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(Stroke. 1997;28:899-905.)
© 1997 American Heart Association, Inc.

Articles

Bilateral Increase in CO₂ Reactivity After Unilateral Carotid Endarterectomy

G. H. Visser, MD; A. C. van Huffelen, MD, PhD; G. H. Wieneke, PhD; B. C. Eikelboom, MD, PhD

From the Department of Clinical Neurophysiology, University Hospital Utrecht and Rudolf Magnus Institute for Neurosciences, Utrecht (G.H.V., A.C. van H., G.H.W.); and the Department of Vascular Surgery, University Hospital Utrecht (B.C.E.), the Netherlands.

Correspondence to G.H. Visser, Department of Clinical Neurophysiology (F.02.230), University Hospital Utrecht, Heidelberglaan 100, 3584 CX Utrecht, PO Box 85500, 3508 GA Utrecht, Netherlands.

	Abstract

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Background and Purpose A low or absent CO₂ reactivity is considered indicative of a compromised hemodynamic compensatory capacity in patients with internal carotid artery (ICA) stenosis or occlusion. The aim of the present study was to investigate whether patients with preoperatively decreased or absent CO₂ reactivity show an improvement of CO₂ reactivity 3 months after carotid endarterectomy (CEA) and whether the preoperative CO₂ reactivity is correlated with clinical classification and hemodynamic factors.

Methods A group of 65 patients with >70% ICA stenosis was studied. CO₂ reactivity was measured by bilateral transcranial Doppler sonography before and 3 months after CEA.

Results The preoperative CO₂ reactivity was not significantly different in subgroups formed according to the presenting clinical symptoms. Patients with severe ICA stenosis with contralateral ICA occlusion had mean low preoperative CO₂ reactivity on both sides. Furthermore, patients with reversed flow in the ophthalmic artery had low mean preoperative CO₂ reactivity on the same side. The CO₂ reactivity was not significantly different in the subgroups of patients with signs of collateral blood flow through the anterior or posterior communicating artery. In particular, patients with low preoperative CO₂ reactivity (approximately <30%) showed an evident increase after the operation. Such an inverse correlation was found bilaterally, although it was more pronounced on the CEA side.

Conclusions CEA can increase CO₂ reactivity in both hemispheres. This effect is most pronounced in patients with low (<30%) preoperative CO₂ reactivity. If this group represents patients who would be at risk from low-flow stroke, then testing of CO₂ reactivity might help select a subset of patients with an especially high probability of benefit from CEA.

Key Words: carbon dioxide • carotid endarterectomy • ultrasonics

	Introduction

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The hemodynamic effect of ICA stenosis is determined by factors such as the severity of stenosis, the quality of the collateral circulation, and the presence of compensatory vasodilatation (cerebral autoregulation).^{1 2} Under normal physiological conditions, hypercapnia induces vasodilatation, resulting in an increase in CBF, which enables an increased washout of CO₂. However, an already existing vasodilatation to compensate for a decrease in CPP will interfere with the ability of the cerebral vessels to dilate further in response to hypercapnia (CO₂ reactivity). Thus, CO₂ reactivity provides information about the extent of preexisting vasodilatation, which in turn reflects the reserve capacity of the cerebral autoregulation. According to this hemodynamic model, a diminished or even absent CO₂ reactivity indicates a decreased reserve capacity in patients with ICA stenosis or occlusion and is considered a risk factor for ischemic cerebral complications.^{1 3 4}

TCD is a method to measure the BFV in the larger intracranial vessels and has the advantage of being noninvasive, safe, and inexpensive. Several studies have shown a good correlation between changes in BFV, induced by acetazolamide or hypercapnia and measured with TCD, and changes in CBF, as measured with xenon inhalation methods or single-photon emission CT.^{5 6 7} This is especially true if BFV changes are expressed relative to the baseline BFV. Therefore, a hypercapnia-induced relative change in BFV in the MCA can be interpreted as reflecting the CO₂ reactivity of the cerebral vessels. However, one should realize that the method used measures only the TCD effect of CO₂ inhalation and that in some subjects another reason for diminished reactivity might exist (such as lactic acidosis). In the present study, we used CO₂ as a vasodilator stimulus because it is easy to use, it is noninvasive, and it has fewer side effects than acetazolamide, which has a similar vasodilator effect.^{8 9} We used the time-averaged mean of the maximum BFV as TCD variable, which is widely accepted and is considered superior to other BFV parameters (R. Aaslid, personal communication, 1995). The maximum BFV means the maximum velocity (or Doppler frequency shift) measured at any moment of the cardiac cycle, often represented by a so-called "envelope."

The aim of the present study was to investigate whether patients with low preoperative CO₂ reactivity would show the most improvement in CO₂ reactivity after CEA. If so, then patients with low CO₂ reactivity would especially benefit from CEA from a hemodynamic point of view. If low or absent CO₂ reactivity is found on the side of the intended operation, an increase in CO₂ reactivity can be expected on this side after the operation because blood supply by the ICA to the MCA is restored. However, the blood supply to the circle of Willis may also be improved postoperatively. Therefore, an impaired blood supply to the contralateral hemisphere can be expected to improve after CEA because of improved collateral blood supply to that hemisphere. For these reasons, simultaneous bilateral CO₂ reactivity tests were performed before and 3 months after the operation. We chose 3 months because we expected that postoperative hemodynamic changes would have stabilized by this time and that there would be no major overall changes in nonoperated carotid arteries and intracranial vessels. We also determined whether the preoperative CO₂ reactivity was correlated with the clinical classification of the patients, with the presence of contralateral ICA occlusion, and with signs of collateral circulation through the OA, ACoA, or PCoA. The objective of these investigations was to identify, on hemodynamic grounds, a subgroup of patients who might especially benefit from CEA.

To avoid confusion about references to side, the side of operation is consistently referred to as the "CEA side" and the other side as the "contralateral side."

	Subjects and Methods

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Sixty-five patients with ICA stenosis of 70% who were to undergo CEA and who had undergone preoperative and postoperative CO₂ reactivity tests were included in the study. During this study period, ultrasound studies could not be performed because of the absence of an ultrasound window in the temporal bone in 8 patients, technical or organizational reasons in 7 patients, and medical contraindications in 5 patients (severe lung emphysema, recent myocardial infarction, laryngotomy, nervousness). The study was approved by the ethics committee of the University Hospital Utrecht, and the patients gave their informed consent. The degree of ICA stenosis was determined by angiography (70% stenosis according to NASCET criteria) or duplex examination (peak systolic velocity 210 cm/s). The data in the radiology report were taken as evidence of >70% ICA stenosis.

The mean±SD age of the 65 patients was 67±9 years, and 77% were men (n=50). In 22% of the subjects an occlusion of the ICA was found contralateral to the side of the operation (n=14), in 20% a contralateral stenosis of 70% (n=13), and in 25% a contralateral stenosis of <70% (n=16). In the year before surgery, 8% (n=5) of the subjects had had a minor stroke in the CEA-side hemisphere, and 35% (n=23) had had a CEA-side transient ischemic attack within 24 hours. Fourteen percent (n=9) had experienced only CEA-side ocular symptoms (ie, amaurosis fugax or impaired vision due to chronic retinal ischemia). In addition, 29% (n=19) of the patients were asymptomatic in both hemispheres, whereas 14% (n=9) were symptomatic in the contralateral hemisphere only.

The TCD examination was performed with a DWL Multidop-X device with two 2-MHz pulsed Doppler probes (the OA was investigated with a 4-MHz probe). First, a standard TCD examination was performed and included the bilateral insonation of the MCA, the A1 segment of the ACA, the P1 segment of the posterior cerebral artery, the OA, and the basilar artery. Special attention was paid to the direction of blood flow in the ACA, which is indicative of collateral flow through the ACoA, and to the direction of blood flow in the OA, which is indicative of a decreased intra-arterial pressure in the corresponding distal part of the ICA. Collateral blood flow in the PCoA was considered present if the BFV in the posterior cerebral artery was higher than in the MCA at the same side. If an intracranial vessel was not found, this was treated as a missing value and was not included in the statistical analysis.

The BFV was assessed bilaterally by simultaneous monitoring of both MCAs while the patients were lying down with their eyes closed. TCD probes were fitted in a light metal frame that was firmly fixed to the head with two earpieces and an adjustable nose saddle (manufactured by DWL). A gas mixture of 5% CO₂ and 95% O₂ (carbogene), the vasodilator stimulus, was inhaled through a mouthpiece connected to a respiratory balloon. A nose clip ensured proper inhalation of carbogene. The CO₂ content of the breathing gas was continuously monitored with an infrared gas analyzer (Mijnhardt). After a 2-minute baseline period, patients inhaled carbogene for another 2 minutes. A spectral TCD recording of 5-second duration was made during the baseline period and after 1.5 minutes of carbogene inhalation. At the same time, blood pressure was measured with an automatic device (Omega 1000; Invivo Research Laboratories Inc).

The CO₂ reactivity test was performed 2 days before and 3 months after CEA. The CO₂ reactivity was measured as relative change in BFV from baseline after 1.5 minutes of inhalation of carbogene. The mean of the maximal BFV during the spectral TCD recordings was used in this calculation.

All values are given as mean±SD unless otherwise indicated. ANOVA was used for the first overall analysis of differences. When the ANOVA procedure showed a significant difference, paired t tests were used for further analysis of differences. Paired differences were computed within subjects before determination of the standard deviation. The relation between two variables is expressed as the correlation coefficient.

	Results

Top Abstract Introduction Subjects and Methods Results Discussion References

 
The baseline CO₂ reactivity values and the changes after operation are summarized for the CEA side in Table 1 and for the contralateral side in Table 2. Overall, the increase in CO₂ reactivity after the operation was 14±21% on the CEA side (P<.001). On the contralateral side, there was no significant postoperative change in CO₂ reactivity. However, for both sides, there was a clear correlation between the preoperative CO₂ reactivity and the change after the operation. Subjects with low preoperative CO₂ reactivity showed an evident increase in reactivity after the operation, whereas subjects with high (presumably normal) preoperative reactivity did not show an overall change. For the CEA side the correlation coefficient was -.78, and for the contralateral side it was -.60 (both P<.001; Fig 1). The preoperative end-tidal CO₂ during the baseline period of the CO₂ reactivity test was 37.4±3.2 mm Hg, and the increase after 1.5 minutes of carbogene inhalation was 12.2±2.6 mm Hg. This was not statistically different from the values during the postoperative CO₂ reactivity test (37.1±3.3 and 12.4±2.4 mm Hg, respectively).

View this table: [in this window] [in a new window]   Table 1. Baseline CO2 Reactivity and Changes After CEA on CEA Side

View this table: [in this window] [in a new window]   Table 2. Baseline CO2 Reactivity and Changes After CEA on Contralateral Side

View larger version (18K): [in this window] [in a new window]   Figure 1. Bilateral baseline CO2 reactivity and changes after CEA for individual patients () and linear regression line with average value ().

The baseline mean blood pressure before CEA was 114±15, and blood pressure after CEA was not significantly different from this value (116±15; paired difference 1.9±11.1; P>.05). Also, no significant correlation was found between changes in mean blood pressure after CEA and changes in CO₂ reactivity on either the CEA side or contralaterally (correlation coefficient, -.13 and -.06, respectively; both P=NS).

There was no statistically significant difference between subjects with or without cerebrovascular ischemic events with respect to preoperative CO₂ reactivity or the change after CEA. One patient had a minor stroke in the hemisphere contralateral to the side of the operation in the 3-month follow-up period. Four other patients experienced minor and reversible ischemic events in the perioperative period, such as transient ischemic attack or amaurosis fugax.

Interestingly, differences were found when patients were grouped according to the following hemodynamic factors. A contralateral occlusion of the ICA appeared to have an effect on the CO₂ reactivity of both hemispheres (Fig 2). On the CEA side, the mean preoperative CO₂ reactivity was significantly lower (27±17%) in patients with a contralateral occlusion than in patients without a contralateral occlusion (40±19%; P<.05). Also, the mean preoperative CO₂ reactivity at the same side of an ICA occlusion, contralateral to the side of operation, was significantly lower (18±16%) than it was in patients without an occlusion (48±20%; P<.001). After the operation, the mean CO₂ reactivity on the CEA side increased significantly in the groups with or without contralateral ICA occlusion (P.001). On the side contralateral to the operation, the mean CO₂ reactivity increased significantly only in the patients with an ICA occlusion (12±14%; P<.01). At the CEA side, a significant correlation was found between the preoperative CO₂ reactivity and the change after the operation (correlation coefficient, -.87; P<.001), which was comparable with the correlation found for the whole group. At the contralateral side, no significant correlation was found. A more differentiated classification of the patients based on contralateral ICA occlusion, 70% stenosis, <70% stenosis, or no stenosis did not reveal group differences in baseline CO₂ reactivity or changes after CEA.

View larger version (14K): [in this window] [in a new window]   Figure 2. Bilateral baseline CO2 reactivity and changes after CEA for patients with ICA occlusion contralateral to the side of the operation. indicates individual values; , average value.

Subjects with a reversed flow in the OA had a significantly lower mean preoperative CO₂ reactivity on the side of the reversed flow than did the subjects with a normal direction of flow. Before CEA, mean CO₂ reactivity on the side of the planned operation was 28% when OA blood flow on that side was reversed and 40% when blood flow was in a normal direction (difference with P<.05). On the side contralateral to the planned operation, mean CO₂ reactivity was 20% when OA blood flow on this contralateral side was reversed and 50% when blood flow was in the normal direction (difference with P<.001). After the operation, mean CO₂ reactivity on the CEA side was increased by 20% when preoperative OA blood flow was reversed on this side and by 9% when blood flow was in the normal direction (nonsignificant difference). On the side contralateral to the operation, mean CO₂ reactivity was increased by 10% when preoperative OA blood flow on this side was reversed and by 1% when blood flow was in the normal direction (nonsignificant difference). However, after the operation there was a significant increase in mean CO₂ reactivity (P<.05) on the side contralateral to the operation when preoperative OA blood flow was reversed on this contralateral side.

Preoperative CO₂ reactivity and postoperative changes in CO₂ reactivity on the CEA side were not significantly different between subjects with reversed flow in the ipsilateral ACA (A1 segment) and subjects with a normal direction of flow in the ACA. However, mean CO₂ reactivity increased significantly after the operation only in subjects with a normal direction of flow in the ACA (P<.001). Findings in patients with signs of a collateral blood flow through the PCoA (BFV in the posterior cerebral artery higher than in the MCA), either on the CEA side or contralaterally, were not significantly different from those in their counterparts.

Finally, patients were selected on the basis of the preoperative CO₂ reactivity with an arbitrarily chosen limit of 30%. At the CEA side, all patients below this 30% limit showed an increase in CO₂ reactivity postoperatively. In this subgroup of patients, the mean increase in CO₂ reactivity after the operation was highly significant (P<.001) on the CEA side (33% increase) and on the contralateral side (16% increase).

	Discussion

Top Abstract Introduction Subjects and Methods Results Discussion References

 
CEA is performed to prevent embolic stroke caused by a stenotic lesion in the ipsilateral ICA. Large multicenter trials have shown an overall beneficial effect of CEA in preventing future cerebral ischemic events in a subgroup of patients with severe ICA stenosis and ipsilateral symptoms of cerebral ischemia.^{10 11} However, in NASCET, the risk of a major or fatal ipsilateral stroke after 2 years was 13% in the medically treated patients and 2.5% in the surgical patients.¹⁰ In other words, 87% of patients selected for surgery according to the NASCET criteria will not have a major or fatal ipsilateral stroke if they are only medically treated. Thus, many patients selected for surgery may not benefit from the operation and are thus unnecessarily exposed to the risk of the procedure. For this reason, there is a need to identify patient subgroups who will especially benefit from CEA. Such subgroups could be selected on the basis of the detection of either a stenotic ICA lesion with a high risk of embolism or an evident cerebral hemodynamic effect of a stenosis. With respect to the hemodynamic effect of ICA stenosis, there may be a subgroup of patients in whom poststenotic intra-arterial pressure is particularly low because collateral blood flow is inadequate to compensate for severe carotid artery stenosis. Such an inadequate collateral blood supply can be expected in patients with more extensive vascular lesions, such as a contralateral ICA occlusion that prevents collateral blood flow from that ICA. These patients would also be expected to manifest a hemodynamic dysfunction on the side of the ICA occlusion, since the adequacy of the collateral blood flow from the contralateral stenotic ICA to this side is in jeopardy. Although other collateral pathways can exist, for instance through the PCoA, these pathways alone are not always capable of providing adequate compensation. A reversed OA flow can be indicative of a low ipsilateral CPP in the anterior cerebral circulation and as such of seriously disordered hemodynamics.

Factors such as contralateral ICA occlusion or information about collateral flow patterns can be detected with Doppler sonography or angiography, but these techniques provide less information about the quantitative contribution of an existing collateral pathway and thus less information about the resulting hemodynamic consequences of ICA stenosis or occlusion. Methods such as positron emission tomography, or CBF or BFV measurements before and after provocation with vasodilator stimuli, are necessary to obtain this quantitative information about the cerebral circulation. These methods have shown that some patients with ICA stenosis have disordered ipsilateral cerebral hemodynamics and that the accompanying cerebral ischemia is predominantly of a hemodynamic low-flow type, producing watershed infarction instead of an embolic type.^{12 13 14 15 16 17 18} Low or absent CO₂ reactivity is considered indicative of an impaired reserve capacity of the cerebral autoregulation and has been shown to be a risk factor for subsequent cerebral ischemic events.^{19 20 21} Furthermore, the detection of patients with ICA stenosis and impaired reserve capacity might be especially useful if it could be shown that hemodynamics improve after CEA in these patients.

Our results are in accordance with the above-mentioned considerations. In patients with ICA stenosis and contralateral occlusion, the mean preoperative CO₂ reactivity was relatively low on both sides, and in patients with preoperative reversed OA flow, the preoperative mean CO₂ reactivity was lower on the same side than it was in patients with a normal direction of flow in the OA. An evident correlation has not as yet been found between the degree of ICA stenosis and the resulting disordered hemodynamics, based on positron emission tomography measurements and/or based on a marked decrease in hypercapnic or acetazolamide reactivity. However, as in the present study, an ICA occlusion is often distinguished from less severe stenoses by a marked decrease in CO₂ reactivity.^{13 19 22 23 24 25 26 27 28 29 30 31} Results about disordered hemodynamics in patients with reversed OA flow are more consistent.^{15 24 31 32} This is to be expected because reversed OA flow occurs when the intra-arterial pressure in the distal ICA is markedly reduced, which is often accompanied by markedly reduced CPP, thus greatly reducing the CO₂ reactivity. Although the specificity of reversed flow in the OA appears to be high, its sensitivity to detect markedly decreased CPP is low.^{24 31} In the present study, signs of collateral blood flow through the ACoA or PCoA were not associated with statistically significant differences in CO₂ reactivity. In studies where a difference based on clinical signs was found, the CO₂ reactivity ipsilateral to a symptomatic hemisphere was lower than that on the asymptomatic side.^{16 31 33 34} However, in other studies no differences were found when a classification based on the severity of preceding ischemic events was used, which we found as well.^{28 29 30 32}

On the basis of an increased mean CO₂ reactivity, CEA appears to improve hemodynamics in the ipsilateral hemisphere, as has been shown in other studies using similar or alternative methods.^{23 33 35 36 37 38 39 40} Additionally, our study showed that the increase in CO₂ reactivity was more pronounced when the preoperative value was relatively low (<30%). Fürst et al⁴¹ found a similar inverse relation using a reactivity index based on changes in the pulsatility of the TCD signal (Pourcelot's index). However, in their study the overall improvement in reactivity on the side of CEA was not statistically significant, which may be related to the use of the Pourcelot index. Interestingly, we also found such an inverse relation on the contralateral side, but this improvement occurred only when the preoperative CO₂ reactivity in that hemisphere was relatively low or even absent (<30%). Such a contralateral improvement has been reported before, but it is usually in relation to an ICA occlusion at this side and not merely based on CO₂ reactivity.^{22 33 39 40}

Not all patients with ICA occlusion showed a marked decrease in CO₂ reactivity. Therefore, the selection of patients who might show hemodynamic improvement on the side of an ICA occlusion after contralateral CEA on the basis of the existence of an ICA occlusion appears to be inferior to a selection protocol in which impaired CO₂ reactivity is taken into account. Widder et al³³ found an improvement in CO₂ reactivity in patients with ICA occlusions who did not undergo surgery. Such a spontaneous improvement occurred mainly during the first few months. They found less improvement when the ICA at the other side was more severely stenotic. In contrast, we found a larger increase in mean CO₂ reactivity at the CEA side when the contralateral ICA showed more stenosis, particularly in case of an occlusion. If these findings are combined, the measured improvement after CEA cannot be explained by spontaneous improvement but must be a genuine effect of CEA.

The results of the present study contribute to the growing evidence that assessment of CO₂ reactivity is a useful additional method for hemodynamic evaluation of patients with carotid artery disease. TCD with CO₂ reactivity can be used to determine the reserve capacity of the cerebral autoregulation, irrespective of the severity of stenosis or clinical signs or symptoms, because the CO₂ reactivity measured is the product of the many factors involved. Patients with carotid artery stenosis and absent or evidently decreased preoperative CO₂ reactivity in either hemisphere can be expected to benefit from CEA. These patients can be considered a subgroup with inadequate collateral blood supply, which results in markedly decreased CPP and impairment of further autoregulatory compensatory capacity. After CEA, CPP in the affected hemisphere might be restored within the range necessary for adequate cerebral autoregulation, as was shown by a highly significant mean increase in CO₂ reactivity after the operation. The clinical consequence of the increase in CO₂ reactivity remains to be demonstrated. However, since decreased CO₂ reactivity in patients with ICA stenosis is a risk factor for ischemic cerebral events,^{1 3 4} it is tempting to consider these patients as one of the subgroups who will especially benefit from CEA.

	Selected Abbreviations and Acronyms

 

ACA = anterior cerebral artery ACoA = anterior communicating artery BFV = blood flow velocity CBF = cerebral blood flow CEA = carotid endarterectomy CPP = cerebral perfusion pressure ICA = internal carotid artery MCA = middle cerebral artery NASCET = North American Symptomatic Carotid Endarterectomy Trial OA = ophthalmic artery PCoA = posterior communication artery TCD = transcranial Doppler sonography

Received September 10, 1996; revision received January 20, 1997; accepted January 20, 1997.

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