Ann Thorac Surg 2010;89:187-194. doi:10.1016/j.athoracsur.2009.09.030
© 2010 The Society of Thoracic Surgeons
Original Articles: Pediatric Cardiac
Cardiopulmonary Bypass Increases Permeability of the Blood-Cerebrospinal Fluid Barrier
Toru Okamura, MD,
Nobuyuki Ishibashi, MD,
David Zurakowski, PhD,
Richard A. Jonas, MD*
Department of Cardiovascular Surgery, Children's National Medical Center, Washington, DC
Accepted for publication September 14, 2009.
* Address correspondence to Dr Jonas, Department of Cardiac Surgery, Children's National Medical Center, 111 Michigan Ave NW, Washington, DC 20010 (Email: rjonas{at}cnmc.org).
Presented at the Poster Session of the Forty-fifth Annual Meeting of The Society of Thoracic Surgeons, San Francisco, CA, Jan 26–28, 2009.
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Abstract
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Background: The integrity of the blood-cerebrospinal fluid (CSF) barrier during cardiopulmonary bypass (CPB) with hypothermic circulatory arrest (HCA) has not been systematically studied, especially in children. We tested the hypothesis that the blood-CSF barrier is disrupted by CPB.
Methods: The study randomized 25 piglets (mean weight, 11 kg) to five groups (5 per group): anesthesia alone (control); CPB at 37°C with full-flow (FF); CPB at 25°C with very low flow (LF); and HCA at 15°C and 25°C. pH-stat strategy was applied during CPB. An epidural catheter was inserted into the cisterna magna for collection of CSF. CSF and blood samples were collected at seven points: after induction of anesthesia (baseline), at 10, 50 and 115 minutes after start of CPB, just before the end of CPB, and at 30 and 120 minutes after CPB. Albumin levels in CSF and plasma were measured to assess blood-CSF barrier integrity and the albumin ratio (CSF/plasma) was calculated (Q
Alb).
Results: In both HCA groups, the Q
Alb was significantly higher than in the control and 37°C FF groups (all p < 0.05), whereas Q
Alb in the 37°C group was not significantly different vs control.
Conclusions: The blood-CSF barrier is impaired by CPB with 1 hour of 15°C or 25°C HCA. Further investigations are needed to understand the behavior of the blood-CSF barrier during CPB and its role in neuroprotection.
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Introduction
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Cognitive impairment has been consistently observed after cardiopulmonary bypass (CPB) [1] and in adults has been associated with the number of microemboli detected during coronary artery bypass grafting. However, there are many other potential sources of brain injury in children. In a study commissioned by the National Institutes of Health, the incidence of neurologic complications in children undergoing cardiac operations at various institutions was 1% to 25% [2].
The brain is a unique tissue, being protected from free exchange of blood by the blood-brain barrier (BBB), located at the tight junctions and cell walls of the cerebral endothelium. In addition, two fluid compartments are present: the brain interstitial fluid, surrounding the neurons and glia, and the cerebrospinal fluid (CSF). CSF fills the ventricles and the external surfaces of the brain, acting both as a fluid cushion and drainage route for the products of cerebral metabolism [3].
The complex functions of the brain are critically dependent on the homeostasis of these two fluids, and any variation in their ionic, amino acid, or peptide composition will markedly affect brain function. The homeostasis of the brain interstitial fluid depends on complex functions of the BBB and the blood-CSF barrier (BCSFB), which are located at the choroid plexuses and the arachnoid membrane between the dura and subarachnoid fluid [4, 5]. The endothelium, therefore, does not form a barrier to the movement of small molecules. Instead, the BSCFB at the choroid plexus is formed by the epithelial cells and the tight junctions that link them. The other part of the BCSFB is the arachnoid membrane, which envelops the brain. The cells of this membrane are linked by tight junctions.
Damage to the BBB and BCSFB during CPB is one reason for neurologic dysfunction after heart operations [6, 7]. Studies of BBB and BCSFB during CPB in children are few, and the effect of CPB on the BBB and BCSFB is controversial. The mechanisms underlying this susceptibility are not completely understood. Moreover, some studies have not demonstrated BCSFB dysfunction and leakage of plasma proteins from CPB [8, 9].
The CSF/plasma ratio of albumin is used as an indicator of permeability of the BCSFB [10]. The calculated CSF/plasma concentration quotient for albumin, Q
Alb(CSFAlb/plasmaAlb = Q
Alb), has a higher sensitivity for barrier dysfunction than the absolute CSF concentrations. We developed a new model for collecting CSF samples intermittently during CPB. The purpose of this study was to test the hypothesis that the BCSFB is disrupted by CPB using albumin concentrations in CSF and plasma.
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Material and Methods
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Surgical Procedure
Twenty-five experiments (n = 5 in each group) were performed on 5- to 6-week-old Yorkshire piglets (Archer Farms Inc, Darlington, MD) with average body weight of 11.5 ± 1.3 kg. All animals received humane care in compliance with the Guide for the Care and Use of Laboratory Animals (National Institutes of Health publication 85-23, revised 1985).
The piglets were sedated with intramuscular ketamine (20 mg/kg) and xylazine (4 mg/kg). After endotracheal intubation (cuffed 5-mm tube) and an intravenous bolus of fentanyl (25 µg/kg), the piglets were ventilated with a pressure-controlled respirator using an inspiratory oxygen fraction of 21% pre-CPB and 100% post-CPB (rate 10 to 18 breaths/min) to achieve arterial pressure of carbon dioxide (PaCO
2) of 38 to 42 mm Hg. Anesthesia was maintained with fentanyl (25 µg/kg/h), midazolam (0.2 mg/kg/h), and pancuronium (0.2 mg/kg/h) using an infusion pump.
Animals were placed supine on a water-circulating heating mat to prevent hypothermia. Esophageal and rectal temperature probes were placed. The left femoral artery was cannulated and the catheter was advanced into the descending aorta for monitoring of blood pressure and blood gases. Blood pressure and body temperature were continuously monitored and recorded every 10 minutes. Blood gases were checked for pH, partial pressure of oxygen (PO
2) and carbon dioxide (PCO
2), sodium, potassium, calcium, glucose, and lactate every 20 minutes during CPB in 0.5-mL samples using a blood-gas analyzer (Siemens, Rapidlab 1265, Erlangen, Germany). A catheter was placed through the femoral vein into the vena cava for drug infusion.
The piglet was placed prone for inserting an epidural catheter, which was used to draw the CSF intermittently from the cisterna magna. A small pillow was placed under the shoulder to facilitate flexing the neck. After the midline of the occipital and cervical area was opened and the atlanto-occipital membrane was dissected, the dura mater of the cisterna magna was found. A purse-string suture of 6-0 Prolene (Ethicon, Sommerville, NJ) was placed on the dura mater, and an epidural catheter (Perifix mini set, B. Braun Medical Company, Allentown, PA) was gently inserted under that membrane, without any blood contamination, and was fixed to the dura mater (Fig 1).
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Fig 1. Introduction of the catheter into subdural space. The piglet was placed prone for inserting an epidural catheter, which was used to draw the cerebrospinal fluid intermittently from the cisterna magna. A small pillow was placed under the shoulder to facilitate flexing the neck. After the midline of the occipital and cervical area was opened and the atlanto-occipital membrane was dissected, the dura mater of the cisterna magna was found. A purse-string suture was placed on the dura mater. An epidural catheter was gently inserted under that membrane, without any blood contamination, and was fixed to the dura mater.
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The animal was returned supine, the right femoral artery was exposed for arterial CPB cannulation, and an anterolateral thoracotomy was performed in the third intercostal space. Heparin (300 IU/kg) was administered, and an 8F arterial cannula (Bio-Medicus, Medtronic, Minneapolis, MN) was advanced through the femoral artery into the abdominal aorta. A 28F venous cannula (Harvey; Bard, Tewksbury, MA) was inserted into the right atrium. The heart was not opened during the procedure.
CPB Management
A roller pump (Polystan, Vaerlose, Denmark) was used to generate nonpulsatile pump flow at 100 mL/kg in all experiments. The oxygenator gas mixture consisted of 5% CO2 and 95% O2 in all CPB groups. pH-stat management strategy was used in all CPB groups. The CPB circuit consisted of a 1000-mL filtered hard-shell venous reservoir (1361 Minimax, Medtronic, Minneapolis, MN), a membrane oxygenator (3381 Minimax Plus, Medtronic), a 40-µm arterial filter (Terumo, Tokyo, Japan), and 0.25-inch tubing. Venous drainage was by gravity. No cardiotomy suction was used. The venous catheter was left open during circulatory arrest.
A sterile circuit was used in each experiment. The CPB circuit was primed with 800 mL of blood. The blood used for priming of the CPB circuit to achieve a hematocrit of 30% on CPB was drawn on the morning of the experiment from an adult donor pig. Before the start of CPB and just before reperfusion, methylprednisolone (30 mg/kg), sodium bicarbonate 7.4% (10 mL), and furosemide (0.25 mg/kg) were added to the prime. After 10 minutes of normothermic bypass, piglets in the 15° and 25°C HCA groups and the 25°C LF group underwent 40 minutes of cooling to an esophageal temperature of 15° and 25°C, respectively. After a 60-minute period of HCA at 15°, 25°C, and 10 mL/kg/min low-flow CPB at 25°C, animals were rewarmed on CPB to 37°C for 50 minutes. In the 37°C FF group, the esophageal temperature was kept at 37°C during CPB. Esophageal temperature in the control group was maintained at 37°C without CPB. After weaning from CPB, animals were observed for 120 minutes. Topical cooling was applied for the hypothermic temperature groups.
CSF and Blood Sample Collection
Seven CSF and blood samples were collected from the epidural and arterial catheters during the perioperative period: baseline (pre-CPB), at 10, 50, and 115 minutes after the start of CPB, just before end of CPB (160 minutes after start of CPB), and at 30 (p-30) and 120 (p-120) minutes after the end of CPB. Plasma was prepared by centrifuging blood samples at 2000g for 15 minutes at room temperature. CSF and plasma were reserved directly into polypropylene tubes and frozen at –20°C.
Analysis of pH, PO 2, PCO 2, and Lactate in CSF and Plasma
Data for pH, PO
2, PCO
2, and lactate were measured using the blood gas machine (Rapid Lab 1246; Bayer, Germany) immediately to avoid mixing with room air, after drawing samples of CSF and blood.
Albumin Concentrations in CSF and Plasma Samples
Piglet albumin concentration in CSF was determined using a Piglet Albumin ELISA (enzyme-linked immunosorbent assay) Quantitation Kit (Bethyl Laboratories Inc, Montgomery, TX) according to the manufacturer's protocol. Briefly, 96-well plates were coated with 100 µL of capture antibody (10 µg/mL) for porcine albumin for 1 hour at room temperature and postcoated with 200 µL of 1% bovine serum albumin–Tris-buffered saline for 30 minutes. The 100-µL samples and standard solutions were incubated for 1 hour, and detective reaction by 100 µL of antibody/enzyme conjugate was performed for 1 hour. Then 100 µL of tetramethyl benzidine was reacted for 10 minutes. The reaction was stopped by 100 µL of sulfuric acid (0.5M), and absorbance was read at 450 nm using a plate reader. Mean values and standard deviations were calculated from three independent experiments determined in duplicate. Albumin concentrations in plasma samples were measured using BCP assay (BioAssay Systems, Hayward, CA).
Statistical Analysis
Continuous variables are expressed as mean ± standard deviation (SD). The Q
Alb, the albumin ratio (CSF/plasma), and other outcome variables were compared between the five experimental groups at the seven different times (baseline through 280 minutes) using repeated-measures analysis of variance (ANOVA) with the Bonferroni method for multiple group comparisons. Slopes were compared by the group-by-time two-way interaction F test, where a highly significant interaction indicates that differences between groups are conditional on specific time points. A significant group-by-time interaction can also indicate that certain groups, but not all groups, demonstrate changes in a variable over time (ie, different time-related slopes or profiles). Power analysis indicated that sample sizes of 5 piglets per group (measured at each of seven times) would provide 80% power to detect 30% mean differences in pH and lactate (plasma and CSF levels) between CPB experimental conditions and the control group by repeated-measures ANOVA, assuming a pooled standard deviation of 20% (nQuery Advisor, Statistical Solutions, Saugus, MA). Statistical analysis was performed with SPSS 16.0 software (SPSS Inc, Chicago, IL). Two-tailed values at p < 0.05 were considered statistically significant.
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Results
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Baseline data for age, weight, pH, PaO
2, PaCO
2, hematocrit level, mean arterial pressure (MAP), and saturation of the right atrium were compared between the five experimental groups and presented for all five experimental groups, reflecting no differences by the F tests in one-way ANOVA (all p > 0.10; Table 1).
The pH, PO
2, and PCO
2 were analyzed in CSF (Fig 2A, B, and C). The pH was significantly lowered towards acidosis levels in both HCA groups during HCA relative to the control group. In particular, pH at 115 minutes and just before the end of CPB in both HCA groups was significantly lower than in the other three groups. PO
2 of both HCA groups and 25°C LF piglets was significantly higher at 50 minutes than in other groups. The values of both HCA groups were higher at 115 minutes than in the others. PCO
2 in the continuous bypass groups was significantly higher at 115 minutes than in the control. The values in both HCA groups were significantly higher at 115 minutes than in the continuous bypass groups.
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Fig 2. (A) Changes of pH in cerebrospinal fluid (CSF) for all cardiopulmonary bypass (CPB) groups. Levels for both 15°C and 25°C hypothermic circulatory arrest (HCA) groups were significantly lower than the control group. The pH of both HCA groups at 115 and 160 minutes was lower than the other three groups. *p < 0.05, repeated-measures analysis of variance (ANOVA). (p-30 = 30 minutes after the end of cardiopulmonary bypass (CPB), p-120 = 120 min after the end of CPB; FF = fast flow; LF = low flow.) (B) Changes of partial oxygen pressure (PO
2) in CSF for all groups. PO
2 of both HCA and 25°C, low flow (LF) groups was significantly higher at 50 minutes than in others. The values of both HCA groups were higher at 115 minutes than in others. *p < 0.05, one-way factorial ANOVA. (C) Changes of partial carbon dioxide pressure (PCO
2) in the CSF is shown for all groups. PCO
2 levels in the bypass groups were significantly higher at 115 minutes than in the control. The values in both HCA groups were significantly higher at 115 minutes than in other bypass groups, * p < 0.05, repeated-measures ANOVA. Error bars show the standard deviation.
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Plasma lactate levels at 25°C with LF and in both HCA groups (Fig 3A and B) were significantly increased compared with control. Lactate levels in the CSF in both HCA groups at 115, 160, p-30, and p-120 minutes were significantly increased compared with the others (p < 0.05). Levels in the control and 37°C with FF groups were not increased during the experimental time course.
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Fig 3. (A) Changes of lactate levels in plasma are shown for all cardiopulmonary bypass (CPB) groups. Lactate levels in 25°C with low flow (LF) and both hypothermic circulatory arrest (HCA) groups were significantly increased compared with control. *p < 0.05, repeated-measures analysis of variance (ANOVA). (B) Changes of lactate levels in cerebrospinal fluid (CSF) are shown for all groups. Lactate levels in both HCA groups at 115, 160, p-30 (30 minutes after CPB) and p-120 minutes (120 minutes after CPB) were significantly increased compared with others. *p < 0.05, repeated-measures ANOVA. Error bars show the standard deviation.
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Tables 2, 3, and 4
present the exact outcome data in terms of means and standard deviations as well as specific results from two-way repeated-measures ANOVA showing the p values for within-group (7 time points: baseline through 120 minutes after CPB), between-group (5 groups), and the group-by-time interaction (ie, slope test). Significant interactions are followed by post hoc Bonferroni comparisons to assess where differences lie. Table 2 presents pH, PO
2, and PCO
2 data, Table 3 summarizes the lactate data, and Table 4 the albumin ratio (CSF/plasma). Six variables are summarized in Tables 2, 3, and 4 and, therefore, within-group, between-group, and interaction p value (3 columns) for each of these 6 variables. All 6 group-by-time interaction tests are highly significant (p < 0.001), indicating that for each variable there are significant differences between the experimental groups, although only at certain time points. For example, the analysis of the albumin concentration data reported in Table 4 indicates significant differences between the groups, but only at 115 and 160 minutes after onset of CPB and at p-30. The interaction test also confirmed, by virtue of Bonferroni comparisons, significant changes in the albumin (CSF/plasma) ratio, Q
Alb, but only for the first three experimental groups, 15° and 25°C HCA, and 25°C LF. Specifically, repeated-measures ANOVA revealed no significant group differences in Q
Alb at baseline (p = 0.88), 10 minutes (p = 0.81), or 50 minutes (p = 0.86); however, the albumin ratio was significantly higher in the 15°C HCA group compared with 37°C FF and 37°C control at 115, 160 minutes, and p-30 (all p < 0.05). In addition, Q
Alb in the 25°C HCA group was significantly higher compared with 25°C LF at 115 minutes (p = 0.03), 37°C FF at 115, 160, and 190 minutes (all p < 0.01), and compared with 37°C control at 115 (p < 0.01), 160 (p < 0.01), and 190 minutes (p = 0.03). At p-120 minutes, none of the five experimental groups showed any differences with respect to the albumin ratio (p = 0.31).
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Table 2 pH, PO
2 and PCO
2 in the Cerebrospinal Fluid for Each Group From Baseline Through 120 Minutes After Cardiopulmonary Bypass
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Table 3 Lactate Measured in Plasma and Cerebrospinal Fluid for Each Group Baseline Through 120 Minutes After Cardiopulmonary Bypass
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Table 4 Albumin Ratio (Cerebrospinal Fluid/Plasma) for Each Group From Baseline Through 120 Minutes After Cardiopulmonary Bypass
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Changes in the Q
Alb were in themselves indicative of disruption of the BCSFB. Both HCA groups demonstrated a significant increase in BCSFB permeability after reperfusion (p < 0.01). The leakage of albumin was still maintained even after the end of bypass. There were no changes in Q
Alb at 37°C FF. Anesthesia alone did not affect the permeability of BCSFB over 6 hours (Fig 4).
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Fig 4. Albumin quotient (QAlb) of cerebrospinal fluid/plasma is shown for experimental cardiopulmonary bypass (CPB) groups at each time point. Error bars denote standard deviations. Asterisks indicate higher QAlb (reflecting greater permeability) compared with 37°C fast flow (FF) and 37°C off (control). *p < 0.05, analysis of variance with Bonferroni correction. QALB in 25°C hypothermic circulatory arrest (HCA) was higher than 25°C low flow (LF) at 115 minutes (p = 0.03), 37°C FF at 115, 160, and 190 minutes (all p < 0.01), and 37°C off (control) at 115 minutes (p < 0.01), 160 minutes (p < 0.01), and 190 minutes (p = 0.03).
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Comment
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We are aware of only a small number of investigations regarding the BCSFB during CPB [11–13]. No systematic research studies have evaluated the effects of CPB on the BCSFB in children. In the current study, we examined the integrity of the BCSFB during various CPB techniques using a new experimental model. The values of PO
2 and PCO
2 in CSF, in contrast to the pH, remained within the normal range at the end of CPB under this protocol. It is generally reported that CO2 in blood diffuses easily to CSF through the BCSFB. On the other hand, pH in CSF tends to acidosis after reperfusion, and time is required to return to the normal range. Some investigators have reported that the decline toward acidosis in the CSF results in brain impairment [14, 15]. A bypass condition such as a deep HCA of 15°C did not eliminate acidosis in the CSF. In this study, however, ultra low-flow bypass reduced acidosis in the CSF; specifically, LF bypass at 25°C was effective and adequate for maintaining pH.
This experiment has also demonstrated that changes in CSF and blood lactate levels vary according to bypass condition. Lactate levels in CSF in the 25°C HCA group, which is the experimental setting that poses the greatest ischemic effect, were highest among all groups [16]. Although CSF pH levels were stable with continuous LF at 25°C, plasma lactate levels increased at 25°C within the LF group. These data suggest that ultra low-flow bypass at 25°C is adequate for maintaining oxygen supply to the brain, not but to other organs, and that LF bypass is preferable to deep HCA at 15°C for oxygen supply [17]. Khaladj and colleagues [18] concluded that lactate levels in CSF appear to be sensitive in terms of the time course of events in characterizing an oxygen supply shortage to the central nervous system and that lactate in the CSF potentially may mark anaerobic metabolism without necessarily being associated with any permanent cellular damage. The mechanism or mechanisms underlying these changes remain unclear; however, they may be partly due to a failure of the blood-brain barrier or of altered metabolism during ischemia. Our data suggest that 25°C LF with pH-stat strategy during CPB was adequate for oxygen supply to the brain.
The piglet model we have developed confirms that the BCSFB is indeed disrupted by CPB. The CSF/plasma ratio of albumin is used as an indicator of permeability of the BCSFB [10]. The calculated CSF/plasma concentration quotient, Q, (eg, for albumin: CSFAlb/plasmaAlb = Q
Alb) has a higher sensitivity for barrier dysfunction than the absolute CSF concentrations. In particular, if CSF and plasma are analyzed in the same analytical run, the precision of quotients is higher and values are independent of method. In this study, the Q
Alb showed the increase of permeability of the BCSFB and in both HCA groups, and the increase of Q
Alb demonstrated a correlation with ischemic impact. In short, the disruption and dysfunction of BCSFB was considerable in the both HCA groups. It suggests that cerebral ischemia occurs during CPB and this is related to lactate levels in CSF and plasma. It should be noted that ultra low-flow bypass reduced the albumin leakage from the BCSFB. However, Q
Alb was not improved during experiments, even after the end of bypass.
Our data suggest that ischemic effect and reperfusion injury of CPB and post-CPB inflammation affect the barrier function. There were no significant changes in albumin levels for the control and 37°C with FF conditions. Anesthesia alone and 37°C with FF did not affect the BCSFB. Ischemia was one cause for breaching of the BCSFB. However the lactate levels in plasma and increased in the 25°C with LF group despite unchanging lactate levels in the CSF. The BCSFB was maintained in the 25°C with LF group. Even ultra-low flow bypass might be useful for barrier protection. Further studies are needed to understand the restoration of a barrier function.
In summary, we have shown increased permeability of the BCSFB during CPB using a new experimental piglet model. A bypass condition of 25°C with low flow was effective in maintaining cerebral oxygen metabolism, but was inadequate for supplying oxygen to other organs. This new piglet model has advantages for investigating and understanding the behavior of the BCSFB function during CPB. Future studies should assess the optimal combination of bypass conditions, including temperature, bypass flow, and possible drug treatment for maintaining the barrier function.
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Acknowledgments
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This study was supported by grant RO1-HL060922 from the National Institutes of Health.
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Abstract
Introduction
