ASAIO Journal 2015 Review Article
Management of Refractory Hypoxemia During Venovenous
Extracorporeal Membrane Oxygenation for ARDS
Andrea Montisci, Giulia Maj, Alberto Zangrillo, Dario Winterton, and Federico Pappalardo
Venovenous extracorporeal membrane oxygenation (VV
ECMO) in acute respiratory distress syndrome (ARDS) is
currently a widely used therapeutic strategy. However,
patients are often still hypoxemic despite complete ECMO
support. The major determinants of peripheral oxygen satu-
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ration (SpO2) during VV ECMO are pump flow, degree of
recirculation, patient’s systemic venous return and its oxy-
gen saturation, hemoglobin concentration and residual lung
function. Current guidelines state that the support can be
considered adequate when the patient’s SpO2 is equal or
greater than 80%, but a possible objection could be that
such a value of O2-tension may be too low and may worsen
the patient’s prognosis. Moving from the pathophysiology of
hypoxemia during VV ECMO, this review focuses on recircu-
lation of blood and on the possible strategies to minimize it,
on the pharmacologic modulation of intrapulmonary shunt
and on the questions related to management of ECMO flow
and the risks and benefits of permissive hypoxemic states.
Transfusional strategy during VV ECMO, administration of
neuromuscular blocking agents and sedatives, therapeutic
hypothermia, and prone positioning is also reviewed. The
potential advantages of β-blockers are discussed. Finally,
transition from VV ECMO to venoarterial ECMO (VA ECMO)
or a hybrid configuration is also examined. ASAIO Journal
2015; 61:227–236.
Key Words:  ARDS, ECMO, Hypoxemia.
A ccording to the recent criteria of the Berlin definition, acute
respiratory distress syndrome (ARDS) is defined as an acute, dif-
fuse lung injury syndrome that appears within 1 week of a known
clinical insult or new or worsening respiratory symptoms.1
Despite the progress in medical therapies and ventilation
management, ARDS still carries a high mortality risk increas-
ing with stages of ARDS from mild (20%) to moderate (41%)
to severe (52%).1
From the Department of Anesthesia and Intensive Care, San Raffaele
Scientific Institute, Milan, Italy
Submitted for consideration January 2015; accepted for publication
in revised form January 2015.
Disclosure: The authors declared they have no conflicts of interests
or source of funding to be disclosed.
Correspondence: Andrea Montisci, Department of Anesthesia and
Intensive Care, San Raffaele Scientific Institute, Via Olgettina 60, 20132
Milan, Italy. Email: montisci.andrea@hsr.it
Copyright © 2015 by the American Society for Artificial Internal
Organs
DOI: 10.1097/MAT.0000000000000207
227
Extracorporeal membrane oxygenation (ECMO) is a modi-
fied cardiopulmonary bypass that provides gas exchange
(venovenous [VV] ECMO) and ensures systemic perfusion
(venoarterial [VA] ECMO) to sustain the cardiopulmonary
function of the patient.2
The recent pandemic of H1N1 influenza, and its consider-
able risks of evolution to ARDS in previously healthy young
people, has kindled the interest and the research on ECMO, a
supportive therapy of the failing heart and lungs already used
in past decades with various indications.
Current evidence and future applications of VV ECMO have
been recently summarized by Agerstrand et al.3 Two studies
conducted in 2009, involving the use of current ECMO tech-
nology, showed a survival benefit in ARDS patients treated
with ECMO. The Conventional ventilation or ECMO for Severe
Adult Respiratory failure (CESAR) trial,4 a multicenter ran-
domized trial conducted in United Kingdom, in which ARDS
patients were randomized to receive conventional mechani-
cal ventilation versus referral to an ECMO center, showed a
16% reduction in the ECMO-referred group in the primary
end point considered (death or severe disability at 6 months).
Davies et al.5,6 in the Australia and New Zealand ECMO
experience, reported an in-hospital mortality rate of 25% in the
group of ARDS patients treated with ECMO during the H1N1
influenza pandemic. A common observation after venovenous
bypass positioning is that hypoxic and cyanotic patients, with
SaO2 values close to 80%, reacquire normal oxygenation and
CO2 tension.
Extracorporeal Life Support Organization (ELSO) guidelines
suggest that during VV ECMO for ARDS the achievement of a
SaO2 > 80% and a SvO2 > 70% indicates adequate support,7
and that the compensatory increase of cardiac output (CO) and
the achievement of an hematocrit more than 40% ensure suf-
ficient O2 delivery (DO2).7,8
A possible objection could be that O2 tension might be
too low and worsen the patient’s prognosis.9 Moreover, this
concept assumes a normal cardiac function, which can com-
pensate for hypoxemia, and that the patient is ventilated in a
protective manner.
This review focuses on that subset of patients who remain
hypoxemic during VV ECMO, on its pathophysiological issues
and on the possible strategies for treatment, addressing clinical
scenarios in which the hypoxemia is not related to treatable
causes (i.e., pneumothorax or equipment failure) but just to the
severity of underlying lung disease.
The management of mechanical ventilation during VV
ECMO is beyond the scope of this review, and a comprehen-
sive review on this topic is referenced.10
228 MONTISCI et al.
What O2 Peripheral Saturation Target During VV ECMO?
As stated above, during VV ECMO for ARDS, patients are
often hypoxic despite the extracorporeal support, with partial
pressure of oxygen (PaO2) values of 45–55 mm Hg.
Neither the safe PaO2 lower limit in critically ill patients nor
the threshold at which the brain is injured, is known.
In many clinical situations, as in utero development or in
case of exposure to hypobaric hypoxia at high altitude, humans
are exposed to sustained hypoxia, during which many nones-
sential cellular processes may be temporarily suspended. This
phenomenon, called oxygen conformance, is reversible and
not associated with long-term negative effects.11
A great number of studies have evaluated the lower limit of
PaO2 at which healthy, acclimatized subjects can be exposed
without evidence of neurocognitive impairment. In a recent
study, arterial blood gases in climbers breathing ambient air
on Mount Everest were evaluated, reporting values among the
lowest ever documented in humans: at 8400 m, mean PaO2,
mean PaCO2, and mean SaO2 were, respectively, 24.6 mm Hg,
13.3 mm Hg, and 54%.12
However, such reports are not applicable to critically ill
patients, who might be not able to activate the necessary com-
pensatory mechanisms, like increase in minute ventilation,
CO, and hemoglobin levels.
The key question is to understand if hypoxemia can be
accepted without fear of a worse prognosis that is to say if
these oxygen values can be considered adequate to meet the
patient’s needs.
To date, the pivotal question of tolerability of subnormal
PaO2 in an ARDS patient, raised by the consensus conference
in 1994, is still unanswered. Moreover, there is no data defini-
tively demonstrating that higher PaO2 values are linked to bet-
ter outcome.
Indeed, in the setting of ARDS patients, therapies associ-
ated with better outcome are not directly linked to improved
oxygenation, as demonstrated by a review of 101 studies on
this topic,13 in which the authors stated that PaO2/inspired
fraction of oxygen (FiO2) index was not a reliable predictor
of outcome.
A therapeutic strategy often used in ARDS patients is permis-
sive hypoxemia that consists of the tolerance of values of SaO2
close to 80%, on the basis that normal oxygen saturation is
not needed or impossible to achieve, recognizing that other
variables of oxygen delivery, like CO or hemoglobin concen-
tration, may be more effectively modified.
Moreover, employing an oxygenation target of 55–80 mm
Hg, the potential oxidative stress and the harms of an aggres-
sive management of mechanical ventilation are avoided.
Three main objections to this treatment strategy may be
highlighted: 1) randomized controlled trials (RCTs) have never
demonstrated a survival benefit in critically ill patients when
the CO or hemoglobin concentration was modified to augment
DO2 to supernormal values, compensating for the hypoxemia;
2) conflicting results in animal studies do not demonstrate
that a constant oxygen delivery predicts a constant oxygen
uptake14; 3) there are no definitive endpoints available to con-
firm the adequacy of tissue oxygen supply, above all this during
VV ECMO, as SvO2 is not a reliable marker of global oxygen
balance. Moreover, if permissive hypoxemia may be agreeable
in a short-term prospective, the long-term prospective must
prioritize care that results in optimal long-term result, i.e., in
the light of positive neurologic outcomes.15
The burden of cognitive impairment in survivors from ARDS
is high. Mikkelsen et al.16 in the ARDS cognitive outcomes
study (ACSOS) assessed neuropsychological functions in a sub-
set of survivors enrolled in Fluid and Catheter Treatment Trial
(FACCT). They found a cognitive impairment in 41 of 75 (55%)
survivors at 12 months. Lower PaO2 and enrollment in the
conservative-fluid management strategy of the FACCT study
were independently associated with cognitive impairment at
12 months. The difference in terms of PaO2 was 15 mm Hg
(71 mm Hg in impaired patients and 86 mm Hg in not impaired
patients, P = 0.02).
Already in 1999, the study of Hopkins et al.,17 evaluating
neuropsychological sequelae in survivors of ARDS, enrolled
168 patients, 55 of which completed the follow up at 1 year.
At the time of hospital discharge, all patients had a cogni-
tive impairment. At 1 year, a significant improvement was
observed, but 17 of 55 (30%) experienced deficit in cognitive
function, and 43 of 55 (78%) had an impairment of at least one
cognitive function, such as memory, attention, or concentra-
tion. There were significant correlations between the amount
of time spent below normal values (<90%) and the impaired
performance on intelligence, attention, speed of processing,
visuospatial skills, and executive function test.
The authors, on the basis of correlation of hypoxemia and
neurocognitive sequelae, hypothesized that the cerebral
hypoxia might be a possible explanation of this phenomenon,
not previously described in ARDS.
Cognitive impairment was correlated with neuroradiologic
findings in another study conducted by the same author. Hop-
kins et al.18 found that in 15 ARDS patients, in comparison
with matched control subjects, 53% had atrophy or lesions
by radiological report. Even if a correlation between ventricu-
lar volumes was not established with duration or severity of
hypoxemia, the authors hypothesized that the observed brain
atrophy might be attributed to hypoxia, on the basis of similar-
ity of the cerebral lesions to those reported in other pathologic
states where hypoxia is a landmark (cardiac arrest, asthma, and
monoxide poisoning).
In the light of these unsolved questions, Mikkelsen et al.19
have proposed a resetting of arterial oxygenation target in
ARDS, balancing potential advantages and disadvantages of
each strategy waiting for a more sound knowledge of long-
term effects of oxygenation on short and long outcomes of
ARDS patients.
Finally, it must to be underlined that the majority of medical
literature on the topic of hypoxia is based on the concept of
oxygen content and oxygen delivery, whose formulas are often
shortened dropping the contribution of dissolved oxygen. This
approach, however, is misleading, as tissues derive the means
to support their metabolic aerobic activity from dissolved oxy-
gen in the blood, and therefore, the contribution of dissolved
O2 is never negligible and becomes particularly important
when anemia is present.20
Pathophysiology of Hypoxemia During ARDS
A recent study, performed by Messaï et al.,21 identified the
main causes of hypoxemia during VV ECMO in low oxy-
gen partial pressure in blood leaving the oxygenator, high
 REFRACTORY HYPOXEMIA DURING VV ECMO 229
recirculation, elevated patient CO, and low mixed venous
saturation. In their study, evaluating a new formula linking
all these parameters for determining arterial oxygenation in
ARDS patients treated with VV ECMO, the authors found
a good correlation between predicted SaO2 and measured
SaO2.
Excluding equipment failure, factors that contribute to
hypoxemia during VV ECMO are 1) mixture between ECMO-
oxygenated blood and patient’s own venous blood, 2) recir-
culation, 3) intrapulmonary shunt, and 4) flow exceeding
oxygenator performances (not further treated because of the
rarity of this scenario with the current technology).9
Mixture Between Blood Oxygenated by ECMO
and Patient’s Own Venous Blood
During venovenous bypass, oxygenated blood from the infu-
sion cannula reaches the venous circulation and mixes with
the patient’s systemic venous return in the right atrium.
This situation implies that, assuming that there is no gas
exchange across the lung, the oxygen saturation of the blood in
right ventricle is equal to oxygen saturation of the arterial side
of circulation; and, furthermore, that the use of mixed venous
saturation as an index of systemic tissue oxygenation is mislead-
ing because the O2 saturation in pulmonary artery results from
the mixture between oxygenated (from the reinfusion cannula)
and deoxygenated blood (patient’s systemic venous return).22–24
Interactions between native CO and ECMO flow are well
depicted in a recent study,25 elegantly demonstrating that, dur-
ing VV ECMO for ARDS in patients whose native lung func-
tion was completely abolished, the factors determining the
patient’s arterial oxygenation were VV ECMO blood flow and
the inspired fraction of O2 of sweep gas (ECMO FiO2). Specifi-
cally, a ratio between VV ECMO flow and patient’s CO ≥ 60%
was always associated with SaO2 > 90% and arterial PaO2 >
60 mm Hg. Moreover, a strong linear correlation was found
between ECMO FiO2 and SaO2 and PaO2.
For these reasons, ELSO guidelines3 suggest setting a blood
flow of 60–80 ml/kg for adults, which usually guarantees an
oxygen delivery of 3 ml/kg/min. At these values of blood flow,
the ratio between pump flow and deoxygenated arterial blood
is usually 3:1.8
However, this ratio may be quite different if we look at the
situation of a septic patient, in which CO is usually elevated,
and the ratio with ECMO flow can be maintained only at
expense of flow augmentation or CO manipulation.
Recirculation
Recirculation in VV ECMO is defined as the fraction of oxy-
genated blood that is infused into the right atrium and is then
aspirated back into the venous line of the ECMO circuit.
A recent review on this topic identified in pump speed;
blood flow rates; intrathoracic, intracardiac, and intra-abdominal
pressure; cannula type, size, and position; and direction of
extracorporeal blood flow the main factors to which recircula-
tion is linked.26
Although there are many methods for the calculation of
the recirculation fraction, like the use of indicator dilution
technique or thermodilution or ultrasound-based technique,
these are expensive or unavailable in many clinical settings;
nevertheless, it is very important to have simple methods to
exclude large fraction of recirculation.
A published formula27 is based on the blood oxygen satu-
ration (SO2) of the drainage and the reinfusion cannulas and
the pulmonary artery O2 saturation: R = (SO2preoxy − SvO2)/
(SO2postoxy − SvO2), where SO2preoxy is the saturation of
blood in the venous (entering the oxygenator) cannula, SO2pos-
toxy is the saturation of blood in the arterial cannula (leaving
the oxygenator), and SvO2 is the mixed venous saturation.
However, as already highlighted,28 the use of SvO2 during
VV ECMO is misleading because the pulmonary artery satura-
tion measures the mixing of deoxygenated blood of the native
circulation and the oxygenated blood from the venous cannula
of ECMO, and therefore, it is impossible to refer to SvO2 in
conventional terms.22–24
One study29 suggests that it is possible to exclude at least
significant recirculation volume if, by performing a conven-
tional blood gas analysis from the drainage and the reinfusion
cannulas, the pO2 of the drained blood is in the normal range
(median 42 mm Hg) and below 10% of pO2 of the infusion
cannula; moreover, a blood oxygen saturation in the drainage
cannula below 75% may exclude meaningful recirculation.7
Intrapulmonary Shunt and Its Modulation
The main mechanism of hypoxemia during ARDS is intra-
pulmonary shunt30: this is linked to the pathological changes
of the alveoli and the interstitium, with alveolar filling of
protein rich fluid, red blood cells, and neutrophil infiltra-
tion31 (Figure 1).
According with Sangalli et al.,32 for the purposes of this
review, we have defined intrapulmonary shunt as the extreme
of ventilation/perfusion mismatching, in which an alveolus is
perfused but not ventilated. Blood passing through such alveo-
lar units reaches the left side of the heart without gas exchange.
Intrapulmonary shunt or true shunt can be calculated using
values from a pulmonary artery catheter, while breathing oxy-
gen at 100%: Qs/Qt = 100 × (CcO2 – CaO2)/(CcO2 – CvO2),
Figure 1. Chest X-ray showing a whiteout appearance of the
lungs, with a femoro-jugular dual cannulas configuration for veno-
venous extracorporeal membrane oxygenation (VV ECMO).
230 MONTISCI et al.
where CcO2, CaO2, and CvO2 are, respectively, the content
of oxygen in pulmonary capillary, arterial, and venous blood.
In healthy subjects there is a certain amount of shunt, caused
by the bronchial circulation and to the coronary venous blood
drained directly into the left ventricle. This can be calculated
from the same formula but at FiO2 lower than 100%, and
encompasses three components: ventilation/perfusion mis-
matching, diffusion limitation, and true (intrapulmonary) shunt.
In ARDS, when the pulmonary function is completely abol-
ished, we can assume that the shunt fraction is close to 100%.
The degree of intrapulmonary shunting is influenced by sev-
eral factors, such as vascular pressures, vasoactive substances,
and the degree of lung inflation.33 Several studies, however,
have highlighted the importance of CO per se in determining
the degree of shunt.
Lynch et al.34 have reported the results of pharmacologic and
mechanical modulation of CO on intrapulmonary shunt: there
is a significant linear correlation between CO and the fraction
of intrapulmonary shunt.
In a series of ARDS patients, Dantzker et al.35 noted a strong
correlation between CO reduction and intrapulmonary shunt
reduction, when the CO was reduced by lowering of the venous
return with incremental positive end-expiratory pressure (PEEP)
or incremental tidal volumes. They also observed an improve-
ment in arterial oxygenation; however, they highlighted that
this strategy, while improving arterial oxygenation, may lead to
reduced overall tissue oxygenation.
Even though data on arterial oxygenation are controversial, with
nonhomogeneous findings in animal and human studies, modula-
tion of CO can be a strategy to optimize peripheral oxygenation
in VV ECMO, with two major objectives: ameliorate the balance
between pump flow and patient’s native flow and reduce the
degree of hypoxemia directly attributable to intrapulmonary shunt.
Strategies to Improve Peripheral Oxygenation
Available treatment strategies can be classified as follows:
1.Strategies to increase the blood’s oxygen content:
i.increase of ECMO flow;
ii.increase of blood oxygen-carrying capacity.
2.Strategies to reduce recirculation.
3.Strategies to reduce oxygen consumption:
i.sedation and neuromuscular blockade;
ii.therapeutic hypothermia.
4.Manipulation of CO and intrapulmonary shunt:
i.β-blockers infusion;
ii.prone positioning.
5.Switch to venoarterial or a hybrid configuration.
Strategies Addressed to an Increase
of Blood’s Oxygen Content
Increase of ECMO flow.  During VV ECMO for ARDS, it is
a common practice8 to start with a flow of 60–80 ml/kg, which
usually corresponds to an oxygen delivery of 3 ml/kg/min at
CO values of 5 L/min and hemoglobin concentration of 15 g/dl.
The first action often undertaken in case of hypoxemia and
pump flow below the maximum level allowed by the circuit is
to increase the flow rate (assuming that the ECMO FiO2 is 1).
Indeed, the major determinants of oxygenation during extra-
corporeal support are ECMO flow and FiO2 of sweep gas.8,25
The possibility of developing a certain flow is determined
by the characteristics of the vascular access, drainage tubing
resistance, and pump properties.
Besides this, often the increase of ECMO flow does not
improve the oxygenation because of the augmented recircula-
tion fraction.
Higher flows also carry a greater risk of hemolysis. With cur-
rent ECMO technology, this risk is related to the contemporary
presence of these conditions: elevated RPM and occlusion of
the venous line (clinically evident as venous line chattering),
i.e., during coughing, kinking of the cannulas or hypovolemia,
thereby determining an extreme negative pressure across the
pump head. In these conditions, a vacuum is created in the
pump head (because the pump continues to run and ejects
the blood whereas the venous line is occluded), and it leads to
cavitation and hemolysis.36
Increase of blood oxygen-carrying capacity.  Extracorporeal
membrane oxygenation support is one of the most blood-
expensive settings, partly owing to the high frequency of
bleeding-related complications (in respiratory ECMO, the
2012 ELSO Registry reported bleeding from cannulas sites and
surgical sites as a significant problem associated with worse
prognosis).37
Besides bleeding, transfusion needs are because of the
attempt to increase peripheral oxygen delivery in hypoxic
patients with the increase of the blood’s oxygen-carrying
capacity through administration of packed red blood cells.
Extracorporeal Life Support Organization guidelines, in fact,
state that during ECLS it is mandatory to maintain an hemoglo-
bin level of 12–14 g/dl and a normal hematocrit, owing to the
fact that DO2 is determined by blood flow through the artificial
lung, and if an anemic condition is present, a higher blood flow
will be necessary to obtain the same level of oxygen delivery.
To optimize the risk–benefit ratio related to such a transfu-
sional strategy, it is experts’ opinion that the need of higher
blood flow, the associated risks of hemolysis, the reduction of
blood volume, and the related administration of fluids are a
much greater hazard than the transfusion-related risks.38
To date, there are no clinical prospective studies on the
impact of restrictive transfusion protocols on ECMO patients
for cardiac or respiratory failure, and there are also little data
on transfusion strategies in adult patients receiving ECMO.
However, in the setting of ARDS, two studies39,40 have identi-
fied red blood cell transfusion as clinical predictor of mortality.
Strategies to Reduce Recirculation
There are various systems to diminish the recirculation
fraction.
The most used technique is to maximize the distance
between the two cannulas, thereby reducing the possibil-
ity that the blood leaving the reinfusion cannula reaches the
drainage cannula.
Addressing cannulas configuration, one study41 has com-
pared the femoroatrial (FA) configuration (femoral drainage
and atrial reinfusion; Figure 2) with the atriofemoral (AF)
 REFRACTORY HYPOXEMIA DURING VV ECMO 231

Figure 2. Venovenous extracorporeal membrane oxygenation (VV ECMO) with femoroatrial configuration for VV ECMO in an extubated
patient.

configuration (atrial drainage and femoral reinfusion). Femo- Strategies to Reduce the Oxygen Consumption
roatrial configuration provides higher maximal ECMO flow
Sedation and neuromuscular blockade.  Neuromuscular
and higher pulmonary arterial mixed venous saturation and
blocking drugs (NMBDs) administration can have multiple
requires comparatively less flow to maintain an equivalent
beneficial effects on ARDS patients, but, while some of these
mixed venous oxygen saturation than the AF configuration.
have been demonstrated, others remain matter of speculation.
Ichiba et al.42 described a three cannulas VV ECMO circuit
The ARDS and Curarisation Systématique (ACURASYS)
composed of two drainage cannulas (one of these in the inter-
study reported that in patients with severe ARDS early admin-
nal jugular vein and the other one in the left femoral vein) and
istration of a NMBD improved the adjusted 90-day survival
one long return cannula in the right femoral vein, allowing an
and increased the time off of the ventilator without increasing
improved venous drainage.
muscle weakness.46
Another study43 shows that the so-called χ-configuration—in
The effects of NMBDs on mortality in ARDS are the object of a
which a multihole drainage cannula is positioned in the right
recent review47 in which the authors concluded that a short-term
atrium with the terminal segment just below the superior vena
cysatracurium besylate infusion is associated with a reduced
cava, and the infusion cannula customized in a manner to
28-day, intensive care unit (ICU) and in-hospital mortality, with-
form an angle of 60° in its terminal segment, so as to be posi-
out increasing the risk of ICU-acquired muscular weakness.
tioned in proximity to the tricuspid valve—allows near com-
plete drainage of desaturated blood and a preferential inflow
through the tricuspid valve, thereby reducing the recirculation
and improving the patient’s oxygenation.
A new double lumen cannula (DLC) has recently been intro-
duced, designed to be inserted through the internal jugular
vein44 (Figures 3 and 4). The cannula has a drainage lumen
whose tip ends, if properly inserted, in inferior vena cava (IVC).
The drainage lumen drains blood from the superior and IVC
through proximal and distal openings, respectively. The infu-
sion lumen opens in the right atrium 10 cm from the cannula
tip toward the tricuspid valve (Figure 5). In the animal experi-
ments, this technique allows a very low recirculation fraction.
Camboni et al.45 performed a comparison of flow character-
istics of DLC with standard two vessels cannulation. The two
vessel configuration allows higher flows, less negative pres-
sures for drainage at a fixed flow because of the possibility to
use larger cannulas.
Double lumen cannula can offer an alternative to two site
cannulation in the case of prolonged support, allowing a more
safe mobilization of the patient, or in the evenience of unfavor- Figure 3. Detail of a double lumen cannula inserted percutane-
able groin anatomy. ously through the right internal jugular vein.
232 MONTISCI et al.
Figure 4. Venovenous extracorporeal membrane oxygenation (VV
ECMO) with double lumen cannula in a patient suffering from acute
respiratory distress syndrome (ARDS) because of Neisseria menin-
gitidis purpura fulminans.
During VV ECMO, deep sedation and NMBDs are almost
always used during the early phase of support, to aid cannula-
tion and cardiorespiratory stabilization.
In the context of hypoxemia volume-controlled ventilation,
deep sedation and neuromuscular blockade are established.
On the basis of the aforementioned studies, it is conceivable
that the suppression of breathing work during a phase of refrac-
tory hypoxemia can reduce the systemic oxygen needs, but
there is no data about the direct contribution of such maneu-
vers to hypoxemia during VV ECMO.
Therapeutic hypothermia.  The term therapeutic hypother-
mia (TH) refers to deliberate lowering of body temperature to
36–25°C and can be classified as mild (34–35.9°C), moderate
(32–33.9°C), moderate-deep (30–31.9°C), and deep (<30°C)
hypothermia.48
The physiologic response to TH and its protective effects are
very complex and are not just related to the achieved tem-
perature, but also to the speed of induction, duration, speed of
rewarming, and prevention of side effects.
For the purpose of this review, we will only discuss the
effects and application of mild TH.
To date, there are no studies on TH during VV ECMO in
ARDS.
The main method to achieve TH during ECMO is the manip-
ulation of the heat exchanger.
Many mechanisms can affect the oxygen transport and its
peripheral utilization during TH: metabolic rate (MR), O2 solu-
bility, acid–base status, oxygen–hemoglobin dissociation, CO
or regional blood flow, and hemoglobin concentration.49
In many biological systems, there is a reduction of 50% of
MR for 10°C reduction.
Figure 5. Drawing showing the correct position of a double lumen
cannula (DLC) with the infusion port located toward the tricuspid
valve and the draining holes located in the superior and inferior vena
cava.
Hypothermia can also affect the solubility of O2 in blood and
water: at a given partial pressure, hypothermia augments the
amount of dissolved O2. This phenomenon is very interesting in
the ARDS setting when dealing with very low values of PaO2. CO
is globally reduced, but the contemporary drop of oxygen con-
sumption (VO2) causes the VO2/DO2 ratio to remain the same.
A common side effect of TH, shivering, determines a large
increase in MR but can be effectively controlled with many
drugs.
The use of TH in ARDS is object of anecdotal experiences:
Villar and Slutsky50 assigned 19 ARDS and septic patients to
receive conventional treatment or conventional treatment plus
hypothermia as a last resort. They found a significant improve-
ment in oxygenation, in the presence of unchanged VO2 and
increased O2 extraction ratio, and increased survival in the
hypothermia-treated patients.
In conclusion, on the basis of available literature, the cool-
ing of a hypoxemic patient during VV ECMO can be consid-
ered as a possible strategy to reduce the oxygen consumption
and to improve, in doing so, the DO2/VO2 ratio.
Manipulation of CO and intrapulmonary shunt
β-Blocker infusion.  An emerging technique to treat refrac-
tory hypoxemia in ARDS patients during VV ECMO is esmolol
administration.
Esmolol is a cardioselective β1-blocker agent, characterized
by ultrashort half-life that allows for quickly reversible modula-
tion of its pharmacologic effects.
 REFRACTORY HYPOXEMIA DURING VV ECMO 233
When esmolol is administered as a bolus followed by con-
tinuous infusion, the onset of activity occurs within 2 min-
utes, with 90% of β-blockade at 5 minutes. Full recovery from
β-blockade takes 18–30 minutes after stopping the infusion.51
A recent case series of three ARDS patients treated with
esmolol for refractory hypoxemia during VV ECMO revealed
the feasibility of this strategy to augment the PaO2 reducing
CO and thereby ameliorating the match CO/Pump flow (PF),
without a significant reduction of oxygen delivery.9
More specifically, three patients with ARDS and refrac-
tory hypoxemia despite protective mechanical ventilation
and high flows of VV ECMO, with an hemodynamic profile
characterized by high CO (>7 L/min), were treated with a
continuous infusion of esmolol at a dosage of 50–80 mcg/
kg/min. Hemodynamic evaluation during the first 12 hours
demonstrated a significant reduction of CO and heart rate
(HR) and a significant improvement of peripheral oxygen-
ation, as demonstrated by the increase of PaO2 from the
radial artery samples.
Furthermore, calculated DO2 did not significantly vary dur-
ing the treatment. The absence of metabolic acidosis and the
decreasing trend of blood lactates during the treatment further
confirm the absence of peripheral hypoperfusion because of
reduced CO.
A possible objection could be that reduction of CO might
jeopardize peripheral oxygen delivery. However, this tech-
nique does not entail a low CO state, which should be strictly
monitored by means of markers of tissue hypoxia, such as lac-
tates or metabolic acidosis.
On the pathophysiological side, the most prominent effect
of esmolol infusion is the reduction of HR and CO in patients
characterized by tachycardia and high CO states, like ARDS
septic patients.
By reducing CO, esmolol produces two main effects, namely
improves the ratio between ECMO flow and patient’s native
flow and, in doing so, prevents the need of dangerous ECMO
flow increases; moreover, as stated above, the reduction of CO
is a well-known mechanism of intrapulmonary shunt reduction
that is a paramount mechanism of hypoxemia in patients with
ARDS.
However, β-blocker administration may have other advantages.
Myocardial dysfunction is often present in the shocked
septic patient, and various studies reported high incidence of
reduced left ventricular ejection fraction, ranging from 24% to
50% of affected patients,52 and there are also consistent find-
ings regarding impaired left ventricular diastolic function and
right ventricular dysfunction.53
During septic shock, alterations of β-adrenergic signaling
altered oxygen use in cardiomyocites, because of macrocir-
culatory and microcirculatory changes, disoxya, because of
altered mitochondrial function and direct effects on cardiac
performance, because of circulating myocardial depressant
factor like cytokines and bacterial endotoxins may all play a
role in the etiology of cardiac dysfunction.
Recently, Macchia et al.54 have conducted a pharmacoepi-
demiologic study, evaluating whether septic patients taking
chronically β-blocker therapy had a different mortality rate
than those who did not receive chronic treatment.
They found lower mortality rate at 28 days in patients previ-
ously taking β-blockers admitted to ICU for sepsis and devel-
oping organ dysfunction.
Interestingly, Morelli et al.55 have recently reported that, in
septic patients with a HR of 95/min or higher, requiring high-
dose norepinephrine to maintain a mean arterial pressure of
65 mm Hg or higher, treated with esmolol versus standard care
to achieve a target value of HR between 80 and 94 beats per
minute, there was a strong benefit in mortality.
However, although increasing evidence suggests the pos-
sible beneficial role of β-blockers in sepsis, the topic is still
controversial.
Prone positioning.  Prone positioning is a well-known sys-
tem to improve oxygenation in patients under mechanical ven-
tilation suffering from ARDS.
The physiologic effects of prone positioning are attributable
to changes in the stiffness of the whole chest wall; redistri-
bution of regional alveolar inflation from ventral dependent
regions to dorsal nondependent regions; relief from the heart
pressure on the lungs; changes of hypoxic vasoconstriction;
and reduction of ventilator induced lung injury (VILI).56,57
Very recently, a multicenter RCT assigned 466 patients with
severe ARDS to prone-positioning session of at least 16 hours
daily, or supine positioning. The prone group had a significant
lower 28-day and 90-day mortality, with an incidence of com-
plications that did not differ between the two groups, except
for cardiac arrest, more frequent in the supine-positioned
patients.58
However, the pronation of ECMO patients poses major
dilemmas regard as catastrophic complications as cannulas
dislodgement or pump failure.
Very recently, Guervilly et al.59 reported the largest series
of patients turned to prone positioning during VV ECMO
therapy. Fifteen ARDS patients were turned into prone
position, without major complications, if they had severe
hypoxemia (PaO2/FiO2 ratio below 70) despite maximal
oxygenation, injurious ventilation parameters with plateau
pressure exceeding 32 cm H2O, or failure of attempt to wean
ECMO after at least 10 days on ECMO support. The main
findings of the study are significant improvement in PaO2/
FiO2 ratio at 6 hours (P = 0.03) and 12 hours (P = 0.007) after
reversal. The improvement in oxygenation persisted 1 hour
(P = 0.017) and 6 hours (P = 0.013) after being turned back
to the supine position.
Before this experience, the combined treatment of VV
ECMO and prone positioning has been reported only in small
case series and in a retrospective study involving few patients,
without control group.60,61
A retrospective cohort of 9 ARDS patients treated with VV
ECMO and positioning therapy was published.62 The patients
received a median of 20 hours of positioning therapy during
ECMO course. An improvement in oxygenation and lung com-
pliance was observed after 72 hours from initiation of position-
ing therapy, with no differences in outcome.
These limited experiences does not allow inference about
the effects on the outcome of patients treated with VV ECMO
and positioning therapy, but there is convincing evidence
about the feasibility and safety of such a strategy in case of
severely hypoxemic patients, provided by trained teams in
patient prone positioning (Figure 6).
Transition to VA ECMO
There is a paucity of data addressing this specific issue.
234 MONTISCI et al.

Figure 6. Prone positioning during venovenous extracorporeal membrane oxygenation (VV ECMO).

In ARDS, we can consider switching to VA ECMO as a con- only VA ECMO may provide adequate support. The general
sequence of two main conditions: risks of VA versus VV ECMO must be taken into account, with
the VA configuration usually being associated with more fre-
1.  refractory hypoxemia, when all the strategies listed above
quent and severe complications. Cheng et al.66 recently pub-
have failed, but the cardiac function is normal;
lished a meta-analysis including 1866 patients treated with VA
2.  when a cardiac dysfunction supervenes in terms of septic
ECMO, reporting a cumulative rate of neurologic complica-
myocardial dysfunction or right ventricular dysfunction
tions associated to hemorrhagic or ischemic stroke of 13.3%, a
(acute cor pulmonale) during respiratory failure.
cumulative rate of major or significant bleeding up to 40.8%,
Switching to a VA ECMO circuit allows for supernormal and a pooled estimate rate of vascular complication of 16.9%.
PaO2 on the arterial side as the native lung is completely Finally, as reported by the experience of Biscotti et al.,67 the
bypassed and also provides hemodynamic support in case of consideration of an hybrid configuration of the circuit may
failing left and right ventricle. However, this is not straight- overcome both the limitations in hemodynamic support linked
forward in acute lung failure. As part of cannulation tech- to VV ECMO and in oxygenation of the upper body linked to
nique, if the lung is failing, arterial cannulation should be as VA ECMO. For the purpose of this review, the discussion will
close as possible to the heart to avoid “Harlequin syndrome,” be limited to venous-venoarterial (V-VA) ECMO. Although
in which the patients appear with a blue head and red legs. the concept of reinfusing blood from both the arterial and
This is because of the competition between the anterograde venous side is conceptually appealing, it is, however, techni-
blood flow related to native CO and ECMO flow delivered by cally demanding as pressures, and therefore, flows through the
a femoral cannula and may compromise an adequate perfu- circuit cannot be effectively controlled; it requires continuous
sion of the upper body. attendance of a perfusionist and does not provide any consis-
Femoral cannulation should be avoided unless using a tent benefit, as arterial cannulation is required (Figure 8).
long cannula to reach the aortic arch, entailing a high risk In clinical practice, transition to VA ECMO in patients with
of hemolysis. Appropriate strategies include axillary artery or ARDS should, therefore, encompass a multifaceted evaluation
central cannulation through the chest. Axillary artery cannu- addressing not only arterial oxygen tension, but also a thor-
lation has gained widespread application for aortic surgery, ough evaluation of the risks involved with arterial cannulation.
but it has many limitations for ECMO: upper limb ischemia,
edema, bleeding, and infection (Figure 7). Javidfar et al.63
reported good results in terms of adequate oxygenation, suf-
ficient ventricular unloading, and low complication rate with
subclavian artery cannulation. Moreover, as the heart is nor-
mal, it will continue to beat even if fully drained from the
circuit, and therefore, deoxygenated blood will be ejected
into the coronary arteries and brain. Also, as the right upper
arm is perfused by the ECMO, SpO2 monitoring will prove
unreliable.
However, the need to switch to a VA configuration may be
suggested by an ongoing hemodynamic instability because of
right ventricular dysfunction. Recently, Vieillard-Baron et al.64
reported the results of a series of studies addressing right ven-
tricular failure in ARDS patients. In the era of protective ventila-
tion, Boissier et al.65 reported an incidence of 22% of acute cor
pulmonale (ACP) in patients who met the criteria of the Berlin
definition for moderate to severe ARDS. Hemodynamic con-
sequences of ACP included tachycardia, hypotension, shock, Figure 7. Axillary artery cannulation complicated by right-hand
and the need for hemodynamic support.65 In such a scenario, ischemia treated by distal reperfusion.
 REFRACTORY HYPOXEMIA DURING VV ECMO 235
4. Peek GJ, Mugford M, Tiruvoipati R, et al; CESAR trial collabora-
6. Davies A, Jones D, Gattas D: Extracorporeal membrane oxygen-
7. Extracorporeal Life Support Organization: ELSO Guidelines for
8. Zwischenberger JB, Bartlett RH: Management of blood flow
Figure 8. Hybrid configuration.
10. Schmidt M, Pellegrino V, Combes A, Scheinkestel C, Cooper DJ,
Conclusions
Management of refractory hypoxemia during VV ECMO for
ARDS poses a great number of questions that still remain unan-
swered by current knowledge.
If some of the strategies proposed here are supported by
sound experimental and clinical evidence, like the deter-
minants of patient’s oxygenation during VV ECMO or the
transfusion management, others, like therapeutic hypother-
mia and prone positioning, still need validation in larger
studies.
Among promising approaches, β-blockade seems to be of
utmost interest, on the basis of pleiotropic beneficial effects
that β-blockers appear to have in septic shock, but these find-
ings need to be evaluated in adequately powered studies.
However, a critical topic is still waiting for response: para-
doxically, even if hypoxemia is the trigger for starting extra-
corporeal life support in ARDS patients, little is known about
the limits of tolerability of sustained hypoxia in critically ill
patients, especially in a long-term perspective.
Therefore, despite the improved results guaranteed by
the use of extracorporeal support, many issues in this field
require a thorough focus, which might translate into further
improvements.
Author Contributions
A.M. and G.M. contributed toward conception of the study,
literature search, and writing up the first draft of the paper; A.Z.
and D.W. contributed toward critical revision of the paper; and
F.P. contributed toward conception of the study, critical revi-
sion, and final approval of the paper.
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