Journal of Cardiothoracic and Vascular Anesthesia 33 (2019) 1375 1381

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Journal of Cardiothoracic and Vascular Anesthesia

journal homepage: www.jcvaonline.com

Review Article
Hypoxia and Complications of Oxygenation in
Extracorporeal Membrane Oxygenation
Adrian Alexis-Ruiz, MDa, Kamrouz Ghadimi, MDb,
Jesse Raiten, MDa, Emily Mackay, DOa, Kristof Laudanski, MDa,
Jeremy Cannon, MDc, Harish Ramakrishna, MDd,
Adam Evans, MDe, John G. Augoustides, MDa,
Prashanth Vallabhajosyula, MDf, Rita Milewski, MDf,
Michael McDonald, MDa, Prakash Patel, MD1,a,
William Vernick, MDa, Jacob Gutsche, MD a
a
Cardiovascular and Thoracic Section, Department of Anesthesiology and Critical Care, Perelman School of
Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
b
Department of Anesthesiology and Critical Care, Duke University, Durham, North Carolina
c
Division of Traumatology, Surgical Critical Care and Emergency Surgery, Perelman School of Medicine at
the University of Pennsylvania, Philadelphia, Pennsylvania
d
Division of Cardiovascular and Thoracic Anesthesiology, Mayo Clinic, Phoenix, Arizona
e
Department of Anesthesiology, Morristown Medical Center, Morristown, New Jersey
f
Division of Cardiovascular Surgery, Department of Surgery, Perelman School of Medicine, University of
Pennsylvania

Key Words: ECMO; ARDS; hypoxia; hemorrhage; transfusion; ventilator-dependent respiratory failure; critical illness; shock

EXTRACORPOREAL MEMBRANE OXYGENATION Brief Overview of ECMO

(ECMO) use is increasing annually at a rapid rate.1 According
to data reported by the Extracorporeal Life Support Organiza-
tion (ELSO), outcomes for ECMO have shown steady
improvement over the past decade.1 Much like the evolution
of the equipment used for ECMO has improved the durability
of the circuits, increased numbers of patients managed with
ECMO have yielded a better understanding of its complica-
tions and management. One of the common complications in
patients on ECMO is hypoxia, which can be multifactorial,
challenging to detect, and difficult to treat. In this review, the
physiology and management of hypoxia in patients on ECMO
are discussed
1 used in patients who fail to wean from cardiopulmonary
Address correspondence to Jacob T. Gutsche, MD, University of Pennsylva-
nia, School of Medicine, Department of Anesthesiology and Critical Care,
3400 Spruce St., 680 Dulles Building, Philadelphia, PA 19104.
E-mail address: jacob.gutsche@uphs.upenn.edu (J. Gutsche).
ECMO can be divided roughly into the categories of
veno-arterial (VA), which is used for circulatory and/or
pulmonary support, and veno-venous (VV), which is used
solely for pulmonary support. The VA-ECMO circuit con-
sists of venous drainage to a centrifugal pump in series
with a membrane oxygenator and return of oxygenated
blood to the arterial circulation to maintain end-organ per-
fusion. There are numerous acute and subacute indications
for VA-ECMO, but most can be classified as severe car-
diac insufficiency causing end-organ ischemia.2 Cannula-
tion strategies for VA-ECMO can be divided broadly into
central and peripheral. Central cannulation generally is
bypass after cardiotomy. Access is obtained by direct can-
nulation of the right atrium (RA) and aorta. The benefit of

https://doi.org/10.1053/j.jvca.2018.05.028
1053-0770/Ó 2018 Elsevier Inc. All rights reserved.
1376 A. Alexis-Ruiz et al. / Journal of Cardiothoracic and Vascular Anesthesia 33 (2019) 1375 1381
central cannulation includes the ability to place large diam-
eter cannulae and direct insertion of a left ventricular (LV)
drainage catheter (vent), but cannula placement may pre-
clude closure of the chest unless placed through the chest
wall. In addition, central aortic cannulation eliminates the
risk of limb ischemia associated with peripheral arterial
cannulation. Peripheral VA-ECMO cannulation includes
one or more venous drainage catheters and an outflow can-
nula inserted into the arterial system. Any large peripheral
artery may be used, but the usual method is placement of a
cannula in the femoral artery via the percutaneous Sel-
dinger technique.
Practitioners determining the need for VA-ECMO versus
VV-ECMO in cases of pulmonary insufficiency must evaluate
right ventricular and LV function. Although no established
standards exist for minimum ventricular function that should
trigger the use of VA-ECMO, patients with severe right or left
heart dysfunction will not benefit from VV-ECMO. In general,
VV-ECMO is considered in patients with life-threatening but
potentially reversible respiratory failure who otherwise have
no contraindications to extracorporeal life support.3
The 3 commonly used VV-ECMO cannulation options are
discussed briefly in the following:
1. Femoro-femoral venous drainage is performed with a fem-
orally introduced cannula in which the inflow (drainage)
cannula tip is placed 5 to 10 cm below the inferior vena
cava-RA (IVC-RA) junction. Return is via a long (>50
cm) cannula inserted into the contralateral femoral vein
and advanced so its tip lies in the RA. Ideally, VV-ECMO
cannula configuration should maximize flow and minimize
recirculation.4 Flow can be maximized by placement of
larger drainage cannulae (typically these are multiport
[>50 cm] 23 F to 29 F drainage cannulae with the tip posi-
tioned in the IVC).
2. Femoro-atrial-venous drainage is via a femorally inserted
cannula placed 5 to 10 cm below the RA-IVC junction.
Oxygenated blood typically is returned via a short cannula
placed in the right internal jugular vein at the superior vena
cava (SVC)-RA junction.
3. A single cannula technique, resulting from advances in
cannula design that have led to the creation of dual-lumen
catheters for exclusive right internal jugular placement,
can be used to advance the cannula until the tip lies in the
mid-IVC, just distal to the hepatic vein. Drainage is from
both SVC and IVC. The return lumen opens 10 cm from
the tip of the cannula and is designed to return blood to the
RA.5 Imaging during insertion commonly is assisted by
transesophageal echocardiography and fluoroscopy. Posi-
tioning is critically important because, if the distal tip or
the return jets (directed toward the tricuspid valve) are not
placed accurately, low flows or significant recirculation
can occur. Advantages with this technique or cannulae
include technical simplicity with one catheter, low rates of
recirculation if appropriately positioned, and easier use of
prone positioning.
Differential Hypoxia
The most common site to insert ECMO cannulae is the fem-
oral blood vessels due to ease of access and ability to place the
cannulae at the bedside. In patients undergoing peripheral VA-
ECMO, blood is drained from the femoral vein and returned to
the femoral artery. Most ECMO circuits are designed to flow
to a maximum of 7 L/min, which may not be sufficient to fully
empty the heart in large patients. Blood that returns to the
heart, bypassing the ECMO circuit, may be ejected in a patient
with residual cardiac function. If this blood is poorly oxygen-
ated due to inadequate pulmonary function, it may compete
with the blood flowing into the aorta from the peripheral arte-
rial cannula. This complication, known as differential hypoxia,
occurs in patients undergoing peripheral VA-ECMO who have
poor pulmonary gas exchange capability, due to pulmonary
edema, acute respiratory distress syndrome (ARDS), or other
pulmonary pathology. Differential hypoxia also is known as
north-south syndrome, proximal-distal syndrome, and Harle-
quin syndrome. The point in the aorta that the blood ejected
from the heart mixes with the blood flowing from the femoral
arterial catheter is called the mixing point (Fig 1).
With a peripheral cannulation strategy, blood has 3 ways to
bypass the ECMO circuit and contribute to hypoxia. Bronchial
blood flow, which usually accounts for about 2% of the cardiac
output, returns to the left atrium via the pulmonary veins.
Venous blood flow that has perfused the pericardium also may
return directly to the cardiac chambers via the Thebesian
veins. Lastly, blood that returns to the heart, having bypassed
the venous drainage cannula, may traverse the heart and be
ejected through the aortic valve in the case of residual cardiac
function. If pulmonary function is compromised, this blood
may be poorly oxygenated. In addition, patients with atrial or
ventricular septal defects may have an intracardiac shunt,
which may further contribute to poorly oxygenated blood
being delivered to the body.
It is unusual for patients with central VA-ECMO to sustain
differential hypoxia because the outflow cannula is placed
directly into the aortic arch, allowing well-oxygenated blood
from the ECMO circuit to perfuse the entire aorta. The only
instances in which a patient with central VA-ECMO will have
poorly oxygenated blood perfusing the aortic arch are during
low flow from the ECMO circuit, combined with poor pulmo-
nary function and cardiac ejection, or when the ECMO oxy-
genator function is inadequate and is delivering poorly
oxygenated blood. To avoid this complication, it is important
to measure the oxygen concentration of the post-oxygenator
blood regularly.
Detecting Differential Hypoxia
Any patient undergoing peripheral VA-ECMO may develop
differential hypoxia. It can be difficult to predict the exact
location of this mixing point without the aid of transesopha-
geal echocardiography6; therefore, it is imperative to continu-
ously monitor the myocardium and innominate artery for
 A. Alexis-Ruiz et al. / Journal of Cardiothoracic and Vascular Anesthesia 33 (2019) 1375 1381 1377

Fig 1. Differential hypoxia. (A) Mixing point at the level of the aortic valve. (B) Mixing point in the ascending aorta resulting in hypoxic blood delivered to the
coronary circulation. (C) Mixing point in the descending thoracic aorta resulting in hypoxic blood delivered to the coronary and cerebral circulation. A, artery; Ao,
aorta; AV, aortic valve; ECMO, extracorporeal membrane oxygenation; DTA, descending thoracic aorta; LCCA, left common carotid artery; LMCA, left main cor-
onary artery; LScA, Left subclavian artery; RCA, right coronary artery; VA, veno-arterial.

evidence of hypoxia. In patients in whom the mixing point is
in the ascending aorta (see Fig 1, B), the myocardium should
be monitored using continuous telemetry analyzing for evi-
dence of myocardial ischemia such as ST-segment depression
or elevation.
In patients with recovered LV function, the mixing point
may be located within or distal to the aortic arch (see Fig 1,
C). In these patients, the perfusion of the innominate artery is
monitored with continuous pulse oximetry placed on the right
hand or right ear. Frequently, patients on VA-ECMO will lack
pulsatile flow in the aorta, or if it is present, pulsatility will be
low amplitude, which can make pulse oximeters unreliable.
Alternatively, reflectance oximeters such as cerebral oximeters
have been demonstrated to effectively trend cerebral oxygen
saturation in patients with nonpulsatile flow.7 The authors use
cerebral oximeters as a standard monitor to detect differential
hypoxia and on the legs to detect cannula-related ischemia for
all patients undergoing VA-ECMO. Second-to-second changes
in cerebral oximeter readings may not correlate with clinical
changes in perfusion, so the overall trend of the oximeter
reading should be used to guide management. There may be
significant interindividual variability in the baseline cerebral
oximeter saturation readings.8 The authors document the value
each hour for the right and left forehead. Any measurement
<40% saturation or a drop in saturation >25% from baseline
requires an examination of the brain perfusion.
Preventing Differential Hypoxia
One strategy to avoid differential hypoxia is to use VV-
ECMO when possible. In some instances, patients who are
candidates for ECMO due to pulmonary failure will have high
inotrope and vasopressor requirements. It is crucial to care-
fully evaluate the right ventricular and LV function in this situ-
ation. In the case of borderline cardiac function, the authors
often will perform a trial of VV-ECMO to correct hypoxia and
acidosis due to hypercarbia and to optimize ventilator settings.
Optimizing metabolic and ventilator parameters often will
lead to improvement in the hemodynamic status and avoid the
need for VA-ECMO.6
1378 A. Alexis-Ruiz et al. / Journal of Cardiothoracic and Vascular Anesthesia 33 (2019) 1375 1381
In patients with severe pulmonary and cardiac disease
requiring VA-ECMO, it is important to maintain adequate
venous drainage and optimal ECMO flows. There is evidence
in animals that advancing the IVC venous drainage cannula
into the SVC will improve venous drainage and help improve
differential hypoxia.9 Optimal venous drainage typically
depends on the following 2 factors: cannula position and size
of the drainage cannula. In patients with a single drainage can-
nula in the femoral vein, it is preferable to have the distal tip
positioned in the SVC. To facilitate this, the wires and cannula
should be inserted using transesophageal or fluoroscopic guid-
ance to avoid damage to the heart or other structures. For fem-
oral vein cannulation, the authors usually use a 22 F or 25 F
cannula, depending on patient size. Alternatively, a larger 29
F cannula may be placed. In patients who appear to have inad-
equate drainage with an adequate sized cannula in the IVC,
an internal jugular catheter may be inserted and connected to
the inflow portion of the ECMO circuit.
In some cases, ineffective management of the ventilator can
contribute to hypoxic blood being ejected from the left ventri-
cle. In patients with ARDS, lung protective ventilation strate-
gies should be used, including tidal volumes of 4 to 6 mL/kg
and targeting plateau pressures 30 cm water.10 Poor compli-
ance with low tidal volume ventilation is significantly associ-
ated with higher mortality.11 Needham et al. demonstrated that
an increase in the initial tidal volume from 6 mL/kg of pre-
dicted body weight to 7 mL/kg was associated with a 23%
increase in intensive care unit mortality.12 It is unclear whether
there is benefit to restrict tidal volumes even further in patients
with ARDS. Evidence from a study comparing Australian
with French outcomes, which used different ventilation strate-
gies (low v ultra-low stretch), demonstrated worse outcomes
in the center using ultra-low stretch ventilation.13 In that study,
Schmidt et al.13 found that patients ventilated with a higher
mean positive end-expiratory pressure (PEEP) had a lower
mortality.
A patient with a bronchopleural fistula probably would ben-
efit the most from ultra-low stretch ventilation, a condition
that can accompany necrotizing pneumonia or ventilator-
related barotrauma.14 In these patients, it may be prudent to
limit PEEP and tidal volumes to minimize airway pressures
and promote lung healing.
Acquired Lung Dysfunction With ECMO (Transfusion-
Associated Lung Injury, Ventilator-Associated Pneumonia,
and Pulmonary Hemorrhage)
Two common problems that may occur during the course of
ECMO are transfusion-associated lung injury and ventilator-
associated pneumonia (VAP). Transfusion-associated lung
injury is a neutrophil-associated lung injury that may occur
with large-volume blood product transfusion, most commonly
with plasma transfusion.15,16 Because bleeding is the most
common complication associated with ECMO, patients under-
going ECMO often receive blood products. Bleeding may be
secondary to coagulopathy or surgically related, such as bleed-
ing at the site of cannula insertion.
Coagulopathy may be more difficult to manage due to the
need to maintain the patient in an anticoagulated state while
undergoing ECMO. The authors have observed lower rates of
bleeding by using activated partial thromboplastin time levels
to guide anticoagulation management, in contrast to activated
clotting times, which are unreliable for estimating the degree
of coagulopathy at the lower levels of anticoagulation needed
for ECMO. Targeting a lower activated partial thromboplastin
time than what normally is used in patients with mechanical
aortic valves and permanent ventricular assist devices has
been successful and associated with rare bleeding and throm-
botic complications.17
In some instances, it may be prudent to hold anticoagulation
for a short time to manage bleeding and transition to lower
therapeutic targets. In addition, factor Xa levels can be moni-
tored to more precisely titrate heparin dosing. Thrombocytope-
nia and platelet dysfunction may contribute to bleeding;
acquired qualitative defects have been studied, but the mecha-
nism is unclear.18,19 In addition, patients undergoing ECMO
commonly are taking medications that may alter platelet func-
tion such as antiplatelet agents, milrinone, H2 receptor block-
ers, prostaglandins, and select antibiotics. Historically, the
authors have maintained platelet counts >100/m to prevent
bleeding but more recently have started to tolerate lower levels
unless there is evidence of bleeding.20
VAP may occur in patients undergoing ECMO. There is
some evidence that subglottic suction endotracheal tubes may
reduce the incidence of VAP.21 These tubes have a suction
port above the tracheal balloon that is connected to suction
tubing, and there is a possibility that this can cause erosions if
placed on continuous suction, which can be complicated by
bleeding.22 Chlorhexidine mouth care also has been demon-
strated to significantly decrease the rate of VAP.23
Positioning the patient with a VA-ECMO cannula in the
groin historically has meant that the patient must remain flat,
with no elevation of the head of bed. A standard of care to pre-
vent VAP is to maintain the head of bed 30 degrees to pre-
vent passive regurgitation and aspiration.24 The authors have
found that the head of bed can be elevated safely in patients
with femoral venous and arterial cannulae without impairing
limb perfusion or venous return.
Treatment of Differential Hypoxia
Venous-Arterial-Venous ECMO
In patients with differential hypoxia who are undergoing
peripheral VA-ECMO, one may add a venous outflow cannula
to oxygenate blood returning to the RA, which would provide
oxygenated blood to the myocardial and carotid circulations.25
Because the outflow circuit would be connected to both the
high-pressure arterial circulation and the low-pressure venous
circulation, the team will need to add an adjustable clamp,
such as the Hoffman clamp, to reduce blood flow to the low-
pressure venous side and maintain adequate flow to the arterial
circulation.
 A. Alexis-Ruiz et al. / Journal of Cardiothoracic and Vascular Anesthesia 33 (2019) 1375 1381
Alternatively, the ECMO outflow may be transitioned to the
right subclavian artery by sewing a 6 or 8 mm tube graft to the
artery.26
VV-ECMO
The ELSO guidelines27 define adequate oxygen support as
arterial oxygen saturation >80%. These guidelines also rec-
ommend a hematocrit >40% to optimize oxygen delivery.
Currently there are a lack of data to define a safe partial pres-
sure of oxygen target in critically ill patients. The differential
for hypoxia during VV-ECMO is broad and includes excessive
recirculation, inadequate venous drainage and flow, and oxy-
genator malfunction.
Recirculation is defined as the variable proportion of oxy-
genated blood from the return cannula that enters the drainage
cannula.28 Recirculation can contribute to hypoxemia by
reducing the delivery of oxygenated blood in the pulmonary
and systemic circulations. Palmer et al.29 demonstrated that
the cannula type can affect recirculation. In their study, the
use of multistage cannulae was associated with less recircula-
tion compared with standard single-stage cannulae. Their data
also suggested that cannula position can be optimized using
chest radiography and ultrasound dilution technique. Although
their positioning can be challenging, dual lumen cannulae
have been shown to have less recirculation.30 ECMO recircu-
lation also has been observed to increase along with circuit
flow rate.31
Prone ventilation has been shown to be effective when treat-
ing ARDS patients. Benefits of proning include decreasing
shunting due to better lung aeration, more homogenous venti-
lation, decreased ventilation-perfusion mismatch, less lung
compression from anterior mediastinal and abdominal struc-
tures, and improved clearance of respiratory secretions.
Because VV-ECMO patients often are managed with lung-
protective ventilation, this can lead to an increase in lung area,
which is poorly ventilated. Prone positioning can help recruit
the dorsal region of the lungs. A meta-analysis from several
randomized controlled trials suggested that prolonged duration
of proning, ranging from 17 to 24 hours per day, reduces inten-
sive care unit mortality in ARDS patients.32
Proning on VV-ECMO is feasible and has led to improved
outcomes in small studies.33,34 Combining ECMO and prone
positioning can be logistically difficult and carries several the-
oretical risks because these patients have catheters, tubes, and
cannulae that must be secured and monitored. Potential com-
plications include accidental extubation, cannula dislodgment,
and bleeding around the cannula sites. Even though there is a
paucity of studies examining these complications specifically,
combining ECMO and prone positioning appears to be safe.35
Additional studies are necessary to help delineate specific indi-
cations to initiate proning in ARDS patients already undergo-
ing VV-ECMO.
Membrane oxygenators are a key component of the VV-
ECMO circuit, allowing gas and heat exchange to occur. Sev-
eral types of materials have been developed, including solid
rubber silicone, microporous hollow fiber, and
1379
nonmicroporous hollow fiber. Oxygenators with the latter
allow for less transfusion requirements and improved durabil-
ity while maintaining efficient gas exchange.36 Even though
all ECMO patients are anticoagulated, polymethyl pentene -
coated oxygenators may be coated with heparin, which is an
important characteristic that reduces contact activation of
coagulation factors. Data from Khohsbin et al.37 indicate that
polymethyl pentene coated oxygenators allow for better gas
exchange. Oxygenator function typically is assessed by trend-
ing pre-oxygenator and postoxygenator arterial blood gasses.
It also is important to assess the pressure within the circuit
before and after the oxygenator is used. An increase in postox-
ygenator pressure can be a sign of increased resistance, which
occurs over time as the oxygenator deteriorates.38 Worsening
gas exchange, increasing transmembrane pressure gradient
across the oxygenator, and laboratory and clinical data point-
ing toward thrombosis should promptly alert the clinician that
transmembrane oxygenator thrombosis may be developing.
This should lead to consideration for exchange of the
oxygenator.39
Oxygen delivery is a function of blood flow, hemoglobin
concentration, hemoglobin saturation, fraction of inspired oxy-
gen and oxygenator function. The ELSO guidelines recom-
mend VV-ECMO blood flows of 60 to 80 mL/kg/min for
adults.27 As native lung function recovers, ECMO flow is
decreased. Flow is influenced by vascular access, tubing resis-
tance, and pump properties. Badheka et al.40 proposed that
flow monitoring gives the clinician additional data points to
ensure optimal ECMO function and can be used to help detect
oxygenator or return cannula obstruction. Flow monitoring
could prove to be a useful adjunct to pressure monitoring, but
more studies are necessary to validate its use in humans. Mul-
tistage cannulae have been proven to attain a greater effective
ECMO flow. When using the Avalon (Getinge; Gothenburg,
Sweeden) bicaval and double lumen cannulae, it has been
demonstrated that adding a femoral venous drainage cannula
can help increase flow rate and the longevity of the ECMO
circuit.41
In addition to lung protective ventilation and ECMO, there
are different adjunct pharmacotherapies that can be used to
treat ARDS. These include inhaled nitric oxide (iNO), inhaled
prostacyclin, steroids, and surfactant. These medications can
be used before, during, or after initiation of VV-ECMO.
iNO acts as a pulmonary vasodilator through the endoge-
nous activation of guanylate cyclase. It has minimal effects on
the systemic vasculature. Data from the pediatric literature
suggest that iNO during VV-ECMO leads to worse outcomes
overall. Tadphale et al. showed that the use of iNO was associ-
ated with prolonged length of stay, prolonged duration of
ECMO support, increased cost, and no mortality benefit.42 It is
important to keep in mind that this was a pediatric patient pop-
ulation and that initiation of ECMO was a consequence of
either cardiac or respiratory failure. A 2003 meta-analysis that
included both adult and pediatric patients demonstrated some
mild improvement in oxygenation for up to 72 hours; however,
these data again point to no improvement with the use of iNO
in ARDS patients.
1380 A. Alexis-Ruiz et al. / Journal of Cardiothoracic and Vascular Anesthesia 33 (2019) 1375 1381
Muscle relaxants are another option to facilitate a lung
protective strategy of ventilation for patients undergoing
ECMO. Theoretical benefits include lower oxygen require-
ment, lower pulmonary transvascular pressure gradients,
and increased ability for the patient to tolerate greater lev-
els of PEEP. Data from the ARDS patient population favor
early use of neuromuscular blockers. Benefits include a
decrease in the inflammatory response, improved oxygen-
ation, more ventilator-free days, and potentially decreased
intensive care unit mortality.43,44 There is a paucity of data
on ECMO combined with muscle relaxants, but data from
the ARDS patient population tend to suggest a role for
muscle relaxants during ECMO.
ELSO publishes anticoagulation guidelines for patients
undergoing ECMO. However, it is important for the clinician
to balance these against the 2 major threats of bleeding and
thromboembolism. A small study by Trudzinski et al.45 dem-
onstrated the incidence of venous thrombosis and thromboem-
bolism in patients undergoing ECMO due to respiratory
failure to be 46.1%. For most of these cases, thrombosis was
cannula-associated.45 Pulmonary embolism was found in
11.1% of the patients. Time on ECMO was associated with an
increased risk of thrombotic disease.
In general, anticoagulation regimens should be tailored to
each patient individually. It is interesting to note that ECMO
also can be accomplished without systemic anticoagulation.
Lamarche et al.46 examined VA-ECMO patients who were not
exposed to any systemic anticoagulant except at time of wean-
ing and found that this method may decrease bleeding compli-
cations and transfusion requirements without an increased risk
of thromboembolism.
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