Elsevier Editorial System(tm) for Journal of

Cardiothoracic and Vascular Anesthesia

Manuscript Draft

Manuscript Number: JCVA-D-12-00329R1

Title: Intraoperative Electrophysiologic Monitoring In Aortic Surgery

Article Type: Review Article

Keywords: Thoracic Aortic Aneurysms; Somatosensory Evoked Potentials;

Motor evoked potentials; Spinal cord ischemia

Corresponding Author: Dr. Tod Sloan,

Corresponding Author's Institution: University of Colorado School of

Medicine

First Author: Tod Sloan

Order of Authors: Tod Sloan; Harvey Edmonds, Ph.D.; Antoun Koht, M.D.

Joel A. Kaplan, M.D. Editor in Chief Journal of Cardiothoracic and Vascular Anesthesia Ref.: Ms. No. JCVA-D-12-00329 Perioperative Electrophysiologic Monitoring during Aortic Surgery Dear Dr. Kaplan, Thank you for considering our paper for publication in the JOURNAL OF CARDIOTHORACIC AND VASCULAR ANESTHESIA. We are pleased to offer this revision with the changes suggested by your reviewers. I have detailed our changes to each of the reviewers below. I believe you will find this paper strengthened by their comments and will appreciate your consideration for publication. We look forward to your response. Sincerely, Tod Sloan

*Cover Letter

Response to Reviewers Comments: Overall comments. We have tightened the organization based on the comments of several reviewers, especially Reviewer 2. We have changed the title to reflect a focus on intraoperative electrophysiological techniques and have removed the discussion of non-electrophysiological techniques (e.g. TCD, cerebral oximetry) which could be a review in a future paper. We have added the citations suggested by the reviewers to strengthen and highlight the issues they raise. I have detailed these additions below. Response to specific reviewer comments. I must note that since we have reorganized the paper (suggestion of several reviewers, especially Reviewer 2), some of the comments and responses no longer occur on the original page numbers. If the reviewers would like a more detailed map of the suggested changes we will be glad to provide this. Changes from Reviewer #1:

1) We appreciate the comments regarding the notation that the only Class I recommendation at present for spinal cord protection in patients at high risk of spinal cord ischemic injury undergoing open or endovascular thoracic aortic repair is cerebrospinal fluid drainage. We have explicitly stated in the manuscript that while there is a role for neurophysiological monitoring of the spinal cord, CSF drainage is a Class I indication, while neurophysiological monitoring is a class IIb indication.

2) In addition we have commented that the use of neurophysiological monitoring of the spinal cord to detect spinal cord ischemia and to guide reimplantation of intercostal arteries is a Class IIb Indication.

3) The suggested reference regarding these indications has been added. 4) We have also stated that CSF drainage combined with neurophysiologic

monitoring can make a very effective preventative and therapeutic management strategy; we have indicated that CSF drainage is most effective when combined with neurophysiologic monitoring.

5) We have also indicated that the added reference (noted in 3 above) provides IIb indication use of neurophysiological monitoring of the spinal cord (somatosensory evoked potentials or motor evoked potentials) as a strategy to detect spinal cord ischemia and to guide reimplantation of intercostal arteries and/or hemodynamic optimization to prevent or treat spinal cord ischemia.

6) We have changed Page 2 as suggested in the last paragraph, first sentence: Change to ".warn of brain ischemia."

7) We have added a couple of sentences with respect to pharmacological protection of the brain with respect to DHCA to strengthen the manuscript (i.e., stating how drugs can possibly be used to further protect against brain ischemia along with monitoring).

8) We have corrected the double periods on Page 9, first paragraph, last sentence.

Changes from Reviewer #2:

*Revision Notes

1) As suggested, we have tightened the focus and organization by changing the title to “Intraoperative Electrophysiologic Monitoring in Aortic Surgery” and removed the discussion and key words relating to Transcranial Doppler and Near Infrared Spectroscopy.

2) Further, as suggested, we have reorganized the manuscript by first discussing the relevant anatomy and physiology of the spinal cord and brain and noting where there are similarities and differences. This paper then follows with a clear description of the EEG, SSEP and MEP including the advantages or disadvantages of one over the other, and their anesthetic implications. We have included here the importance of synapses in the neural pathways for specific monitoring modalities.

3) Finally, we have presented the use of these modalities for the different clinical scenarios.

4) More specifically, I have included that simply reducing metabolism as important aspect of neural protection is dated. As suggested we have included that most would likely regard the reduction in metabolism as being secondary to some of the same receptor mediated neuroprotective effects rather than the primary effector. We referenced the work of Warner showed that in rodents maximal metabolic suppression as evidenced by EEG suppression did not result in better neurological outcomes than a lighter level of anesthesia. We utilized the suggestion that "...guiding the techniques, which can improve blood flow or alter other mechanisms to decrease..."

5) We have clarified that the spinal cord may not have the same ischemic thresholds as the brain and that huge inter-individual variations may make the numbers indicated may not be applicable for a given individual.

6) We have clarified the use of the term SSEP, specifically clarifying when the discussion regards the cortically measured response and other responses by using the term “cortical-SSEP”. Similarly we have used the term “muscle-MEP” to clarify when we were referring to the measurement of muscle responses to transcranial motor evoked potentials.

7) We have clarified the comment on Page 4 about the MEP and its utilization when most useful intracranially when end-arteries with no collaterals e.g. lenticulostriate are at risk. We have also clarified the relative value of SSEP and MEP when more global areas are at risk and that the MEP makes anesthetic management harder.

8) We have specified which monitors were used in the study with 1,721 CPB patients.

9) We have emphasized why synapses are important. 10) We have explained the comment that "the risk is central to the spinal

cord"? 11) We have removed the comment about spinal cord injury occurring during

coronary artery bypass surgery since it does not specifically relate to aortic surgery.

12) We have rewritten the sentence which includes “Hence, it is beneficial....benefits".

13) We have discussed the issue of percent change for SSEP that reflects danger, but that a similar rule for MEP has not been clarified due to substantial amplitude variability. We have included this in the further work to be done as suggested by reviewer (below).

14) We have amplified and clarified the last paragraph previously located on Page 11.

15) We have been more specific about the use of muscle relaxants during these cases with avoidance when possible, or by infusion and fixed degree of paralysis maintained constant when necessary.

16) We have noted the effects of temperature and anemia on evoked potentials.

17) We have included comments about the methods using IOM to identify the critical arteries needing reimplantation (previously on Page 13).

18) We have commented on the loss of SSEP and MEP due to vascular access and their subsequent utilization for monitoring in these cases.

Changes from Reviewer #3:

1) As above, we have changed the title and focus to intraoperative electrophysiologic monitoring

2) We have changed the abbreviation for thoracoabdominal aortic aneurysms to TAAA from TAA.

3) A reference has been added for the last statement of the introduction. 4) As commented by the other reviewers, we have focused on

electrophysiological techniques and have removed the discussion of the utility of cerebral oximetry in retrograde cerebral perfusion.

5) We have included references for the discussion on CSF monitoring which include the original studies that demonstrate the utility of this modality (i.e. Safi et al.) and what pressures have been recommended.

6) In the discussion on MEPs we have included references to the various studies by Safi and Estrera on the predictive properties of MEPs.

7) As suggested by the reviewers above we have added a section on the effect of anesthetic agents on SSEPS and MEPs.

8) In the conclusion we have emphasized the fact that there should be a synergy of effort by the surgical team when MEPS and/or SSEPs are lost. (i.e. decrease CSF pressure, increased perfusion pressure, reanastomosis of intercostals. etc.)

9) In the conclusion we have mentioned some research that is still needed. Changes from Reviewer #5:

1) We have changed the title as suggested to Intraoperative electrophysiological monitoring … (as also suggested by other reviewers).

2) We have eliminated the reference to D and I waves in the paragraph which outlines the motor pathways since these are not used clinically in this application.

3) We have expanded the conclusion using some of the suggestions of the other reviewers, in particular the mention of pros and cons of using this monitoring.

Changes from Reviewer #6:

1) We have included the comments that excellent outcome has been seen without cerebral monitoring (and suggested references included). As noted above by the suggestions of other reviewers, references to TCD and cerebral oximetry have been removed.

2) The pros and cons related to this have been included in the conclusion. (Gega A et al. Ann Thorac Surg. 2007:84:759-67), (Percy A et al. Ann Thorac Surg.2009;87:117-23).

3) We have attempted to improve the balanced view of the use of these techniques by including the suggested comments about the response to MEP deterioration and the use of other techniques which are commonly done (“All centers use adjunctive perfusion, some hypothermia, spinal fluid drainage, and efficient conduct of anatomizes. Many centers use spinal artery visualization (pre-op) with reimplantation when subtended in the resection”). We have discussed that there may be nothing more to do even if MEP signals fail. As indicated in clinical publications some authors indicate an increase in distal flow or an additional reimplantation may be done and prove beneficial. We have emphasized that the use of monitoring and the response to changes is still a learning process to keep the presentation balanced.

4) We have expanded the section of the use of muscle relaxants to include comments about the problems with paralysis and the utility of MEP monitoring.

5) We have included the problem of false positives and false negatives which do occur and are incompletely understood in the discussion.

6) We have referenced the debate on the merits/demerits of spinal cord monitoring, which recently appeared in Cardiology Clinics (Vol 28, 2010), which can give the interested reader access to additional information on both sides of the monitoring issue.

1

Intraoperative Electrophysiologic Monitoring In Aortic Surgery

Tod B. Sloan MD MBA PhDa, Harvey L. Edmonds, Jr., PhDb, Antoun Koht, MDc

a Professor, Department of Anesthesiology, University of Colorado School of Medicine b Emeritus Research Professor, Department of Anesthesiology and Perioperative Medicine,

University of Louisville School of Medicine c Professor of Anesthesiology, Neurological Surgery and Neurology Departments of

Anesthesiology, Neurological Surgery and Neurology, Northwestern University

Address for correspondence:

Tod B. Sloan MD MBA PhD Professor of Anesthesiology University of Colorado School of Medicine Department of Anesthesiology, Academic Office West (AO1), MS 8202 12631 E 17th Avenue, Aurora, Colorado 80045 Email: Tod. Sloan@ucdenver. edu

Keywords: Thoracic Aortic Aneurysms, Somatosensory Evoked Potentials, Motor evoked potentials, Spinal cord ischemia

*Title Page (complete with Author details)

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Introduction

Intraoperative monitoring (IOM) has been used to reduce cerebral and spinal cord injury

during repair of thoraco-abdominal aorta aneurysms (TAAA). The risks of cerebral injury when the

ascending aorta is repaired and of paraplegia when the descending thoracic aorta is involved have

prompted the application of numerous techniques to measure blood flow, assess the balance of

blood flow and metabolism, or warn of ischemia to prompt corrective measures.1, 2 The

neurological risk varies with the portion and length of the aorta that is diseased; the highest risk

occurs with Crawford types I and II because both include part of the ascending and the entire

descending thoracic aorta.3

The most common mechanism of central nervous system (CNS) injury during these

procedures is ischemia caused by inadequate arterial perfusion and embolic phenomena. The

importance of adequate blood flow to alter the risk of CNS injury is shown in Figure 1. In the brain,

as cerebral blood flow falls below an ischemic threshold, the time to infarction decreases.4-6 For

example, cell death may occur after 3-4 hours when the perfusion is just below the ischemic

threshold with normal metabolism. Infarction occurs at shorter periods of time as the flow is

further lowered and or metabolism increased; with no perfusion and normal metabolism, cell

death occurs in a very short interval (3-5 minutes). The times and flows in Figure 1 are average

values and vary among individuals; however, the general concept of the loss of electrophysiology

being an early warning sign and that time becomes a critical element when flow is reduced

remains. The concepts also apply to the spinal cord; however the values are not well-characterized.

Hence, during ischemia, an increase in blood flow increases the margin of safety by extending the

allowable ischemic time to complete the procedure.

*Revised Manuscript

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With surgery to repair the ascending, transverse, or descending aortic arch, monitoring is

used to identify the onset of global or focal hypoperfusion in the brain and spinal cord to allow

correction of the cause (e.g. hypotension, mechanical blood flow compromises) and to evaluate the

effectiveness of corrective maneuvers (e.g. raising blood pressure). Failure to correct the blood

flow may result in stroke in as many as 12% of patients.7 Embolic phenomena may also occur which

can contribute to stroke, either by interrupting blood flow or aggravating hypoperfusion (which

may also reduce the clearance of particulates or gas bubbles).8, 9 With surgery on the descending

aorta the concern for CNS injury shifts to concerns for paraplegia from spinal cord ischemia. The

incidence of immediate and late post-operative paraplegia ranges from 2.7- 5.3%, which is higher in

redo operations (as high as 10.7%).10, 11 The application of these IOM techniques rests on their

anatomic location in the CNS and their sensitivity to ischemia.

The importance of a method to identify spinal cord ischemia with surgery on TAAA is

enhanced because the vascular anatomy is altered by the disease process. With TAAA, patients

frequently develop collateral circulation to supplement blood flow as arteries are occluded by

mural thrombi, arterial plaques or aortic flaps. The specific vascularity for each patient is not known

and the perfusion of the spinal cord behaves as a meshwork that receives perfusion from proximal

(e.g. subclavian artery), distal (e.g. internal iliac, hypogastric artery), and aortic sources (radicular

arteries including the artery of Adamkiewicz, ARM).12 Since patients vary in their dependency on

each of these components, monitoring can be helpful to determine the critical contribution of the

cephalad, aortic radicular arteries, and lumbar/pelvic vascularity for each patient. Some patients

will be dependent on adequate pressure in a distal bypass perfusion,13, 14 while others will require

reimplantation of intercostal radicular perforators from the aorta.13, 15-19

The value of electrophysiological monitoring is also shown in Figure 1 where the alteration

in cortical electrical activity accompanies the decline in cerebral blood flow that precedes the risk

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of neurological injury. As depicted, cerebral blood flow can be reduced from normal (50

cc/min/100gm.) to about 44% (22 cc/min/100gm) while maintaining normal electrical activity.

Below this level hypoperfusion occurs and electrical activity is altered. When blood flow reaches

about 15 cc/min/100 gm., the ischemic threshold is reached and normal neural synaptic activity

ceases (i.e. electrical activity is lost).4

Techniques of Electrophysiologic Monitoring and Anesthesia Implications

Monitoring for ischemia occurring in the brain during aortic surgery can be done with the

electroencephalogram (EEG) or evoked potentials. The EEG is useful to warn of ischemia because it

is produced by the synaptic activity of the cortex which is very sensitive to ischemia (EEG loss

occurs within 20-30 seconds of the cessation of cortical blood flow). As shown in Figure 1, the

alteration and loss of EEG activity correlates with the onset of the risk for neurological injury and is

the basis for its use in carotid endarterectomy. As with all of the electrophysiological techniques,

anesthetic agents and physiological changes (such as hypothermia) can alter the synaptic function

leading to EEG changes.20 Fortunately, except for higher doses of most anesthetics which depress

EEG activity (usually 1-1 ½ minimal alveolar concentration of inhalational anesthetics, MAC), the

EEG is usually well-maintained with the usual medications for general anesthesia. A few agents

(e.g. etomidate, ketamine) can increase EEG activity but are not usually used for this reason. As

such, the electroencephalogram (EEG) can be used to warn of brain ischemia with aorta surgery

when there is a shift to slow frequencies or significant loss of amplitude.

The SSEP can be used to monitor the brain and spinal cord because its neural pathway

traverses these regions. The SSEP is produced in response to electrical stimulation of large, mixed

motor and sensory peripheral nerves at the wrist (median n., ulnar n.) and ankle (posterior tibial

n.). (Figure 2) The response follows the pathway of proprioception and vibration that enters the

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spinal cord via the posterior nerve roots and ascends in the ipsilateral dorsal column. It makes its

first synapse near the nucleatus cuneatus and nucleatus gracillis, crosses the midline near the

cervico-medullary junction, ascending through the brainstem via the contralateral medial

lemniscus. It makes a second synapse in the ventro-postero-lateral nucleus of the thalamus and

then continues to the sensory cortex. The most commonly recorded response is that of the sensory

cortex (cortical-SSEP). However, the response can be recorded at many points along the pathway

including over the peripheral nerves, lumbar or brachial plexus (such as Erb’s point), and spinal

cord (commonly over the posterior cervical spine called the subcortical response).21

Because of the dependence on cortical synapses, the cortical-SSEP is a good monitor for

regional cerebral ischemia and indirectly indicates the level of perfusion in the middle cerebral

arteries (upper extremity cortical-SSEP) and anterior cerebral arteries (lower extremity cortical-

SSEP).21 Although white matter signal conduction is less affected by ischemia than synaptic

transmission, SSEP cortical response suppression will still occur. Thus, the cortical-SSEP has also

been used to warn of ischemia in the somatosensory pathway in the brainstem and spinal cord

(e.g. ischemia in the dorsal columns served by the posterior spinal arteries). The peripheral nerves

of the SSEP pathway are even less sensitive to ischemia but remain useful to monitor for impending

peripheral nerve injury such as with cardio-thoracic surgery where the risk of brachial plexus injury

is 1.5% to 24%.22-26 The differences in sensitivity to ischemia are listed in Table 1. When the

cortical-SSEP is used with monitoring, loss of amplitude of 50% or more of the cortical-SSEP

suggests a significant alteration in the pathway that warrants evaluation.

Since the cortical-SSEP is produced by the synaptic activity of the sensory cortex, it is also

sensitive to anesthetic agents and with changes in physiology. However, the cortical response is

somewhat more affected by anesthetic agents than the EEG, usually allowing recording with ½ to 1

MAC of inhalational agents and the usual doses of intravenous agents. Like the EEG, the cortical-

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SSEP response is enhanced by etomidate and ketamine such that some individuals have used these

agents to improve recording in some spine cases.27 Similarly, the cortical-SSEP is sensitive to

changes in temperature, blood pressure, anemia and other physiological effects which alter

synaptic function. 28-30

The third electrophysiological technique used to warn of ischemia is the motor evoked

potential (MEP).31, 32 (Figure 2) This is produced by transcranial electrical stimulation of the motor

cortex which directly stimulates the pyramidal cells resulting in a wave of depolarization that

involves 4-5% of the cortico-spinal tract (CST). The motor pathway descends from the motor cortex,

crossing the midline in the medulla and descends in the CST of the spinal cord. The electrical

activity depolarizes the anterior horn cell resulting in activation of alpha motor neurons and of the

peripheral nerve which traverses the neuromuscular junction to produce a compound muscle

action potential (CMAP). The response is traditionally measured as the muscle response (muscle-

MEP) and it is usually monitored simultaneously in several muscles (e.g. upper and lower

extremity) with each stimulation of the motor cortex.

The primary locations of synapses in the MEP pathway are in the anterior horn cell of the

spinal cord and in the neuromuscular junction. The lack of reliance on cortical synapses makes the

MEP technique less useful than the cortical-SSEP to detect cortical ischemia except when the

ischemia involves the MEP pathway served by end-arteries with no collaterals (e.g. lenticulostriate).

However, with ischemia in the spinal cord in the anterior spinal artery territory, the presence of

synapses in the grey matter makes the muscle-MEP response more sensitive than the cortical-SSEP

which does not have synapses in the spinal cord. With spinal cord ischemia not involving the grey

matter, the muscle-MEP will be similarly sensitive to anterior spinal artery ischemia as the cortical-

SSEP is to white matter ischemia in the posterior spinal arteries.32-39 (Table 1) Since the white

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matter tracts are located in different vascular territories, differences in sensitivity to ischemia will

also occur with differences in anterior versus posterior artery ischemia.

Also similar to the cortical-SSEP, the muscle-MEP will detect ischemia of the peripheral

nerve or muscle such as when the blood supply is interrupted (such as with placement of vascular

cannulas). Because of substantial normal muscle-MEP amplitude variability, a percentage loss of

muscle-MEP amplitude has not been identified like that for the cortical-SSEP. However, near or

complete loss of the muscle-MEP responses or a significant increase in the transcranial voltage

necessary to elicit the response suggests ischemia in the brain, brainstem, spinal cord, or peripheral

nerve.

Unfortunately, the MEP technique is more sensitive to anesthetic medications than the EEG

or cortical-SSEP (notably with respect to neuromuscular blockade and the use of inhalational

anesthetic agents).40 For comparison, muscle-MEP monitoring may require that the use of

inhalational anesthetics be restricted to less than ½ MAC and general anesthesia using only

intravenous infusions of anesthetics (opioids and sedatives) are often required.29, 41 Further, the

muscle-MEP response can be eliminated by neuromuscular blocking agents. Thus if neuromuscular

blocking agents are required, muscle-MEP monitoring may not be possible unless partial

neuromuscular blockade can be accomplished in a carefully controlled infusion (maintenance of at

least one response in the train-of four ).42, 43 Similar to the EEG and cortical-SSEP, etomidate and

ketamine enhance the muscle recordings but are rarely used for this purpose.44, 45 Similar to the

cortical-SSEP and EEG, the muscle-MEP is also sensitive to physiological changes such as

temperature.29 The sensitivity to anesthetic agents and physiological effects may also be the reason

that the muscle response is quite variable from trial to trial and can lead to false positive signal loss.

Monitoring During Surgery on the Aortic Arch

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During surgery on the aortic arch, these electrophysiological monitors can be used to

identify possible ischemia in the brain and guide maneuvers to improve blood flow or methods

used to decrease ischemic risk and improve neurological outcome. For example, these can guide

deep hypothermic circulatory arrest (DHCA) using cardiopulmonary bypass (CPB) to extend the

time before CNS injury occurs and minimize cerebral and spinal neurological injury. It also reduces

the enzymatic activity that is associated with ischemic cellular injury (lipases, proteases, etc.). In

addition, hypothermia generally reduces metabolism more than cerebral and spinal blood flow

such that there is excess of flow (luxury perfusion).46-48

With DHCA, a silent EEG may insure adequate cooling.49 Since the scalp EEG reflects the 40-

50% of neuronal metabolism related to electrical activity, it can be used to gauge the metabolic

suppression from hypothermia. It reflects adequate cooling because temperature alone is not

sufficient to define the appropriate endpoint.50 The cortical-SSEP can detect suppression of cortical

metabolic activity with hypothermia. Although the EEG identifies cortical ischemia (such as with

carotid endarterectomy), EEG suppression with hypothermia will prevent its use for that reason.

However, the cortical-SSEP may still be present such that it can detect ischemia in its pathway

similar to its use in carotid endarterectomy. Since many of these patients also have vascular

pathology in the carotid or intracranial arteries, cortical-SSEP monitoring improves potential

detection of ischemia in the brainstem, subcortical and cortical regions similar to its use during

intracranial vascular surgery. Similarly, the muscle-MEP can also be used to monitor for ischemia in

the cortical and subcortical ischemia along its pathway (also similar to its use in intracranial

vascular surgery).

At deep levels of hypothermia the EEG, cortical-SSEP, and muscle-MEP are less useful to

detect ischemia because the electrical activity is minimized. Other techniques such as transcranial

Doppler (TCD) or cerebral oximetry using near infrared spectroscopy (NIRS) have been used during

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DHCA. The effectiveness of these monitors during patients at risk for brain ischemia has been

shown in a study of 1,721 patients undergoing cardiac surgery with CPB. The use of IOM (EEG, TCD,

NIRS) was associated with a significantly lower incidence of perioperative major neurologic

complications (0% v 4.06%) and significantly shorter periods of mechanical ventilation and

intensive care unit stays.51 Another study demonstrated substantial reductions in length of hospital

stay, costs, and neurologic complications, with a suggestion of possible benefit to other vital organ

systems.52

A variety of pharmacological agents (including some anesthetics) have been evaluated in

order to protect the CNS from ischemia. A large number of these are based on the concept of

reduction of the neuronal metabolism via synaptic suppression which can be assessed using the

EEG. Although agents have been shown to be successful in animal models, no agents have proven

efficacious in human trials.53 Part of this lack of benefit may relate to the intrinsic loss of synaptic

activity with ischemia (likely from energy depletion); in addition, studies in animals have shown

that protection does not always correlate with metabolic suppression.54 The development of

protective agents may rest on examining agents which act by non-metabolic mechanisms thought

to be active with hypothermia (e.g. reduced glutamate release, reduced gama-amino-butyric-acid

mediated hyperpolarization, reduced calcium influx, reduced inflammation, and increased anti-

apoptotic proteins.55-58 Hence, although the EEG can be used to guide the management of

hypothermia, it does not appear at present to be an effective guide for the use of pharmacologic

agents to reduce neural risk.

Surgery on the Thoracic Aorta

The major monitoring modalities utilized on TAAA surgery are the cortical-SSEP and the

muscle-MEP since the major area at risk is the spinal cord. As above, compared to cortical-SSEP, the

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muscle-MEP has the advantage of more sensitive detection of spinal cord grey matter ischemia and

the advantage of a better correlation with postoperative motor function. The differences between

the cortical-SSEP and muscle-MEP are further enhanced by the fact that cardiothoracic surgery

(especially surgery on the aorta) is more likely to compromise the blood flow in the anterior spinal

artery (which supplies the motor tracts) than compromise the posterior spinal arteries (which

supply the dorsal column SSEP pathway). Because the risk involves the spinal cord and not nerve

roots, electromyography (EMG), which is used extensively in spinal surgery to monitor nerve root

function, is not utilized in surgery for TAAA.

These properties have made monitoring with cortical-SSEP and muscle-MEP particularly

useful in assessing the spinal cord ischemia which inevitably accompanies the clamping of the aorta

with TAAA surgery. The desire to keep the ischemic time at a minimum must be balanced with the

extra time taken to restore critical arterial supply. IOM is used to identify when spinal cord

ischemia occurs such that the time required to improve the arterial supply can be effectively used;

if no change occurs then time is not wasted.

IOM is used to assess the impact of cross-clamping the proximal aorta during the surgical

correction of TAAA. In patients completely dependent on blood flow originating below the cross-

clamp, global spinal cord ischemia begins once the cross-clamp is placed. As depicted in Figure 1,

the time to spinal cord injury with ischemia varies with the residual blood flow. Complete loss of

blood flow may result in spinal cord neuronal death in about 8 minutes,59 with incomplete ischemia

resulting in paralysis usually after 15 minutes. As cross-clamp time increases, a gradual increase in

the risk and severity of paralysis occurs until at approximately 60 minutes where the incidence of

paralysis is nearly 100%.60, 61 Consequently, many surgeons attempt to limit cross-clamp time to no

more than 30-40 minutes, but the actual acceptable ischemic time varies greatly among patients.19,

62, 63 IOM using cortical-SSEP and muscle-MEP to assess the functional status of the neural tracts

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provides an index of the adequacy of the residual flow similar to monitoring of cerebral function; a

sudden loss of response signals the need to determine potential causes and corrective measures.

The bypass perfusion pump (e.g. axillo-femoral, left pulmonary vein-femoral artery)

between the proximal and distal aorta provides the distal spinal cord perfusion for patients who

are dependent on the caudal vessels.13 In these patients the loss of IOM responses can signal the

need for higher bypass perfusion pressures, since the 60–70 mmHg that is generally accepted as

adequate may not be sufficient (reports indicate some patients may require 90-110 mmHg).33, 37, 64

IOM has been reported to reduce the risk of paralysis to about 10% from the inherent risk of 30-

50% seen with cross-clamping without bypass.65 The quality of the evidence supporting use of IOM

as a strategy to manage hemodynamic optimization has been considered Class IIb.66

This bypass also reduces the proximal hypertension associated with cross-clamping. Since

proximal hypertension is associated with an elevation of cerebrospinal fluid pressure (CSFP) in the

brain and spinal cord, the net spinal cord perfusion pressure is reduced (SCPP=mean arterial

pressure – CSFP). 59 Studies have shown a role of a lumbar drain can be used to drain cerebrospinal

fluid (CSF) and reduce CSFP (e.g. to a CSFP of 10 mmHg or less) and improve arterial blood flow in

the spinal cord.67, 68 This CSF drainage is considered a Class I indication and may be most effective

when combined with neurophysiologic monitoring in a preventative and therapeutic management

strategy.35, 66, 69

For some patients, adequate spinal cord perfusion requires re-anastomosis of “critical”

radicular arteries. When needed, this usually involves re-implanting one to five intercostal radicular

perforators from the aorta, most commonly in the location of the arteria radicularis magna (ARM)

(T8 to L4).13, 15-19 Since visual and angiographic methods cannot always identify the critical arteries,

IOM loss occurring during selective clamping of aortic segments or test clamping of individual

radicular arteries can signal the need to reimplant these critical radicular arteries.70 Selective re-

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11

implantation of critical vessels reduces the risk of paralysis, but the challenge is that the time

required will increase the overall ischemic time. Hence, to minimize the incidence of paralysis

techniques are needed to identify and re-implant only the necessary critical arteries. The use of

IOM with cortical-SSEP and muscle-MEP is considered a Class IIb indication as a strategy to detect

spinal cord ischemia and to guide reimplantation of intercostal arteries.66

The differential sensitivity of the various components of the SSEP and MEP pathways (Table

1), and the arterial supply in the various portions of the SSEP and MEP pathways have been used to

infer the probable location of ischemia when IOM signals change. For example, clinical

observations suggest that a slow onset of cortical-SSEP or muscle-MEP change after cross-clamping

(>15 minutes) indicates a peripheral nerve ischemia such as from occlusion of the femoral artery by

the bypass cannula.71 If change occurs within 15 minutes, it has been assumed to be of spinal cord

origin, either from inadequate distal bypass perfusion 62, 72, 73 or from loss of critical intercostals.73-75

Animal data suggest that cortical-SSEP disappearance within 7-10 minutes is due to loss of

perfusion from critical intercostal vessels,76 although longer periods have been noted (7-30

minutes). 34, 64, 71

Monitoring with muscle-MEP has been adopted in some centers in TAAA surgery due to its

ability to allow a more rapid detection of ischemia compared to the cortical-SSEP. Since ischemia in

TAAA surgery frequently involves the anterior spinal artery, the muscle-MEP will have the best

sensitivity because of involvement of the spinal grey matter. Muscle-MEP monitoring has a better

correlation with motor outcome because it monitors the CST.

Although monitoring of the cortical-SSEP has been associated with an improved

neurological outcome,77-79 motor loss is best correlated when the cortical-SSEP loss occurs rapidly

after cross-clamping or when the duration of the cortical-SSEP loss was prolonged (40-60

minutes).62, 76, 80 For example, in one study there was an increased relative risk of paralysis of 21

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12

times when the muscle-MEP had amplitude loss greater than 50% five minutes after cross-clamping

and a 30.9 odds ratio for paraplegia with persistent muscle-MEP loss.17 Other work by Safi and

Estrera has also demonstrated the usefulness and predictive ability of the muscle-MEP and cortical-

SSEP when integrated into the surgery.81, 82 These clinical studies suggest that muscle-MEP

monitoring provides significant additional information to the cortical-SSEP to reduce paraplegia.35,

83

As an example of surgery on the thoracic aorta, consider the muscle-MEP tracings in Figure

3 recorded during a TAAA repair.37 The muscle-MEP response is lost in the lower extremity. This

loss could be caused by one of several factors noted in Table 2. Aside from technical problems,

unfavorable positioning, or a change in the anesthesia management, the differential includes

problems along the motor or sensory pathway. Determining which of these are the contributing

factors and the needed corrective actions will revolve around 1) the procedural actions preceding

the change, 2) the speed of onset of the loss, 3) the physiological management (e.g. blood

pressure), and 4) the state of other monitors (e.g. cortical-SSEP, TCD, NIRS). As shown, this change

occurred following loss of spinal cord perfusion from lumbar arteries and recovered following their

reperfusion. Of note, the monitoring indicated there was no need for re-anastomosis of radicular

arteries cephalad to T12.

Thus, in summary, cortical-SSEP and muscle-MEP monitoring can be used to assess the

various factors that may be contributing to CNS ischemia to help guide specific measures to reduce

neural risk while minimizing overall ischemic time by focusing efforts only on the necessary

maneuvers. These techniques are complementary so that monitoring using both techniques may

offer better neural vigilance. In particular, if the responses are maintained, then ischemia is unlikely

and time spent re-implanting intercostals arteries may not be necessary.84

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13

Monitoring During Aortic Stent Placement

Although the open surgical technique is often considered the definitive repair for aorta

abnormalities, thoracic endovascular aortic repair (TEVAR) has been established as an elective

method with advantages in patients whose co-morbid conditions predispose to significant

morbidity or mortality after an open procedure.2, 85 In TEVAR, the aortic stent may occlude critical

radicular arteries which cannot then be re-implanted.86 Hence, methods using test occlusion have

been developed to identify the critical arteries prior to stent deployment.2, 7, 86-90 This has also

prompted the use of combined procedures with stents deployed during limited open procedures

(hybrid techniques).2 The vascular access needed for the stent may result in leg ischemia

eliminating cortical-SSEP and muscle-MEP monitoring from that leg. The presence of vascular

disease may require that the vascular access be moved to the axillary vessels, which can cause loss

of upper extremity cortical-SSEP or muscle-MEP. When the cortical-SSEP or muscle-MEP is lost due

to vascular access, monitoring from that limb will no longer be useful and monitoring will have to

rely on responses from other limbs.

Although TEVAR is associated with a lower risk of spinal cord ischemia compared to the

open surgical repair (3-6% vs. 14%), paraplegia is clearly a risk with TEVAR.91 The risk correlates

with the length of the aorta covered by endovascular stent.92, 93 Also similar to the open procedure,

many of the ancillary techniques which reduce risk to the spinal cord are useful in endovascular

procedures and monitoring can assist in identifying or adjusting their effectiveness.12 Experience to

date suggests IOM with cortical-SSEP and muscle-MEP is an effective method to detect spinal cord

ischemia and assist in improving outcome in deployment of aortic stents.94

Discussion

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14

During the last decade, there has been substantial growth in use of neuromonitoring during

major vascular thoracic aortic surgery. The majority of U.S. cardiovascular centers now utilize some

form of neuromonitoring either routinely or in selected cases.95 The advancing age and increased

incidence of reduced organ function in our patients, coupled with the risk of neural injury

emphasizes the need for techniques to guide procedural decision-making and to extend time

allowable for the procedure by improving the blood flow.96

Cortical-SSEP and muscle-MEP monitoring in aortic surgery was the issue of a recent pro-

con debate97, 98 which indicated that the use is different than spinal surgery where sufficient

evidence for their use is considered convincing.99 Part of the controversy revolves around

understanding the integration of the monitoring into the procedure. In particular other techniques

such as adjunctive perfusion, some hypothermia, spinal fluid drainage, and efficient conduct of

anastomosis are commonly used and some centers have excellent outcomes without IOM.100, 101

Furthermore, many centers use preoperative spinal artery visualization with reimplantation when

subtended in the resection. Hence, the response to the loss of muscle-MEP signals may not always

be clear. This emphasizes that when monitoring suggests ischemia may be occurring it is important

that all members of the procedural team (surgeon, anesthesia, monitoring team) work in synergy

to consider means to insure the neural environment is optimal for the best outcome. For example

evaluating the distal perfusion pressure, determining if intercostals arteries need reimplanting,

providing CSF drainage, and other possible factors (Table 2).98

The limitations of most IOM modalities are that they are either highly regional, and thus

may miss significant cerebral or spinal cord ischemia resulting in false negatives, or that they are

global in nature and relatively insensitive to regional ischemia. Hence, multimodality CNS

monitoring, incorporating different complementary techniques to assess CNS functioning, would

appear to be the most appropriate approach to the detection and avoidance of perioperative CNS

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15

injury. Each of these techniques has specific limitations and risks, including the possibility of

misleading information.97 The challenge is to incorporate them into the overall procedural strategy

including other adjunctive methods to enhance decision-making and improve patient outcome.

Where monitoring has been studied, cortical-SSEP and muscle-MEP monitoring show an

excellent correlation with outcome lending support to their further investigation. 13, 17, 33, 37, 64, 71, 102

Clearly additional experience with monitoring will allow an improved understanding of how to

most effectively integrate the monitoring into the decision-making process during the surgery or

procedure.

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16

Figure Legends

Figure 1 Depiction of cortical electrical activity and the occurrence of neural infarction as average

cerebral blood flow is reduced from normal (50 cc/min/100 gm.). The electroencephalogram

becomes abnormal below 22 cc/min/100 gm. (ischemic threshold) and absent when blood flow

reaches 15 cc/min/100 gm. Infarction occurs at 17-18 cc/min/100 gm. after 3-4 hours and

progressively shorter periods with blood flow below this level. (Reproduced from Sloan with

permission.6)

Figure 2 Pathways of the motor evoked potential (MEP) and somatosensory evoked potential

(SSEP) are depicted. The muscle-MEP (left) is produced by transcranial electrical stimulation of the

motor cortex (arrow). The response travels down the cortico-spinal tract, crossing the midline in

the medulla. It continues in the white matter tracts of the spinal cord and activates the motor

nuclei in the anterior horn cell of the spinal cord. The response travels via the ventral root to the

neuromuscular junction where the response is usually measured as a compound muscle action

potential (CMAP). The cortical-SSEP (right) is produced by electrical stimulation of a peripheral

sensory nerve (arrow). It enters the spinal cord via the dorsal root and ascends the spinal cord in

the dorsal columns. It synapses in the cervico-medullary junction, crosses the midline and synapses

in the thalamus before producing a response in the sensory cortex. The response is typically

recorded over the sensory cortex (cortical-SSEP) and over the cervical spine (subcortical response).

Figure 3 Effect of ischemia on the lower extremity muscle-MEP response and recovery after

reperfusion during surgery for a type 1 TAAA. During the thoracic part of the operation no muscle-

MEP changes were observed and eight intercostal arteries were ligated. During the abdominal part

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17

of the operation muscle-MEP changes were observed within 2 minutes after placement of the

clamps between T-12 and the bifurcation. Two large lumbar arteries were identified and

reattached to the graft. Muscle-MEPs returned 15 minutes after the blood flow in the reattached

lumbar arteries was restored. (Reproduced from deHaan37 with permission).

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18

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Table 1 Sensitivity of Neural Tissue to Ischemia

Tissue

Time to loss of response with

ischemia1

Cortex 20-30 seconds (EEG)

Spinal Cord Sensory white matter 7-18 minutes (SSEP)

Spinal Cord Motor white matter 11-17 minutes (MEP)

Spinal Cord grey matter 1-2 minutes (MEP)

Peripheral nerve 20-30 minutes (SSEP and MEP)

1 Data from multiple sources. 66,68,75,76

Table 1

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Table 2 Regions of Ischemia Leading to Loss of MEP or SSEP

Cerebral ischemia (motor or sensory cortex)

Subcortical or brainstem ischemia in SSEP or MEP pathway

Spinal Cord Ischemia in dorsal columns or corticospinal tract

Proximal- subclavian or vertebral arteries

Loss critical radicular arteries

High cerebral spinal fluid pressure

Inadequate distal bypass perfusion pressure

Ischemia of leg due to occlusion femoral artery by bypass cannula

Table 2

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Figure 1Click here to download high resolution image

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Figure 2Click here to download high resolution image

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Figure 3Click here to download high resolution image