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Anesth Analg 1999;89:823
© 1999 International Anesthesia Research Society

CARDIOVASCULAR ANESTHESIA

Cerebrovascular Cytokine Responses During Coronary Artery Bypass Surgery: Specific Production of Interleukin-8 and Its Attenuation by Hypothermic Cardiopulmonary Bypass

Koichiroh Nandate, MD*,{dagger}, Alain Vuylsteke, MD{dagger}, Alan E. Crosbie, PhD{dagger}, Souad Messahel, PhD*, Amo Oduro-Dominah, MRCP, FRCA{dagger}, and David K. Menon, MD, PhD*

Departments of Anaesthesia, *University of Cambridge and {dagger}Papworth Hospital, Cambridge, United Kingdom

Address correspondence and reprint requests to Dr. David K. Menon, University Department of Anaesthesia, Addenbrooke’s Hospital, Hills Road, Cambridge, CB2 2QQ, UK.


   Abstract
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 Abstract
Introduction
 Methods
 Results
 Discussion
 References
 
Brain dysfunction after cardiopulmonary bypass (CPB) is common, and it has been hypothesized that this injury might be due partly to activation of inflammatory processes in the brain. We measured juguloarterial gradients for interleukin-1ß, interleukin-6, and interleukin-8 (IL-8) as indices of local proinflammatory cytokine production in the brain and studied the effect of temperature during CPB on these changes. Twelve patients undergoing coronary artery bypass graft surgery (normothermic CPB n = 6, hypothermic CPB n = 6) were studied. Cytokine levels were measured in paired arterial and jugular bulb samples obtained before, during, and after CPB. Although systemic levels of all three cytokines increased during and after CPB, increases in juguloarterial cytokine gradients were observed only for IL-8. Juguloarterial IL-8 gradients started to increase 1 h post-CPB and were significantly elevated 6 h post-CPB (P < 0.05). At this time point, the median (interquartile range) juguloarterial IL-8 gradients were significantly larger in the normothermic CPB group (25.81 [24.49–39.51] pg/mL) compared with the hypothermic CPB group (6.69 [-0.04 to 15.47] pg/mL; P < 0.05). These data imply specific and significant IL-8 production in the cerebrovascular bed during CPB and suggest that these changes may be suppressed by hypothermia during CPB.

Implications: Using juguloarterial gradients to measure cerebrovascular cytokine production is novel in the setting of cardiopulmonary bypass and implicates the cerebral activation of inflammatory processes, which may contribute to brain dysfunction. Hypothermia during cardiopulmonary bypass may significantly attenuate this response.


   Introduction
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 Abstract
 Introduction
Methods
 Results
 Discussion
 References
 
Brain dysfunction after cardiac surgery with cardiopulmonary bypass (CPB) is not uncommon (1), but its pathophysiological mechanisms remain unclear. Many reports have documented an increase in proinflammatory processes after CPB (2), and there is accumulating evidence that inflammation may be important in the setting of acute neuronal injury resulting from trauma (3) and ischemia (4). Plasma, cerebrospinal fluid (CSF), or tissue levels of interleukin-1ß (IL-1ß), interleukin-6 (IL-6), and interleukin-8 (IL-8) have been reported to increase both experimental (5) and clinical (6) brain injury. However, it is not known whether these systemic increases in proinflammatory mediators reflect brain cytokine responses or contribute to the brain dysfunction observed after CPB.

We sought to characterize local cytokine responses in the brain and to document their temporal course. Because it is not feasible to obtain samples of CSF or brain tissue from patients after CPB, we measured plasma cytokine levels, localized their production to the brain by measuring levels in both jugular bulb and arterial blood samples, and calculated juguloarterial gradients. Although this technique has been used to localize changes in mediator levels to the brain in other clinical settings (7–9), it has not been used in the study of cerebral inflammatory processes during CPB. This approach negates the effects of hemodilution at any given time point and can provide useful information on regional processes in the brain.


   Methods
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 Abstract
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 Methods
Results
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This was an unblinded, observational, prospective study. After local research ethics committee approval and informed written consent, 12 patients undergoing elective and primary coronary artery bypass graft were enrolled in the study. Patients were managed with a standardized CPB protocol and were assigned to the normothermic or hypothermic subgroups based on surgical preference. Half of the patients (n = 6) were scheduled for hypothermic (30°C) and the other half (n = 6) for normothermic (37°C) CPB. Patients with a history of neurological, cerebrovascular, or significant neuropsychiatric disease were excluded from this study. Aspirin and other nonsteroidal antiinflammatory drugs were discontinued 7 days before surgery.

After premedication with morphine (15 mg) and scopolamine (0.3 mg), anesthesia was induced with midazolam (0.1 mg/kg) and fentanyl (15 µg/kg) and was maintained with a propofol infusion (3 mg · kg-1 · h-1). Neuromuscular blockade was achieved with the administration of pancuronium (0.1 mg/kg). Ventilation was performed with an air/oxygen mixture, and PaCO2 was maintained at 35–40 mm Hg during mechanical ventilatory support. Arterial and central venous blood pressures were invasively monitored throughout the procedure by using catheters inserted in the left radial artery and the right internal jugular vein, respectively. Body temperature was monitored with a nasopharyngeal temperature (NPT) probe (Mon-a-therm; Mallinckrodt Medical, St. Louis, MO). After anesthetic induction, a retrograde internal jugular catheter (Vygon Leader Cath 14G; Vygon, Gloucs, UK) was inserted in the left jugular bulb. The position of the catheter tip was checked radiologically in the postoperative period, and its tip was confirmed to lie lateral to the mastoid process and opposite the bodies of the first or second cervical vertebra.

A standard CPB technique was used in all patients. Heparin (300 Us/kg) was administered before aortic cannulation. The CPB circuit consisted of a hollow fiber membrane oxygenator (Maxima®; Medtronic, Anaheim, CA) and a roller pump (Cobe Laboratory, Denver, CO), which was primed with a standard solution consisting of crystalloid (1000–1150 mL) and mannitol (350–500 mL). A hard-shell venous reservoir, open to air, was used with an integral cardiotomy reservoir. Nonpulsatile CPB was used with flow rates of 2.4 L · min-1 · m-2 in the normothermic group and 1.8 L · min-1 · m-2 in the hypothermic group. Perfusion pressure was maintained between 50 and 60 mm Hg. PaCO2 during CPB was controlled with the {alpha}-stat method (temperature uncorrected). Immediately after commencement of CPB, the ascending aorta was cross-clamped, and cardioplegic solution was administered. During CPB, NPT was maintained at 37°C in the normothermic group and 30°C in the hypothermic group. In the hypothermic group, NPT was gradually restored to 37.5°C after the distal anastomosis of the last graft was performed. During rewarming, the temperature of the water from the heat exchange was never more than 10°C warmer than NPT.

Blood samples were collected simultaneously from the radial artery and jugular bulb catheter at the following times: after anesthetic induction (T0, baseline), immediately after initiation of CPB (T1), 15 and 30 min after the achievement of the target temperature (T2 and T3), immediately after weaning from CPB (T4), and 60 and 360 min after weaning from CPB (T5 and T6). Plasma was immediately separated by centrifugation at 3000 rpm for 10 min and frozen at -80°C for later analysis.

Plasma levels of all three cytokines (IL-1ß, IL-6, IL-8) were measured in duplicate by using an enzyme-linked immunosorbent assay method (QuantikineTM Immunoassay; R & D Systems, Oxon, UK). Intraassay coefficients of variation were measured for those cytokines that exhibited significant juguloarterial gradients to provide an estimate of the clinical significance of measured juguloarterial gradients. Ten standards of known concentration in the range of clinically measured values (0–125 pg/mL) were assayed four times on one plate.

All clinical data are presented as median (interquartile range). All results were corrected for hemodilution using concurrent hematocrit values (10). Sequential increases in systemic (arterial) levels and juguloarterial gradients of the three cytokines were compared with baseline values by using the Wilcoxon signed rank test. Differences in systemic cytokine levels and juguloarterial gradients between the normothermic and hypothermic groups at individual time points were compared by using the Mann-Whitney U-test. All multiple comparisons were corrected with Bonferonni corrections, and P values < 0.05 were considered significant.


   Results
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 Methods
 Results
Discussion
 References
 
There were no significant differences between the normothermic and hypothermic groups in age, height, weight, total CPB time, and aortic cross-clamp time (Table 1). Arterial levels of all three cytokines increased in all patients during and after CPB and were significantly different from baseline at T2, T3, T4, T5, and T6 (P < 0.05) (Figure 1). Subgroup data showed that arterial levels of all three cytokines during CPB were significantly higher in the normothermic CPB group compared with the hypothermic CPB group (P < 0.05) (Figure 2).


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  		Table 1. Demographic and Operative Characteristics of All Patients
 


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  		Figure 1. Median, 25th and 75th percentiles, and ranges (vertical bars) of arterial plasma concentrations of (A) interleukin 8 (IL-8), (B) interleukin 6 (IL-6), and (C) interleukin 1ß (IL-1ß) and juguloarterial gradients in the plasma concentrations. T0 = pre-CPB (baseline), T1 = immediately after initiation of CPB, T2 = 15 min after target temperature had been obtained, T3 = 30 min after target temperature had been obtained, T4 = immediately after weaning from CPB, T5 = 60 min post-CPB, and T6 = 360 min post-CPB. Data in both white and gray boxes are from all subjects (*P < 0.05 for comparisons versus baseline values, corrected for multiple comparisons). CPB = cardiopulmonary bypass.

 


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  		Figure 2. Median, 25th, and 75th percentiles, and ranges (vertical bars) of arterial plasma concentrations of (A) interleukin 8 (IL-8), (B) interleukin 6 (IL-6), and (C) interleukin 1ß (IL-1ß). T0 = pre-CPB (baseline), T1 = 30 s after initiation of CPB, T2 = 15 min after target temperature had been obtained, T3 = 30 min after target temperature had been obtained, T4 = immediately after weaning from CPB, T5 = 60 min post-CPB, and T6 = 360 min post-CPB. *P < 0.05, corrected for multiple comparisons, between the normothermic and hypothermic groups. CPB = cardiopulmonary bypass.

 
No significant increases in juguloarterial cytokine gradients from baseline values were observed before or during CPB in any patient group (Figure 1). Furthermore, no significant juguloarterial gradients were observed for IL-1ß or IL-6 in the post-CPB period (Figure 1, B and C). However, after weaning from CPB, a progressive increase in the juguloarterial IL-8 gradient was observed, which achieved significance 6 h post-CPB. At this time point, the median juguloarterial gradient was 27.2% of median systemic arterial levels, implying a large and robust difference in IL-8 levels across the brain (Figure 1A, Table 2).


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  		Table 2. Arterial Plasma Concentration and Juguloarterial Gradients of Interleukin-8 in All Patients
 
Comparison of the normothermic and hypothermic subgroups at this time point showed a significant difference in juguloarterial IL-8 gradients (P < 0.05), with significantly higher values in the normothermic CPB group (Figure 3, Table 3). At this time point, NPT did not differ significantly between the normothermic (37.4 [37–37.5]°C) and hypothermic (37.1 [36.5–37.3]°C) CPB subgroups. There were no significant increases in juguloarterial gradients for IL-8 in the hypothermic group at any time point compared with baseline.



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  		Figure 3. Median, 25th and 75th percentiles, and ranges (vertical bars) of juguloarterial gradients for interleukin-8 (IL-8). T0 = pre-CPB (baseline), T1 = 30 s after initiation of CPB, T2 = 15 min after target temperature had been obtained, T3 = 30 min after target temperature had been obtained, T4 = immediately after weaning from CPB, T5 = 60 min post-CPB, and T6 = 360 min post-CPB. *P < 0.05, corrected for multiple comparisons, between the normothermic and hypothermic groups. CPB = cardiopulmonary bypass.

 

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  		Table 3. Juguloarterial Interleukin-8 Gradients in the Normo- and Hypothermic Subgroups
 
Measurement of the intraassay reproducibility for IL-8 showed a mean coefficient of variance of 6.9%. These data suggest that juguloarterial differences >15% of systemic levels (>2 coefficient of variance values) are unlikely to be due to lack of reproducibility of the assay technique.


   Discussion
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 Abstract
 Introduction
 Methods
 Results
 Discussion
References
 
We demonstrated significant gradients of IL-8 across the cerebral circulation in the post-CPB period, whereas the juguloarterial gradients of neither IL-1ß nor IL-6 increased during this period. Furthermore, we showed that these increases in juguloarterial IL-8 gradients are significantly attenuated by hypothermia during CPB.

The systemic changes that we observed in cytokine levels are consistent with previous data (11,12). We found that hypothermic bypass management attenuated the increases in systemic levels of the three cytokines that we studied during and after CPB, but these differences only achieved significance during CPB. Although these findings are partially consistent with previous data (13), the effect of hypothermia on systemic cytokine levels after CPB remains a subject of debate (14).

It is relevant to consider the causes and consequences of increased cerebral IL-8 production associated with CPB. Cerebral dysfunction is common after cardiac surgery (1). The pathophysiological mechanisms have not been fully elucidated, but it is generally believed that CPB plays an important role. Global hypoperfusion and focal embolic ischemia during CPB may expose the brain to ischemia-reperfusion episodes, which up-regulate chemokine production by the brain (15).

IL-8 and related chemokines play a pivotal role in promoting neutrophil recruitment to sites of inflammation, with consequent amplification of inflammatory processes (16). Although there are no data regarding cerebral cytokine production after CPB, marked increases in IL-8 and cytokine-induced neutrophil chemoattractant have been detected after cerebral ischemia-reperfusion episodes in animals (17). Furthermore, antibodies to IL-8 have been shown to reduce cerebral edema and infarct volume in a cerebral ischemia-reperfusion injury model (18). These data are consistent with our findings and support the possibility that IL-8 plays a key role in producing the brain injury after CPB.

We showed that, at least until 6 h post-CPB, using hypothermic bypass significantly attenuates the cerebral IL-8 response after CPB. This effect of hypothermia on IL-8 production in the post-CPB period seems to be relatively specific to the brain because there were no significant differences in systemic IL-8 levels between these two groups at these time points. It is unclear from these data whether this suppression of cerebral IL-8 responses 6 h post-CPB provides evidence of actual attenuation of the inflammatory response in the brain by hypothermia or merely reflects a delay in the cerebral cytokine responses associated with CPB.

The differences in juguloarterial gradients may reflect differences in cerebral blood flow (CBF) rather than a difference in IL-8 generation in the cerebrovascular bed. This seems unlikely because the most significant differences were observed 6 h postbypass, when the effects of CPB temperature on CBF would be minimal. The confounding effect of CBF changes would be to increase juguloarterial gradients in the group in which CBF was lower. The literature suggests that CBF during hypothermic CPB is lower than that during normothermic CPB (19), which would tend to result in lower juguloarterial gradients for indicators produced in the cerebrovascular bed in normothermic patients. We observed a greater juguloarterial gradient for IL-8 in the normothermic group despite the confounding effect of temperature, rather than because of it.

Although IL-8 production would be expected to result in local neutrophil accumulation and degranulation with subsequent tissue injury (16), we have no data on this subject. Future studies should address the consequences of IL-8 production in the brain and investigate the factors, including temperature management during CPB, that modulate its release. Furthermore, several investigators have emphasized the need to consider the balance between pro- and antiinflammatory cytokines in any clinical setting (20). Although these concepts have been explored in the setting of systemic mediator production after CPB, we need to acquire data on cerebral cytokine balance in the same setting.

We observed no significant juguloarterial gradients for either IL-6 or IL-1ß at any stage of the study. These findings have several potential interpretations. It may be that IL-6 and IL-1ß are not released into the cerebrovascular bed after the insult provided by CPB. Alternatively, we may have missed significant cerebral IL-6 or IL-1ß generation in the brain if such production was extremely short-lived or did not coincide with our sampling time points. We believe that the latter explanation is unlikely because animal studies show that production of these mediators in other forms of brain injury is not a transient phenomenon, and previous publications have documented increases in juguloarterial IL-6 gradients after head injury and subarachnoid hemorrhage (7). Further, IL-1ß is produced early after injury (21) and should have been detected at the sampling points that were used in this study. However, IL-6 production in the brain may be a delayed event after acute brain injury (22), and later sampling points might have been useful in detecting increases in cerebral IL-6 production.

Finally, it is significant that IL-8 has a significantly shorter plasma half-life than either IL-1ß or IL-6 (8 vs 100 and 240 min, respectively) (23–25). Analysis of plasma kinetics suggests that a short half-life would favor the detection of dynamic changes in cerebral production of IL-8 compared with the other two cytokines.

In summary, we demonstrated significant juguloarterial gradients for IL-8 in the cerebral circulation 6 h post-CPB, which was suppressed by hypothermia during CPB. These results suggest that IL-8, a potent chemokine, is activated in the brain in the post-CPB period and that temperature management during CPB may significantly attenuate this response.


   Acknowledgments
 
Support for these studies was provided by grants from The Critical Care Foundation, UK, and Zeneca Pharmaceuticals, UK.


   Footnotes
 
KN was supported by a grant from the Fukuda Foundation for Medical Technology, Japan.


   References
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 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 

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Accepted for publication February 25, 1999.




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Lippincott, Williams & Wilkins Anesthesia & Analgesia® is published for the International Anesthesia Research Society® by Lippincott Williams & Wilkins and Stanford University Libraries' HighWire Press®. Copyright 1999 by the International Anesthesia Research Society. Online ISSN: 1526-7598   Print ISSN: 0003-2999 HighWire Press