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Spinal cord ischemia in thoracoabdominal aneurysm surgery: monitoring and conditioning thespinal cord

de Haan, P.

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Citation for published version (APA):de Haan, P. (1999). Spinal cord ischemia in thoracoabdominal aneurysm surgery: monitoring and conditioningthe spinal cord.

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Download date: 19 Feb 2021

n

General introduction: ~o

ischemic spinal cord injury and fl> thoracoabdominal aneurysm surgery: -5

an overview of anatomical and physiological considerations

Introduction

Strategies to maintain adequate spinal cord blood flow

-Distal aortic perfusion

-Cerebro-spinalfluiddrainage

-Control of proximal hypertension

Management with regard to intercostal arteries

Identification of blood supply to the spinal cord

Spinal cord function monitoring

Hypothermic spinal cord protection

Delayed neurologic deficits

Conclusion

Outline of the thesis

General introduction

Introduction Thoracoabdominal or descending thoracic aneurysm surgery carries the risk of ischemic

spinal cord injury. Since the first thoracoabdominal reconstructions in the early 1950s the

risk of paraplegia and paraparesis was soon recognized as a major complication of these

procedures. The paradigm for paraplegia causation, the interruption of the de-segmented

blood supply to the anterior spinal artery, was established by Adams. ' Crawford classified

thoracoabdominal aortic aneurysms (TAAA) as follows (figure 1): Type I involves the

descending aorta from the left subclavian to renal arteries. Type II includes the entire

descending thoracic and abdominal aorta, and is the most extensive. Type III starts at the

level of T6 and extends down to the aortic bifurcation, and type IV involves the whole

abdominal aorta.2 In 1509 patients who had undergone repair for the treatment of

thoracoabdominal aortic disease, Svensson found that type I, II, III, and IV aneurysms were

associated with lower extremity neurologic deficit rates of 15%, 3 1 % , 7%, and 4%,

respectively.3 The incidence of overall neurologic deficits in that series was 16%. In another

large series of patients, which were equally distributed between types I to IV aneurysms,

the survivors (>30 days) had a 4 .4% incidence of paraplegia and a 5% incidence of

paraparesis.2 In contrast, after elective abdominal aortic aneurysms surgery the incidence

of lower extremity neurologic deficits was 0.16 - 0.25%.4S Following repair for coarctation

of the aorta, the incidence of paraplegia was 0.4% to 1.5%.6-7 Repair of aneurysms confined

?4^r ^(L^-^r rty?<=^r rf^P^p^ • ^ = = s ^ = J ^ =

Figure 1. The Crawford classification of thoraco-abdominal aneurysms (modified from Safi et al. J Vase Surg 1994; 20: 434-43).

11

Chapter 1

to the descending thoracic aorta resulted in paraplegia in 6.5% of the patients.8 Despite

recent advances in the treatment of thoracoabdominal aneurysms, postoperative paraparesis

or paraplegia remains a distinct possibility after an otherwise successful operation. Variables

predictive of neurologic deficits of the lower extremities include aortic clamp time, the

presence of rupture or dissection, the extent of aneurysm, a history of smoking, postoperative

hypotension and age.2,3-9,10

The etiology of neurologic injury after aortic operations is thought to be a temporary or

permanent interruption of spinal cord blood supply, resulting in neuronal hypoxia.1' Like

brain tissue, the anterior horn motor neurons and the spinal motoneuronal system have a

high metabolic rate. As a result, the cord grey matter is especially vulnerable to ischemia.12

Although the cord white matter is relatively resistant to ischemia, axonal ischemic vulnerability

has been described.'3

Irreversible injury to motor neurons will result in lower extremity neurologic deficits. When

the aorta is simply cross-clamped and replaced without adjuncts to protect the spinal cord,

there is a sigmoidal relationship between duration of thoracic aortic cross-clamping and

the probability of spinal cord injury. If the time of aortic clamping does not exceed 30

minutes, the risk of postoperative neurologic deficits appears to be small. The probability

of paraplegia increases linearly between 30 and 60 minutes of ischemia, to almost 90%

after one hour of thoracic occlusion.14

In the past four decades numerous strategies have been described that protect the spinal

cord during TAAA surgery. The prevention of irreversible ischemic spinal cord injury is

based on three principles. First, to minimize degree and duration of ischemia during aortic

cross-clamping, by means of techniques that maintain spinal cord blood flow. Second, to

restore spinal cord blood supply. This necessitates reattachment of segmental arteries to

the graft. Third, to apply protective strategies that improve neuronal survival following

transient spinal cord ischemia (hypothermia and pharmacological neuroprotection).

A monitoring technique that allows rapid detection of spinal cord ischemia might be a

valuable adjunct, i.e., protective strategies can be applied and adjusted according to the

monitoring results.

In this chapter, a synopsis of the arterial vascularisation of the spinal cord is provided. The

experimental models of spinal cord ischemia, that are used to assess the efficacy of spina

cord protective measures are described. Thereafter the strategies that aim to decrease the

rate of lower limb neurologic deficits following TAAA surgery will be discussed. Pharma­

cological neuroprotection will be reviewed in chapter 2.

'2

General introduction

Arterial vascularisation of the spinal cord The intrinsic circulation of the spinal cord consists of a single anterior and paired posterior

spinal arteries which travel in the anterior median sulcus and over the posterior columns,

respectively. The perforating central arteries from the anterior spinal artery supply up to

75% of the spinal cord, including the anterior horn gray matter and the corticospinal

tracts. The posterior spinal arteries supply the dorsal columns and the head of the posterior

horns.15 The anterior spinal artery has been regarded as continuous with occasional

narrowing, predominantly in the middle or lower thoracic region, while in some cases it

has been described as anatomically and functionally discontinuous.16 '7 The diameter of

the anterior spinal artery just cephalad to the anastomotic point of the arteria radicularis

L-5 L-2

Figure 2. The human anterior spinal artery and feeding vessels. The arteria radicularis magna (Adamkiewicz) originated from T-8, T-9 and T-11, respectively. Of note is the small diameter of the anterior spinal artery above the junction with the arteria radicularis magna (modified from: Domisse GF: The blood supply of the spinal cord. J Bone and Joint Surg 56: 225-235, 1974).

13

Chapter 1

magna is extremely small, whereas caudally it is relatively wide, facilitating cephalocaudal

flow.I6 Therefore, it is understandable that the lower thoracic cord has been referred to as

the critical zone of the spinal cord blood supply.16

There are 25 to 30 pairs of segmental arteries that arise from the aorta, and that can potentially

anastomose with the anterior spinal artery, forming the extrinsic circulation of the spinal cord.

A mean of 8 radicular feeders supply the spinal cord in man.16 Even in the non-pathological

state, the human spinal cord circulation has an extreme inter-individual variability (figure 2). The

anterior spinal artery in the cervical region and the upper thoracic region (T2) is well supplied by

branches of the vertebral artery and several radicular arteries. The mid-thoracic spinal cord has

up to one radicular artery,17'18 and in the lower thoracic and lumbar region the anterior spinal

artery is supplied by 3 to 5 radicular arteries.15 The major radicular supply in the thoracolumbar

spinal cord is provided by the arteria radicularis magna (ARM) which was originally described

byAdamkiewiczm 1882. Although the ARM arises between T9-12 in 75% and L1-2 in 10% of

cases, all segments between T5 and L5 can give rise to this artery.17

These anatomical observations should be extrapolated with care to the patient with a

TAAA and arteriosclerotic disease. An extensive collateral circulation might have developed

in patients with occlusion of segmental arteries by atherosclerotic plaques and mural thrombi.

Consequently, the architecture of the spinal cord blood supply might have changed

completely. The importance of the collateral circulation has been underscored by the

following observations. In surgical repair for type B dissection (descending aorta), neurologic

complications occurred in 32% of patients with acute dissection versus 9% in chronic

dissection.19 This difference might be explained by the lack of development of collateral

circulation in acute dissections. Another clinical study describing TAAA repairs revealed

that only ligation of more than 10 segmental arteries carried an increased risk of paraplegia.9

The authors concluded that the spinal cord blood supply did not depend on a single artery

of Adamkiewicz in patients with extensive aneurysms and degenerative atherosclerotic

disease. They suggested that a model of an anterior spinal artery with multiple inter­

changeable inputs was more accurate.

There are four possible collateral or substitution pathways for the provision of spinal cord

blood supply when segmental arteries are occluded by a mural thrombus. The most

significant adaptive mechanism may be enlargement of the anterior spinal artery. The

second substitution pathway is formed by the anastomoses between the segmental arteries

through posterior muscular branches.17 Indeed, angiographic studies have shown that one

or more segmental arteries can contribute to the ARM.77 The third collateral system is

dependent on branches of the internal iliac, lateral and median sacral arteries that perfuse

the conus medullaris.17 The fourth pathway constitutes of anastomoses between the anterior

~-i

General introduction

and posterior spinal arteries. However, the superficial plexus between the anterior and

posterior spinal arteries is insufficient and supplies only the white matter of the anterior

spinal cord, while the intramedullary anastomoses are without functional value.17

Experimental models of spinal cord ischemia

Several experimental models of spinal cord ischemia were used to evaluate the efficacy of

the spinal cord protective strategies. In this section the species used are briefly described.

In the rabbit, temporary occlusion of the abdominal aorta is a highly reproducible model

for the production of spinal ischemic lesions, since there is a clear relationship between the

time of occlusion, histopathological changes and the resultant clinical levels of function.21

The biood supply to the rabbit spinal cord originates from segmental arterial branches of

the abdominal aorta/2 Well-defined ischemic lesions can be made by obstructing blood

f low at a given level in the aorta, inducing complete ischemia below the level of occlusion.

The method was first described by Waud and was further developed by Zivin et a/.23"25 This

model of producing ischemic lesions is mainly used to evaluate and compare pharmacological

strategies that improve neuronal survival following a period of spinal cord ischemia. The

actual aortic occlusion can be produced by clamping the aorta through a trans- or a

retroperitoneal approach, or by inflating a balloon-tipped catheter that is advanced in the

abdominal aorta through the femoral artery.2627 The latter method is obviously less invasive.

The rabbit spinal cord arterial system is almost purely segmental and is therefore completely

different from that in humans. In contrast, the human and porcine spinal cord blood

supply have a high degree of resemblance. In both humans and pigs the ARM is the largest

feeder of the thoraco-lumbar spinal cord and has a downward hairpin bend with a relatively

small diameter of the anterior spinal artery above the junction with the ARM.1628 As in

man, the porcine anterior spinal artery is continuous from the medulla oblongata to the

conus medullaris.16'28 A plurisegmental spinal cord blood suppiy, i.e. more than five radicular

arteries supplying the spinal cord, was described in both human and porcine anatomical

studies.1628 The porcine model is mostly used to simulate specific situations that are

encountered during TAAA surgery. For example, using porcine models, the importance of

the artena radicularis magna was determined, and various strategies for distal aortic

perfusion were compared.29 30 In chapter 6 of this thesis we modified this model; instead of

clamping an aortic segment, the complete thoracoabdominal aorta was exposed and the

individual segmental arteries were clamped. This technique has the advantage that visceral

and hind limb perfusion can be maintained during the production of spinal cord ischemia

and that the hemodynamic response resulting from aortic cross-clamping does not interfere

with the experimental design.

15

Chapter 1

In the rat, reproducible spinal cord ischemia can be produced by occluding the aorta

below the level of the left subclavian artery with concomitantly inducing hypovolemia, or

by occluding the aorta and both the left and right subclavian artery.3132 In the rat,

sophisticated neurologic assessment and detection of subtle degrees of neurologic

impairment is possible.32 Although the spinal vascular anatomy of the rat and the human

spinal cord have some resemblance, there is a factor 100 in size separating the human and

the rat anatomical situation, which discourages extrapolation. In addition, the hypovolemia

used in this model might induce counter-regulatory mechanisms that interfere with outcome.

In the dog, spinal cord ischemia can be produced by clamping the aorta immediately distal

of the left subclavian artery. However, this model is less suitable because of the extensive

collateral supply of the spinal cord. This is emphasized by the observation that even a

permanent occlusion of the aorta, or ligation of all intercostal arteries did not consistently

result in paraplegia.33,34

Strategies to maintain adequate spinal cord blood flow In TAAA surgery, the duration of aortic cross-clamping has been a consistent predictor of

ischemic spinal cord injury.23'3739 Using a simple clamp-repair technique ("clamp and sew",

"clamp and go"), the aorta is cross-clamped and the aneurysm is rapidly replaced without

spinal cord protective measures which might increase cross-clamp time, i.e., distal aortic

perfusion and segmental artery preservation. The rationale for this modality is to limit

cross-clamp time to 30 min, a threshold that is associated with a low risk of irreversible

deficits.'4 Using a "clamp and go" technique, an open distal anastomosis is performed.

Proximal hypertension can be controlled with vasodilators and permissive partial

exsanguination (backbleeding through the distal aorta and through segmental vessels).40-41

In patients with aneurysms confined to the descending thoracic aorta, Scheinm and Cooley

described average clamp times of 22 minutes,41 and Crawford reported a 0.9% paraplegia

rate.42 However, in 260 patients with thoracoabdominal aneurysms, the simple clamp-

repair technique resulted in an incidence of paraplegia and paraparesis of 5% and 10%,

respectively.38 Therefore, during TAAA surgery, additional strategies should be applied

that maintain cord blood supply during aortic cross-clamping.

Distal aortic perfusion

Using retrograde or distal aortic perfusion, the aorta and corresponding segmental arteries

can be perfused below the level of repair during graft inclusion. Therefore, this technique

has the potential to maintain spinal cord perfusion during TAAA surgery (figure 3).

16

General introduction

a Figure 3. Schematic representation of distal aortic perfusion with a centrifugal pump. Oxygenated blood from the left atrium is pumped to the femoral artery. With this technique, perfusion of segmental arteries branching below the level of repair can be maintained.

Distal aortic perfusion can be realized either by a passive shunt or by various bypass

techniques. In addition, these techniques reduce aortic pressure proximal to the ciamp and

decrease left ventricle afterload, often without the need of pharmacological interventions.

An important distinction in currently used surgical techniques for TAAA repair is based on

the use of distal aortic perfusion; simple clamp-repair vs. operations with distal perfusion,

double aortic clamping, and sequential repair.

Passive aortic shunts were first described by Gott.43 This so-called Gott-shunt consists of a

tube with an internal diameter of 5 - 6 mm and a nonthrombogenic luminal coating, and

is positioned (arterial-arterial) to bypass the cross-clamped aortic segment, for example

between the ascending and descending aorta. As a result of the heparin coating, the

shunt obviates the need for systemic heparinisation. In 359 patients undergoing elective

repair of aneurysms confined to the descending thoracic aorta, no lower extremity neurologic

deficits were encountered with the use of a Gott shunt.44 However, there are several

disadvantages of passive shunting. Maximum shunt f low is insufficient to unload the proximal

circulation.~b The static blood f low in the shunt can not be regulated to address specific

problems encountered during cross-clamping. In addition, the Gott shunt only provided

distal pressures less than 40 mmHg.30

Among the various techniques to accomplish active distal aortic perfusion, partial

cardiopulmonary bypass (femoral vein to femoral artery), has the distinct disadvantage of

Chapter

requiring full heparinisation. Partial left heart bypass (left atrium-femoral artery) with the

use of a simple centrifugal pump obviates the difficulties associated with active roller pumps

as well as passive shunts. With this technique flow can be regulated, minimal heparinisation

is required, selective organ perfusion can be used, and a heat exchanger can be applied/548

In a porcine experiment, active distal perfusion resulted in distal aortic pressures significantly

higher than those achieved by passive shunting. Furthermore, the use of atrio-femoral

bypass maintained CSF pressures at baseline levels during cross-clamping, while passive

shunting increased CSF pressures significantly (increased CSF pressures might compromise

spinal cord blood supply).30 Distal aortic perfusion in combination with sequential and

segmental repairs of the aorta maintained spinal cord electrophysiological activity while

the proximal anastomosis was performed.49 Coselli50 and de Mol51 reported a reduced

duration of intercostal ischemic time with atrio-femoral bypass.

Despite these obvious advantages, distal aortic perfusion with a centrifugal pump did not

consistently improve neurologic outcome. In some clinical studies describing TAAA surgery,

atrio-femoral bypass was associated with a decrease in the incidence of paraplegia and

paraparesis.37-39'5253 In a prospective non-randomized study of 99 patients, atrio-femoral

bypass improved neurologic outcome, especially when distal bypass was combined with

sequential aortic clamping and segmental repairs.37 In a retrospective analysis of 370 patients,

distal aortic perfusion and CSF drainage were beneficial if extended cross-clamp times

were used, particularly in extensive aneurysms.53 However, other studies reported both

equal and increased rates of paraplegia in association with distal aortic perfusion

techniques.3'8'50'5458

There are several explanations for the fact that distal aortic perfusion did not consistently

improve neurologic outcome. Coselli reported that the use of a distal bypass technique

increased duration of aortic clamping in type I and II aneurysms,50 while Safi demonstrated

that the risk of paraplegia remained dependent on the duration of aortic clamping, even

when distal aortic perfusion was employed.39 The relation of aortic clamp time vs. risk of

paraplegia was merely shifted to the right. Consequently, if a shunt is protective, this

protective effect might not outweigh the increased risk of neurologic deficits that result

from the increased clamping time. In addition, the spinal cord will remain ischemic even in

the face of excellent distal aortic perfusion if the arteries supplying the anterior spina

artery arise from the excluded segment of the aorta.36 In canine experiments and human

observations it was reported that distal aortic pressure had to be maintained above a

mean of 60-70 mmHg in order to have a protective effect on the spinal cord.5960 Clinical

data suggested that in some patients pressures higher than 80 mmHg were necessary to

General introduction

preserve electrophysiological function.49 Therefore, merely applying distal aortic perfusion

is insufficient to prevent spinal cord ischemia; distal aortic pressures have to be maintained

at least above 60 mmHg. Furthermore, if distal perfusion resulted in perfusion of the ARM,

some authors demonstrated that only lumbar cord flow was increased, whereas thoracic

spinal cord blood flow was not increased.61-62 This can be explained by human and animal

anatomical observations; the anterior spinal artery has a small diameter above the junction

with the ARM.16,28'61 Because blood flow is inversely proportional to the fourth power of

the radius (Poiseuille's equation), this caliber change has consequences for the distribution

of blood flow to the thoraco-lumbar spinal cord. Calculations on post-mortem specimens

in humans have revealed that the resistance to upward flow is at least 11 times greater,

thus forcing blood in a caudal direction along the length of the spinal cord.61 Accordingly,

the ARM will preferentially perfuse the lumbar spinal cord, while the thoracic spinal cord

remains at risk.

Shunts and bypass techniques are not without risk. Complications of distal perfusion

techniques include the technical problems which may arise from cannulation of the left

atrium or cannulation of the diseased femoral or iliac arteries. Emboli from the aneurysm

sac thrombus during shunt perfusion (especially if sequential clamping is used) also pose a

risk. In addition, the use of a shunt or bypass with partial extracorporeal circulation and

heparinisation resulted in a significant increase in bleeding- and pulmonary complications.8'55

In an analysis of 596 patients undergoing surgery for traumatic rupture of the aorta, mortality

rates associated with bypass, passive shunts or a clamp and go technique were 16.7%,

11.4% and 5.8% respectively.63 In another study the mortality rate associated with atrio-

femoral bypass was 4% compared to 11% with the use of cardiopulmonary bypass.64

In conclusion, distal aortic perfusion with left heart bypass and the use of a centrifugal

pump, might decrease the incidence of paraplegia and paraparesis, especially when this

technique is combined with sequential aortic clamping and segmental repair. Distal aortic

pressures should be maintained at least above 60 mmHg. The use of distal aortic perfusion

does not automatically imply adequate spinal cord perfusion. The advantage of distal aortic

perfusion is limited when the vessels critically supplying the cord are located in the clamped

aortic segment.

Cerebrospinal fluid drainage

A significant rise in cerebrospinal fluid (CSF) pressure after cross-clamping the aorta was

described in animal studies.29-65 During TAA resections, pressures up to 43 mmHg were

observed after clamping the aorta.06-57 The spinal cord can, be subjected to a compartment

syndrome, because the bony vertebra! channel and dura can be regarded as non-distensible.

19

Chapter

The apparent compliance of the spinal canal is created by the volume of displaced blood

by venous drainage. During thoracic aortic occlusion a volume distribution to the upper

half of the body occurs, resulting in an increased central venous pressure (CVP).68 The

resultant increase in volume of the venous capacitance beds within the dural space is

thought to be the mechanism for the increased CSF pressure during aortic clamping.69

Indeed, CSF pressure was observed to correlate with increases in CVP.29 In addition, when

CSF pressure exceeds the local venous pressure in the spinal cord, the drainage network is

forced to contract and outflow resistance decreases the compliance of the spinal canal.69

Spinal cord perfusion pressure (SCPP) is calculated as mean arterial pressure minus the CSF

pressure or the CVP, whichever of the two outflow pressures is higher. Consequently, a

rise in CSF pressure will decrease SCPP. Spinal cord blood flow (SCBF) is autoregulated

between perfusion pressures of 50 and 120 mmHg.70,71 Below pressures of 50 mmHg,

flow decreases in proportion to SCPP. If a rise in CSF pressure decreases SCPP below 50

mmHg, SCBF will be affected. Therefore, CSF drainage (in order to maintain CSF pressure

below 10 mmHg) was proposed as an adjunct to prevent paraplegia during and after

TAAA surgery. The importance of CSF drainage was asserted by observations that a SCPP

of 20 mmHg was sufficient to preserve spinal cord integrity.65-72'7'1 Consequently, if atrio-

femoral bypass is not used to maintain distal aortic pressure, CSF drainage is especially

important to maintain perfusion pressure above 20 mmHg below the level of repair.

The influence of CSF drainage on neurologic outcome in experimental studies was

equivocal. In dogs, CSF drainage (cisterna magna) repeatedly reduced the incidence of

paraplegia following periods of simple aortic cross-clamping.65'667577 In canine experiments,

the improved neurologic outcome with CSF drainage correlated with increased SCBF in

the lower thoracic and lumbar spinal cord.78 After double thoracic aortic cross-clamping

CSF drainage was not effective in reducing the incidence of paraplegia in the dog.79 In

addition, CSF drainage was not able to reduce the degree of permanent spinal cord

damage in the baboon and in the pig.2936

Most human studies studying the effect of CSF drainage had methodological limitations.

They were uncontrolled, i.e., compared the results against a historical control group, or

were merely descriptive.39'53'58'66-80'82 Despite these limitations, it was consistently observed

that CSF drainage, alone and combined with other spinal cord protective measures,

provided significant better neurologic outcome when a single clamp-repair technique for

aneurysm replacement was used.66s(SJ During TAAA surgery with the use of distal aortic

perfusion techniques, CSF drainage alone did not improve functional outcome.53 CSF

drainage combined with atrio-femoral bypass however, was associated with a reduced

incidence of lower limb neurologic deficits.3953

20

General introduction

The only prospective randomized study of CSF drainage included 98 patients undergoing

TAAA surgery with the use of atrio-femoral bypass.10 The authors could not demonstrate

that CSF drainage reduced neurologic deficits. Limitations of this study were a restriction

of the volume of CSF drainage to 50 ml, and limitation of CSF drainage to the intraoperative

period. Therefore, spinal cord decompression was probably inadequate. In addition, the

power analysis of this study assumed a 80% decrease in neurologic deficits, but considering

the multifactorial etiology of spinal cord ischemia following TAAA surgery, a 50% reduction

would be more realistic for studying the effect of CSF drainage alone. However, in the latter

situation, the study group should have been three times larger.83 Therefore, it is questionable

if this investigation was able to detect a difference between the study groups.

In conclusion, there is only circumstantial evidence that CSF drainage alone is protective if a

"clamp and sew" technique for graft inclusion is performed. Although CSF drainage is a

secondary adjunct compared to adequate revascularisation and distal aortic perfusion, CSF

drainage is simple and safe to perform and can prevent detrimental increases in CSF pressure.

Control of proximal hypertension

Proximal hypertension following cross-clamping of the aorta is inherent to thoracic aortic

surgery. If untreated, the proximal hypertension can cause left ventricular failure, myocardial

infarction and/or hemorrhagic cerebral events. The measures used to control proximal

hypertension have an effect on CSF pressure and SCPP. If these measures decrease the

SCPP below 50 mmHg, they may play a role in the sequence of events resulting in ischemic

spinal cord injury.

Sodium nitroprusside is widely used to control proximal hypertension. However, nitroprusside

has a deleterious effect on SCPP: it increases CSF pressure (by increasing cerebral blood

flow) and decreases distal aortic pressure.73 In addition, nitroprusside causes a loss of

autoregulation of SCBF, and blood flow to the upper segments of the spinal cord is increased

(nitroprusside steal)."3 CSF drainage could not reverse the effect of nitroprusside infusion

on CSF pressure, because the compliance of the spinal canal was reduced through

nitroprusside induced oedema of the spinal cord itself.34 The effect of nitroprusside on

SCPP is especially detrimental if a single clamp-repair technique for graft inclusion is

employed.85 Aortic pressures below the clamp are reduced to values below 50 mmHg. In

normal conditions (SCPP > 50 mmHg) and in the presence of autoregulation of SCBF, an

increase in CSF pressure does not influence SCBF. However, if the arterial pressure is below

50 mmHg any nitroprusside-induced increase in CSF pressure will compromise SCBF further.

Nitroglycerine has a different impact on CSF dynamics and autoregulation of blood flow.

21

Chapter 1

Although nitroglycerine also increased CSF pressure, the nitroglycerine induced CSFP increase

could be counteracted by CSF drainage.74-86

Partial exsanguination can also be used to control proximal hypertension after aortic

clamping. In a canine experiment this modality effectively improved SCPP and decreased

the incidence of postoperative paraplegia as compared to nitroprusside.37 In the clinical

setting, partial exsanguination and rapid reinfusion from a reservoir can be used in

conjunction with an active distal perfusion technique.9

It can be concluded that in order to control proximal pressures during aortic clamping,

nitroprusside should be avoided. In contrast, nitroglycerine might be safer only if CSF drainage

is performed. Active distal aortic perfusion also allows unloading of the proximal circulation,

and this technique obviates to a substantial extent the use of nitroglycerine and nitroprusside.

Management with regard to intercostal arteries The main questions during TAAA repair are whether intercostal or lumbar arteries should

be preserved at all, and which arteries should be reattached. In order to prevent neurologic

deficits following TAAA surgery, blood supply to the spinal cord should be restored. In the

literature most attention was focused on reattachment of the ARM. However, considerable

inter-individual variation exists in the origin of this vessel. Additional anatomic diversity is

created by the aneurysm, because atherosclerosis may occlude originally important

segmental vessels, leaving the spinal cord dependent on unusual and diverse collaterals.38

It was observed that most patients with a dissection had patent intercostal and lumbar

arteries, with intense backbleeding at all levels, while patients with non dissecting aneurysms

had occlusion of many segmental arteries, some patients even with complete occlusion at

all levels.7 Occlusion of segmental arteries suggests the presence of substantial collateral

circulation to the spinal cord. Or the opposite may be true: a single intercostal artery with

minimal backbleeding might be one of the few vessels that critically supply the cord, and

thus should be reattached at all expense. In the case of dissection, the question arises

whether the frequently present and profusely backbleeding segmental arteries are a

reflection of an extensive collateral supply of the spinal cord, and consequently no segmental

arteries need to be reattached. In the alternative case, backbleeding might be the result of

interconnected segmental arteries that do not reach the cord, and should it be interpreted

that alternate vessels to the cord have not developed. In the latter case all segmental

vessels should be preserved in the hope that one or more give rise to the radicular artery

that reaches the spinal cord.

22

General introduction

In the literature only few studies describe ligation of all segmental arteries,82 and in some

studies the usefulness of segmental artery reattachment is questioned/1 The majority of

studies favour re-implantation of either some or all segmental arteries.37'47'49'50'80'89-91'151

Despite the inter-individual anatomical variation of spinal cord blood supply, and the

uncertainty regarding the necessity to re-anastomose segmental arteries, some general

statements can be made on the management of intercostal and lumbar arteries.

When the aneurysm is opened, profusely backbleeding intercostal arteries tend to drain

blood away from the spinal cord. In porcine experiments, the prevention of this "steal-

phenomenon" significantly increased the pressure in the arterial vascular bed in the thoracic

spinal cord.02 '9 ' During TAAA surgery, the insertion of intravascular blockers, in order to

stop backbleeding could reverse electrophysiological evidence of spinal cord ischemia.49

In the studies that describe the influence of segmental artery preservation on neurologic

outcome, a possible confounder is the observation of Svensson, that patients with no or

few patent segmental arteries in the aneurysmatic tract had a lower risk of paraplegia or

paraparesis than patients with patent arteries.37

Reattachment of segmental arteries increases aortic cross-clamp time. Multiple studies

have shown that the most important predictor of neurologic deficit is the duration of

aortic cross-clamping.23'5253'58 Therefore, preserving segmental arteries might increase the

incidence of neurologic lower limb deficits caused by temporary ischemia as a result of the

increased duration of aortic clamping. Consequently, the protection provided by segmental

artery reattachment might not outweigh the risk associated with longer cross-clamp times.

Indeed, using a single clamp-repair technique, reimplantation of segmental arteries had no

beneficial effect on the incidence of postoperative neurologic deficits, and even was a

significant predictor of paraplegia and paresis.2 In another series of patients, paraplegia

rate was increased almost threefold when segmental arteries were reattached using simple

aortic cross-clamping.94 Consequently, additional measures that maintain spinal cord

perfusion should be applied if segmental arteries are preserved. When atno-femoral bypass

was used during TAAA surgery, reattachment of patent segmental arteries most likely to

give rise to the ARM was associated with a significantly decreased risk of paraplegia or

paresis.37-89

A problem of reattached segmental arteries is the possibility that they can occlude. Indeed,

highly selective angiograms obtained postoperatively in patients with preserved segmental

arteries revealed occlusion of these vessels in a significant percentage of patients.49'95

Occlusion of preserved vessels is probably the result of emboli or thrombosis.

It can be concluded that segmental artery reattachment without distal perfusion had no

23

Chapter 1

beneficial effect on neurologic outcome, because the reattached vessels probably did not

compensate for the deleterious effect of longer cross-clamping. Distal aortic perfusion

provided adequate time to preserve segmental arteries. Using this technique, reattachment

of segmental arteries most likely to give rise to the ARM decreased the rate of lower limb

neurologic deficits.

Identification of blood supply to the spinal cord During TAAA repair, spinal cord blood supply should be restored. "Blindly" preserving a

large cluster of backbleeding intercostal arteries has gained widespread acceptance. A

more logical approach would be to pre- or intra-operatively identify the vessels that supply

the anterior spinal artery. This targeted reattachment might reduce cross clamp time, which

is the most important predictor of paraplegia. This approach might also increase the rate

of successful spinal cord revascularisations. The angiographic localisation of spinal cord

blood supply, however, has not become a routine procedure because of the fear that

manipulation with an atherosclerotic ostium or direct injection of contrast material will by

itself result in lower limb neurologic deficits. Indeed, the incidence of neurologic deficits,

including paraplegia, was 0 - 4.6%, after angiographic spinal cord blood supply localisa­

t a 18,20,88,96,97 other reported major complications associated with spinal arteriography

are retroperitoneal hemorrhage, pancreatitis, cortical blindness, aneurysm rupture, fever,

and atheromatous arterial emboli resulting in death.18'20

In the studies describing preoperative spinal cord angiography, the origin of the ARM

could be found in 55% to 69% of the cases.rs^RS'J7 Despite identification and reattachment

of the ARM the incidence of neurologic deficits remained as high as 14%.2088 No significant

difference in occurrence of neurologic injury was observed between patients in which the

ARM could or could not be identified preoperatively.20 If the thoracic radicular arteries

supplying the spinal cord were also identified and preserved, a lower incidence of neurologic

deficits was reported (5%).,s In the latter study distal aortic perfusion was not used.

Postoperative neurologic deficits are caused by a permanent interruption of spinal cord

blood supply or by a temporary interruption of sufficient duration. Distal aortic perfusion

might shorten spinal cord ischemic time during TAAA repair, and reduce the risk of neurologic

deficits resulting from temporary ischemia. Indeed, combined atrio-femoral bypass,

preoperative spinal angiography and targeted intercostal preservation resulted in only 2.3%

lower limb neurologic deficits.97

An intra-operative technique for identifying the vessels supplying the spinal cord is the

24

General introduction

Hydrogen Induced Current. With this technique, a platinum electrode is placed intrathecal^

alongside the spinal cord. A saline solution saturated with hydrogen is injected into a

clamped aortic segment or a segmental artery ostium. If hydrogen reaches the spinal cord,

a Hydrogen Induced Current is generated from the electrode, indicating that the segmental

artery or the aortic section supplies the spinal cord with blood.11'95'98 In a porcine experiment,

spinal cord blood supply could be accurately identified using this technique.'* In a pilot

study in humans undergoing TAAA repair, post operative angiography confirmed that this

technique accurately identified spinal cord blood supply.95 However, using the hydrogen

technique postoperative paresis remained a distinct possibility (13%).95'98

It can be concluded that the identification of spinal cord blood supply provides additional

value in a multimodality approach to reduce lower limb neurologic deficits. However, the

rate of serious complications associated with angiographic localisation of spinal cord blood

supply limits its clinical value.

Spinal cord function monitoring One of the most important limitations of the strategies that aim to maintain and restore

spinal cord blood supply, is the inability to actually assess the adequacy of spinal cord

blood flow. If a particular strategy fails to maintain or restore spinal cord blood supply, this

insufficiency will be detected only after the patient wakes up. At that time irreversible

damage has already occurred. Continuous measurement of spinal cord blood flow would

enable the surgeon to selectively apply and adjust protective strategies that aim to optimize

spinal cord perfusion. For example, proximal and distal pressures can be adjusted according

to monitoring results, and segmental arteries can be either safely iigated or preserved

during replacement of an aortic segment. There is currently no on-line monitor of SCBF in

humans. Neurophysiologic assessment of spinal cord conduction can serve as a proxy

measure of SCBF. Neurons in the brain and grey matter of the spinal cord have high

metabolic demands, and will cease to function immediately after interruption of flow. This

phenomenon is the basis of monitoring the electroencephalogram during carotid

endarterectomy, where cross-clamping the carotid artery will produce hemispheric

asymmetry if the circle of Willis does not provide adequate collateral flow. Adequacy of

SCBF can be assessed neurophysiologically with Somatosensory Evoked Potentials (SEP)

and Motor Evoked Potentials (MEP). SEP mainly monitors signal transmission through the

dorsal columns, whereas MEP especially monitors the function of the anterior horn grey

matter and the corticospinal tracts. The relatively new technique of Motor Evoked Potentials

is evaluated in chapter 3, 4 and 5. This paragraph will discuss the SEP.

25

Chapter 1

Amplifier

somatosensory cortex

dorsal columns

posterior tibial nerve

Disk storage/printer

Digitizer Averager

Cortical SEP

Latency •4 •

Amplitude

Stimulator

Figure 4. Example of a technique to monitor somatosensory evoked potentials. The posterior tibial nerve is stimulated, the signal is conducted by the peripheral nerve and the dorsal columns, and is recorded from the scalp (cortical SEP).

SEP monitoring is a non-invasive technique that can be readily applied in the operating

room (figure 4). Lower limb peripheral nerves or the lumbar spinal cord are stimulated

electrically with brief pulses. The signal is transmitted via the dorsal columns and to a lesser

extent via the anterolateral tracts, and can be recorded from the scalp (cortical SEP), or the

high thoracic or cervical cord.5d '99 '00 At least 100 stimuli need to be averaged to obtain a

reproducible cortical evoked potential. On empirical grounds an increase in the latency to

the first positive peak (P1) of more than 10%, or a decrease in cortical peak to peak

amplitude of more than 50% was considered a reason for intervention.101'102

Monitoring per se does not improve the incidence of neurologic deficits. In order to guide

spinal cord protective strategies, the monitoring technique should afford a short interval

between onset and detection of the spinal cord ischemia. In addition, information regarding

the functional status of the ischemia sensitive motoneuronal system should be provided.

26

General introduction

SEP monitoring does not meet these requirements. The SEP is thought to conduct afferent

information in a non-synaptic fashion. This results in a relatively long delay between onset

and detection of ischemia (8-18 min) because of the relative resistance of axonal conduction

to ischemia (propagation of an action potential with little expenditure of energy).103 Simple

cross-clamping resulted in disappearance of SEPs in 17 ± 8 min.59 This SEP loss is preceded

4 - 6 min by a increase in latency of 10% from baseline position.10''- In general 10 min is

allowed for SEPs to detect ischemia.9 This relatively slow response time might be incompatible

with rapid application and adjustment of protective strategies.

SEPs reflect only conduction in the dorsal columns. Following an interruption of spinal cord

blood flow, the ischemia sensitive central gray matter and lateral and ventral fasciculi are

often primarily affected.105'106 As a consequence, false negative monitoring results with

SEPs have been repeatedly reported.9'54'10'109 The dorsal columns are supplied from the

posterior spinal artery. Therefore, SEPs do not even reflect blood supply of the anterior

spinal artery feeding the motor neurons. This is in accordance with the observation that

SEPs returned to normal while irreversible damage of the anterior horn had occurred.110

SEP changes similar to those resulting from spinal cord ischemia can result from hypothermia,

peripheral ischemia and halogenated anesthetics.111112 Using a modality with spinal cord

stimulation decreased the incidence of these false positive responses.;:ir:

Although SEP monitoring improved the surgical strategy in several studies,9'38'51'59"3 in a

prospective study of 198 patients, SEP monitoring in combination with distal aortic perfusion

could not significantly improve neurologic outcome, because of the high incidence of false

negative (13%) and false positive responses (67%).',4 In another clinical study, localisation

of critical sources of cord blood supply using SEP monitoring was not effective as a result

of the low specificity of SEPs.114

In the postoperative phase SEPs may provide useful information. In a large series of patients,

SEPs detected compromised cord blood flow resulting from a decrease in SCPP in several

occasions.9 In that study, the evidence of spinal cord ischemia was successfully reversed by

measures that increased spinal cord perfusion pressure, and none of these patients developed

lower limb neurologic deficits.

In conclusion, SEPs can provide indirect information regarding spinal cord blood flow.

However, monitoring spinal cord function during TAAA repair using SEPs has serious

limitations. The response time is too slow to be of practical use. In addition, SEPs do not

provide information regarding anterior horn motor function and anterior horn blood supply,

whereas the motor neurons in the anterior horn are most likely to sustain ischemic injury.

27

Chapter 1

Hypothermic spinal cord protection The rationale for the use of hypothermia during TAA resections is to increase the tolerance

of the spinal cord to ischemia, so that blood flow can be re-established before the onset of

irreversible damage. Hypothermia can be applied either regionally (confined to the spinal

cord) or systemically. In chapter 2, the pharmacological possibilities to provide protection

against spinal cord ischemia will be reviewed.

Oxygen requirements in neural tissue are known to decrease 6 - 7% for each degree decre­

ment in cord temperature.115 The neuroprotective effect of hypothermia was presumed to

be secondary to a decreased metabolic rate and to a generalized reduction of energy

consuming processes in the cell. However, already in 1944 it was demonstrated that the

protection provided by hypothermia exceeded the processes involved in oxygen metabolism

of the spinal cord."6 Thus, as the temperature was lowered, the destruction of nerve cells

decreased to a greater extent than the oxygen uptake. Recently, it was shown that the

mechanism of hypothermic spinal cord protection indeed is complex, involving reduced

release of excitatory neurotransmitters and membrane stabilisation.117

Profound hypothermia (IS- 19°C) and circulatory arrest is commonly used for surgery

of the transverse aortic arch, and has also been described for TAAA surgery. It is an attractive

technique because it provides cardiac, as well as visceral and spinal cord protection.

Therefore, time to reattach all segmental arteries in extensive aneurysms is allowed.91'118'120

Lower extremity neurologic deficits occurred up to 7.5% in these series. However, this

approach carries the risk of cerebral neurologic deficits, massive fluid shifts, and full

heparinisation and extracorporeal circulation related problems like coagulopathy and

haemorrhagic pulmonary complications. Therefore, Kouchoukos proposed to limit this

technique to complex and therefore prolonged aortic surgery,9'118 while Safi recommended

to leave this option as last alternative in cases with catastrophic intra-operative bleeding.121

Moderate systemic hypothermia (30 - 33°C) can be accomplished either as permissive

hypothermia (spontaneous cooling), or actively with an in-line heat exchanger combined

with atno-femoral bypass; the latter permits rapid cooling and rapid rewarming at the end

of the procedure. The degree of hypothermia achieved with this method, is limited by the

potential risk for cardiac arrhythmia's. Moderate hypothermia was effective in experimental

models of spinal cord ischemia and in clinical studies during TAAA surgery.80-122123

Mild systemic hypothermia (33 - 35°C) exerted powerful neuroprotective properties in

cerebral ischemia.124 Mild hypothermia in the setting of spinal cord ischemia is discussed in

chapter 7 of this thesis.

Regional cooling of the spinal cord has theoretical advantages, because lower cord

temperatures can be achieved without the systemic complications. Subarachnoid perfusion

28

Gênerai introduction

(2 - 6°C, 25 ml /min inflow, passive outflow), was demonstrated to be protective in several

experimental models of spinal cord ischemia. The spinal cord temperature could be decreased

to temperatures of approximately 15°C at the expense, however, of increased CSF

pressures.79125126 Several authors showed that epidural infusion (5°C) protected against

experimental spinal cord ischemia.127130 In dogs, epidural perfusion (bolus 8 ml/kg and

additional infusion of 20 ml/kg during aortic clamping) resulted in moderate levels of cord

hypothermia (~ 29°C).,2S129 Deep hypothermia was possibly not reached because the epidural

space is less well insulated from the systemic circulation than the subarachnoid space.

Spinal cord temperatures below 15°C could only be reached with epidural cooling in a

smaller animal model (rabbit), but lethal increases in CSF pressure occurred in some

animals.12" In clinical practice, iced saline (4°C) was infused into the epidural space at the

level of T11-12 in 70 patients.131 The average infused volume was 1400 ml, which resulted

in a CSF temperature of 25 ± 1 °C. Using this technique, which included a "clamp and sew"

protocol and segmental artery reattachment, 2.9% lower extremity neurologic deficits

were reported. Remarkably, one patient in that series had a cervical cord infarction. The

major disadvantage of this technique was the increased CSF pressure, which was more

than doubled from baseline values.131132 A rise in CSF pressure is thought to contribute to

the development of postoperative paraplegia and paresis. Consequently, it can be postulated

that the increased CSF pressure was distributed equal along the entire cord whereas the

extent of protection provided by cooling was locally limited, which might account for the

cervical infarction in this series of patients.

Another possibility to apply regional hypothermia is the direct infusion of cold perfusate

into isolated aortic segments, with the intention that the spinal cord is cooled through the

segmental arteries. In several experimental models, this technique provided protection

against ischemic spinal cord injury.115'133135 Spinal cord temperatures as low as 18 - 20°C

could be obtained.13" An advantage of this technique was that additives like adenosine or

lidocaine could be included in the perfusion solution.11136 In 23 patients with extensive

(type I and II) aneurysms, the aortic segment giving rise to the segmental arteries to be

preserved (T8 - L2) was perfused with 400 cc crystalloid solution containing heparin, methyl-

prednisolone and mannitol at 8°C.137 In this series, one patient (4.3%) awoke paraplegic

after the operation.

Hypothermia can also be applied after the onset of ischemia. It was demonstrated as early

as 1968, that delayed localized cooling initiated 4 hours after spinal cord injury completely

prevented neurologic deficits. In a rat model of focal cerebral ischemia mild hypothermia

instituted within 30 min after the onset of ischemia significantly reduced infarct size.138

The delayed application of hypothermia after spinal cord ischemia has not been described.

29

Chapter 1

Some critical notes on hypothermia should be made. In experimental spinal cord ischemia,

hypothermia during the ischemic period did not protect against late onset paraplegia.H<:

Deep hypothermia may not be without risk, spinal cord temperatures of 10°C have been

described to result in irreversible neuronal injury.139

In conclusion, induced hypothermia is a powerful strategy to increase ischemic neuronal

tolerance, and it appears that hypothermia always provides a marked degree of protection,

irrespective of the method of cooling.

Delayed neurologic deficits One third of the neurologic deficits after TAAA surgery developed in the postoperative period.2

This phenomenon can not readily be explained. Several likely explications are provided.

Inadequate spinal cord blood supply If segmental arteries feeding the spinal cord were

ligated during the operation, there might be areas of marginal perfusion. If spinal cord

blood supply or spinal oxygenation is compromised further in the postoperative period,

ischemia can develop. Indeed, postoperative episodes of hypotension or increases in CSF

pressure resulted in delayed neurologic deficits.2 sc Decreased oxygen delivery as a result of

postoperative respiratory insufficiency also resulted in delayed neurologic deficits.140 Another

cause is the occlusion of reattached segmental arteries.""95 A further deterioration of a

compromised spinal cord blood supply, as explanation for delayed neurologic deficits, is

supported by the notion that acute CSF drainage reversed lower limb neurologic deficits

up to 14 days following TAAA repair in several studies (CSF drainage lowers CSF pressure

and thus increases SCPP).9-80-141'142

Reperfusion injury During TAAA repair, a short period of SCI will probably not result in

direct injury. However, following reperfusion, further neuronal damage may result from

the burst of oxygen free radicals, cytotoxic actions of leukocytes and microglia, micro-circulation

defects by vasospastic prostaglandins, and vascular smooth muscle contractions.I43'146 These

combined actions may ultimately lead to irreversible damage and delayed neurologic deficits.

Apoptosis Recent studies have suggested that delayed neuronal death after transient

spinal cord ischemia has apoptotic features.12-147"149 In contrast to ischemic cell death,

apoptose is a form of programmed cell death, with the activation of a genetic program in

which the apoptosis effector genes promote cell death. The advantage of apoptotic cell

death is that the cell is smoothly removed by phagocytosis of neighbouring cells. In contrast,

lysis that occurs with necrotic cell death is accompanied by excitatory ammo acid release

and macrophage activation, which might aggravate the insult.150

30

General introduction

Conclusion Spinal cord ischemic injury during thoracoabdominal aneurysm surgery is the result of a

permanent or temporary interruption of spinal cord blood supply. The permanent

interruption is related both to the variable and unpredictable anatomy of the arterial

vascularisation of the spinal cord, as well as the extent of the aneurysm. The temporary

interruption is dependent on the duration that arteries critically supplying the spinal cord

are not perfused.

In order to restore cord blood supply, at least the intercostal arteries most likely to give rise

to the ARM should be re-anastomosed to the graft. However, extending aortic clamp time

for re-anastomosis of intercostal or lumbar vessels increases the risk of irreversible neurologic

deficits resulting from temporary ischemia. Therefore, additional strategies need to be

applied to maintain adequate spinal cord perfusion during aortic clamping. Distal aortic

perfusion techniques, sequential aortic repair, the maintenance of low CSF pressure using

CSF drainage, and the avoidance of nitroprusside all have the potential to increase the

tolerable duration of cross-clamping. In addition, if a period of ischemia is likely to occur,

the application of systemic or regional hypothermia will enhance neuronal survival.

If a monitoring technique would be available that allows rapid detection of ischemia,

protective strategies can be applied and adjusted according to monitoring results, i.e., the

management of segmental arteries, and the guidance of distal perfusion techniques in

respect of maintaining proximal and distal pressures that are sufficient to preserve spinal

cord function.

Outline of the thesis This thesis addresses a new technique to assess spinal cord function during TAAA surgery.

Monitoring motor evoked potentials to transcranial electrical stimulation (tc-MEPs) has the

potential to rapidly detect spinal cord ischemia. In a rabbit model of transient spinal cord

ischemia, responses recorded from the muscles of the hind leg (myogenic tc-MEPs) are

compared with responses recorded from the epidural space. Thereafter, the clinical use of

myogenic tc-MEPs is evaluated in 20 patients undergoing TAAA surgery (Chapter 3, 4, 5).

Most attention in the surgical strategy is focused to preserve the arteria radicularis magna.

The importance of segmental arteries primarily "non-critical" for spinal cord blood supply is

assessed in a porcine model of spinal cord ischemia (chapter 6).

Despite maintenance and restoration of spinal cord blood supply during TAAA surgery,

transient spinal cord ischemia is likely to occur. The studies that tested the efficacy of

31

Chapter 1

neuroprotective agents in experimental spinal cord ischemia are systematically reviewed

and analyzed in chapter 2. The protective abilities of mild hypothermia and the 21-

aminosteroid, used alone or in combination, are evaluated in a rabbit model of spinal cord

ischemia (chapter 7).

In a rabbit model of transient spinal cord ischemia, the protective ability of ischemic

preconditioning is evaluated against a clinically relevant duration of ischemia (chapter 8).

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Chapter 1

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3 S

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