**6. Neurological monitoring**

There are currently no consensus guidelines for neuromonitoring on ECMO, with variations in practice at different institutions. Neuromonitoring may include assessment of brain structure or morphology via imaging, assessment of brain function via EEG or SSEPs, assessment of cerebral perfusion via cerebral oximetry or transcranial doppler, and assessment for neurological injury via biomarkers. Bembea and colleagues performed a systematic review of the literature; 39 observational and case-control studies met inclusion criteria, with most of the literature coming from neonatal studies [52]. There was very little data in pediatric and adult cohorts, and the study found limited data on the use and effectiveness of monitoring technologies. A recent review by Lin et al. discusses neuromonitoring in the neonatal ECMO patient [53].

#### **6.1 Exam**

Neuromonitoring of the ECMO patient should begin with daily neurologic assessments that are documented in the patients chart. These are limited by reliability when performed by multiple providers from different disciplines, however are useful for obtaining a daily baseline that can be suggestive of injury when a change is noted. This would also require daily sedation holidays for accurate assessments as well as using the least amount of sedation to keep the patient safe and comfortable. Use of neuromuscular blockade should be reserved for extremely ill patients and those whose movement limits ECMO flows. A change in neurologic exam is often the trigger for seeking additional information such as through neuroimaging.

#### **6.2 Neuroimaging**

Cranial or head ultrasound (HUS) is a mode of imaging limited to neonates and infants with open fontanelles. Ultrasound uses high frequency sound waves transmitted via a probe that are reflected back based on the tissue's composition as well as distance from the probe. Changes in tissue density from hemorrhage or ischemia will reflect back sound waves differently from surrounding tissue. Cranial ultrasounds are portable, easy to use, relatively inexpensive, and do not carry radiation risks. Most neonatal ECMO programs will obtain a HUS prior to ECMO cannulation as well as daily HUS for the 1st few days on ECMO. While it is best for detecting hemorrhages, ischemic changes are harder to interpret on HUS [54]. HUS can also give information on changes in ventricular size that would be seen in hydrocephalus. It is not as sensitive as other imaging techniques and a study showed that MRI was significantly more sensitive for detection of CNS lesions than HUS alone [55, 56]. The quality of images depends on the skill level of the ultrasound technician and interpretation of acquired images can be subjective and variable. HUS findings have not consistently correlated with neurodevelopmental outcomes and should not be used for predicting outcomes in neonatal ECMO survivors [37, 56].

**209**

*Neurologic Complications and Neuromonitoring on ECMO*

Computed tomography (CT) is a diagnostic imaging modality that utilizes X-Rays directed at the patient that are picked up by a detector and sent to a computer to create thin 2D image slices, at different tissue depths. Multiple images can then be stacked to create a 3D picture. It is the most frequently used imaging modality for diagnosis of acute intracranial injury for patients on ECMO. A CT scan can be quickly obtained and has better sensitivity and specificity for detecting intracranial hemorrhage that might lead to clinical changes in management [53]. A disadvantage is exposure to radiation and its associated risks. Transporting a patient on ECMO to a CT scanner in the radiology department can be challenging in the absence of a portable scanner that can be brought to bedside. ELSO currently recommends a CT scan prior to hospital discharge for patients less than 4 years of age and if there is an abnormal neurologic exam for patients older than 4 years of age as part of post-ECMO follow up [57]. Magnetic Resonance Imaging (MRI) is a non-invasive technology that creates 3D anatomic images without exposing the patient to radiation. A strong magnetic field is used to force protons in the body into alignment. Then a brief radiofrequency pulse stimulates protons causing a change in alignment. The scanner can detect electromagnetic energy transmitted as the protons realign. It is reserved for patients after decannulation from ECMO, due to MRI incompatible materials in the cannulae and circuits. MRI is the most sensitive and specific imaging technique available. However it takes much longer time to obtain the study compared to a CT and is more expensive. While diffusion-restriction can be seen up to 10 days after acute ischemic injury, the optimal timing for obtaining an MRI after ECMO remains unclear [53].

While neuroimaging provides information on the structure of the brain, EEG provides real-time information on the electrical activity of the brain. Information is obtained via electrodes placed on the scalp, connected to a monitor, with very little burden to the patient that would include scalp abrasions. Continuous EEG (cEEG) monitoring requires technicians to set up the electrodes as well as neurologists to read the EEGs, which can be time consuming. Amplitude-integrated EEG (aEEG) compresses the raw EEG data from 1 to 2 leads, is easier to set up and interpret, but due to lower sensitivity, can be used as a screening tool or in resource limited settings [53]. Ischemic and hemorrhagic injuries can predispose a patient to seizures that require prompt treatment. Continuous EEG monitoring is important for early identification and treatment of subclinical seizures or electrical status epilepticus that may not be otherwise detected, although studies are needed to show its benefit in improving long term outcomes. EEG monitoring is especially useful in paralyzed patients in whom a neurological exam cannot be elicited. EEG can be used to detect early cerebral ischemia through loss of fast alpha and beta frequencies to slowing and even suppression of all electrical activity as might be seen in an infarct. In 2011, the American Clinical Neurophysiology Society deemed ECMO as a high risk clinical scenario in neonates that would warrant long term EEG monitoring due to cardiac or pulmonary risks for acute brain injury and clinical encephalopathy [58]. This recommendation is supported by ELSO in their guidelines for management of neonatal respiratory failure [59]. In their 2015 consensus statement on continuous EEG in critically ill adults and children, the American Clinical Neurophysiology Society recommended continuous EEG monitoring for patients treated with pharmacologic paralysis, including patients on ECMO [60].

This is a non-invasive, portable test that is based on the Doppler effect. A Doppler probe is used to emit high frequency sound waves through the cranium that are reflected

*DOI: http://dx.doi.org/10.5772/intechopen.85103*

**6.3 Electroencephalography (EEG)**

**6.4 Transcranial doppler ultrasound (TCD)**

*Advances in Extracorporeal Membrane Oxygenation - Volume 3*

**6. Neurological monitoring**

neonatal ECMO patient [53].

**6.1 Exam**

**6.2 Neuroimaging**

gas is decreased to 0.5 –1 L/minute and oxygen increased to 100% FiO2 through the circuit, without any changes to extracorporeal blood flow [50, 51]. In-line gas monitoring on the ECMO circuit can be used to trend venous paCO2, but serial arterial blood gas analysis should be used to confirm the lack of ventilation secondary to central apnea. For patients on VA ECMO, hemodynamics should be maintained through circuit flows and use of vasoactive medications as needed. Patients found to

There are currently no consensus guidelines for neuromonitoring on ECMO, with variations in practice at different institutions. Neuromonitoring may include assessment of brain structure or morphology via imaging, assessment of brain function via EEG or SSEPs, assessment of cerebral perfusion via cerebral oximetry or transcranial doppler, and assessment for neurological injury via biomarkers. Bembea and colleagues performed a systematic review of the literature; 39 observational and case-control studies met inclusion criteria, with most of the literature coming from neonatal studies [52]. There was very little data in pediatric and adult cohorts, and the study found limited data on the use and effectiveness of monitoring technologies. A recent review by Lin et al. discusses neuromonitoring in the

Neuromonitoring of the ECMO patient should begin with daily neurologic assessments that are documented in the patients chart. These are limited by reliability when performed by multiple providers from different disciplines, however are useful for obtaining a daily baseline that can be suggestive of injury when a change is noted. This would also require daily sedation holidays for accurate assessments as well as using the least amount of sedation to keep the patient safe and comfortable. Use of neuromuscular blockade should be reserved for extremely ill patients and those whose movement limits ECMO flows. A change in neurologic exam is often the trigger for seeking additional information such as through neuroimaging.

Cranial or head ultrasound (HUS) is a mode of imaging limited to neonates and infants with open fontanelles. Ultrasound uses high frequency sound waves transmitted via a probe that are reflected back based on the tissue's composition as well as distance from the probe. Changes in tissue density from hemorrhage or ischemia will reflect back sound waves differently from surrounding tissue. Cranial ultrasounds are portable, easy to use, relatively inexpensive, and do not carry radiation risks. Most neonatal ECMO programs will obtain a HUS prior to ECMO cannulation as well as daily HUS for the 1st few days on ECMO. While it is best for detecting hemorrhages, ischemic changes are harder to interpret on HUS [54]. HUS can also give information on changes in ventricular size that would be seen in hydrocephalus. It is not as sensitive as other imaging techniques and a study showed that MRI was significantly more sensitive for detection of CNS lesions than HUS alone [55, 56]. The quality of images depends on the skill level of the ultrasound technician and interpretation of acquired images can be subjective and variable. HUS findings have not consistently correlated with neurodevelopmental outcomes and should not

be used for predicting outcomes in neonatal ECMO survivors [37, 56].

be brain dead on ECMO can be considered as candidates for organ donation.

**208**

Computed tomography (CT) is a diagnostic imaging modality that utilizes X-Rays directed at the patient that are picked up by a detector and sent to a computer to create thin 2D image slices, at different tissue depths. Multiple images can then be stacked to create a 3D picture. It is the most frequently used imaging modality for diagnosis of acute intracranial injury for patients on ECMO. A CT scan can be quickly obtained and has better sensitivity and specificity for detecting intracranial hemorrhage that might lead to clinical changes in management [53]. A disadvantage is exposure to radiation and its associated risks. Transporting a patient on ECMO to a CT scanner in the radiology department can be challenging in the absence of a portable scanner that can be brought to bedside. ELSO currently recommends a CT scan prior to hospital discharge for patients less than 4 years of age and if there is an abnormal neurologic exam for patients older than 4 years of age as part of post-ECMO follow up [57].

Magnetic Resonance Imaging (MRI) is a non-invasive technology that creates 3D anatomic images without exposing the patient to radiation. A strong magnetic field is used to force protons in the body into alignment. Then a brief radiofrequency pulse stimulates protons causing a change in alignment. The scanner can detect electromagnetic energy transmitted as the protons realign. It is reserved for patients after decannulation from ECMO, due to MRI incompatible materials in the cannulae and circuits. MRI is the most sensitive and specific imaging technique available. However it takes much longer time to obtain the study compared to a CT and is more expensive. While diffusion-restriction can be seen up to 10 days after acute ischemic injury, the optimal timing for obtaining an MRI after ECMO remains unclear [53].

### **6.3 Electroencephalography (EEG)**

While neuroimaging provides information on the structure of the brain, EEG provides real-time information on the electrical activity of the brain. Information is obtained via electrodes placed on the scalp, connected to a monitor, with very little burden to the patient that would include scalp abrasions. Continuous EEG (cEEG) monitoring requires technicians to set up the electrodes as well as neurologists to read the EEGs, which can be time consuming. Amplitude-integrated EEG (aEEG) compresses the raw EEG data from 1 to 2 leads, is easier to set up and interpret, but due to lower sensitivity, can be used as a screening tool or in resource limited settings [53]. Ischemic and hemorrhagic injuries can predispose a patient to seizures that require prompt treatment. Continuous EEG monitoring is important for early identification and treatment of subclinical seizures or electrical status epilepticus that may not be otherwise detected, although studies are needed to show its benefit in improving long term outcomes. EEG monitoring is especially useful in paralyzed patients in whom a neurological exam cannot be elicited. EEG can be used to detect early cerebral ischemia through loss of fast alpha and beta frequencies to slowing and even suppression of all electrical activity as might be seen in an infarct. In 2011, the American Clinical Neurophysiology Society deemed ECMO as a high risk clinical scenario in neonates that would warrant long term EEG monitoring due to cardiac or pulmonary risks for acute brain injury and clinical encephalopathy [58]. This recommendation is supported by ELSO in their guidelines for management of neonatal respiratory failure [59]. In their 2015 consensus statement on continuous EEG in critically ill adults and children, the American Clinical Neurophysiology Society recommended continuous EEG monitoring for patients treated with pharmacologic paralysis, including patients on ECMO [60].

### **6.4 Transcranial doppler ultrasound (TCD)**

This is a non-invasive, portable test that is based on the Doppler effect. A Doppler probe is used to emit high frequency sound waves through the cranium that are reflected back by moving red blood cells in the blood vessels. The difference in frequencies of emitted and reflected waves is proportional to the cerebral blood flow. Studies have found that TCD velocities (TCDV) are much lower for pediatric patients on ECMO when compared to normative values for healthy and critically-ill children [15, 61]. While there was no significant association between global TCDV (systolic flow velocity, diastolic flow velocity, mean flow velocity) and neurologic injury, increased pulsatility index and regional increases in velocities or asymmetries might be predictive of neurologic injury.

#### **6.5 Cerebral near infra-red spectroscopy (NIRS)**

NIRS monitoring is a non-invasive technology that uses near-infrared wavelength of light that penetrates brain tissue via a scalp electrode. It provides a continuous measurement of regional tissue oxygen saturation (rSO2), which is a marker of the balance between oxygen delivery and demand in the tissues. When the probe is placed on the forehead, it measures cerebral oximetry. An analysis of adult patients on VA ECMO showed that cerebral desaturation was common and mortality higher for patients with cerebral desaturation compared to those without [21]. A sudden decrease in cerebral saturation can be associated with an acute neurological event, prompting further investigation. It can also serve as an early predictor of inadequate oxygenation and cardiac output especially peri-cannulation [62]. It can influence management by prompting a need for increased flows in VA ECMO or alternate cannulation strategies if there is differential hypoxia. A very high rSO2 could also be suggestive of very poor oxygen extraction and poor neurologic outcomes.

#### **6.6 Biomarkers**

Several plasma proteins have been evaluated as potential markers for brain injury [63]. These biomarkers include substances associated with glial injury (glial fibrillary acidic protein and s-100b), neuronal injury (neuron-specific enolase and brain-derived neurotrophic factor) and neuro-inflammation (intercellular adhesion molecue-5). Unfavorable neurologic outcomes have been associated with higher biomarker concentrations [64], with combinations of biomarkers providing higher sensitivities and specificities for detection of neurologic injury. These tests are more expensive and require laboratory equipment and processing availability. While not currently a routine component of neuromonitoring on ECMO in most institutions, there is potential for further research and applicability if these results can be obtained in real time to influence management.

#### **6.7 Somato-sensory evoked potentials (SSEPs)**

SSEPs measure electrical signals in the somatosensory cortex after a peripheral stimulus, assessing the pathway of neuronal conduction from the peripheral nerve to the cortex. They are assessed as normal, abnormal (increased latency) or absent. ECMO cannulation is not thought to alter the ability to assess SSEPs from the hemispheres [65]. Small studies have shown an association between abnormal SSEPs and poor neurologic outcome after ECMO [66], but the predictive value of evoked potentials remains to be determined. In one study, absence of bilateral SSEPs was associated with progression to brain death for patients treated with ECPR [67].

#### **6.8 Optic nerve sheath diameter (ONSD)**

It is a simple bedside test used to detect elevated intracranial pressure. A cut-off of 5.2 mm is sensitive and specific for intracranial hypertension [68]. Its use in

**211**

provided the original work is properly cited.

\*Address all correspondence to: vlpinto@bcm.edu

*Neurologic Complications and Neuromonitoring on ECMO*

ECMO management is still in its infancy, although a study showed that higher ONSD was associated with poor neurological outcome after ECPR [69].

Therapeutic hypothermia has been shown to be neuroprotective for term neonates at risk of hypoxic ischemic encephalopathy secondary to perinatal asphyxia. However a randomized controlled study out of the United Kingdom did not show an improvement in outcomes for neonates on ECMO treated with mild hypothermia [70]. On the other hand, therapeutic hypothermia has been associated as a risk factor for intracranial hemorrhage and should be avoided [30]. In 2015, the American Heart Association recommended targeted temperature management of 32–36°C for comatose patients with return of spontaneous circulation after cardiac arrest [71]. This was also applied to patients who suffered in- hospital cardiac arrest leading to ECPR. A more recent large, multicenter, randomized control trial failed to show a benefit in survival with favorable neurological outcome for children with in-hospital cardiac arrest. There is no data to support routine therapeutic hypothermia for children undergoing ECPR although maintaining normothermia is still encouraged.

Neurologic complications contribute to significant morbidity and mortality for patients on ECMO, who constitute a high risk population. There are many modalities currently available for neuromonitoring, and as we gain more experience and information through more frequent use, we will be able to develop consensus guidelines and protocols to provide better care. A multimodal approach to active surveillance, early recognition and prompt management of neurologic injuries as

they arise, may improve outcomes for patients on ECMO.

The author has no "conflict of interest" to disclose.

*DOI: http://dx.doi.org/10.5772/intechopen.85103*

**7. Therapeutic hypothermia**

**8. Conclusion**

**Conflict of interest**

**Author details**

Venessa Lynn Pinto

© 2019 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium,

Texas Children's Hospital and Baylor College of Medicine, Houston, Texas, USA

ECMO management is still in its infancy, although a study showed that higher ONSD was associated with poor neurological outcome after ECPR [69].
