Chronic Porcine Model Research Articles

An In Vivo Evaluation of a Novel Spiral Cut Flexible Ureteral Stent

The flow characteristics, ureteral conformance, and histopathologic changes of a novel spiral cut flexible ureteral stent (Percuflex Helical, Boston Scientific, Boston, MA) were evaluated in vivo in an acute and chronic porcine model. Flow characteristics and ureteral conformance of the novel stent were determined in 6 acute and 6 chronic swine models and compared with a control ureteral stent (Percuflex Plus, Boston Scientific). The flow characteristics were determined in vivo after ligating the renal vessels and via a nephrostomy tube delivering a standard rate of 0.9% saline at 35 cm H(2)O. Flows in the unobstructed ureter, normal stent, intraluminally obstructed stent, extraluminal obstructed stent, and both intraluminally and extraluminally obstructed conditions were determined. In the chronic animals, flow was determined at day 10, with the stent in place and immediately after stent removal. Conformance and hydronephrosis was assessed on pyelograms. Histopathologic changes were also evaluated in the chronic animals. The acute and chronic flow characteristics in the novel stent were equivalent to the control stent. Size and weight of the kidney, degree of hydronephrosis, stent migration, and presence of urinary tract infection were also similar between the test and control stents. There were no differences seen in histopathologic grading or degree of encrustation in either stent. The novel stent appeared to conform better to the shape of the ureter in both acute and chronic animals. The novel helical stent appears to drain as well as a standard stent and causes no increased degree of histopathologic changes in the ureter.

Performance of a Novel Dual-Electrode Bipolar Radiofrequency Ablation Device a Chronic Porcine Study

: Over recent years, a variety of energy sources, including bipolar radiofrequency, have been used to replace the traditional incisions of the Cox-Maze procedure for the surgical treatment of atrial fibrillation (AF). The purpose of this study was to evaluate the safety and efficacy of a novel dual-electrode bipolar radiofrequency ablation device Synergy (Atricure, Inc., Cincinnati, OH USA) for AF in a chronic porcine model. : Six domestic pigs underwent a modified Cox-Maze IV procedure without cardiopulmonary bypass using the Synergy device. Animals survived for 30 days. Each pig then underwent induction of AF and was killed to remove the heart en bloc for histologic assessment. Each ablation line was dissected perpendicularly at 5-mm intervals to assess the lesion width, depth, and transmurality. : All animals survived the operation. Electrical isolation of the left atrial appendage and the pulmonary veins were documented by pacing acutely and at 30 days after the operation in all six animals. All animals failed to be induced in AF at 30 days. There was no gross evidence of intra-atrial thrombus formation or stricture of the pulmonary veins. All ablations (n = 209) examined were discrete, linear, and transmural, with a mean lesion width of 3.0 ± 0.7 mm and a mean lesion depth of 5.4 ± 3.3 mm. The mean ablation time was 16.3 ± 4.4 seconds, with a mean total energy delivery of 238 ± 170 J. : The Atricure Synergy was able to create reliable chronic transmural lesions of the modified Cox-Maze IV procedure on a porcine beating heart without cardiopulmonary bypass. The ablation lines were significantly wider when compared with its predecessor, the Isolator II.

Electrical colonic stimulation reduces mean transit time in a porcine model

Electrical stimulation is a new way to treat digestive disorders such as constipation. Colonic propulsive activity can be triggered by battery operated devices. This study aimed to demonstrate the effect of direct electrical colonic stimulation on mean transit time in a chronic porcine model. The impact of stimulation and implanted material on the colonic wall was also assessed. Three pairs of electrodes were implanted into the caecal wall of 12 anaesthetized pigs. Reference colonic transit time was determined by radiopaque markers for each pig before implantation. It was repeated 4 weeks after implantation with sham stimulation and 5 weeks after implantation with electrical stimulation. Aboral sequential trains of 1-ms pulse width (10 V; 120 Hz) were applied twice daily for 6 days, using an external battery operated stimulator. For each course of markers, a mean value was computed from transit times obtained from individual pig. Microscopic examination of the caecum was routinely performed after animal sacrifice. A reduction of mean transit time was observed after electrical stimulation (19 +/- 13 h; mean +/- SD) when compared to reference (34 +/- 7 h; P = 0.045) and mean transit time after sham stimulation (36 +/- 9 h; P = 0.035). Histological examination revealed minimal chronic inflammation around the electrodes. Colonic transit time measured in a chronic porcine model is reduced by direct sequential electrical stimulation. Minimal tissue lesion is elicited by stimulation or implanted material. Electrical colonic stimulation could be a promising approach to treat specific disorders of the large bowel.

Characterization of myocardial remodeling with diffusion tensor magnetic resonance imaging in chronic porcine model using the toroid-based representation

Characterization of myocardial remodeling with diffusion tensor magnetic resonance imaging in chronic porcine model using the toroid-based representation

A catheter based chronic porcine model of post-infarct dilated heart failure

Objectives. New surgical treatments for post-infarct antero-septal myocardial akinesia have been developed but evaluation of their mode of function is hampered by absence of suitable large animal heart failure models. We aimed to develop and evaluate a human compatible model for chronic post-infarct left ventricular (LV) remodeling. Design. Fourteen female 50 kg pigs underwent catheter-based coronary artery occlusion (one hour) distal to the first LAD diagonal. Eight weight- and age-matched healthy animals served as controls. LV geometry and function were assessed after 6 weeks with cardiovascular MRI. Results. All animals recovered from interventions. Three animals died during follow-up. All intervention animals had antero-septal akinetic infarcts (mean 26.5% of LV myocardium). Intervention animals had significantly increased end-diastolic and end-systolic volumes, and decreased stroke volume, ejection fraction and cardiac output. Detailed functional analysis showed significant systolic- and diastolic-dysfunction in intervention animals. Conclusions. We have established a feasible model of post-infarct LV remodeling, which accurately simulates human pathogenesis and pathophysiology. The model may be suitable for evaluation of novel surgical alleviations for heart failure.

A model for left ventricular hypertrophy enabling non-invasive assessment of cardiac function

Objective.To develop a porcine model for Left Ventricular Hypertrophy (LVH) in which cardiac performance could be quantified non-invasively by Doppler ultrasound. Design.Sixteen 5 kg piglets were divided into two groups. In the first group (n=12) we performed an aortic banding and in the second group (n=4) a sham-operation. Endpoints were echo-assessed left ventricular midseptal and free-wall thickness, heart/body-weight ratio and cardiac myocyte diameter. Results.Free-wall thickness: 0.77±0.013 cm in the intervention group and 0.60±0.006 cm in the control group (p=0.015). Midseptal thickness: 0.79±0.015 cm in the intervention group and 0.58±0.010 cm in the control group (p=0.012). Heart/body-weight ratio: 7.73±0.970 in the intervention group and 6.23±0.430 in the control group (p=0.003). Cardiac myocyte diameter: 19.6±4.9 µm in the intervention group and 11.0±1.9 µm in the control group (p=0.000). Conclusion. A chronic porcine model for LVH has been established in which Doppler ultrasound can be used to quantify cardiac function non-invasively.

Chronic in-vivo experience with an endoscopically delivered and retrieved duodenal-jejunal bypass sleeve in a porcine model

The role of duodenal bypass as an underlying mechanism of action in gastric bypass surgery has received considerable attention. We report the initial feasibility study of a totally endoscopically delivered and retrieved duodenal-jejunal bypass sleeve in a chronic porcine model. The implant consists of a 60-cm fluoropolymer sleeve that is endoscopically deployed via a coaxial catheter system into the jejunum and fixed in the proximal duodenum with a Nitinol anchor. The system creates a proximal biliopancreatic diversion. Six female Yorkshire pigs were endoscopically implanted; all survived. Four animals (group 1) were slated to survive 90 days, two animals (group 2) for 120 days, and three animals (group 3) underwent sham endoscopy and were survived 120 days. Animals were fed standard dry pig chow 0.5 kg three times daily. Data points included daily general health, weekly weight, serum blood tests (complete blood count, amylase, lipase, liver function tests), and monthly evaluation of anchor/sleeve position/patency by fluoroscopy and endoscopy. Following the in-vivo period, the devices were endoscopically removed and the animals were sacrificed. Duodenal and jejunal tissue samples were assessed histologically. All six test animals were implanted and explanted without significant adverse events. In group 1, the first animal had no device-related issues. The second animal had a pivoted anchor requiring repositioning at day 63. That animal had no further difficulties. The third animal had an incidental partial rotation of the anchor noted at the 90 day explantation. The fourth animal was incidentally implanted with a crossover of the anchor struts, which was endoscopically corrected on day 14. However, on day 20 the animal had persistent vomiting, and the device was explanted. Both group 2 animals survived 120 days. One animal had a partially rotated anchor but was asymptomatic. The average weight gain between test and sham groups was 0.23 kg/day and 0.42 kg/day, respectively (p = 0.01). A totally endoscopic and reversible bypass of the duodenum and proximal jejunum has been achieved for 90-120 days. Initial experience suggests patency of the sleeve and acceptable tissue response. Reduced weight gain in the test animals suggests device efficacy. Further investigation is warranted.

CHEMICALLY MODIFIED TETRACYCLINE PREVENTS THE DEVELOPMENT OF SEPTIC SHOCK AND ACUTE RESPIRATORY DISTRESS SYNDROME IN A CLINICALLY APPLICABLE PORCINE MODEL

Sepsis causes more than with 215,000 deaths per year in the United States alone. Death can be caused by multiple system organ failure, with the lung, in the form of the acute respiratory distress syndrome (ARDS), often being the first organ to fail. We developed a chronic porcine model of septic shock and ARDS and hypothesized that blocking the proteases neutrophil elastase (NE) and matrix metalloproteinases (MMP-2 and MMP-9) with the modified tetracycline, COL-3, would significantly improve morbidity in this model. Pigs were anesthetized and instrumented for hemodynamic monitoring and were then randomized to one of three groups: control (n = 3), laparotomy only; superior mesenteric artery occlusion (SMA) + fecal blood clot (FC; n = 7), with intraperitoneal placement of a FC; and SMA + FC + COL (n = 5), ingestion of COL-3 12 h before injury. Animals emerged from anesthesia and were monitored and treated with fluids and antibiotics in an animal intensive care unit continuously for 48 h. Serum and bronchoalveolar lavage fluid (BALF) were sampled and bacterial cultures, MMP-2, MMP-9, NE, and multiple cytokine concentrations were measured. Pigs were reanesthetized and placed on a ventilator when significant lung impairment occurred (PaO2/FiO2 < 250). At necropsy, lung water and histology were assessed. All animals in the SMA + FC group developed septic shock evidenced by a significant fall in arterial blood pressure that was not responsive to fluids. Lung injury typical of ARDS (i.e., a fall in lung compliance and PaO2/FiO2 ratio and a significant increase in lung water) developed in this group. Additionally, there was a significant increase in plasma IL-1 and IL-6 and in BALF IL-6, IL-8, IL-10, NE, and protein concentration in the SMA + FC group. COL-3 treatment prevented septic shock and ARDS and significantly decreased cytokine levels in plasma and BALF. COL-3 treatment also significantly reduced NE activity (P < 0.05) and reduced MMP-2 and MMP-9 activity in BALF by 64% and 34%, respectively, compared with the SMA + FC group. We conclude that prophylactic COL-3 prevented the development of ARDS and unexpectedly also prevented septic shock in a chronic insidious onset animal model of sepsis-induced ARDS. The mechanism of this protection is unclear, as COL-3 inhibited numerous inflammatory mediators. Nevertheless, COL-3 significantly reduced the morbidity in a clinically applicable animal model, demonstrating the possibility that COL-3 may be useful in reducing the morbidity associated with sepsis and ischemia/reperfusion injury in patients.

Cooling to 10�C and treatment with Cyclosporine A improve cerebral recovery following prolonged hypothermic circulatory arrest in a chronic porcine model

This study was undertaken to assess whether cooling to 10 degrees C and/or treatment with Cyclosporine A (CsA) can reduce neurological injury during prolonged hypothermic circulatory arrest (HCA) in a chronic animal model. In this blinded study, 24 pigs (20-23 kg) were randomized to HCA for 90 min at 20 degrees C (n=8), at 10 degrees C (n=8), or at 10 degrees C with 5 mg/kg CsA (n=8). CsA (or placebo) were given intravenously before and for 3 days after HCA. Hemodynamics and neurophysiological data were monitored periodically throughout the experiment and for 3 h after HCA, as well as intracranial pressure (ICP), which has been shown to correlate with outcome. Daily neurological/behavioral evaluation (mental status, coordination and appetite; 12=normal and 0=coma or death) was carried out until sacrifice on postoperative day (POD) 3. Overall survival rate was 83.3%: one 20 degrees C control, two 10 degrees C controls, and one 10 degrees C/CsA pig died and were replaced. Basic hemodynamic data revealed no significant differences between groups. ICP differed significantly among the groups during the first 3 h postoperatively (P=0.003 by repeated measures ANOVA); it was higher in the 20 degrees C group than in the 10 degrees C/CsA or 10 degrees C control groups. Recovery of visual evoked potentials was significantly better in the 10 degrees C/CsA group than in the 10 degrees C control group; no recovery was seen by 3 h in the 20 degrees C control group. Postoperative behavioral scores also differed significantly between the groups, P=0.03: a good behavioral outcome--a score >9 on POD3--was more prevalent among CsA-treated pigs (75%) than among 10 degrees C controls (50%), or 20 degrees C controls (12.5%, P=0.06). The data suggest that cooling to 10 degrees C and CsA treatment are both of benefit in improving cerebral recovery after HCA when compared with untreated 20 degrees C controls, and may be synergistic.

Pharmacologic inhibition of intracellular caspases after myocardial infarction attenuates left ventricular remodeling: a potentially novel pathway

Objective Myocyte death occurs by necrosis and caspase-mediated apoptosis in the setting of myocardial infarction. In vitro studies suggest that caspase activation within myocytes causes contractile protein degradation without inducing cell death. Thus, caspase activation may evoke left ventricular remodeling through 2 independent processes post-myocardial infarction. However, the effects of caspase activation on left ventricular geometry post-myocardial infarction remain unclear. This project applied broad-spectrum caspase inhibition to a chronic porcine model of myocardial infarction. Methods Coronary snares and sonomicrometry crystals in remote and area-at-risk regions were placed in pigs (n = 22, 34 kg). Geometric measurements at end diastole and end systole, including left ventricular area by echocardiography and interregional distance by sonomicrometry, were obtained at baseline. Coronary occlusion was instituted for 60 minutes, followed by reperfusion and repeated geometric measurements at 7 days, including left ventriculography. At reperfusion, pigs were randomized to saline (n = 12) or caspase inhibition (n = 10, IDN6734, 2 mg/kg intravenously, then 2 mg · kg · h for 24 hours) at a dose that achieved desired plasma concentrations (790 ± 142 ng/mL) as predicted by prior pharmacokinetic studies. Results Infarct size and 24-hour troponin-I values were not significantly different between the saline and caspase inhibition groups (51% ± 8% vs 42% ± 6% and 189 ± 20 ng/mL vs 152 ± 26 ng/mL, respectively, P > .10). At 7 days, end-diastole volume was increased in both groups compared with reference control values (47 ± 1 mL, P < .05), but it was decreased with caspase inhibition (72 ± 4 mL) compared with saline (84 ± 4 mL, P < .05). Similarly, end-diastole and end-systole areas increased by 32% ± 3% and 81% ± 16% in the saline group but were attenuated with caspase inhibition (19% ± 3% and 31% ± 10%, respectively, P < .05). End-diastole interregional distance increased by 30% ± 7% in the saline group but was attenuated with caspase inhibition (12% ± 5%, P < .05). Conclusion Despite equivalent degrees of myocardial injury, caspase inhibition reduced post-myocardial infarction left ventricular remodeling as evidenced by multiple, independent assessments of left ventricular dilation. Thus, caspase activation alters left ventricular geometry in the absence of significant effects on myocardial injury.

Importance of extrasegmental vessels for spinal cord blood supply in a chronic porcine model.

Our purpose was to investigate the interaction of the important components of spinal cord blood supply in the pig model to enable its use for future studies of spinal cord protection. Twenty-five juvenile pigs (20-22 kg) underwent serial intercostal (IC) or lumbar artery (LA) ligation until disappearance of motor evoked potentials (MEPs). Pigs underwent sequential craniocaudal IC/LA ligation alone (n=5); following clamping of both subclavian arteries (n=4), or clamping of the median sacral artery (MSA, n=4). Animals also underwent serial caudocranial clamping of LA/IC alone (n=4); preceded by clamping of the subclavian arteries (n=4), or of the MSA (n=4). Results were verified by Tarlov's scores and perioperative angiography. All animals with MEP loss suffered postoperative paraplegia. Groups were equivalent with regard to stable arterial pressures (64.6+/-3.1 degrees C) throughout the experiment, temperature (36+/-1.1 degrees C) and other physiological parameters. Mean number of clamped IC/LA before MEP loss for cranio-caudal clamping direction was 12.8+/-0.8 for segmental arteries isolated, 9+/-0.8 if both subclavian arteries were ligated previously and only 4.3+/-0.5 IC if the median sacral artery was clamped before. Mean number of clamped LA for caudo-cranial clamping direction was 5.8+/-0.9 for segmental lumbar arteries, 5.5+/-0.6 LA if both subclavian arteries were ligated previously and 3.5+/-0.6 if the median sacral artery was clamped before. This study confirms the importance of lumbar and MSA arteries to cord viability. It documents the interaction of the subclavian and MSA (roughly equivalent to the hypogastric arteries in humans) with segmental vessels in providing spinal cord blood supply. It also provides the physiologic basis for use of the pig model for studies of spinal cord protection in aortic surgery.

Potential neuroprotective benefits of erythropoietin during experimental hypothermic circulatory arrest

Objective: Recent studies have shown that erythropoietin protects neurons from glutamate toxicity and ischemia. This study was performed to evaluate the potential neuroprotective effect of erythropoietin during experimental hypothermic circulatory arrest. Methods: Twenty pigs were randomized to receive intravenously either 500 IU/kg recombinant human erythropoietin or saline before a 75-minute period of hypothermic circulatory arrest at an intracerebral temperature of 18°C. Results: After the administration of erythropoietin, its concentration in the cerebrospinal fluid increased 4.5-fold 8 hours after the start of rewarming, whereas it did not increase in control animals. The 7-day survival rate was 60% in the erythropoietin group and 70% in the control group (P = 1.0). No significant differences were observed between the study groups in terms of electroencephalography, behavioral score, and histopathologic score. The erythropoietin group had higher vascular resistance and mean arterial pressure values, lower intracerebral concentrations of glutamate and glycerol, higher brain tissue oxygen tension, and lower apoptotic index. Conclusions: Administration of 500 IU/kg erythropoietin intravenously before hypothermic circulatory arrest was followed by an increased erythropoietin concentration in the cerebrospinal fluid. Although previous studies have demonstrated neuroprotective effects of erythropoietin during brain ischemia, the present study, using a chronic porcine model, failed to show any significant benefit after administration of erythropoietin in terms of mortality or brain histopathology. Lower intracerebral concentrations of glutamate and glycerol, higher brain tissue oxygen tension, and lower apoptotic index observed in the erythropoietin group, however, suggest that a distinct neuroprotective effect of erythropoietin might be achieved at different dosages and timing of administration.J Thorac Cardiovasc Surg 2002;124:714-23

Impact of high intracranial pressure on neurophysiological recovery and behavior in a chronic porcine model of hypothermic circulatory arrest.

This review was undertaken to determine whether high intracranial pressure (ICP) during reperfusion after hypothermic circulatory arrest (HCA) correlates with evidence of suboptimal cerebral protection in a chronic porcine model. In concurrent studies of cerebral protection, 48 control pigs (24-31 kg) underwent 90 min of HCA at 20 degrees C using a strictly standardized protocol. Hemodynamic measurements, ICP and neurophysiological data (EEG, SSEP) were assessed before HCA and until 3 h postoperatively. ICP was measured using a Codman microtip catheter inserted directly into brain parenchyma. Neurological/behavioral evaluation (9=full recovery) was carried out daily through postoperative day (POD) 3. There were no significant hemodynamic or metabolic differences between individual animals. ICP (mmHg) increased significantly for the first 3 h after HCA: from baseline levels of 6.2+/-2.1 to 10+/-2.6 at 1 h, 11+/-3.2 at 2 h and 10+/-3.6 mmHg at 3 h; P<0.001 for the trend. EEG recovery 3 h after HCA was observed in 13 animals (27%), and correlated with lower ICP during reperfusion (P<0.001): with each 1 mmHg increase in ICP at 3 h, the odds of early EEG recovery decreased by a factor of 0.72. Lower ICP during reperfusion was also significantly associated with higher behavioral scores on POD 1 and 2, P<0.001. A significant rise in ICP may help explain the prolonged obtundation and confusion often seen clinically after HCA. If these small but consistent increases in ICP contribute to rather than reflect ischemic neuronal damage, simple maneuvers to reduce ICP may improve cerebral recovery after HCA.

Increase of Intracranial Pressure after Hypothermic Circulatory Arrest in a Chronic Porcine Model

Objective: An increase in intracranial pressure has been shown to threaten the outcome of patients with ischemic or traumatic brain injury. Its impact on the outcome of pigs undergoing hypothermic circulatory arrest has been evaluated in this study. Design: Fifty-six pigs underwent a 75-min period of hypothermic circulatory arrest at 20°C. Intracranial pressure, cerebral microdialysis, hemodynamic and metabolic parameters were monitored throughout the experiment. The animals were allowed to survive until the 7th postoperative day and, then, electively killed. Results: The 7-day survival rate was 60.7%, and among survivors, 20 of them (58.8%) developed brain infarction. A significant increase in intracranial pressure as compared with the baseline level was observed since the end of cooling ( p = 0.047) and the difference became larger during all the postoperative intervals ( p < 0.0001). Animals that died postoperatively tended to have higher intracranial pressure levels during all the postoperative intervals, but such a difference reached significance only at the 4-h postoperative interval ( p = 0.040). The same tendency was observed among animals that survived until the 7th postoperative day and that developed brain infarction or not, but the difference between these two groups did not reach statistical significance. The animals that died or developed postoperatively brain infarction had higher intracranial pressure values postoperatively as compared with those that survived without developing brain infarction and such a difference reached significance at the 2-h ( p = 0.015) and 4-h postoperative intervals ( p = 0.035). The peak intracranial pressure was 17.2 mmHg (IQR, 13.7-20.8) in animals that died or developed brain infarction and 14.1 mmHg (IQR, 11.8-16.4) in those that survived 7 days without developing brain infarction ( p = NS). Conclusion: Intracranial pressure increases significantly after 75 min of experimental hypothermic circulatory arrest and such an increase is associated with a high risk of postoperative death and brain infarction.

LAPAROSCOPIC BLADDER FLAP URETERAL REIMPLANTATION: SURVIVAL PORCINE STUDY

The bladder or Boari flap is a useful technique for ureteroneocystostomy when the distal ureter is too short to reach the bladder without undue tension. We report our experience with laparoscopic Boari flap ureteroneocystostomy in the chronic porcine model. Six female farm pigs underwent unilateral laparoscopic Boari bladder flap ureteroneocystostomy. Refluxing direct ureteral reimplantation was performed in the initial 3 animals. In the next 3 animals a submucosal tunnel was formed to achieve nonrefluxing ureteroneocystostomy into the Boari flap. The animals were sacrificed 6 weeks after surgery. At sacrifice ascending cystography, ipsilateral antegrade pyelography and autopsy examination of the ureteroneocystostomy site was performed. No intraoperative or postoperative complications were noted. Average operative time was 140 minutes. Postoperatively serum creatinine and hemoglobin were normal in all pigs. All 3 animals with direct ureteroneocystostomy into the Boari flap had free reflux into the kidney and all 3 with a submucosal tunnel reimplant had no reflux on ascending cystography and free drainage on antegrade pyelography. Autopsy confirmed a patent anastomotic site in all 6 cases. Laparoscopic ureteroneocystostomy using the Boari bladder flap technique is feasible. Our survival porcine model confirms the successful application of the refluxing and nonrefluxing technique of ureteral reimplantation. Clinical application of the technique has the potential to decrease patient morbidity associated with traditional open surgery.

Cyclosporine A as a potential neuroprotective agent: a study of prolonged hypothermic circulatory arrest in a chronic porcine model.

To assess whether Cyclosporine A (CsA) or cycloheximide (CHX) can reduce ischemia-induced neurological damage by blocking apoptotic pathways, we assessed their effects on cerebral recovery in a chronic animal model of hypothermic circulatory arrest (HCA). Twenty-eight pigs (28-33 kg) underwent 90 min of HCA at 20 degrees C. In this blinded study, animals were randomized to placebo (n=12), 5 mg/kg CsA (n=8), given intravenously before and subcutaneously for 7 days after HCA, or a single dose of 1 mg/kg CHX (n=8), given after weaning from cardiopulmonary bypass. Hemodynamics, intracranial pressure (ICP) and neurophysiological data (EEG, SSEP) were assessed for 3 h after HCA; early behavioral recovery was scored, and neurological/behavioral evaluation (9=normal) was carried out daily until elective sacrifice on postoperative day (POD) 7. Brains were selectively perfused and evaluated histopathologically for apoptosis. Basic hemodynamic data revealed no differences between CsA or CHX and control groups. ICP was significantly lower throughout rewarming (P=0.009) and reperfusion (P=0.05) in the CsA group. EEG recovery 3 h after HCA was observed in four of eight CsA animals but in only 1 of 12 controls (P=0.11) and one of eight CHX animals; cortical SSEP recovery also seemed faster in CsA animals, but failed to reach significance. Some early recovery scores were significantly better in the CsA group, and daily behavioral scores were consistently and significantly higher in the CsA-treated animals from POD1 through POD4. The data indicate that treatment with Cyclosporine A but not cycloheximide has a positive effect on cerebral recovery following HCA. Whether CsA results in inhibition of neuronal apoptosis, and/or inhibits release of cytokines and thereby reduces postischemic cerebral edema remains to be elucidated. The neuroprotective effect of CsA, if confirmed in further studies, would make its clinical application conceivable.

The N-methyl-D -aspartate antagonist memantine has no neuroprotective effect during hypothermic circulatory arrest: A study in the chronic porcine model

Glutamate excitotoxicity has an important role in the development of brain injury after prolonged hypothermic circulatory arrest. The goal of the present study was to determine the potential efficacy of memantine, an N -methyl-D -aspartate receptor antagonist, to mitigate cerebral injury after hypothermic circulatory arrest. Twenty pigs (23-33 kg) were randomly assigned to receive memantine (5 mg/kg) or placebo in a blinded fashion before a 75-minute period of hypothermic circulatory arrest at 20 degrees C. Hemodynamic, electroencephalographic, and metabolic monitoring were carried out. The intracerebral concentrations of glucose, lactate, glutamate, and glycerol were measured by means of enzymatic methods on a microdialysis analyzer. Daily behavioral assessment was performed until the animals died or were put to death on day 7. Histologic analysis of the brain was carried out in all animals. In the memantine group, 5 of 10 animals survived 7 days compared with 9 of 10 in the placebo group. The median behavioral score at day 7 was 3.5 in the memantine group and 7.5 in the placebo group (P >.2). Among the surviving animals, medians were 9.0 and 8.0 on day 7 (P >.2), respectively. The medians of recovered electroencephalographic bursts were equal in both groups. The median of total histopathologic score was 16 in the memantine group and 14 in the placebo group (P >.2). There was a negative correlation between glutamate levels and electroencephalographic burst recovery (tau = -0.377, P =.043). A positive correlation was found between the highest individual glutamate value and histopathologic score (tau = 0.336, P =.045). The present study demonstrates that memantine has no neuroprotective effect after hypothermic circulatory arrest in the pig. In addition, we have shown the accuracy of cerebral glutamate measurements to predict histopathologic injury after hypothermic ischemia.

The Role of Cerebral Microdialysis in Predicting the Outcome after Experimental Hypothermic Circulatory Arrest

Objective –To evaluate whether and which of the cerebral microdialysis parameters are predictive of postoperative outcome after an experimental 75-min period of hypothermic circulatory arrest (HCA) in a chronic porcine model. Design –Seventy-four juvenile female pigs underwent a 75-min period of HCA at 20°C. A microdialysis catheter was placed into the cortex gray matter and brain extracellular concentrations of glucose, lactate, glycerol and glutamate were measured throughout the experiment by enzymatic methods using a microdialysis analyzer. Surviving animals were sacrificed on the 7th postoperative day and histopathological examination of the brain was performed. Results –Brain glucose concentrations were higher in animals that survived ( p = 0.017), especially from the 90-min until the 7-h interval after the start of rewarming. The blood venous concentrations of glucose were also higher among survivors, and correlated significantly with the brain glucose levels at 2-h and 4-h intervals after the start of rewarming. Higher concentrations of brain lactate, glycerol and glutamate were observed throughout the study among animals that died postoperatively. Brain glutamate and glycerol concentrations were significantly, negatively correlated with brain glucose concentrations. The lactate/glucose ratio was significantly lower among survivors during the postoperative period ( p = 0.014). Furthermore, brain glucose concentrations were higher and brain glycerol concentrations lower among the animals that did not develop brain infarction, but such differences did not reach statistical significance. Conclusion –Cerebral microdialysis is a useful tool for cerebral monitoring during experimental HCA. Low brain glucose concentrations and high brain lactate/glucose ratios after HCA are strong predictors of postoperative death. Brain glucose concentrations are negatively correlated with brain glycerol and glutamate concentrations.

Leukocyte filtration improves brain protection after a prolonged period of hypothermic circulatory arrest: A study in a chronic porcine model

Background: Ischemic cerebral injury follows a well-attested sequence of events, including 3 phases: depolarization, biochemical cascade, and reperfusion injury. Leukocyte infiltration and cytokine-mediated inflammatory reaction are known to play a pivotal role in the reperfusion phase. These events exacerbate the brain injury by impairing the normal microvascular perfusion and through the release of cytotoxic enzymes. The aim of the present study was to determine whether a leukocyte-depleting filter (LeukoGuard LG6, Pall Biomedical, Portsmouth, United Kingdom) could improve the cerebral outcome after hypothermic circulatory arrest. Methods: Twenty pigs (23-30 kg) were randomly assigned to undergo cardiopulmonary bypass with or without a leukocyte-depleting filter before and after a 75-minute period of hypothermic circulatory arrest at 20°C. Electroencephalographic recovery, S-100β protein levels, and cytokine levels (interleukin 1β, interleukin 8, and tumor necrosis factor α) were recorded up to the first postoperative day. Postoperatively, all animals were evaluated daily until death or until electively being put to death on day 7 by using a quantitative behavioral score. A postmortem histologic analysis of the brain was carried out on all animals. Results: The rate of mortality was 2 of 10 in the leukocyte-depletion group and 5 of 10 in control animals. The risk for early death in control animals was 2.5 (95% confidence interval, 0.63-10.0) times higher than that of the leukocyte-depleted animals. The median behavioral score at day 7 was higher in the leukocyte-depletion group (8.5 vs 3.5; P = .04). The median of total histopathologic score was 8.5 in the leukocyte-depletion group and 15.5 in the control group (P = .005). Conclusion: A leukocyte-depleting filter improves brain protection after a prolonged period of hypothermic circulatory arrest. (J Thorac Cardiovasc Surg 2000;120:1131-41)

Radiofrequency ablation of the kidney: acute and chronic histology in porcine model

Objectives. To our knowledge, the chronic histopathologic effects of radiofrequency ablation (RFA) of renal parenchyma have not been extensively documented. In this study, we report the light and electron microscopic features of renal RFA in acute and chronic porcine models. Methods. Eleven animals underwent renal RFA of the lower pole kidney bilaterally. RFA was performed laparoscopically in 6 acute animals and percutaneously in 5 chronic animals. Acute animals were killed immediately following surgery. One chronic animal each was killed on postoperative day 3, 7, 14, 30, and 90. Histopathologic evaluation of all renal tissue specimens was carried out with light and electron microscopy. Results. Acutely, the renal radiolesion appeared as a yellowish white, well-circumscribed, necrotic area on gross examination, with evidence of extensive coagulative necrosis and marked inflammation on microscopic examination. From day 1 through 90, light and electron microscopy revealed evidence of progressive, irreversible cell death and necrosis with diminishing inflammatory response in the glomeruli, tubules, and renal interstitium. RFA lesions underwent gradual spontaneous resorption of the necrotic area with ultimate autoamputation. Conclusions. RFA results in necrosis of the ablated renal parenchyma.