The Effect of Extracorporeal Life
Support on the Brain: A Focus on ECMO
Billie Lou Short, MD
Extracorporeal membrane oxygenation (ECMO) therapy has significantly improved outcome in the newborn, pediatric, and adult patient in respiratory and cardiac failure. Despite
this therapy providing a life-saving technology, the morbidity in patients treated with ECMO
therapy is primarily related to neurologic alterations and not pulmonary findings. For
ECMO, this is not unexpected since most patients are being placed on ECMO support
because of severe hypoxemia, with ECMO being considered a rescue therapy for respiratory failure in most instances. As use of ECMO becomes common place for infants and
children in respiratory failure, our investigations into the outcome of these children must
focus not only on survival versus nonsurvival, but on the causes of morbidity in this
population. A further understanding of factors associated with morbidity may allow us to
alter techniques used in extracorporeal life support (ECLS), hopefully to improve our
long-term outcome in this population, while allowing us to expand use of these technologies to other populations such as the premature infant. This article will focus on the effect
of ECMO on the brain, with the following chapter by Dr. Richard Jonas outlining the effect
of cardiopulmonary bypass on the brain.
Semin Perinatol 29:45-50 © 2005 Elsevier Inc. All rights reserved.
KEYWORDS extracorporeal membrane oxygenation (ECMO), venoarterial ECMO, venovenous
ECMO, extracorporeal life support (ECLS), cerebral blood flow, cerebral autoregulation,
nitric oxide
P
otential cerebral injury in the extracorporeal membrane
oxygenation (ECMO) patient can be attributed to several
events including both pre-ECMO- and ECMO-related phenomenon, and/or their combined effects.1-7 Pre-ECMO
events to be considered include exposure to profound hypoxia and/or asphyxia, which may have resulted in cerebral
injury before the initiation of ECMO, or may have altered
cerebral physiologic processes such as cerebral autoregulation; the risk from therapeutic measures such as profound
respiratory or metabolic alkalosis or the use of prolonged
hypercapnia; and the combined effect of the above with cardiovascular instability. The risks associated with the ECMO
procedure itself include prolonged systemic heparinization;
ligation of the carotid artery and jugular vein in venoarterial
(VA) ECMO and the jugular vein in venovenous (VV) ECMO;
alterations of pulsatile flow seen in VA ECMO; microthrombi
from the ECMO circuit; and potential exposure to toxic
Division of Neonatology, Children’s National Medical Center, Washington,
DC.
Address reprint requests to Billie Lou Short, MD, Chief, Division of Neonatology, Children’s National Medical Center, 111 Michigan Ave., NW,
Washington, DC 20010. E-mail: bshort@cnmc.org
0146-0005/05/$-see front matter © 2005 Elsevier Inc. All rights reserved.
doi:10.1053/j.semperi.2005.02.007
agents such as phthalate esters (plasticizers), which are
known to come off the plastic tubing in the ECMO circuit.8,9
Pre-ECMO Events
Asphyxia in ECMO infants is usually mild to moderate, with
the average Apgar score in this population 5 at 1 minute and
7 at 5 minutes.10 Most ECMO infants have experienced profound hypoxia for hours to days, thus making hypoxia one of
the most concerning factors in the development of cerebral
injury. The brain responds to hypoxia by increasing cerebral
blood flow (CBF), which results in a maintenance of cerebral
oxygen transport (OT) and cerebral oxygen metabolism
(CMRO2).11 Mild forms of hypoxia can be tolerated without
major concerns for cerebral injury. Prolonged periods of severe hypoxia can result in a loss of cerebral autoregulation
and therefore the ability of the brain to maintain OT and
CMRO2, resulting in brain injury. This risk for cerebral injury
can be increased when the cardiac output becomes compromised by the prolonged hypoxia, thus decreasing OT to a
greater degree. The incidence and exact time period during
an infant’s course when this phenomenon occurs is difficult
to measure in the clinical setting.
45
B.L. Short
46
Figure 1 Lower end of an autoregulation curve in newborn lambs
after 2 hours of exposure to hypoxia (SaO2 40%). Control animals
(diamond) maintain autoregulation to a cerebral perfusion pressure
(CPP) of 25 mm Hg, while animals exposed to hypoxia and then
recovered by turning the ventilator FIO2 to maintain normoxia
(square) lost autoregulation at a CPP of 25 to 39 mm Hg (P ⱕ 0.05).
Animals recovered using ECMO to maintain normoxia (triangle)
loss autoregulation at a CPP of 40 to 55 mm Hg (P ⱕ 0.05).
Systemic insults such as severe asphyxia, hypoxia, and
hypercarbia can disrupt cerebral autoregulation leaving the
cerebral microcirculation vulnerable to alterations in systemic blood pressure.12-15 In this state, hypotension can result in ischemic cerebral damage, whereas hypertension can
cause cerebral hyperemia and thus the risk for cerebral hemorrhage. Loss of autoregulation in an already injured brain, in
the presences of systemic heparinization, such as occurs with
ECMO, can result in cerebral hemorrhage. Tweed and coworkers and Short and coworkers have demonstrated in the
newborn lamb that exposure to prolonged hypoxia resulted
in loss of cerebral autoregulation during the recovery phase
from hypoxia.16,17 In the study by Tweed and coworkers, a
20-minute exposure to a PaO2 of 30 torr resulted in loss of
cerebral autoregulation for 6 hours after the hypoxic insult.
Short and coworkers exposed newborn lambs to 2 hours of
severe hypoxia (SaO2s of 40%) combined with carotid artery
and jugular vein ligation, simulating that seen in pre-ECMO
events. Cerebral autoregulation was evaluated 1 hour after
the hypoxic insult and found to be altered. When recovery
from hypoxia was done by placing the animal on ECMO
instead of increasing FIO2 in the ventilator, the effect on
cerebral autoregulation was even more profound (see Fig. 1).
Of more concern was the finding that, at the cerebral perfusion pressure level that CBF decreased, significant differences
in right-to-left CBF were noted, indicating that if a pathophysiologic event such as hypotension would occur during
this period, then vessel ligation may be a risk factor for unilateral cerebral injury. Supporting this concern was the observation that CMRO2 also decreased at this point, indicating
the potential for cerebral injury.
Ashwal and coworkers have also shown in the fetal lamb
that the hyperemic, posthypoxia state lasts 4 hours after recovery from the hypoxia.18 These animal studies with those
of Short and Tweed all indicate that the brain may be vulnerable to further insults such as hypotension and/or hyperten-
sion during the recovery period from severe hypoxia, and
that this high risk period can be quite prolonged. Exposure in
these studies was relatively short-term, making concern for
the actual length of this vulnerable time in the ECMO patient
who has been exposed to hours and days of hypoxia of great
concern.
Other factors placing these infants at risk for intracranial
injury can be our clinical management, with specific concerns for our respiratory management of these infants, ie,
hyperventilation or gentle ventilation with hypercapnia. Although controversial, hyperventilation is still used in some
infants with pulmonary hypertension today.19 Alkalosis can
be achieved by either respiratory or metabolic means. If respiratory alkalosis is used, the effect of lowering systemic
pCO2 on the cerebral circulation must be taken into account.
As hyperventilation causes vasodilation in the pulmonary
bed, it causes vasoconstriction in the cerebral circulation,
which can reduce cerebral blood flow. Outcome studies evaluating infants treated with severe hyperventilation, although
small, indicate that neurodevelopmental outcome can be adversely affected by this therapy.20-22 Several studies in animals evaluating the effect of hyperventilation on the brain
have shown an initial decrease of 20% to 30%, with normalization of the CBF after 4 to 6 hours of hyperventilation.
Gleason and coworkers, in the newborn lamb, showed this
same pattern with hyperventilation, but extended the study
to evaluate the posthyperventilation period.23 In their model,
after 6 hours of hyperventilation, animals were made acutely
normocarbic, simulating what happens when placing an infant on ECMO. At this point, extreme hyperemia occurred,
with an increase in CBF by 104%. This hyperemia lasted for
the remaining 90 minutes of the study. Since the study did
not extend beyond 90 minutes, the exact period needed to
normalize the CBF after normalization of pCO2 was not determined. As a result of this study, we now normalize the
patient’s pCO2 over a 24-hour period. The exact period
needed to accomplish this safely is unknown.
Hino and coworkers studied the effect on CBF of acute
normalization of pCO2 after exposure to prolonged hypercapnia24 in the newborn lamb. It could be hypothesized that
a period of cerebral ischemia might occur. Although CBF
increased dramatically during hypercarbia (a normal reaction), normalization of pCO2 did not result in ischemia. Although these finding were assuring, for many centers are now
changing respiratory management to include a “gentle ventilation” or hypercapnic approach to therapy pre-ECMO, only
CBF was studied, not the effect of this prolonged hypercarbia
on cerebral autoregulation.
ECMO Risk Factors
When infants are being placed on VA ECMO, there is a time
period during cannulation that the infant is still hypoxic, and
both the carotid artery and jugular vein must be ligated as the
catheters are placed. Short and coworkers undertook a study
in newborn lambs to determine whether this combination of
exposure to prolonged hypoxia (4 hours) followed by vessel
ligation altered cerebral blood flow and metabolism.25 In this
ECMO and the brain
study, after exposure to 4 hours of an arterial PaO2 of 40 torr,
either the jugular vein or carotid artery was ligated (randomized to determine the effect of ligation of each separately),
followed by the opposite vessel ligated (evaluating the effect
of ligation of both the carotid artery and jugular vein). The
results showed that this degree of hypoxia caused a 100%
increase in CBF with maintenance of OT and CMRO2, and
that during this hyperemic period, ligation of either the carotid artery, jugular vein, or both did not alter CBF, OT, or
CMRO2. Klein and associates also evaluated the effect of vessel ligation on the brain.26 MRI studies immediately post
study in this same model did not reveal any difference in the
ligated and nonligated animals. Although the results of this
study are reassuring, it does not address the events which
may occur if other pathophysiologic events are superimposed during this period, such as systemic hypotension or
hypertension.
Concerns of the potential effect of the ECMO procedure
itself on the brain have been observed both clinically and in
the laboratory. Outcome studies showing that most ECMO
deaths are not secondary to respiratory causes, but to intracranial hemorrhage, have made many investigators attempt
to evaluate the timing and type of intracranial hemorrhage,
and the relationship of ICH to clinical and ECMO events. A
full discussion of the risk associated with ICH and neurodevelopmental outcome of the ECMO population is outlined in
this series by Bulas and Glass.27
The concern for ligation of the carotid artery resulted in the
development of the single-double lumen venovenous catheter, and the use of VV ECMO. It is of interest that both
Doppler blood flow studies and angiographic evaluation of
the brain by magnetic resonance have shown antegrade flow
in the carotid artery and/or the circle of Willis in 35% to 50%
of infants with permanent ligation of the carotid artery.28-31
These findings indicate that collateral flow can develop quite
quickly in these infants. The only long-term follow-up study
to date evaluating flow in the right internal carotid artery of
post-VA-ECMO children has been conducted by Lott and
coworkers. In this study, although there was flow on the
right, it was reduced by 74%.28 Lohrer and associates examined blood flow velocities of the internal carotid artery in VA
ECMO patients before, during, and after ECMO.29 Changes
in carotid blood flow velocities did not correlate with major
intracranial insults. Perlman and coworkers examined the
cerebral blood flow patterns in infants post-VA ECMO using
positron emission tomography and found symmetric hemispheric CBF.31 Serial electroencephalographic (EEGs) studies
were performed in infants before and while on ECMO by
Streletz and coworkers.32 Their findings corroborate that of
neuroimaging data that no acute change in EEG rhythm or
amplitude over the right hemisphere was noted after ligation,
or during ECMO, with their conclusion that carotid ligation
in the short-term is a safe procedure.
VV ECMO has its own risk. Although the carotid artery is
spared, the internal jugular vein must still be ligated and
there are concerns for the obstructive nature of the large
venovenous catheter to superior vena cava flow. A high incidence of posterior-fossa hemorrhages in the ECMO popula-
47
Figure 2 Doppler flow changes see in the pericallosal artery of an
infant pre-ECMO and while on ECMO. The increase in diastolic
flow is secondary to flow from the nonpulsatile ECMO pump. Studies indicate that this change alters the endothelial production of
nitric oxide, and thus alters vasodilation in vessels exposure to this
shear stress/flow changes.
tion have made the concern for venous congestion secondary
to ligation of this vessel a concern.33,34 Another phenomenon
which has been noted in the ECMO population pointing
toward venous congestion is the high incidence of widened
interhemispheric fissure seen on CT scans in as many as 68% of
patients treated with VV ECMO.35 This incidence in VV
ECMO is much greater then that seen in VA ECMO, where it
has been reported to be only 5% to 10%,33 raising further
concerns for venous congestion caused by the VV catheter.
The exact etiology of this finding and the long-term consequences of this observation are unknown.
Doppler studies of the pericallosal artery of infants on VAECMO showed a significant change in diastolic flow velocities as seen in Fig. 2, representing the effect of the nonpulsatile
flow coming from the ECMO pump. When cerebral blood
flow changes were compared with left ventricular output
data, in a study conducted by Taylor and coworkers, in VA
ECMO infants, as suspected, left ventricular output decreased as the pump flows were increased, and that with this
change, the anterior cerebral artery pulsatility index decreased.36,37 These findings also indicate the effect of the takeover of cardiac output by the nonpulsatile ECMO pump.
These findings are not seen in VV ECMO, where the heart
acts as the pump.38 The effect of this altered blood flow pattern in VA ECMO on brain is not fully understood, but may
play a role in the altered cerebral autoregulation seen secondary to ECMO as described in the next section.
Key physiologic studies on the effect of ECMO on the brain
include the initiation of both VA and VV ECMO, CO2 responsiveness of the brain while on ECMO, cerebral autoregulation
on ECMO, the initiation of ECMO after exposure to hypoxia,
and the combined effect of pre-ECMO exposure to hypoxia
and recovery from hypoxia using ECMO, on cerebral autoregulation.39-43 Initial findings by Short and coworkers, of the
acute effects of initiation of VA ECMO on brain did not show
48
Figure 3 The effect of intraluminal acetylcholine infusion on vascular diameter in control, nonpulsatile (VA) and pulsatile (VV) ECMO.
Vasodilation is noted in the vessels from control and VV ECMO
animals, with vasoconstriction in vessels exposed to VA or nonpulsatile ECMO, indicating altered endothelial reactivity.45
altered CBF, CMRO2, cerebral OT, or cerebral oxygen extraction.39 These studies were conducted at ECMO flows of 150
mL/kg/min. Studies by Rosenberg and Kinsella, at ECMO
flow rates ⬍100 mL/kg/min, showed a drop in CBF.40 The
differences in flow rates may be responsible for the differing
findings between these studies.
In the newborn VA ECMO lamb model, Walker and coworkers were able to show that CO2 reactivity of the brain
was preserved while on VA ECMO.41 Short and coworkers, in
the same lamb model, evaluated the effect on cerebral autoregulation of exposure to VA ECMO.42 One hour of exposure
to VA ECMO in the healthy newborn lamb resulted in alteration of cerebral autoregulation. As seen with hypoxia, when
CBF decreased in this study, right-to-left blood flow differences were seen. Although autoregulation changes were seen
in VV ECMO, they were less severe than those seen in VA
ECMO, and no right–left CBF differences were noted.43 Studies by Russo and coworkers, using the closed cranial window
(pial cerebral artery method) technique, corroborated findings by Short and coworkers. In their study, cerebral arteriolar vasodilatation during VA ECMO was markedly altered
(data presented at the 6th Annual ELSO Meeting, October
1994).
Further studies by Short and colleagues in isolated vessel
chamber studies have shown that VA ECMO significantly
alters vessel reactivity to acetylcholine (an endothelial-dependent vasodilator), while VV ECMO does not alter this
reactivity (Fig. 3). The vasoconstrictive effect of exposure to
NG-nitro-L-arginine methyl ester (L-NAME, a potent blocker
of nitric oxide production) was markedly blunted in cerebral
arteries from animals exposed to VA ECMO compared with
controls with normal pulsatility (Fig. 4).44 These findings
indicate that the flow and shear stress changes in VA ECMO
may alter endothelial reactivity through alterations in the
nitric oxide pathway (Fig. 2).45 This alteration may be responsible for the altered autoregulatory changes seen in the
VA ECMO animals. This hypothesis has been corroborated
by findings that the altered vessel reactivity can be returned
B.L. Short
Figure 4 The effect of the intraluminal infusion of LG-nitro-L-arginine methyl ester (L-NAME) on vascular diameter in control and
nonpulsatile VA ECMO animals. Control animals had a significant
vasoconstrictive response compared with animals exposed to VA
ECMO (P ⱕ 0.05), indicating an altered production of nitric oxide
in the vessels of animals exposed to VA ECMO.44
to normal after exposure to a nitric oxide donor (see Fig. 5).
Other studies indicating endothelial dysfunction have been
noted in a hypothermic lamb model of cardiopulmonary bypass.46 Autoregulation changes have been related to endothelial alterations caused by pressure changes in a piglet model
studied by Martinez-Orgado and colleagues.47 Peckel and
colleagues showed an altered autoregulatory response after
Figure 5 The effect of the nitric oxide donor, 3-morpholinyl sydnonelmine chloride (SIN-1), on vessel diameter, comparing vessels
from control animals (white bar), vessels from animals exposed to
VA ECMO (black bar), and vessels from animals exposure to VV
ECMO (hatch bar). The increased vasodilation in the VA ECMO
vessels indicates that these vessels have an altered production of
nitric oxide, with marked vasodilation after replacement of nitric
oxide with SIN-145
ECMO and the brain
nitric oxide blockage in their rat model, implicating endothelial dysfunction.48
ECMO and the Brain:
Conclusions
In summary, ECMO infants are at risk for cerebral injury
secondary to their critical pre-ECMO state, and possibly from
the ECMO therapy itself. The animal studies described in this
chapter indicate that the recovery period from hypoxia,
whether with or without ECMO, is a vulnerable period,
where physiologic alterations such as hypotension or hypertension may place the brain at risk for injury. If these studies
in ECMO animals can be extrapolated to the newborn human
infant, VA ECMO may increase this risk, indicating that stabilization of the infant during the initial recovery period on
ECMO, and treatment of such events such as hypertension
and hypotension, should be undertaken in an expedient
manner. Further studies are needed to understand the mechanisms of these alterations, which would hopefully allow us
to alter our therapies such that this potential risk could be
decreased.
Acknowledgment
This work is supported in part by: NINDS, 1R21NS4038101A2, PI: BL Short.
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