated patients may improve oxygenation in the
setting of increased secretions. Mucolytics, such as nebulized N-acetylcysteine may aid in breaking up mucus
in COPD patients, but risks inducing bronchospasm, and it is not approved for this use in the United States.
Recombinant DNAse has been used in the treatment of excessive mucus in patients with cystic fibrosis, but it
has not been found to be beneficial in other disorders (one trial actually found it to be harmful in patients with
COPD). Surfactant is also being studied as a possible mucolytic, but it is profoundly expensive, of unclear
benefit, and not available at most centers.

Bronchodilation

The most effective bronchodilators are β agonists (e.g. albuterol). In addition to relaxing bronchial smooth
muscle, they may decrease mast cell mediator release, inhibit neutrophil and eosinophil function, and increase
mucociliary transport. Anticholinergic drugs (e.g. ipratropium) are also important bronchodilators, which act by
blocking the M3 muscarinic receptors on bronchial smooth muscle by competing with acetylcholine at these
receptor sites.

These medications can be delivered either by jet nebulizer or by a metered-dose inhaler (MDI) with a spacer.
Although the total dose delivered by nebulizer well exceeds that delivered by MDI, the bronchodilation response
is nearly identical. As MDIs are substantially less expensive than nebulizers, they are generally the mode of
delivery of choice in patients awake enough to be compliant with their use.

Diuresis
Intravenous diuretics such as furosemide can be enormously beneficial in patients who have a component of
pulmonary edema.
Reducing O 2 Requirements

This can be accomplished by treating fever, agitation, shivering, and preventing overfeeding. Paralysis in
intubated patients who are agitated, are significantly overbreathing, or are fighting the ventilator can improve
oxygenation as well. A significant portion of total blood flow can be directed to the diaphragm during extreme
dyspnea.

Increasing CO

Although it was originally speculated that patients who had their cardiac output artificially raised to supranormal
levels would have improved oxygen delivery and improved outcomes, this has not been demonstrated in recent
studies.

Increasing Hb

Although it initially seems that an increased level of hemoglobin would improve oxygen delivery, and ease the
need for achieving a normal SaO2, studies have found that with the exception of cardiac patients and those with
ongoing bleeding, transfusions are generally not necessary for Hb levels greater than 7.0g/dL. Patients with
ongoing myocardial ischemia, or possibly those with underlying stable CAD, should be transfused to 9-10g/dL.

Use of supplemental oxygen in patients with chronic hypercapnia:

There has been a historical fear of giving O2 to patients with chronic hypercapnia (such as those with COPD) for
fear that this would blunt their respiratory drive. It was previously thought that the primary drive to breathe in
these patients was hypoxia. More recent data shows that the worsening of hypercapnia seen in these patients
when given high amounts of supplemental O2 is likely due to worsened V/Q mismatch as a result of attenuation
of hypoxic vasoconstriction. In addition, there is decreased affinity of Hb for CO2 in the presence of higher SaO2
(the Haldane effect). Although it is not necessary to worry that a COPD patient will stop breathing when placed
on oxygen, one does need to be concerned over supplying too high an FIO2. However, this should not prevent
treatment of significant levels of hypoxia, as patients with acute of chronic respiratory failure generally have
greater risk from hypoxemia than from hypercapnia.

Goals of oxygen therapy in COPD patients should be to prevent significant tissue hypoxia without leading to
clinically significant worsening of hypercapnia. In general, SaO2 should be kept at 88–93%, and PaO2 should be
between 60-70mmHg. If these goals cannot be achieved without developing severe hypercapnia (PaCO2 > 85-
90mmHg), then serious consideration should be given to intubation and mechanical ventilation. In many cases
NIPPV may allow intubation to be avoided.
 Acute Respiratory Distress Syndrome

Definition:
Acute respiratory distress syndrome (ARDS) refers to the severe-end of the spectrum of respiratory failure as a
result of acute lung injury. Both acute lung injury (ALI) and ARDS are syndromes of acute and persistent
respiratory dysfunction associated with inflammation and increased vascular permeability, leading to diffuse
pulmonary edema. Unlike hydrostatic edema, permeability edema resists clearance by diuretics.

Criteria for diagnosis:

Acute Lung Injury ARDS

1. Bilateral infiltrates on CXR 1. Bilateral infiltrates on CXR

2. PaO2 (mmHg) / FIO2 (0.21-1.00) = 201 – 300
(regardless of the level of PEEP)
3. No clinical evidence of left-sided heart failure.
If measured, PCWP must be less than
18mmHg.
2. PaO2 (mmHg) / FIO2 (0.21-1.00) ≤ 200
(regardless of the level of PEEP)
3. No clinical evidence of left-sided heart failure.
If measured, PCWP must be less than
18mmHg.

Although hypoxia is required for a diagnosis of ARDS, its severity does not accurately predict either the extent of
underlying pathology, or the expected clinical course and prognosis.

Pathophysiology:
Pro-inflammatory cytokines (such as TNF, IL-1, and IL-8) released in response to any of a large number of
possible stimuli are either released in the lung (as in inhalational injuries) or, more commonly, brought to the
lungs via bloodstream after release elsewhere in the body. These cytokines recruit and activate neutrophils,
which release toxic oxygen radicals and proteases which breakdown the alveolar-capillary barrier. Protein
escapes from the intravascular space into the interstitial space, and ultimately the alveoli, along with fluid. In
addition, functional surfactant is lost, resulting in alveolar collapse. The net result of this process includes:

1. Impaired gas exchange – Hypoxia develops from a combination of V/Q mismatching and
physiologic shunting. Although hypercapnia (prior to mechanical ventilation) is uncommon, minute
ventilation may be significantly increased to maintain a normal PaCO2.
2. Decreased lung compliance – Low compliance is due to the stiffness of the poorly aerated lung in
the setting of diffuse pulmonary edema. As only the aerated segments of the lungs take place in gas
exchange, even small tidal volumes can exceed the lung’s inspiratory capacity resulting in elevated
airway pressures.
3. Pulmonary hypertension – This is due to the combination of hypoxic vasoconstriction and vascular
compression by positive pressure ventilation.

Etiologies:
Current cigarette smoking is the only major epidemiologic risk factor. Predisposing conditions however, are
many.
Conditions Predisposing to ARDS:

More Common Less Common

Sepsis (most common, and the risk is especially high Near drowning
in septic patients with a history of alcoholism) Smoke inhalation
Aspiration (ARDS develops in 1/3 of hospitalized Cardiopulmonary bypass
patients with clinically significant aspiration. Pulmonary contusion
Stomach contents do not need to be acidic to lead Following relief of upper airway obstruction (more
to ARDS.) common in children than in adults)
Bacterial pneumonia Multiple fractures
Severe trauma / surface burns (the appearance of Venous air embolism (now rare in the US, as trauma
ARDS in victims of severe trauma does not victims are effectively immobilized prior to transport
independently raise their overall mortality.) to the hospital)
Massive blood transfusion Amniotic fluid embolism
Leukoagglutinin reactions Acute eosinophilic pneumonia
Pancreatitis Cryptogenic organizing pneumonia
Drug overdose (seen with ASA, cocaine, opiods, Miliary tuberculosis
phenothiazines, and TCAs) Lung and bone marrow transplantation
Idiosyncratic drug reactions (seen with protamine,
nitrofurantoin, and radiocontrast dye)

In the differential diagnosis of ARDS, it is important to also consider malignancies (particularly acute leukemias
and lymphomas) and diffuse alveolar hemorrhage as possible etiologies of severe hypoxia and diffuse bilateral
pulmonary infiltrates on CXR. Although the cause of ARDS is usually evident from the history and overall
clinical presentation, when the cause cannot be determined, both bronchoscopy and open lung biopsy can
frequently provide the answer.

Clinical course:
ARDS typically develops over the course of 4 to 48 hours, and lasts for days to weeks. A small subset of cases
which fall loosely under the term ARDS are not associated with significant inflammation, and may resolve
relatively quickly (e.g. as in neurogenic pulmonary edema, heroin-induced pulmonary edema, and limited
chlorine or ammonia gas inhalation). There are 3 distinct stages to the evolution of ARDS:

1. Early/Exudative Stage (Day 0-2) – Patients develop tachypnea, dyspnea, hypoxemia, and diffuse
rales on exam. Lab findings may include leukocytosis and lactic acidosis, along with a respiratory
alkalosis and elevated A-a gradient. The CXR typically shows diffuse, fluffy alveolar infiltrates in
multiple lung zones with prominent air bronchograms. Pathologically, this stage is characterized by
diffuse alveolar damage and pulmonary edema.
2. Late/Proliferative Stage (Days 2-7) – Pulmonary edema may resolve, but patients continue to have
large dead space fractions and a high minute ventilation requirement. Barotrauma and nosocomial
infections may develop. On CXR, radiographic densities become less opaque, while interstitial
infiltrates remain. Pathologically, this stage is characterized by proliferation of type II pneumocytes,
squamous metaplasia, interstitial infiltration by myofibroblasts, and early deposition of collagen.
3. Very late/Fibrotic Stage (Day 7 and beyond) – Not occurring in all patients, this stage is
characterized by obliteration of normal lung architecture, diffuse fibrosis, and cyst formation. CXR may
have a honeycomb appearance, and progressive pulmonary hypertension may result.

Mechanical Ventilation in ARDS:

Nearly all patients with ARDS require mechanical ventilation, due to a combination of high ventilatory
requirements, increased alveolar dead space, and decreased lung compliance. Mechanical ventilation allows a
higher FIO2 to be delivered, it decreases the overall work of breathing by resting the patient’s respiratory
muscles, positive pressure decreases venous return to the heart (which in turn reduces pulmonary capillary
hydrostatic pressure and edema formation in early ARDS), and it helps recruit atelectatic lung units.
Mode of Ventilation

Patients with ARDS can be ventilated using either volume controlled (VCV) or pressure controlled (PCV) modes.
PCV and VCV are nearly interchangeable because pulmonary mechanics in ARDS tend to be relatively stable
from hour to hour. This results in PCV producing predictable tidal volumes, and VCV producing predictable
airway pressures. Modes of ventilation offering full support are favored over partially-supported modes (i.e.
SIMV), particularly early in the course of disease. In general, the choice of ventilator mode is less important
than choosing appropriate ventilatory goals and strategies, discussed further below.

Ventilatory strategies

Lung protective ventilation (aka low tidal volume ventilation) – In this approach, patients are ventilated with VT ≤
6 mL/kg of ideal body weight (IBW), and high respiratory rates are tolerated. Plateau pressures should be kept
< 30 cm H2O. A benefit to low tidal volumes was found by the ARDS network trial, which was stopped
prematurely after interim analysis concluded significantly lower mortality was seen in patients receiving such
treatment (though this finding has been subsequently criticized). Patients treated with lung protective ventilation
may be more prone to developing auto-PEEP, and should be carefully monitored for the development of
hemodynamic compromise as a result.

“Open lung” ventilation - In this approach, VT is kept ≤ 6 mL/kg, PEEP is set at 2 cm H2O above the lower
inflection point of the pressure-volume curve (PEEP is set at 16 cmH2O if the lower inflection point cannot be
determined), driving pressure is kept ≤ 20 cm H2O, and peak pressure is limited to 40cm H2O. Patients are
ventilated using pressure-controlled inverse ratio ventilation or pressure support ventilation, and the respiratory
rate is kept below 30 breaths per minute. When this approach is used, the ability of PEEP to improve gas
exchange needs to be balanced by its potential negative hemodynamic consequences. One study which
compared open lung ventilation to the more common lung protective ventilation found no mortality difference.

Prolonging inspiratory time – Because ARDS is a heterogeneous process, different areas of the lung may
require different inflation times to ventilate. Prolonging inspiratory time may recruit more lung to participate in
gas exchange by giving diseased units more time to open. This can be accomplished in PCV by directly
increasing the I:E ratio, and in VCV by either decreasing the peak inspiratory flow rate, by using a decelerating
wave form, or by providing a breath hold at end-inspiration. This approach improves oxygenation only in some
patients, and increases the risk of barotrauma, air-trapping, and hemodynamic instability. Furthermore, it also
requires significant sedation and possibly paralysis.

Optimal level of PEEP – There is no such thing as an “optimal level” of PEEP for all patients with ARDS, and the
appropriate level of PEEP must be decided upon on a case by case basis. PEEP can improve oxygenation by
increasing end-expiratory volume, increasing alveolar recruitment, decreasing perfusion of unventilated alveoli,
and improving V/Q matching, however, excessive PEEP can possibly increase the risk of barotrauma, and,
particularly in combination with hypovolemia, can decrease cardiac output from impaired venous return.
Although higher PEEP may increase SaO2 and allow lower levels of FIO2 to be used, reduced CO may lead to an
overall reduction in oxygen delivery.

Permissive hypercapnia – This is not a ventilatory strategy, per se, but rather a consequence of lung protective
ventilation as hypercapnia develops when tidal volume is decreased and the VD/VT ratio is increased.
Contraindications to permissive hypercapnia include predisposition to increased ICP, hemodynamic instability,
and treatment with β-blockers, because an adequate catecholamine response is required to maintain
hemodynamic stability during hypercapnia.

Batotrauma in ARDS

Macrobarotrauma – Whether macrobarotrauma results from high airway pressure, or is rather a marker of
severe disease is unclear. It can be manifested as pneumothorax, air embolism, pneumomediastinum,
interstitial emphysema, and subcutaneous emphysema (only the first two of which are usually acutely
dangerous). Although anecdotally believed to be associated with higher levels of PEEP, one retrospective
analysis found that mean airway pressure, plateau pressure, and driving pressure (plateau pressure – PEEP)
were not predictive of the development of macrobarotrauma.
Microbarotrauma – Less clear than macrobarotrauma is the role in which over-inflation of alveoli perpetuate
acute lung injury. Animal studies suggest that over-inflation is more important in this regard than is high airway
pressures. Based on this, most clinicians now employ limited tidal volumes in ventilated patients with ARDS, as
discussed above.

Approach to Mechanical Ventilation in ARDS (adapted from NEJM 2000; 342: 1301):

Initial ventilator settings: Mode – Volume assist-control

Tidal Volume (VT)– 8 mL/kg of IBW, titrated downward to 6 mL/kg over 1-3 hours
RR – Adjust to match baseline minute ventilation (with 35 breaths/min maximum)

Setting PEEP: PEEP should be set according to the FIO2 required to maintain SaO2 88-95% or
PaO2 55-80 mmHg.

F IO 2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0

PEEP 5 5-8 8-10 10 10-14 14 14-18 18-22
(cm H2O)

Subsequent tidal volume Check inspiratory plateau pressures with a 0.5 second inspiratory pause, at least
adjustments: once every 4 hours, and after each change in PEEP or VT.

(Adjusting to Pplateau goal If Pplateau > 30 cm H2O  Decrease VT in 1 mL/kg steps to 5 mL/kg IBW, (or to 4
of 25-30 cm H2O) mL/kg IBW if necessary)

If Pplateau < 25 cm H2O  Increase VT in 1 mL/kg steps to maximum of 6 mL/kg

IBW.

If auto-PEEP (or breath stacking) is occurring, VT may be increased to 7 or 8

mL/kg IBW if Pplateau remains ≤ 30 cm H2O.

Adjusting Inspiratory If oxygenation requires FIO2 ≥ 0.6, consider decreasing flow rate to prolong
Time: inspiratory time.

Additional Measures to Improve Oxygenation:

Diuresis – Even in patients who are not volume overloaded may benefit from diuresis, and a trial of diuresis is
reasonable provided that hypotension and organ hypoperfusion are avoided.

Prone Positioning – The theoretical benefit of prone positioning is related to the observation that
consolidation in ARDS is most severe in the dependent lung zones which remain the best perfused, resulting in
significant V/Q mismatching. Other potential benefits include an increase in functional residual capacity and
better mobilization of secretions. There are no studies to date which have found a survival benefit to prone
position ventilation in patients with ARDS.

Decreased Oxygen Consumption – In states of pulmonary shunting, SaO2 may be improved by increasing
SvO2. This can be accomplished through decreased oxygen consumption by aggressively treating fever and
anxiety, and by providing sedation and possibly paralysis.
Novel Therapies:
Inhaled Vasodilators – Inhaled nitric oxide (NO) has been widely studied for use in hypoxic respiratory failure
in doses of 1 to 40 parts per million. As it is inhaled, it selectively dilates vessels receiving better ventilation. As
it acts locally and has a very short half-life, it has few systemic effects. NO does not reverse hypoxia in all
patients. Patients with baseline high pulmonary pressures are more likely to respond favorably, whereas septic
patients may be less responsive than non-septic patients. The improvement in V/Q matching may be enhanced
by concurrent administration of IV almitrine, which enhances hypoxic vasoconstriction, however, this may
worsen right ventricular afterload, and this medication is not available in the U.S. Although NO has been
demonstrated to have significant physiologic benefit, studies to date have failed to find a significant
improvement in mortality. Inhaled prostacyclin has also been investigated, and found to have similar properties
to NO (along with no mortality benefit).

Exogenous Surfactant – Multiple abnormalities of endogenous surfactant have been described in ARDS,
which is thought to contribute to its pathophysiology, as surfactant normally prevents atelectasis, facilitates
mucous clearance, clears oxygen radicals, and suppresses inflammation. However, randomized controlled
trials of exogenous surfactant have failed to find mortality benefit.

High-Frequency Ventilation (HPV) – There are 3 types of HPV (positive pressure, jet, and oscillation), all
of which uses tidal volumes below that of the anatomic dead space at frequency in excess of 60 breaths/min.
The theoretical benefits of these ventilatory modes are decreased barotrauma, improved V/Q matching, and
less hemodynamic compromise, however actually improvements in outcome remain unproven.

Liquid Ventilation – Liquid ventilation consists of filling the lungs with a perfluorocarbon, a dense liquid
capable of gas transport, and commencing mechanical ventilation with the liquid in place. Benefits include
improved oxygenation, decreased barotrauma, and reduction in the diffuse alveolar damage characteristic of
ARDS. This technique has only been tried in a small number of patients, and its future role in ARDS treatment
remains undetermined.

Extracorporeal Membrane Oxygenation (ECMO) – ECMO involves withdrawing venous blood, passing it
through a membrane oxygenator external to the body, and returning to the arterial circulation. Venous to
venous circuits have also been tried. Initial curiosity in ECMO generated in the 1970s waned after there was no
survival benefit found, but some interest has been renewed in recent years. However, ECMO requires
uncommon equipment and substantial expertise in its use, and thus is used at only a few centers.

Anti-Inflammory Medications – Systemic corticosteroids clearly have a role in steroid-responsive causes of

ARDS (e.g. acute eosinophilic pneumonia), and may have a role during the fibroproliferative phase of ARDS
(pending further studies). Ibuprofen, ketoconazole, neutrophil elastase inhibitors, and prostaglandin E1 have all
also been investigated as treatment in ARDS (or for prevention of ARDS in high-risk patients), and studies in all
have yielded mixed results.

Antioxidant Therapy – Studies investigating drugs designed to replete stores of intracellular glutathione (N-
acetylcysteine and Procysteine) have yielded mixed results, though these studies have all been small and
without substantial statistical power. One study also examined lisophylline, which is thought to decrease the
level of circulating free fatty acids (which may be oxidized in systemic inflammation and act as proinflammatory
mediators), however this study found no difference in survival (or interestingly enough, differences in circulating
FFA levels).

Prognosis:
Overall mortality from ARDS is in the range of 35-40%. In most non-survivors, the actual mechanism of death is
related more directly to the etiology of ARDS, and not due to the respiratory failure itself. Because of this, the
severity of physiologic impairment (degree of hypoxemia, required PEEP, radiographic appearance) at
presentation and early in the disease does not predict mortality. One possible exception to this is the ratio of
dead space to tidal volume (VD/VT), as one study found that an increase in this ratio was correlated with higher
mortality rates. Persistent symptoms one year after recovery from ARDS correlate with duration of mechanical
ventilation and an FIO2 requirement greater than 60% for longer than 24 hours. Aside from residual pulmonary
symptoms, surviving patients not infrequently also develop impairments of memory and concentration.