This document discusses the pathophysiology and management of acute respiratory distress syndrome (ARDS). It notes that ARDS is characterized by pulmonary edema due to increased capillary permeability. Conservative fluid strategies aiming for zero balance can improve outcomes in ARDS patients without shock by reducing pulmonary pressures and edema. A biphasic approach starting with liberal fluids then transitioning to conservative is recommended as hemodynamics stabilize. Diuretics, fluid restriction, and potentially beta-2 agonists or albumin with furosemide in hypoproteinemic patients may help resolve edema. Central pressures, weight, fluid balance, and extravascular lung water should be monitored.

1. Yasser Nassar, MD, DIU-CI
Assistant Professor
Critical Care Medicine
Cairo University Hospitals

2. 300 million Alveoli , Surface area 160m2 size of a Tennis Court
Interstitial space can accommodate upto 500 ml of Edema Fluid
before Alveolar Flooding ( Matthay MA, Physiol Rev 2002)

3.  Incidence Higher than Past Estimates
150,000 – 200,000 per year in US alone.
• Sepsis most common associated cause
• Mortality persists at 30-45%
• Current Rx is supportive only
• There remains a major need for novel
therapeutic strategies to treat ARDS.

7. -- Compliance ++WOB
-- Gas Exchange Hypoxia
++ PVR Pulm HTN, RVF
Heterogenous VALI, Inflamation

8. Epithelial Damage ++ HMW Ptns
 -- Alv Clearance
 -- Gas Exchange
 Hypoxia
Inflam cell Accum Septic Shock
 Pulm Fibrosis
 Prolonged MV
 MOF

11. Single Layer of Alveolar Epithelium on Basement Membrane
Single Layer of Vascular Endothelium on Basement Membrane
So Close that Basement Membranes may FUSE

12.  Hydrostatic pressure gradient producing a flow of fluid
out Vs Oncotic pressure gradient,opposing this
transudation.
 Jv : flow of fluid through the capillary wall
 K :capillary hydraulic filtration coefficient reflecting
 endothelial water permeability
 Pc : capillary hydrostatic pressure
 Pi : interstitial hydrostatic pressure
 S : oncotic reflection coefficient,reflecting endothelial protein
and oncotics permeability
 πc : capillary oncotic pressure
 πi : interstitial oncotic pressure

13.  Two principal mechanisms can work toward an increase
in pulmonary water
 Increase in Pulmonary Microvascular Pressure
 Increase in Alveolocapillary Memb Permeability.
 (a fundamental element in the formation of pulmonary
edema in ARDS) (Dudek et al , J Appl Physiol 2001,91:1487-1500.)

14.  Interstitial water is drained by the lymphatic network. Interstitial pressure is
always low, with the pressure remaining in favor of transudation of the vascular
sector toward the interstitium (i.e. resorption of interstitial edema is not by
pulmonary vascular resorption ).

15.  Interstitial water is drained by the lymphatic network.
 Once the Lymphatic network is saturated, fluid accumulates in the loose peri-
bronchovascular conjunctive tissue of the hilar zones, the first accumulation
site in pulmonary edema and they have very low resistance to fluid flux .
 Interstitial drainage will depend on the capacity of lymphatic flow to increase
as well as the capacity of the perihilar tubes to drain into the mediastinum and
the interstitial edema to evacuate toward the pleura and then the lymphatic
system.

16.  Alveolar water is active transported with an alongside ionic osmotic gradient
from apical to basolateral side of Epithelial Cell Type II Interstitial edema
drainage circuit.
 ARDS damage of epithelial cells and alveolocapillary barrier, alters active
transport of ions and fluid by the epithelium leading to diminished Alveolar
Clearance


17.  Pulmonary lymphatic vessels are classically along the peribronchial
vascular sheaths, interlobular septa, and pleural connective tissue.
Lymphatic capillaries are lined by a single layer of overlapping endothelial
cells, and in contrast to blood vessels,lack a continuous basement
membrane and pericyte coverage.They ensure the drainage of excess
proteins and fluid in this part of the lung. (Swartz 2001).

18.  Lymphatic channels are present emerging from interalveolar
interstitium,and around small blood vessels constituting the
paraalveolar lymphatics.This intralobular lymphatic network may play a
key pathophysiological role in a wide variety of alveolar and interstitial
lung diseases.
 (J Histochem Cytochem 57:643–648,2009)

19. PAOP < 18 REMOVED ,as high PAOP hydrostatic PE & ARDS may Coexist

20.  1) PAOP underestimates capillary filtration
pressure,especially in ARDS where the pulmonary
venous resistance is increased .
 2) Critical hydrostatic pressure above which
pulmonary edema will develop will be lower than in
normal lungs permeability.
 e.g. If the capillary hydraulic filtration coefficient is
doubled,critical hydrostatic pressure is only 10
mmHg in abnormal memb permeability ARDS.
 This constitutes the theoretical justification for
limiting pulmonary filtration pressure

21.  The majority of patients with ARDS have a PAOP that is
superior to critical filtration pressure values when the
barrier is damaged

22. 300 million Alveoli , Surface area 160m2 size of a Tennis Court
Interstitial space can accommodate upto 500 ml of Edema Fluid
before Alveolar Flooding ( Matthay MA, Physiol Rev 2002)

23. Edema drainage is enhanced if:
 Right Atrial Pressure (CVP )
 Pleural pressure (Ppl)
Decreasing Edema formation if:
 PAOP

24. Decreases Pulmonary Capillary Pressure
By: Hypovolemia
 Low CVP
 Low PAOP

25. Reduction of PAOP in ARDS patients
improves mortality. ( Humphrey et al, Chest 1990,
97:1176-1180)
Lung water amount indexed with PBW on
day 1 of ARDS was predictive of death.
 (Phillips CR et al ,Crit Care Med 2008, 36:69-73.)
 Surviving Sepsis Campaign recommends a conservative
fluid strategy in patients with ARDS and in the absence of
shock.
 (Dellinger RP, et al Intensive Care Med 2008, 34:17-60.)

26.  Edema forms faster and at a lower hydrostatic
pressure threshold when one has first damaged
the alveolocapillary barrier before progressively
increasing the left atrium pressure.
 (Guyton Circ Res 1965,16:452-460.)
 Modest decrease in pulmonary capillary
pressure in ARDS animal models can limit the
formation of pulmonary edema
 ( Prewitt RM et al. J Clin Invest 1981, 67:409-418.)
 Reducing edema may have beneficial effects on
respiratory function and eventually outcome

30.  Goal was to obtain a CVP of 8 mmHg or less in
the “conservative-strategy”group or 14
 mmHg in the “liberal-strategy”group.
 In the patients monitored by pulmonary arterial
catheter, the objectives of PAOP were 12 mmHg
in the “conservative-strategy”group and 18
mmHg in the “liberal-strategy”group.
 The protocol was applied for 7 days after
inclusion of the patient but was not applied in
cases of hypotension.

31.  Conservative vs Liberal fluid :
 Improved the oxygenation index
 Improved Lung Injury Score
 Lowered plateau airway pressure
 Increased the number of ventilator-free days
 (14.6 ± 0.5vs. 12.1 ± 0.5; P = .0002)
Increased ICU-free days
(13.4 ± 0.4 vs 11.2 ± 0.4;P =.0003) to day 28.
Nonsignificant Reduction 2.9% in the 60-day
mortality 25.5%vs.28.4%,respectively;p=0.30
 Better neurological status -desedated earlier because of
 better respiratory status, perhaps less severe cerebral edema.
 Fewer transfusions with its potentially deleterious role.

32.  During early phase of aggressive inflammation
when the edema is developing,therapeutic
strategy is usually oriented toward systemic
hemodynamic resuscitation with volume and
vasopressors !! (i.e. contradictory with goals to
reduce the pulmonary capillary pressure).
 Difficulty of measuring and evaluating
pulmonary capillary filtration pressure.
Hypovolemia diminishes pulmonary capillary
pressure,whereas local vasoconstrictors or
myocardial depression can increase it.

33.  In ARDS complicating septic shock.
 Nonperformance of early adapted fluid administration and
the Absence of a negative fluid balance during a minimum
of the first 2 consecutive days within the 7 days following
 the occurrence of septic shock were independent mortality
factors in multivariate analysis.
 This highlights the importance of a “Biphase”fluid
strategy.
 (Murphy CV,et al Chest 2009,136:102-109).
 Surviving Sepsis Campaign recommends a conservative
fluid strategy in patients with ARDS and in the absence of
shock.
 (Dellinger RP, et al Intensive Care Med 2008, 34:17-60.)

34. Early Phase (Unstable Hemodynamics):
Sepsis, Hypovolemia Fluids
or else organ dysfunction and mortality
Later phase (Stabilized Hemodynamics)
 Zero balance.

35.  Resorption of alveolar edema does not occur by manipulation of
vascular pressures, but rather by stimulation of active water
transport from the alveoli toward interstitium.
 Despite severe epithelial lesions in ARDS, alveolar clearance is
usually pharmacologically stimulable.
 cAMP agonists,in particular beta-2 agonists,accelerates the
resolution of edema through an increase in the quantity and
activity of Na/K pumps in the basal membrane and Na canals in
the pneumocyte apical membrane whose effect is to increase
the sodium gradient between the alveoli and the interstitium
and therefore the absorption of water.


36. IV salbutamol 15 μg/kg/h for 7 d in ARDS patients made it possible to
diminish the quantity of pulmonary water measured by transpulmonary
thermodilution without affecting oxygenation, duration of mechanical
ventilation, or outcome.
(Perkins GD,a Am J Respir Crit Care Med 2006, 173:281-287).

37.  Whereas pulmonary edema begins to develop
 at a pressure of 24 mmHg when oncotic pressure is normal,it
begins at 11 mmHg when it is reduced.(Guyton AC .Circ Res
1965, 16:452-460).
 Hypoprotinemia therefore facilitates the development of
hydrostatic pulmonary edema.However,the importance of
oncotic pressure in the limitation of flux is only conceivable
if the barrier is intact.
 In case of endothelial lesions (ARDS),an interstitial edema
will be all the richer in proteins than the plasma,
theoretically limiting the interest of increasing the plasmatic
oncotic pressure.

38. 37 mechanically ventilated pts with ALI and
serum protein ≤ 5.0 g/dl 2.
Randomized to receive five-day protocolized
regimen of 25g albumin every 8 hours with
continuous infusion of furosemide
vs. dual placebo
Furosemide titrated every 8 hours to achieve a
daily weight loss ≥ 1 kg/day

39. Improved fluid balance 5.3 kg more weight loss in treatment
group (p =.04)
Improved oxygenation PaO2/FiO2 - 171 to 236 (p =.02)
Improved hemodynamics
MAP increased 80 to 88 mmHg (p = .10)
Heart rate decreased 110 to 95 (p = .008)
Trend towards improved mortality –not powered
Follow-up study showed increased efficacy furosemide
with albumin vs. furosemide alone in 40 hypoproteinemic
ALI pts

40.  A discrete improvement in oxygenation
when albumin (75 g/d) for 5 days was
associated with diuretic treatment
compared with diuretic
 treatment alone.
 (Martin GS, Crit Care Med 2005,33:1681-1687).
 At this stage, the very limited clinical data
do not make it possible to recommend the
administration of albumin with the goal to
improve pulmonary function and respiratory
morbidity in ARDS patients.

41.  ARDS is particularly characterized by pulmonary edema
caused by an increase in pulmonary capillary permeability.
Epithelial damage is more prominent than Endothelial
damage.
 Conservative fluid strategy aiming for Zero fluid balance in
ARDS patients ( without shock or renal failure needing early
and adapted vascular filling ) significantly increases the
number of days without mechanical ventilation.

 Biphasic fuild strategy (Liberal followed by Conservative
strategies ) are complementary and should ideally follow
each other as hemodynamic state progressively stabilizes.

42.  Albumin treatment has been suggested to
improve oxygenation transiently in ARDS
patients, but no sufficient evidence to date
justifies its use to mitigate pulmonary edema.
 Resorption of alveolar edema occurs through an
active mechanism,which can be
pharmacologically upregluated.
 Beta-2 agonists may be beneficial but further
studies are needed to confirm preliminary
promising results.

43.  ARDS not in shock :
 . Diuretics
 . Fluid restriction
 . Albumin+furosemide in selected patients
with hypoproteinemia
 B2 agonists
 Monitoring:
 Central pressures,Weight, fluid balance, EVLW
 ( Charles Philips MD ,ISICEM 2009)