TCCS and TCD in Specific

Clinical Situations
Table of Contents
 Preface
 TCCS and TCD in Pop of Cardiac Surgery
 Introduction
 Extracorporeal Circulation Pump
 Role in the Non Invasive Neurological Monitoring
 TCCS and TCD Clinical Utility in ICU
 Conclusion
 TCCS and TCD in ECMO and ECCO2R
 Introduction
Cerebral Haemodynamic Changes During ECMO
 Non Invasive Neuro Monitoring During ECMO
 Clinical Considerations in ECMO
 Conclusion
TCCS and TCD in Specific Clinical Situations

Current Status 2019

Completed
This module is updated and maintained by the (NIC) section

Latest Update
First Edition

Neuro-Intensive Care
Chair
Fabio Silvio Taccone MD, Assistant Professor, Department of Intensive Care,
Erasme Hospital, Professor of Emergency Medicine, the Université Libre de
Bruxelles (ULB), Brussels, Belgium

Deputy
Chiara Robba MD, PhD, Anaesthesia and Intensive Care, IRCCS for Oncology,
Genova, Italy

Section Editor
Valentina Della Torre MD, MSc, Department of Critical Care, Imperial College
NHS Foundation Trust, London, UK

ELearning Committee
Chair
Kobus Preller Dr., Consultant, John Farman ICU, Cambridge University Hospitals
NHS Foundation Trust, Cambridge, UK

Deputy
Mo Al-Haddad MD, Consultant in Anaesthesia and Critical Care, Queen Elizabeth
University Hospital; Honorary Clinical Associate Professor University of Glasgow,
Glasgow UK

Project Manager
Estelle Pasquier , European Society of Intensive Care Medicine

First Edition 2020

Module Authors
 Camilo N. Rodríguez MD, Intensive Care Physician,Hospital Nacional Prof. Dr. A.
Posadas, Buenos Aires, Argentina. University of Buenos Aires (UBA), Buenos
Aires, Argentina. Neurointensive Care section member – ESICM, Neurointensive
Care committee member – FEPIMCTI, Neurointensive Care section member –
AMCI, ESNCH Member
Deborah Pugin MD, Intensive Care Physician, Intensive Care Department.
University Hospital of Geneve, Geneve, Switzerland
Corina Puppo MD, Intensive Care Physician, Intensive Treatment Center,
Hospital of Clinical, University of the Republic, Montevideo, Uruguay,
Neurointensive Care committee member - FEPIMCTI
Francisco Chacon Lozsan MD, MESC, Ms Intensive Care Physician, Anesthesia
and Intensive Care Péterfy Sándor Utcai Hospital-Clinic and Trauma Centre
Budapest, Hungary
Loic Le Guennec MD, Intensive Care Physician, Chief of Clinical Assistant
Intensive Care Medicine - Institut of Cardiology Pitié-Salpêtrière Hospital, Paris,
France

Section Editor
Valentina Della Torre MD, MSc, Department of Critical Care, Imperial College
NHS Foundation Trust, London, UK
Carmen Lopez Soto MD, MSc, EDIC, Department of Critical Care, King's College
NHS Foundation Trust, London, UK

CoBaTrICE Mapping Contributors

Valentina Della Torre MD, MSc, Department of Critical Care, Imperial College
NHS Foundation Trust, London, UK
Carmen Lopez Soto MD, MSc, EDIC, Department of Critical Care, King's College
NHS Foundation Trust, London, UK

Co-Ordinating Editor
Stephanie C. Cattlin MBBS, Bsc, FRCA, FFICM, Consultant in Intensive Care,
Imperial College Healthcare NHS Trust, London, UK

Executive Editor
Mo Al-Haddad MD, Consultant in Anaesthesia and Critical Care, Queen Elizabeth
University Hospital; Honorary Clinical Associate Professor University of Glasgow,
Glasgow UK

Update Info

Intended Learning Outcomes

Neurosonology Part 4 TCCS and TCD in Specific Clinical

Situations
 1. Estimate the Peak systolic flow velocity (FVs), mean flow velocity (FVm)
and diastolic flow velocity (FVd) in the most important vessels of the Circle
of Willis.
2. Integrate each of hemodynamic and parenchymal measurements acquired
from critically ill patients bedside by TCD/TCCS monitoring.
3. Interpret the hemodynamic and parenchymal measurements individualizing
each clinical context of each critical patient.
4. Implement individual therapeutic decisions for each clinical context, once all
patient clinical information from TCD/TCCS measurements was completely
collected.

eModule Information

Relevant Competencies from CoBaTrICE

Neurosonology Part 4 TCCS and TCD in Specific Clinical

Situations

2.9 Monitors and responds to trends in physiological variables.

3.1 Manages the care of the critically ill patient with specific acute medical
conditions.
3.6 Recognises and manages the patient with neurological impairment.
12.2 Communicates effectively with members of the health care team.
12.3 Maintains accurate and legible records / documentation.
12.12 Formulates clinical decisions with respect for ethical and legal principles.

Faculty Disclosures:
The authors of this module have not reported any disclosures.
1. TCCS and TCD in Postoperative of Cardiac Surgery

1. 1. Introduction
Brain autoregulation can adapt to several haemodynamic and hypoxemic insults with
outstanding performance. In the cardiovascular patient, however, extreme conditions
in cardiac pathophysiology like cardiac arrest and shock or complex procedures like
extracorporeal circulation or coronary catheterization can lead to secondary brain
injuries; using TCD/TCCS may help with early detection and treatment of these
complications.

1. 2. Extracorporeal Circulation Pump: Cerebral

Haemodynamic Impact
During extracorporeal circulation, cerebral blood flow decreases 65% and after 16
minutes flow is restored in 95% of the basal values and may increase a 7% over the
control levels. In some patients signs of impaired auto regulation have also been
observed, specially during hypothermia. Some predicting factors for impaired
autoregulation included: male patients, cerebral blood flow velocities, PaCO2 and
perioperative aspirin treatment. The use of roller pumps in older pump models was
associated with greater reduction in cerebral blood flow compared with the current
centrifugal pumps, which have been reported to provide continuous cerebral blood
flow.

Pump flow is characterized by decrease in systolic upstroke, lack of dicrotic notch and
continuous diastolic flow. The loss of pulsatile flow may be responsible for the
impairment of cerebral autoregulation (Figure 1A). The pulsatility index (PI) usually
decreases during extracorporeal circulation, and if it rises may be an indicator of
cerebral pathology.
 Figure 1: TCCS: (A) During extracorporeal
circulation and (B) Normal flow (pulsatility flow).

 Note

Hemodynamic repercussions in brain circulation during extracorporeal

circulation for cardiac surgery are important and TCD/TCCS can provide a
useful tool to monitor these changes and choose the best clinical options in
order to reduce brain insults.

 Note
Extracorporeal circulation causes a hypoperfusion status that can be measured
and monitor using the TCD/TCCS.

In text References

(Polito et al. 2006; Kubota. 1968; Kazmi et al. 2018)

 References
Polito A, Ricci Z, Di Chiara L, Giorni C, Iacoella C, Sanders SP, Picardo S. ,
Cerebral blood flow during cardiopulmonary bypass in pediatric cardiac
surgery: the role of transcranial Doppler--a systematic review of the
literature., 2006, PMID:17166253
Kazmi SO, Sivakumar S, Karakitsos D, Alharthy A, Lazaridis C., Cerebral
Pathophysiology in Extracorporeal Membrane Oxygenation: Pitfalls in Daily
Clinical Management., 2018, PMID:29744226
Kubota Y., Clinical study of the cerebral hemodynamics during
extracorporeal circulation, 1968, PMID:5704919

1. 3. TCCS and TCD Role in the Non Invasive Neurological

Monitoring Before and After Cardiac Surgery
The brain can be considered as an excellent index for organ perfusion, when cerebral
perfusion is compromised, other organs may be inadequately perfused as well.
Periods of brain hypoperfusion may occur frequently during cardiac surgery due to
reduced cardiac output and pump flow, decreased perfusion pressure. All these factors
can lead to brain tissue injury and adverse outcomes. TCCS/TCD has gained
relevance by measuring the flow of the middle cerebral arteries (which carry around
40% of the brain flow); comparing systolic and diastolic flows pre and during surgery
can help to determine hypoperfusion: when flow is reduced around 60% from baseline
or in absence of diastolic flow; but also to set an ischemic threshold when systolic
velocity of MCA is reduced by 80% or in presence of non-pulsatile flow.

According to recent data, around 70% of patients after coronary artery bypass graft
can have some degree of psychological deficit like depression and delirium, and
among these patients, 15% may have postoperative secondary brain injury like post-
ischemic encephalopathy. Most of these brain insults can be the result of microembolia
during extracorporeal circulation. This sort of injury can also be also found after
cardiac catheterization, coronary angiography, angioplasty and electrical
cardioversion.

Microembolia detection by TCCS/TCD, by consensus, has been identified as: short

lasting (<0,01-0,03sec) unidirectional intensity increase, and intensity increase (>3dB)
within the doppler frequency spectrum. These can appear randomly and produce a
clicking sound when passing through the insonated artery. The different signs between
gas or solid particles, like fat, platelet aggregates or atheroma particles, are based on
the principle that solid particles reflect ultrasound at higher frequency than gaseous
emboli, and the best frequency to detect them are between 2 and 2,5MHz.

 Note
TCD can play a role in perioperatory cardiac surgery and help to avoid
secondary brain injury.

 Note
TCCS/TCD monitoring can detect microembolia.

In text References

(Kubota. 1968; Kazmi et al. 2018; Dabbagh. 2018; Stygall et al. 2000; Telman et al.
2010; Vuković-Cvetković. 2012; Polito et al. 2006)

 References
Dabbagh A., Postoperative Critical Care for Adult Cardiac Surgical Patients,
2018, ISBN:9783319757476
Stygall J, Kong R, Walker JM, Hardman SM, Harrison MJ, Newman SP.,
Cerebral microembolism detected by transcranial Doppler during cardiac
procedures, 2000, PMID:11022086
Telman G, Mesica O, Kouperberg E, Cohen O, Bolotin G, Agmon Y,
Microemboli monitoring by trans-cranial doppler in patient with acute
cardioemboliogenic stroke due to atrial myxoma, 2010, PMID:21577341
Vuković-Cvetković V., Microembolus detection by transcranial Doppler
sonography: review of the literature, 2012, PMID:22195291
 Polito A, Ricci Z, Di Chiara L, Giorni C, Iacoella C, Sanders SP, Picardo S. ,
Cerebral blood flow during cardiopulmonary bypass in pediatric cardiac
surgery: the role of transcranial Doppler--a systematic review of the
literature., 2006, PMID:17166253
Kazmi SO, Sivakumar S, Karakitsos D, Alharthy A, Lazaridis C., Cerebral
Pathophysiology in Extracorporeal Membrane Oxygenation: Pitfalls in Daily
Clinical Management., 2018, PMID:29744226
Kubota Y., Clinical study of the cerebral hemodynamics during
extracorporeal circulation, 1968, PMID:5704919

1. 4. TCCS and TCD Clinical Utility in ICU

Present literature on the use of the TCU in general ICU is still limited, however its use
has been described in patients at high risk of brain injury or secondary brain injury
related with primary diseases. As described by Robba C et al, TCD has a role in
neurointensive care and emergency room as a non invasive tool to estimate
intracranial pressure and cerebral perfusion, cerebral autoregulation, critical closing
pressure, brain compliance, cerebrovascular dynamics, and as a tool to identify and
stratify vasospasm, especially in patients with traumatic brain injury, hydrocephalus
and/or subarachnoid hemorrhage.

In the more general ICU settings, the use of TDU has been described for monitoring
and diagnosis cerebral hemodynamic and metabolic changes due to acute liver failure.
In patients with acute liver failure, loss of autoregulation contributes with a rise in
intracranial pressure. Moreover, TCD allows to monitor brain dynamics after stroke,
sepsis, post-cardiac arrest, pre-eclampsia, and during extracorporeal support or
surgery.

In septic patients, hypotension and low cardiac output are related to higher risk of
developing sepsis- encephalopathy and may be a cause of delirium. TCD may help
early detection of reduced brain perfusion pressure and to prevent secondary brain
injuries caused by sepsis.
In patients with acute respiratory distress syndrome (ARDS) and brain injury, the use
of ultrasound can play an important role in the assessment of the critically ill patient.
Using combined cardiac, lung and brain ultrasound may help identifying a better
ventilation strategy, based on balance between oxygenation and cerebral perfusion.

Lastly TCD can have a role in the diagnosis of brain death. Clinical examination has
been the preferred form to diagnose brain death. However,, brain stem testing can be
challenging because of several factors, including trauma to the middle or inner ear or
non-cerebral pupillary paralysis. Moreover, the use of standard image techniques
capable to demonstrate the absence of brain function as a complement to the clinical
examination is limited in unstable patients. Recent data suggests that TCD has a
sensitivity of 0,90 (95% CI, 0,87-0,92) and specificity of 0,98 (95% CI, 0,96-0,99) to
diagnose brain death, when identifying flow patterns of circulatory arrest (Figure 2)

Figure 2:Flow patterns of circulatory arrest for

diagnosis of brain death. Modified from Robba C,
et al, Intensive care Medicine.2019

Figure 2: Flow patterns of circulatory arrest for diagnosis of brain death. (A)
Circulatory arrest pattern: when the intracranial pressure is bigger than the diastolic
blood pressure and the end diastolic flow is zero, you can observe only a systolic flow
>10cm/sec and rise pulsatility index. (B) Circulatory arrest pattern with reverberant
flow: the intracranial pressure is equal of bigger than systolic blood pressure and the
brain perfusion pressure drops, observing an anterograde flow in systole with an
inverted diastolic flow been the cerebral blood flow equal to cero. (C) Circulatory arrest
pattern without diastolic flow: it is observed when the intracranial pressure raises more
than the systolic blood pressure and only systolic spikes can be observed less than
200msec and small amplitude, less than 50cm/sec without diastolic flow. (D)
Circulatory arrest pattern without flow signal: it is observed when the intracranial
pressure is too high that produce obstruction of every proximal artery observing total
absence in doppler signal.

In text References

(Robba et al. 2019; Chacon-Lozsan and Pacheco. 2018; Naqvi et al. 2013; Zampieri et
al. 2011; Della Torre et al. 2017; Lau and Arntfield. 2017; D'Andrea et al. 2016)

 References
Naqvi J, Yap KH, Ahmad G, Ghosh J., Transcranial Doppler ultrasound: a
review of the physical principles and major applications in critical care,
2013, PMID:24455270
Zampieri FG, Park M, Machado FS, Azevedo LC, Sepsis-associated
encephalopathy: not just delirium, 2011, PMID:22012058
 Della Torre V, Badenes R, Corradi F, Racca F, Lavinio A, Matta B, Bilotta F,
Robba C., Acute respiratory distress syndrome in traumatic brain injury:
how do we manage it?, 2017, PMID:29312748
Lau VI, Arntfield RT., Point-of-care transcranial Doppler by intensivists,
2017, PMID:29030715
Chacon-Lozsan F, Pacheco C. , Fluid Management In The Neurointensive
Care Patient Using Transcranial Doppler Ultrasound: Preliminary Study,
2018,
https://www.sciencedirect.com/science/article/abs/pii/S2210844018300972?
via%3Dihub
Robba C, Goffi A, Geeraerts T, Cardim D, Via G, Czosnyka M, Park S,
Sarwal A, Padayachy L, Rasulo F, Citerio G, Brain ultrasonography:
methodology, basic and advanced principles and clinical applications. A
narrative review., 2019, PMID:31025061
D'Andrea A, Conte M, Scarafile R, Riegler L, Cocchia R, Pezzullo E,
Cavallaro M, Carbone A, Natale F, Russo MG, Gregorio G, Calabrò R.,
Transcranial Doppler Ultrasound: Physical Principles and Principal
Applications in Neurocritical Care Unit., 2016, PMID:28465958

1. 5. Conclusion
Ultrasound can be a useful tool in intensive care unit in the process of diagnosis,
treatment and monitoring of critical patients. TCD is becoming increasingly useful.
Constant practice and study of this reliable method helps improving patients’ care.

 Note
TCCS/TCD can play an important role in diagnosis and follow up of secondary
insults related to general ICU common pathologies.
2. TCCS and TCD in ECMO and ECCOR

2. 1. Introduction
Extra Corporeal Membrane Oxygenation (ECMO) is an emergency support procedure
used to provide cardiac and/or pulmonary support in patients refractory to conventional
therapies. Over recent years, the number of patients treated with ECMO has increased
and risk–benefit balance ratio has improved 1 2. ECMO circuit is either in veno-venous
(VV) configuration or in veno-arterial (VA) configuration. The ECMO circuit is coupled
with a centrifugal pump, which provides continuous flow in the circuit, and with a
membrane oxygenator. VV ECMO is used in acute respiratory distress syndrome
(ARDS), and VA ECMO in refractory cardiogenic shock and cardiac arrest.

In VA ECMO, the circuit includes an inflow cannula which drains blood from the
venous system, and an outflow cannula which delivers the warmed oxygenated blood
back into the arterial system in order to restore circulatory flow. It is used for refractory
cardiac dysfunction, regardless of the underlying cardiac pathology (myocarditis,
cardiomyopathy, postcardiotomy heart failure, primary graft failure after heart
transplantation, ventricular dysfunction in patients with acute coronary syndrome,
acute intoxications due to cardiotropic drugs, cardiac arrest). Intra-aortic balloon pump
(IABP) is often added in those patients to protect against hydrostatic pulmonary
edema 3, or to improve coronary bypass graft flow and cardiac function in refractory
postoperative cardiogenic shock 45. IABP reduces left ventricular afterload, improves
coronary perfusion, and provide pulsatile blood flow.

In VV ECMO, the outflow cannula delivers oxygenated and decarboxylated blood to

the vena cava and the right atrium. The aim of this configuration is to ensure normal
blood gas 6.
The Extracorporeal Life Support Organization (ELSO) collects data since 2002 from
359 ECMO centers worldwide. ELSO reported overall outcomes in 2018 in 35,632
adult patients, among which 15,686 were VV ECMO with survival rate of 66%, and
15,201 were VA ECMO with a survival rate of 55%; there were also 4745
extracorporeal cardiopulmonary resuscitation with a survival rate of 38%. These data
highlight a higher survival rate in VV than in VA ECMO.

The use of ECMO is associated with several cerebrovascular complications (anoxic

cerebral injury, ischemic stroke and cerebral hemorrhage, epileptic seizures, coma and
brain death), responsible for high morbidity and mortality 7. Many pre-ECMO factors
are associated with neurological injury, but also the modality, VA/ VV is diversely
associated to cerebrovascular complications. Stroke occurs mainly during VA ECMO
8, whereas cerebral hemorrhage is mostly observed during VV ECMO 9. These
complications have an important impact in terms of outcome, and consequently on
multidisciplinary teams decisions.

It is likely that both VA and VV ECMO affect CBF and impact cerebral hemodynamics
8-12. IABP might also play a role in CBF modification in patients with cardiac failure
13. Early detection and specific care for neurological complications could improve the
prognosis of these patients. Indeed, because of the critical condition of these patients
and the use of deep sedation and anesthesia, it can be difficult to diagnose
neurological events under ECMO. Moreover, there is a practical difficulty in transfer of
ECMO patients to neuroimaging suites.

TCD/TCCS is a non invasive monitoring procedure able to detect cerebral

hemodynamics changes in real-time, as well as microembolism, and has been used
extensively in neurological and neurosurgical patients to monitor CBF velocities; there
is increasing interest about TCD use in ECMO patients, to detect ECMO-related
cerebrovascular complication.

In text References

2. 2. Cerebral Haemodynamic Changes During ECMO

In adult patients, there is limited literature about cerebral autoregulation (CA)
impairment during ECMO. Pre-ECMO factors, such as hypoxia, hypercapnia,
hypoperfusion or hypertension can disrupt systemic blood flow regulation, leaving the
brain vulnerable to changes in blood pressure 1; it has been shown that cannulation of
great blood vessels and pulsatile flow alterations during the course of ECMO can also
affect CA 2. Most of these studies have been done in pediatric patients with near
infrared spectrophotometry (NIRS) to assess this impairment. Thus, both pre- and
ECMO factors may contribute to cerebrovascular complications commonly seen in
ECMO.

 Note
Non-pulsatile blood flow caused by the ECMO pump might affect cerebral
autoregulation.

Multiple factors can alter CBF during VA and VV ECMO, and noninvasive monitoring
procedures able to detect those cerebral hemodynamics changes in real-time might be
useful in everyday medical practice.

2. 2. 1. VA-ECMO
Various factors can alter CBF during ECMO. One of the main hypotheses is that the
laminar blood flow caused by the ECMO pump affects CA through the myogenic
response. The effect of nonpulsatile flow on the brain has been of concern first in
cardiopulmonary bypass (CPB). An experimental animal study in the eighties
compared pulsatile and nonpulsatile bypass in a canine stroke model and found that
pulsatile flow increased CBF significantly over nonpulsatile flow, showing the
importance of pulsatile blood flow in ischemic brain disease 3. In adults patients
undergoing CPB, the mean lower limit of autoregulation, under which a drop in
cerebral perfusion pressure (CPP) results in a loss of CBF, has been found to be a
mean arterial blood pressure (MAP) of 66mmHg 4, but instead of targeting a specific
MAP, CA monitoring using cerebral oximetry index to individualize optimal blood
pressure is widely used to prevent neuronal injury 5.

During VA ECMO, CA has been evaluated in the early nineties in newborn lambs 6.
Non-pulsatile roller-pump where used in this work. CA was evaluated during the
course of ECMO by lowering the CPP via an increase in intracranial pressure through
infusion of artificial cerebrospinal fluid into the lateral ventricle. CA was found to be
impaired in lamb on VA ECMO (flow rates of 120–150 mL/kg/min) compared to control
animals with right jugular vein and carotid artery ligation. Multiple studies using NIRS
and neuroimaging have shown abnormal CA in infants undergoing VA ECMO 789, but
those studies are lacking in adult patients. Indeed, in neonates, the outflow arterial
cannulation site can be the carotid artery, which can itself impact on CBF, whereas
outflow arterial cannulation site in adult is often the femoral artery. However, when the
outflow arterial cannula is the femoral artery, clinicians fear that the brain receives
hypoxemic and undercarboxylated blood ejected from a residual activity of the left
ventricle, in patients with poor lung function. This upper body differential hypoxemia,
defined as “Harlequin syndrome” 10, is usually detected by the monitoring of oxygen
saturation within the right upper limb, and could also impact CA.

The addition of IABP in conjunction with VA ECMO to protects against hydrostatic

pulmonary edema 11, or to improve coronary bypass graft flows and cardiac function
in refractory postoperative cardiogenic shock 121314, has also been shown to modify
cerebral hemodynamics. Indeed, one study has shown, in patients with refractory
cardiogenic shock after cardiac surgery requiring VA ECMO, that the addition of IABP
influences CBF depending on the systolic antegrade blood flow by patients’
spontaneous cardiac function. In this study, the addition of IABP to VA ECMO support
decreased the CBF in patients with cardiac stun, and increased CBF in patients
without cardiac stun 15.

 Note
VA-ECMO is used in refractory cardiogenic shock and cardiac arrest, whereas
VV ECMO is used in acute respiratory distress syndrome (ARDS).

 Note
Stroke occurs mainly during VA ECMO, whereas cerebral hemorrhage is mostly
observed during VV ECMO.
2. 2. 2. VV-ECMO
The main metabolic factors known to cause significant changes in CBF are PaCO2
and pH. These parameters can rapidly change during VV ECMO 16. Intracranial
bleeding is the most frequent cerebrovascular complication during VV ECMO, and it
has been found that a decrease in PaCO2 after ECMO cannulation was independently
associated with this complication 17. However, because rapid decrease in PaCO2
leads to cerebral vasoconstriction, the relationship between PaCO2 change and
cerebral bleeding is difficult to understand. One hypothesis could be that these
cerebral bleeding were in fact secondary to hemorrhagic transformation after cerebral
infarction due to cerebral vasoconstriction induced by too rapid PaCO2 lowering after
VV ECMO implantation.

 Note
Another factor that could impairs cerebral hemodynamics during VV ECMO is
the internal jugular vein occlusion due to the inflow cannula, which can cause
cerebral venous hypertension, resulting in decreased CBF within the first hours
of cannulation, as it has been described in newborn 18. In these studies, this
effect tends to disappear after 24 hours of VV ECMO, with CBF normalization
18 19.
Too-rapid hypercapnia correction after VV ECMO cannulation might lead to
cerebral vasoconstriction and cerebrovascular complications.

In text References

2. 3. Non Invasive Neuro Monitoring During ECMO

Studies looking at TCD/TCCS on adult patients treated with ECMO are very limited in
literature. However this tool can be useful to assess CA during ECMO and has
numerous advantages compared to other modalities, as it is a noninvasive technique,
available at bedside, repeatable, without any risk of radiation.

2. 3. 1. VA ECMO
In 2016, a study in 8 VA ECMO patients without IABP has shown a correlation
between lowering of cerebral pulsatility indexes (PIs) and left ventricular ejection
fraction (LVEF) 1. Indeed, as the heart systolic function gives rise to the upstroke
observed on TCDs, patients with severely reduced LVEF displayed lower or non-
computable PIs. In this study, ejection fraction (EF) of less than 10% resulted in a
nonpulsatile TCD waveform. Moreover, in those patients, the measurement of the
diastolic phase during TCD for calculation of PIs corresponded to the nonpulsatile flow
generated by the ECMO circuit. In an expected manner, when the EF increased during
recovery, the systolic upstroke increases in amplitude, resulting in higher PIs values
and back to normal. This study shows that low or incomputable PIs and lack of systolic
upstroke should not be mistaken with cerebral vasodilation in VA ECMO patients with
laminar flow, and that rising of their PIs during the course of ECMO can be related to
cardiac recovery. However, focal or asymmetrical PIs modifications still suggest
changes of vascular resistance, and should evoke acute focal cerebrovascular disease
23.

As IABP is increasingly used in addition to VA ECMO to improve coronary bypass graft

flow and cardiac function, in order to protect against hydrostatic pulmonary edema in
critically ill patients 4-6, some studies have evaluated the impact of this combination
on CBF. In the literature, the effect of IABP alone on CBF is controversial, with
contradictory results. For example, a study in patients with IABP support after cardiac
surgery found that IABP was associated with small, but significant, increase in systolic
antegrade mean flow velocity in the middle cerebral artery, but 30% of those patients
displayed transient end-diastolic reversal of intracranial blood, resulting in no influence
on average flow velocity 7. In another study with 56 patients on IABP assistance, it has
been shown a reduction of 11.6% in the ocular blood flow measured by ocular
pneumoplethysmography 8. However, the effect of combined VA ECMO and IABP on
CBF is not well known. Only one prospective study has investigated IABP effect on
CBF in patient with VA ECMO 9. In this work, 12 adult patients receiving VA ECMO
and IABP combination for refractory postcardiotomy cardiogenic shock after coronary
artery bypass were analyzed. The IABP was implanted before VA ECMO. The CBF
velocity were measured once every 12 hours, under “turned on” IABP and “turned off”
IABP support. Patients provided their own control values through the “turned off” IABP
condition. All 12 patients were successfully weaned from the IABP and VA ECMO, 8
patients were discharged from the hospital, and survival rate was 66.7%.
Cerebrovascular complications were not observed in this study. Concerning their CBF,
no statistically significant differences for the mean CBFs were observed between VA
ECMO alone and VA ECMO with IABP support, but the authors divided patients into
two groups, considering their cardiac functional state and their basal pulsatile pressure
without IABP support. Their conclusions were that the addition of IABP to VA ECMO
significantly decreased the mean CBF in patients with basal pulsatile pressure under
10 mmHg, and led to a significant increase in the mean CBF values in patients with
basal pulsatile pressure higher than 10 mmHg. The CBF decrease in cardiac stunned
patient with VA ECMO and IABP seems to be due to the diastolic inflation of the IABP,
that might intermittently compromise the retrograde flow, as it has been described in
patients with cardiogenic shock and IABP alone 7.

Finally, in a recent retrospective study performed in 20 VA ECMO patients implanted

for cardiogenic shock and/or cardiac arrest, four differents TCD waveform were
correlated to LVEF values and IABP support 32; (1) Double systolic peak pattern in
patients with both cardiac systole and IABP waves detectable; (2) Normal waveform
pattern in patient with detectable cardiac systole wave with no IABP or IABP turned
off; (3) Systolic IABP peak into a continuous demodulate waveform pattern in patient
with undetectable cardiac systolic wave; (4) Continuous and non-pulsatile flow
corresponding to VA ECMO flow in patient without detectable cardiac systole and no
IABP, or IABP turned off. In that study, cardiac systolic peaks could be detected by
TCD when LVEF was above 20%.

 Note
In VA ECMO patients without IABP, there is a correlation between LVEF and low
PIs, and patients with EF lower than 10% display a nonpulsatile TCD waveform.

 Note
In patients with VA ECMO and IABP combination, the addition of IABP on VA
ECMO influences CBF depending on the systolic antegrade blood flow by
patients’ spontaneous cardiac function. It decreases CBF in patients with
cardiac stun because of transient end-diastolic reversal of intracranial blood flow
induced by this device.

2. 3. 2. VV ECMO
Concerning VV ECMO, a pediatric study has shown in 19 newborns that CBF was
either maintained or gradually increased before and during VV ECMO, except in one
patient with cerebral hemorrhage where velocities in each cerebral arteries were
higher compared with cases without cerebral complications 11. Because most of these
newborns were treated with double-lumen cannula, introduced into the right internal
jugular vein, CBF decreased within the first hours of cannulation, probably because of
transitory cerebral venous hypertension 12. As described before, this effect tends to
disappear in the first day of VV ECMO, with CBF normalization.

 Note
During VV ECMO internal jugular vein is used for the inflow cannula,
responsible for cerebral venous hypertension and decreased CBF within the first
hours of cannulation. This effect tends to disappear after 24 hours of VV ECMO,
with CBF normalization.

In text References

2. 4. Clinical Considerations in ECMO

In this paragraph we will focus on ischemic stroke and cerebral hemorrhage during
ECMO, and TCCS/TCD contribution in their early detection and specific care. We will
also discuss about brain death, and the specific management of brain-dead donor
supported by ECMO, and the potential use of TCCS/TCD in this particular situation,
even if cerebral death is mainly due to pre-ECMO factors rather than ECMO itself.

2. 4. 1. Ischemic stroke
2. 4. 1. 1. VA ECMO
Ischemic strokes are more commonly observed in VA ECMO patients 1. In 2016, a
series of 137 VA ECMO patients reported 10% incidence of stroke 2. However, this
number was estimated at 50% in a 2006 study in which cerebral magnetic resonance
imaging (MRI) was performed systematically during follow-up of survivors, with median
follow-up at five years 1. Finally, in a study of 84 patients undergoing VA ECMO, where
brain autopsies were performed in 25% of non-survivors (10 patients), ischemic brain
lesions were found in 70% of them, although neurological disorder was not notified
during their stay 3. Regarding the risk factors for ischemic stroke, a recent study of
171 patients including 80% of VA ECMO reported that lactate levels > 10 mmol/L
before ECMO cannulation was an independent risk factor of ischemic stroke
occurrence 4. A recent study in 878 VA ECMO patients has reported 5.3% of ischemic
strokes occurring after a median of 11 days of support 5. The only risk factor
associated with ischemic strokes was a platelet level > 350 giga/L 5.

 Note
MES count is higher in VA ECMO patient than VV ECMO or ECCO2R.

2. 4. 1. 2. VV ECMO
Ischemic stroke is less common in patients with VV ECMO compared to VA ECMO.
The largest cohort study that investigated neurological complications in patients
undergoing VV ECMO reported its incidence at 2% 6. In this study, ischemic strokes
occurred after a median of 21 days after VV ECMO implantation 6. In 2006, in a study
in which brain MRI was performed in survivors, no ischemic injury was found 1.
Studies with brain autopsy of patients undergoing VV ECMO have not been published
so far.

2. 4. 1. 3. Pathophysiological mechanisms and TCCS/TCD contribution

Responsible mechanisms for ischemic strokes are most likely to be different
depending on ECMO type. Regarding the mechanism of ischemic injury in patients
undergoing VA ECMO, no study has analyzed their origin; the main cause is likely to
be cardio-embolic stroke.
The role of the ECMO circuit in these strokes remains unclear, but might be a source
of embolism, regardless of the underlying disease. Indeed, the shear stress imposed
by the flow pump generates an increased platelet activation, responsible for their
aggregation 7. This is particularly observed with centrifugal pumps, widely used
nowadays because of decreased hemolysis compared to old roller-pump systems 7.

Another mechanism that can explain the high frequency of ischemic stroke in VA
ECMO patients is cerebral hypoperfusion during initial cardiogenic shock. In this
situation, cerebral infarctions have a particular topography, called “watershed cerebral
infarction”, also known as “border zone infarcts”, because they occurred at the border
between cerebral vascular territories, where the tissue is farthest from arterial supply,
and thus most vulnerable to perfusion reductions. They are observed at the level of
anastomoses between different cerebral arterial territories, anterior, middle and
posterior.
For patients under VV ECMO, stroke physiopathology is less obvious than for VA
ECMO. A mechanism involving paradoxical embolism, responsible for 2% of ischemic
strokes 8, could happen during VV ECMO, especially in ARDS patients with elevation
of right atrial pressures induced by ultra-protective mechanical ventilation and high
level of positive end-expiratory pressure; this mechanism is responsible for foramen
ovale reopening, and therefore, a higher risk of venous thromboembolism towards the
arterial circulation. Finally, too-rapid correction of hypercapnia can result in metabolic
alkalemia in these patients, and may be responsible for cerebrovascular
vasoconstriction and reduction in CBF that may cause ischemic injury 9.
TCD can be used to identifying vessel occlusions and to monitor stroke’s response to
treatment 10. It is also used for Microembolic signals (MES) detection 40. MES are
high-intensity transient signals detected by TCD, and have been shown to correspond
to microemboli made of air, platelet, fibrinogen, or atheromatous material 11. Their
detection is correlated with recurrent ischemic stroke in patient with acute cerebral
infarction 12. They are also used as predictors of cerebral events in patients with
symptomatic and asymptomatic carotid disease 13. As cerebral infarctions might be
caused by microemboli created in the arterial line during the ECMO support, studies
have investigated if TCD can aid in detecting microemboli arising from the ECMO
circuit 1415. In 2010, a study with 6 VA ECMO patients evaluated MES 14. Among
them, 4 had refractory postcardiotomy cardiogenic shock, and 2 were implanted
because of cardiac arrest. All patients were assisted with IABP and with continuous
renal replacement therapy. The authors reported a correlation between MES count and
high flow rate of ECMO support (≥ 4 l/min). In 2016, a largest study in 55 patients with
VA, VV ECMO, and Extracorporeal CO2 Removal (ECCO2R) had been performed,
and investigated if MES could be correlated to neurological outcome 15. In this study,
MES count was higher in VA ECMO patient than other, but no correlation was made
between MES and ECMO flow rate, or between MES and neurological outcome.

2. 4. 2. Cerebral hemorrhage
It can be difficult to distinguish between primary cerebral hemorrhage and secondary
hemorrhagic transformation after cerebral infarction, which is correlated with the size
of cerebral infarction 16.

2. 4. 2. 1. VA ECMO
In 2013, the ELSO registry reported a rate of intracranial hemorrhage of 2% in patients
undergoing VA ECMO. In 1999, a retrospective study searching for risk factors of
cerebral hemorrhage during VA ECMO reported that neither the underlying disease
nor the site of cannulation were associated with an increased risk of cerebral
hemorrhage, as well as MAP, ECMO flow rate or ECMO duration 46. In addition, there
was no evidence of an association between high Activated Clotting Time (ACT) or low
Prothrombin Time (PTT) and intracranial hemorrhage. In contrast, thrombocytopenia
<50,000 / mm3 was an independent risk factor associated with higher risk of cerebral
hemorrhage. Acute renal failure and hemodialysis were also associated with risk of
intracranial bleeding. Unexpectedly, female sex was an independent risk factor for
cerebral hemorrhage 17. A recent study in 878 VA ECMO patients has reported 2.8%
of intracranial bleeding, occurring after a median of 5 days of support 5 .Risks factors
for intracranial bleeding were female sex, central VA-ECMO and platelets < 100 giga/L
at ECMO start. Rapid CO2-level change from before-to-after ECMO start also seemed
to be associated with intracranial bleeding 5.

2. 4. 2. 2. VV ECMO
In 2013, the ELSO registry reported a higher rate of HIC in patients under VV ECMO
at 4% 18, and this number was up to 15% in a recent study with 25 patients 19. The
largest serie specifically dealing with cerebrovascular complications in VV ECMO
reported a rate of brain bleeding of 7.5% 6. In this study, the average onset of cerebral
bleeding was three days after VV ECMO implantation. Intracranial hemorrhage was
independently associated with acute renal failure upon admission to intensive care,
too-rapid correction of PaCO2 upon VV ECMO initiation, and was not associated with
patient’s age or hemostasis disorders.

2. 4. 2. 3. Pathophysiological mechanisms and TCD contribution

In the same way as for ischemic stroke, it is likely that pathophysiological mechanisms
causing cerebral bleeding are different depending on the type of ECMO.
In VA ECMO patients, sudden restoration of brain flow could lead to intracranial
edema, equivalent to cerebral hyperperfusion syndrome, leading to hemorrhagic
transformation, particularly in patients with previous ischemic stroke, similarly to what
is observed in patients undergoing carotid endarterectomy 20.
For VV ECMO, rapid correction of hypercapnia is an independent risk factor for
cerebral hemorrhage 6. Cerebral vasoconstriction induced by this too rapid decline in
PaCO2 at the initiation of VV ECMO could be responsible for cerebral edema, with
initial ischemic lesions evolving rapidly to secondary hemorrhagic transformation 9.
No study has yet investigated the usefulness of TCD to prevent and monitor
intracranial hemorrhage during VA or VV ECMO.

2. 4. 2. 4. Brain death during ECMO

Eighty-four percent of brain death cases under ECMO are directly related to pre-
ECMO factors and to cerebral edema secondary to cardiac arrest 21. Other causes
are represented by ischemic strokes or intracranial bleeding occurring during ECMO
support, representing respectively 4% and 12% of brain death during ECMO 21.
Patients on ECMO, and particularly patients implanted for refractory cardiac arrest, are
increasingly regarded as potential organ donors, but high plasma levels of sedative
drugs and hypothermia can make electroencephalogram examination unreliable, and
can delay brain death confirmation, as well as neurovascular imaging, because of the
difficulty to transport these patients to radiology. TCD could overcome all these
limitations. To confirm cerebral circulatory arrest with TCD, several patterns are
mandatory, such as reverberating flow, systolic spikes, and absence of signal, while
mean flow velocity value detection is not required 22.
In 2018, a retrospective analysis has been performed in 25 patients (20 VA ECMO and
5 CPB), to evaluate the feasibility of cerebral circulatory arrest diagnosis by TCD
during the circulatory support 23. Indeed, TCD is a worldwide accepted technique for
cerebral circulatory arrest diagnosis for brain death confirmation 24. In that study, brain
death occurred in 5 patients. Those patients with VA ECMO were either assisted with
IABP, or had LVEF higher than 20%. TCD brain death patterns were found in all 5
patients. The lack of brain dead patients without IABP or with very low cardiac output
in this study is highlighted by their authors as a major limitation to conclude whether
TCD can be used to confirm cerebral circulatory arrest in patients with laminar,
nonpulsatile arterial flow.

2. 4. 3. Practical considerations and limitations

The specific management of cerebrovascular complications remains the same as that
of brain-damaged patients 25. However, patients’ evolution on ECMO support includes
events that impose several constraints, for example on patients’ coagulation and
oxygenation state, thus limiting specific therapeutic possibilities of cerebrovascular
complications. Even if TCD is a practical tool to monitor cerebral hemodynamics state
in patients on ECMO support, the therapeutic impact of TCD monitoring can be limited
due to the many restrictions imposed by this circulatory device. Indeed, the
heterogeneity of patients under ECMO requires individualized therapeutic strategies
concerning ECMO flow rate or IABP use, which can rely on extra-neurological failures.
In the following paragraphs, we will exemplify two situations were TCD findings should
not be followed by circulatory device support parameters changes.

2. 4. 3. 1. VA ECMO
IABP is often added to VA ECMO, particularly in non-pulsatile patient with very low
LVEF, in order to off-load the left ventricle and to protect against hydrostatic pulmonary
edema 26. TCD has shown that in this subpopulation, IABP activation decreases CBF
due to transient end-diastolic reversal of intracranial blood flow during the diastolic
inflation of the IABP 27. Common sense should therefore avoid this device in patients
with cardiac stun, but without IABP the probability that those VA ECMO patients
develop severe hydrostatic pulmonary edema and ARDS is high. During the cardiac
recovery process on ECMO, the heart might eject desaturated blood from the left
ventricle, and evolved toward “Harlequin syndrome” 28 which is deleterious for the
brain, and might be responsible for hypoxic-ischemic encephalopathy. Therefore, IABP
should be added in those VA ECMO patients with cardiac stun, even if it results in CBF
reduction.

2. 4. 3. 2. VV ECMO
Some ARDS patients develop severe hypercapnia with respiratory acidosis, and
consequently, display cerebral vasodilatation patterns and decreased CBF on TCD
monitoring 29. After VV ECMO cannulation, common sense would tend to restore
normal PaCO2 in order to restore physiological pH and normal CBF but intracranial
bleeding is the most frequent cerebrovascular complication during VV ECMO,
associated with rapid hypercapnia correction due to too-high extracorporeal gas flow
on the circuit after cannulation 6. Therefore, hypercapnia after cannulation should be
respected within the first hours of VV ECMO, even if TCD shows vasodilatation pattern
with a decreased CBF.
  Note

TCCS/ TCD is a good tool to assess cerebral circulatory arrest during ECMO,
but only in patients with LVEF higher than 20%.

In text References

2. 5. Conclusion
TCD studies of patient undergoing ECMO are useful, however, due to lack of evidence
regarding TCD’s usefulness during extra circulatory report, it is not yet recommended
as a regular and systematic monitoring tool during the follow-up of those patients for
early detection or specific care of ECMO-induced neurological complications.
TCD can represent a useful bedside tool to detect cerebral hemodynamic changes in
real-time in sedated and critically ill patients, in which clinical examination can hardly
diagnose neurological complications. Indeed, some medical centers, as “Baylor St.
Luke's Medical Center” in Houston (Texas, United-State) have established a
neuromonitoring protocol for patients on ECMO support, in which daily TCDs are
performed (Kazmi et al. 2018).

 References
Kazmi SO, Sivakumar S, Karakitsos D, Alharthy A, Lazaridis C., Cerebral
Pathophysiology in Extracorporeal Membrane Oxygenation: Pitfalls in Daily
Clinical Management., 2018, PMID:29744226

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