Xenon attenuates cardiopulmonary bypass-induced neurologic and neurocognitive dysfunction in the rat

BACKGROUND: With clinical data suggesting a role for excitatory amino acid neurotransmission in the pathogenesis of cardiopulmonary bypass (CPB)-associated brain injury, the current study was designed to determine whether xenon, an N-methyl-D-aspartate receptor antagonist, would attenuate CPB-induced neurologic and neurocognitive dysfunction in the rat. METHODS: Following surgical preparation, rats were randomly divided into four groups: (1) sham rats were cannulated but did not undergo CPB; (2) CPB rats were subjected to 60 min of CPB using a membrane oxygenator receiving a gas mixture of 30% O2, 65% N2, and 5% CO2; (3) CPB + MK801 rats received MK801 (0.15 mg/kg intravenous) 15 min prior to 60 min of CPB with the same gas mixture; and (4) CPB + xenon rats underwent 60 min of CPB using an oxygenator receiving 30% O2, 60% xenon, 5% N2, and 5% CO2. Following CPB, the rats recovered for 12 days, during which they underwent standardized neurologic and neurocognitive testing (Morris water maze). RESULTS: The sham and CPB + xenon groups had significantly better neurologic outcome compared to both the CPB and CPB + MK801 groups on postoperative days 1 and 3 (P < 0.05). Compared to the CPB group, the sham, CPB + MK801, and CPB + xenon groups had better neurocognitive outcome on postoperative days 3 and 4 (P < 0.001). By the 12th day, the neurocognitive outcome remained significantly better in the CPB + xenon group compared to the CPB group (P < 0.01). CONCLUSION: These data indicate that CPB-induced neurologic and neurocognitive dysfunction can be attenuated by the administration of xenon, potentially related to its neuroprotective effect via N-methyl-D-aspartate receptor antagonism.     

Xenon Impairs Neurocognitive and Histologic Outcome after Cardiopulmonary Bypass Combined with Cerebral Air Embolism in Rats

Background: The neuroprotective properties of xenon may improve cerebral outcome after cardiac surgery using cardiopulmonary bypass (CPB). However, its disposition to expand gaseous bubbles that during CPB present as cerebral air emboli (CAE) could abolish any beneficial effect or even worsen cerebral outcome. Therefore, the authors studied the impact of xenon on neurologic, cognitive, and histologic outcome after CPB combined with CAE in rats.

Methods: With institutional review board approval, 40 rats were assigned to four groups (n = 10). In two CPB-CAE groups, rats were subjected to 90 min of normothermic CPB with 10 repetitively administered CAEs (0.3 [mu]l/bolus). Rats in two sham groups were not exposed to CPB and CAE. Groups were further subdivided into xenon (56%; 20 min before, during, and 30 min after CPB) and nitrogen groups. Neurologic and cognitive function was tested until postoperative day 14, when cerebral infarct volumes were determined.

Results: Animals of the CPB-CAE groups showed transient deficits in gross neurologic function. Further, rats of the CPB-CAE-xenon group demonstrated impaired fine motor and cognitive performance persisting until postoperative day 14. Consistently, infarct volumes were larger in the CPB-CAE-xenon group compared with the CPB-CAE-nitrogen group (P = 0.03).     

Cardiopulmonary bypass induces neurologic and neurocognitive dysfunction in the rat.

BACKGROUND: Neurocognitive dysfunction is a common complication of cardiac surgery using cardiopulmonary bypass (CPB). Elucidating injury mechanisms and developing neuroprotective strategies have been hampered by the lack of a suitable long-term recovery model of CPB. The purpose of this study was to investigate neurologic and neurocognitive outcome after CPB in a recovery model of CPB in the rat. METHODS: Fasted rats (n = 10) were subjected to 60 min of normothermic (37.5 degrees C) nonpulsatile CPB using a roller pump and a membrane oxygenator. Sham-operated controls (n = 10) were not subjected to CPB. Neurologic outcome was assessed on days 1, 3, and 12 after CPB using standardized functional testing. Neurocognitive outcome, defined as the time (or latency) to finding a submerged platform in a Morris water maze (an indicator of visual-spatial learning and memory), was evaluated daily from post-CPB days 3-12. Histologic injury in the hippocampus was also evaluated. RESULTS: Neurologic outcome was worse in the CPB versus the sham-operated controls at all three measurement intervals (P < 0.001). The CPB group also had longer water maze latencies compared with the sham-operated controls (P = 0.004), indicating significant neurocognitive dysfunction after CPB. No difference in histologic injury between groups was observed. CONCLUSIONS: CPB caused both neurologic and neurocognitive impairment in a rodent recovery model. This model could potentially facilitate the investigation of CPB-related injury mechanisms and possible neuroprotective interventions.     

Cardiopulmonary Bypass Induces Neurologic and Neurocognitive Dysfunction in the Rat

Background : Neurocognitive dysfunction is a common complication of cardiac surgery using cardiopulmonary bypass (CPB). Elucidating injury mechanisms and developing neuroprotective strategies have been hampered by the lack of a suitable long-term recovery model of CPB. The purpose of this study was to investigate neurologic and neurocognitive outcome after CPB in a recovery model of CPB in the rat.

Methods : Fasted rats (n = 10) were subjected to 60 min of normothermic (37.5[degrees]C) nonpulsatile CPB using a roller pump and a membrane oxygenator. Sham-operated controls (n = 10) were not subjected to CPB. Neurologic outcome was assessed on days 1, 3, and 12 after CPB using standardized functional testing. Neurocognitive outcome, defined as the time (or latency) to finding a submerged platform in a Morris water maze (an indicator of visual-spatial learning and memory), was evaluated daily from post-CPB days 3-12. Histologic injury in the hippocampus was also evaluated.

Results : Neurologic outcome was worse in the CPB versus the sham-operated controls at all three measurement intervals (P < 0.001). The CPB group also had longer water maze latencies compared with the sham-operated controls (P = 0.004), indicating significant neurocognitive dysfunction after CPB. No difference in histologic injury between groups was observed.     

Xenon impairs neurocognitive and histologic outcome after cardiopulmonary bypass combined with cerebral air embolism in rats

BACKGROUND: The neuroprotective properties of xenon may improve cerebral outcome after cardiac surgery using cardiopulmonary bypass (CPB). However, its disposition to expand gaseous bubbles that during CPB present as cerebral air emboli (CAE) could abolish any beneficial effect or even worsen cerebral outcome. Therefore, the authors studied the impact of xenon on neurologic, cognitive, and histologic outcome after CPB combined with CAE in rats. METHODS: With institutional review board approval, 40 rats were assigned to four groups (n = 10). In two CPB-CAE groups, rats were subjected to 90 min of normothermic CPB with 10 repetitively administered CAEs (0.3 microl/bolus). Rats in two sham groups were not exposed to CPB and CAE. Groups were further subdivided into xenon (56%; 20 min before, during, and 30 min after CPB) and nitrogen groups. Neurologic and cognitive function was tested until postoperative day 14, when cerebral infarct volumes were determined. RESULTS: Animals of the CPB-CAE groups showed transient deficits in gross neurologic function. Further, rats of the CPB-CAE-xenon group demonstrated impaired fine motor and cognitive performance persisting until postoperative day 14. Consistently, infarct volumes were larger in the CPB-CAE-xenon group compared with the CPB-CAE-nitrogen group (P = 0.03). CONCLUSIONS: This is the first demonstration in which the neurologic effects of CAE have been examined in a rat model of CPB. Xenon exposure aggravated the neurologic dysfunction that is produced by CAE during CPB; potential neuroprotective effects of xenon may have been masked by the effects of xenon on CAE.     

体外循环对大鼠体内白介素．6的释放、大脑NF-κB的表达及神经认知功能的影响

背景心外科手术中,体外循环（cardiopulmonary bypass,CPB）术后发生的神经认知功能障碍一直影响着患者的生活质量。炎症反应可能是其中的因素之一。本实验中我们检测了年轻大鼠围术期体内IL-6的浓度,海马NF-κB的表达含量和神经认知功能,同时评估了氧合器的大小对上述指标的影响。方法将大鼠随机分为4组：空白对照组（n=7）,假手术组（n=10,麻醉、置管、不连接体外循环）和两组体外循环实验组,CPB组大鼠在麻醉、置管后行90分钟的体外循环,分别使用小容量的大鼠氧合器（n=10）和新生儿氧合器（n=10）。在术前、CPB结束时和CPB结束后2小时采集血样检测IL-6的含量。在术后第21天采用免疫组化的方法检测海马NF—κB的表达含量。在术前和术后的21天内对神经功能采用改良孔板实验进行评估。结果CPB组与假手术组相比,IL-6的水平明显升高,新生儿氧合器组在CPB结束后2小时与大鼠氧合器组相比IL-6的水平更高[CPB／大鼠氧合器组：220pg／ml（16～415）;CPB／新生儿氧合器组：1400pg／ml（592～5812）]（P〈0．05）。3组实验组中海马NF—KB的表达含量与对照组（10±4）相比明显升高。CPB组与假手术组（173±24）相比NF．KB表达含量更高（CPB／新生儿氧合器组：271±57;CPB／大鼠氧合器组：269±72）。神经认知功能和行为学的评估结果显示组间没有差异。结论CPB引发显著的全身性炎症反应并伴随着海马中NF-κB蛋白表达的增多并没有导致神经认知功能的损伤。由此可推断,排除体外循环和炎症反应这两个因素,可能有其他因素最终导致了患者CPB术后神经认知功能的障碍。     

Xenon and the inflammatory response to cardiopulmonary bypass in the rat

OBJECTIVE: The purpose of this study was to investigate the effect of xenon on the inflammatory response to cardiopulmonary bypass. DESIGN: Prospective, randomized experimental study. SETTING: University research laboratory. PARTICIPANTS: Sprague-Dawley rats. INTERVENTIONS: After surgical preparation, rats were randomly divided into 4 groups: (1) SHAM rats were cannulated but did not undergo cardiopulmonary bypass; (2) cardiopulmonary bypass rats were subjected to 60 minutes of cardiopulmonary bypass using an oxygenator receiving a 30% O(2), 65% N(2), and 5% CO(2) gas mixture; (3) MK801 rats received MK801 (0.15 mg/kg intravenous) 15 minutes before 60 minutes of cardiopulmonary bypass with the same gas mixture; and (4) xenon rats underwent 60 minutes of cardiopulmonary bypass receiving a 30% O(2), 60% xenon, 5% N(2), and 5% CO(2) gas mixture. MEASUREMENTS AND MAIN RESULTS: All bypass groups showed elevations in both cytokines compared with the SHAM-operated group. However, the inflammatory response to cardiopulmonary bypass in the group receiving xenon was no different from the other bypass groups. CONCLUSIONS: Xenon appears to have no effect on the inflammatory response to cardiopulmonary bypass, making its previously described neuroprotective effect during cardiopulmonary bypass likely independent of any inflammation modulation.     

Cerebral air emboli differentially alter outcome after cardiopulmonary bypass in rats compared with normal circulation

BACKGROUND: Cerebral air emboli (CAE) are thought to contribute to adverse cerebral outcomes following cardiac surgery with cardiopulmonary bypass (CPB). This study was designed to investigate the effect of escalating volumes of CAE on survival and neurologic and histologic outcomes. In addition, the effect of xenon administration during CAE on these outcomes was determined. METHODS: With institutional review board approval, four groups were studied (n = 15). In two CPB-CAE groups, rats were subjected to 90 min CPB with 10 repetitively administered CAE. Rats in two sham-CAE groups were also exposed to CAE but not to CPB. Rats were randomly assigned to sequential dose cohorts receiving CAE ranging from 0.2 to 10 microl in a dose-escalating fashion. Groups were further subdivided into xenon (56%) and nitrogen groups. Rats with severe neurologic damage were killed; others were neurologically tested until postoperative day 7, when infarct volumes were determined. Survival and neurologic and histologic outcomes were tested with logistic regression analyses (P < 0.05). RESULTS: This study demonstrates a dose-dependent relation between CAE volumes and survival, neurologic outcome, and histologic outcome. For all outcomes, CPB adversely affected the dose-effect curves compared with sham-CAE groups (P < 0.05). Xenon demonstrated no impact on either outcome. CONCLUSIONS: This study describes the successful incorporation of CAE in a rodent CPB model and allows identifying suitable CAE volumes for subsequent studies. CAE exhibit a differential effect on outcome in rats undergoing CPB versus those not exposed to CPB. Perioperative administration of xenon remained without any effect on outcome.     

Cerebral Air Emboli Differentially Alter Outcome after Cardiopulmonary Bypass in Rats Compared with Normal Circulation

Background: Cerebral air emboli (CAE) are thought to contribute to adverse cerebral outcomes following cardiac surgery with cardiopulmonary bypass (CPB). This study was designed to investigate the effect of escalating volumes of CAE on survival and neurologic and histologic outcomes. In addition, the effect of xenon administration during CAE on these outcomes was determined.

Methods: With institutional review board approval, four groups were studied (n = 15). In two CPB-CAE groups, rats were subjected to 90 min CPB with 10 repetitively administered CAE. Rats in two sham-CAE groups were also exposed to CAE but not to CPB. Rats were randomly assigned to sequential dose cohorts receiving CAE ranging from 0.2 to 10 [mu]l in a dose-escalating fashion. Groups were further subdivided into xenon (56%) and nitrogen groups. Rats with severe neurologic damage were killed; others were neurologically tested until postoperative day 7, when infarct volumes were determined. Survival and neurologic and histologic outcomes were tested with logistic regression analyses (P < 0.05).

Results: This study demonstrates a dose-dependent relation between CAE volumes and survival, neurologic outcome, and histologic outcome. For all outcomes, CPB adversely affected the dose-effect curves compared with sham-CAE groups (P < 0.05). Xenon demonstrated no impact on either outcome.     

Effects of cardiopulmonary bypass on neurocognitive performance and cytokine release in old and diabetic rats

Background: Age and diabetes mellitus have been identified as independentrisk factors for cognitive decline after cardiac surgery withcardiopulmonary bypass (CPB). We tested the effects of CPB oncognitive function in aged and diabetic rats utilizing the Morriswater maze (MWM). Methods: Aged rats (26 months) were randomized into a sham group (cannulationbut no CPB, n = 11) and a 90 min CPB group (n = 11). In addition,young rats (n = 14) were made diabetic with streptozotocin 9weeks before experimentation and randomized to a sham or 90min CPB group. Cytokine release [interleukin (IL-6)] and short-termMWM performance (days 8–14 after operation) were assessedin all animals. Long-term MWM performance (8 weeks after operation)was assessed in aged rats only. Results: There were no differences between the aged groups in short-term(P = 0.58) or long-term MWM performances (P = 0.69). The diabeticanimals also showed no differences between the sham and CPBgroups in MWM performance (P = 0.64). IL-6 assays showed anincreased inflammatory response after CPB in the diabetic animals,but not in the elderly groups. Conclusions: Ninety minutes of normothermic CPB had no deleterious effecton neurocognitive outcome in elderly or chronically diabeticanimals, suggesting that CPB in itself is not a sufficient stressorof the rat central nervous system.     

Insufflation of Hydrogen Gas Restrains the Inflammatory Response of Cardiopulmonary Bypass in a Rat Model

Systemic inflammatory responses in patients receiving cardiac surgery with the use of the cardiopulmonary bypass (CPB) significantly contribute to CPB‐associated morbidity and mortality. We hypothesized that insufflated hydrogen gas (H₂) would provide systemic anti‐inflammatory and anti‐apoptotic effects during CPB, therefore reducing proinflammatory cytokine levels. In this study, we examined the protective effect of H₂ on a rat CPB model. Rats were divided into three groups: the sham operation (SHAM) group, received sternotomy only; the CPB group, which was initiated and maintained for 60 min; and the CPB + H₂ group in which H₂ was given via an oxygenator during CPB for 60 min. We collected blood samples before, 20 min, and 60 min after the initiation of CPB. We measured the serum cytokine levels of (tumor necrosis factor‐α, interleukin‐6, and interleukin‐10) and biochemical markers (lactate dehydrogenase, aspartate aminotransferase, and alanine aminotransferase). We also measured the wet‐to‐dry weight (W/D) ratio of the left lung 60 min after the initiation of CPB. In the CPB group, the cytokine and biochemical marker levels significantly increased 20 min after the CPB initiation and further increased 60 min after the CPB initiation as compared with the SHAM group. In the CPB + H₂ group, however, such increases were significantly suppressed at 60 min after the CPB initiation. Although the W/D ratio in the CPB group significantly increased as compared with that in the SHAM group, such an increase was also suppressed significantly in the CPB + H₂ group. We suggest that H₂ insufflation is a possible new potential therapy for counteracting CPB‐induced systemic inflammation.     

体外循环对大鼠脑血管功能的影响

目的 观察不同体外循环时间和体外循环模式对脑血管功能的影响.方法 将30只大鼠平均分为5组,分别建立不同体外循环模型.取右大脑中动脉,在不同压力下进行肌源性活动功能检测,观察在不同浓度乙酰胆碱溶液中内皮细胞相关舒张反应强度和利用硝普钠和血管紧张素观察平滑肌细胞相关血管舒缩反应.取海马区脑组织进行微血管内皮细胞超微结构观察.结果 各组大鼠均成功建立和脱离体外循环.代表肌源性活动功能的MCA收缩百分率深低温低流量组为(34.62±2.36)%,深低温停循环组为(33.83±2.28)%,较正常对照组(37.75±1.92)%明显受损(P<0.05).在不同乙酰胆碱浓度下,体外循环组内皮细胞相关的血管舒张率为(8.59±1.48)%,较正常组(24.26±1.90)%明显受损(P<0.05).深低温低流量组和深低温停循环组损伤较常温组明显加重.血管平滑肌相关的收缩舒张功能各组均处于正常范围.结论 体外循环早期即可引起脑血管内皮细胞相关的血管舒张功能受损,深低温转流可引起脑血管自主调节功能降低.而这可能是体外循环后脑损伤的重要机制之一.     

The Neuroprotective Effect of Xenon Administration during Transient Middle Cerebral Artery Occlusion in Mice

Background: Xenon has been shown to be neuroprotective in several models of in vitro and in vivo neuronal injury. However, its putative neuroprotective properties have not been evaluated in focal cerebral ischemia. The purpose of this study was to determine if xenon offers neuroprotection in a mouse model of middle cerebral artery occlusion.

Methods: C57BL/6 mice underwent 60 min of middle cerebral artery occlusion. The animals (n = 21 per group) were randomized to receive either 70% xenon + 30% O2, 70% N2O + 30% O2, or 35% xenon + 35% N2O + 30% O2. After 24 h, functional neurologic outcome (on three independent scales: four-point, general, and focal deficit scales) and cerebral infarct size were evaluated.

Results: The 70% xenon + 30% O2 group showed improved functional outcome (median [interquartile range], four-point scale: 2 [2], 70% xenon + 30% O2versus 3 [2], 70% N2O + 30% O2, P = 0.0061; general deficit scale: 9 [6], 70% xenon + 30% O2versus 10 [4], 70% N2O + 30% O2, P = 0.0346). Total cerebral infarct volumes were reduced in the 70% xenon + 30% O2 group compared with the 70% N2O + 30% O2 group (45 +/- 17 mm3versus 59 +/- 11 mm3, respectively; P = 0.0009).     

Neurologic and cognitive outcomes associated with the clinical use of xenon: a systematic review and meta-analysis of randomized-controlled trials

Background

Xenon has been shown to have positive neurologic effects in various pre-clinical models. This study systematically reviewed the randomized-controlled trials (RCTs) investigating neurologic and cognitive outcomes associated with the clinical use of xenon.

Methods

We searched PubMed, CENTRAL, EMBASE, CINAHL, elibrary.ru (for Russian studies), Google Scholar (for Russian studies), and Wanfang (for Chinese studies) for appropriate RCTs comparing neurologic or cognitive outcomes after clinical use of xenon with control treatment or with other anesthetic agents.

Results

Seventeen RCTs met the inclusion criteria. Two studies investigated the effects of xenon plus therapeutic hypothermia to treat neonatal asphyxia or out-of-hospital cardiac arrest. Compared with therapeutic hypothermia alone, xenon and therapeutic hypothermia reduced cerebral white matter abnormalities after cardiac arrest but had no effect on neurocognitive outcome and mortality. Xenon had no added value when used to treat neonatal asphyxia. Thirteen RCTs compared neurocognitive effects of xenon with other anesthetic agents in surgical patients. While xenon may be associated with improved short-term (< three hours) cognitive outcome, no medium-term (six hours to three months) advantage was observed, and longer-term data are lacking. No differences in biochemical (S-100β, neuron-specific enolase) and neuropsychologic (attentional performance) outcomes were found with xenon compared with other anesthetic drugs. Finally, two studies suggest that brief, intermittent administration of sub-anesthetic doses of xenon to patients during the acute phase of substance withdrawal may improve neurocognitive outcomes.

Conclusions

Despite promising pre-clinical results, the evidence for positive clinical neurologic and cognitive outcomes associated with xenon administration is modest. Nevertheless, there is some evidence to suggest that xenon may be associated with better neurologic outcomes compared with the standard of care therapy in certain specific clinical situations. More clinical trials are needed to determine any potential benefit linked to xenon administration.

     

Concurrent Spinal Infusion of MK801 Blocks Spinal Tolerance and Dependence Induced by Chronic Intrathecal Morphine in the Rat

Background: MK801, an N-methyl-D-aspartate receptor antagonist, has recently been reported to attenuate tolerance to, and withdrawal from morphine. This study analyzes tolerance and withdrawal in a chronic intrathecal coinfusion model of morphine and MK801.

Methods: Intrathecal catheters, attached to 7-day miniosmotic infusion pumps, were implanted in rats and infused with saline, 20 nM/h morphine, MK801 (10 and 3 nM/h) + morphine; and 10 nM/h MK801. Analgesia was measured on the hot plate daily. On the day 7, groups received 3 mg/kg intraperitoneal naloxone and six signs of withdrawal were assessed: vocalization to air motion or light touch, abnormal posture, spontaneous vocalization, escape attempts, "wet dog shakes," and ejaculation. Similar groups were tested only on days 1 and 7. Intrathecal morphine dose-response curves were obtained on day 8. A separate morphine-tolerant group received 10 nM MK801 on day 7. Rats from each group received 10 nM intrathecal morphine 1 week later.

Results: Coinfusion of MK801 with morphine resulted in a dose-dependent preservation of effect, and attenuated three of six signs of withdrawal. Coinfusion of MK801 (10 and 3 nM/h) prevented the reduction of potency observed with morphine alone. ED50 values (maximum percent effect, nM morphine) were: saline (16), morphine (496), MK801 (10 nM/h) + morphine (4), and 10 nM/h MK801 (0.3). Acute administration of MK801 was ineffective in restoring sensitivity to morphine. One week after cessation of infusion, there was no significant difference between groups.     

Biocompatibility of Heparin-Coated Membrane Oxygenator During Cardiopulmonary Bypass

Abstract: The biocompatibility of the cardiopulmonary bypass (CPB) circuit, in which an oxygenator is solely heparinized, was assessed by systemic inflammatory reactions as an indicator during CPB. Fourteen patients, 11 males and 3 females, underwent coronary artery bypass surgery and were randomly divided into 2 groups of 7 patients each. For the heparin–coated oxygenator group (Group H), a heparin–coated membrane oxygenator was used in the CPB circuit, and in the control (Group C) an uncoated membrane oxygenator was employed. Systemic inflammatory reactions, such as platelet activation, prostaglandin production, complement activation, and activated granulocyte released substance, were measured prior to, during, and 6 h after CPB. The number of platelets decreased after protamine administration in both groups (14. 5 ±4. 7 times 10⁴/μl in Group H and 13. 8 ± 8. 7 times 10⁴/μd in Group C) and returned to baseline levels in Group H while it remained decreased in Group C at 6 h after CPB. The platelet factor 4 level was significantly lower in Group H (181 ± 40 ng/ml) than in Group C (297 ±131 ng/ml) after protamine administration. Thromboxane–B₂ (TXB₂) rose during CPB in both groups; however, there were significantly different levels of TXB₂ between the 2 groups at 60 min after CPB (293±258 pg/ml in Group H versus 408 ± 120 pg/ml in Group C) and after protamine administration (259 ± 122 pg/ml in Group H versus 709 ± 418 pg/ml in Group C). Plasma concentrations of granulocyte elastase were significantly lower in Group H at 30, 60 and 90 min, immediately after, and post–CPB than those of Group C. Although the oxygenator was solely heparinized in the CPB circuit, it was sufficiently effective to reduce inflammatory reactions during coronary artery bypass operation, and the heparin–coated surface seems to be more endothelium–like.     

The effect of diuretics on renal hemodynamics during cardiopulmonary bypass

The effect of cardiopulmonary bypass (CPB) on renal hemodynamics was studied in 15 dogs using ¹³³xenon washout. Ten control dogs had no diuretics administered and five diuretic dogs were given furosemide immediately before and during CPB. A catheter was inserted into the right renal artery under fluoroscopic guidance via the left femoral artery and a bolus of ¹³³xenon injected. Washout curves were obtained with a collimater placed over the kidney before CPB and after 15 and 90 min of CPB. Total CPB was undertaken at normothermia using venous gravity drainage, an arterial roller pump, a heat exchanger and a Kolobow membrane oxygenator. Washout curves were analyzed and four components of renal blood flow (RBF) developed: I, cortex; II, juxtamedulla; III, inner medulla; and IV, hilar fat. Percentage of total radioactivity and regional blood flow was derived for each component and total RBF calculated.Total RBF in the control group decreased progressively during CPB (457 → 269 → 158 ml/100 g/min after 90-min CPB). This decrease in RBF was associated with a marked shunt of flow from cortical to juxtamedullary region. Percentage of flow to the cortex decreased as well (68% → 33% → 23% after 90 min) while activity to the juxtamedulla increased (24% → 47% → 50% after 90 min).RBF in the diuretic treated group decreased during CPB but significantly less than in the control group (436 → 397 → 273 ml/100 g/min after 90-min CPB). The intrarenal shunt seen in the control group during CPB was significantly reduced in the diuretic treated group. While percent flow to the cortex was reduced as bypass progressed (67% → 56% → 47% after 90 min), cortical activity remained greater than juxtamedullary (29% → 36% → 38% after 90 min) throughout the 2 hr of bypass. It was apparent from this study that cortical ischemia associated with CPB can be substantially reduced by diuretic therapy during CPB.     

The neuroprotective effect of xenon administration during transient middle cerebral artery occlusion in mice

BACKGROUND: Xenon has been shown to be neuroprotective in several models of in vitro and in vivo neuronal injury. However, its putative neuroprotective properties have not been evaluated in focal cerebral ischemia. The purpose of this study was to determine if xenon offers neuroprotection in a mouse model of middle cerebral artery occlusion. METHODS: C57BL/6 mice underwent 60 min of middle cerebral artery occlusion. The animals (n = 21 per group) were randomized to receive either 70% xenon + 30% O2, 70% N2O + 30% O2, or 35% xenon + 35% N2O + 30% O2. After 24 h, functional neurologic outcome (on three independent scales: four-point, general, and focal deficit scales) and cerebral infarct size were evaluated. RESULTS: The 70% xenon + 30% O2 group showed improved functional outcome (median [interquartile range], four-point scale: 2 [2], 70% xenon + 30% O2 versus 3 [2], 70% N2O + 30% O2, P = 0.0061; general deficit scale: 9 [6], 70% xenon + 30% O2 versus 10 [4], 70% N2O + 30% O2, P = 0.0346). Total cerebral infarct volumes were reduced in the 70% xenon + 30% O2 group compared with the 70% N2O + 30% O2 group (45 +/- 17 mm3 versus 59 +/- 11 mm3, respectively; P = 0.0009). CONCLUSIONS: In this model of transient focal cerebral ischemia, xenon administration improved both functional and histologic outcome.     

Cerebral Oxygenation during Pediatric Cardiac Surgery Using Deep Hypothermic Circulatory Arrest

Background: Deep hypothermic circulatory arrest is a widely used technique in pediatric cardiac surgery that carries a risk of neurologic injury. Previous work in neonates identified distinct changes in cerebral oxygenation during surgery. This study sought to determine whether the intraoperative changes in cerebral oxygenation vary between neonates, infants, and children and whether the oxygenation changes are associated with postoperative cerebral dysfunction.

Methods: The study included eight neonates, ten infants, and eight children without preexisting neurologic disease. Cerebrovascular hemoglobin oxygen saturation (ScO2), an index of brain oxygenation, was monitored intraoperatively by near-infrared spectroscopy. Body temperature was reduced to 15 degrees Celsius during cardiopulmonary bypass (CPB) before commencing circulatory arrest. Postoperative neurologic status was judged as normal or abnormal (seizures, stroke, coma).

Results: Relative to preoperative levels, the age groups experienced similar changes in ScO2 during surgery: Sco sub 2 increased 30 plus/minus 4% during deep hypothermic CPB, it decreased 62 plus/minus 5% by the end of arrest, and it increased 20 plus/minus 5% during CPB recirculation (all P < 0.001); after rewarming and removal of CPB, ScO2 returned to preoperative levels. During arrest, the half-life of ScO2 was 9 plus/minus 1 min in neonates, 6 plus/minus 1 min in infants, and 4 plus/minus 1 min in children (P < 0.001). Postoperative neurologic status was abnormal in three (12%) patients. The ScO2 increase during deep hypothermic CPB was less in these patients than in the remaining study population (3 plus/minus 2% versus 33 plus/minus 4%, P < 0.00l). There were no other significant ScO2 differences between outcome groups.     

The calcium channel blocker nifedipine fails to inhibit leucocyte elastase release during cardiopulmonary bypass

Circulating concentrations of leucocyte elastase were measured in 16 adult patients undergoing cardiopulmonary bypass (CPB) with a flat-sheet membrane oxygenator. Eight patients (Group I) received the calcium channel blocker nifedipine (9 µmUg · kg^-1 · h^-1) during CPB. Eight patients (Group II) did not receive any calcium channel blocker during surgery and served as the control group. Elastase concentrations were measured at 7 time points: 2 before, 2 during, and 3 after CPB. The bypass procedure was associated with elevation in elastase concentrations (P<0.001). Comparing to baseline values elastase concentrations were significantly elevated (P<0.05) 60 min after the start of CPB and on all measurements done after CPB. Elastase concentrations correlated with the duration of CPB (rs = 0.76, P<0.001), and were not influenced by nifedipine infusion as revealed by comparing the two groups. This study demonstrates moderate elastase release during CPB with a fiat-sheet membrane oxygenator and fails to confirm inhibition of elastase release by nifedipine infusion during CPB.