This document discusses acute respiratory distress syndrome (ARDS) and extracorporeal membrane oxygenation (ECMO). It provides details on ARDS phenotypes, biomarkers, and treatments including prone positioning, neuromuscular blockade, and various ventilation strategies. ECMO is described as a rescue therapy for severe respiratory failure, with venovenous and venoarterial configurations outlined. Major complications of ECMO discussed include bleeding, thrombosis, and infection due to anticoagulation and the foreign body effect of the circuit.

1. Acute
Respiratory
Distress
Syndrome
Dr. Kaveh Kazemian
Pharm-D
Board Certified of Clinical Pharmacy
Fellowship Assistant of Critical Care Pharmacotherapy

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Dr. Kaveh Kazemian. Pharm-D. Board Certified of Clinical Pharmacy. Fellowship Assistant of Critical Care Pharmacotherapy
mild 27%, moderate 32%, and severe 45%

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Dr. Kaveh Kazemian. Pharm-D. Board Certified of Clinical Pharmacy. Fellowship Assistant of Critical Care Pharmacotherapy

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Dr. Kaveh Kazemian. Pharm-D. Board Certified of Clinical Pharmacy. Fellowship Assistant of Critical Care Pharmacotherapy

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Dr. Kaveh Kazemian. Pharm-D. Board Certified of Clinical Pharmacy. Fellowship Assistant of Critical Care Pharmacotherapy

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Dr. Kaveh Kazemian. Pharm-D. Board Certified of Clinical Pharmacy. Fellowship Assistant of Critical Care Pharmacotherapy

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Dr. Kaveh Kazemian. Pharm-D. Board Certified of Clinical Pharmacy. Fellowship Assistant of Critical Care Pharmacotherapy
Treatment of underlying
disease
Fluids and hemodynamic
managements
Nutrition
Mechanical ventilation Pharmacologic ECMO

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Dr. Kaveh Kazemian. Pharm-D. Board Certified of Clinical Pharmacy. Fellowship Assistant of Critical Care Pharmacotherapy
 Phenotypes of ARDS (hyper-inflammatory and hypo-inflammatory)
different biomarker profiles and clinical courses and respond differently to the random
application of positive end expiratory pressure (PEEP) and fluid management strategies
 High-frequency oscillatory ventilation, application of recruitment maneuvers,
higher PEEP, extracorporeal membrane oxygenation
Keratinocyte growth factor, beta-2 agonists, and aspirin did not improve outcomes

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Dr. Kaveh Kazemian. Pharm-D. Board Certified of Clinical Pharmacy. Fellowship Assistant of Critical Care Pharmacotherapy
 Prone positioning and early neuromuscular blockade have
demonstrated mortality benefit, and clinical guidelines now
recommend their use

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Dr. Kaveh Kazemian. Pharm-D. Board Certified of Clinical Pharmacy. Fellowship Assistant of Critical Care Pharmacotherapy
 The “hyper-inflammatory” phenotype as opposed to the “hypo-inflammatory”:
 Higher concentrations of plasma inflammatory biomarkers
 Higher prevalence of vasopressor use
 Lower serum bicarbonate levels
 Higher prevalence of sepsis
 Outcomes of mortality, ventilator-free days, and organ failure-free days were all
worse in the “hyper-inflammatory” phenotype

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Dr. Kaveh Kazemian. Pharm-D. Board Certified of Clinical Pharmacy. Fellowship Assistant of Critical Care Pharmacotherapy
Response to treatment
 High PEEP improved outcomes only in the hyper inflammatory phenotype, while
liberal fluid management worsened mortality.
 Conservative fluid management strategy was harmful in the hypo-inflammatory
phenotype

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Dr. Kaveh Kazemian. Pharm-D. Board Certified of Clinical Pharmacy. Fellowship Assistant of Critical Care Pharmacotherapy
Neuromuscular blockade
• Facilitating ventilator synchrony, especially in early ARDS, (prevention
double triggering)
• Preventing loss of PEEP by active exhalation (prevention of atelectrauma)
 Vitamin D to improve outcomes by leveraging early treatment
 Statins, beta-2 adrenergic agents, and keratinocyte growth factor (KGF)
and aspirin failed to reduce the incidence of ARDS

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Dr. Kaveh Kazemian. Pharm-D. Board Certified of Clinical Pharmacy. Fellowship Assistant of Critical Care Pharmacotherapy
Multiple biologic pathways in ARDS:
 Endothelial and epithelial Dysfunction
 Innate immune activation with
immune cell recruitment
 Intravascular coagulation
 Intraalveolar fibrosis.
One of the earliest reported genetic
associations with ARDS is with a
common deletion located in the
human ACE gene that results in a
higher plasma and tissue angiotensin
converting enzyme (ACE) activity
and a higher risk of ARDS

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Dr. Kaveh Kazemian. Pharm-D. Board Certified of Clinical Pharmacy. Fellowship Assistant of Critical Care Pharmacotherapy
ACE is responsible for the conversion of angiotensin I to
angiotensin II in the pulmonary vasculature, which results in
vasoconstriction among other effects
 Therapeutics that negatively regulate the ACE axis, including ACE2, are
currently being developed for ARDS

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Dr. Kaveh Kazemian. Pharm-D. Board Certified of Clinical Pharmacy. Fellowship Assistant of Critical Care Pharmacotherapy
Similar to genetics, another approach to endotyping ARDS
is to measure biomarkers representative of the activation of
particular biologic pathways
 Markers of inflammation:
Interleukin 6, 8
 Endothelial activation and/ or injury
Ang-2, VWF
 Impaired coagulation
protein C

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Dr. Kaveh Kazemian. Pharm-D. Board Certified of Clinical Pharmacy. Fellowship Assistant of Critical Care Pharmacotherapy
Another plasma biomarker that may identify an endotype of ARDS is the
IL-1 receptor antagonist (IL1RA). IL1RA is an inhibitory anti-
inflammatory cytokine that competes with proinflammatory cytokines IL-
1α and IL-1β to bind the IL-1 receptor without triggering receptor
signaling
The reactive phenotype was associated with a higher mortality and could be
accurately identified using five biomarkers:
IL-6, interferon gamma, angiopoietin, plasminogen activator inhibitor-1

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Dr. Kaveh Kazemian. Pharm-D. Board Certified of Clinical Pharmacy. Fellowship Assistant of Critical Care Pharmacotherapy

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Dr. Kaveh Kazemian. Pharm-D. Board Certified of Clinical Pharmacy. Fellowship Assistant of Critical Care Pharmacotherapy

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Dr. Kaveh Kazemian. Pharm-D. Board Certified of Clinical Pharmacy. Fellowship Assistant of Critical Care Pharmacotherapy
Their use is limited in real
clinical world for they have
low positive predictive
value and some of these
scoring systems are only
for pre-operative patients

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Dr. Kaveh Kazemian. Pharm-D. Board Certified of Clinical Pharmacy. Fellowship Assistant of Critical Care Pharmacotherapy
These instruments
have short comings in
that they are complex,
time-consuming to
calculate, and they are
not specifically
designed for ARDS
patients

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Dr. Kaveh Kazemian. Pharm-D. Board Certified of Clinical Pharmacy. Fellowship Assistant of Critical Care Pharmacotherapy

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Dr. Kaveh Kazemian. Pharm-D. Board Certified of Clinical Pharmacy. Fellowship Assistant of Critical Care Pharmacotherapy
• In 2017, García-Laorden et al. reported that biomarkers representing
epithelial apoptosis, such as Fas and FasL, as well as biomarkers
reflecting extracellular matrix injury, such as procollagen peptide III
(PCP III) and procollagen peptide I (PCP I), were elevated in ARDS
BALF samples

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Dr. Kaveh Kazemian. Pharm-D. Board Certified of Clinical Pharmacy. Fellowship Assistant of Critical Care Pharmacotherapy
Biomarkers associated with ARDS diagnosis

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Dr. Kaveh Kazemian. Pharm-D. Board Certified of Clinical Pharmacy. Fellowship Assistant of Critical Care Pharmacotherapy
Biomarkers associated with ARDS mortality

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Dr. Kaveh Kazemian. Pharm-D. Board Certified of Clinical Pharmacy. Fellowship Assistant of Critical Care Pharmacotherapy
 KL-6, lactate dehydrogenase (LDH), SRAGE, von Willebrand factor
(vWF), and IL-8 displayed the highest effect size for ARDS diagnosis
Interleukin-4 (IL-4), IL-2, Angiopoietin-2 (Ang-2), and KL-6 had the highest
effect size for ARDS prognosis
 ARDS diagnosis is correlated with tissue damage, whereas
ARDS mortality is correlated with systemic inflammation

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Dr. Kaveh Kazemian. Pharm-D. Board Certified of Clinical Pharmacy. Fellowship Assistant of Critical Care Pharmacotherapy
 Their immune-modulating effects, anti-bacterial action, lack of
rejection molecules as well as relative ease of isolation and
characterisation make these cells an ideal therapeutic for ARDS.

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Dr. Kaveh Kazemian. Pharm-D. Board Certified of Clinical Pharmacy. Fellowship Assistant of Critical Care Pharmacotherapy
Embryonic stem cells (ESCs)
 These cells can differentiate into all other progenitor cell types and are
viable treatment option for tissue regeneration. Studies using human ESCs
have Diabetes mellitus, Parkinson’s disease, ischemic stroke
Wang et al., observed that ESC-derived alveolar-
epithelial type II cells (AECII) attenuated
bleomycin-induced lung injury in mice and thus
showed potential promise as a therapeutic
 The pluripotency of ESCs is a double-edged sword; the same plasticity that
permits ESCs to generate hundreds of different cell types also makes them difficult
to control after in vivo transplantation

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Dr. Kaveh Kazemian. Pharm-D. Board Certified of Clinical Pharmacy. Fellowship Assistant of Critical Care Pharmacotherapy
Induced pluripotent stem cells (iPSCs)
iPSCs solve the ethical concerns of ESCs, retaining plasticity and
also allowing for autologous transplants. However, iPSCs still
present the risk of teratoma formation, for example c-Myc activity
has been linked to tumorigenesis
• A recent study showed that iPSCs significantly alleviated
histological damage and cell leakage in a murine model of
endotoxin-induced lung injury

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Dr. Kaveh Kazemian. Pharm-D. Board Certified of Clinical Pharmacy. Fellowship Assistant of Critical Care Pharmacotherapy
Mesenchymal stromal/stem cells
 They can be isolated from numerous sources, including
BM, umbilical cord (UC) and adipose tissue (AD), and
can be differentiated into mesenchymal lineage cells
Their therapeutic potential, low immunogenicity, ease
of harvest and isolation, and low production costs
compared with other stem cells have made them the
focus of research and consequently, the rest of this
review

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Dr. Kaveh Kazemian. Pharm-D. Board Certified of Clinical Pharmacy. Fellowship Assistant of Critical Care Pharmacotherapy

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Both VV ECMO and VA ECMO
can be used as a rescue therapy in
acute respiratory failure to buy
time and maintaining life awaiting
improvement of the underlying
disease. ECMO is used to provide
oxygenation and CO2 removal, or
both while the lungs recover, or as
a bridge to transplant in case of end
stage lung disease
ECMO

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 In VV ECMO, the patient must
have stable hemodynamics.
 When single venous cannula is
used, the blood is extracted
from the vena cava or right
atrium circulated and returned
to the right atrium

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 VA ECMO provides both
respiratory and hemodynamic
support; the ECMO circuit here
is connected in parallel to the
heart and lungs, while in VV
ECMO the circuit is connected
in series to the heart and lungs
 During VA ECMO,
blood will bypass both
the heart and the lungs

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 The amount of oxygen provided via artificial lung is a directly related to
the blood flow. The blood flow required during veno-venous approach to
achieve acceptable arterial oxygenation is usually between 3 and 6
L/min
• Oxygenation is partially dependent on the
cardiac output of the patient (as it is connected
in series with the heart), and the hemoglobin
concentration and saturation

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ECMO complications
 These complication could be related to the
underlining pathology needed ECMO, or of the
ECMO condition itself (surgical insertion, circuit
tubing, anticoagulation etc.)
 VV ECMO has fewer complications than VA
ECMO, the children have less complications than
adults except for neurologic complications

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The most frequent complication during ECMO is
hemorrhage, ranging between 10-30%. 34% in VA
ECMO and 17% VV ECMO required surgery for
bleeding issues, Bleeding may occur at the surgical
site, at the cannula site, or into the site of a previous
invasive procedure
Intrathoracic, abdominal, or retroperitoneal
hemorrhage may also occur.
Bleeding is increased because of systemic
heparinization, platelet dysfunction, and clotting factor
hemodilution. Bleeding is managed by decreasing or
stopping heparin and infusion of platelets and clotting
factors.
Infusion of activated factor VII has been reported with
mixed results and should only be considered
for life threatening hemorrhage
 Pulmonary hemorrhage is
seen commonly in patients
on ECMO. Management
includes bleeding control as
above, using steroids, and
frequent bronchoscopy to
clear the airway over time.

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Intracerebral hemorrhage or infarction occurs in
approximately 10-15% of ARDS patients on ECMO
Systemic thromboembolism is greater with VA ECMO
than VV ECMO because infusion is into the systemic
circulation
Heparin-induced thrombocytopenia (HIT) can occur in patients
receiving ECMO. When HIT is proven, heparin infusion should
be replaced by a non-heparin anticoagulant. We favor using
Bivalirudin in spite of Heparin even without HIT when
anticipating long term ECMO use. Some authors prefer to use
Argatroban because its half life is short and a similar ACT
target range is effective

41. Medical complications
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Dr. Kaveh Kazemian. Pharm-D. Board Certified of Clinical Pharmacy. Fellowship Assistant of Critical Care Pharmacotherapy
• Hypertension is a dangerous complication because of the risk of
hemorrhage and stroke
• Arrhythmias may occur as a result of hypoxia and electrolyte
imbalance or an underlining cardiac pathology
• Oliguria is a commonly observed renal complication during the early
part of ECMO; acute tubular necrosis is observed in some patients
and may require hemofiltration and dialysis

42. Medical complications
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Dr. Kaveh Kazemian. Pharm-D. Board Certified of Clinical Pharmacy. Fellowship Assistant of Critical Care Pharmacotherapy
• Septic complications may also result because the
• ECMO circuit represents a large intravascular foreign
• body, and frequent manipulation increases the risk of
• infection. Metabolic complications include electrolyte
• imbalances, and hypo or hyperglycemia. ECMO may alter
• serum concentration of drugs due to increased volume
• of distribution, and decreased Kidney or liver function.
• Caution is warranted when narrow therapeutic drugs are
• administered, and dose alterations may be necessary

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Dr. Kaveh Kazemian. Pharm-D. Board Certified of Clinical Pharmacy. Fellowship Assistant of Critical Care Pharmacotherapy