Journal of Cardiothoracic and Vascular Anesthesia 31 (2017) 1847–1848
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journal homepage: www.jcvaonline.com
Editorial
Eliminating Neurologic Complications of
Extracorporeal Membrane Oxygenation—A
Multifaceted Challenge
The use of extracorporeal membrane oxygenation (ECMO) for
patients suffering from refractory respiratory or cardiac failure
has seen significant increases over the past decade. Indeed, the
rate of ECMO usage in adults in the United States has increased
more than 400% between 2006 and 2011 in one analysis.1
Despite this increase, there are few large randomized trials
comparing the efficacy of ECMO with conventional cardiopul-
monary support. Perhaps the only large randomized controlled
trial to evaluate EMCO for adult respiratory failure, the “Efficacy
and Economic Assessment of Conventional Ventilatory Support
versus Extracorporeal Membrane Oxygenation for Severe Adult
Respiratory Failure” (CESAR) trial, did show a benefit to
considering ECMO therapy in patients with severe, potentially
reversible respiratory failure. There have been no similar trials
evaluating ECMO as therapy for acute cardiogenic shock.
Although potentially lifesaving for many patients, ECMO is
an invasive and complication-fraught therapy. Studies have
yielded important data about complication rates and risk
factors, but there remains much to be learned. Neurologic
complications, including stroke and cognitive dysfunction, are
common, and unlike minor complications that may be
managed definitively without long-term consequence, neuro-
logic injury may be particularly devastating and lifelong.
Xie et al’s review of neurologic complications of ECMO2
offered us a comprehensive picture of the wide range of
neurologic dysfunction that may occur in patients. Although
complication rates must be viewed in the framework of a
dearth of standardized diagnostic criteria, and therefore a high
degree of variability in diagnosis, Xie et al noted that meta-
analyses have demonstrated a 5.9%-to-7.8% risk of ischemic
and/or hemorrhagic stroke in adult patients on Venous-arterial
(VA)-ECMO. Recognizing the extremely low in-hospital
survival rate in patients on VA-ECMO who suffer a cerebral
hemorrhage (11% in one recent study3), efforts to minimize
the systemic anticoagulation requirement have the potential to
greatly reduce this devastating complication.
Anticoagulation for ECMO traditionally has utilized unfrac-
tionated heparin, although therapeutic Partial thromboplastin time
http://dx.doi.org/10.1053/j.jvca.2017.05.007
1053-0770/& 2017 Elsevier Inc. All rights reserved.
(PTT) targets vary among hospitals. At the University of
Pennsylvania, we use varying PTT goals between 40 and 70
depending on an individual patient’s risk of bleeding. From a
research perspective, there is considerable effort to minimize
heparin usage by improving ECMO circuit composition, as well
as employing novel anticoagulant therapies directed at mitigating
the inflammatory pathway activation that accompanies blood
contact with the circuit. For example, the use of phosphorylcho-
line, albumin, and heparin coating on ECMO circuits may reduce
the risk of coagulation cascade activation and coagulopathy.4
On the medication front, there is interest in agents that target
factor XII (FXII) as a novel mechanism to provider a safer means
of anticoagulation.5 FXII plays a central role in thrombosis, but its
inhibition does not create a prohemorrhagic environment at a site
of vascular injury. 3F7, an inhibitor antibody targeting FXII, has
been studied as a potential therapeutic anticoagulant for use in
ECMO.5 Any mechanism capable of providing anticoagulation
without increasing hemorrhagic risk would be a welcome strategy
in this patient population.
In contrast to the acute presentation of an intracranial
hemorrhage, not all of the neurologic complications of ECMO
present so abruptly. Xie et al noted multiple studies document-
ing neurodevelopmental impairment in pediatric ECMO sur-
vivors, and appropriately questioned whether these conditions
were related to the ECMO itself or the underlying medical
conditions that necessitated ECMO in the first place.2
Numerous questions exist about the contribution of prolonged
sedation during ECMO toward long- and short-term cognitive
impairment. On an even more fundamental level, our under-
standing of basic pharmacokinetics of sedatives in patients on
ECMO is limited.6 Drug sequestration in the circuit, a robust
systemic inflammatory response, and alterations in drug clearance
all contribute to abnormal pharmacokinetics.6,7 Intensive care unit
delirium, for which sedation is a risk factor, is well known to be
associated with worse outcomes including increased mortality,
prolonged hospitalization, and cognitive dysfunction.8 Patients on
ECMO frequently have multiple risk factors for delirium, notwith-
standing any impact from altered sedative and drug metabolism.
1848 Editorial / Journal of Cardiothoracic and Vascular Anesthesia 31 (2017) 1847–1848
The challenges of sedation on ECMO are numerous and often
entail a balancing act between providing adequate sedation and
negatively impacting hemodynamics. In clinical practice, a
vicious cycle may develop, initiated by patient-ventilator dyssyn-
chrony leading to increased sedation, and subsequently worsened
hemodynamics and increased vasopressor requirements. Too
often this cycle ends in the prolonged use of muscle relaxants
and an increased risk for critical illness myopathy, another
neurologic complication seen in patients after ECMO therapy.
Optimizing sedation practices while patients are on ECMO,
particularly focusing on medications that are less prone to
causing intensive care unit delirium, is a high-yield area of
study, with the potential for direct patient impact. Dexmede-
tomidine (DEX) is one medication that has shown promise in
reducing delirium in patients following cardiac surgery.9
Cozzolino et al reported a series of 7 patients on VV-ECMO
who received DEX in an effort to reduce or eliminate the need
for other sedatives while weaning ECMO.10 In the majority of
patients the use of DEX allowed for reductions in the doses of
other sedatives, and in 1 patient it was used as the sole
sedating agent. DEX's minimal respiratory depressant effects
are also a favorable feature of this drug toward facilitating
ventilator weaning. Recognizing that patients may develop
opioid or benzodiazepine dependence after prolonged periods
of sedation, some institutions, including the University of
Pennsylvania, initiate oral opioids and benzodiazepines to
facilitate earlier transition off of intravenous agents.
Although improving techniques of anticoagulation and seda-
tion for patients on ECMO are promising areas of research and
hold tremendous potential toward improving patient outcomes,
delays or inability to recognize developing neurologic injury are
common in sedated and hemodynamically unstable patients. For
this reason, identifying markers of neurologic injury in patients
on ECMO that can be measured objectively is important for
monitoring and prognostication. Glial fibrillary acidic protein
(GFAP), a filament protein that is upregulated during central
nervous system injury, has been studied as a marker of brain
injury in patients after stroke and cardiac arrest.11 In a
prospective observational study by Bembea et al, high levels
of GFAP in pediatric ECMO patients also have been associated
with brain injury and death.11 Bembea et al proposed that serial
measurements of GFAP could be used to monitor neurologic
status and the success of any potential neuroprotective strategies
while on ECMO. Important information about biochemical
markers of neurologic injury on ECMO also may be gleaned
from the search for similar markers in patients undergoing
cardiopulmonary bypass (CPB) for cardiac surgery. Although
key differences distinguish ECMO therapy from CPB, including
the much more prolonged nature of EMCO compared with the
relatively brief period most patients require CPB, there are
similarities in terms of systemic inflammation, anticoagulation,
and sedation/anesthetic requirement. Numerous markers of
neurologic status have been studied related to CPB, including
S-100b, neuron-specific enolase, and tau protein.12
1
Address reprint requests to Jesse M. Raiten, MD, Perelman School of Medicine at the University of Pennsylvania, 3400 Spruce Street, Dulles 6, Philadelphia,
PA 19104. E-mail address: j.raiten@gmail.com (J.M. Raiten).
The use of ECMO as a rescue therapy for patients with
pulmonary or cardiopulmonary failure is rapidly increasing
worldwide. Like any major intervention, ECMO is associated
with a host of complications, and the potential for significant
morbidity and mortality. The severity and often permanent
nature of neurologic injury raise this category of morbidity to
the forefront of importance, both from a clinical and research
perspective. Therapeutic options for severe brain injury are
relatively few and far between, compared with similar insults of
other organ systems, which we often can support mechanically
or with organ transplantation. Although options to cure brain
injury remain elusive, improving strategies of anticoagulation
and sedation, along with identifying better markers and prog-
nostic tools for tracking neurologic injury, must parallel the
expanding use of ECMO in both pediatric and adult patients.
Jesse M. Raiten, MD1
Hanjo Ko, MD
Jacob T. Gutsche, MD
Perelman School of Medicine
University of Pennsylvania
Philadelphia, PA
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